You are on page 1of 31

Top Heterocycl Chem (2012) 29: 47–76

DOI: 10.1007/7081_2012_79
# Springer-Verlag Berlin Heidelberg 2012
Published online: 15 March 2012

Furans and Benzofurans

Kap-Sun Yeung

Abstract This chapter reviews the significant developments in the metalation of


furans and benzofurans and applications of the resulting metalated species in the
past decade. New and interesting metalated furan and benzofuran derivatives and
their novel reactions are featured. Topics encompass lithiation, magnesation and
zincation, the use of boronated and other metalated furans and benzofurans in cross-
coupling reactions, as well as the use of metalated furans and benzofurans in
addition reactions. Examples of regioselective metalation are highlighted, and
metalation of related furo heterocycles is also summarized.

Keywords Addition reactions  Benzofurans  Cross-coupling  Furans 


Metalation

Contents
1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
2 Lithiation of Furans and Benzofurans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3 Magnesation of Furans and Benzofurans, and Their Applications . . . . . . . . . . . . . . . . . . . . . . . . . 52
4 Zincation of Furans and Benzofurans, and Their Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
5 Boronated Furans and Benzofurans in Cross-Coupling Reactions . . . . . . . . . . . . . . . . . . . . . . . . . 59
6 Other Metalated Furans and Benzofurans in Cross-Coupling Reactions . . . . . . . . . . . . . . . . . . . 62
7 Regioselective Functionalization of Poly-halogenated Furans and Benzofurans . . . . . . . . . . 65
8 Metalated Furans and Benzofurans in Addition Reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67
9 Lithiation of Related Furo Heterocycles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 70
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

K.-S. Yeung (*)


Bristol-Myers Squibb Research and Development, 5 Research Parkway,
P.O. Box 5100, Wallingford, CT 06492, USA
e-mail: kapsun.yeung@bms.com
48 K.-S. Yeung

1 Introduction

Furan and benzofuran are common structural elements present in numerous bioac-
tive natural products as well as pharmaceuticals, molecular electronic and func-
tional polymers [1]. Recent noteworthy examples from natural sources, as shown in
Fig. 1, include the cytotoxic diterpenoid salvileucalin B [2] and the selective
phosphoinositide-3-kinase a inhibitor liphagal [3]. The total syntheses of both of
these unusual molecular structures have recently been accomplished [3, 4]. Due to
their electron-rich character, furans also function as versatile precursors to a variety
of functional moieties as well as carbocycles and heterocycles through the transfor-
mation of the furan nucleus, for example, by oxidation and cycloaddition reactions
[5–7].
A broadly employed approach for the incorporation of furan and benzofuran
rings is by utilizing their metalated species that participate primarily in metal-
catalyzed cross-coupling reactions and as nucleophiles in addition reactions. Con-
ventionally, direct deprotonation of furan and benzofuran takes place at the most
acidic C2 position (or the C5 position in 2-substituted furans) by using alkyl
lithiums with or without TMDEA, or using lithium amide bases. For example, as
shown in Scheme 1, lithiation using n-BuLi presumably generated a 2,5-dianion,

O
OH
HO
CHO
O
O
O

O O
Salvileucalin B Liphagal

Fig. 1 Furan- and benzofuran-containing natural products

TMSO Et n-BuLi (2 equiv.) TMSO Et


O O
TMSCl
O O
THF, 78 oC, 5 min
80% TMS O
O

40% AcO2H (4 equiv.) TMSO Et


NaOAc (4 equiv.) O
O
CH2Cl2, 0 oC to rt, 48 h
76% O O

Scheme 1 Direct metalation of furan at C2 (C5) position


Furans and Benzofurans 49

which was regioselectively silylated at the less hindered C5 position [8]. The
incorporation of the TMS group directed the subsequent regioselective oxidation
to the g-butenolide.
Metalation at the C3 position of furan generally requires lithium–halogen
exchange using alkyl lithium bases. As exemplified in Scheme 2, Li–Br exchange
of 3-bromo-2-triisopropylsilyloxyfuran occurred smoothly under standard
conditions. The anion formed can be quenched with C, S, Se, Si, and halogen
electrophiles to generate a-substituted g-butenolides after acidic hydrolysis [9].
However, metalation outcomes were influenced by the stoichiometries of
3-bromofuran and n-BuLi used. For example, as demonstrated in a key addition
reaction of furyllithium to an aldehyde during a synthesis of chettaphanin shown in
Scheme 3 [10], mixing equimolar amounts of the two reactants generated
3-furyllithium as expected, while metalation occurred at the C2 position when
half an equivalent of n-BuLi was used.
Lithiation followed by transmetalation of lithiofurans is commonly used to
generate various metalated furan derivatives. Earlier developments in the
metalation of furans and benzofurans and their applications have been reviewed
extensively [6, 11, 12]. This chapter serves to capture the significant advances in
these areas in the past decade, highlighting new and interesting metalated furan and
benzofuran species and their novel transformations. Examples of regioselective
metalation are described, and metalation of related furo heterocycles is also
summarized.

Br n-BuLi (1.1 equiv.) Cl Cl


THF, 78 oC aq. HCl

OTIPS C2Cl6 OTIPS 87% O


O O O
25 oC to rt

Scheme 2 Lithium–bromide exchange of furan at C3 position

OH
1:1 3-bromofuran/n-BuLi
CHO
O THF, 78 oC, 30 min O
90%
O
OH Br
2:1 3-bromofuran/n-BuLi
CO2Me
THF, 78 oC, 30 min O
92%

Scheme 3 Metalation of 3-bromofuran using different equivalent of n-BuLi


50 K.-S. Yeung

2 Lithiation of Furans and Benzofurans

An interesting counter-steric regioselectivity was unexpectedly obtained in the


lithiation of 3-phenyl as well as (E)- and (Z)-3-styrylfurans under conventional
conditions using n-BuLi. The lithiation preferentially occurred at the more hindered
C2-position, as illustrated in Scheme 4 [13]. The regioselectivity was increased by a
phenyl ring bearing an electron-withdrawing group, attributed to the stabilization of
the furyl anion in a late transition state.
The lithiation of 3-(N-tert-butoxycarbonyl)furan by using t-BuLi occurred
regioselectively at the C2 position as assisted by the apparent ortho-directing effect
of N-tert-butoxycarbonyl group to provide 2-substituted 3-(N-tert-butoxycarbonyl)
furans after quenching with a range of electrophiles [14], as exemplified in
Scheme 5. This is in contrast to an example of lithiation/cyanation of 2-(N-tert-
butoxycarbonyl)furan, which took place at the C5 position [15].
Directed ortho metalation could occur remotely at the C3 position of benzofuran
as illustrated in a synthesis of a coumestan depicted in Scheme 6 [16].

n-BuLi
TMSCl CF3
O TMS
O THF, 25 to 25 oC
CF3 (Z): 81%, single isomer
(E): 85%, 20:1

Scheme 4 Regioselective lithiation of (E)- and (Z)-3-styrylfurans

t-BuLi (2.5 equiv.)


NHBoc TMEDA (2.5 equiv.) NHBoc
TMSCl

O THF, 40 oC O TMS
52%

t-BuLi (2 equiv.)
PhOCN
NHBoc NC NHBoc
O THF, 20 oC, 1 h O
71%

Scheme 5 Regioselective lithiation of 3- and 2-(N-tert-butoxycarbonyl)furans

NEt2
1) LDA O
O
MeO O THF, 0 oC, 30 min MeO O

2) AcOH
reflux, 2 h O
O 79%

Scheme 6 Directed ortho remote metalation of benzofuran


Furans and Benzofurans 51

1) n-BuLi (2 equiv.)
TMDEA (2 equiv.)
Et2O, 40 oC to rt

2) EtOCONMe2 O O
O
Et2O, 70 oC to rt 48%

Scheme 7 Dilithiation of 3-phenylbenzofuran

n-BuLi (5 equiv.)
OH
O THF, 78 to 0 oC
70%
O >95:5 O
[1,2]-product

s-BuLi (5 equiv.)
O THF, 78 to 0 oC
69% O
O 98:2 OH
[2,3]-product

Scheme 8 Deprotonation at the ethereal a position of 3-furylmethyl ethers

1) n-BuLi (1.1 equiv.) TBSO


CHO Et2O, 78 oC, 30 min nBu
Ph
TBS 2) PhCHO
O O
1:1 HMPA/Et2O OH
78 oC to rt, 3 min
73%

Scheme 9 Addition of organolithium reagent to 2-TBS-3-formylfuran

Dilithiation of 3-phenylbenzofuran also followed an ortho remote manner.


As demonstrated in Scheme 7, this method was used for the synthesis of
hetarenoindanones, which were reduced to provide hetarenoindenes [17].
Deprotonation at the ethereal a position of 3-furylmethyl ethers by alkyl lithiums
(n-, s-, or t-BuLi) or LDA occurred more readily than deprotonation at the furan C2
position. As illustrated in Scheme 8, products arising from a formal [1,2]- and [2,3]-
Wittig rearrangements were selectively obtained by using different bases [18].
A furan C2 anion was regioselectively generated via the addition of organo-
lithium reagents to 2-TBS-3-formylfuran and subsequent 1,4-Brook silyl migration
of the intermediate lithium alkoxide [19]. Quenching the anion with aldehydes and
ketones provided 2,3-disubstituted furans as exemplified in Scheme 9.
52 K.-S. Yeung

OTBS OH
n-BuLi, HMPA
THF, 78 oC to rt, 6 h TBS
O O
89%

Scheme 10 retro-Brook rearrangement of a 2-lithiofuran

PhLi (2 equiv.) ClCO2Me

PhMe 78 oC to rt
O SOPh 78 oC, 10 min 71% O CO2Me

Scheme 11 Regioselective lithiation of furan via sulfoxide–lithium exchange

Br 1) t-BuLi (2 equiv.) nBu3Sn


Et2O, 78 oC, 30 min
Ph 2) n-Bu3SnCl (1.1 equiv.) Ph
O O
Et2O, 78 to 20 oC
78%

Scheme 12 Lithium–bromide exchange of 4-bromo-2-phenylbenzofuran using t-BuLi

Interestingly, lithiation of the 3-furylmethyl TBS ether shown in Scheme 10


initiated a retro-Brook rearrangement of the corresponding 2-lithiofuran that con-
veniently installed a silyl blocking group regioselectively at the furan C2 position
[20].
Another example of regioselective lithiation of furan resulted from a lithium–
sulfoxide exchange that was carried out by using phenyllithium as a base [21], as
shown in Scheme 11.
As depicted in Scheme 12, lithium–bromide exchange of 4-bromobenzofuran
required the use of the strong base t-BuLi to generate 4-benzofuranyllithium, which
was converted to the tin derivative [22].

3 Magnesation of Furans and Benzofurans,


and Their Applications

Metalation of furans and benzofurans can be performed at or near ambient temper-


ature under new conditions that seek to avoid undesirable side reactions resulted
from high reactivity and nucleophilicity of lithium bases. Deprotonation at the C2
position of unsubstituted furan and benzofuran at room temperature was achieved
by using lithium magnesates Bu3MgLi and Bu4MgLi2 [23], and the resulting
lithium 2-furylmagnesate was stable and reactive toward Kumada-type cross-
coupling, as exemplified in Scheme 13.
Furans and Benzofurans 53

1) n-Bu3MgLi (1/3 equiv.)


THF, rt, 2 h N
O
O 2) 2-bromopyridine
Pd(dppf)Cl2 (1 mol%)
reflux, 18 h 64%

Scheme 13 Magnesation of furan using Bu3MgLi and the subsequent cross-coupling

TMPMgCl. LiCl (1.1 equiv.) DMF


O MgCl O CHO
O THF, 25 oC, 24 h 81%

Scheme 14 Magnesation of furan using TMPMgClLiCl

MgCl.LiCl
TMPMgCl.LiCl (1.1 equiv.)
Br O CO2Et
THF, 25 oC, 0.5 h Br O CO2Et

HO O
O CHO

83% Br CO2Et
O

Scheme 15 Regioselective magnesation of ethyl 5-bromofuran-2-carboxylate

As represented in Scheme 14, direct magnesation of unsubstituted furan by using


a mixed Mg/Li amide TMPMgClLiCl (TMP ¼ 2,2,6,6,-tetramethylpiperidine)
also occurred at room temperature to generate 2-furylmagnesium chloride in situ,
which was quenched with an electrophile [24].
Interestingly, regioselective direct magnesation at the C3 position of ethyl
5-bromofuran-2-carboxylate, presumably activated by the carboxylate group, has
been demonstrated by employing TMPMgClLiCl at lower temperature as depicted
in Scheme 15 [24].
2-(4-Methoxyphenyl)sulfinyl-substituted benzofuran and 5-trimethylsilylfuran
were also magnesated at the C3-position by using TMPMgClLiCl and then
transmetalated to the corresponding zinc reagents for Negishi coupling
[25, 26]. Subsequent sulfoxide–magnesium exchange was performed by using
i-PrMgClLiCl for the formation of 2,3-disubstituted derivatives as illustrated in
Scheme 16.
As represented in Scheme 17, further manipulation of the C4 and C5 positions of
2,3-disubsituted-5-trimethylsilylfurans again by consecutive application of these
two different magnesium bases, i.e. iodide–magnesium exchange with i-
PrMgClLiCl followed by magnesation using TMPMgClLiCl, led to tetrasub-
stituted furans.
54 K.-S. Yeung

1) TMPMgCl. LiCl (1.1 equiv.) CO2Et


THF, 40 oC, 20 min
TMS O SOAr
2) ZnCl2, THF
Ar = 4-MeOC6H4 ethyl 4-iodobenzoate
Pd(PPh3)4 (2 mol%) TMS SOAr
77% O

CO2Et
1) i-PrMgCl.LiCl (1.1 equiv.)
2-MeTHF, 50 oC, 2 h

2) ZnCl2, THF
4-chloro-iodobenzoate TMS O
Pd(PPh3)4 (2 mol%) Cl
25 oC, 1 h 68%

Scheme 16 Magnesation of 2-(4-methoxyphenyl)sulfinyl-5-trimethylsilylfuran

CO2Et 1) ICl, 0 oC, 1 h CO2Et


2) i-PrMgCl.LiCl
40 oC, 20 min

3) NCCO2Et
TMS O EtO2C O
25 oC, 3 min
Cl Cl
86% 86%

1) TMPMgCl. LiCl CO2Et


40 oC, 25 min tBu O
2) ZnCl2, 40 oC, 30 min

3) t-BuCH2COCl EtO2C O
CuCN.2LiCl Cl
25 oC, 30 min 93%

Scheme 17 Consecutive application of magnesium bases, i-PrMgClLiCl and TMPMgClLiCl,


on a 2,3-disubstituted-5-trimethylsilylfuran

Efficient magnesium–bromide exchange of methyl 5-bromofuran-2-carboxylate


could be performed at 22 C by using i-PrMgBr in the presence of bis[2-(N,
N-dimethylamino)ethyl] ether [27]. The resulting Grignard reagent was presumably
stabilized by the formation of a tridentate complex with the diamine, leading
to a 95% conversion as shown in Scheme 18. Addition of the complex to
trimethylborate provided the corresponding boronic acid in high yield compared
to the reaction without using the diamine.
As shown in Scheme 19, a palladium-catalyzed Kumada coupling of the above
Grignard reagent, generated via the usual Knochel’s Mg/I exchange protocol, with
an aryl iodide proceeded at lower temperature than is commonly used in the
presence of SPhos as a ligand [28].
Furans and Benzofurans 55

i-PrMgCl.LiCl
Me2N NMe2
O
MeO2C O Br MeO2C O MgCl
THF, 22 oC, 15 min
95% (57%)

B(OMe)3
MeO2C O B(OH)2
77% (28%)

Scheme 18 Magnesation of methyl 5-bromofuran-2-carboxylate in the presence of bis[2-(N,


N-dimethylamino)ethyl] ether. The numbers in brackets correspond to the yields of the reactions
in the absence of the diamine.

I
+ MeO C MgCl.LiCl
2 O
N
Boc
Pd(dba)2 (2 mol%)
SPhos (3 mol%)
O CO2Me
PhMe/THF, 20 oC BocN
86%

Scheme 19 Kumada coupling of (5-(methoxycarbonyl)2-furyl)magnesium chloride at low


temperature

Br
Br Mg, LiCl B(OBu)2MgBr
B(OBu)3 (0.5 equiv.) 2 +
O THF, 25 oC, 30 min O O O

NEt2
O NEt2
Pd(dppf)Cl2 (4 mol%)
Cs2CO3 (2 equiv.)
O
1:4:4 DMF/EtOH/THF
65 oC, 3 h O 86%

Scheme 20 Suzuki–Miyaura coupling of magnesium dibenzofuranylboronate

The interesting magnesium dibenzofuranylboronate depicted in Scheme 20 was


prepared from 3-bromobenzofuran under Grignard-type conditions in the presence
of 0.5 equivalents of B(OBu)3. This type of boronate was reactive toward Suzuki–
Miyaura coupling, as illustrated [29].
4-Chlorobenzofuran was sufficiently reactive toward a nickel-catalyzed sp3–sp2
Kumada coupling with an alkylmagnesium bromide, as depicted in Scheme 21 [22].
56 K.-S. Yeung

Cl n-BuMgBr (1.2 equiv.) nBu


Ni(dppp) (1 mol%)
Ph Et2O, reflux Ph
O 80% O

Scheme 21 Nickel-catalyzed Kumada coupling of 4-chloro-2-phenylbenzofuran

1) ZnCl2.TMEDA (0.25 equiv.)


LiTMP (0.75 equiv.) Cl
THF, rt, 2 h N
N
O 2) 2,4-Cl2pyrimidine O
PdCl2 (2 mol%), dppf (2 mol%)
25 oC, 12 h 49%

Scheme 22 Zincation of benzofuran using ZnCl2TMEDA/LiTMP and subsequent cross-


coupling with aryl chloride

(TMP)2Zn.2MgCl.LiCl Zn
(0.55 equiv.) 2
NO2
O THF, 25 oC, 1.5 h NO2
O

Br

CuCN.2LiCl (5 mol%) NO2


80% O

Scheme 23 Zincation of 2-nitrobenzofuran and subsequent Negishi coupling

4 Zincation of Furans and Benzofurans, and Their Applications

Zincates at the C2 position of unsubstituted furan and benzofuran were prepared at


room temperature by using a mixed base generated in situ from a 1:3 mixture of
ZnCl2TMEDA/LiTMP [30, 31], and used for the addition to aldehydes or a
palladium-catalyzed coupling with aryl and heteroaryl chlorides and bromides, as
illustrated in Scheme 22.
Addition of 0.5 equivalent of ZnCl2 to TMPMgClLiCl generated a complex
mixed base (TMP)2Zn2MgCl2LiCl [32]. This was used for zincation of arenes and
heteroarenes bearing sensitive functional groups, e.g., aldehyde and nitro groups
that are not compatible with lithium or magnesium bases, at or near ambient
temperature. For example, as shown in Scheme 23, the zincate of 2-nitrobenzofuran
Furans and Benzofurans 57

1) CdCl2.TMEDA (0.5 equiv.)


LiTMP (1.5 equiv.)
THF, rt, 2 h
O O
2) 1-Br-4-ClC6H4 Cl
Pd(OAc)2 (6 mol%), dppf (2 mol%)
reflux, 18 h 46%

Scheme 24 Cross-coupling of 2-furyl cadmate with arylbromide

EtO n-BuLi EtO ZnCl2 EtO


O TMEDA O O
Li ZnCl
EtO o
25 C to rt EtO
EtO THF
25 oC

EtO EtO EtO


O Zn O ZnLi O ZnLi2
EtO 2 EtO 3 EtO 4

EtO 2,5-Cl2pyridine
O Cl
ZnLi Pd(dppf)Cl2 O
EtO OHC
3 THF, 50 oC N
(0.35 equiv.) then 5N HCl 89%

Scheme 25 Palladium-catalyzed cross-coupling of 2-furyl zincate

was formed smoothly at the C3 position using this base and then subjected to a
copper-catalyzed Negishi coupling with 3-cyclohexenylbromide.
Similar to zincation, unsubstituted furan and benzofuran were also metalated at
room temperature by using a cadmium–lithium mixed base generated in situ by
mixing 0.5 equivalent of CdCl2TMDEA with LiTMP [33]. The resulting 2-furyl
cadmate directly participated in reaction with acid chlorides to form ketones and
palladium-catalyzed cross-coupling with arylbromides, as demonstrated in
Scheme 24. However, competing homocoupling and the toxicity associated with
cadmium species may limit the application of this metalation method.
As shown in Scheme 25, a 2-furylzinc chloride as well as the corresponding di-,
tri-, and higher order zincates were prepared from the 2-lithiofuran by
transmetalation using the appropriate stoichiometries of ZnCl2 [34]. These zincates
were found to transfer all of the furyl groups during a palladium-catalyzed cross-
coupling reaction, as exemplified in Scheme 25.
The related 5-(1,3-dioxolan-2-yl)-2-furylzinc was prepared by the direct inser-
tion of Rieke’s active zinc to the corresponding bromide at room temperature as
shown in Scheme 26 [35]. However, furylzinc reagents could also be generated
from unprotected 5-iodo-2-furaldehyde and ethyl 5-bromofuran-2-carboxylate by a
LiCl-mediated direct insertion of zinc powder at room temperature, as
demonstrated in Scheme 27 [36].
58 K.-S. Yeung

O Zn (1.5 equiv.) O
O Br O ZnBr
O THF, rt, 3 h O

O
I2 O I
O

>98% by GC

Scheme 26 Formation of 2-furylzinc by the direct insertion of active zinc to 2-bromofuran

Zn.LiCl (1.4 equiv.) Br

OHC ZnI.LiCl
+
OHC I
O THF, 25 oC, 2.5 h O CO2Et

CO2Et
THF, 0 oC, 1 h OHC O
81%

Scheme 27 Formation of 5-formyl-2-furylzinc by LiCl-mediated direct insertion of zinc to


5-iodo-2-furaldehyde

EtO2C O ZnCl
Pd(PPh3)4 (1 mol%) O
+ EtO2C CHO
THF, rt O
83%
Br O CHO

Scheme 28 Palladium-catalyzed cross-coupling of 5-bromo-2-furaldehyde

5-Aryl- and 5-heteroaryl-2-furaldehydes were also prepared from the cross-


coupling of 5-bromo-2-furaldehyde with zinc reagents by employing 1 mol% of
(Ph3Ph)4Pd as catalyst [36, 37], as shown by the interesting example summarized in
Scheme 28.
A new palladium-N-heterocyclic carbene (Pd-PEPPSI-IPent) complex was effi-
cient for the Negishi coupling of a 2-furylzinc, enabling the reaction to proceed at
room temperature, as depicted in Scheme 29 [38]. This catalyst was also useful for
the Suzuki–Miyaura coupling of 3-furylboronic acid and 2-benzofuranylboronic
acid [39]. A one-pot zincation of ethyl 5-bromofuran-2-carboxylate using Zn/LiCl
followed by a Negishi coupling employing an i-Pr analog of Pd-PEPPSI-IPent as a
catalyst was also reported [40].
The utility of zinc reagents of 2-furaldehyde derivatives as described above in
Negishi coupling was further exemplified by a key step in a total synthesis of the
marine natural product bipinnatin J, as shown in Scheme 30 [41].
A Negishi coupling of 2-furylzinc with aryltrimethylammonium iodides was
promoted by a nickel catalyst, as represented in Scheme 31 [42].
Furans and Benzofurans 59

Ar N N
Ar
Cl Pd Cl Ar =
N

Cl

Pd-PEPPSI-IPent
EtO2C ZnBr (2 mol%)
O ZnCl2 (1 equiv.) N N
+ O CO2Et
N N THF, r.t., 24 h Ph
79%
Ph Cl

Scheme 29 Negishi coupling of 2-furylzinc using Pd-PEPPSI-IPent catalyst

t-BuLi (1 equiv.)
ZnCl2 (1.2 equiv.)
+ MOM
O O ZnCl
O THF, 78 oC O
O O I

O O
O
MOM
Pd(dppf)Cl2 O
THF, 0 oC, 2 h O
100%
O O

Scheme 30 A key Negishi coupling in a total synthesis of bipinnatin J

NMe3I
Ni(PCy3)2Cl2 (2 mol%)
ZnCl
+ O
O 1:1 THF/NMP
90 oC, 8 h
83%

Scheme 31 Nickel-catalyzed cross-coupling of furylzinc with phenyltrimethylammonium iodide

5 Boronated Furans and Benzofurans in Cross-Coupling


Reactions

Potassium 2-furyl, 3-furyl, and 2-benzofuranyl trifluoroborates served as efficient


nucleophilic coupling partners in equimolar amount in Suzuki–Miyaura cross-
coupling reaction. By employing RuPhos as a ligand, the reaction proceeded even
with less reactive aryl and heteroaryl chlorides [43]. An interesting example is
depicted in Scheme 32. Potassium 2-furyl trifluoroborate, which was prepared by
60 K.-S. Yeung

Pd(OAc)2 (3 mol%) OHC


OHC RuPhos (6 mol%)
O Na2CO3 (2 equiv.) O
+ O
EtOH, 85 oC
BF3K O
Cl 81%

Scheme 32 Suzuki–Miyaura cross-coupling of potassium 2-furyl trifluoroborate with 5-chloro-


2-furaldehyde

O Pd(OAc)2 (2.5 mol%)


SPhos (5 mol%)
Me2N BF3K O
K2CO3 (3 equiv.)
+ O
Me2N CHO
1:5 H2O/PhMe
Cl O CHO 85 oC, 14 h
73%

Scheme 33 Suzuki–Miyaura cross-coupling of 5-chloro-2-furaldehyde with potassium


b-trifluoroborato amide

MeN Pd(OAc)2
O SPhos, K3PO4
O O
B
O + 1:5 H2O/dioxane
Cl
O 60 oC, 6 h
O
97%

Scheme 34 Suzuki–Miyaura cross-coupling of 2-furyl MIDA boronate

the addition of KHF2 to 2-furylboronic acid, exhibited stability at ambient temper-


ature for 3 months without sign of proto-deboronation.
Interestingly, 5-chloro-2-furaldehyde reacted with primary alkyl [44] and
aminomethyl tetrafluoroborate [45] potassium salts, as well as potassium
b-trifluoroborato amide [46], as shown in Scheme 33. Note that the reaction using
SPhos as a ligand was sufficiently efficient to prevent undesirable b-hydride
elimination.
Cross-coupling methods were developed to circumvent the problem of instabil-
ity of certain aryl and heteroaryl boronic acids, including 2-furyl and
2-benzofuranyl boronic acids, particularly during the reaction with unactivated
substrates, e.g., aryl chlorides. 2-Furyl and 2-benzofuranyl N-methyliminoacetic
acid (MIDA) boronates demonstrated bench-top stability compared to the
corresponding boronic acids. Slow release of the boronic acid via in situ hydrolysis
of the boronate using K3PO4 increased the reaction efficiency of Suzuki–Miyaura
cross-coupling, as exemplified by the reaction with the hindered aryl chloride
shown in Scheme 34 [47]. Another method employed a XPhosPd precatalyst
[48], as illustrated by the benzylic sp3–sp2 coupling depicted in Scheme 35, to
ensure a rapid formation of the catalytically active XPhosPd(0) species for the
transmetalation of the boronic acids.
Furans and Benzofurans 61

OH
O B
OH XPhos Pd NH2 O
+ Cl
Cl pre-catalyst (2 mol%)
2:1 K3PO4 (0.5 M)/THF CF3
40 oC, 30 min
CF3
86%

Scheme 35 Suzuki–Miyaura cross-coupling of 2-furyl boronic acid using a XPhosPd precatalyst

R
Ni(COD)2 (10 mol%) R
R BF3K PCy3HBF4 (20 mol%)
O K3PO4 (7.2 equiv.)
R
+ OMs O
1:1 t-BuOH/H2O
furan R = H, 79%
110 oC, 4 h
benzofuran R-R = C4H4, 81%

Scheme 36 Nickel-catalyzed cross-coupling of potassium 2-furyl and 2-benzofuranyl trifluor-


oborates with naphthalen-1-yl mesylate

B(OH)2 Ni(PCy3)2Cl2 (5 mol%)


O K3PO4 (4.5 equiv.) O
+ OSO NMe
2 2
PhMe, 110 oC, 24 h
67%

OMe OMe

Scheme 37 Nickel-catalyzed cross-coupling of 2-benzofuranyl boronic acid with naphthalen-1-yl


dimethylsulfamates

Cross-couplings of boronated furans and benzofurans were expanded to those


with halide equivalents as electrophilic partners. For example, potassium 2-furyl,
3-furyl, and 2-benzofuranyl trifluoroborates reacted with various aryl and
heteroaryl mesylates in a nickel-catalyzed reaction, providing cross-coupling
products in good yields [49], as represented by the examples shown in Scheme 36.
Cross-coupling of 2-benzofuranyl boronic acid and 3-furyl boronic acid with
naphthalen-1-yl dimethylsulfamates was accomplished by using NiCl2(PCy3)2 as a
catalyst [50], as represented in Scheme 37. An example of (BINAP)PdCl2-
catalyzed coupling of 3-furyl boronic acid with naphthalen-1-yl imidazolyl-
sulfonate was also reported [51].
62 K.-S. Yeung

B(OH)2
O Pd/C (5 mol%) O
+ N BF
2 4
MeOH, 50 oC, 20 min
61%

OMe OMe

Scheme 38 Pd/C-catalyzed cross-coupling of 2-benzofuranyl boronic acid with arenediazonium


salt

PdCl2 (1.6 mol%) O O


OH O O K2CO3 (2 equiv.)
OHC O OHC O
B + S S
OH Cl Ph 1:3 H2O/Me2CO Ph
25 oC, 1 h
82%

Scheme 39 Reaction of 2-furyl boronic acid with phenylsulfonyl chloride

2-Benzofuranyl boronic acid also underwent a fast cross-coupling reaction with


an arenediazonium salt under ligand-free Pd/C-catalyzed conditions in methanol, as
shown in Scheme 38 [52].
As shown in Scheme 39, a 2-furyl boronic acid also reacted with an arylsulfonyl
chloride under palladium catalysis to give unsymmetrical diaryl sulfones at ambient
temperature [53].

6 Other Metalated Furans and Benzofurans


in Cross-Coupling Reactions

2-Trimethylsilylbenzofuran underwent a palladium-catalyzed Hiyama-type cou-


pling with aryl iodides in the presence of AgNO2/KF as an activator [54], as
depicted in Scheme 40. Homocoupling to form 2,20 -bibenzofuran also occurred
under these conditions.
Sodium dimethyl(2-furyl)silanolate [55], and sodium dimethyl(2-benzofuryl)
silanolate [56] participated in palladium-catalyzed cross-couplings with aryl
iodides and bromides through a palladium silanolate complex, which underwent
transmetalation at the furan (benzofuran) C2 position. Cross-coupling of the
2-benzofurylsilanolate with aryl chlorides was also made possible by using
allylpalladium chloride as a palladium source and SPhos as a ligand, as represented
in Scheme 41.
Various metalated furan species were postulated as intermediates in the
decarboxylative coupling of furan-2-carboxylic acid. Decarboxylation of
Furans and Benzofurans 63

1-I-4-CNC6H4
Pd(PPh3)2Cl2 (3 mol%)
AgNO2/KF (1.5 equiv.)
TMS CN
O DMSO, 100oC, 6 h O
85%

Scheme 40 Hiyama-type cross-coupling of 2-trimethylsilylbenzofuran

PdCl
Si(Me2)ONa (2.5 mol%)
O SPhos (5 mol%)
+ OMe
THF, 60 oC, 3.5 h O
Cl OMe
77%

Scheme 41 Palladium-catalyzed cross-couplings of sodium dimethyl(2-benzofuryl)silanolate


with aryl chloride

Ag2CO3 (1 equiv.) Tol


Pd(TFA)2 (7.5 mol%) O
Tol CO2H
O 5:95 DMSO/DMF, 120 oC Tol O
56%

Scheme 42 Decarboxylative homocoupling of 5-tolylfuran-2-carboxylic acid

Cu2O (5 mol%)
1,10-phenanthroline (10 mol%)
OTf PdI2 (2 mol%)
(4-tol)3P (6 mol%)
+ O
O CO2H
NMP, 170 oC, 24 h
75%

Scheme 43 Decarboxylative hetero-coupling of furan-2-carboxylic acid

5-tolylfuran-2-carboxylic acid or 3-methylbenzofuran-2-carboxylic acid derivatives


by silver carbonate generated a (benzo)furan-2-yl silver species that underwent a
subsequent palladium-catalyzed homocoupling to give 2,20 -bi(benzo)furan
products, as illustrated in Scheme 42 [57]. In the presence of AsPPh3, cross-
coupling of 3-methylbenzofuran-2-carboxylic acid with 4-iodoanisole could be
achieved [58]. However, the generality of this type of decarboxylative coupling
of furan and benzofuran substrates has not been demonstrated.
Another example of decarboxylative hetero-coupling of furan-2-carboxylic acid
with 4-tolyl triflate, as depicted in Scheme 43, involved a 2-furyl copper species in
the catalytic cycle that underwent transmetalation with palladium [59, 60].
64 K.-S. Yeung

PhBr (1 equiv.)
R R
(t-Bu3P)2Pd (5 mol%)
n-Bu4NCl.H2O (1 equiv.)
R O CO2H R O Ph
Cs2CO3 (1.5 equiv.)
(2 equiv.) DMF, microwave furan R = H, 86%
178 oC, 8 min benzofuran R-R = C4H4, 86%

Scheme 44 Palladium-catalyzed decarboxylative coupling of furan- and benzofuran-2-carbox-


ylic acids

1) n-BuLi (2.5 equiv.)


TMDEA (2.5 equiv.)
THF, reflux, 30 min
nBuTe O TenBu
O 2) Te (2.5 equiv.), 25 oC
3) n-BuBr (3 equiv.) 90%
25 oC, 6 h

CH2OH Ph
PdCl2 (20 mol%) PdCl2 (20 mol%)
Et3N O TenBu Et3N
THF, 25 oC, 6h HO MeOH, 25 oC, 5 h
82% 65%

O Ph
HO

Scheme 45 Palladium-catalyzed cross-coupling of 2,5-bis(butyltelluro)furan with acetylenes

A related palladium-catalyzed decarboxylative coupling only proceeded


with furan- and benzofuran-2-carboxylic acids, but not with the corresponding
3-carboxylic acid, as represented in Scheme 44 [61]. A mechanism that involved
an electrophilic palladation at the furan C3 position followed by C3–C2 palladium
migration and decarboxylation was postulated.
2-Furyl zinc chloride reacted with vinyl tellurides in a Pd-catalyzed cross-
coupling in the presence of CuI [62]. As demonstrated in Scheme 45,
2-(butyltelluro)furan [63] and 2,5-bis(butyltelluro)furan [64] were prepared via
lithiofuran. Successive palladium-catalyzed coupling of 2,5-bis(butyltelluro)furan
with different acetylenes was feasible, forming unsymmetrical 2,5-bis-alkynyl
furans [64], as represented. 2-(Butyltelluro)furan is also reactive toward
(Ph3P)4Pd-catalyzed Ag2O-promoted cross-coupling with potassium phenyl
tetrafluoroborate [65].
Furans and Benzofurans 65

7 Regioselective Functionalization of Poly-halogenated


Furans and Benzofurans

Earlier chemistry focused on the regioselective functionalization of 2,3-


dibromofurans and 2,4-dibromofuran, as depicted in Fig. 2, through Suzuki–Miyaura,
Stille and Sonogashira cross-couplings with reaction occurring initially at the C2
position has been demonstrated and recently reviewed [66].
A recent example in this area is the preparation of a template for the synthesis of
a skeletally diverse small molecule library [67] through an sp3–sp2 Suzuki–Miyaura
coupling between a solid support-bound alkyl borane and 4,5-dibromo-
2-furaldehyde, as shown in Scheme 46. Competitive b-hydride elimination was
minimized by the use of Pd(dppf)Cl2 as a catalyst.
Interestingly, the Suzuki–Miyaura coupling of (Z)-2-(2-bromo-2-nitroethenyl)-
5-bromofuran with one equivalent of a boronic acid also occurred regioselectively
at the C2 position rather than at the exocyclic carbon–bromine bond, as illustrated
in Scheme 47 [68].

Br Br
2 2
R O Br O Br
R = CO2Me, or CHO

Fig. 2 2,3-Dibromofurans and 2,4-dibromofuran

Pd(dppf)Cl2 Br
Br aq. NaOH
B +
1:5 H2O/THF O CHO
4 Br O CHO 4
MO 65 oC, 18 h MO

Scheme 46 Regioselective sp3–sp2 Suzuki–Miyaura coupling of 4,5-dibromo-2-furaldehyde


(M ¼ macrobead)

OH (Ph3P)4Pd (3 mol%)
S Br
B K3PO4 (2 equiv.)
OH + NO2
Br 1:6 H2O/dioxane O
90 oC, 8 h S
NO2
Br O 87%

Scheme 47 Suzuki–Miyaura coupling of (Z)-2-(2-bromo-2-nitroethenyl)-5-bromofuran with


boronic acid
66 K.-S. Yeung

F
4-MeC6H4B(OH)2 (1 equiv.)
Br Pd(PPh3)4 (5 mol%)
K2CO3 (2 M aq.)
Br dioxane, 70 oC, 6 h
O 4-FC6H4B(OH)2 (1 equiv.)
dioxane, 80 oC, 6 h O
79%

Scheme 48 Regioselective Suzuki–Miyaura coupling of 2,3-dibromobenzofuran

Br 4-MeOC6H4ZnCl Br
Br Pd(PPh3)2Cl2 Br
Br THF, 25 oC OMe
O O
66%

MgCl Br
Ni(dppe)Cl2
OMe
THF, rt
O
71%

Scheme 49 Regioselective cross-coupling of 2,3,5-tribromobenzofuran

Regioselective cross-coupling of polybromobenzofuran is also feasible. The


selectivity is based on the electronic nature of the substituted carbon atom, with
the initial reaction occurs at the less electron-rich carbon atom. As illustrated in
Scheme 48, 2,3-dibromobenzofuran could be sequentially functionalized at the C2
position and then the C3 position in a one-pot fashion in a (Ph3Ph)4Pd-catalyzed
Suzuki–Miyaura coupling reaction using two different aryl boronic acids [69].
Benzofuran-3-yl triflates, prepared from benzofuran-3-ones, participated in
palladium-catalyzed Stille, Heck, Suzuki–Miyaura and Sonogashira couplings
[70]. A Stille coupling of 2-bromobenzofuran-3-yl triflate was observed to occur
at the C3 position in a modest ~2:1 selectivity [71]. A related Stille coupling of
2,5-dibromo-7-methoxybenzofuran, however, took place predominantly at the C2
position [72].
Negishi and Sonogashira couplings also occurred at the C2 position of 2,3,5-
tribromobenzofuran first [73]. However, it was more challenging to differentiate
the C3 and C5 positions by a palladium-catalyzed coupling. This was solved by
a lithium–bromide exchange with t-BuLi that occurred selectively at the C3
position or by a nickel-catalyzed C5-selective Kumada coupling as shown in
Scheme 49 [74]. The approach was applied to the synthesis of eupomatenoids
[75].
Furans and Benzofurans 67

8 Metalated Furans and Benzofurans in Addition Reactions

Metalated furans have been increasingly used in diastereoselective and


enantioselective addition reactions. For example, reaction of 2-furyllithium with a
chiral tert-butanesulfinyl imine provided the adduct with >12:1 diastereomeric
ratio [76]. Addition of 2-furyllithium or 2-benzofuryllithium to chiral SMAP-
hydrazone furnished the adduct in >95% diastereomeric excess [77]. A diastereo-
selective and enantioselective addition of a sterically bulky 3-(2-trityloxymethyl)
furyllithium, prepared in situ from the corresponding 3-bromofuran and n-BuLi, to
nitroalkene was realized by the use of a chiral amino ether ligand, as shown in
Scheme 50 [78]. This method provided an access to interesting furo-fused piperi-
dine ring.
2-Furylmagnesium bromide acted as a base and then a nucleophile in the
reaction with a tert-butyl (phenylsulfonyl)alkyl-N-hydroxycarbamate to form the
furyl-substituted hydroxylamine product through a N-Boc nitrone intermediate, as
depicted in Scheme 51 [79].
3-Furyltitanium, [(3-furyl)Ti(Oi-Pr)3]2, was prepared from the reaction of 3-
furyllithium with Ti(Oi-Pr)3Cl in THF at 78 C. Addition of this reagent to a range
of acetophenone derivatives at 0 C in the presence of (S)-BINOL furnished tertiary
3-furanylcarbinols with ee up to 97% [80]. Similarly, the use of 2-furylaluminum
(2-furyl)AlEt2(THF) provided 2-furanylcarbinols with ee up to 93% [81].
3-Furyltitanium also appeared to be more effective in addition to aliphatic
aldehydes compared to the corresponding lithium, magnesium, and zinc reagents.
As exemplified in a total synthesis of (+)-ricciocarpins A shown in Scheme 52, the

Li Ph Ph
NO2
+ Me2N O
PhMe, 95 oC, 30 min NO2
O
OTr MeO cis/trans = 89:11 O
(2.1 equiv.) 91% ee, 90% OTr

Scheme 50 Asymmetric addition of 3-(2-trityloxymethyl)furyllithium to nitroalkene

O MgBr HO Boc
HO Boc HO Boc N
N (2 equiv.) N
O
i Bu SO2Ph 1:5 THF/PhMe i Bu
rt, 45 min i Bu
86%

Scheme 51 Reaction of 2-furylmagnesium bromide with tert-butyl (phenylsulfonyl)alkyl-


N-hydroxycarbamate
68 K.-S. Yeung

O
O Et2O H
H (i-PrO)3Ti
78 oC, 4 h O
OMe +
CHO 85%
O dr = 5.7:1 H
H
O

Scheme 52 Addition of 3-furyltitanium to an aliphatic aldehyde

MeO MeO CeCl2 i-Pr


1) n-BuLi (1 equiv.)
O THF, 50 oC, 5 h O
+
2) CeCl3 (1 equiv.) N
Cl NTIPS THF, 78 oC, 2 h Cl SEM
NTIPS
O
i-Pr

THF MeO N
rt, overnight OH SEM
O
62%

Cl NTIPS

Scheme 53 Addition of 2-furylcerium to a ketone

use of the titanium reagent provided the highest yield and diastereoselectivity in the
reaction with the penultimate aldehyde bearing an acidic a-proton [82].
2-Furylcerium derivatives are less commonly used; however, they also appear to
show high nucleophilicity to allow reactions with ketones and sterically demanding
substrates. A remarkable example is the key penultimate reaction in a total synthe-
sis of roseophilin, as shown in Scheme 53 [83]. Note that the furan C2 position was
exclusively lithiated and transmetalated primarily due to the steric hindrance
around the pyrrole C2 position that was imparted by the bulky TIPS group.
2-Benzofuranyl boronic acid and its potassium trifluoroborate salt reacted as
nucleophiles in an enantioselective organocatalytic Friedel–Crafts alkylation with
crotonaldehyde, as shown in Scheme 54. An example using potassium 2-furyl
trifluoroborate was also reported [84]. This method was employed in a total
synthesis of (+)-frondosin B [85].
A similar type of reaction involves the addition of 2-trimethylsilylbenzofuran
to benzylic acetates in the presence of a catalytic amount of FeCl3/AgOTf to form
2-benzyl substituted benzofurans as shown in Scheme 55 [86].
Potassium 2-benzofuranyl trifluoroborate reacted with trichloroisocyanuric acid
to furnish 2,3-dichlorobenzofuran, as depicted in Scheme 56 [87]. Although it was
shown that the dichloro product was not derived from an initial chlorodeboronation,
the mechanism of this reaction remains uncertain.
Furans and Benzofurans 69

N
HN
tBu
N HCl
MeO Bn OHC
BF3K (20 mol%) MeO
O
+ HF (1.0 equiv.) O
CHO DME, 20 oC, 24 h
94% yield , 92% ee

Scheme 54 Nucleophilic addition of potassium 2-benzofuranyl trifluoroborate to crotonaldehyde

FeCl3 (5 mol%)
OAc AgOTf (15 mol%)
TMS +
O Ph CiCH2CH2Cl O Ph
80 oC, 16 h 69%

Scheme 55 Iron-catalyzed addition of 2-trimethylsilylbenzofuran to benzylic acetate

O
Cl
Cl Cl open flask
N N
BF3K +
1:1 H2O/EtOAc Cl
O O N O rt, 30 min O
Cl 86%

Scheme 56 Reaction of potassium 2-benzofuranyl trifluoroborate with trichloroisocyanuric acid

OH
O O
B
OH Rh(acac)(C2H4)2 (3.3 mol%)
dppf (6.6 mol%)
(5 equiv.) O
+
1:10 H2O/dioxane N
100 oC, 5 h
80%
NH2 CF3 CF3

Scheme 57 Rhodium-catalyzed hydroarylation of a b-aminophenyl alkynone with 2-furyl-2-


boronic acid

Hydroarylation of a b-aminophenyl alkynone with 2-furylboronic acid to pro-


vide a quinolone derivative was achieved by using a rhodium catalyst, as illustrated
in Scheme 57 [88].
70 K.-S. Yeung

O n-Bu2CuLi (2.2. equiv.) O


Li Bu Bu2Cu Bu
Et2O-Me2S
78 to 0 oC

2
Bu O Bu H2O O Bu
Cu +
2Li
68%
Bu Bu

Scheme 58 1,2-Metalate rearrangement of 2-furylcuprate

1) n-BuLi (2 equiv.)
N N
5 THF, 78 oC, 1 h
2 SMe
O 2) MeSSMe (2 equiv.) O
THF, 78 oC, 1 h 89% (isolated yield)

Scheme 59 Lithiation of 4-azabenzofuran (furo[3,2-b]pyridine) using n-BuLi

1) LiTMP (6 equiv.) Br
N N
THF, 78 oC
Br
O 2) CBr4 (9 equiv.) O
THF, 95 oC, 1 h Br 54% (GC yield)

Scheme 60 Lithiation of 4-azabenzofuran (furo[3,2-b]pyridine) using LiTMP

The 2-furylcuprate shown in Scheme 58 underwent a 1,2-metalate rearrange-


ment to provide the ring-opened product [89].

9 Lithiation of Related Furo Heterocycles

Lithiation of 4-azabenzofuran (furo[3,2-b]pyridine) using n-BuLi in THF occurred


predominantly at the C2 position, which was quenched with various electrophiles
(e.g., Br, Si, Sn, S, and B), as exemplified in Scheme 59 [90]. The use of an
increased excess amount of LiTMP resulted in the di- and tri-lithiation at the C2,
C3, and C7 positions as indicated by the 2,3-dibromo and 2,3,7-tribromo
derivatives that were detected (Scheme 60). It was observed that the corresponding
C3 mono-lithiated species was unstable and the lithiation at the C5 position had not
occurred under these conditions.
The corresponding lithiation of 6-azabenzofuran (furo[2,3-c]pyridine) using
n-BuLi in THF also occurred exclusively at the C2-position [91]. If the C2 position
Furans and Benzofurans 71

1) n-BuLi (1.5 equiv.)


THF, 78 oC, 1 h
TMS
N N O
O 2) TMSCl (2 equiv.)
THF, 78 oC, 1 h 77%

1) n-BuLi/LiDMAE (3 equiv.)
hexane, 45 oC, 1 h TMS
N O
2) C2Cl6 (3 equiv.)
THF, 78 oC, 1 h Cl 85%

1) n-BuLi/LiDMAE (4 equiv.) Cl
hexane, 45 oC, 1 h TMS
N O
2) C2Cl6 (4 equiv.)
THF, 78 oC to rt, 1 h Cl 80%

Scheme 61 Sequential lithiation of 6-azabenzofuran (furo[2,3-c]pyridine)

O n-BuLi O n-BuLi O
2 TMSCl TMSCl TMS
o
THF, 0 oC TMS THF, 0 C TMS
S 5 S S
78%, 96:4 97%

Scheme 62 Lithiation of thieno[3,2-b]furan

was blocked by a TMS group, deprotonation occurred at the C7 position followed


by at the C5 position using an n-BuLi/lithium dimethylaminoethoxide (LiDMAE)
mixed base, as illustrated in Scheme 61.
However, deprotonation of thieno[3,2-b]furan, first isolated in 2009, using
n-BuLi occurred predominantly at the C5 position [92]. Deprotonation at both the
C2 and C5 was feasible by using two equivalents of the base, as shown in
Scheme 62.

References

1. Keay BA, Hopkins JM, Dibble PW (2008) Chapter 3.08: Furans and their benzo derivatives:
applications. In: Katritzky AR, Ramsden CA, Scriven EFV, Taylor RJK (eds) Comprehensive
heterocyclic chemistry III. Elsevier, Oxford
2. Aoyagi Y, Yamazaki A, Nakatsugawa C, Fukaya H, Takeya K, Kawauchi S, Izumi H (2008)
Selvileucalin B, a novel diterpenoid with an unprecedented rearranged neoclerodane skeleton
from Salvia ieucantha Cav. Org Lett 10:4429–4432
3. Marion F, Williams DE, Patrick BO, Hollander I, Mallon R, Kim SC, Roll DM, Feldberg L,
Van Soest R, Anderson RJ (2006) Liphagal, a selective inhibitor of PI3 kinase a isolated from
the sponge Aka coralliphaga: structure elucidation and biomimetic synthesis. Org Lett
8:321–324
72 K.-S. Yeung

4. Levin S, Nani RR, Reisman SE (2011) Enantioselective total synthesis of (+)-selvileucalin B.


J Am Chem Soc 133:774–776
5. Wright DL (2005) Chapter 1: Furans as versatile synthons for target-oriented and diversity-
oriented synthesis. In: Gribble GW, Joule JA (eds) Progress in heterocyclic chemistry, vol 17.
Elsevier, Oxford
6. Wong HNC, Yeung K-S, Yang Z (2008) Chapter 3.06: Furans and their benzo derivatives:
reactivity. In: Katritzky AR, Ramsden CA, Scriven EFV, Taylor RJK (eds) Comprehensive
heterocyclic chemistry III. Elsevier, Oxford
7. Yeung K-S, Yang Z, Peng X-S, Hou X-L (2010) Chapter 5.3: Five-membered ring systems:
furans and benzofuran. In: Gribble GW, Joule JA (eds) Progress in heterocyclic chemistry,
vol 22. Elsevier, Oxford
8. Lee HK, Wong HNC (2002) An enantioselective synthetic pathway towards plakortones.
Chem Commun 2114–2115
9. Boukouvalas J, Loach RP (2008) General, regiodefined access to a-substituted butenolides
through metal-halogen exchange of 3-bromo-2-silyloxyfurans. Efficient synthesis of an anti-
inflammatory gorgonian lipid. J Org Chem 73:8109–8112
10. Marcos IS, Hernández FA, Sexmero MJ, Basabe DDP, Pedrero AB, Garcı́a N, Urones JG
(2003) Synthesis and absolute configuration of (2)-chettaphanin I and (2)-chettaphanin II.
Tetrahedron 59:685–694
11. Chinchilla R, Nájera C, Yus M (2004) Metalated heterocycles and their applications in
synthetic organic chemistry. Chem Rev 104:2667–2722
12. Li JJ, Gribble GW (2000) Chapter 6: Furans and benzo[b]furans. In: Palladium in heterocyclic
chemistry. A guide for the synthetic chemist. Pergamon, Oxford
13. Tofi M, Georgiou T, Montagnon T, Vassilikogiannakis G (2005) Regioselective ortho
lithiation of 3-aryl and 3-styryl furans. Org Lett 7:3347–3350
14. Stanetty P, Kolodziejczyk K, Roiban G-D, Mihovilovic MD (2006) Establishing the NHBoc
functionality as ortho-metallating group for furan. Synlett 789–791
15. Sato N, Yue Q (2003) An efficient synthesis of cyanoarenes and cyanoheteroarenes via
lithiation followed by electrophilic cyanation. Tetrahedron 59:5831–5836
16. James CA, Coelho AL, Gevaert M, Forgione P, Snieckus V (2009) Combined directed ortho
and remote metalation – Suzuki cross-coupling strategies. Efficient synthesis of heteroaryl-
fused benzopyranones from biaryl O-carbamates. J Org Chem 74:4094–4103
17. Kashulin IA, Nifant’ev IE (2004) Efficient method for the synthesis of hetarenoindanones
based on 3-arylhetarenes and their conversion into hetarenoindenes. J Org Chem
69:5476–5479
18. Tsubuki M, Okita H, Kaneko K, Shigihara A, Honda T (2009) Witting rearrangement of
3-furylmethyl ethers: facile synthesis of 3-methyl-2-furylmethanols and 3-furylmethanols.
Heterocycles 77:433–444
19. Devarie NO, Kim W-S, Smith AB III, Xian M (2009) Multicomponent type II anion relay
chemistry (ARC): one-pot synthesis of 2,3-disubstituted furans and thiophenes. Org Lett
11:1861–1864
20. Shanmugham MS, White JD (2004) A new route to furanoeremophilane sesquiterpenoids.
Synthesis of ()-6b-hydroxyeuryopsin. Chem Commun 44–45
21. Akai S, Kawashita N, Satoh H, Wada Y, Kakiguchi K, Kuriwaki I, Kita Y (2004) Highly
regioselective nucleophilic carbon-carbon bond formation on furans and thiophenes initiated
by Pummerer-type reaction. Org Lett 6:3793–3796
22. Sanz R, Castroviejo MP, Fernández Y, Fañanás FJ (2005) A new and efficient synthesis of
4-functionalized benzo[b]furans from 2,3-dihalophenols. J Org Chem 70:6548–6551
23. Mongin F, Bucher A, Bazureau JP, Bayh O, Awad H, Trecourt F (2005) Deprotonation of
furans using lithium magnesates. Tetrahedron Lett 46:7989–7992
24. Krasovsky A, Krasovskaya V, Knochel P (2006) Mixed Mg/Li amides of the type
R2NMgCl·LiCl as highly efficient bases for the regioselective generation of functionalized
aryl and heteroaryl magnesium compounds. Angew Chem Int Ed 45:2958–2961
Furans and Benzofurans 73

25. Melzig L, Rauhut CB, Knochel P (2009) 2,3-Functionalization of furans, benzofurans and
thiophenes via magnesiation and sulfoxide–magnesium exchange. Chem Commun 3536–3538
26. Melzig L, Rauhut CB, Naredi-Rainer N, Knochel P (2011) Difunctionalisation of arenes and
heteroarenes by directed metallation and sulfoxide–magnesium exchange. Chem Eur J
17:5362–5372
27. X-j W, Sun X, Zhang L, Xu Y, Krihnamurthy D, Senanayake CH (2006) Noncryogenic I/Br-
Mg exchange of aromatic halides bearing sensitive functional groups using i-PrMgCl-bis[2-
(N,N-dimethylamino)ethyl]ether complexes. Org Lett 8:305–307
28. Martin R, Buchwald SL (2007) Pd-catalyzed Kumada-Corriu cross-coupling reactions at low
temperatures allow the use of Knochel-type Grignard reagents. J Am Chem Soc
129:3844–3845
29. Haag BA, Samann C, Jana A, Knochel P (2011) Practical one-pot preparation of magnesium di
(hetero)aryl- and magnesium dialkenylboronates for Suzuki–Miyaura cross-coupling
reactions. Angew Chem Int Ed 50:7290–7294
30. L’Helgoual’ch J-M, Seggio A, Chevallier F, Yonehara M, Jeanneau E, Uchiyama M, Mongin
F (2008) Deprotonative metalation of five-membered aromatic heterocycles using mixed
lithium-zinc species. J Org Chem 73:177–183
31. Snégaroff K, Komagawa S, Chevallier F, Gros PC, Golhen S, Roisnel T, Uchiyama M, Mongin
F (2010) Deprotonative metalation of substituted benzenes and heteroaromatics using amino/
alkyl mixed lithium–zinc combinations. Chem Eur J 16:8191–8201
32. Wunderlich SH, Knochel P (2007) (tmp)2Zn2MgCl22LiCl: a chemoselective base for the
directed zincation of sensitive arenes and heteroarenes. Angew Chem Int Ed 46:7685–7688
33. Snégaroff K, L’Helgoual’ch J-M, Bentabed-Ababsa G, Nguyen TT, Chevallier F, Yonehara
M, Uchiyama M, Derdour A, Mongin F (2009) Deprotonative metalation of functionalized
aromatics using mixed lithium–cadmium, lithium–indium, and lithium–zinc species. Chem
Eur J 15:10280–10290
34. Gauthier DR Jr, Szumigala RH Jr, Dormer PG, Armstron JD III, Volante RP, Reider PJ (2002)
Synthesis of 5-pyridyl-2-furaldehydes via palladium-catalyzed cross-coupling with triorgano-
zincates. Org Lett 4:375–378
35. Rieke RD, Kim S-H (2011) 5-(1,3-Dioxolan-2-yl)-2-furanylzinc bromide; direct preparation,
and its application for the synthesis of 5-substituted furan derivatives. Tetrahedron Lett
52:1128–1131
36. Krasovskiy A, Malakhov V, Gavryushin A, Knochel P (2006) Efficient synthesis of
functionalized organozinc compounds by the direct insertion of zinc into organic iodides
and bromides. Angew Chem Int Ed 45:6040–6044
37. Kim S-H, Rieke RD (2010) A convenient synthesis of 5-aryl- and 5-heteroaryl-2-furaldehydes
by the cross-coupling reaction of organozincs. Tetrahedron Lett 51:2657–2659
38. Valente C, Belowich ME, Hadei N, Organ MG (2010) Pd-PEPPSI complexes and the Negishi
reaction. Eur J Org Chem 4343–4354
39. Organ MG, Calimsiz S, Sayah M, Hoi KH, Lough AJ (2009) Pd-PEPPSI-IPent: an active,
sterically demanding cross-coupling catalyst and its application in the synthesis of tetra-ortho-
substituted biaryls. Angew Chem Int Ed 48:2383–2387
40. Sase S, Jaric M, Metzger A, Malakhov V, Knochel P (2008) One-pot Negishi cross-coupling
reactions of in situ generated zinc reagents with aryl chlorides, bromides, and triflates. J Org
Chem 73:7380–7382
41. Huang Q, Rawal VH (2006) Total synthesis of ()-bipinnatin J. Org Lett 8:543–545
42. Xie L-G, Wang Z-X (2011) Nickel-catalyzed cross-coupling of aryltrimethylammonium
iodides with organozinc reagents. Angew Chem Int Ed 50:4901–4904
43. Molander GA, Canturk B, Kennedy LE (2009) Scope of the Suzuki-Miyaura cross-coupling
reactions of potassium heteroaryltrifluoroborates. J Org Chem 74:973–980
44. Dreher SD, Lim S-E, Sandrock DL, Molander GA (2009) Suzuki-Miyaura cross-coupling
reactions of primary alkyltrifluoroborates with aryl chlorides. J Org Chem 74:3626–3631
74 K.-S. Yeung

45. Molander GA, Gormisky PE, Sandrock DL (2008) Scope of aminomethylations via Suzuki-
Miyaura cross-coupling of organotrifluoroborates. J Org Chem 73:2052–2057
46. Molander GA, Jean-Gérard L (2009) Use of potassium b-trifluoroborato amides in
Suzuki-Miyaura cross-coupling reactions. J Org Chem 74:5446–5450
47. Knapp DM, Gillis EP, Burke MD (2009) A general solution for unstable boronic acids:
slow-release cross-coupling from air-stable MIDA boronates. J Am Chem Soc 131:6961–6963
48. Kinzel T, Zhang Y, Buchwald SL (2010) A new palladium precatalyst allows for the fast
Suzuki-Miyaura coupling reactions of unstable polyfluorophenyl and 2-heteroaryl boronic
acids. J Am Chem Soc 132:14073–14075
49. Molander GA, Beaumard F (2010) Nickel-catalyzed C–O activation of phenol derivatives with
potassium heteroaryltrifluoroborates. Org Lett 12:4022–4025
50. Quasdorf KW, Antoft-Finch A, Liu P, Silberstein AL, Komaromi A, Blackburn T, Ramgren
SD, Houk KN, Snieckus V, Garg NK (2011) Suzuki-Miyaura cross-coupling of aryl
carbamates and sulfamates: experimental and computational studies. J Am Chem Soc
133:6352–6363
51. Albaneze-Walker J, Raju R, Vance JA, Goodman AJ, Reeder MR, Liao J, Maust MT, Irish PA,
Espino P, Andrews DR (2009) Imidazolylsulfonates: electrophilic partners in cross-coupling
reactions. Org Lett 11:1463–1466
52. Taylor RH, Felpin F-X (2007) Suzuki-Miyaura reactions of arenediazonium salts catalyzed by
Pd(0)/C. One-pot chemoselective double cross-coupling reactions. Org Lett 9:2911–2914
53. Bandgar BP, Bettigeri SV, Phopase J (2004) Unsymmetrical diaryl sulfones through
palladium-catalyzed coupling of aryl boronic acids and arylsulfonyl chlorides. Org Lett
6:2105–2108
54. Matsuda S, Takahashi M, Monguchi D, Mori A (2009) C–H and C–Si functionalization of
furan derivatives: palladium-catalyzed homocoupling and arylation reactions. Synlett
1941–1944
55. Denmark SE, Baird JD, Regens CS (2008) Palladium-catalyzed cross-coupling of
five-membered heterocyclic silanolates. J Org Chem 73:1440–1455
56. Denmark SE, Smith RC, Chang W-TT, Muhuhi JM (2009) Cross-coupling reactions of
aromatic and heteroaromatic silanolates with aromatic and heteroaromatic halides. J Am
Chem Soc 131:3104–3118
57. Cornella J, Lahlali H, Larrosa I (2010) Decarboxylative homocoupling of (hetero)aromatic
carboxylic acids. Chem Commun 46:8276–8278
58. Becht J-M, Catala C, Le Drian C, Wagner A (2007) Synthesis of biaryls via decarboxylative
Pd-catalyzed cross-coupling reaction. Org Lett 9:1781–1783
59. Goossen LJ, Rodriguez N, Linder C (2008) Decarboxylative biaryl synthesis from aromatic
carboxylates and aryl triflates. J Am Chem Soc 130:15248–15249
60. Goossen LJ, Rodriguez N, Linder C, Lange PP (2009) Biaryl and aryl ketone synthesis via Pd-
catalyzed decarboxylative coupling of carboxylate salts with aryl triflates. Chem Eur J
15:9336–9349
61. Forgione P, Brochu M-C, St-Onge M, Thesen KH, Bailey MD, Bilodeau F (2006) Unexpected
intermolecular Pd-catalyzed cross-coupling reaction employing heteroaromatic carboxylic
acids as coupling partners. J Am Chem Soc 128:11350–11351
62. Zeni G, Alves D, Braga AL, Stefani HA, Nogueria CW (2004) Stereoselective sp2–sp2 bond
formation via Negishi cross-coupling of vinylic tellurides and 2-heteroarylzinc chlorides.
Tetrahedron Lett 45:4823–4826
63. Zeni G, L€udtke DS, Nogueria CW, Panatieri RB, Braga AL, Silveira CC, Stefani HA, Rocha
JBT (2001) New acetylenic furan derivatives: synthesis and anti-inflammatory activity. Tetra-
hedron Lett 42:8927–8930
64. Zeni G, Nogueria CW, Silva DO, Menezes PH, Braga AL, Stefani HA, Rocha JBT (2003)
Palladium(II) chloride catalyzes the cross-coupling reaction of 2,5-bis-(butyltelluro)-furan and
1-alkynes. Tetrahedron Lett 44:1387–1390
Furans and Benzofurans 75

65. Cella R, Cunha RLOR, Reis AES, Pimenta DC, Klitzke CF, Stefani HA (2006) Suzuki-
Miyaura cross-coupling reactions of aryl tellurides with potassium aryltrifluoroborate salts. J
Org Chem 71:244–250
66. Schr€oter S, Stock C, Bach T (2005) Regioselective cross-coupling reactions of multiple
halogenated nitrogen-, oxygen-, and sulfur-containing heterocycles. Tetrahedron
61:2245–2267
67. Burke MD, Berger EM, Schreiber SL (2004) A synthesis strategy yielding skeletally diverse
small molecules combinatorially. J Am Chem Soc 126:14095–14104
68. Tuan DT, Tung DT, Langer P (2006) Synthesis of 2-(2-arylethenyl)-5-arylfurans by
regioselective palladium(0)-catalyzed coupling reactions of 2-(2-bromo-2-nitroethenyl)-5-
bromofuran. Synlett 2812–2814
69. Hung NT, Hussain M, Malik I, Villinger A, Langer P (2010) Site-selective Suzuki cross-
coupling reactions of 2,3-dibromobenzofuran. Tetrahedron Lett 51:2420–2422
70. Morice C, Garrido F, Mann A, Suffert J (2002) Palladium assisted substitution of 3-benzo[b]
furan triflates. Synlett 501–503
71. Masters K-S, Flynn BL (2010) An efficient synthesis of ()-frondosin B using a Stille–Heck
reaction sequence. Org Biomol Chem 8:1290–1292
72. Lin S-Y, Chen C-L, Lee Y-J (2003) Total synthesis of ailanthoidol and precursor XH14 by
Stille coupling. J Org Chem 68:2968–2971
73. Bach T, Bartels M (2001) 2,3-Disubstituted and 2,3,5-trisubstituted benzofurans by
regioselective Pd-catalyzed cross-coupling reactions; a short synthesis of eupomatenoid-15.
Synlett 1284–1286
74. Bach T, Bartels M (2002) Synthesis of eupomatenoids by three consecutive transition
metal-catalyzed cross-coupling reactions. Tetrahedron Lett 43:9125–9127
75. Bach T, Bartels M (2003) Regioselective C–C bond formation reactions on 2,3-dibromo- and
2,3,5-tribromobenzofuran as an access to multiply substituted benzofurans. Total syntheses of
eupomatenoids 3, 4, 5, 6, and 15. Synthesis 925–939
76. Luo Y-C, Zhang H-H, Liu Y-Z, Cheng R-L, Xu P-F (2009) An asymmetric approach to 5-O-
carbamoyl-2-epi-polyoxamic acid and the total synthesis of 200 -epi-polyoxin J. Tetrahedron
Asymmetry 20:1174–1180
77. Enders D, Del Signore G (2004) Efficient asymmetric synthesis of a-(heteroaryl)alkylamines
by 1,2-addition of lithiated hetarenes to aldehyde-SAMP-hydrazones. Tetrahedron Asymmetry
15:747–751
78. Yamashita M, Yamada K-i, Tomioka K (2004) Construction of arene-fused-piperidine motifs
by asymmetric addition of 2-trityloxymethylaryllithiums to nitroalkenes: the asymmetric
synthesis of a dopamine D1 full agonist, A-86929. J Am Chem Soc 126:1954–1955
79. Guinchard X, Denis J-N (2008) Reactions of in situ generated N-Boc nitrones with aromatic
and heteroaromatic Grignard reagents: application to the synthesis of zileuton. J Org Chem
73:2028–2031
80. Zhou S, Chen C-R, Gau H-M (2010) Highly enantioselective 3-furylation of ketones using
(3-furyl)titanium nucleophile. Org Lett 12:48–51
81. Wu K-H, Chuang D-W, Chen C-A, Gau H-M (2008) Chiral tertiary 2-furyl alcohols:
diversified key intermediates to bioactive compounds. Their enantioselective synthesis via
(2-furyl)aluminium addition to ketones catalyzed by a titanium catalyst of (S)-BINOL. Chem
Commun 2343–2345
82. Sibi MP, He L (2004) Application of enantioselective radical reactions: synthesis of
(þ)-ricciocarpins a and b. Org Lett 6:1749–1752
83. Furstner A, Weintritt H (1998) Total synthesis of roseophilin. J Am Chem Soc 120:2817–2825
84. Lee S, MacMillan DWC (2007) Organocatalytic vinyl and Friedel-Crafts alkylations with
trifluoroborate salts. J Am Chem Soc 129:15438–15439
85. Reiter M, Torssell S, Lee S, MacMillan DWC (2010) The organocatalytic three-step total
synthesis of (+)-frondosin B. Chem Sci 1:37–42
76 K.-S. Yeung

86. Chan LY, Kim S, Chung WT, Long C, Kim S (2011) Fe(OTf)3-catalyzed reaction of benzylic
acetates with organosilicon compounds. Synlett 415–419
87. Molander GA, Cavalcanti LN (2011) Metal-free chlorodeboronation of organotrifluoroborates.
J Org Chem 76:7195–7203
88. Abbiati G, Arcadi A, Marinelli F, Rossi E, Verdecchia M (2006) Rh-catalyzed sequential
hydroarylation/hydrovinylation–heterocyclization of b-(2-aminophenyl)-a,b-ynones with
organoboron derivatives: a new approach to functionalized quinolines. Synlett 3218–3224
89. Pommier A, Stepanenko V, Jarowicki K, Kocienski PJ (2003) Synthesis of (+)-manoalide via a
copper(I)-mediated 1,2-metalate rearrangement. J Org Chem 68:4008–4013
90. Chartoire A, Comoy C, Fort Y (2008) Furo[3,2-b]pyridine: a convenient unit for the synthesis
of polyheterocycles. Tetrahedron 64:10867–10873
91. Chartoire A, Comoy C, Fort Y (2010) Toolbox for regioselective lithiations of furo[2,3-c]
pyridine. J Org Chem 75:2227–2235
92. Henssier JT, Matzgar AJ (2009) Facile and scalable synthesis of the fused-ring heterocycles
thieno[3,2-b]-thiophene and thieno[3,2-b]furan. Org Lett 11:3144–3147
http://www.springer.com/978-3-642-31790-3