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Asymmetric Organocatalysis

Research Article • DOI: 10.2478/asorg-2013-0001 • ASORG • 2013 • 24–31

Trienamines: Their Key Role in Extended Organocatalysis

for Diels-Alder Reactions

Silvia Reboredo1, José Alemán2#
Activation via trienamine intermediates is a synthetically useful protocol for
Alejandro Parra2*,
performing asymmetric Diels-Alder reactions controlled by a remote chiral
catalyst (a secondary or primary amine). Key features underpinning this
concept are the conformation towards the trienamine formation and also
Departamento de Química Orgánica I, 2
Departamento de Química Orgánica
Facultad de Químicas, Universidad (Módulo 1), Facultad de Ciencias,
the use of highly electrophilic dienophiles. This cycloaddition reaction allows
Complutense de Madrid Universidad Autónoma de Madrid
the application of asymmetric organocatalysis at a remote position, and the Cantoblanco, 28049-Madrid
synthesis of complex molecules short synthetic sequences is possible.

Keywords Received 14 March 2013

Trienamine • Organocatalysis • Asymmetric catalysis • Diels-Alder reaction • Tandem Accepted 06 April 2013

© Versita Sp. z o.o.

Asymmetric organocatalysis has received increasing the first amino-catalyzed Diels-Alder reaction (DA) by using
attention over the last decade due to the establishment of trienamine intermediates derived from dienals was described.
organocatalysis as a useful synthetic tool. Atypical reactivities This successful approach was rationalized by DFT-calculations
and hitherto unachievable asymmetric transformations are which indicated that ε-activation was favored by a sterically
some of the highlights of organocatalysis [1]. This bio-mimetic demanding single-bond rotation and, in addition, that only one
“organocatalytic revolution” has inspired original modes of of the generated dienes could be selectively activated (Figure 2).
activation, especially in the area of carbonyl group chemistry. NMR experiments showed that a strongly acidic medium
Activation by chiral amines has been demonstrated as a (o-fluorobenzoic acid) was essential for the formation of the
powerful method, since HOMO [2], LUMO [3], and SOMO [4] trienamine intermediate.
activations are well-established techniques and they have The concept was satisfactorily evaluated using 3-olefinic
found widespread use in asymmetric synthesis. The concept oxindoles and cyanoacetates as dienophiles (Scheme 1).
of LUMO lowering activation (β-functionalization) was first Thus, a sterically demanding catalyst, chlorinated solvent, and
employed in 2000 [3], while HOMO raising activation was an acidic additive were crucial to the success of the reaction.
employed for activating both carbonyl groups via enamine The interest in this transformation is related to the wide range
(α-functionalization) [2a-b] in 2000 and dienamine [2c-d] of analogous substituent patterns present in a large number of
catalysis (γ-functionalization) in 2006 (Figure 1). The application natural products [8].
of asymmetric aminocatalysis to more remote sites has long
been considered however, it has taken several years (in contrast
to the remarkably quick achievements in the field of the chiral
auxiliaries [5]) for this goal to be realized.
In order to achieve the aims of remote induction using more
extended conjugated systems with chiral amines, two issues
have to be addressed. On the one hand, the catalytic system
must control the regioselectivity in the α−δ−ε positions (HOMO-
raising positions) [6]. On the other hand, the stereocontrol
performed by the employed amine catalyst must be efficient,
taking into account that six bonds exist separating the chiral
moiety and the reactive position (right panel in Figure 1).
Recently, this new asymmetric activation mode was reported
by Chen and Jørgensen [7]. In this conceptually attractive work, Figure 1. Evolution of activation modes using aminocatalysis.

E-mail: * jose.aleman@uam.es,
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Trienamines: Their Key Role in Extended Organocatalysis
for Diels-Alder Reactions

Figure 2. Trienamine intermediates and conformational studies.

OH C R1 Ph O Ar
N Ph
N Ar R1
O ( 20 m o l% ), CH 2 C l2 (2 0 m o l% ) , C HC l3 OH C
N R5
o-F BA ( 20 m o l% ) o-F B A (2 0 m o l% )
R2 NC CO 2 R 6
R3 C O2R6
Y ie ld: 4 7 -9 9 % R5 Y ie ld : 71 - 97 %
e e : 9 4 -9 9 % R4 R1 CN e e : 8 5- 8 9%
d r : 7 8 :22 - >9 5 :5 O A r= P h or d r: 7 8 :2 2 -9 0 :1 0
N 4-O Me -3,5- (t-B u) 2 C 6 H 2

Scheme 1. First catalytic asymmetric trienamine reaction by Jørgensen and Chen.

Encouraged by these novel results, Chen et al. [9] were obtained in high ee´s (90-93%), good dr´s (11:1 to >20:1),
independently explored the possibility of using nitroalkenes and low (22%) to excellent yields (96%). For other dienophiles
as dienophiles (left equation, Scheme 2). Unfortunately, such as methyleneindolines, the results were also excellent in
these types of styrenes did not provide any product even at terms of enantioselectivity, but in some cases dr’s were found
80°C when 2,4-hexadienal was used, indicating that higher to be lower (right panel, Scheme 3). Based on computational
activated dienophiles are required. Thus, the introduction studies, a [4+2] process was proposed, using an exo-approach in
of electron donating groups in the trienamine moiety the case of nitroalkenes (favored by π(Ph)-π(diene) interactions)
raised the HOMO energy, allowing the reaction of dienals and an endo-approach in the case of methyleneindoline (π(C=O)-
and nitroalkenes. Almost simultaneously, Jørgensen et al. π(diene) interactions). Very recently, in 2013, the same research
[10] studied trienamine formation and its reaction with (Z)- group [12] applied this strategy to the stereoselective synthesis
olefinic azlactones (right equation, Scheme 2). In this case, the of tetrahydrocarbazoles using sequential Diels-Alder/benzoin
use of o-fluorobenzoic acid was not necessary (higher yields reactions under trienamine-carbene catalysis.
were obtained without additives), and the obtained aldehyde Once again, in 2012, Chen et al. [13] evaluated trienamine
was later derivatized to afford α,β-unsaturated products (via catalysis involving in the Diels-Alder reaction of 2,4-dienones.
Wittig or Ramirez olefinations). Excellent enantioselectivities The authors demonstrated the inability of performing this reaction
(ee´s) were obtained with diastereomeric ratios (dr) ranging with alkyl-dienyl-ketones because of the low reactivity derived
from 4:1 to 8:1. More interestingly, these final products allowed from the use of primary amine catalyst (cinchona derivatives).
amino acid derivatives and polycyclic compounds to be The aryl-dienyl-ketones seemed to be more reactive, which
accessed. make them good substrates for the DA reaction. However, this
Only a few months later, Melchiorre et al. [11] were able to use reaction was only catalyzed when the remote double bond was
this strategy for the formation of o-quinodimethane derivatives disubstituted by an alkyl group (e.g., R2= Me), yielding racemic
and described subsequent reactions of these intermediates products when the double bond was monosubstituted (R2= H)
with nitroalkenes and methyleneindolines (Scheme 3). The use (Scheme 4).
of 3-methyl-indoles bearing a α,β-unsaturated aldehyde at the After initial screening, it was found that a quinine derived
3-position, which facilitated dearomatization of the system was catalyst gave the best results. The reaction tolerated a wide
a key feature (see the range of aromatic groups at the ketone moiety, even a 2-styryl
o-quinodimethane intermediate below, Scheme 3). In the case group (R1), whereas the substitution pattern at the double bond
of nitroalkenes, the resulting compounds (tetrahydrocarbazoles) was more restricted (R3= Me, Ph, and R2; R3= cyclohexyl). In all

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S. Reboredo et al.

Ph Ph
3 N O R7 R6
R2 R4 (2 0 m o l% ), C HC l3 H OTMS
o-F B A (2 0 m ol% ) R1 (1 0 m o l% ), C HC l3 O
R1 N O2 th en PP h 3 =X Ph
NO 2 N
R4 O
C HO R5 R5
Y ie ld: 4 7 -9 3 % N O Y ie ld: 4 7 -9 0 %
e e : 9 1 -9 4 % Ph e e : 9 6 -9 9 %
d r : 8 6 :14 - >9 5 :5 C h e n et al Jø r ge n se n et al d r : 4 :1- 8 :1

Scheme 2. Independent works of Jørgensen and Chen et al. in trienamine chemistry.

Ph Ph H
R4 N O Ph
R5 N Ph H N N O2
O (2 0 m o l% ) ( 20 m o l% ) R6
OH C BA (2 0 m o l% ) BA (2 0 m o l% )
N B o c CH Cl , 7 0 ºC N
2 2 T olu e n e, 7 0 ºC
R5 N R6 R2
R1 R3 R2 2
Y ield : 53 - 98 % O Y ield : 22 - 96 %
ee : 9 5 ->9 9 % N e e : 9 0- 9 3%
R 4
d r : 1 :1 ->2 0 :1 d r: 1 0 :1 -> 2 0 :1
Ph Ph


o- quinodimethane

Scheme 3. o-Quinodimethane intermediate generated using trienamine strategy.

Scheme 4. Initial trienamine chemistry using ketones (Chen et al.).

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Trienamines: Their Key Role in Extended Organocatalysis
for Diels-Alder Reactions

cases, yields ranged from moderate to excellent (47–93%), only theoretical calculations to investigate the selectivities found in
one diastereomer was observed (>95:5), and good to excellent these Diels−Alder reactions. Kinetic and thermodynamic control
ee´s (82–96%) were obtained (for selected examples, see the top in the formation of zwitterionic intermediates could be used
row in Figure 3). In the same work, it was also demonstrated to explain the [4+2] cycloaddition reactions between cyclic
that the reaction was compatible with methyleneindolines, trienamines and oxindoles.
deactivated alkenes, and nitroalkenes as dienophiles (bottom Tetrahydroxanthone derivatives are commonly present
row, Figure 3). in nature and they possess interesting biological properties.
In the same year, Jørgensen et al. [14] described a novel and Jørgensen et al. [16] synthesized a range of these materials
interesting concept termed a “cross-trienamine” intermediate. through a H-bonding-directed approach for trienamine mediated
This intermediate can be involved in a highly enantioselective [4+2] cycloadditions. Thus, a squaramide-based organocatalyst
Diels-Alder reaction with different dienophiles, such as 3-olefinic [17] interacted with a nitrile group present in the chromone
oxindoles, 5-olefinic azlactones and even with bis-sulfonyl alkenes derivative (dienophile) by hydrogen bond interaction, ensuring
(Scheme 5). In all cases, total regioselectivity was observed via both high reactivity and diastereoselectivity (Scheme 6). The
the cross-trienamine, and excellent enantioselectivities (up to obtained adducts were chemoselectively transformed into the
99%) were usually obtained. Very recently, Houk et al. [15] used desired products.

Me Me Ph
N Ph N p-B rC 6 H 4 N p-B rC 6 H 4

O Ph O O
Y ie ld : 7 5 % Y ie ld : 8 0 % Y ie ld : 4 6 %
ee: 92% ee: 96% ee: 85%

E tO 2 C Ph p- Br C 6 H 4
O CO 2 E t NO 2
P hOC p- To lO C
Y ie ld : 7 0 % Y ie ld : 8 0 % Y ie ld : 7 0 %
e e: 9 4 % e e: 9 0 % e e: 9 1 %
d .r .: >9 5 :5 d .r .: >9 5 :5 d .r .: >9 5 :5

 elected examples from Chen’s research.

Figure 3. S

N Bo c
R4 O
2 R1 R2
Ph R
Ph Ph E tO 2 C
Ph N Ph
O NR* H O TM S +
N (1 0 m o l% ),C H Cl 3,
BA ( 2 0 m o l% ), (1 0 m o l% ) ,C HC l3 ,
R5 O R3
R2 4 0 -5 0 ºC o- FB A (2 0 m o l% )
R1 R1 N Bo c
O R4 4
O R5
O R2 3 R1 R2
N E tO 2 C
Ph B oc
th e n P P h 3 C H 2 CO 2 Et,
Y ie ld : 3 4- 5 8% Y ie ld : 5 4 -7 5 %
e e : 9 2 -9 9 % 4 0 ºC
e e : 9 2 -9 9 %
d r: 3 :1 -5 :1 d r: 7 :1 -2 0 :1
 eactivity of cross-trienamine.
Scheme 5. R

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S. Reboredo et al.

In an attempt to overcome the traditional challenge of the out to be unreactive. With regards to anthracene substitution,
high energetic barrier for disrupting aromaticity, Jørgensen et al. substituents on outer rings (R1 and R3) ) gave better results than
[18] proposed direct HOMO-raising activation of polycyclic inner ring substitution (R2) (Scheme 7).
π-systems (anthracene derivatives) using aminocatalysis. The Ye et al. [20] have recently described an interesting
evaluation of the [4+2] cycloaddition model reaction between Diels-Alder reaction between rhodanine derivatives and
nitrostyrene and 2-(anthracen-9-yl)acetaldehyde indicated 2,4-dienals catalyzed by the Jørgensen-Hayashi catalyst. For
that a bifunctional catalyst would be most appropriate (left, pharmacological scientists, analogues of this dipolarophile
Scheme  7). This catalyst would activate the anthracene prove to be of great importance due to their biological activities.
derivative by an enamine formation and also would form a Rhodadyn was reacted with 2,4-hexadienal in the model reaction.
hydrogen bond with nitrostyrene, thus restricting the approach High yields and excellent diastereo- and enantioselectivities
of the dienophile to only one of the possible enantiotopic faces. were achieved under optimized conditions (Scheme 8). The
The reaction requires only 2 mol% of catalyst and is compatible reactions of thiohydantoin derivatives (R3 and R4) and dienals
with a wide range of nitrostyrene derivatives having different (R1 and R2) afforded the desired products in excellent enantio-
substitution patterns on aryl group and also with various 9,10- and good diastereoselectivities (Scheme 8). It is hoped this work
substituted anthracenes. High yields and excellent ee´s were may lead to further development of valuable motifs in new drug
reported (left, Scheme 7). discovery and the synthesis of natural products.
In a subsequent work, the same authors [19] performed Very recently, Chen et al. [21] reported the exo-Diels-Alder
DFT calculations in an effort to broaden the developed method reaction by using HOMO-raising trienamine activation. A series
for the Diels-Alder reaction with anthracene derivatives since of spirocyclic compounds were prepared by means of a Diels-
it was limited to both the dipole and the dipolarophile being Alder reaction between trienamine intermediates derived from
activated by the catalyst. They found that the reaction can 2,4-dienals and methiodide salts of Mannich bases. In order to
proceed with maleimide derivatives, and in this case, a C2- generate the reactive vinyl ketone, 2.0 equivalents of sodium
symmetric catalyst was used. The scope of this cycloaddition benzoate were used, affording products in good yields (41-75%)
included maleimides (aromatic and non-aromatic) with and excellent enantioselectivities (up to 97%) (right, Scheme 9).
differing electronic demands as well as maleic anhydride and Interestingly, in the case of cyclohexenones (as dienophiles) the
cyclopentenedienone. Noncyclic dienophiles, however, turned use of 20 mol% of (S,S)-TADDOL increased the final conversion

. O O CF3
O ( 16 m o l% ) O
N H H CF 3 O
+ R1
R1 R4
CH Cl 3 (0 .0 5 M ), DE A (8 e q.), 4 0 -6 0 o C R4
R 2 O R2
H 3
R3 R
Yie ld : 5 9 -9 8 %
e e: 8 5 -9 1 %
d r: > 20 :<1

 nantioselective synthesis of tetrahydroxanthones.

Scheme 6. E

. O O CF3
( 2 m o l% ) Ph P h ( 10 m o l% )
CF 3
H P h CO 2 H ( 10 m o l% ), CH Cl 3 O
N O2 1 ) D EA ( 2 e q .), C H 2 Cl 2, r t, C HO
Ar N O2 O
2 ) Na B H 4 , M e O H , 0 o C -3 0 to 4 0 o C , 2 4 or 4 8 h
R2 R1 R2 R3 R2
R1 R3
R 1 =R 3 = H
Y ield : 6 9- 9 8% Yie ld : 7 0 -9 6 %
e e : 9 2 -9 8 % ee : 7 6 -9 6 %

Scheme 7. Asymmetric Diels-Alder reaction with anthracene derivatives.

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Trienamines: Their Key Role in Extended Organocatalysis
for Diels-Alder Reactions

since the intermediate ketone can be activated by hydrogen development, for instance, reactions other than the Diels-Alder
bonding interactions (left, Scheme 9). reaction may be explored.
In conclusion, Jørgensen and Chen demonstrated a new
protocol for carrying out asymmetric Diels-Alder reactions Abreviations
controlled by a remote chiral catalyst (a secondary or primary
amine). Key features underlying this process are the conformation DA: Diels-Alder
towards the trienamine formation and also the use of highly o-FBA: ortho-Fluorobenzoic acid
electrophilic dienophiles. A limited number of aldehydes/ketones BA: Benzoic Acid
and some very reactive dienophiles have been employed TADDOL: α,α,α,α-Tetraaryl-1,3-dioxolane-4,5- dimethanol
successfully. This new mode of activation is open to further DEA: Diethylacetamide

O Ph O
N Ph (2 0 m o l% ) S
o-FB A (2 0 m o l% ) R2 N R4
X 4
R3 O
C DC l3 5 0 o C R3
O 1
Y ie ld : 6 4- 9 8%
e e : 9 2 -9 9 %
d r : 1 0:1 ->1 9 :< 1

 minocatalyzed Diels-Alder reaction.

Scheme 8. A

O R2 A r= 3 ,5 -t-Bu 2 -4 -M eO C 6 H 2 A r= 3 ,5 - t-B u 2 - 4- M e O C 6 H 2
R5 Ar
R1 Ar Ar
N Ar
(1 0 m ol% ),CH Cl 3 , O R2
T A DD O L (2 0 m o l% ), (2 0 m o l% ) ,
or P h CO 2 N a (2 e q .) P h CO 2 N a (2 e q.)
R3 R1 R4 R1
O R3 O X
O R2 R2 CH O
R 5
R1 R Y ie ld : 4 1 -7 5 %
X e e : 8 3 -9 7 %
R6 n
CH O or C H 2 Cl 2 , 6 0 ºC d r: 9 :1 -1 9 :1

Y ield : 3 2- 7 6% N I
e e : 8 4 -9 7 %
d r: 4 :1 ->1 9 :1 R6

Scheme 9. e xo-Diels-Alder reaction reported by Chen et al.


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for Diels-Alder Reactions

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