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AbstractA new mild method allowing the removal of carbamates using TBAF in THF is reported. Reactions were performed on indole,
indoline, N-methyl aniline, aniline and tryptamine derivatives. The observed selectivity according to the carbamates or the substrates is
discussed. A mechanism is postulated.
q 2004 Published by Elsevier Ltd.
1. Introduction
The selection of a protective group is often a crucial step in
organic synthesis;1 the development of new protective
groups and novel efficient methods for their introduction or
cleavage remains of prime importance in synthetic
methodology.
Many protective groups have been developed for the amino
functionality, in peptide, protein, and nucleotide syntheses
as well as in heterocyclic chemistry. Among them, may be
the most useful and popular are the carbamates. Actually,
carbamates are not only used as protective but also as
efficient directing metallation groups.2 Carbamates are
generally obtained from an amine by reaction with the
adequate chloroformate or anhydride. It is of prime interest
to dispose of a wide range of methods allowing the selective
cleavage of a definite protective group on a given nitrogen
atom in the presence of other N-protected sites.3,4 There are
a lot of conditions allowing the recovery of the free amino
group; catalytic hydrogenolysis, acidic or basic3 treatments
are generally appropriate to remove most of the different
carbamates used in organic synthesis. Nevertheless several
drawbacks constitute sometimes a limitation of the
efficiency of these methods. For instance, the presence of
a sulfur atom is commonly incompatible with a catalytic
hydrogenolysis.5 The acidic cleavage of a Boc group can
generate t-butyl cations and in some cases, scavengers have
to be used to prevent undesirable alkylation or electrophilic
additions.6 The unwanted formation of heterocycles by an
intramolecular cyclisation has been as well reported in the
course of reactions involving methyl and ethyl carbamates.7,8
Keywords: Carbamates; Deprotection; Bu4NF; Protective groups.
* Corresponding author. Tel.: C33-2-38-49-45-89.; fax: C33-2-38-41-7281; e-mail: gerard.coudert@univ-orleans.fr
00404020/$ - see front matter q 2004 Published by Elsevier Ltd.
doi:10.1016/j.tet.2004.07.071
10040
effective after a much longer reaction time for all the other
carbamate protective groups (entries 1b4b). By performing
the reaction in refluxing THF, however, all the carbamates
were cleaved after 1.5 h (entries 1a5a). Allyl and phenyl
derivatives 4 and 6 were particularly sensitive and were
cleaved in only 20 and 15 min respectively (entries 3a, 5a).
In the cases of compounds 5 and 6, were also detected
benzyl alcohol 8 and phenol 9 along with indole 1.
Decreasing the amount of reagent Bu4NF to 1.2 equiv
(instead of 5 equiv) and performing the reaction at reflux,
slowed down the rate of cleavage (entries 1c5c), but the
order of sensitivity of the different carbamates remained
unchanged: phenyl, allylObenzyl, Me, EtOt-Bu.
The phenyl carbamate was nearly totally cleaved in 24 h at
rt, using 1.2 equiv of TBAF (entry 5d), whereas in the same
conditions the deprotection was partial with the other
derivatives, but starting material was always recovered
(entries 1d4d, 6d).
2.2. Cleavage of amines carbamates
2.2.1. Primary and secondary aromatic amines. Carbamates 1428 were prepared from indoline 11, N-methylaniline 12 and aniline 13 using standard procedures (Fig. 2).
The Boc carbamates 18, 2332and 2833 were first submitted to
the action of TBAF (5 equiv) in refluxing THF for 8 h
(Table 2). While the protection of the secondary amines
remained intact, the Boc derivative 28 was quantitatively
deprotected (entry 10).
The indoline derivatives 143416,35 17 were then submitted
to TBAF (5 equiv) in the same conditions. After hydrolysis,
deprotected indoline 11 was generally isolated in low yield
and the starting material was recovered; no significant
Reactant
Bu4NF (equiv)
Time
T (8C)
5.0
5.0
1.2
1.2
5.0
5.0
1.2
1.2
5.0
5.0
1.2
1.2
5.0
5.0
1.2
1.2
5.0
5.0
1.2
1.2
5.0
5.0
2
1.2
40 min
8 h.
2 h 15
24 h
1 h 30
8h
4 h 30
24 h
20 min
6 h 45
2h
8h
1 h 30
3h
8h
8h
15 min
30 min
15 min
24 h
8h
24 h
24 h
24 h
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
Reflux
rt
1 (97)
1 (90)
1 (98)
1(54), 2 (14)
1 (97)
1 (70), 3 (26)
1 (97)
1 (30), 3 (66)
1 (97)
1 (84), 4 (11)
1 (87), 4 (10)
1 (34), 4 (62)
1 (75),b 8 (ND)c
1 (76),b 8 (ND)c
1 (98),b 8 (ND)c
1 (64), 5 (36), 8 (ND)c
1 (82)b,c
1 (78),b 9 (ND)c
1 (77),b 9 (ND)c
1 (78), 6 (5), 9 (ND)c
1 (98)
7 (99)
1 (81), 7 (7)
1 (39), 7(51)
NDnot determined.
a
Yield given after flash chromatography.
b
Quantitative on TLC.
c 1
H NMR of the crude mixture shows an equimolar composition of compound 1 and of the liberated benzyl alcool 8 or phenol 9.
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Figure 3. (a) For 30 NEt3, 1.05 equiv, PhOCOCl 1.05 equiv CH2Cl2, rt,
30 min 85%; for 31, Boc2O 1.2 equiv, 4-DMAP 1.05 equiv, CH3CN, rt, 4 h,
quant. (b) Bu4NF, THF, see text.
Figure 2. 14 EtOCOCl 1.2 equiv, NaH 1.5 equiv, THF, rt, 1 h, 88%; 15
AllylOCOCl 1.5 equiv, NaH 1.2 equiv, THF, rt, 1 h, quant.; 16 PhCH2OCOCl 1.2 equiv, NaH 1.5 equiv, DMF, rt, 2 h, 30%; 17 PhOCOCl
1.2 equiv, NaH 1.1 equiv, DMF, rt, 2 h, 72%; 20 AllylOCOCl 1.2 equiv,
NaH 1.5 equiv, THF, rt, 1 h, quant.; 21 PhCH2OCOCl 1.2 equiv, NaH
1.5 equiv, DMF, rt, 18 h, 72%; 22 PhOCOCl 1.2 equiv, NaH 1.1 equiv,
DMF, 0 8C to rt, 2 h, 83%; 23 Boc2O 1.5 equiv, 4-DMAP 1 equiv, NEt3
1.5 equiv, THF, rt, 5 h, 95%; 24 EtOCOCl 1.2 equiv, NaH 1.4 equiv, THF,
rt, 2 h, quant.; 25 AllylOCOCl 1.2 equiv, NaH 1.5 equiv, THF, rt, 6 h, 21%;
26 PhCH2OCOCl 1.2 equiv, NaH 1.5 equiv, DMF, rt, 18 h, 55%; 27
PhOCOCl 1.1 equiv, NEt3 1.2 equiv, CH2Cl2, 3 h, quant.; 18, 19, 28
commercially available.
Bu4NF (equiv)
Reactant
14
15
16
17
18
24
25
26
27
28
5.0
5.0
5.0
5.0
5.0
5.0
5.0
5.0
1.2
5.0
Time
8h
8h
8h
8h
8h
6h
3h
2.5 h
5 min
8h
T (8C)
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
rt
Reflux
Products (%)
11 (18), 14 (79)
11 (16), 15 (57)
11 (22), 16 (74)
11 (68), 17 (35)
No reaction
13 (quant.)a
13 (quant.)a
13 (quant.)a
13 (quant.)a
13 (quant.)a
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Figure 4. (a) Boc2O 2.0 equiv, NEt3 1 equiv, 4-DMAP 1.5 equiv, THF, rt,
12 h, 90%; (b) Bu4NF 10 equiv, THF, reflux, 6 h, quant.; (c) Boc2O
1.5 equiv, 4-DMAP 10%, THF, rt, 4 h, 83%; (d) Bu4NF 5 equiv, THF,
reflux, 7 h, quant. in TLC; (e) Bu4NF 5 equiv, THF, reflux, 5 h, quant.; (f)
Bu4NF 5 equiv, THF, reflux, 6 h, 88%; (g) Bu4NF 5 equiv, THF, reflux, 7 h,
quant.
Reactant
Conditions
35 (67), 32 (30)
35
35 (quant.)
33
35
36 (83)a,b
34
36
34
a
b
32
36 (39),a,b 37 (25)b
36
37
No degradation.
Total conversion of starting material.
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3. Conclusion
In this paper, we have studied the cleavage of various
aromatic and aliphatic carbamates. Whatever the amino
function (aliphatic, aromatic), the phenyl carbamate is very
easily cleaved except for secondary aromatic amine. Nprotected indolic compounds were always cleaved in the
order phenyl, allylObenzyl, Me, EtOt-Bu. The presence of
an aliphatic or vinylic methyl ester seems to inhibit the
previous reaction and aliphatic methyl esters were hydrolyzed to the corresponding acids without affecting the
protective group. All these results are useful to easily
remove various carbamates on substrates, which contain
other organic functions not compatible with acidic, basic or
catalyzed deprotections generally described in the literature.
4. Experimental
4.1. Chemistry
1
(20 mL) was added and the aqueous phase was extracted
with CH2Cl2 (3!20 mL). The combined organic layers
were dried over MgSO4, filtered and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether/EtOAc
8/2) to afford compound 30 as a white solid (698 mg, 85%).
Mp 74 8C; Rf (petroleum ether/EtOAc 8/2): 0.15; IR (KBr,
cmK1) n 3321, 3050, 2950, 2882, 1707, 1537, 1493, 1292,
1249, 1205; 1H NMR (CDCl3) d 2.85 (t, 2H, JZ7 Hz), 3.52
(q, 2H, JZ6.5 Hz), 5.1 (bs, 1H), 7.047.41 (m, 8H); 13C
NMR (CDCl3) d?35.1 (CH2), 42.0 (CH2), 121.5 (2CH),
125.4 (CH), 128.2 (CH), 129.3 (2CH), 130.6 (CH), 130.7
(CH), 132.5 (Cq), 138.8 (Cq), 150.8 (Cq), 154.5 (Cq); MS
(IS) 310/312 (MCH)C, 332/334 (MCNa)C. HRMS-EI
(MC): 309.03233 calcd for C15H13Cl2NO2, found 309.0318.
4.1.4. [2-(3,4-Dichloro-phenyl)-ethyl]-carbamic acid tertbutyl ester (31). A solution of 3,4-dichlorophenylethylamine 29 (500 mg, 2.64 mmol), 4-DMAP (322 mg
2.64 mmol) and Boc2O (690 mg, 3.16 mmol) in acetonitrile
(15 mL) was stirred at rt under argon. After 4 h, water
(20 mL) was added and the aqueous phase was extracted
with EtOAc (3!20 mL). The combined organic layers were
dried over MgSO4, filtered and the solvent was removed
under reduced pressure. The crude product was purified by
flash chromatography (petroleum ether then petroleum
ether/ EtOAc 6/4) to afford compound 31 as white solid
(762 mg, quant.). Mp 86 8C. Rf (petroleum ether/EtOAc 5/
5): 0.54; IR (KBr, cmK1) n 3338, 2979, 2925, 1687, 1534,
1283, 1168; 1H NMR (CDCl3) d: 1.44 (s, 9H), 2.79 (t, 2H,
JZ6.7 Hz), 3.39 (m, 2H), 4.57 (s, 1H), 7.02 (d, 1H, JZ
8.3 Hz), 7.29 (s, 1H), 7.36 (d, 1H, JZ8.3 Hz); 13C NMR
(CDCl3) d 28.7 (CH3), 35.7 (CH2), 41.8 (CH2), 79.9 (Cq),
128.6 (CH), 130.8 (CH), 131.2 (CH), 132.8 (Cq), 139.6
(Cq), 156.2 (Cq); MS (IS) 290/292 (MCH)C. HRMS-ESI
(MCNaC): 312.05340 calcd for C13H17NO2Cl2Na, found
312.0539.
4.1.5. 3-(2-tert-Butoxycarbonylamino-ethyl)-indole-1carboxylic acid tert-butyl ester (32). A solution of
tryptamine hydrochloride (1.38 g, 7.57 mmol), 4-DMAP
(1.11 g, 9.08 mmol) and Boc2O (3.46 g, 15.89 mmol) in
acetonitrile (20 mL) was stirred at rt under argon. After
12 h, water (50 mL) was added and the aqueous phase was
extracted with EtOAc (3!50 mL). The combined organic
layers were dried over MgSO4, filtered and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography (petroleum ether then
petroleum ether/ EtOAc 8/2) to afford compound 32 as a
waxy solid (2.45 g, 90%). Rf (petroleum ether/EtOAc 9/1):
0.24; IR (KBr, cmK1) n 3374, 2976, 2930, 1724, 1722, 1545,
1254, 1160, 1091; 1H NMR (CDCl3) d: 1.44 (s, 9H), 1.66 (s,
9H), 2.89 (t, 2H, JZ7.0 Hz), 3.46 (m, 2H), 4.63 (s, 1H),
7.23 (m, 2H), 7.41 (s, 1H), 7.53 (d, 1H, JZ7.8 Hz), 8.13 (d,
1H, JZ8.0 Hz); 13C NMR (CDCl3) d 26.0 (CH2), 28.6
(CH3), 28.8 (CH3), 40.7 (CH2), 79.5 (Cq), 83.8 (CH3), 115.7
(CH), 118.2 (Cq), 119.4 (CH), 122.8 (CH), 123.5 (CH),
124.8 (CH), 130.8 (Cq), 135.9 (Cq), 150.1 (Cq), 156.4 (Cq);
MS (IS) 361 (MCH)C. HRMS-ESI (MCNaC): 383.19468
calcd for C20H28N2O4Na, found 383.1948.
4.1.6. 3-(2-tert-Butoxycarbonylamino-ethyl)-indole-1carboxylic acid phenyl ester (33). A solution of compound
10045
10046
1H, JZJ 0 Z7.3 Hz), 7.32 (dd, 1H, JZJ 0 Z7.3 Hz), 7.44 (s,
1H), 7.53 (d, 1H, JZ7.0 Hz), 8.13 (bd, 1H, JZ7.6 Hz); 13C
NMR (CDCl3) d: 28.3 (3CH3), 29.8 (CH2), 41.3 (CH2), 83.6
(Cq), 115.4 (CH), 117.9 (Cq), 119.1 (CH), 122.6 (CH),
123.4 (CH), 124.5 (CH), 129.8 (Cq), 135.5 (Cq), 149.7 (Cq);
MS (IS) 261 (MCH)C, 161 (MCHKBoc)C. HRMS-ESI
(MCH C): 261.16030 calcd for C15 H21 N2 O2, found
261.1611.
4.1.9. 1,3-Bis-[2-(1H-indol-1- carboxylic acid tert-butyl
ester-3-yl)-ethyl]-urea (37). A solution of 34 (202 mg,
0.53 mmol) and TBAF (2.65 mL, 1 M in THF, 0.265 mmol)
in dry THF (5 mL) was stirred under argon at rt. After 5 min
water (5 mL) was added and the aqueous phase was
extracted with EtOAc (3!5 mL). The combined organic
layers were dried over MgSO4, filtered and the solvent was
removed under reduced pressure. The crude product was
purified by flash chromatography using petroleum ether/
EtOAc 5/5 to afford compound 37 (36 mg, 25%) as yellow
oil and MeOH to afford compound 36 (54 mg, 39%). Rf
(petroleum ether/EtOAc 5/5):0.46; IR (NaCl, cmK1) n 3319,
3046, 1716, 1599, 1532, 1491, 1443, 1318, 1224, 1202,
1023; 1H NMR (CDCl3) d: 1.64 (s, 18H), 2.86 (t, 4H, JZ
6.5 Hz), 3.47 (q, 4H, JZ6.5 Hz), 4.42 (t, 2H, JZ5.8 Hz),
7.167.33 (m, 4H), 7.39 (s, 2H), 7.50 (d, 2H, JZ7.6 Hz),
8.10 (d, 2H, JZ7.9 Hz); 13C NMR (CDCl3) d: 25.8 (CH2),
28.1 (3CH3), 40.0 (CH2), 83.5 (Cq), 115.2 (CH), 117.9 (Cq),
118.9 (CH), 122.4 (CH), 123.0 (CH), 124.4 (CH), 130.4
(Cq), 135.4 (Cq), 149.6 (Cq), 158.1 (Cq); MS (IS) 547.5
(MCH)C. HRMS-ESI (MCNaC): 569.27399 calcd for
C31H38N4O5Na, found 569.2743.
4.1.10. 4-(tert-Butoxy-hydroxy-methyl)-4H-benzo[1,4]
oxazine-2-carboxylic acid (45). A solution of compound
4447 (110 mg, 0.36 mmol) in dry THF (4 mL) was stirred at
rt under argon. Bu4NF (1.8 mL, 1 M in THF) was added and
the reaction mixture was refluxed for 5 h. After cooling, a
solution of NH4Cl satd. (10 mL) was added and the aqueous
phase was extracted with EtOAc (3!10 mL). The combined organic layers were dried over MgSO4, filtered and
the solvent was removed under reduced pressure. Compound 45 was obtained as a white solid (99 mg, quant.). Mp
184 8C dec. Rf (CH2Cl2/MeOH 9/1): 0.12; IR (KBr, cmK1) n
3386, 2975, 2771, 1581, 1731, 1682, 1495, 1151, 755; 1H
NMR (CDCl3) d: 1.51 (s, 9H), 6.84 (m, 3H), 7.27 (s, 1H),
7.83 (d, 1H, JZ8.3 Hz), 10.3 (s, 1H, exchange D2O); 13C
NMR (CDCl3) d 28.6 (CH3), 83.1 (Cq), 116.9 (CH), 117.2
(CH), 119.7 (CH), 121.1 (CH), 127.2 (CH), 134.6 (Cq),
147.9 (Cq) 150.2 (Cq), 164.6 (Cq); MS (IS) 278 (MCH)C.
HRMS-ESI (MKHC2Na C): 322.06674 calcd for
C14H14NO5Na2, found 322.0669.
4.1.11. 3-(2-{3-[2-(3,4-Dichloro-phenyl)-ethyl]-ureido}ethyl)-indole-1-carboxylic acid tert-butyl ester (50). A
solution of 34 (173 mg, 0.455 mmol) and TBAF (2.27 mL,
1 M in THF, 0.265 mmol) in dry THF (5 mL), amine 29
(86 mg, 0.455 mmol) was stirred under argon at rt for 5 min.
Water (5 mL) was added and the aqueous phase was
extracted with EtOAc (3!5 mL). The combined organic
layers were washed with a saturated aqueous solution of
NaCl (5 mL) and dried over MgSO4, filtered and the solvent
was removed under reduced pressure. The crude product
was purified by flash chromatography (petroleum ether/
Acknowledgements
We thanks La fondation pour la Recherche Medicale (FRM)
and La Ligue contre le Cancer Region Centre for their
financial support.
10047