Boc-protected amines via a mild and efficient one-pot curtius rearrangement

Article abstract of DOI:10.1021/ol051428b

(Chemical Equation Presented) The reaction of a carboxylic acid with di-tert-butyl dicarbonate and sodium azide allowed the formation of an acyl azide intermediate, which undergoes a Curtius rearrangement in the presence of tetrabutylammonium bromide and zinc(II) triflate. The trapping of the isocyanate derivative in the reaction mixture led to the desired tert-butyl carbamate in high yields at low temperature. These reaction conditions are compatible with a variety of substrates, including malonate derivatives, which provide access to protected amino acids.

Full text of DOI:10.1021/ol051428b

ORGANIC
LETTERS
2005
Vol. 7, No. 19
4107-4110
Boc-Protected Amines via a Mild and
Efficient One-Pot Curtius Rearrangement
He´le`ne Lebel* and Olivier Leogane
De´partement de chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
helene.lebel@umontreal.ca
Received June 20, 2005
ABSTRACT
The reaction of a carboxylic acid with di-tert-butyl dicarbonate and sodium azide allowed the formation of an acyl azide intermediate, which
undergoes a Curtius rearrangement in the presence of tetrabutylammonium bromide and zinc(II) triflate. The trapping of the isocyanate derivative
in the reaction mixture led to the desired tert-butyl carbamate in high yields at low temperature. These reaction conditions are compatible with
a variety of substrates, including malonate derivatives, which provide access to protected amino acids.
The Curtius rearrangement describes the degradation of an
acyl azide into an isocyanate through a concerted mecha-
nism.1 The isocyanate can be trapped by a variety of
nucleophiles, including alcohols, which provides the corre-
sponding carbamate. It is one of the most widely used
methods to synthesize amine derivatives, and over 1000
references can be found in the literature related to the Curtius
rearrangement. A number of methods have been developed
to access acyl azides from carboxylic acid derivatives, such
as hydrazides,2 acyl chlorides,3 and mixed anhydrides.4,5 In
these cases, acyl azides are isolated, and the rearrangement
is then performed in a separate step. However, acyl azides
are well-known to be unstable; thus, one-pot processes that
allow the direct conversion of carboxylic acids into carbam-
ates have become very popular.6,7 The most widely used
reagent for this purpose is diphenylphosphorazidate.8,9 How-
ever, there are a number of drawbacks associated with the
use of this reagent, including the high temperature and the
difficulty to purify the desired product from the phosphorus
(4) Selected examples: (a) Weinstock, J. J. Org. Chem. 1961, 26, 3511.
(b) Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J. Org. Chem.
1978, 43, 2164-2167. (c) Kaiser, C.; Weinstock, J. Organic Syntheses;
Wiley: New York, 1988; Collect. Vol. VI, p 910. (d) Guichard, G.; Semetey,
V.; Rodriguez, M.; Briand, J.-P. Tetrahedron Lett. 2000, 41, 1553-1557.
(e) Remen, L.; Vasella, A. HelV. Chim. Acta 2002, 85, 1118-1127. (f)
Kuramochi, K.; Osada, Y.; Kitahara, T. Tetrahedron 2003, 59, 9447-9454.
(g) Englund, E. A.; Gopi, H. N.; Appella, D. H. Org. Lett. 2004, 6, 213-
215. (h) Boeckman, R. K., Jr.; Reeder, L. M. Synlett 2004, 1399-1403. (i)
Dussault, P. H.; Xu, C. Tetrahedron Lett. 2004, 45, 7455-7457.
(5) Alternative methods: (a) Lee, J. G.; Kwak, K. H. Tetrahedron Lett.
1992, 33, 3165-3166. (b) Froyen, P. Phosphorus, Sulfur Silicon Relat. Elem.
1994, 89, 57-61. (c) Rawal, V. H.; Zhong, H. M. Tetrahedron Lett. 1994,
35, 4947-4950. (d) Elmorsy, S. S. Tetrahedron Lett. 1995, 36, 1341-
1342. (e) Gumaste, V. K.; Bhawal, B. M.; Deshmukh, A. R. A. S.
Tetrahedron Lett. 2002, 43, 1345-1346. (f) Bandgar, B. P.; Pandit, S. S.
Tetrahedron Lett. 2002, 43, 3413-3414. (g) Tale, R. H.; Patil, K. M.
Tetrahedron Lett. 2002, 43, 9715-9716. (h) Bose, D. S.; Reddy, A. V. N.
Tetrahedron Lett. 2003, 44, 3543-3545. (i) Bao, W. L.; Wang, Q. A. J.
Chem. Res., Synop. 2003, 700-701.
(1) (a) Smith, P. A. S. Org. React. 1946, 3, 337-349. (b) Shioiri, T. In
ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon
Press: Oxford, 1991; Vol. 6, p 795. (c) Scriven, E. F.; Turnbull, K. Chem.
ReV. 1988, 88, 297-368.
(2) Selected examples: (a) Jean, L.; Baglin, I.; Rouden, J.; Maddaluno,
J.; Lasne, M. C. Tetrahedron Lett. 2001, 42, 5645-5649. (b) Nettekoven,
M. Synlett 2001, 1917-1920. (c) Macor, J. E.; Mullen, G.; Verhoest, P.;
Sampognaro, A.; Shepardson, B.; Mack, R. A. J. Org. Chem. 2004, 69,
6493-6495.
(3) Selected examples: (a) Washburne, S. S.; Peterson, W. R., Jr. Synth.
Commun. 1972, 2, 227-230. (b) Van Reijendam, J. W.; Baardman, F.
Synthesis 1973, 413-414. (c) Brandstrom, A.; Lamm, B.; Palmertz, I. Acta
Chem. Scand. 1974, 28, 699-701. (d) Erhardt, P. W. J. Org. Chem. 1979,
44, 883-884. (e) Warren, J. D.; Press: J. B. Synth. Commun. 1980, 10,
107-110. (f) Pfister, J. R.; Wymann, W. E. Synthesis 1983, 38-40. (g) Lo
Scalzo, R.; Mascitelli, L.; Scarpati, M. L. Gazz. Chim. Ital. 1988, 118, 819-
820. (h) Khoukhi, M.; Vaultier, M.; Benalil, A.; Carboni, B. Synthesis 1996,
483-487. (i) Govindan, C. K. Org. Proc. Res. DeV. 2002, 6, 74-77. (j)
Kende, A. S.; Lan, J.; Arad, D. Tetrahedron Lett. 2002, 43, 5237-5239.
(k) Patil, B. S.; Vasanthakumar, G.-R.; Babu, V. V. S. J. Org. Chem. 2003,
68, 7274-7280.
(6) (a) Ende, D. J. a.; DeVries, K. M.; Clifford, P. J.; Brenek, S. J. Org.
Proc. Res. DeV. 1998, 2, 382-392. (b) Nettekoven, M.; Jenny, C. Org.
Proc. Res. DeV. 2003, 7, 38-43.
(7) Affandi, H.; Bayquen, A. V.; Read, R. W. Tetrahedron Lett. 1994,
35, 2729-2732.
10.1021/ol051428b CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/19/2005

residues.10 Herein, we wish to disclose a new process to
perform the Curtius rearrangement starting with a carboxylic
acid, di-tert-butyl dicarbonate, and sodium azide to form the
corresponding tert-butyl carbamate in high yields. Further-
more, the use of transition-metal complexes and Lewis acids
as catalysts for the Curtius rearrangement will be presented.
Our initial goal was to develop an efficient one-pot process
for the synthesis of carbamates from carboxylic acids through
the Curtius rearrangement. The optimal reagent should
include both the azide and the tert-butoxy moiety while
activating the carboxylic acid substrate. tert-Butyl azidofor-
mate or BocN3 appears as the reagent of choice for this
purpose.11 However, the isolation of this reagent is not an
easy task, since detonation during the required distillation
under reduced pressure has been reported. Furthermore, neat
tert-butyl azidoformate is sensitive to both heat and shock.
Conversely, we found that we could safely prepare BocN3
as a solution in THF from di-tert-butyl dicarbonate and an
excess of sodium azide in the presence of a phase transfer
catalyst. Moreover, addition of 1-adamantanecarboxylic acid
to this reaction mixture led to the formation of the corre-
sponding acyl azide 1 (eq 1). When the reaction mixture was
We postulated that the addition of a transition metal or a
Lewis acid complex as a catalyst could favor the formation
of carbamate 2 from 1-adamantane carboxylic acid.12,13
Indeed, the addition of protic acids led to the formation of
carbamate 2 in 20-25% yields (entries 3 and 4), while strong
Lewis acids showed no activity (entries 5-7). Some late
transition metal and lanthanide complexes catalyzed the
formation of carbamate 2 with modest yields (entries 8-13),
similarly to copper and silver salts (entries 14-18). Con-
versely, zinc complexes were very efficient at promoting the
Curtius rearrangement and the formation of carbamate 2
directly from 1-adamantanecarboxylic acid (entries 19 and
20).
Further optimization showed that the most efficient catalyst
was zinc triflate, although zinc chloride and zinc bromide
still provided the desired carbamate in 60-70% yield (Table
2, entry 5 vs 2 and 3).
Table 2. Zinc-Catalyzed Curtius Rearrangement (eq 3)a
entry
ZnX2
ZnF2
ZnCl2
ZnBr2
ZnI2
Zn(OTf)2 THF, 40 °C
Zn(OTf)2 THF, 30 °C
Zn(OTf)2 THF, 40 °C
conditions
convb (%)
1
2
3
4
5
6
7
8
9
THF, 40 °C
THF, 40 °C
THF, 40 °C
THF, 40 °C
40
60
70
20
g95
5
30c
e5d
70d
e5d
e5d
20d
heated to 80 °C, the Curtius rearrangement occurred and led
to the desired carbamate 2 quantitatively (Table 1, entry 2).
Table 1. Curtius Rearrangement of 1-Adamantanecarboxylic
Acid: Catalyst Optimization (eq 2)a
Zn(OTf)2 TABI (15 mol %), THF, 40 °C
Zn(OTf)2 TBACl‚H2O (15 mol %), THF, 40 °C
10 Zn(OTf)2 TBAF (15 mol %), THF, 40 °C
11 Zn(OTf)2 DME, 40 °C
12 Zn(OTf)2 dioxane, 40 °C
a Conditions: Boc2O (1.1 equiv), NaN3 (3.5 equiv), Bu4NBr (15 mol
%), ZnX2 (3.3 mol %), 24 h. b Conversion by GC-MS; acyl azide and
isocyanate are the remaining product. c NaN3 (2.5 equiv). d Reaction time:
15 h.
entry
catalyst
none
none
HCl
HOTf
BF3‚OEt2
MgBr2
convb (%)
entry catalyst convb (%)
1
2
3
4
5
6
7
8
9
e5
95c
20
11
12
13
14
15
16
17
18
19
20
Pd2(dba)3
La(OTf)3
Sc(OTf)3
CuCl
Cu(OTf)2
Cu(OAc)2
CuCl2
AgOTf
ZnCl2
Zn(OTf)2
55
55
e5
e5
5d
40
35
20
90
g95
No Curtius rearrangement occurred at 30 °C (entry 6), and
lower yields were obtained when less than 3 equiv of sodium
azide was used (entry 7). Tetrabutylammonium bromide
could be substituted with the corresponding chloride, al-
though the reaction did not reach completion (entry 9). In
contrast, no reaction was observed with tetrabutylammonium
iodide or fluoride, which is consistent with the result obtained
with the zinc salts (entries 8-10 vs 1-4). The solvent proved
instrumental, as low conversions were observed with solvents
other than THF (entries 10-12).
25
e5
e5
e5
60
55
e5
TiCl4
Fe(acac)3
Rh2(OAc)4
ClRh(PPh3)3
10
a Conditions: Boc2O (1.1 equiv), NaN3 (7 equiv), Bu4NBr (15 mol %),
catalyst (3.3 mol %), 24 h. b Conversion by GC-MS; acyl azide and
isocyanate are the remaining product. c The reaction was run at 80 °C.
d Catalyst loading was 5 mol %.
A variety of substrates were tested under the optimal
reaction conditions using 1.1 equiv of di-tert-butyl dicar-
Although acyl azide 1 formed the corresponding isocyanate
at 40 °C, carbamate 2 was only obtained with a low yield
(entry 1). This observation suggested that the addition of
the tert-butoxy moiety to the isocyanate intermediate was
slow at 40 °C.
(8) (a) Shioiri, T.; Ninomiya, K.; Yamada, S. J. Am. Chem. Soc. 1972,
94, 6203-6205. (b) Ninomiya, K.; Shioiri, T.; Yamada, S. Tetrahedron
1974, 30, 2151-2157. (c) Murato, K.; Shioiri, T.; Yamada, S. Chem. Pharm.
Bull. 1975, 23, 1738-1740. (d) Capson, T. L.; Poulter, C. D. Tetrahedron
Lett. 1984, 25, 3515-3518. (e) Wolff, O.; Waldvogel, S. R. Synthesis 2004,
1303-1305.
4108
Org. Lett., Vol. 7, No. 19, 2005

of carbamate 9 together with the corresponding tert-butyl
ester, which probably resulted from the addition of the tert-
butoxy moiety onto the corresponding ketene, generated from
the elimination of hydrazoic acid (entry 8).14
Table 3. Zinc-Catalyzed Curtius Rearrangement (eq 4)a
We have examined our new reaction conditions for the
Curtius rearrangement of chiral enantioenriched R-substituted
carboxylic acid 10 (eq 5). Indeed, the rearrangement
proceeded with retention of configuration. However, under
the standard reaction conditions described before, carbamate
11 was recovered with only 91% ee (49% yield) indicating
an erosion of the enantiomeric excess during the process.15
To decrease the basicity of the reaction mixture, 0.5 equiv
of tert-butyl alcohol was added; under these new reaction
conditions, the desired product was obtained in 49% yield
and with almost no loss in the enantiomeric excess.16
Malonate derivatives are interesting substrates for the
Curtius rearrangement as they lead to the formation of
protected amino acids.17, Monosaponification of 2,2-disusb-
stituted malonates18 led to the formation of the corresponding
monoester malonic acid, the requisite substrate to perform
the Curtius degradation. The rearrangement is slower with
these types of substrates and it was required to increase the
temperature of the reaction mixture. We found that under
the standard reaction conditions using di-tert-butyl dicar-
bonate and sodium azide but at 50 °C, racemic R,R-
disubstituted protected amino acids were efficiently prepared
in 60-75% yields (Table 4).
a Conditions: Boc2O (1.1 equiv), NaN3 (3.5 equiv), Bu4NBr (15 mol
%), Zn(OTf)2 (3.3 mol %), 16-24 h. b Isolated yield.
bonate, 3.5 equiv of sodium azide, 15 mol % of tetrabuty-
lammonium bromide, and 3.3 mol % of zinc triflate (Table
3). The reaction proceeded very well with tertiary and
secondary carboxylic acids to provide carbamates 2 and 3
in more than 90% isolated yield (entries 1 and 2). Primary
protected amines were also obtained in good yields (entries
3-7). Furthermore, the reaction conditions are compatible
with unprotected ketones and alcohols; thus carbamates 5
and 8 were isolated in 68% and 72% yield, respectively
(entries 4 and 7). 2-Phenylbutanoic acid led to the formation
Table 4. Zinc-Catalyzed Curtius Rearrangement of Malonate
Substrates (eq 6)a
(9) Selected recent examples: (a) Ma, D.; Sun, H. J. Org. Chem. 2000,
65, 6009-6016. (b) Migawa, M. T.; Swayze, E. E. Org. Lett. 2000, 2,
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6260-6263. (f) Ecija, M.; Diez, A.; Rubiralta, M.; Casamitjana, N.; Kogan,
M. J.; Giralt, E. J. Org. Chem. 2003, 68, 9541-9553. (g) Goeksu, S.; Kazaz,
C.; Suetbeyaz, Y.; Secen, H. HelV. Chim. Acta 2003, 86, 3310-3313. (h)
Hakogi, T.; Taichi, M.; Katsumura, S. Org. Lett. 2003, 5, 2801-2804. (i)
Kambourakis, S.; Rozzell, J. D. AdV. Synth. Catal. 2003, 345, 699-705.
(j) Spino, C.; Gobdout, C. J. Am. Chem. Soc. 2003, 125, 12106-12107.
(k) Wipf, P.; Pierce, J. G.; Wang, X. Tetrahedron: Asymmetry 2003, 14,
3605-3611. (l) Chien, T.-C.; Meade, E. A.; Hinkley, J. M.; Townsend, L.
B. Org. Lett. 2004, 6, 2857-2859. (m) Doussineau, T.; Durand, J. O.;
Granier, M.; Smaihi, M.; Valtchev, V. Synlett 2004, 1735-1738. (n) Gomez-
Sanchez, E.; Marco-Contelles, J. Tetrahedron 2005, 61, 1207-1219.
a Conditions: Boc2O (1.1 equiv), NaN3 (3.5 equiv), Bu4NBr (15 mol
%), Zn(OTf)2 (3.3 mol %), 48 h. b Isolated yield.
Org. Lett., Vol. 7, No. 19, 2005
4109

In conclusion, we have developed a very efficient process
for the Curtius rearrangement which allows the direct
conversion of carboxylic acids into carbamates. The use of
a mixture of di-tert-butyl dicarbonate and sodium azide
allows the transformation of aliphatic carboxylic acids into
alkyl azides, which rearrange spontaneously at 40 °C to
produce the corresponding isocyanate. Our inital studies
established that the zinc catalyst is not involved in this step.
Conversely, the addition of tert-butyl alcohol onto the
isocyanate is the slowest step of the process and is accelerated
by heating the reaction mixture or adding a mixture of
tetrabutylammonium bromide and zinc triflate (presumably
through the formation of a zinc carbamoyl bromide species).
Studies are currently underway to establish the exact kinetics
and the mechanism of this reaction, and the results of these
studies will be reported in due course.
Acknowledgment. This research was supported by
NSERC (Canada), the Canada Foundation for Innovation,
Boehringer Ingelheim (Canada) Lte´e, Merck Frosst Canada,
and the Universite´ de Montre´al. O.L. thanks the “Conseil
ge´ne´ral de la Guadeloupe” for a graduate fellowship. We
thank the Charette group (Universite´ de Montre´al) for the
use of chiral columns.
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VI, p 207.
Supporting Information Available: Experimental pro-
cedures, compound characterization data, and 1H spectra of
all the products. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL051428B
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(14) The corresponding tert-butyl ester was the major product formed
under the thermal reaction conditions (at 80 °C without Zn(OTf)2), and
only 33% of carbamate 9 was isolated.
(15) Similar erosion of the ee for compound 11 (86%) was observed
when the reaction was performed at 80 °C without Zn(OTf)2. However,
carbamate 11 was obtained with only 20% yield.
(16) The enantiomeric excess was determined by supercritical-fluid
chromatography (SFC) using a Chiracel OD, and a difference of 1% ee is
within the experimental error.
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4110
Org. Lett., Vol. 7, No. 19, 2005