Highly efficient carbamate formation from alcohols and hindered amino acids or esters using N, N′-disuccinimidyl carbonate (DSC)

Article abstract of DOI:10.1055/s-0030-1260584

A highly efficient and straightforward protocol to prepare carbamates from alcohols and hindered amino acids/esters mediated by N,N′-disuccinimidyl carbonate (DSC) in the presence of catalytic amount of pyridine is described. This method could be carried out under mild conditions in one pot, and a wide variety of carbamates were obtained in high yield with excellent purity. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260584

1454
LETTER
Highly Efficient Carbamate Formation from Alcohols and Hindered Amino
Acids or Esters Using N,N¢-Disuccinimidyl Carbonate (DSC)
C
arbamate Forma
t
o
ion from
A
lc
n
ohols and
H
i
ndered Amin
m
o Acids/Esters ei Li,* Cheng-yi Chen, Jaume Balsells Padros
Department of Process Research, Merck Research Laboratories, P.O. Box 2000, Rahway, NJ 07065-0900, USA
Fax +1(732)5941499; E-mail: hongmei_li@merck.com
Received 7 February 2011
hindered amino acids/esters mediated by N,N¢-disuccin-
Abstract: A highly efficient and straightforward protocol to pre-
pare carbamates from alcohols and hindered amino acids/esters me-
diated by N,N¢-disuccinimidyl carbonate (DSC) in the presence of
catalytic amount of pyridine is described. This method could be car-
ried out under mild conditions in one pot, and a wide variety of car-
bamates were obtained in high yield with excellent purity.
imidyl carbonate in the presence of catalytic amount of
pyridine.
As shown in Scheme 1, carbamate 4 serves as a key build-
ing block for the synthesis of MK-7009. We recently en-
countered some problems in the preparation of highly
pure carbamate 4 from alcohol 5 and the hindered amino
acid, L-tert-leucine, using the commonly employed CDI
protocol (Scheme 2). Activation of alcohol 5 by CDI went
smoothly in DMF at 40 °C, however, the carbamate for-
mation with L-tert-leucine required high temperatures
(>90 °C) and long reaction times (12 h) due to low solu-
bility and poor reactivity of L-tert-leucine in the reaction
media. The reaction generated the desired carbamate 4 in
only 80% yield and was plagued by the formation of ca.
17% of impurity 6 which then required additional chroma-
tography or salt formation for the purification of the de-
sired product.
Key words: carbamate, N,N¢-disuccinimidyl carbonate, DSC, hin-
dered amino acids/esters, pyridine
Formation of carbamates is of great importance in the syn-
thetic organic chemistry due to its wide applications in the
fields of pharmaceutics, agriculture, and polymer indus-
try.1 For example, carbamate moieties constitute key ele-
ments in the structure of MK-7009, a novel HCV protease
inhibitor, that is currently at the late-stage clinical devel-
opment.2 The chemical development of this compound to
support preclinical/clinical studies called for a highly effi-
cient protocol for the carbamate formation especially
from the hindered amino acids with alcohols. Among
many known methods developed for the carbamate for-
mation, 1,1-carbonyldiimidazole (CDI)-promoted synthe-
sis from alcohol and amine appeared to be most
straightforward and practical.3 Additionally, N,N¢-disuc-
cinimidyl carbonate (DSC)-mediated carbamates synthe-
sis reported by Ghosh et al. at our research laboratories
could serve as an alternative to the CDI protocol.4 How-
ever, application of these methods to hindered amino ac-
ids or their derivative still remained elusive. We herein
wish to report a general, highly efficient, and straightfor-
ward protocol to prepare carbamate from alcohols and
H
O
N
COOH
O
1) CDI, DMF
40 °C
4
OH
+
H N
CO2H
2)
2
O
5
NMe2
O
Et3N, 90 °C
~80%
6
Scheme 2 Carbamate formation with L-tert-leucine using CDI
O
O
N
CO2Me
N
N
O
O
O
NBoc
O
Br
O
O
O
H
3
N
S
O
N
+
N
N
H
H
H
O
O
N
OMe
N
H
O
O
O
O
N
CO2H
O
O
O
1 MK-7009
2
4
Scheme 1 Retrosynthetic analysis of MK-7009
SYNLETT 2011, No. 10, pp 1454–1458
x
x
.x
x
.2
0
1
1
Advanced online publication: 26.05.2011
DOI: 10.1055/s-0030-1260584; Art ID: S03311ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Carbamate Formation from Alcohols and Hindered Amino Acids/Esters
1455
O
O
O
O
O
N
N
N
O
O
O
H2N
CO2H
O
O
O
O
DSC
Et3N (3 equiv), DMF
H
7
+
O
N
COOH
OH
K3PO4–H2O
~87%
O
O
5
4
O
O
8
Scheme 3 Carbamate formation with L-tert-leucine using DSC
In 1992, Ghosh et al.4 at Merck Research Laboratories re-
ported an efficient and mild method for carbamate forma-
tion from various amines and alcohols by using
commercially available DSC. This reagent has been rec-
ognized as a versatile reagent to activate amino and car-
boxyl groups to form asymmetric ureas and amide
linkages.5 Armed with this knowledge we decided to ex-
plore the DSC protocol for the formation of carbamate 4
from L-tert-leucine and alcohol 5 (Scheme 2). Activation
of alcohol 5 with DSC in the presence of three equivalents
of Et3N in acetonitrile or DMF gave ca. 94% conversion
into a mixture of 87% of intermediate 7 and 7% of carbon-
ate 8. We were delighted to find that subsequent reaction
of intermediate 7 with hindered L-tert-leucine proceeded
smoothly under mild conditions: aqueous media at ambi-
ent temperature. Furthermore, we noticed that no byprod-
uct 6 was generated under these conditions.
Table 1 Base Screening for DSC Activation of Alcohol 5
O
O
N
O
O
O
DSC, base
DMF
7
OH
+
8
5
Entry Base (equiv)
Temp Time Conv. Yield of 7
(°C)
(h)
(%)
(GCAP, %)
1
2
Et3N (2.0)
Et3N (0.2)
r.t.
4
94
87
86
87
40
15
4
95
3
Hünig’s base (2.0) r.t.
96
4
DBU (2.0)
40
40
40
40
40
40
40
1
ca. 90 ca. 50, messy
ca. 95 ca. 70
Encouraged by this exciting lead we set to further opti-
mize the activation of alcohol 5 by using DSC and a vari-
ety of bases in order to maximize efficiency for the
coupling step (Scheme 3). Bases were screened for the ac-
tivation as summarized in Table 1. Et3N predominantly
induced the formation of the mixed succinimide carbonate
7 (Table 1, entry 1) in 94% conversion after four hours at
room temperature. When the reaction temperature was in-
creased to 40 °C, the reaction went to 95% conversion af-
ter 15 hours in the presence of only a catalytic amount of
Et3N (Table 1, entry 2). Hünig’s base worked equally well
as Et3N as a base (Table 1, entry 3). However, 5–9% of
carbonate 8 was detected when using either Et3N or
Hünig’s base. Stronger organic bases such as DBU and
DABCO led to high conversion for the reaction but a poor
impurity profile (Table 1, entry 4 and 5). Inorganic bases,
such as potassium carbonate, were ineffective for the ac-
tivation and led to poor conversion into the mixed succin-
imide carbonate 7 after 15 hours at 40 °C (Table 1, entry
6). We were delighted to find that 1–2 equivalents of py-
ridine effectively facilitated the activation such that the
mixed succinimide carbonate 7 was obtained in quantita-
tive yield in only 1–2 hours (Table 1, entry 7 and 8). In
fact, catalytic amount of pyridine and DMAP (20 mol%)
both effectively promoted the reaction to full conversion
and clean reaction profiles after 15 hours at 40 °C. Based
on these results, 20 mol% of pyridine was selected as the
optimal base for the activation of alcohol 5.
5
DABCO (2.0)
K2CO3 (2.0)
pyridine (2.0)
pyridine (1.0)
pyridine (0.2)
DMAP (0.2)
1
6
15
1
40
40
7
100
100
100
100
ca. 100
ca. 100
ca. 100
ca. 100
8
2
9
15
15
10
With the optimized conditions, alcohol 5 was activated
with 1.2 equivalents of DSC in the presence of catalytic
amount of pyridine (20 mol%) in DMF at 40 °C with
>99% conversion into 7. Subsequent addition of water, L-
tert-leucine and 2–3 equivalents of K3PO4 at ambient tem-
perature, smoothly afforded the desired carbamate 4 in
nearly quantitative yield with excellent purity in 2–4
hours.6 As a result, no further purification or salt forma-
tion was required to upgrade the purity. The carbamate 4
exists as amide rotamers as observed by the 1H NMR,
13C NMR, and NOE spectrum.7
As summarized in Table 2, this protocol was successfully
applied to the carbamate formation from a variety of pri-
mary and secondary alcohols and hindered amino acid/
ester.7 Neopentyl alcohol 5 was coupled well with differ-
ent hindered amino acids/esters giving corresponding car-
bamates in high yields (Table 2, entries 1–4). A less
Synlett 2011, No. 10, 1454–1458 © Thieme Stuttgart · New York

1456
H. Li et al.
LETTER
hindered primary alcohol also worked well with primary entry 10) with no eperimization detected by HPLC and
and secondary amino acid/ester to provide carbamates in NMR analysis. These examples prove that this protocol
high yield (Table 2, entries 5 and 6). The reaction could be preserves the stereochemical integrity of the carbamates
readily extended to secondary alcohols (entry 7–12) derived from a variety of highly hindered amino acids and
which formed carbamates bearing hindered primary and chiral alcohols (Table 2, entry 8–12). Tertiary alcohols,
amino acid/ester moieties. Coupling of a secondary alco- for example, tert-butanol and thiol, however, gave poor
hol and aryl-substituted amino acid [(S)-(+)-2-phenylgly- conversion under the current conditions for the DSC acti-
cine] led to carbamate formation (up to 99%, Table 2, vation step and hence warrant further investigation.
Table 2 Preparation of Carbamates from Hindered Amino Acids/Esters.
O
O
O
1)
2)
, Py (0.2 equiv), DMF
N
O
O N
O
R2
N
O
O
R1-OH
O
R1
OR4
O
O
R3
R2HN
OR4 , K3PO4, H2O
R3
Entry
1
Product
Yield (%)
96
O
O
N
H
COOH
O
2
99
N
H
COOMe
O
O
O
O
3
4
5
93
99
99
N
H
COOMe
COOH
N
H
O
O
O
H
N
OH
O
OH
6
7
98
99
O
N
COOMe
O
O
H
O
O
N
OH
O
8
96
H
O
N
OH
O
Synlett 2011, No. 10, 1454–1458 © Thieme Stuttgart · New York

LETTER
Carbamate Formation from Alcohols and Hindered Amino Acids/Esters
1457
Table 2 Preparation of Carbamates from Hindered Amino Acids/Esters. (continued)
O
O
O
1)
2)
, Py (0.2 equiv), DMF
N
O
O N
O
R2
N
O
O
R1-OH
O
R1
OR4
O
O
R3
R2HN
OR4 , K3PO4, H2O
R3
Entry
Product
Yield (%)
O
9
87
H
N
O
OMe
O
O
H
N
10
99
O
OH
O
O
H
N
O
11
90
OH
O
NH
OH
12
91
O
N
O
O
OMe
In conclusion, we have developed an efficient and chro- Acknowledgment
matography-free protocol for the preparation of carbam-
We thank Ms Lisa Dimichele for her help with NOE analysis and
ates from primary or secondary alcohols with a variety of
highly hindered amino acids/esters using commercial
available N,N¢-disuccinimidyl carbonate (DSC) and cata-
lytic amount of pyridine in the presence of inorganic
bases. This two-step method was easily carried out under
mild conditions in one pot, and desired carbamates were
obtained in an excellent yield and purity. We believe the
current protocol could serve as a valuable addition to car-
bamate synthesis methodology, especially in the case of
hindered amino acids or esters.
13C NMR resample of compound 4.
References and Notes
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Synlett 2011, No. 10, 1454–1458 © Thieme Stuttgart · New York

1458
H. Li et al.
LETTER
(6) General Procedure for Preparation of Carbamate 4
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To a solution of alcohol 5 (0.5 g, 3.9 mmol) in anhyd DMF
(3 mL) was added DSC (1.2 g, 1.2 equiv) and pyridine (63
mL, 0.2 equiv). The mixture was heated and aged at 40 °C
for 15 h until complete activation of 5 was observed as
monitored by GC (>99% conversion). The mixture was
cooled to ambient temperature for addition of H2O (3 mL),
keeping temperature below 30 °C. L-tert-Leucine (0.53 g,
1.0 equiv) and K3PO4 (1.66 g, 2 equiv), keeping the reaction
temperature below 30 °C. The reaction mixture was then
stirred at ambient temperature for 3–6 h until complete
carbamate formation was observed as monitored by HPLC
or TLC. To the reaction mixture was charged H2O (10 mL)
and EtOAc (10 mL). The organic layer was separated, and
the aqueous layer was extracted with EtOAc (5 mL). Both
organic layers were combined, washed sequentially with 1 N
HCl, H2O and brine, and dried (MgSO4). Concentration of
the organic solution afforded the carbamate 4 as an oil,
amide rotamers exists by NMR spectrum. 1H NMR (500
MHz, CDCl3): d = 0.93 (s, 6 H), 1.05 (s, 9 H), 1.35–1.38 (m,
2 H), 2.01–2.06 (m, 2 H), 3.80–3.82 (d, J = 10.0 Hz, 1 H),
3.87–3.89 (d, J = 10.0 Hz, 1 H), 3.98 (br, 0.3 H, minor
rotamer), 4.21–4.23 (d, J = 10.0 Hz, 0.7 H, major rotamer),
4.93–4.95 (d, J = 10.0 Hz, 1 H), 5.01–5.04 (d, J = 15.0 Hz, 1
H), 5.27–5.29 (d, J = 10.0 Hz, 0.7 H, major rotamer), 5.78–
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C
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Synlett 2011, No. 10, 1454–1458 © Thieme Stuttgart · New York