One-pot synthesis of carbamates and thiocarbamates from Boc-protected amines

Article abstract of DOI:10.1016/j.tetlet.2016.09.038

A highly efficient one-pot procedure for the synthesis of carbamates and thiocarbamates has been described. In the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, the isocyanate intermediates were generated in situ for further reactions with alcohols and thiols to afford the desired carbamates and thiocarbamates in high yields.

Full text of DOI:10.1016/j.tetlet.2016.09.038

Accepted Manuscript
One-pot Synthesis of Carbamates and Thiocarbamates from Boc-protected
Amines
Hee-Kwon Kim, Anna Lee
PII:
S0040-4039(16)31197-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.09.038
TETL 48108
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
12 August 2016
5 September 2016
8 September 2016
Please cite this article as: Kim, H-K., Lee, A., One-pot Synthesis of Carbamates and Thiocarbamates from Boc-
protected Amines, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.09.038
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One-pot Synthesis of Carbamates and
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Thiocarbamates from Boc-protected Amines
*
*
Hee-Kwon Kim and Anna Lee

Tetrahedron Letters
One-pot Synthesis of Carbamates and Thiocarbamates from Boc-protected
Amines
Hee-Kwon Kim and Anna Leec,
a,b,*
a
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Department of Nuclear Medicine, Molecular Imaging and Therapeutic Medicine Research Center, Biomedical Research Institute, Chonbuk National University
b
Medical School and Hospital, Jeonju, Jeonbuk 54907, Republic of Korea
c
Department of Chemistry, Myongji University, Yongin 17058, Republic of Korea
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A highly efficient one-pot procedure for the synthesis of carbamates and thiocarbamates has
been described. In the presence of 2-chloropyridine and trifluoromethanesulfonyl anhydride, the
isocyanate intermediates were generated in situ for further reactions with alcohols and thiols to
afford the desired carbamates and thiocarbamates in high yields.
Available online
2
009 Elsevier Ltd. All rights reserved.
Keywords:
One-pot Synthesis
Carbamates
Thiocarbamates
Isocyanate intermediates
12b
1. Introduction
explosive azides (Curtius rearrangement).
The Lossen
rearrangement generates isocyanates under relatively mild
Carbamates and thiocarbamates are found in numerous
13
reaction conditions. Hydroxamic acids have been employed for
bioactive compounds such as agrochemicals and pharmaceutical
candidates. For example, they have been applied in various
12b,14
the synthesis of carbamates via this process.
However, the
formation of by-products during the Lossen rearrangement would
1
1b
commodity chemicals such as herbicides, pesticides,
12b,13
be problematic for making this a green alternative.
2
3
bactericides and antiviral agents. Given the importance of this
class of biologically active compounds, the synthesis of
carbamates and thiocarbamates is a high-value endeavor.
Numerous preparations of carbamates and thiocarbamates
have been reported. The traditional method involves the use of
toxic phosgene or triphosgene and transition metal species such
4
5
4b,6
as palladium, nickel, and rhodium.
Recently, more
environmentally benign procedures also have been developed.
7
8
For example, carbonates, N-N’-carbonyldiimidazole, 1,1′-
9
10
carbonylbisbenzotriazole, S,S-dimethylthiocarbonate, and S-
Scheme 1. Synthesis of carbamates and thiocarbamates using in
situ-generated isocyanates.
11
methylthiocarbamate have been used for the synthesis of
carbamates and thiocarbamates. In addition, the isocyanate group
has been widely employed as a precursor for carbamate moieties.
There are various procedures for generating the desired
isocyanate intermediates. Transformation of carboxylic acid
derivatives to the corresponding isocyanates has been achieved
via oxidative rearrangements such as Hofmann or Curtius
Alternatively, the isocyanate intermediate could be generated
in situ under mild reaction conditions in the presence of a base
and trifluoromethanesulfonyl anhydride. This strategy has been
employed in several reactions. For example, 2-chloropyridine
and trifluoromethanesulfonyl anhydride have been used to
1
5
12
generate the isocyanate intermediate in Friedel-Crafts acylation,
rearrangements. However, there are certain limitations in
oxidative rearrangements such as the use of strong hypervalent
iodine reagents (Hofmann rearrangement) and potentially
16
17
cyclodehydration reactions, and urea synthesis. Encouraged
by these reports and our continuing interest in the synthesis of
bioactive-relevant compounds, we explored a one-pot reaction
—
——

Corresponding author. e-mail: annalee@mju.ac.kr (A. Lee); e-mail: hkkim717@gmail.com (H. –K. Kim)

for the synthesis of carbamates and thiocarbamates. Herein we
report the first one-pot protocol of carbamates and
thiocarbamates from Boc-protected amines (Scheme 1).
11–15). The yield dropped when the amount of 2-chloropyridine
was reduced (65%, entry 12). However, similar reactivity was
observed with increased amounts of 2-chloropyridine (entry 11).
Reducing the amount of alcohol resulted in a slightly lower yield
2. Results and Discussion
(76%, entry 14). However, increasing the amount of alcohol did
not affect the yield (87%, entry 15).
The main problem in the synthesis of carbamates starting from
Boc-protected amines is the relatively weak nucleophilicity of the
alcohols which react with in situ-generated isocyanates to afford
the desired carbamates.
a
Table 2. Synthesis of carbamates from Boc-protected amines.
a
Table 1. Optimization of one-pot synthesis of carbamate 3a
b
Entry
Substrate
Alcohol (2)
Product
Tf
2
O
Alcohols
b
1
Entry Base (equiv)
Yield (%)
(equiv) (equiv)
1
2
3
Et
3
N (3.0)
1.5
1.5
1.5
3.0
3.0
3.0
0
0
10
DMAP (3.0)
Pyridine (3.0)
2
3
4
2
-Me-pyridine
3.0)
-Cl-pyridine
3.0)
2-Cl-pyridine
3.0)
2-Cl-pyridine
3.0)
4
5
1.5
1.5
1.5
1.5
3.0
3.0
3.0
3.0
15
30
89
87
(
2
(
c
6
(
c,d
7
(
2
-Br-Pyridine
3.0)
8
1.5
1.5
3.0
3.0
25
84
(
5
6
c
2-Br-pyridine
3.0)
9
(
c,d
c
2-Br-pyridine
3.0)
2-Cl-pyridine
5.0)
2-Cl-pyridine
1.5)
2-Cl-pyridine
3.0)
2-Cl-pyridine
3.0)
2-Cl-pyridine
3.0)
1
0
1.5
1.5
1.5
3.0
1.5
1.5
3.0
3.0
3.0
3.0
1.5
5.0
85
88
65
88
76
87
(
1
1
(
c
c
c
c
1
1
1
1
2
3
4
5
7
8
9
(
(
(
(
a
b
All reactions performed on 1.0 mmol scale. Yields are of isolated product
after column chromatography. Triethylamine (3.0 equiv) was added.
Reaction conducted at 50 C in 1,2-dichloroethane.
c
d
o
We hypothesized that the weak nucleophiles (e.g., alcohols)
1
1
1
1
0
1
2
3
could be activated by changing the reaction conditions. To test
our hypothesis, we chose the reaction of Boc-protected amine 1a
and isobutanol as our model (Table 1). Various amines were
tested in the reaction. The reaction did not proceed in the
presence of triethylamine or DMAP (entries 1 and 2). Pyridine
and 2-methylpyridine provided the product, albeit in low yields
(
entries 3 and 4). 2-Chloropyridine also afforded the desired
carbamate, but again in low yields (30%, entry 5). However, 2-
chloropyridine, in conjunction with dropwise addition of
triethylamine to the in situ-generated isocyanates, gave
dramatically improved yield (89%, entry 6). Also, 2-
bromopyridine was a good base, though slightly lower yields
were observed (84–85%, entries 9 and 10). No significant
difference was observed when the temperature was changed
a
b
All reactions performed on 1.0 mmol scale. Yields are of isolated product
after column chromatography. Reaction performed at 10 mmol scale.
c
(
entries 7 and 10).
Having determined the optimal reaction conditions, we
explored the scope of this one-pot methodology for the synthesis
of carbamates (Table 2). Various Boc-protected amines and
Next, we examined the effect of changing the amounts of the
base, trifluoromethanesulfonyl anhydride and alcohol (entries

alcohols, including aromatic and aliphatic substrates, were
employed in the reaction (entries 1–13). Gratifyingly, the desired
carbamates were obtained in high yields (80–93% yields).
Interestingly, this reaction system gave high yields for small
alcohols such as methanol (entries 3 and 7). In addition, electron-
deficient alcohol 2h provided the desired carbamate in high
yields (80%, entry 13).
tolerant of aliphatic thiols such 4-chlorobenzenemethanethiol and
1-butanethiol and the products were obtained in high yields (82–
92%, entries 9 and 10).
3. Conclusion
We have developed a highly efficient one-pot reaction for the
synthesis of carbamates and thiocarbamates from Boc-protected
amines. The in situ-generated isocyanates react successfully with
relatively weak nucleophiles such as alcohols and thiols,
producing the resulting carbamates and thiocarbamates in high
yields. This one-pot process facilitates rapid access to carbamates
and thiocarbamates and further studies on the synthesis of
biologically active compounds via in situ-generated isocyanate
protocol are in progress.
a
Table 3. Synthesis of thiocarbamates.
b
Entry
Substrate
Thio (4)
Product
Acknowledgments
This research was supported by Basic Science Research
Program through the National Research Foundation of Korea
1
(NRF)
funded
by
the
Ministry
of
Education
(
2014R1A1A2057943)
2
3
4
5
6
References and notes
1
1
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1
1
0
1
a
b
All reactions performed on 1.0 mmol scale. Yields are of isolated product
after column chromatography. Reaction performed at 10 mmol scale.
1
c
Next, we determined if the reaction could be applied in the
synthesis of thiocarbamates (Table 3). Thiols have been known to
18
14. P.Dube´; Nathel, N. F. F.-.; Vetelino, M.; Couturier, M.;
Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Org.
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reaction proceeded in the absence of additional bases (e.g.,
triethylamine). Both aromatic and aliphatic thiols were
determined as suitable substrates in the reaction. The resulting
thiocarbamates were obtained in high yields under the reaction
conditions (76–92% yields, entries 1–10). Aromatic and aliphatic
amines reacted with electron-rich and electron-deficient aromatic
thiols to provide the desired thiocarbamates in high yields (76–
1
2
1
1
4
1
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9
2%, entries 1–8). In addition, the reaction turned out to be
(
b) Lai, Z.; Wang, Z.; Sun, J. Org. Lett. 2015, 17, 6058-6061.

Title: One-pot Synthesis of Carbamates and Thiocarbamates from Boc-protected Amines
a,b,*
*c
Authors: Hee-Kwon Kim
and Anna Lee
Highlights



One-pot reaction for the synthesis of carbamates and thiocarbamates using Boc-protected amines were realized.
In situ-generated isocyanates react with relatively weak nucleophiles such as alcohols and thiols.
The reactivity of alcohols was improved by changing the reaction conditions.
a.
b.
Department of Chemistry, Purdue University, West Lafayette, IN 47907, USA
Department of Nuclear Medicine, Molecular Imaging and Therapeutic Medicine Research Center, Biomedical Research Institute, Chonbuk
National University Medical School and Hospital, Jeonju, Jeonbuk 54907, Republic of Korea
Department of Chemistry, Myongji University, Yongin 17058, Republic of Korea
E-mail: annalee@mju.ac.kr
c.