Rapid and straightforward transesterification of sulfonyl carbamates

Article abstract of DOI:10.1016/j.tetlet.2016.02.071

A fast and convenient method for the alkoxy exchange of sulfonyl carbamates by simply heating in a chosen alkyl alcohol is described. No catalysts or additives are required. Microwave heating at 100-120 °C for 20-60 min resulted in good to excellent yields (53-93%) of alkyl (arylsulfonyl)carbamates where the alkyl part originates from the alcohol solvent. The developed protocol was applied to the synthesis of an angiotensin II type 2 receptor (AT2R) ligand.

Full text of DOI:10.1016/j.tetlet.2016.02.071

Tetrahedron Letters 57 (2016) 1476–1478
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Tetrahedron Letters
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Rapid and straightforward transesterification of sulfonyl carbamates
Rebecka Isaksson a, Ilze Kumpinßa a, Mats Larhed b, Johan Wannberg b,
⇑
a Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, Uppsala University, Box-574, SE-751 23 Uppsala, Sweden
b Department of Medicinal Chemistry, Science for Life Laboratory, Uppsala University, Box-574, SE-751 23 Uppsala, Sweden
a r t i c l e i n f o
a b s t r a c t
Article history:
A fast and convenient method for the alkoxy exchange of sulfonyl carbamates by simply heating in a cho-
sen alkyl alcohol is described. No catalysts or additives are required. Microwave heating at 100–120 °C for
20–60 min resulted in good to excellent yields (53–93%) of alkyl (arylsulfonyl)carbamates where the
alkyl part originates from the alcohol solvent. The developed protocol was applied to the synthesis of
an angiotensin II type 2 receptor (AT2R) ligand.
Received 15 January 2016
Revised 15 February 2016
Accepted 17 February 2016
Available online 18 February 2016
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Sulfonyl carbamates
O-alkyl exchange
Transesterification
Carboxylic acid bioisosteres
AT2R ligand
Introduction
propensity for this non-catalyzed or self-catalyzed, type of
trans-O-alkylation of sulfonyl carbamates. As alkyl alcohols are
The acidic properties of sulfonyl carbamates have been known
since at least the late 1960’s with pKa values being in the same
range as carboxylic acids.1,2 Sulfonyl carbamates have thus found
use as carboxylic acid bioisosteres in drug discovery and develop-
ment, for example, ligands to the angiotensin II type 1 receptor
(AT1R) and angiotensin II type 2 receptor (AT2R, Fig. 1).3
Another use for sulfonyl carbamates is as nitrogen nucleophiles
in Mitsunobu reactions.4 Sulfonyl carbamates have also been
reported as protecting groups for alcohols.5
generally more frequently available and less expensive than the
corresponding alkyl chloroformates, this type of transformation
would serve as a smooth, less toxic, and cost effective alternative
to using alkyl chloroformates in the synthesis of a series of alkyl
(arylsulfonyl)carbamates.
Based on our initial observation, we embarked on a quest to find
fast and convenient conditions for the self-catalyzed trans-O-alky-
lation of alkyl (arylsulfonyl)carbamates using methyl tosylcarba-
mate as a model substrate.
Sulfonyl carbamates are stable under strongly aqueous alkaline
conditions (as the corresponding anions) but are somewhat sus-
ceptible to hydrolysis in neutral aqueous solutions, especially at
elevated temperatures.2 This is reportedly due to a self-catalyzed
process including the acidic protons. Sulfonyl carbamates are fur-
ther also sensitive to thermally induced aminolysis to give sulfonyl
ureas,6 a well-known synthetic route to this class of antidiabetic
drugs (e.g., tolbutamide, glibenclamide).7
After leaving a sample of a butyl (arylsulfonyl)carbamate in a
methanol solution over the weekend at room temperature, it was
found that a fraction of the O-butyl groups had been exchanged
for O-methyl. Having worked with alkyl (arylsulfonyl)carbamates
for about 15 years within AT2R related projects,8,9 we were sur-
prised that this had not been noticed before. Furthermore, a liter-
ature search did not reveal any prior knowledge of the
Results and discussion
As the transesterification reaction of alkyl (aryl)sulfonylcarba-
mates appeared to be too slow to be practical at room temperature,
a temperature optimization study was performed. Methyl tosylcar-
bamate was heated using microwave irradiation10–12 for 20 min in
n-butanol at various temperatures using septum-sealed vials. The
reactions were relatively clean with starting material (1a), product
(2a), and one by-product (primary tolylsulfonamide, 3) being the
only three peaks observed in the UV and MS-traces upon LC–MS
analysis of the reaction mixtures. The peak area percent of each
component from the 254 nm chromatogram is summarized in
Table 1. At the lower temperatures (entries 1 and 2, Table 1)
incomplete conversion of 1a to 2a was observed and no primary
sulfonamide
3 could be detected. As the temperature was
increased to 100 °C and above, the primary sulfonamide 3 became
detectable. At 100 °C (entry 3) a small amount of 1a still remained
⇑
Corresponding author. Tel.: +46 184714124; fax: +46 184714474.
E-mail address: johan.wannberg@scilifelab.uu.se (J. Wannberg).
http://dx.doi.org/10.1016/j.tetlet.2016.02.071
0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

R. Isaksson et al. / Tetrahedron Letters 57 (2016) 1476–1478
1477
Table 3
N
O
Reacting various methyl (aryl)carbamates with n-butanol
N
O
S
O
O
S
O
O
O
n-BuOH
N
O
N
O
H
H
MW
R
R
O
O
1b-e
4b-e
S
N
O
S
H
O
S
O
O
S
O
O
O
C21
N
O
N
O
H
H
Figure 1. AT2R agonist C21.
MeO
F3C
4b 93%a
85%a
4d
O
S
O
O
O
O
O
O
S
N
O
N
Table 1
Temperature optimization
H
H
Br
O2N
4e 63%b
4c 80%a
a MW heating at 120 °C for 20 min. b MW heating at 100 °C for
20 min. All yields are isolated yields after purification using silica gel
flash chromatography, see ESI.
O
S
O
O
N
O
H
O
O
S
H
O
2a
n-BuOH
N
O
O
S
O
MW
NH2
whereas at 120 °C and 140 °C (entries 4 and 5) the reactions pro-
ceeded to completion with by-product 3 increasing with higher
temperature. The optimal temperature under these conditions
was in the 100–120 °C range.
As we never detected an intermediate sulfonyl isocyanate, we
believe the reaction mechanism follows an acid catalyzed Fis-
cher-type transesterification pathway.
The presence of 3 is thought to be due to hydrolysis and subse-
quent decomposition to give the primary sulfonamide. A test reac-
tion using the same conditions as above (microwave heating at
120 °C for 20 min) carried out in acetonitrile and water (1:1) pro-
duced only 3 (confirmed by 1HNMR and LC–MS).
20 min
1a
3
Entry
Temp. (°C)
Area (%) of 1aa
Area (%) of 2aa
Area (%) of 3a
b
1
2
3
4
5
60
80
100
120
140
93
55
4
7
—
—
b
45
94
95
89
2
5
11
b
—
—
b
a
Reactions were run for 20 min at the indicated temperature. Results are
reported as peak area percent of the 254 nm chromatogram using LC–MS.
b
Not detectable.
The scope of the reaction was investigated using the starting
material 1a and various primary, secondary, and tertiary alcohols
(Table 2). Initially the reaction conditions were fixed to 120 °C
and 20 min as these conditions had proven optimal during the
temperature screen for achieving complete conversion while still
minimizing the risk of hydrolysis. The model reaction to give 2a
(Table 2) was also run at 120 °C, displaying a slightly higher iso-
lated yield compared to the 100 °C reaction. As the reactions in
Table 2 were conducted, we quickly learned that these conditions
were not optimal for all alcohols tested. For products 2b, 2f, 2g, and
2j, running the reaction at 120 °C for 20 min worked well, yielding
complete conversions and good yields. For the preparation of com-
pounds 2c and 2i a lower temperature (100 °C) was preferable due
to a larger extent of decomposition at the higher temperature
(120 °C) as deduced by LC–MS. To achieve full conversion when
producing compound 2d the reaction had to be conducted at
100 °C for 30 min, and as can be seen with products 2e and 2h this
temperature and longer reaction times (60 min and 30 min,
respectively) resulted in similar (2e) or higher yield (2h).
Table 2
Reacting methyl tosylcarbamate with various alcohols
O
S
O
O
S
O
O
O
R
R OH
MW
N
O
N
O
H
H
1a
2a-j
O
S
O
O
S
O
O
O
N
O
N
O
H
H
2f 78%b
2a 88%a, 90%b
O
S
O
O
S
O
O
O
N
O
N
O
H
H
74%b
76%b
2b
2g
O
S
O
O
S
O
O
O
O
Cl
O
N
N
O
Cl
H
H
Other methyl (aryl)sulfonylcarbamates were also investigated
where the effect of electron donating and withdrawing groups in
the aryl part was studied. As depicted in Table 3, no dramatic
effects were observed. Microwave heating at 120 °C for 20 min
resulted in complete conversion and with no detectable levels of
decomposition for products 4b–d. For product 4e the temperature
had to be decreased to 100 °C to avoid the increased decomposition
65%a
64%c, 57%b
2c
2h
O
S
O
O
S
O
O
O
O
N
O
N
H
H
74%c
2d
2i 70%a
O
O
O
O
S
O
O
O
S
N
N
O
H
H
O
S
O
O
S
O
O
O
2e 88%d, 88%b
2j 53%b
EtOH
MW 120 oC
20 min
N
O
N
O
H
H
a MW heating at 100 °C for 20 min. b MW heating at 120 °C for
20 min. c MW heating at 100 °C for 30 min. d MW heating at 100 °C
for 60 min. All yields are isolated yields after purification using
silica gel flash chromatography, see ESI.
2a
5a
84%
Scheme 1. Synthesis of ethyl tosylcarbamate from n-butyl tosylcarbamate.

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R. Isaksson et al. / Tetrahedron Letters 57 (2016) 1476–1478
Acknowledgments
N
O
N
N
N
This work was supported by a travel grant from 7th Framework
Program Project InnovaBalt (REGPOT-CT-2013-316149-Innova-
Balt), by Science for Life Laboratory and by Uppsala University.
O
O
O
O
EtOH
MW 120 oC
20 min
O
S
S
Supplementary data
N
N
O
O
S
S
H
H
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.02.
071.
C21
6 82%
Scheme 2. Synthesis of AT2R ligand 6. For biological data see Ref.13
References and notes
observed at the higher temperature. In general, flash column chro-
matography was performed in order to ensure isolation of high
purity products.
As a test of the generality of the method, n-butyl tosylcarba-
mate (2a) was heated in ethanol at 120 °C for 20 min resulting
in an isolated yield of 84% of ethyl tosylcarbamate (5a)
(Scheme 1).
This was then taken further to a medicinal chemistry-type sce-
nario where the AT2R agonist C21 was reacted with ethanol at
120 °C for 20 min to produce the reported AT2R ligand (6)13 in
82% isolated yield (Scheme 2).
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Angiotensin System; Elsevier, 2015.
4. Campbell, J. A.; Hart, D. J. J. Org. Chem. 1993, 58, 2900.
5. Manabe, S.; Yamaguchi, M.; Ito, Y. Chem. Commun. 2013, 49, 8332.
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Wallinder, C.; Namsolleck, P.; Dahlöf, B.; Unger, T. Curr. Opin. Pharmacol. 2011,
11, 187.
9. Larhed, M.; Isaksson, R.; Hallberg, A. The Protective Arm of the Renin Angiotensin
System (RAS); Elsevier, 2015; pp 131–140.
10. Gabriel, C.; Gabriel, S.; Grant, E. H.; Halstead, B. S. J.; Michael-P.-Mingos, D.
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Conclusion
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13. Wu, X.; Wan, Y.; Mahalingam, A. K.; Murugaiah, A. M. S.; Plouffe, B.; Botros, M.;
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7160.
A method for the rapid and simple transesterification of alkyl
alcohols with alkyl (arylsulfonyl)carbamates was developed.14,15
Using methyl tosylcarbamate as a model substrate, heating at
100–120 °C resulted in complete transcarbamoylation with the
alcohol solvent within 20–60 min. A wide range of alkyl alcohols
were used as solvent/reactants with primary and secondary alco-
hols working excellent and even tert-butanol providing useful
yield of Boc-sulfonamide (2j). Allyl and chloroalkyl alcohols were
tolerated, as were alcohols with a terminal acetylene. The elec-
tronic properties of the aryl part did not seem to influence the
reaction yields. As a medicinal chemistry application, the proce-
dure was used in the synthesis of an AT2R ligand in a good
yield. In parallel with this work, a microwave-assisted flow-
chemistry method is being developed which will be reported
elsewhere.16
14. Temperature controlled microwave irradiation was chosen as
a safe and
reproducible heating source for the development of this method, producing
rapid heating and full control of temperature and pressure in the reaction vials.
Pressures recorded in the reaction vials were in the 0–3 bar range. The reaction
itself works equally well in closed vessels using conventional heating,
providing the use of high quality vials and screw-caps or septa that do not
leak or rupture under pressure when using low boiling alcohols.
15. General procedure for O-alkyl exchange/transesterification: the 4-substituted
methyl (phenylsulfonyl)carbamate was dissolved in the chosen alcohol (2 mL)
in a microwave vial, which was sealed using an aluminum open-top seal with a
PTFE-faced septum. The reaction mixture was heated under microwave
irradiation at 100–120 °C for 20–60 min. The crude reaction mixture was
concentrated under reduced pressure and the residue purified using silica gel
column chromatography to yield the desired alkyl (aryl)sulfonyl carbamate.
16. Kumpinßa, I.; Isaksson, R.; Sävmarker, J.; Wannberg, J.; Larhed, M. Org. Process
Res. Dev. 2016. http://dx.doi.org/10.1021/acs.oprd.5b00323.