Preparation of Sulfamates and Sulfamides Using a Selective Sulfamoylation Agent

Article abstract of DOI:10.1021/acs.orglett.1c00504

Sulfamates and sulfamides are prevalent in biological molecules, but their universal synthetic methods are limited. We herein report a sulfamoylation agent with high solubility and shelf stability. Various sulfamates and sulfamides can be synthesized directly from alcohols or amines by employing this agent with high selectivity and high yields. This protocol was also successfully used for late-stage sulfamoylation of pharmaceuticals containing a hydroxyl or amino group.

Full text of DOI:10.1021/acs.orglett.1c00504

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Letter
Preparation of Sulfamates and Sulfamides Using a Selective
Sulfamoylation Agent
Hai-Ming Wang, Chao-Dong Xiong, Xiao-Qu Chen, Chun Hu,* and Dong-Yu Wang*
Cite This: Org. Lett. 2021, 23, 2595−2599
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ABSTRACT: Sulfamates and sulfamides are prevalent in biological molecules, but their universal synthetic methods are limited. We
herein report a sulfamoylation agent with high solubility and shelf stability. Various sulfamates and sulfamides can be synthesized
directly from alcohols or amines by employing this agent with high selectivity and high yields. This protocol was also successfully
used for late-stage sulfamoylation of pharmaceuticals containing a hydroxyl or amino group.
he sulfamate1 and sulfamide2 moieties are important
Tstructural elements in numerous biological molecules
with a wide range of activities, including anticonvulsant,
antiepileptic, antibiotic, and antitumor features. They are
usually considered as isosteric replacements for sulfonamide,
urea, carbamate, sulfate, and phosphate functionalities.
Until now, strategies for the preparation of primary
sulfamates or sulfamides from alcohols or amines have been
limited (Scheme 1). The most common method involves the
sulfamoylation with unstable chlorosulfonamide or N-(tert-
butoxycarbonyl)sulfamoyl chloride (A). The instability and
overly strong reactivity of A limited their applications for
sulfamoylation on polyfunctional compounds. In 2001, Winum
et al. developed a novel Burgess-type reagent (B) that could
react with various compounds containing an NH2 group.3
However, this sulfamoylation reagent has no reactivity toward
alcohols. In 2012, Zhu and co-workers reported another solid
Burgess-type reagent (C), used for selective sulfamoylation of
alcohols as well as phenols.4 Unfortunately, this reagent
showed poor solubility in the solvent MeCN. In our control
experiment, its saturated solubility in acetonitrile-d3 is 0.06
mol/L (for details, see the Supporting Information). In their
procedure, the mixture was too thick to stir efficiently, so larger
volumes of solvent and heat were necessary.5,6 In addition, the
process of sulfamoylation required anhydrous HCl (≤0.4
equiv) to accelerate the nucleophilic reaction, leading to a
chlorinated byproduct. Recently, Miller et al. reported a
catalytic sulfamoylation of alcohols with pentachlorophenyl
sulfamate.7 However, this reagent exhibits toxicity that derives
from pentachlorophenol, and the sulfamoylation selectivity
toward polyols is not obvious.
Scheme 1. Strategies for Sulfamoylation of Alcohols and
Amines
Due to different deficiencies, the previous sulfamoylation
agents were not efficiently used in the selective late-stage
functionalization of pharmaceuticals containing an OH or NH2
group. Developing a sulfamoylation agent that can balance
reactivity and selectivity and exhibit satisfactory physical
properties is in demand. Although few works have reported
an N-(tert-butoxycarbonyl)aminosulfonylpyridinium salt as a
Received: February 10, 2021
Published: March 22, 2021
https://doi.org/10.1021/acs.orglett.1c00504
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2595−2599
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Burgess-type intermediate8 for the synthesis of limited
sulfamides, the separation, characterization, and further
application of this useful reagent have been largely neglected.
This is most likely due to the development of other methods9
for the preparation of sulfamides. Pyridine (pKa = 5.23) is a
better leaving group than DMAP (pKa = 9.70) in the
substitution reaction due to its weaker nucleophilicity.10 We
guess a pyridine Burgess-type complex should be more reactive
toward a relatively weak nucleophile alcohol in the
sulfamoylation reaction.
Scheme 3. Substrate Scope of Sulfamoylation of ROH
Including Various Pharmaceuticals and Bioactive
a
Molecules
On the basis of our previous experience with substitution
reactions,11 we herein report an efficient and easy-handling
method for the selective conversion of ROH or RNH2 into
sulfamate or sulfamide through a reaction of sulfamoylation
agent 1 at room temperature. This protocol could be
successfully used for a late-stage sulfamoylation of biological
molecules.
First, according to the preparation of sulfamoylation agent
C,4 N-(tert-butoxycarbonyl)sulfamoyl chloride was synthesized
with chlorosulfonyl isocyanate and tert-butyl alcohol (1.1
equiv) in dichloromethane or toluene (Scheme 2). Then, 2.2
Scheme 2. Preparation of Sulfamoylation Reagent 1
equiv of pyridine was added in situ to afford N-(tert-
butoxycarbonyl)-aminosulfonylpyridinium salt and pyridine
hydrochloride as a 1:1 mixture (1) in 92% yield. Our attempts
to separate this mixture with different recrystallization solvents
were unsuccessful. This sulfamoylation agent 1 is a white solid,
can be prepared on 100 g scale, and has been stored at room
temperature for 7 months without a decrease in activity.
Reagent 1 also exhibited good solubility in the organic solvent.
The saturated solubility in acetonitrile-d3 is 0.40 mol/L (for
details, see the Supporting Information), which is evidently
better than that of reagent C.
Next, we examined the reaction of 2-(naphthalen-2-yl)-
ethan-1-ol (2a) with reagent 1 as the model reaction to
establish the optimum reaction conditions (for details, see the
Supporting Information). It was found that sulfamate product
3a could be obtained in the best yield with 2.0 equiv of reagent
1 in dichloromethane (0.2M) without any base or additive at
room temperature (20−25 °C) in 3 h. The chlorinated side
product was not detected.
Under the optimized conditions, we started to investigate
the functional group compatibility and substrate scope of this
transformation. Sulfamoylation with primary (2a and 2b) and
secondary (2c) alcohols proceeded smoothly to afford
corresponding products 3a−3c in 80−90% yields. Unfortu-
nately, we could hardly obtain the products from tertiary
alcohols due to the sluggish sulfamoylation of bulky tertiary
alcohols as well as the chlorinated and eliminated byproducts.
It was found that the reaction of 2-naphthol (2d) and phenols
with an electron-donating substituent, including a phenoxy
group (2e), a tert-butyl group (2f), or a methoxy group (2g),
proceeded very well, giving the corresponding products 3e−3g
in 75−86% yields (Scheme 3A). Phenols with an electron-
deficient group such as bromo (2h), ester (2i), or benzoyl (2j)
reacted slightly slower but still gave 65−76% yields.
a
Yields were obtained on the basis of 1H NMR with mesitylene as an
internal standard and purification (in parentheses).
To investigate the applicability of this sulfamoylation agent,
various pharmaceuticals and bioactive molecules containing an
OH moiety were subjected to the sulfamoylation conditions
followed by the removal of a Boc group by HCl to provide the
targeted sulfamate (Scheme 3B). Not only primary alcohols
(4a and 4b) but also secondary alcohols (4d−4f) reacted with
1 smoothly and provided the corresponding products 5a and
5d−5f, respectively, in moderate to high yields. The weak
nucleophilic phenol (4g−4i) underwent the same reaction,
giving 5g−5i, respectively, with high efficiency (79−85%
yields). It is noteworthy that the yield was not significantly
reduced when sterically bulky phenol (4c) was used.
Considering the successful sulfamoylation of alcohol and
phenol, we continued to explore the potential of the reaction
with aniline or amine from reagent 1 under similar conditions.
As shown in Scheme 4A, 2-naphthylamine (6a) and anilines
bearing a dimethylamino (6b), acetyl (6c), or trifluoromethyl
(6d) substituent reacted smoothly with only 1.5 equiv of
reagent 1 to give 7a−7d in 75−85% yields. Secondary amines,
including N-methylaniline (6e), diphenylamine (6f), and
tetrahydroquinoline (6g), were also converted in high yields
(80−88%) to sulfamides 7e−7g, respectively. Aliphatic amines
(6h−6j) were found to react smoothly with 1 to provide
products 7h−7j, respectively, in moderate to high yields.
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Scheme 4. Substrate Scope of Sulfamoylation of RNHR′(H)
Scheme 5. Selective Sulfamoylation of Compounds with
Different Nucleophilic Groups
Including Various Pharmaceuticals and Bioactive
a
Molecules
respectively, to give 11d and 11e in 70% and 62% yields,
respectively.
Finally, we attempted to apply this method to the efficient
preparation of first-in-class NAE inhibitor pevonedistat
(MLN4924).12 Pevonedistat, a structural analogue of AMP,
was developed by Takeda Pharmaceutical Co. Ltd. as a clinical
cancer treatment.13 It was granted Breakthrough Therapy
Designation by the U.S. Food and Drug Administration in July
2020 for the treatment of patients with higher-risk myelodys-
plastic syndromes (HR-MDS). For a practical and scalable
synthesis, the late-stage selective sulfamoylation on the primary
OH group (10f) presented a considerable challenge. In the
current cGMP process, sulfamoylation of 10f by reagent C
(Scheme 1) afforded 11f in only 50% yield.5 The reaction
mixtures contained starting material (SM), the primary
sulfamate product, the secondary byproduct, and the bis
byproduct in a 5.3:7.4:1.0:0.4 ratio, as well as a trace of the
olefin byproduct. In Miller’s procedure with PCPS as a
sulfamoylation agent,7 the corresponding ratio was
1.1:4.7:1.0:1.1, and pevonedistat was obtained in only 38%
yield.
a
Yields were obtained on the basis of 1H NMR with mesitylene as an
internal standard and purification (in parentheses).
Pharmaceutical anilines also afforded the sulfamoyl deriva-
tives (9a−9d) without difficulty. Aliphatic amines easily
proceeded through the sulfamoylation process, providing the
amino acid derivatives (9e and 9f) in 75−79% yields. To
illustrate the scalability and robustness of this procedure,
sulfamoylations of metronidazole (4b) and benzocaine (6b)
were treated with 1 on a gram scale under standard conditions.
The corresponding products 5b (1.17 g) and 9b (1.22 g) were
obtained in 80% and 83% yields, respectively.
In contrast, by employing our sulfamoylation agent 1,
MLN4924 could be synthesized in high yield (80%) and
selectivity (Scheme 6). According to a LCMS analysis, the
ratio of the reaction mixture (SM:ene:secondary:primary:bis)
was 1.1:1.2:0.2:19.5:1.0. We believe this method could be used
in the GMP production of pevonedistat and other similar diol
pharmaceuticals.
Substitution selectivity toward complex pharmaceuticals
with multiple nucleophilic groups usually denotes significance
as well as a considerable challenge. Recently, our group
reported several selective substitutions of different heteroatom
nucleophiles.10 To investigate the selectivity of this method,
sulfamoylation toward multiple nucleophilic groups was
examined (Scheme 5). Diol with a phenolic -OH group and
a primary alcoholic -OH group reacted smoothly with 1 at the
primary alcoholic -OH position to give 11a in 80% yield as the
sole sulfamoylation products. Compounds 10b and 10c
bearing both -OH and -NH2 groups were also found to react
with 1 selectively. The relative reactivity decreased in the
following order: anilino NH2 > primary alcoholic -OH >
phenolic -OH. It is noteworthy that agent 1 could be applied
to the selective sulfamoylation of biological diols. The sex
hormone drug β-estradiol (10d) and pentacyclic triterpene
natural product botulin (10e) were tested to react with 1, and
we found that the substitution reactions occurred exclusively
on the secondary alcoholic -OH and primary alcoholic -OH,
Scheme 6. Selective Sulfamoylation of Diols for the
Preparation of Pevonedistat
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In summary, we re-examined N-(tert-butoxycarbonyl)-
aminosulfonylpyridinium salt and developed a sulfamoylation
agent 1 with the advantages of high solubility, shelf stability,
and a large scale. Various sulfamates and sulfamides can be
synthesized by employing this agent in high yields. These
transformations performed efficiently at room temperature
within a few hours and provided a good selectivity toward
substrates with multiple nucleophilic groups. A wide range of
pharmaceuticals and bioactive molecules containing an OH or
NH2 moiety were highly compatible with this protocol.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00504.
Experimental information, detailed experimental proce-
dures, and full spectroscopic data (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
Dong-Yu Wang − School of Pharmacy, Shanghai Jiao Tong
University, Shanghai 200240, China; orcid.org/0000-
0002-3977-9619; Email: wangdongyu@sjtu.edu.cn
Chun Hu − Key Laboratory of Structure-based Drug Design &
Discovery, Ministry of Education, School of Pharmaceutical
Engineering, Shenyang Pharmaceutical University, Shenyang
110016, China; Email: chunhu@syphu.edu.cn
Authors
Hai-Ming Wang − Key Laboratory of Structure-based Drug
Design & Discovery, Ministry of Education, School of
Pharmaceutical Engineering, Shenyang Pharmaceutical
University, Shenyang 110016, China; School of Pharmacy,
Shanghai Jiao Tong University, Shanghai 200240, China
Chao-Dong Xiong − CAS Key Laboratory of Receptor
Research, Shanghai Institute of Materia Medica (SIMM),
Chinese Academy of Sciences, Shanghai 201203, China;
University of Chinese Academy of Sciences, Beijing 100049,
China
(6) Armitage, L.; McCarron, A.; Zhu, L. Process pevelopment and
GMP production of a potent NEDD8-activating enzyme (NAE)
inhibitor: Pevonedistat. ACS Symp. Ser. 2016, 1240, 13−62.
(7) Rapp, P. B.; Murai, K.; Ichiishi, N.; Leahy, D. K.; Miller, S. J.
Catalytic sulfamoylation of alcohols with activated aryl sulfamates.
Org. Lett. 2020, 22, 168−174.
(8) (a) Masui, T.; Kabaki, M.; Watanabe, H.; Kobayashi, T.; Masui,
Y. Practical one-pot synthesis of N-(tert-butoxycarbonyl)sulfamide
from chlorosulfonyl isocyanate via N-(tert-butoxycarbonyl)-
aminosulfonylpyridinium salt. Org. Process Res. Dev. 2004, 8, 408−
410. (b) Masui, Y.; Watanabe, H.; Masui, T. One-pot synthesis of N-
acyl-substituted sulfamides from chlorosulfonyl isocyanate via the
Burgess-type intermediates. Tetrahedron Lett. 2004, 45, 1853−1856.
(9) Jun, J. J.; Xie, X.-Q. Implementation of diverse synthetic and
strategic approaches to biologically active sulfamides. ChemistrySelect
2021, 6, 430−469.
Xiao-Qu Chen − School of Pharmacy, Shanghai Jiao Tong
University, Shanghai 200240, China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00504
Notes
The authors declare no competing financial interest.
(10) Scriven, E. F. V. 4-Dialkylaminopyridines: super acylation and
alkylation catalysts. Chem. Soc. Rev. 1983, 12, 129−161.
ACKNOWLEDGMENTS
■
(11) (a) Wang, D.-Y.; Yang, Z.-K.; Wang, C.; Zhang, A.; Uchiyama,
M. From anilines to aryl ethers: A facile, efficient, and versatile
synthetic method employing mild conditions. Angew. Chem., Int. Ed.
2018, 57, 3641−3645. (b) Wang, D.-Y.; Wen, X.; Xiong, C.-D.; Zhao,
J.-N; Ding, C.-Y.; Meng, Q.; Zhou, H.; Wang, C.; Uchiyama, M.; Lu,
X.-J; Zhang, A. Non-transition metal-mediated diverse aryl-heter-
oatom bond formation of arylammonium salts. iScience. 2019, 15,
307−315. (c) Zhao, J. N.; Kayumov, M.; Wang, D. Y.; Zhang, A.
Transition-metal-free aryl-heteroatom bond formation via C-S bond
cleavage. Org. Lett. 2019, 21, 7303−7306.
This work was supported by grants from the National Natural
Science Foundation of China (21702216). Grants from the
National Science & Technology Major Project “Key New Drug
Creation and Manufacturing Program” (2018ZX09711002-
006-003) were also appreciated.
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