Catalytic Sulfamoylation of Alcohols with Activated Aryl Sulfamates

Article abstract of DOI:10.1021/acs.orglett.9b04119

We report a new catalytic method for alcohol sulfamoylation that deploys electron-deficient aryl sulfamates as activated group transfer reagents. The reaction utilizes the simple organic base N-methylimidazole, proceeds under mild conditions, and provides

Full text of DOI:10.1021/acs.orglett.9b04119

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Catalytic Sulfamoylation of Alcohols with Activated Aryl Sulfamates
Peter B. Rapp,† Koichi Murai,‡ Naoko Ichiishi,‡ David K. Leahy,*,‡ and Scott J. Miller*,†
†Department of Chemistry, Yale University, P.O. Box 208107, New Haven, Connecticut 06520-8107, United States
‡Process Chemistry Development, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: We report a new catalytic method for alcohol
sulfamoylation that deploys electron-deficient aryl sulfamates
as activated group transfer reagents. The reaction utilizes the
simple organic base N-methylimidazole, proceeds under mild
conditions, and provides intrinsic selectivity for 1° over 2°
alcohols (up to >40:1 for certain nucleosides). The requisite
aryl sulfamate donors are stable crystalline solids that can be readily prepared on a large scale. Mechanistic considerations
support the intermediacy of HNSO2 “aza-sulfene” in the transfer reaction.
Scheme 1. Comparison of Methods for Alcohol
Sulfamoylation
ulfamates (ROSO2NR2) are stable ester derivatives of
sulfamic acid with unique chemical and pharmacological
S
properties.1 Since their classical application to alcohol
dehydration was first described by Burgess,2 sulfamates have
been deployed in a burgeoning array of modern synthetic
transformations. Classical N-acyl sulfamates stereoselectively
transform 1,2-diols into sulfamidates3 and can also facilitate
rapid alcohol oxidation.4 N,N-Dialkyl sulfamates are useful
metalation directors as well as electrophiles in Ni-catalyzed
aminations5 and cross-coupling reactions.6 Primary sulfamates
(ROSO2NH2) are an effective nitrogen source en route to
amines, aziridines, sulfamides, and various 1,3-difunctionalized
products via Rh-catalyzed C−H activation.6d,7 The interest in
sulfamates as pharmacophores derives from their isosteric
resemblance to sulfates and phosphates, together with their
charge neutrality at biological pH (pKa ∼ 8−9).8 This unique
combination of properties enables sulfamates to modulate the
bioavailability and bioactivity of many drugs and enzymes.9
Currently, methods for synthesizing primary sulfamates
directly from alcohols are limited. The most common strategy
involves the direct reaction of alcohols with sulfamoyl chloride
(H2NSO2Cl),10 an unstable reagent that normally must be
generated in situ by decarboxylation of highly reactive
chlorosulfonyl isocyanate (Scheme 1).11 Spontaneous decom-
position of H2NSO2Cl necessitates an excess of the reagent to
achieve high conversion, largely precluding the possibility of
selective (i.e., 1° over 2°) sulfamoylation of polyols.11d,12
Furthermore, both the decarboxylation and chloride decom-
position reactions exhibit runaway kinetics in certain solvents
and are therefore prone to explosive gas evolution on scale-up.13
A second sulfamoylation strategy employs Burgess-type
reagents to convert alcohols into elimination-prone N-
alkoxycarbonyl-protected sulfamates.2,3,14 Armitage and co-
workers reported the use of 1,4-diazabicyclo[2.2.2]octane
(DABCO)-derived Burgess-type reagent 1 to generate Boc-
protected sulfamates (Scheme 1).15 The steric bulk of 1 retards
elimination and provides modest selectivity for 1° over 2°
alcohols. Unfortunately, 1 exhibits low solubility in organic
solvents, and the reaction requires HCl (up to 0.4 equiv),
leading to chlorinated side products. Intriguingly, the 4-(N,N-
dimethylamino)pyridine (DMAP) analogue of 1 reacts with
amines and anilines to afford sulfamides but is unreactive toward
alcohols.16
Here we report the development of an organocatalytic
method for transferring the sulfamate group to alcohols and
phenols (Scheme 1). We demonstrate efficient and selective
sulfamoylation of 1° over 2° alcohols (up to >40:1 for certain
nucleosides) using electron-deficient aryl sulfamate donors
activated for transfer by the simple organic base N-
methylimidazole (NMI). Our methodology is complementary
to the existing methods and opens the door to late-stage catalyst-
controlled enantio- or site-selective delivery of sulfamates to
complex polyols, including natural products.
Received: November 18, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Reaction Development
Table 1. Screening of Electron-Deficient Sulfamates under
Base-Catalyzed Conditions
a
Initially, we hypothesized that sulfamoyl chloride itself might be
activated for group transfer in a nucleophilic mode using a
sufficiently π-nucleophilic base catalyst such as DMAP or NMI,
together with hindered stoichiometric amine bases to consume
the liberated HCl byproduct. This general group transfer
framework is well-precedented for other chlorinated C-, P-, and
S-centered electrophiles.17 However, we found that the rate of
background alcohol sulfamoylation with H2NSO2Cl and
stoichiometric base in the absence of a DMAP or NMI catalyst
was considerable, even at cryogenic temperatures. Attempts to
activate various Burgess-type reagents4 including 1 using basic
or acidic peptide catalysts similarly failed to accelerate the
addition reaction above the background rate.
We were subsequently drawn to a report by Lathrop and co-
workers describing the convergent assembly of sulfamide
heterodimers via the amination of N-alkyl-2,6-difluorophenyl-
sulfamated fragments in the presence of excess DMAP.18
Reasoning that primary aryl sulfamates could serve as stabilized
yet sufficiently activated analogues of sulfamoyl chloride, we
prepared a series of electron-deficient sulfamates 2−8 with
varying degrees of leaving group acidity (Figure 1) and screened
b
c
entry
sulfamate (R)
pKa
cat. (mol %)
T (°C)
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2 (4-FP)
3 (2-FP)
9.9
8.7
9.3
7.0
7.5
7.5
7.5
7.5
7.5
5.5
5.5
4.7
4.7
4.7
4.7
NMI (20)
NMI (20)
NMI (20)
NMI (20)
NMI (20)
−
NMI (20)
NMM (20)
DMAP (20)
NMI (20)
NMI (10)
NMI (20)
NMI (10)
−
30
30
30
30
30
30
4
30
30
30
30
rt
9
33
41
44
63
0
28
45
62
77
62
86
71
7
4 (HFIP)
5 (NPhth)
6 (2,6-DFP)
6 (2,6-DFP)
6 (2,6-DFP)
6 (2,6-DFP)
6 (2,6-DFP)
7 (PFP)
7 (PFP)
8 (PCP)
8 (PCP)
8 (PCP)
rt
rt
4
8 (PCP)
NMI (20)
90
a
Reaction conditions: THF (0.2 M), 0.1 mmol of alcohol, 1.5 equiv of
b
c
sulfamate donor, 18 h. pKa of the ROH leaving group. Yields were
determined by peak integration on LC−MS and represent averages of
two independent trials.
a
Scheme 2. Scope of Catalytic Sulfamoylation with PCPS
Figure 1. Electron-deficient sulfamate donors screened. The pKa of the
corresponding leaving group (data taken from the literature19) is shown
in red below each donor.
them for their ability to donate sulfamate to 2-(2-naphthyl)-
ethanol in the presence of catalytic amounts of base (Table 1).
Mildly acidic aryl sulfamates gave low to moderate yields of the
sulfamoylated product at 30 °C in the presence of 20 mol %
NMI (entries 1−4). The yields improved appreciably with the
reagent 2,6-difluorophenyl sulfamate (2,6-DFPS, 6) (entries 5−
7), and no background transfer was detected in the absence of
base (entry 6). Interestingly, DMAP and the non-nucleophilic
base N-methylmorpholine (NMM) both exhibited turnover
with 6 (entries 8 and 9). The use of pentafluorophenyl sulfamate
(PFPS, 7) further improved the yield and enabled a reduction in
catalyst loading to 10 mol % (entries 10 and 11). Gratifyingly,
pentachlorophenyl sulfamate (PCPS, 8), a shelf-stable but
highly electron-deficient sulfamate donor, provided high yields
(>71%) of sulfamoylated product at or below room temperature
with minimal background and catalyst loadings as low as 10 mol
% (entries 12−15).
a
Conditions unless otherwise stated: R−OH (1.0 mmol, 1.0 equiv),
PCPS (1.2 equiv), NMI (12 mol %), THF (0.2 M), rt, 18 h. Average
isolated yields from two independent trials are shown. PCPS (1.5
equiv), NMI (20 mol %). Reaction time 3 h. Slow addition of PCPS
over 1.5 h. 0.5 mmol scale.
b
c
d
e
Substrate Scope
Under the optimized conditions (Scheme 2), primary (9a), β-
branched (9b), and secondary (9c) alcohols were converted in
high yields (73−82%) to the corresponding primary sulfamates
10a−c. The reaction is compatible with more complex
substrates such as Cbz-protected serine 9d (69%), 2-(4-
imidazolylphenoxy)ethanol (9e) (60%), dehydroepiandroster-
one (9f) (86%), and tetrabenzylated glucopyranoside 9g (77%)
B
DOI: 10.1021/acs.orglett.9b04119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Inherent selectivity toward complex 1,3-diols. (A) Catalytic sulfamoylation with N6-benzoyl-2′-deoxyadenosine (11), a model anti-1,3-diol,
gives a >40:1 ratio of 1° to 2° sulfamate product, ultimately furnishing the desired 1° monosulfamate 12 in 47% isolated yield. Shown are RP-HPLC
traces of the crude reaction mixture. (B) Application of similar conditions to syn-1,3-diol 13 furnishes primary sulfamate 14 (TAK-924) with a
selectivity of 4.7:1.0 in an isolated yield of 38%. aIsolated yield.
to give sulfamates 10d−g, respectively. Success with 9e is
notable, as the reaction is likely autocatalytic because of the
basicity of the imidazolyl substrate. Cinnamyl alcohol (9h) is a
poor substrate for the reaction, providing cinnamyl sulfamate
(10h) in only 20% yield. Despite the low yield, the partial
sulfamoylation of 9h is notable, as Boc-DABCO reagent 1 fails
to provide any product for allylic and propargyl alcohols.15
Acetamidophenol (9i) gives the corresponding phenyl
sulfamate 10i in 75% yield. We have found that many primary
alkyl sulfamates (10a−g) are nearly isopolar with their
corresponding alcohols (9a−g), rendering separation of
unreacted starting material difficult by standard flash chroma-
tography. Increasing the catalyst loading to 12 or 20 mol % (for
1° or 2° alcohols, respectively) usually effects quantitative
conversion of the starting material, thereby simplifying
purification.
During the preparation of this Letter, we became aware of
certain toxicity concerns related to sulfamate donor 8, a
derivative of pentachlorophenol. Once widely used as a
pesticide, pentachlorophenol is now highly regulated because
of its potential to be contaminated with trace dioxins. These
concerns are alleviated by the pentafluoro reagent 7, which
provides similar yields of sulfamoylated product as 8 (cf. Table 1,
entries 10 and 11). Both sulfamate reagents are benchtop-stable
when stored dry,20 an appealing property given the spontaneous
decomposition of H2NSO2Cl and the sensitivity of the Boc-
DABCO reagent 1 toward hydrolysis.15
phores, e.g., 5′-O-sulfamoyladenosine is a broad-spectrum
antibiotic that inhibits bacterial aminoacyl-tRNA synthetases.9d
Under standard reaction conditions, N6-benzoyl-2′-deoxyade-
nosine (11), a model anti-1,3-diol, was converted to the primary
sulfamate 12 in 47% isolated yield with a high site selectivity of
42.7:1.0 for 1° over 2° alcohol modification (Figure 2A).
To test whether this selectivity is obtained with syn-1,3-diols,
we applied similar reaction conditions to substrate 13. Diol 13 is
a precursor of primary sulfamate 14, also known as TAK-924, a
structural analogue of AMP that inhibits NEDD8-activating
enzyme (NAE).21 TAK-924 (pevonedistat) is currently under-
going evaluation in multiple clinical trials for the treatment of
human cancers22 via deregulation of S-phase DNA synthesis.
The current cGMP process route to TAK-924 involves
sulfamoylation of 13 by Boc-DABCO reagent 1, providing 14
in 50% yield in the penultimate step.23 Catalytic sulfamoylation
with PCPS performs comparably to this reagent, furnishing 14
with a selectivity of 4.7:1.0 and an isolated yield of 38% (Figure
2B). The yield suffers from the stringent purification steps (three
columns) necessary to remove the residual 2° regioisomer and
bisfunctionalized material.
Mechanistic Insight
Toward the synthesis of N-substituted sulfamate esters,24 our
success with primary aryl sulfamate donors suggested that
secondary (ArOSO2NHR) as well as tertiary (ArOSO2NR2) aryl
sulfamates might also engage in catalytic group transfer. To test
this hypothesis, we prepared pentachlorophenyl methylsulfa-
mate (15) and pentachlorophenyl dimethylsulfamate (16) and
evaluated their donor activities under base-catalyzed conditions
(Figure 3). Whereas 15 converted 2-(2-naphthyl)ethanol to the
corresponding N-methylsulfamate in 47% yield, 16 furnished
only trace amounts of the corresponding N,N-dimethylsulfa-
mate. Intriguingly, this stark difference in reactivity between 15
and 16 was mirrored by their relative stabilities. Whereas 15 was
prone to decomposition during aqueous workup, 16 is highly
Selectivity toward Polyols
An appealing feature of 1 is its ability to selectively sulfamoylate
1° over 2° alcohols, although the degree of selectivity is
somewhat substrate-dependent, ranging from >99:1 to 4.3:1 for
similar 1,2-diols.15 We set out to evaluate the intrinsic site
selectivity of the catalytic sulfamoylation reaction on deoxy-
nucleoside analogues containing unprotected 1,3-diols. Mono-
sulfamoylated primary nucleosides are important pharmaco-
C
DOI: 10.1021/acs.orglett.9b04119
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Organic Letters
Letter
a
Scheme 3. Plausible Reaction Mechanism
Figure 3. Evaluation of N-methyl- and N,N-dimethylsulfamates 15 and
a
16 under base-catalyzed group transfer conditions. Yields with NMI
(without NMI) were determined by peak integration on LC−MS.
Reaction conditions: THF (0.2 M), 0.1 mmol of alcohol, 1.5 equiv of
sulfamate donor, 12 h, room temperature.
thermostable and can be purified by recrystallization from hot
acetone. It has also been shown that N,N-dialkylsulfamates are
1011-fold more stable toward hydrolysis than the corresponding
N-alkylsulfamates.25
These reactivity and stability differences bear mechanistic
relevance, as they seem unlikely to arise solely from increased
steric hindrance around the sulfamoyl nitrogen. Bulky
arylsulfonyl chlorides are effectively activated for transfer by
nucleophilic attack of base at the SIV center.17h In contrast, the
transfer of alkylsulfonyl chlorides is mechanistically distinct,
proceeding through an elimination mechanism to generate
reactive sulfene species (RR′CSO2).26 Both alkylsulfonyl
chlorides and primary aryl sulfamates are particularly susceptible
to hydrolysis at high pH, implicating elimination in the latter
process.27 Quantum-mechanical calculations of aryl sulfamate
hydrolysis further suggest that an elimination pathway (E1cb) is
11.3 kcal mol−1 more favorable than direct substitution with
hydroxide (SN2).28
a
Group transfer is initiated by deprotonation of the aryl sulfamate
with catalytic base, followed by elimination of phenol to generate an
aza-sulfene electrophile, which is subsequently trapped by the alcohol
to afford the sulfamate. The catalytic base is buffered by a salt pair,
preventing off-cycle catalyst deactivation.
We infer from these findings that catalytic sulfamoylation may
be initiated by deprotonation of the weakly acidic
H−RNO2SOR sulfamoyl proton with base, rather than by
nucleophilic attack of the base at the SVI center. The absence of
such a proton in 16 precludes it from serving as an effective
sulfamate donor. Elimination of the acidic phenol, either
simultaneous with or subsequent to deprotonation (E2 or
E1cb, respectively), generates the aza-sulfene electrophile
HNSO2. Subsequent trapping of this species by the alcohol
furnishes the desired sulfamate (Scheme 3). Acid−base
equilibria are consistent with this proposal: a regression analysis
of known aryl sulfamate acidities as a function of the leaving
group19b,25,27b,29 (see Table S1) predicts that the pKa of
ArOSO2NH2 is less than the pKBH of NMI for the most effective
sulfamate donors 7 and 8 (Figure 4). Furthermore, the relatively
high acidity of the eliminated phenols (pKa ∼ 5.5 from 7 and 4.7
from 8)19b implies that NMI (pKBH ∼ 7.1) is effectively buffered
as a salt pair throughout the reaction. This presumably
minimizes interception of HNSO2 by the catalyst itself in an
off-cycle pathway (Scheme 3), which could deactivate the
catalyst as a Burgess-type inner salt. Consistent with a general-
base mechanism, the non-nucleophilic base NMM provided
moderate turnover using the pKa-matched sulfamate donor 6
(Table 1, entry 8).
Figure 4. Correlations between the acidity of the phenol leaving group
and the aryl sulfamate donor are consistent with the proposed
mechanism. Donors 7 (PFPS )and 8 (PCPS) are acidic enough to be
deprotonated by NMI (pKa for ArOSO2NH2 < pKBH), which is
subsequently buffered by the phenol (pKa for ArOH < pKBH). The pKa
values for 2−8 (white circles, predicted) were obtained from a
regression analysis of 10 known aryl sulfamate acidities as a function
of their phenol leaving group acidities (shaded circles, measured).
underwent mildly exothermic polymerization upon warming to
room temperature in the absence of a nucleophile but could be
trapped as a cycloadduct with electron-rich alkenes.30 Although
the existence of HNSO2 was proposed prior to Burgess by Appel
and Goehring in 1952,31 its existence remained experimentally
unconfirmed until very recent vacuum flash pyrolysis experi-
ments detected it in the gas phase.32 Our method can be
considered a catalytic implementation of Burgess’ original
protocol with HNSO2, facilitated by a fortuitous cooperativity
among reagent acidities. Although sporadic references to N-alkyl
or N-aryl aza-sulfenes occur throughout the literature,11c,33 their
utility as synthetic intermediates pales in comparison to the
compendium of useful transformations established for classical
sulfenes.34 We hope that our new findings spur renewed
exploration of the chemistry of this interesting electrophile class.
The aza-sulfene electrophile HNSO2 represents the simplest
member of the N-sulfonylamine family originally defined by
Burgess.30 In his seminal 1967 report, Burgess found that N-
ethylsulfonylamine (EtNSO2) could be generated from the
corresponding chloride (EtHNSO2Cl) by treatment with
stoichiometric base at cryogenic temperatures. This species
D
DOI: 10.1021/acs.orglett.9b04119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Conclusion
Letter
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We have developed a new catalytic method for alcohol
sulfamoylation that harnesses electron-deficient aryl sulfamates
as activated group transfer reagents. Advantages of the new
method include room-temperature stability of the requisite
sulfamate donors, high yields under mild reaction conditions,
and intrinsic selectivity for primary over secondary alcohols.
These attractive features may render the method broadly useful
for the synthesis of complex primary and N-alkylsulfamates,
which are of increasing pharmacological interest.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04119.
Detailed experimental protocols, 1H and 13C NMR
spectra for all compounds, and crystallographic data for
7 and 16 (PDF)
Accession Codes
CCDC 1962269 and 1962270 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
e-mailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, U.K.; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
(8) Lo, Y. S.; Nolan, J. C.; Maren, T. H.; Welstead, W. J.; Gripshover,
D. F.; Shamblee, D. A. Synthesis and physiochemical properties of
sulfamate derivatives as topical antiglaucoma agents. J. Med. Chem.
1992, 35, 4790−4794.
*scott.miller@yale.edu
*david.leahy@takeda.com
ORCID
Peter B. Rapp: 0000-0002-9586-2126
David K. Leahy: 0000-0003-4128-7792
Scott J. Miller: 0000-0001-7817-1318
Funding
(9) (a) Winum, J.-Y.; Vullo, D.; Casini, A.; Montero, J.-L.; Scozzafava,
A.; Supuran, C. T. Carbonic Anhydrase Inhibitors. Inhibition of
Cytosolic Isozymes I and II and Transmembrane, Tumor-Associated
Isozyme IX with Sulfamates Including EMATE Also Acting as Steroid
Sulfatase Inhibitors. J. Med. Chem. 2003, 46, 2197−2204. (b) Winum,
J.-Y.; Vullo, D.; Casini, A.; Montero, J.-L.; Scozzafava, A.; Supuran, C.
T. Carbonic Anhydrase Inhibitors: Inhibition of Transmembrane,
Tumor-Associated Isozyme IX, and Cytosolic Isozymes I and II with
Aliphatic Sulfamates. J. Med. Chem. 2003, 46, 5471−5477. (c) Yu, X. Y.;
Hill, J. M.; Yu, G.; Wang, W.; Kluge, A. F.; Wendler, P.; Gallant, P.
Synthesis and structure-activity relationships of a series of novel
thiazoles as inhibitors of aminoacyl-tRNA synthetases. Bioorg. Med.
Chem. Lett. 1999, 9, 375−380. (d) Winum, J.-Y.; Scozzafava, A.;
Montero, J.-L.; Supuran, C. T. Sulfamates and their therapeutic
potential. Med. Res. Rev. 2005, 25, 186−228.
We thank Takeda Pharmaceuticals International Co. for
generous research support.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Takeda Pharmaceuticals International Co. for
supplying the precursor to TAK-924 (substrate 13) and for
help with characterization and purification of the reaction
(product 14). We thank Brandon Q. Mercado (Yale CBIC) for
assistance with X-ray crystallography and structure refinement.
(10) (a) Graf, R. Reactions with N-Carbonylsulfamoyl Chloride.
Angew. Chem., Int. Ed. Engl. 1968, 7, 172−182. (b) Kloek, J. A.;
Leschinsky, K. L. An improved synthesis of sulfamoyl chlorides. J. Org.
Chem. 1976, 41, 4028−4029.
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