Synthesis of N-Substituted Sulfamate Esters from Sulfamic Acid Salts by Activation with Triphenylphosphine Ditriflate

Article abstract of DOI:10.1021/acs.orglett.7b03059

A general approach to access sulfamate esters through preparation of sulfamic acid salts, subsequent activation with triphenylphosphine ditriflate, and nucleophilic trapping is disclosed. The method proceeds in modest to excellent yields to incorporate nucleophiles derived from aliphatic alcohols and phenols. This approach can be employed to furnish differentially substituted sulfamides.

Full text of DOI:10.1021/acs.orglett.7b03059

Letter
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
pubs.acs.org/OrgLett
Synthesis of N‑Substituted Sulfamate Esters from Sulfamic Acid Salts
by Activation with Triphenylphosphine Ditriflate
†
†
J. Miles Blackburn, Melanie A. Short, Thomas Castanheiro, Suraj K. Ayer, Tobias D. Muellers,
and Jennifer L. Roizen*
Department of Chemistry, Duke University, Box 90346, Durham, North Carolina 27708-0354, United States
*
S Supporting Information
ABSTRACT: A general approach to access sulfamate esters
through preparation of sulfamic acid salts, subsequent
activation with triphenylphosphine ditriflate, and nucleophilic
trapping is disclosed. The method proceeds in modest to
excellent yields to incorporate nucleophiles derived from
aliphatic alcohols and phenols. This approach can be employed to furnish differentially substituted sulfamides.
he sulfamate ester functional group has found broad
Scheme 2. Methods To Prepare Sulfamate Esters
T
utility, including use as nitrogen sources for amination and
1
aziridination reactions, as electrophiles in cross-coupling
2
reactions, and as an alcohol-masking moiety to modulate the
bioactivity and bioavailability of pharmacologically relevant
3
compounds (Scheme 1). One classical approach to access
Scheme 1. Utility of Sulfamate Esters
effective protocol to prepare sulfamate esters based on this
approach (Scheme 3).
Scheme 3. Disclosed Strategy
sulfamate esters relies on the use of sulfuryl chloride to furnish
sulfamoyl or sulfonyl chloride intermediates. These procedures
are inefficient or ineffective when the involved nucleophiles are
4
,5
sterically hindered or electron-deficient (Scheme 2, eq 3).
Although several alternative methods to access sulfamate esters
6
−8
have been reported (Scheme 2, eqs 4−6),
there are no
As anticipated, the reaction of amines with sulfur trioxide
sources provided facile access to diverse sulfamic acid salts
operationally straightforward, efficient, general methods to
prepare acyclic O-alkyl sulfamate esters incorporating primary
or secondary alkyl substituents on the nitrogen. To identify a
protocol that would provide access to these types of sulfamate
esters with varied electronic and steric properties, we
(
Table 1). Initially, treatment of 2,2,2-trifluoroethylamine with
sulfur trioxide·pyridine complex and triethylamine in acetoni-
trile furnished sulfamic acid salt 2a in quantitative yield as an oil
without need for purification. Solid trimethylammonium salt 2b
could be prepared through the reaction of 2,2,2-trifluoroethyl-
9
anticipated that initial sulfamation of an amine with a sulfur
trioxide complex would furnish a sulfamic acid salt. We
hypothesized that the use of sulfamic acid salts would allow us
to investigate an array of esterification strategies to install the
sulfamate ester S−O bond. Described herein is a broadly
Received: September 29, 2017
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03059
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Preparation of Sulfamic Acid Salts
Table 2. Optimization of Sulfamate Ester Preparation
a
b
entry
activating agent
yield of 4a (%)
1
2
3
4
5
PCl (2.0 equiv)
41
44
<5
5
POCl (2.0 equiv)
3
SOCl (2.0 equiv)
2
c
(COCl) (10.0 equiv)
nd
2
trichlorotriazine (1.0 equiv)
DIAD, PPh3
<5
50
56
71
78
95
94
d
6
7
Tf O (1.0 equiv), Ph PO (2.1 equiv)
2
3
e
8
Tf O (1.5 equiv), Ph PO (3.15 equiv)
2 3
e
9
ef
,
Tf O (1.5 equiv), Ph PO (1.65 equiv)
2 3
1
0
1
Tf O (1.5 equiv), Ph PO (1.65 equiv)
2 3
,
fg
1
Tf O (1.5 equiv), Ph PO (1.65 equiv)
2
3
a
General reaction conditions: 1.0 equiv of n-pentanol (3a), 1.0 equiv
of sulfamate 2a, CH Cl , 2.0 equiv of Et N, Tf O (1.5 equiv), Ph PO
2
2
3
2
3
b
c
d
(1.65 equiv), 18 h, −78 → 22 °C. Isolated yields. Not detected. No
e f g
Et N. 1.5 equiv of 2a. 3.0 equiv of Et N. 1.5 equiv of 2b.
3
3
a
General reaction conditions: 1.0 equiv of amine 1, 1.0 equiv of sulfur
trioxide·pyridine complex (SO ·pyr), 0.33 M acetonitrile, 1.5 equiv of
3
b
6
Et N, 30 min, 0 → 22 °C. 1 equiv of SO ·NMe in place of SO ·pyr
chloride (Scheme 2, eq 4); however, N-methyl- and N-
ethylsulfamate esters cannot be accessed via a similar strategy.
In principle, these N-alkyl sulfamates could be prepared in a
two-step approach featuring monoalkylation of O-pentyl
3
3
3
3
c
and Et N. >90% purity.
3
amine with sulfur trioxide·trimethylamine complex and then
recrystallized to purity. While the analogous sodium salt could
be prepared from chlorosulfonic acid, incorporation of the
ammonium cation simplified the isolation and offered a better
solubility profile in subsequent reactions. By this strategy,
sulfamic acid salts have been prepared efficiently from anilines,
primary and secondary amines, enantioenriched amines, and
amines with pendant heteroaromatic functionality.
7
sulfamate (Scheme 2, eq 5). Neither of these methods
would be appropriate to access enantioenriched sulfamate ester
4i, which is generated without any stereochemical erosion using
the disclosed approach.
The optimized protocol is less effective at transforming salts
that have been generated from secondary amines or that
incorporate heteroaromatic substituents. When triethylammo-
nium N,N-diethyl sulfamate (2h) is employed, diethylsulfamate
ester 4h forms in 17% yield (see the Supporting Information).
Fortunately, this reaction proceeds in 68% yield when sulfamate
2h is treated with 1 equiv of sodium pentoxide as the
nucleophile. Notably, sulfamic acid salts incorporating nitrogen-
containing heterocycle substituents were converted to
sulfamate esters 4j and 4k. These products were not detected
These readily accessible salts enabled us to interrogate a
variety of tactics for esterification of 2,2,2-trifluoroethylsulfamic
acid salt 2a with n-pentanol (3a) to install a sulfamate ester S−
O bond. While sulfamoyl chlorides have been used for efficient
1
,2
access of unsubstituted sulfamate esters, activation by in situ
generation of a sulfamoyl chloride furnished, at best, modest
yields of N-(2,2,2-trifluoroethyl)sulfamate ester 4a (Table 2,
entries 1−5). Anticipating that the reaction might be driven
forward by the formation of a strong phosphorus−oxygen
when PCl was utilized to activate the sulfamic acid salt via
sulfamoyl chloride intermediates.
5
double bond, DIAD and PPh were used to activate the salt and
Under the optimized conditions, a variety of alcohols serve as
effective nucleophiles to generate sulfamate esters in modest to
excellent yields (Table 3, 4l−w). Primary and secondary
aliphatic alcohols and phenols, including electron-deficient p-
hydroxybenzonitrile (3o), are converted to sulfamate esters in
high yield. In principle, phenol-derived 4p could be generated
from an activated sulfonyl imidazolium species (Scheme 2, eq
3
furnish the desired sulfamate ester 4a in moderate yield (entry
10
6). As an extension of this approach, the Hendrickson reagent
furnished the desired sulfamate ester 4a in slightly increased
yield (entry 7). Under the optimal conditions, 1.5 equiv of
triethylammonium sulfamate 2a was activated by addition to a
solution of triphenylphosphine ditriflate, which was generated
in situ from 1.5 equiv of Tf O and 1.65 equiv of Ph PO (entry
8
6). However, when sulfonyl imidazolium reagents are used for
2
3
1
0). Subsequent treatment with 3 equiv of triethylamine and 1
the synthesis of sulfamate esters, the alcohol portion must be
installed first, and the approach does not tolerate electron-rich
or -neutral aliphatic alcohols. The disclosed reaction tolerates
the benzyl and silyl ether groups in alcohols 3r and 3s,
respectively, and the phthalimide moiety in alcohol 3t,
providing potential strategies for site-specific sulfamoylation
of polylols and amino alcohols. As expected, these conditions
efficiently incorporate more elaborate hydrocarbon scaffolds,
such as those of tetrahydrogeraniol and 5α-cholestan-3β-ol,
into sulfamate esters 4u−w.
equiv of 3a at −78 °C furnished sulfamate ester 4a in 95%
isolated yield. Trimethylammonium sulfamate salt 2b reacted
with similar efficiency under the optimal conditions (entry 11).
Under the optimized conditions, a range of N-substituted
salts 2 can be converted to sulfamate esters 4 in modest to
excellent yields (Table 3). While aryl and electron-deficient N-
alkyl substituents are well-tolerated in the transformation (4a−
d), more electron-rich N-alkyl substituents result in modest
yields of sulfamate esters 4e−g. Of these, N-tert-butylsulfamate
esters can be prepared in similar yield using tert-butanol and
chlorosulfonyl isocyanate to generate N-tert-butylsulfamoyl
In addition to alcohols, nitrogen nucleophiles can be
incorporated into sulfamides under the reaction conditions to
B
DOI: 10.1021/acs.orglett.7b03059
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 3. N- and O-Substitutent Variations
To conclude, the disclosed method employs inexpensive and
readily available sulfur trioxide sources, primary and secondary
alkyl amines, and aliphatic or aromatic alcohols to prepare
sulfamate esters, many of which are not efficiently accessible
through other known methods. Furthermore, the intermediate
salts can be employed to generate differentially substituted
sulfamides. This new approach provides ready access to a
powerful, pharmacologically relevant, and synthetically versatile
motif.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03059.
Full experimental details and copies of NMR spectra
(PDF)
AUTHOR INFORMATION
Corresponding Author
j.roizen@duke.edu
■
*
ORCID
Jennifer L. Roizen: 0000-0002-6053-5512
Author Contributions
†J.M.B. and M.A.S. contributed equally. The manuscript was
written through contributions of all authors. All authors have
given approval to the final version of the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This project was funded by the American Chemical Society
Petroleum Research Fund Doctoral New Investigator Program
(
PRF 54824-DNI1) and by Duke University. J.M.B. was
supported by the National Institute of General Medical
Sciences (T32GM007105-41) and the Burroughs Wellcome
Fellowship. M.A.S. was supported by an NSF Predoctoral
Fellowship (NSF DGF 1106401). T.D.M. was supported by the
Williams College Alumni Fund. HRMS data were obtained by
George Dubay and Matias Horst of Duke University.
Characterization data were obtained on instrumentation
secured by funding from the NSF (CHE-0923097, ESI-MS,
George Dubay, Duke Department of Chemistry Instrument
Center), or the NSF, the NIH, HHMI, the North Carolina
Biotechnology Center, and Duke University (Duke Magnetic
Resonance Spectroscopy Center).
a
General reaction conditions: 1.0 equiv of alcohol 3 or amine 5, 1.5
equiv of sulfamic acid salt 2, CH Cl , 3.0 equiv of Et N, Tf O (1.5
2
2
3
2
b
equiv), Ph PO (1.65 equiv), 18 h, −78 → 22 °C. Sulfamic acid salt 2i
incorporates Me NH as a counterion. 1.0 equiv of sodium pentoxide,
3
+
c
3
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DOI: 10.1021/acs.orglett.7b03059
Org. Lett. XXXX, XXX, XXX−XXX