Rh(II)-catalyzed intermolecular oxidative sulfamidation of aldehydes: A mild efficient synthesis of N-sulfonylcarboxamides

Article abstract of DOI:10.1021/ja073872a

Rh(II)-catalyzed oxidative coupling of aldehydes and sulfonamides has been developed to provide N-sulfonylcarboxamides in one step. A variety of sulfonamides were found to react with aromatic and aliphatic aldehydes to afford the desired products in good to excellent yields. Mechanistic data, including kinetic isotope effect experiments, suggest that the transformation proceeds through a concerted asynchronous nitrene insertion into an aldehydic hydrogen. Copyright

Full text of DOI:10.1021/ja073872a

Published on Web 10/30/2007
Rh(II)-Catalyzed Intermolecular Oxidative Sulfamidation of Aldehydes:
A Mild Efficient Synthesis of N-Sulfonylcarboxamides
Johann Chan,* Kyle D. Baucom, and Jerry A. Murry
Chemical Process Research and DeVelopment, Amgen Inc., Thousand Oaks, California 91320
Received May 29, 2007; E-mail: johannc@amgen.com
Table 1. Oxidative Coupling Optimization
The development of mild oxidative C-H functionalization
reactions remains a significant challenge in organic chemistry. In
particular, major efforts in recent years on the utilization of nitrenes
for C-H activation have led to considerable improvements in these
protocols.1 Accordingly, these advancements have resulted in
application of such technology in the context of complex molecule
syntheses.2
entry
metala
oxidant
solvent
yieldb
Recently we initiated a program directed toward the use of
nitrenes for C-H activation as a means of preparing biologically
active nitrogen containing heterocycles. During the course of that
work, we were pleased to discover that aldehydes and sulfonamides
react under rhodium(II) catalysis in the presence of an oxidant to
afford N-sulfonylcarboxamides.3,4 In this Communication, we report
the scope and limitations of this methodology as well as preliminary
mechanistic studies on this new transformation (eq 1).
1
None
PhI(OC(O)tBu)2
PhI(OAc)2
IPAC
IPAC
benzene
dichloroethane
IPAC
IPAC
IPAC
IPAC
0
14
29
79
99
61
3
2c
3c
4
Rh2(OAc)4
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(oct)4
Rh2(tfa)4
PhI(OC(O)tBu)2
PhI(OC(O)tBu)2
PhI(OC(O)tBu)2
PhI(OC(O)tBu)2
PhI(OC(O)tBu)2
PhI(OC(O)tBu)2
5d
6
7
8
Rh2(dosp)2
13
a Rh2(esp)2 ) Rh2(R,R,R′,R′,-tetramethyl-1,3-benzenedipropionate). b H-
PLC assay yield based on purified standard. c Reaction run using 1.0 equiv
benzaldehyde vs 1.2 equiv sulfonamide. d Reaction conducted at 23 and
50 °C.
Scheme 1. Plausible Mechanisms of Rhodium-Catalyzed
Coupling
We began our investigations by examining various rhodium(II)
salts in the presence of a sulfonamide, a hypervalent iodine oxidant
and an aldehyde (Table 1). Exceptional to all conditions screened
5
was the performance of Rh2(esp)2 which catalyzed the oxidative
coupling in benzene in 29% yield (Table 1, entry 3). Examination
of different solvents revealed that IPAC (isopropyl acetate) was
the best medium for this reaction. Investigation of starting material
stoichiometries revealed that a slight excess of aldehyde (1.2-1.5
equiv) was necessary to drive the sulfonamide to full conversion.6
Higher yields were obtained when PhI(OC(O)tBu)2 was used as
the oxidant. Overall, under our optimized conditions, desired
product 2a was obtained in near quantitative yield.
A variety of sulfonamides were found to react with aromatic
and aliphatic aldehydes to afford coupling products in good to
excellent yields (Table 2). Remarkable functional group tolerability
was observed with coupling occurring in the presence of nitro, aryl
halides, trifluoromethyl, activated olefins, enolizable protons, and
N-containing heterocycles. Interestingly, no products arising from
primary benzylic C-H insertion or aziridination were observed
(Table 2, entries 3, 9, and 10). Electron-poor sulfonamides make
the most efficient coupling partners, whereas more electron-rich
sulfonamides must be coupled at lower temperatures to attenuate
decomposition.7
To examine the viability of an oxaziridine intermediate presum-
ably formed via the carbonyl-imine dipole (path a), compound 3
was independently synthesized8 and subjected to the optimized
reaction conditions. While the desired product was formed under
these conditions, the rate of conversion was dramatically slower
than the observed rates for the direct oxidative coupling. Less than
50% of the desired N-sulfonylcarboxamide was formed over 24 h
as opposed to full conversion in 1 h at 0 °C in the oxidative
sulfamidation reaction. In addition, oxaziridine 3, which may be
expected to accumulate in the reaction, was not detected by in-situ
NMR monitoring (vide infra).
To test a pathway that would involve the intermediacy of a
sulfonylaldimine (path b), sulfonylaldimine 4 containing 20%
benzaldehyde was subjected to the reaction conditions. However,
conversion to either oxaziridine 3 or N-sulfonylcarboxamide 2g9
was not observed suggesting that sulfonylaldimine 4 is also unlikely
to be on the reaction pathway.
This transformation may be envisioned to proceed through
several plausible mechanisms as summarized in Scheme 1. To
differentiate between these pathways, we utilized several mecha-
nistic probes. First, a primary isotope effect (kH/kD ) 2.5) was
observed when sulfonamide (1a) was reacted with an equimolar
mixture of benzaldehyde and d6-benzaldehyde indicating that C-H
bond cleavage was occurring at the rate-determining step.
The coupling between benzene sulfonamide (1d) and 13C
(carbonyl) benzaldehyde was monitored by 13C NMR. No ac-
9
14106
J. AM. CHEM. SOC. 2007, 129, 14106-14107
10.1021/ja073872a CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Investigation of Oxidative Coupling Scope
dation was isolated in 75% yield without any signs of decarbony-
lation.14 This observation supports a nonradical-based mechanism
within the kd value of phenylacetaldehyde and is consistent with
similar radical clock experiments conducted in C-H amidation
chemistry.15
In summary, we have developed a general synthesis of N-
sulfonylcarboxamides from the oxidative coupling of sulfonamides
and aldehydes. An array of functional groups are tolerated under
the mild conditions with respect to both sulfonamide and aldehyde.
Investigations into the mechanism did not provide any evidence
for the intermediacy of an oxaziridine or sulfonylaldimine. Current
mechanistic data, including kinetic isotope effects and relative
kinetics are consistent with a reaction that proceeds through a
concerted asynchronous nitrene insertion into an aldehydic hydro-
gen. Applying this method to the synthesis of interesting medicinal
agents as well as providing additional mechanistic insight is the
subject of ongoing investigations.
Acknowledgment. We are grateful to Chris Wilde, Randy
Jensen, and Paul Schnier for NMR structural work and assistance
with isotope labeling experiments. We would also like to thank
Prof. Gregory C. Fu for helpful discussions.
Supporting Information Available: Experimental procedures and
data; tabulated NMR data and spectra of N-sulfonylcarboxamides (2a-
l). This material is available free of charge via the Internet at http://
pubs.acs.org.
References
(1) For recent reviews on nitrene insertions into C-H bonds see: (a) Mu¨ller,
P.; Fruit, C. Chem. ReV. 2003, 103, 2905. (b) Diaz-Requejo, M. M.;
Belderrain, T. R.; Nicasio, M. C.; Trofimenko, S.; Perez, P. J. J. Am.
Chem. Soc. 2003, 125, 12078. (c) He, L.; Chan, P. W. H.; Tsui, W.-M.;
Yu, W.-Y.; Che, C.-M Org. Lett. 2004 6, 2405. (d) Davies, H. M. L.;
Long, M. S. Angew. Chem., Int. Ed. 2005, 44, 3518. (e) Leung, S. K.-A;
Tsui, W. M.; Huang, J. S.; Che, C.-M.; Liang, J. L.; Zhu, N. J. Am. Chem.
Soc. 2005, 127, 16629. (f) Dick, A. R.; Sanford, M. S. Tetrahedron 2006,
62, 2439. (g) Fructos, M. R.; Trofimenko, S.; Diaz-Requejo, M. M.; Perez,
P. J. J. Am. Chem. Soc. 2006, 128, 11784. (h) Espino, C. G.; Du Bois, J.
Modern Rhodium-Catalyzed Organic Reactions; Evans, P. A., Ed.; Wiley-
VCH: Weinheim, Germany, 2005; pp 379-416.
a HPLC assay yield denoted in parentheses. b Reaction conducted at 0 °C.
(2) (a) Hinman, A.; Du Bois, J. J. Am. Chem. Soc. 2003, 125, 11510. (b)
Fleming, J. J.; Du Bois, J. J. Am. Chem. Soc. 2006, 128, 3926.
(3) For oxidative coupling of amines and aldehydes: (a) Marko, I. E.;
Mekhalfia, A. Tetrahedron Lett. 1990, 31, 7237. (b) Naota, T.; Murahashi,
S. Synlett 1991, 693. (c) Enders, D.; Amaya, A. S.; Pierre, F. New J.
Chem. 1999, 261. (d) Tillack, A.; Rudloff, I.; Beller, M. Eur. J. Org.
Chem. 2001, 523. (e) Shie, J.-J.; Fang, J.-M. J. Org. Chem. 2003, 68,
1158. (f) Lee, D.; Otte, R. D. J. Org. Chem. 2004, 69, 3569. (e) Yoo, W.
J.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 13064.
(4) For oxidative coupling of sulfonamides and aldehydes: (a) Vogt, H.;
Baumann, T.; Nieger, M.; Bra¨se, S. Eur. J. Org. Chem. 2006, 5315. (b)
Baumann, T.; Ba¨chle, M.; Bra¨se, S. Org. Lett. 2006, 8, 3797.
(5) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc.
2004, 126, 15378.
cumulation of observable intermediates was detected during the
course of reaction. Given that the rate determining step is C-H
bond cleavage, these data suggest that the C-H bond breaking and
C-N bond formation may proceed through a concerted process
(path c). To probe the electronic nature of the reaction, a competitive
rate experiment comparing p-anisaldehyde and benzaldehyde was
performed in analogy with the reported correlations of both C-H
amidation and aziridination chemistry (eq 2).10 We found a slight
increase in relative rate with p-anisaldehyde (1.5:1)11 suggesting
that the insertion itself is likely asynchronous in nature where
positive charge is accumulated on the carbonyl in the transition
state.12
(6) Benzaldehyde was found to oxidize to benzoic acid under the reaction
conditions.
(7) A reaction run in the absence of aldehyde with p-toluenesulfonamide
exhibited decomposition <15 min at 50 °C.
(8) Davis, F. A.; Chattopadhyay, S.; Towson, J. C.; Lal, S. L.; Reddy, T. J.
Org. Chem. 1988, 53, 2087.
(9) Confirmed by 1H NMR.
(10) (a) Mu¨ller, P.; Baud, C.; Jacquier, Y.; Moran, M.; Na¨geli, I. J. Phys. Org.
Chem. 1996, 9, 341. (b) Mu¨ller, P.; Baud, C.; Na¨geli, I. J. Phys. Org.
Chem. 1998, 11, 597. (c) Zhang, J.; Chan, P. W. H.; Che, C.-M.
Tetrahedron Lett. 2005, 46, 5403. (d) Fiori, K. W.; Du Bois, J. J. Am.
Chem. Soc. 2007, 129, 562.
(11) Competition of p-anisaldehyde and benzaldehyde in the amidation of ethyl
benzene afforded a 5:1 increase in relative rate.
(12) In the process of obtaining a direct Hammett correlation, we found no
significant rate changes with p-Cl, p-tBu, or p-CN. (see Supporting
Information.)
(13) Decarbonylation of phenylacetyl radical has been measured at kd ) 5.2
× 107 s-1 at 25 °C which is within the order of magnitude of other radical
clock substrates such as ethylcyclopropane (kd ) 2 × 107 s-1 (ref 10b)).
See also: Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317.
(14) Reactivity was still observed when BHT (1 equiv) was introduced to the
coupling of benzene sulfonamide (1a) and benzaldehyde.
It is plausible that during the process of oxidative C-H aldehydic
insertion, the nitrene could be acting as either a one- or two-electron
oxidant. To discern between a resonance stabilized cationic charge
in the transition state versus a C-H abstraction/radical rebound
pathway, phenyl acetaldehyde was employed in the reaction as an
acyl radical clock.13 The desired product from oxidative sulfami-
(15) Na¨geli, I.; Bernardinelli, G.; Jacquier, Y.; Moran, M.; Mu¨ller, P. HelV.
Chim. Acta 1997, 80, 1087.
JA073872A
9
J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007 14107