Oxidative cyclization of sulfamate esters using NaOCl - A metal-mediated Hoffman-L?ffler-Freytag reaction

Article abstract of DOI:10.1055/s-0028-1087392

Intramolecular C-H amination with sulfamate esters occurs under the action of dinuclear Rh catalysts and iodine(III) oxidants, and has recently emerged as a powerful tool for synthesis. Insights gained through mechanistic studies of this process suggest t

Full text of DOI:10.1055/s-0028-1087392

CLUSTER
143
Oxidative Cyclization of Sulfamate Esters Using NaOCl – A Metal-Mediated
Hoffman–Löffler–Freytag Reaction
O
xidative Cyclizat
a
ionof Sulfa
v
mate
E
stersid N. Zalatan, J. Du Bois*
Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA
E-mail: jdubois@stanford.edu
Received 2 September 2008
O
O
O
O
Rh2(O2CR)4
(1–2 mol%)
Abstract: Intramolecular C–H amination with sulfamate esters oc-
curs under the action of dinuclear Rh catalysts and iodine(III) oxi-
dants, and has recently emerged as a powerful tool for synthesis.
Insights gained through mechanistic studies of this process suggest
that other terminal oxidants, including common halogenating
agents such as NaOCl, could function to promote the cyclization re-
action. Results described in this report demonstrate that the combi-
nation of NaOCl and 3 mol% Rh2(oct)4 is effective in select cases
for converting sulfamate substrates to the corresponding [1,2,3]-
oxathiazinane-2,2-dioxide heterocycles. The mechanism for C–H
functionalization, however, is distinct from that induced by hyper-
S
S
S
S
H2N
O
HN
O
PhI(OAc)2
MgO
R
R
R
O
O
O
O
catalyst
H2N
O
HN
O
Cl+ or Br+
oxidant
R
Scheme 1 Identifying new oxidants for sulfamate ester cyclization
valent iodine reagents and likely involves the intermediacy of an N-
centered radical.
O
O
O
O
O
O
Br
S
Br
S
Br+
base
Key words: C–H amination, catalysis, rhodium, bleach, oxathia-
zinane
N
O
N
O
S
H2N
Ph
O
H
Na
1
Ph
Ph
O
O
2
3
Br
S
Catalytic methods for C–H and p-bond amination have
emerged recently as selective and practical tools for fine-
chemicals synthesis.1 Starting from any one of a number
of amine derivatives (e.g., carbamates, ureas, guanidines,
sulfamates, sulfonamides, sulfamides), intramolecular C–H
insertion is effected under the action of a dinuclear Rh(II)
catalyst and a diacyloxyiodobenzene oxidant (Scheme 1).
Experimental and theoretical studies suggest that this pro-
cess occurs through an iodoimine (RN = IPh), which is in-
tercepted by the Rh complex to generate a transient
metallonitrene intermediate.2,3 The reactive nitrenoid is
capable of oxidizing C–H bonds and does so through a
concerted asynchronous insertion step. Consideration of
this mechanism as well as reports describing the applica-
tion of chlora- and bromamine-T [TsN(Na)X] as ‘nitrene’
equivalents have led us to examine alternative oxidants in
place of PhI(O2CR)2.4–7 These studies ask whether a sur-
rogate species of the iodoimine can be generated in situ
under conditions compatible with the dirhodium complex.
The discovery of substitute oxidants for the C–H amina-
tion process has important practical consequences as well
as the potential to bring with it the identification of new
catalyst systems.
N
O
catalytic
Rh2(O2CR)4
LnRh
4
O
O
O
N
O
O
O
LnRh
H
LnRh
S
S
S
– NaBr
HN
O
O
N
O
Ph
Ph
Ph
7
6
5
Scheme 2 A proposed catalytic cycle that mirrors the reaction with
hypervalent iodine oxidants
NaBr (i.e., NaOBr) under biphasic alkaline conditions
(CH2Cl2, aq Na2HPO4) affords N-bromosulfamate 2.8 Al-
though this material is not formed cleanly and attempts to
isolate 2 were not made, the combination of these reagents
and 3 mol% Rh2(oct)4 results in an efficient cyclization
event to furnish the corresponding [1,2,3]-oxathiazinane-
2,2-dioxide 7 (Scheme 3).9,10 While other brominating
agents such as N-bromosuccinimide and Br2 can be used
in place of NaOCl/NaBr, none give results that are com-
parable to our optimized protocol.11,12
Following these exploratory investigations, analysis of
the reaction scope began to expose striking differences be-
tween this process and that employing PhI(OAc)2 as the
terminal oxidant (Table 1).13
The reported reactivity of haloamine-T salts with metal
catalysts for C–H and p-bond functionalization led us to
examine initially reactions of 1 with common halogenat-
ing agents (Scheme 2).6 The admixture of NaOCl and
Both electron-rich and electron-deficient 3-arylpropyl-
sulfamate derivatives are consumed completely under the
NaOCl/NaBr conditions to give the respective hetero-
cycles (Table 1, entry 1). The decreased yield of the p-
methoxyphenyl substrate is likely the result of overoxida-
tion of the oxathiazinane and does not stem from an inher-
SYNLETT 2009, No. 1, pp 0143–0146
x
x.
x
x.
2
0
0
8
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087392; Art ID: S08108ST
© Georg Thieme Verlag Stuttgart · New York

144
D. N. Zalatan, J. Du Bois
CLUSTER
The inability to oxidize the tertiary C–H bond in isoamyl-
sulfamate provided the first indication that the NaOCl/
NaBr reaction was, in all likelihood, not proceeding
through an intermediate Rh-nitrene. Our previous work to
develop amination chemistry has established that sub-
strates possessing tertiary centers are among the very best
for intramolecular Rh-catalyzed insertion.2b,c In light of
the result from entry 4 (Table 1), we speculated that a
stepwise mechanism involving the formation of an N-cen-
tered radical might be operative under the NaOCl/NaBr
conditions. While such supposition does not account for
all of the observed performance trends (i.e., the inability
to effect cyclization of the indole substrate), it is consis-
tent with a reaction process that favors benzylic over ter-
tiary C–H oxidation. Accordingly, we wondered if metal
salts or complexes other than Rh2(oct)4 could catalyze
oxathiazinane formation.
O
O
Rh2(oct)4
(3 mol%)
O
O
S
S
H2N
Ph
O
HN
O
63% isolated
yield
NaOCl, NaBr
Ph
CH2Cl2/aq Na2HPO4
1
7
Scheme 3
Table 1 Sulfamate Ester Oxidation with NaOCl
Entry Substrate
Product
Yield (%)a
O
O
O
O
S
S
HN
O
H2N
O
R = CF3 71
1
R = OMe 33b
R
R
O
O
O
O
S
S
Attempts to oxidize sulfamate 1 using different metal cat-
alysts delivered surprising results (Table 2). While none
of the complexes tested performed more effectively than
Rh2(oct)4, all gave discernible amounts of product. Subse-
quent studies further demonstrated that ambient light
could promote modest conversion of 1 to oxathiazinane 7.
The photochemically driven process could be further im-
proved by the addition of 0.5 equivalent of ZnCl2 (100%
conversion). These data provide circumstantial evidence
for a reaction mechanism that parallels the classic
Hoffman–Löffler–Freytag (HFL) and proceeds through a
reactive amidyl species.15
HN
O
H2N
O
Me
Me
2
3
85
TsN
N
TsN
N
Me
Me
O
O
O
O
S
S
H2N
O
HN
O
10c
N
N
Boc
Boc
O
O
O
O
S
S
H2N
O
HN
O
4
5
0
0
Table 2 Oxidation Reaction Promoted by Different Metal Catalysts
Me
Me
Me
Me
O
O
O
O
O
S
S
H2N
O
catalyst (10 mol%)
H2N
Ph
O
HN
O
HN
O
O
NaOCl, NaBr
Ph
CH2Cl2/aq Na2HPO4
1
7
Catalyst
Conversion
(%)
Catalyst
Conversion
(%)
a Reaction performed with 3 mol% Rh2(oct)4, NaOCl, NaBr in
CH2Cl2–Na2HPO4 (aq); yields are based on isolated material.
b Product overoxidation is likely responsible for reduced yield.
c Yield is estimated based on analysis of the unpurified 1H NMR
spectrum.
none
trace
30
RhCl2
MnCl2
20
20
65
50
FeCl2
CuCl2
ZnCl2
30
Mn(salen)Cl
ent inefficiency in the cyclization reaction. Oxidation of
3-heteroaryl-substituted sulfamates affords surprisingly
disparate results, with the pyrazole adduct proving to be
one of the top performing substrates (entry 2). By con-
trast, the indole-based sulfamate gives only trace product,
returning mostly starting material instead (entry 3). The
same substrate, when treated with a Rh-tetracarboxylate
catalyst and PhI(OAc)2 affords >75% yield of the oxa-
thiazinane product.13a Other disparities between the
NaOCl/NaBr protocol and that employing PhI(OAc)2 are
noted in reactions of isoamylsulfamate and 2-phenethyl-
carbamate (entries 4 and 5). Neither of these substrates
form product under the former set of conditions; both cy-
clize efficiently, however, when treated with a Rh-tetra-
carboxylate catalyst and PhI(OAc)2.13a,14
trace
ambient hn
Two additional experiments were performed to give
weight to our mechanistic hypothesis. Oxidation of the
optically enriched, tertiary benzylic substrate 8 would be
expected to give product of reduced enantiopurity for a
process involving the intermediate formation of a carbon-
centered radical (Scheme 4). When subjected to the reac-
tion conditions, sulfamate 8 afforded a modest yield of ra-
cemic oxathiazinane 9 in addition to tertiary alcohol 10.
The alcohol product does not cyclize under the reaction
conditions; its formation is likely the result of hydrolysis
of the corresponding tertiary bromide. The same starting
material 8 has been oxidized with catalytic Rh2(oct)4 and
Synlett 2009, No. 1, 143–146 © Thieme Stuttgart · New York

CLUSTER
Oxidative Cyclization of Sulfamate Esters
145
PhI(OAc)2, conditions that result in the stereospecific for-
mation of the heterocycle. As a final control experiment,
N,N-dimethylsulfamate 11 was treated with Rh2(oct)4 and
NaOCl/NaBr (Scheme 5). This substrate, without the abil-
ity to form an N-halogenated species, is entirely unreac-
tive towards the oxidizing mixture.
O
O
O
O
O
O
Br
S
Br
S
NaOCl
NaBr
N
O
N
O
S
H2N
Ph
O
H
–Br•
Na
1
Ph
Ph
O
O
2
3
S
N
O
MLn
catalyst
LnM
O
O
O
O
O
O
Rh2(oct)4
(3 mol%)
14
S
S
S
H2N
O
HN
O
HO
O
NH2
O
O
O
O
O
O
S
S
S
NaOCl, NaBr
aq Na2HPO4
CH2Cl2
Ph
Ph
Ph
HN
O
LnMHN
O
LnMHN
Ph
O
Me
Me
9, 17%
racemic
Me
10, 51%
Ph
Ph
8
Br
99% ee
7
16
15
Scheme 6 Proposed catalytic cycle for NaOCl-based oxidation pro-
ceeds through amidyl intermediate 14
Scheme 4 Optical purity of the starting material is not preserved
Collectively, these data have led us to postulate a stepwise
mechanism for sulfamate oxidation with NaOCl/NaBr
(Scheme 6). The process is reminiscent of the HFL reac-
tion, requiring N-halogenation as a first step.15 Metal- or
light-promoted decomposition of this intermediate results
in the generation an N-centered radical 14, which is capa-
ble of abstracting a benzylic C–H bond. Benzylic haloge-
nation and subsequent intramolecular SN2 displacement
afford the oxathiazinane product. Although we have never
isolated a benzylic bromide derivative, the formation of
such an intermediate is inferred from isolation of 10.16
References and Notes
(1) For general reviews, see: (a) Espino, C. G.; Du Bois, J. In
Modern Rhodium-Catalyzed Organic Reactions; Evans,
P. A., Ed.; Wiley-VCH: Weinheim, 2005, 379–416.
(b) Dauban, P.; Dodd, R. H. Synlett 2003, 1571. (c) Halfen,
J. A. Curr. Org. Chem. 2005, 9, 657. (d) Lebel, H.;
Leogane, O.; Huard, K.; Lectard, S. Pure Appl. Chem. 2006,
78, 363. (e) Li, Z. G.; He, C. Eur. J. Org. Chem. 2006, 4313.
(f) Davies, H. M. L.; Manning, J. R. Nature (London) 2008,
451, 417. (g) Díaz-Requejo, M. M.; Pérez, P. J. Chem. Rev.
2008, 108, 3379.
(2) (a) Müller, P.; Baud, C.; Nägeli, I. J. Phys. Org. Chem. 1998,
11, 597. (b) Fiori, K. W.; Du Bois, J. J. Am. Chem. Soc.
2007, 129, 652. (c) Fiori, K. W.; Espino, C. G.; Brodski,
B. H.; Du Bois, J. Tetrahedron, in press.
(3) Lin, X.; Zhao, C.; Che, C.-M.; Ke, Z.; Phillips, D. L. Chem.
Asian J. 2007, 2, 1101.
We have developed an operationally simple procedure for
C–H amination using NaOCl as the terminal oxidant. This
process is mechanistically distinct from analogous reac-
tions that employ hypervalent iodine reagents, and likely
occurs through amidyl-directed C–H halogenation.17 Al-
beit limited in scope when compared to other C–H amina-
tion methods, the application of this chemistry in select,
large-scale processes may have considerable value. These
findings also raise questions as to the operative mecha-
nism in catalytic systems that utilize haloamine-T re-
agents and have been suggested to take place through
nitrenoid pathways.
(4) (a) Vyas, R.; Chanda, B. M.; Bedekar, A. V. Tetrahedron
Lett. 1998, 39, 4715. (b) Albone, D. P.; Aujla, P. S.; Taylor,
P. C. J. Org. Chem. 1998, 63, 9569. (c) Simkhovich, L.;
Gross, Z. Tetrahedron Lett. 2001, 42, 8089. (d) Chanda,
B. M.; Vyas, R.; Bedekar, A. V. J. Org. Chem. 2001, 66, 30.
(e) Gullick, J.; Taylor, S.; McMorn, P.; Bethell, D.;
Bulman Page, P. C.; Hancock, F. E.; King, F.; Hutchings, G.
J. Mol. Catal. A. 2002, 180, 85. (f) Kumar, G. D. K.;
Baskaran, S. Chem. Commun. 2004, 1026. (g) Vyas, R.;
Gao, G.-Y.; Harden, J. D.; Zhang, X. P. Org. Lett. 2004, 6,
1907. (h) Albone, D. P.; Challenger, S.; Derrick, A. M.;
Fillery, S. M.; Irwin, J. L.; Parsons, C. M.; Takada, H.;
Taylor, P. C.; Wilson, D. J. Org. Biomol. Chem. 2005, 3,
107. (i) Fructos, M. R.; Trofimenko, S.; Díaz-Requejo,
M. M.; Pérez, P. J. J. Am. Chem. Soc. 2006, 128, 11784.
(j) Bhuyan, R.; Nicholas, K. M. Org. Lett. 2007, 9, 3957.
(k) Harden, J. D.; Ruppel, J. V.; Gao, G.-Y.; Zhang, X. P.
Chem. Commun. 2007, 4644. (l) Antunes, A. M. M.;
Bonifácio, V. D. B.; Nascimento, S. C. C.; Lobo, A. M.;
Branco, P. S.; Prabhakar, S. Tetrahedron 2007, 63, 7009.
(5) N-Arylsulfonyloxycarbamates have been shown to be
effective for C–H and p-bond amination, see: (a) Barani,
M.; Fioravanti, S.; Pellacani, L.; Tardella, P. A. Tetrahedron
1994, 50, 11235. (b) Lebel, H.; Huard, K.; Lectard, S. J. Am.
Chem. Soc. 2005, 107, 14198. (c) Lebel, H.; Huard, K. Org.
Lett. 2007, 9, 639. (d) Liu, R.; Herron, S. R.; Fleming, S. A.
J. Org. Chem. 2007, 72, 5587.
Rh2(oct)4
(3 mol%)
O
O
O
O
S
S
Me2N
O
R
O
NMe2
no reaction
X
NaOCl, NaBr
Ph
Ph
Me
11
Me
aq Na2HPO4
CH2Cl2
12: R = Br
13: R = OH
Scheme 5 No observed reaction of N,N-dimethylsulfamate ester
Acknowledgment
D.N.Z. is supported by an Achievement Rewards for College Scien-
tists (ARCS) Foundation Stanford Graduate Fellowship. This work
has been made possible in part by a grant from the NIH and with
gifts from Pfizer, Amgen, and GlaxoSmithKline.
Synlett 2009, No. 1, 143–146 © Thieme Stuttgart · New York

146
D. N. Zalatan, J. Du Bois
CLUSTER
mixture was stirred for 2 h, following which time the
reaction was quenched by the addition of 1.0 mL of 1.0 M aq
NaHSO3. The contents were transferred to a separatory
funnel with CH2Cl2 (10 mL) and H2O (5 mL). The organic
layer was collected and the aqueous layer was extracted with
CH2Cl2 (1 × 10 mL). The combined organic fractions were
dried over Na2SO4 and concentrated under reduced pressure
to a yellow oil. Purification of this material by
(6) For Fe- and Cu-catalyzed amination using N-bromosuccin-
imide, see: (a) Wang, Z.; Zhang, Y.; Hua, F.; Jiang, Y.;
Zhao, Y. Org. Lett. 2008, 10, 1863. (b) Liu, X.; Zhang, Y.;
Wang, L.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2008,
73, 6207.
(7) Amination reactions have been performed with peroxide
oxidants. For select examples, see: (a) Kohmura, Y.;
Kawasaki, K.-i.; Katsuki, T. Synlett 1997, 1456.
(b) Pelletier, G.; Powell, D. A. Org. Lett. 2006, 8, 6031.
(c) Thu, H.-Y.; Yu, W.-Y.; Che, C.-M. J. Am. Chem. Soc.
2006, 128, 9048. (d) Zhang, Y.; Fu, H.; Jiang, Y.; Zhao, Y.
Org. Lett. 2007, 9, 3813.
chromatography on SiO2 (hexanes–EtOAc) afforded the
desired oxathiazinane product.
(13) (a) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am.
Chem. Soc. 2001, 123, 6935. (b) Wehn, P. M.; Lee, J.;
Du Bois, J. Org. Lett. 2003, 5, 4823.
(14) Espino, C. G.; Du Bois, J. Angew. Chem. Int. Ed. 2001, 40,
598.
(15) (a) Wolff, M. E. Chem. Rev. 1963, 63, 55. (b) Mackiewicz,
P.; Furstoss, R. Tetrahedron 1978, 34, 3241. (c) For a
modern-day variant of the HFL reaction, see: Chen, K.;
Richter, J. M.; Baran, P. S. J. Am. Chem. Soc. 2008, 130,
7247.
(16) Consistent with the proposed mechanism, when N-methyl-3-
phenylpropylsulfamate is subjected to the reaction
conditions, an oxidized product is formed. This material has
been tentatively assigned as N-methyl-3-bromo-3-phenyl-
sulfamate.
(8) Tentative structural assignment of 2 is based on 1H NMR
analysis of the reaction mixture.
(9) The rather modest isolated yield of this material is likely due
to product overoxidation. Analysis of the 1H NMR spectrum
of the unpurified reaction mixture is quite clean, however.
We assume that product(s) of overoxidation are removed in
the aqueous workup.
(10) (a) We have found that Rh2(a,a,a¢,a¢-tetramethyl-1,3-
benzenedipropionate)2 [also known as Rh2(esp)2, see ref.
10b] gives results comparable to those of Rh2(oct)4.
(b) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am.
Chem. Soc. 2004, 126, 15378.
(11) The overall efficiency of the reaction is reduced when NaBr
is excluded.
(12) Optimized Reaction Protocol
(17) In general, reactions of iodoimine derivatives with certain
metal catalysts (e.g., complexes of Mn, Fe, Ru, Cu) afford
amine derivatives through an apparent C–H abstraction–
radical rebound-type mechanism. For examples, see ref. 1
and: (a) Mahy, J.-P.; Bedi, G.; Battioni, P.; Mansuy, D.
Tetrahedron Lett. 1988, 29, 1927. (b) Mahy, J.-P.; Bedi, G.;
Battioni, P.; Mansuy, D. New J. Chem. 1989, 13, 651.
To a biphasic solution of CH2Cl2 (2.5 mL) and sat. Na2HPO4
(2.5 mL, pH ca. 9) was added sequentially sulfamate (0.25
mmol), Rh2(oct)4 (6 mg, 7.5 mmol, 0.03 equiv), and NaBr (77
mg, 0.75 mmol, 3.0 equiv). The reaction flask was wrapped
in aluminum foil prior to the dropwise addition of 1.6 M aq
NaOCl (Acros, 470 mL, 0.75 mmol, 3.0 equiv). The biphasic
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