Exploring new uses for C-H amination: Ni-catalyzed cross-coupling of cyclic sulfamates

Article abstract of DOI:10.1021/ol051896l

(Chemical Equation Presented) Benzene-fused cyclic sulfamates are prepared from ortho-substituted phenolic starting materials through selective C-H amination or olefin aziridination. These unique heterocycles will engage in Ni-catalyzed cross-coupling reactions with aryl- and alkyl-Grignard reagents. Application of modern tools for C-N and C-C bond formation thus makes readily available functional amine derivatives and augments the possible uses for C-H amination in synthesis.

Full text of DOI:10.1021/ol051896l

ORGANIC
LETTERS
2005
Vol. 7, No. 21
4685-4688
Exploring New Uses for C−H
Amination: Ni-Catalyzed Cross-Coupling
of Cyclic Sulfamates
Paul M. Wehn and J. Du Bois*
Department of Chemistry, Stanford UniVersity, Stanford, California 94305-5080
jdubois@stanford.edu
Received August 7, 2005
ABSTRACT
Benzene-fused cyclic sulfamates are prepared from ortho-substituted phenolic starting materials through selective C
aziridination. These unique heterocycles will engage in Ni-catalyzed cross-coupling reactions with aryl- and alkyl-Grignard reagents. Application
of modern tools for C N and C C bond formation thus makes readily available functional amine derivatives and augments the possible uses
for C H amination in synthesis.
−H amination or olefin
−
−
−
The advent of new methods for the selective amination of
C-H and CdC bonds has facilitated the synthesis of unique
heterocyclic structures.1 1,2,3-Oxathiazinane-2,2-dioxides
represent one such class of products that are assembled
efficiently and stereoselectively through oxidative cyclization
of primary sulfamate esters.2 The strong bias for six-
membered ring formation is a distinguishing feature of this
process. The same reaction conditions that promote insertion
at sp3 centers, however, do not effect the amination of aryl
C-H bonds. Consequently, we have been able to develop a
high yielding preparation of benzo-fused oxathiazinane
heterocycles 2 from ortho-substituted phenolic sulfamates 1
(Figure 1). Such compounds, although not without precedent,
have received little attention in synthesis.3,4 As highlighted
in this report, 3,4-dihydro-1,2,3-benzoxathiazine-2,2-dioxides
2 and related cyclic structures can serve as effective starting
materials for cross-coupling reactions with Grignard re-
agents.5 The combination of modern catalytic tools for C-H
amination and C-C bond formation thereby affords rapid
entry to important functionalized amines, constituents of both
natural and synthetic products.
(1) (a) Espino, C. G.; Du Bois, J. In Modern Rhodium-Catalyzed Organic
Reactions; Evans, P. A., Ed.; Wiley-VCH: Weinheim, 2005; pp 379-416.
(b) Halfen J. A. Curr. Org. Chem. 2005, 9, 657-669. (c) Mu¨ller, P.; Fruit,
C. Chem. ReV. 2003, 103, 2905-2920. (d) Dauban, P.; Dodd, R. H. Synlett
2003, 1571-1586.
(2) Espino, C. G.; Wehn, P. M.; Chow, J.; Du Bois, J. J. Am. Chem.
Soc. 2001, 123, 6935-6936.
(3) (a) Peters, R. H.; Chao, W.-R.; Sato, B.; Shigeno, K.; Zaveri, N. T.;
Tanabe, M. Steroids 2003, 68, 97-110. (b) Dhar, D. N.; Bag, A. K. Indian
J. Chem. 1983, 22B, 627-631. (c) Stokker, G. E.; Deana, A. A.; deSolms,
S. J.; Schultz, E. M.; Smith, R. L.; Cragoe, E. J., Jr.; Baer, J. E.; Russo, H.
F.; Watson, L. S. J. Med. Chem. 1982, 25, 735-742.
Figure 1. Applications in cross-coupling for products of C-H
amination.
10.1021/ol051896l CCC: $30.25
© 2005 American Chemical Society
Published on Web 09/17/2005

Phenolic sulfamates 1 may be conveniently prepared by
either of two protocols using ClSO2NCO or ClSO2NH2.6
These crystalline compounds react with PhI(OAc)2, MgO,
and 2 mol % Rh2(OAc)4 to give the desired benzoxathiazine
products (e.g., 4-6, Figure 2) in high yield. In all cases that
cross-coupling conditions employed led simply to cleavage
of the acyl moiety and returned the parent heterocycle. Our
subsequent efforts thus turned to the N-methylated deriva-
tive 13, which was easily prepared following a standard
protocol.12
A preliminary test of 13 against several Ni and Pd salts
revealed Ni(dppp)Cl2 as an optimal catalyst for cross-
coupling of MeMgBr (entries 5 and 9, Table 1).13,14
Table 1. Screen of Reaction Conditions for Cross-Coupling
entry
catalyst
solvent
% conversiona
1
2
3
4
5
6
7
8
Ni(dppe)Cl2
Ni(PPh3)Cl2
Ni(acac)2
Ni(dppf)Cl2
Ni(dppp)Cl2
Ni(cod) + dppp
Ni(dppp)Cl2
Ni(dppp)Cl2
Ni(dppp)Cl2
Pd(dppf)Cl2
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
C6H5CF3
C6H6
C6H6
<5
20
70
100b
100
<5
<5
40
Figure 2. Oxidative methods for the preparation of benzo-fused
cyclic sulfamates.
we have examined, no products resulting from aryl C-H
insertion are observed. Alternatively, unsaturated sulfamates,
as exemplified by 7, will cyclize under oxidizing conditions
to furnish bicyclic aziridines (e.g., 8).7,8 Subsequent nucleo-
philic addition of alcohols or H2O to 8 occurs selectively to
furnish the rather unusual eight-membered ring structures 9
and 10.9
9
10c
100
<5
a Reactions performed at 25 °C; conversion based on 1H NMR analysis
of the unpurified reaction mixture. b The desired product was formed in
addition with other unidentified materials. c Reaction performed at 55 °C.
Despite their structural homology to triflates and tosylates,
sulfamate esters and oxathiazines had, to our knowledge,
never been described as partners in cross-coupling reactions.10
An initial screen of catalysts and nucleophiles examined the
use of various Ni and Pd salts with Grignard reagents,
boronic acids, and mono- or dialkyl zinc reagents. To
minimize potential side reactions, benzoxathiazine 11 was
chosen as the test substrate for investigation (eq 1). We
Somewhat surprisingly, however, the combination of Ni(cod)2
and dppp failed to give any of the amine product 14, as only
starting material was recovered (entry 6). Reactions con-
ducted with alternative Ni2+ phosphine adducts typically
afforded some of the desired compound, although consump-
tion of benzoxathiazine 13 was incomplete. Palladium
catalysts, on the other hand, showed very little activity
regardless of the ligand employed. The choice of solvent
also proved critical for successful cross coupling. Weakly
coordinating (Et2O) or noncoordinating (C6H6) solvents were
(9) We and others have observed aziridine ring opening in these types
of bicyclic sulfamates to be strongly biased for nucleophilic attack at the
internal C-N bond; see ref 7 for examples. Wehn, P. M.; Du Bois, J.
Unpublished results.
(10) A very recent report by Snieckus highlights Ni-catalyzed cross-
coupling reactions of N,N-diethyl-O-phenylsulfamates with ArMgX reagents;
see: Macklin, T. K.; Snieckus, V. Org. Lett. 2005, 7, 2519-2522.
(11) N-Acylation of aliphatic oxathiazinanes increases dramatically the
rate of nucleophilic displacement of the C-O bond; see ref 2.
(12) These conditions have also been employed to synthesize N-nPr, iPr,
iBu, allyl, Bn, and PMB derivatives,
reasoned that N-acylation of 11 might facilitate oxidative
addition of the reduced metal species into the C-O bond.11
This modification proved ineffective, however, as almost all
(4) Contemporaneous work by Fruit and Mu¨ller has also demonstrated
oxidative cyclization reactions of phenolic sulfamates; see: Fruit, C.; Mu¨ller,
P. Tetrahedron: Asymmetry 2004, 15, 1019-1026.
(5) We refer to such heterocycles as benzoxathiazines for short.
(6) With ClSO2NCO, see: Kamal, A.; Rao, A. B.; Sattur, P. B. J. Org.
Chem. 1988, 53, 4112-4114. The method using ClSO2NH2 is generally
preferred. For a representative procedure, see ref 2.
(7) For examples of intramolecular aziridination of homoallyl sulfamate
esters, see: (a) Wehn, P. M.; Lee, J.; Du Bois, J. Org. Lett. 2003, 5, 4823-
4826. (b) Duran, F.; Leman, L.; Ghini, A.; Burton, G.; Dauban, P.; Dodd,
R. H. Org. Lett. 2002, 4, 2481-2483.
(8) The product of benzylic C-H insertion is formed in trace amounts
(<5%).
(13) Related conditions were described by Snieckus for Kumada-type
reactions with aryl carbamates and aryl triflates; see: Sengupta, S.; Leite,
M.; Raslan, D. S.; Quesnelle, C.; Snieckus, V. J. Org. Chem. 1992, 57,
4066-4068. Also see: (a) Milburn, R. R.; Snieckus, V. Angew. Chem.,
Int. Ed. 2004, 43, 888-891. (b) Dankwardt, J. W. Angew. Chem., Int. Ed.
2004, 43, 2428-2432. (c) Cho, C.-H.; Yun, H.-S.; Park, K. J. Org. Chem.
2003, 68, 3017-3025. (d) Dallaire, C.; Kolber, I.; Gingras, M. Org. Synth.
2000, 78, 42-50.
(14) We have tested both PhLi and nBuLi with Ni(dppp)Cl2 but have
observed none of the cross-coupled products. A small amount (∼10%) of
biaryl material was obtained when 3 equiv of PhZnBr was employed.
4686
Org. Lett., Vol. 7, No. 21, 2005

superior to 1,2-dimethoxyethane (DME), dioxane, and THF,
the latter of which appears to greatly inhibit the reaction and
gives isolable amounts of the product arising formally from
C-O bond reduction (vide infra).15
(PMB) groups can be employed, however, and thus con-
veniently removed if desired from the amine product.
Kumada-type coupling of N-alkyl cyclic sulfamates against
a variety of Grignard reagents demonstrates the versatility
of this method (Table 2). As a general rule, both alkyl- and
arylmagnesium salts may be employed with 5 mol % of the
Ni catalyst. In one notable exception (entry 2), use of
tBuMgBr as a cross-coupling partner led to reduction of the
C-O bond. This latter result is in accord with other
observations we have made that show the considerable
influence of steric factors on reaction performance. Accord-
ingly, attempts to cross-couple oxathiazine 15 (eq 2) with
The protocol for Ni(dppp)Cl2-catalyzed cross-coupling of
benzoxathiazine 13 now established, variation of both the
N-alkyl group on 11 and the Grignard reagent was explored.
n
i
Replacement of the N-Me group with either Pr, Bu, or
benzyl (Bn) did not adversely affect the reaction performance
i
(Table 2). Conversely, the use of Pr, CH3OCH2 (MOM),
Table 2. Cross-Coupling of Cyclic Sulfamates with RMgX
MeMgBr using Ni catalysts have proven unsuccessful.16
Nevertheless, the current state of the art makes available a
large number of structurally disparate amine derivatives from
readily available components. The desired products are
obtained following a requisite acid workup to cleave the
sulfated amine intermediate.17 In many cases, products are
then purified by chromatography; alternatively, isolation of
highly polar compounds is facilitated by acylating the impure
material with (CF3CO2)O or Boc2O. Finally, as a demonstra-
tion of the overall ease of operation and utility of this
protocol, the cross-coupling reaction shown in entry 4 (Table
2) was conducted on a 1 g scale with 2 mol % Ni(dppp)Cl2
n
and 1.3 equiv of BuMgCl. Under these conditions, the
secondary amine is furnished in 86% yield.
The ineffectiveness of the cross-coupling reaction in THF
and the isolation of the C-O reduced product (e.g., 18,
Figure 3) prompted an investigation of the reaction mech-
Figure 3. Experimental test confirms â-hydride elimination of
Ni2+-alkyl intermediate.
a Reactions performed with 5 mol % Ni(dppp)Cl2 and 2 equiv RMgX at
0.1 M in substrate. b Product isolated following treatment of the unpurified
amine with (CF3CO2)2O. Yield is reported for two steps. c Reaction
performed with 10 mol % catalyst. d Reaction performed at 25 °C. e Reaction
t
performed with 2 mol % catalyst. f TBS ) BuMe2Si; product isolated
anism. Such findings are suggestive of a pathway involving
the intermediacy of aryl radical species.18 An experiment
conducted with 17 in d8-THF, however, gave no incorpora-
following treatment of the unpurified amine with (Boc)2O. Yield is reported
for two steps.
(15) Similar findings have been observed in Ni-catalyzed cross-coupling
when THF was used as solvent; see: Tamao, K.; Sumitani, K.; Kiso, Y.;
Zembayashi, M.; Fujioka, A.; Kodama, S.; Nakajima, I.; Minato, A.;
Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49, 1958-1969.
(16) Starting material was recovered quantitatively.
(17) Kim, B. M.; Sharpless, K. B. Tetrahedron Lett. 1989, 30, 655-
658.
and allyl as N-blocking groups either decreased product yield
or inhibited the reaction altogether. The lack of reactivity
observed with the N-allylated benzoxathiazine is not surpris-
ing given that the allyl moiety is rapidly cleaved under the
reaction conditions. Both benzyl and p-methoxybenzyl
Org. Lett., Vol. 7, No. 21, 2005
4687

tion of a deuterium label. Presumably, the reduced product
18 follows from â-hydride elimination of the Ni-alkyl
species, [(dppp)Ni(aryl)(nBu)]. For reasons not entirely
transparent, this side reaction is promoted in a more polar
added, aryl-substituted amines and expands the number of
possible uses for Rh-mediated C-H amination in synthesis.
Acknowledgment. P.M.W. is the recipient of an Eli Lilly
graduate fellowship. This work was funded by grants from
the NSF and the Beckman Foundation, and with generous
gifts from Abbott, Amgen, Boehringer Ingelheim, Bristol-
Myers Squibb, Eli Lilly, GlaxoSmithKline, Johnson Matthey,
Merck, and Pfizer.
-
solvent such as THF. We speculate that the pendant SO3
group may play a role in stabilizing the Ni2+ intermediate
and that THF could promote its dissociation from the metal,
thereby triggering the unproductive â-hydride elimination.
Selective amination of sp3 C-H bonds enables the
preparation of a large and varied number of benzo-fused
heterocyclic sulfamate structures. These compounds, interest-
ing in their own right, can function as electrophilic partners
with Ni-catalyzed cross-coupling reaction of Grignard re-
agents.19 Such chemistry thus offers easy access to value-
Supporting Information Available: General experimen-
tal protocols and characterization data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL051896L
(18) A mechanism involving a Ni+/Ni3+ cycle has been discussed for
related Kumada couplings; see: (a) Tasler, S.; Lipshutz, B. H. J. Org. Chem.
2003, 68, 1190-1199. (b) Tsou, T. T.; Kochi, J. K. J. Am. Chem. Soc.
1979, 101, 7547-7560.
(19) Initial investigations have demonstrated coupling of ArB(OH)2 to
benzoxathiazines with both Ni(IMes)Cl2 and certain Pd catalysts.
4688
Org. Lett., Vol. 7, No. 21, 2005