Nickel-catalyzed regio- and enantioselective annulation reactions of 1,2,3,4-benzothiatriazine-1,1(2H)-dioxides with allenes

Article abstract of DOI:10.1002/anie.201001918

(Figure Presented) Extrusion of N₂:1,2,3,4-Benzothiatriazine1,1 (2H)-dioxides reacted with alienes in the presence of a nickel (0)/(R)-quinap complex to produce a variety of substituted 3,4-dihydro-1,2-benzothiazine1,1 (2H)-dioxides in a regio- and enantioselective fashion. An intermediate nickelacycle was generated through denitrogenative activation of the triazo moiety which allowed the intermolecular incorporation of an aliene group. quinap = 1-(2diphenylphosphino-1-naphthyl)isoquinoline.

Full text of DOI:10.1002/anie.201001918

Angewandte
Chemie
DOI: 10.1002/anie.201001918
Asymmetric Synthesis
Nickel-Catalyzed Regio- and Enantioselective Annulation Reactions of
1,2,3,4-Benzothiatriazine-1,1(2H)-dioxides with Allenes**
Tomoya Miura, Motoshi Yamauchi, Akira Kosaka, and Masahiro Murakami*
Transition metal complexes promote various annulation
reactions, which provide efficient methods for the synthesis
of heterocyclic molecules.[1] Such reactions often involve
heteroatom-containing metalacycles as the key intermediate,
and unsaturated organic compounds are incorporated into
heterocyclic skeletons through migratory insertion and reduc-
tive elimination. It has been shown that heterocyclic com-
pounds, such as triazoles,[2] phthalimides,[3a] phthalic anhydri-
de,[3b] and isatoic anhydride[3c] serve as the precursor to
heteroatom-containing metalacycles through oxidative addi-
tion to a low-valent transition metal, and the extrusion of
gaseous molecules like N2, CO, and CO2.[4] We recently
developed a nickel-catalyzed denitrogenative annulation
reaction of 1,2,3-benzotriazin-4(3H)-ones with alkynes[5a]
and allenes,[5b] in which a five-membered ring azanickelacycle
was formed as the precursory platform. We next examined the
use of 1,2,3,4-benzothiatriazine-1,1(2H)-dioxides as a triazo
substrate for an annulation reaction because of the medicinal
importance of the resulting 1,2-benzothiazine-1,1(2H)-diox-
ide derivatives.[6] Herein, we report the enantioselective
synthesis of substituted 3,4-dihydro-1,2-benzothiazine-
1,1(2H)-dioxides by the nickel-catalyzed denitrogenative
annulation of 1,2,3,4-benzothiatriazine-1,1(2H)-dioxides
with allenes.
nesulfonamide (2a) is reduced using zinc to give ortho-amino-
N-methylbenzenesulfonamide (3a). The following HONO-
mediated ring-closing reaction affords 4a as a white solid.[7]
Initially, activation of the triazo moiety with nickel(0) was
examined using achiral phosphines in the reaction with a
mono-substituted allene, and PMe2Ph was found to be a
suitable ligand for the activation. A mixture of 4a and
cyclohexylpropa-1,2-diene (5a, 2 equiv) was heated in the
presence of [Ni(cod)2] (10 mol%) and PMe2Ph (20 mol%) in
1,4-dioxane at 1008C. Substrate 4a was consumed in 3 hours.
Workup of the reaction mixture, followed by chromato-
graphic isolation gave 3,4-dihydro-1,2-benzothiazine-
1,1(2H)-dioxide (6aa) in 84% yield as a single regioisomer
(Scheme 2). Other phosphine ligands, such as PMe3, PMePh2,
The model substrate, 2-methyl-1,2,3,4-benzothiatriazine-
1,1(2H)-dioxide (4a), can be readily prepared from ortho-
nitrobenzenesulfonyl chloride (1), which is commercially
available, in three steps (Scheme 1); 1 is coupled with
methylamine and the resulting ortho-nitro-N-methylbenze-
Scheme 2. Ni0-catalyzed denitrogenative annulation using achiral phos-
phine. cod=1,5-cyclooctadiene.
PPh3, and dppf gave inferior results. The annulation reaction
À
is considered to consist of 1) oxidative addition of the N N
bond to nickel(0), 2) extrusion of N2 to give five-membered
ring azanickelacycle A, 3) insertion of an allene to form p-
allylnickel intermediate B, and 4) allylic amidation at the
more-substituted carbon[8,9] to release 6aa and nickel(0).
Thus, the triazo moiety of 4a could be activated by
nickel(0), with the extrusion of N2. We next examined chiral
ligands using 4a and 5a as the substrates (Table 1). C2-
symmetric bidentate bisphosphine ligands, such as (S)-
binap,[10] (S,S’,R,R’)-tangphos,[11] and (R,R)-Me-duphos,[12]
were considerably inferior to PMe2Ph in terms of reactivity
(Table 1, entries 1–3). The yield and selectivity were both
improved when unsymmetrical bidentate P,N-type ligands,
such as (S,S)-iPr-foxap,[13] were employed (Table 1, entries 5
and 6). Optically active 6aa was formed stereoselectively
along with a small amount of 7aa. In particular, (R)-quinap[14]
gave the best enantioselectivity for 6aa (96%).
Scheme 1. a) NH2Me, Et3N, CH2Cl2, RT, 36h, 89%; b) Zn, NH4Cl,
MeOH, RT, 6h, 96%; c) NaNO2, HCl, EtOH, 08C, 9h, 82%.
[*] Dr. T. Miura, Dr. M. Yamauchi, A. Kosaka, Prof. Dr. M. Murakami
Department of Synthetic Chemistry and Biological Chemistry
Kyoto University, Katsura, Kyoto 615-8510 (Japan)
Fax: (+81)75-383-2748
E-mail: murakami@sbchem.kyoto-u.ac.jp
Homepage: http://www.sbchem.kyoto-u.ac.jp/murakami-lab/
[**] This work was supported by MEXT (Scientific Research on Priority
Areas “Chemistry of Concerto Catalysis” No. 20037032), the
Mitsubishi Chemical Corporation Fund, the Sumitomo Foundation,
and the Astellas Award in Synthetic Organic Chemistry (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001918.
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Table 1: Ni0-catalyzed enantioselective annulation: Screening of chiral
ligands.[a]
Table 2, entry 5). Steric repulsion arising around the bulky
tert-butyl group changed the preferred site of allylic amida-
tion to the primary allylic carbon. para-Tolyl-substituted
substrate 4g was also converted into the corresponding
product 6ga, albeit in low yield (Table 2, entry 6).
Functionalized benzo groups were briefly examined
(Scheme 3). Substrates 4h and 4i, which have electron-
donating and electron-withdrawing ring substituents, both
worked well with 5a to furnish the corresponding products
Entry[a]
Chiral ligand
Yield [%][b]
ee [%][c]
[d]
1
2
3
4
5
6
(S)-binap
<5
<5
13 (99:1)
30 (97:3)
92 (94:6)
87 (94:6)
–
–
[d]
(S,S’,R,R’)-tangphos
(R,R)-Me-duphos
(R)-(S)-ppfa
(R,R)-iPr-foxap
(R)-quinap
52
61
92
96
[a] Conditions: 4a (0.1 mmol), 5a (0.2 mmol), [Ni(cod)2] (10 mol%),
chiral ligand (10 mol%) in 1,4-dioxane (1 mL) at 608C for 6 h. [b] Total
yield of isomers: the 6aa/7aa ratio is given in parentheses. [c] Deter-
mined by HPLC analysis on a chiral stationary phase using a Chiralcel
OD-H column. [d] Not determined.
Scheme 3. Ni0-catalyzed enantioselecitve annulation: Scope of the
substituent on the benzene ring of 4.
6ha and 6ia with high yield and enantioselectivity, respec-
tively.
Various monosubstituted allenes 5 were subjected to the
annulation reaction with 4a (Table 3). The reaction pro-
ceeded smoothly at 608C to give 6 as the major product,
except in the case of tert-butylpropa-1,2-diene (5e). The
reaction of 5e was slower at 608C, probably owing to steric
reasons, and thus required a higher temperature for it to
proceed to completion. Enantioselectivities in the range 81–
85% were observed with simple allenes that contain a
primary, secondary, tertiary, or phenyl substituent (Table 3,
The scope of the substituents on the nitrogen atom of 4
was examined in the reaction with 5a using the nickel(0)/(R)-
quinap catalyst (Table 2). Primary and secondary alkyl groups
were suitable, and the corresponding products 6ba-ea were
produced with good regio- and enantioselectivities (Table 2,
entries 1–4). On the other hand, tert-butyl-substituted sub-
strate 4 f favored the formation of 7 fa (6 fa/7 fa = 13:87;
Table 2: Ni0-catalyzed enantioselecitve annulation: Scope of the sub-
stituent on the nitrogen atom of 4.[a]
Table 3: Ni0-catalyzed enantioselecitve annulation of 4a with Allenes
5b–i.[a]
Entry
4
R1
6
7
Yield [%][b]
ee [%][c]
Entry
5
R2
6
7
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
4b
4c
4d
4e
4 f
Et
Bn
PMB
iPr
tBu
p-Tol
6ba
6ca
6da
6ea
6 fa
6ga
7ba
7ca
7da
7ea
7 fa
7ga
84 (92:8)
97
97
91
88
74 (94:6)[d]
69 (98:2)[d]
77 (91:9)[e]
67 (13:87)[f]
28 (88:12)
1
2
3
4
5
6
7
8
5b
5c
5d
5e
5 f
5g
5h
5i
n-Hex
CH2Cy
c-Pent
tBu
Ph
6ab
6ac
6ad
6ae
6af
6ag
6ah 7ah
6ai 7ai
7ab
7ac
7ad
7ae
7af
87 (96:4)
92 (98:2)
97 (97:3)
92 (87:13)[d]
99 (86:14)
98 (91:9)
91 (93:7)
95 (93:7)
85
81
85
84
85
72
73
76
[g]
-
4g
86
(CH2)2OTBS
(CH2)2OBn
(CH2)2N(Phth)
7ag
[a] Conditions: 4 (0.1 mmol), 5a (0.2 mmol), [Ni(cod)2] (10 mol%), (R)-
quinap (10 mol%) in 1,4-dioxane (1 mL) at 1008C for 12 h unless
otherwise noted. [b] Total yield of isomers: the 6/7 ratio is given in
parentheses. [c] Determined by HPLC analysis using a chiral column.
[d] Using toluene (1 mL). [e] Using [Ni(cod)2] (20 mol%), (R)-quinap
(20 mol%). [f] Using [Ni(cod)2] (20 mol%), (R)-quinap (20 mol%) at
1208C. [g] Not determined. PMB=para-methoxybenzyl.
[a] Conditions: 4a (0.1 mmol), 5 (0.2 mmol), [Ni(cod)2] (10 mol%), (R)-
quinap (10 mol%) in THF/CH3CN (0.5:0.5 mL) at 608C for 3–12 h.
[b] Total yield of isomers: the 6/7 ratio is given in parentheses.
[c] Determined by HPLC analysis on a chiral stationary phase. [d] 808C.
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entries 1–5). Functional groups such as siloxy, benzyloxy, and
N-phthalimidoyl groups on the alkyl chains were tolerated
under the reaction conditions, although the enantioselectiv-
ities decreased to 72–76% ee (Table 3, entries 6–8).
The para-methoxybenzyl group in the product 6da was
easily removed on treatment with trifluoroacetic acid to give
the unprotected 3,4-dihydro-1,2-benzothiazine-1,1(2H)-diox-
ide 8a with retention of the enantiopurity [Eq. (1)].[15]
Keywords: annulation · asymmetric synthesis · nickel ·
nitrogen heterocycles · synthetic methods
.
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Furthermore, product 6aa could be derivatized to b-
methylphenethylamine 10aa by stereoselective hydrogena-
tion and subsequent reductive removal of the SO2 moiety
[Eq. (2)].[16] There are only a few reports in the literature on
its preparation with high diastereo- and enantioselectivi-
ties.[17]
[5] a) T. Miura, M. Yamauchi, M. Murakami, Org. Lett. 2008, 10,
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[6] a) E. W. Brooke, S. G. Davies, A. W. Mulvaney, M. Okada, F.
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[7] For the synthesis of 2-phenyl-1,2,3,4-benzothiatriazine-1,1(2H)-
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analysis and impact-sensitivity testing.
In summary, we have demonstrated that a highly reactive
azanickelacycle can be generated from 1,2,3,4-benzothiatria-
zine-1,1(2H)-dioxide through extrusion of N2. The azanickel-
acycle incorporates a variety of allenes in a regio- and
enantioselective manner, providing a new synthetic route to
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Experimental Section
Typical procedure for the nickel-catalyzed annulation reaction: In an
N2-filled glove-box, 4a (39.7 mg, 0.20 mmol), [Ni(cod)2] (5.6 mg,
0.02 mmol), (R)-quinap (8.8 mg, 0.02 mmol), 1,4-dioxane (2 mL), and
5a (58 mL, 0.40 mmol) were added at room temperature to an oven-
dried 4 mL vial containing a stirrer bar. The vial was sealed with a
Teflon cap and taken out of the glove box. After being heated at 608C
for 6 h, the reaction mixture was cooled to room temperature and
stirred for 1 h in open air. The resulting mixture was passed through a
pad of Florisil and eluted with ethyl acetate. The filtrate was
concentrated under reduced pressure. The residue was purified by
preparative thin-layer chromatography (hexane/ethyl acetate 5:1) to
give an isomeric mixture of 6aa and 7aa (50.7 mg, 0.17 mmol, 87%
total yield, 6aa/7aa = 94:6). The enantiomeric excess of the major
[10] R. Noyori, H. Takaya, Acc. Chem. Res. 1990, 23, 345.
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[14] N. W. Alcock, J. M. Brown, D. I. Hulmes, Tetrahedron: Asym-
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[15] B. Hill, Y. Liu, S. D. Taylor, Org. Lett. 2004, 6, 4285.
[16] W. Zeng, S. R. Chemler, J. Am. Chem. Soc. 2007, 129, 12948.
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À
isomer 6aa was determined by HPLC analysis using a Chiralcel OD
H column.
Received: March 31, 2010
Published online: June 8, 2010
Angew. Chem. Int. Ed. 2010, 49, 4955 –4957
ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
4957