Asymmetric synthesis of isothiazoles through Cu catalysis: Direct catalytic asymmetric conjugate addition of allyl cyanide to α,β-unsaturated thioamides

Article abstract of DOI:10.1002/anie.201102467

Twice the catalyst: The simultaneous activation of an allyl cyanide (pronucleophile) and an α,β-unsaturated thioamide (electrophile) was achieved using a Cu-based soft Lewis acid/hard Bronsted base cooperative catalyst, thus resulting in the formation of

Full text of DOI:10.1002/anie.201102467

Communications
DOI: 10.1002/anie.201102467
Homogeneous Catalysis
Asymmetric Synthesis of Isothiazoles through Cu Catalysis: Direct
Catalytic Asymmetric Conjugate Addition of Allyl Cyanide to a,b-
Unsaturated Thioamides**
Yuka Yanagida, Ryo Yazaki, Naoya Kumagai,* and Masakatsu Shibasaki*
Heterocycles are frequently used in pharmaceutical sciences
owing to their wide range of biological activities. A number of
isothiazole derivatives manifest specific biological activities,[1]
e.g. antiproliferative,[2] antiviral,[3] and antipsychotic,[4] and
are applicable as bioisosteric replacements of isoxazoles to
enhance lipophilicity. The common synthetic protocol for
isothiazoles is a halogen-mediated oxidative coupling of a
sulfur atom and a nitrogen atom that are tethered by a three-
carbon unit (Scheme 1a).[1] Herein, we document a distinct
The process not only represents an unprecedented route to
the isothiazole nucleus, but also demonstrates the power of
Cu catalysis; all three bond-forming events were promoted by
a Cu catalyst which is a soft Lewis acid and exhibits redox
characteristics.
We have been engaged in a program aimed at the
development of soft Lewis acid/hard Brønsted base cooper-
ative catalysis, specifically for the activation of soft Lewis
basic substrates.[5,6] Recently, we reported the simultaneous
activation of soft Lewis basic pronucleophiles and electro-
philes, represented by the catalytic asymmetric conjugate
addition of terminal alkynes to a,b-unsaturated thioamides 1
under proton-transfer conditions.[7] Although a,b-unsaturated
thioamides 1 have received little attention in asymmetric
catalysis,[8] their specific activation by a soft Lewis acid and
divergent transformation of the thioamide functionality high-
light their potential utility. In this context, we envisaged the
catalytic asymmetric conjugate addition of other soft Lewis
basic pronucleophiles to a,b-unsaturated thioamides 1. We
selected allyl cyanide (2) as the soft Lewis basic pronucleo-
phile.[6a,b,d,9,10] Initial studies based on a soft Lewis acid/hard
Brønsted base cooperative catalyst[6,7] comprised of a cationic
CuI salt/chiral bisphosphine ligand/Li aryloxide revealed that
a [Cu(CH3CN)4]PF6/(R)-DTBM-segphos/Li(OC6H4-p-OMe)
catalytic system promoted the asymmetric conjugate addition
of 2 to 1 (Table 1). Although the catalytic efficiency was not
satisfactory with 5 mol% of the catalyst, 2 underwent
exclusive g addition to 1a to afford the Z-configured a,b-
unsaturated nitrile 3a in 83% ee (Table 1, entry 1). The use of
a catalytic amount of phosphine oxide as a hard Lewis base
was previously found to enhance the Brønsted basicity of
Li(OC6H4-p-OMe) through a hard–hard interaction with the
Li cation,[11] thus facilitating the deprotonation of the
relatively weakly acidic pronucleophile 2 to trigger the
reaction.[6d,12] The soft Lewis acid/hard Brønsted base/hard
Lewis base ternary catalytic system was successful in the
present reaction, as evidenced by the significant improvement
in the yield (Table 1, entries 2–6). Bisphosphine oxides 4 and
5 exhibited higher conversion, albeit with the concomitant
formation of unidentified by-products. The reaction with
ꢀ
ꢀ
approach through a cascade C C and S N bond formation
promoted by Cu catalysis to furnish the isothiazole nucleus
(Scheme 1b). The requisite substrates, containing thioamide
and nitrile functionalities, were synthesized by a Cu-catalyzed
asymmetric conjugate addition of allyl cyanide to a,b-
unsaturated thioamides under proton-transfer conditions.
Scheme 1. Formation of isothiazoles.
[*] Y. Yanagida, R. Yazaki, Dr. N. Kumagai, Prof. Dr. M. Shibasaki
Institute of Microbial Chemistry, Tokyo
3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021 (Japan)
E-mail: nkumagai@bikaken.or.jp
mshibasa@bikaken.or.jp
Homepage: http://www.bikaken.or.jp/research/group/shibasaki/
shibasaki-lab/index.html
Y. Yanagida, R. Yazaki
Graduate School of Pharmaceutical Sciences
The University of Tokyo
=
Ph3P O in EtOAc was determined to be optimal, with
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033 (Japan)
minimal formation of by-products (Table 1, entry 6).[13]
Decreasing either the catalyst loading or the amount of 2
led to a marginally lower conversion (Table 1, entries 7 and
8). When either CuI or Li aryloxide was removed from the
catalytic system, this impaired catalyst failed to promote the
reaction (Table 1, entries 9 and 10), thus confirming the
cooperative nature of a soft Lewis acid and hard Brønsted
[**] This work was financially supported by a Grant-in-Aid for Scientific
Research (S) from JSPS. N.K. thanks the Sumitomo Foundation for
financial support. R.Y. thanks JSPS for a predoctoral fellowship. Dr.
M. Shiro at Rigaku Corporation is gratefully acknowledged for X-ray
crystallographic analysis of 7a and the enamine derived from 11.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201102467.
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Table 1: Initial screening.[a]
Entry
x
y
Phosphine oxide
[mol%]
Solvent
t
[h]
Yield[b]
[%]
ee
[%]
1
2
3
4
5
6
7
8
5
5
5
5
5
5
5
2
5
5
5
5
5
5
5
5
2
5
5
5
–
toluene
toluene
toluene
toluene
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
AcOEt
24
24
24
24
24
24
22
22
24
24
9
83
95
95
95
97
97
96
97
–
4 (5)
5 (5)
Ph3P O (5)
5 (5)
Ph3P O (5)
=
Ph3P O (5)
Ph3P O (5)
Ph3P O (5)
76
81
74
77
84
77
54
0
=
Scheme 2. Cu-thioamide enolate as a Brønsted base.
=
cycle, thereby demonstrating efficient proton-transfer catal-
ysis. The more convenient [Cu(CH3CN)4]PF6/LiHMDS
system provided a similar reaction outcome. The present
catalyst system failed to promote the reaction of the
corresponding N,N-dibenzylcinnamamide, thus indicating
that simultaneous activation of both the pronucleophile and
the electrophile is crucial.
=
=
9[c]
10[d]
=
Ph3P O (5)
0
–
[a] Used 0.2 mmol of 1a. [b] Determined by 1H NMR analysis using 2-
methoxynaphthalene as an internal standard. [c] The reaction was
performed without [Cu(CH3CN)4]PF6/(R)-DTBM-segphos. [d] The reac-
tion was performed without Li(OC6H4-p-OMe). DTBM=3,5-di-tert-butyl-
4-methoxy.
The g and Z selectivity are consistent in the reaction of a
range of thioamides 1, as summarized in Table 2.[16] The
reaction can be performed on a gram scale without any
detrimental effects (Table 2, entry 2). The ortho substituent
had a negative impact on the enantioselectivity (Table 2,
entry 3). The reactivity of the a,b-unsaturated thioamide 1
was dependent on its electronic nature; the reaction with
halogenated substrates 1d–f proceeded rapidly (Table 2,
entries 5–7), whereas the methoxy-substituted substrates
required an elevated temperature to complete the reaction
(Table 2, entries 8 and 9). The reaction with b-3-pyridyl
thioamide 1i proceeded with a mesitylcopper catalyst to
afford 3i with high enantioselectivity, albeit with moderate
yield (Table 2, entry 10).[17] b-Alkyl thioamides 1j–1l were
also suitable substrates, thus affording the corresponding
products with excellent enantioselectivity for the Z product
(Table 2, entries 11–13). A careful inspection of the by-
products in the reaction of 1a and 2 revealed that a small
amount of isothiazole 7a was formed (Figure 2).[18] The
comparable enantiomeric purity of 7a indicated that 7a was
produced through the conjugate addition product 3a by the
proposed mechanism delineated in Table 3. When the isolated
3a was subjected to CuOTf/Li(OC6H4-p-OMe), in 50 mol%
and 1.1 equiv, respectively, isothiazole 7a was obtained in
98% yield (entry 1). CuOTf/Li(OC6H4-p-OMe) generated
the copper thioamide enolate of 3a, which would
base. The exclusive Z-olefin formation is intriguing and can
be ascribed to the simultaneous activation of 1a and 2
(Figure 1). The initially formed a-C-copper nucleophile
proceeds to the eight-membered transition state upon coor-
dination of 1a; in this transition state the terminal olefin is
located s-cis to the nitrile group and overlaps with the
b position of 1a from the Re face. The reaction through the
g-C-copper nucleophile by 1,3-transposition[14] would be
unlikely because of the anticipated formation of the E,Z mix-
ture of the g-C-copper nucleophile. The intermediary copper
thioamide enolate 6 functioned as a Brønsted base to
generate the active nucleophile, as revealed by the control
experiments outlined in Scheme 2. A mesitylcopper[15] cata-
lyst initiated the reaction by irreversible deprotonation of 2,
followed by enantioselective addition to 1a, and the thus
formed 6 deprotonated 2 to drive the subsequent catalytic
subsequently undergo 6-exo-dig cyclization to give
CuI imide 8a. The oxidation or disproportiona-
tion[19] of 8a along with a deprotonation would lead
to CuII complex 9a, and the subsequent reductive
ꢀ
elimination would form a S N bond to afford 7a
and Cu0.[20] Re-oxidation of Cu0 was reluctant, and
a substoichiometric amount of CuI salt was essen-
tial to reach completion, even in an oxygen
atmosphere (Table 3, entries 2 and 3). Oxidant
screening revealed that TEMPO functioned as an
effective oxidant in the presence of a catalytic
Figure 1. Plausible transition state.
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Table 2: Catalytic asymmetric conjugate addition of allyl cyanide (2) to
Table 3: A proposed mechanism of isothiazole formation and optimi-
a,b-unsaturated thioamide 1.[a]
zation.[a]
Entry Thioamide 1
Product
T
[8C]
t
[h]
Yield[b]
[%]
ee
[%]
R
1
Ph
Ph
1a
1a
1b
1c
1d
1e
1 f
1g
1h
1i
3a
3a
3b
3c
3d
3e
3 f
3g
3h
3i
0
0
0
0
0
0
0
40
40
0
0
40
40
2
3
9
3.5
1.5
3
81
87
77
85
81
82
82
63
43
40
83
80
64
97
97
87
97
98
97
97
89
99
93
99
99
98
2[c]
3
Entry
CuOTf
(x mol%)
Oxidant
t
[h]
Yield[b]
[%]
o-MeC6H4
p-MeC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
o-MeOC6H4
p-MeOC6H4
3-pyridyl
Me
4
5
6
7
1
2
3
4
5
6
7
8
50
10
30
10
10
10
10
0
–
–
16
16
16
24
24
24
24
24
98
16
6
O2 atmosphere (1 atm)
TEMPO (1.1 equiv)
NMO (1.1 equiv)
pyridine N-oxide (1.1 equiv)
TEMPO (1.1 equiv)
TEMPO (1.1 equiv)
3
24
73[c]
36
33
69[c]
0
8
9[d]
10[e]
11
12[d]
13[d]
24
3
21
20
21
1j
1k
1l
3j
3k
3l
iPr
cHex
[a] Used 0.2 mmol of 3a. [b] Determined by 1H NMR analysis using 2-
methoxynaphthalene as an internal standard. [c] Yield of the isolated
product. Bn=benzyl, NMO=N-methylmorpholine N-oxide,
TEMPO=2,2,6,6-tetramethylpiperidine-N-oxyl, Tf=trifluoromethane-
sulfonyl, THF=tetrahydrofuran.
[a] Used 0.2 mmol of 1 and 1.0 mmol of 2. [b] Yield of the isolated
product. [c] 1.20 g of 1 was used. [d] Yield was determined by 1H NMR
spectroscopic analysis using 2-methoxynaphthalene as an internal
standard. [e] 5 mol% of mesitylcopper/(R)-DTBM-segphos was used as
the catalyst.
isothiazole-forming reaction was applicable to other conju-
gate addition products (3) to furnish enantioenriched fused
isothiazoles (Scheme 3). However, the hydrogenated sub-
strate 3a’ did not provide the corresponding isothiazole 7a’,
thus suggesting that the conformational restriction by a Z-
configured olefin is indispensable to the initial 6-exo-dig
cyclization [Eq. (2)]. The catalytic asymmetric conjugate
Figure 2. Ortep drawing of isothiazole 7a.
amount of Cu to afford 7a from 3a (Table 3, entries 4–6).[21]
The amount of TEMPO could be reduced to 0.1 equiv and no
reaction proceeded in the absence of CuOTf (Table 3,
entries 7 and 8).[22] Although intermediate 8a (or its proton-
ated form) was not isolated, a two-step reaction sequence
using iPrMgBr and then CuOTf for the reaction of N,N-
dibenzylthioacetamide and benzonitrile afforded isothiazole
10 via intermediate 11,[23] thus suggesting that isothiazole 7a
was likely formed through 8a [Eq. (1)].[24] The Cu-catalyzed
addition and isothiazole formation could be performed in a
one-pot Cu-based catalysis, thus showcasing the dual roles of
Cu as a soft Lewis acid and redox catalyst [Eq. (3)].
In summary, we have developed a new route to enan-
tioenriched fused isothiazoles. The substrates for a Cu-
catalyzed cascade cyclization were obtained by a catalytic
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Angew. Chem. Int. Ed. 2009, 48, 5026; c) M. Iwata, R. Yazaki,
Y. Suzuki, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2009,
131, 18244; d) R. Yazaki, N. Kumagai, M. Shibasaki, J. Am.
Chem. Soc. 2010, 132, 5522.
[7] R. Yazaki, N. Kumagai, M. Shibasaki, J. Am. Chem. Soc. 2010,
132, 10275.
[8] For a,b-unsaturated thioamides as electrophiles, see: alkyl-
lithium or magnesium: a) Y. Tamaru, T. Harada, H. Iwamoto, Z.
Yoshida, J. Am. Chem. Soc. 1978, 100, 5221; b) Y. Tamaru, M.
Kagotani, Z. Yoshida, Tetrahedron Lett. 1981, 22, 3409; c) Y.
Tamaru, T. Harada, S. Nishi, Z. Yoshida, Tetrahedron Lett. 1982,
23, 2383; lithium enolates: d) Y. Tamaru, T. Harada, Z. Yoshida,
J. Am. Chem. Soc. 1979, 101, 1316; nitroalkanes: e) J. G.
Scheme 3. Cu-catalyzed isothiazole formation. [a] Yield of the isolated
product.
´
Sosnicki, Tetrahedron 2009, 65, 1336.
[9] For allylic cyanides as pronucleophiles, see: a) P. B. Kisanga,
J. G. Verkade, J. Org. Chem. 2002, 67, 426; b) J. Aydin, K. J.
Szabꢂ, Org. Lett. 2008, 10, 2881.
[10] For the catalytic asymmetric conjugate addition of allylic groups
to electron-deficient olefins with organometallic reagents, see:
a) J. D. Sieber, J. P. Morken, J. Am. Chem. Soc. 2008, 130, 4978;
b) M. Shizuka, M. L. Snapper, Angew. Chem. 2008, 120, 5127;
Angew. Chem. Int. Ed. 2008, 47, 5049.
[11] For a comprehensive review of Lewis base catalysis, see: S. E.
Denmark, G. L. Beutner, Angew. Chem. 2008, 120, 1584; Angew.
Chem. Int. Ed. 2008, 47, 1560, and references therein.
[12] Other possibilities that cannot be ruled out at this stage:
1) phosphine oxide accelerated the conversion of the initially
formed lithiated allyl cyanide into an a-C-copper nucleophile or
asymmetric conjugate addition of allyl cyanide (2) to a,b-
unsaturated thioamides 1 by soft Lewis acid/hard Brønsted
base/hard Lewis base cooperative catalysis. The soft Lewis
acidic nature and redox characteristics of copper were
successfully coupled to form three covalent bonds in a
catalytic manner. Application of the present protocol to the
synthesis of biologically active compounds is ongoing.
Received: April 9, 2011
Published online: July 5, 2011
Keywords: allyl cyanides · asymmetric catalysis · cyclization ·
2) shifted the equilibrium between {CuPF6
+ LiOAr} and
.
homogeneous catalysis · isothiazoles
{CuOAr + LiPF6} to the latter.
[13] The solvent effect was thoroughly studied. See the Supporting
Information.
[14] G. Sklute, I. Marek, J. Am. Chem. Soc. 2006, 128, 4642, and
references therein.
[1] For a general review, see: F. Clerici, M. L. Gelmi, S. Pellegrino,
D. Pocar, Top. Heterocycl. Chem. 2007, 9, 179.
[15] a) T. Tsuda, T. Yazawa, K. Watanabe, T. Fujii, T. Saegusa, J. Org.
Chem. 1981, 46, 192; b) E. M. Meyer, S. Gambarotta, C. Floriani,
A. Chiesi-Villa, C. Guastini, Organometallics 1989, 8, 1067.
Mesitylcopper prepared by the procedure described in Ref. [15a]
was used.
[16] The reaction with pent-3-enenitrile (g-methyl allyl cyanide) did
not proceed under the optimized reaction conditions. In
entries 9, 12, and 13, the chromatographic separation of the
substrate and the product was difficult and the chemical yield
determined by 1H NMR was reported.
[17] The reaction using a [Cu(CH3CN)4]PF6/(R)-DTBM-segphos/
Li(OC6H4-p-OMe) catalyst (5 mol%) resulted in low yield
(5%), probably because of the competitive coordination of the
pyridine moiety of 1i, thus disturbing the effective deprotona-
tion of 2. The mesitylcopper/(R)-DTBM-segphos system, in the
absence of aryloxide and protonated p-methoxyphenol,
appeared to partially circumvent the low reaction efficiency
owing to the more efficient deprotonation of 2 through Cu
thioamide enolate 6.
[2] a) E. E. Swayze, J. C. Drach, L. L. Wotring, L. B. Townsend, J.
Med. Chem. 1997, 40, 771; b) J. S. Beebe, J. P. Jani, E. Knauth, P.
Goodwin, C. Higdon, A. M. Rossi, E. Emerson, M. Finkelstein,
E. Floyd, S. Harriman, J. Atherton, S. Hillerman, C. Soderstrom,
K. Kou, T. Gant, M. C. Noe, B. Foster, F. Rastinejad, M. A.
Marx, T. Schaeffer, P. M. Whalen, W. G. Roberts, Cancer Res.
2003, 63, 7301.
[3] a) A. Garozzo, C. C. C. Cutrꢀ, A. Castro, G. Tempera, F.
Guerrera, M. C. Sarvꢁ, E. Geremia, Antiviral Res. 2000, 45,
199; b) S. Yan, T. Appleby, E. Gunic, J. H. Shim, T. Tasu, H. Kim,
F. Rong, H. Chen, R. Hamatake, J. Z. Wu, Z. Hong, N. Yao,
Bioorg. Med. Chem. Lett. 2007, 17, 28.
[4] a) H. R. Howard, J. A. Lowe III, T. F. Seeger, P. A. Seymour,
S. H. Zorn, P. R. Maloney, F. E. Ewing, M. E. Newman, A. W.
Schmidt, J. S. Furman, G. L. Robinson, E. Jackson, C. Johnson, J.
Morrone, J. Med. Chem. 1996, 39, 143; b) T. Shiwa, T. Amano, H.
Matsubayashi, T. Seki, M. Sasa, N. Sakai, Jpn. J. Pharmacol. Sci.
2003, 93, 114.
[5] For, recent reviews on cooperative catalysis, see: a) J.-A. Ma, D.
Cahard, Angew. Chem. 2004, 116, 4666; Angew. Chem. Int. Ed.
2004, 43, 4566; b) H. Yamamoto, K. Futatsugi, Angew. Chem.
2005, 117, 1958; Angew. Chem. Int. Ed. 2005, 44, 1924; c) T.
Ikariya, K. Murata, R. Noyori, Org. Biomol. Chem. 2006, 4, 393;
d) D. H. Paull, C. J. Abraham, M. T. Scerba, E. Alden-Danforth,
T. Lectka, Acc. Chem. Res. 2008, 41, 655; e) J.-K. Lee, M. C.
Kung, H. H. Kung, Top. Catal. 2008, 49, 136; f) Y. J. Park, J.-W.
Park, C.-H. Jun, Acc. Chem. Res. 2008, 41, 222; g) M. Shibasaki,
M. Kanai, S. Matsunaga, N. Kumagai, Acc. Chem. Res. 2009, 42,
1117, and references therein.
[18] The absolute configuration of 7a was determined by X-ray
crystallographic analysis. CCDC 820988 (7a) contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Summary of crystallographic analysis and the crystal structure
was provided in Supporting Information.
[19] 2CuIÐCu0 + CuII is assumed.
[20] The possibility of reductive elimination via a CuIII intermediate
to give CuI and 7a cannot be ruled out. See the Supporting
Information for further discussion.
[6] a) R. Yazaki, T. Nitabaru, N. Kumagai, M. Shibasaki, J. Am.
Chem. Soc. 2008, 130, 14477; b) Y. Suzuki, R. Yazaki, N.
Kumagai, M. Shibasaki, Angew. Chem. 2009, 121, 5126;
[21] The oxidation of 8a to 9a was likely mediated by TEMPO as
well as O2.
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[22] TEMPO would be regenerated by O2 dissolved in the solvent.
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif. Summary of crystallographic analysis and the crystal
structure was provided in Supporting Information.
For the reoxidation of TEMPO-OH to TEMPO by oxygen, see:
P. Gamez, I. W. C. E. Arends, R. A. Sheldon, J. Reedijk, Adv.
Synth. Catal. 2004, 346, 805.
[24] Recently, the concomitant formation of benzoisothiazole was
reported in the CuI-catalyzed alkylation of S-acyl 2-mercapto-
acetophenone oxime with arylboronic acid or arylstannanes, see:
Z. Zhang, M. G. Lindale, L. S. Liebeskind, J. Am. Chem. Soc.
2011, 133, 6403.
[23] The enamine derived from 11 was characterized by NMR
spectroscopy and X-ray crystallographic analysis. See the
Supporting Information for details. CCDC 820989 (11) contains
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
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