Direct catalytic asymmetric addition of acetonitrile to N-thiophosphinoylimines

Article abstract of DOI:10.1039/c3cc47117a

Direct catalytic addition of acetonitrile pronucleophiles to thiophosphinoylimines is described. Soft Lewis acid-hard Bronsted base cooperative catalysis is crucial to promote this elusive carbon-carbon bond-forming reaction in an enantioselective fashion

Full text of DOI:10.1039/c3cc47117a

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Direct catalytic asymmetric addition of acetonitrile to
N-thiophosphinoylimines†
Yuji Kawato,ab Naoya Kumagai*a and Masakatsu Shibasaki*ac
Cite this: Chem. Commun., 2013,
49, 11227
Received 17th September 2013,
Accepted 10th October 2013
DOI: 10.1039/c3cc47117a
www.rsc.org/chemcomm
Direct catalytic addition of acetonitrile pronucleophiles to thiophos-
phinoylimines is described. Soft Lewis acid–hard Brønsted base
cooperative catalysis is crucial to promote this elusive carbon–
carbon bond-forming reaction in an enantioselective fashion.
Enantioselective catalysis for carbon–carbon bond-forming
reactions to construct enantioenriched carbon frameworks
has been a sustained subject in organic chemistry. In contrast to
extensive research devoted to catalytic carbon–carbon bond for-
mation based on enolate nucleophiles,1 the catalytic asymmetric
addition of a-cyano carbanions derived from nitriles has been
much less explored.2 The rich chemistry of enolate as a privileged
carbon nucleophile fostered the development of direct-type
catalytic asymmetric addition of unmodified enolate precursors,
in which enolates are catalytically generated in situ and undergo
subsequent carbon–carbon bond-forming reactions. This direct-
type methodology obviates the mandatory preparation of enolate
in a separate step and allows for atom-economical access to the
identical reaction products. In contrast to the significant advances
in direct-type reactions of carbonyl-type enolate precursors,3,4
Fig. 1 Direct catalytic asymmetric addition of nitrile pronucleophiles
imines 1.
2 to
direct carbanion formation from alkylnitriles has been rarely reactive pronucleophiles under mild basic conditions.6–8 However,
achieved in a catalytic fashion because of their poorly acidic only a limited number of catalytic systems that were able to
nature (e.g., CH3CN: pKa = 31.3 in DMSO5). In fact, acetonitrile promote the direct addition of alkylnitriles have been revealed,
and propionitrile, the simplest alkylnitriles, are generally regarded even in racemic reactions (Fig. 1b).9 In 2005, we reported direct
as inert chemical entities and frequently used as solvents. To catalytic asymmetric addition of acetonitrile to aldehydes using a
circumvent the intrinsic reluctance of nitriles to generate a-cyano catalyst consisting of CuOtBu and chiral phosphine ligands, in
carbanions, appendages of anion-stabilizing substituents, e.g., which the highest enantioselectivity was 77% ee.10 Obviously, the
electron-withdrawing groups, aromatic groups, and a vinyl group direct use of a low acidic alkylnitrile as a pronucleophile in
have been used (Fig. 1a). Indeed, the introduction of an aromatic catalytic asymmetric carbon–carbon bond-forming reactions is
or vinyl group significantly increases the acidity of the a-proton, still in its infancy and, to the best of our knowledge, there is no
and phenylacetonitrile and allylic cyanide have been exploited as report on a catalytic asymmetric direct addition of alkylnitrile to
imines.11,12 In our continuing program on nitrile pronucleophiles,
a Institute of Microbial Chemistry (BIKAKEN), Tokyo, 3-14-23 Kamiosaki,
Shinagawa-ku, Tokyo 141-0021, Japan. E-mail: nkumagai@bikaken.or.jp,
mshibasa@bikaken.or.jp; Fax: +81-3-3441-7589
we envisaged the enantioselective addition of in situ-generated
a-cyano carbanions derived from acetonitrile to N-thiophos-
phinoylimines. The simultaneous activation strategy through
soft–soft interaction was the key to promote this elusive reaction
in a catalytic manner.
b Graduate School of Pharmaceutical Sciences, The University of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Tokyo, Japan
c JST, ACT-C, 3-14-23 Kamiosaki, Shinagawa-ku, Tokyo 141-0021, Japan
† Electronic supplementary information (ESI) available: Experimental procedures
and characterization of new compounds. See DOI: 10.1039/c3cc47117a
In our study on the Cu-based soft Lewis acid–hard Brønsted
base cooperative catalytic system,13 we were convinced that
c
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Chem. Commun., 2013, 49, 11227--11229 11227

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activation of the nitrile functionality by a soft Lewis acid
allowed for the deprotonation of acetonitrile under mild basic
conditions. To facilitate the subsequent addition to imines,
we envisioned that using imines bearing a soft Lewis basic
functionality leads to the productive association of activated
nucleophiles and electrophiles around the soft Lewis acid in a
chiral environment. In this context, we selected N-thiophos-
phinoylimine 3a14 derived from benzaldehyde as the electro-
phile of choice and conducted an initial screening of the
reaction conditions (Table 1). With 10 mol% of the cationic
copper source [Cu(CH3CN)4]PF6 as the soft Lewis acid and
KOtBu as the hard Brønsted base, various types of chiral
bisphosphine ligands were screened (entries 1–9). Low conversion
was observed in reactions with (R,R)-Ph-BPE and (R)-QuinoxP
(entries 1 and 2). (R)-DTBM-Segphos and (R,Rp)-Walphos produced
the desired adduct 4a in high yield, albeit with low enantioselectivity
(entries 5 and 7). Ferrocene-embedded bisphosphine ligand
(R,Rp)-Ph-Taniaphos gave the highest enantioselectivity (30% ee)
Fig. 2 Attempts at reaction using N-phosphinoylimine 5.
(entry 9), which was further improved to 44% ee by changing the
solvent from DMF to DME (entry 12). Although Et3N was totally
ineffective as the Brønsted base,15 amidine or guanidine base
promoted the catalytic generation of a-cyano carbanions from
acetonitrile and higher yields were obtained without affecting the
enantioselectivity (entries 14 and 15). The use of MS 3A was
beneficial to prevent hydrolysis of imine 3a and higher chemical
yield was observed with prolonged reaction time (entry 16). No
reaction proceeded at all in the absence of soft Lewis acid Cu(I) or
Brønsted base, suggesting that cooperative catalysis was crucial to
catalytic generation of the a-cyano carbanion (entries 17 and 18).
Moreover, under the optimized reaction conditions (entry 16), the
reaction using analogous N-phosphinoylimine 5 without the soft
Lewis basic functionality barely proceeded (Fig. 2), indicating that
the simultaneous activation of acetonitrile and N-thiophosphinoyl-
imines was operative.
Table 1 Initial screeninga
Time Yieldb eec
Table 2 Direct catalytic asymmetric addition of acetonitrile to N-thiophosphi-
noylimines 3a
Entry Ligand
Base
Solvent (h)
(%)
(%)
1
2
3
4
5
6
7
8
(R,R)-Ph-BPE
(R)-QunioxP
(R)-BINAP
KOtBu
KOtBu
KOtBu
KOtBu
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
THF
24
24
24
24
24
24
24
24
24
24
31
22
34
61
95
72
99
81
77
65
21
44
—
65
75
81
—
—
À6
À24
À8
À5
À17
À16
À13
7
30
36
45
44
—
43
43
47
—
—
(R)-Difluorphos
(R)-DTBM-Segphos KOtBu
(R)-Josiphos
(R)-Walphos
KOtBu
KOtBu
(R,Rp)-Cy-Taniaphos KOtBu
(R,Rp)-Ph-Taniaphos KOtBu
(R,Rp)-Ph-Taniaphos KOtBu
(R,Rp)-Ph-Taniaphos KOtBu
(R,Rp)-Ph-Taniaphos KOtBu
(R,Rp)-Ph-Taniaphos Et3N
(R,Rp)-Ph-Taniaphos DBU
9
10
11
12
13
14
15
16 f
17 f
18 f, g
CPMEd 24
DMEe 24
DME
DME
24
24
24
40
40
40
(R,Rp)-Ph-Taniaphos Barton’s base DME
(R,Rp)-Ph-Taniaphos Barton’s base DME
(R,Rp)-Ph-Taniaphos
—
DME
—
Barton’s base DME
a
b
3a: 0.2 mmol, solvent–CH3CN = 5/1, 0.1 M in 3a. Yield was deter-
mined by 1H NMR analysis with 1,1,2,2-tetrachloroethane as an internal
standard. ee was determined by HPLC analysis. Minus sign indicates
the formation of the S enantiomer as the major enantiomer. Cyclo-
pentyl methyl ether. 1,2-Dimethoxyethane. MS 3A was used as an
c
d
e
f
a
3: 0.2 mmol, DME–CH3CN = 10/1, 0.1 M in 3. Isolated yields are
g
additive. DME–CH3CN = 10/1. Without [Cu(CH3CN)4]PF6.
shown.
c
11228 Chem. Commun., 2013, 49, 11227--11229
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4 For reviews of direct Mannich(-type) reactions, see: (a) M. M. B.
Marques, Angew. Chem., Int. Ed., 2006, 45, 348; (b) A. Ting and
S. E. Schaus, Eur. J. Org. Chem., 2007, 5797; (c) J. M. M. Verkade,
L. J. C. van Hemert, P. J. L. M. Quaedflieg and F. P. J. T. Rutjes,
Chem. Soc. Rev., 2008, 37, 29.
5 F. G. Bordwell, Acc. Chem. Res., 1988, 21, 456.
6 Examples of catalytic asymmetric addition using benzylnitriles:
´
(a) J. Aydin, C. S. Conrad and K. J. Szabo, Org. Lett., 2008,
10, 5175; (b) K. Hyodo, S. Nakamura, K. Tsuji, T. Ogawa,
Y. Funahashi and N. Shibata, Adv. Synth. Catal., 2011, 353, 3385.
7 Examples of catalytic asymmetric addition using allyl cyanide:
(a) R. Yazaki, T. Nitabaru, N. Kumagai and M. Shibasaki, J. Am.
Chem. Soc., 2008, 130, 14477; (b) R. Yazaki, N. Kumagai and
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N. Kumagai and M. Shibasaki, J. Am. Chem. Soc., 2010, 132, 5522;
(d) Y. Yanagida, R. Yazaki, N. Kumagai and M. Shibasaki, Angew.
Chem., Int. Ed., 2011, 50, 7910; (e) Y. Otsuka, H. Takada, S. Yasuda,
N. Kumagai and M. Shibasaki, Chem.–Asian J., 2013, 8, 354.
8 A review on silyl ketene imines as an alternative for a-cyanocarba-
nions: S. E. Denmark and T. W. Wilson, Angew. Chem., Int. Ed., 2012,
51, 9980.
9 Selected examples on catalytic generation of active nucleophile from
alkylnitriles: (a) B. A. D’Sa, P. Kisanga and J. G. Verkade, J. Org.
Chem., 1998, 63, 3961; (b) P. Kisanga, D. McLeod, B. D’Sa and
J. G. Verkade, J. Org. Chem., 1999, 64, 3090; (c) A. L. Rodriguez,
T. Bunlaksananusorn and P. Knochel, Org. Lett., 2000, 2, 3285;
(d) P. Kisanga and J. G. Verkade, J. Org. Chem., 2000, 65, 5431;
(e) P. Kisanga and J. G. Verkade, Tetrahedron, 2001, 57, 467;
( f ) J. G. Verkade and P. Kisanga, Tetrahedron, 2003, 59, 7819;
(g) Y. Suto, N. Kumagai, S. Matsunaga, M. Kanai and
M. Shibasaki, Org. Lett., 2003, 5, 3147; (h) N. Kumagai,
S. Matsunaga and M. Shibasaki, J. Am. Chem. Soc., 2004,
126, 13632; (i) L. Fan and O. V. Ozerov, Chem. Commun., 2005,
4450; ( j) N. Kumagai, S. Matsunaga and M. Shibasaki, Chem.
Commun., 2005, 3600; (k) N. Kumagai, S. Matsunaga and
M. Shibasaki, Tetrahedron, 2007, 63, 8598; (l) A. Goto, K. Endo,
Y. Ukai, S. Irle and S. Saito, Chem. Commun., 2008, 2212;
(m) T. Poisson, V. Gembus, S. Oudeyer, F. Marsais and
V. Levacher, J. Org. Chem., 2009, 74, 3516; (n) A. Goto, H. Naka,
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Fig. 3 Transformation of the product.
Table 2 summarizes the substrate scope of the reaction.
Imines bearing an ortho-substituent exhibited very low reactivity.
Similar enantioselectivity to 4a was observed in the reactions using
the imines without heteroatom functional groups (entries 1–3).
Halogenated imines generally gave the corresponding product with
slightly inferior enantioselectivity (entries 4–9). Catalyst loading
could be reduced to 5 mol% without affecting the yield and ee
(entry 5).16 Imines having the m-MeO substituent gave the corres-
ponding adduct in 66% yield with the highest enantioselectivity
(52% ee) (entry 10). Imines derived from heteroaromatic aldehydes
afforded enantioselectivity above 50% ee, albeit with moderate yield
(entries 12 and 13). The thiophosphinoyl group on nitrogen was
readily removed by treatment with 4 N HCl–1,4-dioxane at 60 1C to
give b-amino nitrile 7 (Fig. 3). The N-thiophosphinoyl group can
serve as a protecting group. Nitrile was diversely transformed into
primary amine 8 and tetrazole 917 by reduction with Red-Al and
cycloaddition with NaN3, respectively.
In conclusion, a direct catalytic asymmetric addition of
acetonitrile to imines was developed. Simultaneous activation of
acetonitrile and N-thiophosphinoylimine was the key to promote
the elusive reaction in an enantioselective fashion. Although the
yield and enantioselectivity were moderate, this work is an impor-
tant first step towards this unprecedented reaction.
This work was financially supported by JST, ACT-C, and
KAKENHI (25713002) from JSPS. YK thanks JSPS for a predoctoral
fellowship.
10 Y. Suto, R. Tsuji, M. Kanai and M. Shibasaki, Org. Lett., 2005,
7, 3757.
11 For catalytic addition of a-trimethylsilylnitrile to imines in racemic
system: (a) Y. Kawano, H. Fujisawa and T. Mukaiyama, Chem. Lett.,
2005, 1134; (b) T. Mukaiyama and M. Michida, Chem. Lett., 2007,
1244. For catalytic addition of allylic cyanides to imines in racemic
´
system: (c) J. Aydin and K. J. Szabo, Org. Lett., 2008, 10, 2881; For
catalytic decarboxylative addition of a-cyanoacetic acids to imines in
racemic system: (d) J. C. Pelletier and M. P. Cava, Synthesis, 1987, 474;
For catalytic asymmetric decarboxylative addition of a-cyanoacetic
acids to imines; (e) L. Yin, M. Kanai and M. Shibasaki, J. Am. Chem.
Soc., 2009, 131, 9610; ( f ) L. Yin, M. Kanai and M. Shibasaki, Tetra-
hedron, 2012, 68, 3497; (g) K. Hyodo, M. Kondo, Y. Funahashi and
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Notes and references
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3 For reviews of direct catalytic asymmetric aldol reactions, see:
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12 For catalytic addition of non-activated alkylnitrile to imines in
racemic system: see ref. 9h, k.
13 N. Kumagai and M. Shibasaki, Angew. Chem., Int. Ed., 2011, 50, 4760.
14 X. Xu, C. Wang, Z. Zhou, Z. Zeng, X. Ma, G. Zhao and C. Tang,
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´
15 D. H. R. Barton, J. D. Elliott and S. D. Gero, J. Chem. Soc., Perkin
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16 Lower catalyst loading retarded the imine decomposition during the
reaction and similar chemical yield was observed.
17 H. Yoneyama, Y. Usami, S. Komeda and S. Harusawa, Synthesis,
2013, 1051.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 11227--11229 11229