Direct catalytic asymmetric addition of allylic cyanides to ketoimines

Article abstract of DOI:10.1021/ja806572b

Direct catalytic asymmetric addition of allylic cyanides to N-diphenylphosphinoyl ketoimines with a bimetallic catalytic system comprising Ph-BPE/[Cu(CH₃CN)₄]ClO₄/LiOAr is described. Intermediary α-adducts readily isomerized to afford synthetically useful α,β-unsaturated nitriles bearing an optically active tetrasubstituted carbon. Applicability to aromatic, heteroaromatic, and aliphatic ketoimines exemplifies wide substrate generality. Transformation of the product into densely functionalized material showcases the utility of the present protocol. Copyright

Full text of DOI:10.1021/ja806572b

Published on Web 10/10/2008
Direct Catalytic Asymmetric Addition of Allylic Cyanides to Ketoimines
Ryo Yazaki, Tatsuya Nitabaru, Naoya Kumagai,* and Masakatsu Shibasaki*
Graduate School of Pharmaceutical Sciences, The UniVersity of Tokyo, 7-3-1 Hongo, Bunkyo-ku,
Tokyo, 113-0033, Japan
Received August 23, 2008; E-mail: mshibasa@mol.f.u-tokyo.ac.jp; nkumagai@mol.f.u-tokyo.ac.jp
Catalytic enantioselective construction of a chiral tetrasub-
stituted carbon center through an intermolecular C-C bond-
forming reaction remains an intriguing challenge in modern
organic synthesis.1 Catalytic asymmetric additions to
ketoimines1c using active organosilicon or organometallic nu-
cleophiles, e.g., TMSCN,2 allylboronates,3 enol silyl ethers,4 and
dialkyllzinc,5 were recently developed as a new entry in this
category. The formation of a C-C bond via proton transfer
Figure 1. Exploitation of allylic cyanides as nucleophiles.
through catalytic generation of nucleophiles from otherwise
inactive pronucleophiles, however, is an obviously more advan-
Table 1. Initial Screeninga
tageous protocol6 that has been rarely explored in this class of
reactions except for HCN2a,7 or highly active R-alkoxycarbon-
ylketoimines.8 Diastereoselective or racemic direct addition of
nitroalkanes to ketoimines has been outlined via proton transfer
conditions.9 In this context, our particular interest was directed
toward asymmetric addition of nitrile pronucleophiles to ke-
toimines because (1) nitriles are readily available and stable
enough to allow easy handling; (2) their unique topology poses
minimal steric bias, making them well suited to the highly
congested transition state with ketoimines; and (3) they can be
viewed as a masked carboxylic acid derivative or amine, which
promises diverse transformation of the reaction product (Figure
1). Herein, we report a direct catalytic asymmetric addition of
allylic cyanides to N-diphenylphosphinoyl (Dpp) ketoimines,
affording R,ꢀ-unsaturated nitriles with a stereogenic tetrasub-
stituted carbon. An exquisite combination of a soft Lewis acid
and an alkali metal aryloxide enables the catalytic generation
of an active nitrile nucleophile and the subsequent addition to
N-Dpp ketoimines.
Despite the versatility of nitrile functionality from a synthetic
standpoint,10 its inertness toward deprotonation hampers the
catalytic generation of nucleophiles from alkylnitriles.11 We
identified allylic cyanides as a viable pronucleophile bearing an
R-proton with reasonable acidity (pKa ) 21.1 in DMSO)12 that
is suitable for achieving catalyst turnover via proton transfer.13
In the reaction of N-Dpp ketoimine1c,14 1a and allyl cyanide
(2a),15 initial attempts were performed with 10 mol % each of
soft Lewis acidic metal and (S,S)-iPr-DuPHOS in combination
with lithium p-methoxyphenoxide as the base (Table 1, entries
1-3). CuOAc promoted the R-addition sluggishly at 0 °C in
THF, and the R-adduct rapidly isomerized to give R,ꢀ-unsatur-
ated nitrile 3aa in 59% yield and 33% ee with almost exclusive
geometric control.16 The yield was diminished by the partial
deamination reaction of the intermediary R-adduct to give the
undesired diene. Although the cationic Pd(II) and Ag(I) complex
failed the reaction, the cationic Cu(I) complex exhibited an
enhanced catalytic activity, allowing the reaction at -20 °C to
reach 65% ee (entry 5). [Cu(CH3CN)4]ClO4 was identified as
the best Cu source and at -20 °C afforded 3aa in 95% yield
and 53% ee (entry 6). The use of Ph-BPE17 and CH2Cl2/THF
a 1a/2a ) 0.2 mmol/2.0 mmol. b Determined by 1H NMR analysis
with Bn2O as an internal standard. c The formation of diene was
observed. d Solvent was CH2Cl2/THF ) 2/1. e Na(OC6H4-p-OMe) was
used instead of Li(OC6H4-p-OMe). f K(OC6H4-p-OMe) was used instead
of Li(OC6H4-p-OMe).
solvent further improved the enantioselectivity to 86% ee (entry
7). Despite the marginal difference in enantioselectivity, the use
of Na or K aryloxide instead of Li(OC6H4-p-OMe) resulted in
inferior conversion, likely due to variable stability of the
bimetallic system (entries 8,9).
The substrate generality of the present protocol is summarized
in Table 2. The use of Li(OC6H4-p-OPh) instead of Li(OC6H4-
9
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2008 American Chemical Society
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C O M M U N I C A T I O N S
Table 2. Substrate Generalitya
Scheme 1. Control Experiments
equiv of 2a, affording the product 3ca in acceptable yield with
excellent ee (entry 5). Ketoimines with heteroaromatics were
suitable substrates exhibiting high E/Z selectivity and ee (entries
7,8). Attenuated reactivity and ee were observed with ketoimines
derived from ethyl ketone, due to the enhanced steric congestion
and more severe enantiodifferentiation (entry 9). High E/Z and
enantioselectivity were observed in the reaction with aliphatic
ketoimines (entries 10, 11). Allylic cyanide with alkyl substituent
2b required an extended reaction time to give diastereomeric
R-adducts, which isomerized to afford 3cb with high E selectivity
upon treatment with DBU at room temperature (entry 12).
Next we directed our focus toward the mechanistic aspects
of the present catalysis. 1H NMR and ESI-MS of a 1:1 Ph-BPE/
[Cu(CH3CN)4]ClO4 mixture indicated the formation of a Ph-
BPE/Cu 1:1 complex,18 which gave Ph-BPE/CuOAr and LiClO4
upon addition of LiOAr.19 2a would be activated through
coordination to Cu and deprotonated by the neighboring ary-
loxide rather than the alkali metal aryloxide to afford a C-bound
or N-bound active nitrile nucleophile.20 The cooperative bimetal-
lic catalysis of soft Lewis acid Cu and hard Lewis acid Li is
intriguing. An attempted reaction using 10 mol % of Li-free
Ph-BPE/Cu(OC6H4-p-OMe) catalyst prepared from mesitylcop-
per(I), Ph-BPE, and p-methoxyphenol provided trace amounts
of 3ba with 88% ee (Scheme 1a).21 The Li-free catalyst regained
catalytic activity upon the addition of 10 mol % of LiClO4 to
afford 3ba in comparable yield to that obtained under the optimal
conditions, suggesting that LiClO4 generated in situ was essential
to drive the reaction efficiently (Scheme 1b).22 The reaction
conditions lacking [Cu(CH3CN)4]ClO4 provided only 8% of the
product, verifying that soft Lewis acid Cu was required to
promote the reaction (Scheme 1c).
a 1/2 ) 0.2 mmol/2.0 mmol, CH2Cl2/THF ) 2/1. b Isolated yield
of E and Z geometrical isomers. c Determined by 1H NMR analysis
of the crude mixture. d (S,S)-Ph-BPE was used. e 3 equiv (0.6 mmol)
of 2a were used. f The reaction was conducted at 0.5 M in THF.
Li(OC6H4-p-OMe) was used instead of Li(OC6H4-p-OPh). g Reaction
time was 60 h. h Isolated yield after two steps (R-addition/
isomerization by DBU). i Opposite absolute configuration.
p-OMe) marginally impacted the asymmetric environment to
improve the enantioselectivity, albeit with a slight detrimental
effect on the reaction rate. The reaction of aryl methyl ketoimines
(1a-1d) proceeded smoothly to give isomerized R-adducts
3aa-3da in high yield and enantioselectivity (entries 1-6). The
catalyst loading could be reduced to 5 mol % without significant
loss of ee (entry 4). The reaction could be conducted with 3
The merit of the present protocol is a divergent transformation
of product 3. Here we demonstrated a preliminary transformation
into a densely functionalized material (Scheme 2). 3ba was
treated with 30% aqueous hydrogen peroxide under basic
conditions to provide epoxyamide 4ba as a single diastereomer.
Exposure of 4ba to acidic media removed the Dpp group,
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C O M M U N I C A T I O N S
Scheme 2. Transformation of the Producta
(10) For reviews: (a) Arseniyadis, S.; Kyler, K. S.; Watt, D. S. Org. React.
1984, 31, 1. (b) Fleming, F. F.; Shook, B. C. Tetrahedron 2002, 58, 1. (c)
Fleming, F. F.; Iyer, P. S. Synthesis 2006, 893.
(11) Selected examples on catalytic generation of active nucleophile from
alkylnitriles: (a) Verkade, J. G.; Kisanga, P. B. Aldrichimica Acta 2004,
37, 3. (b) Rodriguez, A. L.; Bunlaksananusorn, T.; Knochel, P. Org. Lett.
2000, 2, 3285. (c) Suto, Y.; Tsuji, R.; Kanai, M.; Shibasaki, M. Org. Lett.
2005, 7, 3757. (d) Kumagai, N.; Matsunaga, S.; Shibasaki, M. J. Am. Chem.
Soc. 2004, 126, 13632. (e) Fan, L.; Ozerov, O. V. Chem. Commun. 2005,
4450. (f) Goto, A.; Endo, K.; Ukai, Y.; Irle, S.; Saito, S. Chem. Commun.
2008, 2212.
a Reaction conditions: (a) 30% H2O2 aq., K2CO3, DMSO, rt, 16 h, y.
76%; (b) 12N HCl aq., 70 °C, 2 h, y. quant.
(12) Calculated at the B3LYP/6-31G+(d,p) level. See Supporting Information
for details.
affording an optically active ꢀ′-amino R,ꢀ-epoxyamide 5ba
bearing two contiguous tetrasubstituted carbons.
(13) (a) Kisanga, P. B.; Verkade, J. G. J. Org. Chem. 2002, 67, 426. (b) Aydin,
J.; Szabo´, K. J. Org. Lett. 2008, 10, 2881. (c) Swartz, B. D.; Reinartz,
N. M.; Brennessel, W. W.; Garc´ıa, J. J.; Jones, W. D. J. Am. Chem. Soc.
2008, 130, 8548. See also ref 11a.
In conclusion, we developed a direct catalytic asymmetric
addition of allylic cyanides to ketoimines. CuOAr furnished with
Ph-BPE worked cooperatively with LiClO4 to render this
otherwise less accessible transformation feasible, although a
ketoimine derived from ethyl ketone exhibited limited reactivity.
Facile and divergent conversion of the product streamlines the
synthesis of chiral nitrogen synthons with tetrasubstituted carbon.
More detailed mechanistic studies are ongoing.
(14) For a review, see: Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205.
(15) An inexpensive C4 unit. $193.7/500 mL from TCI America as of Aug
2008.
(16) Olefin geometry of major geometrical isomer was determined to be Z by
NOE analysis. Isomerization of double bond was observed in aldol-type
addition of allylic cyanide (refs 11a and 13a) and a direct Mannich-type
reaction of ꢀ,γ-unsaturated ester; see: Yamaguchi, A.; Aoyama, N.;
Matsunaga, S.; Shibasaki, M. Org. Lett. 2007, 9, 3387.
(17) Pilkington, C. J.; Zanotti-Gerosa, A. Org. Lett. 2003, 5, 1273.
(18) Suggested by 1H NMR and ESI-MS analysis. Analogous catalysts derived
from Me or Et-BPE did not promote the reaction at all. For further
discussions, see Supporting Information.
Acknowledgment. This work is supported by a Grant-in-Aid
for Scientific Research (S) and Grant-in-Aid for Young Scientists
(B) from JSPS. Dr. Motoo Shiro at Rigaku Corporation is
gratefully acknowledged for the assistance of X-ray crystal-
lographic analysis of 4ba.
(19) Formation of CuOAr upon addition of alkali metal aryloxide to Cu(I) salt;
see: Eller, P. G.; Kubas, G. J. J. Am. Chem. Soc. 1977, 99, 4346.
(20) For C- or N-bound nitrile nucleophile, see: Naota, T.; Tannna, A.; Kamuro,
S.; Hieda, M.; Ogata, K.; Murahashi, S.-I.; Takaya, H. Chem.sEur. J. 2008,
14, 2482, and references cited therein For allylcopper nucleophile in
asymmetric catalysis, see: Kanai, M.; Wada, R.; Shibuguchi, T.;
Shibasaki, M. Pure Appl. Chem. 2008, 80, 1055, and references cited
therein.
(21) Formation of CuOAr upon addition of ArOH to arylcopper; see: Kubota,
M.; Yamamoto, A. Bull. Chem. Soc. Jpn. 1978, 51, 2909.
Supporting Information Available: Experimental details and
characterization of new compounds. This material is available free
of charge via the Internet at http://www.acs.org.
(22) At this stage, there are three possibilities: (1) At least 2 Ph-BPE/CuOAr
would work together to deprotonate allyl cyanide (2a) if 2a coordinates to
Cu in an end-on fashion, because intramolecular proton transfer in Ph-
BPE/Cu(NCCH2CHdCH2)OAr would be topologically unlikely. A Li cation
would be beneficial for the association of Ph-BPE/CuOAr complexes
through a hard-hard interaction between the Li cation and aryloxide,
resulting in the acidic protons of Cu-coordinated 2a being located close to
another Ph-BPE/CuOAr, which would facilitate the deprotonation of 2a
(see the following figure). (2) The Li cation would function as a hard Lewis
acid to activate ketoimine 1 for nucleophilic addition. (3) LiClO4 would
replace Cu-bound aryloxide, thereby enhancing the Lewis acidity of Cu to
facilitate deprotonation and/or addition reaction (for a special salt effect of
LiClO4, see: Winstein, S.; Friedrich, E. C.; Smith, S. J. Am. Chem. Soc.
1964, 86, 305. In the reaction using Na or K aryloxide instead of Li(OC6H4-
p-OMe), the enantioselectivity was almost identical to that obtained with
Li aryloxide, suggesting that the Li cation would not be involved in the
nucleophilic addition to 1 (Table 1, entry 8 Vs 9). In addition, a preliminary
study of the reaction with more reactive N-Dpp aldimine in the absence of
LiClO4 provided the product only in 10% yield, implying that LiClO4 was
beneficial for the deprotonation process. Possibility (1) would be the most
likely.
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