Michael addition reactions of α-acyloxy nitrile anions

Article abstract of DOI:10.1016/S0040-4039(99)02017-1

The Michael addition reactions of α-acyloxy nitrile anions with Michael acceptors are followed by a shift of the acyl group to the α-carbon of the Michael acceptor. Michael acceptors such as acrylates, acrylonitrile and methyl vinyl ketone can be used. Ac

Full text of DOI:10.1016/S0040-4039(99)02017-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 21–24
Michael addition reactions of α-acyloxy nitrile anions
George A. Kraus ∗ and Elena Dneprovskaia
Department of Chemistry, Iowa State University, Ames, IA 50011, USA
Received 22 September 1999; revised 22 October 1999; accepted 25 October 1999
Abstract
The Michael addition reactions of α-acyloxy nitrile anions with Michael acceptors are followed by a shift of the
acyl group to the α-carbon of the Michael acceptor. Michael acceptors such as acrylates, acrylonitrile and methyl
vinyl ketone can be used. Acetoxy nitriles are selectively deprotonated α to the nitrile. © 1999 Elsevier Science
Ltd. All rights reserved.
In comparison with other acyl carbanion equivalents such as dithianes and nitro groups, nitrile carba-
nions substituted by heteroatom functional groups in the α-position have seen little use in organic synthe-
sis. Cyanohydrin ethers have been employed in intermolecular reactions as acyl carbanion equivalents.1,2
Recently we demonstrated an intramolecular cyclization of the anion of a silylated cyanohydrin with a
ketone.3 Related work has led to the use of cyanophthalides for the regiospecific synthesis of polycyclic
quinones.4
Hoffman and coworkers prepared α-acyloxy nitriles in one step by the reaction of acyl cyanides with
aldehydes.5 Using Hoffman’s conditions, we synthesized α-acyloxy nitriles 1, 2, 3 and 4 in 62%, 65%
36% and 52% isolated yields, respectively.
Carbanions of α-acyloxy nitriles such as 1 have not been reported. Deprotonation of these nitriles with
a strong base such as LDA or lithium hexamethyldisilazane (LiHMDS) would likely be rapid. Nitrile 2
and acetaldehyde were reacted with LiHMDS at −78°C (Scheme 1).
Scheme 1.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02017-1
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The product, 5, was produced in 67% yield. The choice of base proved to be crucial, since the reaction
with lithium diisopropylamide afforded unidentifiable product mixtures. Unexpectedly, the order of the
addition of the reagents was also important, because attempts to prepare the α-benzoyloxy nitrile anion
in the absence of the aldehyde led to degradation of the compound, possibly via the intermediacy of the
alkoxy epoxide intermediate shown in Scheme 2.6
Scheme 2.
However, when a mixture of the aldehyde and the nitrile was treated with LiHMDS, product 5 was
isolated as essentially the only product. Ketone 5 is produced from the initial alkoxide product by an
intramolecular acyl shift of the benzoyl group followed by the elimination of cyanide ion. The alkoxide
of a cyanohydrin is well known to be unstable and rapidly generates the ketone.
If the anion of nitrile 1 were effective as a donor in the Michael addition reaction, the anion produced
as a result of the Michael addition might also undergo addition to the benzoyloxy group, providing the
adduct 6. Nitrile 1 reacted with methyl acrylate and LiHMDS at −78°C to produce adduct 6 (Scheme 3)
in 65% isolated yield, the result of a Michael addition followed by an intramolecular shift of the benzoyl
group and the generation of a ketone.7
Scheme 3.
This addition reaction is applicable to several base-sensitive Michael acceptors, including methyl
vinyl ketone. The reactions of nitriles 1, 2, 3 and 4 with Michael acceptors are depicted in Table 1.8
Interestingly, the α-acyloxy nitrile carbanions react in good to excellent yield with substituted acrylates,
acrylonitrile and unsaturated ketones. The Michael addition reactions are always accompanied by the
shift of the acyl group followed by the generation of the ketone.
The results shown in Table 1 indicate that α-acyloxy nitrile carbanions can be successfully employed
in Michael addition reactions. The Michael acceptors with a β-substituent reacted better than Michael
acceptors with an α-substituent. This is counter to the usual observations in Michael addition reactions.
Perhaps the Michael acceptors without an α-substituent afforded better yields because the acyl transfer
step proceeded more effectively. In those cases where the Michael acceptor does not have an α-
substituent, the acyl transfer step produces a β-keto nitrile that can form a stable anion. Remarkably,
in the final three entries in Table 1, deprotonation α to the nitrile occurred selectively in the presence of
the acetoxy group.
The results of the addition reactions described above demonstrate some synthetic utility of α-acyloxy
nitrile carbanions. The ease of preparation of α-acyloxy nitriles, their selective deprotonation and their
reactions under mild reaction conditions combine to make them convenient synthetic building blocks.
The products of the novel tandem Michael addition–acyl transfer–decyanation reaction9 are generated in
good yields.

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Table 1
Reaction of 4a–c with Michael acceptors
Acknowledgements
We thank the Environmental Protection Agency and the Center for Advanced Technology Develop-
ment at Iowa State University for financial support of this work.
References
1. Silyl cyanohydrins: Ward, R. S.; Pelter, A.; Brizzi, A.; Sega, A.; Paoli, P. J. Chem. Res., Synop. 1998, 226–227, 1056–1080.
Cunico, R. F.; Kuan, C. P. J. Org. Chem. 1992, 57, 1202–1205. Boche, G.; Bosold, F.; Niessner, M. Tetrahedron Lett. 1982,
23, 3255–3256. Jacobson, R. M.; Lahm, G. P.; Clader, J. W. J. Org. Chem. 1980, 45, 395–405. Huenig, S.; Wehner, G. Chem.
Ber. 1979, 112, 2062–2067.
2. Ethers: Zervos, M.; Wartski, L.; Seyden-Penne, J. Tetrahedron 1986, 42, 4963–4973. Albright, J. D. Tetrahedron 1983, 39,
3207–3233. Ferrino, S. A.; Maldonado, L. A. Synth. Commun. 1980, 10, 717–723. Stork, G.; Maldonado, L. J. Am. Chem.
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3. Kraus, G. A.; Wan, Z. Tetrahedron Lett. 1997, 38, 6509–6512.
4. Kraus, G. A.; Sugimoto, H. Tetrahedron Lett. 1978, 2263–2266. Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto, H.;
Prugh, S. J. Org. Chem. 1983, 48, 3439–3444.
5. Hoffman, H. M. R.; Ismael, Z. M.; Hollweg, R.; Zein, A. R. Bull. Soc. Chem. Jpn. 1990, 63, 1807–1810.
6. This rearrangement is analogous to the Favorski rearrangement.
7. Representative procedure: To a solution of cyanohydrin ester (1 equiv.) and Michael acceptor (1.2–1.6 equiv.) in THF at
−78°C was added dropwise LiHMDS (1.2 equiv.) over 10 min. The reaction was stirred at −78°C for 2 h and then allowed
to warm to 0°C over 30 min. It was quenched with saturated NH4Cl and extracted twice with ether. The organic extracts
were washed with brine, dried over sodium sulfate and concentrated in vacuo to provide a residue which was purified by
1
column chromatography using hexanes:ethyl acetate. Adduct of 2 with methyl acrylate: H NMR (CDCl3) 1.78–1.79 (m,

24
3H), 3.34–3.52 (m, 2H), 3.60 (s, 3H), 4.91–4.96 (dd, J=6, 15 Hz, 1H), 5.77–5.78 (m, 1H), 6.03 (s, 1H), 7.39–7.44 (m, 2H),
7.49–7.54 (m, 1H), 7.98–8.01 (m, 2H). 13C NMR (CDCl3) 17.5, 37.4, 48.5, 52.7, 125.9, 128.8, 128.9, 133.7, 136.0, 143.7,
169.8, 194.8, 198.4. HRMS m/z for C15H16O4 calcd 260.1049, found 260.1047. Adduct of 4 with methyl acrylate: 1H NMR
(CDCl3) 1.84–1.85 (m, 3H), 2.39 (s, 3H), 3.19–3.27 (dd, 1H, J=18, 5.6 Hz), 3.40–3.49 (dd, 1H, J=18, 8.3 Hz), 3.74 (s, 3H),
4.0–4.1 (dd, 1H, J=5.6, 8.3 Hz), 5.82 (m, 1H), 6.06 (s, 1H). 13C NMR: 17.4, 30.2, 36.5, 52.7, 53.6, 125.8, 143.6, 169.4, 198.6,
202.4. HRMS m/z for C10H14O4 calcd 198.2120, found 198.2115.
8. All compounds exhibited spectra (1H NMR, 13C NMR and high resolution mass spectra/elemental analysis) in accord with
the assigned structures.
9. For a review of tandem reactions, see Bunce, R. A. Tetrahedron 1995, 51, 13103–13159.