Reductive alkylation of γ-cyano-α,β-unsaturated ketones. A modified Robinson annulation process to α,α-disubstituted-β,γ-unsaturated cyclohexanone system

Article abstract of DOI:10.1055/s-2001-10788

Reductive alkylation of various 4-cyano-2-cyclohexenones, readily available from α-cyano ketones via a Robinson annulation process, gave rise to the corresponding 2,2-disubstituted-3-cyclohexenone derivatives in a completely regioselective manner. Application of this methodology resulted in an efficient synthesis of the marine natural product nanaimoal in racemic form.

Full text of DOI:10.1055/s-2001-10788

214
LETTER
Reductive Alkylation of -Cyano- , -unsaturated Ketones. A Modified
Robinson Annulation Process to , -Disubstituted- , -unsaturated
Cyclohexanone System
Chia-Liang Tai,a Tai Wei Ly,b,c Jen-Dar Wu,a Kak-Shan Shia,a Hsing-Jang Liua,b,c
*
aDepartment of Chemistry, National Tsing Hua University, Hsinchu, Taiwan 30013, R.O.C.
bDepartment of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada
cInstitute of Chemistry, Academia Sinica, Nankang, Taipei, Taiwan 11529, R.O.C.
Fax +886-3-5720711; E-mail: hjliu@mx.nthu.edu.tw
Received 24 November 2000
addition followed by aldol condensation. The Michael
process, which is facilitated by the presence of the doubly
activated methylene group in the Michael donor, could be
effected by two different methods. In one method (method
Abstract: Reductive alkylation of various 4-cyano-2-cyclohex-
enones, readily available from -cyano ketones via a Robinson an-
nulation process, gave rise to the corresponding 2,2-disubstituted-3-
cyclohexenone derivatives in a completely regioselective manner.
Application of this methodology resulted in an efficient synthesis of A) aluminum oxide4 was used as the reagent. In a typical
the marine natural product nanaimoal in racemic form.
experiment, the -cyano ketone was added to activated
(100 °C, 4 h) aluminum oxide at room temperature fol-
lowed by dropwise addition of the Michael acceptor. This
reaction has the advantage of being rapid (20 min) and
easy to workup (dilution with ether followed by filtra-
tion). However, neither -cyanocyclopentanone (2) nor -
substituted methyl vinyl ketone derivatives was amenable
to this reaction. A more universal procedure (method B)
involves the treatment of a dimethoxyethane (DME) solu-
tion of -cyano ketones with a Michael acceptor in the
presence of 1,4-diaza[2.2.2]bicyclooctane (DABCO).5
Subsequent to the Michael addition, the adducts 5-106
were individually treated with p-toluenesulfonic acid (1
eq) in refluxing benzene with azeotropic removal of water
to effect the aldol condensation, giving bicyclic enones
11-16 in good yields. These results are compiled in Table
1.
Key words: ketones, cyano compounds, reduction, alkylation
It was recently discovered in our laboratories that -cyano
ketones undergo facile reductive alkylation upon sequen-
tial treatment with lithium naphthalenide (LN) and an
alkylating agent (Scheme 1).1 As a result of this finding, it
became of interest to explore the reductive alkylation of
vinylogous -cyano ketones. The preliminary experimen-
tal results disclosed in this paper showed that the reduc-
tive alkylation is highly efficient and completely
regioselective with the alkylation occurring specifically at
the -carbon with simultaneous transposition of the dou-
ble bond towards the -carbon. In essence, this methodol-
ogy allows the expeditious formation of a quaternary
center bearing a vinyl group. Such a system is found in a
wide variety of naturally occurring compounds (e.g. nan-
aimoal (1)2) and is not readily accessible by existing
methods.
Each of the Robinson annulation products was subjected
to reductive alkylation with LN in THF7. A variety of
alkylating agents were used (Table 2). The reductive re-
moval of the cyano group was found to be rapid (30 min)
even at -78 °C. In general, the subsequent alkylation also
occurred smoothly, giving rise to the expected product in
good yield (Entries 1-7) within a day at -78 °C. As a typ-
ical example, at -78 °C, a 0.98 M solution of LN (3 eq) in
THF was added dropwise to a solution of cyano enone 13
in THF (ca. 0.5 mmol/mL) under a nitrogen atmosphere.
After 30 minutes at -78 °C, benzyl bromide (3 eq) was in-
troduced. The resulting solution was stirred at -78 °C for
20 h at which time saturated aqueous ammonium chloride
was added. Extraction with ether followed by standard
workup of the extracts and flash chromatography (silica
gel; EtOAc:hexanes (1:400)) gave the desired product 176
in virtually quantitative yield. This procedure applies well
to all the -substituted cyano enones studied (Entries 1-7).
However, when the unsubstituted enone 15 was applied,
the expected mono alkylated product 28 was not formed
cleanly. Instead, a mixture consisting of the mono-, di-,
and unalkylated products 28, 24, and 29 (ca. 3:2:8) was
Scheme 1
A series of -cyano- , -unsaturated ketones was readily
prepared via Robinson annulation of -cyano ketones 2-
4.3 The Robinson annulation was found to be most effec-
tive when carried out in two separate operations: Michael
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LETTER
Reductive Alkylation of -Cyano- , -unsaturated Ketones
Table 1 Robinson Annulation of Various -Cyano Ketones
215
aA separable diastereomeric mixture of the Michael adduct was obtained in a 1:1 ratio.
The yield refers to that of the mixture.
bThe other diastereomer also gave identical results in the aldol condensation reaction.
produced. Apparently, under the reaction conditions, di-
alkylation at the expense of the mono-alkylated product
occurred as a result of a proton transfer process between
the originally formed enolate and the mono-alkylated
product 28. As a consequence of this observation, a pro-
cedure to facilitate dialkylation was developed. Thus, se-
quential treatment of compound 15 with 4 eq of LN at
-78 °C and 4 eq of benzyl bromide at room temperature
gave ketone 24 as the sole product (Table 2, Entry 8). This tones facilitates the formation of , -disubstituted- , -
procedure proved to be general for direct dialkylation of unsaturated ketones in a completely regioselective man-
several other cases (Entries 9-11), giving the dialkylation ner. Both symmetrical and unsymmetrical substitution
products 25-27 in synthetically useful yields.
patterns can be achieved. The current work represents a
modified Robinson annulation process which allows the
expeditious formation of , -disubstituted- , -unsaturat-
ed cyclohexanones which cannot be effectively prepared
The experimental results described above demonstrate
that reductive alkylation of -cyano- , -unsaturated ke-
Synlett 2001, No. 2, 214–217 ISSN 0936-5214 © Thieme Stuttgart · New York

216
C.-L. Tai et al.
Table 2 Reductive Alkylation of -Cyano- , -unsaturated Enones
LETTER
aA: LN (3 eq), -78 °C, 30 min, then alkylating agent (4 eq), -78 °C; B: LN (4 eq), -78 °C,
30 min, then alkylating agent (4 eq), r.t.
bAn inseparable mixture of diastereomers was obtained in a ratio of 10 : 1. The relative
stereochemistry of the products remains to be ascertained.
by Robinson annulation. This modified process is ex- demonstrated in the total synthesis, in racemic form, of
pected to find broad synthetic utility, especially towards nanaimoal (1) (Scheme 2), a marine natural product
the synthesis of various natural products containing a qua- isolated from the dorid nudibranch Acanthodoris nan-
ternary center bearing a vinyl group. An application is aimoensis.2
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LETTER
Reductive Alkylation of -Cyano- , -unsaturated Ketones
217
a: i) (C6H5)3PCH3Br, n-BuLi, THF, -78°C to r.t., 30 min; ii) 2.48N HCl(aq), 17 h, 96%;
b: DABCO, EVK, DME, 0°C to r.t., 23 h, 74%; c: p-TsOH, benzene, -H2O, 2 h, 88%;
d: LN, THF, -78°C, 45 min; then CH3I, -78°C, 20 h, 77%; e: H2NNH2, KOH, DEG,
110-120 °C, 2 h; then 210-220°C, 4 h, 76%; f: i) Sia2BH, THF, 0 °C to r.t., 25 h;
ii) PCC, CH2Cl2, reflux, 3 h, 66%.
Scheme 2
Dicyano aldehyde 308 was subjected to Wittig reaction
with methylenetriphenylphosphorane in THF at a temper-
ature range of -78 °C - 20 °C over a period of 30 min. In-
terestingly, under the reaction conditions, the Thorpe-
Ziegler reaction occurred simultaneously to give a 96%
yield of the desired cyano ketone 319 after acid hydrolysis.
Subsequent addition of ethyl vinyl ketone (EVK)
(31 32) in the presence of DABCO followed by acid cat-
alyzed aldol condensation resulted in the formation of cy-
ano enone 33 in 65% yield. Reductive alkylation of 33
with LN and methyl iodide gave ketone 34 in 77% yield.
The ketone carbonyl was subsequently removed by
Wolff-Kishner reduction and the diene 35 thus obtained in
76% yield was subjected to hydroboration with di-
siamylborane and oxidation with pyridinium chlorochro-
mate (PCC)10 to give ( )-nanaimoal (1)11 (66% yield)
whose spectroscopic data were found to be in good agree-
ment with those reported in the literature.2
(6) Satisfactory spectral and elemental or HRMS analytical data
were obtained for all new compounds. Compound 13: IR
(neat): 2229 (CN), 1676 (C=O), 1622 cm-1 (C=C); 1H NMR
(400 MHz, CDCl3): 2.77 (dt, J1 = 16 Hz, J2 = 4 Hz, 1H), 2.54
(dd, J1 = 16 Hz, J2 = 4 Hz, 1H), 2.41 (dt, J1 = 16 Hz, J2 = 4 Hz,
1H), 2.25 (dt, J1 = 12 Hz, J2 = 4 Hz, 1H), 2.10 (dm, J1 = 12 Hz,
2H), 1.88 (m, 1H), 1.87 (dd, J1 = 16 Hz, J2 = 4 Hz, 1H), 1.74
(m, 2H), 1.70 (s, 3H), 1.40 (m, 1H), 1.30 (m, 1H); 13C NMR
(100 MHz, CDCl3): 196.0 (C=O), 150.1 (C= ), 131.8 (C= ),
120.6 (CN), 38.9 (CH2), 34.0 (CH2), 33.1 (CH2), 28.4 (CH2),
25.4 (CH2), 22.3 (CH2), 10.8 (CH3); HRMS M+: 189.1163
(calcd. for C12H15NO: 189.1154). Compound 17: IR (neat):
1707 (C=O), 1601 cm-1 (C=C); 1H NMR (400 MHz, CDCl3):
7.15 (m, 3H), 6.95 (dd, J1 = 8 Hz, J2 = 1 Hz, 2H), 3.06 (d,
J = 16 Hz, 1H), 2.72 (d, J = 16 Hz, 1H), 2.25 (ddd, J1 = 16 Hz,
J2 = 9 Hz, J3 = 7 Hz, 1H), 2.08 (m, 2H), 2.04 (dt, J1 = 16 Hz,
J2 = 5 Hz, 1H), 1.87 (m, 2H), 1.81 (dm, J = 16 Hz, 1H), 1.39-
1.75 (m, 5H), 1.21 (s, 3H); 13C NMR (100 MHz, CDCl3):
215.8 (C=O), 138.1 (C= ), 131.2 (C= ), 130.4 (C= ), 129.8
(CH= ), 127.5 (CH= ), 126.1 (CH= ), 53.0 (C), 43.3 (CH2),
37.6 (CH2), 30.7 (CH2), 28.6 (CH2), 24.5 (CH2), 23.6 (CH3),
22.6(CH2), 22.5 (CH2); HRMS M+: 254.1669 (calcd. for
C18H22O: 254.1671).
Acknowledgement
(7) For the preparation of a stock solution of LN in THF, see Liu,
H. J.; Shang, X. Tetrahedron Lett. 1998, 39, 367.
(8) Zondler, H.; Pfleiderer, W. Liebigs Ann. Chem. 1972, 759, 84.
Zondler, H.; Pfleiderer, W. Helv. Chim. Acta 1975, 58, 2261.
(9) Diastereomeric mixtures were obtained for compounds 31, 32,
and 33.
(10) Rao, C. G.; Kulkarni, S. U.; Brown, H. C. J. Organomet.
Chem. 1979, 172, C20. Brown, H. C.; Kulkarni, S. U.; Rao, C.
G. Synthesis 1980, 151.
(11) For previous syntheses of 1, see: Yamada, T.; Takabe, K.
Chem. Lett. 1993, 29. Omodani, T.; Shishido, K. J. Chem.
Soc., Chem. Commun. 1994, 2781. Engler, T. A.; Ali, M. H.;
Takusagawa, F. J. Org. Chem. 1996, 61, 8456. Ref. 2.
We are grateful to the National Science Council of the Republic of
China (NSC 88-2113-M-007-042) and the Natural Sciences and En-
gineering Research Council of Canada for financial support.
References and Notes
(1) Liu, H. J.; Zhu, J. L.; Shia, K. S. Tetrahedron Lett. 1998, 39,
4183.
(2) Ayer, S. W.; Hellou, J.; Tischler, M.; Andersen, R. J.
Tetrahedron Lett. 1984, 25, 141.
(3) These compounds were readily prepared by Thorpe-Ziegler
reaction of the corresponding alkanedicarbonitrile.
(4) Ranu, B. C.; Bhar, S.; Sarkar, D. C. Tetrahedron Lett. 1991,
32, 2811. Ranu, B. C.; Bhar, S. Tetrahedron 1992, 48, 1327.
(5) Liu, H. J.; Wynn, H. Can. J. Chem. 1986, 64, 649. Liu, H. J.;
Wynn, H. Can. J. Chem. 1986, 64, 658.
Article Identifier:
1437-2096,E;2001,0,02,0214,0217,ftx,en;Y18500ST.pdf
Synlett 2001, No. 2, 214–217 ISSN 0936-5214 © Thieme Stuttgart · New York