Chemoselective conjugate addition of dimethylzinc-mediated ether and acetal radicals to alkylidenemalonates and asymmetric reactions

Article abstract of DOI:10.1021/jo801541m

(Chemical Equation Presented) Cyclic and acyclic ether or acetal radicals were generated directly from ethers or acetals by the action of dimethylzinc-air, and their subsequent conjugate addition reaction with alkylidenemalonates afforded the corresponding conjugate adducts in reasonably high yields. The reaction with benzylidenemalonates bearing formyl and imino groups gave chemoselectively the conjugate addition products. The asymmetric reaction of bis(8-phenylmenthyl) benzylidenemalonate proceeded diastereoselectively to provide the adduct with 93:7 dr.

Full text of DOI:10.1021/jo801541m

Chemoselective Conjugate Addition of Dimethylzinc-Mediated Ether
and Acetal Radicals to Alkylidenemalonates and Asymmetric
Reactions†
Ken-ichi Yamada, Masaru Maekawa, Tito Akindele, Mayu Nakano, Yasutomo Yamamoto,
and Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Yoshida, Sakyo-ku,
Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
ReceiVed July 13, 2008
Cyclic and acyclic ether or acetal radicals were generated directly from ethers or acetals by the action of
dimethylzinc-air, and their subsequent conjugate addition reaction with alkylidenemalonates afforded
the corresponding conjugate adducts in reasonably high yields. The reaction with benzylidenemalonates
bearing formyl and imino groups gave chemoselectively the conjugate addition products. The asymmetric
reaction of bis(8-phenylmenthyl) benzylidenemalonate proceeded diastereoselectively to provide the adduct
with 93:7 dr.
Introduction
reactions of carbon-centered radicals with aldehydes,7 ary-
lamines, alkoxyamines, and dialkylhydrazines.8 A diastereoface-
selective addition of R-alkoxyalkyl radicals to chiral N-sulfiny
limines provided a reasonably efficient methodology for the
asymmetric synthesis of oxygenated amine derivatives.9 With
a view of widening the applicability of the radical reaction, we
investigated conjugate addition of carbon-centered ether radicals
to Michael acceptors.10 Although an ene-imine was found to
be a good Michael acceptor, a good precursor of ether radical
was limited to THF.11 A wider applicability of ether and acetal
A conjugate addition reaction of nucleophilic radicals with
olefins activated by an electron-withdrawing group is recognized
as a powerful tool in organic synthesis.1,2 Our recent reports3
indicated that carbon-centered radicals were generated directly
from ethers or acetals,4 unfunctionalized cycloalkanes,5 and
primary alkyl iodides6 by the action of dimethylzinc and air.
These radicals add to the C)N bond of imines to give the adduct
amines in good to excellent yields. We have also reported the
† This paper is dedicated to the memory of Mrs. Joan and Prof. A. I. Meyers.
(1) (a) Perlmutter, P. Conjugate Addition Reaction in Organic Synthesis;
Pergamon Press: Oxford, 1992. (b) Tomioka, K. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 12. (c) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033–8061. (d) Krause, N.; Hoffmann-Ro¨der,
A. Synthesis 2001, 171–196.
(2) (a) Radicals in Organic Synthesis; Renaud, P., Sibi, M. P., Eds.; Wiley-
VCH: Weinheim, 2001; Vols. 1 and 2. (b) Srikanth, G. S. C.; Castle, S. L.
Tetrahedron 2005, 61, 10377–10441.
(6) (a) Yamada, K.; Nakano, M.; Maekawa, M.; Akindele, T.; Tomioka, K.
Org. Lett. 2008, 10, 3805–3808. (b) Yamada, K.; Yamamoto, Y.; Maekawa,
M.; Akindele, T.; Umeki, H.; Tomioka, K. Org. Lett. 2006, 8, 87–89.
(7) Yamamoto, Y.; Yamada, K.; Tomioka, K. Tetrahedron Lett. 2004, 45,
795–797.
(8) Yamamoto, Y.; Maekawa, M.; Akindele, T.; Yamada, K.; Tomioka, K.
Tetrahedron 2005, 61, 379–384.
(3) Review: Yamada, K.; Yamamoto, Y.; Tomioka, K. J. Synth. Org. Chem.
Jpn. 2004, 62, 1158–1165.
(4) (a) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Tomioka, K. J. Org.
Chem. 2004, 69, 1531–1534. (b) Yamada, K.; Yamamoto, Y.; Tomioka, K. Org.
Lett. 2003, 5, 1797–1799. (c) Yamada, K.; Fujihara, H.; Yamamoto, Y.; Miwa,
Y.; Taga, T.; Tomioka, K. Org. Lett. 2002, 4, 3509–3511.
(9) Akindele, T.; Yamamoto, Y.; Maekawa, M.; Umeki, H.; Yamada, K.;
Tomioka, K. Org. Lett. 2006, 8, 5729–5732.
(10) Recent examples for conjugate addition of R-hydroxy or R-alkoxyalkyl
radicals: (a) Oka, R.; Nakayama, M.; Sakaguchi, S.; Ishii, Y. Chem. Lett. 2006,
35, 1104–1105. (b) Bagal, S. K.; Tournier, L.; Zard, S. Z. Synlett 2006, 1485–
1490. (c) Geraghty, N. W. A.; Lally, A. Chem. Commun. 2006, 4300–4302. (d)
Ferna´ndez, M.; Alonso, R. Org. Lett. 2005, 7, 11–14. (e) Ghosh, A. K.;
Leshchenko, S.; Noetzel, M. J. Org. Chem. 2004, 69, 7822–7829.
(5) Yamada, K.; Yamamoto, Y.; Maekawa, M.; Chen, J.; Tomioka, K.
Tetrahedron Lett. 2004, 45, 6595–6597.
10.1021/jo801541m CCC: $40.75
Published on Web 09/17/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 9535–9538 9535

Yamada et al.
SCHEME 1. Me2Zn-Air-Initiated Radical Conjugate
Addition of THF (1a) to 2a
SCHEME 3. Me2Zn-Air-Initiated Radical Conjugate
Addition of Acyclic and Cyclic Ethers 1 to 2
SCHEME 2. Me2Zn-Air-Initiated Radical Conjugate
Addition of THF (1a) to 2
radicals was found to be possible by the reaction with alky-
lidenemalonates as a Michael acceptor.
donors for the Michael reaction. It is important to note that boron
trifluoride diethyl etherate was omitted in the reaction when
acid-labile ethers were used as radical precursors.
Conjugate Addition of Ether and Acetal Radicals
The ability of other radical-generating agents, diethylzinc12
and triethylborane,13,14 was comparatively evaluated in the
reaction of THF (1a) with 2a (R1 ) Ph) (Scheme 4). The
reaction with diethylzinc gave 3a in 49% yield as well as ethyl
adduct 4 in 41% yield. The reaction with triethylborane produced
a mixture of much more complex products which comprised
3a in 34%, its ethylation derivative 5 in 26%, 4 in 14%, and its
ethylation derivative 6 in 18% yields. These outcomes clearly
indicate the higher efficiency of dimethylzinc in the direct
generation of THF radical and also its conjugate addition
reaction.
The conjugate addition products 3 are synthetic precursors
of antitumor butyrolactones (Scheme 5).15 Adduct 3i was
converted into 4,5-disubstituted butyrolactones 9 and 10 through
acidic hydrolysis to separable 7 and 8 and demethoxycarbony-
lation. 3,4-Disubstituted butyrolactone 11 was obtained in 86%
yield from 3k via triethylsilane reduction of the acetal moiety
and lactonization.
Although attempted radical addition reaction of THF (1a) with
cinnamate failed to give the desired adduct, dimethyl ben-
zylidenemalonate (2a) was found to be a better Michael acceptor
to give a 55:45 diastereomeric mixture of THF adduct 3a in
59% yield at room temperature after 6 h (Scheme 1). The
reaction efficiency was improved by the addition of boron
trifluoride diethyl etherate. Thus, the reaction of 1a with 2a was
conducted by the action of 3 equiv of dimethylzinc and 2 equiv
of boron trifluoride diethyl etherate in THF at room temperature
for 1.5 h to give 3a in 86% yield.
A plausible mechanism is as follows: Methyl radical, gener-
ated by the action of dimethylzinc and air oxygen, would
abstract an R-hydrogen of THF to give THF-2-yl radical, which
undergoes conjugate addition to 2a to produce C-centered radical
stabilized by the adjacent two ester functionalities. Finally, the
radical regenerates methyl radical by the reaction with dimeth-
ylzinc to form zinc enolate, which gives product 3a after
aqueous workup.
The reaction is of generality with respect to a variety of
alkylidenemalonates 2 as summarized in Scheme 2. Malonates
bearing aryl (phenyl, naphthyl), heterocyclic (furyl, pyridyl),
and methyl groups (R1 in 2) were converted within 6.5 h at
room temperature to the corresponding adducts 3 in 62-86%
yield.
(11) Yamada, K.; Umeki, H.; Maekawa, M.; Yamamoto, Y.; Akindele, T.;
Nakano, M.; Tomioka, K. Tetrahedron 2008, 64, 7258–7265.
(12) Bazin, S.; Feray, L.; Bertrand, M. P. Chimia 2006, 60, 260–265.
(13) (a) Olliver, C.; Renaud, P. Chem. ReV. 2001, 101, 3415–3434. (b)
Yorimitsu, H.; Oshima, K. In Radicals in Organic Synthesis; Renaud, P., Sibi,
M. P., Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vol. 1, pp 11-27. (c)
Yoshimitsu, T. In Electronic Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Fuchs, P. L., Wipf, P., Crich, D., Eds.; John Wiley and Sons:
West Sussex, 2005.
(14) Triethylborane-air-initiated addition of R-alkoxy and R-alkylamino alkyl
radicals to aldehydes: (a) Yoshimitsu, T.; Matsuda, K.; Nagaoka, H.;
Tsukamoto, K.; Tanaka, T. Org. Lett. 2007, 9, 5115–5118. (b) Yoshimitsu,
T.; Arano, Y.; Nagaoka, H. J. Am. Chem. Soc. 2005, 127, 11610–11611. (c)
Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2005, 70, 2342–2345.
(d) Yoshimitsu, T.; Makino, T.; Nagaoka, H. J. Org. Chem. 2003, 68, 7548–
7550. (e) Yoshimitsu, T.; Arano, Y.; Nagaoka, H. J. Org. Chem. 2003, 68, 625–
627. (f) Yoshimitsu, T.; Tsunoda, M.; Nagaoka, H. Chem. Commun. 1999, 1745–
1746.
The reaction of benzylidene- and ethylidenemalonates (R1
) Ph, Me) 2a,e was also examined using a variety of ethers 1
as summarized in Scheme 3. Among the acyclic ethers
examined, diethyl ether was the best donor, giving 3f in 96%
yield, whereas tert-butyl methyl ether and methoxymethyl
methyl ether were worse donors, giving the corresponding
adducts 3g and 3h in 23% and 21% yields, respectively. On
the contrary, cyclic ethers such as THF, 2,2-dimethyl-1,3-
dioxolane, and 4,4,5,5-tetramethyl-1,3-dioxolane were good
(15) Blazis, V. J.; Hawkins, E. S.; Baker, D. C. Carbohydr. Res. 1994, 253,
225–233.
9536 J. Org. Chem. Vol. 73, No. 24, 2008

ChemoselectiVe Conjugate Addition of Dimethylzinc-Mediated Ether
SCHEME 4. Et2Zn- and Et3B-Initiated Radical Reactions of
THF (1a) with 2a
SCHEME 7. Asymmetric Conjugate Addition and
Conversion to 21
SCHEME 5. Conversion into γ-Lactones
aldehyde indicate the order of reactivity: Michael acceptor >
imine > aldehyde.4a,b
Asymmetric Reaction of Bis(8-phenylmenthyl) Benzylidenema-
lonate
Extension of the radical conjugate addition reaction to an
asymmetric variant was the next challenge. We selected a
menthyl malonate as a chiral Michael acceptor. Dimenthyl
benzylidenemalonate 1516 was prepared from benzaldehyde and
dimenthyl malonate 14 (R ) l-menthyl) according to the
reported procedure (Scheme 7). The reaction of 15 with 4,4,5,5-
tetramethyl-1,3-dioxolane was conducted under the conditions
of 3 equiv of dimethylzinc and 2 equiv of boron trifluoride
diethyl etherate at room temperature for 5 h to give adduct 16
in 79% yield. However, it was disappointing to find that the
ratio of diastereomers was 60:40, i.e., 20% de. The poor 60:40
dr was dramatically improved using 8-phenylmenthyl17 ester
in place of menthyl ester. Bis(8-phenylmenthyl) benzyliden-
emalonate 18 was prepared by the reaction of benzaldehyde
with bis(8-phenylmenthyl) malonate 17 (R ) l-8-phenylmen-
thyl). The radical reaction of 18 was again conducted under
the same conditions at room temperature for 6 h to give a
conjugate addition product 19 with 93:7 dr in 86% yield.
Hydrolysis of sterically bulky 8-phenylmenthyl ester of 19 with
KOH in aqueous DMSO at 140 °C for 2 h and methyl
esterification with trimethylsilyldiazomethane gave a methyl
ester 20 in 80% yield. It is worthy to note that 8-phenylmenthol
was recovered quantitatively. Triethylsilane reduction of 20 in
trifluoroacetic acid gave lactone (S)-(+)-2118 with 85% ee in
94% yield.
SCHEME 6. Chemoselective Radical Conjugate Addition of
THF (1a) to Aldehyde 12a and Imine 12b
Chemoselective Conjugate Addition
The sense of chemoselectivity of the radical conjugate
addition reaction was determined by examining the reaction of
THF (1a) with 12a bearing a formyl group and its imine 12b
(Scheme 6).4a,b,7 The reaction of 1a with aldehyde 12a was
mediated by 3 equiv of dimethylzinc at room temperature for
1.5 h to give chemoselectively the conjugate addition product
13a in 76% yield. The reaction of imine 12b also gave, after
hydrolysis of the imine moiety through alumina column, 13a
in 53% yield along with amine 13b in 12% yield. These
preferences for conjugate addition as well as that for imine over
Summary
R-Alkoxyalkyl radicals, generated from ethers and acetals by
the action of dimethylzinc-air, were chemoselectively reacted
(16) Katagiri, N.; Watanabe, N.; Sakaki, J.; Kawai, T.; Kaneko, C. Tetra-
hedron Lett. 1990, 32, 4633–4636.
(17) Corey, E. J.; Ensley, H. E. J. Am. Chem. Soc. 1975, 97, 6908–6909.
(18) Defieber, C.; Paquin, J.; Serna, S.; Carreira, E. M. Org. Lett. 2004, 6,
3873–3876.
J. Org. Chem. Vol. 73, No. 24, 2008 9537

Yamada et al.
acetate/hexane 1/5) gave 3k (298 mg, 85%) as a colorless solid,
which was recrystallized from a mixture of ethyl acetate and hexane
to give colorless prisms. Mp: 121.5-122 °C. Rf ) 0.33 (ethyl
with Michael acceptors, mainly without addition to aldehyde
and imine moieties. Dimethylzinc was confirmed to be a better
initiator than triethylborane and diethylzinc, which caused
competitive ethyl addition. An efficient asymmetric radical
addition was developed by using bis(8-phenylmenthyl) ben-
zylidenemalonate as a chiral Michael acceptor.
1
acetate/hexane 1/3). H NMR δ: 1.03 (s, 3H), 1.11 (s, 3H), 1.12
(s, 3H), 1.14 (s, 3H), 3.39 (s, 3H), 3.69 (dd, J ) 5.8, 11, 1H), 3.76
(s, 3H), 3.98 (d, J ) 11, 1H), 5.22 (d, J ) 5.8, 1H), 7.20-7.29 (m,
5H). 13C NMR δ: 22.0 (CH3), 22.4 (CH3), 23.7 (CH3), 23.8 (CH3),
50.6 (CH), 52.2 (CH3), 52.5 (CH3), 53.8 (CH), 82.3 (C), 82.4 (C),
101.2 (CH), 127.3 (CH), 128.0 (CH), 129.5 (CH), 137.1 (C), 168.0
(C), 168.7 (C). IR (KBr) ν: 2938, 1736, 1157, 1026. EIMS (m/z):
350 (M+), 221 (M - C7H13O2), 129 (C7H13O2). Anal. Calcd for
C19H26O6: C, 65.13; H, 7.48. Found: C, 64.97; H, 7.48.
Experimental Section
Although a 1.0 M solution of Me2Zn in hexane is easily handled
and we haVe not experienced spontaneous combustion, dialkylzinc
is pyrophoric and there is a potential danger of ignition.
Dimethyl 2-[Phenyl(4,4,5,5-tetramethyl-1,3-dioxolan-2-yl)meth-
yl]malonate (3k). A dry three-necked, round-bottomed flask was
equipped with a stir bar and dimethyl 2-benzylidenemalonate (2a)
(220 mg, 1.0 mmol). The flask was filled with argon by evacuation
and refilled three times. 4,4,5,5-Tetramethyl-1,3-dioxolane (36 mL,
250 mmol) was added at room temperature. To the stirred solution
were added boron trifluoride diethyl etherate (0.25 mL, 2.0 mmol)
and a 1.0 M hexane solution of dimethylzinc (3.0 mL, 3.0 mmol).
The argon source was replaced with a NaOH drying tube, and air
was injected into the reaction mixture via an air bubbler at a rate
of 0.5 mL/h. The reaction mixture was stirred for 2.5 h followed
by quenching with saturated ammonium chloride (20 mL). The
aqueous layer was extracted with ethyl acetate (3 × 20 mL). The
combined organic layers were washed with brine (20 mL), dried
over sodium sulfate, filtered, and concentrated under reduced
pressure to give a colorless oil. Column chromatography (ethyl
Acknowledgment. This research was partially supported by
the 21st Century Center of Excellence Program “Knowledge
Information Infrastructure for Genome Science”, a Grant-in-
Aid for Young Scientists (B), a Grant-in-Aid for Scientific
Research on Priority Areas “Advanced Molecular Transforma-
tions”, and a Grant-in-Aid for Scientific Research from the Japan
Society for the Promotion of Science (JSPS) and the Ministry
of Education, Culture, Sports, Science and Technology, Japan.
M.M. and T.A. thank JSPS for a fellowship.
Supporting Information Available: Experimental details and
characterization data of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO801541M
9538 J. Org. Chem. Vol. 73, No. 24, 2008