Highly efficient arylation of malonates with diaryliodonium salts

Full text of DOI:10.1021/jo981065b

1338
J . Org. Chem. 1999, 64, 1338-1340
Ta ble 1. Ar yla tion s of Ma lon a tes w ith Dia r yliod on iu m
High ly Efficien t Ar yla tion of Ma lon a tes
Sa lts in DMF
w ith Dia r yliod on iu m Sa lts
Chang Ho Oh,* J oo Sung Kim, and Hyung Hoon J ung
Department of Chemistry, Hanyang University,
Haengdang-17 Sungdong-Gu, Seoul 133-791, Korea
Received J une 3, 1998
Unlike alkyl halides and their equivalents, aryl halides
are not reactive enough to undergo intermolecular dis-
placement reactions with metal enolates under normal
conditions. Direct arylations of malonates have been
accomplished by utilizing copper catalysts in low yields.1
With the aid of palladium catalysts, however, malono-
nitriles, phenylsulfonylacetonitriles, and ethyl cyanoac-
etates have been arylated in good to high yields.2 It has
been known that the presence of a cyano group in the
enolates seemed to be crucial in the palladium catalyzed
arylations.3 Although there were a few reports on pal-
ladium-catalyzed intramolecular arylations of malonates
or 1,3-diketones, no successful intermolecular arylation
has yet been reported.4 In most cases, dialkyl 2-arylma-
lonates (B) have been prepared in two steps: by conden-
sation of arylacetonitriles (A) with diethyl carbonate,
followed by esterification of the cyano group (eq 1).5
with the iodonium salts afforded the arylated esters only
in low to moderate yields,8 although the nucleophilicities
of keto and ester enolates are almost identical. During
our total synthesis of sesquiterpene laurene and its
analogues,9 we needed an efficient arylation methodology
that could access structurally diverse arylated malonate
esters. We thought that direct arylations of active me-
thylene compounds could be achieved by employing more
reactive electrophiles; here we wish to note our results
from the synthetic point of view. Our first study was
focused on the reaction of diethyl methylmalonate with
diphenyliodonium tetrafluoroborate, as summarized in
Table 1.
Recently, high valent iodonium salts have been revis-
ited as reactive aryl iodide equivalents in organic reac-
tions.6 In early studies on high valent iodonium salts,
some keto enolates reacted with diaryliodonium salts to
give arylated ketones in good yields,7 but ester enolates
The sodium enolate derived from diethyl malonate (1)
with diphenyliodonium tetrafluoroborate or ditolyliodo-
nium triflate in dimethylformamide did not react at room
temperature but reacted at 70 °C to give the correspond-
ing phenylmalonate 4a or p-tolylmalonate 4b, respec-
tively, in low yields (entries 1 and 2). Sodium enolates
derived from diethyl allylmalonate (2) and diethyl methyl-
malonate (3), however, reacted smoothly with diphenyl-
iodonium tetrafluoroborate at room temperature to give
the corresponding phenyl malonates 5a and 6a , respec-
tively. Diphenyliodonium triflate and ditolyliodonium
triflate, prepared according to the known procedure,10
also reacted with the three selected malonate enolates
* To whom correspondence should be addressed. Tel: + 82-2-
2900932. Fax: +82-2-2990762. E-mail: changho@email.hanyang.ac.kr.
(1) Tsuji, J . In Palladium Reagents and Catalysts; J ohn Wiley &
Sons, Ltd.: Chichester, U.K., 1995; pp 244.
(2) (a) Uno, M.; Seto, K.; Masuda, M.; Ueda, W.; Takahashi, S.
Tetrahedron Lett. 1985, 26, 1553. (b) Uno, M.; Seto, K.; Takahashi, S.
J . Chem. Soc., Chem. Commun. 1984, 932. (c) Uno, M.; Seto, K.; Ueda,
W.; Masuda, M.; Takahashi, S. Synthesis 1985, 506. (d) Zauhar, J .;
Bandrauk, A. D.; Truong, K. D.; Michel, A. Synthesis 1995, 703. (e)
Sakamoto, T.; Kondo, Y.; Suginome, T.; Ohba, S.; Yamanaka, H.
Synthesis 1992, 552. (f) Suzuki, H.; Kobayashi, T.; Yoshida, Y.; Osuka,
A. Chem. Lett. 1983, 193.
(3) (a) Tsuji, J . In Palladium Reagents and Catalysts; J ohn Wiley
& Sons, Ltd.: Chichester, U.K., 1995; pp 245. (b) For a related work,
see: Semmelhack, M. F.; Bargar, T. J . Am. Chem. Soc. 1980, 102, 7765.
(4) (a) Ciufolini, M. A.; Browne, M. E. Tetrahedron Lett. 1987, 28,
171. (b) Ciufolini, M. A.; Qi, H.-B.; Browne, M. E. J . Org. Chem. 1988,
53, 4149. (c) For similar nickel-catalyzed cyclization, see: Semmelhack,
M. F.; Chong, B. P.; Stauffer, R. D.; Rogerson, T. D.; Chong, A.; J ohnes,
L. D. J . Am. Chem. Soc. 1975, 97, 2507. (e) Fournet, G.; Balme, G.;
Gore, J . Tetrahedron 1990, 46, 7763.
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metry 1993, 4, 2025. (b) Wheland, R. C.; Martin, E. L. J . Org. Chem.
1975, 40, 3101. (c) Osuka, A.; Kobayashi, T.; Suzuki, H. Synthesis 1983,
67. (d) Sandman, D. J .; Garito, A. F. J . Org. Chem. 1974, 39, 1165. (e)
Davis, W. A.; Cava, M. P. J . Org. Chem. 1983, 48, 2774.
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(b) Beringer, F. M.; Porgione, P. S. J . Org. Chem. 1963, 28, 714. (c)
Barton, D. H. R.; Finet, J .-P.; Giannotti, C.; Halley, F. J . Chem. Soc.,
Perkin Trans. 1. 1987, 241. (d) For arylation of Meldrum’s acid, see:
Chen, Z.-C.; J in, Y.-Y.; Stang, P. J . J . Org. Chem. 1987, 52, 4115.
(9) (a) Wartten, S. J .; Faulkner, D. J . J . Org. Chem. 1977, 42, 3343.
(b) Irie, T.; Yasunari, Y.; Suzuki, T.; Imai, N.; Kurosawa, E.; Masam-
une, T. Tetrahedron Lett. 1965, 6, 3619. (c) Bailey, W. F.; J iang, X.-L.;
McLeod, C. E. J . Org. Chem. 1995, 60, 7791. (d) Kulkarni, M. G.;
Pendharkar, D. S. J . Chem. Soc., Perkin Trans. 1 1997, 3127. (e) Hall,
J . G.; Reiss, J . A. Aust. J . Chem. 1986, 39, 1401. (f) McMurry, J . E.;
von Beroldingen, L. A. Tetrahedron 1974, 30, 2027. (g) Taber, D. F.;
Anthony, J . M. Tetrahedron Lett. 1980, 21, 2779. (h) Schuda, P. F.;
Potlock, S. J .; Ziffer, H. Tetrahedron 1987, 43, 363. (i) Srikrishna, A.;
Sunderbabu, G. Tetrahedron Lett. 1989, 30, 3561. (j) Srikrishna, A.;
Sunderbabu, G. Tetrahedron 1991, 47, 481.
(6) (a) Varvoglis, A. Hypervalent Iodine in Organic Synthesis;
Academic Publishers: New York, 1997. (b) For a recent review, see:
Stang, P. J .; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123.
(7) (a) Ryan, J . H.; Stang, P. J . Tetrahedron Lett. 1997, 38, 5061.
(b) Beringer, F. M.; Daniel, W. J .; Galton, S. A.; Rubin, G. J . Org. Chem.
1966, 31, 4315. (c) Rossi, R. A.; Bunnett, J . F. J . Am. Chem. Soc. 1974,
96, 112.
10.1021/jo981065b CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/04/1999

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1339
Ta ble 2. Selective Ar yla tion of Dieth yl Meth ylm a lon a te
w ith Dia r yliod on iu m Sa lts
in the presence or absence of the palladium catalyst
(entries 2, 5, and 9). Although Pd(PPh3)4 seemed to serve
as a little better catalyst to produce the desired arylation,
it might not be critical, indicating that the high valent
iodonium salts should be reactive enough toward the
enolate nucleophiles (entries 3 and 6). As expected, direct
phenylation of diethyl methylmalonate (3) with p-iodo-
toluene under palladium catalysis occurred only slightly
even at high temperature (120 °C).
We expected that malonates could react better with an
electron-deficient aryl group than with an electron-rich
aryl group when unsymmetrical biaryl iodonium salts
were employed. Thus, we prepared diverse aryl-substi-
tuted iodonium salts 7a -e to determine chemoselectivity
attempted reaction of the iodonium salt 7c with the
malonate 3. Under the optimal condition, as seen in eq
3, the arylated products 6b and 6c were isolated in 74%
in aryl group transfers.
The arylations of diethyl methylmalonate (3) with
diaryliodonium triflate 7a in DMF proceeded cleanly to
give a 3:1 mixture of the corresponding products 6a and
6b in 91% yield, as shown in eq 2.
and 8% yields, respectively. This implies that the mixed
iodonium salt 7c could be an alternative to ditolyliodo-
nium salt because of its ease of preparation and its
thermal stability. The iodonium salt 7c also reacted with
â-ketoester (8) smoothly as seen in eq 4. The aryl group
Even a slight difference in the two aryl groups of
diaryliodonium salt 7a resulted in selective arylation,
implying that the best selectivity could be obtained from
a diaryliodonium salt possessing two electronically dif-
ferent aryl groups. In fact, the diaryliodonium salt 7b
with diethyl methylmalonate under similar conditions
resulted in better chemoselective arylation, as sum-
marized in Table 2.
When iodonium salt 7b reacted with the enolate of
diethyl methylmalonate under the given conditions, the
phenyl group was transferred about 10 times more
rapidly than the p-methoxyphenyl group, giving products
in ratios in the range of 91:9 to 93:7. Instead of sodium
hydride, potassium tert-butoxide provided similar results
but in a slightly lower selectivity of 83:17, presumably
because the more ionic potassium enolate lowered the
selectivity as a result of its higher reactivity. Other bases,
such as triethylamine, sodium carbonate, and lithium
hydride,11 did not give the desired product. Among the
solvents tried, DMF gave the best result for this aryla-
tion, whereas THF, ether, dichloromethane, and toluene
were not optimal. With these preliminary results, we next
transfer occurred selectively in an 80:20 ratio when
monitored by GC. The reaction was also clean enough to
be synthetically useful to give the products 9a and 9b in
65% and 14% isolated yields, respectively. As an extreme
case, (2,4,6-trimethoxyphenyl)(p-tolyl)iodonium salt (7d )
was prepared. The reaction with the malonate enolate 3
afforded tolylmalonate (6b) as the sole arylated product
along with 2,4,6-trimethoxyiodobenzene as a byproduct
in 90% and 84% yields, respectively, as shown in eq 5.
Finally, we prepared (2,4,6-trimethoxyphenyl)phenyl-
iodonium salt (7e) and reacted it with various enolates
to explore the scope and the limitation of this present
methodology, as summarized in Table 3. Note that only
the phenyl group in the iodonium salt 7e has been
selectively transferred to the enolates derived from
diethyl methylmalonate or R-alkylated â-ketoesters.
Simple â-ketoesters 10a and 10c, however, did not
undergo arylation under our conditions.
(10) (a) Sharefkin, J . G.; Saltzman, H. Organic Syntheses; Wiley:
New York, 1973; Collect. Vol. V, pp 660-662. (b) Saltzman, H.;
Sharefkin, J . G. Organic Syntheses; Wiley: New York, 1973; Collect.
Vol. V, pp 658-659. (c) Kitamura, T.; Matsuyuki, J .-i.; Nagata, K.;
Furuki, R.; Taniguchi, H. Synthesis 1992, 945. (d) Okuyama, T.;
Takino, T.; Sueda, T.; Ochiai, M. J . Am. Chem. Soc. 1995, 117, 3360.
(e) Kang, S.-K.; Yamaguchi, T.; Kim, T.-H.; Ho, P.-S. J . Org. Chem.
1996, 61, 9082.
(11) Insoluble lithium hydride in DMF could not abstract a proton
from the malonate 3, because lithium hydride was still highly reactive
when water was added into the reaction mixture.

1340 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
Ta ble 3. Selective Ar yla tion w ith
(2,4,6-Tr im eth oxyp h en yl)p h en yliod on iu m Sa lt (7e) in
DMF
ates I like phosphines; the tricoordinated iodine inter-
mediates I then undergo reductive elimination to give
the products and aryl iodide.
In conclusion, the present study showed that 2-alkyl
substituted malonates and R-alkyl substituted â-keto-
esters were efficiently arylated with diaryliodonium salts
in the presence of a base to give the corresponding aryl
derivatives under mild conditions. J udging from the fact
that the electron-deficient aryl group was selectively
transferred to the nucleophiles, we propose that the
present arylation reaction proceeds via ion-pair com-
plexes to give tricoordinated iodine intermediates, which
then undergo reductive elimination to yield the corre-
sponding arylated malonates. A more detailed study,
including the application to sesquiterpene laurene, is
currently underway.
Exp er im en ta l Section
Sch em e 1
Gen er a l. All arylations were carried out under an atmosphere
of dry argon. Commercial reagents were used as received without
further purification. Diaryliodonium salts were prepared ac-
cording to the known procedure.10c The analytical GLC to
determine the product ratios was carried out with a Hewlett-
Packard 5880A gas chromatography employing a DB-1 bonded-
phase methylsilicon capillary column and flame-ionization de-
tector. All products were purified by flash chromatography using
silica gel 60 (70-230 mesh, Merck) and identified with 1H and
13C NMR spectral data obtained from a Varian Unity 300 MHz
NMR spectrometer using tetramethylsilane as an internal
standard.5,8
Typ ica l P r oced u r e. Ar yla tion of Dieth yl Meth ylm a -
lon a te (3). To a dry 2 mL DMF suspension of 60% sodium
hydride (2.0 mmol) was added a 2 mL DMF solution of diethyl
methylmalonate (3, 1.5 mmol) at 0 °C under argon atmosphere.
To the enolate solution, after it was stirred for 10 min, was added
a 2 mL DMF solution of diaryliodonium salt 7c (2.0 mmol). The
yellow reaction mixture was stirred until the reaction was
complete by TLC and then quenched with water (2 mL) at 0 °C.
After GC analysis, extractive workup and flash chromatography
using a 10:90 mixture of ethyl acetate and hexane as an eluent
afforded the corresponding products 6b and 6c in 74% and 8%
yields, respectively. 6b: 1H NMR (CDCl3, 300 MHz) δ 7.31 (d, J
) 8.4 Hz, 2H), 7.15 (d, J ) 8.4 Hz, 2H), 4.20 (q, J ) 7.0 Hz, 4H),
2.32 (s, 3H), 1.83 (s, 3H), 1.26 (t, J ) 7.0 Hz, 6H). 6c: 1H NMR
(CDCl3, 300 MHz) δ 7.26 (d, J ) 8.2 Hz, 2H), 6.88 (d, J ) 8.2
Hz, 2H), 4.18 (q, J ) 7.0 Hz, 4H), 3.72 (s, 3H), 1.78 (s, 3H), 1.22
(t, J ) 7.0 Hz, 6H).
Although a radical mechanism has been proposed in
reactions involving high valent iodonium salts,12 we could
not detect any reduced products such as benzene, toluene,
anisole, or 1,3,5-trimethoxybenzene. GC analysis of the
reaction mixture after a short path filtration through a
pad of silica gel showed only product peaks and their
byproduct peaks corresponding to 4-methoxyiodobenzene
or 4-iodotoluene. We reasoned that if a radical mecha-
nism in these reactions is operating, the product aryl-
malonates possessing electron-donating methoxy groups
should be a major product, because the 4-methoxyphenyl
radical is more stable than the phenyl radical as a result
of the electron-donating effect of the methoxy group.
Based on the reverse selectivity observed in our study,
we propose the addition-elimination mechanism shown
in Scheme 1.
Our observations strongly support the unified mech-
anism, originally proposed by Grushin and co-workers,13
in which the reactions of diaryliodonium salts with
malonates should form tricoordinated iodine intermedi-
Ack n ow led gm en t. This work was supported by the
Research Fund of Hanyang University (Project HYU-
98-064). We are also grateful to Prof. S.-K. Kang, Sung
Kyun Kwan University, for his valuable comments and
discussions.
(12) (a) Beringer, F. M.; Galton, S. A.; Huang, S. J . J . Am. Chem.
Soc. 1962, 84, 2819.
(13) (a) Grushin, V. V. Acc. Chem. Res. 1992, 25, 529. (b) Grushin,
V. V.; Demkina, I. I.; Tolstaya, T. P. J . Chem. Soc., Perkin Trans. 2
1992, 505.
J O981065B