A tandem epoxide isomerization-aldol condensation process catalyzed by palladium acetate-tributylphosphine

Full text of DOI:10.1021/jo961584j

7656
J . Org. Chem. 1996, 61, 7656-7657
A Ta n d em Ep oxid e Isom er iza tion -Ald ol
Con d en sa tion P r ocess Ca ta lyzed by
P a lla d iu m Aceta te-Tr ibu tylp h osp h in e
J i-Hyun Kim and Robert J . Kulawiec*,1
initial rapid isomerization of the epoxide to phenylac-
etaldehyde, followed by slower aldol condensation. We
saw no evidence for an initial aldol addition product (i.e.,
3-hydroxy-2,4-diphenylbutanal).
Department of Chemistry, Georgetown University,
Washington, DC 20057-1227
The isomerization-condensation reaction proceeds in
modest to good yield in a variety of solvents, with best
yields in polar media; we chose 2-methyl-2-propanol as
our standard solvent because of its superior yields and
moderate reflux temperature. This observation is in
accord with our recent discovery that the isomerization
of aryl-substituted epoxides proceeds much faster and in
higher yields in polar, protic solvents than in aromatic
hydrocarbons.10 Preliminary catalyst studies show that
3-12 mol % Pd(OAc)2 and a Pd:PBu3 ratio of 1:3 provides
satisfactory reaction time and yield. Using Pd(OAc)2-
PPh3 (1:3) as catalyst, rapid epoxide isomerization oc-
curs,10 but subsequent aldol condensation proceeds more
slowly than with PBu3, providing the enal in lower overall
yield (65% in 24 h).
Reaction of a variety of aryl-substituted epoxides under
these conditions produces the analogous (E)-2,4-diaryl-
2-butenals in moderate to good yields (Table 1, eq 2).11,12
In each case, the reaction mixture was refluxed until GC
indicated no further conversion of arylacetaldehyde to
enal, and the yields refer to isolated products, purified
by column chromatography. In the presence of 5 equiv
of another aldehyde, styrene oxide undergoes a tandem
isomerization-crossed aldol condensation reaction to
afford the corresponding (E)-3-substituted 2-phenylpro-
penal, as shown in eq 3 (Table 2).12,13 Under these
conditions, the reaction is completely chemoselective for
the crossed-condensation product; no self-condensation
(i.e., formation of enal 1) is observed. The stereochem-
Received August 15, 1996
The importance of developing new strategies designed
to increase synthetic efficiency in organic chemistry
continues to increase.2 One particular strategy that has
received a great deal of attention in recent years is the
development of sequential reactions3 (also known as
tandem or domino reactions), in which two or more
distinct bond-forming processes are carried out in a single
synthetic operation, without requiring isolation of inter-
mediates. While most cases of sequential reactions
documented in the recent literature involve ionic, radical,
and/or pericyclic reactions, the number of transition-
metal-mediated tandem reactions, many of which involve
Pd-catalyzed combinations of π-bonds, is increasing
rapidly.4 We have initiated a research program directed
toward the discovery and development of synthetically
useful reactions of small-ring heterocycles catalyzed by
transition metal complexes and now report a novel
palladium-catalyzed synthesis of R,â-unsaturated alde-
hydes under mild conditions, via a tandem isomeriza-
tion-aldol condensation reaction of aryl-substituted
epoxides.5
We recently described the application of electron-rich
palladium(0) complexes, generated in situ from Pd(OAc)2
and PR3 (R ) n-Bu, Ph),6 as catalysts for the chemo- and
regioselective isomerization of epoxides to carbonyl com-
pounds.7 During the course of these studies, we noticed
that prolonged reaction of 2-aryloxiranes with Pd(OAc)2-
PBu3 afforded, in addition to the expected arylacetalde-
hyde, an R,â-unsaturated aldehyde apparently arising via
aldol self-condensation of the primary isomerization
product. Thus, reaction of styrene oxide with Pd(OAc)2
(3 mol %) and PBu3 (3 equiv/Pd) in t-BuOH (reflux, 10
h) yielded (E)-2,4-diphenyl-2-butenal (1) in 79% isolated
yield (eq 1).8,9 Monitoring the reaction by capillary GC
clearly demonstrates that the overall process involves
(8) A representative experimental procedure is as follows:
A
suspension of Pd(OAc)2 (10 mg, 45 µmol, 3 mol %) in deoxygenated
t-BuOH (1.0 mL) was treated with tributylphosphine (33 µL, 0.13
mmol, 9 mol %) under N2, resulting in rapid formation of the yellow
Pd(0) catalyst. Styrene oxide (170 µL, 1.49 mmol) was added, and the
homogeneous solution was refluxed under N2 for 10 h. The mixture
was chromatographed directly on silica gel (6:1 hexane-ethyl acetate)
to afford (E)-2,4-diphenyl-2-butenal9 (1, 130.5 mg, 79%, Rf ) 0.43). 1
H
NMR (270 MHz, CDCl3): δ 9.66 (s, 1H), 7.44-7.15 (m, 10H), 6.87 (t,
J ) 7.3 Hz, 1H), 3.70 (d, J ) 7.3 Hz, 2H). IR (neat): 3085, 2925, 2849,
2712, 1687, 1633, 1520, 1494, 1453, 1369, 1232.
* To whom correspondence should be addressed. E-mail: kulawiecr@
guvax.georgetown.edu.
(1) Camille and Henry Dreyfus Foundation New Faculty Awardee,
1992.
(9) (E)-2,4-Diphenyl-2-butenal was previously prepared via aldol
self-condensation of phenylacetaldehyde and characterized by X-ray
crystallography; see: Axelsson, O.; Becker, H. D.; Skelton, B. W.;
Sørenson, H.; White, A. H. Aust. J . Chem. 1988, 41, 727-733.
(10) Kulasegaram, S.; Kulawiec, R. J . Abstracts of Papers, 29th
Middle Atlantic Regional Meeting of the American Chemical Society,
Washington, DC, 1995; poster no. 253.
(11) Product stereochemistry is assigned by analogy to compound
1, the double-bond geometry of which was determined unambiguously;
see ref 9.
(2) (a) Hudlicky, T. Chem. Rev. 1996, 96, 3-30. (b) Trost, B. M.
Angew. Chem., Int. Ed. Engl. 1995, 34, 259-281. (c) Wender, P. A.;
Miller, B. L. In Organic Synthesis: Theory and Applications; Hudlicky,
T., Ed.; J AI Press: Greenwich, CT, 1993; Vol. 2, pp 27-66.
(3) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115-136. (b) Tietze, L. F.;
Beifuss, U. Angew. Chem., Int. Ed. Engl. 1993, 32, 131-163. (c) Ho,
T.-L. Tandem Organic Reactions; Wiley: New York, 1992.
(4) For leading examples, see: (a) Carpenter, N. E.; Kucera, D. J .;
Overman, L. E. J . Org. Chem. 1989, 54, 5846-5848. (b) Grigg, R.;
Dorrity, M. J .; Malone, J . F.; Sridharan, V.; Sukirthalingam, S.
Tetrahedron Lett. 1990, 31, 1343-1346. (c) Zhang, Y.; Wu, G.; Agnel,
G.; Negishi, E. J . Am. Chem. Soc. 1990, 112, 8590-8592. (d) Oppolzer,
W.; De Vita, R. J . J . Org. Chem. 1991, 56, 6256-6257. (e) Trost, B.
M.; Shi, Y. J . Am. Chem. Soc. 1993, 115, 9421-9438. (f) Padwa, A.;
Weingarten, M. D. Chem. Rev. 1996, 96, 223-269.
(5) Part of this work has been communicated: Kim, J .-H.; Kulawiec,
R. J . Abstracts of Papers, 210th National Meeting of the American
Chemical Society, Chicago, IL; American Chemical Society: Washing-
ton, DC, 1995; ORGN 0151.
(6) Mandai, T.; Matsumoto, T.; Tsuji, J .; Saito, S. Tetrahedron Lett.
1993, 34, 2513-2516.
(7) Kulasegaram, S.; Kulawiec, R. J . J . Org. Chem. 1994, 59, 7195-
7196.
(12) All new compounds have been fully characterized by spectro-
scopic techniques.
(13) A representative experimental procedure is as follows: The Pd-
(0) catalyst was generated from Pd(OAc)2 (20 mg, 89 µmol, 12 mol %)
and tributylphosphine (66 µL, 0.27 mmol, 36 mol %) in deoxygenated
t-BuOH (1.0 mL). After addition of benzaldehyde (377 µL, 3.73 mmol,
5 equiv), the mixture was stirred at room temperature for 20 min, and
styrene oxide (85 µL, 0.75 mmol) was added. After the mixture was
refluxed for 48 h, only benzaldehyde, phenylacetaldehyde, and the
crossed-aldol condensation product were observed by GC; the latter,
(E)-2,3-diphenylpropenal (2, 51 mg; 33% based on epoxide), was
isolated by chromatography (silica gel, 6:1 hexane-ethyl acetate, Rf
) 0.48). 1H NMR (270 MHz, CDCl3): δ 9.78 (s, 1H), 7.40-7.18 (m,
11H). IR (neat): 3061, 2891, 2717, 1695, 1628, 1544, 1461, 1419, 1218,
1095. For a previous synthesis, see: Nerdel, F.; Weyerstahl, P.; Ku¨hne,
D.; Lengert, H.-J . Liebigs Ann. Chem. 1968, 718, 115-119.
S0022-3263(96)01584-8 CCC: $12.00 © 1996 American Chemical Society

Communications
J . Org. Chem., Vol. 61, No. 22, 1996 7657
Ta ble 1
Although a number of reports describe the direct eno-
lization of activated carbonyl compounds by low-valent
metal catalysts,16 suggesting the possible relevance of a
Pd-enolate intermediate in the present case, we believe
that traces of base (most likely acetate17) present in the
reaction mixture may also be responsible in part for the
aldol condensation. This hypothesis is supported by our
observation that the yield of enal formed in the tandem
isomerization-aldol condensation of p-fluorostyrene ox-
ide is increased from 60% to 66% upon addition of 6 mol
% NaOAc. Similarly, addition of tributylamine (1 equiv)
improves the yield of 2 formed via isomerization-crossed
condensation of styrene oxide with benzaldehyde from
33% to 57%.
Ar
timeb (h)
yieldc (%)
C6H5
p-MeC6H4
p-FC6H4
p-MeOC6H4
2-naphthyl
10
22
23
23
50
79 (1)
81
60
48
48
a
Pd(OAc)2 (3-5 mol %), PBu3 (3 equiv/Pd), t-BuOH, reflux.
b
Time after which no further conversion to enal was observed.
c All yields refer to isolated, purified compounds and are unopti-
mized.
In summary, this report demonstrates the novel con-
cept that 2-aryloxiranes can serve as synthons for aryl-
acetaldehyde enolates in a novel tandem epoxide isomer-
ization-aldol condensation process, in which both self-
and crossed-condensations are possible. Although yields
are sometimes moderate, they represent overall yields
for both steps in the reaction sequence and in many cases
are comparable to those obtained in classical crossed-
aldol condensation reactions.18 We have also shown that
relatively unactivated carbonyl compounds can undergo
direct enolization under mild conditions in the presence
of Pd(OAc)2-PBu3 and are continuing to explore the
implications of these findings for other palladium-medi-
ated enolate reactions.
Ta ble 2
R
time (h)
yieldb (%)
C6H5
48
24
48
26
48
33 (2)
62
43
11
33
2-furyl
p-FC6H4
p-MeOC6H4
CH3CH2CH2
a
Pd(OAc)2 (12 mol %), PBu3 (3 equiv/Pd), 5 equiv of RCHO per
b
styrene oxide, t-BuOH, reflux. Time after which no further
conversion to enal was observed. c All yields (unoptimized) are
based on epoxide and refer to isolated, purified compounds.
Ack n ow led gm en t. We are grateful to Georgetown
University for financial support (in particular, for a
Summer Academic Grant to R.J .K.), to Dr. Miroslav
Rapta for the X-ray crystallographic study of 2, to Mr.
Admassu Regassa for assistance with the molecular
mechanics calculations, to Dr. Lewis Pannell of the
NIDDK for high-resolution mass spectrometry, and to
Ms. Sanjitha Kulasegaram for preliminary studies that
led to this work. R.J .K. thanks the Camille and Henry
Dreyfus Foundation for a New Faculty Award.
istry of one of the aldol condensation products ((E)-2,3-
diphenylpropenal, 2) was determined unambiguously by
a single-crystal X-ray diffraction study.14 The tandem
isomerization-condensation process also occurs with
alkanals; thus, reaction of styrene oxide with butanal (eq
3) produced (E)-2-phenyl-2-hexenal in 33% yield.12 How-
ever, in the presence of 2-butanone (5 equiv) we isolated
only enal 1 in 40% yield, with no trace of ketone-derived
condensation products, demonstrating chemoselectivity
for condensation with aldehydes over ketones.
In a control experiment, treatment of phenylacetalde-
hyde under the same conditions employed in eq 2 (Pd-
(OAc)2-PBu3, reflux, 10 h) also yielded the aldol conden-
sation product 1, albeit in considerably lower yield (eq
4). The epoxide isomerization reaction is thought to
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures, including characterization data for all new com-
pounds, preliminary X-ray data on compound 2, and details
of the molecular mechanics study (17 pages).
J O961584J
(15) For literature precedent for this mechanistic proposal, see: (a)
Calhorda, M. J .; Galva˜o, A. M.; U¨ naleroglu, C.; Zlota, A. A.; Frolow,
F.; Milstein, D. Organometallics 1993, 12, 3316-3325. (b) Milstein,
D.; Calabrese, J . C. J . Am. Chem. Soc. 1982, 104, 3773-3774 and
references therein.
(16) For representative examples, see: (a) Ito, Y.; Sawamura, M.;
Hayashi, T. J . Am. Chem. Soc. 1986, 108, 6405-6406. (b) Paganelli,
S.; Schionato, A.; Botteghi, C. Tetrahedron Lett. 1991, 32, 2807-2810.
(c) Lin, Y.; Zhu, X.; Xiang, M. J . Organomet. Chem. 1993, 448, 215-
218. (d) Murahashi, S.-I.; Naota, T.; Taki, H.; Mizuno, M.; Takaya,
H.; Komiya, S.; Mizuho, Y.; Oyasato, N.; Hiraoka, M.; Hirano, M.;
Fukuoka, A. J . Am. Chem. Soc. 1995, 117, 12436-12451.
(17) (a) Amatore and co-workers have shown17b that reduction of
Pd(OAc)2 by PR3 generates Pd(OAc)(PR3)n-, HOAc, and R3PdO; thus,
acetate is likely to be present in our reactions. (b) Amatore, C.; Carre´,
E.; J utand, A.; M’Barki, M. A.; Meyer, G. Organometallics 1995, 14,
5605-5614. (c) We also find that NaOAc (5 mol %) catalyzes the aldol
self-condensation of phenylacetaldehyde to 1; however, other likely
impurities (Pd(OAc)2, PBu3, HOAc) do not. See the supporting informa-
tion for details.
proceed via a metal hydrido-enolate complex intermedi-
ate,15 which may undergo an aldol addition reaction with
free aldehyde; however, the result depicted in eq 4
demonstrates that direct enolization of the arylacetalde-
hyde must also occur under these reaction conditions.
(14) See the supporting information for details of the crystal-
lographic study. The indicated stereochemistry of the crossed-
condensation products is supported by molecular mechanics calcula-
tions (MM+). In all cases, optimization using the Polak-Ribiere
algorithm with a root mean square gradient of 0.4 kcal/[Å mol] gave
the (E) stereoisomer as the stable configuration; see the supporting
information for details.
(18) Nielsen A. T.; Houlihan, W. J . Org. React. 1968, 16, 1-438.