Lewis acid catalyzed reaction of aromatic vinyl halides with aromatic aldehydes: A novel aldol-type condensation mimic

Article abstract of DOI:10.1055/s-2001-14664

In the presence of catalytic amounts of Lewis acid, aromatic α-vinyl halides readily undergo reaction with aromatic aldehydes at ambient temperatures to give a variety of substituted transchalcones in moderate to excellent yields. These compounds are potentially useful synthetic intermediates for organic synthesis as well as compounds of significance in terms of their ability to exhibit a wide spectrum of biological activity. This is the first reported example in which haloalkenyl derivatives other than metallooxyalkenes can participate in the Mukaiyama-aldol type carbon-carbon formation reaction.

Full text of DOI:10.1055/s-2001-14664

910
LETTER
Lewis Acid Catalyzed Reaction of Aromatic Vinyl Halides with Aromatic
Aldehydes: A Novel Aldol-type Condensation Mimic
Philip W. H. Chan, Shin Kamijo, Yoshinori Yamamoto*
Department of Chemistry, Graduate School of Science, Tohoku University, Sendai 980-8578, Japan
Fax +81-22-217-6784; E-mail: yoshi@yamamoto1.chem.tohoku.ac.jp
Received 12 January 2001
thesis but also provides ease of access to a class of com-
Abstract: In the presence of catalytic amounts of Lewis acid, aro-
pounds known to exhibit antibacterial, antiviral, gastric
matic -vinyl halides readily undergo reaction with aromatic alde-
protectant, antimutagenic, retinoid, antimitotic and antiin-
hydes at ambient temperatures to give a variety of substituted trans-
chalcones in moderate to excellent yields. These compounds are po-
flammatory activities in their own right.3
tentially useful synthetic intermediates for organic synthesis as well
as compounds of significance in terms of their ability to exhibit a
hyde 2a was initially chosen to establish the optimum
wide spectrum of biological activity. This is the first reported exam-
The reaction between -bromostyrene 1a and benzalde-
temperature, solvent and catalyst conditions (Scheme 1
ple in which haloalkenyl derivatives other than metallooxyalkenes
and Table 1). Thus, whilst pleased that the reaction pro-
ceeded smoothly at high temperature in the absence of
both a catalyst and solvent to give trans-chalcone 4a4 in
good yield (entry 1), it gave us greater satisfaction to
achieve similar results at room temperature in a few cases
with the introduction of a variety of stiochiometric
amounts of Lewis acid catalysts in CH2Cl2 (entries 2-10).
Under these applied conditions optimum yields were ob-
tained when the reaction was carried out with BF3 Et2O
(entry 4).
can participate in the Mukaiyama-aldol type carbon-carbon forma-
tion reaction.
Key words: Lewis acid, catalysis, -halostyrenes, aromatic alde-
hydes, substituted trans-chalcones
The emergence of the Mukaiyama-aldol protocol over the
latter part of the 20th century has established the aldol re-
action as one of the most powerful tools in organic synthe-
sis.1 Relying on the use of Lewis acid catalyzed metal
generated enol ether nucleophiles, the ability to furnish With the catalyst of choice established, a variety of sol-
important synthetic intermediates and target compounds vents were surveyed to establish the influence of the reac-
in an expedient and stereoselective manner has played a tion medium on yield. In comparing the yield obtained for
significant role in its rise to prominence. To date, much at- the model study carried out in CH2Cl2 (entry 4), the use of
tention within this field has primarily focused upon the relatively less polar solvents furnished 4a in moderately
development of this particular aspect of the reaction with lower yields (entries 11, 12). As for solvents of relatively
the view of optimizing yields and stereoselectivity. In higher polarity, with the exception of MeCN (entry 13),
studies directed towards exploring the possibility of relat- either trace product formation was observed or no reaction
ed reactions, we report herein a novel aldol-type conden- was detected (entries 14, 15). In contrast, optimum yields
sation mimic. This involved a variety of aromatic vinyl were obtained when the reaction was carried out in the ab-
halides and aldehydes to readily undergo reaction when sence of solvent with the reaction requiring only a catalyt-
subjected to catalytic amounts of Lewis acid at ambient ic amount of BF3·Et2O (20mol%). Under these conditions,
temperatures to give the corresponding diaryl propenones a mixture of the -halo ketone intermediate 3a5 and 4a in
in moderate to excellent yields.2 This new one step car- 19% and 66% yield respectively was obtained with the
bon-carbon bond formation procedure not only delivers former readily converting to 4a upon purification (entry
potentially useful synthetic intermediates for organic syn- 16).6
X
O
O
X
see Table 1
RT, 24hrs
+
R2CHO
+
R1
R1
R2
R2
R1
2
3
4
1
2a, R2 = Ph
1a, R1 = Ph, X = Br
2b, R2 = p-CF3 (C6H4)
2c, R2 = p-NO2(C6H4)
2d, R2 = 1-naph
1b, R1 = Ph, X = I
1c, R1 = p-Me(C6H4), X = I
1d, R1 = p-CF3 (C6H4), X = I
1e, R1 = p-F(C6H4), X = I
Et3N, CH2Cl2
RT, 30min
2e, R2 = p-Me(C6H4)
Scheme 1
Synlett 2001, SI, 910–913 ISSN 0936-5214 © Thieme Stuttgart · New York

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LETTER
Table 1 The Reaction of -Bromostyrene 1a with Benzaldehyde
2a under Various Conditions
give the corresponding product(s) 3 and 4 in moderate to
excellent yields (Table 2). Reaction of -iodostyrene 1b7
with benzaldehyde 2a, for example, afforded trans-chal-
cone 4a exclusively as the sole product in 84% yield (en-
try 1). Similarly, the reaction of 1a with aromatic
aldehydes bearing electron withdrawing groups (EWG)
afforded mixtures of the corresponding products 3b and
4b, and 3c and 4c in excellent overall yields (entries 2-3).
In both cases, the conversion of the former to the latter
was readily achieved in quantative yields on addition of
Et3N. In comparison, the reaction of 1a with aromatic al-
dehydes bearing electron donating groups (EDG) pro-
ceeded to give the corresponding adducts 4d and 4e in
only moderate to good yields (entries 4-5). Conversely,
the opposite was observed for reactions of a variety of ar-
omatic vinyl halides bearing either EDG or EWG with
benzaldehyde 2a. Thus, in the case of reaction of 1c bear-
ing a methyl EDG with 2a, the corresponding adduct 4f
was furnished in 61% yield despite its relative instability
under acidic conditions (entry 6). In contrast, the analo-
gous reaction of 2a with 1e bearing an F EWG gave 4h in
only 44% yield whilst reaction of 2a with 1d bearing an
even stronger EWG in the form of CF3 gave no reaction
(entries 7, 8).
aGC yields.
bCarried out at 120 °C for 24 h.
cIsolated yield.
d1 molar equivalent.
e0.2 molar equivalent.
f3a was also obtained in 19% yield.
In an attempt to understand the mechanism of our novel
vinyl halide-aldehyde protocol, the reaction of 1c with
benzaldehyde-d8 was undertaken to give the deuterated
product 4i in 21% yield (Scheme 2). H NMR spectro-
scopic analysis of 4i enabled its d-content to be deter-
The generality of the present novel reaction was next in-
vestigated. In employing either CH2Cl2 or solvent-free
conditions in the presence of a catalytic amount of
BF3·Et2O (20mol%), a variety of other aromatic vinyl ha-
lides 1 and aldehydes 2 proceeded in a similar manner to
1
mined to be nearly 100%. This was achieved by observing
Table 2 The Reaction of a Variety of Substituted Aromatic Vinyl Halides 1 and Aldehydes 2
aUsed as a 1M solution in CH2Cl2.
bUsed as a 2M solution in CH2Cl2.
cNo reaction under a variety of conditions.
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LETTER
I
BF3.Et2O
Ph
D
I
O
D
CH2Cl2, RT
O
Ph
BF3.Et2O
Me
Me
5
1c
O
I
D
O
D
Ph
H
Ph
Me
Me
3f
4i
Scheme 2
the complete absence of the AB system in 4i, as seen to be in which alkenyl derivatives other than metallooxyalk-
present in its non-deuterated analogous adduct 4f,9 along enes can participate in the Mukaiyama-aldol type carbon-
with the replacement of this splitting pattern with a singlet carbon formation reaction.
signal at 7.52. More significantly, this analysis also
strongly implied the most probable involvement of an ex-
Acknowledgement
clusively intramolecular hydrogen transfer step at some
point in the reaction mechanism.10 Consequently, on the
This work was partially financially supported by a Grant-in-Aid for
Scientific Research from the Ministry of Education, Science and
Culture of Japan.
basis of this data, we reasoned that the mechanism of our
present reaction proceeded via the cationic intermediate 5
generated from the initial 1,2-addition of the vinyl halide
1 to the aldehyde 2. Preferential intramolecular rearrange-
ment of this reactive intermediate in the form of a 1,3-hy-
dride shift then furnished the more stable -halo ketone 3.
The isolation of 3 (Table 1, entry 16 and Table 2, entries
2-3) in a few cases, in turn, augmented the credibility of
our proposed mechanism. The , -unsaturated carbonyl
product 4 is then finally afforded upon subsequent hydro-
gen halide elimination, the rate of which is further en-
hanced when exposed to basic conditions (Scheme 2).
References and Notes
(1) For general reviews see: (a). Heathcock, C. H. In
Comprehensive Organic Synthesis, (Eds.: Trost. B. M.;
Fleming, I.), Pergamon Press, Oxford 1991, Vol. 2, pp 133-
179, 181-238. (b). Moon Kim, B.; Williams S. F.; Masamune,
S. In Comprehensive Organic Synthesis, (Eds.: Trost. B. M.;
Fleming, I.), Pergamon Press, Oxford 1991, Vol. 2, pp 239-
275. (c). Paterson, I. In Comprehensive Organic Synthesis,
(Eds.: Trost. B. M.; Fleming, I.), Pergamon Press, Oxford
1991, Vol. 2, pp 301-319. (d). Gennari, C. In Comprehensive
Organic Synthesis, (Eds.: Trost. B. M.; Fleming, I.),
Pergamon Press, Oxford 1991, Vol. 2, pp 629-660. (e). Braun,
M. In Stereoselective Synthesis (Houben-Weyl, Methods of
Organic Chemistry), (Eds.: Helmchen, G.; Hoffmann, R. W.;
Mulzer J.; Schaumann, E.), George Thieme Verlag, Stuttgart
1995, Vol. E21b, pp 1603-1666, 1713-1735. (f). Franklin A.
S.; Paterson, I. Contemp. Org. Syn. 1994, 1, 317-338.
(g). Mahrwald, R. Chem. Rev. 1999; 99, 1095-1120.
(2) Dhar, D. N. Chemistry of Chalcones and Related Compounds,
Wiley, New York 1981.
In order to determine the structure of the product unam-
biguously, the ozonolysis of 4b was carried out under
standard conditions (Scheme 3). As anticipated, in obtain-
ing benzaldehye 2a as the sole product, this result also
confirmed the structure of the aldol-type product.
O
O3, 4/1 MeOH:CH2Cl2
F3C
PhCHO
PPh3, -78oC-RT
Ph
(3) (a). Batt, D. G.; Goodman, R.; Jones, D. G.; Kerr, J. S.;
Mantegna, L. R.; McAllister, C.; Newton, R. C.; Nurnberg, S.;
Welch, P. K.; Covington, M. B. J. Med. Chem. 1993, 36,
1434-1442 and references therein. (b). Bowden, K.; Dal
Pozzo, A.; Duah, C. K. J. Chem. Res, Synop. 1990, 12, 2801-
30.
4b
2a
Scheme 3
(4) For a comparison of spectroscopic data, refer to: Pouchert C.
J.; Behnke, J. The Aldrich Library of 13C and 1H FT NMR
Spectra, ed. I, 2, 875C.
(5) For a comparison of spectroscopic data, refer to: Le Roux, C.;
Gaspard-Iloughmane, H.; Dubac, J. J. Org. Chem. 1994, 59,
2238-2240.
(6) Typical procedure: To an argon flushed solution of
-bromostyrene 1a (0.5mmol) and benzaldehyde 2a
(0.5mmol) was added BF3·Et2O (0.1mmol) at r.t. and allowed
to stir at this temperature for 24 h. The reaction mixture was
then quenched with water, extracted with CH2Cl2 (3 25 mL)
and the combined organic layers were dried over MgSO4 and
In conclusion, we have demonstrated a novel aldol-type
condensation mimic that allows access to a variety of sub-
stituted diaryl -halopropanones 3 and biologically active
trans-chalcones 4 based on the facile Lewis acid mediated
reaction of aromatic vinyl halides with aldehydes at
ambient temperatures. We have also provided strong ex-
perimental evidence to propose a plausible reaction mech-
anism for this new transformation. Although the scope of
the present novel reaction is limited to aromatic deriva-
tives at the present stage, this is the first reported example
Synlett 2001, SI, 910–913 ISSN 0936-5214 © Thieme Stuttgart · New York

913
LETTER
(9) 4f: 1H NMR (300 MHz, [CDCl3], 25 °C, TMS) 7.87 (d,
filtered. Concentration and purification by recrystallization
(CH2Cl2/n-hexanes) gave the bromide intermediate 3a,
followed by silica gel chromatography and recycle
3J(H,H) 8.3Hz, 2H, ArCH), 7.74 (d, 3J(H,H) 15.7Hz, 1H,
C = CH), 7.57 (dd, 3J(H,H) 6.0 & 4.0Hz, 2H, ArCH), 7.47 (d,
3J(H,H) 15.7Hz, 1H, CH = C), 7.33 (dd, 3J(H,H) 5.6 & 2.4Hz,
3H, ArCH), 7.23 (d, 3J(H,H) 8.1Hz, 2H, ArCH), 2.36 (s, 1H,
CH3); 4i: 1H NMR (300MHz, [CDCl3], 25°C, TMS) 7.92 (d,
3J(H,H) 8.1Hz, 2H, ArCH), 7.61-7.65 (m, 2H, ArCH), 7.52 (s,
1H, CH = C), 7.38-7.41 (m, 3H, ArCH), 7.23-7.30 (m, 2H,
ArCH), 2.42 (s, 1H, CH3).
preparatory HPLC for analytical purposes, to furnish trans-
chalcone 4a. 3a: 1H NMR (300 MHz, [CDCl3], 25 °C, TMS)
7.94 (m, 2H, ArCH), 7.25-7.61 (m, 8H, ArCH), 5.67 (dd,
3J(H,H) 7.9 & 6.0Hz, 1H, PhC(I)H), 4.11 (dd, 3J(H,H) 17.5 &
8.1Hz, 1H, C(I)CH), 3.80 (dd, 3J(H,H) 17.5 & 6.0Hz, 1H,
C(I)CH); MS (70V): m/z (%): 290 (3) [M+H], 105 (100)
[C7H6O-H]; HRMS: Calcd. for C15H13BrO: 288.0150. Found:
288.0155; 4a: 1H NMR (300MHz, [CDCl3], 25°C, TMS)
7.94-8.20 (m, 1H, ArCH), 7.65-7.79 (m, 1H, ArCH), 7.56-
7.65 (m, 1H, ArCH), 7.31-7.42 (m, 9H, ArCH & CH = CH);
MS (70V): m/z (%): 208 (100) [M·]; HRMS: Calcd. for
C15H12O: 208.0888. Found: 208.0890
(10) For other examples of known reactions resulting in hydride
extraction occurring from initial nucleophilic addition, refer
to: (a). Ashby, E. C.; Coleman D.; Gamasa, M. J. Org. Chem.
1987, 52, 4079-4085. (b). Swain, C. G.; Powell, A. L.;
Sheppard W. A.; Morgan, C. R. J. Am. Chem. Soc. 1979, 101,
3576-3583. (c). March, J. Advanced Organic Chemistry, John
Wiley and Sons, New York 1992, 1235.
(7) Lee, K; Wiemer, D. F. Tetrahedron Lett. 1993, 34, 2433-2436.
(8) Babler, J. H.; Invergo, B. J. Tetrahedron Lett. 1980, 22, 11-14.
Article Identifier:
1437-2096,E;2001,0,SI,0910,0913,ftx,en;Y20400ST.pdf
Synlett 2001, SI, 910–913 ISSN 0936-5214 © Thieme Stuttgart · New York