A unique cascade reaction between 3-arylprop-2-inylcarboxylates and benzaldehydes leading to the formation of Morita-Baylis-Hillman adducts

Article abstract of DOI:10.1021/ol303319a

During an alkyne-carbonyl metathesis reaction between electron-rich 3-arylprop-2-inylcarboxylates and electron-poor benzaldehydes, a smooth migration of carboxylate groups takes place. This unique cascade reaction allows the formation of Morita-Baylis-Hillman (MBH) adducts unavailable via a traditional MBH reaction.

Full text of DOI:10.1021/ol303319a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
A Unique Cascade Reaction between
3‑Arylprop-2-inylcarboxylates and
Benzaldehydes Leading to the Formation
of MoritaÀBaylisÀHillman Adducts
Ieva Karpaviciene and Inga Cikotiene*
Department of Organic Chemistry, Faculty of Chemistry, Vilnius University,
Naugarduko 24, LT-03225, Vilnius, Lithuania
inga.cikotiene@chf.vu.lt
Received December 4, 2012
ABSTRACT
During an alkyne-carbonyl metathesis reaction between electron-rich 3-arylprop-2-inylcarboxylates and electron-poor benzaldehydes, a smooth
migration of carboxylate groups takes place. This unique cascade reaction allows the formation of MoritaÀBaylisÀHillman (MBH) adducts
unavailable via a traditional MBH reaction.
The MoritaÀBaylisÀHillman adducts (MBHAs) and
their derivatives are useful intermediates in organic synthe-
sis and therefore are widely used in target-oriented synthe-
sis.1 Various natural products and molecules of biological
interest were synthesized from MBHAs.2 Moreover, some
MBHAs showed antiparasitic, antibacterial, antifungal,
herbicidal, and in some cases antitumor activities.3
a reaction between aldehydes and activated alkenes.4 How-
ever the formation of MBHAs from arylvinyl ketones
during a classical MBH reaction usually fails due to the
high reactivity of starting materials.5 Therefore, there are
only a few examples of a successful synthesis of MBHAs
from arylvinyl ketones in the literature.6 Thus, Trofimov
and Gevorgyan utilized a sila-MBH reaction using an
R-silylated arylvinyl ketone in the presence of a phosphine
catalyst.6a Some time later, Oh and Li reported a coopera-
tive catalyst system of proline and brucine N-oxide.6b And
very recently, Kim et al. reported on the use of 4-nitrophe-
nol as a proton donor for a successful MBH reaction.6c
During investigation of the synthesis of various biologi-
cally important unsaturated ketones via alkyne-carbonyl
metathesis reactions,7 we observed the really unique re-
activity of some substrates. We noticed that during Lewis
acid catalyzed reactions between 3-arylprop-2-inylcarbox-
ylates and aromatic aldehydes, four possible products can
Classically MBHAs are synthesized via a highly efficient
MoritaÀBaylisÀHillman reaction which basically involves
(1) (a) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511 and references
therein. (b) Wang, Y.; Liu, L.; Zhang, T.; Zhong, N. J.; Wang, D.; Chen,
Y. J. J. Org. Chem. 2012, 77, 4143. (c) Xu, S.; Chen, R.; Quin, Z.; Wu, G.;
He, Z. Org. Lett. 2012, 14, 996. (d) Wu, C.; Liu, Y.; Zeng, H.; Liu, L.;
Wang, D.; Chen, Y. Org. Biomol. Chem. 2011, 9, 253.
(2) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Chem. Rev. 2010, 110,
5447 and references therein.
(3) (a) Lima-Junior, C. G.; Vasconcellos, M. L. A. A. Bioorg. Med.
Chem. 2012, 20, 3954 and references therein. (b) Kohn, L. K.; Pavam,
C. H.; Veronese, D.; Coelho, F.; De Carvalho, J. E.; Almeida, W. P. Eur.
J. Med. Chem. 2006, 41, 738.
(4) (a) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968,
41, 2815. (b) Baylis, A. B.; Hillman, M. E. D. German Patent 2155113,
1972. (c) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007,
46, 4614. (d) Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 18, 2905. (e)
Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. Rev. 2003, 103, 811.
(f) Krafft, M. E.; Haxell, T. F. N. J. Am. Chem. Soc. 2005, 127, 10168.
(g) Declerck, V.; Martinez, J.; Lamaty, F. Chem. Rev. 2009, 109, 1. (h) Shi,
M.; Wang, F.-J.; Zhao, M.-X.; Wei, Y. The Chemistry of the MoritaÀ
BaylisÀHillman Reaction; RSC Publishing: Cambridge, U.K., 2011.
(5) (a) Shi, M.; Li, C.-Q.; Jiang, J.-K. Helv. Chim. Acta 2002, 85, 1051.
(b) Basavaiah, D.; Gowriswari, V. V. L; Bharathi, T. K. Tetrahedron
Lett. 1987, No. 28, 4591. (c) Shi, M.; Li, C.-Q.; Jiang, J.-K. Molecules
2002, 7, 721.
(6) (a) Trofimov, A.; Gevorgyan, V. Org. Lett. 2009, 11, 253. (b) Oh,
K.; Li, J.-Y. Synthesis 2011, 1960. (c) Kim, S. H.; Kim, S. H.; Lim, C. H.;
Kim, J. N. Bull. Korean Chem. Soc. 2012, 33, 2023.
r
10.1021/ol303319a
XXXX American Chemical Society

Table 1. Diversity of Products Formed during Reactions between 3-Arylprop-2-inylcarboxylates and Aldehydes
reaction
overall
entry
starting alkyne
aldehyde
R1 = c-Hex
time
2:3:4:5
1:0:0:0
products
2aa
yield, %
1
1a: Ar = Ph; R = Me
24 h
49%
69%
38%
22%
12%
61%
47%
24%
61%
45%
77%
67%
40%
À
2
1a
R1 = 2,4-Cl2C6H3
R1 = 2-NO2C6H4
R1 = 4-MeC6H4
R1 = 4-MeOC6H4
R1 = 4-NO2C6H4
R1 = C6F5
30 h
2:1:0:0
2.8:1:0:0
0:0:1:0
0:0:1:0
5:1.6:0:1
0:1:0:3.3
1:0:0:0
4.5:1:0:0
4.8:4:0:1
1:2.6:0:1.5
0:0:0:1
0:0:0:1
À
2ab, 3ab
3
1a
72 h
2ac, 3ac
4
1a
120 h
1.5 ha
48 h
4ad
5
1a
4ae
6
1a
2af, 3af, 5afb
7
1a
48 h
3ah, 5ahc
8
1b: Ar = Ph; R = Ph
R1 = c-Hex
24 h
2ba
9
1b
R1 = 2,4-Cl2C6H3
R1 = 2-NO2C6H4
R1 = 2-NO2-4-(CF3)C6H3
R1 = 2,4-(NO2)2C6H3
R1 = C6F5
48 h
2bb, 3bb
10
11
12
13
14
15
16
17
18
19
20
21
22
1b
24 h
2bc, 3bc, 5bcd
1b
48 h
2bd, 3bd, 5bde
1b
24 h
5be
5bf
À
1b
48 h
1c: Ar = 4-NO2C6H4; R = Ph
R1 = c-Hex
n.r.
1c
R1 = 2,4-(NO2)2C6H3
R1 = C6F5
n.r.
À
À
À
1c
n.r.
À
À
À
1d: Ar = 4-MeOC6H4; R = Me
R1 = Me
5 min
5 min
5 min
5 min
10 min
5 min
1:0:0:0
0:0:1:0
0:0:0:1
0:0:0:1
0:0:0:1
0:0:0:1
2da
4db
5dc
5dd
5ea
5eb
52%
38%
86%
82%
88%
70%
1d
R1 = 4-MeOC6H4
R1 = 2,4-Cl2C6H3
R1 = 4-NO2C6H4
R1 = 2,4-Cl2C6H3
R1 = 4-NO2C6H4
1d
1d
1e: Ar = 4-MeOC6H4; R = Ph
1e
a The reaction mixture was refluxed. b 2af and 5af were isolated as a mixture due to same Rf’s. Their ratio was determined from 1H NMR spectrum.
c 3ah and 5ah were not isolated as individual compounds due to the same Rf’s. Their ratio was determined from 1H NMR spectrum. d 3bc and 5bc were not
isolated as individual compounds due to the same Rf’s. Their ratio was determined from 1H NMR spectrum. e Products were not isolated as individual
compounds due to similar Rf’s. Their ratio was determined from 1H NMR spectra.
be obtained. We were pleasantly surprised to see that in
some cases the derivatives of MBHAs formed as main
reaction products. Keeping in mind that 2-aroyl-1-arylal-
lylcarboxylates are privilleged structures and they are not
easily synthetically available, we decided to study reactions
between 3-arylprop-2-inylcarboxylates and aromatic alde-
hydes and to determine the factors dictating the outcome
of the reactions. So herein, we report the results of our
investigations and present a unique cascade reaction com-
prising the formal alkyne-carbonyl metathesis followed by
the sigmatropic [3,3] migration of carboxylate.
catalyzed coupling reaction with aldehydes. Several Lewis
acids such as BF3*Et2O, FeCl3, AgSbF6, SbF5, BBr3,
TMSOTf, different solvents (DCM, DCE, CH3CN, THF,
CH3NO2), and different reaction temperatures were ex-
amined. After this brief search of the most suitable reac-
tion conditions, we came to conclusion that 1 equiv of
BF3*Et2O in dichloromethane at rt gave the best results.
The data for reactions between 3-arylprop-2-inylcarbox-
ylates 1aÀe and various aldehydes under the optimal
conditions are summarized in Table 1.
It should be noted that the rate of the reactions strongly
depends on the substituents on the arene moiety of
3-arylprop-2-inylcarboxylates 1. Thus, the reaction of
unsubstituted 3-phenylprop-2-inylcarboxylates 1a,b with
various aldehydes generally required one to several days
forfull conversionof thestartingmaterials(Table1, entries
1À4; 6À13). Unfortunately, introduction of an electron-
withdrawing nitro group into the 3-arylprop-2-inylcarbox-
ylate structure (compound 1c) deactivates the starting
material toward coupling with aldehydes (entries 14À16).
In these cases the starting material was recovered after
the workup of reaction mixtures. On the other hand, the
First, we prepared the starting 3-arylprop-2-inylcarbox-
ylates 1 by means of the classical Sonogashira coupling8
between aryliodides and propargyl acetates or benzoates.
Then we tested their reactivity toward the Lewis acid
(7) (a) Viswanathan, S. G.; Li, C.-J. Tetrahedron Lett. 2002, 43, 1613.
(b) Xu, L. W.; Li, L.; Xia, C. G.; Zhao, P. Q. Helv. Chim. Acta 2004, 87,
3080. (c) Curini, M.; Epifano, F.; Maltese, F.; Rosati, O. Synlett 2003,
552. (d) Rhee, J. U.; Krische, M. J. Org. Lett. 2005, 7, 2493. (e) Hsung,
R. P.; Zificsak, C. A.; Wei, L. L.; Douglas, C. J.; Xiong, H.; Mudler, J. A.
Org. Lett. 1999, 1, 1237.
(8) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett.
1975, 16, 4467.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Synthesis of MBHA Carboxylates by the Presented Method
aldehyde;
reaction
time
entry
starting alkyne
1b: Ar = Ph; R = Ph
Ar1:
product
yield, %
1
2,4-(NO2)2C6H3
C6F5
24 h
5be
67%
40%
86%
82%
60%
54%
68%
87%
88%
70%
90%
59%
66%
52%
51%
79%
85%
2
1b
48 h
5bf
3
1d: Ar = 4-MeOC6H4; R = Me
2,4-Cl2C6H3
4-NO2C6H4
C6F5
5 min
5 min
1 h
5dc
4
1d
5dd
5de
5df
5
1d
6
1d
3-NO2C6H4
2,4-(NO2)2C6H3
2-NO2-4-(CF3)C6H3
2,4-Cl2C6H3
4-NO2C6H4
2,4-(NO2)2C6H3
2-ClC6H4
5 min
5 min
5 min
10 min
10 min
10 min
5 min
30 min
5 min
3 min
10 min
5 min
7
1d
5dg
5dh
5eaa
5eba
5eca
5eda
5eea
5faa
5fba
5gaa
5gba
8
1d
9
1e: Ar = 4-MeOC6H4; R = Ph
10
11
12
13
14
15
16
17
1e
1e
1e
1e
C6F5
1f: Ar = 2,4-(MeO)2C6H3; R = Me
2-NO2C6H4
4-NO2C6H4
2,4-Cl2C6H3
4-NO2C6H4
1f
1g: Ar = 2,3,4-(MeO)3C6H2; R = Ph
1g
a Formation of hydrolyzed product together with benzoylated MBHAs is possible in the case of nonabsolute solvent.
presence of an electron-donating methoxy group in
3-arylprop-2-inylcarboxylates (1d, 1e) shortened the reac-
tion time to up to 10 min (entries 17À22).
purification, and the Z-isomer 3af (entry 6). After care-
ful study of the spectral data for impure compound 2af,
we came to the conclusion that the impurity could be
acetylated MBHA 5af.11 During the reaction of 1a with
2,3,4,5,6-pentafluorobenzaldehyde, the mixture of two
products (Z isomer 3ah and the major product acetylated
MBHA 5ah) was formed (entry 7). We became deeply
intrigued by these results and decided to investigate the
scope and the reasons for formation of MBHAs. It is
obvious that the formation of 5af and 5ah occurs during
migration of the acetoxy group. We envisioned that the
migration of the benzoyloxy group could be more favored
due to stabilization of the intermediate carbocation by the
neighboring phenyl group. Indeed, while the reaction of 1b
with 2-nitrobenzaldehyde or 2-nitro-4-trifluoromethyl-
benzaldehyde led to the formation of three compounds
(E isomer 2, Z isomer 3, and MBHA 5) (entries 10, 11),
the use of more electron-poor 2,4-dinitrobenzaldehyde or
pentafluorobenzaldehyde (entries 12, 13) gave the desired
benzoylated MBHAs 5be, 5bf as sole reaction products.
And finally, we were pleasantly intrigued in finding that
the reactions between starting 3-(4-methoxyphenyl)prop-
2-inylcarboxylates (1d, 1e) and dichloro- or nitrosubsti-
tuted benzaldehydes were smooth and selective, leading to
good-yielding formation of MBHAs 5dc, 5dd, 5ea, and 5eb
(entries 19À22).
Next, we found the general dependence between the
product formed and the structure of the aldehyde. In all
cases where aliphatic carbaldehydes were used (entries 1, 8,
17) the selective formation of E-configurated alkyne-
carbonyl metathesis products 2took place in low or moderate
yields.9 However, the mixtures of E (2) and Z (3) isomers of
the corresponding R,β-unsaturated ketones were formed
during reaction of 1a,b with aromatic aldehydes, especially
those having an ortho-substituent (Table 1, entries 2, 3, 9).
The reactions of 1a,d with benzaldehydes bearing an
electron-donating group in the para-position (entries 4, 5,
18) were complicated10 and required a longer reaction time
(entry 4) or heating (entry 5) for full conversion of the
alkyne. After workup of the reaction mixtures, 2:1 adducts
4ad, 4ae, 4db were isolated in poor yields as sole reaction
products.
The reaction of 1a with 4-nitrobenzaldehyde led to
the formation of three products: the major one, 2af, which
had the same Rf as its impurity, resulting in unsuccessful
(9) Aliphatic aldehydes undergo a self-condensation reaction in the
presence of Lewis acids; therefore the yields of alkyne-carbonyl metathe-
sis products are not satisfactory.
(10) The reactions with electron-rich aldehydes usually led to the
formation of big amounts of tars.
So it can be summarizedthat the outcome of the reaction
is dictated by the structures of both starting 3-arylprop-2-
inylcarboxylates and aldehydes. While the use of aliphatic
aldehydes always leads to the E isomer of an R,β-unsatu-
rated ketone, the reaction with aromatic aldehydes gives
(11) In the 1H NMR spectrum of the 2af and 5af mixture there were
two doublets at 5.94 ppm (1H, d, J = 0.9 Hz) and 6.18 ppm (1H, d, J =
1.5 Hz) together with broad singlet at 2.18 ppm (2H, br.s.). The 13C
NMR of the same mixture showed the presence of a tertiary CHÀO
carbon (signal at 73.07 ppm).
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 1. Possible Mechanism of the Formation of MBHA Carboxylates
mixtures of E and Z isomers. The presence of an electron-
donating group on benzaldehydes diminishes the reaction
rates and stimulates the formation of a 2:1 adduct.12 An
electron-withdrawing group on benzaldehydes is crucial
for the formation of MBHAs. And the combination of an
electron-donating group onto starting 3-arylprop-2-inyl-
carboxylates with an electron-withdrawing group on ben-
zaldehydes afforded a very smooth and selective formation
of the acetylated or benzoylated MoritaÀBaylisÀHillman
adducts.
be initiated during intermolecular reactions between pro-
pargylic esters and benzaldehydes. Our mechanistic con-
siderations offer support for the migration of a carboxylate
during an alkyne-carbonyl metathesis stage. First, the
starting alkynes did not undergo an acyl shift in the
presence of BF3 Et2O. Second, the addition of BF3 Et2O
3
3
to the mixture of 2af, 3af, and 5af in DCM did not lead to
either an increase in 5af amount or a change in the 2af, 3af,
and 5af ratio after 24 h of stirring at rt. These facts
confirmed that the formation of MBHA carboxylates
proceeded neither from unsaturated ketones 2, 3 nor via
rearranged 3-arylprop-2-inylcarboxylates 1.
Therefore, we have prepared various 2-aroyl-1-arylal-
lylcarboxylates 5 by the presented method. The results are
summarized in Table 2.
In conclusion, we have developed a simple, highly
efficient approach to 3-aroyl-1-arylallylcarboxylates via a
reaction between 3-arylprop-2-inylcarboxylates and aro-
matic aldehydes. This protocol proceeds via a new formal
alkyne-carbonyl metathesis/[3,3] sigmatropic rearrange-
ment cascade and allows the mild and efficient synthesis
of structural units unavailable via a traditional MBH reac-
tion. Further studies of these transformations are under-
way in our laboratory, and the results will be published in
due course.
Mechanistically, we believe that the formation of
MBHA carboxylates proceeds via coordination of carbo-
nyl oxygen to the Lewis acid, followed by stepwise ionic
formation of the intermediates A and B (Scheme 1).13 This
initial step is consistent with the good results obtained with
electron-rich Ar moieties. Then, the subsequent electro-
cyclic oxete ring opening followed by [3,3]-sigmatropic
rearrangement leads to the desired 3-aroyl-1-arylallylcar-
boxylates 5.
Propargylic esters are able to undergo a gold catalyzed
1,2- or 1,3-acyl shift leading to the formation of gold
carbene intermediates, poised for subsequent functionaliza-
tion.14 Herein we have shown that [3,3] rearrangement can
Acknowledgment. The research was funded by the
European Social Fund under the Global Grant measure
ꢀ
(Grant No. VP1-3.1-SMM-07-K-01-002).
(12) For the structural elucidation and possible mechanism, see the
Supporting Information.
(13) An ionic process of a Lewis acid catalyzed alkyne-carbonyl
metathesis was proposed in: Oblin, M.; Rajzman, M.; Pons, M.
Tetrahedron 2001, 57, 3099.
(14) (a) Marion, N.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2750.
(b) Peng, Y.; Cui, L.; Zhang, G.; Zhang, L. J. Am. Chem. Soc. 2009, 131,
5062. (c) Cran, J. W.; Krafft, M. E. Angew. Chem., Int. Ed. 2012, 51, 9398.
(d) Zhang, L. J. Am. Chem. Soc. 2005, 127, 1684.
Supporting Information Available. A complete descrip-
tion of experimental details, products characterization,
possible mechanism of formation of products 4, copies of
1H, 13C NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX