A practical and expedient synthesis of 2-heterocycle (C-N bond) substituted 4-oxo-4-arylbutanoates

Article abstract of DOI:10.1016/j.tetlet.2007.02.101

A practical and expedient synthesis of the titled compounds is described. Using the same simple procedure (DBU was reacted with the mixture of an alkynol and a nitrogen heterocycle in CH₂Cl₂ at rt for 16 h), a wide variety of diverse

Full text of DOI:10.1016/j.tetlet.2007.02.101

Tetrahedron Letters 48 (2007) 2845–2849
A practical and expedient synthesis of 2-heterocycle
(C–N bond) substituted 4-oxo-4-arylbutanoates
Xiaojun Han*
Department of Neuroscience Chemistry, Pharmaceutical Research Institute, Bristol-Myers Squibb Company,
5 Research Parkway, Wallingford, CT 06492, United States
Received 12 February 2007; revised 20 February 2007; accepted 22 February 2007
Available online 25 February 2007
Dedicated to Professor E. J. Corey and Professor Richard C. Larock
Abstract—A practical and expedient synthesis of the titled compounds is described. Using the same simple procedure (DBU was
reacted with the mixture of an alkynol and a nitrogen heterocycle in CH2Cl2 at rt for 16 h), a wide variety of diverse NH-containing
nucleophiles such as pyrazoles, indazoles, indoles, imidazoles and benzoimidazole, oxazolidinone and benzooxazolone, triazoles,
phthalimides, and N-formyl anilines, have been reacted with 4-aryl-4-hydroxy-alkynyl esters to afford good yields of desired prod-
ucts. This reaction proceeded by the DBU catalyzed redox isomerization of ethyl 4-aryl-4-hydroxybut-2-ynoate to (E)-ethyl 4-aryl-4-
oxobut-2-enoate, followed by the DBU catalyzed aza-Michael reactions with the isomerized product in one-pot.
Ó 2007 Elsevier Ltd. All rights reserved.
The importance of nitrogen containing heterocyclic
compounds in medicine can be very well appreciated
by looking at the structures of many marketed drugs.1
It is important that general methods to synthesize or
to modify such compounds are developed. One such
reaction is the aza-Michael reaction of NH-containing
heterocycles and unsaturated aldehydes, ketones, esters,
and others. There are many very recent reports on this
reaction focused on using different reagents to catalyze
or mediate this reaction,2 or under some specific condi-
tions.3 Asymmetric version of this reaction has been
rare,4 although the asymmetric aza-Michael reaction
of amines (NHR1R2; R1, R2 = alkyl, aryl, OBn, H)
have been well developed.5 Despite these many interest-
ing and useful developments, no single method has
found success with a variety of diverse NH-containing
heterocycles (pyrazoles, indazoles, imidazole, benzoimi-
dazole, indoles, oxazolidinone, and benzooxazolone,
triazoles, phthalimides, etc.).
4-arylbutanoic acids, useful for their antibacterial activ-
ity, made by the reaction of 4-oxo-4-arylbutenoic acids
with heterocycles, such as pyrazoles,6 anilines,7 imidazoles
R1
Y
R2
Z
X
M
R3
O
N
Ar
CO2Et
and 1,2,4-triazoles.8 Encouraged by these reports,
alkenoate 1 was reacted with pyrazole 2 in CH2Cl2 at
rt for 16 h with different bases, such as DABCO,
DBU, pyridine, and Et3N. To my delight, when DBU
was used as the base, 3 was formed in 70% yield, while
DABCO, pyridine and Et3N all gave incomplete conver-
sion and lower yields.
N
O
DBU, CH2Cl2
rt, 16 h
N
NH
O
N
+
Ph
CO2Et
(1)
70% yield
Ph
CO2Et
As part of a medicinal chemistry project, we needed to
make 2–heterocycle (C–N bond) substituted 4-oxo-4-
arylbutanoates as shown below. There are several
reports of 2-heterocycle (C–N bond) substituted 4-oxo-
1
2
3
Although 1 was commercially available, other aryl
substituted examples have to be made in several steps.9
In 1949, Nineham and Raphael10 reported the first
example of base catalyzed redox isomerization of
*
Tel.: +1 203 677 7879; fax: +1 203 677 7702; e-mail: xiaojun.han@
bms.com
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.02.101

2846
X. Han / Tetrahedron Letters 48 (2007) 2845–2849
4-aryl-4-hydroxy-2,3-alkynyl esters 4 to trans-4-aryl-4-
oxobut-2-enoate 5 [Et3N (neat), rt, 16 h, then distilla-
tion. Ar = Ph, 94% yield]. In the beginning of 2006,
Koide and Sonye11 described a DABCO (10–20 mol
%) catalyzed redox isomerization in DMSO (rt, 4 h,
Ar = Ph, 72% yield). Since alkynols 4 are more readily
accessible than alkenoates 5, by the reaction of ethyl
propionate with aromatic aldehydes,12 I was interested
in the direct reaction of alkynols 4 with NH-containing
heterocycles to form compounds like 3.
and a NH-containing heterocycle (2.0 mmol) in CH2Cl2
(5 mL or 10 mL, depending on the solubility of the
NH-containing heterocycle in CH2Cl2). The mixture
was stirred at rt for 16 h and then directly poured onto
a silica gel column eluting with EtOAc/hexanes to afford
the desired products.
The products formed using this general procedure are
summarized in Table 2. Pyrazoles with substituents of
different electronic and steric properties could be used
for this reaction. Compounds 7, 9, 10, 11, 13, and 15
were all formed as the sole products, while 8a–b,
14a–b, and 16a–b were all formed as a mixture of two
regioisomers. This indicated that regioselectivity was
controlled by both steric hindrance and substituent
electronegativity. Alkynols 4 with different Ar substitu-
tion such as 4-H, 4-MeO and 4-MeO2C could also be
used in this reaction with roughly equal efficiency (7 vs
13, 15). Indazoles closely followed the pattern of pyr-
azoles. Compounds 17 and 20 were formed as the sole
products, while 18a–b and 19a–b were formed as a mix-
ture of two isomers in the same ratio due to the presence
of 7-Me in the indazole core.
OH
bases
solvents
O
Ar
rt or heating
Ar
CO2Et (2)
CO2Et
4
5
To find the best conditions for this direct transforma-
tion, the reaction of alkynol 6 and pyrazole 2 was used
as a model reaction. Different bases and solvents were
screened and the results are summarized in Table 1.
Although DBU, Cy2NMe, Et3N, DABCO, DMAP,
and Cs2CO3 all gave complete conversion, only DBU
afforded 3 in a good isolated yield (73%) in CH2Cl2.
When pyridine or K2CO3 was used as the base, <20%
of conversion was observed. Various solvents were then
evaluated with DBU as base. PhMe, THF, EtOAc all
afforded 3 in ca. 55% yield, while acetone gave 3 in
31% yield and MeOH produced no product.
1,2,4-Triazole also reacted well, but 1,2,3-triazole and
benzotriazole did not give any desired products nor
isomerized product 5 despite 100% conversion (21–23),
instead complex mixtures were formed in both cases.
Electron rich indoles afforded no products, but elec-
tron-deficient indoles gave good yield of product prob-
ably due to the better stability of the nucleophiles
after deprotonation (24 vs 25). It was very pleasing to
find that benzoxazolone and oxazolidinone also afforded
desired products in good yields (26–28) since they are
normally considered poor nucleophiles.2 When a chiral
oxazolidinone was used, chiral induction was not
observed (27). The low yield of 28 was because of the
stability of benzooxaolone in the presence of strongly
basic DBU. It was equally satisfying to see that strong
basic and weak nucleophiles such as imidazole and
benzoimidazole2 could also be used in this reaction to
afford the desired products, albeit in lower yields
(29–30). Finally, acyl anilines, phthalimides and benz-
oimidazolones also reacted with alkynols 4 to afford
products in good yields (31–33). However, aniline or
1-methylimidazolidin-2-one did not produce any desired
product despite 100% conversion (34–35). In the former
reaction, a complex mixture was formed and in the latter
reaction, isomerized product 5 was formed in 52% yield.
As a result of these studies, a general procedure was deter-
mined to be as follows: DBU (1.1 mmol) was added
drop-wise at rt to a mixture of alkynol 4 (1.0 mmol)
Table 1. The base and solvent optimization of reaction 6 and 2 to form
3a
base, CH2Cl2
rt, 16 h OR
OH
N
N
3
O
N
NH
+
Ph
DBU, solvent,
rt, 16 h
Ph
CO2Et
CO2Et
6
2
Entry Base (CH2Cl2 Solvent (DBU Conversion Yieldb
as solvent)
as solvent)
(%)
(%)
1
2
3
4
5
6
7
8
9
10
11
12
13
DBU
Cy2NMe
Et3N
DBACO
DMAP
Pyridine
K2CO3
Cs2CO3
DBU
DBU
DBU
DBU
DBU
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
100
100
100
100
100
<20d
<20d
100
100
100
100
100
100
73
10
20
0c
0c
0c
0c
The structures of applicable compounds were deter-
mined primarily by NMR analysis. The chemical shift
20
56
58
31
56
0c
1
of each proton and carbon was assigned by H, 13C,
THF
DEPT, COSY, and HMQC. The connectivity of key
protons and carbons were determined by HMBC, thus
the structures of compounds (Chart 1) with the
assistance of 1D NOE. See Supplementary data for
details.
Acetone
EtOAc
MeOH
a A base was added to the solution of ethyl 4-hydroxy-4-phenylbut-2-
ynoate (0.5 mmol) and 3,5-dimethyl-1H-pyrazole (1.0 mmol) in a
solvent (2.5 mL) in a 10 mL of vial at rt and the mixture was stirred
at rt for 16 h.
Since DBU was required as the base, the employment of
acetyl containing nucleophiles such as 3-acetylpyrazole,
AcNHPh, and indolin-2-one, resulted in the decomposi-
tion of the starting alkynols. Tetrazoles did not partici-
b Isolated yields after flash chromatography.
c No compound 3 was formed by TLC analysis.
d By 1H NMR integration using anisole as the internal standard.

X. Han / Tetrahedron Letters 48 (2007) 2845–2849
2847
Table 2. The products with yields and regioselectivity produced by the general procedure
Pyrazoles:
Me
F3C
Me
p-Tol
F3C
EtO2C
N
N
N
N
N
N
N
Me
Me
Me
+
O
O
O
O
O
O
O
N
N
N
N
N
N
N
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
8a-b 66% (2.3:1)
3
72%
7
78%
9
70%
10 61%
11 64%
Me
F3C
Me
F3C
Me
N
N
N
N
N
N
N
N
Me
Me
Me
Me
Me
CO2Et
+
CO2Et Ar1
O
O
O
O
O
O
O
N
N
N
N
N
N
+
Ar1
CO2Et
Ar1
CO2Et
Ar1
CO2Et
Ar2
CO2Et
15 54%
Ar2
CO2Et
16a-b 40% (1.9:1)
Ar2
14a-b 64% (2.7:1)
12 64%
13 68%
Indazoles:
Br
CHO
Br
Br
CHO
CO2Et
Me
Me
+
+
N
N
N
N
N
N
O
O
O
O
O
O
N
N
N
N
N
N
Me
CO2Et
Me
CO2Et
Ph
CO2Et
17 70%
Ph
Ph
CO2Et
Ph
Ph
CO2Et
Ph
CO2Et
20 76%
18a-b 65% (1.9:1)
19a-b 70% (2.2:1)
Triazoles:
Indoles:
CO2Me
N
N
N
N
Me
N
N
O
O
O
O
O
N
N
N
N
N
Ph
CO2Et
21 58%
Ph
CO2Et
22 0%
Ph
CO2Et
23 0%
Ph
CO2Et
24 0%
Ar1
CO2Et
25 58%
Benzooxazolone and oxazolidinone:
Imidazoles and Benzoimidazoles:
Ph
O
O
O
N
N
Br
O
O
O
O
O
N
O
N
O
O
N
N
N
Ph
CO2Et
26 65%
Ph
CO2Et
27a,b 82% (1:1)
Ph
CO2Et
28 41%
Ph
CO2Et
Ph
CO2Et
30 52%
29 43%
Acyl anilines, phthalimides, and benzoimidazolones
N
N
N
N
O
O
O
O
O
O
O
Ar1 =4-MeOPh
Ph
Ph
O
O
N
N
HN
O
Ar2 =4-MeO2CPh
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
Ph
CO2Et
34 0%
Ph
CO2Et
35 0%
31 51%
32 72%
33 75%
pate in the reaction due to their strong acidity and the
starting alkynol was recovered unchanged. When N-
Boc-aniline or carbazole was used as a nucleophile, only
the rearranged product 5 was formed in 65% and 70%
isolated yields, respectively, conjugate addition did not
proceed probably due to steric crowding around the
nucleophile.
F3C
p
-Tol
H
H
H
N
N
H
O
N
N
O
N
H
H
Ph
CO2Et
Ph
CO2Et
7
9
Br
F3C
To further elucidate the mechanism of this reaction, 4-
MeO–PhSH, a highly-reactive nucleophile, was coupled
with alkynol 6 under the standard conditions, with for-
mation of the direct conjugate addition product 36. This
suggests that addition of thiophenol to alkynol 6 was
complete in 2 min before the addition of DBU which
could not facilitate the isomerization process because
N
H
N
O
O
N
H
H
H
Ph
CO2Et
Ph
CO2Et
10
17
Chart 1. Structural determination of products by NMR (red arrows
showed key hydrogen–carbon connectivity determined by HMBC).

2848
X. Han / Tetrahedron Letters 48 (2007) 2845–2849
of the presence of b-ArS moiety.13 When alkynol 6 was
treated with DBU under the standard procedure but
without any nucleophiles, isomerized product 5 was
formed in 50% yield. This reaction provided easy access
to this class of compounds exemplified by compound 36,
which was prepared previously via a much longer reac-
tion sequence.14
13
12
11
10
18
8
3
9
N
7
O
4
N
15
1
14
O
6
16
17
2
5
O
5
9
OH
SH
OH
standard
Ph
CO2Et
(126 MHz, CDCl3) d ppm 196.43 (C4), 169.21 (C1),
152.26 (C9), 137.47 (C12), 136.39 (C14), 133.64 (C17),
131.82 (C7), 130.78 (C18), 129.27 (C16), 128.76 (C11),
128.33 (C15), 125.77 (C10), 103.13 (C8), 62.15 (C5),
60.01 (C2), 40.59 (C3), 21.31 (C13), 14.09 (C6). LRMS
363.18 (MH+), calcd for C22H22N2O3 362.16.
+
Ph
procedure
84% yield
S
(3)
CO2Et
OMe
OMe
6
36
I believe that the reactions proceeded via two steps, re-
dox isomerization followed by conjugate addition.
DBU was required for the first step as well as the conju-
gate addition step. This one-pot process provided prod-
ucts more conveniently and in higher yields than the
discrete two step process, probably due to the in situ for-
mation of trans-4-aryl-4-oxobut-2-enoate, which is not
very stable in the presence of DBU.
Acknowledgements
I thank Drs. John Macor and Gene Dubowchik for their
constant support during the course of this study and
their critical reading of the manuscript and Dr. Yingzi
Wang for assistance in 2D NMR analysis of compound
9.
In conclusion, a practical and expedient synthesis of 2-
heterocycle (C–N bond) substituted 4-oxo-4-arylbutano-
ates was described. The simplicity of the procedure and
its applicability to a wide variety of diverse NH-contain-
ing heterocycles are key features of this procedure. Be-
cause two equivalents of heterocycles was used in the
reaction and there was <20% of conversion when pyri-
dine was used as the base, this general procedure shall
find wider applications in reactions involving more com-
plex starting materials, such as 4-heteroaryl-4-hydroxy-
2,3-alkynyl esters, whose products could be of interest
as potential drug targets.
Supplementary data
1H, 13C NMR (data and spectra) and LRMS data for all
compounds, structural determinations (by COSY,
DEPT, HMQC, HMBC, and 1D NOE) of all applicable
compounds. Supplementary data associated with this
article can be found, in the online version, at
doi:10.1016/j.tetlet.2007.02.101.
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OH
O
standard
NH
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procedure
81% yield
37
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38
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