One-pot multicomponent Michael and Thorpe-Ziegler reaction of aryl methyl ketones

Article abstract of DOI:10.1080/00397911.2010.515349

A regioselective base-promoted Michael and Thorpe-Ziegler reaction between aryl methyl ketones and αβ-unsaturated nitrile was carried out in a single step. Different functional groups in addition to active positions were tolerated under this condition. Re

Full text of DOI:10.1080/00397911.2010.515349

This article was downloaded by: [Duke University Libraries]
On: 19 August 2012, At: 18:26
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
One-Pot Multicomponent Michael and
Thorpe–Ziegler Reaction of Aryl Methyl
Ketones
Vikas Jaitak a , Bandna a , Pralay Das a , V. K. Kaul a , Bikram Singh a
& Neeraj Kumar a
a Institute of Himalayan Bioresource Technology, Palampur, India
Version of record first published: 29 Jun 2011
To cite this article: Vikas Jaitak, Bandna, Pralay Das, V. K. Kaul, Bikram Singh & Neeraj Kumar (2011):
One-Pot Multicomponent Michael and Thorpe–Ziegler Reaction of Aryl Methyl Ketones, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
41:18, 2727-2737
To link to this article: http://dx.doi.org/10.1080/00397911.2010.515349
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation
that the contents will be complete or accurate or up to date. The accuracy of any
instructions, formulae, and drug doses should be independently verified with primary
sources. The publisher shall not be liable for any loss, actions, claims, proceedings,
demand, or costs or damages whatsoever or howsoever caused arising directly or
indirectly in connection with or arising out of the use of this material.

Synthetic Communications1, 41: 2727–2737, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.515349
ONE-POT MULTICOMPONENT MICHAEL AND
THORPE–ZIEGLER REACTION OF ARYL METHYL
KETONES
Vikas Jaitak, Bandna, Pralay Das, V. K. Kaul, Bikram Singh,
and Neeraj Kumar
Institute of Himalayan Bioresource Technology, Palampur, India
GRAPHICAL ABSTRACT
Abstract A regioselective base-promoted Michael and Thorpe–Ziegler reaction between
aryl methyl ketones and a,b-unsaturated nitrile was carried out in a single step. Different
functional groups in addition to active positions were tolerated under this condition. Results
indicated that the reaction proceeds in a consecutive manner as double Michael, triple
Michael, and Thorpe–Ziegler condensation. By applying click chemistry, double Michael
adducts were converted to bis-tetrazoles, which have broad applications in coordination
and medicinal chemistry.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Aryl methyl ketone; tetrazoles; Thorpe–Ziegler condensation; triple Michael
reaction
INTRODUCTION
The Michael reaction involves C-C bond formation and has wide applications
in organic synthesis.[1–3] Several acidic and basic conditions have been tried to
improve the Michael reaction. Side products, frequently encountered in the presence
of strong basic conditions, are due to secondary condensation, polymerization, and
simultaneous addition at all the reactive sites.[4] Few reactions have been reported for
Received April 24, 2010.
IHBT Communication No. 1011.
Address correspondence to V. K. Kaul, Institute of Himalyan Bioresource Technology (CSIR),
Palampur 176 061, H.P., India. E-mail: vkaul2002@yahoo.co.in
2727

2728
V. JAITAK ET AL.
C-C bond formation through double Michael reaction in one pot.[5] Forrester et al.[6]
reported partial double Michael adduct formation while preparing the mono-adduct
from aryl methyl ketone and methacrylonitrile in the presence of potassium methox-
ide in benzene.
Over the past few years, we have been actively engaged in the development of
the Michael reaction under basic and Lewis acidic conditions.[7,8] We report here an
efficient one-pot regioselective triple Michael reaction and Thorpe–Ziegler conden-
sation under basic conditions using NaH. The reaction resulted in the formation
of three C-C bonds, involving construction of a quaternary carbon center, which
has attracted much attention in recent years.[9,10] To the best of our knowledge, this
is the first example of regioselective triple Michael and Thorpe–Ziegler condensation
under an efficient atom-economical conversion of aryl methyl ketones to
electron-deficient alkenes in the presence of NaH in toluene.
RESULTS AND DISCUSSION
According to Basu et al.[7] aryl methyl ketones react with a,b-unsaturated com-
pounds on a KF-alumina surface, yielding selectively double Michael products.
Further addition to the double Michael adduct has not been reported earlier, prob-
ably because of the large size of bases used such as KOtBu and KF-Al2O3, which
were successful only in double Michael addition. In triple Michael addition, these
bases might have caused steric hindrance and were unable to create the carbanion
required to produce the triple Michael adduct. A set of different bases were tested
in the reactions at 0 ꢀC to room temperature using toluene and a solid surface
(Table 1). However, success was achieved with the formation of double Michael
adduct. Although aryl methyl ketone (pKa ca. 18–30) is not a superior Michael
Table 1. Michael and Thorpe–Ziegler reaction
Yield (%)a
Base= Conditions
Entry (%) Reactant (R) equivalent (temp.=time)
Total
yield (%)
Solvent
a
b
c
1
2
H
NaH=1
NaH=2
NaH=3
NaH=4
NaH=5
NaH=3
NaH=3
NaH=3
NaOEt=3
KOtBu=3
rt=12 h
rt=12 h
rt=12 h
rt=12 h
rt=12 h
rt=12 h
rt=12 h
rt=12 h
rt=12 h
rt=12 h
Toluene 10
Toluene 15
Toluene 10
Toluene 20
15
20
40
25
10
35
30
35
—
5b
25
40
65
50
15
60
45
45
15
20
50
5
H
3
H
15b
5b
4
H
5
H
Toluene
5
—
15c
6
Br
OMe
Me
H
Toluene 10
Toluene 15
Toluene 10
Toluene 15 Trace Traceb
Toluene 20 Trace Traceb
7
b þ cc
8
b þ cc
9
10
11
12
13
H
H
KF-Al2O3 60 ꢀC=12 h
—
THF
DMF
50
5
—
Trace
Trace
—
—
—
H
NaH=3
NaH=3
rt=12 h
rt=12 h
H
3
3
aIsolated yields for pure compounds.
b
=
X
NH.
O.
c
X
=

MICHAEL AND THORPE–ZIEGLER REACTION
2729
Scheme 1. Regioselective Michael and Thorpe–Ziegler reaction.
donor, we developed a novel and efficient triple Michael and Thorpe–Ziegler con-
densation reaction using acetophenone in the presence of NaH to solve the problem
in basic chemistry (Scheme 1). The small size of NaH could be a good choice to mini-
mize steric hindrance and facilitate the generation of carbanion, leading to the for-
mation of a triple Michael adduct in good yields. NaH (3 eq.) at 0 ꢀC to room
temperature was most suitable to generate the carbanion of aryl methyl ketone to
produce 3a (10%), 3b (40%), and 3c (15%) in a consecutive manner. Final com-
pounds were characterized by infrared (IR), NMR, and high-resolution mass spec-
troscopic (HRMS) (electrospray ionization) data. The overall isolated yield of the
reaction was 65% in toluene. Under similar reaction conditions, 4-bromoacetophe-
none also produced 6a (10%), 6b (35%), and a mixture of 6b and 6c. Repeated
silica-gel column chromatography of the mixture of 6b and 6c yielded 6c (15%).
Under such conditions, the halogen group of 4-bromoacetophenone was tolerated.
4-Methoxy acetophenone 7 and 4-methylacetophenone 8 under the same conditions
yielded double Michael (7a 15% and 8a 10%), triple Michael (7b 30% and 8b 35%),
and Thorpe–Ziegler products (7b, 7c and 8b, 8c as mixtures).
By using NaOEt and KOtBu (3 eq.) in toluene, double Michael products 9a
and 10a were obtained in 15–20% yield (Table 1) and traces of 9b, 10b and 9c, 10c
were isolated. KF-Al2O3 (Table 1, entry 11) gave the maximum yield of double
Scheme 2. Proposed mechanism of Michael and Thorpe–Ziegler reaction.

2730
V. JAITAK ET AL.
Scheme 3. Michael reaction using KF-Al2O3–NaH and NaOEt conditions. (a) KF-alumina NaH (1:1) at
0 ꢀC to rt for 12 h; (b) NaOEt, toluene at 0 ꢀC to rt for 12 h.
Michael product 11a (50%) under solvent-free conditions. In another study, the reac-
tion was performed using different solvents [tetrahydrofuran (THF) and dimethyl-
formamide (DMF)] under various concentrations of NaH. Contrary to toluene,
THF and DMF solvents under the same basic conditions afforded poor yields of
double and traces of triple Michael products (Table 1, entries 12 and 13). Encour-
aged by the significant results obtained with 3 eq. of NaH in toluene at 0 ꢀC to room
temperature (entry 3), we further planned to convert aryl methyl ketone directly to
the Thorpe–Ziegler condensation product by increasing NaH upto 5 eq. in the reac-
tion mixture. This did not happen, and very poor yields (5–10%) of 5a and 5b were
obtained. After several parallel studies, we concluded that 3 eq. NaH in toluene was
a highly selective method for obtaining double and triple Michael and Thorpe–Zieg-
ler condensation products. Change of substituents in the aromatic ring of the aryl
methyl ketone had no effect on carbonyl methyl. Enolates of acetophenones were
produced under NaH basic conditions (Scheme 2), which further participated in
the Michael reaction. Substituted carbon of acetophenone is more efficient Michael
donor than unsubstituted carbon, and therefore the substituted ketone picked up one
unsaturated nitrile to produce double Michael adduct. Triple Michael addition also
occurred on the same carbon atom and produced triple Michael adducts. After triple
Michael addition, further carbanion generated next to the nitrile carbon participated
Scheme 4. Thorpe–Ziegler condensation of double (3a) and triple Michael (3b) products.

MICHAEL AND THORPE–ZIEGLER REACTION
2731
Scheme 5. Bis-tetrazoles from double Michael product.
in Thorpe–Ziegler-type condensation in one pot. Final products were obtained as
double and triple Michael adducts along with Thorpe–Ziegler condensation product.
When we treated acetophenone with ethyl acrylate (Scheme 3) in the presence of
KF-Al2O3–NaH and NaOEt in basic conditions at 0 ꢀC to room temperature for
12 h, the reaction ended with the formation of major pimelate ester 14 and its mono
and bis-carboxylic acids (15 and 16).
Thorpe–Ziegler condensation reaction was also performed independently from
3a and 3b under NaOEt (0.44 mmol) base in dry toluene (3 mL), refluxing for 4 h.
Completion of the reaction was monitored by thin-layer chromatography (TLC),
and purification was performed by silica-gel column chromatography, affording 17
(75%) and 3c (30%) (Scheme 4). This proved that Thorpe–Ziegler condensation pro-
ducts are also possible directly from double and triple Michael adducts. To broaden
the scope of the reaction, bis-tetrazoles were prepared from double Michael products
using click chemistry, which have wide applications in coordination chemistry[11–14]
and as surrogates for carboxylic acids.[15] Compounds 12a and 13a were treated sep-
arately with NaN3 and ZnCl2 in DMF (3 mL) and refluxed for 15 h. Progress of the
reaction was monitored on TLC, and products were purified by silica-gel column
chromatography yielding 18 (58%) and 19 (52%) (Scheme 5). In addition to tetra-
zoles, derivatives of this reaction have applications for the synthesis of oxadia-
zoles,[16] which have analgesic, herbicidal, muscle relaxant and tranquilizing
effects. The reaction products are also useful in development of dendrimers required
in drug delivery systems.[17–19] The reaction will also facilitate the synthesis of
b-amino acids, which have many therapeutic uses in medicines.[20]
EXPERIMENTAL
Melting points were determined on a Mel-Temp apparatus and are uncor-
1
rected. H and 13C NMR spectra were recorded using a Bruker Avance 300 spec-
trometer operating at 300 MHz (1H) and 75 MHz (13C). Spectra were recorded at
25 ꢀC in CDCl3, C3D6O, or C5D5N with tetramethylsilane (TMS) as internal stan-
dard. Chemical shifts were recorded in d (ppm) relative to the TMS signal, coupling
constants (J) are given in hertz, and multiplicities of signals are reported as follows: s,
singlet; d, doublet; t, triplet; m, multiplet; and br, broad singlet. Mass spectra were
recorded on a Waters Q-TOF-MS with ESI using Waters Masslynx software. Each
sample was dissolved in acetonitrile–water (50:50) and directly injected into the ESI

2732
V. JAITAK ET AL.
source at a flow rate of 5 mL=min. All reagents of high quality were purchased from
Sigma Aldrich. Solvents were procured from SD Fine chemicals. Toluene was freshly
˚
distilled before use and dried over 4-A molecular sieves. NaH (60%) was washed with
hexane and dried under reduced pressure. Commercial reagents and solvents were of
analytical grade and were purified by standard procedures prior to use. TLC was
performed using precoated silica-gel plates 60 F254
.
General Procedure for Michael and Thorpe–Ziegler Reaction
Acetophenone (1 g, 8.32 mmol) was dissolved in 3 mL toluene and cooled to
0 ꢀC, and then NaH (24.96 mmol, 3.0 eq.) was added. After 5 min, acrylonitrile
(16.64 mmol, 2 eq.) was added at 0 ꢀC. The reaction mixture was stirred at room tem-
perature for 12 h until completion, monitored by TLC. The reaction mixture was
acidified with 2 N HCl and extracted with ethylacetate (3 ꢁ 10 mL). The organic
layers were combined, dried with anhydrous Na2SO4, and concentrated under
reduced pressure. The reaction product was purified by silica-gel column chromato-
graphy eluted with ethylacetate–hexane, 1:9 to 3:7 (v=v), to afford corresponding
products (3, 6, 7, and 8).
Selected Data for 3a–c, 6a–c, 7a, 7b, 8a, and 8b
4-Benzoyl heptanedinitrile (3a). Yield: 188 mg (10%); colorless oil. IR
(KBr): 2926, 2854, 2246, 1659, 1583, 1470, 1421, 1391, 1256, 1201, 1171, 1075,
1
965, 838, 766 cmꢂ1. H NMR (300 MHz, CDCl3): d ¼ 1.87–1.92 (m, 2H), 2.14–2.47
(m. 6H), 3.78–3.84 (m, 1H), 7.52 (m, 2H), 7.64 (m, 1H), 8.02 (d, J ¼ 7.5 Hz, 2H).
13C NMR (75 MHz, CDCl3): d ¼ 14.94 (2C), 28.43 (2C), 42.98, 118.87 (2C),
128.40 (2C), 129.94 (2C), 134.21, 135.91, 200.82. HRMS (ESI) data: m=z calcd.
for C14H15N2O [M þ H]þ: 227.2818; found: 227.2881.
4-Benzoyl-4(2-cyanoethyl) heptanedinitrile (3b). Yield: 930 mg (40%);
white solid; mp 96–98 ꢀC. IR (KBr): 2926, 2854, 2246, 1659, 1583, 1470, 1421,
1
1391, 1256, 1201, 1171, 1075, 965, 838, 766 cmꢂ1. H NMR (300 MHz, C3D6O):
d ¼ 2.30–2.36 (m, 6H), 2.51–2.56 (m, 6H), 7.51–7.55 (m, 2H), 7.59–7.64 (m, 1H),
7.81–7.83 (m, 2H). 13C NMR (75 MHz, C3D6O): d ¼ 12.54 (3C), 29.44 (3C), 53.63,
119.98 (3CN), 128.27 (2C), 129.62 (2C), 132.59, 138.87, 204.97. HRMS (ESI) data:
m=z calcd. for C17H18N3O [M þ H]þ: 280.3444; found: 280.3444.
5-Benzoyl-5-(2-cyanoethyl)-2-iminocyclohexane carbonitrile (3c). Yield:
348 mg (15%); colorless oil. IR (KBr): 3433, 3321, 2925, 2242, 2199, 1714, 1675, 1629,
1
1507, 1458, 1378, 1266, 1227, 694. H NMR (300 MHz, CDCl3): d ¼ 1.87 (m, 4H),
2.24–2.25 (m, 2H), 2.30–2.33 (m, 2H), 2.35–2.39 (m, 2H), 2.97–3.03 (m, 1H),
7.45–7.48 (m, 2H), 7.56–7.58 (m, 1H), 7.69–7.72 (m, 2H), 7.81 (s, 1H). 13C NMR
(75 MHz, CDCl3): d ¼ 12.36, 24.52, 25.31, 29.40, 30.95, 33.03, 33.38, 49.06, 88.48,
117.26, 118.92, 127.61 (2C), 128.57 (2C), 132.58, 136.68, 150.56, 168.80, 203.21
HRMS (ESI) data: m=z calcd. for C17H18N3O [M þ H]þ: 280.3444; found 280.3446.
4-p-Bromo-benzoyl heptanedinitrile (6a). Yield: 153.5 mg (10%); colorless
oil. IR (KBr): 2926, 2854, 2250, 1659, 1583, 1478, 1428, 1391, 1256, 1201, 1178, 1075,

MICHAEL AND THORPE–ZIEGLER REACTION
2733
1
975 cmꢂ1. H NMR (300 MHz, CDCl3): d ¼ 1.83–1.94 (m, 2H), 2.12–2.22 (m, 2H),
2.24–2.35 (m, 2H), 2.38–2.48 (m, 2H), 3.76–3.81 (m, 1H), 7.66–7.70 (m, 2H),
7.86–7.92 (m, 2H). 13C NMR (75 MHz, CDCl3): d ¼ 15.39 (2C), 27.56 (2C), 43.32,
119.03 (2CN), 127.12, 130.31 (2C), 132.99 (2C), 134.98, 200.25. HRMS (ESI) data:
m=z calcd. for C14H14BrN2O (M þ H)þ: 306.1778; found: 306.1707.
4-p-Bromo-benzoyl-4(2-cyanoethyl) heptanedinitrile (6b). Yield: 628.92 mg
(35%); white solid; mp 128–130 ꢀC. IR (KBr): 2946, 2894, 2246, 1659, 1588, 1470,
.
1421, 1391, 1276, 1201, 1161, 1095, 965, 848, 776 cmꢂ1 1H NMR (300 MHz,
C3D6O): d ¼ 2.25–2.31 (m, 6H), 2.46–2.51 (m, 6H), 7.68–7.73 (m, 2H), 7.78–7.82
(m, 2H). 13C NMR (75 MHz, C3D6O): d ¼ 12.48 (3C), 29.90 (3C), 53.68, 119.86
(3CN), 127.07, 130.97 (2C), 132.81 (2C), 137.57, 203.91. HRMS (ESI) data: m=z
calcd. for C17H17BrN3O (M þ H)þ: 359.2405; found: 359.2433.
5-p-Bromo-benzoyl-5-(2-cyanoethyl)-2-oxo-cyclohexanecarbonitrile (6c).
Yield: 270.70 mg (15%); colorless oil. IR: 3434, 2926, 2360, 2342, 2247, 1670, 1583,
1
1508, 1458, 1204, 1073, 1008, 721. H NMR (300 MHz, C3D6O): d ¼ 2.38–2.55 (m,
8H), 2.65–2.68 (m, 2H), 3.33–3.36 (m, 1H), 7.72 (d, J ¼ 7.9 Hz, 2H), 7.84 (d,
J ¼ 7.9 Hz, 2H). 13C NMR (75 MHz, C3D6O): d ¼ 12.64, 26.69, 28.17, 29.44, 36.09,
49.34, 119.20, 121.21, 127.40, 129.10 (2C), 132.43 (2C), 137.70, 203.84, 205.77.
HRMS (ESI): m=z calcd. for C17H16BrN2O2 (M þ H)þ: 360.2252; found: 360.2250.
4-p-Methoxy-benzoyl heptane dinitrile (7a). Yield: 256.04 mg (15%); col-
1
orless oil. IR (KBr): 2926, 2246, 1659, 1583, 1470, 1421, 1201, 1171, 1075, 965. H
NMR (300 MHz, CDCl3): d ¼ 1.86–1.91 (m, 2H), 2.16–2.32 (m, 4H), 2.36–2.40 (m,
2H), 3.77–3.81(m, 1H), 3.89 (s, 3H), 6.97–7.02 (m, 2H), 7.99–8.03 (m, 2H). 13C
NMR (75 MHz, CDCl3): d ¼ 15.12 (2C), 27.69 (2C), 42.52, 55.73, 114.48 (2C),
118.97 (2CN), 129.14, 130.98 (2C), 164.60, 199.24. HRMS (ESI) data: m=z calcd.
for C15H17N2O2 (M þ H)þ: 257.3078; found: 257.3006.
4-p-Methoxy-benzoyl-4(2-cyanoethyl) heptane dinitrile (7b). Yield:
618.12 mg (30%); white solid; mp 99–101 ꢀC. IR (KBr): 2936, 2844, 2276, 1669,
1573, 1490, 1421, 1371, 1256, 1214, 1171, 1075, 975, 848; 1H NMR (300 MHz,
C3D6O): d ¼ 2.41–2.43 (m, 6H), 2.48–2.55 (m, 6H), 3.93 (s, 3H), 7.03–7.06 (m,
2H), 7.96–7.99 (m, 2H). 13C NMR (75 MHz, C3D6O): d ¼ 13.30 (3C), 30.40 (3C),
54.13, 56.53, 115.25 (2C), 120.72 (3CN), 129.69, 130.56, 132.16 (2C), 164.50,
202.51. HRMS (ESI) data: m=z calcd. for C18H20N3O2 (M þ H)þ: 310.3704; found:
310.3704.
4-p-Methyl benzoyl heptane dinitrile (8a). Yield: 179 mg (10%); colorless
oil. IR (KBr): 2956, 2824, 2249, 1654, 1582, 1460, 1431, 1371, 1258, 1181, 1095,
1
968, 858, 762. H NMR (300 MHz, CDCl3): d ¼ 1.90–1.91 (m, 2H), 2.14–2.32 (m,
4H), 2.36–2.40 (m, 2H), 2.43 (s, 3H), 3.78–3.84 (m, 1H), 7.34 (d, J ¼ 7.9 Hz, 2H),
7.93 (d, J ¼ 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3): d ¼ 14.21 (2C), 21.82, 27.54
(2C), 42.87, 118.91 (2CN), 128.68 (2C), 130.02 (2C), 133.64, 145.58, 200.51. HRMS
(ESI): m=z calcd. for C15H17N2O (M þ H)þ: 241.3084; found: 241.3044.
4-p-Methyl-benzoyl-4(2-cyanoethyl) heptane dinitrile (8b). Yield:
764.96 mg (35%); white solid; mp 150–152 ꢀC. IR (KBr): 2916, 2824, 2236, 1669,
1593, 1480, 1428, 1398, 1251, 1214, 1170, 1078, 964, 834. 1H NMR (300 MHz,

2734
V. JAITAK ET AL.
C3D6O): d ¼ 2.06–2.09 (br, 2H), 2.31–2.36 (m, 2H), 2.41 (s, 3H), 2.49–2.54 (m, 6H),
7.36 (d, J ¼ 8.0, 2H), 7.79 (d, J ¼ 8.0 Hz, 2H). 13C NMR (75 MHz, C3D6O): d ¼ 13.19
(3C), 21.88, 31.09 (3C), 54.21, 120.64 (3CN), 129.38 (2C), 130.56 (2C), 136.52,
144.17, 204.64. HRMS (ESI): m=z calcd. for C18H20N3O (M þ H)þ: 294.3710; found:
294.3710.
General Procedure for 14, 15, and 16
Condition a. A mixture of acetophenone (240.38 mg, 2 mmol) and ethylacry-
late (600 mg, 6 mmol) was added separately to dry KF-alumina–NaH (1:1), and the
solid was stirred at 0 ꢀC to room temperature for 12 h and monitered by TLC. The
reaction mixture was acidified with 2 N HCl and extracted with ethylacetate
(3 ꢁ 10 mL). The organic layers were combined, dried with anhydrous Na2SO4,
and concentrated under reduced pressure. The reaction product was purified by
silica-gel column chromatography, eluted with ethylacetate–hexane 1:9 to 5:5 (v=v),
and yielded corresponding products 14–16.
Condition b. Acetophenone (0.833 mmol, 1.0 eq.) was dissolved in 3 mL tolu-
ene and cooled to 0 ꢀC, and NaOEt (2.499 mmol, 3.0 eq.) was added. After 5 min,
ethylacrylate (1.66 mmol, 2 eq.) was added at 0 ꢀC. The reaction mixture was stirred
at room temperature for 12 h until completion and was monitored by TLC. The reac-
tion mixture was acidified with 2 N HCl and extracted with ethylacetate (3 ꢁ 10 mL).
The organic layers were combined, dried with anhydrous Na2SO4, and concentrated
under reduced pressure. The crude material was purified by silica-gel column chro-
matography, eluted with ethylacetate–hexane 1:9 to 5:5 (v=v), and yielded corre-
sponding products 14–16.
Selected Data for 14–17
Diethyl-4-benzoyl heptanedioate (14). Yield: condition a, 192.2 mg (30%);
condition b, 66.5 mg (25%); colorless oil. 1H NMR (300 MHz, CDCl3): d ¼ 1.10–1.17
(m, 6H), 1.77 (m, 2H), 1.99–2.28 (m, 6H), 3.55–3.59 (m, 1H), 3.97–4.04 (m, 4H), 7.42
(m, 2H), 7.52 (m, 1H), 7.92 (d, J ¼ 7.3 Hz, 2H). 13C NMR (75 MHz, CDCl3):
d ¼ 14.03 (2C), 26.72 (2C), 31.48 (2C), 43.65, 60.30 (2C), 128.23 (2C), 128.64 (2C),
133.20, 136.82, 172.90, 202.82. HRMS (ESI) data: m=z calcd. for
C18H25O5(M þ H)þ: 321.3881; found: 321.3881.
6-(Ethoxycarbonyl)-4-benzoyl hexanoic acid (15). Yield: condition a,
1
29 mg (5%); condition b, 17 mg (7%); colorless oil. H NMR (300 MHz, CDCl3):
d ¼ 1.18 (m, 3H), 1.73–1.75 (m, 2H), 2.00–2.07 (m, 2H), 2.18–2.34 (m, 4H),
3.56–3.58 (br, 1H), 3.98–4.05 (m, 2H), 7.37–7.50 (m, 3H), 7.89–7.91 (m, 2H). 13C
NMR (75 MHz, CDCl3): d ¼ 14.29, 26.53, 27.01, 31.41, 31.70, 43.90, 60.68, 128.52
(2C), 128.96 (2C), 133.56, 136.97, 173.27, 178.46, 203.03. HRMS (ESI) data: m=z
calcd. for C16H21O5 (M þ H)þ: 293.3349; found: 293.3350.
4-Benzoyl heptanedioic acid (16). Yield: condition a, 53 mg (10%); con-
dition b, 26.3 mg (12%). 1H NMR (300 MHz, CDCl3): d ¼ 1.78–1.83 (m, 2H),
2.13–2.19 (m, 2H), 2.35–2.39 (m, 2H), 2.49–2.54 (m, 2H), 3.77–3.81 (m, 1H),

MICHAEL AND THORPE–ZIEGLER REACTION
2735
7.44–7.49 (m, 2H), 7.54–7.57 (m, 1H), 8.02–8.05 (m, 2H). 13C NMR (75 MHz,
CDCl3): d ¼ 22.86 (2C), 31.44 (2C), 43.41, 128.66 (2C), 129.0 (2C), 133.61, 136.73,
179.54, 202.90. HRMS (ESI) data: m=z calcd. for C14H17O5 (M þ H)þ: 265.2818;
found: 265.2818.
5-Benzoyl-2-iminocyclohexane carboxylic acid (17). To a solution of
NaOEt (30 mg, 0.440 mmol) in toluene (3 mL), 3a (100 mg, 0.440 mmol) was added
at room temperature and stirred for 5 min. The reaction mixture was refluxed for
4 h and monitored by TLC. The reaction mixture was acidified with 2 N HCl and
extracted with ethylacetate (3 ꢁ 10 mL). The organic layers were combined, dried
with anhydrous Na2SO4, and concentrated under reduced pressure gave oil 17.
1
Yield: 81 mg (75% yield); colorless oil. H NMR (300 MHz, CDCl3): d ¼ 1.60–
1.61 (m, 2H), 2.17–2.20 (br, 2H), 2.42 (br, 2H), 2.48–2.49 (m, 1H), 7.27–7.38 (m, 5H),
7.85 (brs,1H). 13C NMR (75 MHz, CDCl3): d ¼ 23.06, 24.55, 29.74, 43.35, 51.51,
126. 45 (2C), 129.15 (2C), 133.41, 143.81, 172.65, 177.87, 203.72. HRMS (ESI) data:
m=z calcd. for C14H16NO3(M þ H)þ: 246.2818; found: 246.2807.
5-Benzoyl-5-(2-cyanoethyl)-2-iminocyclohexane Carbonitrile 3c
(Scheme 4)
To a solution of NaOEt (24.3 mg, 0.358 mmol) in toluene (3 mL), 3b (100 mg,
0.358 mmol) was added at room temperature and stirred for 5 min. The reaction mix-
ture was refluxed for 4 h, monitored by TLC, acidified with 2 N HCl, and extracted
with ethylacetate (3 ꢁ 10 mL). The organic layers were combined, dried with anhy-
drous Na2SO4, and concentrated under reduced pressure to yield oil 3c (30 mg,
30% yield); NMR, HRMS (ESI), and IR data were given previously.
General Procedure for the Synthesis of Bis-Tetrazoles (18 and 19)
from Double Michael Product
To a solution of NaN3 (84.52 mg, 1.3 mmol) in DMF (3 mL), 7a (125 mg,
0.52 mmol) was added at room temperature. To this, ZnCl2 (88.59 mg, 0.65 mmol)
was added. The reaction mixture was refluxed for 15 h until completion and was
monitored by TLC. The reaction mixture was acidified with 2 N HCl and extracted
with ethylacetate (3 ꢁ 10 mL). The organic layers were combined, dried with anhy-
drous Na2SO4, and concentrated under reduced pressure. Compound 18 (58%)
was purified by column chromatography, eluting with hexane–ethylacetate 5:5 to
3:7 (v=v) respectively.
2-[2-(1H-Tetrazol-5-yl)ethyl]-1-(4-methoxy phenyl)-4-(1H-tetrazol-5-yl)
butan-1-one (18). Yield: 77 mg (58%); brown solid; mp 140–142 ꢀC. IR (KBr):
3447, 3138, 3027, 2958, 2862, 2736, 2634, 2486, 2360, 1666, 1603, 1560, 1458,
1426, 1250, 1098, 1070, 1053. 1H NMR (300 MHz, C5D5N): d ¼ 2.28–2.33 (m,
2H), 2.49–2.57 (m, 2H), 3.22 (br, 4H), 3.68 (s, 3H), 4.01–4.03 (m, 1H), 6.92–6.95
(m, 2H), 8.11–8.14 (m, 2H), 8.70 (s, 2H). 13C NMR (75 MHz, C5D5N): d ¼ 21.87
(2C), 30.39 (2C), 44.30, 55.77, 114.64 (2C), 130.27, 131.36, (2C), 156.89, 164.29,
201.34. HRMS (ESI) data: m=z calcd. for C15H19N8O2(MþH)þ: 343.3641; found:
343.3641.

2736
V. JAITAK ET AL.
2-[2-(1H-Tetrazol-5-yl)ethyl]-4-(1H-tetrazol-5-yl)-1-p-tolylbutan-1-one (19).
Yield: 88 mg (52%); brown solid; mp 133–135 ꢀC. IR (KBr): 3447, 3138, 3027, 2958,
2862, 2736, 2634, 2486, 2360, 1666, 1603, 1560, 1458, 1426, 1250, 1098, 1070, 1053.
1H NMR (300 MHz, C5D5N): d ¼ 2.20 (s, 3H), 2.22–2.29 (m, 2H), 2.49–2.56
(m, 2H), 3.13–3.18 (m, 4H), 4.03–4.07(m, 1H), 7.13–7.15 (m, 2H), 8.69–8.70 (m,
2H), 13.20 (br, 2H). 13C NMR (75 MHz, C5D5N): d ¼ 21.54, 21.93 (2C), 30.70
(2C), 44.48, 129.07 (2C), 130.04 (2C), 134.90, 144.66, 157.12, 202.44. HRMS (ESI)
data: m=z calcd. for C15H19N8O (M þ H)þ: 327.3647; found: 327.3647.
CONCLUSION
In summary, we developed a simple and efficient one-pot method for the syn-
thesis of double and triple Michael and Thorpe–Ziegler condensation reactions of
aryl methyl ketones in a consecutive manner. Further, double Michael products were
used for synthesis of tetrazoles, which have versatile applications as bidented ligands.
We believe that the present innovation will open new vistas in supramolecular
chemistry.[21–23] Synthesis of tetrazoles from triple Michael adducts will be reported
subsequently.
SUPPORTING INFORMATION
Spectral data for all compounds have been given (see the Supplemental
Materials available online).
ACKNOWLEDGMENTS
The authors are grateful to Dr. P. S. Ahuja, director of the Institute of
Himalayan Bioresource Technology, for providing the necessary facilities during
the course of the work. Two of the authors, Vikas Jaitak and Bandna, thank the Coun-
cil of Scientific and Industrial Research, New Delhi, for senior research fellowships.
REFERENCES
1. Oare, D. A.; Heathcock, C. H. Stereochemistry of the base-promoted Michael addition
reaction. In Topics in Stereochemistry; E. L. Eliel, S. H. Eilen (Eds.); John Wiley and Sons:
New York, 1989; vol. 19, pp. 277–290.
2. Angelo, J. D.; Revial, G.; Costa, P. R. R.; Castro, R. N.; Antunes, O. A. C. Asymmetric
Michael addition of chiral imines to phenylvinylsulfone: Preparation of key chiral building
blocks for the synthesis of Aspidosperma and Hunteria alkaloids. Tetrahedron: Asymmetry
1991, 2, 199–202.
3. Alexakis, A.; Andrey, O. Diamine-catalyzed asymmetric Michael additions of aldehydes
and ketones to nitrostyrene. Org. Lett. 2002, 4, 3611–3614.
4. Beergmann, E. D.; Ginsburg, D.; Pappo, R. The Michael Reaction in Organic Reaction;
Wiley: London, 1959; vol. 10, pp. 179–555.
5. Giardini, A.; Lesma, G.; Passarella, D.; Perez, M.; Silvani, A. Double Michael reaction of
N-carboethoxy-2,3-dihydropyridin-4-one. Synlett 2001, 132–134.
6. Forrester, A. R.; Irikawa, H.; Thomson, R. H.; Woo, S. O.; King, T. J. Iminyls, part 8:
Intramolecular addition to nitrile groups. J. Chem. Soc., Perkin Trans. 1 1981, 1712–1720.

MICHAEL AND THORPE–ZIEGLER REACTION
2737
7. Basu, B.; Das, P.; Hossain, I. KF-alumina-mediated selective double Michael additions of
aryl methyl ketones: A facile entry to the synthesis of functionalized pimelate esters and
derivatives. Synlett 2004, 12, 2224–2226.
8. Basu, B.; Das, P.; Hossain, I. Synthesis of b-amino esters via aza-Michael addition of
amines to alkenes promoted on silica: A useful and recyclable surface. Synlett 2004, 14,
2630–2632.
9. Denissova, I.; Barriault, L. Stereoselective formation of quaternary carbon centers and
related functions. Tetrahedron 2003, 59, 10105–10146.
10. Christoffers, J.; Baro, A. Stereoselective construction of quaternary stereocenters. Adv.
Syn. Catal. 2005, 347, 1473–1482.
11. Stassen, A. F.; Grunert, M.; Mills, A. M.; Spek, A. L.; Haasnoot, J. G.; Reedijk, J.;
Linert, W. Linkage isomers of dibromobis(1-(2-methoxyethyl)tetrazole)copper (II) con-
taining either a bromide or a unique tetrazole bridge. Dalton Trans. 2003, 3628–3633.
12. Wu, T.; Zhou, R.; Li, D. Crystallographic characterization of the intermediate in the syn-
thesis of tetrazole from nitrile and azide in water. Inorg. Chem. Commun. 2004, 7, 492–494.
13. Ostrovskii, V. A.; Pevzner, M. S.; Kofman, T. P.; Shcherbinin, M. B.; Tselinskii, I. V.
Energetic 1,2,4-triazoles and tetrazoles: Synthesis, structure, and properties. Targets
Heterocycl. Syst. 1999, 3, 467–526.
14. Thornber, C. W. Isosterism and molecular modification in drug design. Chem. Soc. Rev.
1979, 8, 563–580.
15. Butler, R. N. Advances in tetrazole chemistry. Adv. Heterocycl. Chem. 1977, 21, 323–435.
16. Ali, M. A.; Shaharyar, M. Oxadiazole Mannich bases: Synthesis and antimycobacterial
activity. Bioorg. Med. Chem. 2007, 17, 3314–3316.
17. Lankau, H. J.; Unverferth, K.; Grunwald, C.; Hartenhauer, H.; Heinecke, K.; Ster, K. B.;
Dost, R.; Egerland, U.; Rundfeldt, C. New GABA-modulating 1,2,4-oxadiazole deriva-
tives and their anticonvulsant activity. Eur. J. Med. Chem. 2007, 42, 873–879.
18. Dutta, T.; Agashe, H. B.; Gargi, M.; Balasubramanium, P.; Kabra, M.; Jain, N. K.
Poly(propyleneimine) dendrimer based nanocontainers for targeting of efavirenz to
human monocytes=macrophages in vitro. J. Drug Targeting 2007, 15, 89–98.
19. Pavlov, G. M.; Korneeva, E. V.; Meijer, E. W. Molecular characteristics of
poly(propylene imine) dendrimers as studied with translational diffusion and viscometry.
Colloid Polym. Sci. 2002, 280, 416–423.
20. Lelais, G. R.; Seebach, D. 2-Amino acids–Syntheses, occurrence in natural products, and
components of b-peptides. Biopolymers 2004, 76, 206–243.
21. Rajakumar, P.; Kanagalatha, R. Synthesis and optoelectrochemical properties of novel
phenothiazinophanes. Tetrahedron Lett. 2007, 48, 8496–8500.
22. Bond, A. D.; Fleming, A.; Kelleher, F.; Mcginley, J.; Prajapati, V.; Skovsgaard, S.
Synthesis and characterisation of tetra-tetrazole macrocycles. Tetrahedron 2007, 63,
6835–6842.
23. Sprengard, U.; Schudok, M.; Schmidt, W.; Kretzschmar, G.; Kunz, H. Multiple sialyl
Lewis N-glycopeptides: Effective ligands for E-selectin. Angew. Chem. Int. Ed. 1996, 35,
321–324.