Tetra-n-butylammonium fluoride-catalyzed eschenmoser-claisen [3,3]-sigmatropic rearrangement

Article abstract of DOI:10.1080/00397910802374075

Condensation of dibenzofuran and dibenzothiophene carboxaldehydes with various aryl acetic acids followed by esterification of the acid intermediate afforded the 2,3-diaryl acrylates in good overall yields. Reduction of the esters with diisobutylaluminium

Full text of DOI:10.1080/00397910802374075

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Tetra-n-butylammonium
Fluoride–Catalyzed
Eschenmoser–Claisen [3,3]-
Sigmatropic Rearrangement
V. S. Prasada Rao Lingam a b , Ramanatham
Vinodkumar a , Khagga Mukkanti b , Abraham Thomas
a & Balasubramanian Gopalan a
a Glenmark Research Centre, Medicinal Chemistry
Division , MIDC Mahape, Navi Mumbai, India
b Institute of Science and Technology, Jawaharlal
Nehru Technological University , Hyderabad, India
Published online: 22 Dec 2008.
To cite this article: V. S. Prasada Rao Lingam , Ramanatham Vinodkumar ,
Khagga Mukkanti , Abraham Thomas & Balasubramanian Gopalan (2008) Tetra-
n-butylammonium Fluoride–Catalyzed Eschenmoser–Claisen [3,3]-Sigmatropic
Rearrangement, Synthetic Communications: An International Journal for
Rapid Communication of Synthetic Organic Chemistry, 39:2, 332-341, DOI:
10.1080/00397910802374075
To link to this article: http://dx.doi.org/10.1080/00397910802374075
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Synthetic Communications1, 39: 332–341, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802374075
Tetra-n-butylammonium Fluoride–Catalyzed
Eschenmoser–Claisen [3,3]-Sigmatropic
Rearrangement
V. S. Prasada Rao Lingam,1,2 Ramanatham Vinodkumar,1
Khagga Mukkanti,2 Abraham Thomas,1 and
Balasubramanian Gopalan1
1Glenmark Research Centre, Medicinal Chemistry Division, MIDC
Mahape, Navi Mumbai, India
2Institute of Science and Technology, Jawaharlal Nehru Technological
University, Hyderabad, India
Abstract: Condensation of dibenzofuran and dibenzothiophene carboxaldehydes
with various aryl acetic acids followed by esterification of the acid intermediate
afforded the 2,3-diaryl acrylates in good overall yields. Reduction of the esters
with diisobutylaluminium hydride afforded the allylic alcohols, which underwent
a smooth Eschenmoser–Claisen [3,3]-sigmatropic rearrangement on exposure to
N,N-dimethylacetamide dimethylacetal in the presence of tetra n-butylammonium
fluoride as catalyst to give 3,4-diaryl c,d-unstaturated amides in excellent yields.
Keywords: Acrylic acids, allylic alcohols, Eschenmoser–Claisen rearrangement,
tetra-n-butylammonium fluoride trihydrate, c,d-unstaturated amides
INTRODUCTION
Dibenzo[b,d]furan and dibenzo[b,d]thiophene derivatives have been
shown to exhibit a wide range of biological activities and therefore
hold considerable potential as therapeutic agents. For example, some
Received March 9, 2008.
Address correspondence to Khagga Mukkanti, Institute of Science and
Technology, Jawaharlal Nehru Technological University, Hyderabad 500072,
India. E-mail: Kmukkanti@gmail.com
332

TBAF-Catalyzed Eschenmoser–Claisen Rearrangement
333
derivatives have been reported as anti-methicillin-resistant Staphylococ-
cus aureeus (MRSA) agents,[1] endothelin-converting enzyme-1 inhibi-
tors,[2] and DNA-dependent protein kinase (DNK-PK) inhibitors.[3]
Recently our group has reported a similar series of compounds as phos-
phodiesterase IV (PDE-IV) inhibitors.[4,5] In continuation of our work on
dibenzo[b,d]furan and dibenzo[b,d]thiophene derivates, we have been
interested in the synthesis of c,d-unstaturated amides with dibenzo[b,d]-
furan and dibenzo[b,d]thiophene as substituents. In this regard, our
literature survey revealed that Eschenmoser–Claisen [3,3]-sigmatropic
rearrangement[6] of allylic alcohols is an important and useful approach
for the synthesis of c,d-unstaturated amides. The reaction normally
involves coupling of an allyl alcohol or alkoxide with N,N-dimethylace-
tamidedimethyl acetal[7–9] or N,N-diakylalkoxymethylene imminium
salts[10,11] followed by [3,3]-sigmatropic rearrangement of the allyl vinyl
ether intermediate, resulting in the formation of a new carbon–carbon
bond. The reaction generally requires prolonged reaction time and harsh
temperature conditions, which limit the scope of this method. We have
also observed that the rearrangement is not reported on allylic alcohols
with bulky substituents on the olefin. We have been interested in the
modification of this method using an appropriate catalyst to suit our
need for the synthesis of c,d-unstaturated amides with two bulky aryl
substituents. The present article describes our efforts in this direction.
RESULTS AND DISCUSSION
The starting allyl alcohols 4a–j required for the present study were
prepared in three steps as shown in Scheme 1. Perkin reaction[12] of
aldehydes 1a and 1b with various aryl acetic acids in the presence of
triethylamine in refluxing acetic anhydride furnished the trans-2,3-diaryl
acrylic acids 2a–j. Esterification of 2a–j with ethanol in the presence of
Scheme 1. Synthesis of 2,3-diaryl allyl alcohols.

334
V. S. P. R. Lingam et al.
catalytic amounts of sulfuric acid gave corresponding ethyl esters 3a–j.
Attempted reduction of esters 3a–j with lithium aluminum hydride[13]
and lithium borohydride[14] did not give the desired allyl alcohols, which
suggests that the reaction does not give allyl alcohols by means of
conjugate addition=elimination. The reduction was then attempted with
diisobutylaluminum hydride[15] in dry THF at ꢀ78 ꢁC resulted in the
formation of desired allyl alcohols 4a–j, and the results obtained are
summarized in Table 1.
Table 1. Synthesis of acrylic acid 2a–j, ethyl acrylates 3a–j, and allyl alcohols 4a–j
Starting
material
Time Yield
(h)
Entry
Product
(%)
Mp (ꢁC)
1
2
3
4
5
6
7
8
1a, X ¼ O 2a, X ¼ O, Ar ¼ phenyl
1.0
1.5
1.5
1.0
2.0
2.0
1.5
1.5
1.0
0.5
60
73
68
62
69
57
63
67
56
55
97
93
92
95
95
90
92
91
93
90
91
93
94
92
95
85
90
92
96
89
243–245
253–256
260–265
250–253
263–266
246–248
210–213
231–233
256–258
249–252
121–123
93–96
1a, X ¼ O 2b, X ¼ O, Ar ¼ 2-bromophenyl
1a, X ¼ O 2c, X ¼ O, Ar ¼ 2-iodophenyl
1a, X ¼ O 2d, X ¼ O, Ar ¼ 4-chlorophenyl
1a, X ¼ O 2e, X ¼ O, Ar ¼ 4-biphenyl
1a, X ¼ O 2f, X ¼ O, Ar ¼ 1-naphthyl
1b, X ¼ S 2g, X ¼ S, Ar ¼ phenyl
1b, X ¼ S 2h, X ¼ S, Ar ¼ 4-chlorophenyl
1b, X ¼ S 2i, X ¼ S, Ar ¼ 2-chlorophenyl
1b, X ¼ S 2j, X ¼ S, Ar ¼ 1- thienyl
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
2a
2b
2c
2d
2e
2f
3a, X ¼ O, Ar ¼ phenyl
24
3b, X ¼ O, Ar ¼ 2-bromophenyl 18
3c, X ¼ O, Ar ¼ 2-iodophenyl
3d, X ¼ O, Ar ¼ 4-chlorophenyl
3e, X ¼ O, Ar ¼ 4-biphenyl
3f, X ¼ O, Ar ¼ 1-naphthyl
3g, X ¼ S, Ar ¼ phenyl
18
18
24
24
18
24
18
18
90–92
118–119
154–156
137–133
118–120
110–113
123–126
67–69
130–132
50–52
52–55
161–163
166–168
101–103
126–128
138–140
65–67
2g
2h
2i
3h, X ¼ S, Ar ¼ 4-chlorophenyl
3i, X ¼ S, Ar ¼ 2-chlorophenyl
3j, X ¼ S, Ar ¼ 1- thienyl
2j
3a
3b
3c
3d
3e
3f
4a, X ¼ O, Ar ¼ phenyl
0.5
4b, X ¼ O, Ar ¼ 2-bromophenyl
4c, X ¼ O, Ar ¼ 2-iodophenyl
4d, X ¼ O, Ar ¼ 4-chlorophenyl
4e, X ¼ O, Ar ¼ 4-biphenyl
4f, X ¼ O, Ar ¼ 1-naphthyl
4g, X ¼ S, Ar ¼ phenyl
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
3g
3h
3i
4h, X ¼ S, Ar ¼ 4-chlorophenyl
4i, X ¼ S, Ar ¼ 2-chlorophenyl
4j, X ¼ S, Ar ¼ 1- thienyl
3j
131–132

TBAF-Catalyzed Eschenmoser–Claisen Rearrangement
335
Having obtained the required alcohols 4a–j for the synthesis of target
molecules, we have then carried out the Eschenmoser–Claisen [3,3] rear-
rangement with tetra n-butylammonium fluoride trihydrate[16] (TBAF ꢂ
3H2O) as phase-transfer catalyst (PTC). The latter has been previously
employed for several important synthetic transformations such as desily-
lation,[17] fluorination,[18] aldol condensation,[19] Michael addition,[20]
Sonogashira reaction,[21] and alkylation.[22]
The reactions were initially carried out by refluxing allyl alcohol (4a)
with N,N-dimethylacetamide dimethyl acetal (2.0 equiv) in the absence of
any catalyst. The reactions in the absence of catalyst (Table 2, entries
1–3) gave poor to moderate yields of 3-dibenzo[b,d]furan-4-yl-N,
N-dimethyl-4-phenylpent-4-enamide 5a after prolonged reaction time.
Then we attempted the reaction under Johnson–Claisen rearrangement
conditions using excess (3.0 equiv) N,N-dimethylacetamidedimethyl
acetal in refluxing toluene using propionic acid[23] or pivalic acid[24] as
catalyst (entries 4 and 5). Under these conditions, total conversion of
alcohol 4a to less polar imino acetate intermediate was observed (by
thin-layer chromatography, TLC), However, repeated attempts to isolate
the intermediates at this stage were not successful because of the instabil-
ity of the intermediate, and only moderate yield of the amide 5a was
achieved even after 48 h at reflux. Then, to assess the potential of TBAF
for this rearrangement, a series of preliminary experiments was carried
out. Initial studies with 10% catalyst in various polar and nonpolar
solvents at reflux temperatures suggested that polar solvents are not
useful for this rearrangement (entries 11 and 12). Complete conversion
Table 2. Eschenmoser–Claisen rearrangement of 4a under various conditions
Entry
Catalyst
Mole (%)
Solventa
Time (h) 5a yield (%)
1
2
3
4
5
6
7
8
—
—
—
—
—
—
10
10
10
5
10
20
10
10
10
Cyclohexane
Toluene
o-Xylene
Toluene
Toluene
Cyclohexane
Toluene
Toluene
Toluene
o-Xylene
72
18
18
48
48
72
5
3
3
3
48
48
5
42
51
35
40
63
81
92
92
89
15
30
CH3CH2CO2H
(CH3)3CCO2H
(n-Bu)4NF ꢂ 3H2O
(n-Bu)4NF ꢂ 3H2O
(n-Bu)4NF ꢂ 3H2O
(n-Bu)4NF ꢂ 3H2O
(n-Bu)4NF ꢂ 3H2O
(n-Bu)4NF ꢂ 3H2O
(n-Bu)4NF ꢂ 3H2O
9
10
11
12
Tetrahydrofuran
1,4-Dioxane
aAll reactions were carried out at reflux temperature of the solvents specified in
the table.

336
V. S. P. R. Lingam et al.
Scheme 2. Synthesis of c,d-unsaturated amides.
was obtained in both toluene (bp 111 ꢀC) and o-xylene (bp 145 ꢀC) within
3 h. Increasing the temperature of reaction by using o-xylene resulted in
reduction of reaction time by 20–30 min with no significant change in
yield (entry 10). On the other hand, decrease in reaction temperature
by using cyclohexane (bp 81 ꢀC) required around 3 days for completion
even with an excess (3.0 equiv) of N,N-dimethylacetamide dimethyl acetal
(entry 6). Reactions with 5% catalyst (entry 7) required 5 h to complete
the reaction, whereas 20% catalyst (entry 9) did not give any additional
advantage, although yield was not compromised either case.
After these preliminary screening experiments and arriving at the
appropriate conditions for the reaction of 4a to obtain 5a, the methodol-
ogy was extended to different allyl alcohols 4b–j to obtain corresponding
amides 5b–j (Scheme 2), thus establishing the generality of the present
method, and the details are summarized in Table 3.
CONCLUSION
We have successfully demonstrated the use of tetra-n-butylammonium
fluoride trihydrate as a very powerful catalyst for Eschenmoser–Claisen
Table 3. TBAF Á 3H2O-catalyzed Eschenmoser–Claisen rearrangement of 4a–j to
obtain 5a–j
Entry
Allyl alcohols
Yield (%)
Time (h)
Mp (ꢀC)
1
2
3
4
5
6
7
8
9
10
4a
4b
4c
4d
4e
4f
91
95
93
96
91
95
97
97
90
95
3.0
3.5
3.5
3.5
5.0
5.0
3.0
4.0
3.5
3.0
120–123
48–51
56–59
43–45
76–78
53–55
130–134
50–53
39–41
4g
4h
4i
4j
148–150

TBAF-Catalyzed Eschenmoser–Claisen Rearrangement
337
[3,3]-sigmatropic rearrangement of hindered allylic alcohols 4a–j, provid-
ing c,d-unstaturated amides 5a–5j in excellent yields. The advantage of
the present method is its operational simplicity, which proceeds with cat-
alytic amounts of the TBAF ꢂ 3H2O under mild conditions. This feature,
combined with the short reaction times and easy workup procedures,
makes this method an attractive choice over the existing procedure for
Eschenmoser–Claisen rearrangement. Further, the method tolerates bulky
aromatic substituents at 2 and 3 positions of the allyl alcohols. We hope
that the present method will find wide and useful application for practi-
cing chemists in the field.
EXPERIMENTAL
Typical Procedure for the Preparation of Acrylic Acids: Synthesis
of (2Z)-3-Dibenzo[b,d]furan-4-yl-2-phenyl Acrylic Acid (2a)
Triethylamine (7.80 ml, 77.082 mmol) was added to a solution of dibenzo-
furan-1-carboxaldehyde 1a (10 g, 50.968 mmol) and phenyl acetic acid
(7.61 g, 55.971 mmol) in acetic anhydride (25 ml), and the mixture was
stirred under reflux for 1.0 h under nitrogen atmosphere. Water (25 ml)
was added to the hot reaction mixture, and the mixture was slowly
(30 min) allowed to cool to room temperature. The product precipitated
out was collected by filtration, washed with water (2 ꢃ 25 ml), and dried
in an air oven. The material was crystallized from ethyl acetate to give
9.61 g (60%) of (2Z)-3-dibenzo[b,d]furan-4-yl-2-phenylacrylic acid as a
white solid; IR (KBr) 3359 (br) 3050, 2951, 1677, 1606, 1416, 1288, 1182,
1
1117, 835 cmꢀ1; H NMR (300 MHz, DMSO-d6) d 6.78 (d, J ¼ 7.5 Hz,
1H), 7.09 (t, J ¼ 7.8 Hz, 1H), 7.22–7.24 (m, 2H), 7.35–7.37 (m, 3H), 7.42
(t, J ¼ 7.8 Hz, 1H), 7.55 (t, J ¼ 7.5 Hz, 1H), 7.75 (d, J ¼ 7.2 Hz, 1H), 8.04
(d, J ¼ 7.8 Hz, 1H), 8.13 (d, J ¼ 7.8 Hz, 1H), 8.25 (s, 1H), 12.97 (br s, 1H,
exchangeable with D2O); MS m=z (þ cESI): 315.11 (MþH)þ. Anal. calcd.
for C21H14O3 (%): C, 80.24; H, 4.49. Found C, 80.35; H, 4.56.
Typical Procedure for the Preparation of Acrylates: Synthesis of Ethyl
(2Z)-3-Dibenzo[b,d]furan-4-yl-2-phenylacrylate (3a)
Conc. sulfuric acid (0.5 ml, 0.1 mmol) was added to a stirred solution of
(2Z)-3-dibenzo[b,d]furan-4-yl-2-phenylacrylic acid (9.3 g, 29.586 mmol) in
ethanol (50 ml), and the mixture was refluxed for 18 h under nitrogen
atmosphere. The ethanol was evaporated under reduced pressure, and
the residue obtained was diluted with ethyl acetate (50 ml) and water
(50 ml). The layers were separated, and the aqueous layer was extracted

338
V. S. P. R. Lingam et al.
with ethyl acetate (25 ml). The combined organic extracts were washed
with saturated aqueous sodium bicarbonate solution (50 ml) and water
(50 ml). The ethyl acetate solution was dried over anhydrous sodium sul-
fate. The solid obtained after evaporation of the solvent was crystallized
from ethyl acetate and hexane to 9.8 g (97%) white solid; IR (KBr) 3047,
2985, 1707, 1450, 1417, 1236, 1190, 1027, 843 cmꢀ1; 1H NMR (300 MHz,
DMSO-d6) d 1.26 (t, J ¼ 6.9 Hz, 3H), 4.26 (q, J ¼ 6.9 Hz, 2H), 6.77 (d,
J ¼ 7.8 Hz, 1H), 7.09 (t, J ¼ 7.8 Hz, 1H), 7.22–7.25 (m, 2H), 7.35–7.37
(m, 3H), 7.41 (dt, J ¼ 0.6, 7.8 Hz, 1H), 7.55 (dt, J ¼ 1.2, 6.3 Hz, 1H),
7.74 (d, J ¼ 8.4 Hz, 1H), 8.05 (dd, J ¼ 1.2, 6.6 Hz, 1H), 8.13 (dd,
J ¼ 0.9, 6.9 Hz, 1H), 8.24 (s, 1H); MS m=z (þ cESI): 343.22 (MþH)þ.
Anal. calcd. for C23H18O3(%): C, 80.68; H, 5.30. Found C, 80.77; H, 5.39.
Typical Procedure for Ester Reduction: Synthesis of (2Z)-3-
Dibenzo[b,d]furan-4-yl-2-phenylprop-2-en-1-ol (4a)
To a stirred and cooled (ꢀ78 ꢁC) solution of ester 3a (9.7 g, 28.331 mmol)
in dry THF (60 ml), a 20% toluene solution of diisobutylaluminium
hydride (50.4 ml, 70.826 mmol) was added, and the mixture was stirred
at this temperature for 30 min. The reaction mixture was then quenched
with water (20 ml) and diluted with EtOAc (50 ml). The layers were sepa-
rated, and the aqueous layer was extracted with EtOAc (25 ml). The com-
bined organic layers were washed with water (3 ꢃ 50 ml) followed by
brine (20 ml). The solution was dried over anhydrous sodium sulfate.
The solvent was evaporated to give 8.45 g (99%) of 4a as a white solid.
IR (KBr) 3244, 3051, 2945, 1451, 1418, 1186, 1029 cmꢀ1 1H NMR
;
(300 MHz, DMSO-d6) d 4.35 (d, J ¼ 4.5 Hz, 2H), 5.44 (t, J ¼ 3.6 Hz,
1H, exchangeable with D2O), 6.79 (d, J ¼ 7.2 Hz, 1H), 7.03 (t, J ¼ 7.8 Hz,
1H), 7.13 (s, 1H), 7.21 (d, J ¼ 8.1 Hz, 2H), 7.29–7.32 (m, 3H), 7.38 (t,
J ¼ 7.5 Hz, 1H), 7.52 (t, J ¼ 7.5 Hz, 1H), 7.70 (d, J ¼ 8.1 Hz, 1H), 7.88 (d,
J ¼ 7.5 Hz, 1H), 8.10 (d, J ¼ 7.2 Hz, 1H); MS m=z (-cESI): 299.32
(M ꢀ H)ꢀ. Anal. calcd. for C21H16O2(%): C, 83.98; H, 5.37; Found C,
84.08; H, 5.45.
Typical Procedure for Eschenmoser–Claisen [3,3]-sigmatropic
Rearrangement: Synthesis of 3-Dibenzo[b,d ]furan-4-yl-N,N-
dimethyl-4-phenylpent-4-enamide (5a)
To a stirred solution of compound 4a (500 mg, 1.664 mmol) in toluene,
N,N-dimethylacetamide dimethyl acetal (333 mg, 2.500 mmol) and
TBAF ꢂ 3H2O (52.69 mg, 0.116 mmol) were added, and the mixture was
refluxed for 3 h under nitrogen atmosphere. The reaction mixture was

TBAF-Catalyzed Eschenmoser–Claisen Rearrangement
339
then cooled to room temperature and diluted with ethyl acetate (50 ml).
The organic layer was washed with water (3 ꢃ 50 ml) and brine (10 ml)
and dried over anhydrous sodium sulfate. The residue obtained after eva-
poration of the solvent was purified by silica-gel column chromatography
using a mixture of ethyl acetate–petroleum ether as eluent to give 560 mg
(91%) of 5a as a white solid; IR (KBr) 3054, 2920, 1634, 1493, 1449, 1419,
1
1399, 1183, 1144 cmꢀ1; H NMR (300 MHz, CDCl3) d 2.85 (s, 3H), 2.93
(s, 3H), 3.03–3.10 (m, 2H), 5.11 (s, 1H), 5.25 (br s, 1H), 5.45 (s, 1H), 7.20–
7.38 (m, 6H), 7.44–7.55 (m, 3H), 7.59 (d, J ¼ 7.8 Hz, 1H), 7.78 (d,
J ¼ 6.9 Hz, 1H), 7.91 (d, J ¼ 6.9 Hz, 1H); MS m=z (þ cESI): 370.46
(M þ H)þ. Anal. calcd. for C25H23NO2(%): C, 81.27; H, 6.27; N, 3.79.
Found C, 81.18; H, 6.35; N, 3.85.
ACKNOWLEDGMENTS
The authors thank Glenmark Pharmaceuticals Limited for granting per-
mission to carry out the present research work.
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