One-pot stereoselective synthesis of (Z)-β-ketoenamides from β-halo α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/ejoc.201400007

A series of steroidal and non-steroidal β-ketoenamides have been synthesized from their corresponding β-halo α,β-unsaturated aldehydes. This synthetic methodology provides efficient access to (Z)-β-ketoenamides. The structures of these products have been

Full text of DOI:10.1002/ejoc.201400007

FULL PAPER
DOI: 10.1002/ejoc.201400007
One-Pot Stereoselective Synthesis of (Z)-β-Ketoenamides from β-Halo
α,β-Unsaturated Aldehydes
Junali Gogoi,[a] Pranjal Gogoi,*[a] and Romesh C. Boruah*[a]
Keywords: Synthetic methods / Ketoenamides / Aldehydes / Steroids
A series of steroidal and non-steroidal β-ketoenamides have
been synthesized from their corresponding β-halo α,β-unsat-
inexpensive. The required β-halo α,β-unsaturated aldehydes
are synthesized from corresponding ketones using the
urated aldehydes. This synthetic methodology provides ef- Vilsmeier formylation reaction. One of the prepared β-keto-
ficient access to (Z)-β-ketoenamides. The structures of these
products have been unambiguously established by single
crystal XRD studies. This process is found to be mild and
enamides was transformed into its corresponding 2-amino-
dihydroisoquinoline derivative.
Introduction
in the synthesis of carbocycles and heterocycles from β-halo
α,β-unsaturated aldehydes and the application of this syn-
thon to the construction of other valuable intermediates
and products.[15] Additionally, we have extensively utilized
the chemistry of β-formylenamides[16] and have been en-
deavouring to develop an alternative strategy for their syn-
thesis since they have been demonstrated as key synthons
for various heterocycles. We planned to achieve this struc-
tural motif from β-halo α,β-unsaturated aldehydes using in-
expensive ammonium acetate and acetic anhydride in acetic
acid medium. Initially, the synthetic protocol was applied
to a steroidal D-ring β-bromo α,β-unsaturated aldehyde.
Interestingly in this scenario, the reagent system afforded
exclusively D-ring annelated β-ketoenamides. In a typical
experimental procedure, a mixture of β-bromo α,β-unsatu-
rated aldehyde 2, ammonium acetate, acetic acid and acetic
anhydride was stirred at 120 °C for 2 h. The β-ketoenamide
was formed with very good yields (Scheme 1).
The β-ketoenamide functionality is an important struc-
tural motif in a wide range of pharmaceuticals and natural
products.[1] They have proved to be versatile intermediate
for the synthesis of amino alcohols,[2] 1,3-diamines,[3] β-
amino acids,[4] various heterocycles[5] such as pyridines, pyr-
imidines, oxazoles, imidazoles, tetrazoles, and others. In ad-
dition, they are also used as key precursors to valuable chi-
ral products.[2,6] Thus, the synthesis of β-ketoenamides has
drawn great attention from chemists and a number of meth-
ods have been developed for their synthesis.[7] Traditionally,
the condensation of carbonyl derivatives with amides or
acylation of imines are the methods of choice.[8] The stereo-
selective synthesis of thermodynamically less favourable Z-
enamides remains a challenge and has been rarely explored.
Several notable methods, such as Curtius rearrangement,[9]
the Peterson reaction,[10] Pd/Cu-catalyzed oxidative amid-
ation of conjugated olefins,[11] Pd- and/or Cu-catalyzed
cross-coupling of vinyl derivatives (via halides, triflates, tos-
ylates, borates, ethers) with amides,[12] and Pd-catalyzed
hydroamidation of electron deficient terminal alkynes[13]
have been reported for stereoselective enamide synthesis.
However, most of these approaches require rigorous reac-
tion conditions, transition metal catalysts and intricacies in
starting material preparation that often limit their practical
application.
On the other hand, β-halo α,β-unsaturated aldehydes are
versatile organic synthons for a variety of heterocyclic com-
pounds and macrocyclic ligands.[14] We have been interested
Scheme 1. Synthesis of β-ketoenamides from β-halo α,β-unsatu-
rated aldehydes.
Results and Discussion
[a] Medicinal Chemistry Division, CSIR – North East Institute of
Science and Technology,
The scope of our reaction protocol was examined by syn-
thesizing other steroidal β-ketoenamides from their corre-
sponding β-halo α,β-unsaturated aldehydes. The starting β-
halo α,β-unsaturated aldehydes were efficiently synthesized
using the Vilsmeier reaction (Table 1). Various tetralones
Jorhat 785006, India
E-mail: gogoipranj@yahoo.co.uk
rc_boruah@yahoo.co.in
http://www.rrljorhat.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201400007.
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J. Gogoi, P. Gogoi, R. C. Boruah
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and cyclic ketones were treated with Vilsmeier reagent to Acyclic ketones 2-heptanone and 4-chromanone were ef-
generate corresponding β-bromo α,β-unsaturated aldehydes ficiently converted into their corresponding β-bromo α,β-
(Table 1, compounds 2e–g and 2i–j). Steroidal A- and D- unsaturated aldehydes with good yields. Having the requi-
ring annelated β-halo α,β-unsaturated aldehydes were pro- site β-bromo α,β-unsaturated aldehydes, we then attempted
duced, respectively from commercially available cholesterol, our one-pot protocol for the synthesis of β-ketoenamides.
estrone and 16-dehydropregnenolone acetate (16-DPA). Both β-bromo α,β-unsaturated aldehyde and β-chloro α,β-
unsaturated aldehyde were efficiently used in this protocol.
However, the chloro-formyl substrate required a longer re-
Table 1. Synthesis of β-halo α,β-unsaturated aldehydes (2).[a]
Table 2. Synthesis of steroidal and non-steroidal (Z)-β-ketoen-
amides (3).[a]
[a] Reaction conditions: Carbonyl compound 1 (1 mmol), N,N-di-
methylformamide (5 mmol), phosphorus tribromide (2 mmol) in
chloroform (15 mL) were added at 0 °C and the whole reaction
mixture was stirred at room temp. for 12 h. [b] Phosphorus oxy-
chloride (4 mmol) was added instead of phosphorus tribromide.
[c] Refluxed for 3 h.
[a] Reaction conditions: β-Halo α,β-unsaturated aldehyde
2
(1 mmol), ammonium acetate (3 mmol), acetic acid (2 mL) and
acetic anhydride (4 mL) were stirred at 120 °C for 2 h. [b] Isolated
yield. [c] The reaction was stirred at 120 °C for 5 h.
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One-Pot Stereoselective Synthesis of (Z)-β-Ketoenamides
action time compared to the related bromo-formyl substrate Table 3. Synthesis of steroidal and non-steroidal β-bromo α,β-un-
saturated enamide (4).[a]
and the β-bromo α,β-unsaturated aldehyde gave a compara-
tively higher yield than β-chloro α,β-unsaturated aldehydes
(Table 2, Entries 1 and 2).
The synthetic protocol was also applied to non-steroidal
β-bromo α,β-unsaturated aldehydes; β-ketoenamides were
formed with excellent yields. For instance, 1-bromo-3,4-di-
hydronaphthalene-2-carbaldehyde 2e reacted with ammo-
nium acetate and acetic anhydride to afford β-ketoenamide
3e in 85% yield (Table 2, Entry 5). The constitution and
configuration of the product was confirmed by X-ray crys-
tal structure analysis. Interestingly, only (Z)-β-ketoen-
amides were observed, probably as a result of intramolecu-
lar hydrogen bonding between the amido proton and the
carbonyl oxygen (Figure 1).[17]
Figure 1. Solid state structure of (Z)-β-ketoenamide, 3e (ORTEP
[a] Reaction conditions: 2 (1 mmol), ammonium acetate (3 mmol),
plot 50% probability level).
acetic acid (2 mL) and acetic anhydride (4 mL) were stirred at
120 °C for 2 h. [b] Isolated yield.
Similarly, other non-steroidal β-bromo α,β-unsaturated
aldehyde analogues were also used for the synthesis of (Z)-
β-ketoenamides (Table 2. Entries 5–15). In this category,
seven and eight membered β-bromo α,β-unsaturated alde-
hydes were selected for the synthesis of their corresponding
(Z)-β-ketoenamides (Table 2, Entries 9–10). Both products
were formed in good yields (82–85%). Furthermore, acyclic
(Z)-β-ketoenamides were efficiently synthesized from their
corresponding acyclic β-bromo α,β-unsaturated aldehydes
(Table 2, Entries 11–15).
An interesting deviation was observed when the steroidal
A-ring annelated β-bromo α,β-unsaturated aldehyde 2p was
employed for the synthesis of β-ketoenamides; it unexpec-
tedly gave β-bromo α,β-unsaturated enamide 4p (Table 3,
Figure 2. Reaction intermediates and synthesis of (Z)-β-ketoen-
amide 3q.
Entry 1).
For further studies, we considered 2-bromocyclohex-1-
enecarbaldehyde 2q, which also gave N-[(2-bromocyclohex-
2-en-1-ylidene)methyl]acetamide (4q). Product 4q was iso-
lated and further treated with ammonium acetate in acetic
acid for 5 h at 150 °C. Expected β-ketoenamide 3q was
formed in 31% yield. It is proposed that the reaction pro-
ceeds through generation of intermediate A which then tau-
tomerises to β-bromo α,β-unsaturated enamide 4q (Fig-
ure 2). The formation of 3q is rationalized by participation
of intermediate A in the amination reaction to intermediate
B, which in turn, is converted into imine intermediate C
followed by hydrolysis to 3q.
To explore further some possible applications of gener-
ated β-ketoenamides, we carried out the Knoevenagel reac-
tion of 3e to afford a fused aza-heterocycle. Accordingly,
3e was subjected to cyclisation conditions, by treating with
malononitrile under MW conditions in basic alumina.[18]
Anticipated product 2-amino-5,6-dihydrobenzo[f]isoquinol-
ine-1-carbonitrile (5e) was formed in 65% yield (Scheme 2).
Similarly, other β-bromo α,β-unsaturated aldehydes like
2-bromo-4-methylcyclohex-1-enecarbaldehyde (2r) and 2-
bromo-5-ethylcyclohex-1-enecarbaldehyde (2s) were consid-
ered. Both 2r and 2s, when subjected to the reaction condi-
tions, afforded their corresponding conjugated β-bromoen-
amides 4r and 4s in good yields (Table 3, Entries 3 and 4).
Scheme 2. Synthesis of 2-aminodihydroisoquinoline derivative 5e
from β-ketoenamide 3e.
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wise and the reaction mixture was stirred for 12 h at room temp.
The reaction mixture was then poured in ice water. Solid sodium
hydrogen carbonate was carefully added to neutralize the acids and
the mixture was extracted three times with chloroform. The organic
part was then washed with cold water, dried with sodium sulfate
and the solvents evaporated. Purification of the residue was done
by silica gel (60–120 mesh) by column chromatography.
Conclusions
In conclusion, we have developed a simple and inexpen-
sive approach for the one-pot synthesis of β-ketoenamides
from β-halo α,β-unsaturated aldehydes. A series of steroidal
and non-steroidal β-ketoenamides were prepared by this
method. This protocol provides (Z)-β-ketoenamides exclu-
sively and structures of these products have been unambigu-
ously established by single crystal XRD study. In addition,
one of the prepared β-ketoenamides was transformed into
the corresponding 2-aminodihydroisoquinoline derivative.
3β-Acetoxy-17-bromo-16-formylandrost-5,16-diene (2b): Compound
2b was prepared according to general experimental procedure B
noted above. The residue was purified by column chromatography
with a mixture of hexane/EtOAc (95:5) as eluent; Pale yellow solid
(302 mg, yield 72%); m.p. 180–182 °C; Rf = 0.6 (10% EtOAc in
1
hexanes). H NMR (300 MHz, CDCl3): δ = 9.88 (s, 1 H), 5.40 (d,
J = 4.8 Hz, 1 H), 4.55–4.65 (m, 1 H), 2.04 (s, 3 H), 1.07 (s, 3 H),
0.95 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 189.6, 169.8,
154.9, 148.7, 139.0, 137.9, 137.3, 126.0, 121.7, 118.8, 53.2, 51.9,
44.2, 37.1, 33.9, 29.3 (2ϫC), 29.2, 26.9, 25.9, 21.2, 15.3 ppm. IR
Experimental Section
1
General Methods: H NMR and 13C NMR spectra were obtained
with a Bucker Advance DPX 300 MHz and 500 MHz spectrometer
with CDCl3 as solvent and TMS as internal standard. Microwave
(MW) reactions were carried out with a Synthos 3000 (Anton Paar)
microwave reactor. Melting points were determined with a Buchi
M-560 apparatus and are uncorrected. IR spectra were recorded as
thin films using a silicon disc on a PerkinElmer FT-IR spectrome-
ter. ESI mass spectra were recorded with a Bucker Daltonic Data
analysis 2.0 spectrometer. Reactions were monitored by thin-layer
chromatography (TLC) using aluminium-backed MERCK 60 silica
gel plates (0.2 mm thickness); the chromatograms were visualized
first with ultraviolet light (254 nm) and then by immersion in solu-
tions of p-anisaldehyde followed by heating. Flash column
chromatography was performed with Merck silica gel 60 (230–
400 mesh).
(CHCl ): ν = 2944, 2853, 1732, 1673, 1582, 1373, 1240, 1031,
˜
3
771 cm–1. LCMS(ESI): m/z (%) = 420 [M]+. C22H29BrO3 (420.13):
calcd. C 62.71, H 6.94; found C 62.73, H 6.95.
3-Bromo-3-(4-chlorophenyl)acrylaldehyde (2m): Compound 2m was
prepared according to general experimental procedure B noted
above; the residue was purified by column chromatography with a
mixture of hexane/EtOAc (95:5) as eluent, to give 2m as a white
solid (215 mg, yield 88%); m.p. 87–90 °C; Rf = 0.6 (10% EtOAc in
1
hexanes). H NMR (300 MHz, CDCl3): δ = 10.05 (d, J = 6.4 Hz,
1 H), 7.65 (d, J = 8.7 Hz, 2 H), 7.42 (d, J = 8.3 Hz, 2 H), 6.77 (d,
J = 6.5 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 193.0,
143.3, 137.9, 135.8, 129.3 (2ϫC), 129.1 (2ϫC), 127.6 ppm. IR
(CHCl ): ν = 3018, 2876, 1670, 1595, 1129, 815, 662 cm–1.
˜
3
LCMS(ESI): m/z (%) = 245 [M]+. C9H6BrClO (245.50): calcd. C
A. Experimental Procedure for the Synthesis of 3β-Acetoxy-17-
chloro-16-formylandrost-5,16-diene (2a): A solution of N,N-dimeth-
ylformamide (0.5 mL, 6 mmol) in anhydrous chloroform (15 mL)
was cooled to 0 °C. Phosphorous oxychloride (0.4 mL, 4 mmol)
was added dropwise over a period of 10 min. The resulting white
suspension was warmed to room temperature and stirred for an
additional 30 min. A solution of 3β-Acetoxy-androst-5-en-17-one
(376 mg, 1 mmol) in chloroform (15 mL) was added dropwise and
the reaction mixture was refluxed for 3 h. The reaction mixture was
then poured in ice water. Solid sodium hydrogen carbonate was
carefully added to neutralize the acids and the mixture was ex-
tracted several times with chloroform. The organic phase was then
washed with cold water thoroughly, dried with sodium sulfate and
the solvents evaporated. The residue was purified by silica gel (60–
120 mesh) column chromatography with a mixture of hexane/
EtOAc (95:5) as eluent; Pale yellow solid (282 mg, yield 75%); m.p.
164–167 °C; Rf = 0.6 (10% EtOAc in hexanes). 1H NMR
(300 MHz, CDCl3): δ = 9.99 (s, 1 H), 5.40 (d, J = 4.8 Hz, 1 H),
4.55–4.65 (m, 1 H), 2.04 (s, 3 H), 1.07 (s, 3 H), 0.95 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 188.1, 170.5, 162.3, 140.0,
136.4.0, 121.9, 73.7, 53.8, 50.6, 50.2 38.0, 36.8 (2ϫC), 32.9, 30.8,
44.03, H 2.46; found C 44.01, H 2.45.
3-Bromo-3-(4-nitrophenyl)acrylaldehyde (2n): Compound 2n was
prepared according to general experimental procedure B as noted
above; the residue was purified by column chromatography with a
mixture of hexane/EtOAc (95:5) as eluent, to give 2n as a white
solid (225 mg, yield, 88%); m.p. 84–86 °C; Rf = 0.6 (10% EtOAc
in hexanes). 1H NMR (300 MHz, CDCl3): δ = 10.08 (d, J = 6.4 Hz,
1 H), 8.31 (d, J = 8.7 Hz, 2 H), 7.88 (d, J = 8.8 Hz, 2 H), 6.89 (d,
J = 2.1 Hz, 1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 193.0,
149.3, 143.3, 141.3, 129.8, 129.0 (2ϫC), 123.8 (2ϫC) ppm. IR
(CHCl ): ν = 2930, 2856, 1675, 1590, 1521, 1348, 1122, 841,
˜
3
692 cm–1. LCMS(ESI): m/z (%) = 256 [M]+. C9H6BrNO3 (256.05):
calcd. C 42.22, H 2.36, N 5.47; found C 42.25, H 2.43, N 5.57.
2-(1-Bromoethylidene)hexanal (2o): Compound 2o was prepared ac-
cording to general experimental procedure B noted above; the resi-
due was purified by column chromatography with a mixture of hex-
ane/EtOAc (95:5) as eluent, to give 2o as a yellow liquid (170 mg,
yield 83%); Rf = 0.7 (10% EtOAc in hexanes). 1H NMR (300 MHz,
CDCl3): δ = 9.93 (s, 1 H), 2.75 (s, 3 H), 2.29–2.43 (m, 2 H), 1.15–
1.34 (m, 4 H), 0.76–0.91 (m, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 186.4, 147.2, 141.7, 30.2, 29.8, 25.1, 22.7, 13.9 ppm.
30.4, 28.5, 27.7, 21.4, 20.3, 19.2, 15.0 ppm. IR (CHCl ): ν = 2945,
˜
3
2830, 1734, 1674, 1582, 1240, 1029, 771 cm–1. LCMS(ESI): m/z (%)
= 376 [M]+. C22H29ClO3 (376.92): calcd. C 70.10, H 7.76; found C
70.03, H 7.86.
IR (CHCl ): ν = 2958, 2929, 2860, 1681, 1202, 925, 732 cm–1.
˜
3
LCMS(ESI): m/z (%) = 205 [M]+. C8H13BrO (205.09): calcd. C
46.85, H 6.39; found C 46.79, H 6.29.
B. General Procedure for the Synthesis of β-Bromo α,β-Unsaturated
Aldehyde: A solution of N,N-dimethylformamide (5 mmol) in anhy-
drous chloroform (15 mL) was cooled to 0 °C in ice bath. Phospho-
rous tribromide (2 mmol) was added dropwise over a period of
10 min. The resulting white suspension was warmed to room tem-
perature and stirred for an additional 30 min. A solution of carb-
onyl compound (1 mmol) in chloroform (15 mL) was added drop-
2-Bromo-4-methylcyclohex-1-enecarbaldehyde (2r): Compound 2r
was prepared according to general experimental procedure B noted
above; the residue was purified by column chromatography with a
mixture of hexane/EtOAc (95:5) as eluent, to give 2r as yellow li-
quid (172mg, yield 85%); Rf = 0.6 (10% EtOAc in hexanes). 1H
NMR (500 MHz, CDCl3): δ = 10.0 (s, 1 H), 2.80 (dd, J1 = 4.5, J2
= 19.8 Hz, 1 H), 2.35–2.57 (m, 2 H), 2.10–2.20 (m, 1 H), 1.8–1.9
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One-Pot Stereoselective Synthesis of (Z)-β-Ketoenamides
(m, 2 H), 1.2–1.3 (m, 1 H), 1.02 (d, J = 6.5 Hz, 3 H) ppm. 13C 10 H), 2.29 (s, 3 H), 2.14 (s, 3 H), 0.95 (s, 3 H) ppm. 13C NMR
NMR (100 MHz, CDCl3): δ = 193.4, 142.8, 134.7, 46.7, 30.5, 29.1,
24.6, 20.8 ppm. IR (CHCl ): ν = 2950, 2928, 2854, 1680, 1618,
(75MHz, CDCl3): δ = 212.6, 169.9, 168.5, 148.6, 138.0, 137.3,
131.3, 126.3, 121.6, 118.8, 114.6, 49.7, 49.3, 44.0, 37.4, 31.3, 29.3,
˜
3
1208, 931, 721 cm–1. LCMS(ESI): m/z (%) = 203 [M]+. C8H11BrO 27.0, 26.5, 25.7, 23.5, 21.1, 14.5 ppm. IR (CHCl ): ν = 3311, 2930,
˜
3
(203.08): calcd. C 47.32, H 5.46; found C 47.29, H 5.53.
2857, 1762, 1691, 1615, 1492, 1220, 753 cm–1. LCMS(ESI): m/z (%)
= 382 [M+ + 1]. C23H27NO4 (381.46): calcd. C 72.15, H 7.13; found
C 72.10, H 7.15.
2-Bromo-5-ethylcyclohex-1-enecarbaldehyde (2s): Compound 2s was
prepared according to general experimental procedure B noted
above; the residue was purified by column chromatography with a
mixture of hexane/EtOAc (95:5) as eluent, to give 2s as a yellow
(Z)-N-{[1-Oxo-3,4-dihydronaphthalen-2(1H)-ylidene]methyl}-
acetamide (3e): Compound 3e was prepared according to general
experimental procedure C noted above; yellow crystalline solid
1
liquid (184 mg, yield 85%); Rf = 0.6 (10% EtOAc in hexanes). H
NMR (300 MHz, CDCl3): δ = 10.02 (s, 1 H), 2.70–2.87 (m, 2 H), (182 mg, 85% yield); m.p. 150–152 °C; Rf = 0.4 (20% EtOAc in
1
2.48–2.64 (m, 2 H), 1.66–1.93 (m, 3 H), 1.25–1.47 (m, 2 H), 0.94
hexanes). H NMR (300 MHz, CDCl3): δ = 11.57 (d, J = 7.7 Hz,
1 H), 8.02 (d, J = 7.7 Hz, 1 H), 7.48 (m, 2 H), 7.36 (t, J = 7.5 Hz,
1 H), 7.24 (m, 1 H), 2.95 (m, 2 H) 2.72 (m, 2 H), 2.20 (s, 3 H) ppm.
13C NMR (75 MHz, CDCl3): δ = 190.3, 169.0, 143.0, 134.1, 134.0,
133.2, 128.3, 127.4 127.1, 112.5, 29.4, 28.4, 23.8 ppm. IR (CHCl3):
(t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 193.9,
143.7, 134.7, 38.8, 34.0, 29.9, 29.7, 28.3, 11.4 ppm. IR (CHCl ): ν
˜
3
= 2961, 2926, 2856, 1679, 1210, 947, 699 cm–1. LCMS(ESI): m/z
(%) = 217 [M]+. C9H13BrO (217.10): calcd. C 49.79, H 6.04; found
C 49.76, H 6.16.
ν = 3283, 2934, 1708, 1654, 1354, 1225, 1012 cm–1. LCMS(ESI):
˜
m/z (%) = 215 [M]+. C13H13NO2 (215.25): calcd. C 72.54, H 6.09;
C. General Procedure for the Synthesis of β-Ketoenamides: β-Halo
α,β-unsaturated aldehyde (1 mmol, 1 equiv.), ammonium acetate
(3 mmol, 3 equiv.), acetic anhydride (4 mL) in acetic acid (2 mL)
were stirred at 120 °C for 2 h. The mixture was cooled to room
temperature and poured into ice cold water. Sodium hydroxide
solution (0.5 m) was added to neutralize the mixture and extracted
with EtOAc (2ϫ 10 mL). The organic extracts were dried with an-
hydrous sodium sulfate, concentrated under reduced pressure. The
residue was purified by column chromatography (EtOAc in hex-
anes) to get β-ketoenamides.
found C 72.49, H 6.05.
(Z)-N-{[7-Methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene]-
methyl}acetamide (3f): Compound 3e was prepared according to
general experimental procedure C noted above; yellow crystalline
solid (205 mg, 84% yield); m.p. 100–102 °C; Rf = 0.4 (20% EtOAc
in hexanes). 1H NMR (300 MHz, CDCl3): δ = 11.57 (d, J = 8.9 Hz,
1 H), 7.50 (m, 2 H), 7.17 (d, J = 8.3 Hz, 1 H), 7.03–7.08 (m, 1 H),
3.86 (s, 3 H), 2.88 (t, J = 6.7 Hz, 2 H), 2.69 (t, J = 6.7 Hz, 2 H),
2.19 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 190.2, 169.0,
158.7, 135.7, 134.8, 134.1, 129.5, 121.2, 112.4, 109.7, 55.5, 28.6,
3β-Acetoxy-17-oxo-16-(Z)-(acetamidomethylene)androst-5-ene (3a):
Compound 3a was prepared according to general experimental
procedure C noted above; yellow crystalline solid (319 mg, 80%
yield); m.p. 152–155 °C; Rf = 0.3 (20% EtOAc in hexanes). 1H
NMR (300 MHz, CDCl3): δ = 10.75 (d, J = 10.7 Hz, 1 H), 7.34 (d,
28.4, 23.8 ppm. IR (CHCl ): ν = 3298, 2929, 2849, 1710, 1651,
˜
3
1583, 1352, 1245, 1023 cm–1. LCMS(ESI): m/z (%) = 245 [M]+.
C14H15NO3 (245.11): calcd. C 68.56, H 6.16; found C 68.54, H 6.11.
(Z)-N-{[6-Methoxy-1-oxo-3,4-dihydronaphthalen-2(1H)-ylidene]-
J = 10.7 Hz, 1 H), 5.41 (d, J = 4.8 Hz, 1 H), 4.61 (m, 1 H), 2.46 methyl}acetamide (3 g): Compound 3c was prepared according to
(dd, J1 = 6.2, J2 = 14.5 Hz, 1 H), 1.15–2.36 (m, 16 H), 2.13 (s, 3
general experimental procedure C noted above; yellow crystalline
H), 2.04 (s, 3 H), 1.06 (s, 3 H), 0.94 (s, 3 H) ppm. 13C NMR solid (210 mg, 86% yield); m.p. 103–104 °C; Rf = 0.4 (20% EtOAc
(75 MHz, CDCl3): δ = 212.7, 170.5, 168.4, 139.9, 131.1, 121.8, in hexanes). 1H NMR (300 MHz, CDCl3): δ = 11.58 (d, J = 9.3 Hz,
114.6, 73.7, 50.9, 50.1, 48.9, 38.1, 36.9, 36.7, 31.2, 30.9, 30.8, 27.7, 1 H), 8.0 (d, J = 8.7 Hz, 1 H), 7.43 (d, J = 10.7 Hz, 1 H), 6.87 (dd,
27.3, 23.5, 21.4, 20.3, 19.3, 14.3 ppm. IR (CHCl ): ν = 3306, 2939,
J1 = 2.3, J2 = 8.7 Hz, 1 H) 6.71 (s, 1 H), 3.87 (s, 3 H), 2.90 (t, J =
˜
3
2855, 1732, 1617, 1372, 1234, 1027, 769 cm–1. LCMS(ESI): m/z (%)
6.4 Hz, 2 H), 2.69 (t, J = 6.4 Hz, 2 H), 2.18 (s, 3 H) ppm. 13C NMR
= 400 [M+ + 1]. C24H33NO4 (399.52): calcd. C 72.15, H 8.33; found (75 MHz, CDCl3): δ = 189.2, 169.0, 163.6, 145.5, 133.2, 129.8,
C 72.09, H 8.21.
127.5, 113.3, 112.5 (2ϫC), 55.4, 29.7, 28.5, 23.7 ppm. IR (CHCl3):
ν = 3291, 2938, 1705, 1652, 1602, 1354, 1231, 1009 cm–1
.
˜
3-Methoxy-17-oxo-16-(Z)-(acetamidomethylene)estra-1,3,5-triene
(3c): Compound 3c was prepared according to general experimen-
tal procedure C noted above; white crystalline solid (275 mg, 78%
yield); m.p. 116–120 °C; Rf = 0.5 (20 % EtOAc in hexanes). 1H
NMR (300 MHz, CDCl3): δ = 10.69 (d, J = 10.7 Hz, 1 H), 7.29 (d,
LCMS(ESI): m/z (%) = 245 [M]+. C14H15NO3 (245.11): calcd. C
68.56, H 6.16; found C 68.59, H 6.09.
(Z)-N-[(4-Oxochroman-3-ylidene)methyl]acetamide (3h): Com-
pound 3c was prepared according to general experimental pro-
cedure C noted above; white crystalline solid (182 mg, 84% yield);
m.p. 100–102 °C; Rf = 0.3 (20 % EtOAc in hexanes). 1H NMR
(300 MHz, CDCl3): δ = 11.28 (d, J = 6.8 Hz, 1 H), 7.92 (d, J =
J = 10.7 Hz, 1 H), 7.07–7.20 (m, 1 H), 6.64 (dd, J1 = 2.6, J2
=
8.5 Hz, 1 H), 6.56 (d, J = 2.5 Hz, 1 H), 3.69 (s, 3 H), 2.76–2.86 (m,
1 H), 2.47 (dd, J1 = 5.3, J2 = 14.3 Hz, 1 H), 1.18–2.33 (m, 11 H),
2.05 (s, 3 H), 0.86 (s, 3 H) ppm. 13C NMR (75MHz, CDCl3): δ = 7.8 Hz, 1 H), 7.45–7.52 (m, 2 H), 7.06 (t, J = 7.5 Hz, 1 H), 6.97 (d,
212.8, 168.5, 157.6, 137.8, 131.9, 131.2, 129.0, 128.2, 126.2, 114.7,
55.2, 49.7, 49.4, 43.9, 37.8, 31.4, 29.6, 27.0, 26.7, 25.9, 23.5,
J = 8.3 Hz, 1 H), 4.91 (s, 2 H), 2.20 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 185.2, 168.9, 160.9, 135.9, 133.3, 127.2,
14.6 ppm. IR (CHCl ): ν = 3428, 2930, 2851, 1671, 1608, 1579, 122.8, 121.9, 118.0, 108.6, 69.6, 23.7 ppm. IR (CHCl ): ν = 3287,
˜
˜
3
3
1500, 1229, 776 cm–1. LCMS(ESI): m/z (%) = 354 [M+ + 1]. 2925, 2854, 1715, 1662, 1610, 1379, 1215, 1026, 760 cm–1
.
C22H27NO3 (353.2): calcd. C 74.76, H 7.70; found C 74.56, H 7.66.
LCMS(ESI): m/z (%) = 218 [M+ + 1]. C12H11NO3 (217.07): calcd.
C 66.35, H 5.10; found C 66.31, H 5.08.
3-Acetoxy-17-oxo-16-(Z)-(acetamidomethylene)estra-1,3,5-triene
(3d): Compound 3d was prepared according to general experimen-
(Z)-N-[(2-Oxocycloheptylidene)methyl]acetamide (3i): Compound
tal procedure C noted above; white crystalline solid (316 mg, 83% 3i was prepared according to general experimental procedure C
yield); m.p. 180–204 °C; Rf = 0.5 (20 % EtOAc in hexanes). 1H
NMR (300 MHz, CDCl3): δ = 10.76 (d, J = 10.7 Hz, 1 H), 7.37 (d,
noted above; Yellow liquid; (153 mg, 85% yield); Rf = 0.6 (20%
EtOAc in hexanes). H NMR (300 MHz, CDCl3): δ = 11.34 (br. s,
1
J = 10.7 Hz, 1 H), 7.27 (d, J = 8.4 Hz, 1 H), 6.82–6.87 (m, 2 H), 1 H), 7.32 (d, J = 11.2 Hz, 1 H), 2.6 (d, J = 9.9 Hz, 1 H), 2.4 (d,
2.9 (m, 2 H), 2.56 (dd, J1 = 5.2, J2 = 14.3 Hz, 1 H), 1.26–2.44 (m, J = 9.5 Hz, 1 H), 1.67–2.18 (m, 8 H), 1.26 (s, 3 H) ppm. 13C NMR
Eur. J. Org. Chem. 2014, 3483–3490
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3487

J. Gogoi, P. Gogoi, R. C. Boruah
FULL PAPER
(75 MHz, CDCl3): δ = 207.4, 169.3, 134.3, 117.4, 44.8, 32.6, 31.2,
1028, 795 cm–1. LCMS(ESI): m/z (%) = 235 [M+ + 1]. C11H10N2O4
30.6, 25.0, 23.8 ppm. IR (CHCl ): ν = 3279, 2925, 2853, 1711, 1659,
(234.21): calcd. C 56.41, H 4.3; found C 56.29, H 4.15.
˜
3
1586, 1371, 1166, 756 cm–1. LCMS(ESI): m/z (%) = 182 [M+ + 1].
C10H15NO2 (181.23): calcd. C 66.27, H 8.34; found C 66.20, H
8.31.
(Z)-N-(2-Acetylhex-1-en-1-yl)acetamide (3o): Compound 3o was
prepared according to general procedure C noted above; Yellow
liquid (109 mg, yield 60%); Rf = 0.6 (20% EtOAc in hexanes). H
1
NMR (300 MHz, CDCl3): δ = 11.4 (br. s, 1 H), 7.25 (d, J =
11.3 Hz, 1 H), 2.20–2.34 (m, 5 H), 2.13 (s, 3 H), 1.26–1.52 (m, 4
H), 0.93 (t, J = 7 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
203.2, 169.1, 134.5, 116.1, 32.7, 31.3, 28.6, 23.8, 22.3, 13.8 ppm. IR
(Z)-N-[(2-Oxocyclooctylidene)methyl]acetamide (3j): Compound 3j
was prepared according to general experimental procedure C noted
above; Yellow liquid; (159 mg, 82% yield); Rf = 0.6 (20% EtOAc
1
in hexanes), H NMR (300 MHz, CDCl3): δ = 11.50 (br. s, 1 H),
(CHCl ): ν = 2957, 2927, 2856, 1712, 1624, 1258, 1179, 971,
˜
7.28 (d, J = 7.8 Hz, 1 H), 2.61 (t, J = 6.3 Hz, 1 H), 2.47 (t, J =
6.3 Hz, 1 H), 1.47–1.75 (m, 10 H), 2.15 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 208.4, 169.1, 134.6, 116.5, 40.1, 32.7, 30.0,
3
756 cm–1. LCMS(ESI): m/z (%) = 183 [M]+. C10H17NO2 (183.25):
calcd. C 65.54, H 9.35; found C 65.44, H 9.36.
29.6, 26.1, 25.6, 23.8 ppm. IR (CHCl ): ν = 3295, 2926, 2856, 1711,
˜
3
D. General Experimental Procedure for the Synthesis of β-Bromo
α,β-Unsaturated Enamide: β-Halo α,β-unsaturated aldehyde
(1 mmol, 1 equiv.), ammonium acetate (3 mmol, 3 equiv.), acetic
anhydride (4 mL) in acetic acid (2 mL) were stirred at 120 °C for
2 h. The mixture was cooled to room temperature and poured into
ice cold water. Sodium hydroxide solution (0.5 m) was added to
neutralize the mixture and extracted with EtOAc (2ϫ 10 mL). The
organic extracts were dried with anhydrous sodium sulfate, concen-
trated under reduced pressure. The residue was purified by column
chromatography (EtOAc in hexanes) to afford β-ketoenamides.
1655, 1579, 1371, 1116, 770 cm–1. LCMS(ESI): m/z (%) = 196 [M+
+ 1]. C11H17NO2 (195.26): calcd. C 67.66, H 8.78; found C 67.62,
H 8.49.
(Z)-N-[3-Oxo-3-(p-tolyl)prop-1-en-1-yl]acetamide (3k): Compound
3k was prepared according to general experimental procedure C
noted above; White solid (168 mg, 83% yield); m.p. 91–93 °C; Rf =
0.5 (20% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ =
11.77 (d, J = 7.6 Hz, 1 H), 7.83 (d, J = 7.8 Hz, 2 H), 7.63 (t, J =
9.8 Hz, 1 H), 7.26 (d, J = 7.9 Hz, 2 H), 6.23 (d, J = 8.8 Hz, 1 H),
2.40 (s, 3 H), 2.20 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
192.4, 169.1, 143.7, 138.8, 135.5, 129.3 (2ϫC), 128.0 (2ϫC), 100.0,
3-Bromo-2-(acetamidomethylene)cholest-3-ene (4p): Compound 4p
was prepared according to general experimental procedure D noted
above; White solid (310 mg, 60% yield); Rf = 0.4 (20% EtOAc in
23.7, 21.7 ppm. IR (CHCl ): ν = 3243, 2922, 2854, 1708, 1651,
˜
3
1607, 1554, 1251, 1023, 780 cm–1. LCMS(ESI): m/z (%) = 204 [M+
+ 1]. C12H13NO2 (203.24): calcd. C 70.92, H 6.45; found C 70.59,
H 6.36.
1
hexanes). H NMR (300 MHz, CDCl3): δ = 7.32 (d, J = 11 Hz, 1
H), 7.11 (d, J = 10.7 Hz, 1 H), 5.73 (d, J = 2 Hz, 1 H), 2.13 (s, 2
H), 0.94–2.46 (m, 28 H), 0.91 (d, J = 6.3 Hz, 3 H), 0.86 (d, J =
6.6 Hz, 6 H), 0.76 (s, 3 H), 0.66 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 167.0, 133.9, 123.6, 119.4, 115.6, 56.1, 52.9, 48.3, 42.8,
39.9, 39.7, 36.9, 36.5, 36.1, 35.7, 33.0, 32.7 (2ϫC), 26.6 (2ϫC),
24.9, 24.4, 24.1, 23.0, 22.1 21.3, 21.0, 18.9, 16.4, 11.9 ppm. IR
(Z)-N-[3-(4-Methoxyphenyl)-3-oxoprop-1-en-1-yl]acetamide (3l):
Compound 3l was prepared according to general experimental pro-
cedure C noted above; White solid (183 mg, 84% yield); m.p. 114–
116 °C; Rf = 0.5 (20% EtOAc in hexanes). 1H NMR (300 MHz,
CDCl3): δ = 11.79 (d, J = 8.3 Hz, 1 H), 7.93 (d, J = 8.8 Hz, 2 H),
7.62 (t, J = 9.8 Hz, 1 H), 6.96 (d, J = 8.8 Hz, 2 H), 6.23 (d, J =
8.8 Hz, 1 H), 3.88 (s, 3 H), 2.21 (s, 3 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 191.4, 169.4, 163.5, 138.5, 130.8, 130.2 (2ϫC), 114.0
(CHCl ): ν = 3307, 2925, 1667, 1645 cm–1. LCMS(ESI): m/z (%) =
˜
3
519 [M+ + 1]. C30H48BrNO (518.6): calcd. C 69.48, H 9.33; found
C 69.41, H 9.44.
N-[(2-Bromocyclohex-2-en-1-ylidene)methyl]acetamide (4q): Com-
pound 4q was prepared according to general experimental pro-
cedure D noted above; Yellow solid (184 mg, 80% yield); m.p. 130–
132 °C; Rf = 0.3 (20% EtOAc in hexanes), 1H NMR (300 MHz,
CDCl3): δ = 7.30 (br. s, 1 H), 7.23 (br. s, 1 H), 6.16 (t, J = 4.5 Hz,
1 H), 2.32–2.45 (m, 2 H), 2.19–2.28 (m, 2 H), 2.13 (s, 3 H), 1.67–
1.88 (m, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 167.4, 130.6,
(2ϫC), 100.0, 55.5, 23.7 ppm. IR (CHCl ): ν = 3272, 2844, 1698,
˜
3
1607, 1557, 1250, 1023, 781 cm–1. LCMS(ESI): m/z (%) = 220 [M+
+ 1]. C12H13NO3 (219.24): calcd. C 65.74, H 5.98; found C 65.71,
H 5.95.
(Z)-N-[3-(4-Chlorophenyl)-3-oxoprop-1-en-1-yl]acetamide (3m):
Compound 3m was prepared according to general experimental
procedure C noted above; White solid (171 mg, 77% yield); m.p.
123–125 °C; Rf = 0.5 (20 % EtOAc in hexanes). 1H NMR
(300 MHz, CDCl3): δ = 11.73 (br. s, 1 H), 7.87 (d, J = 8.5 Hz, 2
H), 7.68 (dd, J1 = 9.3, J2 = 10.6 Hz, 1 H), 7.45 (d, J = 8.5 Hz, 2
H), 6.20 (d, J = 8.7 Hz, 1 H), 2.23 (s, 3 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 191.5, 169.3, 139.7, 139.3, 136.4, 129.3
122.2, 120.7, 116.3, 27.7, 25.4, 23.4, 21.3 ppm. IR (CHCl ): ν =
˜
3
3307, 2925, 1667, 1645 cm–1. LCMS(ESI): m/z (%) = 231 [M+ + 1].
C9H12BrNO (230.10): calcd. C 46.98, H 5.26; found C 46.86, H
5.14.
N-[(2-Bromo-4-methylcyclohex-2-en-1-ylidene)methyl]acetamide
(4r): Compound 4r was prepared according to general experimental
procedure D noted above; Yellow solid (192 mg, 79% yield); m.p.
129–137 °C; Rf = 0.5 (20 % EtOAc in hexanes). 1H NMR
(300 MHz, CDCl3): δ = 7.46 (d, J = 10.35 Hz, 1 H), 7.26 (d, J =
12.39 Hz, 1 H), 6.01 (d, J = 3.18 Hz, 1 H), 2.43–2.55 (m, 1 H), 2.13
(s, 3 H), 2.21–2.28 (m, 1 H), 1.86–1.91 (m, 2 H), 1.25–1.37 (m, 2
H), 1.05 (d, J = 7.06 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 167.4, 136.6, 122.2, 120.4, 116.4, 33.3, 29.6, 24.3, 23.4,
(2ϫC), 129.0 (2ϫC), 99.6, 23.8 ppm. IR (CHCl ): ν = 3283, 2925,
˜
3
1713, 1651, 1575, 1383, 1009, 774 cm–1. LCMS(ESI): m/z (%) = 224
[M+ + 1]. C11H10ClNO2 (223.66): calcd. C 59.07, H 4.51; found C
59.04, H 4.31.
(Z)-N-[3-(4-Nitrophenyl)-3-oxoprop-1-en-1-yl]acetamide (3n): Com-
pound 3n was prepared according to general experimental pro-
cedure C noted above; White solid (184 mg, 79% yield); m.p. 128–
132 °C; Rf = 0.5 (20% EtOAc in hexanes), 1H NMR (300 MHz,
CDCl3): δ = 11.69 (d, J = 8.2 Hz, 1 H), 8.25–8.37 (m, 2 H), 8.03–
8.12 (m, 2 H), 7.76 (dd, J1 = 8.9, J2 = 10.9 Hz, 1 H), 6.25 (d, J =
8.7 Hz, 1 H), 2.26 (s, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
20.8 ppm. IR (CHCl ): ν = 3290, 2956, 2924, 2868, 1668, 1641,
˜
3
1516, 1269, 748 cm–1. LCMS(ESI): m/z (%) = 245 [M+ + 1].
C10H14BrNO (244.13): calcd. C 49.20, H 5.78; found C 48.9, H
5.50.
190.7, 169.2, 142.9, 141.0, 130.7, 128.8 (2ϫC), 123.9 (2ϫC), 99.4, N-[(2-Bromo-5-ethylcyclohex-2-en-1-ylidene)methyl]acetamide (4s):
29.4 ppm. IR (CHCl ): ν = 2924, 2853, 1727, 1646, 1572, 1346, Compound 4s was prepared according to general experimental pro-
˜
3
3488
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3483–3490

One-Pot Stereoselective Synthesis of (Z)-β-Ketoenamides
cedure D noted above; Yellow solid (193 mg, 75% yield); m.p. 135–
137 °C; Rf = 0.3 (20% EtOAc in hexanes). 1H NMR (300 MHz,
natural scaffolds). J. G. thanks CSIR for the award of a Senior
Research Fellowship. The authors are grateful to the Director,
CDCl3): δ = 7.27 (br. s, 2 H), 6.12 (dd, J1 = 3.1, J2 = 5.9 Hz, 1 H), CSIR-NEIST, Jorhat for his keen interests.
2.49 (dd, J1 = 3.5, J2 = 14.2 Hz, 1 H), 2.24–2.37 (m, 1 H), 2.1 (s,
3 H), 1.82–2.02 (m, 2 H), 1.58–1.73 (m, 1 H), 1.30–1.44 (m, 2 H),
[1] a) S. Kondo, S. Shibahara, S. Takahashi, K. Maeda, H. Umez-
0.93 (t, J = 7.4 Hz, 3 H) ppm. 13C NMR (75 MHz, CDCl3): δ =
awa, M. Ohno, J. Am. Chem. Soc. 1971, 93, 6305–6306; b) J. E.
Clifton, I. Collins, P. Hallett, D. Hartley, L. H. C. Lunts, P. D.
Wicks, J. Med. Chem. 1982, 25, 670–679; c) B. Raju, K. Mor-
tell, S. Anandan, H. O’Dowd, H. Gao, M. Gomez, C. Hack-
barth, C. Wu, W. Wang, Z. Yuan, R. White, J. Trias, D. V. Patel,
Bioorg. Med. Chem. Lett. 2003, 13, 2413–2418; d) M. Ogata,
H. Matsumoto, S. Kida, S. Shimizu, K. Tawara, Y. Kawamura,
J. Med. Chem. 1987, 30, 1497–1502; e) G. Buchi, S. J. Gould,
F. Naf, J. Am. Chem. Soc. 1971, 93, 2492–2501.
167.5, 130.0, 122.4, 120.6, 116.4, 34.3, 33.5, 31.4, 28.4, 23.5,
11.5 ppm. IR (CHCl ): ν = 3296, 2961, 2923, 1668, 1641, 1513,
˜
3
1262 cm–1. LCMS(ESI): m/z (%) = 259 [M+ + 1]. C11H16BrNO
(258.15): calcd. C 51.18, H 6.25; found C 51.07, H 6.20.
E. Experimental Procedures for the Synthesis of β-Ketoenamide (3q)
from β-Bromo α,β-Unsaturated Enamide (4q): β-Bromo α,β-unsatu-
rated enamide (100 mg, 0.43 mmol, 1 equiv.), ammonium acetate
(1.3 mmol, 3 equiv.) in acetic acid (2 mL) were stirred at 150 °C for
5 h. The mixture was cooled to room temperature and poured into
ice cold water. Sodium hydroxide solution (0.5 m) was added to
neutralize the mixture and extracted with EtOAc (2ϫ 10 mL). The
organic extracts were dried with anhydrous sodium sulfate, concen-
trated under reduced pressure. The residue was purified by column
chromatography (EtOAc in hexanes) to get β-ketoenamides.
[2] a) M. Tramontini, Synthesis 1982, 605–644; b) K. T. Wanner,
G. Horner, Tetrahedron 1991, 47, 1895–1910; c) G. Bartoli, C.
Cimarel, G. Palmieri, J. Chem. Soc. Perkin Trans. 1 1994, 537–
543; d) G. E. Keck, A. P. Truong, Org. Lett. 2002, 4, 3131–
3134.
[3] a) G. V. Shustov, S. N. Denisenko, I. I. Chervin, N. L. Asfandi-
arov, R. G. Kostyanovsky, Tetrahedron 1985, 41, 5719–5731; b)
F. Couty, O. David, F. Durrat, G. Evano, S. Lakhdar, J. Marrot,
M. Vargas-Sanchez, Eur. J. Org. Chem. 2006, 3479–3490; c) M.
Nechab, N. Azzi, N. Vanthuyne, M. Bertrand, S. Gastaldi, G.
Gil, J. Org. Chem. 2007, 72, 6918–6923.
[4] a) K. Huang, X. Zhang, H. Geng, S.-k. Li, X. Zhang, ACS
Catal. 2012, 2, 1343–1345 and references cited therein; b) H.
Geng, W. Zhang, J. Chen, G. Hou, L. Zhou, Y. Zou, W. Wu,
X. Zhang, Angew. Chem. Int. Ed. 2009, 48, 6052–6054; Angew.
Chem. 2009, 121, 6168.
[5] a) C. Eidamshaus, H.-U. Reissig, Eur. J. Org. Chem. 2011,
6056–6069; b) T. Lechel, M. Gerhard, D. Trawny, B. Brusilows-
kij, L. Schefzig, R. Zimmer, J. P. Rabe, D. Lentz, C. A. Schal-
ley, H.-U. Reissig, Chem. Eur. J. 2011, 17, 7480–7491; c) P.
Hommes, S. Berlin, H.-U. Ressig, Synthesis 2013, 3288–3294;
d) M. Sugiura, M. Kumahara, M. Nakajima, Chem. Commun.
2009, 3585–3587; e) T. Lechel, H.-U. Reissig, Eur. J. Org. Chem.
2010, 2555–2564; f) T. Lechel, J. Dash, P. Hommes, D. Lentz,
H.-U. Reissig, J. Org. Chem. 2010, 75, 726–732; g) G. Ohta, K.
Koshi, K. Obata, Chem. Pharm. Bull. 1968, 16, 1487–1497.
[6] S. M. Lait, D. A. Rankic, B. A. Keay, Chem. Rev. 2007, 107,
767–796.
[7] M. R. Tracey, R. P. Hsung, J. Antoline, K. C. M. Kurtz, L.
Shen, B. W. Slafer, Y. Zhang, Sci. Synth. 2005, 5, 387–475.
[8] a) A. Couture, E. Deniau, P. Grandclaudon, Tetrahedron Lett.
1993, 34, 1479–1482; b) P. Dupau, P. Le Gendre, C. Brueau,
P. H. Dixneuf, Synlett 1999, 1832–1834; c) X. Wang, J. A.
Porco Jr., J. Org. Chem. 2001, 66, 8215–8221; d) A. Bayer,
M. E. Maier, Tetrahedron 2004, 60, 6665–6677; e) R. K. Boeck-
man Jr., S. W. Goldstein, M. A. Walters, J. Am. Chem. Soc.
1988, 110, 8250–8252; f) W. N. Speckamp, M. J. Moolenaar,
Tetrahedron 2000, 56, 3817–3856; g) S. S. Kinderman, J. H.
van Maarseveen, H. E. Schoemaker, H. Hiemstra, F. P. J. T.
Rutjes, Org. Lett. 2001, 3, 2045–2048; h) O. Flogel, J. Dash, I.
Brudgam, H. Hartl, H.-U. Reissig, Chem. Eur. J. 2004, 10,
4283–4290.
(Z)-N-[(2-Oxocyclohexylidene)methyl]acetamide (3q): Yellow solid
(22 mg, 31% yield); m.p. 140–142 °C; Rf = 0.5 (20% EtOAc in hex-
anes). 1H NMR (300 MHz, CDCl3): δ = 11.34 (br. s, 1 H), 7.23 (d,
J = 7.8 Hz, 1 H), 2.32–2.54 (m, 4 H), 2.14 (s, 3 H), 1.63–1.90 (m,
4 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 203.9, 169.1, 134.1,
112.9, 39.5, 29.7, 28.8, 23.4, 22.4 ppm. IR (CHCl ): ν = 3286, 2930,
˜
3
2839, 1623, 1347, 1167, 997 cm–1. LCMS(ESI): m/z (%) = 168 [M+
+ 1]. C9H13NO2 (167.21): calcd. C 64.65, H 7.84; found C 64.45,
H 7.65.
F. Experimental Procedures for the Synthesis of 2-Amino-5,6-dihy-
drobenzo[f]isoquinoline-1-carbonitrile (5e) from (Z)-N-{[1-Oxo-3,4-
dihydronaphthalen-2(1H)-ylidene]methyl}acetamide (3e): (Z)-N-{[1-
Oxo-3,4-dihydronaphthalen-2(1H)-ylidene]methyl}acetamide
(215 mg, 1 mmol), malononitrile (66 mg, 1 mmol) were intimately
mixed with basic alumina (1 g) and the mixture was irradiated in
a closed vessel of microwave reactor, Synthos 3000 at 360 W,
140 °C, and 10 bar for 5 min. On completion of reaction (vide
TLC), the reaction mixture was treated with water (50 mL), ex-
tracted with dichloromethane (30 mL). The organic portion was
washed with water, dried with anhydrous sodium sulfate and the
solvent removed to obtain a crude product. Column chromatog-
raphy separation using EtOAc/hexane (90:10) as eluent over silica
gel afforded 5e; Yellow crystalline solid (143 mg, yield 65%); m.p.
146–150 °C; Rf = 0.6 (10 % EtOAc in hexanes). 1H NMR
(300 MHz, CDCl3): δ = 8.23–8.31 (m, 1 H), 7.46 (s, 1 H), 7.27–
7.42 (m, 3 H), 5.19 (br. s, 2 H), 2.74–2.84 (m, 2 H), 2.63–2.73 (m,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 152.0, 142.8, 139.9,
135.2, 130.9, 130.5, 128.7, 128.3,127.2, 127.0, 116.3, 94.9, 29.2,
28.2 ppm. IR (CHCl ): ν = 3358, 3241, 2921, 2216, 1219, 1018,
˜
3
772 cm–1. LCMS(ESI): m/z (%) = 221 [M]+. C14H11N3 (221.26):
[9] a) R. Brettle, A. J. Mosedale, J. Chem. Soc. Perkin Trans. 1
1988, 2185–2195; b) K. Kuramochi, H. Watanabe, T. Kitahara,
Synlett 2000, 397–399.
calcd. C 76.00, H 5.01; found C 75.89, H 5.16.
Supporting Information (see footnote on the first page of this arti-
cle): Experimental details, spectroscopic data and selected copies of
1H and 13C NMR of final products. Also provided are experimental
procedures and analytical data for compounds 2c–2l, 2p and 2q.
[10] a) D. J. Ager, Synthesis 1984, 384–398; b) A. Fürstner, C.
Brehm, Y. Cancho-Grande, Org. Lett. 2001, 3, 3955–3957.
[11] a) T. Hosokawa, M. Takano, Y. Kuroki, S.-I. Murahashi, Tetra-
hedron Lett. 1992, 33, 6643–6646; b) J. M. Lee, D.-S. Ahn, D.-
Y. Jung, J. Lee, Y. Do, S. K. Kim, S. Chang, J. Am. Chem. Soc.
2006, 128, 12954–12962; c) X. Liu, K. K. Hii, Eur. J. Org.
Chem. 2010, 5181–5189; d) N. Panda, A. K. Jena, M. Raghav-
ender, ACS Catal. 2012, 2, 539–543.
Acknowledgments
The authors acknowledge the Council of Scientific and Industrial
Research (CSIR), New Delhi for their financial support under the
project CSC-108 (Organic reactions in generating innovative and
[12] a) J. R. Dehli, J. Legros, C. Bolm, Chem. Commun. 2005, 973–
986; b) T. Ogawa, T. Kiji, K. Hayashi, H. Suzuki, Chem. Lett.
1991, 1443–1446; c) R. Shen, J. A. Porco Jr., Org. Lett. 2000,
Eur. J. Org. Chem. 2014, 3483–3490
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3489

J. Gogoi, P. Gogoi, R. C. Boruah
FULL PAPER
2, 1333–1336; d) L. Jiang, G. E. Job, A. Klapars, S. L. Buch-
wald, Org. Lett. 2003, 5, 3667–3669; e) X. Pan, Q. Cai, D. Ma,
Org. Lett. 2004, 6, 1809–1812; f) Y. Kozawa, M. Mori, J. Org.
Chem. 2003, 68, 3064–3067; g) D. J. Wallace, D. J. Klauber, C.-
Y. Chen, R. P. Volante, Org. Lett. 2003, 5, 4749–4752; h) A.
Klapars, K. R. Campos, C.-Y. Chen, R. P. Volante, Org. Lett.
2005, 7, 1185–1188; i) Y. Bolshan, R. A. Batey, Angew. Chem.
Int. Ed. 2008, 47, 2109–2112; Angew. Chem. 2008, 120, 2139; j)
J. L. Brice, J. E. Meerdinka, S. S. Stahl, Org. Lett. 2004, 6,
1845–1848.
2013, 45, 1341–1348; e) P. Gogoi, P. Bezbaruah, R. C. Boruah,
Eur. J. Org. Chem. 2013, 5032–5035.
[16] a) M. G. Barthakur, M. Borthakur, P. Devi, C. J. Saikia, A.
Saikia, U. Bora, A. Chetia, R. C. Boruah, Synlett 2007, 223–
226; b) A. Saikia, M. G. Barthakur, M. Borthakur, C. J. Saikia,
U. Bora, R. C. Boruah, Tetrahedron Lett. 2006, 47, 43–46; c)
A. Chetia, M. Longchar, K. C. Lekhok, R. C. Boruah, Synlett
2004, 1309–1311; d) U. Sharma, S. Ahmed, R. C. Boruah, Tet-
rahedron Lett. 2000, 41, 3493–3495; e) U. Bora, B. S. D. Kumar,
R. C. Boruah, J. S. Sandhu, Tetrahedron Lett. 2002, 43, 2269–
2271; f) R. C. Boruah, S. Ahmed, U. Sharma, J. S. Sandhu, J.
Org. Chem. 2000, 65, 922–925.
[17] CCDC-948876 (for 3e) contains the supplementary crystallo-
graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
[13]
N. Panda, R. Mothkuri, J. Org. Chem. 2012, 77, 9407–9412.
[14] a) S. Brahma, J. K. Ray, Tetrahedron 2008, 64, 2883–2896; b)
S. Hesse, G. Kirsch, Tetrahedron 2005, 61, 6534–6539.
[15] a) P. Bezbaruah, J. Gogoi, K. S. Rao, P. Gogoi, R. C. Boruah,
Tetrahedron Lett. 2012, 53, 4389–4392; b) J. Gogoi, P. Bezba-
ruah, P. Saikia, J. Goswami, P. Gogoi, R. C. Boruah, Tetrahe-
dron Lett. 2012, 53, 1497–1500; c) J. Gogoi, P. Gogoi, P. Bezba-
ruah, R. C. Boruah, Tetrahedron Lett. 2013, 54, 7136–7139; d)
P. Bezbaruah, P. Gogoi, J. Gogoi, R. C. Boruah, Synthesis
[18] U. Sharma, S. Ahmed, R. C. Boruah, Tetrahedron Lett. 2000,
41, 3493–3495.
Received: January 2, 2014
Published Online: April 11, 2014
3490
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© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2014, 3483–3490