Synthetic applications of the Baylis-Hillman adducts: A simple stereoselective synthesis of (E)-3-(nitroxymethyl)alk-3-en-2-ones

Article abstract of DOI:10.1016/S0040-4020(00)00478-6

First simple, stereoselective synthesis of (E)-3-(nitroxymethyl)alk-3-en-2-ones from Baylis-Hillman adducts (4-hydroxy-3-methylenealkan-2-ones) is described. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00478-6

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 5905±5907
Synthetic Applications of the Baylis±Hillman Adducts: A Simple
Stereoselective Synthesis of (E)-3-(Nitroxymethyl)alk-3-en-2-ones
²
*
Deevi Basavaiah, Rachakonda Suguna Hyma and Nagaswamy Kumaragurubaran
School of Chemistry, University of Hyderabad, Hyderabad 500 046, India
Received 7 March 2000; revised 9 May 2000; accepted 25 May 2000
AbstractÐFirst simple, stereoselective synthesis of (E)-3-(nitroxymethyl)alk-3-en-2-ones from Baylis±Hillman adducts (4-hydroxy-3-
methylenealkan-2-ones) is described. q 2000 Elsevier Science Ltd. All rights reserved.
Certain classes of nitrate esters (RONO2) are well known for
their therapeutic importance as drugs for the treatment of
heart and vascular diseases.1,2 As part of our research
program in nitrate esters we have recently reported a simple
and convenient methodology for the synthesis of (1R,2R)
and (1S,2S)-2-nitroxycyclohexan-1-ols in enantiomerically
pure form.3 In recent years the Baylis±Hillman reaction4±6
has attracted the attention of organic chemists as it provides
synthetically useful multifunctional molecules which have
been successfully employed in various stereoselective
processes.4±11 To the best of our knowledge, there is no
report in the literature for the conversion of the Baylis±
Hillman adducts into the corresponding allyl nitrates stereo-
selectively. With a view that these allyl nitrates may be of
interest as potential drugs for vascular and heart diseases
and in continuation of our research program12±15 on the
development of the Baylis±Hillman reaction as a source
for stereoselective processes we herein report the ®rst
simple stereoselective synthesis of (E)-3-(nitroxymethyl)-
alk-3-en-2-ones via the reaction of 4-hydroxy-3-methyl-
enealkan-2-ones with concentrated nitric acid (69%).
useful stereoselective transformations we have directed
our studies to the transformation of these molecules into
3-(nitroxymethyl)alk-3-en-2-ones (2) with de®ned stereo-
chemistry. Accordingly we ®rst treated 4-hydroxy-3-
methylene-4-phenylbutan-2-one (1a) (1 mmol) with 1 mL
of conc. HNO3 (69%) at room temperature. This reaction
is instantaneous and provided the desired (E)-3-(nitroxy-
methyl)-4-phenylbut-3-en-2-one (2a) in 72% yield after
usual work up followed by column chromatography. The
(E)-stereochemistry was established on the basis of 1H
NMR spectral analysis in comparison with that of (3Z)-3-
(halomethyl)alk-3-en-2-ones.16 This success led us to
transform representative 4-hydroxy-3-methylenealkan-2-
ones (1b±i) into stereochemically pure (E)-3-(nitroxy-
methyl)alk-3-en-2-ones (2b±i) under similar reaction
conditions (Eq. (1); Table 1).
Table 1. Synthesis of (3E)-3-(nitroxymethyl)alk-3-en-2-ones (all reactions
were carried out on a 1 mmol scale (alcohols 1a±i) with 1 mL of conc.
HNO3 (69%) at room temperature. Satisfactory spectral [IR, 1H NMR
(200 MHz), 13C NMR (50 MHz)] data and elemental analyses were
Recently we have successfully transformed the Baylis±Hill-
man adducts, i.e. 4-hydroxy-3-methylenealkan-2-ones (1),
obtained from a reactive activated alkene, methyl vinyl
ketone, into functionalized trisubstituted ole®ns i.e. (3Z)-
3-(bromomethyl)alk-3-en-2-ones and (3Z)-3-(chloromethyl)-
alk-3-en-2-ones16 via the treatment with aqueous HBr and
HCl respectively. With an objective of utilizing the 4-
hydroxy-3-methylenealkan-2-ones (1), in various other
1
obtained for all molecules (2a±i). H and 13C NMR indicate the absence
of any (Z)-isomer. (E)-Stereochemistry was established by 1H NMR
spectral analysis.17)
Substrate
R
Product
Yield (%)a
1a
1b
1c
1d
1e
1f
1g
1h
1I
phenyl
p-tolyl
2a
2b
2c
2d
2e
2f
2g
2h
2i
72
79
77
80
76
78
79
58
70
p-isopropylphenyl
p-methoxyphenyl
p-chlorophenyl
o-methoxyphenyl
o-chlorophenyl
n-propyl
²
Preliminary results were presented at the American Chemical Society
218th national meeting in New Orleans, USA, August 22±26, 1999 as a
poster (poster no. 510).
n-heptyl
Keywords: Baylis±Hillman reaction; methyl vinyl ketone; stereo-
selectivity; (E)-3-(nitroxymethyl)alk-3-en-2-ones.
* Corresponding author. E-mail: dbsc@uohyd.ernet.in
a Isolated yields of the products after column chromatography (silica gel,
4% ethyl acetate in hexanes).
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00478-6

5906
D. Basavaiah et al. / Tetrahedron 56 (2000) 5905±5907
131.32, 133.47, 148.23, 197.36; MS (m/z): 221 (M1);
Analysis calcd for C11H11NO4: C, 59.73; H, 5.01; N, 6.33;
found: C, 60.00; H, 4.99; N, 6.35.
ꢀ1†
(3E)-4-(4-Methylphenyl)-3-(nitroxymethyl)but-3-en-2-
one (2b). Colorless liquid. Yield: 79%; IR (neat): 1670,
1622 cm21; 1H NMR: d 2.40 (s, 3H), 2.48 (s, 3H), 5.31 (s,
2H), 7.29 (m, 4H), 7.92 (s, 1H); 13C NMR: d 21.42, 25.54,
66.80, 129.60, 129.86, 130.62, 130.73, 141.24, 148.76,
197.87; Analysis calcd for C12H13NO4: C, 61.27; H, 5.57;
N, 5.95; found: C, 61.50; H, 5.54; N, 5.93.
The (E)-selectivity in the formation of (3E)-3-(nitroxy-
methyl)alk-3-en-2-ones (2a±i) can be explained through
the transition state models A and B. The transition state
model A is more favored than B due to the COMe group
having a larger steric effect than the CH2ONO2 group.
(3E)-4-(4-Isopropylphenyl)-3-(nitroxymethyl)but-3-en-
2-one (2c). Colorless liquid. Yield: 77%; IR (neat): 1670,
1
1620 cm21; H NMR: d 1.25 (d, 6H, Jˆ6.8 Hz), 2.46 (s,
3H), 2.92 (sept, 1H, Jˆ6.8 Hz), 5.29 (s, 2H), 7.19±7.41 (m,
4H), 7.88 (s, 1H); 13C NMR: d 23.69, 25.58, 34.08, 66.88,
127.24, 129.72, 130.61, 131.12, 148.40, 151.93, 197.24;
Analysis calcd for C14H17NO4: C, 63.87; H, 6.51; N, 5.32;
found: C, 63.91; H, 6.53; N, 5.29.
In conclusion, this methodology describes the ®rst simple
stereoselective synthesis of (E)-3-(nitroxymethyl)alk-3-en-
2-ones thus demonstrating the synthetic potential of the
Baylis±Hillman adducts.
(3E)-4-(4-Methoxyphenyl)-3-(nitroxymethyl)but-3-en-2-
one (2d). Colorless solid. Yield: 80%; mp: 70±728C; IR
1
(KBr): 1661, 1622 cm21; H NMR: d 2.48 (s, 3H), 3.86
(s, 3H), 5.33 (s, 2H), 6.98 (d, 2H, Jˆ8.0 Hz), 7.40 (d, 2H,
Jˆ8.0 Hz), 7.87 (s, 1H); 13C NMR: d 25.60, 55.53, 67.05,
114.77, 126.16, 129.47, 131.69, 148.07, 161.76,197.12;
Analysis calcd for C12H13NO5: C, 57.37; H, 5.22; N, 5.58;
found: C, 57.03; H, 5.21; N, 5.58.
Experimental
Melting points were recorded on a Super®t (India) capillary
melting point apparatus and are uncorrected. IR spectra
were recorded on a JASCO-FT-IR model 5300 or Perkin±
Elmer model 1310 spectrometer using samples as neat
liquids or in KBr. 1H NMR (200 MHz) and 13C NMR
(50 MHz) spectra were recorded in deuterochloroform
(CDCl3) on a Bruker-AC-200 spectrometer using tetra-
methylsilane (TMS, dˆ0) as internal standard. Elemental
analyses were recorded on a Perkin±Elmer 240C-CHN
analyzer. Mass spectra were recorded on a micromass VG
7070H instrument. All the required Baylis±Hillman adducts
(starting materials) were prepared by the reaction of the
corresponding aldehydes with methyl vinyl ketone in
presence of a catalytic amount of DABCO according to
the literature procedure.18,19
(3E)-4-(4-Chlorophenyl)-3-(nitroxymethyl)but-3-en-2-
one (2e). Colorless liquid. Yield: 76%; IR (neat): 1674,
1
1626 cm21; H NMR: d 2.48 (s, 3H), 5.25 (s, 2H), 7.33
(d, 2H, Jˆ8.8 Hz), 7.44 (d, 2H, Jˆ8.8 Hz), 7.85 (s, 1H);
13C NMR: d 25.59, 66.39, 129.37, 130.63, 132.07, 136.63,
146.54, 196.91; Analysis calcd for C11H10ClNO4: C, 51.68;
H, 3.94; N, 5.48; found: C, 51.35; H, 3.96; N, 5.50.
(3E)-4-(2-Methoxyphenyl)-3-(nitroxymethyl)but-3-en-2-
one (2f). Colorless liquid. Yield: 78%; IR (neat): 1660,
1621 cm21; 1H NMR: d 2.50 (s, 3H), 3.89 (s, 3H), 5.27 (s,
2H), 6.92±7.11 (m, 2H), 7.25±7.37 (m, 1H), 7.44 (m, 1H),
8.12 (s, 1H); 13C NMR: d 25.61, 55.63, 67.29, 110.98,
120.87, 122.85, 129.85, 131.53, 132.06, 144.22, 157.80,
197.30; Analysis calcd for C12H13NO5: C, 57.37; H, 5.22;
N, 5.58; found: C, 57.61; H, 5.22; N, 5.56.
General procedure for the preparation of (E)-3-(nitroxy-
methyl)alk-3-en-2-ones
(3E)-4-(2-Chlorophenyl)-3-(nitroxymethyl)but-3-en-2-
one (2g). Colorless liquid. Yield: 79%; IR (neat): 1672,
Conc. HNO3 (69%) (1 mL) was added to the Baylis±Hill-
man adduct (1 mmol) at room temperature and swirled
thoroughly for one minute (monitored by TLC). The
reaction mixture was immediately diluted with water
(5 mL) and extracted with ether (2£5 mL). Combined
organic layer was washed with aqueous potassium carbon-
ate solution and dried over anhydrous Na2SO4. The solvent
was evaporated and the crude product was puri®ed by
column chromatography (silica gel, 4% ethyl acetate in
hexanes) to afford the pure (E)-3-(nitroxymethyl)alk-3-en-
2-ones.
1
1620 cm21; H NMR: d 2.50 (s, 3H), 5.19 (s, 2H), 7.34±
7.52 (m, 4H), 8.03 (s, 1H); 13C NMR: d 25.74, 66.50,
127.28, 129.97, 130.05, 131.35, 132.28, 133.25, 134.17,
144.66, 196.92; Analysis calcd for C11H10ClNO4: C,
51.68; H, 3.94; N, 5.48; found: C, 51.45; H, 3.92; N,
5.49.
(3E)-3-(Nitroxymethyl)hept-3-en-2-one (2h). Colorless
1
liquid. Yield: 58%; IR (neat): 1678, 1630 cm21; H NMR:
d 0.99 (t, 3H, Jˆ7.0 Hz), 1.48±1.70 (m, 2H), 2.29±2.50 (m,
5H), 5.23 (s, 2H), 7.03 (t, 1H, Jˆ7.2 Hz); 13C NMR: d
13.72, 21.86, 25.24, 31.34, 65.34, 132.89, 152.47, 196.88;
Analysis calcd for C8H13NO4: C, 51.33; H, 7.00; N, 7.48;
found: C, 51.28; H, 6.96; N, 7.52.
(3E)-3-(Nitroxymethyl)-4-phenylbut-3-en-2-one
(2a).
;
Colorless liquid. Yield: 72%; IR (neat): 1674, 1631 cm21
1H NMR: d 2.48 (s, 3H), 5.28 (s, 2H), 7.42 (m, 5H), 7.95 (s,
1H); 13C NMR: d 25.41, 66.60, 128.91, 129.24, 130.28,

D. Basavaiah et al. / Tetrahedron 56 (2000) 5905±5907
5907
10. Chamakh, A.; Amri, H. Tetrahedron Lett. 1998, 39, 375±378.
11. Lee, H. J.; Seong, M. R.; Kim, J. N. Tetrahedron Lett. 1998,
39, 6223±6226.
(3E)-3-(Nitroxymethyl)undec-3-en-2-one (2i). Colorless
1
liquid. Yield: 70%; IR (neat): 1676, 1631 cm21; H NMR:
d 0.87 (t, 3H, Jˆ6.3 Hz), 1.15±1.61 (m, 10H), 2.31±2.51
(m, 5H), 5.23 (s, 2H), 7.02 (t, 1H, Jˆ7.6 Hz); 13C NMR: d
13.94, 22.54, 25.21, 28.61, 28.94, 29.26, 29.46, 31.62,
65.38, 132.91, 152.36, 196.70; Analysis calcd for
C12H21NO4: C, 59.24; H, 8.70; N, 5.76; found: C, 59.62;
H, 8.72; N, 5.73.
12. Basavaiah, D.; Krishnamacharyulu, M.; Suguna Hyma, R.;
Pandiaraju, S. Tetrahedron Lett. 1997, 38, 2141±2144.
13. Basavaiah, D.; Bakthadoss, M.; Pandiaraju, S. Chem.
Commun. 1998, 1639±1640.
14. Basavaiah, D.; Krishnamacharyulu, M.; Suguna Hyma, R.;
Sarma, P. K. S.; Kumaragurubaran, N. J. Org. Chem. 1999, 64,
1197±1200.
Acknowledgements
15. Basavaiah, D.; Kumaragurubaran, N.; Padmaja, K. Synlett
1999, 1630±1632.
We thank CSIR (New Delhi) for funding this project. We
also thank the UGC (New Delhi) for the Special Assistance
Program in Organic Chemistry, in the School of Chemistry,
University of Hyderabad. RSH and NK thank UGC (New
Delhi) for their research fellowships.
16. Basavaiah, D.; Suguna Hyma, R.; Padmaja, K.;
Krishnamacharyulu, M. Tetrahedron 1999, 55, 6971±6976.
17. In the 1H NMR spectrum of trisubstituted alkenes with ketone
group, the vinylic proton cis to the carbonyl group appears down-
®eld in comparison with that of the vinylic proton trans to the
carbonyl group.20,21 In the 1H NMR spectrum of (3Z)-3-
(halomethyl)alk-3-en-2-ones16 (Rˆaryl) the vinylic proton cis to
the carbonyl group appears at < d 7.60±7.90 as a singlet. In the
case of compounds 2a±2g (Rˆaryl) the vinylic proton appears at
< d 7.85±8.12 as a singlet. Therefore we have assigned (E)-stereo-
chemistry to the compounds 2a±2g. The vinylic proton cis to the
carbonyl group in the case of (3Z)-3-(halomethyl)alk-3-en-2-
ones16 (Rˆalkyl) appears at < d 6.80 as a triplet. In the case of
compounds 2h±2i (Rˆalkyl) the vinylic proton appears at < d
7.00 as a triplet. Therefore we assigned (E)-stereochemistry to
the molecule 2h±2i.
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