Aryl-fused nitrogen heterocycles by a tandem reduction-Michael addition reaction

Full text of DOI:10.1021/jo991899+

J . Org. Chem. 2000, 65, 2847-2850
2847
Sch em e 1. Syn th esis of Cycliza tion Su bstr a tesa
Ar yl-F u sed Nitr ogen Heter ocycles by a
Ta n d em Red u ction -Mich a el Ad d ition
Rea ction
Richard A. Bunce,* Derrick M. Herron,1 and
Matthew L. Ackerman1
Department of Chemistry, Oklahoma State University,
Stillwater, Oklahoma 74078-3071
Received December 9, 1999
In tr od u ction
The 1,2,3,4-tetrahydroquinoline, 3,4-dihydro-2H-1,4-
benzoxazine, and 1,2,3,4-tetrahydroquinoxaline ring sys-
tems are important structural units in many bioactive
compounds.2-4 A review of the literature2-4 reveals that
while the parent molecules are easily prepared, substi-
tuted cases are considerably more challenging. As part
of our synthetic studies, we sought to prepare derivatives
of these compounds by a tandem reduction-Michael
addition reaction using suitably substituted nitroarenes.
Such an approach would permit the synthesis of struc-
tures bearing unique substitution patterns, including
functionality that could be further elaborated in subse-
quent synthetic steps.
Previously reported tandem sequences involving ni-
troarenes include reduction-reductive amination5 and
reduction-lactam formation.6 In these processes, the
aromatic nitro group is easily reduced7 in the presence
of an aldehyde, ketone, or ester, and the resulting amine
reacts with the carbonyl group in a subsequent step.
When evaluating reaction conditions for a reduction-
Michael procedure, the sensitivity of the acceptor moiety
must be considered. The reagent must selectively reduce
a
Key: (a) CH2dC(R)CH2I, K2CO3, 18-crown-6, CH3CN, 82 °C,
92%; (b) (i) NaOH, aqueous dioxane; (ii) K2CO3, DMF, 50 °C, 92%;
(c) for R ) H, (i) O3, CH3OH, -78 °C; (ii) (CH3)2S, HOAc, -78 °C
f rt; (iii) Ph3PdCHCO2Et, PhH, 80 °C, 52-56%; for R ) CH3, (i)
O3, CH3OH, -78 °C; (ii) (CH3)2S, p-TsOH, -78 °C f rt; (iii)
(MeO)2P(O)CH2CO2Et, NaH, THF-DMSO, rt, 61%; (d) BrCH2-
C(R)dCHCO2Et (R ) H, 7a , R ) CH3, 7b), K2CO3, acetone, 0 °C,
55-58%; (e) 7a or 7b (0.5 equiv), 100 °C, 70-75%.
(1) Oklahoma State University Freshman Research Scholar, 1999-
2000.
(2) For recent reviews on tetrahydroquinolines, see: (a) Kouznetsov,
V.; Palma, A.; Ewert, C.; Varlamov, A. J . Heterocycl. Chem. 1998, 35,
761-785. (b) Katritsky, A. R.; Rachwal, S.; Rachwal, B. Tetrahedron
1996, 52, 15031-15070. See also: (c) Gilchrist, T. L.; Rahman, A. J .
Chem. Soc., Perkin Trans. 1 1998, 1203-1207. (d) Nagata, R.; Tanno,
N.; Kodo, T.; Ae, N.; Yamaguchi, H.; Nishimura, H.; Antoku, F.;
Tatsuno, T.; Kato, T.; Tanaka, Y.; Nakamura, M.; Ogita, K.; Yoneda,
Y. J . Med. Chem. 1994, 37, 3956-3968.
(3) For a recent review on benzoxazines, see: (a) Sainsbury, M.
Rodd’s Chem. Carbon Compd., 2nd ed.; Elsevier: Amsterdam, 1998;
pp 465-511. See also: (b) Matsuoka, H.; Ohi, N.; Mihara, M.; Suzuki,
H.; Miyamoto, K.; Maruyama, N.; Tsuji, K.; Kato, N.; Akimoto, T.;
Takeda, Y.; Yano, K.; Kuroki, T. J . Med. Chem. 1997, 40, 105-111.
(4) For reviews on quinoxalines, see: (a) Sakata, G.; Makino, K.;
Kurasawa, Y. Heterocycles 1988, 27, 2481-2515. (b) Cheeseman, G.
W. H.; Werstiuk, E. S. G. Adv. Heterocycl. Chem. 1978, 22, 367-431.
See also (c) Awad, I. M. A. J . Chem. Technol. Biotechnol. 1992, 53,
227-236. (d) Kleim, J .-P.; Bender, R.; Billhardt, U.-M.; Meichsner, C.;
Riess, G.; Ro¨sner, M.; Winkler, I.; Paessens, A. Antimicrob. Agents
Chemother. 1993, 37, 1659-1664. (e) Kleim, J .-P.; Ro¨sner, M.; Winkler,
I.; Paessens, A.; Kirsch, R.; Hsiou, Y.; Arnold, E.; Riess, G. Proc. Natl.
Acad. Sci. U.S.A. 1996, 93, 34-38.
the nitro group in the presence of an R,â-unsaturated
ester and, in the case of dihydrobenzoxazines and tet-
rahydroquinoxalines, be mild enough to preserve allylic
ether and amine functionality. We wish to report that
the use of iron powder in refluxing glacial acetic acid
successfully carries out this transformation in high yield.
Syn th esis of th e Cycliza tion Su bstr a tes. Scheme
1 summarizes the synthesis of the cyclization substrates.
Precursors for the tetrahydroquinoline systems were
prepared from methyl (2-nitrophenyl)acetate (1)8 by a
sequence involving (a) alkylation of the activated benzylic
carbon with an allylic iodide to give 2,9 (b) ester hydroly-
sis and decarboxylation to give 3,10 and (c) ozonolysis-
Wittig11 (or Wadsworth-Emmons)12 conversion of the
(5) Reduction-reductive amination: (a) Rylander, P. N. Hydrogena-
tion Methods; Academic Press: New York, 1985; pp 82-93. (b) Artico,
M.; DeMartino, G.; Filacchione, G. Giuliano, R. Farmaco, Ed. Sci. 1969,
24, 276-284; Chem Abstr. 1970, 70, 96775a.
(6) Reduction-lactam formation: (a) Floyd, D. M.; Moquin, R. V.;
Atwal, K. S.; Ahmed, S. Z.; Spergal, S. H.; Gougoutas, J . Z.; Malley,
M. F. J . Org. Chem. 1990, 55, 5572-5579. (b) Tapia, R. A.; Centella,
C. R.; Valderrama, J . A. Synth. Commun. 1999, 29, 2163-2168.
(7) For a survey of most of the methods for nitroarene reduction,
see Hudlicky, M. Reductions in Organic Chemistry, 2nd ed.; American
Chemical Society: Washington D.C., 1996.
(8) The acid was esterified using MeOH/HCl (g); see: Furniss, B.
S.; Hannaford, A. J .; Smith, P. W. G.; Tatchell, A. R. Vogel’s Textbook
of Practical Organic Chemistry, 5th ed.; Longman: New York, 1989;
p 700.
(9) Makosza, M.; Tyrala, A. Synth. Commun. 1986, 16, 419-423.
(10) Bull D. J .; Fray, M. J .; Mackenny, M. C.; Malloy, K. A. Synlett
1996, 647-648.
(11) Bunce, R. A.; Pierce, J . D. Org. Prep. Proced. Int. 1987, 19, 67-
71.
(12) Balsevich, J . Can. J . Chem. 1983, 61, 1053-1059.
10.1021/jo991899+ CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/28/2000

2848 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
Ta ble 1. Rin g Closu r es by Ta n d em Red u ction -Mich a el
however, that the Z olefin reacted more rapidly and gave
higher yields than the E isomer. This observation likely
reflects the higher reactivity of the Z acrylate as well as
the decreased steric interaction between the ester and
the approaching nucleophile for the Z acceptor.
Ad d ition
Earlier studies reported iron to be an extremely mild
reagent that permits reduction of nitroarenes bearing
halogens and carbonyl-containing groups.7,23,24 Our re-
sults have confirmed and extended this finding. In the
current reaction, iron powder was used directly in re-
fluxing glacial acetic acid with no reduction or degrada-
tion of the side chain.
Several other reducing agents were also investigated
but gave less satisfactory results.25 The same tandem
sequence occurred using 6 equiv of iron powder in water
containing 0.25 equiv of FeSO4‚7H2O at 100 °C,26 but
yields were 10-20% lower and some side chain cleavage
(10-15%) was observed in the ether-containing sub-
strates.27 Reduction of 4a , 8a E and 10a with 6 equiv of
Na2S2O4 (sodium dithionite)28 in aqueous ethanol con-
taining excess NaHCO3 at 60 °C gave less than 40% of
the desired heterocycles along with several minor side
products. Finally, hydrogenation of 8a E at 1 atm over
5% Pd/C in ethanol at 30 °C resulted in reduction of both
the nitro group and the side chain double bond; none of
the heterocyclic product was detected.
substrate
X
R
product
yield (%)
4a
4b
CH2
CH2
O
O
O
H
CH3
H
H
CH3
H
11a
11b
11c
11c
11d
11e
11f
98
89
94
98
88
89
86
8a E
8a Z
8bE
10a
10b
NH
NH
CH3
side chain double bond to afford acrylate 4. Starting
materials for the dihydrobenzoxazines were prepared
from 2-nitrophenol (5) and 2-allyloxy-1-nitrobenzene
(6).13,14 Direct alkylation of 5 with ethyl (E)-4-bromo-2-
butenoate (7a ) using K2CO3 in acetone at 0-20 °C
afforded 8a E;15,16 similar alkylation with ethyl (E)-4-
bromo-3-methyl-2-butenoate (7b)17 gave 8bE. Ozonolysis
of 6 followed by Wittig11 olefination produced 8a Z.18
Finally, tetrahydroquinoxaline precursors 10a and 10b
were generated by heating 2-nitroaniline (9) with 7a and
7b, respectively.19
In summary, we have developed a tandem reduction-
Michael addition sequence for the preparation of several
types of aryl-fused nitrogen heterocycles. The procedure
is simple, clean, inexpensive and efficient, providing the
target ring systems in 2-5 steps. The yields for the ring
closure are excellent, and the products are easily purified
by chromatography. We are continuing our work to
explore new synthetic approaches to heterocyclic systems.
Resu lts a n d Discu ssion
The results of our tandem reduction-Michael addition
synthesis of aryl-fused nitrogen heterocycles are sum-
marized in Table 1. Treatment of 1 equiv of each
substrate with 6 equiv of iron powder in glacial acetic
acid at 115 °C for 30 min gave the indicated yields after
purification by preparative thin-layer chromatography.
Yields were uniformly high regardless of double-bond
geometry or substitution at the Michael terminus.
The mechanism of the reaction involves initial reduc-
tion of the nitro group to an amine which undergoes
Michael addition to the pendent acrylate by a favorable
six-exo-trig process.20 The use of 6 equiv (a 2-fold excess)
of iron assured that the required six electrons were
available for the reduction.21 Ring closure by Michael
addition proceeded rapidly under the reaction conditions,
even in cases where a methyl group on the acrylate
acceptor hindered cyclization.22 Double-bond geometry
also had little effect on the cyclization. It was noted,
Exp er im en ta l Section
Commercial reagents and solvents were used as received.
Potassium carbonate was ground to a fine powder, dried under
vacuum at 120 °C for 24 h, and stored in an oven at 120 °C.
Methyl (2-nitrophenyl)acetate (1),8 2-allyloxy-1-nitrobenzene
(6),13 and ethyl (E)-4-bromo-3-methyl-2-butenoate (7b)17 were
prepared by literature methods. All reactions were run under
dry N2 in oven-dried glassware. The HCl (0.2, 1, and 6 M), NaOH
(0.2 and 1 M), NaHCO3 (saturated), and NaCl (saturated) used
(22) See, for example: (a) Bunce, R. A.; Peeples, C. J .; J ones, P. B.
J . Org. Chem. 1992, 57, 1727-1733. (b) Bunce, R. A.; Bennett, M. J .
Synth. Commun. 1993, 23, 1009-1020.
(23) For reductions using activated iron, see: (a) Hazlet, S. E.;
Dornfeld, C. A. J . Am. Chem. Soc. 1944, 66, 1781-1782. (b) Eisch, J .
J .; Kovacs, C. A.; Rhee, S.-G. J . Organomet. Chem. 1974, 65, 289-
301.
(13) See ref 8, p 986.
(14) Fletcher, R. J .; Lampard, C.; Murphy, J . A.; Lewis, N. J . Chem.
Soc., Perkin Trans. 1 1995, 623-633.
(15) Sunitha, K.; Balasubramanian, K. K. Tetrahedron 1987, 43,
3269-3278.
(16) Attempts to perform the alkylation with ethyl (E)-4-bromo-2-
butenoate in refluxing acetone resulted in alkylation and double-bond
migration to give ethyl (Z)-4-(2-nitrophenyl)-3-butenoate. See: (a)
Reference 15. (b) Balakumar, A.; J anardhanam, S.; Rajagopalan, K.
Indian J . Chem. 1993, 32B, 313-317.
(17) Safaryn, J . E.; Chiarello, J .; Chen, K.-M.; J oullie, M. M.
Tetrahedron 1986, 42, 2635-2642.
(18) Wittig reactions of R-alkoxyaldehydes with stabilized ylides in
polar solvents (CH3OH) have been found to give predominantly the Z
olefin; see: Valverde, S.; Martin-Lomas, M.; Herradon, B.; Garcia-
Ochoa, S. Tetrahedron 1987, 43, 1895-1901. In the current procedure,
the crude aldehyde contained some residual methanol from the
ozonolysis reaction and DMSO from the reductive workup procedure.
(19) Speziale, A. J .; J aworski, E. G. J . Org. Chem. 1960, 25, 728-
732.
(20) Baldwin, J . E. J . Chem. Soc., Chem. Commun. 1976, 734-736.
(21) (a) Norman, R. O. C.; Coxon, J . M. Principles of Organic
Synthesis, 3rd ed.; Chapman and Hall: New York, 1993; pp 666-668.
(b) Use of 3-5 equiv of iron gave less consistent yields.
(24) For reductions using iron in the presence of acids, see: (a)
Reference 7. (b) West, R. W. J . Chem. Soc. 1925, 127, 494-495. (c)
Wertheim, E. Organic Syntheses; Wiley: New York, 1943; Collect. Vol.
II, pp 471-473. (d) Mosby, W. L. J . Org. Chem. 1959, 24, 421-423. (e)
Wulfman, D. S.; Cooper, C. F. Synthesis 1978, 924-925.
(25) Other mild conditions for nitroarene reductions have also been
reported, but were not investigated for the current reaction; see: (a)
Alper, H.; Gopal, M. J . Chem. Soc., Chem. Commun. 1980, 821. (b)
Sarmah, P.; Barua, N. C. Tetrahedron Lett. 1990, 31, 4065-4066. (c)
Baruah, R. N. Indian J . Chem. 1994, 33B, 758. (d) Desai, D. G.; Swami,
S. S.; Hapase, S. B. Synth. Commun. 1999, 29, 1033-1036. (e) Hari,
A.; Miller, B. L. Angew. Chem., Int. Ed. Engl. 1999, 38, 2777-2779.
(26) For reductions using iron in the presence of added salts, see:
(a) Lyons, R. E.; Smith, L. T. Chem. Ber. 1927, 60, 173-182. (b)
Hodgson, H. H.; Whitehurst, J . S. J . Chem. Soc. 1945, 202-204. (c)
Senkus, M. Ind. Eng. Chem. 1948, 40, 506-508.
(27) Water containing FeSO4‚7H2O (0.25 mmol/4.00 mL) was found
to have a pH of 4. This appears to be sufficiently acidic to slowly cleave
the allylic ethers.
(28) (a) Grandmougin, E. Chem Ber. 1906, 39, 3561-3564. (b) Fieser,
L. F.; Fieser, M. J . Am. Chem. Soc. 1934, 56, 1565-1578.

Notes
J . Org. Chem., Vol. 65, No. 9, 2000 2849
in various procedures refer to aqueous solutions. Reactions were
monitored by TLC on silica gel GF plates (Analtech no. 21521)
or capillary GC (SE-30 column, 6 m × 0.25 mm i.d., 0.25 µm
film thickness) with FI detection programmed between 50 and
300 °C. Preparative separations were performed using flash
column chromatography on silica gel (grade 62, 60-200 mesh)
mixed with Sylvania no. 2282 UV-active phosphor or PTLC on
20-cm × 20-cm silica gel GF plates (Analtech no. 02015); band
elution was monitored using a hand-held UV lamp. Melting
points were uncorrected. IR spectra were run as thin films on
NaCl disks and were referenced to polystyrene. 1H NMR and
13C NMR spectra were measured in CDCl3 at 300 and 75 MHz,
respectively, and were referenced to internal (CH3)4Si. High-
resolution mass spectra (HRMS, EI/DP) were obtained at 70 eV.
Rep r esen ta tive P r oced u r e for Alk yla tion of Meth yl (2-
Nitr op h en yl)a ceta te: Meth yl (()-2-(2-Nitr op h en yl)-4-p en -
ten oa te (2a ). The general procedure of Makosza and Tyrala was
used.9 To a stirred solution of 1.95 g (10.0 mmol) of 1 in 50 mL
of dry CH3CN was added 11.6 g (84.1 mmol) of anhydrous K2-
CO3 and 15 mg of 18-crown-6. To the resulting blue mixture was
added a solution of 2.02 g (1.10 mL, 12.0 mmol) of allyl iodide
in 5 mL of CH3CN and the reaction was stirred at reflux for 8
h. The solids were removed by filtration and the filtrate was
concentrated under vacuum. The remaining oil was purified by
flash chromatography on a 30 cm × 2.5 cm silica gel column
eluted with increasing concentrations of ether in hexanes to give
2.16 g (9.19 mmol, 92%) of 2a as a light yellow oil: IR 1736,
(m, 2 H), 4.76 (s, 1 H), 4.71 (s, 1 H), 3.03 (t, J ) 8.5 Hz, 2 H),
2.34 (t, J ) 8.5 Hz, 2 H), 1.79 (s, 3 H); 13C NMR δ 149.3, 144.5,
137.0, 132.8, 131.9, 127.0, 124.6, 110.9, 38.6, 31.5, 22.4; HRMS
m/z calcd for C11H13NO2 191.0946, found 191.0944.
Anal. Calcd for C11H13NO2: C, 69.11; H, 6.81. Found: C, 69.05;
H, 6.80.
Ozon olysis-Wittig Sequ en ce: Eth yl (E)-5-(2-Nitr op h en -
yl)-2-p en ten oa te (4a ). A solution of 5.27 g (29.8 mmol) of 3a
in 200 mL of CH3OH was treated with O3 at -78 °C as described
previously.11 The crude aldehyde was diluted with benzene, 13.9
g (40.0 mmol) of (carbethoxymethylene)triphenylphosphorane
was added, and the reaction was stirred at reflux for 8 h. The
reaction was cooled and concentrated under vacuum to give a
tan semisolid mass. The residue was layered on top of a 10 cm
× 10 cm plug of silica gel in a sintered glass frit and 2 L of 15%
ether in hexanes was poured through under aspirator vacuum.
Concentration of the filtrate gave the crude nitro acrylate as a
viscous yellow oil. The oil was flash chromatographed on a 60
cm × 2.5 cm silica gel column eluted with increasing concentra-
tions of ether in hexanes. The major band gave 4.15 g (16.7
mmol, 56%) of 4a as a light yellow oil: IR 1723, 1659, 1530,
1
1353 cm-1; H NMR δ 7.94 (dd, J ) 8.1, 1.4 Hz, 1 H), 7.55 (td,
J ) 7.5, 1.4 Hz, 1 H), 7.42-7.33 (complex, 2 H), 7.01 (dt, J )
15.7, 6.9 Hz, 1 H), 5.86 (dt, J ) 15.7, 1.5 Hz, 1 H), 4.19 (q, J )
7.1 Hz, 2 H), 3.03 (t, J ) 7.7 Hz, 2 H), 2.58 (m, 2 H), 1.29 (t, J
) 7.1 Hz, 3 H); 13C NMR δ 166.5, 149.1, 147.0, 135.9, 133.2,
132.0, 127.6, 125.0, 122.5, 60.2, 32.8, 31.7, 14.1; HRMS m/z calcd
for C13H15NO4 249.1001, found 249.1004.
1
1641, 1532, 1350 cm-1; H NMR δ 7.90 (dd, J ) 8.2, 1.4 Hz, 1
H), 7.62-7.51 (complex, 2 H), 7.43 (m, 1 H), 5.73 (ddt, J ) 17.1,
10.1, 6.9 Hz, 1 H), 5.05 (dm, J ) 17.1 Hz, 1 H), 5.01 (dm, J )
10.1 Hz, 1 H), 4.31 (t, J ) 7.5 Hz, 1 H), 3.68 (s, 3 H), 2.91 (m, 1
H), 2.63 (m, 1 H); 13C NMR δ 172.7, 149.5, 134.5, 133.1, 133.0,
130.2, 128.2, 124.8, 117.9, 52.2, 46.0, 36.8; HRMS m/z calcd for
Anal. Calcd for C13H15NO4: C, 62.65; H, 6.02. Found: C, 62.90;
H, 6.07.
Eth yl (Z)-4-(2-n itr op h en oxy)-2-bu ten oa te (8a Z): 5.27 g
(21.0 mmol, 52%); mp 32-34 °C; IR 1716, 1659, 1530, 1352 cm-1
;
1H NMR δ 7.85 (dd, J ) 8.1, 1.6 Hz, 1 H), 7.53 (m, 1 H), 7.11 (d,
J ) 8.5 Hz, 1 H), 7.05 (m, 1 H), 6.54 (dt, J ) 11.6, 4.7 Hz, 1 H),
5.97 (dt, J ) 11.6, 2.5 Hz, 1 H), 5.31 (dd, J ) 4.7, 2.5 Hz, 2 H),
4.22 (q, J ) 7.1 Hz, 2 H), 1.33 (t, J ) 7.1 Hz, 3 H); 13C NMR δ
166.1, 151.7, 145.1, 140.1, 134.2, 125.8, 120.8, 120.7, 114.7, 67.7,
60.6, 14.1; HRMS m/z calcd for C12H13NO5 251.0793, found
251.0795.
C
12H13NO4 235.0844, found 235.0847.
Anal. Calcd for C12H13NO4: C, 61.28; H, 5.53. Found: C, 61.54;
H, 5.58.
Meth yl (()-4-m eth yl-2-(2-n itr oph en yl)-4-pen ten oate (2b):
2.30 g (9.24 mmol, 92%); IR 1744, 1650, 1530, 1353 cm-1 1H
;
NMR δ 7.88 (d, J ) 8.2 Hz, 1 H), 7.58 (m, 2 H), 7.42 (m, 1 H),
4.75 (s, 1 H), 4.65 (s, 1 H), 4.48 (t, J ) 7.5 Hz, 1 H), 3.67 (s, 3
H), 2.87 (dd, J ) 14.4, 7.5 Hz, 1 H), 2.55 (dd, J ) 14.4, 7.5 Hz,
1 H), 1.73 (s, 3 H); 13C NMR δ 172.9, 149.5, 141.8, 133.1, 133.0,
130.0, 128.2, 124.7, 113.2, 52.0, 44.4, 40.7, 22.1; HRMS m/z calcd
for C13H15NO4 249.1001, found 249.0998.
Anal. Calcd for C12H13NO5: C, 57.37; H, 5.18. Found: C, 57.59;
H, 5.24.
Ozon olysis-Wa d sw or th -Em m on s Sequ en ce: Eth yl (E)-
3-Meth yl-5-(2-n itr oph en yl)-2-pen ten oate (4b). Following ozo-
nolysis of 3.03 g (15.9 mmol) of 3b in 150 mL of CH3OH as above,
5.08 g (6.00 mL, 84.9 mmol) of dimethyl sulfide and 200 mg of
p-TsOH were added. The reaction was warmed to room tem-
perature and stirred for 8 h. After concentration, the residue
was dissolved in ether, washed with NaHCO3 (2×) and NaCl
(1×), dried (MgSO4), and concentrated under vacuum. Flash
chromatography on a 30 cm × 2 cm silica gel column eluted with
increasing concentrations of ether in hexanes gave 2.80 g (14.5
mmol, 91%) of 4-(2-nitrophenyl)-2-butanone as a light yellow
oil: IR 1715, 1530, 1352 cm-1; 1H NMR δ 7.93 (dd, J ) 8.1, 1.3
Hz, 1 H), 7.53 (td, J ) 7.5, 1.3 Hz, 1 H), 7.42-7.28 (complex, 2
H), 3.15 (ABt, J ) 7.4 Hz, 2 H), 2.86 (ABt, J ) 7.4 Hz, 2 H),
2.17 (s, 3 H); 13C NMR δ 207.0, 149.4, 136.2, 133.2, 132.4, 127.4,
124.8, 44.1, 29.8, 27.2.
Anal. Calcd for C13H15NO4: C, 62.65; H, 6.02. Found: C, 62.78;
H, 6.05.
Rep r esen ta tive P r oced u r e for Hyd r olysis-Deca r boxy-
la tion : 2-(3-Bu ten yl)-1-n itr oben zen e (3a ). The procedure of
Bull and co-workers was used.10 To a stirred solution of 8.50 g
(36.1 mmol) of 2a in 130 mL of dioxane was added 43.4 mL of 1
M NaOH, and the solution was stirred at room temperature for
3 h. The reaction was concentrated under vacuum, the solid was
dissolved in 500 mL of water, and the solution was acidified to
pH 2 with 6 M HCl. The milky suspension was extracted with
ether (3×), and the combined ether layers were washed with
NaCl (1×), dried (MgSO4), and concentrated under vacuum to
give 7.57 g (34.2 mmol) of the acid as a yellow solid. The crude
acid was dissolved in 110 mL of dry DMF and treated with 4.72
g (34.2 mmol) of anhydrous K2CO3 at 50 °C for 45 min. The
reaction mixture was cooled to room temperature, then poured
into 300 mL of 0.2 M HCl and extracted with ether (2x). The
combined ether layers were washed with NaCl (1x), dried
(MgSO4), and concentrated under vacuum. The resulting brown
oil was purified by flash chromatography on a 50 cm × 2.5 cm
silica gel column eluted with 5% ether in hexane to give 5.86 g
(33.1 mmol, 92%) of 3a as a yellow oil: IR 1644, 1608, 1530,
Using the procedure of Balsevich,12 2.00 g (10.3 mmol) of the
ketone was reacted with 2.29 g (11.7 mmol) of ethyl dimeth-
ylphosphonoacetate in THF-DMSO to give the crude nitro
acrylate. Flash chromatography on a 40 cm × 2 cm silica gel
column eluted with increasing concentrations of ether in hexanes
gave 1.81 g (6.89 mmol, 67%) of 4b as a light yellow oil: IR 1716,
1
1651, 1530, 1353 cm-1; H NMR δ 7.94 (dd, J ) 8.2, 1.4 Hz, 1
H), 7.54 (td, J ) 7.5, 1.4 Hz, 1 H), 7.40-7.31 (complex, 2 H),
5.70 (q, J ) 1.3 Hz, 1 H), 4.15 (q, J ) 7.1 Hz, 2 H), 3.06 (m, 2
H), 2.47 (m, 2 H), 2.24 (d, J ) 1.3 Hz, 3 H), 1.28 (t, J ) 7.1 Hz,
3 H); 13C NMR δ 166.6, 157.9, 149.2, 136.1, 133.1, 132.0, 127.4,
124.9, 116.6, 59.6, 41.7, 31.6, 18.8, 14.3; HRMS m/z calcd for
C14H17NO4 263.1157, found 263.1156.
1
1353 cm-1; H NMR δ 7.90 (dd, J ) 8.2, 1.4 Hz, 1 H), 7.52 (m,
1 H), 7.36 (m, 2 H), 5.85 (ddt, J ) 17.2, 10.2, 6.8 Hz, 1 H), 5.04
(dm, J ) 17.2 Hz, 1 H), 5.01 (dm, J ) 10.2 Hz, 1 H), 2.99 (t, J
) 8.0 Hz, 2 H), 2.42 (m, 2 H); 13C NMR δ 149.5, 137.2, 136.7,
132.9, 132.1, 127.1, 124.7, 115.8, 34.5, 32.4; HRMS m/z calcd
for C10H11NO2 177.0790, found 177.0789.
Anal. Calcd for C14H17NO4: C, 63.88; H, 6.46. Found: C, 63.96;
H, 6.43.
Anal. Calcd for C10H11NO2: C, 67.80; H, 6.21. Found: C, 67.88;
H, 6.22.
Rep r esen ta tive P r oced u r e for Alk yla tion of 2-Nitr o-
p h en ol: Eth yl (E)-4-(2-Nitr op h en oxy)-2-bu ten oa te (8a E).
A mixture of 2.76 g (20.0 mmol) of 5 and 2.76 g (20.0 mmol) of
anhydrous K2CO3 was treated with 3.86 g (20.0 mmol) of 7a in
75 mL of dry acetone at 0-20 °C according to the procedure of
2-(3-Meth yl-3-bu ten yl)-1-n itr oben zen e (3b): 4.68 g (24.5
mmol, 92%); IR 1644, 1608, 1530, 1353 cm-1 1H NMR δ 7.89
;
(dd, J ) 8.4, 1.4 Hz, 1 H), 7.52 (td, J ) 7.4, 1.4 Hz, 1 H), 7.34

2850 J . Org. Chem., Vol. 65, No. 9, 2000
Notes
Sunitha and Balasubramanian.15 Following workup, the result-
ing solid was recrystallized from ether-pentane to give 2.91 g
(11.6 mmol, 58%) of pure 8a E: mp 56-58 °C; IR 1717, 1662,
1530, 1353 cm-1; 1H NMR δ 7.89 (dd, J ) 8.1, 1.6 Hz, 1 H), 7.54
(m, 1 H), 7.11-7.02 (complex, 3 H), 6.30 (dt, J ) 15.7, 2.1 Hz, 1
H), 4.85 (dd, J ) 3.8, 2.1 Hz, 2 H), 4.22 (q, J ) 7.1 Hz, 2 H),
1.31 (t, J ) 7.1 Hz, 3 H); 13C NMR δ 165.9, 151.3, 140.3, 140.1,
134.2, 125.9, 122.8, 121.1, 114.5, 67.7, 60.7, 14.2; HRMS m/z
calcd for C12H13NO5 251.1079, found 251.1075.
117.3, 114.5, 60.6, 47.8, 40.9, 28.0, 25.6, 14.2; HRMS m/z calcd
for C13H17NO2 219.1259, found 219.1259.
Anal. Calcd for
C13H17NO2: C, 71.23; H, 7.76; N, 6.39.
Found: C, 71.29; H, 7.77; N, 6.42.
Eth yl (()-2-m eth yl-1,2,3,4-tetr ah ydr oqu in olin e-2-acetate
1
(11b): 207 mg (0.89 mmol, 89%); IR 3395, 1730 cm-1; H NMR
δ 6.98 (m, 2 H), 6.63 (td, J ) 7.4, 1.2 Hz, 1 H), 6.51 (dd, J ) 8.2,
1.2 Hz, 1 H), 4.63 (br s, 1 H), 4.15 (q, J ) 7.1 Hz, 2 H), 2.78 (t,
J ) 6.8 Hz, 2 H), 2.55 (ABd, J ) 14.8 Hz, 1 H), 2.43 (ABd, J )
14.8 Hz, 1 H), 1.78 (m, 2 H), 1.29 (d, J ) 0.5 Hz, 3 H), 1.27 (t, J
) 7.1 Hz, 3 H); 13C NMR δ 171.9, 143.3, 129.3, 126.9, 119.8,
117.1, 114.9, 60.3, 50.0, 44.5, 34.0, 26.0, 23.5, 14.2; HRMS m/z
calcd for C14H19NO2 233.1416, found 233.1417.
Anal. Calcd for C12H13NO5: C, 57.37; H, 5.18. Found: C, 57.53;
H, 5.21.
Eth yl (E)-3-m eth yl-4-(2-n itr oph en oxy)-2-bu ten oate (8bE):
1.48 g (5.60 mmol, 40%; 55% based on recovered 7b); mp 71-72
°C; IR 1716, 1666, 1530, 1353 cm-1
;
1H NMR δ 7.88 (dd, J )
Anal. Calcd for C14H19NO2: C, 72.10; H, 8.15; N, 6.01.
Found: C, 72.37; H, 8.19; N, 5.98.
8.1, 1.6 Hz, 1 H), 7.53 (m, 1 H), 7.08 (m, 1 H), 7.03 (dd, J ) 8.4,
1.0 Hz, 1 H), 6.12 (sextet, J ) 1.5 Hz, 1 H), 4.63 (d, J ) 1.5 Hz,
2 H), 4.18 (q, J ) 7.1 Hz, 2 H), 2.22 (d, J ) 1.5 Hz, 3 H), 1.29 (t,
J ) 7.1 Hz, 3 H); 13C NMR δ 166.3, 151.4, 150.6, 148.5, 134.2,
125.9, 121.0, 116.6, 114.6, 72.6, 60.0, 15.5, 14.2; HRMS m/z calcd
for C13H15NO5 265.0950, found 265.0948.
Eth yl (()-3,4-dih ydr o-2H-1,4-ben zoxazin e-3-acetate (11c):
208 mg (0.94 mmol, 94%) from 8a E; 216 mg (0.98 mmol, 98%)
from 8a Z; mp 24-25 °C; IR 3360, 1730 cm-1 1H NMR δ 6.77
;
(m, 2 H), 6.68-6.58 (complex, 2 H), 4.20 (dd, J ) 10.6, 2.6 Hz,
1 H), 4.18 (q, J ) 7.1 Hz, 2 H), 3.96 (dd, J ) 10.6, 6.0 Hz, 1 H),
3.84 (m, 1 H), 3.66 (br s, 1 H), 2.53 (m, 2 H), 1.28 (t, J ) 7.1 Hz,
3 H); 13C NMR δ 171.6, 143.5, 132.5, 121.7, 118.9, 116.5, 115.7,
68.4, 60.7, 46.2, 36.7, 14.2; HRMS m/z calcd for C12H15NO3
221.1052, found 221.1049.
Anal. Calcd for C13H15NO5: C, 58.87; H, 5.66. Found: C, 59.05;
H, 5.71.
R ep r esen t a t ive P r oced u r e for Alk yla t ion of 2-Nit r o-
a n ilin e: Eth yl (E)-4-((2-Nitr op h en yl)a m in o)-2-bu ten oa te
(10a ). A mixture of 6.90 g (50.0 mmol) of 9 and 4.82 g (25.0
mmol) of 7a was heated with stirring at 100 °C for 12 h.19 The
reaction was cooled and the solid transferred to a separatory
funnel with the aid of ether and CH2Cl2. The organic layer was
washed with NaHCO3 (6×) and NaCl (1×), dried (MgSO4), and
concentrated under vacuum. The solid was purified on a 100
cm × 2.5 cm silica gel column eluted with 5-10% ether in
hexanes to give 4.69 g (18.8 mmol, 75%) of pure 10a : mp 50-
Anal. Calcd for C12H15NO3: C, 65.16; H, 6.79; N, 6.33.
Found: C, 65.29; H, 6.83; N, 6.28.
E t h yl (()-3-m et h yl-3,4-d ih yd r o-2H -1,4-b en zoxa zin e-3-
a ceta te (11d ): 207 mg (0.88 mmol, 88%); IR 3381, 1730 cm-1
;
1H NMR δ 6.79 (m, 2 H), 6.66-6.58 (complex, 2 H), 4.55 (br s, 1
H), 4.18 (qd, J ) 7.1, 1.0 Hz, 2 H), 3.96 (ABd, J ) 10.6 Hz, 1 H),
3.86 (ABd, J ) 10.6 Hz, 1 H), 2.69 (ABd, J ) 15.7 Hz, 1 H), 2.43
(ABd, J ) 15.7 Hz, 1 H), 1.30 (d, J ) 0.5 Hz, 3 H), 1.26 (t, J )
7.1 Hz, 3 H); 13C NMR δ 171.6, 142.7, 132.3, 121.8, 118.6, 116.4,
115.8, 73.1, 60.5, 48.9, 40.5, 22.4, 14.2; HRMS m/z calcd for
C13H17NO3 235.1208, found 235.1208.
51 °C; IR 3388, 1716, 1662, 1528, 1351 cm-1 1H NMR δ 8.26
;
(br s, 1 H), 8.20 (dd, J ) 8.5, 1.6 Hz, 1 H), 7.44 (m, 1 H), 7.03
(dt, J ) 15.7, 4.4 Hz, 1 H), 6.74 (d, J ) 8.8 Hz, 1 H), 6.72 (m, 1
H), 6.02 (dt, J ) 15.7, 2.1 Hz, 1 H), 4.19 (q, J ) 7.1 Hz, 2 H),
4.18 (m, 2 H), 1.28 (t, J ) 7.1 Hz, 3 H); 13C NMR δ 165.8, 144.7,
143.0, 136.3, 132.9, 126.9, 122.5, 116.2, 113.8, 60.6, 43.6, 14.2;
HRMS m/z calcd for C12H14N2O4 250.0954, found 250.0950.
Anal. Calcd for C12H14N2O4: C, 57.60; H, 5.60. Found: C,
57.69; H, 5.66.
Anal. Calcd for
C13H17NO3: C, 66.38; H, 7.23; N, 5.96.
Found: C, 66.54; H, 7.25; N, 6.01.
E t h yl
(()-1,2,3,4-t e t r a h yd r oq u in oxa lin e -2-a ce t a t e
(11e): 196 mg (0.89 mmol, 89%); IR 3385, 1728 cm-1; 1H NMR
δ 6.60 (m, 2 H), 6.52 (m, 2 H), 4.21 (br s, 1 H), 4.17 (q, J ) 7.1
Hz, 2 H), 3.84 (m, 1 H), 3.67 (br s, 1 H), 3.40 (dd, J ) 10.9, 3.0
Hz, 1 H), 3.13 (dd, J ) 10.9, 6.3 Hz, 1 H), 2.55 (m, 2 H), 1.28 (t,
J ) 7.1 Hz, 3 H); 13C NMR δ 172.1, 132.9, 132.7, 119.0, 118.7,
114.8, 114.5, 60.7, 46.7, 45.7, 38.7, 14.2; HRMS m/z calcd for
Eth yl (E)-3-m eth yl-4-((2-n itr oph en yl)am in o)-2-bu ten oate
(10b): 1.60 g (6.06 mmol, 70%); mp 69-70 °C; IR 3389, 1715,
1
1666, 1516, 1353 cm-1; H NMR δ 8.31 (br t, J ) 5.5 Hz, 1 H),
8.20 (dd, J ) 8.5, 1.4 Hz, 1 H), 7.43 (m, 1 H), 6.71 (m, 1 H), 6.68
(d, J ) 8.6 Hz, 1 H), 5.84 (q, J ) 1.4 Hz, 1 H), 4.14 (q, J ) 7.1
Hz, 2 H), 4.00 (d, J ) 5.5 Hz, 2 H), 2.22 (d, J ) 1.4 Hz, 3 H),
1.26 (t, J ) 7.1 Hz, 3 H); 13C NMR δ 166.3, 153.3, 148.5, 144.9,
136.3, 126.9, 116.2, 115.6, 113.9, 59.9, 50.1, 16.7, 14.2; HRMS
m/z calcd for C13H16N2O4 264.1110, found 264.1112.
C
12H16N2O2 220.1212, found 220.1208.
Anal. Calcd for C12H16N2O2: C, 65.45; H, 7.27; N, 12.73.
Found: C, 65.62; H, 7.31; N, 12.78.
Eth yl (()-2-m eth yl-1,2,3,4-tetr a h yd r oqu in oxa lin e-2-a c-
eta te (11f): 202 mg (0.86 mmol, 86%); mp 45-46 °C; IR 3388,
1730 cm-1; 1H NMR δ 6.60 (m, 2 H), 6.51 (m, 2 H), 4.14 (q, J )
7.1 Hz, 2 H), 4.03 (br s, 2 H), 3.13 (br s, 2 H), 2.68 (ABd, J )
15.4 Hz, 1 H), 2.43 (ABd, J ) 15.4 Hz, 1 H), 1.29 (d, J ) 0.5 Hz,
3 H), 1.26 (t, J ) 7.1 Hz, 3 H); 13C NMR δ 172.0, 132.2, 132.1,
119.0, 118.6, 115.0, 114.3, 60.3, 51.3, 49.0, 42.4, 24.4, 14.2;
HRMS m/z calcd for C13H18N2O2 234.1369, found 234.1367.
Anal. Calcd for C13H18N2O2: C, 66.67; H, 7.69; N, 11.97.
Found: C, 66.79; H, 7.71; N, 12.05.
Anal. Calcd for C13H16N2O4: C, 59.09; H, 6.06. Found: C,
59.14; H, 6.09.
Rep r esen ta tive P r oced u r e for Ta n d em Red u ction -
Mich a el Ad d ition : Eth yl (()-1,2,3,4-Tetr a h yd r oqu in olin e-
2-a ceta te (11a ). A 100-mL three-necked round-bottomed flask,
equipped with a reflux condenser (N2 inlet) and a magnetic
stirrer was charged with 4.0 mL of acetic acid, 249 mg (1.00
mmol) of 4a , and 335 mg (6.00 mmol) of iron powder (>100
mesh). The reaction was heated with stirring at 115 °C (oil bath
temperature 120 °C) for 30 min and then cooled. The crude
reaction mixture was diluted with 50 mL of ether, transferred
to a separatory funnel, and cautiously washed with NaHCO3
(5×). The aqueous washes were back-extracted with ether (1×),
and the combined ether layers were washed with NaCl (1×),
dried (MgSO4), and concentrated under vacuum. The resulting
yellow oil was purified by PTLC eluted with 15% ether in
hexanes to give 215 mg (0.98 mmol, 98%) of 11a as a light yellow
oil: IR 3395, 1729 cm-1; 1H NMR δ 6.97 (m, 2 H), 6.60 (td, J )
7.3, 1.1 Hz, 1 H), 6.50 (dd, J ) 8.2, 1.3 Hz, 1 H), 4.48 (br s, 1 H),
4.18 (q, J ) 7.1 Hz, 2 H), 3.72 (m, 1 H), 2.89-2.68 (complex, 2
H), 2.50 (m, 2 H), 1.96 (dm, J ) 9.6 Hz, 1 H), 1.71 (m, 1 H), 1.28
(t, J ) 7.1 Hz, 3 H); 13C NMR δ 172.3, 144.0, 129.2, 126.8, 120.8,
Ack n ow led gm en t. We thank the NIH (GM54256)
for support of this research. D.M.H. and M.L.A. are
grateful to Oklahoma State University for support in
the form of Freshman Research Scholarships. Funds for
the 300 MHz NMR spectrometer of the Oklahoma
Statewide Shared NMR Facility were provided by the
NSF (BIR-9512269), the Oklahoma State Regents for
Higher Education, the W. M. Keck Foundation, and
Conoco, Inc. Partial support for our mass spectrometer
by the NIH and the Oklahoma Center for the Advance-
ment of Science and Technology is also appreciated.
J O991899+