N-phenyl-substituted pyrrolidines, piperidines and azabicyclics by a tandem reduction-double reductive amination reaction

Article abstract of DOI:10.1002/jhet.5570400115

N-Phenyl-substituted pyrrolidines and piperidines have been synthesized by catalytic reduction of nitrobenzene in the presence of 4- and 5-oxoaldehydes, respectively. The process involves reduction of the aromatic nitro group to give the N-phenylhydroxylamine or aniline followed by reductive amination with the two carbonyl functional groups. Monocyclic systems are generally formed in high yield and are easily purified. The method has also been extended to the synthesis of fused N-phenylazabicyclics from 2-(3-oxopropyl)cycloalkanones. A high degree of diastereoselectivity for the trans-fused product is observed in substrates having an ester group α to the cycloalkanone carbonyl. Bicyclic precursors lacking this ester group give mixtures of cis and trans products. Finally, contrary to previous reports, we have demonstrated that aniline can be substituted for nitrobenzene in these reactions.

Full text of DOI:10.1002/jhet.5570400115

Jan-Feb 2003
N-Phenyl-Substituted Pyrrolidines, Piperidines and Azabicyclics by a
113
Tandem Reduction-Double Reductive Amination Reaction
Richard A. Bunce,* Derrick M. Herron [1], Jason R. Lewis [1]
and Sharadsrikar V. Kotturi
Department of Chemistry, Oklahoma State University, Stillwater, Oklahoma 74078-3071, USA
Received August 2, 2002
N-Phenyl-substituted pyrrolidines and piperidines have been synthesized by catalytic reduction of
nitrobenzene in the presence of 4- and 5-oxoaldehydes, respectively. The process involves reduction of the
aromatic nitro group to give the N-phenylhydroxylamine or aniline followed by reductive amination with the
two carbonyl functional groups. Monocyclic systems are generally formed in high yield and are easily puri-
fied. The method has also been extended to the synthesis of fused N-phenylazabicyclics from 2-(3-oxo-
propyl)cycloalkanones. A high degree of diastereoselectivity for the trans-fused product is observed in sub-
strates having an ester group α to the cycloalkanone carbonyl. Bicyclic precursors lacking this ester group
give mixtures of cis and trans products. Finally, contrary to previous reports, we have demonstrated that ani-
line can be substituted for nitrobenzene in these reactions.
J. Heterocyclic Chem., 40, 113 (2003).
Introduction.
catalytic sodium bicarbonate [9a] and the crude
ozonolysates were used directly in the hydrogenation. The
ozonolyses of 3a-i, 5a-c and 7a-b to prepare 5-oxoalde-
hydes were less susceptible to cyclization and were carried
out using our previously described procedure [7,12].
Pyrrolidines and piperidines are important structural
components in a large number of biologically active com-
pounds. Many synthetic procedures have been used to
access these ring systems including reduction of aromatic
heterocycles [2], the Hofmann-Löffler reaction [3],
cyclization of hydroxylamines [4], and reductive amina-
tion [5]. This last method has typically involved reaction
of 1,4- or 1,5-dicarbonyl compounds with amines or
ammonium salts in the presence of borohydride reducing
agents. To date, relatively little use has been made of nitro
compounds as latent amines for this reaction [6]. Nitro
compounds, however, have the advantage of being readily
available (especially aromatic derivatives), stable and non-
basic. Earlier work from this laboratory described a highly
diastereoselective synthesis of substituted tetrahydro-
quinoline-4-carboxylate esters using a tandem reduction-
intramolecular double reductive amination procedure
under catalytic hydrogenation conditions [7,8]. We report
here the preparation of N-phenyl-substituted pyrrolidines,
piperidines and azabicyclics from nitrobenzene and a
series of 4- and 5-oxoaldehydes using an intermolecular
variant of this reaction.
Results and Discussion.
The preparation of our cyclization substrates is outlined
in Scheme 1. Alkyl 3-butenyl ketones 1a-i and alkyl 4-pen-
tenyl ketones 3a-i were prepared according to the method
of Molander and Cameron [9]. Substrates 5a-c for the
bicyclic ring closures were prepared by alkylation of the
appropriate 2-oxocycloalkane-carboxylate esters with 4-
iodo-1-butene [10]; substrates 7a-b were generated by
alkylation of the corresponding cycloalkanone dimethylhy-
drazones followed by hydrazone exchange [9]. Since trace
amounts of acid produced in the ozonolyses led to the for-
mation of cyclic peroxides from the alkyl 3-butenyl ketones
[11], reactions of 1a-i were performed in the presence of
The results of our tandem reduction-double reductive
amination synthesis of N-phenyl-substituted pyrrolidines
and piperidines are given in Tables 1 and 2, respectively.
The reaction involves reduction of the aromatic nitro group
followed by reductive amination, first to the less hindered
aldehyde and then to the ketone. The sequence generally
proceeds in good yield (60-80%) for the closure of both
five- and six-membered rings. In all runs, the reaction was
found to work best when at least 25 weight percent (relative

114
R. A. Bunce, D. M. Herron, J. R. Lewis and S. V. Kotturi
Vol. 40
to the dicarbonyl substrate) of 5% palladium-on-carbon
was used [7]. This quantity of catalyst was sufficient to
reduce the excess nitrobenzene and promote the cyclization
despite deactivation by the saturated amine products [13].
pyrrolidines from 1a-g gave optimum results when they
were run on the crude ozonolysate using 3 equivalents of
nitrobenzene. Aniline (from excess nitrobenzene) and
N-methylaniline (from reaction of aniline with
formalde-
Table 1
1
13
Product
R
Yield
H NMR
C NMR
IR
HRMS
Molecular
Formula
Analysis (%)
-1
(deuteriochloroform)
δ (ppm)
(deuteriochloroform)
δ (ppm)
(cm ) (m/z)
Calcd.
Calcd.
Found
H
Found
C
N
9a
CH
74%
9b
[22]
[22]
[22]
161.1205
161.1205
C
C
H
N
N
11 15
3
7.21 (t, 2H, J = 7.3), 6.63 (t, 1H, J = 7.3),
6.55 (d, 2H, J = 7.7), 3.64 (m, 1H), 3.40 (m,
1H), 3.14 (m, 1H), 2.07-1.89 (complex,
3H), 1.81 (m, 1H), 1.69 (m, 1H), 1.43-1.26
(complex, 3H), 0.96 (t, 3H, J = 7.1)
147.3, 129.1, 115.1,
111.7, 58.3, 48.2, 35.3,
30.2, 23.5, 19.8, 14.2
1603
1507
189.1518
189.1516
H
82.54 10.05 7.41
82.66 10.12 7.27
13 19
n-C H
3
7
76%
9c
n-C H
72%
7.21 (t, 2H, J = 7.3), 6.63 (t, 1H, J = 7.3),
6.55 (d, 2H, J = 7.7), 3.62 (m, 1H), 3.40 (m,
1H), 3.13 (m, 1H), 2.07-1.92 (complex, 3H), 32.0, 30.2, 26.4, 23.5,
1.81 (m, 1H), 1.72 (m, 1H), 1.42-1.20
(complex, 7H), 0.90 (t, 3H, J = 6.5)
7.34-7.04 (complex, 7H), 6.62 (t, 1H, J =
147.3, 129.1, 115.0,
111.7, 58.6, 48.2, 33.0,
1603
1507
217.1831
217.1829
C
C
C
H
N
N
N
82.95 10.60 6.45
82.76 10.68 6.51
15 23
5
11
22.7, 14.1
9d
147.1, 141.8, 129.1,
128.4, 126.1, 125.8,
115.2, 111.7, 57.8,
48.1, 34.4, 32.9, 30.1,
23.4
147.2, 129.1, 115.0,
111.7, 56.8, 47.9,
41.6, 30.4, 26.2,
24.1, 23.3, 21.7
1603
1507
251.1674
251.1676
H
86.06 8.37
85.87 8.42
5.58
5.59
18 21
C H (CH ) 7.3), 6.46 (d, 2H, J = 7.8), 3.67 (m, 1H),
6
5
2 2
68%
3,42 (m, 1H), 3.14 (m, 1H), 2.68 (m, 2H),
2.09-1.92 (complex, 4H), 1.89 (m, 1H),
1.60 (m, 1H)
7.21 (t, 2H, J = 7.3), 6.63 (t, 1H, J = 7.3),
6.56 (d, 2H, J = 7.8), 3.75 (m, 1H), 3.39 (m,
1H), 3.13 (m, 1H), 2.07-1.89 (complex,
3H), 1.84 (m, 1H), 1.64 (m, 1H), 1.54 (m,
1H), 1.20 (m, 1H), 1.05 (d, 3H, J = 6.4),
0.93 (d, 3H, J = 6.4)
9e
i-C H
66%
1603
1507
203.1674
203.1675
H
82.76 10.34 6.90
82.65 10.42 6.77
14 21
4
9
9f
i-C H
61%
7.21 (t, 2H, J = 7.3), 6.65 (t, 1H, J = 7.3),
6.63 (d, 2H, J = 7.8), 3.66 (quintet, 1H, J =
3.8), 3.50 (m, 1H), 3.18 (q, 1H, J = 7.5),
2.20 (m, 1H), 2.05-1.80 (complex, 4H),
0.93 (d, 3H, J = 6.9), 0.79 (d, 3H, J = 6.9)
7.21 (t, 2H, J = 7.3), 6.64 (t, 1H, J = 7.3),
6.59 (d, 2H, J = 7.8), 3.61 (m, 1H), 3.47 (m,
1H), 3.13 (q, 1H, J = 8.1), 2.01-1.86
(complex, 3H), 1.84-1.57 (complex, 7H),
1.40-0.92 (complex, 5H)
147.2, 129.0, 115.2,
112.3, 63.2, 49.6,
29.4, 25.6, 24.4,
19.7, 16.5
1603
1506
189.1518
189.1515
C
C
H
N
N
82.54 10.05 7.41
82.58 10.09 7.34
13 19
3
7
9g
c-C H
62%
148.1, 129.0, 115.1,
112.1, 63.0, 49.3,
40.4, 33.9, 30.4, 27.5,
26.7, 26.5, 26.4, 24.4
1603
1506
229.1831
229.1828
H
83.84 10.04 6.11
83.75 10.08 6.14
16 23
6
11
9h
t-C H
54%
7.18 (t, 2H, J = 7.3), 6.76 (d, 2H, J = 7.8),
6.63 (t, 1H, J = 7.3), 3.77 (dd, 1H, J = 8.2,
1.5), 3.61 (m, 1H), 3.26 (dt, 1H, J = 9.3, 8.5), 38.0, 29.7, 27.8, 24.6
2.14-1.72 (complex, 4H), 0.92 (s, 9H)
150.9, 128.5, 115.6,
113.6, 65.3, 52.1,
1603
1502
203.1674
203.1673
C
C
H
N
N
82.76 10.34 6.90
82.54 10.45 6.86
14 21
4
9
9i
[24]
[24]
[24]
223.1361
223.1360
H
16 17
C H
6
5
35%
hyde produced in the ozonolysis) were both easily
separated from the desired heterocycles by flash chro-
matography. For 1h-i, yields were slightly higher when the
intermediate 4-oxoaldehydes were isolated and purified
Overall yields were generally lower for the synthesis of
pyrrolidines than for piperidines. This was due primarily to
lower yields in the ozonolysis step to prepare the
4-oxoaldehydes. It was found that the reactions to prepare

Jan-Feb 2003
N-Phenyl-Substituted Pyrrolidines, Piperidines and Azabicyclics
115
Table 2
1
13
Product
R
Yield
H NMR
C NMR
IR
HRMS
Molecular
Formula
Analysis (%)
-1
deuteriochloroform
δ (ppm)
(deuteriochloroform)
δ (ppm)
(cm ) (m/z)
Calcd.
Calcd.
Found
H
Found
C
N
10a
[22]
[22]
[22]
175.1361 C12H17
175.1359
N
N
CH3
79%
10b
n-C3H7
78%
7.22 (t, 2H, J = 7.2), 6.88 (d, 2H, J = 7.8),
6.75 (t, 1H, J = 7.2), 3.79 (m, 1H), 3.33 (dt,
1H, J = 11.1, 4.0), 2.98 (m, 1H), 1.81-1.40
(complex, 10H), 0.86 (t, 3H, J = 7.2)
7.22 (t, 2H, J = 7.3), 6.88 (d, 2H, J = 7.8), 6.74
(t, 1H, J = 7.3), 3.76 (sextet, 1H, J = 4.0), 3.33
(dt, 1H, J = 11.4, 4.0), 2.98 (m, 1H), 1.77-1.38
151.2, 129.0, 118.0,
116.3, 55.5, 43.6,
29.5, 27.7, 25.5,
1601 203.1764
1501 203.1767
C14H21
C16H25
C19H23
82.76 10.34 6.90
83.98 10.30 6.83
20.1, 19.3, 14.2
10c
n-C5H11
72%
151.2, 129.0, 118.0,
116.3, 55.8, 43.7, 31.9,
27.7, 27.2, 26.6, 25.5,
1603 231.1987
1502 231.1987
N
N
83.12 10.82 6.06
82.94 10.79 6.16
(complex, 8H), 1.23 (m, 6H), 0.84 (t, 3H, J = 6.8) 22.6, 19.3, 14.0
7.27-7.09 (complex, 7H), 6.80 (d, 2H, J = 7.8),
10d
151.3, 142.4, 129.4,
128.7, 128.6, 126.1,
118.5, 116.2, 55.3,
44.0, 33.4, 29.7,
1603 265.1828
1502 265.1831
86.04 8.68 5.28
85.77 8.73 5.38
C6H5(CH2)2 6.74 (t, 1H, J = 7.2), 3.81 (m, 1H), 3.36 (dt, 1H,
74%
J = 12.5, 3.6), 3.01 (m, 1H), 2.65-2.45 (complex,
2H), 1.84 (m, 2H), 1.79-1.57 (complex, 6H)
28.0, 25.7,19.8
10e
i-C4H9
66%
7.22 (t, 2H, J = 7.2), 6.88 (d, 2H, J = 7.8), 6.74
(t, 1H, J = 7.2), 3.91 (m, 1H), 3.34 (dt, 1H, J =
11.0, 3.7), 2.98 (m, 1H), 1.84-1.40 (complex,
7H), 1.26 (m, 2H), 0.85 (d, 6H, J = 6.5)
7.22 (t, 2H, J = 7.2), 6.88 (d, 2H, J = 7.8),
6.74 (t, 1H, J = 7.2), 3.91 (m, 1H), 3.34
(dt, 1H, J = 11.0, 3.7), 2.98 (m, 1H), 1.84-
1.40 (complex, 7H), 0.85 (d, 6H, J = 6.5)
7.18 (t, 2H, J = 7.3), 6.82 (d, 2H, J = 7.9),
6.64 (t, 1H, J = 7.3), 3.49 (m, 2H), 3.08 (m,
1H), 1.90 (m, 1H), 1.85-1.52 (complex,
12H), 1.13 (m, 2H), 0.90 (m, 2H)
151.0, 129.0, 117.9,
116.3, 53.4, 43.2,
36.0, 27.7, 25.4,
25.1, 23.9, 21.8, 19.2
151.5, 129.1, 116.9,
115.5, 62.3, 43.6,
26.8, 25.1, 24.3,
1603 217.1831
1503 217.1830
C15H23
C14H21
C17H25
N
N
N
82.95 10.60 6.45
82.91 10.66 6.47
10f
i-C3H7
56%
1603 203.1674
1503 203.1672
82.76 10.34 6.90
82.94 10.29 6.85
20.4, 20.3, 19.9
10g
c-C6H11
56%
151.4, 129.1, 116.2,
114.7, 60.7, 42.6, 36.3,
30.6, 30.5, 29.9, 26.5,
26.4, 24.8, 24.2, 20.0
1600 243.1987
1503 243.1988
83.95 10.29 5.76
83.74 10.40 5.63
10h
t-C4H9
[a]
10i
C6H5
[b]
[a] Heterocycle 10h was not observed. Product 11 was isolated. [b] Heterocycle 10i was not observed. Products 14 and 15 were isolated.
prior to reductive cyclization. The synthesis of piperidines
was carried out in two stages. Ozonolysis of 3a-i in
methanol followed by reductive workup and treatment with
p-toluenesulfonic acid gave the keto acetals derived from
the expected 5-oxoaldehydes. These compounds were
more easily purified and stored than the dicarbonyl com-
pounds. Prior to reductive cyclization, treatment of each
keto acetal with 3% perchloric acid:tetrahydrofuran (1:1)
regenerated the 5-oxoaldehyde [7,12]. Reaction of these
keto aldehydes with 2 equivalents of nitrobenzene under
catalytic hydrogenation conditions then afforded the piperi-
dine derivatives. Again, the final products were readily
purified by flash chromatography. In accordance with
expected steric effects, ketones flanked by bulky 2° and 3°
alkyl groups gave lower cyclization yields than ketones
substituted with 1° groups.
The results of reactions to prepare N-phenylazabicyclic
compounds are summarized in Tables 3 and 4. Cyclization
of 6a and 6b bearing an ester group α to the ring ketone
gave the trans-fused bicyclic products as single diastere-
omers in 70-75% yield. This diastereoselectivity can be
attributed to a steric effect where the ester shields one side
of the structure during the final reduction and directs the
incoming hydrogen to the opposite face of the molecule.
Reaction of 8a and 8b, which lack the ester group, gave
mixtures of cis- and trans-fused products. Structures for
the bicyclic compounds were assigned using a combina-
tion of COSY-45 [14] and NOESY [15] spectra.

116
R. A. Bunce, D. M. Herron, J. R. Lewis and S. V. Kotturi
Vol. 40
Table 3
1
13
Product
n
Yield
H NMR
C NMR
IR
(cm )
HRMS
(m/z)
Calcd.
Found
Molecular
Formula
Analysis (%)
-1
(deuteriochloroform)
δ (ppm)
(deuteriochloroform)
δ (ppm)
Calcd.
Found
H
C
N
16a
1
72%
7.28 (t, 2H, J = 7.7), 7.13 (d, 2H, J = 7.4),
7.04 (d, 1H, J = 7.3), 3.72 (s, 3H), 3.22
(dddd, 1H, J = 11.2, 4.5, 2.1, 1.0), 2.81
(ddd, 1H, J = 14.8, 12.1, 3.6), 2.56 (m, 2H),
2.25 (m, 1H), 1.99 (m, 1H), 1.88-1.44
(complex, 6H), 1.22 (td, 1H, J = 11.2, 4.5)
7.26 (t, 2H, J = 7.7), 7.15 (d, 2H, J = 7.3),
7.07 (t, 1H, J = 7.3), 3.75 (s, 3H), 3.15
(dddd, 1H, J = 11.1, 4.3, 2.6, 1.6), 2.98
(td, 1H, J = 11.3, 3.7), 2.42 (dd, 1H, J =
12.4, 4.1), 2.32 (dm, 1H, J = 13.2), 2.11
(m, 1H), 1.98 (m, 1H), 1.77-1.58 (complex,
3H), 1.47 (m, 1H), 1.35-1.06 (complex, 5H)
7.16 (t, 2H, J = 7.3), 6.68 (t, 1H, J = 7.3),
6.58 (d, 2H, J = 7.5), 3.72 (bs, 1H), 3.70
(s, 3H), 3.10 (t, 2H, J = 6.9), 2.65 (m,
1H), 2.49 (m, 1H), 2.19-2.03 (complex,
2H), 1.79-1.40 (complex, 10H)
175.6, 152.1, 128.4,
123.8, 123.5, 72.8,
55.4, 53.4, 51.3, 35.0,
34.9, 28.0, 24.6, 19.6
1736
259.1572
259.1570
C
H
NO
74.13
74.33
8.11 5.41
8.18 5.29
16 21
2
2
16b
2
75%
175.2, 151.3, 128.2,
125.9, 124.1, 69.7,
55.5, 51.2, 48.9, 37.8,
37.1, 27.5, 25.7, 24.5,
22.4
1738
273.1729
273.1731
C
H
NO
74.73
74.91
8.42 5.13
8.47 5.03
17 23
17
209.6, 172.9, 148.2,
129.2, 117.1, 112.6,
62.6, 52.2, 44.0,
42.1, 33.0, 32.9, 29.8,
25.6, 24.8, 24.6
3406
1739
1707
303.1834
303.1831
C
H
NO
71.29
71.01
8.25 4.62
8.19 4.80
18 25
3
82%
Attempted cyclization of substrate 6c gave only 17
resulting from reduction of the nitro group and a single
reductive amination with the side chain aldehyde; none
of the bicyclic product was observed. In this case, addi-
tion of the pendant aniline nitrogen to the cycloheptanone
carbonyl is presumably disfavored by internal strain [16]
and steric hindrance with the unsubstituted α' carbon of
the seven-membered ring.
Problems were encountered in the synthesis of piperi-
dine derivatives from tert-butyl- and phenyl-substituted
ketones. While the tert-butyl pyrrolidine precursor 1h
yielded 9h in 54% yield, ring closure was completely
suppressed for piperidine precursor 4h and 2,2-dimethyl-
7-(phenylamino)-3-heptanone (11) was the only product
isolated (Scheme 2). For substrates incorporating a
phenyl ketone, as in 2i and 4i, carbonyl reduction [17]
competed with pyrrolidine formation and was the exclu-
sive process in attempts to prepare the piperidine
(Scheme 2). The observation that these reactions suc-
cessfully yield pyrrolidines but fail in the piperidine
series suggests that the outcome is dictated by more than
simple steric factors. Enthalpy and entropy also play a
large role in determining the reaction path. While
entropy is generally perceived to be more important, it
has been reported [18] that enthalpy is the dominant fac-
tor in comparisons of 5- and 6-membered ring closures.
Thus, a combination of steric hindrance and less
favorable enthalpy slows (or prevents) piperidine forma-
tion and permits competing processes to occur.
While the reaction chronology seems clear, the actual
intermediates involved are less obvious. Earlier work by
others [19] offered evidence that N-phenylhydroxylamine
was the primary nucleophilic intermediate in reductive ami-
nations using nitrobenzene under catalytic hydrogenation
conditions; the alternative intermediate, aniline, was shown
to be virtually unreactive. While the hydroxylamine is
expected to be a stronger nucleophile due to the alpha effect
[20], a control experiment was necessary to assess the possi-
ble role of aniline in the reaction. We therefore repeated the
reaction of 4-oxopentanal and 5-oxohexanal substituting

Jan-Feb 2003
N-Phenyl-Substituted Pyrrolidines, Piperidines and Azabicyclics
117
Table 4
1
13
Product H NMR
n
Yield
C NMR
IR
(cm )
HRMS
(m/z)
Calcd.
Found
Molecular
Formula
Analysis (%)
Calcd.
Found
H
-1
(deuteriochloroform)
δ (ppm)
(deuteriochloroform)
δ (ppm)
C
N
18a
1
67%
7.22 (dd, 2H, J = 8.8, 7.3), 6.92 (d, 2H, J =
8.8), 6.74 (t, 1H, J = 7.3), 4.12 (dt, 1H, J =
9.6, 6.5), 3.38 (dt, 1H, J = 11.9, 3.8), 2.84
(td, 1H, J = 11.5, 3.2), 2.09 (m, 1H), 1.85-
1.45 (complex, 8H), 1.30 (m, 2H)
151.1, 129.0, 117.8,
115.2, 59.7, 43.1,
37.6, 29.4, 26.1,
24.9, 21.6, 20.3
1603
1496
201.1518
201.1515
C
C
C
C
H
N
N
N
N
83.58 9.45
74.33 8.18
6.97
5.29
14 19
19a
1
19%
7.27 (t, 2H, J = 7.4), 7.10 (d, 2H, J = 7.4),
7.02 (t, 1H, J = 7.4), 3.30 (dt, 1H, J = 12.2,
3.1), 2.59 (m, 1H), 2.37 (ddd, 1H, J = 16.5,
10.5, 6.3), 1.95 (m, 1H), 1.78 (m, 3H), 1.60
m, 3H), 1.30 (m, 3H), 1.12 (m, 1H)
153.2, 128.6, 123.3,
123.1, 67.4, 57.9,
45.4, 30.3, 29.8,
28.9, 26.9, 19.9
1602
1495
201.1518
201.1516
H
83.58 9.45
74.91 8.47
6.97
5.03
14 19
18b
2
75%
7.22 (dd, 2H, J = 8.8, 7.2), 6.89 (d, 2H, J = 8.8), 150.7, 129.0, 117.9,
6.74 (t, 1H, J = 7.2), 3.82 (dt, 1H, J = 11.9, 4.3), 115.8, 58.0, 42.0,
3.30 (dt, 1H, J = 12.4, 3.1), 2.87 (td, 1H, J =
12.1, 2.9), 2.06 (m, 1H), 1.82 (m, 1H), 1.77-
1.53 (complex, 6H), 1.47-1.12 (complex, 5H)
1603
1496
215.1674
215.1675
H
83.72 9.77
83.61 9.83
6.51
6.63
15 21
35.8, 31.9, 25.9, 25.8,
23.8, 20.8, 20.3
19b
2
7.29 (t, 2H, J = 7.4), 7.14 (d, 2H, J = 7.4),
7.09 (t, 1H, J = 7.4), 3.12 (dm, 1H, J = 11.3),
152.8, 128.7, 125.6,
124.3, 65.6, 58.0,
1603
1495
215.1674
215.1671
H
83.72 9.77
83.57 9.79
6.51
6.46
15 21
15%
2.71 (td, 1H, J = 11.6, 2.8), 2.34 (m, 1H), 1.91- 42.5, 33.1, 32.4, 31.5,
1.58 (complex, 7H), 1.50-0.95 (complex, 6H) 26.5, 26.2, 25.5
EXPERIMENTAL
aniline (and also N-phenylhydroxylamine) for nitrobenzene.
In each case, the heterocyclic product was produced in a
yield nearly identical to that obtained using nitrobenzene.
Thus, aniline cannot be ruled out as an intermediate in this
process. Furthermore, the option of using aniline in the
reaction dramatically increases the number of possible sub-
stitution patterns on the aromatic reacting partner.
In conclusion, a synthesis of N-phenyl-substituted pyrro-
lidines and piperidines based on the tandem reduction-dou-
ble reductive amination of nitrobenzene with 4- and 5-
oxoaldehydes has been developed. The process is clean,
efficient, operationally simple, and gives yields comparable
to or better than other methods. The reaction has also been
applied to a diastereoselective synthesis of several new
azabicyclic systems. In this application, the degree of
diastereoselectivity appears to depend on the steric bulk of
the substituent α to the ketone involved in the final ring clo-
sure step. Finally, while the use of nitrobenzene offers sev-
eral advantages in manipulating reagents, we have demon-
strated that aniline can also be used in the reaction. We are
currently working to extend this methodology to the syn-
thesis of morpholine and piperazine derivatives.
Commercial reagents and solvents were used as received. All
reactions were run under dry nitrogen in oven-dried glassware.
Reactions were monitored by thin layer chromatography on silica
gel GF plates (Analtech) using ultraviolet or iodine detection or cap-
illary gas chromatography (SE-30 column, 6 m x 0.25 mm i.d., 0.25
µm film thickness, 50-300°) using flame ionization detection.
Preparative separations were performed using flash chromatography
[21] on silica gel (grade 62, 60-200 mesh) mixed with ultraviolet-
active phosphor (Sorbent Technologies no. 5); band elution was
monitored using a hand-held ultraviolet lamp. Melting points were
uncorrected. Ir spectra were run as thin films on sodium chloride
1
13
disks and were referenced to polystyrene. H and C nmr spectra
were measured in deuteriochloroform at 300 MHz and 75 MHz,
respectively, and were referenced to internal tetramethylsilane; cou-
pling constants (J) have been given in Hz. COSY-45 and NOESY
spectra were recorded at 400 MHz. High resolution mass spectra
(direct probe/electron impact) were obtained at 70 electron volts.
All alkyl 3-butenyl and alkyl 4-pentenyl ketones were synthe-
sized according to the literature method [9]. Many of the simple
5-oxoaldehydes as well as 8a and 8b have also been reported
[9a]. Previously unknown 5-oxoaldehydes prepared as part of
this study are given below along with a representative procedure.

118
R. A. Bunce, D. M. Herron, J. R. Lewis and S. V. Kotturi
Vol. 40
Caution: Though we never experienced any problems, addi-
Anal. Calcd. for C H O : C, 72.53; H, 9.89. Found: C,
11 18 2
tion of 5% palladium-on-carbon to methanol can cause fires.
This operation should be performed under a nitrogen atmosphere.
72.25; H, 10.01.
Representative Reduction-Reductive Amination Procedures to
Representative Procedure to Prepare Previously Unreported 5-
Prepare Pyrrolidines: (±)-2-Methyl-1-phenylpyrrolidine (9a).
Oxoaldehydes: 5-Oxodecanal (4c).
A solution of 800 mg (8.16 mmole) of 1a [9a] in 150 mL of
methanol containing 100 mg of sodium bicarbonate was ozonized
at –78° until thin layer chromatography indicated complete con-
sumption of the starting material. The crude ozonolysate was
transferred directly to a stainless steel pressure vessel, 3.01 g (24.5
mmole) of nitrobenzene and 200 mg of 5% palladium-on-carbon
were added (see Caution above), and the mixture was shaken
under 4 atmospheres of hydrogen at 30° for 6 hours. The crude
product was concentrated, diluted with ether and filtered through a
plug of Celite topped with a layer of anhydrous magnesium sul-
fate to remove the catalyst. Removal of the ether afforded a light
brown oil that contained the pyrrolidine along with aniline and N-
methylaniline. The product was purified by flash chromatography
on a 30 cm x 2.5 cm column eluted with 1% ether in hexane.
Band 1 afforded 972 mg (6.04 mmole, 74%) of 9a. The spectral
data matched those reported previously [22]. The same procedure
was used to prepare 9b-g (see Table 1).
A solution of 1.00 g (5.95 mmole) of 3c in 150 mL of methanol
was cooled to –78° and treated with ozone until thin layer chro-
matography indicated complete consumption of starting material.
Excess ozone was removed on a stream of dry nitrogen and 8.00
g (6.77 mL, 109 mmole) of dimethyl sulfide was added. The
reaction was warmed slowly to 0° and 250 mg of p-toluenesul-
fonic acid was added. The reaction was slowly warmed to room
temperature during 2 hours and stirring was continued for 12
hours. The reaction was concentrated, diluted with ether, washed
with sodium bicarbonate and sodium chloride, and dried (magne-
sium sulfate). Removal of the ether gave the expected keto acetal
containing a small amount of the keto aldehyde.
Prior to reductive cyclization, this mixture was treated with 3%
perchloric acid:tetrahydrofuran (1:1) at 0° for 1 hour and at room
temperature for 12 hours, then extracted (two times) with
dichloromethane [12]. The organic layer was washed with
sodium bicarbonate and sodium chloride, dried (magnesium sul-
fate), and concentrated under vacuum to give 970 mg (5.71
mmole, 96%) of 4c as a light yellow oil; ir: 2830, 2722, 1721
In the control experiments, 3.00 equivalents of aniline or N-
phenylhydroxylamine [23] was added in place of nitrobenzene
prior to hydrogenation. The yields of 9a in these control experi-
ments were 77% and 74%, respectively.
-1
1
cm ; H nmr: δ 9.76 (t, 1H, J = 1.4), 2.47 (m, 2H), 2.38 (t, 2H,
J = 7.4), 1.90 (quintet, 2H, J = 7.1), 1.65 (m, 1H), 1.57 (quintet,
(±)-2-tert-Butyl-1-phenylpyrrolidine (9h).
13
2H, J = 7.4), 1.28 (m, 5H), 0.89 (t, 3H, J = 7.1);
C nmr: δ
210.2, 201.9, 43.0, 42.8, 41.3, 31.4, 23.5, 22.4, 16.0, 13.9; hrms:
m/z Calcd. for C H O : 170.1307; Found: 170.1303.
This compound was best prepared by first isolating the 2h
from the ozonolysis (methanol, catalytic sodium bicarbonate,
-78°; dimethyl sulfide workup (no acid), flash chromatography)
of 1h. The resulting 4-oxoaldehyde was dissolved in methanol
and hydrogenated in the presence of 2 equivalents of nitroben-
zene and 25 weight percent (based on the dicarbonyl substrate) of
5% palladium-on-carbon. The final product was purified by flash
chromatography to give 400 mg (1.97 mmole, 54% overall) of 5h
as a light yellow oil. The spectral data are given in Table 1.
10 18
2
Anal. Calcd. for C H O : C, 70.59: H, 10.59. Found: C,
10 18
2
70.83; H, 10.68.
5-Oxo-7-phenylheptanal (4d).
This compound (938 mg, 4.60 mmole, 93%) was obtained as a
-1
1
light yellow oil; ir: 2824, 2728, 1722 cm ; H nmr: δ 9.73 (t,
1H, J = 1.4), 7.28 (m, 2H), 7.21 (m, 3H), 2.90 (t, 2H, J = 7.3),
2.72 (t, 2H, J = 7.3), 2.45 (2 t, 4H, J = 7.1), 1.88 (quintet, 2H, J =
(±)-1,2-Diphenylpyrrolidine (9i).
13
7.1); C nmr: δ 209.2, 201.8, 140.9, 128.5, 128.3, 126.1, 44.2,
42.9, 41.6, 29.7, 15.9; hrms: m/z Calcd. for C
204.1150; Found: 204.1149.
H O :
This compound was best prepared as above by first isolating
the 2i from the ozonolysis of 1i. The resulting 4-oxoaldehyde
was dissolved in methanol and hydrogenated in the presence of 2
equivalents of nitrobenzene and 25 weight percent (based on the
dicarbonyl substrate) of 5% palladium-on-carbon. The final
product was purified by flash chromatography to give 224 mg
(1.00 mmole, 35% overall) of 9i as a light yellow oil that solidi-
fied on standing, mp 35-37°. The spectral data matched those
reported previously [24]. The reductive cyclization also pro-
duced compounds 12 and 13.
13 16 2
Anal. Calcd. for C H O : C, 76.47: H, 7.84. Found: C,
13 16
2
76.66; H, 7.90.
7-Methyl-5-oxooctanal (4e).
This compound (960 mg, 6.15 mmole, 95%) was obtained as a
-1
1
light yellow oil; ir: 2830, 2722, 1718 cm ; H nmr: δ 9.76 (t,
1H, J = 1.5), 2.47 (m, 4H), 2.27 (d, 2H, J = 6.9), 2.13 (nonet, 1H,
J = 6.6), 1.89 (quintet, 2H, J = 7.1), 0.91 (d, 6H, J = 6.6);
13
C
nmr: δ 210.0, 201.9, 51.8, 43.0, 41.8, 24.6, 22.5, 15.9; hrms: m/z
Calcd. for C H O : 156.1150; Found: 156.1148.
(±)-1-Phenyl-4-(phenylamino)butanol (12).
9
16 2
Anal. Calcd. for C H O : C, 69.23; H, 10.26. Found: C,
69.35; H, 10.30.
This compound (236 mg, 0.98 mmole, 33%) was obtained as a
light yellow oil. The spectral data matched those reported previ-
ously [25].
9
16 2
5-Cyclohexyl-5-oxopentanal (4g).
N-(4-Phenylbutyl)benzenamine (13).
This compound (900 mg, 4.95 mmole, 89%) was obtained as a
-1
1
This compound (63 mg, 0.28 mmole, 9%) was obtained as a
light yellow oil; ir: 2835, 2721, 1733, 1711 cm ; H nmr: δ 9.76 (t,
1H, J = 1.5), 2.51 (t, 2H, J = 7.0), 2.48 (m, 2H), 2.31 (m, 1H), 1.89
(quintet, 2H, J = 7.0), 1.92 (complex, 5H), 1.40-1.17 (complex,
-1
1
light yellow oil; ir: 3411 cm ; H nmr: δ 7.28 (t, 2H, J = 7.5),
7.16 (complex, 5H), 6.68 (t, 1H, J = 7.3), 6.58 (d, 2H, J = 7.5),
13
5H); C nmr: δ 213.3, 202.0, 50.8, 43.0, 39.1, 28.4, 25.8, 25.6,
3.58 (br s, 1H), 3.12 (t, 2H, J = 6.9), 2.66 (t, 2H, J = 7.3), 1.80-
13
16.0; hrms: m/z Calcd. for C H O : 182.1307; Found: 182.1308.
1.59 (complex, 4H);
C nmr: δ 148.4, 142.2, 129.2, 128.4,
11 18
2

Jan-Feb 2003
N-Phenyl-Substituted Pyrrolidines, Piperidines and Azabicyclics
119
128.3, 125.8, 117.1, 112.7, 43.8, 35.6, 31.4, 29.7; hrms: m/z
Anal. Calcd. for C H N: C, 85.36; H, 8.79; N, 5.86. Found:
17 21
Calcd. for C H N: 225.1518; Found: 225.1519.
C, 85.09; H, 8.90; N, 5.77.
16 19
Anal. Calcd. for C H N: C, 85.33; H, 8.44; N, 6.22. Found:
C, 85.12; H, 8.52; N, 6.35.
16 19
Representative Procedure for the Preparation of Azabicyclic
Precursors where R = CO CH : Methyl (±)-2-Oxo-1-(3-oxo-
2
3
propyl)cyclopentanecarboxylate (6a).
Representative Reduction-Reductive Amination Procedure to
Prepare Piperidines: (±)-2-Methyl-1-phenylpiperidine (10a).
This compound was prepared from 1.00 g (5.10 mmole) of 5a
[10] by ozonolysis, conversion to the keto acetal, purification,
and hydrolysis as described for 4c. The yield was 980 mg (4.94
mmole, 97%) of 6a as a light yellow oil. This compound was
used without further purification; ir: 2841, 2728, 1756, 1727
A solution of 550 mg (4.82 mmole) of 4a and 1.19 g of
nitrobenzene (9.65 mmole) in 125 mL of methanol was hydro-
genated in the presence of 140 mg of 5% palladium-on-carbon
(see Caution above). Workup and purification as described for
9a gave 674 mg (3.85 mmole, 79%) of 10a as a light yellow oil.
The spectral data matched those previously reported [22]. The
same procedure was used to prepare 10b-g (see Table 2).
In the control experiments, 2.00 equivalents of aniline or N-
phenylhydroxylamine [23] was added in place of nitrobenzene
prior to hydrogenation. The yields of 10a in these control exper-
iments were 76% and 75%, respectively.
-1
1
cm ; H nmr: δ 9.75 (t, 1H, J = 1.1), 3.72 (s, 3H), 2.70 (ddd, 1H,
J = 18.3, 9.5, 5.9), 2.56-2.25 (complex, 4H), 2.19 (ddd, 1H, J =
13
15.1, 9.3, 5.8), 2.10-1.80 (complex, 4H);
C nmr: δ 214.5,
201.0, 171.5, 58.8, 52.6, 39.4, 37.8, 34.0, 25.4, 19.5; hrms: m/z
Calcd. for C H O : 198.0892; Found: 198.0893.
10 14
4
Methyl (±)-2-Oxo-1-(3-oxopropyl)cyclohexanecarboxylate (6b).
This compound (930 mg, 4.38 mmole, 92%) was isolated as a
light yellow oil and used without further purification; ir: 2842,
Attempted Reductive Cyclization of 6,6-Dimethyl-5-oxoheptanal
(4h): 2,2-Dimethyl-7-(phenylamino)-3-heptanone (11).
-1
1
2731, 1748, 1724 cm ; H nmr: δ 9.74 (t, 1H, J = 1.2), 3.75 (s,
3H), 2.59-2.40 (complex, 5H), 2.17 (ddd, 1H, J = 14.3, 9.5, 5.6),
2.02 (m, 1H), 1.89 (m, 1H), 1.76 (m, 1H), 1.65 (m, 2H), 1.47 (m,
This compound (727 mg, 3.12 mmole, 82%) was obtained as a
light yellow oil that crystallized on standing at 0°, mp 26-28°; ir:
13
1H); C nmr: δ 207.6, 201.1, 172.3, 59.9, 52.4, 40.9, 39.3, 36.6,
-1
1
3400, 1701 cm ; H nmr: δ 7.17 (t, 2H, J = 7.3), 6.68 (t, 1H, J =
27.4, 26.8, 22.5; hrms: m/z Calcd. for C H O : 212.1048;
11 16
4
7.3), 6.59 (d, 2H, J = 7.5), 3.62 (br s, 1H), 3.12 (t, 2H, J = 6.7),
Found: 212.1045.
13
2.53 (t, 2H, J = 6.7), 1.63 (m, 4H), 1.14 (s, 9H); C nmr: δ 215.7,
148.3, 129.2, 117.1, 112.6, 44.1, 43.7, 36.0, 29.0, 26.4, 21.3;
Methyl (±)-2-Oxo-1-(3-oxopropyl)cycloheptanecarboxylate (6c).
hrms: m/z Calcd. for C H NO: 233.1780; Found: 233.1777.
15 23
This compound (950 g, 4.19 mmole, 94%) was isolated as a
light yellow oil and used without further purification; ir: 2858,
2725, 1728 cm ; H nmr: δ 9.74 (t, 1H, J = 1.2), 3.73 (s, 3H),
Anal. Calcd. for C H NO: C, 77.25; H, 9.87; N, 6.01.
15 23
Found: C, 77.47; H, 9.94; N, 5.95.
-1
1
2.72-2.38 (complex, 4H), 2.27 (ddd, 1H, J = 14.1, 9.3, 5.6), 2.14
Attempted Reductive Cyclization of 5-Oxo-5-phenylpentanal
(4i).
(dd, 1H, J = 13.1, 8.5), 1.94 (ddd, 1H, J = 14.1, 9.6, 5.6), 1.80-
13
1.61 (complex, 5H), 1.53 (m, 2H);
C nmr: δ 209.3, 201.2,
Hydrogenation of 964 mg (5.48 mmole) of 4i as above gave a
mixture of 14 and 15. The compounds were separated on five 20
cm x 20 cm preparative thin layer chromatography plates eluted
with 5-10% ether in hexane.
172.8, 61.7, 52.3, 42.2, 39.7, 33.8, 29.8, 27.6, 25.5, 24.8; hrms:
m/z Calcd. for C H O : 226.1205; Found: 226.1204.
12 18
4
Representative Reduction-Reductive Amination Procedure to
Prepare Azabicyclics: Methyl (±)-(1S*,6S*)-5-Aza-5-phenyl-
bicyclo[4.3.0]nonanecarboxylate (16a).
(±)-1-Phenyl-5-(phenylamino)pentanol (14).
This compound (936 mg, 3.67 mmole, 67%) was obtained as a
light yellow oil that crystallized on standing at 0°, mp 37-38°; ir:
A solution of 0.98 g (4.94 mmole) of 6a and 1.22 g (9.88
mmole) of nitrobenzene in 150 mL of methanol was hydro-
genated in the presence of 200 mg of 5% palladium-on-carbon
(see Caution above). Workup and purification as described for
9a gave 920 mg (3.56 mmole, 72%) of 16a as a light yellow oil.
The same procedure was used to prepare 16b, 17, 18a-b and
19a-b. The spectral data for 16a-b and 17 are given in Table 3;
data for 18a-b and 19a-b are given in Table 4.
-1
1
3400 cm ; H nmr: δ 7.39-7.26 (complex, 5H), 7.16 (t, 2H, J =
7.3), 6.68 (t, 1H, J = 7.3), 6.58 (d, 2H, J = 7.6), 4.69 (dd, 1H, J =
7.4, 5.8), 3.53 (br s, 1H), 3.10 (t, 2H, J = 7.0), 1.98 (br s, 1H),
1.79 (complex, 2H), 1.63 (quintet, 2H, J = 7.3), 1.54 (m, 1H),
13
1.39 (m, 1H); C nmr: δ 148.3, 144.7, 129.2, 128.5, 127.6,
125.8, 117.2, 112.7, 74.5, 43.8, 38.7, 29.4, 23.4; hrms: m/z
Calcd. for C H NO: 255.1623; Found: 255.1620.
17 21
Acknowledgments.
Anal. Calcd. for C H NO: C, 80.00; H, 8.24; N, 5.49.
17 21
Found: C, 79.81; H, 8.26; N, 5.62.
We wish to thank the Oklahoma Center for the Advancement
of Science and Technology (HR01-015) for support of this
research. D. M. H. wishes to thank Oklahoma State University
for a Wentz Project Scholarship and the Chemistry Department
for a Skinner Scholarship. Funds for the 300 and 400 MHz NMR
spectrometers of the Oklahoma Statewide Shared NMR Facility
were provided by 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
NSF and the Oklahoma Center for the Advancement of Science
and Technology is also appreciated.
N-(5-Phenylpentyl)benzenamine (15).
This compound (105 mg, 0.43 mmole, 8%) was obtained as a
-1
1
light yellow oil; ir: 3404 cm ; H nmr: δ 7.28 (t, 2H, J = 7.5),
7.17 (complex, 5H), 6.68 (t, 1H, J = 7.3), 6.58 (d, 2H, J = 7.5),
3.48 (br s, 1H), 3.09 (t, 2H, J = 7.1), 2.63 (t, 2H, J = 7.5), 1.66 (2
13
quintets, 4H, J = 7.5), 1.45 (m, 2H); C nmr: δ 148.5, 142.5,
129.2, 128.4, 128.3, 125.7, 117.1, 112.7, 43.9, 35.8, 31.2, 29.4,
26.8; hrms: m/z Calcd. for C
239.1673.
H N: 239.1674; Found:
17 21

120
R. A. Bunce, D. M. Herron, J. R. Lewis and S. V. Kotturi
Vol. 40
REFERENCES AND NOTES
Wiley-Interscience, New York, NY, 2001, pp 56-57.
[14a] A. E. Derome, Modern NMR Techniques for Chemistry
Research, Elsevier Science, New York, NY, 1987, pp 227-230; [b] T.
D. W. Claridge, High-Resolution NMR Techniques in Organic
Chemistry, Elsevier Science, New York, NY, 1999, pp 158, 188 and
197-199.
[15] D. Neuhaus, M. P. Williamson, The Nuclear Overhauser
Effect in Structural and Conformational Analysis, VCH, New York,
NY, 1989, pp 253-306.
[*] Corresponding author. E-mail: rab@okstate.edu
[1] Undergraduate research participants: D. H. M. 1999-pre-
sent; J. R. L. 2001-2002.
[2] M. Hudlicky, Reductions in Organic Chemistry, 2nd Ed.,
ACS, Washington D.C., 1996, pp 68-72.
[3] For reviews, see [a] L. Stella, Angew. Chem. Int. Ed. Eng.,
22, 337 (1983); [b] G. Sosnovsky and D. J. Rawlinson, Adv. Free
Radical Chem., 4, 203 (1972); [c] N. C. Deno, Methods Free-
Radical Chem., 3, 135 (1972).
[4] H. O. House, and L. F. Lee, J. Org. Chem., 41, 863 (1976).
[5] Cyclization by reductive amination using amines and
ammonium salts: [a] R. F. Borch and B. C. Ho, J. Org. Chem., 42,
1225 (1977). [b] T. H. Jones, J. B. Franko, M. S. Blum and H. M.
Fales, Tetrahedron Lett., 21, 789 (1980). [c] T. H. Jones, M. S.
Blum, H. M. Fales and C. R. Thompson, J. Org. Chem., 45, 4778
(1980). [d] M. Kawaguchi, J. Ohashi, Y. Kawakami, Y. Yamamoto
and J. Oda, Synthesis, 701 (1985). [e] A. H. Fray, D. J. Augeri and E.
F. Kleinman, J. Org. Chem., 53, 896 (1988). [f] C. Boga, F.
Manescalchi and D. Savoia, Tetrahedron, 50, 4709 (1994). [g] T. T.
Shawe, C. J. Sheils, S. M. Gray and J. L. Conard, J. Org. Chem., 59,
5841 (1994).
[16] E. L. Eliel, S. H. Wilen and L. N. Mander, Stereochemistry
of Organic Compounds, Wiley-Interscience, New York, NY, 1994,
pp 769-771.
[17a] P. N. Rylander, Catalytic Hydrogenation in Organic
Synthesis, Academic Press, New York, NY, 1979, pp 100-107; [b]
See ref. 2, p 152; [c] The exact percentage of each compound varied
with reaction time—longer reaction times resulted in more of the
fully deoxygenated product; [d] Since a large amount of the benzylic
alcohol was isolated in these reactions, it was assumed that the
deoxygenated product was produced in two stages from the phenyl
ketone. A referee, however, pointed out that the fully deoxygenated
product could also arise from hydrogenolysis of the benzylic amine
in the ring-closed product. A control experiment using 1,2-
diphenylpyrrolidine under typical reaction conditions gave some
decomposition, but none of the N-(4-phenylbutyl)benzenamine.
[18a] F. C. Lightstone and T. C. Bruice, Bioorg. Chem., 26, 193
(1998); [b] See also, G. Illuminati and L. Mandolini, Acct. Chem.
Res., 14, 95 (1981).
[19] W. S. Emerson and C. A. Uraneck, J. Am. Chem. Soc., 63,
749 (1941). These reactions were run in ethanol-acetic acid using
platinum(IV) oxide as the catalyst.
[20] M. B. Smith and J. March, Advanced Organic Chemistry,
Reactions, Mechanisms and Structure, 5th Ed., Wiley-Interscience,
New York, NY, 2001, p 445.
[21] W. C. Still, M. Kahn, and A. Mitra, J. Org. Chem., 43,
2923 (1978).
[22] T. Ohsawa, M. Ihara, K. Fukumoto and T. Kametani, J.
Org. Chem., 48, 3644 (1983).
[6] N. Ono, The Nitro Group in Organic Synthesis, Wiley-
VCH, New York, NY, 2001, pp 325-363.
[7] R. A. Bunce, D. M. Herron, L. B. Johnson and S. V.
Kotturi, J. Org. Chem., 66, 2822 (2001).
[8] For several general reviews on tandem reactions, see [a]
T.-L. Ho, Tandem Organic Reactions, Wiley-Interscience, New York,
NY, 1992; [b] L. F. Tietze and U. Beifuss, Angew. Chem. Int. Ed.
Eng., 32, 131 (1993); [c] R. A. Bunce, Tetrahedron, 51, 13103
(1995).
[9a] G. A. Molander and K. O. Cameron, J. Am. Chem. Soc.,
115, 830 (1993); [b] E. J. Corey and D. Enders, Tetrahedron Lett., 3
(1976); [c] For a preparation of N,N-dimethylhydrazones, see G. R.
Newkome and D. L. Fishel, Organic. Syntheses, Coll. Vol. VI, Wiley,
New York, NY, 1988, p 12-13.
[10] D. Belotti, J. Cossy, J. P. Pete and C. Portella, J. Org.
Chem., 51, 4196 (1986).
[11] K. Griesbaum and G. Kiesel, Chem. Ber., 122, 145 (1989).
[12] T. Hudlicky, B. C. Ranu, S. M. Naqvi and A. Srnak, J.
Org. Chem., 50, 123 (1985).
[23] N-Phenylhydroxylamine was prepared and recrystallized
according to the procedure in B. S. Furniss, A. J. Hannaford, P. W. G.
Smith and A. R. Tatchell, Vogel's Textbook of Practical Organic
Chemistry, 5th Ed., Longman, New York, NY, 1989, p 955.
[24] F. D. Lewis, J. M. Wagner-Brennan and A. M. Miller, Can.
J. Chem., 77, 595 (1999).
[13a] M. Freifelder, Practical Catalytic Hydrogenation
Techniques and Applications, Wiley-Interscience, New York, NY,
1971, p 39-47; [b] See ref 2, p 12; [c] S. Nishimura, Handbook of
Heterogeneous Catalytic Hydrogenation for Organic Synthesis,
[25] J. Almena, F. Foubelo and M. Yus, Tetrahedron, 50, 5775
(1994).