Cycloaddition of Enamine and Iminium Ion Intermediates Formed in the Reaction of N -Arylpyrrolidines with T-HYDRO

Article abstract of DOI:10.1055/s-0035-1560185

The reaction of N-arylpyrrolidine derivatives with 70% aqueous tert-butyl hydroperoxide (T-HYDRO) in the presence of NaOAc·3H₂O gives tetracyclic amines in 59-78% yields via cycloaddition of the corresponding iminium ion and enamine intermediates formed in situ in cyclohexane solvent. The iminium ion intermediate reacts with t-BuOK in methanol to give the corresponding cyclic amides in 85-88% yields or undergoes alkylation to give the corresponding nitromethyl product in 74-79% yields using t-BuOK and nitromethane in methanol.

Full text of DOI:10.1055/s-0035-1560185

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© Georg Thieme Verlag Stuttgart · New York
2015, 26, 2231–2236
letter
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G. A. Rao, M. Periasamy
Letter
Synlett
Cycloaddition of Enamine and Iminium Ion Intermediates Formed
in the Reaction of N-Arylpyrrolidines with T-HYDRO
Gunda Ananda Rao
N
Mariappan Periasamy*
R
T-HYDRO
School of Chemistry, University of Hyderabad Central University,
t-BuOK, MeNO2
MeOH
70 °C, 48 h
P. O. Hyderabad 500046, India
mpsc@uohyd.ernet.in
NaOAc•3H2O
cyclohexane
70 °C, 24 h
t-BuOK
MeOH
70 °C, 24 h
Dedicated to Professor K. P. C. Vollhardt for his contributions to chemistry.
NO2
O
N
N
N
N
R
R
74–79% yield
R
R
85–88% yield
59–78% yield
Received: 11.06.2015
Accepted after revision: 30.07.2015
Published online: 02.09.2015
using NaOAc·3H2O in hydrocarbon solvents or to the corre-
sponding cyclic amide upon base hydrolysis and further ox-
idation using t-BuOK in methanol or to the corresponding
2-nitromethyl derivatives using t-BuOK–MeNO2 in metha-
nol.
DOI: 10.1055/s-0035-1560185; Art ID: st-2015-b0195-l
Abstract The reaction of N-arylpyrrolidine derivatives with 70% aque-
ous tert-butyl hydroperoxide (T-HYDRO) in the presence of
NaOAc·3H2O gives tetracyclic amines in 59–78% yields via cycloaddition
of the corresponding iminium ion and enamine intermediates formed
in situ in cyclohexane solvent. The iminium ion intermediate reacts with
t-BuOK in methanol to give the corresponding cyclic amides in 85–88%
yields or undergoes alkylation to give the corresponding nitromethyl
product in 74–79% yields using t-BuOK and nitromethane in methanol.
We have carried out the reaction of N-phenylpyrroli-
dine 1a with T-HYDRO under various conditions (Scheme 1
and Table 1). Whereas the tetracyclic amine 2a is obtained
only in 5% yield without using a base in cyclohexane, it is
obtained in 13–45% yields in the presence of bases like
K2CO3, t-BuOK and NaOAc·3H2O in cyclohexane at room tem-
perature in 24 hours (Table 1, entries 1–4). The reaction us-
ing the base NaOAc·3H2O gives the tetracyclic amine prod-
uct 2a in 32% and 45% yield, in toluene and cyclohexane, re-
spectively, but in more polar solvents like CH2Cl2, MeCN,
and MeOH, this tetracyclic amine product is formed in less-
er yields (12–21%) besides the amide product 3a (5–8%; Ta-
ble 1, entries 5–8). The reaction in MeOH in the presence of
various bases gives only the amide 3a in 33–85% yields (Ta-
ble 1, entries 9–13). The reaction gave higher yields at 70 °C
(Table 1, entries 14–17). Again, whereas the use of MeOH
and MeCN solvents gave a mixture of the tetracyclic amine
2a (in 35% and 28% yields) and the amide 3a (in 33% and
21% yields), the reaction in toluene and cyclohexane sol-
vents was more clean and the tetracyclic amine 2a product
was obtained in 64% and 72% yields, respectively (Table 1,
entries 14–17).
Key words amine, amides, radical cation, iminium ion, enamine
Imines and iminium ions can be generated by the oxida-
tion of C–H bond adjacent to a nitrogen atom of a tertiary
amine.1 Oxidation of tertiary aryl amines with the reagents
like Ti(IV) and copper(II) leads to the corresponding radical
cations which dimerize to give benzidine derivatives.2 Ter-
tiary amine radical cations were also reported to be formed
in the reaction of tertiary amines with 70% aqueous tert-
butyl hydroperoxide (T-HYDRO).3 Recently, it has been re-
ported that iminium and enamine ion intermediates are
formed in situ in the reaction of amines with copper and
iron complexes and anhydrous tert-butyl hydroperoxide
(5.5 M in decane).4 Oxidative Povarov reactions of amines
catalyzed by Lewis acids and Brønsted acids were previous-
ly used for the synthesis of polycyclic amines and natural
products.5 Alternatively, such amines could be accessed by
sequence of reactions involving gold-catalyzed hydroami-
nation and aza-Diels–Alder reaction of propargylic amino-
esters and domino sequence of reactions involving Mannich
and aromatic electrophilic substitution.6
H
H
T-HYDRO
base
N
N
Ph
O
+
N
N
H
solvent
Ph
Ph
1a
3a
2a
We wish to report that the reaction of N-arylpyrrolidine
derivatives with T-HYDRO produces the corresponding
iminium ions which are converted into tetracyclic amines
Scheme 1 Reaction of N-phenylpyrrolidine with T-HYDRO and base
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2231–2236

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G. A. Rao, M. Periasamy
Letter
Synlett
Table 1 Optimization of the Reaction Conditionsa–g
Table 2 Synthesis of Tetracyclic Amine Derivatives 2 by Using
T-HYDROa–d
Entry
Base
Solvent
Yield (%)
Yield (%)
of 2ad
of 3ad
T-HYDRO
N
NaOAc•3H2O
1b
2b
–
cyclohexane
cyclohexane
cyclohexane
cyclohexane
toluene
CH2Cl2
5g
15g
13g
45g
32g
21f
18f
12f
0
0
21
18
0
N
Ar
N
cyclohexane
70 °C, 24 h
t-BuOK
Ar
3b
K2CO3
1
2
4b
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
K2CO3
5b
0
Entry Substrate
Product
Yield
(%)c,d
6b
7
7b
MeCN
5
H
H
8b
MeOH
8
N
N
N
9b
MeOH
33
48
85
35
78
33
21
0
1
72
69
62
H
10b
11c
12b
13c
14c
15c
16c
17c
t-BuOK
MeOH
0
1a
t-BuOK
MeOH
0
2a
2b
NaOH
MeOH
0
NaOH
MeOH
0
N
N
N
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
NaOAc·3H2O
MeOH
35f
28f
64g
72g
2
MeCN
1b
toluene
cyclohexane
0
a All the reactions were carried out with N-arylpyrrolidine 1 (1 mmol), base
(4 mmol), T-HYDRO (4 mmol) for 24 h.
N
N
N
b Reactions were carried out at r.t.
3
c Reactions were carried out at 70 °C.
d Isolated yields of 2a and 3a.
e The products were characterized by spectral data (IR, 1H NMR, 13C NMR).
f The product 2a formed is a 1:1 (approx.) mixture of diastereomers.
g The product 2a formed is a single diastereomer.
1c
N
N
N
Since the use of cyclohexane gave the optimum results,
we carried out reactions using the other aryl amine deriva-
tives in this solvent. The results are summarized in Table 2.
Whereas, the 1-(o-tolyl)pyrrolidine 1b gave the corre-
sponding tetracyclic amine product 2b in 69% yield,
1-(p-tolyl)pyrrolidine 1c gave the tetracyclic amine 2c in
62% yield (Table 2, entries 2 and 3). The reaction using
1-(2,4-dimethylphenyl)pyrrolidine and 1-(naphthalen-1-
yl)pyrrolidine derivatives gave the corresponding tetracy-
clic amines 1d and 1e in 59% and 78% yields, respectively
(Table 2, entries 4 and 5). The reaction with 1-(2-methoxy-
phenyl)pyrrolidine 1f gave the tetracyclic amine 2f in 64%
yield.
The tetracyclic amine 2a was reported to be formed as a
minor product along with an isomeric product 2a′ by cyc-
loaddition of the corresponding iminium ion and enamine
prepared in situ by the reaction of the cyclic amide 3a with
PhMe2SiLi in THF at –78 °C to –20 °C.7 We have confirmed
that the product obtained in the present transformation has
the same stereochemistry as above mentioned minor prod-
uct by comparing the reported X-ray crystal structure with
the X-ray data of the product 2a formed under the present
4
59
78
64
1d
2d
N
N
N
5
1e
2e
H
H
N
N
O
N
6
H
O
O
1f
2f
a All the reactions were carried out with N-phenyl-substituted pyrrolidines
1a–f (1 mmol), base (4 mmol), T-HYDRO (4 mmol) for 24 h.
b Reactions were carried out at 70 °C.
c Isolated yield of 2a–2f.
d The products were characterized by spectral data (IR, 1H NMR, 13C NMR).
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reaction conditions in cyclohexane. Whereas, a 1:1 mixture
of 2a and 2a′ was isolated as a mixture in polar solvents (Ta-
ble 1), only product 2a was obtained in toluene and cyclo-
hexane solvents (Figure 1).
the presence of t-BuOK (4 equiv). Also, the reaction using
the 1-(p-tolyl)pyrrolidine 1f gave the corresponding cyclic
amide 3b in 88% yield under these conditions (Scheme 2).
T-HYDRO
O
H
H
H
H
N
N
t-BuOK, MeOH
70 °C, 24 h
N
N
N
N
H
H
R
R
1a R = H
1f R = Me
3a 85%
3b 88%
2a
2a'
H
H
H
H
Scheme 2 Synthesis of N-aryl-2-pyrrolidones by using T-HYDRO and
t-BuOK in methanol
OMe
OMe
N
N
N
N
H
H
MeO
MeO
We have also observed that the reaction of N-phenyl-
pyrrolidine 1a with T-HYDRO (4 equiv), t-BuOK (4 equiv) in
the presence of nitromethane (0.5 mL) gave the corre-
sponding nitromethyl-substituted product 4a in 74% yield
(Scheme 3). The product 4b was obtained in 79% yield
when p-tolylpyrrolidine was used as the substrate (Scheme
3).
2f'
2f
Figure 1 Possible diastereomeric products
We have obtained crystals suitable for single-crystal
X-ray structure analysis by crystallization of the product 2f
from hexane. The X-ray analysis of 2f showed that all ste-
reogenic hydrogens have syn stereochemistry (Figure 2).8
The corresponding isomeric product 2f′ was not obtained
under the present reaction conditions in cyclohexane.
T-HYDRO
t-BuOK, MeOH
NO2
N
N
MeNO2
70 °C, 48 h
R
R
1a R = H
1f R = Me
4a 74%
4b 79%
Scheme 3 Reaction of N-aryl pyrrolidines, T-HYDRO, t-BuOK and Me-
NO2 in methanol
Mechanism and intermediates outlined in Scheme 4
may be considered for the formation of products 2a, 3a and
4a. The reaction may involve activation of the tert-butyl hy-
droperoxide by the base9 leading to the subsequent forma-
tion of amine radical cation, tert-butoxy radical, iminium
ion and enamine intermediates (Scheme 4). The iminium
ion 5 formed in situ could further react with the base to
give the corresponding enamine 6 which could undergo
Mannich-type reaction with the iminium ion 5 followed by
cyclization to afford the tetracyclic amine product 2a
(Scheme 4). In methanol solvent, the hydroxyl anion
formed in situ could attack the iminium ion 5 to give the
amino alcohol product 7 which after further oxidation
could afford the N-phenyl-2-pyrrolidone 3a (Scheme 4). In
the presence of MeNO2 and t-BuOK, nitromethylation takes
place as outlined in Scheme 4.
Figure 2 ORTEP diagram of 2f
Unfortunately, crystals suitable for single-crystal X-ray
structure analysis were not obtained for the tetracyclic
amine products 2b–e. However, the 13C NMR spectral data
reveal that only one diastereomeric product was obtained
in these cases but at this stage we cannot assign stereo-
chemistry for these products.
We have observed that the cyclic amide 3a was formed
in the reaction of N-phenylpyrrolidine 1a with T-HYDRO (4
equiv) when the reaction was carried out in methanol in
Previously, the tetracyclic amine products 2a and 2a′
were reported to be formed by the reaction of iminium ion
and enamine intermediates formed in situ in the reaction of
N-phenylpyrrolidine 1a with diethyl azodicarboxylate10
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2231–2236

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G. A. Rao, M. Periasamy
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+
N
N
N
N
••
+N
N
2a
base
H
t-BuOOH
NaOAc•3H2O
+
N
•+
N
OH
–OH
O
H
oxidation
N
N
N
t-BuO
t-BuOH
t-BuO
+
5
7
3a
4
1a
MeNO2
–OH
NO2
–CH2NO2
N
4a
Scheme 4 Mechanism and intermediates involved in the reaction of N-phenylpyrrolidine with T-HYDRO
and also in the reduction of N-phenyl-2-pyrrolidone 3a
with lithium aluminum hydride, in addition to the above
mentioned method involving the reaction of PhMe2SiLi and
N-phenyl-2-pyrrolidone 3a.7 Oxidation of N-phenylpyrroli-
dine 1a by a binuclear copper(II) complex of 7-azaindole
under an oxygen atmosphere produced tetracyclic amines
2a along with the oxygenated product N-phenyl-2-pyrroli-
done 3a.11 Also, methods have been reported for the con-
version of N-arylpyrrolidines to the corresponding cyclic
amide12 and 2-nitromethyl products.13 The methods dis-
cussed here involve mild conditions and simple procedures
without using metal and other additives.14 Therefore the
present methodology is a good alternative to these reported
methods. Further systematic investigations of the reactions
and intermediates formed in situ under the present condi-
tions would lead to several new transformations useful in
organic synthesis.
Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1560185.
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References and Notes
(1) (a) Bharathi, P.; Periasamy, M. Org. Lett. 1999, 1, 857.
(b) Periasamy, M.; Jayakumar, K. N.; Bharathi, P. J. Org. Chem.
2005, 70, 5420. (c) Periasamy, M.; Kishorebabu, S. N.;
Jayakumar, K. N. Tetrahedron Lett. 2003, 44, 8939. (d) Srinivas,
G.; Periasamy, M. Tetrahedron Lett. 2002, 43, 2785.
(2) (a) Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012,
134, 5317. (b) Periasamy, M.; Srinivas, G.; Karunakar, G. V.;
Bharathi, P. Tetrahedron Lett. 1999, 40, 7577.
(3) De La Mare, H. E. J. Org. Chem. 1960, 25, 2114.
(4) (a) Min, C.; Sanchawala, A.; Seidel, D. Org. Lett. 2014, 16, 2756.
(b) Liu, W.; Liu, J.; Ogawa, D.; Nishihara, Y.; Guo, X.; Li, Z. Org.
Lett. 2011, 13, 6272.
(5) (a) Sridharan, V.; Suryavanshi, P. A.; Menendez, J. C. Chem. Rev.
2011, 111, 7157. (b) Jiang, X. X.; Wang, R. Chem. Rev. 2013, 113,
5515. (c) Fochi, M.; Caruana, L.; Bernardi, L. Synthesis 2014, 46,
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(6) (a) Brown, P. D.; Willis, A. C.; Sherburn, M. S.; Lawrence, A. L.
Angew. Chem. Int. Ed. 2013, 52, 13273. (b) Fustero, S.; Bello, P.;
Miro, J.; Sanchez-Rosello, M.; Maestro, M. A.; Gonzalez, J.; del
Pozo, C. Chem. Commun. 2013, 49, 1336.
Acknowledgment
We are thankful to the DST-SERB for support under J. C. Bose National
Fellowship and Green Chemistry (Grant No: SB/S5/GC-01/2014) pro-
grams to MP and for the DST support to the School of Chemistry un-
der the FIST and IRPHA programs. Support of the CSIR-HRDG to MP
by a research grant (No: 02(0176/14/EMR-II) and support of the UGC
under UPE and CAS programs to the School of Chemistry are also
gratefully acknowledged. G. A. Rao is thankful to the UGC (New Delhi)
for a research fellowship.
(7) Buswell, M.; Fleming, I. Chem. Commun. 2003, 202.
(8) Compound 2f was characterized by X-ray crystallography.
Crystal data for the compound 2f: Molecular formula:
C
22H26N2O2, MW = 350.45, triclinic, space group: P-1, a =
7.8794(11) Å, b = 15.1286(18) Å, c = 15.5179(16) Å, α =
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2231–2236

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G. A. Rao, M. Periasamy
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Synlett
93.763(9)°, β = 96.324(10)°, γ = 99.219(11)°, v = 1808.2(4) Å3, Z =
4, ρc = 1.287 mgm−3, μ = 0.083 mm–1, T = 293(2) K. Of the 12687
J = 7.4 Hz, 1 H), 5.03 (d, J = 7.6 Hz, 1 H), 3.70–3.81 (m, 2 H), 3.42–
3.55 (m, 2 H), 2.95–3.01 (m, 1 H), 2.70–2.77 (m, 1 H), 2.40 (s, 3
H), 2.39 (s, 3 H), 1.89–2.11 (m, 6 H). 13C NMR (100 MHz, CDCl3):
δ = 150.6, 145.7, 131.9, 131.2, 130.5, 127.0, 126.8, 126.5, 125.8,
121.8, 120.0, 118.5, 62.0, 58.9, 52.5, 51.5, 41.4, 29.6, 25.0, 24.1,
22.1, 19.6. HRMS: m/z [M + H]+ calcd for C22H26N2: 319.2175;
found: 319.2174.
reflections collected, 7375 reflections were unique (Rint
=
0.0459). Refinement on all data converged at R1 = 0.1669, wR2 =
0.1900 (CCDC deposition number: 1054950).
(9) Ochowski, J.; Peczynska-Czoch, W.; Pi-tka-Ottlik, M.;
Wojtowicz-Mlochowska, H. Open Catal. J. 2011, 4, 54.
(10) (a) Kerr, G. H.; Meth-Cohn, O.; Mullock, E. B.; Suschitzky, H. J.
Chem. Soc., Perkin Trans. 1 1974, 1614. (b) Swan, G. A.; Wilcock,
J. D. J. Chem. Soc., Perkin Trans. 1 1974, 885.
(11) Minakata, S.; Ohshima, Y.; Takemiya, A.; Ryu, I.; Komatsu, M.;
Ohshiro, Y. Chem. Lett. 1997, 26, 311.
(12) (a) Kundu, D.; Bhadra, S.; Mukherjee, N.; Sreedhar, B.; Ranu, B.
C. Chem. Eur. J. 2013, 19, 15759. (b) Yong, F.-F.; Teo, Y.-C.; Chua,
G.-L.; Lim, G.-S.; Lin, Y. Tetrahedron Lett. 2011, 52, 1169. (c) Ma,
F.; Xie, X.; Zhang, L.; Peng, Z.; Ding, L.; Zhang, Z. J. Org. Chem.
2012, 77, 5279. (d) Chen, Y.-J.; Chen, H.-H. Org. Lett. 2006, 8,
5609.
(13) (a) Girard, S. A.; Knauber, T.; Li, C.-J. Angew. Chem. Int. Ed. 2014,
53, 74. (b) Li, Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672.
(c) Hari, D. P.; König, B. Org. Lett. 2011, 13, 3852.
(14) General Experimental Procedure for the Preparation of N-
Aryl-Substituted Pyrrolydines 1: To a stirred solution of K2CO3
(5.52 g, 40 mmol), KI (0.17 g, 5 mol%) in MeCN (30 mL) under
nitrogen atmosphere, 1,4-dibromobutane (2.39 mL, 20 mmol)
and aryl amines (25 mmol) were added. The reaction mixture
was refluxed for 8 h. After completion of the reaction, the
solvent was evaporated and EtOAc (50 mL) and H2O (30 mL)
were added. The organic layer was separated and extracted
with EtOAc (20 mL). The combined organic layer was washed
with brine (50 mL), dried over Na2SO4, filtered and concen-
trated. The residue was purified by column chromatography on
silica gel (100–200 mesh) using hexane as eluent to isolate the
N-aryl-substituted pyrrolidines 1 in 82–89% yields.
10-Methyl-1-(p-tolyl)-2,3,3a,3b,4,5,6,11b-octahydro-1H-
dipyrrolo[1,2-a:3′,2′-c]quinoline (2c): colorless oil; yield: 0.10
g, 62%. IR (neat): 3063, 3014, 2964, 2866, 1600, 1496, 1430,
1293, 1096, 756, 712 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.09
(d, J = 8.0 Hz, 2 H), 7.03 (d, J = 8.0 Hz, 1 H), 6.99 (s, 1 H), 6.65 (d, J
= 8.0 Hz, 3 H), 4.41 (d, J = 8.0 Hz, 1 H), 3.69 (t, J = 8.0 Hz, 1 H),
3.49 (t, J = 8.0 Hz, 1 H), 3.29–3.36 (m, 1 H), 2.72–2.87 (m, 2 H),
2.38–2.44 (m, 1 H), 2.32 (s, 3 H), 2.12–2.25 (m, 6 H), 1.98–2.04
(m, 1 H), 1.73–1.86 (m, 2 H). 13C NMR (100 MHz, CDCl3): δ =
147.5, 145.0, 129.6, 128.8, 128.3, 127.6, 127.5, 125.6, 112.8,
112.0, 65.1, 60.1, 49.7, 48.3, 47.6, 31.9, 30.6, 22.3, 20.9, 20.3.
HRMS: m/z [M + H]+ calcd for C22H26N2: 319.2175; found:
319.2174.
1-(2,4-Dimethylphenyl)-8,10-dimethyl-2,3,3a,3b,4,5,6,11b-
octahydro-1H-dipyrrolo[1,2-a:3′,2′-c]quinoline (2d): color-
less oil; yield: 0.10 g, 59%. IR (neat): 2953, 2915, 2866, 1605,
1496, 1474, 1342, 1288, 866, 816 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.06 (s, 1 H), 7.00 (d, J = 8.0 Hz, 1 H), 6.92 (d, J = 8.0
Hz, 1 H), 6.77 (s, 1 H), 6.72 (s, 1 H), 4.85 (d, J = 7.6 Hz, 1 H), 3.75–
3.79 (m, 1 H), 3.66–3.72 (m, 1 H), 3.40–3.44 (m, 2 H), 2.87–2.93
(m, 1 H), 2.64–2.69 (m, 1 H), 2.34 (s, 9 H), 2.17–2.23 (m, 1 H),
2.10 (s, 3 H), 1.95–2.06 (m, 3 H), 1.84–1.92 (m, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 149.0, 143.1, 132.7, 131.8, 131.6, 131.2,
127.8, 127.7, 127.4, 127.1, 125.7, 120.6, 62.9, 58.8, 52.7, 52.5,
41.6, 29.7, 25.7, 24.1, 21.8, 20.7, 20.4, 19.2. HRMS: m/z [M + H]+
calcd for C24H30N2: 347.2488; found: 347.2483.
3-(Naphthalen-1-yl)-2,3,3a,11,12,13,13a,13b-octahydro-1H-
benzo[h]dipyrrolo[1,2-a:3′,2′-c]quinoline (2e): white solid;
yield: 0.15 g, 78%; mp 203–205 °C. IR (KBr): 3036, 2953, 2926,
General Experimental Procedure for the Preparation of Tet-
racyclic Amines 2a–f: A mixture of 1 (1 mmol), T-HYDRO (0.55
mL, 4 mmol), NaOAc∙3H2O (0.54 g, 4 mmol) in cyclohexane (2
mL) was stirred for 24 h at 70 °C. After completion of the reac-
tion, the solvent was evaporated and EtOAc (10 mL) and H2O (5
mL) were added. The combined organic layer was washed with
brine (10 mL), dried over Na2SO4, filtered and concentrated. The
residue was purified by column chromatography on silica gel
(100–200 mesh) using EtOAc–hexane (1:5) as eluent to get tet-
racyclic amines.
1-Phenyl-2,3,3a,3b,4,5,6,11b-octahydro-1H-dipyrrolo[1,2-
a:3′,2′-c]quinoline (2a): white solid; yield: 0.11 g, 72%; mp
154–156 °C. IR (KBr): 3047, 2970, 2838, 2805, 1611, 1501, 1479,
1358, 740 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.29–7.38 (m, 3
H), 7.13–7.16 (m, 1 H), 6.85–6.87 (m, 2 H), 6.72–6.77 (m, 1 H),
6.54–6.59 (m, 1 H), 6.43–6.46 (m, 1 H), 5.16 (d, J = 6.4 Hz, 1 H),
3.77–3.79 (m, 1 H), 3.51–3.55 (m, 1 H), 3.29–3.44 (m, 3 H),
2.52–2.59 (m, 1 H), 2.14–2.20 (m, 1 H), 1.95–2.13 (m, 3 H),
1.84–1.92 (m, 1 H), 1.69–1.79 (m, 1 H). 13C NMR (100 MHz,
CDCl3): δ = 148.9, 143.2, 129.4, 128.8, 128.1, 123.0, 115.8, 115.5,
111.3, 110.3, 57.5, 56.6, 47.4, 46.6, 40.1, 30.3, 23.4, 23.3. HRMS:
m/z [M + H]+ calcd for C20H22N2: 291.1862; found: 291.1860.
8-Methyl-1-(o-tolyl)-2,3,3a,3b,4,5,6,11b-octahydro-1H-
dipyrrolo[1,2-a:3′,2′-c]quinoline (2b): colorless oil; yield: 0.11
g, 69%. IR (neat): 3063, 3024, 2926, 2871, 1599, 1495, 1468,
1254, 1106, 761, 723 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.17–
7.27 (m, 2 H), 6.95–7.01 (m, 3 H), 6.86 (d, J = 7.6 Hz, 1 H), 6.59 (t,
2855, 1556, 1512, 1463, 1397, 1277, 1107, 800, 778, 762 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.19 (d, J = 8.4 Hz, 1 H), 8.01 (d, J
= 8.4 Hz, 1 H), 7.71–7.74 (m, 2 H), 7.67 (d, J = 8.0 Hz, 1 H), 7.57
(t, J = 7.6 Hz, 2 H), 7.32–7.42 (m, 2 H), 7.27 (t, J = 7.6 Hz, 1 H),
7.05 (t, J = 7.6 Hz, 1 H), 6.80 (d, J = 8.8 Hz, 1 H), 6.57 (d, J = 8.8 Hz,
1 H), 4.46 (d, J = 5.6 Hz, 1 H), 4.16–4.21 (m, 1 H), 3.93–3.98 (m, 1
H), 3.53–3.59 (m, 1 H), 3.27–3.33 (m, 1 H), 3.13–3.18 (m, 1 H),
2.37–2.53 (m, 2 H), 2.20–2.26 (m, 1 H), 2.00–2.15 (m, 3 H),
1.87–1.94 (m, 1 H). 13C NMR (100 MHz, CDCl3): δ = 147.6, 142.8,
134.4, 134.0, 132.9, 128.4, 127.9, 127.3, 125.7, 125.5, 125.2,
125.2, 124.8, 124.6, 124.5, 123.9, 121.6, 119.2, 118.9, 63.2, 59.4,
55.0, 53.8, 36.0, 29.2, 27.5, 23.7. HRMS: m/z [M + H]+ calcd for
C
28H26N2: 391.2175; found: 391.2169.
8-Methoxy-1-(2-methoxyphenyl)-2,3,3a,3b,4,5,6,11b-octa-
hydro-1H-dipyrrolo[1,2-a:3′,2′-c]quinoline (2f): white solid;
yield: 0.11 g, 64%; mp 120–122 °C. IR (KBr): 3058, 2964, 2960,
2855, 1600, 1507, 1458, 1227, 1036, 789, 734 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 6.85–6.90 (m, 3 H), 6.61–6.67 (m, 2 H),
6.44–6.49 (m, 2 H), 5.63–5.66 (m, 1 H), 3.92 (s, 3 H), 3.82–3.86
(m, 1 H), 3.78 (s, 3 H), 3.51–3.59 (m, 2 H), 3.13–3.20 (m, 2 H),
2.80–2.86 (m, 1 H), 1.88–2.06 (m, 5 H), 1.73–1.79 (m, 1 H). 13C
NMR (100 MHz, CDCl3): δ = 150.6, 148.2, 138.6, 137.4, 126.6,
121.8, 121.3, 119.9, 118.3, 117.6, 111.3, 110.9, 59.7, 59.6, 55.9,
55.5, 51.7, 47.8, 41.2, 28.8, 23.7, 23.4. HRMS: m/z [M + H]+ calcd
for C22H26N2O2: 351.2073; found: 351.2072.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2231–2236

2236
G. A. Rao, M. Periasamy
Letter
Synlett
General Experimental Procedure for the Preparation of
Cyclic Amides 3: A mixture of the amine 1 (1 mmol), T-HYDRO
(0.55 mL, 4 mmol), t-BuOK (0.45 g, 4 mmol) in MeOH (2 mL)
was stirred for 24 h at 70 °C. After completion of the reaction,
the solvent was evaporated and EtOAc (10 mL) and H2O (5 mL)
were added. The organic layer was washed with brine (10 mL),
dried over Na2SO4, filtered and concentrated. The residue was
purified by column chromatography on silica gel (100–200
mesh) using EtOAc–hexane (15:100) as eluent to isolate cyclic
amides 3.
1-Phenylpyrrolidin-2-one (3a): white solid; yield: 0.14 g, 85%;
mp 70–72 °C. IR (KBr): 3419, 3057, 2964, 2937, 1687, 1583,
1539, 1408, 1309 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J
= 8.4 Hz, 2 H), 7.33–7.38 (m, 2 H), 7.11–7.15 (m, 1 H), 3.83 (t, J =
7.0 Hz, 2 H), 2.58 (t J = 8.0 Hz, 2 H), 2.09–2.16 (m, 2 H). 13C NMR
(100 MHz, CDCl3): δ = 174.1, 139.3, 128.6, 124.3, 119.8, 48.6,
32.6, 17.8.
General Experimental Procedure for the Preparation of 2-
(Nitromethyl)-1-phenylpyrrolidine 4: A mixture of the amine
1 (1 mmol), T-HYDRO (0.55 mL, 4 mmol), t-BuOK (0.45 g, 4
mmol), nitromethane (0.5 mL) in MeOH (2 mL) was stirred for
48 h at 70 °C. After completion of the reaction, the solvent was
evaporated. EtOAc (10 mL) and H2O (5 mL) were added and the
organic layer was washed with brine (10 mL), dried over
Na2SO4, filtered and concentrated. The residue was purified by
column chromatography on silica gel (100–200 mesh) using
EtOAc–hexane (5:100) as eluent to isolate 2-nitromethyl
arylpyrrolidine products 4.
2-(Nitromethyl)-1-phenylpyrrolidine (4a): yellow oil; yield:
0.15 g, 74%. IR (neat): 2966, 2914, 2838, 1593, 1541, 1498, 1358,
1260, 1173, 990, 743 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.27–
7.34 (m, 2 H), 6.79–6.83 (m, 1 H), 6.73 (d, J = 8.0 Hz, 2 H), 4.63–
4.66 (m, 1 H), 4.42–4.46 (m, 1 H), 4.18–4.24 (m, 1 H), 3.49–3.54
(m, 1 H), 3.20–3.27 (m, 1 H), 2.07–2.17 (m, 4 H). 13C NMR (100
MHz, CDCl3): δ = 145.8, 130.0, 117.4, 112.0, 111.7, 75.8, 57.4,
48.1, 29.3, 22.8.
1-(p-Tolyl)pyrrolidin-2-one (3b): white solid; yield: 0.15 g,
88%; mp 90–92 °C. IR (KBr): 2964, 2932, 2871, 1693, 1512,
1392, 1304, 1233, 833 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.50
(d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.4 Hz, 2 H), 3.84 (t, J = 7.0 Hz, 2
2-(Nitromethyl)-1-(p-tolyl)pyrrolidine (4b): yellow oil; yield:
0.17 g, 79%. IR (neat): 2946, 2896, 2841, 1611, 1541, 1503, 1361,
1228, 1155, 807 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.07–7.19
(m, 2 H), 6.59–6.71 (m, 2 H), 4.58–4.72 (m, 1 H), 4.48–4.53 (m, 1
H), 4.13–4.29 (m, 1 H), 3.48–3.53 (m, 1 H), 3.19–3.25 (m, 1 H),
2.31 (s, 3 H), 2.07–2.19 (m, 4 H). 13C NMR (100 MHz, CDCl3): δ =
143.7, 130.2, 126.5, 112.0, 76.0, 57.6, 48.3, 29.3, 22.9, 20.2.
H), 2.60 (t, J = 8.2 Hz, 2 H), 2.34 (s, 3 H), 2.12–2.19 (m, 2 H). 13
C
NMR (100 MHz, CDCl3): δ = 173.9, 136.8, 134.1, 129.2, 120.0,
48.8, 32.6, 20.8, 17.9.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2015, 26, 2231–2236