Simple and convenient approach for synthesis of tetrahydroquinoline derivatives and studies on aza-Cope rearrangement

Article abstract of DOI:10.1080/00397911.2010.493258

A simple and novel synthesis of 1,2,3,4-tetrahydroquinoline derivatives by polyphosphoric acid-assisted reaction of N-aryl allyl anilines prepared from anilines has been reported. The generality and scope of the approach has been demonstrated by extending it to the synthesis of 1,2,5,6-tetrahydro-4H- pyrrolo[3,2,1-ij]quinoline (lilolidine) and 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2, 1-ij]quinoline (julolidine). Further, Lewis acid- mediated aza-Cope rearrangement of various N-aryl allyl anilines has been demonstrated.

Full text of DOI:10.1080/00397911.2010.493258

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Simple and Convenient Approach
for Synthesis of Tetrahydroquinoline
Derivatives and Studies on Aza-Cope
Rearrangement
V. S. Prasada Rao Lingam a b , Abraham Thomas a , Khagga Mukkanti b
& Balasubramanian Gopalan a
a Medicinal Chemistry Division, Glenmark Research Centre, MIDC,
Mahape, Mumbai, India
b Institute of Science and Technology, Jawaharlal Nehru
Technological University, Hyderabad, India
Version of record first published: 29 Apr 2011.
To cite this article: V. S. Prasada Rao Lingam , Abraham Thomas , Khagga Mukkanti
& Balasubramanian Gopalan (2011): Simple and Convenient Approach for Synthesis of
Tetrahydroquinoline Derivatives and Studies on Aza-Cope Rearrangement, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, 41:12, 1809-1828
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Synthetic Communications1, 41: 1809–1828, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.493258
SIMPLE AND CONVENIENT APPROACH FOR
SYNTHESIS OF TETRAHYDROQUINOLINE
DERIVATIVES AND STUDIES ON AZA-COPE
REARRANGEMENT
V. S. Prasada Rao Lingam,1,2 Abraham Thomas,1
Khagga Mukkanti,2 and Balasubramanian Gopalan1
1Medicinal Chemistry Division, Glenmark Research Centre, MIDC,
Mahape, Mumbai, India
2Institute of Science and Technology, Jawaharlal Nehru Technological
University, Hyderabad, India
GRAPHICAL ABSTRACT
Abstract A simple and novel synthesis of 1,2,3,4-tetrahydroquinoline derivatives by poly-
phosphoric acid–assisted reaction of N-aryl allyl anilines prepared from anilines has been
reported. The generality and scope of the approach has been demonstrated by extending
it to the synthesis of 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline (lilolidine) and
2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline (julolidine). Further, Lewis acid–
mediated aza-Cope rearrangement of various N-aryl allyl anilines has been demonstrated.
Keywords Aza-Cope rearrangement; julolidine; lilolidine; polyphosphoric acid;
1,2,3,4-tetrahydroquinolines
INTRODUCTION
1,2,3,4-Tetrahydroquinoline (THQ) derivatives continue to attract interest
because of their importance as key structural elements in several natural products[1]
and their uses as farnesyltransferase[2] inhibitors for antimalarial treatment, cardio-
vascular agents,[3] antihypertesive agents,[4] thrombin inhibitors[5] for anticoagulants,
multidrug-resistant (MDR)[6] agents, and antagonists of transient receptor potential
vanilloid receptor-1 (TRPV1).[7] The THQ moiety is also a core structure in various
fused tricyclic compounds, such as 1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline
Received January 25, 2010.
Address correspondence to Khagga Mukkanti, Institute of Science and Technology, Jawaharlal
Nehru Technological University, Hyderabad 500 072, India. E-mail: kmukkanti@gmail.com
1809

1810
V. S. P. R. LINGAM ET AL.
(lilolidine)[8] and 2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline (julolidine).[9]
Julolidine has been used as an intermediate to synthesize various labeling reagents
for carboxylic acids,[10] amines,[11] and laser dyes.[12] Therefore, the preparation of
these nitrogen-containing heterocyclic compounds has gained considerable attention
in recent years.
The traditional, simple, and very popular synthetic methods for THQs involve
the reduction of quinolines,[13] 1,2-dihydroquinolines,[14] or 3,4-dihydroquinolin-
2(1H)-one[15] over various transition metals and transition-metal complexes.
Other less popular synthetic approaches are intramolecular Friedel–Crafts reac-
tion[16] of 4-anilino-2-butanols, Michael–aldol addition[17] of o-carbonylanilines with
a,b-unsaturated carbonyl compounds, oxidation of N-methylanilines,[18] reaction of
a-aminoalkylbenzotriazole[19] with alkenes, and reaction of Schiff base.[20] All of
these methods have some good advantages but also have several drawbacks, such
as long reaction times, tedious workup procedures, occurrence of several side reac-
tion products, and use of expensive transition metals. Therefore, the search
continues for a better and convenient method for the synthesis of THQs in terms
of operational simplicity, economic viability, and greater selectivity.
RESULTS AND DISCUSSION
In this article, we report our results on the synthesis of substituted Cope
rearranged anilines, THQs, lilolidine, and julolidine from substituted N-allylanilines.
As outlined in Scheme 1, the required starting materials 2a–i for this study were
synthesized by reductive amination of trans-cinnamaldehyde with anilines 1a–i using
sodium triacetoxyborohydride in a mixture of acetic acid and 1,2-dichloroethane.
The allyl anilines 2j–t bearing additional substitutions on the nitrogen were prepared
by alkylation of N-substituted anilines 1j–l, indoline (1m), and THQ (1n) with
various substituted allyl chlorides[21] using anhydrous potassium carbonate in the
presence of catalytic amounts of sodium iodide in N,N-dimethylformamide.
Scheme 1. Studies on aza-Cope rearrangement.

TETRAHYDROQUINOLINE AND AZA-COPE REARRANGEMENT
1811
Attempted amino-Claisen rearrangement of 2a by pyrolysis[22] at 250–270 ꢀC
for 2 h under solvent-free conditions resulted in a tarry material, which on chromato-
graphic purification yielded the starting aniline (1a) in 40% isolated yield, probably
formed via cleavage of C-N bond at high temperature. Refluxing a solution of 2a in
diphenyl ether (ꢁ250 ꢀC) resulted in an unidentifiable more polar product along with
the unreacted allyl aniline 2a. Attempted rearrangement of 2a using 2N sulfuric
acid[22] at 120 ꢀC for 12 h resulted in the formation of sulfate salt quantitatively.
Compound 2a on refluxing in tetrahydrofuran (Table 1, entry 1) for 36 h in the pres-
ence of borontrifluoride etherate[23] (2 equivalents) resulted in a mixture of aza-Cope
rearranged anilines 3a and 4a in 8% and 15% yields respectively but no Claisen rear-
ranged product 5a, as shown in Scheme 1. Increasing the reaction temperature by
using 1,4-dioxane resulted in reduction of reaction time to 8 h with significantly
improved yields of up to 28% of 3a and 41% of 4a (Table 1, entry 2). To investigate
the scope of this rearrangement, different Lewis acids such as AlCl3, ZnCl2, FeCl3,
and AgBF4 were tried, but Claisen rearranged products 5a–g were not obtained with
any of the Lewis acids and resulted in poor yields of 3a and 4a (Table 1, entries 3–7).
From Table 1, it is evident that boron trifluoride is the best catalyst in terms of pro-
duct yields. To further explore the scope of aza-Cope rearrangement, a variety of
fluoro and N-alkyl substituted allyl anilines were subjected to this reaction, although
the Claisen rearranged products 5a–g were not observed in all the cases studied. The
details of these reaction conditions and the product distributions are summarized in
Table 1.
After several experiments, in contrast to other Lewis acids, the compound 2a,
on treatment with excess polyphosphoric acid at 100 ꢀC under a nitrogen atmosphere
for 10 min, formed 4-phenyl-1,2,3,4-tetrahydroquinoline (6a) in 71% isolated yield as
shown in Scheme 2 (physical and spectral characteristics are comparable with the
literature data[15]). No trace of Claisen rearranged product (5a) was detected in
any of these examples.
With the viable strategy in place for the synthesis of THQ derivatives, we sub-
jected various N-allyl anilines to the described reaction conditions, and the results
are given in Table 2. The reaction was found to be very good with N-alkyl-N-
allylaniline (Table 2, entries 10–12), and electron-donating group substitutions on
aniline (Table 2, entries 3–5) showed good yields. Anilines with electron–withdrawing
group, for example, nitro (Table 2, entries 8 and 9), resulted in deallylation only,
with no THQ formation. Both ortho and para fluorosubstituted aniline (Table 2,
entries 2 and 6) provided moderate yields, but difluoroaniline derivative (Table 2,
entry 7) was found to give lower yields as a result of cleavage of quaternary
ammonium salts to corresponding aniline and allyl cation before its cyclization.
The same conditions were applied to easily synthesized N-allylaniline bearing a
substitution on nitrogen, which also underwent a facile cyclization; with a view to
synthesize polynuclear nitrogen-containing heterocycles. The N-allylindolines (2m
and 2n) cleanly afforded the corresponding 6-aryl-1,2,5,6-tetrahydro-4H-
pyrrolo[3,2,1-ij]quinolines (6-aryl-lilolidine, 6m and 6n) in good yields as shown in
Scheme 3.
Similarly, N-allyl-1,2,3,4-tetrahydroquinilines 2o–t, when subjected to cycliza-
tion in the presence of polyphosphoric acid (PPA) at 100–110 ꢀC for 10–15 min,
afforded the desired 1-aryl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline

1812
V. S. P. R. LINGAM ET AL.
Table 1. Lewis acid–mediated aza-Cope rearrangement of allyl anilines (2) to 3 and 4
Product
Entry Substrate
Catalysts
Solvent
Time (h)
3
4
1
BF3 ꢂ Et2O THF
36
2
3
4
5
6
7
2a
2a
2a
2a
2a
2a
BF3 ꢂ Et2O 1,4-Dioxane
8
0.5
6
3a (28%)
complex mixture
3a (19%)
4a (41%)
AlCl3
AlCl3
ZnCl2
FeCl3
AgBF4
Neat
Dichloroethane
Xylene
4a (31%)
4a (10%)
—
18
24
10
—
—
—
Dichloroethane
Dichloroethane
4a (5%)
8
BF3 ꢂ Et2O 1,4-Dioxane
10
9
BF3 ꢂ Et2O 1,4-Dioxane
8
8
—
—
10
BF3 ꢂ Et2O 1,4-Dioxane
11
12
13
BF3 ꢂ Et2O 1,4-Dioxane
BF3 ꢂ Et2O 1,4-Dioxane
BF3 ꢂ Et2O 1,4-Dioxane
8
10
14
—
—

TETRAHYDROQUINOLINE AND AZA-COPE REARRANGEMENT
1813
Scheme 2. Synthesis of 1,2,3,4-tetrahydroquinolines.
(1-aryl-julolidines[24]) 6o–t (Scheme 4) in fairly good yields, demonstrating the scope
of the approach, and the results obtained in all these reactions are summarized in
Table 3.
Table 2. Synthesis of 4-phenyl-1,2,3,4-tetrahydroquinoline
Entry
Allylaniline
Products
Yield (%)a
1
2a
71
2
3
4
5
2b
52
68
66
85
(Continued )

1814
V. S. P. R. LINGAM ET AL.
Table 2. Continued
Entry
Allylaniline
Products
Yield (%)a
6
7
2f
58
2g
30
8
Loss of allyl
0
9
Loss of allyl
0
10
2j
88
11
12
2k
84
85
2l
aAll reactions completed within 10–15 min under a nitrogen atmosphere.

TETRAHYDROQUINOLINE AND AZA-COPE REARRANGEMENT
1815
Scheme 3. Synthesis of 6-aryl-lilolidines.
Scheme 4. Synthesis of 1-aryl-julolidines.
Mechanism of Aza-Cope Rearrangements
The possible reaction pathways for these rearrangements based on these results
and literature reports[25] are discussed herein. To the best of our knowledge, the pro-
posed [3,3] rearrangement mechanism is essentially a charge-accelerated reaction, as
given in Scheme 5. Thus, an initial aniline-BF3 complex (A) can either cleave to ani-
line with loss of allyl cation and intermolecular allyl transfer, or undergo [3,3]
rearrangement through a charge-delocalized transition state (B) to the ortho imine
intermediate (C). The enolization of C and deprotonation of boron complex to Clai-
sen product (5a) usually occurs rapidly with respect to other potential rearrange-
ments in this species, but if the [3,3] migration terminus does not bear a hydrogen,
the ortho imine (C) once again either undergoes [3,3] rearrangement leading to for-
mation of para imine (D), which on enolization gives thermodynamically more stable
Cope rearranged aniline (4a), or undergoes [1,2] migration to form meta imine (E).
The unstable intermediate (E) rearranges to more stable ortho imine (D) or para
imine (F) via [3,3]-sigmatropic rearrangement followed by deprotonation of the
boron complex to give Cope anilines 4a and 3a, respectively. The formation of
Claisen rearranged product (6a) or 1,2,3,4-tetrahydroquinolines (5a) was not
observed in any of the Lewis acid cases studied.
CONCLUSION
This paper highlights the utility of polyphosphoric acid in cyclization of
N-aryl allyl anilines. By employing this approach, 4-phenyl-1,2,3,4-tetrahydroquino-
lines, 6-aryl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinolines, and 4-aryl-2,3,6,7-
tetrahydro-1H,5H-pyrido[3,2,1-ij]quinolines were prepared from easily accessible

1816
V. S. P. R. LINGAM ET AL.
Table 3. Synthesis of 1-aryl-julolidines
Entry
Allylaniline
Products
Yield (%)a
1
69
2
70
3
74
4
65
5
63
(Continued )

TETRAHYDROQUINOLINE AND AZA-COPE REARRANGEMENT
1817
Table 3. Continued
Entry
Allylaniline
Products
Yield (%)a
6
71
Scheme 5. Mechanism of Cope rearrangements.
3-arylprop-2-en-1-yl amine derivatives. We believe that this methodology would be a
valuable addition to the existing methods for the synthesis of polynuclear nitrogen-
containing heterocycles. BF3 ꢂ Et2O-mediated Cope rearrangement of N-aryl allyl
anilines also has been established with moderate yields.
EXPERIMENTAL
General Procedure for Preparation of N-Allylanilines
(Reductive Amination)
Sodium triacetoxyborohydride (2 equivalent) was added to a stirred solution of
anilines (1 equivalent), trans-cinnamaldehyde (1 equivalent), and acetic acid

1818
V. S. P. R. LINGAM ET AL.
(1 equivalent) in 1,2-dichloroethane (30 mL=g), and the mixture was stirred at room
temperature until both the starting materials were completely consumed (5–10 h) as
determined by thin-layer chromatography (TLC; 20% EtOAc in n-hexane). The reac-
tion mixture was slowly quenched with aqueous sodium bicarbonate solution and
diluted with chloroform (50 mL). The layers were separated, and the aqueous layer
was extracted with chloroform (25 mL). The combined organic layers were washed
with water (3 ꢃ 100 mL) followed by brine (50 mL) and dried over anhydrous sodium
sulfate. The residue obtained after evaporation of the solvent was purified by
silica-gel column chromatography using a mixture of 15–30% of EtOAc in petroleum
ether as eluent to afford the title compounds.
Selected Data for 2a–2i
N-[(2E)-3-Phenylprop-2-en-1-yl]aniline (2a). Oil; IR (neat) 3413, 3059,
1
2924, 1601, 1493, 1452, 1324, 1180, 1069, 1028 cmꢄ1; H NMR (300 MHz, CDCl3)
d 3.82 (br s, 1H, exchangeable with D2O), 3.93 (d, J ¼ 5.7 Hz, 2H), 6.33 (dt,
J ¼ 4.5, 5.7 Hz, 1H), 6.58–6.73 (m, 4H), 7.14–7.21 (m, 3H), 7.26–7.36 (m, 4H); MS
m=z (þ cAPCI): 209.56 (M)þ (209.29 calcd. for C15H15N).
2-Fluoro-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2b). Off-white solid; mp
56–58 ꢀC; IR (KBr) 3430, 3057, 2847, 1620, 1513, 1446, 1334, 1248, 1187, 1113,
1
966 cmꢄ1; H NMR (300 MHz, CDCl3) d 3.70 (br s, 1H, exchangeable with D2O),
3.96 (d, J ¼ 5.4 Hz, 2H), 6.30 (dt, J ¼ 4.5, 5.4 Hz, 1H), 6.58–6.50 (m, 2H), 6.73 (t,
J ¼ 7.8 Hz, 1H), 6.92–6.99 (m, 2H), 7.18–7.36 (m, 5H); MS m=z (þc APCI): 228.26
(M þ H)þ (227.28 calcd. for C15H14FN).
2-Methyl-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2c). Off-white solid; mp
40–42 ꢀC; IR (neat) 3435, 3054, 2915, 1605, 1512, 1447, 1317, 1255, 1129, 1052 cmꢄ1
;
1H NMR (300 MHz, CDCl3) d 2.16 (s, 3H), 3.65 (br s, 1H, exchangeable with D2O),
3.97 (d, J ¼ 6.0 Hz, 2H), 6.35 (dt, J ¼ 4.2, 5.4 Hz, 1H), 6.58–6.68 (m, 3H), 7.09–7.13
(m, 2H), 7.18–7.37 (m, 5H); MS m=z (þ cAPCI): 224.14 (M þ H)þ (223.31 calcd. for
C16H17N).
2-Methoxy-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2d). Off-white solid;
mp 60–62 ꢀC; IR (KBr) 3418, 3062, 1601, 1512, 1452, 1245, 1222, 1123, 1026
1
871 cmꢄ1; H NMR (300 MHz, CDCl3) d 3.84 (s, 3H), 3.94 (dd, J ¼ 0.9, 4.5 Hz,
2H), 4.45 (br s, 1H, exchangeable with D2O), 6.33 (dt, J ¼ 3.0, 4.5 Hz, 1H), 6.61
(d, J ¼ 17.7 Hz, 1H), 6.66–6.69 (m, 2H), 6.67 (d, J ¼ 7.8 Hz, 1H), 6.85 (td, J ¼ 0.9,
6.3 Hz,1H), 7.17–7.36 (m, 5H); 13C NMR (75 MHz, CDCl3) d 45.85, 55.30, 109.22,
110.03, 116.50, 121.11, 12613 (2C), 127.03, 127.23, 128.34 (2C), 131.09, 136.73,
137.75, 146.63; MS m=z (þc APCI): 240.09 (M þ H)þ (239.31 calcd. for C16H17NO).
4-Ethyl-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2e). Oil; IR (KBr) 3412,
5057, 2961, 1617, 1519, 1449, 1316, 1258, 1183, 1127, 966 cmꢄ1 1H NMR
;
(300 MHz, CDCl3) d 1.18 (t, J ¼ 7.5 Hz, 3H), 2.54 (q, J ¼ 7.2 Hz, 2H), 3.70 (br s,
1H, exchangeable with D2O), 3.90 (d, J ¼ 5.7 Hz, 2H), 6.32 (dt, J ¼ 3.3, 4.5 Hz,
1H), 6.55–6.61 (m, 3H), 7.01 (d, J ¼ 8.7 Hz, 2H), 7.17–7.35 (m, 5H). MS m=z
(-cAPCI): 236.51 (M ꢄ H)ꢄ (237.34 calcd. for C17H19N).

TETRAHYDROQUINOLINE AND AZA-COPE REARRANGEMENT
1819
4-Fluoro-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2f). Off-white solid; mp
1
74–76 ꢀC; IR (KBr) 3305, 2915, 1508, 1311, 1221, 1116 cmꢄ1; H NMR (300 MHz,
CDCl3) d 3.73 (br s, 1H, exchangeable with D2O), 3.88 (d, J ¼ 5.4 Hz, 2H), 6.29
(dt, J ¼ 4.2, 6.0 Hz, 1H), 6.55–6.62 (m, 3H), 6.87 (t, J ¼ 8.7 Hz, 2H), 7.18–7.35 (m,
5H); MS m=z (-c APCI): 226.36 (M ꢄ H)ꢄ (227.28 calcd. for C15H14FN).
2,4-Difluoro-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2g). Off-white solid;
mp 68–70 ꢀC; IR (KBr) 3419, 3062, 2824, 1600, 1519, 1427, 1221, 1200, 1142,
1
1065, 960 cmꢄ1; H NMR (300 MHz, CDCl3) d 3.15 (br s, 1H, exchangeable with
D2O), 3.92 (d, J ¼ 6.0 Hz, 2H), 6.28 (dt, J ¼ 4.5, 5.7 Hz, 1H), 6.60 (d, J ¼ 16.8 Hz,
1H), 6.47–6.80 (m, 3H), 7.18 (m, 5H); MS m=z (-c APCI): 244.51 (M ꢄ H)ꢄ
(245.27 calcd. for C15H13F2N).
2-Nitro-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2h). Yellow solid; mp
68–70 ꢀC; IR (KBr) 3394, 2850, 1620, 1567, 1513, 1359, 1258, 1153 cmꢄ1 1H
;
NMR (300 MHz, DMSO-d6) d 4.21 (t, J ¼ 5.1 Hz, 2H), 6.39 (dt, J ¼ 5.1, 5.7 Hz,
1H), 6.58–6.72 (m, 2H), 7.05 (d, J ¼ 8.4 Hz, 1H), 7.21 (d, J ¼ 6.9 Hz, 1H),
7.25–7.41 (m, 4H), 7.49 (t, J ¼ 7.8 Hz, 1H), 8.08 (d, J ¼ 8.4 Hz, 1H), 8.41 (br s,
1H, exchangeable with D2O); MS m=z (þc APCI): 255.23 (M þ H)þ (254.28 calcd.
for C15H14N2O2).
4-Nitro-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2i). Yellow solid; mp
1
142–144 ꢀC; IR (KBr) 3357, 1602, 1537, 1471, 1325, 1295, 1108 cmꢄ1; H NMR
(300 MHz, DMSO-d6) d 4.06 (t, J ¼ 5.1 Hz, 2H), 6.35 (dt, J ¼ 5.2, 5.7 Hz, 1H),
6.59 (d, J ¼ 15.9 Hz, 1H), 6.70 (d, J ¼ 9.3 Hz, 2H), 7.23–7.43 (m, 5H), 7.60 (br s,
1H, exchangeable with D2O), 8.00 (d, J ¼ 9.3 Hz, 2H); MS m=z (þc APCI): 255.20
(M þ H)þ (254.28 calcd. for C15H14N2O2).
General Procedure for Preparation of N-Alkyl-N-allylanilines
Anhydrous potassium carbonate (1.5 equivalent) was added to a well-stirred
solution of N-alkyl-anilines, lindoline, or 1,2,3,4-tetrahydroquinilines (1 equivalent)
in dry dimethylformamide (DMF; 10 mL=g), followed by a catalytic amount of
sodium iodide (0.01 equivalents), under an atmosphere of nitrogen. Allyl chloride
(1–1.2 equivalent) was added, and the reaction mixture was stirred until the com-
pletion of starting materials (18–24 h) as judged by TLC (10% EtOAc in n-hexanes).
The reaction mixture was partitioned between EtOAc and water, and the layers were
separated. The aqueous layer was extracted with EtOAc, and the combined organic
extracts were washed with water and brine and dried over anhydrous sodium sulfate.
The organic layer was concentrated under reduced pressure to afford crude products.
The crude was purified on silica-gel column chromatography using a mixture of
5–15% of EtOAc in petroleum ether as eluent to afford the title compounds.
Selected Data for 2j–2t
N-Methyl-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2j). Sticky solid; IR
1
(neat) 3025, 2926, 1598, 1505, 1447, 1353, 1200, 1117, 1034, 963 cmꢄ1; H NMR
(300 MHz, CDCl3) d 2.96 (s, 3H), 4.06 (d, J ¼ 4.8 Hz, 2H), 6.24 (dt, J ¼ 5.1,

1820
V. S. P. R. LINGAM ET AL.
5.4 Hz, 1H), 6.49 (d, J ¼ 15.0 Hz, 1H), 6.69 (t, J ¼ 6.9 Hz, 1H), 6.76 (d, J ¼ 7.8 Hz,
2H), 7.19–7.33 (m, 7H); MS m=z (þ cAPCI): 224.12 (M þ H)þ (223.31 calcd. for
C16H17N).
N-Ethyl-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2k). White solid; mp
1
48–50 ꢀC; IR (KBr) 3050, 2967, 1594, 1503, 1444, 1349, 1270, 1178, 966 cmꢄ1; H
NMR (300 MHz, CDCl3) d 1.19 (t, J ¼ 7.5 Hz, 3H), 3.42 (q, J ¼ 7.2 Hz, 2H), 4.04
(d, J ¼ 4.8 Hz, 2H), 6.24 (dt, J ¼ 4.5, 4.8 Hz, 1H), 6.49 (d, J ¼ 15.6 Hz, 1H), 6.65 (t,
J ¼ 6.9 Hz, 1H), 6.72 (d, J ¼ 7.8 Hz, 2H), 7.16–7.33 (m, 5H); MS m=z (þ cAPCI):
238.09 (M þ H)þ (237.34 calcd. for C17H19N).
N-Benzyl-N-[(2E)-3-phenylprop-2-en-1-yl]aniline (2l). White solid; mp
110–112 ꢀC; IR (KBr) 3029, 2907, 1598, 1505, 1367, 1357, 1232, 1175, 970 cmꢄ1
;
1H NMR (300 MHz, CDCl3) d 4.16 (d, J ¼ 4.5 Hz, 2H), 4.59 (s, 2H), 6.26 (dt,
J ¼ 3.0, 4.5 Hz, 1H), 6.49 (d, J ¼ 15.6 Hz, 1H), 6.68 (t, J ¼ 7.5 Hz, 1H), 6.76 (d,
J ¼ 8.4 Hz, 2H), 7.15–7.33 (m, 12H); MS m=z (þc APCI): 300.14 (M þ H)þ
(299.41 calcd. for C22H21N).
1-[(2E)-3-Phenylprop-2-en-1-yl]indoline (2m). Viscous oil; IR (neat) 3024,
2844, 1606, 1487, 1459, 1356, 1266, 1223, 1155, 1022, 966 cmꢄ1; 1H NMR (300 MHz,
CDCl3) d 2.96 (t, J ¼ 8.1 Hz, 2H), 3.70 (t, J ¼ 8.1 Hz, 2H), 3.85 (d, J ¼ 6.0 Hz, 2H),
6.28 (dt, J ¼ 5.7, 6.0 Hz, 1H), 6.53–6.67 (m, 3H), 7.01–7.04 (m, 1H), 7.22–7.36 (m,
6H); MS m=z (þc APCI): 236.07 (M þ H)þ (235.32 calcd. for C17H17N).
1-[(2E)-3-(4-Fluorophenyl)prop-2-en-1-yl]indoline (2n). Off-white solꢄid1;
mp 59–60 ꢀC; IR (KBr) 3025, 2804, 1599, 1507, 1485, 1371, 1223, 1158, 969 cm
;
1H NMR (300 MHz, CDCl3) d 2.96 (t, J ¼ 7.8 Hz, 2H), 3.36 (t, J ¼ 8.4 Hz, 2H),
3.84 (d, J ¼ 5.7 Hz, 2H), 6.19 (dt, J ¼ 3.3, 6.6 Hz, 1H), 6.52–6.63 (m, 2H), 6.65 (t,
J ¼ 6.9 Hz, 1H), 6.94–7.08 (m, 4H), 7.28–7.33 (m, 2H); MS m=z (þ cAPCI): 254.12
(M þ H)þ (253.31 calcd. for C17H16FN).
1-[(2E)-3-Phenylprop-2-en-1-yl]-1,2,3,4-tetrahydroquinoline
IR (neat) 3060, 2930, 1633, 1574, 1496, 1329, 1277, 1155, 965 cmꢄ1
(2o). Oil;
1H NMR
;
(300 MHz, CDCl3) d 1.94–2.02 (m, 2H), 2.77 (t, J ¼ 6.3 Hz, 2H), 3.30 (t, J ¼ 5.7 Hz,
2H), 4.01 (d, J ¼ 4.5 Hz, 2H), 6.23 (dt, J ¼ 4.8, 5.4 Hz, 1H), 6.49–6.63 (m, 3H), 6.94
(d, J ¼ 7.2 Hz, 1H), 7.01 (t, J ¼ 7.8 Hz, 1H), 7.15–7.34 (m, 5H); 13C NMR (75 MHz,
CDCl3) d 22.37, 28.14, 49.09, 53.36, 110.92, 115.73, 122.33, 125.40, 126.11 (2C),
126.98, 127.14, 128.31 (2C), 128.81, 130.81, 136.73, 145.14; MS m=z (þc APCI):
250.15 (M þ H)þ (249.35 calcd. for C18H19N).
1-[(2E)-3-(3-Chlorophenyl)prop-2-en-1-yl]-1,2,3,4-tetrahydroquinoline (2p).
Oil; IR (neat) 2937, 1595, 1492, 1456, 1307, 1216, 1199, 1078 cmꢄ1 1H NMR
;
(300 MHz, CDCl3) d 1.97–2.02 (m, 2H), 2.78 (t, J ¼ 6.3 Hz, 2H), 3.30 (t, J ¼ 6.0 Hz,
2H), 4.01 (d, J ¼ 3.9 Hz, 2H), 6.24 (dt, J ¼ 1.2, 6.0 Hz, 1H), 6.45 (d, J ¼ 15.6 Hz, 1H),
6.57–6.60 (m, 2H), 6.95 (d, J ¼ 7.5 Hz, 1H), 7.01 (t, J ¼ 7.8 Hz, 1H), 7.17–7.20 (m,
3H), 7.31 (s, 1H). MS m=z (þcAPCI): 284.62 (M þ H)þ (283.79 calcd. for
C18H18ClN).
1-[(2E)-3-(4-Fluorophenyl)prop-2-en-1-yl]-1,2,3,4-tetrahydroquinoline (2q).
White solid; mp 45–47 ꢀC; IR (KBr) 3064, 2921, 1599, 1507, 1495, 1339, 1226,

TETRAHYDROQUINOLINE AND AZA-COPE REARRANGEMENT
1821
1159, 970 cmꢄ1 1H NMR (300 MHz, CDCl3) d 1.96–2.00 (m, 2H), 2.77 (t,
;
J ¼ 6.3 Hz, 2H), 3.30 (t, J ¼ 6.0 Hz, 2H), 4.00 (d, J ¼ 4.2 Hz, 2H), 6.13 (dt, J ¼ 4.8,
5.7 Hz, 1H), 6.47 (d, J ¼ 16.2 Hz, 1H), 6.56–6.16 (m, 2H), 6.92–7.02 (m, 4H),
7.23–7.30 (m, 2H); MS m=z (þc APCI): 268.13 (M þ H)þ (267.34 calcd. for
C18H18FN).
1-[(2E)-3-(2-Naphthyl)prop-2-en-1-yl]-1,2,3,4-tetrahydroquinoline (2r).
Off-white solid; mp 54–58 ꢀC; IR (neat) 3058, 2923, 1599, 1496, 1330, 1299, 1169,
;
1153, 971 cmꢄ1 1H NMR (300 MHz, CDCl3) d 1.96–2.04 (m, 2H), 2.78 (t,
J ¼ 5.7 Hz, 2H), 3.33 (t, J ¼ 5.4 Hz, 2H), 4.06 (d, J ¼ 4.8 Hz, 2H), 6.35 (dt, J ¼ 5.4,
5.4 Hz, 1H), 6.54–6.69 (m, 3H), 6.95 (d, J ¼ 7.5 Hz, 1H), 7.02 (t, J ¼ 7.2 Hz, 1H),
7.35–7.43 (m, 2H), 7.54 (d, J ¼ 8.1 Hz, 1H), 7.66 (s, 1H), 7.71–7.75 (m, 3H). MS
m=z (þ cAPCI): 300.01 (M þ H)þ (299.41 calcd. for C22H21N).
1-[(2E)-3-(6-Methoxy-2-naphthyl)prop-2-en-1-yl]-1,2,3,4-tetrahydroq-uinoline
(2s). White solid; mp 128–130 ꢀC; IR (KBr) 3053, 2933, 1601, 1503, 1482, 1270,
1210, 1166, 1026 cmꢄ1
;
1H NMR (300 MHz, CDCl3) d 2.00 (t, J ¼ 6.0 Hz, 2H),
2.78 (t, J ¼ 6.3 Hz, 2H), 3.35 (t, J ¼ 6.0 Hz, 2H), 3.89 (s, 3H), 4.05 (d, J ¼ 4.8 Hz,
2H), 6.29 (dt, J ¼ 5.1, 5.4 Hz, 1H), 6.54–6.66 (m, 3H), 6.95 (d, J ¼ 6.9 Hz, 1H),
7.01–7.09 (m, 3H), 7.51 (d, J ¼ 8.7 Hz, 1H), 7.60–7.65 (m, 3H); MS m=z (þ cAPCI):
330.32 (M þ H)þ (329 calcd. for C23H23NO).
1-[(2E)-3-Dibenzo[b,d]furan-4-ylprop-2-en-1-yl]-1,2,3,4-tetrahydroquinoline
(2t). White solid; mp 145–148 ꢀC; IR (KBr) 3062, 2928, 1601, 1505, 1450, 1417,
;
1344, 1186, 1115, 970 cmꢄ1 1H NMR (300 MHz, CDCl3) d 1.90–2.06 (m, 2H),
2.80 (t, J ¼ 6.3 Hz, 2H), 3.37 (t, J ¼ 6.0 Hz, 2H), 4.14 (d, J ¼ 4.2 Hz, 2H), 6.57 (t,
J ¼ 7.5 Hz, 1H), 6.69 (d, J ¼ 8.4 Hz, 1H), 6.74–6.91 (m, 2H),6.96 (d, J ¼ 7.2 Hz,
1H), 7.03 (t, J ¼ 7.8 Hz, 1H), 7.24–7.45 (m, 4H), 7.57 (d, J ¼ 6.9 Hz, 1H), 7.77 (d,
J ¼ 7.2 Hz, 1H), 7.91 (d, J ¼ 7.5 Hz, 1H); MS m=z (þ cAPCI): 339.92 (M)þ (339.43
calcd. for C24H21NO).
General Procedure for Aza-Cope Rearrangement
A solution of N-allylanilines (2) (1 equivalent) and boron trifluoride etherate
(2 equivalent) in 1,4-dioxane (10 mL) was refluxed under nitrogen atmosphere until
the starting material was completely consumed as determined by TLC (20% EtOAc
in n-hexane mixture). The cold reaction mixture was poured into ice-cold water and
basified with 1 N sodium hydroxide solution. The aqueous layer was extracted with
EtOAc (2 ꢃ 50 mL), and the combined extracts were washed with water (3 ꢃ 100 mL)
followed by brine (50 mL) and dried over anhydrous sodium sulfate. The crude
residue obtained after evaporation of solvent under reduced pressure was chromato-
graphed on silica gel using 15–25% EtOAc and n-hexane mixture to give aza-Cope
products.
Selected Data for 3a–3e and 4a, 4b, 4e–4g
2-[(2E)-3-Phenylprop-2-en-1-yl]aniline (3a). Sticky solid; IR (neat) 3445,
1
3059, 2924, 1601, 1492, 1452, 1028 cmꢄ1; H NMR (300 MHz, CDCl3) d 3.45 (d,

1822
V. S. P. R. LINGAM ET AL.
J ¼ 6.9 Hz, 2H), 3.68 (br s, 2H, exchangeable with D2O), 6.30 (dt, J ¼ 3.9, 6.0 Hz,
1H), 6.44 (d, J ¼ 16.2 Hz, 1H), 6.68 (d, J ¼ 7.2 Hz, 1H), 6.75 (t, J ¼ 7.5 Hz, 1H),
7.04–7.07 (m, 2H), 7.18–7.33 (m, 5H); MS m=z (þc APCI): 210.25 (M þ H)þ
(209.29 calcd. for C15H15N).
4-[(2E)-3-Phenylprop-2-en-1-yl]aniline (4a). Sticky solid; IR (neat) 3365,
3056, 2894, 1621, 1515, 1495, 1277, 1178 cmꢄ1 1H NMR (300 MHz, CDCl3) d
;
3.44 (d, J ¼ 6.3 Hz, 2H), 3.57 (br s, 2H, exchangeable with D2O), 6.23–6.44 (m,
2H), 6.65 (d, J ¼ 8.4 Hz, 2H), 7.03 (d, J ¼ 8.4 Hz, 2H), 7.12–7.33 (m, 5H); MS m=z
(þc APCI): 210.48 (M þ H)þ (209.29 calcd. for C15H15N).
2-Fluoro-6-[(2E)-3-phenylprop-2-en-1-yl]aniline (3b). Oil; IR (neat) 3394,
1
3019, 1629, 1479, 1215, 970 cmꢄ1; H NMR (300 MHz, CDCl3) d 3.45 (br s, 2H,
exchangeable with D2O), 3.49 (d, J ¼ 6.0 Hz, 2H), 6.31 (dt, J ¼ 5.7 & 9.9 Hz, 1H),
6.45 (d, J ¼ 16.2 Hz, 1H), 6.67–6.90 (m, 3H), 7.25–7.33 (m, 5H); MS m=z (þ cAPCI):
228.14 (M þ H)þ (227.28 calcd. for C15H14FN).
2-Fluoro-4-[(2E)-3-phenylprop-2-en-1-yl]aniline (4b). Oil; IR (neat) 3394,
1
3019, 1636, 1519, 1439, 1215, 966 cmꢄ1; H NMR (300 MHz, CDCl3) d 3.43 (d,
J ¼ 6.3 Hz, 2H), 3.56 (br s, 2H, exchangeable with D2O), 6.30 (dt, J ¼ 6.6 &
6.9 Hz, 1H), 6.42 (d, J ¼ 15.6 Hz, 1H), 6.71–6.89 (m, 3H), 7.18–7.39 (m, 5H); MS
m=z (þ cAPCI): 226.26 (M ꢄ H)ꢄ (227.28 calcd. for C15H14FN).
4-Fluoro-2-[(2E)-3-phenylprop-2-en-1-yl]aniline (3c). Sticky solid; IR
1
(neat) 3349, 3058, 2897, 1624, 1597, 1051, 1437, 1235, 1145, 967 cmꢄ1; H NMR
(300 MHz, CDCl3) d 3.42 (d, J ¼ 6.3 Hz, 2H), 3.55 (br s, 2H, exchangeable with
D2O), 6.29 (dt, J ¼ 3.3, 6.3 Hz, 1H), 6.43 (d, J ¼ 15.6 Hz, 1H), 6.61 (dd, J ¼ 3.9,
4.8 Hz, 1H), 6.74–6.84 (m, 2H), 7.17–7.34 (m, 5H); MS m=z (þ cAPCI): 228.21
(M þ H)þ (227.11 calcd. for C15H14FN).
2,4-Difluoro-6-[(2E)-3-phenylprop-2-en-1-yl]aniline (3d). Oil; IR (neat)
1
3384, 3020, 1596, 1495, 1215, 1113, 991 cmꢄ1; H NMR (300 MHz, CDCl3) d 3.46
(d, J ¼ 5.7 Hz, 2H), 3.58 (br s, 2H, exchangeable with D2O), 6.29 (dt, J ¼ 5.7 &
6.6 Hz, 1H), 6.39 (d, J ¼ 15.6 Hz, 1H), 6.67–6.75 (m, 2H), 7.12–7.34 (m, 5H); MS
m=z (þ cAPCI): 246.10 (M þ H)þ (245.27 calcd. for C15H13F2N).
N-Methyl-2-[(2E)-3-phenylprop-2-en-1-yl]aniline (3e). Off-white solid; mp
56–58 ꢀC; IR (KBr) 3418, 3026, 2864, 1602, 1554, 1508, 1461, 1449, 1302, 1258,
1
978 cmꢄ1; H NMR (300 MHz, CDCl3) d 2.83 (s, 3H), 3.42 (d, J ¼ 5.4 Hz, 2H),
3.77 (br s, 1H, exchangeable with D2O), 6.31 (dt, J ¼ 5.7, 6.3 Hz, 1H), 6.42 (d,
J ¼ 15.9 Hz, 1H), 6.64 (d, J ¼ 7.8 Hz, 1H), 6.71 (t, J ¼ 7.2 Hz, 1H), 7.08 (d,
J ¼ 6.3 Hz, 1H), 7.16–7.31 (m, 6H); MS m=z (þ cAPCI): 224.27 (M þ H)þ (223.31
calcd. for C16H17N).
N-Methyl-4-[(2E)-3-phenylprop-2-en-1-yl]aniline (4e). Oil; IR (neat) 3415,
3023, 2891, 1615, 1520, 1495, 1316, 1266, 1181, 1153, 965 cmꢄ1; 1H NMR (300 MHz,
CDCl3) d 2.81 (s, 3H), 3.43 (d, J ¼ 5.7 Hz, 2H), 3.61 (br s, 1H, exchangeable with
D2O), 6.33–6.42 (m, 2H), 6.55 (d, J ¼ 8.1 Hz, 2H), 7.04 (d, J ¼ 8.1 Hz, 2H), 7.16
(d, J ¼ 6.9 Hz, 1H), 7.22–7.33 (m, 4H); MS m=z (þ cAPCI): 224.30 (M þ H)þ
(223.31 calcd. for C16H17N).

TETRAHYDROQUINOLINE AND AZA-COPE REARRANGEMENT
1823
N-Ethyl-4-[(2E)-3-phenylprop-2-en-1-yl]aniline (4f). Sticky solid; IR (neat)
1
3403, 3024, 2968, 1615, 1519, 1318, 1260, 1147, 965 cmꢄ1; H NMR (300 MHz,
CDCl3) d 1.24 (t, J ¼ 6.9 Hz, 3H), 3.13 (q, J ¼ 6.9 Hz, 2H), 3.42 (d, J ¼ 6.0 Hz,
2H), 3.63 (br s, 1H, exchangeable with D2O), 6.30–6.40 (m, 2H), 6.55 (d, J ¼ 8.4 Hz,
2H), 7.03 (d, J ¼ 8.1 Hz, 2H), 7.16–7.33 (m, 5H); MS m=z (þ cAPCI): 238.31
(M þ H)þ (237.34 calcd. for C17H19N).
N-Benzyl-4-[(2e)-3-phenylprop-2-en-1-yl]aniline (4g). Oil; IR (neat) 3321,
3029, 2895, 1614, 1519, 1494, 1452, 1322, 1267, 1181, 965 cmꢄ1; 1H NMR (300 MHz,
CDCl3) d 3.42 (d, J ¼ 6.0 Hz, 2H), 3.95 (br s, 1H, exchangeable with D2O), 4.30 (s,
2H), 6.25–6.44 (m, 2H), 6.57 (d, J ¼ 8.4 Hz, 2H), 7.02 (d, J ¼ 8.1 Hz, 2H), 7.15–7.35
(m, 10H); MS m=z (þ cAPCI): 300.15 (M þ H)þ (299.41 calcd. for C22H21N).
General Procedure for Cyclization
A mixture of N-allylanilines, N-allylindoline, or N-allyl-1,2,3,4-tetrahydroqui-
nilines and polyphosphoric acid (6–8 times wt=wt) was heated at 100–110 ꢀC for
10–15 min under an N2 atmosphere. The reaction mixture was cooled to room tem-
perature, poured into ice-cold water (50 mL), and basified with aqueous ammonia
solution. The aqueous layer was extracted with EtOAc (2 ꢃ 25 mL), and the com-
bined organic layer was washed with water (2 ꢃ 20 mL) followed by brine (10 mL)
and dried over sodium sulfate. Evaporation of the EtOAc layer under vacuum
yielded the crude products. The crude products were purified with silica-gel column
chromatography using a solvent mixture of 15–20% EtOAc in n-hexane to obtain
pure compounds.
Selected Data for 6a–6g and 6j–6t
4-Phenyl-1,2,3,4-tetrahydroquinoline (6a)[15]. Off-white solid; mp 73–
75 ꢀC (literature value 72–74 ꢀC); IR (neat) 3416, 2850, 1601, 1492, 1452, 1313,
1
1216, 1029 cmꢄ1; H NMR (300 MHz, CDCl3) d 1.99–2.09 (m, 1H), 2.15–2.25 (m,
1H), 3.18–3.32 (m, 2H), 3.92 (br s, 1H, exchangeable with D2O), 4.13 (t, J ¼ 5.7 Hz,
1H), 6.51–6.56 (m, 2H), 6.72 (d, J ¼ 7.8 Hz, 1H), 6.98 (t, J ¼ 7.8 Hz, 1H), 7.10–7.29
(m, 5H). MS m=z (þc ESI): 210.23 (M þ H)þ. Anal. calcd. for C15H15N: C, 86.08; H,
7.22; N, 6.69. Found: C, 86.17; H, 7.31; N, 6.61.
8-Fluoro-4-phenyl-1,2,3,4-tetrahydroquinoline (6b). Oil; IR (neat) 3341,
2925, 1624, 1508, 1499, 1437, 1321, 1222 cmꢄ1 1H NMR (300 MHz, CDCl3) d
;
2.01–2.11 (m, 1H), 2.16–2.26 (m, 1H), 3.10 (br s, 1H, exchangeable with D2O),
3.12–3.37 (m, 2H), 4.14 (t, J ¼ 6.3 Hz, 1H), 6.40–6.47 (m, 1H), 6.52 (d, J ¼ 7.8 Hz,
1H), 6.78–6.85 (m, 1H), 7.09 (d, J ¼ 6.6 Hz, 2H), 7.16–7.29 (m, 3H). MS m=z (þ
cAPCI): 228.12 (M þ H)þ. Anal. calcd. for C15H14FN: C, 79.27; H, 6.21; F, 8.36;
N, 6.16. Found: C, 79.12; H, 6.35; N, 6.28.
8-Methyl-4-phenyl-1,2,3,4-tetrahydroquinoline (6c). Off-white solid; mp
56–58 ꢀC; IR (KBr) 3435, 2932, 1599, 1492, 1461, 1359, 1309, 1265, 1061,
;
1029 cmꢄ1 1H NMR (300 MHz, CDCl3) d 2.00–2.09 (m, 1H), 2.13 (s, 3H),
2.15–2.25 (m, 1H), 3.24–3.39 (m, 2H), 3.81 (br s, 1H, exchangeable with D2O),

1824
V. S. P. R. LINGAM ET AL.
4.16 (t, J ¼ 5.7 Hz, 1H), 6.48 (t, J ¼ 6.3 Hz, 1H), 6.62 (d, J ¼ 7.8 Hz, 1H), 6.90
(d, J ¼ 7.2 Hz, 1H), 7.10 (d, J ¼ 6.9 Hz, 2H), 7.14–7.28 (m, 3H). MS m=z (þ cAPCI):
224.28 (M þ H)þ. Anal. calcd. for C16H17N: C, 80.05; H, 7.67; N, 6.27. Found: C
86.16; H, 7.78; N, 6.21.
8-Methoxy-4-phenyl-1,2,3,4-tetrahydroquinoline (6d). White solid; mp
72–74 ꢀC; IR (KBr) 3425, 2947, 1585, 1508, 1449, 1341, 1250, 1104, 1057,
1
1013 cmꢄ1; H NMR (300 MHz, CDCl3) d 1.98–2.07 (m, 1H), 2.18–2.26 (m, 1H),
3.22–3.33 (m, 2H), 3.85 (s, 3H), 4.15 (t, J ¼ 6.0 Hz, 1H), 4.20 (br s, 1H, exchangeable
with D2O), 6.39 (d, J ¼ 7.2 Hz, 1H), 6.50 (t, J ¼ 7.5 Hz, 1H), 6.63 (d, J ¼ 7.8 Hz, 1H),
7.11 (d, J ¼ 6.9 Hz, 2H), 7.17–7.28 (m, 3H); 13C NMR (75 MHz, CDCl3) d 31.06,
38.53, 42.53, 55.32, 107.34, 115.42, 122.32, 122.91, 125.84, 128.02 (2C), 128.44
(2C), 134.68, 145.91, 146.56. MS m=z (þ cAPCI): 240.24 (M þ H)þ. Anal. calcd.
for C16H17NO: C, 80.30; H, 7.16; N, 5.85; O, 6.69. Found: C, 80.18; H, 7.09; N, 5.79.
6-Ethyl-4-phenyl-1,2,3,4-tetrahydroquinoline (6e). Sticky solid; IR (neat)
3401, 2958, 1616, 1508, 1492, 1353, 1312, 1270, 1155, 1029 cmꢄ1 1H NMR
;
(300 MHz, CDCl3) d 1.08 (t, J ¼ 7.2 Hz, 3H), 1.96–2.06 (m, 1H), 2.16–2.25 (m,
1H), 2.40 (q, J ¼ 7.8 Hz, 2H), 3.15–3.29 (m, 2H), 3.87 (br s, 1H, exchangeable with
D2O), 4.12 (t, J ¼ 5.7 Hz, 1H), 6.49 (d, J ¼ 8.4 Hz, 1H), 6.57 (s, 1H), 6.84 (d,
J ¼ 7.8 Hz, 1H), 7.19–2.29 (m, 5H). MS m=z (þ cAPCI): 238.28 (M þ H)þ. Anal.
calcd. for C17H19N: C, 86.03; H, 8.07; N, 5.90. Found: C, 86.21; H, 8.00; N, 5.84.
6-Fluoro-4-phenyl-1,2,3,4-tetrahydroquinoline (6f). Off-white solid; mp
56–58 ꢀC; IR (KBr) 3419, 2918, 1508, 1490, 1315, 1247, 1230, 1140 cmꢄ1 1H
;
NMR (300 MHz, CDCl3) d 1.99–2.08 (m, 1H), 2.14–2.24 (m, 1H), 3.18–3.29 (m,
2H), 3.81 (br s, 1H, exchangeable with D2O), 4.09 (t, J ¼ 5.7 Hz, 1H), 6.42–6.48
(m, 2H), 6.70 (dt, J ¼ 3.0, 5.7 Hz, 1H), 7.09–7.12 (m, 2H), 7.17–7.30 (m, 3H). MS
m=z (þ cAPCI): 228.23 (M þ H)þ. Anal. calcd. for C15H14FN: C, 79.27; H, 6.21;
F, 8.36; N, 6.16. Found: C,79.19; H, 6.31; N, 6.03.
6,8-Difluoro-4-phenyl-1,2,3,4-tetrahydroquinoline (6g). Off-white solꢄid1;
mp 69–72 ꢀC; IR (KBr) 3443, 2963, 1595, 1508, 1423, 1262, 1111, 1080, 958 cm
;
1H NMR (300 MHz, CDCl3) d 2.03–2.11 (m, 1H), 2.16 (m, 1H), 3.23–3.18 (m,
2H), 3.31 (br s, 1H, exchangeable with D2O), 4.09 (t, J ¼ 6.3 Hz, 1H), 6.28 (d,
J ¼ 9.3 Hz, 1H), 6.631 (dt, J ¼ 2.1, 8.4 Hz, 1H), 7.09 (d, J ¼ 6.9 Hz, 2H), 7.18–7.31
(m, 3H); MS m=z (þ cAPCI): 246.31 (M þ H)þ. Anal. calcd. for C15H13F2N: C,
73.45; H, 5.34; F, 15.49; N, 5.71. Found: C, 73.38; H, 5.12; N, 5.52.
1-Methyl-4-phenyl-1,2,3,4-tetrahydroquinoline (6j). Oil; IR (neat) 2924,
1
1602, 1573, 1501, 1458, 1325, 1208, 1027, 1008 cmꢄ1; H NMR (300 MHz, CDCl3)
d 2.03–2.11 (m, 1H), 2.24–2.26 (m, 1H), 2.93 (s, 3H), 3.12–3.21 (m, 2H), 4.11 (t,
J ¼ 5.7 Hz, 1H), 6.53 (t, J ¼ 6.6 Hz, 1H), 4.65 (d, J ¼ 8.4 Hz, 1H), 6.71 (d, J ¼ 6.6 Hz,
1H), 7.07–7.28 (m, 6H). MS m=z (þ cAPCI): 224.29 (M þ H)þ. Anal. calcd. for
C16H17N: C, 86.05; H, 7.67; N, 6.27. Found: C, 86.14; H, 7.59; N, 6.41.
1-Ethyl-4-phenyl-1,2,3,4-tetrahydroquinoline (6k). Sticky solid; IR (neat)
1
2967, 1601, 1502, 1454, 1343, 1270, 1192, 1076 cmꢄ1; H NMR (300 MHz, CDCl3)
d 1.15 (t, J ¼ 7.2 Hz, 3H), 2.04–2.08 (m, 1H), 2.20–2.28 (m, 1H), 3.17 (q, J ¼ 7.2 Hz,
2H), 3.30–3.46 (m, 2H), 4.10 (t, J ¼ 6.0 Hz, 1H), 6.49 (t, J ¼ 6.9 Hz, 1H), 6.66

TETRAHYDROQUINOLINE AND AZA-COPE REARRANGEMENT
1825
(d, J ¼ 8.4 Hz, 1H), 6.72 (d, J ¼ 6.9 Hz, 1H), 7.05–7.07 (m, 3H), 7.16–7.27 (m, 3H).
MS m=z (þ cAPCI): 238.27 (M þ H)þ. Anal. calcd. for C17H19N: C, 86.03; H,
8.07; N, 5.90. Found: C, 85.96; H, 8.16; N, 6.01.
1-Benzyl-4-phenyl-1,2,3,4-tetrahydroquinoline (6l). Off-white solid; mp
1
47–49 ꢀC; IR (neat) 2922, 1601, 1504, 1451, 1337, 1307, 1258, 1169, 1053 cmꢄ1; H
NMR (300 MHz, CDCl3) d 2.10–2.22 (m, 1H), 2.28–2.40 (m, 1H), 3.25–3.35 (m,
2H), 4.52 (s, 2H), 6.52 (t, J ¼ 7.2 Hz, 1H), 6.58 (d, J ¼ 8.4 Hz, 1H), 6.77 (d,
J ¼ 7.2 Hz, 1H), 6.98 (t, J ¼ 6.6 Hz, 1H), 7.11 (d, J ¼ 6.9 Hz, 2H), 7.19–7.33 (m,
9H). MS m=z (þ cAPCI): 300.15 (M þ H)þ. Anal. calcd. for C22H21N: C, 88.25;
H, 7.07; N, 4.68. Found: C, 88.39; H, 7.01; N, 4.75.
6-Phenyl-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline (6m). Oil; IR
(neat) 2805, 1600, 1489, 1454, 1337, 1281, 1274, 1179, 1063 cmꢄ1 1H NMR
;
(300 MHz, CDCl3) d 2.14–2.21 (m, 1H), 2.32–2.38 (m, 1H), 2.93 (m, 3H),
3.06–3.11 (m, 1H), 3.16–3.24 (m, 1H), 3.35–4.40 (m, 1H), 4.08 (t, J ¼ 6.3 Hz, 1H),
6.54 (d, J ¼ 7.2 Hz, 2H), 6.94 (t, J ¼ 7.2 Hz, 1H), 7.13–7.28 (m, 5H). MS m=z (þ
cAPCI): 236.21 (M þ H)þ. Anal. calcd. for C17H17N: C, 86.77; H, 7.28; N, 5.95.
Found: C, 86.85; H, 7.08; N, 5.74.
6-(4-Fluorophenyl)-1,2,5,6-tetrahydro-4H-pyrrolo[3,2,1-ij]quinoline (6n).
White solid; mp 60–61 ꢀC; IR (KBr) 2948, 1598, 1509, 1492, 1338, 1282, 1217, 1159,
.
1013 cmꢄ1 1H NMR (300 MHz, CDCl3) d 2.06–2.18 (m, 1H), 2.28 (m, 1H),
2.88–3.00 (m, 3H), 3.02–3.19 (m, 1H), 3.16–3.24 (m, 1H), 3.35–3.42 (m, 1H), 4.06
(t, J ¼ 6.9 Hz, 1H), 6.50–6.54 (m, 2H), 6.92–6.97 (m, 3H), 7.07–7.12 (m, 2H). MS
m=z (þ cAPCI): 254.22 (M þ H)þ. Anal. calcd. for C17H16FN: C, 80.60; H, 6.37;
F, 7.50; N, 5.53. Found: C, 80.68; H, 6.49; N, 5.47.
1-Phenyl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline (6o). Sticky
solid; IR (neat) 2937, 1597, 1491, 1455, 1309, 1189, 1108 cmꢄ1 1H NMR
;
(300 MHz, CDCl3) d 1.98–2.18 (m, 3H), 2.20–2.25 (m, 1H), 2.80 (t, J ¼ 6.3 Hz,
2H), 3.08–3.18 (m, 4H), 4.09 (t, J ¼ 6.0 Hz, 1H), 6.42 (t, J ¼ 7.2 Hz, 1H), 6.53 (d,
J ¼ 7.5 Hz, 1H), 6.80 (d, J ¼ 6.9 Hz, 1H), 7.09–7.26 (m, 5H); 13C NMR (75 MHz,
CDCl3) d 22.17, 27.86, 30.91, 43.49, 47.36, 50.15, 115.53, 121.36, 123.46, 125.86,
127.24, 127.83, 128.08 (2C), 128.52 (2C), 142.94, 146.77. MS m=z (þ cAPCI):
250.21 (M þ H)þ. Anal. calcd. for C18H19N: C, 86.70; H, 7.68; N, 5.62. Found: C,
86.63; H, 7.51; N, 5.75.
1-(3-Chlorophenyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline (6p).
1
Sticky solid; IR (neat) 2927, 1601, 1505, 1457, 1344, 1193, 1090 cmꢄ1; H NMR
(300 MHz, CDCl3) d 1.98–2.09 (m, 3H), 2.17–2.24 (m, 1H), 2.78 (t, J ¼ 6.6 Hz,
2H), 3.01–3.11 (m, 2H), 3.14–3.17 (m, 2H), 4.07 (t, J ¼ 6.0 Hz, 1H), 6.42 (t,
J ¼ 7.5 Hz, 1H), 6.51 (d, J ¼ 7.2 Hz, 1H), 6.80 (d, J ¼ 7.5 Hz, 1H), 6.97 (d, J ¼ 6.9 Hz,
1H), 7.10–7.22 (m, 3H). MS m=z (þ cAPCI): 284.73 (M þ H)þ. Anal. calcd. for
C18H18ClN: C, 76.18; H, 6.39; Cl, 12.49; N, 4.94. Found: C, 76.01; H, 6.46; N, 5.05.
1-(4-Fluorophenyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline (6q).
Off-white solid; mp 53–55 ꢀC; IR (neat) 2939, 1599, 1506, 1456, 1310, 1220, 1156,
1
1076, 834 cmꢄ1; H NMR (300 MHz, CDCl3) d 1.96–2.07 (m, 3H), 2.16–2.26 (m,
1H), 2.79 (t, J ¼ 6.3 Hz, 2H), 3.00–3.11 (m, 2H), 3.16 (t, J ¼ 6.0 Hz, 2H), 4.08

1826
V. S. P. R. LINGAM ET AL.
(t, J ¼ 6.3 Hz, 1H), 6.42 (t, J ¼ 7.2 Hz, 1H), 6.51 (d, J ¼ 6.6 Hz, 1H), 6.80 (d,
J ¼ 6.3 Hz, 1H), 6.94 (t, J ¼ 8.4 Hz, 2H), 7.03–7.08 (m, 2H). MS m=z (þ cAPCI):
268.22 (M þ H)þ. Anal. calcd. for C18H18FN: C, 80.87; H, 6.79; F, 7.11; N, 5.24.
Found: C, 80.96; H, 6.62; N, 5.31.
1-(2-Naphthyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline (6r).
White solid; mp 68–71 ꢀC; IR (KBr) 2941, 1597, 1505, 1493, 1455, 1308, 1216cmꢄ1
;
1H NMR (300 MHz, CDCl3) d 1.99–2.06 (m, 2H), 2.13–2.33 (m, 2H), 2.82 (t,
J ¼ 6.9 Hz, 2H), 3.06–3.20 (m, 4H), 4.26 (t, J ¼ 6.6 Hz, 1H), 6.41 (t, J ¼ 7.5 Hz,
1H), 6.54 (d, J ¼ 7.2 Hz, 1H), 6.82 (d, J ¼ 6.9 Hz, 1H), 7.29 (d, J ¼ 8.1 Hz, 1H),
7.37–7.44 (m, 2H), 7.52 (s, 1H), 7.73–7.79 (m, 3H). MS m=z (þ cAPCI): 300.29
(M þ H)þ. Anal. calcd. for C22H21N: C, 88.25; H, 7.07; N, 4.68. Found: C, 88.16;
H, 7.29; N, 4.56.
1-(6-Methoxy-2-naphthyl)-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]-
quinoline (6s). White solid; mp 102–105 ꢀC; IR (KBr) 2929, 1606, 1438, 1330, 1260,
1
1215, 1104 cmꢄ1; H NMR (300 MHz, CDCl3) d 2.04 (t, J ¼ 6.0 Hz, 2H), 2.18–2.30
(m, 2H), 2.82 (t, J ¼ 6.9 Hz, 2H), 3.12–3.18 (m, 4H), 3.89 (s, 3H), 4.22 (t, J ¼ 6.3 Hz,
1H), 6.41 (t, J ¼ 7.2 Hz, 1H), 6.54 (d, J ¼ 6.3 Hz, 1H), 6.81 (d, J ¼ 7.2 Hz, 1H),
7.08–7.10 (m, 2H), 7.24 (d, J ¼ 6.9 Hz, 1H), 7.45 (s, 1H), 7.64 (d, J ¼ 6.6 Hz, 2H);
1H NMR (75 MHz, CDCl3) d 22.10, 27.77, 30.96, 43.50, 47.65, 50.16, 55.28,
105.55, 115.67, 118.58, 121.53, 123.78, 126.80, 127.10, 127.38, 127.50, 128.13,
128.86, 129.12, 133.12, 142.03, 143.20, 157.25; MS m=z (þ cAPCI): 330.23 (M þ H)þ.
Anal. calcd. for C23H23NO: C, 83.85; H, 7.04; N, 4.25; O, 4.86. Found: C, 83.91; H,
7.12; N, 4.17.
Dibenzo[b,d]furan-4-yl-2,3,6,7-tetrahydro-1H,5H-pyrido[3,2,1-ij]quinoline
(6t). White solid; mp 150–153 ꢀC; IR (KBr) 2936, 1598, 1494, 1451, 1302, 1184,
1
1108, cmꢄ1; H NMR (300 MHz, CDCl3) d 2.03 (t, J ¼ 6.0 Hz, 2H), 2.32–2.38 (m,
2H), 2.79–2.83 (m, 2H), 3.08–3.12 (m, 2H), 3.19 (t, J ¼ 5.4 Hz, 2H), 4.82 (t,
J ¼ 6.0 Hz, 1H), 6.43 (t, J ¼ 7.5 Hz, 1H), 6.60 (d, J ¼ 7.2 Hz, 1H), 6.83 (d, J ¼ 6.9 Hz,
1H), 6.94 (d, J ¼ 7.2 Hz, 1H), 7.19 (t, J ¼ 7.2 Hz, 1H), 7.31 (t, J ¼ 7.5 Hz, 1H), 7.43 (t,
J ¼ 7.2 Hz, 1H), 7.56 (d, J ¼ 7.8 Hz, 1H), 7.77 (d, J ¼ 7.8 Hz, 1H), 7.93 (d, J ¼ 7.2 Hz,
1H). MS m=z (þ cAPCI): 340.18 (M þ H)þ. Anal. calcd. for C24H21NO: C, 84.92; H,
6.24; N, 4.13; O, 4.71. Found: C, 84.83; H, 4.13; N, 4.77.
ACKNOWLEDGMENT
The authors thank Glenmark Pharmaceuticals Limited for granting permission
to carry out the research work.
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