Practical one-pot procedure for the synthesis of 1,2,3,4- tetrahydroquinolines by the imino-Diels-Alder reaction

Article abstract of DOI:10.1080/00397910701820988

A novel-one-pot procedure for the synthesis of tetrahydroquinolines via the imino-Diels-Alder reaction is described. This procedure gives better yields and exhibits better versatility for alkene substrates than the existing hemi-aminal based methodologies

Full text of DOI:10.1080/00397910701820988

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Practical One‐Pot Procedure for the Synthesis
of 1,2,3,4‐Tetrahydroquinolines by the
Imino‐Diels‐Alder Reaction
Christoph M. Dehnhardt a , Yomery Espinal a & Aranapkam M. Venkatesan a
a Chemical and Screening Sciences , Wyeth Research , Pearl River, New York,
USA
Published online: 15 Feb 2008.
To cite this article: Christoph M. Dehnhardt , Yomery Espinal & Aranapkam M. Venkatesan (2008) Practical
One‐Pot Procedure for the Synthesis of 1,2,3,4‐Tetrahydroquinolines by the Imino‐Diels‐Alder Reaction,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
38:5, 796-802, DOI: 10.1080/00397910701820988
To link to this article: http://dx.doi.org/10.1080/00397910701820988
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Synthetic Communicationsw, 38: 796–802, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701820988
Practical One-Pot Procedure for the
Synthesis of 1,2,3,4-Tetrahydroquinolines
by the Imino-Diels-Alder Reaction
Christoph M. Dehnhardt, Yomery Espinal,
and Aranapkam M. Venkatesan
Chemical and Screening Sciences, Wyeth Research, Pearl River,
New York, USA
Abstract: A novel-one-pot procedure for the synthesis of tetrahydroquinolines via the
imino-Diels-Alder reaction is described. This procedure gives better yields and exhibits
better versatility for alkene substrates than the existing hemi-aminal based
methodologies.
Keywords: Imino-Diels-Alder reaction, one-pot procedure, tetrahydroquino lines
Many tetrahydroquinolines with biologically interesting properties have been
discovered in the past few years, and they have been investigated as drug can-
didates against type II diabetes,[1] cancer,[2] obesity,[3] depression,[4] inflam-
mation,[5] and heart failures.[6] Therefore, research directed toward the
discovery of better methodologies to prepare tetrahydroquinolines is an
ongoing effort. One of the most powerful tools for the synthesis of tetrahydro-
quinolines is the imino-Diels-Alder reaction, where the tetrahydroquinoline
(4) is formed by the condensation of 3 with an alkene (Scheme 1). In the
past, the azadiene (3) was generated in situ (pathway A) or from a hemi-aminal
2a–c (pathway B, Scheme 1).
Received in the USA September 26, 2007
Address correspondence to Christoph M. Dehnhardt, Chemical and Screening
Sciences, Wyeth Research, 401 N. Middletown Rd., Pearl River, NY 10965, USA.
E-mail: dehnhac@wyeth.com
796

1,2,3,4-Tetrahydroquinolines
797
Scheme 1. Synthesis of 1,2,3,4-tetrahydroquinoline 4 by imino-Diels-Alder reaction.
However, there are reports that early imino-Diels-Alder reactions were
carried out using pathway A and gave tetrahydroquinolines in good yields
but worked only with specific alkene substrates.[7] For example, Hesse[7]
obtained tetrahydroquinolines by condensation of N-methylaniline and
b-methylstyrene in the presence of aqueous formaldehyde and sulfuric acid.
However, this procedure works only with styrenes. Another one-pot procedure
was developed by Posson et al.[8] in which they reacted a mixture of aqueous for-
maldehyde and hydrochloride salts of N-alkylanilines to generate tetrahydroqui-
nolines. Still, this method works only with cyclopentadiene.
A different one-pot procedure that works well with electron-rich alkenes was
introduced by Chen and Qian.[9] According to this methodology, N-methylaniline
and enol ethers were condensed in the presence of Dy(OTf)3 catalyst. Even though
this method works well with electron-rich olefins, it gives only moderate yields
with isolated olefins such as 1-hexene and styrene. In addition to the previously
mentioned methods, newer procedures[10–12] were introduced to synthesize tetra-
hydroquinolines 4 from hemi-aminals 2a–c. In these procedures, the iminium
intermediate (3) is generated via pathway B and reacted with a variety of
alkenes. These procedures work well with alkenes of varying reactivities,
although this better flexibility for alkene substrates comes at the expense of an
additional chemical step, namely the formation of the hemi-aminals, 2a–c.
For example, Shonos et al.[10] formed the iminium intermediate (3) by
treating an electrochemically generated methoxy-N-methylaniline (2a) with
titanium tetrachloride. The iminium ion (3) thus generated reacted with
various alkenes to form tetrahydroquinolines 4 in moderate to good yields.
Beifuss et al.[11] generated iminium 3 from a-arylaminosulfones 2b,
followed by cycloaddition with styrenes in good yields. On a preparative
scale, the most useful method to synthesize tetrahydroquinolines was intro-
duced by Katrizky et al.[12] They generated 3 from a-aminoalkyl
benzotriazol 2c upon Lewis acid treatment, followed by reaction with a

798
C. M. Dehnhardt, Y. Espinal, and A. M. Venkatesan
variety of activated and unactivated alkenes, to obtain tetrahydroquinolines 4
in good yields with good regioselectivity. This method works well with unac-
tivated mono- and disubstituted alkenes, cyclic alkenes, and styrenes.
However, the overall synthesis of 4 with all the previously mentioned
methods, calls for two synthetic steps, namely (a) formation of the
hemi-aminals (2a–c) and (b) subsequent condensation reaction.
In the present work, 1,2,3,4-tetrahydroquinolines 4 were synthesized in a
one-pot procedure starting from N-methylaniline and formaldehyde in the
presence of a Lewis acid. Different alkenes, solvents, and a variety of
Lewis acids were investigated for this mentioned transformation. Among
the various solvents tried, acetonitrile turned out to be preferred. In a
typical experiment, a mixture of substituted alkenes, a formaldehyde source,
N-methylaniline, and a variety of Lewis acids (2.5 eq) were suspended in
acetonitrile at 08C and stirred for 16 h at room temperature. After workup,
the products were purified and the yields determined as listed in Table 1.
Initially, we studied the effect of different formaldehyde sources for this
reaction, using BF3 as Lewis acid and cyclopentene as alkene. As can be seen
from entries 1–4, the highest yields were achieved in this order:
paraformaldehyde . 1,3,5 trioxan . aqueous formaldehyde solution,
whereas the use of 1,1-dimethoxymethane led only to the formation of side
Table 1. New one-pot procedure for the synthesis of tetrahydroquinolines 4
Entry
Product
R1
R2
Lewis acid
Formaldehyde source Yield (%)
.
1
2
4a
(CH2)3
BF3 OEt2
Paraformaldehyde
1,3,5-Trioxan
87
76
21
—
94
59
—
67
77
59
68
78
—
84
67
.
(CH2)3
(CH2)3
(CH2)3
(CH2)3
(CH2)3
(CH2)3
BF3 OEt2
.
3
BF3 OEt2
37% aq HCHO-sol.
Dimethoxymethane
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
Paraformaldeyde
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
Paraformaldehyde
.
BF3 OEt2
4
5
SnCl4
ZrCl4
TiCl4
.
BF3 OEt2
SnCl4
.
BF3 OEt2
SnCl4
.
BF3 OEt2
6
7
8
4b
4c
4d
n-Bu
H
H
H
H
H
H
9
n-Bu
n-Hex
n-Hex
Ph
10
11
12
13
14
15
Ph
4e (trans) Ph
4f (cis) Ph
SnCl4
.
Me BF3 OEt2
.
Me BF3 OEt2

1,2,3,4-Tetrahydroquinolines
799
products. Next, the effect of several Lewis acids was investigated using para-
formaldehyde, N-methylaniline, and cyclopentene (Table 1, entries 5–7).
.
Interestingly, SnCl4 (entry 5) works as well as BF3 ZrCl4 (entry 6), and
TiCl4 (entry 7) gave lower yields of final product 4a. Finally, the versatility of
this methodology was demonstrated by reacting N-methylaniline with
1-octene or 1-hexene in the presence of either BF3 or SnCl4, using paraformal-
dehyde as the aldehyde source (entries 8–11). The actual yields for 4b and for
4c with the present one-pot procedure are higher than literature yields using
hemi-aminal methodologies.[11–13] Our methodology also works well with
styrenes (entries 12–15) using BF3 as the Lewis acid. However, when
SnCl4 was used as the Lewis acid (entry 13), no product was isolated, and
this may be due to competing styrene polymerization.
To gain insight into the reaction mechanism, Z- and E-b-methylstyrene
were used as dienophiles (entries 14 and 15). Using E-b-methylstyrene tetra-
hydroquinoline 4e (trans) was formed exclusively in 84% yield, but when Z-b-
methylstyrene was used, the tetrahydroquinoline 4f (cis) and 4e (trans) were
formed as a mixture of stereoisomers in a 3:1 ratio. The formation of 4e
(trans) under these reaction conditions (entry 15) can be explained either by
isomerization of the Z-b-methylstyrene or the product 4f (cis), or alternatively
by a partly stepwise mechanism for the ring formation. We could show exper-
imentally that isomerization of the product or the starting material did not play
a role in the formation of 4e (trans) by subjecting both compounds to the
reaction conditions for 2 days. Therefore, the generation of 4e (trans) must
have occurred during the cyclization step and should be rationalized by the
reaction mechanism. The formation of both syn- and anti-tetrahydroquinolines
4f (cis) 4e (trans) suggests the pericyclic [4 þ 2] cycloaddition may be in com-
petition with a stepwise mechanism involving a cationic species. Both mech-
anisms have been reported earlier for this reaction.[10,12]
CONCLUSION
In summary, a novel one-pot procedure for the synthesis of tetrahydroquino-
lines was introduced. The method is facile for both cyclic and acyclic alkenes
and works well with activated and unactivated 1-alkenes and 1,2-alkenes. The
current method offers an advantage over existing methods because it avoids
the use of hemi-aminals.
Avoiding a chemical step, namely the formation of hemi-aminal, is
especially important in scaling the reaction, because an additional chemical
step means additional costs. Our method is also environmentally friendlier
then older methods because of its better atom economy.
Overall, the present procedure is a useful variation of existing methods
that will be valuable for the preparation of biologically important 1,2,3,4-
tetrahydroquinoline derivatives.

800
C. M. Dehnhardt, Y. Espinal, and A. M. Venkatesan
EXPERIMENTAL
General Experimental Procedure for the Synthesis of
Tetrahydroquinolines 4
To a stirred solution/suspension of N-methylaniline (15 mmol), alkene (4 eq),
and formaldehyde source (1.4 eq) in anhydrous acetonitrile (17 mL) at 08C,
Lewis acid (2.5 eq) was added over a period of 5 min. The reaction mixture
was stirred for 16 h. After 16 h, another 0.3 eq of formaldehyde source was
added, and the reaction mixture was stirred for another 12 h. After evaporation
of solvents, aqueous NaOH (2.5 N) (25 mL) was added, and the aqueous layer
was extracted with ether (3 ꢀ 50 mL). The combined organic layer was dried
over MgSO4, and the tetrahydroquinoline was isolated by flash chromato-
graphy using hexane/ethyl acetate (40:1). For yields, see Table 1.
5-Methyl-2,3,3a,4,5,9b-hexahydro-1H-cyclopenta[c]quinoline (4a)
1H NMR (300 MHz, DMSO-d6): d ¼ 7.04–6.96 (m, 2H), 6.63–6.58 (m, 2H),
2.98–2.78 (m, 2H), 2.63 (t, J ¼ 9.93 Hz, 1H), 2.33 (m, 1H), 2.13 (m, 1H), 1.93
(m, 1H), 1.60–1.34 (m, 4H) ppm. 13C NMR (100 MHz, DMSO-d6): d ¼ 146.6,
129.0, 127.1, 126.2, 116.7, 111.0, 53.4, 40.5, 39.1, 35.5, 35.5, 29.3, 23.0 ppm.
IR (neat, cm21): 2945, 2862, 2806, 1601, 1574, 1498, 1446, 1281, 1206, 1087,
1048, 742. HRMS (FT) [M þ H] calcd. for C13H17N 188.14338; found 188.14303.
4-Butyl-1-methyl-1,2,3,4-tetrahydroquinoline (4b)
1H NMR (300 MHz, DMSO-d6): d ¼ 7.16–6.90 (m, 2H), 6.57–6.49 (m, 2H),
3.32–3.19 (m, 1H), 3.17–3.09 (m, 1H), 2.81 (s, 3H), 2.64–2.62 (m, 1H), 1.85–
1.82 (m, 1H), 1.77–1.75 (m, 1H), 1.34–1.25 (m, 8H), 0.88 (t, J ¼ 6.8 Hz, 3H)
ppm. 13C NMR (100 MHz, DMSO-d6): d ¼ 145.7, 128.0, 126.7, 126.3, 115.4,
110.6, 46.8, 38.5, 35.9, 35.4, 29.4, 25.8, 22.2, 13.9 ppm. IR (neat, cm21): 2925,
2857, 1601, 1501, 1466, 1429, 1322, 1208, 1010, 738. HRMS (FT) [M þ H]
calcd. for C14H21N 204.17468; found 204.17431.
4-Hexyl-1-methyl-1,2,3,4-tetrahydroquinoline (4c)
1H NMR (300 MHz, DMSO-d6): d ¼ 7.16–6.90 (m, 2H), 6.56–6.35 (m, 2H),
3.25–3.15 (m, 1H), 3.14–3.07 (m, 1H), 2.81 (s, 3H), 2.63 (m, 1H), 1.90–1.75
C
(m, 1H), 1.68–1.58 (m, 1H) 1.68–1.58 (m, 1H), 1.56–1.18 (m, 10H) ppm. 13
NMR (100 MHz, DMSO-d6): d ¼ 144.6, 127.0, 125.6, 125.3, 114.3, 109.5,
45.7, 37.4, 35.1, 34.3, 30.2, 27.2, 25.2, 24.7, 21.0, 12.9 ppm. IR (neat,
cm21): 2924, 2855, 1602, 1502, 1466, 1322, 1209, 907, 729. HRMS (FT)
[M þ H] calcd. for C16H25N 232.20598; found 232.20512.

1,2,3,4-Tetrahydroquinolines
801
1-Methyl-4-phenyl-1,2,3,4-tetrahydroquinoline (4d)
1H NMR (300 MHz, DMSO-d6): d ¼ 7.35–7.27 (m, 2H, 7.21 (tt, J ¼ 7.1,
1.2 Hz, 1H), 7.08–7.03 (m, 3H), 6.66 (d, J ¼ 8.0 Hz, 1H), 6.58
(d, J ¼ 7.1 Hz, 1H), 6.47 (tt, J ¼ 7.3, 1.2 Hz, 1H), 4.1 (t, J ¼ 6.1 Hz, 1H),
3.18 (m, 1H), 2.87 (s, 3H), 2.14 (m, 1H), 2.01–1.07 (m, 1H) ppm. 13C
NMR (100 MHz, DMSO-d6): d ¼ 146.9, 146.8, 129.6, 128.7, 128.6, 127.7,
126.3, 124.7, 116.0, 111.3, 48.0, 42.8, 39.1, 30.7 ppm. IR (neat, cm21):
2943, 1601, 1503, 1451, 1325, 1208, 1033, 905, 727, 699. HRMS (FT)
[M þ H] calcd. for C16H17N 224.14338; found 224.14342.
trans-1,3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline (4e)
1HNMR(300 MHz, DMSO-d6): d ¼ 7.30–7.27(m, 2H), 7.21 (m, 1H), 7.09–7.06
(m, 2H), 7.00 (m, 1H), 6.64 (d, J ¼ 8.3 Hz, 1H), 6.44 (m, 2H), 3.64 (d, J ¼ 8.6 Hz,
1H), 3.17 (dd, J ¼ 11.3, 3.8 Hz, 1H), 2.94 (m, 1H), 2.88 (s, 3H), 2.12 (m, 1H), 0.84
(d, J ¼ 7.0 Hz, 1H) ppm. 13C NMR (100 MHz, DMSO-d6): d ¼ 146.7, 146.0,
130.0, 129.2, 128.6, 127.4, 126.5, 125.2, 116.3, 111.1, 55.9, 51.1, 39.3, 34.5,
18.2 ppm. IR (neat, cm21): 3022, 2965, 2880, 1596, 1571, 1497, 1449, 1429,
1332, 1213, 1201, 769, 756, 703. MS: (m/z) 238.2 (M þ H). Anal. calcd. for
C17H19N: C, 86.03; H, 8.07; N, 5.29. Found: C, 86.03; H, 8.19; N, 5.75.
cis-1,3-Dimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline (4f)
1H NMR (300 MHz, DMSO-d6): d ¼ 7.25–7.16 (m, 3H), 7.07–6.94 (m, 3H),
6.75 (d, J ¼ 8.0 Hz, 1H), 6.44 (m, 2H), 6.69 (d, J ¼ 12.1 Hz, 1H), 6.46 (m, 1H),
3.97 (d, J ¼ 6.6 Hz, 1H), 3.00 (dd, J ¼ 12.1, 4.6 Hz, 1H), 2.92 (s, 3H), 2.92–
2.85 (m, 1H), 2.25 (m, 1H), 0.68 (d, J ¼ 6.8 Hz, 3H) ppm. 13C NMR (100 MHz,
DMSO-d6): d ¼ 146.0, 143.2, 130.0, 130.0, 127.9, 127.8, 126.3, 125.0, 115.9,
110.9, 53.0, 48.3, 38.8, 30.9, 16.6 ppm. IR (neat, cm21): 2952, 2898, 1601,
1504, 1280, 1208, 1044, 998, 748, 699. MS: (m/z) 238.2 (M þ H). Anal. calcd.
for C17H19N: C, 86.03; H, 8.07; N, 5.29. Found: C, 86.16; H, 7.78; N, 5.67.
ACKNOWLEDGMENTS
The authors want to thank Tarek Mansour and Semiramis Ayral-Kaloustian for
overseeing the Wyeth summer intern program and for their constant support and
encouragement. Further thanks belong to the discovery analytical chemistry
(DAC) group at Wyeth, Pearl River, for analytical support, and my laboratory
coworkers Zecheng Chen and Oswaldo DosSantos for their help in the laboratory.

802
C. M. Dehnhardt, Y. Espinal, and A. M. Venkatesan
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