C-N bond forming reaction under copper catalysis: a new synthesis of 2-substituted 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines

Article abstract of DOI:10.1016/j.tetlet.2009.06.041

We report copper-catalyzed intramolecular cyclization of 8-alkynyl-1,2,3,4-tetrahydroquinolines, obtained via a Pd/C-mediated Sonogashira coupling in water, to afford 2-substituted 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines. Further functionalization of t

Full text of DOI:10.1016/j.tetlet.2009.06.041

Tetrahedron Letters 50 (2009) 4878–4881
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Tetrahedron Letters
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C–N bond forming reaction under copper catalysis: a new synthesis
of 2-substituted 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines
Mohosin Layek a,b, A. V. Dhanunjaya Rao a, Vikas Gajare a, Dipak Kalita a,
Deepak Kumar Barange a, Aminul Islam a, K. Mukkanti b, Manojit Pal c,
*
a Dr. Reddy’s Laboratories Ltd, Bollaram Road, Miyapur, Hyderabad 500049, India
b Chemistry Division, Institute of Science and Technology, JNT University, Kukatpally, Hyderabad 500072, India
c New Drug Discovery, R&D Center, Matrix Laboratories Ltd, Anrich Industrial Estate, Bollaram, Jinnaram Mandal, Medak District, Andra Pradesh 502 325, India
a r t i c l e i n f o
a b s t r a c t
Article history:
We report copper-catalyzed intramolecular cyclization of 8-alkynyl-1,2,3,4-tetrahydroquinolines,
obtained via a Pd/C-mediated Sonogashira coupling in water, to afford 2-substituted 5,6-dihydro-4H-pyr-
rolo[3,2,1-ij]quinolines. Further functionalization of the compounds synthesized was carried out under
Heck, Sonogashira, and Suzuki reaction conditions.
Received 1 April 2009
Revised 5 June 2009
Accepted 9 June 2009
Available online 12 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Pyrrolo[3,2,1-ij]quinoline
Palladium
Copper
C–N bond
C–C bond
Because of their interesting pharmacological properties,1
5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline framework (A, Fig. 1),
has attracted particular attention in the area of new drug discovery.
For example, derivatives of compound A have shown potent hista-
mine and platelet activating factor antagonism and 5-lipoxygenase
inhibitory properties.2 A promising compound KC 11404 that
belongs to this class was identified as a lead candidate for the poten-
tial treatment of asthma. Another series of pyrrolo[3,2,1-ij]quino-
lines have been reported to be agonists at 5-HT2c (5-
hydroxytryptamine) with selectivity over 5-HT2a for the potential
treatment of epilepsy and obesity.3 They were also found to be key
intermediates for the synthesis of bioactive compounds.4,5
catalysts, this methodology was not established as a general proce-
dure for the synthesis of 2 or similar class of compounds. No de-
tailed study was conducted on the effect of other substituents
present on the alkynyl moiety. Due to our continuing interest in
the Cu-mediated cyclization processes7 herein, we report
a
new synthesis of 2-substituted 5,6-dihydro-4H-pyrrolo[3,2,1-ij]-
quinolines (2) under Cu-catalysis (path 2, Scheme 1) and their
use in the preparation of diversity-based compounds under Pd-
catalysis.
The starting alkynes (1) were prepared following a Pd/C-medi-
ated coupling reaction in water.8 Thus, 8-iodo-6-bromo-1,2,3,4-tet-
rahydroquinoline (3), prepared according to a known procedure,6
was reacted with a number of terminal alkynes in the presence of
10%Pd/C–CuI–PPh3 in water using 2-aminoethanol as a base to
afford the desired coupled products (1) in good yields. The results
are summarized in Table 1.
The intramolecular cyclization of alkyne 1a was examined using
a number of catalysts under various reaction conditions, for exam-
ple, (a) ICl or I2 in CH2Cl2 at 30 °C for 12 h or (b) I2/K2CO3 in aceto-
nitrile at 30 °C for 12 h or (c) AgSbF6/Et3N in ethanol at 30 °C for
36 h. However the best results were obtained by using CuI in
DMF at 100 °C for 12 h when the cyclized product 2a was isolated
in 85% yield (Table 2, entry 1). The use of other copper catalyst, for
example, Cu(OAc)2 was also examined but afforded lower yield of
product. To assess the generality of Cu-mediated intramolecular
C–N bond forming reaction7,9 we then treated other alkynes,
Whilea numberof methodshavebeenreported6 forthe synthesis
of compounds containing the moiety A, all these strategies can be
classified into two major categories, for example, construction of
(i) six-membered saturated ring using an indole template B or (ii)
five-membered ring using a suitably substituted 1,2,3,4-tetrahydro-
quinoline C. Recently, using the second approach, a Pd(II)-mediated
intramolecular cyclization of 8-arylethynyl-1,2,3,4-tetrahydroquino-
lines leading to 2-aryl derivatives of A has been reported6 (path 1,
Scheme 1). Perhaps due to the requirement of expensive Pd(II)
* Corresponding author at present address: Institute of Life Sciences, University
of Hyderabad Campus, Gachibowli, Hyderabad 500 046, Andhra Pradesh, India. Tel.:
+91 40 6657 1500; fax: +91 40 6657 1581.
E-mail addresses: manojitpal@rediffmail.com, manojitp@ilsresearch.org (M. Pal).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.041

M. Layek et al. / Tetrahedron Letters 50 (2009) 4878–4881
4879
construction of
6-membered ring
construction of
5-membered ring
N
NH
N
H
A
C
B
Figure 1. Pyrroloquinoline (A) and strategies for its synthesis.
were isolated in 50–72% yields (Table 3, entries 4–6). Suzuki reac-
tions were carried out by using 2a (1.0 equiv), a boronic acid
(1.5 equiv), (PPh3)4Pd (0.1 equiv), and 2.0 M Na2CO3 (3 equiv) in
1,4-dioxane at 80 °C (Table 3, entries 7–9).
Overall, compound 2a participated well in Pd-mediated C–C
bond forming reactions providing an array of appropriately func-
tionalized 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines (4). Thus an
easy access to 8-alkenyl or alkynyl or aryl-substituted products
Path 1 (Ref 6)
PdCl2,CH3CN,reflux,16h
R = 3,5-dimethyl phenyl; X
= Br (70%), CN (87%)
CO2Et (70%)
X
X
N
H
N
R
2
1
Path 2
R
Cu-cat.
R = aryl, alkyl; X = Br
Table 2
Synthesis of 2-substituted 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines (2) under Cu-
Scheme 1. Transition metal-mediated synthesis of 2-substituted 5,6-dihydro-4H-
pyrrolo[3,2,1-ij]quinolines.
catalysisa
Entry Alkynes
Time
(h)
Products
(2)
Yields
(%)
(1)
Table 1
Pd/C-mediated synthesis of 8-alkynyl-1,2,3,4-tetrahydroquinolines (1) in watera
Br
Br
R
N
H
Br
N
Br
10%Pd/C,CuI,PPh3
1
12.0
12.0
18.0
85
70
92
N
H
2-aminoethanol
H2O
N
H
I
2a
1a
1
3
R
Br
Br
Entry
Alkynes; R =
Time (h)
Products (1)
Yields (%)
N
H
1
2
3
4
5
C6H5
4.0
3.0
30.0
16.0
18.0
1a
1b
1c
1d
1e
85
95
40
57
51
N
C6H4CH3-p
C6H4NO2-o
CH2CH2OH
(CH2)3OH
2
a
All reactions were carried out by using
(3.0 equiv), 1:4:2 ratio of Pd/C–PPh3–CuI and 2-aminoethanol (3 equiv) in water at
3 (1.0 equiv), terminal alkyne
1b
1c
2b
2c
80 °C.
Br
Br
N
H
N
that is, 1b–e with CuI in DMF and the results are presented in
Table 2. All the 8-arylethynyl-1,2,3,4-tetrahydroquinolines (1a–c)
provided the desired products (2a–c) in good yields (Table 2,
entries 1–3) whereas the 8-alkylethynyl derivatives (1d–e) affor-
ded the corresponding products (2d–e) in moderate yields (Table
2, entries 4 and 5).10
3
NO2
NO2
Br
Br
Br
Having prepared a number of 8-bromo derivatives of 2-substi-
tuted 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinoline we decided to
explore the reactivity of bromo group toward palladium-catalyzed
reactions. Conversely, to demonstrate the scope of this Cu-medi-
ated reaction we opted for further structural elaboration of the
compounds synthesized. Accordingly, bromo derivative 2a was ex-
posed to Heck, Sonogashira, and Suzuki coupling reactions (Table
3). Heck reactions were carried out by using 2a (1.0 equiv), an
appropriate alkene (4.0 equiv), Pd(OAc)2 (0.1 equiv), n-Bu4NCl
(1.0 equiv), and Na2CO3 (3 equiv) in DMF at 85 °C. After usual
workup corresponding coupled products were isolated in good to
moderate yields (Table 3, entries 1–3). Sonogashira reactions were
carried out using 2a (1.0 equiv), a terminal alkyne (3.0 equiv),
(PPh3)2PdCl2 (0.1 equiv), CuI (0.06), and Et3N (5.0 equiv) in acetoni-
trile at refluxing temperature. The corresponding internal alkynes
N
H
N
CH2CH OH2
4
18.0
50
CH CH OH1d
2
2
2d
Br
N
H
N
5
12.0
57
CH2CH2CH2OH
CH2CH2CH2OH
2e
1e
a
All reactions were carried out by using 1 (1.0 equiv) and CuI (0.1 equiv) in DMF
at 100 °C.

4880
M. Layek et al. / Tetrahedron Letters 50 (2009) 4878–4881
Table 3
Heck, Sonogashira, and Suzuki coupling reactions of 2a
C-C bond forming
reaction
W
Br
W = alkenyl (Heck)
= alkynyl (Sonogashira)
= aryl (Suzuki)
N
N
Pd-catalysis
Ph
Ph
2a
4
Entry no.
Reactants
Time (h)
Products
Yielda (%)
H3CO2C
O
1
24.0
70
N
O
Ph
4a
C2H5O2C
O
O
2
3
36.0
36.0
60
55
N
O
O
Ph
4b
4c
ButO2C
N
Ph
Ph
4
5
24.0
30.0
72
54
N
Ph
4d
HO
OH
N
Ph
4e
HO
Ph
6
7
36.0
12.0
50
70
N
OH
Ph
4f
OH
OH
B
N
Ph
4g
O
H3COC
HOH2C
8
4.0
6.0
70
50
OH
OH
B
N
Ph
4h
4i
OH
9
OH
OH
N
B
Ph
a
Isolated yields.

M. Layek et al. / Tetrahedron Letters 50 (2009) 4878–4881
4881
Br
Br
+ BH+
-Cu (I)
2
N
N
R
H
B
Cu(I)
(I) Cu
R
Y
X
B = DMF
Scheme 2. Probable mechanism for the Cu-mediated intramolecular cyclization of alkyne 1.
2. Paris, D.; Cottin, M.; Demonchaux, P.; Augert, G.; Dupassieux, P.; Lenoir, P.;
Peck, M. J.; Jasserand, D. J. Med. Chem. 1995, 38, 669–685.
3. Isaac, M.; Slassi, A.; O’Brien, A.; Edwards, L.; MacLean, N.; Bueschkens, D.; Lee,
D. K. H.; McCallum, K.; Lannoy, I. D.; Demchyshyn, L.; Kamboj, R. Bioorg. Med.
Chem. Lett. 2000, 10, 919–921.
4. Al-awar, R. S.; Ray, J. E.; Hecker, K. A.; Huang, J.; Waid, P. P.; Shih, C.; Brooks, H.
B.; Spencer, C. D.; Watkins, S. A.; Patel, B. R.; Stamm, N. B.; Ogg, C. A.; Schultz, R.
M.; Considine, E. L.; Faul, M. M.; Sullivan, K. A.; Kolis, S. P.; Grutsch, J. L.; Joseph,
S. Bioorg. Med. Chem. Lett. 2004, 14, 3217–3220.
5. Zhu, G.; Conner, S. E.; Zhou, X.; Chan, H.-K.; Shih, C.; Engler, T. A.; Al-awar, R. S.;
Brooks, H. B.; Watkins, S. A.; Spencer, C. D.; Schultz, R. M.; Dempsey, J. A.;
Considine, E. L.; Patel, B. R.; Ogg, C. A.; Vasudevan, V.; Lytle, M. L. Bioorg. Med.
Chem. Lett. 2004, 14, 3057–3061.
6. Marchand, P.; Puget, A.; Baut, G. L.; Emig, P.; Czech, M.; Günther, E. Tetrahedron
2005, 61, 4035–4041. and references cited therein.
7. Barange, D. K.; Nishad, T. C.; Swamy, N. K.; Bandameedi, V.; Kumar, D.;
Sreekanth, B. R.; Vyas, K.; Pal, M. J. Org. Chem. 2007, 72, 8547.
8. Pal, M.; Batchu, V. R.; Subramanian, V.; Parasuraman, K.; Swamy, N. K.; Kumar,
S. Tetrahedron 2005, 61, 9869.
9. Ezquerra, J.; Pedregal, C.; Lamas, C.; Barluenga, J.; Prez, M.; Garca-Martin, G. A.;
Gonzlez, J. M. J. Org. Chem. 1996, 61, 5804.
has been demonstrated via Heck, Sonogashira, or Suzuki reaction,
respectively.
AplausiblemechanismfortheCu-mediatedintramolecularcycli-
zation of alkyne 1 is shown in Scheme 2. The reaction seemed to pro-
ceed via initial activation of the triple bond of 1 via coordination to
the Cu-salt to form the
r-complex X. Regioselective nucleophilic
attack of the tetrahydroquinoline moiety to the Cu-coordinated tri-
ple bond through its nitrogen in an endo dig fashion provides the Cu-
vinyl species Y. This on subsequent protonation in situ regenerates
the catalyst producing the pyrroloquinolines (2).
In conclusion, we have developed a new strategy for the intra-
molecular cyclization of 8-alkynyl 1,2,3,4-tetrahydroquinoline to
afford 5,6-dihydro-4H-pyrrolo[3,2,1-ij]quinolines directly with
high regioselectivity. The reaction proceeds via C–N bond forming
reaction in the presence of Cu-catalyst. Further functionalization of
the compounds synthesized was carried out under Sonogashira,
Heck, and Suzuki reaction conditions. The methodology therefore
should find applications in the short synthesis of pyrroloquino-
line-based compounds of potential pharmacological interest.
10. Spectra data for selected compounds: compound 2a: white solid; mp 103–
105 °C; Rf (10% ethyl acetate/n-hexane) 0.35; 1H NMR (DMSO-d6, 400 MHz) d
7.62–7.41 (m, 6H, Ar-H), 7.03 (s, 1H, Ar-H), 6.54 (s, 1H, –CH@), 4.19 (t,
J = 5.2 Hz, 2H, –CH2), 2.93 (t, J = 5.6 Hz, 2H, –CH2), 2.07–2.13 (m, 2H, –CH2); 13
C
NMR (DMSO-d6, 200 MHz) d 22.4 (–CH2), 23.9 (–CH2), 43.3 (–CH2), 99.5, 112.1,
119.5, 120.7, 124.5, 126.9, 127.9, 128.2 (2C), 128.4, 128.7, 131.4, 133.4, 140.5;
IR (cmÀ1, KBr) 2929, 1475, 763; Mass (ES) m/z 314.1 (M+3, 100%); HRMS (ESI):
calcd for C17H15BrN (M+H)+ 312.039, found 312.038; compound 2b: yellow
solid; mp 92–95 °C; Rf (10% ethyl acetate/n-hexane) 0.35; 1H NMR (DMSO-d6,
400 MHz) d 7.5 (m, 3H, Ar-H), 7.30 (d, J = 7.8 Hz, 2H, Ar-H), 7.01 (s, 1H, Ar-H),
6.49 (s, 1H, –CH@), 4.17 (t, J = 5.2 Hz, 2H, –CH2), 2.92 (t, J = 5.6 Hz, 2H, –CH2),
2.37 (s, 3H, CH3), 2.12–2.07 (m, 2H, –CH2); 13C NMR (DMSO-d6, 200 MHz) d
20.7 (–CH3), 22.4 (–CH2), 23.9 (–CH2), 43.2 (–CH2), 99.0, 112.0, 119.3, 120.5,
124.4, 126.9, 128.1 (2C), 128.5, 129.3 (2C), 133.4, 137.4, 140.6; IR (cmÀ1, KBr)
2924, 1720, 1477, 829; Mass (ES) m/z 326.0 (M+1, 100%); HRMS (ESI): calcd for
C18H17BrN (M+H)+ 326.054, found 326.054; compound 2d: colorless liquid; Rf
(50% ethyl acetate/n-hexane) 0.3; 1H NMR (DMSO-d6, 400 MHz) d 7.39 (d,
J = 1.9 Hz, 1H, Ar-H), 6.89 (d, J = 1.5 Hz, 1H, Ar-H), 6.14 (s, 1H, –CH@), 4.65 (br s,
1H, –CH2OH), 4.04 (t, J = 5.6 Hz, 2H, –CH2), 3.68 (t, J = 6.8 Hz, 2H, –CH2), 2.90–
2.87 (m, 4H, –CH2), 2.13–2.06 (m, 2H, –CH2); 13C NMR (DMSO-d6, 200 MHz) d
22.1 (–CH2), 23.8 (–CH2), 36.1 (–CH2), 41.1 (–CH2), 60.2 (–CH2), 97.7, 111.4,
118.6, 119.4, 123.4, 126.9, 132.5, 139.1; IR (cmÀ1, CHCl3) 2928, 1717, 1480,
1216, 769; Mass (ES) m/z 282.0 (M+3, 100%); HRMS (ESI): calcd for C13H15BrNO
(M+H)+ 280.033, found 280.033.
Acknowledgments
The authors thank Dr. V. Dahanukar and Mr. A. Mukherjee for
their encouragement and the analytical group of DRL for spectral
data. Mr. M.L. thanks CPS-DRL, Hyderabad, India for allowing him
to pursue this work as a part of his Ph.D. program.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.06.041.
References and notes
1. Stanton, J. L.; Ackerman, M. H. J. Med. Chem. 1983, 26, 986–989.