Synthesis of novel pyrrolo-[3,2-c]quinolines via iron-catalyzed cross-coupling reaction of grignard reagents

Article abstract of DOI:10.1080/00397910802550039

Cross-coupling reaction of alkyl and aryl magnesium halides with 4-chloro-pyrrolo-[3,2-c]quinoline in the presence of a catalytic amount of iron salt is described. The reactions are completed in 30min, resulting in moderate to excellent yields of 52-94% i

Full text of DOI:10.1080/00397910802550039

This article was downloaded by: [Michigan State University]
On: 25 March 2015, At: 04:19
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of Novel Pyrrolo-
[3,2-c]quinolines via Iron-
Catalyzed Cross-Coupling
Reaction of Grignard Reagents
Evelina Colacino a , Hafid Benakki a b , Farhate
Guenoun b , Jean Martinez a & Frédéric Lamaty a
a Institute of Biomolecules Max Mousseron,
University of Montpellier , Montpellier, France
b My Ismaïl University, Faculty of Sciences , Meknès,
Morocco
Published online: 02 Apr 2009.
To cite this article: Evelina Colacino , Hafid Benakki , Farhate Guenoun , Jean
Martinez & Frédéric Lamaty (2009) Synthesis of Novel Pyrrolo-[3,2-c]quinolines
via Iron-Catalyzed Cross-Coupling Reaction of Grignard Reagents, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 39:9, 1583-1591, DOI: 10.1080/00397910802550039
To link to this article: http://dx.doi.org/10.1080/00397910802550039
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,

or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with
primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communications1, 39: 1583–1591, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802550039
Synthesis of Novel Pyrrolo-[3,2-c]quinolines via
Iron-Catalyzed Cross-Coupling Reaction of
Grignard Reagents
Evelina Colacino,1 Hafid Benakki,1,2 Farhate Guenoun,2
1
Jean Martinez, and Frederic Lamaty
1
´ ´
1Institute of Biomolecules Max Mousseron, University of Montpellier,
Montpellier, France
2
`
My Isma¨ıl University, Faculty of Sciences, Meknes, Morocco
Abstract: Cross-coupling reaction of alkyl and aryl magnesium halides with
4-chloro-pyrrolo-[3,2-c]quinoline in the presence of a catalytic amount of iron salt
is described. The reactions are completed in 30 min, resulting in moderate to
excellent yields of 52–94% in a tetrahydrofuran (THF)–N-methylpyrrolidinone
(NMP) solvent mixture.
Keywords: Cross-coupling, imidoyl chloride, iron catalysis, nitrogen heterocycles,
organomagnesium reagents
Very few metal-catalyzed cross-coupling reactions of imidoyl chlorides
have been studied, and most of the reported reactions require the use
of expensive palladium or toxic nickel catalysts.[1] Despite their excellent
compatibility with many functional groups, their high cost, toxicity, the
need for ancillary ligands, extended reaction time, and elevated tempera-
ture are the most common disadvantages of their use. In contrast, Fe(acac)3
as catalyst for cross-coupling reaction is very cheap, easily available,
nontoxic, environmentally benign, and easy to handle (nonhygroscopic),
Received September 11, 2008.
Address correspondence to Frederic Lamaty, Institut des Biomolecules
´ ´
Max Mousseron, UMR 5247 CNRS, Universite Montpellier, 1 et Universite
´
´
Montpellier 2, Place Eugene Bataillon, 34095 Montpellier cedex 05, France.
´
`
E-mail: frederic.lamaty@univ-montp2.fr
1583

1584
E. Colacino et al.
and the reactions are usually characterized by high rates under mild
conditions.[2–7]
As a continuation of our ongoing studies of the development of novel
routes for the synthesis of substituted pyrroles,[8–10] we decided to
investigate the cross-coupling reaction between the 4-chloro-1H-
pyrrolo-[3,2-c]quinoline 1, synthesized as previously reported by us,[10]
in the presence of alkyl and aryl Grignard reagents, catalyzed by an iron
salt. No examples are described in the literature for the cross-coupling
reaction between imidoyl chloride, confined in a pyrrolo-quinoline struc-
ture, and Grignard reagents in the presence of Fe(acac)3 as catalyst.
In a typical experiment, the imidoyl chloride 1 was reacted in the
presence of Fe(acac)3 (5 mol%) with different Grignard reagents in a
10:1 mixture of tetrahydrofuran (THF)=NMP at room temperature,
leading to a new series of pyrrolo-[3,2-c]quinoline derivatives 2–7
(Scheme 1, Table 1). The results are summarized in Table 1.
Under iron-free reaction conditions, no reaction occurred, confirming
the importance of iron catalyst in the rapid and high-yielding reactions.
The kinetic study by thin-layer chromatography (TLC) and high per-
formance liquid chromatography (HPLC) showed a completed reaction
after only 30 min at room temperature. Our reaction conditions proved
to be general for the formation of Csp2 ꢀ Csp3 and Csp2 ꢀ Csp2 bonds,
and the ortho-substitution on the imidoyl chloride with the pyrrole ring
does not affect the yield.
The analysis of the crude products by HPLC and liquid chromato-
graphy–mass spectrometry (LC-MS) showed the formation of the
expected products along with some by-products, according to four main
secondary reactions responsible for the moderate yield obtained in some
cases: (i) dehalogenation reaction of imidoyl chloride 1 to afford the cor-
responding unsubstituted imine (entries 2–6); (ii) hydrolysis of the imine
function in 1 to afford the corresponding cyclic amide[10] (entries 1–3);
(iii) homocoupling of imidoyl chloride 1 (entry 7); and (iv) the oxidative
dimerization of the Grignard reagents.[3]
For alkyl Grignard reagents (entries 1–4, Table 1), independent of
the nature of halogen atom (RMgX, X ¼ I, Br, Cl), the cross coupling
products 2–5 were obtained in moderate to good yields. Contrary to pre-
vious reports on the reactivity of the secondary alkyl Grignard, for which
[Fe(salen)Cl][2,3] should be used to achieve the cross-coupling reaction, in
our case a good yield of product 4 could be obtained in the presence of
Fe(acac)3. With the more sterically demanding 2-methyl-2-phenylpropyl-
magnesium chloride (entry 8), coupling with imidoyl chloride 1 was
unsuccessful, and the unreacted substrate 1 was recovered. When the less
hindered substrate benzylmagnesium chloride (entry 5) was used, the
cross-coupling product 6 was obtained in a satisfactory yield.

Novel Pyrrolo-[3,2-c]quinolines
1585
Table 1. Cross-coupling product of imidoyl chloride 1 in the presence of RMgX
Entry
1
RMgX
MeMgI
Product
Yield (%)a
52
2
3
2
3
EtMgBr
74
86
i-PrMgCl
4
4
5
BuMgCl
5
6
64
PhCH2MgCl
60
(Continued )

1586
E. Colacino et al.
Table 1. Continued
Entry
6
RMgX
Product
Yield (%)a
CH2¼CHCH2MgBr
7
8
Traces
7
PhMgCl
94b
8
(CH3)2CH(Ph)MgCl
–
9
0
aIsolated yield after purification on column chromatography;
bThe product was recovered by crystallization from CH2Cl2.
Only traces of product 7 (entry 6) were obtained in the presence
of allyl magnesium bromide, and the result could not be improved by
adding some more catalyst (10% mol), extending the reaction time (up
to 24 h), adding an excess of Grignard reagent, or heating the mixture
up to 60ꢁC, classically or under microwave activation. In all cases,
unreacted 1 was recovered.
To our great satisfaction, the aryl–aryl bond formation was successful
when phenyl magnesium chloride was coupled with imidoyl chloride 1,
affording compound 8 in a very high yield (entry 7). In this case, the cat-
alytic decomposition of the Grignard reagent[11–13] to afford biphenyl in
the presence of transition-metal salts and aryl halides acting as oxidizing
agents is diminished. This is may be due to the lower oxidizing power of
the pyrrolo-quinoline aromatic system, showing that the reaction is applic-
able to p-electron-deficient heterocycles,[3,5] associated with a stabilization
of frontier orbital energy, which allow the reaction to proceed.
In conclusion, we have shown that the developed conditions are quite
general and mild for the formation of Csp2 ꢀ Csp3 and Csp2 ꢀ Csp2 bonds,
affording differently substituted pyrrolo-quinoline derivatives, which are
useful scaffolds for medicinal chemistry.[14,15]

Novel Pyrrolo-[3,2-c]quinolines
1587
EXPERIMENTAL
General
All reagents were purchased from Aldrich Chemical Co. and used without
further purification. 1H and 13C NMR analyses were performed with Bru-
ker Avance DPX 200-MHz, Bruker Avance AM 300-MHz or Bruker AC
400-MHz instruments, reported in parts per million (ppm), and calibrated
using residual undeuterated solvents as an internal reference. Data are
reported as br ¼ broad, s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
and m ¼ multiplet, and coupling constant(s) are in Hertz (Hz). Mass spec-
tra (electrospray ionization mode, ESI-MS) were recorded on a Platform
II (Micromass, Manchester, U.K.) quadrupole mass spectrometer fitted
with an electrospray interface. The mass spectrometer was calibrated in
the positive- and negative-ion ESI mode. The samples were dissolved in
H2O=CH3CN (50=50 v=v). Fast atom bombardment (FAB) mass spectra
and HRMS (high-resolution mass spectrum) were recorded on a Jeol JMS
DX300-S ꢂ 102 instrument in positive mode using NBA (3-nitrobenzylal-
cool) or GT (mixture of glycerol=thioglycerol 50=50 v=v) as matrix. Infra-
red (IR) spectra were recorded by diffuse reflectance or by transmittance
in KBr salt plates on a Nicolet Avatar 330FT-IR instrument. Data are
reported according their group absorption regions as s ¼ strong,
m ¼ medium, and w ¼ weak. Analytical high-performance liquid chroma-
tography (HPLC) was performed on a Waters Millenium 717 instrument
equipped with autosampler and a variable-wavelength diode detector
using a Chromolith RP18 column (50 ꢂ 4.6 mm) [flow 5 mL=min, linear
gradient CH3CN in water 0–100% (þ0.1% TFA)] in 4.5 min.
Representative Experimental Procedure for the Iron-Catalyzed
Synthesis of Compounds 2–8
A flame-dried flask was charged under nitrogen with 4-chloro-1H-pyrrolo-
[3,2-c]quinoline 1[7] (0.093 mmol, 20 mg), Fe(acac)3 (0.05 mol, 1.64mg), and
THF=NMP 10:1 v=v (2.2 mL). A solution of the Grignard reagent (2.0 M
in THF, 0.1 mL, 0.186 mmol) was added via syringe to the solution, and
the resulting mixture was stirred for 30 min at room temperature.
Then, the reaction mixture was diluted with Et2O (10 mL) and carefully
quenched upon addition of sat. NH4Cl (5 mL). The organic phase was
washed with water (2 ꢂ 10mL) and with sat. NaCl (1 ꢂ 10 mL). The
organic phase was dried on MgSO4, filtered, and evaporated. The crude
was purified by column chromatography (compounds 3–6; eluent is

1588
E. Colacino et al.
given in brackets for each compound) or by hot recrystallization
(compounds 2 and 8).
Data
1,4-Dimethyl-1H-pyrrolo[3,2-c]quinoline (2)
Hot crystallization from n-pentane afforded 9.39 mg (52% yield) of com-
1
pound 2. Product decomposes at temperatures greater than 200ꢁC. H
NMR (CDCl3, Me4Si) d (ppm): 3.23 (s, 3H), 4.34 (s, 3H), 6.92 (d,
J ¼ 3.2 Hz, 1H), 7.29 (d, J ¼ 3.2 Hz, 1H), 7.67–7.76 (m, 2H), 8.39 (d,
J ¼ 8.2 Hz, 1H), 8.97 (d, J ¼ 8.2 Hz, 1H); 13C NMR (CDCl3, Me4Si) d
(ppm) 17.77, 38.56, 104.84, 116.63, 120.40, 120.77, 122.98, 128.08,
129.56, 133.37, 134.97, 135.74, 152.41; ESI-MS m=z 197.2 [M þ H]þ.
HRMS calcd. for C13H13N2 197.1082; found 197.1079.
4-Ethyl-1-methyl-1h-Pyrrolo[3,2-c]quinoline (3)
Purification of the crude by column chromatography [cyclohexane=Et2O:
linear gradient 100=0–30=70 v=v) afforded 14 mg (74% yield) of 3. Mp
1
84–88ꢁC; H NMR (CDCl3, Me4Si) d (ppm): 1.38–1.43 (t, J ¼ 7.5 Hz,
3H), 3.13–3.2 (q, J ¼ 7.5 Hz, 4H), 4.22 (s, 3H). 6.67 (d, J ¼ 2.9 Hz, 1H),
7.03 (d, J ¼ 2.9 Hz, 1H), 7.44–7.56 (m, 2H), 8.18 (d, J ¼ 7.4 Hz, 1H),
1
8.30 (d, J ¼ 8.0 Hz, 1H); H NMR [(CD3)2CO, Me4Si] d (ppm): 8.35
(dd, J ¼ 6.8 and 1.5 Hz, 1H), 7.97 (dd, J ¼ 6.8 and 1.5 Hz, 1H), 7.49–
7.31 (m, 2H), 7.17 (d, J ¼ 3.1 Hz, 1H), 6.62 (d, J ¼ 3.1 Hz, 1H), 4.15 (s,
3H), 3.03 (q, J ¼ 7.3 Hz, 2H), 1.29 (t, J ¼ 7.3 Hz, 3H); 13C NMR (CDCl3,
Me4Si) d (ppm): 13.78, 29.69, 38.02, 101.79, 118.23, 120.19, 120.76,
125.00, 126.30, 129.42, 134.14, 159.35; 13C NMR [(CD3)2CO, Me4Si] d
(ppm): 136.18, 132.4 (2C), 132.0, 128.6, 128.2, 127.3, 127.2, 124.3,
123.6, 122.9, 121.1, 39.9, 15.1. ESI-MS m=z 211.1 [MþH]þ HRMS calcd.
for C14H15N2 211.1235; found 211.1238.
4-Isopropyl-1-methyl-1H-pyrrolo[3,2-c]quinoline (4)
Purification of the crude by column chromatography [cyclohexane=Et2O:
1
linear gradient 100=0–80=20 v=v) afforded 18 mg (86% yield) of 4. H
NMR (CDCl3, Me4Si) d (ppm): 1.44 (d, J ¼ 6.9 Hz, 6H), 3.52–3.61 (m,
1H), 8.38 (s, 3H), 6.69 (d, J ¼ 2.5 Hz, 1H), 7.00 (d, J ¼ 2.5 Hz, 1H),
7.41–7.54 (m, 2H), 8.19 (d, J ¼ 6.7 Hz, 1H), 8.27 (d, J ¼ 8.00 Hz, 1H);

Novel Pyrrolo-[3,2-c]quinolines
1589
13C NMR (CDCl3, Me4Si) d (ppm): 22.69, 29.70, 38.08, 118.13, 120.13,
121.22, 125.08, 126.33, 129.43, 131.40, 134.31, 162.42; ESI-MS m=z
225.1 [MþH]þ.
4-Butyl-1-methyl-1H-pyrrolo[3,2-c]quinoline (5)
Purification of the crude by column chromatography [cyclohexane=Et2O:
linear gradient 100=0–80=20 v=v) afforded 14 mg (64% yield) of com-
1
pound 5. Mp 80–82ꢁC; H NMR (CDCl3, Me4Si) d (ppm): 0.85–0.96
(t, J ¼ 3.0 Hz, 3H), 1.38–1.49 (m, 2H), 1.80–1.86 (m, 2H), 3.1 (t,
J ¼ 8.0 Hz, 2H), 4.22 (s, 3H), 6.65 (d, J ¼ 3.7 Hz, 1H); 7.01 (d, J ¼ 3.7 Hz,
Hz, 1H), 7.42–7.55 (m, 2H), 8.13 (d, J ¼ 8.2 Hz, 1H), 8.30 (d, J ¼ 8.2 Hz,
1H); 13C NMR (CDCl3, Me4Si) d (ppm): 14.26, 23.27, 32.05, 36.63, 38.21,
101.98, 118.48, 120.38, 121.46, 125.00, 126.32, 129.40, 134.19, 158.76;
ESI-MS m=z 239.0 [MþH]þ. HRMS calcd. for C16H19N2 239.1545;
found 239.1548.
4-Benzyl-1-methyl-1H-pyrrolo[3,2-c]quinoline (6)
Purification of the crude by column chromatography [cyclohexane=Et2O:
linear gradient 100=0–60=40 v=v) afforded 15 mg (60% yield) of com-
pound 6. Mp 68–70ꢁC; 1H NMR (CDCl3, Me4Si) d (ppm): 4.17 (s,
3H), 4.5 (s, 2H), 6.52 (d, J ¼ 3.0 Hz, 1H), 7.01 (d, J ¼ 3.0 Hz, 1H),
7.06–7.11 (m, 3H), 7.15–7.19 (m, 2H), 7.45–7.58 (m, 2H), 8.22 (d,
J ¼ 7.9 Hz, 1H), 8.30 (d, J ¼ 8.3 Hz, 1H); 13C NMR (CDCl3, Me4Si) d
(ppm): 42.72, 53.42, 102.38, 118.31, 120.22, 121.24, 125.42, 126.28,
126.51, 128.17, 128.43, 128.93, 129.34, 129.75, 129.95, 134.52, 139.05,
155.86, ESI-MS m=z 273.2 [MþH]þ. HRMS calcd. for C19H17N2
273.1393; found 273.1392.
1-Methyl-4-phenyl-1H-pyrrolo[3,2-c]quinoline (8)
Hot crystallization from CH2Cl2 afforded 22.3 mg (94% yield) of
1
compound 8. Mp 124–126ꢁC; H NMR (CDCl3, Me4Si) d (ppm): 4.25
(s, 3H), 6.78 (d, J ¼ 3.1 Hz, 1H), 7.23 (d, J ¼ 3.1 Hz, 1H), 7.40–7.61
(m, 5H), 7.97 (d, J ¼ 2.9 Hz, 2H), 8.34 (d, J ¼ 2.9 Hz, 2H); 13C NMR
(CDCl3, Me4Si) d (ppm): 38.2, 102.4, 118.3, 120.2, 120.4, 125.3,
126.3, 128.8, 129.1, 129.7, 130.7, 134.9, 140,7, 144.7, 154.7; ESI-MS
m=z 259.19 [M þH]þ. HRMS calcd. for C18H15N2 259.1235; found
259.1238.

1590
E. Colacino et al.
ACKNOWLEDGMENT
`
We thank the Ministere de l’Education Nationale, de la Recherche et de
la Technologie (MENRT), the Centre National de la Recherche Scienti-
fique (CNRS), and la Ligue contre le Cancer for financial support.
REFERENCES
1. Ottesen, L. K.; Ek, F.; Olsson, R. Iron-catalyzed cross-coupling of imidoyl
chloride with Grignard reagents. Org. Lett. 2006, 8, 1771–1773 and references
cited therein.
2. Furstner, A.; Leitner, A. Iron-catalyzed cross-coupling reactions of alkyl-
¨
Grignard ragents with aryl chlorides, tosylates, and triflates. Angew. Chem.
Int. Ed. 2002, 41, 609–612.
3. Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. Iron-catalyzed cross-
¨
coupling reactions. J. Am. Chem. Soc. 2002, 124, 13856–13863.
4. Furstner, A.; Leitner, A. A catalytic approach to (R)-(þ)-muscopyridine with
¨
integrated self-clearance. Angew. Chem. Int. Ed. 2003, 42, 308–311.
`
5. Quintin, J.; Franck, X.; Hocquemiller, R.; Figadere, B. Iron-catalyzed
arylation of heteroaryl halides by Grignard reagents. Tetrahedron Lett.
2002, 43, 3547–3549.
6. Bo¨lm, C.; Legros, J.; Le Paih, J.; Zani, L. Iron-catalyzed reactions in organic
synthesis. Chem. Rev. 2004, 104, 6217–6254.
7. Furstner, A.; Martin, R. Advances in iron-catalyzed cross-coupling reactions.
¨
Chem. Lett. 2005, 34, 624–629.
8. Declerck, V.; Ribiere, P.; Martinez, J.; Lamaty, F. Sequential aza-Baylis-
Hillman=ring closing methatesis=aromatization as a novel route for the
synthesis of substituted pyrroles. J. Org. Chem. 2004, 69, 8372–8381.
9. Declerck, V.; Allouchi, H.; Martinez, J.; Lamaty, F. 2-Trimethylsilylethane-
sulfonyl (SES) versus Tosyl (Ts) protecting group in the preparation of
nitrogen-containing five-membered rings. A novel route for the synthesis of
substituted pyrrolines and pyrrolidines. J. Org. Chem. 2007, 72, 1518–1521.
´
10. Benakki, H.; Colacino, E.; Andre, C.; Guenoun, F.; Martinez, J.; Lamaty, F.
Microwave-assisted multistep synthesis of novel pyrrolo-[3,2-c] quinoline
derivatives. Tetrahedron 2008, 64, 5949–5955.
11. Kharasch, M. S.; Reinmuth, O. Grignard Reactions of Nonmetallic
Substances; Prentice Hall: New York, 1954.
12. Kharasch, M. S.; Fields, E. K. Factors determining the course and mechanisms
of Grignard eactions. IV. The effect of metallic halides on the reaction of aryl
Grignard reagents and organic halides. J. Am. Chem. Soc. 1941, 63, 2316–2320.
13. Kharasch, M. S.; Nudenberg, W.; Archer, S. Factors determining the course
and mechanisms of Grignard reactions. VIII. The effect of metallic halides on
the reaction of Grignard reagents with aromatic acyl halides. J. Am. Chem.
Soc. 1943, 65, 495–498.
14. Brown, T. H.; Ife, R. J.; Keeling, D. J.; Laing, S. M.; Leach, C. A.; Parsons,
M. E.; Price, C. A.; Reavill, D. R.; Wiggall, K. J. Reversible inhibitors of the

Novel Pyrrolo-[3,2-c]quinolines
1591
gastric (Hþ=Kþ)-ATPase. 1. 1-Aryl-4-methylpyrrolo[3,2-c]quinolines as
conformationally restrained analogs of 4-(arylamino)quinoleines. J. Med.
Chem. 1990, 33, 527–533.
15. Cappelli, A.; Anzini, M.; Vomero, S.; Canullo, L.; Mennuni, L.; Makovec,
F.; Doucet, E.; Hamon, M.; Menziani, M. C.; De Benedetti, P. G.; Bruni,
G.; Romeo, M. R.; Giorgi, G.; Donati, A. Novel potent and selective central
5-HT3 receptor ligands provided with different intrinsic efficacy. 2. Molecular
basis of the intrinsic efficacy of arylpiperazine derivatives at the central 5-HT3
receptors. J. Med. Chem. 1999, 42, 1556–1575.