AlCl3 induced C-arylation/cyclization in a single pot: A new route to benzofuran fused N-heterocycles of pharmacological interest

Article abstract of DOI:10.1016/j.tetlet.2011.12.096

A new and one-pot synthesis of benzofuran fused N-heterocycles has been accomplished via AlCl₃-mediated C-C followed by C-O bond formation between 2,3-dichloropyrazine or its derivatives and phenols. The methodology provided novel compounds as

Full text of DOI:10.1016/j.tetlet.2011.12.096

Tetrahedron Letters 53 (2012) 1134–1138
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
AlCl3 induced C-arylation/cyclization in a single pot: a new route
to benzofuran fused N-heterocycles of pharmacological interest
K. Shiva Kumar a, Raju Adepu a, Ravikumar Kapavarapu a, D. Rambabu a, G. Rama Krishna b,
C. Malla Reddy b, K. Krishna Priya a, Kishore V. L. Parsa a, Manojit Pal a,
⇑
a Institute of Life Sciences, University of Hyderabad Campus, Gachibowli, Hyderabad 500 046, India
b Department of Chemical Sciences, Indian Institute of Science Education and Research, Kolkata, West Bengal 741 252, India
a r t i c l e i n f o
a b s t r a c t
Article history:
A new and one-pot synthesis of benzofuran fused N-heterocycles has been accomplished via AlCl3-
mediated C–C followed by C–O bond formation between 2,3-dichloropyrazine or its derivatives and
phenols. The methodology provided novel compounds as potential inhibitors of PDE4B. The single crystal
X-ray data of a synthesized benzofuran derivative are presented. Scope of the methodology, in vitro phar-
macological data of some of the synthesized compounds, along with docking study of an active compound
are described.
Received 6 December 2011
Revised 19 December 2011
Accepted 22 December 2011
Available online 30 December 2011
Keywords:
Benzofuran
2,3-Dichloropyrazine
AlCl3
Ó 2011 Elsevier Ltd. All rights reserved.
X-ray
PDE4
Conformational restriction of bioactive molecules offers the
possibility of generating attractive structures that may provide
valuable insights regarding the interaction of the precursory flexi-
ble molecule with the putative receptor or enzyme. A series of
polycyclic derivatives B therefore were generated by introducing
restrictions in the parent compounds A (Fig. 1).1a
Since this strategy has been viewed as a potential opportunity
for the identification of compounds possessing increased potency,
we became interested in the synthesis and pharmacological evalu-
ation of a series of nitrogen containing heterocycles C possessing
benzofuran moiety as a central ring ( Fig. 2). We were further
encouraged by the pharmacological properties of similar class of
compounds, for example, D (Elbfluorene—ALX-270-389) as selec-
OR
OR
X
X
N
O
N
O
B
A
Figure 1. Design of polycyclic structure B via conformational restriction of ether
derivative A.
N
N
O
O
N
tive inhibitor of cyclin-dependent kinase
1 (CDK1/cyclin B;
N
N
IC50 = 4.2
l
M)1b or a benzofuro[3,2-d]pyrimidine derivative MP-
N
N
OH
470 (E) as an inhibitor of multitargeted receptor tyrosine kinase
(Fig. 2).2 Both the compounds are presently undergoing phase 1
clinical trials. In our effort3 to identify novel inhibitors of PDE4
(phosphodiesterase 4) we were particularly interested in assessing
PDE4 inhibitory properties of compounds C in vitro. While PDE4
inhibitory properties of benzofuran derivatives have been reported
earlier4–6 to the best of our knowledge the use of benzofuran fused
N-heterocycle has not been explored as a potential template for the
discovery of novel PDE4 inhibitors.
O
O
O
O
S
N
H
C
E
D
Figure 2. Benzofuran fused N-heterocycles: designed compound C and reported
bioactive molecules D and E.
A number of methods have been reported for the synthesis of
benzo[4,5]furo heterocycles1,7 which include (i) construction of
the heterocyclic ring on the furan ring of benzofuran moiety, (ii)
intramolecular cyclization (C–C bond formation) leading to a furan
⇑
Corresponding author. Tel.: +91 40 6657 1500; fax: +91 40 6657 1581.
E-mail addresses: manojitpal@rediffmail.com, palmanojit@yahoo.co.uk (M. Pal).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.12.096

K. S. Kumar et al. / Tetrahedron Letters 53 (2012) 1134–1138
1135
Table 1
The reaction of 1a with 2a under various conditionsa
N
N
Cl
Cl
N
N
AlCl3
O
+
N
OH
N
N
Cl
Cl
O
HO
1,2-dichloroethane
80 °C
AlCl3
+
N
Solvent
heat
3
1
2
2a
Solvent
1a
3a
Scheme 1. One-pot synthesis of benzofuran fused N-heterocycles.
Entry
Timeb (h)
%Yieldc
ring fused between the benzene and heterocyclic moiety pre-con-
nected through an ether linkage, and (iii) intramolecular cyclization
(C–O bond formation) of o-hydroxyaryl heteroarenes. All these ap-
proaches however require lengthy multistep synthesis or harsh
reaction conditions or the use of special reagents/transition metal
catalysts. While the third approach offers notable synthetic oppor-
tunities as its application in the synthesis of benzofuran fused N-het-
erocycles represented by C is less common.7a,8 Recently, we have
observed that derivatives of 2,3-dichloropyrazine reacted smoothly
with phenols in the presence of AlCl3 to give benzofuran fused N-
heterocycles in a good yield. In this Letter we present our prelimin-
ary results of this AlCl3 induced C–C followedby C–O bond formation
leading to the compound C (or 3, Scheme 1).
1
2
3
4
5
6
7
ClCH2CH2Cl
ClCH2CH2Cl
CH2Cl2
CHCl3
EtOAc
1
8
12
12
3
89
85d
62d
78d
75
CH3CN
Toluene
4
6
80
40
a
All the reactions were carried out using compound 1a (1.0 equiv), 2a (1.0 equiv)
and AlCl3 (1.0 equiv) in a solvent (5 mL) at 80 °C followed by addition of extra
quantity of AlCl3 (1.0 equiv) and then stirring again at 80 °C.
b
Total time taken to yield the product 3a.
c
Isolated yield.
d
The reaction was carried out at 40–60 °C for both the step.
AlCl3-induced C–C bond forming reaction between heteroaryl
chlorides containing –C(Cl)@N– moiety and various arenes or
heteroarenes has been explored by us earlier.9 We envisaged that
a similar reaction between heteroaryl chlorides containing –
N@C(Cl)–C(Cl)@N– moiety using phenols may proceed one-step
further, that is, intramolecular cyclization via a C–O bond forma-
Table 2
Synthesis of benzofuran fused N-heterocycles (3) via AlCl3-mediated C–C and C–O bond forming reaction between 1 and 2a
Entry
Hetaryl chlorides (1)
Phenols (2)
Products (3)
Yieldb (%)
N
Cl
Cl
OH
O
N
N
1a
1
85
N
2a
3a
OH
O
N
Br
2
1a
84
N
2b
Br
3b
O
OH
N
N
3
4
5
1a
1a
1a
80
78
78
OH
OH
3c
2c
OH
N
N
O
OMe
OEt
O
OMe
OEt
3d
2d
OH
N
N
O
3e
2e
OH
OH
N
N
O
6
7
1a
1a
80
OPr-n
3f
2f
N
N
O
75
O
OBu-n
2g
3g
(continued on next page)

1136
K. S. Kumar et al. / Tetrahedron Letters 53 (2012) 1134–1138
Table 2 (continued)
Entry
Hetaryl chlorides (1)
Phenols (2)
Products (3)
Yieldb (%)
N
N
O
HO
O
O
O
O
8
9
1a
80
3h
2h
O
N
HO
N
1a
1a
80
75
3i
2i
OH
O
O
N
10
11
OCHEt
Me
N
N
2j
3j
OH
O
O
N
1a
1a
80
O
2k
3k
HO
EtO2C
CO2Et
O
O
N
12
13
78
80
O
2l
N
N
3l
OH
H3C
(CH2)7
O
O
N
1a
1a
O(CH2)7CH3
2m
3m
O
OH
N
N
14
15
16
OH
80
78
OCH2Ph
3c
2n
N
N
Cl
Cl
O
N
N
2a
N
N
1b
3n
O
N
1b
2b
2a
78
75
N
N
Br
3o
N
N
Cl
Cl
O
N
N
17
1c
3p
a
All the reactions were carried out using compound 1 (1.0 equiv), 2 (1.0 equiv) and AlCl3 (1.0 equiv) in 1,2-dichloroethane (5 mL) at 80 °C followed by addition of extra
quantity of AlCl3 (1.0 equiv) and then stirring again at 80 °C.
b
Isolated yield.

K. S. Kumar et al. / Tetrahedron Letters 53 (2012) 1134–1138
1137
Figure 3. X-ray crystal structure of 3e (ORTEP diagram). Thermal ellipsoids are drawn at 50% probability level.
summarized in Table 2. Phenols containing bromo (2b), hydroxy
(2c), alkoxy (2d–g, 2j–n), allyloxy (2h), and prop-2-ynyloxy (2i)
groups were employed successfully to afford the desired products
3b–3m (Table 2, entries 2–13) in good yields. Notably, correspond-
ing debenzylated product was obtained when 2-benzyloxy phenol
(2n) was used (Table 2, entry 14). The dichloro N-heterocycles used
other than 1a include 2,3-dichloropyrido[2,3-b]pyrazine10 (1b) and
2,3-dichloropyrazine (1c) (Table 2, entries 15–17). All the com-
pounds synthesized were well characterized by spectral (NMR,
MS, and IR) data. Additionally, the molecular structure of a repre-
sentative compound 3e was established unambiguously by single
crystal X-ray diffraction (Fig. 3). 12
AlCl3
N
AlCl3
N
Cl
Cl
Cl
Cl
AlCl3
X
of 3n or 3o
N
N
N
N
N
Regioisomer
unfavored
N
1b
AlCl3
Cl
Cl
Cl
Cl
N
N
N
N
3n or 3o
AlCl3
AlCl3
Mechanistically, the reaction seems to proceed (Scheme 2) via
(i) complexation of one of the azomethine nitrogen [–C(Cl)@N–]
of 1 with AlCl3 followed by (ii) nucleophilic attack by 2 at the adja-
cent chlorine bearing carbon atom, (iii) release of AlCl3 affording
the intermediate o-hydroxyaryl heteroarene, (iv) complexation of
the other azomethine nitrogen [–C(Cl)@N–] of o-hydroxyaryl het-
eroarene with AlCl3 and finally (v) intramolecular cyclization via
C–O bond formation to give 3. The regioselective formation of
products 3n and 3o can be explained based on the preferred tran-
sition state formed due to the complexation of AlCl3 with 1b as
shown in Scheme 2.
To demonstrate the scope of this methodology ester 3l was hydro-
lyzed using 1 N NaOH to give the corresponding acid 4 in an 85% yield
(Scheme 3). The carboxylic acid obtained was then reacted with
morpholine and an amino acid ester, that is, (S)-methyl 2-amino-
3-phenylpropanoate separately in the presence of HBTU [2-(1H-ben-
zotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate]
and diisopropyl ethyl amine to give the corresponding amide,
that is, 2-(benzofuro[3,2-b]quinoxalin-3-yloxy)-1-morpholinoetha-
none (5) and (S)-methyl 2-(2-(benzofuro[3,2-b]quinoxalin-3-
yloxy)acetamido)-3-phenylpropanoate (6) in 72% and 65%, yields,
respectively.
Scheme 2. Probable explanation for the regioselective formation of product 3n and
3o.
tion after the formation of initial C–C bond in the same pot.
Accordingly, 2,3-dichloroquinoxaline10 (1a, 1.0 equiv) was reacted
with 2-naphthol (2a, 1.0 equiv) in 1,2-dichloroethane (5 mL) in the
presence of AlCl3 (1.0 equiv) at 80 °C for 30 min.11 Then the mix-
ture was cooled to room temperature and additional quantity of
AlCl3 (1.0 equiv) was added. The mixture was stirred again at
80 °C for another 30 min when napthofuro[3,2-b]quinoxaline (3a)
was obtained as the only product in an 89% yield (Table 1, entry
1). A decrease in reaction temperature increased the reaction time
significantly (Table 1, entry 2). The use of other solvents was exam-
ined (entries 3–7) and found to be inferior in comparison to 1,2-
dichloroethane.
Having optimized reaction conditions in hand, we then exam-
ined the generality and scope of this AlCl3 induced C-arylation/
cyclization process. Accordingly, a number of phenols (2) were re-
acted with a variety of dichloro N-heterocycles and the results are
O
HO2C
O
O
N
N
O
O
O
N
H
N
O
N
18h
HBTU
N
5 (72%)
1N NaOH
(i-Pr)2NEt
H
N
3l
Ph
MeOH
rt, 30 min
16h
Ph
N
CH2Cl2
0 oC-rt,
O
O
CO2Me
4 (85%)
N
O
H2N
CO2Me
6 (65%)
Scheme 3. Preparation of amides 5 and 6 from ester 3l.

1138
K. S. Kumar et al. / Tetrahedron Letters 53 (2012) 1134–1138
3. (a) Kodimuthali, A.; Jabaris, S. S. L.; Pal, M. J. Med. Chem. 2008, 51, 5471; (b)
We evaluated some of the compounds synthesized initially for
Reddy, G. R.; Reddy, T. R.; Joseph, S. C.; Reddy, K. S.; Reddy, L. S.; Kumar, P. M.;
Krishna, G. R.; Reddy, C. M.; Rambabu, D.; Kapavarapu, R.; Lakshmi, C.; Meda,
T.; Priya, K. K.; Parsa, K. V. L.; Pal, M. Chem. Commun. 2011, 47, 7779; (c) Kumar,
P. M.; Kumar, K. S.; Mohakhud, P. K.; Mukkanti, K.; Kapavarapu, R.; Parsa, K. V.
L.; Pal, M. Chem. Commun. 2012, 48, 431; (d) Pal, S.; Durgadas, S.; Nallapati, S.
B.; Mukkanti, K.; Kapavarapu, R.; Lakshmi, C.; Parsa, K. V. L.; Pal, M. Bioorg. Med.
Chem. Lett. 2011, 21, 6573.
their PDE4B inhibitory potential13,14 in vitro using PDE4B enzyme
assay.15 Rolipram16 was used as a reference compound in this as-
say. A number of compounds showed inhibition at 30 lM (see Sup-
plementary data) and 3p being the best among them. The
preliminary data indicated that compounds containing a substitu-
ent on the benzofuran moiety showed moderate activities and the
presence of a smaller substituent was tolerated rather than a larger
or bulky group in terms of PDE4 inhibition. The docking results of
3p with PDE4B protein (see Supplementary data) showed H-bind-
ing of the benzofuran oxygen of 3p with the –NH group of the
GLU443 moiety of the PDE4B protein (binding energy À9.69 Kcal/
mol) indicating key role played by the benzofuran moiety in PDE4B
inhibition. Since inhibitors of PDE417 are expected to be beneficial
for the treatment of inflammatory and immunological diseases the
present class of compounds therefore may have therapeutic
potential.
4. McGarry, D. G.; Regan, J. R.; Volz, F. A.; Hulme, C.; Moriarty, K. J.; Djuric, S. W.;
Souness, J. E.; Miller, B. E.; Travis, J. J.; Sweeney, D. M. Bioorg. Med. Chem. 1999,
7, 1131.
5. Buckley, G.; Cooper, N.; Dyke, H. J.; Galleway, F.; Gowers, L.; Gregory, J. C.;
Hannah, D. R.; Haughan, A. F.; Hellewell, P. G.; Kendall, H. J.; Lowe, C.; Maxey,
R.; Montana, J. G.; Naylor, R.; Picken, C. L.; Runcie, K. A.; Sabin, V.; Tuladhar, B.
R.; Warneck, J. B. H. Bioorg. Med. Chem. Lett. 2000, 10, 2137.
6. Buckley, G. M.; Cooper, N.; Davenport, R. J.; Dyke, H. J.; Galleway, F. P.; Gowers,
L.; Haughan, A. F.; Kendall, H. J.; Lowe, C.; Montana, J. G.; Oxford, J.; Peake, J. C.;
Picken, C. L.; Richard, M. D.; Sabin, V.; Sharpe, A.; Warneck, J. B. H. Bioorg. Med.
Chem. Lett. 2002, 12, 509.
7. For recent examples, see: (a) Liu, J.; Fitzgerald, A. E.; Mani, N. S. J. Org. Chem.
2008, 73, 2951. and references cited therein; (b) Murai, M.; Miki, K.; Ohe, K.
Chem. Commun. 2009, 3466.
8. (a) Anderson, R. K.; Cheeseman, G. W. H. J. Chem. Soc., Perkin I 1974, 129; (b)
Zamet, J.-J.; Haddadin, M. J.; Issidorides, C. H. J. Chem. Soc., Perkin I 1974, 1687;
(c) Fryšová, I.; Slouka, J.; Gucky´, T. ARKIVOC 2005, 30.
In conclusion, a direct synthesis of benzofuran fused N-hetero-
cycles has been accomplished for the first time using AlCl3-medi-
9. For leading references, see: (a) Pal, M.; Batchu, V. R.; Parasuraman, K.;
Yeleswarapu, K. R. J. Org. Chem. 2003, 68, 6806; (b) Pal, M.; Batchu, V. R.;
Dager, I.; Swamy, N. K.; Padakanti, S. J. Org. Chem. 2005, 70, 2376; (c) Kumar, K.
S.; Chamakuri, S.; Vishweshwar, P.; Iqbal, J.; Pal, M. Tetrahedron Lett. 2010, 51,
3269.
10. Komin, A. P.; Carmack, M. J. Heterocycl. Chem. 1976, 13, 13.
11. The isolated product at this stage was identified as 3-(naphthalen-1-
yl)quinoxalin-2-ol that was thought to be an intermediate in this process.
Indeed, this compound provided 3a when treated with AlCl3 in 1,2-
dichloroethane at 80 °C.
12. Crystallographic data (excluding structure factors) for 3e have been deposited
with the Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC 824431.
13. The selective inhibition of PDE4A and/or PDE4B without affecting the other
isoforms (thought to be responsible for undesired side effects such as nausea
and emesis) is the emerging strategy to develop a safer drug. Indeed, gene
knock-out studies of mice deficient in either PDE4B or PDE4D, suggested that
PDE4D is related to the undesired side-effects, see: Robichaud, A.; Stamatiou, P.
B.; Jin, S. L. C.; Lachance, N.; MacDonald, D.; Laliberté, F.; Liu, S.; Huang, Z.;
Conti, M.; Chan, C. C. J. Clin. Invest. 2002, 110, 1045.
ated C-arylation/cyclization strategy in
a single pot. The
methodology is operationally simple, does not require the use of
expensive reagents or catalysts, and therefore amenable for
scale-up preparation. This research also reveals the potential of
benzofuran fused N-heterocycle as a new template for the discov-
ery of PDE4 inhibitors.
Acknowledgements
M.P. and K.P. thank DBT, New Delhi, India for financial support
(Grant No. BT/PR12829/Med/30/222/2009). K.S. thanks UGC, New
Delhi, India for a Dr. D. S. Kothari Post doctoral fellowship [No.
F.4-2/2006(BSR)/13-324/2010(BSR)]. R.A. thanks CSIR, New Delhi,
India for a Junior Research Fellowship.
Supplementary data
14. PDE4B selective inhibitor could provide basis for an effective anti-
inflammatory treatment without causing emesis, see: Jin, S. L. C.; Conti, M.
Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 7628. Thus, development of PDE4B inhibitor
is desirable.
15. Wang, P.; Myers, J. G.; Wu, P.; Cheewatrakoolpong, B.; Egan, R. W.; Billah, M. M.
Biochem. Biophys. Res. Commun. 1997, 19, 320.
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.12.096.
16. Demnitz, J.; LaVecchia, L.; Bacher, E.; Keller, T. H.; Muller, T.; Schurch, F.;
Weber, H. P.; Pombo-Villar, E. Molecules 1998, 3, 107.
References and notes
17. For various computational studies on PDE4 inhibitors, see: (a) Chakraborti, A.
K.; Gopalakrishnan, B.; Sobhia, M. E.; Malde, A. Bioorg. Med. Chem. Lett. 2003,
13, 2473; (b) Chakraborti, A. K.; Gopalakrishnan, B.; Sobhia, M. E.; Malde, A.
Bioorg. Med. Chem. Lett. 2003, 13, 1403.
1. (a) Hazeldine, S. T.; Polin, L.; Kushner, J.; White, K.; Corbett, T. H.; Horwitz, J. P.
Bioorg. Med. Chem. 2006, 14, 2462; (b) Voigt, B.; Meijer, L.; Lozach, O.;
Schächtele, C.; Totzke, F.; Hilgeroth, A. Bioorg. Med. Chem. Lett. 2005, 15, 823.
2. Oliveira, A. M. A. G.; Raposo, M. M. M.; Oliveira-Campos, A. M. F.; Machado, A. E.
H.; Puapairoj, P.; Pedro, M.; Nascimento, M. S. J.; Portela, C.; Afonso, C.; Pinto,
M. Eur. J. Med. Chem. 2006, 41, 367.