Palladium-mediated reductive Heck cyclization for the formation of dibenzoazepinone framework

Article abstract of DOI:10.1055/S-0029-1218298

The dibenzoazepinone framework has been synthesized through a palladium-mediated Sonogashira cross-coupling followed by a reductive Heck cyclization. The reactions are simple, straightforward, and have been carried out under ligand-free conditions.

Full text of DOI:10.1055/S-0029-1218298

LETTER
3127
Palladium-Mediated Reductive Heck Cyclization for the Formation of
Dibenzoazepinone Framework
Formationof
D
ibe
.
nzoazepinon
C
e
Framework . Majumdar,*a Santanu Chakravorty,a Tapas Ghosh,a B. Sridharb
a
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
E-mail: kcm_ku@yahoo.co.in
b
Laboratory of X-ray Crystallography, IICT, Hyderabad 500007, India
Received 15 September 2009
F
O
Abstract: The dibenzoazepinone framework has been synthesized
through a palladium-mediated Sonogashira cross-coupling fol-
lowed by a reductive Heck cyclization. The reactions are simple,
straightforward, and have been carried out under ligand-free condi-
tions.
O
O
H
N
N
N
F
N
H
OH
O
H2N
O
Key words: dibenzoazepinone, reductive Heck, Sonogashira cross
coupling, Pd(PPh3)4
oxcarbazepine
LY411575
O
H
N
Palladium-mediated reactions are the most developed
methods for the construction of carbon–carbon and car-
bon–heteroatom bonds.1 Among the many intramolecular
processes provided by palladium catalyst in heterocyclic
chemistry, the Heck reaction is particularly valuable for
the formation of rings of various sizes. Most often this
type of reaction is used for the formation of five- and six-
membered rings.2 However, there is a growing number of
O
N
N
Darenzepine
reports in recent years that demonstrate the synthetic util- Figure 1
ity of the intramolecular Heck reaction for the assembly of
medium-sized rings (n ≥ 7).3,4 In most cases, the substrates
The required precursors for the reductive Heck cycliza-
tion were synthesized in three steps: bromination of the
amines, Sonogashira coupling of the bromo derivatives
with phenylacetylene, and subsequent amide-formation
reaction with iodobenzoylchloride. The brominations of
amines were carried out with N-bromosuccinimide in ac-
etonitrile at room temperature. The Sonogashira coupling
of all the bromo derivatives were carried out with phenyl-
acetylene using Pd(PPh3)2Cl2 as catalyst and CuI as the
co-catalyst in anhydrous DMF containing triethylamine
under heating for four to six hours (Scheme 1).
contain a suitably placed substituent to affect arylation,
leading to exclusive formation of exo3 or endo4 products.
In the absence of such stereodirecting groups, the out-
come can be unpredictable, often leading to mixtures of
products. Ways of controlling the regioselectivity of this
cyclization are rarely studied.5
Dibenzoazepinone framework is widespread among natu-
ral compounds and important pharmaceuticals. Consider-
able efforts have been made toward the synthesis of
oxacarbazepine,6 (Figure 1) the active ingredient of Tri-
leptal, LY4115757 (Figure 1) a g-secretase inhibitor and
N-substituted Darenzepine8 as selective avb3 antagonists.
The subsequent amide formation reactions of substrate
2a–f,g were carried out with 2-iodobenzoylchloride
(which was in turn prepared by refluxing 2-iodobenzoic
acid with thionyl chloride) under phase-transfer-catalysis
conditions using tetrabutylammonium hydrogen sulfate
(TBAHS) as a catalyst and potassium carbonate as a base
(Scheme 2). However, attempts of amide formation using
all the reported protocols failed in the case of substrates
2h,i. Perhaps due to steric hindrance for the former (2h)
and the presence of the pyridine nitrogen for the latter (2i).
Our first attempt to find optimal conditions for the reduc-
tive Heck reaction (Table 1) was carried out with the
amide 3f. The reaction was run under conventional heat-
ing (at 120 °C) in the presence of 3 mol% of Pd(PPh3)4 as
the catalyst and sodium formate as the reducing agent.
Most often the construction of the medium-sized ring of
dibenzoazepinone framework is achieved via intramolec-
ular Friedel–Crafts alkylation. However, this method de-
mands an excess of Lewis acid and lacks flexibility for
variation of substituent. Alternatively, ring closure is ac-
complished upon formation of the C–N bond via intramo-
lecular reductive amination. In this particular paper we
have elaborated a new pathway towards the synthesis of
dibenzoazepinone framework based on palladium-medi-
ated intramolecular reductive Heck cyclization.
SYNLETT 2009, No. 19, pp 3127–3130
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x
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x
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0
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Advanced online publication: 15.10.2009
DOI: 10.1055/s-0029-1218298; Art ID: G30409ST
© Georg Thieme Verlag Stuttgart · New York

3128
K. C. Majumdar et al.
LETTER
H
N
The optimal solvent system for the cyclization was found
to be a DMF–water mixture. Under these optimized con-
ditions we obtained 7-exo-cyclized product 4f regioselec-
tively and in 85% yield. The structure of the obtained
compound 4f was fully confirmed from its X-ray crystal
structure.9 The reaction failed in the absence of water
probably due to ineffectiveness of the reducing agent un-
der anhydrous conditions.
H
N
(i)
R
R
R2
Br
R2
Ph
1a R1 = Me, R2 = Me
1b R1 = H, R2 = Me
1c R1 = Me, R2 = H
1d R1 = Et, R2 = Me
2a R1 = Me, R2 = Me
2b R1 = H, R2 = Me
2c R1 =Me, R2 = H
2d R1 = Et, R2 = Me
Ph
Table 1 Optimization of the Reaction Conditions10,11
Br
H
N
R
H
N
Ph
R
(i)
H
I
O
O
O
O
O
Ph
1e R = Me
1f R = Et
2e R = Me
2f R = Et
N
Heck
conditions
N
Ph
O
O
O
O
O
3f10
4f11
Br
NHMe
NHMe
(i)
Entry Solvent
Catalysta
Baseb
Temp Yield of
(°C)c 4f (%)
120 85
80 45
1g
NHMe
2g
NHMe
1
2
3
4
5
6
7
8
9
DMF–H2O (7:3) Pd(PPh3)4
MeCN–H2O (7:3) Pd(PPh3)4
–
–
–
–
Ph
Br
(i)
DMF
Pd(PPh3)4
120 n.r.
120 35
1h
2h
DME–H2O (7:3) Pd(PPh3)4
DMF–H2O (7:3) Pd(PPh3)4
NH2
Br
NH2
(i)
K2CO3 120 n.r.
Br
N
1i
Br
N
DMF–H2O (7:3)
DMF
Pd(OAc)2
Pd(OAc)2
–
120 n.r.
2i
Ph
Cs2CO3 120 n.r.
Scheme 1 Reagents and conditions: (i) phenylacetylene, dry DMF,
Et3N, Pd(PPh3)2Cl2, CuI, heat, 120 °C, 4–6 h.
DMF–H2O (7:3) Pd(PPh3)4
–
–
150 45
120 n.r.
DMF–H2O (7:3) Pd(PPh3)2Cl2
R1
a All the reactions were carried out using 3 mol% of catalyst.
b All the reactions were carried out for 4 h.
H
N
N
R1
(i)
c Sodium formate used as a reducing agent for entries 1–4, 6, and 8.
O
I
R2
R2
Ph
Ph
2a R1 = Me, R2 = Me
2b R1 = H, R2 = Me
2c R1 = Me, R2 = H
2d R1 = Et, R2 = Me
3a R1 = Me, R2 = Me
3b R1 = H, R2 = Me
3c R1 = Me, R2 = H
3d R1 = Et, R2 = Me
Catalysts like Pd(OAc)2 and Pd(PPh3)2Cl2 were found to
be ineffective. Solvents like acetonitrile or DME with wa-
ter resulted in the formation of a small amount of cyclized
product along with unidentified products. Addition of a
base like K2CO3 or Cs2CO3 caused decomposition of the
starting material. Increasing the temperature led to de-
composition of the cyclized products.
Ph
Ph
R
N
H
N
R
(i)
The regioselective formation of exo-cyclized products
during reductive Heck cyclization can be rationalized via
a probable mechanism as depicted in Scheme 3.
O
I
O
O
O
O
2e R = Me
2f R = Et
3e R = Me
3f R = Et
Initially generated aryl palladium p-complex 6 is trans-
formed into s-vinyl palladium complex 7 via simulta-
neous syn addition to the triple bond. The endo cyclization
via a hypothetical intermediate 8 is fairly unlikely due to
high strain exerted by the trans geometry around the dou-
ble bond in the eight-membered ring. The Pd(0) catalyst is
regenerated by the reducing agent present in the reaction
mixture.
Ph
Ph
I
Me
N
NHMe
(i)
O
2g
3g
Scheme 2 Reagents and conditions: (i) 2-iodobenzoyl chloride,
CHCl3–H2O, TBAHS, K2CO3.
Synlett 2009, No. 19, 3127–3130 © Thieme Stuttgart · New York

LETTER
Formation of Dibenzoazepinone Framework
3129
Ph
Ph
[Pd]
Ph
I
IPd
O
N
O
O
N
N
O
O
O
O
O
O
3f
5
6
[Pd]
[Pd]
Ph
Ph
H
O
O
Ph
N
O
N
N
O
O
O
O
O
O
8
7
4f
Scheme 3 Probable mechanism of the cyclization
Table 2 Results of Reductive Heck Cyclization
Table 2 Results of Reductive Heck Cyclization (continued)
Substrate
Time Product
(h)
Yield
(%)
Substrate
Time Product
(h)
Yield
(%)
Ph
Ph
Me
N
I
O
4.2
4.5
4.1
90
87
85
O
Ph
O
I
5
65
N
N
N
Me
O
Me
Ph
Me
3a
3b
4a
4b
4g
3g
Ph
H
N
To explore general applicability of this strategy for the
synthesis of medium-sized rings we applied this protocol
to other amides 3a–e,g, and in all cases we obtained the
desired exo-cyclized products in 65–90% yields
(Table 2).
O
I
N
H
O
Ph
Ph
Me
In summary, we have developed an efficient new protocol
for the synthesis of dibenzoazepinone framework. The
medium-sized ring is constructed by applying reductive
intramolecular Heck cyclization, which occurs regiose-
lectively.
N
O
N
I
N
O
Ph
Me
3c
4c
Ph
Supporting Information for this article is available online at
4.3
4.2
75
80
http://www.thieme-connect.com/ejournals/toc/synlett.
O
I
N
O
Ph
Acknowledgment
3d
4d
We thank the DST (New Delhi) for financial assistance. Two of us
are grateful (S.C., T.G.) to the CSIR (New Delhi) for fellowships.
Ph
O
Me
Me
Ph
References and Notes
N
N
(1) (a) Link, J. T. Org. React. (N. Y.) 2002, 60, 157. (b) Dyker,
G. In Handbook of Organopalladium Chemistry for
Organic Synthesis, Vol. 1; Negishi, E.-I.; de Meijere, A.,
Eds.; Wiley: New York, 2002.
O
I
O
O
O
O
4e
3e
(2) (a) Liu, P.; Huang, L.; Lu, Y.; Dilmeghani, M.; Baum, J.;
Xiang, T.; Adams, J.; Tasker, A.; Larsen, R.; Faul, M. M.
Tetrahedron Lett. 2007, 48, 2307. (b) Mangeney, P.; Pays,
C. Tetrahedron Lett. 2003, 44, 5719. (c) Higuchi, K.;
Synlett 2009, No. 19, 3127–3130 © Thieme Stuttgart · New York

3130
K. C. Majumdar et al.
LETTER
solution of acid chloride. To this reaction mixture an aq
solution of K2CO3 (556 mg, 4.03 mmol) was added slowly.
After stirring for 5 h at r.t., the solution was washed with 5%
HCl (2 × 20 mL) and then with 5% aq NaOH (2 × 20 mL).
The organic layer was dried (Na2SO4) and the solvent
evaporated under reduced pressure. The residue was purified
by column chromatography over silica gel using PE–EtOAc
(7:3) as an eluent.
Comins, D. L. Beilstein J. Org. Chem. 2007, 3, 1.
(d) Majumdar, K. C.; Sinha, B.; Maji, P. K.; Chattopadhyay,
S. K. Tetrahedron 2009, 65, 2751. (e) Majumdar, K. C.;
Chakravorty, S.; De, N. Tetrahedron Lett. 2008, 49, 3419.
(f) Majumdar, K. C.; Chakravorty, S.; Shyam, P. K.; Taher,
A. Synthesis 2009, 403. (g) Majumdar, K. C.; Chakravorty,
S.; Ray, K. Synthesis 2008, 2991. (h) Majumdar, K. C.;
Sinha, B.; Chattopadhyay, B.; Ray, K. Tetrahedron Lett.
2008, 49, 4405.
Compound 3f: white solid, yield 78%, mp 176–178 °C. IR
(KBr): nmax = 2212, 1738, 1651, 1565 cm–1. 1H NMR (400
MHz, CDCl3): d = 1.08 (t, 3 H, J = 7.2 Hz), 3.56–3.68 (m, 1
H), 4.49–4.61 (m, 1 H), 6.48 (d, 1 H, J = 9.6 Hz), 6.82–6.83
(m, 1 H), 7.03–7.11 (m, 1 H), 7.21–7.26 (m, 2 H), 7.45–7.47
(3) (a) Di Fabio, R.; Micheli, F.; Baraldi, D.; Bertani, B.; Conti,
N.; Dal Forno, G.; Feriani, A.; Donati, D.; Marcchioro, C.;
Messeri, T.; Missio, A.; Pasquarello, A.; Pentassuglia, G.;
Pizzi, D. A.; Provera, S.; Quaglia, A. M.; Sabbatini, F. M.
Farmaco 2003, 58, 723. (b) Hayashi, M.; Sai, H.; Horikawa,
H. Heterocycles 1998, 48, 1331. (c) Majumdar, K. C.;
Chattopadhyay, B.; Ray, K. Tetrahedron Lett. 2007, 48,
7633. (d) Majumdar, K. C.; Chattopadhyay, B.; Samanta, S.
Tetrahedron Lett. 2009, in press. (e) Cropper, E. L.;
Andrew, J. P.; White, A. F.; Hii, K. K. J. Org. Chem. 2006,
71, 1732.
(m, 3 H), 7.56–7.70 (m, 4 H), 8.15 (d, 1 H, J = 9.6 Hz). 13
C
NMR (100 MHz, CDCl3): d = 12.8, 43.7, 82.1, 93.6, 117.0,
117.6, 121.5, 126.7, 127.0, 127.6, 128.7, 128.8, 129.9,
130.1, 131.7, 131.9, 132.6, 139.8, 141.3, 141.9, 153.0,
159.6, 169.7. HRMS: m/z found for C26H18INO3: 542.1890
[M+ + Na]. Anal. Calcd for C26H18INO3: C, 60.13; H, 3.49;
N, 2.70. Found: C, 60.33; H, 3.29; N, 2.93.
(4) (a) Arnold, L. A.; Luo, W.; Guy, R. K. Org. Lett. 2004, 6,
3005. (b) Gibson, S. E.; Jones, J. O.; Kalindjinan, S. B.;
Knight, J. D.; Steed, J. W.; Tozer, M. J. Chem. Commun.
2002, 1938. (c) Alcaide, B.; Polanco, C.; Sierra, M. A. Eur.
J. Org. Chem. 1998, 2913. (d) Gibson, S. E.; Middleton,
R. J. J. Chem. Soc., Chem. Commun. 1995, 1743.
(e) Majumdar, K. C.; Chattopadhyay, B.; Sinha, B.
Tetrahedron Lett. 2008, 49, 1319. (f) Majumdar, K. C.;
Chattopadhyay, B. Synlett 2008, 979. (g) For a recent
review on this topic, see: Majumdar, K. C.; Chattopadhyay,
B. Curr. Org. Chem. 2009, in press.
(5) For example, see: (a) Santos, L. S.; Pilli, R. A. Synthesis
2002, 87. (b) Tietze, L. F.; Sommer, K. M.; Schneider, G.;
Tapolzsanyi, P.; Wolfling, J.; Muller, P.; Noltemeyer, M.;
Terlau, H. Synlett 2003, 1494.
(6) Kaufmann, D.; Fünfschilling, P. C.; Beutler, U.; Hoehn, P.;
Lohse, O.; Zaugg, W. Tetrahedron Lett. 2004, 45, 5275.
(7) Fauq, A. H.; Simpson, K.; Maharvi, G. M.; Golde, T.; Das,
P. Bioorg. Med. Chem. Lett. 2007, 17, 6392.
(11) General Procedure for Reductive Heck Cyclization of
Compound 3f
A mixture of compound 3f12 (100 mg, 0.19 mmol),
HCOONa (19.6 mg, 0.29 mmol), Pd(PPh3)4 (6.6 mg,
5.7×10–3 mmol) in DMF–H2O (10 mL, 7:3) was heated with
continuous stirring at 120 °C for 4.2 h. After completion of
the reaction as monitored by TLC, the reaction mixture was
cooled and H2O (5 ml) was added. This was then extracted
with CH2Cl2 (3 × 10 mL). The CH2Cl2 extract was washed
with H2O (3 × 10 mL) followed by brine (10 mL). The
organic layer was dried (Na2SO4). Evaporation of CH2Cl2
furnished a crude mass, which was purified by column
chromatography over silica gel. Elution of the column with
PE–EtOAc (3:1) afforded product 4f.
Compound 4f: white solid, yield 85%, mp 198–200 °C. IR
(KBr): nmax = 1724, 1633 cm–1. 1H NMR (400 MHz, CDCl3):
d = 1.19–1.27 (m, 3 H), 3.74–3.81 (m, 1 H), 4.69–4.76 (m, 1
H), 6.18 (d, 1 H, J = 9.8 Hz), 6.98 (s, 1 H), 7.08–7.09 (m, 2
H), 7.19–7.20 (m, 3 H), 7.28–7.31 (m, 2 H), 7.38–7.41 (m, 1
H), 7.45–7.49 (m, 1 H), 7.57 (d, 1 H, J = 9.0 Hz), 7.63 (d, 1
H, J = 9.8 Hz), 7.89 (dd, 1 H, J = 0.8, 7.6 Hz). 13C NMR (100
MHz, CDCl3): d = 13.9, 44.3, 114.3, 116.9, 117.3, 124.9,
127.8, 128.4, 128.5, 128.8, 128.9, 130.9, 131.7, 131.9,
132.2, 132.4, 132.8, 134.6, 135.4, 136.4, 140.5, 145.04,
152.2, 159.9, 167.6. HRMS: m/z calcd for C26H19NO3:
394.1438 [M+ + H]; found: 394.1406 [M+ + H]. Anal. Calcd
for C26H19NO3: C, 79.37; H, 4.87; N, 3.56. Found: C, 79.58;
H, 5.04; N, 3.75.
(8) Kling, A.; Backfisch, G.; Delzer, J.; Geneste, H.; Graef, C.;
Holzenkamp, U.; Hornberger, W.; Lange, U. E. W.;
Lauterbach, A.; Mack, H.; Seitz, W.; Subkowski, T. Bioorg.
Med. Chem. Lett. 2002, 12, 441.
(9) CCDC 747690 contains supplementary crystallographic
data for the structure 4f.
(10) General Procedure for the Formation of Amide 3f
A mixture of 2-iodobenzoic acid12 (500 mg, 2.01 mmol) and
SOCl2 was stirred at 100 °C for 3 h. After evaporation of the
solvent, the residue was dissolved in CH2Cl2 (20 mL). A
solution of amine 2f (583 mg, 2.01 mmol) in CH2Cl2 (20
mL) and TBAHS (cat. amount) was added to the stirred
(12) 2-Bromobenzoic acid can also be used to give the
corrosponding 2-bromo derivative 3 which also undergoes
reductive Heck cyclization to afford 4f (yield 80%).
Synlett 2009, No. 19, 3127–3130 © Thieme Stuttgart · New York