New Heck coupling strategies for the arylation of secondary and tertiary amides via palladium-catalyzed intramolecular cyclization

Article abstract of DOI:10.1016/j.tetlet.2008.01.035

A new synthetic protocol has been developed for the arylation of secondary and N-alkylated amide Heck precursors by the implementation of the palladium-catalyzed intramolecular Heck reaction strategies.

Full text of DOI:10.1016/j.tetlet.2008.01.035

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1609–1612
New Heck coupling strategies for the arylation of secondary and
tertiary amides via palladium-catalyzed intramolecular cyclization
K. C. Majumdar *, Buddhadeb Chattopadhyay, Sanjay Nath
Department of Chemistry, University of Kalyani, Kalyani 741235, WB, India
Received 27 November 2007; revised 25 December 2007; accepted 9 January 2008
Available online 12 January 2008
Abstract
A new synthetic protocol has been developed for the arylation of secondary and N-alkylated amide Heck precursors by the
implementation of the palladium-catalyzed intramolecular Heck reaction strategies.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Biaryl coupling; Heck reaction; Intramolecular cyclization; Amino coumarin; Palladium catalysts; Amide
The search of new methods for the construction of
organic molecules from simple starting materials is an
ongoing challenge for the organic chemists. Intramolecular
aryl–aryl coupling reactions involving a palladium reagent
have been used to synthesize many condensed heteroaro-
matic compounds.1–6 A number of protocols have been
developed for the synthesis of condensed heteroaromatic
compounds using biaryl coupling reaction with palladium
reagents7–12 by the regioselective C–H bond activation with
the intramolecular coordination of the amine to palla-
dium.13–16 It has been reported17,18 that the palladium-
catalyzed cyclization by the implementation of the intra-
molecular Heck reaction had failed where a secondary
amide was used as the starting material. Recently, Trauner
and co-workers, reported19 a concise synthesis of rhazini-
lam through direct palladium-catalyzed intramolecular
cyclization, with the MOM amide protecting starting mate-
rial, for the success of this cyclization. They observed only
deiodination with the free amide. Ripper and co-workers,20
also attempted the same type of reaction with the second-
ary amide; but their attempts to carry out the palladium-
catalyzed cyclization reaction using secondary amide as
the starting material afforded no indication of the cycli-
zation product. Subsequently Joseph and co-workers,21
tried the reaction and their attempts of Heck reaction of
free amide or N-methyl derivatives of the secondary amide
led to low yields of the cyclized product (15–17% yields).
Therefore, the above-mentioned findings have prompted
us to undertake a study of the Heck reaction on the free
amide or N-alkyl protected amide as the starting materials,
with a view to synthesize the condensed heteroaromatic
COOH
COCl
I
I
(i)
2
1
O
R
R
COCl
I
NH
+
I
N
(ii)
O
O
O
3(a-c)
O
O
4(a-c)
CH3
2
CH3
COCl
I
I
(ii)
+
NH
R
O
5(a-c)
O
O
O
6(a-c)
N
R
2
*
Scheme 1. Reagents and conditions: (i) DCM, DMF, (COCl)2, 0 °C,
Corresponding author. Tel.: +91 33 2582 7521; fax: +91 33 2582 8282.
30 min; (ii) DCM, Et3N, DMAP, rt, 2 h. R = Et, Me, H.
E-mail address: kcm_ku@yahoo.co.in (K. C. Majumdar).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.035

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K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 1609–1612
compounds. Additional interest is derived from our long
standing efforts on the synthesis of heterocycles with bio-
active moieties, and the coumarin system is well known
for its bioactivity.22–28
The synthesis of the amide starting materials 4 and 6 for
this investigation is shown in Scheme 1. The reaction of the
acid chloride 2 (prepared from the 2-iodo benzoic acid with
the oxalyl chloride in dichloromethane in the presence of a
catalytic amount of DMF) with 3 and/or 5 in DCM–trieth-
ylamine in the presence of a catalytic amount of DMAP at
rt for 2 h gave the corresponding amide precursors29 4(a–c)
and 6(a–c).
Based on the precedence of one generalized intramole-
cular reaction that has been used for the synthesis of hetero-
cyclic compounds by treatment with tributyltin hydride in
the presence of AIBN30 as radical initiator, we decided to
carry out the cyclization via this established protocol.
However, only the reductive deiodination product was
obtained under these and related conditions rather than
the desired cyclized amide product. These negative results
led us to explore an intramolecular palladium-catalyzed
cyclization. When the Heck reaction was performed31 with
4a as amide precursor in the presence of Pd(OAc)2 as the
catalyst and anhydrous potassium acetate as a base, tetra-
butylammonium bromide (TBAB) as additive in dry DMF
under a nitrogen atmosphere for 10 h, the cyclized amide
product 7a was obtained in 91% yield. The optimum con-
ditions for the cyclization were found through a series of
experiments where sequential changes were made to the
catalyst, base, ligand and solvent used (Table 1). We found
that the catalysts and ligands have a profound effect on the
reaction yield. The catalyst, Pd(OAc)2, which is mostly
used in this type of cyclization reaction, provided a 91%
yield of product 7a, whereas PdCl2 provided 7a in 51%
yield. The ligand triphenylphosphine (entries 5 and 6) also
proved to be effective in this case and gave 68% and 31%
yield using Pd(OAc)2 and PdCl2 as the catalysts, res-
pectively. However, these catalytic systems were not so
effective as Pd(OAc)2 or PdCl2 (entries 3 and 4).
With Pd(OAc)2/Ag2CO3/PPh3 and PdCl2/Ag2CO3/PPh3,
the reaction was extremely slow and afforded 7a in 39%
and 27%, respectively, with unreacted starting material,
4a, remaining even after 72 h.
Table 2
Summarized results of the amide cyclizationa by Pd-catalyzed Heck
reaction
Entry Amide precursors
Product
Yieldb (%)
O
O
1
91
I
I
I
N
N
N
N
N
N
Et
Et
O
O
O
7a
O
O
O
4a
O
O
2
88
Me
Me
O
7b
O
4b
Table 1
Palladium-catalyzed cyclizationa of 4a to 7a
O
H
O
H
O
O
3c
59
I
N
N
Et
Et
O
O
O
7c
O
O
O
4c
O
O
O
O
4a
7a
CH3
CH3
Entry Catalystb Basec
Ligandd Additivee Solvent Yieldf (%)
I
I
I
4
84
82
61
1
2
3
4
5
6
7
8
9
10
11
12
a
Pd(OAc)2 KOAc
PdCl2 KOAc
Pd(OAc)2 Et3N
PdCl2 Et3N
Pd(OAc)2 Et3N
—
—
—
—
PPh3
PPh3
TBAB
TBAB
TBAB
TBAB
—
—
—
—
TBAB
TBAB
TBAB
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
91
51
78
40
68
31
39
27
34
0
O
O
O
O
O
O
O
6a
N
O
7d
N
Et
Et
CH3
CH3
PdCl2
PdCl2
Et3N
Ag2CO3 PPh3
5
O
O
O
6b
N
O
O
O
7e
N
Pd(OAc)2 Ag2CO3 PPh3
Me
Me
PdCl2
PdCl2
PdCl2
Ag2CO3
KOAc
KOAc
—
PPh3
PPh3
DMF
CH3CN
Dioxane
CH3CN
CH3
CH3
0
0
Pd(OAc)2 Ag2CO3 PPh3
6c
All reactions were carried out at 120 °C for 10 h.
Catalyst used in the reaction 10 mol %.
KOAc and Et3N used in the reaction is 1.2 equiv, Ag2CO3 used in the
O
6c
N
H
O
7f
N
H
b
c
a
reaction is 2 equiv.
All reactions were performed at optimized conditions except 4c and 6c.
Isolated yields.
Compounds 4c and 6c underwent cyclization at 160 °C using Ag2CO3
d
b
c
20 mol % ligand used in the reaction.
The additive used in each case in the reaction is 2.75 equiv.
Isolated yields.
e
f
as the base.

K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 1609–1612
1611
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9
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8
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T.; Abe, H.; Takeuchi, Y. J. Chem. Soc., Perkin Trans. 1 2001, 523.
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20. Lindahl, K. F.; Carroll, A.; Quinn, R. J.; Ripper, J. A. Tetrahedron
Lett. 2006, 47, 7493.
Fig. 1.
The effect of base on the reaction was also investigated.
With KOAc as the base the reaction was over in 10 h (entry
1). The replacement of KOAc with an organic base such as
Et3N was found to be less effective. Other bases that have
been explored include Ag2CO3 though this was not as effec-
tive as KOAc except in the case of 4a and 6c.
A study of the influence of various solvents (DMF,
CH3CN and dioxane) suggested that DMF is the best
choice. No reaction was found to occur at 80 °C or at lower
temperatures. To examine the versatility of this intramole-
cular palladium-catalyzed cyclization, a number of amino
coumarin-annulated cyclic amide derivatives were synthe-
sized by employing the optimized reaction condition,
Pd(OAc)2/KOAc/TBAB/DMF. The results are summa-
rized in Table 2.
21. Putey, A.; Joucla, L.; Picot, L.; Besson, T.; Joseph, B. Tetrahedron
Lett. 2007, 63, 867.
22. Majumdar, K. C.; Muhuri, S.; Rahaman, H.; Islam, R.; Roy, B.
Chem. Lett. 2006, 35, 1430.
23. Majumdar, K. C.; Rahaman, H.; Roy, B. Lett. Org. Chem. 2006, 3,
526.
24. Majumdar, K. C.; Chattopadhyay, B. Synth. Commun. 2006, 36,
3125.
25. Majumdar, K. C.; Mukhopadhyay, P. P.; Basu, P. K. Synth.
Commun. 2005, 35, 1291.
26. Majumdar, K. C.; Chattopadhyay, S. K. Tetrahedron Lett. 2004, 45,
6871.
27. Majumdar, K. C.; Bhattacharyya, T. Tetrahedron Lett. 2001, 42,
4231.
28. Majumdar, K. C.; Chattopadhyay, B.; Taher, A. Synthesis 2007,
3647.
29. General procedure for the preparation of the amide precursors:
DMAP (5 mg) and Et3N (2 ml) were added to a dry dichloromethane
solution of 3a (300 mg, 1.6 mmol) at ice-bath temperature. 2-
Iodobenzoyl chloride (prepared from 2-iodobenzoic acid and oxalyl
chloride) in dry dichloromethane solution (10 ml) was added drop-
wise. The reaction mixture was stirred for 2 h at the same temper-
ature. The mixture was then washed with water (3 Â 15 ml) and brine
(20 ml) and dried (Na2SO4). Evaporation of the DCM gave a crude
mass which was purified by chromatography by 40% ethyl acetate–
pet. ether to afford product 4a. Compounds 4(b,c) and 6(a–c) were
obtained by the same procedure.
Here it is important to note that under these optimized
conditions the free amides 4c and 6c did not undergo cycli-
zation perhaps due to the low reactivity of the palla-
dium(II) complexes 8 and 9 (which are likely to be
formed in the presence of a base) to undergo the reaction.
However, at elevated temperature (160 °C) and in the pres-
ence of the base Ag2CO3 (4 equiv) the reaction gave the
desired cyclized products 7c and 7f, respectively (Fig. 1).
In conclusion, we have developed a convenient and high
yielding method for the synthesis of cyclic amide deriva-
tives by the intramolecular Heck cyclization starting from
the secondary amide and N-alkylated tertiary amide pre-
cursors. This method is new and highly efficient for the
cyclization of the biaryl systems and is found to be a
straightforward approach, whereas the radical mediated
cyclization protocol failed to afford any cyclized product.
Acknowledgements
We thank the CSIR (New Delhi) for financial assistance.
One of us (B.C.) is grateful to the CSIR (New Delhi) for a
Junior research fellowship. We also thank the DST (New
Delhi) for providing UV–vis and IR Spectrometer under
the DST-FIST programme.
Compound 4a: Yield: 84%; solid; mp 120–122 °C. IR. (KBr):
m
max = 1650, 1732 cmÀ1 1H NMR (CDCl3, 400 MHz): dH = 1.27 (t,
.
3H, J = 7.1 Hz, CH2–CH3), 3.98 (q, 2H, J = 7.1 Hz, N–CH2), 6.39 (d,
1H, J = 9.6 Hz, C3–H of coumarin), 6.84 (t, 1H, J = 7.2 Hz, ArH),
7.01 (d, 1H, J = 7.2 Hz, ArH), 7.11–7.22 (m, 2H, ArH), 7.33–7.34 (m,
2H, ArH), 7.44 (d, 1H, J = 8.99 Hz, ArH), 7.53 (d, 1H, J = 9.6 Hz,
C4–H of coumarin). 13C NMR (CDCl3, 125 MHz): dC 7.9, 39.5, 88.5,
112.5, 112.6, 113.9, 122.1, 122.6, 123.2, 125.0, 126.6, 132.9, 134.3,
137.0, 137.4, 147.6, 154.9, 159.3. MS: m/z = 419 [M+]. Anal Calcd for
C18H14INO3: C, 51.57; H, 3.37; N, 3.34. Found: C, 51.59; H, 3.41; N,
3.27%.
References and notes
1. Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons: New
York, 2004; p 176.
2. Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry;
Pergamon: Oxford, 2000.
Compound 4c: Yield: 81%; solid; mp 210–212 °C. IR (KBr):
3. Dyker, G. Chem. Ber. 1997, 130, 1567.
m .
max = 1660, 1712, 3332 cmÀ1 1HNMR (DMSO-d6, 400 MHz):

1612
K. C. Majumdar et al. / Tetrahedron Letters 49 (2008) 1609–1612
d
H = 6.51 (d, 1H, J = 9.6 Hz, C3–H of coumarin), 6.95–6.99 (m, 2H,
The preparation of compounds 7c and 7f are by the same procedure
except that the reagents used were Ag2CO3 (4 equiv), catalyst
Pd(OAc)2 (20 mol %), ligand PPh3 (40 mol %) and solvent DMF at
160 °C for 10 h.
ArH), 7.43 (dd, 2H, J = 8.9 Hz, J = 2.4 Hz, ArH), 7.82 (dd, 1H,
J = 8.9 Hz, J = 2.4 Hz, ArH), 7.95 (dd, 1H, J = 7.8 Hz, J = 1.2 Hz,
ArH), 8.11 (d, 1H, J = 9.6 Hz, C4–H of coumarin), 8.16 (d, 1H,
J = 2.4 Hz, ArH), 10.58 (s, 1H, NH). MS: m/z = 391 [M+]. Anal.
Calcd for C16H10INO3: C, 49.13; H, 2.58; N, 3.58. Found: C, 49.19;
H, 2.43; N, 3.61.
Compound 7a: Yield: 91%; solid; mp 200–202 °C. IR (KBr):
m
max = 1650, 1727 cmÀ1 1H NMR (CDCl3, 400 MHz): dH = 1.42 (t,
.
3H, J = 6.9 Hz, CH2–CH3), 4.47 (q, 2H, J = 6.9 Hz, N–CH2), 6.55
(d, 1H, J = 10.0 Hz, C3–H of coumarin), 7.53 (d, 1H, J = 9.3 Hz,
ArH), 7.62 (d, 1H, J = 9.3 Hz, ArH), 7.68 (t, 1H, J = 7.2 Hz, ArH),
7.80 (t, 1H, J = 7.7 Hz, ArH), 8.08 (d, 1H, J = 10.0 Hz, C4–H of
coumarin), 8.61 (d, 2H, J = 9.9 Hz, ArH). 13C NMR (CDCl3,
125 MHz): dC 7.9, 33.2, 110.5, 111.5, 112.2, 113.1, 113.5, 121.9,
122.7, 123.9, 124.3, 126.9, 128.8, 129.2, 136.9, 146.1, 156.2, 158.5.
HRMS: calcd for C18H13NO3: 292.0895 [M+H]; found: 292.0899
[M+H]. Anal. Calcd for C18H13NO3: C, 74.22; H, 4.50; N, 4.81.
Found: C, 74.29; H, 4.44; N, 4.99.
30. Ganguly, A. K.; Wang, C. H.; David, M.; Bartner, P.; Chan, T. M.
Tetrahedron Lett. 2002, 43, 6865.
31. General procedure for the intramolecular Heck cyclization:
A mixture of compound 4a (100 mg, 0.23 mmol), anhydrous potas-
sium acetate (28 mg, 0.28 mmol), tetrabutylammonium bromide
(211 mg, 0.65 mmol) and Pd(OAc)2 (5.3 mg, 10 mol %) was heated
in dry DMF under nitrogen atmosphere at 120 °C for 10 h with
continuous stirring. After completion of the reaction as monitored by
TLC, the reaction mixture was cooled and water was added (3 ml). It
was extracted with ethyl acetate (3 Â 25 ml) and washed with water
(3 Â 15 ml) followed by brine (20 ml). The organic layer was dried
(Na2SO4). Evaporation of ethyl acetate furnished the crude mass,
which was purified by column chromatography over silica-gel.
Elution of the column with 30% ethyl acetate–pet. ether afforded
product 7a. Similarly the other substrates 4b and 6(a,b) were
subjected to the reaction under the same conditions to give products
7(b,d,e).
Compound 7c: Yield: 59%; solid; mp 140–142 °C. IR (KBr):
m
max = 1665, 1714 cmÀ1 1H NMR (CDCl3, 400 MHz): 6.44 (d, 1H,
.
J = 9.5 Hz, C3–H of coumarin), 7.03 (d, 1H, J = 8.3 Hz, ArH), 7.13
(t, 1H, J = 7.5 Hz, ArH), 7.31 (d, 1H, J = 8.8 Hz, ArH), 7.40 (dd,
1H, J = 8.9 Hz, J = 2.4 Hz, ArH), 7.51 (m, 1H, ArH), 7.72 (d, 1H,
J = 9.5 Hz, C4–H of coumarin), 8.27–8.30 (m, 1H, ArH), 10.19 (s,
1H, NH). MS: m/z = 263 [M+]. Anal. Calcd for C16H9NO3: C, 73.00;
H, 3.45; N, 5.32. Found: C, 73.09; H, 3.61; N, 5.21.