Pd(0)-catalyzed intramolecular Heck reaction: a versatile route for the synthesis of dibenzoazocinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2009.06.030

Two efficacious synthetic methodologies for the construction of medium-sized nitrogen heterocycles dibenzoazocinones have been developed. The phosphine-assisted protocol afforded better yields of the dibenzoazocinones (73-82%).

Full text of DOI:10.1016/j.tetlet.2009.06.030

Tetrahedron Letters 50 (2009) 4866–4869
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd(0)-catalyzed intramolecular Heck reaction: a versatile route
for the synthesis of dibenzoazocinone derivatives
*
K. C. Majumdar , Srikanta Samanta, Buddhadeb Chattopadhyay
Department of Chemistry, University of Kalyani, Kalyani 741 235, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Two efficacious synthetic methodologies for the construction of medium-sized nitrogen heterocycles
dibenzoazocinones have been developed. The phosphine-assisted protocol afforded better yields of the
dibenzoazocinones (73–82%).
Received 22 April 2009
Revised 4 June 2009
Accepted 8 June 2009
Available online 11 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Heck reaction
Palladium catalyst
Benzoazocinone
8-Exo-trig
Aza-Claisen rearrangement
The advancement of new efficient synthetic protocols for the
basic skeletons of various heterocyclic compounds is a challenging
task. Usually, synthesis of bicyclic or tricyclic fused-heterocycles
containing nitrogen attached to an aromatic ring (including ben-
zazepine, benzoxazine, benzoxazepine, benzthiazine, and ben-
zthiazepine) is crucial, since these often form the core structures
of medicines or clinical candidates.1 However, there are only few
synthetic methods available to prepare eight-membered diben-
zoazocinone derivatives. Construction of the basic skeletons is rel-
atively difficult and usually requires lengthy synthetic procedures
when conventional methods are employed, such as lactamization
and reduction.2–4 It is well known that a number of important fea-
tures make reactions involving palladium catalysts and reagents
particularly useful and versatile among the transition metals used
in organic synthesis. In general, palladium catalysts offer wide
scope for the C–C bond formation. The importance of the C–C bond
formation in organic synthesis needs no explanation. No other
transition metal can offer such versatility of the C–C bond forma-
tion as palladium. Moreover, the motivation is that this type of
azocine architecture is found in several nitrogen-based natural
products of biological interest.5
exo-counterparts under Jeffery-type conditions.8 Jeffery’s two-
phase ligandless conditions involve the addition of more than equi-
molar amounts of tetraalkylammonium salts as a phase transfer
catalyst and solid base without ligands. A large amount of rate
enhancement has been observed using Jeffery’s conditions. This
regiochemical outcome is reversed under more standard condi-
tions. Similarly, Gibson et al. showed9 that dehydroamino acid-de-
rived substrates, in which the intermediate palladium species
resulting from exo-carbopalladation are unable to undergo b-hy-
dride elimination, generate reasonable to good yields of the prod-
ucts resulting from endo-cyclization. At first sight, these reports
appear surprising since, based on a combination of entropic and
thermodynamic considerations, the formation of ‘medium’ ring-
containing heterocycles (8–10-membered) remains a synthetic
challenge.10,11
To this end, we have synthesized different types of Heck precur-
sors for the investigation of intramolecular Heck reactions which
O
R2
COCl
The examples of 8-endo-trig cyclizations are rare. However, in
certain instances it appears possible that the corresponding
eight-membered ring-containing products may also form compet-
itively.6 For example, Rigby demonstrated7 that for one substrate
class, 7- and 8-endo-trig cyclizations occur in preference to their
NH
I
N
I
R2
i
R1
+
R1
3
1
2
3a, R1 = R2 = H
3d, R1 = 4-Me, R2 = Ts
3e, R1 = 4-OMe, R2 = Ts
3f, R1 = 2-Me, R2 = Ts
3b, R1 = H, R2 = Ts
3c, R1 = 2-F, R2 = Ts
* Corresponding author. Tel.: +91 033 25827521; fax: +91 033 582 8282.
E-mail address: kcm_ku@yahoo.co.in (K.C. Majumdar).
Scheme 1. Reagents and conditions: (i) CH2Cl2, DMF–Et3N, DMAP, 0 °C to rt, 8 h.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.030

K. C. Majumdar et al. / Tetrahedron Letters 50 (2009) 4866–4869
4867
are depicted in Scheme 1. Different C-allylanilines 1a–f were pre-
Ts
N
O
pared by BF3-catalyzed aza-Claisen rearrangement in good
yields.12 The reaction of acyl chloride 2 (prepared from 2-iodoben-
zoic acid with the oxalyl chloride in CH2Cl2 in presence of a cata-
lytic amount of DMF) with 2-allylanilines 1a–f in CH2Cl2–Et3N in
presence of a catalytic amount of DMAP at 0 °C to rt for 8 h affor-
ded the amides 3a–f (Scheme 1).
The first set of experiments was carried out with 3a as the mod-
el substrate under ligand-free conditions. Substrate 3a was initially
allowed to react in dry DMF at 90 °C in the presence of palladium
acetate as catalyst, potassium acetate as base, and tetrabutylam-
monium bromide as phase transfer catalyst13 in dry DMF under
nitrogen atmosphere. No reaction occurred under these conditions
and the starting material was recovered unchanged. We then re-
peated this reaction under phosphine-assisted standard Heck reac-
tion conditions which also ended with no reaction. The reason for
the failure may be due to the fact that the palladium catalyst loses
its catalytic activity by the formation of the following types of che-
late-complexes14,15 between the palladium metal and the amide
carbonyl oxygen atom (Fig. 1).
7a
6a
Ts
N
B
Ts
N
O
O
I
A
3b
Me
Scheme 2. Heck reactions of 3b under phosphine-free and phosphine-assisted
conditions: (A) 10 mol % Pd(OAc)2, 2.75 equiv KOAc, 1.2 equiv TBAB, DMF, N2, 59%;
(B) 10 mol % Pd(OAc)2, 20 mol % PPh3, 1.2 equiv NaOAc, DMA, N2, 82%.
Table 1
Optimization of the Heck reactiona
Ts
N
O
Ts
N
Therefore, we conducted the Heck reaction with the substrate
3b under two different reaction conditions. Substrate 3b was al-
lowed to react with phosphine-free Jeffery’s two-phase protocol,
that is, Pd(OAc)2/KOAc/TBAB/DMF/90 °C/N2 conditions and pleas-
ingly the cyclized product 6a was obtained in 59% yield. When
the reaction was performed with the same substrate 3b using
Pd(OAc)2 as catalyst, NaOAc as base, and Ph3P as ligand in dry
DMA at 90 °C for 3.5 h the corresponding exo-Heck product 7a
was obtained as the sole product in 82% yield (without TBAB as
phase transfer catalyst).13 Generally, Heck reactions are carried
out in the presence of a solid–liquid phase transfer catalyst,
namely, TBAB, TBAC, and TBAHS. But, we successfully accom-
plished the Heck reaction in the absence of any phase transfer cat-
alyst (Scheme 2).
Here it is important to note that substrates containing an unac-
tivated allylic moiety usually undergo intramolecular Heck cycliza-
tion to give a mixture of exo- and endo-Heck products.16 However,
the substrates possessing an activated Michael type of olefinic
fragment9a,17 usually undergo Heck cyclization to afford the corre-
sponding endo-Heck, as the sole product. However, the phosphine-
free method A is more important than method B.
O
I
7a
3b
Entries
Catalyst
Solvent
Base
Yieldsb (%)
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMF
KOAc
KOAc
NaOAc
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
Et3N
65
72
82
24
2
DMA
DMA
DMF
DMF
Toluene
Et3N
3c
4
Pd(PPh3)2Cl2
PdCl2
5
6
7
8
NRd
NRd
NRd
32
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)2Cl2
PdCl2
THF
9
Dioxane
CH3CN
DMF
DMF
DMA
DMA
NRd
23
10
11
12
13
14
Ag2CO3
K2CO3
NaOAc
NaOAc
NRd
NRd
25
30
a
All reactions were carried out using 20 mol % PPh3.
Isolated yield.
Optimized reaction condition.
No reaction.
b
c
d
Between the two eight-membered dibenzoazocinones 6a and
7a, compound 7a possesses exo-methylene function in the azocine
ring suitable for further functionalization. We therefore, studied
the Heck reaction of the substrate 3c by the application of the
aforesaid protocols (phosphine-free and phosphine-assisted).
Expectedly, in this case also the azocinones 6b and 7b were
obtained.
From the results it is clear that the Jeffery’s two-phase protocol
would be applicable for the construction of the endo-cyclic product
and the other protocol (phosphine-assisted method B) will be appli-
cable for the synthesis of the exo-cyclic product. Due to further
application potential of the exo-cyclic product, we excluded the first
method and continued with our newly developed method B.
To find out the optimization conditions of our phosphine-as-
sisted protocol, a series of experiments were conducted where
sequential changes were made to the catalyst, base, and solvent
(Table 1).
The use of Pd(PPh3)2Cl2 as the catalyst was also found to be
effective but the yield of the Heck product 7a was low (24%). We
have studied the effect of the base employed and NaOAc was found
to be most effective whereas Ag2CO3, K2CO3, and Et3N were not
suitable. An examination of the influence of various solvents such
as DMF, DMA, MeCN, dioxane, toluene, and THF suggested that
DMA is the best choice and therefore, the optimized conditions
are: 10 mol % Pd(OAc)2/20 mol % PPh3/1.2 equiv NaOAc/10 mL
DMA/90 °C/N2.
After achieving the optimized conditions, other substrates 3c–f
were similarly treated under the optimized reaction conditions to
afford the corresponding exo-Heck-cyclized products dibenzoazo-
cinone derivatives 7b–e in 73–82% yields. The results are summa-
rized in Table 2.
The formation of the products may easily be explained by con-
sidering two different modes of the intramolecular Heck reaction.
During the course of the intramolecular cyclization by the applica-
tion of the phosphine-free and phosphine-assisted conditions two
different products 6 and 7 are formed. The formation of the prod-
uct 7 may be explained via the 8-exo-trig mode of cyclization and it
is quite reasonable due to the less steric demanding environment
O
[Pd]
H
N
NH
I
O
[Pd]
4
5
Figure 1. Chelate-complexes.

4868
K. C. Majumdar et al. / Tetrahedron Letters 50 (2009) 4866–4869
Table 2
Synthesis of dibenzoazocinones by Heck reaction
Entry
Starting
Product
Conditions
Yields (%)
O
I
O
H
N
H
N
1
Method A
Method B
0
0
3a
3b
Ts
N
O
Ts
N
O
O
I
2
3
4
5
6
7
8
Method B
Method A
Method B
Method A
Method B
Method B
Method B
82
59
73
49
82
76
79
7a
Ts
N
Ts
N
O
O
O
I
I
I
3b
6a
Me
O
Ts
N
Ts
N
F
F
3c
7b
Ts
N
Ts
N
O
F
F
3c
6b
Me
Ts
O
Ts
N
I
O
N
MeO
MeO
3d
7c
Ts
O
Ts
I
O
N
N
Me
Me
Me
Me
3e
7d
Ts
N
O
Ts
N
I
O
3f
7e
and this is also the kinetically-controlled product. But, in case of
the product 6, it is quite difficult to say whether it is actually
endo-Heck product via 8-endo-trig mode of cyclization or exo-Heck
thermodynamically-controlled double-bond-isomerized product.
For the 8-endo-trig pathway to operate, the allylic double bond
of the substrate 6 would have to be isomerized to afford the
endo-Heck precursors and under basic conditions this type of
migration may be possible.18 To get more insight into the mecha-
nism we have subjected product 7a to the reaction under condi-
tions of method A. However, no reaction occurred. As the exo-
cyclic product 7a is not convertible to 6a under the conditions of
method A the question of double bond isomerization after the
occurrence of exo-trig mode of cyclization is ruled out. Therefore,
the formation of product 6a should have occurred with prior dou-
ble bond isomerization in 3 followed by 8-endo-trig mode of
cyclization.
In conclusion, we have developed two distinct regioselective
synthetic protocols for the construction of the dibenzoazocinone
derivatives possessing diversity relevant to drug design and drug
discovery. The developed protocols are simple, general, and high
yielding.
Acknowledgments
We thank CSIR (New Delhi) and DST (New Delhi) for financial
assistance. Two of us (B.C. and S.S.) are thankful to CSIR (New Del-
hi) for the fellowships.

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4869
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