Palladium-catalyzed regio- and chemoselective ortho-benzylation of C-H bond using a functionalizable primary amide directing group: A concise synthesis of dibenzo[b,e]azepin-6-ones

Article abstract of DOI:10.1039/c3cc43835j

A palladium-catalyzed regio- and chemoselective direct benzylation of primary benzamides with 2-bromobenzyl bromides under a mild basic condition has been developed affording various substituted diarylmethanes in good yields. Furthermore, the directing amide group (-CONH₂) was subjected to intramolecular N-arylation with the aryl bromide moiety present in diarylmethanes leading to a concise synthesis of dibenzoazepinones. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc43835j

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Palladium-catalyzed regio- and chemoselective
ortho-benzylation of C–H bond using a
Cite this: DOI: 10.1039/c3cc43835j
functionalizable primary amide directing group:
a concise synthesis of dibenzo[b,e]azepin-6-ones†
Received 21st May 2013,
Accepted 9th July 2013
DOI: 10.1039/c3cc43835j
Joydev K. Laha,* Pooja U. Shah and Krupal P. Jethava
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A palladium-catalyzed regio- and chemoselective direct benzylation chemoselective direct C–H functionalization would present a
of primary benzamides with 2-bromobenzyl bromides under a mild challenge especially when more than one of both nucleophiles and
basic condition has been developed affording various substituted electrophiles are present. These challenges are further exacerbated
diarylmethanes in good yields. Furthermore, the directing amide by the requirement of the directing group to be functionalizable
group (–CONH2) was subjected to intramolecular N-arylation with after the desired operation. Very recently, a primary amide group
the aryl bromide moiety present in diarylmethanes leading to a (–CONH2) has been demonstrated for the first time to act as a
concise synthesis of dibenzoazepinones.
directing group in the palladium-catalyzed ortho-arylation of
primary benzamides with aryl iodides under acidic condition in
Diarylmethanes are privileged structures ubiquitously found in phar- the presence of silver oxide affording biaryls in 33–84% yields.8
maceuticals and biologically active compounds1 and employed in the To the best of our knowledge, no other report of direct
design of supramolecular structures.2 Consequently, development of C–H functionalization via C–H bond activation employing a
an efficient method for the construction of substituted diaryl- directing primary amide group is available. Herein we report a
methanes has spurred intense interest. As a result, Friedel–Crafts method for palladium-catalyzed regio- and chemoselective
benzylations,3 transition metal-catalyzed cross-coupling reactions of a ortho-benzylation of primary benzamides with 2-bromobenzyl
stoichiometric organometallic aryl with benzyl halides,4 and transition bromides under a mild basic condition. Our continued efforts
metal-catalyzed directed benzylations of electron-deficient arenes and to develop concise (one or two-step) syntheses of nitrogen-
heteroarenes have been successfully developed.5 While a wide variety containing fused heterocycles9 led us to explore the application
of functional groups have been evaluated as directing groups in arene of this protocol to the synthesis of dibenzo-fused azepinones
C–H functionalizations, only the use of a secondary amide directing that are prevalent in biologically active molecules.10 Notably,
group containing an 8-aminoquinoline moiety in direct ortho-benzyla- this constitutes a rare example of regio- and chemoselective
tion has been realized so far. The palladium6 or nickel-catalyzed7 direct C–H functionalization using a transformable directing
direct alkylations of the ortho C–H bond in secondary benzamides group.
containing an 8-aminoquinoline moiety as a bidentate directing
At the outset, the choice of the appropriate benzylic electrophile
group have been developed, wherein a few examples of ortho- for palladium-catalyzed direct benzylation of primary benzamides
benzylations have been included (see ESI†). While bidentate- was crucial (see ESI†). We chose 3-methoxybenzyl bromide in our
chelation assistance of the directing group makes these directed optimization study. When the reaction of benzamide (1) and
ortho-benzylations more attractive, the directing group requires 3-methoxybenzyl bromide (2) was carried out in the presence of
prior installation of the 8-aminoquinoline moiety and subse- 10 mol% Pd(OAc)2, 20 mol% PPh3 and 1.2 equiv. of Cs2CO3 in
quent removal for further transformation.
toluene at 110 1C for 18 h, the desired benzylated product 3 was
The development of new types of directing groups continues isolated as a major product in 30% yield together with formation of
to be important, in terms of exploring novel regio- and chemo- N-benzyl benzamide, and C,N-dibenzylated and 2,6-dibenzylated
selective direct C–H functionalizations that cannot be achieved derivatives (Table 1, entry 1). Noticeably, a significant amount of
when conventional directing groups are used. The regio- and starting material remained unreacted even after prolonging the
reaction to 36 h. Subsequent efforts to improve upon the reaction
Department of Pharmaceutical Technology (Process Chemistry), National Institute of
using other ligands, bases, and solvents were ineffective (see ESI†).
Gratifyingly, the yield of 3 was increased to 45% using dioxane as the
solvent (entry 2). A lower catalyst loading (5 mol%) was beneficial in
Pharmaceutical Education and Research, S. A. S. Nagar, Punjab 160062, India.
E-mail: jlaha@niper.ac.in; Fax: +91 172-2214692
† Electronic supplementary information (ESI) available: Additional information
reducing the amount of undesired products. Thus, compound 3 was
best obtained in 60% yield by heating 1 and 2 in the presence of
on this study, detailed experimental procedure and analytical data for all new
compounds. See DOI: 10.1039/c3cc43835j
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Table 1 Optimization study for the direct benzylationa
Table 2 Regioselective direct ortho-benzylation of primary benzamides with
benzyl bromides
Entry
Pd-source
Ligand
Base
Solvent
Yield (%)
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PPh3
PPh3
PPh3
PPh3
PPh3
—
—
—
PPh3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
Toluene
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
t-Amyl-OH
Dioxane
30
45
3b
4d
5e
6f
7
60c
38
30–35
52
38
20
0
8g
9h
Cs2CO3
a
Reagents and conditions: 1 (0.2 mmol), 2 (0.2 mmol), Pd(OAc)2 (10 mol%),
PPh3 (20 mol%), base (0.24 mmol), solvent (500 mM), 110 1C, 18 h. b Used
Pd(OAc)2 (5 mol%) and PPh3 (10 mol%). c Also isolated N-benzyl benzamide
e
(8%). d Used 2 (2 equiv.). Used Pd(OAc)2 (1.25–2.50 mol%) and PPh3
f
g
(2.5–5.0 mol%). Used Pd(PPh3)4 (10 mol%). Ref. 6. h Employed
secondary benzamide (N-methylbenzamide or N-phenylbenzamide) as one
of the coupling partners using 5 mol% Pd(OAc)2 and 10 mol% PPh3.
We also investigated the reactions of 3-substituted benzamides
with 3-trifluoromethylbenzyl bromide under the optimized condi-
5 mol% Pd(OAc)2, 10 mol% PPh3 and 1.2 equiv. Cs2CO3 in dioxane tion. Pleasantly, both 3-methylbenzamide and 3-methoxybenzamide
at 110 1C (entry 3). It should be noted here that in addition to the reacted with 3-trifluoromethylbenzyl bromide affording diaryl-
desired diarylmethane 3, the formation of N-benzyl benzamide (8%), methanes 9 and 10 in 65% and 45% yields, respectively.
C,N-dibenzylated derivatives, and other unidentified products Similarly, 3,4,5-trimethoxybenzamide gave highly substituted
account for the mass balance of the conversion of benzamide into diarylmethane 11 in 56% yield. It is noteworthy that in several
products. The use of excess 2 (2 equiv.) in this reaction was instances the yields of diarylmethanes obtained in palladium-
detrimental (entry 4). Similarly, further lowering of the catalyst catalyzed ortho-benzylation directed by a primary amide group
loading to 2.5 mol% or 1.25 mol% was deleterious (entry 5). are comparable to that obtained using a secondary amide group
Replacing Pd(OAc)2 by Pd(PPh3)4 resulted in slightly reduced containing an 8-aminoquinoline moiety.6
yield of 3 (entry 6). However, the optimized condition excluding
After successfully developing the protocol for regioselective
PPh3 gave the desired ortho-benzylated benzamide in reduced benzylation, our subsequent efforts were directed to the develop-
yield (38% vs. 60%, entry 7). Interestingly, we observed that the ment of more challenging regio- and chemoselective direct
reaction of 1 and 2 could give 3 in 20% yield under the benzylation of benzamides with 2-bromobenzyl bromides invol-
conditions described in the literature,6 however, the N-benzyl ving more than one competitive nucleophile and electrophile
benzamide was found to be a major compound in this reaction (Table 3). Taking advantage of the different reactivity of the two
(entry 8). Similarly to previous observations,6,7 the reaction of a bromo-groups present in 2-bromobenzyl bromide, Suzuki or Stille
secondary benzamide (N-methylbenzamide or N-phenylbenzamide) cross-coupling reactions employing 2-bromobenzyl bromides
with 2 did not produce the corresponding direct benzylated have been described, wherein chemoselective C-benzylation has
product under the best conditions (entry 9, see ESI†).
been achieved over C-arylation.11 However, regio- and chemo-
With the optimized condition [5 mol% Pd(OAc)2, 10 mol% selective direct C–H functionalization using 2-bromobenzyl
PPh3, 1.2 equiv. of Cs2CO3, dioxane (500 mM), 110 1C, 18 h] in bromide is unprecedented. Under the optimized conditions,
hand, we next examined the scope of the reaction to the extent for 3-methylbenzamide reacts with 2-bromobenzyl bromide yield-
regioselective direct ortho-benzylation (Table 2). To our delight, the ing 12 in 81% yield. Benzamides with an electron-donating
reaction of 3-methylbenzamide and 2 under the optimized condi- or -withdrawing group at the 3-position sustain similar reactivity
tions gave diarylmethane 4 in 65% yield indicating complete to 2-bromobenzyl bromide, affording 13 and 14 in 56% and
regiocontrol in terms of C-benzylation prevailed in this reaction. 52% yields, respectively. 4-Methoxybenzamide was also found
The effect of an electron-donating or -withdrawing group at the to react with 2-bromobenzyl bromide to give 15 in 48% yield.
3-position of benzamide was also investigated. While an electron- Similarly to our previous observation, 3,5-difluorobenzamide
donating group as in 3-methoxybenzamide resulted the formation reacted with 2-bromobenzyl bromide regioselectively yielding
of 5 in slightly reduced yield (57%), the electron-withdrawing group compound 16 in 65% yield. A similar trend of reactivity was
present in 3-trifluoromethylbenzamide restored the yield (68%) of observed with benzamide, 3-methylbenzamide, or 4-methoxy-
diarylmethane 6. Instead, an electron-withdrawing group at the benzamide and 5-bromo-6-bromomethyl-1,3-benzodioxole, yielding
4-position (as in 4-fluorobenzamide) afforded the direct benzyla- diarylmethanes 17, 18, and 19 in 50%, 53%, and 64% yields,
tion product 7 in reduced yield (55%). The C–H bond adjacent respectively. In addition, 4-fluorobenzamide and 3,5-difluoro-
to the amide group in 3,5-difluorobenzamide undergoes regio- benzamide reacted with 5-bromo-6-bromomethyl-1,3-benzo-
selective ortho-benzylation giving the diarylmethane 8 in 52% yield. dioxole to give 20 and 21 in 60% and 62% yields, respectively.
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Table 3 Regio- and chemoselective direct ortho-benzylation of primary benza-
A palladium-catalyzed direct ortho-benzylation has been
developed for the first time in the presence of an easily
functionalizable directing group (–CONH2). Furthermore,
regio- and chemoselective direct ortho-benzylation of primary
benzamides with 2-bromobenzyl bromides was also achieved.
Finally, the application of this novel protocol has been demon-
strated in the concise synthesis of fused dibenzoazepinone
heterocycles that are invariably obtained in multi-step synthesis.
Taken together, these novel findings confer a new direction
towards the development of regio- and chemoselective direct
C–H functionalization.
mides with 2-bromobenzyl bromides
We thank the CSIR, New Delhi for financial support.
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.