Cascade palladium catalysis: A predictable and selectable regiocontrolled synthesis of N-arylbenzimidazoles

Article abstract of DOI:10.1002/anie.201306007

By choice: The palladium-catalyzed cascade reaction of 2-chloroaryl sulfonates with arylamine and amide nucleophiles provides direct access to N-arylbenzimidazoles. This strategy selectively produces the heterocycles based on chemoselective oxidative addi

Full text of DOI:10.1002/anie.201306007

Angewandte
Chemie
DOI: 10.1002/anie.201306007
Homogeneous Catalysis
Cascade Palladium Catalysis: A Predictable and Selectable
Regiocontrolled Synthesis of N-Arylbenzimidazoles**
Nathan T. Jui and Stephen L. Buchwald*
Dedicated to Professor Irina Beletskaya
À
Nitrogen-containing heterocyclic groups are pervasive struc-
tural elements in natural products, medicines, agricultural
chemicals, and functional materials. As a result, the con-
struction and functionalization of these is a central focus in
organic synthesis. Our group, among others, has a long-
standing interest in developing catalytic methods which
enable the efficient and selective formation of carbon–
nitrogen bonds,[1] and we seek to apply these technologies
to the preparation or modification of a broad array of
heterocyclic scaffolds, including benzimidazoles. Regioselec-
tive benzimidazole alkylation or arylation is challenging
because of the relatively similar electronic properties exhib-
ited by the non-equivalent nitrogen atoms contained within
the imidazole moiety.[2]
C N bond-forming reactions involving a 2-chloroaryl sulfo-
nate (or similar) substrate and two discrete nitrogen-based
nucleophiles which are added at the same time [Eq. (2)]. The
outlined three-component coupling method represents
a potentially powerful alternative approach to heterocycle
synthesis and would provide modular access to a broad range
of functionalized benzimidazoles with predictable and poten-
tially selectable regiocontrol.
While transition-metal catalysts have evolved to effi-
ciently install aryl units directly onto benzimidazole sub-
strates,[3] regioisomeric mixtures are formed in the absence of
significant steric differentiation of the two nitrogen atoms
[Eq. (1)].[4] As a result, a number of methods have been
developed to overcome this issue.[5] The most commonly
utilized strategy involves intramolecular cyclization of aryl-
amidine structures,[6] and both cross-coupling[6a–h] and oxida-
tive cyclization[6i,j] technologies have been explored exten-
sively. In addition, a number of elegant cascade processes
have emerged and enable in situ arylamidine formation with
subsequent cyclization.[7] In addition to the groups of Ma[8a,c]
and Clark,[9b,c] we have developed an alternative approach
wherein catalytic amination[8] or amidation[9] of 2-chloroani-
line derivatives and subsequent condensation delivers the
desired azole products. We envisioned a complimentary
strategy for the direct construction of benzimidazoles by
a regio- and chemoselective cascade of palladium-catalyzed
[*] Dr. N. T. Jui, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18-490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
The proposed proccess, shown in Equation (2), involves
selective oxidative addition of a palladium catalyst into the
1
À
C X bond of the diactivated arene 1 to form the organo-
palladium intermediate 5. Arylation of an arylamine substrate
(2), in preference to the amide nucleophile, would provide the
ortho-haloaniline 6. A second palladium insertion and
subsequent coupling with the amide 3 would yield the o-
phenylenediamine derivative 8 which, after condensation,
would convert into the desired benzimidazole 4. While the
outlined process would require two different fundamental
E-mail: sbuchwal@mit.edu
[**] This project was funded by the National Institutes of Health (S.L.B.:
GM58160; N.T.J.: GM099817. The content is the sole responsibility
of the authors and is not necessarily representative of the official
views held by the National Institutes of Health. The Varian 500 MHz
spectrometer used in this work was purchased with funds from the
National Science Foundation (CHE-9808061). We thank Dr. Andrew
DeAngelis for helpful discussions. This manuscript is dedicated to
Professor Irina Beletskaya in recognition of her contributions to the
field of metal-catalyzed reactions.
steps to occur with high levels of chemoselectivity, namely
1
À
oxidative addition to X and C N coupling, we anticipated
that both elements would be possible because 1) relative rates
of oxidative addition to aryl electrophiles are understood to
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306007.
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generally follow the pattern: I > OTf ꢀ Br> Cl > OMs,[10] and
2) it has been demonstrated that arylamines can react
preferentially with aryl palladium complexes in the presence
of amides.[11] Herein, we describe the realization of this design
and its application to a process which exploits the orthogonal
reactivity of aryl triflates and aryl mesylates to produce either
of the two possible benzimidazole regioisomers in a selectable
manner from a single 2-chlorophenol precursor.
We have developed a family of dialkylbiaryl phosphines
which are highly efficient ligands for a number of palladium-
catalyzed processes,[12] including amination[13] and amida-
tion[14] reactions. From the outset, we recognized that the
identification of a single catalyst that could perform the
chemo- and regioselective coupling of both aniline and amide
nucleophiles was critical and we expected that the ligand
would be key to the success of this method. Given the facile
access to 2-chlorophenols, we were first interested in devel-
oping this cascade reaction using 2-chlorophenyl triflate, one
equivalent of aniline, and a slight excess of acetamide
(Table 1). When treated with [(allylPdCl)2] (1 mol%), phos-
have been employed in amination or amidation reactions of
aryl chlorides, were less effective supporting ligands in this
cascade (entries 4–6; up to 63% yield), the catalyst based on
tBuBrettPhos (L4) provided the desired benzimidazole in
77% yield (entry 7). The yield was further improved by
employing the recently described 4-aminobiphenyl-derived
tBuBrettPhos mesylate precatalyst P1,[15] which delivered the
desired product in 88% GC yield (86% yield of isolated
product; Table 1, entry 8). Additionally, we found that 2-
chloro-1-bromobenzene and 1,2-dichlorobenzene can also
function as the electrophilic component of this system, further
demonstrating the utility of this process.
Having identified reaction conditions which enable this
cascade process, we evaluated the substrate scope of this
transformation. As highlighted in Table 2, a range of sub-
stituted arylamines bearing electron-donating or electron-
Table 2: Complex benzimidazole synthesis by a palladium-cascade.[a]
Table 1: Cascade amination/amidation: Catalyst identification.[a]
Entry
X1
X2
Ligand
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
OTf
OTf
OTf
OTf
OTf
OTf
OTf
OTf
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
PPh3
PCy3
PtBu3
L1
L2
L3
L4
0
0
0
trace
47
63
77
88 (86)
87
P1[c] (2mol%)
P1[c] (2mol%)
P1[c] (2mol%)
Cl
70
[a] Reaction conditions: aryl halide (0.5 mmol), aniline (0.5 mmol),
acetamide (0.65 mmol), [(allylPdCl)2] (3 mol%), ligand (3 mol%),
Cs2CO3 (1.2 mmol), tBuOH (1.0 mL), 1108C, 12 h. [b] Yield determined
by GC using tetradecane as an internal standard. Yield of isolated
product given within parentheses. [c] The precatalyst P1 was used
instead of [(allylPdCl)2] and ligand. TF=trifluoromethanesulfonyl.
phine ligand (3 mol%), 2.4 equivalents of cesium carbonate,
and tert-butanol at 1108C for 12 hours, the desired benzimi-
dazole was provided in varying amounts (Table 1, entries 1–
7). Although the use of tripheny-, tricyclohexyl-, or tri-tert-
butylphosphine was unsuccessful in this context (entries 1–3),
catalysts based on biarylphosphine ligands did result in
formation of the desired product. While tBuXPhos (L1),
Me4tBuXPhos (L2), or BrettPhos (L3), phosphines which
[a] Reaction conditions: aryl halide (1.0 mmol), arylamine (1.0 mmol),
amide (1.3 mmol), P1 (2–5 mol%), Cs2CO3 (2.4 mmol), tBuOH
(1.5 mL), 1108C, 12 h. Yields are those of isolated product as an average
of two runs. [b] Reaction was conducted at 458C for 1 h then at 1108C for
12 h.
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withdrawing substituents readily participate in this process as
do aminopyridine and aminopyrazole substrates. In addition
to formamide, simple straight-chain-alkyl-, branched-alkyl-,
vinyl-, and aryl-substituted amides react smoothly under
standard reaction conditions (54–85% yield), although some
substrate combinations require slightly elevated catalyst
loading to proceed to completion in the 12 hour period (up
to 5 mol%). Moreover, we found that a range of 4- or 5-
substituted 2-chloroaryl triflates provide access to the corre-
sponding benzimidazoles in moderate to good yield as single
regioisomers. While 2-chloroaryl triflates are generally the
best substrates in this chemistry, competitive hydrolysis of the
triflate function was observed in the presence of electron-
withdrawing substituents. However, the corresponding 2-
chloroaryl bromides could be used to circumvent this issue
(4j, 4k; Table 2). In all of the cases examined, selective
amination of the aryl triflate (or bromide) was observed, but
in some cases, significant amounts of diaminated electrophile
were observed. We found that the yield of the desired product
in these examples was increased by stirring the reaction
mixture for 1 hour at 458C followed by 12 h at 1108C (4a, 4i,
4k; Table 2). While this process is efficient for a range of 4- or
5-substituted deactivated electrophiles, substitution at the 3-
or 6-positions was not well tolerated, presumably because of
the bulky nature of the palladium catalyst. In addition,
selective amination of the more activated 2-position of 2,3-
dichloropyridine was possible under the same treatment to
finally give rise to the imidazo[4,5,b]pyridine product 4l in
useful yield (61%) with complete regiocontrol.
To further evaluate the power of this modular cascade
strategy, we questioned whether it could be employed to
ultimately arrive at either of the possible benzimidazole
regioisomers from the same 2-chlorophenol starting material.
This would be especially interesting because, while a broad
range of 3- or 4-substituted 2-chlorophenols are commercial
or readily accessible, it is rare that both isomers are available.
This strategy would allow one to generally access either
product (in a selectable fashion) from the most convenient
starting material, an appealing feature which is absent in
current methods for regioselective benzimidazole synthesis.
As described above (and shown in Table 3), 4-substituted-2-
chloroaryl triflates react under standard reaction conditions
to provide the corresponding 5-substituted N-arylbenzimida-
zoles (denoted regioisomer A in Table 3) with complete
regioselectivity. Given the relatively low reactivity of aryl
mesylates toward oxidative addition, we reasoned that
palladium insertion into Ar-Cl of the corresponding chloro-
aryl mesylate might preclude Ar-OMs insertion and that the
reaction would deliver the opposite regioisomer (B). We
found that, although the mesylate cascade required higher
catalyst loading and reaction time (6 mol% Pd and 24 h),
generic access to 6-substituted benzimidazole products can be
Table 3: Selectable regiocontrolled synthesis of either benzimidazole isomer from starting materials derived from the same chlorophenol.[a]
[a] Yield of isolated product from reaction run on a 1.0 mmol scale (average of two runs). Regiochemical assignments were made by steady-state nOe
difference spectra or by analogy. [b] Reaction was conducted for 24 h. [c] 3.0 mmolK3PO4 was used as base. [d] Reaction was conducted at 458C for 1 h
then at 1108C for 12 h. [e] Reaction was conducted at room temperature for 2 h then at 1108C for 24 h. Ms=methanesulfonyl.
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lective arylation dictated by an adjacent substituent: S. Ueda, M.
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achieved in this manner. As shown in Table 3, this strategy
was applied to 2-chlorophenols bearing alkyl, fluoro, aryl, or
trifluoromethyl substitution to predictably access either of the
corresponding regioisomeric benzimidazoles in a selectable
manner. While the standard reaction conditions efficiently
provided both regioisomers in the presence of electron-
neutral (fluoro and phenyl) substituents on the difunctional
electrophile (6A, 6B and 7A, 7B), significant sulfonate
hydrolysis was observed with the 4-isopropyl-substituted 2-
chlorophenyl mesylate and both of the 4-trifluoromethyl-2-
chlorophenyl sulfonates. We found that replacing Cs2CO3
with K3PO4 as the base enabled these processes to occur,
thus delivering the desired products with acceptable levels of
chemical efficiency (62–81% yield).
In summary, we have developed a novel approach to
regioselective N-arylbenzimidazole synthesis which involves
cascade intermolecular amination and amidation reactions of
2-chloroaryl sulfonates (or halides). We found that a single
catalyst, based on tBuBrettPhos, is able to selectively perform
both catalytic elements of this process for a broad range of
arylamine (or heteroarylamine), amide, and bifunctional
electrophile substrates to afford the corresponding benzimi-
dazole products with complete regioselectivity. Moreover, we
have demonstrated that different 2-chloroaryl sulfonates
(triflate versus mesylate), which are derived from the same
chlorophenols, can be reacted under very similar reaction
conditions to exclusively afford the opposite regioisomeric
heterocycles. In addition to offering a complementary method
for regioselective benzimidazole synthesis, we anticipate that
the described cascade strategy represents a potentially power-
ful approach to streamlining chemical synthesis, particularly
within the realm of palladium-catalyzed reactions.
Received: July 10, 2013
Published online: && &&, &&&&
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4678 – 4681.
[10] J. Hartwig, Organotransition Metal Chemistry, University Sci-
ence Books, Saulsalito, 2010, and references therein.
Keywords: chemoselectivity · cross-coupling · heterocycles ·
palladium · synthetic methods
.
À
[1] For selected reviews of catalytic C N bond formation, see:
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Blanchard, M. Toumi, Chem. Rev. 2008, 108, 3054 – 3131.
[2] M. R. Grimmett, Imidazole and Benzimidazole Synthesis (Ed.:
O. Meth-Cohn), Academic Press, New York, 1997.
[11] X. Huang, K. W. Anderson, D. Zim, L. Jiang, A. Klapars, S. L.
Buchwald, J. Am. Chem. Soc. 2003, 125, 6653 – 6655.
À
[12] Dialkylbiaryl phosphines in C C bond formation: R. Martin,
À
S. L. Buchwald, Acc. Chem. Res. 2008, 41, 1461 – 1473; In C N
bond formation: D. Surry, S. L. Buchwald, Chem. Sci. 2011, 2,
27 – 50.
[3] Copper-catalyzed benzimidazole arylation: a) A. Kiyomori, J.-F.
Marcoux, S. L. Buchwald, Tetrahedron Lett. 1999, 40, 2657 –
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[16] MIT holds or has filed patents on the ligands and precatalysts
used in this work for which S.L.B. receives royalty payments.
[4] Nonselective benizimidazole arylation: D. Yang, H. Fu, L. Hu, Y.
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4
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Chemie
Communications
Homogeneous Catalysis
N. T. Jui, S. L. Buchwald*
&&&& — &&&&
Cascade Palladium Catalysis: A
Predictable and Selectable
Regiocontrolled Synthesis of N-
Arylbenzimidazoles
By choice: The palladium-catalyzed cas-
cade reaction of 2-chloroaryl sulfonates
with arylamine and amide nucleophiles
provides direct access to N-arylbenzimi-
dazoles. This strategy selectively produ-
ces the heterocycles based on chemo-
selective oxidative addition. 2-Chloroaryl
triflates (Tf) produce one regioisomer
and the corresponding 2-chloroaryl
mesylates (Ms) deliver the other in
a selectable manner.
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