Aromatic ortho-benzylation reveals an unexpected reductant

Article abstract of DOI:10.1021/ol802185x

(Chemical Equation Presented) The discovery of a novel arylpalladium(II) reduction enables the synthesis of diarylmethanes via reductive benzylation. Benzyl chlorides were found to be the major source of hydride, acting as an alkylating agent and an aprotic surrogate for benzyl alcohol. This represents the first example of an arylpalladium(II) reduction mediated by a benzyl halide.

Full text of DOI:10.1021/ol802185x

ORGANIC
LETTERS
2008
Vol. 10, No. 21
5095-5097
Aromatic ortho-Benzylation Reveals an
Unexpected Reductant
Andrew Martins and Mark Lautens*
DaVenport Research Laboratories, Department of Chemistry, UniVersity of Toronto,
80 St. George Street, Toronto, Ontario, Canada M5S 3H6
mlautens@chem.utoronto.ca
Received September 18, 2008
ABSTRACT
The discovery of a novel arylpalladium(II) reduction enables the synthesis of diarylmethanes via reductive benzylation. Benzyl chlorides were
found to be the major source of hydride, acting as an alkylating agent and an aprotic surrogate for benzyl alcohol. This represents the first
example of an arylpalladium(II) reduction mediated by a benzyl halide.
The palladium-catalyzed transfer hydrogenolysis of aryl
halides generally employs stable, easily handled hydrogen
transfer reagents (HCO2Na, R3SiH, ROH, etc.) as the hydride
source, enabling the formation of hydridoarylpalladium(II)
species via transmetalation or ꢀ-hydride elimination path-
ways.1 When incorporated into domino processes,2 hydro-
genolysis reactions often suffer from the reduction of
transient palladium(II) intermediates. Thus, selective domino
hydrogenolysis reactions are highly desirable, especially
when reagents can play multiple roles in the reaction
sequence.3 Herein, we report a reductive palladium-catalyzed,
norbornene-mediated synthesis of diarylmethanes based upon
the Catellani4 method of ortho-C-H functionalization.
Through our discovery and mechanistic study of this reaction,
benzyl halides were found to act as both alkylating agents
and reductants in a selective domino sequence.
While exploring Catellani-type reactions with benzyl
chlorides as reaction partners, we isolated diarylmethane 3a
(Scheme 1), the product of ortho-benzylation and ipso
Scheme 1. Optimized Reductive Benzylation Sequence
(1) (a) Tsuji, J. In Palladium Reagents and Catalysts: New PerspectiVes
for the 21st Century; Tsuji, J., Ed.; Wiley-VCH: Weinheim, 2004. (b)
Negishi, E.-I. In Handbook of Organopalladium Chemistry for Organic
Synthesis; Negishi, E.-I., Eds.; Wiley-VCH: Weinheim, 2002.
(2) Tietze, L. F.; Brasche, G.; Gericke, K. In Domino Reactions in
Organic Synthesis; Tietze, L. F., Ed.; Wiley-VCH: Weinheim, 2007.
(3) Excellent examples of this concept include the recent work of Krische
and coworkers. See: (a) Patman, R. L.; Williams, V. M.; Bower, J. F.;
Krische, M. J. Angew. Chem., Int. Ed. 2008, 47, 5220–5223. (b) Kim, I. S.;
Ngai, M.-Y.; Krische, M. J. J. Am. Chem. Soc. 2008, 130, 6340–6341. (c)
Shibahara, F.; Bower, J. F.; Krische, M. J. J. Am. Chem. Soc. 2008, 130,
6338–6339.
reduction of aryl iodide 1a, in low yield. Our previous
observation of an ortho-alkylation/reduction sequence oc-
curred in the presence of electrophiles containing ꢀ-hydro-
gens,5 thus the isolation of 3a was surprising to us, as benzyl
chloride 2a is not susceptible to traditional ꢀ-hydride
elimination pathways. We believed that the reduction must
be mechanistically distinct from our previous findings, so
(4) (a) Catellani, M.; Frignani, F.; Rangoni, A. Angew. Chem., Int. Ed.
Engl. 1997, 36, 119–122; Angew. Chem. 1997, 109, 142-145. (b) Catellani,
M.; Mealli, C.; Motti, E.; Paoli, P.; Perez-Carreno, E.; Pregosin, P. S. J. Am.
Chem. Soc. 2002, 124, 4336–4346. (c) Catellani, M. Synlett 2003, 298–
313. (d) Catellani, M. Top. Organomet. Chem. 2005, 14, 21–53.
(5) Wilhelm, T.; Lautens, M. Org. Lett. 2005, 7, 4053–4056. The
reductants were found to be alkyl halide and isopropylboronic acid.
10.1021/ol802185x CCC: $40.75
Published on Web 10/08/2008
2008 American Chemical Society

Scheme 2
.
Deuterium Labeling Studies
Table 1. Reductive Dehalogenation of 1a
entry
additives
yielda
1
2
3
4
5
none
6
PhCH2OH (2 equiv)
PhCH2Cl (2 equiv)
PhCH2Cl (2 equiv) + CsI (10 mol %)
PhCH2Cl (2 equiv) + CsI (1 equiv)
70b
7
50
61
a Relative to mesitylene internal standard. b Isolated yield.
we were prompted to optimize the reaction and further
investigate the reductive mechanism.
strictly anhydrous conditions, and those with added water
all produced identical yields of product. The nucleophilicity
of carbonate9 and bicarbonate10 anions toward alkyl halides
and pseudohalides has been well documented, thus we
proposed that the in situ formation of a benzyl carbonate or
bicarbonate species could decarboxylate to form a benzyl
alkoxide or alcohol species, which could then be used as a
reductant for arylpalladium(II) species.
Through screening of reaction parameters, we identified
the conditions outlined in Scheme 1 to be optimal, affording
compound 3a in 86% yield. The mechanism of ortho-
benzylation is fairly well understood based upon the work
of Catellani with stoichiometric palladium,6,7 so we decided
to perform deuterium labeling studies to help elucidate the
mechanism of arylpalladium(II) reduction. We synthesized
R,R-dideuterobenzyl chloride (2a-d2) and 4,6-dideutero 1a
(1a-d2) and set up the coupling reactions in Scheme 2in an
anhydrous, inert atmosphere glovebox. When 2a-d2 was used
as a coupling partner, 56% deuterium incorporation at the
ipso position was observed. When the reaction was set up
under ambient conditions (i.e., traces of water may have been
present), there was no change in deuterium incorporation.
The use of 1a-d2 led to 7% ipso deuterium incorporation;
however, when set up under ambient conditions, no deute-
rium incorporation was observed. When we used both 1a-
d2 and 2a-d2 in conjunction under anhydrous conditions, the
algebraic sum of deuterium incorporation was observed as
there was 63% deuterium at the ipso position.
To further test this hypothesis, we performed a reductive
dehalogenation of aryl iodide 1a under our reaction condi-
tions without norbornene (Table 1). In the absence of
additives, only a small amount of dehalogenation product 4
was observed. In the presence of base, benzyl alcohol was
an effective reductant, so we next examined a mixture of
benzyl chloride (2a) and Cs2CO3 as a prereductant. This did
not improve the yield, suggesting that benzyl chloride is
unreactive toward carbonate under the reaction conditions.
We noted that CsI, a byproduct of the ortho-benzylation
reaction, could increase the reactivity of the benzyl halide
through nucleophilic displacement. The addition of CsI in
catalytic (entry 4) and stoichiometric (entry 5) amounts
significantly increased the yield of 4 to levels comparable
with benzyl alcohol. From these results, we propose the
mechanism of reduction as depicted in Scheme 3, where the
From these labeling experiments, we conclude that there
are several co-operative mechanistic pathways for arylpal-
ladium(II) reduction. As the majority of deuterium incorpo-
ration came from the R-position of the benzyl halide, we
sought to determine the fate of the benzyl donor. Analysis
1
of the crude reaction by H NMR revealed the production
Scheme 3. Proposed Mechanism of Reduction
of an aldehyde, and we were able to isolate 4-chlorobenzal-
dehyde in 57% yield from the reaction of 1a and 4-chlo-
robenzyl chloride (vide infra). We suspected that the in situ
formation of a benzyl alcohol, a known reductant of
arylpalladium(II) species,8 was the culprit. Hydrolysis of the
benzyl chloride may form benzyl alcohol; however, experi-
ments conducted under ambient conditions, those under
(6) Catellani, M.; Fagnola, M. C. Angew. Chem., Int. Ed. Engl. 1994,
33, 2421–2422. This reaction was stoichiometric in palladium and involved
the benzylation of the ortho C-H bonds, followed by hydrogenolysis with
H2 or NaBH4 of the resultant arylpalladium(II) species
.
(7) Catellani, M.; Cugini, F.; Tiefenthaler, D. Can. J. Chem. 2001, 79,
catalytic formation of benzyl iodide initiates the reductive
mechanism. Moreover, the benzyl halide acts as an aprotic
surrogate for benzyl alcohol in the hydrogenolysis reaction
742–751
.
(8) Deledda, S.; Motti, E.; Catellani, M. Can. J. Chem. 2005, 83, 741–
747.
5096
Org. Lett., Vol. 10, No. 21, 2008

Table 2. Scope of Aryl Iodidesa
Table 3. Scope of Benzyl Chloridesa
a See Scheme 1 for reaction conditions. b Isolated yield (%). c 1 equiv
of 2g used.
a See Scheme 1 for reaction conditions. b Isolated yield (%).
coordinating functional group was ortho to the benzylic
carbon (as in 2d), yields were slightly reduced. Bifunctional
benzyl halide 2g gave a poor yield of product; however, when
the amount of 2g was reduced to 1 equiv, a considerable
amount of the (bis)diarylmethane product 3o was obtained.
In summary, we have identified a novel and interesting
mechanism for the hydrogenolysis of arylpalladium(II)
species which was further applied to the synthesis of
diarylmethanes. Although we have significant insight into
part of the mechanistic puzzle, we are currently working
toward determining the source of the remaining reducing
equivalents, which will be reported in due course.
and, to the best of our knowledge, represents the first example
of an arylpalladium(II) reduction mediated by a benzyl
halide.
We explored the scope of the domino reaction by screening
ortho-substituted aryl iodides with a variety of functional
groups (Table 2). Overall, electron-deficient aryl iodides
containing an ortho-methyl group performed best, while
electron-rich aryl iodides or those without an ortho-methyl
group (such as 1h) afforded little to no desired product.
Electron-deficient aryl iodides with Lewis basic ortho
functional groups solely afforded the unsymmetrical biaryl
dimer.8 Chemoselective aromatic benzylation was observed
for aromatic amide 1e and carbamate 1f, affording solely
desired products 3e and 3f in good yields with no products
of N-benzylation detected.
Acknowledgment. We thank the National Science and
Engineering Council of Canada and Merck Frosst Canada
& Co. for financial support in the form of an Industrial
Research Chair. We also thank Prof. D. B. Collum (Cornell
University) for helpful suggestions.
We also screened several benzyl chlorides as coupling
partners (Table 3). Both electron-rich and electron-deficient
benzyl chlorides worked quite well. However, when a
Supporting Information Available: Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(9) (a) Shi, M.; Shen, Y.-M. Molecules 2002, 7, 386–393. (b) Verdecchia,
M.; Feroci, M.; Palombi, L.; Rossi, L. J. Org. Chem. 2002, 67, 8287–
8289.
(10) Bosworth, N.; Magnus, P.; Moore, R. J.C.S. Perkin 1 1973, 2694–
2697.
OL802185X
Org. Lett., Vol. 10, No. 21, 2008
5097