An efficient dehydroxymethylation reaction by a palladium catalyst

Article abstract of DOI:10.1039/c2cc36951f

A general method for selective dehydroxymethylation has been discovered by using widely available Pd(OAc)₂. The present study offers a new synthetic strategy for the regioselective functionalization by employing the steric, electronic and coordinating nature of the hydroxymethyl (-CH ₂OH) group temporarily.

Full text of DOI:10.1039/c2cc36951f

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An efficient dehydroxymethylation reaction by a palladium catalystw
Atanu Modak, Togati Naveen and Debabrata Maiti*
Received 25th September 2012, Accepted 9th October 2012
DOI: 10.1039/c2cc36951f
A general method for selective dehydroxymethylation has been
discovered by using widely available Pd(OAc)2. The present
study offers a new synthetic strategy for the regioselective
functionalization by employing the steric, electronic and coordinating
nature of the hydroxymethyl (–CH2OH) group temporarily.
Non-functional fused-ring aryl compounds were investigated
first and all gave the desired products efficiently (Table 1, 1–4).
As anticipated, biphenyl-4-methanol resulted in biphenyl (6) in
high yield (93%). Various arenes bearing common functional
groups such as an ester (8), a phenolic –OH (11), a cyano10 (18)
and even a free amine (–NH2) at the ortho position (15) were
tolerated under the current reaction conditions. These examples
demonstrate the power of this strategy to effect selective removal of
the hydroxymethyl group.8b Electron deficient substrates such as
those substituted with nitro (7 and 12) and trifluoromethyl (14)
groups were found to be compatible under the reaction conditions.
Of interest, 4-benzyloxy benzyl alcohol, which is highly prone
to alkyl benzyl ether C–O bond cleavage,11,12 gave the expected
dehydroxymethylation product (20) in moderate yield. Benzyl
alcohol (10) was generated as the major product (60%) from
1,4-phenylenedimethanol.13 Even a slightly crowded –CH2OH
group (17) can be tolerated under the present protocol.13
The entries in Table 1 demonstrate that the present dehydroxy-
methylation strategy can be implemented successfully in complex
molecular settings with various functional groups.
The hydroxymethyl group (–CH2OH) can control the stereo- and
regiochemical outcome of a reaction through its ability to interact
with the incoming reagent or by the complex-induced proximity
effect.1,2 A number of natural products were reported based on a
crucial dehydroxymethylation reaction involving two separate cata-
lysts to promote oxidation of alcohol to aldehyde and subsequent
decarbonylation.3 Removal of the hydroxymethyl group in a step-
wise manner has also been suggested in biological chemistry.4 For
example, dehydroxymethylation is a key process in DNA demethyl-
ase activity which involves (1) oxidation of R–CH2OH to R–CHO
and (2) subsequent decarbonylation of R–CHO to R–H.4 A single
catalyst that can selectively remove the –CH2OH group, therefore,
is expected to have considerable synthetic applications.
Oxidation of alcohol to the corresponding aldehyde has
previously been reported in the literature.5 Although aldehyde
decarbonylation was known,6 only recently we reported a
Pd-catalyzed decarbonylation reaction.7 Subsequently, we
envisaged that a dehydroxymethylation reaction might be
successful by using palladium (Scheme 1) as it can promote
both oxidation5 and decarbonylation reactions.7
Lower product yields, as seen in few cases, can be attributed
to incomplete conversion of R–CH2OH, generation of R–CHO
(vide infra) and/or due to the formation of R–CH3.13 Side-
products R–CH3 were successfully isolated (entries 1, 6 and 11).
In all other cases, yields of the minor products were determined
based on GC-results. We also found that amounts of these side-
products vary with catalyst loadings.13
Consistent with our expectations, upon optimization, high yields
of the desired products from aromatic hydroxymethyl groups were
obtained under aerobic conditions with Pd(OAc)2 as the catalyst
and Na2CO3 as the base. Control experiments in which the metal
was omitted resulted in no product formation. This ‘‘ligand-free’’,9
operationally simple and scalable method is tested with a range of
substrates of varying complexity. Notably, a CO scavenger was not
required for the smooth functioning of the present protocol.
To examine and explore the scope of the present method
further, heterocyclic and aliphatic derivatives were evaluated
under the optimized conditions (Table 2). In general, the
reactions were as effective as that of the aryl-CH2OH deriva-
tives to yield the desired product. High yields using quinoline
(21), azaindole (24) and dibenzo[b,d]thiophene (28) containing
substrates were observed. Five membered heterocyclic sub-
strates with two heteroatoms (23 and 25) performed well under
these reaction conditions. In addition, the more challenging
substrates such as 2-hydroxymethyl indole (22) and 2-hydroxy-
methyl benzo[b]thiophene (26) gave the desired product in
preparatively useful yields. As we anticipated, the N-protected
azaindole (24) has performed better than the unprotected
indole (22). Simple alkane (32 and 33) and alkenyl (30 and
31) substrates were also dehydroxymethylated despite their
propensity to undergo b-H elimination and formation of
homo-coupled side products.
Scheme 1 Pd-catalyzed removal of the –CH2OH group.
Department of Chemistry, Indian Institute of Technology, Powai,
Mumbai, 400076, India. E-mail: dmaiti@chem.iitb.ac.in
w Electronic supplementary information (ESI) available: Experimental
procedures and characterization data for all compounds. See DOI:
10.1039/c2cc36951f
Since hydroxymethyl groups are found in biologically and
pharmaceutically relevant compounds,2 we decided to test our
c
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Table 1 Scope of dehydroxymethylation reactions13
Table 2 Heterocyclic and aliphatic substrates13
a
e
b
Cyclohexane, 48 h. 24 h. 5% aldehyde isolated. 36 h.
c
d
f
12 mol% Pd, 24 h, cyclohexane. 10% ethylbenzene and 5%
g
3-phenylpropan-1-1-ol were detected. 10% homocoupled product.
h
i
GC yield. 30 mol% Pd. 5% ethylbenzene was detected.
j
Table 3 Application to natural product derivatives13
a
Minor products, R–CH3, are depicted in parentheses. b 36 h. c 48 h.
d 12 mol% Pd, 24 h, cyclohexane. e 16 mol% Pd, 48 h, cyclohexane. f GC
g
h
mol% Pd, 24 h, cyclohexane. Aniline was detected
yield. 8
(7–14%). 12 mol% Pd, 36 h, cyclohexane. 8% benzene and 4%
i
j
k
l
m
PhCHO. 20 mol% Pd, 48 h, cyclohexane. 24 h. 1,2-Diphenyl-
ethane was detected (20%).
method in complex settings (Table 3). In this context, a
substrate derived from cholestan-3-ol of the steroid cholesterol
family that comprises seven contiguous stereo centers was
selectively dehydroxymethylated in an excellent yield (36).13
Natural product derived substrates containing (multiple) alkene
and an amide (34) or an ester (35) can further reinforce the
utility of this method in complex molecular settings.13
a
b
20 mol% Pd, 29% recovered starting material. 20 mol% Pd, 20%
c
d
recovered starting material. 20 mol% Pd. 50 mol% Pd, isolated
respective aldehyde 28%, 5% recovered starting material.
Having tested a dehydroxymethylation reaction in complex
natural product derivatives, we sought to apply the protocol in
diverse synthetic transformations. In this respect, one can synthesize
biphenyl from benzyl alcohol by implementing the dehydroxy-
methylation strategy in the final step (Scheme 2).1b Ethylbenzene
can be generated from cinnamyl alcohol by taking advantage of the
present protocol (Table 2).2,14 These results (Scheme 2) highlight the
importance of the –CH2OH functional as a directing group2 and
demonstrate the use of it in suitable settings.
5% entry 25) under the reaction conditions. A high catalyst loading
is needed since two catalytic cycles operate in sync to generate the
desired dehydroxymethylated product.13 On a related note, neither
the corresponding carboxylic acid from dehydroxymethylation
reaction was detected in any case (Tables 1–3,) nor an appreciable
amount of decarboxylation product was observed by reacting
the respective carboxylic acids under present conditions.13
Moreover, when 1-naphthalene–CD2OH was subjected to
Catalytic ‘‘cycle 1’’ can be suggested based on the well-
established literature involving oxidation of alcohol to aldehyde
under similar conditions (Scheme 3).5 ‘‘Cycle 2’’ is proposed
based on our previous work on Pd-catalyzed decarbonylation
reaction under similar conditions.7,15
Consistent with the proposal in Scheme 3, we have isolated
aldehyde as the by-product (e.g. 4% entry 10, 28% entry 37,
Scheme 2 Synthetic application.13
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Scheme 3 Proposed catalytic cycles.
Scheme 4 Proposed pathways5 for generation of R–CH3.
Scheme 5 Large scale reaction.
the reaction conditions, 1-naphthalene–CD2H was detected by
GC-MS (B5%).13 These observations helped us to suggest a
mechanism for the generation of minor products under the present
conditions (Scheme 4).5 Note that in the absence of any exogenous
ligand, substrates under study such as R–CH2OH or R–CHO,
which are generated during the course of the reaction, may act as
the ligand for palladium.9
8 (a) Just recently, a Rh-catalyzed photocatalytic alcohol decarbonylation
has been developed H.-A. Ho, K. Manna and A. D. Sadow, Angew.
Chem., Int. Ed., 2012, 51, 8607–8610. Our Pd-catalyzed method is found
to be complementary to this report. The Rh-catalyzed method is
efficient with aliphatic substrates, whereas a much better substrate scope
of aromatic and heteroaromatic moieties is obtained with Pd(OAc)2;
(b) The Rh-catalyzed method8a failed completely (yield, 0%) with
substituted benzyl alcohol (4-X–C6H4CH2OH; X = NO2, CO2Me,
etc.), whereas our method produces acceptable yields of the expected
product (Table 1, entries 7, 8, etc.).
Additionally, the reaction proved to be scalable, with
2-naphthalenemethanol on a gram scale, delivering 70% of the
desired product (Scheme 5). Aside from the wide substrate scope
and functional group tolerance, it is worth noting that this method
works under air and without any need for solvent purification.
We are presently studying the detailed mechanism of this reac-
tion and also working on increasing the turnover number of the
catalyst. Nevertheless, the results of this work have demonstrated
that the selective cleavage of the –CH2OH group can be conducted
by simply using widely available Pd(OAc)2.16 The scope of the
reaction is broad, allowing the dehydroxymethylation of aryl
substrates, as well as the extension of this protocol to hetero-
aromatic and aliphatic moieties. The present study also offers a
new synthetic strategy for the regioselective functionalization by
employing the steric, electronic and coordinating nature of the
–CH2OH group temporarily. This advance clearly impacts one of
the limitations of the existing practice of dehydroxymethylation,
which usually required two separate catalytic systems.
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13 See ESIw.
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This work is supported by DST (R/S1/IC–24/2011) and
CSIR (P81102); India. Financial support received from CSIR-
India (fellowship to A.M. and T.N.) is gratefully acknowledged.
Palladium catalysts were obtained as a gift from Johnson
Matthey Chemicals, MIDC Taloja, India.
15 Note that mechanistically Rh-catalyzed methods are different
compared to the Pd-catalyzed process discussed here8.
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16 A patent on this work has been filed, Indian Patent Application
No: 3280/MUM/2011.
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This journal is The Royal Society of Chemistry 2012
Chem. Commun.