Bronsted acid catalyzed α-alkylation of aldehydes with diaryl methyl alcohols

Article abstract of DOI:10.1002/chem.201102623

A proton does the two jobs: Bronsted acids alone catalyze the α-alkylation of aldehydes with diaryl alcohols. In this type of transformation, the acid-catalysis approach offers a broader substrate scope compared to the previously used enamine catalysis methods. The acid plays two important roles: one is to mediate the alcohol dehydration for carbocation formation; the other is to accelerate the rate-determining aldehyde enolization (see scheme). Copyright

Full text of DOI:10.1002/chem.201102623

DOI: 10.1002/chem.201102623
Brønsted Acid Catalyzed a-Alkylation of Aldehydes with Diaryl Methyl
Alcohols
Chong Xing,[a] Hui Sun,[b] Junmin Zhang,[a] Guohui Li,*[b] and Yonggui Robin Chi*[a]
The catalytic a-alkylation of carbonyl compounds is a
common approach in organic synthesis. In recent years,
many efforts have been directed towards the activation of
ketones and aldehydes by means of enamine catalysis to
react with a broad range of electrophiles.[1] In 2004, List re-
ported an elegant intramolecular alkylation of aldehydes
with alkyl halides using proline-based amine catalysts.[2]
While the long-sought intermolecular versions of such en-
amine-catalytic SN2-type a-alkylation of aldehydes[3] remain
challenging, research by the groups of Melchiorre, Cozzi, Ja-
cobsen and others have pioneered the amine-mediated SN1-
type intermolecular reactions between aldehydes and aryl-
sulfonyl indoles,[4] diaryl alcohols,[5] or halides.[6] In the ap-
proach used by Cozzi and others, amine catalysts were used
to activate the aldehydes via enamine intermediates, and
Brønsted acids were used to mediate the formation of diaryl
methyl cations from the corresponding diaryl methanols.
Despite the success of this amine/acid co-catalysis approach
for diaryl methyl alcohols (e.g., 1a) that generate highly sta-
bilized carbocations, the scope of the reactions still remains
limited: diaryl methyl alcohols (such as 1b–f) that lead to
“less stabilized” diaryl methyl carbocation electrophiles are
ineffective substrates in these alkylation reactions.[5b]
Instead of using enamine catalysis for aldehyde activation,
here we disclose the use of Brønsted acids[7] alone to cata-
lyze these SN1 type aldehyde alkylations. The acid catalyst is
believed to facilitate the formation of alcohol-derived carbo-
cations and to accelerate the enolization of aldehydes. A
much broader scope of substrates is thereby realized: diaryl
methyl alcohols that lead to less stabilized carbocations can
be used; aldehydes with a,a-disubstituents react efficiently
as well to generate products containing quaternary carbon
centers.
Our work began by using diaryl methanol 1b as a model
substrate to develop an acid-catalysis approach. According
to the Mayr reactivity scales,[8] such substrates lead to less-
stabilized carbocations (e.g., compared to that from 1a) and
were ineffective using the enamine/acid co-catalytic strat-
egies. The results of our initial studies are summarized in
Table 1. Weak acids, such as acetic acid, could not mediate
Table 1. Brønsted acid catalyzed alkylation of 2a with 1b.[a]
Entry
Acid ([mol%])
Additive
3a Yield [%][b]
1
2
3
4
5
6
–
–
–
–
–
<1
<1
55
28
HOAc (10)
p-TSA (10)
DNBA (10)
p-TSA (20)
p-TSA (10)
–
63
tBuOH (1.0 equiv)
87(95)[c]
[a] 2a (1.2 mmol) and 1b ( 0.4 mmol) were reacted in CH2Cl2 (2 mL).
[b] 1H NMR yield. [c] Yield of isolated compound after 19 h.
[a] C. Xing, Dr. J. Zhang, Prof. Dr. Y. R. Chi
Division of Chemistry & Biological Chemistry
School of Physical & Mathematical Sciences
Nanyang Technological University
Singapore 637371 (Singapore)
this reaction. We then found that by using 10 mol% p-tolue-
nesulfonic acid (p-TSA) in CH2Cl2, the SN1-type alkylation
product 3a was detected in 55% yield (Table 1, entry 3).
Additional studies showed that solvents have dramatic ef-
fects on the reaction yield,[9] and CH2Cl2 was finally found
as an optimal solvent for this reaction. Acids slightly stron-
ger than p-TSA, such as 2,4-dinitrobenzenesulfonic acid
(DNBA), showed decreased yields under the otherwise
identical conditions (Table 1, entry 4).
Fax : (+65)67911961
E-mail: robinchi@ntu.edu.sg
[b] Dr. H. Sun, Prof. Dr. G. Li
State key Laboratory of Molecular Reaction Dynamics
Dalian Institute of Chemical Physics
Chinese Academy of Sciences
457 Zhongshan Rd. Dalian, 116023 (P. R. China)
Fax : (+86)0411-8467-5584
Further optimizations with respect to typical parameters,
such as acid catalysts and reaction temperatures, could not
improve the yield to over 70%. We then found that self-
E-mail: ghli@dicp.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102623.
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Chem. Eur. J. 2011, 17, 12272 – 12275

COMMUNICATION
redox reactions[10,11] of the ether intermediate 4a (formed
from 1b under acid catalysis[5e,10a]) led to a significant con-
sumption of the alcohol substrate to generate undesired
products. Finally, by using 1.0 equivalents of tBuOH as an
additive,[9] the self-redox formation of 5a/b was almost com-
pletely suppressed and the reaction led to quantitative for-
mation of the aldehyde alkylation product (Table 1, entry 6).
As intended, tBuOH can compete in ether formation, and
the resulting cross-ether (4b) has a smaller tendency to un-
dergo self-redox reactions (Scheme 1).
bocation (than that from 1b), a higher loading of the p-TSA
catalyst and longer reaction time were needed to generate
product 3e and 3 f. DNBA was used for diaryl methanol 1d
and 1e (Table 2, products 3g–j). The carbocation generated
from bis(4-chlorophenyl)methanol (1 f) was listed as the
least stabilized diaryl cation of this series in Mayrꢁs scale.[8]
By using triflic acid as the catalyst, the alkylation products
(Table 2, 3k and 3l) were obtained in moderate yields. Fur-
ther pushing the limits to diaryl alcohols with strong elec-
tron-withdrawing groups, such as a CF3 group on the ben-
zene ring, resulted in complicated reactions without isolable
amounts of the desired product under a range of conditions.
Although it was not the focus of this study, we also tested
diaryl alcohol 1a, which was previously used in the enam-
ine/acid catalysis. As expected, this less-challenging alcohol
also worked well under the acid catalysis.
We next investigated the use of a,a-disubstituted alde-
hydes as the nucleophilic substrate (Table 3). In all cases,
the reactions proceeded cleanly to afford the products in ex-
cellent yields. The acid catalysis approach was also extended
to allylic alcohols[12] that can generate allylic carbocations,
as exemplified in Table 4.
Scheme 1. Proposed self-redox pathway and its suppression pathway.
We then examined the scope of the reaction. In particular,
we focused on alcohols that led to the challenging less-stabi-
lized diaryl carbocations (Table 2). Due to the different re-
activities (including the undesired reactivities) of the diaryl
methyl alcohols, it was difficult to find a “universal” catalyst
or condition that is optimal for different substrates. Thus, we
slightly tuned the conditions for each substrate. For diaryl
alcohol 1c, which will generate an even less-stabilized car-
Table 3. Alkylation of a,a-disubstituted aldehydes.
Table 2. Scope of diaryl alcohols and aldehydes.
[a] Reaction in Bu2O at 508C. [b] Isolated after reduction to the corre-
sponding alcohol. [c] Reaction in MeNO2. [d] Reaction in MeNO2 at
508C.
Table 4. Alkylation of aldehydes with allylic alcohols.
[a] With 1 equiv tBuOH as additive. [b] Reaction at 508C. [c] Reaction at
808C in MeNO2. [d] Isolated after reduction to the corresponding alco-
hol. [e] BINOL-derived phosphoric acid.
Chem. Eur. J. 2011, 17, 12272 – 12275
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R. Chi, G. Li et al.
The reaction pathways were briefly explored by means of
DFT calculations using the reaction between aldehyde 2a
and alcohol 1e in CH3NO2 as a model reaction (Scheme 2).
Experimental Section
General procedures: Diaryl alcohol (0.4 mmol), aldehyde (1.2 mmol) and
acid catalyst in solvent (2 mL) as indicated were placed in a 5 mL vial
equipped with a magnetic stir bar. The mixture was stirred at the indicat-
ed conditions. The reaction progress was monitored by means of
1H NMR analysis of the crude reaction mixture. When the reaction
neared completion, the reaction mixture was directly subjected to SiO2
column chromatography purification eluting with EtOAc/hexane to give
the desired product.
Acknowledgements
We thank the financial supports from Singapore National Research Foun-
dation and Nanyang Technological University. Dr. G. Li and H. Sun
(computational work) thank the fund supports from the National High-
tech Research and Development Program of China (2009AA01 A137)
and the National Natural Science Foundation of China (31070641/
C050101).
Scheme 2. Proposed reaction pathways studied by DFT calculations. All
activation barriers [kcalmolÀ1] were calculated relative to the infinitely
separated reactants.
Keywords: alcohols · aldehydes · alkylation · Brønsted acid ·
carbocations
The enolization of aldehyde 2a was found to be the rate-de-
termining step in this acid-catalyzed alkylation reaction. The
activation energy for the aldehyde enolization was calculat-
ed to be 18.36 and 35.96 kcalmolÀ1 in the presence and ab-
sence of the acid catalyst, respectively, indicating the impor-
tant role of the acid catalyst in this step.[14] The acid-cata-
lyzed formation of diphenyl methyl cation IM2 has an
energy barrier of 7.1 kcalmolÀ1, and the aldehyde alkylation
starting from enol IM1 and carbocation IM2 appears to be
facile, with an energy barrier of 2.7 kcalmolÀ1. The pathways
for two major side reactions were also investigated. The
self-aldol reaction[13,15] of the aldehyde (activation energy:
19.1 kcalmolÀ1) is hard to eliminate under these reaction
conditions, since the aldehyde enolization has a similar
energy barrier (18.4 kcalmolÀ1). Experimentally, self-aldol
reactions were observed to different extents in nearly all the
reactions, although high yields of the desired products could
still be obtained after optimizations. The interconversion of
the diphenyl methyl cation intermediate IM2 and the ether
side product 10 is facile, requiring relatively low activation
energies. This agrees with the experimental results that the
reversible ether formation itself does not affect the reaction
outcome.[16]
In summary, we have introduced the use of Brønsted
acids as the sole catalyst to mediate the SN1-type alkylation
of aldehydes with diaryl alcohols. In this acid catalysis, the
challenging diaryl alcohols that generate less-stable carbo-
cation intermediates are effective substrates. The a,a-disub-
stituted aldehydes can also be employed to give highly effi-
cient reactions. Mechanistic studies by means of DFT calcu-
lations have also been performed. Ongoing work in our lab
includes the development of an asymmetric version of this
reaction,[17] and the expansion of substrates to simpler alco-
hols that generate highly unstable carbocations.
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Acid-Catalyzed a-Alkylation of Aldehydes
COMMUNICATION
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[17] It is worth noting that our attempts to develop an enantioselective
version of this reaction using the recently reported chiral BINOL-
based phosphoric acid catalysts (ref. [7]) were unsuccessful at this
point. The addition of diarylprolinol ethers as chiral amine catalysts
(ref. [5]) to acid-catalyzed reactions with less-stabilized carbocations
did not lead to any enantioselectivity either. Thereby, the amine cat-
alysts were consumed through reactions with the alcohol substrates.
Received: August 23, 2011
Published online: September 20, 2011
Chem. Eur. J. 2011, 17, 12272 – 12275
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