Highly efficient and facile aryl transfer to aldehydes using ArB(OH) 2-GaMe3

Article abstract of DOI:10.1055/s-0028-1087552

A rapid and efficient procedure for the synthesis of diarylmethanols has successfully been achieved by the aryl transfer to aldehydes using the ArB(OH)₂-GaMe₃ combined systems in excellent yields (up to 98%) at room temperature. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087552

LETTER
495
Highly Efficient and Facile Aryl Transfer to Aldehydes
Using ArB(OH)2–GaMe3
F
acile Aryl Transf
u
er to
A
ldehy
e
s
feng Jia,a Ling Fang,a Aijun Lin,a Yi Pan,a Chengjian Zhu*a,b
a
School of Chemistry and Chemical Engineering, State Key Laboratory of Coordination Chemistry, Nanjing University,
Nanjing 210093, P. R. of China
Fax +86(25)83594886; E-mail: cjzhu@nju.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, P. R. of China
b
Received 26 August 2008
KOt-Bu3c or K3PO4;4d,e (b) harsh reaction conditions (80–
100 °C) and longer reaction time (16–48 h) are required
when transition-metal complexes are used as catalyst;3,5
(c) the transmetalation of arylboronic acid and diethylzinc
reagent take place at 60 °C for 12 hours in the ArB(OH)2–
Et2Zn system. Therefore the search for more efficient
method to produce diarylmethanols still remains an im-
portant goal in this area.
Abstract: A rapid and efficient procedure for the synthesis of di-
arylmethanols has successfully been achieved by the aryl transfer to
aldehydes using the ArB(OH)2–GaMe3 combined systems in excel-
lent yields (up to 98%) at room temperature.
Key words: aryl transfer, benzaldehyde, phenylboronic acid, tri-
methylgallium, diarylmethanol
Recently, organogallium chemistry has attracted consid-
erable attention in synthetic organic chemistry.9 Our
group presented the first example of enantioselective iso-
cyanosilylation of meso-epoxides using TMSCN to form
b-isocyanohydrins catalyzed by chiral organogallium and
Diarylmethanols are valuable compounds in the pharma-
ceutical field as active ingredients or as synthetic interme-
diates.1 There are several routes to obtain these important
compounds. They can be synthesized by carbon–carbon
bond formation of aromatic aldehydes and the appropriate
organometallic compounds, by nucleophilic displacement
at the benzylic position, or by reduction of the C=O bonds
of the corresponding diaryl ketones, respectively. Among
them, the addition of arylboronic acid derivatives to alde-
hydes in the presence of transition-metal catalysis pro-
vides an efficient and practical method for the synthesis of
diarylmethanols. Since Miyaura et al. reported the first ex-
ample of rhodium(I)-catalyzed addition of arylboronic ac-
ids to aldehydes in 1998,2 special attention has been
focused on the arylation of aldehydes using a combination
of the rhodium catalyst and arylboronic acid.3 The use of
metals cheaper than the rhodium catalyst, such as
palladium4 and nickel catalysts,5 were also developed by
some research groups for this aryl transfer reaction to
aromatic aldehydes with arylboronic acid derivatives.
One interesting approach to the preparation of diarylmeth-
anols has been recently introduced by Bolm and co-work-
ers. They employed the Ph2Zn–Et2Zn6 and the ArB(OH)2–
Et2Zn7 as aryl sources to improve the performance of the
aryl transfer. Many publications on the synthesis of di-
arylmethanols using ArB(OH)2–Et2Zn systems have been
reported by some research groups in recent years.8
Table 1 The Reaction of Phenylboronic Acid and Trimethylgallium
with Benzaldehyde under Different Conditionsa
OH
B(OH)2
1) solvent, r.t.
Me3Ga
+
2) PhCHO, r.t.
Entry
PhB(OH)2
(equiv)
Me3Ga
(equiv)
Solvent
Yield
(%)b
1
2
3
4
5
6
7
8
1.5
1.5
1.5
2
3
toluene
toluene
toluene
toluene
toluene
hexane
CH2Cl2
THF
30
3.75
4.5
6
58
88
90
2
3
21
1.5
1.5
1.5
4.5
4.5
4.5
74c
64c
10c,d
a All reactions were carried out in anhyd solvent at r.t. for 10 h unless
stated otherwise.
Although great progress has been made in the aryl transfer
to aldehydes using boronic acid as the aryl source, there
are still some drawbacks as follows: (a) the reaction needs
the combination of the expensive transition metal with
ligands, together with the use of stronger base such as
b Isolated yields based on the benzaldehyde.
c Conditions: PhB(OH)2 (0.3 mmol) was dissolved in corresponding
anhyd solvent (3 mL) followed by the addition of Me3Ga (0.9 mmol,
1 M solution in toluene), and the resulting mixture was stirred for 2 h
at r.t. before the addition of benzaldehyde (0.2 mmol).
d Reaction time: 20 h.
SYNLETT 2009, No. 3, pp 0495–0499
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x.
x
x.
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Advanced online publication: 21.01.2009
DOI: 10.1055/s-0028-1087552; Art ID: W15308ST
© Georg Thieme Verlag Stuttgart · New York

496
X. Jia et al.
LETTER
organoindium complexes with moderate to excellent halogen groups, the yield of the product decreased slightly
enantioselectivities.10 We also have successfully achieved (entries 5–8). 4-Methoxybenzaldehyde and 3-methylben-
the first asymmetric addition of organogallium to alde- zaldehyde also produced the corresponding diarylmetha-
hydes catalyzed by chiral titanium catalysts.11 In connec- nols in high yields when two equivalents of phenylboronic
tion with our current interests in the synthetic application acid and six equivalents of trimethylgallium were used in
of organogallium reagents,12 we describe herein our ef- the reaction (entries 9 and 10). In the case of o-tolualde-
forts toward the synthesis of useful diarylmethanols hyde, the product was isolated in 89% yield under the op-
through the combination of trimethylgallium with arylbo- timal reaction conditions, but longer reaction time was
ronic acid.
needed (entry 11). The arylation of 2-naphthaldehyde fur-
nished the corresponding product with 84% yield (entry
12). It should be noted that a,b-unsaturated cinnamalde-
hyde proceeded also well for this reaction and only 1,2-
addition product was obtained (entry 13). We have also
checked the aryl transfer reaction to aliphatic aldehydes
such as isovaleraldehyde with phenylboronic acid under
optimized conditions. The corresponding product was iso-
lated in 61% yield, but a longer time was required (20 h).
Initially, we investigated the reaction of phenylboronic
acid and trimethylgallium with benzaldehyde. Phenylbo-
ronic acid (1.5 equiv) and trimethylgallium (3 equiv) were
stirred in toluene for two hours at room temperature be-
fore the addition of benzaldehyde, the desired product
diphenylmethanol was isolated in 30% yield (Table 1, en-
try 1). When the amount of trimethylgallium was gradual-
ly increased, we found that the yield of the product
increased significantly. When 1.5 equivalents of phenyl- In order to examine if different aryl groups could be trans-
boronic acid and 4.5 equivalents of trimethylgallium were ferred to aldehydes under same reaction conditions, giv-
employed in this reaction, the product was obtained in ing access to a range of substituted diarylmethanols, the
88% yield (Table 1, entry 3). We further improved the aryl transfer reactions of substituted phenylboronic acids
amount of phenylboronic acid (2 equiv) and trimethylgal- with aromatic aldehydes were studied (Table 3). To our
lium (6 equiv), an excellent yield was obtained (Table 1, delight we found that substituted aryls were transferred
entry 4). However, when the reaction was carried out us- smoothly, affording corresponding products in good
ing two equivalents of phenylboronic acid and three yields. The arylboronic acid with the electron-donating
equivalents of trimethylgallium, the yield of the product group transferred more easily than those with the electron-
decreased sharply (Table 1, entry 5). It is possible that the withdrawing group. When 4-methoxyphenylboronic acid
hydroxy groups of the arylboronic acids can consume two was used as aryl source, electron-deficient aldehydes pro-
equivalents of organogallium reagent.8g These experimen- vided higher yields than electron-rich aldehydes. These
tal results indicated that a twofold excess of trimethylgal- results indicated that the reaction was facilitated by plac-
lium was essential for this reaction. However, from the ing electron-donating groups on the transferred aryl group
point of economy, the amount of phenylboronic acid (1.5 and on the electron-withdrawing group on the aldehyde
equiv) and trimethylgallium (4.5 equiv) was selected as substrate. This was in agreement with the literature re-
standard reaction conditions to carry out further experi- sults.2a,8g
ments. Then the solvent effect on this reaction was also
The detailed mechanism of this reaction has not been
examined. Toluene proved to be the best solvent. In con-
clarified at this stage. We speculate that the first step of re-
trast, in the case of dichloromethane and hexane, the yield
action involves the formation of activate arylgallium spe-
of the product decreased sharply (Table 1, entries 6 and
cies (Ar1GaMe2) in situ by
a
boron-to-gallium
7). When THF was used as reaction solvent, only a small
amount of the product was obtained after reacting for 20
hours (Table 1, entry 8).
transmetalation of arylboronic acid and trimethylgalli-
um,15 which is most likely as the arylating reagent, and the
reaction proceeds through the nucleophilic attack of the
The scope of this novel aryl transfer reaction with other aryl group to the carbonyl of aldehydes to produce the cor-
different aldehydes was then explored under optimized re- responding diarylmethanols in the second step
action conditions,13 and the results are listed in Table 2. (Scheme 1). The experimental results demonstrated that
We were pleased to find that all the aromatic aldehydes the aryl group on gallium species is more easily trans-
examined were smoothly converted into the correspond- ferred to aldehydes than the alkyl group (Me) on gallium.
ing diarylmethanols under the treatment of phenylboronic
acid and trimethylgallium in good to excellent yields. The
Me3Ga
electronic nature of the substituents on the aromatic ring
Ar1GaMe2
Ar1B(OH)2
had a slight influence on the reactivity of different alde-
hydes. In general, benzaldehyde derivatives with elec-
tron-withdrawing substituents were more reactive than
those with electron-donating substituents. The nitro-
substituted benzaldehyde gave the corresponding prod-
ucts in almost quantitative yields disregarding the position
of the nitro group on the aromatic ring (entries 2–4).14
Changing the substituent from nitro to trifluoromethyl or
transmetalation
arylgallium species
Ar2CHO
OH
Ar1
Ar2
Scheme 1 Proposed reaction course
Synlett 2009, No. 3, 495–499 © Thieme Stuttgart · New York

LETTER
Facile Aryl Transfer to Aldehydes
497
Table 2 The Reaction of Different Aromatic Aldehydes with
In summary, we have developed an efficient and practical
method for the synthesis of useful diarylmethanols by the
arylation of aldehydes with the arylboronic acid as aryl
source in the presence of trimethylgallium. This new
methodology offers interesting advantages over previous-
ly reported methods: (i) it avoids the use of expensive
transition metals (Rh, Pd) and some base; (ii) compared to
diethylzinc, the activated arylgallium species can be
formed very quickly by the transmetalation of arylboronic
acid and trimethylgallium at room temperature; and (iii)
the excellent yields are obtained in very short time under
mild conditions. Further work on the reaction mechanism
and a catalytic asymmetric version of this reaction is un-
der way in our laboratory.
Phenylboronic Acid under Optimized Conditionsa (continued)
OH
B(OH)2
1) toluene, r.t.
+
Me3Ga
Ar
2) ArCHO, r.t
2
3a–m
1
Entry Ar
Product
Time Yield
(h) (%)b
OH
7
8
2-CF3C6H4
3-BrC6H4
3g
3h
8
90
CF3
OH
Table 2 The Reaction of Different Aromatic Aldehydes with
3
92
Phenylboronic Acid under Optimized Conditionsa
OH
B(OH)2
Br
1) toluene, r.t.
2) ArCHO, r.t
+
Me3Ga
Ar
OH
9
4-MeOC6H4
3i
3j
3
3
90c
95c
2
3a–m
1
MeO
Entry Ar
Product
Time Yield
(h) (%)b
OH
OH
10 3-MeC6H4
1
2
Ph
3a 10 88
Me
OH
OH
11 2-MeC6H4
3k 12 89
4-O2NC6H4
3-O2NC6H4
3b
3c
3
3
98
95
Me
OH
O2N
OH
OH
12 2-C10H7
3l
8
8
84
88
3
OH
NO2
13 PhCH=CH
3m
4
5
6
2-O2NC6H4
4-ClC6H4
2-ClC6H4
3d
3e
3f
3
8
96
87
a All reactions were performed on 0.2 mmol scale of substrates with
1.5 equiv of PhB(OH)2 and 4.5 equiv of Me3Ga in toluene for indicat-
ed time. See ref. 13 for experimental details.
NO2
OH
b Isolated yields.
c Conditions: 2 equiv of PhB(OH)2 and 6 equiv of Me3Ga were used.
Cl
OH
Cl
10 89
Synlett 2009, No. 3, 495–499 © Thieme Stuttgart · New York

498
X. Jia et al.
LETTER
Table 3 The Reaction of Aromatic Aldehydes with Substituted Phenylboronic Acids under Optimized Conditionsa
OH
1) toluene, r.t.
Ar1B(OH)2
+
Me3Ga
Ar1
Ar2
4a–f
2) Ar2CHO, r.t.
Entry
1
Ar1
Ar2
Product
Time (h)
6
Yield (%)b
91
OH
4-ClC6H4
4-ClC6H4
4-O2NC6H4
3-BrC6H4
4a
4b
O2N
Cl
OH
2
6
90
Cl
Cl
Br
OH
Me
3
4
4-ClC6H4
2-MeC6H4
4c
6
8
85
93
OH
4-MeOC6H4
4-O2NC6H4
4d
O2N
NO2
Me
OMe
OH
OH
5
6
4-MeOC6H4
4-MeOC6H4
3-O2NC6H4
3-MeC6H4
4e
4f
8
8
90
80
OMe
OMe
a All reactions were carried out on 0.2 mmol scale of aromatic aldehydes with 1.5 equiv of Ar1B(OH)2 and 4.5 equiv of Me3Ga in toluene for
indicated time. See ref. 13 for experimental details.
b Isolated yields.
3284. (e) Schmidt, F.; Stemmler, R. T.; Rudolph, J.; Bolm,
C. Chem. Soc. Rev. 2006, 35, 454.
(2) (a) Sakai, M.; Ueda, M.; Miyaura, N. Angew. Chem. Int. Ed.
1998, 37, 3279. (b) Ueda, M.; Miyaura, N. J. Org. Chem.
2000, 65, 4450.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
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We gratefully acknowledge the National Natural Science Foundati-
on of China (20672053, 20832001) and the National Basic Re-
search Program of China (2007CB925103) for their financial
support. The Program for New Century Excellent Talents in the
University of China (NCET-06-0425) is also acknowledged.
References and Notes
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Synlett 2009, No. 3, 495–499 © Thieme Stuttgart · New York

LETTER
Facile Aryl Transfer to Aldehydes
499
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(13) General Experimental Procedure
The arylboronic acid (0.3 mmol, 1.5 equiv) was dissolved in
anhyd toluene (2 mL) in a 20 mL flame-dried Schlenk
reaction tube under argon atmosphere. A commercially
available 1 M solution of Me3Ga in toluene (0.9 mmol, 4.5
equiv) was added via syringe dropwise, and the resulting
mixture was stirred for 2 h at r.t. followed by the addition of
aldehyde (0.2 mmol). After completion of the reaction
(monitored by TLC), the reaction solution was quenched
with H2O (3 mL) and further extracted with EtOAc (3 × 5
mL). The combined organic layer was dried over Na2SO4.
Evaporation of the solvent gave the crude product, which
was further purified by preparative TLC (PE–EtOAc, 5:1) to
give corresponding pure diarylmethanols.
Westermann, B.; Wessjohann, L.; Lüdtke, D. S.; Braga,
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Maseras, F.; Pericàs, M. A. Angew. Chem. Int. Ed. 2008, 47,
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(14) The reactivity of nitro-substituted benzaldehyde is in
agreement with the experimental results in references 3c,
4d–f, but 4-nitrobenzaldehyde is not reactive in reference 2a.
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transmetalation has been clarified by theoretical calculations
and experimental study. In this process, the mixed zinc
species (ArZnEt) is formed.
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M. Org. Lett. 2006, 8, 5077. (b) Nishimura, Y.; Amemiya,
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(c) Nishimura, Y.; Shiraishi, T.; Yamaguchi, M.
Tetrahedron Lett. 2008, 49, 3492.
Synlett 2009, No. 3, 495–499 © Thieme Stuttgart · New York

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