Expedient synthesis of functionalized triarylmethanols through tandem formation of geminal C-C and C-O bonds

Article abstract of DOI:10.1002/adsc.201200664

The rearrangement/oxidation of N,N-disubstituted anilines and the formal dehydrogenative cross-coupling of diarylmethanols with aniline derivatives have been developed for the preparation of symmetric and unsymmetric functionalized triarylmethanols. Both reactions proceed smoothly in trifluoroacetic acid in the presence of an inexpensive oxidant (manganese dioxide or potassium persulfate) and a catalytic amount of palladium diacetate to give a range of functionalized triarylmethanols in moderate to good yields and with extremely high regioselectivity. The two unprecedented reactions involve tandem formation of geminal C-C and C-O bonds, and they are synthetically useful, atom-efficient, and operationally simple.

Full text of DOI:10.1002/adsc.201200664

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DOI: 10.1002/adsc.201200664
Expedient Synthesis of Functionalized Triarylmethanols through
À
À
Tandem Formation of Geminal C C and C O Bonds
Yu Tian,a Yi Sui,a Yonghong Gu,a,* and Shi-Kai Tiana,b,*
a
Joint Laboratory of Green Synthetic Chemistry, Department of Chemistry, University of Science and Technology of
China, Hefei, Anhui 230026, Peopleꢀs Republic of China
Fax : (+86)-551-360-1592; e-mail: tiansk@ustc.edu.cn or ygu01@ustc.edu.cn
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry, Chinese
b
Academy of Sciences, Shanghai 200032, Peopleꢀs Republic of China
Received: July 26, 2012; Published online: November 28, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200664.
Abstract: The rearrangement/oxidation of N,N-di-
ACHTUNGTRENNUNGsubstituted anilines and the formal dehydrogenative
cross-coupling of diarylmethanols with aniline de-
rivatives have been developed for the preparation
of symmetric and unsymmetric functionalized triar-
ylmethanols. Both reactions proceed smoothly in
trifluoroacetic acid in the presence of an inexpen-
sive oxidant (manganese dioxide or potassium per-
sulfate) and a catalytic amount of palladium diace-
tate to give a range of functionalized triarylmetha-
nols in moderate to good yields and with extremely
high regioselectivity. The two unprecedented reac-
À
tions involve tandem formation of geminal C C
and C O bonds, and they are synthetically useful,
atom-efficient, and operationally simple.
Scheme 1. Approaches to the synthesis of triarylmethanols.
À
Keywords: anilines; oxidation; rearrangement; re-
gioselectivity; triarylmethanols
metals. In contrast, the last two approaches require
triarylmethyl-containing starting materials, the prepa-
ration of which, however, is inconvenient and costly.
Hence, it is very desirable to explore new approaches
that expand the scope and meanwhile simplify the
procedures for the synthesis of triarylmethanols.
Triarylmethanols display interesting biological activi- Herein, we report two synthetically useful, atom-effi-
ties such as antimicrobial and antiproliferative proper- cient, and operationally simple reactions leading to
ties, and serve as blockers of Ca2+-activated potassium symmetric and unsymmetric functionalized triarylme-
ion channels underlying neuronal hyperpolarization thanols: the rearrangement/oxidation of N,N-disubsti-
and potent vasodilators of the rat coronary microcir- tuted anilines and the formal dehydrogenative cross-
culation.[1] Moreover, triarylmethanols are useful re- coupling of diarylmethanols with aniline derivatives
agents employed for the protection of the hydroxy [Scheme 1, (b)].
groups in chemical synthesis.[2] In this context, a few
In the course of exploring the synthetic utilities of
3
[6]
À
methods are available for the synthesis of triarylme- sp C N bond cleavage, we succeeded in extending
thanols including the addition of arylmetals (ArM, the Hofmann–Martius rearrangement to N-aryl-N-di-
M=Li, Mg, etc.) to diaryl ketones or aryl carboxy- arylmethylacetamides.[7] For example, treatment of N-
lates,[3] the oxidation of triarylmethanes,[4] and the hy- phenyl-N-benzhydrylacetamide (1a) with trifluoroace-
drolysis of triarylmethyl halides, triarylmethyl carbox- tic acid (TFA) in the air at 408C led to the formation
ylic acids, or 1-triarylmethylimidazoles [Scheme 1, of N-(4-benzhydrylphenyl)acetamide (5a) as the de-
(a)].[1b,c,5] Whereas the first two approaches are most sired product in 84% yield and with extremely high
frequently employed, they do not tolerate many func- para-selectivity (Table 1, entry 1).[8] Moreover, a care-
tional groups due to the very high reactivity of aryl- ful analysis of the reaction mixture revealed that triar-
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Yu Tian et al.
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Table 1. Optimization of the reaction conditions.[a]
Table 2. Synthesis of triarylmethanols from N-aryl-N-diaryl-
AHCTUNGTRENNUNG
methylacetamides.[a]
[a]
[b]
Reaction conditions: amide 1a–h (0.30 mmol), MnO2
(0.60 mmol), Pd
(0.30 mL), 408C.
Isolated yield.
ACHTUNGRTEN(NUNG OAc)2 (5 mol%), trifluoroacetic acid
[a]
Reaction conditions: amide 1a (0.30 mmol), oxidant
(0.60 mmol), Pd source (5 mol%), trifluoroacetic acid
(0.30 mL), 408C, 24 h.
Isolated yield.
[b]
[c]
N-(4-Benzhydrylphenyl)acetamide (5a) was obtained in
84% yield.
ylmethanol 2a was formed in a trace amount, and we
reasoned that triarylmethanol 2a could be generated
from triarylmethane 5a through oxidation in the air.
To enhance the yield for the formation of triarylme-
thanol 2a, we employed manganese dioxide as the ox-
idant and obtained triarylmethanol 2a in 67% yield
and with extremely high para-selectivity (Table 1,
entry 2). Moreover, the addition of 5 mol% palladium
diacetate further improved the yield to 81% while
keeping the extremely high para-selectivity (Table 1,
entry 3). A few readily available oxidants and palladi-
um sources were examined, but the corresponding re-
action gave a lower yield or even resulted in no de- Scheme 2. Proposed reaction pathways.
sired product at all (Table 1, entries 4–12). In addi-
tion, the desired reaction did not occur when tri-
fluoroacetic acid was replaced with acetic acid.
bocation 4, which undergo the Friedel–Crafts reaction
A range of N-aryl-N-diarylmethylacetamides was to give triarylmethane 5. Although the Hofmann–
treated with trifluoroacetic acid, manganese dioxide, Martius rearrangement was reported previously to
and palladium diacetate (5 mol%), and structurally give a mixture of regioisomers,[7,8] in our case the re-
diverse symmetric and unsymmetric triarylmethanols action afforded extremely high para-selectivity proba-
were formed in moderate to good yields (Table 2). It bly due to the introduction of an acyl group to the
is noteworthy that the reaction only gave a single re- aniline nitrogen atom. The N-acyl group not only de-
gioisomeric product and it tolerated alkyl-, fluoro-, creases the reactivity of the aromatic ring, but also
chloro-, and bromo-substituted aromatic rings.
provides steric hindrance to make it very difficult for
On the basis of the generally accepted mechanism the side reaction to occur at the ortho-position. Final-
for the Hofmann–Martius rearrangement,[7] we pro- ly, selective oxidation of triarylmethane 5 gives triar-
pose the following reaction pathway for the synthesis ylmethanol 2.[9]
of triarylmethanols from N,N-disubstituted anilines
In the reaction of aniline derivative 1a, we were
(Scheme 2, path a). The acid-catalyzed cleavage of able to isolate two intermediates: N-phenylacetamide
3
À
the sp C N bond of N,N-disubstituted aniline 1 re- (3a) and triarylmethane 5a. Furthermore, treatment
sults in the formation of aniline derivative 3 and car- of triarylmethane 5a with trifluoroacetic acid, manga-
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Expedient Synthesis of Functionalized Triarylmethanols
Table 4. Synthesis of triarylmethanols from aniline deriva-
tives and diarylmethanols.[a]
Scheme 3. Oxidation of triarylmethane 5a.
nese dioxide, and palladium diacetate (5 mol%) led
to the formation of triarylmethanol 2a in 80% yield
(Scheme 3). These experiments substantially support
the reaction pathway (path a) depicted in Scheme 2.
Based on the aforementioned mechanistic analysis,
we envisioned that the acidic reaction conditions
could be utilized to generate carbocation 4 from
carbon electrophile 6 having an appropriate leaving
group (Scheme 2, path b).[10] To our delight, the reac-
tion of N-phenylacetamide (3a) with benzhydrol (6aa)
took place under our previous conditions (except that
the loading of palladium diacetate was increased to
10 mol%) to give triarylmethanol 2a in 72% yield and
with extremely high para-selectivity (Table 3, entry 1).
Replacing manganese dioxide with potassium persul-
fate enhanced the yield to 78% (Table 3, entry 2), but
the use of other palladium sources gave a lower yield
or even led to no desired product at all (Table 3, en-
tries 4–6). It is noteworthy that the absence of palladi-
um diacetate just led to a very sluggish reaction
(Table 3, entry 7). We examined a few other carbon
[a]
Reaction conditions: aniline derivative 3 (0.36 mmol), al-
cohol 6a (0.30 mmol), K2S2O8 (0.60 mmol), Pd
(10 mol%), trifluoroacetic acid (0.30 mL), 408C.
Isolated yield.
ACHTUNGTRENNUNG(OAc)2
[b]
electrophiles such as sulfonamide 6ba, bromide 6ca, cases (Table 3, entries 8–10). Finally, the oxidative
and chloride 6da, and obtained lower yields in these conditions were taken advantage of to oxidize diphe-
nylmethane (6ea) to form the carbocation intermedi-
ate, and the corresponding reaction gave triarylme-
thanol 2a in 24% yield (Table 3, entry 11).
Table 3. Optimization of the reaction conditions.[a]
The optimized reaction conditions allowed a range
of aniline derivatives to undergo the formal dehydro-
genative cross-coupling reaction with diarylmethanols
to give functionalized triarylmethanols in moderate to
good yields and with extremely high para-selectivity
(Table 4). It is noteworthy that either an electron-
withdrawing group or an electron-donating group
could be introduced to the aromatic rings of triaryl-
methanols and the reaction tolerated alkyl-, alkoxy-,
fluoro-, chloro-, bromo-, and sulfonate-substituted ar-
omatic rings.
In summary, we have developed, for the first time,
two synthetically useful, atom-efficient, and opera-
tionally simple reactions leading to symmetric and un-
symmetric functionalized triarylmethanols: the rear-
rangement/oxidation of N,N-disubstituted anilines and
the formal dehydrogenative cross-coupling of diaryl-
AHCTUNGTREGmNNNU ethanols with aniline derivatives. Both reactions in-
[a]
Reaction conditions: amide 3a (0.36 mmol), compound
6aa–ea (0.30 mmol), oxidant (0.60 mmol), Pd source
(10 mol%), trifluoroacetic acid (0.30 mL), 408C, 12 h.
Isolated yield.
À
À
volve tandem formation of geminal C C and C O
bonds, and they proceed smoothly in trifluoroacetic
acid in the presence of an inexpensive oxidant (man-
ganese dioxide or potassium persulfate) and a catalytic
[b]
[c]
1.20 mmol of K2S2O8 were used.
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C. Metais, S. Y. Wang, S. L. Alper, F. W. Sellke, J. Surg.
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Experimental Section
General Procedure for the Synthesis of Triaryl-
methanols from N-Aryl-N-diarylmethylacetamides
A mixture of acetamide 1a–h (0.30 mmol), manganese diox-
ide (52.2 mg, 0.60 mmol), palladium diacetate (3.4 mg,
5 mol%), and trifluoroacetic acid (0.30 mL) was stirred at
408C for the time as specified in Table 2. After being cooled
to room temperature, the mixture was diluted with ethyl
acetate (12 mL), and washed successively with water, satu-
rated aqueous sodium bicarbonate, and brine. The organic
layer was dried over anhydrous magnesium sulfate and con-
centrated. The residue was purified by preparative TLC, de-
veloping with ethyl acetate/dichloromethane (1:10), to give
the corresponding triarylmethanol.
General Procedure for the Synthesis of Triaryl-
methanols from Aniline Derivatives and Diaryl-
methanols
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A mixture of aniline derivative 3 (0.36 mmol), diarylmetha-
nol 6a (0.30 mmol), potassium persulfate (162 mg,
0.60 mmol), palladium diacetate (6.7 mg, 10 mol%), and tri-
fluoroacetic acid (0.30 mL) was stirred at 408C for the time
as specified in Table 4. After being cooled to room tempera-
ture, the mixture was diluted with ethyl acetate (12 mL),
and washed successively with water, saturated aqueous
sodium bicarbonate, and brine. The organic layer was dried
over anhydrous magnesium sulfate and concentrated. The
residue was purified by preparative TLC, developing with
ethyl acetate/dichloromethane (1:10) [for entries 4–6 of
Table 4, ethyl acetate/petroleum ether (1:2)], to give the cor-
responding triarylmethanol.
Acknowledgements
We are grateful for the financial support from the National
Natural Science Foundation of China (21172206, 21072180,
20972147, and J1030412), the National Basic Research Pro-
gram of China (973 Program 2010CB833300), and the Pro-
gram for Changjiang Scholars and Innovative Research
Team in University (IRT1189).
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