Palladium-catalyzed selective C-H benzylation towards functionalized azoles with a quaternary carbon center

Article abstract of DOI:10.1002/adsc.201200025

The direct C-H benzylation of azoles with benzyl chlorides proceeds efficiently, via sequential cleavage of one sp² C-H bond and two sp³ C-H bonds in the presence of a palladium catalyst, to generate a wide range of tribenzylated azoles with a quaternary carbon center efficiently. The same catalyst could also promote the mono- and di-benzylation reactions through fine turning of the base and reaction conditions. Copyright

Full text of DOI:10.1002/adsc.201200025

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DOI: 10.1002/adsc.201200025
À
Palladium-Catalyzed Selective C H Benzylation towards
Functionalized Azoles with a Quaternary Carbon Center
Pan Xie,a Hanmin Huang,a,* Yinjun Xie,a Shengmei Guo,a and Chungu Xiaa,*
a
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese
Academy of Sciences, Lanzhou 730000, Peopleꢀs Republic of China
Fax : (+86)-931-496-8129; phone: (+86)-931-496-8326; e-mail: hmhuang@licp.cas.cn or cgxia@licp.cas.cn
Received: January 9, 2012; Revised: February 22, 2012; Published online: June 5, 2012
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200025.
À
Abstract: The direct C H benzylation of azoles
with benzyl chlorides proceeds efficiently, via se-
electrophiles for introduction of the benzyl group
through transition metal-catalyzed coupling reac-
tions.[5,6] Recently, Ackermann and Miura have devel-
oped the palladium-catalyzed direct benzylation of
2
3
À
quential cleavage of one sp C H bond and two sp
À
C H bonds in the presence of a palladium catalyst,
to generate a wide range of tribenzylated azoles
with a quaternary carbon center efficiently. The
same catalyst could also promote the mono- and di-
benzylation reactions through fine turning of the
base and reaction conditions.
À
azoles with benzyl carbonates via direct C H activa-
tion, where a series of monobenzylated azoles has
been prepared efficiently and the dibenzylated prod-
ucts could also be obtained via a step by step pro-
cess.[7] Intrigued by these results and the recent stud-
[2]
À
ies on direct C H functionalization of azoles, we
À
Keywords: azoles; benzyl chlorides; palladium; qua-
ternary carbon centers; selective C H benzylation
reasoned that the sequential C H activation would
À
occur in one-pot under appropriate conditions, which
will lead to formation of tribenzylated azoles contain-
ing an all quaternary carbon center. Herein, we de-
scribe the first example of the palladium-catalyzed se-
À
lective C H benzylation through the cleavage of one
2
3
À
À
Azoles are important heterocyclic scaffolds present in sp C H bond and two sp C H bonds under basic
many compounds of biological significance.[1] Meth- conditions to provide a wide variety of tribenzylated
ods to transform simple azoles into more substituted azoles, which contain a quaternary carbon center. Fur-
variants are of immense importance to enable the thermore, this protocol could also afford the mono-
synthesis of new structures of potential significance. and dibenzylated azoles through fine turning of the
Among the many types of methods for the functional- base.
ization of azoles have been documented, the direct
C H functionalization of azoles provides an efficient based on the Pd catalyst that has been frequently
Our approach to the benzylation reaction was
À
À
and straightforward access to these heteroaryl com- used for a variety of C H functionalization reac-
pounds.[2] However, current reactions for forming tions.[4] Thus, the proposal was evaluated in the reac-
À
À
C C bonds through C H bond activation are typical- tion of benzoxazole 1a with benzyl chloride 2a under
ly limited to the construction of secondary or tertiary basic conditions using a series of palladium precursors
carbon centers. In contrast, the construction of quater- combined with dppp as ligand. As shown in Table 1,
À
nary carbon centers via sequential C H functionaliza- use of PdACTHNUGRTNE(UNG OAc)2 as a catalyst precursor and K3PO4 as
tion has not yet been explored, even though the con- base at 1208C produced the desired tribenzylated
gested quaternary carbon centers are found in azole 5aa in 10% yield (Table 1, entry 1) together
a broad range of organic compounds, including impor- with the corresponding mono- and dibenzylated prod-
tant bioactive natural products and medicinal ucts, which indicated that the proposed sequential
agents.[3] Therefore, further development for the con- C H activation reaction was indeed possible, al-
À
struction of quaternary centers around the azole rings though the desired product 5aa was obtained in rela-
[4]
À
via direct C H activation would be highly desired.
tive lower yield. The structure of the compound 5aa
Benzyl derivatives such as benzyl halides and was confirmed by X-ray analysis.[8] Screening of other
benzyl carbonates are readily available and versatile palladium sources revealed Pd
ACHTUNGRTEN(UNNG MeCN)2Cl2 as the
compounds, which have been frequently utilized as most effective catalyst precursor for delivering the de-
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Palladium-Catalyzed Selective C H Benzylation towards Functionalized Azoles
Table 1. Optimized reaction conditions.[a]
Entry
Catalyst
Base
Solvent
Yield [%][b]
3aa
4aa
5aa
1
2
3
4
5
6
7
8
Pd
Pd2A
Pd(MeCN)2Cl2
DPPE-PdCl2
Pd(CF3COO)2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
Pd(MeCN)2Cl2
N
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Et3N
TMEDA
DABCO
Na2CO3
Cs2CO3
KOH
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
LiO-t-Bu
Cs2CO3
Na2CO3
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMA
DMA
DMA
DMF
DMA
DMF
57
33
5
31
46
0
0
0
70
50
38
trace
trace
trace
trace
trace
trace
89
20
32
48
33
38
0
0
0
11
30
31
37
28
trace
29
trace
77
trace
10
19
30
12
trace
0
0
N
0
9
trace
trace
11
54
64
90
62
89
trace
trace
10
11
12
13
14[c]
15[c,d]
16[c,d]
17[d,e]
18[f]
[a]
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), [Pd] (5 mol%), dppp (6 mol%), base (1.5 mmol), solvent (2 mL),
1208C, 16 h.
Yield of isolated product relative to the benzoxazole.
1a (0.5 mmol), 2a (1.8 mmol), LiO-t-Bu (1.8 mmol).
608C instead of 1208C.
1a (0.5 mmol), 2a (1.2 mmol), Cs2CO3 (1.2 mmol).
1a (0.5 mmol), 2a (2 mmol), Na2CO3 (2 mmol).
[b]
[c]
[d]
[e]
[f]
sired product 5aa (Table 1, entry 3), while other palla- When the ratio of 2a/1a was increased from 3/1 to 3.6/
dium sources afforded inferior results. With 1, the yield of the product 5aa dramatically increased
PdACHTUNGTRENNUNG(MeCN)2Cl2 as the catalyst precursor, we went on to 90% (Table 1, entry 14). Running the reaction at
with investigations of the other reaction parameters. 608C instead of 1208C, only 62% yield of desired
Various commercially available phosphine ligands product 5aa was obtained under otherwise identical
were screened and the results demonstrated that bi- reaction conditions. But to our delight, the efficiency
dentate ligands were better than the monodentate of the reaction is nearly completely maintained when
ones and 30% yield was obtained when dppp served the reaction temperature was deceased to 608C when
as the ligand (see Supporting Information). The DMF was used as solvent (Table 1, entry 16).
choice of base is crucial for the success of the present
Having defined a highly effective catalyst system
catalytic reaction. Among the various bases exam- and optimal reaction conditions for the selective tri-
ined, the organic bases such as Et3N, DABCO or benzylation of benzoxazole 1a with benzyl chloride
TMEDA did not give the desired product at all, but 2a, we then examined the scope of this method. The
the inorganic base such as LiO-t-Bu could produce results are summarized in Table 2. Both electron-rich
the desired product 5aa in moderate yields (Table 1, and electron-deficient benzoxazoles could be smooth-
entry 12). Na2CO3 was also effective in giving mono- ly transformed into the desired products in good to
benzylated product 3aa in a relatively higher yield excellent yields. Furthermore, substituents at different
(Table 1, entry 9). Solvent optimization results positions on the arene group did not affect the reac-
showed that the reaction was found to proceed more tion efficiency. It is noteworthy that halo-substituted
efficiently in polar solvents than in non-polar ones, benzoxazoles were tolerated well, thus affording halo-
and DMA was found to be the best choice at the containing products, which could be used for the fur-
higher temperature (see Supporting Information). ther transformations. In addition, benzothiazole was
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Table 2. Substrate scope for the tri-benzylation reaction.[a]
[a]
[b]
Reaction conditions: 1 (0.5 mmol), 2 (1.8 mmol), PdACTHNUGTRNEUNG(MeCN)2Cl2 (5 mol%),
dppp (6 mol%), LiO-t-Bu (1.8 mmol), DMF (2 mL), 608C, 16 h, isolated yield.
DMA, 1208C, 24 h.
also successfully employed for the tribenzylation reac- entries 9 and 12). These results suggested that selec-
tion at higher temperature with DMA as solvent, and tive synthesis of mono- or dibenzylated benzoxazoles
the corresponding 2-(1,2,3-triphenylpropan-2-yl)ben- would be possible by finely turning the base. With
zo[d]thiazole 5ai was obtained in 83% yield. Further- this in mind, we further optimized the reaction condi-
more, 2-phenyl-1,3,4-oxadiazole could also undergo tions and found that the dibenzylated products could
the tribenzylation reaction and gave the correspond- be exclusively generated when Cs2CO3 was employed
ing product 5aj in 77% yield by carrying out the reac- as the base and carrying out the corresponding reac-
tion at 1208C and with DMA as solvent. It appeared tion in DMA at 608C (Table 1, entry 16). Under these
that the steric property of the substituents on the optimized conditions, the scope of the substituted
phenyl ring of the benzyl chloride had a very obvious benzoxazoles and benzyl chlorides was investigated
influence on the reaction yields. Substitution at the (Table 3). The benzoxazoles bearing methyl, phenyl,
para-position of the benzyl chloride was tolerated, and tert-butyl substituents at the 5- or 6-position
and both electron-poor and electron-rich benzyl could be transformed into the corresponding products
groups could be efficiently installed on the azole ring. 4ab–4ae in good yields. Substrates containing chloro
However, benzyl chlorides containing substituents on and bromo groups could only produce the tribenzylat-
the ortho- and meta-positions did not afford the de- ed products under these reaction conditions. Gratify-
sired products.
ing, the chloro-containing dibenzylated products 4af
As shown in Table 1, the selectivity of the catalytic and 4ag were obtained in 70% and 69% yield by car-
benzylation reaction was substantially affected by the rying out the reaction in DMF with K2CO3 as base.
base. For example, with Na2CO3 as the base, only But the 5-bromobenzo[d]oxazole could only give the
mono-benzylation product could be obtained, but corresponding product in 19% yield even when the
LiO-t-Bu can selectively promote the tri-benzylation reaction was run under the further optimized condi-
reaction under the same reaction conditions (Table 1, tions. However, benzothiazole and 2-phenyl-1,3,4-oxa-
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Palladium-Catalyzed Selective C H Benzylation towards Functionalized Azoles
Table 3. Substrate scope for the di-benzylation reaction.[a]
[a]
Reaction conditions: 1 (0.5 mmol), 2 (1.2 mmol), PdACTHNUGRTNEUNG(MeCN)2Cl2 (5 mol%), dppp
(6 mol%), Cs2CO3 (1.2 mmol), DMA (2 mL), 608C,16 h, isolated yield.
K2CO3 as base, DMF as solvent.
DMF and dioxane (1:1) as solvent.
[b]
[c]
diazole cannot be converted into the desired products, sponding products in good yields. Those substituted
but only starting materials were recovered under the benzyl chlorides bearing an electron-withdrawing
optimized reaction conditions. One important reason group, such as 1-chloro-4-(chloromethyl)benzene,
for this fact is probably attributable to the weaker could also be used as benzyl source for the mono-ben-
CH acidity at C-2 of the azoles.[9] In addition to zylation of azoles with NaHCO3 as base (Table 4).
benzyl chloride 2a, 1-chloro-4-(chloromethyl)benzene
Control experiments to gain a preliminary under-
and 1-(chloromethyl)-4-methylbenzene could survive standing of the reaction mechanism revealed that the
À
the reaction conditions to give the corresponding palladium catalyst was essential for these C H benzy-
functionalized benzoxazole products 4ba and 4da in lation reactions since no product was formed in the
26% and 71% yield, respectively.
absence of palladium catalyst under the standard re-
Among the bases tested, the weaker base Na2CO3 action conditions (Scheme 1, a). However, the mono-
could selectively lead to the monobenzylated products benzylated azole 3aa and dibenzylated azole 4aa
(Table 1, entry 9), and when the ratio of 2a/1a was in- could be transformed into the corresponding dibenzy-
creased from 3/1 to 4/1, the yield of the product 3aa lated and tribenzylated azoles in good yields promot-
dramatically increased to 89% (Table 1, entry 18). ed by an appropriate base when the palladium cata-
Then we sought to further explore the scope of lyst was removed from the reaction medium
mono-benzylation reaction. The reactions of 5-, and (Scheme 1, b). This result suggests that the initial ben-
6-methylbenzoxazoles with benzyl chloride took place zylation reaction takes place under the control of the
smoothly to furnish the desired mono-benzylation palladium catalyst and the catalyst may not be in-
products 3ab and 3ac, which were isolated in 81% volved in the subsequent di- and tribenzylation reac-
and 77% yield, respectively. Upon substitution of tions.
electron-withdrawing groups (Cl, Br) at the 5- and 6-
On the basis of the above investigations and previ-
positions in benzoxazoles we only obtained a small ous work,[6,7] a tentative reaction pathway for this se-
amount of product, but with NaHCO3 as base, the re- lective benzylation reaction is depicted in Scheme 2.
action could proceed smoothly and furnish the corre- The oxidative addition of benzyl chloride onto a palla-
sponding products in good yields. The benzyl chlor- dium(0) species generates the benzylpalladium(II)
ides bearing methyl and methoxy substituents at the complex B.[10] Next, complex C could be formed by
para-position could be transformed into the corre- transmetalation with the preformed lithium/azole spe-
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Table 4. Substrate scope for the mono-benzylation reaction.[a]
[a]
Reaction conditions: 1 (0.5 mmol), 2 (2 mmol), PdACTHNURGTENUNG(MeCN)2Cl2 (5 mol%), dppp
(6 mol%), Na2CO3 (2 mmol), DMF (2 mL), 1208C, 16 h; isolated yield.
NaHCO3 as base.
24 h.
[b]
[c]
Scheme 1. Control experiments.
cies A resulting from the benzoxazole.[11] The subse- ternary carbon center was effectively constructed
2
À
quent reductive elimination affords the mono-benzy- through the sequential cleavage of one sp C H bond
3
À
lated product 3 with regeneration of the active palla- and two sp C H bonds under mild reaction condi-
dium species. Then di- or tri-benzylated product could tions. Moreover, the discovery of the profound effects
À
be selectively generated via nucleophilic substitutions of bases on this type of C H functionalization reac-
with benzyl chloride under the action of an appropri- tion has allowed us to chemoselectively prepare
ate base.
mono- and di-benzylated azole derivatives by finely
In summary, we have developed an effective and turning the base and reaction conditions. This catalyt-
À
simple palladium catalyst system for the direct C H ic process provides a reliable and straightforward
benzylation of azoles with benzyl chlorides. The qua- access to a wide variety of functionalized azoles,
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Palladium-Catalyzed Selective C H Benzylation towards Functionalized Azoles
Scheme 2. Proposed mechanism.
general procedure and purified by flash column chromatog-
raphy to give a white solid; yield: 87%. H NMR (400 MHz,
1
which should find broad applications in medicinal and
material chemistry.
CDCl3): d=2.47 (s, 3H), 3.63 (s, 4H), 6.74–6.75 (m, 4H),
7.05–7.15 (m, 9H), 7.24–7.26 (m, 4H), 7.58–7.61 (m, 1H);
13C NMR (100 MHz, CDCl3): d=21.8, 42.1, 51.4, 110.9,
119.4, 125.4, 126.5, 127.1, 127.6, 127.8, 128.3, 130.5, 135.3,
136.8, 138.6, 142.6, 150.9, 169.2; HR-MS (ESI): m/z=
404.2013, calcd. for C29H26NO [M+H]: 404.2009.
Experimental Section
General Procedure for Pd-Catalyzed Tribenzylation
5-tert-Butyl-2-(1,2,3-triphenylpropan-2-yl)benzo[d]oxazole
(5ad): The title compound was prepared according to the
general procedure and purified by flash column chromatog-
PdACHTUNGTRENNUNG(MeCN)2Cl2 (6.5 mg, 5 mol%), dppp (12.7 mg, 6 mol%),
the benzoxazole derivative (0.5 mmol, 1 equiv), the benzyl
chloride (227 mg, 3.6 equiv.), LiO-t-Bu (144 mg, 3.6 equiv.)
and DMA (2 mL) were added to a 25-mL flame-dried
Young-type tube under an N2 atmosphere, and then the re-
sulting mixture was stirred at 608C for 16 h. Then the mix-
ture was cooled to room temperature, and washed with
water, extracted with diethyl ether for three times. The or-
ganic layer was dried over anhydrous Na2SO4 and concen-
trated under reduced pressure. The residue was purified by
flash column chromatography on a silica gel to give the de-
sired product 5aa.
raphy to give
a
colorless oil; yield: 86%. 1H NMR
(400 MHz, CDCl3): d=1.39 (s, 9H), 3.64 (s, 4H), 6.74–6.76
(m, 4H), 7.05–7.17 (m, 8H), 7.24–7.27 (m, 3H), 7.34–7.39
(m, 2H), 7.76–7.77 (m, 1H); 13C NMR (100 MHz, CDCl3):
d=31.8, 34.9, 42.1, 51.3, 109.8, 116.6, 122.6, 126.5, 127.1,
127.6, 127.8, 128.3, 130.5, 136.8, 140.7, 142.6, 147.7, 148.6,
169.9; HR-MS (ESI): m/z=446.2473, calcd. for C32H32NO
[M+H]: 446.2478.
5-Phenyl-2-(1,2,3-triphenylpropan-2-yl)benzo[d]oxazole
(5ae): The title compound was prepared according to the
general procedure and purified by flash column chromatog-
2-(1,2,3-Triphenylpropan-2-yl)benzo[d]oxazole (5aa): The
title compound was prepared according to the general pro-
cedure and purified by flash column chromatography to give
1
raphy to give a white solid; yield: 80%. H NMR (400 MHz,
CDCl3): d=3.66 (s, 4H), 6.76–6.79 (m, 4H), 7.06–7.13 (m,
8H), 7.15–7.18 (m, 3H), 7.25–7.29 (m, 1H), 7.35–7.39 (m,
3H), 7.45–7.49 (m, 1H), 7.51–7.64 (m, 2H), 7.92–7.93 (m,
1H); 13C NMR (100 MHz, CDCl3): d=42.3, 51.7, 111.4,
120.1, 125.3, 126.6, 127.3, 127.6, 127.9, 128.4, 129.7, 130.4,
136.5, 141.9, 142.2, 149.1, 171.3; HR-MS (ESI): m/z=
456.2318, calcd. for C34H28NO [M+H]: 456.2322.
1
a white solid; yield: 89%. H NMR (400 MHz, CDCl3): d=
3.65 (d, J=3.2 Hz, 4H), 6.76 (s, 4H), 7.06–7.16 (m, 8H),
7.24–7.34 (m, 5H), 7.44–7.46 (m, 1H), 7.73 (d, J=1.6 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=42.2, 51.5, 110.7,
120.1, 124.2, 124.9, 126.5, 127.1, 127.6, 127.8, 128.3, 130.5,
136.6, 140.8, 142.5, 150.5, 169.7; HR-MS (ESI): m/z=
412.1663, calcd. for C28H23NNaO [M+Na]: 412.1672.
6-Chloro-2-(1,2,3-triphenylpropan-2-yl)benzo[d]oxazole
(5af): The title compound was prepared according to the
general procedure and purified by flash column chromatog-
6-Methyl-2-(1,2,3-triphenylpropan-2-yl)benzo[d]oxazole
(5ab): The title compound was prepared according to the
general procedure and purified by flash column chromatog-
1
raphy to give a white solid; yield: 90%. H NMR (400 MHz,
1
CDCl3): d=3.58–3.66 (m, 4H), 6.74 (d, J=7.6 Hz, 4H),
7.06–7.14 (m, 8H), 7.26–7.33 (m, 4H), 7.46 (d, J=2.0 Hz,
1H), 7.61 (d, J=8.4 Hz, 1H); 13C NMR (100 MHz, CDCl3):
d=42.2, 51.6, 111.3, 120.6, 124.9, 126.6, 127.3, 127.5, 127.9,
128.3, 130.4, 130.5, 136.4, 139.5, 142.2, 150.7, 170.5; HR-MS
(ESI): m/z=446.1276, calcd. for C28H22ClNNaO [M+Na]:
446.1282.
raphy to give a white solid; yield: 86%. H NMR (400 MHz,
CDCl3): d=2.47 (s, 3H), 3.63 (s, 4H), 6.74–6.75 (m, 4H),
7.05–7.15 (m, 9H), 7.25–7.27 (m, 4H), 7.58 (d, J=8.0 Hz,
1H); 13C NMR (100 MHz, CDCl3): d=21.8, 42.1, 51.3, 110.9,
119.4, 125.4, 126.5, 127.1, 127.6, 127.8, 128.3, 130.5, 135.2,
136.8, 138.6, 142.6, 150.8, 169.2; HR-MS (ESI): m/z=
404.2016, calcd. for C29H26NO [M+H]: 404.2009.
5-Chloro-2-(1,2,3-triphenylpropan-2-yl)benzo[d]oxazole
(5ag): The title compound was prepared according to the
5-Methyl-2-(1,2,3-triphenylpropan-2-yl)benzo[d]oxazole
(5ac): The title compound was prepared according to the
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general procedure and purified by flash column chromatog-
raphy to give a white solid; yield: 92%. H NMR (400 MHz,
2-(1,2,3-Tri-p-tolylpropan-2-yl)benzo[d]oxazole (5da): The
title compound was prepared according to the general pro-
cedure and purified by flash column chromatography to give
1
CDCl3): d=3.60–3.68 (m, 4H), 6.75 (d, J=6.0 Hz, 4H),
7.07–7.13 (m, 8H), 7.28–7.30 (m, 4H), 7.36–7.38 (m, 1H),
7.70 (s, 1H); 13C NMR (100 MHz, CDCl3): d=42.4, 51.8,
72.2, 111.5, 120.2, 125.3, 126.7, 127.3, 127.6, 127.7, 127.8,
127.9, 128.4, 128.5, 129.8, 130.5, 136.5, 141.9, 142.3, 149.2,
1
a white solid; yield: 70%. H NMR (400 MHz, CDCl3): d=
2.23 (s, 6H), 2.33 (s, 3H), 3.57 (s, 4H), 6.61–6.63 (m, 4H),
6.86–6.88 (m, 4H), 7.03–7.09 (m, 4H), 7.29–7.32 (m, 2H),
7.43–7.45 (m, 1H), 7.71–7.73 (m, 1H); 13C NMR (100 MHz,
CDCl3): d=21.0, 21.1, 41.6, 51.0, 110.7, 120.1, 124.1, 124.8,
127.5, 128.5, 129.0, 130.4, 133.7, 135.9, 136.7, 139.7, 140.9,
150.6, 170.3; HR-MS (ESI): m/z=432.2322, calcd. for
C31H30NO [M+H]: 432.2314.
171.3; HR-MS (ESI): m/z=446.1285, calcd.
C28H22ClNNaO [M+Na]: 446.1282.
for
5-Bromo-2-(1,2,3-triphenylpropan-2-yl)benzo[d]oxazole
(5ah): The title compound was prepared according to the
general procedure and purified by flash column chromatog-
1
raphy to give a white solid; yield: 89%. H NMR (400 MHz,
General Procedure for Pd-Catalyzed
Monobenzylation
CDCl3): d=3.58–3.66 (m, 4H), 6.74–6.75 (m, 4H), 7.06–7.13
(m, 8H), 7.26–7.33 (m, 4H), 7.42–7.45 (m, 1H), 7.84–7.85
(m, 1H); 13C NMR (100 MHz, CDCl3): d=42.3, 51.7, 111.9,
116.9, 123.1, 126.6, 127.3, 127.5, 127.8, 127.9, 128.3, 130.4,
136.4, 142.2, 142.4, 149.5, 171.1; HR-MS (ESI): m/z=
490.0769, calcd. for C28H22BrNNaO [M+Na]: 490.0777.
2-(1,2,3-Triphenylpropan-2-yl)benzo[d]thiazole (5ai): The
title compound was prepared according to the general pro-
cedure and purified by flash column chromatography to give
PdACTHNUTRGNE(UGN MeCN)2Cl2 (6.5 mg, 5 mol%), dppp (12.7 mg, 6 mol%),
benzoxazole derivative (0.5 mmol, 1 equiv.), benzyl chlorides
(252 mg, 4 equiv.), Na2CO3 (212 mg, 4 equiv.) and DMF
(2 mL) were added to a 25-mL flame-dried Young-type tube
under an N2 atmosphere, and then the resulting mixture was
stirred at 1208C for 16 h. Then the mixture was cooled to
room temperature, and washed with water, extracted with
diethyl ether for three times. The organic layer was dried
over anhydrous Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash column chroma-
tography on silica gel and eluted with EtOAc/hexanes (1/
50–1/30) to afford the desired product 3aa; yield: 89%.
1H NMR (400 MHz, CDCl3): d=4.27 (s, 2H), 7.25–7.30 (m,
3H), 7.31–7.39 (m, 4H), 7.43–7.47 (m, 1H), 7.67–7.70 (m,
1H); 13C NMR (100 MHz, CDCl3): d=35.3, 110.5, 119.9,
124.2, 124.7, 127.3, 128.9, 129.0, 134.8, 141.4, 151.1, 165.2;
HR-MS (ESI): m/z=210.0919, calcd. for C14H12NO [M+H]:
210.0913.
1
a yellow oil; yield: 83%. H NMR (400 MHz, CDCl3): d=
3.65–3.72 (m, 4H), 6.72–6.74 (m, 4H), 7.02–7.13 (m, 6H),
7.26–7.37 (m, 6H), 7.44–7.48 (m, 1H), 7.77–7.79 (m, 1H),
8.02 (d, J=7.6 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=
43.9, 54.4, 121.5, 123.2, 124.9, 125.7, 126.4, 127.1, 127.7,
128.1, 128.2, 130.6, 135.7, 135.9, 145.0, 152.3, 179.1; HR-MS
(ESI): m/z=406.1610, calcd. for C28H24NS [M+H]:
406.1624.
2-Phenyl-5-(1,2,3-triphenylpropan-2-yl)-1,3,4-oxadiazole
(5aj): The title compound was prepared according to the
general procedure and purified by flash column chromatog-
1
raphy to give a white solid; yield: 77%. H NMR (400 MHz,
General Procedure for Pd-Catalyzed Dibenzylation
CDCl3): d=3.58–3.67 (m, 4H), 6.81–6.83 (m, 4H), 7.08–7.13
(m, 8H), 7.26–7.29 (m, 3H), 7.41–7.51 (m, 3H), 7.87–7.89
(m, 2H); 13C NMR (100 MHz, CDCl3): d=42.3, 49.5, 122.9,
125.7, 125.9, 126.3, 126.6, 126.9, 127.3, 127.9, 129.5, 130.5,
135.2, 140.2, 163.8, 168.8; HR-MS (ESI): m/z=417.1957,
calcd. for C29H25N2O [M+H]: 417.1961.
PdACTHNUTRGNE(UGN MeCN)2Cl2 (6.5 mg, 5 mol%), dppp (12.7 mg, 6 mol%),
the benzoxazole derivative (0.5 mmol, 1 equiv.), the benzyl
chloride (151 mg, 2.4 equiv.), Cs2CO3 (391 mg, 2.4 equiv.)
and DMA (2 mL) were added to a 25-mL flame-dried
Young-type tube under N2 atmosphere, and then the result-
ing mixture was stirred at 608C for 16 h. Then the mixture
was cooled to room temperature, and washed with water,
extracted with diethyl ether for three times. The organic
layer was dried over anhydrous Na2SO4 and concentrated
under reduced pressure. The residue was purified by flash
column chromatography on silica gel and eluted with
EtOAc/hexanes (1/100–1/50) to afford the desired product
2-[1,2,3-Tris(4-chlorophenyl)propan-2-yl]benzo[d]oxazole
(5ba): The title compound was prepared according to the
general procedure and purified by flash column chromatog-
1
raphy to give a white solid; yield: 72%. H NMR (400 MHz,
CDCl3): d=3.50–3.61 (m, 4H), 6.64–6.66 (m, 4H), 7.04–7.07
(m, 6H), 7.27–7.28 (m, 1H), 7.33–7.39 (m, 2H), 7.45–7.47
(m, 1H), 7.72–7.74 (m, 1H); 13C NMR (100 MHz, CDCl3):
d=42.4, 51.2, 110.7, 120.3, 124.6, 125.3, 128.1, 128.5, 129.0,
131.6, 132.8, 133.4, 134.6, 140.2, 140.5, 150.4, 168.3; HR-MS
(ESI): m/z=514.0496, calcd. for C28H20Cl3NNaO [M+Na]:
514.0503.
1
4aa; yield: 77%. H NMR (400 MHz, CDCl3): d=3.35 (dd,
J1 =7.6 Hz, J2 =6.0 Hz, 1H), 3.73 (dd, J1 =7.6 Hz, J2 =
6.0 Hz, 1H), 4.49 (t, J=8.0 Hz, 1H), 7.09–7.23 (m, 6H),
7.27–7.35 (m, 6H), 7.44–7.46 (m, 1H), 7.69–7.72 (m, 1H);
13C NMR (100 MHz, CDCl3): d=40.7, 48.2, 110.5, 119.9,
124.1, 124.7, 126.4, 127.4, 128.1, 128.3, 128.7, 129.0, 138.7,
139.3, 141.3, 150.8, 167.5; HR-MS (ESI): m/z=300.1382,
calcd. for C21H18NO [M+H]: 300.1383.
2-[1,2,3-Tris(4-bromophenyl)propan-2-yl]benzo[d]oxazole
(5ca): The title compound was prepared according to the
general procedure and purified by flash column chromatog-
1
raphy to give a white solid; yield: 71%. H NMR (400 MHz,
CDCl3): d=3.48–3.59 (m, 4H), 6.57–6.59 (m, 4H), 6.99–7.01
(m, 2H), 7.18–7.21 (m, 4H), 7.33–7.38 (m, 2H), 7.39–7.46
(m, 3H), 7.71–7.73 (m, 1H); 13C NMR (100 MHz, CDCl3):
d=42.4, 51.2, 110.7, 120.3, 120.9, 121.5, 124.6, 125.4, 129.4,
131.1, 131.5, 132.0, 135.1, 140.5, 140.7, 150.4, 168.2; HR-MS
(ESI): m/z=625.9147, calcd. for C28H21Br3NO [M+H]:
625.9168.
1698
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ꢁ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2012, 354, 1692 – 1700

À
Palladium-Catalyzed Selective C H Benzylation towards Functionalized Azoles
i) D. A. Colby, R. G. Bergman, J. A. Ellman, Chem.
Acknowledgements
Rev. 2010, 110, 624–655; j) C.-L. Sun, B.-J. Li, Z.-J. Shi,
Chem. Commun. 2010, 46, 677–685; k) A. Gunay, K. H.
Theopold, Chem. Rev. 2010, 110, 1060; l) T. W. Lyons,
M. S. Sanford, Chem. Rev. 2010, 110, 1147–1169;
m) C. S. Yeung, V. M. Dong, Chem. Rev. 2011, 111,
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This work was supported financially by the Chinese Acade-
my of Sciences and National Natural Science Foundation of
China (21172226 and 21133011).
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Adv. Synth. Catal. 2012, 354, 1692 – 1700