Organic Letters
Letter
well as practical applications of these directing groups during the
course of reaction. However, various methods have been
reported using metal catalyzed 1,4-addition of the ortho C−H
bond to the maleimides with assistance of a variety of directing
groups.14 Remarkably, aldehyde directed ortho C−H function-
alization of benzaldehydes with maleimides has not been
reported so far, which may be due to the poorer coordination
ability of the aldehyde group. Hence, we disclose herein,
ruthenium catalyzed weakly coordinating, free hydroxy group
directed C−H alkylation of primary and secondary benzyl
alcohols with maleimides under mild reaction conditions
(Scheme 1c).
We initiated our studies by choosing the C−H alkylation
reaction between benzyl alcohol (1a) and N-benzylmaleimide
(2a) as the model reaction (Table 1). First, we examined the
reactivity of various transition metal catalysts in the presence of
additive AgSbF6, Cu(OAc)2 in 1,2-dichloroethane (DCE) at
120 °C (entries 1−7) for 24 h. The results indicated that
catalysts Cp*Co(CO)I2 (C1), [RuCl2(PPh3)3] (C2), and
[CpRu(CH3CN)3]PF6 (C3) failed to generate C−H activation
product. Surprisingly, when [RuCl2(p-cymene)]2 (C4) and
[Cp*RuCl2]2 (C5) were employed as the catalyst, benzyl
alcohol 1a underwent C−H activation with maleimide 2a
followed by further oxidation to afford o-succinimide substituted
benzaldehyde 3a exclusively in 40 and 35% yield, respectively.
Similarly, catalysts [Cp*RhCl2]2 (C6) and RuCl[(R,R)-
Tsdpen](p-cymene) (C7) independently generated the product
3a in 20% yield under the same reaction conditions. It was found
that variation in the reaction temperature has a significant effect
on the outcome of the reaction. When reaction was performed at
80 °C, yield of the product 3a jumped from 40% to 56% (entries
8−10). To our delight, there was substantial enhancement in the
yield (70%) when the reaction was carried out by increasing the
amount of Cu(OAc)2·H2O from 1.0 to 1.5 equiv at 80 °C and
further increment to 2.1 equiv afforded desired product in 85%
yield (entries 11 and 12). Eventually, various solvents were
screened but did not yield better results (entries 13−19).
Similarly, screening of various halogen scavengers such as
AgBF4, AgPF6, and NH4PF6 were performed, but none of them
were successful in improving the reaction yield (entries 20−22).
When the reaction was performed using other acetate salts by
replacing Cu(OAc)2·H2O with NaOAc and AgOAc, it did not
provide satisfactory results (enties 23 and 24). Hence, it was
found that entry 12 is the best reaction conditions to explore the
scope of various benzyl alcohols.
a
Table 1. Optimization of Reaction Conditions
Before exploring the substrate scope of C−H alkylation
reaction, few preliminary experiments were performed to
confirm whether the C−H activation reaction was directed
either by hydroxy group or by in situ generated aldehyde group.
Initially, when benzyl alcohol 1a was treated under standard
catalytic conditions in the absence of electrophile maleimide 2a,
oxidation of benzyl alcohol to benzaldehyde 1a′ was not
observed (Scheme 2a). Next, we planned reaction of
h
catalyst
silver salt
20 mol %
additive 1.0
equiv
yield 3a
entry
(5 mol %)
solvent
(%)
b
1
2
3
4
5
6
7
8
C1
C2
C3
C4
C5
C6
C7
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
C4
AgSbF6
AgSbF6
Cu(OAc)2
Cu(OAc)2
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
0
b
0
b
Scheme 2. Preliminary Reactions
0
b
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgBF4
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
NaOAc
40
35
20
20
40
56
38
70
b
b
b
c
d
9
DCE
DCE
DCE
e
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
df
,
dg
,
DCE
dioxane
TFE
HFIP
toluene
DCM
CH3CN
t-AmOH
DCE
DCE
DCE
DCE
DCE
85
dg
,
0
60
50
dg
,
dg
,
dg
,
trace
eg
,
35
dg
,
trace
trace
dg
,
dg
,
70
60
0
benzaldehyde 1a with maleimide 2a to check whether benzyl
alcohol is getting oxidized in situ and then C−H activation is
happening with the help of a weakly coordinating carbonyl
group of the aldehyde. Interestingly, no reaction was observed
(Scheme 2b). These results clearly indicated that the C−H
alkylation reaction of benzyl alcohol with maleimide was
proceeding via the hydroxy group assistance. Moreover, 3-
nitrobenzyl alcohol 1-NO2 afforded only C−H activated
product 3′-NO2 without undergoing further oxidation to
produce the corresponding benzaldehyde derivative which
further confirmed that reaction proceeds via hydroxy directed
C−H activation (Scheme 2c). This result also provides
information about the mechanism where β-hydride elimination
dg
,
AgPF6
dg
,
NH4PF6
AgSbF6
AgOAc
dg
,
trace
dg
,
0
a
Reaction conditions: 1a (0.2 mmol), 2a (0.25 mmol), [Ru(p-
cymene)Cl2]2 (5 mol %), silver salt (20 mol %), and additive (1.0
equiv) in a specific solvent (2.0 mL) for 24 h. TFE = trifluoroethanol,
HFIP = hexafluoroisopropanol, t-AmOH = t-amyl alcohol. Reaction
b
c
d
conducted at 120 °C. Reaction conducted at 100 °C. Reaction
e
f
conducted at 80 °C. Reaction conducted at 60 °C. Reaction carried
g
out using 1.5 equiv of Cu(OAc)2·H2O. Reaction carried out using
h
2.1 equiv of Cu(OAc)2·H2O. Isolated yields are of product 3a.
B
Org. Lett. XXXX, XXX, XXX−XXX