882
F. Gao et al. / Tetrahedron Letters 55 (2014) 880–883
decreasing yield of 90% or 86% (Table 3, entries 4, 5), respectively.
Due to steric hindrance, o-bromotoluene and o-bromoanisole gave
lower yields than their para isomers (Table 3, entries 4–7). The
stronger electron donating group of MeO resulted in lower yields
than Me (Table 3, entries 4, 6 compared with entries 5, 7 respec-
tively). Compared with 4-methyl or 2-methyl bromobenzene (en-
try 4 or 6), 2, 4-Dimethyl bromobenzene gives lower yields of
67% (Table 3, entry 8). With electron withdrawing groups, 3-fluoro
or 4-chloro bromobenzene could still give better yields of 83% or
85% (Table 3, entries 9 and 10), respectively, which indicates small
difference between these electron withdrawing and donating
groups. Other aryl bromides such as 1-bromonaphthalene or
2-bromothiophene afforded the corresponding product in good
yields of 68% or 74% (Table 3, entries 11–12), respectively.
To further evaluate the scope of this reaction, a variety of esters
were exploited as the reactants. Bromobenzene and bromotoluene
could give the corresponding products in good to high yields
(Table 3, entries 13–26). The steric hindrance on alcohol or acid
parts of esters has resulted in slightly decreasing yield of over
80% (Table 3, entries 13–19). The structure difference of secondary
to 7 equiv resulted in the close yield of 73% (Table 4, entries 5).
Meanwhile, 4 equiv of butyl bromide and magnesium could give
the good yield of 74% in dry THF (Table 4, entries 6–8).
Under this conditions, 2-bromobutane, benzyl bromide, bromo-
cyclohexane, and 2-bromomethyl-1, 3-dioxolane could react with
ethyl acetate to give the products in medium yields of 51–61%
(Table 5, entries 2–5), which indicate the effect of steric hindrance.
The steric hindrance of ester also results in medium yields of the
reactions of butyl bromide with butyl butyrate and ethyl 2-methyl
propanate (Table 5, entries 6–7).
The reaction results in better yields in dry THF than THF and is
restrained by adding even 0.1 mL of water in 15 mL of THF (Tables
2 and 4). Thus, we conjecture that the reaction may involve the for-
mation of Grignard reagent. Another possible way is the copper re-
duced by magnesium participates in the reaction. But when copper
was employed directly, the reaction would not occur. To further
probe the role of CuO, the reactions of bromobenzene with iso-but-
anal, cyclohexanone and acetyl chloride were carried out under the
optimized conditions for esters. No products of iso-butanal and
cyclohexanone could be detected. Acetyl chloride gave product
3a in 85% yield also. When 1 equiv of CuO based on ester was em-
ployed, the reaction of phenyl bromide with iso-butanal or cyclo-
hexanone, resulted in less than 10% of GC yield for iso-butanal or
no product was detected for cyclohexanone, respectively. When
other copper catalysts such as CuI or CuBr2 were employed, the
reaction of phenyl bromide with iso-butanal or cyclohexanone
could yield 40–60% of products, which indicates the unique role
of CuO. According to the reaction of Grignard reagent, aldehyde,
ketone, and acyl chloride are more reactive than ester, and acyl
chloride should yield some amount of ketone product. Thus, we
could infer that the reaction process catalyzed by CuO is obviously
different with the typical nucleophilic addition of Grignard re-
agent. It may involve the leaving groups RO of ester or Cl of acetyl
chloride in the reacting process.
or tertiary
a carbon of esters did not cause a deal of difference in
yields. Although alkyl chloride could form Grignard reagent
also, ethyl 3-chloropropanoate could still obtain better yields of
81% (Table 3, entry 19). The possible reason is the less reactivity
of alkyl halide in this reaction, which could be supported by the
results in Table 4. Displaying the similar rule with bromobenzene,
4-bromotoluene reacted with different esters to afford corresponding
products in slightly lower yields of 88–72% (Table 3, entries 20–26)
than those of bromobenzene.
Although Grignard reagent could be reacted with the ester to
give tertiary alcohol compounds, the addition of phenyl or 4-meth-
ylphenyl Grignard reagent to ethyl acetate could only give the cor-
responding product in lower yields of 56%13 or 26%,14 respectively.
In order to gain high yields, more reactive but expensive ketones
have to be employed.15 Obviously, the method in this paper is
more simple, convenient, economic, and effective.
We have also applied butyl bromide in the reaction. However,
the yield of the product obtained was only 41% under the same
optimized conditions as above (Table 4, entry 1). We tried to im-
prove the yield via increasing the amount of butyl bromide. As
shown in Table 4, 6 equiv of butyl bromide and magnesium to
ethyl acetate could give good yield of 74% (Table 4, entry 4).
Further increasing the amount of butyl bromide and magnesium
On the basis of the mechanistic studies, a plausible reaction
pathway is proposed in Figure 1. Initially, RX reacts with magne-
sium to form RMgX, then CuO inserts into RMgX to form com-
pound 1,16 which reacts with RMgX to give organocopper 2.17 It
reacts with ester to yield addition intermediate 3. Negative ion 5
could be formed by intramolecular nucleophilic substitution of
the leaving group RO with R, which gives product 6 after gaining
Table 5
Screening of the optimum reacting condition for synthesis of tertiary alcohol
compoundsa
Table 4
Effect of butyl bromide and Mg amount on the reactiona
O
OH
R1
CuO, Mg
R3
R1
R1Br
+
R2
O
R2
O
THF, 65 °C
Mg (X equiv), THF
OH
+
Br
O
CuO, 65 °C
Entry
1
R1Br
R1 = n-C4H9
R2COOR3
Products
Yieldb (%)
74
1equiv
X equiv
R2 = CH3
5a
5b
5c
5d
5e
5f
R3 = C2H5
R2 = CH3
Entry
CH3CH2CH2CH2Br,
Mg (equiv)
Solvent
(15 ml)
Yieldb
(%)
2
3
4
5
6
R
R
R
R
R
1 = i-C4H9
51
55
72
58
52
R3 = C2H5
R2 = CH3
1 = c-C6H11
1 = PhCH2
1 = n-C4H9
1 = n-C4H9
1
2
3
4
5
6
7
8
3.0
4.0
5.0
6.0
7.0
3.0
4.0
5.0
THF
THF
THF
THF
41
54
61
74
75
57
73
75
R3 = C2H5
R2 = CH3
R3 = C2H5
R2 = n-C3H7
R3 = n-C4H9
R2 = i-C3H7
R3 = C2H5
THF
Dry THF
Dry THF
Dry THF
a
a
Reaction conditions: R1Br (15 mmol), Mg (15 mmol), R2COOR3(2.5 mmol), CuO
Reaction conditions: n-BuBr (X mmol), Mg (X mmol), AcOEt (2.5 mmol), CuO
(15 mol %), 15 mL of THF(THF or dry THF) at 65 °C for 4 h.
(15 mol %), 15 mL of THF at 65 °C for 4 h.
b
b
Isolated yield.
Isolated yield.