Organic Letters
Letter
primary alkyl alcohols, and considerable amounts of a7 and a8
were recovered. A reaction involving sterically bulky tert-butyl
alcohol (a9) gave only a trace of product 9. To evaluate the
synthetic utility of this alkoxycarbonylation protocol, we scaled
up the reaction of a1 (8 mmol, 0.3 M) with MeOH (60
mmol), which gave 1 in 72% isolated yield. To our delight, we
also found that the reaction of furoic acid (c1) (10 mmol, 0.3
M) in MeOH gave 1 (52%) in a single step.
a
Heteroarenes
Because unsymmetrical difuroates have potential applica-
23
tions in plastification, we next turned our attention to the
synthesis of these compounds by means of our alkoxycarbo-
nylation protocol (Scheme 3). Reactions of MeOH and CHCl3
a
Scheme 3. Synthesis of Unsymmetrical Difuroates
a
Reactions were performed on a 0.3 mmol scale in CHCl (0.3 M)
3
containing Cu(OAc) (0.2 equiv), TBPB (2.5 equiv), and MeOH
2
b
c
(
2.5 equiv) at 120 °C for 12 h. Isolated yield of byproduct 1. The
reaction was carried out at 110 °C for 9 h.
In addition, furans bearing a strongly electron-withdrawing
group (nitro or cyano) also afforded complex mixtures in
which the desired products (35 and 36) were not detected.
The above-described results clearly indicate that a moderately
electron-deficient furan ring is required for this transformation.
It is noteworthy that further investigation revealed that
benzofuran and thiophene rings, which have greater
aromaticity than the furan ring, were also suitable, affording
products 37−42. Finally, benzothiazole and 1-methyl-1H-
pyrrole-2-carboxylate afforded 43 and 44, respectively.
a
Reactions were performed on a 0.3 mmol scale in CHCl (0.3 M)
3
containing Cu(OAc) (0.2 equiv), TBPB (2.5 equiv), and MeOH
2
b
(
2.5 equiv) at 120 °C for 12 h. Isolated yield of byproduct 1.
with various 2-furoates (R ≠ Me, a2−16) were examined.
Predictably, ester exchange was unavoidable; however, it could
be partially suppressed by decreasing the amount of MeOH to
To gain insight into the reaction mechanism, we carried out
several control experiments (Scheme 5). Under the standard
conditions, the reaction was completely inhibited by the radical
scavengers TEMPO and BHT. In both of these experiments,
C Cl was detected by GC−MS, which indicates that ·CCl
2
.5 equiv, despite the formation of a small amount of 1. When
R was a linear primary alkyl group (Et, n-butyl, n-hexyl, n-octyl,
or benzyl), the desired products 10−14 were obtained in
moderate to good yields (52−75%), accompanied by small
amounts of 1. A set of furoates bearing a branched primary
alkoxyl group (2-cyclohexylethyl, isopropyl, or 2-ethyloctyl)
were also effective substrates, giving 15−17 in moderate yields.
Furoates with secondary alkyl groups afforded the correspond-
ing difuroates 18−23 in 53−70% yield. However, difuroate 24
was not detected when sterically bulky tert-butyl furoate was
used as the substrate.
2
6
3
radical may be generated as an intermediate. However, no
direct evidence of the formation of a ·CCl radical intermediate
3
was obtained until we used highly reactive alkene 46 as a
radical quencher to obtain trichloromethylated product 47
(Scheme 5A). Next, to elucidate the origin of the promotional
effect of the Cu(OAc)2 additive, we conducted several
experiments. First, when the reaction temperature was
We further explored the scope of this transformation by
evaluating a variety of structurally diverse heteroarene
substrates (Scheme 4). First, furans with α-substituents other
than an alkoxycarbonyl group were screened, and the
electronic nature of the substituent was found to strongly
influence the reaction. Specifically, furans substituted with a
moderately electron-withdrawing α-amide smoothly afforded
the desired products 25−30. Furthermore, furans bearing acyl
groups also underwent the reaction, giving the desired
products 31 and 32 in moderate yields, and an electron-
neutral phenyl-substituted furan gave a 46% yield of the
desired product 33. However, the reaction of a substrate
bearing an electron-donating ethyl group generated a complex
mixture that contained none of the desired product 34,
possibly because of oxidative polymerization of the furan ring.
decreased from 120 to 80 °C and Cu(OAc) was omitted,
2
target product 1 was not produced from methyl 2-furoate. In
contrast, reaction at 80 °C in the presence of Cu(OAc)2
generated 1 in 35% yield (Scheme 5B, eqs (a) and (b)). In the
absence of both MeOH and Cu(OAc) at 80 °C, intermediate
2
45 was not detected after reaction for 1.5 h (which is shorter
than the standard duration of 12 h); however, when the copper
salt was present, 45 was acquired after 1.5 h in 16% yield
(Scheme 5B, eqs (c) and (d)). When amide 46 was used as the
substrate instead of a1, trichloromethylated product 47 was
formed (Scheme 5B, eq (e)), indicating that ·CCl radical was
3
not reactive enough to attack the furan ring at 80 °C. On the
basis of these results, at 80 °C the copper salt acted as a
catalyst rather than as a promoter, which is in sharp contrast to
its role at 120 °C. Finally, the reaction of trichloromethylben-
C
Org. Lett. XXXX, XXX, XXX−XXX
Jiang, Huanfeng
