Angewandte
Communications
Chemie
Table 2: Scope of the reaction.[a]
were obtained with 4-nitrophenol (N4; entry 4). Gratifyingly,
high yield of the corresponding active ester 2 was obtained
using HFIP alcohol (N5; entry 5). However, its sterically
more hindered analogue, N6, was not efficient (entry 6). We
found the observed high efficiency of HFIP alcohol in this
reaction is quite unusual. Although, it is known to undergo
transition metal catalyzed alkoxycarbonylation of aryl hal-
ides,[9] there is no data on its employment in C H function-
ꢀ
alization reactions. Moreover, this weakly nucleophilic alco-
hol[10] has been used as either a solvent or cosolvent for
improvement of the efficiency of certain challenging
ꢀ
palladium(II)-catalyzed C H functionalization reactions
with no incorporation of the HFIP moiety into the reaction
products observed.[11] Since HFIP alcohol is known to act as
a potent hydrogen-bond donor,[12] we hypothesized that it
could have coordinated to the “spectator” nitrogen atom of
the pyrimidine DG (e.g. I; Scheme 1). This arrangement
potentially, could have double-fold beneficial effect for this
transformation by: a) decreasing the basicity of the DG and
thus enhancing its activity in the C H activation event,[13] and,
ꢀ
at the same time, by b) increasing the nucleophilicity of the
hydrogen-bonded HFIP alcohol.[14] The following initial
experiments provide certain support for this assumption.
Thus, the performed NMR studies confirmed the existence of
strong hydrogen bonding between 1a and HFIP alcohol.[15] In
contrast, employment of an even more nucleophilic, but much
less potent hydrogen-bond-donor alcohol, such as isopropa-
nol,[15] resulted in no reaction (entry 7). These data support
the importance of the hydrogen bonding for the activation of
the DG. This data was further supported by the fact that the
reaction of a 1a analogue possessing a stronger coordinating
and thus expectedly less efficient pyridyl directing group,
resulted in much lower efficiency of the alkoxycarbonylation
(entry 8). Furthermore, employment of ethanol as a nucleo-
phile in combination with carboxylic acids (entries 9 and 10)
was also inefficient, thus suggesting that HFIPꢀs role in this
transformation is beyond simple protonation of the directing
group.[16]
Next, the scope of this alkoxycarbonylation reaction
toward making active HFIP benzoates was tested (Table 2).
Substrates with both electron-donating and electron-with-
drawing groups gave the corresponding products in good to
excellent yields. Importantly, a number of useful function-
alities, including aryl halides (2d, 2e, 2o–r), alkyl and aryl
esters (2g, 2h), ketone (2i), amides (2j, 2x, 2y), protected
aldehyde (2k), alkyl chloride (2r), and nitrile (2s), were
tolerated under these reaction conditions. Notably, the
synthetically valuable BPin-containing substrate also reacted
well (2l).[17] Importantly, alkoxycarbonylation of substrates
possessing other potential directing groups,[18] such as
methoxy, ketone, ester, and amide, exclusively led to the
PyrDipSi-directed products (2c, 2h–j, 2n, 2x, 2y). In the
event where the aryl silane contained two possible reactive
[a] Reaction conditions: Pd(OAc)2 (10 mol%), Ac-Leu-OH (20 mol%),
AgOAc (4 equiv), HFIP alcohol (2–5 equiv), CO (balloon), DCE, 508C,
18–48 h. Yields are those of isolated products. See the Supporting
Information for experimental details. Piv=pivaloyl.
The synthetic usefulness of the developed method was
illustrated by the preparation and further transformations of
the HFIP ester of tetrahydroquinoline, which is a medicinally
important heterocyclic core.[19] Thus, the PyrDipSi group was
efficiently installed at C6 of N-pivalate tetrahydroquinoline
(3) by gold-catalyzed iodination[20a] (4) followed by rhodium-
catalyzed cross-coupling of the formed aryl iodide with
PyrDipSiH[7a–d] to produce 1y in 75% overall yield (Sche-
ꢀ
me 2A). The C H bond alkoxycarbonylaton reaction of the
latter proceeded smoothly to deliver the active HFIP ester 2y
in 75% yield as a single regioisomer. Expectedly, the silyl and
active ester moieties of 2y could independently be converted
into other synthetically useful groups. Thus, simple nucleo-
philic substitution reactions, followed by one-pot protodesi-
lylations or iododesilylations, converted 2y into the corre-
sponding aryl ester 5, iodo aryl ester 6, aryl amide 7, and iodo
aryl amide 8, in good to excellent yields. It is worth
mentioning that the C7-substituted tetrahydroquinolines are
challenging scaffolds to synthesize.[21] Accordingly, this
ꢀ
ꢀ
sites, C H alkoxycarbonylation occurred preferentially at the
approach represents an unprecedented protocol for meta C
sterically less hindered site (2m–y). Remarkably, this method
can be extended beyond benzoates. Thus, active HFIP esters
of different heterocycles, including thiophene (2u), dibenzo-
furan (2v), carbazole (2w), indoline (2x), and tetrahydroqui-
noline (2y), can efficiently be obtained using this approach.
H alkoxycarbonylation of tetrahydroquinoline. Moreover, the
3,4-benzocoumarin core 9, a widely found motif in natural and
bioactive molecules,[22] was also functionalized using this
methodology (Scheme 2B). Thus, the directing group was
efficiently installed onto 9 by sequential iodination[20b] (10)
2
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Angew. Chem. Int. Ed. 2017, 56, 1 – 6
These are not the final page numbers!
Wang, Yang
