Organic Letters
various piperidine derivatives were tolerated to provide 3-
piperidinyl-2-azulenols in acceptable to moderate yields. For
example, piperidine derivatives bearing electron-withdrawing
groups, such as 3- or 4-carboxylic ester groups, gave the
desired products 3d and 3e in 42% and 69% yields,
respectively. 4-Carbonyl-substituted piperidine and the
protected 4-carbonyl piperidine gave the desired 3f and 3g,
too, albeit in lower yields. Piperidine derivatives bearing
electron-donating groups afforded the desired products in
good yields. Thus, 3-benzoisooxazolyl, methoxy, and Boc-
protected amino groups gave the desired products 3h, 3i, and
3
j in 60%, 58%, and 63% yields, respectively. The long-chain
substituent on piperidine was compatible, although it
provided 3k in low yield. Furthermore, the seven-membered
amine, 4-Boc-protected 1,4-diazepane, was attached at the 3-
position of 2-azulenol in 37% yield (3l). Moreover, piperazine
was proved to be a good amination motif for 2-azulenols. For
example, 4-N-Boc-piperazine was installed at the 3-position of
2
-azulenol in 66% yield (3m). 4-N-phenyls bearing halide
substituents gave the desired products smoothly, too, thus
fluoro (3n), chloro (3o), and trifluoromethyl (3p) sub-
stituents on the phenyl ring gave the desired products in
5
0%, 60%, and 61% yields, respectively. These functional
groups provided extra handles for the synthesis of
complicated conjugate materials. 4-(2-Pyrimidinyl)-piperazine
gave the desired 3q in 71% yield. 4-N-Diarylmethyl
piperazines provided the desired 2-zazulenols 3r and 3s in
6
2% and 42% yield, respectively. A medicinal molecule was
also a good N-resource. Amoxapine was successfully used in
the amination of 2-azulenol, and the desired product 3t was
provided in 72% yield. Lastly, other carboxylic esters were
also compatible, and the desired products were given in good
yields (3u−3w).
Figure 2. Synthetic elaboration.
Scheme 4. Proposed Catalytic Cycle
This protocol is good for synthetic uses. First, products can
be prepared on the gram scale. For example, the reaction of
2
.16 g of 1a with 2a affords 1.41 g of 3a in one batch
reaction. Second, the aminated products are good for further
synthetic elaboration. For instance, the free hydroxyl group
on 3a can react with AcCl or Tf O to provide 4a and 4b. 4b
2
can further undergo Pd-catalyzed Suzuki coupling or
Sonogashira coupling to provide the 2-aryl- or 2-alkylyl-
substituted azulenes 4c and 4d. (Figure 2).
According to our previous mechanistic study of the Cu-
catalyzed ortho-dearomative amination of simple phenols with
9
RR′N−OBz, we propose the following catalytic mechanism
I
(
Scheme 4). The ligand exchange of Cu with azulenolate
I
affords Cu azulenolate species A. The oxidative addition of
RR′N−OBz to Cu gives Cu species B. The rapid
equilibration of B gives the corresponding Cu −N-centered
radical form C, Cu − NRR′. The N-centered radical attacks
azulenol at the ortho-position to give D via a pseudo five-
membered ring through inner-sphere electron-transfer model,
I
III
II
II
•
I
ASSOCIATED CONTENT
sı Supporting Information
and at the same time to regenerate Cu to close the catalytic
■
*
cycle. The rearomatization of D provides the final product 3.
In conclusion, we have developed a practical copper-
catalyzed amination of 2-azulenols at the 3-position. This
transformation proceeds under mild conditions, and a variety
of functional groups on the amine motif are tolerated.
1H NMR, 13C NMR, 19F NMR, HRMS, and the
experimental procedure (PDF)
C
Org. Lett. XXXX, XXX, XXX−XXX
Li, Meng
