Decarboxylative Alkynyl Termination of Palladium-Catalyzed Catellani Reaction: A Facile Synthesis of α-Alkynyl Anilines via Ortho C - H Amination and Alkynylation

Article abstract of DOI:10.1021/acs.orglett.5b00830

A palladium-catalyzed synthesis of α-alkynyl anilines is reported. The reaction proceeds via Catellani ortho C-H amination followed by decarboxylative alkynylative amination. Different terminal alkyne precursors were screened, and it was found that alkyny

Full text of DOI:10.1021/acs.orglett.5b00830

Letter
pubs.acs.org/OrgLett
Decarboxylative Alkynyl Termination of Palladium-Catalyzed
Catellani Reaction: A Facile Synthesis of α‑Alkynyl Anilines via Ortho
C−H Amination and Alkynylation
Fenggang Sun and Zhenhua Gu*
Department of Chemistry, University of Science and Technology of China, 96 Jinzhai Road, Hefei, Anhui 230026, China
*
S Supporting Information
ABSTRACT: A palladium-catalyzed synthesis of α-alkynyl
anilines is reported. The reaction proceeds via Catellani ortho
C−H amination followed by decarboxylative alkynylative
amination. Different terminal alkyne precursors were screened,
and it was found that alkynyl carboxylic acids were superior
over other alkynes, which led to operationally simple reaction
conditions (no gradual addition of alkynes) and broad
substrate scope. The reactivity of three different components
matched well; as a result, relatively higher reaction temperature could be used, greatly shortening the reaction time to 4 h from
the previously reported 144 h.
ynthetic organic chemistry, as well as medicinal chemistry
and material sciences, are beneficiaries of the developments
with Pd catalysis. Various termination reagents, including
internal or external alkenes, cyanide, arylboronic acids, electron-
rich arenes, amines, amides, and carbenes, etc., have been
subjected to the reactions, and quite a number of useful and
structurally complex molecules were synthesized using this
S
in transition-metal-catalyzed transformations. Among them,
special attention has been paid to palladium-catalyzed reactions
due to their broad functional group tolerance and diverse
reaction pathways. The Catellani reaction, which was
4
methodology. In sharp contrast to the well-studied Sonoga-
1
5
discovered by Catellani in the 1990s and further developed
shira coupling, the Catellani reaction terminated by Sonoga-
by the groups of Catellani and Lautens et al., is a powerful
method for the synthesis of polyfunctionalized arenes. As
shira coupling is still challenging due to mismatched reactivity
of terminal alkynes and other substrates. To the best of our
knowledge, there was only one report described by Catellani
and co-workers in 2004 in this field (Scheme 2A). Because of
the high reactivity of terminal alkynes, the reaction only gave
2
depicted in Scheme 1, it is generally believed that the key steps
of the Catellani reaction are the formation of palladacycle III
and the oxidative addition of alkyl halides to five-membered
6
3
3
(
0% conversion of aryl iodides under the standard conditions
conditions A) and only afforded a complex mixture, including
the expected product 3 (8%) as well as side products 4−6
palladacycle IV. The reductive elimination of IV, followed by
norbornene extrusion, gives rise to arylpalladium intermediate
VI, which subsequently undergoes classic reactions associated
(
Scheme 2A). Moderate to good yields (66−79% brsm yields)
with 82−90% conversions could be achieved after a very careful
optimization (conditions B); however, the conditions still have
limitations: (1) large excess of alkyl bromides were used; (2)
Scheme 1. Proposed Catalytic Cycle
very slow addition both of alkyl bromide and phenylacetylenes
7
(
within 72 h) via syringe pump was necessary; (3) ambient
reaction temperature was important to avoid side reactions,
resulting the requirement for an additional 72 h of stirring to
obtain a reasonable conversion. Thus, it is desirable yet still
challenging to develop new practical synthetic methods to
construct polysubstituted arenes bearing alkyne functionalities
via the Catellani ortho C−H functionalization followed by
Sonogashira-type termination reactions.
Following our ongoing interests in the study of the Catellani
reaction for the synthesis of multisubstituted arenes and related
2
d,4e
complex natural products,
we found it was critical to match
Received: March 20, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00830
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Catellani Reactions Terminated with
Sonogashira-Type Coupling
Table 1. Reaction Conditions: Optimization
b
entry
alkyne
ligand
PPh3
solvent
yield of 10a (%)
1
2
3
4
5
6
7
8
9
9a
9b
9c
9d
9d
9d
9d
9d
9d
9d
9d
9d
9d
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
5
6
PPh3
PPh3
60
87
65
8
PPh3
P(2-furyl)3
P(o-tolyl)3
P(p-tolyl)3
PPh3
79
c
12
d
PPh3
17
10
11
12
13
PPh3
CH CN
34
55
67
39
3
PPh3
dioxane
PPh3
(CH Cl)2
2
PPh3
DMF
a
The reaction was conducted on 0.20 mmol of 7a, 0.24 mmol of 8a,
0.30 mmol of 9, 1.20 mmol of norbornene, 0.60 mmol of Cs CO , 5
the reactivity of all three components. On the basis of the
analysis of Catellani’s results, it was hypothesized that the high
reactivity of terminal alkynes is one of the main reasons for the
formation of side products. We reasoned that compared to
terminal alkynes, alkynyl analogues or precursors with relatively
lower reactivity had the following advantages: (1) the insertion
reaction of arylpalladium I with norbornene would be favored
rather over the direct Sonogashira coupling, and (2)
intermediate II would undergo C−H palladation to form
palladacycle III instead of the formation of products like 5
through cross-coupling. As a result, no gradual addition would
be required, and a relatively high temperature would be
tolerable, thus significantly shortening the reaction time. Herein
we report our primary results on the palladium-catalyzed
Catellani reaction with a very rare alkynyl termination reaction
2
3
b
mol % of Pd(OAc) , and 12.5 mol % of phosphine. Isolated yields.
2
d
c
K PO was used. K CO was used.
3
4
2
3
bulky phosphine P(o-tolyl) as the ligand gave low conversion,
3
with only 8% of 10a being isolated (entry 6). The Pd(OAc)2/
P(p-tolyl)3 catalytic system showed similar activity in
comparison with Pd(OAc) /PPh3 (entry 7). Other bases,
2
such K PO and K CO , were not effective for this reaction
3
4
2
3
(entries 8 and 9). Upon switching the solvent from toluene to
others, it was found that no improvement in yields could be
achieved (entries 10−13).
We evaluated this protocol by applying a series of ortho-
substituted aryl iodides to synthesize different alkynyl-
substituted anilines. The reaction of 2-methoxyl-, 2-phenyl-,
and 2-(O-TBS)-hydroxymethyl iodobenzenes gave the desired
products in moderate to excellent yields (Scheme 3, 10b−d).
The reaction of 1-iodonaphthalene also proceeded smoothly to
deliver 10e in 87% yield. 2-Chloro- and 2-fluoroiodobenzenes
are also compatible substrates (10f and 10g), although a
relatively low yield for the 2-fluoro compound 10g was
obtained. Introducing electron-withdrawing groups at the ortho
position gave 55−88% yields of the corresponding products
(10h−j). Varying the electronic property of substituents at the
para position of 2-methyliodobenzene had little effect on the
yields (10k−l).
(
Scheme 2B).
Our initial examination began with the cross-coupling
between alkynes, 2-methyliodobenzene and N-(benzoyloxy)-
morpholine, which has recently been proven to be a class of
efficient ortho-amination reagents in Catellani reaction by Dong
8
and Chen groups (Table 1). It was found that alkynylstannane
(9a) or -silane (9b) were not effective reagents and the
reactions delivered the desired product in very low yields, with
most of the stannane and silane being unchanged (Table 1,
entries 1 and 2). By the use of 2-methyl-4-phenylbut-3-yn-2-ol
9
c as the alkyne partner, the yield of 10a was significantly
improved (entry 3). Inspired by the seminal work of Goossen,
Tunge, and other groups,
To further explore the generality of this reaction, different
substituted O-benzoylhydroxylamines and alkynyl carboxylic
acids were tested (Scheme 4). Other N,N-disubstituted O-
benzoylhydroxylamines were equally compatible for this
multicomponent reaction (10n−q), albeit relatively lower
yields were obtained for some cases, such as pyrrolidine
product 10q. Electronic effects were investigated by varying the
substituent at the para position of phenylpropiolic acids. With
electron-donating groups at the para position, good to excellent
yields could be achieved (10r−t). However, electron-with-
drawing groups on phenylpropiolic acids were disadvantageous
9,10
who disclosed transition-metal-
catalyzed cross-coupling by the use of carboxylic acids via a
decarboxylative process instead of organometallic reagents, 3-
phenylpropiolic acid was chosen as an alkyne precursor. To our
delight, when alkynyl carboxylic acid 9d was used, the reaction
afforded the desired alkynyl aniline 10a in 87% isolated yield
(
1
entry 4). It is striking that the reaction could be conducted at
00 °C without significantly increase in the amount of the side
reactions. The use of tri(2-furyl)phosphine as the ligand
resulted in a relatively lower yield (entry 5). The reaction with
B
DOI: 10.1021/acs.orglett.5b00830
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Substrate Scope with Various Aryl Iodides
for this transformation, and yields were significantly decreased,
where the major side products were 5-type bicyclo compounds
1
1
(
10u and 10v). The reactions with other substituted
phenylpropiolic acids (10w−z), even 2-pyridinylpropiolic
acid, proceeded uneventfully (10A). The compatibility of this
reaction with aliphatic alkynes was also striking, showing
1
2
significant advantages over the previous method. For
example, the reactions with 2-butynoic acid, 2-pentynoic acid,
and 2-octynoic acid proceeded smoothly to give the
corresponding products in 66−75% yields (10B−D).
In conclusion, we reported a palladium-catalyzed Catellani
ortho-amination reaction, which was terminated by decarbox-
ylative alkynylation for the efficient synthesis of substituted α-
alkynyl anilines. The newly developed protocol has advantages
6
over the previous method: (1) the well-matched reactivity of
alkynyl carboxylic acids with other components resulted in
simple reaction conditions with easy operation, where no
gradual addition was necessary; (2) in contrast to the previous
methods, both aliphatic and aromatic alkynes, as well as
heteroaromatic alkynes were suitable for cross-coupling; and
(
3) a relatively high temperature could be used, thus
significantly shortening the reaction time to 4 h (previous
reaction time: 144 h).
ASSOCIATED CONTENT
Supporting Information
■
*
S
a
The reaction was conducted on 0.20 mmol of iodides7, 1.2 equiv of
a, 1.5 equiv of 9d, 6.0 equiv of norbornene, 0.60 mmol of Cs CO , 5
1
13
Experimental procedures, characterization data, and H and C
NMR spectra for new compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
8
2
3
mol % of Pd(OAc) , and 12.5 mol % of PPh in toluene at 100 °C for
4
2
3
b
h. 10 mol % of Pd(OAc) was used.
2
a
AUTHOR INFORMATION
Corresponding Author
■
Scheme 4. Substrate Scope
*
E-mail: zhgu@ustc.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the ‘973’ project from the MOST
of China (2015CB856600), NSFC (21272221, 21472179), the
Recruitment Program of Global Experts, and the Fundamental
Research Funds for the Central Universities (WK 2060190028
and 2060190026). The Foundation for the Author of National
Excellent Doctoral Dissertation (201423) is also acknowledged.
We thank Professor Zakarian (University of California, Santa
Barbara) for the help during the revision of this manuscript.
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(
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D
DOI: 10.1021/acs.orglett.5b00830
Org. Lett. XXXX, XXX, XXX−XXX