Palladium-catalyzed difunctionalization of alkynes via C-N and S-N cleavages: A versatile approach to highly functional indoles

Article abstract of DOI:10.1021/ol5024745

Palladium-catalyzed intramolecular addition of C-N and S-N bond to alkynes with the migration of functional groups has been achieved. A wide range of functional groups including acyl, pyruvoyl, amide, and sulfonyl groups can migrate smoothly and be conveniently introduced at the C-3 postion of indoles in our catalytic system. The operational simplicity and broad substrate scope demonstrate the great potential of this method for the synthesis of highly functional indoles.

Full text of DOI:10.1021/ol5024745

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Difunctionalization of Alkynes via C−N and S−N
Cleavages: A Versatile Approach to Highly Functional Indoles
Fei Zhao,† Dengyou Zhang,† Yong Nian, Lei Zhang, Wei Yang, and Hong Liu*
State Key Laboratory of Drug Research, CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese
Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, P. R. China
S
* Supporting Information
ABSTRACT: Palladium-catalyzed intramolecular addition of C−
N and S−N bond to alkynes with the migration of functional
groups has been achieved. A wide range of functional groups
including acyl, pyruvoyl, amide, and sulfonyl groups can migrate
smoothly and be conveniently introduced at the C-3 postion of
indoles in our catalytic system. The operational simplicity and
broad substrate scope demonstrate the great potential of this method for the synthesis of highly functional indoles.
ransition-metal-catalyzed addition of alkynes has become
scope, especially with regard to the limited kinds of migrating
groups. In addition, one obvious disadvantage of these two
methods is that one specific metal only catalyzed the migration of
one kind of functional group.
T
an important strategy for the functionalization of carbon−
carbon triple bonds.1 Among the reported synthetic methods,
palladium-catalyzed addition of carbamoyl derivatives to alkynes,
constituting an important synthetic route to functionalized
alkenes, has captured wide attention (Scheme 1a). Generally, the
Palladium complexes exhibited no sufficient catalytic activity
compared to platinum catalysts in the aminoacylation of alkynes
according to Yamamoto’s results.6 This reflects the significant
challenges that exist for these transformations using palladium as
the catalyst. Since the previous palladium-catalyzed addition of
carbamoyl derivatives to alkynes relies on the activation of
alkynes by the Pd(II) species as a π-acidic catalyst generated from
Pd(0) in situ, we expect an appropriate Pd(II) catalyst can
directly activate the alkyne moiety followed by the migration of
functional groups, thus forging a new catalytic system for the
difunctionalization of the carbon−carbon triple bonds. Herein,
we present our efforts on palladium-catalyzed difunctionalization
of alkynes via C−N and S−N cleavages (Scheme 2). In our new
Scheme 1. Pd-Catalyzed Addition of Carbamoyl Derivatives
to Alkynes
Scheme 2. Palladium-Catalyzed Difunctionalization of
Alkynes via C−N and S−N Cleavages
transformation involves the initial oxidative addition of the labile
C−X bonds, such as the C−S,2 C−Se,2 C−CN,3 C−Cl,4 and C−
H5 bond, to the Pd(0) center to form the Pd(II) species as a π-
acidic catalyst, which coordinates with the alkynes with
subsequent simultaneous construction of C−C and C−X
bonds through reductive elimination. Despite the remarkable
achievements made, however, it is still a great challenge to realize
the addition of carbamoyl C−N bond to alkynes using palladium
as the catalyst, which prompts us to investigate the new
disconnection catalyzed by palladium (Scheme 1b). Although
pioneering works reported by Yamamoto6 realized the intra-
molecular aminoacylation of alkynes using PtCl2 through the
migration of the acyl group, this reaction suffered from the
disadvantage of deacylation. Subsequent intramolecular amino-
sulfonylation of alkynes was also achieved by using a Au catalyst
by Yamamoto.7 Li8 also achieved the annulation of alkynes with
amides employing a Ru(II) catalyst, but with limited substrate
catalytic system, the migration of a series of functional groups,
including acyl, pyruvoyl, amide, and sulfonyl, can smoothly take
place, and various substituents (R3) on the nitrogen atom are well
tolerated, thus affording a versatile approach to highly functional
indoles.
Received: August 21, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol5024745 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Initial screening experiments were performed employing 1aa
as the model substrate to optimize the reaction conditions (Table
1). As we expected Pd(II) catalysts could directly activate the
Scheme 3. Substrate Scope of Pd-Catalyzed Intramolecular
Aminoacylation of Alkynes
a
a
Table 1. Optimization of the Reaction Conditions
b
entry
[Pd]
solvent
toluene
yield (%)
c
1
PdCl2(dppf)2
Pd(OAc)2
0
c
2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
0
c
3
Pd2Cl2C6H10
11
4
PdCl2(dppe)2
Na2PdCl4
72
82
85
92
5
6
PdCl2(PhCN)2
PdCl2(CH3CN)2
Pd(PPh3)4
7
c
8
0
c
9
Pd2(dba)3
0
10
11
12
13
14
15
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
PdCl2(CH3CN)2
64
88
74
99
1,2-dichloroethane
1,4-dioxane
CH3CN
EtOH
c
5
DMF
12
a
Reaction conditions: 1aa (0.5 mmol), [Pd] (0.025 mmol), and
solvent (2.0 mL) under an argon atmosphere at 90 °C for 8 h.
b
c
Isolated yield. 1aa was recovered.
alkyne moiety followed by the migration of functional groups,
various Pd(II) catalysts were chosen to test the hypothesis.
Treatment of 1aa with Pd(II) catalysts such as PdCl2(dppf)2 and
Pd(OAc)2 did not afford the desired product (entries 1 and 2).
Pleasingly, 2aa was achieved when an allylpalladium(II) chloride
dimer was used as the catalyst, albeit with a low yield (entry 3).
Encouraged by this result, an investigation of other Pd(II)
sources was carried out (entries 4−7). Among them,
PdCl2(CH3CN)2 displayed the highest catalytic reactivity,
providing product 2aa in 92% yield (entry 7). As we anticipated,
treatment of 1aa with Pd(0) catalysts such as Pd(PPh3)4 and
Pd2(dba)3 in toluene at 80 °C for 8 h did not give the desired
product at all (entries 8 and 9). The screening of solvents
revealed the transformation was strongly influenced by the
solvents used (entries 10−15), and CH3CN turned out to be the
most suitable solvent for this reaction resulting in almost
quantitative yield (entry 13).
Then, we examined the generality of the process as
summarized in Scheme 3. Substrates with alkyl groups at R1
furnished the corresponding products in excellent yields (2aa−
2ac), while the reaction of 1ad bearing a bulky tert-butyl group
did not give the desired product (2ad). A high yield (89%) was
also achieved from 1ae with a benzyl group at R1 (2ae). The
reactions of 1af−1ai carrying aromatic rings at the alkynyl moiety
afforded the corresponding products 2af−2ai in moderate yields
(68−74%) because of the formation of 3-deformylated indole
byproducts. To our delight, various functional groups such as
alkenyl, halide, ester, and BocNH at the alkynyl moiety were well
tolerated with moderate to high yields (2aj−2an). The protocol
was also compatible with substrates bearing electron-donating
substituents (MeO, Me), halides (F, Cl, Br), and an electron-
a
Reaction conditions: 1 (0.5 mmol), PdCl2(CH3CN)2 (0.025 mmol),
and CH3CN (2.0 mL) under an argon atmosphere at 90 °C for 8 h. b
The reaction was performed in toluene at 110 °C.
withdrawing substituent (CF3) at R2, which produced the
corresponding products in excellent yields (2ao−2at). It is worth
noting that various functional groups were well tolerated in this
transformation, which makes this method very useful for
synthesizing highly functional indole skeletons. In addition,
different substituents at R3 were also briefly investigated. The
reaction of 1au having an ethyl group at R3 proceeded smoothly,
providing 2au in 92% yield. In particular, 2av was also obtained in
high yield (93%) from 1av bearing a benzyl group at R3 under our
catalytic system, while only a poor yield was achieved from 1av
using a Ru catalyst.8
B
dx.doi.org/10.1021/ol5024745 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Next, various migrating groups on the nitrogen were explored
(Scheme 4). Compared to the formyl migration, the bulky acyl
a
Scheme 4. Investigation of Migrating Groups
Based on the above results, a plausible mechanism was
proposed as shown in Scheme 5. Coordination of alkyne to
PdCl2(CH3CN)2 yields intermediate A, followed by nucleophilic
attack of nitrogen to the alkyne, affording the intermediate B. An
intramolecular [1,3]-migration of the formyl group then gives
intermediate C, which affords the product and regenerates the
catalyst.
Scheme 5. Proposed Reaction Mechanism
a
Reaction conditions: 1 (0.5 mmol), PdCl2(CH3CN)2 (0.025 mmol),
and toluene (2.0 mL) under an argon atmosphere at 110 °C for 8 h. b
The reaction was performed in CH3CN at 90 °C for 8 h.
migration was sluggish under the standard conditions. The use of
toluene instead of acetonitrile and elevation of the reaction
temperature successfully addressed the problem. The acetyl
migration of substrate 1ba took place smoothly and gave the
corresponding product in 85% yield. The migration of more
bulky propionyl, isobutyryl, phenylacetyl, and benzoyl groups
also proceeded very well (2bb−2bf). Even the sterically
congested pivaloyl group could migrate successfully and afforded
the desired product (2bd). Particularly, we first proved that a
pyruvoyl group can be used as the migrating group and gave the
desired product in excellent yield (2bg). It should be emphasized
that this new method allows ready installation of the amide and
sulfonyl groups at the C-3 position of indoles, which is difficult to
achieve by traditional electrophilic substitution (2bh−2bj). In
addition, when the substrates were secondary amines with the
formyl/acyl/amide/sulfonyl group, the amines did react with
carbon−carbon triple bonds to produce indoles but the formyl/
acyl/amide/sulfonyl group did not migrate to the 3-position of
the indoles under our catalytic system.9
Mechanistic studies were also carried out with the deuterium-
labeling experiments. As shown in eq 1, the reaction of the
deuterium-labeled substrate 1aa-d1 afforded the corresponding
deuterium-labeled product 2aa-d1 in 98% yield. Addtionally, no
crossover products of the acyl group were observed when we
mixed equimolar 1ab and 1bb under the standard reaction
conditions (eq 2), indicating that this palladium-catalyzed
addition of the C−N bond to alkynes proceeds in an
intramolecular manner.
In conclusion, we have developed an efficient approach to
construct highly functional indoles by palladium-catalyzed
intramolecular C−N and S−N bond addition to alkynes. The
new protocol features a low catalyst loading, operational
simplicity, and excellent functional tolerability. Particularly, a
wide range of fuctional groups such as acyl, pyruvoyl, amide, and
sulfonyl can migrate smoothly and be conveniently introduced at
the C-3 postion of indoles in our catalytic system. We believe that
this new synthetic method will find wide applications in the
future.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and characterization data for all
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
C
dx.doi.org/10.1021/ol5024745 | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: hliu@mail.shcnc.ac.cn
Author Contributions
†F.Z. and D.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge financial support from the National
Natural Science Foundation of China (Grants 21021063,
91229204, and 81025017) and National S&T Major Projects
(2012ZX09103101-072, 2012ZX09301001-005, 2013ZX09507-
001, and 2014ZX09507002-001).
REFERENCES
■
(1) (a) Wang, C.-Y.; Hsieh, Y.-F.; Liu, R.-S. Adv. Synth. Catal. 2014,
356, 144. (b) Liang, Z.-Q.; Ma, S.-M.; Yu, J.-H.; Xu, R.-R. J. Org. Chem.
2007, 72, 9219. (c) Nakamura, I.; Mizushima, Y.; Yamamoto, Y. J. Am.
Chem. Soc. 2005, 127, 15022. (d) Nakamura, I.; Mizushima, Y.; Gridnev,
I. D.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 9844. (e) Nakamura, I.;
Bajracharya, G. B.; Wu, H.-Y.; Oishi, K.; Mizushima, Y.; Gridnev, I. D.;
Yamamoto, Y. J. Am. Chem. Soc. 2004, 126, 15423. (f) Iwai, T.; Fujihara,
T.; Terao, J.; Tsuji, Y. J. Am. Chem. Soc. 2009, 131, 6668. (g) Hirner, J. J.;
Faizi, D. J.; Blum, S. A. J. Am. Chem. Soc. 2014, 136, 4740. (h) Nakamura,
I.; Mizushima, Y.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 127, 15022.
(i) Cheng, Q.; Zhao, J.; Ishikawa, Y.; Asao, N.; Yamamoto, Y.; Jin, T.
Org. Lett. 2013, 15, 5766. (j) Nakamura, I.; Sato, T.; Terada, M.;
Yamamoto, Y. Org. Lett. 2008, 10, 2649. (k) Nakamura, I.; Sato, T.;
Terada, M.; Yamamoto, Y. Org. Lett. 2007, 9, 4081. (l) Zhang, Q.-W.;
An, K.; He, W. Angew. Chem., Int. Ed. 2014, 53, 5667. (m) Fielding, M.
R.; Grigg, R.; Urch, C. J. Chem. Commun. 2000, 22, 2239. (n) Janreddy,
D.; Kavala, V.; Kuo, C.-W.; Kuo, T.-S.; He, C.-H.; Yao, C.-F. Tetrahedron
2013, 69, 3323.
(2) Toyofuku, M.; Fujiwara, S.; Shinike, T.; Kuniyasu, H.; Kambe, N. J.
Am. Chem. Soc. 2005, 127, 9706.
(3) Kobayashi, Y.; Kamisaki, H.; Yanada, R.; Takemoto, Y. Org. Lett.
2006, 8, 2711.
(4) Fielding, M. R.; Grigg, R.; Urch, C. J. Chem. Commun. 2000, 22,
2239.
(5) Fujihara, T.; Katafuchi, Y.; Iwai, T.; Terao, J.; Tsuji, Y. J. Am. Chem.
Soc. 2010, 132, 2094.
(6) Shimada, T.; Nakamura, I.; Yamamoto, Y. J. Am. Chem. Soc. 2004,
126, 10546.
(7) Nakamura, I.; Yamagishi, U.; Song, D.; Konta, S.; Yamamoto, Y.
Angew. Chem., Int. Ed. 2007, 46, 2284.
(8) Wu, C.-Y.; Hu, M.; Liu, Y.; Song, R.-J.; Lei, Y.; Tang, B.-X.; Li, R.-J.;
Li, J.-H. Chem. Commun. 2012, 48, 3197.
(9) See Supporting Information for details.
D
dx.doi.org/10.1021/ol5024745 | Org. Lett. XXXX, XXX, XXX−XXX