Versatile synthesis of functionalized β- And γ-carbolines: Via Pd-catalyzed C-H addition to nitriles/cyclization sequences

Article abstract of DOI:10.1039/c8cc00040a

The first example of versatile synthesis of functionalized β-carbolines and γ-carbolines via redox-free Pd-catalyzed C-H addition of indole to nitrile/cyclization sequences is reported. A wide range of functionalized β-carbolines and γ-carbolines can be prepared from readily accessible indoles and nitriles in good to excellent yields under the optimal conditions.

Full text of DOI:10.1039/c8cc00040a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: T. Wang, D. Zhang
and W. Liao, Chem. Commun., 2018, DOI: 10.1039/C8CC00040A.
This is an Accepted Manuscript, which has been through the
Volume 52 Number
1 4 January 2016 Pages 1–216
Royal Society of Chemistry peer review process and has been
accepted for publication.
ChemComm
Accepted Manuscripts are published online shortly after
Chemical Communications
www.rsc.org/chemcomm
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1359-7345
COMMUNICATION
Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc3N@C2n (2n 68 and 80). Synthesis of the
first methanofullerene derivatives of Sc N@D5h-C80
=
3
rsc.li/chemcomm

Please do not adjust margins
Page 1 of 4
ChemComm
View Article Online
DOI: 10.1039/C8CC00040A
Journal Name
COMMUNICATION
Versatile Synthesis of Functionalized β and γ-Carbolines via Pd-
Catalyzed C-H Addition to Nitriles/Cyclization Sequences
Ting-Ting Wang, ‡ Di Zhang ‡ and Wei-Wei Liao*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first example of versatile synthesis of functionalized β-
carbolines and γ-carbolines via a redox-free Pd-catalyzed C–H
addition of indole to nitrile/cyclization sequence is reported. A
wide range of functionalized β-carbolines and γ-carbolines can
be prepared from readily accessible indoles and nitriles in good
to excellent yields under the optimal conditions.
A. previous works on TM-catalyzed oxdiative pathway
1) Jiao and Chiba's works:
R4
R5
N
N
N
N
R3
cat. Pd (II), O2
R2 R2
R4
R5
+
or
R2
or
N
cat. Rh (III), Cu (II)
R1
regioselectivity:
5/1-1/1
C(3), C(2)-
substituted indoles
N
R4
R2 R5
Carbolines (pyrido[x,y-b]indoles) constitute one of the most
important and abundant nitrogen-containing heterocyclic ring
systems. In particular, the privileged pyrido[3,4-b]indole (β-
carboline) and pyrido[4,3-b]indole (γ-carboline) scaffolds are
significant structural motifs and prevalent in a variety of
2) Ray's works:
N
N
X
2
3
N
Ts
or
Br
Cl
cat. Pd (II), Cu (II)
4
B
A
regioselectivity:
2.8/1-1.4/1
NHTs
A = N, B = C, X = Br (4)
A = C, B = N, X = Cl (3);
N
Ts
bioactive natural products and medicinally relevant
1
B. this work: Pd-Catalyzed redox-free pathway
compounds.
They also have found many important
R2
R5
applications in synthetic chemistry1b, 2 and materials science. 3
Consequently, many protocols have been developed for the
synthesis of these azaheterocyclic systems. 1b, 4 Among them,
the approaches based on the Pictet–Spengler (PS) and
Bischler–Napieralski (B-N) reactions for β-carbolines, and the
Graebe–Ullman method for γ-carbolines are the most widely
used. 1b, 5 Recently, transition-metal catalyzed cyclization has
emerged as an alternative approach to access those scaffolds. 4,
O
N
N
R3
N
cat. Pd (II)
cat. Ligand
R1 R4
+
R4-CN
R2
or
N
R1
R4
C(3), C(2)-
substituted indoles
N
R1
R5
R2
Scheme 1 Synthetic strategy
a
Pd-mediated oxidative annulation reaction via
6
Notably, the annulation via transition-metal catalyzed C–H
8d
intramolecular C–H/N–H activation (Scheme 1, A-2).
However, these methods need oxidants, and suffered from the
low regioselectivities and the limited accessibility of a variety
of substitution patterns with regard to the fused-pyridine core
ring. Therefore, a general and straightforward synthesis of β-
carbolines and γ-carbolines from available starting material
with high efficiency is still highly desirable.
Nitriles are common platform chemicals in the commodity
chemical industry, and the low cost coupled with versatile
transformations of these molecules underlies their use in
industrial and academic communities. Although several
transition-metal catalyzed [2+2+2] cyclization reaction
between diynes and nitriles have been demonstrated to
prepare carbolines,9 the construction of cyclic frameworks
incorporating nitriles as key components via transition-metal
catalyzed C–H bond functionalization is still underdeveloped,
presumably due to the inherently inert nature of nitriles,
bond functionalization has proven to be an attractive and
powerful synthetic strategy to prepare heterocycles due to its
7
efficient and sustainable features, but received limited
successes in the construction of both β-carboline and γ-
carboline scaffolds. Jiao and co-workers reported a Pd-
catalyzed direct dehydrogenative annulation reaction of
internal alkynes and performed imines for the preparation of
β-carbolines and γ-carbolines, and Chiba et al demonstrated
the similar transformation to construct β-carbolines via Ru-
catalysis (Scheme 1, A-1). 8a-c Subsequently, Ray et al. reported
Department of Organic Chemistry, College of Chemistry, Jilin University, Changchun
130012, P. R. China. E-mail: wliao@jlu.edu.cn
‡ These authors contributed equally to this work.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
ARTICLE
Journal Name
despite its holding the potential in constructing azaheterocycle has not been developed. The results are illustrated in Table 1.
View Article Online
DOI: 10.1039/C8CC00040A
The initial investigation was examined by the reaction of 1-(1-
compounds serving as C-N building block.
Recently, remarkable advances in transition-metal-catalyzed methyl-1H-indol-3-yl)propan-2-one
1a
with
4-
C-H bond additions to nitriles have been accomplished, but methoxyphenylacetonitrile 2a in NMA/HOAc (3/1) in the
they normally provide acyclic aryl ketone products, in which presence of Pd(OAc)2 (10 mol %), and 2,2’-bipyridine (bpy) (12
nitriles serve as only C building block.10 In principle, resultant mol %) at 120 oC, which were previously identified as the
ketimine intermediates of this process may be utilized in the optimal reaction conditions for the intramolecular indoyl (2)C-
assembling azaheterocyclic skeletons as C-N building blocks in H addition to nitriles.11 However, no reaction occurred, and
an atom economic way upon coupling with appropriate the similar result was obtained when NMA was employed as a
functional groups, instead of the hydrolysis to afford ketones. sole solvent (Table 1, entries 1-2). To our delight, the expected
We recently disclosed the Pd-catalyzed intramolecular C–H C–H addition/cyclization sequence occurred by using HOAc as
addition of indoles bearing cyanohydrin components to nitriles a solvent, which afforded the desired β-carboline 3a, but with
for the synthesis of carbazoles and tetrahydropyrido[1,2- low yield and conversion (Table 1, entry 3). The influence of
a]indole derivatives.11 With the goal of the development of a ligand on the reaction outcome was subsequently probed
practical and efficient synthetic approach for the construction (Table 1, entries 4-8). The similar result was obtained when
of various N-heterocycles from readily available starting 5,5’-dimethyl-2,2’-bipyridyl (L-2) was employed, while 1,10-
materials via direct C-H bond functionalization, herein, we phenanthroline (phen) and 4,4'-dimethyl-2,2'-bipyridyl (L-1)
report a diverse synthesis of functionalized β-carbolines and γ- gave the marginal increasing yields of 3a, but with the higher
carbolines via a redox-free Pd-catalyzed C–H addition of indole conversions of 1a. No reaction happened in the presence of
to nitrile/cyclization sequence (Scheme 1, B).
6,6’-dimethyl-2,2’-bipyridyl (L-3) or the absence of ligand. The
former is presumably ascribed to the steric hindrance effect of
L-3. Other Pd(II) catalysts such as Pd(TFA)2 and Pd(acac)2 were
surveyed, and both provided inferior results, with regard to
the yield of 3a and conversion of 1a (Table 1, entries 9-10).
Further investigation on solvents revealed that both THF/HOAc
(3/1) and DCE/HOAc (3/1) gave improved yields of the desired
product, while THF/HOAc (3/1) as a solvent system was more
promising (Table 1, entries 11-14). Screening of other solvents
did not improve the chemical outcome of this transformation.
Table 1 Optimization of the reaction conditions a
t
Yield Conv.
Entry
Cat.
Ligand
Solvent
(h)
28
28
28
28
28
28
28
28
28
28
28
28
(%)b
(%)c
12
In addition, the addition of AgSbF6 (30 mol %) which may
1
2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(acac)2
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
bpy
bpy
bpy
phen
L-1
L-2
L-3
-
NMA/HOAc=3/1
NMA
nr
-
conduce to the generation of cationic Pd(II) intermediate, and
thereby activate nitrile, failed to give the desired product
(Table 1, entry 15). Notably, the increasing yield was obtained
when the reaction was performed in 120 oC for 48 hours (Table
1, entry 16). Further survey on other reaction parameters such
as additives, reaction temperature, concentration, and the
ratio of 1a and 2a did not improve the chemical outcome of
this transformation (for details see the SI).
Under the optimized reaction conditions, we next explored
the generality of the Pd-catalyzed C-H addition/cyclization
sequence for the preparation of β-carboline derivatives (Table
2). Other than N-methyl 3-substituted indole 1a, N-benzyl
substituted analogue 1b can give the desired product 3b in
relatively low yield. Notably, free (NH) indole could also be
employed in the cyclization reaction to deliver the desired
product 3c with the similar yield to that of substrate 1a, which
can easily be transformed into other β-carboline derivatives
with different N-substituents. The reaction between indole
bearing ethyl ketone unit with 4-methoxyphenylacetonitrile
proceeded smoothly, and gave substituted β-carboline 3d in
56% yield. In addition, both electron-donating and electron-
nr
-
3
HOAc
26
28
29
24
< 1
< 1
30
26
39
12
16
30
< 1
57
28
80
40
28
-
4
HOAc
5
HOAc
6
HOAc
7
HOAc
8
HOAc
90
50
63
42
13
28
84
>95
68
9
bpy
bpy
bpy
bpy
bpy
bpy
bpy
bpy
HOAc
10
11
12
13
14
15d
16
HOAc
THF/HOAc=3/1
DMF/HOAc=3/1
dioxane/HOAc=3/1 28
DCE/HOAc=3/1
THF/HOAc=3/1
THF/HOAc=3/1
28
10
48
a
Reaction conditions: 1a (0.2 mmol), 2a (0.3 mmol), catalyst (10 mol %) and
b
c
ligand (12 mol %) in solvent (c = 0.4 M). Isolated yields. Based on recovered
starting material 1a. AgSbF6 (30 mol %) was added. bpy: 2,2’-bipyridine; phen:
d
1,10-phenanthroline; L-1: 4,4'-Dimethyl-2,2'-bipyridyl; L-2: 5,5'-Dimethyl-2,2'-
bipyridyl; L-3: 6,6'-Dimethyl-2,2'-bipyridyl; NMA: N-methylacetamide
Our study began with the evaluation of Pd-catalyzed (2)C–H withdrawing substituents at the benzene ring of indole core
addition of indole to nitrile/cyclization sequence to prepare β- were tolerated, affording the desired products 3e and 3f in
carbolines. Although Pd(II)-catalyzed intermolecular indoyl 52% and 43% yields respectively. Next, we investigated the
(3)C-H addition to nitrile, which furnished ketone derivatives, reactions of N-methyl 3-substituted indole 1a with various
10d,
e
has been reported,
the employment of 3-substituted nitriles. Significantly, a broad range of aromatic substituents of
indoles in such intermolecular C–H addition transformation phenylacetonitriles were tolerated, with both electron-
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Page 3 of 4
ChemComm
Journal Name
ARTICLE
Table 2 Substrates scope for preparation of β-carbolines a
tolerated, delivering the cyclization products (5e
-
5Vgie)wiAnrti5cl0e-O6n5lin%e
yields. In addition, a variety of phDeOnyI:l1a0c.e10t3o9n/iCtr8iCleCs000w4i0thA
different aromatic substituents and aliphatic nitriles were also
evaluated, leading to the corresponding hydroxy substituted γ-
R3
R3
O
R2 (R5)
Pd(OAc)2 (10 mol %)
bpy (12 mol %)
R4 CN
R2
+
N
N
R1
THF/HOAc = 3/1
N
120 o
C
R1 R4
carboline derivatives (5h
to the preparation β-carbolines from aryl nitriles, the reactions
between 2-substituted indole with aryl nitriles worked well,
with both electron-donating and electron-withdrawing
substituents affording the desired products (5p 5t) in 40-68%
-5o) in good to high yields. In contrast
1
2
3
R3
Me
N
Me
Et
2
N
N
N
N
N
R1 PMB
PMB
Me PMB
Me
3a (R1 = Me): 57%
3b (R1 = Bn): 34%
3c (R1 = H): 56%
3d: 56%
3e (R3 = MeO): 52%
3f (R3 = Cl): 43%
-
yields. Notably, ethyl 2-(1-methyl-1H-indol-2-yl)propanoate
Me
Me
Table 3 Substrates scope for preparation of γ-carbolines a
N
N
N
Me CH2Ph
N
R4
R3
Me CH2R
Pd(OAc)2 (10 mol %) R3
bpy (12 mol %)
O
N
3h (R = 2-MeC6H4): 55%
3i (R = 3-ClC6H4): 60%
3j (R = 4-ClC6H4): 60%
3k (R = 4-BrC6H4): 62%
3l (R = 3,4-Cl2C6H3): 60%
R4 CN
+
R2
3g: 57%
N
R5
N
NMA/HOAc = 3/1
120 o
R1 R6
R1 R6
C
2
4
5
Me
PMB
N
PMB
N
N
OAc
Me
N
Me
N
N
N
R1
R5
N
N
N
Me
Me R4
Me Me
Me
R2 = OEt:
R2 = Me:
R
3m (R4 = Me) b: 60%
3n (R4
nPr) b: 56%
3q e: 28%
3o (R = H) c: < 10% d
3p (R = CF3) c: 40%
5b (R1 = Me, R5 = OCOPh) b: 90%
5c (R1 = Bn, R5 = OCOPh) b: 65%
5d (R1 = H, R5 = OH): 65%
5a (R5 = Me): 56%
=
(R2 = OEt, R5 = OAc)
a
CH2R
N
R
N
Bn
Reaction conditions: 1 (0.4 mmol), 2 (0.6 mmol), Pd(OAc)2 (10 mol %), bpy (12
mol %) and solvent (THF/HOAc = 3/1, c = 0.4 M) in 120 oC for 48 h. Yields shown
4
3
5
6
N
R3
2
are of isolated products. 2 (1 mL). 2 (3 equiv.). Impure. e Acetylation of
corresponding pyrido[3,4-b]indol-3-ol led to esterified product 3q with good
solubility. PMB = p-Methoxybenzyl
b
c
d
N
OCOPh
N
OCOPh
N
OAc
Me
R2 = OEt:
Me
R2 = OEt:
Ac
R2 = OEt:
5h (R = C6H5) b: 88%
5n (R = Me) b, c: 92%
5o (R = nPr) b, c: 89%
5e (R3 = 5-MeO) b: 65%
5f (R3 = 5-Cl) b: 50%
5g (R3 = 6-Cl) b: 53%
5i (R = 2-MeC6H4) b: 90%
5j (R = 3-ClC6H4) b: 90%
5k (R = 4-ClC6H4) b: 88%
5l (R = 4-BrC6H4) b: 80%
5m (R = 3,4-Cl2C6H3) b: 90%
donating and electron-withdrawing substituents affording the
desired products (3g-3l) in 55-62% yields, regardless of the
Ar
N
Bn
N
substitution patterns. Aliphatic nitriles such as acetonitrile and
butyronitrile can also serve as good reaction partners, and
react with 1a to give the corresponding alkyl substituted β-
carbolines in 56-60% yields. When aryl nitriles were employed,
the reactions proceeded rather sluggishly. The reaction with 4-
(trifluoromethyl)benzonitrile delivered the desired product 3p
in 40% yield. Furthermore, Pd-catalyzed cyclization of N-
methyl indole-3-acetic acid ethyl ester with acetonitrile was
examined, and the expected cyclization sequence furnished
N
OCOPh
N
OCOPh
Me Me
Me
R2 = OEt:
5u b: 87%
R2 = OEt:
5p (Ar = Ph) b, d: 55%
5q (Ar = 4-MeC6H4) b, d: 40%
5r (Ar = 4-ClC6H4) b, d: 50%
5s (Ar = 4-CF3C6H4) b, d: 68%
5t (Ar = 4-NCC6H4) b, d: 59%
a
Reaction conditions: 4 (0.4 mmol), 2 (0.6 mmol), Pd(OAc)2 (10 mol %), bpy (12
mol %) and solvent (NMA/HOAc = 3/1, c = 0.4 M) in 120 oC for 9-48 h. Yields
shown are of isolated products. b Acylation of corresponding pyrido[4,3-b]indol-3-
ols (R2 = OEt) led to esterified products 5 with good solubility. c 2 (1 mL). d 2 (3
equiv.).
the desired pyrido[3,4-b]indol-3-ol, which underwent further
acetylation to give esterified product 3q
relatively low yield.
13
,
albeit with
We next turned our attention to the synthesis of γ-
carbolines by employing 2-substituted indole substrates with
nitriles. Under the modified reaction conditions (NMA/HOAc
(3/1) as a solvent system), 1-(1-methyl-1H-indol-2-yl)propan-2-
one reacted with 4-methoxyphenylacetonitrile 2a producing
the desired product 5a in 56% yield. Notably, unlike 3-
can also serve as a suitable substrate to provide the desired
multi-substituted γ-carboline 5u in high yield.14 In addition, the
structures of functionalized β- and γ-carbolines were
unambiguously confirmed by the exemplification of X-ray
15
crystal structural analyses of products 3g and 5a
.
substituted indole
1 with ester unit, the reaction between
ethyl 2-(1-methyl-1H-indol-2-yl)acetate and 2a proceeded
smoothly, providing the desired hydroxy substituted γ-
carboline followed by the acylation to give 5b in high yield. 13
Both N-benzyl and N-unsubstituted analogues can provide the
desired pyrido[4,3-b]indol-3-ol derivatives (5c and 5d), but
with relatively low yields. Electron-donating group (OMe) and
electron-withdrawing group (Cl) at the 5-or 6-positions of the
Scheme 2 Pd-catalyzed double C–H addition of indoles to nitriles/cyclization
sequence
aromatic rings of N-unsubstituted indoles
4 were well
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
ARTICLE
Journal Name
Sun, Anti-cancer Agents Med. Chem., 2015, 15, 537 and
Furthermore, treatment of ethyl 2-(1-methyl-1H-indol-2-
yl)acetate 4b with 2,2'-(1,3-phenylene)diacetonitrile 2o can
afford bis-γ-carboline derivative in good yield via a Pd-
catalyzed double C–H addition of indole to nitrile/cyclization
sequence under the modified reaction conditions.
View Article Online
references cited therein.
2
(a) G. Domínguez and J. Pérez-CasteDllOs,I:E10u.r1.03J.9/OC8rgC.CC00h0e4m0.A,
2011, 7243; (b) H. M.-F. Viart, A. Bachmann, W. Kayitare and
R. Sarpong, J. Am. Chem. Soc., 2017, 139, 1325.
Y. Im and J. Y. Lee, Chem. Commun., 2013, 49, 5948.
For selected reviews, please see: (a) O. B. Smirnova, T. V.
Golovko and V. G. Granik, Pharm. Chem. J., 2011, 44, 654; (b)
M. Milen and P. Ábrányi-Balogh, Chem. Heterocycl. Compd.,
2016, 52, 996.
6
3
4
5
6
(a) K. Pulka, Curr. Opin. Drug Discovery Dev., 2010, 13, 669;
(b) Y.-P. Zhu, M.-C. Liu, Q. Cai, F.-C. Jia and A.-X. Wu, Chem.
Eur. J., 2013, 19, 10132; (c) G. C. Condie and J. Bergman, Eur.
J. Org. Chem., 2004, 1286; (d) C. Graebe and F. Ullmann,
Liebigs Ann. Chem., 1896, 16, 291.
Recent examples: (a) Q. Yan, E. Gin, M. G. Banwell, A. C.
Willis and P. D. Carr, J. Org. Chem., 2017, 82, 4328; (b) C. H. A.
Esteves, P. D. Smith and T. J. Donohoe, J. Org. Chem., 2017,
82, 4435; (c) S. Dhiman, U. K. Mishra and S. S. V. Ramasastry,
Angew. Chem., Int. Ed., 2016, 55, 7737 and references cited
therein.
Selected reviews with alkenes: (a) C. Jia, T. Kitamura and Y.
Fujiwara, Acc. Chem. Res., 2001, 34, 633; (b) E. M. Ferreira, H.
M. Zhang and B. M. Stoltz, Tetrahedron, 2008, 64, 5987; (c) X.
Chen, K. M. Engle, D. H. Wang and J. Q Yu, Angew. Chem., Int.
Ed., 2009, 48, 5094; (d) D. A. Colby, A. S. Tsai, R. G. Bergman
and J. A. Ellman, Acc. Chem. Res., 2012, 45, 814. With alkynes:
(e) L. Ackermann, Acc. Chem. Res., 2014, 47, 281.
Scheme 3 Proposed mechanism
7
Proposed mechanism was illustrated in Scheme 3 for the Pd-
catalyzed cyclization with the exemplification of C-3
substituted indole substrate
1 with nitrile. In analogy to other
processes involving Pd-catalyzed C-H bond functionalization,
10d-e, 11 this catalytic process may involve a direct palladation at
8
9
(a) S. Ding, Z. Shi and N. Jiao, Org. Lett., 2010, 12, 1540; (b) Z.
Shi, Y. Cui and N. Jiao, Org. Lett., 2010, 12, 2908; (c) P. C. Too,
S. H. Chua, S. H. Wong and S. Chiba, J. Org. Chem., 2011, 76,
6159; (d) S. Dhara, R. Singha, A. Ahmed, H. Mandal, M.
Ghosh, Y. Nuree and J. K. Ray, RSC Adv., 2014, 4, 45163.
(a) F. Nissen, V. Richard, C. Alayrac and B. Witulski, Chem.
Commun., 2011, 47, 6656; (b) S. P. Mulcahy, J. G. Varelas,
Tetrahedron Lett., 2013, 54, 6599.
the C-2 position of indole core with [(bpy)Pd(OAc)2]
gives a palladium complex . The coordination of the nitrile
provides intermediate , which undergoes an addition of the
indolyl group to the nitrile to form the corresponding ketimine
Pd(II) complex . The reaction between intermediate and
neighboring carbonyl group would led to species , which
undergoes the protonolysis and aromatization to give product
and regenerates the Pd(II) species
In summary, we have developed a new protocol for the
A, which
B
C
D
D
E
10 (a) C. X. Zhou and R. C. Larock, J. Am. Chem. Soc., 2004, 126,
2302; (b) C. X. Zhou and R. C. Larock, J. Org. Chem., 2006, 71,
3551; (c) H. Takaya, M. Ito and S.-I. Murahashi, J. Am. Chem.
Soc., 2009, 131, 10824. (d) T. S. Jiang and G. W. Wang, Org.
Lett., 2013, 15, 788; (e) Y. H. Ma, J. S. You and F. J. Song,
Chem. Eur. J., 2013, 19, 1189; (f) T. S. Jiang and G. W. Wang,
Adv. Synth. Catal., 2014, 356, 369; (g) B. W. Zhou, Y. Y. Hu
and C. Y. Wang, Angew. Chem., Int. Ed., 2015, 54, 13659.
11 T.-T. Wang, L. Zhao, Y.-J. Zhang and W.-W. Liao, Org. Lett.,
2016, 18, 5002.
3
A.
diverse synthesis of functionalized β-carbolines and γ-
carbolines via a redox-free Pd-catalyzed C–H addition of indole
to nitrile/cyclization sequence. Under the optimal conditions, a
diversity of functionalized β-carbolines and γ-carbolines can be
prepared from readily available starting materials in good to
high yields. The catalytic system tolerates a broad substrate
scope. Further studies on the synthetic application of this
strategy to the catalytic construction of other azaheterocyclic
frameworks is in progress in our laboratory.
12 For details, see the Supporting Information.
13 Acylation of corresponding products (R2 = OEt) is necessary
to obtain derived products
3
or
5
with good solubility for the
purification and NMR analysis.
14 The corresponding 2-substituted analogue
1
did not give the
We are thankful for the financial support from the National
Natural Science Foundation of China (No. 21772063).
desired multi-substituted β-carboline under the optimized
reaction conditions.
15 CCDC 1813722 (compound 3g
)
and CCDC 1813723
(compound 5a), see the Supporting Information for details.
Conflicts of interest
There are no conflicts to declare.
Notes and references
1
For reviews, please see: (a) R. Cao, W. Peng, Z. Wang and A.
Xu, Curr. Med. Chem., 2007, 14, 479; (b) R. S. Alekseyev, A. V.
Kurkin and M. A. Yurovskaya, Chem. Heterocycl. Compd.,
2009, 45, 889; (c) O. B. Smirnova, T. V. Golovko and V. G.
Granik, Pharm. Chem. J., 2011, 45, 389; (d) M. Zhang and D.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins