γ-Carboline synthesis enabled by Rh(iii)-catalysed regioselective C-H annulation

Article abstract of DOI:10.1039/d0cc04740f

A redox-neutral Rh(iii)-catalyzed C-H annulation of indolyl oximes was developed. Relying on the use of various alkynyl silanes as the terminal alkyne surrogates, the reaction exhibited a reverse regioselectivity, thus giving an exclusive and easy way for the synthesis of a wide range of substituent free γ-carbolines at C3 position with high efficiency. Deuterium-labelling experiments and kinetic analysis have preliminarily shed light on the working mode of this catalytic system. This journal is

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Conformational control of nonplanar free base porphyrins:
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DOI: 10.1039/D0CC04740F
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γ-Carboline synthesis enabled by Rh(III)-catalysed regioselective
C-H annulation
a
Bo Jiang, ‡ Jingwen Jia, ‡a Yufei Sun,a Yichun Wang,a Jing Zeng,a Xiubin Bu,a Liangliang Shi,c Xiaoying
Received 00th January 20xx,
Accepted 00th January 20xx
Suna and Xiaobo Yang*a, b
DOI: 10.1039/x0xx00000x
A redox-neutral Rh(III)-catalyzed C-H annulation of indolyl oximes maintaining the chelation and to serve as the nitrogen source.8
was developed. Relying on the use of various alkynyl silanes as the Meanwhile, numerous reaction partners had been employed
terminal alkyne surrogates, the reaction exhibited a reverse to fulfil the annulations, delivering five or six membered N-
regioselectivity, thus giving an exclusive and easy way for the heterocycles.9 Among them, alkynes such as internal alkynes,
synthesis of a wide range of substituent free γ-carbolines at C3 terminal alkynes and other surrogates were identified as the
position with high efficiency. Deuterium-labelling experiments most popular and ideal participants depending on their easy
and kinetic analysis have preliminarily shed light on the working availability and versatile reactivity.10 They often performed
mode of this catalytic system.
well and accomplished the annulations with high efficiency.
However, in most cases, symmetric internal alkynes were
adopted, avoiding to generate the mixture caused by the low
regioselectivity which was following the use of asymmetric
internal alkynes (Scheme 1a).11 For terminal alkynes and their
surrogates, as a kind of more challenged substrates in C-H
activations, in the limited reports, 2,1-insertion occurred only
(Scheme 1b).12 To the best of our knowledge, no contrary
regioselectivity has been observed in transition-metal
catalysed C-H annulations. In this context, how to control and
adjust the regioselectivity in the using of asymmetric internal
alkynes and get the reverse regioselectivity in the using
terminal alkynes leaves much room to do. Surprisingly, some
pioneering works
γ-Carboline, as a very important class of alkaloid, frequently
occurs in natural products, bioactive compounds and drugs.1
To date, it has been found to exhibit a variety of bioactivities,
including antiviral, antibacterial, antitumor activities and so
on.2 To satisfy the needs of preparing multifarious γ-carbolines
in high-throughput screening and the research of structure-
activity relationship (SAR), many successful synthetic methods3
(for example, transition-metal catalysed coupling,4 acid
catalysed condensation5 and photoinduced cyclization6) had
been developed in the past few decades. However, some
methods suffer tedious reaction steps, harsh reaction
conditions, low efficiency and regioselectivity. With this
regard, it is still highly desirable to develop novel strategies for
the easy and rapid synthesis of diverse substituted γ-carboline
scaffolds from readily available substrates.
Previous works:
transition-metal
N
N
N
catalyst
(a)
R1
R2
+
Ar
and
Ar
R2
R1
H
Recently, the application of transition-metal catalysed direct
C-H activation/cyclization in the synthesis of N-heterocycles
has emerged as a facile strategy due to its high step-economy
and atom-economy.7 In these applications, nitrogen-contained
groups always played a dual role, to be the directing group
R1
R2
When R1 R2, mixture was always obtained.
≠
transition-metal
catalyst
N
N
N
(b)
R
H
+
Ar
Ar
Ar
R
H
H
H
R
No contrary regioselctivity was obseved.
This work:
NOMe
H
a. Institute of Catalysis for Energy and Environment, College of Chemistry and
Chemical Engineering, Shenyang Normal University, Shenyang 110034, P. R.
China.
R1
N
[Rh(III)]
R1
R3
Si
(c)
H
+
TFE, 120
,
℃
N
N
R2
R3
R2
air, 24 h
b. Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University, Beijing
100084, P. R. China.
1
2
3
A reverse regioselectiity
c. Tianjin Lisheng Pharmaceutical Co., Ltd., Tianjin 300385, P. R. China.
†Electronic supplementary information (ESI) available: Experimental procedures
and characterization data of all compounds. CCDC 1961904. For ESI and
Scheme 1 Transition-metal catalysed C-H annulations for the synthesis of N-
heterocycles with alkynes
crystallographic
data
in
CIF
or
other
electronic
format
see
DOI: 10.1039/x0xx00000x
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COMMUNICATION
Journal Name
Ph
Ph
H
a)
NOMe
H
[Cp*RhCl2]2 (2.5 mol %)
R1
ViNew Article Online
NOMe
AgSbF6 (10 mol %)DOI: 10.1039/DH0CC04740F
N
N
R1
[Rh(III)]
+
Bpin
Ar
2
Si
(0.15 mmol)
3aa
N
R2
H
TFE, 120 , air,
H
Ph
℃
N
Ar
Na2CO3
,
N
R2
sealed tube, 24 h
N
N
Ph
H
TFE, 120
air, 12 h
,
℃
1
3
(0.1 mmol)
Ph
COOH
1a
3aa
4aa
R1
N
R1 = H (
), 79%
N
b)
R1 = F (
), 61%
3ea
R1
H
R1 = Me (
R1 = OMe (
), 70%
3ca
H
3ba
R1 = Cl ( ), 69%
3fa
NOMe
N
N
Ph
TMS
), 80%
R1 = OMe (
Ph
N
N
Ph
3ga
), 77%
R1 = Cl (
), 62%
3da
2a
H
H
N
[Rh(III)], Na2CO3
,
N
R2 = H ( ), 46%
N
N
Ph
3ja
TFE, 120 , air,
℃
R2 = Et (
), 45%
H
Cl
H
H
3ka
12 h
1a
3aa, 62%
CCDC 1961904
N
R2= nPr ( ), 63%
N
N
3la
Ph
Ar
Ph
R2
R2 = Allyl (
), 83%
3ma
R2 = Bn (
3hl
, 68%
Ar=3,4,5-trimethoxyphenyl
3na
), 78%
3ia
, 80%
Scheme 2 Rh(III)-catalysed C-H annulations of indolyl oximes with terminal
alkynes and surrogates
Scheme 3 Indolyl oximes scope in Rh (III)-catalysed regioselective C-H
reported previously brought some enlightenments to face this
challenge.13 For instance, Ma and co-workers developed an
efficient and selective synthesis of fully substituted allenes
from arenes and tertiary propargylic carbonates via Rh-
catalysed C-H activation in 2015.14 In this approach, the
excellent regioselectivity for the alkyne insertion was derived
from O-coordination and the steric effect of tertiary carbon
centre. In 2017, Glorius et al. reported a redox-neutral Mn(I)-
catalysed C-H annulation for the synthesis of N-heterocycles,
in which a traceless directing group on alkynes was employed
to guide and control the high regioselectivity for
unsymmetrical alkynes.15
Inspired by these pioneering works, we surmise that a
suitable alkyne partner with steric factors or coordination sites
might determine and change the regioselectivity in the related
transition-metal catalysed C-H annulations, especially for the
asymmetric alkynes. Based on this, to continue our interests
on Rh-catalysis and the synthesis of N-heterocycles, herein, we
disclose an efficient γ-carboline synthesis enabled by Rh(III)-
catalysed C-H activation/cyclization of indolyl oximes under
redox-neutral reaction conditions, in which, the contrary
regioselectivity is obtained solely by the use of bulky alkynyl
silanes as terminal alkyne surrogates (Scheme 1c).
annulations
section IV). For the potential compatible transition-metal
catalysts, [Cp*RhCl2]2/AgSbF6 was deemed to be the only
successful one rather than Ru, Co and Ir complex. Addition of
base or acid was not helpful to improve the productivity.
Increasing the reaction time to 24 h led a considerable
promotion of conversion, and 3aa was isolated in 79% yield.
For organic solvents, HFIP (hexafluoro-2-propanol), as another
fluorinated solvent, possessing unique and magic effects17 in
transition-metal catalysed C-H activations, also proved to be
effective, giving 3aa in similar yield with TFE. Control
experiments showed that [Cp*RhCl2]2 and AgSbF6 were both
necessary for this transformation. Notably, inert gas
atmosphere is needless for this approach and the reaction
proceeded smoothly under air in a sealed tube.
With the optimized reaction conditions established, the
scope of indolyl oximes was then investigated (Scheme 3).
Pleasingly, a wide range of different substituted indolyl oximes
on the indole ring reacted with aromatic alkynyl silanes well,
regardless of substituent locations, which delivered the
corresponding substituent free γ-carbolines at C3 position in
moderate to good yields (3aa-3ia). Fluoro indolyl oxime (3ea)
and chloro indolyl oxime (3da, 3fa, 3hl) all participated the C-H
annulations smoothly to produce the desired γ-carbolines in
In Rh-catalysed chelation-directed C-H bond activations, the
oxime moiety is a very charming directing group which always
can accomplish the reductive elimination without external
satisfied yields, providing
a good chance for further
modification. Apart from N, O-methyl/indolyl oximes, N-free
indolyl oxime (3ja) other N-substituted indolyl oximes (3ka-
3na) were also compatible for this transformation, but N-free
indolyl oxime (3ja), N-ethyl indolyl oxime (3ka) and N-propyl
indolyl oxime (3la) all gave lower conversions and yields
relatively. Notably, for all tested indolyl oximes, only one
regio-isomer was observed, and the high and reverse
regioselectivity remained along with substituent variations.
Next, we probed the versatility and generality of this Rh(III)-
catalysed C-H activation/cyclization with various alkynyl silanes
(Scheme 4). For para-substituted phenyl alkynyl silanes, alkyl
(3ab, 3ac), bromo (3ad), phenyl (3ae), ester (3af), cyano (3ag),
even overly sensitive formyl (3ah) were all well-tolerated,
affording the desired product in 45-80% yields with high
regioselectivity. Except for para-substituted phenyl alkynyl
silanes, ortho-substituted (3ai, 3aj) phenyl alkynyl silanes and
meta-substituted (3ak, 3al) phenyl alkynyl silanes were both
feasible substrates, revealing that the substitution positions
16
oxidants.8, Therefore, N, O-methyl/indolyl oxime (1a) was
employed as the model substrate to perform the Rh(III)-
catalysed C-H annulations for the synthesis of γ-carbolines.
Four different terminal alkynes and surrogates were firstly
subjected to the reactions with 1a to probe the feasibility of
our envision on how to control the regioselectivity. As shown
in Scheme 2a, using [Cp*RhCl2]2/AgSbF6 as the catalyst, Na2CO3
as the additive, in trifluoroethanol (TFE), under air, at 120 °C
for 12 h, phenylacetylene, alkynyl boronate ester and
phenylpropiolic acid all failed to carry out the C-H annulation.
No target product (3aa or 4aa) was obtained, accompanying
with the considerable amount of oxime remain and
decomposition. To our surprise, when we used phenylalkynyl
silane 2a as the reaction partner, in striking contrast with
previous reports, only one isomer 3aa was isolated in 62%
yield with a reverse regioselectivity (Scheme 2b), as confirmed
by single-crystal X-ray analysis (see details in the ESI: section
VI). Subsequently, we moved our attention to gain the best
reaction efficiency depending on the extensive screening of
reaction parameters (see details in ESI:
2 | J. Name., 2012, 00, 1-3
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Journal Name
COMMUNICATION
NOR
NOMe
H
[Cp*RhCl2]2 (2.5 mol %)
AgSbF6 (10 mol %)
N
R=H,
3aa, trace
R=Ac, 3aa, 33%
R1
Standard reaction
conditions
View Aa)rticle Online
(
R=H, Ac, Piv
+
2a
H
H
R1
3aa
R3
Si
R=Piv,
, N.D.
+
DOI: 10.1039/D0CC04740F
N
N
TFE, 120 , air,
℃
N
R3
sealed tube, 24 h
Ph
[Si]
Standard reaction
conditions
[Si]=TIPS, 3aa, 56%
[Si]=TBDS, 3aa, 59%
(b)
1a
+
1
2
3
(0.1 mmol)
(0.15 mmol)
[Si]=TIPS or TBDS
38% D
85% D
3ab
3ac
3ad
R = Me (
R = tBu (
R = Br (
R = Ph (
), 70%
), 75%
N
H
N
H/D
NOMe
H/D
H/D
NOMe
H/D
H
3ai
R = OMe ( ), 83%
), 72%
3ae
Standard reaction conditions
1a
N
54% D
N
R
98% D (c)
), 78%
R = Br (3aj), 64%
N
N
3af
), 80%
3ah
R = COOMe ( ), 73%
3ag
R = CN (
R = CHO (
90% recovery
(CF3CH2OH:CD3OD=1:1)
90% recovery
(CF3CD2OD)
), 45%
R
N
8% D
Standard reaction conditions
36% D
63% D
H/D
H/D
R1
H
N
H
R1 = Cl (
R1 =OMe (
), 68%
95% D
(d)
3fn
N
N
N
3ak
R = Me (
), 84%
1a
+
2a
3gn
), 83%
H/D
H/D
N
3al
R = Cl ( ), 83%
N
N
OMe
OMe
Ph
Ph
R
3aa and [D]-3aa, 58%
(CF3CH2OH:CD3OD=1:1)
3aa and [D]-3aa, 74%
(CF3CD2OD)
N
3am
Ar=3,5-dimethylpheny (
), 73%
20% D
20% D
N
H
3ao
), 75%
Ar=3,4,5-trimethoxylpheny(
Ar=2,3-dihydrobenzo[b][1,4]dioxin-6-yl (
Ar=thiophen-3-yl (
H
H/D
H/D
NOMe
H/D
3ap
), 60%
93% D
H/D
N
N
3aq
R3
), 61%
), 72%
Standard reaction conditions
CF3CD2OD, 12 h
(e)
N
+
R3=H (3as), 92%; R3=Et (3at), 89%
R3=n-Pr (
3ar
1a
Ar=naphthalen-1-yl (
+
2a
Ar
N
N
3
15% D
30% recovery
3av
3ax
), 83%
Ph
), 92%; R =Cy (
3aa and [D]-3aa, 66%
N
N
H
N
NOMe
H
tBu
[Cp*RhCl2]2 (2.5 mol %), AgSbF6 (10 mol %)
N
H
N
N
N
H
H/D
+
2a
(f)
TFE, 120 , air, sealed tube
℃
N
N
Ph
3au
3au'
and
, 91% (1:1, determined by 1H NMR)
3aw
, 88%
kH/kD=2.63
1a or [D1]-1a
3aa
Reaction conditions:
N
TMS
N
H
Standard reaction conditions, 2 h, 100% desilylation occurred
(g)
Without AgSbF6, 2 h, 100% desilylation occurred
Desilylation
Scheme 4 Alkynyl silanes scope in Rh(III)-catalysed regioselective C-H
Without [Cp*RhCl2]2, 2 h, 100% desilylation occurred
+TMS-OH
Only 10 mol% AgSbF6, r.t., 2 h, 5% desilylation occurred
annulations
have no obvious impact on the reaction efficiency and
selectivity. It is worth noting that the reaction of polymethyl-
substituted (3am) phenyl alkynyl silane and polyalkoxy-
substituted (3fn, 3gn, 3ao and 3ap) phenyl alkynyl silanes
proceeded efficiently to give the desired polysubstituted γ-
carbolines which are important for the research of SAR in drug
discovery.1, 2 Moreover, we were delighted to find that thienyl
alkynyl silane and naphthyl alkynyl silane could also furnish the
3aq and 3ar respectively in synthetically useful yields. To fully
explore the scope of alkynyl silanes, several alkyl alkynyl
silanes were examined as the reaction partners. Remarkably,
as more challenged substrates for the current protocol, all of
them performed the annulation well. Four desired products
(3as, 3at, 3av and 3ax) were obtained in excellent yields
affording the consistent regioselectivity with phenyl alkynyl
silanes. However, along with the change of steric-hindrance
difference for alkyl group, the regioselectivity varied
consequently (3au and 3au’), and for t-butyl trimethylsilyl
acetylene (3aw), the regioselectivity returned to normal
probably due to the similar size between t-butyl and
trimethylsilyl.
To delineate the working mode of the present catalytic
system and the reason of reverse regioselectivity, several
mechanistic studies were conducted. At first, under the
standard reaction conditions, switching O-methyl/indolyl
oxime (1a) into O-free/indolyl oxime resulted in extremely low
reactivity and only trace amounts of 3aa was observed. The
substrates 1 with acetyl group or pivaloyl group were also
tested, unfortunately, target γ-carboline was obtained in
incredibly low yields because of the considerable side
reactions (Scheme 5a). The introduction of bulkier alkynyl
silanes (TIPS, TBDS) maintained the reverse regioselectivity
despite slightly lower output, which indicated that the bulky
alkylsilyl groups might be vital in achieving the contrary
regioselectivity (Scheme 5b). Afterwards, several H/D
exchange experiments of 1a were carried out by the
replacement of the solvent into isotopically
Scheme 5 Mechanistic studies
labelled solvent. Without the reaction partner 2a, the H/D
scrambling difference demonstrated two potential reactive
sites in C-H activation, and C2 position of indole was
favourable at 120 °C, which was consistent with previous
related literature reports18 (Scheme 5c). Meanwhile, the H/D
scrambling with 2a implied a possibility of desilylation and
subsequent H-abstraction from the solvent (Scheme 5d). The
reaction of 1a and 2a in CF3CD2OD terminated at the early
stage was conducted. It was found that the C-H cleavage could
be reversible, and 3aa was obtained in following competitive
transformations (Scheme 5e). Moreover, two parallel
independent kinetic experiments of 1a and [D1]-1a suggested
an evident kinetic isotope effect (kH/kD=2.63), which indicated
that the C-H bond cleavage might be the rate-determining step
of the catalytic cycle (Scheme 5f). Additionally, an investigation
with 2-trimethylsilyl pyridine to imitate the desilylation
-
process was performed, indicating the anion SbF6 and trace
amounts of water in the solvent possibly played the
prominent role in this step (Scheme 5g).
In accordance with the above experimental observations,
surveying the previous related reports,10-15, 19, 20 the following
reaction pathway for producing 3aa is proposed (Scheme 6). A
dissociation of [Cp*RhCl2]2 occurs with AgSbF6 initially,
affording a cationic Rh(III) species. Then the rhodacycle
intermediate I (A similar rhodacycle (CCDC 2023824) was
captured by the reaction of stoichiometric amounts of
[Cp*RhCl2]2 with 1a in the absence of AgSbF6, see details in ESI:
section V and VI) is generated through a competitive C-H
cleavage at C2 position and C4 position of 1a. Subsequent
coordination of bulky alkynyl silanes 2a to rhodium centre and
a steric effect guided regioselective alkyne insertion delivers
the seven-membered rhodacycle II. Next, intermediate II
undergoes a redox-neutral
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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COMMUNICATION
Journal Name
[Cp*RhCl2]2
1a
Chem., 2016, 2016, 5024; (c) T.-T. Wang, D. Zhang and W.-W.
View Article Online
AgSbF6
Liao, Chem. Commun., 2018, 54, 2048.DOI: 10.1039/D0CC04740F
(a) S. Biswas, P. K. Jaiswal, S. Singh, S. M. Mobin and S.
Samanta, Org. Biomol. Chem., 2013, 11, 7084; (b) A. Dagar, S.
Biswas and S. Samanta, RSC Adv., 2015, 5, 52497.
J. K. Laha, S. M. Barolo, R. A. Rossi and G. D. Cuny, J. Org.
Chem., 2011, 76, 6421.
OMe
N
Cp*
Ph
5
Rh
OMe
N
N
2a
Rh
TMS
N
CCDC 2023824
1a
Cp*
unfavor
6
7
I
OMe
N
(a) S. H. Cho, J. Y. Kim, J. Kwak and S. Chang, Chem. Soc. Rev.,
2011, 40, 5068; (b) J. Wencel-Delord, T. Dröge, F. Liu and F.
Glorius, Chem. Soc. Rev., 2011, 40, 4740; (c) P. Gandeepan
and C.-H. Cheng, Chem. -Asian J., 2016, 11, 448; (d) D. C.
Blakemore, L. Castro, I. Churcher, D. C. Rees, A. W. Thomas,
D. M. Wilson and A. Wood, Nat. Chem., 2018, 10, 383.
(a) Z. Chen, B. Wang, J. Zhang, W. Yu, Z. Liu and Y. Zhang,
Org. Chem. Front., 2015, 2, 1107; (b) H. Huang, X. Ji, W. Wu
and H. Jiang, Chem. Soc. Rev., 2015, 44, 1155; (c) R.-Y. Zhu,
M. E. Farmer, Y.-Q. Chen and J.-Q. Yu, Angew. Chem. Int. Ed.,
2016, 55, 10578.
Cp*
Rh
[Cp*Rh(III)OMe]
TMS
N
Redox-neutral
process
Ph
N
OMe
Steric effect guided
regioselective alkyne insertion
TMS
N
Cp*
N
Rh
Ph
III
TMS
N
N
H
8
9
Ph
[SbF6] and water
promoted desilylation
II
N
Ph
3aa
Scheme 6 A possible reaction pathway for producing 3aa
J. R. Hummel, J. A. Boerth and J. A. Ellman, Chem. Rev., 2017,
117, 9163.
process (see details in ESI: section V) to produce the cyclization
product III, accompanying the regeneration of Rh catalyst via
N-O cleavage. Finally, anion SbF6 and water in the solvent
assisted desilylation occurs, and the following hydrogen
abstraction from the protic solvent delivers the desired γ-
carboline 3aa.
In summary, we report here a regioselective Rh(III)-catalysed
C-H activation/cyclization for the synthesis of potentially
bioactive γ-carbolines. By virtue of combining indolyl oximes
with alkynyl silanes, this protocol allows a broad substrate
scope, high reaction efficiency, redox-neutral conditions and a
unique reverse regioselectivity coached by the steric
hinderance. We believe that it could facilitate the construction
of γ-carboline molecular library for drug discovery and
screening. Further studies to understand the complementary
regioselectivity are underway.
This work was supported by Natural Science Foundation of
Liaoning Province (20180550882), the Program for Creative
Talents in University of Liaoning Province, Innovation and
Entrepreneurship Training Program for College Students
(201910166285).
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/D0CC04740F
TOC
NOMe
R1
H
N
N
R2
R1
N
H
Rh(III)
R1
Rh(III)
H
R3
N
R2
R3
+
N
R2
R3
TMS
Redox-neutral Rh catalysis
Reverse and high regioselectivity
Broad substrate scope and high efficency
●
●
●
A Rh(III)-catalysed C-H annulation of indolyl oximes with alkynyl silanes was developed,
delivering diverse γ-carbolines with unexpected reverse regioselectivity.