Substrate-Controlled Regio- and Stereoselective Synthesis of (Z)- and (E)- N-Styrylated Carbazoles, Aza-carbazoles, and γ-Carbolines via Hydroamination of Alkynes

Article abstract of DOI:10.1021/acs.joc.8b01642

We report herein the substrate-controlled regio- and stereoselective hydroamination of carbazoles, aza-carbazoles, and γ-carbolines with functionalized aromatic as well as aliphatic alkynes in a KOH/DMSO system in good yields. The electronic effect of the substrates governs the stereochemistry of the product. Electron-donating alkynes provided (Z)-stereoselective products, and electron-withdrawing alkynes provided (E)-stereoselective products. This approach also provides an easy route for the synthesis of mono- and bis-hydroaminated product. The deuterium-labeling studies were also conducted to support the mechanistic pathway.

Full text of DOI:10.1021/acs.joc.8b01642

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Article
Substrate Controlled Regio- and Stereoselective Synthesis
of (Z) and (E) N–Styrylated Carbazoles, Aza–Carbazoles
and #–Carbolines via Hydroamination of Alkynes
Vineeta Garg, Pradeep Kumar, and Akhilesh K. Verma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01642 • Publication Date (Web): 24 Aug 2018
Downloaded from http://pubs.acs.org on August 24, 2018
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_
Substrate Controlled Regio and Stereoselective Synthesis
of (Z) and (E) N–Styrylated Carbazoles, Aza–Carbazoles
and γ–Carbolines via Hydroamination of Alkynes
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Vineeta Garg, Pradeep Kumar, and Akhilesh K. Verma*
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry,
University of Delhi, Delhi–110007, India
Email: averma@acbr.du.ac.in
ABSTRACT: We report herein the substrate controlled regio- and stereoselective
hydroamination of carbazoles, aza–carbazoles and γ–carbolines with functionalized aromatic as
well as aliphatic alkynes in KOH/DMSO system in good yields. The electronic effect of the
substrates governs the stereochemistry of the product. Electron–donating alkynes provided (Z)–
stereoselective products and electron–withdrawing alkynes provided (E)–stereoselective
products. This approach also provides an easy route for the synthesis of mono and bis–
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hydroaminated product. The deuterium labeling studies were also conducted to support the
mechanistic pathway.
INTRODUCTION
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Carbazole, discovered over century ago is a privileged heterocyclic motif, and its analogs
exhibit plentiful applications due to unique structural and electronic features. Most importantly,
the abundance of carbazoles in natural product and medicines, made them highly demanding
3
due to their versatile implications as anti-tumor, anti–oxidative, anti–inflammatory, and
a
3b
3c
3
d
anti–mutagenic agents. During the past few decades, aza–carbazoles and γ–carbolines have
attracted a huge interest of chemists relatively due to the broad spectrum of their biological
4
activity. Aza–carbazole nucleus are found in many natural alkaloids such as neocryptolepine
-6
and, they have the ability to interact with DNA as intercalators to inhibit the topoisomerase II
7
activity. N-Alkylated γ–Carbolines are present in biologically active antihistamine drug
8
molecules such as latrepirdine or dimebon A (a marketed drug) (Figure 1).
Figure 1. Biologically active core of carbazole derivatives
The distinctive electronic environment of carbazoles and their analogs made them widely
9
susceptible key motifs in the development of organic light–emitting materials. These are
potential candidates for electronic devices, such as color display, organic semiconductor lasers,
1
solar cells, etc. Further the styrylated derivatives of carbazoles (B) are used in polymer
0
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chemistry due to the tendency of alkenes to undergo polymerization and leading to polyvinyl
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carbazoles (PVC) (Figure 1).
Owing to the widespread application of carbazole analogs, various methods have been
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developed for their synthesis. The N–functionalized carbazoles are in high demand as their
solubility in water, or organic solvents have been a major concern, which strongly depends on
N–substituted hydrophilic or hydrophobic chain. The N–alkenylation of heterocycles has been
1
3-19
well reported using transition–metal catalyst,
however, the regio– and stereoselective C−N
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bond formation reaction are in high demand.
Scheme 1. Synthesis of N–alkenylated Carbazoles
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In 2005 and 2007 Marciniec group investigated the sequential silylative and Hiyama
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1a-b
coupling for the synthesis of styryl carbazoles
using ruthenium and palladium complexes
respectively (Scheme 1, i). Later on, the copper-catalyzed coupling of vinyl halides with
carbazoles was reported by Xi and co-workers in 2009 for the formation of corresponding
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vinylated carbazoles (Scheme 1, ii). In 2014, Dodd et al., synthesized the N–vinylated
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heterocycles including carbazole by employing ynamides as a coupling partner (Scheme 1, iii).
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20b
In continuation of our ongoing research on N–alkenylation of heterocycles and our interest in
24a-c
the carbazole synthesis,
herein we have designed the substrate controlled regio– and
stereoselective synthesis of (Z) and (E) N–styryl carbazoles, aza–carbazoles and γ–carbolines via
hydroamination of alkynes in presence of KOH/DMSO (Scheme 1, iv).
RESULTS AND DISCUSSION
In order to obtain the stereoselectivity of the products, various reaction conditions were
examined using carbazole 1a as our model substrate (Table 1). Initially, we treated phenyl
acetylene 2a with carbazole 1a, using our previous reported condition that is KOH (0.5 equiv) in
25
DMSO at 120 °C for 0.5 h. Gratifyingly, the (Z)–styryl product 3a was obtained in 74% yield
(
Table 1, entry 1). Inferior results were obtained by altering the amount of base (entries 2 and 3).
In order to attain (E)–selective product, the reaction was allowed to run from 2 to 24 h using 0.5
equiv of KOH however; no change in the stereochemistry of the product 3a was obtained (entries
4
–7). Further, increasing the amount of base and reaction time also provided the (Z)–
stereoselective product 3a in moderate yields (entries 8–10). Next, to get the optimal temperature,
o
we perform the reaction at 100 C and 80 C, however; the product 3a was observed in 56% and
o
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8% yields, respectively (entries 11-12). No product was observed on further carrying the reaction
up to room temperature (entries 13-14). Further, to obtained the stereoselective (E) product, we
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employed an electron-withdrawing alkyne; 1-ethynyl-4-(trifluoromethyl)benzene 2r with 1a using
0
.5 equiv of KOH, product 5a was obtained in 65% yield (entry 15). To control the
stereochemistry of the product, the amount of base as well as temperature was decreased; however
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the E-isomer 5a was obtained instead of Z-isomer 3a (entries 16–17). No improvement was
observed in the yield of the product 5a on increasing the equivalent of KOH (entries 18–19).
t
Other bases such as NaOH, CsOH.H O, and KO Bu provided the desired product 3a in
2
lower yields (entries 20–22). However, organic base (Et N) failed to provide the hydroaminated
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product 3a (entry 23). Therefore, (entry 1) 0.5 equiv of KOH in DMSO at 120 °C for 0.5 h with
electron-donating alkyne was chosen as the optimal reaction conditions for the synthesis of (Z)–
styrylated carbazole 3a and 0.5 equiv of KOH in DMSO at 120 °C for 0.5 h with electron-
withdrawing alkyne for the synthesis of (E)–styrylated carbazole 5a (entry 15).
a
Table 1. Optimization of the Reaction Conditions
b
yield (%) 3a/5a (Z:E)
entry
alkyne
base (equiv)
solvent
time (h)/T °C
1
2a
KOH (0.5)
DMSO
0.5 / 120
74 (100:00)
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2a
2a
2a
2a
2a
KOH (1.0)
KOH (0.2)
KOH (0.5)
KOH (0.5)
KOH (0.5)
DMSO
DMSO
DMSO
DMSO
DMSO
0.5 / 120
0.5 / 120
2.0 / 120
8.0 / 120
12 / 120
68 (100: 00)
60 (100:00)
74 (100:00)
70 (100:00)
70 (100:00)
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DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
24 / 120
70 (100:00)
68 (100: 00)
68 (100:00)
65 (100:00)
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NR
KOH (1.0)
KOH (2.0)
KOH (4.0)
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.5)
KOH (0.2)
KOH (0.2)
KOH (1.0)
KOH (2.0)
NaOH (0.5)
24 / 120
30 / 120
30 / 120
0.5 / 100
0.5 / 80
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0.5 / 80
65 (00:100)
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60 (00:100)
48 (00:100)
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62 (100:00)
60 (100:00)
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0.5 / 120
0.5 / 120
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24 / 120
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CsOH.H O (0.5)
2
t
KO Bu (0.5)
Et N (0.5)
3
a
Reactions were performed using carbazole 1a (0.5 mmol), alkyne 2a/2r (0.5 mmol) in 2.0 mL of
b
DMSO. Yield.
After optimizing the reaction conditions, we synthesized a variety of styrylated carbazole
o
derivatives 3a–l with aromatic terminal alkynes using 0.5 equiv KOH at 120 C for 0.5 h (Table 2).
The reaction of substrate 1a with phenylacetylene 2a and 1-butyl-4-ethynylbenzene 2b provided
the desired products 3a–b in good yields (entries 1 and 2). Similarly, the reaction of carbazole 1a
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with alkyne 2c afforded the hydroaminated product 3c in 70% yield (entry 3). Significantly, 3-
ethynylaniline 2d and 4-ethynyl-N, N-dimethylaniline 2e afforded the desired products 3d and 3e
in 68% and 69% yields, respectively (entries 4 and 5). When the reaction was performed using
electron-rich alkyne 3-ethynylthiophene 2f, the desired product 3f was obtained in 65% yield
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(entry 6). We next extended the substrate scope by employing substituted carbazoles bearing
hydroxy and a methoxy group at C–2 position. Chemoselective addition of 2–hydroxycarbazole 1b
on to 1-ethynyl-3-methoxybenzene 2c provided the mixture of isomers 3g (Z/E = 40:60) in 70%
yield (entry 7), however; the reaction of 2–methoxy carbazole 1c with electron neutral alkyne 2a
provided the corresponding Z-addition product 3h in 72% yield (entry 8). The formation of the
mixture of isomers in 3g as compare to single isomer in 3h, might be due to the presence of
methoxy group on meta position on the alkyne which creates steric hindrance with the hydroxyl
group of carbazole. Interestingly, halogen substituted carbazole 1d gave the addition products 3i–j
in 69% and 71% yields, respectively (entries 9 and 10). Carbazole bearing electron-withdrawing
groups such as 1e and 1f were also capable of providing the hydroaminated product 3k–l in good
yields (entries 11 and 12).
To further extend the scope and generality of protocol, various symmetrical and
unsymmetrical internal alkynes were explored with electronically varied carbazoles 1a–b to afford
the N-styryl carbazoles 3m–r in good yields with excellent regioselectivity. The reaction of 1a
with diphenylacetylene 2i gave the desired product 3m in 70% yield (entry 13). Next, when 1a was
reacted with unsymmetrical internal alkyne 2j and 2k, the products 3n and 3o were obtained in 70
and 68% yields, respectively (entries 14 and 15). Carbazoles 1a reacted with a highly electron-
withdrawing group having 3-((4-nitrophenyl)ethynyl)thiophene 2l to afford the corresponding
product 3p in 67% yield (entry 16). Diphenylacetylene 2i reacted smoothly with 9H-carbazol-2-ol
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b and we obtained the product 3q in 62% yield, without affecting the hydroxy group (entry 17).
The reaction of 3-bromo-9H-carbazole 1g with symmetrical alkyne 2m provided the desired
product 3r in 65% yield (entry 18).
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a
Table 2. Scope of Carbazoles with Terminal and Internal Alkynes
entry
1
carbazoles
alkyne 2
product 3
yield (%)
2a
3a
74
1
a
nBu
2
3
4
1a
1a
1a
3b
3c
3d
70
70
68
N
2
b
2c
2d
b
5
6
1a
1a
2e
2f
69
3
e
3f
65
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2c
3g
3h
70
72
1
b
(Z:E::40:60)
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2a
2a
2g
2h
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c
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3i
3j
69
71
68
1
d
10
11
1d
3k
1
e
12
2f
3l
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1f
c
1
3
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1a
2i
2j
3m
3n
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g
a
The reactions were performed using carbazole 1 (0.5 mmol), 0.5 mmol of alkyne 2, 0.5 equiv of
o
KOH in 2.0 mL of DMSO at 120 C for 0.5 h. 24 h. 1.5 equiv of KOH for 24 h.
b
c
It is important to note that the electronic nature of the groups on the alkynes play a key
role for the high regioselectivity of the reaction (Figure 2). The presence of electron-donating
and electron-withdrawing group on the triple bond decreases the electron density on carbon
2
6
(C ) and increases on carbon (C ) of the triple bond. Owing to this electronic effect, the
a
b
nucleophile (N-heterocyclic) attacks on positively charged carbon centre (C ) to provide the
a
regioselective products. The regioselectivity of the reaction was further recognized by
NOESY studies (see ESI).
1
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Electronic effect of substituents in unsymmetrical internal alkynes
Next, we explore the scope of the reaction by using aza–carbazoles 1h with alkynes 2
for the synthesis of Z-selective isomer 4a–e in good yields (Scheme 2). The aza–carbazole 1h
reacted with phenylacetylene 2a to afford the corresponding product 4a in 78% yield. The
reaction with electron donating alkynes such as of 1-ethyl-4-ethynylbenzene 2n and 1-ethynyl-
3
-methoxybenzene 2c with aza-carbazole 1h provided the addition product 4b–c in 75% and
70% yields, respectively. The heteroalkyne 2f was well tolerated in the reaction to gave the
hydroaminated product 4d in good yield. Interestingly, aza–carbazole 1h was successfully
o
reacted with internal alkyne diphenylacetylene 2i using 1.5 equiv of KOH at 120 C for 36 h, to
afford the desired product 4e in 70% yield.
In continuation, we extended the reaction by taking biologically active gamma–
carbolines 1i with terminal and internal alkynes 2 to synthesize the styrylated product 4f-l in
good yields (Scheme 2). The addition of gamma–carbolines 1i on alkyne 2a by using KOH (0.5
o
equiv) at 120 C for 4 h, leads to the formation of (Z)-9-styryl-9H-pyrido[2,3-b]indole 4f in
7
5% yield. When the reaction of 1i was carried out with 1-(tert-butyl)-4-ethynylbenzene 2h and
-ethynyl-4-(trifluoromethoxy)benzene 2o, the corresponding products 4g and 4h were
1
obtained in 70% and 72% yields, respectively. The thienyl ring containing alkyne 2f gave the
desired product 4i in 72% yield. The successful addition of the gamma–carbolines onto
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1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
terminal alkynes encouraged us for the addition of 1i onto symmetrical and unsymmetrical
internal alkynes. The reaction of 1, 2-di-p-tolylethyne 2p with 1i provided the hydroaminated
product 4j in 70% yield. Electron-withdrawing alkyne such as 1-nitro-4-
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(phenylethynyl)benzene 2q and 3-((4-nitrophenyl)ethynyl)thiophene 2l also provided the
regioselective styryl gamma carbolines 4k–l in good yields (see Figure 2).
a
Scheme 2. Hydroamination on Alkynes using Aza-Carbazole and γ–Carboline
a
The reactions were performed using N–heterocycle 1 (0.5 mmol), 0.5 mmol of alkynes 2,
o
b
c
.5 equiv of KOH in 2.0 mL of DMSO at 120 C for 4 h. 1.5 equiv of KOH for 36 h. 0.5
0
d
equiv of KOH for 2 h. 1.5 equiv of KOH for 24 h.
After achieving the successful results with electron-donating alkynes, we next extend
the scope of electron-withdrawing alkynes (2r–v), for the synthesis of (E)–addition products
5
a-j in good yields (Scheme 3). The reaction of 1a with 1-ethynyl-4-(trifluoromethyl)benzene
2r afforded the E–addition product 5a in 65% yield. Cyano (2s) and flouro (2t) group
containing aromatic terminal alkynes reacted in the same fashion to afford the (E)–selective
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product 5b and 5c in good yields. It was interesting to note that the electron-deficient
heteroaromatic alkyne 2u also gave the corresponding product 5d in 1 h. Furthermore, we
examine the reactivity of aliphatic alkyne that is ethyl propiolate 2v with 1a. To our delight, the
E–stereoselective product 5e was obtained in 65% yield. The aza–carbazole 1h reacted
smoothly with alkyne 2r to provide the E–isomer 5f in moderate yield. Similarly, carbazole like
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
, 3, 4, 9-tetrahydro-1H-carbazole 1j reacted with alkyne 2r and 2v to give thermodynamically
stable (E)-addition product 5g–h in 62-70% yields, respectively. Other analogs like gamma–
carboline 1i provided the trans hydroaminated product 5i and 2, 3, 4, 5-tetrahydro-1H-pyrido
[
4, 3-b]indole 1k provided the bis-styrylated product 5j in good yield. The above results
indicated that the electron-withdrawing and electron-releasing group of alkynes plays an
important role in controlling the regio- and stereoselectivity of the product.
a
Scheme 3. Synthesis of Functionalized (E)–9-Styryl-9H-carbazoles analogs
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
a
The reactions were performed using N–heterocycles 1 (0.5 mmol), 0.5 mmol of alkynes 2, 0.5
o
equiv of KOH in 2.0 mL of DMSO at 120 C for 0.5 h. 0.25 h. 1 h.
b
c
Encourage from the above nucleophilic addition of carbazoles, aza-carbazoles and gamma
carbolines onto the aromatic terminal and internal alkynes, we intended to explore the reaction
over aliphatic alkynes (Table 3). We synthesized a library of compounds 6a–f in good yields.
The reaction of ethynyltrimethylsilane 2aa and carbazole 1a using 0.5 equiv of KOH in DMSO
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
o
at 120 C for 2 h, provided the addition product 6a in 62% yield with the elimination of –TMS
group (entry 1). Carbazole 1a reacts smoothly with phenyl propargyl ether 2ba to gave the
desired product 6b in 65% yield (entry 2). Interestingly, when 1-ethynylcyclohex-1-ene 2ca was
subjected towards the hydroamination reactions, the desired product was obtained in 64% yield
(entry 3). Ethynylcyclopropane 2da was found to be effective with substrate 1d to afford the
corresponding product 6d in 60% yield (entry 4). Aza–carbazole 1h and gamma carboline 1i
reacted incredibly with aliphatic alkynes. The reaction of 1-but-3-yn-1-ylbenzene 2ea with 1h
afforded the hydroaminated product 6e in 72% yield (entry 5). Addition of gamma–carboline 1i
onto methyl propargyl ether 2fa provided the desired product 6f in 65% yield (entry 6).
a
Table 3. Scope of Aliphatic Alkynes
entry
1
carbazoles
alkyne 2
product 6
yield (%)
62
2aa
6a
1
a
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b
2
3
4
1a
1g
2ba
2ca
65
64
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
6c
1d
1h
1i
2da
2ea
2fa
6d
6e
6f
60
72
65
b
5
6
a
The reactions were performed using N–heterocycles 1 (0.5 mmol), 0.5 mmol of alkynes 2,
o
.5 equiv of KOH in 2.0 mL of DMSO at 120 C for 2 h. 12 h.
b
0
In order to support the proposed mechanistic pathways several isotopic labelling
experiments were conducted (Scheme 4, i-iii). The varieties of deuterated compounds 7a–d
were synthesized in good yields using KOH/DMSO–d catalytic system (Scheme 4, i). The
6
incorporation of deuterium at styryl position in compounds 7a–b and 7d reveal that the
incoming protons were provided by the solvent. However, in the case of compound 7c, the
70% H-D exchange occurred at C-6 and C-8 positions of the core moiety along with the styryl
deuteration. This might be due to the high electron-density of the indole ring of gamma
25
carboline 1i as compared to carbazole 1a and aza-carbazole 1h (Figure 3 see ESI). Based on
the above evidence, the reaction pathway was proposed for the synthesis of N-styrylated
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1
1
1
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1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
carbazole analogs (Scheme 4, ii). The reaction was initiated by the in situ formation of
2
deuterated alkyne 2a–d from phenylacetylene by KOH/DOH which was present in the
7
1
2
solution due to the scrambling of DMSO–d in KOH. Simultaneously, the anion of carbazole
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
derivatives A was formed by abstraction the proton in super basic system. The attack of species
A on alkyne 2a–d in anti-markonikov fashion generate the species B which on subsequent
1
deuteration forms the desired compound 7a–d.
Scheme 4. Mechanistic Investigation
(
i).Deuteratium Labelling
D
Y
R
2
R
Y
R
2
KOH/DMSO-d6
KOH/DMSO-d6
N
X
N
120 oC, 15 min
EWG
X
120 oC, 0.5 h
ERG
D
N
H
R
X
D
1
D
a-c
7
7
d
D
0%
7
8
8%
NMe
D
N
N
N
D
N
CF3
N
7
0% D
88%
D
D
D
8
8%
77%
88%
D
88%
D
6%
D
7
8
8%
7c, 72%
7
d, 65%
7
a, 72%
7b, 75%
(
ii). Scrambling of DMSO and Mechanistic Pathway
O
S
O
S
O
S
O
S
O
S
OH
HOH
OH
D
D
D
H
HOH
OH
D
H
D
H
D
D
D
D
D
D
OH
D
D
D
DOH
H
DOH
D
D
D
D
D
D
D
D
D
D
KOH
HOH
C K
Ph
DOH
D
Ph
Y
Y
Ph
DOH KOH
2a-d1
2
a
X
D
Y
X
N
Y
N
KOH
X
D
X
N
N
D
H
K
A
K
B
1a
7
(iii). (E) and (Z) selectivity of the substrate
Y
Y
Y
Y
Y
Y
ERG
ERG
R
EWG
EWG
EWG
N
N
N
N
N
X
N
X
X
X
X
X
D
C
3
E
F
7
Negative Charge Destabilised
No rotation across C-C single bond
Negative Charge Stabilised
Free rotation across C-C single bond
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While investigating the substrate scope of the reaction, we found that the electronic effect of
the alkynes influences the stereoselectivity of the product. This anomaly has been governed by
the electron-donating and electron-withdrawing nature of the alkyne. After observing the
substrate controlled behavior, we proposed the possible reason for their reactivity (Scheme 4,
iii). In the case of electron-rich alkynes, the flow of electron was not feasible probably due to
the electronic effect of the phenyl ring. Therefore, the benzyl anion species D was not formed.
While in the case of electron-deficient alkynes the benzyl anion species F was stabilized by the
electron-withdrawing group. Now, the species F is free to rotate across C-C single bond and
formed the desired (E)–addition product. However, the rotation was not possible in case of
species C probably due to the instability of benzylic anion.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Bis-carbazolyl analogues bridged by phenyl, biphenyl and pyrenes as linker A are
2
widely used as electroluminescent devices and the compound B act as an antibacterial
8
2
agent which effectively inhibit the growth of S. aureus. We further explore the possibility of
9
22
the reaction with dialkynes (Scheme 5). Inspired by the Marciniec et.al
protocol we
endeavor to synthesized mono and di–styrylated carbazolyl compounds 8a–d in a single step
o
under metal-free environment by using KOH/DMSO at 120 C for 0.5 h. An interesting
observation was found when ether-linkage dialkyne 2w was reacted with carbazole 1b, the
mono hydroaminated product 8a was obtained in 70% yield. Aza–carbazole 1h reacted
o
smoothly with alkyne 2x at 120 C, for 6 h to provide the mono hydroaminated product 8b in
62% yield. The reaction of 1,4-diethynylbenzene 2y in the presence of 1a using KOH (0.5
o
equiv) at 120 C, for 0.5 h provided the (E)-9-(4-Ethynylstyryl)-9H-carbazole 8c in 65%
o
yield, however; when the reaction was carried out using KOH (1.2 equiv) at 120 C, for 0.5 h,
the desired product 8d was obtained in 60% yield (Scheme 5).
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9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
_
Scheme 5. Synthesis of Mono and Bis hydroaminated heterocycles
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Regio– and stereoselective hydroamination of carbazoles provided the products 3j which
30a-b
30b-c
30d-e
was further diversified by the palladium-catalyzed Sonogashira,
Heck
and Suzuki
coupling reactions (Scheme 6). The synthesized carbazole 3j was subjected towards the Heck
coupling reactions using 1-chloro-4-vinylbenzene 10 and Suzuki cross-coupling in the presence
of phenyl boronic acid 11 the coupling products 9a–b was obtained in 60 and 68% yields,
respectively. The C-C coupling of 3j with alkyne 2z gave a mixture of mono– 9d and di–
sonogashira 9c coupled product. Further, the mono-sonogashira coupled product 9d was
converted into di-sonogashira product 9e using alkyne 2n as a coupling partner. The
3
hydrogenation of 3a using 10 mol % of Pd/C in EtOAc:MeOH (4:1) leads to the formation of
0f
reduced product 9-phenethyl-9H-carbazole 9f in 60% yield.
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Scheme 6. Synthetic Elaboration
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(A) Heck Coupling: The reactions were performed using 3j (1.0 equiv), 1-chloro-4-vinylbenzene
o
1
0 (10 equiv), PdCl /PPh (10/30 mol%) Et N (10 equiv) in DMF at 100 C for 24 h. (B) Suzuki
2 3 , 3
Coupling: Compound 3j (1.0 equiv), phenylboronic acid 11 (2.2 equiv), PdCl /PPh (10/20
2
3
o
mol%) K CO (6 equiv) in Dioxane:Water (1:1) at 100 C for 2 h. (C) Sonogashira Coupling:
,
2
3
Compound 3j (1equiv), 1-ethynyl-4-methoxybenzene 2z (2.0 equiv), PdCl /PPh (10/20 mol%)
,
2
3
o
Et N (3 equiv) in acetonitrile at 70 C for 4 h. (C’) Compound 3j (1equiv), 1-ethyl-4-
3
o
ethynylbenzene 2n (1.0 equiv), PdCl /PPh (5/10 mol%) Et N (1.5 equiv) in acetonitrile at 70 C
2
3
,
3
for 2 h. (D) Compound 3a with Pd/C (10 mol%), EtOAc:MeOH (4:1).
CONCLUSIONS
In conclusion, we reported the regio- and stereoselective hydroamination reaction of
carbazoles, aza–carbazoles and γ–carbolines with electron-neutral, electron-rich and electron-
deficient alkynes to yield a variety of (Z) and (E) styryl carbazoles derivatives. The protocol was
driven through the electronic nature of the alkyne, electron–donating alkyne provided (Z)–
stereoselective product and electron-withdrawing alkyne provided (E)–stereoselective products.
The superbasic system of KOH/DMSO shows commendable results in case of aliphatic alkynes
with tricyclic heterocycles. The reaction of 1,3 and 1,4 dialkynes with carbazoles provided a
feasible route for the construction of mono– and bis– styrylated carbazoles. Synthesized
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1
1
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1
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1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
carbazoles were further synthetically elaborated by palladium–catalyzed cross coupling reaction
and reduction reaction which increases the efficacy of the synthesized products. The deuterium-
labeling experiments support the proposed mechanistic pathway.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
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EXPERIMENTAL SECTION
General Information and Method. All the reactions were performed in an oven˗dried
Schlenk flask under an argon atmosphere. Column chromatography was performed using silica
gel (mesh 100˗200). TLC analysis was performed on commercially prepared 60 F254 silica gel
plates. Visualization of spots on TLC plate was accomplished with UV light (254 nm) and
1 13
staining over I chamber. H NMR (400 MHz) and C NMR (100 MHz) spectra were recorded
2
in CDCl and (CD ) SO. Chemical shifts for carbons are reported in ppm from tetramethylsilane
3 3 2
and are referenced to the carbon resonance of the solvent. Data are reported as follows: chemical
shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, dd = doublet of
doublet, br s = broad singlet), coupling constants in Hertz, and integration. High−resolution mass
spectra were recorded with q−TOF electrospray mass spectrometer. All purchased chemicals
were used as received. All melting points are uncorrected.
General Procedure for the Synthesis of N-Styryl Cabazoles (3a–l and 3m–r) with Aromatic
Terminal and Internal Alkynes: In an oven dried pressure tube, to a solution of carbazole 1a–f
(0.5 mmol) in 2.0 mL of DMSO, finely crushed KOH (0.5 equiv, 14 mg, 0.25 mmol) and alkynes
2
a–h (1.0 mmol), was added then, the resulting reaction mixture was heated at 120 °C for 0.5 h
for the synthesis of products 3a-l. Similarly for the synthesis of compounds 3m-r we initiated the
reaction with carbazole 1a–b and 1g (0.5 mmol) in 2.0 mL of DMSO, finely crushed KOH (1.5
equiv, 42 mg, 0.75 mmol) and alkynes 2i–m (1.0 mmol), was added then, the resulting reaction
mixtures was heated at 120 °C for 24 h. Progression of the reaction was monitored by TLC,
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while noticing complete consumption of alkynes, reaction was brought to room temperature. The
reaction mixture was diluted with ethyl acetate (10 mL) and water (15 mL). Organic layer was
concentrated under reduced pressure. The crude material so obtained was purified by column
chromatography on silica gel mesh size 100–200 (hexane).
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(Z)-9-Styryl-9H-carbazole (3a). The product was obtained as a yellow solid (99.5 mg, 74%
1
yield), mp: 90–92 °C, H NMR (400 MHz, CDCl ) δ 8.01 (d, J = 7.6 Hz, 2H), 7.26 (t, J = 8.3
3
Hz, 3H), 7.19–7.12 (m, 4H), 7.03–7.01 (m, 2H), 6.94–6.91 (m, 2H), 6.74 (d, J = 9.1 Hz, 1H),
1
3
1
6.57 (d, J = 9.1 Hz, 1H); C{ H}NMR (100 MHz, CDCl ) δ 139.4, 131.7, 131.3, 128.7, 127.1,
3
_
25.9, 125.6, 125.2, 123.9, 121.2, 120.1, 111.1; HRMS (ESI TOF) m/z: (M+H) Calcd for
+
1
C H N 270.1283; found 270.1263.
16
20
(Z)-9-(4-Butylstyryl)-9H-carbazole (3b). The product was obtained as a yellow needles (113.7
1
mg, 70% yield), mp: 89–91 °C, H NMR (400 MHz, CDCl ) δ 8.14 (d, J = 7.6 Hz, 2H), 7.39 (t,
3
J = 7.6 Hz, 2H), 7.30 (t, J = 11.4 Hz, 2H), 7.25 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 7.6 Hz, 2H), 6.94
(d, J = 7.6 Hz, 2H), 6.87 (d, J = 9.1 Hz, 1H), 6.67 (d, J = 9.1 Hz, 1H), 2.51 (t, J = 7.3 Hz, 2H),
1
1.56–1.50 (m, 2H), 1.34–1.27 (m, 2H), 0.91 (t, J = 6.8 Hz, 3H); C{ H}NMR (100 MHz,
3
1
CDCl ) δ 142.8, 139.3, 132.0, 128.7, 128.3, 126.7, 125.8, 123.9, 121.1, 120.11, 120.06, 111.1,
3
_
+
3
5.3, 33.2, 22.2, 13.9; HRMS (ESI TOF) m/z: (M+H) Calcd for C H N 326.1909; found
24 24
326.1900.
(Z)-9-(3-Methoxystyryl)-9H-carbazole (3c). The product was obtained as a fluorescent yellow oil
1
(
104.6 mg, 70% yield), H NMR (400 MHz, CDCl ) δ 8.10 (d, J = 7.6 Hz, 2H), 7.40–7.35 (m,
3
2
1
3
H), 7.28 (t, J = 7.6 Hz, 2H), 7.22 (d, J = 8.3 Hz, 2H), 7.07–7.03 (m, 1H), 6.95 (d, J = 10.6 Hz,
H), 6.74 (d, J = 7.6 Hz, 1H), 6.70–6.65 (m, 1H), 6.66 (d, J = 8.3 Hz, 1H), 6.54 (s, 1H), 3.32 (s,
13
1
H); C{ H}NMR (100 MHz, CDCl ) δ 159.2, 139.1, 135.8, 129.1, 126.2, 125.9, 123.8, 122.0,
3
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21.6, 120.2, 120.1, 114.4, 113.3, 111.1, 54.7; HRMS (ESI TOF) m/z: (M+H) Calcd for
+
1
C H NO 300.1388; found 300.1388.
18
21
(Z)-3-(2-(9H-Carbazol-9-yl)vinyl)aniline (3d). The product was obtained as a brown needles
1
0
1
2
3
4
5
6
7
8
9
0
1
2
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6
7
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(
96.5 mg, 68% yield), mp: 130–132 °C, H NMR (400 MHz, CDCl ) δ 8.08 (d, J = 6.8 Hz, 2H),
3
7
.38–7.34 (m, 3H), 7.27 (s, 1H), 7.23–7.20 (m, 3H), 6.91–6.86 (m, 3H), 6.57 (d, J = 8.3 Hz, 1H),
1
.51 (d, J = 7.6 Hz, 1H), 6.46 (d, J = 6.8 Hz, 1H), 6.40 (br s, 1H); C{ H}NMR (100 MHz,
3
1
6
CDCl ) δ 146.1, 139.3, 135.7, 129.1, 126.4, 125.9, 123.9, 121.8, 120.2, 120.0, 119.5, 115.2,
3
_
+
1
14.8, 111.2; HRMS (ESI TOF) m/z: (M+H) Calcd for C H N 285.1392; found 285.1405.
20 17 2
(Z)-4-(2-(9H-Carbazol-9-yl)vinyl)-N,N-dimethylaniline (3e). The product was obtained as a
1
brown needles (107.6 mg, 69% yield), mp: 85–87 °C, H NMR (400 MHz, CDCl ) δ 8.10 (d, J =
3
7
.6 Hz, 2H), 7.38–7.34 (m, 2H), 7.28–7.23 (m, 4H), 6.93 (d, J = 8.3 Hz, 2H), 6.66 –6.58 (m,
1
3
1
2
H), 6.40 (d, J = 9.1 Hz, 2H), 2.84 (s, 6H); C{ H}NMR (100 MHz, CDCl ) δ 150.1, 139.6,
3
_
132.3, 130.1, 127.9, 125.8, 123.7, 120.0, 119.8, 117.9, 111.7, 111.1, 40.1; HRMS (ESI TOF)
+
m/z: (M+H) Calcd for C H N 313.1705; found 313.1725.
2
2
21
2
(Z)-9-(2-(Thiophen-3-yl)vinyl)-9H-carbazole (3f). The product was obtained as a off white
1
needles (89.3 mg, 65% yield), mp: 128–130 °C, H NMR (400 MHz, CDCl ) δ 8.08 (d, J = 7.6
3
Hz, 2H), 7.37–7.33 (m, 2H), 7.28–7.20 (m, 4H), 6.99 (s, 1H), 6.97–6.94 (m, 1H), 6.78–6.73 (m,
13
1
2
1
H), 6.58–6.56 (m, 1H); C{ H}NMR (100 MHz, CDCl ) δ 139.5, 135.5, 127.8, 125.9, 125.8,
3
_
25.6, 125.2, 123.8, 122.3, 120.7, 120.2, 110.9; HRMS (ESI TOF) m/z: (M+H) Calcd for
+
C H NS 276.0847; found 276.0843.
14
18
9
-(3-Methoxystyryl)-9H-carbazol-2-ol (3g). The product was obtained as a brown needles (110.2
1
mg, 70% yield), mp: 126–128 °C, H NMR (400 MHz, CDCl ) (stereoisomers E:Z :: 60:40) δ
3
7.96 (d, J = 7.6 Hz, 2.01 H), 7.90–7.87 (m, 2 H), 7.64 (d, J = 7.6 Hz, 0.78 H), 7.58 (d, J = 14.5
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Hz, 1.0 H major regioisomer), 7.41 (t, J = 7.6 Hz, 0.86 H), 7.32–7.27 (m, 2.99 H), 7.25–7.22 (m,
1
.6 H), 7.16–7.14 (m, 2.05 H), 7.09–7.05 (m, 1.2 H), 7.03–7.01 (m, 2.04 H), 6.95 (d, J = 14.5 Hz,
1.0 H), 6.87–6.84 (m, 0.8 H), 6.83–6.76 (m, 3.24 H), 6.72–6.68 (m, 2.37 H), 6.629–6.623 (m,
1
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1
.08 H), 6.56 (d, J = 9.1 Hz, 1.3H minor regioisomer), 6.54–6.53 (m, 1.53 H), 5.85 (br s, 1.66 H),
13
.86 (s, 2.4 H), 3.33 (s, 3.04 H); C{ H}NMR (100 MHz, CDCl ) (stereoisomers E:Z :: 60:40)
1
3
3
δ 159.8, 159.1, 155.1, 154.8, 140.8, 140.5, 139.6, 139.2, 137.6, 135.8, 129.8, 129.2, 126.3, 125.0,
1
1
24.6, 124.2, 123.9, 123.4, 121.9, 121.7, 121.1, 121.0, 120.8, 120.3, 119.3, 119.2, 118.4, 117.9,
17.6, 114.3, 113.7, 112.6, 111.3, 110.9, 110.3, 109.6, 109.2, 97.6, 97.3, 55.3, 54.7; HRMS
_
ESI TOF) m/z: (M+H) Calcd for C H NO 316.1338; found 316.1341.
+
(
21 18 2
(Z)-2-Methoxy-9-styryl-9H-carbazole (3h). The product was obtained as a brown semi–solid
1
(
107.6 mg, 72% yield), H NMR (400 MHz, CDCl ) δ 7.91–7.88 (m, 1H), 7.84 (d, J = 8.3 Hz,
3
1
H), 7.33 (t, J = 7.6 Hz, 1H), 7.17–7.15 (m, 1H), 7.13–7.11 (m, 1H), 7.04–7.00 (m, 5H), 6.84–
6.82 (m, 1H), 6.76 (dd, J = 8.7 and 1.5 Hz, 1H), 6.56 (d, J = 9.1 Hz, 1H), 6.48–6.47 (m, 1H),
1
3
1
3
1
.65 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ 158.9, 140.3, 139.4, 135.0, 128.9, 128.7, 128.3,
3
27.8, 125.9, 125.7, 124.6, 122.1, 120.7, 120.4, 119.2, 110.7, 109.3, 95.4, 55.4; HRMS
_
ESI TOF) m/z: (M+H) Calcd for C H NO 300.1388; found 300.1388.
+
(
(
(
21 18
Z)-3,6-Dibromo-9-styryl-9H-carbazole (3i). The product was obtained as a light yellow needles
1
146.2 mg, 69% yield), mp: 154–156°C, H NMR (400 MHz, CDCl ) δ 8.20–8.17 (m, 2H),
3
7
.67–7.58 (m, 1H), 7.53–7.50 (m, 2H), 7.24–7.17 (m, 2H), 7.13 (d, J = 9.9 Hz, 2H), 7.08–7.06
1
3
1
(m, 2H), 6.90 (d, J = 8.3 Hz, 1H), 6.79 (d, J = 8.3 Hz, 1H); C{ H}NMR (100 MHz, CDCl ) δ
3
1
38.0, 134.1, 129.2, 128.5, 128.4, 128.2, 127.6, 124.3, 123.0, 120.8, 113.4, 112.5; HRMS
_
ESI TOF) m/z: (M+H) Calcd for C H Br N 425.9493; found 425.9493.
+
(
20 14 2
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(
Z)-3,6-Dibromo-9-(4-methylstyryl)-9H-carbazole (3j). The product was obtained as a white
1
needles (155.4 mg, 71% yield), mp: 161–163 °C, H NMR (400 MHz, CDCl ) δ 8.108–8.104
3
(m, 2H), 7.42 (dd, J = 10.6 and 2.2 Hz, 2H), 7.04 (d, J = 8.3 Hz, 2H), 6.90–6.83 (m, 4H), 6.73 (d,
1
3
1
0
1
2
3
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9
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1
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3
4
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6
7
8
9
0
J = 8.3 Hz, 1H), 6.65 (d, J = 9.1 Hz, 1H), 2.21 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ
3
1
38.3, 138.1, 131.2, 129.3, 129.2, 128.6, 128.1, 124.3, 123.1, 120.0, 113.4, 112.6, 21.2; HRMS
_
+
ESI TOF) m/z: (M+H) Calcd for C H Br N 439.9649; found 439.9641.
(
21 16 2
(Z)-9-(4-(tert-Butyl)styryl)-9H-carbazole-3-carbonitrile (3k). The product was obtained as a
1
yellow oil (119.0 mg, 68% yield), H NMR (400 MHz, CDCl ) δ 8.39 (s, 1H), 8.12 (d, J = 7.6
3
Hz, 1H), 7.55 (dd, J = 8.3 and 1.5 Hz, 1H), 7.49–7.47 (m, 1H), 7.45–7.41 (m, 2H), 7.20 (d, J =
9.1 Hz, 1H), 7.11 (d, J = 8.3 Hz, 2H), 6.91 (d, J = 8.3 Hz, 2H), 6.83–6.76 (m, 2H), 1.19 (s, 9H);
13
1
C{ H}NMR (100 MHz, CDCl ) δ 151.8, 140.9, 140.2, 130.9, 130.0, 129.3, 129.1, 128.5, 127.4,
3
1
25.9, 125.5, 125.0, 122.6, 121.4, 120.6, 119.8, 111.7, 111.3, 102.9, 34.6, 31.0; HRMS
_
(ESI TOF) m/z: (M+H) Calcd for C H N 351.1861; found 351.1856.
+
2
5
23
2
(Z)-9-(2-(Thiophen-3-yl)vinyl)-9H-carbazole-3,6-dicarbonitrile (3l). The product was obtained
1
as a brown needles (105.6 mg, 65% yield), mp: 158–160 °C, H NMR (400 MHz, CDCl ) δ
3
7
2
.73–7.72 (m, 1H), 7.62–7.60 (m, 1H), 7.38–7.37 (m, 2H), 7.11–7.10 (m, 1H), 6.96–6.92 (m,
1
H), 6.65 (d, J = 11.4 Hz, 1H), 6.13–6.09 (m, 2H), 5.72 (d, J = 11.4 Hz, 1H); C{ H}NMR (100
3
1
MHz, CDCl ) δ 141.8, 139.2, 133.7, 129.1, 128.8, 127.2, 126.7, 126.6, 125.6, 124.5, 120.9,
3
_
+
1
18.6, 111.5; HRMS (ESI TOF) m/z: (M+H) Calcd for C H N S 326.0752; found 326.0754.
20 12 3
(
Z)-9-(1,2-Diphenylvinyl)-9H-carbazole (3m). The product was obtained as a off white needles
1
(120.7 mg, 70% yield), mp: 149–151 °C, H NMR (400 MHz, CDCl ) δ 8.14–8.12 (m, 2H),
3
7
.34 (s, 1H), 7.33–7.20 (m, 9H), 7.07–7.03 (m, 2H), 7.02–6.96 (m, 3H), 6.86–6.84 (m, 2H);
13
1
C{ H}NMR (100 MHz, CDCl ) δ 139.5, 137.7, 134.7, 133.7, 131.6, 128.74, 128.68, 128.5,
3
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28.4, 128.0, 127.4, 126.0, 125.9, 123.6, 120.2, 119.9, 111.1; HRMS (ESI TOF) m/z: (M+H)
+
1
Calcd for C H N 346.1596; found 346.1604.
20
2
6
(Z)-9-(1-Phenylprop-1-en-2-yl)-9H-carbazole (3n). The product was obtained as a pale yellow
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
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0
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0
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8
9
0
1
2
3
4
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7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
needles (99.0 mg, 70% yield), mp: 120–122 °C, H NMR (400 MHz, CDCl ) δ 8.12 (d, J = 7.6
3
Hz, 2H), 7.52–7.47 (m, 4H), 7.46–7.42 (m, 2H), 7.35 (t, J = 6.8 Hz, 2H), 7.29–7.25 (m, 1H),
1
3
1
7
.25 (s, 2H), 6.87 (s, 1H), 2.39 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ 140.2, 135.7, 133.3,
3
_
31.6, 130.6, 129.0, 128.5, 127.5, 125.8, 123.2, 120.3, 119.5, 109.9, 17.5; HRMS (ESI TOF)
1
+
m/z: (M+H) Calcd for C H N 284.1439; found 284.1415.
2
1
18
(
Z)-9-(2-(2-Bromophenyl)-1-(4-methoxyphenyl)vinyl)-9H-carbazole (3o). The product was
1
obtained as a white needles (154.0 mg, 68% yield), mp: 180–182 °C, H NMR (400 MHz,
CDCl ) δ 8.06 (d, J = 7.6 Hz, 2H), 7.49–7.47 (m, 1H), 7.33–7.32 (m, 1H), 7.27–7.19 (m, 6H),
3
7
.06 (d, J = 8.3 Hz, 2H), 6.83–6.79 (m, 3H), 6.61–6.57 (m, 1H), 6.46 (d, J = 10.6 Hz, 1H), 3.79
1
3
1
(s, 3H); C{ H}NMR (100 MHz, CDCl ) δ 160.4, 139.9, 135.5, 132.4, 129.6, 128.8, 128.3,
3
_
27.8, 127.1, 125.9, 124.3, 124.0, 123.5, 120.0, 119.9, 114.2, 111.1, 55.3; HRMS (ESI TOF)
1
+
m/z: (M+H) Calcd for C H BrNO 454.0807; found 454.0807.
2
7
21
(Z)-9-(2-(4-Nitrophenyl)-1-(thiophen-3-yl)vinyl)-9H-carbazole (3p). The product was obtained
1
as a straw yellow needles (132.6 mg, 67% yield), mp: 126–128 °C, H NMR (400 MHz, CDCl )
3
δ 8.16–8.14 (m, 2H), 7.83–7.81 (m, 2H), 7.34 (s, 1H), 7.33–7.31 (m, 1H), 7.29–7.26 (m, 4H),
1
.22–7.20 (m, 1H), 7.08–7.06 (m, 2H), 6.93 (s, 1H), 6.91–6.90 (m, 2H); C{ H}NMR (100
3
1
7
MHz, CDCl ) δ 146.3, 141.0, 139.03, 138.98, 133.3, 128.8, 127.1, 126.2, 125.2, 124.8, 123.70,
3
_
+
1
23.66, 123.5, 120.5, 120.4, 110.7; HRMS (ESI TOF) m/z: (M+H) Calcd for C H N O S
24 17 2 2
3
97.1011; found 397.1004.
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(
Z)-9-(1,2-Diphenylvinyl)-9H-carbazol-2-ol (3q). The product was obtained as a yellow needles
1
(111.9 mg, 62% yield), mp: 135–138 °C, H NMR (400 MHz, CDCl ) δ 7.95–7.93 (m, 1H), 7.88
3
(d, J = 8.3 Hz, 1H), 7.26 (s, 1H), 7.21–7.18 (m, 2H), 7.15–7.14 (m, 3H), 7.14–7.11 (m, 3H),
0
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8
9
0
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7
8
9
0
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7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
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7
8
9
0
6
1
1
.98–6.91 (m, 3H), 6.82–6.80 (m, 3H), 6.67 (dd, J = 10.8 and 2.2 Hz, 1H), 6.42 (d, J = 2.2 Hz,
13
1
H); C{ H}NMR (100 MHz, CDCl ) δ 154.7, 141.0, 139.6, 137.5, 134.6, 128.8, 128.7, 128.5,
3
_
28.4, 128.1, 127.5, 125.9, 124.8, 121.1, 120.0, 119.3, 110.8, 109.1, 97.2; HRMS (ESI TOF)
+
m/z: (M+H) Calcd for C H NO 362.1545; found 362.1547.
2
6
20
(Z)-9-(1,2-bis(3-Methoxyphenyl)vinyl)-3-bromo-9H-carbazole (3r). The product was obtained as
1
a orange needles (156.9 mg, 65% yield), mp: 142–143 °C, H NMR (400 MHz, CDCl ) δ 8.148–
3
8
6
6
=
.146 (m, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.26–7.25 (m, 1H), 7.20 (d, J = 8.3 Hz, 1H), 7.16 (d, J =
.8 Hz, 2H), 7.10 (t, J = 7.6 Hz, 1H ), 7.01 (d, J = 8.3 Hz, 1H), 6.89 (d, J = 8.3 Hz, 2H), 6.79–
.76 (m, 1H), 6.73 (s, 1H), 6.70 (d, J = 8.3 Hz, 1H), 6.52 (dd, J = 8.3 and 1.5 Hz, 1H), 6.47 (d, J
13
1
7.6 Hz, 1H), 6.08 (s, 1H), 3.63 (s, 3H), 3.10 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ 160.0,
3
1
59.3, 139.9, 138.9, 138.2, 135.5, 133.2, 129.9, 129.3, 128.7, 127.8, 126.8, 125.2, 122.9, 122.4,
121.7, 120.4, 120.3, 118.4, 115.2, 114.0, 112.9, 112.4, 112.1, 111.7, 111.2, 55.2, 54.5; HRMS
_
ESI TOF) m/z: (M+H) Calcd for C H BrNO 484.0912; found 484.0912.
+
(
28 23 2
General Procedure for the Synthesis of N−Styryl Aza-cabazoles (4a–e) and N−Styryl γ–
Carbolines with Aromatic Alkynes (4f–l): In an oven dried pressure tube, to a solution of aza-
cabazole 1i (0.5 mmol) in 2.0 mL of DMSO, finely crushed KOH (0.5 equiv, 14mg, 0.25 mmol)
and alkynes 2 (0.5 mmol) were added then, the resulting reaction mixture was heated at 120 °C
for 4 h for the synthesis of products 4a–e. Similarly, for the synthesis of compounds 4f–l we
initiated the reaction with γ–carboline 1j (0.5 mmol) in 2.0 mL of DMSO, finely crushed KOH
(0.5 equiv, 14mg, 0.25 mmol) and alkynes 2 (0.5 mmol), the resulting reaction mixtures was
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heated at 120 °C for 2 h. Progression of the reaction was monitored by TLC, while noticing
complete consumption of alkynes, reaction was brought to room temperature. The reaction
mixture was diluted with ethyl acetate (10 mL) and water (15 mL). Organic layer was
concentrated under reduced pressure. The crude material so obtained was purified by column
chromatography on silica gel mesh size 100–200 (hexane).
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(Z)-9-Styryl-9H-pyrido[2,3-b]indole (4a). The product was obtained as a light brown needles
1
(105.3 mg, 78% yield), mp: 132–134 °C, H NMR (400 MHz, CDCl ) δ 8.50–8.49 (m, 1H), 8.33
3
(d, J = 7.6 Hz, 1H), 8.05 (d, J = 6.8 Hz, 1H), 7.29–7.22 (m, 3H), 7.15 (d, J = 9.1 Hz, 1H), 7.10–
13
.04 (m, 5H), 6.99 (d, J = 8.3 Hz, 1H), 6.76 (d, J = 9.1 Hz, 1H); C{ H}NMR (100 MHz,
1
7
CDCl ) δ 151.6, 146.4, 137.5, 134.9, 128.7, 128.19, 128.15, 127.8, 126.8, 126.7, 121.4, 121.0,
3
_
+
1
20.7, 116.9, 116.3, 112.2; HRMS (ESI TOF) m/z: (M+H) Calcd for C H N 271.1235; found
19 15 2
2
71.1207.
(Z)-9-(4-Ethylstyryl)-9H-pyrido[2,3-b]indole (4b). The product was obtained as a brown needles
1
(111.7 mg, 75% yield), mp: 120–122 °C, H NMR (400 MHz, CDCl ) δ 8.42 (dd, J = 5.3 and 1.5
3
Hz, 1H), 8.26 (dd, J = 7.6 and 1.5 Hz, 1H), 7.98 (d, J = 7.6 Hz, 1H), 7.55–7.52 (m, 1H), 7.17–
7
.14 (m, 2H), 7.00 (d, J = 9.1 Hz, 1H), 6.96 (d, J = 8.3 Hz, 1H), 6.90–6.82 (m, 4H), 6.67 (d, J =
1
.1 Hz, 1H), 2.43 (q, J = 7.6 Hz, 2H), 1.04 (t, J = 7.6 Hz, 3H); C{ H}NMR (100 MHz, CDCl )
3
1
9
3
δ 151.6, 146.4, 144.0, 137.7, 132.1, 130.1, 128.8, 127.7, 127.3, 126.7, 125.9, 121.4, 120.7, 120.1,
_
+
1
16.8, 116.2, 112.3, 28.5, 15.2; HRMS (ESI TOF) m/z: (M+H) Calcd for C H N 299.1548;
21 19 2
found 299.1562.
(Z)-9-(3-Methoxystyryl)-9H-pyrido[2,3-b]indole (4c). The product was obtained as a brown
1
semi–solid (105.0 mg, 70% yield), H NMR (400 MHz, CDCl ) δ 8.43–8.42 (m, 1H), 8.26 (d, J
3
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=
7.6 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 7.24–7.20 (m, 1H), 7.18–7.15 (m, 2H), 7.09 (d, J = 8.3
Hz, 1H), 6.95–6.91 (m, 2H), 6.67 (d, J = 9.1 Hz, 1H), 6.62–6.58 (m, 2H), 6.44 (s, 1H), 3.25 (s,
1
3
1
3H); C{ H}NMR (100 MHz, CDCl ) δ 159.2, 151.6, 146.4, 137.6, 136.0, 129.1, 128.2, 126.8,
3
0
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26.7, 121.6, 121.3, 121.1, 120.8, 120.7, 116.8, 116.3, 114.3, 113.3, 112.3, 54.7; HRMS
_
ESI TOF) m/z: (M+H) Calcd for C H N O 301.1341; found 301.1342.
+
(
20 17 2
(Z)-9-(2-(Thiophen-3-yl)vinyl)-9H-pyrido[2,3-b]indole (4d). The product was obtained as a off–
1
white needles (99.3 mg, 72% yield), mp: 126–128 °C, H NMR (400 MHz, CDCl ) δ 8.42–8.41
3
(m, 1H), 8.27 (dd, J = 7.6 and 1.5 Hz, 1H), 8.00 (d, J = 8.3 Hz, 1H), 7.30–7.27 (m, 1H), 7.22–
7
.20 (m, 1H), 7.18–7.14 (m, 2H), 7.06 (d, J = 8.3 Hz, 1H), 6.93–6.89 (m, 2H), 6.79 (d, J = 8.3
13
1
Hz, 1H), 6.48–6.46 (m, 1H); C{ H}NMR (100 MHz, CDCl ) δ 151.7, 146.5, 138.1, 135.5,
3
1
28.2, 127.7, 126.8, 125.7, 125.1, 122.9, 121.3, 120.83, 120.78, 119.7, 116.7, 116.2, 111.9;
_
HRMS (ESI TOF) m/z: (M+H) Calcd for C H N S 277.0799; found 277.0800.
+
1
7
13
2
(Z)-9-(1,2-Diphenylvinyl)-9H-pyrido[2,3-b]indole (4e). The product was obtained as a light
1
yellow needles (121.0 mg, 70% yield), mp: 145–147 °C, H NMR (400 MHz, CDCl ) δ 8.31–
3
8
1
.28 (m, 2H), 8.05 (d, J = 6.8 Hz, 1H), 7.44 (s, 1H), 7.26 (t, J = 8.3 Hz, 1H), 7.21 (d, J = 7.6 Hz,
H), 7.18–7.16 (m, 5H), 7.10–7.07 (m, 2H), 6.94–6.87 (m, 3H), 6.80–6.79 (m, 2H);
1
3
1
C{ H}NMR (100 MHz, CDCl ) δ 151.4, 146.9, 138.9, 137.6, 134.8, 132.6, 128.7, 128.5, 128.4,
3
_
28.30, 128.25, 127.9, 127.1, 125.6, 121.0, 120.9, 120.7, 116.5, 115.9, 111.2; HRMS (ESI TOF)
1
+
m/z: (M+H) Calcd for C H N 347.1548; found 347.1520.
2
5
19
2
(Z)-2-Methyl-5-styryl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4f). The product was obtained
1
as a brown needles (108.0 mg, 75% yield), mp: 140–142 °C, H NMR (400 MHz, CDCl ) δ
3
7
.45–7.41 (m, 1H), 7.37 (t, J = 7.3 Hz, 1H), 7.26–7.24 (m, 1H), 7.15–7.12 (m, 2H), 7.11–7.09 (m,
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H), 7.00–6.98 (m, 2H), 6.73 (d, J = 9.1 Hz, 1H), 6.52 (d, J = 8.7 Hz, 1H), 3.73–3.72 (m, 2H),
1
3
1
2
.73–2.70 (m, 2H), 2.60–2.57 (m, 2H), 2.53 (s, 3H); C{ H}NMR (100 MHz, CDCl ) δ 136.3,
3
135.6, 134.7, 133.0, 128.8, 128.5, 128.4, 127.9, 127.0, 125.7, 122.3, 119.9, 117.4, 110.8, 52.4,
_
+
1
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0
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9
0
5
1.6, 45.5, 23.2; HRMS (EI TOF) m/z: (M) Calcd for C H N 288.1626; found 288.1625.
20 20 2
(Z)-5-(4-(tert-Butyl)styryl)-2-methyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole
(4g).
The
1
product was obtained as a brown semi–solid (120.4 mg, 70% yield), H NMR (400 MHz, CDCl )
3
δ 7.37–7.31 (m, 1H), 7.08–7.05 (m, 3H), 7.04–7.00 (m, 2H), 6.86 (d, J = 8.3 Hz, 2H), 6.57 (d, J
= 8.3 Hz, 1H), 6.43 (d, J = 8.3 Hz, 1H), 3.65 (s, 2H), 2.65–2.63 (m, 2H), 2.55–2.52 (m, 2H), 2.45
1
3
1
(s, 3H), 1.15 (s, 9H); C{ H}NMR (100 MHz, CDCl ) δ 151.1, 135.8, 133.3, 131.6, 128.4,
3
1
27.8, 126.4, 125.4, 121.5, 121.3, 119.8, 117.4, 110.8, 110.7, 52.4, 51.7, 45.6, 34.5, 31.1, 23.2;
_
HRMS (ESI TOF) m/z: (M+H) Calcd for C H N 345.2331; found 345.2351.
+
24 29
2
(Z)-2-Methyl-5-(4-(trifluoromethoxy)styryl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4h). The
1
product was obtained as a yellow semi–solid (133.9 mg, 72% yield), H NMR (400 MHz,
DMSO-d ) δ 7.83–7.81 (m, 1H), 7.77–7.72 (m, 1H), 7.41–7.37 (m, 1H), 7.33 (d, J = 9.1 Hz, 1H),
6
7
2
1
2
.16–7.12 (m, 2H), 7.03–6.99 (m, 3H), 6.67 (d, J = 9.6 Hz, 1H), 3.54 (s, 2H), 2.61–2.58 (m, 2H),
1
3
1
.43 (s, 2H), 2.37 (s, 3H); C{ H}NMR (100 MHz, DMSO-d ) δ 147.3, 134.6, 134.0, 133.1,
6
29.9, 127.3, 126.0, 124.5, 123.5, 121.1, 120.8, 119.8, 117.5, 111.4, 110.5, 51.7, 51.0, 45.1,
_
+
2.8; HRMS (EI TOF) m/z: (M) Calcd for C H F N O 372.1444; found 372.1450.
2
1
19
3
2
(Z)-2-Methyl-5-(2-(thiophen-2-yl)vinyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (4i). The
1
product was obtained as a brown semi–solid (105.8 mg, 72% yield), H NMR (400 MHz, CDCl )
3
δ 7.45–7.43 (m, 1H), 7.13–7.09 (m, 3H), 7.03–7.01 (m, 1H), 6.96–6.95 (m, 1H), 6.64–6.58 (m,
2
H), 6.50–6.49 (m, 1H), 3.73 (s, 2H), 2.76–2.73 (m, 2H), 2.65–2.63 (m, 2H), 2.54 (s, 3H);
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