Regio- and Stereoselective Domino Synthesis of Oxazolo Fused Pyridoindoles and Benzofurooxazolo Pyridines from ortho-Alkynylarylaldehydes

Article abstract of DOI:10.1021/acs.joc.6b02062

An environmentally benign Au(III)-catalyzed regio- and stereoselective domino synthesis of oxazolo fused pyridoindoles 7a-v and benzofurooxazolo pyridines 8a-n by the reaction of o-alkynylaldehydes 4a-t and 5a-k with (S)-phenylglycinol 6a and (R)-phenylglycinol 6b under mild reaction conditions using water as reaction medium is reported. The reaction proceeded via selective C-N bond formation on the more electrophilic alkynyl carbon through 6-endo-dig cyclization. The reaction tolerates a wide variety of functional groups. The developed chemistry has been successfully extended for the synthesis of a diverse class of carbolines and benzofuro[3,2-c]pyridines using corresponding ester hydrochlorides of serine, threonine, and cystine as a nitrogen source.

Full text of DOI:10.1021/acs.joc.6b02062

Subscriber access provided by CORNELL UNIVERSITY LIBRARY
Article
Regio- and Stereoselective Domino Synthesis of Oxazolo fused Pyridoindoles
and Benzofurooxazolo Pyridines from ortho-Alkynylarylaldehydes
Shilpi Pal, Deepak Choudhary, Mohit Jainth, Sonu Kumar, Rakesh K. Tiwari, and Akhilesh K. Verma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02062 • Publication Date (Web): 14 Sep 2016
Downloaded from http://pubs.acs.org on September 14, 2016
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Regio- and Stereoselective Domino Synthesis of Oxazolo
fused Pyridoindoles and Benzofurooxazolo Pyridines from
ortho-Alkynylarylaldehydes
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
†
†
†
†
∥
Shilpi Pal, Deepak Choudhary, Mohit Jainth, Sonu Kumar, Rakesh K. Tiwari, and
†
Akhilesh K. Verma*
†
Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of
Delhi, Delhi, 110007, India
∥Chapman University School of Pharmacy, Harry and Diane Rinker Health Science Campus,
9
401 Jeronimo Road, Irvine, California 92618, United States
averma@acbr.du.ac.in
ꢀ
ꢀ
ABSTRACT: An environmentally benign Au(III)-catalyzed regio- and stereoselective domino
synthesis of oxazolo fused pyridoindoles 7a–v and benzofurooxazolo pyridines 8a–n by the
reaction of o-alkynylaldehydes 4a–t and 5a–k with (S)-phenylglycinol 6a and (R)-
phenylglycinol 6b under mild reaction condition using water as reaction medium is reported.
The reaction proceeded via selective C–N bond formation on the more electrophilic alkynyl
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 55
1
2
3
4
5
6
7
8
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
carbon through 6-endo-dig cyclization. The reaction tolerates a wide variety of functional
groups. The developed chemistry has been successfully extended for the synthesis of diverse
class of γ-carbolines and benzofuro[3,2-c]pyridines using corresponding ester hydrochlorides of
serine, threonine and cystine as a nitrogen source.
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
INTRODUCTION
N-heterocycles and their derivatives are privileged scaffolds for the synthesis of bioactive
molecules as they offer improved solubility, bioavailability and have wide spread applications in
1
2–4
pharmaceutical industry. Domino reactions are very familiar to generate complex structure by
forming many bond and functionality at once without changing the reaction condition. Formation
of C–C and C–N bond through transition-metal-catalysts have been extensively studied and
5
attracts the interest of many organic chemists. An easily accessible synthetic methodologies to
produce analogues of natural product-like compounds under mild reaction conditions are in high
demand. In this context, catalytic cyclization of heteroatom-functionalized alkynes is one of the
fundamental approaches. Among the transition metals, gold has unique properties like
6
7–8
alkynophilicity, soft Lewis acidity which makes it versatile and intriguing catalyst for various
C-C bond forming reactions for the synthesis of heterocycles.
Literature reports revealed that pyridoindoles and benzofuropyridines have vast
9–11
12–14
biological importance
and are also used as pharmaceutically active
compounds.
1
5
16
Pyridoindoles possesses potent anti-BVDV activity, in-vitro cytotoxic activity against
different human cancer cell lines and present in various antitumor agents. γ-Carbolines which are
analogues of pyridoindoles are found in various natural products, and demonstrated as an anti-
1
7
18a-b
18c
alzheimer, (Figure 1, A) antimalarial (Figure 1, B)
and antiplasmodial agent.
Benzofuropyridines and its derivatives are known to involved in the central nervous system
ACS Paragon Plus Environment

Page 3 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
19
activity (Figure 1, C). Similarly, oxazolo fused derivatives are extensively studied for their
antitumor, antimicrobial activities and present in anti-inflammatory drug like Flunoxaprofen
2
0
(
Figure 1, D). Pyridine substituted benzoxazoles and quinoline fused oxazoles have been
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
disclosed as a cryptosporidium parvum inosine 5’-monophosphate dehydrogenase (CpIMPDH)
2
1
inhibitor (Figure 1, E).
ꢀ
Figure 1. Examples of biologically active: Pyridoindoles, Benzofuropyridines and Fused
oxazoles.
2
2
Previously, Robinson and Thornley reported the multistep synthesis of pyridoindoles
from 4-chloropyridine and o-phenylene diamine. Clark et.al synthesized carbolines via
2
3
photocyclization of anilino-pyridines. Later, pyridoindoles were obtained by using Fischer
24
25,26
reaction
,
Graebe Ullmann method
and by using transition-metal-catalyzed coupling
2
7
reactions. In 1999, Sakamoto explained palladium-catalyzed amination and arylation reaction
2
8a
to generate carbolines. ꢀ Larock and co-workers reported the synthesis of β and γ-Carbolines
28b-c
using alkynes substrate by the palladium/copper-catalyzed electrophilic cyclization.
In 2012,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 55
1
2
3
4
5
6
7
8
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
Nagarajan et.al. reported the synthesis pyrido[2,3-b]indoles via Pd-catalyzed amidation followed
2
8d
by cyclization.
Correspondingly, several methods are available in literature for the synthesis of
furopyridines (Scheme 1i). In 2007, Miyazaki designed a template for the synthesis of furo[3,2-
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
8e
c]pyridines from furan-2-carbaldehyde in four steps. Later, Doucet et. al. reported one-pot
methodology for the synthesis of furoquinolines through sequential amination and intramolecular
2
8f
palladium-catalyzed direct arylation. Very recently, our group have noted a silver-catalyzed
tandem strategy for the synthesis benzofuropyridines by the reaction of o-alkynylaldehyde with
5a
tert-butylamine. Despite the numerous findings, development of eco-friendly protocols which
offers low environment impact remains elusive. Thus aqueous reaction which makes aqueous
2
9
suspension, feasible and prominent with high efficiency protocols are challenging. Water as a
solvent fulfill many criteria such as nontoxic, nonflammable, inexpensive, readily availability.
Organic compounds show hydrophobic interaction with water which imparts a significant effect
on rate and selectivity, hence reduce the unwanted side products.
Stereoselective syntheses of heterocyclic cores have emerging significance due to the
difference in biological activity of each isomer. The significant importance of chiral heterocycles
justifies the development of new synthetic methodologies. Literature survey revealed that in the
past ten year a wide range of heterocyclic scaffolds have been synthesized from o-
alkynyldehydes; however, the stereoselective synthesis of heterocycles has not been much
explored. Recently for the first time we have reported the stereoselective synthesis of thiazolo
and oxazolo fused naphthyridines, thienopyridines, isoquinolines and pyrroloquinolines from o-
2
8g-h
alkynyldehydes (Scheme 1ii and iii).
ACS Paragon Plus Environment

Page 5 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Scheme 1. Designed Domino Approach for the Regio- and Stereoselective Synthesis of
Oxazolo fused Pyridoindoles and Benzofurooxazolo Pyridines
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ
In continuation of our ongoing efforts on the domino and tandem synthesis of
4
b,5a-c,30
heterocycles from o-alkynyaldehydes,
we envisioned that the reaction of indolo- and
benzofurano o-alkynyldehydes with chiral (S)-phenylglycinol and (R)-phenylglycinol might offer
an opportunity for the regio- and stereoselective synthesis of oxazolo fused pyridoindoles and
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 55
1
2
3
4
5
6
7
8
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
benzofurooxazolo pyridines under mild reaction condition. This domino synthesis would
minimize the required chemical quantity, unwanted side products and processing time in step
economical. Optically active heterocyclic core moiety having N-atom are used in asymmetric
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
31
32
fusion working as chiral templates or ligands.
RESULTS AND DISCUSSION
Preparation of ortho-Alkynylaldehydes. To probe the viability of the designed domino strategy,
ortho-alkynylaldehydes 4a–t and 5a–k were readily prepared by standard Sonogashira cross-
coupling reaction of commercially available and readily accessible ortho-haloaldehydes 1 and 2
3
3
with terminal alkynes 3a–v (Scheme 2). This coupling procedure has readily accommodated a
large variety of functional groups and provided the coupling products 4a–t and 5a–k in good to
excellent yields.
Scheme 2. Preparation of ortho-Alkynylaldehydes
ACS Paragon Plus Environment

Page 7 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ꢀ
In order to find the optimal reaction condition, we selected (phenylethynyl)N-
methylindole (4a) and (S)-2-phenylglycinol (6a) as a model substrates for the reaction (Table 1).
Various transition-metal-catalysts along with different solvents were examined. Reaction of
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
alkyne 4a (0.5 mmol) with 6a (0.55 mmol) using 5 mol % of AgNO
°C for 12 h; the desired product oxazolo fused pyridoindole 7a was not observed (Table 1, entry
). When reaction was performed using DCE as a solvent at 60 °C for 24 h; product 7a was
3 2 2
in 2.0 mL of CH Cl at 25
1
observed in 5% yield along with γ–carboline 9a in 10% yield (entry 2). Increase in the
temperature from 60 to 80 °C and catalyst loading from 5 to 10 mol %, product 7a was obtained
in 15% and 9a in 20% yield (entry 3). Further increase in the reaction temperature and change the
solvent provided the product 9a in 30% yield; however the yield of the desired product 7a
remained same (entry 4). When reaction was carried out using EtOH as solvent at 80 °C, desired
product 7a was obtained in 25% yield and 9a in 35% yield (entry 5). Interestingly when we
performed the reaction in water, product 7a was formed exclusively in 40% yield without the
formation of product 9a (entry 6). Employing other silver catalysts with different counteranions,
such as AgOAc, AgOTf and AgI resulted in 25–35% yield of the product 7a (entries 7–9).
Transition-metal-catalysts other than silver, such as PdCl
2
, Pd(OAc)
2
and Cu(OTf)
2
provided the
in H
product 7a in 10–20% yield (entries 10–12). Impressive results were obtained with AuCl
3
2
O
at 80 °C for 8 h, afforded 7a in 80% yield as a sole product (entry 13). Reaction time increases by
decreasing the amount of catalyst from 10 to 5 mol % afforded lower yield of 7a (entry14).
Increasing the amount of AuCl
(entry 15). No significant effect in the yield of product 7a was observed by using other gold
catalysts like HAuCl and AuCl (entries 16 and 17). Trace amount of product 7a was obtained
after 24 h by using other lewis acid like AlCl (entry 18). However, in the absence of catalyst, the
3 2
from 10 to 15 mol % in H O afforded the product 7a in 70%
4
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 55
1
2
3
4
5
6
7
8
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
reactant remained almost unchanged even after 30 h (entry 19). After analysis it was observed
that the 10 mol % AuCl
3
in water at 80 °C was efficient reaction condition for the synthesis of
product 7a.
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
Table 1. Optimization of Reaction Conditions
ꢀ
entry catalyst (mol %)
conditions
yield (%)
o
solvent
CH Cl
temp ( C) time (h)
7a
9a
1
2
.
.
AgNO
AgNO
3
3
(5)
(5)
2
2
25
60
80
110
80
80
80
80
80
80
80
80
80
80
12
24
24
24
24
24
24
24
24
24
24
24
8
NR NR
DCE
DCE
DMF
EtOH
5
10
3.
AgNO
AgNO
AgNO
AgNO
3
3
3
3
(10)
(10)
(10)
(10)
15
15
25
40
30
35
25
15
20
10
80
45
20
30
35
00
00
00
00
00
00
00
00
00
4
5
.
.
6.
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
H
2
O
O
O
O
O
O
O
O
O
7
8
.
.
AgOAc (10)
AgOTf (10)
AgI (10)
9.
1
0.
1.
2.
3.
PdCl
Pd(OAc)
Cu(OTf)
AuCl
AuCl
2
(10)
1
1
1
2
(10)
(10)
2
3
(10)
(5)
14.
3
18
ACS Paragon Plus Environment

Page 9 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
1
1
5.
6.
7.
8.
AuCl
HAuCl
AuCl (10)
AlCl (10)
3
(15)
H
H
H
H
H
2
2
2
2
2
O
O
O
O
O
80
80
80
70
80
8
8
70
45
50
10
-
00
15
10
00
-
4
(10)
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
24
30
19.
-
a
The reactions were performed using 0.5 mmol of o-alkynylaldehyde 4a, 0.55 mmol of amine 6a
in 2.0 mL of solvent. DCE = 1,2-Dichloroethane. DMF = N,N-Dimethylformamide. NR = no
reaction.
1
The formation of regioselective 6-endo-dig cyclized product 7a was characterized by H
1
3
NMR, C NMR, mass and 2D spectroscopic data. Appearence of peaks at 6.04 ppm as a
1
multiplet, 4.98 and 4.12 ppm as diastereotopic protons in H NMR of 7a and disappearance of the
1
3
two characteristic peaks of alkynyl carbons in C NMR spectrum suggested the formation of the
desired cyclized product 7a. No distinct NOE effect was observed between H and H in
are located in
b
a
compounds 7h, 7n, 8e and 8m (Figure 2). These results suggested that H
a
and H
b
the trans orientation (see supporting information).
ꢀ
Figure 2. NOESY interactions of 7h, 7n, 8e and 8m.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 55
1
2
3
4
5
6
7
8
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
Synthesis of oxazolo fused pyridoindoles (7a–v). Subsequently, we checked the scope and
generality of this domino strategy. As shown in table 2, the reaction is feasible towards a
variety of o-alkenylaldehydes (4a–t) containing different alkynyl substituents. We commenced
our strategy by reacting o-alkenylaldehydes 4 with (S)-2-phenylglycinol (6a) which is an amine
source (Table 2). The observation shows that use of amino alcohols 6a and 6b gave good yield
and have equal reactivity towards the substrate 4. When electronically neutral and donating
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
groups such as Ph (4a), 4–N(Me (4b), 4–OMe–C
2
)–C
6
H
4
6 4 6 4 6 4
H (4c), 2–Me–C H (4d), 4–Et–C H
(4e), 4–nBu–C (4f), and 4–tBu–C H (4g) were used, the reaction proceeded well and
6
H
4
6 4
afforded the products 7a–g in 82–90% yields (Table 2, entries 1–7). While diastereomeric
mixture of compound 7d and 7d’ was obtained when ortho-tolyl substituted alkyne was used
(
entry 4), which may be due to the steric hindrance of methyl group present at ortho position.
Product 7h was obtained in 90% yield with thienyl substituted alkyne (entry 8). With aliphatic
alkynes such as –CH –OPh and –CH OH, the reaction provided the desired products 7i and 7j
2
2
in 60 and 58% yields, respectively (entries 9 and 10). Alkyne 4k, bearing two methoxy groups
at meta positions on the phenyl ring, afforded the cyclized product 7k in 65% yield (entry 11),
which may be due to the reduced electrophilicity at the proximal end of the alkyne thereby
reduced the efficiency of the desired transformation. Encouraged by the above results, we
further extended the same protocol with (R)-2-phenylglycinol (6b). Reaction of substrate 4c, 4l,
4m, 4f and 4n with (R)-2-phenylglycinol (6b) afforded the desired product 7l–p in 81–87%
yields (entries 12–16). When 4o alkyne was used, diastereomeric mixture of product 7q and 7q’
was observed (entry 17), which may be due to the steric hindrance of phenanthrene ring. During
the course of our study, we observed that the diastereomeric mixtures of 7d and 7q were not
affected by the H
2
O. The reaction was well tolerated with alkynes 4p-r, bearing a cyclopropyl,
ACS Paragon Plus Environment

Page 11 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
cyclohexyl and n-butyl group gave the desired products 7r–t in 62–70% yields (entries 18–20).
Reaction of o-alkynylaldehydes 4s and 4t bearing electron withdrawing groups such as 3–OMe
and 4–CF
3
groups, provided the corresponding products 7u–v in 68% and 60% yields
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
respectively.
a
Table 2. Domino Synthesis of Oxazolo Fused Pyridoindoles ꢀꢀ
entry
1
Substrate
ꢀ
amine
Product
ꢀ
yield (%)
80
4a
7a
ꢀ
(S) 6aꢀ
6aꢀ
ꢀ
2
3
4b
4c
7b
7c
90
88
ꢀ
ꢀ
ꢀ
6a
ꢀ
4
4dꢀ
6aꢀ
7d
87
(55:45)
ꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 55
1
2
3
4
5
6
7
8
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
7
d’
ꢀ
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
5
6
4e
4f
6aꢀ
6aꢀ
7e
87
86
ꢀ
ꢀ
7f
ꢀ
ꢀ
7
8
4gꢀ
4hꢀ
6aꢀ
6aꢀ
7g
7h
82
90
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
9
4i
4j
6aꢀ
6aꢀ
7i
60
58
ꢀ
1
0
1
7j
ꢀ
ꢀ
1
4k
6a
7k
65
ꢀ
ꢀ
ACS Paragon Plus Environment

Page 13 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
1
2
3
4c
7l
87
86
ꢀ
ꢀ
(
R) 6b
6aꢀ
4l
7m
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ꢀ
ꢀ
1
1
4
5
4m
4f
6b
6b
7n
7o
84
82
1
6
4n
4o
6b
7p
7q
81
17
6aꢀ
78
(
54:46)
ꢀ
ꢀ
7
q’
ꢀ
b
1
8
4p
6aꢀ
7r
70
ꢀ
ꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 55
1
2
3
4
5
6
7
8
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
b
1
9
4q
6aꢀ
7s
65
ꢀ
ꢀ
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
b
20
4r
4s
6b
6b
7t
62
2
2
1
2
7u
68
60
4t
6b
7v
a
Reactions were performed using o-alkynylaldehyde 4 (0.5 mmol), amine 6a–b (0.55 mmol), 10
b
3 2
mol % of AuCl in 2.0 mL of H O at 80 °C for 7 h. Reaction time= 8 h.
Synthesis of benzofurooxazolo pyridine (8a–n). Benzofuropyridine nucleus has a wide range
34
of biological and pharmaceutical properties. To gain further insight into successful
transformation of a variety of tetrahydrooxazolo[3ˈ,2ˈ:1,2]pyrido[4,3-b]indoles, we continued
our investigation by examining various fused furan substrates 5a–k with phenylglycinol 6a and
6
b. The reaction afforded the benzofuro fused oxazolopyridine 8a–n in good to excellent yields
and required less reaction time (8 vs 6 h) (Table 3). Reaction of alkynes 5a and 5b, bearing
electron-donating substituent such as 4–Me and 2–Me to the triple bond of the phenyl ring
showed the capability to trigger the 6-endo-dig cyclization and provided the respective products
8a–b in 86 and 82% yields respectively (Table 3, entries 1 and 2). However, product 8b and
8
b’was observed as a diastereomeric mixture. Substrate 5c bearing an electron-rich heterocycle
ACS Paragon Plus Environment

Page 15 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
thiophene on reaction with amine 6a proved to be favorable for the reaction and afforded the
desired product 8c in 89% yield. The product 8d and 8d’was obtained as diastereomeric
mixture in 70% yield when substrate having 3–OMe at the phenyl ring was used. Next, we
extended our strategy with (R)-2-phenylglycinol (6b). Reaction of 5a, 5b and 5e–h bearing
electron-neutral and releasing groups afforded the desired product 8e–j comparatively in
satisfactory yields (entries 5–10). When 2-methyl substituted phenyl ring was used, product 8j
and 8j’ was observed as a diastereomeric mixture. Substrate 5c with a thienyl group
successfully provided the product 8k in 88% yield; however, cyclohexyl-substituted as a o-
alkynylaldehydes 5i gave the product 8l in 69% yield (entry 12). When an electron–
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
withdrawing group (3,5 di–Methoxy and 4–CF ) on the phenyl ring was reacted, subsequent
products 8m and 8n were obtained in good yields (entries 13 and 14).
a
Table 3. Domino Synthesis of Benzofuro Fused Oxazolopyridine ꢀꢀ
entry
substrate
amine
product
yield (%)
86
1
.
5a
5b
8a
8b
(
S) 6a
2
.
6a
82
(55:45)
8
b’
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 55
1
2
3
4
5
6
7
8
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
3
.
5c
6a
6a
8c
89
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
4.
5d
8d
70
(
53:47)
8d’
8e
5
6
.
.
5e
5f
74
86
(R) 6b
6b
8f
7.
5a
5g
6b
6b
8g
8h
85
82
8
9
.
.
5h
6b
8i
81
ACS Paragon Plus Environment

Page 17 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
0.
5b
6b
8j
80
(
55:45)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8
j’
8k
8l
1
1.
5c
5i
6b
6b
88
b
12.
69
1
1
3.
4.
5j
6b
6b
8m
8n
62
60
5k
a
The reactions were performed using o-alkynylaldehyde 5 (0.5 mmol), amine 6a–b (0.55 mmol),
b
1
0 mol % of AuCl
3 2
in 2.0 mL of H O at 80 °C for 5 h. Reaction time = 6 h.
With above successful results, we further extended our investigation for the synthesis of
γ-carbolines (Scheme 3) and benzofuropyridines (Scheme 4). During the course of our study, we
thought that if amine would attack first onto the alkyne then it generate quartery ammonium ion
which leads to the formation of γ-carbolines, if electron-withdrawing group was introduced at
alpha carbon of the amine (see Scheme 5, Path B). For this, we selected amino esters, serine 6c,
threonine 6d and cysteine 6e as an amine source. We initiated to optimize the reaction by using
4a and 6c as a model substrate (Table 4). Reaction of 4a (0.5 mmol) with 6c (0.55 mmol) using
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 55
1
2
3
4
5
6
7
8
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
1
0 mol % of AgNO
3
in 2.0 mL of DCE at 60 °C afforded the product 9a in 8% yield after 24 h
(Table 4, entry 1). Increasing the temperature from 60 to 80 °C, slightly increased the product
yield 9a (entry 2). When DMF was used as a solvent at 110 °C, 9a was formed in 25% yield
after 24 h (entry 3). When EtOH was used as a solvent, a significant improvement in the yield of
the product 9a was observed (entry 4). Water was ineffective for this reaction (entry 5).
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
3
Interestingly, using 5 mol % of AuCl in DCE at 70 °C afforded the product 9a in 60% yield
even after 7 h. Increasing the catalyst loading from 5 to 10 mol % afforded the product 9a in
82% yield after 6 h. We also tried this reaction using threonine 6d and cysteine 6e as an amine
source and found that 9a was formed in lower yields (entries 9 and 10). 10 mol % of AuCl
DMF at 110 °C after 5h afforded 9a in 65% yield (entry 11).
3
in
a
Table 4. Optimization of the Reaction Conditions
entry catalyst (mol %)
conditions
temp
yield (%)
solvent
time (h)
7a’
9a
o
( C)
1
2
3
.
.
.
AgNO
AgNO
AgNO
AgNO
AgNO
3
3
3
3
3
(10)
(10)
(10)
(10)
(10)
(5)
DCE
DCE
DMF
EtOH
60
80
24
24
24
24
24
24
0
0
0
0
0
0
8
10
25
35
0
110
80
4.
5
6
.
.
H
2
2
O
O
80
AuCl
3
H
80
0
ACS Paragon Plus Environment

Page 19 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7
8
9
.
.
.
AuCl
AuCl
3
(5)
DCE
DCE
DCE
DCE
DMF
80
80
7
6
6
6
5
0
0
0
0
0
60
82
76
72
65
3
(10)
b
AuCl
3
(10)
(10)
80
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
c
1
0.
AuCl
3
80
11.
AuCl
3
(10)
120
a
The reactions were performed using 0.5 mmol of o-alkynylaldehyde 4a, 0.55 mmol of amine 6c,
b
c
0
3
.6mmol of Et N in 2.0 mL of solvent. Threonine 6d was used. Cysteine 6e was used. DCE =
1,2-Dichloroethane. DMF = N,N-dimethylformamide.ꢀ
a
Scheme 3. Domino Synthesis of γ-Carbolines
a
The reactions were performed using o-alkynylaldehyde 4 (0.5 mmol), L-Serine methyl ester
hydrochloride 6c (0.55 mmol), Et
3
N (0.6 mmol), 10 mol % of AuCl
3
in 2.0 mL of DCE at 80 °C
b
c
for 6 h. L-Threonine methyl ester hydrochloride 6d was used. L-Cysteine methyl ester
hydrochloride 6e was used.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 55
1
2
3
4
5
6
7
8
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
Synthesis of Substituted γ-Carbolines (9a–i). The scope and generality of the reaction was
examined by employing o-alkynyl-1H-indole-3-carbaldehydes 4a, 4c, 4m, 4f, 4h, 4p, 4u, 4r and
4
t with L-Serine methyl ester hydrochloride 6c for the synthesis of a diversely substituted
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
pyrido[4,3-b]indole 9a–i (Scheme 3). The substrates 4a having phenyl group gave 9a in 83%
yield; whereas, 4c, 4m and 4f bearing an electron-donating substituents such as p-OMe, p-Me, p-
nBu, provided the corresponding products 9b, 9c and 9d in slightly better yields as 87%, 85%
and 84% respectively as compare to 9a. Using thienyl group as an alkyne source afforded the
2 2
product 9e in 88% yield. Aliphatic alkynes such as cyclopropyl, -CH -CH -Ph and n-hexyl were
also feasible in providing the desired product 9f, 9g and 9h in 75%, 72% and 70% yields
respectively. However, electron withdrawing group such as p-CF
3
lowered the yield of product
9
i.
a
Scheme 4. Domino Synthesis of Benzofuro[3,2-c]pyridines
ꢀ
Synthesis of Substituted Benzofuro[3,2-c]pyridines. Inspired by the above results, we
explored the reaction with the o-alkynylbenzofuran-3-carbaldehydes 5d, 5g and 5j with L-Serine
3 3
methyl ester hydrochloride 6c. Nevertheless it gave better results with AgNO instead of AuCl
catalyst and furnished differently substituted benzofuro[3,2-c]pyridines 10a–c in 60–75% yields
after 24 h (Scheme 4).
In the light of these above preliminary results, a catalytic cycle for this domino
transformation was proposed as shown in Scheme 5. Initially reaction of o-alkynyl aldehyde 4
and 5 with nucleophilic amine 6 produced condensation species P. After this, two possibilities
ACS Paragon Plus Environment

Page 21 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
exist for the formation of compound 7, 8 i.e. either ring A forms first than ring B or vice versa.
Ring A could be formed prior as P on activation by AuCl
nucleophilic attack of OH group onto imine carbon to afford Q. Intramolecuar proton transfer
would then produce R which upon π-activation by AuCl would undergo second intramolecular
nucleophic attack of -NH onto the triple bond to afford S to give desired compound 7 and 8.
Alternatively, ring B could be formed initially by the activation of triple bond by AuCl to give
3
would undergo first intramolecular
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
3
Q' followed by second intramolecular nucleophilic attack to furnish S' which after subsequent
deprotonation would give compound 7 and 8. Subsequently Path C shows the product formation
of Pyrido[4,3-b]indole and Benzofuro[3,2-c]pyridines which favours that path B is more
enthusiastic over path A.
Scheme 5. Probable Mechanism
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 55
1
2
3
4
5
6
7
8
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
CONCLUSIONS
In summary, we have developed Au(III)-catalyzed domino protocol in water which
allowed a facile access to a vast variety of pyridoindole/benzofuropyridine fused oxazole using
readily available starting materials in good yields with high regioselectivity under mild reaction
conditions. The reaction proceeded with high 6-endo-dig regioselectivity. This methodology
appeared to be very general and compatible with differently substituted starting materials having
different electronic properties thus, increasing its applicability to various functional groups.
From a synthetic point of view, the net transformation involves a one-step conversion of simple,
inexpensive and readily available starting materials into an interesting class of fused heterocyclic
scaffolds. It is likely that the efficiency of this environment friendly method combined with its
operational simplicity will make it attractive for the construction of variety of heterocyclic
compounds.
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
EXPERIMENTAL SECTION
1
13
General Information. H NMR (400 MHz) and C NMR (100 MHz) spectra were recorded in
CDCl and DMSO-d6. Chemical shifts for protons are reported in ppm from tetramethylsilane
with the residual CHCl and DMSO resonance as internal reference. Chemical shifts for carbons
3
3
are reported in ppm from tetramethylsilane 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), coupling constants in Hertz, and integration. High-resolution
mass spectra were recorded on QqTOF mass analyzer. TLC analysis was performed on
commercially prepared 60 F254 silica gel plates and visualized by either UV irradiation or by
2
staining with I . Chemical yields are referred to the pure isolated substances Chromatographic
purification of the label compounds was accomplished by column chromatography using 100–
ACS Paragon Plus Environment

Page 23 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
00 mesh size silica gel. Anhydrous forms of all reagents such as diethyl ether, hexanes, ethyl
3 3
acetate, DCE, DMF, Et N, AuCl , AuCl, Silver nitrate, palladium salts and copper salts were
used directly as obtained commercially unless otherwise noted.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Procedure for the Synthesis of Starting materials 4 and 5.ꢀThe starting materials 4 and 5 were
3
6,6a
prepared by the Sonogashira coupling reaction
of corresponding haloaldehyde with terminal
alkynes using the reported procedure and confirmed by comparison of its physical and spectral
1
13
data ( H NMR, C NMR, and HRMS). The structure and purity of the known starting materials
3
3
28b
33
5a
1
4a, 4q, 4r and 5a–j were confirmed by comparison of their physical and spectral data ( H
13
NMR and C NMR) with those reported in literature.
2
-((4-(Dimethylamino)phenyl)ethynyl)-1-methyl-1H-indole-3-carbaldehyde (4b). The product
1
was obtained as brown semi-solid (142.1 mg, 94%): H NMR (400 MHz, CDCl
3
) δ 10.15 (s,
1
H), 8.22 (d, J = 6.8 Hz, 1H), 7.38 (d, J = 8.3 Hz, 2H), 7.27–7.19 (m, 3H), 6.57 (d, J = 9.2 Hz,
1
3
1
2H), 3.77 (s, 3H), 2.93 (s, 6H); C{ H} NMR (100 MHz, CDCl
3
) δ 185.0, 150.9, 137.4, 133.8,
1
33.1, 124.54, 124.48, 123.2, 121.9, 118.7, 111.6, 109.5, 107.1, 103.6, 75.9, 40.0, 31.0; HRMS
+
(
18 2
ESI) [M+H] Calcd for [C20H N O] 303.1497, found 303.1495.
2-((4-Methoxyphenyl)ethynyl)-1-methyl-1H-indole-3-carbaldehyde (4c). The product was
1
obtained as brown needles (133.1 mg, 92%): mp 162–166 °C; H NMR (400 MHz, CDCl
3
) δ
1
0.16 (s, 1H), 8.23 (d J = 6.88 Hz, 1H), 7.46 (d, J = 8.4 Hz, 2H), 7.29–7.17 (m, 3H), 6.85–6.83
1
3
1
(m, 2H), 3.79–3.76 (m, 6H); C{ H} NMR (100 MHz, CDCl
3
) δ 185.2, 160.8, 137.4, 133.5,
1
32.7, 124.8, 124.5, 123.5, 122.0, 119.4, 114.3, 113.1, 109.6, 101.6, 76.4, 55.4, 31.1; HRMS
+
(
2
ESI) [M+H] Calcd for [C19H15NO ] 290.1181, found 290.1198.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 55
1
2
3
4
5
6
7
8
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
1
-Methyl-2-(o-tolylethynyl)-1H-indole-3-carbaldehyde (4d). The product was obtained as brown
1
needles (123.0 mg, 90%): mp 158–162 °C; H NMR (400 MHz, CDCl
3
) δ 10.19 (s, 1H), 8.25 (d
J = 9.6 Hz, 1H), 7.44 (d, J = 8.28 Hz, 2H), 7.32–7.23 (m, 3H), 7.16 (d, J = 8.2 Hz, 2H), 3.84 (s,
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
13
1
3
H), 2.22 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 185.2, 140.3, 137.5, 131.7, 129.5, 124.9,
+
124.4, 123.5, 122.2, 119.7, 118.1, 109.6, 101.6, 70.1, 31.2, 21.7; HRMS (ESI) [M+H] Calcd for
19
[C H15NO] 274.1232, found 274.1251.
2
-((4-Ethylphenyl)ethynyl)-1-methyl-1H-indole-3-carbaldehyde (4e). The product was obtained
1
as brown needles (127.9 mg, 89%): mp 148–152 °C; H NMR (400 MHz, CDCl
3
) δ 10.19 (s,
1
3
H), 8.25 (d J = 8.4 Hz, 1H), 7.46 (d, J = 7.6 Hz, 2H), 7.31–7.23 (m, 4H), 7.18–7.16 (m, 1H),
1
3
1
.82 (s, 3H), 2.62 (q, J = 7.64, 15.28 Hz, 2H), 1.19 (t, J = 7.24 Hz, 3H); C{ H} NMR (100
MHz, CDCl
3
) δ 185.3, 146.6, 137.2, 131.8, 128.2, 126.4, 125.0, 124.9, 124.0, 123.4,123.3,
+
1
22.0, 121.0, 119.5, 115.1, 109.6, 76.8, 31.7, 28.9, 15.3; HRMS (ESI) [M+H] Calcd for
20
[C H17NO] 288.1388, found 288.1405.
2-((4-Butylphenyl)ethynyl)-1-methyl-1H-indole-3-carbaldehyde (4f). The product was obtained
1
as pale yellow needles (138.8 mg, 88%): mp 154–158 °C; H NMR (400 MHz, CDCl
3
) δ 10.16
(s, 1H), 8.23 (d, J = 7.3 Hz, 1H), 7.42 (d, J = 7.9 Hz, 2H), 7.27–7.18 (m, 3H), 7.13 (d, J = 7.9
Hz, 2H), 3.76 (s, 3H), 2.56 (t, J = 7.6 Hz, 2H), 1.54–1.51 (m, 2H), 1.30-1.23 (m, 2H), 0.88–0.85
13
1
(m, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 185.2, 139.7, 137.0, 132.7, 128.53, 128.45, 126.7,
1
24.6, 124.2, 123.3, 122.0, 119.5, 109.5, 102.3, 70.1, 34.3, 32.4, 30.8, 21.8, 14.1; HRMS (ESI)
+
[M+H] Calcd for [C22H21NO] 316.1701, found 316.1721.
2
-((4-(tert-Butyl)phenyl)ethynyl)-1-methyl-1H-indole-3-carbaldehyde (4g). The product was
1
3
obtained as brown needles (134.0 mg, 85%): mp 139–143 °C; H NMR (400 MHz, CDCl ) δ
ACS Paragon Plus Environment

Page 25 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
7
1
0.27 (s, 1H), 8.33 (d, J = 8.4 Hz, 1H), 7.56 (d, J = 8.4 Hz, 2H), 7.45 (d, J = 7.64 Hz, 2H), 7.38–
1
3
1
3
.33 (m, 3H), 3.92 (s, 3H), 1.35 (s, 9H); C{ H} NMR (100 MHz, CDCl ) δ 185.3, 153.2, 131.6,
25.8, 124.9, 124.5, 123.5, 122.1, 119.6, 118.2, 109.6, 101.6, 76.8, 34.8, 31.2, 31.1; HRMS
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
(
ESI) [M+H] Calcd for [C22
H
21NO] 316.1701, found 316.1721.
1
-Methyl-2-(thiophen-3-ylethynyl)-1H-indole-3-carbaldehyde (4h). The product was obtained as
1
pale yellow needles (126.0 mg, 95%): mp 146–150 °C; H NMR (400 MHz, CDCl
3
) δ 10.19 (s,
1
H), 8.28 (d, J = 7.6 Hz, 1H), 7.68–7.67 (m,1H), 7.36–7.33 (m, 2H), 7.32–7.30 (m, 1H), 7.28–
1
3
1
7.26 (m, 1H), 7.25–7.24 (m, 1H), 3.82 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 185.1, 137.4,
1
32.1, 130.9, 129.6, 126.2, 124.9, 124.3, 123.4, 122.0, 120.2, 119.7, 109.6, 96.3, 31.1; HRMS
+
(
ESI) [M+H] Calcd for [C16H11NOS] 266.0640, found 266.0661.
1
-Methyl-2-(3-phenoxyprop-1-yn-1-yl)-1H-indole-3-carbaldehyde (4i). The product was
1
obtained as brown oily (107.1 mg, 74%): H NMR (400 MHz, CDCl
3
) δ 10.13 (s, 1H), 8.02–8.00
(
m, 1H), 7.28–7.21 (m, 4H), 6.94 (t, J = 6.8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 4.45 (s, 2H), 3.60
1
3
1
(s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 184.5, 157.3, 137.1, 129.8, 123.5, 122.9, 122.0,
+
1
2
14.4, 110.0, 72.6, 36.3, 30.1; HRMS (ESI) [M+H] Calcd for [C19
H15NO
2
] 290.1181, found
90.1198.
2-(3-Hydroxyprop-1-yn-1-yl)-1-methyl-1H-indole-3-carbaldehyde (4j). The product was
1
obtained as brown semi-solid (75.7 mg, 71%): mp 132–136 °C; H NMR (400 MHz, CDCl
3
) δ
1
3
1
1
0.03 (s, 1H), 8.23 (d, J = 3.8 Hz, 1H), 7.33–7.26 (m, 3H), 4.62 (s, 2H), 3.54 (s, 3H); C{ H}
NMR (100 MHz, CDCl
3
) δ 185.6, 137.0, 125.0, 123.54, 123.51, 122.9, 121.8, 119.6, 109.7, 73.2,
+
5
1.2, 30.9; HRMS (ESI) [M+H] Calcd for [C13
H
11NO
2
] 214.0868, found 214.0838.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 55
1
2
3
4
5
6
7
8
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
2
-((3,5-Dimethoxyphenyl)ethynyl)-1-methyl-1H-indole-3-carbaldehyde (4k). The product was
1
obtained as brown needles (111.8 mg, 70%): mp 153–157 °C; H NMR (400 MHz, CDCl
3
) δ
1
0.27 (s, 1H), 8.33 (d J = 7.64 Hz, 1H), 7.39–7.23 (m, 3H), 6.77–7.76 (m, 2H), 6.57 (s, 1H), 3.89
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
13
1
3
(s, 3H), 3.86–3.85 (m, 6H); C{ H} NMR (100 MHz, CDCl ) δ 185.1, 160.7, 137.4, 131.9,
125.0, 123.5, 122.1, 119.8, 109.7, 109.5, 106.2, 103.0, 101.2, 76.8, 60.4, 55.5, 31.2; HRMS
+
(ESI) [M+H] Calcd for [C20
H17NO
3
] 320.1287, found 320.1310.
1
-Methyl-2-((4-phenoxyphenyl)ethynyl)-1H-indole-3-carbaldehyde (4l). The product was
1
obtained as dark brown needles (158.1 mg, 90%): mp 165–169 °C; H NMR (400 MHz, DMSO-
) δ 10.16 (s, 1H), 8.17–8.11 (m, 1H), 7.76 (d, J = 9.16 Hz, 1H), 7.61–7.56 (m, 1H), 7.49–7.43
m, 2H), 7.38 (t, J = 8.4 Hz, 1H), 7.32–7.20 (m, 3H), 7.15–7.10 (m, 3H), 7.06 (d, J = 9.1 Hz,
d
6
(
1
3
1
1H), 3.92 (s, 3H); C{ H} NMR (100 MHz, DMSO-d
6
) δ 184.1, 158.6, 155.3, 134.1, 130.4,
1
30.3, 124.9, 124.5, 120.8, 120.0, 119.7, 118.6, 118.2, 114.8, 111.0, 77.9, 76.9, 31.2; HRMS
+
2
(ESI) [M+H] Calcd for [C24H17NO ] 352.1338, found 352.1332.
1-Methyl-2-(p-tolylethynyl)-1H-indole-3-carbaldehyde (4m). The product was obtained as pale
1
brown needles (121.6 mg, 89%): mp 158–162 °C; H NMR (400 MHz, CDCl
3
) δ 10.19 (s, 1H),
8
.25 (d, J = 9.6 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.32–7.23 (m, 3H), 7.16 (d, J = 8.2 Hz 2H),
1
3
1
3.84 (s, 3H), 2.34 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 185.2, 140.3, 137.5, 131.7, 129.4,
+
1
24.9, 124.5, 123.5, 122.2, 119.7, 118.1, 109.6, 101.6, 69.6, 31.2, 21.7; HRMS (ESI) [M+H]
Calcd for [C19 15NO] 274.1232, found 274.1251.
H
1-Methyl-2-(m-tolylethynyl)-1H-indole-3-carbaldehyde (4n). The product was obtained as brown
1
needles (123.0 mg, 90%): mp 156–160 °C; H NMR (400 MHz, CDCl
3
) δ 10.19 (s, 1H), 8.25 (d
J = 9.6 Hz, 1H), 7.44 (d, J = 8.28 Hz, 2H), 7.32–7.23 (m, 3H), 7.16 (d, J = 8.2 Hz, 2H), 3.84 (s,
ACS Paragon Plus Environment

Page 27 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
13
1
3
1
H), 2.37 (s, 3H); C{ H} NMR (100 MHz, CDCl
3
) δ 185.4, 140.4, 137.4, 131.7, 129.4, 124.9,
+
24.5, 123.4, 122.1, 119.6, 118.1, 109.6, 101.6, 31.0, 21.6; HRMS (ESI) [M+H] Calcd for
[
19
C H15NO] 274.1232, found 274.1251.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1
-Methyl-2-(phenanthren-9-ylethynyl)-1H-indole-3-carbaldehyde (4o). The product was
1
obtained as brown needles (156.3 mg, 87%): mp 145–149 °C; H NMR (400 MHz, DMSO) δ
1
1
0.35 (s, 1H), 8.92 (d, J= 8.4 Hz, 1H), 8.86 (d, J = 8.4 Hz, 1H), 8.53 (s, 1H), 8.47 (d, J = 7.6 Hz,
H), 8.17 (d, J = 8.4 Hz, 1H), 8.08 (d, J = 8.4 Hz, 1H), 7.89–7.76 (m, 3H), 7.73–7.66 (m, 2H),
1
3
1
7.43 (t, J = 6.84 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 4.07 (s, 3H); C{ H} NMR (100 MHz,
CDCl ) δ 184.0, 137.3, 133.9, 130.9, 130.5, 130.3, 129.7, 129.5, 129.0, 128.8, 128.0, 127.9,
27.8, 126.0, 125.1, 123.9, 123.6, 123.5, 123.1, 120.8, 119.1, 117.0, 111.2, 99.3, 81.9, 79.2,
3
1
+
31.7; HRMS (ESI) [M+H] Calcd for [C26H17NO] 360.1388, found 360.1352.
2
-(Cyclopropylethynyl)-1-methyl-1H-indole-3-carbaldehyde (4p). The product was obtained as
1
red oily (89.3 mg, 80%): H NMR (400 MHz, CDCl
3
) δ 10.27 (s, 1H), 8.17–8.15 (m, 1H), 7.34–
1
3
1
7.30 (m, 3H), 3.68 (s, 3H) 2.13–2.07 (m, 1H), 1.12–1.08 (m, 2H), 0.97–0.92 (m, 2H); C{ H}
NMR (100 MHz, CDCl
3
) δ 184.0, 137.1, 123.2, 122.7, 119.4, 114.0, 109.8, 30.1, 17.7, 9.4;
13NO] 224.1075, found 224.1077.
+
HRMS (ESI) [M+H] Calcd for [C15
H
2-((3-Methoxyphenyl)ethynyl)-1-methyl-1H-indole-3-carbaldehyde (4s). The product was
1
obtained as yellow needles (108.5 mg, 75%): mp 162–166 °C; H NMR (400 MHz, CDCl
3
) δ
1
0.17 (s, 1H), 8.23 (d, J = 6.9 Hz, 1H), 7.47 (d, J = 8.4 Hz, 2H), 7.29–7.21 (m, 3H), 6.84 (t, J =
1
3
1
8.4 Hz, 2H), 3.80 (s, 6H); C{ H} NMR (100 MHz, CDCl
3
) δ 185.1, 160.9, 137.5, 133.4, 132.7,
+
1
24.9, 124.52, 123.45, 122.1, 119.5, 114.4, 113.2, 109.6, 101.6, 55.3, 31.0; HRMS (ESI) [M+H]
Calcd for [C19 ] 290.1181, found 290.1198.
H15NO
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 55
1
2
3
4
5
6
7
8
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
1
-Methyl-2-((4-(trifluoromethyl)phenyl)ethynyl)-1H-indole-3-carbaldehyde (4t). The product
1
was obtained as pale yellow needles (139.1 mg, 85%): mp 158–162 °C; H NMR (400 MHz,
3
CDCl ) δ 10.17 (s, 1H), 8.23 (d J = 8.4 Hz, 1H), 7.69–7.58 (m, 4H), 7.32–7.23 (m, 3H), 3.8 (s,
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
13
1
3
3
H); C{ H} NMR (100 MHz, CDCl ) δ 184.9, 137.6, 132.0, 130.8, 128.9, 125.8 (q, JC-F = 3.8
Hz, 1C), 125.61, 125.57, 125.3, 125.0, 124.3, 123.7, 123.4, 122.8, 122.2, 120.3, 109.9, 99.3,
+
7
9.6, 31.2; HRMS (ESI) [M+H] Calcd for [C19
H
12
F
3
NO] 328.0949, found 328.0965.
1
-Methyl-2-(4-phenylbut-1-yn-1-yl)-1H-indole-3-carbaldehyde (4u). The product was obtained
1
as brown solid (112.0 mg, 78%): mp 132–136 °C; H NMR (400 MHz, CDCl
3
) δ 10.03 (s, 1H),
8
3
.29–8.27 (m, 1H), 7.36–7.32 (m, 3H), 7.31–7.28 (m, 3H), 7.26–7.23 (m, 2H), 3.64 (s, 3H),
1
3
1
3
.02–2.98 (m, 2H), 2.93–2.89 (m, 2H); C{ H} NMR (100 MHz, CDCl ) δ 185.2, 139.7, 137.0,
132.7, 128.53, 128.45, 126.7, 124.6, 124.2, 123.3, 122.0, 119.5, 109.5, 102.3, 70.1, 34.3, 30.8,
+
2
1.8; HRMS (ESI) [M] calcd for [C20
H
17NO] 287.1310, found 287.1309.
2
-((4-(Trifluoromethyl)phenyl)ethynyl)benzofuran-3-carbaldehyde (5k). The product was
1
obtained as yellow needles (113.1 mg, 72%): mp 146–150 °C; H NMR (400 MHz, CDCl
3
) δ
1
0.35 (s, 1H), 8.18 (d, J = 6.88 Hz, 1H), 7.70 (q, J = 8.4, 22.16 Hz, 4H), 7.52–7.38 (m, 3H);
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 185.2, 154.8, 146.9, 132.3, 127.5, 125.7 (q, JC-F = 1.2 Hz,
+
1C), 125.6, 124.5, 123.2, 122.6, 111.3, 98.9, 79.0; HRMS (ESI) [M+H] Calcd for [C18
H
9
F
3
O
2
]
3
15.0633, found 315.0648.
Procedure for the Synthesis of Compound 7 and 8. To a solution of 0.5 mmol of o-alkynyl
aldehyde 4 and 5 in 2.0 mL H O, was added 0.55 mmol of amine 6a–b followed by the addition
of 10 mol % of AuCl . The reaction mixture was allowed to stir at 80 °C for 5–8 h. The
2
3
disappearance of the starting material was determined by TLC. The reaction mixture was then
ACS Paragon Plus Environment

Page 29 of 55
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
washed with brine solution and was extracted with ethyl acetate (2 x 10 mL). The combined
2 4
organic fractions were dried over anhydrous Na SO and concentrated under vacuum to yield the
crude product. The crude product was purified by column chromatography on neutral
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
alumina/silica gel using chloroform/methnol as the eluent.ꢀ
(3S,11cR)-7-Methyl-3,5-diphenyl-2,3,7,11c-tetrahydrooxazolo[3',2':1,2]pyrido[4,3-b]indole
3
1
(
7a). The product was obtained as pale yellow needles (151.4 mg, 80%): mp 110–114 °C; [α]
D
1
=
˗115.0 (c 0.1, CHCl
3
); H NMR (400 MHz, CDCl
3
) δ 10.09 (s, 1H), 8.58 (d, J = 7.3 Hz, 1H),
7.55–7.50 (m, 2H), 7.40–7.30 (m, 5H), 7.26–7.22 (m, 3H), 6.99–6.92 (m, 3H), 6.07–6.04 (m,
1
3
1
1
3
H), 4.98 (t, J = 11 Hz, 1H), 4.16–4.11 (m, 1H), 3.78 (s, 3H); C{ H} NMR (400 MHz, CDCl )
δ 150.4, 145.2, 142.3, 136.7, 135.6, 133.1, 130.5, 129.4, 129.1, 129.0, 127.1, 123.6, 123.4, 120.3,
+
120.1, 110.1, 108.3, 70.1, 61.8, 30.4; HRMS (ESI) m/z [M+H] calcd for C26
22 2
H N O 379.1810,
found 379.1804.
N,N-Dimethyl-4-((3S,11cR)-7-methyl-3-phenyl-2,3,7,11c-tetrahydrooxazolo[3',2':1,2]pyrido
[4,3-b]indol-5-yl)aniline (7b). The product was obtained as pale brown needles (189.7 mg,
3
1
1
9
1
0%): mp 129–133 °C; [α]
D
3 3
= –80.0 (c 0.05, CHCl ): H NMR (400 MHz, CDCl ) δ 9.91 (s,
H), 8.56 (d, J = 8.4 Hz, 1H), 7.49–7.47 (m, 1H), 7.40 (s, 1H), 7.35–7.31 (m, 3H), 7.19–7.16 (m,
4H), 6.95–6.91 (m, 2H), 6.64–6.62 (m, 2H), 6.21–6.18 (m, 1H), 4.96–4.91 (m, 1H), 4.24–4.16
13
1
(
m, 1H), 3.80 (s, 3H), 2.92 (s, 6H); C{ H} NMR (400 MHz, CDCl
3
) δ 152.3, 151.3, 145.8,
1
42.4, 136.8, 136.3, 130.9, 129.5, 129.1, 128.9, 127.1, 123.7, 123.5, 120.7, 120.0, 119.8, 111.7,
+
110.0, 108.3, 69.3, 61.6, 40.0, 29.6; HRMS (ESI) m/z [M+H] calcd for C28
27 3
H N O 422.2232,
found 422.2224.
ACS Paragon Plus Environment