Chemoselective and Highly Rate Accelerated Intramolecular Aza-Morita-Baylis-Hillman Reaction

Article abstract of DOI:10.1021/acs.joc.8b02310

Despite being a very useful C-C bond forming and highly applicative reaction, Morita-Baylis-Hillman (MBH) reaction has been limited by its excessive slow reaction rate, including its intramolecular version. In certain cases, reaction time may even go to weeks and months. A highly chemoselective and rate accelerated intramolecular MBH reaction of just 15 min has been developed. The product dihydroquinoline, being unstable, was converted to an important quinoline framework. In some cases IMBH adducts were isolable, thus confirming the reaction path. Control experiments toward mechanism investigation have been carried out. Use of sodium sulfide has emerged as a rate accelerating catalyst in DMF-EtOH solvent system. Reaction intermediate for IMBH pathway was isolated and characterized. Other aspects such as the application of IMBH adduct for Michael addition and amidation have also been carried out.

Full text of DOI:10.1021/acs.joc.8b02310

Subscriber access provided by Kaohsiung Medical University
Article
Chemoselective and highly rate accelerated
intramolecular aza-Morita-Baylis-Hillman reaction
Kishor Chandra Bharadwaj
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02310 • Publication Date (Web): 15 Nov 2018
Downloaded from http://pubs.acs.org on November 16, 2018
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 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 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.
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 25
The Journal of Organic Chemistry
1
2
3
4
5
6
Chemoselective and highly rate accelerated intramolecular aza-
Morita-Baylis-Hillman reaction
7
8
9
Kishor Chandra Bharadwaj
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
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, India-
221005
kishorbharadwaj@gmail.com
Ar1
SH Ar1
O
O
X
nor
S
N
Ar2
Ar1
H
N
H
Ar2
O
Na2S
Ar1
DMF, EtOH
O
N
Ar2
rt, 15 min
N
Ar2
H
Abstract
Despite being a very useful C-C bond forming and highly applicative reaction, Morita-Baylis-Hillman
(MBH) reaction has been limited by its excessive slow reaction rate, including its intramolecular version.
In certain cases, reaction time may even go to weeks and month. A highly chemoselective and rate
accelerated intramolecular MBH reaction of just 15 minutes has been developed. The product
dihydroquinoline, being unstable were converted to important quionline framework. In some cases
IMBH adduct were isolable, thus confirming the reaction path. Control experiments towards mechanism
investigation have been carried out. Use of sodium sulphide has emerged as a rate accelerating catalyst
in DMF-EtOH solvent system. Reaction intermediate for IMBH pathway was isolated and characterized.
Other aspects such as application of IMBH adduct for Michael addition and amidation have also been
carried out.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 25
1
2
3
4
Introduction
5
6
7
8
Amongst the important methodologies discovered in the last few decades, Morita-Baylis-Hillman (MBH)
reaction is considered to be one of the most useful C-C bond forming reaction.1,2 It’s an atom economy
reaction which couples a Michael acceptor with an aldehyde or imine to give densely substituted
molecules called as MBH adducts. With the close vicinity of functional groups, these MBH adducts have
been further used for various synthetic transformation.1c,2 Numerous applications for the development
of novel methodologies,3 including synthesis of various pharmacologically useful synthons4 have been
achieved owing to the synthetic utility of these MBH adducts. Consequently the reaction along with the
application of it’s adduct has gained huge popularity in the recent past. However, in spite of its
enormous usefulness, the reaction has certain limitations. One of the main challenges lie in the
sluggishness of reaction.5 The reaction requires longer reaction time (usually in days). Even reaction time
of weeks and month have also been reported on less reactive substrates.6 The slow reaction rate not
only hampers the development of reaction but also retards utilization of MBH adducts on real
applicative scale.
9
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
Consisting of three distinct reactions in the mechanism, there is an overall reduction in rate of reaction
(Figure 1). Initiated by a catalyst, mostly a neutral molecule, the reaction goes through sequences of
Michael, Aldol and Elimination (Figure 1). Several approaches such as protic additives,7 use of Lewis
acid,8 special catalysts,9 and others10 have been explored towards rate acceleration but the reaction still
requires longer reaction time11 and opens scope for improvement.
OH
EWG
Mortia Baylis Hillman
Nu
EWG
R
Michael
addition
Elimination
O
H
Aldol
EWG
EWG
R
O
R
Nu
Nu
Figure 1. MBH reaction and the steps involved
2
ACS Paragon Plus Environment

Page 3 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Intramolecular MBH (IMBH) reaction is yet another important endeavor in this area which leads to
construction of carbocyclic and heterocyclic frameworks.12, 13 However these reactions too, in spite of
having both reacting partners within close proximity, have been relatively beleaguered with slow
reaction rate.14 For example, to accelerate rate of IMBH reaction, reports of forcing conditions such as
higher temperature,15 use of microwave16 and others17 have been documented.
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
Since the initial Michael addition of MBH reaction is being carried out by a neutral molecule, rate
acceleration can also be visualized by using anions, which could undergo fast Michael addition (Figure
1). However, use of such species or the ones having labile proton usually leads to stable Michael-Aldol
adduct (eq. 1).18, 19 The reagent after addition, fails to eliminate (a classic case of domino additions).
Contrary, conventional neutral catalysts such as DABCO, DBU, phosphines and others are helpful for
elimination from MBH perspective. They become positively charged after Michael addition and readily
undergo required elimination in the last step. Thus, a balance of reactivity would be ideal where a
charged anion would initially carry out quick Michael addition, but still would have facile elimination
ability to expel and give final MBH adduct.20 In continuation of our research interest for rate acceleration
and IMBH reactions,21 a catalyst system for an extremely fast IMBH reaction was discovered. The details
are being disclosed in the present manuscript.
OH
O
EWG
EWG
X
Michael & Aldol
(1)
X
anion
Result and Discussion
During the course of studies for annulation strategies, a template 1a (Scheme 1) having dual
electrophilic site was synthesized. Initially annulation reaction aimed towards the synthesis of thio-
framework was investigated. Interestingly, when 1a was treated with Na2S in DMF, the desired thio-
annulated product was not observed. Moreover, the tetrahydro-quinoline arising from tandem addition
was also not seen. Interestingly an aza IMBH adduct 2a was observed in a reaction time of as low as 15
minutes. The product being unstable was subsequently oxidized using DDQ to give Quinoline which was
characterized by various spectroscopic data and confirmed with literature (vide infra). The results were
promising as it lead to discovery of Na2S as highly rate accelerating catalyst in the field of MBH reaction.
Therefore the reaction was further investigated.
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 25
1
2
3
4
Scheme 1. Initial investigation of 1a with Na2S.
5
6
7
8
Ph
S
O
9
X
X
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
N
Ar
H
Ph
SH Ph
Na2S, DMF
rt, 15 min
O
O
N
H
Ar
Ph
N
Ar
1a
O
Ar = 4-ClPh
N
H
Ar
2a
, 60%
To begin with, standardization of reaction was carried out (Table 1). Lowering of catalyst loading to 1
equivalent gave comparable yield of product (entry 2). Further reduction in loading of Na2S (0.5 equiv.)
led to 45 minutes reaction time and gave slightly lower yield (entry 3). Use of conventional catalysts
such as TPP, DABCO and DBU did not give product even in 12 hours reaction time (entries 4-6). DBU
upon prolonged reaction time of 96 hours gave only trace of product (entry 7). Other ionic sources were
also explored for their ability to carry out IMBH reaction (entries 8-12). Iodide has been considered as
good nucleophile. However, replacing Na2S with NaI or TBAI didn’t give any product. Use of thio-acetate
in the form of CH3COSK was also not helpful. Similarly, other reagents such as CH3CO2Na or NaNO2 were
ineffective. Thus, Na2S was selected as choice of catalyst for further studies. Subsequently different
solvents were screened (entries 13-16). Use of DCM, Toluene and Dioxane didn’t give any product.
Usage of EtOH was helpful and gave product in 52% yield, although in 3h (entry 16). In the light of
results obtained from entries 2&16, use of mix solvents was investigated. Using DMF and EtOH in 1:1
ratio led to higher yield of IMBH adduct (86%, entry 17). Use of other protic solvents in place of EtOH
such as MeOH and t-BuOH along with DMF gave inferior results (entries 18 &19). Thus 1 equiv. of Na2S
in DMF-EtOH mixture (1:1) at room temperature was identified as best reaction condition for optimal
yield and reaction time (entry 17). With the best possible conditions in hand, the scope of the reaction
was further explored on different substrates (Scheme 2).
4
ACS Paragon Plus Environment

Page 5 of 25
The Journal of Organic Chemistry
1
2
3
4
Table 1. Development of aza IMBH reaction.
5
6
Ph
Ph
7
8
9
O
O
Conditionsa
N
Ar
N
H
Ar
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
1a
2a
Ar = 4-ClPh
S. No. Catalyst
Solvent
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
Time (h)
Yieldb (%)
1c
2
Na2S
Na2S
Na2S
TPP
0.25
0.25
0.75
12
60
56
3d
4
50
-
5
DABCO
DBU
12
-
6
12
-
7
DBU
96
trace
8
NaI
16
-
9
TBAI
16
-
10
11
12
13
14
15
16
17
CH3COSK
16
-
CH3CO2Na DMF
16
-
NaNO2
Na2S
Na2S
Na2S
Na2S
Na2S
DMF
16
-
DCM
16
-
Toluene
Dioxane
EtOH
16
-
16
-
3
52
86
DMF/EtOH
(1:1)
0.25
18
19
Na2S
Na2S
DMF/MeOH 0.25
(1:1)
50
30
DMF/tBuOH
(1:1)
3
(a) All reactions were carried out on 0.5 mmol scale of 1a using 1.0 mL of solvent and 1.0 equiv. of
catalyst at rt. (b) Isolated yield. (c) 2 equiv. of catalyst was used. (d) 0.5 equiv. of catalyst was used.
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 25
1
2
3
4
Scheme 2. Substrate scope for IMBH reaction.
5
6
7
8
9
Ar1
Ar1
Ar1
R
R
R
Na2S (1 eq.)
DMF/EtOH (1:1)
DDQ (1.2 eq.)
O
O
O
DCM
N
Ar2
N
H
2
Ar2
N
Ar2
rt, 30 min
rt, 15 min
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
yield over 2 steps
3
Cl
Me
Br
OMe
Ar1 =
Ar1
3a
, 82%
3e
, 84%
Cl
3d
, 62%
3b
76%, g scale
, 65%
3c
, 83%
O
MeO
N
Cl
Cl
MeO
Cl
3g
, 77%
Br
3h
, 92%
3f
, 66%
3i
, 94 %
Me
MeO
Ar2 =
3k
, 62%
3j
, 51%
3m
3l
, 62%
, 77%
F
O
Ar2
N
Br
Br
Cl
3q
, 61%
3o
3n
, 83%
3p
, 80%
, 71%
Me
Br
R
O
O
O
N
R
N
N
3u
3v
, R = OMe, 71%
, R = Cl, 81%
Cl
3r
, R = OMe, 72%
3s
3t
, 70%
Cl
, R = H, 71%
Me
S
O
O
O
N
O
N
N
N
N
N
, 85%
Cl
3z
, 63%
3y
, 35%
3x
, 80%
3w
Cl
Cl
6
ACS Paragon Plus Environment

Page 7 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
A number of precursors were subjected to optimized reaction condition, delivering the required IMBH
dihydro-quionline derivatives. The IMBH adduct being unstable were oxidized to quionline using DDQ in
DCM. Quinoline framework is one of the most privileged skeleton and has attracted significant attention
from synthetic chemist worldwide.22
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
Initially variations across Michael acceptor were studied (Ar1, 3a-3i). The reaction was found to work
well on different substitution positions such as ortho, meta and para. Furthermore, both electron
releasing and electron withdrawing groups gave the required product in good yields. Thereafter
variations were made across imine aryl group (Ar2, 3j22b-3q). Varying substitutions also included multi-
substituted phenyl ring and biaryl-naphthyl moieties (3p & 3q). Electron withdrawing substitution gave
better yields then electron donating. Simultaneous variations were also carried out on precursor’s
framework (3r-3t22b). Subsequently variations were made across quionline ring. The required products
(3u, 3v) were obtained in event free manner. To broaden the reaction scope, precursors with
heterocycle unit were also studied. Pyridine and quionline derived precursor gave good conversion to
corresponding product (3w & 3x). In case of thiophene derived precursor, lesser yield of IMBH adduct
(3y) was observed. Reaction was also applicable to aliphatic ketone 3z. A gram scale study was also done
on 1a. Thus investigating reaction on 3.0 mmol scale of 1a (1.035 g) gave the product in 3a 76% yield.
Scheme 3. Exploration for ketimines.
Ph
O
O
Ph
15 h
Ph
X
N
Ph
Ph
Ph
N
4
79%
Ph
p-TSA
EtOH
80 0C
O
NH2
Me
4 h
Me
O
N
5
Me
N
Ph
4
O
19%
61%
O
Me
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 25
1
2
3
4
5
6
7
8
9
To broaden the generality of protocol, reaction scope was tried for ketimine derivatives (Scheme 3).
However, required ketimine from benzophenone could not be prepared even under forcing conditions.
Instead it resulted in the synthesis of 2-phenylquionline 4.21a When acetyl acetone was used in place of
benzophenone, a new kind of quionline precursor 523 was obtained along with 4. Formation of 5 could
be explained via elimination of acetophenone group from the moiety.
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
Scheme 4. Isolable dihydroQuinoline
Ar1
Na2S
DMF/EtOH (1:1)
rt, 15 min
Ar1
O
O
N
H
Ar2
N
Ar2
2
1
R1
2c
2h
, R1 = 4Br, R2 = 4Cl, 87%
, R1 = 2Cl, R2 = 4Cl, 95%
, R1 = 4Br, R2 = 3OMe, 77%
O
R2
2r
N
H
Ph
O
Ph
O
F
N
OMe
N
H
H
Br
2m
, 68%
2p
, 86%
During the course of studies, it was observed that some dihydroquinoline were relatively more stable
and were isolated and characterized (Scheme 4). This further confirmed IMBH reaction. Synthetic
potential was further expanded by carrying out successful Michael addition of one of the dihydro
precursor 2g, using methyl vinyl ketone, to obtain 6 (Scheme 5). Similarly amidation of 2a gave benzoyl
adduct 7.
8
ACS Paragon Plus Environment

Page 9 of 25
The Journal of Organic Chemistry
1
2
3
4
Scheme 5. Application of IMBH adduct.
5
6
Ar1
7
8
9
O
K2CO3, rt, 3d
76%
N
O
Ar2
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
6
O
Ar1
Ar1 = 2-MeOC6H4
Ar2 = 4-ClC6H4
O
N
Ar2
H
Ph
Et3N, DCM
rt, 12 h, 81%
O
N
Ar2
Cl
O
Ph
O
Ph
7
Ar2 = 4-ClC6H4
After exploring various aspects of the reaction, the mechanism of reaction was then studied. During the
course of standardization and substrate scope evaluation, formation of tetrahydroquinoline (8a) was
also observed (eq. 2). This resulted from ethoxide addition across enone, followed by ring closure.
Therefore, the role of ethoxide anion (if any) in IMBH reaction was then studied.24
Ph
Et
Na2S
DMF/EtOH
(1:1)
Ph
O
Ph
O
O
O
(2)
N
Ar
N
H
Ar
N
H
Ar
1a
rt, 15 min
2a
, 86%
8a
, 7%
Ar = 4-ClPh
Initially role of NaOEt was evaluated in absence of Na2S. Carrying out reaction in the presence of Na2CO3
(to generate NaOEt insitu), did not give any product and only starting material was observed (eq. 1,
Scheme 6). Replacing Na2CO3 with a stronger base NaOH, in DMF-EtOH led to the formation of 8a in 31%
and 2a in 44% yields (eq. 2, Scheme 6). Using NaOEt in DMF (in absence of EtOH) also led to the
formation of 2a in 55% yield (eq. 3, Scheme 6). Pleasingly these results highlighted the independent
catalytic activity of NaOEt. However as mentioned earlier, (entries 1-3, table 1) Na2S can also catalyze
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 25
1
2
3
4
Scheme 6. Mechanistic investigation of aza IMBH reaction.
5
6
Ph
Na2CO3 (1eq.)
DMF/EtOH (1:1)
7
8
9
O
(1)
starting material
N
1a
Ar
rt, 8 h
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
Ar = 4-ClPh
Ph
Et
Ph
O
Ph
NaOH (1eq.)
DMF/EtOH (1:1)
O
O
O
(2)
(3)
N
Ar
rt, 0.25 h
N
Ar
N
H
Ar
H
1a
Ar = 4ClPh
8a
, 31%
Ph
2a
, 44%
Ph
NaOEt (1eq.)
O
O
DMF
N
H
2a
Ar
rt, 0.25 h
N
Ar
1a
, 55%
Ar = 4-ClPh
Ph
O
Ph
NaOH (1eq.)
O
DMF
(4)
N
H
2a
Ar
rt, 0.5 h
N
Ar
1a
Ar = 4-ClPh
, 20%
Et
Ph
O
Ph
Et
O
Ph
O
Na2S (1eq.)
DMF/EtOH (1:1)
O
O
(5)
N
H
Ar
rt, 0.5 h
N
H
Ar
N
H
Ar
2a
, 46%
8a
, 39%
8a
Ar = 4-ClPh
Ph
Et
Ph
O
Ph
Na2S (1eq.)
DMF/EtOH (1:1)
O
O
O
(6)
N
H
Ar
rt, 0.5 h
N
H
Ar
N
H
Ar
2a
8a
, 10%
2a
, 70%
Ar = 4-ClPh
Ph
catalyst
O
(7)
DMF
or
DMF/EtOH (1:1)
rt, 24 h
Starting material
N
Ar
1a
Ar = 4-ClPh
10
ACS Paragon Plus Environment

Page 11 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
independently IMBH reaction and was necessary to get higher yield of IMBH reaction (entry 17, table 1
Vs eq. 2 scheme 6). Using NaOH in DMF led to poor yields of 20% of IMBH adduct (eq. 4, Scheme 6).
Subsequently inter-conversion of 2a and 8a was studied (eq. 5&6, Scheme 6). Towards this end 2a and
8a were independently subjected to optimized reaction conditions. As expected higher conversion of
Michael adduct towards the IMBH adduct was observed then vice versa. Another possibility of 6π
electrocyclization followed by 1,5-H shift, for the formation of 2a was also investigated. Reactions
carried out in absence of catalyst, either in DMF or in DMF-EtOH solvent system, didn’t lead to any
reaction (eq. 7, scheme 6). This, rules out the possibility of background 6π electrocyclization.
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
Conclusions
The above studies lead to discovery of Na2S as a new and promising catalyst for IMBH reactions.
Chemoselective nature of protocol was another added advantage. Extremely high rate acceleration
observed for IMBH reaction was very encouraging. This can be helpful in developing other catalytic
systems. Shorten reaction time could lead to quick access to IMBH adducts and can be further helpful in
the application of IMBH adduct. Organic thiols, especially under deprotonative conditions can also be
investigated. This opens up the possibility for use of chrial thiols and thus development of asymmetric
versions. Further, catalytic activity of NaOEt was also encouraging. As mentioned in limited literature24
and present studies, alkoxides could be another class of reagents for MBH reactions.
Experimental
General Remarks All the reactions were carried out using dry solvents and under inert atmosphere until
unless mentioned. Room temperature (rt) stands for 20-25 oC. Column chromatography was performed
using silica gel mesh 100-200. TLC Aluminium Sheets Silica Gel 60 F254 was used for TLC. Melting Points
were recorded on a Perfit (India) capillary melting point apparatus and were uncorrected. Infrared
spectra were recorded on a Perkin Elmer FT-IR spectrometer Spectrum Two. 1H NMR and 13C NMR were
recorded on a Jeol 500 MHz and 125 MHz spectrometer respectively. HRMS spectra were recorded on
Bruker Daltonics MicroTOF-Q-II with electron spray ionization (ESI).
Representative procedures
(2E)-3-((E)-2-(4-chlorobenzylideneamino)phenyl)-1-phenylprop-2-en-1-one (1a);18c To a solution of
amine21a (E)-3-(2-aminophenyl)-1-phenylprop-2-en-1-one (0.446 g, 2.0 mmol) in EtOH (8.0 mL) was
added 4-chlorobenzaldehyde (0.286 g, 2.04 mmol) and the reaction was stirred for 12h at rt during
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 25
1
2
3
4
5
6
which the imine precipitated. The reaction mixture was cooled to 0 oC and filtered to afford the required
Schiff base 1a (0.6 g). The filtrate was further evaporated and filtered to yield additional 0.042 g of 1a.
The combined 1a (0.642 g, 93%) was dried and used as such for next step.
7
8
9
(2-(4-chlorophenyl)-1,2-dihydroquinolin-3-yl)(phenyl)methanone (2a); To a suspension of 1a (0.172 g,
0.5 mmol) in DMF-EtOH (0.5 mL each), was added crushed Na2S (60%) (0.065 g, 0.5 mmol) and the
reaction was stirred for 15 minutes at rt, leading to a red colored solution. Water was added to it and
aqueous phase was extracted with EtOAc. Organic layer was dried over Na2SO4, filtered and
concentrated. The residue obtained was purified by a short column chromatography (EtOAc:hexane,
15:85), to obtain 2a (0.148 g) in 86% yield. 2a was used immediately for next step.
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
(2-(4-chlorophenyl)quinolin-3-yl)(phenyl)methanone (3a); To a solution of 2a (0.148 g, 0.43 mmol) in
DCM (1.2 mL) was added DDQ (0.116 g, 0.51 mmol) and the reaction was stirred at rt, for 30 minutes.
DCM was added to reaction mixture and organic layer was washed with NaHCO3 solution. Organic layer
was dried over Na2SO4, filtered and concentrated. The residue obtained was purified by column
chromatography (EtOAc:hexane, 1:9), to obtain 3a (0.139 g) in 82% yield over two steps.
Gram scale synthesis of 2-(4-chlorophenyl)quinolin-3-yl)(phenyl)methanone (3a); To a suspension of
1a (1.035 g, 3.0 mmol) in DMF-EtOH (3.0 mL each), was added crushed Na2S (60%) (0.39 g, 3.0 mmol)
and the reaction was stirred at rt for 15 minutes, leading to a red colored solution. Water was added to
it and aqueous phase was extracted with EtOAc. Organic layer was dried over Na2SO4, filtered and
concentrated. The residue obtained was purified by a short column chromatography (EtOAc:hexane,
15:85), to obtain 2a (0.849 g) in 82% yield. 2a was used immediately for next step. To a solution of 2a
(0.849 g, 2.5 mmol) in DCM (7.0 mL) was added DDQ (0.67 g, 2.9 mmol) and the reaction was stirred at
rt, for 30 minutes. DCM was added to reaction mixture and organic layer was washed with NaHCO3
solution. Organic layer was dried over Na2SO4, filtered and concentrated. The residue obtained was
purified by column chromatography (EtOAc:hexane, 1:9), to obtain 3a (0.78 g) in 76% yield over two
steps.
4-(2-(4-chlorophenyl)-3-(2-methoxybenzoyl)quinolin-1(2H)-yl)butan-2-one (6); To a solution of 2g
(0.100 g, 0.27 mmol) in MVK (0.5 mL) was added K2CO3 (0.37 g, 0.27 mmol) and the reaction was stirred
for 3 days at rt. The reaction mixture was filtered and concentrated. The residue obtained was purified
by column chromatography (EtOAc:hexane, 15:85), to yield 6 (0.09 g) as orange solid in 76% yield.
12
ACS Paragon Plus Environment

Page 13 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(2-(4-chlorophenyl)quinoline-1,3(2H)-diyl)bis(phenylmethanone) (7); To a solution of 2a (0.103 g, 0.3
o
mmol) in DCM was added Et3N (0.06 mL, 0.41 mmol) and PhCOCl (0.04 mL, 0.36 mmol) at 0 C and the
reaction mixture was stirred for 12h at rt. Subsequently DCM was added and organic phase was washed
with NaHCO3 solution. Organic layer was dried over Na2SO4, filtered and concentrated. The residue
obtained was purified by column chromatography (EtOAc:hexane, 1:5), to obtain 7 (0.108 g) in 81%
yield.
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
(2-(4-chlorophenyl)quinolin-3-yl)(phenyl)methanone (3a); Yield: 0.139 g, 82%; White solid; mp: 152-
156 oC; IR (KBr): ν 1656 cm_1; 1H NMR (500 MHz, CDCl3): δ 7.27-7.29 (m, 2H) 7.36-7.39 (m, 2H), 7.53 (app
t, J = 7.5 Hz, 1H), 7.57-7.58 (m, 2H), 7.64 (app t, J = 7.5 Hz, 1H), 7.73-7.75 (m, 2H), 7.85 (app t, J = 7.5 Hz,
1H), 7.91 (d, J = 8.5 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 125.9,
127.6, 128.2, 128.65, 128.72, 129.7, 130.1, 130.6, 131.5, 132.6, 133.7, 135.2, 136.9, 137.8, 138.2, 148.4,
156.2, 196.8; HRMS (ESI): calculated for C22H15ClNO, 344.0842 (M+H)+, found: 344.0855.
(2-(4-chlorophenyl)quinolin-3-yl)(p-tolyl)methanone (3b); Yield: 0.116 g, 65%; White solid; mp: 168-
o
1
170 C; IR (KBr): ν 1271, 1603, 1655 cm_1; H NMR (500 MHz, CDCl3): δ 2.38 (s, 3H), 7.17-7.18 (m, 2H)
7.27-7.29 (m, 2H), 7.58-7.66 (m, 5H), 7.83 (app t, J = 7.5 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.0
13
Hz, 1H), 8.29 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 21.8, 125.9, 127.5, 128.1, 128.7, 129.4, 129.7,
130.3, 130.6, 131.3, 132.8, 134.4, 135.2, 137.5, 138.3, 144.8, 148.3. 156.2, 196.4; HRMS (ESI): calculated
for C23H17ClNO, 358.0999 (M+H)+, found: 358.0991.
(4-bromophenyl)(2-(4-chlorophenyl)quinolin-3-yl)methanone (3c); Yield: 0.174 g, 83%; White solid;
o
1
mp: 172-174 C; IR (KBr): ν 1583, 1656 cm_1; H NMR (500 MHz, CDCl3): δ 7.28-7.30 (m, 2H), 7.49-7.51
(m, 2H), 7.55-7.59 (m, 4H), 7.64 (app t, J = 7.5 Hz, 1H), 7.85 (app t, J = 7.5 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H),
13
8.23 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 125.8, 127.7, 128.2, 128.8, 129.1,
129.7, 130.6, 131.4, 131.6, 132.0, 132.1, 135.4, 135.7, 137.8, 138.1, 148.4, 155.9, 195.8; HRMS (ESI):
calculated for C22H14BrClNO, 421.9947 (M+H)+, found: 421.9941.
(2-(4-chlorophenyl)quinolin-3-yl)(4-methoxyphenyl)methanone (3d); Yield: 0.116 g, 62%; White solid;
mp: 148-150 oC; IR (KBr): ν 1169, 1257, 1599, 1653 cm_1; 1H NMR (500 MHz, CDCl3): δ 3.85 (s, 3H), 6.84-
6.86 (m, 2H), 7.28-7.30 (m, 2H), 7.60-7.64 (m, 3H), 7.72-7.74 (m, 2H), 7.83 (app t, J = 7.5 Hz, 1H), 7.89 (d,
13
J= 8.0 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.29 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 55.6, 114.0, 125.9,
127.5, 128.1, 128.7, 129.7, 129.9, 130.6, 131.2, 132.6, 133.0, 135.2, 137.3, 138.3, 148.3, 156.1, 164.1,
195.3; HRMS (ESI): calculated for C23H17ClNO2, 374.0948 (M+H)+, found: 374.0938.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 25
1
2
3
4
5
6
7
8
9
(4-chlorophenyl)(2-(4-chlorophenyl)quinolin-3-yl)methanone (3e); Yield: 0.158 g, 84%; White solid; mp:
o
1
174-178 C; IR (KBr): ν 1584, 1663 cm_1; H NMR (500 MHz, CDCl3): δ 7.28-7.30 (m, 2H), 7.32-7.34 (m,
2H), 7.55-7.57 (m, 2H), 7.62-7.66 (m, 3H), 7.85 (app t, J = 7.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 8.23 (d, J =
8.5 Hz, 1H), 8.32 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 125.8, 127.7, 128.2, 128.8, 129.0, 129.7, 130.6,
131.3, 131.6, 132.1, 135.2, 135.4, 137.8, 138.1, 140.3, 148.4, 155.9, 195.6; HRMS (ESI): calculated for
C22H14Cl2NO, 378.0452 (M+H)+, found: 378.0443.
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
(2-(4-chlorophenyl)quinolin-3-yl)(3-methoxyphenyl)methanone (3f); Yield: 0.123 g, 66%; White solid;
o
1
mp: 166-170 C; IR (KBr): ν 1594, 1660 cm_1; H NMR (500 MHz, CDCl3): δ 3.81 (s, 3H), 7.09 (d app t, J =
7.5, 2.0 Hz, 1H), 7.24-7.27 (m, 2H), 7.29-7.30 (m, 2H), 7.35 (s, 1H), 7.57-7.59 (m, 2H), 7.63 (app t, J = 7.5
13
Hz, 1H), 7.85 (app t, J = 7.5 Hz, 1H), 7.90 (d, J = 8.0 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H); C{1H}
NMR (125 MHz, CDCl3): δ 55.5, 113.8, 120.4, 123.3, 125.8, 127.6, 128.2, 128.7, 129.6, 129.7, 130.6,
131.4, 132.6, 135.2, 137.7, 138.2, 148.3, 156.2, 159.8, 196.5; HRMS (ESI): calculated for C23H17ClNO2,
374.0948 (M+H)+, found: 374.0942.
(2-(4-chlorophenyl)quinolin-3-yl)(2-methoxyphenyl)methanone (3g); Yield: 0.144 g, 77%; White solid;
mp: 172-176 oC; IR (KBr): ν 1253, 1483, 1655 cm_1; 1H NMR (500 MHz, CDCl3): δ 3.53 (s, 3H), 6.75 (d, J =
8.5 Hz, 1H), 6.95 (app t, J= 7.5 Hz, 1H), 7.24-7.26 (m, 2H), 7.41 (d app t, J = 8.5, 2.0 Hz, 1H), 7.54-7.61 (m,
4H), 7.81 (d app t, J = 8.0, 2.0 Hz, 1H), 7.89 (d, J = 7.5 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 8.32 (s, 1H); 13C{1H}
NMR (125 MHz, CDCl3): δ 55.4, 111.4, 120.7, 126.2, 127.2, 127.5, 128.2, 128.4, 129.5, 130.8, 131.1,
131.5, 134.4, 134.8, 135.2, 137.1, 138.4, 148.1, 156.5, 158.4, 195.9; HRMS (ESI): calculated for
C23H17ClNO2, 374.0948 (M+H)+, found: 374.0939.
(2-chlorophenyl)(2-(4-chlorophenyl)quinolin-3-yl)methanone (3h); Yield: 0.173 g, 92%; Light yellow
o
1
solid; mp: 144-148 C; IR (KBr): ν 1680 cm_1; H NMR (500 MHz, CDCl3): δ 7.19 (d app t, J = 8.0, 1.5 Hz,
1H), 7.27-7.29 (m, 3H), 7.31 (dd, J = 7.0, 1.5 Hz, 1H), 7.35 (dd, J = 8.0, 1.5 Hz, 1H), 7.52-7.54 (m, 2H), 7.63
(app t, J = 7.5 Hz, 1H), 7.85 (app t, J = 7.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.46 (s,
1H); 13C{1H} NMR (125 MHz, CDCl3): δ 126.2, 126.7, 127.6, 128.5, 128.7, 129.7, 130.7, 130.8, 131.5,
132.0, 132.7, 132.78, 132.85, 135.0, 137.3, 138.3, 139.4, 148.6, 156.9, 195.3; HRMS (ESI): calculated for
C22H14Cl2NO 378.0452 (M+H)+, found: 378.0445.
(2,4-dichlorophenyl)(2-(4-chlorophenyl)quinolin-3-yl)methanone (3i); Yield: 0.193 g, 94%; White solid;
o
1
mp: 126-128 C; IR (KBr): ν 1583, 1677 cm_1; H NMR (500 MHz, CDCl3): δ 7.17 (dd, J = 8.0, 1.5 Hz, 1H),
7.29-7.32 (m, 4H), 7.51-7.53 (m, 2H), 7.65 (app t, J = 7.5 Hz, 1H), 7.87 (app t, J = 7.5 Hz, 1H), 7.94 (d, J =
14
ACS Paragon Plus Environment

Page 15 of 25
The Journal of Organic Chemistry
1
2
3
4
13
8.0 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.46 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 126.1, 127.1, 127.7,
5
6
7
128.6, 128.7, 129.7, 130.7, 132.2, 132.4, 133.8, 135.3, 135.7, 138.2, 138.5, 139.4, 148.7, 156.6, 194.3;
HRMS (ESI): calculated for C22H13Cl3NO 412.0063 (M+H)+, found: 412.0058.
8
9
o
phenyl(2-phenylquinolin-3-yl)methanone (3j);22b Yield: 0.079 g, 51%; White solid; mp: 128-130 C; IR
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
(KBr): ν 1657 cm_1; 1H NMR (500 MHz, CDCl3): δ 7.28-7.35 (m, 5H), 7.48 (app t, J = 7.5 Hz, 1H), 7.61-7.64
(m, 3H), 7.71-7.73 (m, 2H), 7.84 (app t, J = 8.0 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H),
13
8.35 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 125.9, 127.4, 128.2, 128.47, 128.49, 128.9, 129.3, 129.7,
130.1, 131.3, 132.9, 133.4, 137.1, 137.7, 139.8, 148.4, 157.6, 197.1; HRMS (ESI): calculated for
C22H16NO, 310.1232 (M+H)+, found: 310.1225.
o
phenyl(2-p-tolylquinolin-3-yl)methanone (3k); Yield: 0.100 g, 62%; White solid; mp: 138-142 C; IR
(KBr): ν 1273, 1660 cm_1; 1H NMR (500 MHz, CDCl3): δ 2.28 (s, 3H), 7.09-7.10 (m, 2H), 7.33-7.36 (m, 2H),
7.48-7.53 (m, 3H), 7.60 (app t, J = 7.5 Hz, 1H), 7.74-7.75 (m, 2H), 7.83 (app t, J = 7.5 Hz, 1H), 7.89 (d, J =
13
8.5 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.30 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 21.3, 125.7, 127.2,
128.1, 128.5, 129.2, 129.7, 130.1, 131.2, 132.9, 133.4, 136.9, 137.1, 137.5, 138.9, 148.4, 157.6, 197.1;
HRMS (ESI): calculated for C23H18NO 324.1388 (M+H)+, found: 324.1379.
(2-(3-bromophenyl)quinolin-3-yl)(phenyl)methanone (3l); Yield: 0.149 g, 77%; Light brown solid; mp:
140-142 oC; IR (KBr): ν 1661 cm_1; 1H NMR (500 MHz, CDCl3): δ 7.12 (app t, J = 8.0 Hz, 1H), 7.35-7.40 (m,
3H), 7.46 (d, J = 7.5 Hz, 1H), 7.51 (app t, J = 7.0 Hz, 1H), 7.65 (app t, J = 7.5 Hz, 1H), 7.71-7.72 (m, 2H),
13
7.85-7.88 (m, 2H), 7.92 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.37 (s, 1H); C{1H} NMR (125 MHz,
CDCl3): δ 122.7, 126.0, 127.7, 127.9, 128.2, 128.6, 129.7, 129.8, 129.9, 131.5, 131.8, 132.3, 132.6, 133.6,
137.0, 138.0, 141.7, 148.3, 155.8, 196.6; HRMS (ESI): calculated for C22H1581BrNO, 390.0317 (M+H)+,
found: 390.0325.
(2-(3-methoxyphenyl)quinolin-3-yl)(phenyl)methanone (3m); Yield: 0.105 g, 62%; White solid; mp: 112-
114 oC; IR (KBr): ν 1660 cm_1; 1H NMR (500 MHz, CDCl3): δ 3.74 (s, 3H), 6.81 (d, J = 7.5 Hz, 1H), 7.16-7.21
(m, 3H), 7.33-7.36 (m, 2H), 7.48 (app t, J = 7.0 Hz, 1H), 7.63 (app t, J = 7.5 Hz, 1H), 7.72-7.73 (m, 2H), 7.84
(app t, J = 7.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H); 13C{1H} NMR (125 MHz,
CDCl3): δ 55.3, 114.2, 115.3, 121.9, 125.9, 127.4, 128.1, 128.4, 129.5, 129.7, 129.9, 131.2, 132.9, 133.4,
137.0, 137.5, 141.0, 148.3, 157.2, 159.6, 196.9; HRMS (ESI): calculated for C23H18NO2, 340.1338 (M+H)+,
found: 340.1337.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 25
1
2
3
4
5
6
7
8
9
(2-(2-bromophenyl)quinolin-3-yl)(phenyl)methanone (3n); Yield: 0.137 g, 71%; White solid; mp: 100-
102 oC; IR (KBr): ν 1265, 1657 cm_1; 1H NMR (500 MHz, CDCl3): δ 7.19 (app t, J = 7.5 Hz, 1H), 7.36 (app t, J
= 7.5 Hz, 1H), 7.40-7.43 (m, 2H), 7.48-7.51 (m, 2H), 7.55 (app t, J = 7.0 Hz, 1H), 7.67 (app t, J = 7.5 Hz,
1H), 7.80-7.82 (m, 2H), 7.87 (app t, J = 7.5 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.40 (s,
13
1H); C{1H} NMR (125 MHz, CDCl3): δ 122.1, 125.9, 127.4, 127.8, 128.37, 128.44, 129.7, 129.9, 130.4,
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
131.6, 131.7, 132.3, 132.7, 133.2, 136.9, 138.3, 140.7, 148.1, 157.8, 195.3; HRMS (ESI): calculated for
C22H1581BrNO, : 390.0317 (M+H)+, found: 390.0313.
(2-(2-chlorophenyl)quinolin-3-yl)(phenyl)methanone (3o); Yield: 0.142 g, 83%; White solid; mp: 112-
o
1
114 C; IR (KBr): ν 1657, cm_1; H NMR (500 MHz, CDCl3): δ 7.25-7.30 (m, 2H), 7.33 (d app t, J = 7.5, 1.5
Hz, 1H), 7.40-7.43 (m, 2H), 7.53-7.56 (m, 2H), 7.66 (app t, J = 7.0 Hz, 1H), 7.80-7.81 (m, 2H), 7.86 (d app t,
13
J = 8.5, 1.5 Hz, 1H), 7.92 (d, J = 8.5 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.38 (s, 1H); C{1H} NMR (125 MHz,
CDCl3): δ 125.9, 127.0, 127.8, 128.39, 128.45, 129.5, 129.76, 129.83, 130.3, 131.62, 131.63, 132.2, 132.6,
133.2, 136.9, 138.2, 138.9, 148.2, 156.6, 195.3; HRMS (ESI): calculated for C22H15ClNO, : 344.0842
(M+H)+, found: 344.0837.
(2-(2-bromo-5-fluorophenyl)quinolin-3-yl)(phenyl)methanone (3p); Yield: 0.162 g, 80%; White solid;
o
1
mp: 140-144 C; IR (KBr): ν 1260, 1654 cm_1; H NMR (500 MHz, CDCl3): δ 6.94 (d app t, J = 8.0, 3.0 Hz,
1H), 7.27 (dd, J = 8.5, 3.0 Hz, 1H), 7.44-7.47 (m, 3H), 7.58 (app t, J = 7.0 Hz, 1H), 7.69 (app t, J = 7.5 Hz,
1H), 7.83-7.84 (m, 2H), 7.89 (d app t, J = 7.5, 1.0 Hz, 1H), 7.94 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H),
13
8.41 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 116.3 (d, J = 3.1 Hz), 117.1 (d, J = 22.5 Hz), 118.8 (d, J =
23.8 Hz), 126.0, 128.1, 128.47, 128.52, 129.7, 130.4, 131.87, 131.92, 133.3, 133.9 (d, J = 8.0 Hz), 136.7,
138.7, 142.6 (d, J = 7.9 Hz), 148.0, 156.9, 161.8 (d, J = 246.6 Hz), 194.9; HRMS (ESI): calculated for
C22H1481BrFNO, 408.0222 (M+H)+, found: 408.0217.
(2-(naphthalen-1-yl)quinolin-3-yl)(phenyl)methanone (3q); Yield: 0.109 g, 61%; White solid; mp: 130-
132 oC; IR (KBr): ν 1257, 1651 cm_1; 1H NMR (500 MHz, CDCl3): δ 7.07-7.10 (m, 2H), 7.26 (app t, J = 7.0 Hz,
1H), 7.33 (app t, J = 7.5 Hz, 1H), 7.39-7.44 (m, 3H), 7.48-7.49 (m, 2H), 7.67-7.71 (m, 2H), 7.74-7.75 (m,
1H), 7.88 (d app t, J = 7.5, 1.5 Hz, 1H), 7.91-7.92 (m, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H),
13
8.50 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 124.9, 125.7, 125.9, 126.1, 126.6, 127.6, 127.9, 128.2,
128.4, 129.2, 129.3, 129.8, 131.5, 131.6, 132.8, 133.7, 134.5, 137.1, 137.2, 137.7, 148.3, 157.5, 196.6;
HRMS (ESI): calculated for 360.1388 C26H18NO, (M+H)+, found: 360.1386.
16
ACS Paragon Plus Environment

Page 17 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(4-bromophenyl)(2-(3-methoxyphenyl)quinolin-3-yl)methanone (3r); Yield: 0.150 g, 72%; White solid;
mp: 164-168 oC; IR (KBr): ν 1581, 1662, cm_1; 1H NMR (500 MHz, CDCl3): δ 3.77 (s, 3H), 6.83 (dd, J = 8.0,
2.0 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 7.17-7.20 (m, 2H), 7.45-7.47 (m, 2H), 7.55-7.56 (m, 2H), 7.63 (app t, J
= 7.5 Hz, 1H), 7.85 (app t, J = 7.5 Hz, 1H), 7.915 (d, J = 8.0 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.34 (s, 1H);
13C{1H} NMR (125 MHz, CDCl3): δ 55.3, 114.3, 115.3, 121.9, 125.9, 127.5, 128.2, 128.7, 129.6, 129.7,
131.3, 131.4, 131.8, 132.4, 135.8, 137.7, 140.9, 148.4, 157.0, 159.7, 196.0; HRMS (ESI): calculated for
C23H17BrNO2, 418.0443 (M+H)+, found: 418.0455.
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
(4-bromophenyl)(2-phenylquinolin-3-yl)methanone (3s); Yield: 0.137 g, 71%; White solid; mp: 180-184
1
oC; IR (KBr): ν 1583, 1660 cm_1; H NMR (500 MHz, CDCl3): δ 7.29-7.32 (m, 3H), 7.44-7.46 (m, 2H), 7.54-
7.56 (m, 2H), 7.59-7.61 (m, 2H), 7.63 (app t, J = 7.5 Hz, 1H), 7.85 (app t, J = 7.5 Hz, 1H), 7.92 (d, J = 8.0 Hz,
13
1H), 8.25 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 125.8, 127.5, 128.2, 128.6,
128.7, 129.1, 129.3, 129.8, 131.4, 131.5, 131.8, 132.4, 135.8, 137.8, 139.6, 148.5, 157.3, 196.1; HRMS
(ESI): calculated for C22H15BrNO, 388.0337 (M+H)+, found: 388.0342.
(2-(2-chlorophenyl)quinolin-3-yl)(p-tolyl)methanone (3t);22b Yield: 0.125 g, 70%; White solid; mp: 170-
o
1
174 C; IR (KBr): ν 1654 cm_1; H NMR (500 MHz, CDCl3): δ 2.41 (s, 3H), 7.22-7.23 (m, 2H), 7.27-7.31 (m,
2H), 7.34 (d app t, J = 7.0, 1.5 Hz, 1H), 7.55 (dd, J = 7.0, 1.5 Hz, 1H), 7.65 (app t, J = 7.0 Hz, 1H), 7.72-7.74
(m, 2H), 7.86 (d app t, J = 7.0, 1.5 Hz, 1H), 7.91 (d, J = 8.0 Hz, 1H), 8.24 (d, J = 8.5 Hz, 1H), 8.35 (s, 1H);
13C{1H} NMR (125 MHz, CDCl3): δ 21.8, 125.9, 127.0, 127.8, 128.4, 129.1, 129.5, 129.75, 129.79, 130.6,
131.5, 131.6, 132.2, 132.8, 134.3, 138.0, 139.0, 144.2, 148.1, 156.6, 194.9; HRMS (ESI): calculated for
C23H17ClNO, 358.0999 (M+H)+, found: 358.0996.
(2-(4-chlorophenyl)-6-methoxyquinolin-3-yl)(phenyl)methanone (3u); Yield: 0.132 g, 71%; White solid;
mp: 190-194 oC; IR (KBr): ν 1226, 1661 cm_1; 1H NMR (500 MHz, CDCl3): δ 3.95 (s, 3H), 7.14 (d, J = 3.0 Hz,
1H), 7.25-7.26 (m, 2H), 7.35-7.38 (m, 2H), 7.48-7.51 (m, 2H), 7.53-7.56 (m, 2H), 7.72-7.73 (m, 2H), 8.11
(d, J = 9.5 Hz, 1H), 8.21 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 55.7, 105.2, 124.4, 127.0, 128.58,
128.61, 130.0, 130.5, 131.1, 132.8, 133.6, 134.8, 136.4, 136.9, 138.3, 144.5, 153.7, 158.6, 197.0; HRMS
(ESI): calculated for C23H17ClNO2, 374.0948 (M+H)+, found: 374.0958.
(6-chloro-2-(4-chlorophenyl)quinolin-3-yl)(phenyl)methanone (3v); Yield: 0.153 g, 81%; White solid;
mp: 204-208 oC; IR (KBr): ν 1660 cm_1; 1H NMR (500 MHz, CDCl3): δ 7.26-7.28 (m, 2H), 7.36-7.39 (m, 2H),
7.52-7.57 (m, 3H), 7.71-7.73 (m, 2H), 7.77 (dd, J = 9.0, 2.0 Hz, 1H), 7.88 (d, J = 1.5 Hz, 1H), 8.16 (d, J = 9.5
13
Hz, 1H), 8.23 (s, 1H); C{1H} NMR (125 MHz, CDCl3): δ 126.5, 126.7, 128.7, 128.8, 130.1, 130.6, 131.3,
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 25
1
2
3
4
5
6
132.3, 133.39, 133.43, 133.9, 135.4, 136.6, 136.7, 137.8, 146.7, 156.4, 196.4; HRMS (ESI): calculated for
C22H14Cl2NO, 378.0452 (M+H)+, found: 378.0445.
phenyl(2-(pyridin-3-yl)quinolin-3-yl)methanone (3w); Yield: 0.132 g, 85%; Colorless solid; mp: 138-140
7
8
9
1
oC; IR (KBr): ν 1662 cm_1; H NMR (500 MHz, CDCl3): δ 7.25 (dd, J = 8.0, 5.0 Hz, 1H), 7.37-7.40 (m, 2H),
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
7.53 (app t, J = 7.5 Hz, 1H), 7.66 (app t. J = 7.5 Hz, 1H), 7.76-7.77 (m, 2H), 7.88 (app t, J = 7.5 Hz, 1H), 7.93
(d, J = 8.0 Hz, 1H), 7.96 (appt d, J = 7.5, 1.5 Hz, 1H), 8.25 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H), 8.525 (d, J = 5.0
13
Hz, 1H), 8.85 (d, J = 1.5 Hz, 1H); C{1H} NMR (125 MHz, CDCl3): δ 123.2, 125.9, 127.9, 128.3, 128.7,
129.8, 130.2, 131.7, 132.6, 133.8, 135.5, 136.5, 136.9, 138.0, 148.5, 149.8, 150.1, 154.6, 196.4; HRMS
(ESI): calculated for C21H15N2O, 311.1184 (M+H)+, found: 311.1174.
(2'-chloro-[2,3'-biquinolin]-3-yl)(phenyl)methanone (3x); Yield: 0.158 g, 80%; Light brown solid; mp:
100-104 oC; IR (KBr): ν 1660 cm_1; 1H NMR (500 MHz, CDCl3): δ 7.44-7.47 (m, 2H), 7.57-7.60 (m, 2H), 7.71
(app t, J = 7.5 Hz, 1H), 7.75 (app t, J = 7.5 Hz, 1H), 7.86-7.87 (m, 2H), 7.89-7.93 (m, 2H), 7.96 (d, J = 8.0 Hz,
13
1H), 8.02 (d, J = 8.5 Hz, 1H), 8.26 (d, J = 8.5 Hz, 1H), 8.43 (s, 1H), 8.45 (s, 1H); C{1H} NMR (125 MHz,
CDCl3): δ 126.0, 127.2, 127.3, 128.1, 128.3, 128.4, 128.6, 129.8, 130.5, 130.9, 132.07, 132.14, 133.46,
133.48, 136.6, 138.8, 140.1, 147.5, 148.1, 148.3, 155.3, 195.1; HRMS (ESI): calculated for C25H16ClN2O,
395.0951 (M+H)+, found: 395.0960.
(2-(4-chlorophenyl)quinolin-3-yl)(thiophen-2-yl)methanone (3y); Yield: 0.061 g, 35%; White solid; mp:
o
1
168-172 C; IR (KBr): ν 1581, 1662 cm_1; H NMR (500 MHz, CDCl3): δ 7.04 (app t, J = 4.5 Hz, 1H), 7.33-
7.34 (m, 2H), 7.37 (d, J = 3.5 Hz, 1H), 7.62-7.65 (m, 3H), 7.705 (d, J = 5.0 Hz, 1H), 7.85 (app t, J = 7.5 Hz,
1H), 7.91 (d, J = 8.0 Hz, 1H), 8.22 (d, J = 8.5 Hz, 1H), 8.40 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 125.8,
127.7, 128.2, 128.4, 128.8, 129.7, 130.6, 131.5, 132.4, 135.3, 135.6, 135.8, 137.4, 138.1, 144.2, 148.4,
155.8, 188.6; HRMS (ESI): calculated for C20H13ClNOS, 350.0406 (M+H)+, found: 350.0415.
1-(2-(4-chlorophenyl)quinolin-3-yl)ethan-1-one (3z); Yield: 0.088 g, 63%; colorless viscous liquid; IR:
1692 ν cm_1; 1H NMR (500 MHz, CDCl3): δ 2.25 (s, 3H), 7.49-7.50 (m, 2H), 7.61-7.64 (m, 3H), 7.83 (app t, J
= 7.0 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 8.39 (s, 1H); 13C{1H} NMR (125 MHz, CDCl3):
δ 30.5, 126.2, 127.6, 128.5, 129.2, 129.6, 130.5, 131.7, 134.5, 135.7, 137.2, 138.8, 148.3, 155.7, 202.6;
HRMS (ESI): calculated for C17H13ClNO, 282.0686 (M+H)+, found: 282.0632.
(4-bromophenyl)(2-(4-chlorophenyl)-1,2-dihydroquinolin-3-yl)methanone (2c); Yield: 0.184 g, 87%; Red
o
1
solid; mp: 174-176 C; IR (KBr): ν 1619, 2928, 3366 cm_1; H NMR (500 MHz, CDCl3): δ 4.56 (s, 1H), 5.91
(d, J = 2.0 Hz, 1H), 6.49 (d, J = 8.0 Hz, 1H), 6.64 (app t, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 7.11 (s, 1H),
18
ACS Paragon Plus Environment

Page 19 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
7.14 (app t, J = 8.5 Hz, 1H), 7.22-7.24 (m, 2H), 7.35-7.36 (m, 2H), 7.46-7.47 (m, 2H), 7.57-7.58 (m, 2H);
13C{1H} NMR (125 MHz, CDCl3): δ 54.3, 113.4, 117.6, 118.1, 126.5, 127.6, 129.0, 130.3, 130.5, 131.1,
131.7, 133.2, 133.7, 137.2, 138.8, 143.1, 144.6, 193.9; HRMS (ESI): calculated for C22H1681BrClNO,
426.0083 (M+H)+, found: 426.0067.
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
(2-chlorophenyl)(2-(4-chlorophenyl)-1,2-dihydroquinolin-3-yl)methanone (2h); Yield: 0.180 g, 95%;
Yellow solid; mp: 140-144 oC; IR (KBr): ν 1617, 3394 cm_1; 1H NMR (500 MHz, CDCl3): δ 4.65 (s, 1H), 5.91
(d, J = 1.0 Hz, 1H), 6.47 (d, J = 8.0 Hz, 1H), 6.60 (app t, J = 7.0 Hz, 1H), 6.94-6.96 (m, 2H), 7.12 (app t, J =
7.5 Hz, 1H), 7.195 (d, J = 8.0 Hz, 1H), 7.23-7.25 (m, 2H), 7.30 (d app t, J = 7.5, 1.5 Hz, 1H), 7.36-7.42 (m,
13
4H); C{1H} NMR (125 MHz, CDCl3): δ 53.5, 113.5, 117.6, 118.0, 126.6, 127.8, 128.77, 128.84, 130.1,
130.6, 130.7, 131.2, 131.3, 133.5, 133.6, 138.4, 140.7, 142.9, 144.9, 193.4; HRMS (ESI): calculated for
C22H16Cl2NO, 380.0609 (M+H)+, found: 380.0589.
(2-(3-methoxyphenyl)-1,2-dihydroquinolin-3-yl)(phenyl)methanone (2m); Yield: 0.116 g, 68%; Yellow
solid; mp: 150-154 oC; IR (KBr): ν 1607, 3293 cm_1; 1H NMR (500 MHz, CDCl3): δ 3.73 (s, 3H), 4.58 (s, 1H),
5.95 (s, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.60 (app t, J = 7.5 Hz, 1H), 6.77 (dd, J = 8.0, 2.0 Hz, 1H), 6.98-7.00
(m, 2H), 7.03 (d, J = 8.0 Hz, 1H), 7.10 (app t, J = 7.5 Hz, 1H), 7.13 (s, 1H), 7.19 (app t, J = 7.5 Hz, 1H), 7.41-
7.44 (m, 2H), 7.52 (app t, J = 7.0 Hz, 1H), 7.61-7.63 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3): δ 54.6, 55.2,
112.0, 113.0, 113.2, 117.7, 117.9, 118.6, 128.3, 128.9, 129.8, 130.1, 131.5, 131.6, 132.7, 138.5, 138.6,
144.7, 146.3, 159.8, 195.2; HRMS (ESI): calculated for C23H20NO2, 342.1494 (M+H)+, found: 342.1496.
(2-(2-bromo-5-fluorophenyl)-1,2-dihydroquinolin-3-yl)(phenyl)methanone (2p); Yield: 0.175 g, 86%;
Yellow solid; mp: 144-146 oC; IR (KBr): ν 1626, 3413 cm_1; 1H NMR (500 MHz, CDCl3): δ 4.98 (s, 1H), 6.19
(s, 1H), 6.45 (d, J = 8.0 Hz, 1H), 6.65 (app t, J = 7.5 Hz, 1H), 6.835 (d app t, J = 7.5, 3.0 Hz, 1H), 7.03 (dd, J =
9.0 , 2.5 Hz, 1H), 7.07-7.12 (m, 2H), 7.47-7.58 (m, 5H), 7.69-7.71 (m, 2H); 13C{1H} NMR (125 MHz, CDCl3):
δ 53.6, 114.1, 115.9 (d, J = 23.4 Hz), 116.6 (d, J = 22.6 Hz), 118.2, 118.4, 128.5, 129.0, 129.2, 130.3,
131.7, 133.0, 134.5 (d, J = 7.6 Hz), 138.1, 141.2, 143.2 (d, J = 5.3 Hz), 143.8, 162.5 (d, J = 246.1 Hz), 194.1;
HRMS (ESI): calculated for C22H1681BrFNO, 410.0379 (M+H)+, found: 410.0381.
(4-bromophenyl)(2-(3-methoxyphenyl)-1,2-dihydroquinolin-3-yl)methanone (2r); Yield: 0.161 g, 77%;
Red solid; mp: 104-108 oC; IR (KBr): ν 1617, 3360 cm_1; 1H NMR (500 MHz, CDCl3): δ 3.73 (s, 3H), 4.59 (s,
1H), 5.92 (d, J = 1.0 Hz, 1H), 6.48 (d, J = 8.0 Hz, 1H), 6.62 (app t, J = 7.5 Hz, 1H), 6.77 (dd, J = 8.0 , 2.0 Hz,
1H), 6.96 (d, J = 2.0 Hz, 1H), 6.99 (d, J = 7.5 Hz, 1H), 7.01 (d, J = 8.0 Hz, 1H), 7.09 (s, 1H), 7.12 (app t, J =
13
7.5 Hz, 1H), 7.20 (app t, J = 8.0 Hz, 1H), 7.48-7.50 (m, 2H), 7.56-7.58 (m, 2H); C{1H} NMR (125 MHz,
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 25
1
2
3
4
5
6
CDCl3): δ 54.7, 55.2, 112.1, 113.0, 113.3, 117.7, 117.9, 118.6, 126.3, 129.9, 130.2, 130.5, 131.3, 131.6,
133.0, 137.4, 138.6, 144.8, 146.2, 159.9, 194.1; HRMS (ESI): calculated for C23H1981BrNO2, 422.0579
(M+H)+, found: 422.0589.
7
8
9
4-(2-(4-chlorophenyl)-3-(2-methoxybenzoyl)quinolin-1(2H)-yl)butan-2-one (6); Yield: 0.09 g, 76%;
Orange solid; mp: 150-154 oC; IR (KBr): ν 1623 cm_1; 1H NMR (500 MHz, CDCl3): δ 2.09 (s, 3H), 2.53-2.60
(m, 1H), 2.75-2.81 (m, 1H), 3.56-3.64 (m, 2H), 3.67 (s, 3H), 5.90 (s, 1H), 6.55 (d, J = 8.5 Hz, 1H), 6.61 (app
t, J = 7.5 Hz, 1H), 6.89 (s, 1H), 6.92 (d, J = 8.5 Hz, 1H), 6.93-6.98 (m, 2H), 7.10 (d, J = 8.0 Hz, 1H), 7.20-7.24
(m, 3H), 7.31-7.32 (m, 2H), 7.39 (d app t, J = 8.0, 1.5 Hz, 1H); 13C{1H} NMR (125 MHz, CDCl3): δ 30.5, 40.9,
44.2, 55.7, 60.7, 110.7, 111.5, 116.9, 119.6, 120.3, 128.2, 128.6, 128.8, 131.1, 131.2, 132.3, 133.2, 133.5,
138.3, 141.5, 144.9, 157.0, 194.6, 207.1; HRMS (ESI): calculated for C27H25ClNO3, 446.1523 (M+H)+,
found: 446.1520.
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
(2-(4-chlorophenyl)quinoline-1,3(2H)-diyl)bis(phenylmethanone) (7); Yield: 0.108 g, 81%; yellow
1
viscous liquid; IR (neat): ν 1644, 1713 cm_1; H NMR (500 MHz, CDCl3): δ 6.60 (d, J = 7.0 Hz, 1H), 6.98
(app t, J = 7.5 Hz, 1H), 7.05-7.08 (m, 2H), 7.18-7.19 (m, 2H), 7.27-7.31 (m, 5H), 7.37-7.41 (m, 3H), 7.45 (s,
13
1H), 7.50-7.53 (m, 2H), 7.61 (app t, J = 7.5 Hz, 1H), 7.74-7.76 (m, 2H); C{1H} NMR (125 MHz, CDCl3): δ
53.8, 125.2, 125.96, 126.04, 128.3, 128.6, 128.7, 128.8, 128.9, 129.18, 129.23, 130.3, 131.0, 132.3,
133.8, 134.9, 136.9, 137.0, 137.3, 137.5, 137.7, 170.0, 194.0; HRMS (ESI): calculated forC29H20ClNO2Na,
472.1080 (M+Na)+, found: 472.1081.
(2-(4-chlorophenyl)-4-ethoxy-1,2,3,4-tetrahydroquinolin-3-yl)(phenyl)methanone (8a); Yield: 0.014 g,
1
7%; colorless liquid; IR : ν 1088, 1486, 1672, 3372 cm_1; H NMR (500 MHz, CDCl3): δ 1.00 (t, J = 7.0 Hz,
3H) 3.40-3.46 (m, 1H), 3.61-3.67 (m, 1H), 4.01 (bs, 1H), 4.12 (app t, J = 10.0 Hz, 1H), 4.755 (d, J = 10.0 Hz,
1H), 5.07 (d, J = 9.5 Hz, 1H), 6.57 (d, J = 8.0 Hz, 1H), 6.79 (app t, J = 7.5 Hz, 1H),7.01-7.14 (m, 3H), 7.27-
13
7.32 (m, 4H), 7.375 (d, J = 8.0 Hz, 1H), 7.45 (app t, J = 7.0 Hz, 1H), 7.67-7.69 (m, 2H); C{1H} NMR (125
MHz, CDCl3): δ 15.4, 53.4, 59.2, 67.5, 78.7, 113.9, 118.1, 123.1, 126.8, 128.1, 128.4, 128.6, 128.8, 129.0,
133.1, 133.9, 138.4, 138.7, 143.4, 203.1. C24H23ClNO2, 392.1417 (M+H)+, found: 392.1416.
Associated Content
Supporting information
The Supporting Information is available free of charge on the ACS Publications website
Copies of 1H and 13C NMR Spectra (PDF)
20
ACS Paragon Plus Environment

Page 21 of 25
The Journal of Organic Chemistry
1
2
3
4
Author Information
5
6
Corresponding author
7
8
9
E-mail: kishorbharadwaj@gmail.com
Notes
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
The author declare no competing financial interest
Acknowledgments
KCB is thankful to CSIR, New Delhi for funding [13(8930-A) 2017], Prof. R. M. Singh BHU, for valuable
support and director CBMR, for HRMS.
References
1. (a) Pellissier, H. Recent developments in the asymmetric organocatalytic Morita-Baylis-Hillman
reaction. Tetrahedron 2017, 73, 2831-2861. (b) Wei, Y.; Shi, M. Recent Advances in
Organocatalytic Asymmetric Morita-Baylis-Hillman/aza-Morita-Baylis-Hillman Reactions. Chem.
Rev. 2013, 113, 6659-6690. (c) Basavaiah, D.; Reddy, B. S.; Badsara, S. S. Recent Contributions
from the Baylis-Hillman Reaction to Organic Chemistry. Chem. Rev. 2010, 110, 5447-5674.
2. (a) Xie, P.; Huang, Y. Morita-Baylis-Hillman adduct derivatives (MBHADs): versatile reactivity in
Lewis base-promoted annulation. Org. Biomol. Chem. 2015, 13, 8578-8595. (b) Liu, T.-Y.; Xie, M.;
Chen, Y.-C. Organocatalytic asymmetric transformations of modified Morita-Baylis-Hillman
adducts. Chem. Soc. Rev. 2012, 41, 4101-4112. (c) Singh, V.; Batra, S. Advances in the Baylis-
Hillman reaction-assisted synthesis of cyclic frameworks. Tetrahedron 2008, 64, 4511-4574.
3. (a) Gu, J.; Xiao, B.-X.; Chen, Y.-R.; Li, Q.-Z.; Ouyang, Q.; Du, W.; Chen, Y.-C. Interrupted Morita-
Baylis-Hillman-Type Reaction of α‑Substituted Activated Olefins. Org. Lett. 2018, 20, 2088-2091.
(b) Zhong, Y.; Zhao, X.; Gan, L.; Hong, S.; Jiang, X. Phosphine-Catalyzed Enantioselective [4 + 2]
Cycloaddition-Semipinacol-Type-Rearrangement Reaction of Morita-Baylis-Hillman Carbonates.
Org. Lett. 2018, 20, 4250-4254. (c) Enevoldsen, M. V.; Overgaard, J.; Pedersen, M. S.; Lindhardt,
A. T. Organocatalyzed Decarboxylative Trichloromethylation of Morita-Baylis-Hillman Adducts in
Batch and Continuous Flow. Chem. Eur. J. 2018, 24, 1204-1208. (d) Kamlar, M.; Císařová, I.;
Hybelbauerová, S.; Veselý, J. Asymmetric Allylic Amination of Morita-Baylis-Hillman Carbonates
with Silylated tert-Butylhydroxycarbamate Derivatives. Eur. J. Org. Chem. 2017, 1926-1930. (e)
Gupta, T.; Bharadwaj, K. C.; Singh, R. M. Cascade SN2′–SNAr, Elimination, and 1,5-Hydride Shift
Reactions by Acetylacetone/Acetoacetic Esters: Synthesis of 9,10-Dihydroacridines. Eur. J. Org.
Chem. 2016, 4981-4984. (f) Basavaiah, D.; Pal, S.; Veeraraghavaiah, G.; Bharadwaj, K. C. The
Baylis-Hillman acetates as a source of ambiphilic molecules: a simple synthesis of 1,3-thiazinane-
2-thione frameworks. Tetrahedron 2015, 71, 4659-4664.
4. Reddy, T. N.; Rao, V. J. Importance of Baylis-Hillman adducts in modern drug discovery.
Tetrahedron Lett. 2018, 59, 2859-2875.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 25
1
2
3
4
5
6
7
8
9
5. (a) Pawar, B.; Padalkar, V.; Phatangare, K.; Nirmalkar, S.; Chaskar, A. Miceller media accelerated
Baylis-Hillman reaction. Catal. Sci. Technol. 2011, 1, 1641-1644. (b) Lee, K. Y.; GowriSankar, S.;
Kim, J. N. N,N,N’,N’-Tetramethyl-1,3-propanediamine as the catalyst of choice for the Baylis-
Hillman reaction of cycloalkenone: rate acceleration by stabilizing the zwitterionic intermediate
via the ion-dipole interaction. Tetrahedron Lett. 2004, 45, 5485-5488. (c) Lee, W.-D.; Yang, K.-S.;
Chen, K. A remarkable rate acceleration of the Baylis-Hillman reaction. Chem. Commun. 2001,
1612-1613. (d) Aggarwal, V. K.; Mereu, A.; Tarver, G. J.; McCague, R. Metal- and Ligand-
Accelerated Catalysis of the Baylis-Hillman Reaction. J. Org. Chem. 1998, 63, 7183-7189.
6. (a) Areces, P.; Carrasco, E.; Mancha, A.; Plumet, J. Tandem β-Elimination-Morita-Baylis-Hillman
Reaction in α,β-Unsaturated Sugar Aldehydes. Synthesis, 2006, 946-948. (b) Guo, W.; Wu, W.;
Fan, N.; Wu, Z.; Xia, C. Synthesis of α-Substituted N-Aryl Acrylamide Derivatives Through Baylis-
Hillman Reaction. Synth. Commun. 2005, 35, 1239-1251. (c) Faltin, C.; Fleming, E. M.; Connon, S.
J. Acrylamide in the Baylis-Hillman Reaction: Expanded Reaction Scope and the Unexpected
Superiority of DABCO over More Basic Tertiary Amine Catalysts. J. Org. Chem. 2004, 69, 6496-
6499. (d) Gatri, R.; Gaïed, M. M. E. Imidazole-catalysed Baylis-Hillman reactions: a new route to
allylic alcohols from aldehydes and cyclic enones. Tetrahedron Lett. 2002, 43, 7835-7836. (e)
Nayak, S. K.; Thijs, L.; Zwanenburg, B. Baylis-Hillman Reaction of N-Trityl Aziridine-2-(S)-
Carboxaldehyde. Tetrahedron Lett. 1999, 40, 981-984.
7. (a) Park, K.-S.; Kim, J.; Choo, H.; Chong, Y. Octanol-Accelerated Baylis-Hillman Reaction. Synlett
2007, 395-398. (b) Luo, S.; Wang, P. G.; Cheng, J.-P. Remarkable Rate Acceleration of Imidazole-
Promoted Baylis-Hillman Reaction Involving Cyclic Enones in Basic Water Solution. J. Org. Chem.
2004, 69, 555-558. (c) Aggarwal, V. K.; Dean, D. K.; Mereu, A.; Williams, R. Rate Acceleration of
the Baylis-Hillman Reaction in Polar Solvents (Water and Formamide). Dominant Role of
Hydrogen Bonding, Not Hydrophobic Effects, Is Implicated. J. Org. Chem. 2002, 67, 510-514. (d)
Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Dramatic Rate Acceleration of the Baylis-Hillman Reaction in
Homogeneous Medium in the Presence of Water. Org. Lett. 2002, 4, 4723-4725.
8. (a) Balan, D.; Adolfsson. H. Titanium Isopropoxide as Efficient Catalyst for the Aza-Baylis-Hillman
Reaction. Selective Formation of α-Methylene-β-amino Acid Derivatives. J. Org. Chem. 2002, 67,
2329-2334. (b) Walsh, L. M.; Winn, C. L.; Goodman, J. M. Sulfide-BF3·OEt2 mediated Baylis-
Hillman reactions. Tetrahedron Lett. 2002, 43, 8219-8222. (c) Kataoka, T.; Iwama, T.; Tsujiyama,
S.-i. The chalcogeno-Baylis-Hillman reaction: the first examples catalysed by chalcogenides in
the presence of Lewis acids. Chem. Commun. 1998, 197-198.
9. (a) Meng, X.; Huang, Y.; Chen, R. A Novel Selective Aza-Morita–Baylis–Hillman (aza-MBH)
Domino Reaction and Aza-MBH Reaction of N-Sulfonated Imines with Acrolein Catalyzed by a
Bifunctional Phosphine Organocatalyst. Chem. Eur. J. 2008, 14, 6852-6856. (b) He, L.; Jian, T.-Y.;
Ye S. N-Heterocyclic Carbene Catalyzed Aza-Morita-Baylis-Hillman Reaction of Cyclic Enones
with N-Tosylarylimines. J. Org. Chem. 2007, 72, 7466-7468. (c) Tang, X.; Zhang, B.; He, Z.; Gao,
R.; He, Z. 1,3,5-Triaza-7-phosphaadamantane (PTA): A Practical and Versatile Nucleophilic
Phosphine Organocatalyst. Adv. Synth. Catal. 2007, 349, 2007-2017.
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
10. (a) Lin, Y.-S.; Lin, C.-Y.; Liu, C.-W.; Tsai, T. Y. R. A highly active ionic liquid catalyst for Morita-
Baylis-Hillman reaction. Tetrahedron 2006, 62, 872-877. (b) Deb, I.; Dadwal, M.; Mobin, S. M.;
Namboothiri, I. N. N. Hydroxyalkylation of Conjugated Nitroalkenes with Activated
22
ACS Paragon Plus Environment

Page 23 of 25
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Nonenolizable Carbonyl Compounds. Org. Lett. 2006, 8, 1201-1204. (c) Dadwal, M.; Mobin, S.
M.; Namboothiri, I. N. N. Highly efficient hydrazination of conjugated nitroalkenes via imidazole
or DMAP mediated Morita-Baylis-Hillman reaction. Org. Biomol. Chem. 2006, 4, 2525-2528. (d)
Rafel, S.; Leahy, J. W. An Unexpected Rate Acceleration-Practical Improvements in the Baylis-
Hillman Reaction. J. Org. Chem. 1997, 62, 1521-1522.
11. (a) Kim, K. H.; Lee, H. S.; Kim, Y. M.; Kim, J. N. Remarkable Rate Acceleration of Baylis-Hillman
Reaction of Notorious α,β-Unsaturated Aldehydes Catalyzed by Proton Donor. Bull. Korean
Chem. Soc. 2011, 32, 1087-1090. (b) Souza, R. O. M. A. de.; Meireles, B. A.; Aguiar, L. C. S.;
Vasconcellos, M. L. A. A. Hexamethylenetetramine as a Cheap and Convenient Alternative
Catalyst in the Baylis-Hillman Reaction: Synthesis of Aromatic Compounds with Anti-Malarial
Activity. Synthesis 2004, 1595-1600. (c) Luo, S.; Zhang, B.; He, J.; Janczuk, A.; Wang, P. G.; Cheng,
J.-P. Aqueous Baylis-Hillman reactions of cyclopent-2-enone using imidazole as catalyst.
Tetrahedron Lett. 2002, 43, 7369-7371.
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
12. Bharadwaj, K. C. Intramolecular Morita-Baylis-Hillman and Rauhut-Currier reactions. A catalytic
and atom economic route for carbocycles and heterocycles. RSC Adv. 2015, 5, 75923-75946.
13. (a) Li, K.; Jin, Z.; Chan, W.-L.; Lu, Y. Enantioselective Construction of Bicyclic Pyran and
Hydrindane Scaffolds via Intramolecular Rauhut-Currier Reactions Catalyzed by Thiourea-
Phosphines. ACS Catal. 2018, 8, 8810-8815. (b) Satpathi, B.; Wagulde, S. V.; Ramasastry, S. S. V.
An enantioselective organocatalytic intramolecular Morita-Baylis-Hillman (IMBH) reaction of
dienones, and elaboration of the IMBH adducts to fluorenones. Chem. Commun. 2017, 53, 8042-
8045. (c) Kishi, K.; Arteaga, F. A.; Takizawa, S.; Sasai, H. Multifunctional catalysis: stereoselective
construction of α-methylidene-γ-lactams via an amidation/Rauhut-Currier sequence. Chem.
Commun. 2017, 53, 7724-7727. (d) Su, X.; Zhou, W.; Li, Y.; Zhang, J. Design, Synthesis, and
Application of a Chiral Sulfinamide Phosphine Catalyst for the Enantioselective Intramolecular
Rauhut-Currier Reaction. Angew. Chem. Int. Ed. 2015, 54, 6874-6877. (e) Zhang, X.; Ma, P.;
Zhang, D.; Lei, Y.; Zhang, S.; Jiang, R.; Chen, W. Bifunctional Ferrocene-based
squaramidephosphine as an organocatalyst for highly enantioselective intramolecular Morita-
Baylis-Hillman reaction. Org. Biomol. Chem. 2014, 12, 2423-2426. (f) MacKay, J. A.; Landis, Z. C.;
Motika, S. E.; Kench, M. H. The Intramolecular Allenolate Rauhut-Currier Reaction. J. Org. Chem.
2012, 77, 7768-7774. (g) Andrews, I. P.; Kwon, O. Enantioselective total synthesis of (+)-
ibophyllidine via an asymmetric phosphine-catalyzed [3 + 2] annulation. Chem. Sci. 2012, 3,
2510-2514. (h) Song, H.-L.; Yuan, K.; Wu, X.-Y. Chiral phosphine-squaramides as enantioselective
catalysts for the intramolecular Morita-Baylis-Hillman reaction. Chem. Commun. 2011, 47, 1012-
1014. (i) Sirasani, G.; Andrade, R. B. Sequential One-Pot Cyclizations: Concise Access to the ABCE
Tetracyclic Framework of Strychnos Alkaloids. Org. Lett. 2009, 11, 2085-2088.
14. (a) Ghandi, M.; Bozcheloei, A. H.; Nazari, S. H.; Sadeghzadeh, M. Solvent-Dependent Reactions
for the Synthesis of β-Keto-Benzo-δ- Sultone Scaffolds via DBU-Catalyzed O-
Sulfonylation/Intramolecular Baylis-Hillman/1,3-H Shift or Dehydration Tandem Sequences. J.
Org. Chem. 2011, 76, 9975-9982. (b) Trifonov, V. V.; Goncharov, V. I.; Aksenov, A. V. NOVEL
APPLICATION OF THE BAYLIS-HILLMAN REACTION. Chem. Hetrocycl. Compd. 2006, 42, 955-956.
15. (a) Okuma, K.; Koga, T.; Ozaki, S.; Suzuki, Y.; Horigami, K.; Nagahora, N.; Shioji, K.; Fukuda, M.;
Deshimaru, M. One-pot synthesis of dibenzo[b,h][1,6]naphthyridines from 2-
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 25
1
2
3
4
5
6
7
8
9
acetylaminobenzaldehyde: application to a fluorescent DNA-binding compound. Chem.
Commun. 2014, 50, 15525-15528. (b) Basavaiah, D.; Reddy, G. C.; Bharadwaj, K. C. The
Acrylamide Moiety as an Activated Alkene Component in the Intramolecular Baylis-Hillman
Reaction: Facile Synthesis of Functionalized α-Methylene Lactam and Spirolactam Frameworks.
Eur. J. Org. Chem. 2014, 1157-1162. (c) Yin, D.; Wang, W.; Peng, Y.; Ge, Z.; Cheng, T.; Wang, X.;
Li, R. Synthesis of furo[3,4-c]quinolin-3(1H)-one derivatives through TMG catalyzed
intramolecular aza-MBH reaction based on the furanones. RSC Adv. 2014, 5, 17296-17299. (d)
Basavaiah, D.; Reddy, G. C.; Bharadwaj, K. C. Less reactive ketones as electrophiles and
acrylamides as activated alkenes in intramolecular Baylis-Hillman reaction: facile synthesis of
functionalized γ-lactam frameworks. Tetrahedron 2014, 70, 7991-7995.
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
16. (a) Wang, Y.; Jaunet, A.; Geoffroy, P.; Miesch, M. Phosphine-Catalyzed Reactions of Activated
Olefins Tethered to Cycloalkanones. Substrate- and Solvent-Controlled Synthesis of
Bicyclo[3.2.1]octanones, Mixed Acetals, and Morita-Baylis-Hillman Products. Org. Lett. 2013, 15,
6198-6201. (b) Duarte, M. O.; Stedele, G.; Pazinatto, M.; Oliveira, E. R. de.; Eifler-Lima, V. L. New
Solid-Phase Approach to Synthesize a Hyacinthacine Core Using the L-Proline as a Building Block.
Lett. Org. Chem. 2009, 6, 90-93.
17. (a) Ressault, B.; Jaunet, A.; Geoffroy, P.; Goudedranche, S.; Miesch, M. Access to
Polyfunctionalized Diquinanes, Hydrindanes, and Decalines via TiCl4 Promoted Michael-Aldol
and Baylis-Hillman Reactions. Org. Lett. 2012, 14, 366-369. (b) Keck, G. E.; Welch, D. S.
Intramolecular Baylis-Hillman and Morita Reactions Using Unsaturated Thiol Ester Substrates
Containing Enolizable Aldehydes. Org. Lett. 2002, 4, 3687-3690.
18. (a) Tan, H. R.; Ng, H. F.; Chang, J.; Wang, J. Highly Enantioselective Assembly of Functionalized
Tetrahydroquinolines with Creation of an All-Carbon Quaternary Center. Chem. Eur. J. 2012, 18,
3865-3870. (b) Sousa, B. A.; Keppler, A. F.; Gariani, R. A.; Comasseto, J. V.; Santos, A. A. D.
Metallic chalcogenolates mediated modular Michael-aldol cascade reaction: an easy route to
multi-functionalized chalcogenides and Morita-Baylis-Hillman adducts. Tetrahedron 2012, 68,
10406-10413. (c) Jia, Z.-X.; Luo, Y.-C.; Xu, P.-F. Highly Enantioselective Synthesis of
Polysubstituted Tetrahydroquinolines via Organocatalytic Michael/Aza-Henry Tandem
Reactions. Org. Lett. 2011, 13, 832-835. (d) Davies, S. G.; Mujtaba, N.; Roberts, P. M.; Smith, A.
D.; Thomson, J. E. A Tandem Conjugate Addition/ Cyclization Protocol for the Asymmetric
Synthesis of 2-Aryl-4-aminotetrahydroquinoline-3-carboxylic Acid Derivatives. Org. Lett. 2009,
11, 1959-1962.
19. (a) Ding, R.; Zheng, B.; Wang, Y.; Peng, Y. A Cation-Directed Enantioselective Sulfur-Mediated
Michael/ Mannich Three-Component Domino Reaction involving Chalcones as Michael
Acceptors. Org. Lett. 2015, 17, 4128-4131. (b) Velez, E. V.; Desnous, C.; Clivio, P. Study of the
Pyrimidine Nucleobase C5-C6 Bond Reactivity Under Thio-Michael/Aldol Tandem Reaction
Conditions. J. Heterocycl. Chem. 2006, 43, 1095-1098. (c) Richards, E. L.; Murphy, P. J.; Dinon, F.;
Fratucello, S.; Brown, P. M.; Gelbrich, T.; Hursthouse, M. B. Accessing the scope of the tandem
Michael/intramolecular aldol reaction mediated by secondary amines, thiols and phosphines.
Tetrahedron 2001, 57, 7771-7784.
20. (a) Selig, P. S.; Miller, S, J. ortho-Acidic aromatic thiols as efficient catalysts of intramolecular
Morita-Baylis-Hillman and Rauhut-Currier reactions. Tetrahedron Lett. 2011, 52, 2148-2151. (b)
24
ACS Paragon Plus Environment

Page 25 of 25
The Journal of Organic Chemistry
1
2
3
4
5
Erguden, J.-K.; Moore, H. W. A New Tandem Route to Angular Tetraquinanes. Synthesis of the
Waihoensene Ring System. Org. Lett. 1999, 1, 375-377.
21. (a) Bharadwaj, K. C. Acrylamide in Rauhut-Currier reaction; intramolecular isomerization of
activated alkenes for quinolone synthesis. Tetrahedron 2017, 73, 5690-5699. (b) Bharadwaj, K.
C. Acryl Activation by Intramolecular Hydrogen Bond: Morita Baylis Hillman Reaction of
Acrylamide with Broad Substrate Scope. ChemistrySelect 2017, 2, 5384-5389. (c) Bharadwaj, K.
C.; Tiwari, D. K. Double Morita-Baylis-Hillman (MBH) strategy; an intermolecular and a chemo
selective intramolecular MBH reactions for 5/6 substituted, functionalized piperidine unit.
Tetrahedron 2016, 72, 312-317. (d) Singh, R. M.; Bharadwaj, K. C.; Tiwari, D. K. Morita-Baylis-
Hillman reaction of acrylamide with isatin derivatives. Beilstein J. Org. Chem. 2014, 10, 2975-
2980.
22. (a) Trofimov, B. A.; Belyaeva, K. V.; Nikitina, L. P.; Mal’kina, A. G.; Afonin, A. V.; Ushakov, I. A.;
Vashchenko, A. V. Transition metal-free one-pot double C-H functionalization of quinolines with
disubstituted electron-deficient acetylenes. Chem. Commun. 2018, 54, 5863-5866. (b) Li, Y.; Cao,
X.; Liu, Y.; Wan, J.-P. Regioselective three-component synthesis of 2,3-disubstituted quinolines
via the enaminone modified Povarov reaction. Org. Biomol. Chem. 2017, 15, 9585-9589. (c)
Zheng, J.; Li, Z.; Huang, L.; Wu, W.; Li, J.; Jiang, H. Palladium-Catalyzed Intermolecular Aerobic
Annulation of o-Alkenylanilines and Alkynes for Quinoline Synthesis. Org. Lett. 2016, 18, 3514-
3517. (d) Yu, Z.-H.; Zheng, H.-F.; Yuan, W.; Tang, Z.-L.; Zhang, A.-D.; Shi, D.-Q. An unexpected
6
7
8
9
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
one-pot synthesis of multi-substituted quinolines via
a
cascade reaction of
Michael/Staudinger/aza-Wittig/aromatization of ortho-azido-β-nitro-styrenes with various
carbonyl compounds. Tetrahedron 2013, 69, 8137-8141. (e) Kikuchi, S.; Iwai, M.; Fukuzawa, S.-i.
A Novel and Facile Method for the Synthesis of 2,3-Disubstituted Quinolines by a Three-
Component Coupling Reaction. Synlett 2007, 2639-2642.
23. Rajawinslin, R. R.; Gawande, S. D.; Kavala, V.; Huang, Y.-S.; Kuo, C.-W.; Kuo, T.-S.; Chen, M.-L.;
He, C.-H; Yao, C.-F. Iron/acetic acid mediated intermolecular tandem C-C and C-N bond
formation: an easy access to acridinone and quinoline derivatives. RSC Adv. 2014, 4, 37806-
37811.
24. (a) Han, J.-c.; Li, F.; Li, C.-c. Collective Synthesis of Humulanolides Using a Metathesis Cascade
Reaction. J. Am. Chem. Soc. 2014, 136, 13610-13613. (b) Luo, S.; Mi, X.; Xu, H.; Wang, P. G.;
Cheng, J.-P. Efficient Baylis-Hillman Reactions of Cyclic Enones in Methanol As Catalyzed by
Methoxide Anion. J. Org. Chem. 2004, 69, 8413-8422.
25
ACS Paragon Plus Environment