Three Sequential C-N Bond Formations: Tert-Butyl Nitrite as a N1 Synthon in a Three Component Reaction Leading to Imidazo[1,2-a]quinolines and Imidazo[2,1-a]isoquinolines

Article abstract of DOI:10.1021/acs.joc.7b02815

tert-Butyl nitrite serves the dual role of an oxidant as well as a N1 synthon in a multicomponent reaction involving quinolines, isoquinolines, and styrenes. Herein, two sp² C-H functionalizations of styrenes and one sp² C-H functionalization of quinolines and isoquinolines lead to the formation of fused quinolines and isoquinolines via three sequential C-N bond formations.

Full text of DOI:10.1021/acs.joc.7b02815

Subscriber access provided by UNIV OF NEW ENGLAND ARMIDALE
Note
Three Sequential C-N Bond Formation: tert-Butyl Nitrite
as a N1 Synthon in a Three Component Reaction Leading
to Imidazo[1,2-a]quinolines/ Imidazo[2,1-a]isoquinolines
Prasenjit Sau, Amitava Rakshit, Anju Modi, Ahalya Behera, and Bhisma K. Patel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02815 • Publication Date (Web): 20 Dec 2017
Downloaded from http://pubs.acs.org on December 22, 2017
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 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Three Sequential C−N Bond Formation: tertꢀButyl Nitrite as a N1 Synthon in
a Three Component Reaction Leading to Imidazo[1,2ꢀa]quinolines /
Imidazo[2,1ꢀa]isoquinolines
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Prasenjit Sau, Amitava Rakshit, Anju Modi, Ahalya Behera and Bhisma K. Patel*
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahatiꢀ781039, India
Fax: (+91)361ꢀ26909762.
Eꢀmail: patel@iitg.ernet.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: tertꢀButyl nitrite serves the dual role of an oxidant as well as a N1 synthon in a
2
multiꢀcomponent reaction involving quinolines/isoquinolines and styrenes. Herein two sp C−H’s
functionalization of styrenes and one of quinolines/isoquinolines leads to the formation of fused
quinolines/isoquinolines via three sequential C−N bond formation.
Further functionalization and late stage functionalization of biologically important
organic frameworks amplifies its activity towards pharmaceutical and medicinal chemistry.
Quinolines and isoquinolines are integral part in many natural products and building blocks of
1
several pharmaceuticals. The functionalized derivatives of those viz. imidazo[1,2ꢀa]quinoline (I,
II and IV) and imidazo[2,1ꢀa]isoquinoline (III) exhibit effective biological activities such as
inhibitors of Shiga Toxin, hypertensive, antiallergic, contraceptive and antiasthmatic anxiolytic
2
(Figure 1).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 29
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
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 1. Representative Biologically Active Imidazo[1,2ꢀa]quinolines and Imidazo[2,1ꢀ
a]isoquinolines
Various functionalizations of quinolines and isoquinolines has been documented in the
3
a,b
3c
3d
3eꢀg
literature viz. alkylation,
halogenation, sulfonation, trifluoromethylation etc.
Of late,
C H functionalization is an alternative strategy to create complex structural frameworks from
small organic molecules. Consequently, the C H functionalization protocols have been applied
to quinoline and isoquinoline moieties. In this regard, Liu et.al. demonstrated a novel route for
the synthesis of C1ꢀbenzyl and benzoyl substituted isoquinolines through a direct oxidative C H
4
a
functionalization of isoquinolines using alkyl benzene as the coupling partner. Our group has
also developed a Lewis acid catalyzed C1 or C2 arylation of isoquinolines and quinolines
4b
4b
(
Scheme 1a) using methylarenes as the aroyl surrogates.
On the other hand direct 1,2ꢀdifunctionalization of alkenes with or without the
2
involvement of sp C–H bonds have played a vital role in building complex molecules. Bisꢀ
5
6
7
functionalization of olefins such as dihydroxylation, hydroalkylation, oxyamination,
8
9
10
11
12
carbohalogenation,
oxyarylation,
aminofluorination,
aminocyanation,
nitration,
1
3
14
carboboration, and others are well documented in the literature. Our group has recently
reported an efficient synthesis of isoxazolines via 1,2ꢀdifunctionalization of styrene in the
ACS Paragon Plus Environment

Page 3 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
presence of quinoline (as a base), tertꢀbutyl nitrite as the N−O source in the presence of catalyst
1
5
Sc(OTf) (Scheme 1b). Taking cues from these radical mediated reactions, especially, nitration
3
1
2
4
of alkenes using tertꢀbuty nitrite and C1 or C2 aroylation of Nꢀheterocycles, we envisaged a
double functionalization of styrene and a concomitant C2 functionalization of quinoline or a C1
functionalization of isoquinoline leading to the synthesis of fused heterocycles.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 1. Strategies for C−H Functionalization of NꢀHeterocycles with Alkyl benzene and
Styrenes
By judiciously choosing the catalyst and other reaction parameters it was possible to fuse
styrene onto both quinoline and isoquinoline moieties in the presence of tertꢀbutyl nitrite (TBN)
(Scheme 1c). Our initial investigation started using quinoline (0.25 mmol), styrene (0.625
mmol), Cu(OTf) (10 mol %), Cs CO (2 equiv) and tertꢀbutylnitrite (2 equiv) in 1,2ꢀ
3
2
3
ο
dichloroethane (DCE) at 80 C. Interestingly, the reaction resulted in the formation of a new
product (1a, 41%), spectroscopic analysis confirmed its structure to be 2ꢀphenylimidazo[1,2ꢀ
16
a]quinoline (1a). In this structure the incorporation of a new N atom is associated with the
formation of three C−N bonds. We believe that TBN to be the possible source of additional
nitrogen atom in this product. So far TBN has been exploited mainly as a source of NO and NO2
12,20
radicals.
Besides this it has been employed as a nitrogenating agent in the formation of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 29
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
17a
17b
nitriles from alkylbenzene and terminal aryl alkenes. Prior to this report there is only one
illustration where TBN has been used as a N1 synthon in the synthesis of cinnolines from 2ꢀvinyl
1
7c
aniline. In spite of the recent surge in the use of TBN, we feel it is an underutilized reagent,
thus exploring alternative pattern of reactivity would open novel avenues for synthetic chemists.
Herein, we disclose a copper catalyzed threeꢀcomponent synthesis of Nꢀfused heterocycles
involving quinoline/isoquinoline, styrene and TBN as the N1 synthon via three sequential C−N
bond formations.
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
Encouraged by the above unprecedented three component reaction, further optimization
were carried out by varying various reaction parameters using styrene (a) and quinoline (1) as
t
the coupling partners in the presence of BuONO. Initially, a variety of nonꢀpolar solvents such
as pꢀxylene (31%), toluene (29%) and chlorobenzene (36%) and polar aprotic solvents such as
DMF (21%) and DMSO (0%) were tested (Table 1, entries 2−6). However, all the solvents tested
were found to be less effective compared to DCE (41%) (Table 1, entry 1). Other Cu(I) and
Cu(II) salts such as Cu(OAc) (33%), CuCl (35%) and CuCl (39%) (Table 1, entries 7−9) gave
2
2
poor yields compared to Cu(OTf) (43%) whereas, CuBr and CuI provided improved yields of
2
4
5% and 49% respectively (Table 1, entries 10 and 11). With CuI as the suitable catalyst, other
t
inorganic (K CO and KO Bu) and organic (DMAP and DBU) bases were screened. Inorganic
2
3
t
bases K CO (43%) (Table 1, entry 12) gave lower yield compared to Cs CO whereas, KO Bu
2
3
2
3
furnished an improved yield of 53% (Table 1, entry 13). However, no encouraging results could
be obtained using organic bases such as DMAP (31%) and DBU (29%) (Table 1, entries 14 and
1
5). When the reaction was carried out in the absence of Cuꢀcatalyst no product formation was
detected (Table 1, entry 16), suggesting the involvement of copper salt in facilitating the
1
8
reaction, possible via the formation of an iminium carbocation. When the reaction was
ACS Paragon Plus Environment

Page 5 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
performed in the absence of base under otherwise identical condition resulted in a suppressed
yield (27%) of (1a) (Table 1, entry 17). These results suggest the involvement of both catalyst
and base in this multiꢀcomponent reaction. In a pursuit to improve the yield, further reactions
were carried out in the presence of oxidants. Interestingly, the use of various oxidants such as diꢀ
tertꢀbutyl peroxide (61%), DDQ (56%), K S O (55%), tertꢀbutyl peroxybenzoate (53%)
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
8
significantly improved the product yield, with DTBP being the most effective (Table 1, entries
8−21). Increasing the catalyst loading to 15 mol % improved the yield up to 66% (Table 1,
1
entry 22). No noticeable enhancement in the yield (68%) was observed when the catalyst loading
was increased up to 20 mol % (Table 1, entry 23). There was no enhancement in the yield (66%)
when the additive (DTBP) loading was increased to 4 equiv (Table 1, entry 24) however the
yield of the product decreased to 62% when the quantity of additive (DTBP) was reduced to 2
ο
ο
equiv (Table 1, entry 25). Reaction carried out both at higher 100 C (53%) or lower 60 C
(40%) temperature were detrimental to the product formation. (Table 1, entries 26 and 27). After
screening of various reaction parameters, the optimized condition for this transformation is the
t
use of quinoline (0.25 mmol), styrene (0.625 mmol), CuI (15 mol %), BuOK (0.5 mmol), tertꢀ
ο
butylnitrite (0.5 mmol) and DTBP (0.75 mmol) at 80 C in DCE solvent (Table 1, Entry 22).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 29
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
a
Table 1. Optimization of the Reaction Conditions
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
entry catalyst (mol %)
base
solvent
DCE
pꢀxylene
toluene
PhCl
DMF
DMSO
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
additive yield %
1
2
3
4
5
6
7
8
9
Cu(OTf) (10.0) Cs CO
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
43
31
29
36
21
0
33
35
39
45
49
43
53
31
29
0
2
2
3
3
Cu(OTf) (10.0) Cs CO
2
2
Cu(OTf) (10.0) Cs CO
2
2
3
3
3
3
3
3
3
3
3
Cu(OTf) (10.0) Cs CO
2
2
Cu(OTf) (10.0) Cs CO
2
2
Cu(OTf) (10.0) Cs CO
2
2
Cu(OAc) (10.0) Cs CO
2
2
CuCl (10.0)
Cs CO
2
2
CuCl (10.0)
CuBr (10.0)
CuI (10.0)
CuI (10.0)
CuI (10.0)
CuI (10.0)
CuI (10.0)
ꢀ
CuI(10.0)
CuI (10.0)
CuI (10.0)
CuI (10.0)
CuI (10.0)
CuI (15.0)
CuI (20.0)
CuI (15.0)
CuI (15.0)
CuI (15.0)
CuI (15.0)
Cs CO
2
1
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
Cs CO
2
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
Cs CO
2
K CO
2
3
t
KO Bu
DMAP
DBU
t
KO Bu
ꢀ
27
61
56
55
53
66
68
t
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
BuOK
DTBP
DDQ
K S O
2 2 8
TBPB
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
t
t
t
t
t
t
c
66
62
t
d
e
t
BuOK
BuOK
53f
t
40
a
Reaction conditions: Quinoline (1) (0.25 mmol), styrene (a) (0.625 mmol),
catalyst (mol %), base (0.5 mmol), tertꢀbutylnitrite (0.5 mmol) and additive
0.75 mmol) at 80 C. Yield after 8 h. DTBP 4 equiv DTBP 2 equiv
ο
b
c
d
(
e
ο
f
ο
Temperature 100 C. Temperature 60 C.
This multiꢀcomponent synthesis of imidazo[1,2ꢀa]quinolines was then explored with
various quinolines and aromatic terminal alkenes (Scheme 2) under the optimized reaction
t
condition. Styrenes having electronꢀdonating substituents such as pꢀMe (b), pꢀ Bu (c) and pꢀOMe
(
d) successfully coupled with quinoline (1), yielding their corresponding imidazo[1,2ꢀ
a]quinolines (1b, 49%), (1c, 53%) and (1d, 45%) in moderate yields (Scheme 2).
ACS Paragon Plus Environment

Page 7 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Scheme 2. Substrate Scope for Synthesis of
Imidazo[1,2ꢀa]quinolines
a,b
CuI (15 mol %)
tBuONO (2 equiv) R
1
N
N
DTBP (3 equiv)
R1
N
R2
t
BuOK (2 equiv)
(1-3)
(a-g)
(1a-3g)
o
DCE, 80 C, 8 h.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
R2
Me
N
R2
N
R2
N
2
N
R = H (1a, 66%)
2
c
2
R = H (1a, 62%)
R = H (2a, 62%)
2
2
R = p-Me (1b, 49%)
R = p-Br (2e, 63%)
2
2
R = p-tert-butyl (1c, 53%)
R = p-Cl (2f, 67%)
2
2
R = p-OMe (1d, 45%)
R = p-F (2g, 70%)
2
N
2
R = p-Br (1e, 64%)
R = m-Cl (2h, 69%)
Me
N
2
R = p-Cl (1f, 67%)
2
R2
R = p-F (1g 69%)
2
R = p-Cl (3f, 70%)
2
R = p-F (3g, 71%)
a
Reaction conditions: quinoline (1) (0.25 mmol), styrene (a) (0.625
t
mmol), CuI (0.038 mmol), BuOK (0.5 mmol), tertꢀbutylnitrite (0.5
ο
b
mmol) and DTBP (0.75 mmol) at 80 C in DCE (1.5 mL). Yield
after 8 h. Yield reported for 1 mmol scale
c
Styrenes bearing electronꢀwithdrawing substituents such as pꢀBr (e), pꢀCl (f) and pꢀF (g), all
provided their respective imidazo[1,2ꢀa]quinolines (1e, 64%), (1f, 67%) and (1g, 69%) in
moderate yields. In order to expand the scope of this methodology, substituted quinolines such as
3ꢀmethylquinoline (2) and 6ꢀmethylquinoline (3) were tested with various substituted styrenes
(a), (e), (f), (g) and (h) and all afforded their respective fused products (2a, 62%), (2e, 63%), (2f,
6
7%), (2g, 70%), (2h, 69%), (3f, 70%) and (3g, 71%) in good yields (Scheme 2).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 29
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
Scheme 3. Substrate Scope for Synthesis of
Imidazo[2,1ꢀa]isoquinolines
a,b
CuI (15 mol %)
tBuONO (2 equiv)
N
R1
N
DTBP (3 equiv)
N
R2
R1
t
BuOK (2 equiv)
(4-6)
(a-j)
(4a-6b)
o
DCE, 80 C, 8 h.
R2
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
Me
NO2
N
N
N
N
N
N
R2
R2
2
R2 = H (5a, 61%)
R = H (4a, 64%)
R2
2
2
R = p-Me (4b, 53%)
= p-Cl ( , 66%)
5f
2
R
R = H (6a, 60%)
2
2
R = p-tert-butyl (4c, 55%) R = p-F (5g, 72%)
R = p-Br (4e, 65%)
2
R = p-Me (6b, 51%)
2
2
R = m-Cl (5h, 68%)
2
2
R = p-Cl (4f, 68%)
R = m-F (5i, 74%)
R2 = m-Me (5j, 60%)
2
R = p-F (4g, 71%)
a
Reaction conditions: isoquinoline (1) (0.25 mmol), styrene
t
(
a) (0.625 mmol), CuI (0.038 mmol), BuOK (0.5 mmol),
ο
tertꢀbutylnitrite (0.5 mmol) and DTBP (0.75 mmol) at 80 C
in DCE (1.5 mL). Yield after 8 h.
b
Owing to the importance of isoquinoline framework in many biological systems and with the
positive outcome of the present coupling strategy with quinoline, we sought to test the similar
fusion of isoquinoline with styrene. To our delight, the reaction of isoquinoline (4) with styrene
(a) under the identical condition lead to the synthesis of analogues coupled product 2ꢀ
phenylimidazo[2,1ꢀa]isoquinoline (4a, 64%) (Scheme 3). Encouraged by this positive result we
further executed this strategy to other styrenes and isoquinolines. Styrenes having electronꢀ
t
donating such as pꢀMe (b), pꢀ Bu (c) or electronꢀwithdrawing such as pꢀBr (e), pꢀCl (f) and pꢀF
(g) substituents, all underwent effective coupling with isoquinoline (4) to produce their desired
products [(4b, 53%), (4c, 55%), (4e, 65), (4f, 68%) and (4g, 71%)] as shown in Scheme 3. The
structure of the product (4f) has been further confirmed by single crystal Xꢀray diffraction study
(Figure 2).
ACS Paragon Plus Environment

Page 9 of 29
The Journal of Organic Chemistry
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
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 2. Ortep diagram of compound (4f)
Furthermore, substituted isoquinolines such as 3ꢀmethylisoquinoline (5) and 5ꢀ
nitroisoquinoline (6) both reacted smoothly with various substituted styrenes (a), (b), (f), (g), (h),
(i) and (j) affording their corresponding imidazo[2,1ꢀa]isoquinolines (5a, 61%), (5f, 66%), (5g,
72%), (5h, 68%), (5i, 74%), (5j, 60%), (6a, 60%) and (6b, 51%) in modest yields (Scheme 3). In
this protocol, both electronꢀdonating and electronꢀwithdrawing substituents on either of the
substrate provided almost identical yields of their product. This may be due to the higher
reactivity of reaction intermediates, in this multiꢀstep strategy. However, in this process aliphatic
alkenes failed to react completely which may be due to the instability of the radical generated
during the reaction.
Scheme 4. Synthesis of 4ꢀ((2ꢀPhenylimidazo[2,1ꢀa]isoquinolinꢀ3ꢀyl)methyl)morpholine
(4ak).
4
ꢀ((2ꢀPhenylimidazo[2,1ꢀa]isoquinolinꢀ3ꢀyl)methyl)morphꢀoline hydrochloride (4ak) is a
2d
very important compound possessing significant range of biological activities. It has been
2
d
successfully applied in determining the functional activity of several living organisms.
Compound (4ak) was successfully synthesized from (4a) by coupling it with morpholine (k).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 29
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
The later serve the dual role of a oneꢀcarbon synthon as well as the morpholine unit following
1
9
the protocol of Hajra et.al (Scheme 4).
In order to elucidate a plausible mechanism, an experiment was performed in the
presence of a radical scavenger 2,2,6,6ꢀtetramethylpiperidineꢀ1ꢀoxyl (TEMPO, 3 equiv) under
otherwise identical condition. Retardation in the desired product (1a, <5%) formation suggest the
radical nature of the reaction (See supporting information). Based on the intermediates detected
by the HRMS analysis of the reaction mixture at various time intervals and from the literature
reports, a plausible mechanism has been proposed for this transformation (Scheme 5). The
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
·
20
heterolytic cleavage of tertꢀbutyl nitrite generates a NO radical which attacks at the more
4
,21
electrophilic C2 position of quinoline to generate a radical intermediate (A).
The nitrogen
radical intermediate (A) then attacks at the terminal carbon of the styrene to form a benzylic
radical species (B), which underwent an intramolecular radical coupling with the adjacent NO
group to give a radical intermediate (C). The Nꢀoxide radical intermediate (C) abstract a
2
2
prtoton from the solvent DCE or a benzylic/allylic CꢀH to form a Nꢀhydroxy intermediate (D).
t
A base ( BuOK) mediated dehydration of which resulted in the formation of intermediate (E). In
the presence of CuI and DTBP, the intermediate (E) generates an iminium carbocation (F) via
1
8
two sequential single electron transfer (SET) process. Finally loss of a proton from
intermediate (F) leads to the formation of the desired product (1a). Intermediacy of (B), (C) and
(F) have been detected by the HRMS analysis of reaction mixtures at various time intervals (see
the Supporting Information). Formation of intermediates (B) and (C) are further confirmed by
radical trapping experiments (See supporting information). A similar mechanism is expected to
operate for isoquinoline (4) leading to 2ꢀphenylimidazo[2,1ꢀa]isoquinoline (4a).
ACS Paragon Plus Environment

Page 11 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Scheme 5. Proposed Mechanism for Imidazo[1,2ꢀa]quinolines Synthesis
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
In conclusion, selective C1 or C2 functionalizations of isoquinolines or quinolines with
concurrent bisꢀfunctionalization of styrenes in the presence of tertꢀbutyl nitrite and Cu catalyst
leads to the construction of imidazo[2,1ꢀa]isoquinolines or imidazo[1,2ꢀa]quinolines. In this
radical mediated reaction tertꢀbutyl nitrite serve as a N1 synthon and assist in the simultanious
installation of three new C−N bonds. This is an excellent illustration of novel reactivity of tertꢀ
butyl nitrite thereby, expending its utility towards the synthesis of complex molecules.
EXPERIMENTAL SECTION
General information:
All the reagents were commercial grade and purified according to the established
procedures. Organic extracts were dried over anhydrous sodium sulphate. Solvents were
removed in a rotary evaporator under reduced pressure. Silica gel (60ꢀ120 mesh size) was used
for the column chromatography. Reactions were monitored by TLC on silica gel 60 F254 (0.25
mm). NMR spectra were recorded in CDCl with tetramethylsilane as the internal standard for
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 29
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
13
H NMR (400 and 600 MHz) and in for C NMR (100 and 150 MHz) CDCl as the internal
3
standard. MS spectra were recorded using ESI mode. IR spectra were recorded in KBr or neat.
General Procedure for the Synthesis of 2ꢀPhenylimidazo[1,2ꢀa]quinoline (1a) from
Quinoline (1) and Styrene (a):
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
To an ovenꢀdried 10 mL round bottom flask fitted with a reflux condenser was added
quinoline (1) (32 mg, 0.25 mmol), styrene (a) (65 mg, 0.625 mmol), CuI (7.2 mg, 0.038 mmol),
t
BuOK (56 mg, 0.5 mmol), tertꢀbutylnitrite (52 mg, 0.5 mmol), DTBP (110 mg, 0.75 mmol) and
1
, 2ꢀdichloroethane (1.5 mL). The reaction mixture was refluxed in an oil bath preheated to 80
o
C for 8 h. The reaction mixture was cooled to room temperature, admixed with ethyl acetate (25
mL) and the organic layer was washed with saturated sodium bicarbonate solution (1 x 5 mL).
The organic layer was dried over anhydrous sodium sulfate (Na SO ), and solvent was
2
4
evaporated under reduced pressure. The crude product so obtained was purified over a column of
silica gel (hexane / ethyl acetate, 9.5:0.5) to give pure 2ꢀphenylimidazo[1,2ꢀa]quinoline (1a) (40
mg, yield 66%). The identity and purity of the product was confirmed by spectroscopic analysis.
General Procedure for the Synthesis of 4ꢀ((2ꢀPhenylimidazo[2,1ꢀa]isoquinolinꢀ3ꢀ
yl)methyl)morpholine (4ak) from 2ꢀPhenylimidazo[2,1ꢀa]isoquinoline (4a): To a dried sealed
tube was added 2ꢀphenylimidazo[2,1ꢀa]isoquinoline (4a) (49 mg, 0.2 mmol), morpholine (b) (35
mg, 0.4 mmol), PIDA (129 mg, 0.4 mmol) and stirred at room temperature for 15 min. After
completion of the reaction the reaction mixture was quenched with water (2 mL) and ethyl
acetate (5 mL). Then the reaction mixture was admixed with ethyl acetate (25 mL) and the
organic layer was washed with saturated sodium bicarbonate solution (1 x 5 mL). The organic
layer was dried over anhydrous sodium sulfate (Na SO ), and solvent was evaporated under
2
4
ACS Paragon Plus Environment

Page 13 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
reduced pressure. The crude product so obtained was purified over a column of silica gel (hexane
/
ethyl acetate, 7:3) to give pure 4ꢀ((2ꢀphenylimidazo[2,1ꢀa]isoquinolinꢀ3ꢀyl)methyl)morpholine
(4ab) (55 mg, yield 80%). The identity and purity of the product was confirmed by spectroscopic
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
analysis.
General Procedure for Free Radical Trapping Experiments:
TEMPO Experiment 1:
To an ovenꢀdried 10 mL round bottom flask fitted with a reflux condenser was added quinoline
t
(
1) (32 mg, 0.25 mmol), styrene (a) (65 mg, 0.625 mmol), CuI (7.2 mg, 0.038 mmol), BuOK (56
mg, 0.5 mmol), tertꢀbutylnitrite (52 mg, 0.5 mmol), DTBP (117 mg, 0.75 mmol), TEMPO (110
mg, 0.75 mmol) and 1, 2ꢀdichloroethane (1.5 mL). The reaction mixture was refluxed in an oil
o
bath preheated to 80 C for 8 h. Then the reaction mixture was cooled and taken for HRMS
analysis (See supporting information).
TEMPO Experiment 2:
To an ovenꢀdried 10 mL round bottom flask fitted with a reflux condenser was added quinoline
t
(
1) (32 mg, 0.25 mmol), styrene (a) (65 mg, 0.625 mmol), CuI (7.2 mg, 0.038 mmol), BuOK (56
mg, 0.5 mmol), tertꢀbutylnitrite (52 mg, 0.5 mmol), DTBP (117 mg, 0.75 mmol) and 1, 2ꢀ
o
dichloroethane (1.5 mL). The reaction mixture was refluxed in an oil bath preheated to 80 C for
1
h. After 1 h, radical scavenger TEMPO (117 mg, 0.75 mmol) was added to the reaction
mixture and the reaction mixture was allowed to reflux for another 1h. Then the reaction mixture
was cooled and taken for HRMS analysis (See supporting information).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 29
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
16a,b
2
2
2
ꢀPhenylimidazo[1,2ꢀa]quinoline (1a):
1
Yield: 66% (40mg) as a brownish solid; mp = 103.4–105.6 °C; H
NMR (CDCl , 600 MHz): δ 8.34 (s, 1H), 8.01 (d, 2H, J = 7.8 Hz),
3
7
.97 (d, 1H, J = 8.4 Hz), 7.83 (d, 1H, J = 7.8 Hz), 7.67 (t, 1H, J =
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
7.8 Hz), 7.61 (d, 1H, J = 9.6 Hz), 7.54 (d, 1H, J = 9.0 Hz),
1
3
7
.49−7.45 (m, 3H), 7.35 (t, 1H, J = 7.5 Hz); C NMR (CDCl , 150
3
MHz): δ 144.7, 144.2, 133.6, 132.6, 129.4, 129.1, 128.9, 128.1,
ꢀ1
1
26.9, 126.1, 125.1, 123.6, 116.9, 115.3, 107.0; IR (KBr, cm ):
2958, 2923, 2852, 1637, 1603, 1557, 1538, 1505, 1463, 1447;
+
HRMS (ESI/QꢀTOF) (m/z): calcd for C H N , [M+H] :
1
7
13
2
2
45.1073, found 245.1072.
ꢀ(pꢀTolyl)imidazo[1,2ꢀa]quinoline (1b):
1
Yield: 49% (32 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.29 (s, 1H), 7.96 (d, 1H, J = 8.4 Hz), 7.90 (d, 2H, J = 8.4
Hz), 7.82 (d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.62 (d, 1H,
J = 9.6 Hz), 7.53 (d, 1H, J = 9.0 Hz), 7.47 (t, 1H, J = 7.2 Hz),
1
3
7
.28−7.26 (m, 2H), 2.40 (s, 3H); C NMR (CDCl , 100 MHz): δ
3
144.8, 144.1, 137.9, 132.6, 130.7, 129.7, 129.4, 129.1, 126.8,
ꢀ1
1
25.9, 125.0, 123.6, 116.9, 115.4, 106.6, 21.5; IR (KBr, cm ):
2
958, 2921, 2851, 1635, 1601, 1551, 1531, 1461, 1421; HRMS
+
(ESI/QꢀTOF) (m/z): calcd for C H N , [M+H] : 259.1230, found
1
8
15
2
2
59.1233.
ꢀ(4ꢀ(tertꢀButyl)phenyl)imidazo[1,2ꢀa]quinoline (1c):
1
Yield: 53% (40 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.30 (s, 1H), 7.97 (d, 1H, J = 8.4 Hz), 7.94 (d, 2H, J = 8.4
Hz), 7.82 (d, 1H, J = 7.2 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.62 (d, 1H,
J = 9.6 Hz), 7.53 (d, 1H, J = 9.6 Hz), 7.50−7.46 (m, 3H), 1.37 (s,
13
9
H); C NMR (CDCl , 100 MHz): δ 151.2, 144.9, 144.2, 132.7,
3
130.9, 129.5, 129.1, 126.6, 125.9, 125.8, 124.9, 123.6, 117.1,
ACS Paragon Plus Environment

Page 15 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
ꢀ1
1
15.4, 106.6, 34.9, 31.6; IR (KBr, cm ): 2959, 2924, 2853, 1638,
1614, 1556, 1493, 1462, 1447, 1418; HRMS (ESI/QꢀTOF) (m/z):
+
calcd for C H N , [M+H] : 301.1699, found 301.1691.
21 21
2
2
ꢀ(4ꢀMethoxyphenyl)imidazo[1,2ꢀa]quinoline (1d):
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
Yield: 45% (32 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.25 (s, 1H), 7.96 (d, 1H, J = 8.4 Hz), 7.94 (d, 2H, J = 9.0
Hz), 7.83 (d, 1H, J = 7.8 Hz), 7.67 (t, 1H, J = 7.8 Hz), 7.63 (d, 1H,
J = 9.0 Hz), 7.55 (d, 1H, J = 9.6 Hz), 7.48 (t, 1H, J = 7.5 Hz), 7.00
13
(
d, 2H, J = 8.4 Hz), 3.86 (s, 3H); C NMR (CDCl , 150 MHz): δ
3
1
59.9, 143.9, 143.7, 134.1, 132.4, 129.6, 129.4, 127.5, 125.3,
ꢀ1
123.7, 116.3, 115.4, 114.5, 114.1, 106.1, 55.6; IR (KBr, cm ):
2
953, 2927, 2850, 1638, 1612, 1559, 1511, 1495, 1461; HRMS
+
(
ESI/QꢀTOF) (m/z): calcd for C H N O, [M+H] : 275.1179,
1
8
15
2
found 275.1169.
16c
2
ꢀ(4ꢀBromophenyl)imidazo[1,2ꢀa]quinoline (1e):
Yield: 64% (51 mg) as a deep brownish solid; mp = 149.5–153.1
1
°
C; H NMR (CDCl , 600 MHz): δ 8.30 (s, 1H), 7.93 (d, 1H, J =
3
8
.4 Hz), 7.86 (d, 2H, J = 8.4 Hz), 7.81 (d, 1H, J = 7.8 Hz), 7.66 (t,
1
H, J = 7.2 Hz), 7.58−7.56 (m, 3H), 7.53 (d, 1H, J = 9.6 Hz), 7.48
1
3
(t, 1H, J = 7.2 Hz); C NMR (CDCl , 100 MHz): δ 144.4, 143.9,
3
1
1
32.8, 132.6, 132.1, 129.5, 129.2, 127.5, 126.9, 125.1, 123.6,
ꢀ1
21.9, 117.0, 115.3, 107.1; IR (KBr, cm ): 2957, 2922, 2848,
1633, 1559, 1535, 1473, 1446, 1416; HRMS (ESI/QꢀTOF) (m/z):
+
calcd for C H N Br, [M+H] : 323.0178, found 323.0172.
17 12
2
2
ꢀ(4ꢀChlorophenyl)imidazo[1,2ꢀa]quinoline (1f):
1
Yield: 67% (46 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.30 (s, 1H), 7.95 (d, 1H, J = 8.4 Hz), 7.91 (d, 2H, J = 8.4
Hz), 7.83 (d, 1H, J = 7.8 Hz), 7.67 (t, 1H, J = 7.6 Hz), 7.60−7.54
1
3
(
m, 2H), 7.49 (t, 1H, J = 7.9 Hz), 7.42 (d, 2H, J = 8.4 Hz); C
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 29
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
NMR (CDCl , 150 MHz): δ 144.4, 143.9, 133.9, 132.7, 132.3,
3
129.6, 129.3, 129.2, 127.3, 127.1, 125.2, 123.7, 116.9, 115.3,
ꢀ1
1
07.1; IR (KBr, cm ): 2955, 2923, 2852, 1633, 1557, 1479, 1467,
1
448, 1416; HRMS (ESI/QꢀTOF) (m/z): calcd for C H N Cl,
1
7
12
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
[
M+H] : 279.0684, found 279.0680.
2
ꢀ(4ꢀFluorophenyl)imidazo[1,2ꢀa]quinoline (1g):
1
Yield: 69% (45 mg) as a brownish solid; mp = 90.4–95.1 °C; H
NMR (CDCl , 600 MHz): δ 8.26 (s, 1H), 7.97−7.94 (m, 3H), 7.82
3
(d, 1H, J = 7.8 Hz), 7.66 (t, 1H, J = 7.8 Hz), 7.59 (d, 1H, J = 9.0
Hz), 7.54 (d, 1H, J = 9.6 Hz), 7.48 (t, 1H, J = 7.5 Hz), 7.14 (t, 2H,
1
3
J = 8.4 Hz); C NMR (CDCl , 100 MHz): δ 164.1, 161.7, 159.6,
3
1
44.4, 144.1, 132.7, 129.5, 129.2, 127.8 (d, J = 8.1 Hz), 126.9,
19
1
25.1, 123.6, 116.9, 115.9 (d, J = 21.6 Hz), 115.3, 106.7, F NMR
ꢀ1
(
CDCl + Hexafluorobenzene): δ ꢀ117.3 (s); IR (KBr, cm ): 2955,
3
2922, 2851, 1635, 1555, 1538, 1510, 1493, 1463, 1448, 1407;
+
HRMS (ESI/QꢀTOF) (m/z): calcd for C H N F, [M+H] :
1
7
12
2
2
63.0979, found 263.0975.
4
ꢀMethylꢀ2ꢀphenylimidazo[1,2ꢀa]quinoline (2a):
1
Yield: 62% (40 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.32 (s, 1H), 8.03 (d, 2H, J = 7.2 Hz), 7.92 (d, 1H, J = 8.4
Hz), 7.74 (d, 1H, J = 7.8 Hz), 7.59 (t, 1H, J = 7.8 Hz), 7.47−7.43
13
(
m, 3H), 7.35−7.33 (m, 2H), 2.72 (s, 3H); C NMR (CDCl , 100
3
MHz): δ 145.2, 144.7, 134.2, 131.9, 128.9, 128.6, 127.90, 127.87,
ꢀ
126.9, 126.2, 124.9, 124.5, 124.1, 115.2, 107.3, 17.6; IR (KBr, cm
1
): 2958, 2923, 2853, 1637, 1556, 1532, 1461, 1411; HRMS
+
(
ESI/QꢀTOF) (m/z): calcd for C H N , [M+H] : 259.1230, found
1
8
15
2
2
59.1233.
ACS Paragon Plus Environment

Page 17 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
ꢀ(4ꢀBromophenyl)ꢀ4ꢀmethylimidazo[1,2ꢀa]quinoline (2e):
1
Yield: 63% (53 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.30 (s, 1H), 7.91−7.89 (m, 3H), 7.74 (d, 1H, J = 7.8 Hz),
7
3
1
.60−7.55 (m, 3H), 7.44 (t, 1H, J = 7.5 Hz), 7.33 (s, 1H), 2.69 (s,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
13
H); C NMR (CDCl , 100 MHz): δ 145.2, 143.5, 133.2, 131.9,
3
31.8, 128.6, 127.9, 127.7, 126.8, 124.9, 124.7, 124.1, 121.7,
ꢀ1
115.1, 107.4, 17.5; IR (KBr, cm ): 2955, 2923, 2853, 1637, 1615,
1
531, 1458, 1415; HRMS (ESI/QꢀTOF) (m/z): calcd for
+
C H N Br, [M+H] : 337.0335, found 337.0330.
18
14
2
2ꢀ(4ꢀChlorophenyl)ꢀ4ꢀmethylimidazo[1,2ꢀa]quinoline (2f):
1
Yield: 67% (49 mg) as a brownish solid; mp = 141.3–144.5 °C; H
NMR (CDCl , 600 MHz): δ 8.28 (s, 1H), 7.95 (d, 2H, J = 8.4 Hz),
3
7.88 (d, 1H, J = 8.4 Hz), 7.73 (d, 1H, J = 7.8 Hz), 7.58 (t, 1H, J =
1
3
7
.2 Hz), 7.45−7.39 (m, 3H), 7.32 (s, 1H), 2.69 (s, 3H); C NMR
(
CDCl , 100 MHz): δ 145.2, 143.5, 133.5, 131.8, 129.1, 128.6,
3
1
27.9, 127.4, 126.8, 124.9, 124.7, 124.1, 115.1, 107.4, 17.5; IR
ꢀ1
(KBr, cm ): 2955, 2926, 2850, 1631, 1604, 1530, 1463, 1435,
+
1
405; HRMS (ESI/QꢀTOF) (m/z): calcd for C H N Cl, [M+H] :
1
8
14
2
2
93.0840, found 293.0837.
2
ꢀ(4ꢀFluorophenyl)ꢀ4ꢀmethylimidazo[1,2ꢀa]quinoline (2g):
1
Yield: 70% (48 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.25 (s, 1H), 7.99−7.98 (m, 2H), 7.89 (d, 1H, J = 8.4 Hz),
7
.74 (d, 1H, J = 7.8 Hz), 7.58 (t, 1H, J = 7.8 Hz), 7.44 (t, 1H, J =
13
7
.5 Hz), 7.32 (s, 1H), 7.14 (t, 2H, J = 8.7 Hz), 2.70 (s, 3H); C
NMR (CDCl , 100 MHz): δ 164.0, 161.6, 145.2, 143.8, 131.8,
3
1
30.4, 128.6, 127.9 (d, J = 3.6 Hz), 127.8, 126.8, 124.9, 124.7,
1
9
1
24.1, 115.8 (d, J = 21.5 Hz), 115.1, 106.9, 17.6, F NMR (CDCl
3
ꢀ1
+ Hexafluorobenzene): δ ꢀ117.8 (s); IR (KBr, cm ): 2956, 2923,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 29
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
848, 1633, 1605, 1552, 1533, 1493, 1460, 1420, 1407; HRMS
+
(ESI/QꢀTOF) (m/z): calcd for C H N F, [M+H] : 277.1136,
18
14
2
found 277.1135.
2
ꢀ(3ꢀChlorophenyl)ꢀ4ꢀmethylimidazo[1,2ꢀa]quinoline (2h):
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
Me
Yield: 69% (50 mg) as a light brownish solid; mp = 95.3–99.8 °C;
1
H NMR (CDCl , 600 MHz): δ 8.31 (s, 1H), 8.03 (s, 1H), 7.89 (d,
3
N
N
2
H, J = 7.8 Hz), 7.74 (d, 1H, J = 7.8 Hz), 7.59 (t, 1H, J = 7.5 Hz),
7.44 (t, 1H, J = 7.5 Hz), 7.38 (t, 1H, J = 7.8 Hz), 7.32 (s, 1H), 7.29
Cl
1
3
(d, 1H, J = 8.4 Hz), 2.70 (s, 3H); C NMR (CDCl , 100 MHz): δ
3
1
45.2, 143.3, 136.1, 134.9, 131.8, 130.2, 128.6, 127.9, 127.8,
126.9, 126.2, 125.0, 124.8, 124.2, 124.1, 115.1, 107.7, 17.5; IR
ꢀ1
(KBr, cm ): 2960, 2923, 2852, 1637, 1601, 1569, 1532, 1459,
1
427, 1410; HRMS (ESI/QꢀTOF) (m/z): calcd for C H N Cl,
1
8
14
2
+
[
M+H] : 293.0840, found 293.0841.
2
ꢀ(4ꢀChlorophenyl)ꢀ7ꢀmethylimidazo[1,2ꢀa]quinoline (3f):
Yield: 70% (51 mg) as a deep brownish solid; mp = 145.1–147.6
1
°
C; H NMR (CDCl , 600 MHz): δ 8.22 (s, 1H), 7.89 (d, 2H, J =
3
8
.4 Hz), 7.79 (d, 1H, J = 8.4 Hz), 7.57 (s, 1H), 7.54 (d, 1H, J = 9.6
Hz), 7.45 (d, 2H, J = 9.0 Hz), 7.39 (d, 2H, J = 8.4 Hz), 2.50 (s,
1
3
3H); C NMR (CDCl , 100 MHz): δ 144.2, 143.5, 134.9, 133.6,
3
1
1
1
32.4, 130.7, 130.5, 129.1, 127.2, 126.8, 123.5, 116.8, 115.1,
ꢀ1
06.9, 21.3; IR (KBr, cm ): 2950, 2922, 2853, 1628, 1616, 1567,
529, 1482, 1465, 1423, 1403; HRMS (ESI/QꢀTOF) (m/z): calcd
+
for C H N Cl, [M+H] : 293.0840, found 293.0831.
18 14
2
2
ꢀ(4ꢀfluorophenyl)ꢀ7ꢀmethylimidazo[1,2ꢀa]quinoline (3g):
1
Yield: 71% (49 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.21 (s, 1H), 7.96−7.94 (m, 2H), 7.81 (d, 1H, J = 8.4 Hz),
7
.58 (s, 1H), 7.55 (d, 1H, J = 9.6 Hz), 7.46 (d, 2H, J = 9.6 Hz),
1
3
7.13 (t, 2H, J = 8.7 Hz), 2.51 (s, 3H); C NMR (CDCl , 100
3
ACS Paragon Plus Environment

Page 19 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MHz): δ 164.0, 161.6, 144.2, 143.9, 134.8, 130.8, 130.5, 130.2,
130.1, 129.1, 127.7 (d, J = 8.1 Hz), 126.7, 123.6, 116.9, 115.9 (d, J
1
9
=
21.6 Hz), 115.1, 106.5, 21.3,
F NMR (CDCl3
ꢀ1
+
Hexafluorobenzene): δ ꢀ117.6 (s); IR (KBr, cm ): 2958, 2923,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
848, 1634, 1604, 1508, 1492, 1458, 1421; HRMS (ESI/QꢀTOF)
+
(m/z): calcd for C H N F, [M+H] : 277.1136, found 277.1126.
1
8
14
2
16b,d
2
ꢀPhenylimidazo[2,1ꢀa]isoquinoline (4a):
1
Yield: 64% (39 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.76 (d, 1H, J = 7.8 Hz), 8.01 (d, 2H, J = 7.8 Hz), 7.91 (d,
1
H, J = 7.2 Hz), 7.83 (s, 1H), 7.70 (d, 1H, J = 7.8 Hz), 7.65 (t, 1H,
J = 7.3 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.46 (t, 2H, J = 7.8 Hz), 7.33
t, 1H, J = 7.2 Hz), 7.05 (d, 1H, J = 7.2 Hz); 13C NMR (CDCl3,
50 MHz): δ 144.0, 143.4, 133.9, 129.7, 128.9, 128.5, 128.4,
127.9, 127.1, 126.1, 123.84, 123.78, 123.1, 113.5, 110.1; IR (KBr,
(
1
ꢀ1
cm ): 2955, 2922, 2851, 1631, 1605, 1541, 1490, 1455; HRMS
+
(
ESI/QꢀTOF) (m/z): calcd for C H N , [M+H] : 245.1073, found
1
7
13
2
2
45.1083.
1
6d
2
ꢀ(pꢀTolyl)imidazo[2,1ꢀa]isoquinoline (4b):
1
Yield: 53% (34 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.77 (d, 1H, J = 7.8 Hz), 7.92−7.89 (m, 3H), 7.80 (s, 1H),
N
7
.70 (d, 1H, J = 7.8 Hz), 7.64 (t, 1H, J = 7.5 Hz), 7.57 (t, 1H, J =
N
7
.5 Hz), 7.26−7.24 (m, 2H), 7.05 (d, 1H, J = 7.2 Hz), 2.39 (s, 3H);
1
3
C NMR (CDCl , 150 MHz): δ 144.1, 143.3, 137.7, 129.7, 129.6,
3
128.43, 128.38, 127.1, 126.0, 123.8, 123.1, 113.4, 109.7, 21.5; IR
Me
ꢀ1
(
KBr, cm ): 2958, 2930, 2849, 1635, 1603, 1553, 1545, 1480,
+
1
453; HRMS (ESI/QꢀTOF) (m/z): calcd for C H N , [M+H] :
18
15
2
259.1230, found 259.1239.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 29
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
16d
2
ꢀ(4ꢀ(tertꢀButyl)phenyl)imidazo[2,1ꢀa]isoquinoline (4c):
1
Yield: 55% (41 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 8.74 (d, 1H, J = 7.8 Hz), 7.94−7.90 (m, 3H), 7.80 (s, 1H),
7
.70 (d, 1H, J = 7.8 Hz), 7.64 (t, 1H, J = 7.5 Hz), 7.57 (t, 1H, J =
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
7.5 Hz), 7.48 (d, 2H, J = 8.4 Hz), 7.04 (d, 1H, J = 7.2 Hz), 1.37 (s,
1
3
9
1
1
H); C NMR (CDCl , 150 MHz): δ 150.9, 144.2, 143.3, 131.2,
3
29.7, 128.4, 127.1, 125.88, 125.85, 123.9, 123.8, 123.1, 113.3,
ꢀ1
09.8, 34.9, 31.6; IR (KBr, cm ): 2958, 2923, 2850, 1635, 1551,
1461, 1454; HRMS (ESI/QꢀTOF) (m/z): calcd for C H N ,
2
1
21
2
+
[
M+H] : 301.1699, found 301.1689.
1
6d
2ꢀ(4ꢀBromophenyl)imidazo[2,1ꢀa]isoquinoline (4e):
1
Yield: 65% (52 mg) as a brownish solid; mp = 132.1–134.6 °C; H
NMR (CDCl , 600 MHz): δ 8.70 (d, 1H, J = 7.8 Hz), 7.88 (t, 3H, J
3
=
7.2 Hz), 7.81 (s, 1H), 7.70 (d, 1H, J = 7.8 Hz), 7.65 (t, 1H, J =
13
7
.5 Hz), 7.59−7.56 (m, 3H), 7.05 (d, 1H, J = 7.2 Hz); C NMR
(
CDCl , 100 MHz): δ 143.6, 143.1, 133.1, 132.0, 129.7, 128.6,
3
128.5, 127.6, 127.2, 123.9, 123.7, 123.1, 121.7, 113.6, 110.2; IR
ꢀ1
(
KBr, cm ): 2955, 2922, 2845, 1637, 1556, 1539, 1513, 1455,
1
474, 1400; HRMS (ESI/QꢀTOF) (m/z): calcd for C H N Br,
1
7
12
2
+
[M+H] : 323.0178, found 323.0174.
1
6d
2
ꢀ(4ꢀChlorophenyl)imidazo[2,1ꢀa]isoquinoline (4f):
1
Yield: 68% (47 mg) as a brownish solid; mp = 160.6–165.3 °C; H
NMR (CDCl , 600 MHz): δ 8.71 (d, 1H, J = 7.8 Hz), 7.94 (d, 2H, J
3
N
=
8.4 Hz), 7.89 (d, 1H, J = 7.2 Hz), 7.79 (s, 1H), 7.70 (d, 1H, J =
N
7.8 Hz), 7.65 (t, 1H, J = 7.5 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.41 (d,
1
3
2
H, J = 8.4 Hz), 7.04 (d, 1H, J = 7.2 Hz); C NMR (CDCl , 100
3
Cl
MHz): δ 143.6, 143.1, 133.5, 132.7, 129.7, 129.1, 128.5, 128.4,
ꢀ1
1
27.3, 127.2, 123.9, 123.7, 123.1, 113.6, 110.1; IR (KBr, cm ):
2960, 2923, 2850, 1633, 1554, 1543, 1475, 1456, 1404; HRMS
ACS Paragon Plus Environment

Page 21 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
+
(
ESI/QꢀTOF) (m/z): calcd for C H N Cl, [M+H] : 279.0684,
17 12 2
found 279.0689.
16e
2
ꢀ(4ꢀFluorophenyl)imidazo[2,1ꢀa]isoquinoline (4g):
Yield: 71% (46 mg) as a brownish solid; mp = 135.2–137.5 °C;
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
H NMR (CDCl , 600 MHz): δ 8.71 (d, 1H, J = 8.4 Hz),
3
N
7
1
7
.98−7.96 (m, 2H), 7.90 (d, 1H, J = 7.2 Hz), 7.77 (s, 1H), 7.70 (d,
N
H, J = 7.8 Hz), 7.65 (t, 1H, J = 7.5 Hz), 7.58 (t, 1H, J = 7.5 Hz),
13
.14 (t, 2H, J = 8.7 Hz), 7.05 (d, 1H, J = 7.2 Hz); C NMR
F
(
CDCl , 100 MHz): δ 163.9, 161.5, 143.5, 143.3, 130.39, 130.36,
3
1
29.7, 128.4 (d, J = 5.2 Hz), 127.7 (d, J = 8.1 Hz), 127.2, 123.9,
1
9
123.7, 123.1, 115.8 (d, J = 21.5 Hz), 113.4, 109.7, F NMR
ꢀ1
(
CDCl + Hexafluorobenzene): δ ꢀ117.9 (s); IR (KBr, cm ): 2958,
3
2
923, 2853, 1642, 1555, 1515, 1494, 1480, 1454; HRMS (ESI/Qꢀ
+
TOF) (m/z): calcd for C H N F, [M+H] : 263.0979, found
17
12
2
263.0986.
5
ꢀMethylꢀ2ꢀphenylimidazo[2,1ꢀa]isoquinoline (5a):
1
Yield: 61% (39 mg) as a brownish solid; mp = 109.3–113.7 °C; H
NMR (CDCl , 600 MHz): δ 8.73 (d, 1H, J = 7.8 Hz), 8.05 (d, 2H, J
Me
3
N
=
7.2 Hz), 7.80 (s, 1H), 7.65 (d, 1H, J = 7.8 Hz), 7.60 (t, 1H, J =
N
6
.9 Hz), 7.55 (t, 1H, J = 7.2 Hz), 7.46 (t, 2H, J = 7.8 Hz), 7.33 (t,
1
3
1H, J = 7.2 Hz), 6.88 (s, 1H), 2.66 (s, 3H); C NMR (CDCl , 100
3
MHz): δ 144.1, 143.9, 134.3, 131.6, 130.2, 128.9, 128.3, 127.8,
ꢀ
1
1
27.4, 126.4, 126.1, 123.7, 122.6, 111.8, 107.4, 18.9; IR (KBr, cm
)
: 2955, 2921, 2845, 1648, 1605, 1557, 1520, 1474, 1456, 1445,
+
1
404; HRMS (ESI/QꢀTOF) (m/z): calcd for C H N , [M+H] :
18 15
2
2
59.1230, found 259.1232.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 29
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
ꢀ(4ꢀChlorophenyl)ꢀ5ꢀmethylimidazo[2,1ꢀa]isoquinoline (5f):
Yield: 66% (48 mg) as a light brownish solid; mp = 128.9–134.1
1
°
C; H NMR (CDCl , 600 MHz): δ 8.69 (d, 1H, J = 7.8 Hz), 7.97
3
(
d, 2H, J = 8.4 Hz), 7.75 (s, 1H), 7.64 (d, 1H, J = 7.2 Hz), 7.60 (t,
1H, J = 6.9 Hz), 7.55 (t, 1H, J = 6.9 Hz), 7.41 (d, 2H, J = 8.4 Hz),
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
6
.87 (s, 1H), 2.63 (s, 3H); C NMR (CDCl , 100 MHz): δ 143.9,
3
1
42.8, 133.4, 132.7, 131.6, 130.2, 129.0, 128.5, 127.5, 127.3,
ꢀ
1
126.4, 123.7, 122.4, 112.0, 107.5, 18.8; IR (KBr, cm ): 2955,
2
923, 2853, 1639, 1554, 1473, 1458, 1405; HRMS (ESI/QꢀTOF)
+
(
m/z): calcd for C H N Cl, [M+H] : 293.0840, found 293.0842.
1
8
14
2
2ꢀ(4ꢀFluorophenyl)ꢀ5ꢀmethylimidazo[2,1ꢀa]isoquinoline (5g):
Yield: 72% (50 mg) as a light brownish solid; mp = 129.5–132.6
Me
1
°
C; H NMR (CDCl , 600 MHz): δ 8.70 (d, 1H, J = 7.8 Hz),
3
N
8
.01−7.99 (m, 2H), 7.72 (s, 1H), 7.64 (d, 1H, J = 7.8 Hz), 7.59 (t,
H, J = 7.5 Hz), 7.55 (t, 1H, J = 7.5 Hz), 7.14 (t, 2H, J = 8.7 Hz),
N
1
13
6.87 (s, 1H), 2.64 (s, 3H); C NMR (CDCl , 100 MHz): δ 163.9,
3
F
1
61.5, 143.9, 143.2, 131.6, 130.52, 130.48, 130.2, 128.4, 127.7 (d,
J = 7.9 Hz), 127.4, 126.4, 123.6, 122.5, 115.8 (d, J = 21.4 Hz),
1
9
1
11.8, 107.1, 18.8, F NMR (CDCl + Hexafluorobenzene): δ ꢀ
3
ꢀ
1
117.9 (s); IR (KBr, cm ): 2958, 2923, 2853, 1631, 1559, 1492,
1
458, 1408; HRMS (ESI/QꢀTOF) (m/z): calcd for C H N F,
1
8
14
2
+
[
M+H] : 277.1136, found 277.1134.
2
ꢀ(3ꢀChlorophenyl)ꢀ5ꢀmethylimidazo[2,1ꢀa]isoquinoline (5h):
Yield: 68% (49 mg) as a light brownish solid; mp = 120.4–123.9
Me
1
°
C; H NMR (CDCl , 600 MHz): δ 8.70 (d, 1H, J = 7.8 Hz), 8.04
3
N
(s, 1H), 7.91 (d, 1H, J = 7.8 Hz), 7.78 (s, 1H), 7.64 (d, 1H, J = 7.8
N
Hz), 7.60 (t, 1H, J = 7.2 Hz), 7.56 (t, 1H, J = 7.5 Hz), 7.37 (t, 1H, J
1
3
= 7.8 Hz), 7.29 (d, 1H, J = 7.8 Hz), 6.88 (s, 1H), 2.64 (s, 3H); C
Cl
NMR (CDCl , 100 MHz): δ 143.9, 142.6, 136.2, 134.9, 131.6,
3
ACS Paragon Plus Environment

Page 23 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
30.2, 130.1, 128.5, 127.6, 127.4, 126.4, 126.1, 124.1, 123.7,
ꢀ1
122.5, 112.0, 107.8, 18.8; IR (KBr, cm ): 2955, 2852, 1633, 1604,
1
555, 1530, 1460, 1447, 1420; HRMS (ESI/QꢀTOF) (m/z): calcd
+
for C H N Cl, [M+H] : 293.0840, found 293.0845.
1
8
14
2
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2ꢀ(3ꢀFluorophenyl)ꢀ5ꢀmethylimidazo[2,1ꢀa]isoquinoline (5i):
1
Yield: 74% (51 mg) as a brownish gummy; H NMR (CDCl , 600
3
Me
MHz): δ 8.71 (d, 1H, J = 7.8 Hz), 7.80−7.76 (m, 3H), 7.63 (d, 1H,
J = 7.8 Hz), 7.59 (t, 1H, J = 7.2 Hz), 7.56 (t, 1H, J = 7.5 Hz),
N
N
7
.41−7.38 (m, 1H), 7.02−6.99 (m, 1H), 6.86 (s, 1H), 2.63 (s, 3H);
1
3
C NMR (CDCl , 100 MHz): δ 164.7, 162.3, 143.9, 142.9, 136.6
3
F
(d, J = 8.5 Hz), 131.6, 130.3 (t, J = 9.8 Hz), 128.5, 127.4, 126.4,
1
2
23.7, 122.5, 121.59, 121.56, 114.5 (d, J = 21.2 Hz), 112.9 (d, J =
19
2.6 Hz), 112.0, 107.8, 18.8,
F
NMR (CDCl3
+
ꢀ1
Hexafluorobenzene): δ ꢀ116.5 (s); IR (KBr, cm ): 2959, 2921,
2
851, 1629, 1601, 1555, 1521, 1460; HRMS (ESI/QꢀTOF) (m/z):
+
calcd for C H N F, [M+H] : 277.1136, found 277.1135.
1
8
14
2
5ꢀMethylꢀ2ꢀ(mꢀtolyl)imidazo[2,1ꢀa]isoquinoline (5j):
1
Yield: 60% (41 mg) as a brownish solid; mp = 110.4–113.7 °C; H
NMR (CDCl , 600 MHz): δ 8.74 (d, 1H, J = 8.4 Hz), 7.91 (s, 1H),
3
7.82 (d, 1H, J = 7.8 Hz), 7.78 (s, 1H), 7.64 (d, 1H, J = 7.8 Hz),
7.60 (t, 1H, J = 7.2 Hz), 7.55 (t, 1H, J = 7.2 Hz), 7.34 (t, 1H, J =
7.5 Hz), 7.15 (d, 1H, J = 7.2 Hz), 6.87 (s, 1H), 2.65 (s, 3H), 2.45
1
3
(s, 3H); C NMR (CDCl , 100 MHz): δ 144.1, 143.7, 138.5,
3
1
1
2
34.0, 131.6, 130.2, 128.8, 128.6, 128.3, 127.3, 126.8, 126.3,
ꢀ1
23.8, 123.2, 122.5, 111.8, 107.4, 21.7, 18.9; IR (KBr, cm ): 2958,
921, 2854, 1637, 1605, 1557, 1531, 1465, 1410; HRMS (ESI/Qꢀ
+
TOF) (m/z): calcd for C H N , [M+H] : 273.1386, found
19 17
2
2
73.1376.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 29
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
ꢀNitroꢀ2ꢀphenylimidazo[2,1ꢀa]isoquinoline (6a):
Yield: 60% (43 mg) as a deep brownish solid; mp = 139.3–141.5
1
°
C; H NMR (CDCl , 600 MHz): δ 9.08 (d, 1H, J = 8.4 Hz), 8.28
3
(
d, 1H, J = 7.2 Hz), 8.09 (d, 1H, J = 7.8 Hz), 8.01 (d, 2H, J = 7.2
Hz), 7.90 (s, 1H), 7.85 (d, 1H, J = 7.8 Hz), 7.72 (t, 1H, J = 7.8 Hz),
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
7
.47 (t, 2H, J = 7.5 Hz), 7.36 (t, 1H, J = 7.5 Hz); C NMR
(
CDCl , 100 MHz): δ 145.3, 142.1, 133.5, 129.7, 129.1, 128.36,
3
128.35, 127.4, 126.19, 126.16, 125.6, 125.3, 122.5, 110.4, 107.5;
ꢀ1
IR (KBr, cm ): 2960, 2923, 2852, 1632, 1550, 1515, 1468, 1446;
+
HRMS (ESI/QꢀTOF) (m/z): calcd for C H N O , [M+H] :
17
12
3
2
2
90.0924, found 290.0927.
7
ꢀNitroꢀ2ꢀ(pꢀtolyl)imidazo[2,1ꢀa]isoquinoline (6b):
1
Yield: 51% (39 mg) as a brownish gummy; H NMR (CDCl , 600
3
MHz): δ 9.08 (d, 1H, J = 7.8 Hz), 8.29 (d, 1H, J = 7.8 Hz), 8.10 (d,
1
H, J = 7.8 Hz), 7.90 (d, 2H, J = 8.4 Hz), 7.88 (s, 1H), 7.85 (d, 1H,
J = 7.8 Hz), 7.72 (t, 1H, J = 8.1 Hz), 7.28 (d, 2H, J = 7.8 Hz), 2.41
1
3
(s, 3H); C NMR (CDCl , 100 MHz): δ 145.5, 142.0, 138.2,
3
1
1
1
30.7, 129.76, 129.71, 127.3, 126.2, 126.09, 126.06, 125.5, 125.3,
ꢀ1
22.5, 110.1, 107.4, 21.5; IR (KBr, cm ): 2957, 2923, 2853, 1630,
555, 1523, 1462; HRMS (ESI/QꢀTOF) (m/z): calcd for
+
C H N O , [M+H] : 304.1081, found 304.1079.
18
14
3
2
4
ꢀ((2ꢀPhenylimidazo[2,1ꢀa]isoquinolinꢀ3ꢀyl)methyl)morpholine (4ak):
O
Yield: 80% (55 mg) as a light brownish solid; mp = 140.7–144.2
1
°
C; H NMR (CDCl , 600 MHz): δ 8.74 (d, 1H, J = 7.8 Hz), 8.27
3
N
N
(
d, 1H, J = 7.2 Hz), 7.83 (d, 2H, J = 7.2 Hz), 7.73 (d, 1H, J = 7.8
Hz), 7.63 (t, 1H, J = 7.5 Hz), 7.58 (t, 1H, J = 7.5 Hz), 7.48 (t, 2H, J
7.5 Hz), 7.38 (t, 1H, J = 7.5 Hz), 7.09 (d, 1H, J = 7.2 Hz), 3.98
N
=
1
3
(s, 2H), 3.68 (t, 4H, J = 3.9 Hz), 2.50 (s, 4H); C NMR (CDCl ,
3
1
00 MHz): δ 143.7, 143.0, 134.8, 129.7, 129.1, 128.7, 128.4,
ACS Paragon Plus Environment

Page 25 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
28.1, 127.7, 126.9, 123.8, 123.7, 122.8, 117.9, 112.6, 67.2, 53.4,
ꢀ1
52.2; IR (KBr, cm ): 2948, 2917, 2850, 1638, 1521, 1454; HRMS
+
(ESI/QꢀTOF) (m/z): calcd for C H N O, [M+H] : 344.1757,
22 22
3
found 344.1752.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
AUTHOR INFORMATION
Corresponding Author
*
E mail: patel@iitg.ernet.in
ACKNOWLEDGMENT
B. K. P acknowledges the support of this research by the Department of Science and
Technology (DST/SERB) (EMR/2016/007042) and MHRD: 5ꢀ5/2014ꢀTSꢀVII (SB/S1/OCꢀ
5
3/2013), New Delhi and CIF for instrumental facilities. A. M. thanks the CSIR for fellowship.
Supporting Information Available
The Supporting Information is available free of charge on the ACS Publications website at
http://pubs.acs.org.
Mechanistic investigation, Xꢀray data for 4f (CIF)
PDF).
, spectral and analytical data of all products
(
REFERENCES
(
1) (a) Patel, R. V.; Park, S. W. Eur. J. Med. Chem. 2014, 71, 24. (b) Shang, X. F.; Natschke, S.
L. M.; Liu, Y. Q.; Guo, X.; Xu, X. S.; Goto, M.; Li, J. C.; Yang, G. Z.; Lee, K. H. Med. Res.
Rev. 2017, 1. (c) Huang, C. Y.; Kavala, V.; Kuo, C. W.; Konala, A.; Yang, T. H.; Yao, C. F.
J. Org. Chem. 2017, 82, 1961. (d) Iranshahy, M.; Quinn, R. J.; Iranshahi, M. RSC Adv. 2014,
4
, 15900. (e) Kumar, S.; Bawa, S.; Gupta, H. Mini. Rev. Med. Chem. 2009, 9, 1648.
(
2) (a) Ager, I. R.; Barnes, A. C.; Danswan, G. W.; Hairsine, P. W.; Kay, D. P.; Kennewell, P.
D.; Matharu, S. S.; Miller, P.; Robson, P.; Rowlands, D. A.; Tully, W. R.; Westwood, R. J.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 29
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
Med. Chem. 1988, 31, 1098. (b) Kemnitzer, W.; Kuemmerle, J.; Jiang, S.; Zhang, H. Z.;
Sirisoma, N.; Kasibhatla, S.; Grundy, C. C.; Tseng, B.; Drewe, J.; Cai, S. X. Bioorg. Med.
Chem. Lett. 2008, 18, 6259. (c) Gueiffier, C. E.; Musiu, S.; Henry, N.; Véron, J. B.; Mavel,
S.; Neyts, J.; Leyssen, P.; Paeshuyse, J.; Gueiffie, A. Eur. J. Med. Chem. 2013, 64, 448. (d)
National Center for Biotechnology Information. PubChem Compound Database;
CID=16188015, https://pubchem.ncbi.nlm.nih.gov/compound/16188015.(accessed july.13,
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
017).
(
3) (a) Chang, Y. M.; Park, Y. S.; Lee, S. H.; Yoon, C. M. Tetrahedron. Lett. 2004, 45, 9049. (b)
Louërat, F.; Fort, Y.; Mamane, V. Tetrahedron. Lett. 2009, 50, 5716. (c) Brown, W. D.;
Gouliaev, A. H. Synthesis 2002, 1, 83. (d) Lai, J. Y. Q.; Ferguson, Y.; Jones, M. synthetic.
Commun. 2003, 33, 3427. (e) Loska, R.; Majcher, M.; Makosza, M. J. Org. Chem. 2007, 72,
5
574. (f) Loska, R.; Maükosza, M. J. Org. Chem. 2007, 72, 1354. (g) Nishida, T.; Ida, H.;
Kuninobu, Y.; Kanai, M. Nat. Commun. 5:3387 doi: 10.1038/ncomms4387 (2014).
4) (a) Wan, M.; Lou, H.; Liu, L. Chem. Commun. 2015, 51, 13953. (b) Ali, W.; Behera, A.;
Guin, S.; Patel, B. K. J. Org. Chem. 2015, 80, 5625.
(
(
(
(
(
5) Jensen, K. H.; Webb, J. D.; Sigman, M. S. J. Am. Chem. Soc. 2010, 132, 17471.
6) Chudasama, V.; Fitzmaurice, R. J.; Caddick, S. Nat. Chem. 2010, 2, 592.
7) Xie, Y.; Hu, J.; Xie, P.; Qian, B.; Huang, H. J. Am. Chem. Soc. 2013, 135, 18327.
8) (a) Kalyani, D.; Sanford, M. S. J. Am. Chem. Soc. 2008, 130, 2150. (b) Kalyani, D.;
Satterfield, A. D.; Sanford, M. S. J. Am. Chem. Soc. 2010, 132, 8419.
(
9) Kirchberg, S.; Fröhlich, R.; Studer, A. Angew. Chem., Int. Ed. 2010, 49, 6877.
10) Qiu, S.; Xu, T.; Zhou, J.; Guo, Y.; Liu, G. J. Am. Chem. Soc. 2010, 132, 2856.
(
(11) Miyazaki, Y.; Ohta, N.; Semba, K.; Nakao, Y. J. Am. Chem. Soc. 2014, 136, 3732.
ACS Paragon Plus Environment

Page 27 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
(
12) (a) Maity, S.; Togati, N.; Sharma, U.; Maiti, D. Org. Lett. 2013, 15, 3384. (b) Dutta, U.;
Maity, S.; Kancherla, R.; Maiti, D. Org. Lett. 2014, 16, 6302.
(13) Kageyuki, I.; Osaka, I.; Takaki, K.; Yoshida, H. Org. Lett. 2017, 19, 830.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
(14) Egami, H.; Yoneda, T.; Uku, M.; Ide, T.; Kawato, Y.; Hamashima, Y. J. Org. Chem.
2
016, 81, 4020.
(
15) Sau, P.; Santra, S. K.; Rakshit, A.; Patel, B. K. J. Org. Chem. 2017, 82, 6358.
16) (a) Phelps, A. M.; Chan, V. S.; Napolitano, J. G.; Krabbe, S. W.; Schomaker, J. M.;
Shekhar, S. J. Org. Chem. 2016, 81, 4158. (b) He, C.; Hao, J.; Xu, H.; Mo, Y.; Liu, H.; Hana,
J.; Lei, A. Chem. Commun. 2012, 48, 11073. (c) Artyomov, V. A.; Shestopalov, A. M.;
Litvinov, V.P. Synthesis. 1996, 927. (d) Donthiri, R. R.; Pappula, V.; Reddy, N. N. K.;
Bairagi, D.; Adimurthy, S. J. Org. Chem. 2014, 79, 11277. (e) Prasanna, P.; Kumar, S. V.;
Gunasekaran, P.; Perumal, S. Tetrahedron Lett. 2013, 4, 126.
(
(17) (a) Shu, Z.; Ye, Y.; Deng, Y.; Zhang, Y.; Wang, J. Angew. Chem., Int. Ed. 2013, 52,
0573. (b) Dutta, U.; Lupton, D. W.; Maiti, D. Org. Lett. 2016, 18, 860. (c) Pang, X.; Zhao,
1
L.; Zhou, D.; He, P. Y.; An, Z.; Ni, J. X.; Yan, R. Org. Biomol. Chem. 2017, 15, 6318.
18) (a) Sun, C. L.; Li, B. J.; Shi, Z. J. Chem. Rev. 2011, 111, 1293. (b) Girard, S. A.;
Knauber, T.; Li, C. J. Angew. Chem., Int. Ed. 2014, 53, 74. (c) Gogoi, A.; Sau, P.; Ali, W.;
Guin, S.; Patel, B. K. Eur. J. Org. Chem. 2016, 1449. (d) Zhang, G.; Ma, Y.; Wang, S.;
Zhang, Y.; Wang, R. J. Am. Chem. Soc. 2012, 134, 12334. (e) Gogoi, A.; Guin, S.; Rout, S.
K.; Patel, B. K. Org. Lett. 2013, 15, 1802.
(
(
19) Mondal, S.; Samanta, S.; Singsardar, M.; Hajra, A. Org. Lett. 2017, 19, 3751.
20) (a) Kilpatrick, B.; Heller, M.; Arns, S. Chem. Commun. 2013, 49, 514. (b) Taniguchi, T.;
Yajima, A.; Ishibashi, H. Adv. Synth. Catal. 2011, 353, 2643. (c) Galliker, B.; Kissner, R.;
(
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 29
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
Nauser, T.; Koppenol, W. H. Chem. Eur. J. 2009, 15, 6161. (d) Taniguchi, T.; Sugiura, Y.;
Hatta, T.; Yajima, A.; Ishibashi, H. Chem. Commun. 2013, 49, 2198. (e) Wu, X. F.;
Schranck, J.; Neumann, H.; Beller, M. Chem. Commun. 2011, 47, 12462.
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
(
21) Siddaraju, Y.; Lamani, M.; Prabhu, K. R. J. Org. Chem. 2014, 79, 3856.
22) Taniguchi, T.; Yajima, A.; Ishibashi, H. Adv. Synth. Catal. 2011, 353, 2643.
(
ACS Paragon Plus Environment

Page 29 of 29
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Three Sequential C−N Bond Formation: tertꢀButyl Nitrite as a N1 Synthon in a Three
Component Reaction Leading to Imidazo[1,2ꢀa]quinolines/ Imidazo[2,1ꢀa]isoquinolines
Prasenjit Sau, Amitava Rakshit, Anju Modi, Ahalya Behera and Bhisma K. Patel*
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
ACS Paragon Plus Environment