Rh-Catalyzed Annulations of N-Methoxybenzamides and Ketenimines: Sterically and Electronically Controlled Synthesis of Isoquinolinones and Isoindolinones

Article abstract of DOI:10.1021/acs.joc.7b00258

Rhodium-catalyzed C-H activation/annulation reactions of ketenimines with N-methoxybenzamides are reported. The outcome of reactions is dependent on the structure of ketenimines. The β-alkyl-substituted ketenimines furnish 3-iminoisoquinolin-1(2H)-ones in a formal [4 + 2] annulation manner, while the β-ester substituted ketenimines afford 3-aminoisoindolin-1-ones in a formal [4 + 1] annulation manner. The synthesized [4 + 2] products undergo an intramolecular Cu-catalyzed C-N coupling to be converted to benzo[4,5]imidazo[1,2-b]isoquinolin-11-ones, which can be directly prepared from ketenimines and N-methoxybenzamides by a one-pot Rh-catalyzed annulation/Cu-catalyzed C-N coupling sequence.

Full text of DOI:10.1021/acs.joc.7b00258

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Article
Rh-catalyzed annulations of N-methoxybenzamides and ketenimines: Steric-
and electronic-controlled synthesis of isoquinolinones and isoindolinones
Xiaorong Zhou, Zhiyin Zhang, Hongyang Zhao, Ping Lu, and Yanguang Wang
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Mar 2017
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Rh-catalyzed annulations of N-methoxybenzamides and
ketenimines: Steric- and electronic-controlled synthesis of
isoquinolinones and isoindolinones
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Xiaorong Zhou, Zhiyin Zhang, Hongyang Zhao, Ping Lu,* and Yanguang Wang*
Department of Chemistry, Zhejiang University, Hangzhou 310027, P. R. China
ABSTRACT: Rhodiumꢀcatalyzed CꢀH activation/annulation reactions of ketenimines with
Nꢀmethoxybenzamides are reported. The outcome of reactions is dependent on the structure
of ketenimines. The βꢀalkylꢀsubstituted ketenimines furnish 3ꢀiminoisoquinolinꢀ1(2H)ꢀones
through a formal [4+2] annulation manner, while the βꢀester substituted ketenimines afford
3
ꢀaminoisoindolinꢀ1ꢀones through a formal [4+1] annulation manner. The synthesized [4+2]
products undergo an intramolecular Cuꢀcatalyzed CꢀN coupling to be converted to
benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11ꢀones, which can be directly prepared from
ketenimines and Nꢀmethoxybenzamides by a oneꢀpot Rhꢀcatalyzed annulation /Cuꢀcatalyzed
CꢀN coupling sequence.
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INTRODUCTION
Azaꢀheterocycles are privilege scaffolds in a variety of natural compounds and biologically
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active molecules. They play important roles in the pharmaceutical and agrochemical
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industries. Both benzimidazole and isoquinolinone are well known structural motifs in
medicinal chemistry. Benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11ꢀone derivatives, the fused form
of isoquinolinone and benzimidazole frameworks, exhibited diverse bioactivties and some of
4
5
them have been demostrated as potential antiꢀTrypanosoma Cruzi agents, PDE inhibitors 4
6
and anticancer agents (Figure 1). However, most biological properties of this class of
compounds remain unexplored due to the lack of accessible synthetic methods for these
skeletons. Consequently, developing convenient methods for the synthesis of such molecules
has attracted much attention from medicinal and synthetic chemists. The published
approaches to the benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11ꢀone ring system include the
condesention of benzeneꢀ1,2ꢀdiamines with 2ꢀ(carboxymethyl)benzoic acids or their
7
analogues (Scheme 1, route a),
the copper(I)ꢀcatalyzed crossꢀcoupling of
2ꢀhaloꢀNꢀ(2ꢀhalophenyl)benzamides with alkyl 2ꢀcyanoacetates or malononitrile (Scheme 1,
8
9
route b), the Ugiꢀtype multicomponent reaction (Scheme 1, route c), and the Amberlystꢀ15
mediated intramolecular cyclization of 3ꢀaminoꢀ2ꢀ(2ꢀaminophenyl)isoquinolinꢀ1(2H)ꢀones
5
(
Scheme 1, route d).
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Figure 1. Examples of biolobically active benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11ꢀones
O
NHBoc
1
R NH
2
NC
+
OEt
MeO2C
O
N
+
C
N
Cu(I)
c
OHC
R CO H
H
2
Br
b
2
Br
O
N
d
CO H
a
2
N
H
O
R
CO H
2
N
+
This work
NH2
NH
2
NH
2
O
NH2
OMe
N
H
Br
+
N
H C
3
C
Ph
Scheme 1. Construction of benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11ꢀones
Ketenimines have been demonstrated as an important and vesatile synthesis intermediates
1
0
in organic synthesis. Their chemical properties have been widely explored and they can
undergo various reactions like nucleophilic/electronphilic additions, cycloadditions and
sigmatropic rearrangements. To the best of our knowledge, the insertions of transition metal
to the C=C bond of ketenimine moleculars have never been reported although these reactions
have been explored and applied in other C=C bond containing compounds, such as regular
11
alkene, allene, and thus afforded a variety of useful products. Rhodium (III)ꢀcatalyzed CꢀH
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activation/annulation is becoming a successful strategy in constructing azaꢀheterocycles.
Recently, we reported a Rh(III)ꢀcatalyzed annulations of Nꢀmethoxybenamides and
ketenimines, furnishing the formal [4+1] and [3+2] annulation products. In these cases, the
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insertion of CꢀRh bond to C=N bond occured. In continuation of our interest in the
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chemistry of ketenimines, we herein reported a Rh(III)ꢀcatalyzed CꢀH activation/insertion of
C=C bond/annulation reaction between Nꢀmethoxybenzamide and ketenimines. This reaction
led to the formal [4+2] annulation products, 3,4ꢀdihydroisoquinolinꢀ1(2H)ꢀones, which could
be further converted to benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11(6H)ꢀones.
RESULT AND DISCUSSION
To start with, we probed the reaction conditions for the envisioned rhodiumꢀcatalyzed CꢀH
activation. In our primary test, the reaction of Nꢀmethoxybenzamide (1a) with
2
2 2 3 2
ꢀmethylꢀ2ꢀphenylꢀNꢀ(pꢀtolyl)ethenimine (2a) under [Cp*RhCl ] (5 mol %) and Cl CCO Cs
o
(30 mol %) in 1,2ꢀdichloroethane (DCE) at 80 C for 10 hours afforded a [4+2] annulation
product 3a in 40% yield (Table 1, entry 1). The structure of 3a was established by its single
1
5
crystal analysis. We screened other solvents (e.g. CH
,4ꢀdioxane), but no better result was afforded (Table 1, entries 2ꢀ5). We then screened other
bases, such as PivOCs, CsOAc, NaOAc, K CO as well as Cs CO , and Cs CO was found to
give a better yield (45%) (Table 1, entries 6ꢀ10). A decreased yield was observed when the
loading of Cs CO was increased (Table 1, entry 11). The results were not improved when the
2 2
Cl , acetone, toluene, and
1
2
3
2
3
2
3
2
3
ratio of 1a was added or adding 1,2,3,4ꢀtetraphenylcyclopentdiene as a steric ligand (Table 1,
entries 12 and 13 ). [Cp*RhCl ] was found to be indispensiable catalyst to this reaction,
2
2
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while no desired product was obtained using [Cp*IrCl ] or [Ru(cymene)Cl ] as the catalyst
2
2
2 2
(
Table 1, entries 14 and 15). Finally, the optimized conditions were confirmed: 1a (0.36
2 2 2 3
mmol), 2a (0.3 mmol), [Cp*RhCl ] (0.015 mmol) , Cs CO (0.09 mmol) and 4Å MS (60 mg)
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o
in DCE (2 mL) at 80 C for 10 h (Table 1, entry 10). We also tried other benzamide
substances such as Nꢀpivaloylbenzamide, but no better yields were obtained.
a
Table 1 Optimization of the [4+2] reaction conditions
b
entry
base
catalyst
solvent
DCE
yield (%)
40
1
2
3
4
5
6
7
8
9
Cl
Cl
Cl
3
3
3
CCO
CCO
CCO
2
2
2
Cs
Cs
Cs
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
2
2
2
]
]
]
2
2
2
DCM
32
acetone
toluene
1,4ꢀdioxane
DCE
30
Cl CCO Cs
3
[Cp*RhCl2]2
35
2
Cl
3
CCO
2
Cs
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
[Cp*RhCl
2
2
2
2
]
2
]
2
]
2
]
2
19
PivOCs
CsOAc
NaOAc
K CO
38
DCE
25
DCE
17
[Cp*RhCl2]2
[Cp*RhCl
DCE
30
2
3
10
Cs
2
CO
3
2
]
2
DCE
45
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c
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Cs CO
[Cp*RhCl2]2
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DCE
DCE
DCE
DCE
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Cs
Cs
Cs
Cs
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CO
CO
CO
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[Cp*RhCl
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]
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]
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[Cp*IrCl
2
]
2
N.D.
N.D.
1
[Ru(cymene)Cl ]
2 2
a
The reaction conditions: 1a (0.36 mmol), 2a (0.3 mmol), catalyst (0.015 mmol), base (0.09
o
b
c
mmol), 4 Å MS (60 mg), solvent (2 mL), N
2
2 3
, 80 C, 10 h. Isolated yield refers to 2a. Cs CO
d
e
(
0.3 mmol) was used. 1a (0.6 mmol) was used. 1,2,3,4ꢀTetraphenylcyclopentdiene (10
mol %) was added.
With the optimized conditon in hand, we invesitgated the substrate scope. As shown in
Scheme 2,3ꢀiminoꢀisoquinolinꢀ1(2H)ꢀones 3bꢀn were obtained in moderate to good yields
when 2ꢀalkylꢀ2ꢀarylꢀNꢀarylethenimines 2bꢀn were used as the reaction component. The yields
of products 3bꢀf were found to be relatively lower. The situation changed as the aryl on
nitrogen atom of ketenimine changed from pꢀmethylphenyl to mꢀbromophenyl and
oꢀmethylphenyl. Thus, 3f and 3g were obtained in 49% and 67% yields, respectively. Higher
yields were also obtained for those with Nꢀ(oꢀethyl)phenyl ketenimine (product 3h, 66% yield)
and Nꢀ(oꢀbromo)phenyl ketenimine (product 3i, 70% yield). However, the less steric and
more electronꢀdeficient oꢀfluorophenyl substituted ketenimine afforded rather lower yield
(
39%) of the desired product 3j. In the cases where 3i and 3kꢀl were produced, tautomerism
could be identified in their NMR spectra. The alkyl group on the terminal carbon of
ketenimine could be methyl or ethyl. As the steric hindrance of the alkyl group increased
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from methyl (products 3k and 3m, 54% and 58% yields) to ethyl (products 3l and 3n, 38%
and 46% yields), the yields decreased.
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a
Scheme 2. Synthesis of 3ꢀiminoꢀisoquinolinꢀ1(2H)ꢀones 3
a
2 2 2 3
Reaction conditions: 1a (0.36 mmol), 2 (0.3 mmol), [Cp*RhCl ] (0.015 mmol), Cs CO
o
(
0.09 mmol), 4 Å MS (60 mg), DCE (2 mL), N
2
, 80 C, 10 h; Isolated yields refer to 2.
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As next step, we turned our sight to the derivation of products 3. We envisioned that 3
could be easily transformed to benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11(6H)ꢀone by an
intramolecular CꢀN bond coupling. The most easily prepared compound 3i was chosen as the
ideal candidate for the intramolecular NꢀArylation. By screened some classical
BuchwardꢀHartwig reaction and Ullmann reaction conditions (Table 2), we obtained the
desired cyclization product 4a in almost quantitative yield (Table 2, entry 3). A slight
decrease in yield was observed when the solvent was changed from toluene to DCE (Table 2,
entry 4). However, using DCE as solvent, we could conveniently conduct a twoꢀstep oneꢀpot
procedure for the preparation of benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11(6H)ꢀones by directly
adding the catalyst and additives after the CꢀH activation/annulation reaction.
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a
Table 2. Optimization of the intramolecular Nꢀarylation of compound 3i
entry
1
reaction conditions
yield (%)
63
2
5 mol % Pd(OAc) , 7.5 mol % dppf, 2 equiv of tꢀBuONa,
toluene, reflux, 10 h
2
10 mol % CuI, 20 mol % Lꢀproline, 2 equiv of NaH,
toluene, reflux,10 h
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10 mol % CuI, 20 mol % TMEDA, 2 equiv of Cs
2
CO
3
,
,
98
92
toluene, reflux,10 h
10 mol % CuI, 20 mol % TMEDA, 2 equiv of Cs
2
CO
3
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DCE, reflux, 10 h
a
All the reactions were conducted in 0.1 mmol scale. TMEDA
=
1
1
2
2
N ,N ,N ,N ꢀtetramethylethaneꢀ1,2ꢀdiamine.
We then tried to combine the two step reaction in one pot by adding CuI, TMEDA and
Cs CO after the annulation of 1 and 2. As shown in Scheme 3, the oneꢀpot preparation of
2
3
benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11(6H)ꢀone 4a was achieved successfully with a total
yield up to 60%. Subsequently, we investigated the substrate scope for this procedure. Several
substituted Nꢀmethoxybenzamides were examined. The substituent on 4ꢀposition in phenyl
ring of 1 could be either electronꢀdonating (e.g. MeO and Me) or electronꢀwithdrawing (e.g.
3
Cl and CF ). Thus, the corresponding products 4bꢀe were obtained with the yields ranging
from 42% to 61%. The substituent on 3ꢀposition of 1 could be Me (4f), Cl (4g) and NO
2
(4h).
Substitution on the 2ꢀposition of Nꢀmethoxybenzamides might retard the reaction due to steric
hindrance and poor yields of the corresponding products 4i and 4j were isolated.
NꢀMethoxyꢀ1ꢀnaphthamide (1b) was also examined and the desired product 4k was obtained
in 25% yield. The substituent on the terminal carbon of ketenimine could be either
pꢀmethylphenyl
or
mꢀchlorophenyl.
In
this
case,
the
desired
benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11(6H)ꢀones 4l and 4m were isolated in 55% and 60%,
respectively.
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a
Scheme 3. Oneꢀpot preparation of benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11(6H)ꢀones 4
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2 2 2 3
Reaction conditions: 1) 1 (0.24 mmol), 2 (0.2 mmol), [Cp*RhCl ] (0.01 mmol), Cs CO
o
(
0.06 mmol), 4Å MS (40 mg), DCE (2 mL), N
2
, 80 C, 10 h; 2) 10 mol% CuI (0.02 mmol),
o
TMEDA (0.04 mmol), Cs CO (0.4 mmol), N
2
3
2
, 80 C, 10 h; Isolated yield refer to 2.
Interestingly，by further extending the substrate scope of ketenimines, we found that
βꢀester group substituted ketenimines 5 were suitable for the standard reaction conditions, but
they resulted in a different reaction pathway to give the [4+1] annulation products (Table 3).
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In these cases, 3ꢀaminoindolinꢀ1ꢀones 6a~6i were obtained along with their stereoisomers
6
a'~6i' in moderate to excellent yields. For 6a and 6d~6g, the corresponding stereoisomers
a' and 6d'~6g' could be isolated and pure products were obtained. For 6b, 6c, 6h and 6i,
6
10
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however, we just isolated a mixture of these compounds and their stereoisomers 6b', 6c', 6h'
and 6i', respectively. The (2R,3S)/(2S,3R)ꢀconfiguration of 6e was established by its single
15
1
2
1
crystal analysis. Both R and R in ketenimines 5 could be either alkyl or aryl. Altering R
from methyl to aryl (5d~5i), higher dr values were obtained for products 6d~6i (Table 3,
2
entries 4~9). When the alkyl group (R ) on nitrogen of ketenimine became bulkier, from ethyl
to isopropyl, the yield decreased (Table 3, entries 8 and 9). When the alkyl was tertꢀbutyl, no
reaction occurred (Table 3, entry 10). Formation of the enantiomeric pair with absolute
configuration of (2R,3S)ꢀ6 and (2S,3R)ꢀ6 was found to be dominant in all cases as illustrated
in Figure 2. The steric hindrance raised when products 6 adopted the conformation of
(2S,3S)ꢀ6 and (2R,3R)ꢀ6.
a
Table 3. Synthesis of 3ꢀaminoisoindolinꢀ1ꢀones 6
1
2
3)
entry 5 (R /R /R
yield of
yield of
dr
b
b
(2R,3S)/(2S,3R)ꢀ6
(2R,3R) /(2S,3S)ꢀ6'
1
2
5a (CH /4ꢀClC H /Et)
6a/64%
6a'/20%
3.3:1
2.3:1
3
6
4
c
5b (CH /4ꢀClC H /nꢀBu)
3
6
4
(6b + 6b')/ 72%
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c
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1
5c (CH /4ꢀClC H /CH Ph)
(6c + 6c')/ 46%
2.2:1
6.4:1
5:1
3
6
4
2
5d (Ph/4ꢀClC H /Et)
6
4
6d/74%
6e/76%
6f/35%
6g/67%
6d'/ 12%
6e'/15%
5e (4ꢀBrC H /4ꢀClC H /Et)
6
4
6
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0
5f (4ꢀMeOC H /4ꢀClC H /Et)
6f'/ 7%
5:1
6
4
6
4
5g (Ph/4ꢀCH C H /Et)
3
6
4
6g'/13%
5.1:1
5.5:1
6.5:1
c
c
5h (Ph/Et/Et)
(6h + 6h')/98%
(6i + 6i')/57%
N.R.
5i (Ph/iꢀPr/Et)
5j (Ph/tꢀBu/Et)
0
a
2 2 3 2
Reaction conditions: 1a (0.36 mmol), 5 (0.3 mmol), [Cp*RhCl ] (0.015 mmol), Cl CCO Cs
o
b
c
(0.09 mmol), 4Å MS (60 mg), DCE (2 mL) under N
2
, 80 C, 10 h. Isolated yields refer to 2.
1
Determined by H NMR.
Figure 2. Predominant formation of (2R,3S)ꢀ6 and (2S,3R)ꢀ6
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To probe the reaction mechanism for the formation of compounds 3, the reactions of 1a
2 2 2
with 2a were examined using 5 mol % [Cp*RhCl ] and 15 mol % AgNTf (Scheme 4, eq 1).
The addition product 7 was isolated in 95% yield. Further investigation revealed that
imidamide 7 was stable to the standard conditions. Furthermore, when the reaction of 1a was
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2
conducted with the addition of 1 equivalent of D O under the standard conditions in the
absence of ketenimine, a deuterium incorporated product was obtained. This result indicated
that the CꢀH activation was reversible (Scheme 4, eq 2). Kinetic isotope effect (KIE) was
16
carried out in parallel experiments (Scheme 4, eq 3). By treatment of 1a or 1a-d
5
under
standard reaction conditions for 30 minutes, KIE of the [4+2] reaction was determined to be
.1. This value indicated that the CꢀH activation was not the rate determining step.
1
Scheme 4. Mechanistic Experiments
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4
4
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5
5
5
5
5
6
On the basis of the above experiments, a possible mechanism is proposed in Scheme 5. In
2 3 3 2 2 2
the presence of Cs CO or Cl CCO Cs, catalyst [Cp*RhCl ] is activated to species A.
Subsequent arene electrophilic rhodation of 1 provides the complex B, followed by its
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
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5
6
7
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9
0
1
2
3
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5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
coordination to ketenimine. Thereafter, there are two distinct reaction pathways depending on
the nature of substituents on ketenimine. When methyl or primary alkyl occupied on the
1
terminal carbon of ketenimine (R = Me or CH
2
R), the formation of πꢀcomplex C is dominant.
Subsequently, the migratory insertion into C=C bond leads to the formation of D, which
17
undergoes an intramolecular oxidation/reductive elimination to form E. After metalꢀH
exchange, E undoubtedly generates in the [4+2] annulation product 3. When one ester group
13
1
1
2
or two aryls occupies on the terminal carbon of ketenimine (i.e., R = COOR or R = R
=
aryl), Rh coordinates to the nitrogen atom of ketenimine to afford σꢀcomplex F. Upon
migratory insertion into C=N bond, complex G is generated. Then, G undergoes a migratory
insertion into C=C bond to form complex H. Finally, the [4+1] annulation product 6 is
generated by the metalꢀH exchange.
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[
Cp*RhCl2]2
[
4+1] product
[4+2] product
CsX
6
3
Cp*RhX2
O
A
O
Cp*
Rh
OMe
HX
HX
N
1
N
OMe
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R3
Cp*
X
Rh
R2
R3 NH
N
R1
Ar CH2
R
HX
H
O
E
HX
N OMe
Rh
X = CO 2 or
-
3
O
O
OMe
-
OMe
Cl CCO2
R1
R2
R3
C N
3
Cp*
N
N
B
Rh Cp*
Rh Cp*
N
R3
N
R3
Ar
CH2
1
R1
R = CO R or
R = R = aryl
O
2
R
R2
O
1
2
D
G
OMe
1
N
R = aryl,
R = alkyl
N OMe
2
Rh
Cp*
Rh
Cp*
R3
RCH2
Ar
R1
N
R3
C N
C
R2
F
C
Scheme 5. Possible mechanism for stericꢀand electronicꢀcontrolled formation of 3 and 6
Competitive formations between πꢀcomplex C and σꢀcomplex F play an important role in
13
the outcome of reaction. Geometry of 2c, 5a, and 2,2ꢀdiphenylꢀNꢀ(pꢀtolyl)ethenꢀ1ꢀimine (8)
was obtained by B3LYP/6ꢀ31G method on Gaussian 09 program (Figure 3). For ketenimine 8,
coordination of C=C bond to rhodium is effectively inhibited by two twisted aryl groups. As a
result, the nitrogen of ketenimine coordinates to rhodium with higher priority. When one of
the two aryls is altered into methyl, especially when the nitrogen bears a steric
ortho-substituted phenyl, the C=C bond of 2c could coordinate to rhodium. For ketenimine 5a,
the electronꢀwithdrawing effect of ester group is dominant which induced double Michael
additions on the central carbon of ketenimine.
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0
1
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5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
Figure 3. Geometry of 2c, 5a and 8
CONCLUSION
In conclusion, we have developed the rhodiumꢀcatalyzed CꢀH activation/annulations of
ketenimines with Nꢀmethoxybenzamides. The reaction outcomes were found to be dependent
on the molecular structure of the ketenimine component. The βꢀalkyl substituted ketenimines
furnished 3ꢀiminoisoquinolinꢀ1(2H)ꢀones through a formal [4+2] annulation manner, while
the βꢀester group substituted ketenimines afforded 3ꢀaminoisoindolinꢀ1ꢀones through a formal
[
4+1] annulation manner. Possible mechanism for the selective formation of [4+2] and [4+1]
annulations products was proposed on the basis of experimental and computational results.
Furthermore, the synthesized [4+2] products could undergo an intramolecular Cuꢀcatalyzed
CꢀN coupling to be converted to benzo[4,5]imidazo[1,2ꢀb]isoquinolinꢀ11ꢀones, which could
be directly prepared from ketenimines and Nꢀmethoxybenzamides by a oneꢀpot Rhꢀcatalyzed
annulation /Cuꢀcatalyzed CꢀN coupling sequence. The resulted heterocyclic products are an
important in medicinal chemistry.
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EXPERIMENTAL SECTION
General considerations. Unless otherwise mentioned, solvents and reagents were
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purchased from commercial sources and used as received. THF and toluene were distilled
2 2 2
from Na before use. MeCN, CH Cl and DCE were distilled from CaH . Melting points were
measured with a micro melting point apparatus. Infrared spectra were obtained with an FTIR
1
spectrometer. NMR spectra were operating at 500 MHz or 400 MHz for H NMR, 125 MHz
13
or 100 MHz for C NMR. Unless otherwise noted, all the NMR spectra were recorded at
room temperature. Chemical shifts were quoted in parts per million (ppm) referenced to the
appropriate solvent peak or 0.0 ppm for tetramethylsilane. Chemical shifts (in ppm) were
referenced to tetramethylsilane (δ = 0 ppm) in CDCl and d ꢀDMSO as an internal standard.
3
6
13
C NMR spectra were obtained by using the same NMR spectrometers and chemical shifts
were reported in ppm referenced to the center line of a triplet at 77.0 ppm of CDCl or the
center line of a heptet at 39.52 ppm of d ꢀDMSO. The following abbreviations are used to
3
6
describe peak patterns as appropriate: s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet. Coupling constants J were reported in hertz unit (Hz). Highꢀresolution mass spectra
(
HRMS) data were obtained with an electron ionization timeꢀofꢀflight (EIꢀTOF) mass
spectrometer. Flash column chromatography was performed employing 300ꢀ400 mesh silica
gel. Thin layer chromatography (TLC) was performed on silica gel HSGF254. Compounds
1
7, 18
1
a–k and 1a-d
5
were prepared according to the literature procedures.
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5
5
6
General Procedure for the Preparation of Ketenimines 2. To a mixture of the
3 2 2
coresponding Nꢀ(triphenylphosphoranylidene)anilines (2 mmol), Et N (2.4 mmol) in CH Cl
(
2 2
5 mL) was added a solution of 2ꢀphenylpropanoyl chloride (2 mmol) in CH Cl (5 mL)
0
1
2
3
4
5
6
7
8
9
0
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2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
dropwise. The mixture was stirred at room temperature for 15 min and then evaporated on
vacuum. The residue was subjected to silica gel column chromatography with petroleum ether
as eluent (The column should be eluted previously with petroleum ether/Et N (10:1, v/v).
3
1
N-(2-Ethylphenyl)-2-phenylprop-1-en-1-imine (2b). Yellow oil; 70 % (329 mg). H NMR
(
(
(
400 MHz, CDCl
t, J = 7.2 Hz, 1H), 2.86 (q, J = 7.5 Hz, 2H), 2.12 (s, 3H), 1.27 (t, J = 7.5 Hz, 3H). C NMR
100 MHz, CDCl ) δ 192.6, 139.5, 139.2, 135.9, 129.4, 128.6, 127.3, 126.8, 124.9, 124.3,
22.6, 66.4, 24.9, 15.3, 12.3 . IR (ATR): 2967, 2004, 1597, 1489, 1449, 1373, 1257, 1063,
3
) δ 7.31 (t, J = 7.7 Hz, 2H), 7.27 – 7.21 (m, 3H), 7.21 – 7.15 (m, 3H), 7.11
13
3
1
7
ꢀ1
+
56, 694 cm . HRMS (EI) m/z calcd for C17
H
17N [M ]: 235.1361; found: 235.1365.
1
2-Phenyl-N-(o-tolyl)prop-1-en-1-imine (2c). Yellow oil; 60 % (266 mg). H NMR (400
MHz, CDCl
1.9 Hz, 3H), 2.12 (d, J = 1.8 Hz, 3H). C NMR (100 MHz, CDCl
33.1, 131.0, 128.6, 127.1, 126.8, 124.9, 124.3, 122.5, 66.2, 18.0, 12.3. IR (ATR): 3023, 2919,
3
) δ 7.35 – 7.28 (m, 2H), 7.26 – 7.21 (m, 3H), 7.21 – 7.08 (m, 4H), 2.45 (d, J =
13
3
) δ 192.6, 140.1, 135.8,
1
ꢀ1
2000, 1583, 1488, 1445, 1373, 1254, 1108, 1065, 754, 691 cm . HRMS (EI) m/z calcd for
+
C
16
H
15N [M ]: 221.1204; found: 221.1201.
1
N-(2-Bromophenyl)-2-phenylprop-1-en-1-imine (2h). Yellow oil; 54 % (310 mg). H NMR
400 MHz, CDCl ) δ 7.62 (dd, J = 8.0, 1.3 Hz, 1H), 7.36 – 7.23 (m, 6H), 7.17 – 7.07 (m, 2H),
2.14 (s, 3H). C NMR (100 MHz, CDCl ) δ 195.7, 140.6, 134.8, 133.4, 128.7, 128.3, 128.1,
(
3
13
3
125.5, 124.6, 123.7, 118.6, 67.5, 12.2. IR (ATR): 3059, 2922, 2000, 1583, 1469, 1439, 1372,
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ꢀ
1
+
1
257, 1067, 1027, 753, 692, 663 cm . HRMS (EI) m/z calcd for C H NBr [M ]: 285.0153;
15 12
found: 285.0153.
1
N-(2-Fluorophenyl)-2-phenylprop-1-en-1-imine (2i). Yellow oil; 83 % (373 mg). H NMR
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
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42
43
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48
49
50
51
52
53
54
55
56
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58
59
60
(
400 MHz, CDCl ) δ 7.36 – 7.28 (m, 3H), 7.27 – 7.23 (m, 2H), 7.23 – 7.18 (m, 1H), 7.17 –
3
13
7
.09 (m, 3H), 2.13 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 196.9, 156.2 (d, J = 252.4 Hz),
1
35.0, 129.5 (d, J = 10.3 Hz), 128.7, 128.3 (d, J = 7.7 Hz), 125.2 (d, J = 9.2 Hz), 124.6, 124.6
(
d, J = 4.1 Hz), 116.6 (d, J = 19.5 Hz), 66.5, 12.2. IR (ATR): 2000, 1596, 1493, 1452, 1374,
ꢀ1
+
1
259, 1128, 1101, 1066, 1027, 837, 754, 693 cm . HRMS (EI) m/z calcd for C15
H
12NF [M ]:
2
25.0954; found: 225.0956.
1
N,2-Di-p-tolylprop-1-en-1-imine (2j). Yellow oil; 49 % (230 mg). H NMR (400 MHz,
CDCl ) δ 7.21 (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.3 Hz, 2H), 7.12 (s, 4H), 2.35 (s, 3H), 2.32 (s,
3
13
3
H), 2.10 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 194.7, 139.1, 137.3, 134.8, 132.4, 130.0,
129.4, 124.3, 123.6, 67.3, 21.1, 21.0, 12.3. IR (film): 3022, 2922, 1997, 1605, 1579, 1512,
ꢀ1
+
1
504, 1371, 1252, 1061, 813 cm . HRMS (EI) m/z calcd for C17
H
17N [M ]: 235.1361;
found:235.1360.
1
N-(o-Tolyl)-2-(p-tolyl)prop-1-en-1-imine (2k). Yellow oil; 37 % (176 mg). H NMR (400
MHz, CDCl
3
) δ 7.25 – 7.20 (m, 1H), 7.19 – 7.11 (m, 7H), 2.45 (s, 3H), 2.32 (s, 3H), 2.10 (d, J
13
=
0.8 Hz, 3H). C NMR (100 MHz, CDCl
3
) δ 193.6, 140.4, 134.6, 133.1, 132.5, 130.9, 129.4,
126.9, 126.8, 124.2, 122.4, 66.2, 21.0, 18.0, 12.4. IR (ATR): 2923, 2000, 1512, 1487, 1456,
ꢀ1
+
1
373, 1257, 1110, 1060, 813, 758, 673 cm . HRMS (EI) m/z calcd for C17
H
17N [M ]:
235.1361; found: 235.1357.
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2
2
2
2
2
2
2
2
2
2
3
3
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3
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5
5
5
5
5
6
1
N-(o-Tolyl)-2-(p-tolyl)but-1-en-1-imine (2l). Yellow oil; 45 % (233 mg). H NMR (400
MHz, CDCl ) δ 7.25 – 7.19 (m, 2H), 7.17 – 7.10 (m, 6H), 2.51 (qd, J = 7.4, 1.1 Hz, 2H), 2.45
3
1
3
(
s, 3H), 2.32 (s, 3H), 1.24 (td, J = 7.3, 1.2 Hz, 3H). C NMR (100 MHz, CDCl
3
) δ 193.4,
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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4
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0
1
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5
6
7
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40.6, 134.7, 133.1, 132.0, 130.9, 129.4, 126.9, 126.8, 124.6, 122.0, 74.0, 21.0, 19.9, 18.0,
ꢀ1
2.9. IR (ATR): 2966, 2925, 1999, 1512, 1488, 1456, 817, 759 cm . HRMS (EI) m/z calcd
+
for C H N [M ]: 249.1517; found: 249.1514.
18
19
1
N-(2-Bromophenyl)-2-(p-tolyl)prop-1-en-1-imine (2m). Yellow oil; 39 % (193 mg). H
NMR (400 MHz, CDCl ) δ 7.62 (dd, J = 8.0, 1.4 Hz, 1H), 7.31 – 7.22 (m, 2H), 7.18 – 7.08 (m,
3
13
5
1
1
H), 2.33 (s, 3H), 2.13 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 196.7, 140.9, 135.2, 133.4,
31.5, 129.5, 128.3, 128.0, 124.6, 123.7, 118.7, 67.5, 21.0, 12.3. IR (film): 2921, 2000, 1583,
ꢀ1
513, 1472, 1437, 1372, 1255, 1044, 1028, 814, 755 cm . HRMS (EI) m/z calcd for
+
C
16
H
14NBr [M ]: 299.0310; found: 299.0309.
1
N-(2-Bromophenyl)-2-(p-tolyl)but-1-en-1-imine (2n). Yellow oil; 43 % (269 mg). H NMR
400 MHz, CDCl ) δ 7.65 – 7.60 (m, 1H), 7.31 – 7.25 (m, 2H), 7.20 – 7.01 (m, 6H), 2.53 (q, J
= 7.4 Hz, 2H), 2.32 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H). C NMR (100 MHz, CDCl
41.1, 135.3, 133.4, 131.0, 129.5, 128.3, 128.1, 124.9, 123.3, 118.9, 75.2, 21.0, 20.0, 12.8. IR
(
3
13
3
) δ 196.6,
1
ꢀ1
(ATR): 2967, 2925, 2000, 1687, 1584, 1513, 1468, 1028, 816, 755 cm . HRMS (EI) m/z
+
calcd for C17
H
16NBr [M ]: 313.0466; found: 313.0468.
General procedure for the preparation of 3-imino-3,4-dihydroisoquinolin-1(2H)-ones
3: To an ovenꢀdried Schlenk tube equipped with a magnetic stirring bar were added
2 2 2 3
sequentially 1 (0.36 mmol), 2 (0.3 mmol), [Cp*RhCl ] (0.015 mmol), Cs CO (0.09 mmol),
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Å MS (60 mg) and dry DCE (2 mL) under N atmosphere. The reaction vessel was heated to
2
o
80 C in oil bath for 10 hours. Upon completion, the reaction mixture was cooled to room
temperature and then the solvent was evaporated in vacuum. The residue was purified by
column chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give pure
product.
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4-Methyl-4-phenyl-3-(p-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3a). White solid;
o
1
yield 45% (46 mg); mp 146 – 148 C. H NMR (400 MHz, CDCl
3
) δ 8.20 (dd, J = 7.8, 1.5 Hz,
1
3
H), 7.76 (s, 1H), 7.59 (td, J = 7.6, 1.5 Hz, 1H), 7.45 (td, J = 7.6, 1.2 Hz, 1H), 7.34 – 7.26 (m,
H), 7.26 – 7.20 (m, 3H), 7.12 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 8.2 Hz, 2H), 2.31 (s, 3H), 2.17
13
(
s, 3H). C NMR (100 MHz, CDCl
3
) δ 162.6 , 155.8 , 145.6 , 145.3 , 143.9 , 134.0 , 133.7 ,
130.4 , 128.4 , 128.1 , 127.8 , 127.4 , 127.1 , 126.9 , 125.0 , 120.0 , 49.4 , 27.9 , 20.8 . IR
(
ATR): 3361, 3195, 2924, 1689, 1655, 1603, 1503, 1461, 1361, 1285, 1150, 1032, 910, 759,
ꢀ1
+
731, 703 cm . HRMS (EI) calcd for C23
20 2
H N O [M ] 340.1576, found 340.1580.
3-((4-Bromophenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one (3b).
o
1
White solid; yield 43% (52 mg); mp 170 – 172 C. H NMR (400 MHz, CDCl
3
) δ 8.20 (dd, J
=
7.8, 1.5 Hz, 1H), 7.66 (s, 1H), 7.60 (td, J = 7.7, 1.5 Hz, 1H), 7.50 – 7.40 (m, 3H), 7.34 –
13
7.28 (m, 2H), 7.28 – 7.24 (m, 2H), 7.23 – 7.19 (m, 2H), 6.67 – 6.59 (m, 2H), 2.17 (s, 3H). C
NMR (100 MHz, CDCl ) δ 162.5 , 156.5 , 145.7 , 145.3 , 134.2 , 132.9 , 128.5 , 128.2 , 127.8 ,
3
127.6 , 127.2 , 127.0 , 124.7 , 122.1 , 117.2 , 49.5 , 28.1 . IR (ATR): 3191, 3066, 2924, 2854,
ꢀ1
1687, 1654, 1461, 1362, 1288, 1211, 1150, 1069, 909, 840, 759, 732 cm . HRMS (EI) calcd
+
for C H N OBr [M ] 404.0524, found 404.0520.
22
17
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-((4-Methoxyphenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one
(3c).
o
1
White solid; yield 41% (44 mg); mp 147 – 148 C. H NMR (500 MHz, CDCl
3
) δ 8.20 (d, J =
7
.7 Hz, 1H), 7.82 (s, 1H), 7.59 (td, J = 7.6, 1.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.33 – 7.26
0
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8
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(
m, 3H), 7.26 – 7.19 (m, 3H), 6.87 (d, J = 8.7 Hz, 2H), 6.69 (d, J = 8.7 Hz, 2H), 3.78 (s, 3H),
1
3
2
.17 (s, 3H). C NMR (125 MHz, CDCl
3
) δ 162.6 , 156.4 , 156.0 , 145.6 , 145.3 , 139.5 ,
1
34.0 , 128.4 , 128.1 , 127.7 , 127.4 , 127.0 , 126.9 , 124.9 , 121.2 , 115.1 , 55.5 , 49.4 , 27.9 .
IR (ATR): 3361, 3199, 3063, 2933, 1689, 1654, 1604, 1503, 1462, 1362, 1285, 1240, 1034,
ꢀ1
+
9
11, 841, 756, 705, 644 cm . HRMS (EI) calcd for C23
H
20
N
2
O
2
[M ] 356.1525, found
3
56.1528.
4-Methyl-4-phenyl-3-(phenylimino)-3,4-dihydroisoquinolin-1(2H)-one (3d). White solid;
o
1
yield 41% (40 mg); mp 108 – 110 C. H NMR (400 MHz, CDCl ) δ 8.21 (dd, J = 7.8, 1.5 Hz,
3
1
H), 7.71 (br, 1H), 7.60 (td, J = 7.6, 1.5 Hz, 1H), 7.46 (td, J = 7.6, 1.2 Hz, 1H), 7.36 – 7.27
(m, 5H), 7.27 – 7.20 (m, 3H), 7.13 – 7.06 (m, 1H), 6.74 (dd, J = 8.3, 1.1 Hz, 2H), 2.19 (s, 3H).
13
3
C NMR (100 MHz, CDCl ) δ 162.6 , 155.8 , 146.6 , 145.5 , 145.3 , 134.1 , 129.9 , 128.5 ,
128.2 , 127.8 , 127.5 , 127.1 , 127.0 , 124.9 , 124.3 , 120.1 , 49.4 , 27.9 . IR (ATR): 3363,
216, 3061, 2925, 1692, 1656, 1597, 1490, 1461, 1360, 1284, 1211, 1149, 1071, 1030, 909,
3
ꢀ1
+
759, 700 cm . HRMS (EI) calcd for C22
18 2
H N O [M ] 326.1419, found 326.1415.
4-Methyl-4-(p-tolyl)-3-(p-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3e). White solid;
o
1
yield 42% (45 mg); mp 154 – 157 C. H NMR (500 MHz, CDCl
3
) δ 8.19 (dd, J = 7.8, 1.5 Hz,
1
H), 7.74 (s, 1H), 7.59 (td, J = 7.7, 1.5 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H), 7.28 (d, J = 7.9
Hz, 1H), 7.12 (d, J = 8.1 Hz, 2H), 7.10 (s, 4H), 6.64 (d, J = 8.1 Hz, 2H), 2.31 (s, 6H), 2.15 (s,
13
3
H). C NMR (125 MHz, CDCl
3
) δ 162.7 , 155.9 , 145.5 , 144.0 , 142.7 , 136.7 , 134.0 ,
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33.7 , 130.4 , 129.1 , 128.1 , 127.7 , 127.3 , 126.8 , 124.9 , 120.0 , 49.1 , 27.9 , 20.9 , 20.8 .
ꢀ1
IR (ATR): 2924, 2855, 1693, 1658, 1510, 1461, 1374, 1281, 817, 753 cm . HRMS (EI) calcd
+
for C24
H
22
N
2
O [M ] 354.1732, found 354.1730.
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60
3
-((3-Bromophenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one
(3f).
o
1
White solid; yield 49% (59 mg); mp 125 – 126 C. H NMR (400 MHz, CDCl
3
) δ 8.20 (dd, J
=
7.8, 1.5 Hz, 1H), 7.71 (br, 1H), 7.60 (td, J = 7.6, 1.5 Hz, 1H), 7.46 (td, J = 7.6, 1.2 Hz, 1H),
7
1
1
4
8
4
.34 – 7.28 (m, 2H), 7.28 – 7.16 (m, 6H), 6.91 (t, J = 1.9 Hz, 1H), 6.67 (dt, J = 7.3, 1.7 Hz,
13
H), 2.17 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 162.5 , 156.7 , 148.1 , 145.3 , 145.2 , 134.2 ,
31.1 , 128.5 , 128.2 , 127.8 , 127.5 , 127.20 , 127.18 , 126.9 , 124.6 , 123.4 , 123.3 , 118.9 ,
9.4 , 28.1 . IR (ATR): 3194, 3061, 1688, 1653, 1584, 1460, 1360, 1286, 1150, 1031, 994,
ꢀ1
+
77, 758, 736, 701, 677 cm . HRMS (EI) calcd for C H N OBr [M ] 404.0524, found
22 17
2
04.0526.
4-Methyl-4-phenyl-3-(o-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3g). Yellow oil;
1
yield 67% (68 mg). H NMR (400 MHz, CDCl
3
) δ 8.21 (dd, J = 7.8, 1.5 Hz, 1H), 7.68 (s, 1H),
7.56 (td, J = 7.7, 1.5 Hz, 1H), 7.43 (td, J = 7.6, 1.2 Hz, 1H), 7.34 – 7.23 (m, 5H), 7.20 (d, J =
.7 Hz, 1H), 7.14 (t, J = 7.9 Hz, 2H), 6.98 (td, J = 7.5, 1.3 Hz, 1H), 6.61 (d, J = 7.7 Hz, 1H),
7
13
2.23 (s, 3H), 1.89 (s, 3H). C NMR (100 MHz, CDCl
34.1 , 131.1 , 128.7 , 128.4 , 128.0 , 127.3 , 127.2 , 127.09 , 127.06 , 124.5 , 124.3 , 119.3 ,
49.3 , 28.5 , 17.4 . IR (ATR): 3359, 3213, 3062, 1691, 1657, 1599, 1488, 1458, 1357, 1285,
3
) δ 162.5 , 155.4 , 145.9 , 145.4 , 144.8 ,
1
ꢀ1
+
1
148, 1113, 1033, 808, 757, 702 cm . HRMS (EI) calcd for C23
H
20 2
N O [M ] 340.1576, found
340.1579.
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-((2-Ethylphenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one
(3h).
o
1
White solid; yield 66% (70 mg); mp 95 – 97 C. H NMR (400 MHz, CDCl
3
) δ 8.22 (dd, J =
7
7
2
1
1
2
.9, 1.5 Hz, 1H), 7.72 (s, 1H), 7.57 (td, J = 7.6, 1.5 Hz, 1H), 7.44 (td, J = 7.6, 1.2 Hz, 1H),
0
1
2
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0
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0
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2
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8
9
0
1
2
3
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5
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7
8
9
0
.34 – 7.11 (m, 8H), 7.02 (td, J = 7.5, 1.4 Hz, 1H), 6.60 (dd, J = 7.7, 1.3 Hz, 1H), 2.23 (s, 3H),
13
3
.21 (q, J = 7.5 Hz, 2H), 0.91 (t, J = 7.5 Hz, 3H). C NMR (100 MHz, CDCl ) δ 162.5 ,
55.2 , 145.9 , 145.4 , 144.3 , 135.1 , 134.1 , 129.5 , 128.3 , 128.0 , 127.9 , 127.3 , 127.2 ,
27.1 , 127.0 , 124.6 , 124.5 , 119.3 , 49.3 , 28.4 , 24.6 , 14.2 . IR (ATR): 3359, 3205, 3062,
ꢀ1
967, 1691, 1656, 1599, 1487, 1457, 1358, 1285, 1215, 1148, 1117, 1031, 755, 702 cm .
+
HRMS (EI) calcd for C24
H
22
N
2
O [M ] 354.1732, found 354.1731.
3-((2-Bromophenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one
(3i).
o
1
White solid; yield 70% (85 mg); mp 123 – 124 C. H NMR (400 MHz, CDCl ) δ 8.22 – 8.19
3
(
1H), 7.73 (br, 0.17H), 7.64 – 7.52 (m, 2.65 H), 7.49 – 7.41 (1H), 7.36 – 7.16 (m, 7H), 7.09 (t,
J = 7.5 Hz, 0.17 H), 6.95 (td, J = 7.8, 1.6 Hz, 0.87 H), 6.73 (1H), 2.25 (s, 2.55 H), 2.18 (s,
.46 H). IR (ATR): 3357, 3194, 3063, 2924, 1691, 1658, 1602, 1460, 1360, 1289, 1149, 1029,
0
ꢀ1
+
909, 757, 730, 701 cm . HRMS (EI) calcd for C22
17 2
H N OBr [M ] 404.0524, found 404.0529.
3-((2-Fluorophenyl)imino)-4-methyl-4-phenyl-3,4-dihydroisoquinolin-1(2H)-one
(3j).
o
1
White solid; yield 39% (40 mg); mp 138 – 139 C. H NMR (500 MHz, CDCl
3
) δ 8.20 (d, J =
7
.7 Hz, 1H), 7.72 (s, 1H), 7.59 (td, J = 7.7, 1.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 1H), 7.34 – 7.29
1
3
(m, 2H), 7.28 – 7.22 (m, 4H), 7.12 – 7.02 (m, 3H), 6.82 – 6.76 (m, 1H), 2.20 (s, 3H).
C
NMR (125 MHz, CDCl
3
) δ 162.5 , 157.8 , 152.8 (d, J = 245.5 Hz), 145.5 , 145.1 , 134.2 ,
133.9 (d, J = 12.8 Hz), 128.4 , 128.1 , 127.8 , 127.4 , 127.2 , 127.1 , 125.4 (d, J = 7.2 Hz),
1
25.0 (d, J = 3.6 Hz), 124.5 , 122.9 (d, J = 2.1 Hz), 116.6 (d, J = 19.5 Hz), 49.8 , 28.4 . IR
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(
ATR): 3364, 3196, 3067, 1691, 1658, 1603, 1491, 1460, 1363, 1289, 1251, 1150, 1101, 1031,
ꢀ1
+
9
17 2
10, 756, 648 cm . HRMS (EI) calcd for C22H N OF [M ] 344.1325, found 344.1329.
3-((2-Bromophenyl)imino)-4-methyl-4-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one
(3k).
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60
1
Pale yellow oil; yield 58% (73 mg). H NMR (400 MHz, CDCl
3
) δ 8.19 (dd, J = 7.8, 1.5 Hz,
1
7
2
1
H), 7.73 (br, 0.19 H), 7.61 (br, 0.8 H), 7.59 – 7.54 (2H), 7.47 – 7.39 (1H), 7.35 – 7.16 (4H),
.15 – 7.10 (2H), 7.10 – 7.05 (m, 0.20 H), 6.94 (td, J = 7.7, 1.6 Hz, 0.87 H), 6.76 – 6.68 (1H),
.32 –2.31 (d, J = 2.8 Hz, 3H), 2.22 (s, 2.49 H), 2.16 (s, 0.50 H). IR (ATR): 3361, 3197, 3065,
ꢀ1
691, 1657, 1601, 1512, 1460, 1360, 1288, 1149, 1027, 909, 820, 758, 730 cm . HRMS (EI)
+
calcd for C23
H
19
N
2
OBr [M ] 418.0681, found: 418.0678.
3
-((2-Bromophenyl)imino)-4-ethyl-4-(p-tolyl)-3,4-dihydroisoquinolin-1(2H)-one (3l). Pale
1
yellow oil; yield 46% (60 mg). H NMR (400 MHz, CDCl ) δ 8.21 (dt, J = 7.8, 1.9 Hz, 1H),
3
7
.87 (br, 0.26 H), 7.73 (br, 0.71 H), 7.58 – 7.52 (m, 1.68 H), 7.46 – 7.38 (m, 1H), 7.31 (t, J =
7.9 Hz, 0.57 H), 7.27 – 7.09 (m, 6H), 7.08 – 7.04 (m, 0.23 H), 6.93 (td, J = 7.7, 1.6 Hz, 0.75
H), 6.71 (d, J = 8.1 Hz, 0.51 H), 6.66 (d, J = 7.8 Hz, 0.69 H), 3.25 – 3.01 (1H), 2.50 – 2.36 (m,
1H), 2.30 (s, 3H), 0.92 – 0.85 (3H). IR (ATR): 3359, 3199, 3065, 2970, 1690, 1653, 1600,
ꢀ1
1
512, 1459, 1362, 1306, 1267, 1229, 1148, 1027, 909, 816, 756, 729 cm . HRMS (EI) calcd
+
for C24
H
21
N
2
OBr [M ] 432.0837, found 432.0837.
4
-Methyl-4-(p-tolyl)-3-(o-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3m). Pale yellow
1
oil; yield 54% (57 mg). H NMR (500 MHz, CDCl
3
) δ 8.20 (dd, J = 7.8, 1.4 Hz, 1H), 7.66 (s,
1
H), 7.56 (td, J = 7.7, 1.5 Hz, 1H), 7.42 (t, J = 7.2 Hz, 1H), 7.21 (d, J = 7.9 Hz, 1H), 7.17 –
7.09 (m, 6H), 6.98 (t, J = 7.5 Hz, 1H), 6.61 (d, J = 7.6 Hz, 1H), 2.31 (s, 3H), 2.20 (s, 3H),
13
1
.92 (s, 3H). C NMR (125 MHz, CDCl
3
) δ 162.6 , 155.6 , 146.1 , 144.9 , 142.5 , 136.7 ,
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34.0 , 131.1 , 129.1 , 128.7 , 127.94 , 127.90 , 127.3 , 127.1 , 124.5 , 124.2 , 119.4 , 49.1 ,
8.6 , 20.9 , 17.5 . IR (ATR): 3359, 3213, 2925, 1693, 1659, 1599, 1511, 1460, 1359, 1286,
2
ꢀ1
+
1189, 1149, 1113, 1038, 910, 822, 755, 730 cm . HRMS (EI) calcd for C24
22 2
H N O [M ]
0
1
2
3
4
5
6
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8
9
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1
2
3
4
5
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0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
354.1732, found 354.1735.
4-Ethyl-4-(p-tolyl)-3-(o-tolylimino)-3,4-dihydroisoquinolin-1(2H)-one (3n). Pale yellow
1
oil; yield 38% (42 mg). H NMR (400 MHz, CDCl ) δ 8.22 (dd, J = 7.9, 1.5 Hz, 1H), 7.77 (s,
3
1H), 7.56 (td, J = 7.7, 1.5 Hz, 1H), 7.42 (td, J = 7.6, 1.2 Hz, 1H), 7.18 – 7.08 (m, 7H), 6.98
(
td, J = 7.5, 1.3 Hz, 1H), 6.59 (d, J = 7.7 Hz, 1H), 3.17 (dq, J = 14.4, 7.2 Hz, 1H), 2.42 (dq, J
1
3
=
14.0, 6.9 Hz, 1H), 2.30 (s, 3H), 1.86 (s, 3H), 0.87 (t, J = 7.3 Hz, 3H). C NMR (100 MHz,
) δ 162.6 , 154.7 , 145.0 , 144.5 , 143.4 , 136.7 , 134.2 , 131.2 , 129.1 , 129.0 , 128.2 ,
27.7 , 127.17 , 127.15 , 125.8 , 124.3 , 119.4 , 53.6 , 34.0 , 21.0 , 17.5 , 9.5 . IR (ATR): 2926,
CDCl
3
1
1
ꢀ1
692, 1657, 1600, 1459, 1362, 1307, 1265, 1149, 1041, 911, 814, 755, 731 cm . HRMS (EI)
+
calcd for C25
H
24
N
2
O [M ] 368.1889, found 368.1887.
General procedure for the preparation of benzo[4,5]imidazo[1,2-b]isoquinolin-
1-ones 4: To an ovenꢀdried Schlenk tube equipped with a magnetic stirring bar were added
1
sequentially 1 (0.24 mmol), 2 (0.2 mmol), [Cp*RhCl
2
]
2
2 3
(0.01 mmol), Cs CO (0.06 mmol),
4Å MS (40 mg) and dry DCE (2 mL) under N atmosphere. The reaction vessel was heated to
2
o
80 C in oil bath for 10 hours. Then, to the reaction mixture was added CuI (0.02 mmol),
2 3 2
TMEDA (0.04 mmol) and Cs CO (0.4 mmol), and the reaction was refluxed under N
atmosphere for another 10 hours. Upon completion, the reaction mixture was cooled to room
temperature and the solvent was evaporated in vacuum. The residue was purified by column
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chromatography on silica gel (petroleum ether/ethyl acetate = 10:1) to give pure product.
6-Methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4a). White solid;
o
1
yield 60% (39 mg); mp 118 – 120 C. H NMR (400 MHz, CDCl
3
) δ 8.55 – 8.44 (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
7
1
.76 – 7.74 (m, 1H), 7.67 – 7.60 (m, 1H), 7.57 – 7.49 (m, 1H), 7.75 – 7.37 (m, 2H), 7.35 –
13
.18 (m, 6H), 2.30 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 160.6, 159.0, 146.7, 144.6, 143.0,
34.6, 131.2, 128.7, 128.4, 127.7, 127.3, 127.1, 125.4, 125.0, 124.9, 119.8, 115.7, 46.2, 29.5.
IR (ATR): 3061, 2926, 2870, 1704, 1604, 1538, 1481, 1450, 1370, 1342, 1268, 1232, 1149,
ꢀ1
+
970, 890, 793, 750, 698 cm . HRMS (EI) calcd for C22
H
16
N
2
O [M ] 324.1263, found
324.1266.
6,8-Dimethyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4b). Pale yellow
o
1
solid; yield 61% (41 mg); mp 118 – 120 C. H NMR (500 MHz, CDCl ) δ 8.49 (dd, J = 7.3,
3
1.3 Hz, 1H), 8.35 (d, J = 8.1 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.43 – 7.36 (m, 2H), 7.34 – 7.31
13
(m, 1H), 7.30 – 7.20 (m, 6H), 7.08 (s, 1H), 2.38 (s, 3H), 2.29 (s, 3H). C NMR (125 MHz,
CDCl ) δ 160.7, 159.1, 146.6, 145.7, 144.7, 142.9, 131.2, 128.9, 128.8, 128.70, 128.67, 127.2,
3
127.1, 125.2, 124.8, 122.4, 119.7, 115.7, 46.0, 29.3, 22.0. IR (ATR): 3059, 2926, 1706, 1611,
ꢀ1
1537, 1451, 1365, 1343, 1230, 1148, 971, 890, 842, 794, 769, 746, 699 cm . HRMS (EI)
+
calcd for C23
H
18
N
2
O [M ] 338.1419, found 338.1422.
8-Methoxy-6-methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4c). Pale
o
1
yellow solid; yield 58% (41 mg); mp 202 – 204 C. H NMR (400 MHz, CDCl
3
) δ 8.51 – 8.46
(
m, 1H), 8.42 (d, J = 8.8 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.43 – 7.35 (m, 2H), 7.32 – 7.18 (m,
13
5H), 7.04 (dd, J = 8.8, 2.5 Hz, 1H), 6.72 (d, J = 2.5 Hz, 1H), 3.82 (s, 3H), 2.29 (s, 3H). C
NMR (100 MHz, CDCl
3
) δ 164.5, 160.3, 159.1, 149.1, 144.6, 142.9, 131.3, 131.2, 128.8,
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2
2
2
2
2
2
2
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3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
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4
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5
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5
5
5
6
1
2
8
3
27.3, 127.0, 125.1, 124.8, 119.7, 117.9, 115.7, 113.6, 113.5, 55.6, 46.4, 29.5. IR (ATR): 2924,
846, 1701, 1605, 1574, 1535, 1494, 1450, 1364, 1338, 1281, 1257, 1232, 1148, 1032, 970,
ꢀ1
+
88, 848, 767, 737, 698 cm . HRMS (EI) calcd for C23
18 2 2
H N O [M ] 354.1368, found
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
54.1367.
8-Chloro-6-methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4d). Pale
o
1
yellow solid; yield 59% (42 mg); mp 168 – 170 C. H NMR (400 MHz, CDCl ) δ 8.49 – 8.45
3
(
m, 1H), 8.41 (d, J = 8.4 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.50 (dd, J = 8.4, 2.0 Hz, 1H), 7.46 –
13
7
1
1
1
.37 (m, 2H), 7.34 – 7.21 (m, 6H), 2.30 (s, 3H). C NMR (100 MHz, CDCl
3
) δ 159.8, 158.4,
48.4, 143.8, 143.0, 141.2, 131.1, 130.3, 129.0, 128.48, 128.46, 127.6, 127.0, 125.5, 125.2,
23.4, 119.9, 115.7, 46.3, 29.4. IR (ATR): 2925, 2854, 1706, 1596, 1539, 1451, 1411, 1364,
ꢀ1
339, 1230, 1149, 1099, 971, 886, 842, 765, 746, 696 cm . HRMS (EI) calcd for
+
C
22
H
15
N
2
OCl [M ] 358.0873, found 358.0876.
6-Methyl-6-phenyl-8-(trifluoromethyl)benzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one
o
1
3
(4e). White solid; yield 42% (33 mg); mp 161 – 163 C. H NMR (500 MHz, CDCl ) δ 8.61
(d, J = 8.2 Hz, 1H), 8.51 – 8.45 (m, 1H), 7.81 – 7.73 (m, 2H), 7.56 (s, 1H), 7.47 – 7.40 (m,
13
2H), 7.34 – 7.29 (m, 2H), 7.28 – 7.20 (m, 3H), 2.34 (s, 3H). C NMR (125 MHz, CDCl ) δ
3
159.4, 158.2, 147.4, 143.6, 143.0, 136.0 (q, J = 33.0 Hz), 131.1, 129.6, 129.0, 127.80, 127.76,
27.0, 125.8, 125.4 (q, J = 3.8 Hz), 125.3, 124.5 (q, J = 3.6 Hz), 123.1 (q, J = 273.3 Hz),
1
120.0, 115.7, 46.4, 29.4. IR (ATR): 2956, 2925, 2855, 1711, 1672, 1595, 1541, 1453, 1425,
ꢀ1
1373, 1334, 1266, 1231, 1174, 1135, 1073, 1024, 751, 700 cm . HRMS (EI) calcd for
+
C H N OF [M ] 392.1136, found 392.1140.
2
3
15
2
3
6,9-Dimethyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4f). Pale yellow
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o
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solid; yield 64% (43 mg); mp 170 – 172 C. H NMR (400 MHz, CDCl ) δ 8.54 – 8.45 (m,
3
1
2
1
2
1
3
H), 8.26 (d, J = 0.8 Hz, 2H), 7.78 – 7.70 (m, 1H), 7.47 – 7.35 (m, 3H), 7.31 – 7.16 (m, 6H),
13
3
.48 (s, 3H), 2.28 (s, 3H). C NMR (100 MHz, CDCl ) δ 160.8, 159.2, 144.8, 143.8, 143.0,
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
37.7, 135.7, 131.3, 128.8, 128.7, 128.3, 127.2, 127.1, 125.3, 124.9, 124.7, 119.8, 115.8, 45.9,
9.4, 21.0 . IR (ATR): 2925, 2856, 1706, 1614, 1538, 1495, 1451, 1422, 1363, 1343, 1271,
ꢀ1
+
246, 1177, 1149, 830, 798, 768, 748, 700 cm . HRMS (EI) calcd for C H N O [M ]
23
18
2
38.1419, found 338.1421.
-Chloro-6-methyl-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4g). Pale
9
o
1
yellow solid; yield 61% (44 mg); mp 173 – 175 C. H NMR (400 MHz, CDCl
3
) δ 8.49 – 8.45
(
m, 1H), 8.43 (d, J = 2.3 Hz, 1H), 7.77 – 7.71 (m, 1H), 7.58 (dd, J = 8.5, 2.4 Hz, 1H), 7.46 –
1
3
7
.37 (m, 2H), 7.33 – 7.20 (m, 6H), 2.28 (s, 3H). C NMR (100 MHz, CDCl ) δ 159.4, 158.5,
3
1
45.0, 144.0, 143.0, 134.7, 134.1, 131.1, 130.1, 128.9, 128.3, 127.5, 127.0, 126.4, 125.6,
125.2, 119.9, 115.7, 46.0, 29.4 . IR (ATR): 2926, 2856, 1708, 1603, 1540, 1480, 1452, 1420,
ꢀ1
1
364, 1342, 1265, 1229, 1150, 1094, 831, 750, 699 cm . HRMS (EI) calcd for C22
H
15
N
2
OCl
+
[M ] 358.0873, found 358.0878.
6
-Methyl-9-nitro-6-phenylbenzo[4,5]imidazo[1,2-b]isoquinolin-11(6H)-one (4h). Pale
o
1
yellow solid; yield 30% (22 mg); mp 223 – 225 C. H NMR (500 MHz, CDCl
3
) δ 9.30 (d, J
=
2.5 Hz, 1H), 8.53 – 8.46 (m, 1H), 8.43 (dd, J = 8.7, 2.5 Hz, 1H), 7.79 – 7.72 (m, 1H), 7.50
(d, J = 8.7 Hz, 1H), 7.47 (td, J = 7.6, 1.5 Hz, 1H), 7.44 (td, J = 7.6, 1.5 Hz, 1H), 7.36 – 7.30
13
(
m, 2H), 7.30 – 7.26 (m, 1H), 7.25 – 7.21 (m, 2H), 2.34 (s, 3H). C NMR (125 MHz, CDCl
3
)
δ 158.5, 157.7, 152.8, 147.3, 143.1, 143.0, 130.9, 130.3, 129.2, 128.4, 128.0, 127.0, 126.3,
1
26.0, 125.5, 124.2, 120.1, 115.8, 46.7, 29.5 . IR (ATR): 2955, 2924, 1709, 1613, 1530, 1452,
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