Nucleophilic lewis base dependent addition reactions of allenoates with trifluoromethylated cyclic ketimines

Article abstract of DOI:10.1021/jo500356t

A detailed investigation on the different reactivity patterns shown by phosphorus- and nitrogen-containing Lewis base catalysts in the reactions of allenoates with cyclic trifluoromethyl ketimines was accomplished. With PPh ₃, [3 + 2] annulations proceeded smoothly to afford dihydropyrrole derivatives in excellent yields. Under the catalysis of DABCO, [2 + 2] annulations occurred, producing azetidine derivatives in good to high yields. However, in the presence of pyridine, α,α′-disubstituted allenoates were obtained in very high yields via aza-Morita-Baylis-Hillman reactions. These studies provide an opportunity for diverse synthesis of a variety of N-heterocyclic compounds from the same starting materials.

Full text of DOI:10.1021/jo500356t

Article
pubs.acs.org/joc
Nucleophilic Lewis Base Dependent Addition Reactions of Allenoates
with Trifluoromethylated Cyclic Ketimines
Li-Jun Yang, Shen Li, Shuai Wang, Jing Nie, and Jun-An Ma*
Department of Chemistry, Key Laboratory of Systems Bioengineering (The Ministry of Education), Tianjin University, Collaborative
Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300072, People’s Republic of China
S
* Supporting Information
ABSTRACT: A detailed investigation on the different reactivity patterns shown by phosphorus- and nitrogen-containing Lewis
base catalysts in the reactions of allenoates with cyclic trifluoromethyl ketimines was accomplished. With PPh3, [3 + 2]
annulations proceeded smoothly to afford dihydropyrrole derivatives in excellent yields. Under the catalysis of DABCO, [2 + 2]
annulations occurred, producing azetidine derivatives in good to high yields. However, in the presence of pyridine, α,α′-
disubstituted allenoates were obtained in very high yields via aza-Morita−Baylis−Hillman reactions. These studies provide an
opportunity for diverse synthesis of a variety of N-heterocyclic compounds from the same starting materials.
Since Lu’s pioneer work on the application of N-Ts aldimines
in formal [3 + 2] cycloadditions with allenoates under Lewis
base catalysis,3 electron-deficient imines have become one of
the most commonly employed electrophilic-coupling partners
in this type of transformation to furnish nitrogen-containing
molecules with complexity.4,5 Furthermore, this strategy has
been successfully applied to the synthesis of natural products
and compounds of pharmaceutical significance.6 However,
unlike the widely studied aldimines, the use of less reactive
ketimines as electrophiles in the Lewis base catalyzed allenoate
reaction was not disclosed until recently by Ye and co-
workers.4k,l The authors reported Lewis base catalyzed
annulations of allenoates with cyclic ketimines bearing strong
electron-withdrawing N-sulfonyl groups to give various N-
heterocyclic compounds. Owing to the higher electrophilicity of
α-trifluoromethyl ketimines7 in comparison with their non-
fluorinated analogues, we envisioned that a trifluoromethyl-
substituted quinazolin-2(1H)-one8,9 might be active enough to
react with allenoates by using an appropriate Lewis base
catalyst. Moreover, it is worth mentioning that the generated
trifluoromethyl dihydroquinazoline derivatives could lead to the
formation of druglike substances.10 Very recently, we
demonstrated that bisphosphine DPPP could catalyze a one-
pot sequential [3 + 2]/[3 + 2] annulation process of ethyl 2,3-
butadienoate 1 with cyclic trifluoromethyl ketimines 2,
providing the N-fused polycyclic compounds 3 in excellent
INTRODUCTION
■
The Lewis base catalyzed1 nucleophilic activation of allenoates
followed by reaction with electrophiles has experienced a great
expansion over the past few decades.2 In general, such reactions
are initiated with the generation of a zwitterionic intermediate
upon conjugate addition of a Lewis base to an allenoate
(Scheme 1). Depending on the nature of the Lewis base and
Scheme 1. Zwitterionic Intermediates upon Conjugate
Addition of Lewis Bases to Allenoates
different reaction conditions, the formed zwitterionic inter-
mediate may be depicted in several ways, which include anion
localization at the α carbon or γ carbon or delocalization, such
as a 1,3-dipole. These structurally diverse intermediates provide
an opportunity for the construction of a variety of complex
scaffolds from the same starting materials.
Received: February 13, 2014
Published: April 2, 2014
© 2014 American Chemical Society
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Scheme 2. Reactions of Ethyl 2,3-Butadienoate 1 with Cyclic Trifluoromethyl Ketimines 2 Catalyzed by Lewis Bases
Table 1. Catalyst Screening and Reaction Optimization for the Reaction of Ethyl 2,3-Butadienoate (1) with Cyclic
a
Trifluoromethyl Ketimine 2a Catalyzed by Monophosphine Lewis Bases
b
yield (%)
entry
1
phosphine
solvent
temp (°C)
3a
4a
PBu3
toluene
toluene
toluene
toluene
toluene
toluene
THF
25
25
25
25
25
0
59
42
54
35
43
13
11
23
8
28
20
44
31
34
85
86
66
88
12
96
78
c
2
PCy3
3
PPh3
4
P(NMe2)3
P(NEt2)3
PPh3
5
6
7
PPh3
0
8
PPh3
Et2O
0
9
PPh3
DCM
0
10
PPh3
CH3CN
DCM
0
14
d
11
de
,
PPh3
0
12
PPh3
DCM
0
a
Typical conditions: a mixture of 1 (0.20 mmol), 2a (0.10 mmol), and phosphine (20 mol %) in solvent (1.0 mL) was stirred at a certain
b
c
d
temperature for 12 h under an N2 atmosphere. PMB = p-methoxybenzyl. Isolated yield. The reaction mixture was stirred for 24 h. 0.15 mmol of 1
was used. 10 mol % of PPh3 was added.
e
regio- and diastereoselectivities (Scheme 2).11 Considering that
subtle variations about the Lewis base catalysts often give rise to
different reaction outcomes, herein we wish to report our
detailed investigation on the different reactivity patterns shown
by phosphorus- and nitrogen-containing catalysts in the
reactions of allenoate 1 with cyclic ketimines 2.
previous results, bis-phosphine mainly provided the sequential
[3 + 2]/[3 + 2] annulation product 3a, whereas mono-
phosphine showed markedly different behavior, providing [3 +
2] cycloadduct 4a together with the [3 + 2]/[3 + 2]
cycloadduct 3a (Table 1, entries 1−5). The structure of
product 4a was unambiguously established by a single-crystal
X-ray analysis (see the Supporting Information).12 Among the
tested monophosphine Lewis bases, PPh3 gave the highest yield
of dihydropyrrole derivative 4a at 44% (Table 1, entry 3).
Additionally, the bulky PCy3 showed low catalytic efficiency
with 31% of the starting material 2a recovered (Table 1, entry
RESULTS AND DISCUSSION
■
We first focused our effort on the investigation of phosphines
for their ability to catalyze the reaction of ethyl 2,3-
butadienoate (1) with cyclic ketimine 2a. On the basis of our
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2). In the presence of P(NMe2)3 and P(NEt2)3, similar results
were obtained (Table 1, entries 4 and 5). A subsequent change
of the reaction temperature and the solvents revealed that the
yield of 4a could be significantly improved to 88% when the
reaction was carried out in dichloromethane at 0 °C (Table 1,
entry 9). To our delight, reducing the amount of ethyl 2,3-
butadienoate (1) from 2.0 to 1.5 equiv led to the complete
conversion of cyclic ketimine 2a to [3 + 2] cycloadduct 4a in
nearly quantitative yield (Table 1, entry 11). Finally, an attempt
to diminish the amount of PPh3 to 10 mol % led to a negative
result, giving 4a in 78% isolated yield with 18% of 2a left (Table
1, entry 12).
trifluoromethyl group was replaced with a phenyl or methyl
group, no annulation products were observed (Table 2, entries
15 and 16). These results indicated that the strongly electron
withdrawing difluoromethyl or trifluoromethyl group is critical
for the [3 + 2] annulation to occur.
In comparison to phosphines, amines display a markedly
different behavior in the reactions of allenoates with electro-
philic partners. However, the amine-catalyzed reaction of ethyl
2,3-butadienoate (1) with cyclic ketimines 2 has not been
documented yet. Our further studies focused on the
investigation of several commonly used nitrogen-containing
Lewis bases for their ability to catalyze this reaction. Ketimine
2a was chosen as the model substrate, and the reaction was
initially performed in toluene at room temperature (25 °C) for
12 h. As shown in Table 3, DMAP and DABCO could promote
a [2 + 2] annulation under the standard conditions, affording
the corresponding cyclization product 5a containing an
azetidine ring in isolated yields of 25% and 50%, respectively
(Table 3, entries 1 and 2). The structure of 5a, including the
assignment of the olefin as the E isomer, was determined by
single-crystal X-ray structural analysis (see the Supporting
Information).13 Neither DBU nor Et3N provided any reactivity
in this reaction (Table 3, entries 3 and 4). Notably, pyridine
was found to undergo a mechanistically divergent pathway,
rather than giving [2 + 2] cyclization product 5a, leading to the
formation of the aza-MBH adduct 6a in an extremely high yield
(Table 3, entry 5).
We then chose DABCO as the [2 + 2] annulation catalyst
and examined the solvent effects (Table 3, entries 6−11).
Among the tested solvents, 1,4-dioxane was found to be the
solvent of choice, improving the yield of 5a to 81% (Table 3,
entry 11). The next investigation showed that there was no
positive effect observed when increasing the catalyst loading
from 20 to 30 mol % (Table 3, entry 12), whereas reducing the
catalyst amount to 10 mol % resulted in a slight decrease of the
product yield (Table 3, entry 13). Finally, in order to maximize
the yield of 5a, we also attempted to elevate the reaction
temperature to 60 °C; however, no expected improvement was
obtained (Table 3, entry 14).
Next, we turned to study the catalytic behavior of pyridine in
the aza-MBH reaction of ethyl 2,3-butadienoate (1) with cyclic
ketimine 2a. The reaction was performed with 20 mol % of
pyridine at room temperature for 24 h in various solvents
(Table 3, entries 15−19). Similar to the DABCO-catalyzed
annulation, solvent also played an important role in this
reaction. Toluene was proved to be the best solvent (Table 3,
entry 5). Other solvents, such as dichloromethane, THF, and
ether, gave product 6a in lower yields (Table 3, entries 15−17).
The reaction could hardly occur in acetonitrile or DMF (Table
3, entries 18 and 19). To our delight, the reaction could be
performed at as low as 10 mol % catalyst loading without
compromising the reactivity (Table 3, entries 20 and 21).
Decreasing the amount of ethyl 2,3-butadienoate (1) from 2.0
to 1.5 equiv did not affect the yield of product 6a (Table 3,
entry 22).
Having identified the optimal reaction conditions, we set out
to examine the scope and the limitations of the Lewis base
catalyzed [2 + 2] annulation, as well as the aza-MBH reaction.
Table 4 gives the results of DABCO-catalyzed [2 + 2]
annulation of ethyl 2,3-butadienoate (1) with a series of cyclic
ketimines 2. Ketimines bearing electron-withdrawing groups at
the 5- and/or 6-position of the aromatic ring (2a−f) showed
superior activities, affording the cycloadducts 5a−f in very high
With the optimized reaction conditions in hand, we next
tested a variety of cyclic ketimines 2 in the PPh3-catalyzed [3 +
2] annulation. As shown in Table 2, a wide range of cyclic
Table 2. PPh3-Catalyzed [3 + 2] Annulation Reaction of
a
Ethyl 2,3-Butadienoate (1) with Cyclic Ketimines 2
time
(h)
yield
b
entry
2 (R1, R2, R3)
product 4
(%)
1
2a (6-Cl, PMB, CF3)
2b (6-F, PMB, CF3)
2c (6-Br, PMB, CF3)
2d (5,6-F2, PMB, CF3)
2e (5-F-6-Cl, PMB, CF3)
2f (6-CF3, PMB, CF3)
2g (H, PMB, CF3)
12
12
12
12
12
12
12
12
12
24
12
12
24
12
24
24
4a
4b
4c
4d
4e
4f
96
94
94
93
93
95
92
93
94
86
98
94
52
97
0
2
3
4
5
6
7
4g
4h
4i
8
2h (6-Me, PMB, CF3)
2i (6-iPr, PMB, CF3)
2j (6-MeO, PMB, CF3)
2k (6-Cl, 1-naphthylmethyl, CF3)
2l (6-Cl, TMB, CF3)
2m (6-Cl, H, CF3)
9
10
11
12
13
14
15
16
4j
4k
4l
4m
4n
4o
4p
2n (6-Cl, PMB, CHF2)
2o (H, Bn, Ph)
2p (6-Cl, PMB, Me)
0
a
Reaction conditions are the same as those in Table 1, entry 11. TMB
b
= 2,4,6-trimethylbenzyl. Isolated yield.
trifluoromethyl ketimines 2a−i could readily react with ethyl
2,3-butadienoate (1) regardless of the steric and electronic
properties of the substituents on the aromatic ring, providing
the corresponding cycloadducts 4a−i in excellent yields (Table
2, entries 1−9). In addition, ketimine 2j showed relatively low
reactivity due to its poor solubility in dichloromethane at 0 °C
(Table 2, entry 10). The change of N-protecting groups at the
cyclic ketimines did not have a significant effect on the reaction
activity, giving the annulation products 4k,l in equally excellent
yields (Table 2, entries 11 and 12). A ketimine without a
protecting group on the nitrogen atom (2m) could also be
tolerated, although only a moderate yield was obtained with the
requirement of a prolonged reaction time (Table 2, entry 13).
When the trifluoromethyl group on the substrates was replaced
with a difluoromethyl group (2n), the [3 + 2] annulation
proceeded smoothly to afford the corresponding cycloadduct
4n in 97% yield (Table 2, entry 14). However, when the
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Table 3. Catalyst Screening and Reaction Optimization for the Reaction of Ethyl 2,3-Butadienoate (1) with Cyclic
a
Trifluoromethyl Ketimine 2a Catalyzed by Nitrogen-Containing Lewis Bases
b
yield (%)
entry
Lewis base (x (mol %))
solvent
time (h)
5a
6a
1
DMAP (20)
DABCO (20)
DBU (20)
toluene
toluene
toluene
toluene
toluene
DCM
12
12
12
12
24
12
12
12
12
12
12
12
12
12
24
24
24
24
24
24
24
24
25
50
2
3
4
Et3N (20)
5
pyridine (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (20)
DABCO (30)
DABCO (10)
DABCO (20)
pyridine (20)
pyridine (20)
pyridine (20)
pyridine (20)
pyridine (20)
pyridine (10)
pyridine (5)
pyridine (10)
95
6
32
63
55
30
27
81
79
72
80
7
THF
8
Et2O
9
MeCN
DMF
10
11
12
13
dioxane
dioxane
dioxane
dioxane
DCM
c
14
15
16
17
18
19
20
21
82
93
87
7
THF
Et2O
MeCN
DMF
toluene
toluene
toluene
96
71
95
d
22
a
Typical conditions: a mixture of 1 (0.20 mmol), 2a (0.10 mmol), and amine (5−30 mol %) in solvent (1.0 mL) was stirred at 25 °C for the stated
b
c
d
time under an N2 atmosphere. PMB = p-methoxybenzyl. Isolated yield. Reaction was carried out at 60 °C. 0.15 mmol of 1 was used.
yields within 12 h (Table 4, entries 1−6). In contrast, ketimine
2g and those bearing electron-donating groups at the 6-position
of the aromatic ring (2h−j) only gave products 5g−j in
moderate to good yields even with prolonged reaction times
(Table 4, entries 7−10). The N-(1-naphthylmethyl)-protected
and the N-TMB-protected cyclic ketimines (2k,l) were found
to be equally effective substrates, delivering 5k,l in isolated
yields of 80% and 79%, respectively (Table 4, entries 11 and
12). However, a dramatic decrease in yield was observed when
an N-protecting-group-free substrate (2m) was subjected to the
reaction (Table 4, entry 13). This result indicated that the
protecting group on the nitrogen atom of cyclic ketimines was
indispensable in this reaction. In addition, a ketimine that
replaced the trifluoromethyl group on the quinazolin-2(1H)-
one ring with a difluoromethyl group (2n) or a phenyl group
(2o) was not a suitable substrate (Table 4, entries 14 and 15).
These results revealed that the strongly electron withdrawing
trifluoromethyl group is also critical for the [2 + 2] annulation
to proceed smoothly.
high yields could still be obtained, although an extended
reaction time was required (Table 5, entries 7−10). Ketimines
with different N-protecting groups (2k,l) also proceeded
efficiently to produce the aza-MBH adducts 6k,l in excellent
yields (Table 5, entries 11 and 12). Surprisingly, the reaction
also tolerated the N-protecting-group-free ketimine (2m),
although resulting in a reduced yield in comparison with the
previous examples (Table 5, entry 13). A ketimine with a
difluoromethyl group instead of the trifluoromethyl moiety on
the quinazolin-2(1H)-one ring (2n) was well tolerated in the
reaction (Table 5, entry 14); however, the analogous substrate
that possesses a phenyl group (2o) was completely unreactive
under the reaction conditions (Table 5, entry 15). These results
once again clearly proved that the strongly electron with-
drawing difluoromethyl or trifluoromethyl group in the
substrates was indispensable.
The aza-MBH products 6 can be readily converted into
various N-heterocyclic compounds (Scheme 3). Under the
catalysis of 20 mol % DPPP, an intramolecular cyclization of
allenoate 6a could occur to afford dihydropyrrole derivative 4a
in 98% yield (Scheme 3a). In the presence of 20 mol % DPPP
and 1.5 equiv of ethyl 2,3-butadienoate (1), the N-fused
polycyclic compound 3a was obtained through a one-pot
sequential intramolecular cyclization/intermolecular [3 + 2]
annulation process (Scheme 3b).
As shown in Table 5, the pyridine-catalyzed aza-MBH
reaction was proved to be efficient for a range of cyclic
ketimines 2. Extremely high yields of the corresponding α,α′-
disubstituted allenoates 6a−f were obtained with the ketimines
bearing electron-withdrawing groups (2a−f; Table 5, entries 1−
6). In the case of the substrates bearing electron-neutral or
electron-donating groups on the aromatic ring (2g−j), very
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butadienoate (1) to form the zwitterionic intermediate IA, IB,
or IC. In the PPh3-catalyzed pathway, cycloaddition of 1,3-
dipole IA with ketimine 2 gives ylide intermediate IIA, which is
stabilized by the phosphonium moiety. This ylide IIA then
undergoes proton transfer and catalyst regeneration to afford
dihydropyrrole derivative 4. In the case of DABCO, the allylic
carbanion IB reacts with ketimine 2 through γ addition to give
the intermediate IIB. Subsequent intramolecular nucleophilic
attack gives the zwitterionic intermediate IIIB, which then
undergoes catalyst elimination along with double-bond
formation to produce azetidine derivative 5 with concomitant
regeneration of DABCO. With the aid of pyridine, the formed
enolate intermediate IC may be stabilized by the pyridyl
aromatic system and it can undergo α addition with ketimine 2.
The newly generated IIC cannot undergo a second C−C bond-
formation step because the ammonium ion cannot similarly
stabilize the ylide. Therefore, a proton transfer of the most
acidic proton followed by a catalyst regeneration step yields the
aza-MBH adduct 6.
Table 4. DABCO-Catalyzed [2 + 2] Annulation Reaction of
Ethyl 2,3-Butadienoate (1) with Cyclic Ketimines 2
a
time
(h)
yield
b
entry
2 (R1, R2, R3)
product 5
(%)
1
2a (6-Cl, PMB, CF3)
2b (6-F, PMB, CF3)
2c (6-Br, PMB, CF3)
2d (5,6-F2, PMB, CF3)
2e (5-F-6-Cl, PMB, CF3)
2f (6-CF3, PMB, CF3)
2g (H, PMB, CF3)
12
12
12
12
12
12
24
24
24
24
12
12
48
48
48
5a
5b
5c
5d
5e
5f
81
85
78
87
88
77
64
53
57
62
80
79
13
18
0
2
3
4
5
6
7
5g
5h
5i
8
2h (6-Me, PMB, CF3)
2i (6-iPr, PMB, CF3)
2j (6-MeO, PMB, CF3)
2k (6-Cl, 1-naphthylmethyl, CF3)
2l (6-Cl, TMB, CF3)
2m (6-Cl, H, CF3)
9
10
11
12
13
14
15
5j
5k
5l
CONCLUSION
■
In summary, a detailed investigation on the different reactivity
patterns shown by phosphorus- and nitrogen-containing
catalysts in the reactions of allenoates with cyclic ketimines
was accomplished. With PPh3, [3 + 2] annulations proceeded
smoothly to afford dihydropyrrole derivatives in excellent
yields. Nitrogen-containing Lewis bases were applied to the
reactions of allenoates and cyclic ketimines for the first time.
Under the catalysis of DABCO, [2 + 2] annulations occurred
instead of [3 + 2] annulations, producing azetidine derivatives
in good to high yields. In the presence of pyridine, α,α′-
disubstituted allenoates were obtained in very high yields via
aza-Morita-Baylis-Hillman reactions. These studies provide an
opportunity for diverse synthesis of a variety of N-heterocyclic
compounds from same starting materials. Detailed mechanistic
investigations and the development of enantioselective variants
of these protocols are currently ongoing in our laboratory.
5m
5n
5o
2n (6-Cl, PMB, CHF2)
2o (H, Bn, Ph)
a
Reaction conditions are the same as those in Table 3, entry 11. TMB
b
= 2,4,6-trimethylbenzyl. Isolated yield.
Table 5. Pyridine-Catalyzed Aza-Morita−Baylis−Hillman
Reaction of Ethyl 2,3-Butadienoate (1) with Cyclic
a
Ketimines 2
time
(h)
yield
b
entry
2 (R1, R2, R3)
product 6
(%)
EXPERIMENTAL SECTION
■
1
2a (6-Cl, PMB, CF3)
2b (6-F, PMB, CF3)
2c (6-Br, PMB, CF3)
2d (5,6-F2, PMB, CF3)
2e (5-F-6-Cl, PMB, CF3)
2f (6-CF3, PMB, CF3)
2g (H, PMB, CF3)
24
24
24
24
24
24
60
60
60
60
24
24
60
60
60
6a
6b
6c
6d
6e
6f
95
92
90
94
96
93
80
74
75
78
89
93
70
88
0
1
General Information. H, 13C, and 19F NMR were recorded at
2
400 or 600 MHz (1H NMR), 100 or 150 MHz (13C NMR), and 376
or 565 MHz (19F NMR). Chemical shifts were reported in ppm
downfield from internal Me4Si and external CCl3F, respectively.
Multiplicity is indicated as follows: s (singlet), d (doublet), t (triplet),
q (quartet), m (multiplet), dd (doublet of doublets), br (broad).
Coupling constants are reported in hertz (Hz).
Materials. Tetrahydrofuran (THF), ether, toluene, and 1,4-dioxane
were distilled from sodium/benzophenone; CH2Cl2 (DCM) and
DMF were distilled from CaH2; CH3CN was distilled from P2O5. All
commercially available reagents were used without further purification.
Analytical thin-layer chromatography was performed on 0.20 mm silica
gel plates. Silica gel (200−300 mesh) was used for flash
chromatography. Ethyl 2,3-butadienoate was prepared according to
the literature.15 The ketimines were synthesized according to the
literature.10
General Procedure for the [3 + 2] Annulation of Ethyl 2,3-
Butadienoate (1) with Cyclic Ketimines 2 in the Presence of
PPh3. Under a N2 atmosphere, a mixture of cyclic ketimine 2 (0.10
mmol), ethyl 2,3-butadienoate (1; 0.15 mmol), and PPh3 (0.02 mmol)
in DCM (1.0 mL) was stirred at 0 °C. After completion of the reaction
(monitored by TLC), the resulting residue was purified on a silica gel
column (1.3 × 20 cm) with the eluent (petroleum ether/ethyl acetate
8/1 to 4/1) to give the product 4.
3
4
5
6
7
6g
6h
6i
8
2h (6-Me, PMB, CF3)
2i (6-iPr, PMB, CF3)
2j (6-MeO, PMB, CF3)
2k (6-Cl, 1-naphthylmethyl, CF3)
2l (6-Cl, TMB, CF3)
2m (6-Cl, H, CF3)
9
10
11
12
13
14
15
6j
6k
6l
6m
6n
6o
2n (6-Cl, PMB, CHF2)
2o (H, Bn, Ph)
a
Reaction conditions are the same as those in Table 3, entry 22. TMB
b
= 2,4,6-trimethylbenzyl. Isolated yield.
On the basis of earlier reports14 and our experimental results,
possible mechanism processes under the catalysis of phospho-
rus- and nitrogen-containing Lewis bases are proposed in
Scheme 4. Each catalytic cycle involves initial attack of the
nucleophilic catalyst on the electrophilic β carbon of ethyl 2,3-
Ethyl 9-chloro-6-(4-methoxybenzyl)-5-oxo-10b-(trifluoromethyl)-
3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate (4a):
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Scheme 3. Further Transformation of aza-MBH Product 6a
Scheme 4. Proposed Mechanisms for the Lewis Base Catalyzed Reactions of Ethyl 2,3-Butadienoate (1) with Cyclic Ketimines 2
1
46.2 mg; 96% yield; white solid; mp 128−130 °C; H NMR (400
MHz, CDCl3) δ 8.28 (d, J = 1.2 Hz, 1H), 7.46 (s, 1H), 7.21−7.14 (m,
3H), 6.84 (d, J = 8.6 Hz, 2H), 6.81 (d, J = 9.0 Hz, 1H), 5.23 (d, J =
16.4 Hz, 1H), 4.96 (d, J = 16.4 Hz, 1H), 4.69 (d, J = 18.4 Hz, 1H),
4.52 (d, J = 18.4 Hz, 1H), 4.40 (d, J = 7.0 Hz, 1H), 4.37 (d, J = 7.0 Hz,
1H), 3.77 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.3, 159.0, 151.9, 146.4, 136.9, 133.0, 130.3, 128.5, 128.4,
128.1, 128.0, 124.8 (q, J = 289.5 Hz), 118.7, 116.3, 114.4, 72.4 (q, J =
32.0 Hz), 62.1, 55.4, 53.8, 46.6, 14.2; 19F NMR (376 MHz, CDCl3) δ
−77.67; IR (KBr) ν 3096, 2982, 2936, 2362, 1725, 1677, 1619, 1507,
1425, 1247, 1177, 1095, 1030, 945, 811, 760, 545 cm−1; HRMS
(Supporting Information) found m/z 503.0950 [M + Na]+, calcd for
C23H20ClF3N2O4 + Na 503.0956.
Ethyl 9-fluoro-6-(4-methoxybenzyl)-5-oxo-10b-(trifluoromethyl)-
3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate (4b):
43.6 mg; 94% yield; white solid; mp 123−125 °C; H NMR (600
MHz, CDCl3) δ 8.08 (dd, J = 9.6, 2.2 Hz, 1H), 7.47 (s, 1H), 7.18 (d, J
= 8.4 Hz, 2H), 6.96−6.92 (m, 1H), 6.86−6.81 (m, 3H), 5.22 (d, J =
16.4 Hz, 1H), 4.98 (d, J = 16.4 Hz, 1H), 4.70 (d, J = 18.6 Hz, 1H),
4.53 (d, J = 18.6 Hz, 1H), 4.38 (d, J = 7.1 Hz, 1H), 4.36 (d, J = 7.1 Hz,
1H), 3.77 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.3, 159.0, 158.2 (d, J = 240.5 Hz), 152.0, 146.4, 134.6,
1
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133.0, 128.6, 128.0, 124.9 (q, J = 289.0 Hz), 118.6 (d, J = 8.9 Hz),
117.0 (d, J = 22.6 Hz), 116.2 (d, J = 7.8 Hz), 115.7 (d, J = 26.5 Hz),
114.4, 72.4 (q, J = 32.0 Hz), 62.0, 55.4, 53.7, 46.7, 14.2; 19F NMR (376
MHz, CDCl3) δ −77.65 (s, 3F), −119.73 to −119.81 (m, 1F); IR
(KBr) ν 2932, 2361, 1725, 1675, 1511, 1444, 1247, 1183, 1093, 1028,
818, 757, 670 cm−1; HRMS (Supporting Information) found m/z
487.1248 [M + Na]+, calcd for C23H20F4N2O4 + Na 487.1251.
Ethyl 9-bromo-6-(4-methoxybenzyl)-5-oxo-10b-(trifluorometh-
yl)-3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate
(4c): 49.4 mg; 94% yield; white solid; mp 128−130 °C; 1H NMR (400
MHz, DMSO) δ 8.30 (d, J = 1.5 Hz, 1H), 7.66 (s, 1H), 7.55 (d, J = 8.8
Hz, 1H), 7.19 (d, J = 8.5 Hz, 2H), 6.96 (d, J = 8.9 Hz, 1H), 6.87 (d, J
= 8.5 Hz, 2H), 5.19 (d, J = 16.4 Hz, 1H), 4.96 (d, J = 16.4 Hz, 1H),
4.68 (d, J = 18.0 Hz, 1H), 4.44 (d, J = 18.0 Hz, 1H), 4.35 (d, J = 7.1
Hz, 1H), 4.31 (d, J = 7.1 Hz, 1H), 3.71 (s, 3H), 1.31 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 159.1, 151.9, 146.3,
137.4, 133.3, 133.1, 131.3, 128.4, 128.0, 124.8 (q, J = 289.7 Hz), 119.1,
116.7, 115.4, 114.5, 72.3 (q, J = 32.0 Hz), 62.1, 55.4, 53.8, 46.6, 14.3;
19F NMR (376 MHz, CDCl3) δ −77.64; IR (KBr) ν 2918, 2848, 2362,
Information) found m/z 537.1219 [M + Na]+, calcd for
C24H20F6N2O4 + Na 537.1220.
Ethyl 6-(4-methoxybenzyl)-5-oxo-10b-(trifluoromethyl)-
3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate (4g):
41.1 mg; 92% yield; white solid; mp 51−53 °C; 1H NMR (400
MHz, CDCl3) δ 8.18 (d, J = 7.7 Hz, 1H), 7.44 (s, 1H), 7.27 (d, J = 9.1
Hz, 1H), 7.22 (d, J = 8.2 Hz, 2H), 7.05 (t, J = 7.4 Hz, 1H), 6.92 (d, J =
8.3 Hz, 1H), 6.86 (d, J = 8.2 Hz, 2H), 5.26 (d, J = 16.4 Hz, 1H), 5.03
(d, J = 16.4 Hz, 1H), 4.72 (d, J = 18.6 Hz, 1H), 4.55 (d, J = 18.6 Hz,
1H), 4.40 (d, J = 7.0 Hz, 1H), 4.37 (d, J = 7.0 Hz, 1H), 3.78 (s, 3H),
1.40 (t, J = 7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.6, 158.9,
152.2, 145.8, 138.2, 133.4, 130.3, 129.0, 128.2, 128.0, 126.5, 125.0 (q, J
= 289.2 Hz), 117.3, 115.1, 114.3, 72.6 (q, J = 32.0 Hz), 61.8, 55.4,
53.8, 46.5, 14.3; 19F NMR (376 MHz, CDCl3) δ −77.67; IR (KBr) ν
2933, 2362, 1727, 1674, 1511, 1463, 1402, 1246, 1177, 1095, 1029,
930, 758, 673 cm−1; HRMS (Supporting Information) found m/z
469.1349 [M + Na]+, calcd for C23H21F3N2O4 + Na 469.1346.
Ethyl 6-(4-methoxybenzyl)-9-methyl-5-oxo-10b-(trifluorometh-
yl)-3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate
1
(4h): 42.8 mg; 93% yield; white solid; mp 60−62 °C; H NMR (400
1725, 1676, 1619, 1509, 1397, 1247, 1177, 1095, 1028, 942, 808, 740,
537 cm−1; HRMS (Supporting Information) found m/z 547.0458 [M
+ Na]+, calcd for C23H20BrF3N2O4 + Na 547.0451.
MHz, DMSO) δ 7.76 (s, 1H), 7.55 (s, 1H), 7.18 (d, J = 8.4 Hz, 2H),
7.14 (d, J = 7.9 Hz, 1H), 6.89 (d, J = 8.6 Hz, 1H), 6.86 (d, J = 8.4 Hz,
2H), 5.17 (d, J = 16.4 Hz, 1H), 4.94 (d, J = 16.4 Hz, 1H), 4.66 (d, J =
18.2 Hz, 1H), 4.41 (d, J = 18.2 Hz, 1H), 4.34 (d, J = 7.0 Hz, 1H), 4.31
(d, J = 7.0 Hz, 1H), 3.70 (s, 3H), 2.21 (s, 3H), 1.31 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 158.9, 152.3, 145.7,
135.8, 133.5, 132.2, 130.9, 129.2, 128.5, 128.0, 125.1 (q, J = 289.5 Hz),
117.2, 115.0, 114.3, 72.6 (q, J = 31.9 Hz), 61.8, 55.4, 53.8, 46.4, 20.8,
14.3; 19F NMR (376 MHz, CDCl3) δ −77.59; IR (KBr) ν 2933, 2362,
1773, 1729, 1677, 1513, 1247, 1176, 1029, 815, 672, 511 cm−1; HRMS
(Supporting Information) found m/z 483.1498 [M + Na]+, calcd for
C24H23F3N2O4 + Na 483.1502.
Ethyl 9,10-difluoro-6-(4-methoxybenzyl)-5-oxo-10b-(trifluoro-
methyl)-3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxy-
late (4d): 44.9 mg; 93% yield; white solid; mp 116−118 °C; 1H NMR
(400 MHz, CDCl3) δ 7.16 (d, J = 8.5 Hz, 2H), 7.06 (q, J = 9.0 Hz,
1H), 6.93 (s, 1H), 6.84 (d, J = 8.5 Hz, 2H), 6.65−6.60 (m, 1H), 5.19
(d, J = 16.4 Hz, 1H), 4.97 (d, J = 16.4 Hz, 1H), 4.63 (d, J = 17.6 Hz,
1H), 4.52 (d, J = 17.6 Hz, 1H), 4.36 (d, J = 7.1 Hz, 1H), 4.32 (d, J =
7.1 Hz, 1H), 3.77 (s, 3H), 1.35 (t, J = 7.1 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 163.5 (d, J = 2.5 Hz), 159.0, 151.9, 147.8 (dd, J =
248.9 Hz, J = 15.2 Hz), 146.3 (dd, J = 243.9 Hz, J = 14.6 Hz) 140.2,
133.1 (d, J = 3.4 Hz), 128.1, 128.0, 124.3 (q, J = 288.7 Hz), 118.7 (d, J
= 17.9 Hz), 114.5 (d, J = 3.0 Hz), 114.4, 110.5, 107.4 (d, J = 15.3 Hz),
71.7 (q, J = 33.3 Hz), 61.9, 55.3, 54.1, 47.0, 14.0; 19F NMR (376 MHz,
CDCl3) δ −77.10 (d, J = 5.6 Hz, 3F), −133.53 to −133.63 (m, 1F),
−144.14 to −144.24 (m, 1F); IR (KBr) ν: 2934, 2362, 1740, 1681,
1508, 1472, 1391, 1283, 1249, 1175, 1116, 1030, 828, 618 cm−1;
HRMS (Supporting Information) found m/z 505.1163 [M + Na]+,
calcd for C23H19F5N2O4 + Na 505.1157.
Ethyl 9-isopropyl-6-(4-methoxybenzyl)-5-oxo-10b-(trifluoro-
methyl)-3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxy-
1
late (4i): 45.9 mg; 94% yield; white solid; mp 70−72 °C; H NMR
(400 MHz, CDCl3) δ 8.04 (s, 1H), 7.39 (s, 1H), 7.21 (d, J = 8.4 Hz,
2H), 7.10 (d, J = 8.5 Hz, 1H), 6.87−6.79 (m, 3H), 5.21 (d, J = 16.3
Hz, 1H), 4.99 (d, J = 16.3 Hz, 1H), 4.69 (d, J = 18.5 Hz, 1H), 4.52 (d,
J = 18.5 Hz, 1H), 4.45−4.38 (m, 1H), 4.37−4.30 (m, 1H), 3.76 (s,
3H), 2.89−2.79 (m, 1H), 1.38 (t, J = 7.1 Hz, 3H), 1.20 (d, J = 4.0 Hz,
3H), 1.18 (d, J = 4.0 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.8,
158.9, 152.3, 145.5, 143.3, 136.0, 133.6, 129.2, 128.3, 128.1, 126.1,
125.1 (q, J = 288.7 Hz), 117.1, 114.9, 114.3, 72.7 (q, J = 30.5 Hz),
61.8, 55.4, 53.8, 46.4, 33.5, 24.1, 24.0, 14.3; 19F NMR (376 MHz,
CDCl3) δ −77.67; IR (KBr) ν 2962, 2362, 1727, 1672, 1619, 1512,
1401, 1247, 1176, 1098, 1029, 816, 759, 672 cm−1; HRMS
(Supporting Information) found m/z 511.1822 [M + Na]+, calcd for
C26H27F3N2O4 + Na 511.1815.
Ethyl 9-chloro-10-fluoro-6-(4-methoxybenzyl)-5-oxo-10b-(tri-
fluoromethyl)-3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-car-
1
boxylate (4e): 46.4 mg; 93% yield; white solid; mp 141−143 °C; H
NMR (600 MHz, DMSO) δ 7.61 (t, J = 8.4 Hz, 1H), 7.24−7.16 (m,
3H), 6.93−6.87 (m, 3H), 5.19 (d, J = 16.1 Hz, 1H), 4.98 (d, J = 16.1
Hz, 1H), 4.63 (d, J = 17.5 Hz, 1H), 4.42 (d, J = 17.5 Hz, 1H), 4.36−
4.14 (m, 2H), 3.70 (s, 3H), 1.27 (t, J = 6.9 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ 163.5 (d, J = 3.2 Hz), 159.1, 155.0 (d, J = 248.3 Hz),
151.9, 139.9, 138.8 (d, J = 4.8 Hz), 133.5 (d, J = 3.2 Hz), 132.0, 128.0,
127.9, 124.4 (q, J = 289.3 Hz), 115.5 (d, J = 19.7 Hz), 114.5, 111.6 (d,
J = 3.5 Hz), 107.0 (d, J = 19.2 Hz), 72.2 (q, J = 31.7 Hz), 61.9, 55.4,
54.2, 47.1, 14.1; 19F NMR (376 MHz, CDCl3) δ −77.16 (d, J = 5.6 Hz,
3F), −110.38 to −110.41 (m, 1F); IR (KBr) ν 2983, 2935, 2361, 1739,
1682, 1613, 1489, 1389, 1248, 1174, 1112, 1027, 949, 805, 766, 583
cm−1; HRMS (Supporting Information) found m/z 521.0859 [M +
Na]+, calcd for C23H19ClF4N2O4 + Na 521.0862.
Ethyl 9-methoxy-6-(4-methoxybenzyl)-5-oxo-10b-(trifluorometh-
yl)-3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate
1
(4j): 41.0 mg; 86% yield; white solid; mp 54−56 °C; H NMR (400
MHz, DMSO) δ 7.69 (s, 1H), 7.60 (s, 1H), 7.19 (d, J = 8.5 Hz, 2H),
6.97−6.90 (m, 2H), 6.86 (d, J = 8.5 Hz, 2H), 5.17 (d, J = 16.3 Hz,
1H), 4.93 (d, J = 16.3 Hz, 1H), 4.67 (d, J = 18.2 Hz, 1H), 4.42 (d, J =
18.2 Hz, 1H), 4.35−4.26 (m, 2H), 3.70 (s, 3H), 3.67 (s, 3H), 1.30 (t, J
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 162.7, 158.9, 155.2,
152.2, 146.2, 133.3, 131.7, 129.2, 128.0, 125.1 (q, J = 289.7 Hz), 118.2,
116.1, 116.0, 114.3, 113.7, 72.6 (q, J = 31.7 Hz), 61.9, 55.7, 55.4, 53.7,
46.5, 14.3; 19F NMR (376 MHz, CDCl3) δ −77.64; IR (KBr) ν 2920,
2843, 2362, 1725, 1670, 1619, 1512, 1457, 1401, 1247, 1178, 1096,
1027, 814, 737 cm−1; HRMS (Supporting Information) found m/z
499.1455 [M + Na]+, calcd for C24H23F3N2O5 + Na 499.1451.
Ethyl 9-chloro-6-(naphthalen-1-ylmethyl)-5-oxo-10b-(trifluoro-
methyl)-3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxy-
late (4k): 49.1 mg; 98% yield; white solid; mp 207−209 °C; 1H NMR
(600 MHz, CDCl3) δ 8.37 (s, 1H), 8.06 (d, J = 8.3 Hz, 1H), 7.92 (d, J
= 8.0 Hz, 1H), 7.77 (d, J = 8.1 Hz, 1H), 7.61 (t, J = 7.4 Hz, 1H), 7.56
(t, J = 7.4 Hz, 1H), 7.52 (s, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.14−7.08
(m, 2H), 6.62 (d, J = 8.9 Hz, 1H), 5.68 (d, J = 17.2 Hz, 1H), 5.57 (d, J
= 17.2 Hz, 1H), 4.75 (d, J = 18.6 Hz, 1H), 4.57 (d, J = 18.6 Hz, 1H),
4.41 (q, J = 6.3 Hz, 2H), 1.42 (t, J = 7.1 Hz, 3H); 13C NMR (100
Ethyl 6-(4-methoxybenzyl)-5-oxo-9,10b-bis(trifluoromethyl)-
3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate (4f):
48.9 mg; 95% yield; white solid; mp 54−56 °C; 1H NMR (400
MHz, DMSO) δ 8.54 (s, 1H), 7.73 (d, J = 8.4 Hz, 1H), 7.69 (s, 1H),
7.25−7.17 (m, 3H), 6.88 (d, J = 8.5 Hz, 2H), 5.25 (d, J = 16.4 Hz,
1H), 5.04 (d, J = 16.4 Hz, 1H), 4.71 (d, J = 18.2 Hz, 1H), 4.47 (d, J =
18.2 Hz, 1H), 4.36−4.27 (m, 2H), 3.70 (s, 3H), 1.29 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 162.3, 159.2, 151.7, 146.3,
141.1, 133.1, 128.2, 128.0, 127.6 (d, J = 3.3 Hz), 126.0 (d, J = 3.6 Hz),
124.9 (q, J = 33.3 Hz), 124.8 (q, J = 289.3 Hz), 124.1 (q, J = 269.8
Hz), 117.6, 115.2, 114.5, 72.5 (q, J = 32.1 Hz), 62.2, 55.4, 53.9, 46.8,
14.2; 19F NMR (376 MHz, CDCl3) δ −62.08 (s, 3F), −77.83 (s, 3F);
IR (KBr) ν 2937, 2912, 2362, 1726, 1681, 1621, 1514, 1333, 1247,
1169, 1093, 1025, 818, 673, 516 cm−1; HRMS (Supporting
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MHz, CDCl3) δ 162.3, 151.7, 146.5, 137.0, 134.1, 133.1, 130.7, 130.6,
130.4, 129.2, 128.5, 128.2, 127.9, 126.6, 126.1, 125.6, 124.9 (q, J =
289.3 Hz), 123.2, 122.5, 118.5, 116.5, 72.5 (q, J = 31.7 Hz), 62.1, 53.8,
45.2, 14.3; 19F NMR (376 MHz, CDCl3) δ −77.59; IR (KBr) ν 3056,
2980, 2362, 1725, 1679, 1500, 1401, 1277, 1244, 1181, 1094, 1016,
945, 795, 758 cm−1; HRMS (Supporting Information) found m/z
523.1009 [M + Na]+, calcd for C26H20ClF3N2O3 + Na 523.1007.
Ethyl 9-chloro-5-oxo-10b-(trifluoromethyl)-6-(2,4,6-trimethyl-
benzyl)-3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxy-
late (4l): 46.3 mg; 94% yield; white solid; mp 151−153 °C; 1H NMR
(400 MHz, DMSO) δ 8.18 (d, J = 1.8 Hz, 1H), 7.60 (s, 1H), 7.53 (d, J
= 8.9 Hz, 1H), 7.36 (d, J = 9.0 Hz, 1H), 6.78 (s, 2H), 5.05 (d, J = 15.1
Hz, 1H), 4.90 (d, J = 15.1 Hz, 1H), 4.59 (d, J = 18.3 Hz, 1H), 4.37−
4.28 (m, 3H), 2.23 (s, 6H), 2.17 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ 162.3, 152.0, 146.3, 137.8, 137.2, 137.1,
130.4, 129.9, 129.8, 129.0, 128.7, 127.9, 124.5 (q, J = 288.4 Hz), 118.5,
115.4, 72.5 (q, J = 32.0 Hz), 62.1, 53.9, 43.6, 30.8, 20.2, 14.2; 19F NMR
(376 MHz, CDCl3) δ −77.09; IR (KBr) ν 2962, 2929, 2362, 1726,
1678, 1498, 1399, 1245, 1179, 1094, 1018, 808, 757, 554 cm−1; HRMS
(Supporting Information) found m/z 515.1314 [M + Na]+, calcd for
C25H24ClF3N2O3 + Na 515.1320.
Ethyl 9-chloro-5-oxo-10b-(trifluoromethyl)-3,5,6,10b-
tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate (4m): 18.8 mg;
52% yield; white solid; mp 106−108 °C; 1H NMR (600 MHz,
DMSO) δ 10.25 (s, 1H), 8.14 (s, 1H), 7.61 (s, 1H), 7.43 (d, J = 8.3
Hz, 1H), 7.04 (d, J = 8.5 Hz, 1H), 4.58 (d, J = 18.8 Hz, 1H), 4.36−
4.26 (m, 3H), 1.29 (t, J = 6.9 Hz, 3H); 13C NMR (100 MHz, DMSO)
δ 162.1, 150.6, 148.5, 136.8, 130.4, 130.3, 127.1, 125.3, 124.9 (q, J =
289.5 Hz), 116.5, 115.4, 72.6 (q, J = 31.2 Hz), 61.5, 53.0, 13.8; 19F
NMR (376 MHz, DMSO) δ −77.61; IR (KBr) ν 3525, 3441, 3122,
1718, 1700, 1682, 1653, 1400, 1167, 1086, 945, 767, 530 cm−1; HRMS
(Supporting Information) found m/z 383.0380 [M + Na]+, calcd for
C15H12ClF3N2O3 + Na 383.0386.
cm−1; HRMS (Supporting Information) found m/z 503.0955 [M +
Na]+, calcd for C23H20ClF3N2O4 + Na 503.0961.
(E)-Ethyl 2-(8-fluoro-5-(4-methoxybenzyl)-4-oxo-9b-(trifluoro-
methyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)-
1
acetate (5b): 39.5 mg; 85% yield; white solid; mp 123−125 °C; H
NMR (400 MHz, CDCl3) δ 7.15 (d, J = 8.4 Hz, 2H), 7.03−6.94 (m,
2H), 6.87 (d, J = 4.8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.06 (s, 1H),
5.26 (d, J = 16.3 Hz, 1H), 4.80 (d, J = 16.3 Hz, 1H), 4.16 (q, J = 7.1
Hz, 2H), 3.92 (d, J = 16.5 Hz, 1H), 3.82−3.73 (m, 4H), 1.27 (t, J = 7.2
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 159.3, 158.8 (d, J =
244.6 Hz), 155.8, 150.0, 135.3 (d, J = 2.4 Hz), 128.0, 127.6, 124.1 (q, J
= 282.5 Hz), 119.5 (d, J = 7.4 Hz), 117.8 (d, J = 30.5 Hz), 117.7,
114.6, 113.7 (d, J = 24.1 Hz), 98.3, 66.9 (q, J = 32.6 Hz), 60.2, 55.4,
46.4, 40.8, 14.5; 19F NMR (376 MHz, CDCl3) δ −81.32 (s, 3F),
−118.44 to −118.49 (m, 1F); IR (KBr) ν 2980, 1719, 1661, 1514,
1491, 1358, 1336, 1250, 1178, 1033, 835, 743 cm−1; HRMS
(Supporting Information) found m/z 487.1253 [M + Na]+, calcd for
C23H20F4N2O4 + Na 487.1257.
(E)-Ethyl 2-(8-bromo-5-(4-methoxybenzyl)-4-oxo-9b-(trifluoro-
methyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)-
1
acetate (5c): 41.0 mg; 78% yield; white solid; mp 58−60 °C; H
NMR (400 MHz, CDCl3) δ 7.41−7.33 (m, 2H), 7.14 (d, J = 8.5 Hz,
2H), 6.84 (d, J = 8.5 Hz, 2H), 6.77 (d, J = 9.5 Hz, 1H), 6.06 (s, 1H),
5.26 (d, J = 16.3 Hz, 1H), 4.79 (d, J = 16.3 Hz, 1H), 4.16 (q, J = 7.1
Hz, 2H), 3.92 (d, J = 16.5 Hz, 1H), 3.82−3.74 (m, 4H), 1.27 (t, J = 7.1
Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 159.3, 155.7, 149.8,
138.2, 133.9, 129.5, 128.0, 127.4, 124.0 (q, J = 282.1 Hz), 119.8, 117.8,
116.5, 114.6, 98.5, 66.8 (q, J = 32.8 Hz), 60.2, 55.4, 46.3, 40.9, 14.5;
19F NMR (376 MHz, CDCl3) δ −81.36; IR (KBr) ν 2961, 1719, 1662,
1506, 1446, 1361, 1251, 1180, 1035, 838 cm−1; HRMS (Supporting
Information) found m/z 547.0453 [M + Na]+, calcd for
C23H20BrF3N2O4 + Na 547.0456.
(E)-Ethyl 2-(8,9-difluoro-5-(4-methoxybenzyl)-4-oxo-9b-(trifluor-
omethyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)-
Ethyl 9-chloro-10b-(difluoromethyl)-6-(4-methoxybenzyl)-5-oxo-
1
acetate (5d): 42.0 mg; 87% yield; white solid; mp 43−45 °C; H
3,5,6,10b-tetrahydropyrrolo[1,2-c]quinazoline-1-carboxylate (4n):
1
NMR (600 MHz, CDCl3) δ 7.14 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.7
Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.64 (d, J = 7.9 Hz, 1H), 6.05 (s,
1H), 5.26 (d, J = 16.2 Hz, 1H), 4.77 (d, J = 16.2 Hz, 1H), 4.16 (dd, J =
13.2, 6.3 Hz, 2H), 3.94 (q, J = 16.9 Hz, 2H), 3.75 (s, 3H), 1.27 (t, J =
6.6 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 166.7, 159.2, 155.9,
149.5, 147.5 (dd, J = 250.8 Hz, J = 15.5 Hz), 146.6 (dd, J = 246.2 Hz, J
= 11.9 Hz), 135.9, 128.0, 127.2, 124.0 (q, J = 282.8 Hz), 119.3 (d, J =
18.0 Hz), 114.5, 111.7, 107.9 (d, J = 16.5 Hz), 98.5, 65.0 (q, J = 34.7
Hz), 60.2, 55.3, 46.5, 39.9, 14.4; 19F NMR (376 MHz, CDCl3) δ
−81.35 (d, J = 11.3 Hz, 3F), −137.23 to −137.40 (m, 1F), −142.69 to
−142.78 (m, 1F); IR (KBr) ν 2979, 1721, 1665, 1506, 1359, 1337,
1252, 1180, 1114, 1034, 836, 807 cm−1; HRMS (Supporting
Information) found m/z 505.1157 [M + Na]+, calcd for
C23H19F5N2O4 + Na 505.1163.
44.9 mg; 97% yield; white solid; mp 142−144 °C; H NMR (400
MHz, CDCl3) δ 7.74 (d, J = 2.1 Hz, 1H), 7.24 (s, 1H), 7.19 (d, J = 8.5
Hz, 2H), 7.14 (d, J = 8.8 Hz, 1H), 6.83 (d, J = 8.5 Hz, 2H), 6.78 (d, J
= 8.9 Hz, 1H), 6.29 (t, J = 55.4 Hz, 1H), 5.30 (d, J = 16.4 Hz, 1H),
4.88 (d, J = 16.4 Hz, 1H), 4.70 (dd, J = 18.5, 1.7 Hz, 1H), 4.56 (dd, J =
18.5, 1.7 Hz, 1H), 4.42 (d, J = 7.1 Hz, 1H), 4.38 (d, J = 7.1 Hz, 1H),
3.76 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
164.0, 158.9, 152.7, 143.7, 137.2, 133.6 (d, J = 4.0 Hz), 129.7, 128.7,
128.1 (d, J = 1.7 Hz), 127.7, 126.2, 120.9 (d, J = 4.3 Hz), 116.3, 115.6
(t, J = 250.7 Hz), 114.3, 72.3 (t, J = 19.8 Hz), 62.1, 55.4, 54.7, 46.5,
14.3; 19F NMR (376 MHz, CDCl3) δ −128.44 (dd, J = 269.2, 55.3 Hz,
1F), δ −134.39 (dd, J = 269.2, 55.6 Hz, 1F); IR (KBr) ν 2962, 2935,
2362, 1712, 1674, 1505, 1398, 1247, 1078, 1029, 812, 767, 674, 525
cm−1; HRMS (Supporting Information) found m/z 485.1055 [M +
Na]+, calcd for C23H21ClF2N2O4 + Na 485.1050.
(E)-Ethyl 2-(8-chloro-9-fluoro-5-(4-methoxybenzyl)-4-oxo-9b-(tri-
fluoromethyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-
ylidene)acetate (5e): 43.9 mg; 88% yield; white solid; mp 65−67 °C;
1H NMR (400 MHz, CDCl3) δ 7.35−7.27 (m, 1H), 7.14 (d, J = 8.5
General Procedure for the [2 + 2] Annulation of Ethyl 2,3-
Butadienoate (1) with Cyclic Ketimines 2 in the Presence of
DABCO. Under an N2 atmosphere, a mixture of cyclic ketimine 2
(0.10 mmol), ethyl 2,3-butadienoate (1; 0.20 mmol), and DABCO
(0.02 mmol) in 1,4-dioxane (1.0 mL) was stirred at room temperature
(25 °C). After completion of the reaction (monitored by TLC), the
resulting residue was purified on a silica gel column (1.3 × 20 cm)
with the eluent (petroleum ether/ethyl acetate 20/1 to 8/1) to give
the product 5.
Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 6.67 (d, J = 9.0 Hz, 1H), 6.06 (s,
1H), 5.27 (d, J = 16.3 Hz, 1H), 4.78 (d, J = 16.3 Hz, 1H), 4.17 (q, J =
7.1 Hz, 2H), 4.01−3.86 (m, 2H), 3.77 (s, 3H), 1.28 (t, J = 7.1 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ 166.7, 159.4, 155.9, 155.1 (d, J =
250.4 Hz), 149.5, 139.3 (d, J = 4.5 Hz), 132.6, 128.0, 127.2, 124.0 (q, J
= 282.3 Hz), 116.3 (d, J = 17.3 Hz), 114.6, 112.5 (d, J = 3.7 Hz), 107.4
(d, J = 19.8 Hz), 98.7, 65.3 (q, J = 34.0 Hz), 60.3, 55.4, 46.6, 40.0,
14.5; 19F NMR (376 MHz, CDCl3) δ −81.29 (d, J = 11.7 Hz, 3F),
−115.05 to −115.16 (m, 1F); IR (KBr) ν 2961, 1721, 1664, 1615,
1515, 1495, 1357, 1337, 1251, 1183, 1037, 836, 743 cm−1; HRMS
(Supporting Information) found m/z 521.0862 [M + Na]+, calcd for
C23H19ClF4N2O4 + Na 521.0867.
(E)-Ethyl 2-(5-(4-methoxybenzyl)-4-oxo-8,9b-bis(trifluoromethyl)-
4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)acetate (5f):
39.6 mg; 77% yield; white solid; mp 64−66 °C; 1H NMR (400 MHz,
CDCl3) δ 7.54 (d, J = 8.8 Hz, 1H), 7.50 (s, 1H), 7.16 (d, J = 8.5 Hz,
2H), 7.01 (d, J = 8.7 Hz, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.09 (s, 1H),
5.31 (d, J = 16.3 Hz, 1H), 4.86 (d, J = 16.3 Hz, 1H), 4.17 (q, J = 7.1
(E)-Ethyl 2-(8-chloro-5-(4-methoxybenzyl)-4-oxo-9b-(trifluoro-
methyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)-
1
acetate (5a): 39.0 mg; 81% yield; white solid; mp 74−76 °C; H
NMR (600 MHz, CDCl3) δ 7.22 (d, J = 8.5 Hz, 2H), 7.14 (d, J = 8.5
Hz, 2H), 6.87−6.80 (m, 3H), 6.06 (s, 1H), 5.26 (d, J = 16.2 Hz, 1H),
4.79 (d, J = 16.2 Hz, 1H), 4.17 (d, J = 7.0 Hz, 1H), 4.14 (d, J = 7.0 Hz,
1H), 3.92 (d, J = 16.6 Hz, 1H), 3.79 (d, J = 16.6 Hz, 1H), 3.76 (s, 3H),
1.27 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 166.4, 158.9,
155.6, 149.4, 137.4, 130.7, 128.8, 127.7, 127.2, 126.3, 123.8 (q, J =
282.3 Hz), 119.1, 117.3, 114.2, 98.0, 66.5 (q, J = 32.9 Hz), 59.8, 54.9,
45.9, 40.5, 14.1; 19F NMR (376 MHz, CDCl3) δ −81.36; IR (KBr) ν
2838, 1719, 1663, 1514, 1493, 1359, 1337, 1251, 1179, 1033, 836
3554
dx.doi.org/10.1021/jo500356t | J. Org. Chem. 2014, 79, 3547−3558

The Journal of Organic Chemistry
Article
Hz, 2H), 3.98 (d, J = 16.5 Hz, 1H), 3.84 (d, J = 16.5 Hz, 1H), 3.77 (s,
3H), 1.28 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8,
159.4, 155.5, 149.7, 142.0, 128.3 (q, J = 3.7 Hz), 128.0, 127.1, 126.1
(q, J = 33.4 Hz), 124.0 (q, J = 282.0 Hz), 123.9 (q, J = 3.4 Hz), 123.6
(q, J = 270.2 Hz), 118.4, 116.5, 114.7, 98.9, 67.0 (q, J = 33.4 Hz), 60.3,
55.4, 46.6, 41.0, 14.5; 19F NMR (376 MHz, CDCl3) δ −62.28 (s, 3F),
−81.53 (s, 3F); IR (KBr) ν 2963, 1721, 1664, 1624, 1513, 1358, 1332,
1255, 1176, 1131, 1088, 1033, 834, 741 cm−1; HRMS (Supporting
Information) found m/z 537.1215 [M + Na]+, calcd for
C24H20F6N2O4 + Na 537.1225.
(E)-Ethyl 2-(5-(4-methoxybenzyl)-4-oxo-9b-(trifluoromethyl)-4,5-
dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)acetate (5g):
28.6 mg; 64% yield; white solid; mp 42−44 °C; 1H NMR (600
MHz, CDCl3) δ 7.25−7.21 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.09 (t,
J = 7.4 Hz, 1H), 6.88 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.4 Hz, 2H),
6.03 (s, 1H), 5.25 (d, J = 16.2 Hz, 1H), 4.81 (d, J = 16.2 Hz, 1H), 4.14
(d, J = 7.0 Hz, 1H), 4.12 (d, J = 7.0 Hz, 1H), 3.90 (d, J = 16.6 Hz,
1H), 3.77 (d, J = 16.6 Hz, 1H), 3.74 (s, 3H), 1.24 (t, J = 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 167.1, 159.1, 156.3, 150.2, 138.9,
(E)-Ethyl 2-(8-chloro-5-(naphthalen-1-ylmethyl)-4-oxo-9b-(tri-
fluoromethyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-
ylidene)acetate (5k): 40.1 mg; 80% yield; white solid; mp 179−181
°C; 1H NMR (600 MHz, CDCl3) δ 7.89 (d, J = 8.3 Hz, 1H), 7.80 (d, J
= 8.0 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.49 (t, J = 7.4 Hz, 1H), 7.44
(t, J = 7.4 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.18 (s, 1H), 7.03 (d, J =
7.0 Hz, 2H), 6.56 (d, J = 8.9 Hz, 1H), 6.00 (s, 1H), 5.67 (d, J = 17.1
Hz, 1H), 5.23 (d, J = 17.1 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H), 3.87 (d, J
= 16.5 Hz, 1H), 3.76 (d, J = 16.5 Hz, 1H), 1.18 (t, J = 7.2 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 166.9, 155.7, 149.7, 137.7, 134.0,
131.1, 130.6, 129.6, 129.4, 129.3, 128.2, 126.7, 126.6, 126.2, 125.5,
124.0 (q, J = 282.0 Hz), 123.4, 122.3, 119.2, 117.6, 98.5, 66.9 (q, J =
33.0 Hz), 60.2, 44.6, 40.9, 14.5; 19F NMR (376 MHz, CDCl3) δ
−81.22; IR (KBr) ν 3056, 2981, 1719, 1662, 1494, 1359, 1335, 1183,
1038, 795, 738 cm−1; HRMS (Supporting Information) found m/z
523.1008 [M + Na]+, calcd for C26H20ClF3N2O3 + Na 523.1012.
(E)-Ethyl 2-(8-chloro-4-oxo-9b-(trifluoromethyl)-5-(2,4,6-trime-
thylbenzyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)-
1
acetate (5l): 38.9 mg; 79% yield; white solid; mp 155−157 °C; H
NMR (600 MHz, CDCl3) δ 7.34 (d, J = 8.9 Hz, 1H), 7.24 (s, 1H),
7.04 (d, J = 9.0 Hz, 1H), 6.84 (s, 2H), 6.06 (s, 1H), 5.32 (d, J = 14.9
Hz, 1H), 4.62 (d, J = 14.9 Hz, 1H), 4.14 (qd, J = 7.0, 1.8 Hz, 2H), 3.89
(d, J = 17.1 Hz, 1H), 3.74 (d, J = 17.1 Hz, 1H), 2.34 (s, 6H), 2.25 (s,
3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 166.8,
155.8, 150.2, 138.7, 137.6, 137.4, 131.0, 129.8, 129.1, 128.8, 126.8,
123.8 (q, J = 282.0 Hz), 119.5, 116.4, 98.8, 67.1 (q, J = 32.9 Hz), 60.1,
43.0, 41.3, 21.0, 20.0, 14.5; 19F NMR (376 MHz, CDCl3) δ −80.59; IR
(KBr) ν 3132, 1720, 1663, 1493, 1398, 1336, 1178, 1038, 884, 837
cm−1; HRMS (Supporting Information) found m/z 515.1319 [M +
Na]+, calcd for C25H24ClF3N2O3 + Na 515.1325.
131.0, 129.0, 128.0, 126.6, 124.2 (q, J = 282.0 Hz), 123.8, 117.9, 116.2,
114.4, 98.0, 67.1 (q, J = 32.8 Hz), 60.1, 55.4, 46.2, 40.8, 14.5; 19F NMR
(376 MHz, CDCl3) δ −81.49; IR (KBr) ν 2963, 1717, 1661, 1513,
1383, 1250, 1175, 1148, 752 cm−1; HRMS (Supporting Information)
found m/z 469.1351 [M + Na]+, calcd for C23H21F3N2O4 + Na
469.1351.
(E)-Ethyl 2-(5-(4-methoxybenzyl)-8-methyl-4-oxo-9b-(trifluoro-
methyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)-
1
acetate (5h): 24.4 mg; 53% yield; white solid; mp 45−47 °C; H
NMR (600 MHz, CDCl3) δ 7.16 (d, J = 8.3 Hz, 2H), 7.09−7.02 (m,
2H), 6.83 (d, J = 8.3 Hz, 2H), 6.79 (d, J = 8.2 Hz, 1H), 6.05 (s, 1H),
5.26 (d, J = 16.2 Hz, 1H), 4.81 (d, J = 16.2 Hz, 1H), 4.16 (d, J = 7.0
Hz, 1H), 4.14 (d, J = 7.0 Hz, 1H), 3.91 (d, J = 16.7 Hz, 1H), 3.78 (d, J
= 16.7 Hz, 1H), 3.75 (s, 3H), 2.29 (s, 3H), 1.27 (t, J = 7.0 Hz, 3H);
13C NMR (150 MHz, CDCl3) δ 167.2, 159.0, 156.5, 150.3, 136.5,
133.7, 131.5, 128.0, 128.0, 127.0, 124.3 (q, J = 281.7 Hz), 117.8, 116.0,
(E)-Ethyl 2-(8-chloro-4-oxo-9b-(trifluoromethyl)-4,5-dihydro-1H-
azeto[1,2-c]quinazolin-2(9bH)-ylidene)acetate (5m): 4.7 mg; 13%
1
yield; white solid; mp 216−218 °C; H NMR (600 MHz, CDCl3) δ
9.24 (s, 1H), 7.28 (d, J = 7.6 Hz, 1H), 7.17 (s, 1H), 6.86 (d, J = 8.2
Hz, 1H), 5.95 (s, 1H), 4.13−4.05 (m, 2H), 3.82 (d, J = 16.4 Hz, 1H),
3.71 (d, J = 16.4 Hz, 1H), 1.20 (t, J = 6.6 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 166.7, 155.8, 151.1, 136.3, 131.4, 129.5, 126.3, 124.0
(q, J = 283.0 Hz), 117.7, 116.8, 98.9, 68.1 (q, J = 33.4 Hz), 60.4, 40.7,
14.5; 19F NMR (376 MHz, CDCl3) δ −81.72; IR (KBr) ν 3672, 2954,
1724, 1662, 1493, 1363, 1178, 1035, 834, 744 cm−1; HRMS
(Supporting Information) found m/z 383.0384 [M + Na]+, calcd for
C15H12ClF3N2O3 + Na 383.0386.
114.4, 97.7, 67.1 (q, J = 32.6 Hz), 60.1, 55.4, 46.1, 40.8, 20.6, 14.5; 19
F
NMR (376 MHz, CDCl3) δ −81.39; IR (KBr) ν 2927, 1717, 1660,
1622, 1575, 1513, 1362, 1251, 1174, 1035, 838, 750 cm−1; HRMS
(Supporting Information) found m/z 483.1502 [M + Na]+, calcd for
C24H23F3N2O4 + Na 483.1508.
(E)-Ethyl 2-(8-isopropyl-5-(4-methoxybenzyl)-4-oxo-9b-(trifluoro-
methyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)-
acetate (5i): 27.8 mg; 57% yield; white solid; mp 44−46 °C; 1H NMR
(600 MHz, CDCl3) δ 7.18 (d, J = 8.4 Hz, 2H), 7.13 (d, J = 8.4 Hz,
1H), 7.08 (s, 1H), 6.87−6.80 (m, 3H), 6.05 (s, 1H), 5.25 (d, J = 16.2
Hz, 1H), 4.82 (d, J = 16.2 Hz, 1H), 4.17 (d, J = 7.1 Hz, 1H), 4.14 (d, J
= 7.1 Hz, 1H), 3.93 (d, J = 16.5 Hz, 1H), 3.80 (d, J = 16.5 Hz, 1H),
3.76 (s, 3H), 2.89−2.82 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 1.20 (s,
3H), 1.19 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 167.2, 159.1,
156.5, 150.3, 144.7, 136.8, 128.9, 128.2, 128.1, 124.5, 124.3 (q, J =
282.1 Hz), 117.8, 116.1, 114.5, 97.7, 67.2 (q, J = 32.7 Hz), 60.1, 55.4,
46.2, 40.8, 33.4, 24.0, 14.5; 19F NMR (376 MHz, CDCl3) δ −81.43; IR
(KBr) ν 2962, 1717, 1659, 1615, 1462, 1362, 1251, 1174, 1034, 834,
743 cm−1; HRMS (Supporting Information) found m/z 511.1821 [M
+ Na]+, calcd for C26H27F3N2O4 + Na 511.1821.
(E)-Ethyl 2-(8-chloro-9b-(difluoromethyl)-5-(4-methoxybenzyl)-4-
oxo-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)acetate
1
(5n): 8.3 mg; 18% yield; white solid; mp 63−65 °C; H NMR (600
MHz, CDCl3) δ 7.22−7.17 (m, 2H), 7.15 (d, J = 8.4 Hz, 2H), 6.84 (d,
J = 8.4 Hz, 2H), 6.80 (d, J = 8.7 Hz, 1H), 6.03 (s, 1H), 6.07−5.84 (m,
2H), 5.22 (d, J = 16.2 Hz, 1H), 4.81 (d, J = 16.2 Hz, 1H), 4.16 (d, J =
7.0 Hz, 1H), 4.14 (d, J = 7.0 Hz, 1H), 3.79 (d, J = 16.8 Hz, 1H), 3.76
(s, 3H), 3.73 (d, J = 16.8 Hz, 1H), 1.27 (t, J = 7.1 Hz, 3H); 13C NMR
(150 MHz, CDCl3) δ 167.1, 159.2, 156.3, 150.1, 137.6, 130.4, 129.1,
128.0, 127.6, 126.4, 120.6, 117.3, 114.6, 114.5 (t, J = 246.9 Hz), 98.1,
66.8 (t, J = 24.5 Hz), 60.1, 55.4, 46.2, 39.9, 14.5; 19F NMR (565 MHz,
CDCl3) δ −129.19 (dd, J = 287.6, 55.4 Hz, 1F), δ −130.70 (dd, J =
287.6, 54.8 Hz, 1F); IR (KBr) ν 2979, 1715, 1656, 1514, 1494, 1360,
1335, 1250, 1206, 1133, 1034, 815, 740 cm−1; HRMS (Supporting
Information) found m/z 485.1049 [M + Na]+, calcd for
C23H21ClF2N2O4 + Na 485.1056.
(E)-Ethyl 2-(8-methoxy-5-(4-methoxybenzyl)-4-oxo-9b-(trifluoro-
methyl)-4,5-dihydro-1H-azeto[1,2-c]quinazolin-2(9bH)-ylidene)-
General Procedure for the Aza-MBH Reaction of Ethyl 2,3-
Butadienoate (1) with Cyclic Ketimines 2 in the Presence of
Pyridine. Under a N2 atmosphere, a mixture of cyclic ketimine 2
(0.10 mmol), ethyl 2,3-butadienoate (1; 0.15 mmol), and pyridine
(0.01 mmol) in toluene (1.0 mL) was stirred at room temperature (25
°C). After completion of the reaction (monitored by TLC), the
resulting residue was purified on a silica gel column (1.3 × 20 cm)
with the eluent (petroleum ether/ethyl acetate 6/1 to 3/1) to give the
product 6.
Ethyl 2-(6-chloro-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-
1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6a): 45.7 mg;
95% yield; yellow solid; mp 177−179 °C; 1H NMR (600 MHz,
CDCl3) δ 7.24−7.18 (m, 3H), 7.15 (d, J = 8.8 Hz, 1H), 6.86 (d, J = 8.5
1
acetate (5j): 29.5 mg; 62% yield; white solid; mp 121−123 °C; H
NMR (600 MHz, CDCl3) δ 7.16 (d, J = 8.3 Hz, 2H), 6.83 (d, J = 8.3
Hz, 2H), 6.82−6.76 (m, 3H), 6.04 (s, 1H), 5.25 (d, J = 16.3 Hz, 1H),
4.79 (d, J = 16.3 Hz, 1H), 4.16 (d, J = 7.1 Hz, 1H), 4.13 (d, J = 7.1 Hz,
1H), 3.91 (d, J = 16.5 Hz, 1H), 3.78 (d, J = 16.5 Hz, 1H), 3.75 (s, 3H),
3.74 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ
167.2, 159.1, 156.3, 156.0, 150.2, 132.3, 128.1, 128.0, 124.2 (q, J =
281.5 Hz), 119.0, 117.3, 116.0, 114.5, 112.2, 97.7, 67.1 (q, J = 32.6
Hz), 60.1, 55.8, 55.4, 46.2, 40.8, 14.5; 19F NMR (376 MHz, CDCl3) δ
−81.19; IR (KBr) ν 2921, 1716, 1660, 1509, 1459, 1365, 1250, 1176,
1035, 837, 744 cm−1; HRMS (Supporting Information) found m/z
499.1448 [M + Na]+, calcd for C24H23F3N2O5 + Na 499.1457.
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Article
Hz, 2H), 6.74 (d, J = 8.9 Hz, 1H), 6.40 (s, 1H), 5.55 (d, J = 15.0 Hz,
1H), 5.46 (d, J = 15.0 Hz, 1H), 5.20 (d, J = 11.9 Hz, 1H), 5.05 (d, J =
11.9 Hz, 1H), 4.15−4.10 (m, 1H), 4.09−4.03 (m, 1H), 3.77 (s, 3H),
1.13 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 212.8, 163.2,
158.9, 152.2, 136.9, 130.2, 128.4, 127.6, 127.3, 126.8, 124.1 (q, J =
285.9 Hz), 118.1, 115.9, 114.4, 98.5, 83.3, 64.5 (q, J = 27.3 Hz), 61.6,
55.3, 45.4, 14.0; 19F NMR (376 MHz, CDCl3) δ −77.18; IR (KBr) ν
3431, 3077, 2936, 1975, 1720, 1682, 1511, 1428, 1393, 1249, 1181,
1027, 811, 553 cm−1; HRMS (Supporting Information) found m/z
503.0956 [M + Na]+, calcd for C23H20ClF3N2O4 + Na 503.0961.
Ethyl 2-(6-fluoro-1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-
1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6b): 42.7 mg;
92% yield; yellow solid; mp 164−166 °C; 1H NMR (600 MHz,
CDCl3) δ 7.22 (d, J = 8.4 Hz, 2H), 7.00 (d, J = 7.8 Hz, 1H), 6.92−6.88
(m, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.77 (dd, J = 9.1, 4.5 Hz, 1H), 6.74
(s, 1H), 5.50 (d, J = 15.0 Hz, 1H), 5.42 (d, J = 15.0 Hz, 1H), 5.21 (d, J
= 15.2 Hz, 1H), 5.05 (d, J = 15.2 Hz, 1H), 4.14−4.09 (m, 1H), 4.09−
4.03 (m, 1H), 3.76 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 212.8, 163.2, 158.9, 157.8 (d, J = 240.5 Hz), 152.3,
134.5, 128.6, 127.6, 124.1 (q, J = 285.9 Hz), 117.9 (d, J = 7.2 Hz),
117.0 (d, J = 22.2 Hz), 116.0 (d, J = 7.6 Hz), 114.4, 114.1 (d, J = 25.2
Hz), 98.6, 83.3, 64.6 (q, J = 28.2 Hz), 61.7, 55.4, 45.6, 14.0; 19F NMR
(376 MHz, CDCl3) δ −77.15 (s, 3F), −121.16 to −121.26 (m, 1F); IR
(KBr) ν 3435, 3132, 1972, 1720, 1683, 1514, 1401, 1387, 1249, 1169,
1065, 814, 556 cm−1; HRMS (Supporting Information) found m/z
487.1250 [M + Na]+, calcd for C23H20F4N2O4 + Na 487.1257.
Ethyl 2-(6-bromo-1-(4-methoxybenzyl)-2-oxo-4-(trifluorometh-
yl)-1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6c): 47.3
45.8, 14.1; 19F NMR (376 MHz, CDCl3) δ −77.43 (d, J = 17.3 Hz,
3F), −111.71 to −111.88 (m, 1F); IR (KBr) ν 3432, 3080, 2989, 1971,
1717, 1685, 1612, 1587, 1513, 1498, 1451, 1397, 1249, 1173, 1025,
750, 614 cm−1; HRMS (Supporting Information) found m/z 521.0862
[M + Na]+, calcd for C23H19ClF4N2O4 + Na 521.0867.
Ethyl 2-(1-(4-methoxybenzyl)-2-oxo-4,6-bis(trifluoromethyl)-
1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6f): 47.8 mg;
93% yield; yellow solid; mp 173−175 °C; 1H NMR (600 MHz,
CDCl3) δ 7.48 (s, 1H), 7.45 (d, J = 8.7 Hz, 1H), 7.23 (d, J = 8.5 Hz,
2H), 6.99 (s, 1H), 6.92 (d, J = 8.7 Hz, 1H), 6.87 (d, J = 8.5 Hz, 2H),
5.55 (d, J = 15.0 Hz, 1H), 5.44 (d, J = 15.0 Hz, 1H), 5.25 (d, J = 14.5
Hz, 1H), 5.11 (d, J = 14.5 Hz, 1H), 4.13−4.08 (m, 1H), 4.08−4.03
(m, 1H), 3.77 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 212.9, 163.2, 159.1, 152.1, 141.1, 128.1, 127.7, 127.5 (d, J =
3.6 Hz), 124.2 (q, J = 33.3 Hz), 124.1, 124.1 (q, J = 285.3 Hz), 123.9
(q, J = 269.9 Hz), 117.0, 114.9, 114.5, 98.5, 83.6, 64.7 (q, J = 27.6 Hz),
61.8, 55.4, 45.6, 14.0; 19F NMR (376 MHz, CDCl3) δ −62.00 (s, 3F),
−77.39 (s, 3F); IR (KBr) ν 3411, 3078, 2938, 1968, 1719, 1687, 1625,
1515, 1396, 1332, 1250, 1175, 1124, 530 cm−1; HRMS (Supporting
Information) found m/z 537.1217 [M + Na]+, calcd for
C24H20F6N2O4 + Na 537.1225.
Ethyl 2-(1-(4-methoxybenzyl)-2-oxo-4-(trifluoromethyl)-1,2,3,4-
tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6g): 35.7 mg; 80%
1
yield; yellow solid; mp 139−141 °C; H NMR (600 MHz, CDCl3) δ
7.27 (d, J = 7.9 Hz, 1H), 7.23 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 7.7 Hz,
1H), 6.96 (t, J = 7.4 Hz, 1H), 6.86 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.3
Hz, 1H), 6.11 (s, 1H), 5.52 (d, J = 14.9 Hz, 1H), 5.46 (d, J = 14.9 Hz,
1H), 5.23 (d, J = 3.6 Hz, 1H), 5.08 (d, J = 3.6 Hz, 1H), 4.14−4.07 (m,
1H), 4.07−4.00 (m, 1H), 3.77 (s, 3H), 1.09 (t, J = 7.0 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 212.8, 163.4, 158.9, 152.2, 138.1, 130.4,
128.9, 127.7, 127.1, 124.3 (q, J = 285.9 Hz), 122.1, 116.2, 114.8, 114.4,
99.1, 83.2, 64.8 (q, J = 28.4 Hz), 61.6, 55.4, 45.4, 14.0; 19F NMR (376
MHz, CDCl3) δ −77.22; IR (KBr) ν 3438, 1964, 1718, 1680, 1636,
1510, 1429, 1397, 1250, 1080, 746, 553 cm−1; HRMS (Supporting
Information) found m/z 469.1345 [M + Na]+, calcd for
C23H21F3N2O4 + Na 469.1351.
1
mg; 90% yield; yellow solid; mp 170−172 °C; H NMR (600 MHz,
CDCl3) δ 7.35 (s, 1H), 7.28 (d, J = 8.8 Hz, 1H), 7.20 (d, J = 8.4 Hz,
2H), 6.85 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 9.2 Hz, 2H), 5.53 (d, J =
15.0 Hz, 1H), 5.43 (d, J = 15.0 Hz, 1H), 5.19 (d, J = 14.7 Hz, 1H),
5.04 (d, J = 14.7 Hz, 1H), 4.15−4.10 (m, 1H), 4.09−4.03 (m, 1H),
3.77 (s, 3H), 1.12 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ
212.8, 163.2, 158.9, 152.0, 137.4, 133.2, 129.6, 128.3, 127.6, 124.1 (q, J
= 285.7 Hz), 118.4, 116.4, 114.6, 114.4, 98.6, 83.5, 64.5 (q, J = 27.7
Hz), 61.7, 55.4, 45.5, 14.0; 19F NMR (376 MHz, CDCl3) δ −77.21; IR
(KBr) ν 3430, 3093, 1973, 1720, 1682, 1510, 1424, 1390, 1248, 1179,
1026, 530 cm−1; HRMS (Supporting Information) found m/z
547.0453 [M + Na]+, calcd for C23H20BrF3N2O4 + Na 547.0456.
Ethyl 2-(5,6-difluoro-1-(4-methoxybenzyl)-2-oxo-4-(trifluoro-
methyl)-1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6d):
Ethyl 2-(1-(4-methoxybenzyl)-6-methyl-2-oxo-4-(trifluorometh-
yl)-1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6h): 34.1
1
mg; 74% yield; yellow solid; mp 160−162 °C; H NMR (600 MHz,
CDCl3) δ 7.22 (d, J = 8.4 Hz, 2H), 7.04 (s, 1H), 6.99 (d, J = 8.3 Hz,
1H), 6.84 (d, J = 8.4 Hz, 2H), 6.71 (d, J = 8.4 Hz, 1H), 6.11 (s, 1H),
5.53 (d, J = 14.8 Hz, 1H), 5.47 (d, J = 14.8 Hz, 1H), 5.20 (d, J = 15.5
Hz, 1H), 5.05 (d, J = 15.5 Hz, 1H), 4.13−4.08 (m, 1H), 4.08−4.01
(m, 1H), 3.76 (s, 3H), 2.23 (s, 3H), 1.09 (t, J = 7.1 Hz, 3H); 13C
NMR (150 MHz, CDCl3) δ 212.8, 163.4, 158.8, 152.2, 135.7, 131.6,
131.0, 129.0, 127.6, 127.4, 124.3 (q, J = 285.4 Hz), 116.0, 114.7, 114.3,
99.2, 83.2, 64.8 (q, J = 27.8 Hz), 61.6, 55.4, 45.4, 20.7, 14.0; 19F NMR
(376 MHz, CDCl3) δ −77.13; IR (KBr) ν 3425, 3080, 2935, 1968,
1722, 1679, 1514, 1433, 1399, 1248, 1183, 1028, 809, 534 cm−1;
HRMS (Supporting Information) found m/z 483.1506 [M + Na]+,
calcd for C24H23F3N2O4 + Na 483.1508.
1
45.3 mg; 94% yield; yellow solid; mp 162−164 °C; H NMR (600
MHz, CDCl3) δ 7.19 (d, J = 8.4 Hz, 2H), 7.02 (dd, J = 17.5, 8.9 Hz,
1H), 6.96 (s, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.56 (d, J = 6.8 Hz, 1H),
5.49 (d, J = 14.8 Hz, 1H), 5.37 (d, J = 14.8 Hz, 1H), 5.22 (d, J = 14.4
Hz, 1H), 5.02 (d, J = 14.4 Hz, 1H), 4.16−4.11 (m, 1H), 4.11−4.07
(m, 1H), 3.77 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 212.7 (d, J = 1.8 Hz), 163.5, 159.0, 152.1, 148.2 (dd, J =
250.6 Hz, J = 14.4 Hz), 146.3 (dd, J = 242.1 Hz, J = 13.1 Hz), 135.3,
128.2, 127.6, 124.3 (q, J = 287.4 Hz), 118.2 (d, J = 18.0 Hz), 114.5,
109.9 (d, J = 3.9 Hz), 107.1 (d, J = 10.5 Hz), 97.7, 83.5, 62.8 (q, J =
29.4 Hz), 61.6, 55.4, 45.8, 14.1; 19F NMR (376 MHz, CDCl3) δ
−77.51 (d, J = 18.0 Hz, 3F), −135.16 to −135.38 (m, 1F), −144.87 to
−144.96 (m, 1F); IR (KBr) ν 3431, 3080, 1981, 1718, 1683, 1514,
1473, 1399, 1249, 1191, 1027, 804, 532 cm−1; HRMS (Supporting
Information) found m/z 505.1157 [M + Na]+, calcd for
C23H19F5N2O4 + Na 505.1163.
Ethyl 2-(6-isopropyl-1-(4-methoxybenzyl)-2-oxo-4-(trifluoro-
methyl)-1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6i):
36.6 mg; 75% yield; yellow solid; mp 63−65 °C; 1H NMR (600
MHz, CDCl3) δ 7.24 (d, J = 8.4 Hz, 2H), 7.09−7.03 (m, 2H), 6.86 (d,
J = 8.4 Hz, 2H), 6.79−6.64 (m, 2H), 5.51 (d, J = 14.7 Hz, 1H), 5.41
(d, J = 14.7 Hz, 1H), 4.13−4.06 (m, 1H), 4.04−3.98 (m, 1H), 5.35−
5.15 (m, 1H), 5.15−4.90 (m, 1H), 3.76 (s, 3H), 2.83−2.76 (m, 1H),
1.15 (s, 3H), 1.14 (s, 3H), 1.03 (t, J = 7.0 Hz, 3H); 13C NMR (150
MHz, CDCl3) δ 212.8, 163.5, 158.7, 152.5 (d, J = 6.5 Hz), 142.6,
135.7, 129.0 (d, J = 1.4 Hz), 128.0, 127.6, 125.1, 124.3 (q, J = 285.9
Hz), 116.0 (d, J = 4.1 Hz), 114.5, 114.2, 99.0, 83.2, 64.7 (q, J = 27.6
Hz), 61.5, 55.3, 45.3, 33.2, 23.9, 14.0; 19F NMR (565 MHz, CDCl3) δ
−77.09; IR (KBr) ν 3432, 3138, 2935, 1711, 1646, 1514, 1400, 1246,
1112, 1027, 874, 434 cm−1; HRMS (Supporting Information) found
m/z 511.1819 [M + Na]+, calcd for C26H27F3N2O4 + Na 511.1821.
Ethyl 2-(6-methoxy-1-(4-methoxybenzyl)-2-oxo-4-(trifluorometh-
yl)-1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6j): 37.2
Ethyl 2-(6-chloro-5-fluoro-1-(4-methoxybenzyl)-2-oxo-4-(trifluor-
omethyl)-1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6e):
1
47.9 mg; 96% yield; yellow solid; mp 172−174 °C; H NMR (600
MHz, CDCl3) δ 7.22 (d, J = 8.3 Hz, 1H), 7.19 (d, J = 8.4 Hz, 2H),
7.02 (s, 1H), 6.86 (d, J = 8.4 Hz, 2H), 6.60 (d, J = 9.0 Hz, 1H), 5.49
(d, J = 14.8 Hz, 1H), 5.36 (d, J = 14.8 Hz, 1H), 5.23 (d, J = 13.8 Hz,
1H), 5.03 (d, J = 13.8 Hz, 1H), 4.16−4.11 (m, 1H), 4.11−4.06 (m,
1H), 3.77 (s, 3H), 1.15 (t, J = 7.1 Hz, 3H); 13C NMR (150 MHz,
CDCl3) δ 212.7 (d, J = 1.9 Hz), 163.5, 159.0, 155.3 (d, J = 250.6 Hz),
152.0 (d, J = 6.9 Hz), 138.6 (d, J = 3.6 Hz), 131.5, 128.1, 127.6, 124.2
(q, J = 286.4 Hz), 115.2 (d, J = 18.9 Hz), 114.5, 111.1 (d, J = 3.4 Hz),
106.6 (d, J = 14.2 Hz), 97.8, 83.5, 62.9 (q, J = 29.1 Hz), 61.6, 55.4,
1
mg; 78% yield; yellow solid; mp 143−145 °C; H NMR (600 MHz,
CDCl3) δ 7.22 (d, J = 8.0 Hz, 2H), 6.85 (d, J = 8.0 Hz, 2H), 6.82 (s,
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Article
1H), 6.77−6.69 (m, 2H), 6.47 (s, 1H), 5.49 (d, J = 14.8 Hz, 1H), 5.41
(d, J = 14.8 Hz, 1H), 5.19 (d, J = 10.5 Hz, 1H), 5.03 (d, J = 10.5 Hz,
1H), 4.14−4.07 (m, 1H), 4.06−4.01 (m, 1H), 3.76 (s, 3H), 3.70 (s,
3H), 1.09 (t, J = 6.9 Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 212.8,
163.3, 158.8, 154.6, 152.1, 131.8, 129.1, 127.7, 124.3 (q, J = 286.6 Hz),
117.4, 115.6, 114.8, 114.3, 113.6, 99.0, 83.1, 64.8 (q, J = 28.1 Hz), 61.6,
55.7, 55.4, 45.4, 14.0; 19F NMR (376 MHz, CDCl3) δ −76.94; IR
(KBr) ν 3415, 3077, 2935, 1968, 1722, 1677, 1516, 1438, 1402, 1297,
1248, 1181, 1024, 740, 621 cm−1; HRMS (Supporting Information)
found m/z 499.1449 [M + Na]+, calcd for C24H23F3N2O5 + Na
499.1457.
(Supporting Information) found m/z 485.1048 [M + Na]+, calcd for
C23H21ClF2N2O4 + Na 485.1056.
Procedure for the Synthesis of Dihydropyrrole Derivative
4a from 6a. Under a N2 atmosphere, a mixture of allenoate 6a (0.10
mmol) and DPPP (0.02 mmol) in toluene (1.0 mL) was stirred at
room temperature (25 °C). After completion of the reaction
(monitored by TLC), the resulting residue was purified on a silica
gel column (1.3 × 20 cm) with the eluent (petroleum ether/ethyl
acetate 8/1 to 4/1) to give the product 4a (47.2 mg, yield 98%) as a
white solid.
Procedure for the Synthesis of N-Fused Polycyclic Com-
pound 3a from 6a. Under a N2 atmosphere, a mixture of allenoate
6a (0.10 mmol), ethyl 2,3-butadienoate (1; 0.15 mmol), and dppp
(0.02 mmol) in toluene (1.0 ml) was stirred at room temperature (25
°C). After completion of the reaction (monitored by TLC), the
resulting residue was purified on a silica gel column (1.3 × 20 cm)
with the eluent (petroleum ether/ethyl acetate 10/1 to 5/1) to give
the product 3a (54.0 mg, yield 91%) as a white solid.
Ethyl 2-(6-chloro-1-(naphthalen-1-ylmethyl)-2-oxo-4-(trifluoro-
methyl)-1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6k):
1
44.6 mg; 89% yield; yellow solid; mp 238−240 °C; H NMR (600
MHz, DMSO) δ 8.77 (s, 1H), 8.22 (d, J = 8.2 Hz, 1H), 7.98 (d, J = 8.0
Hz, 1H), 7.83 (d, J = 8.1 Hz, 1H), 7.64 (t, J = 7.2 Hz, 1H), 7.59 (t, J =
7.3 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H), 7.34 (s, 1H), 7.25 (d, J = 8.7 Hz,
1H), 7.17 (d, J = 6.9 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 6.07 (d, J =
15.4 Hz, 1H), 5.87 (d, J = 15.4 Hz, 1H), 5.61 (s, 2H), 4.15 (dt, J =
17.8, 7.1 Hz, 1H), 4.09 (dt, J = 17.8, 7.1 Hz, 1H), 1.14 (t, J = 7.0 Hz,
3H); 13C NMR (150 MHz, DMSO) δ 212.3, 163.0, 150.8, 137.4,
133.4, 131.3, 130.3, 130.2, 128.6, 127.2 (d, J = 3.3 Hz), 126.3 (d, J =
2.1 Hz), 126.1 (d, J = 1.6 Hz), 126.0, 125.5, 125.3, 124.2 (q, J = 286.5
Hz), 123.0, 121.7, 117.8, 116.1 (d, J = 4.9 Hz), 97.0, 84.2, 63.8 (q, J =
27.2 Hz), 61.0, 43.1, 13.9 (d, J = 4.0 Hz); 19F NMR (376 MHz,
DMSO) δ −76.43; IR (KBr) ν 3410, 3118, 2987, 1968, 1718, 1686,
1506, 1425, 1399, 1249, 1171, 1027, 796, 773 cm−1; HRMS
(Supporting Information) found m/z 523.1007 [M + Na]+, calcd for
C26H20ClF3N2O3 + Na 523.1012.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Figures giving H, 19F, and 13C NMR spectra for the products
4a−n, 5a−n, and 6a−n and figures and CIF files giving
crystallographic data for compounds 4a and 5a. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail for J.-A.M.: majun_an68@tju.edu.cn.
■
Ethyl 2-(6-chloro-2-oxo-4-(trifluoromethyl)-1-(2,4,6-trimethyl-
benzyl)-1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6l):
Notes
1
45.8 mg; 93% yield; yellow solid; mp 172−174 °C; H NMR (600
The authors declare no competing financial interest.
MHz, CDCl3) δ 7.22 (s, 1H), 7.10 (d, J = 8.9 Hz, 1H), 6.83 (s, 2H),
6.67 (s, 1H), 6.64 (d, J = 8.9 Hz, 1H), 5.60 (d, J = 16.3 Hz, 1H), 5.51
(q, J = 15.0 Hz, 2H), 4.92 (d, J = 16.3 Hz, 1H), 4.15−4.10 (m, 1H),
4.10−4.05 (m, 1H), 2.35 (s, 6H), 2.25 (s, 3H), 1.17 (t, J = 7.1 Hz,
3H); 13C NMR (150 MHz, CDCl3) δ 212.7, 163.3, 152.0, 137.4,
136.8, 136.4, 130.3, 130.3, 130.0, 127.2, 126.9, 123.9 (q, J = 285.6 Hz),
117.7, 115.6, 99.1, 83.4, 64.6 (q, J = 27.6 Hz), 61.7, 42.9, 20.9, 20.2,
14.1; 19F NMR (376 MHz, CDCl3) δ −76.61; IR (KBr) ν 3441, 3202,
3132, 1968, 1723, 1681, 1423, 1400, 1385, 1248, 1186, 1172, 1035,
1022, 548 cm−1; HRMS (Supporting Information) found m/z
515.1318 [M + Na]+, calcd for C25H24ClF3N2O3 + Na 515.1325.
Ethyl 2-(6-chloro-2-oxo-4-(trifluoromethyl)-1,2,3,4-tetrahydro-
quinazolin-4-yl)buta-2,3-dienoate (6m): 25.2 mg; 70% yield; yellow
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Nos. 21172170, 21225208, and
21302137), and the National Basic Research Program of
China (973 Program, 2014CB745100).
REFERENCES
■
(1) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47,
1560.
(2) For reviews, see: (a) Lu, X.; Zhang, C.; Xu, Z. Acc. Chem. Res.
2001, 34, 535. (b) Methot, J. L.; Roush, W. R. Adv. Synth. Catal. 2004,
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1
solid; mp 66−68 °C; H NMR (600 MHz, CDCl3) δ 9.92 (s, 1H),
7.19 (s, 1H), 7.16 (d, J = 8.4 Hz, 1H), 6.83 (s, 1H), 6.76 (d, J = 8.3
Hz, 1H), 5.54 (d, J = 15.1 Hz, 1H), 5.48 (d, J = 15.1 Hz, 1H), 4.12−
4.01 (m, 2H), 1.12 (t, J = 6.8 Hz, 3H); 13C NMR (150 MHz, CDCl3)
δ 212.6, 163.4, 153.7, 135.5, 130.6, 127.6, 126.7, 124.0 (q, J = 285.2
Hz), 116.4, 116.0, 98.5, 83.6, 65.3 (q, J = 27.6 Hz), 61.8, 13.9; 19F
NMR (376 MHz, CDCl3) δ −77.00; IR (KBr) ν 3430, 3210, 3125,
1968, 1694, 1501, 1436, 1398, 1251, 1176, 1020, 824 cm−1; HRMS
(Supporting Information) found m/z 383.0377 [M + Na]+, calcd for
C15H12ClF3N2O3 + Na 383.0386.
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Ethyl 2-(6-chloro-4-(difluoromethyl)-1-(4-methoxybenzyl)-2-oxo-
1,2,3,4-tetrahydroquinazolin-4-yl)buta-2,3-dienoate (6n): 40.7 mg;
88% yield; yellow solid; mp 138−140 °C; 1H NMR (600 MHz,
CDCl3) δ 7.22 (d, J = 1.7 Hz, 1H), 7.18 (d, J = 8.4 Hz, 2H), 7.12 (d, J
= 8.8 Hz, 1H), 6.84 (d, J = 8.4 Hz, 2H), 6.73 (d, J = 8.9 Hz, 1H), 6.24
(t, J = 55.3 Hz, 1H), 6.00 (s, 1H), 5.41 (d, J = 15.0 Hz, 1H), 5.37 (d, J
= 15.0 Hz, 1H), 5.15 (d, J = 13.5 Hz, 1H), 5.04 (d, J = 13.5 Hz, 1H),
4.21−4.16 (m, 1H), 4.16−4.11 (m, 1H), 3.76 (s, 3H), 1.20 (t, J = 7.1
Hz, 3H); 13C NMR (150 MHz, CDCl3) δ 213.2, 164.2, 158.9, 152.7,
136.9, 129.7, 128.5, 127.6, 127.2, 126.6, 119.2, 116.0, 114.6 (t, J =
252.6 Hz), 114.4, 101.6, 83.6 (t, J = 6.5 Hz), 62.2 (t, J = 21.9 Hz), 61.8
(t, J = 6.7 Hz), 55.4 (d, J = 6.3 Hz), 45.5, 14.1; 19F NMR (376 MHz,
CDCl3) δ −127.99 (dd, J = 274.1, 54.9 Hz, 1F), δ −130.85 (dd, J =
274.1, 55.6 Hz, 1F); IR (KBr) ν 3201, 3078, 2960, 2933, 1968, 1722,
1680, 1607, 1513, 1457, 1404, 1248, 1183, 1024, 753 cm−1; HRMS
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dx.doi.org/10.1021/jo500356t | J. Org. Chem. 2014, 79, 3547−3558