Intramolecular ipso -halocyclization of 4-(p -unsubstituted-aryl)-1-alkynes leading to spiro[4,5]trienones: Scope, application, and mechanistic investigations

Article abstract of DOI:10.1021/jo300037n

A new, general method for the synthesis of spiro[4,5]trienones is described by the intramolecular ipso-halocyclization of 4-(p-unsubstituted-aryl)-1- alkynes. In the presence of halide electrophiles, a variety of 4-(p-unsubstituted-aryl)-1-alkynes underwent the intramolecular ipso-halocyclization with water smoothly, affording the corresponding halo-substituted spiro[4,5]trienones in moderate to good yields. The obtained spiro[4,5]trienones can be applied in constructing the azaquaternary tricyclic skeleton via Pd-catalyzed Heck reaction. Notably, the prepared spiro[4,5]trienones and azaquaternary tricycles are of importance in the areas of pharmaceuticals and agrochemicals. The mechanism of the intramolecular ipso-halocyclization reaction is also discussed according to the ¹⁸O-labeling experiments and DFT calculations.

Full text of DOI:10.1021/jo300037n

Article
pubs.acs.org/joc
Intramolecular ipso-Halocyclization of 4-(p-Unsubstituted-aryl)-1-
alkynes Leading to Spiro[4,5]trienones: Scope, Application, and
Mechanistic Investigations
Bo-Xiao Tang,‡ Yue-Hua Zhang,‡ Ren-Jie Song,† Dong-Jun Tang,‡ Guo-Bo Deng,† Zhi-Qiang Wang,†,‡
Ye-Xiang Xie,† Yuan-Zhi Xia,¶ and Jin-Heng Li*,†
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China
‡Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University,
Changsha 410081, China
¶College of Chemistry and Materials engineering, Wenzhou University, Wenzhou, 325035, China
S
* Supporting Information
ABSTRACT: A new, general method for the synthesis of
spiro[4,5]trienones is described by the intramolecular ipso-
halocyclization of 4-(p-unsubstituted-aryl)-1-alkynes. In the
presence of halide electrophiles, a variety of 4-(p-unsubsti-
tuted-aryl)-1-alkynes underwent the intramolecular ipso-
halocyclization with water smoothly, affording the correspond-
ing halo-substituted spiro[4,5]trienones in moderate to good
yields. The obtained spiro[4,5]trienones can be applied in
constructing the azaquaternary tricyclic skeleton via Pd-
catalyzed Heck reaction. Notably, the prepared spiro[4,5]trienones and azaquaternary tricycles are of importance in the areas
of pharmaceuticals and agrochemicals. The mechanism of the intramolecular ipso-halocyclization reaction is also discussed
according to the 18O-labeling experiments and DFT calculations.
reaction partner to react with ICl, Na2CO3, and H2O, affording
a spiro[4,5]trienone product (eq 1 in Scheme 2).4 In 2005,
Larock and Zhang developed a general intramolecular electro-
philic ipso-cyclization protocol, which is compatible with a wide
range of 4-(4-methoxyaryl)-1-alkynes to give the corresponding
spiro[4,5]trienones in moderate to excellent yields using the
ICl, I2/NaHCO3, or Br2 electrophilic system (eq 2 in Scheme
2).5a Recently, we extended the intramolecular ipso-iodocycliza-
tion process to 4-(p-methylaryl)-1-alkynes (eq 3 in Scheme
2).6b However, these methods are restricted with arylalkynes
bearing some para-substituents, such as methoxy, N,N-
dimethylamino, or alkyl groups, on the aryl ring.4,5,6a,b
Alternatively, a novel electrophilic ipso-cyclization of para-
unsubstituted arylalkynes approach to spiro[4,5]trienyl acetates
and ethers has been developed employing HOAc6c or
polyfluoro alcohols6d as the cationic captors and NIS (N-
iodosuccimide) as the electrophile (eq 4 in Scheme 2). To the
best of our knowledge, however, a general route to 3-halo
spiro[4,5]trienones by the electrophilic ipso-cyclization of para-
unsubstituted arylalkynes with halide electrophiles has not yet
been reported (eq 5 in Scheme 2). Moreover, the mechanism
for the electrophilic ipso-cyclization method was not studied in
detail.
INTRODUCTION
■
The intramolecular electrophilic cyclization reactions have
emerged as one of the most important methods for
constructing important carbocycles and heterocycles via the
formation of both a carbon−carbon bond and a carbon−
heteroatom bond in a single reaction.1−4 Until now, there are
two types of intramolecular electrophilic cyclization routes
(Scheme 1): one involves the introduction of a substituent onto
Scheme 1. Two Intramolecular Electrophilic Cyclization
Routes
its ortho-position of the aromatic ring,1−3 and the other is onto
its ipso-position of the aromatic ring.1,4−6 Although the latter is
a useful tool for the synthesis of spiro-heterocycles, only a few
papers have been reported. In 2003, Fanghanel and co-workers
̈
first described an interesting intramolecular electrophilic
cyclization method that utilized the ipso-position of the
aromatic ring in bis(4-methoxybenzylthio)acetylene as a
Received: January 11, 2012
Published: February 23, 2012
© 2012 American Chemical Society
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the position of several preexisting functional groups (olefine
and halo groups) in its products, facilitating the generation of
analogues with a new structural feature for further elaboration.
Here, we report a new, general protocol for the synthesis of
3-halospirotrienones by the electrophilic ipso-cyclization of
para-unsubstituted arylalkynes with halide electrophiles and
water (eq 5 in Scheme 2). We have examined aspects of the
electrophilic ipso-cyclization reaction by synthetic, applied, and
mechanistic investigations. The synthetic and applied inves-
tigations will focus on (1) the 4-(p-unsubstituted-aryl)-1-alkyne
scope for the electrophilic ipso-cyclization with halide electro-
philes and water, (2) the development of an intramolecular
Heck process for cyclization of 3-halo-1-(2-halobenzyl)-4-
substituted-1-azaspiro[4.5]deca-3,6,9-triene-2,8-diones, con-
structing the erythratidinone analogues, and (3) the cross-
coupling of the pre-existing olefinic and halo groups on the
erythratidinone analogues. The mechanistic investigations will
focus on (1) 18O-labeling experiments under Larock’s and our
conditions in the presence of H218O13 and (2) a computational
study including DFT calculations on each step for the related
intermediates to understand the 18O-labeling experiments.14
Scheme 2. The Intramolecular Electrophilic ipso-Cyclization
Reactions
RESULTS AND DISCUSSION
■
Intramolecular ipso-Halocyclization of 4-(p-Unsubsti-
tuted-aryl)-1-alkynes. N-Methyl-N,3-diphenylpropiolamide
(1a) was used as a model substrate, reacting with various
halide electrophiles and water, to screen the optimal reaction
conditions (Table 1). Initially, the reaction of substrate 1a with
NBS (N-bromosuccimide) and water was investigated (Table 1,
entries 1−7). We found that the amount of water had a
fundamental influence on the reaction (Table 1, entries 1−5).
While 16.7 mmol H2O gave the corresponding product 2 in a
low yield (Table 1, entry 1), 2.8 mmol H2O enhanced the yield
to 76% (Table 1, entry 4). The yield of 2 was reduced to 56%
when 1.5 mmol H2O was added (Table 1, entry 5). It was
found that the reactivity of substrate 1a was lowered sharply at
either 80 °C or 2 equiv of K2CO3 (Table 1, entries 6 and 7).
Gratifyingly, the reaction of substrate 1a with NIS and H2O was
also carried out smoothly at 120 °C, affording the
corresponding product 3 in 73% yield (Table 1, entry 8).
However, the yield was decreased to 50% when the reaction
was conducted at 60 °C (Table 1, entry 9). Finally, the
compatibility of the other electrophiles, including NCS (N-
chlorosuccimide), ICl, I2, and CuBr, was investigated, and the
results demonstrated that they displayed less activity in the ipso-
cyclization reaction (Table 1, entries 10−16): NCS, for
instance, reacted with substrate 1a and H2O at 130 °C after
48 h to furnish the target product 4 in 33% yield (Table 1,
entry 11). It is noteworthy that the structure of 3 was
unambiguously confirmed by the X-ray single-crystal diffraction
analysis.15
Spirocycles, particularly the primary N-containing spirocycle
products described in this paper, are found in numerous
biologically active molecules, such as the erythrina, amaryllida-
ceae, aspidosperma, and strychnos families (Figure 1).7 Efforts
to construct the core spirocyclic structure include intra-
molecular cyclization reactions, such as the radical cyclizations,8
electrophilic substitution cyclizations on N-acyliminium inter-
mediates or Pummerer-induced cyclizations,9 transition metal-
mediated cyclization reactions (often Heck reactions),10,11 and
anionic substitution reactions.12 However, many methods are
restricted to relatively harsh reaction conditions, inaccessible
substrates, and/or expensive catalytic systems. Access to this
class of compounds by the intramolecular electrophilic ipso-
cyclization of arylalkynes would have advantages over the
reported strategies because it would allow for easy variation of
the aromatic component and introduction of new groups on
Figure 1. Representative biologically active spirocycles with curare-like, hypnotic, sedative, hypotensive, neuromuscular blocking, and CNS activity.
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a
Table 1. Screening Optimal Conditions
entry
X+
H2O (mmol)
T (°C)
time (h)
isolated yield (%)
1
2
3
4
5
6
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NIS
NIS
NCS
NCS
ICl
16.7
11.1
5.6
2.8
1.5
2.8
2.8
2.8
2.8
2.8
2.8
2.8
2.8
2.8
2.8
2.8
120
120
120
120
120
80
24
24
24
24
24
24
24
8
35 (2)
68 (2)
64 (2)
76 (2)
56 (2)
35 (2)
trace (2)
73 (3)
50 (3)
26 (4)
33 (4)
30 (3)
5 (3)
b
7
120
120
60
c
8
c
9
8
10
11
12
13
14
120
130
120
rt
24
48
24
24
24
24
24
ICl
I2
120
rt
trace (3)
21 (3)
trace (2)
d
15
I2
e
16
CuBr
120
a
b
c
Reaction conditions: 1a (0.3 mmol), X+ (1.5 equiv), H2O, and MeCN (1 mL). K2CO3 (2 equiv). NIS (2 equiv) was averagely added two times in
d
e
3 h. NaHCO3 (2 equiv) was added. CuBr (3 equiv) combined with 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate (1.5 equiv) was added.
With the optimal reaction conditions in hand, the scope of 4-
(p-substituted aryl)-1-alkynes for the ipso-cyclization reaction
was explored (Table 2). The results demonstrated that several
substituents, including aryl or aliphatic groups, at the terminal
alkyne of propiolamide were tolerated well, and the order of
substituent reactivity was electron-rich aryl groups and aliphatic
groups > electron-deficient aryl groups (Table 2, entries 1−6).
4-Methoxyaryl-substituted substrate 1c, for instance, was
treated with NBS to give the desired product 6 in 75% yield
(Table 2, entry 2). However, the reactivity of 4-nitroaryl alkyne
1e was lowered, affording the corresponding 9 in 52% yield
(Table 2, entry 5). It was noted that moderate yields were
obtained from the reaction of substrate 1d with either NBS or
NIS in the presence of H2O (Table 2, entries 3 and 4).
Interestingly, a number of functional groups, such as methyl,
chloro, bromo, and iodo groups, on the aryl moiety of N-
arylpropiolamides 1g−1l were compatible with the optimal
conditions (Table 2, entries 7−14). For example, substrate 1h
with an ortho-methyl group was treated with either NBS or NIS
smoothly, furnishing the corresponding products 13 and 14 in
83% and 65% yields, respectively (Table 2, entries 9 and 10).
Good yields were still achieved from the reactions of substrates
1j−1l with an ortho-chloro, bromo, or iodo groups (Table 2,
entries 12−14). Gratifyingly, the analogous amides with the N-
methyl group replaced by either a benzyl or a 2-iodobenzyl
group were also suitable substrates to selectively afford the
corresponding 1-azaspiro[4.5]deca-3,6,9-triene-2,8-diones 19−
21 in good yields (Table 2, entries 15−17).
acetoxy-susbtituted substrate 1q, a moderate yield was still
achieved (Table 2, entry 20). We were pleased to discover that
aliphatic alkyne 1r was also successful for the ipso-cycylzation
with NBS (Table 2, entry 21). Subsequently, substitutents on
the N-aryl ring were investigated in the presence of NBS and
H2O (Table 2, entries 22−25). While the electron-donating
groups, methyl or methoxy group, on the aryl moiety of N-(2-
halobenzyl)-N-arylpropiolamide were suitable for the reaction
(Table 2, entries 22 and 23), the fluoro or iodo group on the N-
aryl moiety led to low yields (Table 2, entries 24 and 25). The
results disclosed that substrates 1w and 1x, having a Me or
MeO group, on the aromatic ring of the N-(2-iodobenzyl)
moiety could furnish the target products 30 and 31 in good
yields (Table 2, entries 26 and 27). Interestingly, a heterocycle
was introduced into this system, which also makes this
methodology more useful for the preparation of pharmaceut-
icals and natural products (Table 2, entry 28). Notably, two
substrates 1aa and 1ab, an amine and an ester, were also
evaluated, and the results showed that they were consistent
with the optimal conditions (Table 2, entries 30 and 31).
Intramolecular Heck Reaction of 3-Halo-1-(2-haloben-
zyl)-4-substituted-1-azaspiro[4.5]deca-3,6,9-triene-2,8-
diones. The Heck reaction is one the most important methods
for the formation of the carbon−carbon bond.11 To construct
the azaquaternary tricyclic skeleton, the product 20, 3-bromo-1-
(2-iodobenzyl)-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-
dione, was employed to screen the optimal reaction conditions
for the intramolecular Heck reaction (Table 3). We found that
additives played important roles in the selectivity of the Heck
reaction: while treatment of substrate 20 with Pd(OAc)2 and
Et3N afforded two azaquaternary tricyclic products 36 and 37
in 17% and 18% yields, respectively (Table 3, entry 1), TBAB
shifted the selectivity toward 37 with a 61% yield together with
20% yield of 36 (Table 3, entry 2). We were surprised to
disclose that Pd3(dba)2 and Pd(PPh3)4 have no catalytic activity
These encouraged us to examine the substituent effect on N-
(2-halobenzyl)-N-arylpropiolamides 1o−1z (Table 2, entries
18−29). Screening revealed that the optimal conditions were
consistent with various substituents at the terminal propiola-
mide (Table 2, entries 18−21). Substrate 1p with an ortho-
MeO group, for instance, offered the desired product 23 in 57%
yield (Table 2, entry 19). Using electron-withdrawing 4-
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a
Table 2. Intramolecular ipso-Halocyclization of 4-(p-Unsubstituted-aryl)-1-alkynes (1)
a
b
Reaction conditions: 1 (0.3 mmol), E+ (1.5 equiv), H2O (2.8 mmol), and MeCN (1 mL) at 120 °C for 24 h under argon atmosphere. Isolated
c
d
yield. NIS (2 equiv) was averagely added two times in 3 h, and the reaction was then carried out for another 8 h. For 48 h.
for the Heck reaction (Table 3, entries 3 and 4). Interestingly,
the product 37 was obtained alone in 80% yield using the
PdCl2(PPh3)2/TBAB/Et3N system (Table 3, entry 5).
revealed that Pd(OAc)2 combined with PPh3 and TBAB was
inferior to the PdCl2(PPh3)2/TBAB/Et3N system (Table 3,
entry 8). To our delight, the selectivity was shifted toward the
product 36 when the Pd(OAc)2/PPh3/NaHCO3 system was
used (Table 3, entry 9). However, two other inorganic bases,
i
However, two other amine bases, Pr2NH and n-Bu3N, were
less effective than Et3N (Table 3, entries 6 and 7). Screening
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a
Table 3. Screening Optimal Conditions for the Intramolecular Heck Reaction
b
isolated yield (%)
36
17
entry
[Pd] (mol %)
additive (equiv)
TBAB (1)
base (equiv)
time (h)
37
18
1
Pd(OAc)2 (5)
Pd(OAc)2 (5)
Pd3(dba)2 (5)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
Et3N (2)
iPr2NH (2)
Bu3N (3)
Et3N (2)
1.5
1.5
1.5
1.5
12
2
20
trace
trace
trace
trace
trace
5
61
trace
trace
80
3
TBAB (1)
4
Pd(PPh3)4 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
PdCl2(PPh3)2 (5)
Pd(OAc)2 (5)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
TBAB (1)
5
TBAB (1)
6
TBAB (1)
12
40
7
TBAB (1)
12
14
8
TBAB (1)/PPh3 (0.1)
PPh3 (0.2)
PPh3 (0.2)
PPh3 (0.2)
3
67
9
NaHCO3 (2)
Na2CO3 (2)
Cs2CO3 (2)
1.5
1.5
1.5
78
15
10
11
58
5
trace
trace
a
b
Reaction conditions: 20 (0.2 mmol), [Pd], additive, and base in DMF (1 mL) at 120 °C under argon atmosphere. Average yield in two runs.
Na2CO3 and Cs2CO3, lowered the reactivity of substrate 20
(Table 3, entries 10 and 11). Notably, the structure of 37 was
also unambiguously confirmed by the X-ray single-crystal
diffraction analysis.15
It is noteworthy that the above azaquaternary tricyclic
products are still useful synthetic blocks because there are
several functional groups, such as olefinic or bromo groups, in
them. To verify it, the cross-coupling reactions of the
azaquaternary tricyclic product 37 were investigated (Scheme
4).16 The Sonogashira reaction of substrate 37 with phenyl-
acetylene was conducted smoothly in 54% yield using the
PdCl2(PPh3)2/CuI catalytic system and Et3N/THF as the
media.16a−c Under our reported conditions, substrate 37 was
reacted with p-tolylboronic acid or tert-butyl acrylate to afford
the corresponding Suzuki product 51 or Heck product 52 in
excellent yields.16d
Consequently, the intramolecular Heck reaction was
conducted in the presence of PdCl2(PPh3)2, TBAB, and
Et3N, and the results are summarized in Table 4. The results
demonstrated that substituents on the five-memebered ring
affected the reaction. Substrate 21 bearing a 3-iodo group gave
a trace of the desired product 38 in the presence of
PdCl2(PPh3)2, TBAB, and Et3N (Table 4, entry 1), whereas
substrates with a 3-bromo group were suitable for the
intramolecular Heck reaction (Table 4, entries 2−11).
Although 3-bromospirotrienones 22, 24, and 25 could
successfully undergo the reaction, substituents at the 4-position
have some effect on the yields: aryl group > aliphatic group
(Table 4, entries 2−4). Subsequently, the effect of the
substituents on the six-memebered ring was also examined
under the standard conditions (Table 4, entries 5−8). In the
presence of PdCl2(PPh3)2, TBAB, and Et3N, substrates 26−28
with a methyl or fluoro group at the 7-position gave the
corresponding azaquaternary tricyclic products in good yields
(Table 4, entries 5−7). However, substrate 29, having an iodo
group in the six-memebered ring moiety, offered the desired
product 45 in a low yield (Table 4, entry 8). Substrate 31,
bearing a methoxy group, on the 2-iodobenzyl moiety was
reacted with PdCl2(PPh3)2, TBAB, and Et3N smoothly in
moderate yield (Table 4, entry 9). Using a heterocycle-
contained substrate 32, moderate yield was still achieved (Table
4, entry 10). Notably, 2-bromobenzyl 1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (33) could be cyclized in 71% yield after
prolonging the reaction time using the PdCl2(PPh3)2/TBAB/
Et3N system (Table 4, entry 11).
Mechanistic Investigation 18O-Labeling Experi-
ments.13 Fanghanel and Larock independently have proposed
̈
a possible mechanism for the ipso-cyclization of 4-(4-
methoxyaryl)-1-alkynes.3a,b The main difference is the oxygen
atom source of the ketone group in spiro[4,5]trienones: from
water or the existing MeO group.
To elucidate the mechanism, 18O-labeling experiments as
listed in Scheme 5 were conducted in the presence of H218O
under five types of reaction conditions including conditions A:
NBS in MeCN at 120 °C; conditions B: NIS in MeCN at 120
°C; conditions C: NIS in MeCN at room temperature;
conditions D (Larock’s conditions): I2 and NaHCO3 in MeCN
at room temperature; and conditions E (Larock’s conditions):
ICl in CH2Cl2 at −78 °C. Notably, the 18O-labeling results
were determined by GC−MS analysis. In the presence of
H218O, the electrophilic ipso-cyclization of N-methyl-N,3-
diphenylpropiolamide (1a) with NBS or NIS afforded the
18O-labeled product (conditions A and B). Identical results
were obtained from N-(4-methoxyphenyl)-N-methyl-3-phenyl-
propiolamide (1ac) under conditions A−D, in which both the
cleavage of C−OMe bond and a new C−O bond-forming take
place. However, no 18O-labeled product was observed when
substrate 1ac was reacted with ICl in the presence of H218O
(conditions E). To verify these results, another substrate 1ad,
1,1,1-trifluoro-N-(4-methoxyphenyl)-N-(3-phenylprop-2-ynyl)-
methanesulfonamide, was tested with H218O under conditions
A, B, D, and E. The results showed that the 18O-labeled
As shown in Scheme 3, another azaquaternary tricyclic
skeleton was constructed in the presence of Pd(OAc)2, PPh3,
and NaHCO3. The results demonstrated that substrates 22 or
24 could react with Pd(OAc)2, PPh3, and NaHCO3 to afford
the corresponding products 48 and 49 in moderate yields.
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group in spiro[4,5]trienones depends on both substrates and
the reaction conditions.
Table 4. PdCl2(PPh3)2-Catalyzed Heck Reaction in the
Presence of TBAB and Et3N
a
Consequently, a possible mechanism outlined in Scheme 6
was proposed.4−6,14 Our experimental works showed that
substrate 1a, in which no para-methoxy group was contained,
could also undergo the intramolecular ipso-halocyclization and
lead to the ketone product 3. They isolated an unstable
intermediate, which was assigned to be intermediate F by GC−
MS analysis.17 DFT calculations supported the experiments
well.14 Intermediate F could be formed from the nucleophilic
attack of H2O to cation E via a transition state similar to TS2-X
with an activation energy of 18 kcal/mol.14 The following
oxidation of alcohol F to ketone 3 is the rate-limiting step of
the whole reaction, which requires an activation energy of 30
kcal/mol.
CONCLUSIONS
■
In summary, we have reported an efficient method for the
intramolecular ipso-halocyclization of 4-(p-unsubstituted-aryl)-
1-alkynes with halide electrophiles and water. This new method
allows numerous N-arylpropiolamides, N-(prop-2-ynyl)anilines,
and aryl propiolates to construct spiro[4,5]trienones in
moderate to excellent yields. Importantly, the products, 3-
halo spiro[4,5]trienones, are found in a wide range of
biologically active molecules, such as the erythrina, amaryllida-
ceae, aspidosperma, and strychnos families,4 and are valuable
intermediates for easy introduction of new groups on the
position of several preexisting functional groups (olefin and
halo groups) to generate their analogues with a new structural
feature for further elaboration. For example, the intramolecular
Heck reaction of these 3-halo spiro[4,5]trienones was carried
out for constructing the azaquaternary tricyclic skeleton. 18O-
labeling experiments have provided insight into the mechanism
of the real oxygen atom source of the ketone moiety in
spiro[4,5]trienones and show that the real oxygen atom source
depends on both substrates and the reaction conditions. Our
synthetic studies show that 4-aryl-1-alkynes with or without a
substituent on their para-position are consistent with the
optimal conditions, and their 3-halo spiro[4,5]trienone
products with several attractive functional groups display
some particular activities for introducing new groups. Addi-
tionally, the results of the GC−MS analysis demonstrate that 8-
hydroxy-3-iodo-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-
trien-2-one (F) is generated, and it can be readily converted
into the corresponding spiro[4,5]trienone (3). The computa-
tional studies predict these results and imply that this step is the
rate-limiting step. Overall, these studies further expand our
understanding of the intramolecular ipso-halocyclization proc-
ess and how each of these contributes to the protocols derived
from them.
EXPERIMENTAL SECTION
The solvent of recrystallization for products 3 and 37 is a mixtue of
ethyl acetate and hexane.
■
a
Reaction conditions: 1a (0.2 mmol), PdCl2(PPh3)2 (5 mol %), TBAB
(1 equiv), and Et3N (2 equiv) in DMF (1 mL) at 120 °C under argon
Typical Experimental Procedure for the Selective Synthesis
1-Azaspiro[4.5]deca-3,6,9-triene-2,8-diones. To a Schlenk tube
were added amide 1 (0.2 mmol) and NBS (1.5 equiv), and then
CH3CN (1 mL) was added to the mixture at room temperature. Then
the tube was stirred at 120 °C (oil bath temperature) for the indicated
time until complete consumption of starting material as monitored by
TLC and GC−MS analysis. After the reaction was finished, the
reaction mixture was diluted in diethyl ether and washed with brine.
The aqueous phase was re-extracted with diethyl ether. The combined
organic extracts were dried over Na2SO4 and concentrated in vacuum,
b
c
atmosphere for 12 h. Average yield in two runs. For 48 h.
product was isolated under these conditions. Interestingly, one
16O atom of CF3SO2 group was also replaced by 18O under
conditions D. It was noted that the 18O-labeled product was
also obtained from the reaction of ester 1ae, 4-methoxyphenyl
3-phenylpropiolate, with H218O and I2 (conditions D). These
results indicate that the oxygen atom source of the ketone
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Scheme 3. Pd(OAc)2/PPh3-Catalyzed Heck Reaction
Scheme 4. Cross-Coupling Reactions of Compound 37
and the resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 4:1) to afford the
corresponding 1-azaspiro[4.5]deca-3,6,9-triene-2,8-diones.
(%) 377 (M+, 17), 250 (39), 129 (100); HRMS (EI) for C16H12INO2
(M+) calcd. 376.9913, found 376.9916.
3-Chloro-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (4).6a Pale yellow solid: mp 201.7−203.5 °C
Typical Experimental Procedure for the PdCl2(PPh3)2-
Catalyzed Heck Reaction. To a Schlenk tube were added amide
1-azaspiro[4.5]deca-3,6,9-triene-2,8-diones (0.2 mmol), PdCl2(PPh3)2
(0.01 mmol), TBAF (0.2 mmol), and Et3N (0.4 mmol), and then
DMF (1 mL) was added to the mixture at room temperature. Then
the tube was charged with Ar (1 atm) and was stirred at 120 °C (oil
bath temperature) for the indicated time until complete consumption
of starting material as monitored by TLC and GC−MS analysis. After
the reaction was finished, the reaction mixture was diluted in diethyl
ether and washed with brine. The aqueous phase was re-extracted with
diethyl ether. The combined organic extracts were dried over Na2SO4
and concentrated in a vacuum, and the resulting residue was purified
by silica gel column chromatography (hexane/ethyl acetate = 4:1) to
afford the corresponding products.
1
(uncorrected); H NMR (500 MHz) δ 7.48−7.46 (m, 2H), 7.42−
7.39 (m, 3H), 6.53 (s, 4H, spiro-ring-H), 2.93 (s, 3H); 13C NMR (125
MHz) δ 183.7, 165.2, 147.3, 144.4, 133.5, 130.4, 129.3, 128.8, 128.5,
127.8, 66.6, 26.4; IR (KBr, cm−1) 1706, 1671; LRMS (EI 70 eV) m/z
(%) 287 (M++2, 21), 285 (M+, 60), 25 (100); HRMS (EI) for
C16H12ClNO2 (M+) calcd. 285.0557, found 285.0560.
3-Bromo-1-methyl-4-p-tolyl-1-azaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (5). Pale yellow solid: mp 182.3−183.6 °C
1
(uncorrected); H NMR (500 MHz) δ 7.26−7.24 (m, 2H), 7.11 (d,
J = 8.0 Hz, 2H), 6.46−6.41 (m, 4H, spiro-ring-H), 2.86 (s, 3H), 2.28
(s, 3H); 13C NMR (125 MHz) δ 183.8, 165.9, 151.3, 144.4, 140.6,
133.4, 129.5, 127.6, 127.3, 119.2, 68.3, 26.6, 21.4; IR (KBr, cm−1)
1711, 1687; LRMS (EI 70 eV) m/z (%) 345 (M++2, 20), 343 (M+,
17), 264 (20), 143 (100); HRMS (EI) for C17H14BrNO2 (M+) calcd.
343.0208, found 343.0211.
3-Bromo-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (2).6a White solid: mp 163.5−164.1 °C (uncor-
1
rected); H NMR (500 MHz) δ 7.43−7.36 (m, 5H), 6.55−6.49 (m,
3-Bromo-4-(4-methoxyphenyl)-1-methyl-1-azaspiro[4.5]-
deca-3,6,9-triene-2,8-dione (6).6a White solid: mp 165.7−166.9 °C
(uncorrected); 1H NMR (500 MHz) δ 7.47−7.44 (m, 2H), 6.90−6.87
(m, 2H), 6.55−6.50 (m, 4H, spiro-ring-H), 3.81 (s, 3H), 2.92 (s, 3H);
13C NMR (125 MHz) δ 183.7, 165.9, 160.9, 150.5, 144.6, 133.1, 129.2,
4H, spiro-ring-H), 2.94 (s, 3H); 13C NMR (125 MHz) δ 183.7, 165.8,
151.3, 144.1, 133.5, 130.3, 130.2, 128.8, 127.8, 119.9, 68.3, 26.6; IR
(KBr, cm−1) 1701, 1670; LRMS (EI 70 eV) m/z (%) 331 (M++2, 14),
329 (M+, 15), 250 (45), 129 (100); HRMS (EI) for C16H12BrNO2
(M+) calcd. 329.0051, found 329.0054.
122.3, 118.2, 114.1, 68.0, 55.2, 26.4; IR (KBr, cm−1) 1713, 1667;
LRMS (EI 70 eV) m/z (%) 361 (M++2, 28), 359 (M+, 28), 280 (5.3),
159 (100); HRMS (EI) for C17H14BrNO3 (M+) calcd. 359.0157,
found 359.0160.
3-Iodo-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-
2,8-dione (3).6a Pale yellow solid: mp 195.5−197.3 °C (uncor-
1
rected); H NMR (500 MHz) δ 7.40−7.35 (m, 3H), 7.30−7.27 (m,
2H), 6.53−6.45 (m, 4H, spiro-ring-H), 2.96 (s, 3H); 13C NMR (125
MHz) δ 183.6, 167.3, 157.9, 144.0, 133.2, 131.8, 130.0, 128.6, 127.6,
98.1, 70.3, 26.9; IR (KBr, cm−1) 1699, 1662; LRMS (EI 70 eV) m/z
4-(4-Acetylphenyl)-3-bromo-1-methyl-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (7). White solid: mp 177.1−179.0 °C
1
(uncorrected); H NMR (500 MHz) δ 7.96−7.94 (m, 2H), 7.50−
2843
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Scheme 5. 18O-Labeling Experiments in the presence of H218O
Scheme 6. Reaction Mechanism for Substrate 1a
7.48 (m, 2H), 6.55−6.49 (m, 4H, spiro-ring-H), 2.95 (s, 3H), 2.59 (s,
3H); 13C NMR (125 MHz) δ 197.0, 183.3, 165.3, 150.2, 143.6, 138.0,
134.6, 133.6, 128.5, 128.1, 121.1, 68.2, 26.7, 26.6; IR (KBr, cm−1)
1712, 1705, 1676; LRMS (EI 70 eV) m/z (%) 373 (M++2, 25), 371
(M+, 27), 292 (63), 171 (100); HRMS (EI) for C18H14BrNO3 (M+)
calcd. 371.0157, found 371.0160.
m/z (%) 376 (M++2, 14), 374 (M+, 15), 295 (100), 174 (70); HRMS
(EI) for C16H11BrN2O4 (M+) calcd. 373.9902, found 373.9905.
3-Bromo-1-methyl-4-pentyl-1-azaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (10). White solid: mp 111.1−113.2 °C (uncorrected);
1H NMR (500 MHz) δ 6.56 (d, J = 10.0 Hz, 2H, spiro-ring-H), 6.36
(d, J = 10.0 Hz, 2H, spiro-ring-H), 2.90 (s, 3H), 2.17−2.13 (m, 2H),
1.48−1.44 (m, 2H), 1.30−1.25 (m, 4H), 0.86 (t, J = 7.0 Hz, 3H); 13
C
4-(4-Acetylphenyl)-3-iodo-1-methyl-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (8).6a Pale yellow solid: mp 228.8−230.2 °C
NMR (125 MHz) δ 183.9, 166.0, 153.6, 144.5, 133.4, 119.1, 68.5, 31.6,
27.6, 27.0, 26.9, 22.0, 13.7; IR (KBr, cm−1) 1713, 1672; LRMS (EI 70
eV) m/z (%) 325 (M++2, 7), 323 (M+, 8), 244 (100); HRMS (EI) for
C15H18BrNO2 (M+) calcd. 323.0521, found 323.0524.
1
(uncorrected); H NMR (500 MHz) δ 7.95 (d, J = 8.0 Hz, 2H), 7.40
(d, J = 8.0 Hz, 2H), 6.53 (d, J = 10.0 Hz, 2H, spiro-ring-H), 6.48 (d, J
= 10.0 Hz, 2H, spiro-ring-H), 2.98 (s, 3H), 2.61 (s, 3H); 13C NMR
(125 MHz) δ 197.0, 183.3, 167.0, 156.8, 143.6, 138.0, 136.4, 133.5,
128.5, 128.1, 99.4, 70.3, 27.0, 26.6; IR (KBr, cm−1) 1706, 1702, 1670;
LRMS (EI 70 eV) m/z (%) 419 (M+, 17), 292 (36), 129 (29), 44
(100).
3-Bromo-1,7-dimethyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-
triene-2,8-dione (11). White solid: mp 187.1−189.6 °C (un-
corrected); 1H NMR (500 MHz) δ 7.33−7.29 (m, 5H), 6.40 (s,
2H, spiro-ring-H), 6.22 (s, 1H, spiro-ring-H), 2.86 (d, J = 6.0 Hz, 3H),
1.87 (s, 3H); 13C NMR (125 MHz) δ 184.5, 165.8, 151.7, 144.0,
140.7, 138.9, 133.2, 130.4, 130.1, 128.7, 127.8, 119.4, 68.9, 26.6, 15.9;
IR (KBr, cm−1) 1700, 1660; LRMS (EI 70 eV) m/z (%) 345 (M++2,
8), 343 (M+, 7), 264 (66), 129 (100); HRMS (EI) for C17H14BrNO2
(M+) calcd. 343.0208, found 343.0211.
3-Bromo-1-methyl-4-(4-nitrophenyl)-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (9). Pale yellow solid: mp 199.3−201.8 °C
1
(uncorrected); H NMR (500 MHz) δ 8.26 (d, J = 8.5 Hz, 2H), 7.59
(d, J = 9.0 Hz, 2H), 6.54 (s, 4H, spiro-ring-H), 2.98 (s, 3H); 13C NMR
(125 MHz) δ 183.0, 165.0, 149.0, 148.6, 143.3, 136.5, 134.0, 129.1,
124.0, 122.5, 68.2, 26.8; IR (KBr, cm−1) 1710, 1693; LRMS (EI 70 eV)
3-Iodo-1,7-dimethyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (12). Pale yellow solid: mp 172.7−174.8 °C
2844
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Article
(uncorrected); 1H NMR (500 MHz) δ 7.36−7.34 (m, 3H), 7.27−7.25
(m, 2H), 6.48−6.42 (m, 2H, spiro-ring-H), 6.29−6.27 (m, 1H, spiro-
ring-H), 2.94 (s, 3H), 1.92 (s, 3H); 13C NMR (125 MHz) δ 184.5,
167.3, 158.4, 143.9, 140.6, 138.8, 133.0, 132.1, 129.9, 128.6, 127.7,
97.7, 70.9, 26.9, 15.8; IR (KBr, cm−1) 1693, 1666; LRMS (EI 70 eV)
m/z (%) 391 (M+, 32), 264 (25), 129 (100); HRMS (EI) for
C17H14INO2 (M+) calcd. 391.0069, found 391.0072.
(76), 165 (45), 91 (100); HRMS (EI) for C22H16BrNO2 (M+) calcd.
405.0364, found 405.0367.
3-Bromo-1-(2-iodobenzyl)-4-phenyl-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (20).6a White solid: mp 145.7−147.3 °C
(uncorrected); 1H NMR (500 MHz) δ 7.74 (d, J = 7.5 Hz, 1H), 7.39−
7.31 (m, 6H), 7.28−7.27 (m, 1H), 6.98−6.94 (m, 1H), 6.36−6.33 (m,
2H, spiro-ring-H), 6.27−6.24 (m, 2H, spiro-ring-H), 4.76 (s, 2H); 13C
NMR (125 MHz) δ 183.8, 166.0, 152.3, 143.4, 139.6, 139.3, 133.0,
130.2, 130.0 (2C), 129.7, 128.7, 128.6, 128.5, 128.3, 127.8, 119.6, 99.5,
68.7, 49.8; IR (KBr, cm−1) 1720, 1699, 1667; LRMS (EI, 70 eV) m/z
(%) 406 (100), 404 (94), 297 (36), 129 (20), 90 (22); HRMS (EI) for
C22H15BrINO2 (M+) calcd. 530.9331, found 530.9334.
3-Bromo-1,6-dimethyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-
triene-2,8-dione (13). White solid: mp 193.3−195.4 °C (un-
1
corrected); H NMR (500 MHz) δ 7.42−7.40 (m, 3H), 7.40−7.38
(m, 2H), 6.54−6.49 (m, 2H, spiro-ring-H), 6.39 (m, 1H, spiro-ring-
H), 2.87 (s, 3H), 1.77 (s, 3H); 13C NMR (125 MHz) δ 184.4, 166.3,
152.6, 151.3, 144.4, 132.9, 132.2, 130.4, 130.0, 128.9, 127.5, 119.7,
70.4, 26.2, 17.7; IR (KBr, cm−1) 1708, 1660; LRMS (EI 70 eV) m/z
(%) 345 (M++2, 29), 343 (M+, 30), 264 (51), 129 (82), 44 (100);
HRMS (EI) for C17H14BrNO2 (M+) calcd. 343.0208, found 343.0211.
3-Iodo-1,6-dimethyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (14). Pale yellow solid: mp 167.3−169.7 °C
3-Iodo-1-(2-iodobenzyl)-4-phenyl-1-azaspiro[4.5]deca-3,6,9-
triene-2,8-dione (21). White solid: mp 187.2−189.4 °C (un-
1
corrected); H NMR (500 MHz) δ 7.74 (d, J = 8.0 Hz, 1H), 7.39−
7.32 (m, 4H), 7.28−7.20 (m, 3H), 6.99−6.93 (m, 1H), 6.35 (d, J =
10.0 Hz, 2H, spiro-ring-H), 6.22 (d, J = 10.0 Hz, 2H, spiro-ring-H),
4.76 (s, 2H); 13C NMR (125 MHz) δ 183.8, 167.4, 158.7, 143.3,
139.4, 138.8, 132.6, 131.5, 130.0, 129.6, 128.9, 128.4, 128.1, 127.6,
99.5, 97.7, 70.5, 49.9; IR (KBr, cm−1) 1703, 1667, 1618; LRMS (EI, 70
eV) m/z (%) 453 (24), 452 (100), 297 (20), 129 (36), 90 (21);
HRMS (EI) for C22H15I2NO2 (M+) calcd. 578.9192, found 578.9195.
3-Bromo-1-(2-iodobenzyl)-4-p-tolyl-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (22). White solid: mp 157.0−158.4 °C
1
(uncorrected); H NMR (500 MHz) δ 7.41−7.35 (m, 3H), 7.34−
7.31 (m, 2H), 6.48 (s, 2H, spiro-ring-H), 6.34 (s, 1H, spiro-ring-H),
2.87 (s, 3H), 1.76 (s, 3H); 13C NMR (125 MHz) δ 184.4, 167.9,
157.9, 152.4, 144.2, 132.8, 132.0, 131.6, 130.3, 128.8, 127.4, 97.9, 72.5,
26.5, 17.7; IR (KBr, cm−1) 1701, 1661; LRMS (EI 70 eV) m/z (%)
391 (M+, 12), 264 (52), 129 (100); HRMS (EI) for C17H14INO2 (M+)
calcd. 391.0069, found 391.0072.
1
(uncorrected); H NMR (500 MHz) δ 7.77−7.75 (m, 1H), 7.39−
7.36 (m, 1H), 7.32−7.28 (m, 1H), 7.22 (d, J = 8.0 Hz, 2H), 7.14 (d, J
= 8.0 Hz, 2H), 6.97−6.94 (m, 1H), 6.33 (d, J = 10.0 Hz, 2H, spiro-
ring-H), 6.27 (d, J = 10.0 Hz, 2H, spiro-ring-H), 4.75 (d, J = 4.5 Hz,
2H), 2.33 (s, 3H); 13C NMR (125 MHz) δ 184.0, 166.1, 152.2, 143.6,
140.6, 139.5, 139.3, 132.9, 130.0, 129.7, 129.3, 128.7, 127.6, 126.9,
119.0, 99.5, 68.6, 49.7, 21.4; IR (KBr, cm−1) 1716, 1671, 1634; LRMS
(EI, 70 eV) m/z (%) 420 (97), 418 (100), 311 (36), 143 (34), 90
(34); HRMS (EI) for C23H17BrINO2 (M+) calcd. 544.9487, found
544.9490.
3-Bromo-1,6,9-trimethyl-4-phenyl-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (15). White solid: mp 182.0−182.9 °C
1
(uncorrected); H NMR (500 MHz) δ 7.35−7.28 (m, 5H), 6.27 (s,
1H, spiro-ring-H), 6.18 (s, 1H, spiro-ring-H), 2.75 (s, 3H), 1.88 (s,
3H), 1.65 (s, 3H); 13C NMR (125 MHz) δ 185.1, 166.2, 152.3, 151.7,
140.2, 139.1, 131.9, 130.3, 130.2, 128.8, 127.5, 119.3, 71.0, 26.1, 17.4,
15.5; IR (KBr, cm−1) 1712, 1674; LRMS (EI 70 eV) m/z (%) 359
(M++2, 33), 357 (M+, 36), 278 (47), 129 (100); HRMS (EI) for
C18H16BrNO2 (M+) calcd. 357.0364, found 357.0367.
3-Bromo-6-chloro-1-methyl-4-phenyl-1-azaspiro[4.5]deca-
3-Bromo-1-(2-iodobenzyl)-4-(2-methoxyphenyl)-1-azaspiro-
3,6,9-triene-2,8-dione (16). White solid: mp 191.3−192.7 °C
[4.5]deca-3,6,9-triene-2,8-dione (23). White solid: mp 159.9−
1
1
(uncorrected); H NMR (500 MHz) δ 7.44−7.38 (m, 3H), 7.36−
161.2 °C (uncorrected); H NMR (500 MHz) δ 7.77−7.74 (m, 1H),
7.34 (m 2H), 6.68 (s, 1H, spiro-ring-H), 6.60 (d, J = 10.0 Hz, 1H,
spiro-ring-H), 6.53−6.51 (m, 1H, spiro-ring-H), 2.91 (s, 3H); 13C
NMR (125 MHz) δ 182.6, 166.0, 150.2, 150.0, 143.3, 133.1, 132.4,
130.5, 129.5, 128.9, 127.7, 121.4, 100.0, 71.4, 26.3; IR (KBr, cm−1)
1722, 1662; LRMS (EI 70 eV) m/z (%) 365 (M++2, 31), 363 (M+,
21), 284 (23), 129 (100); HRMS (EI) for C16H11BrClNO2 (M+)
calcd. 362.9662, found 362.9665.
3,6-Dibromo-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-
triene-2,8-dione (17). White solid: mp 205.6−208.0 °C (un-
corrected); 1H NMR (500 MHz) δ 7.44−7.40 (m, 5H), 6.94 (s,
1H, spiro-ring-H), 6.71 (d, J = 10.0 Hz, 1H, spiro-ring-H), 6.58−6.55
(m, 1H, spiro-ring-H), 2.92 (s, 3H); 13C NMR (125 MHz) δ 181.8,
165.9, 150.5, 143.7, 143.0, 137.2, 132.3, 130.4, 129.4, 128.8, 127.8,
121.4, 71.9, 26.3; IR (KBr, cm−1) 1716, 1670; LRMS (EI 70 eV) m/z
(%) 411 (M++2, 18), 409 (M+, 34), 330 (20), 328 (20), 249 (20), 129
(100); HRMS (EI) for C16H11Br2NO2 (M+) calcd. 406.9157, found
406.9160.
7.62−7.60 (m, 1H), 7.38−7.35 (m, 2H), 7.30−7.28 (m, 2H), 6.97−
6.94 (m, 1H), 6.84 (d, J = 8.5 HZ, 1H), 6.35 (d, J = 10.0 Hz, 2H,
spiro-ring-H), 6.29 (d, J = 10.0 Hz, 2H, spiro-ring-H), 4.74 (d, J = 4.0
Hz, 2H), 3.89 (s, 3H); 13C NMR (125 MHz) δ 183.7, 165.8, 160.8,
157.1, 150.1, 143.8, 131.4, 139.5, 139.1, 132.9, 132.8, 132.7, 129.9,
129.7, 129.3, 128.6, 128.0, 123.2, 119.3, 114.0, 111.8, 111.5, 99.5, 68.4,
56.2, 55.2, 49.6; IR (KBr, cm−1) 1712, 1663, 1626; LRMS (EI, 70 eV)
m/z (%) 436 (17), 434 (18), 217 (12), 40 (100); HRMS (EI) for
C23H17BrINO3 (M+) calcd. 560.9437, found 560.9440.
4-(4-Acetylphenyl)-3-bromo-1-(2-iodobenzyl)-1-azaspiro-
[4.5]deca-3,6,9-triene-2,8-dione (24). White solid: mp 159.0−
1
160.7 °C (uncorrected); H NMR (500 MHz) δ 7.97 (d, J = 8.0 Hz,
1H), 7.93 (d, J = 8.0 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.47−7.37 (m,
3H), 7.30−7.28 (m, 1H), 6.98−6.95 (m, 1H), 6.40 (d, J = 10.0 Hz,
2H, spiro-ring-H), 6.27 (d, J = 10.0, 2H, spiro-ring-H), 4.77 (s, 2H),
2.59 (s, 3H); 13C NMR (125 MHz) δ 196.9, 190.1, 183.4, 165.4,
151.1, 142.9, 142.8, 139.4, 138.9, 137.8, 134.3, 133.0, 132.9, 130.0,
129.7, 129.0, 128.6, 128.4, 128.3, 128.1, 99.5, 68.5, 49.7, 26.5; IR (KBr,
cm−1) 1716, 1699, 1683, 1654; LRMS (EI, 70 eV) m/z (%) 448 (18),
446 (74), 339 (27), 217 (21), 40 (100); HRMS (EI) for
C24H17BrINO3 (M+) calcd. 572.9437, found 572.9440.
3-Bromo-6-iodo-1-methyl-4-phenyl-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (18). White solid: mp 213.3-214.9 °C
1
(uncorrected); H NMR (500 MHz) δ 7.44−7.39 (m, 5H), 7.24 (s,
1H, spiro-ring-H), 6.82 (d, J = 10.0 Hz, 1H, spiro-ring-H), 6.62−6.59
(m, 1H, spiro-ring-H), 2.89 (s, 3H); 13C NMR (125 MHz) δ 180.6,
165.6, 151.1, 145.0, 143.2, 132.4, 130.4, 129.4, 128.8, 127.9, 123.9,
121.5, 72.7, 26.3; IR (KBr, cm−1) 1717, 1667; LRMS (EI 70 eV) m/z
(%) 457 (M++2, 60), 455 (M+, 62), 376 (43), 330 (12), 328 (12), 249
(38), 129 (100); HRMS (EI) for C16H11BrINO2 (M+) calcd.
454.9018, found 454.9021.
3-Bromo-1-(2-iodobenzyl)-4-methyl-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (25). White solid: mp 141.6−143.8 °C
1
(uncorrected); H NMR (500 MHz) δ 7.75 (d, J = 8.0 Hz, 1H),
7.33 (d, J = 7.0 Hz, 1H), 7.25 (t, J = 7.5 Hz, 1H), 6.98−6.94 (m, 1H),
6.33 (d, J = 10.0 Hz, 2H, spiro-ring-H), 6.22 (d, J = 10.0 Hz, 2H, spiro-
ring-H), 4.72 (s, 2H), 1.81 (s, 3H); 13C NMR (125 MHz) δ 183.8,
165.8, 150.6, 143.9, 139.4, 139.1, 132.6, 130.1, 129.6, 128.4, 118.3,
99.4, 68.4, 49.8, 12.2; IR (KBr, cm−1) 1720, 1669, 1683, 1654; LRMS
(EI, 70 eV) m/z (%) 344 (13), 342 (13), 169 (13), 40 (100); HRMS
(EI) for C17H13BrINO2 (M+) calcd. 468.9174, found 468.9177.
3-Bromo-1-(2-iodobenzyl)-6-methyl-4-phenyl-1-azaspiro-
[4.5]deca-3,6,9-triene-2,8-dione (26). White solid: mp 152.1−
1-Benzyl-3-bromo-4-phenyl-1-azaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (19).6a White solid: mp 140.9−142.1 °C (uncor-
1
rected); H NMR (500 MHz) δ 7.30−7.27 (m, 3H), 7.26−7.23 (m,
7H), 6.37−6.26 (m, 4H, spiro-ring-H), 4.59 (s, 2H); 13C NMR (125
MHz) δ 183.7, 165.9, 151.8, 144.1, 136.9, 132.5, 130.1, 130.0, 128.8,
128.5 (2C), 127.9, 127.8, 119.8, 68.7, 45.4; IR (KBr, cm−1) 1708,
1665; LRMS (EI 70 eV) m/z (%) 407 (M++2, 71), 405 (M+, 69), 193
1
153.2 °C (uncorrected); H NMR (500 MHz) δ 7.74 (d, J = 7.5 Hz,
2845
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1H), 7.49−7.47 (m, 1H), 7.39−7.34 (m, 5H), 7.29−7.26 (m, 1H),
6.95 (t, J = 7.5 Hz, 1H), 6.30−6.26 (m, 2H, spiro-ring-H), 6.19 (d, J =
10.0 Hz, 1H, spiro-ring-H), 4.90 (d, J = 15.5 Hz, 1H), 4.47 (d, J = 15.5
Hz, 1H), 1.63 (s, 3H); 13C NMR (125 MHz) δ 184.5, 166.6, 152.1,
151.4, 143.7, 139.3, 138.7, 132.7, 132.0, 130.3 (2C), 129.6, 128.7,
128.5, 127.4, 119.3, 99.6, 70.7, 49.4, 17.5; IR (KBr, cm−1) 1720, 1699,
1667; LRMS (EI, 70 eV) m/z (%) 420 (45), 418 (46), 311 (15), 90
(17), 40 (100); HRMS (EI) for C23H11BrINO2 (M+) calcd. 544.9487,
found 544.9490.
143.0, 141.6, 137.8, 133.2, 132.9, 131.9, 130.9, 130.2, 129.8, 128.6
(2C), 128.3, 127.7, 119.4, 116.8, 68.4, 41.8; IR (KBr, cm−1) 1716,
1699, 1683, 1654; LRMS (EI, 70 eV) m/z (%) 538 (12), 536 (12),
492 (23), 490 (40), 412 (13), 298 (15), 191 (18), 40 (100); HRMS
(EI) for C20H13BrINO2S (M+) calcd. 536.8895, found 536.8898.
3-Bromo-1-(2-bromobenzyl)-4-phenyl-1-azaspiro[4.5]deca-
3,6,9-triene-2,8-dione (33). White solid: mp 147.2−147.8 °C
1
(uncorrected); H NMR (500 MHz) δ 7.41 (d, J = 7.5, 1H), 7.37−
7.30 (m, 6H), 7.24 (t, J = 7.5 Hz, 1H), 7.12 (d, J = 7.5 Hz, 1H), 6.37
(d, J = 12.5, 2H, spiro-ring-H), 6.24 (d, J = 12.5 Hz, 2H, spiro-ring-H),
4.79 (s, 2H); 13C NMR (125 MHz) δ 183.6, 165.7, 152.0, 143.2,
136.0, 132.6(2C), 130.5, 130.0, 129.7, 129.5, 128.4(2C), 127.6, 123.8,
119.3, 68.4, 44.6; IR (KBr, cm−1) 1720, 1704, 1683, 1654; LRMS (EI,
70 eV) m/z (%) 406 (21), 404 (20), 297 (7), 129 (9), 40 (100);
HRMS (EI) for C22H15Br2NO2 (M+) calcd. 482.9470, found 482.9473.
3-Bromo-4-phenyl-1-trifluoromethanesulfonyl-1-azaspiro-
[4,5]-deca-3,6,9-trien-2,8-dione (34). White solid: mp 143.6−
144.9.1 °C (uncorrected); 1H NMR (500 MHz) δ 7.38−7.31 (m, 3H),
7.09−7.07 (m, 2H), 6.88 (d, J = 9.5 Hz, 2H, spiro-ring-H), 6.23 (d, J =
10.5 Hz, 2H, spiro-ring-H), 4.73 (s, 2H); 13C NMR (125 MHz) δ
183.5, 144.1, 138.2, 130.5, 129.6, 129.5, 129.1, 119.6 (d, J = 321.6 Hz,
1C), 118.4, 115.6, 74.1, 59.4; IR (KBr, cm−1) 1671, 1389; LRMS (EI
70 eV) m/z (%) 435 (M++2, 3), 432 (1), 302 (47), 300 (48), 221
(100); HRMS (EI) for C16H11BrF3NO3S (M+) calcd. 432.9595, found
432.9598.
3-Bromo-1-(2-iodobenzyl)-6,7-dimethyl-4-phenyl-1-
azaspiro[4.5]deca-3,6,9-triene-2,8-dione (27). White solid: mp
1
152.8−153.5 °C (uncorrected); H NMR (500 MHz) δ 7.72 (d, J =
5.0 Hz, 1H), 7.51 (d, J = 5.5 Hz, 1H), 7.45−7.29 (m, 6H), 6.93−6.92
(m, 1H), 6.30 (d, J = 15.0 Hz, 2H, spiro-ring-H), 4.66 (d, J = 15.0 Hz,
2H), 1.76 (s, 3H), 1.38 (s, 3H); 13C NMR (125 MHz) δ 184.1, 166.6,
152.7, 144.1, 142.9, 139.1, 139.0, 138.1, 131.9, 130.6, 130.1, 129.8,
129.5, 128.6 (2C), 128.5, 119.0, 99.6, 71.0, 49.3, 14.6, 11.6; IR (KBr,
cm−1) 1712, 1687, 1667; LRMS (EI, 70 eV) m/z (%) 434 (54), 432
(61), 325 (13), 129 (15), 40 (100); HRMS (EI) for C24H19BrINO2
(M+) calcd. 558.9644, found 558.9647.
3-Bromo-6-fluoro-1-(2-iodobenzyl)-4-phenyl-1-azaspiro-
[4.5]deca-3,6,9-triene-2,8-dione (28). White solid: mp 155.1−
1
156.7 °C (uncorrected); H NMR (500 MHz) δ 7.81 (d, J = 8.0 Hz,
1H), 7.43−7.30 (m, 5H), 7.22 (d, J = 7.5 Hz, 2H), 7.01 (s, 1H, spiro-
ring-H), 6.97 (d, J = 7.5 Hz, 1H), 6.42 (d, J = 7.0 Hz, 1H, spiro-ring-
H), 6.38−6.35 (m, 1H, spiro-ring-H), 4.96 (d, J = 15.0 Hz, 1H), 4.68
(d, J = 15.0 Hz, 1H); 13C NMR (125 MHz) δ 177.8, 165.6, 151.1
(2C), 143.8, 139.8, 139.0, 130.3, 130.2, 130.1, 129.9, 129.4, 128.9,
128.7, 127.7, 119.8, 108.3, 100.1, 71.4, 49.7; IR (KBr, cm−1) 1716,
1699, 1654; LRMS (EI, 70 eV) m/z (%) 532 (71), 530 (63), 423 (12),
217 (27), 40 (100); HRMS (EI) for C22H14BrFINO2 (M+) calcd.
548.9237, found 548.9240.
3-Bromo-6-methyl-4-phenyl-1-oxaspiro[4.5]deca-3,6,9-tri-
ene-2,8-dione (35). Pale yellow solid: mp 120.0−124.6 °C
1
(uncorrected); H NMR (500 MHz) δ 7.51−7.47 (m, 3H), 7.44−
7.41 (m, 2H), 6.64 (d, J = 10.0 Hz, 1H, spiro-ring-H), 6.43−6.41 (m,
1H, spiro-ring-H, spiro-ring-H), 6.29 (s, 1H, spiro-ring-H), 1.92 (s,
3H); 13C NMR (125 MHz) δ 184.1, 167.3, 159.7, 150.8, 141.9, 131.9,
131.5, 130.7, 129.1, 128.4, 127.2, 112.1, 84.9, 17.2; IR (KBr, cm−1)
1771, 1675; LRMS (EI 70 eV) m/z (%) 332 (M++2, 8), 330 (M+, 8),
251 (18), 129 (100); HRMS (EI) for C16H11BrO3 (M+) calcd.
329.9892, found 329.9895.
3-Bromo-7-iodo-1-(2-iodobenzyl)-4-phenyl-1-azaspiro[4.5]-
deca-3,6,9-triene-2,8-dione (29). White solid: mp 155.5−155.9 °C
1
(uncorrected); H NMR (500 MHz) δ 7.74 (d, J = 6.5 Hz,, 1H),
7.38−7.27 (m, 7H), 6.95 (s, 1H), 6.29−6.19 (m, 2H, spiro-ring-H),
5.98 (d, J = 12.0 Hz, 1H, spiro-ring-H), 4.86 (d, J = 15.5 Hz, 1H), 4.69
(d, J = 15.5 Hz, 1H); 13C NMR (125 MHz) δ 185.5, 185.3, 166.5,
166.1, 150.1, 139.6, 139.3, 137.8, 131.8, 130.3, 130.1, 129.7, 129.0,
128.7, 128.4, 127.5, 120.6, 114.1, 114.0, 99.2, 68.8, 68.6, 49.7; IR (KBr,
cm−1) 1720, 1699, 1683, 1659; LRMS (EI, 70 eV) m/z (%) 424 (100),
422 (94), 315 (24), 183 (17), 129 (21); HRMS (EI) for
C22H14BrI2NO2 (M+) calcd. 656.8297, found 656.8300.
6-Bromo-5-phenyl-2H-pyrrolo[2,1-e]phenanthridine-
2,7(9H)-dione (36).6a White solid: mp 208.5−211.9 °C (uncor-
1
rected); H NMR (500 MHz) δ 7.55−7.37 (m, 6H), 7.33−7.29 (m,
1H), 7.03 (d, J = 8.0 Hz, 2H), 6.75 (d, J = 9.5 Hz, 1H, spiro-ring-H),
6.39 (s, 1H, spiro-ring-H), 6.24 (d, J = 9.5 Hz, 1H, spiro-ring-H), 5.19
(d, J = 15.5 Hz, 1H), 4.17 (d, J = 15.5 Hz, 1H); 13C NMR (125 MHz)
δ 184.1, 171.3, 171.1, 157.1, 150.6, 145.9, 135.9, 132.6, 131.4, 131.0,
129.9, 129.1, 129.0, 128.8, 128.5, 128.3, 126.1, 124.9, 121.0, 72.1, 44.8;
IR (KBr, cm−1) 1716, 1703, 1671; LRMS (EI, 70 eV) m/z (%) 405
(M++2, 15), 403 (M+, 14), 324 (39), 129 (100); HRMS (EI) for
C22H14BrNO2 (M+) calcd. 403.0208, found 403.0211.
3-Bromo-1-(2-iodo-5-methylbenzyl)-4-phenyl-1-azaspiro-
[4.5]deca-3,6,9-triene-2,8-dione (30). White solid: mp 156.7−
1
157.8 °C (uncorrected); H NMR (500 MHz) δ 7.39−7.33 (m, 2H),
7.29−7.27 (m, 2H), 7.15 (t, J = 7.5 Hz, 1H), 7.07 (s, 1H), 7.01 (d, J =
7.0 Hz, 2H), 6.35 (d, J = 10.0 Hz, 2H, spiro-ring-H), 6.26 (d, J = 10.0
Hz, 2H, spiro-ring-H), 4.56 (s, 2H), 2.30 (s, 3H); 13C NMR (125
MHz) δ 183.9, 165.9, 151.7, 144.2, 138.3, 136.7, 132.5, 130.1, 130.0,
129.6, 128.7, 128.6, 128.4, 127.8, 125.9, 119.9, 68.7, 45.4, 21.3; IR
(KBr, cm−1) 1716, 1699, 1650; LRMS (EI, 70 eV) m/z (%) 547 (18),
545 (17), 419 (14), 301 (25), 193 (16), 40 (100); HRMS (EI) for
C23H17BrINO2 (M+) calcd. 544.9487, found 544.9490.
6-Bromo-5-phenyl-1H-pyrrolo[2,1-e]phenanthridine-2,7-
(9H,13bH)-dione (37).6a White solid: mp 218.0−223.3 °C
1
(uncorrected); H NMR (500 MHz) δ 7.51−7.46 (m, 3H), 7.36−
7.34 (m, 2H), 7.23−7.17 (m, 4H), 6.55 (d, J = 10.0 Hz, 1H, spiro-ring-
H), 6.22 (d, J = 10.0 Hz, 1H, spiro-ring-H), 5.32 (d, J = 17.5 Hz, 1H),
4.37 (d, J = 17.0 Hz, 1H), 3.61 (s, 1H, spiro-ring-H), 2.91 (d, J = 16.5
Hz, 1H, spiro-ring-H), 2.25 (d, J = 16.5 Hz, 1H, spiro-ring-H); 13C
NMR (125 MHz) δ 195.1, 163.5, 155.6, 143.5, 134.9, 132.1, 132.0,
131.3, 130.0, 129.2, 127.8 (2C), 127.2, 126.9, 126.5, 120.4, 66.5, 41.3,
40.3, 39.1; IR (KBr, cm−1) 1716, 1663; LRMS (EI, 70 eV) m/z (%)
407 (M++2, 14), 405 (M+, 56), 326 (100), 298 (24), 129 (74); HRMS
(EI) for C22H16BrNO2 (M+) calcd. 405.0364, found 405.0367.
6-Iodo-5-phenyl-1H-pyrrolo[2,1-e]phenanthridine-2,7-
(9H,13bH)-dione (38). White solid: mp 210.6−214.7 °C (un-
3-Bromo-1-(2-iodo-5-methoxybenzyl)-4-phenyl-1-azaspiro-
[4.5]deca-3,6,9-triene-2,8-dione (31). White solid: mp 152.9−
1
154.7 °C (uncorrected); H NMR (500 MHz) δ 7.34−7.32 (m, 6H),
6.98 (s, 1H), 6.71−6.56 (m, 1H), 6.45 (d, J = 10.0 Hz, 2H, spiro-ring-
H), 6.28 (d, J = 10.0 Hz, 2H, spiro-ring-H), 4.74−4.70 (m, 2H), 3.75
(s, 3H); 13C NMR (125 MHz) δ 183.7 (2C), 165.8, 165.7, 159.9,
158.9, 152.1, 143.2, 139.8, 137.0, 133.2, 132.8, 132.7, 130.0, 128.4,
127.7, 119.3, 116.0, 115.3, 87.8, 68.5, 55.4, 44.7; IR (KBr, cm−1) 1716,
1703, 1675, 1654; LRMS (EI, 70 eV) m/z (%) 436 (96), 434 (100),
327 (26), 165 (21), 129 (35); HRMS (EI) for C23H17BrINO3 (M+)
calcd. 560.9437, found 560.9440.
1
corrected); H NMR (500 MHz) δ 7.49 (d, J = 13.5 Hz, 3H), 7.31−
7.17 (m, 6H), 6.52 (d, J = 10.0, 1H, spiro-ring-H), 6.21 (d, J = 10.0
Hz, 1H, spiro-ring-H), 5.34 (d, J = 17.5 Hz, 1H), 4.39 (d, J = 17.0 Hz,
1H), 3.60−3.59 (m, 1H, spiro-ring-H), 2.90 (d, J = 16.5 Hz, 1H, spiro-
ring-H), 2.21 (d, J = 16.5 Hz, 1H, spiro-ring-H); 13C NMR (125
MHz) δ 195.2, 165.0, 162.3, 143.7, 134.7, 134.2, 132.0, 131.4, 130.0,
129.2, 127.8, 127.7, 127.2, 127.0, 126.5, 99.2, 68.4, 41.2, 40.6, 39.2; IR
(KBr, cm−1) 1707, 1683; LRMS (EI, 70 eV) m/z (%) 454 (M++1, 24),
453 (M+, 99), 326 (70), 129 (100); HRMS (EI) for C22H16INO2 (M+)
calcd. 453.0226, found 453.0229.
3-Bromo-1-((3-iodothiophen-2-yl)methyl)-4-phenyl-1-
azaspiro[4.5]deca-3,6,9-triene-2,8-dione (32). White solid: mp
1
163.1−165.5 °C (uncorrected); H NMR (500 MHz) δ 7.42−7.28
(m, 6H), 7.05−7.00 (m, 1H), 6.42−6.29 (m, 4H, spiro-ring-H), 4.58−
4.47 (m, 2H); 13C NMR (125 MHz) δ 183.8, 165.7, 152.3, 143.1,
2846
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Article
6-Bromo-5-p-tolyl-1H-pyrrolo[2,1-e]phenanthridine-2,7-
(9H,13bH)-dione (39). White solid: mp 223.5−225.9 °C (un-
spiro-ring-H), 2.17 (d, J = 16.5 Hz, 1H, spiro-ring-H); 13C NMR (125
MHz) δ 194.4, 194.3, 168.8 (d, JC−F = 293.8 Hz), 163.8, 153.3, 131.4,
131.3, 131.0, 130.3, 129.4, 128.0, 127.6 (2C), 126.8, 126.7, 121.4,
115.4 (d, JC−F = 8.8 Hz), 66.9, 66.7, 40.6, 40.5, 40.2, 39.5; IR (KBr,
cm−1) 1732, 1761, 1683, 1654; LRMS (EI, 70 eV) m/z (%) 425
(M++2, 94), 423 (M+, 100), 344 (79), 324 (41), 129 (97); HRMS
(EI) for C22H15BrFNO2 (M+) calcd. 423.0270, found 423.0273.
6-Bromo-3-iodo-5-phenyl-1H-pyrrolo[2,1-e]phenanthridine-
2,7(9H,13bH)-dione (45). Pale yellow solid: mp 206.5−211.4 °C
1
corrected); H NMR (500 MHz) δ 7.28 (d, J = 8.0 Hz, 2H), 7.24−
7.15 (m, 6H), 6.54 (d, J = 10.0, 1H, spiro-ring-H), 6.22 (d, J = 10.0
Hz, 1H, spiro-ring-H), 5.32 (d, J = 17.5 Hz, 1H), 4.37 (d, J = 17.5 Hz,
1H), 3.59−3.58 (m, 1H, spiro-ring-H), 2.91 (d, J = 17.0 Hz, 1H, spiro-
ring-H), 2.42 (s, 3H), 2.31 (d, J = 17.0 Hz, 1H, spiro-ring-H); 13C
NMR (125 MHz) δ 195.3, 163.6, 155.7, 143.6, 140.3, 134.9, 132.1,
131.3, 129.9, 129.1, 127.8, 127.6, 127.2, 127.0, 126.5, 120.1, 66.5, 41.4,
40.3, 39.2, 21.4; IR (KBr, cm−1) 1716, 1699, 1654; LRMS (EI, 70 eV)
m/z (%) 421 (M++2, 58), 419 (M+, 58), 340 (90), 312 (22), 143
(100); HRMS (EI) for C23H18BrNO2 (M+) calcd. 419.0521, found
419.0524.
1
(uncorrected); H NMR (500 MHz) δ 7.53−7.47 (m, 3H), 7.35 (d, J
= 8.0, 2H), 7.23−7.17 (m, 3H), 6.54 (d, J = 10.0 Hz, 1H, spiro-ring-
H), 6.23 (d, J = 10.0 Hz, 1H, spiro-ring-H), 5.33 (d, J = 17.5 Hz, 1H),
4.38 (d, J = 17.0 Hz, 1H), 3.61−3.60 (m, 1H, spiro-ring-H), 2.91 (d, J
= 17.0 Hz, 1H, spiro-ring-H), 2.25 (d, J = 17.0, 1H, spiro-ring-H); 13C
NMR (125 MHz) δ 195.1, 163.5, 155.6, 143.5, 135.0, 132.2, 132.0,
131.3, 130.1, 129.2, 127.9, 127.8, 127.3, 127.0, 126.6, 120.5, 66.6, 41.4,
40.4, 39.2; IR (KBr, cm−1) 1716, 1703, 1683; LRMS (EI, 70 eV) m/z
(%) 534 (M++3, 3), 532 (M++1, 3), 407 (29), 405 (33), 326 (51), 129
(53), 43 (100); HRMS (EI) for C22H15BrINO2 (M+) calcd. 530.9331,
found 530.9334.
5-(4-Acetylphenyl)-6-bromo-1H-pyrrolo[2,1-e]-
phenanthridine-2,7(9H,13bH)-dione (40). White solid: mp
1
247.8−249.3 °C (uncorrected); H NMR (500 MHz) δ 8.07 (d, J =
8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.24−7.18 (m, 4H), 6.58 (d, J =
10.0, 1H, spiro-ring-H), 6.25 (d, J = 10.0 Hz, 1H, spiro-ring-H), 5.33
(d, J = 17.0 Hz, 1H), 4.39 (d, J = 17.0 Hz, 1H), 3.65−3.64 (m, 1H,
spiro-ring-H), 2.94 (d, J = 17.0 Hz, 1H, spiro-ring-H), 2.66 (s, 3H),
2.22 (d, J = 17.0 Hz, 1H, spiro-ring-H); 13C NMR (125 MHz) δ 197.0,
194.6, 163.1, 154.4, 143.2, 137.9, 136.8, 135.1, 132.0 (2C), 131.1,
129.0, 128.5, 128.3, 127.4, 126.6, 121.4, 66.6, 41.3, 40.4, 39.2, 26.6; IR
(KBr, cm−1) 1716, 1703, 1683; LRMS (EI, 70 eV) m/z (%) 449
(M++2, 71), 447 (M+, 59), 368 (100), 340 (26), 171 (49), 117 (58),
43 (71); HRMS (EI) for C24H18BrNO3 (M+) calcd. 447.0470, found
447.0473.
6-Bromo-11-methoxy-5-phenyl-1H-pyrrolo[2,1-e]-
phenanthridine-2,7(9H,13bH)-dione (46). White solid: mp
1
249.2−253.1 °C (uncorrected); H NMR (500 MHz) δ 7.48 (d, J =
13.5 Hz, 3H), 7.34 (d, J = 6.0 Hz, 2H), 7.13 (d, J = 9.0 Hz, 1H), 6.78
(d, J = 8.5 Hz, 1H), 6.67 (s, 1H), 6.52 (d, J = 10.0 Hz, 1H, spiro-ring-
H), 6.22 (d, J = 10.0 Hz, 1H, spiro-ring-H), 5.29 (d, J = 17.5 Hz, 1H),
4.33 (d, J = 17.0 Hz, 1H), 3.76 (d, J = 11.0 Hz,, 3H, spiro-ring-H),
3.56 (s, 1H), 2.86 (d, J = 17.0 Hz, 1H, spiro-ring-H), 2.22 (d, J = 17.0
Hz, 1H, spiro-ring-H); 13C NMR (125 MHz) δ 195.3, 163.5, 158.4,
155.7, 143.3, 134.9, 132.7, 132.2, 130.1, 129.2, 128.1, 127.8, 124.0,
120.3, 114.2, 111.0, 66.7, 55.3, 40.9, 40.5, 39.2; IR (KBr, cm−1) 1712,
1683, 1658; LRMS (EI, 70 eV) m/z (%) 437 (M++2, 61), 435 (M+,
63), 356 (100), 328 (21), 129 (56); HRMS (EI) for C23H18BrNO3
(M+) calcd. 435.0470, found 435.0473.
6-Bromo-5-methyl-1H-pyrrolo[2,1-e]phenanthridine-2,7-
(9H,13bH)-dione (41). White solid: mp 215.4−219.3 °C (un-
1
corrected); H NMR (500 MHz) δ 7.34 (d, J = 7.5 Hz, 1H), 7.28−
7.22 (m, 2H), 7.16 (d, J = 7.5 Hz, 1H), 6.28 (d, J = 10.0 Hz, 1H, spiro-
ring-H), 6.19 (d, J = 10.0 Hz, 1H, spiro-ring-H), 5.25 (d, J = 17.0 Hz,
1H), 4.32 (d, J = 17.5 Hz, 1H), 3.57−3.56 (m, 1H, spiro-ring-H), 3.38
(d, J = 17.5 Hz, 1H, spiro-ring-H), 3.25 (d, J = 17.5 Hz, 1H, spiro-ring-
H), 2.29 (s, 3H); 13C NMR (125 MHz) δ 194.8, 163.8, 153.4, 145.6,
134.0, 132.1, 131.4, 127.8, 127.3, 126.8, 126.6, 119.8, 65.9, 40.8, 40.3,
39.7, 15.0; IR (KBr, cm−1) 1707, 1683; LRMS (EI, 70 eV) m/z (%)
345 (M++2, 25), 343 (M+, 27), 264 (42), 236 (16), 43 (100); HRMS
(EI) for C17H14BrNO2 (M+) calcd. 343.0208, found 343.0211.
6-Bromo-4-methyl-5-phenyl-1H-pyrrolo[2,1-e]-
phenanthridine-2,7(9H,13bH)-dione (42). Pale yellow solid: mp
6-Bromo-5-phenyl-1H-pyrrolo[1,2-j]thieno[3,4-c]quinoline-
2,7(9H,12bH)-dione (47). White solid: mp 220.5−227.4 °C
1
(uncorrected); H NMR (500 MHz) δ 7.50−7.46 (m, 3H), 7.33−
7.31 (m, 2H), 7.24−7.23 (m, 1H), 6.83 (d, J = 5.5 Hz, 1H), 6.52 (d, J
= 10.5 Hz, 1H, spiro-ring-H), 6.25 (d, J = 10.5 Hz, 1H, spiro-ring-H),
5.29 (d, J = 17.0 Hz, 1H), 4.23 (d, J = 17.0 Hz, 1H), 3.73−3.72 (m,
1H, spiro-ring-H), 2.62 (d, J = 17.5 Hz, 1H, spiro-ring-H), 2.16 (d, J =
17.5 Hz, 1H, spiro-ring-H); 13C NMR (125 MHz) δ 194.1, 163.9,
154.9, 143.0, 134.8, 134.7, 131.8 (2C), 130.2, 129.2, 127.9, 125.8,
124.8, 120.1, 67.0, 41.1, 40.2, 39.1; IR (KBr, cm−1) 1716, 1703, 1683;
LRMS (EI, 70 eV) m/z (%) 413 (M++2, 55), 411 (M+, 51), 332 (64),
129 (33), 123 (100); HRMS (EI) for C20H14BrNO2S (M+) calcd.
410.9929, found 410.9932.
1
223.2−226.4 °C (uncorrected); H NMR (500 MHz) δ 7.48−7.38
(m, 4H), 7.22−7.18 (m, 5H), 6.12 (d, J = 4.5 Hz, 1H, spiro-ring-H),
5.35 (d, J = 17.5 Hz, 1H), 4.21 (d, J = 17.5 Hz, 1H), 3.66−3.65 (m,
1H, spiro-ring-H), 2.91 (d, J = 17.0 Hz, 1H, spiro-ring-H), 2.21 (d, J =
17.0 Hz, 1H, spiro-ring-H), 1.93 (s, 3H); 13C NMR (125 MHz) δ
194.8, 164.4, 155.7, 151.7, 133.6, 132.1, 131.9, 131.3, 130.8, 130.1,
129.2, 129.0, 128.5, 128.4, 128.0, 127.8, 127.5, 127.2, 126.7, 126.5,
126.1, 125.1, 120.2, 69.1, 41.7, 40.4, 38.8, 17.8; IR (KBr, cm−1) 1699,
1663; LRMS (EI, 70 eV) m/z (%) 419 (M+, 72), 404 (6), 340 (51),
129 (69), 43 (100); HRMS (EI) for C23H18BrNO2 (M+) calcd.
419.0521, found 419.0524.
6-Bromo-5-p-tolyl-2H-pyrrolo[2,1-e]phenanthridine-2,7(9H)-
dione (48). White solid: mp 225.2−229.4 °C (uncorrected); 1H
NMR (500 MHz) δ 7.51 (d, J = 7.5 Hz, 1H), 7.44−7.41 (m, 2H),
7.32−7.30 (m, 1H), 7.18 (d, J = 7.5 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H),
6.72 (d, J = 10.0 Hz, 1H, spiro-ring-H), 6.40 (s, 1H, spiro-ring-H),
6.23 (d, J = 10.0 Hz, 1H, spiro-ring-H), 5.18 (d, J = 15.5 Hz, 1H), 4.15
(d, J = 15.0 Hz, 1H), 2.36 (s, 3H); 13C NMR (125 MHz) δ 184.3,
171.5, 157.3, 150.8, 146.2, 140.2, 136.0, 132.8, 131.3, 131.0, 129.2
(2C), 129.0, 128.6, 126.2, 126.1, 124.9, 120.9, 72.2, 44.8, 21.4; IR
(KBr, cm−1) 1728, 1658; LRMS (EI, 70 eV) m/z (%) 419 (M++2, 13),
417 (M+, 11), 338 (25), 143 (100); HRMS (EI) for C23H16BrNO2
(M+) calcd. 417.0364, found 417.0367.
6-Bromo-3,4-dimethyl-5-phenyl-1H-pyrrolo[2,1-e]-
phenanthridine-2,7(9H,13bH)-dione (43). White solid: mp
1
214.2−216.3 °C (uncorrected); H NMR (500 MHz) δ 7.49−7.44
(m, 3H), 7.24−7.14 (m, 6H), 5.33 (d, J = 17.5 Hz, 1H), 4.11 (d, J =
17.5 Hz, 1H), 3.58−3.57 (m, 1H, spiro-ring-H), 2.94 (d, J = 16.5 Hz,
1H, spiro-ring-H), 2.21 (d, J = 16.5, 1H, spiro-ring-H), 1.84 (s, 3H),
1.77 (s, 3H); 13C NMR (125 MHz) δ 194.3, 164.3, 156.4, 143.9,
139.2, 132.3, 132.2, 131.5, 130.0, 129.2, 127.7, 127.4, 127.1, 126.7,
126.4, 119.9, 69.8, 41.2, 40.3, 38.5, 14.6, 12.1; IR (KBr, cm−1) 1699,
1650; LRMS (EI, 70 eV) m/z (%) 435 (M++2, 91), 433 (M+, 95), 354
(52), 129 (100), 115 (49); HRMS (EI) for C24H120BrNO2 (M+) calcd.
433.0677, found 433.0680.
5-(4-Acetylphenyl)-6-bromo-2H-pyrrolo[2,1-e]-
phenanthridine-2,7(9H)-dione (49). White solid: mp 245.0−247.1
1
°C (uncorrected); H NMR (500 MHz) δ 7.96 (d, J = 8.0 Hz, 2H),
7.52 (d, J = 7.5 Hz, 1H), 7.47−7.44 (m, 2H), 7.32 (d, J = 7.0 Hz, 1H),
7.15 (d, J = 8.0 Hz, 2H), 6.77 (d, J = 10.0 Hz, 1H, spiro-ring-H), 6.40
(s, 1H, spiro-ring-H), 6.27 (d, J = 10.0 Hz, 1H, spiro-ring-H), 5.20 (d,
J = 15.5 Hz, 1H), 4.18 (d, J = 15.5 Hz, 1H), 2.62 (s, 3H); 13C NMR
(125 MHz) δ 197.0, 184.0, 171.0, 156.1, 150.7, 145.6, 137.9, 135.9,
133.9, 132.5, 131.6, 131.2, 129.2 (2C), 128.6, 128.3, 126.2, 125.0,
121.7, 71.9, 44.9, 26.6; IR (KBr, cm−1) 1719, 1687, 1650; LRMS (EI,
70 eV) m/z (%) 447 (M++2, 56), 445 (M+, 61), 367 (53), 169 (76),
6-Bromo-4-fluoro-5-phenyl-1H-pyrrolo[2, 1-e]-
phenanthridine-2,7(9H,13bH)-dione (44). White solid: mp
1
206.2−210.9 °C (uncorrected); H NMR (500 MHz) δ 7.52 (d, J =
6.5 Hz, 3H), 7.31 (d, J = 6.0 Hz, 2H), 7.27−7.21 (m, 4H), 6.01 (d, J =
13.5 Hz, 1H, spiro-ring-H), 5.33 (d, J = 17.5 Hz, 1H), 4.32 (d, J = 17.5
Hz, 1H), 3.68−3.67 (m, 1H, spiro-ring-H), 2.93 (d, J = 16.5 Hz, 1H,
2847
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Article
129 (100); HRMS (EI) for C24H16BrNO3 (M+) calcd. 445.0314,
found 445.0317.
2011, 44, 27. (d) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev.
2011, 111, 2937.
5-Phenyl-6-(phenylethynyl)-1H-pyrrolo[2,1-e]-
(2) For selected recent papers on the electrophilic halogenocycliza-
tions of alkynes, see: (a) Stein, A. L.; da Rocha, J.; Menezes, P. He.;
Zeni, G. Eur. J. Org. Chem. 2010, 705. (b) Verma, A. K.; Aggarwal, T.;
Rustagi, V.; Larock, R. C. Chem. Commun. 2010, 4064. (c) Schumacher,
R. F.; Rosario, A. R.; Souza, A. C. G.; Menezes, P. H.; Zeni, G. Org.
Lett. 2010, 12, 1952. (d) Huo, Z.; Gridnev, I. D.; Yamamoto, Y. J. Org.
Chem. 2010, 75, 1266. (e) Zhang, X.; Yao, T.; Campo, M. A.; Larock,
R. C. Tetrahedron 2010, 66, 1177. (f) Chen, Y.; Cho, C.-H.; Shi, F.;
Larock, R. C. J. Org. Chem. 2009, 74, 6802. (g) Manarin, F.; Roehrs, J.
A.; Mozzaquatro Gay, R.; Brandao, R.; Menezes, P. H.; Nogueira, C.
W.; Zeni, G. J. Org. Chem. 2009, 74, 2153. (h) Mehta, S.; Waldo, J. P.;
Larock, R. C. J. Org. Chem. 2009, 74, 1141. (i) Chen, Y.; Cho, C.-H.;
Larock, R. C. Org. Lett. 2009, 11, 173. (j) Fischer, D.; Tomeba, H.;
Pahadi, N. K.; Patil, N. T.; Huo, Z.; Yamamoto, Y. J. Am. Chem. Soc.
2008, 130, 15720. (k) Wen, S.-G.; Liu, W.-M.; Liang, Y.-M. J. Org.
Chem. 2008, 73, 4342. (l) Xie, Y.-X.; Liu, X.-Y.; Wu, L.-Y.; Han, Y.;
Zhao, L.-B.; Fan, M.-J.; Liang, Y.-M. Eur. J. Org. Chem. 2008, 1013.
(m) Just, Z. W.; Larock, R. C. J. Org. Chem. 2008, 73, 2662. (n) Du,
H.-A.; Zhang, X.-G.; Tang, R.-Y.; Li, J.-H. J. Org. Chem. 2009, 74, 7844.
(o) Jiang, T.-S.; Zhang, X.-G.; Li, J.-H. Synthesis 2009, 3029.
(p) Crone, B.; Kirsch, S. F.; Umland, K.-D. Angew. Chem., Int. Ed.
2010, 49, 4661. (q) Majumdar, K. C.; Ansary, I.; Sinha, B.; Roy, B.;
Sridhar, B. Synthesis 2011, 3287. (r) Du, H.-A.; Tang, R.-Y.; Deng, C.-
L.; Liu, Y.; Li, J.-H.; Zhang, X.-G. Adv. Synth. Catal. 2011, 353, 2739.
(s) Ouyang, H.-C.; Tang, R.-Y.; Zhong, P.; Zhang, X.-G.; Li, J.-H. J.
Org. Chem. 2011, 76, 223. (t) Zora, M.; Kivrak, A.; Yazici, C. J. Org.
Chem. 2011, 76, 6726. (u) Chen, X.; Lu, P.; Wang, Y. Chem.Eur. J.
2011, 17, 8105. (v) Yang, F.; Ji, K.-G.; Zhu, H.-T.; Shaukat, A.; Liu, X.-
Y.; Liang, Y.-M. Chem.Eur. J. 2011, 17, 4986. (w) Ali, S.; Zhu, H.-T.;
Xia, X.-F.; Ji, K.-G.; Yang, Y.-F.; Song, X.-R.; Liang, Y.-M. Org. Lett.
2011, 13, 2598. (x) Yang, F.; Jin, T.; Bao, M.; Yamamoto, Y. Chem.
Commun. 2011, 47, 4541. (y) Ji, K.-G.; Zhu, H.-T.; Yang, F.; Shaukat,
A.; Xia, X.-F.; Yang, Y.-F.; Liu, X.-Y.; Liang, Y.-M. J. Org. Chem. 2010,
75, 5670. (z) Zhu, H.-T.; Ji, K.-G.; Yang, F.; Wang, L.-J.; Zhao, S.-C.;
Ali, S.; Liu, X.-Y.; Liang, Y.-M. Org. Lett. 2011, 13, 684. (aa) Likhar, P.
R.; Racharlawara, S. S.; Karkhelikara, M. V.; Subhasa, M. S.; Sridharb,
B. Synthesis 2011, 2407. (ab) Majumdar, K. C.; Ghosh, T.; Shyam., P.
K. Synlett 2011, 2657.
phenanthridine-2,7(9H,13bH)-dione (50). White solid: mp
1
208.8−209.7 °C (uncorrected); H NMR (500 MHz) δ 7.57−7.55
(m, 2H), 7.50−7.48 (m, 3H), 7.40−7.39 (m, 2H), 7.32−7.19 (m, 7H),
6.63 (d, J = 10.0 Hz, 1H, spiro-ring-H), 6.27 (d, J = 10.0 Hz, 1H, spiro-
ring-H), 5.35 (d, J = 17.0 Hz, 1H), 4.34 (d, J = 17.5 Hz, 1H), 3.56−
3.55 (m, 1H, spiro-ring-H), 2.93 (d, J = 17.0, 1H, spiro-ring-H), 2.44
(d, J = 17.0 Hz, 1H, spiro-ring-H); 13C NMR (125 MHz) δ 195.5,
165.2, 159.5, 134.8, 133.1, 132.5, 132.0, 131.6, 130.1, 129.1, 128.9,
128.2, 128.0, 127.8, 127.2, 127.1, 126.6, 122.1, 121.3, 98.5, 80.2, 71.8,
65.1, 41.9, 40.0, 39.3; IR (KBr, cm−1) 1716, 1695, 1683; LRMS (EI, 70
eV) m/z (%) 428 (M++1, 33), 427 (M+, 100), 398 (20), 370 (17), 356
(10), 202 (12), 115 (27); HRMS (EI) for C30H21NO2 (M+) calcd.
427.1572, found 427.1575.
5-Phenyl-6-p-tolyl-1H-pyrrolo[2,1-e]phenanthridine-2,7-
(9H,13bH)-dione (51). White solid: mp 193.7−195.1 °C (un-
1
corrected); H NMR (500 MHz) δ 7.37−7.35 (m, 3H), 7.28−7.18
(m, 8H), 7.03 (d, J = 8.0 Hz, 2H), 6.60 (d, J = 10.0 Hz, 1H, spiro-ring-
H), 6.22 (d, J = 10.0 Hz, 1H, spiro-ring-H), 5.37 (d, J = 17.5 Hz, 1H),
4.36 (d, J = 17.0 Hz, 1H), 3.66−3.65 (m, 1H, spiro-ring-H), 2.88 (d, J
= 17.0 Hz, 1H, spiro-ring-H), 2.28 (s, 3H), 2.22−2.17 (m, 1H, spiro-
ring-H); 13C NMR (125 MHz) δ 195.8, 167.3, 152.5, 145.6, 138.3,
134.4, 134.2, 134.0, 133.8, 133.0, 132.0, 129.4, 129.1, 128.8, 128.6,
128.5, 127.6, 127.2, 127.0, 126.6, 64.5, 41.4, 39.9, 39.4, 21.0; IR (KBr,
cm−1) 1695, 1679, 1613; LRMS (EI, 70 eV) m/z (%) 418 (M++1, 24),
417 (M+, 100), 389 (28), 360 (22), 115 (22); HRMS (EI) for
C29H23NO2 (M+) calcd. 417.1729, found 417.1732.
(E)-tert-Butyl 3-(2,7-Dioxo-5-phenyl-2,7,9,13b-tetrahydro-
1H-pyrrolo[2,1-e] phenanthridin-6-yl) Acrylate (52). Yellow
1
solid: mp 178.7−179.8 °C (uncorrected); H NMR (500 MHz) δ
7.50−7.45 (m, 3H), 7.36−7.20 (m, 7H), 7.19−7.08 (m, 1H), 6.51 (d, J
= 10.0 Hz, 1H, spiro-ring-H), 6.21 (d, J = 10.0 Hz, 1H, spiro-ring-H),
5.33 (d, J = 17.5 Hz, 1H), 4.33 (d, J = 17.0 Hz, 1H), 3.56−3.55 (m,
1H, spiro-ring-H), 2.89 (d, J = 17.0 Hz, 1H, spiro-ring-H), 2.23 (d, J =
17.0 Hz, 1H, spiro-ring-H), 1.46 (s, 9H); 13C NMR (125 MHz) δ
195.3, 166.4, 166.2, 158.5, 144.3, 134.8, 132.5, 132.1, 131.6, 131.3,
130.0, 129.5, 129.2, 128.3, 127.7, 127.2, 127.0 (2C), 126.6, 80.7, 71.8,
64.6, 41.4, 39.6, 39.0, 28.0; IR (KBr, cm−1) 1716, 1699, 1683; LRMS
(EI, 70 eV) m/z (%) 454 (M++1, 13), 453 (M+, 37), 397 (100), 380
(27), 352 (22), 324 (14), 115 (39); HRMS (EI) for C29H27NO4 (M+)
calcd. 453.1940, found 453.1943.
(3) For special papers, see: (a) Barluenga, J.; Vazquez-Villa, H.;
Ballesteros, A.; Gonzalez, J. M. J. Am. Chem. Soc. 2003, 125, 9028.
(b) Barluenga, J.; Vazquez-Villa, H.; Ballesteros, A.; Gonzalez, J. M.
Org. Lett. 2003, 5, 4121. (c) Barluenga, J.; Trincado, M.; Rubio, E.;
Gonzalez, J. M. Angew. Chem., Int. Ed. 2003, 42, 2406. (d) Barluenga,
J.; Trincado, M.; Rubio, E.; Gonzalez, J. M. Angew. Chem., Int. Ed.
2006, 45, 3140. (e) Barluenga, J.; Palomas, D.; Rubio, E.; Gonzalez, J.
M. Org. Lett. 2007, 9, 2823 and references cited therein.
ASSOCIATED CONTENT
■
S
* Supporting Information
Computational details, crystal data (CIF files), and copies of
spectra. This material is available free of charge via the Internet
at http://pubs.acs.org.
(4) Appel, T. R.; Yehia, N. A. M.; Baumeister, U.; Hartung, H.;
Kluge, R.; Strohl, D.; Fanghanel, E. Eur. J. Org. Chem. 2003, 47.
̈
̈
(5) (a) Zhang, X.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 12230.
(b) Li, C.-W.; Wang, C.-I.; Liao, H.-Y.; Chaudhuri, R.; Liu, R.-S. J. Org.
Chem. 2007, 72, 9203. (c) Okitsu, T.; Nakazawa, D.; Kobayashi, A.;
Mizohata, M.; In, Y.; Ishida, T.; Wada, A. Synlett 2010, 203.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jhli@hnu.edu.cn.
(6) (a) Tang, B.-X.; Yin, Q.; Tang, R.-Y.; Li, J.-H. J. Org. Chem. 2008,
73, 9008. (b) Yu, Q.-F.; Zhang, Y.-H.; Yin, Q.; Tang, B.-X.; Tang, R.-
Y.; Zhong, P.; Li, J.-H. J. Org. Chem. 2008, 73, 3658. (c) Tang, B.-X.;
Tang, D.-J.; Tang, S.; Yu, Q.-F.; Zhang, Y.-H.; Liang, Y.; Zhong, P.; Li,
J.-H. Org. Lett. 2008, 10, 1063. (d) Wang, Z.-Q.; Tang, B.-X.; Zhang,
H.-P.; Wang, F.; Li, J.-H. Synthesis 2009, 891.
(7) (a) Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.;
White, C. T. The Total Synthesis of Natural Products; Apsimon, J., Ed.;
Wiley-Interscience: New York, 1983; Vol. 5, p 264. (b) Yoneda, K.;
Yamagata, E.; Nakanishi, T.; Nagashima, T.; Kawasaki, I.; Yoshida, T.;
Mori, H.; Miura, I. Phytochemistry 1984, 23, 2068. (c) Sakamoto, K.;
Tsujii, E.; Abe, F.; Nakanishi, T.; Yamashita, M.; Shigematsu, N.;
Izumi, S.; Okuhara, M. J. Antibiot. 1996, 49, 37. (d) Biard, J. F.; Guyot,
S.; Roussakis, C.; Verbist, J. F.; Vercauteren, J.; Weber, J. F.; Boukef, K.
Tetrahedron Lett. 1994, 35, 2691. (e) Blackman, A. J.; Li, C.; Hockless,
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(No. 20872112 and 21172060) and Fundamental Research
Funds for the Central Universities (Hunan University) for
financial support.
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