Divergent reaction pathways of homologous and isosteric propargyl amides in sequential Ru/Pd-catalyzed annulations for the synthesis of heterocycles

Article abstract of DOI:10.1021/jo400246d

Cu-catalyzed three-component coupling of imines with benzoyl chloride and terminal arylalkynes followed by enyne ring-closing metathesis (RCM) and Heck cyclization afforded medicinally relevant benzoindolines, cyclopropane-fused indenopyridines, pyrroloquinolines, or 1,7-tetrahydrophenanthrolines via divergent cyclization pathways. Unexpectedly, the Pd-catalyzed cyclization of heterocyclic dienes proceeded via regiodivergent 5-exo or 6-endo pathways depending on the ring size (n = 1, 2) or the presence of isosteric groups (CH vs N). A one-pot protocol for the enyne-RCM/Heck annulation featuring a sequential addition of the Ru and Pd catalysts was developed maximizing the synthetic efficiency.

Full text of DOI:10.1021/jo400246d

Article
pubs.acs.org/joc
Divergent Reaction Pathways of Homologous and Isosteric Propargyl
Amides in Sequential Ru/Pd-Catalyzed Annulations for the Synthesis
of Heterocycles
Sandeep N. Raikar and Helena C. Malinakova*
Department of Chemistry, The University of Kansas, 1251 Wescoe Hall Drive, Lawrence, Kansas 66045, United States, and Center of
Excellence in Chemical Methodologies and Library Development, The University of Kansas, 2034 Becker Drive, Lawrence, Kansas
66047, United States
S
* Supporting Information
ABSTRACT: Cu-catalyzed three-component coupling of imines
with benzoyl chloride and terminal arylalkynes followed by enyne
ring-closing metathesis (RCM) and Heck cyclization afforded
medicinally relevant benzoindolines, cyclopropane-fused indenopyr-
idines, pyrroloquinolines, or 1,7-tetrahydrophenanthrolines via
divergent cyclization pathways. Unexpectedly, the Pd-catalyzed
cyclization of heterocyclic dienes proceeded via regiodivergent 5-
exo or 6-endo pathways depending on the ring size (n = 1, 2) or the
presence of isosteric groups (CH vs N). A one-pot protocol for the
enyne−RCM/Heck annulation featuring a sequential addition of the Ru and Pd catalysts was developed maximizing the synthetic
efficiency.
cyclizations has been controlled by steric effects of substituents
on the vinyl component9 or distinct conformational preferences
of the substrates.10 Alternatively, the regiocontrol was achieved
by the choice of the catalyst composition11 or by trapping of
the product of 5-exo cyclization under reductive Heck
conditions.12 In our system, the structural features of the
homologous and isosteric substrates determine whether the 5-
exo or the 6-endo carbopalladation step leads to a synthetically
productive pathway. The efficiency of the synthetic protocol
described herein was maximized by uncovering reaction
conditions that allowed for the Ru-catalyzed enyne RCM and
the Pd(0)-catalyzed Heck reaction to be performed for the first
time as a one-pot operation via a sequential addition of the
transition metal catalysts. Sequences of Ru-catalyzed meta-
theses and Pd-catalyzed C−C bond-forming reactions,
including Tsuji−Trost reaction, cross-coupling, and the Heck
reaction, have been utilized in synthesis in the past.13 However,
only Trost and Grigg investigated the possibility of combining
the two catalytic reactions into one-step processes. Trost
described a one-pot enyne cross-metathesis (CM) followed by
an enantioselective Tsuji−Trost allylation involving a sequen-
tial addition of the Ru and Pd catalysts for the preparation of N-
and O-heterocycles.13f Grigg identified the difficulties arising
from interactions of the components of the catalytic systems
when diene RCM and the Heck annulations were performed in
one pot with both sequential and concomitant additions of the
two catalysts.14 Notably, when challenging RCM reactions were
involved, low yields of the heterocycles resulted both from the
INTRODUCTION
■
An important goal of the current synthetic organic chemistry is
to maximize the efficiency of methodologies for the preparation
of complex structures.1 In the search for the “ideal synthesis”,
much effort has been directed toward improving the “step
economy”2 by the application of multicomponent reactions3
and by performing sequences of reactions as one-pot
operations.4 This task has proven to be particularly difficult
when transition-metal-catalyzed reactions were involved due to
the likelihood of catalyst poisoning in complex reaction
mixtures.5 The recent advances in diversity-oriented synthesis
underscore the value of divergent synthetic pathways that can
be used to construct libraries of compounds with multiple
distinct core structures.6 Herein, we describe a divergent
methodology that delivers structurally distinct N-heterocycles
by applying multicomponent reactions3 and one-pot sequential
transition-metal-catalyzed transformations to homologous and
isosteric7 substrates (Figure 1).
Cu(I)-catalyzed coupling of imines, acyl chlorides, and
alkynes8 afforded enynes I that were subjected to Ru(II)-
catalyzed ring-closing metathesis (RCM) and Pd(0)-catalyzed
Heck annulation, unexpectedly yielding either benzoindolines
III or cyclopropane-fused tetrahydroindenopyridines IV via
divergent 6-endo and 5-exo Heck cyclization pathways,
respectively, depending on the ring size (Figure 1). The course
of the Heck cyclization was altered by the presence of the
additional N-heteroatom in enynes I (X = N) delivering
pyrroloquinolines V and 1,7-tetrahydrophenanthrolines VI via
6-endo Heck cyclization (Figure 1).
In previously reported studies, selectivity for possible
divergent 5-exo vs 6-endo pathways of various Heck
Received: February 6, 2013
Published: March 22, 2013
© 2013 American Chemical Society
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Scheme 1. Cu(I)-Catalyzed Three-Component Coupling and
RCM with Acroyl Chloride
Scheme 2. Cu(I)-Catalyzed Three-Component Coupling and
RCM with Benzoyl Chloride
Figure 1. Synthetic methodology.
sequential and concomitant catalyst additions. This problem
could only be addressed by a physical separation of the catalysts
using solid-supported or fluorous phase-localized Pd catalysts
for the Heck reactions.14
The one-pot sequential Ru/Pd-catalyzed protocol for the
annulation of enyne amides I described herein provides an
attractive and modular alternative to the synthetic methods
currently available for the preparation of benzoindolines III,
indenopyridines IV, pyrroloquinoline V, and 1,7-phenanthro-
lines VI and related heterocycles.15 The most relevant known
methods include Au-catalyzed annulation of diynes15a for
benzolindolines, sequential hetero-Diels−Alder/Friedel−Crafts
reaction15c yielding structures related to indenopyridines, and a
classical stepwise annulation of the pyrrolidine ring15f for the
synthesis of oxidized analogues of pyrroloquinolines. Hetero-
cycles III−VI represent druglike scaffolds16 potentially
endowed with valuable medicinal properties.17
a
b
Grubbs I catalyst was used Grubbs II catalyst was used.
O)NH(CH2)nCHCH2 (n = 1, 2) arising from a premature
hydrolysis of the N-acyliminium salts. In contrast to enyne 2,
the RCM reaction with amides 5a−8a under ethylene
atmosphere proceeded efficiently to afford dienes 9a−12a in
good yields (69−93%).18 The N-homoallylic analogs 6a and 8a
(n = 2) performed better in reactions catalyzed by the more
active Grubbs II catalyst (Scheme 1).19 The pyrrolidine
derivatives 9a and 11a (n = 1) proved to be somewhat
unstable and had to be used within 24 h, whereas the piperidine
analogues 10a and 12a (n = 2) were stable compounds.
Next, we explored pathways available for Pd-catalyzed
annulations of dienes 9a−12a (Scheme 3). The Heck
cyclization of dienes 9a−12a may proceed via the kinetically
favored 5-exo pathway20 or the 6-endo route20 generating an
allylpalladium intermediate.21 Initially, we anticipated that the
5-exo cyclization would be favored. To the contrary, catalysis of
the cyclization of diene 9a22 either with the ligandless catalyst
[conditions A: Pd(OAc)2, NaOAc]8a or with an added
phosphine [conditions B: Pd(OAc)2/PPh3/Cs2CO3]22 both
in DMF, afforded benzoindoline 13a in 71% and 73% yields,
respectively, pointing to the preference for 6-endo cyclization
(Scheme 3). The homologous diene 10a yielded cyclopropane-
fused indenopyridine 14a (55%) when treated under
RESULTS AND DISCUSSION
■
Method Development. We envisioned that properly
functionalized enynes incorporating the propargylic amide
functional group would provide useful substrates for diverse
sequences of transition-metal-catalyzed annulation reactions.
Seeking the ideal arrangement of the functional groups, the
Cu(I)-catalyzed coupling of N-benzylimine 1a, acroyl chloride
with phenylacetylene8 was used to prepare N-benzyl enyne 2
(58%) (Scheme 1). However, enyne 2 proved to be a
challenging substrate for the RCM reaction,18 providing low
yields of pyrrolidone 3 (23%) and cyclohexenenone 4 (35%)
(Scheme 1). Alternatively, N-allyl- and N-homoallylimines 1b−
e derived from 2-bromobenzaldehyde and 2-bromopyridine-3-
carbaldehyde afforded enyne amides 5a−8a (55−62%) via the
Cu-catalyzed coupling with benzoyl chloride and phenyl-
acetylene (Scheme 2). The moderate yields of enynes 5a−8a
were caused by the formation of amide byproducts PhC(
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pathway was disfavored by the N-heteroatom. The structures of
heterocycles 15a and 16a were assigned by NMR analyses and
X-ray crystallography on 16a.23
Scheme 3. Exploration of the Divergent Pathways in the
Heck Cyclizations
The observed reactivity of dienes 9a−12a suggests that the
divergent reaction pathways are not controlled by the choice of
the catalyst composition (conditions A vs B) but rather by the
structural features of the substrates. We propose that
intermediates A and D formed by oxidative addition of the
Pd(0) catalysts initially undergo kinetically favored 5-exo
cyclization20 (Figure 2).
The intermediate E (n = 2), which is less conformationally
restricted than the intermediate B (n = 1), rapidly undergoes 3-
exo cyclization giving rise to the cyclopropane ring24 in
a
b
Conditions A were used. Conditions B were used.
conditions A [Pd(OAc)2, NaOAc] and the indenopyridine 14a
(80%) accompanied by a separable benzoquinoline 17 (10%)
when treated under conditions B [Pd(OAc)2/PPh3/Cs2CO3]
(Scheme 3). The results indicate the operation of the 5-exo
pathway. The position of the phenyl substituent in benzoindo-
lines 13a and 17 and the relative stereochemistry in
indenopyridine 14a (vide infra) were established by X-ray
crystallography, utilizing an indenopyridine analogue 14b
prepared as shown in Table 1 (vide infra).23 The protocol
was successfully extended to the synthesis of pyridine-fused N-
heterocyclic cores (Scheme 3). Diene 11a (X = N, n = 1)
delivered the expected pyrroloquinoline 15a upon the treat-
ment under conditions A [Pd(OAc)2/NaOAc] or conditions B
[Pd(OAc)2/PPh3/Cs2CO3] in 77% and 78% yields, respec-
tively. Unexpectedly, diene 12a (X = N, n = 2) afforded
tetrahydro-1,7-phenanthroline 16a (65%) via the 6-endo
cyclization when treated under conditions B [Pd(OAc)2/
PPh3/Cs2CO3]. The application of conditions A [Pd(OAc)2,
NaOAc] for the reaction of diene 12a afforded the same
product 16a (49%), but the conversion of substrate 12a was
not complete (Scheme 3). Apparently, the 5-exo cyclization
Figure 2. Proposed mechanistic rationale.
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indenopyridines 14. Reversible ß-hydride elimination, H−
Pd(II) readdition, and β-carbon elimination25 from the
diastereomeric Pd-intermediate delivers the minor product
17. In contrast, the conformationally restricted pyrrolidine-
derived intermediate B (n = 1) engages in reversible
carbopalladation, ultimately affording intermediate C and
benzoindolines 13 or pyrroloquinolines 15 via 6-endo
cyclization. The diene intermediate H (n = 2) carrying the
additional N-heteroatom (X = N) also undergoes a fast 5-exo
cyclization. However, the chelation of the N-heteroatom to the
Pd(II) center in the intermediate G slows the 3-exo-trig
cyclization, directing the reversible carbopalladation toward the
6-endo cyclization yielding the intermediate I and ultimately
1,7-tetrahydrophenanthrolines 16.
Development of the One-Pot Protocol. To improve the
synthetic efficiency of the method, we sought to perform the
Ru- and Pd-catalyzed reactions as a one-pot operation. A
catalytic system that could realize both the RCM and the Heck
cyclizations in toluene was needed. Experimentation with
different bases and additives for the Heck reaction revealed that
achieving a good stability of the Pd catalyst by the addition of a
phosphine ligand and identifying a base with a sufficient
solubility in toluene were the critical factors. The solution to
this problem was found when we employed the original
conditions B [Pd(OAc)2/PPh3/Cs2CO3] (Scheme 4) for the
Pd-catalyzed annulation in toluene instead of DMF as the
solvent. The sequence of enyne−RCM/Heck reactions could
then be performed successfully in one-pot with a sequential
addition of the Ru and Pd catalysts via the series of operations
including (i) treatment of toluene solutions of the dienes 5a−
8a under an atmosphere of ethylene with the Grubbs I catalyst
for 2 h for the N-allylic substrates or with the Grubbs II catalyst
for 8 h for the N-homoallylic substrates; (ii) purging the
reaction mixtures with argon; (iii) addition of the solid
components of the Heck catalyst mixture [Pd(OAc)2, PPh3,
Cs2CO3]; (iv) heating the reactions mixtures at 120 °C for 15
h; (v) and finally purification of the crude products by flash
chromatography (Scheme 4). Using this one-pot protocol,
heterocycles 13a, 14a, and 15a were obtained in 69%, 75%, and
71% yields calculated per the enynes 5a, 6a, and 7a, respectively
(Scheme 4). The tetrahydrophenanthroline 16a was accom-
panied by residual diene 12a formed by the RCM reaction
(Schemes 3 and 4). The crude mixture of 16a and 12a was
easily separated by flash chromatography over silica, delivering
pure tetrahydrophenanthroline 16a in 61% yield calculated per
the enyne 8a (Scheme 4). The one-pot protocol provides for
more economical syntheses by avoiding the expense of time,
silica, and solvents involved in chromatographic purification of
the RCM products 9a, 10a, 11a, and 12a. The most significant
improvements in the yields of the target heterocycles were
observed for the pyridine-derived pyrroloquinoline 15a (71%
from 7a) and tetrahydrophenanthroline 16a (61% from 8a)
when compared to the yields of 15a (53% from 7a, difference
of 18%) and 16a (44% from 8a, difference of 17%) calculated
from the yields of the two sequential reactions reported in
Schemes 2 and 3. Elimination of the material loss during the
chromatographic purification of dienes 11a (69% yield via
RCM) and 12a (69% yield via RCM) appears to be largely
responsible for the success of the one-pot protocol for the
preparation of heterocycles 15a and 16a. The improvement in
the yield of tetrahydrophenanthroline 16a in the one-pot
process despite the presence of unreacted diene 12a is notable.
The proposed involvement of the N−Pd chelation interactions
en route to 16a (Figure 2), as well as interferences of the RCM
catalytic system with the Pd-catalyst provide for a challenging
Heck cyclization process, and additional optimization may be
needed to finetune this protocol specifically for the preparation
of 1,7-phenanthrolines.
Scheme 4. Development of the One-Pot Protocol for
Sequential Ru/Pd-Catalyzed Annulations
Scope of the Synthetic Methodology. To assess whether
electronic effects may influence the regioselectivity of the Pd-
catalyzed annulations, as well as to evaluate the scope and
merits of the one-pot protocol, a series of substituted arylimines
1 (R1 = 4,5-OMe, 5-F) and terminal arylalkynes (R2 = 4-F, 4-
OMe) were employed in the described method using both the
two-step reaction sequence and the one-pot protocols (Table
1). The moderate yields of enynes 5−8 (45−58%) were caused
by the formation simple amides [PhC(O)NH(CH2)nCH
CH2)] arising via a premature hydrolysis of the N-
benzoyliminium ions. The enyne RCM reaction afforded
dienes 9a−e (63−93%) and 10a−e (80−92%) in good yields.
Lower yields of the RCM reaction providing the pyridine-
derived (X = N) dienes 11a,b (60−69%) and 12a−c (58−
69%) were caused by a strong retention of the products on the
silica column during the purification steps, emphasizing need
for the one-pot protocol. Enynes bearing the electron-rich p-
methoxyphenyl substituent afforded the lowest yields in the
RCM reactions. In fact, the diene bearing substituents X = N, n
= 1, R1 = H, R2 = OMe could not be efficiently prepared via
RCM in appreciable quantities. However, the subsequent Heck
reaction on such diene (X = N, n = 1, R1 = H, R2 = OMe) was
found to be facile. In all the cases, the regioselectivity of the
Heck annulation uncovered in the original studies (Scheme 3)
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Table 1. Scope of the Two-Step and One-Pot Ru/Pd-Catalyzed Protocol
i
i
13−16 (%)
from 9−12
13−16 (%)
i
i
j
entry
1
n
X
R1
R2
5 − 8 (%) 9 − 12 (%)
from 5−8
yield increase in one pot (%)
1
1b
1f
1
1
1
1
1
2
2
2
2
2
1
1
2
2
2
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
N
H
H
5a (55)
5b (49)
5c (52)
5d (53)
5e (61)
6a (55)
6b (45)
6c (52)
6d (58)
6e (53)
7a (59)
7b (60)
8a (62)
8b (61)
8c (63)
9a (93)
13a (71)
13b (68)
13c (65)
13d (78)
13e (66)
14a (80)
14b (78)
14c (71)
14d (81)
14e (80)
15a (77)
13a (69)
+3
2
4,5-(OMe)2
H
9b (81)
9c (72)
3
1g
1b
1b
1c
1h
1i
5-F
H
13c (61)
+14
4
H
F
9d (87)
9e (63)
5
H
OMe
H
13e (64)
14a (75)
+22
+2
6
H
10a (92)
10b (87)
10c (88)
10d (85)
10e (80)
11a (69)
11b (60)
12a (69)
12b (62)
7
4,5-(OMe)2
H
8
5-F
H
H
H
H
H
H
H
H
14c (69)
+7
9
1c
1c
1d
1d
1e
1e
1e
F
10
11
12
13
14
15
OMe
H
14e (70)
15a (71)
+6
+18
k
N
F
15b (65)
N
H
16a (65)
16b (61)
16c (59)
16a (61) +12a (25%)
16b (56) +12b (29%)
+17
+18
N
F
N
OMe
12c (58)
a
b
Conditions A: CuCl (20 mol %), DIPEA (1.5 equiv), MeCN, rt, 1 h. Conditions B: Same as conditions A except for a reversed order of addition
c
d
and DIPEA (1.2 equiv). Conditions C: Grubbs I (Ru) (10 mol %), ethylene, toluene, 85 °C, 2 h. Conditions D: Same as conditions C except for
Grubbs II (Ru) (10 mol %) and 8 h. Conditions E: Pd(OAc)2 (10 mol %), NaOAc (1.1 equiv), DMF, 120 °C, 12 h. Conditions F: Pd(OAc)2 (10
mol %), Cs2CO3 (2.0 equiv), PPh3 (20 mol %), DMF, 120 °C, 15 h. Conditions G: One-pot protocol described in Scheme 4, using Grubbs I
catalyst. Conditions H: One-pot protocol described in Scheme 4 using Grubbs II catalyst. Isolated yield. Calcutated as the % yield (column 10) −
[% yield (column 9) × % yield (column 8)/100]. Obtained in a mixture with aromatized oxidation product (8.5% by GC−MS).
e
f
g
h
i
j
k
was followed, delivering the series of heterocycles 13a−e (66−
71%), 14a−e (78−81%), 15a,b (65−77%), and 16a−c (59−
65%) (Table 1). Thus, no electronic effects of the substituents
on the course of the Pd-catalyzed annulations were detected.
protocol (56−75% calculated per the enynes 5, 6, 7, and 8)
represent 2−22% improvement in comparison to the yields of
heterocycles 13, 14, and 15 achieved via the two-step process
from enynes 5, 6, 7, and 8 (calculated from the data in Table 1)
involving the isolation of the dienes resulting from the enyne−
RCM. In agreement with prior results of the one-pot
preparation of 16a, phenanthroline 16b was accompanied by
unreacted RCM product 12b in the crude reaction mixture.
The mixture was easily separated by flash chromatography,
affording the phenanthroline 16b in 56% yield, that was 18%
higher when compared to the calculated yield of 16b from 8b
(38%) achieved via the two-step process.
1
The H NMR analyses of crude reaction mixtures from the
reactions providing indenopyridines 14b−e indicated the
presence (less than 10%) of benzoquinoline byproducts
analogous to heterocycle 17 (Scheme 3), which were easily
separated by column chromatography and except for hetero-
cycle 17 were not isolated and characterized. The electron-
deficient pyrroloquinoline 15b was isolated along with an
impurity (8.5% by GC−MS) with the mass corresponding to
the fully aromatized product of air oxidation, the content of
which only increased upon further purification.
CONCLUSIONS
■
The yields of the products from both the two-step sequence
and the one-pot protocol are provided in Table 1. The yields of
heterocycles 13, 14, 15, and 16 obtained via the one-pot
In conclusion, a novel methodology for the construction of
complex N-heterocycles via sequential transition-metal catalysis
was described. Regiodivergent Heck annulation afforded
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1425; HRMS (ES+) calcd for C25H21BrNO (M + H)+ 430.0807, found
430.0812.
distinct heterocyclic cores from homologous or isosteric (X =
CH or N) substrates. A protocol for one-pot enyne−RCM/
Heck annulation was developed, underscoring the practicality
of the new methodology.
N-Allyl-N-(1-(2-bromophenyl)-3-phenylprop-2-yn-1-yl)-
benzamide (5a). The treatment of imine 1b (0.33 g, 1.48 mmol, 1.0
equiv), benzoyl chloride (260 μL, 2.22 mmol, 1.5 equiv), and
phenylacetylene (210 μL, 2.22 mmol, 1.5 equiv) with EtN-i-Pr2 (385
μL, 2.22 mmol, 1.5 equiv) and CuCl (0.055 g, 0.55 mmol, 0.2 equiv)
according to the general procedure described above followed by flash
chromatography over basic alumina eluting with EtOAc/hexane (1:4)
afforded enyne 5a (0.349 g, 55%) as a light yellow solid: mp 98−101
EXPERIMENTAL SECTION
■
General Methods. Unless otherwise indicated, all NMR data were
collected at room temperature in CDCl3 with internal CHCl3 as the
reference (δ 7.26 ppm for 1H and 77.00 ppm for 13C). IR spectra were
measured as thin films on salt (NaCl) plates. Melting points are
uncorrected and were taken in open capillary tubes. MS were
measured under electrospray ionization (ES+) conditions. Analytical
thin-layer chromatography (TLC) was carried out on commercial
Merck silica gel 60 plates, 250 mm thickness, with fluorescent indicator
(F-254) or stained with aqueous KMnO4 solution. Column
chromatography was performed with 32−63 mm silica gel (Sorbent)
or with 150 mesh 58 Å pore size basic alumina. Where appropriate,
neat liquid reagents were added via microliter syringes. Tetrahy-
drofuran (THF) was freshly distilled from sodium/benzophenone.
Methylene chloride and toluene were distilled over CaH2 and sodium
metal, respectively. DMF and ACN were kept over 3 Å (8−12 mesh)
molecular sieves under an atmosphere of dry argon; other solvents
were used as received. Unless otherwise specified, all reactions were
carried out under an atmosphere of dry argon in oven-dried (at least
6h at 140 °C) glassware. All imines were prepared26 by condensation
of a 1:1 mixture of aldehyde and amine in methylene chloride in the
presence of activated 3 Å (8−12 mesh) molecular sieves for 24 h at rt
followed by filtration through Celite and removal of solvent under
vacuum to afford pure imines that were used immediately. Grubbs I
catalyst, benzylidenebis(tricyclohexylphosphine)dichlororuthenium,
and Grubbs II catalyst, (1,3-bis(2,4,6-trimethylphenyl)-2-
imidazolidinylidene)dichloro(phenylmethylene)(tricyclohexylphos-
phine)ruthenium, were purchased from a commercial supplier and
used as such. Other materials were used as received from commercial
suppliers.
1
°C; Rf = 0.55 (EtOAc/hexane 3:7); H NMR (400 MHz, CDCl3) δ
8.01 (d, J = 7.6 Hz, 1H), 7.79 (br s, 1H), 7.67−7.57 (m, 4H), 7.49−
7.33 (m, 7H), 7.25 (t, J = 6.8 Hz, 1H), 7.09 (br s, 0.5H), 6.08 (br s,
0.5H), 5.62 (br s, 1H), 4.86 (d, J = 10 Hz, 1.5H), 4.77 (br s, 0.5H),
4.01 (br s, 1.5H), 3.66 (br s, 0.5H); 13C NMR (125 MHz, CDCl3) δ
49.5, 50.8, 86.0, 116.5, 122.3, 124.6, 127.3 (2C), 127.5, 128.2 (2C),
128.4, 128.7, 129.8, 130.2, 131.70, 131.76 (2C), 133.4 (2C), 134.1,
1
135.4, 136.1, 170.7. Significant broadening of some signals in H and
13C NMR arises due to hindered rotation about the amide bond.
1
Temperature-dependent H NMR spectra were recorded (vide infra).
In the 13C NMR spectra only one signal for the two sp carbons was
observed. IR (cm−1) 2223, 1643, 1394; HRMS (ES+) calcd for
C25H21BrNO (M + H)+ 430.0807, found 430.0808.
N-Allyl-N-(1-(2-bromo-4,5-dimethoxyphenyl)-3-phenylprop-2-yn-
1-yl)benzamide (5b). The treatment of imine 1f (0.275 g, 0.97 mmol,
1.0 equiv), benzoyl chloride (170 μL, 1.46 mmol, 1.5 equiv), and
phenylacetylene (139 μL, 1.46 mmol, 1.5 equiv) with EtN-i-Pr2 (255
μL, 1.46 mmol, 1.5 equiv) and CuCl (0.029 g, 0.28 mmol, 0.2 equiv)
according to the general procedure described above followed by flash
chromatography over basic alumina eluting with EtOAc/hexane (1:3)
afforded enyne 5b (0.232 g, 49%) as a light yellow oil: Rf = 0.46
(EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 7.76 (br s,
1.75H), 7.55 (t, J = 4.0 Hz, 3.25H), 7.49−7.34 (m, 6H), 7.06 (br s,
1H), 6.01 (br s, 1H), 5.69 (br s, 1H), 4.91 (d, J = 8.4 Hz, 1.25H), 4.83
(br s, 0.75H), 4.05 (br s, 1H), 3.93 (s, 3H), 3.92 (s, 3H), 3.70 (br s,
1
1H); In the H NMR, the signal for the methine proton appeared to
integrate for only 0.4H due to extensive broadening (see the
General Procedure for the Synthesis of Enynes 2 and 5a−e
and 6a−e (Conditions A, Table 1). Imines (1.0 equiv, 0.67−1.58
mmol), benzoyl chloride (1.5 equiv, 1.01−2.37 mmol), and alkynes
(1.5 equiv, 1.01−2.37 mmol) were mixed in acetonitrile (5−10 mL)
and stirred for 5 min at rt under argon. The resulting yellow solution
and neat EtN-i-Pr2 (1.5 equiv, 1.01−2.37 mmol) were added dropwise
simultaneously to a solution of CuCl (0.2 equiv, 0.135−0.32 mmol) in
acetonitrile (2 mL). The reaction mixture was stirred at rt under argon
for 2 h. Solvents were removed under reduced pressure to afford crude
products that were separated by flash chromatography over basic
alumina eluting with EtOAc/hexanes mixtures to yield pure enynes 2,
5a−e, and 6a−e.
1
temperature-dependent H NMR spectra for 5a). However, the signal
was recorded as 1H (6.01 ppm). 13C NMR (125 MHz, CDCl3) δ 42.4,
(45.9), 49.3, (50.3), (56.0), 56.1, (56.2), 56.3, 86.4, 114.4, 114.8,
115.8, 116.3, 122.4, 127.2, 128.2 (2C), 128.5 (2C), 128.6, 128.8, 129.8,
131.6 (2C), 134.4, 136.2 (2C), 148.0, 149.7, 171.5. Signals for the
minor rotamer are given in parentheses. In the 13C NMR spectra only
one signal for the two sp carbons was observed. IR (cm−1) 1643, 1477,
1236, 1035; HRMS (ES+) calcd for C27H25BrNO3 (M + H)+
490.1018, found 490.1018.
N-Allyl-N-(1-(2-bromo-5-fluorophenyl)-3-phenylprop-2-yn-1-yl)-
benzamide (5c). The treatment of imine 1g (0.276 g, 1.14 mmol, 1.0
equiv), benzoyl chloride (200 μL, 1.71 mmol, 1.5 equiv), and
phenylacetylene (165 μL, 1.71 mmol, 1.5 equiv) with EtN-i-Pr2 (295
μL, 1.71 mmol, 1.5 equiv) and CuCl (0.022 g, 0.22 mmol, 0.2 equiv)
according to the general procedure described above followed by flash
chromatography over basic alumina eluting with EtOAc/hexane (1:9)
afforded enyne 5c (0.264 g, 52%) as a colorless heavy oil: Rf = 0.65
(EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 7.75 (dd, J = 9.6
Hz, J = 3.2 Hz 1H), 7.60−7.53 (m, 4H), 7.49−7.36 (m, 7H), 6.99 (dt,
J = 8.4 Hz, J = 2.8 Hz 1H), 5.63 (br s, 1H), 4.88 (dd, J = 10.0 Hz, J =
0.8 Hz 1H), 4.81 (br s, 1H), 4.06−3.97 (m, 1H), 3.79 (br s, 1H). In
N-Benzyl-N-(1-(2-bromophenyl)-3-phenylprop-2-yn-1-yl)-
acrylamide (2). The treatment of imine 1a (0.43 g, 1.58 mmol, 1.0
equiv), acryloyl chloride (195 μL, 2.37 mmol, 1.5 equiv), and
phenylacetylene (225 μL, 2.37 mmol, 1.5 equiv) with EtN-i-Pr2 (410
μL, 2.37 mmol, 1.5 equiv) and CuCl (0.031 g, 0.32 mmol, 0.2 equiv)
according to the general procedure described above followed by flash
chromatography over basic alumina eluting with EtOAc/hexane (1:4)
afforded enyne 2 (0.393 g, 58%) as a colorless oil: Rf = 0.6 (EtOAc/
1
hexane 3:7); H NMR (400 MHz, CDCl3) δ 7.83 (br s, 0.8H), 7.63
(br s, 0.2H), 7.51 (br s, 1H), 7.43−6.88 (m, 12H), 6.50−6.32 (m,
1
1
the H NMR the signal for methine proton could not be detected
2H), 5.72 (br s, 1H), 4.75−4.44 (m, 2H). In the H NMR, the signal
likely due to extensive broadening (see the temperature-dependent 1H
NMR spectra for 5a). 13C NMR (125 MHz, CDCl3) δ (46.2), 49.4,
50.5, (55.9), 85.2, 116.8, 117.2 (d, J = 22.3 Hz), 118.5 (d, J = 3.2 Hz),
119.0 (d, J = 24.5 Hz), (122.0), 125.5, 126.8, (127.3), 128.2 (2C),
(128.44), 128.49 (2C), 128.7 (d, J = 26.1 Hz), 128.9, 129.9, 130.0,
(130.4), 131.8 (2C), (133.8), 134.5 (d, J = 7.7 Hz), 135.9 (2C),
(137.9), 161.8 (d, J = 246.2 Hz), 171.7. Signals for the minor rotamer
are given in parentheses. In the 13C NMR spectra only one signal for
the two sp carbons was observed. IR (cm−1) 1647, 1467; HRMS (ES+)
calcd for C25H20BrFNO (M + H)+ 448.0712 found, 448.0707.
for the methine proton was not detected due extensive broadening
1
(see the temperature-dependent H NMR spectra for 5a): 13C NMR
(125 MHz, CDCl3) δ (48.0), 48.1, (49.9), 50.9, (85.4), 85.6, 86.4,
(86.9), (122.3), 124.5, 126.1 (2C), 127.0, 127.3, 127.8, 128.1, 128.2
(2C), (128.40), 128.46, (128.5), 128.6, (129.6), (129.8), 130.0, 131.0,
131.5, 131.7 (2C), 133.3 (2C), (135.8), 137.5, (137.6), 138.0, 166.6,
(166.8). Signals for the minor rotamer are given in parentheses.
Significant broadening of some signals in 1H and 13C NMR arises due
to hindered rotation about the amide bond. Temperature-dependent
1H NMR spectra were recorded (vide infra); IR (cm−1) 1654, 1490,
3837
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The Journal of Organic Chemistry
Article
N-Allyl-N-(1-(2-bromophenyl)-3-(4-fluorophenyl)prop-2-yn-1-yl)-
benzamide (5d). The treatment of imine 1b (0.212 g, 0.95 mmol, 1.0
equiv), benzoyl chloride (165 μL, 1.42 mmol, 1.5 equiv), and p-
fluorophenylacetylene (0.171 g, 1.42 mmol, 1.5 equiv) with EtN-i-Pr2
(210 μL, 1.42 mmol, 1.5 equiv) and CuCl (0.019 g, 0.19 mmol, 0.2
equiv) according to the general procedure described above followed by
flash chromatography over basic alumina eluting with EtOAc/hexane
(1:9) afforded enyne 5d (0.225 g, 53%) as a light white solid: mp 89−
93 °C; Rf = 0.72 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ
7.98 (d, J = 7.6 Hz, 1H), 7.61 (br s, 2H), 7.58−7.50 (m, 3H), 7.49−
7.36 (m, 4H), 7.25 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 8.0 Hz, 2H), 6.09
(br s, 1H), 5.62 (br s, 1H), 4.86 (dd, J = 10.0 Hz, J = 1.2 Hz 1H), 4.77
(br s, 1H), 4.01 (d, J = 14.0 Hz, 1H), 3.70 (br s, 1H). In the 1H NMR,
the signal for methine proton appeared to integrate for only 0.1H due
to extensive broadening (see the temperature-dependent 1H NMR
spectra for 5a). However, the signal was recorded as 1H (6.09 ppm).
13C NMR (125 MHz, CDCl3) δ 46.3, (49.0), 50.4, (56.1), 85.7, 115.7
(d, J = 21.8 Hz, 2C), 116.5, 118.4, 124.6, 127.2, 127.3 (2C), 128.2
(2C), 129.8, 130.2 (d, J = 43.8 Hz), 131.6, 133.4, 133.7 (d, J = 8.3 Hz,
2C), 133.9, 135.3, 136.1, 162.7 (d, J = 248.6 Hz), 171.7. Signals for the
minor rotamer are given in parentheses. In the 13C NMR spectra only
one signal for the two sp carbons was observed. IR (cm−1) 2227, 1643,
1506; HRMS (ES+) calcd for C25H20BrFNO (M + H)+ 448.0712
found, 448.0707.
128.49, 128.7, (128.8), 129.8, 130.3, 131.3 (2C), 131.7 (2C), 133.5
(2C), (135.5), 136.4, 171.6. Signals for the minor rotamer are given in
parentheses. In the 13C NMR spectra only one signal for the two sp
carbons was observed. IR (cm−1) 2223, 1641, 1402; HRMS (ES+)
calcd for C26H22BrNONa (M + Na)+, 466.0782, found 466.0778.
N-(1-(2-Bromo-4,5-dimethoxyphenyl)-3-phenylprop-2-yn-1-yl)-
N-(but-3-en-1-yl)benzamide (6b). The treatment of imine 1h (0.329
g, 1.11 mmol, 1.0 equiv), benzoyl chloride (190 μL, 1.66 mmol, 1.5
equiv), and phenylacetylene (160 μL, 1.66 mmol, 1.5 equiv) with EtN-
i-Pr2 (285 μL, 1.66 mmol, 1.5 equiv) and CuCl (0.022 g, 0.22 mmol,
0.2 equiv) according to the general procedure described above
followed by flash chromatography over basic alumina eluting with
EtOAc/hexane (1:4) afforded enyne 6b (0.248 g, 45%) as a colorless
1
oil: Rf = 0.45 (EtOAc/hexane 3:7); H NMR (400 MHz, CDCl3) δ
7.89−7.71 (m, 1H), 7.68−7.50 (m, 4H), 7.49−7.33 (m, 6H), 7.08 (br
s, 1H), 7.05 (br s, 0.5H) 6.35−5.91 (m, 0.5H), 5.87−5.35 (m, 1H),
5.21−5.10 (m, 0.2H), 4.92 (br s, 1.8H), 3.95 (s, 3H), 3.92 (s, 3H),
1
3.60−2.86 (m, 2H), 2.67−2.25 (m, 1H), 1.88 (br s, 1H). In the H
NMR the signal for the methine proton appeared as a broad singlet
and a multiplet (7.05 and 6.35−5.91 ppm) that integrate for only 0.5H
when combined, due to extensive broadening (see the temperature-
dependent 1H NMR spectra for 6a). However, the signals are
presented herein as 0.5H (7.05 ppm) and 0.5H (6.35−5.91 ppm). 13C
NMR (125 MHz, CDCl3) δ 32.6, (33.9), 43.1, (46.0), (50.1), 55.9,
56.21, 56.29, 86.6, 114.0, 114.6, (115.2), 115.9, (116.3), 117.4,
(122.1), 126.8, (127.5), 128.2 (2C), 128.54 (2C), 128.58, (128.9),
129.8, 131.3, 131.6 (2C), 131.7, (134.7), 135.3, (135.6), 136.4 (2C),
148.1, 149.7, (167.4), 171.5. Signals for the minor rotamer are given in
parentheses. In the 13C NMR spectra only one signal for the two sp
carbons was observed. IR (cm−1) 2225, 1487, 1280, 1031; HRMS
(ES+) calcd for C28H26BrNO3Na (M + Na)+, 526.0994, found
526.0985.
N-Allyl-N-(1-(2-bromophenyl)-3-(4-methoxyphenyl)prop-2-yn-1-
yl)benzamide (5e). The treatment of imine 1b (0.15 g, 0.673 mmol,
1.0 equiv), benzoyl chloride (120 μL, 1.01 mmol, 1.5 equiv), and p-
methoxyphenylacetylene (122 μL, 1.01 mmol, 1.5 equiv) with EtN-i-
Pr2 (0.13 g, 174 μL, 1.01 mmol, 1.5 equiv) and CuCl (0.013 g, 0.135
mmol, 0.2 equiv) according to the general procedure described above
followed by flash chromatography over basic alumina eluting with
EtOAc/hexane (1:4) afforded enyne 5e (0.19 g, 61%) as a colorless
heavy oil: Rf = 0.55 (EtOAc/hexane 3:7); 1H NMR (400 MHz,
CDCl3) δ 8.01 (d, J = 7.2 Hz, 1H), 7.82 (br s, 1H), 7.59 (br s, 2H),
7.50 (d, J = 8.8 Hz, 2H), 7.47−7.35 (m, 4H), 7.24 (t, J = 6.8 Hz, 1H),
7.08 (br s, 0.5H), 6.92 (d, J = 8.0 Hz, 2H), 6.05 (br s, 0.5H), 5.61 (br
s, 1H), 4.84 (d, J = 10.4 Hz, 1H), 4.7 (br s, 1H), 3.98 (br s, 1.5H), 3.86
(s, 3H), 3.68 (br s, 0.5H). In the 1H NMR, the signal for the methine
proton appeared as two broad singlets (7.08 and 6.05 ppm) that
integrate for only 0.5H when combined due to extensive broadening
N-(1-(2-Bromo-5-fluorophenyl)-3-phenylprop-2-yn-1-yl)-N-(but-
3-en-1-yl)benzamide (6c). The treatment of imine 1i (0.32 g, 1.25
mmol, 1.0 equiv), benzoyl chloride (215 μL, 1.87 mmol, 1.5 equiv),
and phenylacetylene (180 μL, 1.87 mmol, 1.5 equiv) with EtN-i-Pr2
(240 μL, 1.87 mmol, 1.5 equiv) and CuCl (0.025 g, 0.25 mmol, 0.2
equiv) according to the general procedure described above, followed
by flash chromatography over basic alumina eluting with EtOAc/
hexane (1:9), afforded enyne 6c (0.299 g, 52%) as a colorless oil: Rf =
0.6 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 8.16 (dd, J =
7.2 Hz, J = 1.2 Hz, 0.25H), 7.77 (d, J = 7.6 Hz, 1.25H), 7.71 (t, J = 7.2
Hz, 0.5H), 7.64−7.52 (m, 4H), 7.50−7.34 (m, 7H), 7.01 (td, J = 8.0
Hz, J = 2.8 Hz, 1H), 6.20−5.35 (m, 1H), 5.25−4.72 (m, 2H), 3.75−
2.90 (m, 2H), 2.49 (br s, 1H), 2.16−2.05 (m, 0.15H), 1.92 (br s,
0.85H); 13C NMR (125 MHz, CDCl3) δ (32.6), 33.8, 43.2, (46.3),
(50.3), 56.0, 85.4, [115.4, (d, J = 24.7 Hz)], [116.5, (d, J = 3.2 Hz)],
117.3, (117.4), 118.3 (d, J = 3.3 Hz), 118.6 (d, J = 24.3 Hz), 126.8,
(127.4), 128.3 (2C), 128.4 (d, J = 9.6 Hz), 128.5 (d, J = 8.0 Hz),
128.8, (129.0), 129.87 (2C), (129.89), (129.9), 130.3, 131.4, 131.8
(2C), 133.9, 134.8 (d, J = 7.7 Hz), [135.0, (d, J = 7.8 Hz)], (135.5),
136.2 (2C), (138.0), (164.1), 161.8 (d, J = 246.6 Hz), [161.9, (d, J =
246.8 Hz)], 171.7, (172.8). Signals for the minor rotamer are given in
parentheses. In the 13C NMR spectra only one signal for the two sp
1
(see the temperature-dependent H NMR spectra for 5a). However,
the signals are presented herein as 0.5H (7.08 ppm) and 0.5H (6.05
ppm). 13C NMR (125 MHz, CDCl3) δ 44.0, (47.2), 48.6, 53.4, (54.4),
82.6, 112.1, 114.5, 122.6, 125.3 (2C), 125.5, 126.2 (2C), 126.4, 127.9,
128.2, 129.8 (2C), 131.2 (2C), 131.4, 132.1, 133.7, 134.3, 158.0, 169.7.
1
Significant broadening of some signals in the H and 13C NMR arises
due to hindered rotation about the amide bond (see the temperature-
dependent 1H NMR spectra for 5a). In the 13C NMR spectra only one
signal for the two sp carbons was observed. IR (cm−1) 2210, 1643,
1396, 1027; HRMS (ES+) calcd for C26H23BrNO2 (M + H)+
460.0912, found 460.0911.
N-(1-(2-Bromophenyl)-3-phenylprop-2-yn-1-yl)-N-(but-3-en-1-
yl)benzamide (6a). The treatment of imine 1c (0.325 g, 1.36 mmol,
1.0 equiv), benzoyl chloride (235 μL, 2.04 mmol, 1.5 equiv), and
phenylacetylene (195 μL, 2.04 mmol, 1.5 equiv) with EtN-i-Pr2 (350
μL, 2.04 mmol, 1.5 equiv) and CuCl (0.027 g, 0.27 mmol, 0.2 equiv)
according to the general procedure described above followed by flash
chromatography over basic alumina eluting with EtOAc/hexane (1:4)
afforded enyne 6a (0.332 g, 55%) as a white solid: mp 75−80 °C; Rf =
1
carbons was observed. Significant broadening of some signals in H
and 13C NMR arises due to hindered rotation about the amide bond
1
(see the temperature-dependent H NMR spectra for 6a). IR (cm−1)
1643, 1467; HRMS (ES+) calcd for C26H22BrFNO (M + H)+
462.0869, found 462.0877.
1
0.6 (EtOAc/hexane 3:7); H NMR (400 MHz, CDCl3) δ 8.04 (br s,
N-(1-(2-Bromophenyl)-3-(4-fluorophenyl)prop-2-yn-1-yl)-N-(but-
3-en-1-yl)benzamide (6d). The treatment of imine 1c (0.193 g, 0.811
mmol, 1.0 equiv), benzoyl chloride (140 μL, 1.21 mmol, 1.5 equiv),
and p-fluorophenylacetylene (0.145 g, 1.21 mmol, 1.5 equiv) with
EtN-i-Pr2 (210 μL, 1.21 mmol, 1.5 equiv) and CuCl (0.016 g, 0.16
mmol, 0.2 equiv) according to the general procedure described above
followed by flash chromatography over basic alumina eluting with
EtOAc/hexane (1:9) afforded enyne 6d (0.22 g, 58%) as a colorless
oil: Rf = 0.6 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 8.01
(d, J = 7.6 Hz, 1H), 7.86−7.59 (m, 2H), 7.54 (dd, J = 5.2 Hz, J = 3.2
Hz, 2H), 7.49−7.39 (m, 4H), 7.25 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 8.0
1H), 7.79 (br s, 1H), 7.69−7.53 (m, 4H), 7.50−7.36 (m, 7H), 7.31−
7.23 (m, 1H), 7.06 (br s, 0.5H), 6.05 (br s, 0.5H), 5.80−5.36 (m, 1H),
4.89 (br s, 2H), 3.58−2.86 (m, 2H), 2.46 (br s, 1H), 1.81 (br s, 1H).
1
In the H NMR the signal for the methine proton appeared as two
broad singlets (7.06 and 6.05 ppm) that integrate for only 0.5H when
combined, due to extensive broadening (see the temperature-
dependent 1H NMR spectra for 6a). However, the signals are
presented herein as 0.5H (7.06 ppm) and 0.5H (6.05 ppm). 13C NMR
(125 MHz, CDCl3) δ 32.5, (33.9), 43.3, (46.0), (50.4), 56.2, 86.2,
116.3, (116.7), 122.2, 124.4, 127.1, 127.5 (2C), 127.6, 128.2, 128.41,
3838
dx.doi.org/10.1021/jo400246d | J. Org. Chem. 2013, 78, 3832−3846

The Journal of Organic Chemistry
Article
Hz, 2H), 7.03 (br s, 0.5H), 6.03 (br s, 0.5H), 5.83−5.27 (m, 1H), 4.89
(br s, 2H), 3.94−2.86 (m, 2H), 2.40 (br s, 1H), 1.81 (br s, 1H). In the
1H NMR the signal for the methine proton appeared as two broad
131.8(2C), 133.4, 133.9, 135.7, 139.9, 144.0, 149.8, 171.8. Signals for
the minor rotamer are given in parentheses; IR (cm−1) 2223, 1643,
1400; HRMS (ES+)calcd for C24H19BrN2ONa (M + Na)+, 453.0578,
found 453.0571.
singlets (7.03 and 6.03 ppm) that integrate for only 0.5H when
combined, due to extensive broadening (see the temperature-
dependent 1H NMR spectra for 6a). However the signals are
presented herein as 0.5H (7.03 ppm) and 0.5H (6.03 ppm). 13C NMR
(125 MHz, CDCl3) δ 32.5, (33.8), 43.3, (46.0), 50.1, (56.1), 85.9,
115.8 (d, J = 21.6 Hz, 2C), 116.6, (118.3), 124.4, 125.5, (127.2), 127.5,
128.2, 128.4, 128.6, [128.7 (d, J = 5.2 Hz)], 129.8 (d, J = 5.2 Hz),
130.5, 131.2 (2C), 133.6 (2C), 133.7 (d, J = 8.3 Hz, 2C), (135.4),
136.3, 138.9, 162.8 (d, J = 248.6 Hz), (171.0), 172.6. Signals for the
minor rotamer are given in parentheses. In the 13C NMR spectra only
one signal for the two sp carbons was observed. IR (cm−1) 2225, 1643,
1400; HRMS (ES+) calcd for C26H21BrFNONa (M + Na)+, 484.0688,
found 484.0685.
N-Allyl-N-(1-(2-bromopyridin-3-yl)-3-(4-fluorophenyl)prop-2-yn-
1-yl)benzamide (7b). The treatment of imine 1d (0.12 g, 0.53 mmol,
1.0 equiv), benzoyl chloride (0.091 g, 75 μL, 0.64 mmol, 1.2 equiv)
and p-fluorophenylacetylene (0.076 g, 73 μL, 0.64 mmol, 1.2 equiv)
with EtN-i-Pr2 (0.082 g, 110 μL, 0.64 mmol, 1.2 equiv) and CuCl
(0.011 g, 0.11 mmol, 0.2 equiv) according to the general procedure
described above followed by flash chromatography over silica eluting
with EtOAc/hexane (1:3) afforded enyne 7b (0.142 g, 60%) as a
colorless oil: Rf = 0.4 (EtOAc/hexane 3:7); 1H NMR (400 MHz,
CDCl3) δ 8.39 (br s, 1H), 8.27 (d, J = 6.0 Hz, 1H), 7.83 (br s, 0.75H),
7.77−7.31 (m, 7.25H), 7.09 (t, J = 7.6 Hz, 2H), 6.91 (br s, 0.5H), 6.40
(br s, 0.5H), 5.98 (br, 0.30H), 5.68 (br s, 0.70H), 5.25 (dd, J = 34.8
Hz, J = 16.8 Hz, 0.5H), 4.82 (dd, J = 42.8 Hz, J = 9.6 Hz, 1.5H), 4.72−
N-(1-(2-Bromophenyl)-3-(4-methoxyphenyl)prop-2-yn-1-yl)-N-
(but-3-en-1-yl)benzamide (6e). The treatment of imine 1c (0.19 g,
0.798 mmol, 1.0 equiv), benzoyl chloride (140 μL, 1.19 mmol, 1.5
equiv), and p-methoxyphenylacetylene (155 μL, 1.19 mmol, 1.5 equiv)
with EtN-i-Pr2 (205 μL, 1.19 mmol, 1.5 equiv) and CuCl (0.016 g,
0.16 mmol, 0.2 equiv) according to the general procedure described
above followed by flash chromatography over basic alumina eluting
with EtOAc/hexane (1:4) afforded enyne 6e (0.2 g, 53%) as a
1
4.42 (m, 2H). In the H NMR the signal for the methine proton
appeared as two broad singlets (6.91 and 6.40 ppm) that integrate for
only 0.5H when combined, due to extensive broadening (see the
temperature-dependent 1H NMR spectra for 5a). However, the signals
are presented herein as 0.5H (6.91 ppm) and 0.5H (6.40 ppm). 13C
NMR (125 MHz, CDCl3) δ 33.1, 84.4, 99.9, 115.8 (d, J = 22.0 Hz),
116.7, (116.9), (118.0), 122.6 (2C), (123.4), 126.9 (2C), 127.3, 128.5
(d, J = 27.3 Hz, 2C), 130.2, 131.5, (133.3), 133.8 (d, J = 9.3 Hz, 2C),
133.9, (134.2), 135.6, (138.0), 139.8, 144.0, 149.8, (154.5), 162.9 (d, J
= 249.4 Hz), 171.9. Signals for the minor rotamer are given in
parentheses. IR (cm−1) 2223, 1643, 1400; HRMS (ES+) calcd for
C24H18BrFN2ONa (M + Na)+, 471.0484, found 471.0487.
N-(1-(2-Bromopyridin-3-yl)-3-phenylprop-2-yn-1-yl)-N-(but-3-en-
1-yl)benzamide (8a). The treatment of imine 1e (0.12 g, 0.5 mmol,
1.0 equiv), benzoyl chloride (0.084 g, 70 μL, 0.6 mmol, 1.2 equiv), and
phenylacetylene (0.061 g, 57 μL, 0.6 mmol, 1.2 equiv) with EtN-i-Pr2
(0.078 g, 104 μL, 0.6 mmol, 1.2 equiv) and CuCl (0.010 g, 0.1 mmol,
0.2 equiv) according to the general procedure described above
followed by flash chromatography over silica eluting with EtOAc/
hexane (1:3) afforded enyne 8a (0.137 g, 62%) as a colorless oil: Rf =
0.4 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 8.41 (dd, J =
4.4 Hz, J = 1.2 Hz, 1H), 8.32 (d, J = 5.4 Hz, 1H), 7.67 (br s, 2H), 7.56
(dd, J = 7.6 Hz, J = 2.4 Hz, 2H), 7.52−7.36 (m, 7H), 6.83 (br s, 0.5H),
6.05 (br s, 0.5H), 5.60 (br s, 1H), 4.97−4.81 (m, 2H), 3.55−3.43 (m,
1H), 3.25 (br s, 1H), 2.47 (br s, 1H), 1.95 (br s, 1H). In the 1H NMR
the signal for the methine proton appeared as two broad singlets (6.83
and 6.05 ppm) that integrate for only 0.5H when combined, due to
extensive broadening (see the temperature-dependent 1H NMR
spectra for 6a). However the signals are presented herein as 0.5H
(6.83 ppm) and 0.5H (6.05 ppm). 13C NMR (125 MHz, CDCl3) δ
33.0, (33.6), 43.5, (47.0), 50.0, (55.4), 84.8, 117.0, 121.8, 122.7 (2C),
127.2, 128.3 (2C), 128.5 (2C), 128.8, 129.1, 129.8, 130.0, 131.7 (2C),
136.0, 139.5, 143.8, 149.8, 171.8. Signals for the minor rotamer are
given in parentheses. In the 13C NMR spectra only one signal for the
two sp carbons was observed. IR (cm−1) 1637, 1490, 1446; HRMS
(ES+) calcd for C25H21BrN2ONa (M + Na)+, 467.0735, found
467.0741.
1
colorless oil: Rf = 0.6 (EtOAc/hexane 3:7); H NMR (400 MHz,
CDCl3) δ 8.04 (br s, 1H), 7.80 (br s, 1H), 7.60 (br s, 2H), 7.50 (d, J =
10.4 Hz, 2H), 7.47−7.38 (m, 4H), 7.30−7.22 (m, 1H), 7.04 (br s,
0.5H), 6.92 (d, J = 7.2 Hz, 2H), 6.03 (br s, 0.5H), 5.80−5.13 (m, 1H),
4.90 (br s, 2H), 3.86 (s, 3H), 3.56−2.82 (m, 2H), 2.47 (br s, 1H), 1.79
(br s, 1H). In the 1H NMR the signal for the methine proton appeared
as two broad singlets (7.04 and 6.03 ppm) that integrate for only 0.5H
when combined, due to extensive broadening (see the temperature-
dependent 1H NMR spectra for 6a). However the signals are
presented herein as 0.5H (7.04 ppm) and 0.5H (6.03 ppm). 13C NMR
(125 MHz, CDCl3) δ 32.4, (33.9), 43.3, (46.0), (50.4), 55.3, 56.3,
84.7, 114.3, 116.2, (116.8), 124.4, 126.9, 127.5 (2C), 128.2, 128.6,
129.8, 130.2, 131.4 (2C), 133.2 (2C), 133.4, 133.5 (2C), 135.6, 136.5,
160.0, 171.6. Signals for the minor rotamer are given in parentheses. In
the 13C NMR spectra only one signal for the two sp carbons was
observed. IR (cm−1) 2221, 1643, 1510, 1027; HRMS (ES+) calcd for
C27H25BrNO2 (M + H)+ 474.1069, found 474.1072.
General Procedure for the Preparation of Enynes 7a,b and
8a−c (Conditions B, Table 1). Imine (1.0 equiv, 0.5−0.694 mmol),
benzoyl chloride (1.2 equiv, 0.6−0.832 mmol), and alkyne (1.2 equiv,
0.6−0.832 mmol) were mixed in acetonitrile (5 mL) and stirred at rt
under argon for 5 min to afford a yellow solution. To this solution
were added neat EtN-i-Pr2 (1.2 equiv, 0.6−0.832 mmol) and the
solution of CuCl (0.2 equiv, 0.1−0.14 mmol) in acetonitrile (1 mL)
simultaneously dropwise. The reaction mixture was stirred at rt under
argon for 1 h. Solvents were removed under reduced pressure, and the
resulting crude product was separated by flash chromatography over
silica eluting with EtOAc/hexanes mixtures to yield pure enynes 7a−b
and 8a−c.
N-Allyl-N-(1-(2-bromopyridin-3-yl)-3-phenylprop-2-yn-1-yl)-
benzamide (7a). The treatment of imine 1d (0.12 g, 0.53 mmol, 1.0
equiv), benzoyl chloride (0.091 g, 75 μL, 0.64 mmol, 1.2 equiv), and
phenylacetylene (0.065 g, 61 μL, 0.64 mmol, 1.2 equiv) with EtN-i-Pr2
(0.082 g, 110 μL, 0.64 mmol, 1.2 equiv) and CuCl (0.011 g, 0.11
mmol, 0.2 equiv) according to the general procedure described above
followed by flash chromatography over silica eluting with EtOAc/
hexane (1:3) afforded enyne 7a (0.135 g, 59%) as a colorless oil: Rf =
0.4 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 8.39 (dd, J =
4.6 Hz, J = 1.6 Hz, 1H), 8.30 (d, J = 7.6 Hz, 1H), 7.65 (br s, 1.5H),
7.56 (dd, J = 7.6 Hz, J = 2.4 Hz, 2.5H), 7.50−7.39 (m, 5.75H), 7.37
(dd, J = 7.6 Hz, J = 4.4 Hz, 1.25H), 5.69 (br s, 1H), 4.87 (d, J = 10.4
Hz, 1H), 4.76 (dd, J = 17.2 Hz, J = 1.2 Hz, 1H), 4.29−3.56 (m, 2H).
N-(1-(2-Bromopyridin-3-yl)-3-(4-fluorophenyl)prop-2-yn-1-yl)-N-
(but-3-en-1-yl)benzamide (8b). The treatment of imine 1e (0.15 g,
0.627 mmol, 1.0 equiv), benzoyl chloride (0.128 g, 106 μL, 0.752
mmol, 1.2 equiv), and p-fluorophenylacetylene (0.092 g, 87 μL, 0.752
mmol, 1.2 equiv) with EtN-i-Pr2 (0.072 g, 97 μL, 0.752 mmol, 1.2
equiv) and CuCl (0.013 g, 0.13 mmol, 0.2 equiv) according to the
general procedure described above followed by flash chromatography
over silica eluting with EtOAc/hexane (1:3) afforded enyne 8b (0.175
1
g, 61%) as a colorless oil: Rf = 0.4 (EtOAc/hexane 3:7); H NMR
(400 MHz, CDCl3) δ 8.42 (dd, J = 4.8 Hz, J = 2.0 Hz, 1H), 8.30 (br s,
1H), 7.78−7.58 (m, 2H), 7.57−7.51 (m, 2H), 7.49−7.37 (m, 4H),
7.10 (t, J = 8.4 Hz, 2H), 5.95−5.38 (m, 1H), 4.90 (dd, J = 22.8 Hz, J =
10.4 Hz, 2H), 3.60−3.40 (m, 1.25H), 3.23 (br s, 0.75H), 2.55−2.34
1
In the H NMR the signal for the methine proton was not detected
1
1
due extensive broadening (see the temperature-dependent H NMR
(m, 1H), 1.95 (br s, 1H). In the H NMR the signal for the methine
spectra for 5a); 13C NMR (125 MHz, CDCl3) δ 50.1, 55.8, 84.7, 99.9,
proton was not observed, due to extensive broadening (see the
116.8, 121.9, 122.5 (2C), 127.3, 128.3 (2C), 128.5 (2C), 129.0, 130.1,
temperature-dependent 1H NMR spectra for 6a). 13C NMR (125
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MHz, CDCl3) δ 84.6, 115.9 (d, J = 22 Hz, 2C), (117.0), 117.5,
(122.6), 122.7 (2C), 126.7, 127.2, 128.4 (2C), 128.5, 130.0, 131.4,
133.7 (d, J = 8.5 Hz, 2C), (135.3), 135.9, 139.4, 143.8, 149.9, 163.0 (d,
J = 249 Hz), 171.8. In the 13C NMR spectra only one signal for the
two methylene carbons and only one signal for the two sp carbons was
observed. No signal was observed for methine due to significant
broadening. Signals for the minor rotamer are given in parentheses. IR
(cm−1) 2230, 1643, 1506, 1400; HRMS (ES+) calcd for
C25H20BrFN2ONa (M + Na)+, 485.0641, found 485.0640.
cooled to rt, directly loaded on a silica column, and purified by flash
chromatography eluting with EtOAc/hexane mixtures to afford pure
dihydropyrroles 9a−e and 11a,b.
N-Benzoyl-2-(2-bromophenyl)-3-(1-phenylvinyl)-2,5-dihydro-1H-
pyrrole (9a). The treatment of enyne 5a (0.07 g, 0.16 mmol, 1.0
equiv) with Grubb’s I catalyst (0.013 g, 0.016 mmol, 0.1 equiv)
according to the general procedure described above followed by flash
chromatography over silica eluting with EtOAc/hexane (1:4) afforded
dihydropyrrole 9a (0.065 g, 93%) as a colorless oil: Rf = 0.6 (EtOAc/
hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 8.0 Hz, 1H),
7.54 (d, J = 6.4 Hz, 1H), 7.41 (t, J = 7.2 Hz, 3H), 7.35−7.31 (m,
4.3H), 7.24−7.19 (m, 2.7H), 7.14 (t, J = 7.6 Hz, 1H), 7.04−6.96 (m,
1H), 6.64 (s, 0.7H), 6.11 (s, 0.3H), 5.92 (s, 0.3H), 5.75 (s, 0.7H), 5.38
(s, 0.7H), 5.28 (s, 0.3H), 5.16 (s, 0.7H), 5.09 (s, 0.3H), 4.84−4.66 (m,
1.3H), 4.27 (d, J = 16.0 Hz, 0.7H). The signals that integrate for less
than 1H arise due to hindered rotation as confirmed by the
N-(1-(2-Bromopyridin-3-yl)-3-(4-methoxyphenyl)prop-2-yn-1-yl)-
N-(but-3-en-1-yl)benzamide (8c). The treatment of imine 1e (0.166
g, 0.694 mmol, 1.0 equiv), benzoyl chloride (0.115 g, 95 μL, 0.832
mmol, 1.2 equiv), and p-methoxyphenylacetylene (0.110 g, 108 μL,
0.832 mmol, 1.2 equiv) with EtN-i-Pr2 (0.107 g, 144 μL, 0.832 mmol,
1.2 equiv) and CuCl (0.014 g, 0.14 mmol, 0.2 equiv) according to the
general procedure described above followed by flash chromatography
over silica eluting with EtOAc/hexane (1:3) afforded enyne 8c (0.207
1
temperature-dependent H NMR spectra recorded for the diene 9a.
1
g, 63%) as a colorless oil: Rf = 0.3 (EtOAc/hexane 3:7); H NMR
13C NMR (125 MHz, CDCl3) δ (54.3), 56.9, (60.4), 67.6, (116.9),
(400 MHz, CDCl3) δ 8.41 (dd, J = 4.4 Hz, J = 1.2 Hz, 1H), 8.36−8.26
(m, 1.4H), 7.67 (br s, 1.6H), 7.53−7.36 (m, 6H), 6.92 (d, J = 8.4 Hz,
1H), 6.91 (br s, 0.5H), 6.80 (d, J = 9.2 Hz, 1H), 6.01 (br s, 0.5H),
5.76−5.44 (m, 1H), 5.04−4.76 (m, 2H), 3.86 (s, 2H), 3.82 (s, 1H),
3.57−2.87 (m, 2H), 2.45 (br s, 0.75H), 2.17−1.82 (m, 1.25H). In the
1H NMR the signal for the methine proton appeared as two broad
117.6, 125.0, 125.9, 127.2 (2C), 127.6, 127.7, 128.0, 128.1 (2C),
128.25 (2C), 128.28 (2C), 128.5, 129.1, (129.2), 130.1, 133.5, 136.1,
(136.8), 139.5, (140.5), 140.7, 142.1, (142.2), 169.5, (171.1). Signals
for the minor rotamer are given in parentheses. IR (cm−1) 1643, 1492,
1469; HRMS (ES+) calcd for C25H21BrNO (M + H)+ 430.0807, found
430.0801.
singlets (6.91 and 6.01 ppm) that integrate for only 0.7H when
combined, due to extensive broadening (see the temperature-
dependent 1H NMR spectra for 6a). However the signals are
presented herein as 0.5H (6.91 ppm) and 0.5H (6.01 ppm). 13C NMR
(125 MHz, CDCl3) δ 33.4, 49.1, 55.33, (55.39), 56.5, (83.4), 83.8,
88.7, 113.8, (113.9), 114.1, (114.6), 115.7, 122.6, 122.7 (2C), (127.3),
128.3 (2C), (130.0), (133.1), 133.2 (2C), 135.9, 136.0, 136.3, 139.6
(2C), (140.6), 143.8, 144.2, 149.1, (149.8), 159.7, 171.8; IR (cm−1)
2221, 1641, 1510, 1029; HRMS (ES+) calcd for C26H24BrN2O2 (M +
H)+ 475.1021, found 475.1017.
N-Benzoyl-2-(2-bromo-4,5-dimethoxyphenyl)-3-(1-phenylvinyl)-
2,5-dihydro-1H-pyrrole (9b). The treatment of enyne 5b (0.072 g,
0.15 mmol, 1.0 equiv) with Grubb’s I catalyst (0.012 g, 0.015 mmol,
0.1 equiv) according to the general procedure described above
followed by flash chromatography over silica eluting with EtOAc/
hexane (1:3) afforded dihydropyrrole 9b (0.058 g, 81%) as a yellow
1
oil: Rf = 0.33 (EtOAc/hexane 3:7); H NMR (400 MHz, CDCl3) δ
7.55 (d, J = 7.2 Hz, 1H), 7.46−7.38 (m, 3H), 7.36−7.26 (m, 4H), 7.22
(t, J = 6.8 Hz, 2H), 7.04 (d, J = 7.6 Hz, 2H), 6.82 (s, 0.5H), 6.48 (s,
0.5H), 5.93 (s, 0.4H), 5.76 (s, 0.6H), 5.36 (s, 0.7H), 5.25 (s, 0.3H),
5.17 (s, 0.7H), 5.10 (s, 0.3H), 4.83- 4.65 (m, 1.5H), 4.28 (d, J = 24.4
Hz, 0.5H), 3.87 (s, 2H), 3.86 (s, 2H), 3.82 (s, 2H). The signals that
integrate for less than 1H arise due to hindered rotation as confirmed
by the temperature-dependent 1H NMR spectra recorded for the
diene 9a. 13C NMR (125 MHz, CDCl3) δ (54.2), (55.9), 56.0, 56.1,
56.9, 67.9, 116.0, (116.9), 117.6, 124.7, 125.9, 127.2 (2C), 127.71
(2C), 127.76, 128.0, 128.2 (2C), 128.3 (2C), 128.4, 129.2, 130.2,
(130.9), 136.2, 140.7, 142.2, 148.6, 149.0, 169.7. Signals for the minor
rotamer are given in parentheses. IR (cm−1) 1643, 1444, 1159, 1026;
HRMS (ES+) calcd for C27H25BrNO3 (M + H)+ 490.1018, found
490.1024.
1-Benzyl-5-(2-bromophenyl)-4-(1-phenylvinyl)-1,5-dihydro-2H-
pyrrol-2-one (3) and 1-Benzyl-6-(2-bromophenyl)-5-methylene-4-
phenyl-5,6-dihydropyridin-2(1H)-one (4). The solution of enyne 2
(0.13 g, 0.30 mmol, 1.0 equiv) in toluene (20 mL) was degassed with
ethylene for 5 min, Grubb’s II catalyst (0.025 g, 0.03 mmol, 0.1 equiv)
was added, and the reaction mixture was stirred at 85 °C under
ethylene atmosphere for 20 h. The mixture was cooled to rt, directly
loaded on a silica column, and purified by flash chromatography,
eluting with EtOAc/hexane (1:9) to afford pure diene 4 (0.045 g,
35%) as a colorless heavy oil, and continuous elution with EtOAc/
hexane (1:4) afforded pure diene 3 (0.03 g, 23%) as a colorless heavy
oil.
N-Benzoyl-2-(2-bromo-5-fluorophenyl)-3-(1-phenylvinyl)-2,5-di-
hydro-1H-pyrrole (9c). The treatment of enyne 5c (0.094 g, 0.21
mmol, 1.0 equiv) with Grubb’s I catalyst (0.018 g, 0.02 mmol, 0.1
equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (1:9)
afforded dihydropyrrole 9c (0.068 g, 72%) as a colorless oil: Rf = 0.75
1
Analytical data for 3: Rf = 0.45 (EtOAc/hexane 3:7); H NMR
(400 MHz, CDCl3) δ 7.59 (d, J = 8.0 Hz, 1H), 7.37−7.31 (m, 5H),
7.25−7.16 (m, 7H), 7.07 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 6.13 (s,
1H), 5.90 (s, 1H), 5.38 (s, 1H), 5.26 (s, 1H), 5.01 (d, J = 15.2 Hz,
1H), 3.71 (d, J = 15.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 44.0,
64.2, 120.1, 125.1, 127.3, 127.5, 128.00, 128.03 (2C), 128.2, 128.3
(2C), 128.4 (2C), 128.5 (2C), 130.2, 130.4, 133.2, 135.2, 137.2, 139.4,
141.6, 158.9, 170.8; IR (cm−1) 1650, 1494, 1261; HRMS (ES+) calcd
for C25H21BrNO (M + H)+ 430.0807, found 430.0803.
1
(EtOAc/hexane 3:7); H NMR (400 MHz, CDCl3) δ 7.58−7.47 (m,
2H), 7.46−7.35 (m, 3H), 7.31 (t, J = 6.8 Hz, 3H), 7.24−7.14 (m, 2H),
7.09 (dd, J = 9.2 Hz, J = 2.8 Hz, 1H), 7.02 (d, J = 7.6 Hz, 0.75H), 6.87
(td, J = 8.4 Hz, J = 2.8 Hz, 1H), 6.74 (br s, 0.25H), 6.57 (s, 0.75H),
6.03 (s, 0.25H), 5.94 (s, 0.25H), 5.76 (s, 0.75H), 5.34 (s, 0.75H), 5.23
(s, 0.25H), 5.16 (s, 0.75H), 5.09 (s, 0.25H), 4.81- 4.63 (m, 1.25H),
4.26 (d, J = 16.0 Hz, 0.75H). The signals that integrate for less than
1H arise due to hindered rotation as confirmed by the temperature-
dependent 1H NMR spectra recorded for the diene 9a. 13C NMR (125
MHz, CDCl3) δ (54.3), 56.7, 67.4, 116.5 (d, J = 22.3 Hz, 2C), 117.7,
125.3, (125.5), 125.9, (126.5), 127.2 (2C), 127.83, 127.89, 127.9,
128.25 (2C), 128.27 (d, J = 19.1 Hz, 2C), 128.6, (129.0), 129.4, 130.3,
134.6 (d, J = 7.6 Hz), 135.8, (136.6), (140.2), 140.5, (141.8), 142.0,
161.3 (d, J = 245.2 Hz), 169.6. Signals for the minor rotamer are given
in parentheses. IR (cm−1) 1641, 1465, 1400; HRMS (ES+) calcd for
C25H20BrFNO (M + H)+ 448.0712, found 448.0720.
1
Analytical data for 4: Rf = 0.52 (EtOAc/hexane 3:7); H NMR
(400 MHz, CDCl3) δ 7.63 (d, J = 8.0 Hz, 1H), 7.53 (d, J = 7.6 Hz,
1H), 7.38−7.31 (m, 8H), 7.25−7.17 (m, 4H), 6.21 (s, 1H), 5.83 (s,
1H), 5.75 (s, 1H), 5.45 (d, J = 14.8 Hz, 1H), 5.16 (s, 1H), 3.57 (d, J =
14.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 46.1, 61.0, 119.1, 119.6,
121.3, 126.1, 126.2, 126.9, 127.15 (2C), 127.16 (2C), 127.18 (2C),
127.2 (2C), 127.8, 128.3, 132.2, 135.3, 135.5, 137.5, 138.9, 147.0,
162.8; IR (cm−1) 1689, 1494, 1265; HRMS (ES+) calcd for
C25H21BrNO (M + H)+ 430.0807, found 430.0808.
General Procedure for the Preparation of Dihydropyrroles
9a−e and 11a,b (Conditions C, Table 1). The solution of 1,6-
enynes 5a−e or 7a,b (1.0 equiv, 0.147−0.21 mmol) in toluene (5−15
mL) was degassed with ethylene for 5 min, Grubb’s I catalyst (0.1
equiv, 0.015−0.02 mmol) was added, and the reaction mixture was
stirred at 85 °C under ethylene atmosphere for 2 h. The mixture was
N-Benzoyl-2-(2-bromophenyl)-3-(1-(4-fluorophenyl)vinyl)-2,5-di-
hydro-1H-pyrrole (9d). The treatment of enyne 5d (0.079 g, 0.17
mmol, 1.0 equiv) with Grubb’s I catalyst (0.015 g, 0.017 mmol, 0.1
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equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (1:5)
afforded dihydropyrrole 9d (0.069 g, 87%) as a colorless heavy oil: Rf
CDCl3) δ 8.32 (br s, 0.8H), 8.1 (br s, 0.2H), 7.72 (d, J = 7.2 Hz, 1H),
7.56 (d, J = 6.4 Hz, 2H), 7.49−7.38 (m, 4H), 7.25−7.14 (m, 1H),
7.08−6.97 (m, 3.5H), 6.47 (s, 0.5H), 6.10−5.90 (m, 0.3H), 5.8 (s,
0.7H), 5.31 (s, 1H), 5.16 (s, 1H), 4.85−4.65 (m, 1.3H), 4.25 (d, J =
16.8 Hz, 0.7H). The signals that integrate for less than 1H arise due to
hindered rotation as confirmed by the temperature-dependent 1H
NMR spectra recorded for the diene 9a. 13C NMR (125 MHz, CDCl3)
δ 57.9, 67.8, 115.2 (d, J = 21.3 Hz, 2C), 117.8, 122.9, (125.2), 125.7,
126.0, 127.2 (2C), 128.2 (d, J = 6.3 Hz), 128.42 (2C), 128.48, (128.8),
(129.5), 129.8 (d, J = 7.7 Hz, 2C), 130.1, 130.5, (133.5), 135.7, 136.2,
141.1, 149.2, 162.3 (d, J = 245.2 Hz), 170.0. Signals for the minor
rotamer are given in parentheses. IR (cm−1) 1643, 1465, 1409; HRMS
(ES+) calcd for C24H18BrFN2ONa (M + Na)+, 471.0484 found
471.0481.
General Procedure for the Synthesis of Dihydropyridines
10a−e and 12a−c (Conditions D, Table 1). The solution of 1,7-
enynes 6a−e or 8a−c (1.0 equiv, 0.11−0.27 mmol) in toluene (5−10
mL) was degassed with ethylene for 5 min, Grubb’s II catalyst (0.1
equiv, 0.011−0.027 mmol) was added, and the mixture was stirred at
85 °C under ethylene atmosphere for 8 h. The mixture was cooled to
rt, directly loaded on a silica column, and purified by flash
chromatography eluting with EtOAc/hexanes mixtures to afford
dihydropyridines 10a−e and 12a−c.
1
= 0.47 (EtOAc/hexane 3:7); H NMR (400 MHz, CDCl3) δ 7.62−
7.49 (m, 2H), 7.47−7.36 (m, 2H), 7.33 (t, J = 7.6 Hz, 1H), 7.68−7.10
(m, 5H), 7.02 (q, J = 8.8 Hz, 3H), 6.62 (s, 0.7H), 6.09 (s, 0.3H), 5.91
(s, 0.3H), 5.72 (s, 0.7H), 5.37 (s, 0.7H), 5.27 (s, 0.3H), 5.13 (s, 0.7H),
5.06 (s, 0.3H), 4.84−4.66 (m, 1.5H), 4.28 (d, J = 16.4 Hz, 0.5H). The
signals that integrate for less than 1H arise due to hindered rotation as
1
confirmed by the temperature-dependent H NMR spectra recorded
for the diene 9a. 13C NMR (125 MHz, CDCl3) δ (54.3), 56.9, 67.6,
115.1 (d, J = 21.3 Hz, 2C), (117.0), 117.7, (124.0), 125.1, 125.9, 127.2
(2C), 127.7, 128.2 (2C), 128.5, 129.1, 129.2, [129.5, (d, J = 7.8 Hz,)],
129.5 (d, J = 8.0 Hz, 2C), 130.2, (132.6), 133.6, 136.1, (136.4), 136.7
(d, J = 3.1 Hz), (136.8), 139.4, 141.1, (141.2), (142.6), [162.4, (d, J =
245.5 Hz,)], 162.3 (d, J = 245.0 Hz), 169.6, (171.1). Signals for the
minor rotamer are given in parentheses. IR (cm−1) 1643, 1508, 1448;
HRMS (ES+) calcd for C25H19BrFNONa (M + Na)+ 470.0532, found
470.0537.
N-Benzoyl-2-(2-bromophenyl)-3-(1-(4-fluorophenyl)vinyl)-2,5-di-
hydro-1H-pyrrole (9e). The treatment of enyne 5e (0.09 g, 0.2 mmol,
1.0 equiv) with Grubb’s I catalyst (0.016 g, 0.02 mmol, 0.1 equiv)
according to the general procedure described above, followed by flash
chromatography over silica eluting with EtOAc/hexane (3:7) afforded
dihydropyrrole 9e (0.057 g, 63%) as a colorless oil: Rf = 0.45 (EtOAc/
N-Benzoyl-2-(2-bromophenyl)-3-(1-phenylvinyl)-1,2,5,6-tetrahy-
dropyridine (10a). The treatment of enyne 6a (0.12 g, 0.27 mmol, 1.0
equiv) with Grubb’s II catalyst (0.023 g, 0.027 mmol, 0.1 equiv)
according to the general procedure described above followed by flash
chromatography over silica eluting with EtOAc/hexane (1:8) afforded
dihydropyridine 10a (0.108 g, 92%) as a colorless oil: Rf = 0.6
(EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 7.70 (br s, 1H),
7.51 (d, J = 7.6 Hz, 3H), 7.45−7.40 (m, 3H), 7.37−7.31 (m, 6H), 7.22
(t, J = 7.2 Hz, 1H), 6.97 (br s, 1H), 5.98 (br s, 1H), 5.15 (br s, 1H),
5.04 (br s, 1H), 3.57 (br s, 1H), 3.16 (br s, 1H), 2.26 (br s, 1H), 2.11
(br s, 1H). The broadening of some signals arise due to hindered
1
hexane 3:7); H NMR (400 MHz, CDCl3) δ 7.60−7.52 (m, 2H),
7.46−7.36 (m, 3H), 7.32 (t, J = 7.6 Hz, 1H), 7.22 (d, J = 8.4 Hz,
2.5H), 7.18−7.09 (m, 1.5H), 7.00 (t, J = 7.2 Hz, 1H), 6.85 (t, J = 9.2
Hz, 2H), 6.62 (br s, 0.7H), 6.09 (br s, 0.3H), 5.93 (s, 0.4H), 5.76 (s,
0.6H), 5.32 (s, 0.6H), 5.20 (br s, 0.4H), 5.12 (s, 0.6H), 5.05 (s, 0.4H),
4.82−4.68 (m, 1.4H), 4.28 (d, J = 16.0 Hz, 0.6H), 3.82 (s, 3H). The
signals that integrate for less than 1H arise due to hindered rotation as
1
confirmed by the temperature-dependent H NMR spectra recorded
for the diene 9a. 13C NMR (125 MHz, CDCl3) δ (54.3), 55.2, 56.9,
67.6, 115.9, 116.7, (124.0), 124.8, 125.9, 127.2 (2C), 127.6, (127.8),
(128.1), 128.2 (2C), 128.4, 129.0 (2C), 129.2, 129.3 (2C), (129.7),
130.1, (132.6), 132.9, 133.2, 133.5, 136.2, (136.8), (139.5), 141.60,
(141.65), (142.9), 159.1, (159.2), 169.5, (171.2). Signals for the minor
rotamer are given in parentheses. IR (cm−1) 1643, 1398, 1027; HRMS
(ES+) calcd for C26H23BrNO2 (M + H)+ 460.0912, found 460.0904.
N-Benzoyl-2-(2-bromopyridin-3-yl)-3-(1-phenylvinyl)-2,5-dihy-
dro-1H-pyrrole (11a). The treatment of enyne 7a (0.072 g, 0.17
mmol, 1.0 equiv) with Grubb’s I catalyst (0.014 g, 0.017 mmol, 0.1
equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (1:3)
afforded dihydropyrrole 11a (0.05 g, 69%) as a colorless oil: Rf = 0.55
1
rotation as suggested by the temperature-dependent H NMR spectra
recorded for the diene 9a. 13C NMR (125 MHz, CDCl3) δ 26.7, 40.1,
52.9, 115.1, 125.1, 126.8, 127.3, 127.5, 127.7, 128.0 (2C), 128.4, 128.9
(2C), 129.3, 129.9 (2C), 131.0, 133.8 (2C), 135.8, 137.1, 138.6, 141.1,
147.0, 171.3; IR (cm−1) 1645, 1465, 1409; HRMS (ES+) calcd for
C26H23BrNO (M + H)+ 444.0963, found 444.0964.
N-Benzoyl-2-(2-bromo-4,5-dimethoxyphenyl)-3-(1-phenylvinyl)-
1,2,5,6-tetrahydropyridine (10b). The treatment of enyne 6b (0.055
g, 0.11 mmol, 1.0 equiv) with Grubb’s II catalyst (0.0093 g, 0.011
mmol, 0.1 equiv) according to the general procedure described above
followed by flash chromatography over silica eluting with EtOAc/
hexane (1:4) afforded dihydropyridine 10b (0.048 g, 87%) as a
colorless heavy oil: Rf = 0.4 (EtOAc/hexane 3:7); 1H NMR (400
MHz, CDCl3) δ 7.68−7.49 (m, 3H), 7.48−7.28 (m, 7H), 7.16 (br s,
1H), 7.02 (s, 1H), 6.88 (br s, 1H), 6.00 (br s, 1H), 5.20 (br s, 1H),
5.06 (br s, 1H), 3.91 (s, 3H), 3.88 (s, 3H), 3.61 (br s, 1H), 3.21 (br s,
1H), 2.28 (br s, 1H), 2.11 (br s, 1H). The broadening of some signals
arise due to hindered rotation as suggested by the temperature-
dependent 1H NMR spectra recorded for the diene 9a. 13C NMR (125
MHz, CDCl3) δ 26.8, 40.2, 52.8, 56.18, 56.19, 114.1, 115.3, 116.4,
127.4, 127.5, 127.9, 128.1 (2C), 128.3, 128.6, 128.8 (2C), 129.9 (2C),
130.6, 135.9, 137.5, 141.0, 146.9, 147.6 (2C), 149.0, 171.1; IR (cm−1)
1643, 1440, 1205, 1026; HRMS (ES+) calcd for C28H26BrNO3Na (M
+ Na)+, 526.0994, found 526.0994.
N-Benzoyl-2-(2-bromo-5-fluorophenyl)-3-(1-phenylvinyl)-1,2,5,6-
tetrahydropyridine (10c). The treatment of enyne 6c (0.09 g, 0.19
mmol, 1.0 equiv) with Grubb’s II catalyst (0.016 g, 0.019 mmol, 0.1
equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (1:9)
afforded dihydropyridine 10c (0.079 g, 88%) as a yellow heavy oil: Rf
= 0.55 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 7.63 (br
s, 1H), 7.52−7.48 (m, 2H), 7.45−7.35 (m, 6H), 7.34−7.30 (m, 2H),
7.24 (dd, J = 9.6 Hz, J = 2.8 Hz, 1H), 7.10−6.75 (m, 2H), 6.01 (br s,
1H), 5.13 (br s, 1H), 5.06 (br s, 1H), 3.60 (br s, 1H), 3.14 (br s, 1H),
2.25 (br s, 1H), 2.11 (br s, 1H). The broadening of some signals arise
due to hindered rotation as suggested by the temperature-dependent
1
(EtOAc/hexane 7:3); H NMR (400 MHz, CDCl3) δ 8.31 (ddd, J =
10.0 Hz, J = 6.0 Hz, J = 1.6 Hz, 0.7H), 8.19 (br s, 0.3H), 7.78 (dd, J =
7.6 Hz, J = 1.6 Hz, 0.5H), 7.71 (dd, J = 8.0 Hz, J = 1.6 Hz, 0.5H), 7.56
(d, J = 7.2 Hz, 2H), 7.42 (q, J = 7.2 Hz, 3H), 7.38−7.30 (m, 4H),
7.23−7.29 (m, 1H), 7.20 (br s, 1H), 7.03 (br s, 0.5H), 6.49 (s, 0.5H),
6.15−5.90 (m, 0.3H), 5.83 (s, 0.7H), 5.34 (s, 0.5H), 5.28 (s, 0.5H),
5.19 (d, J = 4.0 Hz, 0.7H), 5.11 (d, J = 11.2 Hz, 0.3H), 4.82−4.67 (m,
1.3H), 4.31 (d, J = 16.4 Hz, 0.7H). The signals that integrate for less
than 1H arise due to hindered rotation as confirmed by the
1
temperature-dependent H NMR spectra recorded for the diene 9a.
13C NMR (125 MHz, CDCl3) δ (54.3), 57.1, (66.4), 67.8, 117.4,
(117.7), (122.6), 122.9, (125.7), 125.81, (125.89), 127.2 (2C), 127.91,
127.96, 128.1 (2C), 128.2 (2C), 128.4 (2C), 128.7, 128.8, (129.7),
130.4, (134.2), 135.7, (136.5), (140.0), 140.2, 142.0, (142.1), 148.7,
(148.8), 149.1, (150.2), 169.9. Signals for the minor rotamer are given
in parentheses. IR (cm−1) 1643, 1497, 1400; HRMS (ES+) calcd for
C24H20BrN2O (M + H)+ 431.0759, found 431.0769.
N-benzoyl-2-(2-bromopyridin-3-yl)-3-(1-(4-fluorophenyl)vinyl)-
2,5-dihydro-1H-pyrrole (11b). The treatment of enyne 7b (0.066 g,
0.147 mmol, 1.0 equiv) with Grubbs I catalyst (0.012 g, 0.015 mmol,
0.1 equiv) according to the general procedure described above
followed by flash chromatography over silica eluting with EtOAc/
hexane (1:3) afforded dihydropyrrole 11b (0.039 g, 60%) as a
1
colorless oil: Rf = 0.5 (EtOAc/hexane 7:3); H NMR (400 MHz,
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Article
1H NMR spectra recorded for the diene 9a. 13C NMR (125 MHz,
1H), 7.74 (dd, J = 7.2 Hz, J = 1.6 Hz, 1H), 7.52 (dd, J = 7.6 Hz, J = 1.2
Hz, 2H), 7.47−7.39 (m, 3H), 7.32 (dd, J = 4.8 Hz, J = 2.8 Hz, 1H),
7.30−7.22 (m, 2H), 7.06 (t, J = 8.6 Hz, 2H), 6.86 (br s, 1H), 6.08 (s,
1H), 5.13 (br s, 1H), 5.05 (s, 1H), 3.64 (br s, 1H), 3.05 (br s, 1H),
2.31 (br s, 1H), 2.14 (br s, 1H).The broadening of some signals arise
due to hindered rotation as suggested by the temperature-dependent
1H NMR spectra recorded for the diene 9a. 13C NMR (125 MHz,
CDCl3) δ 26.6, 40.2, 52.7, 115.2, 116.8, [117.7, (d, J = 22.1 Hz)],
118.2 (d, J = 24.0 Hz), (119.1), 126.8, 127.4 (d, J = 12.0 Hz, 2C),
128.1 (2C), 128.4, 128.81, 128.88 (2C), (129.3), 129.9, 130.1, 130.4,
133.8, 134.9 (d, J = 7.6 Hz, 2C), (135.6), 136.7, 140.8, 146.9, 161.6 (d,
J = 245.1 Hz), [161.9, (d, J = 246.7 Hz)], (171.4), 172.6. Signals for
the minor rotamer are given in parentheses. IR (cm−1) 1649, 1465,
1445; HRMS (ES+) calcd for C26H22BrFNO (M + H)+ 462.0869,
found 462.0862.
CDCl3) δ 26.5, 40.2, 52.4, 115.1 (d, J = 21.2 Hz, 2C), 115.66, 115.68,
122.1, 127.5 (2C), 128.5, 129.5, 130.2 (2C), 130.3 (d, J = 8.0 Hz, 2C),
135.4, 135.8, 136.4 (d, J = 3.2 Hz), 139.0, 144.8, 146.0, 149.2, 162.3
(d, J = 245 Hz), 171.7; IR (cm−1) 1645, 1508, 1402; HRMS (ES+)
calcd for C25H20BrFN2ONa (M + Na)+ 485.0641, found 485.0634.
N-Benzoyl-2′-bromo-3-(1-(4-methoxyphenyl)vinyl)-1,2,5,6-tetra-
hydro-2,3′-bipyridine (12c). The treatment of enyne 8c (0.1 g, 0.21
mmol, 1.0 equiv) with Grubb’s II catalyst (0.018 g, 0.021 mmol, 0.1
equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (2:3)
afforded dihydropyridine 12c (0.058 g, 58%) as a colorless oil: Rf = 0.3
(EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 8.37 (d, J = 3.6
Hz, 1H), 7.75 (dd, J = 7.6 Hz, J = 1.6 Hz, 1H), 7.53 (dd, J = 7.6 Hz, J
= 1.6 Hz, 2H), 7.48−7.39 (m, 3H), 7.30 (dd, J = 4.8 Hz, J = 2.8 Hz,
1H), 7.23 (d, J = 8.8 Hz, 2H), 6.94−6.88 (m, 2H), 6.87 (br s, 1H),
6.10 (s, 1H), 5.09 (br s, 1H), 5.04 (s, 1H), 3.85 (s, 3H), 3.64 (br s,
1H), 3.04 (br s, 1H), 2.31 (br s, 1H), 2.10 (br s, 1H). The broadening
of some signals arise due to hindered rotation as suggested by the
N-Benzoyl-2-(2-bromophenyl)-3-(1-(4-fluorophenyl)vinyl)-
1,2,5,6-tetrahydropyridine (10d). The treatment of enyne 6d (0.08 g,
0.17 mmol, 1.0 equiv) with Grubb’s II catalyst (0.015 g, 0.017 mmol,
0.1 equiv) according to the general procedure described above
followed by flash chromatography over silica eluting with EtOAc/
hexane (1:9) afforded dihydropyridine 10d (0.068 g, 85%) as a
1
colorless oil: Rf = 0.6 (EtOAc/hexane 3:7); H NMR (400 MHz,
CDCl3) δ 7.70 (br s, 1H), 7.62−7.47 (m, 4H), 7.44−7.38 (m, 3H),
7.36−7.30 (m, 2H), 7.24−7.30 (m, 1H), 7.05 (t, J = 8.4 Hz, 2H), 6.93
(br s, 1H), 5.98 (br s, 1H), 5.15 (br s, 1H), 5.02 (br s, 1H), 3.60 (br s,
1H), 3.17 (br s, 1H), 2.28 (br s, 1H), 2.12 (br s, 1H). The broadening
of some signals arise due to hindered rotation as suggested by the
1
temperature-dependent H NMR spectra recorded for the diene 9a.
13C NMR (125 MHz, CDCl3) δ 26.7, 40.1, 53.0, 114.9 (d, J = 21.2 Hz,
2C), 115.4, 125.1, 126.8, 127.5, 128.4, 128.9, 129.4, 130.0 (2C), 130.4
(d, J = 7.8 Hz, 2C), 130.9, 133.9 (2C), 135.8, 136.9 (d, J = 3.3 Hz),
137.3, 138.5, 146.1, 160.2 (d, J = 244.5 Hz), 171.3; IR (cm−1) 1643,
1440, 1402; HRMS (ES+) calcd for C26H21BrFNONa (M + Na)+
484.0688, found 484.0688.
1
temperature-dependent H NMR spectra recorded for the diene 9a.
13C NMR (125 MHz, CDCl3) δ 26.5, 40.3, 52.5, 55.1, 113.5 (2C),
114.8, 122.1, 127.5, 128.4 (2C), 129.1, 129.8 (2C), 130.1 (2C), 132.8,
135.5, 136.0, 136.6, 139.1, 144.8, 146.5, 149.1, 159.1, 171.7; IR (cm−1)
1647, 1458, 1400; HRMS (ES+) calcd for C26H24BrN2O2 (M + H)+
475.1021, found 475.1018.
N-Benzoyl-2-(2-bromophenyl)-3-(1-(4-methoxyphenyl)vinyl)-
1,2,5,6-tetrahydropyridine (10e). The treatment of enyne 6e (0.079
g, 0.17 mmol, 1.0 equiv) with Grubb’s II catalyst (0.014 g, 0.017 mmol,
0.1 equiv) according to the general procedure described above
followed by flash chromatography over silica eluting with EtOAc/
hexane (1:8) afforded dihydropyridine 10e (0.063 g, 80%) as a
General Procedure for the Synthesis of Benzoindolines
13a−e and Pyrroloquinolines 15a,b (Conditions E, Table 1). A
solution of the dienes 9a−e and 11a−b (1 equiv, 0.065−0.12 mmol)
in DMF (2 mL) was added to a mixture of solid Pd(OAc)2 (0.1 equiv,
0.006−0.012 mmol) and NaOAc (1.1 equiv, 0.07−0.13 mmol) in a
sealed tube. The tube was flushed with argon and capped, and the
reaction mixture was stirred at 120 °C for 12 h. The mixture was
cooled to rt, cold water (2 mL) was added, and the mixture was
extracted with EtOAc (3 × 20 mL). Combined organic layers were
washed with brine, dried (anhydrous MgSO4), and solvents were
removed under reduced pressure to afford the crude products that
were purified by flash chromatography over silica eluting with EtOAc/
hexane mixture to afford benzoindolines 13a−e and pyrroloquinolines
15a−b.
N-Benzoyl-4-phenyl-2,3-dihydro-1H-benzo[g]indole (13a). The
treatment of diene 9a (0.048 g, 0.11 mmol, 1.0 equiv) with Pd(OAc)2
(0.0026 g, 0.01 mmol, 0.1 equiv) and NaOAc (0.01 g, 0.12 mmol, 1.1
equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (1:9)
afforded benzoindoline 13a (0.028 g, 71%) as a white solid: mp 178−
180 °C; Rf = 0.6 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ
7.91−7.82 (m, 3H), 7.81−7.76 (m, 1H), 7.74 (s, 1H), 7.58−7.35 (m,
9H), 7.43−7.38 (m, 1H), 4.29 (t, J = 7.6 Hz, 2H), 3.22 (t, J = 7.6 Hz,
2H); 13C NMR (125 MHz, CDCl3) δ 30.9, 55.1, 123.8, 125.2, 125.5,
125.7 126.4, 127.4, 128.3, 128.52 (2C), 128.54 (2C), 128.56 (2C),
128.9 (2C), 130.3, 131.5, 133.9, 135.9, 136.5, 139.5, 140.2, 170.8; IR
(cm−1) 1650, 1494, 1386; HRMS (ES+) calcd for C25H19NONa (M +
Na)+ 372.1364, found 372.1375.
1
colorless oil: Rf = 0.45 (EtOAc/hexane 3:7); H NMR (400 MHz,
CDCl3) δ 7.69 (br s, 1H), 7.50 (d, J = 6.4 Hz, 3H), 7.46−7.37 (m,
3H), 7.34 (t, J = 7.6 Hz, 1H), 7.30−7.17 (m, 3H), 6.94 (br s, 1H),
6.91 (d, J = 8.8 Hz, 2H), 6.03 (br s, 1H), 5.11 (br s, 1H), 5.02 (br s,
1H), 3.84 (s, 3H), 3.56 (br s, 1H), 3.16 (br s, 1H), 2.27 (br s, 1H),
2.11 (br s, 1H). The broadening of some signals arise due to hindered
1
rotation as suggested by the temperature-dependent H NMR spectra
recorded for the diene 9a. 13C NMR (125 MHz, CDCl3) δ 25.3, 39.1,
52.0, 54.3, 112.3 (2C), 113.3, 124.3, 125.7, 126.5, 127.3, 127.6, 128.2,
128.90 (2C), 128.93 (2C), 130.0, 132.3, 132.8 (2C), 134.8, 136.4,
137.6, 145.6, 157.8, 170.3; IR (cm−1) 1639, 1485, 1446; HRMS (ES+)
calcd for C27H25BrNO2 (M + H)+ 474.1069, found 474.1069.
N-Benzoyl-2′-bromo-3-(1-phenylvinyl)-1,2,5,6-tetrahydro-2,3′-bi-
pyridine (12a). The treatment of enyne 8a (0.065 g, 0.15 mmol, 1.0
equiv) with Grubb’s II catalyst (0.012 g, 0.015 mmol, 0.1 equiv)
according to the general procedure described above followed by flash
chromatography over silica eluting with EtOAc/hexane (2:3) afforded
dihydropyridine 12a (0.045 g, 69%) as a colorless heavy oil: Rf = 0.3
1
(EtOAc/hexane 3:7); H NMR (400 MHz, CDCl3) δ 8.37 (s, 1H),
7.78 (d, J = 7.6 Hz, 1H), 7.53 (d, J = 7.2 Hz, 2H), 7.47−7.30 (m, 9H),
6.92 (s, 1H), 6.05 (s, 1H), 5.14 (s, 1H), 5.07 (s, 1H), 3.63 (br s, 1H),
3.05 (br s, 1H), 2.27 (br s, 1H), 2.11 (br s, 1H). The broadening of
some signals arise due to hindered rotation as suggested by the
1
temperature-dependent H NMR spectra recorded for the diene 9a.
13C NMR (125 MHz, CDCl3) δ 26.5, 40.2, 52.3, 115.4, 122.2, 127.5
(2C), 127.7, 128.1 (2C), 128.4, 128.7 (2C), 129.5, 130.2 (2C), 135.5,
136.0, 136.2, 139.1, 140.6, 144.8, 146.8, 149.1, 171.7; IR (cm−1) 1643,
1446, 1402; HRMS (ES+) calcd for C25H21BrN2ONa (M + Na)+
467.0735, found 467.0742.
N-Benzoyl-7,8-dimethoxy-4-phenyl-2,3-dihydro-1H-benzo[g]-
indole (13b). The treatment of diene 9b (0.035 g, 0.07 mmol, 1.0
equiv) with Pd(OAc)2 (0.0016 g, 0.007 mmol, 0.1 equiv) and NaOAc
(0.0063 g, 0.077 mmol, 1.1 equiv) according to the general procedure
described above, followed by flash chromatography over silica eluting
with EtOAc/hexane (1:3) afforded benzoindoline 13b (0.02 g, 68%)
N-Benzoyl-2′-bromo-3-(1-(4-fluorophenyl)vinyl)-1,2,5,6-tetrahy-
dro-2,3′-bipyridine (12b). The treatment of enyne 8b (0.1 g, 0.22
mmol, 1.0 equiv) with Grubb’s II catalyst (0.019 g, 0.022 mmol, 0.1
equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (2:3)
afforded dihydropyridine 12b (0.062 g, 62%) as a colorless oil: Rf =
1
as a yellow oil: Rf = 0.23 (EtOAc/hexane 3:7); H NMR (400 MHz,
CDCl3) δ 7.84 (d, J = 6.8 Hz, 2H), 7.60 (s, 1H), 7.57−7.45 (m, 7H),
7.39 (t, J = 6.8 Hz, 1H), 7.18 (s, 1H), 7.02 (s, 1H), 4.28 (t, J = 7.2 Hz,
2H), 4.03 (s, 3H), 3.91 (s, 3H), 3.21 (t, J = 7.6 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 30.6, 55.2, 55.8, 55.9, 104.3 106.6, 119.6, 124.8,
1
0.35 (EtOAc/hexane 3:7); H NMR (400 MHz, CDCl3) δ 8.38 (s,
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127.1, 128.4 (2C), 128.5 (2C), 128.6, 128.7 (2C), 130.0, 131.31,
131.35 (2C), 134.7, 136.3, 138.3, 140.4, 149.0, 149.9, 170.2; IR (cm−1)
1649, 1498, 1161, 1012; HRMS (ES+) calcd for C27H24O3N (M + H)+
410.1756, found 410.1756.
N-Benzoyl-8-fluoro-4-phenyl-2,3-dihydro-1H-benzo[g]indole
(13c). The treatment of diene 9c (0.029 g, 0.065 mmol, 1.0 equiv)
with Pd(OAc)2 (0.0015 g, 0.006 mmol, 0.1 equiv) and NaOAc (0.006
g, 0.07 mmol, 1.1 equiv) according to the general procedure described
above followed by flash chromatography over silica eluting with
EtOAc/hexane (1:9) afforded benzoindoline 13c (0.016 g, 65%) as a
heavy oil: Rf = 0.72 (EtOAc/hexane 3:7); 1H NMR (400 MHz,
CDCl3) δ 7.95−7.82 (m, 3H), 7.75 (s, 1H), 7.64−7.38 (m, 8H), 7.28
(d, J = 1.2 Hz, 2H), 4.30 (t, J = 6.4 Hz, 2H), 3.23 (t, J = 6.8 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 30.9, 55.0, 109.2 (d, J = 23.0 Hz),
with EtOAc/hexane (2:3) afforded pyrroloquinoline 15b (0.016 g,
65%) as a yellow oil in a mixture with aromatized oxidation product
(8.5% by GC−MS, M+ 366.2; see the Supporting Information): Rf =
0.3 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 8.92 (dd, J =
4.4 Hz, J = 1.6 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.01 (s, 1H), 7.85 (d,
J = 7.2 Hz, 2H), 7.59 (d, J = 7.2 Hz, 1H), 7.55−7.51 (m, 4H), 7.38
(dd, J = 8.4 Hz, J = 4.0 Hz, 1H), 7.19 (t, J = 8.8 Hz, 2H), 4.34 (t, J =
7.6 Hz, 2H), 3.24 (t, J = 7.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
30.6, 55.1, 115.7 (d, J = 21.3 Hz, 2C), 119.4, 120.2, 127.3, 128.6 (2C),
128.7 (2C), 130.1 (d, J = 8.1 Hz, 2C), 130.6, 131.8, 134.0, 135.4, 130.5
(d, J = 3.2 Hz), 138.8, 139.4, 148.1, 150.3, 162.5 (d, J = 246 Hz),
171.0; IR (cm−1) 1637, 1440, 1400; HRMS (ES+) calcd for
C24H17FN2ONa (M + Na)+ 391.1223, found 391.1231.
General Procedure for the Preparation of Indenopyridines
14a−e and Tetrahydrophenanthrolines 16a−c (Conditions F,
Table 1). To a mixture of solid Pd(OAc)2 (0.1 equiv, 0.008−0.023
mmol), PPh3 (0.2 equiv, 0.016−0.045 mmol), and Cs2CO3 (2.0 equiv,
0.16−0.45 mmol) in a sealed tube under argon was added a solution of
dienes 10a−e and 12a−c (1.0 equiv, 0.08−0.23 mmol) in DMF (2.0
mL). The tube was flushed with argon and capped, and the reaction
mixture was stirred at 120 °C for 15 h. The mixture was cooled to rt,
water (2 mL) was added, and the mixture was extracted with EtOAc (3
× 20 mL). The combined organic layers were washed with brine and
dried (anhydrous MgSO4), and solvents were removed under reduced
pressure to afford crude products that were separated by flash
chromatography over silica to afford indenopyridines 14a−e and
tetrahydrophenanthroline 16a−c.
(4aR*,5aR*,9bS*)-N-Benzoyl-5a-phenyl-2,5,5a,9b-tetrahydro-
1H-cyclopropa[2,3]indeno[1,2-b]pyridine (14a) and N-Benzoyl-6-
phenyl-1,2,3,4-tetrahydrobenzo[h]quinoline (17). The treatment of
diene 10a (0.1 g, 0.23 mmol, 1.0 equiv) with Pd(OAc)2 (0.005 g,
0.023 mmol, 0.1 equiv), Cs2CO3 (0.147 g, 0.45 mmol, 2.0 equiv), and
PPh3 (0.012 g, 0.045 mmol, 0.2 equiv) according to the general
procedure described above followed by flash chromatography over
silica eluting with EtOAc/hexane (1:8) afforded indenopyridine 14a
(0.066 g, 80%) as a fluffy white solid, and continuous elution with
EtOAc/hexane (1:8) afforded benzoquinoline 17 (0.008 g, 10%) as a
white solid.
Analytical data for 14a: mp 73−78 °C; Rf = 0.45 (EtOAc/hexane
3:7); 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 7.2 Hz, 1H), 7.52−
7.42 (m, 5H), 7.35 (t, J = 7.6 Hz, 2H), 7.30−7.22 (m, 4H), 7.20 (t, J =
6.8 Hz, 1H), 6.98 (d, J = 7.2 Hz, 1H), 6.09−6.01 (m, 2H), 5.47 (dd, J
= 9.2 Hz, J = 2.8 Hz, 1H), 4.16−3.95 (m, 1H), 3.59 (d, J = 15.6 Hz,
1H), 2.31 (d, J = 5.6 Hz, 1H), 1.46 (d, J = 5.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 31.0, 40.1, 43.1, 46.5, 59.6, 123.6, 126.8 (2C),
126.9, 127.0, 127.1, 127.9, 128.4 (2C), 128.5 (2C), 129.2, 129.6, 129.7
(2C), 131.2, 136.5, 138.5, 142.8, 149.0, 170.5; IR (cm−1) 1627, 1600,
1444; HRMS (ES+) calcd for C26H21NONa (M + Na)+ 386.1521,
found 386.1519.
116.3 (d, J = 25.2 Hz), 124.8 (d, J = 9.9 Hz), 126.3, 127.5 (2C), 128.5
(2C), 128.6 (2C), 128.8 (2C), 130.7, 130.8, 131.0, 131.5, 131.6, 135.7,
135.8 (d, J = 2.7 Hz), 139.3 (d, J = 5.4 Hz), 139.9, 160.1 (d, J = 245.1
Hz), 170.7; IR (cm−1) 1650, 1496, 1357; HRMS (ES+) calcd for
C25H19FNO (M + H)+ 368.1451, found 368.1446.
N-Benzoyl-4-(4-fluorophenyl)-2,3-dihydro-1H-benzo[g]indole
(13d). The treatment of diene 9d (0.038 g, 0.085 mmol, 1.0 equiv)
with Pd(OAc)2 (0.002 g, 0.008 mmol, 0.1 equiv) and NaOAc (0.0078
g, 0.094 mmol, 1.1 equiv) according to the general procedure
described above followed by flash chromatography over silica eluting
with EtOAc/hexane (1:9) afforded benzoindoline 13d (0.024 g, 78%)
1
as a heavy oil: Rf = 0.75 (EtOAc/hexane 3:7); H NMR (400 MHz,
CDCl3) δ 7.92−7.87 (m, 3H), 7.81 (t, J = 3.2 Hz, 1H), 7.72 (s, 1H),
7.61−7.58 (m, 1H), 7.53 (d, J = 7.6 Hz, 2H), 7.50−7.45 (m, 4H), 7.18
(t, J = 8.8 Hz, 2H), 4.31 (t, J = 7.6 Hz, 2H), 3.20 (t, J = 7.2 Hz, 2H);
13C NMR (125 MHz, CDCl3) δ 30.9, 55.1, 115.4 (d, J = 21.2 Hz, 2C),
123.9, 125.2, 125.6, 125.8, 126.3, 128.3, 128.5 (2C), 128.8 (2C),
130.15, 130.18 (d, J = 25.2 Hz, 2C), 131.6, 133.9, 135.5, 135.9, 136.2
(d, J = 10.4 Hz), 139.6, 162.1 (d, J = 245.0 Hz), 170.8; IR (cm−1)
1650, 1504, 1446; HRMS (ES+) calcd for C25H18FNONa (M + Na)+
390.1270, found 390.1270.
N-Benzoyl-4-(4-methoxyphenyl)-2,3-dihydro-1H-benzo[g]indole
(13e). The treatment of diene 9e (0.055 g, 0.12 mmol, 1.0 equiv) with
Pd(OAc)2 (0.0027 g, 0.012 mmol, 0.1 equiv) and NaOAc (0.011 g,
0.13 mmol, 1.1 equiv) according to the general procedure described
above followed by flash chromatography over silica eluting with
EtOAc/hexane (1:4) afforded benzoindoline 13e (0.03 g, 66%) as
1
colorless oil: Rf = 0.45 (EtOAc/hexane 3:7); H NMR (400 MHz,
CDCl3) δ 7.93−7.84 (m, 3H), 7.80 (d, J = 5.6 Hz, 1H), 7.73 (s, 1H),
7.61−7.50 (m, 3H), 7.49−7.43 (m, 4H), 7.02 (d, J = 8.8 Hz, 2H), 4.30
(t, J = 7.2 Hz, 2H), 3.89 (s, 3H), 3.23 (t, J = 7.6 Hz, 2H); 13C NMR
(125 MHz, CDCl3) δ 31.0, 55.1, 55.3, 113.9 (2C), 123.6, 125.2, 125.3,
125.6, 126.1, 128.2, 128.5 (2C), 128.8 (2C), 129.6 (2C), 130.4, 131.5,
132.6, 134.0, 136.0, 136.1, 139.4, 159.0, 170.7; IR (cm−1) 1650, 1446,
1074; HRMS (ES+) calcd for C26H21NO2Na (M + Na)+ 402.1470,
found 402.1466.
N-Benzoyl-4-phenyl-2,3-dihydro-1H-pyrrolo[2,3-f ]quinoline
(15a). The treatment of diene 11a (0.032 g, 0.07 mmol, 1.0 equiv)
with Pd(OAc)2 (0.0016 g, 0.007 mmol, 0.1 equiv) and NaOAc
(0.0063 g, 0.077 mmol, 1.1 equiv) according to the general procedure
described above followed by flash chromatography over silica eluting
with EtOAc/hexane (2:3) afforded pyrroloquinoline 15a (0.02 g, 77%)
as a colorless oil: Rf = 0.2 (EtOAc/hexane 3:7); 1H NMR (400 MHz,
CDCl3) δ 8.92 (d, J = 2.4 Hz, 1H), 8.23 (d, J = 8.4 Hz, 1H), 8.06 (s,
1H), 7.86 (d, J = 8.0 Hz, 2H), 7.62−7.47 (m, 7H), 7.43 (t, J = 7.2 Hz,
1H), 7.38 (dd, J = 8.4 Hz, J = 4.0 Hz, 1H), 4.33 (t, J = 7.6 Hz, 2H),
3.27 (t, J = 7.6 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ 30.7, 55.2,
119.5, 120.0, 127.1, 127.9, 128.2, 128.5 (2C), 128.6 (2C), 128.70
(2C), 128.77 (2C), 130.9, 131.8, 134.4, 135.5, 139.3, 139.4, 140.1,
149.8, 170.9; IR (cm−1) 1649, 1556, 1490; HRMS (ES+) calcd for
C24H19N2O (M + H)+ 351.1497, found 351.1490.
Analytical data for 17: mp 169−171 °C; Rf = 0.5 (EtOAc/hexane
1
3:7); H NMR (400 MHz, CDCl3) δ 7.89−7.80 (br m, 1.7H), 7.69−
7.62 (m, 2.3H), 7.56−7.41 (m, 7H), 7.24−7.19 (m, 2H), 7.06 (t, J =
6.8 Hz, 0.7H), 6.98 (t, J = 7.2 Hz, 1.3H), 5.06−4.82 (m, 0.5H), 4.36−
4.12 (m, 0.5H), 3.62−3.51 (m, 0.4H), 3.43−3.33 (m, 0.6H), 3.16−
3.01 (m, 1H), 2.86−2.68 (m, 1H), 2.53−2.41 (m, 0.5H), 2.15−1.98
(m, 0.5H), 1.87−1.69 (m, 1H). The signals that integrate for less than
1H arise due to hindered rotation. 13C NMR (125 MHz, CDCl3) δ
(24.8), 24.9, (25.3), 25.9, 43.1, (47.8), 122.6, (123.1), (125.5),
(125.6), 125.7, 126.2, 126.8, (127.1), 127.30, (127.35), 127.4 (2C),
(127.5), 127.6, (127.8), 128.02 (2C), (128.07), (128.2), (128.3), 128.3
(2C), 128.6, (129.4), 129.6 (2C), (129.9), 130.0, (130.1), 130.8,
(130.9), (132.0), 132.2, 132.3, (136.0), 136.5, (136.7), 138.9, (139.6),
140.3, (140.9), 170.3, (172.6). Signals for the minor rotamer are given
in the parentheses; IR (cm−1) 1641, 1490, 1467; HRMS (ES+) calcd
for C26H22NO (M + H)+ 364.1701, found 364.1696.
N-Benzoyl-4,4-fluorophenyl)-2,3-dihydro-1H-pyrrolo[2,3-f ]-
quinoline (15b). The treatment of diene 9b (0.03 g, 0.067 mmol, 1.0
equiv) with Pd(OAc)2 (0.0015 g, 0.0067 mmol, 0.1 equiv) and NaOAc
(0.006 g, 0.07 mmol, 1.1 equiv) according to the general procedure
described above followed by flash chromatography over silica eluting
(4aR*,5aR*,9bS*)-N-Benzoyl-7,8-dimethoxy-5a-phenyl-
2,5,5a,9b-tetrahydro-1H-cyclopropa[2,3]indeno[1,2-b]pyridine
(14b). The treatment of diene 10b (0.04 g, 0.08 mmol, 1.0 equiv) with
Pd(OAc)2 (0.0018 g, 0.008 mmol, 0.1 equiv), Cs2CO3 (0.058 g, 0.16
mmol, 2.0 equiv), and PPh3 (0.0042 g, 0.016 mmol, 0.2 equiv)
3843
dx.doi.org/10.1021/jo400246d | J. Org. Chem. 2013, 78, 3832−3846

The Journal of Organic Chemistry
Article
according to the general procedure described above followed by flash
chromatography over silica eluting with EtOAc/hexane (1:4) afforded
indenopyridine 14b (0.026 g, 78%) as a light yellow solid: mp 220−
222 °C; Rf = 0.35 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3)
δ 7.51−7.43 (m, 5H), 7.39−7.32 (m, 2H), 7.31−7.23 (m, 4H), 6.48 (s,
1H), 6.03−5.96 (m, 2H), 5.44 (dd, J = 9.2 Hz, J = 2.8 Hz, 1H), 4.08−
3.98 (m, 1H), 3.80 (s, 3H), 3.75 (s, 3H), 3.61 (d, J = 15.6 Hz, 1H),
2.29 (d, J = 5.6 Hz, 1H), 1.40 (d, J = 5.2 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 31.0, 40.0, 43.1, 46.3, 56.0, 56.1, 59.7, 106.3, 109.4,
126.80, 126.84 (2C), 128.4 (2C), 128.5 (2C), 129.1, 129.4 (2C),
129.6, 131.3, 134.1, 136.5, 138.6, 140.9, 148.7, 149.2, 170.4; IR (cm−1)
1625, 1423, 1130, 1116; HRMS (ES+) calcd for C28H26NO3 (M + H)+
424.1913, found 424.1913.
mmol, 2.0 equiv), and PPh3 (0.0065 g, 0.02 mmol, 0.2 equiv)
according to the general procedure described above followed by flash
chromatography over silica eluting with EtOAc/hexane (2:3) afforded
phenanthroline 16a (0.022 g, 65%) as a light yellow powder: mp 190−
193 °C; Rf = 0.3 (EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ
8.93 (br s, 0.2H), 8.68 (br s, 0.3H), 8.15 (d, J = 6.4 Hz, 0.3H), 8.05−
7.90 (m, 1.5H), 7.82 (d, J = 5.2 Hz, 0.7H), 7.65−7.38 (m, 7H), 7.32−
7.24 (m, 1H), 7.22 (d, J = 7.2 Hz, 1H), 7.09 (t, J = 7.2 Hz, 1H), 7.00
(t, J = 6.8 Hz, 1H), 4.86 (q, J = 8.4 Hz, 0.5H), 4.25 (br s, 0.5H), 3.57
(br s, 0.5H), 3.42 (br s, 0.5H), 3.14 (d, J = 15.2 Hz, 0.5H), 2.93−2.70
(m, 1.5H), 2.47 (br s, 0.5H), 2.06 (br s, 0.5H), 1.81 (br s, 1H). The
signals that integrate for less than 1H arise due to hindered rotation as
1
confirmed by the temperature-dependent H NMR spectra recorded
for the phenanthroline 16a. 13C NMR (125 MHz, CDCl3) δ (24.9),
25.0, (25.8), 43.5, (47.9), 53.4, 120.3, (120.8), 122.8, (122.9), (127.5),
127.7 (2C), (127.8), 127.9, 128.1 (2C), (128.2), (128.3), 128.4 (2C),
128.8, (129.2), 129.5 (2C), 130.3, 131.0, (131.1), (132.1), 132.5,
(135.1), (135.5), 136.0, 136.4, 139.6, (140.1), 142.6, (143.5), 146.7,
150.0, (170.2), 172.9. Signals for minor rotamer are given in the
parentheses. IR (cm−1) 1643, 1444, 1394; HRMS (ES+) calcd for
C25H20N2ONa (M + Na)+ 387.1473, found 387.1475.
(4aR*,5aR*,9bS*)-N-Benzoyl-8-fluoro-5a-phenyl-2,5,5a,9b-tetra-
hydro-1H-cyclopropa[2,3]indeno[1,2-b]pyridine (14c). The treat-
ment of diene 10c (0.06 g, 0.13 mmol, 1.0 equiv) with Pd(OAc)2
(0.003 g, 0.013 mmol, 0.1 equiv), Cs2CO3 (0.085 g, 0.26 mmol, 2.0
equiv), and PPh3 (0.0068 g, 0.026 mmol, 0.2 equiv) according to the
general procedure described above, followed by flash chromatography
over silica eluting with EtOAc/hexane (1:4) afforded indenopyridine
14c (0.034 g, 71%) as a colorless heavy oil: Rf = 0.5 (EtOAc/hexane
1
1:9); H NMR (400 MHz, CDCl3) δ 7.52−7.40 (m, 6H), 7.32−7.28
N-Benzoyl-5-(4-fluorophenyl)-1,2,3,4-tetrahydro-1,7-phenan-
throline (16b). The treatment of diene 12d (0.055 g, 0.12 mmol, 1.0
equiv) with Pd(OAc)2 (0.0027 g, 0.012 mmol, 0.1 equiv), Cs2CO3
(0.078 g, 0.24 mmol, 2.0 equiv), and PPh3 (0.0063 g, 0.024 mmol, 0.2
equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (2:3)
afforded phenanthroline 16b (0.03 g, 61%) as a colorless oil: Rf = 0.3
(EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 8.91 (br s,
0.25H), 8.67 (br s, 0.25H), 8.15 (d, J = 6.8 Hz, 0.25H), 7.91 (d, J = 8.8
Hz, 1.5H), 7.82 (d, J = 6.0 Hz, 0.75H), 7.62−7.52 (m, 1.25H), 7.51−
7.35 (m, 2.75H), 7.25−7.15 (m, 4H), 7.09 (t, J = 7.6 Hz, 1H), 7.00 (t,
J = 7.6 Hz, 1H), 4.94−4.80 (m, 0.5H), 4.30−3.05 (m, 0.5H), 3.72−
3.72 (m, 0.5H), 3.42 (br s, 0.5H), 3.09 (d, J = 14.0 Hz, 0.5H), 2.85−
2.70 (m, 1.5H), 2.48 (br s, 0.5H), 2.12−2.00 (m, 0.5H), 1.92−1.73
(m, 1H). The signals that integrate for less than 1H arise due to
hindered rotation as confirmed by the temperature-dependent 1H
NMR spectra recorded for the phenanthroline 16a. 13C NMR (125
MHz, CDCl3) δ (24.9), 25.0, (25.8), 43.4, 47.9, (53.4), 115.2, 115.5
(d, J = 21.3 Hz, 2C), [115.5 (d, J = 21.3 Hz,)], 120.4, (121.0), (122.9),
126.8, 127.7 (2C), (128.0), 128.1 (2C), 128.2, (128.5), (128.6), 128.8,
(129.3), (129.9), (130.2), 130.3 (d, J = 5.0 Hz), [130.8 (d, J = 7.6
Hz,)], 130.9, 131.1 (d, J = 7.5 Hz, 2C), [131.4 (d, J = 8.2 Hz,)], 131.9,
(132.3), (135.4), (135.6), 135.9, (136.6), 141.4, (142.3), 146.7,
(149.5), 150.2, 162.5 (d, J = 247 Hz), 170.2, (172.9). Signals for the
minor rotamer are given in parentheses. IR (cm−1) 1643, 1467, 1402;
HRMS (ES+) calcd for C25H20FN2O (M + H)+ 383.1560, found
383.1547.
(m, 2H), 7.30−7.21 (m, 3H), 6.90 (d, J = 6.4 Hz, 2H), 6.09−5.97 (m,
2H), 5.45 (dd, J = 9.2 Hz, J = 2.8 Hz, 1H), 4.13−4.01 (m, 1H), 3.60
(d, J = 16.0 Hz, 1H), 2.29 (d, J = 5.6 Hz, 1H), 1.44 (d, J = 5.2 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 30.9, 40.3, 43.2, 45.7, 59.3, 113.5
(d, J = 22.5 Hz), 115.1 (d, J = 23.0 Hz), 124.5 (d, J = 9.0 Hz), 126.8
(2C), 127.0, 128.4 (2C), 128.5 (2C), 129.1, 129.6 (2C), 129.7, 131.0,
136.2, 138.3, 144.5 (d, J = 2.7 Hz), 144.9 (d, J = 8.1 Hz), 162.1 (d, J =
242.8.1 Hz), 170.5; IR (cm−1) 1625, 1600, 1483; HRMS (ES+) calcd
for C26H21NFO (M + H)+ 382.1607, found 382.1599.
(4aR*,5aR*,9bS*)-N-Benzoyl-5a-(4-fluorophenyl)-2,5,5a,9b-tet-
rahydro-1H-cyclopropa[2,3]indeno[1,2-b]pyridine (14d). The treat-
ment of diene 10d (0.06 g, 0.13 mmol, 1.0 equiv) with Pd(OAc)2
(0.003 g, 0.013 mmol, 0.1 equiv), Cs2CO3 (0.084 g, 0.26 mmol, 2.0
equiv), and PPh3 (0.007 g, 0.026 mmol, 0.2 equiv) according to the
general procedure described above, followed by flash chromatography
over silica eluting with EtOAc/hexane (1:9) afforded indenopyridine
14d (0.04 g, 81%) as a colorless oil: Rf = 0.55 (EtOAc/hexane 3:7); 1H
NMR (400 MHz, CDCl3) δ 7.70 (d, J = 7.2 Hz, 1H), 7.54−7.41 (m,
5H), 7.26−7.18 (m, 4H), 7.03 (t, J = 8.8 Hz, 2H), 6.94 (d, J = 7.6 Hz,
1H), 6.10−5.99 (m, 2H), 5.45 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 4.13−
4.01 (m, 1H), 3.56 (d, J = 15.6 Hz, 1H), 2.25 (d, J = 5.6 Hz, 1H), 1.46
(d, J = 5.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 31.2, 40.0, 43.0,
45.7, 59.5, 115.3 (d, J = 21.2 Hz, 2C), 123.4, 126.8 (2C), 127.1, 127.2,
128.0, 128.5 (2C), 129.3, 129.6, 131.1, 131.2 (d, J = 8.1 Hz, 2C), 134.3
(d, J = 3.1 Hz), 136.4, 142.7, 148.8, 161.4 (d, J = 244.1 Hz), 170.5; IR
(cm−1) 1625, 1598, 1427; HRMS (ES+) calcd for C26H20FNONa (M
+ Na)+ 404.1427, found 404.1419.
(4aR*,5aR*,9bS*)-N-Benzoyl-5a-(4-methoxyphenyl)-2,5,5a,9b-
tetrahydro-1Hcyclopropa[2,3]indeno[1,2-b]pyridine (14e). The
treatment of diene 10e (0.038 g, 0.08 mmol, 1.0 equiv) with
Pd(OAc)2 (0.002 g, 0.008 mmol, 0.1 equiv), Cs2CO3 (0.052 g, 0.16
mmol, 2.0 equiv), and PPh3 (0.0042 g, 0.016 mmol, 0.2 equiv)
according to the general procedure described above followed by flash
chromatography over silica eluting with EtOAc/hexane (1:8) afforded
indenopyridine 14e (0.025 g, 80%) as a colorless oil: Rf = 0.4 (EtOAc/
hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 7.69 (d, J = 6.8 Hz, 1H),
7.52−7.42 (m, 5H), 7.26−7.15 (m, 4H), 6.95 (d, J = 7.2 Hz, 1H), 6.88
(d, J = 8.8 Hz, 2H), 6.09−5.99 (m, 2H), 5.48 (dd, J = 9.2 Hz, J = 2.8
Hz, 1H), 4.12−4.00 (m, 1H), 3.82 (s, 3H), 3.58 (d, J = 15.2 Hz, 1H),
2.24 (d, J = 5.6 Hz, 1H), 1.40 (d, J = 5.2 Hz, 1H); 13C NMR (125
MHz, CDCl3) δ 31.3, 39.9, 43.0, 45.9, 55.2, 59.5, 113.8 (2C), 123.5,
126.9 (2C), 127.0, 127.1, 127.9, 128.5 (2C), 129.0, 129.5, 130.6, 130.8
(2C), 131.5, 136.6, 142.6, 149.3, 158.5, 170.5; IR (cm−1) 1625, 1598,
1245; HRMS (ES+) calcd for C27H23NO2Na (M + Na)+ 416.1626,
found 416.1626.
N-Benzoyl-5-(4-methoxyphenyl)-1,2,3,4-tetrahydro-1,7-phenan-
throline (16c). The treatment of diene 12c (0.08 g, 0.169 mmol, 1.0
equiv) with Pd(OAc)2 (0.0038 g, 0.017 mmol, 0.1 equiv), Cs2CO3
(0.11 g, 0.338 mmol, 2.0 equiv), and PPh3 (0.009 g, 0.038 mmol, 0.2
equiv) according to the general procedure described above followed by
flash chromatography over silica eluting with EtOAc/hexane (2:3)
afforded phenanthroline 16c (0.04 g, 59%) as a colorless oil: Rf = 0.25
(EtOAc/hexane 3:7); 1H NMR (400 MHz, CDCl3) δ 8.91 (br s,
0.25H), 8.66 (br s, 0.5H), 8.11 (d, J = 6.1 Hz, 0.25H), 7.93 (d, J = 8.4
Hz, 1.5H), 7.82 (d, J = 5.2 Hz, 0.5H), 7.57 (s, 1.25H), 7.49−7.33 (m,
3H), 7.21 (d, J = 7.2 Hz, 1.25H), 7.13−6.96 (m, 4.5H), 4.91−4.78 (m,
0.5H), 4.27−3.99 (m, 0.5H), 3.92 (s, 2H), 3.90 (s, 1H), 3.70−3.52 (m,
0.5H), 3.41 (br s, 0.5H), 3.17 (d, J = 15.6 Hz, 0.5H), 2.93−2.70 (m,
1.5H), 2.47 (br s, 0.5H), 2.06 (br s, 0.5H), 1.92−1.75 (m, 1H). The
signals that integrate for less than 1H arise due to hindered rotation as
1
confirmed by the temperature-dependent H NMR spectra recorded
for the phenanthroline 16a. 13C NMR (125 MHz, CDCl3) δ (25.0),
25.1, (25.8), 43.5, 47.9, (53.4), (55.3), 55.4, (113.7), 113.9 (2C),
120.2, (120.7), 122.7, (122.8), (126.8), 127.73 (2C), (127.76), 128.1
(2C), (128.2), (128.3), 128.6, 128.8, (130.3), 130.4, 130.7 (2C),
130.9, (131.1), 131.9, (132.5), 132.7, (135.0), (135.5), 136.0, 136.4,
142.2, (143.1), (146.8), 149.9, (159.0), 159.3, 170.2, (172.9). Signals
N-Benzoyl-5-phenyl-1,2,3,4-tetrahydro-1,7-phenanthroline
(16a). The treatment of diene 12a (0.04 g, 0.09 mmol, 1.0 equiv) with
Pd(OAc)2 (0.002 g, 0.01 mmol, 0.1 equiv), Cs2CO3 (0.059 g, 0.18
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Article
for the minor rotamer is given in the parentheses. IR (cm−1) 1637,
1402, 1027; HRMS (ES+) calcd for C26H23N2O2 (M + H)+ 395.1760,
found 395.1763.
(4aR*,5aR*,9bS*)-N-Benzoyl-8-fluoro-5a-phenyl-2,5,5a,9b-tetra-
hydro-1H-cyclopropa[2,3]indeno[1,2-b]pyridine (14c). Treatment of
enyne 6c (0.041 g, 0.09 mmol) in toluene (4 mL) with Grubbs II
catalyst (0.008 g, 0.009 mmol) Pd(OAc)2 (0.002 g, 0.009 mmol), PPh3
(0.007 g, 0.018 mmol), and Cs2CO3 (0.059 g, 0.18 mmol) according
to the general procedure described above, followed by flash
chromatography over silica eluting with EtOAc/hexane (1:4) afforded
indenopyridine 14c (0.023 g, 69%) as a colorless heavy oil.
(4aR*,5aR*,9bS*)-N-Benzoyl-5a-(4-methoxyphenyl)-2,5,5a,9b-
tetrahydro-1H-cyclopropa[2,3]indeno[1,2-b]pyridine (14e). Treat-
ment of enyne 6e (0.032 g, 0.07 mmol) in toluene (3 mL) with
Grubbs II catalyst (0.006 g, 0.007 mmol), Pd(OAc)2 (0.002 g, 0.007
mmol), PPh3 (0.005 g, 0.014 mmol), and Cs2CO3 (0.046 g, 0.14
mmol) according to the general procedure described above followed
by flash chromatography over silica eluting with EtOAc/hexane (1:8)
afforded indenopyridine 14e (0.019 g, 70%) as a colorless oil.
N-Benzoyl-5-phenyl-1,2,3,4-tetrahydro-1,7-phenanthroline
(16a). Treatment of enyne 8a (0.043 g, 0.1 mmol) in toluene (3 mL)
with Grubbs II catalyst (0.008 g, 0.01 mmol), Pd(OAc)2 (0.002 g, 0.01
mmol), PPh3 (0.007 g, 0.02 mmol), and Cs2CO3 (0.065 g, 0.2 mmol)
according to the general procedure described above followed by flash
chromatography over silica eluting with EtOAc/hexane (2:3) afforded
phenanthroline 16a (0.022 g, 61%) as a light yellow powder along with
diene 12a (0.011 g, 25%).
One-Pot Protocol for the Synthesis of Benzoindolines 13a,
13c, and 13e and Pyrroloquinoline 15a (Conditions G, Table
1). Ethylene was bubbled for 5 min through the solutions of enynes
5a, 5c, 5e, and 7a (1.0 equiv, 0.08−0.18 mmol) in toluene (3−4 mL)
in a 25 mL two-neck round-bottom flask fitted with a reflux condenser.
Grubbs I catalyst (0.1 equiv, 0.008−0.018 mmol) was added as a solid,
and the reaction mixtures were stirred at 85 °C under ethylene
atmosphere for 2 h, cooled to rt, and purged with argon for 10 min.
Pd(OAc)2 (0.1 equiv, 0.008−0.018 mmol), PPh3 (0.2 equiv, 0.017−
0.037 mmol), and Cs2CO3 (2.0 equiv, 0.17−0.37 mmol) were added
as solids. The reaction mixtures were stirred at 120 °C for 15 h and
cooled to rt. Upon evaporation of toluene the crude mixtures were
loaded on silica columns and were purified by flash chromatography
over silica eluting with EtOAc/hexane mixtures to afford pure
benzoindolines 13a, 13c, 13e, and pyrroloquinoline 15a.
N-Benzoyl-4-phenyl-2,3-dihydro-1H-benzo[g]indole (13a). Treat-
ment of enyne 5a (0.08 g, 0.18 mmol) in toluene (4 mL) with Grubbs
I catalyst (0.015 g, 0.018 mmol), Pd(OAc)2 (0.004 g, 0.018 mmol),
PPh3 (0.012 g, 0.03 mmol), and Cs2CO3 (0.097 g, 0.37 mmol)
according to the general procedure described above followed by flash
chromatography over silica eluting with EtOAc/hexane (1:9) afforded
pure benzoindoline 13a (0.045 g, 69% yield) as a white solid.
N-Benzoyl-8-fluoro-4-phenyl-2,3-dihydro-1H-benzo[g]indole
(13c). Treatment of enyne 5c (0.037 g, 0.08 mmol) in toluene (4 mL)
with Grubbs I catalyst (0.007 g, 0.008 mmol), Pd(OAc)2 (0.002 g,
0.008 mmol), PPh3 (0.005 g, 0.017 mmol), and Cs2CO3 (0.055 g, 0.17
mmol) according to the general procedure described above followed
by flash chromatography over silica eluting with EtOAc/hexane (1:9)
afforded pure benzoindoline 13c (0.019 g, 61% yield) as a heavy oil.
N-Benzoyl-4-(4-methoxyphenyl)-2,3-dihydro-1H-benzo[g]indole
(13e). Treatment of enyne 5e (0.04 g, 0.087 mmol) in toluene (4 mL)
with Grubbs I catalyst (0.008 g, 0.009 mmol) Pd(OAc)2 (0.002 g,
0.009 mmol), PPh3 (0.005 g, 0.017 mmol) and Cs2CO3 (0.055 g, 0.17
mmol) according to the general procedure described above, followed
by flash chromatography over silica eluting with EtOAc/hexane (1:4)
afforded pure benzoindoline 13e (0.021 g, 64% yield) as a colorless oil.
N-Benzoyl-4-phenyl-2,3-dihydro-1H-pyrrolo[2,3-f ]quinoline
(15a). Treatment of enyne 7a (0.051 g, 0.12 mmol) in toluene (4 mL)
with Grubbs I catalyst (0.01 g, 0.012 mmol), Pd(OAc)2 (0.003 g,
0.012 mmol), PPh3 (0.009 g, 0.024 mmol), and Cs2CO3 (0.078 g, 0.24
mmol) according to the general procedure described above followed
by flash chromatography over silica eluting with EtOAc/hexane (2:3)
afforded pure benzoindoline 15a (0.03 g, 71% yield) as a colorless oil.
One-Pot Protocol for the Synthesis of Indenopyridines 14a,
14c, and 14e and Phenanthrolines 16a and 16b (Conditions H,
Table 1). Ethylene was bubbled for 5 min through the solutions of
enynes 6a, 6c, 6e, 8a, and 8b (1 equiv, 0.07−0.20 mmol) in toluene
(3−10 mL) in a 25 mL two-neck round-bottom flask fitted with a
reflux condenser. Grubbs II catalyst (0.1 equiv, 0.007−0.02 mmol) was
added as a solid, and the reaction mixtures were stirred at 85 °C under
ethylene atmosphere for 8 h, cooled to rt, and purged with argon for
10 min. Pd(OAc)2 (0.1 equiv, 0.007−0.02 mmol), PPh3 (0.2 equiv,
0.014−0.04 mmol), and Cs2CO3 (2.0 equiv, 0.14−0.46 mmol) were
added as solids. The reaction mixtures were stirred at 120 °C for 15 h
and cooled to rt. Upon evaporation of toluene, the crude mixtures
were purified by flash chromatography eluting with EtOAc/hexane
mixtures to afford indenopyridines 14a, 14c, and 14e and phenanthro-
lines 16a and 16b.
N-Benzoyl-5-(4-fluorophenyl)-1,2,3,4-tetrahydro-1,7-phenan-
throline (16b). Treatment of enyne 8b (0.034 g, 0.07 mmol) in
toluene (3 mL) with Grubbs II catalyst (0.006 g, 0.007 mmol),
Pd(OAc)2 (0.002 g, 0.007 mmol), PPh3 (0.005 g, 0.014 mmol), and
Cs2CO3 (0.046 g, 0.14 mmol) according to the general procedure
described above followed by flash chromatography over silica eluting
with EtOAc/Hexane (2:3) afforded phenanthroline 16b (0.015 g,
56%) as a colorless oil along with diene 12b (0.01g, 29%).
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra for all new compounds
prepared in this study, 2D NMR data for compounds 3 and 4,
1
the variable-temperature H NMR spectra for compounds 5a,
6a, 9a, and 16a, quantitative GC−MS chromatograms with MS
spectra for compounds 15a,b, 16a−c, and thermal ellipsoid
diagrams for compounds 13a, 14b, 16a, and 17. This material is
available free of charge via Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: hmalina@ku.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support from the NIH via the KU Center for Methodology and
Library Development (P 50 GM063966) and NSF-MRI (CHE-
0923449) is acknowledged. We thank our colleagues Dr. Victor
Day (University of Kansas) for the X-ray crystallographic
analyses and Dr. Justin Douglas (University of Kansas) for his
assistance with NMR spectroscopy.
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(0.001 g, 12%) as a white solid.
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