Palladium(II)-catalyzed oxidative cascade cyclization reactions of anilides and anilines: Scope and mechanistic investigations

Article abstract of DOI:10.1002/asia.201100242

With Pd(OAc)₂/pyridine as the catalyst system and molecular oxygen as a green oxidant, acrylanilides and N-allylanilines undergo oxidative cascade cyclization to form heterocyclic rings in high yields. This methodology is applicable to acrylani

Full text of DOI:10.1002/asia.201100242

FULL PAPERS
DOI: 10.1002/asia.201100242
Palladium(II)-Catalyzed Oxidative Cascade Cyclization Reactions of
Anilides and Anilines: Scope and Mechanistic Investigations
Kai-Tai Yip and Dan Yang*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
Abstract: With Pd
(OAc)2/pyridine as
revealed that cyclization of acrylani-
lides proceeded through an intramolec-
ular syn-amidopalladation pathway.
The reversible nature of amidopallada-
tion serves as a “scavenging process”
to prevent b-hydride elimination from
occurring halfway through the catalytic
cycle, thus favoring the formation of
cascade cyclization products. In addi-
tion, internal coordination between an
s-alkylpalladium species and a tethered
olefinic C=C double bond also appears
to disfavor b-hydride elimination.
the catalyst system and molecular
oxygen as a green oxidant, acrylani-
lides and N-allylanilines undergo oxi-
dative cascade cyclization to form het-
erocyclic rings in high yields. This
methodology is applicable to acrylani-
lides of different substitution patterns
on olefinic units. Mechanistic studies
Keywords: cyclizations
·
domino
reactions · homogeneous catalysis ·
palladium · reaction mechanism
Introduction
Palladium-catalyzed
cascade
cyclization reactions are direct,
versatile, and fundamental syn-
thetic strategies for building
polycyclic ring structures and
establishing multiple stereocen-
ters in a single step.[1] Over the
last few decades, numerous ex-
amples of natural product syn-
theses have been reported by
utilizing palladium(0)-catalyzed
cascade cyclization reactions,
many of which are intramolecu-
lar
Heck
cyclizations
Scheme 1. Top route: Heck-type cyclization involves oxidative addition to preactivated carbon nucleophiles,
thus requiring Pd0 catalysis. Bottom route: Oxidative cyclization is initiated through nucleophilic attacks on
PdII–olefin complexes and external oxidants are required to regenerate PdII from Pd0 species.
(Scheme 1).[2] However, draw-
backs of these reactions include
1) the inevitable involvement of
prefunctionalized
precursors,
such as aryl (or vinyl) triflates and halides, 2) palladium
complexes as catalysts that usually feature air-sensitive phos-
phine ligands, and 3) the scope is mostly restricted to
carbon–carbon bond formation, rather than the more-versa-
tile carbon–heteroatom bond formation.[3] Therefore, further
development of cascade cyclization reactions to make it
more atom-economical[4] and allow carbon–heteroatom
bonds to form remains an important goal in the synthesis of
complex polycyclic molecules.
[a] Dr. K.-T. Yip, Prof. Dr. D. Yang
Department of Chemistry
The University of Hong Kong
Pokfulam Road, Hong Kong (P.R. China)
Fax : (+ 852)2859-2159
E-mail: yangdan@hku.hk
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100242.
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À
À
À
In recent years, a variety of oxidative C C, C O, and C
N bond-forming reactions have been reported when using
palladium catalysts in the presence of external oxidants, in
particular, molecular oxygen.[5] In particular, carbocycles
and heterocycles have been constructed through intramolec-
cyclizations would allow us to extend the scope toward com-
plex polycyclic ring structures.[14]
Scheme 3 illustrates the steps involved in these palladium-
catalyzed oxidative cascade cyclizations. Cyclization of ani-
lide 1 is catalyzed by PdII complexes, which could be either
achiral or chiral, depending on the choice of ligands. The
electron-deficient PdII complex coordinates to the ortho-
allyl group of anilide 1 to generate intermediate 2, which
undergoes amidopalladation to give s-alkylpalladium inter-
mediate 3. Following intramolecular olefin insertion, the s-
alkylpalladium intermediate 4 is formed, which is trans-
formed into product 5 upon subsequent b-hydride elimina-
tion.
[6]
[7]
[8]
À
À
C O,
À
ular formation of C C,
and C N
bonds
(Scheme 2). Such oxidative palladium catalysis can be ap-
In this study, we investigated the mechanism of the palla-
dium-catalyzed oxidative cascade cyclization reaction with
respect to: 1) the electronic effects of the oxidative cascade
cyclization, 2) the stereochemistry of amidopalladation, and
3) the reasons why the monocyclization product was not
formed in the reaction.
Results and Discussion
Electronic Effects
A reactivity trend of palladium-catalyzed oxidative cascade
cyclizations was observed when employing a series of para-
substituted anilides 1a–f (Table 1). Electron-deficient ani-
lides cyclized faster than their electron-rich counterparts.
For example, shorter reaction times were required to ach-
ieve complete conversion of anilides 1b (X=Cl, Table 1,
entry 2), 1c (X=F, entry 3), and 1d (X=COOMe, entry 4)
Scheme 2. Palladium-catalyzed oxidative cascade cyclization reactions.
DIPEA=N,N-diisopropylethylamine.
plied to cascade reactions, pro-
vided that the organopalladium
intermediates generated in situ,
upon the formation of the new
bond, can be further manipulat-
ed in various ways, including
carbonylation,[9] heteroatom in-
corporation,[10] olefin inser-
tion,[11] and arene insertion.[12]
However, the development of
palladium-catalyzed oxidative
cascade cyclization is challeng-
ing because of the possibility of
undesired b-hydride elimination
occurring halfway through the
Scheme 3. Oxidative cascade cyclization through sequential amidopalladation/olefin insertion.
catalytic cycle. Recently, we re-
ported that oxidative cascade
cyclizations employing amides
as nitrogen-centered nucleophiles could afford a variety of
racemic and enantioenriched indoline derivatives, when
using PdII/pyridine, PdII/(À)-sparteine, and PdII/quinoline–
oxazoline as the catalytic system, respectively (Scheme 2).[13]
Importantly, our oxidative cascade cyclization reactions did
not produce any undesired monocyclization products, even
in the absence of tandem relays, which are usually required
in cascade reactions.[1a] Understanding the selectivity of such
than those of 1e (X=Me, entry 5) and 1 f (X=OMe,
entry 6). Notably, the cyclizations of electron-rich anilides
1e and 1 f were particularly slow (less than 50% conversion
after 48 h) as a result of extensive aggregation of palladium
catalyst when pyridine was used as the ligand. Replacing
pyridine with triphenylphosphine resulted in a more effi-
cient cyclization of 1e (entry 5) and 1 f (entry 6).
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K.-T. Yip and D. Yang
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Table 1. Oxidative cascade cyclization of para-substituted anilides.[a]
Table 2. Scope of the PdII-catalyzed oxidative cascade cyclization of anili-
des.[a]
Entry
1
Substrate
Product
t [h]
Yield [%][b]
Entry Substrate
Product
t [h] Yield [%][b]
19
95
92
14
1[c]
(d.r. 5.9:1)[d]
2
3
4
1b (X=Cl)
1c (X=F)
1d (X=COOMe)
1e (X=Me)
1 f (X=OMe)
5b
5c
5d
5e
5 f
19
12
7
22
48
83
89
88
85
74
5[c]
6[c]
2
3
23
19
84
82
[a] Unless otherwise indicated, all reactions were performed at 508C by
using the substrate (0.3 mmol), pyridine (40 mol%), and Pd(OAc)2
(10 mol%) in toluene (3 mL) under O2 (1 atm.). [b] Isolated yields.
[c] PPh3 (40 mol%) was used instead of pyridine.
AHCTUNGTRENNUNG
Kinetic studies of the oxidative cascade cyclization reac-
tions were performed by monitoring the relative initial rates
of reactions of anilides 1a–f under identical reaction condi-
tions (i.e., 40 mol% pyridine and 10 mol% PdACTHNURGTNEUNG(OAc)2). The
investigation provided a quantitative measure of the relative
reactivities of 1a–f. A linear Hammett plot with a positive
slope, 1=+1.23, was obtained (Figure 1).[15] The trend re-
veals the presence of a significant electronic effect in palla-
dium-catalyzed oxidative cascade cyclizations.
10 (5j)[e]
70 (6j)
4
20
(d.r. 1.8:1)[d]
17 (5k)
63 (6k)
5
36
AHCTUNGTRENNUNG
(dr 7:1)[d]
50 (6l)
6[f]
36
19
(d.r. 24:1)[d]
Figure 1. Hammett plot for PdII-catalyzed oxidative cascade cyclizations.
Substrate Scope
7
72
Oxidative cascade cyclization of anilides bearing ortho-mon-
osubstituted olefins (1g–m) took place efficiently when
using a PdII/pyridine catalyst system (Table 2). Diastereose-
lective cascade cyclization (diastereomeric ratio (d.r.) 5.9:1)
of 1g furnished 5g and its minor diastereomer in 92% yield
(Table 2, entry 1). Anilides 1h and 1i, which have E and Z
configurations, respectively, afforded products 5h and 5i, re-
spectively (entries 2 and 3), thereby demonstrating that the
[a] Unless otherwise indicated, all reactions were performed at 508C by
using the substrate (0.3 mmol), pyridine (40 mol%), and Pd(OAc)2
(10 mol%) in toluene (3 mL) under O2 (1 atm.). [b] Isolated yields.
ACHTUNGTRENNUNG
[c] 5 mol% PdACHTNUGRTENUNG(OAc)2 and 20 mol% pyridine were used. [d] Ratio deter-
mined by 1H NMR spectroscopy; major diastereomer is depicted.
[e] Mixture of stereoisomers. [f] Quinoline (40 mol%) was used instead
of pyridine.
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Oxidative Cascade Cyclization Reactions of Anilides and Anilines
olefin geometry of the product is determined by that of the
starting material. When 1j and 1k were used as substrates,
olefin-insertion products 5 and 6 were obtained. In the cycli-
zation of 1j, 5j was formed in 10% yield as a mixture of ste-
reoisomers, whereas olefin-migration products (6j and its
diastereomer) were obtained in 70% yield (d.r. 1.8:1,
entry 4). On the other hand, cyclization of 1k led to 5k in
17% yield and olefin-migration products in 63% yield (6k
as major diastereomer; d.r. 7:1, entry 5). By replacing the
pyridine ligand with quinoline, 6l was obtained in excellent
diastereoselectivity from 1l (d.r. 24:1, entry 6). Notably, 1m
with two unactivated olefinic groups could also be cyclized,
leading to 5m in 72% yield (entry 7).
med.[16a] Interestingly, cascade cyclization of 1o preferential-
ly proceeded with a N-acrylic olefin instead of a tethered
olefin, resulting in fused-indoline 5o in 59% yield (entry 2).
Alternatively, spiro-indoline 5p was formed from 1p, albeit
less efficiently (entry 3). Cyclization of 1q was stereospecific
and afforded 5q as the only product (64% yield, entry 4).
Its relative configuration (i.e., the b-phenyl group is syn to
the angular hydrogen) was determined by 2D NOESY ex-
periments. On the contrary, cyclization of 1r yielded product
5r exclusively (53% yield, entry 5). These results support
the proposal that syn-amidopalladation is the only mode of
cyclization (path a, Scheme 4). Hence, the anti-amidopalla-
dation pathway (path b) should be ruled out as it is not con-
cordant to the observed outcomes.[17]
With the PdII/quinoline system, anilides 1n–r containing
an ortho-olefinic unit of other substitution patterns (1,1- and
1,2-disubstitution) are useful to establish quaternary or con-
tiguous stereogenic centers (Table 3). For instance, 1n cy-
clized to furnish 5n in 91% yield (Table 3, entry 1). The
exocyclic olefin moiety of 5n is stable under optimized reac-
tion conditions and no olefin isomerization product was for-
Table 3. Scope of the PdII-catalyzed oxidative cascade cyclization of anili-
des.[a]
Entry Substrate
Product
t [h] Yield [%][b]
1
48
91
2
3
48
48
59
58[c]
4[d]
48
48
64[e]
Scheme 4. Stereospecific Pd-catalyzed oxidative cascade cyclization.
Structure–Reactivity Relationship: Origin of Selectivity in
Oxidative Cascade Cyclization Reactions
5[d]
53[e]
Applying a Pd-catalyzed cyclization strategy to the construc-
tion of multiple-ring systems is challenging because midway
b-hydride elimination[18] is usually a competing pathway, re-
sulting in mixtures of monocyclization and cascade cycliza-
tion products (Scheme 5).[19] In both Pd0- and PdII-catalyzed
cascade cyclization reactions, undesired b-hydride elimina-
[a] Unless otherwise indicated, all reactions were performed at 508C by
using the substrate (0.3 mmol), quinoline (40 mol%), and Pd(OAc)2
(10 mol%) in toluene (3 mL) under O2 (1 atm.). [b] Isolated yields.
[c] Yield based on 52% conversion. [d] At 708C. [e] Single diastereomer
was formed.
AHCTUNGTRENNUNG
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K.-T. Yip and D. Yang
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In the seminal works report-
ed by Hegedus and co-work-
ers,[16] palladium-assisted amina-
tion of olefins was initiated
with an excess amount (2 equiv
or more) of aliphatic amines.
An aliphatic amine would
attack the palladium(II)–olefin
complex reversibly to give the
b-aminoalkylpalladium
inter-
mediate, which is rather stable
towards further transformations
(Scheme 7). Owing to the stron-
ger coordinating ability of ali-
phatic amines than olefins to-
wards PdII, addition reactions
to olefins can proceed only in
Scheme 5. Midway b-hydride elimination disrupting oxidative cascade cyclization.
Scheme 7. Hegedusꢁs model on palladium-mediated amination of olefin.
Scheme 6. Common tandem relays to avoid b-hydride elimination.
the preformed PdII–olefin complexes.[21] In this context, pal-
ladium-catalyzed oxidative amination of olefins becomes ef-
ficient only when electron-deficient nitrogen-centered nucle-
ophiles are used (i.e., anilides in our case). In the cyclization
of 1a, it is likely that b-heteroatom elimination (the reversal
of amidopalladation) serves as a “scavenging process” to
convert 3a-1 and 3a-2 back to 2a instead of undergoing
midway b-hydride elimination (Scheme 8). As an efficient
leaving group, electron-deficient nitrogen nucleophiles favor
b-heteroatom elimination in 3a-1 over b-hydride elimina-
tion.[22]
tion occurring halfway through the catalytic cycle can be
avoided by designing substrates possessing tandem relays,
such as substituted alkynes or 1,1-disubstituted alkenes
(Scheme 6), rendering b-hydride elimination either energeti-
cally unfavorable or impossible (no b-hydrogen atom avail-
able).
As monosubstituted alkenes are not conventionally re-
garded as tandem relays, we were particularly interested in
identifying the origin of the selectivity of our oxidative cas-
cade cyclization reactions. Applying the PdACTHNURGTNEUNG(OAc)2/pyridine
catalyst system, cyclization of anilide 1a yielded the cascade
cyclization product 5a exclusively without producing mono-
cyclization product (Table 1, entry 1). In contrast, anilide 1s
cyclized to afford 6s in modest yield[20] after 48 hours
With an acryl olefinic unit, efficient and relatively rapid
olefin insertion/b-hydride elimination sequence takes place
in 3a-1 and 3a-2, driving the cascade cyclization to comple-
tion. The carbonyl moiety might coordinate to the alkyl–PdII
species[12b,16d,17a,23] in 3a-2 in an intramolecular fashion,
maintaining a staggered conformation. As a result, midway
À
[Eq. (1)] even though the acidity of the N H bond is similar
in 1a and 1s.
À
b-hydride elimination in 3a-2, which requires the Pd Ca and
[24]
À
Cb H bonds to be aligned in a syn-orientation, would be
suppressed.
À
Owing to the similar acidities of the N H bond of 1a and
1s, the formation of intermediates 2s and 3s should be quite
À
similar to that of 2a and 3a, that is, a rapid N H deprotona-
tion and a slow syn-amidopalladation process (Scheme 9).
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Oxidative Cascade Cyclization Reactions of Anilides and Anilines
product (5t, 18%) and mono-
cyclization product (6t, 71%).
In addition, the cyclization of
1t proceeded faster (9 h) than
that of anilide 1a (19 h;
Table 1, entry 1) under identical
reaction conditions. It was
postulated that monocyclization
product 6t and cascade cycliza-
tion product 5t were formed
through b-hydride elimination
and intramolecular olefin inser-
tion, respectively, from s-alkyl-
palladium intermediate 3t,
which was generated from the
first 5-exo-trig cyclization of
aniline 1t (Scheme 10). Owing
À
to its greater basicity, N H de-
protonation of 1t to furnish 2ta
would be more difficult than
that of 1a. In addition, anilines
are more nucleophilic than ani-
lides, thereby making aminopal-
ladation of 1t to afford 2tb
more efficient than that of 1a.
Therefore, the possibility of 1t
converting into 3t through an
Scheme 8. Mechanistic pathways of the cascade cyclization of 1a.
À
aminopalladation/N H depro-
tonation pathway could not be
excluded.
The fate of 3t may not be re-
stricted to b-heteroatom elimi-
nation (the reverse of amino-
palladation) and intramolecular
olefin insertion, which eventual-
ly yields the cascade cyclization
product 5t upon b-hydride
elimination from 4t. Instead, b-
hydride elimination of 3t could
be an alternative competing
process for two reasons. Firstly,
the p-coordination between the
N-allyl unit and the palladium center in 3t could be readily
Scheme 9. Mechanistic pathways of the cascade cyclization of 1s.
As 3s does not possess an acryl olefinic unit for subsequent
insertion, it readily reverts back to 2s through b-heteroatom
elimination. Indeed, the conversion of 1s to 6s was ineffi-
cient at 508C but it could be improved at elevated tempera-
tures,[20] which implies that b-hydride elimination of 3s
could not compete efficiently with b-heteroatom elimination
at lower temperature.
À
disrupted through the rapid and unrestricted N C single-
bond rotation to give intermediate 7t, from which b-hydride
elimination took place readily to give 6t.[25] Secondly, be-
cause aniline 1t possesses a more basic nitrogen-centered
nucleophile than anilide 1a does, b-heteroatom elimination
of 3t would proceed significantly slower than both intramo-
lecular olefin insertion and, in particular, the b-hydride
elimination processes; in other words, b-heteroatom elimina-
tion of 3t would be inefficient to serve as a “scavenging pro-
cess” as is the case for 3a. Therefore, cyclization reaction of
1t yielded a mixture of cascade cyclization product 5t and
monocyclization product 6t.
In contrast to the cyclization of 1a, N-allylaniline 1t was
cyclized [Eq. (2)] to afford a mixture of cascade cyclization
To improve the cyclization selectivity on aniline-type sub-
strates, one solution is to avoid midway b-hydride elimina-
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K.-T. Yip and D. Yang
FULL PAPERS
Scheme 10. Mechanistic pathways of the cascade cyclization of 1t.
tion of intermediate 3. To this end, increasing the rotational
tion of 5a and cyclopropanation gave 8a in 52% yield
À
barrier about the N Ca bond might serve this purpose. To
under one-pot conditions [Eq. (4)].
test this hypothesis, N-allylaniline 1u possessing a gem-di-
methyl moiety at the N-allylic position was prepared. Inter-
estingly, cyclization of aniline 1u gave 5u as the exclusive
cyclization product (58% yield; 86% conversion), whereas
the corresponding monocyclization product was not formed
[Eq. (3)]. The result is different from the cyclization of 1t.
Conclusions
In summary, we demonstrated herein the palladium(II)-cata-
lyzed oxidative cascade cyclization of unsaturated anilides
as an efficient synthetic method to construct nitrogen het-
erocycles. The methodology involves the sequential forma-
À
À
tion of C N and C C bonds by using PdACTHNUTRGNEUNG(OAc)2/pyridine as
As both 1t and 1u are N-alkyl anilines, b-heteroatom
eliminations of the corresponding intermediates 3t and 3u
are expected to be inefficient (Scheme 11). The presence of
a gem-dimethyl group[26] in aniline 1u should increase the
the catalyst system and molecular oxygen (1 atm.) as a
green oxidant. Studies of electronic effects, rate-determining
step of cascade cyclization, stereochemical modes of amido-
palladation, and selectivities of cascade cyclization products
gave useful insights into the reaction mechanism. On the
basis of kinetic studies (Hammett relationship), we propose
À
rotational barrier of the N C bond and, thus, enhance the
internal coordination between the olefinic group and the
palladium center in intermediates 3ua and 3ub, leading to
the formation of the cascade cyclization product 5u. In con-
trast, the intermediate 3uc is disfavored because of severe
steric repulsion between the gem-dimethyl substituents and
the s-alkylpalladium moiety.
À
a mechanistic pathway that consists of a rapid N H depro-
tonation followed by slow amidopalladation to form an N-
palladium–anilide intermediate. In addition, the oxidative
cascade cyclizations of specific prochiral substrates proceed
in a stereoselective manner with the establishment of two
defined stereogenic centers. The stereochemical outcomes
suggest a syn-amidopalladation pathway.
Furthermore, we propose that the exclusive formation of
cascade cyclization products from acrylanilides is due to the
reversible nature of the amidopalladation process. The b-
heteroatom elimination (the reverse process of amidopalla-
Indoline 5a is capable of undergoing further transforma-
tions. Under hydrogenation conditions, diastereoselective re-
duction took place to establish two stereogenic centers in 7a
(Scheme 12). On the other hand, PdACTHNUTRGNENUG(OAc)2-cyclopropana-
tion of electron-deficient olefins with diazomethane fur-
nished 8a in 81% yield. Notably, oxidative cascade cycliza-
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Oxidative Cascade Cyclization Reactions of Anilides and Anilines
Scheme 11. Mechanistic pathways of the cascade cyclization of 1u.
over calcium hydride and stored over
activated 4 ꢂ molecular sieves
(beads). Reactions were monitored by
TLC using E. Merck silica gel 60 pre-
coated glass plates with 0.25 mm thick-
ness. Components were visualized by
illumination with a short-wavelength
ultraviolet light and/or staining in
phosphomolybdic acid (PMA) solution
followed by heating. Flash column
chromatography was performed on E.
Merck silica gel 60 (230–400 mesh
Scheme 12. Synthetic transformation of cascade cyclization product 5a.
ASTM) by using ethyl acetate/n-hexane as eluting solvents.
dation) of b-amidopalladium intermediate 3 serves as a
“scavenging process” to prevent the undesired b-hydride
elimination. This finding exemplifies the potential synthetic
importance (serving as tandem relay in our case) of b-heter-
oatom elimination from b-amidopalladium intermediates.
Meanwhile, we have extended the substrate scope of the ox-
idative cascade cyclization to N-allylaniline. These studies
1H and 13C NMR spectra were recorded in deuterated chloroform
(CDCl3) with tetramethylsilane (TMS) as an internal standard at ambient
temperature, unless otherwise indicated, on a Bruker Avance DPX 300
Fourier Transform Spectrometer operating at 300 MHz for 1H and
75 MHz for 13C NMR, or a Bruker Avance DPX 400 Fourier Transform
Spectrometer operating at 400 MHz for 1H and 100 MHz for 13C NMR.
IR absorption spectra were recorded as a solution in CH2Cl2 with a Bio-
Rad FTS 165 Fourier Transform spectrophotometer. Mass spectra were
recorded with a Finnigan MAT 95 mass spectrometer for both low and
high resolution mass spectra. Melting points were determined by Axiolab
ZEISS microscope apparatus and were uncorrected.
À
have prompted us to develop new C N bond-forming cycli-
zation strategies to synthesize structurally versatile and bio-
logically important N-heterocycles.
Typical procedure for PdII-catalyzed oxidative cascade cyclizations (Table
1, entry 1)
Experimental Section
In a 5 mL round-bottomed flask equipped with a magnetic stirrer bar,
Pd
the solution was stirred at room temperature. After 5 min (or until all
the Pd(OAc)2 was dissolved), pyridine (9.7 mL, 0.12 mmol) was added to
the mixture by microsyringe. After 15 min, substrate 1a (0.3 mmol) in
toluene (1 mL) was transferred to the solution mixture containing palla-
ACHTUNGRTEN(NNUG OAc)2 (6.7 mg, 0.03 mmol) was dissolved in dry toluene (2 mL) and
General Methods
All reactions were performed in oven-dried flasks. Palladium(II) acetate
was purchased from Aldrich and was used as received. All other commer-
cially available chemicals were used as received. Toluene was distilled
ACHTUNGTRENNUNG
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K.-T. Yip and D. Yang
FULL PAPERS
dium complexes. The reaction flask was assembled with an air condenser,
sealed with a rubber septum, connected to an oxygen atmosphere, and
heated to 508C. After 19 h, the reaction mixture was cooled, filtered
through a short pad of silica gel (EtOAc as eluent), and concentrated in
vacuo. The crude residue was purified by flash column chromatography
(EtOAc and n-hexane as eluents) to give 5a in 95% yield.
rified by flash column chromatography (EtOAc and n-hexane as eluents)
to give 8a in 52% yield (from 1a).
Product 8a
Pink solid; m.p. 96–978C; analytical TLC (silica gel 60), 30% EtOAc in
n-hexane, Rf =0.44; 1H NMR (300 MHz, CDCl3): d=7.59 (d, J=7.7 Hz,
1H), 7.24–7.19 (m, 2H), 7.02 (dt, J=7.5, 0.9 Hz, 1H), 4.75–4.69 (m, 1H),
3.21 (dd, J=15.5, 8.4 Hz, 1H), 2.90 (dd, J=15.5, 10.5 Hz, 1H), 2.35 (dd,
J=12.4, 9.4 Hz, 1H), 2.20 (dd, J=12.4, 7.0 Hz, 1H), 1.39–1.32 (m, 1H),
1.14–1.07 (m, 1H), 1.00–0.93 (m, 1H), 0.74–0.68 ppm (m, 1H); 13C NMR
(75 MHz, CDCl3): d=173.7, 140.1, 134.2, 128.0, 125.5, 124.2, 114.8, 60.3,
37.1, 36.5, 27.5, 15.8, 11.1 ppm; IR (CH2Cl2): n˜ =3055, 2988, 1693, 1486,
1422 cmÀ1; LRMS (EI, 20 eV): m/z: 199 (100) [M]+; HRMS (EI): m/z:
calcd for C13H13NO: 199.0997 [M]+; found: 199.0996.
Product 5a
White solid; m.p. 83–848C; analytical TLC (silica gel 60), 30% EtOAc in
n-hexane, Rf =0.30; 1H NMR (300 MHz, CDCl3): d=7.67 (d, J=7.7 Hz,
1H), 7.25–7.17 (m, 2H), 7.04 (dt, J=7.5, 0.9 Hz, 1H), 6.04 (dd, J=3.3,
1.6 Hz, 1H), 5.40 (dd, J=2.8, 1.3 Hz, 1H), 4.61–4.50 (m, 1H), 3.23–3.10
(m, 2H), 2.87 (dd, J=15.4, 10.7 Hz, 1H), 2.75–2.65 ppm (m, 1H);
13C NMR (75 MHz, CDCl3): d=164.5, 143.9, 139.8, 134.2, 127.9, 125.5,
124.9, 117.4, 115.2, 60.2, 36.3, 34.2 ppm; IR (CH2Cl2): n˜ =3055, 2987,
2915, 1693, 1658, 1606, 1484, 1442 cmÀ1; LRMS (EI, 20 eV): m/z: 185
(100) [M]+; HRMS (EI): m/z: calcd for C12H11NO: 185.0841 [M]+;
found: 185.0844.
Acknowledgements
Hydrogenation of 5a (Scheme 12)
This work was supported financially by the University of Hong Kong and
the Hong Kong Research Grants Council (HKU 705807P).
A methanol solution (8 mL) of 5a (149 mg, 0.8 mmol) was degassed with
argon for 30 min. The reaction flask was evacuated and refilled with
argon three times. After the addition of 10% Pd/C (149 mg), the flask
was evacuated and refilled with a H2 balloon three times. The reaction
mixture was stirred at room temperature for 14 h. The solution was fil-
tered through a short pad of Celite (Et2O as eluent) and concentrated in
vacuo. The residue was purified by flash column chromatography
(EtOAc and n-hexane as eluents) to afford 7a and its minor diastereo-
mer in 75% total yield.
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Product 7a
White solid; m.p. 77–788C; analytical TLC (silica gel 60), 30% EtOAc in
n-hexane, Rf =0.46; 1H NMR (500 MHz, CDCl3): d=7.60 (d, J=7.8 Hz,
1H), 7.23–7.17 (m, 2H), 7.02 (dt, J=7.5, 0.8 Hz, 1H), 4.54–4.47 (m, 1H),
3.18 (dd, J=15.7, 8.5 Hz, 1H), 2.95–2.83 (m, 2H), 2.68–2.63 (m, 1H),
1.65–1.58 (m, 1H), 1.25 ppm (d, J=7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3): d=174.2, 139.4, 134.0, 127.7, 125.3, 124.0, 114.8, 60.2, 41.9, 38.8,
35.8, 15.1 ppm; IR (CH2Cl2): n˜ =3055, 2986, 2932, 1694, 1605, 1486,
1405 cmÀ1; LRMS (EI, 20 eV): m/z: 187 (59) [M]+, 118 (100); HRMS
(EI): m/z: calcd for C12H13NO: 187.0997 [M]+; found: 187.0993.
Minor diastereomer
White solid; m.p. 125–1268C; analytical TLC (silica gel 60), 30% EtOAc
in n-hexane, Rf =0.31; 1H NMR (500 MHz, CDCl3): d=7.59 (d, J=
7.8 Hz, 1H), 7.23–7.17 (m, 2H), 7.03 (dt, J=7.5, 1.0 Hz, 1H), 4.78–4.71
(m, 1H), 3.17 (dd, J=15.5, 8.4 Hz, 1H), 2.90–2.80 (m, 2H), 2.22–2.13 (m,
2H), 1.39 ppm (d, J=7.6 Hz, 3H); 13C NMR (125 MHz, CDCl3): d=
175.0, 139.3, 134.4, 127.7, 125.2, 124.2, 115.0, 61.0, 43.0, 36.4, 36.0,
16.5 ppm; IR (CH2Cl2): n˜ =3055, 2987, 1691, 1604, 1486, 1407 cmÀ1
;
LRMS (EI, 20 eV): m/z: 187 (59) [M]+, 118 (100); HRMS (EI): m/z:
calcd for C12H13NO: 187.0997 [M]+; found: 187.1000.
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Cyclization/cyclopropanation of 1a under one-pot conditions [Eq. (4)]
In a 10 mL round-bottomed flask equipped with a magnetic stirrer bar, a
mixture of Pd
0.06 mmol) in dry toluene (3 mL) was stirred at room temperature. After
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2174
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Received: March 8, 2011
Published online: June 7, 2011
Chem. Asian J. 2011, 6, 2166 – 2175
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
2175