Substituted benzocarbocycles by palladium-catalyzed cascade reactions featuring a C(sp3) - H activation step

Article abstract of DOI:10.1002/adsc.200700099

Valuable 4- and 5-membered benzocarbocycles were synthesized via selective palladium-catalyzed cascade reactions which combined C(sp³)-H activation, Heck cyclization, Heck arylation or olefin hydrogenation. In all cases, all mechanistically independent steps were catalyzed by a single multi-functional catalyst.

Full text of DOI:10.1002/adsc.200700099

UPDATES
DOI: 10.1002/adsc.200700099
Substituted Benzocarbocycles by Palladium-Catalyzed Cascade
3
ꢀ
Reactions Featuring a C
A
Julien Hitcea and Olivier Baudoinb,*
a
Institut de Chimie des Substances Naturelles – CNRS, avenue de la Terrasse, 91198Gif-sur-Yvette, France
ICBMS, UniversitØ Lyon 1, bât. CPE, 43 boulevard du 11 Novembre 1918, 69622 Villeurbanne, France
b
Fax : (+33)-4-7243-2963; e-mail: olivier.baudoin@univ-lyon1.fr
Received: February 14, 2007
Supporting information for this article is available on the WWW under http://asc.wiley-vch.de/home/.
Abstract: Valuable 4- and 5-membered benzocarbo-
cycles were synthesized via selective palladium-cat-
3
ꢀ
alyzed cascade reactions which combined C
A
activation, Heck cyclization, Heck arylation or
olefin hydrogenation. In all cases, all mechanistical-
ly independent steps were catalyzed by a single
multi-functional catalyst.
ꢀ
Keywords: benzocarbocycles; cascade reactions; C
H activation; Heck reaction; hydrogenation; palla-
dium
Scheme 1. Palladium-catalyzed dehydrogenation.
Results and Discussion
Introduction
According to our initial studies,[4] we envisioned that
In recent years, the transition metal-catalyzed activa- if the dehydrogenation reaction was carried out on
[1]
ꢀ
tion of C H bonds has emerged as a reliable tool to 2,6-dihalophenylacetonitrile derivatives, the resulting
transform otherwise unreactive bonds into carbon- olefins could react further by intramolecular Heck re-
heteroatom or carbon-carbon[2] bonds to access valua- action (Scheme 2). The latter would be initiated by
ble synthetic targets.[3] In this context, we recently re- the oxidative addition of the remaining aromatic
ported on the Pd(0)-catalyzed intramolecular func- carbon-halogen bond to Pd(0) and it could afford a
3
ꢀ
tionalization of C
(sp ) H bonds in benzylic alkane functionalized indene by 5-endo-trig cyclocarbopalla-
segments, that afforded olefins adjacent to a quater- dation[8] or an exo-methylenebenzocyclobutene by a
nary benzylic carbon atom.[4] The fluorinated phos- much more unusual 4-exo-trig cyclocarbopalladation.
phine F-TOTP [tris(5-fluoro-2-methylphenyl)phos- To the best of our knowledge, only one synthetically
phine] proved to be optimal for this transformation useful case of 4-exo-trig Heck cyclization has been re-
(Scheme 1).
ported to date.[9]
3
ꢀ
On the other hand, cascade processes are now well
This novel Pd-catalyzed C(sp ) H activation/Heck
A
established methods to access complex molecular cyclization pseudo-domino process[10] was investigated
scaffolds in a short, economical and ecological fash- with the transformation of 1b into 3a and 4a as the
ion.[5] Herein, we describe the design of Pd(0)-cata- model reaction (Scheme 2). Under conditions that we
lyzed domino and one-pot sequences[6] which rely on reported previously[4b] [Pd
(OAc)2 5 mol%, F-TOTP
C
a single catalyst precursor, able to combine an intra- 10 mol%, K2CO3 2 equivs., DMF, 1008C] traces of
3
ꢀ
molecular C
A
nistically distinct transformations,[7] thereby giving 1H NMR. However, the very low conversion (<5%)
access to high molecular complexity in a concise prompted us to undertake a complete reoptimization
manner.
of the reaction conditions (Table 1).
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Substituted Benzocarbocycles by Palladium-Catalyzed Cascade Reactions
UPDATES
3
ꢀ
Scheme 2. C
A
3
[a]
ꢀ
Table 1. Optimization of conditions for the C(sp ) H activation/Heck cyclization cascade reaction.
A
Entry
Compound
Palladium source
Ligand
Base
Solvent
Yield [%][b]
3a
4a
1
2
3
4
5
6
7
1b
1b
1b
1b
1b
1b
1b
1b
1b
1c
1c
Pd
Pd
Pd
C
F-TOTP
F-TOTP
F-TOTP
F-TOTP
F-TOTP
F-TOTP
F-TOTP
F-TOTP
JohnPhos
F-TOTP
JohnPhos
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
KOAc
Na2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF
NMP
DMA
DMA
DMA
DMA
DMA
DMA
DMF
DMA
DMF
14
20
2829
12
46
76
68
839
77
5
28
24
Pd2
G
4
6
Pd
Pd
Pd
Pd2
Pd
<1[c]
<1[c]
8[d]
9[e]
10[d]
11[e]
G
2
71
H
831
[a]
Reaction conditions: 10 mol% Pd(0), 20 mol% F-TOTP or 10 mol% JohnPhos, 1308C.; JohnPhos=
.
[b]
[c]
[d]
[e]
Isolated yields.
Undetectable by H NMR.
The reaction was carried out at 1608C.
The reaction was carried out at 1508C.
1
First, the effect of the solvent was assessed at bases. In addition, with Pd
A
1308C with a catalyst generated from Pd(OAc)2 and obtained as the major product in 39% yield by in-
AHCTREUNG
F-TOTP (entries 1–3). DMA gave the best yield creasing the reaction temperature to 1608C (entry 8).
albeit with no regioselectivity, 3a and 4a being ob- Finally we assessed the use of much more electron-
tained as an inseparable 1:1 mixture. Several other rich phosphines, in combination with Pd
palladium sources were assayed, including Pd
2(dba)3, estingly, Buchwaldꢁs JohnPhos[11] afforded 3a in 77%
PdBr2 and Pd(acac)2. With the latter, catalyst deacti- yield with excellent regioselectivity (entry 9) which
A
AHCTREUNG
ACHTREUNG
vation occurred before full conversion whereas the re- proved that the ligand was also critical to the product
action went to completion with the other palladium distribution. To summarize these optimization studies,
sources (entries 4 and 5). The nature of the precata- it was not only possible to perform consecutive
3
ꢀ
lyst had a dramatic influence on both yield and regio-
selectivity. For example, the replacement of Pd
C
(sp ) H functionalization and Heck cyclization with
(OAc)2 a single catalyst but also to control the cyclization
for PdBr2 favored 5-endo cyclization (entries 3 and 5). mode by a proper choice of each reaction parameter.
The reaction outcome was also highly dependent on We then applied the two optimal complementary
the choice of the base. Notably, the poor regioselec- sets of conditions, that is, Pd(OAc)2/F-TOTP/K2CO3
tivity observed with K2CO3 (entry 3) contrasted with in DMA at 1608C (conditions A) or Pd2(dba)3/John-
AHCTREUNG
AHCTREUNG
the exclusive formation of 3a using KOAc (entry 6) Phos/K2CO3 in DMF at 1508C (conditions B), to the
and Na2CO3 (entry 7), thus revealing a strong influ- 2-bromo-6-chloro analogue 1c. Much satisfyingly,
ence of both the cation and anion of these inorganic under conditions A (entry 10), this substrate afforded
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Julien Hitce and Olivier Baudoin
UPDATES
Table 2. Scope of the C
(sp3)-H activation/Heck cyclization/Heck arylation sequence.
N
Entry
Substrate
Aryl bromide[a]
Product
Yield [%][b]
1
2
3
4
5
1c
1b
1c
1b
1c
5a
5b
5b
5c
5c
58[c]
24
35
28
47
6
7
1c
1c
5d
5e
31
34
8
9
1c
1c
1c
5f
5g
5h
32
19
25
10
[a]
1.5 equivs. of electron-neutral and electron-rich aryl bromides (entries 1–7), 4 equivs. of electron-poor aryl bromides (en-
tries 8–10).
Isolated yields.
[b]
[c]
GC yield (compound 5a could not be isolated in pure form).
the 3a/4a mixture in a better yield and regioselectivity uct. When starting from this substrate, the product
(5% 3a, 71% 4a) than 1b. 1H NMR and GC/MS mon- may decompose to a lesser extent as it is formed later
itoring revealed that starting from 1b, Heck cycliza- in the process, and the overall yield is thus im-
tion was so fast that only traces of the brominated in- proved.[12] Interestingly, the cyclization of intermedi-
termediate 2b could be observed during the course of ate 2c constitutes a rare example of intramolecular
the reaction. On the contrary, with substrate 1c the Heck reaction of an unactivated aryl chloride.[13] Un-
sequence proceeded stepwise: the chlorinated inter- expectedly, when 1c was reacted under conditions B
mediate 2c cyclized only when conversion of 1c was (entry 11), the yield was lower and the regioselectivity
almost complete. Given that the overall reaction was reversed compared to substrate 1b.
times are similar for both substrates, the relative dif-
In order to functionalize further the unusual exo-
ference in the rates of both steps observed with start- methylenebenzocyclobutene moiety resulting from
ing material 1c is better suited to the synthesis of the the cascade reaction under conditions A, we decided
heat-sensitive exo-methylenebenzocyclobutene prod- to perform a third sequential transformation in the
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Substituted Benzocarbocycles by Palladium-Catalyzed Cascade Reactions
UPDATES
same reaction vessel. We envisioned that employing cause of prolonged reaction times and incomplete
an intermolecular Heck coupling as this third step conversion of the intermediate olefin 4a prior to cata-
3
(sp ) H activation/Heck lyst deactivation.[16] Thus, starting from 1c the reaction
ꢀ
would lead to a modular C
cyclization/intermolecular Heck sequence that would with 4’-bromoacetophenone and 4-bromobenzonitrile
not require re-addition of catalyst. To probe this con- afforded the target coupling products 5f–g in 32%
cept, bromobenzene was added directly to the mix- and 19% yields, respectively (entries 8and 9). The re-
ture resulting from the reaction of substrate 1c using action could also be performed in the presence of an
the Pd(OAc)2/F-TOTP catalyst. To our delight, when additional halogen atom: with 1-bromo-4-chloroben-
A
performed at 1208C the intermolecular Heck reaction zene, the chlorinated benzocyclobutene 5h was che-
smoothly afforded the expected trisubstituted olefin moselectively obtained from 1c in a moderate 25%
5a in 58% GC yield (Table 2, entry 1).
yield (entry 10).
This procedure (conditions C) was employed to
The products resulting from this versatile method-
evaluate the scope of this sequence starting from sub- ology displayed an original 4-membered ring-bridged
strates 1b and 1c and a variety of substituted aryl bro- cis-stilbene scaffold. Notably, compound 5e featuring
mides (Table 2).[14]
a trimethoxyphenyl moiety can be considered as a
In all cases, the products were successfully isolated conformationally restricted analogue of the antimicro-
as single olefin isomers. Electron-donating substitu- tubule
natural
product
combretastatin
A-4
ents on the aryl bromide were well tolerated. The re- (Figure 1).[17] The antimicrotubule activity of 5e was
action product from 1c and p-bromoanisole was iso- evaluated using colchicine as reference. It was found
lated as a single stereoisomer in 35% yield (average to be 13” less active (IC50 =49 mm) than colchicine
of 70% yield per step, entry 3). The double bond ge- (IC50 =3.8 mm). Further structural optimization of 5e
ometry was evidenced to be E by NOE correlations is underway to improve this encouraging activity.
between the protons of the olefin and the ethyl ben-
The precipitation of palladium black during the
zylic substituent.[15] The di- and trimethoxy analogues course of the transformations described above sug-
were isolated in 31% and 34% yields, respectively gested the intermediate formation of metal nanoparti-
(entries 6 and 7). Similarly, a satisfaying overall yield cles.[18] Considering this observation, we tried to take
(47%) was obtained by reaction with 4-bromo-N,N- advantage of the in situ modification of our catalyst
dimethylaniline (entry 5). Products 5b and 5c could by performing an additional hydrogenation step.[7a]
also be formed from dibromo substrate 1b but, as ex-
Substrate 1a was chosen for a proof-of-concept ex-
pected, with lower yields (entries 2 and 4). Electron- periment (Scheme 3). Dehydrogenation was carried
poor aryl bromides also participated in the 3-step se- out under conditions that were previously reported
quence although the yields were lower, mainly be- for this substrate.[4b] The formation of palladium
nanoparticles during the course of this reaction was
evidenced by transmission electronic microscopy
(TEM) analysis of aliquots of the reaction mixture.[19]
After complete conversion of 1a into olefin 2a, the re-
action mixture was placed under a hydrogen atmos-
phere. Satisfyingly, the hydrogenation product of 2a
could be isolated in 73% yield after stirring at room
temperature for 15 h.
This in situ hydrogenation was applied to the bicy-
clic olefins obtained from the cascade processes de-
scribed above (Table 3). Conditions A, B and C all al-
lowed the formation of an active hydrogenation cata-
lyst.
Starting from 1c, the in situ hydrogenation of inter-
mediate 4a obtained under conditions A afforded
Figure 1. Combretastatin A-4 and the conformationally re-
stricted analogue 5e.
3
ꢀ
Scheme 3. C
A
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Julien Hitce and Olivier Baudoin
UPDATES
Table 3. Scope of the in situ hydrogenation process.[a]
Entry
Substrate
Intermediate olefin (conditions)
Product
Yield [%][b]
1
2
3
1c
1b
1b
4a (A)
6a
6a
6b
44
28
49
4a (A)
3a (B)
4
1d
1b
3b (B)
5a (C)
6c
26
5
6d
47[c]
[a]
Conditions A: Pd
G
N
mol%), JohnPhos (10 mol%), K2CO3 (2 equivs.), DMF, 1508C; conditions C: conditions A, then PhBr (1.5 equivs.),
1208C.
Isolated yields.
GC yield.
[b]
[c]
benzocyclobutene 6a that was isolated in 44% yield by developing versatile, regio- and stereoselective pal-
(average of 76% yield per step) as a single diastereo- ladium-catalyzed cascade reactions that all feature a
3
ꢀ
isomer, the cis-relative stereochemistry of which was
C
A
assigned from a NOESY experiment (entry 1).[15] Fol- tional palladium catalysts and proceed with moderate
lowing the same procedure, 6a was isolated in a lower to good overall yields. Notably, original functionalized
28% yield from 1b (entry 2). Five-membered rings benzocyclobutenes were obtained,[20] including a con-
obtained under conditions B were also smoothly hy- formationally restricted analogue of combretastatin
drogenated, giving indanes 6b and 6c in 49% and A-4 (5e) with promising antimicrotubule activity.
26% isolated yields, respectively. Finally, the in situ
hydrogenation of the trisubstituted olefin 5a resulting
from the 3-step dehydrogenation/Heck cyclization/
Heck arylation sequence (Table 2, entry 1; Table 3,
Experimental Section
entry 5) also occurred and displayed good diastereo-
selectivity (dr 10:1, from H NMR of the crude mix-
ture). The major diastereoisomer 6d was formed in
47% GC yield.
General Considerations
1
Reagents were commercially available and used without fur-
ther purification except 2-bromo-6-chlorotoluene which was
filtered through a pad of silica before use. All solvents were
distilled from the appropriate drying agents immediately
before use. The dihalophenylacetonitrile substrates 1b–d
were prepared from the corresponding 2,6-dihalotoluenes
according to standard methods (see Supporting Informa-
tion). The F-TOTP ligand was synthesized from 2-bromo-4-
Conclusions
We have disclosed novel approaches to functionalized
4- and 5-membered benzocarbocyclic building blocks fluorotoluene according to a reported procedure.[4b] Yields
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Substituted Benzocarbocycles by Palladium-Catalyzed Cascade Reactions
UPDATES
refer to chromatographically and spectroscopically homoge-
neous materials. Merck silica gel 60 (particle size 40–63 mm)
was used for flash column chromatography, 1 mm and 2 mm
SDS silica gel coated glass plates (60 F254) were used for
preparative TLC using UV light as visualizing agent. NMR
spectra were recorded on Bruker Avance 300 or Avance 500
instruments, at 295 K with tetramethylsilane or residual pro-
tiated solvent used as an internal reference. Assignments
were made on the basis of 2D experiments (COSY, HMQC,
HMBC). 3D structures supporting NOE analyses (see spec-
tra copies) were obtained by molecular mechanics energy
minimization (MM2 force field, minimun RMS gradient=
0.050, CambridgeSoft Chem3D 9.0). IR spectra were record-
ed on a Perkin–Elmer Spectrum BX spectrometer and only
the strongest or structurally most important peaks were
listed. Products that had been reported previously were iso-
(1.5 mL) was injected under argon and the mixture was
stirred at 1508C (preheated oil bath) for 1.5 h. The reaction
mixture was treated as described above for the preparation
of compound 4a and the crude product was purified by
preparative TLC (2 mm silica gel, heptanes/diethyl ether,
9:1) to afford 3a as a colourless oil (40 mg, 78%); 1H NMR
(300 MHz, CDCl3): d=1.05 (dd, J=7.4, 7.4 Hz, 3H), 1.84
(dq, J=14.5, 7.4 Hz, 1H), 2.15 (dq, J=14.3, 7.4 Hz, 1H),
6.41 (d, J=5.5 Hz, 1H), 6.91 (d, J=5.4 Hz, 1H), 7.26–7.38
(m, 3H), 7.53 (d, J=6.8Hz, 1H); 13C NMR (75.5 MHz,
CDCl3): d=9.9, 30.4, 50.7, 120.0, 122.2, 122.9, 126.8, 128.8,
134.1, 134.7, 142.6, 143.5; GC/MS (EI, DB-5 ms column,
1 min at 908C then 90!2208C at 88Cminꢀ1): 9.5 min (m/z=
169 [M+]); IR (film): n=1457, 2232, 2972 cmꢀ1.
3
ꢀ
1
C
A
lated in greater than 95% purity, as determined by H NMR
Arylation Process (Table 2)
and capillary gas chromatography (GC). GC analyses were
performed with a Shimadzu QP2010 GC/MS apparatus, with
a simultaneous double injection on a DB-5 ms column
linked with a mass or a FID detection system. GC yields
were evaluated using tetradecane as an internal standard.
Conditions C: Representative procedure for amine 5c: Sub-
strate 1c (100 mg, 0.35 mmol) was reacted with Pd(OAc)2,
A
F-TOTP and K2CO3 in dry DMA at 1608C as described
above for the preparation of 4a. When the reaction was
almost over, the brown reaction medium turned black (after
80 min) and this mixture was transferred to an oil bath at
1208C. A solution of 4-bromo-N,N-dimethylaniline (105 mg,
0.52 mmol) in DMA (200 mL) was then added and the mix-
ture was stirred at 1208C for 1 h. After cooling, the mixture
was diluted with diethyl ether (15 mL) and filtered through
celite. The filtrate was washed with water (15 mL) and the
aqueous layer was extracted with diethyl ether (15 mL”3).
The organic layers were combined, washed with brine
(25 mL) and dried over magnesium sulfate. The solvent was
evaporated and the residue was purified by flash chromatog-
raphy (silica gel, heptanes/ethyl acetate, 5:1) to afford 5c as
3
ꢀ
C
A
Process (Scheme 2, Table 1)
Conditions A: Representative procedure for exo-methylene-
benzocyclobutene 4a: A dry Schlenk tube containing a mag-
netic rod was charged with substrate 1c (100 mg,
0.35 mmol), palladium acetate (7.8mg, 0.035 mmol), F-
TOTP (25.0 mg, 0.07 mmol) and potassium carbonate
(96 mg, 0.70 mmol). The Schlenk tube was twice evacuated
and backfilled with argon, then capped with a rubber
septum. Dry N,N-dimethylacetamide (1.7 mL) was injected
under argon and the mixture was stirred at 1608C (pre-
heated oil bath) for 1.5 h. After cooling, the mixture was di-
luted with diethyl ether (15 mL) and filtered through celite.
The organic solution was washed with water (15 mL) and
the aqueous layer was extracted with diethyl ether (15 mL ”
3). The combined organic layers were washed with brine
(25 mL), dried over magnesium sulfate and evaporated. The
residue was purified by flash chromatography (silica gel,
heptanes/diethyl ether, 9:1) to afford a 3a/4a mixture as an
1
an orange oil (47 mg, 47%); H NMR (500 MHz, CDCl3):
d=1.22 (dd, J=7.5, 7.5 Hz, 3H), 2.01 (dq, J=14.4, 7.5 Hz,
1H), 2.24 (dq, J=14.3, 7.5 Hz, 1H), 3.02 (s, 6H,), 6.44 (s,
1H), 6.77 (d, J=8.3 Hz, 2H), 7.28–7.40 (m, 3H), 7.47 (d, J=
9.0 Hz, 2H), 7.52 (d, J=7.5 Hz, 1H); 13C NMR (75.5 MHz,
CDCl3): d=10.4, 30.1, 40.3, 50.9, 112.1, 121.2, 121.4, 121.6,
122.7, 123.7, 129.0, 129.2, 129.8, 134.6, 143.3, 144.9, 150.2;
HR-MS (ESI, MeOH+CH2Cl2): m/z=289.1708, calcd. for
C20H21N2 [(M+H)+]: 289.1705; IR (film): n=1520, 1605,
2228, 2967 cmꢀ1.
1
oil (3a:4a=7:93 by H NMR, 45 mg, 5% 3a, 71% 4a). This
mixture was further purified by another careful flash chro-
matography (silica gel, heptanes/diethyl ether, 95:5) in order
to obtain an analytically pure sample of 4a for characteriza-
3
ꢀ
C
(sp ) H Activation/Heck Reactions/Hydrogenation
One-Pot Sequences (Table 3)
1
tion purpose; H NMR (500 MHz, CDCl3): d=1.19 (dd, J=
7.4, 7.4 Hz, 3H), 1.98(dq, J=14.7, 7.4 Hz, 1H), 2.16 (dq, J=
14.8, 7.4 Hz, 1H), 5.22 (d, J=2.1 Hz, 1H), 5.43 (d, J=
2.1 Hz, 1H), 7.25–7.39 (m, 4H); 13C NMR (75.5 MHz,
CDCl3): d=10.4, 29.8, 51.4, 104.4, 120.2, 120.5, 121.9, 129.9,
130.1, 143.3, 144.8, 146.5; GC/MS (EI, DB-5 ms column,
1 min at 908C then 90!2208C at 88Cminꢀ1): 9.0 min (m/z=
169 [M+]); IR (film): n=1460, 2231, 2970 cmꢀ1.
Representative procedure for benzocyclobutene 6a: Substrate
1c (100 mg, 0.35 mmol) was reacted with Pd(OAc)2,
A
F-TOTP and K2CO3 in dry DMA at 1608C as described
above for the preparation of 4a. After 1.5 h the reaction
mixture was cooled to room temperature and the Schlenk
tube was purged with dihydrogen. The mixture was stirred
under 1 atm of dihydrogen at room temperature for 16 h. It
was then diluted with diethyl ether (15 mL) and filtered
through celite. The solution was washed with water (15 mL)
and the aqueous layer was extracted with diethyl ether
(15 mL”3). The organic layers were combined, washed with
brine (25 mL) and dried with magnesium sulfate. The sol-
vent was removed under reduced pressure and the residue
was purified by flash chromatography (silica gel, heptanes/
Conditions B: Representative procedure for indene 3a: A
dry Schlenk tube containing a magnetic rod was charged
with substrate 1b (100 mg, 0.30 mmol), Pd2(dba)3·CHCl3
G
(15.6 mg, 0.015 mmol), JohnPhos (9.0 mg, 0.030 mmol) and
potassium carbonate (83 mg, 0.60 mmol). The Schlenk tube
was twice evacuated and backfilled with argon, then capped
with
a
rubber septum. Dry N,N-dimethylformamide
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Julien Hitce and Olivier Baudoin
UPDATES
diethyl ether, 95:5) to afford 6a as a colourless oil (26 mg,
44%); 1H NMR (500 MHz, CDCl3): d=1.22 (dd, J=7.4,
7.4 Hz, 3H), 1.58(d, J=7.2 Hz, 3H), 1.90–2.02 (m, 2H),
3.49 (q, J=7.2 Hz, 1H), 7.13 (dd, J=7.1, 0.8Hz, 1H), 7.22
(d, J=7.2 Hz, 1H), 7.27–7.30 (m, 2H); 13C NMR
(125.8MHz, CDCl 3): d=10.7, 16.9, 30.7, 48.5, 50.6, 120.4,
122.0, 122.6, 128.3, 129.4, 142.2, 146.7; GC/MS (EI, DB-5 ms
column, 1 min at 908C then 90!2208C at 88Cminꢀ1):
8.3 min (m/z=171 [M+]); IR (film): n=1458, 2231,
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3942; e) C.-G. Dong, Q.-S. Hu, Org. Lett. 2006, 8,
5057–5060; f) A. Pinto, L. Neuville, P. Retailleau, J.
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2968cm ꢀ1
.
[7] a) J.-P. Leclerc, M. AndrØ, K. Fagnou, J. Org. Chem.
2006, 71, 1711–1714; b) R. B. Bedford, M. Bentham, J.
Org. Chem. 2006, 71, 9403–9410.
[8] For a recent related example of 5-endo-trig Heck cycli-
zation, see: P. Vital, P.-O. Norrby, D. Tanner, Synlett
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[9] S. Brꢂse, Synlett 1999, 10, 1654–1656.
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[11] JohnPhos: 2-(di-tert-butylphosphino)biphenyl, see: A.
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[12] On the contrary, starting from 1b, the final product is
formed earlier in the process and is consequently more
prone to decomposition. This may partly account for
the modest yields observed with this substrate when
the 4-membered ring is favored.
Acknowledgements
This work was financially supported by ICSN-CNRS. We
thank Prof. C. Colliex and Dr. O. StØphan (UniversitØ Paris-
Sud 11, France) for TEM analysis and S. Thoret (ICSN-
CNRS) for biological assays.
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