Radical cascade cyclizations and platinum(II)-catalyzed cycloisomerizations of ynamides

Article abstract of DOI:10.1016/j.tet.2005.11.092

Ynamides are tested as new partners in radical and organometallic transformations. A radical cascade involving a 5-exo-dig cyclization followed by a 6-endo-trig radical trapping transforms ynamides into hetero-polycyclic compounds such as isoindoles, isoindolinones and pyrido-isoindolones. Various ene-tosylynamides react with platinum(II) chloride and lead to bicyclic nitrogenated heterocycles. This unprecedented and easily operated process can be coupled with a hydrolysis of the intermediate cyclic tosylenamides in a one-pot transformation, which provides cyclobutanones.

Full text of DOI:10.1016/j.tet.2005.11.092

Tetrahedron 62 (2006) 3856–3871
Radical cascade cyclizations and platinum(II)-catalyzed
cycloisomerizations of ynamides
*
´ ´
Frederic Marion, Julien Coulomb, Aurore Servais, Christine Courillon,
*
*
Louis Fensterbank and Max Malacria
´ ´
Universite Pierre et Marie Curie, Laboratoire de Chimie Organique, associe au CNRS,
´ ` ´
Institut de Chimie Moleculaire FR2769, 04 place Jussieu, Tour 44-54 2eme etage, B229, 75252 Paris Cedex 05, France
Received 14 November 2005; accepted 26 November 2005
Available online 28 February 2006
Abstract—Ynamides are tested as new partners in radical and organometallic transformations. A radical cascade involving a 5-exo-dig
cyclization followed by a 6-endo-trig radical trapping transforms ynamides into hetero-polycyclic compounds such as isoindoles,
isoindolinones and pyrido-isoindolones. Various ene–tosylynamides react with platinum(II) chloride and lead to bicyclic nitrogenated
heterocycles. This unprecedented and easily operated process can be coupled with a hydrolysis of the intermediate cyclic tosylenamides in a
one-pot transformation, which provides cyclobutanones.
q 2006 Elsevier Ltd. All rights reserved.
1. Introduction
methods for the synthesis of ynamides is due to their
original and very diverse reactivity and to the synthetic
importance of these versatile building blocks. Indeed
ynamides can undergo metal-catalyzed [2C2C2]24 and
[2C2C1]14,15,25 cycloadditions, [2C2]12,26 and [4C2]12,27
cycloadditions, ring-closing metatheses,28 addition
reactions,29 palladium-catalyzed cross-couplings,30 electro-
cyclic processes31 and carbometallation reactions.32 Being
deeply involved both in radical and organometallic
mechanistical studies as well as synthetic processes, we
examined ynamides as new partners in the two types of
approaches.
As a coincidence, the pioneer works on ynamines were
reviewed 30 years ago in our university by late Professor
Jacqueline Ficini.1 She, and other groups successfully
prepared and studied a moiety bearing a very high organic
synthetic potential, the triple bond, attached to a nitrogen
atom whose both electron donating ability and natural
abundance are seminal for chemical processes and target
oriented strategies.2–4 However, the reactivity of ynamines
has not been developed until recently due to their high
sensitivity towards hydrolysis and to their difficult prep-
aration.5 Interestingly, the substitution of the nitrogen atom
with an electron withdrawing group helps stabilizing the
yne–nitrogen association under the form of an ynamide,
which reaches a compromise between reactivity and
stability. The most frequently reported ynamides are
sulfonamides, cyclic carbamates and lactams. Since the
first preparation of ynamides by Viehe in 1972, numerous
methods have been described in the literature.6–21 Very
recently copper-mediated N-alkynylations as synthetic
preparations of ynamides were reported by Danheiser and
Hsung to obtain carbamates, sulfonamides and lactams
mainly.22,23 The growing development of several efficient
First, our interest in radical cyclization cascades33 and in the
discovery of new radical reaction partners34 together with
the emergence of radical chemistry in the field of
heterocyclic synthesis35 prompted us into the study of
ynamides radical transformations (pathway (a) in
scheme 1).36 Second, we investigated the platinum(II)
dichloride catalyzed cycloisomerization of ene–tosylyn-
amides (pathway (b) in Scheme 1), targeting the promotion
of charge controlled processes on the nitrogen substituted
triple bond by PtCl2.
Keywords: Cycloisomerization; Heterocycles; Platinum; Radical Cascades;
Radical cyclization; (Tosyl)-ynamides.
*
Corresponding authors. Tel.: C33 14427 5996; fax: C33 14427 7360
(C.C.); tel.: C33 14427 7068; fax: C33 14427 7360 (L.F.); tel.: C33
14427 3586; fax: C33 14427 7360 (M.M.); e-mail
addresses: christine.courillon@upmc.fr; louis.fensterbank@upmc.fr;
max.malacria@upmc.fr
Scheme 1.
0040–4020/$ - see front matter q 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.11.092

F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
3857
2. Radical cyclization cascades of ynamides
2.1. Synthesis of precursors
We report herein the first use of ynamides in radical
cyclizations leading to polycyclic nitrogen heterocycles.
Initially, the silylated carboxamides precursors 1–11 of type
I and II were easily prepared according to Witulski’s14
method, which involves the Michael addition of an amide to
an alkynyliodonium salt, whilst sulfonylynamides 12–16
were obtained in less satisfying yields (Scheme 2).
We have tested other preparation methods, especially
following Hsung’s and Danheiser’s procedures.22,23 For
instance, coupling of 2-bromobenzyltosylamide 18 with
phenylethynylbromide succeeds in a yield of 75 and 80%,
respectively, in the presence of copper(I) iodide in pyridine
and with copper (II) sulfate and 1,10-phenantroline. This
result is comparable with the transformation of benzyltosyl-
amide 17 reported in the literature.22,23,37 When we
submitted conjugated carboxamides such as 19 or 20 to
the same set of experimental conditions, we could only
recover the starting material. (Scheme 3) This lack of
reactivity may be due to the deactivation of the copper
catalyst by the amide as reported by Riddell26 and
Buchwald.38
Therefore, we rather prepared the carboxamides precursors
1–11 by reacting them as depicted in scheme 2, whilst
further desilylation14 and subsequent alkylation17a of
compounds 2, 3, 7 and 9 gave an easy access to various
substituted ynamides 23–28 (Scheme 4).
2.2. Radical cyclization
Scheme 2.
We first examined the 5-exo-dig cyclization with differently
protected ynamides (sulfonylynamides 12–17, type I
Scheme 3.

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F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
insaturation. Gratifyingly, we could assist to the radical
cyclization cascade with good yields when reacting type I
precursors, which contain an activated double bond
(Table 1).
In the case of bromobenzyl precursors (entries 1–3 and 6–9),
the cyclization products could be observed only with
silylated ynamides (entries 1, 2 and 6–8). Slow addition of
tin hydride was necessary to obtain the cascade products in
good yields (entries 2 and 7).
For iodobenzyl compounds, the cyclization products were
obtained in good yields without slow addition and in the
case of silylated and monosubstituted triple bonds (Table 1,
entries 4 and 5). This suggests that the addition of the
tributylstannyl radical39 to the triple bond is competitive
with the bromine atom abstraction and is the major pathway
when the ynamide is monosubstituted. The use of
tristrimethylsilylsilane40 as the reductor in order to try to
avoid this side reaction did not allow us to isolate any
cyclization product in the case of the cyclohexenyl
precursor (entries 8 and 9). The observed products were
issued from a radical cascade, which involves a 5-exo-dig
cyclization followed by radical trapping in a 6-endo-trig
mode for an activated terminal or endocyclic double bond.
This cascade shows an excellent regioselectivity in the case
of type I precursors, which contain activated acceptors.
Scheme 4.
compounds 1–7 and type II compounds 7–11) obtained
either from the corresponding amides (Scheme 1) or by
desilylation of the triple bond and further substitution if
necessary (Scheme 4).
The same 5-exo-dig/6-endo-trig regioselectivity was
observed when reacting type II compounds with non-
activated acceptors (Table 1). The substitution on the triple
bond was studied on type II compounds. In order to avoid
the addition of tin on the triple bond, we have also chosen an
iodo-precursor. We obtained good yields for mono- and
di-substituted ynamides.(Table 1) The yield decreased when
the triple bond was activated with an ester group. The
addition of tin became then possible and the yield could not
be improved with slow addition of the hydride.
Since radical cyclization of various sulfonamides has been
well studied in the literature,35 in our first attempts we
submitted sulfonylynamides 12–17 to tributyltin hydride/
AIBN initiation conditions in benzene. Cyclization failed
and the results could not be improved upon changing the
halogen atom or the electronic properties of the sulfonyl
group. These precursors reacted slowly and sluggishly to
give only trace amounts of the 5-exo-dig products in the case
of the methanesulfonyl- and the trifluoromethanesulfonyl-
protected ynamides. The outbreak of a deep purple colour in
the reaction mixture leads us in speculating about the
formation of a persistent radical, which would not allow the
cascade process to evolve and proceed.
In the case of ynamides 4, 5, 8 and 10, an aromatic acceptor
is either conjugated with the amide or linked to it through a
methylene group (Table 2). We observed that type I
precursors 4 and 5 react differently than type II compounds
8 and 10. When compound 4 reacts with tributyltinhydride,
azabisisobutyronitrile in benzene at 80 8C, the aromatized
tetracyclic product 37 is isolated after 2 h in 67% yield
(entry 1). The formation of compound 37 under reducing
conditions and the absence of traces of the reduced
vinylsilane indicate that the cascade process is faster than
the reduction of the intermediate vinyl radical. This could
also be observed for the methoxysubstituted ynamide 5,
which cyclizes slightly less rapidly for 16 h and gives
compound 38 in a lower yield of 54% (entry 2). No product
issued from an ipso cyclization followed by a rearrangement
was isolated.35d,41
Next, we turned our attention to the trifluoroacetamide 1,
which cyclized in refluxing benzene in the presence of tin
hydride and AIBN in 78% yield to give the isoindole 29 as a
mixture of two diastereomers on the double bond in a 2/1
ratio (Scheme 5). NOE experiments have shown that the Z
diastereomer was the main compound, suggesting that the
reduction of the vinylic radical was governed by its stability
and therefore by allylic strain.
Reaction (under the same classical radical conditions
mentionned above) of type II ynamide 8 gives a 1/1
mixture of the two diastereomeric forms of compound 40
in a yield of 57% whilst traces of the tetracyclic compound
39 could be identified in the crude material (entry 3).
Compound 10 was transformed into a mixture of the
tetracyclic isoindolinone 41 (23%) and the two
Scheme 5.
With this preliminary result in hands, we next assumed that
the intermediate vinylic radical could be trapped by another

F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
3859
Table 1
Entry
Ynamide
R
Yield (%)a
Product
Type I
1
2
3
4
5
2
2
23
7
25
TMS
TMS
H
TMS
H
42
70b
0b
83
54
30
30
30
31
6
7
8
9
3
3
3
24
TMS
TMS
TMS
H
45
32
32
32
75b
54c
0,b 0c
Type II
10
11
12
13
9
TMS
H
CH3
CO2Et
90
78
84
45
33
34
35
36
26
27
28
a A benzene solution (15 mL) of ynamide (0.25 mmol), tin hydride (2 equiv) and AIBN (0.5 equiv) was refluxed until the starting material disappeared.
b Slow addition of the hydride was performed.
c Tristrimethylsilylsilane was used as reductor.
Table 2
Entry
Ynamide
Yield (%)a
Product
Type I
1
2
3
4
5
8
67
54
57
37
38
40 (Z/E:1/1)
Type II
4
5
6
10
8
10
94
41 (23%)C42 (71%) (Z/E: 2:1)
39
41
46a
62a
37:RZH, 38:RZOMe
40:RZCH2Ph, 42:RZPh
41
39
a Photolysis of hexabutylditin in toluene is used in the reaction.
diastereomers (Z/E: 2:1) of compound 42 (71%) (entry 4).
Slow addition of tributyltin hydride (0.25 mmol hK1
ipso42 cyclisation and an oxidative fragmentation pro-
cess.(Scheme 6)
)
neither increased the formation of compound 39 nor
significantly modified the ratio of compounds 41 and 42.
When we carried out the reaction under atom transfer
conditions (photochemical homolytic cleavage of hexabu-
tylditin in toluene) in order to try to avoid the intermediate
reduction products, the type II precursors gave only the
tetracyclic products 39 and 41, respectively, in a yield of
46 (40 h) and 62% (7 h) (entries 5 and 6). The difference in
behaviour between type I and type II ynamides bearing an
aromatic moiety, which plays the role of trapping the
intermediate vinyl radical speaks for the importance of the
place of the amide function. When the ynamide bears an
heteroaromatic ring as the acceptor moiety such as a
furanyl substituent the reaction developed differently in the
case of type I and II compounds. We failed in initiating the
radical transformation of compound 6 whilst compound 11
was transformed into a compound that we could identify
as the highly conjugated aldehyde 11a probably via an
Scheme 6.
We have demonstrated that ynamides are excellent partners
for radical chemistry. We have described a new radical
cyclization cascade process, which leads to isoindole,
isoindolinones and pyrido-isoindolones in good yields.
These results bring new perspectives for the development
of ynamides and the application of their reactivity in the
field of heterocyclic chemistry.

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F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
3. Platinum(II) chloride catalyzed cycloisomerization
of ynamides
between the amide function and the carbon–carbon double
bond like precursors 45 and 47. We show here a completely
distinct and original reactivity of these substrates in the
presence of platinum dichloride. Thus, in the case of ene–
tosylynamide 45, cyclization occurred and yielded the
bicyclic[4.2.0] compound 46.48 This fragile structure,
partially degrading during the purification process, was
obtained in 34% yield, which we had some difficulty to
reproduce since these reactions proved to be sensitive to
moisture. The bicyclic derivative 48 was similarly obtained
by reacting the b-dimethyl-substituted ene–ynamide 47 with
5 mol equiv of PtCl2 in 71% yield. The structural assign-
The transition metal catalyzed cycloisomerization of enyne
systems is a powerful synthetic tool that has witnessed
intense development.43 Nevertheless, there is still room for
the implementation of new partners in this process. Among
all potential candidates, ene–tosylynamides are highly
appealing substrates. Because of the presence of the
nitrogen atom directly attached to the triple bond, one can
anticipate charge controlled processes.5,24a,31b This led us to
the use of platinum(II) dichloride as catalyst, since this
versatile reagent is known to promote charge build-up on
enyne systems.44,45 In addition, the resulting products
should incorporate valuable nitrogen heterocycles. This
has also been demonstrated by Hsung with the development
of a PtCl2-catalyzed keteniminium Pictet–Spengler cycliza-
tion.46 Herein, we describe our results of a versatile
organometallic process, which transforms different
ene–tosylynamides, in the presence of PtCl2, into bicyclic
nitrogenated heterocycles.
1
ment for 46 and 48 was based on the following data: H
NMR spectra show no stereogenic centre and 13C NMR
spectra display no CH signal, indicating that the double
bond is shared by the two cycles. Quaternary carbon signals
around 122 and 135 ppm confirm the structure of the
bicyclic product. These platinum(II)-catalyzed cyclizations
could not easily be monitored by TLC because of close Rf
for the product and the starting material which, in addition,
reveal as faint spots. Therefore, we followed the consump-
tion of the ene–ynamide by IR spectroscopy and checked
the vanishing of the triple bond band.
3.1. Synthesis of precursors
Because of the general lability of the final products,49 we
decided to transform the crude bicyclic products directly
into more stable compounds through a second reaction in a
one-pot process.
The precursors we have used in this part were prepared
following the Bru¨ckner’s alternative transformation of
formamides.7 After a Mitsonobu transformation, the
alkylated tosylamines are formylated with Katritsky’s
reagent: N-formylbenzotriazole.47 Dichloroolefination and
a butyllithium-triggered Fritsch–Buttenberg–Wiechell
rearrangement sets the alkyne function. This procedure
allowed us to obtain various ene–tosylynamides, which are
utilized in this work as precursors of original PtCl2-
catalyzed cycloisomerizations (Scheme 7).
First, we performed ozonolysis, which provided easily
isolated keto-lactams 50–52, that could be useful building
blocks in total synthesis of more complex alkaloid natural
products. Nevertheless, the moderate yields (Table 3), yet
consistent with literature,50 drove us to switch to a
hydrolysis reaction as the second step. Thus, after
cycloisomerization reaction in presence of 10 mol% of
PtCl2, addition of a 1 M HCl solution to the crude
cycloisomerized product gave cyclobutanones formed by
hydrolysis of the intermediate enamines. The results of this
cyclization–hydrolysis sequence are summarized in Table 3.
3.2. Cycloisomerizations
Our first attempt consisted in exposing ene–ynamide 43 to
PtCl2 (5 mol%) in toluene at 80 8C and led to the metathesis
product 44 in 98% yield, whose structure was secured by
comparing to Mori’s data. (Scheme 8). Mori has indeed
investigated the ring-closing metathesis transformation of
43 and found out that this reaction was accelerated in the
presence of the second generation Grubb’s catalyst.28b
Moreover, she performed efficient ring-closing metathesis
with several precursors bearing a different carbon tether
The four atom-tethered substrates 45 and 47 are transformed
in good yields into the corresponding cyclobutanones 53,
56. Alkyl substitution is tolerated both on the alkyne partner
(precursor 59) and on the alkene one (precursors 54 and 57).
In the case of 57, the non-opened bicyclic aminal 58,
presumably cis51 was obtained in 76% yield. As anticipated,
Scheme 7.

F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
3861
Table 4
Ynamides
Cyclobutanones
45
47
53 (65%)
56 (85%)
60 (70%)
Scheme 8.
59
Table 3
Ynamides
Keto-lactams
Yield
(%)
55 (54%)
58 (76%)
54
20
45
50
57
37,24
nZ1:47, nZ2:49
49
61 (40%)
nZ1:51, nZ2:52
introduction of a gem-dimethyl group in the tether resulted
in improved yields (substrate 45 and 47 vs 54 and 57).52
favourable, giving products F. This is supported by the
isolation of 46 and 48. However, in the case of precursors 54
and 57, intermediate F is not attainable. Instead, intermediate
of type E54 could also lead to the hydrolysis products 55
and 58 (Scheme 9).
Lengthening the tether up to five atoms, corresponding to an
intermediate [5,2,0]-bicyclic adduct still gave a satisfactory
yield of cyclobutanone 61. In this case, some aminal could
also be observed in the crude product but was not isolated
after separation on silica gel (Table 4).
3.3. Mechanism
The original results summarized in Scheme 8 and in both
Tables 3 and 4 show two types of products whose formation
would be dependent from the tether length. For nZ1, which
corresponds to a 1,6-enyne precursor, the formal metathesis
diene (44) is isolated; for nZ2, bicyclo[nC2.0.2] products
are obtained. Although the formation of 1,3-dienes does not
necessarily transit via a cyclobutene,53 the proposition of a
common reaction pathway involving bicyclic intermediate E
with two distinct evolutions appears appropriate. Ring strain
associated with the cyclobutene moiety would direct the fate
of this intermediate. Presumably, for nZ1, the severe ring
strain would promote the electrocyclic ring opening of E to
provide the diene 44. With a six-membered ring fused to the
cyclobutene, the strain is reduced and isomerization of the
double bond from exo to endo at the ring junction would be
Scheme 9.

3862
F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
Several mechanistic scenarios are possible for the genera-
tion of key intermediate E. All begin with the electrophilic
activationofthe yne partner bythe p-Lewisacid (complexA).
Then, as supported by DFT calculations of Soriano,51 and
consitent with Echavarren modelizations,55 evolution of a
cyclopropylplatina carbene intermediate B could lead to D.
Alternatively, a ketenimium intermediate C, as proposed by
Hsung46 would undergo a [2C2] cycloaddition and ensure the
construction of the cyclobutyl ring. Both pathways could
transit via stabilized carbocation D to provide E. ‘Homoallyl-
cyclopropylmethyl-cyclobutyl’ cation D could also originate
from Fu¨rstner’s cationic manifold proposal.44d
All melting points are uncorrected. THF and Et2O are
distilled from sodium benzophenone ketyl, CH2Cl2, pentane
and toluene are distilled, respectively, from CaH2 and Na/K.
5.1. General procedure for the formation of ynamides
To a solution of amide (2 mmol) in toluene (60 mL) was
added at ambient temperature KHMDS (powder,
2.2 mmol), the resulting mixture was sonicated for
30–60 min. The reaction medium was then heated to
70–80 8C and the iodonium salt (2.5 mmol) was added
under vigorous stirring. After 30 min the temperature was
raised to rt and silica (10 g) was added. The solvent was then
removed under reduced pressure and chromatography on
silica gel (9:1 petroleum ether/ethyl acetate) of the crude
residue afforded ynamides.
4. Conclusion
We herein report the first use of ene–ynamides as versatile
partners for radical cyclizations and PtCl2-catalyzed
cycloisomerization reactions. Efficient and original new
accesses to nitrogenated polycyclic derivatives have been
worked out. The radical approach implies two main classes
of ynamides, which were designed to be precursors to an
aryl radical that is suitably placed for cyclization onto the
ynamide. On type I and II N-alkynylcarboxamides, 5-exo
cyclization was easily and efficiently carried out, and
examples of tandem 5-exo, 6-endo-cyclizations have led to
nitrogen-containing heterocyclic compounds. The key
factors that affected the success of these reactions were
shown to be the starting halide, and the degree of
substitution of the alkyne. The extension of this cascade
process to substrates in which the final cyclization would
occur onto an aryl or an heteroaryl ring completes this
study and opens it towards future synthetic developments
in the field of medicinal chemistry. In the case of the Pt(II)
chemistry,56 a formal [2C2] cycloaddition gives birth to
versatile cyclobutenyl bicyclic substrates that we could
ozonolyse to provide medium-sized nitrogen heterocycles,
and hydrolyze to give various cyclobutanone derivatives.
In the latter case, the reaction corresponds to an
intramolecular addition of a ketene on the alkene partner
via a nitrogen tether. These preliminary elements of
reactivity confirm the high synthetic potential of the
introduction of ene–ynamides in organometallic chemistry
and pave the way for important applications we will
disclose in due course.
5.1.1. N-(2-Bromo-benzyl)-2,2,2-trifluoro-N-trimethylsil-
anylethynyl-acetamide 1. YieldZ77%. Clear oil; 1H NMR
(CDCl3, 400 MHz): 7.62 (d, JZ7.6 Hz, 1H), 7.36–7.23 (m,
3H), 4.91 (s, 2H), 0.10 (s, 9H); 13C NMR (CDCl3, 100 MHz):
158.3 (q, 1C, IV, JZ36.4 Hz), 133.2 (III), 132.99 (IV), 130.9
(III), 130.22 (III), 127.7 (III), 124.46 (IV), 117.1–114.2 (q,
1C, IV, JZ287.2 Hz), 90.9 (IV), 78.0 (IV), 53.30 (II), K0.4
(3C, I); 19F NMR (CDCl3, 376 MHz): K71.5; IR (neat) cmK
1: 3064, 2187, 1725, 1251, 1154.
5.1.2. N-(2-Bromo-benzyl)-N-trimethylsilanylethynyl-
acrylamide 2. YieldZ65%. Pale yellow solid; mp 40–
1
43 8C; H NMR (CDCl3, 400 MHz): 7.58 (d, JZ8.0 Hz,
1H), 7.31 (m, 2H), 7.17 (t, JZ8.0 Hz, 1H), 7.14 (dd, JZ
16.8, 10.2 Hz, 1H), 6.54 (dd, JZ16.8, 1.6 Hz, 1H), 5.88 (dd,
JZ10.2, 1.6 Hz, 1H), 4.89 (s, 2H), 0.12 (s, 9H); 13C NMR
(CDCl3, 100 MHz): 166.3 (IV), 134.7 (IV), 132.8 (III),
131.3 (II), 130.3 (III), 129.4 (III), 127.5 (III), 126.5 (III),
124.1 (IV), 95.6 (IV), 76.5 (IV), 51.3 (II), K0.1 (3C, I); IR
(neat) cmK1: 3065, 3032, 2173, 1685, 1625, 1244. Anal.
Calcd for C15H18BrNOSi (336.29): C, 53.57; H, 5.39; N,
4.16. Found: C, 53.42; H, 5.45; N, 4.08.
5.1.3. Cyclohex-1-enecarboxylic acid (2-bromo-benzyl)-
trimethylsilanylethynyl-amide 3. YieldZ56%. Pale
yellow solid; mp 37–39 8C; H NMR (CDCl3, 200 MHz):
1
7.55 (d, JZ7.4 Hz, 1H), 7.28 (m, 3H), 7.15 (m, 1H), 6.52 (h,
JZ2.0 Hz, 1H), 4.79 (s, 2H), 2.34 (m, 2H), 2.14 (m, 2H),
1.64 (m, 4H), 0.04 (s, 9H); 13C NMR (CDCl3, 100 MHz):
172.2 (IV), 135.2 (IV), 134.7 (III), 132.9 (III), 132.6 (IV),
130.3 (III), 129.3 (III), 127.4 (III), 124.1 (IV), 97.6 (IV),
74.7 (IV), 52.0 (II), 25.3 (II), 25.0 (II), 22.0 (II), 21.6 (II),
0.1 (3C, I); IR (neat) cmK1: 3064, 3032, 2164, 1679, 1278.
Anal. Calcd for C19H24BrNOSi (390.38): C, 58.46; H, 6.20;
N, 3.53. Found: C, 58.47; H, 6.08; N, 3.53.
5. Experimental
1H and 13C NMR spectra were recorded at rt at 400 and
100 MHz, respectively, on an ARX 400 Bruker spec-
trometer. Chemical shifts are reported in parts per million
referenced to the residual proton resonances of the solvents.
Coupling constants are expressed in Hertz. We use (I), (II),
(III) and (IV) to caracterize primary, secondary, tertiary and
quaternary carbons.
5.1.4. N-(2-Bromo-benzyl)-N-trimethylsilanylethynyl-
benzamide 4. YieldZ32%. Pale yellow solid; mp 51–
53 8C; 1H NMR (C6D6, 400 MHz): 8.04 (dd, JZ6.6, 2.0 Hz,
2H), 7.39 (td, JZ8.1, 1.5 Hz, 2H), 7.15 (m, 3H), 6.98 (td,
JZ7.6, 1.5 Hz, 1H), 6.75 (td, JZ8.1, 2.0 Hz, 1H), 5.03 (s,
2H), 0.06 (s, 9H); 13C NMR (CDCl3, 100 MHz): 170.7 (IV),
135.1 (IV), 133.2 (IV), 133.0 (III), 131.7 (III), 130.6 (III),
129.6 (III), 129.1 (2C, III), 127.4 (2C, III), 127.5 (III), 124.3
(IV), 97.4 (IV), 75.9 (IV), 52.6 (II), K0.2 (3C, I); IR
(neat) cmK1: 3086, 3067, 3029, 3006, 2171, 1673, 1286.
Infrared (IR) spectra were recorded with a Bruker tensor 27
(ATR diamond spectrometer). Thin-layer chromatography
(TLC) was performed on Merck silica gel 60 F 254. Silica
gel Merck Geduran SI (40–63 mm) was used for column
chromatography using Still’s method.

F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
3863
Anal. Calcd for C19H20BrNOSi (386.36): C, 59.07; H, 5.22;
N, 3.63. Found: C, 59.15; H, 5.21; N, 3.52.
JZ7.5 Hz, 1H), 6.01 (m, 1H), 5.34 (dd, JZ17.1, 1.2 Hz,
1H), 5.19 (dd, JZ10.3, 1.0 Hz, 1H), 4.28 (d, JZ6.0 Hz,
2H), 0.06 (s, 9H); 13C NMR (CDCl3, 100 MHz): 171.2 (IV),
141.4 (IV), 138.8 (III), 130.8 (III), 130.7 (III), 127.7 (III),
127.7 (III), 119.4 (II), 96.1 (IV), 92.2 (IV), 75.6 (IV), 50.2
(II), K0.0 (3C, I); IR (neat) cmK1: 3085, 3053, 3021, 2170,
1685, 1644, 1291. Anal. Calcd for C15H18INOSi (383.29):
C, 47.00; H, 4.73; N, 3.65. Found: C, 47.08; H, 4.65; N,
3.62.
5.1.5. N-(2-Bromo-benzyl)-2-methoxy-N-trimethylsilanyl-
ethynyl-benzamide 5. YieldZ57%. Pale yellow solid; mp
1
96–98 8C; H NMR (C6D6, 200 MHz): 7.65 (dd, JZ7.6,
1.3 Hz, 1H), 7.50 (dd, JZ7.6, 1.3 Hz, 1H), 7.42 (d, JZ
7.6 Hz, 1H), 7.18 (t, JZ7.6 Hz, 1H), 7.08 (td, JZ7.5,
1.1 Hz, 1H), 6.80 (m, 2H), 6.56 (d, JZ8.2 Hz, 1H), 5.14 (s,
2H), 3.45 (s, 3H), 0.02 (s, 9H); 13C NMR (CDCl3, 50 MHz):
170.8 (IV), 156.6 (IV), 135.1 (IV), 132.9 (III), 131.6 (III),
129.6 (III), 129.3 (III), 128.5 (III), 127.6 (III), 124.7 (IV),
123.7 (IV), 120.5 (III), 110.9 (III), 97.1 (IV), 74.27 (IV),
55.8 (I), 51.6 (II), 0.00 (3C, I); IR (neat) cmK1: 3065, 3029,
3009, 2178, 1681, 1273. Anal. Calcd for C20H22BrNO2Si
(416.38): C, 57.69; H, 5.33; N, 3.36. Found: C, 57.71; H,
5.37; N, 3.53.
5.1.10. 2-Iodo-N-phenyl-N-trimethylsilanylethynyl-
benzamide 10. YieldZ86%. Pale yellow solid; mp 86–
88 8C; 1H NMR (C6D6, 400 MHz): 7.89 (d, JZ7.5 Hz, 2H),
7.59 (dd, JZ8.0, 1.0 Hz, 1H), 7.21 (m, 2H), 7.15 (dd, JZ
7.5, 1.5 Hz, 1H), 7.05 (t, JZ7.5 Hz, 1H), 6.92 (td, JZ7.5,
1.0 Hz, 1H), 6.62 (td, JZ7.8, 1.5 Hz, 1H), 0.07 (s, 9H); 13C
NMR (CDCl3, 100 MHz): 171.0 (IV), 141.5 (IV), 138.8
(III), 138.2 (IV), 130.9 (III), 129.2 (2C, III), 127.9 (III),
127.9 (III), 127.7 (III), 124.8 (III), 95.9 (IV), 92.4 (IV), 75.5
(IV), K0.2 (3C, I); IR (neat) cmK1: 3075, 3058, 3028, 2172,
1697, 1301. Anal. Calcd for C18H18INOSi (419.33): C,
51.56; H, 4.33; N, 3.34. Found: C, 51.54; H, 4.14; N, 3.27.
5.1.6. Furan-2-carboxylic acid (2-bromo-benzyl)-tri-
methylsilanylethynyl-amide 6. YieldZ63%. Pale yellow
solid; mp 113 8C; 1H NMR (CDCl3, 400 MHz): 7.66 (d, 1H,
JZ3.5 Hz), 7.64 (d, JZ1.0 Hz, 1H), 7.60 (d, JZ8.1 Hz,
1H), 7.38 (dd, JZ7.6, 1.5 Hz, 1H), 7.31 (t, JZ7.6 Hz, 1H),
7.20 (td, JZ1.5, 7.1 Hz, 1H), 6.54 (dd, JZ3.5, 1.5 Hz, 1H),
5.01 (s, 2H), 0.13 (s, 9H); 13C NMR (CDCl3, 100 MHz):
158.6 (IV), 146.1 (III), 145.3 (IV), 134.7 (IV), 132.9 (III),
132.8 (IV), 130.6 (III), 128.5 (III), 127.5 (III), 124.3 (IV),
119.1 (III), 111.5 (III), 96.8 (IV), 76.7 (IV), 52.6 (II), K0.1
(3C, I); IR (neat) cmK1: 2958, 2164, 1662, 1465, 1294, 839,
744. Elemental Anal. Calcd for C17H18BrNO2Si (376.32):
C, 54.26; H, 4.82; N, 3.72. Found: C, 54.16; H, 4.90; N,
3.64.
5.1.11. N-Furan-2-ylmethyl-2-iodo-N-trimethylsilanyl-
ethynyl-benzamide 11. YieldZ67%. 1H NMR (C6D6,
400 MHz): 7.58 (d, 1H, JZ7.6 Hz, 1H), 7.15 (d, JZ
1.0 Hz, 1H), 7.08 (dd, JZ7.6, 2.0 Hz, 1H), 6.87 (dt, JZ7.6,
1.0 Hz, 1H), 6.57 (dt, JZ7.6, 2.0 Hz, 1H), 6.42 (d, JZ
3.0 Hz, 1H), 6.13 (dd, JZ3.0, 2.0 Hz, 1H), 4.81 (s, 2H),
0.05 (s, 9H); 13C NMR (CDCl3, 100 MHz): 171.0 (IV),
148.6 (IV), 142.7 (III), 141.0 (IV), 138.8 (III), 130.8 (III),
127.8 (III), 127.7 (III), 110.5 (III), 110.2 (III), 95.7 (IV),
92.1 (IV), 76.2 (IV), 44.2 (II), K0.3 (3C, I); IR (neat) cmK1
:
2171, 1685.
5.1.7. N-(2-Iodo-benzyl)-N-trimethylsilanylethynyl-
acrylamide 7. YieldZ38%. Pale yellow solid; mp 34–
36 8C; 1H NMR (CDCl3, 400 MHz): 7.86 (dd, JZ7.8,
1.0 Hz, 1H), 7.32 (m, 2H), 7.11 (dd, JZ16.9, 10.4 Hz, 1H),
7.00 (td, JZ7.8, 1.9 Hz, 1H), 6.55 (dd, JZ16.9, 1.9 Hz,
1H), 5.89 (dd, JZ10.4, 1.9 Hz, 1H), 4.83 (s, 2H), 0.11 (s,
9H); 13C NMR (CDCl3, 100 MHz): 166.4 (IV), 139.5 (III),
137.8 (IV), 131.3 (II), 129.6 (III), 129.5 (III), 128.3 (III),
126.5 (III), 99.4 (IV), 95.5 (IV), 76.7 (IV), 55.7 (II), K0.0
(3C, I); IR (neat) cmK1: 3058, 2172, 1685, 1236. Anal.
Calcd for C15H18INOSi (383.29): C, 47.00; H, 4.73; N, 3.65.
Found: C, 47.14; H, 4.78; N, 3.58.
5.1.12. 3-(5-Oxo-1-trimethylsilanyl-5H-pyrrolo[2,1-a]-
isoindol-2-yl)-propenal 11a. YieldZ11%. 1H NMR
(C6D6, 400 MHz): 9.60 (d, JZ7.6 Hz, 1H), 7.52 (d, JZ
7.6 Hz, 1H), 7.24 (m, 1H), 7.19 (d, JZ15.7 Hz, 1H), 6.99 (s,
1H), 6.97 (t, JZ7.6 Hz, 1H), 6.73 (t, JZ7.6 Hz, 1H), 6.35
(dd, JZ7.6, 15.7 Hz, 1H), 0.32 (s, 9H).
5.1.13. N-(2-Bromo-benzyl)-4-methyl-N-trimethylsilanyl-
ethynyl-benzenesulfonamide 12. YieldZ55%. Pale
yellow solid; mp 70 8C; 1H NMR (CDCl3, 400 MHz):
7.85 (d, JZ8.6 Hz, 2H), 7.55 (dd, JZ8.1, 1.0 Hz, 1H), 7.43
(dd, JZ7.6, 1.0 Hz, 1H), 7.38 (d, JZ8.1 Hz, 2H), 7.31 (dd,
JZ8.6, 1.0 Hz, 1H), 7.18 (dt, JZ7.6, 1.0 Hz, 1H), 4.59 (s,
2H), 2.44 (s, 3H), 0.05 (s, 9H); 13C NMR (CDCl3,
100 MHz): 144.9 (IV), 134.2 (IV), 133.8 (IV), 132.8 (III),
130.5 (III), 129.7 (2C, III), 127.9 (3C, III), 127.5 (III), 123.7
(IV), 95.0 (IV), 73.8 (IV), 55.0 (II), 21.7 (I), 0.0 (3C, I); IR
(neat) cmK1: 2956, 2160, 1679, 1594, 1442, 1368, 1248.
Elemental Anal. Calcd for C19H22BrNO2SSi (436.44): C,
52.29; H, 5.08; N, 3.21. Found: C, 52.42; H, 5.26; N, 3.11.
5.1.8. N-Benzyl-2-iodo-N-trimethylsilanylethynyl-benz-
amide 8. YieldZ50%. Pale yellow solid; mp 46–48 8C;
1H NMR (C6D6, 400 MHz): 7.58 (m, 3H), 7.25 (m, 2H),
7.18 (m, 1H), 7.08 (dd, JZ7.5, 1.6 Hz, 1H), 6.88 (td, JZ
7.5, 1.0 Hz, 1H), 6.57 (td, JZ7.8, 1.6 Hz, 1H), 4.83 (s, 2H),
0.03 (s, 9H); 13C NMR (CDCl3, 100 MHz): 171.2 (IV),
141.3 (IV), 138.8 (III), 135.3 (IV), 130.7 (III), 129.2 (2C,
III), 128.4 (2C, III), 128.1 (III), 127.8 (III), 127.7 (III), 96.3
(IV), 92.2 (IV), 79.2 (IV), 51.6 (II), K0.0 (3C, I); IR
(neat) cmK1: 3066, 3023, 2170, 1686, 1297, Anal. Calcd for
C19H20INOSi (433.36): C, 52.66; H, 4.65; N, 3.23. Found:
C, 52.40; H, 4.87; N, 3.18.
5.1.14. N-(2-Bromo-benzyl)-N-trimethylsilanylethynyl-
methanesulfonamide 13. YieldZ51%. Pale yellow solid;
mp 63 8C; 1H NMR (CDCl3, 400 MHz): 7.61 (d, JZ7.6 Hz,
1H), 7.52 (d, JZ7.6 Hz, 1H), 7.37 (t, JZ7.6 Hz, 1H), 7.23
(td, JZ8.1, 1.5 Hz, 1H), 4.77 (s, 2H), 3.17 (s, 3H), 0.11 (s,
9H); 13C NMR (CDCl3, 100 MHz): 133.9 (IV), 133.0 (III),
132.2 (IV), 130.9 (III), 130.0 (III), 127.7 (III), 124.0 (IV),
5.1.9. N-Allyl-2-iodo-N-trimethylsilanylethynyl-benz-
amide 9. YieldZ47%. Pale yellow solid; mp 36–38 8C;
1H NMR (C6D6, 400 MHz): 7.59 (d, JZ7.5 Hz, 1H), 7.13
(dd, JZ7.5, 1.5 Hz, 1H), 6.91 (t, JZ7.5 Hz, 1H), 6.60 (t,

3864
F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
94.0 (IV), 74.6 (IV), 54.8 (II), 38.7 (I), 0.0 (3C, I); IR
(neat) cmK1: 2950, 2161, 1600, 1353, 1166, 952.
product as an oil: compounds 2122,23,37 or 22, respectively,
in 78 or 75% yield.
5.3. General procedure for Hsung’s method23
5.1.15.
N-(2-Bromo-benzyl)-C,C,C-trifluoro-N-tri-
methylsilanylethynyl-methanesulfonamide 14. YieldZ
27%. 1H NMR (CDCl3, 400 MHz): 7.30–7.20 (m, 2H),
6.90 (td, JZ7.5, 1.2 Hz, 1H), 6.73 (td, JZ7.8, 1.6 Hz, 1H),
4.65 (s, 2H), 0.10 (s, 9H); 13C NMR (CDCl3, 100 MHz):
133.5 (III), 132.6 (IV), 131.3 (III), 130.9 (III), 128.2 (III),
124.7 (IV), 120.0 (q, JZ322.6 Hz, IV), 90.1 (IV), 75.6 (IV),
57.0 (II), K0.0 (3C, I); IR (neat) cmK1: 2900, 2180, 1411,
1228, 1198, 1134, 841.
The bromoalkyne (1.1 mmol, 1.1 equiv) was diluted in
toluene (0.5 mL) and then the amide 17 or 18 (1 mmol,
1 equiv), potassium carbonate (2 equiv), copper sulfate
pentahydrate (10 mol%) and phenantroline (20 mol%)
were added. The reaction mixture was then sonicated
and heated at 65 8C. The reaction was monitored by thin-
layer chromatography (petroleum ether/ethylacetate
80:20). After 50 h, the reaction mixture was diluted in
chloroform (30 mL), filtered through Celite and concen-
trated under reduced pressure to give an orange oil, which
was purified on silica gel to give the product as an oil:
compounds 2122,23,37 or 22, respectively, in 96 and 80%
yield.
5.1.16. N-(2-Bromo-benzyl)-4-nitro-N-trimethylsilanyl-
1
ethynyl-benzenesulfonamide 15. YieldZ47%. H NMR
(CDCl3, 400 MHz): 7.70–7.0 (m, 4H), 7.8 (dd, JZ7.6,
1.5 Hz, 1H), 7.28 (m, 1H), 6.88 (td, JZ7.6, 1.0 Hz, 1H),
6.69 (td, JZ7.6, 1.5 Hz, 1H), 4.62 (s, 2H), 0.15 (s, 9H); 13C
NMR (CDCl3, 100 MHz): 150.7 (IV), 142.6 (IV), 133.0
(III), 130.9 (III), 130.2 (III), 129.1 (2C, IIICIV), 128.4 (III),
127.7 (III), 124.3 (2C, III), 124.1 (IV), 93.7 (IV), 75.0 (IV),
55.5 (II), K0.0 (3C, I); IR (neat) cmK1: 3103, 2956, 2897,
2166, 1529, 1345, 1000, 842.
5.3.1. N-(2-Bromobenzyl)-4-methyl-N-(phenylethynyl)-
benzenesulfonamide 22. Yellow oil; 1H NMR (CDCl3)
400 MHz 7.55 (dd, JZ8.1, 1.2 Hz, 1H), 7.49 (dd, JZ7.8,
1.5 Hz, 1H), 7.37 (d, JZ8.3 Hz, 2H), 7.31 (dt, JZ7.6,
1.0 Hz, 1H), 7.24 (br s, 5H), 7.18 (dt, JZ7.6, 1.5 Hz, 1H),
4.73 (s, 2H), 2.46 (s, 3H); 13C NMR (CDCl3) 100 MHz:
145.0 (IV), 134.5 (IV), 134.0 (IV), 133.0 (III), 131.2 (III,
2C), 130.5 (III), 130.0 (III, 2C), 129.8 (III), 128.3 (III, 2C),
128.0 (III, 2C), 127.8 (III), 127.7 (III), 123.8 (IV), 122.8
5.1.17. N-(2-Iodo-benzyl)-4-methyl-N-trimethylsilanyl-
ethynyl-benzenesulfonamide 16. YieldZ33%. Pale
yellow solid; mp 115 8C; 1H NMR (CDCl3, 400 MHz):
7.84 (m, 2H), 7.37 (m, 5H), 7.01 (m, 1H), 4.57 (s, 2H), 2.49
(s, 3H), 0.08 (s, 9H); 13C NMR (CDCl3, 100 MHz): 145.0
(IV), 139.5 (III), 136.8 (IV), 134.3 (IV), 128.9 (III), 129.8
(2C, III), 128.4 (2C, III), 128.1 (2C, III), 99.0 (IV), 95.0
(IV), 82.5 (IV), 71.3 (IV), 55.4 (II), 21.8 (I); IR (neat) cmK1
3063, 2924, 2237, 1702, 1357, 1167.
:
5.3.2. N-(2-Bromo-benzyl)-N-ethynyl-acrylamide 23.
(IV), 74.0 (IV), 59.6 (II), 21.8 (I), 0.0 (3C, I); IR (neat) cmK1
2954, 2159, 1364, 1247, 1164, 836, 745.
:
1
YieldZ95%. Clear oil; H NMR (CDCl3, 400 MHz): 7.59
(d, JZ8.6 Hz, 1H), 7.29 (m, 2H), 7.17 (m, 2H), 6.56 (dd,
JZ16.7, 1.7 Hz, 1H), 5.90 (dd, JZ10.4, 1.7 Hz, 1H), 4.91
(s, 2H), 2.97 (s, 1H); 13C NMR (CDCl3, 100 MHz): 166.6
(IV), 134.5 (IV), 132.9 (III), 131.6 (II), 129.4 (III), 127.6
(III), 126.3 (III), 123.6 (IV), 76.8 (IV), 62.4 (III), 51.3 (II);
IR (neat) cmK1: 3223, 3052, 3035, 2135, 1671, 1620. Anal.
Calcd for C12H10BrNO (264.12): C, 54.57; H, 3.82; N, 5.30.
Found: C, 54.202; H, 4.29; N, 5.32.
5.2. General procedure for Danheiser’s method22
Copper iodide was purified with THF for 24 h in a Soxhlet
extractor. Pyridine was distilled and degassed with argon.
The amide 17 or 18 (1 mmol) was introduced in a reaction
vessel, and three vacuum-argon cycles were done.
Degassed pyridine (4.5 mL) was added via syringe and
the temperature was lowered to 0 8C. KHMDS (0.5 M
solution in toluene, 2 mL, 1 mmol, 1 equiv) was added via
syringe over 4 min and the mixture was stirred during
10 min. Copper iodide (1 mmol, 1 equiv) in pyridine
(2 mL) was then added in one batch through a canula,
which was then rinsed with pyridine (1 mL). The
temperature was raised to rt and after 2 h of stirring, the
bromoalkyne (2 M solution in toluene, 1 mL, 2 equiv) was
added over 1 h. The reaction was monitored by thin-layer
chromatography (petroleum ether/ethylacetate 80:20). After
20 h, the reaction mixture was diluted in ether (30 mL) and
washed trice with a solution of saturated aq ammonium
chloride and ammonia (NH4Cl/NH4OH 2:1, 3!10 mL).
The aqueous layer was extracted trice with ether (3!
10 mL). The combined organic layers were washed with a
5% solution of copper sulfate (to remove the pyridine) and
washed with brine. An acidic wash may also be done but is
not compatible with certain substrates (tosylated amines for
example). The organic layers were dried on magnesium
sulfate and concentrated under reduced pressure to give a
brown oil, which was purified on a silica gel to give the
5.3.3. Cyclohex-1-enecarboxylic acid (2-bromo-benzyl)-
ethynyl-amide 24. YieldZ98%. Pale yellow solid; mp 38–
1
40 8C; H NMR (CDCl3, 400 MHz): 7.59 (d, JZ7.6 Hz,
1H), 7.32 (m, 2H), 7.18 (m, 1H), 6.57 (h, JZ1.5 Hz, 1H),
4.85 (s, 2H), 2.79 (s, 1H), 2.37 (m, 2H), 2.20 (m, 2H), 1.67
(m, 4H); 13C NMR (CDCl3, 100 MHz): 172.4 (IV), 135.0
(IV), 134.9 (III), 133.0 (III), 132.4 (IV), 129.6 (III), 129.3
(III), 127.5 (III), 123.7 (IV), 78.4 (IV), 60.90 (III), 52.1 (II),
25.4 (II), 25.1 (II), 22.0 (II), 21.5 (II); IR (neat) cmK1: 3231,
3061, 3032, 2136, 1659. Anal. Calcd for C16H16BrNO
(318.21): C, 60.39; H, 5.07; N, 4.40. Found: C, 60.48; H,
5.12; N, 4.29.
5.3.4. N-Ethynyl-N-(2-iodo-benzyl)-acrylamide 25.
YieldZ91%. Paste; 1H NMR (CDCl3, 400 MHz): 7.86
(dd, JZ8.1, 1.0 Hz, 1H), 7.34 (td, JZ7.7, 1.0 Hz, 1H), 7.25
(dd, JZ7.7, 1.5 Hz, 1H), 7.14 (dd, JZ16.9, 10.4 Hz, 1H),
7.00 (td, JZ7.7, 1.5 Hz, 1H), 6.57 (dd, JZ16.9, 1.8 Hz,
1H), 5.91 (dd, JZ10.4, 1.8 Hz, 1H), 4.84 (s, 2H), 2.98 (s,
1H); 13C NMR (CDCl3, 100 MHz): 166.6 (IV), 139.6 (III),
137.5 (IV), 131.7 (II), 129.5 (III), 128.7 (III), 128.5 (III),

F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
3865
126.3 (III), 98.7 (IV), 76.7 (IV), 62.7 (III), 55.8 (II); IR
(neat) cmK1: 3294, 3058, 2139, 1681, 1623. Anal. Calcd for
C12H10INO (311.12): C, 46.33; H, 3.24; N, 4.50. Found: C,
46.41; H, 3.24; N, 4.34.
Atom transfer conditions. A degassed solution of ynamide
(0.25 mmol) and hexabutylditin (0.375 mmol, 1.5 equiv) in
toluene 15 mL was refluxed and irradiated with a sun lamp
(300 W) until the monitoring of the reaction by TLC
showed total consumption of the starting material. The
precedent treatment was applied to afford cyclization
products.
5.3.5. N-Allyl-N-ethynyl-2-iodo-benzamide 26. YieldZ
83%. Pale yellow solid; mp 43–45 8C; H NMR (CDCl3,
1
400 MHz): 7.84 (d, JZ8.1 Hz, 1H), 7.40 (td, JZ7.4,
1.1 Hz, 1H), 7.32 (dd, JZ7.5, 1.1 Hz, 1H), 7.13 (td, JZ
7.5, 1.6 Hz, 1H), 6.02 (ddt, JZ6.2, 10.2, 17.0 Hz, 1H), 5.44
(dd, JZ17.0, 1.0 Hz, 1H), 5.35 (d, JZ10.2 Hz, 1H), 4.32 (d,
JZ6.2 Hz, 2H), 2.65 (s, 1H); 13C NMR (CDCl3, 100 MHz):
171 (IV), 141.0 (IV), 139.1 (III), 131.0 (III), 130.7 (III),
127.9 (III), 127.7 (III), 119.6 (II), 92.1 (IV), 76.7 (IV), 61.4
(I), 50.5 (II); IR (neat) cmK1: 3237, 3096, 3052, 3012, 2141,
1669, 1646. Anal. Calcd for C12H10INO (297.09): C, 46.33;
H, 3.24; N, 4.50. Found: C, 46.52; H, 3.57; N, 4.27.
5.3.8. 2,2,2-Trifluoro-1-(1-trimethylsilanylmethylene-
1,3-dihydro-isoindol-2-yl)-acetamide 29. YieldZ78%.
Two diastereomers Z/E: 2:1; pale yellow solid; mp 56–
58 8C; 1H NMR (C6D6, 400 MHz): 7.80 (d, JZ7.5 Hz,
1Hm), 7.56 (se, 1Hm), 7.25 (m, 1HM), 7.10 (m, 2HMC
2Hm), 6.69 (m, 1HMC1Hm), 5.92 (s, 1HM), 4.39 (s, 2Hm),
4.34 (s, 2HM), 0.54 (s, 9HM), 0.42 (s, 9Hm); 13C NMR
(C6D6, 100 MHz): major compound 155.3 (q, 1C, IV, JZ
26.29 Hz), 148.0 (IV), 136.2 (IV), 134.8 (IV), 129.1 (III),
128.1 (III), 122.3 (III), 120.5 (III), 117.9 (q, 1C, IV, JZ
287.00 Hz), 109.7 (III), 52.2 (II), 1.5 (3C, I); minor
compound 155.2 (q, 1C, IV, JZ26.2 Hz), 149.6 (IV),
136.7 (IV), 135.0 (IV), 129.1 (III), 127.6 (III), 123.2 (III),
122.5 (III), 117.7 (q, 1C, IV, JZ287.2 Hz), 109.9 (III), 51.9
(II), K0.9 (3C, I); 19F NMR (CDCl3, 376 MHz): K72.5
(m), K73.2 (M); IR (neat) cmK1: 3043, 3024, 1696, 1248,
1132.
5.3.6. N-Allyl-2-iodo-N-prop-1-ynyl-benzamide 27.
1
YieldZ62%. Clear oil; H NMR (CDCl3, 400 MHz): 7.84
(d, JZ8.1 Hz, 1H), 7.40 (td, JZ7.3, 1.0 Hz, 1H), 7.33 (dd,
JZ7.7, 1.8 Hz, 1H), 7.10 (td, JZ7.7, 1.5 Hz, 1H), 6.00 (ddt,
JZ6.0, 10.6, 16.9 Hz, 1H), 5.42 (dd, JZ16.9, 1.3 Hz, 1H),
5.32 (dd, JZ10.1, 1.0 Hz, 1H), 4.30 (d, JZ6.0 Hz, 2H),
1.68 (s, 3H); 13C NMR (CDCl3, 100 MHz): 171.0 (IV),
141.6 (IV), 138.9 (III), 131.3 (III), 130.7 (III), 127.8 (III),
127.7 (III), 119.0 (II), 92.3 (IV), 73.7 (IV), 68.2 (IV), 50.6
(II), 3.1 (I); IR (neat) cmK1: 3080, 3013, 2263, 1731, 1674.
5.3.9. 1-Trimethylsilanyl-2,6-dihydro-3H-pyrido[2,1-a]-
isoindol-4-one 30. YieldZ70%. White solid; mp 136–
1
138 8C; H NMR (C6D6, 400 MHz): 7.79 (d, JZ7.7 Hz,
1H), 7.12 (t, JZ7.3 Hz, 1H), 7.05 (t, JZ7.7 Hz, 1H), 6.87
(d, JZ7.3 Hz, 1H), 4.75 (s, 2H), 2.32 (m, 2H), 2.23 (m, 2H),
0.35 (s, 9H); 13C NMR (C6D6, 100 MHz): 168.2 (IV), 146.8
(IV), 139.1 (IV), 135.0 (IV), 128.4 (III), 126.8 (III), 123.8
(III), 123.3 (III), 105.5 (IV), 50.0 (II), 30.8 (II), 26.0 (II), 0.1
(3C, I); IR (neat) cmK1: 3078, 3051, 3034, 1672, 1241.
Anal. Calcd for C15H19NOSi: C, 69.99; H, 7.44; N, 5.44.
Found: C, 69.49; H, 7.61; N, 5.08.
5.3.7. [Allyl-(2-iodo-benzoyl)-amino]-propynoic acid
ethyl ester 28. YieldZ90%. Clear oil; H NMR (CDCl3,
1
400 MHz): 7.87 (dd, JZ8.4, 1.0 Hz, 1H), 7.44 (td, JZ7.6,
1.0 Hz, 1H), 7.33 (dd, JZ7.6, 1.5 Hz, 1H), 7.18 (td, JZ7.6,
1.8 Hz, 1H), 5.98 (ddd, JZ16.9, 10.2, 6.3 Hz, 1H), 5.46 (d,
JZ16.9 Hz, 1H), 5.38 (d, JZ10.2 Hz, 1H), 4.35 (d, JZ
5.6 Hz, 2H), 4.06 (q, JZ7.1 Hz, 2H), 1.19 (t, JZ7.1 Hz,
3H); 13C NMR (CDCl3, 100 MHz): 170.9 (IV), 153.8 (IV),
139.7 (IV), 139.3 (III), 131.6 (III), 130.0 (III), 128.0 (III),
127.8 (III), 120.4 (II), 92.0 (IV), 82.4 (IV), 68.9 (IV), 61.5
(II), 50.7 (II), 14.0 (I); IR (neat) cmK1: 3085, 2225, 1693.
5.3.10. 2,6-Dihydro-3H-pyrido[2,1-a]isoindol-4-one 31.
1
YieldZ54%. Paste; H NMR (C6D6, 400 MHz): 7.23 (d,
JZ7.3 Hz, 1H), 7.07 (m, 2H), 6.82 (d, JZ7.4 Hz, 1H), 5.14
(t, JZ4.3 Hz, 1H), 4.69 (s, 2H), 2.40 (t, JZ8.3 Hz, 2H),
2.10 (m, 2H); 13C NMR (CDCl3, 100 MHz): 168.8 (IV),
140.5 (IV), 136.7 (IV), 133.8 (IV), 129.0 (III), 127.9 (III),
123.3 (III), 120.4 (III), 94.9 (III), 50.3 (II), 30.8 (II), 21.0
(II); IR (neat) cmK1: 3071, 1727, 1644.
Standard cyclization conditions. A degassed solution of
ynamide (0.25 mmol), tributyltin hydride (0.5 mmol,
2 equiv) and AIBN (0.12 mmol, 0.5 equiv) in benzene
(15 mL) was refluxed until the monitoring of the reaction by
TLC showed total consumption of the starting material.
Once the mixture was back to rt, aq NaOH (1 M, 15 mL)
was added and stirred for 30 min. The organic phase was
extracted with ethyl acetate (2!20 mL), dried over MgSO4
and concentrated under vacuum. Purification of the residue
by silica gel flash chromotography (pentane/ethyl acetate/
triethylamine 80:20:1) afforded cyclization products. In
case of ynamides in Table 2 the eluent was pentane/ethyl
acetate/triethylamine 70:30:1.
5.3.11. 12-Trimethylsilanyl-2,3,4,4a,7,12a-hexahydro-
1H-isoindolo[2,1-b]isoquinolin-5-one 32. YieldZ75%.
White solid; mp 120–123 8C; H NMR (C6D6, 400 MHz):
1
7.83 (d, JZ7.6 Hz, 1H), 7.13 (t, JZ7.6 Hz, 1H), 7.06 (t, JZ
7.1 Hz, 1H), 6.87 (d, JZ7.6 Hz, 1H), 4.85 (AB, JAB
Z
17.0 Hz, 2H), 2.94 (m, 1H), 2.54 (m, 2H), 1.9–1.2 (m, 7H),
0.42 (s, 9H); 13C NMR (C6D6, 100 MHz): 169.9 (IV), 145.7
(IV), 139.4 (IV), 135.3 (IV), 132.4 (IV), 128.5 (III), 127.0
(III), 123.9 (III), 123.5 (III), 50.2 (II), 40.8 (III), 40.3 (III),
28.8 (II), 26.7 (II), 25.0 (II), 22.8 (II), 0.4 (3C, I); IR
(neat) cmK1: 3070, 3034, 1730, 1669, 1249; MS (C.I.), m/z
312 (MHC), 269, 182.
Slow addition conditions. A degassed solution of tin hydride
(0.5 mmol, 2 equiv) and AIBN (0.12 mmol, 0.5 equiv) in
benzene (5 mL) was added over a period of 2 h via a syringe
pump to a refluxing degassed solution of ynamide
(0.25 mmol) in benzene (10 mL). When the addition was
finished, the precedent treatment was applied to afford
cyclization product.
5.3.12. 1-Trimethylsilanyl-3,4-dihydro-2H-pyrido[2,1-a]-
isoindol-6-one 33. White solid; mp 128–130 8C; 1H
NMR (C6D6, 400 MHz): 8.09 (d, JZ7.3 Hz, 1H), 7.82

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F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
(d, JZ7.8 Hz, 1H), 7.21 (td, JZ7.3, 1.2 Hz, 1H), 7.12 (td,
JZ7.3, 0.7 Hz, 1H), 3.65 (t, JZ5.8 Hz, 2H), 2.03 (t, JZ
6.0 Hz, 2H), 1.39 (m, 2H), 0.34 (s, 9H); 13C NMR (CDCl3,
50 MHz): 166.1 (IV), 140.2 (IV), 135.0 (IV), 131.1 (III),
131.1 (IV), 128.7 (III), 123.5 (III), 123.3 (III), 119.9 (IV),
C20H21NO2Si (335.47): C, 71.60; H, 6.31; N, 4.18. Found:
C, 71.49; H, 6.41; N, 4.09.
5.3.18. 12-Trimethylsilanyl-5H-isoindolo[2,1-b]isoqui-
nolin-7-one 39. YieldZ46%. Yellow solid; mp 126–
128 8C; 1H NMR (C6D6, 400 MHz): 7.98 (d, 1H, JZ
7.1 Hz), 7.75 (d, 1H, JZ7.6 Hz), 7.34 (d, 1H, JZ7.0 Hz),
7.15 (m, 3H), 7.02 (td, 1H, JZ7.6, 1.3 Hz), 6.86 (d, 1H, JZ
7.6 Hz), 4.73 (s, 2H), 0.50 (s, 9H); 13C NMR (C6D6,
100 MHz): 165.9 (IV), 144.1 (IV), 136.9 (IV), 135.7 (IV),
131.0 (IV), 130.5 (III), 130.0 (IV), 129.3 (III), 128.4 (III),
126.8 (III), 126.8 (III), 126.6 (III), 124.5 (III), 123.4 (III),
117.2 (IV), 42.8 (II), 2.0 (3C, I); IR (neat) cmK1: 3058,
3016, 1691, 1251.
38.9 (II), 28.6 (II), 22.1 (II), 0.3 (3C, I); IR (neat) cmK1
3082, 3058, 3022, 1685, 1281.
:
5.3.13. 3,4-Dihydro-2H-pyrido[2,1-a]isoindol-6-one 34.
Paste; 1H NMR (C6D6, 400 MHz): 8.00 (dt, JZ7.6,
1.0 Hz, 1H), 7.31 (d, JZ7.6 Hz, 1H), 7.21 (td, JZ8.6,
1.3 Hz, 1H), 7.14 (td, JZ7.6, 1.0 Hz, 1H), 5.34 (t, JZ
4.6 Hz, 1H), 3.58 (m, 2H), 1.86 (m, 2H), 1.38 (m, 2H); 13C
NMR (C6D6, 100 MHz): 164.9 (IV), 135.5 (IV), 135.0 (IV),
130.8 (III), 130.6 (IV), 128.6 (III), 128.1 (III), 123.0 (III),
119.2 (III), 102.7 (III), 38 (II), 22.1 (II), 21.2 (II); IR
(neat) cmK1: 3053, 1690, 1664.
5.3.19. 2-Benzyl-3-trimethylsilanylmethylene-2,3-dihydro-
isoindol-1-one 40. YieldZ57%. Two diastereomers (1/1):
paste; 1H NMR (C6D6, 400 MHz): 8.05 (d, JZ7.3 Hz, 1H),
7.95 (d, JZ7.6 Hz, 1H), 7.81 (d, JZ7.8 Hz, 1H), 7.43 (d, JZ
7.6 Hz, 1H), 7.30–7.00 (m, 14H), 5.58 (s, 1H), 5.28 (s, 1H),
5.19 (s, 2H), 4.95 (s, 2H), 0.27 (s, 9H), 0.12 (s, 9H); 13C NMR
(CDCl3, 100 MHz): 168.4 (IV), 167.1 (IV), 146.6 (IV), 145.8
(IV), 138.1 (IV), 137.1 (IV), 136.7 (IV), 136.3 (IV), 132.1
(III), 131.7 (III), 130.5 (IV), 129.4 (III), 129.3 (III), 128.6
(4C, III), 128.4 (IV), 127.2 (III), 127.1 (2C, III), 127.0 (III),
125.8 (2C, III), 123.5 (III), 123.1 (III), 122.9 (III), 120.0 (III),
106.8 (III), 102.8 (III), 44.0 (II), 42.7 (II), 1.2 (3C, I), 0.3 (3C,
I); IR (neat) cmK1: 3087, 3063, 3031, 1705, 1606, 1249.
5.3.14. 1-Methyl-3,4-dihydro-2H-pyrido[2,1-a]isoindol-
6-one 35. YieldZ84%. White solid; mp 98–100 8C; 1H
NMR (C6D6, 400 MHz): 8.14 (d, JZ7.4 Hz, 1H), 7.53 (d,
JZ7.6 Hz, 1H), 7.25 (m, 1H), 7.16 (t, JZ7.3 Hz, 1H), 3.61
(m, 2H), 1.80 (s, 3H), 1.76 (m, 2H), 1.38 (m, 2H); 13C NMR
(C6D6, 100 MHz): 164.4 (IV), 135.4 (IV), 131.2 (IV), 130.7
(III), 129.4 (IV), 127.7 (III), 123.3 (III), 122.6 (III), 116.8
(IV), 37.7 (II), 30.3 (II), 21.2 (II), 18.5 (I); IR (neat) cmK1
3058, 3029, 1662.
:
5.3.15. 6-Oxo-2,3,4,6-tetrahydro-pyrido[2,1-a]isoindole-
1-carboxylic acid ethyl ester 36. YieldZ45%. White solid;
mp 62–65 8C; H NMR (C6D6, 400 MHz): 9.15 (d, JZ
5.3.20. 11-Trimethylsilanyl-isoindolo[2,1-a]indol-6-one
41. YieldZ62%. Yellow solid; mp 139–142 8C; H NMR
1
1
(C6D6, 400 MHz): 8.26 (d, JZ7.8 Hz, 1H), 7.65 (m, 2H),
7.47 (d, JZ7.6 Hz, 1H), 7.18 (td, JZ7.6, 1.0 Hz, 1H), 7.08
(td, JZ8.0, 1.0 Hz, 1H), 7.01 (td, JZ7.5, 1.0 Hz, 1H), 6.83 (t,
JZ7.3 Hz, 1H), 0.47 (s, 9H); 13C NMR (CDCl3, 100 MHz):
162.5 (IV), 144.3 (IV), 139.1 (IV), 135.5 (IV), 134.3 (IV),
133.9 (IV), 133.6 (III), 128.6 (III), 126.1 (III), 125.3 (III),
123.6 (III), 123.5 (III), 122.6 (III), 116.0 (IV), 113.2 (III), 0.6
(3C, I); IR (neat) cmK1: 3051, 1763, 1725, 1245.
8.2 Hz, 1H), 7.98 (dt, JZ7.6, 1.0 Hz, 1H), 7.33 (td, JZ8.1,
1.3 Hz, 1H), 7.14 (td, JZ7.3, 0.7 Hz, 1H), 4.17 (q, JZ
7.3 Hz, 2H), 3.44 (m, 2H), 2.33 (t, JZ6.0 Hz, 2H), 1.27 (m,
2H), 1.13 (t, JZ7.1 Hz, 3H); 13C NMR (C6D6, 100 MHz):
166.5 (IV), 165.5 (IV), 141.6 (IV), 134.4 (IV), 132.1 (III),
130.9 (IV), 130.1 (III), 127.3 (III), 122.7 (III), 109.6 (IV),
60.2 (II), 38.1 (II), 25.3 (II), 20.1 (II), 14.1 (I); IR
(neat) cmK1: 3073, 1693, 1603.
5.3.21. 2-Phenyl-3-trimethylsilanylmethylene-2,3-
dihydro-isoindol-1-one 42. YieldZ71%. Two diastereo-
mers Z/E: 2:1; yellow solid; mp 136–138 8C; 1H NMR
(C6D6, 400 MHz): 8.06 (d, JZ7.6 Hz, 1Hm), 7.97 (d, JZ
7.6 Hz, 1HM), 7.93 (d, JZ7.8 Hz, 1Hm), 7.43 (d, JZ
7.8 Hz, 1HM), 7.32–7.30 (m, 2HMC2Hm), 7.24–7.08 (m,
5HMC5Hm), 5.59 (s, 1HM), 5.45 (s, 1Hm), 0.29 (s, 9Hm),
K0.07 (s, 9HM); 13C NMR (C6D6, 100 MHz): major
compound 167.3 (IV), 147.7 (IV), 138.5 (IV), 136.9 (IV),
132.0 (III), 129.4 (2C, III), 129.1 (2C, III), 127.9 (2C, III),
123.3 (III), 119.9 (III), 102.8 (III), 0.1 (3C, I); IR
(neat) cmK1: 3062, 3043, 1713, 1609, 1247; minor
compound 165.8 (IV), 148.3 (IV), 136.4 (IV), 135.1 (IV),
131.6 (III), 129.5 (2C, III), 129.3 (2C, III), 129.2 (2C, III),
123.8 (III), 123.0 (III), 105.1 (III), 0.0 (3C, I); IR
(neat) cmK1: 3062, 3043, 1713, 1609, 1247. IEMS: m/z
(%)Z293 [(MC), 3], 276 [MCK17, 100], 232 [MCK63, 17].
5.3.16. 12-Trimethylsilanyl-7H-isoindolo[2,1-b]isoqui-
nolin-5-one 37. YieldZ67%. Yellow solid; mp 132–
134 8C; 1H NMR (C6D6, 400 MHz): 9.01 (dd, JZ8.1,
1.5 Hz, 1H), 7.87 (dd, JZ7.1, 3.0 Hz, 2H), 7.42 (td, JZ6.6,
1.5 Hz, 1H), 7.31 (t, JZ7.1 Hz, 1H), 7.10 (m, 2H), 6.93 (d,
JZ7.6 Hz, 1H), 4.85 (s, 2H), 0.56 (s, 9H); 13C NMR (C6D6,
100 MHz): 161.1 (IV), 149.8 (IV), 142.8 (IV), 140.3 (IV),
136.1 (IV), 131.1 (III), 129.7 (III), 128.7 (III), 128.2 (III),
127.1 (III), 126.7 (III), 126.2 (III), 123.7 (III), 107.3 (IV),
52.5 (II), 3.7 (3C, I); IR (neat) cmK1: 3053, 3035, 1644,
1603, 1249.
5.3.17. 4-Methoxy-12-trimethylsilanyl-7H-isoindolo-
[2,1-b]isoquinolin-5-one 38. YieldZ54%. Yellow solid;
mp 135–136 8C; H NMR (C6D6, 200 MHz): 8.68 (d, 1H,
1
JZ8.0 Hz), 7.99 (d, 1H, JZ8.0 Hz), 7.32–6.92 (m, 4H),
6.69 (d, 1H, JZ7.8 Hz), 4.88 (s, 2H), 3.41 (s, 3H), 0.52 (s,
9H); 13C NMR (C6D6, 50 MHz): 160.6 (IV), 155.9 (IV),
149.7 (IV), 139.8 (IV), 136.4 (IV), 134.1 (IV), 129.5 (III),
126.8 (III), 126.5 (III), 126.4 (III), 123.3 (III), 119.9 (III),
111.5 (III), 104.1 (IV), 54.1 (I), 52.3 (II), 3.1 (3C, I); IR
(neat) cmK1: 3069, 3033, 1713, 1645, 1234. Anal. Calcd for
5.4. Svnthesis of cycloisomerization precursors:
a representative example (Scheme 10)
5.4.1. N-tert-Butoxycarbonyl-N-(4-methylpent-4-enyl)-4-
methylbenzenesulfonamide 54a. Ts-NH–Boc (12.25 g,

F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
3867
Scheme 10.
45.2 mmol, 1 equiv), PPh3 (11.86 g, 45.2 mmol, 1 equiv)
and 4-methylpent-4-en-1-ol (4.52 g, 45.2 mmol, 1 equiv)
were introduced in 100 mL of THF. The mixture was cooled
to 0 8C and 8.96 mL (45.2 mmol, 1 equiv) of DIAD were
added dropwise. After stirring for 5 min, the mixture was
allowed to warm up to rt and stirred for l h. The solvent was
removed and the residue was purified by flash column
chromatography on silica gel (PE/Et2O 9:1–4:1) to give 54a
(14.43 g, 90%) as a yellow oil; 1H NMR (CDCl3,
400 MHz): 7.79 (d, JZ8.2 Hz, 2H), 7.31 (d, JZ8.2 Hz,
2H), 4.76 (br s, 2H), 3.83 (t, JZ7.6 Hz, 2H), 2.44 (s, 3H),
2.08–2.12 (m, 2H), 1.91–1.95 (m, 2H), 1.77 (s, 3H), 1.35 (s,
9H); 13C NMR (CDCl3, 100 MHz): 150.9 (IV), 144.4 (IV),
144.0 (IV), 137.5 (IV), 129.2 (2C, III), 127.7 (2C, III), 110.4
(II), 83.9 (IV), 46.9 (II), 34.7 (II), 31.8 (II), 27.8 (3C, I), 22.2
(I), 21.5 (I); IR (neat) cmK1: 2984, 1718, 1649, 1350, 1152.
Anal. Calcd for C18H27O4NS (353.28): C, 61.17; H, 7.69; N,
3.96. Found: C, 61.00; H, 7.77; N, 4.10.
34.6 (II), 25.7 (II), 22.1 (I), 21.6 (I); IR (neat) cmK1: 3072,
2935, 1697, 1650, 1596, 1355, 1161. Anal. Calcd for
C14H19O3NS (281.37): C, 59.77; H, 6.80; N, 4.98. Found: C,
59.67; H, 6.89; N, 5.15.
5.4.4. N-(2,2-Dichlorovinyl)-N-(4-methylpent-4-enyl)-4-
methylbenzenesulfonamide 54d. To a solution of 54c
(9.79 g, 34.83 mmol, 1 equiv) and PPh3 (27.41 g,
104.49 mmol, 3 equiv) in THF (350 mL) at 60 8C was
added 33.7 mL of CCl4 (348.29 mmol, 10 equiv) over 6 h.
After addition of saturated NaHCO3 aq, the aqueous layer
was extracted with Et2O. The organic layer was washed
with brine, dried over MgSO4, and concentrated. The
residue was purified by flash column chromatography on
silica gel (PE/Et2O 9:1, then PE/EA 9:1–4:1) to give 54d
1
(12.12 g, 100%) as a yellow solid; mp 85 8C; H NMR
(CDCl3, 400 MHz): 7.67 (d, JZ8.1 Hz, 2H), 7.31 (d, JZ
8.1 Hz, 2H), 6.25 (s, 1H), 4.71 (br s, 1H), 4.65 (br s, 1H),
3.29 (t, JZ7.3 Hz, 2H), 2.42 (s, 3H), 2.01 (t, JZ7.5 Hz,
2H), 1.68 (s, 3H), 1.60–1.68 (m, 2H); 13C NMR (CDCl3,
100 MHz): 144.4 (IV), 144.2 (IV), 135.4 (IV), 130.0 (2C,
III), 127.3 (2C, III), 125.0 (III), 124.8 (IV), 110.7 (II), 49.0
5.4.2. N-(4-Methylpent-4-enyl)-4-methylbenzenesulfona-
mide 54b. Consistent with literature (Larock, R. C.; Yang, H.;
Weinreb, S. M.; Herr, R. J. J. Org. Chem. 1994, 59, 4172).
(II), 34.6 (II), 26.4 (II), 22.4 (I), 21.6 (I); IR (neat) cmK1
3067, 2969, 1650, 1598, 1353, 1164.
:
In a flask containing a solution of 54a (13.94 g, 39.49 mmol,
1 equiv) in methanol (400 mL) was added K2CO3 (27.29 g,
197.45 mmol, 5 equiv). After refluxing for 3 h, water
(100 mL) was introduced and the aqueous layer was
extracted with CH2Cl2. The organic layer was washed
with brine, dried over MgSO4 and concentrated to give 54b
(9.99 g, 100%) as a yellow oil.
5.4.5. Ynamide 54. Under argon, n-BuLi (9.57 mL, 2.3 M
solution in hexane, 22 mmol, 2.2 equiv) was added to a
solution of 54d (3.48 g, 10 mmol, 1 equiv) in anhydrous
THF (50 mL) at K78 8C and the mixture was stirred during
45 min, 80 mL (2 mmol, 0.2 equiv) of MeOH were then
added and the mixture was allowed to warm up to rt over 1 h
30. After addition of saturated NaHCO3 aq, the aqueous
layer was extracted with Et2O. The organic layer was
washed with brine, dried over MgSO4, and concentrated.
The residue was purified by flash column chromatography
on silica gel (pentane/EA/NEt3 90:10:1) to give 54 (1.97 g,
71%) as a yellow solid; mp 49 8C; 1H NMR (CDCl3,
400 MHz): 7.77 (d, JZ7.8 Hz, 2H), 7.33 (d, JZ7.8 Hz,
2H), 4.70 (s, 1H), 4.64 (s, 1H), 3.27 (t, JZ6.4 Hz, 2H), 2.74
(s, 1H), 2.41 (s, 3H), 1.98–2.01 (m, 2H), 1.72–1.80 (m, 2H),
1.66 (s, 3H); 13C NMR (CDCl3, 100 MHz): 144.7 (IV),
144.0 (IV), 134.4 (IV), 129.7 (2C, III), 127.5 (2C, III), 110.6
(II), 75.9 (IV), 59.1 (III), 50.7 (II), 34.0 (II), 25.4 (II), 22.4
(I), 21.5 (I); IR (neat) cmK1: 3294, 3073, 2933, 2132, 1650,
1596, 1362, 1166. Anal. Calcd for C15H19O2NS (277.38): C,
64.95; H, 6.90; N, 5.05. Found: C, 64.82; H, 7.05; N, 5.09.
5.4.3. N-Formyl-N-(4-methylpent-4-enyl)-4-methylben-
zenesulfonamide 54c. Under argon, n-BuLi (18.8 mL,
2.3 M solution in hexane, 43.16 mmol, 1.1 equiv) was
added to a solution of 54b (9.93 g, 39.23 mmol, 1 equiv) in
THF (200 mL) at 0 8C. After stirring for 5 min, N-for-
mylbenzotriazole (6.92 g, 47.08 mmol, 1.2 equiv) was
added, and the mixture was stirred at rt for 1 h. After
addition of saturated NaHCO3 aq, the aqueous layer was
extracted with Et2O. The organic layer was washed with
brine, dried over MgSO4, and concentrated. The residue was
purified by flash column chromatography on silica gel (PE/
Et2O 9:1–4:1) to give 54c (9.85 g, 89%) as a colourless oil;
1H NMR (CDCl3, 200 MHz): 9.09 (s, 1H), 7.74 (d, JZ
8.0 Hz, 2H), 7.36 (d, JZ8.0 Hz, 2H), 4.69 (br s, 1H), 4.62
(br s, 1H), 3.40 (t, JZ7.8 Hz, 2H), 2.44 (s, 3H), 1.95 (t, JZ
8.3 Hz, 2H), 1.58–1.70 (m, 2H), 1.66 (s, 3H); 13C NMR
(CDCl3, 50 MHz): 161.2 (IV), 145.4 (IV), 144.0 (IV), 135.0
(IV), 130.3 (2C, III), 127.3 (2C, III), 110.6 (II), 42.4 (II),
Ynamides 45, 47, 49 and 57 were prepared according to this
method.

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F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
5.4.6. Ynamide 45. Consistent with literature (Ref. 28b).
YieldZ82%.
the reaction vessel was plunged in a pre-heated oil bath
(80 8C). PtCl2 (7 mg, 0.025 mmol, 0.05 equiv) was then
added, and the mixture was stirred until the IR spectrum
indicated the vanishing of the triple bond. The solvent was
removed and the residue was purified by flash chromatog-
raphy (PE/Et2O/NEt3 85:15:1) to give the desired cycliza-
tion product.
Anal. Calcd for C14H17O2NS (263.36): C, 63.85; H, 6.51; N,
5.32. Found: C, 63.73; H, 6.70; N, 5.38.
5.4.7. Ynamide 47. Consistent with literature (Ref. 28b).
YieldZ69%. White solid; mp 53 8C.
5.5.1. Dienamide 44. Consistent with literature (Ref. 28b).
YieldZ98%.
5.4.8. Ynamide 49. YieldZ56%. White solid; mp 38 8C; 1H
NMR (CDCl3, 200 MHz): 7.82 (d, JZ4.2 Hz, 2H), 7.37 (d,
JZ4.2 Hz, 2H), 5.81 (ddt, JZ17.0, 10.1, 6.4 Hz, 1H), 4.92–
5.07 (m, 2H), 3.15 (s, 2H), 2.70 (s, 1H), 2.46 (s, 3H), 1.99–
2.11 (m, 2H), 1.41–1.50 (m, 2H), 1.03 (s, 6H); 13C NMR
(CDCl3, 50 MHz): 144.7 (IV), 138.9 (III), 134.3 (IV), 129.7
(2C, III), 127.8 (2C, III), 114.2 (II), 78.7 (IV), 61.5 (II), 58.3
(III), 38.8 (II), 35.7 (IV), 28.2 (II), 25.2 (2C, I), 21.6 (I); IR
(neat) cmK1: 3276, 3081, 2968, 2133, 1643, 1598, 1355,
1168. Anal. Calcd for C17H23O2NS (305.44): C, 66.85; H,
7.59; N, 4.59. Found: C, 66.67; H, 7.78; N, 4.62.
5.5.2. Bicyclic enamide 46. YieldZ44%. Pale yellow oil;
1H NMR (C6D6, 400 MHz): 7.72 (d, JZ8.1 Hz, 2H), 6.77
(d, JZ8.1 Hz, 2H), 3.20–3.22 (m, 2H), 3.09 (quint., JZ
3.2 Hz, 2H), 2.15–2.18 (m, 2H), 1.86 (s, 3H), 1.35–1.38 (m,
2H), 1.18–1.21 (m, 2H); 13C NMR (C6D6, 100 MHz): 141.3
(IV), 136.8 (IV), 134.2 (IV), 129.8 (2C, III), 127.6 (2C, III),
122.3 (IV), 45.7 (II), 33.1 (II), 28.7 (II), 22.5 (II), 22.0 (II),
21.1 (I); IR (neat) cmK1: 3074, 2920, 1691, 1597, 1353,
1166.
5.4.9. Ynamide 57. YieldZ66%. White solid; mp 77 8C; 1H
NMR (CDCl3, 400 MHz): 7.80 (d, JZ8.2 Hz, 2H), 7.35 (d,
JZ8.2 Hz, 2H), 4.88 (br s, 1H), 4.67 (br s, 1H), 3.16 (s, 2H),
2.68 (s, 1H), 2.45 (s, 3H), 2.07 (s, 2H), 1.78 (s, 3H), 1.05 (s,
6H); 13C NMR (CDCl3, 100 MHz): 144.8 (IV), 142.5 (IV),
134.5 (IV), 129.9 (2C, III), 128.0 (2C, III), 115.3 (II), 79.0
(IV), 63.0 (II), 58.5 (III), 48.0 (II), 36.7 (IV), 25.6 (3C, I),
21.8 (I); IR (neat) cmK1: 3274, 3070, 2964, 2133, 1638,
1597, 1355, 1168. Anal. Calcd for C17H23O2NS (305.44): C,
66.85; H, 7.59; N, 4.59. Found: C, 67.00; H, 7.82; N, 4.38.
5.5.3. Bicyclic enamide 48. YieldZ71%. Pale yellow oil;
1H NMR (C6D6, 400 MHz): 7.76 (d, JZ4.2 Hz, 2H), 6.79
(d, JZ8.2 Hz, 2H), 3.11 (m, JZ2.8 Hz, 2H), 2.94 (s, 2H),
2.20 (br s, 2H), 1.84 (s, 3H), 1.31 (br s, 2H), 0.69 (s, 6H);
13C NMR (C6D6, 100 MHz): 143.1 (IV), 137.2 (IV), 132.6
(IV), 129.8 (2C, III), 127.6 (2C, III), 118.9 (IV), 55.9 (II),
36.6 (II), 32.0 (II), 31.6 (IV), 28.5 (II), 26.6 (2C, I), 21.1 (I);
IR (neat) cmK1: 2958, 2927, 1696, 1598, 1356, 1163.
5.6. General one-pot procedure (cycloisomerization–
ozonolysis)
5.4.10. Ynamide 59. To a solution of LiHMDS (343 mg,
2.13 mmol, 1.3 equiv) in THF (8 mL) at K78 8C was added
n-BuLi (0.92 mL, 2.3 M solution in hexane, 2.13 mmol,
1.3 equiv). The mixture was stirred for 10 min, then a
solution of ynamide 47 (476 mg, 1.64 mmol, 1 equiv) in
THF (8 mL) was canulated. The reaction medium was
allowed to warm up to K40 8C and was stirred for 1 h, and
then MeI (0.51 mL, 8.18 mmol, 5 equiv) was slowly added.
The mixture was stirred for 30 min at K40 8C, then allowed
to warm up to rt and stirred for 20 h. To the mixture was
added saturated NaHCO3 aq, and the aqueous layer was
extracted with Et2O. The organic layer was washed with
brine, dried over MgSO4, and concentrated. The residue was
purified by flash column chromatography on silica gel
In a dry schlenk under argon was introduced 0.5 mmol of
ynamide in 20 mL of anhydrous toluene. The reaction
medium was degassed by the freeze-pump-thaw method and
the reaction vessel was plunged in a pre-heated oil bath
(80 8C). PtCl2 (7 mg, 0.025 mmol, 0.05 equiv) was then
added, and the mixture was stirred until the IR spectrum
indicated the end of the reaction. The solvent was removed
and CH2Cl2 (20 mL) was added. The mixture was cooled
down to K78 8C and O3 was allowed to bubble in the
solution until the mixture becomes blue. One millilitre of
SMe2 was then added and the mixture was allowed to warm
up to rt over 2 h. The solvent was removed and the residue
was purified by flash chromatography (pentane/EA 9:1–1:1)
to give the desired lactam.
1
(pentane/EA 95:5) to give 59 (420 mg, 84%); H NMR
(CDCl3, 400 MHz): 7.76 (d, JZ8.2 Hz, 2H), 7.33 (d, JZ
8.2 Hz, 2H), 5.80 (ddt, JZ16.9, 10.4, 7.3 Hz, 1H), 4.99–
5.06 (m, 2H), 3.06 (s, 2H), 2.44 (s, 3H), 2.08 (d, JZ7.6 Hz,
2H), 1.84 (s, 3H), 0.98 (s, 6H); 13C NMR (CDCl3,
100 MHz): 144.3 (IV), 134.7 and 134.6 (IVCIII), 129.7
(2C, III), 127.8 (2C, III), 117.8 (II), 74.9 (IV), 64.8 (IV),
61.8 (II), 44.5 (II), 35.8 (IV), 25.2 (2C, I), 21.7 (I), 3.3 (I); IR
(neat) cmK1: 3074, 2966, 2259, 1638, 1597, 1363, 1170.
Anal. Calcd for C17H23O2NS (305.44): C, 66.85; H, 7.59; N,
4.59. Found: C, 67.21; H, 7.69; N, 4.26.
1
5.6.1. Ketolactam 50. YieldZ20%. Pale yellow oil; H
NMR (CDCl3, 400 MHz): 7.91 (d, JZ8.2 Hz, 2H), 7.35 (d,
JZ8.2 Hz, 2H), 4.00 (t, JZ5.7 Hz, 2H), 2.68–2.76 (m, 4H),
2.54 (t, JZ6.4 Hz, 2H), 2.46 (s, 3H), 2.13–2.20 (m, 2H); 13C
NMR (CDCl3, 100 MHz): 211.4 (IV), 172.3 (IV), 145.3
(IV), 135.6 (IV), 129.4 (2C, III), 129.3 (2C, III), 46.6 (II),
46.6 (II), 37.8 (II), 33.0 (II), 27.9 (II), 21.9 (I); IR
(neat) cmK1: 2924, 2854, 1694, 1597, 1340, 1157;
HRMS: m/z calcd for C14H17O4NS (MHC) 318.0776;
found 318.0792.
5.5. General procedure for cycloisomerizations
1
5.6.2. Ketolactam 51. YieldZ37%. Pale yellow oil; H
In a dry schlenk under argon was introduced 0.5 mmol of
ynamide in 20 mL of anhydrous toluene. The reaction
medium was degassed by the freeze-pump-thaw method and
NMR (CDCl3, 400 MHz): 7.84 (d, JZ8.2 Hz, 2H), 7.29 (d,
JZ8.2 Hz, 2H), 3.87 (br s, 2H), 2.65 (s, 4H), 2.44 (s, 2H),
2.42 (s, 3H), 1.19 (s, 6H); 13C NMR (CDCl3, 100 MHz):

F. Marion et al. / Tetrahedron 62 (2006) 3856–3871
3869
208.5 (IV), 172.7 (IV), 145.0 (IV), 136.1 (IV), 129.3 (2C,
III), 129.2 (2C, III), 56.5 (II), 51.0 (II), 43.7 (II), 37.5 (IV),
32.5 (II), 27.2 (2C, I), 21.8 (I); IR (neat) cmK1: 2966, 1698,
1597, 1345, 1167.
39.0 (II), 34.1 (IV), 26.1 (I), 24.9 (I), 21.6 (I), 18.9 (II); IR
(neat) cmK1: 3281, 3064, 2959, 1772, 1598, 1327, 1157.
Anal. Calcd for C16H23O3NS (309.42): C, 62.11; H, 7.48; N,
4.53. Found: C, 61.97; H, 7.58; N, 4.51.
1
5.7.4. Aminal 58. YieldZ76%. 1H NMR (CDCl3,
400 MHz): 7.81 (d, JZ8.5 Hz, 2H), 7.32 (d, JZ8.5 Hz,
2H), 3.33 (s, 1H), 3.01 (d, JZ12.9 Hz, 1H), 2.81 (m, 1H),
2.75 (d, JZ12.9 Hz, 1H), 2.45 (s, 3H), 2.35 (m, 1H), 1.72
(m, 1H), 1.52 (m, 1H), 1.35 (d, JZ14.4 Hz, 1H), 1.27 (d,
JZ14.4 Hz, 1H), 1.17 (s, 3H), 0.91 (s, 3H), 0.90 (s, 3H); 13C
NMR (CDCl3, 100 MHz): 143.4 (IV), 137.8 (IV), 129.5
(2C, III), 127.7 (2C, III), 87.3 (IV), 52.1 (II), 45.7 (II), 44.2
(IV), 33.8 (II), 31.4 (IV), 29.2 (I), 28.1 (II), 27.8 (I), 24.7 (I),
21.6 (I); IR (neat) cmK1: 3506, 3027, 2958, 1603, 1347,
1163.
5.6.3. Ketolactam 52. YieldZ24%. Pale yellow oil; H
NMR (CDCl3, 400 MHz): 7.79 (d, JZ8.2 Hz, 2H), 7.28 (d,
JZ8.2 Hz, 2H), 3.74 (s, 2H), 2.60–2.67 (m, 4H), 2.47 (t, JZ
6.7 Hz, 2H), 2.40 (s, 3H), 1.66 (t, JZ6.7 Hz, 2H), 1.11 (s,
6H); 13C NMR (CDCl3, 100 MHz): 212.6 (IV), 174.3 (IV),
144.9 (IV), 136.2 (IV), 129.4 (2C, III), 129.1 (2C, III), 54.7
(II), 39.7 (II), 36.9 (II), 36.6 (IV), 33.9 (II), 31.3 (II), 26.8
(2C, I), 21.8 (I); IR (neat) cmK1: 2957, 2871, 1688, 1596,
1348, 1164.
5.7. General one-pot procedure (cycloisomerization–
hydrolysis)
1
5.7.5. Cyclobutanone 60. YieldZ70%. H NMR (CDCl3,
In a dry schlenk under argon was introduced 0.5 mmol of
ynamide in 20 mL of anhydrous toluene. The reaction
medium was degassed during 10 min. 7 mg of PtCl2
(0.025 mmol, 0.05 equiv) were added and the reaction
vessel was plunged in a pre-heated oil bath (80 8C). At the
end of 10 min, 7 mg of PtCl2 (0.025 mmol, 0.05 equiv) were
added. The mixture was stirred until the IR spectrum
indicated the end of the reaction. Then, the mixture was
quickly cooled to rt with a water bath, and 2.5 mL
(2.5 mmol, 5 equiv) of HCl 1 M were added with 20 mL
of ethyl acetate. The resulting mixture was stirred during
2 h. The mixture was then neutralized with a saturated
solution of NaHCO3, the organic layer was washed with
brine, dried over Na2SO4 and concentrated under reduced
pressure. The residue was purified by flash chromatography
(pentane/EA 6:4) to give the desired cyclobutanone.
400 MHz): 7.74 (d, JZ8.2 Hz, 2H), 7.29 (d, JZ8.2 Hz,
2H), 5.25 (t, JZ7.1 Hz, 1H), 3.14–3.30 (m, 2H), 2.65
(ABX, 1H), 2.60 (ABX, 1H), 2.41 (s, 3H), 1.82 (t, JZ
8.1 Hz, 2H), 1.69 (dd, JZ14.5, 7.1 Hz, 1H), 1.37 (dd, JZ
14.5. 7.1 Hz. 1H), 1.18 (d, JZ7.6 Hz, 3H), 0.88 (s, 3H),
0.83 (s, 3H); 13C NMR (CDCl3, 100 MHz): 216.8 (IV),
143.3 (IV), 137.1 (IV), 129.7 (2C, III), 127.0 (2C, III), 53.5
(III), 52.7 (II), 52.2 (III), 39.8 (II), 34.2 (II), 31.2 (II), 25.8
(I), 24.9 (I), 21.6 (I), 15.3 (I); IR (neat) cmK1: 3283, 2960,
1768, 1599, 1327, 1158.
1
5.7.6. Cyclobutanone 61. YieldZ40%. H NMR (CDCl3,
400 MHz): 7.73 (d, JZ4.2 Hz, 2H), 7.30 (d, JZ8.2 Hz,
2H), 4.78 (t, JZ6.9 Hz, 1H), 3.18 (m, 1H), 3.00 (m, 1H),
2.87 (m, 1H), 2.59–2.70 (ABX, 2H), 2.42 (s, 3H), 2.15 (m,
1H), 1.56 (m, 1H), 1.51 (m, 1H), 1.35 (m, 1H), 1.23–1.27
(m, 2H); 13C NMR (CDCl3, 100 MHz): 212.5 (IV), 143.4
(IV), 137.1 (IV), 129.9 (2C, III), 127.2 (2C, III), 60.7 (III),
52.6 (II), 44.6 (II), 36.4 (II), 33.8 (IV), 25.0 (I), 23.8 (II),
21.7 (I), 16.9 (II); IR (neat) cmK1: 3284, 2958, 1773, 1598,
1326, 1158.
1
5.7.1. Cyclobutanone 53. YieldZ65%. H NMR (CDCl3,
400 MHz): 7.73 (d, JZ8.5 Hz, 2H), 7.31 (d, JZ8.5 Hz,
2H), 4.63 (t, JZ6.3 Hz, 1H), 3.22 (m, 1H), 2.83–3.08 (m,
4H), 2.42 (s, 3H), 2.16 (m, 1H), 1.47–1.66 (m, 5H); 13C
NMR (CDCl3, 100 MHz): 212.1 (IV), 143.4 (IV), 136.8
(IV), 129.7 (2C, III), 127.0 (2C, III), 59.6 (III), 44.4 (II),
42.8 (II), 27.1 (II), 26.4 (II), 21.5 (I), 16.8 (I); IR (neat) cmK1
3282, 2925, 1772, 1598, 1325, 1157.
:
Acknowledgements
Authors’ thanks go to Pierre Fabre Laboratories, which paid
´ ´
1
5.7.2. Cyclobutanone 55. YieldZ54%. H NMR (CDCl3,
400 MHz): 7.73 (d, JZ7.9 Hz, 2H), 7.29 (d, JZ7.9 Hz,
2H), 5.22 (t, JZ6.1 Hz, 1H), 2.85–3.02 (m, 4H), 2.41 (s,
3H), 1.81 (m, 1H), 1.68 (m, 1H), 1.37–1.56 (m, 4H), 1.10 (s,
3H); 13C NMR (CDCl3, 100 MHz): 215.7 (IV), 143.4 (IV),
136.9 (IV), 129.7 (2C, III), 127.1 (2C, III), 63.4 (IV), 43.3
(II), 42.2 (II), 32.8 (II), 24.7 (II), 24.0 (II), 21.5 (I), 20.4 (I);
IR (neat) cmK1: 3277, 2925, 1769, 1598, 1325, 1155. Anal.
Calcd for C15H21O3NS (295.40): C, 60.99; H, 7.17; N, 4.74.
Found: C, 61.01; H, 7.27; N, 4.55.
for the grants of Frederic Marion (CIFRE) and Aurore
Servais (BDI co-financed by CNRS) and to Institut
Universitaire de France for general support of this work.
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