Synthetic applications of the nickel-catalyzed cyclization of alkynes combined with addition reactions in a domino process

Article abstract of DOI:10.1002/chem.201100967

Carbonickelations of alkynes and functionalization of the resulting vinylnickel moiety have been performed efficiently in a nickel-catalyzed domino cyclization-condensation process. This reaction, which does not require the preparation of any other organometallic reagent, proceeds only by exo-dig cyclization. This convenient and mild method constitutes a one-pot synthesis of substituted dihydrobenzofurans, chromans, isochromans, indoles, or indanes. Theses valuable products are generally obtained in good yields and high stereoselectivity. They are shown to be useful synthons for rapid access to functionalized polycyclic skeletons. Yes nickel can! Carbonickelation of alkynes and functionalization of the resulting vinylnickel moiety occurs efficiently. Overall, a domino cyclization-condensation process propagated by substoichiometric nickel catalysis takes place (see scheme). This one-pot synthesis provides substituted polyheterocyclic compounds in good yields and high stereoselectivity.

Full text of DOI:10.1002/chem.201100967

FULL PAPER
DOI: 10.1002/chem.201100967
Synthetic Applications of the Nickel-Catalyzed Cyclization of Alkynes
Combined with Addition Reactions in a Domino Process
Muriel Durandetti,* Lucie Hardou, Rudy Lhermet, Mathieu Rouen, and
Jacques Maddaluno*[a]
Abstract: Carbonickelations of alkynes
and functionalization of the resulting
vinylnickel moiety have been per-
formed efficiently in a nickel-catalyzed
domino cyclization–condensation pro-
cess. This reaction, which does not re-
quire the preparation of any other or-
ganometallic reagent, proceeds only by
exo-dig cyclization. This convenient
and mild method constitutes a one-pot
synthesis of substituted dihydrobenzo-
furans, chromans, isochromans, indoles,
or indanes. Theses valuable products
are generally obtained in good yields
and high stereoselectivity. They are
shown to be useful synthons for rapid
access to functionalized polycyclic skel-
etons.
Keywords: alkynes · carbonickela-
tion · domino reactions · nickel ·
vinylnickel
Introduction
handle, or to less-reactive nickel–phosphine complex pre-
catalysts. For example, nucleophilic N-heterocyclic carbenes
have attracted attention as possible ligands for Ni0, recently
demonstrated by Montgomery in the reductive coupling of
aldehydes and alkynes,[11a–c] or in the cross-coupling of aryl
bromides with organomanganese reagents.[11d] Despite these
advances, cross-coupling reactions that involve nickel still
rely on the preparation of an organometallic reagent on the
one hand and the addition of nickel salts on the other.
Therefore, the development of direct procedures that allow
For several decades, nickel catalysis has been successfully
applied in a number of industrial processes, particularly in
the oligomerization of alkenes and alkynes, as well as car-
bonylation reactions.[1] However, nickel chemistry has found
sporadic use among organic chemists, relative to palladium
chemistry. Nickel-catalyzed couplings originated with the re-
action of Grignard reagents with vinyl and aryl halides, as
reported by Kumada et al.[2] and Corriu and Masse.[3] Since
these pioneer works, various organometallic reagents, such
as organomagnesium,[4] organozinc,[5] organoborane,[6] or or-
ganotin[7] compounds, have also been employed in nickel-
catalyzed couplings. The complementary role of nickel salts
in the activation of organometallic compounds is clear in
the Nozaki–Hiyama–Kishi (NHK) reaction, in which the re-
active vinylchromium reagents are obtained by transmetala-
tion of the corresponding vinylnickel precursors,[8] and also
in the carbozincation of aryl-substituted alkynes.[9]
ꢀ
C C bond formation, yet avoid a preliminary preparation of
sensitive organometallic species, remains of great interest,
especially when functionalized precursors are at stake. A
few years ago, we developed electrochemical cross-coupling
reactions based on the sacrificial anode process in the pres-
ence of catalytic amount of [NiBr2bipy] (bipy=2,2ꢀ-bipyrid-
yl), which is reduced in situ to active Ni0.[12] Although these
methods lead to good yields of heterocoupling product, elec-
trochemical syntheses lie outside the scope of standard or-
ganic protocols and are rarely used on greater than labora-
tory scale. Thus, a conventional chemical route is often pre-
ferred. Our group, and others, have developed novel chemi-
cal processes to avoid an electrochemical step or prelimina-
ry formation of organometallic reagents through a direct
activation of organic halides. The cross-coupling occurs in
the presence of a complex of Ni0 generated in situ by a
metal reducing agent. For example, an intermolecular se-
quence catalyzed solely by nickel was recently brought to
the fore by Cheng et al., who showed that arylnickels add
efficiently to triple bonds[13a–b] to afford functionalized qui-
A survey of recent literature[10] shows that nickel is be-
coming increasingly popular in the organic chemistry com-
munity. This new “nickel rush” has probably been triggered
by the development of alternatives to catalytic [NiACHTNUTRGNEUNG(cod)2]
(cod=1,5-cyclooctadiene), which is relatively difficult to
[a] Dr. M. Durandetti, Dr. L. Hardou, R. Lhermet, M. Rouen,
Dr. J. Maddaluno
Laboratoire des Fonctions Azotꢁes & Oxygꢁnꢁes Complexes
de l’IRCOF
CNRS UMR 6014 & FR 3038
Universitꢁ de Rouen et INSA de Rouen
76821 Mont St Aignan Cedex (France)
Fax : (+33)235-522-971
E-mail: muriel.durandetti@univ-rouen.fr
jmaddalu@crihan.fr
nolines and isoquinolines.[13c–e] Also,
a nickel-catalyzed
cross-coupling of aryl halides with alkyl halides has been de-
veloped that does not require the preparation of any other
organometallic compounds.[14] We have described a tandem
sequence that relies on: 1) intramolecular carbonickelation
of alkynes to give nucleophilic vinylnickel reagents; 2) inter-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201100967.
Chem. Eur. J. 2011, 17, 12773 – 12783
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
12773

molecular trapping of these nickel intermediates by various
electrophiles. This nickel-catalyzed reaction, which does not
require the preparation of any other organometallic reagent,
provides a convenient and mild method for the one-pot syn-
thesis of substituted benzofur-
of iodoaryl propargylic compounds to afford nucleophilic vi-
nylnickel reagents, which can be trapped, in a tandem pro-
cess, by various electrophiles introduced at the onset of the
reaction (Scheme 2).
ans and chromans.[15] Further-
more, the combination of these
two elementary processes af-
fords a domino sequence that
conveniently works with no
more than 10 mol% NiII. The
experimental conditions have
been adapted from recent
works,[16] which show that Ni0
Scheme 2. Heterocyclization by carbonickelation.
can be easily engendered by re-
duction of [NiBr2bipy] by Mn0,
employed as a finely ground
metallic powder. Under these conditions, no other organo-
metallic reagent has to be employed in conjunction with the
nickel catalysis. Good overall yields and selectivities were
returned in most cases. The mild conditions under which
this sequence proceeds made us confident for its extension
to other important targets, for example, indoles, benzothio-
phenes, or carbocycles, such as indanes.
Practicability and optimization of the process: Our first ex-
periments were run with bromoaryl 1a, a substrate easily
prepared by methodology directly inspired from our previ-
ous paper concerned with carbolithiation.[18a] Following a
protocol optimized for the arylnickel reagent synthesis, we
exposed 1a to a mixture of [NiBr2bipy] (1 equiv), finely
ground manganese (2 equiv), and trace amounts of trifluoro-
acetic acid in DMF at room temperature. Disappointingly,
the only new product recovered was o-bromophenol. This
suggested that the Ni0 formed in situ was probably com-
plexed by the triple bond and underwent a competitive oxi-
Results and Discussion
ꢀ
Very little is known about the “pure” carbonickelation of
triple bonds; to our knowledge, the recent papers by
Cheng[13] and ourselves[15] are the only reports in the field.
In contrast, nucleophilic organolithium entities are prone to
dative addition into the propargyl C O bond, similar to p-
allyl-complex chemistry, and described previously by Oli-
vero and Dunach.[19] To favor oxidative addition into the
aryl–halogen bond, we applied the same conditions to io-
doaryl 1b. This time, the heterocyclization–rearomatization–
[17]
ꢁ
undergo addition to C C triple bonds.
Hence, we have
described a method that provides highly functionalized het-
erocycles by intramolecular carbolithiation of an acetylenic
triple bond. This efficient and stereocontroled reaction,
which most likely proceeds through a carbolithiation–elimi-
nation sequence, transforms phenyl propargyl ethers into 3-
vinylbenzofurans, furopyridines, and indoles (Scheme 1).[18]
However, an acetal moiety on the propargylic chain was
shown to be essential for the cyclization to occur. For sub-
strates bearing a homopropargylic chain, another restriction
was that 6-exo-dig cyclizations were impossible. To evade
these limitations, we developed a new procedure based on
the carbonickelation of similar alkynes.
elimination product 2 (Scheme 3) was identified after
Scheme 3. Carbonickelation of propargylic ether 1.
Here we discuss the details and applications of Ni0-cata-
30 min and a mild acidic workup (50% yield, Z/E=50:50).
Thus, a 5-exo-dig ring closure, followed by elimination of
ethoxide comparable to that observed with aryllithiums, was
the only process observed. The acidic workup was the most
likely origin of the elimination, so we repeated the reaction
and ran the final hydrolysis under neutral conditions. The
expected 5-exo-dig cyclization product 3 was obtained quan-
AHCTUNGTRENNUNG
lyzed syn intramolecular carbonickelation of the triple bond
titatively after 30 min, as a single isomer.[20] The H NMR
1
spectra of the crude product recorded in CDCl3 and C6D6,
as well as a 2D NOESY experiment, showed that this
isomer exhibits a Z configuration, a result of syn addition of
the arylnickel intermediate to the triple bond. Therefore,
Scheme 1. Anionic heterocyclization of propargylic acetal in benzofuran.
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Chem. Eur. J. 2011, 17, 12773 – 12783

Nickel-Catalyzed Cyclization of Alkynes
FULL PAPER
lithium and nickel appear to be very complementary metals,
and provide the E- or Z-olefin, respectively.
Ni0 to aryl iodide 1c decreased rapidly and a longer reaction
time (ꢂ1 h) became necessary. Under these conditions, a
metathesis process has time to occur, which led to a large
amount of dimer 5 (Table 1, entry 2). In the presence of a
1 equiv excess of bipy, no cyclization was observed (Table 1,
entry 3) and the only product obtained was iodophenol, as
previously observed with aryl bromides. This could be due
to the decrease of the rate constant of the oxidative addition
of ArI to Ni0 in the presence of additional bipy. As a conse-
quence, when the bipy/nickel ratio is increased, the com-
plexation of the triple bond to Ni0 prevails over the forma-
tion of ArNiX, and ArOH becomes the main product. Final-
ly, with only a 0.3 mmol excess of bipy, the chemical yield is
enhanced (Table 1, entry 4), whereas the stereoselectivity is
unchanged. Note that the reaction does not proceed by
direct insertion of Mn0; the cyclization of 1c does not pro-
ceed in the absence of the [NiBr2bipy] catalyst, even after
3 days at RT (Table 1, entry 5).
The scope of this cyclization was next extended to other
aryl propargylic ethers. Because the carbolithiation required
a propargylic acetal moiety, we wondered if the carbonicke-
lation could remove this restriction. We prepared butynol-
derived ether 1c and submitted it to the carbonickelation
procedure (Scheme 4). The temperature and the amount of
ligand were varied and the results are reported in Table 1.
The investigation of the effects of the various parameters
led us to employ an experimental procedure fully described
in the Experimental section. Note that even though the best
results obtained for 1c required 1.3 equiv of bipy, we pre-
fered to run the reaction with equimolar bipy to avoid reop-
timization of this parameter for each substrate consid-
ered.[22]
Scheme 4. Carbonickelation of compound 1c.
Thus, [NiBr2bipy] (1 equiv) was added to aryl halide 1c and
manganese metal in DMF. After 30 min, no starting material
remained and we isolated the expected dihydrobenzofuran 4
as a single isomer but in moderate yield (46%, Z/E=100:0,
Table 1, entry 1). Again, a syn carbonickelation occurs after
oxidative addition of the in situ generated Ni0. This demon-
strates that the acetal moiety is not necessary to the nickel-
catalyzed process.
Synthetic applications: Because the benzofuran and indole
moieties are present in an extremely large number of natu-
ral products, in particular alkaloids, new methods to access
to these binuclear heterocycles represent a perpetual chal-
lenge in organic chemistry. Mainly, two processes are em-
ployed that rely on heteroannulation[23] or carbometala-
tion.[17] In particular, palladium-catalyzed cyclization is one
of the most powerful methods for the construction of het-
erocycles.[24] This process generally involves oxidative addi-
tion of Pd0 to afford a s-arylpalladium(II), which undergoes
rapid insertion into a double or triple bond.[18b,25] Subse-
quent tandem cross-coupling can sometimes occur.[26] Other
metals, for example magnesium[27] and lithium,[18a,28] are also
known to promote cyclization by carbometalation.
Indium,[29] chromium,[30] gold,[31] and rhodium[32] can all be
used for carbometalations of multiple bonds; the latter
allows the carbometalation of triple bonds by arylzinc deriv-
atives, which leads to indolinones in good yield. Finally, in-
tramolecular radical cyclization reactions have been proven
efficient for the generation of heterocyclic compounds, but
generally lead to lower stereocontrol of the double bond
that results from addition to an alkyne.[33] Electrochemical
reactions involving the reductive generation of NiI inter-
mediates, which induce a radical-type reactivity, constitute a
convenient alternative method.[34]
Table 1. Optimization of the carbonickelation reaction of aryl iodide 1c
catalyzed by [NiBr2bipy].[a]
Entry
Extra 2,2’-bipy
4 [%][b]
5 [%][b]
1
none added
none added
+1 mmol
60 (46)
50
40 (36)
50
0
20 (20)
0
2[c]
3
0[d]
4
5
+0.3 mmol
no [NiBr2bipy]
80 (65)
0[e]
[a] Typical procedure: aryl iodide 1c (1 mmol), manganese metal
(2 mmol), [NiBr2bipy] (1 mmol), 2,2’-bipy (see table), DMF (5 mL),
under argon. [b] GC yields, based on initial aryl iodide 1c. Isolated yields
in parentheses. [c] Reaction conducted at 08C. [d] Iodophenol was ob-
tained as the major product. [e] Compound 1c was recovered after 3 d
and 10% of reduction product ArH was obtained.
However, significant amounts of the dimeric byproduct 5
were also obtained (ꢂ40%, single isomer). The formation
of this symmetrical dimer suggests that a slow disproportio-
nation of the vinylnickel intermediate occurs, which leads to
(vinyl)2Ni and [NiBr2bipy] (Scheme 4).[12d,21]
Stabilizing the vinylnickel intermediate was expected to
avoid the formation of dimer 5. Thus, we tried to run the re-
action at lower temperature, or in the presence of an excess
of bipy ligand. At 08C, the rate of the oxidative addition of
Scope of the reaction: We began our study by varying the
substituents on the substrate. The problem of the sensitivity
of the propargylic ether skeleton to the presence of “criti-
cal” functional groups remained to be tackled. The first
series of variations we attempted is summarized in Table 2.
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12775

J. Maddaluno, M. Durandetti, et al.
Table 2. Scope of the cyclization of iodoaryls 1 by intramolecular carbon-
examples in literature, and they principally use palladium
catalysis[37] or radical cyclization.[33a–d,38]
ickelation of the triple bond.[a]
Complementarily, we probed the influence of a substitu-
ent on the propargylic position
Scheme 5).
a to X (for X=O,
Entry ArI
X
R
n
Product Yield [%] Z/E
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1h
1i
O
O
O
O
O
O
CH
Me
Ph
(OEt)2
1
1
1
1
2
3
1
1
1
1
1
1
3[b]
4
6
–
7
8
–
9
10
11
11
12
53
100:0
100:0
83:17
–
0:100
0:100
–
85:15
0:100
100:0
92:8
100:0
65[c]
54
H
0
62
Me
Me
Me
Me
Me
28
CO2
CH2O
CH2
0[d]
44
9
1j
39
10
11
12
1k
1k
1l
NBoc[e] Me
34
NBoc[e] Me
50[c]
39[f]
NH
Me
[a] A typical procedure is described in Table 1 and the Experimental sec-
tion. [b] Compound 3 is the only product in the crude mixture but is con-
taminated with 2 (29%) during purification (see text and Ref. [20]).
[c] Extra bipy (0.3 equiv) was added. [d] ArH (30%) was the only prod-
uct isolated in this case. [e] The synthesis of the starting N-Boc-iodoani-
line 55 is described in the Supporting Information. [f] 3-Ethylene indoline
rearranged quickly into 3-ethylindol 12 during workup.
Scheme 5. Synthesis and cyclization of a-substituted substrate 1m
(LDA=lithium diisopropylamide, DIAD=diisopropyl azodicarboxy-
late).
In all cases, the conversion is complete and the selectivity is
high to total syn addition.[35] The incomplete selectivities ob-
served for reaction of 1d and 1i (Table 2, entries 3 and 8)
are probably due to postcylization isomerization of the vi-
nylnickel intermediate, previously described for styrylnickel
reagents.[36] Unfortunately, our isolated yields are fair to
medium. Two factors can explain these disapointing figures:
1) the tendency of the vinylnickel intermediates to dimerize,
as noted above (Scheme 4); 2) the limited stability of these
dihydrobenzo-furanylidenes in the presence of silica gel (the
uncontrolled migration of the exocyclic double bond is prob-
ably the origin of the polymerization of part of the materi-
al). Notably, neither terminal alkyne 1e nor o-iodobenzoate
1h are substrates for this transformation (Table 2, entries 4
and 7). The failure of the latter is probably related to intra-
molecular coordination of the arylnickel moiety to the
oxygen of the ester carbonyl group. On the other hand, the
method is relatively general because it can be applied to the
synthesis of dihydrobenzofurans 3, 4, and 6 (Table 2, en-
tries 1–3), dihydrochroman 7 and isochroman 9 (Table 2, en-
tries 5 and 8), tetrahydrobenzoxepine 8 (Table 2, entry 6),
indane 10 (Table 2, entry 9), and protected indoline 11
(Table 2, entries 10 and 11). In fact, the indoline nitrogen
atom does not need to be protected; free indole 12 was re-
covered in similar yield to protected indole 11 (Table 2,
entry 12). Note that all these yields can most likely be im-
proved by fine-tuning the excess of bipy (compare Table 2,
entries 10 and 11). The 6-exo-dig and, particularly, 7-exo-dig
character of the cyclizations of 1 f and 1g (Table 2, entries 5
and 6, respectively) are worth underlining because, to our
knowledge, there are only a limited number of comparable
Thus, we prepared substrate 1m, which bears a m-me-
thoxyphenyl appendage, from the perspective of a formal
synthesis of lawsonicin, a natural product that exhibits some
antimicrobial activity.[39] Compound 1m was readily pre-
pared by reaction of anisaldehyde with the acetylide 13 (de-
rived from 3,3-diethoxypropyne), then Mitsunobu condensa-
tion between the resulting alcohol 14 and 2-iodophenol.
However, the isolated yield of the desired product 15 was
disappointingly low (26%), even though a single Z isomer
was obtained. The elimination product and the aldehyde
were found as byproducts after purification. Again, the pu-
rification process is probably responsible for this low yield;
a tandem sequence that involved the same substrate was ex-
tremely efficient (see below, Table 3, entry 11).
The dimerization of the vinylnickel intermediate remains
a problem that tends to diminish the efficiency of these
transformations (20–40% of 5-like dimers is recovered from
these reactions) independently of the poor stability of the
methylidene dihydrobenzofuran skeleton. This prompted us
to take advantage of these highly reactive intermediates by
trapping them, in a tandem process, with electrophiles intro-
duced to the medium at the onset of the reaction.
Tandem processes: The nucleophilic character of the inter-
mediate vinylnickel species was first assessed with benzalde-
hyde, a highly reactive electrophile, supposedly inert toward
Ni0. We cyclized 1c (1 equiv) in the presence of benzalde-
hyde (1 equiv) under Barbier conditions [NiII (1 equiv) and
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Chem. Eur. J. 2011, 17, 12773 – 12783

Nickel-Catalyzed Cyclization of Alkynes
FULL PAPER
Mn0 (2 equiv)] and the expected alcohol 16 was recovered in
88% isolated yield after 15 min at room temperature
(Scheme 6).
Table 3. Scope of the domino cyclization–condensation process of iodoar-
yls 1 and benzaldehyde by catalytic substoichiometric intramolecular car-
bonickelation of the triple bond.[a]
Entry ArI
X
R
n
Product Yield [%][b] Z/E
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1 f
1g
1i
1j
O
O
O
O
O
O
CH
Me
Ph
H
Me
Me
(OEt)2
1
1
1
1
2
3
1
1
1
1
1
17
16
6
48 (94)
91
10
0
59
60
43
54
100:0
0:100
73:27
–
100:0
100:0
0:100
100:0
0:100
0:100
100:0
Scheme 6. Domino process involving substrate 1c and benzaldehyde.
–
18
19
20
21
22
23
24
Despite this interesting preliminary result, we wanted to
reduce the use of significant amounts of nickel salts and de-
cided to explore the possibility of developing a substoichio-
metric catalytic version of this transformation.
The most important condition for such a catalytic cycle to
be efficient is that the nickel alkoxide that results from the
condensation has to be transmetallated by MnII, this will re-
inject NiII back into the catalytic cycle (Scheme 7). Such a
hypothesis has already been successfully tested in the
nickel-catalyzed Reformatsky reaction.[16a]
CH2O Me
CH2 Me
NBoc Me
NH
O
9
10
11
1k
1l
64
Me
CH
66[c]
92
1m[d]
ACHTUNGERTN(NUNG OEt)2
[a] For a typical procedure, see the Experimental section. [b] Isolated
yields (quantitative GC yields in parentheses, based on an internal stan-
dard). [c] Reaction carried out in MeCN/DMF (9:1) to facilitate purifica-
tion. [d] See Scheme 5 for the structure of 1m.
(Table 3, entry 11). The result of the cyclization–condensa-
tion of 1m is much more satisfying than that given by the
simple cyclization (92% 24 versus 26% 15, Table 3, entry 11
and Scheme 5). This is probably due to the fact that 24 is a
solid, therefore flash chromatographic purification can be
avoided. The same remark applies to product 16 (Table 3,
entry 2), also a solid. The detrimental effect of silica gel pu-
rification is also apparent for compound 17; a 94% yield in
the crude mixture (quantitative GC data) translates to a
48% isolated yield (Table 3, entry 1). In fact, in all cases,
the 1H NMR spectrum of the crude mixture suggests that
the conversion is almost quantitative. Note that the terminal
alkyne 1e does not cyclize, as already underlined above
(Table 2). On the other hand, this procedure is applicable to
the 5-, 6-, and 7-exo-dig cyclizations of 1c, 1 f, and 1g
(Table 3, entries 2, 5, and 6), as well as to the synthesis of
indane and indoline skeletons 22–24 (Table 3, entries 8–10).
Varying the workup conditions can lead to different prod-
ucts: acid-sensitive products 17 and 18 can be directly trans-
formed into the corresponding dienes 25 and 26 (Scheme 8),
Scheme 7. Proposed catalytic cycle involving a NiII ! MnII transmetalla-
tion.
Thus, we repeated the experiment described in Scheme 6
but with only 10 mol% [NiBr2bipy]. A comparable yield
could be obtained after 2h in DMF, provided the reaction
temperature was raised to 508C. Most substrates tested in
the first examples of stoiochiometric cyclization (Table 2)
were re-employed in the tandem process under these new
catalytic conditions. The results are displayed in Table 3.
Overall, the yields are comparable or better than those
presented in Table 2 (Table 3, entries 2, 8, and 10), probably
because of the inhibition of the vinylnickel dimerization
route. The selectivity of the addition remains in complete
accord with a syn carbonickelation of the alkyne, the Z to E
inversions noted in Table 3 correspond to the Cahn–Ingold–
Prelog rule priorities. Note, however, that the terminal
phenyl group prevents the aldehyde condensation; product
6 (cyclization stopped before condensation occurs) was re-
covered in amounts proportional to the NiII salt (Table 3,
entry 3). In contrast, the presence of an aryl group a to the
oxygen atom does not prevent the domino sequence
following
a dehydration/double-bond migration process
(plus hydrolysis of the acetal in the case of 17). These new
products are more stable, therefore the overall yields are
improved.
Another important aspect of this work was to examine
the chemical tolerance of the sequence to aryl substituents.
We prepared aryliodide 1n by a Mitsunobu condensation of
commercially available 5-iodovanillin and 2-butynol. Sub-
strate 1n was employed in the tandem protocol described
above (PhCHO (1 equiv), [NiBr2bipy] (10 mol%), DMF,
508C; Scheme 9). The expected alcohol 27 was isolated in
57% yield, which shows that the sensitive carboxaldehyde
function is perfectly compatible with the tandem intermolec-
ular process, without the necessity for any protection.
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12777

J. Maddaluno, M. Durandetti, et al.
sequence, as shown by the GC yields (Table 4, entries 1–4).
The isolated yields, after purification, are limited to 50–
60%. Activated alkyl halides and acetates are also reactive
(Table 4, entries 5–12). Note, however, that 1.3 equiv of elec-
trophile had to be employed (1.8 equiv in the case of benzyl
chloride, which is prone to a Ni0-catalyzed dimerization side
reaction). As expected, methyl chloropropionate give slight-
ly better yields than methyl chloroacetate because of the
sensitivity of these electrophiles toward Ni0.[12c] Note that
the syn-addition products are always the major isomers.
However, with milder electrophiles, such as benzyl chloride,
the reaction lasted 1 h and a mixture of E- and Z-isomers
was recovered (Table 4, entries 5 and 6), probably due to
isomerization of the vinylnickel intermediate before the re-
action occured.[36] The chroman-derived vinylnickel reagent,
which seems less reactive than the benzofuran-derived coun-
terpart, also undergoes an isomerization before cross-cou-
pling.
Scheme 8. Formation of dienes 25 and 26 upon acidic workup of the
tandem process applied to 17 and 18.
Similar results were obtained with allyl acetate (Table 4,
entries 7 and 8). In this latter case, the desired product was
obtained as a mixture of regioisomers due to reconjugation
of the double bond in varying proportions (Scheme 10). A
Scheme 9. Application of the tandem process to the synthesis of function-
alized alcohol 27.
Clearly, the next step of this study was to replace benzal-
dehyde with a series of other electrophiles (Table 4). This in-
vestigation was restricted, in most cases, to iodoaryls 1c (di-
hydrobenzofuran products) and 1 f (dihydrobenzopyran
products). Aliphatic aldehydes are good substrates for the
Scheme 10. Application of the tandem process to allyl acetate and aryl
iodide 1c.
Table 4. Scope of the electrophile in the domino cyclization–condensa-
tion of iodoaryls by catalytic substoichiometric intramolecular carbonick-
elation of the triple bond.
series of unsaturated esters were also employed with aryl
iodide 1c to assess the ability of vinylnickel reagents to pro-
mote conjugate additions (Table 4, entries 13–15). Under
standard conditions ([NiBr2bipy] (10 mol%), activated
olefin (1.3 equiv), 508C), the desired products of the tandem
cyclization–conjugate addition were contaminated with 50%
starting material and benzofuran 4. Thus, the vinylnickel in-
termediate seems relatively sluggish toward this kind of
electrophile. Conversions were increased by raising the tem-
perature (80 versus 508C) and use of 40 mol% Ni salt
(Table 4, entries 13 and 14). The substitution pattern on the
unsaturated ester also plays a role. Methyl methacrylate is
relatively less reactive than ethyl acrylate, and ethyl croto-
nate was revealed to be totally inert under our conditions
(Table 4, entry 15).
Entry ArI Electrophile
Product Yield [%][a]
Z/E
ꢀ
1
2
3
4
5
6
7
8
1c
1 f
1j
n-C8H17 CHO
28
29
30
31
32
33
34
35
36
37
38
39
40
41
–
47
56
53
58
60
64
69
71
42
23
54
44
28
26
–
(84)
(70)
(62)
(66)
(70)
(80)
(81)[b]
(86)[b]
(70)
–
(80)
(60)
(65)
(40)
–
0:100
100:0
100:0
0:100
15:85
70:30
0:100
85:15
0:100
79:21
0:100
70:30
15:85
42:58
–
ꢀ
n-C8H17 CHO
ꢀ
n-C8H17 CHO
ꢀ
1k
1c
1 f
1c
1 f
1c
1 f
1c
1 f
1c
1c
1c
n-C8H17 CHO
BnCl
BnCl
ꢀ
allyl OAc
allyl OAc
ClCH2CO2Me
ClCH2CO2Me
ꢀ
9
10
11
12
13
14
15
Tandem intramolecular processes: Next, we tried to develop
an intramolecular version of this tandem reaction by appli-
cation of our protocol to aldehyde 46. The substrate was
prepared from commercially available hex-5-yn-1-ol, by a
route reported by Hogdson and Wells.[30] The alcohol was
first protected as its tetrahydropyran (THP) derivative 42,
the lithium acetylide of which was condensed onto formal-
dehyde to afford propargyl alcohol 43. Subsequent Mitsuno-
bu condensation, then THP deprotection and oxidation of
ClCH
A
ClCHACHTUNGTRENNUNG
[c]
ꢀ
CH2=CH CO2Et
[c]
ꢀ
CH2=CHMe CO2Me
[c]
ꢀ
Me-CH=CH CO2Et
[a] Isolated yields (quantitative GC yields in parentheses, based on an in-
ternal standard). [b] A mixture of the nonconjugated and conjugated
dienic isomers was obtained (70:30– 85:15, see Scheme 10). [c] Reaction
was conducted with activated olefin (4.0 equiv) at 808C in presence of
NiII salt (40 mol%).
12778
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 12773 – 12783

Nickel-Catalyzed Cyclization of Alkynes
FULL PAPER
Under the conditions of the
carbonickelation
described
above, iodoaldehyde 52a pro-
vides a mixture of unidentified
products (trace amounts of the
cyclized product were ob-
served). The results obtained
with the meta isomer 1n
(Scheme 9) suggest that it is the
ortho position of the carboxal-
dehyde moiety that is trouble-
some in this case. The homo-
logue 53 led to the expected
cyclization–condensation tricy-
Scheme 11. Synthesis of aldehyde 46 (DHP=3,4-dihydropyran, PPTS=pyridinium p-toluenesulfonate,
DIAD=diisopropyl azodicarboxylate, PTSA=p-toluenesulfonic acid, PCC=pyridinium chlorochromate).
the intermediate alcohol 45 with PCC led to the expected al-
dehyde 46 in 52% overall yield (Scheme 11).
Aldehyde 46 was employed in the tandem cyclization pro-
cess described above with 10 mol% of NiII. The resulting bi-
cyclic alcohol 47 was obtained in 66% yield, as a single E
isomer. Note that the cyclization of this substrate in a NHK-
type sequence had been studied by the same team whose
procedure we followed for its preparation.[30] The same
product was obtained by these authors, but in only 11%
yield.
Dehydration of this alcohol under acidic conditions led to
the expected benzofuran 48, albeit in modest yield. To fur-
ther illustrate the synthetic potential of such 3-vinylbenzo-
furans as dienes,[18c] 48 was reacted in a [4+2] cycloaddition
with N-methyl maleimide under hyperbaric conditions
Scheme 12. Cycloaddition of benzofuran 48 and N-methyl maleimide
under hyperbaric conditions.
(16 kbar, 508C; Scheme 12). A single endo isomer was ob-
tained in 50% yield.
The same reaction conducted under similar conditions
(16 kbar, 508C) in the presence of ethyl acrylate as the dien-
ophile led to the tetracyclic adduct 50 in a good isolated
yield of 69%, but as a mixture of four inseparable isomers
in the ratio 56:8:31:5 (Scheme 13). Several bi-dimensional
NMR spectroscopic analyses were needed to determine the
structure of the four isomers. Overall, a good endo/exo se-
lectivity of about 9:1 was observed, but associated with a
moderate regioselectivity of 64:36. This downside is proba-
bly due to the modest polarization of the diene in 48, which
is 1,4-substituted by two antagonistic electron-donating
groups.[18c]
Scheme 13. Cycloaddition of benzofuran 48 and ethyl acrylate under hy-
perbaric conditions.
The limits of the intramolec-
ular tandem process were
reached with aldehydes 52a,
52b, and 53 (Scheme 14). Aryl
iodides 52a and 52b were pre-
pared by a Mitsunobu conden-
sation between 2-iodo-isovanil-
lin (51; obtained by iodination
of commercially available isova-
nillin) and but-2-yn-1-ol or
pent-3-yn-1-ol, respectively. Ho-
mologue 53 was obtained, in
modest yield, from aldehyde
52a through a Wittig reaction
and acidic hydrolysis.
Scheme 14. Synthesis of aldehydes 52 and 53 from isovanillin (DIAD=diisopropyl azodicarboxylate,
KHMDS=potassium bis(trimethylsilyl)amide)).
Chem. Eur. J. 2011, 17, 12773 – 12783
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12779

J. Maddaluno, M. Durandetti, et al.
corded at 75 MHz; chemical shifts (d) are given in parts per million
(ppm) and the coupling constants (J) in hertz (Hz).
clic product 54, albeit in low yield (ꢂ20% as an inseparable
mixture with the dehydrated form 54b; Scheme 14). Note
that this skeleton displays interesting similarities with indole
analogues, such as those found in the hapalindoles series, a
family of alkaloids extracted from the blue-green algae Ha-
palosiphon fontinalis.[40] The expected coordination of nickel
by the carbonyl group in the arylnickel intermediate is prob-
ably responsible for these failures. Finally, the best results
were obtained for the homopropargyl iodoaldehyde 52b, for
which the cyclization–condensation sequence seems to be ef-
fective. However, the product isolated after purification was
not the expected alcohol 54c, nor its dehydrated analogue,
but the dehydroxylated product 54d (20% isolated yield).
The origin of the surprising reduction of this benzylic posi-
tion is not known yet.
General procedure for the intramolecular carbonickelation of alkynes
(Schemes 3 and 4 and Table 2): Aryl halide 1a–l (1 mmol) was added to
DMF (5 mL) in a stirred flask under argon at RT. Finely ground Mn
(0.11 g, 2 mmol) and [NiBr2bipy] (0.374 g, 1 mmol) were introduced se-
quentially, followed by CF3CO2H (20 mL) to activate the Mn. The reac-
tion was conducted at RT, monitored by GC, and stopped after 1 was
consumed (ca. 30 min). The mixture was hydrolyzed with water (10 mL)
and diluted with diethyl ether (10 mL). The crude mixture was filtered
through Celite. The aqueous layer was extracted with diethyl ether (2ꢃ
10 mL), the combined organic layers were washed with water (to ensure
complete removal of DMF) and saturated NaCl solution, dried over an-
hydrous MgSO4, and the solvent was evaporated under vacuum . The
crude oil was purified by column chromatography (pentane/diethyl
ether) to give compounds 3–12 and 15.
Compound 11: 1H NMR (300 MHz, CDCl3): d (Z isomer)=1.60 (s, 9H),
1.77 (dt, J=7.2, 2.1 Hz, 3H), 4.52 (s, 2H), 5.94 (qt, J=7.1, 3.2 Hz, 1H),
6.93 (td, J=7.7, 1.0 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.8 Hz,
1H), 7.78 ppm (s, 1H); d (E isomer)=1.57 (s, 9H), 2.02 (dt, J=7.5,
2.4 Hz, 3H), 4.52 (s, 2H), 5.63 (qt, J=7.1, 3.2 Hz, 1H), 6.99 (td, J=7.7,
1.0 Hz, 1H), 7.16 (t, J=7.7 Hz, 1H), 7.35 (d, J=7.8 Hz, 1H), 7.55 ppm
(d, J=7.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d (Z isomer)=14.7, 28.6
(3C), 51.7, 77.4, 112.7, 115.2, 115.3, 119.4, 122.4, 128.8, 133.9, 142.9,
155.9 ppm; 2D NOESY NMR Z isomer correlation between 1.77 (dt, J=
7.2, 2.1 Hz, 3H) and 4.50 (s, 2H), between 5.94 (m, 1H) and 7.35 ppm (d,
J=7.8 Hz, 1H); m/z: 245 [M+], 189, 174, 144 (base), 130, 115, 77, 57; ele-
mental analysis calcd (%) for C15H19NO2: C 73.44, H 7.81, N 5.71; found:
C 77.35, H 7.63, N 5.35.
Conclusion
The optimized domino cyclization–condensation process of
alkynes described in this paper proceeds by using catalytic
amounts (10 mol%) of simple, shelf-stable reagents
([NiBr2bipy], Mn). Neither glovebox chemistry, nor tedious
preparation of sophisticated intermediate organometallic de-
rivatives is required. This domino process gives access to a
large set of useful fused bicycles and heterocycles, such as
dihydrobenzofurans, chromans, isochromans, tetrahydroben-
zoxepines, dihydroindoles, indolines, and indanes. The
tandem aspect of this reaction has been shown to apply to a
significant variety of activated electrophiles, and products
that bear quite diverse functionalities can be obtained in
generally good yields, albeit limited by purification issues of
these delicate vinylidenic heterocycles. When the substrate
bears an aldehyde, either on the side chain or on the aro-
matic nucleus, an intramolecular trapping of the vinylnickel
intermediate takes place, which affords the expected tricy-
clic aldol products. In one case, the dehydration of this
latter function provided a diene that could be employed in a
Diels–Alder cycloaddition with a classical dienophile, de-
spite the aromatic character of one of the double bonds.
This supplementary step gives access to functionalized tetra-
cyclic structures of interest from the perspective of natural
product synthesis.
1
Compound 15: H NMR (300 MHz, CDCl3): d=1.02–1.32 (m, 6H), 3.12–
3.74 (m, 4H), 3.77 (s, 3H), 4.79 (d, J=6.3 Hz, 1H), 6.03 (dd, J=6.3,
3 Hz, 1H), 6.22 (d, J=3 Hz, 1H), 6.83–7.08 (m, 5H), 7.21–7.27 (m, 2H),
7.43 ppm (dd, J=7.5, 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=15.5
(2C), 55.3, 60.0 (2C), 61.6, 86.2, 98.5, 110.7, 113.7, 114.5, 116.6, 120.4,
121.0, 121.1, 125.7, 129.6, 131.1, 140.1, 142.4, 160.0, 161.9 ppm; 2D
NOESY NMR correlation between 4.79 (d, J=6.3 Hz, 1H) and 6.22 (d,
J=3 Hz, 1H), between 6.03 (dd, J=6.3, 3 Hz, 1H) and 7.43 ppm (dd, J=
7.5, 0.9 Hz, 1H); m/z: 340 [M+], 294 (base), 265, 248, 237, 222, 205, 194,
178, 165; IR: n˜ =3422, 2975, 1597, 1466, 1265, 1051, 747 cmꢀ1; HRMS
(API+): m/z calcd for C19H19O3: 295.1334 [M+H+ꢀEtOH]; found:
295.1342.
General procedure for the domino cyclisation–condensation of iodoaryl
(Tables 3 and 4): Aryl iodide 1b–m (1 mmol) and electrophile (1.3–
1.8 mmol) were added to a stirred flask under argon at 508C with DMF
(5 mL). Mn (0.11 g, 2 mmol) and [NiBr2bipy] (0.0374 g, 0.1 mmol) were
introduced sequentially, followed by CF3CO2H (20 mL) to activate man-
ganese metal. The reaction was conducted at 508C, monitored by GC-
analysis, and quenched after the aryl halide was consumed (ca. 2 h). The
mixture was then hydrolyzed with water (10 mL) and diluted with ethyl
acetate (10 mL). The crude mixture was filtered through Celite. The
aqueous layer was extracted with ethyl acetate (2ꢃ10 mL), the combined
organic layers were washed with water (to ensure complete removal of
DMF) and saturated NaCl solution, dried over anhydrous MgSO4 and
the solvent was evaporated under reduced pressure. The product was iso-
lated by column chromatography (pentane/ethyl acetate) to give com-
pounds 16–24 and 27–41.
Interesting preliminary results have been obtained with
alkenes, and they suggest that an extension of comparable
chemistry in that direction could be envisaged; details will
be disclosed in due time.
Compound 19: M.p. 92–948C.1H NMR (300 MHz, [D6]DMSO, 608C): d=
1.56 (s, 3H), 1.78–2.01 (m, 2H), 2.19 (brs, 1H), 2.68 (brs, 1H), 3.95 (brs,
1H), 4.23 (brs, 1H), 5.18 (d, J=4.1 Hz, 1H), 5.42 (d, J=4.1 Hz, 1H),
6.97–7.03 (m, 2H), 7.16–7.41 ppm (m, 7H); 13C NMR (75 MHz, CDCl3):
d=11.8, 29.5, 30.6, 72.4, 73.3, 121.5 (2C), 123.3, 125.3, 126.7, 128.2 (2C),
128.5, 129.7, 133.2, 134.6, 136.9, 142.9, 157.7 ppm; NMR 2D NOESY cor-
relation between 1.56 (s, 3H) and 1.78–2.01 (m, 2H); m/z: 280 [M+], 262
[MꢀH2O], 247 [MꢀH2OꢀCH3], 147 (base); IR: n˜ =3424, 3025, 2930,
1599, 1480, 1228, 1054, 1008 cmꢀ1; HRMS (EI): m/z calcd for C19H20O2:
280.1463; found: 280.1477.
Experimental Section
General: GC analysis was carried out by using a 24 m HP-methyl silicon
capillary column. Mass spectra were recorded with a quadrupolar MS in-
strument coupled to a gas chromatograph. Elemental analyses were per-
formed by the Laboratoire de Microanalyse Organique (CNRS, IRCOF,
Rouen). Column chromatography was performed on standard silica gel
(230–400 mesh) or basic alumina. 1H NMR spectra were recorded in
CDCl3, C6D6, or [D6]DMSO at 300 MHz, and 13C NMR spectra were re-
Compound 20: 1H NMR (300 MHz, CDCl3): d=1.66 (s, 3H), 2.09 (brs,
1H), 4.56 (s, 2H), 4.62 (s, 2H), 6.09 (d, J=2.1 Hz, 1H), 7.15–7.40 ppm
12780
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ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2011, 17, 12773 – 12783

Nickel-Catalyzed Cyclization of Alkynes
FULL PAPER
(m, 9H); 13C NMR (75 MHz, CDCl3): d=13.1, 67.5, 68.6, 73.1, 125.0,
126.3 (2C), 127.1, 127.3, 127.4, 128.1, 128.6 (2C), 130.6, 132.37, 132.44,
137.7, 142.2 ppm; NMR 2D NOESY correlation between 1.66 (s, 3H)
and 4.56 (s, 2H), between 6.09 (d, J=2.1 Hz, 1H) and 7.15–7.40 ppm (m,
9H); m/z: 266 [M+], 248 [M+ꢀH2O], 233, 205, 144, 132, 105 (base), 91,
77; IR: n˜ =3417, 2914, 2852, 1449, 1105, 1021, 761, 700 cmꢀ1; HRMS (EI):
m/z calcd for C18H16O: 248.1201 [M+ꢀH2O]; found: 248.1199.
3418, 2919, 1684, 1542, 1461, 1030 cmꢀ1; HRMS (EI): m/z: calcd for
C20H28: 268.2191 [M+ꢀH2O]; found: 268.2180.
1
Compound 31: H NMR (300 MHz, CDCl3): d=0.88 (brs, 3H), 1.20–1.40
(m, 15H), 1.59 (s, 9H), 1.78 (s, 3H), 4.45 (s, 2H), 5.17 (s, 1H), 6.95 (t, J=
7.7 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.47 (d, J=7.8 Hz, 1H), 7.86–
7.87 ppm (brs, 1H); 13C NMR (75 MHz, [D6]DMSO): d=14.0, 14.6, 22.1,
25.2, 28.0 (3C), 28.7, 29.0, 29.2, 31.3, 34.8, 52.6, 68.0, 74.2, 114.5, 122.2,
124.3, 125.5, 127.9, 128.3, 129.9, 134.2, 150.9 ppm, NMR 2D NOESY cor-
relation between 1.78 (s, 3H) and 4.45 (s, 2H), between 5.17 (s, 1H) and
7.47 (d, J=7.8 Hz, 1H); elemental analysis calcd (%) for C24H37NO3: C
74.38, H 9.62, N 3.61; found: C 74.50, H 9.39, N 3.50.
Compound 21: 1H NMR (300 MHz, CDCl3): d=1.72 (s, 3H), 2.35 (d, J=
3.9 Hz, 1H), 2.74–2.89 (m, 2H), 2.98–3.03 (m, 2H), 6.37 (d, J=3.9 Hz,
1H), 7.14–7.39 (m, 6H), 7.45–7.56 (m, 2H), 7.53 ppm (d, J=7.5 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=15.4, 30.2, 31.8, 71.8, 124.5, 125.5, 126.1
(2C), 126.5, 127.1, 127.5, 128.4 (2C), 130.0, 140.2, 140.3, 142.1,
148.1 ppm; NMR 2D NOESY correlation between 1.72 (s, 3H) and 2.74–
2.89 (m, 2H), between 6.37 (d, J=3.9 Hz, 1H) and 7.53 ppm (d, J=
7.5 Hz, 1H); m/z: 250 [M+], 232 [M+ꢀH2O], 217 (base), 202, 115; IR:
Compound 37: 1H NMR (300 MHz, CDCl3): d Z isomer=1.90 (s, 3H),
2.63 (t, J=5.8 Hz, 2H), 3.44 (s, 2H), 3.77 (s, 3H), 4.28 (t, J=5.8 Hz, 2H),
6.83 (t, J=8 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 7.14 (td, J=8, 1.8 Hz,
1H), 7.30 ppm (dd, J=7.6, 1.8 Hz, 1H); d E isomer=2.11 (s, 3H), 2.59
(t, J=5.8 Hz, 2H), 3.24 (s, 2H), 3.65 (s, 3H), 4.05 (t, J=5.8 Hz, 2H), 6.83
(t, J=8.0 Hz, 1H), 6.86 (d, J=7.6 Hz, 1H), 7.14 (td, J=8.0, 1.8 Hz, 1H),
7.30 ppm (dd, J=7.6, 1.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d Z
isomer=19.6, 27.9, 41.1, 52.1, 66.9, 116.7, 119.8, 122.7, 123.4, 128.5, 128.8,
129.3, 154.8, 172.9 ppm, d E isomer=21.7, 29.8, 40.4, 52.0, 67.6, 116.6,
119.2, 122.8, 123.3, 123.5, 128.6, 128.7, 154.7, 171.9 ppm, NMR 2D
NOESY Z isomer: correlation between 1.90 (s, 3H) and 2.63 (t, J=
5.8 Hz, 2H), between 3.44 (s, 2H) and 7.30 ppm (dd, J=7.6, 1.8 Hz, 1H);
E isomer correlation between 2.11 (s, 3H) and 7.28 ppm (dd, J=7.6,
1.8 Hz, 1H); m/z: 232 [M+] (base), 173, 158, 145, 131, 91, 77, 59; IR: n˜ =
n˜ =3405, 2919, 1447, 1016, 754 cmꢀ1; HRMS (EI): m/z calcd for C18H16
232.1252 [M+ꢀH2O]; found: 232.1260.
:
Compound 22: 1H NMR (300 MHz, CDCl3): d=1.60 (s, 9H), 1.68 (t, J=
1.7 Hz, 3H), 1.99 (s, 1H), 4.53 (s, 2H), 6.38 (s, 1H), 6.93 (td, J=7.8,
0.9 Hz, 1H), 7.21 (d, J=8.1 Hz, 1H), 7.30–7.35 (m, 3H), 7.43 (d, J=
7.4 Hz, 2H), 7.57 (d, J=7.8 Hz, 1H), 7.92 ppm (s, 1H); 13C NMR
(75 MHz, CDCl3): d=15.2, 28.5 (3C), 53.0, 70.6, 81.2, 115.3, 122.4, 123.9,
125.8 (2C), 127.0, 127.3, 128.4 (2C), 128.8, 129.7, 130.5, 141.5, 145.8,
151.9 ppm, NMR 2D NOESY correlation between 1.65 (s, 3H) and 4.34–
4.50 ppm (m, 2H); m/z: 350 [M+ꢀH], 349, 233 (base), 218; IR: n˜ =3412,
3052, 2980, 1703, 1472, 1383, 1163, 725 cmꢀ1; elemental analysis calcd
(%) for C22H25NO3: C 75.19, H 7.17, N 3.99; found: C 74.91, H 7.69, N
3.90.
2976, 2872, 2242, 1731, 1448, 1382, 1113, 909, 737 cmꢀ1
.
Compound 39: 1H NMR (300 MHz, CDCl3): d Z isomer=1.30 (d, J=
6.9 Hz, 3H), 1.95 (s, 3H), 2.50–2.60 (m, 1H), 2.75–2.84 (m, 1H), 3.68 (s,
3H), 3.75 (q, J=6.9 Hz, 1H), 4.18–4.26 (m, 1H), 4.28–4.37 (m, 1H),
6.79–6.88 (m, 2H), 7.12 (td, J=7.5, 1.8 Hz, 1H), 7.28 ppm (dd, J=8.4,
1.5 Hz, 1H), d E isomer=1.29 (d, J=6.9 Hz, 3H), 1.76 (s, 3H), 2.50–2.60
(m, 1H), 2.62–2.68 (m, 1H), 3.69 (q, J=6.9 Hz, 1H), 3.71 (s, 3H), 4.18–
4.26 (m, 1H), 4.28–4.37 (m, 1H), 6.79–6.88 (m, 2H), 7.19 (td, J=7.5,
1.5 Hz, 1H), 7.37 ppm (dd, J=7.5, 1.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d Z isomer=14.9, 16.8, 27.6, 42.6, 52.0, 67.6, 116.5, 119.1, 123.6,
127.7, 128.1, 128.7, 129.5, 154.7, 174.8 ppm; dE isomer=14.8, 15.9, 27.9,
42.7, 52.1, 67.8, 116.8, 119.7, 123.5, 128.1, 128.3, 128.4, 128.8, 154.8,
175.2 ppm; NMR 2D NOESY: Z isomer correlation between 1.95 (s, 3H)
and 4.28–4.37 ppm (m, 1H); m/z: 246 [M+] (base), 215, 187, 163, 145,
120, 91; IR: n˜ =2977, 2872, 2242, 1731, 1448, 1111, 910, 741 cmꢀ1; HRMS
(EI): m/z calcd for C15H18O3: 246.1256; Z isomer found: 246.1256, E
isomer found: 246.1264.
Compound 48: 1H NMR (300 MHz, CDCl3): d=2.08 (quint, J=7.5 Hz,
2H), 2.58–2.65 (m, 2H), 2.69–2.76 (m, 2H), 6.33 (m, 1H), 7.29–7.36 (m,
2H), 7.51 (dd, J=7.8, 1.8 Hz, 1H), 7.57 (s, 1H), 7.85 ppm (dd, J=7.8,
2.4 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=22.8, 33.6, 34.4, 111.7, 118.6,
121.4, 123.0, 124.5, 126.3, 126.6, 133.8, 142.2, 155.8 ppm; m/z: 184 [M+]
(base), 169, 165, 141, 127, 115, 102, 89, 77, 63, 51; HRMS (EI): m/z: calcd
for C13H12O: 184.0888; found: 184.0888.
1
Compound 23: H NMR (300 MHz, [D6]DMSO): d=1.48 (s, 3H), 4.10 (s,
2H), 5.54 (d, J=4.2 Hz, 1H), 6.01 (s, 1H), 6.13 (d, J=4.2 Hz, 1H), 6.51
(t, J=7.5 Hz, 1H), 6.58 (d, J=7.9 Hz, 1H), 6.97 (t, J=7.6 Hz, 1H), 7.21
(t, J=7H, 1H), 7.31 (t, J=7.5 Hz, 2H), 7.35–7.39 ppm (m, 3H);
13C NMR (75 MHz, [D6]DMSO): d=14.7, 51.1, 69.3, 109.4, 116.6, 123.9,
125.5, 125.6 (2C) 126.5, 128.0 (2C), 128.5, 128.6, 133.1, 143.5, 156.1 ppm;
NMR 2D NOESY correlation between 1.47 (s, 3H) and 4.09 ppm (s,
2H); m/z: 233 [M+ꢀH2O] (base), 218, 144, 116, 90, 77; elemental analysis
calcd (%) for C17H17NO: C 81.24, H 6.82, N 5.57; found: C 80.81, H 7.23,
N 5.64.
Compound 24: Isolated as a 1:1 mixture of two inseparable diastereoiso-
1
mers ratio. H NMR (300 MHz, CDCl3): d=0.83 (brs, 1H), 1.05–1.23 (m,
13H), 3.40–3.54 (m, 8H), 3.64 (s, 3H), 3.70 (s, 3H), 3.92 (s, 1H), 3.95 (s,
1H), 4.75–4.80 (m, 2H), 5.16 (s, 1H), 5.28 (s, 1H), 6.55–6.95 (m, 10H),
7.05–7.30 (m, 15H), 7.59 ppm (dd, J=7.8, 1.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=15.05 (2C), 15.10 (2C), 46.9, 47.8, 55.15, 55.20,
60.6, 60.79, 60.84, 60.93, 77.75, 77.82, 91.3, 91.4, 113.1, 113.3, 114.1, 114.3,
115.2, 120.9, 121.2, 122.2, 126.6, 127.1, 127.8, 127.99 (2C), 128.02 (2C),
129.3, 129.5, 130.0, 138.6, 138.7, 138.8, 140.7, 140.8, 155.2, 159.4,
159.6 ppm, m/z: 202 (base), 174, 145, 115, 103, 77; IR: n˜ =3422, 2970,
1601, 1455, 1048, 700 cmꢀ1
.
Cycloadduct endo-49: Diene 48 (0.088 g, 0.48 mmol) and N-methylmalei-
mide (0.111 g, 2 equiv, 1 mmol) were added to THF (5 mL). After 24 h
under hyperbaric conditions (16 kbar) at RT, the solvent was concentrat-
ed under reduced pressure and the crude solid was purified by column
chromatography on silica gel (pentane/AcOEt, 50:50) to provide endo-49
as a white solid (0.071 g, 50%). 1H NMR (300 MHz, CDCl3): d=1.76–
1.88 (m, 2H), 2.05–2.16 (m, 1H), 2.38–2.59 (m, 4H), 2.78 (s, 3H), 3.19 (t,
J=8.1 Hz, 1H), 3.71 (t, J=8.0 Hz, 1H), 5.11–5.16 (m, 1H), 6.91 (t, J=
7.5 Hz, 1H), 7.01 (d, J=8.1 Hz, 1H), 7.18 (t, J=7.7 Hz, 1H), 7.29 ppm
(d, J=7.5 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=25.1, 27.1, 27.7, 29.9,
39.7, 41.9, 44.1, 80.9, 110.7, 121.3, 122.6, 124.1, 127.4, 129.6, 134.0, 163.4,
174.1, 177.0 ppm; NMR 2D NOESY: correlation between 2.38–2.59 (m,
4H) and 5.11–5.16 (m, 1H), between 3.19 (t, J=8.1 Hz, 1H) and 5.11–
5.16 (m, 1H), between 3.71 (t, J=8.0 Hz, 1H) and 5.11–5.16 ppm (m,
1H); m/z: 295 [M+], 210 [MꢀC2O2NMe], 197, 184 (base), 165, 152, 128,
112; HRMS (ESI+): m/z calcd for C18H18NO3: 296.1287 [M+H+]; found:
296.1297.
Compound 27: 1H NMR (300 MHz, CDCl3): d=1.62 (t, J=1.6 Hz, 3H),
2.67 (s, 1H), 3.95 (s, 3H), 5.25 (q, J=1.6 Hz, 2H), 6.34 (s, 1H), 7.27–7.38
(m, 4H), 7.43 (d, J=7.4 Hz, 2H), 7.70 (d, J=0.9 Hz, 1H), 9.73 ppm (s,
1H); 13C NMR (75 MHz, CDCl3): d=15.1, 56.2, 71.1, 76.7, 111.1, 121.1,
125.6 (2C), 126.1, 127.6, 128.6 (2C), 130.7, 130.8, 131.0, 141.2, 145.8,
158.8, 190.8 ppm; NMR 2D NOESY correlation between 1.62 (t, J=
1.6 Hz, 3H) and 5.25 (q, J=1.6 Hz, 2H), between 6.34 (s, 1H) and
7.70 ppm (d, J=0.9 Hz, 1H); m/z: 309 [M+ꢀH], 292 [M+ꢀH2O] (base),
277, 261, 249, 231, 218, 204, 189, 178, 165; elemental analysis calcd (%)
for C19H18O4: C 73.53, H 5.85; found: C 73.63, H 5.89.
1
Compound 30: H NMR (300 MHz, CDCl3): d=0.87–0.90 (m, 3H), 1.20–
1.30 (m, 14H), 1.85 (s, 3H), 2.30 (brs, 1H), 2.68–2.75 (m, 2H), 2.94 (t,
J=6.9 Hz, 2H), 5.13–5.17 (m, 1H), 7.16–7.28 (m, 3H), 7.49–7.52 ppm (m,
1H); 13C NMR (75 MHz, CDCl3): d=14.2, 14.6, 22.8, 26.1, 29.4, 29.7,
29.9, 30.2, 31.7, 32.0, 35.0, 70.7, 124.9, 125.4, 126.3, 127.1, 131.6, 138.6,
140.3, 147.9 ppm; NMR 2D NOESY correlation between 1.84 (s, 3H)
and 2.72 (m, 2H), between 5.12 (m, 1H) and 7.48 ppm (d, J=7.2 Hz,
1H); m/z: 268 [M+ꢀH2O], 183, 169 (base), 155, 141, 128, 115, 91; IR: n˜ =
Cycloadduct 50: The cycloaddition reaction was conducted under similar
conditions to those described above for endo-49 (16 kbar, RT) in pres-
Chem. Eur. J. 2011, 17, 12773 – 12783
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12781

J. Maddaluno, M. Durandetti, et al.
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Adduct endo-50a: 1H NMR (300 MHz, CDCl3): d=1.15–1.23 (m, 1H),
1.29 (t, J=7.1 Hz, 3H), 1.69–1.86 (m, 4H), 2.44 (dt, J=11.8, 4.5 Hz, 1H),
2.49–2.70 (m, 2H), 2.82–2.87 (m, 1H), 2.94 (ddd, J=12.8, 8.8, 4.2 Hz,
1H), 4.18 (q, 7.1 Hz, 2H), 5.02–5.13 (m, 1H), 6.84 (d, J=8.1 Hz, 1H),
6.90 (td, J=7.5, 1.2 Hz, 1H), 7.15 (td, J=7.8, 1.2 Hz, 1H), 7.25 ppm (d,
J=7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=14.4, 23.2, 27.4, 28.4,
28.8, 37.6, 41.6, 60.6, 83.3, 109.8, 120.7, 123.0, 126.0, 129.0, 130.7, 134.7,
162.1, 173.9 ppm, NMR 2D NOESY: correlation between 2.94 (ddd, J=
12.8, 8.8, 4.2 Hz, 1H) and 5.02–5.13 (m, 1H), between 2.82–2.87 (m, 1H)
and 2.94 ppm (ddd, J=12.8, 8.8, 4.2 Hz, 1H); m/z: 284 [M+], 211 (base),
183, 165, 141, 131, 115; HRMS (ESI+): m/z calcd for C18H21O3: 285.1491
[M+H+]; found: 285.1485.
Adduct exo-50a: 1H NMR (300 MHz, CDCl3): d=1.15–1.23 (m, 1H),
1.29 (t, J=7.1 Hz 3H), 1.69–1.86 (m, 4H), 2.44 (dt, J=11.8, 4.5 Hz, 1H),
2.49–2.70 (m, 2H), 2.82–2.87 (m, 1H), 2.94 (ddd, J=12.8, 8.8, 4.2 Hz,
1H), 4.26 (q, 7.2 Hz, 2H), 5.25–5.29 (m, 1H), 6.84 (d, J=8.1 Hz, 1H),
6.90 (td, J=7.5, 1.2 Hz, 1H), 7.15 (td, J=7.8, 1.2 Hz, 1H), 7.25 ppm (d,
J=7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=14.3, 24.8, 29.2, 29.8,
31.0, 40.0, 45.0, 61.0, 84.1, 110.1, 120.7, 122.6, 126.0, 128.7, 129.8, 136.3,
162.0, 174.9 ppm; m/z: 284 [M+], 211 (base), 183, 165, 141, 131, 115.
Adduct endo-50b: 1H NMR (300 MHz, CDCl3): d=0.96 (t, J=7.1 Hz,
3H), 1.34–1.44 (m, 1H), 1.60 (ddd, J=13.8, 7.1, 5.0 Hz, 1H), 1.69–1.86
(m, 1H), 1.89–1.96 (m, 1H), 2.09 (dt, J=13.8, 7.9 Hz, 1H), 2.04–2.14 (m,
1H), 2.28–2.37 (m, 1H), 2.49–2.70 (m, 2H), 3.39 (td, J=7.5, 4.9 Hz, 1H),
3.96 (qd, J=7.2, 4.1 Hz, 2H), 5.02–5.13 (m, 1H), 6.83 (d, J=8.1 Hz, 1H),
6.89 (td, J=7.5, 0.9 Hz, 1H), 7.11 (td, J=7.8, 1.2 Hz, 1H), 7.28 ppm (d,
J=7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=14.0, 25.7, 26.8, 29.3,
33.5, 39.7, 42.8, 60.4, 81.9, 109.8, 120.8, 122.4, 126.3, 126.6, 128.4, 137.0,
162.4, 172.5 ppm; NMR 2D NOESY: correlation between 3.39 (td, J=
7.5, 4.9 Hz, 1H) and 5.02–5.13 ppm (m, 1H); m/z: 284 [M+], 211 (base),
183, 165, 141, 131, 115; HRMS (ESI+): m/z calcd for C18H21O3: 285.1491
[M+H+]; found: 285.1485.
Adduct exo-50b: 1H NMR (300 MHz, CDCl3): d=0.89 (t, J=7.2 Hz,
3H), 1.34–1.44 (m, 1H), 1.60 (ddd, J=13.8, 7.1, 5.0 Hz, 1H), 1.69–1.86
(m, 1H), 1.89–1.96 (m, 1H), 2.09 (dt, J=13.8, 7.9 Hz, 1H), 2.04–2.14 (m,
1H), 2.28–2.37 (m, 1H), 2.49–2.70 (m, 2H), 3.39 (td, J=7.5, 4.9 Hz, 1H),
3.96 (qd, J=7.2, 4.1 Hz, 2H), 5.02–5.13 (m, 1H), 6.83 (d, J=8.1 Hz, 1H),
6.89 (td, J=7.5, 0.9 Hz, 1H), 7.11 (td, J=7.8, 1.2 Hz, 1H), 7.28 ppm (d,
J=7.8 Hz, 1H); 13C NMR (75 MHz, CDCl3): d=14.2, 25.5, 26.6, 33.1,
33.2, 41.0, 43.5, 60.8, 81.2, 110.0, 120.8, 122.6, 125.7, 125.8, 128.0, 135.0,
162.3, 176.1 ppm; m/z: 284 [M+], 211 (base), 183, 165, 141, 131, 115.
Compound 54d: M.p. 102–1038C; 1H NMR (300 MHz, CDCl3): d=2.01
(s, 3H), 2.71–2.79 (m, 2H), 3.28 (s, 2H), 3.88 (s, 3H), 4.30 (t, J=5.7 Hz,
2H), 6.62 (d, J=7.9 Hz, 1H), 6.88 ppm (d, J=7.9 Hz, 1H); 13C NMR
(75 MHz, CDCl3): d=13.7, 24.4, 42.8, 56.4, 67.7, 108.3, 115.9, 127.2, 134.0,
134.1, 134.4, 139.1, 145.7 ppm; m/z: 202 [M+] (base), 187 [M+ꢀMe], 171
[M+ꢀOMe], 115; IR: n˜ =3054, 2930, 1500, 1265 cmꢀ1; elemental analysis
calcd (%) for C13H14IO2: C 77.20, H 6.98; found: C 77.36, H 6.97.
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12782
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Chem. Eur. J. 2011, 17, 12773 – 12783

Nickel-Catalyzed Cyclization of Alkynes
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Received: March 29, 2011
Revised: July 28, 2011
Published online: September 28, 2011
Chem. Eur. J. 2011, 17, 12773 – 12783
ꢂ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
12783