The reaction of o-alkynylarene and heteroarene carboxaldehyde derivatives with iodonium ions and nucleophiles: A versatile and regioselective synthesis of 1H-isochromene, naphthalene, indole, benzofuran, and benzothiophene compounds

Article abstract of DOI:10.1002/chem.200501505

The reaction of o-alkynyl-benzaldehydes 1 with different alcohols, silylated nucleophiles 5, electronrich arenes 10, and heteroarenes 12 in the presence of the reagent IPy₂BF₄, at room temperature, gave functionalized 4-iodo-1H-isochromenes 2, 6, 11, and 13 in a regioselective manner. When alkynes 16 and alkenes 19 and 20 were used as nucleophiles, a regioselective benzannulation reaction took place to form 1-iodonaphthalenes 17 and 1-naphthyl ketones 18, respectively. Moreover, the latter process has been adapted to accomplish the synthesis of indole, benzofuran, and benzothiophene derivatives (23, 27, and 28, respectively). The three patterns of reactivity observed for the o-alkynylbenzaldehyde derivatives with IPy₂BF ₄ stem from a common iodinated isobenzopyrylium ion intermediate, A, that evolves in a different way depending on the nucleophile present in the reac-tion medium. A mechanism is proposed and the different reaction pathways observed as a function of the type of nucleophile are discussed. Furthermore, the reaction of the o-hexynyl-benzaldehyde 1b with styrene was monitored by NMR spectroscopy. Compound III, a resting state for the common intermediate in the absence of acid, has been isolated. Its evolution in acid media has been also tested, thereby providing support to the proposed mechanism.

Full text of DOI:10.1002/chem.200501505

DOI: 10.1002/chem.200501505
The Reaction of o-Alkynylarene and Heteroarene Carboxaldehyde
Derivatives with Iodonium Ions and Nucleophiles: A Versatile and
Regioselective Synthesis of 1H-Isochromene, Naphthalene, Indole,
Benzofuran, and Benzothiophene Compounds
JosØ Barluenga,* Henar Vµzquez-Villa, Isabel Merino, Alfredo Ballesteros, and
JosØ M. Gonzµlez[a]
Abstract: The reaction of o-alkynyl-
benzaldehydes 1 with different alco-
hols, silylated nucleophiles 5, electron-
rich arenes 10, and heteroarenes 12 in
the presence of the reagent IPy2BF4, at
room temperature, gave functionalized
4-iodo-1H-isochromenes 2, 6, 11, and
13 in a regioselective manner. When al-
kynes 16 and alkenes 19 and 20 were
used as nucleophiles, a regioselective
benzannulation reaction took place to
form 1-iodonaphthalenes 17 and 1-
naphthyl ketones 18, respectively.
Moreover, the latter process has been
adapted to accomplish the synthesis of
indole, benzofuran, and benzothio-
phene derivatives (23, 27, and 28, re-
spectively). The three patterns of reac-
tivity observed for the o-alkynylbenzal-
dehyde derivatives with IPy2BF4 stem
from a common iodinated isobenzo-
pyrylium ion intermediate, A, that
evolves in a different way depending
on the nucleophile present in the reac-
tion medium. A mechanism is pro-
posed and the different reaction path-
ways observed as a function of the type
of nucleophile are discussed. Further-
more, the reaction of the o-hexynyl-
benzaldehyde 1b with styrene was
monitored by NMR spectroscopy.
Compound III, a restingstate for the
common intermediate in the absence
of acid, has been isolated. Its evolution
in acid media has been also tested,
thereby providingsupport to the pro-
posed mechanism.
Keywords: cyclization · electrophil-
ic addition
iodonium ions
reactions
·
halogenation
multicomponent
·
·
Introduction
of aniline and the imine functionality, easy to elaborate
from the parent benzenecarboxaldehyde buildingblock, are
amongthe nucleophiles beingfrequently employed as re-
sponsible for the ultimately observed heterocyclization pro-
Electrophilic activation of alkynes toward intramolecular
addition reactions of heteronucleophiles has become a
useful method for the preparation of heterocyclic com-
pounds.[1] In particular, the cyclization reactions of easily ac-
cessible o-alkynyl-substituted aniline, benzenecarboxalde-
hyde, phenol, or benzenecarboxylic acid derivatives have
become a popular methodology for the synthesis of relevant
heterocycles, such as indoles,[2] isoquinolines,[3] benzofur-
ans,[4] and isocoumarins.[5] In those studies, the amino group
A
dehyde or ketone has also been, albeit less commonly, con-
sidered as a suitable nucleophile to furnish related neutral
heterocyclic compounds.[6] In this synthetic scenario, differ-
ent domino processes involving electrophile-triggered cycli-
zation of o-alkynylbenzaldehyde derivatives with concomi-
tant incorporation of an additional nucleophile have recent-
ly emerged as a powerful tool for preparing benzoheterocy-
clic cores and polycyclic hydrocarbons. Various transition-
metal catalysts have been employed for this purpose. Two
major pathways have been postulated to rationalize the dif-
ferent types of compounds obtained, as concisely outlined in
Scheme 1.
[a] Prof. Dr. J. Barluenga, Dr. H. Vµzquez-Villa, Dr. I. Merino,
Dr. A. Ballesteros, Dr. J. M. Gonzµlez
Instituto Universitario de Química Organometµlica “Enrique Moles”
Unidad Asociada al C.S.I.C., Universidad de Oviedo
C/Juliµn Clavería, 8; 33006 Oviedo (Spain)
Fax : (+34)98-510-3450
Thus, Yamamoto and his group reported an elegant cycli-
zation of that class of acetylenic aldehydes that yielded
E-mail: barluenga@uniovi.es
Supportinginformation for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
cyclic alkenyl ethers (path a, Scheme 1) by usingPd (OAc)2
A
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FULL PAPER
alternative to the powerful metal-catalyzed entry to the het-
erocyclic core that is referred to above and, furthermore,
this iodonium chemistry was found to be compatible with a
broad range of nucleophiles. Moreover, through the use of
both alkynes and alkenes as nucleophiles, it has permitted
the establishment of a regioselective synthesis of naphtha-
lenes and benzoheterocycles featuringdifferent patterns of
substitution.[18] Herein, we report a detailed study of the
synthetic profile and mechanistic insights for this iodonium-
promoted reaction between o-alkynylbenzaldehyde deriva-
tives and different types of nucleophiles that resulted in a
suitable route to access iodinated isochromenes,[16a] naphtha-
lenes,[18a] and either benzo[b]pyrrole, furan, or thiophene de-
rivatives.[18b]
Scheme 1. Transition-metal-catalyzed cyclization reactions of o-alkynyl-
benzaldehydes. L=ligand, M=metal.
as a dual-role catalyst, which acts first as a Lewis acid to ac-
tivate the carbonyl group toward the addition of the alcohol
and then as a transition-metal catalyst to promote the attack
Results and Discussion
[7]
of the resultinghemiacetal onto the alkyne.
This process
was later improved through the combination of copper(i)
The description of the results has been arranged in different
sections that offer an appropriate context for their discus-
sion and, at the same time, that allows them to be placed in
a general context. As already stated in the introduction, the
momentum that the use of metal salts, particularly from pre-
cious metals, has created in this context is of great interest.
Thus, whenever relevant, a comparison of the outcome of
the iodonium approach with the metal-driven method has
been incorporated. Also, comments on alternative iodonium
donors are included. In Scheme 2, the different sections and
their contents are graphically summarized.
iodide and N,N-dimethylformamide (DMF).[8]
Basic carbocyclic skeletons were also prepared from this
class of precursors through related domino processes that
employed alkynes as efficient partners. Therefore, substitut-
ed naphthyl ketones were prepared by AuCl3-catalyzed
formal [4+2] benzannulation between o-alkynylbenzalde-
hyde derivatives and alkynes (path b, Scheme 1).[9] The po-
tential of this methodology has been rapidly recognized and
nicely exploited in the synthesis of natural products.[10]
When alkenes were used in this formal cycloaddition pro-
ACHTREUNG
ACHTREUNG
thanesulfonyl).[11] Furthermore, electron-rich heteroaromatic
compounds[12] were also shown to be active components for
those reaction sequences, as was, remarkably, the enol form
in equilibrium with common carbonyl precursors.[13] More
recently, fully intramolecular versions of these transition-
metal-catalyzed [4+2] benzannulation reactions of alkynyl
and alkenyl enynones and enynals have been disclosed,
overall giving rise to a powerful and attractive entry for con-
[14]
structingpolycyclic hydrocarbons.
Amongall these stud-
ies, the initial formation of the ate isobenzopyrylium com-
plex[15] shown in Scheme 1 (path b) was invoked. This kind
of species was recognized as a key intermediate that leads
to the observed naphthalene derivatives upon [4+2] cyclo-
addition with the correspondingunsaturated partner and
further evolution.
Scheme 2. Outline of results discussion. FG=functional group, N-Ts=N-
toluene-4-sulfonyl, Nu=nucleophile.
It has been recently shown that iodonium ions can be suc-
cessfully used to trigger formally related cyclization reac-
tions of o-alkynylbenzenecarbaldehyde or ketone deriva-
tives to give a wide set of 4-iodo-1H-isochromenes.[16] In our
approach,[16a] while searchingfor new transformations, the
Cyclization of carbonyl groups onto alkynes promoted by
reaction with IPy2BF4 and different nucleophiles: The reac-
tion of o-alkynylbenzaldehyde derivatives 1 towards the ver-
satile iodinatingreagent IPy 2BF4.and alcohols was first ex-
amined. Isochromenes 2 were regioselectively formed upon
sequential treatment of a solution containingIPy 2BF4 and
HBF4 with compounds 1 and then with different types of al-
cohols. The results, summarized in Table 1, show this iodo-
reagent bis(pyridine) iodonium tetrafluoroborate (IPy2BF4)
A
was routinely used as an iodine donor on the basis of its
proven versatility and selectivity to act as a convenient and,
in many cases, unique source of iodonium ions for a wide
range of synthetically valuable transformations.[17] The iodo-
nium approach represents an attractive and complementary
1
cyclization reaction as beingcompatible with different R
groups in the alkyne moiety. The substitution pattern of the
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J. Barluenga et al.
Table 1. Iodocyclization of o-alkynylbenzaldehydes 1 with IPy2BF4 and
trappingwith alcohols.
Related o-(alkynyl)arylketones also entered into this
process. In this case, a different cyclization mode was ob-
served. So, the reaction of o-(alkynyl)ketones 3a,b with
IPy2BF4 and CH3OH, at low temperature, under the influ-
ence of acid, gave products 4a,b, respectively. This selective
cyclization–functionalization sequence is depicted in
Scheme 4.[19] The cyclization followed the more commonly
Entry
1
R1
R2OH
2
Yield [%][a]
1
1a
1a
1a
1a
1b
1b
1b
1c
Ph
Ph
Ph
Ph
CH3OH
CH3OH
2a
2a
2b
2c
2d
2d
2e
2 f
63
84
61
57
58
87
68
62
2[b]
3
A
4[c]
5
HC CCH2OH
CH3OH
ꢀ
nBu
nBu
nBu
1-cyclohexenyl
6[b]
7[d,e]
8
CH3OH
ACHTREUNG
[a] Yield of isolated compound 2, with respect to 1 (1 mmol scale).
[b] 5 mmol of the appropriate startingmaterial 1 were used. [c] Reaction
time after R2OH addition=4 h. [d] Reaction was carried out without ad-
dition of HBF4. [e] Reaction time after R2OH addition=6 h.
Scheme 4. Iodocyclization of o-(alkynyl)ketones 3a,b with methanol trap-
ping.
alcohol was also representatively modified. For the case
with tBuOH, the reaction must be carried out in the absence
of added HBF4 to avoid major decomposition of the alcohol.
observed 5-exo-dig cyclization mode,[20] thereby furnishinga
five-membered heterocycle, rather than the alternative six-
membered ringthat was previously formed from aldehydes
1 as the result of a competitive 6-endo cyclization path.[21]
The low yield in which product 4a was obtained could be
reasonably associated with the instability in acid media of
both the enolizable ketone 3a and the labile acetal 4a. In
this regard, the yield for that cyclization product was im-
proved to 48% by a low-temperature reaction with the
The outcome of the process without addingHBF
was
4
tested for other alcohols. The compounds depicted in
Table 1 were still formed but the process was sluggish. For
instance, the reaction of 1a and IPy2BF4 with CH3OH took
up to 7 h to afford 2a in a comparable yield to that indicat-
ed in Table 1 for the acid-assisted reaction. Although the
yields for compounds 2 were found to be dependent on the
reaction scale (Table 1, entries 1, 2, 5, and 6), essentially
quantitative conversion of 1 into 2 was observed for each
compound, as evidenced by NMR analysis of the crude reac-
tion mixtures. These crude mixtures do not provide evidence
for the occurrence of any significant side product. In each
case, 2 was formed as a single regioisomer.
system IPy2BF4/B(OMe)3, as depicted in Scheme 5.
A
The iodinated cycloalkenyl ethers 2a, 2d, and 2 f can be
accessed from 1 followingan alternative procedure that
avoids explicit addition of methanol. The reaction of 1 with
Scheme 5. Iodocyclization of 3a by employingthe system IPy 2BF4/B-
(OMe)3.
AHCTREUNG
a mixture of IPy2BF4 and B(OMe)3 led to the formation of
A
the target isochromene derivatives 2 (Scheme 3). In this
A sharp and differentiatingfeature of this iodonium-
mediated cyclization approach is the possibility of conduct-
ingthe process in a sequential manner. As a consequence of
the flexibility of the experimental protocol, not only alco-
hols but, interestingly, also a set of carbon-based nucleo-
philes 5 can be successfully employed as productive nucleo-
philic partners for this reaction sequence. In this sense, dif-
ferent types of silyl-masked C-nucleophiles have been
used,[22] thereby enablinga facile and straihgt access into
more elaborate and densely functionalized heterocycles 6
(Table 2).[23] These reactions represent the first examples of
formal Mukaiyama aldol[24] and Hosomi–Sakurai allyla-
tion[25] reactions formally triggered by a b-iodovinyl cation.
The initial interaction of the iodonium ion with the alkyne
Scheme 3. Iodocyclization of o-alkynylbenzaldehydes 1 with IPy2BF4/B-
A
process, B(OMe)3 acts both as a Lewis acid and as the
E
source for the desired nucleophile (transferringa methoxy
group) to furnish compounds 2.
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Cyclization Reactions
FULL PAPER
Table 2. Iodocyclization of 1 and trappingwith silyl-masked C-nucleo-
philes.
When 2-(trimethylsilyloxy)furan (5 f) was employed, a
single isomer 6g was obtained in a diastereo- and regioselec-
tive process (Table 2). Its structure was established by
means of NMR spectroscopy, while the relative configura-
tion of the two formed stereogenic centers was unambigu-
ously ascertained by means of an X-ray diffraction analysis
(Figure 1). This vinylogous formal Mukaiyama aldol reac-
R1
Ph
t [h]
Nu-SiMe3 5
6
Yield [%][a]
1
42
Ph
1
55
Ph
1
1
60
63
nBu
5c
Figure 1. ORTEP drawing of 6g.[27]
tion furnished syn-6g as the only reaction product, as the
result of a like approach of 2-(trimethylsilyloxy)furan (5 f)
to the iodinated isobenzopyrylium ion intermediate.[26]
Once it was proved that formal latent enolate aldol addi-
tions can be successfully accomplished by usingthis iodoni-
um technology, the possibility of using heteroarene carbox-
aldehyde derivatives as the startingmaterials was also ex-
plored. Interestingly, the cyclization–addition sequence of
such systems would offer a simple entry for the synthesis of
skeletons featuringfused heterocyclic cores. In this regard,
when 3-alkynylpyrrole-2-carboxaldehyde (7a) or the related
3-alkynylthiophene-2-carboxaldehyde (8b) were subjected
to the iodonium-mediated reaction with silylketene acetal
Ph
Ph
2
1
63
55[b]
Ph
1
5
72[c]
5c, the 1,7-dihydropyrano
A
thieno[2,3-c]pyran (9b), respectively, were accessed in a
AHCTREUNG
straightforward manner (Scheme 6).
We also explored the possibility of conductingthe kind of
transformation depicted in both Table 2 and Scheme 6 by
Ar[d]
5c
53
[a] Yield of isolated compounds 6, with respect to 1 (1 mmol scale).
1
[b] 1:1 mixture of diastereoisomers indicated by H NMR spectroscopy of
the crude reaction mixture. [c] Compound 6g was obtained as a single di-
astereoisomer. [d] Ar=4-NO2C6H4.
might give rise to those reactive species that, eventually,
would facilitate the attack of the correspondingnucleophile
onto the carbonyl group.
Scheme 6. Synthesis of fused heterocyclic compounds by iodocyclization
with nucleophilic trapping.
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J. Barluenga et al.
usingiodine as the source for the required iodonium ions,
because soon after our initial discovery this was shown by
Larock and co-workers to be efficient in promotingthe cyc-
lization of o-alkynylcarbonyl derivatives with primary alco-
hols as nucleophiles.[16] We tested the reaction of 7a with 5c
in the presence of I2 and K2CO3, with CH2Cl2 as the solvent,
at room temperature.[28] However, Mukaiyama aldol prod-
ucts were formed that arose from direct attack of the latent
enolate on the carbonyl functionality, without the participa-
tion of the alkyne component. Thus, for processes that re-
quire a sequential protocol, the nature of the iodonium
donor plays a key role in allowingthe desired transforma-
tion to take place, as is the case for the given examples. In
this context, IPy2BF4 was proven to behave as the iodonium
donor of choice in terms of broad scope.
This iodonium-promoted entry to 1H-isochromene rings
allows electron-rich arenes to be used as the ultimately in-
corporated nucleophile (Scheme 7).
Overall, arylation of the carbonyl group with nucleophiles
[16a]
lackingnet charges was achieved.
For arenes 10a,b, reac-
Scheme 7. Electron-rich arenes as nucleophiles in the iodocyclization re-
action.
tion exclusively at the para-position was noted. In keeping
with this trend, adduct 11c, which arose from an O- rather
than a C-alkylation process, was
isolated as the only product
when 4-methylphenol (10c) was
employed. For the purpose of
incorporating 10b into the
target isochromene skeleton,
iodine was shown to be an al-
ternative reagent that allowed a
more efficient process to
occur.[16b] However, no report
on the related reaction of
phenol was disclosed.
As depicted in Scheme 8, the
same type of reaction can be
accomplished by usingfive-
membered heteroarene rings
(N-methylpyrrol (12a), furan
(12b), and thiophene (12c)), as
well as N-methylindole (12d).
These heteroaromatic com-
pounds reacted selectively
Scheme 8. Reaction of o-alkynylbenzaldehyde 1a with heteroarenes.
across the C2-position in the
case of the heteroarenes 12a–c, whereas the C3-position was
involved for indole 12d, to yield the correspondingisochro-
mene derivatives 13a–d, as expected from their reactions
with an electrophile. These examples contribute to enlarge
the previously noted scope of this process and its synthetic
impact.[16]
The iodonium-induced cyclization of enynal 14 in the
presence of the silylketene acetal 5c was investigated.
Under the standard reaction conditions, the formation of
the corresponding2 H-pyran derivative 15a alongwith an
open-chain product (15b) was realized (Scheme 9). The
cyclic product 15a was formed accordingto the 6- endo-dig
cyclization mode, as previously observed for the case of the
Scheme 9. Cyclization of the 4-alkynyl-2-pentenal 14.
related benzene carboxaldehyde derivatives. The acyclic
product 15b could be the result of the evolution of 15a in
acid media, although a thermal electrocyclic ring-opening
reaction of 15a cannot be ruled out as a viable alternative
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Cyclization Reactions
FULL PAPER
at present.[29] These results proved the compatibility of this
methodology with substrates other than arene or heteroar-
ene carboxaldehyde derivatives.
As a conclusion of this initial section, the iodonium-in-
duced reaction of o-alkynylbenzaldehydes with alcohols rep-
resents a useful and complementary addition to the metal-
catalyzed approach to trigger related cyclizations. The elec-
tion of the iodonium donor has been shown to influence the
reaction outcome and, in some cases, it is crucial for accom-
plishingthe desired transformation. For the case of primary
alcohols, for reactions up to the 1 mmol scale, higher yields
optimization stage showed that 1b (R=nBu) reacts with
phenylacetylene (16a), IPy2BF4, and HBF4 (2.2 equiv, for ac-
tivating the iodinating reagent) to yield regioselectively 1-
iodo-2-phenylnaphthalene (17a) as the major reaction prod-
uct (Scheme 11). Besides 17a, the naphthyl ketone 18a was
found to be present in the crude reaction mixture as a
minor byproduct of this new transformation.[31]
were accomplished by followingthe modification with I in-
2
troduced by Larock than our method with IPy2BF4; howev-
er, virtually comparable results were obtained when the re-
action with IPy2BF4 was conducted on a 5 mmol scale. Inter-
estingly, the initially reported IPy2BF4-triggered cyclization
offers a significant advantage in terms of the scope of the
nucleophile. Thus, not only can a larger set of alcohols,
arenes, and heteroarenes be used as nucleophiles, but, re-
markably, a wide collection of silylated nucleophiles can par-
ticipate as masked C-nucleophile partners in this process,
thereby offeringsmooth access to a variety of interestingde-
rivatives of the target isochromene skeleton.
Scheme 11. Synthesis of 1-iodo-2-phenylnaphthalene (17a).
By usingthe reaction conditions described above for 17a,
the generality of the reaction was explored by modifying the
alkyne. The results are summarized in Table 3. These trans-
formations proceeded in a regioselective manner and both
aryl- and alkyl-substituted terminal alkynes 16 (Table 3, en-
tries 1–6) reacted productively with 1b to furnish 1-iodo-
naphthalenes 17 as the major reaction products in moderate
yield after isolation.[32] Internal alkynes react in a similar
way to afford 1,2,3-substituted naphthalene derivatives in a
selective manner. With the internal alkynes 16g,h (Table 3,
entries 7 and 8), the transformation is more selective toward
the formation of the 1-iodonaphthalene derivatives 17g,h
and no significant amounts of the related naphthyl ketones
were isolated after chromatographic purification of the
crude reaction mixture (see Table 3, footnote [b]).
Benzannulation reaction through iodonium-initiated [4+2]
cycloaddition of o-alkynylbenzaldehydes with both alkynes
and alkenes: A further step in the study of the reactivity of
o-alkynylbenzaldehydes 1 with iodonium ions was the use of
alkynes and alkenes as nucleophiles. The cyclization reaction
with these unsaturated substrates afforded regioselectively
substituted naphthalenes,[30] thereby giving rise to novel
benzannulation processes. Interestingly, the reaction with al-
kynes yielded 1-iodonaphthalene derivatives 17, while relat-
ed naphthyl ketone derivatives 18 were obtained when al-
kenes were used (Scheme 10). This unique and tunable
manifold has not been previously observed with alternative
reagents. These results, put together with those in the previ-
ous section, set up the basis for a rapid entry to the assem-
bly of carbo- and heterocyclic scaffolds by mixingan o-sub-
stituted benzaldehyde derivative that is accessible on a mul-
tigram basis with IPy2BF4 and a nucleophile. The latter can
be chosen from a wide diversity of commercially available,
or easy to prepare, compounds.
Reaction with alkenes for the synthesis of naphthyl ketones:
The scope of this approach to access naphthalene deriva-
tives was significantly broadened by the proof that alkenes
are good partners in the cycloaddition reactions. The reac-
tive iodonium ion allows both unsaturated functionalities to
become involved in this multicomponent process. The reac-
tion between o-alkynylbenzaldehydes 1 and olefins 19, in
the presence of IPy2BF4 and HBF4 (1.1 equiv), resulted in a
general method for the regioselective preparation of naph-
thyl ketone derivatives 18 as the sole reaction products. The
reaction with alkenes complements the one previously ob-
served with alkynes, in terms of the reaction product. The
results obtained for this new cyclization reaction with olefins
are summarized in Tables 4 and 5.
Reaction with alkynes for the synthesis of 1-iodonaphtha-
lenes: As reported previously,[18a] our initial studies ad-
dressed the effect that the amount of added HBF4, as well
as that of the R1 group attached to the triple bond in 1, has
over the reaction outcome and the product distribution. An
This novel approach to the benzannulation reaction was
found to be independent of the
aliphatic or aromatic nature of
the R1 group in 1, as both types
of substituents gave satisfactory
results (Table 4, entries 1 and
2). Additionally, the reaction
took place with a high degree
Scheme 10. Iodonium-triggered reactions of o-alkynylbenzene carboxaldehyde with alkynes and alkenes.
of selectivity, with all of the as-
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5795

J. Barluenga et al.
Table 3. Iodonium-promoted reaction of o-alkynylbenzaldehyde 1b with
alkynes 16.
Table 4. The iodonium-promoted reaction of o-alkynylbenzaldehydes 1
with alkenes 19.
Entry
16
R1
R2
t [h]
17
Yield [%][a,b]
Entry
1
R1
R
19
R2
R3
t [h] 18
Yield [%][a]
18a 70
18b 78
1
2
3
4
5
6
7
8
16a
16b
16c
16d
16e
16 f
16g
16h
Ph
nPr
H
H
H
H
H
H
Me
CO2Et
1
1
1
3
0.5
2
0.5
3
17a
17b
17c
17d
17e
17 f
17g
17h
68
60
61
35
42
26
65
44
1
2
3
4
5
6
7
1b nBu
1a Ph
1a Ph
1a Ph
1a Ph
1a Ph
H
H
H
H
H
H
19a Ph
19a Ph
19b n-Bu
19c Ph
19d Ph
19e Et
H
H
H
Me
CO2Me 19
Me
H
2
1
2
1
p-Me-C6H4
p-NO2-C6H4
p-OMe-C6H4
2-thienyl
Ph
18c 73
18d 65
18e 74
18 f 61[b]
18g 52
2
0.5
1d nBu OMe 19a Ph
Ph
[a] Yield of isolated compounds 18, with respect to 1 (1 mmol scale).
[b] 1.7:1 mixture of regioisomers indicated by GC analysis of the crude
reaction mixture. Major regioisomer: R2 =Et and R3 =Me.
[a] Yield of isolated compounds 17, with respect to 1b (1 mmol scale).
[b] In all cases the crude reaction mixture contained variable amounts of
the correspondingketone 18 (see Scheme 9): Entry (GC ratio 17:18)
from crude reaction mixture: 1 (10:1), 2 (8:1), 3 (7.5:1), 4 (5:1), 5 (2.5:1),
6 (2:1), 7 (15:1), and 8 (17:1). These 1-naphthyl ketones are described in
the SupportingInformation.
a benzannulation reaction at only one double bond is also
worth noting(Table 5, entry 6).
Table 5. Benzannulation reaction of o-alkynylbenzaldehydes 1 with cyclic alkenes 20.[a]
sayed olefins 19, that is, both
aliphatic- and aromatic-substi-
tuted terminal olefins, as well
as internal alkenes, beingsuita-
ble components for the cycliza-
tion process (Table 4, entries 3–
7).
Entry
1
R1
20
t [h]
18
Yield [%][b]
1
1a
Ph
2
70
As depicted in Table 5, cyclo-
alkenes 20 reacted nicely, there-
by openingup a reliable alter-
native for the rapid assembly of
2,3-disubstituted 1-naphthyl ke-
tones. Fused polycycles can be
synthesized by usingthis proc-
ess. This findingis of interest,
as the alternative gold-cata-
lyzed approach to access 1-
naphthyl ketones would recog-
nize a cycloalkyne as a precur-
sor and those beingrequired to
prepare 18h–m turn out not to
be accessible. Electron-rich cy-
cloalkenes, such as the enol
ether 20c (Table 5, entry 3) and
the glucal derivative 20d
(Table 5, entry 4), were also
employed and cocyclized, there-
by giving access to the tricycle
18j and the hybrid core present
in 18k, respectively.
2
3
1a
1a
Ph
Ph
1.5
44
49
1
4
1a
Ph
12
35
5
6
1b
1a
nBu
3
2
40
63
Ph
The fact that, under the
standard reaction conditions,
conjugated dienes, such as 1,3-
[a] The reaction was performed by using o-alkynylbenzaldehydes 1 (1 equiv) and alkenes 20 (1.2 equiv) in the
presence of IPy2BF4 (1 equiv) and HBF4 (1.1 equiv) in CH2Cl2 at room temperature. [b] Yield of isolated com-
cyclohexadiene (20 f), undergo pounds 18, with respect to 1 (1 mmol scale).
5796
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Cyclization Reactions
FULL PAPER
When a nonaromatic aldehyde, such as enynal 14, was
employed the benzoannulation reaction also occurred. Thus,
the reaction of 14 with either styrene (19a) or cyclohexene
(20a) afforded the correspondingdienes 21 and 22, respec-
tively (Scheme 12). These examples illustrate that the origi-
nally developed benzannulation process could be adapted to
prepare polysubstituted carbocycles featuringa 1,3-diene
functionality.
Scheme 13. Iodonium-mediated benzannulation approach for preparing
indoles.
mediated entry to both 4,5-disubstituted and 4,5,6-trisubsti-
tuted indoles 23, dependingon the degree of substitution of
the startingalkene. Thus, indoles 23 were regioselectively
obtained from 7a,b upon treatment with the system
IPy2BF4/HBF4 and further treatment with the corresponding
alkene. The results are summarized in Table 6.
Both simple alkyl- and aryl-substituted acyclic olefins are
compatible substrates for this process and give the desired
indoles in moderate to satisfactory yields after isolation. Cy-
cloalkenes also undergo this transformation and lead to tri-
and tetracyclic compounds. Amongthe alkenes used in the
reaction, 2,3-dihydropyran (20c), indene (20e), and 1,2-di-
hydronaphthalene (20h) furnished structurally complex
indole derivatives in a regioselective and relatively simple
process (Table 6, entries 3, 7, and 8). For simple cycloal-
kenes, it was found that cyclopentene (20g; Table 6, entry 6)
could participate in the reaction under slightly modified
conditions (0.5 equiv HBF4, 608C, dichloroethane). Under
these modified reaction conditions other cyclic olefins, such
as cyclohexene, failed to react, with the startingmaterial
beingrecovered unaltered after the reaction workup. These
modified reaction conditions were tested with a set of repre-
sentative alkenes and proved to be superior to those previ-
ously employed (1.1 equiv of HBF4, room temperature, di-
chloromethane) in that they gave an improvement in the re-
action yields. Thus, 23e was obtained in 61% yield under
the new reaction conditions; this represents an increased
yield over that obtained by usingthe standard reaction con-
ditions (Table 6, entry 5).
Duringthe study of the scope of this new methodology
for the synthesis of the indole core, we tried to find alterna-
tives to overcome the lack of reactivity evidenced by simple
cycloalkenes, such as cyclohexene, and by terminal aliphatic
alkenes, such as 1-hexene, for producingthe expected indole
derivatives. Interestingly, we found that enamines can be
used as good reaction partners for assembling indoles, there-
by offeringan alternative to override these limitations. En-
amines derived from both aldehydes and ketones were rec-
ognized as active components for this reaction, although
they gave different compounds, as a function of their own
structural features. The reaction of the enamine 24a, derived
from pyrrolidine and cyclohexanone, offers a viable alterna-
tive for the assembly of indole 23i and nicely covers the fail-
ure of cyclohexene to access this indole through the iodoni-
um-driven stepwise cycloaddition approach. Thus, in di-
chloromethane, at room temperature, the sequential reac-
tion of the 3-alkynylpyrrol-2-carboxaldehyde 7a with
IPy2BF4 followed by the addition of the enamine 24a af-
Scheme 12. Formation of cycloalkyldienes upon iodonium-mediated an-
nulation of enynals.
Synthesis of indoles and other benzo-fused heterocycles by
related benzannulation processes: Although many efforts
have been devoted to the study of the reactivity of o-alky-
nylbenzaldehyde systems, no attempt to apply the new reac-
tivity found for these systems to target the synthesis of rele-
vant benzo-fused heterocycles has been disclosed, to the
best of our knowledge.
The indole skeleton is a “privileged” structure present in
many natural products and drugs; thus, the search for new
methodologies to obtain this scaffold with different substitu-
tion patterns has been the subject of much interest in the
last few decades.[33,34] However, out of the many processes
developed for the synthesis of indoles, only a few alterna-
tives are well suited for obtaininghighly substituted benzo-
functionalized derivatives that, at the same time, are com-
patible with access to the 2,3-unsubstituted motif in the
target ring.[35,36] Moreover, the synthetic sequence involving
the construction of a benzene ringonto a pyrrole to gener-
[37]
ate the correspondingindole has been rarely considered.
The novel strategy presented above for the synthesis of
the naphthalene skeleton, based on the key role of iodoni-
um ions as efficient promoters of the cycloaddition reaction
between o-alkynylbenzaldehyde and alkenes, could provide
a suitable alternative for the synthesis of the indole struc-
ture if the appropriate startingmaterial is chosen, in which
the aldehyde and alkyne functions would be connected
through a pyrrole ring (Scheme 13). We have successfully
developed the application of this iodonium-based methodol-
ogy for the synthesis of 2,3-unsubstituted indoles, by relying
on pyrrole-3-carboxaldehyde derivatives as valuable synthet-
ic precursors.[18b]
Initial studies were conducted on the study of the reaction
of N-tosyl-protected 3-alkynylpyrrol-2-carboxaldehydes 7a
(R=Ph) and 7b (R=nBu) with several alkenes. These stud-
ies quickly proved the feasibility of the proposed iodonium-
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J. Barluenga et al.
Table 6. Indoles 23 from reaction of pyrroles 7, alkenes and IPy2BF4.
Entry
1
Alkene
t [h]
23
Yield [%][a]
2
62
Scheme 14. Enamines as efficient partners in the iodonium-promoted
entry to indoles 23.
2
3
4
3
2
1
45
41
72
ed behavior could be anticipated as a function of the struc-
ture of the enamine accordingto our proposal to rationalize
the mechanism of these benzannulation reactions and will
be discussed in the next section.
In this context, we attempted to promote the same indoli-
zation process by using 7a, molecular iodine (1.2 equiv) as
the source of the required iodonium ion, and 24a as the en-
amine. The reaction was conducted in CH2Cl2 in the pres-
ence of a base (K2CO3, 1 equiv). Unfortunately, no cyloaddi-
tion was observed. This is in sharp contrast with the out-
come of the reaction of 7a with styrene (19a), which was
19a
19c
satisfactorily verified by usingI /K2CO3 and gave 23d in a
2
5
3
48 (61[b]
)
comparable 62% yield.[39]
The deprotection of the N-tosyl-masked compound to
afford the corresponding1 H-indole derivative was also
tested.[40] Thus, the free-NH indole 25 was easily obtained
[41]
from 23e upon reaction with NaOH in boilingethanol.
6
7
8
2
1
4
37[b]
We have also expanded the scope of this approach to tackle
the synthesis of related heterocycles other than indole.
These results are depicted in Table 7, which illustrates the
feasibility of usingthis transformation to prepare both ben-
zofuran 27 and benzothiophenes 28a–c, simply by starting
from either the correspondingfuran 26 or thiophene deriva-
tives 8a,b. Although the products were isolated only in mod-
erate yields, this method represents a valuable alternative
for the synthesis of these systems, the preparation methods
of which are scarce and more limited when compared to
those for the synthesis of indoles.[42]
36
42
Reaction mechanism: In this article, three different three-
component processes are reported from the reaction of o-al-
kynylbenzaldehyde derivatives with the reagent IPy2BF4,
with the observed pathway dependingon the nature of the
added nucleophile. A plausible mechanism that accounts for
these transformations would assume the formation of a ben-
[a] Yield of isolated compounds 23, with respect to 7 (1 mmol scale).
[b] The reaction was performed with HBF4 (0.5 equiv) in ClCH2CH2Cl at
608C in a sealed tube.
forded the indole 23i (Scheme 14).[38] However, reaction of
7a with the enamine 24b, derived from hexanal, under the
same experimental conditions furnished the indole 23j,
which retains the amine functionality from the enamine at-
tached to the indole skeleton (Scheme 14). This differentiat-
zo[c]pyrylium cation
A
as
a
common intermediate
(Scheme 15). Thus, as the initial step, we propose the attack
of the iodonium ion, liberated from the IPy2BF4 by treat-
ment with HBF4, onto the alkyne, assisted by the neighbor-
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Cyclization Reactions
FULL PAPER
Table 7. Synthesis of benzofuran 27 and benzothiophene 28 followinga common approach.
In this framework, the ability of
the alkyne substituents to stabi-
lize the developingpositive
charge along the reaction path
would explain the high regiose-
lectivity observed for the over-
all process. From C, a formal
retro-[4+2] cycloaddition reac-
tion would explain the forma-
tion of the major reaction prod-
ucts, the 1-iodonaphthalenes 17.
This seems to be a high-energy
process because of the genera-
tion of a labile acylium ion; it
could be facilitated by previous
nucleophilic attack of fluoride
Entry
1
Alkynyl aldehyde 26/8
26: X=O, R1 =Ph
Alkene 19/20
t [h]
Benzoheterocycle 27/28
Yield [%][a]
6
36
2
3
8a: X=S, R1 =nBu
8a: X=S, R1 =nBu
3
8
44
39
À
(liberated from BF4 ) on the
charged carbonyl moiety, fol-
lowed by the retro-[4+2] cyclo-
addition. Alternatively, the loss
of an iodonium ion from C
would afford the naphthyl ke-
tones 18, which are observed as
minor reaction products. To
provide evidence for this mech-
anistic proposal, the reaction
mixture obtained after the reac-
tion of 1b with the correspond-
ingalkyne was quenched with
4
8b: X=S, R1 =Ph
24
31
[a] Yield of isolated compounds 27/28, with respect to 26/8 (1 mmol scale).
1-octanol and, besides the desired naphthalene compound,
octylpentanoate was found to be present in the crude reac-
tion mixture. The formation of this ester provides additional
evidence for the participation of an intermediate of type C
duringthe process of formation of the iodonaphthalenes 17.
The formation of only naphthyl ketones when alkenes
were used as nucleophiles could be explained by a mecha-
nistic pathway based on the previous experience of the
parent-alkyne transformation. Thus, the participation of a
new reaction intermediate E formed by the nucleophilic
attack of the alkene onto A is proposed. Evolution of the in-
termediate E by loss of a proton would produce the polycy-
clic compound F. The loss of an HI molecule and concomi-
tant aromatization would yield the obtained naphthyl ke-
tones 18, the only reaction products observed for this trans-
formation.
This mechanism could also be invoked to account, in a
straightforward manner, for the synthesis of indoles and
other benzoheterocycles by the reaction of correspondingal-
dehyde–heterocycle derivative with alkenes. Interestingly,
when enamine 24a was used as a more reactive surrogate
for cyclohexene, the indole 23i was formed with concomi-
tant loss of the amine fragment present in 24a. The forma-
tion of the product 23i can also be rationalized by the mech-
anism proposed. In this case, the intermediate of type F
lacked the hydrogen atom in the b-position with respect to
iodine that was required for the b-elimination reaction,
Scheme 15. Proposed common intermediate for the iodonium-induced
functionalization reactions of o-alkynylbenzene carbaldehydes.
ingcarbonyl group, to furnish the reactive species A. This
intermediate A could be in equilibrium with species A’
which might reversibly incorporate some of the nucleophiles
already present in the reaction media (pyridine, fluoride;
Scheme 15). Subsequent incorporation of the externally
added nucleophile would give rise to the corresponding
products, as will be discussed in the followingparagraphs.
A possible evolution of the species A/A’ that accounts for
the observed products is outlined in Scheme 16. For simple
nucleophiles such as alcohols, silyl-masked nucleophiles,
electron-rich arenes, and heteroarenes, the addition of the
nucleophile to species A would directly furnish the forma-
tion of the observed compounds 6.
When an alkyne is added to the reaction media, stepwise
reaction through an intermediate B, resultingfrom the nu-
cleophilic attack of the alkyne onto A, followed by intramo-
lecular trappingof the cationic species by the b-iodoenol
ether fragment would lead to the polycyclic intermediate C.
eventually resultingin the aromatization pro cess; instead,
A
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J. Barluenga et al.
13C NMR spectra were recorded
at 258C after different reaction
times (Figure 2).[43] After 6 h, a
complete transformation of 1b
(Figure 2, spectrum A) into the
correspondingadduct resulting
from the incorporation of pyri-
dine into the benzo[c]pyrilium
cation I (Figure 2, spectrum B)
was observed. The 1H NMR
chemical shift of the hydrogen
atom sited in the a-position to
the oxygen atom (d=7.90 ppm)
indicates the formation of the
proposed pyrilium salt deriva-
tive I. At this point, styrene
(1.2 equiv) was added to the
NMR tube and a progressive
transformation of the benzo[c]-
pyrilium cation I into a new
compound III was observed,
while the styrene signals de-
creased in intesnity (Figure 2,
Scheme 16. Proposed pathways for transformingthe benzo[ c]pyrylium cation A. Py+ =pyridinium.
an alternative cleavage of the b-amino functionality present
in F drove the process and the indole 23i was the observed
reaction product (Scheme 17).
spectrum C). The transformation of I into III was complete
in three days (Figure 2, spectrum D).[44] The disappearance
of compound I could be monitored through the slow disap-
pearance of the characteristic
singlet at d=7.90 ppm; the
transformation gave rise a new
1
set of H NMR signals, the fur-
ther analysis of which led to the
structural characterization of
compound III.[45]
This NMR experiment was
repeated in dichloromethane
for a 1 mmol scale reaction and
a compound was isolated as an
orange solid after simple evapo-
ration of the solvent. Surpris-
ingly, when this orange solid,
with the structure assigned to
compound III (Figure 3 shows
Scheme 17. Product diversity as a function of the enamine.
1
its H NMR spectrum), was dis-
solved in CDCl3, 1H NMR
monitoringrevealed that the correspondingnaphthyl ketone
18a was gradually formed in a process that was finished in
14 h. Most probably, the traces of acid present in the deuter-
ated solvent catalyzed the transformation of III into 18a. It
did not occur duringthe NMR studies of the reaction, prob-
ably due to the presence of pyridine molecules in the reac-
By contrast, for the reaction of the enamine 24b, the re-
sultingintermediate F showed a hydrogen atom attached to
the same carbon atom as the pyrrolidine fragment (R2 =pyr-
rolidine), thereby allowingthe aromatization step to occur
through loss of HI and resulting in the formation of 23j,
which still retained the amine incorporated in the indole
framework.
tion media, arisingfrom the IPy BF4 reagent; these mole-
2
The reaction of the o-alkynylbenzaldehyde 1b with styr-
ene was monitored by NMR spectroscopy with the aim of
findingnew evidence to support the mechanism proposed.
For this NMR study, the reaction was carried out in the ab-
sence of tetrafluoroboric acid; thus, 1b (1 equiv) was added
to a solution of IPy2BF4 (1 equiv) in CD2Cl2 and 1H and
cules would preclude this possibility by neutralizingthe
traces of acid present in the deuterated solvent.
The proposed sequence for the formation and evolution
of the different intermediates observed duringthe NMR
studies is depicted in Scheme 18. The structure of III was
determined by one- and two-dimensional NMR spectrosco-
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Cyclization Reactions
FULL PAPER
Figure 2. NMR study of the iodocyclization of the o-alkynylbenzaldehyde 1b with styrene.
Conclusion
In summary, new metal-free protocols for the synthesis of
different types of substituted isochromenes, naphthalenes,
and benzoheterocycles have been developed. The combina-
tion of o-alkynylbenzaldehyde derivatives, iodonium ions,
and either alcohols, silylated nucleophiles, alkynes, or al-
kenes occurs in a predictable manner to produce the corre-
spondingfamily of compounds. The synthesis of benzo-fused
heterocycles with interestingdi- and trisubstitution patterns
and featuringthe 2,3-unsubstituted ringmotif has been es-
tablished. Significant mechanistic insights have been gained
and are reported that should contribute to further expand
the opportunities raised by this synthetic strategy. In this
synthetic scenario, an iodonium ion acts as an electrophilic
promoter and allows the incorporation of a synthetically
useful iodine atom in some of the final products, thereby of-
feringa valuable complement to related transition-metal-
based cyclizations and openingmany synthetic possibilities
for the use of the assembled iodinated rings as building
blocks in diversity-oriented synthesis, just by relyingon
well-established metal-catalyzed cross-couplingreactions.
Figure 3. 1H NMR spectrum of compound III.
py, as well as mass spectrometry experiments. As is shown,
the formation of III could be driven by the basic reaction
conditions, since pyridine could cause isomerization of the
double bond of intermediate II to an exocyclic position. Fi-
nally, when intermediate III is exposed to acid media, the
transformation to the observed naphthyl ketone 18a would
occur through rapid equilibration with its isomer II.
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J. Barluenga et al.
to
a
solution of IPy2BF4 (0.37 g,
1 mmol, 1 equiv) in dry dichlorome-
thane (10 mL) and the resultant solu-
tion was stirred at room temperature
for 1h. After this time, tert-butyl alco-
hol (115 mL, 1.2 mmol, 1.2 equiv) was
added and the solution was stirred
until the benzaldehyde startingmateri-
al had disappeared (6 h). The reaction
mixture was quenched with saturated
aqueous NaHCO3 and vigorously stir-
red. The organic layer was washed
with
a
5% aqueous solution of
Na2S2O3 (50 mL) and water (50 mL),
dried over sodium sulfate, and concen-
trated. The crude residue was purified
by flash column chromatography (neu-
tral aluminum oxide, hexane/EtOAc)
to afford pure compound 2d (275 mg,
68%).
Scheme 18. Different reaction pathways in the presence and absence of added acid.
General procedure for the synthesis of
4-iodo-1-methoxy-1H-isochromenes 2a,d,f by using IPy2BF4 and trime-
thylborate: Trimethylborate (0.22 mL, 2 mmol, 2 equiv) was added to a
solution of IPy2BF4 (0.37 g, 1 mmol, 1 equiv) in CH2Cl2 (10 mL) at 08C.
After 10 min, the appropriate 2-alkynylbenzaldehyde 1a–c (1 mmol,
1 equiv) was added and the solution was stirred at room temperature
until the aldehyde startingmaterial had disappeared. The reaction mix-
ture was quenched with saturated aqueous NaHCO3. The organic layer
was washed with a 5% aqueous solution of Na2S2O3 (50 mL) and water
(50 mL), dried over sodium sulfate, and concentrated. The crude residue
was purified by flash column chromatography (neutral aluminum oxide,
hexane/EtOAc) to afford pure compounds 2a,d,f.
Experimental Section
General: All reactions were conducted by usingoven-dried lgassware
under an atmosphere of nitrogen. Dichloromethane and 1,2-dichloro-
ethane were distilled from CaH2 before use. Ethanol and the solvents
used in column chromatography, hexane and ethyl acetate, were obtained
from commercial suppliers and used without further distillation. TLC
was performed on aluminum-backed plates coated with silica gel 60 with
F254 indicator (Merck). Flash chromatography was carried out over
silica gel. NMR spectra were measured at room temperature on Bruker
AC-200 MHz, Bruker DPX-300 MHz, Bruker AV-300 MHz, and Bruker
AV-400 MHz spectrometers. 2D-NMR experiments were recorded on a
Bruker AV-400 MHz spectrometer. Chemical shifts are reported in ppm
with the solvent resonance used as the internal standard (deuterochloro-
form: d=7.26 ppm in 1H NMR spectra, d=77.00 ppm in 13C NMR spec-
tra). Carbon multiplicities were assigned by DEPT techniques. High-reso-
lution mass spectra were recorded on a Finnigan-Matt 95 mass spectrom-
eter by usingEI at 70 eV. Infrared spectra were obtained on a Unicam
Mattson 3000 FTIR spectrometer; only the most significant IR absorp-
tions are given. Elemental analyses were carried out on Perkin–
Elmer 2400 and Carlo Erba 1108 microanalyzers. Meltingpoints were
measured on a Büchi Totoli apparatus.
Reaction of o-(alkynyl)ketones 3a,bwith IPy BF4 and alcohols
2
a) Reaction of 3a,b by using the system IPy2BF4/HBF4: Tetrafluoroboric
acid (54% solution in diethyl ether; 0.15 mL, 1.1 mmol, 1.1 equiv) was
added to a stirred solution of IPy2BF4 (0.37 g, 1 mmol, 1 equiv) in CH2Cl2
(10 mL) at À608C. After 10 min, the appropriate o-(alkynyl)ketone 3a,b
(1 mmol, 1 equiv) was added. After the mixture was stirred for 30 min,
methanol (48 mL, 1.2 mmol, 1.2 equiv) was added and the resultingsolu-
tion was stirred at À608C for 24 h. The reaction mixture was quenched
with saturated aqueous NaHCO3. The organic layer was washed with a
5% aqueous solution of Na2S2O3 (50 mL) and water (50 mL), dried over
sodium sulfate, and concentrated. The crude residue was purified by flash
column chromatography (neutral aluminum oxide, hexane/EtOAc) to
afford pure compounds 4a,b.
The crystallographic structure determination for 6g was performed on a
Bruker SMART 1000 diffractometer with MoKa radiation (l=0.71073 Š),
at 120 K. Spectroscopic data for all of the compounds described may be
found in the SupportingInformation.
b) Reaction of 3a by using the system IPy2BF4/B(OMe)3: Trimethylborate
A
General procedure for the synthesis of 4-iodo-1H-isochromenes 2, 6, 11,
and 13 by using IPy2BF4 and HBF4: IPy2BF4 (0.37 g, 1 mmol, 1 equiv)
was dissolved in dry CH2Cl2 (10 mL). The solution was cooled at 08C
and tetrafluoroboric acid (54% solution in diethyl ether; 0.15 mL,
1.1 mmol, 1.1 equiv) was added. After 10 min, 2-alkynylbenzaldehyde 1
(1 mmol, 1 equiv) was added and the solution was stirred for 30 min at
room temperature. After this time, the appropriate nucleophile (alcohols,
silylated compounds 5, arenes 10, or heteroarenes 12; 1.2 mmol,
1.2 equiv) was added and the solution was stirred further until the benzal-
dehyde startingmaterial disappeared (the reaction times are given in the
text). The reaction mixture was quenched with saturated aqueous
NaHCO3 and vigorously stirred. The organic layer was washed with a
5% aqueous solution of Na2S2O3 (50 mL) and water (50 mL), dried over
sodium sulfate, and concentrated. The crude residue was purified by flash
column chromatography (neutral aluminum oxide, hexane/EtOAc) to
afford pure compounds 2, 6, 11, and 13.
(0.22 mL, 2 mmol, 2 equiv) was added to a solution of IPy2BF4 (0.37 g,
1 mmol, 1 equiv) in CH2Cl2 (10 mL) at À608C. After 10 min, 2-(phenyl-
A
resultant solution was allowed to reach 08C for 24 h. The reaction mix-
ture was then quenched with saturated aqueous NaHCO3. The organic
layer was washed with a 5% aqueous solution of Na2S2O3 (50 mL) and
water (50 mL), dried over sodium sulfate, and concentrated. Flash
column chromatography (neutral aluminum oxide, hexane/EtOAc) of the
crude residue gave the pure compound 4a (182 mg, 48%).
Reaction of enynal 14 with IPy2BF4 and silylketene acetal 5c: IPy2BF4
(0.37 g, 1 mmol, 1 equiv) was dissolved in dry CH2Cl2 (10 mL). The solu-
tion was cooled at 08C and tetrafluoroboric acid (54% solution in diethyl
ether; 0.15 mL, 1.1 mmol, 1.1 equiv) was added. After 10 min, the enynal
14 (0.16 g, 1 mmol, 1 equiv) was added and the solution was stirred for
30 min at room temperature. After this time, the silylketene acetal 5c
(243 mL, 1.2 mmol, 1.2 equiv) was added and the solution was stirred fur-
ther until the aldehyde startingmaterial had disappeared (1h). The reac-
tion mixture was quenched with saturated aqueous NaHCO3 and vigo-
rously stirred. The organic layer was washed with a 5% aqueous solution
of Na2S2O3 (50 mL) and water (50 mL), dried over sodium sulfate, and
concentrated. The crude residue was purified by flash column chromatog-
For the reaction of the pyrrole and thiophene derivatives 7a and 8b, the
same procedure was used to obtain the correspondingbiheterocyclic
compounds 9a,b.
Reaction of o-alkynylbenzaldehyde 1b with IPy2BF4 and tert-butyl alco-
hol: o-(1-Hexynyl)benzaldehyde (1b; 0.19 g, 1 mmol, 1 equiv) was added
5802
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Chem. Eur. J. 2006, 12, 5790 – 5805

Cyclization Reactions
FULL PAPER
raphy (neutral aluminum oxide, hexane/EtOAc) to afford pure com-
pounds 15a (23%, 90 mg) and 15b (31%, 120 mg).
and the solution was stirred for 30 min at room temperature. After this
time, cyclopentene (20g; 110 mL, 1.24 mmol, 4 equiv) was added and the
solution was further stirred at 608C for 2 h. The reaction mixture was al-
lowed to reach room temperature and was then quenched with saturated
aqueous NaHCO3 and vigorously stirred. The organic layer was washed
with a 5% aqueous solution of Na2S2O3 (25 mL) and water (25 mL),
dried over sodium sulfate, and concentrated. The crude residue was puri-
fied by flash column chromatography (silica gel, hexane/EtOAc) to
afford pure compound 23 f (47 mg, 37%).
General procedure for the reaction of o-(1-hexynyl)benzaldehyde (1b)
and alkynes 16 by using IPy2BF4 and HBF4: IPy2BF4 (0.37 g, 1 mmol,
1 equiv) was dissolved in dry CH2Cl2 (10 mL). The solution was cooled to
08C and tetrafluoroboric acid (54% solution in diethyl ether; 0.30 mL,
2.2 mmol, 2.2 equiv) was added. After 10 min, 1b (0.19 g, 1 mmol,
1 equiv) was added and the solution was stirred for 30 min at room tem-
perature. After this time, the correspondingalkyne
16 (1.2 mmol,
General procedure for the synthesis of the indoles 23i and 23j by using
IPy2BF4: IPy2BF4 (115 mg, 0.31 mmol, 1 equiv) was dissolved in dry
CH2Cl2 (5 mL) and 3-phenylethynyl-N-tosylpyrrole-2-carboxaldehyde
(7a; 108 mg, 0.31 mmol, 1 equiv) was added at room temperature. After
the solution has been stirred for 30 min, the correspondingenamine [1-
pyrrolidino-1-cyclohexene (24a; 199 mL, 1.24 mmol, 4 equiv) or 1-pyrroli-
dino-1-hexene (24b; 224 mg, 1.24 mmol, 4 equiv)] was added and the sol-
ution was further stirred at room temperature for 12 h. The reaction mix-
ture was quenched with saturated aqueous NaHCO3 and vigorously stir-
red. The organic layer was washed with a 5% aqueous solution of
Na2S2O3 (25 mL) and water (25 mL), dried over sodium sulfate, and con-
centrated. The crude residue was purified by flash column chromatogra-
phy (silica gel, hexane/EtOAc) to afford pure compound 23i (41 mg,
31%) or pure compound 23j (70 mg, 43%).
1.2 equiv) was added and the solution was further stirred at room temper-
ature (reaction times are given in Table 3). The reaction mixture was
quenched with saturated aqueous NaHCO3 and vigorously stirred. The
organic layer was washed with a 5% aqueous solution of Na2S2O3
(50 mL) and water (50 mL), dried over sodium sulfate, and concentrated.
The crude residue was purified by flash column chromatography (silica
gel, hexane/EtOAc) to afford pure 1-iodonaphthalenes 17 with variable
amounts of the correspondingnaphthyl ketones 18 as minor products.
General procedure for the reaction of o-alkynylbenzaldehyde 1 and al-
kenes 19 and 20 by using IPy2BF4 and HBF4: Tetrafluoroboric acid (54%
solution in diethyl ether, 0.15 mL, 1.1 mmol, 1.1 equiv) was added to a
stirred solution of IPy2BF4 (0.37 g, 1 mmol, 1 equiv) in CH2Cl2 (10 mL) at
08C. After 10 min, the appropriate o-(alkynyl)benzaldehyde 1 (1 mmol,
1 equiv) was added. After the mixture was stirred for 30 min at room
temperature, the correspondingalkene 19 or 20 (1.2 mmol, 1.2 equiv) was
added and the resultingsolution was stirred at room temperature until
the benzaldehyde startingmaterial had disappeared (reactions times are
given in Tables 4 and 5). The reaction mixture was quenched with satu-
rated aqueous NaHCO3. The organic layer was washed with a 5% aque-
ous solution of Na2S2O3 (50 mL) and water (50 mL), dried over sodium
sulfate, and concentrated. The crude residue was purified by flash
column chromatography (silica gel, hexane/EtOAc) to afford pure com-
pounds 18.
Procedure for the synthesis of compound III: IPy2BF4 (0.37 g, 1 mmol,
1 equiv) was dissolved in dry CH2Cl2 (4 mL) and o-(1-hexynyl)benzalde-
hyde (1b; 0.19 g, 1 mmol, 1 equiv) was added at room temperature. After
the solution had been stirred for 6 h, styrene (19a; 114 mL, 1 mmol,
1 equiv) was added and the solution was stirred further at room tempera-
ture for 3 days. The solvent was removed under pressure to afford the
pure compound III as an orange solid in quantitative yield.
Reaction of enynal 14 with alkenes by using IPy2BF4 and HBF4: IPy2BF4
(0.37 g, 1 mmol, 1 equiv) was dissolved in dry CH2Cl2 (10 mL). The solu-
tion was cooled to 08C and tetrafluoroboric acid (54% solution in diethyl
ether; 0.15 mL, 1.1 mmol, 1.1 equiv) was added. After 10 min, the enynal
14 (0.16 g, 1 mmol, 1 equiv) was added and the solution was stirred for
30 min at room temperature. After this time, the correspondingalkene
19a or 20a (1.2 mmol, 1.2 equiv) was added and the solution was stirred
further until the aldehyde startingmaterial had disappeared. The reaction
mixture was quenched with saturated aqueous NaHCO3 and vigorously
stirred. The organic layer was washed with a 5% aqueous solution of
Na2S2O3 (50 mL) and water (50 mL), dried over sodium sulfate, and con-
centrated. The crude residue was purified by flash column chromatogra-
phy (silica gel, hexane/EtOAc) to afford the corresponding diene 21 or
22.
Acknowledgements
This research was supported by the Spanish DGI (Grant no.: CTQ2004-
08077-C02-01). A predoctoral fellowship (to H.V.-V. from the Spanish
MCYT) is gratefully acknowledged. Generous support from Merck,
Sharp, & Dohme is gratefully acknowledged. The collaboration of Dr.
Antonio L. Llamas-Saiz, from the X-ray facility (RIAIDT) of the Univer-
sity of Santiago, is acknowledged for the X-ray crystallographic analysis
of compound 6g. The authors wish to thank the referees for valuable and
constructive suggestions to improve the reading of this article.
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[28] To test this possibility in that experiment, we have adapted the ex-
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[29] The structure of 15a was assigned on the basis of two-dimensional
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unambiguously established; however, an unequivocal assignment of
the correspondingstereochemistry of C5–C6 was not possible on
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18a of only 5:1. Poorer selectivity was observed when startingfrom
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Chem. Eur. J. 2006, 12, 5790 – 5805

Cyclization Reactions
FULL PAPER
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[38] For the case of enamines, the reaction was conducted without addi-
tion of HBF4 to avoid competitive degradation reactions.
[39] Thus, for reactions with labile nucleophiles, the election of the iodo-
nium donor is crucial. To search for new reactions, IPy2BF4 is a very
helpful synthetic tool that allows fine adjustments of the experimen-
tal protocol.
[40] When pyrrolecarboxaldehydes with free NH groups were employed
as precursors, the reaction did not take place and the startingmate-
rials were recovered.
[41] Method adapted from: L. W. Knight, J. W. Huffman, M. L. Isher-
wood, Synlett 2003, 1993–1996.
[42] a) For a recent review on the synthesis of benzo[b]furans, see: X.-L.
Hou, Z. Yang, H. N. C. Wong, Prog. Heterocycl. Chem. 2003, 15,
167–205; b) for recent examples on the synthesis of benzo[b]furans
by usingiodonium chemistry, see: A. Arcadi, S. Cacchi, G. Fabrizi,
F. Marinelli, L. Moro, Synlett 1999, 1432–1434; c) for recent reports
on the use of electrophiles for the synthesis of benzo[b]thiophene,
see: B. L. Flynn, P. Verdier-Pinard, E. Hamel, Org. Lett. 2001, 3,
651–654; d) D. Yue, R. C. Larock, J. Org. Chem. 2002, 67, 1905–
1909.
[43] The reaction was conducted in an NMR tube and the spectra were
recorded at 258C on a Bruker AV-400 spectrometer operatingat
1
400.13 MHz and 100.61 MHz for H and 13C acquisitions.
[44] Free pyridine signals were also observed at this point.
[45] A full assignment of the 1H and 13C NMR spectra of compounds I
and III is reported in the SupportingInformation.
Received: December 2, 2005
Published online: May 19, 2006
Chem. Eur. J. 2006, 12, 5790 – 5805
ꢀ 2006 Wiley-VCH VerlagGmbH & Co. KGaA, Weinheim
www.chemeurj.org
5805