Reaction of bicyclic zirconacyclopentenes with aldehydes and a potential pathway to condensed 5-7-6(Ar) ring systems

Article abstract of DOI:10.1002/ejoc.201500248

Bicyclic zirconacyclopentenes prepared by the reactions of 1,6- and 1,7-enynes with [Cp₂ZrBu₂] (Negishi reagent) reacted with a plethora of aldehydes (aryl, heteroaryl, alkyl, α,β-unsaturated) by chemo- and stereoselective insertion

Full text of DOI:10.1002/ejoc.201500248

FULL PAPER
DOI: 10.1002/ejoc.201500248
Reaction of Bicyclic Zirconacyclopentenes with Aldehydes and a Potential
Pathway to Condensed 5–7–6(Ar) Ring Systems
[a]
[a]
[a]
ˇ
Nikola Topolovcan, Illia Panov, and Martin Kotora*
Dedicated to Professor Tamotsu Takahashi on the occasion of his 60th birthday
Keywords: Homogeneous catalysis / Zirconium / Metallacycles / Cyclization / Insertion / Fused-ring systems / Aldehydes
Bicyclic zirconacyclopentenes prepared by the reactions of
dehyde were also subjected to intramolecular coupling in the
1,6- and 1,7-enynes with [Cp2ZrBu2] (Negishi reagent) re- presence of CuCl and additives, and compounds possessing
acted with a plethora of aldehydes (aryl, heteroaryl, alkyl,
α,β-unsaturated) by chemo- and stereoselective insertion into
the sp3 C–Zr bond to give the corresponding oxazircona-
the condensed 5–7–6(aryl) ring system were obtained in rea-
sonable isolated yields (32–46%). The same ring system was
also prepared by the Pd-catalyzed coupling of dihalo deriva-
cycloheptenes. Subsequent hydrolysis or halogenolysis pro- tives 10 (38–42% 1H NMR yields). Moreover, the mechanism
vided the corresponding alcohols 4 (31–74% isolated yields)
or halides 10 (35–50% isolated yields). The oxazircona-
cycloheptenes prepared by the insertion of 2-iodobenzal-
of the unproductive side-reaction leading to ketones during
the reaction with CuCl was elucidated.
Introduction
Zirconacycles are a class of bis-nucleophiles that readily
react with a number of electrophiles to provide a variety of
differently substituted compounds and such processes have
also been used for the formation of carbocyclic com-
pounds.[1] Typical examples are the reactions of zirconacy-
clopentadienes with alkynes to give substituted benzenes,[2]
with allyl and propargyl halides to form cyclohexadienes,[3]
with o-dihaloarenes to yield naphthalenes,[4] and with o-di-
(halomethyl)arenes to form benzooctatrienes.[5] Zircona-
cycles also react with 3-iodoenones to form spirocyclic com-
pounds.[6] Also worth mentioning are the reactions of zir-
conacyclopentanes and -cyclopentadienes with acyl hal-
ides[7] or aldehydes[8] to give five-membered ring com-
pounds. As far as the formation of seven-membered ring
compounds using zirconacycles is concerned, two methods
have been reported: The reactions of zirconacyclopentadi-
enes with bis-functional allyl halides[3a] and o-iodobenzyl
bromides[9] to provide cycloheptadienes and benzocyclo-
heptatrienes, respectively (Scheme 1). In this respect, an
early example of the synthesis of tricyclic compounds based
on carbene insertion into zirconacyclopentanes reported by
Whitby and co-workers should also be acknowledged.[10]
Scheme 1. Formation of compounds with a cycloheptane scaffold
from zirconacyclopentadienes.
Although the above-mentioned processes allows the
preparation of a variety of carbocyclic compounds pos-
sessing five- to eight-membered rings, there are still other
opportunities for developing new synthetic protocols. In
particular, the synthesis of polycyclic compounds pos-
sessing seven-membered rings is of considerable synthetic
interest because such compounds are often an important
structural motif in natural and biologically active com-
pounds.[11]
In principal, zirconacyclopentenes can react with alde-
hydes and other compounds possessing the carbonyl group
in two ways. The reaction may proceed either by the ex-
trusion of ethylene from the zirconacyclopentenes to form
oxazirconacyclopentenes that yield allylic alcohols after hy-
drolysis[12] or by insertion into the sp3 C–Zr bond to give
oxazirconacycloheptenes, which upon hydrolysis give rise to
pent-4-en-1-ols and derivatives thereof. As far as the latter
pathway is concerned, it has been shown that monocyclic
zirconacyclopentenes (along with one example of a bicyclic
zirconacyclopentene) react with aromatic and aliphatic al-
[a] Department of Organic Chemistry, Faculty of Science, Charles
University in Prague,
Hlavova 8, 128 43 Praha 2, Czech Republic
E-mail: martin.kotora@natur.cuni.cz
https://www.natur.cuni.cz/chemistry/orgchem/kotora?set_
language=en
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201500248.
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Reaction of Bicyclic Zirconacyclopentenes with Aldehydes
dehydes to form the corresponding oxazirconacyclohept- decided to screen the reaction of the bicyclic zirconacyclo-
enes, which, after hydrolysis, give the expected pent-4-en-1- pentene 1a with variously substituted aromatic, heteroaro-
ols.[13] The treatment of the intermediate oxazirconacycles matic, α,β-unsaturated, and alkyl aldehydes followed by
with transition-metal salts (CuCl) and additional Lewis protonolysis (Scheme 3).
acids resulted in the formation of tetrahydrofurans[14] or
homoallyl ketones.[15,16] Interestingly, the reactions of re-
lated titanacyclopentenes with aldehydes proceed exclu-
sively by the insertion of the carbonyl group into the sp2
C–Ti bond.[17] In this respect, it is worth noting that the
reaction of the α-vinylzirconacyclopentene with aldehydes
proceeds at the sp2 C–Zr bond by an allylic rearrangement
instead of by insertion into the sp3 C–Zr bond to provide
homoallenyl alcohols.[18]
Although the oxazirconacycloheptenes obtained by the
Scheme 3. Reactions of 2 with 1 and subsequent protonolysis.
insertion of aldehydes might be considered interesting inter-
mediates for subsequent synthetic elaboration, their further
reactions with carbon-based nucleophiles (alkyl, allyl, alk-
enyl, or aryl halides) have not yet been reported. In this
respect, the sequential reaction of a bicyclic zirconacyclo-
pentene, prepared by the oxidative dimerization of an en-
yne, with o-halobenzaldehydes, followed by the intramo-
lecular coupling of the sp2 C–Zr bond with an sp2 C–halide
bond in the pendant chain to provide a seven-membered
ring compound, has not yet been explored. The retrosyn-
thetic analysis of this reaction sequence is depicted in
Scheme 2.
The reactions proceeded as expected, usually with the
full conversion of the starting enyne, providing the corre-
sponding alcohols 4 in sensible isolated yields at 0 °C (in
some cases the reduced yields of the isolated compounds
may be attributed to the purification of the products from
side-products; Table 1, Figure 1). Interestingly, the o-substi-
Table 1. Results of the insertion of aldehydes 2 into 1a.
[a]
Entry[a]
2
T [°C]
dr
4
Yield [%][b]
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2c
2c
2d
2e
2f
20
0
20
0
20
0
0
≈5.5:1
≈5.5:1
4aa
4aa
4ab
4ab
4ac
4ac
4ad
4ae
4af
4ag
4ag
4ah
4ai
40 (61)
35 (61)
70
55 (73)
33
57 (75)
52 (77)
70
Ͼ20:1[c]
Ͼ20:1[c]
≈15:1
≈15:1
Ͼ20:1[c]
Ͼ20:1[c]
Ͼ20:1[c]
Ͼ20:1[c]
Ͼ20:1[c]
Ͼ20:1[c]
≈5.5:1
0
9
–10
20
0
0
0
0
0
0
0
53
31
10
11
12
13
14
15
16
17
2g
2g
2h
2i
32 (46)
62 (72)
60
74 (88)
31 (51)
62 (81)
62 (80)
2j
Ͼ20:1[c]
≈19:1
4aj
2k
2l[d]
2m
4ak
4al
4am
Ͼ20:1[c]
≈5.5:1
Scheme 2. Retrosynthetic analysis of seven-membered ring forma-
tion from enynes and o-halobenzaldehydes.
[a] The dr value was determined by 1H NMR spectroscopy. [b] Iso-
lated yields. The H NMR yields are given in parentheses. [c] The
second diastereoisomer was not detected in the reaction mixture or
after isolation. [d] 3 equiv. of 2l were used.
If such a reaction could be successfully accomplished,
it would represent a new and synthetically straightforward
approach to the synthesis of polycyclic condensed carbo-
cycles possessing 6–7–6(aryl) and 5–7–6(aryl) ring sys-
tems[19] from simple and easily accessible building blocks
such as enynes[20] and aromatic aldehydes. The 6–7–6(Ar)
condensed ring structural motif is commonly found in natu-
ral compounds, for example, in members of the icetaxane
family.[21] On the other hand, the 5–7–6(Ar) framework is
rather rare and, to the best of our knowledge, has so far
been identified in just one compound with the isodolastane
skeleton.[22]
1
Results and Discussion
Insertion of Aldehydes into the sp3 C–Zr Bond in
Zirconacyclopentenes
Because there is a lack of information on the reactions
of bicyclic zirconacyclopentenes with aldehydes, we initially zirconacylopentene 1a.
Figure 1. Alcohols 4 obtained by the insertion of aldehydes 2 into
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N. Topolovcˇan, I. Panov, M. Kotora
FULL PAPER
tuted benzaldehydes gave higher yields of the desired prod- 1b–1f. The insertion of 2e into zirconacycle 1b was initially
ucts. The reaction of 1a with 4-pyridinecarbaldehyde was carried out at 0 °C and gave the corresponding product 4be
tested as well, but the reaction furnished an intractable re- in 60% yield; however, carrying out the reaction at 20 °C
action mixture in which the expected product could not be resulted in an improved yield of 84% (entries 2 and 3). Zir-
detected. The reactions of 1a with aldehydes 2a–2c and 2g conacyclopentene 1c bearing a hydroxylated side-chain re-
were also carried out at 20 °C for comparison (entries 1, 3, acted with 2e uneventfully at 0 °C to give the desired prod-
5, and 10). In general, the higher reaction temperature did uct 4ce in a good yield of 75% (entry 4). In an analogous
not affect the diastereoselective ratios, which are essentially manner, the insertion into the bicyclic zirconacyclopentene
the same as those at 0 °C, or the isolated yields of 4aa–4ac 1d yielded the product 4de in 86% yield (entry 5). Then the
and 4ag. Nevertheless, greater amounts of unidentified side- reaction of the zirconacyclopentene possessing a nitrogen
products were observed. The generally high diastereoselec- atom (1e) was attempted with 2d and 2e; the reactions pro-
tivity of the insertion process is worth noting. We assume ceeded in both cases to furnish the corresponding insertion
that the aldehydes favored approach to the sp3 C–Zr bond products 4ed and 4ee in isolated yields of 55 and 32% (en-
from the less sterically hindered side leading to the preferen- tries 6 and 7), respectively. In a similar manner, the reaction
tial formation of (S*,S*) diastereoisomers with Ͼ99% of 1f with 2e gave 4fe in 57% isolated yield (entry 8). In
selectivity in most cases. On the other hand, it should be most cases the products were obtained with excellent dia-
mentioned that the reactions with 2a, 2c, 2i, 2k, and 2m stereoselectivities.
gave lower diastereoselectivities (entries 1, 2, 5, 6, 13, 15,
and 17).
Table 2. Insertion of o-iodobenzaldehyde (2e) into zirconacyclo-
pentenes 1a–1f.
The assumption regarding the formation of the (S*,S*)
diastereoisomers was confirmed by theoretical calculations,
which showed that the (S*,S*) diastereoisomer of zircona-
cyclopentene 3 (R1 = R2 = Ph) is 8 kJmol–1 more stable
than the (S*,R*) diastereoisomer (the optimized geometries
and energies can be found in the Supporting Infor-
mation).[23] The predicted relative stereochemistry of the
products, that is, (S*,S*), was confirmed by a single-crystal
X-ray analyses of 4fe (Figure 2) and 4ed (see the Supporting
Information).
[a]
Entry[a]
1
T [°C]
dr
Product
Yield [%][b]
1
2
3
4
1a
1b
1b
1c
1d
1e
1e
1f
0
0
20
0
0
0
Ͼ20:1[c]
Ͼ20:1[c]
Ͼ20:1[c]
Ͼ20:1[c]
≈16:1
4ae
4be
4be
4ce
4de
4ed
4ee
4fe
70
31 (60)
52 (84)
53 (75)
63 (86)
55
32 (54)
57
5
6[d]
7
Ͼ20:1[c]
Ͼ20:1[c]
Ͼ20:1[c]
0
0
8
[a] The dr value was determined by 1H NMR spectroscopy. [b] Iso-
1
lated yields. The H NMR yields are given in parentheses. [c] The
second diastereoisomer was not detected in the reaction mixture or
after isolation. [d] The insertion reaction was carried out with o-
bromobenzaldehyde (2d).
Insertion of Aldehydes Followed by Intramolecular Coupling
The high-yielding insertion of o-iodobenzaldehyde (2e)
into the zirconacyclopentene 1a (70%, Table 1, entry 8)
prompted us to investigate an intramolecular cyclization
based on the transmetallation of the sp2 C–Zr bond with
CuCl followed by subsequent reaction of the organocopper
compound formed with the aryl iodide moiety in accord-
ance with the previously successfully applied methodol-
Figure 2. View of (S*,S*)-4fe with the atomic numbering scheme.
The displacement ellipsoids are drawn at the 30% probability level.
Only the position of the iodine atom with 95% occupation is dis-
played.
The result of the insertion of o-iodobenzaldehyde (2e) ogy.[3,4] The insertion of 2e into 1a was followed by the ad-
into zirconacyclopentene 1a prompted us to attempt inser- dition of CuCl (1 equiv.) and 1,3-dimethyl-3,4,5,6-tetra-
tions into bicyclic zirconacyclopentenes 1 possessing other hydro-2-pyrimidinone (DMPU; 2 equiv.) and the mixture
structural features to assess the scope of the reaction was allowed to react at 50 °C for 12 h (Scheme 4). After
(Table 2). The reaction of 1a (entry 1) is also included for acidic work-up, which showed almost full conversion of the
comparison with the reactions of the zirconacyclopentenes starting material, the desired compound 5a was isolated in
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Reaction of Bicyclic Zirconacyclopentenes with Aldehydes
a rather low yield of 11% along with a number of other coupling reactions with aryl halides in zirconocene-based
products, such as 6 (the product of hydrolysis of the par- procedures. The use of a higher amount of CuCl and L1
ental zirconacyclopentene 1a), the products of oxidation of (entry 8) had only a marginal effect on the yield, with the
the sp2 (ketone 7) and sp3 C atoms (alcohol 8; it is clear desired compound 5a being isolated in 46% yield. However,
that these compounds must be formed by the oxidation of this was the best result obtained so far. Finally, bipyridine
the corresponding C–metal bonds, but the origin of the oxi- (L2) was used as an additive in the presence of catalytic
dizing species is not clear at the moment), and, finally, the amounts of [(PPh3)4Pd] and CuCl (entry 9), or a stoichio-
product of oxidation of the intermediate 3ae (ketone 9ae). metric amount of CuCl (entry 10) to provide 5a in yields of
Interestingly, the presence of unreacted alcohol 4ae, the 41 and 48%, respectively. These results, that is, the inability
product of hydrolysis of oxazirconacycloheptene 3ae, was to improve the yield of 5a as well as the isolation of various
not detected.
side-products in the initial experiment, indicated that per-
haps the conversion of 3ae into 5a might be hampered by
a hitherto unreported side-reaction. The reaction condi-
tions of CuCl (1.1 equiv.), JohnPhos (1.25 equiv.), and
[(PPh3)4Pd] (5 mol-%) were also used for the cyclization of
the insertion product 3fe, which resulted in the formation
of the tricyclic compound 5e (Figure 3) in an isolated yield
of 32%. As far as the formation of tetrahydrofuran deriva-
tives observed by others[14] is concerned, we did not detect
any such product.
Table 3. Intramolecular reaction of 3ae to yield 5a under various
conditions.
Entry Catalyst[a]
MXn
(amount
[equiv.])
DMPU Ligand[b] Yield
[equiv.] (amount [%][c]
[equiv.])
1
2
3
–
–
–
–
CuCl (1)
CuCl (1)
CuCl (2)
CuOtBu (1.5)
2
3
2.5
19 (31)
10 (27)
10 (30)
(44)
Scheme 4. Products formed in the reaction of oxazirconacyclo-
hepetene 3ae with CuCl.
4
5
6
[(PPh3)4Pd] CuCl (1)
PEPPSI ZnBr2 (1)
(30)
(30)
3
Because of this unsatisfactory and slightly puzzling result
regarding the products formed, we decided to screen vari-
ous reaction conditions to improve the yield of the desired
tricyclic compound 5a and to elucidate the course of the
reaction. The reaction was performed again under the same
reaction conditions and the subsequent analysis of the reac-
tion mixture revealed that the desired compound 5a was
formed in 31% yield (Table 3, entry 1). (Fortunately, com-
pound 5a has the distinct multiplet in the region δ = 4.96–
4.94 ppm that was not overlapped by other signals, which
allowed us to monitor its presence in reaction mixtures.)
The discrepancy in isolated yields between this result and
the one above can be attributed to problems encountered
during isolation. Increasing the amount of DMPU to
3 equiv. (entry 2) or the amount of CuCl (entry 3) did not
have any effect on the overall yield of 5a, with yields of 27
and 30%, respectively, obtained. However, a considerable
improvement in yield (44%) was seen with Cu(tBuO) as the
transmetallating agent (entry 4). The use of catalytic
amounts of [(PPh3)4Pd] in the absence of DMPU or a com-
7
8
9
10
[(PPh3)4Pd] CuCl (0.2)
[(PPh3)4Pd] CuCl (1.5)
[(PPh3)4Pd] CuCl (0.2)
[(PPh3)4Pd] CuCl (1)
2.5
3
L1 (0.8)
L1 (4)
L2 (0.4)
L2 (2)
(40)
46[d]
(41)
32 (48)
[a] 5 mol-%. [b] L1 = JohnPhos, L2 = bipyridine. [c] 1H NMR yield.
The isolated yields are given in parentheses. [d] It was not possible
to determine the yield in the reaction mixture by 1H NMR analysis
because of overlap with other signals.
Figure 3. Structure of 5e.
Reaction of 3 with CuCl
Our attention was attracted by the presence of oxidation
bination of a Pd–N-heterocyclic carbene complex (PEPPSI) products in the reaction of 1a with o-iodobenzaldehyde
and zinc chloride (instead of CuCl) did not result in better (2e), namely ketone 9ae, because its origin was rather puz-
yields of 5a, which in both cases were around 30% (entries 5 zling. To elucidate its formation, oxazirconacycloheptenes
and 6). Interestingly, a combination of catalytic amounts of 3ab and 3ag, formed by the insertion of 2b and 2g into 1a,
[(PPh3)4Pd] and CuCl in the presence of DMPU and were heated with CuCl at 50 °C for 12 h followed by acidic
1
JohnPhos (L1) provided 5a in 40% yield, as shown by H work-up (Scheme 5). Along with the expected insertion
NMR analysis (entry 7). It is worth noting that this is the products 4ab and 4ag isolated in yields of 10 and 8% and
first example of the use of CuCl in a catalytic amount in 6 obtained in a yield of around 10%, the isolated ketones
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9ab and 9ag were also isolated both in yields of 15%. In mechanism in Scheme 7 to explain the formation of the
addition, the precipitation of metallic copper was observed major side-product (ketone 9) during the reaction of oxazir-
during the course of the reaction. The presence of the conacycloheptenes with CuCl.
ketones and metallic copper unequivocally indicated that
an internal redox process must occur.
Scheme 7. Proposed mechanism for the formation of ketone 9.
The first step is the transmetallation of the Zr–C and
Scheme 5. Reactions of oxazirconacycloheptenes 3ag and 3ab,
formed from 1a and 2g,b, with CuCl.
Zr–O bonds with CuCl giving rise to the corresponding bis-
organocopper compound. Then β-hydrogen elimination en-
sues from the copper alkoxide to form CuH, which in turn
reacts with the sp2 C–Cu bond giving rise to the reduced
product and metallic copper. Whether the last step proceeds
through an ionic pathway or is a radical process at this
point remains undecided.
To gain further insight into the course of the reaction,
the reaction of 1a with 2b was carried out again and
quenched with D2O (Scheme 6). Surprisingly, the incorpo-
ration of deuterium into the products was not observed and
only ketone 9ab was isolated in 11% yield. This indicated
that the hydrogen atom at the sp2 C must come from one
of the reactants. To prove this assumption the reaction with
deuteriated o-ClC6H4CDO (2b-d) was carried out. After
work-up, deuteriated ketone 9ab-d was isolated in 15%
yield with Ͼ99% deuterium incorporation.
Iodonolysis and Coupling
To circumvent this undesirable side-reaction, we decided
to explore a different approach to the formation of the
seven-membered ring. The plan was based on the formation
of a diiodide by iodination of the formed oxazircona-
cycloheptene (Scheme 8). Four zirconacycloheptenes, 3ab,
3ad, 3ae, and 3bd, were prepared and subjected to iodono-
lysis in the presence of a catalytic amount of CuCl,[26] the
corresponding dihalides 10a–10d being obtained in isolated
yields of 35, 41 (74% 1H NMR yield), 50, and 41%, respec-
tively.
Scheme 6. Reaction of 1a with o-chlorobenzaldehyde (2b) followed
by quenching with H+ or D+.
These results indicated that an intermediate copper(I)
compound formed by transmetallation with CuCl could be
assumed to be the only culprit capable of such reactions.
First, it has previously been reported that copper(I) alk-
oxides undergo β-hydrogen elimination to form ketones and
copper(I) hydride.[24] Secondly, copper(I) hydride has been
Scheme 8. Iodonolysis of oxazirconacyclopentenes 3.
Finally, 10c was subjected to a Pd-catalyzed homocou-
reported to react with organocopper compounds to provide pling reaction in the presence of indium (Scheme 9).[27] Ini-
reductive demetallation products and metallic copper.[25]
A
tially the reaction was performed by using Pd/C in the pres-
combination of the results obtained in this work and pub- ence of 0.5 or 1 equiv. of indium metal. The reaction pro-
lished reports has enabled us to propose the reaction vided the corresponding tricyclic compound 5a in a yield of
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Reaction of Bicyclic Zirconacyclopentenes with Aldehydes
CDCl3): δ = 4.68–4.66 (m, 1 H) ppm; the remaining signals are
overlapped by the signals of the major diastereoisomer. 13C NMR
(151 MHz, CDCl3): δ = 135.5, 128.4, 125.9 ppm; the remaining sig-
nals are overlapped by the signals of the major diastereoisomer. IR
42 or 38%, respectively. The use of a combination Pd(OAc)2
and JohnPhos in the presence of 1 equiv. of indium metal
yielded 5a in a similar yield of 41%.
(KBr): νmax = 3360, 3087, 3063, 3025, 2998, 2947, 2935, 2869, 1652,
˜
1506, 1494, 1449, 1048, 869, 806, 752, 704 cm–1. HRMS (TOF-
ESI): calcd. for C21H24ONa 315.17170 [M + Na]+; found
315.17194.
(1S*)-1-(2-Chlorophenyl)-2-[(1S*,2E)-2-(4-methylbenzylidene)-
cyclopentyl]ethanol (4ab): Column chromatography of the residue
on silica gel (4:1 hexanes/EtOAc) yielded 0.228 g (70%) of the title
compound as a yellow oil. Rf (4:1 hexanes/EtOAc) = 0.38. 1H
NMR (600 MHz, CDCl3): δ = 7.66–7.64 (m, 1 H), 7.33–7.30 (m, 2
H), 7.21 (dd, J = 7.2, 1.2 Hz, 1 H), 7.20–7.18 (m, 2 H), 7.12–7.10
(m, 2 H), 6.26–6.25 (m, 1 H), 5.27–5.24 (m, 1 H), 2.95–2.90 (m, 1
H), 2.70–2.65 (m, 1 H), 2.62–2.55 (m, 1 H), 2.32 (s, 3 H), 2.11–2.06
(m, 1 H), 2.04 (d, J = 3.6 Hz, 1 H), 2.01–1.97 (m, 1 H), 1.93–1.87
(m, 1 H), 1.77–1.66 (m, 2 H), 1.56–1.50 (m, 1 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 149.1, 142.6, 135.8, 135.4, 131.4, 129.4,
128.8, 128.3, 128.0, 127.2, 126.7, 120.6, 69.5, 43.1, 43.0, 31.6, 31.3,
Scheme 9. Intramolecular homocoupling of 10c to give 5a.
Conclusions
We have shown that the insertion of aldehydes into the
sp3 C–Zr bond proceeds with a high efficiency and dia-
stereoselectivity (in many cases Ͼ99%). In the case of the 24.9, 21.1 ppm. IR (KBr): ν
= 3404, 3066, 3016, 2950, 2872,
˜
max
1706, 1449, 1048, 1036, 755 cm–1. HRMS (TOF-ESI): calcd. for
insertion of o-iodobenzaldehyde (2e), the oxazirconacy-
cloheptene formed can undergo intramolecular coupling to
yield compounds possessing the tricyclic condensed 5–7–
6(aryl) ring system in moderate yields upon transmetalla-
tion of the remaining sp2 C–Zr bond. The reaction is ham-
pered by a side-reaction that produces ketones thereby di-
minishing the yields of the cyclized products. In this respect,
it was also shown that dihalogenated intermediates, ob-
tained by halogenolysis of the oxazirconacycloheptenes,
could also be converted into tricyclic compounds.
C21H23OClNa 349.13271 [M + Na]+; found 349.13296.
(1S*)-1-(4-Chlorophenyl)-2-[(1S*,2E)-2-(4-methylbenzylidene)-
cyclopentyl]ethanol (4ac): Column chromatography of the residue
on silica gel (4:1 hexanes/EtOAc) yielded 0.178 g (57%) of the title
compound as a yellow oil. Rf (4:1 hexanes/EtOAc) = 0.44. Major
diastereoisomer: 1H NMR (600 MHz, CDCl3): δ = 7.33–7.32 (m,
4 H), 7.20–7.19 (m, 2 H), 7.13–7.12 (m, 2 H), 6.26–6.25 (m, 1 H),
4.81–4.80 (m, 1 H), 2.83–2.78 (m, 1 H), 2.70–2.64 (m, 1 H), 2.60–
2.54 (m, 1 H), 2.33 (s, 3 H), 2.16–2.11 (m, 1 H), 2.07 (s, 1 H), 2.03–
2.0 (m, 1 H), 1.91–1.83 (m, 1 H), 1.70–1.61 (m, 2 H), 1.40–1.33 (m,
1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 148.9, 143.6, 135.6,
135.4, 133.0, 128.9, 128.6, 128.0, 127.1, 120.6, 72.4, 44.6, 42.9, 31.8,
31.4, 24.8, 21.1 ppm. Minor diastereoisomer: 1H NMR (600 MHz,
CDCl3): the signals were overlapped by the signals of the major
diastereoisomer. 13C NMR (151 MHz, CDCl3): δ = 148.4, 142.9,
133.2, 128.7, 128.0, 127.5, 121.0, 77.2, 76.8, 72.8, 43.9, 42.9, 32.2,
30.9 ppm; the remaining signals are overlapped by the signals of
Experimental Section
General Procedure for the Synthesis of Alcohols 4: nBuLi (1.6 m in
hexanes, 1.25 mL, 2.00 mmol) was added dropwise within 5 min
to a solution of bis(cyclopentadienyl)zirconium dichloride (0.292 g,
1.00 mmol) in dry THF (5 mL) cooled to –78 °C and the reaction
mixture was stirred for 1 h at the same temperature. An enyne
(1.00 mmol) was added and the reaction mixture was gradually
warmed to 25 °C. After 3 h freshly distilled aldehyde (1.00 mmol)
was added at 0 °C and the reaction mixture was stirred for 12 h.
After warming to 25 °C, it was quenched with 1 n HCl (10 mL)
and extracted with EtOAc (3ϫ 20 mL). The combined organic
phases were washed with a saturated solution of NaHCO3 (20 mL),
water (2ϫ 20 mL), and brine (20 mL), dried with MgSO4, and the
solution was filtered and concentrated under reduced pressure. Pu-
rification of the residue by column chromatography provided the
corresponding alcohol 4.
the major diastereoisomer. IR (KBr): ν
= 3363, 3019, 2947,
˜
max
2866, 1649, 1509, 1491, 1093, 1057, 1018, 872, 830 cm–1. HRMS
(CI-TOF): calcd. for 326.1437 [M + H]+; found 326.1436.
(1S*)-1-(2-Bromophenyl)-2-[(1S*,2E)-2-(4-methylbenzylidene)-
cyclopentyl]ethanol (4ad): Column chromatography of the residue
on silica gel (5:1 hexanes/Et2O) yielded 0.195 g (52%) of the title
1
compound as a yellow oil. Rf (5:1 hexanes/Et2O) = 0.17. H NMR
(600 MHz, CDCl3): δ = 7.65 (dd, J = 7.8, 1.8 Hz, 1 H), 7.51 (dd,
J = 8.4, 1.2 Hz, 1 H), 7.36 (td, J = 7.8, 1.2 Hz, 1 H), 7.20–7.19 (m,
2 H), 7.15–7.10 (m, 3 H), 6.28–6.27 (m, 1 H), 5.21–5.19 (m, 1 H),
2.96–2.92 (m, 1 H), 2.70–2.64 (m, 1 H), 2.62–2.60 (m, 1 H), 2.32
(s, 3 H), 2.10–2.06 (m, 2 H), 2.00–1.94 (m, 1 H), 1.93–1.90 (m, 1
H), 1.80–1.74 (m, 1 H), 1.73–1.67 (m, 1 H), 1.60–1.54 (m, 1
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 149.2, 144.2, 135.9,
135.4, 132.7, 128.9, 128.7, 128.0, 127.8, 127.1, 121.6, 120.7, 71.8,
(1S*)-2-[(1S*,2E)-2-(4-Methylbenzylidene)cyclopentyl]-1-phenyl-
ethanol (4aa): Column chromatography of the residue on silica gel
(4:1 hexanes/EtOAc) yielded 0.116 g (40%) of the title compound
as a yellow oil. Rf (4:1 hexanes/EtOAc) = 0.42. Major diastereoiso-
43.3, 43.2, 31.5, 31.3, 24.9, 21.1 ppm. IR (KBr): νmax = 3395, 3063,
˜
1
mer: H NMR (600 MHz, CDCl3): δ = 7.41–7.35 (m, 4 H), 7.30–
3022, 2953, 2869, 1706, 1512, 1464, 1437, 1024, 752 cm–1. HRMS
(CI-TOF): calcd. for C21H23OBr 370.0932 [M + H]+; found
370.0919.
7.27 (m, 1 H), 7.20–7.19 (m, 2 H), 7.12–7.10 (m, 2 H), 6.28–6.27
(m, 1 H), 4.86–4.82 (m, 1 H), 2.86–2.80 (m, 1 H), 2.69–2.64 (m, 1
H), 2.60–2.54 (m, 1 H), 2.33 (s, 3 H), 2.20–2.16 (m, 1 H), 2.04–2.00
(m, 1 H), 1.90–1.85 (m, 2 H), 1.71–1.65 (m, 2 H), 1.41–1.36 (m, 1
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 149.1, 145.3, 135.9,
135.4, 128.9, 128.5, 128.1, 127.5, 125.8, 120.6, 73.2, 44.7, 43.0, 31.9,
(1S*)-1-(2-Iodophenyl)-2-[(1S*,2E)-2-(4-methylbenzylidene)cyclo-
pentyl]ethanol (4ae): Column chromatography of the residue on sil-
ica gel (4:1 hexanes/EtOAc) yielded 0.292 g (70%) of the title com-
31.4, 24.8, 21.1 ppm. Minor diastereoisomer: 1H NMR (600 MHz, pound as a yellow oil. Rf (4:1 hexanes/EtOAc) = 0.38. 1H NMR
Eur. J. Org. Chem. 2015, 2868–2878
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2873

N. Topolovcˇan, I. Panov, M. Kotora
FULL PAPER
(600 MHz, CDCl3): δ = 7.80 (dd, J = 7.8, 1.2 Hz, 1 H), 7.61 (dd,
J = 7.8, 1.8 Hz, 1 H), 7.40 (td, J = 7.2, 0.6 Hz, 1 H), 7.20–7.18 (m,
1H NMR (600 MHz, CDCl3): δ = 7.40 (dd, J = 1.8, 1.2 Hz, 1 H),
7.22–7.20 (m, 2 H), 7.14–7.12 (m, 2 H), 6.35–6.34 (m, 1 H), 6.30–
2 H), 7.11–7.10 (m, 2 H), 6.97 (td, J = 7.8, 1.8 Hz, 1 H), 6.27–6.26 6.28 (m, 2 H), 4.86–4.82 (m, 1 H), 2.83–2.78 (m, 1 H), 2.68–2.63
(m, 1 H), 5.03–5.00 (m, 1 H), 2.98–2.92 (m, 1 H), 2.70–2.64 (m, 1
H), 2.62–2.56 (m, 1 H), 2.32 (s, 3 H), 2.11–2.06 (m, 1 H), 2.05 (dd,
J = 3.6, 1.2 Hz, 1 H), 1.94–1.89 (m, 2 H), 1.76–1.69 (m, 2 H), 1.67–
(m, 1 H), 2.61–2.52 (m, 1 H), 2.33 (s, 3 H), 2.28–2.34 (m, 1 H),
1.98–1.81 (m, 4 H), 1.70–1.60 (m, 1 H), 1.37–1.31 (m, 1 H) ppm.
13C NMR (151 MHz, CDCl3): δ = 157.1, 148.9, 141.9, 135.8, 135.5,
1.60 (m, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 149.1, 146.9, 128.9, 128.1, 120.8, 110.2, 105.7, 66.5, 42.6, 40.7, 31.6, 31.3, 24.8,
1
139.3, 135.9, 135.4, 129.1, 128.9, 128.7, 128.1, 126.9, 120.7, 97.2,
76.4, 43.4, 43.2, 31.5, 31.4, 24.9, 21.1 ppm. IR (KBr): ν = 3398,
21.1 ppm. Minor diastereoisomer: H NMR (600 MHz, CDCl3): δ
= 6.31–6.30 (m, 1 H) ppm; the remaining signals are overlapped
by the signals of the major diastereoisomer. 13C NMR (151 MHz,
CDCl3): δ = 156.6, 148.4, 142.1, 135.7, 135.5, 128.1, 121.1, 110.2,
106.2, 66.7, 42.9, 40.6, 32.2, 30.9. ppm; the remaining signals are
overlapped by the signals of the major diastereoisomer. IR (KBr):
˜
max
3049, 3016, 2947, 2866, 1700, 1509, 1461, 1434, 1195, 1057, 1009,
869, 809, 755 cm–1. HRMS (TOF-ESI): calcd. for C21H23OINa
441.06851 [M + Na]+; found 441.0685.
(1S*)-1-(2-Methoxyphenyl)-2-[(1S*,2E)-2-(4-methylbenzylidene)-
cyclopentyl]ethanol (4af): Column chromatography of the residue
on silica gel (4:1 hexanes/EtOAc) yielded 0.171 g (53%) of the title
compound as a yellow oil. Rf (4:1 hexanes/EtOAc) = 0.27. 1H
NMR (600 MHz, CDCl3): δ = 7.35 (dd, J = 7.8, 1.8 Hz, 1 H), 7.26
(td, J = 8.4, 1.8 Hz, 1 H), 7.20–7.19 (m, 2 H), 7.12–7.11 (m, 2 H),
6.98 (td, J = 7.2, 0.6 Hz, 1 H), 6.89 (dd, J = 8.4, 0.6 Hz, 1 H),
6.27–6.26 (m, 1 H), 5.03–5.00 (m, 1 H), 3.86 (s, 3 H), 2.91–2.86 (m,
1 H), 2.70–2.64 (m, 1 H), 2.60–2.54 (m, 2 H), 2.32 (s, 3 H), 2.22–
2.17 (m, 1 H), 2.08–2.03 (m, 1 H), 1.90–1.84 (m, 1 H), 1.72–1.63
(m, 2 H), 1.43–1.37 (m, 1 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 156.3, 149.6, 135.9, 135.2, 132.9, 128.8, 128.2, 128.0, 126.5,
120.7, 120.3, 110.4, 69.5, 55.2, 43.0, 42.5, 32.6, 31.6, 24.8,
ν
= 3333, 3159, 3147, 3120, 3093, 3019, 2947, 2866, 1509, 1449,
˜
max
1431, 1156, 1066, 1045, 1009, 881, 869, 812, 734 cm–1. HRMS
(TOF-MS-CI): calcd. for C19H22O2 282.1620 [M + H]+; found
282.1612.
(1S*)-2-[(1S*,2E)-2-(4-Methylbenzylidene)cyclopentyl]-1-(2-thi-
enyl)ethanol (4aj): Column chromatography of the residue on silica
gel (5:1 hexanes/Et2O) yielded 0.220 g (74%) of the title compound
as a yellow oil. Rf (5:1 hexanes/Et2O) = 0.20. 1H NMR (600 MHz,
CDCl3): δ = 7.27–7.26 (m, 1 H), 7.22–7.20 (m, 2 H), 7.14–7.12 (m,
2 H), 7.03–7.02 (m, 1 H), 7.00–6.98 (dd, J = 5.4, 3.6 Hz, 1 H),
6.30–6.29 (m, 1 H), 5.10–5.07 (m, 1 H), 2.86–2.81 (m, 1 H), 2.68–
2.63 (m, 1 H), 2.61–2.55 (m, 1 H), 2.33 (s, 3 H), 2.30–2.25 (m, 1
H), 2.02–1.97 (m, 2 H), 1.91–1.81 (m, 2 H), 1.71–1.64 (m, 1 H),
1.41–1.35 (m, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 149.2,
148.8, 135.8, 135.5, 128.9, 128.0, 126.7, 124.5, 123.6, 120.8, 68.9,
21.1 ppm. IR (KBr): ν
= 3563, 3404, 3019, 2995, 2944, 2860,
˜
max
2833, 1598, 1586, 1509, 1494, 1464, 1437, 1287, 1236, 1051, 1030,
869, 809, 752 cm–1. HRMS (TOF-ESI): calcd. for C22H26O2Na
345.18261 [M + Na]+; found 345.18250.
44.7, 42.9, 31.7, 31.3, 24.8, 21.1 ppm. IR (KBr): νmax = 3386, 3081,
˜
3066, 3046, 3022, 2995, 2947, 2869, 1506, 1036, 701 cm–1. HRMS
(TOF-ESI): calcd. for C19H22ONaS 321.12833 [M + Na]+; found
321.12836.
(1S*)-1-(4-Methoxyphenyl)-2-[(1S*,2E)-2-(4-methylbenzylidene)-
cyclopentyl]ethanol (4ag): Column chromatography of the residue
on silica gel (4:1 hexanes/EtOAc) yielded 0.103 g (32%) of the title
compound as a yellow oil. Rf (4:1 hexanes/EtOAc) = 0.24. 1H
NMR (600 MHz, CDCl3): δ = 7.34–7.32 (m, 2 H), 7.20–7.19 (m, 2
H), 7.13–7.11 (m, 2 H), 6.91–6.90 (m, 2 H), 6.28–6.27 (m, 1 H),
4.80–4.78 (m, 1 H), 3.81 (s, 3 H), 2.82–2.77 (m, 1 H), 2.68–2.62 (m,
1 H), 2.60–2.53 (m, 1 H), 2.32 (s, 3 H), 2.20–2.16 (m, 1 H), 2.00–
1.96 (m, 1 H), 1.90–1.84 (m, 1 H), 1.83–1.80 (m, 1 H), 1.69–1.64
(m, 2 H), 1.40–1.33 (m, 1 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 159.1, 149.2, 137.4, 135.9, 135.4, 128.9, 128.1, 127.1, 120.6,
113.9, 72.7, 55.3, 44.5, 43.1, 31.9, 31.3, 24.8, 21.1 ppm. IR (KBr):
(2S*,3E)-1-[(1S*,2E)-2-(4-Methylbenzylidene)cyclopentyl]-4-
phenylbut-3-en-2-ol (4ak): Column chromatography of the residue
on silica gel (5:1 hexanes/Et2O) yielded 0.098 g (31%) of the title
compound as a yellow oil. Rf (5:1 hexanes/Et2O) = 0.16. Major
diastereoisomer: 1H NMR (600 MHz, CDCl3): δ = 7.41–7.40 (m,
2 H), 7.34–7.31 (m, 2 H), 7.25–7.23 (m, 1 H), 7.22–7.20 (m, 2 H),
7.13–7.12 (m, 2 H), 6.63 (d, J = 15.6 Hz, 1 H), 6.32–6.25 (m, 2 H),
4.47–4.42 (m, 1 H), 2.84–2.79 (m, 1 H), 2.69–2.63 (m, 1 H), 2.60–
2.54 (m, 1 H), 2.33 (s, 3 H), 2.06–1.95 (m, 2 H), 1.91–1.85 (m, 1 H),
1.70–1.60 (m, 3 H), 1.42–1.36 (m, 1 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 149.2, 136.7, 135.8, 135.4, 132.9, 130.0, 128.9, 128.6,
128.1, 127.7, 126.5, 120.7, 71.6, 42.7, 42.6, 32.0, 31.4 24.8,
ν
= 3354, 3019, 2995, 2947, 2935, 2863, 2836, 1610, 1509, 1245,
˜
max
1174, 1039, 839 cm–1. HRMS (TOF-ESI): calcd. for C22H26O2Na
345.18283 [M + Na]+; found 345.18250.
1
21.1 ppm. Minor diastereoisomer: H NMR (600 MHz, CDCl3): δ
(1S*)-2-[(1S*,2E)-2-(4-Methylbenzylidene)cyclopentyl]-1-(p-tolyl)-
ethanol (4ah): Column chromatography of the residue on silica gel
(5:1 hexanes/Et2O) yielded 0.189 g (62%) of the title compound as
a yellow solid. Rf (5:1 hexanes/Et2O) = 0.24, m.p. 75.8–78.9 °C. 1H
NMR (600 MHz, CDCl3): δ = 7.30–7.29 (m, 2 H), 7.20–7.17 (m, 4
H), 7.12–7.11 (m, 2 H), 6.28–6.26 (m, 1 H), 4.81–4.79 (m, 1 H),
2.84–2.79 (m, 1 H), 2.68–2.63 (m, 1 H), 2.60–2.53 (m, 1 H), 2.36
(s, 3 H), 2.33 (s, 3 H), 2.20–2.16 (m, 1 H), 2.04–1.98 (m, 1 H), 1.91–
1.84 (m, 1 H), 1.82 (d, J = 6.0 Hz, 1 H), 1.70–1.63 (m, 2 H), 1.40–
1.34 (m, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 149.2, 142.3,
137.2, 135.9, 135.4, 129.2, 128.9, 128.1, 125.7, 120.6, 73.0, 44.5,
= 6.61 (d, J = 15.6 Hz, 1 H) ppm; the remaining signals are over-
lapped by the signals of the major diastereoisomer. 13C NMR
(151 MHz, CDCl3): δ = 148.8, 132.3, 130.8, 128.1, 127.7, 126.5,
121.0, 72.1, 42.9, 42.3, 32.3, 31.0, 24.9. ppm; the remaining signals
are overlapped by the signals of the major diastereoisomer. IR
(KBr): νmax = 3348, 3078, 3022, 2947, 2863, 1652, 1509, 1494, 1446,
˜
1069, 1048, 967, 872, 806, 749, 682 cm–1. HRMS (CI-TOF): calcd.
for C23H27O 319.2062 [M + H]+; found 319.2054.
(2S*,3E)-1-[(1S*,2E)-2-(4-Methylbenzylidene)cyclopentyl]non-3-
en-2-ol (4al): Column chromatography of the residue on silica gel
(5:1 hexanes/Et2O) yielded 0.193 g (62%) of the title compound as
a yellow oil. Rf (5:1 hexanes/Et2O) = 0.20. 1H NMR (600 MHz,
CDCl3): δ = 7.20–7.19 (m, 2 H), 7.13–7.11 (m, 2 H), 6.26–6.25 (m,
43.0, 31.9, 31.4, 24.8, 21.1, 21.0 ppm. IR (KBr): νmax = 3357, 3019,
˜
2944, 2866, 1512, 1446, 1051, 809 cm–1. HRMS (CI-TOF): calcd.
for C22H26O 306.1984 [M + H]+; found 306.1975.
(1S*)-1-(2-Furyl)-2-[(1S*,2E)-2-(4-methylbenzylidene)cyclopentyl]- 1 H), 5.72–5.67 (m, 1 H), 5.56–5.52 (m, 1 H), 4.23–4.19 (m, 1 H),
ethanol (4ai): Column chromatography of the residue on silica gel
(5:1 hexanes/Et2O) yielded 0.169 g (60%) of the title compound as
a yellow oil. Rf (5:1 hexanes/Et2O) = 0.26. Major diastereoisomer:
2.77–2.72 (m, 1 H), 2.67–2.62 (m, 1 H), 2.60–2.53 (m, 1 H), 2.33
(s, 3 H), 2.04 (q, J = 7.4 Hz, 2 H), 2.00–1.95 (m, 1 H), 1.94–1.90
(m, 1 H), 1.88–1.83 (m, 1 H), 1.69–1.61 (m, 1 H), 1.51–1.47 (m, 2
2874
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© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2868–2878

Reaction of Bicyclic Zirconacyclopentenes with Aldehydes
H), 1.41–1.36 (m, 2 H), 1.34–1.26 (m, 5 H), 0.89 (t, J = 6.6 Hz, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 149.4, 135.9, 135.3,
133.4, 132.0, 128.9, 128.0, 120.5, 71.6, 42.7, 42.7, 32.2, 32.0, 31.4,
(50:1–5:1 hexanes/Et2O) yielded 0.250 g (63 %) of the title com-
pound as a yellow oil. Rf (5:1 hexanes/Et2O) = 0.35. Major dia-
1
stereoisomer: H NMR (600 MHz, CDCl3): δ = 7.80 (dd, J = 7.8,
31.3, 28.9, 24.8, 22.5, 21.1, 14.0 ppm. IR (KBr): νmax = 3354, 3084, 1.2 Hz, 1 H), 7.54 (dd, J = 7.8, 1.2 Hz, 1 H), 7.37 (td, J = 7.2,
˜
3019, 2956, 2923, 2866, 2857, 1512, 1470, 1455, 973, 869, 812 cm–1. 0.6 Hz, 1 H), 6.95 (td, J = 7.8, 1.8 Hz, 1 H), 5.25 (t, J = 7.2 Hz, 1
HRMS (TOF-MS-CI): calcd. for C22H32O 312.2453 [M + H]+;
found 312.2458.
H), 4.94 (td, J = 9.6, 3.0 Hz, 1 H), 2.48–2.44 (m, 1 H), 2.37 (d, J
= 2.4 Hz, 1 H), 2.25–2.16 (m, 2 H), 2.04–2.01 (m, 2 H), 1.85–1.74
(m, 3 H), 1.71–1.67 (m, 1 H), 1.65–1.60 (m, 1 H), 1.59–1.50 (m, 2
H), 1.46–1.39 (m, 1 H), 1.33–1.30 (m, 4 H), 0.91–0.98 (m, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 146.8, 142.9, 139.2,
128.9, 128.6, 126.9, 122.0, 97.4, 76.9, 42.6, 40.9, 33.4, 32.3, 28.1,
(1S*)-1-Cyclohexyl-2-[(1S*,2E)-2-(4-methylbenzylidene)cyclo-
pentyl]ethanol (4am): Column chromatography of the residue on
silica gel (5:1 hexanes/Et2O) yielded 0.184 g (62%) of the title com-
pound as a colorless solid, m.p. 62.5–64.0 °C. Rf (5:1 hexanes/Et2O)
1
1
26.8, 26.4, 23.4, 22.4, 14.0 ppm. Minor diastereoisomer: H NMR
= 0.21. Major diastereoisomer: H NMR (600 MHz, CDCl3): δ =
(600 MHz, CDCl3): δ = 5.30 (t, J = 7.2 Hz, 1 H), 4.84 (td, J =
10.2, 3.0 Hz, 1 H), 2.56–2.52 (m, 1 H) ppm; the remaining signals
are overlapped by the signals of the major diastereoisomer. 13C
NMR (151 MHz, CDCl3): δ = 140.3, 127.2, 123.2, 41.0, 40.3, 34.2,
32.5, 28.0, 25.7, 22.6, 22.4, 14.0 ppm; the remaining signals are
overlapped by the signals of the major diastereoisomer. IR (KBr):
7.21–7.20 (m, 2 H), 7.13–7.12 (m, 2 H), 6.27–6.26 (m, 1 H), 3.50–
3.47 (m, 1 H), 2.81–2.76 (m, 1 H), 2.70–2.63 (m, 1 H), 2.60–2.54
(m, 1 H), 2.33 (s, 3 H), 2.00–1.96 (m, 1 H), 1.88–1.83 (m, 2 H),
1.80–1.76 (m, 3 H), 1.73–1.61 (m, 3 H), 1.50–1.46 (m, 1 H), 1.45–
1.40 (m, 1 H), 1.38–1.33 (m, 1 H), 1.30–1.21 (m, 3 H), 1.20–1.11
(m, 1 H), 1.10–1.01 (m, 2 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 149.8, 135.9, 135.3, 128.9, 128.0, 120.3, 74.6, 44.5, 42.8, 39.7,
31.7, 31.6, 29.1, 28.1, 26.6, 26.3, 26.2, 24.8, 21.1 ppm. Minor dia-
stereoisomer: 1H NMR (600 MHz, CDCl3): δ = 6.30–6.29 (m, 1
H), 3.60–3.58 (m, 1 H) ppm; the remaining signals are overlapped
by the signals of the major diastereoisomer. 13C NMR (151 MHz,
CDCl3): δ = 149.2, 135.8, 135.4, 128.1, 120.9, 74.8, 43.7, 43.6, 39.1,
32.6, 30.7, 29.5, 27.0, 26.5, 26.3, 24.7 ppm; the remaining signals
are overlapped by the signals of the major diastereoisomer. IR
ν
= 3398, 3055, 2953, 2923, 2851, 1458, 1431, 1057, 1003,
˜
max
758 cm–1. HRMS (CI-TOF): calcd. for C19H26OI 397.1028 [M +
H]+; found 397.1032.
(1S*)-2-[(4S*,3Z)-N-Benzyl-3-(4-methylbenzylidene)pyrrolidin-4-
yl]-1-(2-iodophenyl)ethanol (4ee): Column chromatography of the
residue on silica gel (2:1 hexanes/Et2O) yielded 0.162 g (32%) of
the title compound as a yellow oil. Rf (5:1 hexanes/Et2O) = 0.13.
1H NMR (600 MHz, CDCl3): δ = 7.74 (dd, J = 7.8, 1.2 Hz, 1 H),
7.65 (dd, J = 7.8, 1.8 Hz, 1 H), 7.37–7.34 (m, 5 H), 7.30–7.28 (m,
1 H), 7.13–7.10 (m, 4 H), 6.92 (td, J = 7.2, 1.2 Hz, 1 H), 6.55–6.54
(m, 1 H), 4.90 (dd, J = 10.8, 1.2 Hz, 1 H), 4.04 (d, J = 15.0 Hz, 1
H), 3.96 (d, J = 13.2 Hz, 1 H), 3.64 (d, J = 12.6 Hz, 1 H), 3.15 (d,
J = 9.6 Hz, 1 H), 2.68–2.65 (m, 1 H), 2.32 (s, 3 H), 2.20–2.16 (m,
1 H), 1.65–1.60 (m, 2 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
147.4, 140.4, 138.9, 137.3, 136.3, 134.5, 129.1, 128.8, 128.7, 128.6,
128.4, 128.0, 127.5, 127.4, 123.8, 97.2, 73.7, 60.4, 59.7, 58.0, 44.0,
(KBr): νmax = 3431, 3386, 3087, 3052, 3025, 2998, 2920, 2851, 1512,
˜
1440, 1425, 1404, 1042, 982, 875, 809 cm–1. HRMS (TOF-MS-CI):
calcd. for C21H30O 298.2297 [M + H]+; found 298.2292.
(1S*)-1-(2-Iodophenyl)-2-[(1S*,2E)-2-pentylidenecyclopentyl]ethanol
(4be): Column chromatography of the residue on silica gel (5:1 hex-
anes/Et2O) yielded 0.200 g (52%) of the title compound as a yellow
1
oil. Rf (5:1 hexanes/Et2O) = 0.32. H NMR (600 MHz, CDCl3): δ
= 7.78 (dd, J = 7.8, 1.2 Hz, 1 H), 7.57 (dd, J = 7.8, 1.8 Hz, 1 H),
7.39–7.36 (m, 1 H), 6.95 (td, J = 7.2, 1.8 Hz, 1 H), 5.21–5.18 (m,
1 H), 4.96 (dd, J = 10.2, 1.8 Hz, 1 H), 2.72–2.67 (m, 1 H), 2.34–
2.29 (m, 1 H), 2.26–2.20 (m, 1 H), 2.09 (br. s, 1 H), 2.05–2.00 (m,
1 H), 1.98–1.94 (m, 2 H), 1.80–1.75 (m, 2 H), 1.64–1.48 (m, 3 H),
1.31–1.28 (m, 4 H), 0.90–0.87 (m, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 147.0, 146.3, 139.3, 129.0, 128.6, 126.8, 120.4, 97.2,
76.5, 43.2, 41.3, 32.4, 31.9, 29.1, 29.0, 24.1, 22.4, 14.0 ppm. IR
42.6, 21.2 ppm. IR (KBr): ν
= 3156, 3087, 3058, 3022, 2917,
˜
max
2803, 1509, 1455, 1434, 1120, 1075, 1027, 1012, 896, 806, 752,
689 cm–1. HRMS (TOF-ESI): calcd. for C27H29ONI 510.12873 [M
+ H]+; found 510.12883.
(1S*)-2-[(4S*,3Z)-N-Benzyl-3-(4-methylbenzylidene)pyrrolidin-4-
yl]-1-(2-bromophenyl)ethanol (4ed): Column chromatography of the
residue on silica gel (2:1 hexanes/Et2O) yielded 0.253 g (55%) of
the title compound as a yellow solid, m.p. 49.3–50.1 °C. Rf (2:1
(KBr): νmax = 3357, 3058, 2953, 2869, 2854, 1461, 1434, 1060, 1012,
˜
752 cm–1. HRMS (CI-TOF): calcd. for C18H25OI 384.0950 [M +
H]+; found 384.0940.
1
hexanes/Et2O) = 0.39. H NMR (600 MHz, CDCl3): δ = 7.70 (dd,
J = 7.2, 1.2 Hz, 1 H), 7.45 (dd, J = 7.8, 1.2 Hz, 1 H), 7.38–7.28
(m, 7 H), 7.14–7.12 (m, 2 H), 7.10–7.08 (m, 2 H), 7.07 (dd, J = 7.8,
1.8 Hz, 1 H), 6.48–6.47 (m, 1 H), 5.09 (d, J = 10.2 Hz, 1 H), 4.02
(d, J = 14.4 Hz, 1 H), 3.94 (d, J = 12.6 Hz, 1 H), 3.66 (d, J =
12.6 Hz, 1 H), 3.22–3.18 (m, 2 H), 3.13 (d, J = 9.6 Hz, 1 H), 2.67
(t, J = 7.2 Hz, 1 H), 2.33 (s, 3 H), 2.24–2.20 (m, 1 H), 1.69–1.65
(m, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 144.7, 140.8,
137.4, 136.3, 134.7, 132.3, 129.2, 128.8, 128.7, 128.2, 127.9, 127.6,
127.5, 123.5, 121.5, 69.2, 60.5, 59.8, 58.1, 43.9, 42.6, 21.1 ppm. IR
(1S*)-2-{(1S*,2E)-2-[3-(tert-Butyldimethylsilyloxy)propylidene]-
cyclopentyl}-1-(2-iodophenyl)ethanol (4ce): Column chromatog-
raphy of the residue on silica gel (10:1 hexanes/Et2O) yielded
0.257 g (53%) of the title compound as a yellow oil. Rf (5:1 hex-
1
anes/Et2O) = 0.24. H NMR (600 MHz, CDCl3): δ = 7.78 (dd, J =
7.8, 1.2 Hz, 1 H), 7.56 (dd, J = 7.8, 1.8 Hz, 1 H), 7.37 (t, J =
7.2 Hz, 1 H), 6.95 (td, J = 7.8, 1.8 Hz, 1 H), 5.20–5.18 (m, 1 H),
4.97–4.94 (m, 1 H), 3.58 (t, J = 6.6 Hz, 2 H), 2.71–2.70 (m, 1 H),
2.36–2.32 (m, 1 H), 2.30–2.25 (m, 1 H), 2.21 (q, J = 7.8 Hz, 2 H),
2.09 (d, J = 3.6 Hz, 1 H), 2.05–2.00 (m, 1 H), 1.84–1.75 (m, 2 H),
1.64–1.58 (m, 2 H), 1.54–1.50 (m, 1 H), 0.87 (s, 9 H), 0.03 (s, 6
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 148.7, 147.0, 139.3,
129.0, 128.6, 126.8, 116.0, 97.2, 76.4, 63.0, 43.2, 41.5, 33.3, 32.3,
(KBr): νmax = 3055, 3025, 3004, 2977, 2950, 2908, 2872, 2854, 2812,
˜
2744, 1512, 1464, 1440, 1374, 1362, 1347, 1260, 1099, 800, 752,
707, 513 cm–1. HRMS (FTMS-ESI): calcd. for C27H29ONBr
462.14274 [M + H]+; found 462.14270.
29.1, 26.0, 24.0, 18.4, –5.2 ppm. IR (KBr): νmax = 3416, 2953, 2932,
˜
(1S*)-2-[(4S*,3Z)-N-Benzyl-3-(benzylidene)pyrrolidin-4-yl]-1-(2-
iodophenyl)ethanol (4fe): Column chromatography of the residue on
silica gel (2:1 hexanes/EtOAc) yielded 0.282 g (57%) of the title
compound as a yellow solid, m.p. 55.7–57.0 °C. Rf (2:1 hexanes/
Et2O) = 0.40. H NMR (600 MHz, CDCl3): δ = 7.75 (dd, J = 7.8,
1.2 Hz, 1 H), 7.65 (dd, J = 7.8, 1.2 Hz, 1 H), 7.38–7.28 (m, 8 H),
2896, 2860, 2881, 1461, 1257, 1096, 1012, 836, 779, 752 cm–1
.
HRMS (TOF-ESI): calcd. for C22H35O2INaSi 509.13427 [M +
Na]+; found 509.13432.
1
(1S*)-1-(2-Iodophenyl)-2-[(1S*,2E)-2-(pentylidene)cyclohexyl]-
ethanol (4de): Column chromatography of the residue on silica gel
Eur. J. Org. Chem. 2015, 2868–2878
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2875

N. Topolovcˇan, I. Panov, M. Kotora
7.23–7.18 (m, 3 H), 6.20 (td, J = 7.8, 1.8 Hz, 1 H), 6.58 (s, 1 H), compound as a colorless solid, m.p. 111.6–112.4 °C. Rf (5:1 hex-
FULL PAPER
1
4.92–4.90 (m, 1 H), 4.05 (d, J = 15 Hz, 1 H), 3.94 (d, J = 12.6 Hz,
1 H), 3.68 (d, J = 12.6 Hz, 1 H), 3.24–3.19 (m, 2 H), 3.14 (d, J = 7.8, 1.2 Hz, 1 H), 7.65 (dd, J = 7.8, 1.8 Hz, 1 H), 7.40 (td, J = 7.8,
9.0 Hz, 1 H), 2.68 (t, J = 7.8 Hz, 1 H), 2.22–2.18 (m, 1 H), 1.67– 1.2 Hz, 1 H), 7.15–7.13 (m, 2 H), 7.10–7.08 (m, 2 H), 6.98 (td, J =
1.63 (m, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 147.5, 141.6, 7.2, 1.8 Hz, 1 H), 5.03–5.00 (m, 1 H), 3.20–3.16 (m, 1 H), 2.40–
139.0, 137.4, 137.3, 128.9, 128.7, 128.6, 128.5, 128.4, 128.1, 127.5, 2.34 (m, 1 H), 2.32 (s, 3 H), 2.30–2.24 (m, 1 H), 2.21 (d, J = 4.2 Hz,
127.4, 126.5, 124.0, 97.2, 73.8, 60.4, 59.7, 58.1, 44.0, 42.8 ppm. IR 1 H), 2.09–2.03 (m, 2 H), 2.00–1.94 (m, 1 H), 1.93–1.87 (m, 1 H),
(KBr): νmax = 3084, 3058, 3025, 2938, 2902, 2806, 1494, 1455, 1437,
1.84–1.78 (m, 1 H), 1.70 (td, J = 14.4, 2.4 Hz, 1 H) ppm. 13C NMR
anes/Et2O) = 0.20. H NMR (600 MHz, CDCl3): δ = 7.80 (dd, J =
˜
1117, 1078, 1015, 914, 755, 695 cm–1. HRMS (CI-TOF): calcd. for (151 MHz, CDCl3): δ = 154.5, 146.6, 141.6, 139.3, 137.3, 129.1,
C26H27NOI 496.1137 [M + H]+; found 496.1142.
128.8, 128.7, 128.5, 127.0, 96.9, 89.7, 76.1, 47.7, 41.0, 32.5, 29.9,
25.8, 21.2 ppm. IR (KBr): ν
= 3560, 3443, 3049, 3019, 2950,
˜
max
General Procedure for the Synthesis of Iodinated Alcohols 10: nBuLi
(1.6 m in hexanes, 1.25 mL, 2.00 mmol) was added dropwise within
5 min to a solution of bis(cyclopentadienyl)zirconium dichloride
(0.292 g, 1.00 mmol) in dry THF (5 mL) cooled to –78 °C and the
reaction mixture was stirred for 1 h at the same temperature. Enyne
(1.00 mmol) was added and the reaction mixture was gradually
warmed to 25 °C. After 3 h, freshly distilled aldehyde (1.00 mmol)
was added at 0 °C and the reaction mixture stirred for 12 h. CuCl
(0.018 g, 0.2 mmol) was then added followed by the addition of
solid iodine (0.190 g, 1.5 mmol). After stirring at 25 °C for 24 h the
reaction mixture was quenched with 1 n HCl (10 mL) and extracted
with Et2O (2ϫ 20 mL). The combined organic phases were washed
with a saturated solution of Na2SO3 (20 mL), water (20 mL), and
brine (30 mL), dried with MgSO4, and the solution was filtered
and concentrated under reduced pressure. Purification of residue
by column chromatography yielded the corresponding iodinated
alcohol.
2914, 2872, 2833, 1461, 1437, 1057, 1042, 1006, 791, 770, 755 cm–1.
HRMS (TOF-ESI): calcd. for C21H22OI 543.9760 [M + H]+; found
543.9753.
(1S*)-1-(2-Bromophenyl)-2-[(1S*,2Z)-2-(1-iodopentylidene)cyclo-
pentyl]ethanol (10d): Column chromatography of the residue on sil-
ica gel (5:1 hexanes/Et2O) yielded 0.183 g (41%) of the title com-
pound as a yellow oil. Rf (5:1 hexanes/Et2O) = 0.30. 1H NMR
(600 MHz, CDCl3): δ = 7.64 (dd, J = 7.2, 1.2 Hz, 1 H), 7.49 (dd,
J = 8.4, 1.2 Hz, 1 H), 7.35 (td, J = 8.4, 1.2 Hz, 1 H), 7.12 (td, J =
7.8, 1.8 Hz, 1 H), 5.13–5.11 (m, 1 H), 3.02–2.98 (m, 1 H), 2.44–
2.32 (m, 4 H), 1.99–1.79 (m, 5 H), 1.63 (td, J = 14.4, 2.4 Hz, 1 H),
1.50–1.39 (m, 2 H), 1.31–1.24 (m, 2 H), 0.89 (t, J = 7.8 Hz, 3
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 150.9, 143.9, 132.6,
128.6, 127.8, 127.2, 121.4, 97.8, 71.8, 47.8, 41.7, 40.6, 31.4, 30.8,
29.5, 25.3, 21.5, 14.0 ppm. IR (KBr): ν
= 3452, 3055, 2953,
˜
max
2929, 2869, 1706, 1467, 1437, 1060, 1045, 1024, 931, 755 cm–1
.
(1S*)-1-(2-Chlorophenyl)-2-{(1S*,2Z)-2-[iodo(4-tolyl)methylene]- HRMS (CI-TOF): calcd. for C18H23OBrI 460.9977 [M + H]+;
cyclopentyl}ethanol (10a): Column chromatography of the residue
on silica gel (5:1 hexanes/Et2O) yielded 0.161 g (35%) of the title
compound as a colorless solid, m.p. 142.2–145.0 °C. Rf (5:1 hex-
found 460.9975.
A Typical Example of the Insertion/cyclization Reaction Ϫ Synthesis
of (9S*,10aS*)-4-(4-Tolyl)-1,2,3,9,10,10a-hexahydrobenzo[f]azulen-
9-ol (5a): (Table 3, entry 8). nBuLi (1.6 m in hexanes, 1.25 mL,
2.00 mmol) was added dropwise within 5 min to a solution of
bis(cyclopentadienyl)zirconium dichloride (0.292 g, 1.00 mmol) in
dry THF (5 mL) cooled to –78 °C and the reaction mixture was
stirred for 1 h at the same temperature. Then 1a (1.00 mmol,
0.184 g) was added and the reaction mixture was gradually warmed
to 25 °C. After 3 h 2-iodobenzaldehyde (0.232 g, 1.00 mmol) was
added at 0 °C and the reaction mixture was stirred for 12 h. Then
it was cooled to –15 °C and CuCl (0.148 g, 1.50 mmol) was added.
After stirring for 30 min JohnPhos (1.19 g, 4.00 mmol), [Pd-
(PPh3)4] (0.058 g, 0.05 mmol), and DMPU (0.360 mL, 3.00 mmol)
were added and the reaction mixture was stirred at 50 °C for 12 h.
After cooling to 25 °C, the reaction mixture was quenched with 1 n
HCl (10 mL) and extracted with EtOAc (3ϫ 20 mL). The com-
bined organic phases were washed with a saturated solution of
NaHCO3 (20 mL), water (2ϫ 20 mL), and brine (20 mL), dried
with MgSO4, and then the solution was filtered and concentrated
under reduced pressure. Column chromatography of the residue on
silica gel (6:1 hexanes/EtOAc) yielded 133 mg (46%) of the title
compound as a yellow oil. Rf (6:1 hexanes/EtOAc) = 0.13. 1H
NMR (600 MHz, CDCl3): δ = 7.70–7.69 (m, 1 H), 7.30–7.27 (m, 1
H), 7.19–7.16 (m, 1 H), 7.15–7.13 (m, 2 H), 7.10–7.08 (m, 2 H),
6.88 (dd, J = 7.2, 1.2 Hz, 1 H), 4.96–4.94 (m, 1 H), 2.68–2.63 (m,
1 H), 2.51–2.47 (m, 1 H), 2.43–2.40 (m, 2 H), 2.37 (s, 3 H), 2.25–
2.18 (m, 1 H), 1.94 (br. s, 1 H), 1.88–1.82 (m, 1 H), 1.80–1.72 (m,
2 H), 1.57–1.51 (m, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ =
147.3, 142.8, 140.5, 139.3, 136.0, 130.7, 129.4, 128.6, 128.4, 126.2,
126.2, 122.3, 70.4, 50.3, 39.4, 33.2, 32.8, 25.6, 21.2 ppm. IR (KBr):
1
anes/Et2O) = 0.20. H NMR (600 MHz, CDCl3): δ = 7.69 (d, J =
12 Hz, 1 H), 7.34–7.31 (m, 2 H), 7.21 (t, J = 12 Hz, 1 H), 7.15–
7.14 (m, 2 H), 7.10–7.08 (m, 2 H), 5.25 (d, J = 10.2 Hz, 1 H), 3.17–
3.14 (m, 1 H), 2.38–2.32 (m, 4 H), 2.30–2.24 (m, 1 H), 2.22–2.12
(m, 2 H), 2.03–1.98 (m, 1 H), 1.97–1.92 (m, 1 H), 1.90–1.83 (m, 1
H), 1.82–1.77 (m, 1 H), 1.75–1.71 (m, 1 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 154.5, 142.4, 141.6, 137.3, 131.3, 129.4,
128.8, 128.6, 128.3, 127.2, 126.9, 89.8, 69.5, 47.8, 41.0, 32.6, 30.0,
25.7, 21.2 ppm. IR (KBr): ν
= 3569, 3461, 3060, 3040, 3019,
˜
max
2956, 2941, 2887, 2866, 2839, 1509, 1467, 1443, 1048, 1036, 794,
770, 755 cm–1. HRMS (TOF-ESI): calcd. for C21H22OClI 452.0404
[M + H]+; found 452.0403.
(1S*)-1-(2-Bromophenyl)-2-{(1S*,2Z)-2-[iodo(4-tolyl)methylene]-
cyclopentyl}ethanol (10b): Column chromatography of the residue
on silica gel (5:1 hexanes/Et2O) yielded 0.203 g (41%) of the title
1
compound as a yellow oil. Rf (5:1 hexanes/Et2O) = 0.20. H NMR
(600 MHz, CDCl3): δ = 7.70–7.68 (dd, J = 7.8, 1.8 Hz, 1 H), 7.52–
7.50 (dd, J = 7.8, 1.2 Hz, 1 H), 7.38 (td, J = 7.8, 1.2 Hz, 1 H),
7.16–7.13 (m, 3 H), 7.10–7.08 (m, 2 H), 5.21–5.18 (m, 1 H), 3.18–
3.14 (m, 1 H), 2.39–2.33 (m, 1 H), 2.32 (s, 3 H), 2.30–2.24 (m, 1
H), 2.18 (d, J = 4.8 Hz, 1 H), 2.12–2.08 (m, 1 H), 2.0–1.97 (m, 2
H), 1.91–1.84 (m, 1 H), 1.83–1.77 (m, 1 H), 1.76–1.71 (m, 1
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 154.5, 143.9, 141.6,
137.3, 132.6, 128.8, 128.7, 128.6, 127.8, 127.2, 121.4, 89.8, 71.7,
47.8, 41.0, 32.5, 29.9, 25.8, 21.2 ppm. IR (KBr): νmax = 3578, 3455,
˜
3052, 3016, 2956, 2944, 2866, 1464, 1440, 1054, 1039, 1021, 785,
770, 755 cm–1. HRMS (TOF-ESI): calcd. for C21H22OBrINa
518.97929 [M + Na]+; found 518.97909.
(1S*)-1-(2-Iodophenyl)-2-{(1S*,2Z)-2-[iodo(4-tolyl)methylene]-
ν
= 3330, 3058, 3019, 2935, 2860, 1706, 1509, 1443, 1069, 1039,
˜
max
cyclopentyl}ethanol (10c): Column chromatography of the residue 818, 761, 752 cm–1. HRMS (CI-TOF): calcd. for C21H23O 291.1749
on silica gel (5:1 hexanes/Et2O) yielded 0.271 g (50%) of the title
[M + H]+; found 291.1744.
2876
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2868–2878

Reaction of Bicyclic Zirconacyclopentenes with Aldehydes
[3]
[4]
a) M. Kotora, C. Umeda, T. Ishida, T. Takahashi, Tetrahedron
Lett. 1997, 38, 8355–8358; b) M. Kotora, Y. Noguchi, T. Taka-
hashi, Collect. Czech. Chem. Commun. 1999, 64, 1119–1124; c)
Z. Xi, Z. Li, C. Umeda, H. Guan, P. Li, M. Kotora, T. Taka-
hashi, Tetrahedron 2002, 58, 1107–1117.
(9S*,10aS*)-2-Benzyl-4-phenyl-1,2,3,9,10,10a-hexahydrobenzo-
[4,5]cyclohepta[1,2-c]pyrrol-9-ol (5e): nBuLi (1.6 m in hexanes,
1.25 mL, 2.00 mmol) was added dropwise within 5 min to a solu-
tion of bis(cyclopentadienyl)zirconium dichloride (0.292 g,
1.00 mmol) in dry THF (5 mL) cooled to –78 °C and the reaction
mixture was stirred for 1 h at the same temperature. Then 1f
(1.00 mmol, 0.261 g) was added and the reaction mixture was grad-
ually warmed to 25 °C. After 3 h 2-iodobenzaldehyde (0.232 g,
1.00 mmol) was added at 0 °C and the reaction mixture was stirred
for 12 h. Then it was cooled to –15 °C and CuCl (0.109 g,
1.10 mmol) was added. After stirring for 30 min JohnPhos (0.372 g,
1.25 mmol), [Pd(PPh3)4] (0.058 g, 0.05 mmol), and DMPU
(0.360 mL, 3.00 mmol) were added and the reaction mixture was
stirred at 50 °C for 12 h. After cooling to 25 °C, the reaction mix-
ture was quenched with brine (20 mL) and 1 n HCl (10 mL). Then
a saturated solution of NaHCO3 (40 mL) was added and reaction
mixture was extracted with EtOAc (3ϫ 20 mL). The combined or-
ganic phases were washed with water (2 ϫ 20 mL) and brine
(20 mL), dried with MgSO4, and then the solution was filtered and
concentrated under reduced pressure. Column chromatography of
the residue on silica gel (2:1 hexanes/EtOAc) yielded 117 mg (32%)
of the title compound as a yellow oil. Rf (2:1 hexanes/EtOAc) =
a) T. Takahashi, R. Hara, Y. Nishihara, M. Kotora, J. Am.
Chem. Soc. 1996, 118, 5154–5155; b) T. Takahashi, Y. Li, P.
ˇ
Steˇpnicˇka, M. Kitamura, Y. Liu, K. Nakajima, M. Kotora, J.
Am. Chem. Soc. 2002, 124, 576–582.
T. Takahashi, W.-H. Y. Liu, K. Nakajima, M. Kotora, Organo-
metallics 1998, 17, 3841–3843.
a) M. Kotora, C. Xi, T. Takahashi, Tetrahedron Lett. 1998, 39,
4321–4324; b) C. Xi, M. Kotora, K. Nakajima, T. Takahashi,
J. Org. Chem. 2000, 65, 945–950.
a) T. Takahashi, M. Kotora, Z. Xi, J. Chem. Soc., Chem. Com-
mun. 1995, 1503–1504; b) T. Takahashi, Z. Xi, M. Kotora, C.
Xi, Tetrahedron Lett. 1996, 37, 7521–7524.
C. Zhao, P. Li, X. Cao, Z. Xi, Chem. Eur. J. 2002, 8, 4292–
4298.
T. Takahashi, W.-H. Sun, Z. B.-J. Shen, Org. Lett. 2000, 2,
1197–1199.
M. W. Tuckett, W. J. Watkinsband, R. J. Whitby, Tetrahedron
Lett. 1998, 39, 123–126.
a) E. J. Kantorowski, M. J. Kurth, Tetrahedron 2000, 56, 4317–
4353; b) M. A. Battiste, P. M. Pelphrey, D. L. Wright, Chem.
Eur. J. 2006, 12, 3438–3447; c) N. Blanchard, J. Eustache, in:
Metathesis in Natural Product Synthesis: Strategies, Substrates
and Catalysts (Eds.: J. Cossy, S. Arseniyadis, Ch. Meyer),
Wiley-VCH, Weinheim, Germany, 2010, p. 1–43; d) T. V.
Nguyen, J. M. Hartmann, D. Enders, Synlett 2013, 45, 845–
873.
a) Z. Xi, R. Hara, T. Takahashi, J. Org. Chem. 1995, 60, 4444–
4448; b) T. Takahashi, C. Xi, Z. Xi, M. Kageyama, R. Fischer,
K. Nakajima, E. Negishi, J. Org. Chem. 1998, 63, 6802–6806.
C. Coperét, E. Negishi, Z. Xi, T. Takahashi, Tetrahedron Lett.
1994, 35, 695–698.
a) C. Zhao, J. Lu, J. Yan, Z. Xi, Tetrahedron Lett. 2003, 44,
6895–6898; b) C. Zhao, J. Lu, Z. Li, Z. Xi, Tetrahedron 2004,
60, 1417–1424.
a) C. Zhao, T. Yu, Z. Xi, Chem. Commun. 2002, 142–144; b)
C. Zhao, J. Yan, Z. Xi, J. Org. Chem. 2003, 63, 4355–4360.
For a review, see: C. Wang, Z. Xi, Chem. Soc. Rev. 2007, 36,
1395–1406.
a) H. Urabe, F. Sato, J. Org. Chem. 1996, 61, 6756–6757; b) Q.
Hu, D. Li, H. Zhang, Z. Xi, Tetrahedron Lett. 2007, 48, 6167–
6170.
Y. Zhou, J. Chen, C. Zhao, E. Wang, Y. Liu, Y. Li, J. Org.
Chem. 2009, 74, 5326–5330.
For recent reviews on the synthesis of seven-membered ring
compounds, see: a) K. E. O. Ylijoki, J. M. Stryker, Chem. Rev.
2013, 113, 2244–2266; b) L. Jiao, Z.-X. Yu, J. Org. Chem. 2013,
78, 6842–6848.
[5]
[6]
[7]
[8]
[9]
[10]
[11]
1
0.37. H NMR (600 MHz, CDCl3): δ = 7.72–7.70 (m, 1 H), 7.36–
7.35 (m, 2 H), 7.32–7.27 (m, 5 H), 7.25–7.22 (m, 2 H), 7.16 (td, J
= 7.2, 1.2 Hz, 1 H), 7.13–7.11 (m, 2 H), 6.85 (dd, J = 7.8, 1.2 Hz,
1 H), 5.07–5.04 (m, 1 H), 3.78 (d, J = 12.6 Hz, 1 H), 3.67 (d, J =
14.4 Hz, 1 H), 3.57 (d, J = 13.2 Hz, 1 H), 3.28 (d, J = 14.4 Hz, 1
H), 2.75–2.68 (m, 2 H), 2.45–2.41 (m, 1 H), 2.37–2.35 (m, 1 H),
2.27–2.21 (m, H), 2.00 (v. br. s, 1 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 143.4, 142.9, 141.2, 139.2, 138.8, 130.6, 129.1, 128.6,
128.5, 128.3, 128.0, 127.0, 126.7, 126.6, 126.3, 122.7, 70.0, 60.2,
[12]
59.6, 59.2, 50.1, 39.0 ppm. IR (KBr): ν
= 3060, 3022, 2926,
˜
max
[13]
[14]
2854, 2782, 2729, 1721, 1494, 1476, 1455, 1440, 1341, 1263, 1066,
1045, 776, 758, 701 cm–1. HRMS (TOF-MS-CI): calcd. for
C26H25NO 367.1936 [M + H]+; found 367.1939.
Supporting Information (see footnote on the first page of this arti-
cle): Further experimental details, crystallographic data, and 1H
and 13C spectra of all prepared compounds.
[15]
[16]
[17]
Acknowledgments
This work was supported by the Czech Science Foundation (grant
number 13-15915S). The authors would like to thank Prof. Dr. Jana
Roithová for fruitful cooperation regarding theoretical calculations
and Dr. Ivana Císarˇová for X-ray structure analysis. The authors
also thank Lach-Ner s.r.o. for their generous gift of chemicals as a
part of the award given to M. K.
[18]
[19]
[20]
[21]
C. Aubert, O. Buisine, M. Malacria, Chem. Rev. 2002, 102,
813–834.
[1] For reviews, see: a) E. Negishi, in: Comprehensive Organic Syn-
thesis vol. 5 (Eds: B. M. Trost, I. Fleming), Pergamon Press,
Oxford, UK, 1991, p. 1163–1184; b) E. Negishi, T. Takahashi,
Acc. Chem. Res. 1994, 27, 124–130; c) I. Marek (Ed.), Titanium
and Zirconium in Organic Synthesis Wiley-VCH: Weinheim,
Germany, 2002; d) E. Negishi, Dalton Trans. 2005, 827–848; e)
Z. Xi, Z. Li, Top. Curr. Chem. 2005, 8, 27–56; f) W.-X. Zhang,
S. Zhang, Z. Xi, Acc. Chem. Res. 2011, 44, 541–551; g) F. J.
Fañanás, F. Rodríguez, Eur. J. Org. Chem. 2008, 1315–1329.
[2] a) T. Takahashi, M. Kotora, Z. Xi, J. Chem. Soc., Chem. Com-
mun. 1995, 361–362; b) T. Takahashi, Z. Xi, A. Yamazaki, Y.
Liu, K. Nakajima, M. Kotora, J. Am. Chem. Soc. 1998, 120,
For typical representatives of natural compounds possessing
the 6–7–6(Ar) condensed ring structural motive, see: a) E. M.
Simmons, R. Sarpong, Nat. Prod. Rep. 2009, 26, 1195–1217;
for their isolation, see: b) X. A. Dominguez, H. Gonzalez, R.
Aragon, M. Gutierrez, J. S. Marroquin, W. Watson, Planta
Med. 1976, 30, 237–241; c) W. H. Watson, Z. Taira, Z. Domin-
guez, X. A. Gonzales, H. Guiterrez, M. R. Aragon, Tetrahe-
dron Lett. 1976, 29, 2501–2502.
For natural compounds possessing the 5–7–6(Ar) condensed
ring structural motif, see: Ch. Bhemasankara Rao, G. Trimur-
tulu, D. Venkata Rao, S. C. Bobzin, D. M. Kushlan, J. D.
Faulkner, Phytochemistry 1991, 30, 1971–1976.
Calculations were performed by using density functional
theory model B97D with the LanL2DZ basis set for zirconium
and the 6–311+G(2d,p) basis set for the rest of the atoms and
[22]
[23]
ˇ
1672–1680; c) L. Dufková, H. Matsumura, D. Necˇas, P. Steˇp-
nicˇka, F. Uhlík, M. Kotora, Collect. Czech. Chem. Commun.
2004, 69, 351–364; d) L. Dufková, M. Kotora, I. Císarˇová, Eur.
J. Org. Chem. 2005, 2491–2499.
Eur. J. Org. Chem. 2015, 2868–2878
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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N. Topolovcˇan, I. Panov, M. Kotora
FULL PAPER
taking into account THF solvation by using the PCM solvation
model as implemented in Gaussian 09.
[24] G. M. Whitesides, J. S. Sadowski, J. Lillburn, J. Am. Chem. Soc.
1974, 96, 2829–2835.
[25] G. M. Whitesides, J. San Fillipo Jr., E. R. Stredronsky, C. P.
Casey, J. Am. Chem. Soc. 1969, 91, 6542–6544.
[26]
C. Xi, S. Huo, T. H. Affifi, R. Hara, T. Takahashi, Tetrahedron
Lett. 1997, 38, 4099–4102.
[27] P. H. Lee, D. Seomoon, K. Lee, Org. Lett. 2005, 7, 343–345.
Received: February 20, 2015
Published Online: March 19, 2015
2878
www.eurjoc.org
© 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2015, 2868–2878