Carbocyclization reaction of active methine compounds with unactivated alkenyl or alkynyl groups mediated by TiCl4-Et3N

Article abstract of DOI:10.1021/jo981603k

In the presence of TiCl₄, Et₃N, and I₂, iodocarbocyclization reaction of various active methine compounds having alkenyl groups gave iodocycloalkane derivatives in good yields. On the other hand, TiCl₄ and Et

Full text of DOI:10.1021/jo981603k

9470
J . Org. Chem. 1998, 63, 9470-9475
Ca r bocycliza tion Rea ction of Active Meth in e Com p ou n d s w ith
Un a ctiva ted Alk en yl or Alk yn yl Gr ou p s Med ia ted by TiCl4-Et3N
Osamu Kitagawa, Takashi Suzuki, Tadashi Inoue, Yoko Watanabe, and Takeo Taguchi*
Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, J apan
Received August 6, 1998
In the presence of TiCl4, Et3N, and I2, iodocarbocyclization reaction of various active methine
compounds having alkenyl groups gave iodocycloalkane derivatives in good yields. On the other
hand, TiCl4 and Et3N promote the carbocyclization of active methine compounds with 4-alkynyl
groups in the absence of I2 to give methylenecyclopentane derivatives in good yields. This reaction
proceeds with high streoselectivity through a cis-addition of trichlorotitanium enolates of active
methine compounds to alkynes, and the resulting vinyltitanium intermediates can be further
functionalized by the reaction with various electrophiles.
Sch em e 1
In tr od u ction
The addition reaction of stabilized carbanions prepared
from active methylene and methine compounds to the
activated C-C π-bond is commonly known as the Michael
reaction, while a limited number of examples has been
reported on the addition of these to unactivated alkenes
and alkynes.1-3 On the other hand, in the cases of
unstabilized carbanions, many examples of the inter- and
intramolecular addition to an unactivated C-C π-bond,
such as carbometalation using unstabilized organo-
metallic carbanions, have been reported so far.4 Thus,
the difficulty of the reaction with a stabilized carbanion
may be due to an endothermic process involving the
conversion of a stabilized enolate anion to an unstabilized
sp3 or sp2 carbanion.5
enolate to the C-C π-bond in the presence of Ti(OR)4 and
I2 (Scheme 1).6 In this reaction, iodine is a proper
electrophile to activate the C-C π-bond, while Ti(OR)4
acts as a basic reagent to enhance the nucleophilicity of
the malonate moiety through the formation of a titanium
enolate. Other bases, in particular, a strong base such
as tert-BuOK and NaH, resulted in a marked decrease
in the chemical yield, because dimerization and R-iodi-
nation reaction of the malonate anions occurs at the same
time; thus, a mild base such as Ti(OR)4 may be required
to get the product in a good yield.6b,7 Furthermore, we
have also succeeded in the development of highly enan-
tioselective iodocarbocyclization using a chiral titanium
alkoxide, Ti(TADDOLate)2 catalyst.8 A limitation of the
present reaction is the choice of only malonate derivatives
as substrates, and it could not be applied to a variety of
active methine compounds.
We previously reported iodocarbocyclization reaction
of a malonate derivative having unreactive alkenyl or
alkynyl groups which proceeds in a highly stereospecific
manner through the trans-addition of I2 and a malonate
* Corresponding author. FAX and TEL: 81-426-76-3257, e-mail:
kitagawa@ps.toyaku.ac.jp and taguchi@ps.toyaku.ac.jp.
(1) Examples of intramolecular carbometalation reactions of enolates
with unactivated olefins or alkynes: (a) Fournet, G.; Balme, G.; Gore,
J . Tetrahedron 1990, 46, 7763-7773. (b) Fournet, G.; Balme, G.; Gore,
J . Tetrahedron 1991, 47, 6293-6304. (c) Yeh, M.-C. P.; Chuang, L.-
W.; Ueng, C. H. J . Org. Chem. 1996, 61, 3874-3877. (d) Nakamura,
E.; Sakata, G.; Kubota, K. Tetrahedron Lett. 1998, 39, 2157-2158. (e)
Arcadi, A.; Cacchi, S.; Fabrizi, G.; Manna, F.; Pace, P. Synlett 1998,
446-448. (f) Lorthiois, E.; Marek, I.; Normant, J . F. J . Org. Chem.
1998, 63, 2442-2450 and references therein.
(2) Examples of intermolecular carbometalation reactions of enolates
to unactivated olefins or alkynes: (a) Bertrand, M. T.; Courtois, G.;
Miginiac, L. Tetrahedron Lett. 1974, 1945-1948. (b) Ehrhardt, H.;
Mildenberger, H. Liebigs Ann. Chem. 1982, 989-993. (c) Stack, J . G.;
Simpson, R. D.; Hollander, F. J .; Bergman, R. G.; Heathcock, C. H. J .
Am. Chem. Soc. 1990, 112, 2716-2729. (d) Yamaguchi, M.; Hayashi,
A.; Hirama, M. J . Am. Chem. Soc. 1993, 115, 3362-3363. (e) Yamagu-
chi, M.; Hayashi, A.; Hirama, M. J . Synth. Chem. Org. J pn. 1996, 54,
267-279. (f) Kubota, K.; Nakamura, E. Angew. Chem., Int. Ed. Engl.
1997, 36, 2491-2493.
(3) An example of palladium-catalyzed addition of activated meth-
ylene compounds to allenes: Yamamoto, Y. Al-Masum, M.; Asao, N.
J . Am. Chem. Soc. 1994, 116, 6019-6020.
(4) (a) Knochel, P. In Comprehensive Organic Synthesis; Trost, B.,
Fleming, I., Eds.; New York, Pergamon Press: 1991; Vol. 4, pp 865-
911. (b) Bailey, W. F.; Ovaska, T. V. J . Am. Chem. Soc. 1993, 115,
3080-3090 and references therein. (c) Marek, I.; Normant, J . F. Cross
Coupling Reactions; Diederich, D., Stang, P., Eds.; VCH: New York,
1998.
In this paper, we report the result of iodocarbocycliza-
tion reaction mediated by TiCl4, Et3N, and I2 which is
applicable to various unsaturated active methine com-
pounds (Scheme 2). In addition, in the course of the
related experiment, we found that without the addition
of I2, TiCl4 and Et3N promote the carbocyclization of
(6) (a) Kitagawa, O.; Inoue, T.; Taguchi, T. Tetrahedron Lett. 1992,
33, 2167-2170. (b) Kitagawa, O.; Inoue, T.; Hirano, K.; Taguchi, T. J .
Org. Chem. 1993, 58, 3106-3112. (c) Taguchi, T.; Kitagawa, O.; Inoue,
T.; J . Synth. Org. Chem. J pn. 1995, 53, 770-779. (d) Kitagawa, O.;
Inoue, T. Taguchi, T. Rev. Heteroat. Chem. 1996, 15, 243-262.
(7) (a) Curran D. P.; Chang, C.-T. J . Org. Chem. 1989, 62, 3140. (b)
Cossy, J .; Thellen, A. Tetrahedron Lett. 1990, 31, 1427-1428. (c)
Beckwith, A. L.; Zozer, M. J . Tetrahedron Lett. 1992, 33, 4975-4978.
(8) Inoue, T.; Kitagawa, O.; Saito, A.; Taguchi, T. J . Org. Chem.
1997, 62, 7384-7389 and references therein.
(5) Nakamura, E. Kubota, K. Tetrahedron Lett. 1997, 38, 7099-
7102.
10.1021/jo981603k CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/13/1998

Carbocyclization Reactions Mediated by TiCl4-Et3N
J . Org. Chem., Vol. 63, No. 25, 1998 9471
Ta ble 1. Iod oca r bocycliza tion Rea ction of Va r iou s
Un sa tu r a ted Active Meth in e Com p ou n d sa
Sch em e 2
active methine compounds with a 4-alkynyl group (Scheme
2).9 This reaction proceeds with high stereoselectivity
through an intramolecular cis-addition of trichloro-
titanium enolates of active methine compounds to alkynes,
and the resulting vinyltitanium intermediate can be
further functionalized by the reaction with various elec-
trophiles. As far as we know, carbometalation reaction
of a titanium enolate to an unactivated C-C π-bond has
not been reported so far. The details of this reaction and
stereodivergent synthesis of an (iodomethylene)cyclopen-
tane derivative are also described.
Resu lts a n d Discu ssion
Iod oca r bocycliza tion Rea ction of Va r iou s Active
Meth in e Com p ou n d s. In contrast to alkenylmalonate
derivatives, the iodocarbocyclization reaction of 4-pen-
tenylphosphonoacetate 1a did not proceed in the presence
of Ti(Oi-Pr)4 and I2 in CH2Cl2, and 1a was quantitatively
recovered. Among many additives examined, it was
found that when TiCl4 and Et3N were used in the
presence of I2, an iodocarbocyclized product 2a was
obtained in 78% yield (Table 1, entry 1). As shown in
Scheme 3, the individual use of amines or TiCl4, and the
combination of Et3N with Cl2Ti(Oi-Pr)2 or Ti(Oi-Pr)4, were
ineffective, resulting in a recovery of 1a together with
the formation of an addition product of I2 to the olefin.
On the other hand, the use of basic metal alkoxides such
as LiAl(Ot-Bu)4 and La(Oi-Pr)3 gave an R-iodination
product of 1a and an addition product of I2 to the olefin
without the formation of 2a . Thus, the combination of
TiCl4 and Et3N is essential for the reaction of 1a . In
addition, the cyclopentane derivative 2a having a cis-
relationship between the ester and iodomethyl groups
was obtained as a major isomer with relatively high
diastereoselectivity (12:1). The stereochemistriy of 2a
was determined on the basis of a lactonization experi-
ment; the major isomer of 2a easily gave bicyclic lactone
3a by heating at 140 °C, while the lactone was not
obtained from the minor isomer under the same condi-
tions because of the unfavorable process for the formation
of the trans-fused [3.3.0]-bicyclic ring system (Scheme 4).
The reaction of 4-pentenylsulfonyl acetate 1b also
smoothly proceeded to give (iodomethyl)cyclopentane
derivative 2b in a diastereomeric ratio of 8.6:1 (entry 2).
Similar to the case of 1a , this reaction did not proceed
in the presence of Ti(Oi-Pr)4 and I2. 2b was converted
to lactone 3b in a good yield without the further separa-
Sch em e 3
tion of the diastereomer (Scheme 4),10 because the lac-
tonization of 2b partly occurs during the chromatographic
purification step (silica gel). Similar to 2a , although the
lactonization of the major isomer easily proceeded, the
formation of a bicyclic lactone from the minor isomer was
not observed. In the reactions of 1a and 1b, the separa-
tion of diastereomers of products 2a and 2b was very
(10) In the lactonization of 2b, when simply heating 2b as in the
case of 2a , a chemical yield of 3b was low due to the formation of 1b.
Thus, in this case, the lactonization through alkaline hydrolysis of the
ester group was performed.
(9) Preliminary communication of this work: Kitagawa, O.; Suzuki,
T.; Inoue, T.; Taguchi, T. Tetrahedron Lett. 1998, 39, 7357-7360.

9472 J . Org. Chem., Vol. 63, No. 25, 1998
Kitagawa et al.
Sch em e 4
Sch em e 5
reaction, we found that when the reaction of 4-penty-
nylphosphonoacetate 1g was performed under the above
conditions, (Z)-2g was obtained with complete stereose-
lectivity but not the expected iodocarbocyclized product
(E)-2g (Scheme 5).12,13 The Z-selectivity was also ob-
served in the reaction of 4-pentynylmalonate derivative
1h , which gave (Z)-2h with high stereoselectivity (E/ Z
) 1/30) in the presence of TiCl4-Et3N and I2 (Scheme
5).14
The preferential formation of (Z)-2g and (Z)-2h was
assumed to follow another reaction pathway which
proceeds in a cis-selective manner prior to trans-selective
iodocarbocyclization. Indeed, the cyclization reaction of
1h smoothly proceeded even in the absence of I2 to give
methylenecyclopentane derivative 4h in a good yield
(82%) after quenching by HCl (Scheme 6, Table 2, entry
1).15 Thus, it is obvious that the reaction of 1h with TiCl4
and Et3N proceeds through intramolecular addition of the
trichlorotitanium enolate of 1h to the alkyne. The
stereoselectivity in the carbotitanation process, which
completes within 10 min at room temperature, is almost
perfect and the following stereospecific iodonolysis of the
resulting (Z)-vinyltitanium intermediate 1H gave (Z)-2h
as a single stereoisomer (Scheme 6).16,17 Since we have
already found the stereoselective construction of (E)-2h
through Ti(OR)4-mediated iodocarbocyclization, stereo-
divergent synthesis of 2h can be possible by employing
either reaction conditions (Scheme 5).
difficult, while the bicyclic lactones 3a and 3b could be
easily obtained as single stereoisomers without difficult
separation. The stereochemistry of 3b having a cis-fused
bicyclic ring system was confirmed by X-ray analysis (see
Supporting Information).
The reactions of malonate-monoamide 1c and cyanoac-
etate 1d also proceeded under the above conditions to
give cyclized products 2c and 2d , respectively (entries 3,
4). In the reaction of 1c, almost complete stereoselec-
tivity was observed (entry 3), while the reaction of 1d
gave 2d with low stereoselectivity (1.4:1, entry 4).11 The
steric factor would be one of the possible explanations
for the moderate to high stereoselectivities which were
observed in the reactions of 1a -1c. That is, in the
transition state, the iodine-olefin π-complex part may
favor trans-relationship with phosphonyl, sulfonyl, or
dialkylamide which are bulkier groups in comparison
with the ester group. Therefore, the reaction of 1d with
a sterically less hindered substituent such as nitrile may
result in considerable decrease in the stereoselectivity.
Under the same conditions, the reaction of malonate
derivative 1e which underwent the iodocarbocyclization
as previously reported,6 also gave 2e in a good yield (entry
5). Thus, the present reaction is applicable to various
active methine compounds.
Although high stereoselectivity was not observed, the
three-membered ring-forming reaction with allylphospho-
noacetate 1f also smoothly proceeded to give an (iodom-
ethyl)cyclopropane derivative 2f in a good yield (Entry
6).
It should be also noted that, despite the existence of
Et3N‚HCl in the reaction mixture, most of the vinyltita-
Attempts to extend the reaction to the production of
cyclohexane or cyclobutane derivatives have not yet been
successful. For example, under the above conditions, the
reactions of dimethyl 5-hexenylmalonate and dimethyl
4-butenylmalonate gave dimethyl (5,6-diiodohexyl)ma-
lonate and dimethyl (3,4-diiodobutenyl)malonate as the
major products, respectively, without the formation of
6-exo and 4-exo iodocarbocyclization products.
All the reactions shown in Table 1 proceeded with
complete exo-selectivity; the formation of 4- or 6-endo-
cyclized product was not observed.
In tr am olecu lar Car botitan ation Reaction of Var i-
ou s Act ive Met h in e Com p ou n d s w it h Alk yn yl
Gr ou p s. During the experiment in relation to the above
(12) The stereochemistries of 2g and 4k were determined on the
basis of NOE experiments.
(13) This Z-selective reaction, which was carried out at -15 °C (see
Supporting Information), also gave an addition product of I2 to the
C-C triple bond as a byproduct. On the other hand, the effect of
temperature on the reaction pathways should be noted; that is, when
the reaction of 1g was performed at room temperature, (E)- and (Z)-
2g were obtained in a ratio of E/ Z ) 4/7 in 78% yield due to a
competition of both iodocarbocylization and carbotitanation-iodonoly-
sis processes.
(14) In this reaction, I2 was immediately added to the solution of
1h after the addition of TiCl4 and Et3N.
(15) Excess of TiCl4 (1.8 equiv) to Et3N is required to get the cyclized
product in good yield. Although the reason is not clear, the use of 1.2
equiv of TiCl4 and Et3N to 1 equiv of the substrates resulted in a
considerable decrease in the chemical yield due to the formation of
unidentified byproducts.
(16) After the completion of the carbocyclization was confirmed by
TLC monitoring, I2 was added to the reaction solution.
(17) The formation of the (Z)-vinyltitanium intermediate 1H is in
remarkable contrast to the palladium-catalyzed carbocylization of 1h ,
which exclusively gives the (E)-vinylpalladium species via trans-
addtion of a palladium and a malonate anion.1b
(11) The stereochemistries of iodides 2c and 2d were determined
on the basis of the lactonization experiment in accordance with Scheme
4.

Carbocyclization Reactions Mediated by TiCl4-Et3N
J . Org. Chem., Vol. 63, No. 25, 1998 9473
Ta ble 3. In tr a m olecu la r Ca r botita n a tion Rea ction a
Sch em e 6
Ta ble 2. Ad d itive Effects in th e Ca r bom eta la tion of
4-P en tyn ylm a lon a te 1h a
tion of 1H by the resulting HCl occurs. Thus, Et3N acts
not only as a basic reagent for the deprotonation but also
as an effective HCl scavenger to prevent the protonation
of the vinyltitanium intermediate 1H.
Among the other metallic reagents examined here, the
use of ZnCl2 was also effective for the cyclization reaction.
That is, the reaction of 1h with ZnCl2 and Et3N gave 4h
in good yield (88%, entry 4), while the following iodination
of vinylzinc intermediate failed, because the vinylzinc
intermediate is easily protonated by Et3N‚HCl in the
reaction mixture (Scheme 6). In the reaction of 1h with
Et3N and other metallic reagents such as BBr3, ZrCl4, or
SnCl4, the cyclized product 4h could not be obtained
(entries 5-7). In the reaction with SnCl4, although the
complete disappearance of 1h and the formation of an
olefinic hydrogen indicated the progress of the carbocy-
clization, the product 4h could not be obtained because
of the difficulty of cleavage of the Sn-vinyl bond (entry
7).
The results of carbotitanation of various alkynylated
active methine compounds are shown in Table 3. The
reaction of bisalkynylated malonate 1i proceeded without
any side reaction at an unreacted alkynyl group to give
4i in a good yield (83%, entry 1). Similar to malonate
derivatives 1h and 1i, the reaction of active methine
compounds 1g and 1j with phosphonyl and sulfonyl
groups also gave the products 4g and 4j in good yields
(entries 2, 3). On the other hand, the use of ZnCl2-Et3N,
which gave a good result in the reaction of malonate 1h ,
was not effective for 1g, and the formation of cyclized
product 4g was not observed. This reaction can be also
applied to disubstitued alkyne; that is, although the
reaction required prolonged time in comparison with
nium intermediate 1H is not protonated within 10 min
at room temperature and can be further functionalized
by the reaction with an electrophile. The strong in-
tramolecular coordination of two ester groups to the
titanium atom may stabilize the resulting 1H. As an
example of the C-C bond-forming reaction of 1H, the
reaction of 1H with benzaldehyde gave diene 5h in 64%
via the addition to aldehyde and the following dehydra-
tion (Scheme 6).
In contrast to TiCl4-Et3N, the cyclized product 4h
could not be obtained by the use of Ti(Oi-Pr)4 or Et3N
and Ti(Oi-Pr)4 (Table 2, entry 2). The reaction of 1h with
Cl2Ti(Oi-Pr)2 and Et3N gave 4h in a poor yield (21%,
entry 3). Thus, it is obvious that the strong Lewis acidity
of the titanium atom is required for the efficient activa-
tion of the alkyne part. Although prolonged reaction time
is required (14 h), the present reaction proceeded even
in the absence of Et3N to give 4h in a good yield (80%).
In this case, however, further functionalization of vi-
nyltitanium intermediate 1H could not be performed,
because during the cyclization reaction a rapid protona-

9474 J . Org. Chem., Vol. 63, No. 25, 1998
Kitagawa et al.
9.4, 12.2 Hz), 2.88 (1H, m), 2.28-2.50 (2H, m), 2.10 (1H, m),
those of 1-alkyne 1g-j, 4-hexynylmalonate 1k gave the
product 4k with complete stereoselectivity (cis-addition,
entry 4).12 In the six-membered ring-forming reaction
with 5-hexynylmalonate 1l, a considerable decrease in
the chemical yield was observed (34%, entry 5). In all
the reactions shown in Scheme 6 and Table 3, the exo-
cyclized products were obtained as a single regioisomer
without the formation of endo-cyclized products.
Carbotitanation reaction of an active methine com-
pound with an alkenyl group has not been yet successful.
For example, the reaction of 4-pentenylmalonate 1e did
not proceed under the same conditions, and 1e was
quantitatively recovered. Thus, the reactions in Table 1
should proceed through an iodocarbocyclization process
but not the carbotitanation and following iodination
process.
In conclusion, by using TiCl4, Et3N, and I2, we have
succeeded in the development of an iodocarbocyclization
reaction which is applicable to various unsaturated active
methine compounds. In addition, we have also found
that TiCl4 and Et3N promote the carbotitanation reaction
of 4-alkynylated active methine compounds which pro-
ceeds with high stereoselectivity through an intramo-
lecular cis-addition of trichlorotitanium enolates of active
methine compounds to alkynes. These reactions should
be widely utilized as new methodology for the synthesis
of cyclopentanoid compounds.
1.60-1.92 (3H, m), 1.20-1.35 (9H, m); MS (m/z) 419 (M+
+
1), 373;
(3a R*,6a S*)-Tetr a h yd r o-3a (3H)-d ieth ylp h osp h on o-1H-
cyclop en ta [c]fu r a n -3-on e (3a ). Major-2a (209 mg, 0.5
mmol) was heated for 2h at 140 °C. Purification of the reaction
mixture by column chromatography (hexane/AcOEt ) 1) gave
1
3a (124 mg, 95%). 3a : colorless oil; IR (neat) 1768 cm-1; H
NMR (CDCl3) δ 4.51(1H, dd, J ) 7.4, 9.2 Hz), 4.10-4.30 (6H,
m), 4.03 (1H, dd, J ) 2.1, 9.2 Hz), 3.23 (1H, m), 2.00-2.32
(3H, m), 1.52-1.88 (3H, m), 1.36 (3H, t, J ) 6.7 Hz), 1.33 (3H,
t, J ) 6.9 Hz); 13C NMR (CDCl3) δ 176.3, 72.7 (d, J C-P ) 3.3
Hz), 63.2 (2 carbons, d, J C-P ) 6.8 Hz), 54.8 (d, J C-P ) 146.2
Hz), 43.4, 34.3, 34.1 (d, J C-P ) 4.8 Hz), 26.0 (d, J C-P ) 10 Hz),
16.4 (d, J C-P ) 3.9 Hz), 16.3 (d, J C-P ) 5.7 Hz); MS (m/z) 263
(M+ + 1), 262 (M+). Anal. Calcd for C11H19O5P: C, 50.38; H,
7.30. Found: C, 50.26; H, 7.40.
(3a R*,6a S*)-Tet r a h yd r o-3a (3H )-(p h en ylsu lfon yl)-1H -
cyclop en ta [c]fu r a n -3-on e (3b). 2b was prepared from 1b
(282 mg, 1 mmol) in accordance with general procedure of
iodocarbocyclization. Purification of the residue by column
chromatography (hexane/EtOAc ) 3) gave a mixture of major-
2b, minor-2b, and 1b (major-2b/minor-2b ) 8.6). To the
mixure in THF (3 mL) and H2O (1 mL) was added LiOH‚H2O
(105 mg, 2.5 mmol). After being stirred for 24 h at room
temperature, the mixture was poured into 2% HCl and
extracted with Et2O. The Et2O extracts were washed with
brine, dried over MgSO4, and evaporated to dryness. Purifica-
tion of the residue by column chromatography (hexane/AcOEt
) 2) gave 3b (215 mg, 81%). 3b: colorless solid; mp 135-136
1
°C; IR (KBr) 1771 cm-1; H NMR (CDCl3) δ 7.91 (2H, d, J )
7.5 Hz), 7.70 (1H, t, J ) 7.5 Hz), 7.57 (2H, t, J ) 7.5 Hz), 4.50
(1H, dd, J ) 8.0, 9.2 Hz), 4.05 (1H, dd, J ) 2.2, 9.2 Hz), 3.67
(1H, m), 2.15-2.37 (2H, m), 2.05 (1H, m), 1.88 (1H, m), 1.75
(1H, m), 1.61 (1H, m); 13C NMR (CDCl3) δ 172.5, 135.6, 134.6,
130.3, 128.9, 78.3, 72.8, 42.3, 34.6, 34.4, 25.8; MS (m/z) 266
(M+). Anal. Calcd for C13H14O4S: C, 58.63; H, 5.30. Found:
C, 58.98; H, 5.32.
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded on a 300-MHz spectrometer. In 1H and 13C
NMR spectra, chemical shifts were expressed in δ (ppm)
downfield from CHCl3 (7.26 ppm) and CDCl3 (77.0 ppm),
respectively. Mass spectra were recorded by electron impact
or chemical ionization. Column chromatography was per-
formed on silica gel (75-150 µm). Medium-pressure liquid
chromatography (MPLC) was performed on a 30 × 4 cm i.d.
prepacked column (silica gel, 50 µm) with a UV detector.
(1S*,2R*)-N,N-Diet h yl 1-(Met h oxyca r b on yl)-2-(iod o-
m eth yl)cyclop en ta n e-1-ca r boxa m id e (2c). 2c was pre-
pared from 1c (241 mg, 1 mmol) in accordance with general
procedure of iodocarbocyclization. Purification of the residue
by column chromatography (hexane/EtOAc ) 5) gave 2c (196
mg, 53%). 2c: colorless oil; IR (neat) 1730 cm-1 1H NMR
;
Sta r tin g Ma ter ia ls. Starting materials 1a -1l were pre-
(CDCl3) δ 3.71 (3H, s), 3.61 (1H, dd, J ) 3.3, 9.0 Hz), 3.36 (1H,
q, J ) 7.0 Hz), 3.35 (1H, q, J ) 7.0 Hz), 3.15 (1H, m), 3.30-
3.10 (2H, m), 2.68 (1H, dd, J ) 9.0, 11.4 Hz), 2.60 (1H, m),
2.23 (1H, m), 1.82-1.96 (2H, m), 1.65 (1H, m), 1.43 (1H, m),
1.09 (6H, t, J ) 7.0 Hz); 13C NMR (CDCl3) δ 172.6, 169.5, 62.2,
52.1, 50.7, 40.9, 39.6, 34.8, 31.3, 22.1, 13.1, 12.0, 7.4; MS (m/
z) 367 (M+), 295. Anal. Calcd for C13H22INO3: C, 42.52; H,
6.04; N, 3.81. Found: C, 42.79; H, 6.20; N, 3.88.
Typ ica l P r oced u r e of a n In tr a m olecu la r Ca r botita n a -
tion . To alkynylmalonate 1h (198 mg, 1 mmol) in CH2Cl2 (8
mL) were added Et3N (0.14 mL, 1 mmol) and TiCl4 (0.2 mL,
1.8 mmol) under argon atmosphere at room temperature.
After being stirred for 15 min at room temperature, the
mixture was poured into 2% HCl and extracted with Et2O. The
Et2O extracts were washed with brine, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt ) 30) gave 4h (163 mg, 82%).
Dim eth yl 2-Meth ylen ecyclop en ta n e-1,1-d ica r boxyla te
(4h ). 1H NMR data of 4h coincided with that reported in the
literature.18
pared according to reported procedures.1a,b,18
Typical P r ocedu r e of Iodocar bocyclization . To phospho-
noacetate 1a (292 mg, 1 mmol) in CH2Cl2 (6 mL) were added
Et3N (0.21 mL, 1.5 mmol) and TiCl4 (0.2 mL, 1.8 mmol) under
argon atmosphere at room temperature. After the mixture
was stirred for 10 min, I2 (381 mg, 1.5 mmol) was added, and
then the reaction mixture was stirred for 2h at room temper-
ature. The mixture was poured into 2% HCl and extracted
with Et2O. The Et2O extracts were washed with aqueous
Na2S2O3 solution, dried over MgSO4, and evaporated to dry-
ness. Purification of the residue by column chromatography
(hexane/AcOEt ) 1) gave a mixture of 1a and major- and
minor-2a (major-2a /minor-2a ) 12). Further purification by
MPLC (hexane/AcOEt ) 1.5) gave minor-2a (less polar, 5 mg,
1%), a mixture of major- and minor-2a (201 mg, 48%) and
major-2a (more polar, 121 mg, 29%), respectively.
(1R*,2R*)an d (1R*,2S*)-1-(Dieth ylph osph on o)-1-(eth oxy-
car bon yl)-2-(iodom eth yl)cyclopen tan e (m ajor -2a an d m i-
n or -2a ). Major-2a : colorless oil; IR (neat) 1729 cm-1; 1H NMR
(CDCl3) δ 4.10-4.26 (6H, m), 3.73 (1H, dd, J ) 3.1, 9.4 Hz),
3.04 (1H, dd, J ) 9.4, 11.6 Hz), 2.72 (1H, m), 2.50 (1H, m),
2.22-2.38 (2H, m), 1.82 (1H, m), 1.68 (1H, m), 1.52 (1H, m),
1.33 (6H, t, J ) 7.0 Hz), 1.29 (3H, dt, J ) 1.0, 7.1 Hz); 13C
NMR (CDCl3) δ 170.1, 62.9 (d, J C-P ) 7 Hz), 62.5 (d, J C-P ) 7
1-(Meth oxycar bon yl)-1-(ph en ylsu lfon yl)-2-m eth ylen ecy-
clop en ta n e (4j). 4j was prepared from 1j (281 mg, 1 mmol)
in accordance with general procedure of the intramolecular
carbotitanation. Purification of the residue by column chro-
matography (hexane/EtOAc ) 7) gave 4g (241 mg, 86%). 4j:
colorless oil; IR (neat) 1737 cm-1; 1H NMR (CDCl3) δ 7.90 (2H,
d, J ) 7.3 Hz), 7.65 (1H, t, J ) 7.3 Hz), 7.52 (2H, t, J ) 7.3
Hz), 61.5, 56.7 (d, J C-P ) 144.7 Hz), 49.4, 33.8, 33.2 (d, J C-P
)
11.1 Hz), 22.6 (d, J C-P ) 8.2 Hz), 16.5 (d, J C-P ) 4.4 Hz), 16.4
(d, J C-P ) 5.3 Hz), 14.1, 6.6; MS (m/z) 419 (M+ + 1), 373; HRMS
Calcd for C13H24IO5P (M+) 418.0406, Found 418.0417. Minor-
2a : colorless oil; IR (neat) 1730 cm-1; 1H NMR (CDCl3) δ 4.08-
4.26 (6H, m), 3.90 (1H, dd, J ) 3.2, 9.4 Hz), 3.33 (1H, dd, J )
(18) Monteiro, N.; Gore, J .; Balme, G. Tetrahedron 1992, 48, 10103-
10114.

Carbocyclization Reactions Mediated by TiCl4-Et3N
J . Org. Chem., Vol. 63, No. 25, 1998 9475
Hz), 5.38 (1H, t, J ) 2.1 Hz), 5.36 (1H, t, J ) 2.1 Hz), 3.72
(3H, s), 2.41-2.73 (4H, m), 1.90 (1H, m), 1.69 (1H, m); 13C NMR
(CDCl3) δ 167.6, 144.3, 136.4, 133.9, 131.0, 128.2, 116.6, 80.0,
53.1, 34.6, 34.0, 24.0; MS (m/z) 280 (M+), 241. Anal. Calcd
for C14H16O4S: C, 59.98; H, 5.75. Found: C, 59.84; H, 5.87.
(Z)-Dim eth yl 2-iod om eth ylen ecyclop en ta n e-1,1-d ica r -
boxyla te [(Z)-2h ]. To alkynylmalonate 1h (198 mg, 1 mmol)
in CH2Cl2 (8 mL) was added Et3N (0.14 mL, 1 mmol) and TiCl4
(0.2 mL, 1.8 mmol) under argon atmosphere at room temper-
ature. After the mixture was stirred for 15 min, I2 (508 mg, 2
mmol) was added, and then the reaction mixture was stirred
for 30 min at room temperature. The mixture was poured into
2% HCl and extracted with Et2O. The Et2O extracts were
washed with aqueous Na2S2O3 solution, dried over MgSO4, and
evaporated to dryness. Purification of the residue by column
chromatography (hexane/AcOEt ) 20) gave (Z)-2h (256 mg,
79%). 1H NMR data of (Z)-2h coincided with that reported in
the literature.6b
reaction mixture was stirred for 45 min at room temperature.
The mixture was poured into 2% HCl and extracted with Et2O.
The Et2O extracts were washed with brine, dried over MgSO4,
and evaporated to dryness. Purification of the residue by
column chromatography (hexane/AcOEt ) 30) gave 5h (183
mg, 64%). 5h ; colorless oil; IR (neat) 1733 cm-1 1H NMR
;
(CDCl3) δ 7.40 (2H, d, J ) 7.2 Hz), 7.28-7.33 (2H, t, J ) 7.2
Hz), 7.22 (1H, t, J ) 7.2 Hz), 6.80 (1H, d, J ) 16.5 Hz), 6.74
(1H, d, J ) 16.5 Hz), 6.22 (1H, t, J ) 2.6 Hz), 3.77 (6H, s),
2.53-2.66 (4H, m); 13C NMR (CDCl3) δ 171.6, 139.7, 137.4,
134.2, 130.3, 128.5, 127.5, 126.4, 122.6, 66.6, 52.7, 35.2, 31.0;
MS (m/z) 286 (M+), 227; HRMS calcd for C17H18O4 (M+)
286.1205, found 286.1207.
Su p p or tin g In for m a tion Ava ila ble: Characterization
data and experimental pocedures of 2d -g, 4i, 4g, 4k , and 4l,
and X-ray crystal data of 3b (11 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
(E)-Dim eth yl 2-(2′-P h en yleth en yl)-2-cyclop en ten e-1,1-
d ica r boxyla te (5h ). To alkynylmalonate 1h (198 mg, 1
mmol) in CH2Cl2 (8 mL) were added Et3N (0.14 mL, 1 mmol)
and TiCl4 (0.2 mL, 1.8 mmol) under argon atmosphere at room
temperature. After the mixture was stirred for 15 min,
benzaldehyde (0.1 mL, 1 mmol) was added, and then the
J O981603K