The Cp2TiPh-mediated reductive radical cyclization of cyanoketones and related reactions. Efficient trapping of ketyl radicals by Cp2TiPh- coordinated polar multiple bonds

Article abstract of DOI:10.1021/jo982492s

The reductive radical cyclization of cyanoketones was achieved using Cp₂TiPh. The Ti(III) reagent was prepared by the sequential addition of i- PrMgCl and PhMgBr to commercial Cp₂TiCl₂ in this order and used effectively without isolation. The cyclization of the γ- and δ-cyanoketones was performed in toluene at ambient temperature for several hours to give α- hydroxycyclopentanones and hexanones in moderate to good yields, respectively. The titanium reagent independently coordinates to both the carbonyl and cyano termini. As a result of lowering the LUMO of the cyano group upon coordination of the Ti(III) species, the irreversible cyclization successfully proceeds without formation of the unstable iminyl radical intermediate. The ester group can also be activated by the coordination of Cp₂TiPh, and aromatic ketones with an ester group at the γ position are cyclized to give the corresponding α-hydroxyketones.

Full text of DOI:10.1021/jo982492s

3224
J . Org. Chem. 1999, 64, 3224-3229
Th e Cp 2TiP h -Med ia ted Red u ctive Ra d ica l Cycliza tion of
Cya n ok eton es a n d Rela ted Rea ction s. Efficien t Tr a p p in g of Ketyl
Ra d ica ls by Cp 2TiP h -Coor d in a ted P ola r Mu ltip le Bon d s
Yoshihiko Yamamoto, Daisuke Matsumi, Reiko Hattori, and Kenji Itoh*
Department of Applied Chemistry and Department of Molecular Design and Engineering,
Graduate School of Engineering, Nagoya University, Chikusa, Nagoya 464-8603, J apan
Received December 22, 1998
The reductive radical cyclization of cyanoketones was achieved using Cp2TiPh. The Ti(III) reagent
was prepared by the sequential addition of i-PrMgCl and PhMgBr to commercial Cp2TiCl2 in this
order and used effectively without isolation. The cyclization of the γ- and δ-cyanoketones was
performed in toluene at ambient temperature for several hours to give R-hydroxycyclopentanones
and hexanones in moderate to good yields, respectively. The titanium reagent independently
coordinates to both the carbonyl and cyano termini. As a result of lowering the LUMO of the cyano
group upon coordination of the Ti(III) species, the irreversible cyclization successfully proceeds
without formation of the unstable iminyl radical intermediate. The ester group can also be activated
by the coordination of Cp2TiPh, and aromatic ketones with an ester group at the γ position are
cyclized to give the corresponding R-hydroxyketones.
In tr od u ction
Radical additions to nonpolar C-C multiple bonds
have been extensively employed as one of the commonest
methods for making C-C bonds.1 Especially, radical
cyclizations has been elegantly applied to the synthesis
of complex natural products.2 On the other hand, radical
additions to polar multiple bonds such as a carbonyl
group or a cyano group are not generally efficient because
they generate unfavorable alkoxy or iminyl radicals.1
There has been a series of available kinetic data for the
5-exo radical cyclizations. They indicate such polar bonds
are quite inefficient as a radical acceptor. As shown in
Figure 1, the rate of â-scission of an alkoxy radical
intermediate D [4.7 × 108 s-1 (25 °C), D f C] is about
500 times faster than that of the 5-exo cyclization of C
[8.7 × 105 (25 °C), C f D]. That is why the 5-exo
cyclization of the 5-oxa-5-hexenyl radical C is not general,
although the cyclization is slightly faster compared to
that of the parent 5-hexenyl radical A. As for the cyano
group, cyclization itself is 25 times slower [4 × 103 s-1
(25 °C), G f H] than that of the corresponding 5-hexynyl
radical E [1 × 105 s-1 (25 °C), E f F ]. Despite these above
facts, radical addition to polar multiple bonds might be
successful if the resulting unstable radical intermediates
are effectively scavenged. With this in mind, we devel-
oped a Ti(III)-mediated reductive coupling of cyanoke-
tones and ketoesters leading to R-hydroxycycloalkanones,
in which the Ti(III) complex, Cp2TiPh, coordinates to a
cyano group or an ester carbonyl group so that the
F igu r e 1. Rate constants for 5-exo radical cyclizations.
induced-titanium(IV)-substituted ketyl radical efficiently
cyclizes to the Ti(III)-coordinated polar multiple bonds
without formation of the undesirable iminyl or alkoxy
radical intermediates (Scheme 1). In addition, coordina-
tion of the Lewis acidic Ti(III) species might lower the
LUMO of these acceptors and increase their trapping
ability of ketyl radicals. Herein, we report the full details
of our study on the Cp2TiPh-mediated cyanoketone
cyclization and related reactions with ester carbonyl
activation.3
Resu lts a n d Discu ssion
Red u ction of Nitr iles by Tita n ocen e(III) Com -
p lexes. Titanocene(III) reagents have received much
attention as an efficient one-electron reducing reagent
in organic synthesis.4 For example, Cp2TiCl induces the
diastereoselective pinacol coupling of aromatic and R,â-
unsaturated aldehydes.4a-f The Ti(III) reagent also pro-
motes ring opening of epoxides to generate â-alkoxy
radicals, which are utilized in the cyclization of epoxy-
olefins,4i,l the intermolecular addition of epoxides to
(1) (a) Beckwith, A. L. J .; Ingold, K. U. In Rearrangements in Ground
and Excited States; de Mayo, P., Ed.; Academic Press: New York, 1980;
Vol. 1, Chapter 4. (b) Surzur, J .-M. In Reactive Intermediates; Abra-
movitch, R. A., Ed.; Plenum Press: New York, 1982; Vol. 2, Chapter
3. (c) Curran, D. P. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon Press: Oxford, U.K., 1991; Vol. 4, Chapters 4.2.2 and
4.2.3. (d) Fossey, J .; Lefort, D.; Sorba, J . Free Radicals in Organic
Chemistry; J ohn Wiley & Sons: New York, 1995. (e) Curran, D. P.
Synthesis 1988, 417, 489. (f) Curran, D. P.; Porter, N. A.; Giese, B.
Stereochemistry of Radical Reactions; VCH: Weinheim, 1995.
(2) (a) J asperse, C. P.; Curran, D. P.; Fevig, T. L. Chem. Rev. 1991,
91, 1237. (b) Koert, U. Angew. Chem., Int. Ed. Engl. 1996, 35, 405.
(3) Yamamoto, Y.; Matsumi, D.; Itoh, K. Chem. Commun. 1998, 875.
10.1021/jo982492s CCC: $18.00 © 1999 American Chemical Society
Published on Web 04/02/1999

Reductive Radical Cyclization of Cyanoketones
J . Org. Chem., Vol. 64, No. 9, 1999 3225
Sch em e 1
F igu r e 2. Spin densities of Cp2TiPh-coordinated acetonitrile
and acetone.
Sch em e 2
Sch em e 3
Ta ble 1. Rea ction of Nitr iles a n d a n Ester w ith
Tita n iu m (III) Rea gen ts
reaction
entry
nitriles
PhCN
PhCN
PhCN
n-PrCN
EtO2CCH2CN Cp2TiPh
PhCH2CN Cp2TiPh
PhCH2CO2Me Cp2TiPh
Ti(III)
time (h)
products (yield, %)
PhCOCOPh (94%)
reactions without isolation (see the Experimental Sec-
tion). Benzonitrile reacted with 1.5 equiv6 of Cp2TiPh
followed by acid hydrolysis to give the expected coupling
product 3 in 94% yield (Table 1, entry 1). The phenyl-
titanium bond is essential, since the coupling reaction
did not take place under the same conditions using the
analogous Cp2TiCl generated by the reduction of Cp2TiCl2
with i-PrMgCl in sharp contrast to the report (Table 1,
entry 2).4g,h An alkyl complex, Cp2TiCH2Ph, showed some
reactivity but required a prolonged reaction time, and
the yield of the coupling product was much lower (Table
1, entry 3). In addition, other aliphatic nitriles (n-PrCN,
EtO2CCH2CN, PhCH2CN) gave no coupling products at
all. Phenylation products, instead, were obtained in 23-
35% yields (Table 1, entries 4-6). These results indicate
that the extensive resonance stabilization by the R-phenyl
substituent allows the generation of the unstable sp2-
imidoyl radical 1 from benzonitrile. In other cases,
however, the formation of N-titanaimidoyl radicals was
unfavorable without a stabilizing group at the R-position.
In such cases, the phenyl group transfers from the
coordinating Cp2TiPh to the coordinated cyano group. To
intramolecularly trap the imidoyl radical more efficiently
by an olefin acceptor, benzonitrile derivatives 4a and 4b
were reacted with Cp2TiPh, but no cyclization product
was obtained (Scheme 3). This is in striking contrast to
the successful radical cyclization of selenoimidate 5 to
chromanone 6.5d Moreover, this is consistent with PM3
semiempirical calculations,7 suggestive of the unpaired
spin being localized on the titanium center in Cp2TiPh-
(CH3CN) whereas the unpaired spin is almost completely
transferred to the carbonyl carbon from the titanium
center in Cp2TiPh(CH3COCH3) as shown in Figure 2. In
addition, the LUMO (â-spin) level of CP2TiPh(CH3CN)
(0.3 eV: UHF/PM3) is lower than that of CH3CN (1.4
eV: RHF/PM3), indicative of the Cp2TiPh-coordinated
nitriles being an efficient radical acceptor.
1
2
3
4
5
6
7
Cp2TiPh
1
Cp2TiCl overnight no reaction
Cp2TiBn overnight PhCOCOPh (20%)
Cp2TiPh
1
1
1
1
n-PrCOPh (35%)
Et2OCCH2COPh (30%)
PhCH2COPh (24%)
PhCH2COPh (23%)
activated olefins,4j,l and the stereoselective conversion of
epoxy alcohols into diols.4m,n In 1977, Teuben et al.
reported that Cp2TiCl and related Cp2TiR (R ) Ar, CH2-
Ph) reacted with cyanides to produce titaniumdiimine
complexes 2 via the N-titanaimidoyl radicals 1 (Scheme
2).4g,h We envisaged that if the imidoyl radical intermedi-
ate 1 can be applied to the radical addition chemistry,
unprecedented transformations of nitriles to carbonyl
compounds could be developed.5 Therefore, at the outset
of our study, we examined the generation of imidoyl
radicals from a variety of nitriles by the one-electron
reduction with several titanocene(III) reagents as sum-
marized in Table 1. According to the reported proced-
ures,4g,h Cp2TiPh was prepared and used for further
(4) (a) Hanada, Y.; Inanaga, J . Tetrahedron Lett. 1987, 46, 5717.
(b) Schobert, R. Angew. Chem., Int. Ed. Engl. 1988, 27, 855. (c)
Gansa¨uer, A. J . Chem. Soc., Chem. Commun. 1997, 457. (d) Gansa¨uer,
A. Synlett 1997, 363. (e) Gansa¨uer, A.; Bauer, D. J . Org. Chem. 1998,
63, 2070. (f) Barden, M. C.; Schwartz, J . J . Am. Chem. Soc. 1996, 118,
5484. (g) de Boer, E. J . M.; Teuben, J . H. J . Organomet. Chem. 1977,
140, 41. (h) de Boer, E. J . M.; Teuben, J . H. J . Organomet. Chem. 1978,
153, 53. (i) Nugent, W. A.; RajanBabu, T. V. J . Am. Chem. Soc. 1988,
110, 8561. (j) RajanBabu, T. V.; Nugent, W. A. J . Am. Chem. Soc. 1989,
111, 4525. (k) RajanBabu, T. V.; Nugent, W. A.; Beattie, M. S. J . Am.
Chem. Soc. 1990, 112, 6408. (l) Gansa¨uer, A.; Bluhm, H.; Pierobon,
M. J . Am. Chem. Soc. 1998, 120, 12849. (m) Yadav, J . S.; Srinivas, D.
Chem. Lett. 1997, 905. (n) Chakraborty, T. K.; Dutta, S. J . Chem. Soc.,
Perkin Trans. 1 1997, 1257. (o) Davies, S. G.; Thomas, S. E. Synthesis
1984, 1027. (p) Yanlong, Q.; Guisheng, L.; Huang, Y.-Z. J . Organomet.
Chem. 1990, 381, 29. (q) Spencer, R. P.; Schwartz, J . J . Org. Chem.
1997, 62, 4204.
(5) For radical addition of imidoyl radicals, see: (a) Leardini, R.;
Pedulli, G. F.; Tundo, A.; Zanardi, G. J . Chem. Soc., Chem. Commun.
1984, 1320. (b) Leardini, R.; Nanni, D.; Pedulli, G. F.; Tundo, A.;
Zanardi, G. J . Chem. Soc., Perkin Trans. 1 1986, 1591. (c) Leardini,
R.; Nanni, D.; Tundo, A.; Zanardi, G. J . Chem. Soc., Chem. Commun.
1989, 757. (d) Bachi, M. D.; Denenmark, D. J . Am. Chem. Soc. 1989,
111, 1886. (e) Curran, D. P.; Liu, H. J . Am. Chem. Soc. 1991, 113,
2127. (f) Fukuyama, T.; Chen, X.; Peng, G. J . Am. Chem. Soc. 1994,
116, 3127. (f) Bachi, M. D.; Denenmark, D. J . Org. Chem. 1990, 55,
3442.
(6) Although 1 equiv of the Ti(III) reagent is theoretically required,
1.5 equiv of Cp2TiPh was used to ensure the completion of reaction.
(7) Semiempirical calculations were carried out using MacSpartan
plus (Wavefunction, Inc.). Geometries of Cp2TiPh(CH3CN) and Cp2-
TiPh(CH3COCH3) were optimized at the unrestricted Hartree-Fock
(UHF) level with a PM3 Hamiltonian (Stewart, J . J . R. J . Comput.-
Aided Mol. Des. 1990, 4, 1).

3226 J . Org. Chem., Vol. 64, No. 9, 1999
Yamamoto et al.
Sch em e 4
Sch em e 5
In tr a m olecu la r Ketyl Ra d ica l Ad d ition s to Cp 2-
TiP h -Coor d in a ted C-N Tr ip le Bon d . Although imi-
doyl radicals could not be generated by the single electron
reduction of both aromatic and aliphatic nitriles with
titanocene(III) reagents, Cp2TiPh-coordinated nitriles are
still fascinating as a radical acceptor (vide supra). To
realize the radical addition to coordinated nitriles, we
then investigated the reaction of ketonitriles with the
Ti(III) reagent (Scheme 4).8 To our knowledge, the
intramolecular reductive coupling of ketonitriles is quite
rare, and so far, only few examples using one-electron
Ta ble 2. Cp 2TiP h -Med ia ted Red u ctive Cou p lin g of
Keton itr iles 7a -g
10
reducing agents such as Zn9 and SmI2 were reported
in addition to the electroreductive method.11 In a manner
similar to the above nitrile coupling, 2-cyanoethylcyclo-
pentanone 7a was treated with the preformed solution
of Cp2TiPh in toluene at 0.1 M concentration to afford
the 5-exo cyclization product 8a in 77% yield after
hydrolysis and chromatographic separation (Table 2,
entry 1). The less reactive Cp2TiCl again did not promote
the coupling reaction under the same conditions.
Intramolecular coupling products 8b and 8c were
similarly obtained from cyanoethylcyclohexanone 7b and
cyanoethylcycloheptanone 7c in 70 and 43% yields,
respectively (Table 2, entries 2 and 3). Acyclic ketone 7d
also gave 8d , but the yield was lower than those of the
above cyclic precursors due to the conformational flex-
ibility around the carbonyl group (Table 2, entry 4). A
high dilution and a prolonged reaction time were required
to increase the yield up to 50% (Table 2, entry 5). In
contrast, the inverse addition of the Ti(III) reagent to 7d
decreased the yield (17%). Thus, the high local concentra-
tion of the Ti(III) reagent is critical for the present
cyclization. In general, aromatic ketones are more readily
reduced than aliphatic ketones since the resultant ketyl
radicals are highly stabilized by the R-phenyl group.
Therefore, the aryl-substituted ketone 9 was reported to
be over-reduced to give cyano alcohol 10 under electro-
reduction conditions (Scheme 5).11 On the other hand, 9
was cleanly cyclized by our method to afford the tricyclic
R-hydroxyketone 11 in 58% yield.
ketone. Cyanopropylcyclopentanone 7e was subjected to
reductive cyclization to give the desired product 8e in
only 20% yield at a 0.1 M concentration (Table 1, entry
6). The high dilution conditions (0.04 M) again improved
the yield (45%, entry 7). Similarly, the six-membered
cyanoketone 7f and acyclic cyanoketone 7g afforded
cyclized products 8f and 8g in 69 and 42% yields,
respectively. It is interesting that the trans-fused product
was selectively obtained from 7f, whereas the cis-fused
isomer was exclusive for 8a -c, 11, and 8e. Furthermore,
the reaction of ꢀ-cyanoketone 7h did not give the desired
7-exo reductive cyclization product. Instead, the carbonyl
group and/or the nitrile moiety were phenylated by the
titanium(III) reagent to give 12 and 13 (Scheme 6). The
phenylation product 13 indicates that both the carbonyl
and cyano termini are definitely coordinated by the
Ti(III) complex.
As already described, the 5-exo cyclization of γ-keto-
nitriles was achieved using Cp2TiPh, and cyclic ketones
7a -c and 9 were more readily cyclized than acyclic
ketone 7d . We next examined the 6-exo cyclization of
δ-cyanoketones and the 7-exo cyclization of an ꢀ-cyano-
(8) For radical cyclization involving a nitrile group, see: (a) Clive,
D. L. J .; Beaulieu, P. L.; Set, L. J . Org. Chem. 1984, 49, 1313. (b)
Chenera, B.; Chuang, C.-P.; Hart, D. J .; Hsu, L.-Y. J . Org. Chem. 1985,
50, 5409. (c) Tsang, R.; Fraser-Reid, B. J . Am. Chem. Soc. 1986, 108,
2116. (d) Snider, B. B.; Buckman, B. O. J . Org. Chem. 1992, 57, 322.
(also see refs 9-11).
(9) Corey, E. J .; Pyne, S. G. Tetrahedron Lett. 1983, 24, 2821.
(10) Molander, G. A.; Kenny, C. J . Am. Chem. Soc. 1989, 111, 8236.
(11) Shono, T.; Kise, N.; Fujimoto, T.; Tominaga, N.; Morita, H. J .
Org. Chem. 1992, 57, 7175.
To obtain further insight into the reaction mechanism,
the cyclization of 9 was carried out in the presence of

Reductive Radical Cyclization of Cyanoketones
J . Org. Chem., Vol. 64, No. 9, 1999 3227
Sch em e 6
Sch em e 9
Sch em e 7
Sch em e 10
Sch em e 8
ketoester cyclization depicted in Scheme 9. Cyclic ke-
toesters 16a and acyclic 16b were treated with Cp2TiPh
under the high dilution conditions to selectively afford
the R-hydroxycyclopentanones 11 and 17 in 49 and 39%
yields, respectively. In these cases, the phenyl group R
to the carbonyl is essential. The nonaromatic ketone 16c
gave no cyclized product.13 Therefore, the ketoester
cyclization was limited to aromatic ketones such as 16a
and b due to the less electrophilic character of the Cp2-
TiPh-coordinated ester group.
In addition to the heterocouplings of the ketonitriles
and ketoesters, the homocoupling of diketone was then
investigated (Scheme 10). Diketone 18 was treated with
Cp2TiPh to give the expected pinacol coupling product
19 in 52% yield via a simple intramolecular diradical
coupling (I) or possibly, intramolecular addition of the
more stable, long-lived phenyl-substituted ketyl radical
to the Cp2TiPh-coordinated nonaromatic ketone (J ).
excess i-PrOH. As a result, the hydroxyketone 11 was
obtained in 41% yield; however, the simple reduction
product 10 was not formed at all.11 This observation rules
out an alternative anionic mechanism via a two-electron
reduction of the ketones followed by cyclization of the
resultant R-alkoxy anions to cyano groups. The inter-
mediacy of Cp2TiPh was supported by the experiment
shown in Scheme 7. In situ reduction of the known
complex Cp2Ti(Ph)Cl12 by Zn produces Cp2TiPh, which
mediated the cyclization of 9 to 11 in good yield (Scheme
7). The corresponding catalytic reaction did not take place
because of the low concentration of the Ti(III) species
(vide infra).
The present cyanoketone cyclization is a powerful route
to R-hydroxycycloalkanones. The synthetic potential of
this method was also demonstrated in the double cycliza-
tion of dicyanodiketones 14, giving rise to interesting
angular triquinane derivatives 15 (Scheme 8). Benzo-
fused 14a was treated with Cp2TiPh to give the desired
C2-symmetric tetracyclic product 15a in high yield. The
parent dicyanodiketone 12b showed a lower reactivity,
but the double cyclization product 15b was also obtained
in 40% yield. In contrast, the less strained cyclohexane-
dione derivative 14c gave no cyclization product.
In tr a m olecu la r Ketyl Ra d ica l Ad d ition s to Cp 2-
TiP h -Coor d in a ted C-O Dou ble Bon d s. The ketyl
radical accepting ability of the Ti(III)-coordinated ester
carbonyl group is also demonstrated by the aromatic
In t r a m olecu la r Ket yl R a d ica l Ad d it ion t o C-C
Dou ble Bon d s. Recently, Molander et al. reported the
SmI2-promoted reductive cyclization of δ,ꢀ-unsaturated
ketoesters, demonstrating that the ketyl-trapping ability
of nitriles is lower than those of alkenes, alkynes,
ketones, or aldehydes.10 In our hand, the double coordi-
nation to both the carbonyl and cyano groups by the
(13) The reductive cyclization of ketoester 12c in Na/ammonia was
reported to give a mixture of products given below (Gutsche, G. D.;
Tao, I. Y. C.; Kozma, J . J . Org. Chem. 1967, 32, 1782.).
(12) Waters, J . A.; Mortimer, G. A. J . Organomet. Chem. 1970, 22,
417.

3228 J . Org. Chem., Vol. 64, No. 9, 1999
Yamamoto et al.
Exp er im en ta l Section
Sch em e 11
Gen er a l Meth od s. 1H and 13C NMR spectra were obtained
at 300 and 75 MHz, respectively, for samples in CDCl3
solution. Flash chromatography was performed using a silica
gel column (Merck Silica gel 60) eluted with mixed solvents
(hexane/ethyl acetate). Ether and toluene were distilled from
CaH2, degassed, and stored over Na. Cp2TiCl2 was purchased
from Kanto Chemical Co., Inc.
Cp 2TiP h -Med ia t ed R ed u ct ive Cou p lin g of Ben zo-
n itr ile. To a suspension of Cp2TiCl2 (747 mg, 3.0 mmol) in
dry degassed toluene (10 mL) was added a solution of freshly
prepared i-PrMgCl [i-PrCl (259 mg, 3.3 mmol) and Mg (160
mg, 6.6 mmol)] in dry degassed ether (5 mL) under Ar
atmosphere at room temperature. The reaction mixture was
stirred for 30 min. To the resultant green solution was added
a solution of freshly prepared PhMgBr [PhBr (471 mg, 3.0
mmol) and Mg (146 mg, 6.0 mmol)] in dry degassed ether (5
mmol) at room temperature, and the reaction mixture was
stirred for further 30 min. To the obtained dark-green Cp2-
TiPh solution was added benzonitrile (206 mg, 2 mmol) at room
temperature, and the reaction mixture was stirred for 1 h. The
reaction was quenched by 1 N HCl (10 mL), and the mixture
was stirred for 30 min. The organic layer was separated and
washed with brine (20 mL). The aqueous layer was extracted
with ethyl acetate (20 mL × 3). The combined organic layer
was dried with MgSO4 and concentrated in vacuo. The crude
mixture was purified by silica gel flash column chromatogra-
phy (hexane-AcOEt 20:1) to give benzil 3 (198 mg, 94%) as
white needles. The reactions of Cp2TiPh with other nitriles
and methyl phenylacetate are performed in the same manner.
Products and yields are summarized in Table 1.
Gen er a l P r oced u r e for Cp 2TiP h -Med ia ted Cycliza tion
of Cya n ok eton es. To a suspension of Cp2TiCl2 (747 mg, 3.0
mmol) in dry degassed toluene [10 mL (25 mL for 7d -h )] was
added a solution of freshly prepared i-PrMgCl [i-PrCl (259 mg,
3.3 mmol) and Mg (160 mg, 6.6 mmol)] in dry degassed ether
(5 mL) under Ar atmosphere at room temperature. The
reaction mixture was stirred for 30 min. To the resultant green
solution was added a solution of freshly prepared PhMgBr
[PhBr (471 mg, 3.0 mmol) and Mg (146 mg, 6.0 mmol)] in dry
degassed ether (5 mL) at room temperature, and the reaction
mixture was stirred for a further 30 min. To the obtained dark-
green Cp2TiPh solution was added a solution of cyanoketone
7 (1 mmol) in dry degassed toluene [10 mL (20 mL for 7d -h ,
9)] at room temperature, and the reaction mixture was stirred
for 1 h (2 h for 7d -h , 9). The reaction was quenched by 1 N
HCl (10 mL), and the mixture was stirred for 30 min. The
organic layer was separated and washed with brine (20 mL).
The aqueous layer was extracted with ethyl acetate (20 mL ×
3). The combined organic layer was dried with MgSO4 and
concentrated in vacuo. The crude mixture was purified by silica
gel flash column chromatography to give R-hydroxycyclo-
alkanone 8. The yields are summarized in Table 2, and
R-hydroxycycloalkanones 8a -g, 11 are reported in ref 11.
Compound 17 is reported in ref 15. The reductive cyclizations
of unsaturated cyanides 4a ,b, ketoester 16a ,b, diketone 18,
and ketonitrile 22 were also performed in the same manner
with 7d -h .
Sch em e 12
Ti(III) complex realized the efficient reductive cyclization
of a variety of ketonitriles under mild conditions. In this
context, alkenyl groups are no longer superior to the
cyano group as a ketyl radical acceptor. In fact, R-butenyl
ketone 20 did not give the expected cyclization product
after 24 h and was recovered with the carbonyl group
intact (75% recovery). This result showed that the ketyl
radical formation is reversible, and this reversibility
combined with the steric hindrance of the Cp2TiPh-
coordinated ketyl moiety makes the 5-exo-trig cyclization
of 21 ineffective (Scheme 11). In contrast, a cyano group
on the olefin terminus dramatically enhanced the cy-
clization ability, and as a result, intramolecular cycliza-
tion of 22 gave the cyano alcohol 23 in 64% yield (Scheme
12).14 These facts again demonstrated the efficiency of
the Cp2TiPh-coordinated cyano group as a ketyl radical
acceptor.
Con clu sion s
In conclusion, the Cp2TiPh-mediated reductive radical
cyclization of cyanoketones in both the 5- and 6-exo
modes was successful to provide an easy entry to the 5-
and 6-membered R-hydroxycycloalkanones. The coordina-
tion of Cp2TiPh to the cyano group plays a key role in
the present cyclization; i.e., the titanium reagent coor-
dinates to both the carbonyl and cyano moieties. As a
result, the LUMO of the cyano group is lowered, and
cyclization proceeds irreversibly without formation of the
unstable iminyl radical intermediates. In this situation,
a low concentration of the Ti(III) reagent is unfavorable.
In our hands, the intramolecular reductive radical cy-
clization of aromatic ketoesters also gave the correspond-
ing R-hydroxycycloalkanones, in which Cp2TiPh-coordi-
nated ester group also functions as a ketyl radical
acceptor. Such an effect did not occur for the R-butenyl
ketone, producing no reductive cyclization product. Fur-
thermore, a cyclohexanone with a cyanoolefin terminus
gave an intramolecular Michael-type radical addition
product.
Sp ectr a l d a ta for 11: oil (eluant, hexane-AcOEt 3:1); IR
(neat) 3427 (OH) 1742 (CdO) cm-1; 1H NMR δ 1.74 (1 H, ddt,
J ) 13.1, 10.8, 9.6 Hz), 1.86-2.04 (2 H, m), 2.17 (1 H, dddd, J
) 14.3, 11.4, 6.6, 4.2 Hz), 2.31 (1 H, dd, J ) 19.5, 9 Hz), 2.39
(1 H, ddd, J ) 19.5, 9.6, 5.4 Hz), 2.50 (1 H, ddd, J ) 15.2, 7.5,
3.9 Hz), 2.86 (1 H, ddd, J ) 17.7, 6.6, 3 Hz), 2.95 (1 H, ddd, J
) 17.7, 11.4, 6 Hz), 3.10 (1 H, br s), 7.14-7.27 (3 H, m), 7.42
(1 H, dd, J ) 7.5, 1.5 Hz); 13C NMR δ 19.3, 20.7, 24.5, 33.5,
41.3, 77.2, 126.6, 127.9, 128.3, 129.5, 132.2, 136.8, 217.6; MS
(EI) m/z (rel intensity) 202 (M+, 99), 174 (47), 146 (100). Anal.
Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C, 77.18; H,
6.98.
Sp ectr a l d a ta for 12: oil (eluant, hexane-AcOEt 1:1); IR
(neat) 3447 (OH), 2246 (CtN) cm-1; 1H NMR δ 1.00-2.50 (15
(14) Similar chemoselectivity was observed in the reaction of 5-hex-
enal derivatives with SmI2 (Enholm, E. J .; Trivellas, A. Tetrahedron
Lett. 1989, 30, 1063).
(15) Syper, L. Tetrahedron 1987, 43, 2853.

Reductive Radical Cyclization of Cyanoketones
J . Org. Chem., Vol. 64, No. 9, 1999 3229
H, m), 7.00-7.65 (5 H, m); 13C NMR δ 16.8, 21.5, 25.47, 27.1,
27.5, 29.6, 43.7, 50.9, 76.3, 76.9, 84.0, 120.0, 125.0, 126.7, 128.3,
146.0. Anal. Calcd for C16H21NO: C, 78.97; H, 8.70; N, 5.76.
Found: C, 79.11; H, 9.04; N, 5.57.
Sp ectr a l d a ta for 13: oil (eluant, hexane-AcOEt, 5:1); IR
(neat) 3493 (OH), 1682 (CdO) cm-1; 1H NMR δ 1.00-3.10 (16
H, m), 7.00-8.10 (10 H, m); 13C NMR δ 21.5, 24.2, 27.6, 28.0,
29.5, 38.2, 43.6, 50.7, 80.0, 125.1, 126.5, 128.2, 128.3, 128.7,
133.0, 137.2, 146.3, 200.8. Anal. Calcd for C22H26O2: C, 81.95;
H, 8.13. Found: C, 81.84; H, 8.23.
Red u ctive Cycliza tion of 5e Usin g Cp 2Ti(P h )Cl/Zn /
Me3SiCl. To a solution of Cp2Ti(Ph)Cl (149 mg, 0.6 mmol) and
Zn (39 mg, 0.6 mmol) in dry degassed THF (7 mL) was added
Me3SiCl (0.11 mL, 0.9 mmol), and the solution was stirred for
1 h under Ar atmosphere at room temperature. To the
resultant green solution was added a solution of 9 (60 mg, 0.3
mmol) in dry degassed THF (5 mL) at room temperature, and
the reaction mixture was stirred for a further 2 h. The
standard workup as described above gave 11 (43 mg, 71%).
Cp2TiP h -Mediated Dou ble Cyclization of Dicyan odike-
ton e. According to the procedure for 7d -h , dicyanodiketone
14a (126 mg, 0.5 mmol) was cyclized to afford 96 mg of
tetracyclic R-hydroxyketone 15a (0.37 mmol, 75%) as a solid:
mp 171.5-172.0 °C (eluant, hexane-AcOEt 2:1); IR (CH2Cl2)
Sp ectr a l d a ta for 19: solid; mp 115.5-116.0 °C (eluant,
1
hexane-AcOEt 5:1); IR (CH2Cl2) 3586 (OH) cm-1; H NMR δ
0.66 (1 H, br s), 1.40 (3 H, s), 1.66-2.09 (6 H, m), 1.73 (1 H, br
s), 2.33 (1 H, q, J ) 6.6 Hz), 2.62 (1 H, ddd, J ) 15.3, 6.9, 4.5
Hz), 2.79 (1 H, ddd, J ) 15.3, 9.3, 4.8 Hz), 7.13-7.29 (3 H, m),
7.66 (1 H, dd, J ) 7.5, 1.5 Hz); 13C NMR δ 22.4, 27.7, 27.8,
27.9, 37.5, 48.9, 81.9, 83.8, 126.0, 126.8, 127.3, 128.1, 137.9,
140.9; MS (EI) m/z (rel intensity) 218 (M+, 98), 200 (85), 159
(63), 145 (100). Anal. Calcd for C14H18O2: C, 77.03; H, 8.31.
Found: C, 77.00; H, 8.34.
3530 (OH), 1744 (CdO) cm-1 1H NMR δ 1.71 (2 H, dt, J )
;
12.5, 7 Hz), 2.30 (1 H, dd, J ) 17, 1.5 Hz), 2.32 (1 H, dd, J )
16.5, 0.5 Hz), 2.57 (2 H, ddd, J ) 16.5, 12.5, 7 Hz), 2.64 (1 H,
dd, J ) 9.5, 0.5 Hz), 2.66 (1 H, dd, J ) 9.5, 1.5 Hz), 7.32-7.35
(2 H, m), 7.36-7.39 (2 H, m); 13C NMR δ 26.8, 35.3, 56.1, 87.2,
123.9, 130.5, 142.7, 216.0; MS (EI) m/z (rel intensity) 258 (M+,
85), 240 (82), 185 (93), 159 (100). Anal. Calcd for C15H14O4:
C, 69.76; H, 5.46. Found: C, 69.85; H, 5.37.
Sp ectr a l d a ta for 23: oil (eluant, hexane-AcOEt 2:1); IR
(neat) 3446 (OH), 2249 (CtN) cm-1; 1H NMR δ 1.20-1.80 (12
H, m), 1.90-2.25 (4 H, m), 2.46 (1 H, dd, J ) 16, 5 Hz) [minor
isomer δ 1.05-1.71 (8 H, m), 1.75 (1 H, m), 1.84-2.19 (3 H,
m), 2.22-2.51 (2 H, m)]; 13C NMR δ 16.4, 19.8, 20.7, 22.8, 23.5,
25.6, 27.4, 44.2, 46.9, 77.5, 119.5 [minor isomer δ 17.1, 22.9,
24.3, 27.3, 27.8, 30.0, 34.2, 39.3, 47.6, 80.1, 120.4]; MS (EI)
m/z (rel intensity) 179 (M+, 31), 162 (8), 111 (100). Anal. Calcd
for C11H17NO: C, 73.70; H, 9.56; N, 7.81. Found: C, 73.53; H,
9.73; N, 7.50.
In the same manner, 14b was converted into 15b: solid;
mp 122.5-123.8 °C (eluant, hexane-AcOEt 1:1); IR (CH2Cl2)
3550 (OH), 1742 (CdO) cm-1; 1H NMR δ 1.67 (4 H, m), 2.15 (2
H, m), 2.35-2.64 (6 H, m), 2.79 (2 H, br s); 13C NMR δ 26.2,
35.6, 35.8, 58.8, 86.8, 219.6; MS (EI) m/z (rel intensity) 210
(M+, 10), 192 (19), 182 (50), 137 (100). Anal. Calcd for
C11H14O4: C, 62.85; H, 6.71. Found: C, 62.75; H, 6.81.
Cp 2TiP h -Med ia ted Red u ctive Cycliza tion of 9 in th e
P r esen ce of i-P r OH. To the Cp2TiPh solution prepared as
above [Cp2TiCl2 (747 mg, 3.0 mmol)/toluene (10 mL) with
i-PrMgCl (3.3 mmol)/ether (5 mL) and PhMgBr (3.0 mmol)/
ether (5 mL)] was added a solution of cyanoketone 9 (199 mg,
1 mmol) in toluene (10 mL) and i-PrOH (10 mL) at room
temperature, and the reaction mixture was stirred for 2 h. The
standard workup as described above gave 11 (83 mg, 41%).
Ack n ow led gm en t. We gratefully acknowledge the
financial support (09750947 and 09305059) from the
Ministry of Education, Science, Sports and Culture,
J apanese Government.
J O982492S