Enolate formation from cyclopropyl ketones via iodide-induced ring opening and its use for stereoselective aldol reaction

Article abstract of DOI:10.1016/S0040-4020(00)01094-2

Treatment of cyclopropyl ketones with TiCl₄-n-Bu₄NI mixed reagent provides (Z)-titanium enolates which afford syn-α-iodethyl-β-hydroxyketones stereoselectively upon subsequent reaction with various aldehydes. The aldol adducts are cyclized into trans-acyltetrahydrofurans in good yield by active alumina. In contrast, the use of Et₂AlI in place of TiCl₄-n-Bu₄NI provides the corresponding anti aldol adducts with high stereoselectivity. These methods can complementarily provide both syn and anti isomers of α-iodoethyl-β-hydroxyketones from cyclopropyl ketones and aldehydes.

Full text of DOI:10.1016/S0040-4020(00)01094-2

TETRAHEDRON
Pergamon
Tetrahedron 57 (2001) 987±995
Enolate formation from cyclopropyl ketones via iodide-induced
ring opening and its use for stereoselective aldol reaction
Zhenfu Han, Shigeki Uehira, Takayuki Tsuritani, Hiroshi Shinokubo and Koichiro Oshimap
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Received 13 October 2000; accepted 17 November 2000
AbstractÐTreatment of cyclopropyl ketones with TiCl4-n-Bu4NI mixed reagent provides (Z)-titanium enolates which afford syn-a-
iodethyl-b-hydroxyketones stereoselectively upon subsequent reaction with various aldehydes. The aldol adducts are cyclized into trans-
acyltetrahydrofurans in good yield by active alumina. In contrast, the use of Et2AlI in place of TiCl4-n-Bu4NI provides the corresponding anti
aldol adducts with high stereoselectivity. These methods can complementarily provide both syn and anti isomers of a-iodoethyl-b-hydroxy-
ketones from cyclopropyl ketones and aldehydes. q 2001 Elsevier Science Ltd. All rights reserved.
Conjugate addition reaction of various nucleophiles to a,b-
unsaturated compounds such as 1,2-enones has been recog-
nized as an ef®cient route for enolate formation.1 The
sequential reaction of the resulting enolate with electro-
philes provides an extremely effective methodology for
construction of the carbon framework of organic molecules
(Scheme 1).2 Ring opening of cyclopropyl ketones is also an
attractive method for synthetic chemists to prepare enolates
and has been explored extensively.3,4 Herein we wish to
report that metal iodides can mediate enolate formation
from cyclopropyl ketones, and the sequential trapping
of the resulting metal enolates with aldehydes affords
3-hydroxy-2-(20-iodoethy)ketones stereoselectively.
1. Enolate formation from cyclopropyl ketones via
TiCl4-n-Bu4NI-induced ring opening
Treatment of tetrabutylammonium iodide with TiCl4 in
dichloromethane at 08C provided a dark-red solution.5 To
the resulting solution was added cyclopropyl phenyl ketone
(1a) at 08C. After stirring for 1 h, an addition of benzalde-
hyde afforded syn aldol adduct 3a in 75% yield (Scheme 2).
Results of the aldol reaction of the enolate 2 with various
aldehydes are summarized in Table 1. The titanium enolate
2 is reactive toward both aromatic and aliphatic aldehydes.
For example, acetaldehyde afforded the syn adduct 3e in
80% yield without contamination by the anti-isomer
(entry 5). Ring opening of cyclopropyl methyl ketone (1b)
also proceeds facilely with this reagent. Interestingly, exclu-
sive formation of syn-b-hydroxy ketones 3 was observed in
most cases except the reaction of 1b with acetaldehyde
(entry 8).
Starting from cyclopropyl phenyl ketone (1a), the initial
products, syn-b-hydroxy ketones, were partially converted
into trans-acyltetrahydrofuran derivatives 4 under the reac-
tion conditions. For example, an addition of 2-methyl-
propanal to the titanium enolate 2 derived from 1a and
Scheme 1.
Scheme 2.
Keywords: cyclopropyl ketones; aldol reaction; nucleophiles.
Corresponding author. Tel.: 181-75753-5523; fax: 181-75753-4863; e-mail: oshima@fm1.kuic.kyoto-u.ac.jp
p
0040±4020/01/$ - see front matter q 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)01094-2

988
Z. Han et al. / Tetrahedron 57 (2001) 987±995
Table 1. TiCl4-n-Bu4NI-induced aldol reaction of cyclopropyl ketone
Entry
Cyclopropyl ketone
R0CHO
Yield (%)
(syn/anti)
3
4
1
2
3
4
5
6
7
8
RˆPh: 1aa
RˆPh: 1aa
RˆPh: 1aa
RˆPh: 1aa
RˆPh: 1aa
RˆCH3: 1bb
RˆCH3: 1bb
RˆCH3: 1bb
PhCHO
3a
3b
3c
3d
3e
3f
75 (.99/1)
55 (.99/1)
64 (.99/1)
±
80 (.99/1)
72 (.99/1)
54 (.99/1)
85 (80/20)
4a
4b
4c
4d
±
±
±
±
14
13
23
88
±
±
±
±
n-C9H19CHO
i-C3H7CHO
t-C4H9CHO
CH3CHO
PhCHO
t-C4H9CHO
CH3CHO
3g
3h
a
Cyclopropyl phenyl ketone (1a) was treated at 08C and the aldehyde was added at 2788C.
Cyclopropyl methyl ketone (1b) was treated at 2788C. The aldehyde was added at 2788C and the reaction mixture was warmed to 08C.
b
TiCl4-n-Bu4NI provided trans-2-isopropyl-3-benzoyltetra-
hydrofuran in 23% yield along with the corresponding syn
aldol adduct 3c (Table 1, entry 3). The formation of 4 could
not be prevented in the case of 3a, 3b, 3c and 3d because of
the facile conversion into 4.6 In contrast, the corresponding
tetrahydrofuran 4 could not be found in the crude product
when cyclopropyl methyl ketone (1b) was employed instead
of 1a. The crude products (a mixture of 3 and 4, or 3) were
treated with active alumina in ether to afford 4 as a single
product with high stereoselectivity.7 Results of the sequen-
tial treatment of 1a and 1b with TiCl4-n-Bu4NI and alumina
to provide acyltetrahydrofurans are shown in Table 2.
at the cyclopropane ring occurs perpendicularly to the
carbonyl group in the favored conformation of 1 to furnish
(Z)- enolates 2. The successive aldol reaction takes place
through the six-membered transition state A to provide the
syn-aldol adducts.
2. Enolate formation from cyclopropyl ketones via
Et2AlI-mediated ring opening
Conjugate addition of diethylaluminum iodide (Et2AlI) to
a,b-unsaturated carbonyl compounds and the sequential
aldol condensation of the resulting aluminum enolates
provides a-substituted-a,b-unsaturated carbonyl com-
pounds directly.8 The elimination of HI proceeds rapidly
under the reaction conditions to generate the carbon±carbon
double bond (Scheme 4).
The formation of syn-isomers can be explained as follows
(Scheme 3). The attack of the iodide in the titanium reagent
Table 2. Alumina-induced cyclization of aldol adduct
We found the TiCl4-n-Bu4NI-induced enolate formation as
described in Section 1; then it was anticipated that Et3AlI
Entry
Cyclopropyl ketone
R0CHO
PhCHO
n-C9H19CHO
i-C3H7CHO
CH3CHO
PhCHO
Yield (%)
94
1
2
3
4
5
6
7
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆCH3: 1b
RˆCH3: 1b
RˆCH3: 1b
4a
4b
4c
4e
4f
67
64
78
72
76
60
t-BuCHO
CH3CHO
4g
4h
Scheme 4.
Scheme 3.

Z. Han et al. / Tetrahedron 57 (2001) 987±995
989
Scheme 5.
Table 3. Et2AlI-induced aldol reaction of cyclopropyl ketone
Table 4. Me3SiI-induced ring opening of cyclopropyl ketones and the
sequential aldol reaction
Entry Cyclopropyl ketone 1
Aldehyde
Yield (%) (anti/syn)
Entry
Cyclopropyl ketone 1
Aldehyde
Yield (%) (syn/anti)
1
2
3
4
5
6
7
8
9
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆCH3: 1b
RˆCH3: 1b
RˆCH3: 1b
RˆCH3: 1b
PhCHO 6a
n-C9H19CHO 6b
89 (.99/1)
68 (.99/1)
84 (.99/1)
73 (.99/1)
96 (71/29)
89 (.99/1)
94 (.99/1)
54 (.99/1)
93 (70/30)
1
2
3
4
5
6
7
8
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆPh: 1a
RˆCH3: 1b
RˆCH3: 1b
RˆCH3: 1b
RˆCH3: 1b
RˆCH3: 1b
PhCHO
69 (69/40)
84 (60/40)
86 (67/33)
89 (86/14)
65 (.99/1)
79 (50/50)
78 (70/30)
65 (70/30)
88 (50/50)
49 (86/14)a
74 (50/50)
i-C3H7CHO
t-C4H9CHO
CH3CHO
6c
6d
6e
6f
n-C9H19CHO
n-C6H13CHO
i-C3H7CHO
t-C4H9CHO
CH3CHO
PhCHO
i-C3H7CHO
t-C4H9CHO
CH3CHO
6g
6h
6i
PhCHO
i-C3H7CHO
n-CpH19CHO
t-C4H9CHO
CH3CHO
9
10
11
would also work to open cyclopropyl ketones. Indeed, this
proved to be the case, and the reaction of cyclopropyl
ketones with Et2AlI gave diethylaluminum 4-iodoenolates
5 which provided anti aldol adducts 6 with high stereoselec-
tivity upon treatment with aldehydes. Et2AlI was added to a
solution of cyclopropyl phenyl ketone (1a) in hexane at 08C.
After stirring for 1 h at 08C, ether and benzaldehyde were
added to the resulting aluminum enolate 5a. The reaction
mixture was stirred for another 1 h at 08C. After aqueous
workup, puri®cation of the crude product provided the anti
aldol adduct 6a in 89% yield without contamination by the
syn-isomer (Scheme 5). It should be noted that no products
arising from an elimination of HI from the aldol adduct
could be detected.
a
3-acetyl-2-tert-butyltetrahydrofuran (4g) was obtained in 18% yield.
isomeric mixture of anti-6a and syn-3a (38/62). Complete
isomerization of syn-3a into anti-6a was observed upon
treatment with Et3Al (Scheme 6). On the basis of these
facts, we assume that the exclusive formation of anti aldol
adducts can be attributed to thermodynamic preference.
Whereas the aldol reaction at 2788C proceeds under kinetic
control without isomerization, the equilibrium is achieved
rapidly at 08C via the retro-aldol reaction to give a thermo-
dynamically more stable anti adduct as a single product.9 In
the case of the reaction of acetaldehyde, no variation in the
ratio of anti-6e and syn-3e was observed when the reaction
mixture was stirred at 258C for 3 h. Thus, the equilibrium
was established at this ratio (anti/synˆ70/30).
The results of the aldol reaction with various aldehydes are
shown in Table 3. Cyclopropyl phenyl ketone (1a) and
methyl ketone 1b are equally effective for the reaction. In
each case, anti-3-hydroxy-2-(20-iodoethyl)ketone 6 is
obtained as a single stereoisomer except in the case where
acetaldehyde is employed (entry 5 or 9).
3. Enolate formation from cyclopropyl ketones via
Me3SiI-mediated ring opening
Trimethylsilyl iodide10 is known to open the cyclopropane
ring of cyclopropyl ketones to provide silyl enolates.11
Thus, we investigated the Mukaiyama aldol reaction of
At 2788C, an addition of benzaldehyde to the aluminum
enolate 5a, generated from 1a and Et2AlI, afforded a stereo-
Scheme 6.

990
Z. Han et al. / Tetrahedron 57 (2001) 987±995
TiCl4-n-Bu4NI mixed reagent possesses a nucleophilic
character and low Lewis acidity because of its nature as
an ate-complex. Et2AlI also afforded the primary iodo-
ketone 9 predominantly, whereas trimethylsilyl iodide
exhibited the opposite regioselectivity to provide the
secondary iodide 10 as a major product.
Treatment of 8 with TiCl4-n-Bu4NI followed by an addition
of benzaldehyde afforded the trisubstituted tetrahydrofuran
11 in 61% yield as a single diastereomer (Scheme 8).13 The
syn-aldol adduct 12 was also obtained in 5% yield. On the
other hand, the use of Et2AlI instead of TiCl4-n-Bu4NI
provided the anti-aldol adduct 13 in 72% yield with
excellent stereoselectivity (one major isomer/three other
isomersˆ97/3). The cyclization of the adduct 13 by active
alumina furnished another stereoisomer of tetrahydrofuran
derivative 14 quantitatively.
Scheme 7.
the resulting silyl 4-iodoenolates 7 with TiCl4 in a one-pot
procedure. Treatment of the silyl enolate 7, prepared from
cyclopropyl ketone 1 and Me3SiI, with aldehydes in the
presence of TiCl4 afforded the corresponding aldol adducts
as diastereoisomeric mixtures. The results are shown in
Table 4. In most cases, no signi®cant diastereoselectivity
was observed. Therefore, the former two methods with
TiCl4-n-Bu4NI and Et2AlI are superior to the reaction with
Me3SiI from the viewpoint of diastereoselectivity.
Stereochemical outcome of this reaction can be explained as
follows (Scheme 9). Nucleophilic opening of the cyclo-
propane ring provides enolates 15a and 15b. In 15a, coor-
dination of the iodine atom to the titanium center restricts
conformation of the enolate as shown in Scheme 9. The
addition to benzaldehyde occurs from the opposite face to
the methyl group to provide the aldol adduct 16a. The rela-
tive stereochemistry between C2 and C3 is determined in
the same fashion as shown in Scheme 3. In the case of the
aluminum enolate 15b, the addition proceeds through the
favored conformation A. Isomerization of the stereo-
chemistry at C2 via the retro-aldol reaction as discussed
before affords the anti-aldol adduct 13 after hydrolysis.
4. Regioselective ring opening of substituted
cyclopropyl ketone
Regioselectivity in the ring opening of methyl-substituted
cyclopropyl ketone 8 was examined with various metal
iodides (Scheme 7).12 It is notable that the TiCl4-n-Bu4NI
mixed reagent attacked at the less hindered site of the cyclo-
propane ring exclusively. This fact can indicate that the
Scheme 8.
Scheme 9.

Z. Han et al. / Tetrahedron 57 (2001) 987±995
991
5. Experimental
7.78 (m, 2H); 13C NMR (CDCl3) d 32.09, 54.78, 68.49,
83.14, 125.96, 127.78, 128.56, 128.59, 128.70, 133.43,
136.58, 141.67, 200.04. Found: C, 81.09; H, 6.51%. Calcd
for C17H16O2: C, 80.93; H, 6.39%.
1H NMR (300 MHz) and 13C NMR (75.3 MHz) spectra
were taken on a Varian GEMINI 300 spectrometer in
CDCl3 as a solvent, and chemical shifts were given in d
value with tetramethylsilane as an internal standard. IR
spectra were determined on a JASCO IR-810 spectrometer.
TLC analyses were performed on commercial glass plates
bearing 0.25 mm layer of Merck silica gel 60F254. Column
chromatography was done with silica gel (Wakogel 200
mesh). The analyses were carried out at the Elemental
Analysis Center of Kyoto University. Unless otherwise
noted, materials obtained from commercial suppliers were
used without further puri®cation; however, aldehydes were
distilled and stocked under argon. Dichloromethane was
5.1.2. syn-3-Hydroxy-2-(20-iodoethyl)-1-phenyldodecan-
one (3b). IR (neat 3436, 2920, 2850, 1673, 1665, 1448,
1
1216, 1001, 704 cm21; H NMR (CDCl3) d 0.85 (t, Jˆ
6.6 Hz, 3H), 1.18±1.61 (m, 16H), 2.18±2.38 (m, 2H),
2.43±2.55 (m, 1H), 2.99 (ddd, Jˆ6.6, 9.6, 9.6 Hz, 1H),
3.32 (ddd, Jˆ4.5, 7.2, 9.6 Hz, 1H), 3.77 (dt, Jˆ9.6,
3.6 Hz, 1H), 3.90 (dt, Jˆ9.6, 3.6 Hz, 1H), 7.48±7.58 (m,
2H), 7.59±7.68 (m, 1H), 8.00±8.06 (m, 2H); 13C NMR
(CDCl3) d 5.22, 13.96, 22.52, 25.88, 29.13, 29.32, 29.37,
29.39, 30.55, 31.73, 34.86, 51.22, 71.88, 128.69, 128.94,
133.84, 137.03, 203.76. This compound was unstable to
obtain the analytically pure sample. The elemental analysis
was performed with trans-3-benzoyl-2-phenyltetrahydro-
furan (4a) after cyclization: IR (neat) 2916, 2854, 1679,
Ê
dried with molecular sieves 4 A. Hexane and ether were
dried over slices of sodium metal.
5.1. General procedure for ring opening of cyclopropyl
phenyl ketones with TiCl4-n-Bu4NI
1
1598, 1450, 1217, 777, 701 cm21; H NMR (CDCl3) d
0.86 (t, Jˆ6.9 Hz, 3H), 1.18±1.70 (m, 16H), 2.08±2.39
(m, 2H), 3.63 (ddd, Jˆ7.5, 7.5, 9.6 Hz, 1H), 3.89 (ddd,
Jˆ7.5, 7.5, 7.5 Hz, 1H), 4.02 (ddd, Jˆ5.1, 7.8, 7.8 Hz,
1H), 4.19 (ddd, Jˆ5.1, 7.5, 7.5 Hz, 1H), 7.46±7.62 (m,
3H), 7.95±7.98 (m, 2H); 13C NMR (CDCl3) d 13.98,
22.54, 26.16, 29.16, 29.36, 29.38, 29.47, 31.75, 31.80,
34.87, 51.41, 67.51, 81.99, 128.46, 128.80, 133.37,
136.88, 200.77. Found: C, 79.42; H, 10.00%. Calcd for
C20H30O2: C, 79.19; H, 9.87%.
The reaction of cyclopropyl phenyl ketone (1a) with benz-
aldehyde is representative (entry 1, Table 1). To a solution
of TiCl4 (2.0 mmol) in CH2Cl2 (5 mL) was added a solution
of n-Bu4NI (2.0 mmol) in CH2Cl2 (3 mL) at 08C. After
stirring for 10 min at 08C, to the dark-red solution was
added cyclopropyl phenyl ketone (1a, 0.15 g, 1.0 mmol).
The reaction mixture was stirred for 1 h at 08C and then
cooled to 2788C. Benzaldehyde (0.13 g, 1.2 mmol) was
added and the reaction mixture was stirred for another 1 h.
Finally, the mixture was poured into saturated aqueous
ammonium chloride. The mixture was extracted with ether
(20 mL£3) and organic layers were washed with brine and
dried over anhydrous Na2SO4. Concentration under reduced
pressure and puri®cation by silica gel chromatography
afforded syn-3-hydroxy-2-(20-iodoethyl)-1,3-diphenyl-1-
propanone (3a, 0.29 g, 0.75 mmol) in 75% yield.
5.1.3. syn-3-Hydroxy-2-(20-iodoethyl)-4-methyl-1-phenyl-
pentanone (3c). IR (neat) 2960, 1681, 1647, 1597,
1
1448 cm21; H NMR (CDCl3) d 0.91 (d, Jˆ6.9 Hz, 3H),
1.02 (d, Jˆ6.9 Hz, 3H), 1.73 (dsept, Jˆ7.8, 6.9 Hz, 1H),
2.16 (dddd, Jˆ3.6, 6.6, 9.9, 14.4 Hz, 1H), 2.49 (s, 1H),
2.51 (dddd, Jˆ4.5, 5.7, 9.9, 14.4 Hz, 1H), 2.97 (ddd,
Jˆ5.7, 9.9, 9.9 Hz, 1H), 3.33 (ddd, Jˆ4.5, 6.6, 9.9 Hz,
1H), 3.52 (dd, Jˆ3.6, 7.8 Hz, 1H), 3.96 (ddd, Jˆ3.6, 3.6,
9.9 Hz, 1H), 7.47±7.64 (m, 3H), 7.99±8.03 (m, 2H); 13C
NMR (CDCl3) d 5.61, 18.55, 19.14, 29.73, 31.13, 48.61,
76.87, 128.61, 128.96, 133.82, 136.72, 203.73. This
compound was transformed into trans-3-benzoyl-2-iso-
propyltetrahydrofuran (4c) for the elemental analysis: IR
5.1.1. syn-3-Hydroxy-2-(20-iodoethyl)-1,3-diphenyl-1-pro-
panone (3a). IR (neat) 3440, 1675, 1597, 1449, 1262, 1133,
937, 759, 699 cm21; 1H NMR (CDCl3) d 2.23 (dddd, Jˆ4.8,
7.5, 8.4, 14.4 Hz, 1H), 2.45 (dddd, Jˆ5.4, 7.5, 8.4, 14.4 Hz,
1H), 2.80±3.15 (bs, 1H), 2.90 (ddd, Jˆ7.5, 8.4, 9.9 Hz, 1H),
3.12 (ddd, Jˆ5.4, 7.5, 9.9 Hz, 1H), 4.00 (ddd, Jˆ4.8, 4.8,
8.4 Hz, 1H), 5.10 (d, Jˆ4.8 Hz, 1H), 7.21±7.62 (m, 8H),
7.96 (d, Jˆ7.2 Hz, 2H); 13C NMR (CDCl3) d 4.51, 30.80,
53.39, 73.47, 125.97, 127.80, 128.50, 128.62, 128.85,
133.83, 136.75, 141.33, 204.67. The analytically pure
sample could not be obtained because of its instability.
Thus, the elemental analysis was done with the cyclized
compound 4a. To a mixture of active alumina (2 g) in
ether (5 mL) was added a solution of the aldol adduct 3a
(0.29 g, 0.75 mmol) in ether (2 mL) at 08C. After stirring for
1 h, alumina was ®ltered off and the ®ltrate was concen-
trated. The residual oil was puri®ed by silica gel to afford
(nujol) 2854, 1679, 1466, 1451, 1376, 1211 cm21 1H
;
NMR (CDCl3) d 0.85 (d, Jˆ6.9 Hz, 3H), 0.97 (d, Jˆ
6.9 Hz, 3H), 1.79 (dqq, Jˆ6.9, 6.9, 6.9 Hz, 1H), 2.06
(dddd, Jˆ5.1, 6.9, 7.5, 12.3 Hz, 1H), 2.32 (dddd, Jˆ7.2,
7.8, 9.9, 12.3 Hz, 1H), 3.73 (ddd, Jˆ6.9, 6.9, 9.9 Hz, 1H),
3.88 (ddd, Jˆ7.5, 7.8, 8.1 Hz, 1H) 4.00 (ddd, Jˆ5.1, 7.2,
8.1 Hz, 1H), 4.10 (dd, Jˆ6.9, 6.9 Hz, 1H), 7.46±7.62 (m,
3H), 7.96±8.00 (m, 2H); 13C NMR (CDCl3) d 18.30, 18.61,
32.05, 32.52, 48.50, 67.36, 86.49, 128.12, 128.52, 133.03,
136.44, 200.56. Found: C, 76.79; H, 8.26%. Calcd for
C14H18O3: C, 77.03; H, 8.31%.
5.1.4. trans-3-Benzoyl-2-tert-butyltetrahydrofuran (4d).
trans-3-benzoyl-2-phenyltetrahydrofuran
(4a,
0.19 g,
1
IR (nujol) 1677, 1220, 1198, 1071, 661 cm21, H NMR
0.75 mmol) in quantitative yield: IR (neat) 3058, 3026,
2928, 2868, 1680, 1597, 1581, 1494, 1449, 1360, 1278,
(CDCl3) d 0.89 (s, 9H), 1.99 (dddd, Jˆ7.2, 7.2, 9.9,
12.0 Hz, 1H), 2.30 (dddd, Jˆ5.4, 6.6, 7.2, 12.0 Hz, 1H),
3.81 (ddd, Jˆ6.6, 7.2, 9.9 Hz, 1H), 3.88 (ddd, Jˆ7.2, 7.2,
8.4 Hz, 1H), 3.98 (ddd, Jˆ5.4, 7.2, 8.4 Hz, 1H), 4.20 (d,
Jˆ7.2 Hz, 1H), 7.43±7.60 (m, 3H), 7.95±8.00 (m, 2H);
13C NMR (CDCl3) d 25.89, 33.84, 33.89, 46.26, 68.05,
1217, 1064, 754, 698 cm21 1H NMR (CDCl3) d 2.31
;
(dddd, Jˆ5.4, 7.2, 7.8, 15.0 Hz, 1H), 2.47 (dddd, Jˆ7.5,
8.1, 9.3, 15.0 Hz, 1H), 3.93 (ddd, Jˆ7.2, 7.2, 9.3 Hz, 1H),
4.08 (ddd, Jˆ7.2, 7.5, 7.8 Hz, 1H), 4.27 (ddd, Jˆ5.4, 8.1,
8.1 Hz, 1H), 5.28 (d, Jˆ8.1 Hz, 1H), 7.24±7.58 (m, 8H),

992
Z. Han et al. / Tetrahedron 57 (2001) 987±995
89.29, 128.41, 128.85, 133.33, 136.81, 201.30. Found: C,
77.27; H, 8.61%. Calcd for C15H20O2: C, 77.55; H, 8.68%.
trans-3-acetyl-2-tert-butyltetrahydrofuran (4g) after cycli-
zation of 3g with alumina: IR (neat) 2954, 1713, 1364,
1
1081 cm21; H NMR (CDCl3) d 0.87 (s, 9H), 1.91±2.12
5.1.5. syn-3-Hydroxy-2-(20-iodoethyl)-1-phenylbutanone
(3e). IR (neat) 3414, 2964, 1672, 1596, 1579, 1427, 1215,
941, 698 cm21; 1H NMR (CDCl3) d 1.21 (d, Jˆ6.6 Hz, 3H),
2.20±2.51 (m, 3H), 2.98 (dt, Jˆ6.6, 9.6 Hz, 1H), 3.28 (ddd,
Jˆ5.1, 6.6, 9.9 Hz, 1H), 3.69 (dt, Jˆ9.3, 4.2 Hz, 1H), 4.11
(dq, Jˆ9.3, 6.6 Hz, 1H), 7.44±7.65 (m, 3H), 7.98±8.05 (m,
2H); 13C NMR (CDCl3) d 4.78, 21.10, 31.22, 52.61, 68.11,
128.71, 128.92, 133.86, 137.20 203.66. This compound was
converted into trans-3-benzoyl-2-methyltetrahydrofuran
(4e) upon treatment with alumina to obtain an analytically
pure sample: IR (neat) 2970, 1678, 1598, 1580, 1449, 1372,
(m, 2H), 2.21 (s, 3H), 2.96 (ddd, Jˆ6.0, 6.0, 9.3 Hz, 1H),
3.78 (ddd, Jˆ7.2, 7.5, 8.1 Hz, 1H), 3.86 (d, Jˆ6.0 Hz, 1H),
3.89 (ddd, Jˆ5.4, 6.9, 8.4 Hz, 1H); 13C NMR (CDCl3) d
25.68, 29.26, 30.58, 31.61, 52.41, 68.10, 88.51, 209.44.
HRMS (m/z) Found: 170.1308. Calcd for C10H18O2:
170.1307.
5.2.2. syn-4-Hydroxy-3-(20-iodoethyl)-2-pentanone (3h).
1
IR (neat) 3328, 2966, 1703, 1422, 1099, 459 cm21; H
NMR (CDCl3) d 1.20 (d, Jˆ6.3 Hz, 3H), 1.25 (bs, 1H),
1.98±2.16 (m, 2H), 2.28 (s, 3H), 2.80 (ddd, Jˆ4.2, 4.2,
8.7 Hz, 1H), 3.06 (ddd, Jˆ6.9, 8.7, 9.9 Hz, 1H), 3.29
(ddd, Jˆ5.4, 7.5, 9.9 Hz, 1H), 4.07 (dq, Jˆ4.2, 6.3 Hz,
1H); 13C NMR (CDCl3) d 4.68, 20.61, 30.23, 31.64,
58.93, 67.43, 211.51. The elemental analysis was done
with trans-3-acetyl-2-methyltetrahydrofuran (4h) after
1
1220, 698 cm21; H NMR (CDCl3) d 1.31 (d, Jˆ6.0 Hz,
3H), 2.15 (m, 2H), 3.53±3.61 (m, 1H), 3.84±3.92 (m,
1H), 4.00±4.07 (m, 1H), 4.18±4.27 (m, 1H), 7.42±7.65
(m, 3H), 7.90±8.02 (m, 2H); 13C NMR (CDCl3) d 19.94,
31.55, 52.97, 67.53, 78.07, 128.48, 128.81, 133.42, 136.93,
200.51. Found: C, 75.96; H, 7.51%. Calcd for C12H14O2: C,
75.76; H, 7.42%.
1
cyclization. IR (neat) 2922, 1711, 1448, 1005 cm21; H
NMR (CDCl3) d 1.32 (d, Jˆ6.3 Hz, 3H), 2.10±2.20 (m,
2H), 2.21 (s, 3H), 2.75 (ddd, Jˆ7.5, 7.5, 9.0 Hz, 1H), 3.80
(ddd, Jˆ5.7, 7.2, 8.4 Hz, 1H), 3.95 (ddd, Jˆ5.7, 7.2, 8.4 Hz,
1H), 4.03 (dq, Jˆ6.0, 7.2 Hz, 1H); 13C NMR (CDCl3) d
20.32, 29.58, 29.80, 58.78, 67.20, 77.02, 208.32. HRMS
(m/z) Found: 128.0823. Calcd for C7H12O2: 128.0837.
5.2. General procedure for ring opening of cyclopropyl
methyl ketones with TiCl4-n-Bu4NI
The reaction of cyclopropyl methyl ketone (1b) with benz-
aldehyde is representative (entry 6, Table 1). To a solution
of TiCl4 (2.0 mmol) in CH2Cl2 (5 mL) was added a solution
of n-Bu4NI (2.0 mmol) in CH2Cl2 (3 mL) at 08C. After
stirring for 10 min, to the dark-red solution was added
cyclopropyl methyl ketone (1b, 0.08 g, 1.0 mmol) at
2788C. The reaction mixture was stirred for 1 h. Benz-
aldehyde (0.13 g, 1.2 mmol) was added at 2788C and the
reaction mixture was gradually warmed to 08C with stirring
for 1 h. Then, the mixture was poured into saturated aqueous
ammonium chloride. The mixture was extracted with ether
(20 mL£3) and organic layers were washed with brine and
dried over anhydrous Na2SO4. Concentration followed by
puri®cation by silica gel chromatography afforded syn-4-
hydroxy-3-(20-iodoethyl)-4-phenyl-2-butanone (3f) in 72%
yield: IR (neat) 3392, 2958, 1697, 1493, 1177, 701 cm21; 1H
NMR (CDCl3) d 2.05 (s, 3H), 2.08±2.27 (m, 2H), 2.50 (bs,
1H), 2.92±3.12 (m, 3H), 4.94 (d, Jˆ5.4 Hz, 1H), 7.25±7.40
(m, 5H); 13C NMR (CDCl3) d 4.62, 30.54, 31.48, 59.80,
73.49, 125.98, 128.07, 128.68, 141.42, 211.37. Cyclization
of this compound with alumina provided the analytically
pure sample of trans-3-acetyl-2-phenyltetrahydrofuran
5.3. General procedure for ring opening of cyclopropyl
ketones with Et2AlI
The reaction of cyclopropyl phenyl ketone (1a) with benz-
aldehyde is representative (entry 1, Table 3). To a hexane
solution of Et2AlI (0.4 M, 4.0 mL, 1.6 mmol) was added
cyclopropyl phenyl ketone (1a, 0.12 g, 0.8 mmol) at 08C.
The reaction mixture was stirred for 1 h and then benzalde-
hyde (0.10 g, 0.96 mmol) was added at 08C. The reaction
mixture was stirred for another 1 h, and then, the mixture
was poured into saturated aqueous ammonium chloride. The
mixture was extracted with ether (20 mL£3) and organic
layers were washed with brine and dried over anhydrous
Na2SO4. Concentration and puri®cation by silica gel
chromatography afforded anti-3-hydroxy-2-(20-iodoethyl)-
1,3-diphenyl-1-propanone (6a, 0.27 g, 0.71 mmol) in 94%
yield: IR (neat) 3426, 1672, 1597, 1581, 1493, 1207,
1
700 cm21; H NMR (CDCl3) d 2.01 (dddd, Jˆ6.9, 7.2,
7.8, 14.4 Hz, 1H), 2.28 (dddd, Jˆ6.0, 6.9, 7.2, 14.4 Hz,
1H), 2.98 (ddd, Jˆ7.2, 7.2, 10.2 Hz, 1H), 3.11 (d, Jˆ
5.7 Hz, 1H), 3.14 (ddd, Jˆ6.9, 6.9, 10.2 Hz, 1H), 4.11
(ddd, Jˆ6.0, 6.6, 7.8 Hz, 1H), 4.98 (dd, Jˆ6.6, 5.7 Hz,
1H), 7.22±7.59 (m, 8H), 7.96 (d, Jˆ7.2 Hz, 2H); 13C
NMR (CDCl3) d 3.68, 33.45, 52.63, 75.26, 126.25,
128.10, 128.66, 128.66, 128.75, 133.76, 137.68, 142.11,
204.48. The aldol adduct 6a was unstable to obtain the
analytically pure sample. Then, the compound (0.27 g,
0.71 mmol) was converted into anti-3-hydroxy-2-ethyl-
1,3-diphenyl-1-propanone 6a0 upon treatment with
n-Bu3SnH (0.29 g, 1.0 mmol) and Et3B (0.1 mmol) in
hexane at 258C. After stirring for 30 min, the solvent was
removed under reduced pressure and the residue was
dissolved with ethyl acetate (20 mL). Potassium ¯uoride
(1.0 g) and a saturated aqueous solution of KF (2 mL)
were added and the mixture was vigorously stirred for 2 h.
The mixture was ®ltered through a pad of Celite and the
(4f): IR (neat) 1710, 1364, 1060, 699 cm21 1H NMR
;
(CDCl3) d 2.09 (s, 3H), 2.23 (m, 2H), 3.15 (ddd, Jˆ7.5,
8.4, 8.4 Hz, 1H), 4.00 (ddd, Jˆ6.9, 7.8, 8.4 Hz, 1H), 4.16
(ddd, Jˆ6.3, 7.2, 8.4 Hz, 1H), 4.99 (d, Jˆ7.5 Hz, 1H),
7.21±7.39 (m, 5H); 13C NMR (CDCl3) d 30.17 (2C),
60.12, 68.24, 82.49, 125.90, 127.86, 128.59, 141.59,
207.88. Found: C, 75.86; H, 7.60%. Calcd for C12H14O2:
C, 75.76; H, 7.42%.
5.2.1. syn-4-Hydroxy-3-(20-iodoethyl)-5,5-dimethyl-2-hexan-
one (3g). IR (neat) 3236, 2934, 1711, 1355, 1170,
1
490 cm21; H NMR (CDCl3) d 0.97 (s, 9H), 2.00±2.31
(m, 3H), 2.24 (s, 3H), 2.92±3.13 (m, 2H), 3.29 (ddd,
Jˆ5.4, 6.9, 9.6 Hz, 1H), 3.54 (d, Jˆ3.6 Hz, 1H); 13C
NMR (CDCl3) d 5.59, 26.28, 30.17, 30.31, 30.39, 54.09,
77.08, 210.55. The elemental analysis was done with

Z. Han et al. / Tetrahedron 57 (2001) 987±995
993
®ltrate was concentrated. The residue was puri®ed by silica
gel to provide 6a0 of which spectral data was identical with
the authentic sample.14
702 cm21;1H NMR (CDCl3) d 1.23 (d, Jˆ6.6 Hz, 3H),
2.16±2.52 (m, 3H), 3.12 (dt, Jˆ9.6, 7.2 Hz, 1H), 3.23±
3.34 (m, 1H), 3.76 (dt, Jˆ4.5, 7.5 Hz, 1H), 4.03±4.15 (m,
1H), 7.44±7.65 (m, 3H), 7.98±8.05 (m, 2H); 13C NMR
(CDCl3) d 64.22, 21.69, 32.97, 51.80, 68.13, 128.63,
128.96, 133.97, 137.40, 204.79. Spectral data for the
reduced product 6e0 was as follows: IR (neat) 3358, 2964,
5.3.1. anti-3-Hydroxy-2-(20-iodoethyl)-1-phenyl-1-dodecan-
one (6b). IR (neat) 3420, 2922, 1679, 1449, 1211, 705,
1
446 cm21; H NMR (CDCl3) d 0.85 (t, Jˆ6.6 Hz, 3H),
1
1.10±1.58 (m, 16H), 2.19±2.37 (m, 2H), 2.93 (bs, 1H),
3.15 (ddd, Jˆ6.3, 7.2, 9.9 Hz, 1H), 3.27 (ddd, Jˆ6.6, 7.5,
9.9 Hz, 1H), 3.58±3.85 (m, 2H), 7.47±7.63 (m, 3H), 8.00±
8.04 (m, 2H); 13C NMR (CDCl3) d 4.50, 13.95, 22.49,
25.90, 29.10, 29.26, 29.33, 29.34. 31.71, 33.02, 35.66,
50.07, 72.09, 128.57, 128.91, 133.91, 137.31, 205.24. The
elemental analysis was done with the reduced product 6b0:
IR (neat) 3428, 2918, 1666, 1597, 1459, 1208, 1002,
1678, 1597, 1459, 1212, 703 cm21; H NMR (CDCl3) d
0.91 (t, Jˆ7.5 Hz, 3H), 1.25 (d, Jˆ6.6 Hz, 3H), 1.70±1.90
(m, 2H), 2.89 (d, Jˆ7.2 Hz, 1H), 3.42 (ddd, Jˆ5.7, 5.7,
6.9 Hz, 1H), 4.08±4.21 (m, 1H), 7.44±7.64 (m, 3H),
7.94±8.00 (m, 2H); 13C NMR (CDCl3) d 11.56, 21.54,
23.12, 53.66, 68.35, 128.35, 128.76, 133.41, 137.95,
206.24. Found: C, 74.71; H, 8.44%. Calcd for C12H16O2:
C, 74.97; H, 8.39%.
1
705 cm21; H NMR (CDCl3) d 0.88 (dd, Jˆ6.9, 6.9 Hz,
3H), 0.94 (t, Jˆ7.5 Hz, 3H), 1.18±1.52 (m, 16H), 1.83
(ddq, Jˆ2.1, 7.5, 7.5 Hz, 2H), 2.97 (d, Jˆ8.1 Hz, 1H),
3.46 (ddd, Jˆ4.5, 6.9, 6.9 Hz, 1H), 3.88 (m, 1H), 7.45±
7.65 (m, 3H), 7.93±8.00 (m, 2H); 13C NMR (CDCl3) d
11.80, 13.93, 22.52, 23.33, 25.89, 29.15, 29.39 (2c),
29.42, 31.74, 35.70, 51.80, 72.50, 128.32, 128.77, 133.42,
137.98, 206.75. Found: C, 78.70; H, 10.63%. Calcd for
C20H32O2: C, 78.90; H, 10.59%.
5.3.5. anti-4-Hydroxy-3-(20-iodoethyl)-4-phenyl-2-butan-
1
one (6f). IR (neat) 3398, 1709, 1357, 1172, 700 cm21; H
NMR (CDCl3) d 1.64 (dddd, Jˆ4.8, 6.9, 7.2, 14.4 Hz, 1H),
2.00 (dddd, Jˆ6.0, 8.1, 8.1, 14.4 Hz, 1H), 2.15 (s, 3H), 2.87
(ddd, Jˆ6.9, 8.1, 13.2 Hz, 1H), 2.97 (ddd, Jˆ6.0, 7.2,
13.2 Hz, 1H), 3.05±3.02 (bs, 1H), 3.13 (ddd, Jˆ4.8, 7.8,
8.1 Hz, 1H), 4.66 (d, Jˆ7.8 Hz, 1H), 7.29±7.41 (m, 5H);
13C NMR (CDCl3) d 3.32, 32.23, 32.74, 58.81, 75.11,
126.20, 128.15, 128.62, 141.72, 212.79. Reduction of 6f
with n-Bu3SnH afforded 6f0 which was identical with the
authentic sample.4c
5.3.2. anti-3-Hydroxy-2-(20-iodoethyl)-4-methyl-1-phenyl-
1-pentanone (6c). IR (neat) 3462, 2954, 1664, 1597, 1206,
1
1002, 702 cm21; H NMR (CDCl3) d 0.88 (d, Jˆ6.6 Hz,
3H), 1.02 (d, Jˆ6.6 Hz, 3H), 1.58±1.72 (m, 2H), 2.20±
2.36 (m, 2H), 3.10±3.47 (m, 3H), 3.90±4.00 (m, 1H),
7.45±7.69 (m, 3H), 8.00±8.08 (m, 2H); 13C NMR
(CDCl3) d 4.65, 18.59, 19.54, 32.43, 33.46. 46.78, 77.53,
128.60, 129.03, 134.08, 137.07, 205.98. The elemental
analysis was performed for the reduced product 6c0: IR
5.3.6. anti-4-Hydroxy-3-(20-iodoethyl)-5-methyl-2-hexan-
one (6g). IR (neat) 3390, 2958, 1708, 1357, 1169,
1
981 cm21; H NMR (CDCl3) d 0.94 (d, Jˆ6.9 Hz, 3H),
0.97 (d, Jˆ6.9 Hz, 3H), 1.67 (dd, Jˆ6.6, 6.9 Hz, 1H),
2.00±2.18 (m, 2H), 2.27 (s, 3H), 2.48±2.60 (bs, 1H), 3.02
(ddd, Jˆ5.4, 6.6, 6.9 Hz, 1H), 3.11±3.25 (m, 2H), 3.33 (dd,
Jˆ6.6, 6.9 Hz, 1H); 13C NMR (CDCl3) d 3.82, 17.30, 19.59,
31.61, 32.34, 32.52, 53.86, 77.09, 214.07. The titled
compound was unstable to obtain the analytically pure
sample. The elemental analysis was done with the reduced
product (6g0) which was obtained by treatment with
n-Bu3SnH: IR (neat) 3366, 2910, 1702, 1459, 1364, 1052,
1
(neat) 3440, 2952, 1677, 1597, 1460, 1001, 701 cm21; H
NMR (CDCl3) d 0.87 (t, Jˆ6.9 Hz, 3H), 0.96 (t, Jˆ7.5 Hz,
3H), 0.99 (d, Jˆ6.9 Hz, 3H), 1.69 (dqq, Jˆ6.6, 6.6, 6.6 Hz,
1H), 1.77±1.90 (m, 2H), 3.20 (d, Jˆ8.4 Hz, 1H), 3.50±3.63
(m, 2H), 7.45±7.64 (m, 3H), 7.93±8.01 (m, 2H); 13C NMR
(CDCl3) d 11.90, 17.97, 19.70, 23.89, 32.12, 48.48, 77.93,
128.30, 128.82, 133.51, 137.78, 207.19. Found: C, 76.24; H,
9.24%. Calcd for C14H20O2: C, 76.32; H, 9.15%.
1
983 cm21; H NMR (CDCl3) d 0.88±1.00 (m, 9H), 0.60±
1.80 (m, 3H), 2.22 (s, 3H), 2.49 (d, Jˆ7.5 Hz, 1H), 2.67
(ddd, Jˆ6.6, 6.9, 6.9 Hz, 1H), 3.40±3.52 (m, 1H); 13C NMR
(CDCl3) d 11.65, 16.73, 19.77, 22.38, 31.19, 31.44, 55.84,
77.08, 215.08. HRMS (m/z) Found: 140.1195. Calcd for
C9H18O2-H2O: 140.1201.
5.3.3. anti-3-Hydroxy-2-(20-iodoethyl)-4,4-dimethly-1-
phenyl-1-pentanone (6d). IR (neat) 3448, 2952, 1658,
1
1596, 1205, 1002, 689 cm21; H NMR (CDCl3) d 0.88 (s,
9H), 2.22 (dddd, Jˆ6.0, 6.0, 7.5, 13.5 Hz, 1H), 2.37 (dddd,
Jˆ6.0, 6.0, 7.5, 13.5 Hz, 1H), 3.19±3.33 (m, 2H), 3.43 (d,
Jˆ8.7 Hz, 1H), 3.93 (dd, Jˆ6.0, 7.5 Hz, 1H), 4.59 (d,
Jˆ8.7 Hz, 1H), 7.45±7.66 (m, 3H), 8.04 (d, Jˆ7.2 Hz,
2H); 13C NMR (CDCl3) d 4.68, 26.79, 35.12, 36.06,
43.03, 81.09, 128.58, 129.06, 134.19, 136.47, 206.94. Treat-
ment of 6d with n-Bu3SnH provided the analytically pure
sample: IR (neat) 3450, 2958, 1656, 1450, 1206, 1002,
5.3.7. anti-4-Hydroxy-3-(20-iodoethyl)-5,5-dimethyl-2-
hexanone (6h). IR (neat) 3376, 2868, 1703, 1693, 1365,
1
1166, 458 cm21; H NMR (CDCl3) d 0.92 (s, 9H), 2.01
(dt, Jˆ6.9, 6.9 Hz, 2H), 2.25 (s, 3H), 2.98 (dd, Jˆ6.9,
6.9 Hz, 1H), 3.14±3.21 (m, 4H); 13C NMR (CDCl3) d
4.28, 26.62, 32.25, 34.45, 35.99, 49.87, 80.88, 215.66.
The physical data for the reduced product 6h0 is as follows:
IR (neat) 3434, 2956, 2870, 1692, 1480, 1365, 1166,
688 cm21 1H NMR (CDCl3) d 0.86 (s, 9H), 0.10 (t,
;
Jˆ7.5 Hz, 3H), 1.91 (quin, Jˆ7.5 Hz, 2H), 3.52±3.62 (m,
2H), 4.74 (d, Jˆ9.0 Hz, 1H), 6.48±7.66 (m, 3H), 7.95±8.00;
13C NMR (CDCl3) d 12.38, 26.33, 26.80, 36.15, 44.50,
82.45, 128.37, 129.01, 133.80, 137.38, 208.45. Found: C,
76.88; H, 9.59%. Calcd for C15H22O2: C, 76.88; H, 9.59%.
1002 cm21 1H NMR (CDCl3) d 0.90 (s, 9H), 0.10 (t,
;
Jˆ7.5 Hz, 3H), 1.64±1.88 (m, 2H), 2.27 (s, 3H), 2.69
(ddd, Jˆ2.1, 7.2, 7.2 Hz, 1H), 3.32 (dd, Jˆ2.1, 8.7 Hz,
1H), 4.09 (d, Jˆ8.7 Hz, 1H); 13C NMR (CDCl3) d 12.23,
25.19, 26.60, 32.35, 35.92, 51.50, 81.73, 217.17. HRMS
(m/z) Found: 157.1200. Calcd for C10H20O2-CH3: 157.1229.
5.3.4. anti-3-Hydroxy-2-(20-iodoethyl)-1-phenyl-1-butan-
one (6e). IR (neat) 3352, 2924, 1675, 1448, 1215,
5.3.8. anti-4-Hydroxy-3-(20-iodoethyl)-2-pentanone (6i).

994
Z. Han et al. / Tetrahedron 57 (2001) 987±995
1
IR (neat) 3354, 2966, 1703, 1356, 1111 cm21; H NMR
(CDCl3) d 1.21 (d, Jˆ6.3 Hz, 3H), 1.95±2.21 (m, 2H),
2.25 (s, 3H), 2.38 (s, 1H), 2.79 (dt, Jˆ8.4, 5.4 Hz, 1H),
3.07 (dt, Jˆ9.9, 7.5 Hz, 1H), 3.19 (dt, Jˆ9.9, 6.3 Hz, 1H),
3.91 (dq, Jˆ8.4, 6.3 Hz, 1H); 13C NMR (CDCl3) d 3.56,
21.46, 31.96, 32.14, 58.86, 67.89, 212.76. 6i0: IR (neat)
0.15 g, 0.91 mmol) and benzaldehyde (0.12 g, 1.1 mmol)
in hexane/ether (5 mL/5 mL) was added a hexane solution
of Et2AlI (1.8 mL, 1.0 M, 1.8 mmol) at 08C. The reaction
mixture was stirred for 80 min. The mixture was poured into
saturated aqueous ammonium chloride. The mixture was
extracted with ether (20 mL£3) and organic layers were
washed with brine and dried over anhydrous Na2SO4.
Concentration and puri®cation by silica gel chromatography
afforded (1Rp,2Rp,3Rp)-3-hydroxy-2-(30-iodoprop-20-yl)-
1,3-diphenyl-1-propanone (13, 0.26 g, 0.65 mmol, 97/3
isomeric mixture) in 72% yield: IR (neat) 3464, 2954,
3400, 2958, 1703, 1460, 1377, 936 cm21
;
1H NMR
(CDCl3) d 0.91 (t, Jˆ7.5 Hz, 3H), 1.22 (d, Jˆ6.6 Hz,
3H), 1.60±1.75 (m, 2H), 2.21 (s, 3H), 2.40±2.55 (m, 2H),
3.88±4.08 (m, 1H); 13C NMR (CDCl3) d 11.40, 21.42,
22.01, 31.16, 60.71, 68.05, 214.28. HRMS (m/z) Found:
130.1014. Calcd for C7H14O2: 130.0994.
1
1658, 1450, 1199, 699 cm21; H NMR (CDCl3) d 0.89 (d,
Jˆ6.3 Hz, 3H), 2.00 (dddq, Jˆ3.3, 3.9, 9.0, 6.3 Hz, 1H),
3.41 (dd, Jˆ3.3, 10.2 Hz, 1H), 3.70 (dd, Jˆ3.9, 10.2 Hz,
1H), 3.89 (dd, Jˆ3.6, 9.0 Hz, 1H), 4.24 (s, 1H), 5.11 (d,
Jˆ3.6 Hz, 1H), 7.00±8.00 (m, 10H); 13C NMR (CDCl3) d
17.62, 19.38, 33.28, 55.99, 72.59, 125.28, 127.30, 128.17,
128.27, 128.47, 133.57, 138.21, 142.18, 206.40. Cyclization
of 13 with active alumina gave 14, which was supplied for
an elemental analysis.
5.4. General procedure for ring opening of cyclopropyl
ketones with Me3SiI
The reaction of cyclopropyl phenyl ketone (1a) with benz-
aldehyde is representative (entry 1, Table 4). To a solution
of Me3SiI (0.17 mL, 1.2 mmol) in CH2Cl2 (5 mL) was
added cyclopropyl phenyl ketone (1a, 0.15 g, 1.0 mmol) at
08C and the mixture was stirred for 1 h. The mixture was
cooled to 2788C and benzaldehyde (0.13 g, 1.5 mmol) and
TiCl4 (1.0 mL, 1.0 M CH2Cl2 solution, 1.0 mmol) were
successively added. The reaction mixture was stirred for
another 2 h, and then the mixture was poured into saturated
aqueous ammonium chloride. The mixture was extracted
with ether (20 mL£3) and organic layers were washed
with brine and dried over anhydrous Na2SO4. Concentration
and puri®cation by silica gel afforded 3-hydroxy-2-(20-
iodoethyl)-1,3-diphenyl-1-propanone (0.27 g, 0.69 mmol,
3a/6aˆ60/40) in 69% yield.
5.6.1. (2Sp,3Rp,4Sp)-3-Benzoyl-4-methyl-2-phenyltetra-
hydrofuran (14). IR (neat) 2870, 1736, 1680, 1598, 1450,
1
1241, 1158, 755, 691 cm21; H NMR (CDCl3) d 1.15 (d,
Jˆ6.9 Hz, 3H), 2.84 (dddq, Jˆ6.9, 7.2, 8.1, 6.9 Hz, 1H),
3.64 (dd, Jˆ8.1, 8.4 Hz, 1H), 3.84 (dd, Jˆ6.9, 8.4 Hz,
1H), 4.27 (dd, Jˆ7.2, 8.4 Hz, 1H), 5.25 (d, Jˆ8.4 Hz,
1H), 6.94±6.99 (m, 2H), 7.01±7.06 (m, 3H), 7.32±7.37
(m, 2H), 7.44±7.50 (m, 1H), 7.66±7.69 (m, 2H); 13C
NMR (CDCl3) d 15.73, 35.58, 59.53, 75.23, 82.98,
126.78, 127.63, 127.73, 128.12, 128.40, 132.84, 137.97,
139.13, 198.05. Found: C, 81.22; H, 6.75%. Calcd for
C18H18O2: C, 81.17; H, 6.81%.
5.5. Procedure for ring opening of 2-methylcyclopropyl
phenyl ketones with TiCl4-n-Bu4NI
A solution of n-Bu4NI (0.44 g, 1.2 mmol) in CH2Cl2 (3 mL)
was added to a solution of TiCl4 (1.2 mmol) in CH2Cl2
(7 mL) at 08C. After stirring for 10 min, 2-methylcyclo-
propyl phenyl ketone (8, 0.16 g, 1.0 mmol) was added.
The reaction mixture was stirred for 30 min at 08C and
then cooled to 2788C. Benzaldehyde (0.13 g, 1.2 mmol)
was added and the reaction mixture was stirred for another
1 h. Finally, the mixture was poured into saturated aqueous
ammonium chloride. The mixture was extracted with ether
(20 mL£3) and organic layers were washed with brine and
dried over anhydrous Na2SO4. Concentration under reduced
pressure and puri®cation by silica gel chromatography
afforded (2Rp,3Rp,4Rp)-3-benzoyl-4-methyl-2-phenyltetra-
hydrofuran (11, 0.16 g, 0.61 mmol) in 61% yield: IR
(neat) 2926, 1666, 1598, 1450, 1403, 1223, 753,
References
1. (a) Organocopper Reagents, Taylor, R. J. K., Ed.; Oxford
University: New York, 1994. (b) Jung, M. E. In Compre-
hensive Organic Synthesis, Trost, B. M., Ed.; Pergamon:
New York, 1991; Vol. 4, pp 1±67 (Chapter 1.1). (c) Lee,
V. J. In Comprehensive Organic Synthesis, Trost, B. M.,
Fleming, I., Eds.; Pergamon: New York, 1991; Vol. 4, pp
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Organic Synthesis, Trost, B. M., Fleming, I., Eds.; Pergamon:
New York, 1991; Vol. 4, pp 139±168 (Chapter 1.3).
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York, 1991; Vol. 4, pp 237 (Chapter 1.6).
1
698 cm21; H NMR (CDCl3) d 0.92 (d, Jˆ7.2 Hz, 3H),
3.00 (dddq, Jˆ5.1, 6.3, 8.4, 7.2 Hz, 1H), 3.76 (dd, Jˆ5.1,
8.4 Hz, 1H), 3.99 (dd, Jˆ8.4, 8.4 Hz, 1H), 4.41 (dd, Jˆ6.3,
8.4 Hz, 1H), 5.56 (d, Jˆ8.4 Hz, 1H), 7.20±7.59 (m, 8H),
7.92±7.95 (m, 2H); 13C NMR (CDCl3) d 14.45, 38.41,
58.99, 75.82, 81.18, 125.85, 127.53, 128.21, 128.41,
128.82, 133.44, 137.43, 142.28, 198.90. Found: C, 81.35;
H, 7.06%. Calcd for C18H18O2: C, 81.17; H, 6.81%.
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5.6. Procedure for ring opening of 2-methylcyclopropyl
ketones with Et2AlI
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6. Several attempts to prevent the cyclization into 4 by changing
the reaction conditions resulted in failure.
7. Activated alumina (300 mesh, Wako Pure Chemical
Industries, Ltd.) was used for this cyclization.
12. ITiCl3 was prepared via the disproportionation between TiCl4
and TiI4.
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