Intramolecular cyclization of tethered phenyl ketones. Complementary stereochemical results arising from the indium-promoted ring closure of allyl bromides and the fluoride ion-induced desilylation of allylsilanes

Article abstract of DOI:10.1021/jo981683s

The intramolecular indium-promoted cyclization of 4'-substituted (Z)- and (E)-7-bromo-5-heptenophenones has been examined in aqueous tetrahydrofuran. In every instance, ring closure occurred to deliver the syn- 2-vinylcyclopentanol exclusively. The corresponding allylsilanes have been prepared as well, and the course of their fluoride ion-induced cyclization was also studied. In these systems, a kinetic bias for formation of the anti- 2-vinylcyclopentanol is observed, although not with the same exclusivity. Accordingly, complementarity in product diastereoselectivity can be realized in purposeful fashion. The data acquired in this investigation suggest that the indium-catalyzed reactions involve intramolecularly coordinated transition states where development of a cis 5/6-bicyclic framework is most energetically feasible. In contrast, the silanes appear to utilize open- chain antiperiplanar transition states. While the latter are not particularly sensitive to double-bond geometry, they are responsive to steric compression involving the aryl group.

Full text of DOI:10.1021/jo981683s

J . Org. Chem. 1998, 63, 9061-9068
9061
In tr a m olecu la r Cycliza tion of Teth er ed P h en yl Keton es.
Com p lem en ta r y Ster eoch em ica l Resu lts Ar isin g fr om th e
In d iu m -P r om oted Rin g Closu r e of Allyl Br om id es a n d th e F lu or id e
Ion -In d u ced Desilyla tion of Allylsila n es
Leo A. Paquette* and J ose´ L. Mendez-Andino
Evans Chemical Laboratories, The Ohio State University, Columbus, Ohio 43210
Received August 18, 1998
The intramolecular indium-promoted cyclization of 4′-substituted (Z)- and (E)-7-bromo-5-hep-
tenophenones has been examined in aqueous tetrahydrofuran. In every instance, ring closure
occurred to deliver the syn-2-vinylcyclopentanol exclusively. The corresponding allylsilanes have
been prepared as well, and the course of their fluoride ion-induced cyclization was also studied. In
these systems, a kinetic bias for formation of the anti-2-vinylcyclopentanol is observed, although
not with the same exclusivity. Accordingly, complementarity in product diastereoselectivity can
be realized in purposeful fashion. The data acquired in this investigation suggest that the indium-
catalyzed reactions involve intramolecularly coordinated transition states where development of a
cis 5/6-bicyclic framework is most energetically feasible. In contrast, the silanes appear to utilize
open-chain antiperiplanar transition states. While the latter are not particularly sensitive to double-
bond geometry, they are responsive to steric compression involving the aryl group.
Anionic cyclization reactions continue to be ranked
among the premier ring-forming transformations in
organic synthesis.1 Significant effort has been expended
in order to elucidate the stereochemical aspects of these
processes. During the past several years, our research
group has been probing the fundamental mechanistic
issues and synthetic potential of the indium-promoted
coupling of allyl bromides to open-chain aldehydes under
aqueous conditions.2 A major focus of this thrust has
been to account for the impact of heteroatomic substit-
uents positioned either R or â to the reacting carbonyl
functionality on product stereochemistry. This work has
provided a strong indication for transition-state chelate
organization, notwithstanding the presence of vast
amounts of water.3 In the case of substrates lacking the
potential for chelate organization, stereoinduction ap-
pears to be achieved by adherence to the Felkin-Ahn
paradigm.4
stereochemically from related processes that utilize
“open” geometries to accomplish ring formation.
The present purpose was therefore to examine the
stereochemical course of the intramolecular cyclization
of allylic bromides 1 and 2 with indium metal in water
and to make proper comparison with the fluoride ion-
promoted ring closure of 3 and 4 in organic media.5 If
no constraints are applied to any of the four phenyl
ketones, each reactant has available to it one or more
distinctive limiting transition states. Options to modify
the double-bond geometry on demand and to vary the
electronic character of the carbonyl by substitution at X
have been implemented. The collective results clearly
show a significant difference between 1/2 on one hand
and 3/4 on the other. The important product-determining
features of these reactions are elucidated and shown to
hold considerable synthetic potential for stereocontrolled
2-vinylcyclopentanol production.
In addition to the sensitivity to aldehyde structure,
reaction diastereoselection was found to be controlled by
oxophilic coordination of the In(III) atom to the carbonyl
oxygen. This preorganization is seemingly necessary for
activation of the carbonyl center to SN2′ attack. Should
this mechanistic deduction be generally true, cyclization
reactions carried out in this manner would be expected
to proceed via “closed” transition states and to differ
(1) Thebtaranoth, C.; Thebtaranoth, Y. Cyclization Reactions; CRC
Press: Boca Raton, FL; 1994.
(2) Paquette, L. A. In Green Chemistry: Frontiers in Benign Chemi-
cal Synthesis and Processing; Anastas, P., Williamson, T., Eds.; Oxford
University Press: Oxford, England, 1998.
(3) (a) Paquette, L. A.; Mitzel, T. M. J . Am. Chem. Soc. 1996, 118,
1931. (b) Paquette, L. A.; Lobben, P. C. J . Am. Chem. Soc. 1996, 118,
1917. (c) Paquette, L. A.; Mitzel, T. M.; Isaac, M. B.; Crasto, C. F.;
Schomer, W. W. J . Org. Chem. 1997, 62, 4293. (d) Paquette, L. A.;
Lobben, P. C. J . Org. Chem. 1998, 63, 5604. (e) Lobben, P. C.; Paquette,
L. A. J . Org. Chem. 1998, 63, 6990. (f) Paquette, L. A.; Rothhaar, R.
R.; Isaac, M.; Rogers, L. R.; Rogers, R. D. J . Org. Chem. 1998, 63, 5463.
(g) Paquette, L. A.; Rothhaar, R. R. J . Org. Chem. 1998, 63, in press.
(4) (a) Cherest, M.; Felkin, H.; Prudent, N. Tetrahedron Lett. 1968,
2199. (b) Ahn, N. T.; Eisenstein, O. Nouv. J . Chim. 1977, 1, 61.
Intramolecular anionic allylations of carbonyl com-
pounds that use indium as the activating metal have
been accorded little attention. The only example reports
the conversion of 5 in highly selective fashion to cis-fused
(5) (a) Fleming, I.; Dunogue`s, J . Org. React. 1989, 37, 57. (b)
Schinzer, D. Synthesis 1988, 263.
10.1021/jo981683s CCC: $15.00 © 1998 American Chemical Society
Published on Web 11/06/1998

9062 J . Org. Chem., Vol. 63, No. 24, 1998
Paquette and Mendez-Andino
lactone 6, presumably because of a preference for the
pseudo-chair-chair conformation A over the alternative
chair-boat option.6
of 10a -e and 11 with triphenylphosphine dibromide
furnished 1 without detectable loss of double-bond con-
figuration.
The E allylic bromides 2 were obtained in a comparable
manner from the unsaturated nitrile 12 (Scheme 2).
Sch em e 2
Resu lts
Syn th esis of th e Sta r tin g Ma ter ia ls. The Z allylic
bromides of type 1 were prepared as shown in Scheme
1. Aldehyde 7, readily available from inexpensive cis-2-
Sch em e 1
While this substrate could not be formed from 5-oxopen-
tanenitrile,10 it proved particularly convenient to produce
it from 9 by thiophenol-mediated olefin inversion.11 Upon
heating 9 with 0.5 equiv of thiophenol and 0.3 equiv of
AIBN in benzene for 5-6 h, a 10:1 E/ Z mixture was
formed reproducibly and carried directly into coupling
with the aryl Grignard reagents. The purification of
13a -c was facilitated by the fact that they are low-
melting solids amenable to recrystallization from ligroin/
CH2Cl2 mixtures at 0 to -30 °C.
When it was recognized early on that both stereoiso-
meric allylsilanes underwent cyclization to the same
product alcohol, the decision was made to generate 3 and
4 most simply as 2.5:1 Z/ E mixtures. In this instance,
Sch em e 3
butene-1,4-diol,7 was coupled to the known phosphonium
salt 88 in tetrahydrofuran with potassium hexamethyl-
disilazide serving as the base. The resulting Wittig
product 9 proved to be a versatile intermediate, lending
itself suitably to condensation with five differently sub-
stituted arylmagnesium bromides. For direct conversion
to keto alcohols 10, the reaction mixtures were routinely
processed through a mild acidic workup. The acquisition
of the p-methanesulfonyl derivative 11 required only that
10c be regioselectively oxidized with Oxone.9 Treatment
the route began by Wittig reaction of γ-butyrolactol (14)12
with ylide 155b (Scheme 3). Neither isomer of 16 pre-
(9) Trost, B. M.; Curran, D. F. Tetrahedron Lett. 1981, 22, 1287.
(10) Laronze, J . Y.; Cartier, D.; Laronze, J .; Levy, J . Tetrahedron
Lett. 1980, 21, 4441.
(11) (a) Schwarz, M.; Graminski, G. F.; Waters, R. M. J . Org. Chem.
1986, 51, 260. (b) Annunziata, R.; Cinquini, M.; Cozzi, F.; Gennari,
C.; Raimondi, L. J . Org. Chem. 1987, 52, 4674.
(6) Bryan, V. J .; Chan, T.-H., Tetrahedron Lett. 1996, 37, 5341.
(7) Nicolaou, K. C.; Liu, J . J .; Yang, Z.; Ueno, H.; Sorensen, E. J . J .
Am. Chem. Soc. 1995, 117, 634.
(8) Schaaf, T. K.; Hess, H. J . J . Med. Chem. 1979, 22, 1340.

Intramolecular Cyclization of Tethered Phenyl Ketones
J . Org. Chem., Vol. 63, No. 24, 1998 9063
Ta ble 1. In d iu m -P r om oted Cycliza tion s of Allylic
Ta ble 3. F lu or id e Ion -P r om oted Cycliza tion s of
Br om id es 1 a n d 2 in THF /H2O (1:4) a t 25 °Ca
Allylsila n es 3 a n d 4 in THF a t 25 °C
product ratio
syn
anti
reaction
%
yield,b
%
product product
compd
X
time, h conversiona
syn
anti
reaction
%
yield,b yield,b
ratio
A. Z series
1a
1b
1c
1d
1e
1f
compd
X
time, h conversiona
%
%
syn/anti
H
24
20
24
36
24
9
75
77
83
86
91
50
70
73
67
79
87
38
>98:2
3/4a
3/4b OCH3
3/4c
H
16
16
16
>97
95
82
8
8
11
82
76
11
1:10.3
1:9.5
1:5.8
OCH3
SCH3
CF3
>98:2
>98:2
>98:2
>98:2
>98:2
F
Determined by integration of 300 MHz 1H NMR spectra.
Yields are based on the amount of material obtained after
a
F
b
SO2CH3
B. E series
chromatographic purification.
2a
2b
2c
H
OCH3
F
24
21
25
86
80
89
82
70
86
>98:2
>98:2
>98:2
vinyl proton Ha in 19a (δ 5.74-5.63) appears well
downfield of its counterpart in 20a (δ 5.32-5.21), this
ordering being invariant through the series. This dis-
tinction applies as well to the terminal vinyl protons Hb
and Hc, which are clearly visible in the range δ 4.96-
4.88 in 19a and δ 4.83-4.67 in 20a . Finally, the allylic
proton Hd is also distinctive in the two series, that in syn
isomer 19a (δ 2.68-2.60) appearing upfield of the 20a
example (δ 2.74-2.67). In none of the cases studied was
more than a trace of 20 produced from 1 and 2 as judged
a
Determined by integration of 300 MHz 1H NMR spectra.
b
Yields are based on the amount of material obtained after
chromatographic separation.
Ta ble 2. Com p a r ison of 1H Ch em ica l Sh ifts in 19 a n d 20
(δ Va lu es a t 300 MHz (C6D6 Solu tion )a
compd
X
Ha
Hb/Hc
Hd
19a
19b
19c
19d
19e
19f
H
OCH3
SCH3
CF3
F
5.74-5.63
5.81-5.70
5.78-5.66
5.58-5.46
5.65-5.54
5.63-5.52
4.96-4.88
5.01-4.92
5.15-5.04
4.92-4.80
4.94-4.81
4.91-4.89
2.68-2.60
2.65-2.62
2.91-2.83
2.49-2.41
2.50-2.42
2.48-2.40
1
by 300 MHz H NMR analysis.
a
SO2CH3
20a
20b
20c
H
OCH3
F
5.32-5.21
5.42-5.30
5.25-5.14
4.83-4.67
4.90-4.75
4.81-4.70
2.74-2.67
2.80-2.73
2.67-2.60
a
Data recorded in CDCl3 solution.
sented any special handling problems in that they
underwent ready conversion to iodides 17 in 78% yield
upon reaction with triphenylphosphine and iodine. Treat-
ment of 17 with potassium cyanide in DMF gave nitriles
18 quantitatively. These substances were readily con-
verted to 3/4a -c via the process employed above.
Rin g Closu r e of th e Allylsila n es. Results for the
cyclization of 3 and 4 are tabulated in Table 3. Carbinol
production occurred with isolated yields in the 75-90%
range. In all three examples, the anti isomer was
significantly favored but never formed exclusively. Quite
Cycliza tion Rea ction s In volvin g Br om id es 1 a n d
2. Reactants 1a -f and 2a -c were uniformly subjected
to the action of powdered indium metal (3 equiv) in a
solvent system constituted of 20% THF and 80% water.
In each instance, the progress of reaction was monitored
by thin-layer chromatography. When the rate of cycliza-
tion slowed visibly, product isolated was undertaken. The
global results are compiled in Table 1. The methylsul-
fonyl derivative 1f behaves in somewhat anomalous fash-
ion, with ring closure occurring relatively rapidly at the
outset but coming to a virtual stop after approximately
50% consumption of the reactant. As is customary for
these processes, the purposeful introduction of more indi-
um at this point has no obvious effect, particularly in
advancing the ring closure. The phenomenon is due in
large part to the enhanced acidity of the reaction mix-
tures at this stage (pH ∼4),3a one consequence of which
is to promote rapid solvolysis of the bromide to its corre-
sponding alcohol (10 or 11). The latter were routinely
isolated during the chromatographic purification step.
Carbinols 19a -f were readily obtained in isomerically
pure form. The structural assignment to 19a rests on
NOE data as indicated and chemical shift values recorded
in C6D6 solution. Both parameters distinguish this
isomer clearly from 20a . As is evident in Table 2, the
obviously, the response of the allylsilanes toward fluoride
ion is not as diastereoselective as that of the allylic
bromides toward indium metal. Nonetheless, the pair
of reactions are usefully complementary in their ability
to produce tertiary cyclopentanols having vicinal stereo-
genic centers with good to excellent control of the
stereochemical outcome.
Discu ssion of Resu lts
In d iu m -Med ia ted Cycliza tion s. The ring closure of
bromides 1 and 2 induced by stirring with indium powder
in aqueous THF gave the syn-2-vinylcyclopentanols 19
irrespective of the double-bond geometry in the starting
material. The good yields realized in these intramolecu-
lar 1,2-additions (Table 1) indicate that both isomers
react with comparable efficiency under conditions that
have been held constant. The accepted mechanism for
(12) Corey, E. J .; Cheng, H.; Baker, C. H.; Matsuda, S. P. T.; Li, D.;
Song, X. J . Am. Chem. Soc. 1997, 119, 1277. See also: Wilson, S. R.;
Augelli-Szafran, C. E. Tetrahedron 1988, 44, 3983.

9064 J . Org. Chem., Vol. 63, No. 24, 1998
Paquette and Mendez-Andino
Sch em e 4. Cyclic Allylin d iu m Tr a n sition Sta te
Com p etition Stu d ies. In early studies, ketones were
regarded to be minimally reactive toward allylindium
reagents. Many deviations from this generic assumption
have since been recognized, including the results recorded
here. Since aldehydes are unquestionably more reactive
than ketones in the absence of steric factors, we were
attracted to examine whether the indium reagent derived
from 1a would capture benzaldehyde in an intermolecu-
lar progress more rapidly than undergo intramolecular
cyclization. Although first-order reactions are rarely
observed to be intercepted by higher-order alternatives,
the structural circumstances in this instance could not
be ignored.
Mod els for th e Z- a n d E-Isom er s
In actual fact, when equimolar amounts of 1a and
benzaldehyde were admixed with a comparable quantity
of indium, only ring closure to 19a was observed. This
kinetic preference provides strong supportive evidence
for intramolecular coordination as shown in Scheme 4.
F lu or id e Ion -In d u ced Cycliza tion s. The closely
comparable ring closures of 3 and 4, when performed with
TBAF in THF at room temperature, show the opposite
stereoselectivity, giving rise instead to the anti-cyclopen-
tanols 20 predominantly. This group of reactions is not
stereocontrolled to the extent observed in the indium
examples but provides direct entry into the opposite
configurational series. In line with convention,5 it is most
probable that anionic intermediates generated by the
attack of F- at silicon intervene in a so-called “push-
pull” process (Scheme 5). The antiperiplanar transition-
the activation of allylic bromides by indium,2,13 which
involves oxidative addition of the metal into the C-Br
bond with formation of a reactive In(III) species, is
assumed to be operative presently. Under these circum-
stances, the heavy predominance of syn-19 resulting from
the Z-isomers 1 can be explained in terms of transition
state B (Scheme 4). This cis-fused bicyclic arrangement,
an equivalent to which has been invoked in allylstannane
chemistry,14 allows for unconstrained intramolecular
coordination of the In(III) center with the carbonyl
oxygen while predisposing the aryl substituent in a
quasiequatorial orientation. No other structural option
offers so many comparable advantages. In fact, B
represents the only possibility if coordination of In to the
carbonyl oxygen atom is as important as we consider it
to be.
Sch em e 5
When the double bond is of the E geometry as in 2,
the two reasonable transition states labeled as C and D
are worthy of consideration. The facts are that the
cyclizations of 2 proceed as smoothly as those involving
1, and with an equally strong and overriding preference
for the delivery of syn product. This is as expected for
the cis-fused bicyclic transition state C but is incompat-
ible with the utilization of D. One distinction between
these two options is the boatlike arrangement of the
developing organometallic ring in C, in contrast to its
chairlike character in D. In view of the relatively large
size of indium, these energetic considerations appear to
pale in importance relative to the issue of cis (as in C) or
trans ring junction (as in D). The trans-fused model
gives evidence of not serving as a viable pathway for
product formation, perhaps because it shares in the
thermodynamic instability associated with trans-fused
5-6 ring systems.
state models E and F explain satisfactorily the preference
exhibited by the keto allylsilanes under study. Thus, the
limiting reactive conformation in all six examples corre-
sponds to E. This may be because in F steric compres-
sion develops between the aryl substituent and the
(13) (a) Li, C.-J . Chem. Rev. 1993, 93, 2023. (b) Lubineau, A.; Auge,
J .; Queneau, Y. Synthesis 1994, 741. (c) Li, C.-J . Tetrahedron 1996,
52, 5643. (d) Li, C.-J .; Chan, T.-H. Organic Reactions in Aqueous Media;
J ohn Wiley and Sons: New York, 1997.
(14) Kadota, I.; Kawada, M.; Gevorgyan, V.; Yamamoto, Y. J . Org.
Chem. 1997, 62, 7439.

Intramolecular Cyclization of Tethered Phenyl Ketones
J . Org. Chem., Vol. 63, No. 24, 1998 9065
H), 4.23 (ddd, J ) 12.3, 6.1, 0.3 Hz, 1 H), 4.04 (dd, J ) 12.3,
7.1 Hz, 1 H), 3.83 (m, 1 H), 3.48 (m, 1 H), 2.31 (t, J ) 7.2 Hz,
1 H), 2.22 (q, J ) 7.3 Hz, 1 H), 1.87-1.62 (m, 4 H), 1.61-1.46
(m, 4 H); 13C NMR (75 MHz, CDCl3) δ 130.4, 128.2, 119.4, 97.9,
62.4, 62.1, 30.5, 26.2, 25.3, 25.0, 19.4, 16.3; HRMS m/z (M+)
calcd 209.1416, obsd 209.1406.
interconnective trimethylene chain. Since 3a and 4a
generate the same product distribution, a phenomenon
likewise reflected in the para-substituted derivatives, the
Z or E character of the double bond is clearly a nonin-
fluential factor on product stereochemistry. We do see,
however, that the syn/anti ratio increases from 1:10.3
when X ) H to 1:5.8 when X ) F.
Anal. Calcd for C12H19NO2: C: 68.86; H, 9.15. Found: C,
68.74; H, 9.15.
(Z)-7-Hyd r oxy-5-h ep ten op h en on e (10a ). A 2.03 g (9.69
mmol) sample of 9 was added dropwise to a solution of
phenylmagnesium bromide in ether (110 mL of 0.17 M, 18.7
mmol) at 0 °C. The reaction mixture turned cloudy, and a
white solid precipitated. After 15 min, water (20 mL) was
added, and stirring was maintained for another 15 min. The
ether was evaporated under reduced pressure, and the re-
maining material was taken up in 100 mL of water/methanol
(1:3), cooled to 0 °C, and treated slowly with 15 mL of 10%
HCl. The mixture was allowed to warm to room temperature,
and deprotection with liberation of the allylic alcohol was
monitored by TLC. The product was extracted into CH2Cl2
(4×), and the combined organic phases were washed with
brine, dried, and evaporated. The concentrate was chromato-
graphed on silica gel (elution with 20% ethyl acetate in
petroleum ether) to give 1.80 g (91%) of 10a as a colorless oil:
The more competitive nature of the E/F options as the
para substituent is made increasingly more electron
withdrawing may reflect increased electrophilicity at the
carbonyl carbon in 3/4c, with resultant leveling of the
rates of cyclization along both reaction trajectories.
Su m m a r y
The intramolecular cyclization of allylic bromo ketones
1 and 2 as promoted by indium in water proceeds with
exceptionally high discrimination for the syn-2-vinylcy-
clopentanol irrespective of the E or Z double-bond
geometry and the electronic character of para substituent
X. This notable stereoselectivity is believed to be achieved
because of the adoption of transition states B and C,
which share a distinctive cis-fused 5/6-bicyclic nature.
Ring closure of the structurally related allylsilanes 3 and
4 also proceeds without concern for starting double-bond
geometry. For this series of compounds, however, anti-
cyclopentanol formation is dominant. The stereochemical
bias for the production of 20 is not wholesale, reaching a
maximum level of 10.3:1 in the parent system (X ) H).
Therefore, utilization of acyclic transition state E is
kinetically preferred, but ground is lost to the somewhat
more congested option F as X is made increasingly
electronegative. Nevertheless, the complementary dias-
tereocontrol exhibited by these two classes of reactions
holds synthetic potential as they provide the means for
controlling stereoinduction at a fully substituted carbon
atom. The present reactions bear an overall relationship
to select samarium(II)-promoted cyclizations.15
1
IR (neat, cm-1) 3419, 1682, 1597, 1448; H NMR (300 MHz,
CDCl3) δ 7.92 (d, J ) 8.0 Hz, 2 H), 7.56-7.40 (m, 3 H), 5.69-
5.47 (m, 2 H), 4.16 (d, J ) 6.7 Hz, 2 H), 2.95 (t, J ) 7.2 Hz, 2
H), 2.25 (br s, 1 H), 2.15 (q, J ) 7.3 Hz, 2 H), 1.81 (quintet, J
) 7.2 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 200.4, 136.8, 133.0,
131.6, 129.6, 128.5, 128.0, 58.2, 37.5, 26.6, 23.9; HRMS m/z
(M+) calcd 204.1150, obsd 204.1141.
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C,
76.33; H, 7.86.
(Z)-7-H yd r oxy-4′-m et h oxy-5-h ep t en op h en on e (10b ).
Compound 10b was formed as above in 47% yield: colorless
oil; IR (neat, cm-1) 3422, 1672, 1600; 1H NMR (300 MHz,
CDCl3) δ 7.91 (d, J ) 8.8 Hz, 2 H), 6.91 (d, J ) 8.8 Hz, 2 H),
5.65 (m, 1 H), 5.51 (m, 1 H), 4.15 (d, J ) 6.7 Hz, 2 H), 3.84 (s,
3 H), 2.90 (t, J ) 7.2 Hz, 2 H), 2.15 (q, J ) 7.3 Hz, 2 H), 2.04
(br s, 1 H), 1.80 (quintet, J ) 7.2 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 199.0, 163.4, 131.8, 130.3, 130.2, 129.9, 129.5, 113.6,
58.2, 55.4, 37.2, 26.6, 24.2; HRMS m/z (M+) calcd 234.126, obsd
234.125.
Exp er im en ta l Section
(Z)-7-Hydr oxy-4′-(m eth ylth io)-5-h epten oph en on e (10c).
Compound 10c was formed as above in 47% yield: colorless
crystals; mp 77-78 °C; IR (CHCl3, cm-1) 3614, 3492, 1675,
Gen er a l In for m a tion . Yields were calculated for material
judged to be homogeneous by TLC and NMR. Magnetic
stirring was used for all reactions. Thin-layer chromatography
was performed on Merck Kieselgel 60 F254 aluminum-backed
plates. Flash column chromatography was accomplished in
glass columns with Woelm silica gel (230-400 mesh). NMR
1
1589; H NMR (300 MHz, CDCl3) δ 7.84 (d, J ) 8.5 Hz, 2 H),
7.24 (d, J ) 8.5 Hz, 2 H), 5.70-5.62 (m, 1 H), 5.56-5.50 (m, 1
H), 4.17 (d, J ) 6.7 Hz, 2 H), 2.92 (t, J ) 7.2 Hz, 2 H), 2.50 (s,
3 H), 2.16 (q, J ) 7.2 Hz, 2 H), 1.85-1.76 (m, 3 H); 13C NMR
(75 MHz, CDCl3) δ 199.3, 145.8, 133.1, 131.8 (2 C), 129.5,
128.4, 125.0, 58.3, 37.3, 26.6, 24.1, 14.7; HRMS m/z (M+) calcd
250.103, obsd 250.106.
1
spectra were acquired at 300 MHz for H and 75 MHz for 13C.
Melting points are uncorrected. Solvents were reagent grade
and in most cases dried prior to use. The high-resolution mass
spectra were obtained at The Ohio State University Chemical
Instrumentation Center. Elemental analyses were performed
by Atlantic Microlab, Norcross, GA.
Anal. Calcd for C14H18O2S: C, 67.17; H, 7.25. Found: C,
67.30; H, 7.30.
(Z) -7 -H yd r oxy -4′-(t r iflu or om et h yl) -5 -h ep t en op h e-
n on e (10d ). A solution of [4-(trifluoromethyl)phenyl]magne-
sium bromide (47.8 mmol) in 4:1 benzene/ether (100 mL) was
vigorously refluxed while 9 (5.00 g, 23.9 mmol) was introduced
dropwise. After 15 min of additional heating, the reaction
mixture was cooled to room temperature, quenched with water
(20 mL), and stirred for 15 min. After application of the
predescribed workup, there was isolated 4.65 g (71%) of 10d
as a pale yellow oil: IR (neat, cm-1) 3372, 1691, 1410; 1H NMR
(300 MHz, CDCl3) δ 8.04 (d, J ) 8.1 Hz, 2 H), 7.72 (d, J ) 8.1
Hz, 2 H), 5.68 (m, 1 H), 5.53 (m, 1 H), 4.18 (d, J ) 6.8 Hz, 2
H), 3.00 (t, J ) 7.1 Hz, 2 H), 2.19 (q, J ) 7.3 Hz, 2 H), 1.84
(quintet, J ) 7.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 199.2,
139.5, 134.6, 131.7, 129.7, 128.4, 125.7, 121.8, 58.4, 37.9, 26.6,
23.7; HRMS m/z (M+) calcd 272.1024, obsd 272.0997.
Anal. Calcd for C14H15F3O2: C, 61.76; H, 5.55. Found: C,
61.61; H, 5.56.
(Z)-7-[(Tet r a h yd r o-2H -p yr a n -2-yl)oxy]-5-h ep t en en i-
tr ile (9). A solution of 88 (38.3 g, 90.2 mmol) in dry THF (500
mL) was treated with potassium hexamethyldisilazide (198 mL
of 0.5 M in toluene, 90.2 mmol) and stirred for 1.5 h. Aldehyde
77 (10.0 g, 69.4 mmol) was dissolved in dry THF (30 mL) and
introduced dropwise. After 4 h, the solvent was evaporated
under reduced pressure, and the residue was taken up in ether
prior to filtration through a pad of silica gel. After the pad
was rinsed several times with ether, the filtrate was concen-
trated under reduced pressure. The residue was chromato-
graphed on silica gel (elution with 20% ethyl acetate in
petroleum ether) to give 11.0 g (76%) of 9 as a colorless
liquid: IR (neat, cm-1) 2245, 1656, 1077; 1H NMR (300 MHz,
CDCl3) δ 5.68-5.60 (m, 1 H), 5.52-5.44 (m, 1 H), 5.47 (m, 1
(15) (a) Kan, T.; Nara, S.; Ito, S.; Matsuda, F.; Shirahama, H. J .
Org. Chem. 1994, 59, 5111. (b) Molander, G. A.; Shakya, S. R. J . Org.
Chem. 1996, 61, 5885. (c) Curran, D. P.; Gu, X.; Zhang, W.; Dowd, P.
Tetrahedron 1997, 53, 9023.
(Z)-4′-Flu or o-7-h ydr oxy-5-h epten oph en on e (10e). Com-
pound 10e was prepared as for 10a in 74% yield: colorless
oil; IR (neat, cm-1) 3415, 1684, 1597, 1506; 1H NMR (300 MHz,

9066 J . Org. Chem., Vol. 63, No. 24, 1998
Paquette and Mendez-Andino
CDCl3) δ 7.99-7.94 (m, 2 H), 7.15-7.08 (m, 2 H), 5.70-5.62
(m, 1 H), 5.57-5.47 (m, 1 H), 4.16 (d, J ) 6.7 Hz, 2 H), 2.94 (t,
J ) 7.2 Hz, 2 H), 2.17 (q, J ) 7.2 Hz, 2 H), 1.86-1.77 (m, 3
H); 13C NMR (75 MHz, CDCl3) δ 198.7, 165.7 (d, J ) 255 Hz),
133.3, 131.8, 130.7 (d, J ) 8.8 Hz), 129.6, 115.6 (d, J ) 22
Hz), 58.3, 37.5, 26.6, 23.9; HRMS m/z (M+) calcd 222.1056, obsd
222.1026.
125.64, 125.59, 125.54, 37.8, 26.9, 26.2, 23.1; HRMS m/z (M+)
calcd 334.0189, obsd 334.0152.
(Z)-7-Br om o-4′-flu or o-5-h ep ten op h en on e (1e). Com-
pound 1e was prepared in the manner described above in 81%
yield: colorless oil; IR (neat, cm-1) 1685, 1598, 1506; 1H NMR
(300 MHz, CDCl3) δ 8.01-7.94 (m, 2 H), 7.15-7.07 (m, 2 H),
5.83-5.73 (m, 1 H), 5.64-5.56 (m, 1 H), 3.99 (d, J ) 8.3 Hz, 2
H), 2.97 (t, J ) 7.3 Hz, 2 H), 2.24 (q, J ) 7.3 Hz, 2 H), 1.86
(quintet, J ) 7.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 134.8,
133.3, 130.6 (d, J ) 9.6 Hz), 126.3, 115.6 (d, J ) 21.8 Hz),
37.6, 27.0, 26.2, 23.2; HRMS m/z (M+) calcd 286.0192, obsd
286.0218.
(Z)-7-Br om o-4′-(m eth ylsu lfon yl)-5-h epten oph en on e (1f).
Compound 1f was prepared in the manner described above in
69% yield: colorless oil; IR (neat, cm-1) 1691, 1438, 1398, 1153;
1H NMR (300 MHz, CDCl3) δ 8.08 (d, J ) 8.4 Hz, 2 H), 7.99
(d, J ) 8.4 Hz, 2 H), 5.80-5.71 (m, 1 H), 5.61-5.52 (m, 1 H),
3.96 (d, J ) 8.3 Hz, 2 H), 3.04-2.99 (m, 5 H), 2.22 (q, J ) 7.2
Hz, 2 H), 1.84 (quintet, J ) 7.2 Hz, 2 H); 13C NMR (75 MHz,
CDCl3) δ 198.5, 148.7, 143.9, 134.5, 128.7, 127.6, 126.3, 44.1,
38.0, 27.0, 26.0, 22.8; HRMS m/z (M+) calcd 344.0082, obsd
344.0037.
Anal. Calcd for C13H15FO2: C, 70.25; H, 6.80. Found: C,
70.52; H, 6.87.
(Z) -7 -H yd r oxy -4′ -(m et h ylsu lfon yl) -5 -h ep t en op h e-
n on e (11). Half of a solution of Oxone (730 mg, 1.19 mmol)
in 8 mL of potassium dihydrogen phosphate buffer (pH ) 4.5)
was added dropwise to a solution of 10c (198 mg, 0.79 mmol)
in methanol (8 mL) at 0 °C. The reaction mixture was warmed
to room temperature, and the remainder of the oxidant was
added in four portions during 30 min. Upon completion of this
process, stirring was maintained for 1 h prior to dilution with
water and extraction with CHCl3. The combined extracts were
dried and concentrated to leave a residue that was purified
chromatographically on silica gel (elution with 50% ethyl
acetate in petroleum ether). There was isolated 134 mg (60%)
of 11 as a colorless crystalline solid: mp 70-71 °C; IR (CHCl3,
cm-1) 3615, 1693, 1321; 1H NMR (300 MHz, CDCl3) δ 8.11 (d,
J ) 8.4 Hz, 2 H), 8.04 (d, J ) 8.5 Hz, 2 H), 5.72-5.66 (m, 1
H), 5.55-5.52 (m, 1 H), 4.18 (d, J ) 6.7 Hz, 2 H), 3.08 (s, 3 H),
3.02 (t, J ) 7.1 Hz, 2 H), 2.20 (q, J ) 7.3 Hz, 2 H), 1.85 (quintet,
J ) 7.2 Hz, 2 H), 1.52 (br s, 1 H); 13C NMR (75 MHz, CDCl3)
δ 198.7, 144.1, 140.8, 131.7, 129.7, 128.9, 127.8, 58.4, 44.3, 38.1,
26.6, 23.6; HRMS m/z (M+ - OH) calcd 265.090, obsd 265.090.
Anal. Calcd for C14H18O4S: C, 59.55; H, 6.43. Found: C,
59.43; H, 6.44.
(E)-7-[(Tet r a h yd r o-2H -p yr a n -2-yl)oxy]-5-h ep t en en i-
tr ile (12). To a solution of 9 (2.0 g, 9.5 mmol) and thiophenol
(0.49 mL, 4.25 mmol) in refluxing benzene (200 mL) was added
AIBN (500 mg, 3.0 mmol) in three portions over a 6-h period.
The solvent was evaporated, and the 10:1 E/ Z mixture (1H
NMR analysis) was purified by flash chromatography on silica
gel (elution with 20% ethyl acetate in ligroin) to provide 1.59
g (81%) of 12 as a yellowish oil: IR (neat, cm-1) 2245, 1669,
1
1455; H NMR (300 MHz, CDCl3) δ 5.65 (m, 2 H), 4.62 (m, 1
(Z)-7-Br om o-5-h ep ten op h en on e (1a ). Alcohol 10a (0.95
g, 4.6 mmol) was dissolved in dry CH2Cl2 (50 mL), cooled to
-20 °C, treated with triphenylphosphine (1.34 g, 5.1 mmol),
and stirred for 30 min. Bromine (0.26 mL, 5.1 mmol) was
introduced dropwise, and the reaction mixture was quenched
with methanol after 30 min. The solvent was evaporated
under reduced pressure, and the residue was chromatographed
on Florisil (elution with 5% ether in petroleum ether) to afford
0.89 g (72%) of 1a as a yellowish oil: IR (neat, cm-1) 1684,
H), 4.19 (m, 1 H), 3.90 (m, 2 H), 3.50 (m, 1 H), 2.34 (t, J ) 7.2
Hz, 2 H), 2.20 (m, 2 H), 1.89-1.67 (m, 4 H), 1.66-1.50 (m, 4
H); 13C NMR (75 MHz, CDCl3) δ 130.9, 128.7, 119.5, 98.0, 67.4,
62.3, 31.0, 30.6, 25.4, 24.7, 19.5, 16.4 HRMS m/z (M+) calcd
209.1416, obsd 209.1390.
Anal. Calcd for C12H19NO2: C, 68.87; H, 9.15. Found: C,
68.94; H, 9.22.
(E)-7-Hyd r oxy-5-h ep ten op h en on e (13a ). Compound 13a
was prepared as described above for 10a in 61% yield and
crystallized from CH2Cl2/petroleum ether at -30 °C to yield a
colorless oil at room temperature: IR (neat, cm-1) 3409, 1682,
1
1602, 1443, 1360; H NMR (300 MHz, CDCl3) δ 7.95 (d, J )
7.2 Hz, 2 H), 7.54 (t, J ) 7.2 Hz, 1 H), 7.44 (t, J ) 7.2 Hz, 2
H), 5.80-5.74 (m, 1 H), 5.65-5.57 (m, 1 H), 3.99 (d, J ) 8.3
Hz, 2 H), 3.00 (t, J ) 7.3 Hz, 2 H), 2.25 (q, J ) 7.2 Hz, 2 H),
1.87 (quintet, J ) 7.3 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ
199.8, 136.9, 134.8, 132.9, 128.5, 126.2, 37.6, 27.1, 26.2, 23.3;
HRMS m/z (M+) calcd 265.0228, obsd 265.0197.
1
1597, 1580; H NMR (300 MHz, CDCl3) δ 7.93 (dd, J ) 8.5,
1.4 Hz, 2 H), 7.56-7.50 (m, 1 H), 7.42 (dd, J ) 8.5, 7.1 Hz, 2
H), 5.73-5.53 (m, 2 H), 4.07-4.05 (m, 2 H), 2.95 (t, J ) 7.3
Hz, 2 H), 2.16-2.09 (m, 2 H), 1.82 (quintet, J ) 7.3 Hz, 2 H),
1.78 (br s, 1 H); 13C NMR (75 MHz, CDCl3) 200.3, 136.9, 132.9,
131.8, 129.9, 128.5, 127.9, 63.4, 37.6, 31.6, 23.5; HRMS m/z
(M+) calcd 204.1150, obsd 204.1142.
(Z)-7-Br om o-4′-m eth oxy-5-h ep ten op h en on e (1b). Com-
pound 1a was obtained from 10b as described above in 51%
yield: colorless oil; IR (neat, cm-1) 1674, 1600, 1258, 1170; 1H
NMR (300 MHz, C6D6) δ 7.88 (d, J ) 8.9 Hz, 2 H), 6.67 (d, J
) 8.9 Hz, 2 H), 5.57-5.47 (m, 1 H), 5.30-5.22 (m, 2 H), 3.63
(d, J ) 8.4 Hz, 2 H), 3.22 (s, 3 H), 2.53 (t, J ) 7.1 Hz, 2 H),
1.89 (q, J ) 7.5 Hz, 2 H), 1.67 (quintet, J ) 7.1 Hz, 2 H); 13C
NMR (75 MHz, C6D6) δ 197.1, 163.5, 135.0, 130.7, 130.4, 126.4,
113.9, 54.9, 37.3, 27.1, 26.4, 23.6; HRMS m/z (M+) calcd
296.0142, obsd 296.1379.
(Z)-7-Br om o-4′-(m et h ylt h io)-5-h ep t en op h en on e (1c).
Compound 1c was prepared in the manner described above
in 77% yield: colorless oil; IR (CHCl3, cm-1) 1677, 1556, 1437;
1H NMR (300 MHz, CDCl3) δ 7.85 (d, J ) 8.6 Hz, 2 H), 7.24
(d, J ) 8.6 Hz, 2 H), 5.81-5.71 (m, 1 H), 5.63-5.55 (m, 1 H),
3.98 (d, J ) 8.3 Hz, 2 H), 2.93 (t, J ) 7.4 Hz, 2 H), 2.50 (s, 3
H), 2.23 (q, J ) 7.4 Hz, 2 H), 1.84 (q, J ) 7.4 Hz, 2 H); 13C
NMR (75 MHz, CDCl3) δ 198.8, 145.6, 134.8, 133.2, 128.3,
126.2, 124.9, 37.4, 27.1, 26.2, 23.3, 14.7; HRMS m/z (M+) calcd
312.0183, obsd 312.0142.
(Z)-7-Br om o-4′-(t r iflu or om et h yl)-5-h ep t en op h en on e
(1d ). Compound 1d was produced in 81% yield according to
the predescribed protocol: colorless oil; IR (neat, cm-1) 1693,
1410, 1326, 1128; 1H NMR (300 MHz, C6D6) δ 7.63 (d, J ) 8.2
Hz, 2 H), 7.31 (d, J ) 8.2 Hz, 2 H), 5.59-5.48 (m, 1 H), 5.29-
5.20 (m, 1 H), 3.63 (d, J ) 8.4 Hz, 2 H), 2.39 (t, J ) 7.2 Hz, 2
H), 1.87 (q, J ) 7.2 Hz, 2 H), 1.58 (quintet, J ) 7.2 Hz, 2 H);
13C NMR (75 MHz, C6D6) δ 197.6, 139.9, 134.7, 128.4, 126.6,
Anal. Calcd for C13H16O2: C, 76.44; H, 7.90. Found: C,
76.15; H, 7.93.
(E)-7-H yd r oxy-4′-m et h oxy-5-h ep t en op h en on e (13b ).
Compound 13b was obtained as a thick colorless oil at room
temperature, obtained by crystallization from CH2Cl2/petro-
leum ether at 0 °C in 51% yield: IR (neat, cm-1) 3425, 1666,
1
1595; H NMR (300 MHz, C6D6) δ 8.36 (d, J ) 8.9 Hz, 2 H),
6.68 (d, J ) 8.9 Hz, 2 H), 5.60 (m, 2 H), 4.04 (s, 2 H), 3.28 (s,
3 H), 2.76 (s, 1 H), 2.62 (t, J ) 7.3 Hz, 2 H), 1.99 (m, 2 H), 1.77
(quintet, J ) 7.2 Hz, 2 H); 13C NMR (75 MHz, C6D6) δ 198.2,
163.6, 131.2, 130.9, 130.7, 130.5, 113.9, 63.4, 55.0, 37.5, 32.0,
24.2; HRMS m/z (M+) calcd 234.1256, obsd 234.1247.
Anal. Calcd for C14H18O4S: C, 59.55; H, 6.43. Found: C,
59.43; H, 6.44.
(E)-4′-F lu or o-7-h yd r oxy-5-h ep ten op h en on e (13c): white
crystals; mp 56-57 °C (from CH2Cl2/petroleum ether at 0 °C)
in 81% yield; IR (CHCl3, cm-1) 3609, 1679, 1599; 1H NMR (300
MHz, CDCl3) δ 7.96 (dd, J ) 8.6, 5.4 Hz, 2 H), 7.11 (t, J ) 8.6
Hz, 2 H), 5.67 (m, 2 H), 4.08 (d, J ) 4.1 Hz, 2 H), 2.93 (t, J )
7.3 Hz, 2 H), 2.14 (m, 2 H), 1.84 (q, J ) 7.3 Hz, 2 H), 1.63 (s,
1 H); 13C NMR (75 MHz, CDCl3) δ 198.5, 165.6 (d, J ) 254
Hz), 133.4, 131.9, 130.6 (d, J ) 9.5 Hz), 130.0, 115.6 (d, J )
21.9 Hz), 63.5, 37.6, 31.6, 23.5; HRMS m/z (M+) calcd 222.1056,
obsd 222.1052.
Anal. Calcd for C13H15FO2: C, 70.25; H, 6.80. Found: C,
70.52; H, 6.87.

Intramolecular Cyclization of Tethered Phenyl Ketones
J . Org. Chem., Vol. 63, No. 24, 1998 9067
(E)-7-Br om o-5-h ep ten op h en on e (2a ): colorless oil (67%);
IR (neat, cm-1) 1683, 1597, 1448; 1H NMR (300 MHz, C6D6) δ
7.86 (dd, J ) 8.0, 1.6 Hz, 2 H), 7.22-7.12 (m, 3 H), 5.49-5.32
(m, 2 H), 3.58 (d, J ) 7.2 Hz, 2 H), 2.52 (t, J ) 7.2 Hz, 2 H),
1.84 (q, J ) 7.2 Hz, H), 1.66 (m, 2 H); 13C NMR (75 MHz, C6D6)
δ 198.5, 137.6, 135.5, 132.7, 128.6, 128.2, 127.4, 37.4, 33.1, 31.5,
23.3; HRMS m/z (M+) calcd 266.0306, obsd 266.0324.
(E)-7-Br om o-4′-m eth oxy-5-h ep ten op h en on e (2b): color-
less oil (63%); IR (neat, cm-1) 1674, 1599, 1510; 1H NMR (300
MHz, C6D6) δ 7.86 (d, J ) 8.8 Hz, 2 H), 6.88 (d, J ) 8.8 Hz, 2
H), 5.47-5.27 (m, 2 H), 3.55 (d, J ) 7.2 Hz, 2 H), 3.25 (s, 3 H),
2.52 (t, J ) 7.1 Hz, 2 H), 1.84 (q, J ) 7.1 Hz, 2 H), 1.67 (q, J
) 7.1 Hz, 2 H); 13C NMR (75 MHz, C6D6) δ 197.2, 163.5, 135.7,
130.7, 130.4, 127.3, 113.9, 54.9, 37.1, 33.2, 31.6, 23.5; HRMS
m/z (M+) calcd 296.0412, obsd 296.0430.
(E)-7-Br om o-4′-flu or o-5-h ep ten op h en on e (2c): colorless
oil (62%); IR (neat, cm-1) 1682, 1597, 1505; 1H NMR (300 MHz,
C6D6) δ 7.62 (dd, J ) 8.9, 5.5 Hz, 2 H), 6.68 (t, J ) 8.9 Hz, 2
H), 5.44-5.25 (m, 2 H), 3.51 (d, J ) 7.3 Hz, 2 H), 2.33 (t, J )
7.1 Hz, 2 H), 1.77 (q, J ) 7.1 Hz, 2 H), 1.58 (quintet, J ) 7.1
Hz, 2 H); 13C NMR (75 MHz, C6D6) δ 198.6, 165.7 (d, J ) 253
Hz), 135.3, 133.9 (d, J ) 3 Hz), 130.7 (d, J ) 9 Hz), 127.5,
115.5 (d, J ) 2 Hz), 37.2, 32.9, 31.4, 23.2; HRMS m/z (M+)
calcd 284.0212, obsd 284.0258.
(200 mL), washed with dilute NaHCO3 solution (3 × 50 mL),
dried, and filtered. The filtrate was concentrated, and the
residue was chromatographed on silica gel (elution with
5-10% ether in ligroin) to give 770 mg (100%) of 18 as a
colorless oil (E/ Z ) 2.5:1): IR (neat, cm-1) 2246, 1646, 1456;
1H NMR (300 MHz, C6D6) δ 5.48-5.26 (m, 1 H), 5.01-4.87
(m, 1 H), 1.85-1.75 (m, 2 H), 1.54-1.44 (m, 2 H), 1.39-1.26
(m, 2 H), 1.17-1.04 (m, 2 H), -0.03 (s, 9 H); 13C NMR (75
MHz, C6D6) δ 128.6, 127.7, 126.4, 125.1, 119.3, 31.6, 25.9, 25.5,
22.8, 18.6, 16.1, 15.9, -1.8, -2.0; HRMS m/z (M+) calcd
181.1287, obsd 181.1279.
Anal. Calcd for C10H19NSi: C, 66.23; H, 10.56. Found: C,
66.50; H, 10.71.
Gen er a l P r oced u r e for Gr ign a r d Cou p lin g to 18.
Nitrile 18 (1.0 g, 5.5 mmol) was added to a solution of the aryl
Grignard reagent in ether (approximately 0.5 M, 3 equiv),
stirred for 20 min, cooled in an ice bath, quenched with
saturated NH4Cl solution (15 mL), and diluted with ether
(40 mL) and water (15 mL). The separated aqueous phase
was extracted with ether (2 × 50 mL), and the combined
organic layers were dried, filtered, and concentrated. The
residue was chromatographed on silica gel (elution with
0-10% ether in ligroin) to give the 3/4 ketone mixtures as
colorless oils.
6-(Tr im eth ylsilyl)-4-h exen -1-ol (16). A stirred suspen-
sion of methyltriphenylphosphonium bromide (29.47 g, 82.5
mmol) in dry THF (100 mL) was cooled to 0 °C, treated with
n-butyllithium (56.7 mL of 1.6 M in hexanes, 90.7 mmol),
warmed to room temperature, stirred for 1 h, and recooled to
0 °C. After the addition of (iodomethyl)trimethylsilane (17.67
g, 82.5 mmol), the mixture was again allowed to warm to room
temperature, stirred for 1 h, cooled to -78 °C, and treated
again with n-butyllithium (56.7 mL of 1.6 M in hexanes, 90.7
mmol). The dark red solution was stirred for 1.5 h at 20 °C,
cooled to 0 °C, and treated during 20 min with a solution of
γ-butyrolactol (3.30 g, 37.5 mmol) in dry THF (20 mL). The
mixture was allowed to warm slowly to room temperature,
stirred overnight, and quenched with saturated NH4Cl solution
(100 mL). The aqueous phase was extracted with ether (3 ×
50 mL), and the combined organic layers were washed with
brine (75 mL), dried, and concentrated in vacuo. The residue
was taken up in ligroin (100 mL), filtered, again freed of
solvent, and chromatographed on silica gel (elution with 10-
20% ethyl acetate in ligroin). There was isolated 4.18 g (65%)
of 16 as a colorless oil consisting of a 2.5:1 mixture of E and Z
isomers: IR (neat, cm-1) 3325, 1645, 1248; 1H NMR (300 MHz,
C6D6) δ 5.49-5.23 (m, 2 H), 3.49 (t, J ) 6.4 Hz, 2 H), 2.43 (s,
1 H), 2.06 (m, 2 H), 1.60-1.37 (m, 4 H), -0.01 and -0.03 (2 s,
total 9 H); 13C NMR (75 MHz, C6D6) δ 128.7, 127.4, 126.7,
126.0, 62.3, 62.1, 33.4, 33.2, 29.5, 23.8, 22.8, 18.5, -1.8, -1.9;
HRMS m/z (M+) calcd 172.1283, obsd 172.1297.
For 3a /4a (91%): IR (neat, cm-1) 1688, 1598; 1H NMR (300
MHz, C6D6) δ 7.88 (d, J ) 7.0 Hz, 2 H), 7.22-7.09 (m, 3 H),
5.56-5.24 (m, 2 H), 2.68 (t, J ) 7.2 Hz, 2 H), 2.07 (quintet, J
) 7.2 Hz, 2 H), 1.83 (quintet, J ) 7.2 Hz, 2 H), 1.49 (d, J ) 8.5
Hz, 0.75 × 2 H), 1.42 (d, J ) 7.8 Hz, 0.25 × 2 H), 0.03 (s, 0.75
× 9 H), 0.02 (0.25 × 9 H); 13C NMR (75 MHz, C6D6) δ 198.7,
137.7, 132.6, 128.6, 128.2, 127.2, 126.4, 37.9, 37.7, 32.6, 26.8,
24.7, 24.5, 22.8, 18.6, -1.8, -1.9; HRMS m/z (M+) calcd
260.1596, obsd 260.1575.
Anal. Calcd for C16H24OSi: C, 73.79; H, 9.29. Found: C,
74.02; H, 9.20.
For 3b/4b (88%): IR (neat, cm-1) 1681, 1601; 1H NMR (300
MHz, C6D6) δ 7.87 (d, J ) 8.9 Hz, 2 H), 6.66 (d, J ) 8.9 Hz, 2
H), 5.53-5.20 (m, 2 H), 3.23 (s, 3 H), 2.67 (t, J ) 7.2 Hz, 2 H),
2.06 (quintet, J ) 7.2 Hz, 2 H), 1.83 (quintet, J ) 7.2 Hz, 2
H), 1.46 (d, J ) 8.5 Hz, 0.75 × 2 H), 1.38 (d, J ) 7.7 Hz, 0.25
× 2 H), -0.01 (s, 0.75 × 9 H), -0.02 (s, 0.25 × 9 H); 13C NMR
(75 MHz, C6D6) δ 197.4, 163.4, 130.4, 128.7, 127.3, 127.1, 126.4,
113.8, 54.9, 54.8, 37.7, 37.5, 32.7, 26.9, 24.7, 22.8, 18.6, -1.8,
-1.9; HRMS m/z (M+) calcd 290.1702, obsd 290.1684.
Anal. Calcd for C17H26O2Si: C, 70.29; H, 9.02. Found: C,
70.45; H, 9.09.
For 3c/4c (83%): IR (neat, cm-1) 1688, 1599; 1H NMR (300
MHz, C6D6) δ 7.66 (m, 2 H), 6.70 (t, J ) 8.7 Hz, 2 H), 5.53-
5.18 (m, 2 H), 2.53 (t, J ) 7.3 Hz, 2 H), 2.03 (quintet, J ) 7.3
Hz, 2 H), 1.77 (quintet, J ) 7.3 Hz, 2 H), 1.46 (d, J ) 8.5 Hz,
0.75 × 2 H), 1.40 (d, J ) 7.8 Hz, 0.25 × 2 H), 0.00 (s, 0.75 ×
9 H), -0.02 (s, 0.25 × 9 H); 13C NMR (75 MHz, C6D6) δ 197.2,
165.7 (d, J ) 253 Hz), 134.0 (d, J ) 2 Hz), 130.7 (d, J ) 9 Hz),
128.5, 127.3, 127.1, 126.5, 115.5 (d, J ) 22 Hz), 37.7, 37.6,
32.6, 26.8, 24.6, 24.4, 22.8, 18.6, -1.8, -2.0; HRMS m/z (M+)
calcd 278.1502, obsd 278.1481.
Anal. Calcd for C9H20OSi: C, 62.72; H, 11.70. Found: C,
62.77; H, 11.61.
(6-Iod o-2-h exen yl)tr im eth ylsila n e (17). A mixture of 16
(936 mg, 5.44 mmol), triphenylphosphine (3.55 g, 13.5 mmol),
imidazole (920 mg, 13.5 mmol), and iodine (2.75 g, 10.8 mmol)
in benzene (60 mL) was stirred for 20 min at 20 °C. After the
addition of saturated NaHSO3 solution (30 mL), the reaction
mixture was stirred for 10 min longer and extracted with ethyl
acetate (2 × 60 mL). The combined organic layers were
washed with brine, dried, and concentrated. The residue was
chromatographed on silica gel (elution with ligroin) to give 1.20
g (78%) of 17 as a colorless liquid: IR (neat, cm-1) 1648, 1425,
Anal. Calcd for C16H23FOSi: C, 69.02; H, 8.33. Found: C,
69.30; H, 8.31.
Gen er a l P r oced u r e for th e In d iu m -P r om oted Cycliza -
tion s of 1 a n d 2. The allylic bromide (0.4 mmol) was
dissolved in 4.0 mL of THF/water (1:4), treated with powdered
indium metal (1.2 equiv), and stirred vigorously for the
indicated reaction time. After the cyclization was judged to
be complete (TLC analysis), the reaction mixture was diluted
with ether or chloroform, transferred to a separatory funnel,
and extracted several times with the same solvent. The
combined extracts were dried and concentrated under reduced
1
1248; H NMR (300 MHz, C6D6) δ 5.48-5.38 (m, 1 H), 5.13-
4.98 (m, 1 H), 2.80-2.72 (m, 2H), 1.94-1.85 (m, 2 H), 1.60-
1.49 (m, 2 H), 1.43 (d, J ) 8.0 Hz, 0.75 × 2 H), 1.33 (d, J ) 8.0
Hz, 0.25 × 2 H), -0.03 and -0.06 (2 s, total 9 H); 13C NMR
(75 MHz, C6D6) δ 128.1, 127.2, 126.7, 125.5, 33.8, 33.54, 33.45,
28.0, 22.8, 18.8, 6.5, 6.4, -1.7, -1.9; HRMS m/z (M+) calcd
282.0301, obsd 282.0311.
1
pressure to leave a residue, which was analyzed by H NMR.
This material was next chromatographed. The yield of ring-
closed product was ascertained after the purification step.
For 1a f 19a : 24 h, silica gel (elution with 5% ether in
petroleum ether), 70% yield; colorless oil; IR (neat, cm-1) 3474,
1493, 1334; 1H NMR (300 MHz, C6D6) δ 7.48 (d, J ) 7.9 Hz, 2
H), 7.36 (t, J ) 7.3 Hz, 2 H), 7.27-7.22 (m 1 H), 5.74 (ddd, J
) 17.1, 10.7, 6.0 Hz, 1 H), 5.11 (dd, J ) 17.4, 10.5 Hz, 2 H),
Anal. Calcd for C9H19ISi: C, 38.30; H, 6.79. Found: C,
38.43; H, 6.81.
7-(Tr im eth ylsilyl)-5-h ep ten en itr ile (18). A mixture of
17 (1.20 g, 4.26 mmol), potassium cyanide (0.83 g, 12.8 mmol),
and DMF (10 mL) was stirred overnight, diluted with ether

9068 J . Org. Chem., Vol. 63, No. 24, 1998
Paquette and Mendez-Andino
2.97-2.89 (m, 1 H), 2.19-1.80 (series of m, 7 H); 13C NMR (75
MHz, C6D6) δ 145.8, 135.8, 128.1, 126.5, 125.0, 117.7, 83.4,
54.5, 42.7, 27.9, 21.8; HRMS m/z (M+) calcd 188.1201, obsd
188.1207.
Anal. Calcd for C13H16O: C, 82.94; H, 8.57. Found: C,
82.90; H, 8.56.
the combined organic solutions were dried (Na2SO4) and
evaporated to leave 85.1 mg of crude product. This material
was dissolved in 1:3 ether/petroleum ether and eluted through
a small pipet of Florisil with 50% ether in petroleum ether.
The filtrate was concentrated. After the residue was examined
by 1H NMR, separation was effected chromatographically
(silica gel, 5-10% ether in petroleum ether), and the yields
were determined at this stage.There was recovered 15.2 mg
(71%) of unreacted benzaldehyde, 26.6 mg (63%) of 19b, and
3.7 mg (6%) of 10b.
For 1b f 19b: 20 h, silica gel (elution with 5-10% ether
in petroleum ether), 73% yield; colorless oil; IR (neat, cm-1
)
3492, 1611, 1249, 1179; 1H NMR (300 MHz, C6D6) δ 7.32 (d, J
) 8.8 Hz, 2 H), 6.83 (d, J ) 8.8 Hz, 2 H), 5.81-5.70 (m, 1 H),
5.01-4.92 (m, 2 H), 3.35 (s, 3 H), 2.65-2.62 (m, 1 H), 1.99-
1.75 (m, 5 H), 1.62-1.58 (m, 1 H), 1.34 (s, 1 H); 13C NMR (75
MHz, C6D6) δ 158.6, 138.2, 136.5, 127.9, 127.6, 126.4, 116.9,
113.5, 83.0, 54.7, 54.5, 42.7, 28.4, 21.7; HRMS m/z (M+) calcd
218.1307, obsd 218.1306.
Gen er a l P r oced u r e for F lu or id e Ion -P r om oted Cy-
cliza tion s. Molecular sieves (4 Å, 10 mg) were placed in a
25 mL round-bottomed flask together with 1 mL of dry THF
under nitrogen. A solution of tetra-n-butylammonium fluoride
(100 µL of 1.0 M in THF, 0.25 equiv) was introduced, and the
mixture was stirred for 15 min prior to the introduction of the
3/4 sample (0.4 mmol) dissolved in dry THF (1 mL). After
overnight agitation, water (3 mL) was introduced, and the
product was extracted into ether (3 × 7 mL). The combined
organic phases were dried, filtered, and concentrated. After
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31. Found: C,
77.21; H, 8.58.
There was also isolated alcohol 10b in 15% yield.
For 1c f 19c: 24 h, silica gel (elution with 5% ether in
petroleum ether), 67% yield; colorless oil; IR (neat, cm-1) 3474,
1494, 1096; 1H NMR (300 MHz, C6D6) δ 7.24 (d, J ) 8.5 Hz, 2
H), 7.17 (d, J ) 8.5 Hz, 2 H), 5.84-5.63 (m, 1 H), 4.99-4.89
(m, 2 H), 2.62-2.04 (m, 2 H), 1.9-1.54 (series of m, 6 H), 1.39
(br s, 1 H); 13C NMR (75 MHz, C6D6) δ 143.4, 137.0, 136.4,
126.8, 126.1, 117.3, 83.3, 55.0, 42.9, 28.6, 22.0, 15.6; HRMS
m/z (M+) calcd 234.1078, obsd 234.1083.
1
the residue was examined by H NMR, diastereomer separa-
tion was effected chromatographically and the yields deter-
mined at this stage.
For 3/4a f 20a : >97% conversion, silica gel (elution with
10% ether in petroleum ether), 82% anti/8% syn; colorless oil;
IR (neat, cm-1) 3466, 1507, 1224; 1H NMR (300 MHz, C6D6) δ
7.31-7.27 (m, 2 H), 7.16-7.11 (m, 2 H), 7.08-7.02 (m, 2 H),
5.32-5.21 (m, 1 H), 4.75 (m, 2 H), 2.70 (dd, J ) 13.1, 7.2 Hz,
1 H), 2.15-2.05 (m, 2 H), 1.95-1.74 (m, 1 H), 1.70-1.50 (m, 4
H); 13C NMR (75 MHz, C6D6) δ 145.0, 140.0, 128.0, 127.1,
127.0, 114.5, 85.0, 55.9, 38.0, 29.9, 21.8; HRMS m/z (M+) calcd
188.1201, obsd 188.1205.
Anal. Calcd for C14H18OS: C, 71.75; H, 7.74. Found: C,
71.54; H, 7.83.
For 1d f 19d : 36 h, Florisil (elution with 5% ether in
petroleum ether), 79% yield; colorless oil; IR (neat, cm-1) 3472,
1615, 1325; 1H NMR (300 MHz, C6D6) δ 7.41 (d, J ) 8.4 Hz, 2
H), 7.20 (d, J ) 8.4 Hz, 2 H), 5.58-5.46 (m, 1 H), 4.92-4.80
(m, 2 H), 2.49-2.41 (m, 1 H), 1.98-1.48 (series of m, 6 H),
1.27 (br s, 1 H); 13C NMR (75 MHz, CDCl3) δ 150.1, 135.1,
125.5, 125.1, 125.0, 118.4, 83.2, 54.9, 42.8, 27.9, 21.9; HRMS
m/z (M+) calcd 256.1075, obsd 256.1084.
Anal. Calcd for C13H16O: C, 82.94; H, 8.57. Found: C,
82.69; H, 8.59.
For 3/4b f 20b: 95% conversion, silica gel (elution with
15% ether in petroleum ether), 76% anti/8% syn; colorless oil;
1
Anal. Calcd for C14H15F3O: C, 65.62; H, 5.90. Found: C,
65.72; H, 5.88.
IR (neat, cm-1) 3418, 1613, 1296, 1250; H NMR (300 MHz,
C6D6) δ 7.27 (d, J ) 8.8 Hz, 2 H), 6.79 (d, J ) 8.8 Hz, 2 H),
5.42-5.30 (m, 1 H), 4.90-4.75 (m, 1 H), 3.34 (s, 3 H), 2.80-
2.73 (m, 1 H), 2.23-2.10 (m, 2 H), 1.98-1.81 (m, 1 H), 1.77-
1.54 (m, 4 H); 13C NMR (75 MHz, C6D6) δ 159.1, 140.3, 137.2,
128.1, 114.3, 113.4, 84.7, 55.8, 54.7, 38.0, 29.9, 21.8; HRMS
m/z (M+) calcd 218.1307, obsd 218.1312.
For 1e f 19e: 24 h, silica gel (elution with 5% ether in
petroleum ether), 87% yield; colorless oil; IR (neat, cm-1) 3476,
1509, 1227; 1H NMR (300 MHz, C6D6) δ 7.12 (dd, J ) 8.8, 5.3
Hz, 2 H), 6.81 (t, J ) 8.7 Hz, 2 H), 5.59 (ddd, J ) 17.2, 10.6,
6.6 Hz, 1 H), 4.94-4.81 (m, 2 H), 2.50-2.42 (m, 1 H), 1.91-
1.48 (series of m, 6 H), 1.33 (br s, 1 H); 13C NMR (75 MHz,
C6D6) δ 162.1 (d, J ) 244 Hz), 142.1, 136.2, 127.2 (d, J ) 8.2
Hz), 117.4, 114.9 (d, J ) 20.9 Hz), 83.1, 55.1, 42.9, 28.6, 21.9;
HRMS m/z (M+) calcd 206.1107, obsd 206.1109.
Anal. Calcd for C14H18O2: C, 77.03; H, 8.31 Found: C,
76.93; H, 8.30.
For 3/4c f 20c: 82% conversion, silica gel (elution with 10%
ether in petroleum ether), 64% anti/11% syn; colorless oil; IR
(neat, cm-1) 3389, 1602, 1510; 1H NMR (300 MHz, C6D6) δ
7.14-7.07 (m, 2 H), 6.87-6.72 (m, 2 H), 5.25-5.14 (m, 2 H),
4.81-4.70 (m, 2 H), 2.63 (dd, J ) 13.1, 7.0 Hz, 1 H), 2.15-
1.94 (m, 2 H), 1.68-1.46 (m, 3 H), 1.22 (s, 1 H); 13C NMR (75
MHz, C6D6) δ 162.2 (d, J ) 245 Hz), 140.8 (d, J ) 3 Hz), 139.7,
128.6 (d, J ) 8 Hz), 114.64, 114.63 (d, J ) 21 Hz), 84.5, 55.9,
38.1, 29.9, 21.7; HRMS m/z (M+) calcd 206.1107, obsd 206.1135.
Anal. Calcd for C13H15FO: C, 75.70; H, 7.33. Found: C,
75.22; H, 7.37.
There was also isolated alcohol 10e in 6% yield.
For 1f f 19f: 9 h, silica gel (elution with 25% ethyl acetate
in petroleum ether), 38% yield; colorless solid; mp 90-91 °C;
IR (neat, cm-1) 3516, 1310, 1149; 1H NMR (300 MHz, C6D6) δ
7.78 (d, J ) 8.3 Hz, 2 H), 7.27 (d, J ) 8.3 Hz, 2 H), 5.63-5.52
(m, 1 H), 4.91 (d, J ) 10.5 Hz, 1 H), 4.83 (d, J ) 17.3 Hz, 1 H),
2.48-2.40 (m, 1 H), 2.29 (s, 3 H), 1.89-1.51 (m, 7 H); 13C NMR
(75 MHz, C6D6) δ 152.4, 139.8, 135.8, 127.4, 126.3, 117.7, 83.3,
55.6, 43.8, 43.0, 28.8, 22.1; HRMS m/z (M+) calcd 266.0977,
obsd 266.0959.
Anal. Calcd for C14H18O3S: C, 63.13; H, 6.81. Found: C,
63.03; H, 6.77.
There was also isolated alcohol 11 in 18% yield.
For 2a f 19a : 24 h, 82% yield, spectroscopically identical
to the material described above.
Ack n ow led gm en t. Funds in support of this re-
search were generously provided by the Eli Lilly Co. and
in part by the U.S. Environmental Protection Agency
(Grant No. R82-4725-010).
For 2b f 19b: 21 h, 70% yield, spectroscopically identical
to the material described above.
For 2c f 19c: 25 h, 86% yield, spectroscopically identical
to the material described above.
Com p etition Stu d ies. A mixture of 1b (57.8 mg, 0.20
mmol), benzaldehyde (21.5 mg, 0.20 mmol), and powdered
indium (27.1 mg, 0.20 mmol) in 2.0 mL of 1:3 THF/H2O was
vigorously stirred overnight and diluted with ether (2 mL).
The aqueous phase was extracted with ether (3 × 5 mL), and
Su p p or tin g In for m a tion Ava ila ble: Copies of the high-
resolution 1H and 13C NMR spectra of those new compounds
for which elemental analyses are not reported (22 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
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J O981683S