A new strategy for synthesis of attached rings

Article abstract of DOI:10.1139/v00-022

The first investigation of the use of pinacol-terminated Prins cyclizations to form attached rings is reported. Treatment of triisopropylsilyl ethers of (Z)- or (E)-[2-(6,6-dimethoxyhexylidene)cyclohexanol with SnCl₄ provides bicyclic products having attached rings. The approach is synthetically useful in the Z alkylidenecyclohexane series, proceeding selectively by a pathway involving carbon migration in the pinacol rearrangement step, to provide methoxy epimers of 1-(2-methoxycyclohexyl)cyclopentylcarboxaldehyde. Reaction of the corresponding E stereoisomer is more complex and yields a mixture of products resulting from both hydride and carbon migration in the pinacol rearrangement step.

Full text of DOI:10.1139/v00-022

732
A new strategy for synthesis of attached rings
Larry E. Overman and Lewis D. Pennington
Abstract: The first investigation of the use of pinacol-terminated Prins cyclizations to form attached rings is reported.
Treatment of triisopropylsilyl ethers of (Z)- or (E)-[2-(6,6-dimethoxyhexylidene)cyclohexanol with SnCl4 provides
bicyclic products having attached rings. The approach is synthetically useful in the Z alkylidenecyclohexane series,
proceeding selectively by a pathway involving carbon migration in the pinacol rearrangement step, to provide methoxy
epimers of 1-(2-methoxycyclohexyl)cyclopentylcarboxaldehyde. Reaction of the corresponding E stereoisomer is more
complex and yields a mixture of products resulting from both hydride and carbon migration in the pinacol rearrange-
ment step.
Key words: Prins cyclization, pinacol rearrangement, attached rings.
Résumé : On a réalisé la première étude de l’utilisation de cyclisations de Prins terminées par du pinacol dans le but
de former produits auxquels des cycles sont attachés. Le traitement des éthers triisopropyliques des (Z)- et (E)-[2-(6,6-
diméthoxyhexylidène)]-cyclohexanol avec du SnCl4 conduit à la formation de produits bicycliques auxquels des cycles
sont attachés. L’approche est utile en synthèse dans la série du Z-alkylidènecyclohexane puisque, par le biais d’une
voie impliquant la migration d’un carbone dans l’étape du réarrangement pinacolique, elle conduit d’une façon sélective
aux 1-(2-méthoxycyclohexyl)-cyclopentylcarboxaldéhydes épimères au niveau du méthoxy. La réaction du stéréoisomère
E correspondant est plus complexe et elle conduit à un mélange de produits qui, dans l’étape du réarrangement
pinacolique, résultent de migrations tant d’hydrure que de carbone.
Mots clés : cyclisation de Prins, réarrangement pinacolique, cycles attachés.
[Traduit par la Rédaction] Overman and Pennington 738
Introduction
Myriad opportunities in ring construction are realized by
utilizing a pinacol rearrangement to terminate a Prins cycli-
zation. One of the earliest examples is credited to Mousset
and co-workers (1), who discovered serendipitously the syn-
thesis of substituted tetrahydrofurans by acid-promoted reac-
tion of allylic diols with aldehydes. Recent investigations in
our laboratory (for brief reviews of our early work in this
area, see ref. 2) (3), and elsewhere (for contributions from
other laboratories, see ref. 4) have documented the utility of
“Prins-pinacol” reactions for forming various oxacyclic and
carbocyclic ring systems. We have highlighted the power of
this ring construction method by employing it as the key
strategic element in the synthesis of natural products having
diverse architectures (5). Prins-pinacol reactions have been
most widely employed to form fused polycyclic ring systems
(2–5), while their use to form spirocyclic rings is less devel-
oped (3i). Herein we report the first use of a Prins-pinacol
reaction to access attached rings, rings linked by a C—C σ -
bond (eq. [1]). When the attachment centers are stereogenic,
attached rings pose a notable challenge for stereocontrolled
synthesis (the insect antifeedant azadirachtin is exemplary,
see ref. 6).
Results
The Z and E alkylidenecyclohexanes 1 and 2 were cho-
sen for this exploratory investigation (Scheme 1). The
stereochemical outcome of the Prins-pinacol reactions stud-
ied in our laboratory is accommodated by a sequence in
which stereochemistry is dictated in the Prins cyclization
step, that is pinacol rearrangement occurs more rapidly
than conformational changes of the putative carbocation
generated upon Prins cyclization (3i). Thus, our initial ex-
pectation was that 1 and 2 would cyclize to give aldehyde 3
and ketone 4, respectively. This prediction follows from the
presumption that allylic interactions between the siloxy
group and the alkylidene side chain (A1,3 strain) would fa-
vor cyclization topography A for the Z substrate (7), while
an electronic preference for having an electronegative oxy-
gen substituent in the plane of the nucleophilic alkene π-
system would favor topography C for the E substrate (8).
Received September 25, 1999. Published on the NRC
Research Press website on June 1, 2000.
Dedicated to Professor Stephen Hanessian in recognition of
his many contributions to the science of organic synthesis.
L.E. Overman1 and L.D. Pennington. Department of
Chemistry, 516 Rowland Hall, University of California,
Irvine, CA 92697-2025, U.S.A.
1Author to whom correspondence may be addressed.
Fax: (949) 824-3866. e-mail: leoverma@uci.edu
Can. J. Chem. 78: 732–738 (2000)
© 2000 NRC Canada

Overman and Pennington
733
Scheme 1.
Scheme 3.
Scheme 2.
(10) was prepared in three steps and 72% yield from 6-
bromohexan-1-ol: (i) PCC, CH2Cl2, rt; (ii) p-TsOH·H2O,
MeOH, rt; and (iii) NaI, acetone, rt) and α-siloxycyclo-
hexanone 8, utilizing “salt-free” Wittig conditions (11)
(Scheme 2). The 3:1 mixture of 1 and 2 thus obtained could
be separated by flash chromatography using AgNO3-impreg-
nated silica gel.
Pinacol rearrangement of carbocation B would occur by
migration of a ring carbon to yield 3, since the C1—H σ -
bond is orthogonal to the vacant p-orbital, preventing hy-
dride migration. Pinacol rearrangement of carbenium ion D
would produce 4 if hydride migration occurred in prefer-
ence to migration of ring bond a (for reviews of the pinacol
rearrangement, see ref. (9a)). The relative stereochemistry
at the stereogenic attached carbons of 4 would be governed
by which face of the alkene participated in the transforma-
tion of C → D. Additionally, the stereochemistry of the
methoxy substituent in the products would be determined
by the orientation of the alkene and the oxocarbenium ion
during Prins cyclization. Although our exploratory investi-
gations would be carried out with racemic substrates, one
appeal of the route to 4 proposed in Scheme 1 was the ex-
pectation that 2 would also be readily available in
enantioenriched form.
A route that would lend itself to obtaining enantioenriched
2 by enantioselective reduction of an enone precursor (12)
was also developed (Scheme 3). The key step in this se-
quence was Suzuki coupling of boronic acid 9 generated in
situ from the corresponding alkene (14) by a standard
hydroboration–oxidation sequence (13), and enol triflate 10
(15) (although not mentioned in (15), triflate 10 decomposed
rapidly at room temperature if 2,4,6-collidine was not pres-
ent) to give enone 11. Luche reduction (16) of 11 produced
alcohol 12, which was then silylated to furnish 2.
1H NMR nOe difference experiments readily confirmed
stereochemical assignments for the alkylidene stereoisomers:
2 displayed reciprocal nOe enhancements between the
1
vinylic and C1 hydrogens, while 1 did not. H NMR spectra
Alkylidenecyclohexyl ethers 1 and 2 were initially pre-
pared by coupling phosphonium salt 6 (the known iodide 5
of 1 and 2 suggested somewhat different conformations for
the two substrates. Diagnostic were signals for the C1
© 2000 NRC Canada

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Can. J. Chem. Vol. 78, 2000
Scheme 4.
hydrogen, which for 1 appeared as a broad singlet (wh/2
=
7.7 Hz) at δ 4.71, whereas the corresponding hydrogen of 2
appeared as a multiplet (wh/2 = 15.4 Hz) at δ 4.10. These dif-
ferences reflect the greater proportion of conformers having
the siloxy substituent axial in 1.
Exposure of 1 or 2 in MeNO2 to 0.5 equiv. of SnCl4 at
0°C for 2 h resulted in efficient Prins-pinacol reaction to
give bicyclic products (Scheme 4). No reaction was observed
under identical conditions at –23°C. The Z alkylidene sub-
strate 1 provided exclusively aldehyde products 3a and 3b in
a 1:1.7 ratio. In contrast, the E alkylidene substrate 2 deliv-
ered a complex mixture of six products, in which the ratio of
cyclopentylcarboxyaldehyde to cyclohexanone products was
1.3:1. In this latter case, aldehyde stereoisomer 3a was fa-
vored to the extent of 5.3:1, while two major ketone
stereoisomers 4a and 4b were produced in a 1.9:1 ratio.
With the exception of 4a and 4b, all products could be sepa-
rated by medium pressure liquid chromatography (MPLC).
The mixture of 4a and 4b was contaminated with
triisopropylsiloxy residues, thus the yield and ratio of these
axial disposition of the methoxy substituent in 4a and 4b
was readily apparent from 1H NMR spectra: the ether
methine hydrogens in the 4a–4b mixture appear as partially
overlapping broad singlets at δ 3.39 and δ 3.36, while the
corresponding signals of 4c and 4d appear as diagnostic trip-
let of doublets at δ 3.30 (J = 10.3, 4.0 Hz) and δ 2.84 (J =
9.7, 4.0 Hz), respectively.
1
products are estimates based on H NMR analysis.
The stereochemistry of 3a and 3b were defined by single-
crystal X-ray analysis of thiosemicarbazone derivative 13
prepared from 3b2 (eq. [2]). The relative stereochemistry of
Discussion
The results summarized in Scheme 4 establish that Prins-
pinacol reactions can be profitably employed to prepare at-
tached ring systems. However, our initial expectations were
realized to only a limited extent. As we had anticipated, the
pinacol rearrangement step in the reaction of Z alkylidene
stereoisomer 1 occurs exclusively by ring contraction (car-
bon migration) to form 1-(cyclohexyl)cyclopentylcarbox-
aldehyde products 3 (Scheme 5). Since hydride migration to
form ketone products was not observed, conformational con-
version of B1 or B2 to their pseudoequatorial siloxy counter-
parts apparently was not competitve with pinacol
rearrangement. Attack of the alkene is depicted in Scheme 5
the attached stereogenic carbons of 4a and 4b was deter-
mined by oxidizing (17)
a 1.9:1 mixture of these
stereoisomers with RuO4 to yield a 1.8:1 mixture of the
known diketones 14a and 14b (18) (eq. [3]). These
diketones were readily separated by MPLC and character-
1
ized by their distinctive H and 13C NMR spectra (18). The
2 The authors have deposited atomic coordinates for 13 with the Cambridge Crystallographic Data Centre. The coordinates can be obtained,
on request, from the Director, Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2, 1EZ, U.K.
© 2000 NRC Canada

Overman and Pennington
735
Scheme 5.
to occur opposite the siloxy group in A1 and A2, although
there is no experimental support for this supposition. The
stereochemical information necessary to define face selectiv-
ity is lost since C1 in 3 is not stereogenic.
Fig. 1. Favored synclinal orientations in the Prins cyclization
step of the exocyclic alkene and the α-alkoxycarbenium ion.
The generation of both cyclopentylcarboxaldehyde and
cyclohexanone products from Prins-pinacol reaction of E
stereoisomer 2 is consistent with cyclization–rearrangement
occurring through pathways of similar energy having the
siloxy substituent either pseudoequatorial or pseudoaxial in
the starting cyclohexane ring (Scheme 5). If this group is
axial, cyclopentylcarboxaldehydes 3a and 3b would be
formed (C1 → D1 → 3b and C2 → D2 → 3a). Alterna-
tively, Prins cyclization of oxocarbenium ion conformers
C3 and C4 having the siloxy substituent equatorial, would
initially generate cyclohexyl cations D3 and D4. Migration
of either the ring bond to generate 3a, or methine hydrogen
to generate 4a from D3 (and 4b from D4), is
stereoelectronically feasible (the dihedral angle between
both of these groups and the vacant p-orbital would be ca.
60°C; this analysis assumes that pinacol rearrangement oc-
curs faster than conformational interconversion of the
cyclohexylcarbenium ion (3i)). The typical preference for
hydride migration in stereoelectronically unbiased systems
suggest that 4a and 4b would be the major products of
these latter pathways (for pinacol rearrangements of
cyclohexylcarbenium ions, see ref. (9b)).
one assumes that the stereoisomeric products are generated
by the sequences proposed in Scheme 5, a synclinal orienta-
tion (19) having the methoxy portion of the oxocarbenium
ion oriented away from the siloxy group is favored in both
reaction manifolds (Fig. 1).
The stereochemistry of the methoxy substituent in alde-
hydes 3 and ketones 4 reflects the orientation of the alkene
and the oxocarbenium ion in the Prins cyclization (Fig. 1). If
© 2000 NRC Canada

736
Can. J. Chem. Vol. 78, 2000
Experimental section3
Pure 1 was obtained from the mixture of 1 and 8 as fol-
lows. Sodium borohydride (NaBH4, 41 mg, 1.1 mmol) was
added to a solution of the 1–8 mixture (0.92 g) and MeOH
(5.0 mL). After stirring for 20 min, saturated aqueous
NaHCO3 (5 mL) and hexanes (100 mL) were added, the or-
ganic layer was washed with saturated aqueous NaHCO3 (3
× 50 mL) and brine (100 mL), dried (MgSO4), and concen-
trated. The silyl ether protecting group of the diols derived
from 8 was then selectively removed (to facilitate isolation
of pure 1) by maintaining a solution of this residue, tetra-n-
butylammonium fluoride (TBAF, 0.86 mL, 0.86 mmol,
1.0 M solution in THF), and THF (5.0 mL) at rt for 12 h.
Saturated aqueous NaHCO3 (10 mL) and hexanes (70 mL)
were added, the organic layer was washed with saturated
aqueous NaHCO3 (5 × 50 mL), brine (50 mL), dried
(MgSO4), and concentrated. The crude product was purified
by column chromatography on silica gel (18:1 hexane–ethyl
acetate) to give 0.70 g (42%, 3 steps, 60% conversion during
Wittig coupling) of 1 as a clear yellow oil. 1H NMR
(300 MHz, CDCl3) δ : 5.01 (t, J = 6.9 Hz, 1H), 4.71 (br s,
1H), 4.35 (t, J = 5.6 Hz, 1H), 3.31 (s, 6H), 2.50–2.45 (m,
1H), 2.03–1.22 (m, 15H), 1.04–0.93 (m, 21H). 13C NMR
(75 MHz, CDCl3) δ : 141.8, 121.5, 104.4, 66.0, 52.6, 52.5,
36.1, 32.4, 30.0, 28.9, 27.0, 24.4, 20.5, 18.1, 18.0, 12.3. FT-
IR (neat): 2938, 2864 cm–1. HRMS (FAB): m/z 397.3148
(M–H, 397.3138 calcd. for C23H45O3Si). Anal. calcd. for
C23H46O3Si: C 69.29, H 11.63; found: C 69.38, H 11.53.
2-(Triisopropylsiloxy)cyclohexanone (8)
A mixture of pyridinium p-toluenesulfonate (PPTS,
0.22 g, 0.88 mmol), 2-hydroxycyclohexanone (1.0 g, 8.7 mmol),
and CH2Cl2 (33 mL) was stirred at rt for 3 h. Pyridine
(1.1 mL, 14 mmol), triisopropylsilyl triflate (TIPS-OTf,
3.3 mL, 12 mmol), and 4-(dimethylamino)pyridine (DMAP,
0.11 g, 0.92 mmol) were added sequentially and the result-
ing mixture was stirred at rt for 10 min. The mixture was
partitioned between saturated aqueous NaHCO3 (200 mL)
and pentane (200 mL), the layers were separated and the or-
ganic layer was washed sequentially with H2O (200 mL),
and brine (200 mL), dried (MgSO4), and concentrated. Puri-
fication of the residue by column chromatography on silica
gel (18:1 hexane–ethyl acetate) gave 2.1 g (89%) of 8 as a
clear pale yellow oil. FT-IR (neat): 1727 cm–1. H NMR
1
(300 MHz, CDCl3) δ : 4.21–4.16 (m, 1H), 2.68–2.59 (m,
1H), 2.26–2.17 (m, 1H), 2.08–1.58 (m, 6H), 1.15–0.96 (m,
21H). 13C NMR (75 MHz, CDCl3) δ : 210.4, 39.7, 37.3,
27.7, 22.2, 17.9, 17.7, 12.2. HRMS (FAB): m/z 271.2098
(MH, 271.2093 calcd. for C15H31O2Si). Anal. calcd. for
C15H30O2Si: C 66.61, H 11.18; found: C 66.70, H 11.12.
Z-[2-(6,6-Dimethoxyhexylidene)cyclohexyloxy]triiso-
propylsilane (1)
Calcium carbonate (0.81 g, 8.1 mmol), Ph3P (5.1 g,
19 mmol), and CH3CN (5.0 mL) were added sequentially to
iodide 5 (10, 11, 24) (4.4 g, 16 mmol). After bubbling N2
through the mixture for 5 min, the mixture was heated to re-
flux. After stirring for 2.5 h, the mixture was cooled to rt
and concentrated. The crude product was purified by column
chromatography on neutral alumina (sequential elution, 1:1
hexane–ethyl acetate, to isolate excess Ph3P; 18:1 CH2Cl2–
MeOH, to isolate 6) to give 7.7 g (89%) of slightly impure 6
as a hygroscopic and colorless waxy solid. 1H NMR
(300 MHz, CDCl3) δ : 7.75–7.61 (m, 15H), 4.21 (t, J =
5.5 Hz, 1H), 3.57–3.48 (m, 2H), 3.19 (s, 6H), 1.59–1.23 (m,
8H). HRMS (CI): m/z 407.2131 (M–I, 407.2140 calcd. for
C26H32O2P).
Using a modified version of the general procedure of
Koreeda et al. (12), potassium bis(trimethylsilyl)amide
(KHMDS, 30 mL, 15 mmol, 0.5 M solution in toluene) was
added to a solution of phosphonium salt 6 (7.4 g, 14 mmol)
in THF (83 mL) and hexamethylphosphoramide (HMPA,
9.2 mL) at –40°C. After stirring the resulting mixture for
10 min, a cooled (–40°C) solution of 8 (1.9 g, 9.9 mmol)
and THF (7.7 mL) was added, and the cooling bath was re-
moved. After 1 h, saturated aqueous NaHCO3 (100 mL) and
hexanes (200 mL) were added and the layers were separated.
The organic layer was washed sequentially with saturated
aqueous NaHCO3 (200 mL), 10% aqueous Na2S2O3
(200 mL), H2O (100 mL), brine (100 mL), dried (MgSO4),
and concentrated. The crude product was purified by column
chromatography on AgNO3-impregnated silica gel (9:1
CH2Cl2–benzene), yielding 0.92 g of a mixture of 1 and 8
and 0.13 g of a mixture of 1 and 2.
E-[2-(6,6-Dimethoxyhexylidene)]cyclohexanone (11)
A mixture of 9-borabicyclo[3.3.1]nonane (9-BBN, 2.5 g,
10 mmol) in THF (65 mL) was added to a solution of 1,1-
dimethoxypent-4-ene (15) (2.4 mL, 16 mmol) and THF
(21 mL) at 0°C, and the cooling bath was removed. After
stirring for 6 h, 3 M aqueous NaOH (7.6 mL, 23 mmol) was
added, and after stirring vigorously for an additional 15 min,
the crude organoborane was added by cannula to a solution
of triflate 10 (2.1 g, 8.3 mmol), 2,4,6-collidine (3.0 g,
25 mmol), PdCl2(dppf)!CH2Cl2 (0.93 g, 1.1 mmol), and
THF (40 mL). After stirring for 30 min, the reaction mixture
was partitioned between pentane (200 mL) and H2O
(200 mL) and the layers were separated. The organic layer
was washed sequentially with saturated aqueous CuSO4 (3 ×
200 mL), saturated aqueous NaHCO3 (200 mL), and brine
(200 mL), dried (MgSO4), and concentrated. The residue
was triturated with pentane and the filtrate was concentrated.
The crude product was purified by column chromatography
on silica gel (5:1 hexane–ethyl acetate) to give 2.2 g (80%)
of 11 as a clear pale yellow oil. 1H NMR (300 MHz, CDCl3)
δ : 6.58 (t, J = 7.5 Hz, 1H), 4.32 (t, J = 5.7 Hz, 1H), 3.28 (s,
6H), 2.46–2.37 (m, 4H), 2.08 (q, J = 7.3 Hz, 2H), 1.86–1.30
(m, 10H). 13C NMR (75 MHz, CDCl3) δ : 201.1, 139.2,
136.2, 104.3, 52.6, 40.1, 32.2, 28.2, 27.6, 26.6, 24.3, 23.5,
23.3. FT-IR (neat): 1688, 1615 cm–1. HRMS (FAB): m/z
263.1616 (M+Na, 263.1623 calcd. for C14H24NaO3).
E-[2-(6,6-Dimethoxyhexylidene)]cyclohexanol (12)
Cerium(III) chloride heptahydrate (3.4 g, 9.0 mmol) was
added to a solution of 11 (2.2 g, 9.0 mmol) and MeOH
3 Experimental details for preparation of 5 and correlation of the 4a–4b mixture with diketones 14a and 14b are provided as Supplementary
Material.
© 2000 NRC Canada

Overman and Pennington
737
(49 mL). After stirring for 5 min, NaBH4 (0.37 g, 9.7 mmol)
was added portionwise, and after stirring for an additional
20 min, saturated aqueous NaHCO3 (10 mL) and pentane
(250 mL) were added. The organic layer was washed with
saturated aqueous NaHCO3 (2 × 150 mL), brine (2 ×
150 mL), dried (MgSO4), and concentrated. The crude prod-
uct was purified by column chromatography on silica gel
(5:1 hexane–ethyl acetate) to give 1.7 g (78%) of 12 as a
calcd. for C13H22O2). This product was unstable and was
converted immediately to the corresponding thiosemicar-
bazone 15 for additional characterization (vide infra).
3b
0.039 g (5%) as a clear colorless oil. FT-IR (neat):
1
1714 cm–1. H NMR (300 MHz, CDCl3) δ : 9.28 (s, 1H),
3.11 (s, 3H), 2.67 (td, J = 9.7, 3.7 Hz, 1H), 2.14–2.03 (m,
2H), 1.85–1.04 (m, 15H). 13C NMR (75 MHz, CDCl3) δ :
201.3, 82.1, 58.8, 55.6, 47.5, 31.3, 30.9, 26.9, 25.8, 25.2,
25.1, 24.9, 24.5. HRMS (FAB): m/z 211.1696 (M+H,
211.1698 calcd. for C13H22O2). This product was unstable
and was converted immediately to thiosemicarbazone 13
(vide infra).
1
clear pale yellow oil. H NMR (300 MHz, CDCl3) δ : 5.32
(t, J = 6.8 Hz, 1H), 4.33 (t, J = 5.7 Hz, 1H), 4.04 (br s, 1H),
3.28 (s, 6H), 2.41–2.33 (m, 1H), 2.01–1.33 (m, 16H). 13C
NMR (75 MHz, CDCl3) δ : 141.1, 120.8, 104.4, 73.6, 52.5,
36.1, 32.2, 29.7, 27.2, 26.6, 25.9, 24.2, 22.8. FT-IR (neat):
3440 cm–1. HRMS (FAB): m/z 265.1773 (M+Na, 265.1779
calcd. for C14H26NaO3). Anal. calcd. for C14H26O3: C 69.38,
H 10.81; found: C 69.17, H 10.65.
4a + 4b
1
0.25 g (30%, contaminated with what is estimated by H
NMR analysis to be 40 mg of hydroxytriisopropylsilane,
TIPS-OH) as a clear, pale yellow oil. Characterization data
for this mixture, FT-IR (neat): 1707 cm–1. 1H NMR
(300 MHz, CDCl3) δ : 3.39 (br s, 1H), 3.36 (br s, 1H), 3.25
(s, 3H), 3.21 (s, 3H), 2.61–1.12 (m, 36H). 13C NMR
(75 MHz, CDCl3) δ : 214.3, 77.6, 74.7, 56.2, 55.6, 53.5,
51.9, 42.8, 42.7, 39.5, 39.1, 31.2, 30.9, 29.1, 28.8, 27.8,
27.5, 26.5, 26.0, 25.9, 24.9, 24.8, 23.2, 19.9, 19.8. HRMS
(CI): m/z 211.1696 (M+H, 211.1698 calcd. for C13H22O2).
This mixture was converted immediately to known diketones
14a and 14b (vide infra).
E-[2-(6,6-Dimethoxyhexylidene)cyclohexyloxy]triiso-
propylsilane (2)
Pyridine (0.77 mL, 9.5 mmol), TIPS-OTf (2.6 mL,
9.5 mmol), and DMAP (0.083 g, 0.68 mmol) were added se-
quentially to a solution of 12 (1.7 g, 6.8 mmol) and CH2Cl2
(68 mL). After stirring for 20 min, the reaction mixture was
partitioned between pentane (125 mL) and saturated aqueous
NaHCO3 (100 mL). The organic layer was washed sequen-
tially with saturated aqueous NaHCO3 (100 mL), H2O
(75 mL), saturated aqueous CuSO4 (75 mL), H2O (75 mL),
and brine (2 × 75 mL), dried (MgSO4), and concentrated.
The crude product was purified by column chromatography
on silica gel (18:1 hexane–ethyl acetate) to give 2.0 g (73%)
4c
1
10 mg (1.5%) as a clear, colorless oil. FT-IR (neat):
of 2 as a clear pale yellow oil. H NMR (300 MHz, CDCl3)
1
1707 cm–1. H NMR (300 MHz, CDCl3) δ : 3.30 (td, J =
δ : 5.34 (t, J = 7.3 Hz, 1H), 4.35 (t, J = 5.7 Hz, 1H), 4.11–
4.09 (m, 1H), 3.31 (s, 6H), 2.38–2.35 (m, 1H), 2.01–1.34
(m, 15H), 1.10–0.98 (m, 21H). 13C NMR (75 MHz, CDCl3)
δ : 141.5, 120.4, 104.5, 74.5, 52.6, 37.5, 32.4, 29.8, 27.6,
26.6, 25.9, 24.3, 22.8, 18.1, 12.3. FT-IR (neat): 2939,
2863 cm–1. HRMS (CI): m/z 398.3216 (M, 398.3216 calcd.
for C23H46O3Si). Anal. calcd. for C23H46O3Si: C 69.29. H
11.63; found: C 69.39, H 11.69.
10.3, 4.0 Hz, 1H), 3.26 (s, 3H), 2.61–2.56 (m, 1H), 2.39–
1.02 (m, 17H). 13C NMR (75 MHz, CDCl3) δ : 212.6, 80.4,
55.9, 50.0, 45.2, 42.2, 30.8, 30.0, 26.8, 26.5, 26.1, 24.9.
HRMS (CI): m/z 211.1695 (M+H, 211.1698 calcd. for
C13H22O2).
4d
17 mg (2.3%) as a clear, colorless oil. FT-IR (neat):
1
1707 cm–1. H NMR (300 MHz, CDCl3) δ : 3.24 (s, 3H),
Prins-pinacol rearrangement of 2
2.84 (td, J = 9.7, 4.0 Hz, 1H), 2.62 (m, 1H), 2.46 (m, 1H),
2.29–1.61 (m, 12H), 1.29–0.87 (m, 4H). 13C NMR (75 MHz,
CDCl3) δ : 212.9, 80.3, 55.7, 50.9, 41.7, 30.8, 27.7, 27.5,
27.1, 25.6, 24.7, 24.1. HRMS (FAB): m/z 211.1694 (M+H,
211.1698 calcd. for C13H22O2).
Tin(IV) chloride (SnCl4, 0.20 mL, 1.7 mmol) was added
dropwise to a stirring suspension of 2 (1.4 g, 3.4 mmol) and
MeNO2 (34 mL) at 0°C. After stirring at 0°C for 2 h, Et3N
(15 mL) and MeOH (15 mL) were added sequentially, and
the mixture was warmed to rt and was diluted with hexanes
(250 mL). The organic layer was washed with saturated
aqueous NaHCO3 (3 × 200 mL) and brine (200 mL), dried
(MgSO4), and concentrated. The crude product was purified
by medium pressure liquid chromatography (MPLC) (Lobar
prepacked column, LiChroprepTM Si 60 silica gel; gradient
elution, hexane → 18:1 hexane–ethyl acetate) to give the fol-
lowing fractions.
Prins-pinacol rearrangement of 1
The procedure was identical to that described above for 2;
1 gave 0.11 g (29%) of 3a and 0.17 g (46%) of 3b as clear,
pale yellow oils.
(±)-rel-R,S-[1-(2-Methoxycyclohexyl)cyclopentylmethyl-
ene]thiosemicarbazone (15)
3a
A solution of 3a (0.049 g, 0.23 mmol), glacial acetic acid
(2.3 mL), and thiosemicarbazide (0.043 g, 0.47 mmol) was
maintained at rt for 4 h. The reaction mixture was diluted
with toluene (5.0 mL), concentrated, and the residue was pu-
rified by column chromatography on silica gel (5:1 hexane–
ethyl acetate) to give 66 mg (81%) of 15 as an off-white
solid, mp 175–177°C. FT-IR (KBr): 3435, 3256, 3149, 3029,
0.27 g (37%) as a clear, pale yellow oil. FT-IR (neat):
1
1715 cm–1. H NMR (300 MHz, CDCl3) δ : 9.56 (s, 1H),
3.39 (br s, 1H), 3.15 (s, 3H), 2.27–2.21 (m, 1H), 2.02–1.96
(m, 2H), 1.79–1.13 (m, 14H). 13C NMR (75 MHz, CDCl3)
δ : 203.7, 60.4, 55.7, 53.0, 32.6, 31.4, 27.8, 26.7, 24.8, 24.1,
23.3, 19.9. HRMS (FAB): m/z 211.1703 (M+H, 211.1698
© 2000 NRC Canada

738
Can. J. Chem. Vol. 78, 2000
1
1594, 1534 cm–1. H NMR (300 MHz, CDCl3) δ : 8.99 (br s,
1H), 7.33 (s, 1H), 7.03 (br s, 1H), 6.26 (br s, 1H), 3.47 (br s,
1H), 3.19 (s, 3H), 2.13–1.92 (m, 3H), 1.76–1.13 (m, 14H).
13C NMR (75 MHz, CDCl3) δ : 177.8, 154.8, 77.2, 55.5,
53.3, 52.9, 34.8, 34.7, 28.1, 26.5, 23.7, 23.4, 19.8. HRMS
(CI): m/z 283.1712 (M, 283.1718 calcd. for C14H25N3OS).
Anal. calcd. for C14H25N3OS: C 59.33, H 8.89, N 14.83;
found: C 59.45, H 8.86, N 14.71.
3. (a) P.M. Herrinton, M.H. Hopkins, P. Mishra, M.J. Brown,
and L.E. Overman. J. Org. Chem. 52, 3711 (1987); (b) M.H.
Hopkins and L.E. Overman. J. Am. Chem. Soc. 109, 4748
(1987); (c) G.C. Hirst, P.N. Howard, and L.E. Overman. J.
Am. Chem. Soc. 111, 1514 (1989); (d) T.O. Johnson, Jr.
and L.E. Overman. Tetrahedron Lett. 32, 7361 (1991);
(e) M.H. Hopkins, L.E. Overman, and G.M. Rishton. J. Am.
Chem. Soc. 113, 5354 (1991); (f) M.J. Brown, T. Harrison,
P.M. Herrinton, M.H. Hopkins, K.D. Hutchinson, P. Mishra,
and L.E. Overman. J. Am. Chem. Soc. 113, 5365 (1991);
(g) L.E. Overman and G.M. Rishton. Org. Synth., 71, 63
(1992); (h) S. Ando, K.P. Minor, and L.E. Overman. J. Org.
Chem. 62, 6379 (1997); (i) K.P. Minor and L.E. Overman. Tet-
rahedron, 53, 8927 (1997); (j) M.J. Cloninger and L.E. Over-
man. J. Am. Chem. Soc. 121, 1092 (1999).
4. (a) M. Sworin and W.L. Neumann. J. Org. Chem. 53, 4894
(1988); (b) B.M. Trost and D.C. Lee. J. Am. Chem. Soc. 110,
6556 (1988); (c) T. Nakamura, T. Matsui, K. Tanino, and I.
Kuwajima. J. Org. Chem. 62, 3032 (1997).
5. (a) M.J. Brown, T. Harrison, and L.E. Overman. J. Am. Chem.
Soc. 113, 5378 (1991); (b) G.C. Hirst, T.O. Johnson, and L.E.
Overman. J. Am. Chem. Soc. 115, 2992 (1993); (c) T.A.
Grese, K.D. Hutchinson, and L.E. Overman. J. Org. Chem. 58,
2468 (1993); (d) D.W.C. MacMillan and L.E. Overman. J.
Am. Chem. Soc. 117, 10391 (1995).
(±)-rel-S,S-[1-(2-Methoxycyclohexyl)cyclopentylmethyl-
ene]thiosemicarbazone (13)
The procedure followed was identical to that described for
3a; 3b gave 0.088 g (49%) of 13 as a colorless solid, mp
168–170°C. FT-IR (KBr): 3430, 3269, 3142, 1589,
1522 cm–1. H NMR (300 MHz, CDCl3) δ : 10.03 (br s, 1H),
1
7.29 (s, 1H), 7.05 (d, J = 3.0 Hz, 1H), 6.68 (br s, 1H), 3.21
(s, 3H), 2.76 (td, J =10.0, 3.9 Hz, 1H), 2.13–1.93 (m, 3H),
1.84–0.91 (m, 14H). 13C NMR (75 MHz, CDCl3) δ : 177.4,
154.8, 82.1, 55.4, 52.7, 52.1, 36.4, 32.6, 31.2, 27.3, 25.8,
24.5, 24.2, 23.2. HRMS (CI): m/z 283.1719 (M, 283.1718
calcd. for C14H25N3OS). Anal. calcd. for C14H25N3OS: C
59.33, H 8.89, N 14.83; found: C 59.36, H 8.84, N 14.72.
Conclusions
6. S.V. Ley, A.A. Denholm, and A. Wood. Nat. Prod. Rep. 109
(1993).
This study constitutes the first investigation of the use of
pinacol-terminated Prins cyclizations to form attached rings.
In the Z alkylidenecyclohexane series, the approach is syn-
thetically useful, proceeding selectively by a pathway in-
volving carbon migration, to provide methoxy epimers of 1-
(2-methoxycyclohexyl)cyclopentylcarboxaldehyde. Reaction
of the corresponding E stereoisomer is more complex and
yields a mixture of products resulting from both hydride and
carbon migration. Future efforts to exploit this novel ap-
proach to the synthesis of attached rings should focus on Z
alkylidene substrates.
7. E.L. Eliel and S.H. Wilen. In Stereochemistry of organic com-
pounds. John Wiley & Sons, New York. 1994, p. 738.
8. (a) K.N. Houk, S.R. Moses, W. Yun-Dong, R. Nelson, J.
Volker, R. Schohe, and F.R. Fronczek. J. Am. Chem. Soc. 106,
3880 (1984); (b) K.N. Houk, J. Haller, and T. Strassner. J. Am.
Chem. Soc. 119, 8031 (1997).
9. (a) M. Bartok and A. Molnar. In Chemistry of ethers, crown
ethers, hydroxyl compounds and their sulfur analogs. Part 2.
Edited by S. Patai. New York. 1980; and B. Rickborn. In Com-
prehensive organic synthesis. Vol. 3. Edited by B.M. Trost.
Pergamon Press, Oxford, U.K. 1991; (b) P.L. Barili, G. Berti,
B. Macchia, F. Macchia, and L. Monti. J. Chem. Soc. C, 1168
(1970).
10. B.G. Kovalev, R.N. Vaskan, and E.S. Lavrinenko. Zh. Org.
Khim. 7, 667 (1971).
11. M. Koreeda, P.D. Patel, and L. Brown. J. Org. Chem. 50, 5910
(1985).
12. A.F. Simpson, D.C. Lathbury, and T. Gallagher. Tetrahedron:
Asymmetry, 8, 673 (1997).
13. N. Miyaura and A. Suzuki. Chem. Rev. 95, 2457 (1995).
14. C.C. Price and R.B. Balsley. J. Org. Chem. 31, 3406 (1966).
15. K. Brickmann, F. Hambloch, J. Suffert, and R. Bruckner.
Liebigs Ann. Chem. 457 (1996).
Acknowledgements
This research was supported by NIH grant NS-12389. We
are grateful to Dr. Joseph Ziller for X-ray analyses and Dr.
John Greaves and Dr. John Mudd for mass spectrometric
analyses. NMR and mass spectra were obtained at UCI us-
ing instrumentation acquired with the assistance of NSF and
NIH Shared Instrumentation programs.
References
1. (a) P. Martinet, G. Mousset, and M.C.R. Colineau. Acad. Sci.
Ser. C, 268, 1303 (1969); (b) P. Martinet and G. Mousset.
Bull. Soc. Chim. Fr. 1071 (1970); (c) P. Martinet and G.
Mousset. Bull. Soc. Chim. Fr. 4093 (1971).
16. A.L. Gemal and J.L. Luche. J. Am. Chem. Soc. 103, 5454
(1981).
17. P.H.J. Carlsen, T. Katsuki, V.S. Martin, and K.B. Sharpless. J.
Org. Chem. 46, 3936 (1981).
2. (a) L.E. Overman. Lect. Heterocycl. Chem. 8, 59 (1985);
(b) L.E. Overman. NATO ASI Ser. Ser. C, 289, 1 (1989);
(c) L.E. Overman. Acc. Chem. Res. 25, 352 (1992); (d) L.E.
Overman. Aldrichimica Acta, 28, 107 (1995).
18. S.E. Denmark, C.J. Cramer, and J.A. Sternberg. Tetrahedron
Lett. 27, 3693 (1986).
19. S.E. Denmark, E.J. Weber, T.M. Wilson, and T.M. Willson.
Tetrahedron, 45, 1053 (1989).
© 2000 NRC Canada