Stereoselective synthesis of exocyclic allenes by double hydride reduction of 3-alkynyl-2-cycloalkenones

Article abstract of DOI:10.1016/j.tet.2016.07.058

Exocyclic allene natural products and pharmaceutical agents are rare but interesting compounds: Fucoxanthin, grasshopper ketone, and analogues of prostacyclins, cephalosporins, antithrombic agents and sterol biosynthesis inhibitors are representative. Syntheses of exocyclic allenes commonly rely on extended conjugate additions to e.g., alk-2-en-4-ynones, syn S_N2′-like additions to alkynyl oxiranes, and substitution reactions such as electrophilic substitutions of propargylic silanes. We report that the reaction of 3-alkynyl-2-cycloalkenones with 2?equiv of various hydridoaluminates but not hydridoborates proceeds via diastereoselective 1,4-reduction of a vinylogously propargylic intermediate alcoholate to provide exocyclic allenes as major products. Isomeric 3-alkynylcycloalkanols also are observed.

Full text of DOI:10.1016/j.tet.2016.07.058

Tetrahedron xxx (2016) 1e12
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Stereoselective synthesis of exocyclic allenes by double hydride
reduction of 3-alkynyl-2-cycloalkenones
*
Matthew A. Gubbels, Martin Hulce , John M. Kum, Andrew K. Urick, Eric M. Villa
Department of Chemistry, Creighton University, Omaha, NE, 68178-0323, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Exocyclic allene natural products and pharmaceutical agents are rare but interesting compounds: Fu-
coxanthin, grasshopper ketone, and analogues of prostacyclins, cephalosporins, antithrombic agents
and sterol biosynthesis inhibitors are representative. Syntheses of exocyclic allenes commonly rely on
extended conjugate additions to e.g., alk-2-en-4-ynones, syn SN20-like additions to alkynyl oxiranes, and
substitution reactions such as electrophilic substitutions of propargylic silanes. We report that the
reaction of 3-alkynyl-2-cycloalkenones with 2 equiv of various hydridoaluminates but not hydrido-
borates proceeds via diastereoselective 1,4-reduction of a vinylogously propargylic intermediate alco-
holate to provide exocyclic allenes as major products. Isomeric 3-alkynylcycloalkanols also are
observed.
Received 20 May 2016
Received in revised form 7 July 2016
Accepted 25 July 2016
Available online xxx
Dedicated to Professor Gary H. Posner
Keywords:
Allene
Reduction
Hydride
Red-Al
Ó 2016 Elsevier Ltd. All rights reserved.
1. Introduction
Exocyclic allene analogues of prostacyclins,14 penams, and
cephems15 also have been prepared and investigated for unique
Allenes are the simplest of the cumulene hydrocarbon class.
They are rare in nature, with under 200 allene-containing natural
products having been identified.1,2 Historically, unambiguous
structural assignment of a natural product as containing an allene
sometimes has been challenging,3,4 so that structural revisions are
not uncommon. As a consequence the class has gained a reputation
as being not only rare but perhaps exotic. Nonetheless, with a rigid,
pharmacological activities. Useful as intermediates in the synthesis
of nonallene-containing natural products,16 exocyclic allenes
themselves have been the objects of conjugation, strain, and
isomerization studies.17
Syntheses of exocyclic allenes18 rely on a small set of strategies.
Most popular are additions, including nucleophilic extended con-
jugate additions to alk-2-en-4-ynones and alk-2-en-4-ynonates,19
syn SN20-like alkylations and reductions of alkynyl oxiranes,11d,12b
and rhodium(II)-catalyzed reaction of carbenoids with prop-
argylic alcohols.20 Substitution strategies also are known and in-
clude electrophilic substitution reactions of propargylic
silanes,16d,g,,21 Wittig reactions of ketenes,22 Petasis reaction of
hydroxyketones,23 cross-coupling reactions of allenic zirconium
complexes and aryl halides24 and recently, titanium-catalyzed
Barbier-type cyclization of propargylic halides.25 A titanium based
cyclization method produces exocyclic bis-allenes.26
all-carbon core of orthogonal
p
bonds imposing a 90ꢀ twist and
therefore potential axial chirality, this deceptively simple func-
tional group has found interesting applications in organic
synthesis.5
One allene subclass, the exocyclic allenes, is relatively widely
represented among allene-containing natural products. It is a sub-
unit of the most common carotenoid, the anti-obesity agent fuco-
xanthin,6 as well as other carotenoids, including mimulaxanthin,7
neoxanthin,8 paracentrone,9 and peridinin.10 Consequently, exo-
cyclic allenes are routinely exploited as subunits in convergent
syntheses of allene-containing carotenoids10,11 and carotenoid
metabolites or degradation products, including grasshopper ke-
tone12 and an allenic epoxycyclohexane isolated from Eutypa lata.13
While preparing 3-alkynyl-2-methylcyclohexenols from the
corresponding ketones as intermediates in the synthesis of 1-
alkynyl-6-methylbicyclo[4.1.0]alkan-5-ones for study of ring-
expanding extended conjugate additions leading to 4-(ethenyli-
dene)-2-methylcycloheptanones (e.g., Eq. 1) we noted a surprising
solvent effect: When excess lithium aluminum hydride (LAH) was
used in diethyl ether, the anticipated alcohol resulted; however,
a small quantity of an allenyl alcohol, easily identified by its intense
IR absorption at 1940 cmꢁ1, often was observed.
* Corresponding author. Fax: þ1 402 280 5737; e-mail address: mhulce@
creighton.edu (M. Hulce).
http://dx.doi.org/10.1016/j.tet.2016.07.058
0040-4020/Ó 2016 Elsevier Ltd. All rights reserved.
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2
M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
O
OH
OH
LAH
Et2O
CH2I2, Et2Zn
THF
R
R
93%
80%
R
O
O
ð1Þ
PCC
Nu-M
CH2Cl2
·
Nu
>98%
R
R
R = TMS, Ph
n = 0, 1
In tetrahydrofuran (THF) this allenyl alcohol, a product of double
solvents clearly indicated that double hydride reduction was fa-
vored in more coordinating solvents (Table 1). Structural studies
of the solvation of aluminum hydride reagents28 have determined
that, in contrast to LAH in diethyl ether, benzene or 1,4-dioxane,
LAH in THF exists as a monomeric solvent-separated ion pair,
providing enhanced nucleophilicity. Similar significant solvent
hydride reduction, was observed to be the major product. An iso-
meric alkynyl cycloalkanol also formed (Eq. 2). To the best of our
knowledge, this double hydridereduction is a newstrategyforaccess
to exocyclic allenes. We report here optimization, stereochemical,
and mechanistic studies of this exocyclic allene-forming reaction.
OH
O
OH
+
2.2 equiv LAH
solvent
(CH2)n
(CH2)n
(CH2)n
ð2Þ
0 to 23 o
C
TMS
TMS
TMS
n=1,2
major
minor
minor
major
Et2O
THF
2. Results and discussion
To discover the scope and nature of this double hydride re-
duction, the influence of the identities of solvent, hydride donor,
and substrate were investigated.
influences are observed in addition reactions of alkylaluminum
reagents to expoxides and carbonyl compounds29 and aluminum
hydride reductions of N-benzyl-4-ethoxycarbonylpiperidine30
and various tosylates and halides,28c,31 suggesting that this en-
hanced nucleophilicity is required for successful addition of the
second hydride to 1a.
2.1. Solvent identity
Using 2-methyl-3- trimethylsilylethynyl-2-cyclopentenone27
(1a) as substrate, a series of LAH reductions in commonly used
O
OH
OH
OH
1. [H], solvent
0 to 23 oC
+
+
·
2. aq NH4Cl
TMS
TMS
TMS
TMS
1a
2a
3a
4a
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M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
3
mild, sterically congested hydroaluminates34,35 and diisobutyla-
luminum hydride only reduced the carbonyl, as did sodium
methoxide-modified LAH.36
Table 1
Solvent, hydride and stoichiometry effects
Hydride donor [H]
LAH
Solvent
mol equiv [H] Yield, %a 2a 3a 4a
Diethyl
ether
Benzene
1,4-Dioxane 2.2
THF
THF
THF
Diethyl
ether
2.2
92
45 29 18
2.3. Substrate identity
LAH
LAH
LAH
LAH
LAH
2.3
78 (57b) 78
89
98
98
96
96
13 45 31
45 29 18
0.55
A range of starting cycloalkenones demonstrated that allenes
form as major products regardless of ring size, substitution at the 2-
position of the cycloalkeneone, or identity of the alkynyl sub-
stituent (Table 2). A 3-phenylethynyl substituent (1def) clearly
favored allene formation relative to the isomeric alkynyl cyclo-
alkanol when compared to a 3-trimethylsilylethynyl substituent
(1aec). Isolated yields of a single diastereoisomer of the allene
products ranged from 54 to 96%.
1.1
2.2
2.2
8
51 31
65 31
c
LAHþNaOCH3
96
NaAlH2(OCH2CH2OCH3)2 THF
2.2
2.2
2.1
2.2
2.4
2.2
96
96
98
99
79 19
LiAlH(t-OC4H9)(iC4H9)2
LiAlH(t-OC4H9)3
(iC4H9)2AlH
NaBH4
Li(iC4H9)3BH
THF
THF
THF
THF
THF
96
98
99
d
86
e
a
GC yield.
2.4. Stereochemistry
b
Isolated yield after chromatography.
2:1 LAH: NaOCH3.
3-Ethynyl-2-methyl-2-cyclopentenol.
c
A study of the stereochemical outcome of the reaction first de-
termined that reduction products 4aec predominantly (79 to
ꢂ98%) formed with all-trans, (1R*,2R*,3S*) and (1R*,3S*) relative
configurations. For example, the relative configuration of major
diastereoisomer (1R*,2R*,3S*)-4a, isolated chromatographically
from the reaction of 1a with 2.2 mol equiv of LAH in THF, was de-
termined by NOE spectroscopy: Similar enhancements of the C1
and C3 methine hydrogen NMR signals were observed when the
methyl group was irradiated, and enhancements of the methyl and
C3 methine hydrogen signals were observed when the C1 methine
hydrogen was irradiated (Fig. 1).
The assignment of the relative configuration of 3 was more
challenging. While NOE spectroscopy readily assigned a relative
(1R*,2R*) configuration for the C1 and C2 carbons with a strong
enhancement of the C1 methine hydrogen upon irradiation of the
methyl group of 3a or 3e, the greater distances between the
allene hydrogen and any substituents of the ring made further
use of the technique moot. Long-range coupling constants have
been used to assign allene configurations16g by employing
a Karplus-like dihedral angle versus j5Jj relationship.37 In the case
at hand, analyses of the five-bond coupling networks of the
allene hydrogens of 3a and 3e (Table 3) were ambiguous: Allene
hydrogen-C2 and C4 pseudoaxial hydrogen dihedrals of about
150ꢀ (an anti-like relationship) and about 35ꢀ (a syn-like re-
lationship) determined from a geometry-optimized AM1 model
d
e
2-Methyl-3-(3-methylpentynyl)-2-cyclopentenone.
2.2. Hydride donor and stoichiometry
Using THF as the solvent, the preferred stoichiometry of the
reaction for allene formation was determined. Varying the molar
ratio of LAH to 1a while maintaining a theoretical 10 mol % excess of
the hydride, a minimum of 2 mol equivalents of LAH were required;
the reaction was complete upon warming to room temperature
over 2 h.
To determine if other hydride donor reagents would be effec-
tive in this double addition reaction, some readily available LAH
and sodium borohydride analogues were employed. Sodium bo-
rohydride provided exclusive carbonyl reduction with concomi-
tant desilylation to provide 3-ethynyl-2-methyl-2-cyclopentenol
as the only product. On the other hand, treatment of 1a with
lithium tri-sec-butylborohydride (L-Selectride), otherwise known
to produce cyclopentenols from cyclopentenones,32 resulted in
substitution of the trimethylsilyl moiety for a sec-butyl group. Of
the LAH analogues, only sodium bis(2-methoxyethoxy)aluminum
hydride (Red-Al)33 was effective in forming the allene, with a ca.
20% enhancement in allene production compared to LAH. Other
Table 2
Allene formation versus substrate identity
O
OH
OH
1. 2.2 Red-Al, THF
0 oC to rt, 2 h
R
R
R
+
(CH2)n
(CH2)n
2. H2O
(CH2)n
R'
R'
R'
1
3
4
1
R
R0
n
Yield 3, %
Yield 4, %
a
b
c
d
e
f
CH3
CH3
H
CH3
CH3
H
TMS
TMS
TMS
Ph
Ph
Ph
1
2
2
1
2
2
69
64
15
14
5a
0
0
0
54a
54a
96b
56a
a
Isolated yield after chromatography.
Isolated yield after recrystallization.
b
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4
M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
of 2 formed from addition of LAH to 1 to be a requisite intermediate
H
for subsequent formation of 3. Indeed, when 1a was treated with
LAH in benzene and the corresponding allylic alcohol isolated, then
treated with 2 mol equiv of LAH in THF, the same yield of allene was
observed as that produced from direct treatment of 1a with
2.2 mol equiv of LAH in THF. Similarly, when 2g formed by addition
of methyllithium to 1e was treated with excess Red-Al, allene was
produced in excellent yield (Eq. 3).
OH
1
TMS
3
2
H3C
H
H
Fig. 1. NOE contacts for (1R*,2R*,2S*)-4a.
O
R OH
R OH
RM
[H]
solvent
THF
(CH2)n
(CH2)n
(CH2)n
0 oC to rt
0 oC to rt
R'
ð3Þ
R'
R'
RM solvent
[H]
1a n = 1, R' = TMS LAH benzene 68% 2a, n = 1, R = H, R' = TMS
LAH
66% 3a, n = 1, R = H. R' = TMS
1e n = 2, R' = Ph MeLi THF 67% 2g, n = 2, R = Me, R' = Ph Red-Al 99% 3g, n = 2, R = Me. R' = Ph
of 3a predict the same coupling constant magnitudes. Regardless,
these predicted coupling constants were not in agreement with
those observed. Consequently, single-crystal X-ray diffraction of
3e, which was easily recrystallized from aqueous ethanol, un-
ambiguously established its (1R*,2R*,S*) relative configuration
(Fig. 2).
Deuterium labeling studies further detailed the sequence of
double hydride addition. When 1e was reacted with lithium alu-
minum deuteride and the reaction quenched with aqueous am-
monium chloride, (1R*,2R*,S*)-3e (Eq. 4) was isolated with
deuterium specifically incorporated in the C1 and C2 positions.
Complementary labeling of 1e using LAH followed by quenching
with D2O (Eq. 5) provided (1R*,2R*,S*)-3e with deuterium specifi-
cally incorporated in its alcohol and allene moieties.
Taken together, the data suggest a tandem reaction. Using a 2-
methyl-3-alkynyl-2-cyclohexenone as an example starting mate-
rial (Fig. 3), equatorial aluminum hydride carbonyl reduction38
results in a vinylogous propargylic alanate, 5. Because the addi-
tion of the hydride is anti with respect to the first, intramolecular
addition39 of hydride to C2, perhaps facilitated by a second equiv-
alent of aluminum hydride reagent, results in net syn-1,4-
hydroalumination40 to provide the observed allenyl alcohols after
2.5. Mechanistic studies
To formulate a hypothesis for the mechanism of the reaction, it
was first noted from studying its stoichiometry that production of
allylic alcohol 2 decreased as the amount of LAH used increased.
This suggested that the reaction was stepwise, with the aluminate
Table 3
5
Measured versus predicted j Jj values for 3a
Ha
Ha
OH
He
CH3
H
TMS
3a
5
j Jj
Measured, Hz (1R*,2R*,R*) predicted, Hz (1R*,2R*,S*) predicted, Hz
(HeH2a
(HeH4a
(HeH4e
)
)
)
5.3
0.6
10.8
1.7
2.0
1.8
1.9
1.9
1.9
Fig. 2. Single-crystal X-ray structure of (1R*,2R*,S*)-3e, 50% thermal ellipsoids.
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M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
5
aqueous workup. 1,2-Hydroalumination of propargylic alcohols,41
vinylogous propargylic alcohols,42 and propargylic amines43 is
well-known; generally, hydroalumination of propargylic alcohols
exhibit anti-stereoselectivity, providing thermodynamically more
stable (E)-alkenes.39,43,44 Similarly, equilibration45 of the in-
termediate 6 to propargylic alanate 7 would lead to 4, as observed
when 1aec are reduced.
tert-butoxydiisobutylaluminum hydride, lithium tri-tert-butox-
yaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hy-
dride (Red-Al), sodium borohydride and lithium tri-sec-
butylborohydride were purchased from Acros Organics. Thin layer
chromatography was performed on precoated silica gel F254 glass
plates from Analtech (Newark, DE) with visualization by UV light,
phosphomolybdic acid spray, or iodine vapor. Flash column chro-
matography was performed using 32e63 mm silica gel and medium
pressure column chromatography used LiChroprep Si 60 size A and
B columns. Melting points are uncorrected. Infrared spectra were
obtained using a single-bounce ZnSe ATR accessory; absorptions
are reported in wavenumbers (cmꢁ1). 1H NMR spectra were
recorded at 300 or 400 MHz and 13C NMR spectra at 75 or 100 MHz;
O
HO D
1. 2.6 LAD, THF,
0 oC to rt, 2 h
D
chemical shifts (d) are reported in parts per million (ppm) relative
H3C
to TMS. GC/MSD data were obtained using a 30 m AT-5 capillary
column and the temperature program 120 ꢀC, 3 min; 10 ꢀC/min to
240 ꢀC; 240 ꢀC, 3 min, or using a 30 m ZB-5 capillary column and
the temperature program 60 ꢀC, 3 min; 10 ꢀC/min to 230 ꢀC; 230 ꢀC,
3 min. MALDI-TOF mass spectra were obtained in reflector positive
mode with 2,5-dihydroxybenzoic acid as the matrix and ESI-TOF
mass spectra were obtained in reflector positive mode by infusion
in 0.1% trifluoroacetic acid/acetonitrile.
2. aq NH4Cl
Ph
Ph
H
1e
3e
83%
> 96% D incorporation
ð4Þ
4.2. 2-Methyl-3-(trimethylsilylethynyl)-2-cyclopentenone
(1a)27
Ethylmagnesium bromide (32.7 mL, 32.7 mmol, 1.0 M in THF)
was added to an argon-purged, oven-dried 250 mL round bottom
flask equipped with magnetic stirring bar, constant pressure ad-
dition funnel and an argon inlet. Stirring was begun and the flask
was cooled to 0 ꢀC in an ice water bath. Trimethylsilylethyne
(3.53 g, 36.0 mmol) in THF (35 mL) was added dropwise over
30 min, after which time the ice water bath was removed and the
flask allowed to warm to room temperature. Cooling to ꢁ78 ꢀC was
followed by dropwise addition of 3-isobutoxy-2-methyl-2-
cyclopentenone46 (5.00 g, 29.7 mmol) in THF (65 mL) over
30 min. The cold bath was left to exhaust itself as the reaction
slowly warmed to room temperature overnight.
O
DO H
H
H3C
1. 2.2 LAH, THF,
0 oC to rt, 2 h
2. D2O
Ph
Ph
D
1e
3e
98%
93% incorporation allene D
21% incorporation alcohol D
ð5Þ
The reaction was quenched by the addition of water (10 mL),
followed by K2CO3 (1 g) with rapid stirring. Dilution with diethyl
ether (200 mL) was followed by transfer to a separatory funnel and
washing with water (50 mL). The organic layer subsequently was
washed with aqueous saturated NaHCO3 (20 mL), water (20 mL), and
brine (20 mL). Drying (MgSO4), filtration and concentration by rotary
evaporation gave an amber liquid (8.78 g) which was taken up in
diethyl ether (30 mL), then stirred rapidly with 1 M HCl (10 mL) for
3 h. Dilution with diethyl ether (40 mL) and transfer to a separatory
funnel was followed by washing with aqueous saturated NaHCO3
(20 mL), water (20 mL), and brine (20 mL). Drying (MgSO4), filtration
and concentration by rotary evaporation gave an orange liquid
(4.92 g) that was purified by flash chromatography (9:1 hex-
ane:diethyl ether) to give the title compound 1a (3.25 g, 57%), which
solidified upon standing: Rf (9:1 hexane:diethyl ether) 0.29; bp 50 ꢀC
(0.75 mmHg); mp 34e36 ꢀC; nmax 2960, 2144, 1704, 1615, 885,
3. Conclusion
3-Trimethylsilylethenylidinecycloalkanols
and
3-
phenylethenylidinecycloalkanols can be prepared in 54e96% iso-
lated yields in 2 h from the corresponding alkynylcyclolalkenones
using 2 mol equiv of Red-Al in THF. The reaction proceeds in
a tandem manner, and is highly diastereoselective: Aluminum hy-
dride carbonyl reduction gives a vinylogous propargylic alanate,
which in turn undergoes intramolecular syn-1,4-hydroalumination
to provide the observed products after aqueous workup. Direct and
indirect alkylation strategies that may afford entry into syntheses of
allene-containing carotenoid analogues are under investigation
and will be reported in due course.
846 cmꢁ1
; dH (CDCl3) 2.62e2.56 (m, 2H), 2.39e2.34 (m, 2H), 1.81 (t,
J¼2.2 Hz, 3H), 0.21 (s, 9H); dC (CDCl3) 209.2,149.8,145.8,112.2,100.3,
34.1, 30.1, 9.9, ꢁ0.1; tR 15.8 min, m/z (EI) 192 (40, Mþ), 177 (100).
A sample of 1a (36.8 mg, 0.19 mmol) was dissolved in 95%
ethanol (1.5 mL) and 2,4-dinitophenylhydrazine reagent47
(2.00 mL, 0.28 mmol, 0.14 M) added. A precipitate formed almost
immediately. After stirring for 15 min at room temperature, the
reaction was cooled in an ice water bath, then vacuum filtered. Air
drying gave the crude product (79.6 mg) as an orange solid. Re-
crystallization from hot 95% ethanol gave fine orange needles
(61.9 mg, 87%) of the 2,4-dinitrophenyl hydrazone of 1a: Rf (11:1
hexane:ethyl acetate) 0.58; mp 215e216 ꢀC; nmax 3286, 3113, 2657,
4. Experimental section
4.1. General methods
Diethyl ether, THF, 1,4-dioxane and benzene from Fisher Scien-
tific (Pittsburgh, PA) were dried using sodium-benzophenone and
ꢀ
stored over 4 A molecular sieves. Trimethylsilylethyne, phenyl-
ethyne and tert-butyldimethylsilyl chloride were from Oakwood
Products (West Columbia, SC). All other solvents were from Fisher
Scientific and used as received. Lithium aluminum hydride, lithium
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6
M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
Fig. 3. Mechanistic proposal for tandem 1,2-, 1,4-hydride reduction.
2143, 1594, 1308, 835 cmꢁ1
;
dH (CDCl3) 10.94 (s, 1H), 9.13 (d,
followed by washing with aqueous saturated NaHCO3 (20 mL), water
(20 mL), and brine (20 mL). Drying (MgSO4), filtration and concen-
tration by rotary evaporation provided a clear yellow liquid (7.53 g)
which was purified by kugelrohr distillation (85e90 ꢀC, 2 mmHg) to
give the titlecompound 1b(4.26 g, 69%)asaclear, colorlessliquid:nmax
J¼2.5 Hz, 1H), 8.32 (dd, J¼9.5, 2.5 Hz, 1H), 8.00 (d, J¼9.5 Hz, 1H),
2.84e2.76 (m, 2H), 2.76e2.70 (m, 2H), 2.06 (t, J¼1.9 Hz, 3H) 0.28 (s,
9H); dC (CDCl3) 183.0, 166.2, 145.0, 144.8, 138.1, 136.1, 130.2, 123.8,
116.7, 108.0, 100.8, 32.9, 25.5, 11.2, 0.1; HRMS (MALDI): MHþ, found
373.1361. [C17H21N4O4Si]þ requires 373.1332.
2956, 2139, 1669, 1595, 838 cmꢁ1
; dH (CDCl3) 2.53e2.43 (m, 4H),
2.05e1.95 (m, 2H), 1.99 (t, J¼1.9 Hz, 3H), 0.3 (s, 9H); dC (CDCl3) 198.8,
140.1,137.3,109.4,103.6, 38.1, 31.1, 22.8,14.2,ꢁ0.1;tR 13.6 min, m/z (EI)
206 (32, MþA), 191 (100), 187 (9), 163 (18).
4.3. 2-Methyl-3-(trimethylsilylethynyl)-2-cyclohexenone (1b)27
A sample of 1b (44.9 mg, 0.22 mmol was dissolved in 95% eth-
anol (1.5 mL) and dinitophenylhydrazine reagent47 (2.00 mL,
0.28 mmol, 0.14 M) added. A precipitate formed almost immedi-
ately. After stirring for 15 min at room temperature, the reaction
was cooled in an ice water bath, then vacuum filtered. Air drying
gave the crude product (74.9 mg) as an orange solid. Re-
crystallization from hot 95% ethanol gave fine red-orange needles
(65.7 mg, 77%) of the 2,4-dinitrophenyl hydrazone of 1b: Rf (12:1
hexane:diethyl ether) 0.43; mp 210e212 ꢀC; nmax 3314, 3101, 2956,
Ethylmagnesium bromide (33.1 mL, 33.1 mmol, 1.0 M in THF)
was added to an argon-purged, oven-dried 250 mL round bottom
flask equipped with magnetic stirring bar, constant pressure ad-
dition funnel and an argon inlet. Stirring was begun and the flask
was cooled to 0 ꢀC in an ice water bath. Trimethylsilylethyne
(3.58 g, 36.4 mmol) in THF (35 mL) was added dropwise over
30 min, after which time the ice water bath was removed and the
flask allowed to warm to room temperature. Cooling to ꢁ78 ꢀC was
followed by dropwise addition of 3-isobutoxy-2-methyl-2-
cyclohexenone48 (5.00 g, 30.1 mmol) in THF (65 mL) over 30 min.
The cold bath was left to exhaust itself as the reaction slowly
warmed to room temperature overnight.
The reaction was quenched by the addition of water (10 mL), fol-
lowed by K2CO3 (1 g) with rapid stirring. Dilution with diethyl ether
(200 mL)wasfollowedby transfertoa separatory funnelandwashing
with water (50 mL). The organic layer subsequently was washed with
aqueous saturated NaHCO3 (20 mL), water(20 mL), and brine(20 mL).
Drying (MgSO4), filtration and concentration by rotary evaporation
gave a clear yellow liquid (9.08 g) which was taken up in diethyl ether
(30 mL), then stirred rapidly with 1 M HCl (10 mL) for 3 h. Dilution
with diethyl ether (40 mL) and transfer to a separatory funnel was
2132, 1616, 1591, 13,301, 838 cmꢁ1
; dH (CDCl3) 11.3 (s, 1H), 9.14 (d,
J¼2.6 Hz,1H), 8.37 (dd, J¼9.5, 2.6 Hz, 1H), 8.02 (d, J¼9.5 Hz, 1H) 2.58
(t, J¼6.7 Hz, 2H), 2.46e2.39 (m, 2H), 2.23 (t, J¼1.6 Hz, 3H), 1.94 (p,
J¼6.3 Hz, 2H) 0.24 (s, 9H); dC (CDCl3) 153.6, 145.0, 138.8, 138.4,
130.3, 129.9, 127.5, 123.7, 116.9, 105.5, 50.1, 30.0, 24.5, 21.2, 15.9, 0.2;
HRMS (MALDI): MHþ, 387.1476. [C18H23N4O4Si]þ requires 387.1489.
4.4. 3-(Trimethylsilylethynyl)-2-cyclohexenone (1c)19c
Ethylmagnesium bromide (65.0 mL, 65.0 mmol,1.0 M in THF) was
added to an argon-purged, oven-dried 250 mL round bottom flask
equipped with magnetic stirring bar, constant pressure addition
Please cite this article in press as: Gubbels, M. A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.058

M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
7
funnelandanargoninlet. Stirringwasbegunandthe flask wascooled
to 0 ꢀC in an ice water bath. Trimethylsilylethyne (7.06 g, 71.9 mmol)
inTHF (65 mL) was addeddropwise over 30 min, after which time the
ice water bath was removed and the flask allowed to warm to room
temperature. Coolingto ꢁ78 ꢀC was followed by dropwise addition of
3-isobutoxy-2-cyclohexenone49 (10.00g, 59.4mmol)inTHF(130mL)
over 30 min. The cold bath was left to exhaust itself as the reaction
slowly warmed to room temperature overnight.
(20 mL), then stirred rapidly with 1 M HCl (20 mL) for 2 h. Dilution
with diethyl ether (50 mL) and transfer to a separatory funnel was
followed by washing with aqueous saturated NaHCO3 (20 mL),
water (20 mL), and brine (20 mL). Drying (MgSO4), filtration and
concentration by rotary evaporation gave a yellow liquid (4.75 g)
which was purified by flash chromatography (4:1 petroleum
ether:diethyl ether) to give the title compound 1d (2.78 g, 72%) as an
off-white solid: mp 70.5e71.5 ꢀC (lit.49 mp 85e87 ꢀC); nmax 3061,
The reaction was quenched by the addition of water (20 mL),
followed by K2CO3 (1 g) with rapid stirring. Dilution with diethyl
ether (200 mL) was followed by transfer to a separatory funnel and
washing with water (100 mL). The organic layer subsequently was
washed with aqueous saturated NaHCO3 (40 mL), water (40 mL),
and brine (40 mL). Drying (MgSO4), filtration and concentration by
rotary evaporation gave a clear yellow liquid (18.04 g) which was
taken up in diethyl ether (60 mL), then stirred rapidly with 1 M HCl
(20 mL) for 2.5 h. Dilution with diethyl ether (40 mL) and transfer to
a separatory funnel was followed by washing with aqueous satu-
rated NaHCO3 (20 mL), water (20 mL), and brine (20 mL). Drying
(MgSO4), filtration and concentration by rotary evaporation pro-
vided a clear, yellow liquid (12.85 g) which was purified by frac-
tional distillation to give the title compound 1c (9.01 g, 79%) as
a nearly colorless liquid which solidified upon standing: bp
67e68 ꢀC (0.8 mmHg) [lit.19c 50e55 ꢀC (0.1 mmHg)]; mp 34e35 ꢀC.
A sample of 1c (38.3 mg, 0.20 mmol) was dissolved in 95%
ethanol (1.5 mL) and 2,4-dinitophenylhydrazine reagent47
(2.00 mL, 0.28 mmol, 0.14 M) added. A precipitate formed almost
immediately. After stirring for 15 min at room temperature, the
reaction was cooled in an ice water bath, then vacuum filtered. Air
drying gave the crude product (73.5 mg) as an orange solid. Re-
crystallization from hot 95% ethanol/ethyl acetate gave fine orange
needles (60.0 mg, 81%) of the 2,4-dinitrophenyl hydrazone 1c as
a mixture of diasteromers: Rf (10:1 hexane:ethyl acetate) 0.47 and
0.41; mp 173e189 ꢀC; nmax 3301, 3110, 2954, 2142, 1616, 1592,1369,
2918, 2193, 1683, 1611, 763, 690 cmꢁ1
; dH (CDCl3) 7.60e7.52 (m, 2H),
7.46e7.34 (m, 3H), 2.76 (apparent octet, J¼2.3 Hz, 2H), 2.52e2.45
(m, 2H), 1.96 (t, 2.1 Hz, 3H); dC (CDCl3) 209.2, 150.2, 144.8, 132.1,
129.7, 128.7, 122.3, 105.7, 85.2, 34.2, 30.2, 10.0; tR 18.9 min, m/z (EI)
196 (100, Mþ), 181 (15), 167 (68), 153 (55), 139 (56).
A sample of 1d (35.9 mg, 0.18 mmol) was dissolved in 95%
ethanol (1.5 mL) and 2,4-dinitophenylhydrazine reagent47
(2.00 mL, 0.28 mmol, 0.14 M) added. A precipitate formed almost
immediately. After stirring for 15 min at room temperature, the
reaction was cooled in an ice water bath, then vacuum filtered. Air
drying gave the crude product (65.8 mg) as a red solid. Re-
crystallization from hot 95% ethanol/ethyl acetate gave red prisms
(45.7 mg, 67%) of the 2,4-dinitrophenyl hydrazone of 1d: Rf (10:1
hexane:ethyl acetate) 0.50; mp 240.0e241.0 ꢀC; nmax 3298, 3113,
2923, 1616, 1592, 1514, 1334, 1312 cmꢁ1
; dH (CDCl3) 11.01 (s, 1H),
9.17 (d, J¼2.5 Hz, 1H), 8.35 (dd, J¼9.5, 2.5 Hz, 1H), 8.04 (d, J¼9.7 Hz,
1H), 7.59e7.53 (m, 2H), 7.46e7.33 (m, 3H), 2.99e2.89 (m, 2H),
2.89e2.76 (m, 2H), 2.17 (t, J¼1.8 Hz, 3H); dC (CDCl3) 166.3, 145.0,
143.8, 138.0, 136.3, 132.0, 130.2, 129.4, 129.3, 128.8, 123.9, 122.8,
116.7, 101.9, 85.7, 33.0, 25.6, 11.3; HRMS (MALDI): MHþ, 377.1246.
[C20H17N4O4]þ requires 377.1250.
4.6. 2-Methyl-3-(phenylethynyl)-2-cyclohexenone (1e)
Ethylmagnesium bromide (20.0 mL, 23.6 mmol, 1.2 M in THF)
was added to an argon-purged, oven-dried 250 mL round bottom
flask equipped with magnetic stirring bar, constant pressure ad-
dition funnel and an argon inlet. The addition funnel was washed
with additional THF (5 mL). Stirring was begun and the flask was
cooled to 0 ꢀC in an ice water bath. Phenylethyne (2.46 g,
24.1 mmol) in THF (28 mL) was added dropwise over 30 min, after
which time the ice water bath was removed and the flask allowed
to warm to room temperature. Cooling to ꢁ78 ꢀC was followed by
dropwise addition of 3-isobutoxy-2-methyl-2-cyclohexenone50
(3.64 g, 20.0 mmol) in THF (28 mL) over 30 min. The cold bath
was left to exhaust itself as the reaction slowly warmed to room
temperature overnight.
1331, 843 cmꢁ1
;
dH (CDCl3) 11.48 and 11.32 (s, 1H), 9.16 (d, J¼2.6 Hz,
1H), 8.35 and 8.33 (ddd, J¼9.6, 2.6, 0.6 Hz, 1H) 8.02 and 7.99 (d,
J¼9.5 Hz, 1H), 6.82 and 6.69 (t, J¼1.7 Hz, 1H), 2.60 and 2.59 (t,¼10.2
and 6.7 Hz, 2H), 2.49 and 2.43 (td, J¼6.0, 1.6 Hz, 2H), 2.00 (p,
J¼6.4 Hz, 2H), 0.28 and 0.26 (s, 9H); dC major isomer (CDCl3) 153.4,
144.8, 138.5, 132.9, 130.8, 130.3, 123.7, 116.9, 105.4, 101.2, 29.5, 23.7,
21.2, 6.3; HRMS (MALDI): MHþ, 373.1358. [C17H21N4O4Si]þ requires
373.1332.
4.5. 2-Methyl-3-(phenylethynyl)-2-cyclopentenone (1d)48
Ethylmagnesium bromide (20.6 mL, 24.3 mmol, 1.2 M in THF)
was added to an argon-purged, oven-dried 250 mL round bottom
flask equipped with magnetic stirring bar, constant pressure ad-
dition funnel and an argon inlet. The addition funnel was washed
with additional THF (5 mL). Stirring was begun and the flask was
cooled to 0 ꢀC in an ice water bath. Phenylethyne (2.43 g,
23.8 mmol) in THF (27 mL) was added dropwise over 30 min, after
which time the ice water bath was removed and the flask allowed
to warm to room temperature. Cooling to ꢁ78 ꢀC was followed by
dropwise addition of 3-isobutoxy-2-methyl-2-cyclopentenone46
(3.33 g, 19.8 mmol) in THF (27 mL) over 30 min. The cold bath
was left to exhaust itself as the reaction slowly warmed to room
temperature overnight.
The reaction was quenched by the addition of water (10 mL),
followed by K2CO3 (1 g) with rapid stirring. Transfer to a separatory
funnel was followed by extraction with diethyl ether (50 mL) four
times. The pooled organic extracts were washed with water
(20 mL) twice. The organic layer subsequently was washed with
aqueous saturated NaHCO3 (20 mL), water (20 mL), and brine
(20 mL). Drying (MgSO4), filtration and concentration by rotary
evaporation gave the crude product, which was taken up in THF
The reaction was quenched by the addition of water (10 mL),
followed by K2CO3 (1 g) with rapid stirring. Transfer to a separatory
funnel was followed by extraction with diethyl ether (50 mL) four
times. The pooled organic extracts were washed with water
(20 mL) twice. The organic layer subsequently was washed with
aqueous saturated NaHCO3 (20 mL), water (20 mL), and brine
(20 mL). Drying (MgSO4), filtration and concentration by rotary
evaporation gave the crude product, which was taken up in THF
(20 mL), then stirred rapidly with 1 M HCl (20 mL) for 2 h. Dilution
with diethyl ether (50 mL) and transfer to a separatory funnel was
followed by washing with aqueous saturated NaHCO3 (20 mL),
water (20 mL), and brine (20 mL). Drying (MgSO4), filtration and
concentration by rotary evaporation gave a yellow liquid (6.14 g),
which solidified upon standing. Recrystallization from hot petro-
leum ether gave the title compound 1e (2.85 g, 68%): mp 62e63 ꢀC;
nmax 2945, 2197, 1647,768, 694 cmꢁ1
; dH (CDCl3) 7.57e7.47 (m, 2H),
7.44e7.34 (m, 3H), 2.61 (t of q, J¼1.8, 6.0 Hz, 2H), 2.51 (t, J¼6.5 Hz,
2H), 2.08 (t, J¼3.6 Hz, 3H), 2.60 (p, J¼6.6 Hz, 2H); dC (CDCl3) 198.5,
139.3, 137.6, 131.9, 129.4, 128.7, 122.8, 103.2, 88.5, 38.2, 31.3, 23.0,
14.2; tR 15.1 min, m/z (EI) 210 (100, Mþ), 182 (38), 167 (45), 154 (53),
Please cite this article in press as: Gubbels, M. A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.058

8
M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
139 (30); HRMS (MALDI): MHþ, 211.1108. [C15H15O]þ requires
211.1123.
1305 cmꢁ1
;
dH (CDCl3) 11.53 and 11.35 (two s, 1H), 9.17 (d, J¼2.5 Hz,
1H), 8.44e8.30 (m, 1H), 8.03 (t, J¼9.7 Hz, 1H), 7.63e7.48 (m, 2H),
7.48e7.36 (m, 3H), 6.88 and 6.75 (two t, J¼1.8 and 1.5 Hz, 1H),
2.77e2.49 (m, 4H), 2.15e1.96 (m, 2H); dC (CDCl3) 153.6, 152.3, 145.1,
144.8,138.5,138.1, 137.0, 132.2,132.0,131.9, 131.1, 130.3, 130.2, 129.6,
129.4,129.1,128.8,128.7,123.8,123.7,122.9,122.3,119.7,116.9,116.6,
97.9, 95.7, 90.2, 89.9, 31.7, 31.2, 29.7, 23.8, 22.6, 21.3; HRMS (MALDI):
MHþ, 377.1218. [C20H17N4O4]þ requires 377.1250.
A sample of 1e (31.7 mg, 0.15 mmol) was dissolved in 95% eth-
anol (1.5 mL) and added dropwise with stirring to 2,4-
dinitophenylhydrazine reagent47 (2.00 mL, 0.28 mmol, 0.14 M). A
precipitate formed almost immediately. After stirring for 15 min at
room temperature, the reaction was cooled in an ice water bath,
then vacuum filtered. Air drying gave the crude product (90.6 mg)
as an orange powder. Recrystallization from hot ethyl acetate gave
small dark red prisms (41.0 mg, 70%) of the 2,4-dinitrophenyl
hydrazone 1e: Rf (11:1 hexane:ethyl acetate) 0.44; mp
4.8. Lithium aluminum hydride reduction of 1a in THF:
(1R*,2R*,S*)-2-methyl-3-(trimethylsilylethenylidene)cyclo-
pentanol [(1R*,2R*,S*)-3a] and (1R*,2R*,3S*)-2-methyl-3-(tri-
methylsilylethynyl)cyclopentanol [(1R*,2R*,3S*)-4a]
215e217 ꢀC; nmax 3304, 3113, 2947, 1613, 1589, 1309 cmꢁ1
; dH
(CDCl3) 11.35 (s, 1H), 9.17 (d, J¼2.5 Hz, 1H), 8.36 (dd, J¼2.5, 9.5 Hz,
1H), 8.06 (d, J¼9.5 Hz, 1H), 7.57e7.48 (m, 2H), 7.43e7.34 (m, 3H),
2.65 (t, J¼6.6 Hz, 2H), 2.55 (td, J¼1.4, 6.1 Hz, 2H), 2.34 (t, J¼1.5 Hz,
3H), 2.02 (apparent p, J¼6.4 Hz, 2H); dC (CDCl3) 153.7, 145.0, 138.4,
137.8, 131.8, 130.3, 129.9, 129.0, 128.7, 127.8, 123.8, 123.3, 117.0,
100.0, 89.9, 30.2, 24.6, 21.3, 16.0; HRMS (MALDI): MNaþ, 413.1241.
[C21H18N4O4Na]þ requires 413.1226.
A solution of 1a (39.4 mg, 0.20 mmol) in THF (2.3 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equip-
ped with magnetic stirring bar, serum septum and argon inlet.
Stirring was begun as the reaction was cooled to 0 ꢀC. A solution of
lithium aluminum hydride (430 mL, 0.43 mmol, 1 M in THF) was
added dropwise, then the cold bath removed. The resultant solu-
tion was stirred at room temperature for 2 h. The reaction sub-
sequently was diluted with diethyl ether (20 mL), then aqueous
saturated ammonium chloride (6 drops) added. Filtration through
anhydrous MgSO4 was followed by concentration by rotary evap-
oration to give a colorless oil (37.9 mg).
4.7. 3-(Phenylethynyl)-2-cyclohexenone (1f)48
Butylmagnesium bromide (16.0 mL, 23.5 mmol, 1.5 M in THF)
was added to an argon-purged, oven-dried 250 mL round bottom
flask equipped with magnetic stirring bar, constant pressure ad-
dition funnel and an argon inlet. The addition funnel was washed
with additional THF (16 mL). Stirring was begun and the flask was
cooled to 0 ꢀC in an ice water bath. Phenylethyne (2.46 g,
24.1 mmol) in THF (28 mL) was added dropwise over 30 min, after
which time the ice water bath was removed and the flask allowed
to warm to room temperature. Cooling to ꢁ78 ꢀC was followed by
dropwise addition of 3-isobutoxy-2-cyclohexenone49 (3.37 g,
20.0 mmol) in THF (28 mL) over 30 min. The cold bath was left to
exhaust itself as the reaction slowly warmed to room temperature
overnight.
Purification of a sample of the crude product (69.9 mg) by me-
dium pressure liquid chromatography (2 mL/min, 4:1 hex-
ane:diethyl ether) gave two fractions. Fraction one was
concentrated by rotary evaporation to give a colorless oil (29.5 mg,
42%) consisting of a 92:8 mixture of isomeric alcohols. The major
diastereomer was identified as the title compound (1R*,2R*,S*)-3a:
Rf (4:1 hexane:diethyl ether) 0.21; nmax 3337, 2946, 1940, 1242,
1067, 1042, 856, 836 cmꢁ1
;
dH (CDCl3) 5.04 (ddd, J¼10.8, 5.3, 0.6 Hz,
1H), 3.76 (dd, J¼12.9, 6.7 Hz, 1H), 2.57e2.43 (m, 1H), 2.40e2.22
(two m, 2 H), 1.97e1.84 (m, 1H), 1.54 (s, 1H), 1.58e1.45 (m, 1H), 1.11
(d, J¼6.7 Hz, 3H), 0.10 (s, 9H); dC (CDCl3) 205.5 (C), 99.0 (C), 86.2
(CH), 80.1 (CH), 45.5 (CH), 33.4 (CH2), 26.2 (CH2), 17.1 (CH3), -0.5
(CH3); tR 15.5 min, m/z (EI) 196 (48, Mþ), 163 (23), 105 (31), 91 (83),
75 (95), 73 (100). Minor isomer: tR 14.6 min, m/z (EI) 196 (42, Mþ),
165 (20), 105 (28), 91 (78), 75 (99), 73 (100); HRMS (MALDI): MHþ,
197.1334. [C11H21OSi]þ requires 197.1362. Fraction two was con-
centrated by rotary evaporation to give of a colorless oil (10.7 mg,
15%) consisting of a 93:7 mixture of isomeric alcohols. The major
isomer was identified as the title compound (1R*,2R*,3S*)-4a: Rf (4:1
hexane:diethyl ether) 0.17; nmax 3327, 2956, 2162, 1453, 1248, 846,
The reaction was quenched by the addition of water (10 mL),
followed by K2CO3 (1 g) with rapid stirring. Transfer to a separatory
funnel was followed by extraction with diethyl ether (50 mL) four
times. The pooled organic extracts were washed with water
(20 mL) twice. The organic layer subsequently was washed with
aqueous saturated NaHCO3 (20 mL), water (20 mL), and brine
(20 mL). Drying (MgSO4), filtration and concentration by rotary
evaporation gave the crude product, which was taken up in THF
(20 mL), then stirred rapidly with 1 M HCl (20 mL) for 2 h. Dilution
with diethyl ether (50 mL) and transfer to a separatory funnel was
followed by washing with aqueous saturated NaHCO3 (20 mL),
water (20 mL), and brine (20 mL). Drying (MgSO4), filtration and
concentration by rotary evaporation provided a yellow liquid
(4.18 g) which was purified by kugelrohr distillation to give the title
compound 1f (3.46 g, 88%): bp 110 ꢀC (0.1 mmHg); mp 37e40 ꢀC
(lit.48 mp 90e92 ꢀC); nmax 3078, 2948, 2194, 1663, 1599, 761,
760 cmꢁ1
;
dH (CDCl3) 3.97 (dd, J¼10.4, 4.7 Hz, 1H), 3.02 (dd, J¼14.5,
7.2 Hz, 1H), 2.20e2.03 (m, 1H), 2.02e1.89 (m, 1H), 1.99e1.90 (m,
1H),1.83e1.68 (m,1H),1.62e1.58 (m, 1H),1.05 (d, J¼7.0 Hz, 3H), 0.14
(s, 9H); dC (CDCl3) 107.0 (C), 86.8 (C), 79.3 (CH), 46.0 (CH), 34.1 (CH),
32.9 (CH2), 29.7 (CH2),14.3 (CH3), 0.5 (CH3); tR 14.9 min, m/z (EI) 196
(0.4, Mþ), 195 (1), 181 (62), 165 (51), 163 (59), 152 (31), 91 (30), 75
(100), 73 (64); HRMS (MALDI): MHþ-H2O, 179.1212. [C11H19Si]þ
requires 179.1256. Minor isomer: tR 14.6 min, m/z (EI) 196 (0.6, Mþ),
195 (0.7), 181 (24), 163 (58), 75 (100), 73 (23).
690 cmꢁ1
; dH (CDCl3) 7.55e7.45 (m, 2H) 7.45e7.30 (m, 3H), 6.31 (t,
J¼1.8 Hz, 1H), 2.56 (t of d, J¼5.9, 1.8 Hz, 2H), 2.44 (t, J¼7.2 Hz, 2H),
2.06 (p, J¼7.2 Hz, 2H); dC (CDCl3) 198.7, 143.5, 132.6, 132.2, 129.7,
128.7, 122.3, 99.9, 88.7, 37.6, 30.8, 22.9; tR 16.8 min, m/z (EI) 196
(100, Mþ), 168 (70), 139 (89).
4.9. Lithium aluminum hydride reduction of 1a in benzene:
2-methyl-3-(trimethylsilylethynyl)-2-cyclopentenol (2a)
A sample of 1f (35.8 mg, 0.18 mmol) was dissolved in 95% eth-
anol (1.5 mL) and added dropwise with stirring to 2,4-
dinitophenylhydrazine reagent47 (2.00 mL, 0.28 mmol, 0.14 M). A
precipitate formed almost immediately. After stirring for 15 min at
room temperature, the reaction was cooled in an ice water bath,
then vacuum filtered. Air drying gave the crude product (68.8 mg)
as a red solid. Recrystallization from hot ethyl acetate gave red
crystals (53.9 mg, 80%) of the 2,4-dinitrophenyl hydrazone of 1f as
a 1:1 mixture of diasteromers: Rf (11:1 hexane:ethyl acetate) 0.32
and 0.27; mp 225e228 ꢀC; nmax 3304, 3114, 2946, 1612, 1586, 1331,
Lithium aluminum hydride (19.8 mg, 0.52 mmol) and benzene
(1.0 mL) were added to an argon-purged, oven-dried 25 mL round
bottom flask equipped with magnetic stirring bar, serum septum
and argon inlet. Stirring was begun and the suspension cooled to
0 ꢀC. A solution of 1a (29.8 mg, 0.16 mmol) in benzene (1.0 mL) was
added dropwise. Once the addition was complete, the cold bath was
removed and reaction the stirred at room temperature for 2 h. The
reaction subsequently was diluted with diethyl ether (20 mL), then
Please cite this article in press as: Gubbels, M. A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.058

M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
9
aqueous saturated ammonium chloride (6 drops) added. Filtration
through anhydrous MgSO4 was followed by concentration by rotary
evaporation to give a crude product (25.8 mg) as a colorless oil.
A sample of crude product (141.9 mg) was purified by pre-
parative thin layer chromatography (4:1 hexane:diethyl ether) to
give the title compound 2a (96.2 mg, 68%) as a white solid: Rf (4:1
hexane:diethyl ether) 0.24; mp 63e64 ꢀC; nmax 3188, 2962, 2859,
reduction allene product and (1R*,2R*,3S*)-4a was the major (79:21)
alkyne double reduction product.
4.12. Sodium bis(2-methoxyethoxy)aluminum hydride re-
duction of 1b in THF: (1R*,2R*,S*)-2-methyl-3-(trimethylsily-
lethenylidene)cyclohexanol [(1R*,2R*,S*)-3b] and 2-methyl-3-
(trimethylsilylethynyl)cyclohexanol [(1R*,2R*,3S*)-4b]
2144, 841 cmꢁ1
;
dH (CDCl3) 4.64 (br q, J¼5.9 Hz, 1H), 2.63e2.48 (m,
1H), 2.43e2.24 (m, 2H), 1.91 (p, J¼1.1 Hz, 3H), 1.75e1.61 (m, 1H),
1.60e1.41 (m, 1H), 0.22 (s, 9H); dC (CDCl3) 149.5, 121.5, 101.8, 99.6,
80.3, 33.7, 33.2, 13.4, 0.3; tR 16.0 min, m/z (EI) 194 (37, Mþ), 179
(100), 161 (66), 121 (82).
A solution of 1b (61.2 mg, 0.30 mmol) in THF (4.0 mL) was added
to an argon-purge, oven-dried 25 mL round bottom flask equipped
with magnetic stirring bar, serum septum and argon inlet. Stirring
was begun and the solution cooled to 0 ꢀC. A solution of sodium
A sample of purified 2a (22.1 mg, 0.12 mol) and DMF (1.0 mL) were
added to a dry 25 mL round bottom flask equipped with a magnetic
stirringbar. tert-Butyldimethylsilyl chloride (27.0mg, 0.18 mmol)and
imidazole (20.0 mg, 0.29 mmol) were added sequentially and the
reaction stoppered and stirred overnight at room temperature. Di-
lution with diethyl ether (50 mL) was followed by washing with
water (25 mL) five times. The ether solution thenwas dried (Na2SO4),
filtered and concentrated by rotaryevaporation to provide a colorless
oil (38.4 mg). Purification of this oil by preparative thin layer chro-
matography (hexane) gave 3-(tert-butyldimethylsilyloxy)-2-methyl-
1-(trimethylsilylethynyl)cyclopentene (27.9 mg, 75%): Rf (hexane)
bis(2-methoxyethoxy)aluminum hydride (190 mL, 0.66 mmol, 3.5 M
in toluene) was added dropwise. Once the addition was complete,
the cold bath was removed and the reaction was stirred at room
temperature for 2 h. After recooling to 0 ꢀC the reaction was diluted
with diethyl ether (20 mL), then aqueous saturated ammonium
chloride (10 drops) added. The cold bath was removed and the flask
warmed to room temperature. Filtration through anhydrous MgSO4
was followed by concentration by rotary evaporation to give a pale
yellow oil (66.4 mg). GC/MSD analysis determined the ratio of 2-
methyl-3-(trimethylsilylethenylidene)cyclohexanol
(3b):2-
methyl-3-(trimethylsilylethynyl)cyclohexanol (4b) to be 74:26.
The title compound (1R*,2R*,S*)-3b was the major (86:14) double
reduction allene product and the title compound (1R*,2R*,3S*)-4b
was the major (83:17) alkyne double reduction product.
0.20; nmax 2957, 2858, 2144,1250,1066, 842 cmꢁ1
; dH (CDCl3) 4.68 (t,
J¼4.7 Hz, 1H), 2.59e2.47 (m, 1H), 2.38e2.28 (m, 1H), 2.28e2.16 (m,
1H), 1.89e1.80 (m, 3H), 1.72e1.52 (m, 1H), 0.92 (s, 9H), 0.22 (s, 9H),
0.11 (s, 3H), 0.09 (s, 3H); dC (CDCl3) 150.3,119.7,102.1, 98.5, 80.0, 33.4,
25.8,18.2,13.3, 0.1, -4.5, -4.8; tR 16.8 min, m/z (EI) 308 (9, Mþ), 293 (9),
177 (10), 161 (27), 147 (100), 97 (12), 75 (33); HRMS (MALDI): MHþ,
309.2099. [C17H33OSi2]þ requires 309.2070.
Purification of the crude product by medium pressure liquid
chromatography (1.3 mL/min, 4:1 hexane:diethyl ether) gave
(1R*,2R*,S*)-3b (32.0 mg, 51%) as a colorless oil: Rf (4:1 hex-
ane:diethyl ether) 0.25; nmax 3351, 2955, 2928, 2857, 1941, 1246,
839 cmꢁ1
;
dH (CDCl3) 4.99 (t, J¼4.8 Hz, 1H), 3.24 (apparent heptet,
4.10. Lithium aluminum hydride reduction of 2a in THF:
(1R*,2R*,S*)-3a and (1R*,2R*,3S*)-4a
J¼4.8 Hz, 1H), 2.25 (dt, J¼3.4, 14.2 Hz, 1H), 2.81e1.82 (m, 4H),
1.48e1.25 (m, 3 H),1.11 (d, J¼6.6 Hz, 3H), 0.11 (s, 9H); dC (CDCl3) 206.6,
98.5, 83.9, 76.6, 41.3, 35.3, 31.0, 25.6, 15.6, -0.6; tR 13.2 min, m/z (EI)
210 (42, Mþ),192 (27),177 (44),149 (9),119 (23),105 (42), 91 (37), 75
(83), 73 (100); HRMS (MALDI): MHþ-H2O, 193.1449. [C12H21Si]þ re-
quires 193.1413. It was not possible to isolate a chromatographically
pure fraction of isomeric, slightly more polar (1R*,2R*,3S*)-4b.
A solution of 2a (21.5 mg, 0.11 mmol) and THF (2.0 mL) was
added to an argon-purged, oven-dried 25 mL round bottom flask
equipped with magnetic stirring bar, serum septum and argon in-
let. Stirring was begun and the flask cooled to 0 ꢀC. A solution of
lithium aluminum hydride (245 mL, 0.24 mmol, 1 M in THF) was
added dropwise, then the cold bath removed. The resultant solu-
tion was stirred at room temperature for 2 h. The reaction sub-
sequently was diluted with diethyl ether (20 mL), then aqueous
saturated ammonium chloride (5 drops) added. Filtration through
anhydrous MgSO4 was followed by concentration by rotary evap-
oration to give a colorless oil (25.6 mg). GC/MSD analysis de-
termined the ratio of 3a:4a to be 66:34. (1R*,2R*,S*)-3a was the
major (91:9) double reduction allene product and (1R*,2R*,3S*)-4a
was the major (90:10) alkyne double reduction product.
4.13. Lithium aluminum hydride reduction of 1b in THF:
(R*,2R*,S*)-3b and (1R*,2R*,3S*)-4b
A solution of 1b (40.7 mg, 0.20 mmol) in THF (2.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equipped
with magnetic stirring bar, serum septum and argon inlet. Stirring
was begun and the flask was cooled to 0 ꢀC. A solution of lithium
aluminum hydride (435
mL, 0.43 mmol, 1 M in THF) was added
dropwise. Once the addition was complete, the cold bath was re-
moved and the stirred at room temperature for 2 h. After recooling to
4.11. Sodium bis(2-methoxyethoxy)aluminum hydride re-
0
ꢀC the reaction was diluted with diethyl ether (20 mL), then
duction of 1a in THF: 2a, (1R*,2R*,S*)-3a and (1R*,2R*,3S*)-4a
aqueous saturated ammonium chloride (7 drops) added. The cold
bath was removed and the flask warmed to room temperature. Fil-
tration through anhydrous MgSO4 was followed by concentration by
rotary evaporation to give a clear, colorless oil (40.0 mg). GC/MSD
analysis determined the ratio of 3b:4b to be 74:26. (R*,2R*,S*)-3bwas
the major (89:11) double reduction allene product and (1R*,2R*,3S*)-
4b was the major (88:12) alkyne double reduction product.
A solution of 1a (42.5 mg, 0.22 mmol) in THF (2.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equipped
with magnetic stirring bar, serum septum and argon inlet. Stirring
was begun and the solution cooled to 0 ꢀC. A solution of sodium
bis(2-methoxyethoxy)aluminum hydride (280 mL, 0.98 mmol. 3.5 M
in toluene) was added dropwise. Once the addition was complete,
the cold bath was removed and the reaction was stirred at room
temperature for 2 h. After recooling to 0 ꢀC, the reaction was diluted
with diethyl ether (20 mL), then aqueous saturated ammonium
chloride (15 drops) added. The cold bath was removed and the flask
warmed to room temperature. Filtration through anhydrous MgSO4
was followed by concentration by rotary evaporation to give a pale
yellow oil (47.3 mg). GC/MSD analysis determined the ratio of
3a:4a:2a to be 68:18:14. (1R*,2R*,S*)-3awas the major (96:4) double
4.14. Lithium aluminum hydride reduction of 1c in THF:
(1R*,S*)-3-(trimethylsilylethenylidene)cyclohexanol [(1R*,S*)-
3c] and (1R*,3S*)-3-(trimethylsilylethynyl)cyclohexanol
[(1R*,3S*)-4c]
A solution of 1c (61.0 mg, 0.32 mmol) in THF (4.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equip-
ped with magnetic stirring bar, serum septum and argon inlet.
Please cite this article in press as: Gubbels, M. A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.058

10
M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
Stirring was begun and the flask was cooled to 0 ꢀC. A solution of
lithium aluminum hydride (700 L, 0.70 mmol, 1.0 M in THF) was
reaction was stirred at room temperature for 2 h. After recooling to
0
ꢀC the reaction was diluted with diethyl ether (20 mL), then
m
added dropwise. Once the addition was complete, the cold bath
was removed and the reaction stirred at room temperature for 2 h.
After recooling to 0 ꢀC the reaction was diluted with diethyl ether
(20 mL), then aqueous saturated ammonium chloride (15 drops)
added. The cold bath was removed and the flask warmed to room
temperature. Filtration through anhydrous MgSO4 was followed by
concentration by rotary evaporation to give a clear, colorless oil
(72.2 mg). GC/MSD analysis determined the ratio of 3-(trime-
thylsilylethenylidene)cyclohexanol (3c):3-(trimethylsilylethynyl)
cyclohexanol (4c) to be 80:20. The title compound (1R*,S*)-3c was
the major (69:31) double reduction allene product and only one
diastereoisomer of the alkyne double reduction product, ostensibly
the title compound (1R*,3S*)-4c, was observed.
aqueous saturated ammonium chloride (7 drops) added. The cold
bath was removed and the flask warmed to room temperature.
Filtration through anhydrous MgSO4 was followed by concentra-
tion by rotary evaporation to give a yellow oil (42.9 mg) which was
purified by preparative thin layer chromatography (4:1 hex-
ane:diethyl ether) to yield of the title compound (1R*,2R*,S*)-3d
(20.6 mg, 54%) as a clear, colorless oil: Rf (4:1 hexane:diethyl ether)
0.40; nmax 3354, 3030, 2960, 2928, 2870, 1951, 1598, 1455, 1073,
1047, 693 cmꢁ1
; dH (CDCl3) 7.37e7.29 (m, 4H), 7.26e7.16 (m, 1H),
6.22 (q, J¼4.2 Hz, 1H), 3.92 (q, J¼6.4 Hz, 1H), 2.84e2.46 m, 3H,
2.22e2.04 (m, 1H), 1.82e1.59 (m, 2H), 1.22 (d, J¼7.0 Hz, 3H); dC
(CDCl3) 199.7, 135.8, 128.8, 126.9, 126.7, 111.0, 97.3, 80.0, 47.4, 33.4,
26.7, 17.4; tR 19.2 min, m/z (EI) 200 (76, Mþ), 167 (46), 156 (60), 141
(100), 128 (56), 115 (41), 102 (17), 91 (27); HRMS (MALDI): MHþ,
201.1309. [C14H17O]þ requires 201.1280.
Purification of the crude product by medium pressure liquid
chromatography (1.5 mL/min, 4:1 hexane:diethyl ether) gave
(1R*,S*)-3c (6.4 mg, 10%) as a clear, colorless oil: Rf (4:1 hex-
ane:diethyl ether) 0.25; nmax 3324, 2934, 1947, 1247, 1052,
4.17. Sodium bis(2-methoxyethoxy)aluminum hydride re-
duction of 1e in THF: (1R*,2R*,S*)-2-methyl-3-(phenyl-
ethenylidene)cyclohexanol [(1R*,2R*,S*)-3e]
840 cmꢁ1
; dH (CDCl3) 4.90e4.84 (m, 1H), 3.83e3.72 (m, 1H), 2.50
(m, 1H), 2.20e1.69 (m, 5H), 1.52e1.34 (m, 2H), 1.29 (s, 1H), 0.11 (s,
9H); dC (CDCl3) 206.8, 91.7, 81.9, 70.0, 39.7, 34.9, 30.0, 24.4, -0.6; tR
12.3 min, m/z (EI) 196 (42, Mþ), 178 (29), 163 (64), 105 (27), 91 (80),
73 (100); HRMS (MALDI): MHþ, 197.1367. [C11H21OSi]þ requires
197.1362. A second, more polar fraction returned (1R*,3S*)-4c
(6.2 mg, 10%) as a clear, colorless oil: Rf (4:1 hexane:diethyl ether)
A solution of 1e (34.0 mg, 0.16 mmol) in THF (2.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equipped
with magnetic stirring bar, serum septum and argon inlet. Stirring
was begun and the solution cooled to 0 ꢀC. A solution of sodium
0.14; nmax 3188, 2930, 2165, 841 cmꢁ1
;
dH (CDCl3) 4.06 (s, 1H),
bis(2-methoxyethoxy)aluminum hydride in toluene (105 mL,
2.94e2.85 (m, 1H), 1.98e1.86 (m, 1H), 1.86e1.76 (m, 1H), 1.73e1.55
(m, 5H), 1.48e1.26 (m, 2H), 0.17 (s, 9H); dC (CDCl3) 110.7, 67.0, 39.8,
34.5, 31.3, 27.0, 20.5, 14.4, 0.5; tR 12.1 min, m/z (EI) 196 (5, Mþ), 181
(19), 178 (24), 163 (79), 151 (52), 75 (100); HRMS (ESI): MHþ,
197.1320. [C11H21OSi]þ requires 197.1362.
0.37 mmol, 3.5 M in toluene) was added dropwise. Once the addi-
tion was complete, the cold bath was removed and the reaction was
stirred at room temperature for 2 h. After recooling to 0 ꢀC the re-
action was diluted with diethyl ether (20 mL), then aqueous satu-
rated ammonium chloride (7 drops) added. The cold bath was
removed and the flask warmed to room temperature. Filtration
through anhydrous MgSO4 was followed by concentration by rotary
evaporation to give a white solid (39.3 mg), which was dissolved in
warm hexane (2.0 mL). Slow cooling to ꢁ18 ꢀC and isolation of the
solid that formed by vacuum filtration gave the title compound
(1R*,2R*,S*)-3e (33.3 mg, 96%) as a white solid: Rf (3:1 hex-
ane:diethyl ether) 0.30; mp 112e114 ꢀC; nmax IR 3454, 2981, 2952,
4.15. Sodium bis(2-methoxyethoxy)aluminum hydride re-
duction of 1c in THF: (1R*,S*)-3c and (1R*,3S*)-4c
A solution of 1c (58.4 mg, 0.30 mmol) in THF (3.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equip-
ped with magnetic stirring bar, serum septum and argon inlet.
Stirring was begun and the solution cooled to 0 ꢀC. A solution of
sodium bis(2-methoxyethoxy)aluminum hydride in toluene
2924, 2861, 1952, 1453, 1061, 1031, 1014, 827, 748, 694 cmꢁ1
; dH
(CDCl3) 7.37e7.27 (m, 4H), 7.26e7.16 (m, 1H), 6.20 (t, J¼3.7 Hz, 1H),
3.43 (apparent heptet, J¼4.6 Hz, 1H) 2.42 (dtd, J¼1.5, 3.6, 12.5 Hz,
1H), 2.21e1.90 (m, 4H), 1.71 (d, J¼4.7 Hz, 1H), 1.67e1.41 (m, 2H), 1.18
(d, J¼6.7 Hz, 3H); dC (CDCl3) 201.0, 136.0, 128.8, 126.8, 126.6, 110.2,
95.5, 76.9, 43.0, 35.1, 31.5, 25.7, 15.4; tR 20.1 min, m/z (EI) 214 (100,
Mþ), 181 (59), 167 (23), 155 (38), 143 (87), 129 (67), 115 (49), 91 (60);
(190 mL, 0.67 mmol, 3.5 M in toluene) was added dropwise. Once
the addition was complete, the cold bath was removed and the
reaction was stirred at room temperature for 2 h. After recooling to
0
ꢀC the reaction was diluted with diethyl ether (20 mL), then
aqueous saturated ammonium chloride (11 drops) added. The cold
bath was removed and the flask warmed to room temperature.
Filtration through anhydrous MgSO4 was followed by concentra-
tion by rotary evaporation to give a clear, colorless oil (59.2 mg)
which was purified by preparative thin layer chromatography (2:1
hexane:diethyl ether) to yield two fractions. Fraction 1: (1R*,S*)-3c,
clear, colorless oil (31.6 mg, 54%); Rf (2:1 hexane:diethyl ether) 0.32.
Fraction 2: (1R*,3S*)-4c, clear, colorless oil (2.8 mg, 5%); Rf (2:1
hexane:diethyl ether) 0.20.
HRMS (MALDI): MHþ-H2O, 197.1334. [C15H17 þ requires 197.1330.
]
4.18. Lithium aluminum deuteride reduction of 1e in THF:
(1R*,2R*,S*)-(1,2-2H2)-2-methyl-3-(phenylethenylidene)
cyclohexanol
Lithium aluminum deuteride (16.7 mg, 0.39 mmol) and THF
(1.0 mL) were added to an argon-purged, oven-dried 25 mL round
bottom flask equipped with magnetic stirring bar, serum septum,
and argon inlet. Stirring was begun and the suspension cooled to
4.16. Sodium bis(2-methoxyethoxy)aluminum hydride re-
duction of 1d in THF: (1R*,2R*,S*)-2-methyl-3-(phenyl-
ethenylidene)cyclopentanol [(1R*,2R*,S*)-3d]
0
ꢀC. A solution of 1e (31.8 mg, 0.15 mmol) in THF (1.0 mL) was
added dropwise. Once the addition was complete, the cold bath
was removed and the stirred at room temperature for 2 h. After
recooling to 0 ꢀC the reaction was diluted with diethyl ether
(20 mL), then aqueous saturated ammonium chloride (10 drops)
added. The cold bath was removed and the flask warmed to room
temperature. Filtration through anhydrous MgSO4 was followed by
concentration by rotary evaporation to give the crude title com-
pound (27.0 mg) as an oil which solidified upon standing. 1H NMR
and GC/MSD analyses indicated ꢂ96% deuterium incorporation at
A solution of 1d (38.2 mg, 0.19 mmol) in THF (2.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equip-
ped with magnetic stirring bar, serum septum and argon inlet.
Stirring was begun and the solution cooled to 0 ꢀC. A solution of
sodium bis(2-methoxyethoxy)aluminum hydride in toluene
(122
mL, 0.43 mmol, 3.5 M in toluene) was added dropwise. Once
the addition was complete, the cold bath was removed and the
Please cite this article in press as: Gubbels, M. A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.058

M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
11
positions 1 and 2: dH (CDCl3) 7.39e7.27 (m, 4H), 7.26e7.16 (m, 1H),
6.20 (d, J¼3.6 Hz, 1H), 2.42 (dtd, J¼1.4, 3.7, 14.2 Hz, 1H), 2.21e1.78
(m, 3H), 1.75e1.40 (m, 3H), 1.17 (s, 3H); tR 20.1 min, m/z (EI) 216
(100, Mþ),183 (52),168 (21),156 (33),144 (81),129 (64),115 (27), 91
(39).
to 0 ꢀC. A solution of methyllithium (400
m
L, 0.64 mmol, 1.6 M in
diethyl ether) of was added, followed by dropwise addition of
a solution of 1e (60.1 mg, 0.29 mmol) in THF (4.0 mL). Once the
addition was complete, the reaction was stirred at 0 ꢀC for 1.5 h,
then the cold bath removed and the reaction warmed to room
temperature over 1.5 h. Quenching with aqueous saturated NH4Cl
(0.3 mL) and water (0.3 mL) was followed by dilution with diethyl
ether (20 mL), drying through MgSO4, and concentration by rotary
evaporation. A yellow oil (84.1 mg) resulted and was purified by
preparative thin layer chromatography (3:1 hexane:diethyl ether)
to give the title compound 2g (44.0 mg, 67%) as a colorless oil: Rf (3:1
hexane:diethyl ether) 0.29; nmax 3375, 3055, 2971, 2936, 2866,
4.19. Lithium aluminum hydride reduction of 1e in THF with
deuterium oxide quenching: (1R*,2R*,S*)-2-methyl-3-(2-2H-2-
phenylethenylidene)cyclohexan(2H)ol
A solution of 1e (25.7 mg, 0.12 mmol) in THF (2.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equip-
ped with magnetic stirring bar, serum septum and argon inlet.
Stirring was begun and the flask was cooled to 0 ꢀC. A solution of
1596, 755, 734, 690 cmꢁ1
; dH (CDCl3) 7.50e7.43 (m, 2H), 7.39e7.30
(m, 3H), 2.39e2.20 (m, 2H), 2.09 (t, J¼2.0 Hz, 3H), 1.87e1.69 (m,
4H), (1.57 br s, 1H), 1.38 (s, 3H); dC (CDCl3) 145.1, 131.6, 128.5, 128.2,
124.0, 117.7, 93.0, 89.9, 70.8, 39.3, 30.8, 27.4, 19.8, 16.1; tR 19.4 min,
m/z (EI) 226 (16, Mþ), 211 (100). The total ion chromatogram in-
dicated a propensity for the product to thermally dehydrate: tR
18.1 min, m/z (EI) 208 (100, Mþ), 193 (23), 178 (52), 165 (19), 115
(16).
lithium aluminum hydride (270 mL, 0.27 mmol, 1.0 M in THF) was
added dropwise. Once the addition was complete, the cold bath
was removed and the stirred at room temperature for 2 h. After
recooling to 0 ꢀC the reaction was diluted with diethyl ether
ꢀ
(20 mL), then deuterium oxide (0.5 mL) added dropwise. A few 4 A
molecular sieves were added and the resulting mixture stirred at
room temperature for 10 min. Vacuum filtration was followed by
washing the sieves and precipitate with dry diethyl ether. The fil-
trate and washings were combined and concentrated by rotary
evaporation to give the crude title compound (30.4 mg) with
regioselective 93% incorporation of deuterium at position 2 of the
ethenylidene substituent and 21% incorporation of deuterium at
the hydroxy substituent as determined by 1H NMR and GC/MSD
analyses: dH (CDCl3) 7.43e7.26 (m, 4H), 7.26e7.16 (m, 1H), 3.42 (td,
J¼4.1, 9.6 Hz, 1H), 2.42 (dtd, J¼1.6, 3.7, 13.3 Hz, 1H), 2.21e1.81 (m,
3H), 1.80e1.40 (m, 3H), 1.18 (d J¼6.7 Hz, 3H); tR 20.1 min, m/z (EI)
216 (45, Mþ), 215 (100), 182 (58), 168 (27), 156 (37), 144 (87), 130
(68), 129 (69), 116 (41), 92 (48).
4.22. (1R*,2R*,Sa*)-1,2-Dimethyl-3-(phenylethenylidene)cy-
clohexanol [(1R*,2R*,S*)-3g]
A solution of 2g (44.0 mg, 0.19 mmol) in THF (3.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equip-
ped with magnetic stirring bar, serum septum and argon inlet.
Stirring was begun and the solution cooled to 0 ꢀC. A solution of
sodium bis(2-methoxyethoxy)aluminum hydride (125
mL,
0.43 mmol, 3.5 M in toluene) was added dropwise. Once the ad-
dition was complete, the cold bath was removed and the reaction
left to stir at room temperature for 2 h. After recooling to 0 ꢀC the
reaction was diluted with diethyl ether (20 mL), then aqueous
saturated ammonium chloride (10 drops) added. The cold bath was
removed and the flask warmed to room temperature. Filtration
through anhydrous MgSO4 was followed by concentration by rotary
evaporation to give a colorless oil (51.8 mg). Preparative thin layer
chromatography (2:1 hexane:diethyl ether) gave the title compound
(1R*,2R*,S*)-3g (32.5 mg, 75%) as a colorless oil: Rf (2:1 hex-
ane:diethyl ether) 0.36; nmax 3308, 2967, 2929, 2862, 1948, 1598,
4.20. Sodium bis(2-methoxyethoxy)aluminum hydride re-
duction of 1f in THF: 3-(phenylethenylidene)cyclohexanol (3f)
A solution of 1f (56.2 mg, 0.29 mmol) in THF (3.0 mL) was added
to an argon-purged, oven-dried 25 mL round bottom flask equip-
ped with magnetic stirring bar, serum septum and argon inlet.
Stirring was begun and the solution cooled to 0 ꢀC. A solution of
sodium bis(2-methoxyethoxy)aluminum hydride (180
mL,
1119, 981, 690 cmꢁ1
; dH (CDCl3) 7.37e7.30 (m, 5H), 7.25e7.16 (m,
0.63 mmol, 3.5 M in toluene) was added dropwise. Once the ad-
dition was complete, the cold bath was removed and the reaction
was stirred at room temperature for 2 h. After recooling to 0 ꢀC the
reaction was diluted with diethyl ether (20 mL), then aqueous
saturated ammonium chloride (10 drops) added. The cold bath was
removed and the flask warmed to room temperature. Filtration
through anhydrous MgSO4 was followed by concentration by rotary
evaporation to give a clear oil (59.5 mg), which was purified by
preparative thin layer chromatography (2:1 hexane:diethyl ether)
to give a mixture of diasteromers of the title compound 3f (32.0 mg,
56%) as a colorless oil: Rf (2:1 hexane:diethyl ether) 0.31; nmax 3346,
1H), 6.19 (td, J¼1.0, 3.2 Hz, 1H), 2.46e2.35 (m, 1H), 2.32e2.21 (m,
1H), 2.21e2.08 (m, 1H), 1.92e1.80 (m, 1H) 1.75e1.54 (m, 3H), 1,27 (s,
3H), 1.12 (d, J¼6.9 Hz, 3H); dC (CDCl3) 201.1, 136.1, 128.8, 126.7, 126.7,
109.6, 95.2, 73.7, 45.9, 40.5, 30.4, 24.4, 22.2, 13.0; tR 18.6 min, m/z
(EI) 228 (22, Mþ), 210 (6), 195 (15), 185 (8), 170 (25), 155 (51), 143
(100), 129 (46), 115 (35), 91 (38) 71 (23); HRMS (MALDI): MHþ-H2O,
211.1480. [C16H19]
þ requires 211.1487.
Acknowledgements
3030, 2934, 2890, 2857, 1954, 1598, 1051, 745, 693 cmꢁ1
; dH (CDCl3)
This work was supported by the Creighton University Presi-
7.38e7.27 (m, 4H), 7.26e7.17 (m, 1H), 6.13e6.05 (m, 1H), 4.00e3.88
(m, 1H), 2.63 (t of m, J¼12.9 Hz, 1H), 2.38e2.06 (m, 3H), 2.06e1.87
(m, 2H), 1.72 (s, 1H), 1.71e1.45 (m, 2H); major isomer dC (CDCl3)
201.4, 135.7, 128.8, 126.9, 126.8, 103.4, 93.3, 70.2, 40.1, 34.6, 30.7,
24.4; tR 19.8 min, m/z (EI) 200 (100, Mþ), 181 (23),167 (48),154 (34),
141 (64), 129 (82), 115 (36), 102, (18), 91, (37), 77 (15); HRMS
(MALDI): MHþ, 201.1297. [C14H17O]þ requires 201.1280.
dent’s Faculty Research Fund, grant number 240039-204000.
Supplementary data
Supplementary data related to this article can be found in the
online version, at http://dx.doi.org/10.1016/j.tet.2016.07.058. Crys-
tallographic data for the structure in this paper have been de-
posited with the Cambridge Crystallographic Data Centre as
supplementary publication no. CCDC 1476506. Copies of the data
can be obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK (fax: þ44-(0)1223-336033 or e-mail:
despoit@ccdc.cam.ac.uk.
4.21. 1,2-Dimethyl-3-(phenylethynyl)-2-cyclohexenol (2g)
THF (2.0 mL) was added to an argon-purged, oven-dried 25 mL
round bottom flask equipped with magnetic stirring bar, serum
septum and argon inlet. Stirring was begun as the flask was cooled
Please cite this article in press as: Gubbels, M. A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.058

12
M.A. Gubbels et al. / Tetrahedron xxx (2016) 1e12
Org. Chem. 1990, 55, 964e975; (d) Hayashi, T.; Tokunaga, N.; Inoue, K. Org. Lett.
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Please cite this article in press as: Gubbels, M. A.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.058