Cooperative titanocene and phosphine catalysis: Accelerated C-X activation for the generation of reactive organometallics

Article abstract of DOI:10.1021/jo301726v

The study presented herein describes a reductive transmetalation approach toward the generation of Grignard and organozinc reagents mediated by a titanocene catalyst. This method enables the metalation of functionalized substrates without loss of functional group compatibility. Allyl zinc reagents and allyl, vinyl, and alkyl Grignard reagents were generated in situ and used in the addition to carbonyl substrates to provide the corresponding carbinols in yields up to 99%. It was discovered that phosphine ligands effectively accelerate the reductive transmetalation event to enable the metalation of C-X bonds at temperatures as low as -40 °C. Performing the reactions in the presence of chiral diamines and amino alcohols led to the enantioselective allylation of aldehydes.

Full text of DOI:10.1021/jo301726v

Article
pubs.acs.org/joc
Cooperative Titanocene and Phosphine Catalysis: Accelerated C−X
Activation for the Generation of Reactive Organometallics
Lauren M. Fleury, Andrew D. Kosal, James T. Masters, and Brandon L. Ashfeld*
Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States
S
* Supporting Information
ABSTRACT: The study presented herein describes a reductive transmetalation approach toward the generation of Grignard and
organozinc reagents mediated by a titanocene catalyst. This method enables the metalation of functionalized substrates without
loss of functional group compatibility. Allyl zinc reagents and allyl, vinyl, and alkyl Grignard reagents were generated in situ and
used in the addition to carbonyl substrates to provide the corresponding carbinols in yields up to 99%. It was discovered that
phosphine ligands effectively accelerate the reductive transmetalation event to enable the metalation of C−X bonds at
temperatures as low as −40 °C. Performing the reactions in the presence of chiral diamines and amino alcohols led to the
enantioselective allylation of aldehydes.
stable catalyst. To achieve this objective, we hypothesized that
commercially available Cp2TiCl2 would enable the insertion of
unactivated Zn dust or magnesium turnings from readily
available alkyl halides via a reductive transmetalation event.21
Herein, we present the successful implementation of this
substrate activation approach, for the generation of organozinc
and organomagnesium reagents.
INTRODUCTION
■
Organozinc and organomagnesium intermediates have become
increasingly essential to the development of new synthetic
methods and in the assembly of biologically active natural
products.1 Although generally useful for constructing a diverse
array of carbon−carbon and carbon-heteroatom bonds, these
reagents have become fixtures in the transition metal-catalyzed
cross-couplings.2 As a result, establishing new methods to
prepare these synthetically versatile compounds is paramount
to the construction of structurally complex molecular
architectures.3 Pioneered over a century ago, the oxidative
insertion of Zn0 or Mg0 into C−X bonds is still the most direct
way to generate these organometallics4 despite the challenges
associated with their use.5,6 Therefore, recent studies have
focused on the clean and mild activation of these readily
available metals to generate the corresponding organometallics
without resorting to less attractive conventional activating
agents such as I2,7 TMSCl/Br(CH2)2Br,8 or the expensive and
highly reactive Rieke metals.5b,9 Of these, the accelerating effect
of LiCl on metal C−X insertion, discovered by Knochel and co-
workers,8,10 is one of the most widely used methods for the
generation of organozinc and Grignard reagents due to its
operational simplicity.11 Alternatively, CuI,12 PdII,13 NiII,14
In recent years, a number of prominent research groups have
studied the catalytic behavior of titanocene catalysts22 to enable
some truly remarkable C−C bond constructions.23 Ding,21b
Roy,24 and Oltra/Cuerva,25 independently showed that the
slow addition of allyl bromide to stoichiometric Cp2TiCl (2.5
equiv) and benzaldehyde afforded the corresponding homo-
allylic alcohols in good yields (eq 1).26 A catalytic variant
employing Mn(0) as the stoichiometric reductant was later
discovered to facilitate the allylation event.27 Although the
allylation of aldehydes proceeded smoothly under these
conditions, the addition to ketones and esters proved less
effective.26l Reports from Umani-Ronchi,28 Robles and Oltra,29
Little,21h and Shimizu30 highlight the use of Cp2TiCl2 (cat.)/
Mn(0) in the addition of α-halo carbonyl derivatives to
aldehydes. Ding has proposed that the corresponding
titanocene-catalyzed Reformatsky reaction with Zn(0) dust
proceeds through a zinc enolate in the C−C bond-forming
event.31 To complement these studies, we discovered that the
combination of Cp2TiCl2 (1 mol %) and phosphine (5 mol %)
promoted the formation and subsequent carbonyl addition of
MnII,15 InIII,16 FeIII,17 AlIII and CoII19 complexes can facilitate
18
organozinc formation while the combination of FeCl2 (5 mol
%), MgBr2 (5 mol %), and EtBr (10 mol %) will catalyze the
formation of aryl Grignard reagents derived from 2-
chloropyridines.20 In contrast, we sought a universal method
for the formation of both organozinc and organomagnesium
reagents under ambient conditions using an inexpensive, shelf-
Received: August 20, 2012
© XXXX American Chemical Society
A
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The Journal of Organic Chemistry
Article
a
Table 1. Temperature and Phosphine Effects
b
entry
additive
temperature
yield (%)
1
−
−
−
−
−
rt
0 °C
98
95
91
2
3
−20 °C
−40 °C
−78 °C
−40 °C
−40 °C
−40 °C
−40 °C
−40 °C
−40 °C
−40 °C
−78 °C
c
4
NR
c
5
NR
6
5 mol % PPh3
5 mol % PCy3
5 mol % dppe
5 mol % dppp
5 mol % dppb
5 mol % dppf
5 mol % ( )-BINAP
1 equiv PCy3
96
95
7
organozinc and Grignard reagents at temperatures as low as
−40 °C and in as little as 5 min (eq 2).21c,d
8
>99
>99
50
9
10
11
12
13
RESULTS AND DISCUSSION
■
99
The allylation of carbonyl derivatives is of fundamental
importance to the field of organic synthesis, as it constitutes
one of the principal methods for constructing the ubiquitous β-
hydroxy carbonyl motif.32 Thus, we initially evaluated our
hypothesis that Cp2TiCl2 will catalyze the activation of C−X
bonds for Zn or Mg insertion, in the generation of allylzinc and
allyl Grignard reagents from their corresponding allyl
halides.21d The metalation of allyl bromide (2a) in the presence
of enone 1a, zinc dust, and Cp2TiCl2 (1 mol %) afforded
alcohol 3a in 79% yield at −20 °C and 99% in a mere 5 min at
room temperature (eq 3). Interestingly, enone 1a was
98
10
a
Reactions conducted in THF using 0.4 mmol of benzaldehyde 4a, 1.0
mmol of allyl bromide 2a, 1 mol % Cp2TiCl2, 1.0 mmol zinc dust and
the phosphine indicated (see Supporting Information for details).
b
c
Isolated yields. Reaction was run for ≥48 h.
( )-BINAP) similarly increased the yield of 5a at low
temperatures (entries 7−12). However, at −78 °C the reaction
proved inefficient even in the presence of a stoichiometric
amount of phosphine (entry 13). Additionally, the enhanced
metalation efficiency was observed irrespective of the
phosphine cone angle as illustrated by the excellent yields of
5a obtained with dppe (125°) and PCy3 (170°). These results
would indicate that Cp2TiCl2 can serve as a catalyst for the
formation of organozinc intermediates in the absence of an
electrophile at low temperatures.
To compare phosphines of disparate size and basicity, we
examined PPh3 and nBu3P at varying concentrations (Table 2).
Although, PPh3 provided excellent yields of alcohol 5a in 2−50
recovered quantitatively in the absence of Cp2TiCl2 at −20
°C. Although Cp2TiCl2 is clearly playing a role in the formation
of homoallylic alcohol 3a, we were uncertain as to the nature of
the nucleophilic allyl reagent involved in the C−C bond-
forming event. Based on the sluggish reactivity of (η3-
allyl)TiCp2Cl with ketones,25a,33 we speculated that the rapid
allylation of 1a indicated involvement of an allylzinc species.34
n
mol % (entries 1−5), the addition of 2 or 5 mol % of Bu3P
failed to facilitate metalation at low temperatures (entries 6 and
n
7). The addition of 10, 20, and 50 mol % Bu3P provided
Table 2. Comparison of PPh3 and PnBu3 at Various
a
It is noteworthy that no Cp TiCl-catalyzed Wurtz, McMurry, or
̈
Loadings
2
pinacol coupling products were detected.35 Encouraged by this
preliminary result, we sought to gain further insight into the
role of titanocene in the metalation event.
Effect of Phosphine Additives. We initially chose to
further probe this temperature dependence on the efficiency of
allylzinc formation from allyl bromide (2a) using benzaldehyde
(4a) as the terminal electrophile (Table 1). Although excellent
yields of the resulting homoallylic alcohol 5a were obtained in
5−10 min at temperatures as low as −20 °C in the allylation of
benzaldehyde (4a) with Cp2TiCl2 (1 mol %) and Zn(0) dust,
performing the reaction at lower temperatures resulted in a
significant decrease in yield (entries 1−5). Whereas allylzinc
reagents are known to react readily with aldehydes at
temperatures as low as −78 °C, the titanocene-catalyzed
metalation of 2a failed to occur at −40 °C and lower, leading to
a quantitative recovery of aldehyde 4a (entries 4 and 5). We
discovered that upon addition of 5 mol % PPh3, the rate of
metalation increased to provide alcohol 5a in 96% yield at −40
°C (entry 6). The addition of trialkyl phosphines and
bisphosphines (PCy3, dppp, dppe, dppb, dppf, and
b
entry
additive
yield (%)
1
2 mol % PPh3
5 mol % PPh3
10 mol % PPh3
20 mol % PPh3
50 mol % PPh3
2 mol % PnBu3
5 mol % PnBu3
10 mol % PnBu3
20 mol % PnBu3
50 mol % PnBu3
91
2
96
3
96
4
93
5
>99
trace
trace
29
6
7
8
9
42
10
33
a
Reactions conducted in THF using 0.4 mmol of benzaldehyde 4a, 1.0
mmol of allyl bromide 2a, 1 mol % Cp2TiCl2, 1.0 mmol zinc dust and
the phosphine indicated (see Supporting Information for details).
b
Isolated yields.
B
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alcohol 5a, albeit in low yield (entries 8−10). In each case, the
starting material could be recovered with excellent mass
recovery. Examination of the titanocene-catalyzed metalation
with Mg(0) turnings likewise provided alcohol 5a in excellent
yields at temperatures as low as −40 °C. Recent work from our
group on the role of phosphines in zinc acetylide additions to
aldehydes corroborate these findings, and indicate that
phosphine is likely involved in the metalation event and
present in the transition state leading to the new C−C
bond.21a,c,36 Although the exact role of phosphine is unclear at
this time, this modification appears quite general when
performing the metalation of allyl halides at low temperatures.
While certainly playing a role in the formation of alcohol 5a
at lower temperatures, it was unclear whether the added
phosphine was simply affecting the efficiency of allylzinc
formation, involved in the C−C bond-forming event, or both.
Speculating that if phosphine were involved in the transition
state leading to homoallylic alcohol formation,36,37 examining
the diastereoselectivity in the crotylation of aldehydes would
shed light on the nature of this unusual phosphine effect. Thus,
we targeted homoallylic alcohols 5b and 5c resulting from the
crotylation of cyclohexyl carboxaldehdye 4b with crotyl
bromide (2b) and cinnamyl bromide (2c) respectively (Table
3).38 The addition of 2b to aldehyde 4b using Cp2TiCl2 (1 mol
Although the added phosphine appears to affect the stereo-
chemical outcome, the observed increase in diastereoselectivity
may be simply a kinetic effect resulting from a broader
temperature profile available for the metalation event. We are
continuing to examine the role of phosphines in these and
similar reactions to more fully understand this enhancement.
Although the addition of phosphine enhanced the diaster-
eoselection in the crotylation of aldehydes under the titanocene
reductive metalation conditions, the stereoselective allylation of
α-chiral aldehydes proved more challenging. Treatment of
enantioenriched aldehyde 4c with allyl bromide 2a under our
standard conditions yielded homoallylic alcohol 5d in good
yield as a 1:1 mixture of diastereomers (eq 4).39 Likewise, when
a
Table 3. Diastereoselective Crotylation and Cinnamylation
the allylation of 4c was performed in the presence of PPh3 (5
mol %) at −40 °C, no appreciable 1,2-stereoinduction was
observed in the formation of alcohol 5d. Allylation of aldehyde
4d bearing an α-phenyl substituent at 25 °C in the absence of
phosphine provided alcohol 5e in 93% yield and 2.7:1 ratio
favoring the anti stereoisomer. A modest increase in the
diastereoselectivity to 4.5:1 was observed in the presence of
PPh3 (5 mol %) at −40 °C (eq 5). Although dependent on the
size of the α-substituent, 1,2-stereoinduction is observed in the
allylation of α-chiral aldehydes when paired with an in situ
generated allylmetal species.
Enantioselective Allylations. The enantioselective addi-
tion of highly reactive organometallic reagents is a major
challenge in organic synthesis due to their propensity for rapid,
uncontrolled carbonyl additions even at low temperatures.40 As
a result, a stoichiometric amount of chiral ligand is often
required for useful levels of selectivity.41 Our observation that
phosphine additives facilitated low temperature metalation led
us to hypothesize that an enantioselective allylation with a
highly reactive allylmetal reagent could be performed with a
catalytic amount of chiral agent. By controlling the temperature
and rate of metalation with the addition of phosphine, the
effective concentration of chiral ligand-bound reagent is
maximized while minimizing the amount of unligated organo-
metallic intermediate. Using a series of well-established chiral
diols, diamines and β-amino alcohols L1−L9 in asymmetric
organozinc additions to aldehydes, we began evaluating our
hypothesis by examining the allylation of benzaldehyde (4a)
with allyl bromide (2a) at −40 °C in the presence of dppe (15
mol %) and chiral ligand (Table 4). Employing the salen-
derived ligand L142 and Schiff base L243 provided alcohol
(+)-5a in excellent yield and 18 and 8% ee, respectively (entries
1 and 2). Indene-derived amino alcohol L344 gave alcohol
(+)-5a in 67% ee, and chiral β-amino alcohols L445 and L546
proceeded in 12 and 67% ee, respectively (entries 3−5).47
Likewise, diamine L6 underwent allylation in 68% ee (entry
b
c
entry
2
temperature
additive
yield (%)
anti:syn
1
2
3
4
5
6
7
2b
2b
2b
2b
2c
2c
2c
rt
−
−
PPh3
dppe
−
90
83
59
51
90
88
87
4:1
5:1
−20 °C
−40 °C
−40 °C
rt
9:1
6.5:1
14:1
21:1
20:1
−40 °C
−40 °C
PPh3
dppe
a
Reactions conducted in THF using 0.4 mmol of cyclohexanecarbox-
aldehyde 4b, 1.0 mmol of appropriate bromide, 1 mol % Cp2TiCl2, 1.0
mmol zinc dust and the phosphine indicated (see Supporting
Information for details). Isolated yields. Ratios determined by 500
b
c
1
MHz H NMR.
%) and zinc dust led to an excellent yield (90%) of homoallylic
alcohol 5b in a 4:1 diastereomeric ratio favoring the anti
stereoisomer (entry1). That diastereoselectivity was nominally
increased to 5:1 when the temperature was reduced to −20 °C
(entry 2). Although, further attempts to lower the reaction
temperature to −40 °C proved futile, the addition of PPh3 (5
mol %) restored the combined reactivity of Cp2TiCl2 and zinc
dust and improved the ratio of anti-syn adducts to 9:1 (entry 3).
Employing dppe in place of PPh3 led to only a slight decrease in
diastereoselectivity (entry 4). The addition of cinnamyl
bromide 2c to aldehyde 4b at room temperature provided
homoallylic alcohol 5c in a 14:1 anti-syn ratio (entry 5).
Whereas, the addition of 5 mol % PPh3 permitted a −40 °C
reaction temperature leading to an increase in diastereoselec-
tivity favoring anti-5c in 21:1 dr (entry 6). Unlike crotyl
bromide 2b, the addition of dppe at −40 °C with 2c provided
alcohol 5c in comparable stereoselectivity to PPh3 (entry 7).
C
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a
a
Table 4. Asymmetric Allylation of Benzaldehyde
Table 5. Metallation of Allyl Halides
b
entry
X
M(0)
temperature
yield (%)
1
2
3
4
5
6
Br
Br
I
Zn
Mg
Zn
Mg
Zn
Mg
rt
99
99
rt
rt
78
I
50 °C
rt
56
Cl
Cl
NR
88
50 °C
a
Reactions conducted in THF using 0.4 mmol of enone 1a, 1.0 mmol
of appropriate halide, 1 mol % Cp2TiCl2, 1.0 mmol zinc dust or
magnesium turnings at room temperature (see Supporting Informa-
b
tion for details). Isolated yields.
3a in 88% yield using Mg(0) at 50 °C (entries 5 and 6). It
warrants mention that in comparison to the allyl halides
mentioned, the corresponding acetate, methyl carbonate, and
trifluoroacetate were unreactive.
With the appropriate halide identified, we turned our
attention toward examining the effect of C2 and C3 allyl
substitution using a series of allyl bromides with enone 1a
(Table 6). In general, excellent yields of alcohol 3 were
b
c
entry
ligand
yield
% ee
1
2
3
4
5
L1
L2
L3
L4
L5
L6
L7
L8
L9
92
97
22
99
22
28
5
18
8
67
12
67
68
85
21
8
Table 6. Titanium-catalyzed Metallation of Substituted Allyl
a
d
6
Bromides
7
8
95
97
d
9
a
Reactions conducted in THF using 0.4 mmol of benzaldehyde 4a, 1.0
b
mmol of allyl bromide 2a, 1 mol % Cp2TiCl2, 1.0 mmol zinc dust, 0.06
entry M(0)
R1
R2
R3
2
3
yield (%)
mmol dppe and deprotonated ligand as indicated (see Supporting
c
1
2
3
4
5
6
7
8
Zn
Mg
Zn
Mg
Zn
Mg
Zn
Mg
CH3
CH3
Ph
H
H
2b
2b
2c
2c
2d
2d
2e
2e
3b
3b
3c
3c
3d
3d
3e
3e
85
b
Information for details). Isolated yield after chromatographic
c
c
d
H
H
89
purification. Ratios determined by chiral HPLC. 50 mol % of ligand
c
H
H
90
used.
c
Ph
H
H
91
CH3
CH3
H
CH3
CH3
H
H
95
91
64
95
6).48 In contrast, bis-oxazoline L7 resulted in the highest level
of enantioselectivity (85% ee), but unfortunately also gave
alcohol (+)-5a in the lowest yield (entry 7).49 However,
oxazoline derivatives L8 and L9 proceeded in excellent yields
but only 21 and 8% ee, respectively (entries 8 and 9).50 It
should be noted that the addition of chiral phosphines alone
failed to provide any measurable enantioselectivity in the
allylation, and that prolonged reaction times did not lead to an
increase in yield or enantioselectivity. These results support our
hypothesis that the enantioselective addition of an allyl
organozinc reagent is attainable through a kinetically controlled
metalation event at low temperatures in the presence of
phosphine.
Formation of Allylzinc and Allylmagnesium Reagents.
We next turned our attention toward evaluating the affect the
halogen on the allyl substrate would have on the metalation
event (Table 5). Although, bromide 2a provided alcohol 3a in
excellent yield with unactivated Zn(0) dust or Mg(0) turnings
(entries 1 and 2), this was not found to be a general trend for
other allyl halides. Subjection of allyl iodide provided the
homoallylic alcohol 3a in slightly diminished yield with zinc
dust at room temperature, but the use of magnesium turnings
required slightly elevated temperatures to provide the product
in 56% yield (entries 3 and 4). In contrast, allyl chloride failed
to undergo any reaction in the presence of zinc dust, but gave
H
CH3
CH3
H
H
a
Reactions conducted in THF using 0.4 mmol of enone 1a, 1.0 mmol
of appropriate bromide, 1 mol % Cp2TiCl2, 1.0 mmol zinc dust or
magnesium turnings at room temperature (see Supporting Informa-
b
c
tion for details). Isolated yields. syn:anti = 1:1.
obtained within 5−10 min following treatment with either zinc
dust or magnesium turnings in the presence of 1 mol %
Cp2TiCl2. Crotyl and cinnamyl bromides 2b and 2c underwent
allylation in an SE2′ fashion to provide a 1:1 mixture of syn and
anti alcohols 3b and 3c respectively in 85−91% (entries 1−
4).34d,51 Likewise, prenyl bromide 2d underwent addition in
comparable fashion to yield alcohol 3d containing congruent
quaternary centers in excellent yields (entries 5 and 6).
Methallyl bromide 2e also underwent metalation and carbonyl
addition in the presence of Zn and Mg to yield the desired
alcohol 3e in good yields (entries 7 and 8). Most notably, the
allylation reaction proceeded smoothly at room temperature
without the formation of Wurtz coupling byproducts common
̈
in allyl Grignard generation.52
Application to the Reductive Transmetalation of Non-
Allyl Substrates. Although the formation of allylzinc and allyl
D
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Article
Grignard reagents proved exceptionally facile and efficient, we
discovered that the activation/metalation of less activated alkyl
bromides, and their subsequent addition to ketone 1a, proved
more difficult (Table 7). Consistent with our earlier findings
the carbonyl addition step,54 the addition of ZnCl2 and
stoichiometric Cp2TiCl failed to provide alcohol 7a. These
results support our hypothesis that although an allyltitanium
reagent is formed, a transmetalation to zinc is likely occurring
prior to allylation.55 The involvement of an allylzinc species is
further corroborated by the addition of allylzinc chloride to
enone 1a to yield alcohol 2a in reaction times comparable to
those obtained in the presence of Cp2TiCl2 (cat.) and zinc
dust.34f,56 Finally, the diastereoselectivity observed in the
allylation of 4-t-butylcyclohexanone (1b) gave a 6:1 ratio
favoring the syn alcohol 3f, which is more consistent with the
addition of allylzinc bromide (dr = 6:1)57 as compared to a 2:1
ratio of diastereomers observed with (η3-allyl)TiCpCl (eq
6).25a
a
Table 7. Metallation of Non-allyl Halides
b
entry
M(0)
R−Br
additive
7
yield (%)
1
2
3
4
5
6
7
8
Mg
Zn
nBuBr (6a)
nBuBr (6a)
dppp
dppe
dppp
dppe
dppe
dppp
dppe
dppp
7a
7a
7b
7b
7c
7d
7e
7f
41
17
65
44
39
73
24
49
Mg
Zn
PhCH2Br (6b)
PhCH2Br (6b)
Ph2CHBr (6c)
PhBr (6d)
Mg
Mg
Mg
Mg
(CH3)2CHBr (6e)
H2CCHBr (6f)
a
Reactions conducted in THF using 0.4 mmol of enone 1a, 1.0 mmol
of appropriate bromide, 1 mol % Cp2TiCl2, 1.0 mmol zinc dust or
magnesium turnings at room temperature (see Supporting Informa-
b
tion for details). Isolated yields.
that added phosphines led to improved metalation/alkylation
efficiency, we discovered that the presence of a bidentate
phosphine (5 mol %) led to overall better yields of 7. In
general, magnesium turnings performed better than zinc dust in
the reductive transmetalation, leading to better yields of
alcohols 7a and 7b, while dppp and dppe gave comparable
results under the same conditions (entries 1−4). The
metalation and addition of n-butyl bromide (6a) and benzyl
bromide (6b) proceeded in 41% and 65% yield, respectively in
the presence of magnesium turnings (entries 1 and 3), whereas
alcohols 7a and 7b were obtained in 17% and 44% using zinc
dust as the reducing metal (entries 2 and 4). Treatment of
diphenyl methyl bromide (6c) in the presence of Cp2TiCl2 (2
mol %) and Mg(0) was less effective than 6b, providing alcohol
7c in 39% yield (entry 5). However, bromobenzene (6d)
readily underwent metalation and addition to ketone 1a to give
alcohol 7d in 73% yield (entry 6). The titanocene-catalyzed
metalation protocol also proved effective in the metalation of 2-
bromopropane (6e) and vinyl bromide (6f) to provide alcohols
7e and 7f respectively, albeit in diminished yields (entries 7 and
8). Conventional methods of generating reactive organo-
metallics, Grignard reagents in particular, are well described
and would likely give higher yields in a direct comparison.
However, given the difficultly of generating some reactive alkyl
carbanions under comparably mild conditions using conven-
tional strategies,9a,b,53 these results highlight the utility of this
titanocene-catalyzed reductive transmetalation protocol.
Mechanism of the Reductive Transmetalation. To gain
insight into the mechanism of the titanocene-catalyzed
reductive transmetalation and subsequent carbonyl addition
event, we began by examining the role of titanium and zinc in
the allylation of benzaldehyde (4a). No reaction was observed
without the initial reduction of Cp2TiCl2, and full conversion to
the corresponding alcohol took substantially longer (>6 h) in
the absence of Cp2TiCl. Additionally, we observed no reaction
with stoichiometric Cp2TiCl in the absence of zinc dust after
prolonged reaction times (>24 h). Therefore, it would appear
that both titanium and zinc are participating in the allylation.
Although the in situ generated ZnCl2 may act as a Lewis acid in
Although these results provide compelling support for the
general mechanism described above,58 further evidence for two
rapid single electron reductions of allyl bromide by Cp2TiIIICl
was obtained by utilizing vinylcyclopropane 2f as the allylmetal
precursor (Scheme 1).59 If the substrate were to demonstrate
Scheme 1. Metallation of Cyclopropyl Allyl Bromide
radical character en route to metalation, we would expect to see
strain-driven ring expansion of the cyclopropane. However, if
titanium induces an inner sphere reduction of the allylbromide
followed by rapid radical−radical annihilation, the cyclopropane
ring should remain intact throughout the metalation process.60
Treatment of 2f and either enone 1a or aldehyde 4a to
Cp2TiCl2 (1 mol %) and Zn(0) cleanly provided alcohols 3g
and 5f respectively, absent any evidence of cyclopropane ring-
opening.
On the basis of these findings, it appears that the Lewis acidic
properties of in situ generated MIIX2 and titanocene are not
solely responsible for the overall efficiency of the metalation,
and that Cp2TiCl is likely participating in the formation of the
organometallic intermediate responsible for the ultimate C−C
bond formation. Taking into account the results obtained thus
far, our working hypothesis involves initial reduction of the
precatalyst Cp2TiCl2 followed by metalation of halide 2 or 6 to
yield R-TiIVCp2Cl 8 (Scheme 2).24,26h Reduction of the
titanocene complex 8 provides R-TiIIICp2 9 to facilitate
transmetalation to MIIX2 leading to the formation of reagent
10 and the regeneration of Cp2TiIIIX.61 Subsequent addition of
10 to the carbonyl derivative ketone 1 or aldehyde 4 provides
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allylation of ketone 12b to provide homoallylic alcohol 13b
in 94% yield (eq 8).65 Likewise, cycloheptanol 13c was
obtained in 53% yield after only 10 min by subjection of ketone
12c to our optimized conditions (Scheme 3).66 However, when
Scheme 2. Proposed Catalytic Cycle
Scheme 3. Synthesis of Cycloheptanols
the reaction was stirred for 1 h, bridged bicycle c-13c, resulting
from intramolecular transesterification of the methyl ester
residing syn to the newly formed homoallylic alcohol, is
produced in 93% yield.67 It bears mentioning that the
diastereoselectivity was excellent in each case, providing the
syn diastereomer in ≥99:1 even in the case of the 7-membered
carbocycle 13c.68
Our next set of experiments focused on establishing the
titanocene-catalyzed intramolecular metalation/allylation in the
construction of nitrogen heterocycles.69 Thus, treatment of
ketone 14a, bearing a sulfonamide linker between the carbonyl
and allylbromide motifs, with Cp2TiCl2 (2 mol %) and zinc
dust at room temperature provided pyrrolidine 15a with
complete selectivity for the syn diastereomer, albeit in
diminished yield (eq 9). However, extending this method to
the alkoxide 11. The nature of X (e.g., Cl−, RO−, Br−) ligated to
titanocene at various stages of the catalytic cycle remains
unclear at the present time. It bears mention that catalyst
turnover is facilitated by transmetalation from titanocene to
zinc. Although the exact role of phosphine is purely speculative
at this stage, based on our previous work21a,c,36 we postulate
that it serves to stabilize low valent titanocene intermediates in
the catalytic cycle, while increasing the reactivity of 10 through
an unusual P−MII ligation.62 This method constitutes a general
way to prepare these versatile reagents in a mild and
stoichiometric fashion.
Highly Diastereoselective Intramolecular Carbonyl
Additions. Given the preponderance of small carbocyclic
ring systems in biologically active natural products,63 we next
examined the utility of the titanocene-catalyzed metalation-
carbonyl addition protocol in the formation of 5- and 6-
membered carbocycles. To that end, treatment of allylbromide
12a with Cp2TiCl2 (2 mol %) and zinc dust provided
cyclopentanol 13a in 94% exclusively as the syn diastereomer
after a mere 10 min at room temperature (eq 7).64
the construction of 6-membered heterocycles led to sulfonyl
piperdine 15b from ketone 14b in 98% yield (eq 10). As in
each example thus far, we observed an exceptionally high level
of diastereoselectivity in the formation of 15b. These results
complement the modest stereoselectivity in intramolecular
allylation of ketones using conventional methods.64b,65a
Recently, allenes have attracted the attention of the synthetic
community due to their versatility as functional handles in a
wide assortment of transition metal-catalyzed carbocyclization
reactions.70 Expanding the intramolecular carbonyl addition
reaction to include propargyl bromides would provide the
corresponding carbinols bearing an exocyclic allene moiety.71
Thus, subjection of propargyl bromide 16a to the titanocene-
catalyzed metalation conditions that proved effective for the
intramolecular propargylation reaction, yielded allene 17a in
Interestingly, when polar aprotic solvents, such as acetonitrile
and NMP, were employed the yield of 13a was substantially
reduced to 48% and 36% respectively, and chlorinated solvents
led to little formation of the expected homoallylic alcohol.
Using Mg(0) turnings in place of zinc dust provided only
recovered ketone 12a, whereas indium metal gave the
cyclopentanol in 60% yield. Access to 6-membered carbocycles
in a similar fashion was achieved by the intramolecular
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88% yield after only 10 min at room temperature (eq 11). As
anticipated, the alkylation reaction proceeded with exclusive
tion of allylzinc reagents derived from allylbromide and prenyl
bromide proved compatible with a wide array of substitution
patterns within the carbonyl substrates (Table 8). In general,
good to excellent yields of the corresponding homoallylic
alcohols, derived from the allylation of ketones and aldehydes,
were obtained. Aryl aldehydes gave their respective alcohols in
excellent yields, regardless of whether they were electron rich
(entries 1−5), electron deficient (entries 6−10), or hetero-
aromatic (entry 11). Interestingly, the presence of a free phenol
moiety did not hinder the allylation reaction, as exemplified by
the conversion of aldehydes 4h and 4i to their respective
homoallylic alcohols 5j and 5k (entries 4 and 5). However, the
presence of the nitro group in aldehyde 4n prevented the
formation of alcohol 5p leading to complete recovery of
starting material (entry 10).24,75 The allylation of unsaturated
aldehydes proved highly regioselective, leading to exclusive 1,2-
addition without any of the conjugate addition products
observed (entries 12 and 13). Finally, aliphatic aldehydes,
characterized by cyclohexyl carboxaldehyde (4b) and n-hexanal
(4r), underwent allylation to yield homoallylic alcohols 5t and
5u in 79% and 91% yield, respectively (entries 14 and 15). The
reactivity of prenyl bromide 2d in the allylation of aldehydes
proved comparable to that observed with 2a for aryl and
aliphatic aldehydes (entries 16−18). It is important to note that
the allylzinc reagent derived from 2d underwent exclusive SE2′
carbonyl addition to yield the homoallylic alcohol containing a
vicinal quaternary center.
The corresponding homoallylic tertiary alcohols derived from
ketone electrophiles under the titanocene-catalyzed conditions
were obtained in good to excellent yields. The allylation of
acetophenone provided alcohol 3h in 89% yield (entry 19).
Both electron rich and electron poor cinnamyl derivatives 1d−
1j yielded the corresponding alcohols 3i−3o in yields as high as
97% (entries 20−26). As with the phenols 4g and 4h, the free
phenol in ketone 1g did not impede either the metalation or
subsequent carbonyl addition events (entry 23). However, the
presence of the nitro group in enone 1k again prevented
formation of the corresponding homoallylic alcohol 3p (entry
27). Most notably, the cyclopropane-substituted allylic alcohol
3q was obtained in 97% yield while leaving the cyclopropane
ring intact (entry 28).76 Unsaturated ketones 1m and 1n, and
aliphatic enones 1o−1s underwent smooth allylation to provide
homoallylic alcohols 3r−3x resulting from exclusive 1,2-
addition in excellent yields (entries 29−35). The allylation of
benzophenone (1t) proceeded in excellent yield (97%) to
provide the corresponding homoallylic tertiary alcohol 3y
without elimination, even under the Lewis acidic conditions of
the reaction (entry 36). Not surprisingly, the reaction proved
chemoselective for the more electrophilic carbonyl functionality
(entries 6 and 26). Even in an excess allyl bromide and
reducing metal, homoallylic alcohols 5l and 3o were obtained
in 90% and 81% respectively by carefully monitoring for the
consumption of aldehyde 4j and ketone 1j.
SE2′ selectivity. Lengthening the carbon tether to access the
cyclohexyl-substituted allene 17b from propargyl bromide 16b
proceeded in 77% yield. In contrast to allyl bromide 12c, the
metalation of methyl ketone 16c provided the 7-membered
allene-bearing carbocycle 17c in only 35% yield (eq 12). The
addition of ZnX2 salts, TiCl4, BF3·OEt2, or Brønsted acids to
the reactions of 16b and 16c failed to improve the yields of 17b
and 17c. In addition, the corresponding intermolecular addition
of propargyl bromides to aldehydes and ketones led to an
inseparable mixture of allenic and homopropargylic alcohol.72
The diastereoselectivity in the cyclic and acyclic cases can be
readily understood by invoking a chairlike transition state
similar to that which is generally accepted in the allylation of
carbonyl substrates (Scheme 4).73 The anti-selectivity in the
Scheme 4. Possible Transition States for Diastereoselective
Allylations
intramolecular allylations for the formation of cyclopentanols is
rationalized by examining the envelope-chair transition states
18a and 18b wherein the R group of the carbonyl resides in the
more favorable pseudoequatorial position in 18a to avoid the
transannular diaxial interactions present in 18b.64b Similarly,
the intermolecular crotylations of aldehyde 4b likely proceed
through a chairlike transition state 19 where the crotyl methyl
substituent resides pseudoequatorial, again to minimize
unfavorable 1,3-diaxial interactions, leading to the anti-
homoallylic alcohol 5b.74
Less electrophilic carbonyl derivatives also proved reactive
under the titanocene-catalyzed reductive transmetalation
conditions when in the absence of aldehydes and ketones
(Table 9). The allylation of esters 20a−d with allyl bromide
(2a) proceeded smoothly in the presence of Cp2TiCl2 (1 mol
%) and Zn(0) dust to yield the corresponding tertiary alcohols
resulting from the addition of two equivalents of allylzinc
(entries 1−4). Methyl benzoate 20a and cinnamate derivatives
20b−20d underwent bisallylation to yield the corresponding
tertiary alcohols 21a−d in 75−87% yield. Attempts to isolate
Examination of the Carbonyl Electrophile. The
titanocene-catalyzed reductive transmetalation for the forma-
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a
Table 8. Allylation of Aldehydes and Ketones
b
b
entry
R1
R2
2
yield (%)
entry
R1
R2
2
yield (%)
1
4-Me-C6H4 (4e)
4-MeO-C6H4 (4f)
4-Me2N−C6H4 (4g)
2-HO-C6H4 (4h)
3-HO-4-MeO-C6H3 (4i)
4-MeO2C−C6H4 (4j)
4-F3C−C6H4 (4k)
4−Cl-C6H4 (4l)
4-NC-C6H4 (4m)
4-O2N−C6H4 (4n)
2-furyl (4o)
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2d
2d
2d
84 (5g)
89 (5h)
91 (5i)
97 (5j)
99 (5k)
90 (5l)
90 (5m)
93 (5n)
85 (5o)
NR (5p)
88 (5q)
91 (5r)
83 (5s)
79 (5t)
91 (5u)
99 (5v)
88 (5w)
83 (5x)
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
Ph (1c)
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
-
2a
2a
2a
2a
2a
2a
2a
2a
2a
2f
89 (3h)
83 (3i)
91 (3j)
91 (3k)
97 (3l)
92 (3m)
92 (3n)
81 (3o)
NR (3p)
97 (3q)
98 (3r)
98 (3s)
76 (3t)
89 (3u)
64 (3v)
82 (3w)
98 (3x)
97 (3y)
2
trans-(c-C6H11)CHCH (1d)
trans-(4-MeO-C6H4)CHCH (1e)
trans-(4-Me2N−C6H4)CHCH (1f)
trans-(4-HO-3-MeO-C6H4)CHCH (1g)
trans-(4-F3C−C6H4)CHCH (1h)
trans-(4−Cl-C6H4)CHCH (1i)
trans-(4-MeO2C−C6H4)CHCH (1j)
trans-(4-O2N−C6H4)CHCH (1k)
trans-(c-C3H5)CHCH (1l)
Me2CCH (1m)
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
2f
trans-PhCHCH (4p)
trans-MeCHCH (4q)
c-C6H11 (4b)
-CH2CH2CH2CHCH- (1n)
-CH2CH2CH2CH2− (1o)
-CH2CH2CH2CH2CH2− (1p)
c-C6H9 (1q)
2a
2a
2a
2a
2a
2a
2a
-
-
n-C5H11 (4r)
Me
Me
Me
Ph
Ph (4a)
t-C4H9 (1r)
4-MeO-C6H4 (4f)
n-C5H11 (4r)
PhCH2CH2 (1s)
Ph (1t)
a
Reactions conducted in THF using 0.4 mmol of aldehyde or ketone, 1.0 mmol of appropriate bromide, 1 mol % Cp2TiCl2, 1.0 mmol zinc dust at
b
room temperature (see Supporting Information for details). Isolated yields.
Table 9. Allylation of Less Electrophilic Carbonyl
Derivatives
commercially available and inexpensive Cp2TiCl2 makes this
process attractive from a practical standpoint. Implementation
of this controlled reagent generation strategy affords enhanced
regio-, chemo-, and stereocontrol in the construction of
functionalized synthetic intermediates.
a
b
EXPERIMENTAL SECTION
yield
■
entry
R1
2-Me-C6H4 (20a)
Z
21
(%)
Solvents and reagents were ACS grade and used without purification
unless noted below. Tetrahydrofuran (THF) was passed through a
column of molecular sieves and stored under argon. Benzaldehyde and
p-anisaldehyde were distilled under vacuum over molecular sieves and
stored under nitrogen. Zn(0) dust was rinsed with 1 M HCl, filtered
and washed thoroughly with water, acetone and diethyl ether and
dried under vacuum. Phosphines and ligands L1, L2, L3, L4, L5, L6,
L7, L8 and L9 were obtained from commercial sources taking any
precautions for storage and handling as noted by manufacturer.
1
2
3
OMe
OEt
OEt
21a
21b
21c
87
87
75
trans-(4-MeO-C6H4)CHCH (20b)
trans-(4-Me2N−C6H4)CHCH
(20c)
4
trans-(4−Cl-C6H4)CHCH (20d)
Me (20e)
OEt
21d
21e
83
c
5
NHPh
NR
a
Reactions conducted in THF using 0.4 mmol of ester or amide 20,
1.0 mmol of appropriate bromide, 1 mol % mmol Cp2TiCl2, 1.0 mmol
zinc dust or magnesium turnings at room temperature (see Supporting
Substrates 1d77, 1e78, 1f79, 1g80, 1h81, 1i82, 1j83, 1k82, 1l84, 4c85, 4d86a
,
20b87, 20c81 and 20d81 were synthesized following literature
procedures. 1H nuclear magnetic resonance (NMR) spectra were
obtained at either 300, 400, 500, or 600 MHz. 13C NMR were
obtained at 100, 125, or 150 MHz. Chemical shifts are reported in
parts per million (ppm, δ), and referenced from the solvent or
tetramethylsilane (TMS). Flash column chromatography was
performed according to Still’s procedure.
b
Information for details). Isolated yield after chromatographic
c
purification. Reaction was run for ≥48 h.
the incipient ketones by adding one equivalent of allylzinc
provided only the tertiary alcohol and unreacted ester (∼1:1).
In contrast, amides proved unreactive to the allylation
conditions, as illustrated by the reaction with phenyl acetimide
20e (entry 5).
Representative Allylation Procedure. A clean, oven-dried 4
dram screw cap vial was charged with Cp2TiCl2 (1 mg, 4 μmol) and
zinc dust (66 mg, 1 mmol) under an atmosphere of N2 at room
temperature. THF (2.0 mL) was added via syringe and the reaction
stirred for 10 min or until the solution had turned from red to green. A
solution of aldehyde (0.4 mmol) and appropriate allyl bromide (1.0
mmol) in THF (2.0 mL) was then added via syringe. The reaction was
stirred for 20 min or until all starting material was consumed as
monitored by TLC (p-anisaldehyde). The mixture was diluted with
saturated aqueous NH4Cl (10 mL) and Et2O (10 mL) and the layers
were separated. The aqueous layer was extracted with Et2O (3 × 10
mL), and the combined organic fractions were washed with saturated
aqueous NaCl (30 mL), dried (MgSO4) and concentrated under
reduced pressure. The crude residue was purified by flash
CONCLUSION
■
In summary, this study describes a complementary approach
toward the generation of highly reactive organometallic
reagents under mild conditions through the titanocene-
catalyzed reductive transmetalation of alkyl halides. In contrast
to metal activation employed by conventional methods of
organometallic reagent generation, this strategy utilizes
titanocene as a catalytic substrate activator to facilitate the
overall metal insertion into C−X bonds. The use of
H
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chromatography, eluting with hexanes/EtOAc to give the homoallylic
alcohol.
1-Phenyl-3-buten-1-ol (5a). Purified by flash chromatography
eluting with hexanes/EtOAc (5:1) to provide 58 mg (98%) as a clear,
colorless oil. Spectral data (1H NMR and 13C NMR) consistent with
literature values.88
1-Cyclohexyl-2-methyl-3-buten-1-ol (5b). Purified by flash
chromatography eluting with hexanes/EtOAc (10:1) to provide 45
mg (90%) of a clear, colorless oil and a 4:1 mixture of anti/syn
diastereomers. Spectral data (1H and 13C NMR) consistent with
literature values.73,89
(br s, 1 H), 1.36 (d, J = 4.5 Hz, 3 H), 1.07 (d, J = 6.9 Hz, 3 H); 13C
NMR (125 MHz, CDCl3) δ (Diastereomer A) 140.8, 138.0, 136.2,
129.5, 129.0, 128.3, 127.3, 117.9, 75.3, 50.3, 27.2, 16.3; (Diastereomer
B) 140.8, 138.0, 135.5, 129.5, 128.9, 128.3, 127.3, 117.5, 75.3, 49.4,
26.2, 15.3; IR (neat) 3464, 3451, 3430, 3402, 3090, 3026, 2975, 2933,
1491, 1445, 1386 cm−1; HRMS (FAB-TOF) m/z = 185.1328 [C14H17
(M−OH) requires 185.1330].
(E)-1,4-Diphenyl-3-methyl-1,5-hexadien-3-ol (3c). Purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to provide
107 mg (90%) of a clear, colorless oil and a 1:1.6 ratio of
1
diastereomers as determined by H NMR. Differentiating peaks: δ
6.56 (Diastereomer A, integration 0.66) and 6.51 (Diastereomer B,
1-Cyclohexyl-2-phenyl-3-buten-1-ol (5c). Purified by flash
chromatography eluting with hexanes/EtOAc (4:1) to provide 63
mg (90%) of a clear, colorless oil and a 14:1 mixture of anti/syn
diastereomers. Spectral data (1H NMR and 13C NMR) consistent with
literature values.73,86
2-Methyl-3-hydroxy-1-tertbutyldimethylsiloxy-5-hexene
(5d). Purified by flash chromatography eluting with hexanes/EtOAc
(4:1) to provide 61 mg (83%) of a clear, colorless oil and a 1:1 mixture
of anti/syn diastereomers. Spectral data (1H NMR and 13C NMR)
consistent with literature values.39a,90
2-Phenyl-3-hydroxy-5-hexene (5e). Purified by flash chroma-
tography eluting with hexanes/EtOAc (4:1) to provide 57 mg (93%)
of a clear, colorless oil and a 2.7:1 mixture of syn-anti diastereomers.
Spectral data (1H NMR and 13C NMR) consistent with literature
values.91
integration 1.06) gives dr = 1.61; δ 1.76 (Diastereomer A, integration
1
0.64) and 2.00 (Diastereomer B, integration 1.04) gives dr = 1.62. H
NMR (300 MHz, CDCl3) δ (Diastereomer A) 7.42−7.21 (comp, 10
H), 6.56 (d, J = 7.5 Hz, 1 H), 6.36−6.32 (comp, 1 H), 5.29−5.12
(comp, 2 H), 3.53−3.45 (comp, 1 H), 1.76 (br s, 1 H), 1.37 (s, 3 H);
(Diastereomer B) 7.42−7.21 (comp, 10 H), 6.51 (d, J = 7.8 Hz, 1 H),
6.36−6.32 (comp, 1 H), 5.29 − 5.12 (comp, 2 H), 3.53−3.45 (comp,
1 H), 2.00 (br s, 1 H), 1.35 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ
(Diastereomer A) 139.9, 137.4, 137.0, 135.0, 129.5, 128.3, 128.1,
127.4, 127.0, 126.9, 126.4, 118.2, 74.9, 61.7, 26.9; (Diastereomer B)
140.3, 137.1, 137.0, 134.3, 129.2, 128.6, 128.3, 127.4, 127.0, 126.9,
126.4, 118.8, 74.4, 62.2, 26.6; IR (neat) 3567, 3546, 3481, 3081, 3060,
3028, 2974, 2925, 1610, 1502, 991 cm−1; HRMS (FAB-TOF) m/z =
265.1606 [C19H21O (M+1) requires 265.1592].
(R)-1-Phenyl-3-buten-1-ol [(+)-5a]. A clean, oven-dried 4 dram
screw cap vial was charged with Cp2TiCl2 (2 mg, 8 μmol), zinc dust
(66 mg, 1 mmol) and 1,3-bis(diphenylphosphino)propane (dppp, 24.7
mg, 0.06 mmol) under an atmosphere of N2 at room temperature.
THF (2.0 mL) was added via syringe and the reaction stirred for 10
min or until the solution had turned from red to green before being
cooled to −78 °C. In a separate 2 dram vial a solution of (1S,2S)-
(−)-1,2-diphenylethylenediamine (42.5 mg, 0.2 mmol) in THF (1.0
mL) was deprotonated with nBuLi (0.38 mmol, 2.0 M in hexanes, 0.19
mL) at room temperature and then added via syringe to the reduced
titanium/zinc/dppp solution and stirred for 10 min. A solution of
benzaldehyde (42.4 mg, 0.4 mmol, 40.2 μL) and allyl bromide (121
mg, 1.0 mmol, 87 μL) in THF (1.0 mL) was then added via syringe.
The reaction was allowed to warm from −78 to −40 °C over a period
of 3 h and then kept at −40 °C for 8 h. The mixture was diluted with
saturated aqueous NH4Cl (10 mL) and Et2O (10 mL), filtered
through Celite eluting with Et2O and the layers separated. The
aqueous layer was extracted with Et2O (3 × 10 mL), and the
combined organic fractions were washed with saturated aqueous NaCl
(30 mL), dried (MgSO4) and concentrated under reduced pressure.
The crude residue was purified by flash chromatography, eluting with
hexanes/EtOAc (4:1) to give (+)-5a as a clear, colorless oil. The
enantiomeric excess was determined by HPLC (4.6 × 250 mm
ChiralCel OD, hexanes/iPrOH = 98/2, flow rate =1 mL/min) and
absolute stereochemistry determined in comparison to reported
literature values.92
(E)-1-Phenyl-3,3-dimethyl-1,5-hexadien-3-ol (3d). Purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to provide 84
1
mg (95%) of a clear, colorless oil. H NMR (300 MHz, CDCl3) δ
7.41−7.20 (comp m, 5 H), 6.60 (d, J = 15.9 Hz, 1 H), 6.42 (d, J = 15.9
Hz, 1 H), 6.03 (dd, J = 17.4, 0.6 Hz, 1 H), 5.16−5.08 (comp m, 2 H),
1.67 (br s, 1 H), 1.34 (s, 3 H), 1.11 (s, 6 H); 13C NMR (125 MHz,
CDCl3) δ 145.8, 138.1, 135.4, 129.5, 129.0, 128.2, 127.3, 115.0, 77.3,
45.3, 24.7, 23.5, 22.8; IR (neat) 3512, 3495, 3486, 3463, 3082, 3027,
2991, 2940, 1504, 1462, 1377 cm−1; HRMS (FAB-TOF) m/z =
199.1499 [C15H19 (M−OH) requires 199.1487].
(E)-1-Phenyl-3,5-dimethyl-1,5-hexadien-3-ol (3e). Purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to provide 77
mg (95%) of a clear, slightly yellow oil. Spectral data (1H NMR and
13C NMR) consistent with literature values.94
1-Phenyl-3-methyl-3-hydroxy-1-heptene (7a). Purified by
flash chromatography eluting with hexanes/EtOAc (10:1) to provide
33 mg (41%) of a clear, colorless oil. Spectral data (1H NMR and 13
C
NMR) consistent with literature values.95
1,4-Diphenyl-3-methyl-3-hydroxy-1-butene (7b). Purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to provide 62
mg (65%) of a clear, colorless oil. Spectral data (1H NMR and 13C
NMR) consistent with literature values.96
1,4,4-Triphenyl-3-methyl-3-hydroxy-1-butene (7c). Purified
by flash chromatography eluting with hexanes/EtOAc (4:1) to provide
49 mg (39%) of a clear, pale yellow oil. 1H NMR (500 MHz, CDCl3)
δ 7.55 (app dt, J = 8.0, 1.5 Hz, 2 H), 7.44 (app dt, J = 8.0, 1.5 Hz, 2
H), 7.33 − 7.15 (m, 11 H), 6.52 (d, J = 16.0 Hz, 1 H), 6.37 (d, J = 16.0
Hz, 1 H), 4.11 (s, 1 H), 1.85 (br s, 1 H), 1.41 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 141.2, 141.1, 137.4, 136.4, 130.3, 130.0, 128.8, 128.7,
128.4, 128.2, 127.6, 127.0, 126.8, 126.7, 75.7, 63.2, 28.8; IR (neat)
3442, 3059, 3026, 2975, 2927, 2894, 2868, 1598, 1493, 1449, 1371,
1116, 969 cm−1; HRMS (FAB-TOF) m/z = 337.1585 [C23H22ONa
(M+Na) requires 337.1563].
(E)-1-Phenyl-3-methyl-1,5-hexadien-3-ol (3a). Purified by flash
chromatography eluting with hexanes/EtOAc (4:1) to provide 74 mg
(99%) of a clear, colorless oil. Spectral data (1H NMR and 13C NMR)
consistent with literature values.93
(E)-1-Phenyl-3,4-dimethyl-1,5-hexadien-3-ol (3b). Purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to provide 72
mg (85%) of a clear, colorless oil and a 1.3:1 ratio of diastereomers as
1
determined by H NMR. Differentiating peaks: δ 1.81 (Diastereomer
1,3-Diphenyl-3-hydroxy-1-butene (7d). Purified by flash
chromatography eluting with hexanes/EtOAc (4:1) to provide 65
mg (73%) of a clear, colorless oil. Spectral data (1H NMR and 13C
NMR) consistent with literature values.97
A, integration 1.04) and 1.72 (Diastereomer B, integration 0.78) gives
dr = 1.33; δ 1.09 (Diastereomer A, integration 3.98) and 1.07
1
(Diastereomer B, integration 2.98) gives dr = 1.30. H NMR (300
MHz, CDCl3) δ (Diastereomer A) 7.41−7.21 (m, 5 H), 6.61 (dd, J =
16.2, 1.8 Hz, 1 H), 6.31 (dd, J = 16.2, 3.9 Hz, 1 H), 5.93−5.72 (comp,
1 H), 5.18−5.15 (comp, 1 H), 5.12 (app br t, 1 H), 2.44−2.28 (comp,
1 H), 1.81 (br s, 1 H), 1.36 (d, J = 4.5 Hz, 3 H), 1.09 (d, J = 7.2 Hz, 3
H); (Diastereomer B) 7.41−7.21 (m, 5 H), 6.61 (dd, J = 16.2, 1.8 Hz,
1 H), 6.31 (dd, J = 16.2, 3.9 Hz, 1 H), 5.93−5.72 (comp, 1 H), 5.18−
5.15 (comp, 1 H), 5.12 (app br t, 1 H), 2.44−2.28 (comp, 1 H), 1.72
1-Phenyl-3-hydroxy-3,4-dimethyl-1-pentene (7e). Purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to provide 18
1
mg (24%) of a clear, colorless oil. H NMR (500 MHz, CDCl3) δ
7.40−7.38 (m, 2 H), 7.33−7.30 (m, 2 H), 7.27−7.21 (m, 1 H), 6.60
(d, J = 16.5 Hz, 1 H), 6.30 (d, J = 16.0 Hz, 1 H), 1.81 (m, J = 2.0 Hz, 1
H), 1.50 (br s, 1 H), 1.35 (s, 3 H), 0.97 (d, J = 4.5 Hz, 3 H), 0.95 (d, J
= 4.5 Hz, 3 H); 13C NMR (125 MHz, CDCl3) δ 137.4, 136.0, 128.8,
I
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The Journal of Organic Chemistry
Article
127.9, 127.6, 126.6 75.8, 38.5, 25.7, 17.9, 17.4; IR (neat) 3431, 3062,
3027, 2963, 2929, 2873, 1705, 1494, 1448, 1369, 1176, 1204, 1068
cm−1; HRMS (ESI-TOF) m/z = 213.1282 [C13H18ONa (M+Na)
requires 213.1274].
128.3, 128.1, 127.6, 118.3, 77.4, 56.7, 12.5, 4.9, 4.8; (Diastereomer B)
142.3, 137.7, 127.1, 126.9, 126.2, 117.2, 75.0, 56.0, 11.7, 3.2, 3.1; IR
(neat) 3400, 3076, 3028, 3003, 2957, 2930, 2871, 1638, 1494, 1454,
1424, 1382, 1299, 1196, 1108, 1019, 915 cm−1; HRMS (FAB-TOF)
m/z = 211.1082 [C13H16ONa (M+Na) requires 211.1093].
1-Phenyl-3-hydroxy-3-methyl-1,4-pentadiene (7f). Purified
by flash chromatography eluting with hexanes/EtOAc (5:1) to provide
(E)-Dimethyl 2-(4-Bromobut-2-en-1-yl)-2-(2-oxo-2-
phenylethyl)malonate (12a). Dimethyl 2-(2-oxo-2-phenylethyl)-
malonate100 (400 mg, 1.6 mmol) was added to a slurry of NaH (64
mg, 1.6 mmol) in THF (6 mL, 0.25 M) at 0 °C. The mixture was
allowed to warm to room temperature by removal of the ice bath,
stirred for 15 min, then 1,4-dibromo-2-butene (1.03 g, 4.8 mmol) was
added in one portion. The resulting solution was stirred for 4 h then
diluted with saturated aqueous NH4Cl (10 mL) and DCM (10 mL)
and the layers were separated. The aqueous phase was extracted with
CH2Cl2 (3 × 15 mL), and the combined organic fractions were
washed with saturated aqueous NaCl (30 mL), dried (MgSO4) and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography, eluting with hexanes/EtOAc (3:1) to give
387 mg (1.0 mmol, 62%) of a clear, colorless oil. 1H NMR (400 MHz,
CDCl3) δ 7.98 (d, J = 8 Hz, 2 H), 7.61 (t, J = 7.6 Hz, 2 H), 7.50 (t, J =
7.2 Hz, 1 H), 5.70 (m, 2 H), 3.84 (d, J = 2 Hz, 2 H), 3.78 (s, 6 H),
3.69 (s, 2 H), 2.90 (d, J = 2 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ
196.6, 170.8, 136.4, 133.6, 131.2, 130.0, 128.7, 128.2, 55.4, 53.0, 41.5,
36.0, 32.1; IR (neat) 3059, 3029, 2953, 2844, 1737, 1687, 1597.5,
1448, 1281, 1207, 1058, 973 cm−1; HRMS (ESI-TOF); Calcd for
C17H20BrO5: 383.0489; found: 383.0461 (M+1).
(E)-Dimethyl 2-(4-Bromobut-2-en-1-yl)-2-(3-oxo-3-
phenylpropyl)malonate (12b). Following a similar allylation
procedure listed above for the synthesis of 12a, utilizing dimethyl 2-
(3-oxo-3-phenylpropyl)malonate101 (206 mg, 0.78 mmol) yielded 150
mg (48%) of a clear oil. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 8
Hz, 2 H), 7.59 (t, J = 7.2 Hz, 1 H), 7.48 (t, J = 8 Hz, 2 H), 5.76 (m, 2
H), 3.91 (d, J = 7.2 Hz, 2 H), 3.75 (s, 6 H), 3.03 (t, J = 7.6 Hz, 2 H),
2.72 (d, J = 7.2 Hz, 2 H), 2.33 (t, J = 6.8 Hz, 2 H); 13C NMR (100
MHz, CDCl3) δ 198.9, 171.4, 136.8, 133.4, 131.1, 129.6, 128.8, 128.2,
57.3, 52.8, 37.1, 33.9, 32.4, 27.7; IR (neat) 3003, 2954, 1731, 1687,
1448, 1210, 1079, 973.7, 740 cm−1; HRMS (ESI-TOF); Calcd for
C18H22BrO5: 397.0645; found: 397.0640 (M+1).
(E)-Dimethyl 2-(4-Bromobut-2-en-1-yl)-2-(4-oxopentyl)-
malonate (12c). To a cold solution of pent-4-yn-1-ol (1.48 g, 17.6
mmol, 1.64 mL) and triethylamine (2.18 g, 21.4 mmol, 3.0 mL) in
CH2Cl2 (60 mL, 0.3 M) was added methanesulfonyl chloride (2.46 g,
21.4 mmol, 1.66 mL) dropwise at 0 °C. The mixture was allowed to
warm to room temperature by removal of the cooling bath and stirred
for 4 h. The resulting solution was diluted with saturated aqueous
NH4Cl (50 mL) and CH2Cl2 (40 mL) and the layers were separated.
The aqueous layer was extracted with CH2Cl2 (3 × 30 mL), and the
combined organic fractions were dried (MgSO4) and concentrated
under reduced pressure. The crude residue was added slowly to a
solution of NaH (1.43 g, 35.7 mmol) and dimethyl malonate (5.89 g,
44.6 mmol, 5.1 mL) in THF (71 mL, 0.25 M) at room temperature
and stirred for 8 h. The resulting solution was quenched with saturated
aqueous NH4Cl (80 mL), the layers were separated and the aqueous
phase extracted with CH2Cl2 (3 × 90 mL). The combined organic
fractions were dried (MgSO4) and concentrated under reduced
pressure. Lindlar’s catalyst (195 mg, 10 mg/mmol) was added to the
crude residue and EtOAc (65 mL) was added to the flask at room
temperature. The solution was sparged with H2 then placed under 1
atm of H2 and stirred for 8 h at room temperature. The heterogeneous
mixture was filtered, washed with EtOAc (120 mL), and the filtrate
concentrated under reduced pressure. The crude material was then
diluted with DMF (5 mL) and added to a mixture of CuCl (800 mg,
8.1 mmol) and PdCl2 (238 mg, 1.34 mmol) in DMF/H2O (6.3:1, 0.2
M) that was stirred under 1 atm of O2 for 30 min. The mixture was
stirred at 45 °C for 14 h then diluted with water (100 mL), the layers
separated, and the aqueous phase extracted with CH2Cl2 (3 × 50 mL).
The combined organic fractions were washed sequentially with water
(3 × 30 mL) and saturated aqueous NaCl (100 mL), then dried
(MgSO4) and concentrated under reduced pressure. The crude residue
was purified by flash chromatography, eluting with hexanes/EtOAc
1
34 mg (49%) of a clear, colorless oil whose H NMR and 13C NMR
spectral data was consistent with literature values.98
1-(2-Propene)-4-tertbutyl-cyclohexan-1-ol (3f). Purified by
flash chromatography eluting with hexanes/EtOAc (2:1) to provide
56 mg (71%, 85% overall) of syn-3f as a pale yellow oil and 11 mg
(14%, 85% overall) of anti-3f in a 6:1 ratio of syn/anti diastereomers.
Spectral data (1H and 13C NMR) was consistent with literature
values.99
Cyclopropylallyl Bromide (2f). Was prepared according to
laboratory procedures kindly provided by Professor Peter Wipf59;
PPh3 (1.16 g, 4.4 mmol) was dissolved in dry CH2Cl2 (11 mL), cooled
on ice and treated with Br2 (0.22 mL, 4.4 mmol). The mixture was
stirred at 0 °C for 10 min, followed by imidazole (0.37 g, 5.5 mmol)
and a solution of alcohol (0.27 g, 2.75 mmol) in CH2Cl2 (11 mL). The
mixture was stirred at 0 °C for 25 min, poured into hexanes and
filtered through a pad of silica, washing the pad with CH2Cl2. The
solvent was evaporated and the crude material (∼80%) was used in the
next step. This bromide is very unstable and it decomposes in a matter
of min/h. Initial attempts at isolation for the purpose of character-
ization resulted in decomposition and ring opened products therefore
the crude mixture was immediately transferred to the subsequent
reaction flask and used without further purification.
(E)-1-Phenyl-3-methyl-4-cyclopropyl-1,5-hexadien-3-ol (3g).
Purified by flash chromatography eluting with hexanes/EtOAc (4:1) to
provide 59 mg (65%, 94% based on recovered starting material) of a
clear, colorless oil in a 1.12:1 ratio of diastereomers as determined by
1H NMR. The diastereomers have a ratio of Differentiating peaks: δ
5.91 − 5.83 (m, 1H) − Diastereomer A, integration 1.00 and 5.78−
5.71 (m, 1H) − Diastereomer B, integration 1.11 gives dr = 1.11; δ
2.19 (s, 1H) − Diastereomer A, integration 0.87 and 2.57 (s, 1H) −
Diastereomer B, integration 0.98 gives dr = 1.13. 1H NMR (500 MHz,
CDCl3) δ (Diastereomer A) 7.41−7.21 (comp, 2 H), 7.36−7.31
(comp 2H), 7.25−7.21 (comp, 1H), 6.66 (d, J = 16 Hz, 1 H), 6.44 (d,
J = 16 Hz, 1H), 5.91−5.83 (comp, 1 H), 5.19−5.11 (comp, 2H), 2.19
(s, 1H), 1.61 (t, J = 9 Hz, 1H), 1.45 (s, 3H), 0.89−0.79 (comp, 1H),
0.68−0.59 (comp, 1H), 0.51−0.44 (m, 2 H), 0.11−0.07 (m, 1H);
(Diastereomer B) 7.41−7.21 (comp, 2 H), 7.36−7.31 (comp 2H),
7.25−7.21 (comp, 1H), 6.63 (d, J = 16 Hz, 1 H), 6.41 (d, J = 16 Hz,
1H), 5.78−5.71 (comp, 1H), 5.17−5.08 (comp, 2H), 2.06 (s, 1H),
1.53 (t, J = 9 Hz, 1H), 1.41 (s, 3H), 0.89−0.79 (comp, 1H), 0.68−0.59
(comp, 1H), 0.36−0.30 (m, 2H), 0.06−0.02 (m, 1H); 13C NMR (125
MHz, CDCl3) δ (Diastereomer A) 138.0, 135.9, 128.8, 128.7, 127.7,
118.4, 75.7, 60.0, 27.0, 11.4, 6.5; (Diastereomer B) 137.6, 135.4,
128.01, 127.8, 127.12, 117.8, 75.4, 59.9, 26.4, 10.6, 6.0; IR (neat) 3435,
3078, 3026, 3002, 2975, 2931, 2872, 1494, 1449, 1373, 1333, 1271,
1071, 1021, 1001, 971, 910 cm−1; HRMS (FAB-TOF) m/z =
251.1382 [C16H20ONa (M+Na) requires 251.1406].
1-Phenyl-3-cyclopropyl-3-buten-1-ol (5f). Purified by flash
chromatography eluting with hexanes/EtOAc (4:1) to provide 53
mg (71%, 91% based on recovered starting material) of a clear,
colorless oil in 1.2:1 ratio of diastereomers as determined by 1H NMR.
Differentiating peaks: 2.33 (d, J = 4 Hz, 1H) − Diastereomer A,
integration 0.87 and 2.18 (d, J = 3 Hz, 1H) − Diastereomer B,
integration 1.04 gives dr = 1.19; δ 0.22−0.17 (m, 1 H) − Diastereomer
A, integration 1.05 and −0.11 to −0.16 (m, 1H) − Diastereomer B,
integration 1.22 gives dr = 1.16. 1H NMR (500 MHz, CDCl3) δ
(Diastereomer A) 7.35−7.25 (comp, 5H), 5.81 − 5.74 (comp, 1H),
5.22−5.06 (comp, 2 H), 4.78 (dd, J = 4.0, 6.0 Hz, 1H), 2.33 (d, J = 4
Hz, 1H), 0.74−0.64 (comp, 2 H), 0.56−0.51 (comp, 1H), 0.44 − 0.39
(comp, 1H), 0.22 − 0.16 (m, 1H); (Diastereomer B) 7.35−7.25
(comp, 5H), 5.72−5.65 (comp, 1H), 5.22−5.06 (comp, 2 H), 4.67
(dd, J = 7.0, 3.0 Hz, 1H), 2.18 (d, J = 3 Hz, 1H), 0.50−0.45 (comp,
1H), 0.31−0.25 (comp, 1H), 0.09−0.04 (m, 2H), −0.11 to −0.16 (m,
1H); 13C NMR (125 MHz, CDCl3) δ (Diastereomer A) 143.2, 137.8,
J
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The Journal of Organic Chemistry
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(1:1) to give 756 mg (20%) of dimethyl 2-(4-oxopentyl)malonate as a
clear oil. 1H NMR (400 MHz, CDCl3) δ 3.75 (s, 6 H), 3.38 (t, J = 7.6
Hz, 1 H), 2.48 (t, J = 7.2 Hz, 2 H), 2.15 (s, 3 H), 2.00−1.80 (m, 2 H),
1.60 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 208.2, 169.9, 52.8,
51.7, 43.3, 30.1, 28.4, 21.6; IR (neat) 2957, 1735, 1437, 1251, 1153
cm−1; HRMS (ESI-TOF); Calcd for C10H17O5: 217.1071; found:
217.1057 (M+1).
HRMS (ESI-TOF); Calcd for C23H33O6Si: 433.2041; found: 433.2014
(M+1).
A solution of dimethyl 2-(4-((tert-butyldimethylsilyl)oxy)but-2-yn-
1-yl)-2-(2-oxo-2-phenylethyl)malonate (200 mg, 0.46 mmol) in DCM
(14 mL, 0.03 M) was cooled to 0 °C before portionwise addition of
triphenylphosphine dibromide (215 mg, 0.50 mmol). The solution
was then allowed to warm up to room temperature slowly and stirred
for 8 h before being diluted with saturated aqueous NH4Cl (15 mL)
and separation of the layers. The aqueous layer was extracted with
DCM (3 × 20 mL) and the combined organic fractions were dried
(MgSO4) then concentrated under reduced pressure. The crude
residue was purified by flash chromatography, eluting with hexanes/
EtOAc (3:1) to give 83 mg (47%) of 16a as a clear oil. 1H NMR (400
MHz, CDCl3) δ 8.04 (d, J = 8.4 Hz, 2 H), 7.61 (t, J = 7.6 Hz, 1 H),
7.50 (t, J = 8 Hz, 2 H), 3.91 (s, 2 H), 3.83 (t, J = 2.4 Hz, 2 H), 3.77 (s,
6 H), 3.19 (t, J = 2 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 197.0,
170.2, 136.7, 133.7, 128.8, 128.3, 83.1, 79.3, 55.1, 53.3, 41.4, 24.6 14.9;
IR (neat) 3008, 2954, 2923, 1740, 1686, 1435, 1208 cm−1; HRMS
(ESI-TOF); Calcd for C17H17BrO5Na: 403.0152; found: 403.0154 (M
+Na).
Dimethyl 2-(4-Bromobut-2-yn-1-yl)-2-(3-oxo-3-
phenylpropyl)malonate (16b). Following a similar procedure listed
above for the formation of 2-(4-((tert-butyldimethylsilyl)oxy)but-2-yn-
1-yl)-2-(2-oxo-2-phenylethyl)malonate, 548 mg (1.23 mmol, 77%
yield) of dimethyl 2-(4-((tert-butyldimethylsilyl)oxy)but-2-yn-1-yl)-2-
(3-oxo-3-phenylpropyl)malonate was produced as a clear oil. 1H NMR
(400 MHz, CDCl3) δ 7.97 (d, J = 7.2 Hz, 2 H), 7.57 (t, J = 5.6 Hz, 1
H), 7.46 (t, J = 8 Hz, 2 H), 4.25 (t, J = 2 Hz, 2 H), 3.74 (s, 6 H), 3.04
(m, 2 H), 2.96 (t, J = 2 Hz, 2 H), 2.50 (m, 2 H), 0.92 (s, 9 H), 0.08 (s,
6 H); 13C NMR (100 MHz, CDCl3) δ 198.7, 170.6, 136.7, 133.2,
128.7, 128.1, 82.4, 79.1, 56.4, 52.9, 51.8, 33.8, 27.2, 25.9, 24.4, 18.3,
−5.1; IR (neat) 2955, 2930, 2858, 1738, 1690, 1448, 1254, 1207, 1079,
838 cm−1; HRMS (ESI-TOF); Calcd for C24H35O6Si: 447.2197;
found: 447.2197 (M+1).
Following a similar allylation procedure listed above for the
synthesis of 12a, utilizing dimethyl 2-(4-oxopentyl)malonate (294 mg,
1
1.36 mmol) 421 mg (89%) of 12c was prepared as a clear oil. H
NMR (400 MHz, CDCl3) δ 5.77 (m, 2 H), 3.91 (d, J = 7.2 Hz, 2 H),
3.73 (s, 6 H), 2.67 (s, J =7.2 Hz, 2 H), 2.45 (t, J = 7.2 Hz, 2 H), 2.14
(s, 3 H), 1.84 (m, 2 H), 1.47 (m, 2 H); 13C NMR (100 MHz, CDCl3)
δ 208.1, 171.5, 130.9, 129.8, 57.8, 52.8, 43.5, 35.5, 32.6, 32.2, 30.2,
18.3; IR (neat) 3000, 2954, 1734, 1436, 1205, 1090, 973 cm−1; HRMS
(ESI-TOF); Calcd for C14H22BrO5: 349.0645; found: 349.0641 (M
+1).
(E)-N-(4-Bromobut-2-en-1-yl)-4-methyl-N-(2-oxo-2-
phenylethyl)benzenesulfonamide (14a). To an oven-dried vial
was added 4-methyl-N-(2-oxo-2-phenylethyl)benzenesulfonamide102
(400 mg, 1.38 mmol), K2CO3 (580 mg, 4.14 mmol), 1,4-dibromo-2-
butene (1.18 g, 5.52 mmol), and acetonitrile (9.2 mL, 0.15 M) before
being capped and heated to reflux for 2−3 h. The soution was cooled
to room temperature before addition of water (20 mL). The aqueous
layer was extracted with DCM (3 × 30 mL), and the combined
organic fractions were dried (MgSO4) and concentrated under
reduced pressure. The crude residue was purified by flash
chromatography, eluting with hexanes/EtOAc (2:1) to give 214 mg
1
(0.506 mmol, 37%) of a yellow oil. H NMR (400 MHz, CDCl3) δ
7.91 (d, J = 3.2 Hz, 2 H), 7.77 (d, J = 3.2 Hz, 2 H), 7.61 (t, J = 6.8 Hz,
1 H), 7.48 (t, J = 8 Hz, 2 H), 7.30 (d, 2 H), 5.70 (m, 2 H), 4.74 (s, 2
H), 3.93 (d, J = 6.4 Hz, 2 H), 3.82 (d, J = 6.4 Hz, 2 H), 2.44 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 193.9, 143.7, 136.8, 134.9, 133.9,
131.4, 129.7, 129.5, 128.9, 128.0, 127.6, 52.1, 49.2, 31.1, 21.7; IR
(neat) 3062, 2974, 2867, 1702, 1598, 1340, 1158, 1066, 990 cm−1;
HRMS (ESI-TOF); Calcd for C19H21BrNO3S: 422.0420; found:
422.0407 (M+1).
(E)-N-(4-Bromobut-2-en-1-yl)-4-methyl-N-(3-oxo-3-
phenylpropyl)benzenesulfonamide (14b). Following a similar
allylation procedure for the synthesis of 14a, 220 mg (0.50 mmol,
35%) of 14b was prepared as a clear, colorless oil.103 1H NMR (400
MHz, CDCl3) δ 7.94 (d, J = 7.2 Hz, 2 H), 7.21 (d, J = 8.4 Hz, 2 H),
7.60 (t, J = 7.6 Hz, 1 H), 7.49 (t, J = 6.4 Hz, 2 H), 7.32 (d, J = 8 Hz, 2
H), 5.75 (m, 2 H), 3.86 (comp, 4 H), 3.51 (t, J = 4.4 Hz, 2 H), 3.38 (t,
J = 3.2 Hz, 2 H), 2.46 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 198.5,
143.8, 136.6, 136.5, 133.7, 130.7, 130.4, 130.1, 128.9, 128.3, 127.4,
50.8, 43.9, 39.3, 31.5 21.8; IR (neat) 3062, 2922, 1681, 1449, 1339,
1209, 1156, 1093 cm−1; HRMS (ESI-TOF); Calcd for C20H23BrNO3S:
436.0577; found: 436.0566 (M+1).
Following a similar alkylation procedure for the synthesis of 16a,
141 mg (0.36 mmol, 79%) of 16b was prepared as a clear oil. 1H NMR
(400 MHz, CDCl3) δ 7.96 (d, J = 8 Hz, 2 H), 7.57 (t, J = 7.2 Hz, 1 H),
7.47 (t, J = 7.6 Hz, 2 H), 3.84 (t, J = 2.4 Hz, 2 H), 3.74 (s, 6 H), 3.06
(t, J = 6.4 Hz, 2 H), 2.95 (t, J = 2.4 Hz, 2 H), 2.48 (t, J = 7.6 Hz, 2 H);
13C NMR (100 MHz, CDCl3) δ 198.6, 170.5, 136.6, 133.3, 128.7,
128.2, 82.0, 78.8, 56.4, 53.0, 33.8, 27.4, 24.6, 14.7; IR (neat) 3060,
3006, 2955, 2869, 2237, 1734, 1686, 1598, 1448, 1211, 1072 cm−1;
HRMS (ESI-TOF); Calcd for C18H20BrO5: 395.0489; found:
395.0478 (M+1).
Dimethyl 2-(4-Bromobut-2-yn-1-yl)-2-(4-oxopentyl)-
malonate (16c). Following a similar alkylation procedure listed
above for 2-(4-((tert-butyldimethylsilyl)oxy)but-2-yn-1-yl)-2-(2-oxo-2-
phenylethyl)malonate, dimethyl 2-(4-((tert-butyldimethylsilyl)oxy)-
but-2-yn-1-yl)-2-(4-oxopentyl)malonate (185 mg, 0.46 mmol) was
1
produced as a clear oil in 48% yield. H NMR (400 MHz, CDCl3) δ
Dimethyl 2-(4-Bromobut-2-yn-1-yl)-2-(2-oxo-2-
phenylethyl)malonate (16a). To a slurry of NaH (17 mg, 0.42
mmol) in THF (2 mL, 0.2 M) at 0 °C was added slowly dimethyl 2-
(2-oxo-2-phenylethyl)malonate (100 mg, 0.4 mmol) before warming
to room temperature. The solution was stirred for 15 min followed by
a dropwise addition of silyl protected proparygyl bromide (105 mg, 4
mmol). The mixture was stirred for 8 h before being diluted with
saturated aqueous NH4Cl (4 mL) and DCM (4 mL). The layers were
separated, and the aqueous layer was extracted with DCM (3 × 10
mL) before the organic fractions were combined, dried (MgSO4) and
concentrated under reduced pressure. The crude residue was purified
by flash chromatography, eluting with hexanes/EtOAc (2:1) to give
146 mg (92%) of dimethyl 2-(4-((tert-butyldimethylsilyl)oxy)but-2-
yn-1-yl)-2-(2-oxo-2-phenylethyl)malonate as a clear oil. 1H NMR (400
MHz, CDCl3) δ 8.00 (d, J = 6.4 Hz, 2 H), 7.58 (t, J = 6 Hz, 1 H), 7.49
(t, J = 6.4 Hz, 2 H), 4.22 (t, J = 2 Hz, 2 H), 3.91 (s, 2 H), 3.76 (s, 6
H), 3.16 (t, J = 2 Hz, 2 H), 0.86 (s, 9 H), 0.05 (s, 6 H); 13C NMR
(100 MHz, CDCl3) δ 196.8, 169.9, 136.4, 133.6, 128.7, 128.2, 82.4,
79.8, 77.4, 77.1, 76.8, 54.8, 53.2, 51.8, 41.2, 25.8, 23.8, 18.4, −4.8; IR
(neat) 2955, 2931, 2858, 1743, 1688, 1598, 1436, 1207, 1079 cm−1;
4.24 (t, J = 2 Hz, 2 H), 3.72 (s, J = 6 H), 2.86 (t, J = 2 Hz, 2 H), 2.44
(t, J = 7.6 Hz, 2 H), 2.12 (s, 3 H), 1.99 (m, 2 H), 1.45 (m, 2 H), 0.88
(s, 9 H), 0.08 (s, 6 H); 13C NMR (100 MHz, CDCl3) δ 207.9, 170.6,
81.9, 79.3, 56.9, 52.8, 51.8, 43.5, 31.6, 29.9, 25.8, 23.2, 18.3, 18.3, −4.9;
IR (neat) 2955, 2931, 2857, 1743, 1689, 1599, 1436, 1207, 1091 cm−1;
HRMS (ESI-TOF); Calcd for C20H34O6SiNa: 421.2017; found:
421.2012 (M+Na).
Following a similar allylation procedure for the synthesis of 16a,
1
41.3 mg (0.119 mmol, 35%) of 16c was prepared as a clear oil; H
NMR (400 MHz, CDCl3) δ 3.87 (t, J = 2.4 Hz, 2 H), 3.75 (s, 6 H),
2.90 (t, J = 2.4 Hz, 2 H), 2.48 (t, J = 7.2 Hz, 2 H), 2.15 (s, 3 H), 2.00
(m, 2 H), 1.47 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 208.1,
170.6, 82.3, 78.5, 57.1, 53.1, 43.6, 31.8, 30.1, 23.5, 18.4, 15.0; IR (neat)
2955, 2373, 2345, 1736, 1719, 1439, 1205 cm−1; HRMS (ESI-TOF);
Calcd for C14H20BrO5: 347.0489; found: 347.0484 (M+1).
Representative General Procedure for the Intramolecular
Allylation of Ketones. A clean, oven-dried 4 dram screw cap vial was
charged with Cp2TiCl2 (1.2 mg, 5 μmol, 5 mol %) and zinc dust (16.3
mg, 0.25 mmol, 2.5 equiv) under an atmosphere of N2 at room
temperature. THF (0.9 mL) was added via syringe and the slurry
K
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stirred for 10 min or until the solution had turned from red to green. A
solution of ketone (0.1 mmol, 1 equiv) in THF (0.2 mL) was then
added via syringe dropwise. The reaction was stirred for 20 min or
until all starting material was consumed as monitored by TLC (p-
anisaldehyde or KMnO4). The mixture was diluted with saturated
aqueous NH4Cl (2 mL) and DCM (2 mL) and the layers were
separated. The aqueous layer was extracted with DCM (3 × 4 mL),
and the combined organic fractions were washed with saturated
aqueous NaCl (15 mL), dried (MgSO4) and concentrated under
reduced pressure. The crude residue was purified by flash
chromatography, eluting with hexanes/EtOAc to give the homoallylic
alcohol.
Dimethyl-3-hydroxy-3-phenyl-4-vinylcyclopentane-1,1-di-
carboxylate (13a). Purified by flash chromatography eluting with
hexanes/EtOAc (3:1) to provide 28.6 mg (94%) of a white solid (mp
96−97 °C). 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 8.8 Hz, 2 H),
7.38 (t, J = 7.6 Hz, 2 H), 7.29 (t, J = 7.4 Hz, 1 H), 5.67 (m, 1 H), 5.11
(m, 2 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.14 (m, 1 H), 2.69 (comp, 4
H), 2.28 (s, 1 H); 13C NMR (100 MHz, CDCl3) δ 173.17, 143.4,
134.1, 128.3, 127.2, 125.2, 118.6, 83.3, 53.8, 53.2, 53.1, 50.1, 36.8; IR
(neat) 3520, 3027, 2954, 2925, 1732, 1446, 1264 cm−1; HRMS (ESI-
TOF); Calcd for C17H20O5Na: 327.1203; found: 327.1191 (M+Na).
1H NMR and 13C NMR spectra for opposite diastereomer do not
HRMS (ESI-TOF); Calcd for C20H24NO3S: 358.1471; found:
358.1461 (M+1).
Dimethyl-3-hydroxy-3-phenyl-4-vinylidenecyclopentane-
1,1-dicarboxylate (17a). Purified by flash chromatography eluting
with hexanes/EtOAc (2:1) to provide 26.6 mg (88%) of a viscous
colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.49 (d, J = 7.2 Hz, 2 H),
7.36 (t, J = 8.4 Hz, 2 H), 7.27 (m, 1 H), 4.81 (m, 2 H), 3.83 (s, 3 H),
3.73 (s, 3 H), 3.58 (m, 1 H), 3.14 (m, 1 H), 2.87 (d, J = 14 Hz, 1 H),
2.75−2.50 (m, 2 H); 13C NMR (100 MHz, CDCl3) δ 203.6, 173.2,
144.5, 128.2, 127.4, 125.9, 109.6, 83.6, 80.5, 58.7, 53.4, 53.2, 51.2, 37.9;
IR (neat) 3509, 3001, 2955, 2924, 1957, 1739, 1687, 1448, 1207 cm−1;
HRMS (ESI-TOF); Calcd for C17H18O5Na: 325.1046; found:
325.1067 (M+Na).
Dimethyl-4-hydroxy-4-phenyl-3-vinylidenecyclohexane-1,1-
dicarboxylate (17b). Purified by flash chromatography eluting with
hexanes/EtOAc (2:1) to provide 24.4 mg (77%) a white solid (mp
1
120−121 °C). H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 8.8 Hz, 2
H), 7.45 (t, J = 6.4 Hz, 2 H), 7.30 (m, 1 H), 4.76 (m, 2 H), 3.78 (s, 3
H), 3.73 (s, 3 H), 3.11 (d, J = 13.6 Hz, 1 H), 2.68 (m, J = 14 Hz, 1 H),
2.60−2.30 (m, 2 H), 2.20−1.85 (m, 3 H); 13C NMR (100 MHz,
CDCl3) δ 204.7, 171.3, 143.5, 128.3, 127.7, 126.1, 104.1, 78.1, 73.8,
55.3, 52.8 52.7, 35.8, 33.9, 28.1; IR (neat) 3504, 3057, 2955, 2373,
2245, 1961, 1736, 1439, 1254 cm−1; HRMS (ESI-TOF); Calcd for
C18H20O5Na: 339.1203; found: 339.1201 (M+Na).
match the isolated compound leading to determination of opposite
syn/anti stereochemistry.
Dimethyl-4-hydroxy-4-phenyl-3-vinylidenecycloheptane-
1,1-dicarboxylate (17c). Purified by flash chromatography eluting
with hexanes/EtOAc (2:1) to provide 11.6 mg (35%) of a white solid
(mp 46−47 °C). 1H NMR (400 MHz, CDCl3) δ 4.83 (m, 2 H), 3.71
(s, 6 H), 2.99 (d, J = 14 Hz, 1 H), 2.61 (d, J = 14 Hz, 1 H), 2.20 (m, 1
H), 1.85 (comp m, 3 H), 1.76 (s, 1 H), 1.64 (m, 2 H), 1.35 (s, 3 H);
13C NMR (100 MHz, CDCl3) δ 206.7, 172.5, 106.9, 78.0, 73.2, 57.6,
52.4, 52.2, 41.7, 35.8, 32.3, 30.0, 20.14; IR (neat) 3510, 2953, 1953,
1732, 1436, 1244, 1203 cm−1; HRMS (ESI-TOF); Calcd for
C14H20O5Na: 291.1203; found: 291.1216 (M+Na).
1-(p-Methyl)phenyl-3-buten-1-ol (5g). Purified by flash chro-
matography eluting with hexanes/EtOAc (2:1) to provide 54 mg
(84%) of a yellow oil whose 1H NMR and 13C NMR spectral data was
consistent with literature values.88
1-(p-Methoxy)phenyl-3-buten-1-ol (5h). Purified by flash
chromatography eluting with hexanes/EtOAc (2:1) to provide 63
mg (89%) of clear, colorless oil whose 1H NMR and 13C NMR
spectral data was consistent with literature values.88
Dimethyl-4-hydroxy-4-phenyl-3-vinylcyclohexane-1,1-dicar-
boxylate (13b). Purified by flash chromatography eluting with
hexanes/EtOAc (3:1) to provide 29.9 mg (94%) of a clear crystalline
1
white solid (mp 84−85 °C). H NMR (400 MHz, CDCl3) δ 7.40−
7.15 (comp, 5 H), 5.52 (m, 1 H), 5.08 (m, 2 H), 3.76 (s, 3 H), 3.72 (s,
3 H), 2.92 (m, 1 H), 2.40−2.15 (comp, 4 H), 1.95 (m, 1 H), 1.90−
1.75 (comp, 2 H); 13C NMR (100 MHz, CDCl3) δ 172.7, 171.9,
147.4, 137.2, 128.5, 127.0, 124.8, 117.7, 73.9, 53.0, 52.9, 44.4, 37.0,
30.3, 29.9, 26.8; IR (neat) 3525, 3024, 2954, 1731, 1446, 1251 cm−1;
HRMS (ESI-TOF); Calcd for C18H22O5Na: 341.1359; found:
341.1359 (M+Na).
Dimethyl-4-hydroxy-4-methyl-3-vinylcycloheptane-1,1-di-
carboxylate (13c). Purified by flash chromatography eluting with
hexanes/EtOAc (2:1) to provide 15.8 mg (53%) of a viscous colorless
oil. 1H NMR (400 MHz, CDCl3) δ 5.92 (m, 1 H), 5.07 (m, 2 H), 5.08
(m, 2 H), 3.74 (s, 3 H), 3.70 (s, 3 H), 2.49 (m, 1 H), 2.25−1.95 (m, 4
H), 1.80−1.50 (comp m, 4 H), 1.16 (s, 3 H); 13C NMR (100 MHz,
CDCl3) δ 173.2, 172.8, 139.72, 115.5, 73.1, 57.1, 52.7, 52.4, 48.3, 44.5,
34.9, 32.2, 30.1, 19.8; IR (neat) 3535, 2955, 2929, 1731, 1456, 1233
cm−1; HRMS (ESI-TOF); Calcd for C14H23O5: 271.1540; found:
271.1563 (M+1).
1-(p-Dimethylamino)phenyl-3-buten-1-ol (5i). Purified by
flash chromatography eluting with hexanes/EtOAc (2:1) to provide
1
69 mg (91%) of a yellow oil whose H NMR and 13C NMR spectral
data was consistent with literature values.104
1-(o-Hydroxy)phenyl-3-buten-1-ol (5j). Purified by flash
Methyl-5-methyl-7-oxo-9-vinyl-6-oxabicyclo[3.2.2]nonane-
1-carboxylate (c-13c). Purified by flash chromatography eluting with
hexanes/EtOAc (2:1) to provide 24.3 mg (93%) of a white solid (mp
97−98 °C). 1H NMR (400 MHz, CDCl3) δ 5.83 (m, 1 H), 5.05 (m, 2
H), 3.79 (s, 6 H), 2.57 (m, 1 H), 2.38 (comp, 2 H), 2.20−1.70 (comp
m, 6 H), 1.29 (s, 3 H); 13C NMR (100 MHz, CDCl3) δ 172.8, 171.8,
138.6, 116.0, 84.0, 77.3, 53.0, 43.4, 39.6, 32.4, 30.6, 28.1, 20.4; IR
(neat) 2979, 2952, 1744, 1729, 1450, 1272, 1054 cm−1; HRMS (ESI-
TOF); Calcd for C13H18O4Na: 261.1097; found: 261.1079 (M+Na).
3-Phenyl-1-tosyl-4-vinylpyrrolidin-3-ol (15a). Purified by flash
chromatography eluting with hexanes/EtOAc (2:1) to provide 29.9
mg (38%) of an off-white solid whose 1H NMR and 13C NMR spectral
data was consistent with literature values.82
4-Phenyl-1-tosyl-3-vinylpiperidin-4-ol (15b). Purified by flash
chromatography eluting with hexanes/EtOAc (2:1) to provide 35 mg
(98%) of a white solid (mp 143−144 °C). 1H NMR (400 MHz,
CDCl3) δ 7.72 (d, J = 6.8 Hz, 2 H), 7.45−7.15 (comp, 7 H), 5.43 (m,
1 H), 5.08 (d, J = 10.8 Hz, 1 H), 4.95 (d, J = 17.6 Hz, 1 H), 3.85−3.70
(comp m, 2 H), 3.04 (m, 1 H), 2.80−2.60 (comp, 2 H), 2.47 (s, 3 H),
2.18 (m, 1 H), 1.80 (dt, J = 14, 2.4 Hz, 1 H), 1.65 (d, J = 2 Hz, 1 H);
13C NMR (100 MHz, CDCl3) δ 152.1, 146.0, 143.8, 134.4, 133.6,
chromatography eluting with hexanes/EtOAc (1:1) to provide 64
1
mg (97%) of a clear, colorless oil whose H NMR and 13C NMR
spectral data was consistent with literature values.105
1-(p-Hydroxy-o-methoxy)phenyl-3-buten-1-ol (5k). Purified
by flash chromatography eluting with hexanes/EtOAc (1:1) to provide
1
77 mg (99%) of a white solid (mp 51−53 °C). H NMR (500 MHz,
CDCl3) δ 6.91 (d, J = 1.5 Hz, 1 H), 6.87 (d, J = 8.0 Hz, 1 H), 6.82 (dd,
J = 8.0, 2.0 Hz, 1 H), 5.85−5.76 (m, 1 H), 5.63 (s, 1 H), 5.18−5.12
(comp m, 2 H), 4.66 (dt, J = 7.0, 2.5 Hz, 1 H), 3.86 (s, 3 H), 2.51−
2.48 (comp m, 2 H), 2.06 (br d, J = 3.0 Hz, 1 H); 13C NMR (125
MHz, CDCl3) δ 146.8, 145.2, 136.2, 134.9, 119.1, 118.6, 114.4, 108.5,
73.5, 56.2, 44.1; IR (neat) 3418, 3079, 3007, 2995, 2981, 2940, 2899,
1614, 1519, 1440, 1354, 1330, 1272, 1249, 1155, 1126, 1051, 1037
cm−1; HRMS (FAB-TOF) m/z = 176.0823 [C11H12O2 (M−H2O)
requires 176.0837].
1-(p-Carboxymethyl)phenyl-3-buten-1-ol (5l). Purified by flash
chromatography eluting with hexanes/EtOAc (2:1) to provide 73 mg
1
(90%) of a clear, colorless oil whose H NMR and 13C NMR spectral
data was consistent with literature values.88
1-(p-Trifluoromethyl)phenyl-3-buten-1-ol (5m). Purified by
flash chromatography eluting with hexanes/EtOAc (2:1) to provide 78
1
mg (90%) of a clear, colorless oil whose H NMR and 13C NMR
130.0, 128.7, 127.9, 127.4, 124.7, 119.0, 73.0, 47.2, 45.6, 42.3, 39.4,
21.8; IR (neat) 3509, 3059, 3030, 2925, 2864, 1339, 1162, 925 cm−1;
spectral data was consistent with literature values.88
L
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1-(p-Chloro)phenyl-3-buten-1-ol (5n). Purified by flash chro-
(d, J = 15.9 Hz, 1 H), 6.11 (d, J = 16.2 Hz, 1 H), 5.92−5.78 (comp, 1
H), 5.17 (app br t, 1 H), 5.13−5.12 (comp, 1 H), 2.95 (s, 6 H), 2.47−
2.31 (comp, 2 H), 1.75 (br s, 1 H), 1.38 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 156.2, 151.0, 132.9, 128.2, 128.1, 126.3, 120.0, 113.5,
73.3, 48.4, 41.5, 29.0; IR (neat) 3474, 3412, 3046, 2976, 2929, 2806,
1610, 1521, 1354, 1166 cm−1; HRMS (FAB-TOF) m/z = 231.1638
[C15H21NO (M+) requires 231.1623].
matography eluting with hexanes/EtOAc (2:1) to provide 68 mg
1
(93%) of a clear, colorless oil whose H NMR and 13C NMR spectral
data was consistent with literature values.88
1-(p-Cyano)phenyl-3-buten-1-ol (5o). Purified by flash chro-
matography eluting with hexanes/EtOAc (2:1) to provide 55 mg
1
(85%) of a clear, colorless oil whose H NMR and 13C NMR spectral
data was consistent with literature values.88
(E)-(1-(p-Hydroxy-o-methoxy)phenyl)-3-methyl-1,5-hexa-
dien-3-ol (3l). Purified by flash chromatography eluting with
1-(2-Furyl)-3-buten-1-ol (5q). Purified by flash chromatography
eluting with hexanes/EtOAc (4:1) to provide 48 mg (88%) of a clear,
colorless oil which is volatile when placed under vacuum. Spectral data
(1H and 13C NMR) was consistent with literature values.106
(E)-1-Phenyl-1,5-hexadien-3-ol (5r). Purified by flash chroma-
tography eluting with hexanes/EtOAc (2:1) to provide 70 mg (91%)
1
hexanes/EtOAc (1:1) to provide 63 mg (97%) of a yellow oil. H
NMR (500 MHz, CDCl3) δ 6.91−6.85 (comp m, 3 H), 6.51 (d, J =
16.5 Hz, 1 H), 6.14 (d, J = 16 Hz, 1 H), 5.89−5.80 (m, 1 H), 5.66 (s, 1
H), 5.18−5.14 (comp m, 2 H), 3.91 (s, 3 H), 2.44 (dd, J = 13.5, 6.5
Hz, 1 H), 2.35 (dd, J = 13.5, 8.0 Hz, 1 H), 1.80 (br s, 1 H), 1.39 (s, 3
H); 13C NMR (125 MHz, CDCl3) δ 146.9, 145.6, 134.2, 133.9, 129.7,
127.5, 120.3, 119.6, 114.7, 108.6, 72.6, 56.1, 47.6, 28.3; IR (neat) 3396,
3287, 3073, 2975, 2933, 2868, 1596, 1514, 1427, 1372, 1271, 1233,
1155, 1119, 1034, 968 cm−1; HRMS (FAB-TOF) m/z = 216.1182
[C14H16O2 (M−H2O) requires 216.1150].
(E)-(1-(p-Trifluoromethyl)phenyl)-3-methyl-1,5-hexadien-3-
ol (3m). Purified by flash chromatography eluting with hexanes/
EtOAc (2:1) to provide 92 mg (92%) of a clear, slightly yellow oil. 1H
NMR (300 MHz, CDCl3) δ 7.56 (app dt, J = 4.8 Hz, 2 H), 7.46 (appt
dt, J = 4.8 Hz, 2 H), 6.65 (d, J = 9.6 Hz, 1 H), 6.39 (d, J = 9.6 Hz, 1
H), 5.87−5.79 (comp, 1 H), 5.21 − 5.15 (comp, 2 H), 2.46 (app ddt,
1 H), 2.37 (app ddt, 1 H), 1.94 (br s, 1 H), 1.40 (s, 3 H); 13C NMR
(125 MHz, CDCl3) δ 141.3, 139.7, 134.1, 127.5, 127.5, 127.2, 126.4,
126.4, 120.7, 73.3, 48.1, 28.9; IR (neat) 3431, 3398, 3002, 2979, 1617,
1325, 1165, 1125, 1108, 1068 cm−1; HRMS (FAB-TOF) m/z =
239.1069 [C14H14F3 (M−OH) requires 239.1048].
1
of a pale yellow oil whose H NMR and 13C NMR spectral data was
consistent with literature values.84
(E)-2,6-Heptadien-4-ol (5s). Purified by flash chromatography
eluting with hexanes/EtOAc (4:1) to provide 37 mg (83%) of a clear,
colorless oil which is volatile when placed under vacuum. Spectral data
(1H and 13C NMR) was consistent with literature values.107
1-Cyclohexyl-3-buten-1-ol (5t). Purified by flash chromatog-
raphy eluting with hexanes/EtOAc (5:1) to provide 48 mg (79%) of a
clear, colorless oil which is volatile when placed under vacuum.
Spectral data (1H and 13C NMR) was consistent with literature
values.84
1-Nonen-4-ol (5u). Purified by flash chromatography eluting with
hexanes/EtOAc (4:1) to provide 51 mg (91%) of a clear, colorless oil
which is volatile when placed under vacuum. Spectral data (1H and 13
NMR) was consistent with literature values.84
C
1-Phenyl-2,2-dimethyl-3-buten-1-ol (5v). Purified by flash
chromatography eluting with hexanes/EtOAc (4:1) to provide 70
mg (99%) of a clear, slightly yellow oil whose 1H NMR and 13C NMR
spectral data was consistent with literature values.89
(E)-(1-(p-Chloro)phenyl)-3-methyl-1,5-hexadien-3-ol (3n).
Purified by flash chromatography eluting with hexanes/EtOAc (2:1)
to provide 82 mg (92%) of a clear, colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.29 (m, 4 H), 6.56 (d, J = 15.9 Hz, 1 H), 6.27 (d, J = 16.2
Hz, 1 H), 5.89−5.75 (comp, 1 H), 5.19 (app br t, 1 H), 5.17−5.13
(comp, 1 H), 2.40 (ddt, J = 27.0, 6.6, 1.2 Hz, 2 H), 1.82 (br s, 1 H),
1.38 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ 137.7, 136.3, 134.3,
133.9, 129.6, 128.5, 127.2, 120.5, 73.2, 50.1, 28.9; IR (neat) 3468,
3447, 3374, 3076, 2977, 2929, 1491, 1092 cm−1; HRMS (FAB-TOF)
m/z = 221.0728 [C13H14OCl (M−1) requires 221.0733].
1-(p-Methoxy)phenyl-2,2-dimethyl-3-buten-1-ol (5w). Puri-
fied by flash chromatography eluting with hexanes/EtOAc (2:1) to
1
provide 72 mg (88%) of a clear, pale yellow oil whose H NMR and
13C NMR spectral data was consistent with literature values.108
3,3-Dimethyl-1-nonen-4-ol (5x). Purified by flash chromatog-
raphy eluting with hexanes/EtOAc (5:1) to provide 54 mg (83%) of a
1
clear, colorless oil whose H NMR and 13C NMR spectral data was
consistent with literature values.6
(E)-(1-(p-Carboxymethyl)phenyl)-3-methyl-1,5-hexadien-3-
ol (3o). Purified by flash chromatography eluting with hexanes/EtOAc
1-Methyl-1-phenyl-3-buten-1-ol (3h). Purified by flash chro-
1
(2:1) to provide 82 mg (81%) of a clear, colorless oil. H NMR (300
matography eluting with hexanes/EtOAc (4:1) to provide 58 mg
1
(89%) of a clear, colorless oil whose H NMR and 13C NMR spectral
MHz, CDCl3) δ 7.98 (dd, J = 8.5, 1.5 Hz, 2 H), 7.42 (dd, J = 8.0, 2.0
Hz, 2 H), 6.64 (d, J = 16.0 Hz, 1 H), 6.41 (dd, J = 16.5, 2.0 Hz, 1 H),
5.87−5.78 (comp, 1 H), 5.20−5.16 (comp, 2 H), 3.91 (d, J = 2.0 Hz, 3
H), 2.47−2.34 (comp, 2 H), 1.89 (br s, 1 H), 1.40 (d, J = 1.5 Hz, 3
H); 13C NMR (125 MHz, CDCl3) δ 167.1, 141.6, 139.1, 133.5, 130.1,
129.0, 126.8, 126.5, 119.9, 72.6, 52.3, 47.4, 28.1; IR (neat) 3527, 3503,
3480, 3074, 3032, 2977, 2953, 2930, 1719, 1608, 1436, 1284, 1179,
1111 cm−1; HRMS (FAB-TOF) m/z = 247.1324 [C15H19O3 (M+1)
requires 247.1334].
data was consistent with literature values.94
(E)-1-Cyclohexyl-3-methyl-1,5-hexadien-3-ol (3i). Purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to provide 66
1
mg (83%) of a clear, colorless oil. H NMR (300 MHz, CDCl3) δ
5.85−5.71 (comp, 1 H), 5.56 (dd, J = 15.6, 6.0 Hz, 1 H), 5.47 (dd, J =
15.9, 0.6 Hz, 1 H), 5.14−5.12 (comp, 1 H), 5.11−5.06 (comp, 1 H),
2.34−2.19 (comp, 2 H), 1.99−1.88 (m, 1 H), 1.69 (app br d, 2 H),
1.62 (app br s, 1 H), 1.25 (s, 3 H), 1.21−1.03 (m, 6 H); 13C NMR
(125 MHz, CDCl3) δ 134.2, 133.9, 133.8, 118.8, 71.9, 74.3, 33.1, 33.0,
27.9, 26.2, 26.0; IR (neat) 3387, 2976, 2926, 2852, 1449 cm−1; HRMS
(FAB-TOF) m/z = 193.1602 [C13H21O (M−1) requires 193.1592].
(E)-(1-(p-Methoxy)phenyl)-3-methyl-1,5-hexadien-3-ol (3j).
Purified by flash chromatography eluting with hexanes/EtOAc (2:1)
to provide 40 mg (91%) of a clear, colorless oil. 1H NMR (300 MHz,
CDCl3) δ 7.31 (dt, J = 8.4, 2.7 Hz, 2 H), 6.85 (dt, J = 8.7, 3.0 Hz, 2
H), 6.54 (d, J = 16.2 Hz, 1 H), 6.16 (d, J = 16.2 Hz, 1 H), 5.91−5.77
(comp, 1 H), 5.18 (app br t, 1 H), 5.15−5.11 (comp, 1 H), 3.80 (s, 3
H), 2.47−2.31 (comp, 2 H), 1.85 (br s, 1 H), 1.38 (s, 3 H); 13C NMR
(125 MHz, CDCl3) δ 160.0, 134.9, 130.5, 128.5, 127.7, 120.2, 114.9,
73.2, 56.2, 48.3, 29.0; IR (neat) 3440, 3007, 2976, 2934, 1607, 1512,
1248, 1175 cm−1; HRMS (FAB-TOF) m/z = 218.1325 [C14H18O2
(M+) requires 218.1307].
(E)-(1-(o-Hydroxy)phenyl)-3-methyl-1,5-hexadien-3-ol (3p).
Purified by flash chromatography eluting with hexanes/EtOAc (2:1)
1
to provide 77 mg (94%) of a white solid (mp 86−88 °C). H NMR
(500 MHz, CDCl3) δ 7.34 (dd, J = 8.0, 1.5 Hz, 1 H), 7.12 (td, J = 7.5,
1.5 Hz, 1 H), 6.90 (app td, J = 7.5, 0.5 Hz, 1 H), 6.81−6.79 (m, 2 H),
6.28 (d, J = 16.0 Hz, 1 H), 5.90−5.81 (m, 1 H), 5.39 (s, 1 H), 5.19−
5.15 (comp m, 2 H), 2.46 (dd, J = 13.5, 6.5 Hz, 1 H), 2.38 (dd, J =
13.5, 8.0 Hz, 1 H), 2.00 (br s, 1 H), 1.41 (s, 3 H); 13C NMR (125
MHz, CDCl3) δ 152.9, 138.0, 133.6, 128.6, 127.4, 124.0, 121.9, 120.9,
119.4, 115.9, 72.8, 47.3, 28.0; IR (neat) 3306, 3074, 2977, 2932, 2864,
2804, 2776, 2742, 1603, 1488, 1455, 1390, 1297, 1228, 1122, 1076,
1043 cm−1; HRMS (FAB-TOF) m/z = 186.1060 [C13H14O (M−
H2O) requires 186.1045].
1-Cyclopropyl-3,4,4-trimethyl-1,5-hexadien-3-ol (3q). Puri-
fied by flash chromatography eluting with hexanes/EtOAc (4:1) to
(E)-(1-(p-Dimethylamino)phenyl)-3-methyl-1,5-hexadien-3-
1
ol (3k). Purified by flash chromatography eluting with hexanes/EtOAc
provide 70 mg (97%) of a clear, slightly yellow oil. H NMR (300
1
(2:1) to provide 84 mg (91%) of a yellow oil. H NMR (300 MHz,
MHz, CDCl3) δ 5.99 (dd, J = 10.5, 6.3 Hz, 1 H), 5.71 (dd, J = 9.3, 0.3
Hz, 1 H), 5.13 (dd, J = 9.3, 5.1 Hz, 1 H), 5.09 (dd, J = 6.6, 0.9 Hz, 1
CDCl3) δ 7.28 (dt, J = 9.0 Hz, 2 H), 6.68 (dt, J = 9.0 Hz, 2 H), 6.50
M
dx.doi.org/10.1021/jo301726v | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
H), 5.05 (dd, J = 10.5, 0.9 Hz, 1 H), 1.44 (br s, 1 H), 1.43−1.33
(comp, 1 H), 1.20 (s, 3H), 1.03 (s, 6H), 0.69 (dt, J = 6.3, 2.7 Hz, 2 H),
0.36 (dt, J = 5.4, 2.7 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 146.1,
133.7, 132.8, 114.4, 75.5, 44.9, 24.6, 23.4, 22.8, 14.5, 7.6; IR (neat)
3468, 3449, 2969, 2930, 2874, 1632 cm−1; HRMS (ESI-TOF) m/z =
203.1430 [C12H20ONa (M+Na) requires 203.1406].
= 15.9 Hz, 1 H), 6.07 (d, J = 16.2 Hz, 1 H), 5.94−5.80 (comp, 2 H),
5.19−5.17 (comp, 2 H), 5.15−5.12 (comp, 2 H), 2.96 (s, 6 H), 2.49−
2.33 (comp, 4 H), 1.92 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ
150.3, 133.9, 130.7, 128.5, 127.6, 125.6, 119.2, 112.8, 74.1, 46.0, 40.8;
IR (neat) 3550, 3493, 3459, 3075, 3008, 2978, 2928, 2858, 2802, 1639,
1610, 1522, 1443, 1353, 1266, 1220, 1187, 1165 cm−1; HRMS (FAB-
TOF) m/z = 257.1785 [C17H23NO (M+) requires 257.1780].
(E)-4-(4-Chlorostyryl)-1,6-heptadien-4-ol (21d). Purified by
flash chromatography eluting with hexanes/EtOAc (4:1) to provide
(E)-2,4,5,5-Tetramethyl-2,6-heptadien-4-ol (3r). Purified by
flash chromatography eluting with hexanes/EtOAc (5:1) to provide
1
66 mg (98%) of a clear, colorless oil. H NMR (300 MHz, CDCl3) δ
1
81 mg (83%) of a clear, colorless oil. H NMR (500 MHz, CDCl3) δ
6.02 (dd, J = 17.1, 11.1 Hz, 1 H), 5.34−5.32 (comp, 1 H), 5.10 (dd, J
= 3.3, 1.8 Hz, 1 H), 5.06 (dd, J = 9.6, 1.8 Hz, 1 H), 1.87 (d, J = 1.2 Hz,
3 H). 1.72 (d, J = 1.5 Hz, 3 H), 1.47 (br s, 1 H), 1.27 (s, 3 H), 1.05 (d,
J = 2.4 Hz, 6 H); 13C NMR (125 MHz, CDCl3) δ 145.3, 133.9, 128.2,
113.5, 65.9, 45.3, 27.9, 24.5, 19.0; IR (neat) 3567, 3510, 3490, 2972,
2930, 2878, 1374 cm−1; HRMS (ESI-TOF) m/z = 191.1387
[C11H20ONa (M+Na) requires 191.1406].
7.31−7.26 (m, 4 H), 6.57 (d, J = 16 Hz, 1 H), 6.23 (d, J = 16 Hz, 1 H),
5.87−5.77 (comp, 2 H), 5.19−5.14 (comp, 4 H), 2.46−2.35 (comp, 4
H), 1.94 (s, 1 H); 13C NMR (125 MHz, CDCl3) δ 135.64, 135.62,
133.41, 133.27, 128.96, 127.90, 127.71, 119.67, 74.02, 45.78; IR (neat)
3565, 3498, 3481, 3460, 3078, 3009, 2979, 2930, 2906, 1639, 1491,
1091, 1012, 972, 997 cm−1; HRMS (FAB-TOF) m/z = 249.1046
[C15H18OCl (M+1) requires 249.1046].
1-Cyclohexenyl-1-methyl-3-buten-1-ol (3s). Purified by flash
chromatography eluting with hexanes/EtOAc (5:1) to provide 65 mg
(98%) of a colorless oil that is volatile under reduced pressure. Spectral
data (1H and 13C NMR) was consistent with literature values.109
1-(2-Propene)-1-cyclopentanol (3t). Purified by flash chroma-
tography eluting with hexanes/EtOAc (4:1) to provide 38 mg (76%)
of a colorless oil that is volatile under reduced pressure. Spectral data
(1H and 13C NMR) was consistent with literature values.110
1-(2-Propene)-1-cyclohexanol (3u). Purified by flash chroma-
tography eluting with hexanes/EtOAc (4:1) to provide 50 mg (89%)
of a colorless oil that is volatile under reduced pressure. Spectral data
(1H and 13C NMR) was consistent with literature values.94
1-(2-Propene)-2-cyclohexen-1-ol (3v). Purified by flash chro-
matography eluting with hexanes/EtOAc (4:1) to provide 56 mg
(98%) of a colorless oil that is volatile under reduced pressure. Spectral
data (1H and 13C NMR) was consistent with literature values.94
2,2,3-Trimethyl-5-hexen-1-ol (3w). Purified by flash chromatog-
raphy eluting with hexanes/EtOAc (4:1) to provide 57 mg (82%) of a
colorless oil that is volatile under reduced pressure. Spectral data (1H
and 13C NMR) was consistent with literature values.111
1-Phenyl-3-methyl-5-hexen-3-ol (3x). Purified by flash chroma-
tography eluting with hexanes/EtOAc (4:1) to provide 70 mg (98%)
of a clear, pale yellow oil that is volatile under reduced pressure.
Spectral data (1H and 13C NMR) was consistent with literature
values.89
1,1-Diphenyl-3-buten-1-ol (3y). Purified by flash chromatog-
raphy eluting with hexanes/EtOAc (5:1) to provide 87 mg (97%) of a
white solid whose 1H NMR and 13C NMR spectral data was consistent
with literature values.94
ASSOCIATED CONTENT
■
S
* Supporting Information
Spectra (1H NMR and 13C NMR) of new compounds and
observed nOE values for compounds 13a, 13b, 13c, c-13c and
15b. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*bashfeld@nd.edu
Notes
■
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank Prof. Seth N. Brown of the University of
Notre Dame for helpful discussions and the University of Notre
Dame for financial support of this research.
REFERENCES
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