Diastereoselective Additions of Allylmagnesium Reagents to α-Substituted Ketones When Stereochemical Models Cannot Be Used

Article abstract of DOI:10.1021/acs.joc.1c00553

The stereoselectivities of reactions of allylmagnesium reagents with chiral ketones cannot be easily explained by stereochemical models. Competition experiments indicate that the complexation step is not reversible, so nucleophiles cannot access the widest range of possible encounter complexes and therefore cannot be analyzed easily using available models. Nevertheless, additions of allylmagnesium reagents to a ketone can still be stereoselective provided that the carbonyl group adopts a conformation that leads to one face being completely blocked from the approach of the allylmagnesium reagent.

Full text of DOI:10.1021/acs.joc.1c00553

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Article
Diastereoselective Additions of Allylmagnesium Reagents to
α‑Substituted Ketones When Stereochemical Models Cannot Be
Used
Nicole D. Bartolo, Krystyna M. Demkiw, Elizabeth M. Valentín, Chunhua T. Hu, Alya A. Arabi,
and K. A. Woerpel*
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ABSTRACT: The stereoselectivities of reactions of allylmagnesium
reagents with chiral ketones cannot be easily explained by stereo-
chemical models. Competition experiments indicate that the complex-
ation step is not reversible, so nucleophiles cannot access the widest
range of possible encounter complexes and therefore cannot be
analyzed easily using available models. Nevertheless, additions of
allylmagnesium reagents to a ketone can still be stereoselective
provided that the carbonyl group adopts a conformation that leads to
one face being completely blocked from the approach of the
allylmagnesium reagent.
The reactions of allylmagnesium reagents with aldehydes
and ketones pose a challenge for analysis using stereochemical
models such as the Felkin−Anh model. These reagents do not
generally follow Curtin−Hammett kinetic scenarios.8−12
Competition experiments indicate that once the reagent
encounters the carbonyl compound, the carbon−carbon
bond-forming step is faster than the separation of encounter
complexes.9−11 The fact that this reaction does not follow a
Curtin−Hammett kinetic scenario is likely responsible for the
generally unselective additions of allylmagnesium reagents to
α-alkoxy ketones, which should be stereoselective according to
the chelation-control model.8,10 The rapid rates of bond
formation compared to the rates of other processes may also
account for the low diastereoselectivity observed for other
reactions,13−18 including the additions of many organometallic
nucleophiles to α-alkoxy aldehydes.10,19 Nevertheless, exam-
ples of highly stereoselective additions of allylmagnesium
reagents to chiral ketones have been reported, some of which
follow stereochemical models.8 As a result, using reagents such
as allylmagnesium halides, it is not possible to know whether a
reaction will be highly stereoselective or not.
INTRODUCTION
■
Stereochemical models are valuable tools to explain the
outcomes of reactions that establish new stereogenic centers.
The use of such models requires assessment of the structures
and relative energies of competing transition states leading to
stereoisomeric products. Among the most useful stereo-
chemical models is the Felkin−Anh model,1,2 which explains
the diastereoselectivities of additions of reagents such as
organomagnesium halides to α-substituted carbonyl com-
pounds (Figure 1).3,4 The Felkin−Anh model, like other
Figure 1. Transition states predicted by the Felkin−Anh stereo-
chemical model.
stereochemical models, assumes that the species present before
the irreversible stereochemistry-determining step are in rapid
equilibrium. The different conformational isomers of the
starting materials, aggregation states of the reagent, and
encounter complexes between the reacting partners must
interconvert rapidly so that reactions can proceed through the
lowest energy transition states.5 Consequently, the use of these
models generally requires that reactions follow a Curtin−
Hammett kinetic scenario,6 although reactions can be
stereoselective even if this condition were not met.7
In this paper, we show that additions of allylmagnesium
reagents to chiral ketones can be highly stereoselective for
Received: March 8, 2021
Published: May 12, 2021
https://doi.org/10.1021/acs.joc.1c00553
© 2021 American Chemical Society
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cases that cannot be accommodated readily by models such as
the Felkin−Anh model. We demonstrate that all that is
necessary to observe stereoselectivity is that the carbonyl group
is sufficiently sterically hindered so that addition of the
nucleophile to one diastereoface of the carbonyl group occurs
particularly slowly. Computational studies that support this
analysis are detailed.
Chart 1
RESULTS AND DISCUSSION
■
The general inability to compare the stereoselectivities of
reactions of chiral ketones with allylmagnesium reagents
compared to reactions of other organometallic nucleophiles8
is illustrated in Table 1 for the additions to α-halogenated
Table 1. Additions of Organometallic Nucleophiles to
a
Cyclic α-Haloketones
b
c
entry
n
X
R−M
dr
yield (%)
1
2
3
4
5
6
7
8
1
1
1
1
2
2
2
2
3
3
3
3
Cl
Cl
Br
Br
Cl
Cl
Br
Br
Cl
Cl
Br
Br
PhCC−Li
94:6
76:24
>99:1
87:13
>99:1
79:21
>99:1
87:13
69
87
59
91
52
77
46
80
H2CCHCH2−MgCl
PhCC−Li
H2CCHCH2−MgCl
PhCC−Li
The reactions of eight-membered ring ketones 5a,b with
nucleophiles were different from the reactions observed for the
ketones with smaller rings. Alkyl and aryl organomagnesium
reagents and organolithium reagents (such as n-Pr−MgCl, i-
Pr−MgCl, i-Pr−MgCl·LiCl, Bn−MgCl, Me−MgCl, Me−Li,
Ph−Li) did not add (for example, entry 11), which reflects the
generally low reactivity of eight-membered ring ketones with
nucleophiles.25,26 Additions of allylmagnesium chloride,
however, were rapid, highlighting the high rates of reactions
of this reagent with carbonyl compounds.9,12 In contrast to the
reactions of six- and seven-membered ketones, this addition
was diastereoselective, particularly in the case of 2-
bromocyclooctanone (5b, entry 12). This result also contrasts
with other examples of additions of allylmagnesium reagents to
flexible chiral cyclooctanones, which are not diastereoselec-
tive.27,28
The stereochemical configurations of the products shown in
Table 1 were determined so that the course of the reaction
could be analyzed. These relative configurations were
established by a variety of methods. In the case of six-
membered ring products 6 and 7, the relative stereochemistry
of the products could be determined using spectroscopic
techniques.29 In the case of alcohol anti-10b (Table 1, entry
12), X-ray crystallographic analysis of the product was used.29
In the other cases, chemical correlation was performed, as
illustrated in Scheme 1, by the attempted formation of
epoxides from the halohydrins.30 The minor syn-isomer, as
illustrated for syn-9a, has the appropriate orientation of the
oxygen atom and the halogen atom to cyclize, whereas the
isomer anti-9a does not.30−32 When mixtures of stereoisomers
were subjected to these conditions, as illustrated for anti-9b,
only the syn-stereoisomer underwent cyclization. The stereo-
chemical configurations of alcohols anti-6a,b, anti-8a,b, and
anti-9b were assigned based upon the fact that they did not
H2CCHCH2−MgCl
PhCC−Li
H2CCHCH2−MgCl
PhCC−Li
d
9
−
10
11
12
H2CCHCH2−MgCl
PhCC−Li
89:11
71
−
d
H2CCHCH2−MgCl
94:6
74
a
Additions of organolithium reagents were performed at −78 to 20
°C. Additions of allylmagnesium chloride were performed at −78 °C.
b
All diastereomeric ratios were determined by 13C{1H} NMR
spectroscopy20 and confirmed by H NMR spectroscopy. Isolated
c
1
d
yield. No addition products were observed.
cyclic ketones 3−5. For example, the addition of an
alkynylithium reagent to 2-chlorocyclohexanone was highly
stereoselective (entry 1), but addition of allylmagnesium
chloride was not (entry 2). The same trend was observed for
both six- and seven-membered ring ketones and for ketones
with chlorine or bromine atoms (entries 3−8). The products
of the reactions are illustrated in Chart 1.
The use of the alkynyllithium reagent for comparisons was
less than ideal, but it was not possible to compare the
diastereoselectivities of additions of allylmagnesium reagents
with the results using other organometallic reagents. The α-
haloketones did not react with a variety of organomagnesium
reagents (for example, n-Pr−MgCl, i-Pr−MgCl·LiCl,
Bn−MgCl, Me−MgCl) at low temperatures. Upon warming,
either starting material was recovered (likely because
enolization was favored21) or the halogen atom was removed,
likely through metal−halogen exchange (for example, eq
1).22−24 The alkynyllithium reagent was chosen because it
was sterically small but added sufficient molecular weight to
facilitate isolation and characterization of the products.
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hot THF gave an unidentifiable mixture of products that did
not include allylated product anti-10b, cyclooctanone, or 2-
bromocyclooctanone 5b (entry 7). The stereoselectivity also
increased slightly with decreasing concentration (entries 8, 9,
and 1) but did not increase upon further dilution (cf. entries 1
and 10). This increase in selectivity is unlikely to be attributed
to changes in aggregation given that the reagent is likely
monomeric in THF, particularly at lower concentrations.38,39
Instead, the effect of concentration could indicate that a pre-
equilibrium step before the stereochemistry-determining step
and the stereochemistry-determining step occurred at com-
petitive rates.
Scheme 1. Stereochemical Proofs of Additions to α-
Halocycloheptanones
Analysis of the stereoselectivities observed for the allylations
shown in Tables 1−2 is not straightforward. Initially, it seemed
that they could be analyzed by a stereochemical control model
such as the Felkin−Anh model. Additional experiments,
however, indicated that the analysis of the stereochemical
outcomes of these additions would be more involved.
Competition experiments9 demonstrated that additions of
allylmagnesium chloride to chiral ketones 3−5 and the
corresponding unsubstituted cyclic ketones (11, 13, and 14)
occurred at comparable rates (Table 3). The results with
a
Table 3. Competition Experiments between Cyclic α-
Haloketones and the Corresponding Unhindered Ketones
with Allylmagnesium Chloride
undergo even a trace of cyclization even after extended periods
of time.
Experiments with 2-bromocyclooctanone (5b), the substrate
that reacted with allylmagnesium chloride with the highest
diastereoselectivity (Table 1, entry 12), showed that the
diastereoselectivity did not depend considerably upon reaction
conditions (Table 2). Solvents or counterions, which should
Table 2. Influence of Conditions on Stereoselectivity
b
entry
n
X
anti-6−10/15−17
1
2
3
4
5
6
1
1
2
2
3
3
Cl
Br
Cl
Br
Cl
Br
56:44
30:70
59:41
40:60
42:58
68:32
a
entry
X
solvent
temp (°C)
conc (M)
dr
1
2
3
4
5
6
7
8
9
10
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
THF
THF
Et2O
Et3N
THF
THF
THF
THF
THF
THF
−78
−78
−78
−78
0
20
66
−78
−78
−78
0.1
0.1
0.1
0.1
0.1
0.1
0.1
1.0
0.5
0.01
94:6
88:12
89:11
93:7
96:4
>99:1
b
88:12
87:13
93:7
a
All competition experiments involved dropwise addition of the
nucleophile to a mixture of 4 equiv of each electrophile.9 Ratios for
all competition experiments were determined by 13C{1H} NMR
spectroscopy.20
b
ketone 5b were confirmed by comparison to the rate of
addition to propiophenone (18, Scheme 2), which reacts at
rates approaching the diffusion rate limit.9 By contrast, the
addition of the alkynyllithium reagent could be analyzed more
easily because, for this reaction, the carbon−carbon bond-
forming steps must be slower than the dissociation of an
encounter complex (as illustrated, for example, in Scheme 2).
This preference for addition to the unsubstituted ketone
contradicts similar competition experiments with NaBH4 as the
nucleophile, where only additions to α-haloketones were
observed.40
The competition experiments, particularly those shown in
Scheme 2, complicate the stereochemical analysis for reactions
of allylmagnesium halides. The lack of chemoselectivity
compared to propiophenone9 and the other ketones suggests
that, once the reagent has approached a ketone to form an
a
All diastereomeric ratios were determined by 13C{1H} NMR
spectroscopy20 and confirmed by 1H NMR spectroscopy. Only
b
decomposition was observed.
affect aggregation and the precise composition of the
reagent,33,34 led to only small changes in diastereoselectivity
(entries 1−4). In contrast to what might be anticipated,35 the
diastereoselectivity increased somewhat upon warming (entries
1, 5, 6), which indicates that entropic differences in activation
energies could be important in controlling stereoselectiv-
ity.35−37 Addition of allylmagnesium chloride to ketone 5b in
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Scheme 2. Additional Competition Experiments
Scheme 3. Possible Transition States for Additions to
Ketone 5b
illustrated in structure 23, which corresponds to a higher
energy conformer (<2 kcal/mol),42 would form the major
product through a transition state that avoids approach from
the hindered inside face of the ring. This mode of attack,
however, brings the nucleophile near the large bromine
atom.45 Transition state 24, which would derive from another
low-energy conformer,42 would likely be the least sterically
congested mode of attack of the four transition states
illustrated in Scheme 1. Transition state 24 involves attack
anti to the ring but away from the bromine atom, which is in
accord with the transition state proposed by Karabatsos46,47
with the inner part of the ring serving as RL. In this case, the
Karabatsos model would give the same product as anticipated
by the polar Felkin−Anh model,4 but through a quite different
arrangement of atoms.
Analysis of possible types of nucleophilic attack shown in
Scheme 3 may lead to an explanation for stereoselectivity, but
these schematic drawings ignore a key step of the additions of
Grignard reagents to carbonyl compounds. These additions
involve first forming a complex between the carbonyl group
and the magnesium atom of the reagent (Scheme 4).33,48 The
encounter complex, formation of the carbon−carbon bond
must be competitive with separation of the two components
and exchange for the other ketone. It is therefore not as simple
to invoke a stereochemical model where the widest range of
possible transition states are expected, such as the Felkin−Anh
model (Figure 1), because this reaction does not follow a
Curtin−Hammett kinetic scenario.9
Even without considering the issues associated with violating
the Curtin−Hammett principle, the stereoselectivities of
additions of allylmagnesium halides to these α-halogenated
ketones cannot be explained by considering stabilizing
electronic interactions that are inherent to the Felkin−Ahn
model.41 This inability to rationalize the stereochemical
outcome of the reaction can be seen for the highly
stereoselective addition to ketone 5b (Scheme 3). The polar
Felkin−Anh model cannot be applied because it is not possible
for the ketone to adopt the proper conformation described by
this model (as in 1, Figure 1, with Br as RL) given that R1 and
RM are connected in a ring. Addition to the lowest energy
conformer of the ketone42 is also unlikely. Addition from the
more accessible face (as illustrated by 21, Scheme 3) would
not form the major product. Attack from the other side of the
ring, through transition state 22, would form the major
product, and it would also benefit from electronic stabilization
that might be provided by attack anti to the bromine atom.2,41
This mode of attack would require addition from inside the
ring, which is likely to be sterically inaccessible.43,44 It also does
not correspond to the Felkin−Anh model.
Scheme 4. Complexation Precedes Bond Formation
importance of this step is underscored by the competition
experiments (Table 3 and Scheme 2). Considering that
additions of allylmagnesium reagents to most ketones and
aldehydes occur at similar rates,9,10,12 the complexation step is
not readily reversible (i.e., k2 ≥ k−1). To satisfy this condition,
the activation energy for the carbon−carbon bond formation
(the step associated with k2) must be comparable to the
activation energies for ligand exchanges at magnesium atoms
(about 1−5 kcal/mol).49−53 A detailed analysis of the observed
stereoselectivity under these constraints would require
consideration of complex 26 and would need to consider
how attack on one diastereoface occurs more rapidly than
dissociation of the complex. It must also consider whether
The formation of the major product can be explained using a
different set of conformers. Attack along the trajectory
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transition states leading to attack on the other diastereoface are
higher in energy. This analysis modifies common stereo-
chemical control models by incorporating recent computa-
tional investigations of reactions of carbonyl compounds with
Grignard reagents.48
Scheme 5. Calculated Transition State Free Energies
(ωB97X-D/cc-pVDZ in THF at 298 K)56 for Addition of
Allylmagnesium Chloride to Ketone 5b
Given the importance of this complexation step, the
transition-state structures in Scheme 3 can be analyzed in
more detail. Computational methods were used to suggest the
relative importance of different types of transition states in the
formation of the product. To obtain quantitative results that
could be used to estimate stereoselectivity, it would be
necessary to sample a large number of possible conformational
isomers and complexes of the reactive partners. Considering
the complexity of the conformational preferences of the
substrate,42 the structures and dynamic equilibria available to
the reagent,53 and the number of transition states that could
lead to product,48 a full analysis would likely require combining
quantum-mechanical and molecular-mechanical methods.54,55
Obtaining such precise quantitative data was not the objective
at this point. Instead, it was more useful to know what kinds of
transition states overall should be considered and which were
unlikely to be important. Although the computational studies
would begin to provide quantitative information, our goal was
instead to determine whether the energies for the transition
states made sense with the experimental results (both the
competition experiments and the stereoselectivities).
Considering the objectives of this aspect of the study, some
constraints were established to make the problem computa-
tionally manageable. The reactions of ketone 5b were chosen
for study because the stereoselectivities were high enough that
the preliminary computations planned would likely be
sufficient to provide insight. Complexes of the ketone 5b
were formed with a three-coordinate complex of the
monomeric Grignard reagent complexed to one THF
molecule. The monomeric, four-coordinate complex is the
simplest of many possible complexes, and likely the major one
in THF solution.38,39 Furthermore, recent studies suggest that
other complexes, such as ones from dimeric reagents, would
likely react with similar activation energies.9,10,48 These
complexes were then optimized using different computational
methods.56 Once a low-energy geometry of the complex was
identified, its energy did not change significantly (<1 kcal/
mol) even as the orientations of the allyl group or the THF
ligand were varied. Next, transition states were identified by
examining an energy profile obtained by bringing the terminal
carbon atom of the allyl group into proximity with the carbonyl
carbon atom. In light of recent theoretical57 and experimental
studies,11 only six-centered chair-like transition states for
additions of allylmagnesium reagents were considered. The
relative energies of the complexes and the transition states
were determined using ωB97X-D/cc-pVDZ as the functional58
and basis set using the polarized continuum model to model
THF as a solvent59 (Scheme 5).56
not change the relative energy in most cases.56 The observation
that solvation did not change the conclusions is consistent with
the experimental results shown in Table 2.
The calculations (Scheme 5) support the analysis using
more generalized transition states (Scheme 3). Transition state
21′, which corresponds to transition state 21, would not form
the major product. Transition state 22′ (which is the six-
membered ring transition state corresponding to 22) would
form the major product, but attack from inside the eight-
membered ring is considerably higher in energy, as
anticipated.44
The lowest-energy transition state, 24′, leads to the
formation of the major product observed in the addition
reaction. The ketone fragment would need to adopt what
corresponds to a higher energy conformer (by ≤2 kcal/mol42).
This complex could be accessed by complexation to either the
higher-energy conformer or to a lower-energy conformer. The
latter situation is possible considering that conformational
exchange processes in eight-membered rings are likely to occur
at rates comparable to the rate of dissociation of the
complex.60−64 The low activation energy associated with 24′
(<2 kcal/mol) reflects the high reactivity of allylmagnesium
reagents,9,12 and it is consistent with the activation energy
calculated for the reaction of acetone with allylmagnesium
bromide.57 The low activation energy also explains the
competition experiments: once the allylmagnesium reagent is
complexed to the carbonyl group, carbon−carbon bond
formation through the lowest energy transition state could
be competitive with decomplexation of the ketone.49−52
The relative energies of the transition states also are
consistent with respect to any destabilizing interactions that
would develop upon carbon−carbon bond formation. Tran-
sition state 21′ would be strongly destabilized by an eclipsing
interaction between the bromine atom and the incoming
nucleophile,45 and transition state 22′ would experience two
developing syn-pentane interactions.65 Transition state 23′
involves a closer interaction with the bromine atom than 24′
does, so it should be higher in energy.
The transition states that were identified are shown in
Scheme 5 starting from different conformers of the ketone.
The activation energies listed represent the relative energies
compared to a ground-state complex of the ketone in its lowest
energy conformation42 resembling 21′.56 The relative energies
of the transition states compared to the complex changed
somewhat (0−3 kcal/mol) depending upon the method used
or whether the calculations were conducted in the gas phase or
in solvent, but the ordering of relative energies was almost
unchanged. The configuration at the magnesium atom also did
The analysis of the specific case of cyclooctanones can be
generalized to apply to other reactions of other carbonyl
compounds. Such a generalization is essential to synthetic
chemists because it is impractical to perform extensive
calculations to predict or explain every nucleophilic addition
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to a carbonyl compound. Such general stereochemical models
to explain the reactions of nucleophiles with chiral carbonyl
compounds4 remain valuable because they can provide
qualitatively meaningful explanations and predictions. The
reactions of allylmagnesium reagents, however, do not follow
models such as the Felkin−Anh model (Figure 1), particularly
because these reactions do not adhere to the requirement of a
Curtin−Hammett kinetic scenario to ensure that the lowest
energy transition state can be accessed.8,10 Because of the
failure of the Felkin−Anh model to enable predictions of the
outcomes of reactions of allylmagnesium halides with chiral
ketones, it should be possible to identify more reliable criteria
for analyzing stereoselectivity.
Scheme 6. Additions of Grignard Reagents to Ketone 30
The critical difference between the reactions of eight-
membered ring ketones and the other cyclic ketones involves
the steric accessibility of the two faces (Figure 2). In the case
4). Consequently, addition of n-Pr−MgCl could be explained
by addition through a Felkin−Anh-like transition state (32)
Table 4. Competition Experiments between Ketone 30 and
Ketone 34
Figure 2. Comparison of approach of nucleophiles to six-membered
and eight-membered ring ketones.
of a six-membered ring ketone (28), both faces (the axial and
equatorial faces) would be accessible. As a result, additions to
substituted cyclohexanones, even ones with high conforma-
tional biases, are not generally stereoselective.8,66 If attack from
the axial face is blocked by axial substituents at C3 and C5,
however, additions of allylmagnesium halides to cyclo-
hexanones occur only from the equatorial face.67 In the case
of an eight-membered ring ketone (29), the larger ring
differentiates the faces of the carbonyl group because of the
overall topography of the ring.44 The ring serves the same role
as axial substituents at C3 and C5 do for cyclohexanones: they
block attack from one face. Thus, only attack from the external
face of the carbonyl group can proceed through a low-energy
transition state. The different steric environments of the two
faces is illustrated by comparing transition states 21′ and 22′
(Scheme 5), and it can be seen in the schematic depiction of
those transition states in Scheme 3 (transition states 21 and
22, respectively).
This analysis suggests a general rule for when reactions of
allylmagnesium reagents with carbonyl compounds will be
stereoselective. If a carbonyl compound adopts a three-
dimensional structure that causes one face to become sterically
much less accessible, then the reactions should be stereo-
selective. The highest selectivities would be expected when the
conformational preferences are the greatest and the carbonyl
group is most sterically hindered.
entry
R
temp (°C)
31/35
1
2
n-Pr
H2CCHCH2
20
−78
0:100
34:66
with relatively slow addition to the favored face, but addition of
allylmagnesium chloride is not as easily explained. According
to X-ray crystallographic studies,56 ketone 30 adopts a ground-
state conformation that resembles the conformer expected
from the Felkin−Anh model (structure 33). This conformer is
also strongly favored based upon computational studies.56 The
nucleophile could not approach the face of the carbonyl group
blocked by the large fluorenyl group, so, after complexation of
the reagent to the carbonyl group, attack could occur only
from the less hindered face of the carbonyl group. The product
expected by the Felkin−Anh model would be formed not
because that transition state had some preferred electronic
interaction, but because the ketone had a strong conforma-
tional preference, and that preference rendered only one face
accessible.69−71
A similar analysis can explain reactions of ketone 37
(Scheme 7). The relative configuration of this ketone, which
was prepared from enone 36,72 was established by X-
crystallographic analysis (i.e., 40).56 The conformation in the
solid state, which was also favored according to computational
studies,56 is likely the result of minimization of steric
destabilization caused by the relatively large benzoyl group.73
Like ketone 30, this conformation resembles the conformation
expected for the Felkin−Anh model. Nucleophilic attack could
only occur from one face of the carbonyl group, as shown in
structure 39, because the face nearer the SPh group would be
sterically blocked. This ketone must be highly hindered: it did
not react with most organomagnesium reagents, even at room
temperature. On the other hand, addition of allylmagnesium
bromide occurred within minutes at −78 °C to form the
Those criteria can be used to explain the stereoselective
additions to hindered ketone 30.68 For example, the additions
of n-Pr−MgCl and allylmagnesium chloride to ketone 30
proceeded with high diastereoselectivity (Scheme 6; additions
of Me−Li are also highly diastereoselective68). Competition
experiments gave results similar to those obtained for the cyclic
ketones: n-Pr−MgCl reacted slowly with both ketones but
more slowly with the more reactive face of hindered ketone 30,
whereas allylmagnesium chloride reacted rapidly with both
ketones, giving nearly statistical mixtures of products (Table
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respectively), and AV-600 (600 and 150 MHz, respectively)
spectrometers. Spectroscopic data are reported as follows: chemical
Scheme 7. Additions to Ketone 37 and Competition
Experiment
1
shifts are reported in ppm on the δ scale, H and 13C{1H} NMR
spectra are internally referenced to tetramethylsilane (1H NMR:
CDCl3 δ 0.00; 13C{1H} NMR: CDCl3 δ 0.00), multiplicity (br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constants (Hz), and integration. Ratios of products were
obtained from 1H NMR or 13C{1H} NMR integrations using
diagnostic peaks in the unpurified reaction mixture.20 One-pulse H
1
NMR spectra were taken when determining product ratios. Multi-
plicities of carbon peaks were determined using HSQC experiments.
Infrared (IR) spectra were recorded using a Thermo Nicolet
AVATAR Fourier Transform IR spectrometer using attenuated total
reflectance (ATR). High-resolution mass spectra were acquired on an
Agilent 6224 Accurate-Mass time-of-flight spectrometer and were
obtained using peak matching. The ionization sources used were
either atmospheric pressure chemical ionization (APCI) or electro-
spray ionization (ESI), as indicated. Liquid chromatography was
performed using forced flow (flash chromatography) of the indicated
solvent system on silica gel (SiO2) 60 (230−400 mesh).
Tetrahydrofuran, diethyl ether, dichloromethane, and methanol
were dried and degassed using a solvent purification system before
use. All dry reactions were run under a nitrogen atmosphere in
glassware that had been flame-dried under reduced pressure. Unless
otherwise noted, all reagents and substrates were commercially
available. Ketone 30 was prepared using a known method.68
Diastereoselectivities for the additions of Grignard reagents to ketone
30 were previously published.68 Compounds 15,74 19,10 20,75 and
35b76 are known in the literature. Spectroscopic data (1H NMR or
13C{1H} NMR) for the formation of these products in the course of
competition experiments are consistent with the data reported.
2-Bromocyclohexan-1-one (3b). A reported procedure77 was
adapted to prepare ketone 3b. To a solution of cyclohexanone (1.3
mL, 12.0 mmol) in CH2Cl2 (13 mL) was added p-toluenesulfonic
acid monohydrate (0.306 g, 1.22 mmol). The reaction mixture was
cooled to 0 °C, and N-bromosuccinimide (1.596 g, 13.5 mmol) was
added. After 1 h, the mixture was warmed to 20 °C and stirred for an
additional 14 h. Saturated aqueous Na2S2O3 (10 mL) was then added,
the layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (2 × 10 mL) and brine (1 × 10 mL),
dried over Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (5:95 EtOAc/hexanes) afforded ketone 3b as a
light brown oil (1.026 g, 48%). The spectroscopic data (1H NMR and
13C{1H} NMR) are consistent with the data reported in literature.78
2-Chlorocycloheptan-1-one (4a). A reported procedure77 was
adapted to prepare ketone 4a. To a solution of cycloheptanone (1.3
mL, 11.0 mmol) in CH2Cl2 (12 mL) was added p-toluenesulfonic
acid monohydrate (0.215 g, 1.07 mmol). The reaction mixture was
cooled to 0 °C, and N-chlorosuccinimide (1.561 g, 11.7 mmol) was
added. After 1 h, the mixture was warmed to 20 °C and stirred for an
additional 14 h. Saturated aqueous Na2S2O3 (10 mL) was then added,
the layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were washed with
saturated aqueous NaHCO3 (2 × 10 mL) and brine (1 × 10 mL),
dried over Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (5:95 EtOAc/hexanes) afforded ketone 4a as a
colorless oil (1.943 g, 94%). The spectroscopic data (1H NMR,
13C{1H} NMR, and IR) are consistent with the data reported in
literature:79 HRMS (TOF MS ES+) m/z calcd for C7H11O ((M + H)
− HCl)+ 111.0804, found 111.0802.
product as a single stereoisomer,29 as would be expected upon
approach of the nucleophile from the less hindered face of the
ketone (structure 39). Competition experiments gave similar
results to the other examples reported here: addition to the
major diastereoface of the chiral ketone occurred at a similar
rate as addition to the unhindered face of model ketone 41.
The reaction is stereoselective because, after complexation,
addition to one face is particularly slow because it is so
sterically congested, but it can occur from the opposite face.
This analysis is the same as the analysis for 2-bromocycloocta-
none (Scheme 3).
Taken together, the results presented here suggest that
additions of allylmagnesium nucleophiles to carbonyl com-
pounds can proceed with high stereoselectivities. Computa-
tional models can be useful in analyzing stereoselectivities, but
a more qualitative analysis provided similar conclusions. As
long as the ketone adopts a conformer where the two
diastereofaces of the reagent are sterically differentiated,
reactions can be highly stereoselective. Adherence to the
Curtin−Hammett kinetic regime, which is an assumption
behind stereochemical models,8 is not necessary. This analysis
may help explain the stereoselective reactions of allylmagne-
sium reagents with sterically hindered carbonyl compounds, a
situation that applies frequently in the applications of this
reagent in organic synthesis.8
2-Bromocycloheptan-1-one (4b). A reported procedure77 was
used to prepare ketone 4b. To a solution of cycloheptanone (1.3 mL,
11.0 mmol) in CH2Cl2 (13 mL) was added p-toluenesulfonic acid
monohydrate (0.212 g, 1.07 mmol). The reaction mixture was cooled
to 0 °C, and N-bromosuccinimide (1.411 g, 11.7 mmol) was added.
After 1 h, the mixture was warmed to 20 °C and stirred for an
additional 14 h. Saturated aqueous Na2S2O3 (10 mL) was then added,
the layers were separated, and the aqueous layer was extracted with
CH2Cl2 (2 × 20 mL). The combined organic layers were washed with
EXPERIMENTAL SECTION
■
General Experimental Methods. 1H and 13C{1H} NMR spectra
were obtained at room temperature using Bruker AVIII-400 (400 and
100 MHz, respectively), AVIIIHD-400 (400 and 100 MHz,
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saturated aqueous NaHCO3 (2 × 10 mL) and brine (1 × 10 mL),
dried over Na2SO4, filtered, and concentrated in vacuo. Purification by
flash chromatography (5:95 EtOAc/hexanes) afforded ketone 4b as a
yellow oil (1.720 g, 86%). The spectroscopic data (1H NMR, 13C{1H}
NMR, and HRMS) are consistent with the data reported in
literature.80
configuration of ketone 37 was assigned by X-ray crystallographic
analysis: mp = 90−92 °C; H NMR (600 MHz, C6D6) δ 7.75−7.71
1
(m, 2H), 7.14−7.10 (m, 1H), 7.06−7.02 (m, 4H), 6.84−6.81 (m,
3H), 3.62−3.58 (m, 1H), 3.34−3.30 (m, 1H), 2.13−2.01 (m, 2H),
1.90−1.82 (m, 1H), 1.75−1.66 (m, 2H), 1.60−1.54 (m, 1H), 1.33−
1.27 (m, 1H), 1.16−1.07 (m, 1H); 13C{1H} NMR (150 MHz, C6D6)
δ 200.1, 137.6, 136.3, 132.8, 132.1, 129.0, 128.6, 128.5, 127.0, 50.6,
48.3, 31.3, 25.0, 24.2, 22.4; IR (ATR) 2931, 1679, 1446, 1173, 966,
691 cm−1; HRMS (TOF MS APCI+) m/z calcd for C19H21OS (M +
H)+ 297.1308, found 297.1301. Anal. Calcd for C19H20OS: C, 76.98;
H, 6.80. Found: C, 76.72; H, 6.81.
2-Chlorocyclooctan-1-one (5a). A reported procedure77 was
adapted to prepare ketone 5a. To a solution of cyclooctanone
(3.138 g, 24.9 mmol) in CH2Cl2 (25 mL) was added p-
toluenesulfonic acid monohydrate (0.236 g, 2.62 mmol). The reaction
mixture was cooled to 0 °C and N-chlorosuccinimide (3.503 g, 26.3
mmol) was added. After 1 h, the mixture was warmed to 20 °C and
stirred for an additional 14 h. Saturated aqueous Na2S2O3 (20 mL)
was then added, the layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 30 mL). The combined organic layers
were washed with saturated aqueous NaHCO3 (2 × 20 mL) and brine
(1 × 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (5:95 EtOAc/hexanes) afforded
ketone 5a as a colorless oil (2.389 g, 60%). The spectroscopic data
(1H NMR, 13C{1H} NMR, and IR) are consistent with the data
reported in literature:42 HRMS (TOF MS ES+) m/z calcd for
C8H13O ((M + H) − HCl)+ 125.0961, found 125.0962. Anal. Calcd
for C8H13ClO: C, 59.82; H, 8.16. Found: C, 59.58; H, 8.15.
Representative Procedure for Addition of Grignard
Reagents to Ketones ((1R*,2R*)-1-Allyl-2-chlorocyclohexan-
1-ol (anti-7a) and (1R*,2S*)-1-Allyl-2-chlorocyclohexan-1-ol
(syn-7a)). To a cooled (−78 °C) solution of 2-chlorocyclohexanone
(50 μL, 0.44 mmol) in THF (5 mL) was added allylmagnesium
chloride (300 μL, 2.0 M solution in THF, 0.60 mmol). After 30 min,
H2O (20 mL) and HCl (5 mL, 1.0 M in H2O) were added, and the
aqueous layer was extracted with CH2Cl2 (3 × 20 mL). 1H NMR and
13C{1H} NMR spectroscopic analysis of the unpurified reaction
mixture revealed that alcohols 7a were formed as a 76:24 mixture of
diastereomers (anti-7a:syn-7a). Purification by flash chromatography
(5:95 EtOAc/hexanes) afforded the major diastereomer anti-7a as a
colorless oil (0.050 g, 65%) and the minor diastereomer syn-7a as a
colorless oil (0.017 g, 22%). The relative stereochemical config-
2-Bromocyclooctan-1-one (5b). A reported procedure77 was
adapted to prepare ketone 5b. To a solution of cyclooctanone
(3.124 g, 24.8 mmol) in CH2Cl2 (25 mL) was added p-
toluenesulfonic acid monohydrate (0.263 g, 2.9 mmol). The reaction
mixture was cooled to 0 °C and N-bromosuccinimide (4.679 g, 26.3
mmol) was added. After 1 h, the mixture was warmed to 20 °C and
stirred for an additional 14 h. Saturated aqueous Na2S2O3 (20 mL)
was then added, the layers were separated, and the aqueous layer was
extracted with CH2Cl2 (2 × 30 mL). The combined organic layers
were washed with saturated aqueous NaHCO3 (2 × 20 mL) and brine
(1 × 20 mL), dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (5:95 EtOAc/hexanes) afforded
ketone 5b as a light yellow oil (3.220 g, 64%). The spectroscopic data
(1H NMR, 13C{1H} NMR, and IR) are consistent with the data
reported in literature:42 HRMS (TOF MS ES+) m/z calcd for
C8H14BrO (M + H)+ 205.0223, found 205.0219. Anal. Calcd for
C8H13BrO: C, 46.85; H, 6.39. Found: C, 46.84; H, 6.28.
Cyclohex-1-en-1-yl(phenyl)methanone (36). A reported proce-
dure81 was adapted to prepare ketone 36. To a solution of
phenylmagnesium chloride (4.6 mL, 3.0 M solution in Et2O, 14
mmol) in Et2O (1 mL) was slowly added cyclohexene-1-carbonitrile
(0.070 g, 6.5 mmol) over 5 min. The mixture was then heated to 35
°C in a silicone oil bath for 6 h and then cooled to 20 °C and stirred
for an additional 16 h. The mixture was then slowly poured over a
mixture of ice (60 g) and H2SO4 (20 mL, 9.0 M), the layers were
separated, and the aqueous layer was heated at reflux (100 °C) in a
silicone oil bath for 24 h and then stirred at 20 °C for 2 days. The
aqueous layer was then extracted with PhMe (4 × 20 mL), and the
combined organic layers were dried over Na2SO4, filtered, and
concentrated in vacuo. Purification by flash chromatography (5:95
EtOAc/hexanes) afforded ketone 36 as a white solid (1.150 g, 95%).
The spectroscopic data (1H NMR, 13C{1H} NMR, IR, HRMS) are
consistent with the data reported in literature.82
1
urations of alcohols anti-7a and syn-7a were assigned by H NMR
coupling constants (see the Supporting Information for stereo-
chemical proofs).
Major Diastereomer anti-7a: 1H NMR (400 MHz, CDCl3) δ
5.88−5.76 (m, 1H), 5.17−5.11 (m, 2H), 3.99 (dd, J = 10.3, 5.4, 1H),
2.39 (d, J = 7.5, 2H), 2.06−1.91 (m, 3H), 1.89−1.82 (m, 1H), 1.79−
1.70 (m, 1H), 1.68−1.58 (m, 1H), 1.50−1.36 (m, 2H), 1.33−1.22
(m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 133.1 (CH), 119.0
(CH2), 72.9 (C), 68.4 (CH), 45.4 (CH2), 35.1 (CH2), 32.6 (CH2),
25.6 (CH2), 20.8 (CH2); IR (ATR) 3469, 2938, 1447, 981, 915, 756
cm−1; HRMS (TOF MS ES+) m/z calcd for C9H18NO ((M + NH4)
− HCl)+ 156.1383, found 156.1384. Anal. Calcd for C9H15ClO: C,
61.89; H, 8.66. Found: C, 62.04; H, 8.69.
Minor diastereomer syn-7a: 1H NMR (400 MHz, CDCl3) δ
5.97−5.84 (m, 1H), 5.24−5.14 (m, 2H), 3.97 (dd, J = 7.5, 3.7, 1H),
2.55 (dd, J = 14.2, 6.5, 1H), 2.30 (dd, J = 14.1, 8.4, 1H), 2.20−2.12
(m, 1H), 1.95 (br s, 1H) 1.94−1.88 (m, 1H), 1.82−1.70 (m, 2H),
1.66−1.58 (m, 1H), 1.47−1.33 (m, 3H); 13C{1H} NMR (100 MHz,
CDCl3, diagnostic peaks) δ 132.7 (CH), 119.8 (CH2), 73.5 (C), 21.6
(CH2).
(1R*,2R*)-1-Allyl-2-bromocyclohexan-1-ol (anti-7b) and
(1R*,2S*)-1-Allyl-2-bromocyclohexan-1-ol (syn-7b). Alcohols anti-
7b and syn-7b were prepared using the representative procedure for
additions of Grignard reagents to ketones using ketone 3b (0.210 g,
1.19 mmol) and allylmagnesium chloride (680 μL, 2.0 M solution in
THF, 1.36 mmol) in THF (11 mL) at −78 °C for 30 min. 1H NMR
and 13C{1H} NMR spectroscopic analysis of the unpurified reaction
mixture revealed that alcohols 7b were formed as an 87:13 mixture of
diastereomers (anti-7b:syn-7b). Purification by flash chromatography
(5:95 EtOAc/hexanes) afforded the major diastereomer anti-7b as a
colorless oil (0.191 g, 73%) and the minor diastereomer syn-7b as a
colorless oil (0.046 g, 18%). The relative stereochemical config-
Phenyl((1R*,2R*)-2-(phenylthio)cyclohexyl)methanone (37). A
reported procedure72 was adapted to prepare ketone 37. To a
mixture of ketone 36 (1.120 g, 6.01 mmol) and thiophenol (1.25 mL,
12.3 mmol) was added ammonium cerium(IV) nitrate (0.330 g, 0.60
mmol). The resulting solution was degassed and then heated to 35 °C
in a silicone oil bath. After 6 h, the reaction mixture was cooled to 20
°C. After an additional 16 h, the reaction mixture was filtered through
1
urations of the two compounds were assigned by H NMR coupling
constants (see the Supporting Information for stereochemical proofs).
Major Diastereomer anti-7b: 1H NMR (400 MHz, CDCl3) δ
5.87−5.74 (m, 1H), 5.19−5.12 (m, 2H), 4.20 (dd, J = 11.3, 4.5, 1H),
2.39 (d, J = 7.5, 2H), 2.26−2.06 (m, 2H), 1.95−1.89 (m, 2H), 1.75−
1.62 (m, 2H), 1.54−1.44 (m, 2H), 1.34−1.23 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 133.0 (CH), 119.2 (CH2), 72.7 (C), 65.0
(CH), 46.9 (CH2), 35.1 (CH2), 34.0 (CH2), 26.9 (CH2), 21.0
(CH2); IR (ATR) 3551, 2936, 1122, 980, 915, 738 cm−1; HRMS
(TOF MS ES+) m/z calcd for C9H18NO ((M + NH4) − HBr)+
156.1383, found 156.1387. Anal. Calcd for C9H15BrO: C, 49.33; H,
6.90. Found: C, 49.48; H, 6.89.
1
a 1 cm plug of silica with 50:50 EtOAc/hexanes (20 mL). H NMR
spectroscopic analysis of the unpurified reaction mixture revealed that
ketone 37 was formed as a single diastereomer (dr >99:1).
Purification by flash chromatography (5:95 EtOAc/hexanes) afforded
ketone 37 as a white crystalline solid (1.580 g, 89%). X-ray quality
crystals were grown by slow evaporation of a solution of ketone 37 in
a 5:95 mixture of EtOAc/hexanes. The relative stereochemical
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Minor diastereomer syn-7b: 1H NMR (400 MHz, CDCl3,
diagnostic peaks) δ 5.96−5.85 (m, 1H), 5.25−5.15 (m, 2H), 4.17
(dd, J = 8.6, 3.9, 1H), 2.60 (dd, J = 14.2, 6.3, 1H), 2.36 (dd, J = 14.2,
8.5, 1H); 13C{1H} NMR (100 MHz, CDCl3, diagnostic peaks) δ
132.8 (CH), 119.7 (CH2), 73.2 (C).
10a and syn-10a were prepared using the representative procedure for
additions of Grignard reagents to ketones using ketone 5a (0.082 g,
0.51 mmol) and allylmagnesium chloride (300 μL, 2.0 M solution in
1
THF, 0.60 mmol) in THF (5 mL) at −78 °C for 30 min. H NMR
and 13C{1H} NMR spectroscopic analysis of the unpurified reaction
mixture revealed that alcohols 10a were formed as an 89:11 mixture
of diastereomers (anti-10a:syn-10a). Purification by flash chromatog-
raphy (5:95 EtOAc/hexanes) afforded alcohols anti-10a and syn-10a
as a colorless oil (0.073 g, 71%) with a diastereomeric ratio of 88:12
which was used for characterization. The relative stereochemical
configuration of alcohol anti-10a was assigned by correlation to
alcohol anti-10b (see the Supporting Information). IR (ATR) 3558,
2921, 1469, 1029, 913, 711 cm−1; HRMS (TOF MS ES+) m/z calcd
for C11H19ClO (M + Na)+ 225.1017, found 225.1019. Anal. Calcd for
C11H19ClO: C, 65.17; H, 9.45. Found: C, 65.12; H, 9.68.
(1R*,2R*)-1-Allyl-2-chlorocycloheptan-1-ol (anti-9a) and
(1R*,2S*)-1-Allyl-2-chlorocycloheptan-1-ol (syn-9a). Alcohols anti-
9a and syn-9a were prepared using the representative procedure for
additions of Grignard reagents to ketones using ketone 4a (0.153 g,
1.04 mmol) and allylmagnesium chloride (620 μL, 2.0 M solution in
THF, 1.24 mmol) in THF (10 mL) at −78 °C for 30 min. 1H NMR
and 13C{1H} NMR spectroscopic analysis of the unpurified reaction
mixture revealed that alcohols 9a were formed as a 79:21 mixture of
diastereomers (anti-9a:syn-9a). Purification by flash chromatography
(5:95 EtOAc/hexanes) afforded the major diastereomer anti-9a as a
colorless oil (0.119 g, 61%) and the minor diastereomer syn-9a as a
colorless oil (0.032 g, 16%). The relative stereochemical config-
urations of the two diastereomers were assigned by derivatization of
alcohol syn-9a to epoxide 12.
1
Major Diastereomer anti-10a: H NMR (400 MHz, CDCl3) δ
5.95−5.84 (m, 1H), 5.16−5.09 (m, 2H), 4.25 (dd, J = 8.9, 0.9, 1H),
2.60 (dd, J = 14.5, 6.1, 1H), 2.47−2.37 (m, 1H), 2.30 (dd, J = 14.3,
8.4, 1H), 2.13 (s, 1H), 2.08−2.00 (m, 1H), 1.85−1.73 (m, 3H),
1.71−1.57 (m, 4H), 1.49−1.40 (m, 2H), 1.39−1.28 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 133.8 (CH), 118.4 (CH2), 75.8
Major Diastereomer anti-9a: 1H NMR (400 MHz, CDCl3) δ
5.90−5.79 (m, 1H), 5.17−5.10 (m, 2H), 4.04 (dd, J = 10.0, 2.4, 1H),
2.46−2.36 (m, 2H), 2.23−2.14 (m, 2H), 1.96−1.93 (m, 1H), 1.87−
1.72 (m, 4H), 1.61−1.34 (m, 4H); 13C{1H} NMR (100 MHz,
CDCl3) δ 133.3 (CH), 118.7 (CH2), 75.0 (C), 72.5 (CH), 46.1
(CH2), 35.4 (CH2), 32.8 (CH2), 26.8 (CH2), 24.8 (CH2), 19.8
(CH2); IR (ATR) 3561, 2929, 1639, 1443, 996, 723 cm−1; HRMS
(TOF MS ES+) m/z calcd for C10H17O ((M + H) − HCl)+
153.1274, found 153.1281. Anal. Calcd for C10H17ClO: C, 63.65;
H, 9.08. Found: C, 63.87; H, 8.97.
(C), 72.2 (CH), 44.0 (CH2), 34.2 (CH2), 31.8 (CH2), 28.6 (CH2),
26.8 (CH2), 25.0 (CH2), 21.9 (CH2).
Minor diastereomer syn-10a: 1H NMR (400 MHz, CDCl3,
diagnostic peaks) δ 4.56 (dd, J = 9.9, 4.5, 1H); 13C{1H} NMR (100
MHz, CDCl3) δ 133.6 (CH), 118.5 (CH2), 75.7 (C), 71.2 (CH), 40.1
(CH2), 36.1 (CH2), 34.9 (CH2), 29.8 (CH2), 25.9 (CH2), 25.6
(CH2), 21.1 (CH2).
(1R*,2R*)-1-Allyl-2-bromocyclooctan-1-ol (anti-10b) and
(1R*,2S*)-1-Allyl-2-bromocyclooctan-1-ol (syn-10b). Alcohols anti-
10b and syn-10b were prepared using the representative procedure for
additions of Grignard reagents to ketones using ketone 5b (0.217 g,
1.06 mmol) and allylmagnesium chloride (740 μL, 2.0 M solution in
Minor diastereomer syn-9a: 1H NMR (400 MHz, CDCl3) δ
5.98−5.88 (m, 1H), 5.21−5.16 (m, 2H), 4.07 (dd, J = 8.9, 2.4, 1H),
2.62−2.56 (m, 1H), 2.32−2.26 (m, 1H), 2.25−2.20 (m, 1H), 1.97 (s,
1H), 1.88−1.80 (m, 3H), 1.73−1.50 (m, 6H); 13C{1H} NMR (100
MHz, CDCl3) δ 133.3 (CH), 119.4 (CH2), 76.3 (C), 71.4 (CH), 42.1
(CH2), 36.0 (CH2), 32.4 (CH2), 26.4 (CH2), 23.8 (CH2), 20.4
(CH2); IR (ATR) 3461, 2929, 1639, 1238, 997, 916 cm−1; HRMS
(TOF MS APCI+) m/z calcd for C9H18NO ((M + NH4) − HCl)+
156.1383, found 156.1389.
(1R*,2R*)-1-Allyl-2-bromocycloheptan-1-ol (anti-9b) and
(1R*,2S*)-1-Allyl-2-bromocycloheptan-1-ol (syn-9b). Alcohols anti-
9b and syn-9b were prepared using the representative procedure for
additions of Grignard reagents to ketones using ketone 4b (0.098 g,
0.51 mmol) and allylmagnesium chloride (380 μL, 2.0 M solution in
THF, 0.076 mmol) in THF (5 mL) at −78 °C for 30 min. 1H NMR
and 13C{1H} NMR spectroscopic analysis of the unpurified reaction
mixture revealed that alcohols 9b were formed as an 87:13 mixture of
diastereomers (anti-9b:syn-9b). Purification by flash chromatography
(5:95 EtOAc/hexanes) afforded major diastereomer anti-9b as a
colorless oil (0.060 g, 62%) and the minor diastereomer syn-9b as a
colorless oil (0.017 g, 18%). The relative stereochemical config-
urations of the two compounds were assigned by derivatization of
alcohol syn-9b to epoxide 12.
1
THF, 1.5 mmol) in THF (10 mL) at −78 °C for 30 min. H NMR
and 13C{1H} NMR spectroscopic analysis of the unpurified reaction
mixture revealed that alcohols 10b were formed as a 94:6 mixture of
diastereomers (anti-10b:syn-10b). Purification by flash chromatog-
raphy (5:95 EtOAc/hexanes) afforded major diastereomer anti-10b as
a colorless solid (0.193 g, 74%). X-ray quality crystals were grown by
slow evaporation of a solution of alcohol anti-10b in a 5:95 mixture of
EtOAc/hexanes. The relative stereochemical configuration of alcohol
anti-10b was assigned by X-ray crystallographic analysis.
1
Major Diastereomer anti-10b: mp = 34−35 °C; H NMR (400
MHz, CDCl3) δ 5.94−5.82 (m, 1H), 5.16−5.09 (m, 2H), 4.46 (dd, J
= 8.9, 1.0, 1H), 2.66−2.59 (m, 1H), 2.58−2.47 (m, 1H), 2.35−2.23
(m, 2H), 2.08 (br s, 1H), 1.89−1.83 (m, 2H), 1.80−1.55 (m, 5H),
1.51−1.32 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 133.8
(CH), 118.2 (CH2), 75.6 (C), 68.9 (CH), 45.4 (CH2), 35.2 (CH2),
31.2 (CH2), 29.1 (CH2), 26.7 (CH2), 24.9 (CH2), 22.0 (CH2); IR
(ATR) 3546, 2920, 1639, 1026, 991, 913 cm−1; HRMS (TOF MS ES
+) m/z calcd for C11H19O ((M + H) − HBr)+ 167.1430, found
167.1429. Anal. Calcd for C11H19BrO: C, 53.45; H, 7.75. Found: C,
53.44; H, 7.70.
Major Diastereomer anti-9b: 1H NMR (400 MHz, CDCl3) δ
5.90−5.78 (m, 1H), 5.19−5.13 (m, 2H), 4.25 (dd, J = 10.1, 2.4, 1H),
2.50−2.38 (m, 2H), 2.35−2.24 (m, 1H), 2.19−2.15 (m, 1H), 2.12 (s,
1H), 1.88−1.73 (m, 4H), 1.63−1.34 (m, 4H); 13C{1H} NMR (100
MHz, CDCl3) δ 133.4 (CH), 118.9 (CH2), 75.0 (C), 69.7 (CH), 47.4
(CH2), 35.3 (CH2), 34.0 (CH2), 26.8 (CH2), 26.1 (CH2), 20.0
(CH2); IR (ATR) 3547, 2928, 1639, 1443, 1068, 915 cm−1; HRMS
(TOF MS ES+) m/z calcd for C10H17O ((M + H) − HBr)+
153.1274, found 153.1277. Anal. Calcd for C10H17BrO: C, 51.52;
H, 7.35. Found: C, 51.74; H, 7.40.
Minor diastereomer syn-10b: 1H NMR (400 MHz, CDCl3,
diagnostic peaks) δ 4.81 (dd, J = 10.6, 4.1, 1H); 13C{1H} NMR (100
MHz, CDCl3, diagnostic peaks) δ 133.6 (CH), 118.6 (CH2), 68.0
(CH).
(1R*)-1-Phenyl-1-((2S*)-2-(phenylthio)cyclohexyl)but-3-en-1-ol
(38). Alcohol 38 was prepared using the representative procedure for
additions of Grignard reagents to ketones using ketone 37 (0.100 g,
0.34 mmol) and allylmagnesium bromide (680 μL, 1.0 M solution in
1
THF, 0.68 mmol) in THF (6 mL) at −78 °C for 30 min. H NMR
and 13C{1H} NMR spectroscopic analysis of the unpurified reaction
mixture revealed that alcohol 38 was formed as a single diastereomer
(dr >99:1). Purification by flash chromatography (20:80 Et2O/
hexanes) afforded alcohol 38 as a white solid (0.095 g, 84%). X-ray
quality crystals were grown by slow evaporation of a solution of
alcohol 38 in a 20:80 mixture of EtOAc/hexanes. The relative
stereochemical configuration of alcohol 38 was assigned by X-ray
crystallographic analysis: mp = 74−76 °C; 1H NMR (600 MHz,
Minor diastereomer syn-9b: 1H NMR (400 MHz, CDCl3) δ
5.98−5.87 (m, 1H), 5.22−5.17 (m, 2H), 4.27 (dd, J = 9.5, 2.6, 1H),
2.68−2.63 (m, 1H), 2.41−2.31 (m, 2H), 1.98−1.88 (m, 3H), 1.84−
1.57 (m, 7H); 13C{1H} NMR (100 MHz, CDCl3) δ 133.2 (CH),
119.4 (CH2), 76.0 (C), 67.3 (CH), 43.1 (CH2), 36.0 (CH2), 33.3
(CH2), 26.4 (CH2), 25.3 (CH2), 20.4 (CH2).
(1R*,2R*)-1-Allyl-2-chlorocyclooctan-1-ol (anti-10a) and
(1R*,2S*)-1-Allyl-2-chlorocyclooctan-1-ol (syn-10a). Alcohols anti-
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CDCl3) δ 7.40 (d, J = 7.8, 2H), 7.30 (t, J = 7.6, 2H), 7.24−7.20 (m,
1H), 7.12−7.09 (m, 1H), 7.08−7.04 (m, 2H), 6.81−6.78 (m, 2H),
5.55−5.48 (m, 1H), 4.95−4.89 (m, 2H), 4.16−4.14 (m, 1H), 3.10 (s,
1H), 2.76 (dd, J = 13.8, 7.2, 1H), 2.43 (dd, J = 13.8, 7.0, 1H), 2.21−
2.18 (m, 1H), 2.06−2.00 (m, 1H), 1.98−1.89 (m, 2H), 1.70−1.62
(m, 2H), 1.58−1.53 (m, 1H), 1.51−1.44 (m, 1H), 1.42−1.32 (m,
1H); 13C NMR (125 MHz, CDCl3) δ 145.7, 134.7, 134.1, 131.8,
128.8, 128.1, 127.1, 126.4, 126.0, 117.6, 79.4, 50.9, 49.9, 45.7, 33.2,
26.6, 23.0, 21.0; IR (ATR) 3446, 2929, 2856, 1445, 1064, 704 cm−1;
HRMS (TOF MS APCI+) m/z calcd for C22H25S ((M + H) −
H2O)+ 321.1677, found 321.1671. Anal. Calcd for C22H26OS: C,
78.06; H, 7.74. Found: C, 77.90; H, 7.67.
Chloro-1-(phenylethynyl)cyclohexan-1-ol (syn-6a)). To a sol-
ution of phenylacetylene (145 μL, 1.32 mmol) in THF (7 mL) was
added n-butyllithium (880 μL, 1.5 M solution in hexanes, 1.3 mmol)
dropwise over 5 min at −78 °C. After 1 h, the solution was warmed to
20 °C and added by cannula to a cooled (−78 °C) solution of 2-
chlorocyclohexanone (100 μL, 0.876 mmol) in THF (9 mL). After 1
h, the reaction mixture was warmed to 20 °C and stirred for an
additional 3 h. H2O (10 mL) and HCl (10 mL, 1.0 M in H2O) were
then added, the layers were separated, and the aqueous layer was
extracted with CH2Cl2 (3 × 10 mL). The combined organic layers
were washed with brine (1 × 15 mL), dried over Na2SO4, filtered, and
concentrated in vacuo. 1H NMR spectroscopic analysis of the
unpurified reaction mixture revealed that alcohols 6a were formed
as a 94:6 mixture of diastereomers (anti-6a:syn-6a). Purification by
flash chromatography (5:95 EtOAc/hexanes) afforded major
diastereomer anti-6a as a colorless oil (0.140 g, 68%) and the
minor diastereomer syn-6a as a colorless oil (0.003 g, 1%). The
relative stereochemical configuration of the product was assigned by
attempted derivatization of alcohol anti-6a to the epoxide (see the
Supporting Information for stereochemical proofs).
1-Cyclopropyl-1-phenylbutan-1-ol (35a). Alcohol 35a was
prepared using the representative procedure for additions of Grignard
reagents to ketones using ketone 34 (70 μL, 0.5 mmol) and
allylmagnesium chloride (380 μL, 2.0 M solution in THF, 0.76 mmol)
at 20 °C for 16 h. Purification by flash chromatography (3:97 EtOAc/
1
hexanes) afforded alcohol 35a as a colorless oil (0.029 g, 30%): H
NMR (400 MHz, CDCl3) δ 7.49−7.44 (m, 2H), 7.33 (t, J = 7.6, 2H),
7.25−7.21 (m, 1H), 1.93−1.74 (m, 2H), 1.43 (s, 1H), 1.38−1.25 (m,
2H), 1.22−1.09 (m, 1H), 0.87 (t, J = 7.3, 3H), 0.51−0.44 (m, 2H),
0.41−0.34 (m, 1H), 0.33−0.26 (m, 1H); 13C{1H} NMR (100 MHz,
CDCl3) δ 146.6, 127.9, 126.5, 125.5, 75.0, 44.7, 21.8, 17.0, 14.4, 1.4,
0.6; IR (ATR) 3473, 3085, 2871, 1278, 845 cm−1; HRMS (TOF MS
APCI+) m/z calcd for C13H17 ((M + H) − H2O)+ 173.1325, found
173.1235.
Major Diastereomer anti-6a: 1H NMR (400 MHz, CDCl3) δ
7.47−7.42 (m, 2H), 7.33−7.28 (m, 3H), 4.28 (dd, J = 9.3, 4.0, 1H),
2.63 (br s, 1H), 2.30−2.21 (m, 1H), 2.17−2.08 (m, 1H), 2.07−1.96
(m, 1H), 1.89−1.65 (m, 3H), 1.64−1.55 (m, 1H), 1.48−1.36 (m,
1H); 13C{1H} NMR (100 MHz, CDCl3) δ 131.9 (CH), 128.7 (C),
128.4 (CH), 122.5 (CH), 90.8 (C), 84.7 (C), 70.0 (C), 68.1 (CH),
37.4 (CH2), 31.9 (CH2), 23.6 (CH2), 21.0 (CH2); IR (ATR) 3447,
2940, 1443, 1063, 945, 754 cm−1; HRMS (TOF MS APCI+) m/z
calcd for C14H14Cl ((M + H) − H2O)+ 217.0779, found 217.0777.
Anal. Calcd for C14H15ClO: C, 71.64; H, 6.44. Found: C, 71.48; H,
6.65.
1-Cyclohexyl-1-phenylbut-3-en-1-ol (42). Alcohol 42 was pre-
pared using the representative procedure for additions of Grignard
reagents to ketones using ketone 41 (0.099 g, 0.53 mmol) and
allylmagnesium chloride (530 μL, 2.0 M solution in THF, 1.06 mmol)
in THF (5 mL) at −78 °C for 30 min. Purification by flash
chromatography (5:95 EtOAc/hexanes) afforded alcohol 42 as a
Minor diastereomer syn-6a: 1H NMR (400 MHz, CDCl3) δ
7.51−7.45 (m, 2H), 7.35−7.30 (m, 3H), 3.91 (dd, J = 12.1, 4.1, 1H),
3.02 (br s, 1H), 2.34−2.27 (m, 1H), 2.22−2.14 (m, 1H), 2.06−1.93
(m, 1H), 1.85−1.58 (m, 5H); 13C{1H} NMR (100 MHz, CDCl3) δ
132.0 (CH), 128.7 (C), 128.4 (CH), 122.5 (CH), 88.2 (C), 87.0 (C),
73.7 (C), 69.3 (CH), 38.8 (CH2), 34.4 (CH2), 25.8 (CH2), 23.3
(CH2).
1
colorless oil (0.107 g, 88%): H NMR (100 MHz, CDCl3) δ 7.38−
7.29 (m, 4H), 7.25−7.19 (m, 1H), 5.54−5.42 (m, 1H), 5.16−5.03
(m, 2H), 2.81 (dd, J = 13.7, 5.5, 1H), 2.55 (dd, J = 13.7, 9.0, 1H),
1.97 (br s, 1H), 1.95−1.88 (m, 1H), 1.80−1.72 (m, 1H), 1.69−1.57
(m, 3H), 1.54−1.47 (m, 1H), 1.28−0.91 (m, 5H); 13C{1H} NMR
(100 MHz, CDCl3) δ 145.2 (C), 134.0 (CH), 127.7 (CH), 126.3
(CH), 126.1 (CH), 119.6 (CH2), 77.7 (C), 48.3 (CH), 43.6 (CH2),
27.4 (CH2), 26.9 (CH2), 26.7 (CH2), 26.6 (CH2), 26.4 (CH2); IR
(ATR) 3561, 2927, 1445, 989, 762, 702 cm−1; HRMS (TOF MS ES
+) m/z calcd for C16H21 ((M + H) − H2O)+ 213.1638, found
213.1640.
(1R*,2R*)-2-Bromo-1-(phenylethynyl)cyclohexan-1-ol (anti-6b).
Alcohol anti-6b was prepared using the representative procedure for
the additions of lithium phenylacetylide to ketones. Lithium
phenylacetylide was generated using phenylacetylene (90 μL, 0.82
mmol) and n-butyllithium (500 μL, 1.5 M solution in hexanes, 0.75
mmol) in THF (4 mL), then added to a solution of ketone 3b (0.088
g, 0.50 mmol) in THF (5 mL) at −78 °C for 1 h, and then warmed to
20 °C for 16 h. 13C{1H} NMR spectroscopic analysis of the
unpurified reaction mixture revealed that alcohol anti-6b was formed
as a single diastereomer (dr >99:1). Purification by flash
chromatography (5:95 EtOAc/hexanes) afforded alcohol anti-6b as
a light yellow oil (0.082 g, 59%). The relative stereochemical
configuration of the product was assigned by attempted derivatization
of alcohol anti-6b to the epoxide (see the Supporting Information for
1-Allylcycloheptan-1-ol (16). Alcohol 16 was prepared using the
representative procedure for additions of Grignard reagents to ketones
using cycloheptanone (105 μL, 0.685 mmol) and allylmagnesium
chloride (410 μL, 2.0 M solution in THF, 0.820 mmol) in THF (7
mL) at −78 °C for 30 min. Purification by flash chromatography
(5:95 EtOAc/hexanes) afforded alcohol 16 as a colorless oil (0.096 g,
90%). The spectroscopic data (1H NMR and 13C{1H} NMR) are
consistent with the data reported in literature:83 IR (ATR) 3381,
2921, 1459, 1024, 908, 721 cm−1; HRMS (TOF MS ES+) m/z calcd
for C10H17 ((M + H) − H2O)+ 137.1325, found 137.1324. Anal.
Calcd for C10H18O: C, 77.87; H, 11.76. Found: C, 77.70; H, 11.99.
1-Allylcyclooctan-1-ol (17). Alcohol 17 was prepared using the
representative procedure for additions of Grignard reagents to ketones
using cyclooctanone (0.100 g, 0.792 mmol) and allylmagnesium
chloride (475 μL, 2.0 M solution in THF, 0.950 mmol) in THF (4
mL) at −78 °C for 30 min. Purification by flash chromatography
(5:95 EtOAc/hexanes) afforded alcohol 17 as a colorless oil (0.127 g,
95%): 1H NMR (400 MHz, CDCl3) δ 5.96−5.84 (m, 1H), 5.17−5.07
(m, 2H), 2.22 (d, J = 7.5, 2H), 1.80−1.71 (m, 2H), 1.69−1.59 (m,
5H), 1.57−1.34 (m, 8H); 13C{1H} NMR (100 MHz, CDCl3) δ 134.1
(CH), 118.7 (CH2), 74.4 (C), 46.0 (CH2), 36.2 (CH2), 28.2 (CH2),
25.0 (CH2), 22.2 (CH2); IR (ATR) 3412, 2918, 1447, 1147, 999, 909
cm−1; HRMS (TOF MS ES+) m/z calcd for C11H19 ((M + H) −
H2O)+ 151.1481, found 151.1485.
1
stereochemical proofs): H NMR (400 MHz, CDCl3) δ 7.47−7.42
(m, 2H), 7.34−7.29 (m, 3H), 4.46 (dd, J = 9.3, 4.4, 1H), 2.62 (br s,
1H), 2.37−2.28 (m, 1H), 2.26−2.10 (m, 2H), 1.93−1.83 (m, 1H),
1.81−1.67 (m, 2H), 1.67−1.58 (m, 1H), 1.48−1.37 (m, 1H);
13C{1H} NMR (100 MHz, CDCl3) δ 131.8 (CH), 128.6 (CH), 128.3
(C), 122.3 (CH), 91.1 (C), 84.3 (C), 69.6 (C), 63.4 (CH), 37.5
(CH2), 32.8 (CH2), 24.9 (CH2), 20.9 (CH2); IR (ATR) 3444, 2938,
1443, 1060, 975, 754 cm−1; HRMS (TOF MS ES+) m/z calcd for
C14H14Br ((M + H) − H2O)+ 261.0273, found 261.0279.
(1R*,2R*)-2-Chloro-1-(phenylethynyl)cycloheptan-1-ol (anti-
8a). Alcohol anti-8a was prepared using the representative procedure
for the additions of lithium phenylacetylide to ketones. Lithium
phenylacetylide was generated using phenylacetylene (90 μL, 0.82
mmol) and n-butyllithium (500 μL, 1.5 M solution in hexanes, 0.75
mmol) in THF (4 mL), then added to a solution of ketone 4a (0.077
g, 0.53 mmol) in THF (5 mL) at −78 °C for 1 h, and then warmed to
20 °C for 16 h. 13C{1H} NMR spectroscopic analysis of the
unpurified reaction mixture revealed that alcohol anti-8a was formed
Representative Procedure for the Additions of Lithium
Phenylacetylide to Ketones ((1R*,2R*)-2-Chloro-1-
(phenylethynyl)cyclohexan-1-ol (anti-6a) and (1R*,2S*)-2-
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as a single diastereomer (dr >99:1). Purification by flash
chromatography (5:95 EtOAc/hexanes) afforded alcohol anti-8a as
a light yellow oil (0.054 g, 52%). The relative stereochemical
configuration of the product was assigned by attempted derivatization
of alcohol anti-8a to the epoxide (see the Supporting Information for
Competition Experiment between Ketone 3b and Cyclo-
hexanone for Allylmagnesium Chloride. The competition
experiment with ketone 3b and cyclohexanone was performed
following the representative procedure for competition experiments
with allylmagnesium chloride using ketone 3b (0.052 g, 0.30 mmol)
and cyclohexanone (31 μL, 0.30 mmol) in THF (3 mL) with
allylmagnesium chloride (380 μL, 0.20 M solution in THF, 0.076
mmol). 13C{1H} NMR spectroscopic analysis of the unpurified
reaction mixture revealed a 30:70 mixture of products (anti-7b:15).
Alcohol anti-7b was formed as a single diastereomer (dr >99:1).
Competition Experiment between Ketone 4a and Cyclo-
heptanone for Allylmagnesium Chloride. The competition
experiment with ketone 4a and cycloheptanone was performed
following the representative procedure for competition experiments
with allylmagnesium chloride using ketone 4a (0.045 g, 0.31 mmol)
and cycloheptanone (35 μL, 0.30 mmol) in THF (3 mL) with
allylmagnesium chloride (380 μL, 0.20 M solution in THF, 0.076
mmol). 13C{1H} NMR spectroscopic analysis of the unpurified
reaction mixture revealed a 59:41 mixture of products (anti-9a:16).
Alcohol anti-9a was formed as a single diastereomer (dr >99:1).
Competition Experiment between Ketone 4b and Cyclo-
heptanone for Allylmagnesium Chloride. The competition
experiment with ketone 4b and cycloheptanone was performed
following the representative procedure for competition experiments
with allylmagnesium chloride using ketone 4b (0.060 g, 0.31 mmol)
and cycloheptanone (35 μL, 0.30 mmol) in THF (3 mL) with
allylmagnesium chloride (380 μL, 0.20 M solution in THF, 0.076
mmol). 13C{1H} NMR spectroscopic analysis of the unpurified
reaction mixture revealed a 40:60 mixture of products (anti-9b:16).
Alcohol anti-9b was formed as a single diastereomer (dr >99:1).
Competition Experiment between Ketone 5a and Cyclo-
octanone for Allylmagnesium Chloride. The competition
experiment with ketone 5a and cyclooctanone was performed
following the representative procedure for competition experiments
with allylmagnesium chloride using ketone 5a (0.040 g, 0.30 mmol)
and cyclooctanone (0.038 g, 0.30 mmol) in THF (3 mL) with
allylmagnesium chloride (380 μL, 0.20 M solution in THF, 0.076
mmol). 13C{1H} NMR spectroscopic analysis of the unpurified
reaction mixture revealed a 42:58 mixture of products (10a:17).
Alcohols anti-10a and syn-10a were formed as a 90:10 mixture of
diastereomers.
Competition Experiment between Ketone 5b and Cyclo-
octanone for Allylmagnesium Chloride. The competition
experiment with ketone 5b and cyclooctanone was performed
following the representative procedure for competition experiments
with allylmagnesium chloride using ketone 5b (0.062 g, 0.30 mmol)
and cyclooctanone (0.038 g, 0.30 mmol) in THF (3 mL) with
allylmagnesium chloride (380 μL, 0.20 M solution in THF, 0.076
mmol). 13C{1H} NMR spectroscopic analysis of the unpurified
reaction mixture revealed a 68:32 mixture of products (anti-10b:17).
Alcohol anti-10b was formed as a single diastereomer (dr >99:1).
Competition Experiment between Ketone 5b and Propio-
phenone for Allylmagnesium Chloride. The competition experi-
ment with ketone 5b and propiophenone was performed following the
representative procedure for competition experiments with allylmag-
nesium chloride using ketone 5b (0.064 g, 0.31 mmol) and
propiophenone (31 μL, 0.30 mmol) in THF (3 mL) with
allylmagnesium chloride (380 μL, 0.20 M solution in THF, 0.076
mmol). 13C{1H} NMR spectroscopic analysis of the unpurified
reaction mixture revealed a 31:69 mixture of products (anti-10b:19).
Alcohol anti-10b was formed as a single diastereomer (dr >99:1).
Competition Experiment between Ketone 3a and Cyclo-
hexanone for Lithium Phenylacetylide. To a solution of ketone
3a (34 μL, 0.30 mmol) and cyclohexanone (31 μL, 0.30 mmol) in
THF (3 mL) was added lithium phenylacetylide (380 μL, 0.20 M
solution in THF, 0.076 mmol) dropwise over 5 min. After 4 h, MeOH
(1 mL) was added and the reaction mixture was concentrated in
vacuo. The resulting oil was dissolved in CDCl3 then filtered through a
plug of SiO2. 13C{1H} NMR spectroscopic analysis of the unpurified
1
stereochemical proofs): H NMR (400 MHz, CDCl3) δ 7.45−7.43
(m, 2H), 7.32−7.29 (m, 3H), 4.41−4.38 (m, 1H), 2.80 (br s, 1H),
2.21−2.08 (m, 4H), 1.92−1.79 (m, 2H), 1.74−1.69 (m, 1H), 1.66−
1.51 (m, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 131.8 (CH),
128.5 (CH), 128.3 (CH), 122.4 (C), 91.4 (C), 84.3 (C), 73.0 (C),
72.3 (CH), 38.2 (CH2), 32.1 (CH2), 26.6 (CH2), 23.9 (CH2), 20.4
(CH2); IR (ATR) 3438, 2933, 1490, 1443, 1033, 754 cm−1; HRMS
(TOF MS ES+) m/z calcd for C15H16Cl ((M + H) − H2O)+
231.0935, found 231.0940.
(1R*,2R*)-2-Bromo-1-(phenylethynyl)cycloheptan-1-ol (anti-
8b). Alcohol anti-8b was prepared using the representative procedure
for the additions of lithium phenylacetylide to ketones. Lithium
phenylacetylide was generated using phenylacetylene (95 μL, 0.87
mmol) and n-butyllithium (520 μL, 1.5 M solution in hexanes, 0.94
mmol) in THF (4 mL), then added to a solution of ketone 4b (0.093
g, 0.58 mmol) in THF (5 mL) at −78 °C for 1 h, and then warmed to
20 °C for 2 h. 13C{1H} NMR spectroscopic analysis of the unpurified
reaction mixture revealed that alcohol anti-8b was formed as a single
diastereomer (dr >99:1). Purification by flash chromatography (5:95
EtOAc/hexanes) afforded alcohol anti-8b as a colorless oil (0.078 g,
46%). The relative stereochemical configuration of the product was
assigned by attempted derivatization of alcohol anti-8b to the epoxide
(see the Supporting Information for stereochemical proofs): 1H NMR
(400 MHz, CDCl3) δ 7.45−7.42 (m, 2H), 7.32−7.30 (m, 3H), 4.56
(dd, J = 8.3, 3.1, 1H), 2.76 (s, 1H), 2.32−2.12 (m, 4H), 1.91−1.78
(m, 2H), 1.75−1.70 (m, 1H), 1.66−1.58 (m, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 131.9 (CH), 128.7 (C), 128.4 (CH), 122.5
(CH), 91.7 (C), 84.2 (C), 73.0 (C), 68.0 (CH), 38.7 (CH2), 33.1
(CH2), 26.7 (CH2), 25.4 (CH2), 20.6 (CH2); IR (ATR) 3449, 1489,
1443, 1025, 923, 754 cm−1; HRMS (TOF MS APCI+) m/z calcd for
C15H16Br ((M + H) − H2O)+ 275.0430, found 275.0428. Anal. Calcd
for C15H17BrO: C, 61.45; H, 5.84. Found: C, 61.16; H, 5.83.
Reaction of Ketone 5a with Lithium Phenylacetylide. The
reaction of ketone 5a with lithium phenylacetylide was performed
following the representative procedure for the additions of lithium
phenylacetylide to ketones. Lithium phenylacetylide was generated
using phenylacetylene (110 μL, 1.00 mmol) and n-butyllithium (625
μL, 1.5 M solution in hexanes, 0.94 mmol) in THF (4 mL), then
added to a solution of ketone 5a (0.093 g, 0.58 mmol) in THF (6
mL) at −78 °C for 1 h, and then warmed to 20 °C for 2 h. 13C{1H}
NMR spectroscopic analysis of the unpurified reaction mixture
revealed the presence of only starting material.
Reaction of Ketone 5b with Lithium Phenylacetylide. The
reaction of ketone 5b with lithium phenylacetylide was performed
following the representative procedure for the additions of lithium
phenylacetylide to ketones. Lithium phenylacetylide was generated
using phenylacetylene (90 μL, 0.82 mmol) and n-butyllithium (500
μL, 1.5 M solution in hexanes, 0.75 mmol) in THF (4 mL), then
added to a solution of ketone 5b (0.103 g, 0.51 mmol) in THF (5
mL) at −78 °C for 1 h, and then warmed to 20 °C for 3 h. 13C{1H}
NMR spectroscopic analysis of the unpurified reaction mixture
revealed the presence of only starting material.
Representative Procedure for Competition Experiments
between Two Ketones (Ketone 3a and Cyclohexanone) for
Allylmagnesium Chloride. To a cooled (−78 °C) solution of
ketone 3a (35 μL, 0.31 mmol) and cyclohexanone (31 μL, 0.30
mmol) in THF (3 mL) was added allylmagnesium chloride (380 μL,
0.20 M solution in THF, 0.076 mmol) dropwise over 45 min by
syringe pump. After the full volume of nucleophile was added, MeOH
(1 mL) was added, and the reaction mixture was warmed to room
temperature over 15 min then concentrated in vacuo. The resulting oil
was dissolved in CDCl3 then filtered through a plug of SiO2. 13C{1H}
NMR spectroscopic analysis of the unpurified reaction mixture
revealed a 56:44 mixture of products (7a:15). Alcohols anti-7a and
syn-7a were formed as a 72:28 mixture of diastereomers.
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reaction mixture revealed that alcohol 20 was the only product
formed.
Reaction of Alcohol anti-6a with Potassium Carbonate. To a
solution of alcohol anti-6a (0.024 g, 0.100 mmol, dr >99:1) in MeOH
(5 mL) was added K2CO3 (0.037 g, 0.27 mmol) at 0 °C. After 1 h, the
reaction mixture was warmed to 20 °C and stirred for an additional 16
h. H2O (2 mL) was then added, the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. 1H NMR and 13C{1H} NMR spectroscopic analysis of the
unpurified reaction mixture revealed the presence of only alcohol anti-
6a (dr >99:1).
Reaction of Alcohol anti-6b with Potassium Carbonate. To
a solution of alcohol anti-6b (0.015 g, 0.054 mmol, dr >99:1) in
MeOH (3 mL) was added K2CO3 (0.023 g, 0.17 mmol) at 0 °C. After
1 h, the reaction mixture was warmed to 20 °C and stirred for an
additional 16 h. H2O (2 mL) was then added, the layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo. 1H NMR and 13C{1H} NMR
spectroscopic analysis of the unpurified reaction mixture revealed
the presence of only alcohol anti-6b (dr >99:1).
Reaction of Alcohol anti-8a with Potassium Carbonate. To a
solution of alcohol anti-8a (0.017 g, 0.068 mmol, dr >99:1) in MeOH
(4 mL) was added K2CO3 (0.028 g, 0.20 mmol) at 0 °C. After 1 h, the
reaction mixture was warmed to 20 °C and stirred for an additional 16
h. H2O (2 mL) was then added, the layers were separated, and the
aqueous layer was extracted with CH2Cl2 (3 × 5 mL). The combined
organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. 1H NMR and 13C{1H} NMR spectroscopic analysis of the
unpurified reaction mixture revealed the presence of only alcohol anti-
8a (dr >99:1).
Reaction of Alcohol anti-8b with Potassium Carbonate. To
a solution of alcohol anti-8b (0.010 g, 0.034 mmol, dr >99:1) in
MeOH (4 mL) was added K2CO3 (0.025 g, 0.18 mmol) at 0 °C. After
1 h, the reaction mixture was warmed to 20 °C and stirred for an
additional 16 h. H2O (2 mL) was then added, the layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo. 1H NMR and 13C{1H} NMR
spectroscopic analysis of the unpurified reaction mixture revealed
the presence of only alcohol anti-8b (dr >99:1).
Competition Experiment between Ketone 30 and Ketone
34 for n-Propylmagnesium Chloride. To a solution of ketone 30
(0.090 g, 0.30 mmol) and ketone 34 (41 μL, 0.30 mmol) in THF (3
mL) was added n-propylmagnesium chloride (40 μL, 2.0 M solution
in THF, 0.080 mmol) dropwise over 5 min. After 16 h, MeOH (1
mL) was added and the reaction mixture was concentrated in vacuo.
The resulting oil was dissolved in CDCl3 then filtered through a plug
of SiO2. 13C{1H} NMR spectroscopic analysis of the unpurified
reaction mixture revealed that alcohol 35a was the only product
formed.
Competition Experiment between Ketone 30 and Ketone
34 for Allylmagnesium Chloride. The competition experiment
with ketone 30 and ketone 34 was performed following the
representative procedure for competition experiments with allylmag-
nesium chloride using ketone 30 (0.089 g, 0.30 mmol) and ketone 34
(40 μL, 0.29 mmol) in THF (3 mL) with allylmagnesium chloride
(380 μL, 0.20 M solution in THF, 0.076 mmol). 13C{1H} NMR
spectroscopic analysis of the unpurified reaction mixture revealed a
34:66 mixture of products (31b:35b). Alcohol 31b was formed as a
single diastereomer (dr >99:1).
Competition Experiment between Ketone 37 and Ketone
41 for Allylmagnesium Chloride. The competition experiment
with ketone 37 and ketone 41 was performed following the
representative procedure for competition experiments with allylmag-
nesium chloride using ketone 37 (0.089 g, 0.30 mmol) and ketone 41
(0.056 g, 0.30 mmol) in THF (6 mL) with allylmagnesium chloride
(375 μL, 2.0 M solution in THF, 0.075 mmol). 13C{1H} NMR
spectroscopic analysis of the unpurified reaction mixture revealed a
33:67 mixture of products (38:42). Alcohol 38 was formed as a single
diastereomer (dr >99:1).
(1R*,7R*)-1-Allyl-8-oxabicyclo[5.1.0]octane (12). A reported
procedure30 was adapted to prepare epoxide 12. To a solution of
alcohol syn-9a (0.022 g, 0.12 mmol, dr >99:1) in MeOH (10 mL) was
added K2CO3 (0.075 g, 0.54 mmol) at 0 °C. After 1 h, the reaction
mixture was warmed to 20 °C and stirred for an additional 16 h. H2O
(5 mL) was then added, the layers were separated, and the aqueous
layer was extracted with CH2Cl2 (3 × 15 mL). The combined organic
layers were dried over Na2SO4, filtered, and concentrated in vacuo.
Purification by flash chromatography (5:95 EtOAc/hexanes) afforded
1
epoxide 12 as a colorless oil (0.012 g, 68%): H NMR (400 MHz,
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.1c00553.
■
CDCl3) δ 5.85−5.74 (m, 1H), 5.13−5.06 (m, 2H), 2.92 (dd, J = 6.7,
3.4, 1H), 2.36−2.24 (m, 2H), 1.99−1.73 (m, 4H), 1.54−1.40 (m,
5H), 1.34−1.24 (m, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 133.8
(CH), 117.9 (CH2), 62.9 (C), 61.6 (CH), 42.6 (CH2), 32.7 (CH2),
31.4 (CH2), 29.4 (CH2), 24.9 (CH2), 24.6 (CH2); IR (ATR) 2922,
1641, 1443, 998, 913, 842 cm−1; HRMS (TOF MS APCI+) m/z calcd
for C10H17O (M + H)+ 153.1274, found 153.1272.
sı
Experimental information, crystallographic data, and
spectra (PDF)
Reaction of Alcohol anti-9a with Potassium Carbonate. To a
solution of alcohol anti-9a (0.049 g, 0.26 mmol, dr >99:1) in MeOH
(15 mL) was added K2CO3 (0.095 g, 0.69 mmol) at 0 °C. After 1 h,
the reaction mixture was warmed to 20 °C and stirred for an
additional 16 h. H2O (10 mL) was then added, the layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo. 1H NMR and 13C{1H} NMR
spectroscopic analysis of the unpurified reaction mixture revealed
the presence of only alcohol anti-9a (dr >99:1).
(1R*,7R*)-1-Allyl-8-oxabicyclo[5.1.0]octane (12). A reported
procedure30 was adapted to prepare epoxide 12. To a solution of
alcohols anti-9b and syn-9b (0.010 g, 0.043 mmol, dr = 40:60) in
MeOH (1 mL) was added K2CO3 (0.018 g, 0.13 mmol) at 0 °C. After
1 h, the reaction mixture was warmed to 20 °C and stirred for an
additional 16 h. H2O (2 mL) was then added, the layers were
separated, and the aqueous layer was extracted with CH2Cl2 (3 × 5
mL). The combined organic layers were dried over Na2SO4, filtered,
and concentrated in vacuo. 1H NMR and 13C{1H} NMR
spectroscopic analysis of the unpurified reaction mixture revealed a
mixture of epoxide 12 (56%) and alcohol anti-9b (44%, dr >99:1).
Accession Codes
CCDC 2055343−2055346 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
K. A. Woerpel − Department of Chemistry, New York
University, New York, NY 10003, United States;
orcid.org/0000-0002-8515-0301; Email: kwoerpel@
nyu.edu
Authors
Nicole D. Bartolo − Department of Chemistry, New York
University, New York, NY 10003, United States;
orcid.org/0000-0002-9907-7774
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Article
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Reactions of Allylmagnesium Halides with Carbonyl Compounds:
Reactivity, Structure, and Mechanism. Synthesis 2017, 49, 3237.
(13) Loos, R.; Kobayashi, S.; Mayr, H. Ambident Reactivity of the
Thiocyanate Anion Revisited: Can the Product Ratio Be Explained by
the Hard Soft Acid Base Principle? J. Am. Chem. Soc. 2003, 125,
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Krystyna M. Demkiw − Department of Chemistry, New York
University, New York, NY 10003, United States;
orcid.org/0000-0001-5457-3291
Elizabeth M. Valentín − St. Mary’s College of California,
Moraga, California 94575, United States
Chunhua T. Hu − Department of Chemistry, New York
University, New York, NY 10003, United States;
orcid.org/0000-0002-8172-2202
Alya A. Arabi − Biochemistry Department, College of Medicine
and Health Sciences, United Arab Emirates University, Al
Ain, United Arab Emirates; Centre for Computational
Science, University College London, London WC1H 0AJ,
United Kingdom; orcid.org/0000-0003-3664-314X
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.1c00553
Author Contributions
The manuscript was written through contributions of all
authors. All authors have given approval to the final version of
the manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the National Institutes of
Health, National Institute of General Medical Sciences
(1R01GM129286). We acknowledge NYU’s Shared Instru-
mentation Facility and the support provided by NSF award
CHE-01162222 and NIH award S10-OD016343. We thank
Dr. Chin Lin (NYU) for his help with NMR data. The X-ray
facility at NYU was supported partially by the National Science
Foundation (NSF) Chemistry Research Instrumentation and
Facilities Program (CHE-0840277) and Materials Research
Science and Engineering Center (MRSEC) Program (DMR-
1420073).
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