Mechanistic Insight into Additions of Allylic Grignard Reagents to Carbonyl Compounds

Article abstract of DOI:10.1021/acs.joc.8b01430

Allylic Grignard reagents exhibit high reactivity and low selectivity in additions to carbonyl compounds. Additions of allylic Grignard reagents to carbonyl compounds were investigated using prenylmagnesium chloride as a mechanistic probe. When the carbonyl group is relatively unhindered, the addition proceeds through a six-membered transition state with allylic transposition. This process generally occurs with no diastereoselectivity because the reaction rates approach the diffusion limit. With hindered ketones, however, this pathway is disfavored, and the addition proceeds through a transition state resembling that of other Grignard reagents.

Full text of DOI:10.1021/acs.joc.8b01430

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Article
Mechanistic Insight into Additions of Allylic
Grignard Reagents to Carbonyl Compounds
Nicole D. Bartolo, and K. A. Woerpel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01430 • Publication Date (Web): 06 Aug 2018
Downloaded from http://pubs.acs.org on August 8, 2018
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Mechanistic Insight into Additions of Allylic Grignard Reagents to Carbonyl Compounds
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Nicole D. Bartolo and K. A. Woerpel*
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Department of Chemistry, New York University
100 Washington Square East, New York, New York 10003
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Abstract: Allylic Grignard reagents exhibit high reactivity and low selectivity in additions to
carbonyl compounds. Additions of allylic Grignard reagents to carbonyl compounds were
investigated using prenylmagnesium chloride as a mechanistic probe. When the carbonyl group is
relatively unhindered, the addition proceeds through a six-membered transition state with allylic
transposition. This process generally occurs with no diastereoselectivity because the reaction rates
approach the diffusion limit. With hindered ketones, however, this pathway is disfavored and the
addition proceeds through a four-membered transition state.
Introduction
Commercially available allylic magnesium halides are commonly used to incorporate
alkene functional groups into a molecule.1-3 Their high reactivity enables them to react with
sterically hindered carbonyl compounds in cases where other allylmetal reagents do not add.4-7
Additions of allylmagnesium halides to carbonyl compounds, however, can occur with lower
stereoselectivity than additions of other organomagnesium reagents.1,2 The low selectivity
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observed in reactions of allylic magnesium halides arises because reaction rates approach the
diffusion limit.8-10 The mechanism responsible for this unique behavior has not been established,
however.
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Several mechanisms can be considered to explain the additions of allylic Grignard reagents
to carbonyl compounds.11-16 The additions of Grignard reagents to carbonyl compounds may
proceed through monomeric, four-centered transition states resembling 1 or through dimeric, six-
centered transition states such as 2 (Scheme 1).14,16-18 Allylic Grignard reagents, however, have
two other pathways available. They may add to carbonyl compounds via a monomeric, six-
membered transition state with allylic transposition (3).11,13 An open SE2’-like transition state (4)14
is also possible, although more recent mechanistic data suggest that this pathway is unlikely.1,19,20
In this Article, we provide experimental evidence that is most consistent with the reactions of
allylic Grignard reagents with unhindered carbonyl compounds reacting through a six-membered
transition state with allylic transposition (i.e., transition state 3). Furthermore, we describe
experiments that suggest this transition state is responsible for the rapid and unselective reactions
of allylic Grignard reagents.
Scheme 1. Possible concerted mechanisms for the addition of allylmagnesium halide to a
carbonyl compound.
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Prenylmagnesium chloride 5 was used as a probe to gain insight into the transition state for
addition of allylic Grignard reagents to carbonyl compounds. Spectroscopic data show that
prenylmagnesium halides exist as the regioisomer with the magnesium atom bound to the least
substituted carbon atom (5, eq 1).21-25 Consequently, the regiochemistry of the addition of
prenylmagnesium chloride to a carbonyl compound can be used to infer the pathway through
which allylic Grignard reagents likely react (Scheme 2). Addition may occur through transition
states 1 or 2, resulting in the α-addition product, alcohol 7. If addition proceeds through the six-
membered transition state 3, however, the γ-addition product, alcohol 8, will be observed due to
allylic transposition.13,26 It is also possible that a six-membered transition state resembling 3 could
lead to the α-addition product 7, but such a mechanism would require reaction through the high-
energy isomer of the reagent (i.e., 6), which is unlikely.25,27 Both γ-addition and α-addition
products have been observed in the reactions of allylic Grignard reagents with various carbonyl
compounds,3,28,29 but the origin of the variation in regioselectivity has not been determined.
Furthermore, no studies have shown the transition from one pathway to the other depending upon
the steric hinderance of the electrophile.
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Scheme 2. Potential products of the two concerted pathways for the addition of
prenylmagnesium chloride 5 to a carbonyl compound.
Results and Discussion
Initial studies focused on establishing that prenylmagnesium chloride reacts at a
comparable rate to allylmagnesium halides (i.e., at the diffusion rate limit) with unhindered
ketones.8 Just like allylmagnesium halides, prenylmagnesium chloride was found to be more
reactive with propiophenone (9) than other alkylmagnesium reagents were (eq 2). The addition
products of the other Grignard reagents were not observed when prenylmagnesium chloride was
competed against both methylmagnesium chloride and isopentylmagnesium bromide. When
prenylmagnesium chloride was competed against allylmagnesium chloride, however,
approximately equal amounts of prenylated and allylated products were formed. These
observations indicate that the addition of allylmagnesium chloride and prenylmagnesium chloride
occur at comparable rates. Considering that previous studies indicate that allylmagnesium chloride
reacts at rates approaching the diffusion limit, it may be concluded that prenylmagnesium chloride
also reacts at that rate with relatively unhindered ketones.8
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Intermolecular competition experiments demonstrate that prenylmagnesium chloride, like
allylmagnesium halides, reacts with low chemoselectivity between an aldehyde and a ketone. This
lack of selectivity observed with allylic magnesium reagents is consistent with diffusion-controlled
addition. Competition experiments with Grignard reagents and an excess of benzaldehyde (13) and
acetophenone (14) showed that both allylmagnesium chloride and prenylmagnesium chloride do
not exhibit chemoselectivity in instances where other alkylmagnesium reagents exhibit high
chemoselectivity (Table 1).8 These experiments provide further evidence that prenylmagnesium
chloride reacts at a similar rate as allylmagnesium chloride does.
Table 1. Intermolecular competition experiments to demonstrate chemoselectivity
of addition of Grignard reagents to carbonyl compounds.
Entry
R
Product
15:16a
1
2
3
4
Me
n-Pr
H2C=CHCH2
Me2C=CHCH2
a
b
c
db
221:18
143:18
51:498
60:40
aRatios determined by GC analysis. bRegioisomers
were inseparable by GC.
The lack of chemoselectivity for the allylic Grignard reagents can be explained by
consideration of the possible transition states for the addition. Complexation of the magnesium
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atom to the carbonyl compound (k1) to form a Lewis acid-base complex (17) should occur quickly
after the addition of the Grignard reagent to the carbonyl compound (Scheme 3).30 The rate of
carbon–carbon bond formation with allylic transposition (18) is faster than dissociation of the
complex (k2 >> k–1), resulting in no difference in the rates of addition to different types of carbonyl
compounds. In the addition to unhindered carbonyl compounds, the rate of carbon–carbon bond
formation through the transition state with allylic transposition (18) is much faster than the rate of
carbon–carbon bond formation through the four-membered transition state 19 (k2 >> k3), leading
to almost exclusive formation of the γ-addition product.
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Scheme 3. Reaction rates of addition of prenylmagnesium chloride to a carbonyl
compound
A lack of chemoselectivity was also observed in an intermolecular competition experiment
between chelating ketone 20 and nonchelating ketone 9. Neither allylmagnesium halide nor
prenylmagnesium chloride showed chelation-induced rate acceleration9,31,32 in cases where other
alkylmagnesium reagents exhibited high selectivity for chelating ketone 20 (Table 2).9 These
experiments reinforce the conclusion that additions of both allylmagnesium halides and
prenylmagnesium chloride cannot be expected to exhibit chelation-controlled selectivity because
once the reagent complexes to a carbonyl compound, rapid carbon–carbon bond formation through
the six-membered transition state must occur (Scheme 3).9
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Table 2. Intermolecular competition experiments to demonstrate chelation control
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in the addition of Grignard reagents to carbonyl compounds.
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Entry
R
Product
21:22a
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Me
n-Pr
H2C=CHCH2
Me2C=CHCH2
a
b
104:19
338:19
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49:51
c
db
aRatios determined by GC analysis. bRegioisomers
were inseparable by GC.
Control experiments established that the regioselectivity of these reactions does not result
from reversibility of the addition. In a crossover experiment where prenylmagnesium chloride was
added to one ketone (9) followed by addition of a second ketone (23c) no addition to the second
ketone was observed, even after stirring at 66 °C for twenty hours (eq 3). This observation is
consistent with previous studies of additions of prenylmagnesium halides.33 By contrast, the
additions of allyl and crotyl Grignard reagents to hindered carbonyl compounds are reversible at
elevated temperatures.34-37
In the additions of prenylmagnesium chloride to α-alkoxy ketones, the γ-addition pathway
was the prevailing mode of addition (Table 3). The resulting γ-addition products were formed with
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generally low diastereoselectivity, as has been observed for the additions of allylmagnesium
halides to α-alkoxy ketones.9 Incrementally increasing the steric hindrance at the carbonyl group
only exerted a modest effect on the regioselectivity of addition. For the treatment of more hindered
ketones with prenylmagnesium chloride, α-addition products 25c-e were not observed in
significant quantities.
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Table 3. Treatment of propiophenone-derived ketones with prenylmagnesium
chloride.
d.r. of d.r. of Yield of
Entry R1
R2
H
24:25a
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25a
24 (%)
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Me
>99:1
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Me OMe 96:4
Ph 99:1
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H
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Ph OMe >99:1 75:25
Ph OH >99:1 >99:1
aRatios determined by 1H NMR spectroscopy.
bCompound 23a is the same as compound 9; compound
24a is the same as compounds 10 and 21d; compound
25a is the same as compound 11.
A significant difference in diastereoselectivity was observed between the two regioisomers
of product. Treatment of chelating ketones 23b,d with 5 resulted in low diastereoselectivity for the
γ-addition products 24b,d, similar to the addition of allylmagnesium halides to these ketones.9,38
This outcome is consistent with rapid reactions, which is suggested by the results in Tables 1 and
2.8 The α-addition products 25b, however, was formed as a single diastereomer, suggesting that
addition through a transition-state controlled pathway was slower.9,39 Slower addition to the
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carbonyl group (i.e., k2 in Scheme 3) allows for reaction not with any form of the α-alkoxy ketone,
but instead reaction occurred only with the chelated intermediate, leading to stereoselectivity.9,31,32
High regioselectivity and diastereoselectivity, however, were observed in the addition to
23e through the γ-addition pathway. This addition could proceed either through ketone 23e or the
corresponding magnesium alkoxide, considering that the rate of addition of allylic Grignard
reagents to carbonyl compounds is comparable to the rate of proton transfer.40,41 A control
experiment indicated that addition to the magnesium alkoxide is consistent with the selectivity.
One equivalent of methylmagnesium chloride was first added to benzoin at –78 °C to deprotonate
the hydroxyl group,42 then prenylmagnesium chloride was added to the mixture. In this
experiment, the same regioselectivity and diastereoselectivity were observed as above, although
conversion was low (33%) after 30 minutes at –78 °C. The high diastereoselectivity observed in
this reaction is consistent with chelation-controlled addition because the carbonyl compound with
the α-OMgCl group likely chelates magnesium more strongly than other α-alkoxy carbonyl
compounds,43 leading to chelation-controlled diastereoselectivity.9
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Increasing the steric hinderance at the carbonyl group led to increased quantities of the α-
addition product. The addition of prenylmagnesium chloride to camphor (26) at –78 °C resulted
in little conversion (<5%) after three hours, indicating that steric hinderance had slowed addition.
Addition at –40 °C, however, provided a 96:4 mixture of regioisomers (27:28), favoring the γ-
addition product (Table 4). Addition at 20 °C led to an increase in the amount of α-addition product
28, providing a 72:28 mixture of regioisomers (27:28). Addition to 26 at 66 °C resulted in a 56:44
mixture of regioisomers 27 and 28. In all cases, both regioisomers were formed as single
diastereomers, paralleling the additions of allylmagnesium halides and other organometallic
reagents to camphor.8,44-48
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Table 4. Treatment of camphor (26) with prenylmagnesium chloride.
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d.r. of
27a
>99:1
>99:1
>99:1
d.r. of
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>99:1
>99:1
>99:1
Entry Temp. (°C) 27:28a
1
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3
–40
20
66
96:4
72:28
51:49
aRatios determined by 1H NMR spectroscopy
The outcomes of these reactions can be interpreted by considering the possible transition
states for addition (Scheme 3). With hindered carbonyl compounds, the rate of carbon–carbon
bond formation through the six-membered transition state 18 and the four-membered transition
state 19 are slower than the rate of dissociation (k–1 >> k2, k3) because the transition state for
addition is sterically destabilized. Furthermore, the rates of the two modes of addition must not be
that different. As the temperature was increased, the rates of these slow carbon–carbon bond
forming steps (k2 vs. k3) converge, resulting in decreased regioselectivity. By contrast, no such
temperature dependence was observed when prenylmagnesium chloride was added to
propiophenone (9) over a large temperature range (eq 4), indicating that the inherent difference in
rates of addition through the two transition states must be particularly large (k2 >> k3).
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In additions to highly sterically hindered ketones, the four-membered transition state 19
(k3, Scheme 3, or its dimeric equivalent 2) appears to be the prevailing mode of addition. Treatment
of di-tert-butyl ketone (29) with prenylmagnesium chloride at room temperature resulted in only
the α-addition product (30, eq 5); none of the γ-addition product was observed. These reactions
are particularly slow, however.8,49 Treatment of 29 with prenylmagnesium chloride at –78 °C
resulted in little conversion (<5%) after three hours, suggesting that addition through transition
state 31 is too sterically demanding due to syn-pentane interactions that develop (Scheme 4).50 By
contrast, the addition of allylmagnesium chloride to di-tert-butyl ketone at –78 °C was complete
in less than ten seconds.8
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Scheme 4. Treatment of di-tert-butyl ketone with prenylmagnesium chloride leads
to syn-pentane interactions in the six-membered transition state.
Formation of the α-addition product 30 could result from two distinct pathways. Addition
could proceed through a transition state resembling 3 using the higher-energy regioisomeric
reagent 6.25 In that case, carbon–carbon bond formation could occur rapidly through a six-
membered transition state that would be the regioisomer of transition state 18 (Scheme 3).
Consequently, the rate-limiting step would be isomerization of the reagent. With particularly
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hindered carbonyl compounds, that pathway cannot be discounted. Alternatively, the reagent could
react by transition state 19 without allylic transposition, similar to the addition of other Grignard
reagents. This experiment does not provide information to differentiate between the two
possibilities, although the latter explanation would acknowledge the similarity to other
organomagnesium reagents.
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Additions of prenylmagnesium chloride to the highly hindered ketone fenchone are also
slow and selective for the α-addition product (Table 5). As observed with di-tert-butyl ketone,
treatment of fenchone with prenylmagnesium chloride at –78 °C and –40 °C resulted in little
conversion (<5%) after three hours. Addition at room temperature and at 66 °C, however, resulted
in formation of the α-addition product 34 with high diastereoselectivity.51 As the temperature was
increased, the diastereoselectivity decreased, but the regioselectivity did not.52,53 The exclusive
formation of α-addition product 34 likely arises due to steric congestion in transition state 19,
similar to the addition of prenylmagnesium chloride to ketone 29 (Scheme 4).
Table 5. Treatment of fenchone (32) with prenylmagnesium chloride.
Entry Temp. (°C) 33:34a
d.r. of 33a d.r. of 34a
1
2
20
66
<1:99
<1:99
-
-
95:5
93:7
aRatios determined by 1H NMR spectroscopy
Another possible mechanism was considered for the addition of allylmagnesium reagents
to carbonyl compounds. The γ-addition product could be the result of a single-electron transfer
process through a highly substituted allylic radical (35, Scheme 5).11,12,15,16,54 A mechanism
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involving single-electron transfer has been disproven for the addition of allylmagnesium halide to
an aliphatic aldehyde bearing a radical clock (36),11 but the methyl substituents of radical 35 should
stabilize it compared to a simple allyl radical.55 Experiments with aldehyde 36 provided evidence
against a single-electron transfer pathway for the additions of prenylmagnesium chloride. Addition
of prenylmagnesium chloride to aldehyde 36 provided only addition products 37 and 38 with no
evidence of any ring-opened products that would indicate a single-electron transfer product (eq
6).56
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Scheme 5. Single-electron transfer processes may also be responsible for the
behavior of allylic Grignard reagents.
Taken together, these results are most consistent with a mechanism in which allylic
Grignard reagents react through a six-membered concerted transition state with allylic
transposition. This addition appears to be governed by diffusion with unhindered ketones, leading
to low chemoselectivity and chelation-controlled diastereoselectivity. When the products of the
other transition states are observed in highly hindered ketones, they are formed with high
diastereoselectivity, indicating that addition through these transition states occurs more slowly
through transition state-controlled additions.
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Experimental Section
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General Procedures. 1H NMR spectra were obtained at room temperature using spectrometers
at 400 or 600 MHz, and 13C NMR were recorded at 100 or 150 MHz, respectively. Spectroscopic
data are reported as follows: chemical shifts are reported in ppm on the δ scale, referenced to
residual solvent (1H NMR: CDCl3 δ 7.26; 13C NMR: CDCl3 δ 77.2), 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 NMR integrations using diagnostic peaks
in the unpurified reaction mixture. One-pulse 1H spectra were taken with a relaxation delay of 30
seconds when determining product ratios. Multiplicities of carbon peaks were determined using
HSQC experiments. Product distributions of competition experiments were determined by gas
chromatography (GC), using a gas chromatograph with the carrier gas (helium) set to 15 psi and
equipped with a capillary column (14% cyanopropylphenyl, 86% methylpolysiloxane, 30 m ×
0.321 mm × 0.25 μm). The infrared (IR) spectra were obtained by a spectrometer using attenuated
total reflectance (ATR). High-resolution mass spectra (HRMS) were acquired on a time-of-flight
spectrometer and were obtained using peak matching. The ionization sources used were either
atmospheric pressure chemical ionization (APCI) or electrospray 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 vacuum. Iodosobenzene,57 ketone 20,9,58 ketone 23d,59 and aldehyde 3611 were
prepared by known methods. Unless otherwise noted, all reagents and substrates were
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commercially available. The concentrations of commercially available Grignard reagents were
assumed to be near the concentrations reported by the suppliers.
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2-Methoxy-1-phenylpropan-1-one (23b). A reported procedure60 was adapted to prepare
ketone 23b. To a solution of iodosobenzene (2.415 g, 10.98 mmol) in MeOH (50 mL) was added
BF3•OEt2 (2.5 mL, 20 mmol). The mixture was cooled to –78 °C, and then triethyl((1-phenylprop-
1-en-1-yl)oxy)silane61 was added. After 1 h, the mixture was warmed to room temperature and
stirred for an additional 2 h. The reaction mixture was concentrated in vacuo then diluted with H2O
(50 mL). The acid was neutralized with saturated aqueous NaHCO3 then the mixture was extracted
with CH2Cl2 (3 × 40 mL). The combined organic layers were dried over Na2SO4 and concentrated
in vacuo. Purification by flash chromatography (15:85 EtOAc:hexanes) afforded 23b as a yellow
oil (1.500 g, 91%). The spectra data are consistent with the data reported in the literature:9 1H NMR
(600 MHz, CDCl3) δ 8.06–8.03 (m, 2H), 7.60–7.56 (m, 1H), 7.49–7.45 (m, 2H), 4.63 (q, J = 6.9,
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1H), 3.39 (s, 3H), 1.49 (d, J = 6.9, 3H); C NMR (150 MHz, CDCl3) δ 200.8 (C), 135.0 (CH),
133.6 (CH), 128.9 (C), 128.8 (CH), 80.4 (CH), 57.5 (CH3), 18.7 (CH3); HRMS (APCI) m / z calcd
for C10H11O ((M + H) – H2O)+ 147.0804, found 147.0798.
Preparation of prenylmagnesium chloride in THF. To magnesium turnings (5.312 g, 0.219
mol) was added THF (14.0 mL) and the mixture was cooled to 0 °C. A solution of 1-chloro-3-
methyl-2-butene (6.2 mL, 55 mmol) in THF (96 mL) was added dropwise over 5 h. The solution
was warmed to room temperature and stirred for an additional hour then transferred by cannula to
a Schlenk flask for storage. To determine the concentration of the reagent, prenylmagnesium
chloride (0.500 mL) was added to a solution of propiophenone (0.136 mL, 1.0 mmol) and 1,4-
dimethoxybenzene (0.0693 g, 0.502 mmol) in THF (2 mL). After 10 min, an aliquot (0.5 mL) of
the reaction mixture was removed and diluted with CDCl3 in an NMR tube. After data acquisition,
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the integral values for the vinyl protons of the product were compared to those of 1,4-
dimethoxybenzene and the concentration of the reagent was calculated to obtain a concentration
of 0.36 M.
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Representative procedure for additions of prenylmagnesium chloride to carbonyl
compounds in THF (4,4-dimethyl-3-phenylhex-5-en-3-ol (24a)). To a cooled (–78 °C) solution
of propiophenone (0.270 mL, 2.0 mmol) in THF (10 mL) was added prenylmagnesium chloride
(5.6 mL, 0.54 M solution in THF, 3.0 mmol) dropwise over 5 min. After 30 min, MeOH (1 mL)
was added. The solution was warmed to room temperature then concentrated in vacuo. 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). The combined organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. 1H NMR spectroscopic analysis of the unpurified reaction mixture revealed alcohol 24a as
the only regioisomer formed. Purification by flash chromatography (15:85 EtOAc:hexanes)
afforded alcohol 24a as a colorless oil (0.329 g, 80%): 1H NMR (400 MHz, CDCl3) δ 7.39–7.37
(m, 2H), 7.33–7.29 (m, 2H), 7.25–7.21 (m, 1H), 6.02–5.95 (dd, J = 17.6, 10.8, 1H), 5.13–5.10 (dd,
J = 10.8, 1.5, 1H), 5.08–5.03 (dd, J = 17.6, 1.5, 1H), 2.28–2.18 (m, 1H), 1.86 (s, 1H), 1.84–1.77
(m, 1H), 1.02 (s, 3H), 0.96 (s, 3H), 0.67 (t, J = 7.3, 3H); 13C NMR (100 MHz, CDCl3) 145.6 (CH),
142.3 (C), 128.0 (CH), 127.3 (CH), 126.5 (CH), 114.0 (CH2), 80.5 (C), 45.0 (C), 28.0 (CH2), 22.90
(CH3), 22.88 (CH3), 8.2 (CH3); IR (ATR) 3561, 2972, 2878, 1635, 1446, 1033 cm-1; HRMS
(APCI) m / z calcd for C14H19 ((M + H) – H2O)+ 187.1481, found 187.1477. Anal. Calcd for
C14H20O: C, 82.30; H, 9.87. Found: C, 82.03; H, 10.01.
2-Methoxy-4,4-dimethyl-3-phenylhex-5-en-3-ol (24b) and 2-methoxy-6-methyl-3-phenylhept-
5-en-3-ol (25b). Alcohols 24b and 25b were prepared using the representative procedure for
addition of prenylmagnesium chloride to carbonyl compounds in THF using ketone 23b (0.338 g,
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2.1 mmol) and prenylmagnesium chloride (6.6 mL, 0.36 M solution in THF, 2.4 mmol) in THF
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(10 mL). H NMR spectroscopic analysis of the unpurified reaction mixture revealed a 96:4
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mixture of regioisomers (24b:25b). The minor regioisomer 25b was identified by a multiplet at δ
5.43–5.40 ppm corresponding to the vinyl proton.62 1H NMR spectroscopic analysis of the
unpurified reaction mixture revealed that alcohol 24b was formed as a 61:39 mixture of
diastereomers and that alcohol 25b was the only diastereomer formed. Purification by flash
chromatography (5:95 EtOAc:hexanes) afforded alcohol 24b as a colorless oil with a
diastereomeric ratio of 62:38 (0.275 g, 56%) which was used for characterization: IR (ATR) 3554,
2976, 1095, 914, 703 cm-1; HRMS (APCI) m / z calcd for C15H21O ((M + H) – H2O)+ 217.1587,
found 217.1589. Anal. Calcd for C15H22O2: C, 76.88; H, 9.46. Found: C, 76.76; H, 9.42.
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Major diastereomer 24b: H NMR (600 MHz, CDCl3) δ 7.38–7.37 (m, 2H), 7.30–7.27 (m, 2H),
6.21–6.16 (dd, J = 17.6, 10.8, 1H), 5.07–5.05 (dd, J = 10.9, 1.6, 1H), 5.00–4.97 (dd, J = 17.6, 1.5,
1H), 4.00 (q, J = 6.1, 1H), 3.39 (s, 3H), 2.72 (s, 1H), 0.96 (s, 3H), 0.95 (s, 3H), 0.81 (d, J = 6.1,
3H); 13C NMR (100 MHz, CDCl3) δ 146.6 (CH), 142.9 (C), 128.2 (CH), 127.3 (CH), 126.8 (CH),
112.7 (CH2), 81.2 (C), 79.8 (CH), 55.9 (CH3), 45.4 (C), 24.62 (CH3), 24.57 (CH3), 14.1 (CH3).
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Minor diastereomer 24b’: H NMR (600 MHz, CDCl3, diagnostic peaks) δ 7.61–7.60 (m, 2H),
7.25–7.19 (m, 3H), 6.08–6.03 (dd, J = 17.6,10.8, 1H), 5.11–5.09 (dd, J = 10.8, 1.4, 1H), 5.07–5.04
(dd, J = 17.5, 1.5, 1H), 3.71 (q, J = 6.2, 1H), 3.28 (s, 3H), 2.22 (s, 1H), 1.15 (s, 3H), 1.02 (d, J =
6.2, 3H), 0.98 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.1 (CH), 142.3 (C), 126.9 (CH), 126.6
(CH), 126.5 (CH), 113.4 (CH2), 82.6 (CH), 80.6 (C), 56.3 (CH3), 44.8 (C), 24.9 (CH3), 22.7 (CH3),
14.6 (CH3).
3,3-Dimethyl-1,2-diphenylpent-4-en-2-ol (24c) and 5-methyl-1,2-diphenylhex-4-en-2-ol (25c).
Alcohols 24c and 25c were prepared using the representative procedure for additions of
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prenylmagnesium chloride to carbonyl compounds in THF using deoxybenzoin (0.392 g, 2.0
mmol) and prenylmagnesium chloride (5.6 mL, 0.54 M solution in THF, 2.4 mmol) in THF (10
mL). 1H NMR spectroscopic analysis of the unpurified reaction mixture revealed a 99:1 mixture
of regioisomers (24c:25c). The minor regioisomer 25c was identified by a multiplet at δ 5.47–5.44
ppm corresponding to the vinyl proton.62 Purification by flash chromatography (3:97
EtOAc:hexanes) afforded alcohol 24c as a yellow oil (0.476 g, 89%): 1H NMR (400 MHz, CDCl3)
δ 7.46–7.44 (m, 2H), 7.30–7.28 (m, 2H), 7.23–7.19 (m, 1H), 7.10–7.08 (m, 3H), 6.92–6.89 (m,
2H), 6.23–6.16 (dd, J = 17.6, 10.8, 1H), 5.16–5.13 (dd, J = 10.9, 1.4, 1H), 5.09–5.04 (dd, J = 17.6,
1.3, 1H), 3.53–3.50 (d, J = 13.6, 1H), 3.17–3.14 (d, J = 13.6, 1H), 1.68 (br s, 1H), 1.06 (s, 3H),
1.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 145.6 (CH), 143.3 (C), 136.9 (C), 131.1 (CH), 128.3
(CH), 128.2 (CH), 127.2 (CH), 126.72 (CH), 126.68 (CH), 113.5 (CH2), 80.0 (C), 45.1 (C), 41.7
(CH2), 23.5 (CH3), 22.5 (CH3); IR (ATR) 3568, 3027, 2969, 2874, 1494, 1467, 1099 cm-1; HRMS
(APCI) m / z calcd for C19H21 ((M + H) – H2O)+ 249.1638, found 249.1636. Anal. Calcd for
C19H22O: C, 85.67; H, 8.32. Found: C, 85.37; H, 8.32.
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(1R*,2R*)-1-Methoxy-3,3-dimethyl-1,2-diphenylpent-4-en-2-ol (24d). Alcohol 24d was
prepared using the representative procedure for additions of prenylmagnesium chloride to carbonyl
compounds in THF using ketone 23d (0.236 g, 1.0 mmol) and prenylmagnesium chloride (3.3 mL,
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0.36 M solution in THF, 1.2 mmol) in THF (5 mL). H NMR spectroscopic analysis of the
unpurified reaction mixture revealed that alcohol 24d was the only regioisomer formed. Alcohol
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24d was formed as a 75:25 mixture of diastereomers (24d:24d’) as determined by H NMR
spectroscopic analysis of the unpurified reaction mixture. Purification by flash chromatography
(15:85 EtOAc:hexanes) afforded diastereomers 24d and 24d’ as a colorless oil with a
diastereomeric ratio of 75:25 (0.245 g, 83%) which was used for characterization. Relative
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stereochemistry was assigned by chemical correlation; experimental details are provided later in
this section. IR (ATR) 3548, 2980, 1492, 1089, 914, 754 cm-1; HRMS (APCI) m / z calcd for
C20H23O ((M + H) – H2O)+ 279.1743, found 279.1735. Anal. Calcd for C20H24O2: C, 81.04; H,
8.16. Found: C, 81.33; H, 8.01.
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Major diastereomer alcohol 24d: 1H NMR (400 MHz, CDCl3) δ 7.27–7.25 (m, 2H), 7.12–6.99 (m,
8H), 6.35–6.28 (dd, J = 17.6, 10.8, 1H), 5.18–5.15 (dd, J = 10.8, 1.5, 1H), 5.12–5.07 (dd, J = 17.6,
1.5, 1H), 4.76 (s, 1H), 3.21 (s, 3H), 3.20 (s, 1H), 1.08 (s, 3H), 1.04 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 146.7 (CH), 142.1 (C), 138.3 (C), 129.7 (CH), 127.4 (CH), 127.3 (CH), 127.2 (CH),
126.7 (CH), 126.2 (CH), 113.2 (CH2), 86.4 (CH), 81.5 (C), 56.1 (CH3), 46.2 (C), 24.8 (CH3), 24.5
(CH3).
Minor diastereomer alcohol 24d’: 1H NMR (400 MHz, CDCl3, diagnostic peaks) δ 6.12–6.04 (dd,
J = 17.6, 10.9, 1H), 4.98–4.90 (m, 2H), 4.65 (s, 1H), 3.11 (s, 3H), 2.09 (s, 1H), 1.13 (s, 3H), 0.93
(s, 3H); 13C NMR (100 MHz, CDCl3, diagnostic peaks) δ 145.7 (CH), 142.4 (C), 129.9 (CH),
128.24 (CH), 128.16 (CH), 127.9 (CH), 126.9 (CH), 112.5 (CH2), 88.3 (CH), 81.0 (C), 56.6 (CH3),
44.8 (C), 24.7 (CH3), 23.1 (CH3).
(1R*,2R*)-3,3-Dimethyl-1,2-diphenylpent-4-ene-1,2-diol (24e). Diol 24e was prepared using
the representative procedure for additions of prenylmagnesium chloride to carbonyl compounds in
THF using benzoin (0.425 g, 2.0 mmol) and prenylmagnesium chloride (5.2 mL, 0.46 M solution
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in THF, 2.4 mmol) in THF (10 mL). H NMR spectroscopic analysis of the unpurified reaction
mixture revealed that diol 24e was the only regioisomer formed. 1H NMR spectroscopic analysis
of the unpurified reaction mixture revealed that alcohol 24e was the only diastereomer formed.
Purification by flash chromatography (10:90 EtOAc:hexanes) afforded diol 24e as a white solid
(0.138 g, 31%). Relative stereochemistry was assigned by X-ray crystallography; mp = 129–130
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°C; 1H NMR (400 MHz, CDCl3) δ 7.28 (m, 2H), 7.20–7.18 (m, 2H), 7.12–7.01 (m, 6H), 6.51–6.43
(m, 1H), 5.44 (d, J = 3.9, 1H), 5.24 (s, 1H), 5.21–5.19 (dd, J = 7.6, 1.4, 1H), 3.21 (s, 1H), 2.47 (d,
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J = 3.9, 1H), 1.20 (s, 3H), 0.99 (s, 3H); C NMR (100 MHz, CDCl3) δ 147.2 (CH), 142.1 (C),
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141.4 (C), 128.8 (CH), 127.9 (CH), 127.6 (CH), 127.4 (CH), 126.9 (CH), 126.4 (CH), 113.7 (CH2),
81.5 (C), 77.4 (CH), 45.8 (C), 24.8 (CH3), 23.5 (CH3); IR (ATR) 3511, 2976, 2962, 1444, 1014,
935 cm-1; HRMS (ESI) m / z calcd for C19H21O ((M + H) – H2O)+ 265.1590, found 265.1587.
Anal. Calcd for C19H22O2: C, 80.82; H, 7.85. Found: C, 80.62; H, 7.77.
(1S,2S,4R)-1,7,7-Trimethyl-2-(2-methylbut-3-en-2-yl)bicyclo[2.2.1]heptan-2-ol (27) and
(1S,2R,4R)-1,7,7-trimethyl-2-(3-methylbut-2-en-1-yl)bicyclo[2.2.1]heptan-2-ol (28). Alcohols 27
and 28 were prepared using the representative procedure for additions of prenylmagnesium
chloride to carbonyl compounds in THF using (1R)-(+)-camphor (0.157 g, 1.03 mmol) and
prenylmagnesium chloride (3.0 mL, 0.40 M solution in THF, 1.2 mmol) in THF (5 mL) at –40 °C.
1H NMR spectroscopic analysis of the unpurified reaction mixture revealed a 94:6 mixture of
regioisomers (27:28). The minor regioisomer 28 was identified by a multiplet at δ 5.30–5.25 ppm
corresponding to the vinyl proton.62 1H NMR spectroscopic analysis of the unpurified reaction
mixture revealed that alcohols 27 and 28 were both formed as a single diastereomers. Purification
by flash chromatography (5:95 EtOAc:hexanes) afforded alcohol 27 as a colorless oil (0.132 g,
59%). The spectroscopic data are consistent with the data reported in the literature:63 1H NMR
(400 MHz, CDCl3) δ 6.29–6.22 (dd, J = 17.5, 10.9, 1H), 5.05–5.00 (dd, J = 17.5, 1.3, 1H), 4.98–
4.95 (dd, J = 10.9, 1.3, 1H), 1.90–1.81 (m, 2H), 1.79–1.74 (m, 2H), 1.66–1.61 (m, 2H), 1.33–1.25
(m, 1H), 1.19 (s, 3H), 1.16–1.11 (m, 1H), 1.09 (s, 6H), 0.93 (s, 3H), 0.79 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 147.5, 111.2, 84.1, 55.0, 51.5, 47.0, 44.6, 41.0, 29.5, 26.6, 23.7, 23.6, 22.3, 21.1,
13.1; HRMS (APCI) m / z calcd for C15H25 ((M + H) – H2O)+ 205.1951, found 205.1941.
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3-(tert-Butyl)-2,2,6-trimethyl-5-hepten-3-ol (30). Alcohol 30 was prepared using the
representative procedure for additions of prenylmagnesium chloride to carbonyl compounds in
THF using ketone 29 (0.175 mL, 1.0 mmol) and prenylmagnesium chloride (3.0 mL, 0.40 M
solution in THF, 1.2 mmol) in THF (5 mL) at 20 °C to afford alcohol 30 as a colorless oil (0.164
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g, 77%, unpurified yield). H NMR spectroscopic analysis of the unpurified reaction mixture
revealed that alcohol 30 was the only regioisomer formed. The spectroscopic data are consistent
with the data reported in the literature:64 1H NMR (400 MHz, CDCl3) δ 5.34–5.30 (m, 1H), 2.38
(d, J = 7.3, 2H), 1.74 (s, 3H), 1.66 (s, 3H), 1.56 (s, 1H), 1.07 (s, 18H); 13C NMR (100 MHz, CDCl3)
134.5, 122.2, 79.9, 42.6, 32.7, 29.2, 26.7, 18.3; HRMS (APCI) m / z calcd for C14H27 ((M + H) –
H2O)+ 195.2107, found 195.2105.
(1S,2R,4S)-1,3,3-Trimethyl-2-(3-methylbut-2-en-1-yl)bicyclo[2.2.1]heptan-2-ol (34). Alcohol
34 was prepared using the representative procedure for additions of prenylmagnesium chloride to
carbonyl compounds in THF using (1R)-(–)-fenchone (0.320 mL, 1.99 mmol) and
prenylmagnesium chloride (6.1 mL, 0.40 M solution in THF, 2.4 mmol) in THF (10 mL) at 66 °C.
1H NMR spectroscopic analysis of the unpurified reaction mixture revealed that alcohol 34 was
the only regioisomer formed. Alcohol 34 was formed as a 93:7 mixture of diastereomers (34:34’)
as determined by 1H NMR spectroscopic analysis of the unpurified reaction mixture. Purification
by flash chromatography (5:95 EtOAc:hexanes) afforded alcohol 34 as a colorless oil with a
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diastereomeric ratio of 93:7 (34:34’) (0.206 g, 46%) which was used for characterization: [α]D
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39 (c 0.53, CHCl3); IR (ATR) 3551, 2929, 2871, 1455, 1386, 1043, 901 cm-1; HRMS (APCI) m /
z calcd for C15H25 ((M + H) – H2O)+ 205.1951, found 205.1953.
Major diastereomer alcohol 34: 1H NMR (400 MHz, CDCl3) δ 5.33–5.30 (m, 1H), 2.30–2.20 (m,
1H), 2.06–1.99 (m, 1H), 1.74 (s, 3H), 1.72–1.67 (m, 1H), 1.63 (s, 3H), 1.61–1.60 (m, 2H), 1.57 (s,
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1H), 1.44–1.35 (m, 1H), 1.10–1.07 (m, 1H), 1.06 (s, 3H), 1.04 (s, 3H), 1.01–0.99 (m, 1H), 0.93 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 136.25 (C), 121.0 (CH), 80.5 (C), 52.5 (C), 50.3 (CH), 44.4
(C), 41.2 (CH2), 34.7 (CH2), 30.8 (CH2), 27.9 (CH3), 26.5 (CH3), 25.3 (CH2), 23.0 (CH3), 18.26
(CH3), 18.23 (CH3).
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Minor diastereomer alcohol 34’: 1H NMR (400 MHz, CDCl3, diagnostic peaks) δ 5.28–5.24 (m,
1H); 13C NMR (100 MHz, CDCl3) δ 136.33 (C), 120.3 (CH), 81.4 (C), 53.0 (C), 49.5 (CH), 45.4
(C), 41.8 (CH2), 31.8 (CH2), 30.8 (CH2), 30.7 (CH3), 26.4 (CH3), 26.1 (CH2), 24.4 (CH3), 18.1
(CH3), 17.0 (CH3).
1-(2,2-Diphenylcyclopropyl)-2,2-dimethylbut-3-en-1-ol (37) and 1-(2,2-diphenylcyclopropyl)-
4-methylpent-3-en-1-ol (38). Alcohols 37 and 38 were prepared using the representative procedure
for additions of prenylmagnesium chloride to carbonyl compounds in THF using aldehyde 36
(0.095 g, 0.43 mmol) and prenylmagnesium chloride (2.4 mL, 0.34 M solution in THF, 0.8 mmol)
in THF (1 mL). 1H NMR spectroscopic analysis of the unpurified reaction mixture revealed a 91:9
mixture of regioisomers (37:38). The minor regioisomer 38 was identified by a multiplet at δ 5.44–
5.40 ppm corresponding to the vinyl proton.62 13C NMR spectroscopic analysis of the unpurified
reaction mixture revealed that alcohol 37 was formed as a 82:18 mixture of diastereomers.56 1
H
NMR spectroscopic analysis of the unpurified reaction mixture revealed that alcohol 38 was
formed as a single diastereomer. Purification by flash chromatography (5:95 EtOAc:hexanes)
afforded alcohol 37 as a clear oil of (0.086 g, 68%) and alcohol 37’ as a clear oil (0.020, 16%)
which were used for characterization: IR (ATR) 3588, 3057, 2962, 1599, 1494, 1026, 772 cm-1;
HRMS (APCI) m / z calcd for C21H23 ((M + H) – H2O)+ 275.1794, found 275.1799.
Major diastereomer alcohol 37: 1H NMR (400 MHz, CDCl3) δ 7.46–7.44 (m, 2H), 7.31–7.27 (m,
4H), 7.24–7.13 (m, 4H), 5.96–5.89 (dd, J = 17.4, 10.9, 1H), 5.07–5.06 (m, 1H), 5.04–5.01 (dd, J
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= 11.4, 0.98, 1H), 2.58 (d, J = 10.1, 1H), 1.82–1.76 (m, 1H), 1.63 (br s, 1H), 1.51–1.48 (m, 1H),
1.33–1.29 (dd, J = 9.0, 5.2, 1H), 1.09 (s, 3H), 1.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 146.8
(C), 145.6 (CH), 141.5 (C), 130.2 (CH), 128.9 (CH), 128.6 (CH), 128.5 (CH), 126.8 (CH), 126.3
(CH), 113.1 (CH2), 78.9 (CH), 42.7 (C), 34.1 (C), 28.8 (CH), 24.5 (CH3), 22.6 (CH3), 19.4 (CH2).
Minor diastereomer alcohol 37’: 1H NMR (400 MHz, CDCl3) δ 7.32–7.29 (m, 4H), 7.25–7.14 (m,
6H), 5.94–5.87 (dd, J = 17.9, 10.4, 1H), 5.11 (m, 1H), 5.08–5.07 (m, 1H), 3.18 (d, J = 5.0, 1H),
1.96–1.93 (m, 1H), 1.79–1.76 (m, 1H), 1.18–1.15 (dd, J = 9.3, 4.9, 1H), 1.053 (s, 3H), 1.050 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 147.1 (C), 145.7 (CH), 141.3 (C), 130.1 (CH), 128.62 (CH),
128.55 (CH), 128.5 (CH), 126.7 (CH), 126.2 (CH), 113.1 (CH2), 74.8 (CH), 42.6 (C), 35.1 (C),
27.9 (CH), 23.6 (CH3), 23.0 (CH3), 16.3 (CH2).
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2,2-Dimethyl-1-phenylbut-3-en-1-ol (15d) and 4-methyl-1-phenylpent-3-en-1-ol (15d’).
Alcohols 15d and 15d’ were prepared using the representative procedure for additions of
prenylmagnesium chloride to carbonyl compounds in THF using benzaldehyde (0.205 mL, 2.01
1
mmol) and prenylmagnesium chloride (6.9 mL, 0.35 M solution in THF, 2.4 mmol). H NMR
spectroscopic analysis of the unpurified reaction mixture revealed an 86:14 mixture of
regioisomers (15d:15d’). The minor regioisomer 15d’ was identified by a multiplet at δ 5.43–5.40
ppm corresponding to the vinyl proton.62 Purification by flash chromatography (10:90
EtOAc:hexanes) afforded alcohol 15d as a colorless oil (0.246 g, 70%): 1H NMR (400 MHz,
CDCl3) δ 7.34–7.27 (m, 5H), 5.96–5.89 (dd, J = 17.5, 10.8, 1H), 5.16–5.13 (dd, J = 10.8, 1.3, 1H),
5.11–5.06 (dd, J = 17.5, 1.3, 1H), 4.44 (s, 1H), 2.02 (s, 1H), 1.02 (s, 3H), 0.97 (s, 3H); 13C NMR
(150 MHz, CDCl3) δ 145.3 (CH), 141.0 (C), 128.0 (CH), 127.7 (CH), 127.6 (CH), 114.1 (CH2),
80.9 (CH), 42.5 (C), 24.7 (CH3), 21.2 (CH3); IR (ATR) 3449, 2965, 2870, 1453, 1361, 1186, 1022
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cm-1; HRMS (APCI) m / z calcd for C12H15 ((M + H) – H2O)+ 159.1168, found 159.1169. Anal.
Calcd for C12H16O: C, 81.77; H, 9.15. Found: C, 81.62; H, 9.00.
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3,3-Dimethyl-2-phenylpent-4-en-2-ol (16d). Alcohol 16d was prepared using the
representative procedure for additions of prenylmagnesium chloride to carbonyl compounds in
THF using acetophenone (0.240 mL, 2.0 mmol) and prenylmagnesium chloride (5.6 mL, 0.54 M
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solution in THF, 2.4 mmol). H NMR spectroscopic analysis of the unpurified reaction mixture
revealed that alcohol 16d was the only regioisomer formed. Purification by flash chromatography
(5:95 EtOAc:hexanes) afforded alcohol 16d as a colorless oil (0.252 g, 66%): 1H NMR (400 MHz,
CDCl3) δ 7.44–7.41 (m, 2H), 7.33–7.29 (m, 2H), 7.26–7.22 (m, 1H), 6.00–5.92 (dd, J = 17.6, 10.8,
1H), 5.13–5.10 (dd, J = 10.8, 1.4, 1H), 5.08–5.04 (dd, J = 17.6, 1.4, 1H), 1.92 (s, 1H), 1.59 (s, 3H),
13
1.03 (s, 3H), 0.99 (s, 3H); C NMR (100 MHz, CDCl3) 145.5 (C), 145.3 (CH), 127.33 (CH),
127.27 (CH), 126.7 (CH), 114.0 (CH2), 77.7 (C), 44.6 (C), 25.6 (CH3), 22.9 (CH3), 22.7 (CH3); IR
(ATR) 3476, 3059, 2979, 1445, 1371, 1068 cm-1; HRMS (APCI) m / z calcd for C13H17 ((M + H)
– H2O)+ 173.1325, found 173.1327. Anal. Calcd for C13H18O: C, 82.06; H, 9.54. Found: C, 81.86;
H, 9.68.
1-Methoxy-3,3-dimethyl-2-phenylpent-4-en-2-ol (21d) and 1-methoxy-5-methyl-2-phenylhex-
4-en-2-ol (21d’). Alcohols 21d and 21d’ were prepared using the representative procedure for
additions of prenylmagnesium chloride to carbonyl compounds in THF using ketone 20 (0.308 g,
2.05 mmol) and prenylmagnesium chloride (6.6 mL, 0.37 M solution in THF, 2.4 mmol). 1H NMR
spectroscopic analysis of the unpurified reaction mixture revealed a 94:6 mixture of regioisomers
(21d:21d’). The minor regioisomer 21d’ was identified by a multiplet at δ 5.43–5.40 ppm
corresponding to the vinyl proton.62 Purification by flash chromatography (5:95 EtOAc:hexanes)
afforded alcohol 21d as a colorless oil (0.210 g, 46%): 1H NMR (600 MHz, CDCl3) δ 7.46–7.44
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(m, 2H), 7.33–7.31 (m, 2H), 7.26–7.23 (m, 1H), 6.09–6.04 (dd, J = 17.6, 10.8, 1H), 5.05–5.03 (dd,
J = 10.8, 1.3, 1H), 4.98–4.95 (dd, J = 17.6, 1.3, 1H), 3.98 (d, J = 9.3, 1H), 3.67 (d, J = 9.3, 1H),
3.31 (s, 3H), 2.92 (br s, 1H), 1.02 (s, 3H), 0.94 (s, 1H); 13C NMR (150 MHz, CDCl3) δ 145.2 (CH),
142.6 (C), 127.8 (CH), 127.4 (CH), 126.9 (CH), 112.7 (CH2), 79.3 (C), 75.9 (CH2), 59.6 (CH3),
43.0 (C), 23.1 (CH3), 22.5 (CH3); IR (ATR) 3554, 2981, 2878, 1378, 1068, 799 cm-1; HRMS
(APCI) m / z calcd for C14H20ONa (M + Na)+ 227.1406, found 227.1409. Anal. Calcd for C14H20O2:
C, 76.33; H, 9.15. Found: C, 76.04; H, 9.24.
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6-Methyl-3-phenylheptan-3-ol (12b). To a solution of propiophenone (0.135 mL, 0.995 mmol)
in Et2O (5 mL) was added isopentylmagnesium bromide (0.750 mL, 2.0 M solution in THF, 1.5
mmol). After 6 h, H2O (10 mL) was added. HCl (5 mL, 1.0 M in H2O) was added, and the aqueous
layer was extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuo. Purification by flash chromatography (5:95
EtOAc:hexanes) afforded alcohol 12b as a clear oil (0.123 g, 60%): 1H NMR (400 MHz, CDCl3)
δ 7.38–7.31 (m, 4H), 7.24–7.20 (m, 1H), 1.89–1.84 (m, 2H), 1.81–1.73 (m, 2H), 1.63 (br s, 1H),
1.49–1.42 (m, 1H), 1.21–1.12 (m, 1H), 0.98–0.89 (m, 1H), 0.83 (t, J = 6.9, 6H), 0.76 (t, J = 7.4,
3H); 13C NMR (100 MHz, CDCl3) δ 146.3 (C), 128.2 (CH), 126.4 (CH), 125.6 (CH), 40.5 (CH2),
35.7 (CH2), 32.6 (CH2), 28.6 (CH), 22.8 (CH3), 22.7 (CH3), 8.0 (CH3); IR (ATR) 3471, 2953,
2869, 1446, 1054, 699 cm-1; HRMS (APCI) m / z calcd for C14H21 ((M + H) – H2O)+ 189.1638,
found 189.1638. Anal. Calcd for C14H22O: C, 81.50; H, 10.75. Found: C, 81.26; H, 10.76.
Competition experiment between prenylmagnesium chloride and methylmagnesium
chloride for propiophenone. To a cooled (–78 °C) solution of prenylmagnesium chloride (1.5
mL, 0.40 M solution in THF, 0.6 mmol) and methylmagnesium chloride (0.200 mL, 3.0 M solution
in THF, 0.6 mmol) in THF (1.3 mL) was added propiophenone (0.750 mL, 0.20 M solution, 0.15
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mmol) dropwise over 75 min. After the full volume of propiophenone was added, MeOH (0.5 mL)
was added and the reaction mixture was warmed to room temperature. 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).
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The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. H
NMR spectroscopic analysis of the unpurified reaction mixture revealed addition of only
1
prenylmagnesium chloride to propiophenone. H NMR spectroscopic analysis revealed that the
regioselectivity of the addition of prenylmagnesium chloride to propiophenone was 96:4 (10:11).
Competition experiment between prenylmagnesium chloride and isopentylmagnesium
bromide for propiophenone. To a cooled (–78 °C) solution of prenylmagnesium chloride (1.6
mL, 0.36 M solution in THF, 0.6 mmol) and isopentylmagnesium bromide (0.300 mL, 2.0 M
solution in Et2O, 0.6 mmol) in THF (1.1 mL) was added propiophenone (0.750 mL, 0.20 M
solution, 0.15 mmol) dropwise over 75 min. After the full volume of propiophenone was added,
MeOH (0.5 mL) was added and the reaction mixture was warmed to room temperature. 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). The combined organic layers were dried over Na2SO4, filtered, and concentrated in
vacuo. 1H NMR spectroscopic analysis of the unpurified reaction mixture revealed addition of only
1
prenylmagnesium chloride to propiophenone. H NMR spectroscopic analysis revealed that the
regioselectivity of the addition of prenylmagnesium chloride to propiophenone was 96:4 (10:11).
Competition experiment between prenylmagnesium chloride and allylmagnesium
chloride for propiophenone. To a cooled (–78 °C) solution of prenylmagnesium chloride (1.7
mL, 0.35 M solution in THF, 0.6 mmol) and allylmagnesium chloride (0.300 mL, 2.0 M solution
in THF, 0.6 mmol) in THF (1.0 mL) was added propiophenone (0.750 mL, 0.20 M solution, 0.15
mmol) dropwise over 75 min. After the full volume of propiophenone was added, MeOH (0.5 mL)
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was added and the reaction mixture was warmed to room temperature. H2O (10 mL) and HCl (5
mL, 1.0 M in H2O) were added, and the aqueous layer was extracted with CH2Cl2 (3 × 20 mL).
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The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo. H
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NMR spectroscopic analysis of the unpurified reaction mixture revealed a 52:2:44 mixture of
products (10:11:12c).
Competition experiment between benzaldehyde and acetophenone with
prenylmagnesium chloride. To a cooled (–78 °C) solution of benzaldehyde (0.033 g, 0.31 mmol)
and acetophenone (0.040 g, 0.34 mmol) in THF (3.0 mL) was added prenylmagnesium chloride
(0.380 mL, 0.20 M solution in THF, 0.075 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. An aliquot of the reaction mixture (1 mL) was filtered
through a plug of SiO2 and analyzed by GC (oven temperature = 130 °C) to show a 60:40 mixture
of products (15d:16d), using the retention times of authentic samples prepared as a reference.
Competition experiment between ketone 20 and propiophenone. To a cooled (–78 °C)
solution of ketone 20 (0.043 g, 0.29 mmol) and propiophenone (0.040 mL, 0.30 mmol) in THF
(3.0 mL) was added prenylmagnesium chloride (0.360 mL, 0.20 M solution in THF, 0.075 mmol)
dropwise over 50 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. An
aliquot of the reaction mixture (1 mL) was filtered through a plug of SiO2 and analyzed by GC
(oven temperature = 140 °C) to show a 49:51 mixture of products (21d:22d), using the retention
times of authentic samples prepared as a reference (Section III B).
(1R*,2R*)-1-Methoxy-3,3-dimethyl-1,2-diphenylpent-4-en-2-ol (24d). A reported procedure65
was adapted to prepare alcohol 24d from 24e in order to assign stereochemistry the
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stereochemistry of 24d by correlation. To DMSO (1 mL) was added powdered KOH (0.047 g,
0.84 mmol). After 15 min, diol 24e (0.061 g, 0.23 mmol) and MeI (0.015 mL, 0.24 mmol) were
added. After 36 h, H2O (10 mL) was added then the mixture was extracted with CH2Cl2 (4 × 10
mL). The combined organic layers were washed with H2O (3 × 40 mL) and brine (40 mL), dried
over Na2SO4, then concentrated in vacuo. Purification by flash chromatography (5:95
EtOAc:hexanes) afforded alcohol 24d as a clear oil (0.009 g, 13%). The spectroscopic data (1H,
13C NMR, and HSQC) match the data reported for the major diastereomer obtained through the
addition of prenylmagnesium chloride to ketone 23d.
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(1S,2R,4S)-1,3,3-Trimethyl-2-(3-methylbut-2-en-1-yl)bicyclo[2.2.1]heptan-2-ol
(34).
A
reported procedure66 was adapted to prepare alcohol 34 from (1S,2R,4S)-2-allyl-1,3,3-
trimethylbicyclo[2.2.1]heptan-2-ol47 in order to assign stereochemistry by correlation. To
degassed 2-methyl-2-butene (10 mL, 94 mmol) in a bomb was added (1S,2R,4S)-2-allyl-1,3,3-
trimethylbicyclo[2.2.1]heptan-2-ol47 (0.129 g, 0.664 mmol) and Grubbs II (0.005 g, 0.006 mmol).
After 24 h, the mixture was filtered through a plug of SiO2 and concentrated in vacuo. Purification
by flash chromatography followed by bulb-to-bulb distillation (125 °C/0.08 mm Hg) afforded a
mixture of alcohol 34 and an alcohol tentatively assigned as (1S,2R,4S)-1,3,3-trimethyl-2-(3-
methylpent-2-en-1-yl)bicyclo[2.2.1]heptan-2-ol (0.045 g, 30%) due to contamination of the
13
commercial 2-methyl-2-butene with 2-methyl-1-butene. The spectroscopic data (1H, C NMR,
and HSQC) match the data reported for alcohol 34 obtained through the addition of
prenylmagnesium chloride to (1R)-(–)-fenchone.
Associated Content:
Supporting information
X-ray of 24e, computational details, selected GC traces and NMR spectra
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Author Information:
Corresponding Author
* kwoerpel@nyu.edu
ORCID
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K. A. Woerpel: 0000-0002-8515-0301
Nicole D. Bartolo: 0000-0002-9907-7774
Notes
The authors declare no competing financial interest.
Acknowledgements: Acknowledgment is made to the Donors of the American Chemical Society
Petroleum Research Fund for support of this research (57206-ND1). We thank Dr. Chin Lin
(NYU) for assistance with NMR spectroscopy and mass spectrometry. We also thank the
Molecular Design Institute of NYU for purchasing a single-crystal diffractometer, and Dr.
Chunhua Hu (NYU) for his assistance with data collection and structure determination. The Shared
Instrumentation Facility in the Department of Chemistry was constructed through the support of
the National Center for Research Resources, National Institutes of Health, under Research
Facilities Improvement Award Number C06 RR-16572-01. The cryogenic probe for the 600 MHz
NMR was acquired through the support of the National Institute of Health S10 grant under Award
Number OD016343.
References
(1)
(2)
Bartolo, N. D.; Read, J. A.; Valentín, E. M.; Woerpel, K. A. Reactions of Allylmagnesium
Halides with Carbonyl Compounds: Reactivity, Structure, and Mechanism. Synthesis 2017,
49, 3237.
Yus, M.; Gonzalez-Gomez, J. C.; Foubelo, F. Diastereoselective Allylation of Carbonyl
Compounds and Imines: Application to the Synthesis of Natural Products. Chem. Rev.
2013, 113, 5595.
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