The retro Grignard addition reaction revisited: The reversible addition of benzyl reagents to ketones

Article abstract of DOI:10.1016/j.tet.2013.12.070

The Grignard addition reaction is known to be a reversible process with allylic reagents, but so far the reversibility has not been demonstrated with other alkylmagnesium halides. By using crossover experiments it has been established that the benzyl addition reaction is also a reversible transformation. The retro benzyl reaction was shown by the addition of benzylmagnesium chloride to di-tert-butyl ketone followed by exchange of both the benzyl and the ketone moiety with another substrate. Similar experiments were performed with phenylmagnesium bromide and tert-butylmagnesium chloride, but in these two cases the Grignard addition reaction did not show any sign of a reverse transformation.

Full text of DOI:10.1016/j.tet.2013.12.070

Tetrahedron 70 (2014) 1478e1483
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The retro Grignard addition reaction revisited: the reversible
addition of benzyl reagents to ketones
*
*
Stig Holden Christensen, Torkil Holm , Robert Madsen
Department of Chemistry, Technical University of Denmark, 2800 Kgs. Lyngby, Denmark
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 2 October 2013
Received in revised form 12 December 2013
Accepted 24 December 2013
Available online 31 December 2013
The Grignard addition reaction is known to be a reversible process with allylic reagents, but so far the
reversibility has not been demonstrated with other alkylmagnesium halides. By using crossover exper-
iments it has been established that the benzyl addition reaction is also a reversible transformation. The
retro benzyl reaction was shown by the addition of benzylmagnesium chloride to di-tert-butyl ketone
followed by exchange of both the benzyl and the ketone moiety with another substrate. Similar ex-
periments were performed with phenylmagnesium bromide and tert-butylmagnesium chloride, but in
these two cases the Grignard addition reaction did not show any sign of a reverse transformation.
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Crossover experiment
Grignard reagent
Nucleophilic addition
Reaction mechanism
Retro reaction
1. Introduction
The addition of Grignard reagents to carbonyl compounds is one
of the fundamental reactions in synthetic organic chemistry.1 The
transformation is highly favored since the two bonds formed (CeC
and OeMg) are much stronger than the two bonds broken (CeMg
and C]O). The mechanism has been thoroughly studied and it has
been found that the reaction takes place by two rather different
pathways depending on the nature of the reagent and the substrate
(Scheme 1).2 Electron transfer reactions are observed if the sub-
strate is easily reduced by the acceptance of an electron and the
reagent has an alkyl group, which may form a stabilized radical by
donating an electron to the substrate. Steric hindrance is of little
importance in this stepwise mechanism and the reactivity series
for the Grignard reagents is often tert-butyl>isopropyl>n-
butyl>ethyl>methyl.2 If radical formation is not facilitated, the
reaction takes place by a synchronous shift of the electron pairs.
This four-centered concerted mechanism is highly dependent on
steric factors since the electron shifts require a close approach of
the reacting atoms. The reactivity series is often phenyl>ethyl>n-
butyl>isopropyl>>tert-butyl.2
Scheme 1. Mechanism of Grignard addition reaction.
allylmagnesium halides are extremely well suited for reaction in
a concerted way since the normal high steric requirements of the
magnesium atom with its coordination sphere of solvent molecules
may be circumvented by conjugate addition of the naked g-carbon
in a cyclic six-center mechanism (Scheme 1). The reactions of
allylmagnesium halides with many substrates therefore have half
lives in the microsecond range.3 In fact, allylations are so fast that
they may compete with protonations by water making it possible to
achieve certain allylic Grignard additions in aqueous media.4
Due to the high reactivity of Grignard reagents the addition is
commonly viewed as being irreversible. However, this is not always
completely true. The first suggestion of a retro Grignard addition
Allylic Grignard reagents are special, since by electron donation
they may form the highly stabilized allyl radical and therefore react
very fast by electron transfer mechanisms.3 At the same time
* Corresponding authors. Tel.: þ45 4525 2151; fax: þ45 4593 3968; e-mail ad-
dress: rm@kemi.dtu.dk (R. Madsen).
0040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.12.070

S.H. Christensen et al. / Tetrahedron 70 (2014) 1478e1483
1479
came from the observation that crotylmagnesium bromide, in the
reaction with tert-butyl isopropyl ketone, gave the -methallyl
was investigated where it is important that the Grignard reagents
have little steric requirements and react rapidly with the carbonyl
compounds. This is true for benzylic reagents, which are some of
the most reactive Grignard reagents after the allylic compounds. In
fact, the half life for the addition of benzylmagnesium bromide to
acetone is about 5 ms,3 while the same value for methylmagnesium
bromide is around 0.2 s.11 In the same way, the ketones should be
sterically encumbered and non-enolizable in order to avoid pro-
tonation of the Grignard reagent. Therefore, benzyl Grignard and
di-tert-butyl ketone were selected for the crossover experiments.
First, the exchange of Grignard reagent was investigated starting
from 3-benzyl-2,2,4,4-tetramethylpentan-3-ol (Table 1). The ter-
tiary alcohol was reacted with a large excess of the Grignard re-
agent, which immediately formed the corresponding alkoxide salt.
The mixture was then heated in a sealed vial and the exchange
monitored by GC. With p-methylbenzylmagnesium chloride no
reaction occurred at 100 ꢀC while a very low conversion was ob-
served at 120 ꢀC after 2 days. However, upon heating to 140 ꢀC for 3
days the crossover product, 2,2,4,4-tetramethyl-(p-methylbenzyl)
pentan-3-ol, was obtained in 51% yield after workup together with
48% of the starting alcohol (entry 1). Complete conversion was
observed when the reaction was extended to 10 days where 77%
yield of the exchange product was obtained (entry 2). This may
indicate that the benzyl Grignard addition reaction is a reversible
process although the temperature is significantly higher than for
the corresponding allyl reagent.
a
addition product 1 initially, while after a period of time the crotyl
addition product 2 dominated (Scheme 2).5
Scheme 2.
a-Methallyl versus crotyl adduct.
The process took place at room temperature and the result was
interpreted as a rearrangement of the -methallyl adduct 1 into the
a
crotyl product 2. The rearrangement was postulated to take place by
allylic transposition of 1 into a tert-butyl isopropyl ketoneecro-
tylmagnesium bromide complex, which then collapses through
afour-centeredtransitionstatetothethermodynamicallymorestable
crotyl product 2.5,6 However, it is unlikely that this rearrangement
takes place by a true retro Grignard addition at ambient temperature.
The heat of reaction for the addition of crotylmagnesium bromide to
tert-butyl isopropyl ketone is 105 kJ/mol and the activation energy for
the process is of the order of 30 kJ/mol.7 The reverse reaction must
then overcome a barrier of 135 kJ/mol and even with a favorable en-
tropy of reaction, the reaction at room temperature would require
hundreds of years, while the observed rearrangement occurs within
a few hours.
Table 1
Retro Grignard by exchange of Grignard reagent
That a retro Grignard addition is indeed possible was shown by
another approach where two different crossover experiments were
designed independently at the same time.7,8 In the first, 1,3-
dimethylallylmagnesium bromide was reacted with di-tert-butyl
ketone and the initial adduct split into two batches and treated
with tert-butyl isopropyl ketone and allylmagnesium bromide, re-
spectively.7 In both cases, significant allyl transfer occurred within
an hour at 80 ꢀC.7 An essential requirement for this experiment is
that both the added ketone and the Grignard reagent are more
reactive than the original reactants, which makes the crossover
a favorable transformation when the initial addition is a reversible
reaction. In the second crossover experiment, two different
Grignard adducts were mixed and heated to 65 ꢀC.8 The first was
prepared from di-tert-butyl ketone and allylmagnesium bromide
while the second was obtained from tert-butyl isopropyl ketone
and crotylmagnesium bromide. Again, allyl crossover was observed
indicating that the addition is reversible.8
The reversal process has found synthetic applications since
sterically encumbered homoallylic tertiary alcohols have been used
as allyl transfer reagents in the presence of various metals and
bases.9,10 First, the retro allylation transfers the allyl group to the
metal, which is then followed by allylation of an aldehyde or an
imine. This retro allylation/allylation sequence from homoallylic
alcohols has been mediated by copper, gallium, and rhodium
complexes at temperatures ranging from 25 to 130 ꢀC.9,10
Entry
R
R0MgX
Time (d)
Product
Yield (%)a
1
2
Bn
Bn
pMeBnMgClb
pMeBnMgClb
3
51
77
10
3
4
Bn
Bn
MeMgBrc
PhMgBrd
6
75
7
10
5
6
Ph
Ph
pMeBnMgClb
3
3
d
d
0
0
MeMgBrc
a
Determined by GC.
b
c
0.67 M solution in THF.
3.0 M solution in Et2O.
1.0 M solution in THF.
d
A similar crossover reaction was observed when the added
Grignard reagent was changed to methyl- and phenylmagnesium
bromide. With the former, the methyl addition product was gen-
erated in 75% yield after 6 days with some unreacted starting al-
cohol remaining (entry 3). With the latter, only 7% yield of the
phenyl addition product was formed after 10 days, which may be
due to the lower reactivity of phenylmagnesium bromide towards
di-tert-butyl ketone (entry 4).12 Attempts were also made to react
2,2,4,4-tetramethyl-3-phenylpentan-3-ol with Grignard reagents,
but in this case no conversion was observed indicating that the
phenyl Grignard addition reaction is not a reversible process at
140 ꢀC (entries 5 and 6).
So far, however, the reversal has only been described with allylic
substrates and no studies have been carried out with other
Grignard reagents. Thus, the purpose of the present study is to
investigate whether the reverse Grignard addition reaction is
possible with other alkylmagnesium halides.
2. Results and discussion
The studies were performed by crossover experiments in line
with the earlier work from one of us.7 First, a concerted reaction

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S.H. Christensen et al. / Tetrahedron 70 (2014) 1478e1483
Thus, the benzyl group can be detached from a tertiary mag-
3-ol was subjected to the same experiments, which again confirms
the non-reversibility of the phenyl addition reaction (entries 4 and
5). For comparison, the corresponding allyl adduct was also in-
cluded in the study since this particular crossover experiment has
not previously been performed with the unsubstituted allyl moiety.
As anticipated, the allyl exchange took place at a much lower
temperature and in a shorter time than with the benzyl reagent and
diisopropyl ketone, benzophenone, and benzalpinacolone could all
be employed as the acceptor (entries 6e8).
Grignard additions by an electron transfer mechanism may also
be reversible although this scenario is more complicated since two
consecutive steps are involved. To simplify the picture tert-butyl-
magnesium chloride was selected in this case together with mesityl
phenyl ketone and benzalpinacolone. Both ketones are known to
react with tert-butylmagnesium chloride and afford only one prod-
uct. Benzalpinacolone gives exclusively the 1,4-addition product in
this case,13 while mesityl phenyl ketone only furnishes the corre-
sponding 1,6-adduct.14 The latter is strained and lacks aromatic sta-
bilization making it a good candidate for a reverse addition reaction.
Thus, a small excess of mesityl phenyl ketone was reacted with
tert-butylmagnesium chloride at room temperature for 30 min to
furnish the intermediate 1,6-adduct 3 (Scheme 3). The identity of
this was confirmed by careful workup at 0 ꢀC in the absence of air,
which allowed the enol 4 to be characterized by NMR. Without
workup the 1,6-adduct 3 was treated directly with 1 equiv of ben-
zalpinacolone and the outcome of the subsequent reaction turned
out to depend on the temperature. Upon additional stirring at 0 ꢀC
for 1 h the 1,4-addition product 5 was obtained in 21% yield together
with 6% of diketone 6. However, at 60 ꢀC the ratio between the two
products changed and diketone 6 was obtained in 66% yield along
with 17% of 5.
nesium alkoxide, but in order to substantiate this as a retro
Grignard addition reaction it is also important to trap the benzyl
moiety with a ketone. Otherwise, the observed reaction could in
principle be a result of alkoxide decomposition by a different
mechanism. In fact, when the tertiary magnesium alkoxide was
heated to 140 ꢀC for 8 days in the absence of a Grignard reagent, di-
tert-butyl ketone was formed in 62% yield. The driving force is the
release of strain by converting the sp3-hybridized alcoholate into
the sp2-hydridized ketone, but the pathway could potentially be
different from a retro Grignard addition.
Therefore, the exchange of ketone was investigated next. The
tertiary alcohol was treated with 1 equiv of methylmagnesium
bromide to form the corresponding magnesium alkoxide, which
was followed by addition of the ketone and heating to 140 ꢀC
(Table 2). No crossover occurred with diisopropyl ketone, which
remained completely unreacted after 3 days (entry 1). However,
with benzophenone the exchange product could be observed in
40% yield after the same period along with 60% of di-tert-butyl
ketone (entry 2). A similar exchange was observed with benzalpi-
nacolone, which afforded a mixture of the 1,4- and the 1,2-addition
products in a combined 16% yield (entry 3). Together with the
Grignard crossover experiment this verifies the reversibility of the
benzylmagnesium bromide addition reaction at 140 ꢀC. No ex-
change was observed when 2,2,4,4-tetramethyl-3-phenylpentan-
Table 2
Retro Grignard by exchange of ketone
Entry
1
R
Ketone
Time (d)
3
Product
Yield (%)a
0
Bn
d
2
3
Bn
Bn
3
3
40
11þ5
Scheme 3. Addition of tert-butyl Grignard.
4
Ph
3
d
d
0
These results were not due to unreacted tert-butylmagnesium
chloride from the initial addition to mesityl phenyl ketone. This was
confirmed by repeating the sequence with a significantly larger
excess of mesityl phenyl ketone, which still produced a mixture of 5
and 6 after addition of benzalpinacolone. Hence, if the formation of
these is caused by a retro Grignard addition reaction it should also
be possible to perform a Grignard exchange experiment with ad-
duct 3. Therefore, tert-amylmagnesium chloride and allylmagne-
sium chloride were both allowed to react with 3, but even after 3
days at 60 ꢀC no exchange was observed at all in either of these two
cases. This complete lack of reactivity came as a surprise since es-
pecially the highly reactive allylmagnesium chloride should cap-
ture even the slightest amount of mesityl phenyl ketone.
Consequently, there appears to be no reversal of the tert-butyl
Grignard addition reaction and the formation of products 5 and 6 in
Scheme 3 must be due to a different pathway.
5
Ph
3
0
6b
Allyl
0.75
34
7b
Allyl
Allyl
0.75
0.75
32
50
8b
a
This pathway is believed to involve a slightly different electron
transfer route than the classical tert-butyl Grignard addition
Determined by GC.
Exchange performed at 70 ꢀC.
b

S.H. Christensen et al. / Tetrahedron 70 (2014) 1478e1483
1481
reaction (Scheme 4). Initially, benzalpinacolone coordinates to ad-
duct 3 and then receives an electron to afford allyl radical 7.15 Mesityl
phenyl ketone is regenerated by release of the tert-butyl radical into
the solvent cage with allyl radical 8.16 At low temperature, these will
combine to form 5 after workup. At higher temperature, however,
allyl radical 8 can diffuse out of the cage and react with a second
molecule of benzalpinacolone to form the new benzyl radical 9,17
which then accepts an electron from 3 to give 6 after workup.
argon atmosphere. The reaction was stirred overnight at
room temperature. The mixture was diluted with Et2O and
quenched with H2O. The organic layer was separated and washed
with saturated aqueous NH4Cl and H2O. The organic phase
was dried with MgSO4, filtered, and concentrated. Further puri-
fication was performed either by vacuum distillation or by col-
umn chromatography (heptane/ethyl acetate or heptane/
toluene).
Scheme 4. Mechanism for formation of ketones 5 and 6.
In summary, we have demonstrated that the Grignard addition
reaction is also a reversible process with benzylmagnesium halides.
The reversibility was shown with a ketone, which becomes strained
upon reaction with the Grignard reagent since this transformation
is less exothermic and has a lower heat of activation than other
Grignard addition reactions. On the other hand, the same re-
versibility was not observed with the less reactive phenyl- and tert-
butylmagnesium halides.
3.3. General procedure for Grignard exchange reactions
3-Benzyl-2,2,4,4-tetramethylpentan-3-ol (65 mg, 0.28 mmol)
was added to a 5 mL screw-top vial, which was flushed with argon.
The Grignard solution (4.0 mL of 0.67
M
p-methyl-
benzylmagnesium chloride in THF, or 4.0 mL of 1.0 M phenyl-
magnesium bromide in THF, or 2.5 mL of 3.0 M methylmagnesium
bromide in Et2O) was then added and the vial sealed. The solution
was heated to 140 ꢀC for the indicated time. The mixture was then
allowed to reach room temperature and the reaction diluted with
Et2O and quenched with H2O. The organic layer was separated and
washed with saturated aqueous NH4Cl and H2O. Samples for GC
analysis were taken out and yields were determined by using cal-
ibration curves with n-nonane as internal standard.
3. Experimental section
3.1. General methods
Ketones were purchased from SigmaeAldrich and used as re-
ceived. Benzylic Grignard reagents were prepared in ampoules by
slow addition of the benzylic halide to a magnesium suspension in
freshly distilled THF under an argon atmosphere. The remaining
Grignard reagents were purchased from SigmaeAldrich and used
as received. The base concentration was determined by quenching
1.0 mL of the solution in H2O followed by addition of a few drops of
phenolphthalein and then titrating with nitric acid until a color
shift from pink to colorless occurred.18 THF was distilled from so-
dium and benzophenone while Et2O was dried over sodium. NMR
spectra were recorded on a Varian Mercury 300 or a Bruker Ascend
400 spectrometer with residual solvent signals as reference.
Melting points were measured on a Stuart SMP30 melting point
apparatus and are uncorrected. Gas chromatography was per-
formed on a Shimadzu QP5000 GCeMS instrument fitted with an
3.4. General procedure for ketone exchange reactions
The tertiary alcohol (0.34 mmol) was placed in a 5 mL screw-top
vial, which was flushed with argon. Et2O (1.0 mL) and methyl-
magnesium bromide (0.11 mL, 3.0 mL in Et2O, 0.33 mmol) were
added. When the gas evolution had ceased the ketone (1.43 mmol)
was added. The vial was sealed and heated to the indicated tem-
perature for the time stated. Then the mixture was allowed to reach
room temperature and the reaction was diluted with Et2O and
quenched with H2O. The organic layer was separated and washed
with saturated aqueous NH4Cl and H2O. A sample for GC analysis
was taken out and yields were determined by using calibration
curves with n-nonane as internal standard.
Equity 5, 30 mꢁ0.25 mmꢁ0.25
mm column. High resolution mass
spectra were recorded on an Agilent 1100 LC system, which was
coupled to a Micromass LCT orthogonal time-of-flight mass spec-
trometer equipped with a lock mass probe.
3.5. General procedure for tert-butyl exchange reactions
To mesityl phenyl ketone (525 mg, 2.34 mmol) in dry Et2O
(10.0 mL) was added tert-butylmagnesium chloride (1.5 mL, 1.25 M
in Et2O, 1.90 mmol) under an argon atmosphere. The light brown
suspension was stirred at room temperature for 30 min. The re-
action was set to the indicated temperature and benzalpinacolone
(358 mg, 1.90 mmol) was added. The reaction was stirred at this
3.2. General procedure for synthesis of tertiary alcohols
The ketone was dissolved in Et2O and a small excess of the
Grignard solution in Et2O or THF was added under an

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S.H. Christensen et al. / Tetrahedron 70 (2014) 1478e1483
temperature for 1 h. The mixture was diluted at room temperature
with Et2O and quenched with H2O. The organic layer was separated
and washed with saturated aqueous NH4Cl and H2O. The organic
phase was dried with MgSO4, filtered, and concentrated. A sample
for GC analysis was taken out and yields were determined by using
calibration curves with n-nonane as internal standard.
3.11. 1,1,2-Triphenylethan-1-ol (Table 2, entry 2)
dH (300 MHz, CDCl3) 6.95e7.45 (m, 13H), 6.95e6.89 (m, 2H),
3.56 (s, 2H), 2.23 (s, 1H, OH); dC (75 MHz, CDCl3) 146.7, 135.9, 131.0,
128.2, 127.0, 126.9, 126.3, 78.0, 48.1; nmax (film) 3548, 3086, 3060,
3027, 2956, 2910, 2856,1492,1446,1199 cmꢂ1; HRMS (ESI) calcd for
C
20H18O [MꢂH2OþH]þ m/z 257.1325, found 257.1325. NMR data are
in accordance with literature values.22
3.6. Di-tert-butyl ketone
3.12. 2,2-Dimethyl-5,6-diphenylhexan-3-one (Table 2, entry 3)
3-Benzyl-2,2,4,4-tetramethylpentan-3-ol (68 mg, 0.29 mmol)
was placed in a 5 mL screw-top vial, which was flushed with ar-
gon. Et2O (2.0 mL) and methylmagnesium bromide (0.09 mL of
a 3.0 M solution in Et2O, 0.27 mmol) were added. When the gas
evolution had ceased the vial was sealed and heated to 140 ꢀC for 8
days. The mixture was allowed to reach room temperature, diluted
with Et2O and quenched with H2O. The organic layer was sepa-
rated and washed with saturated aqueous NH4Cl and H2O. A
sample for GC analysis was taken out and a yield of 62% was de-
termined by using a calibration curve with n-nonane as internal
standard.
Mp 82e84 ꢀC; dH (300 MHz, CDCl3) 7.39e6.96 (m, 10H), 3.52
(quint, J¼7.2 Hz, 1H), 3.02e2.81 (m, 3H), 2.74 (dd, J¼17.2, 6.3 Hz,
1H), 1.00 (s, 9H); dC (75 MHz, CDCl3) 214.4, 144.5, 140.1, 129.3, 128.4,
128.2, 127.8, 126.4, 126.1, 44.2, 42.7, 42.7, 42.6, 26.2; nmax (neat)
3024, 2969, 2919, 1694, 1601, 1494, 1452, 1366, 1073 cmꢂ1; HRMS
(ESI) calcd for C20H24O [MþH]þ m/z 281.1905, found 281.1905.
3.13. (E)-3-Benzyl-4,4-dimethyl-1-phenylpent-1-en-3-ol
(Table 2, entry 3)
Mp 103e105 ꢀC; dH (300 MHz, CDCl3) 7.41e7.06 (m, 10H), 6.41
(d, J¼16.0 Hz, 1H), 6.19 (d, J¼16.0 Hz, 1H), 3.03 (d, J¼13.1 Hz, 1H),
2.97 (d, J¼13.0 Hz, 1H), 1.35 (s, 1H, OH), 1.09 (s, 9H); dC (75 MHz,
CDCl3) 137.5, 137.0, 134.0, 131.1, 129.6, 128.6, 128.2, 127.2, 126.7,
126.42, 79.2, 41.8, 38.4, 25.9; nmax (neat) 3560, 3025, 2966, 2937,
3.7. 3-Benzyl-2,2,4,4-tetramethylpentan-3-ol (Table 1, entries
1e4)
dH (300 MHz, CDCl3) 7.43e7.18 (m, 5H), 3.06 (s, 2H), 1.50 (s, 1H,
OH), 1.17 (s, 18H); dC (75 MHz, CDCl3) 139.8, 131.6, 128.0, 125.9, 80.0,
42.9, 38.5, 29.5; nmax (film) 3598, 3085, 3061, 2959, 2916, 2878,
1493, 1481, 1452, 1393, 1086, 1001 cmꢂ1; HRMS (ESI) calcd for
2909, 2872, 1493, 1454, 1393, 1359, 1203, 1105, 1069, 1010 cmꢂ1
;
HRMS (ESI) calcd for C20H24O [MþH]þ m/z 281.1905, found
281.1900.
C
16H26O [MþNa]þ m/z 257.1876, found 257.1875. 1H NMR data are in
accordance with literature values.19
3.14. 3-Allyl-2,2,4,4-tetramethylpentan-3-ol (Table 2, entries
6e8)
3.8. 2,2,4,4-Tetramethyl-3-(p-methylbenzyl)pentan-3-ol
(Table 1, entries 1 and 2)
dH (300 MHz, CDCl3) 5.93 (ddt, J¼17.5, 10.2, 7.5 Hz, 1H),
5.18e5.00 (m, 2H), 2.45 (d, J¼7.5 Hz, 2H), 1.55 (s, 1H, OH), 1.05 (s,
18H); dC (75 MHz, CDCl3) 137.4, 118.7, 78.9, 42.4, 38.0, 28.9; nmax
dH (300 MHz, CDCl3) 7.32 (d, J¼8.0 Hz, 2H), 7.17 (d, J¼8.0 Hz, 2H),
3.06 (s, 2H), 2.40 (s, 3H), 1.54 (s, 1H, OH), 1.21 (s, 18H); dC (75 MHz,
CDCl3) 136.4, 135.3, 131.4, 128.8, 79.8, 42.8, 38.0, 29.4, 21.3; HRMS
(ESI) calcd for C17H28O [MþNa]þ m/z 271.2032, found 271.2032.
(film) 3581, 3076, 2960, 2918, 2878, 1482, 1392, 1370, 1001 cmꢂ1
.
NMR data are in accordance with literature values.23
3.15. 3-Allyl-2,4-dimethylpentan-3-ol (Table 2, entry 6)
3.9. 2,2,3,4,4-Pentamethylpentan-3-ol (Table 1, entry 3)
dH (300 MHz, CDCl3) 5.85 (ddt, J¼17.5, 10.1, 7.4 Hz,1H), 5.11e5.00
(m, 2H), 2.28 (dt, J¼7.4, 1.3 Hz, 2H), 1.89 (sept, J¼6.9 Hz, 2H), 1.26 (s,
1H, OH), 0.92 (d, J¼6.9 Hz, 12H); dC (75 MHz, CDCl3) 135.2, 117.7,
76.9, 38.4, 34.2, 17.6, 17.4; nmax (film) 3500, 3077, 2964, 2880, 1468,
1385, 991 cmꢂ1; HRMS (ESI) calcd for C10H20O [M-H2OþH]þ m/z
139.1481, found 139.1482. 1H NMR data are in accordance with
literature values.24
Mp 39e41 ꢀC, lit.12 39e41 ꢀC; dH (300 MHz, CDCl3) 1.26 (s, 1H,
OH), 1.14 (s, 3H), 1.05 (s, 18H); dC (75 MHz, CDCl3) 79.5, 41.1, 28.9,
21.7; nmax (film) 3506, 2983, 2960, 2916, 2876, 1371, 1106,
1065 cmꢂ1. NMR data are in accordance with literature values.20
3.10. 2,2,4,4-Tetramethyl-3-phenylpentan-3-ol (Table 1, entry 4)
3.16. 1,1-Diphenylbut-3-en-1-ol (Table 2, entry 7)
Bromobenzene (3.0 mL, 29 mmol) was added dropwise to
a suspension of lithium metal (500 mg, 72 mmol) in dry Et2O
(20 mL) under an argon atmosphere. The concentration was mea-
sured to 1.39 M by the phenolphthalein titration method.18 The
phenyllithium solution, thus obtained, was added dropwise to
2,2,4,4-tetramethylpentan-3-one (1.24 g, 8.7 mmol) under an argon
atmosphere and stirred for 10 min. The mixture was diluted with
Et2O and quenched with H2O. The organic layer was separated and
washed with saturated aqueous NH4Cl and H2O. The organic phase
was dried with MgSO4, filtered, and concentrated. No further pu-
rification was needed. dH (300 MHz, CDCl3) 7.77e7.72 (m, 1H),
7.64e7.58 (m, 1H), 7.41e7.33 (m, 1H), 7.29e7.23 (m, 2H), 1.98 (s, 1H,
OH), 1.15 (s, 18H); dC (75 MHz, CDCl3) 145.6, 128.0, 127.6, 127.4,
126.0, 125.8, 83.2, 41.7, 29.8; nmax (film) 3624, 3057, 2961, 2913,
2877,1483,1392,1370,1053 cmꢂ1. NMR data are in accordance with
literature values.21
dH (300 MHz, CDCl3) 7.61e7.53 (m, 4H), 7.45e7.28 (m, 6H), 5.78
(ddt, J¼17.2, 10.1, 7.2 Hz, 1H), 5.40e5.22 (m, 2H), 3.18 (d, J¼7.2 Hz,
2H), 2.75 (s, 1H, OH); dC (75 MHz, CDCl3) 146.5, 133.5, 128.2, 126.9,
126.0, 120.4, 76.9, 46.7; nmax (film) 3554, 3475, 3059, 3025, 2978,
2923, 1493, 1446, 1345, 1166, 990 cmꢂ1. NMR data are in accordance
with literature values.23
3.17. (E)-3-(tert-Butyl)-1-phenylhexa-1,5-dien-3-ol (Table 2,
entry 8)
dH (300 MHz, CDCl3) 7.16e7.46 (m, 5H), 6.58 (d, J¼16.0 Hz, 1H),
6.35 (d, J¼16.0 Hz, 1H), 5.89e5.67 (m, 1H), 5.20e5.17 (m, 1H),
5.16e5.12 (m, 1H), 2.66e2.51 (m, 1H), 2.40 (dd, J¼13.5, 9.3 Hz, 1H),
1.74 (s, 1H, OH), 1.05e1.01 (m, 9H); dC (75 MHz, CDCl3) 137.3, 134.6,
133.5, 129.5, 128.7, 127.3, 126.5, 119.7, 78.2, 40.1, 38.1, 25.7; nmax

S.H. Christensen et al. / Tetrahedron 70 (2014) 1478e1483
1483
(film) 3554, 3079, 3060, 3026, 2958, 2873, 975 cmꢂ1; HRMS (ESI)
calcd for C16H22O [MꢂH2OþH]þ m/z 213.1638, found 213.1638.
NMR data are in accordance with literature values.25
4.5, 3.3 Hz, 1H), 3.11 (d, J¼6.7 Hz, 2H), 2.94 (dd, J¼12.6, 11.1 Hz, 1H),
2.71 (dd, J¼12.6, 3.3 Hz, 1H), 1.10 (s, 9H), 0.74 (s, 9H); dC (75 MHz,
CDCl3) 217.2, 213.7, 143.5, 140.0, 129.4, 128.6, 128.3, 128.1, 126.8,
126.3, 54.0, 44.7, 44.2, 41.1, 35.9, 34.0, 26.6, 26.0; nmax (neat) 3062,
3027, 2968, 1707, 1682, 1476, 1454, 1364 cmꢂ1; HRMS (ESI) calcd for
3.18. (4-(tert-Butyl)cyclohexa-2,5-dien-1-ylidene)(mesityl)
methanol (4)14
C
26H34O2 [MþNa]þ m/z 401.2451, found 401.2452; HRMS (ESI) calcd
for C26H34O2 [MþH]þ m/z 379.2632, found 379.2633.
For minor diastereomer: dH (300 MHz, CDCl3) 7.25e7.02 (m, 8H),
6.97e6.84 (m, 2H), 3.56 (ddd, J¼9.1, 7.4, 5.1 Hz, 1H), 3.49e3.37 (ddd,
J¼10.0, 6.7, 3.4 Hz, 1H), 3.10 (dd, J¼17.2, 10.0 Hz, 1H), 2.77e2.46 (m,
3H), 0.92 (s, 9H), 0.68 (s, 9H); dC (75 MHz, CDCl3) 219.0, 213.2, 142.4,
139.6, 129.3, 128.5, 128.4, 128.4, 126.8, 126.5, 52.9, 44.8, 44.2, 43.4,
39.8, 38.2, 26.3, 26.2.
To mesityl phenyl ketone (222 mg, 0.99 mmol) in dry Et2O
(10 mL) was added tert-butylmagensium chloride (1.0 mL of 1.25 M
solution in Et2O, 1.25 mmol) under an argon atmosphere. The light
brown suspension was stirred at room temperature for 30 min. The
mixture was quenched with an ice-cold solution of saturated
aqueous NH4Cl. The organic layer was removed with an air-tight
syringe and washed inside the syringe with H2O. The organic
phase was transferred to a pear-shaped flask under argon followed
by removal of the solvent by a flow of argon. The remaining col-
orless oil was dissolved in CDCl3 and added to an NMR tube inside
an argon-filled Schlenk flask. dH (400 MHz, CDCl3) 6.90 (s, 2H), 6.83
(dt, J¼10.3, 1.7 Hz, 1H), 5.86 (ddd, J¼10.3, 4.4, 1.9 Hz, 1H), 5.64 (dt,
J¼10.3, 1.6 Hz, 1H), 5.54 (ddd, J¼10.3, 4.2, 1.9 Hz, 1H), 4.01 (s, 1H),
2.80 (tt, J¼4.3, 1.5 Hz, 1H), 2.21 (s, 3H), 2.16 (s, 3H), 2.11 (s, 3H), 0.84
(s, 9H); dC (100 MHz, CDCl3) 144.4, 138.6, 137.8, 137.5, 132.7, 128.5,
128.4, 127.0, 125.4, 125.2, 122.0, 110.9, 48.9, 35.9, 27.4, 21.3, 19.62,
19.60.
Supplementary data
1H and 13C NMR spectra of all compounds. Supplementary data
related to this article can be found at http://dx.doi.org/10.1016/
j.tet.2013.12.070.
References and notes
1. Handbook of Grignard Reagents; Silverman, G. S., Rakita, P. E., Eds.; Marcel
Dekker: New York, NY, 1996.
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Jr., Ed.; John Wiley & Sons: Chichester, UK, 2000; pp 1e26.
3. Holm, T. J. Org. Chem. 2000, 65, 1188e1192.
3.19. 2,2,6,6-Tetramethyl-5-phenylheptan-3-one (5)
4. Osztrovszky, G.; Holm, T.; Madsen, R. Org. Biomol. Chem. 2010, 8, 3402e3404.
5. Benkeser, R. A.; Broxterman, W. E. J. Am. Chem. Soc. 1969, 91, 5162e5163.
6. See also: (a) Benkeser, R. A.; Siklosi, M. P.; Mozdzen, E. C. J. Am. Chem. Soc. 1978,
100, 2134e2139; (b) Barbot, F.; Miginiac, P. Bull. Soc. Chim. Fr. 1977, 113e116.
7. Holm, T. Acta Chem. Scand. Ser. B 1976, 30, 985e990.
8. Benkeser, R. A.; Siklosi, M. P. J. Org. Chem. 1976, 41, 3212e3213.
9. Sai, M.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2011, 50, 3294e3298.
10. Yorimitsu, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2009, 82, 778e792.
11. Holm, T. Acta Chem. Scand. Ser. B 1983, 37, 567e584.
12. Conant, J. B.; Blatt, A. H. J. Am. Chem. Soc. 1929, 51, 1227e1236.
13. Holm, T. Acta Chem. Scand. 1991, 45, 925e929.
14. Holm, T.; Crossland, I. Acta Chem. Scand. 1971, 25, 59e69.
15. Yamazaki, S.; Yamabe, S. J. Org. Chem. 2002, 67, 9346e9353.
16. Holm, T. Acta Chem. Scand. Ser. B 1988, 42, 685e689.
Following the general procedure for tert-butyl exchange, mesityl
phenyl ketone and tert-butylmagnesium chloride were reacted at
0
ꢀC for 1 h. After workup ketone 5 was purified by column chro-
matography (1:50 ethyl acetate/pentane) and recrystallization from
toluene/methanol. Mp 99e100 ꢀC, lit.26 100e101 ꢀC; dH (300 MHz,
CDCl3) 7.25e7.10 (m, 5H), 3.09e3.15 (m, 2H), 2.71 (dt, J¼10.8, 8.9,
8.9 Hz,1H),1.01 (s, 9H), 0.88 (s, 9H); dC (75 MHz, CDCl3) 214.5,143.0,
129.4, 127.6, 126.1, 50.4, 44.4, 37.9, 33.7, 28.4, 26.5; MS m/z 246
[Mþ]; nmax (neat) 2959, 2915, 2867, 1699, 1472, 1365, 1342 cmꢂ1 13C
.
NMR data are in accordance with literature values.27
17. Holm, T.; Crossland, I.; Madsen, J. Ø. Acta Chem. Scand. Ser. B 1978, 32, 754e758.
18. Gilman, H.; Cartledge, F. K. J. Organomet. Chem. 1964, 2, 447e454.
19. Lomas, J. S.; Briand, S.; Fain, D. J. Org. Chem. 1991, 56, 166e175.
20. Napolitano, E.; Giovani, E.; Cecarelli, N.; Pelosi, P. J. Agric. Food Chem. 1996, 44,
2806e2809.
3.20. 4-Benzyl-2,2,8,8-tetramethyl-5-phenylnonane-3,7-di-
one (6)
Following the general procedure for tert-butyl exchange, mesityl
phenyl ketone and tert-butylmagnesium chloride were reacted at
60 ꢀC for 1 h. After workup diketone 6 was obtained as a 3:1 di-
astereomeric mixture, which were separated and purified by col-
umn chromatography (1:50 ethyl acetate/pentane and then 1:1
toluene/heptane) and recrystallization from heptane. For major
diastereomer: Mp 94e95 ꢀC; dH (300 MHz, CDCl3) 7.07e7.35 (m,
8H), 6.90e6.93 (m, 2H), 3.76 (dt, J¼6.7, 4.5 Hz,1H), 3.44 (ddd, J¼11.1,
21. Lomas, J. S.; Bru-Capdeville, V. J. Chem. Soc., Perkin Trans. 2 1994, 459e466.
~
22. Guijarro, D.; Mancheno, B.; Yus, M. Tetrahedron 1992, 48, 4593e4600.
23. Shen, K.-H.; Yao, C.-F. J. Org. Chem. 2006, 71, 3980e3983.
24. Katzenellenbogen, J. A.; Lenox, R. S. J. Org. Chem. 1973, 38, 326e335.
25. Majetich, G.; Casares, A.; Chapman, D.; Behnke, M. J. Org. Chem. 1986, 51,
1745e1753.
ꢀ
ꢀ
ꢀ
26. Alvarez-Ibarra, C.; Arias-Perez, M. S.; Fernandez-Conzalez, F. An. Quim. 1979, 75,
707e711.
ꢀ
ꢀ
ꢀ
27. Alvarez-Ibarra, C.; Arias-Perez, M. S.; de Andres, A.; Balcazar, J. L. Magn. Reson.
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