Development of a flow method for the hydroboration/oxidation of olefins

Article abstract of DOI:10.1039/c5ob00170f

A method for the continuous preparation of alcohols by hydroboration/oxidation of olefins using flow techniques is described. The process allows the isolation of up to 120 mmol h^-1 of the desired alcohol in a very rapid manner with good functional group tolerance. The flow setup can be modified to perform a continuous extraction of the desired alcohol from the biphasic mixture produced by the reaction. This journal is

Full text of DOI:10.1039/c5ob00170f

Organic &
Biomolecular Chemistry
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Development of a flow method for the
hydroboration/oxidation of olefins†
José A. Souto,*a,b Robert A. Stockmanc and Steven V. Leya
Cite this: Org. Biomol. Chem., 2015,
13, 3871
Received 28th January 2015,
Accepted 12th February 2015
DOI: 10.1039/c5ob00170f
www.rsc.org/obc
A method for the continuous preparation of alcohols by hydro- when alkenes presenting two sterically differentiated faces are
boration/oxidation of olefins using flow techniques is described. used.12
The process allows the isolation of up to 120 mmol h−1 of the
Despite these advantages, there are some drawbacks of this
desired alcohol in a very rapid manner with good functional group method, especially when diborane, a simple readily available
tolerance. The flow setup can be modified to perform a continuous reagent, is used.13 Known limitations for broader applications
extraction of the desired alcohol from the biphasic mixture pro- of the reaction, especially at a larger scale, are the high
duced by the reaction.
exothermicity of both steps, and lack of complete regioselecti-
vity for initial hydroboration of the double bond or incompat-
ibility of functional groups under either reducing or oxidative
conditions. Due to the high surface area to volume ratio, flow
chemistry technologies provide a practical solution to over-
come some of these limitations by better mixing, more
efficient heat transfer in highly exothermic reactions and
improved ability to control the rate of transformation,14 com-
pared to the batch mode. Furthermore, the possibility for con-
tinuous production of the desired product with in-line
purification techniques, or for the development of a telescoped
protocol offers an efficient generation of the alcohol functional
group.
Our group has pioneered many advances in the use of flow
protocols for organic synthesis.15 This work has led to reduced
manpower requirements and accelerated reaction optimisation
programmes. In an ongoing effort towards the development of
improved flow processes for the synthesis of compounds of
potential interest for materials, fine chemicals and pharma-
ceutical and agrochemical industries, we began an investi-
gation into the development of hydroboration–oxidation flow
protocol for the introduction of the hydroxyl group into olefi-
nic skeletons.16 For this purpose a flow setup was devised and
a schematic representation is depicted in Fig. 1.
The preparation of molecular entities containing the hydroxyl
functionality is a very important area of research due to the
abundance of this functional group in natural products and
biologically active molecules. The toolbox of chemical reac-
tions contain many examples of procedures that accomplish
this transformation, such as direct oxidation of allylic C–H
bonds by selenium,1 C–H bond2 oxidation by peracids, singlet
oxygen oxidation,3 treatment of diazo compounds with
mineral acids,4 silane oxidation by peracids,5 ozonolysis of
alkenes followed by reductive workup6 or hydroboration–oxi-
dation tandem reaction of alkenes.7 Among them, the hydro-
boration–oxidation reaction has frequently been used for the
insertion of hydroxyl groups either in total synthesis of natural
products8 or drug discovery.9 This is mainly due to the broad
availability of alkenes as starting materials and the orthogonal
reactivity of this functionality to those of the polar functional
groups found in many natural products.10 The reaction is
highly influenced by the steric and electronic character of the
alkene, and occurs with a preference towards the anti-Markow-
nikov borane intermediate that can then be transformed into
the terminal alcohol.11 Another attractive feature of the hydro-
boration reaction is its cis addition across the double bond,
which results in a preference for the thermodynamic product
Using the reactor configuration shown, we began by investi-
gating the influence of different parameters (i.e. borane
source, residence time, solvent mixture) using commercially
available β-pinene as a model substrate (Table 1). An initial
screening of borane sources gave opposing results. We
observed excellent conversion (100%) of the starting material
when either a THF or DMS complex of BH3 was used. However,
using the tertbutylamine complex of diborane resulted in
incomplete conversion of starting materials (entries 1–3).
aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge
CB2 1EW, UK. E-mail: svl1000@cam.ac.uk
bDepartamento de Química Orgánica, Universidade de Vigo, Vigo, 36310, Spain.
E-mail: souto@uvigo.es
cSchool of Chemistry, University of Nottingham, Nottingham, NG7 2RD, UK.
E-mail: robert.stockman@nottingham.ac.uk
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob00170f
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the residence time inside the reactor.17 The pumping was
maintained (entry 16) for 50 min and gave 14.1 g (92% yield)
of the desired material after isolation.
In our hands, a comparable batch-mode reaction (20 g
scale) proceeded with similar yields and selectivity over a
4 hour reaction time period (Scheme 1). However, there are
some notable advantages of the flow process. Firstly, under
continuous operation, the system needs less than two hours to
process the same amount of material. Secondly, in flow the
malodorous BH3·DMS, which is necessary in the batch,18 can
be substituted for BH3·THF; and importantly the flow reaction
can be performed at room temperature. No additional cooling
or heating is required,19 due to the excellent heat transfer pro-
perties of the flow equipment.
Fig. 1 Schematic representation of our hydroboration/oxidation con-
tinuous flow setup.
Having identified optimised reaction conditions we sub-
jected a number of substituted alkenes to the reactor set up in
order to test the scope of the new continuous flow hydrobora-
tion–oxidation protocol (Table 2).
The reaction performed well for simple terminal alkenes
such as 1-hexene 1b and 1-octene 1c with complete selectivity
towards the functionalisation at the terminal position20
(entries 2 and 3). Tolerance towards acetal 1d and silylether 1e
was noticed (entries 4 and 5).
The reaction also proceeded in good yield for more steri-
cally hindered α-pinene 1f (entry 6). Moderate yield was
observed when cycloalkene 1g was used as the substrate (entry
7). Notably, moderate yield was achieved for alcohol 2n, a chal-
lenging substrate due to the presence of a nitrile functional
group, which is also susceptible to reduction. S-(−)-Limonene
1i was processed to the dioxygenated compound in modest
yield of 30%21 (entry 8). Phenyl alkenes (entries 10–12) proved
to have generally lower reactivity under the flow hydroboration
conditions than aliphatic alkenes. Compound 1l required
extended residence times in order to achieve good yields (entry
13). However, the reaction of styrene and its derivatives in flow
showed higher preference towards the primary alcohol, com-
pared to the batch procedure, with a selectivity of 92 : 8 for the
Unfortunately, neither of these experiments could be pro-
gressed to a clean oxidation step (<10% conversion).
Due to the less odorous nature of the THF complex, this
borane source was selected for further investigations. Any
initial attempt to increase the yield of the reaction either by
modifying the residence time, equivalents of borane/oxidant
counterpart or the reaction temperature did not lead to any
improvement in the yield (entries 4–8). Pleasingly, changing
the nature of the solvent mixture, by the addition of ethanol
improved the outcome of the reaction allowing the isolation of
the product in 25% yield (entry 9), although some blockage of
the second reactor by the formation of insoluble inorganic
salts was an issue. Replacement of the previous narrower
reactor coil (1 mm i.d.) by a wider bore (2.4 mm i.d.) resulted
in a more reliable performance and moderate 31% yield (entry
10). Raising the equivalents of the basic oxidative mixture gave
the desired product in 88% yield (entry 11). Attempts to
improve this result by further increasing the equivalents of the
oxidising agent or the amount of ethanol in the mixture did
not afford any improvement of the yield (entries 12 and 13).
Surprisingly, the reaction yield was increased when the trans-
formation was performed at high flow rates (entries 14–16)
allowing the production of up to 120 mmol h−1 within 70 s of
Table 1 Screening of reaction conditions for the optimisation of the hydroboration/oxidation reaction
Flow A
Flow B
Flow C
V2
(mL)
T2
(°C)
Conv
(%)
NMR yield
(%)
Boranea
(mL min−1
)
(mL min−1
)
Solvent (Oxid.)
(mL min−1
)
1
2
3
4
5
6
7
8
BH3·SMe2
BH3·THF
BH3·H2NR
BH3·THF
BH3·THF
BH3·THF
BH3·THFc
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
BH3·THF
0.1
0.1
0.1
0.1
0.1
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.5
1
0.1
0.1
0.1
0.1
0.1
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.5
1
H2O2–H2Ob
0.2
0.2
0.2
0.2
0.6
0.6
0.6
0.6
0.6
0.6
1.2
2
0.02
0.02
0.02
0.3
0.3
2
2
2
2
4.2
4.2
4.2
4.2
4.2
4.2
4.2
25
25
25
25
25
25
25
60
25
25
25
25
25
25
25
25
100
100
0
100
100
100
50
100
100
100
100
100
100
100
100
>99
<10
<10
0
<10
<10
<10
<10
<10
25
31
88
88
52
H2O2–H2Ob
H2O2–H2Ob
H2O2–H2Ob
H2O2–H2Ob
H2O2–H2Ob
H2O2–H2Ob
H2O2–H2Ob
9
H2O2–EtOH–H2Od
H2O2–EtOH–H2Od
H2O2–EtOH–H2Od
H2O2–EtOH–H2Od
H2O2–EtOH–H2Oe
H2O2–EtOH–H2Od
H2O2–EtOH–H2Od
H2O2–EtOH–H2Od
10
11
12
13
14
15
16
1.2
2
4
89
99
99
2
2
8
a 1 equiv. of borane (2.5 mmol scale). b 20 : 80. c 0.5 equiv. of borane. d 20 : 38 : 42. e 20 : 60 : 20.
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Scheme 1 Batch reaction for purposes of comparison.
Table 2 Reaction scope
Fig. 2 Schematic representation of our continuous reaction–extraction
flow setup.
Conv.
(%)
NMR Yielda
[%]
Entry
1
Alkene
1a
Alcohol
styrene and complete anti-Markovnikoff selectivity for the
other examples.22
100
99(92)
An attractive feature of the flow procedure is the potential
to perform additional steps in a telescoped fashion. In this
case, we could expand on the process by incorporating an
inline solvent extractor. An organic solvent phase was delivered
by a fourth pump, and following appropriate mixing the extrac-
tion could be performed by a membrane separator device23
(Fig. 2).
Due to the high water miscibility of the organic solvent
used in the oxidation step (THF and EtOH), the choice of the
organic solvent to perform continuous extraction of this
mixture was crucial. Initial attempts using diethyl ether (Et2O)
as the extracting solvent were unsuccessful as a large amount
2
3
4
1b
1c
1d
100
100
100
97(88)
99(94)
99(99)
5
6
1e
1f
100
100
99(99)
74(70)
7
1g
100
50
8
9
1h
1i
100
60
43(36)
30(28)
10
11
1j
84
85
80(72)b
74(65)
1k
12
13
1l
39
75
34(28)
70(68)c
Fig. 3 Side and top view of an in-house gravity separating funnel and a
Biotage® phase membrane separator for the continuous hydroboration/
oxidation of alkenes.
a 2.5 mmol scale. Isolated yield between brackets. b 98 : 2 regioisomeric
ratio. c 140 s residence time.
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of water and organic solvent passed through the membrane. tive ESI, or a Bruker BioApex 47e FTICR spectrometer using
When dichloromethane was used instead of Et2O, better phase (positive or negative) ESI or EI at 70 eV to within a tolerance
separation was achieved and any residual water in the organic of 5 ppm of the theoretically calculated value. The flow appar-
phase was removed easily using magnesium sulfate. At this atus is the Vapourtec R2 + R4 module commercialized by
stage, the processing scale was limited by the size of the com- Vapourtec.
mercial membrane separator (70 mL), thus each run was
limited to 10 min.
General protocol for the hydroboration–oxidation of olefins in
flow followed by regular workup (Protocol A)
Encouraged by the good performance of the system we
wanted to develop a method for the continuous production of A solution of alkene (2.5 mL, 1 M in THF) and a solution of
alcohols. We designed and incorporated a custom built glass BH3·THF (2.5 mL, 1 M in THF) were combined at a T-piece
extractor device (see Fig. 3) that allowed continuous extraction (each stream runs at 2.0 mL min−1) and reacted at rt in a 2 mL
and collection of the organic phase for more than 30 min PFA reactor coil. The combined stream was then combined at
without issue. An analysis of the organic mixture after drying a T-piece with an aqueous solution of NaOH (0.42 M in H2O2
and removal of volatiles proved the isolation of the desired (20% v/v)–H2O–EtOH 20 : 42 : 38) and reacted at rt in a 4.2 mL
product in 80% yield.24
PFA reactor coil. To the resulting mixture, an aqueous satu-
rated solution of NH4Cl was added, phases were separated and
the organic layer extracted with Et2O (3×). Combined organic
layers were washed with H2O (3×) and brine (1×), dried and
evaporated. Unless otherwise stated a pure compound was iso-
Conclusions
We have developed a continuous method for the hydrobora- lated without further purification.
tion–oxidation reaction of olefins. To the best of our knowl-
edge, this is the first report of such a continuous system.
Under flow conditions, the reaction can be carried out under
General protocol for the hydroboration–oxidation of β-pinene
in batch
milder conditions and with higher selectivity than the batch To a cold solution (0 °C) of β-pinene (24 mL, 148 mmol) in
reaction. Our protocol allows a continuous production of up to THF (56 mL) BH3·SMe2 (74 mL, 148 mmol, 2 M in THF) was
120 mmol h−1 and continuous processing of the biphasic added dropwise and the mixture was stirred at 0 °C for 1 hour.
mixture produced by the reaction with a new liquid/liquid Then, maintaining the solution at 0 °C EtOH (72 mL), NaOH
phase separation device. Investigations towards a fully tele- (80 mL, 1 M in H2O) and H2O2 (36 mL, 30% v/v in H2O) were
scoped functionalisation of the obtained alcohol or further added subsequently in a dropwise manner. The resulting
derivatisation of the alkyl boranes are ongoing in our mixture was stirred for 1 hour, warmed to room temperature
laboratory.
and kept for an additional two hours at 80 °C. The reaction
was then allowed to cool before quenching by the addition of a
saturated aqueous solution of NH4Cl. An aqueous layer was
extracted with Et2O (3×). Combined organic layers were washed
with brine, dried and the solvent was evaporated. The NMR
Experimental section
1H-NMR spectra were recorded on a Bruker Avance DPX-400, yield was determined to be 99%.
with the residual solvent peak as the internal reference
General protocol for the continuous hydroboration–oxidation
followed by in-line workup using the Biotage phase membrane
separator (Protocol B)
(CDCl3 = 7.26 ppm). 1H resonances are reported to the
nearest 0.01 ppm. 13C-NMR spectra were recorded on the
same spectrometer with proton decoupling, with the solvent
peak as the internal reference (CDCl3 = 77.00 ppm). All 13C A solution of alkene (1 M in THF) and a solution of BH3·THF
resonances are reported to the nearest 0.01 ppm. DEPT 135, (1 M in THF) were combined at a T-piece (each stream runs at
COSY, HMQC, and HMBC experiments were used to aid struc- 1.0 mL min−1) and reacted at rt in a 2 mL PFA reactor coil. The
tural determination and spectral assignment. The multi- combined stream was then combined at a T-piece with an
1
plicity of H signals are indicated as: s = singlet, d = doublet, aqueous solution of NaOH (0.42 M in H2O2 (20% v/v)–H2O–
dd = doublet of doublets, ddd = doublet of doublets of doub- EtOH 20 : 42 : 38) (4 mL min−1) and reacted at rt in a 4.2 mL
lets, t = triplet, q = quadruplet, sext = sextet, m = multiplet, br PFA reactor coil. The resulting mixture was mixed at a T-piece
= broad, or combinations thereof. Coupling constant (J) is with DCM (8 mL min−1) and the out stream dropped in a
quoted in Hz and reported to the nearest 0.1 Hz. Where Biotage phase membrane separator collecting the organic layer
appropriate, measures of the same coupling constant are from the output at the bottom.
averaged. Unless stated otherwise, reagents were obtained
from commercial sources and used without purification. The
removal of solvent under reduced pressure was carried out on
a standard rotary evaporator. High resolution mass spec-
General protocol for the continuous hydroboration–oxidation
followed by in-line workup using in-house gravity separating
funnel (Protocol C)
trometry (HRMS) was performed using a Waters Micromass A solution of alkene (1 M in THF) and a solution of BH3·THF
LCT Premier™ spectrometer, using time of flight with posi- (1 M in THF) were combined at a T-piece (each stream runs at
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1.0 mL min−1) and reacted at rt in a 2 mL PFA reactor coil. The (100 MHz, CDCl3): δ = 71.55 (d), 47.78 (d), 47.65 (d), 41.72 (d),
combined stream was then combined at a T-piece with an 38.96 (t), 38.11 (s), 34.32 (t), 27.62 (q), 23.64 (q), 20.69 (q).
aqueous solution of NaOH (0.42 M in H2O2 (20% v/v)–H2O– HRMS (ESI-MS): calcd for C10H18NaO: 177.1250, found:
EtOH 20 : 42 : 38) (4 mL min−1) and reacted at rt in a 4.2 mL 177.1248. Data match those previously reported.25
PFA reactor coil. The resulting mixture was mixed at a T-piece
Cyclooctanol 2g. The titled compound was prepared follow-
with DCM (8 mL min−1) and the out stream dropped in our ing general protocol A. 1H-NMR (400 MHz, CDCl3): δ =
custom built glass separator where continuous collection of 3.91–3.77 (m, 1H), 1.87–1.77 (m, 2H), 1.76–1.61 (m, 4H),
the organic phase at the device output is possible by gravity 1.61–1.42 (m, 9H). 13C-NMR (100 MHz, CDCl3): δ = 71.96 (d),
separation of the aqueous-organic phase.
34.56 (t), 27.36 (t), 25.17 (t), 22.67 (t). Data match those pre-
((1R,2S,5R)-6,6-Dimethylbicyclo[3.1.1]heptan-2-yl)methanol viously reported.29
2a. The titled compound was prepared following either
6-Hydroxyhexanenitrile 2h. The titled compound was pre-
general protocol A, B or C. 1H-NMR (400 MHz, CDCl3): δ = pared following general protocol A. The crude mixture was pur-
3.6–3.5 (m, 2H), 2.4–2.3 (m, 1H), 2.3–2.2 (m, 1H), 2.0–1.9 (m, ified by chromatography on a Biotage SP4 eluting with 0–20%
1H), 1.9–1.8 (m, 3H), 1.5–1.4 (m, 1H), 1.15 (s, 3H), 0.94 (s, 3H). hexane–ethyl acetate over 20 column volumes. 1H-NMR
13C-NMR (100 MHz, CDCl3): δ = 67.57 (t), 44.29 (d), 42.80 (d), (400 MHz, CDCl3): δ = 3.66 (t, J = 6.0 Hz, 2H), 2.36 (t, J =
41.38 (d), 38.53 (s), 33.06 (t), 27.88 (q), 25.91 (t), 23.23 (q), 7.0 Hz, 2H), 1.77–1.33 (m, 6H). 13C-NMR (100 MHz, CDCl3): δ =
18.70 (t). HRMS (ESI-MS): calcd for C10H18NaO: 177.1250, 119.71 (s), 62.22 (t), 31.69 (t), 25.15 (t), 24.98 (t), 17.12 (t). Data
found: 177.1253. Data match those previously reported.25
match those previously reported.30
1-Hexanol 2b. The titled compound was prepared following
(5S)-5-(1-Hydroxypropan-2-yl)-2-methylcyclohexan-1-ol 2i. The
1
general protocol A. H-NMR (400 MHz, CDCl3): δ = 3.64 (t, J = titled compound was prepared following general protocol
6.6 Hz, 2H), 1.6–1.5 (m, 2H), 1.4–1.2 (m, 6H), 0.9–0.8 (m, 3H). A. The crude mixture was purified by chromatography on a
13C-NMR (100 MHz, CDCl3): δ = 62.94 (d), 32.70 (d), 31.61 (d), Biotage SP4 eluting with 10–30% hexane–ethyl acetate over 20
25.39 (d), 22.59 (d), 13.97 (q). Data match those previously column volumes. The compound was isolated as a mixture of
reported.26
diastereomers. Major diastereomer: 1H-NMR (400 MHz,
1-Octanol 2c. The titled compound was prepared following CDCl3): δ = 3.60 (dd, J = 10.7 and 5.9 Hz, 1H), 3.48 (dd, J = 10.7
1
general protocol A. H-NMR (400 MHz, CDCl3): δ = 3.64 (t, J = and 6.4 Hz, 1H), 3.15 (dt, J = 10.2 and 4.2 Hz, 1H), 1.98–1.85
6.6 Hz, 2H), 1.62–1.51 (m, 2H), 1.38–1.23 (m, 11H), 0.94–0.83 (m, 1H), 1.80–1.69 (m, 3H), 1.63–1.41 (m, 3H), 1.33–0.98 (m,
(m, 3H). 13C-NMR (100 MHz, CDCl3): δ = 62.59 (t), 32.64 (t), 4H), 1.11 (d, J = 6.4 Hz, 3H), 0.89 (d, J = 7.6 Hz, 3H) 13C-NMR
31.77 (t), 29.38 (t), 29.24 (t), 25.74 (t), 22.58 (t), 13.95 (q). Data (100 MHz, CDCl3): δ = 76.39 (d), 65.79 (t), 40.38 (d), 40.26 (d),
match those previously reported.27
40.0 (t), 39.84 (d), 33.15 (t), 27.81 (t), 18.36 (q), 15.18 (q). Minor
2-(2,2-Dimethyl-1,3-dioxolan-4-yl)pentan-1-ol 2d. The titled diastereomer: 1H-NMR (400 MHz, CDCl3): δ = 3.62 (dd, J = 10.7
compound was prepared following general protocol and 5.9 Hz, 1H), 3.50 (dd, J = 10.5 and 6.4 Hz, 1H), 3.15 (dt, J =
A. 1H-NMR (400 MHz, CDCl3): δ = 4.20–3.87 (m, 2H), 3.64 10.2 and 4.2 Hz, 1H), 1.98–1.85 (m, 1H), 1.77–1.70 (m, 1H),
(t, J = 6.6 Hz, 2H), 3.50 (t, J = 7.2 Hz, 1H), 1.68–1.27 (m, 10H), 1.65–1.43 (m, 5H), 1.33–1.20 (m, 1H), 1.16–0.98 (m, 3H), 1.02
1.40 (s, 3H), 1.35 (s, 3H). 13C-NMR (100 MHz, CDCl3): δ = (d, J = 6.3 Hz, 3H), 0.91 (d, J = 6.8 Hz, 3H) 13C-NMR (100 MHz,
108.57 (s), 76.05 (d), 69.42 (t), 62.67 (t), 33.45 (t), 32.57 (t), CDCl3): δ = 76.45 (d), 65.79 (t), 40.38 (d), 40.26 (d), 39.84 (t),
29.36 (t), 26.89 (t), 25.69 (t), 25.67 (q), 25.59 (q). HRMS 38.14 (d), 33.26 (t), 30.03 (t), 18.36 (q), 13.47 (q). Data match
(ESI-MS): calcd for C11H22NaO3: 225.1461, found: 225.1466. those previously reported.31
Data match those previously reported.28
2-Phenylethan-1-ol 2j. The titled compound was prepared
7,8-Bis((tert-butyldimethylsilyl)oxy)octan-1-ol 2e. The titled following general protocol A. The crude mixture was purified
compound was prepared following general protocol by chromatography on a Biotage SP4 eluting with 0–20%
1
A. H-NMR (400 MHz, CDCl3): δ = 3.64 (t, J = 6.6 Hz, 2H), 3.51 hexane–ethyl acetate over 20 column volumes. 1H-NMR
(dd, J = 9.9, 5.5 Hz, 1H), 3.40 (dd, J = 9.9, 6.3 Hz, 1H), (400 MHz, CDCl3): δ = 7.40–7.29 (m, 2H), 7.25–7.21 (m, 3H),
1.64–1.25 (m, 10H), 0.89 (s, 18H), 0.05 (s, 12H). 13C-NMR 3.87 (t, J = 6.5 Hz, 2H), 2.88 (t, J = 6.6 Hz, 2H), 1.50 (s, 1H)
(100 MHz, CDCl3): δ = 73.13 (d), 67.44 (t), 63.03 (t), 34.26 (t), 13C-NMR (100 MHz, CDCl3): δ = 138.76 (s), 129.12 (d), 128.58
32.75 (q), 29.64 (q), 25.97 (t), 25.89 (t), 25.70 (q), 25.06 (q), (d), 126.44 (d), 63.55 (t), 39.23 (t). Data match those previously
18.37 (t), 18.15 (t), −4.26 (q), −4.73 (q), −5.31 (q), −5.38 (q). reported.32
HRMS (ESI-MS): calcd for C20H47O3Si2: 391.3058, found:
391.3061. FT-IR neat, ν (cm−1) 3500–3200 (bs), 2929, 2858, following general protocol A. The crude mixture was purified
1472, 1463, 1389, 1361, 1252, 1103, 815, 772. by chromatography on a Biotage SP4 eluting with 0–20%
2-Phenylpropan-1-ol 2k. The titled compound was prepared
(1R,2R,3R,5S)-2,6,6-Trimethylbicyclo[3.1.1]heptan-3-ol 2f. The hexane–ethyl acetate over 20 column volumes. 1H-NMR
titled compound was prepared following general protocol (400 MHz, CDCl3): δ = 7.37–7.30 (m, 2H), 7.28–7.21 (m, 3H),
A. 1H-NMR (400 MHz, CDCl3): δ = 4.1–4.0 (m, 2H), 2.49 (dd, J = 3.71 (d, J = 6.8 Hz, 12H), 3.02–2.87 (m, 1H), 1.28 (d, J = 7.0 Hz,
15.8, 7.4 Hz, 1H), 2.35 (dt, J = 9.7, 6.4 Hz, 1H), 2.0–1.9 (m, 4H), 3H). 13C-NMR (100 MHz, CDCl3): δ = 144.06, 128.60, 127.57,
1.78 (t, J = 5.9 Hz, 1H), 1.69 (ddd, J = 13.9, 4.7, 2.6 Hz, 1H), 126.60, 68.56, 42.46, 17.74. Data match those previously
1.20 (s, 3H), 1.11 (d, J = 7.4 Hz, 3H), 0.90 (s, 3H). 13C-NMR reported.33
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2,2-Diphenylethan-1-ol 2l. The titled compound was
prepared following general protocol A. The crude mixture was
9 (a) R. E. Dolle, S. J. Schmidt, K. F. Erhard and L. I. Kruse,
J. Am. Chem. Soc., 1989, 111, 278; (b) D. H. B. Ripin,
W. Cai and S. J. Brenek, Tetrahedron Lett., 2000, 41, 5817;
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J. M. Casavant, J. L. Doty, M. Flanagan, C. Koecher,
K. W. Laue, K. McCarthy, C. Meltz, M. Munchhoff,
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115.
purified by chromatography on
a Biotage SP4 eluting
with 0–20% hexane–ethyl acetate over 20 column volumes.
1H-NMR (400 MHz, CDCl3): δ = 7.43–7.18 (m, 1H), 4.26–4.21
(m, 1H), 4.17 (d, J = 6.8 Hz, 1H), 1.83 (s, 1H). 13C-NMR
(100 MHz, CDCl3): δ = 141.52 (s), 128.73 (d), 128.37 (d),
126.83 (d), 66.12 (t), 53.67 (d). Data match those previously
reported.34
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Acknowledgements
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We are grateful to the Xunta de Galicia Government (JAS) 12 (a) H. C. Brown, Organic Syntheses via Boranes, Wiley-Inter-
and the EPSRC (SVL, grant no. EP/K0099494/1) for financial
support.
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reported procedures overcoming this classical transform- 24 A regular workup of the aqueous solution left in the phase
ation in flow.
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21 Initial terpene and mixed monooxygenated compounds
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