differences in rates of addition of BunLi, especially as we
attempted to generate increasing amounts of LiCH2Br. At these
higher loadings, we also observed alcohol 6, resulting from
incorporation of three CH2 units. One interesting trend which
can be gleaned from Table 2 is that as the amount of LiCH2Br
used is increased, there is a concomitant increase in the amount
of alcohol 5 resulting from unreacted starting material (compare
entry 1 with 4 and 5).
This observation led us to postulate that homologated
boronate esters such as 7 were more reactive than the seondary
boronate esters 3. This reactivity difference could be ration-
alized by the different steric requirements of 3 cf. primary
homologated derivatives such as 7. To test this hypothesis, we
prepared and isolated 7 and also prepared boronate ester 3A by
hydroboration of p-methylstyrene. A ca. 1+1 mixture of 7 and 3A
was then treated with LiCH2Cl [eqn. (5)]. This homologating
reagent was chosen for two reasons. Firstly, its use would
obviate complications due to double homologations observed
with LiCH2Br; and secondly, as LiCH2Cl is the least reactive of
the homologating reagents, it would presumably be the best
probe of reactivity differences.
Notes and references
† cod = Cycloocta-1,5-diene, dppb = 1,4-bis(diphenylphosphino)butane.
Note that the asymmetric version of this reaction employs binap
[2,2’-bis(diphenylphosphino)-1,1’-binapthyl]. See ref. 4 for appropriate
experimental procedures.
‡ The following procedure is representative. Double homologation with
LiCH2X: in a 10 mL flame dried round bottomed flask, (1-phenethyl)pina-
colboronate 3 (229.8 mg, 1.0 mmol) and BrCH2Br (0.077 mL, 1.1 mmol)
were dissolved in 2.0 mL of THF. After cooling to 278 °C using a N2/
isopropyl alcohol bath (bath temperature monitored by a low temp.
thermometer), BunLi (2.17 M in hexane, 0.50 mL, 1.1 mmol) was added
dropwise over 15 min to the center of the flask with vigorous stirring. The
reaction mixture was then allowed to warm gradually to room temperature
overnight under N2. The solvent was removed in vacuo, and the resulting
residue diluted with 10 mL of saturated aqueous NH4Cl. The aqueous layer
was extracted with light petroleum (bp 30–60 °C, 20 mL 3 4), and the
combined organic layers dried over MgSO4. After filtration and removal of
solvent in vacuo, crude (1-phenylpropyl)pinacolboronate (231 mg) 7 was
obtained.
Boronate ester 7, (231 mg), was dissolved in 10 mL of diethyl ether, 2.0
mL of methanol and 4.0 mL of 1 M NaOH (8.0 mmol). The flask was
flushed with nitrogen and 0.285 mL of H2O2 (30% w/v in H2O, 2.27 mmol)
was added slowly at room temperature. The reaction mixture was left at
room temperature under N2 overnight. The ether layer was separated and the
aqueous layer washed with diethyl ether (20 mL 3 3). The combined
organic layers were dried over MgSO4. After filtration and removal of
solvent in vacuo, a mixture of 1-phenethanol 5 (11%), 2-phenylpropanol 2
(74%) and 3-phenylbutanol 4 (15%) was obtained. The ratio was
determined by 400 MHz 1H NMR. The NMR yields (11, 74 and 15%,
respectively) of the aforementioned products were determined by in-
tegration of the peaks of interest vs. added internal standard (p-
nitrotoluene).
§ For spectral data of compound 2, see ref. 4; compound 4 is commercially
available (Aldrich); and for compound 6, the data are as follows: 1H NMR
(400 MHz, CDCl3) d 7.35–7.19 (m, 5H, C6H5), 3.62 (t, J 6.8 Hz, 2H,
CH2OH), 2.72 (m, 1H, CH), 1.70–1.63 (m, 2H, CH2CH2CH2), 1.55–1.40
(m, 2H, CH2CH2CH2), 1.28 (d, J 7.2 Hz, 3H, CH3), 1.18 (br s, 1H, OH).
13C NMR (100 MHz, CDCl3) d 147.5, 128.6, 127.2, 126.2, 63.3, 40.0,
34.6, 31.2, 22.6.
Much to our surprise, in the presence of a limiting quantity of
LiCH2Cl (50%), boronate esters 7 and 3A gave equal amounts of
homologated products 4 and 2A (19 and 21% respectively)
indicating no difference in the reactivity of the secondary and
primary boronate esters under these conditions. It should be
noted that the introduction of the para methyl substituent will
skew the results somewhat as it alters the electronic nature of the
migrating group. An isotopically labeled analog of 3 is currently
being prepared and the results of this study will be reported in
due course. Experiments are also underway to elucidate the
reason for the remarkable differences in the reactivity of
LiCH2Cl and LiCH2Br.
In conclusion, we have shown that the homologation of
boronate esters derived from the hydroboration of styrene and
its derivatives can be carried out in a sequential, one-pot manner
depending on the nature of the homologating reagent used.
Homologation with LiCH2Cl yields only the product of single
homologation regardless of the number of equivalents used, and
LiCH2Br yields the doubly homologated product even at 1
equivalent loading. Increasing the amount of this reagent leads
to the incorporation of three CH2 units in a single reaction.
The Natural Sciences and Engineering Research Council of
Canada (NSERC) is gratefully acknowledged for support of this
research in terms of research and equipment grants to CMC. The
Department of Chemistry at UNB is thanked for providing a
Wiesner award to Li Ren.
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722
Chem. Commun., 2000, 721–722
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