Oxygen-directed intramolecular hydroboration

Article abstract of DOI:10.1021/ja800402g

Metal-free homoallylic oxygen-directed intramolecular hydroboration is reported. Regioselectivities from 20:1 to 82:1 favoring the 1,3-dioxy-substituted products have been achieved using Me₂S·BH₃/TfOH followed by standard oxidative workup. Branching at the C5 position improves regioselectivity. Copyright

Full text of DOI:10.1021/ja800402g

Published on Web 06/24/2008
Oxygen-Directed Intramolecular Hydroboration
Robert-Andre´ F. Rarig, Matthew Scheideman, and Edwin Vedejs*
Department of Chemistry, UniVersity of Michigan, Ann Arbor, Michigan 48109
Received January 17, 2008; E-mail: edved@umich.edu
Despite repeated efforts over many years and several tantalizing
Scheme 1
empirical results that suggest oxygen-directed hydroboration (ODHB),
definitive examples of this process have been rare.1–4 Evans’ metal-
catalyzed reaction of catecholborane with several unsaturated alcohols,
phosphinites, and carboxamides is the only method known to date with
established synthetic potential for a range of substrates.2 Another case
of ODHB involving an R-methoxy-ꢀ,γ-unsaturated ester was encoun-
tered by Panek et al.3 using Me2S·BH3. This example approaches the
regioselectivity of the Evans result with a homoallylic alcohol (8:1 vs
11:1), but appears to be a special case reflecting unusual reactivity
due to the presence of ester as well as methoxy groups in the starting
material. The other historical examples reveal interesting perturbations
of hydroboration stereoselectivity or regioselectivity by oxygen sub-
stituents,4 but these reactions generally do not give useful product ratios.
Our work reported below demonstrates a mechanistically distinct
version of ODHB using metal-free conditions that afford unprecedented
levels of regiocontrol.
The analogy of amine-directed hydroboration5 suggested that alcohol
borane complexes 6 (Scheme 1) might be accessible from activated
boranes 3 or 4 and homoallylic alcohols 5. This would provide a basis
for regiocontrol and intramolecular hydroboration if the potential
complications from evolution of H2 and weak O-B complexation at
the stage of 6 could be overcome. An SN2-like displacement of the
leaving group X might then lead from 6 to the π-complex 7, which
would afford hydroboration products via the labile O-protonated 1,2-
oxaborolane 8 or related intermediates.
Table 1. Reaction of 5a with 1 or 2 Activated in situa
entry
borane source
activator
time (h)
conversionb (%)
9a:10ab
1
2
3
4
5
1
1
2
2
1
I2
I2
I2
I2
10
19
5
5
5
40
>90
>90
>90
>90
4.3:1
4.7:1
7:1c
18:1d
>20:1
A number of conditions were tested in attempts to activate
dimethylsulfide borane 1 or thioanisole borane 26 with I2 or TfOH at
-78 °C in the presence of (E)-3-pentenol 5a. The resulting solution
was warmed to -20 °C (5-19 h) and then quenched using standard
oxidative workup (Table 1) for assay of the isomeric diols 9a and
10a. Both reactivity and regioselectivity were marginal in attempts to
activate 1 with I2. A control experiment using 1 without I2 gave a
2.2:1 ratio of 9a and 10a at -20 °C, consistent with at least some HB
involving unactivated Me2S·BH3 in entries 1 and 2. Switching to
thioanisole borane 2 improved both reactivity and regioselectivity for
the iodine activation (entries 3 and 4), but this required an inconvenient
procedure using B2H6 gas to generate 2. Good selectivity was also
observed by activating a solution of 5a and 1 with TfOH at -78 °C,
probably because this procedure minimizes any chance of background
reaction. However, product recovery was low (∼20%, entry 5).
Preactivating the borane complex 1 with TfOH was found to be
crucial for improved product recovery. With this modification, a series
of homoallylic alcohols 5 gave useful yields and excellent regiose-
lectivities (Table 2; preactivation at -78 °C and warming to -20 °C).
In the highest yielding example, activation of 1 with TfOH followed
by addition of 5e resulted in conversion on a time scale of hours at
-20 °C. Diol 9e was obtained in 80% yield after oxidative workup
(1.5 mmol scale), and NMR assay after derivatization7 established 56:1
regioselectivity in favor of the 1,3-diol 9e over 10e (entry 5). Both
the (E)- and (Z)-3-hexenols 5b and 5c (entries 2 and 3) reacted with
>20:1 selectivity under these conditions, although the E-isomer gave
TfOH
a A 0.1 M solution of 5 and 2 equiv of 1 or 2 at -78 °C in CH2Cl2
was treated with 2 equiv of activator, warmed to -20 °C, stirred (time),
and quenched with NaOOH/MeOH ·H2O. b NMR assay. c Activated at
-20 °C and warmed to -10 °C. d Warmed to -10 °C.
Table 2. ODHB of Homoallylic Alcohols 5 with Me2S·BH3 + TfOHa
entry
Stg
R2
time (h)
yield (%)
9:10b
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
CH3
10
10
5
10
5
51c
66c
51d
69
80
56
>3
22
59
>20:1
37:1
28:1
>20:1
56:1
82:1
N/D
N/D
>20:1
C2H5
Z-C2H5
nC5H11
cC6H11
tC4H9
Ph
5
20
10
5
Bn
CH2Bn
a Conditions: A 0.2 M solution of 1 (CH2Cl2) at -78 °C was treated
with 1 equiv of TfOH, stirred 30 min, 0.2 M of 5 in CH2Cl2 added
dropwise, and oxidative workup performed after (time) at -20 °C.
b NMR assay. c Five equivalents of cyclohexene present. d Yield after
derivatization.7
the better result (37:1 9b:10b).8 The highest regioselectivity was
achieved in the conversion of 5f to 9f (entry 6), demonstrating that
increased branching adjacent to C4 in 5f compared to 5d or 5e (entries
4 and 5) correlates with higher regioselectivity. In contrast to the
9
9182 J. AM. CHEM. SOC. 2008, 130, 9182–9183
10.1021/ja800402g CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2
gave a better result (61% yield, 50:1 14:15). By comparison, standard
hydroboration using THF/borane (0 °C, 4 h, THF) afforded a 1.4:1
mixture of 14:15. These findings prove that ODHB can take place by
mechanisms involving neither 6 nor the alkoxyborane 11, but do not
rule out these intermediates for the alcohol substrates. If covalently
bound B-O intermediates are involved in all three reactions (alcohol,
Li alkoxide, and ether substrates), then each of the distinct species
represented by structures 6, 16, and 17 may be reactive in ODHB.13
The ether example via 17 would be mechanistically analogous to the
amine borane reactions,5 but the relative merits of 6 and 16 remain
unknown.
Pending the detection of hypothetical intermediates such as 11, 6,
16, or 17, we cannot comment further on the mechanism of ODHB.
However, the preparative results show that the oxygen-directed
intramolecular hydroboration is feasible for homoallylic alcohols,
alkoxides, and ethers using 3 as an activated reagent equivalent to
TfOBH2.14
successful TfOH experiments, attempted preactivation of 1 with iodine
over the same temperature range (-78 to -20 °C) resulted in poor
reactivity and low conversion.
Surprisingly, phenyl substituents near the CdC subunit decreased
reactivity using the TfOH preactivation conditions. Thus, the styrene
5g gave only trace conversion after 20 h at -20 °C, and the benzyl
analogue 5h reacted very slowly compared to other aliphatic substrates
(entry 8). On the other hand, 5i with a CH2CH2 spacer between the
olefin and the phenyl group reacted normally, and good conversion
was observed after 5 h (entry 9).
Entries 1 and 2 (Table 2) describe experiments where the ODHB
reactions of 5a and 5b were conducted in the presence of 5 equiv of
cyclohexene to confirm an intramolecular pathway. Selective con-
sumption of the homoallylic alcohols was observed in both cases, while
cyclohexanol was not detected after oxidative workup, as expected if
the oxygen-directed internal pathway has a significant rate advantage.
When these experiments were repeated in the absence of the cyclo-
hexene, the yields of diols were somewhat lower (41% from 5a, 51%
from 5b), suggesting that the cyclohexene additive serves in a
protective role by scavenging residual triflic acid.9
Although the above experiments establish an intramolecular
hydroboration process for the alcohol substrates, attempts to probe
the sequence of events suggested in Scheme 1 using NMR
spectroscopy provided only limited insight. When 1 was treated
with TfOH at -78 °C, the 11B chemical shift of 1 (δ -20.6 ppm)
was replaced by a major new signal (δ -2.0 ppm, t, J ) 129 Hz)
consistent with the activated borane 3 (X ) OTf). Addition of
substrate 5b at -78 °C and warming to -20 °C produced broad
11B signals (δ 7.5 to -8.0 ppm; tetravalent boron), but no signals
were found from δ 50 to 70 ppm, the range estimated for the
hypothetical trivalent ROBH2 (11)10,11 or oxaborolanes 12 (X )
H or OTf).12
In an attempt to detect 11 or other intermediates, alcohol 5b was
treated with BuLi (1.1 equiv) at -78 °C in DCM, followed by addition
of the resulting alkoxide solution to preformed 3 (X) OTf, 2 equiv).
The 1H and 11B NMR spectra were not definitive. However, quenching
the solution after 5 h at -20 °C by oxidative workup with NaOH/
MeOH/H2O2 gave the diol 9b (56%, >20:1 regioselectivity).8 Using
the best substrate 5e from Table 2, the lithium alkoxide procedure
gave a 63:1 ratio of 9e:10e in 64% yield after derivatization.7 Similar
results were obtained in several other examples, indicating that the
lithium alkoxides are competent substrates for directed hydroboration.
The small difference in regioselectivity compared with Table 2, entry
5, implies that the lithium alkoxide from 5e need not react via the
same regioselectivity-determining transition state as for the alcohol
substrate, but a more convincing differentiation was desired. To this
end, the methoxy ether 13 was subjected to the usual ODHB conditions
using preformed 3 (X ) OTf) at -78 °C (15 min) to -20 °C (10 h).
After oxidative workup, the product was obtained as a 20:1 mixture
of 14:15. In contrast to results with the alcohol substrates, the in situ
procedure (TfOH added to 13 + 1 at -78 °C, 15 min; -20 °C, 10 h)
Acknowledgment. This work was supported by NIH (GM067146;
CBI training Grant GM08597).
Supporting Information Available: Experimental procedures and
characterization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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(7) 1H NMR assay of 9+10 was best done after diaroylation with
2-CF3C6H4COCl (resolved methine H’s for all diol pairs except 9h/10h).
(8) Diols 9b, 9c, and 9f were difficult to purify due to water solubility and
co-elution with Me2SO2 formed from Me2S during oxidative workup.
(9) 1-Phenethyltetrahydrofuran was isolated in 6% yield using ODHB from
5i. Analogous (volatile) byproducts from TfOH-induced cyclization were
detected in ODHB experiments with some of the other alcohols 5. The
corresponding Li alkoxides give no cyclic ethers, but conversion was lower
using 2 equiv of 3 (X ) OTf) and the procedure more tedious.
(10) Alkoxyboranes similar to 11 are unknown. For detection of ROBHThx,
see: Cha, J. S.; Seo, W. W.; Kim, J. M.; Kwon, O. O. Bull. Korean Chem.
Soc. 1996, 17, 892. Activation of 1 afforded 92% of the expected H2 within
30 min at -78 °C and an additional 0.15 equiv of H2 vs the starting TfOH
upon addition of 5b and warming to -20 °C, but further hydrogen evolution
was too slow to measure. In a control experiment, reaction of 1 with EtOH
in DCM at-20 °C gave 5-7% H2 within 20 min, and very slow H2
evolution thereafter (9% total after 1.5 h).
(11) No¨th, H.; Wrackmeyer, B. In Nuclear Magnetic Resonance Spectroscopy
of Boron Compounds; Diehl, P., Fluck, E., Kosfeld, R., Eds.; Springer-
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and 253).
(12) Wrackmeyer, B. In Annual Reports on NMR Spectroscopy; Webb, G. A.,
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(13) The 1H NMR spectrum after mixing 3 (X ) OTf) and 5b at -78 °C and
warming to -20 °C (5 min) revealed a new signal at δ ) 12.5 ppm,
consistent with the O-H subunit of 6. This signal disappeared over 15
min at -20 °C, but the olefinic signals were still present. Activation of
n-Bu4NBH4 in CH2Cl2 at -78 °C with TfOH (2 equiv), addition of 5d,
and warming to -20 °C gave >20:1 9d:10d (60%) after oxidative workup,
suggesting that Me2S plays no major role.
(14) Allylic alcohols such as (E)-2-octenol are not reactive under the standard
conditions of Table 2. Bis-homoallylic alcohols are reactive, but give lower
regioselectivity (5:1 ratio favoring the 1,4-diol from (E)-hex-4-enol).
Homoallylic alcohols containing alkyl groups at C2 react with e1.5:1 dr.
JA800402G
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