Hydroboration. 94. Rates of Hydroboration of 2-Organylapopinenes with 9-Borabicyclo[3.3.1]nonane, Providing B-(2-Organylapoisopinocampheyl)-9-borabicyclo[3.3.1]nonanes, Potentially Valuable for the Asymmetric Reduction of Prochiral Ketones

Article abstract of DOI:10.1021/jo9617169

Five representative enantiomerically pure, hindered terpenes, derived from α-pinene, namely 2-organylapopinenes (2-R-apopinenes, R = Et, Pr, i-Bu, Ph, and i-Pr) have been treated with 9-borabicyclo[3.3.1]nonane (9-BBN) in a 1:1 molar ratio in THF at 24 °C and the rate of hydroboration followed. Increasing the bulk of the 2-R group from the 2-methyl of α-pinene (Ipc, 2-methylapopinene) to 2-ethyl- (Eap), to 2-propyl- (Prap), to 2-isobutyl- (i-Bap), to 2-phenyl- (Pap), and to 2-isopropyl- (i-Prap) significantly lowers the rate of hydroboration with 9-BBN. Thus, the rate of hydroboration of α-pinene with 9-BBN is faster than the rates for the 2-R-apopinenes studied. The sterically bulkier 2-isobutyl-, 2-phenyl-, and 2-isopropylapopinenes reveal a significantly slower rate of hydroboration with 9-BBN. At an elevated temperature, 65 °C, the reaction of 9-BBN (1.0 equiv) with a slight excess of optically pure 2-isobutyl- and 2-phenylapopinenes (1.10-1.20 equiv), under neat conditions, is facilitated to provide the desired B-(2-organylapoisopinocampheyl)-9-borabicyclo[3.3.1]nonanes (2-organyl = isobutyl- and phenyl) in quantitative yield. Unfortunately, this synthesis failed for 2-isopropylapopinene. Fortunately, an indirect synthesis proved satisfactory. Treatment of enantiomerically pure (2-isopropylapoisopinocampheyl)borane, i-PrapBH₂, conveniently synthesized from 2-isopropylapopinene, and 1,5-cyclooctadiene (1,5-COD), provided, after thermal isomerization, the desired 1:1 adduct [B-(2-Rap)-9-BBN; 2-Rap = 2-isopropylapoisopinyl skeleton] in quantitative yield. Consequently, five of the 2-R-apopinenes, R = Et, Pr, i-Bu, Ph, and i-Pr, have been successfully converted into the corresponding B-(2-Rap)-9-BBN derivatives.

Full text of DOI:10.1021/jo9617169

J . Org. Chem. 1997, 62, 865-869
865
Hyd r obor a tion . 94. Ra tes of Hyd r obor a tion of
2-Or ga n yla p op in en es w ith 9-Bor a bicyclo[3.3.1]n on a n e, P r ovid in g
B-(2-Or ga n yla p oisop in oca m p h eyl)-9-bor a bicyclo[3.3.1]n on a n es,
P oten tia lly Va lu a ble for th e Asym m etr ic Red u ction of P r och ir a l
Keton es
Ulhas P. Dhokte1 and Herbert C. Brown*
H. C. Brown and R. B. Wetherill Laboratories of Chemistry, Purdue University,
West Lafayette, Indiana 47907
Received September 6, 1996X
Five representative enantiomerically pure, hindered terpenes, derived from R-pinene, namely
2-organylapopinenes (2-R-apopinenes, R ) Et, Pr, i-Bu, Ph, and i-Pr) have been treated with
9-borabicyclo[3.3.1]nonane (9-BBN) in a 1:1 molar ratio in THF at 24 °C and the rate of
hydroboration followed. Increasing the bulk of the 2-R group from the 2-methyl of R-pinene (Ipc,
2-methylapopinene) to 2-ethyl- (Eap), to 2-propyl- (Prap), to 2-isobutyl- (i-Bap), to 2-phenyl- (Pap),
and to 2-isopropyl- (i-Prap) significantly lowers the rate of hydroboration with 9-BBN. Thus, the
rate of hydroboration of R-pinene with 9-BBN is faster than the rates for the 2-R-apopinenes studied.
The sterically bulkier 2-isobutyl-, 2-phenyl-, and 2-isopropylapopinenes reveal a significantly slower
rate of hydroboration with 9-BBN. At an elevated temperature, 65 °C, the reaction of 9-BBN (1.0
equiv) with a slight excess of optically pure 2-isobutyl- and 2-phenylapopinenes (1.10-1.20 equiv),
under neat conditions, is facilitated to provide the desired B-(2-organylapoisopinocampheyl)-9-
borabicyclo[3.3.1]nonanes (2-organyl ) isobutyl- and phenyl) in quantitative yield. Unfortunately,
this synthesis failed for 2-isopropylapopinene. Fortunately, an indirect synthesis proved satisfactory.
Treatment of enantiomerically pure (2-isopropylapoisopinocampheyl)borane, i-PrapBH2, conve-
niently synthesized from 2-isopropylapopinene, and 1,5-cyclooctadiene (1,5-COD), provided, after
thermal isomerization, the desired 1:1 adduct [B-(2-Rap)-9-BBN; 2-Rap ) 2-isopropylapoisopinyl
skeleton] in quantitative yield. Consequently, five of the 2-R-apopinenes, R ) Et, Pr, i-Bu, Ph,
and i-Pr, have been successfully converted into the corresponding B-(2-Rap)-9-BBN derivatives.
Asymmetric synthesis has become an important branch
of organic synthesis. Consequently, a number of reac-
tions have been discovered to produce enantiomerically
pure compounds using optically active reagents derived
from various chiral auxiliaries.2 In this endeavor, we
have been exploring asymmetric synthesis based on
R-pinene-derived borane reagents.3 Shortly after the
discovery of hydroboration,4a R-pinene [92% enantiomeric
excess (ee)] was selected as an example of an easily
rearranged olefin and subjected to hydroboration to see
if rearrangement during hydroboration would be a prob-
lem. No rearrangement was observed. However, the
product was a dialkylborane, Ipc2BH, instead of the usual
trialkylborane, R3B. Consequently, the first asymmetric
hydroborating agent had been prepared! The possibility
of achieving asymmetric hydroboration was tested with
an olefin of low steric requirements, cis-2-butene.4b The
oxidation of the resulting trialkylborane gave 2-butanol
in 87% ee, the first nonenzymatic synthesis in high ee!
Considerable success was achieved in studying asym-
metric hydroboration with Ipc2BH and isopinocampheyl-
borane, IpcBH2.3 These studies provided convenient
routes to chiral organoboranes, R*B<. It was then
discovered that substitution of the R*B< groups proceeds
predominantly with retention of configuration. Conse-
quently, this approach provided a general synthesis of
enantiomerically pure compounds.
An early attempt was made to use this approach to
achieve the asymmetric reduction of ketones. The hy-
droboration of R-pinene with 9-BBN provided B-isopi-
nocampheyl-9-borabicyclo[3.3.1]nonane (B-Ipc-9-BBN, Al-
pine-Borane, 2a ). This was converted to the borohydride,
lithium B-3-pinanyl-9-borabicyclo[3.3.1]nonyl hydride (Al-
pine-Hydride, 3a ).5 Asymmetric reduction of certain
class of prochiral ketones with this borohydride 3a
provided disappointingly low optical yield for the product
alcohols.
X Abstract published in Advance ACS Abstracts, February 1, 1997.
(1) Present Address: Chemical Process R & D, Lilly Technology
Center, A Division of Eli Lilly & Co., DC 4813, Indianapolis, IN 46285.
(2) (a) Valentine, D., J r.; Scott, J . W. Synthesis 1978, 329. (b) Kagan,
H. B.; Fiaud, J . C. Top. Stereochem. 1978, 10, 175. (c) Meyers, A. I.
Acc. Chem. Res. 1978, 11, 375. (d) Apsimon, J . W.; Sequin, R. P.
Tetrahedron 1979, 35, 2797. (e) Morrison, J . D., Ed. Asymmetric
Synthesis; Academic: New York, 1983; Vols. 1-5. (f) Crosby, J .
Tetrahedron 1991, 47, 4789.
(3) (a) Brown, H. C.; Ramachandran, P. V. Advances in Asymmetric
Synthesis; Hassner, A., Ed.; J AI Press: Greenwich, CT, 1995; Vol. 1,
pp 147-210. (b) Brown, H. C.; Ramachandran, P. V. J . Organomet.
Chem. 1995, 500, 1.
Midland and his co-workers established that the B-Ipc-
9-BBN (2a ) was an excellent reagent for the reduction
of R-deuterioaldehydes, RCDO, giving the primary alco-
(4) (a) Brown, H. C.; Subba Rao, B. C. J . Am. Chem. Soc. 1956, 78,
5694. (b) Brown, H. C.; Zwiefel, G. J . Am. Chem. Soc. 1961, 83, 486.
(5) Krishnamurthy, S.; Vogel, S.; Brown, H. C. J . Org. Chem. 1977,
42, 2534.
S0022-3263(96)01716-1 CCC: $14.00 © 1997 American Chemical Society

866 J . Org. Chem., Vol. 62, No. 4, 1997
Dhokte and Brown
Ta ble 1. Da ta for th e Ra te of Hyd r obor a tion of
hols, RCHDOH, in optical purities approaching 100%.6
This reagent 2a was also excellent for the reduction of
more active ketones, such as acetylenic ketones and keto
esters, but less suitable for the majority of less active
ketones.
2-Or ga n yla p op in en es w ith 9-BBN in a 1:1 Mola r Ra tio
(0.50 M Ea ch ) in THF a t 24 °Ca
formation of trialkylboranea,b (%)
time (h)
2a
2b
2c
2d
2e
2f
We then introduced B-chlorodiisopinocampheylborane
(Ipc2BCl, DIP-chloride, 4a ) and achieved the reduction
of aralkyl ketones, such as acetophenone in an optical
yield of ∼98%. Fluorinated ketones gave satisfying
optical yields.3b Unfortunately, aliphatic ketones, such
as 3-methyl-2-butanone, underwent reduction in only
34% ee. In such reductions the 2-methyl group of the
R-pinene moiety appears to play a very important role.
Indeed, simply by replacing the methyl group by an ethyl,
the resulting reagent, Eap2BCl (4b),7 reduced 3-methyl-
2-butanone in 95% ee.
2
6
10
24
48
72
22
63
84
98
11
37
65
85
98
10
33
44
59
81
93
10
15
17
20
25
28
6
11
16
18
20
22
0
2
7
11
13
Determined by GC analysis (see Experimental Section). b Per-
centage of the reaction is based on the amount of alcohol formed
after oxidation (NaOH/H2O2) of trialkylborane.
a
It is observed that with the increasing steric require-
ments of R, there is an increasing tendency for the
reaction to stop short of the Rap2BH stage, tending to
proceed cleanly to RapBH2 in the cases of R ) Ph (1e)
and i-Pr (1f). Thus, the hydroboration of these 2-R-
apopinenes (1e and 1f) with borane reagents, BMS or
BH3‚THF, provide essentially pure RapBH2 for R ) Ph
(1e) and i-Pr (1f).11 Therefore, in this context it was
interesting to observe the effect of the R groups of the
2-R-apopinenes (1a -f) in their hydroboration with a
bulkier hydroborating reagent, 9-BBN, to provide a new
class of sterically-demanding B-(2-Rap)-9-BBN, poten-
tially important for the asymmetric reduction of certain
classes of prochiral ketones.
Encouraged by these results, we synthesized the asym-
metric hydroborating agents, 2-organylapoisopinocam-
pheylboranes (RapBH2; R ) Et, EapBH2;8 R ) i-Pr,
9
i-PraBH2 ), readily obtained from the sterically-demand-
ing chiral auxiliaries (1b and 1f), which achieve improved
enantioselection for the asymmetric hydroboration of
prochiral alkenes in comparison with that of the less
sterically-demanding IpcBH2.10
These observations persuaded us of the desirability of
making a systematic study of the rate of hydroboration
of sterically-varied 2-R-apopinenes 1a -f with 9-BBN.
Recently, we made a quantitative rate study of the chiral
auxiliaries 1a -f with borane reagents, namely borane
dimethyl sulfide (BH3‚SMe2, BMS) and BH3‚THF.11 This
study was performed in order to understand the proper-
ties of these sterically-varied R-pinene-derived chiral
auxiliaries 1a -f toward relatively less hindered borane
reagents to establish conditions for developing practical
Ra te of Hyd r obor a tion of 2-R-a p op in en es 1a -f
w ith 9-BBN. We have previously reported the synthesis
of 2-R-apopinenes 1a -f.7b,8,11,13 These 2-R-apopinenes
1a -f were subjected to hydroboration with 9-BBN in a
1:1 molar ratio in THF at 24 °C (0.50 M) (eq 2).
12
procedures for the synthesis of optically pure RapBH2
or Rap2BH. In this paper, we wish to report a quantita-
tive study of the rate of hydroboration of the structurally-
varied 2-organylapopinenes with the bulkier hydrobo-
rating agent, 9-BBN in THF at 24 °C, and the synthesis
of optically pure B-(2-organylapoisopinocampheyl)-9-
borabicyclo[3.3.1]nonanes [B-(2-Rap)-9-BBN, 2d -f], by
direct and indirect methods to be discussed, potentially
useful for the selective asymmetric reduction of prochiral
ketones.
The rate of hydroboration was determined by two
methods:11 (i) aliquots of the solution were removed at
appropriate periods of time, hydrolyzed with excess
methanol, oxidized with alkaline peroxide, and analyzed
by GC for the residual 2-R-apopinenes and/or the silyl
ether of the alcohol, produced by hydroboration-oxida-
tion, using a suitable internal standard; (ii) by 11B NMR
spectrum of aliquots taken at appropriate intervals of
time for the formation of trialkylborane 2a -f. These
analytical procedures gave concurrent results. The
results are summarized in Table 1 and depicted graphi-
cally in Figure 1.
It is apparent from the experimental data that the less
sterically-demanding R-pinene reacts with 9-BBN at a
faster rate, compared with the more hindered 2-R-
apopinenes 1b-f, to provide the desired 1:1 adduct with
9-BBN in nearly quantitative yield in 24 h. In the case
of 2-ethyl- (1b) and 2-propylapopinenes (1c), 50% hy-
droboration with 9-BBN proceeds in nearly 10 h but then
proceeds to almost completion at a much slower rate, with
>90% reaction achieved in 48 and 72 h for 2b and 2c,
Resu lts a n d Discu ssion
Recently, we have examined the effect of the steric
requirements of the groups R (Me, Et,8 Pr,7b i-Bu,11 Ph,13
and i-Pr11) of the 2-R-apopinenes 1a -f on the rates of
hydroboration with BMS and BH3‚THF, to provide the
corresponding mono- (RapBH2) and bis(2-R-apoisopi-
nocampheyl)boranes (Rap2BH) (eq 1).11
(6) Midland, M. M.; Greer, S.; Tramontano, A.; Zderic, S. A. J . Am.
Chem. Soc. 1979, 101, 2352.
(9) Dhokte, U. P.; Brown, H. C. Tetrahedron Lett. 1994, 35, 4715.
(10) Brown, H. C.; J adhav, P. K.; Mandal, A. K. J . Org. Chem. 1982,
47, 5074.
(11) Brown, H. C.; Dhokte, U. P. J . Org. Chem. 1994, 59, 2025.
(12) Brown, H. C.; Dhokte, U. P. J . Org. Chem. 1994, 59, 2365.
(13) Brown, H. C.; Weissman, S. A.; Perumal, P. T.; Dhokte, U. P.
J . Org. Chem. 1990, 55, 1217.
(7) (a) Ramachandran, P. V.; Brown, H. C.; Swaminathan, S.
Tetrahedron Asymm. 1990, 1, 433. (b) Brown, H. C.; Ramachandran,
P. V.; Weissman, S. A.; Swaminathan, S. J . Org. Chem. 1990, 55, 6328.
(8) Brown, H. C.; Randad, R. S.; Bhat, K. S.; Zaidlewicz, M.;
Wiessman, S. A.; J adhav, P. K.; Perumal, P. T. J . Org. Chem. 1988,
53, 5513.

Rates of Hydroboration of 2-Organylapopinenes
J . Org. Chem., Vol. 62, No. 4, 1997 867
data that the synthesis of 3d -f is extremely slow in the
reaction of 9-BBN with the 2-R-apopinenes 1d -f in THF
at 24 °C. Previous work has shown that 9-BBN is less
sensitive to steric effects of substrate alkenes than other
bulky dialkylboranes, such as disiamylborane.14 This
observation has been attributed to the increased electro-
philic nature of the boron atom as a result of the steric
strain inherent in the 9-borabicyclo[3.3.1]nonane struc-
ture. Therefore, we explored the possibility of carrying
out the hydroboration of a slight excess (10-20%) of the
2-R-apopinenes 1d -f with 9-BBN, under neat reaction
conditions, at a higher temperature, such as at 65 °C, as
reported for 2a .15 Hopefully, this would provide a simple
route to the desired B-(2-Rap)-9-BBN reagents 2d -f (eq
3).
Indeed, the reaction of optically pure 1d (1.1 equiv)
with 9-BBN (1.0 equiv) under neat favorable conditions
at 65 °C provided the desired 2d in 14 h in quantitative
yield. The chemical and optical purities of this 1:1 adduct
were confirmed by oxidizing 2d with alkaline peroxide
in the presence of an internal standard and analyzing
the products viz. 2-isobutylapopinene (1d ), 2-isobutyl-
apoisopinocampheol, and cis-1,5-cyclooctanediol as their
silyl ethers on GC. The analysis of the reaction mixture
indicated the quantitative formation of the desired 2d .
The silyl ethers were prepared from the reaction of
alcohols with bis(trimethylsilyl)acetamide (BTSA)16 (eq
4).
F igu r e 1. Rate of hydroboration of 2-R-apopinenes (0.50 M)
with 9-BBN (0.50 M) in THF at 24 °C. Molar ratio 1:1.
respectively. Compared with the simpler 2-R-apopinene
derivatives 1a ,c, alkenes 1d -f show an even slower rate
of hydroboration with 9-BBN, with only 13-28% reaction
in 72 h.
On the contrary, the hydroboration of the more hin-
dered 2-R-apopinenes (1d -f) with BMS, a sterically less
demanding borane reagent, in 1:1 molar ratio (0.50 M)
is over in 24 h to the extent of 97-100%, producing >90%
of the desired 1:1 adduct as RapBH2 (R ) i-Bu, Ph, and
i-Pr).11 Under similar conditions, the hydroboration of
2-R-apopinenes 1d -f with the more loosely complexed
borane reagent, BH3‚THF, in a 1:1 molar ratio (0.50 M),
provides almost the same distribution of the products in
1 h for 1d , 2 h for 1e, and 4 h for 1f.11
Similarly, the alcohol was isolated and compared with
1
an authentic sample17 by its H/13C NMR spectra, mixed
These results clearly demonstrate the effect of the
nature of the reagents on the rates of hydroboration of
the sterically-different 2-R-apopinenes. Bulkier reagents,
such as 9-BBN, hydroborate less hindered terpenes such
as R-pinene (1a ), 2-ethyl- (1b), and 2-propylapopinenes
(2c) smoothly to provide the desired 1:1 adducts, i.e., B-(2-
Rap)-9-BBN reagents 2a -c. However, as the bulk on the
2-position of apopinene is increased to isobutyl- (1d ), to
phenyl- (1e), and to isopropyl- (1f), the rate of hydrobo-
ration with 9-BBN, although it is relatively insensitive
to the steric factor,14 is extremely slow in providing the
required B-(2-Rap)-9-BBN reagents 2d -f in adequate
amounts. Consequently, this experimental observation
led us to consider the synthesis of B-(2-Rap)-9-BBN
reagents 2d -f under the conditions reported for the
synthesis of 2a -c,7b,15 which is described in the following
section.
melting point, and optical rotation. The optical rotation
of 2-isobutylapoisopinocampheol in comparison with the
authentic sample of g99% ee suggested the optical purity
of g99% for the desired 1:1 adduct 2d .
In another approach, the chemical and optical purity
of the trialkylborane 2d was confirmed by liberating and
analyzing the optically pure 2-isobutylapopinene (1d )
from 2d in comparison with the authentic sample as
described above. Thus, the treatment of the trialkylbo-
rane 2d with aldehyde, followed by stirring at 24 °C for
2 h, provided a nearly quantitative formation of the
borinate ester (11B NMR, δ 54) and an 81% isolated yield
of optically pure (+)-2-isobutylapopinene (1d ),17 elimi-
nated in the reaction with aldehyde.
Under the same conditions as described for the syn-
thesis of 2d , 2-phenylapopinene (1.20 equiv) was hy-
droborated with 9-BBN (1.0 equiv) to provide the desired
trialkylborane 2e in 24 h in nearly quantitative yield.
The chemical and optical purity of the 2e was determined
B-(2-Or ga n yla p oisop in oca m p h eyl)-9-bor a bicyclo-
[3.3.1]n on a n e 2d ,e. It is observed from the above rate
(14) Brown, H. C.; Liotta, R.; Scouten, C. G. J . Am. Chem. Soc. 1976,
98, 5297.
(15) Brown, H. C.; Pai, G. G. J . Org. Chem. 1985, 50, 1384.
(16) Fieser, M.; Fieser, L. Reagents for Organic Synthesis; Wiley-
Interscience: New York, 1972; Vol. 3, p 23.
(17) Brown, H. C.; Dhokte, U. P. J . Org. Chem. 1994, 59, 5479.

868 J . Org. Chem., Vol. 62, No. 4, 1997
Dhokte and Brown
as described for 2d . However, under these conditions,
the hydroboration of 1f (1.20 equiv) with 9-BBN (1 equiv)
was complicated by the formation of undesired species
(20-25%) along with the required trialkylborane 2f.
Consequently, an indirect method for the synthesis of
trialkylborane 2f was developed.
apopinenes (1.10-1.20 equiv), hydroboration with 9-BBN
(1.0 equiv) is readily achieved under neat conditions at
65 °C in 14-24 h. Unfortunately, hydroboration of the
more sterically-demanding, 2-isopropylapopinene (1f),
with 9-BBN, did not proceed satisfactorily to furnish the
desired B-(2-Rap)-9-BBN (2-Rap ) 2-isopropylapopinyl
skeleton). Fortunately, an indirect method, the reaction
of (2-isopropylapoisopinocampheyl)borane (i-PraBH2) with
1,5-COD, achieves the synthesis of the desired trialkyl-
borane 2f, following thermal isomerization, in nearly
quantitative yield. Consequently, this indirect approach
provides an independent route to the sterically bulkier
B-2-organylapopinyl-9-BBN compounds, difficult to ob-
tain via direct hydroboration. Thus, the syntheses of
these B-2-organylapopinyl-9-BBN compounds 2c-f pro-
vide easy access to them to study the effect of the
2-organyl group on the selective asymmetric reduction
of acetylenic ketones and R-keto esters. Also, the corre-
sponding optically pure lithium trialkylborohydrides
3c-f should provide sterically bulkier analogues of
lithium B-isopinocampheyl-9-borabicyclo[3.3.1]nonyl hy-
dride (Alpine-Hydride),5 possibly more effective for the
asymmetric reduction of prochiral ketones.
Syn th esis of B-(2-Isop r op yla p oisop in oca m p h eyl)-
9-bor a bicyclo[3.3.1]n on a n e (2f). An alternative syn-
thesis of B-(2-isopropylapoisopinocampheyl)-9-borabicyclo-
[3.3.1]-nonane (2f) was developed. It has been demon-
strated in previous work from this laboratory that the
cyclic hydroboration of 1,5-COD with thexylborane (Thx-
BH2) gives two regioisomeric products, arising from the
1,4- and 1,5-cycloaddition in a 4:1 ratio, respectively.18
It has also been reported that the chiral monoalkylbo-
ranes (R1*BH2) react with 1,5-COD to give a 70:30
mixture of the 1,4- and 1,5-cyclic adducts.19 Apparently,
the hydroboration proceeds in two stages. The first step
is the hydroboration of one of the double bonds. The
second stage is the intramolecular cyclic hydroboration,
which favors formation of the five-membered boracyclane
over the six-membered ring (eq 5). The less stable 1,4-
regioisomer is readily isomerized to the 1,5-isomer at 65
°C.19
Exp er im en ta l Section
All glassware was dried at 140 °C overnight, assembled hot,
and cooled to ambient temperature in a stream of nitrogen.20
All reactions involving air- or moisture-sensitive compounds
were performed under a static pressure of dry nitrogen.20
Reported melting points are uncorrected. 11B NMR spectra
were recorded at 96 MHz and were referenced relative to
BF3‚EE. 1H and 13C NMR spectra were recorded at 200 and
50 MHz, respectively, relative to internal tetramethylsilane
(TMS). Chemical shifts in the 1H and 13C NMR spectra are
reported as parts per million (ppm) downfield from TMS. All
materials for which optical rotation information is provided
were purified by preparative GC on a 6 ft × 0.5 in. column
packed with 20%-SE 30 on Chromosorb W (60-80 mesh).
Optical rotations were measured on a digital polarimeter in a
1-dm cell. GC analyses for chemical purity and rate data were
performed using columns packed either with 10%-SE 30 on
Chromosorb W (100-120 mesh) or 10% Carbowax on Chro-
mosorb W (80-100 mesh). Capillary GC analyses were
performed using the SPB-5 column (30 m).
Ma ter ia ls. Tetrahydrofuran (THF) was distilled from
sodium benzophenone ketyl and used as required. Anhydrous
diethyl ether was used without purification. The 2-R-apo-
pinenes 1b-f were synthesized by the known procedures.7b,8,11,13
The 2-R-apopinenes 1b-d ,f were derived from (+)-R-pinene,
while (+)-phenylapopinene (1e) was synthesized from (+)-â-
pinene.13
Gen er a l P r oced u r e for th e Deter m in a tion of th e Ra te
of t h e H yd r ob or a t ion of 2-R -a p op in en es 1a -f w it h
9-BBN. The reactions were carried out in THF at 24 °C. In
all these experiments, 10-12 mmol of 2-R-apopinenes 1a -f
were used for the reaction with 9-BBN. The concentration of
2-R-apopinenes with 9-BBN was maintained at 0.50 M each.
The progress of the reaction was monitored at appropriate time
intervals by the following analytical techniques: (i) 11B NMR
spectral analysis, for trialkylborane and dialkylborane (9-
BBN),21 of an aliquot taken after definite time intervals; (ii)
GC analysis of either residual 2-R-apopinenes or silyl ether
(5a -f) (silylation was done with bis(trimethylsilyl)acetamide
using a catalytic amount of pyridine in THF)16 of the product
2-organylapoisopinocampheol, resulting from the hydrobora-
Thus, the hydroboration of 1,5-COD with an ethereal
solution of (2-isopropylapoisopinocampheyl)borane (i-
PraBH2) at 0 °C for 1 h achieved the quantitative
formation of the 1:1 mixed trialkylboranes as determined
by 11B NMR (δ 81, 86), and the GC analysis of the
products resulted after alkaline peroxide oxidation.17 The
thermal isomerization of the less stable 1,4-isomer to the
more stable desired trialkylborane 2f (11B NMR: δ 83)
was complete in 24 h in refluxing THF. The reaction was
monitored periodically by 11B NMR of aliquots and also
by GC analysis of the silyl ethers of the alcohols, produced
by alkaline peroxide oxidation of the boron components.
Optical and chemical purity of the trialkylborane 2f,
obtained after the isomerization reaction, was determined
as described previously.
Con clu sion s
This paper describes a detailed study of the behavior
of six representative sterically different 2-organylapo-
pinenes (2-R-apopinenes; R ) Me, Et, Pr, i-Bu, Ph and
i-Pr) in the hydroboration with the bulkier 9-BBN in THF
at 24 °C. We have demonstrated that as the R group in
the 2-R-apopinenes become bulkier, the rate of hydrobo-
ration slows, becoming so slow with the latter three 2-R-
apopinenes as to be impractical. However, for sterically-
demanding terpenes, such as 2-isobutyl- and 2-phenyl-
(20) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Synthesis via Boranes; Wiley-Interscience: New York, 1975.
(21) Borane species mentioned in this paper showed distinct 11B
NMR signals adequate for their approximate percentage determina-
tion. Srebnik, N.; Cole, T. E.; Ramachandran, P. V.; Brown, H. C. J .
Org. Chem. 1989, 54, 6085.
(18) Brown, H. C.; Negishi, E. J . Am. Chem. Soc. 1972, 94, 3567.
(19) Brown, H. C.; J oshi, N. N.; Pyun, C.; Singaram, B. J . Am. Chem.
Soc. 1989, 111, 1754.

Rates of Hydroboration of 2-Organylapopinenes
J . Org. Chem., Vol. 62, No. 4, 1997 869
Ta ble 2. Ra te of Hyd r obor a tion of 2-Eth yla p op in en e
(1b) w ith 9-BBN in a 1:1 Mola r Ra tio (0.50 M Ea ch )a in
THF a t 24 °C
Similarly, this reaction was run in the presence of an
internal standard, n-tridecane, the resultant trialkylboranes,
2d ,e, were subjected to alkaline peroxide oxidation, and the
products of the reaction were analyzed as described above. The
2-organylapoisopinocampheols (2-organyl ) isobutyl and phen-
yl) were isolated and purified by the preparative GC for their
optical rotation measurements, which showed g99% ee with
respect to their authentic samples. (-)-2-Isobutylapoisopino-
campheol: mp 91 °C; [R]24 -33.7° (c 1, MeOH) [lit.12 [R]24
residual olefinb
(mmol)
alcoholc formed
(mmol)
time (h)
% reactiond
2
6
10
24
48
10.49
7.53
4.30
1.75
0.23
1.31
4.31
7.54
9.95
11.52
11
37
65
85
g98
D
D
-33.9° (c 1, MeOH)]. (-)-2-Phenylapoisopinocampheol: mp
107 °C; [R]24 -24.7° (c 1, MeOH) [lit.12 [R]20 +24.8° (c 1,
D
D
a
2-Ethylapopinene (1b) (11.7 mmol), 9-BBN (11.7 mmol), and
MeOH)].
b
n-dodecane (5.037 mmol) in THF (20.0 mL). Mmol of residural
Similarly, these alcohols were derivatized as the menthyl
carbonate22 (for 2-isobutylapoisopinocampheol) and the MTPA
ester23 (for 2-phenylapoisopinocampheol) and analyzed on
capillary GC (on an SPB-5, 30 m column) with respect to their
1:1 diastereomeric mixtures.12 These results in turn indicated
g99% chemical and optical purity for the desired trialkylbo-
ranes 2d and 2e.
olefin corresponds to mmol of 1,5-cyclooctanediol. c 2-Ethylapoiso-
d
pinocampheol. Based on the mmol of alcohol formed.
tion-oxidation, using a suitable internal standard whose
response factor had been calculated. In the experiments
involving 2-R-apopinenes 1a ,b, n-dodecane was used as an
internal standard, while for the 2-R-apopinenes 1c-f, n-
tridecane was so used.
In d ir ect R ou t e for t h e Syn t h esis of B-(2-Isop r op yl-
apoisopin ocam ph eyl)-9-bor abicyclo[3.3.1]n on an e (2f). An
ether solution of i-PraBH2 (12 mL of a 0.62 M solution, 7.43
mmol) prepared as described in the literature12 was cooled to
0 °C, followed by the dropwise addition of 1,5-cyclooctadiene
(0.8 g, 7.43 mmol). The reaction was allowed to warm to 24
°C. The 11B NMR showed a quantitative consumption of
i-PraBH2 as evidenced by almost 1:1 peaks at δ 86 and 81.
The ether was evaporated from the reaction flask (10 mmHg,
1 h, rt), 15 mL of dry THF was introduced into the flask, and
the solution was heated under reflux for 24 h. Aliquots were
removed after appropriate time intervals and oxidized as
described above. The resultant alcohols were silylated and
analyzed as described previously. The results of this experi-
ment showed the quantitative formation of 1,5-cyclooctanediol,
formed after complete thermal isomerization of 1,4-cyclic
adduct, after 24 h. The chemical and optical purity of g99%
of the resultant trialkylborane 2f was determined as described
in the preceding experiment. (+)-2-Isopropylapopinene (1e):
[R]24 +38.9° (c 1, MeOH) [lit.12 [R]20 +39.0° (c 1, MeOH)].
The following procedure is representative. One equiv of
solid 9-BBN (11.7 mmol) was dissolved in THF (15.0 mL) and
maintained at 24 °C. The 2-ethylapopinene (1b) (1.76 g, 11.7
mmol) was dissolved in THF (5.0 mL) and added dropwise.
The molarity of the solution was maintained at 0.50 M with
respect to the reactants. At appropriate time intervals, the
11B NMR spectrum was recorded, and also a 2.0 mL aliquot
was removed, dissolved in 3-4 mL of THF, and oxidized
(NaOH/H2O2). The usual workup procedure20 provided a
mixture of products, i.e., 2-ethylapopinene (1b), 2-ethylapoiso-
pinocampheol, and 1,5-cyclootanediol. The resultant mixture
was subjected to silylation [py/THF/bis(trimethylsilylaceta-
mide)].16 GC analysis of the unreacted 2-ethylapopinene (1b),
alcohol, and diol was measured against the internal standard
as described above. These results are presented in the Table
2 and graphically depicted in Figure 1. The rates of hydrobo-
ration of 2-R-apopinenes 1a ,c-f with 9-BBN, under similar
conditions, are summarized in Tables 3-6 provided as Sup-
porting Information.
P r ep a r a tion of B-(2-Or ga n yla p oisop in oca m p h eyl)-9-
bor a bicyclo[3.3.1]n on a n es 2d ,e. The reaction was per-
formed on a 5-10 mmol scale. Solid 9-BBN (5 mmol) was
transferred under nitrogen to 50-mL round-bottom flask.
Optically pure 2-R-apopinene (R ) i-Bu 1d , Ph, 1e) was added
to the flask via a double-ended needle. The flask was heated
in an oil bath at 65 °C (14 h for 2d preparation and 24 h for
2e preparation) to complete the hydroboration (11B NMR: δ
80-83).
D
D
(-)-2-Isopropylapoisopinocampheol: mp 75 °C; [R]24 -16.5°
D
(c 1, MeOH) [lit.12 [R]20 -16.4° (c 1, MeOH)].
D
Ack n ow led gm en t. This work was initiated with
support from the National Institutes of Health (GM
10937) and completed with support from the Borane
Research Fund.
Su p p or tin g In for m a tion Ava ila ble: Tables 3-7 sum-
marizing the results of the rate of hydroboration of 1a ,c-f with
9-BBN (5 pages). This material is contained in libraries on
microfiche, immediately follows this article in the microfilm
version of the journal, and can be ordered from the ACS; see
any current masthead page for ordering information.
A sample of the reagent was treated with 1 equiv of
acetaldehyde, as described in the reported procedure,17 to
liberate 2-R-apopinenes 1d ,e. Treatment with aqueous NaOH
removed the boron components, and the 2-R-apopinene 1d ,e
was extracted into ethyl ether, dried with MgSO4, concen-
trated, distilled, and purified by preparative GC. Gas chro-
matographic analysis was identical with that of an authentic
sample, thus indicating no isomerization had occurred during
J O9617169
the preparation of the reagent. (+)-2-Isobutylapopinene: [R]24
D
(22) Westley, J . W.; Halpern, B. J . Org. Chem. 1968, 33, 3978.
(23) Dale, J . A.; Dull, D. L.; Mosher, H. S. J . Org. Chem. 1969, 34,
2543.
+15.25 (neat) [lit.17 [R]20 +15.29 (neat)]. (+)-Phenylapo-
D
pinene: [R]24 +19.86° (neat) [lit.17 [R]20 -19.89° (neat)].
D
D