(E)-α-substituted γ-alkoxyallylboronic esters as new reagents: Synthesis and reactivity toward aldehydes

Article abstract of DOI:10.1021/jo0622330

(Chemical Equation Presented) We have developed a synthesis of new allylboration reagents based on an allylic rearrangement. This approach led to the α-substituted γ-alkoxyallylboronates 2 with a high stereoselectivity in favor of the E-isomer, independen

Full text of DOI:10.1021/jo0622330

(E)-r-Substituted γ-Alkoxyallylboronic Esters as New Reagents:
Synthesis and Reactivity toward Aldehydes
Franc¸oise Posse´me´, Michael Deligny, Franc¸ois Carreaux,* and Bertrand Carboni
Sciences Chimiques de Rennes, UMR 6226 CNRS-UniVersite´ de Rennes 1, Campus de Beaulieu,
35042 Rennes Cedex, France
francois.carreaux@uniV-rennes1.fr
ReceiVed October 27, 2006
We have developed a synthesis of new allylboration reagents based on an allylic rearrangement. This
approach led to the R-substituted γ-alkoxyallylboronates 2 with a high stereoselectivity in favor of the
E-isomer, independent of the organometallic used. We have also studied the reactivity of these reagents
toward aldehydes, showing that the allylboration reaction occurs with an excellent diastereoselectivity to
give the anti-diol derivatives 5. Moreover, the sequence can be carried out in a “one-pot” procedure
avoiding the purification of allylboronates.
Introduction
ties,4 more problems are associated to the stereoselective
preparation of E-isomer.5 Barrett et al. proposed an alternative
and indirect method using B-[3-((diisopropylamino)dimethyl-
silyl)allyl]diisopinocampheylborane.6 Following the allylboration
reaction, the silyl residue was converted to the desired oxygen
functionality. More recently, two supplementary strategies
emerged for the synthesis of (E)-γ-alkoxyallylborane reagents.
The first one is based on a catalyzed isomerization of γ-alko-
xyvinylboronates,7 while the second one exploits the homolo-
gation reaction with LiCH2Cl to convert vinylboronates into
allylboronates.8 However, to our knowledge, among all pub-
lished methods, none of them described the access to acyclic
R-substituted species.9
Allylboranes represent an important structural class of orga-
noboron derivatives widely employed in organic synthesis.1
Their addition to aldehydes, one of the most powerful methods
to prepare homoallylic alcohols, proceeds via a six-membered
transition state, which accounts for the excellent levels of
stereocontrol mostly observed in these reactions.2 However, the
success of this approach implies a strict control of geometry of
the double bond of the allyborane to secure the obtention of
the corresponding vicinal diol in good diastereo- and enantio-
meric purity. In the field of polyhydroxylated compounds, many
reports have shown interest in using the γ-alkoxyallylboranes.3
If (Z)-γ-alkoxyallylboronates were easily prepared by borylation
of (Z)-γ-alkoxyallyl anions, due to their configurational stabili-
In the light of these observations and due to the synthetic
potential of this class of reagents, we planned to develop a
(1) (a) Chemler, S. R.; Roush, W. R. In Modern Carbonyl Chemistry;
Otera, J., Ed.; Wiley-VCH: Weinheim, 2000; Chapter 11. (b) Denmark,
S. E.; Fu, J. Chem. ReV. 2003, 103, 2763.
(4) (a) Wuts, P. G. M.; Bigelow, S. S. J. Org. Chem. 1982, 47, 2498.
(b) Hoffmann, R. W.; Kemper, B. Tetrahedron Lett. 1982, 23, 845.
(5) (a) Hoffmann, R. W.; Kemper, B. Tetrahedron Lett. 1981, 22, 5263.
(b) Hoffmann, R. W.; Metternich, R. Liebigs Ann. Chem. 1985, 2390.
(6) Barrett, A. G. M.; Malecha, J. W. J. Org. Chem. 1991, 56, 5243.
(7) Yamamoto, Y.; Miyairi, T.; Ohmura, T.; Miyaura, N. J. Org. Chem.
1999, 64, 296 and references cited therein.
(2) (a) Matteson, D. S. Stereodirected Synthesis with Organoboranes;
Springer: Berlin, 1995. (b) Kennedy, J. W. J.; Hall, D. G. In Boronic Acids;
Hall, D. G., Ed.; Wiley-CH: Weinheim, 2005; Chapter 6.
(3) For selected examples, see: (a) Wuts, P. G. M.; Bigelow, S. S.
J. Org. Chem. 1988, 53, 5023. (b) Burgess, K.; Chaplin, D. A.; Henderson,
I. J. Org. Chem. 1992, 57, 1103. (c) Jadhav, P. K.; Woerner, F. J. Tetrahedon
Lett. 1994, 35, 8973. (d) Barrett, A. G. M.; Beall, J. C.; Braddock, D. C.;
Flack, K.; Gibson, V. C.; Salter, M. M. J. Org. Chem. 2000, 65, 6508. (e)
Ramachandran, P. V.; Chandra, J. S.; Reddy, M. V. R. J. Org. Chem. 2002,
67, 7547. (f) Yamamoto, Y.; Kurihara, K.; Yamada, A.; Takahashi, M.;
Takahashi, Y.; Miyaura, N. Tetrahedron 2003, 59, 537 and references cited
therein.
(8) Hoffmann, R. W.; Kru¨ger, J.; Bru¨ckner, D. New J. Chem. 2001, 25,
102.
(9) Some publications reported the synthesis of cyclic γ-alkoxyallylbo-
ronates and their utilization in total synthesis, see: (a) Murata, M.; Oyama,
T.; Watanabe, S.; Masuda, Y. Synthesis 2000, 778. (b) Gao, X.; Hall,
D. G.; Deligny, M.; Favre, A.; Carreaux, F.; Carboni, B. Chem. Eur. J.
2006, 12, 3132 and references cited therein. (c) Carreaux, F.; Favre, A.;
Carboni, B.; Rouaud, I.; Boustie, J. Tetrahedron Lett. 2006, 47, 4545.
10.1021/jo0622330 CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/10/2007
984
J. Org. Chem. 2007, 72, 984-989

(E)-R-Substituted γ-Alkoxyallylboronic Esters as New Reagents
TABLE 1. Optimization of the 1,4-Addition Reaction with n-BuLia
n-BuLib
(equiv)
BF3‚OEt2
(equiv)
convd (%)
c
entry
T (°C)
time (h)
(yielde (%))
1
2
3
4
5
1.2
1.2
1.2
1.2
1.5
rt
rt
-78
-78
-78
12
12
0.25
0.25
0.25
20 (nd)
50 (nd)
50 (nd)
90 (nd)
100 (50)
1
1
2
2
a Reactions were conducted on a 1.5 mmol scale. b n-BuLi was added
at -78 °C. c The Lewis acid was added at -78 °C, 20 min after the addition
of n-BuLi. d Determined by 1H NMR spectroscopy. e Yield of isolated
product after purification by column chromatography on silical gel.
FIGURE 1. Strategy for the synthesis of r-substituted
γ-alkoxyallylboronates.
rane, followed by dealkylation of the isopinocampheyl group
with a large excess of acetaldehyde and transesterification by
2,3-dimethylbutane-2,3-diol (pinacol) (Scheme 1).13,14
SCHEME 1. Synthesis of 1aa
We initially examined the reaction of 1a with organolithium
reagents which are known to react preferentially in SN′ manner
with nonboronated allylic acetals.15 In a first attempt, 1a was
treated with n-BuLi in THF at -78 °C in the absence of Lewis
acid (Table 1, entry 1). The resulting solution was warmed to
room temperature and stirred for 12 h. After workup, the analysis
a Reagents and conditions: (a) (Ipc)2BH (1 equiv), THF, 0 °C, 1 h, then,
rt., 1 h; (b) CH3CHO (20 equiv), 0 °C, 1 h then, rt, 48 h; (c) pinacol (1
equiv), Et2O, rt, 18 h, 60%.
1
of the crude mixture by H NMR indicated the formation of a
single product with a 20% conversion. This product, 2a, was
identified as being the result of a 1,4-addition with concomitant
cleavage of the acetal group on the basis of two signals of vinylic
protons characteristic of an enol ether (δ 4.71 and 6.15). The
reaction is highly stereoselective since the E-isomer was only
detected. Taking into account of this promising result, we then
examined the influence of a Lewis acid that should facilitate
the displacement of the alkoxy group. As expected, the use of
1 equiv of BF3‚OEt2 enhanced the conversion of 1a into 2a,
however, with a concomitant formation of a secondary product.16
Fortunately, this process took place more cleanly when the
temperature was maintained at -78 °C. After several attempts,
full conversion was obtained using 2 equiv of Lewis acid and
1.5 equiv of n-BuLi at -78 °C for 25 min (Table 1, entry 5).
It is important to note that, even in the presence of an excess of
organolithium reagent, the product resulting from a 1,2-addition
was not detected. Under these experimental conditions, the
E-isomer was still obtained exclusively (within the limits of
the 1H NMR measurement) and was isolated in a pure form by
flash chromatography in 50% yield, due to a partial degradation
on deactivated silica gel.
simple and straightforward route to stereodefined R-substituted
γ-alkoxyallylboronates. In our laboratory, we previously dem-
onstrated that boronic esters can be homologated via a 1,2-
migration of an alkyl group from boron to the adjacent atom
with displacement of an alkoxy group.10 We now envisioned
that the borate intermediate A could also rearrange itself to
afford the corresponding γ-alkoxyallylboronates (Figure 1). This
borate could be prepared by treatment of a vinylboronic ester 1
with an organometallic reagent. If a similar migration was
already described in the case of R,â-unsaturated organoboranes
containing an halogen as leaving group,11 no example of such
an SN′ process was hitherto reported with acetal derivatives.12
In this paper, we report our first results in this topic as well as
a study of the reactivity of these new reagents toward aldehydes.
Results and Discussion
Optimization of the Enol Ether Formation. The model
substrate chosen to test this strategy was 2-[(1E)-3,3-diethoxy-
prop-1-en-1-yl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane 1a. It
can be prepared on gram scale by hydroboration of commercially
available 3,3-diethoxyprop-1-yne with diisopinocampheylbo-
Scope of Organometallic Reagent and Substrate. Several
other organometallics were then explored in order to assess the
(13) Rasset-Deloge, C.; Vaultier, M. Bull. Soc. Chim. Fr. 1994, 131,
919.
(14) For other synthesis of 1a, see: (a) Pereira, S.; Srebnik, M.
Organometallics 1995, 14, 3127. (b) Kalinin, A. V.; Scherer, S.; Snieckus,
V. Angew. Chem., Int. Ed. 2003, 42, 3399.
(15) (a) Mioskowski, C.; Manna, S.; Falck, J. R. Tetrahedron Lett. 1984,
25, 519. (b) Bailey, W. F.; Zartun, D. L. J. Chem. Soc., Chem. Commun.
1984, 34. (c) Alexakis, A.; Mhamdi, F.; Lagasse, F.; Mangeney, P.
Tetrahedron: Asymmetry 1996, 7, 3343.
(16) This compound was not definitively identified, but must be probably
the result of a 1,3- boratropic shift.
(10) Carme`s, L.; Carreaux, F.; Carboni, B. J. Org. Chem. 2000, 65, 5403.
(11) (a) Zweifel, G.; Horng, A. Synthesis 1973, 672. (b) Midland,
M. M.; Preston, S. B. J. Org. Chem. 1980, 45, 748. (c) Midland, M. M.;
Preston, S. B. J. Am. Chem. Soc. 1982, 104, 2330. (d) Lombardo, M.;
Morganti, S.; Trombini, C. J. Org. Chem. 2000, 65, 8767. (e) Lombardo,
M.; Morganti, S.; Tozzi, M.; Trombini, C. Eur. J. Org. Chem. 2002, 2823.
(f) Carosi, L.; Lachance, H.; Hall, D. G. Tetrahedron Lett. 2005, 46, 8981.
(12) For the synthesis of R-subsituted (γ-alkoxyallyl)tins from vinyltin
acetals, see: Watrelot, S.; Parrain, J-L.; Quintard, J-P. J. Org. Chem. 1994,
59, 7959.
J. Org. Chem, Vol. 72, No. 3, 2007 985

Posse´me´ et al.
SCHEME 3. Synthesis of 1ba
TABLE 2. Synthesis of (E)-r-Substituted γ-Ethoxyallylboronates
2a-e from 1aa
a Reagents and conditions: (a) n-BuLi (1 equiv.), -78 °C, isopropyl
pinacol borate (1 equiv) and HCl/Et2O, 60%; (b) H2 (20 bar), Pd/CaCO3,
quinoline, dioxane, rt, 94%.
organometallic
R1M
products
entry
T (°C) convb (%) E/Z ratiob (yield, %)c
1
2
3
4
5
6
7
8
n-BuLi
MeLi
PhLi
s-BuLi
n-BuMgCl
n-BuMgCl
i-PrMgCl
i-PrMgCl
-78
-78
-78
-78
-78
-60
-78
-45
100
100
100
100
63
100
0
100
100/0
100/0
100/0
100/0
100/0
100/0
2a (50)
2b (nd)
2c (nd)
2d (65)
2a (nd)
2a (49)
2e (nd)
2e (54)
partial, whereas there was no addition with i-PrMgCl, probably
due to a steric hindrance of the alkyl group. Addition of BF3‚
OEt2 caused the disappearance of the “ate” complex, while the
uncomplexed starting material remained unchanged. These
observations clearly show that the allylic rearrangement only
occurred from a key borate species. Furthermore, taking into
account Midland’s report,11b we assumed that the 1,2-migration
occurred in a SN2′ manner, anti to the leaving group. The
obtention of a single E-isomer can be therefore rationalized by
the presence of an allylic 1,3-strain in transition state B involving
one of the ethoxy groups (Scheme 2).17 The intramolecular
migration involved in this process also explained its high regio-
and stereoselectivity, compared with the results described in
the literature for nonboronated analogues.15,18
100/0
a Reactions were conducted on a 1.5 mmol scale. b Determined by 1H
NMR spectroscopy of the crude product. c Isolated yield after flash
chromatography.
SCHEME 2. Allylic 1,3-Strain in the SN2′ Reaction
To check a possible influence of the geometry of the double
bond of 1a and to confirm our mechanistic hypothesis, we then
decided to test the reaction with the Z-isomer. 2-[(1Z)-3,3-
Diethoxy-1-propenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
1b was previously prepared in the literature by hydrozirconation
of the corresponding 1-alkynylboronate.19 However, the authors
reported a partial decomposition of the acetal under these
experimental conditions. To obtain cleanly 1b with a pure Z
geometry, we developed another route based on the cis-
hydrogenation of the 1-alkynyldioxaborolane 3 (Scheme 3).20
Condensation at -78 °C of isopropyl pinacol borate with lithium
acetylide, obtained from 3,3-diethoxyprop-1-yne, furnished, after
treatment by anhydrous hydrogen chloride, 3 in 60% yield.
Several hydrogenation experiments were conducted in changing
the catalyst, solvent, and pressure of H2.21 The best result was
obtained using the Lindlar catalyst with quinoline in 1,4-dioxane
and a pressure of 20 bar of H2 (94% yield, isomeric purity
>99%).
Compound 1b was treated, as previously described, with
n-BuLi in THF to afford 2a. The stereoselectivity exclusively
in favor of the E-enol ether was maintained. However, the
formation of the “ate” complex from 1b with n-BuLi at
-78 °C is slower than with 1a, as the migration of the butyl
group (complete conversion after 4h at -78 °C for the Z-isomer
compared to 25 min for the E-isomer). After flash chromatog-
raphy on deactivated silica gel, 2a was obtained in 55% yield.
Reactivity of 2 toward Aldehydes under Thermal Condi-
tions. Having in hand an efficient access to allylboronic esters
2, we then turned our attention to their reactivity toward
aldehydes. First, the allylboration reactions were carried out
under standard thermal conditions, using 2 equiv of aldehyde
generality of this methodology (Table 2). In every case,
independent of the size of the entering alkyl group, the 1,4-
addition is the exclusive pathway with a high stereoselectivity
in favor of the E-isomer. Concerning the organolithium reagents,
the allylic rearrangement took place in all cases at -78 °C with
a full conversion. When the reaction was performed at the same
temperature with a Grignard reagent, such as n-BuMgCl, the
conversion was incomplete (63%) while with i-PrMgCl, the
starting material was totally recovered without any decomposi-
tion. To observe a full conversion, it was necessary to carry
out the reaction at -60 °C (n-BuMgCl) or -45 °C (i-PrMgCl),
which allowed a complete complexation on the boron atom
(Table 2, entries 6 and 8). Except when the substituents at the
R position are methyl 2b and phenyl 2c, the (E)-R-substituted-
γ-alkoxyallylboronates 2 were isolated in moderate yields by
flash chromatography due to their low stability during the
purification step.
In order to clarify the mechanism of this transformation, the
reaction of 1a with n-BuLi was followed by 11B NMR. At
-78 °C, the spectrum of the reaction mixture showed that the
starting alkene (δ +29.7 ppm) was completely converted into
an “ate” complex (δ +8.0 ppm), which is the result of the
addition of n-BuLi to the boron atom (Scheme 2). The addition
of the Lewis acid at this same temperature caused a gradual
disappearance of this signal. After treatment with a saturated
(17) Hoffmann, R. W. Chem. ReV. 1989, 89, 1841.
(18) Addition of Grignard reagents to R,â-unsaturated, see: Normant,
J. F.; Commerc¸on, A.; Bourgain, M.; Villieras, J. Tetrahedron Lett. 1975,
44, 3833 and references cited therein.
(19) Deloux, L.; Srebnik, M. J. Org. Chem. 1994, 59, 6871.
(20) For a general synthesis of 1-alkynyldiisopropoxyboranes, see:
Brown, H. C.; Bhat, N. G.; Srebnik, M. Tetrahedron Lett. 1988, 29, 2631.
(21) Srebnik, M.; Bhat, N. G.; Brown, H. C. Tetrahedron Lett. 1988,
29, 2635.
solution of NH4Cl and extraction with dichloromethane, the 11
B
NMR of the crude mixture showed a new peak (2a, δ +33.4
ppm), shifted downfield from the starting material 1a. With
n-BuMgCl, at -78 °C, the complexation of boron was only
986 J. Org. Chem., Vol. 72, No. 3, 2007

(E)-R-Substituted γ-Alkoxyallylboronic Esters as New Reagents
TABLE 3. Allylboration of 2 under Standard Thermal Conditionsa
TABLE 4. Synthesis of Homoallylic Alcohols from 1a Using a
a
One-Pot Process
entry no.
R1
R2
time (h) Z/E ratiob products (yield,c %)
1
2
3
4
5
6
2a n-Bu Ph
144
24
72
192
192
144
75/25
74/26
5/95
nd
75/25
71/29
5a (75)
5b (50)
5c (63)
5d (nd)
5e (76)
5f (71)
2b Me
2c Ph
Ph
Ph
2d s-Bu Ph
2e i-Pr Ph
2f n-Bu C5H11
anti/syn
products
Z/E ratio of 5b (yield,c %)
a Reactions were conducted on 1.5 mmol scale. b Z/E ratio was deter-
mined by 1H NMR spectroscopy of the crude product. c Isolated yield after
flash chromatography.
entry no.
R1
time (h)
ratiob
1
2
3
4
2a
n-Bu
72
24
24
99/1
95/5
88/12
99/1
45/55
37/63
3/97
5a, 6a (66)
5b, 6b (73)
5c, 6c (50)
5d, 6d (49)
2b Me
2c Ph
2d s-Bu
SCHEME 4. Postulated Competing Transition States in the
Allylation of Aldehydes with (E)-r-Substituted
γ-Ethoxyallylboronates 2
144
29/71
a Reactions were conducted on 1.5 mmol scale. b Determined by 1H NMR
spectroscopy of the crude product. c Isolated yield after flash chromatog-
raphy.
two competing chair-type transition states as shown in Scheme
4. When the substituent is a nonpolar alkyl group, the preference
for the Z-homoallylic alcohol was attributed to a disfavored
interaction in transition state 4a between the pseudoequatorial
R-substituent R1 and the bulky glycol component of the
boronate, although there is an unfavorable allylic interaction in
4b. It was also shown in the literature that the Z/E ratio
decreased when the size of the boron substituents increased.25b
In our case, the formation of the Z-isomer is effectively
predominant, but no significant modification was observed with
an isopropyl group compared with a methyl substituent (Table
3, entries 2 and 5), that seems to indicate that, for these new
reagents, the steric effect does not play a decisive role in the
stereocontrol. The stereoselectivity obtained with 2c (R1 ) Ph)
on addition to benzaldehyde can be explained by the fact that
the phenyl group has a preference for the equatorial position,
thus stabilizing 4a compared to 4b.
“One-Pot” 1,4-Addition/Allylboration. Due to the difficul-
ties encountered in the purification of R-substituted γ-ethoxy-
allylboronates 2, we examined the possibility of carrying out
the allylic rearrangement and the allylboration in “one-pot”
process. After completion of the first step, 2 equiv of benzal-
dehyde was added at -78 °C, before the mixture was warmed
at room temperature. After workup with a saturated solution of
NaHCO3, homoallylic alcohols were purified by flash chroma-
tography (Table 4). Using this experimental procedure, the
allylboration reaction is clearly accelerated. The more significa-
tive example is given by the 1,4-addition of the sec-butyl group
on the R-position of the boron atom followed by the addition
to benzaldehyde (entry 4). In the two-step process without Lewis
acid, the allylboration product was not detected at room
temperature after 8 days. By contrast, this latter could be
obtained in 49% yield after 6 days using the one-pot process.
This improvement is probably due to the presence of the
trifluoroborane etherate, which accelerates the allylboration
reaction.26 However, under these conditions, the diastereose-
lectivity was not preserved, although the formation of the anti-
at room temperature. In a general way, the reactivity of 2 is
weaker compared to the corresponding allylboronates with no
substituent in the R-position (several days at room tempera-
ture).22 It is also highly dependent upon the nature of the
R-substituent (R1) as shown in Table 3. The yields of 5, after
purification by flash chromatography, vary from 50 to 76%.
The R-sec-butyl-substituted reagent 2d did not lead to the
formation of the allylboration product with benzaldehyde even
after 192 h at room temperature.23 The anti-diol derivatives were
obtained exclusively, that is in conformity with the formation
of a cyclic six-membered transition state. The relative stereo-
chemistry of these adducts was assigned by analogy with related
additions to aldehydes and on the basis of the coupling constants
between the protons HA and HB (JA,B) 4.0-4.5 Hz).24 Concern-
ing the geometry of the double bond, the formation of the
Z-isomer is mostly favored as expected (isomer Z, J)11.1-
11.9 Hz; isomer E, J)15.4-16.2 Hz). The ratio of Z/E did not
vary significantly with the steric hindrance of the R-substituent
(R1) (entries 1-2 and 5) and the nature of the R2 residue of the
aldehyde (entries 1 and 6). It is worthy to note the inversion of
selectivity when the R-substituent is a phenyl group (entry 3).
According to literature dealing with the origin of stereose-
lectivity in the reactions of R-substituted allylboronates with
aldehydes,25 the ratio of Z/E isomers can be explained from the
(22) Concerning the reactivity of unsubstituted γ-methoxyallylboronates,
see: Hoffmann, R. W.; Kemper, B.; Metternich, R.; Lehmeier, T. Liebigs
Ann. Chem. 1985, 2246.
(23) It is necessary to warm the mixture at reflux to observe the formation
of the allylboration product in 1H NMR. Unfortunately, many decomposition
products are also produced.
(24) The corresponding syn derivatives (6a-d) obtained in presence of
Lewis acid, showed coupling constants of 7.8 to 8.1 Hz for these two
protons.
(25) (a) Hoffmann, R. W.; Landmann, B. Chem. Ber. 1986, 119, 1039.
(b) Hoffmann, R. W.; Wolff, J. J. Chem. Ber. 1991, 124, 563.
(26) Kennedy, J. W. J.; Hall, D. G. Angew. Chem., Int. Ed. 2003, 42,
4732.
J. Org. Chem, Vol. 72, No. 3, 2007 987

Posse´me´ et al.
SCHEME 5. Postulated Competing Transition States for
the Formation of Homoallylic Alcohols 5 in Presence of
Lewis Acid
(THF) (7 mL) under an argon atmosphere. (S)-(-)-R-Pinene (6.67
mL, 42 mmol) was then added dropwise at 0 °C. The mixture stirred
for 10 min followed by 2 h at room temperature. The resulting
white diisopinocampheylborane suspension was cooled to 0 °C, and
propiolaldehyde diethyl acetal (3 mL, 21 mmol) was added slowly.
The resulting mixture was stirred at 0 °C for 1 h, at room
temperature for additional 2h, and cooled back to 0 °C again prior
to the quick addition of freshly distilled acetaldehyde (29 mL). The
solution was stirred for 48 h at room temperature. After evaporation
of solvent and excess acetaldehyde, the residue was dissolved in
Et2O (16 mL) at room temperature, and dry pinacol (2,50 g, 21
mmol) was added. After the mixture was stirred overnight, the
solvent was evaporated under reduced pressure. The crude product
was purified by flash column chromatography (deactivated silica
gel, heptane/ethyl acetate 9/1) to give the pure product 1 as a
colorless oil (3.22 g, 60%): 1H NMR (200 MHz, CDCl3) δ 1.23
(t, J ) 7.1 Hz, 6H), 1.28 (s, 12H), 3.31-3.65 (m, 4H), 4.92 (dd,
J ) 1.2, 4.6 Hz, 1H), 5.78 (dd, J ) 1.2, 18.2 Hz, 1H), 6.51 (dd,
J ) 4.6, 18.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 15.0, 24.9,
61.4, 83.6, 102.0, 121.6, 148.8; 11B NMR (96 MHz, CDCl3/BF3‚
OEt2) δ +29.7 ppm; HRMS (EI) calcd. for C13H25O4B m/z
256.1840, found 256.1840.
products 5 is still favored. The anti/syn ratio varied from 88:12
to 99:1, while, without an activation by BF3‚OEt2, the anti-
diastereoisomer was only observed. These results seem to
indicate that the chairtype cyclic transition state, usually
proposed in the allylboration reaction, is probably in competition
with another open transition state responsible of the formation
of the syn-product (E)-6.27 Concerning the anti-products 5, it is
interesting to note the inversion of selectivity in favor of the
E-isomer compared to the allylboration reaction carried out in
the absence of Lewis acid.
These last observations can be explained by the enhancement
of the electrophicity of the boron atom due to the presence of
BF3‚OEt2 (Scheme 5). Indeed, the Lewis acid can coordinate
the boronate oxygen, which led to the reduction of the length
of the B-O (aldehyde) bond and, on the opposite side, to an
increase of the length of the B-C bond. The interaction between
the R1 substituent and the pinacol group then becomes less
important that the 1,3-strain, thus destabilizing the 7b transition
state and favoring the formation of the E-isomer. In absence of
Lewis acid, the importance of interactions are reversed (see
Scheme 4). This explanation was already postulated in the
literature with other R-substituted allylboronates, and the
stereoselectivity obtained with these new allylboronates is in
agreement with this suggestion.11f,28
General Procedure for the Synthesis of Allylboranes (2).
Preparation of 2-{1-[(E)-2-Ethoxyvinyl]pentyl}-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane (2a). To a solution of 1a (256.2 mg,
1 mmol) in THF (4 mL) was added a solution of n-BuLi (0.94
mL, 1.5 mmol, 1.6 M in hexane) at -78 °C. The mixture was stirred
for 45 min at this temperature before the slow addition of boron
trifluoride etherate (253 µL, 2 mmol). The mixture was then stirred
for an additional 25 min at the same temperature. The reaction was
quenched by addition of a saturated aqueous solution of sodium
hydrogen carbonate (2 mL) and extracted with dichloromethane
(3 × 10 mL). The organic layers were combined, washed with brine
(10 mL), and then dried over anhydrous MgSO4. Evaporation of
the solvent gave a residue that was purified by flash chromatography
(deactivated silica gel, heptane/ethyl acetate 9:1) to afford pure
allylborane 2a (134 mg, 50%) as a colorless oil: 1H NMR (200
MHz, CDCl3) δ 0.72-0.88 (m, 6H), 1.15-1.60 (m, 19H), 3.64 (q,
J ) 7.0 Hz, 2H), 4.71 (dd, J ) 9.1, 12.6 Hz, 1H), 6.15 (d, J )
12.6 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ 14.4, 15.1, 23.0, 25.1,
31.5, 32.0, 64.9, 83.4, 105.5, 145.8; 11B NMR (96 MHz, CDCl3/
BF3‚OEt2) δ +33.4 ppm; HRMS (EI) calcd for C15H29O3B m/z
268.2210, found 268.2207.
Conclusions
In summary, we have reported that the addition of organo-
metallics to vinylboronates 1 (E or Z) possessing an acetal group
in the γ-position occurred exclusively in an SN2′ manner, with
a complete stereoselectivity in favor of the E-isomer. The
reaction seems to be independent of the nature of the metal
and the size of the entering group. This access to the (E)-R-
substituted γ-alkoxyallylboronates, a new class of allylic reagent,
allow the introduction of a great diversity of substituents. In a
preliminary study, the reactivity of these reagents toward
aldehydes was examined. Under standard thermal conditions,
the anti-diol is obtained exclusively with a preference for the
Z-isomer of the enol ether. A loss of diastereoselectivity and
an inversion of stereoselectivity was observed when the al-
lylboration was carried out in the presence of a Lewis acid.
This “one-pot” procedure avoids the tedious purification of the
intermediaries allylboronates. The preparation of enantioenriched
γ-alkoxyallylboronates, as well as the exploration of other
aspects of the reactivity of these bifunctional reagents, are
currently under investigation in our laboratory.
Synthesis of 2-(3,3-Diethoxy-1-propynyl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane (3). To a stirred solution of propiolaldehyde
diethyl acetal (4.6 mL, 32 mmol) in Et2O (20 mL) was slowly added
n-butyllithium (20 mL, 32 mmol, 1.6 M in hexane) at -78 °C under
an argon atmosphere. Another 100 mL round-bottom flask was
charged with 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane
(6.53 mL, 32 mmol) in Et2O (40 mL), and the solution was cooled
to -78 °C. The lithium acetylide from the first flask was slowly
added to the second one by a double-ended needle. The reaction
was maintained at -78 °C for 2 h after which time anhydrous HCl
in Et2O (9.06 mL, 34 mmol) was added. The reaction was then
allowed to warm to room temperature. After filtration to remove
the precipitate LiCl and evaporation of the volatiles under reduced
pressure, the oily slightly pale yellow liquid was distilled to led
the pure product 3 as a colorless oil (4.88 g, 60%): bp 118-120
1
°C/1 mmHg; H NMR (200 MHz, CDCl3) δ 1.22 (t, J ) 7.1 Hz,
6H), 1.27 (s, 12H), 3.64 (dq, J ) 7.1, 9.5 Hz, 2H), 3.73 (dq, J )
7.1, 9.5 Hz, 2H), 5.29 (s, 1H); 13C NMR (50 MHz, CDCl3) δ 15.0,
24.5, 24.6, 61.1, 83.0, 84.5, 91.1, 96.4; HRMS (EI) calcd for
C13H23O4B m/z 254.1689, found 254.1691.
Experimental Section
(27) The hypothesis of a partial isomerization of (E)-5 to give (E)-6 due
to the presence of BF3‚OEt2 via a benzylic carbocation seems to be
unprobable because no corresponding epimerisation was detected with (Z)-
5.
(28) No attempts were conducted to examine this process in the presence
of other Lewis acids or in modifying the quantity of Lewis acid.
General Methods. For details, see the Supporting Information.
Synthesis of 2-[(1E)-3,3-Diethoxy-1-propenyl]-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane (1a). A 100 mL round-bottom flask
equipped with a septum inlet was charged with borane/dimethyl
sulfide complex (10 M, 2.1 mL, 21 mmol) and tetrahydrofuran
988 J. Org. Chem., Vol. 72, No. 3, 2007

(E)-R-Substituted γ-Alkoxyallylboronic Esters as New Reagents
Synthesis of 2-[(1Z)-3,3-Diethoxy-1-propenyl]-4,4,5,5-tetra-
methyl-1,3,2-dioxaborolane (1b). A 30 mL stainless steel glass-
coated autoclave was charged with a solution of 3 (3.81 g, 15 mmol)
in 1,4-dioxane (12 mL), Lindlar catalyst (156 mg, 0.15 mmol), and
quinoline (13 µL, 0.11 mmol). The autoclave was purged three times
with argon, followed by three times with hydrogen, and the final
pressure was adjusted to 20 bar. The mixture was then stirred at
room temperature for 2 h and filtered through Celite. The solvent
was removed, and the product 1b was isolated by Ku¨gelrohr
distillation as a colorless oil (3.6 g, 94%): bp 128-130 °C/1
127.8, 136.2, 136.8, 140.2, 140.5; HRMS (EI) calcd for C9H17O
m/z (M+ - C7H7O), 141.1279, found 141.1281. Anal. Calcd for
C16H24O2: C, 77.34; H, 9.74. Found: C, 77.51; H, 9.78.
General Procedure for the Tandem Reaction. Preparation
of (1S*,2R*)-2-Ethoxy-1-phenyloct-3-en-1-ol ((Z)-5a, (E)-5a) and
(1S*,2S*)-2-Ethoxy-1-phenyloct-3E-en-1-ol ((E)-6a). To a solu-
tion of 1a (256 mg, 1 mmol) in THF (4 mL) was added a solution
of n-BuLi (0.94 mL, 1.5 mmol, 1.6 M in hexane) at -78 °C under
an argon atmosphere. The mixture was stirred for 45 min at this
temperature before the slow addition of boron trifluoride etherate
(253 µL, 2 mmol). The mixture was then stirred for an additional
25 min at the same temperature. Benzaldehyde (200 µL, 2 mmol)
was then added, and the mixture was warmed at room temperature.
The reaction was monitored by TLC and allowed to stir until
complete consumption of 2a. The reaction was quenched by
addition of a saturated aqueous solution of sodium hydrogen
carbonate (2 mL) and extracted with dichloromethane (3 × 10 mL).
The organic layers were combined, washed with brine (10 mL),
and then dried over anhydrous MgSO4. Evaporation of the solvent
gave a residue that was purified by flash chromatography (heptane/
ethyl acetate 9:1) to give a mixture of compounds 5a and 6a (164
mg, 66% as an inseparable 44.5:54.5:1 mixture of (Z)-5a, (E)-5a,
and (E)-6a) as a colorless oil. The NMR and analytical data of
(Z)-5a and (E)-5a have been previously described. (E)-6a: 1H NMR
(200 MHz, CDCl3) δ 4.53 (d, J ) 7.8 Hz, 0.01H). The other peaks
were hidden by those of 5a.
1
mmHg; H NMR (200 MHz, CDCl3) δ 1.05 (t, J ) 7.0 Hz, 6H),
1.15 (s, 12H), 3.32-3.68 (m, 4H), 5.35 (d, J ) 7.6 Hz, 1H), 5.47
(d, J ) 13.9 Hz, 1H), 6.17 (dd, J ) 7.6, 13.9 Hz, 1H); 13C NMR
(50 MHz, CDCl3) δ 15.7, 25.2, 62.0, 83.8, 100.2, 121.2, 148.9;
HRMS (EI) calcd for C13H25O4B m/z 256.1840, found 256.1841.
General Procedure for the Allylboration Reactions under
Thermal Conditions. Preparation of (1S*,2R*)-2-Ethoxy-1-
phenyloct-3-en-1-ol ((Z)-5a, (E)-5a). A solution of 2a (268.2 mg,
1 mmol) and benzaldehyde (212.3 mg, 2 mmol) in 10 mL of THF
was stirred at room temperature under an argon atmosphere. The
reaction was monitored by TLC until complete consumption of 2a.
After addition of a saturated solution of NH4Cl, the aqueous layer
was extracted twice with CH2Cl2. Combined organic layers were
washed with saturated NaCl, dried over anhydrous MgSO4, filtered,
and concentrated under vacuum. The crude product was purified
by column chromatography (heptane/ethyl acetate, 9/1) to yield 5a
(186 mg, 75% as an inseparable 75:25 mixture of Z and E isomers)
as a colorless oil: 1H NMR (200 MHz, CDCl3) δ 0.81-0.92 (m,
3H), 1.10-1.26 (m, 7H), 1.62-2.05 (m, 2H), 2.72 (br s, 0.75H),
2.86 (br s, 0.25H), 3.42 (dq, J ) 7.1, 9.3 Hz, 1H), 3.63 (dq, J )
7.0, 9.3 Hz, 1H), 3.85 (dd, J ) 4.5, 7.8 Hz, 0.25H), 4.28 (ddd,
J ) 1.0, 4.3, 9.6 Hz, 0.75H), 4.84 (d, J ) 4.5 Hz, 0.25H), 4.87 (d,
J ) 4.3 Hz, 0.75 Hz), 5.33 (ddt, J ) 1.5, 9.6, 11.1 Hz, 1H), 5.65
(dt, J ) 7.3, 11.1 Hz, 1H), 7.30-7.38 (m, 5H) (the signals
corresponding of the double bond of the E-isomer, (E)-5a, are
hidden by those of the Z isomer, (Z)-5a); 13C NMR (50 MHz,
CDCl3) δ 13.8, 13.9, 15.1, 15.3, 22.0, 22.2, 27.4, 31.1, 31.5, 31.9,
63.8, 75.6, 75.7, 84.5, 88.6, 125.3, 125.6, 126.8, 127.1, 127.3, 127.7,
Acknowledgment. We thank the University of Rennes 1
and the CNRS for their financial support. F.P. and M.D. also
thank respectively the “Re´gion Bretagne et le Ministe`re de la
recherche” for a research fellowship.
Supporting Information Available: Experimental details,
synthetic procedures, and characterization data for all newly
synthesized compounds and 1H/13C NMR spectra of selected
compounds 1a,b, 2a,d,e, 3, 5a, 6a, 5c, 6c, and 5e. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0622330
J. Org. Chem, Vol. 72, No. 3, 2007 989