Synthesis of tertiary allylboronates from vinylboronates

Article abstract of DOI:10.1055/s-0033-1340282

Allylic boronates are versatile intermediates in organic synthesis. Herein, we present an 'ate-mediated allylic substitution' (AMAS) approach to allylic boronates. Bifunctional vinylboroate/ allylic acetate esters react with Grignard reagents to form tertiary allylic boronates via an AMAS reaction. We demonstrate that the method tolerates a wide range of substrates and Grignard reagents. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340282

LETTER
▌239
lSetyternthesis of Tertiary Allylboronates from Vinylboronates
Synthesis of Tertiary Allylboronates
Brian A. Ondrusek,a Jin Kyoon Park,b D. Tyler McQuade*a
a
Florida State University, Department of Chemistry and Biochemistry, Tallahassee, Florida 32306-4390, USA
Fax +1(850)6648281; E-mail: mcquade@chem.fsu.edu
b
Department of Chemistry and Chemical Institute for Functional Materials, Pusan National University, Busan 609-735, Republic of Korea
Received: 02.09.2013; Accepted after revision: 14.10.2013
1,2-homologations
Abstract: Allylic boronates are versatile intermediates in organic
synthesis. Herein, we present an ‘ate-mediated allylic substitution’
(AMAS) approach to allylic boronates. Bifunctional vinylboroate/
allylic acetate esters react with Grignard reagents to form tertiary
allylic boronates via an AMAS reaction. We demonstrate that the
method tolerates a wide range of substrates and Grignard reagents.
n-BuLi, CH2Cl2
(pin)B
Matteson (1)
Aggarwal (2)
(pin)B
THF, –100 °C
i) s-BuLi, Et2O
OCb
B(pin)
B(pin)
ii)
Ph
Key words: boron, homogeneous catalysis, copper, organometallic
Ph
reactions, allylation
ate-mediated allylic substitutions (AMAS)
PhMgCl
Allylboronates are an interesting and useful subset of or-
ganoboron compounds1,2 because they are allylic alcohol
synthons and intermediates that can undergo allylbora-
tions or Suzuki reactions.3 While a number of strategies
exist to produce allylboronates, we hypothesized that
making them via an ‘ate-mediated allylic substitution’
(AMAS) would also facilitate C–C bond formation.4 Ate
complexes are most commonly encountered with homolo-
gation chemistry, which is well-known in the context of
secondary and tertiary alcohol synthesis,5,6 in most cases
by the 1,2-metalate rearrangement of a boron–ate com-
plex from an α-halo boronic ester. Much of the pioneering
work was reported by Matteson,7 which involved the
homologation of vinylboronate compounds using (halo-
methyl)lithium reagents (Scheme 1, eq. 1). More recently,
Aggarwal has shown that α-lithiation of carbamate deriv-
atives react with boronate esters to yield tertiary allylboro-
nates (Scheme 1, eq. 2).8
(pin)B
Cl
(pin)B
Lombardo (3)
Hall (4)
THF
Ph
EtMgBr
CuTC, ligand
O
B
O
B
Cl
O
CH2Cl2, –78 °C
O
Et
R21B
LG
R2B
3
Nu
2
4
this work (5)
R
Nu
R
Scheme 1 Previously reported methods for the synthesis of allylbo-
ronates, as well as the method presented in this work
borylation of internal alkynes.11 We have recently report-
ed an efficient method for the regioselective borylation of
internal propargylic alcohols using an N-heterocyclic car-
bene copper(I) chloride catalyst (5-NHC),12 which is eas-
ily synthesized by the combination of substituted or
unsubstituted terminal alkynes and aldehydes (Scheme 2).
Yet another route toward these useful compounds is the
allylic substitution of vinylboronates.9 As with previous
examples, this route involves first the formation of a
boron–ate complex via an incoming nucleophile. Subse-
quently, however, this method displaces a leaving group,
via an SN2′ mechanism. The Lombardo group investigated
this route, especially the conditions under which a 1,3-
borotropic shift could be expected en route toward the
synthesis of anti-homoallylic alcohols (Scheme 1, eq. 3).
The Hoffmann and Hall groups have also made contribu-
tions using enantioentriched homoallylic alcohols
(Scheme 1, eq. 4).10 In most cases this process involves
the displacement of a halide from a vinylboronate pre-
pared by hydroboration of a propargyl chloride.
These substrates are obtained easily and in high yields.
Additionally, protection of the resulting allylic alcohol as
an acetate was required for isolation of the compound,
thus making the starting materials for the homologation
process versatile. We report that upon treatment with a va-
riety of organomagnesium nucleophiles one can obtain
highly functionalized tertiary allylboronates quickly and
in high yields.
In addition, the allylboronates made by this process are
benchtop-stable and exclusively the (E)-allylboronate is
obtained, with no evidence of products resulting from a
1,3-borotropic shift, which agrees with previous observa-
tions involving pinacol-based allylboronates.9a
This work seeks to improve upon existing methods by tak-
ing advantage of recent improvements in the selective
We began developing this method by treating vinylboro-
nate 1 with both weak and strong nucleophiles. Table 1
features the outcome of our screening experiments. Both
organolithium and organomagnesium species reacted
SYNLETT 2014, 25, 0239–0242
Advanced online publication: 04.12.2013
DOI: 10.1055/s-0033-1340282; Art ID: ST-2013-R0845-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

240
B. A. Ondrusek et al.
LETTER
AcO
the desired homologated product was produced [>95%
conversion (1H NMR); PhMgBr as the nucleophile]. Con-
centration of the crude filtrate and immediate column
chromatography provided the desired product in high
yield without evidence of byproducts. The use of phenyl-
lithium yielded a mixture of products regardless of how
the reaction was worked up. Noncarbon nucleophiles in-
cluding sodium alkoxides and sodium cyanide did not re-
sult in any observable reaction.
1) n-BuLi
2) 5-NHC-CuCl, B2(pin)2
O
R1
R2
R1
+
H
R2
3) Ac2O, DMAP
(pin)B
R3MgX
R3 can be alkyl or aryl,
and is easily introduced
as a Grignard
R1
R3
R2
exclusively E-allylboronate
With optimal conditions in hand, we then sought to exam-
ine the scope of the reaction. As shown in Table 2, many
Grignard reagents provided good to excellent yields. We
observed that both aryl and alkyl Grignards were success-
ful. Of particular interest are entries 2, as well as entries
8–10 (Table 2), where we demonstrate that congested nu-
cleophiles are well tolerated. These data indicate that this
method will be useful in producing bulky tertiary alcohols
after oxidation of the C–B bond.14
B(pin)
N
no 1,3-borotropic
shift is observed
N
5-NHC-CuCl =
CuCl
Scheme 2 Preparation of tertiary allylboronates from easily accessi-
ble vinylboronates
Table 2 Scope of Tertiary Allylboronate Preparation from Vinyl-
with 1 (Table 1, entries 1–5). We found that the workup
for the reaction was critical to obtain high yields. Aqueous
quenching resulted in a complex mixture of several prod-
ucts as determined by NMR spectroscopy. Careful analy-
sis of the complex mixtures suggested that the presence of
hydroxide and acetate salts resulted in formation of trisub-
stituted olefin via protodeboronation,13 as well as several
other unidentified reaction products. When purified allyl-
boronate was combined with LiOH and water protode-
boronation was observed to occur, supporting our
hypothesis.
boronates Using Grignard Reagentsa
AcO
RMgX
Et2O
0 °C to r.t., 15 min
R
(pin)B
B(pin)
1
2
Entry
Product
R
X
Yield (%)b
1
2
2a
2b
2c
2d
2e
2f
Ph
Br
Br
Br
Br
Cl
Cl
Cl
Br
Br
Cl
Br
93
97
94
81
98
76
68
86
89
71
88
2-MeOC6H4
thienyl
vinyl
Me
Table 1 Optimization Studies
3
AcO
Nu
4
THF, 0 °C to r.t.
Nu
5
(pin)B
B(pin)
6
s-Bu
Bn
1
Entry
Nucleophile
Quench reagent
Resultsa,c
7
2g
2h
2i
8
c-Pr
1
2
3
4
5
6
7
8
PhLi
NH4Cl
NH4Cl
H2O
mixture
mixture
mixture
mixture
full conv.
n.r.
9
i-Pr
PhMgBr
PhMgBr
PhMgBr
PhMgBr
NaOMe
NaOt-Bu
NaCN
10
11
2j
i-Pr
2k
n-Pr
HCl
a Reaction carried out with 1.5 equiv RMgX, at a concentration of
noneb
noneb
noneb
noneb
0.2 M in Et2O.
b Isolated yield.
n.r.
Comparison of organomagnesium bromides and chlorides
revealed that the bromides provide improved yields (Ta-
ble 2, entries 9 and 10). The origin of this counterion ef-
fect is unclear and may reflect chemoselective preferences
for 1,2-addition to the acetate versus AMAS. We are still
studying the system and will provide more insight in due
course. Another interesting feature is the double-bond ge-
ometry of the products. In all cases, we observed solely
the E-configured products as determined from coupling
constants (15–16 Hz; 1H NMR spectra). The origin of this
n.r.
a Reaction results obtained by analysis of the 1H NMR of crude reac-
tion mixture.
b Reaction was quenched by filtering through a pad of silica gel.
c n.r. = no reaction.
We found that if instead of performing an aqueous quench
the reaction was simply filtered through a pad of silica gel
Synlett 2014, 25, 239–242
© Georg Thieme Verlag Stuttgart · New York

LETTER
Synthesis of Tertiary Allylboronates
241
PhMgBr
OTBS
Et2O, 0 °C
B(pin)
AcO
6a 91%
OTBS
(pin)B
3
OTBS
2-MeOC6H4MgBr
Et2O, 0 °C
B(pin)
OMe
6b 91%
AcO
PhMgBr
Et2O, 0 °C
B(pin)
(pin)B
4
7 73%
PhMgBr
OAc
Et2O, 0 °C
B(pin)
(pin)B
5
8 69 %
Scheme 3 Representative vinylboronates
Typical Experimental Procedure for the Ate-Mediated Allylic
Substitution of Vinylboronates
E-selectivity is most likely the necessary antiperiplanar
geometry of the leaving group relative to the carbon nu-
cleophile being transferred.15
A flame-dried and nitrogen-purged Schlenk tube was equipped with
a stir bar and sealed with a rubber septum. Vinylboronate (1 equiv)
in dry Et2O (0.2 M) was charged to the reaction vessel, and the sides
of the reaction vessel were washed with additional Et2O. This reac-
tion mixture was cooled to 0 °C in an ice-water bath before slowly
adding the desired Grignard reagent (1.5 equiv), after which the re-
action vessel was stirred for 15–30 min while warming to r.t. After
the reaction was complete by TLC, the reaction mixture was filtered
through a pad of silica, and the filtrate was concentrated. Flash chro-
matography of the crude product (100% hexanes or 40:1 hexanes–
EtOAc) yielded the desired tertiary allylboronates.
Once we established that a wide range of Grignard re-
agents could be added to our test vinylboronate 1, we sur-
veyed the addition of Grignard reagents to a few
vinylboronates (Scheme 3). Good to excellent yields were
obtained for all substrates tested, and again only the E-iso-
mers were observed. Substrate 3 demonstrates that pro-
tected alcohols do not negatively impact the reaction
indicating that the Grignard cannot eliminate the OTBS
group under these conditions. Substrate 4 illustrates that
modestly acidic protons such as benzylic/allylic protons
are well tolerated. Finally, substrate 5 demonstrates that
terminal double bonds are easily formed under these con-
ditions. While this substrate scope is not exhaustive, it
suggests strongly that this approach can be applied to a
range of vinylboronate substrates.
Acknowledgment
The authors thank NSF (CHE-1152020) and FSU for financial sup-
port.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnuIpofoiprmntgirStanoIuifpog
r
t
iornat
Allylboronates are extremely versatile substrates and in
recent years they have proven to be useful to synthetic
chemists searching for simple ways to create highly func-
tionalized small molecules en route to more complex syn-
thetic targets. With this method, we have demonstrated
that these compounds can be synthesized quite easily from
vinylboronates for which many synthetic methods are
available. Continuing research in this area is focused on
expanding the utility of this method, as well as the use of
these allylboronates toward the synthesis of complex nat-
ural products, and results will be provided in due course.
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Supporting Information.
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