Preparation of Bifunctional Allylboron Reagent and Application to Aldehyde Allylboration

Article abstract of DOI:10.1021/acs.oprd.9b00168

Synthesis of a bifunctional allylboron reagent via Ni-catalyzed borylation of allylic acetate is reported. Subsequent allylation of aldehydes gave homoallylic alcohols in good yields. The allylsilane moiety in the alcohol product serves as a useful handle

Full text of DOI:10.1021/acs.oprd.9b00168

Communication
Cite This: Org. Process Res. Dev. XXXX, XXX, XXX−XXX
pubs.acs.org/OPRD
Preparation of Bifunctional Allylboron Reagent and Application to
Aldehyde Allylboration
Jiaming Liu, Shang Gao, and Ming Chen*
Department of Chemistry and Biochemistry, Auburn University, Auburn, Alabama 36849, United States
*
S Supporting Information
Scheme 2. Approaches to Homoallylic Alcohol 3 via
Bifunctional Allylation Reagents
ABSTRACT: Synthesis of a bifunctional allylboron
reagent via Ni-catalyzed borylation of allylic acetate is
reported. Subsequent allylation of aldehydes gave
homoallylic alcohols in good yields. The allylsilane moiety
in the alcohol product serves as a useful handle for
subsequent transformations.
KEYWORDS: bifunctional allylation reagent,
Ni-catalyzed allylic borylation, allylboronate,
homoallylic alcohol
llylic organometallics (I, Scheme 1) are useful bifunc-
tional allylation reagents in organic synthesis. The
1
,2
A
Scheme 1. Reaction of Aldehyde with Bifunctional
Allylation Reagent I
addition of reagent I to carbonyl compounds, aldehyde for
instance, produces homoallylic alcohols and simultaneously
unveils an allylmetal unit that is poised for a second allyl
addition event. However, complications may arise when the
chemical reactivities of two allylmetal units in reagent I are
similar to each other, and as a result, a mixture of products
organotin reagent B. The development of a nontoxic, air- and
moisture-stable reagent to address these disadvantages is
therefore valuable.
With our continuing interest in allylation chemistry, we set a
goal to develop a reagent to solve this problem. We chose
allylboronate 2 (Scheme 2) as the targeted reagent because it is
not toxic and, moreover, should be stable to air and moisture.
It is quite surprising that such a simple allylboronate reagent
has not been synthesized previously. We report herein the
preparation of this reagent via Ni-catalyzed borylation of the
commercially available allylic acetate 1 (eq 4, Scheme 2).
Reagent 2 readily reacts with aldehyde to give homoallylic
alcohol 3 that has an allylic silane moiety as a useful handle for
subsequent transformations.
(
e.g., II and III) can be generated. Therefore, when designing
such reagents, two allylmetal units often need to have
orthogonal reactivities to eliminate such complications.
Toward this end, several bifunctional allylation reagents I,
which meet such a requirement, have been developed. For
example, the allylstannane unit in reagent B [2-(trimethylsilyl-
methyl) allyltri-n-butylstannane] selectively reacted with
aldehydes to give homoallylic alcohols 3 in the presence of a
3
,4
Lewis acid (eq 1, Scheme 2). By taking advantage of the
different reactivities of allylboron and allylsilane toward
carbonyl addition, Williams and co-workers developed a5
bifunctional allylation reagent C from organotin reagent B.
The reaction of C with aldehydes produced the same alcohol
products 3 (eq 2, Scheme 2). More recently, 2-(trimethylsilyl-
methyl) allylborane reagent E was synthesized from the
We began our studies by developing the reaction conditions
for borylation of allylic acetate 1. The initial experiments were
7
conducted with CuCl as the catalyst for allylic borylation.
1
While the reaction did not occur in the absence of a ligand, H
allylselenium precursor D by the Kadota group (eq 3, Scheme
Special Issue: Honoring 25 Years of the Buchwald-Hartwig
Amination
6
2
). Addition of E to aldehydes also afforded alcohols 3.
However, these important achievements are not without any
drawback. Organoboron reagent E is known to be moisture
and oxygen sensitive, while preparation of reagent C requires
Received: April 23, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.9b00168
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
NMR spectroscopy indicated that allylic acetate 1 was fully
converted to reagent 2 with 5 mol % of Xantphos or dppbz as
the ligand in 24 h at ambient temperature. In addition, the
combination of Ni(cod) and PPh is also an effective catalytic
Scheme 3. Synthesis of Homoallylic Alcohols 3 via Allylic
Borylation and Aldehyde Allylation
,
a b
2
3
8
system to convert allylic acetate 1 to 2. However, although
reagent 2 is not moisture and oxygen sensitive, it is not stable
enough toward flash column chromatography purification.
Therefore, subsequent experiments were conducted to probe
whether the aldehyde allylation step can be carried out in a
one-pot manner. After full consumption of allylic acetate 1,
benzaldehyde was added to the same reaction vessel.
Gratifyingly, the allylation was complete in 30 min at ambient
temperature, and homoallylic alcohol 3a was generated from
the reaction. The reaction catalyzed by CuCl and Xantphos
gave product 3a in 83% yield. In the case of CuCl and dppbz,
3
a was isolated in a much lower yield. The reaction under the
Ni system provided homoallylic alcohol 3a in 73% yield (Table
). In the absence of B pin , however, the Ni-catalyzed
1
2
2
Table 1. Evaluation of the Reaction Conditions for Allylic
a
Borylation and Aldehyde Allylation Reaction Sequence
b
entry
catalyst
ligand
base
yield (3a) (%)
1
2
3
CuCl
CuCl
CuCl
Ni(cod)2
no ligand
Xantphos
dppbz
KOt-Bu
KOt-Bu
KOt-Bu
no base
NR
83
17
c
4
PPh3
73
a
Reaction conditions: allylic acetate 1 (0.15 mmol, 1.5 equiv), CuCl
10 mol %), ligand (10 mol %), KOt-Bu (0.18 mmol, 1.8 equiv),
(
B2pin2 (0.18 mmol, 1.8 equiv), THF (0.3 mL), rt, 24 h; then
b
benzaldehyde (0.1 mmol, 1.0 equiv), rt, 2 h. Yields of isolated
c
products are listed. Allylic acetate 1 (0.15 mmol, 1.5 equiv),
Ni(cod) (5 mol %), PPh (5 mol %), B pin (0.18 mmol, 1.8 equiv),
2
3
2
2
toluene (0.3 mL), 60 °C, 2 h; then benzaldehyde (0.1 mmol, 1.0
equiv), rt.
reaction did not produce any 3a. The Ni catalyst can be
removed by simply filtering the crude reaction mixture through
a short pad of Celite after completion of the reaction. The
obtained stock solution of reagent 2 can be stored at −20 °C
over 2 weeks with only minimal decomposition (<10%; please
see Supporting Information for details). By contrast, it was not
feasible to obtain a stock solution of reagent 2 in the cases of
Cu-catalyzed reactions. Therefore, we chose the catalytic
system of Ni(cod) and PPh to explore the scope of aldehyde
2
3
for this reaction.
The reaction conditions developed for the synthesis of 3a
were then applied to reactions with a variety of aldehydes, and
the results are summarized in Scheme 3. Allylation of aromatic
aldehydes bearing an electron-donating or electron-with-
drawing substituent at the para-position of the arene provided
products 3b−d in 77−92% yields. Halogen-substituted
aromatic aldehydes reacted to afford alcohols 3e−h in 79−
9
8% yields. Similar results were obtained with α,β-unsaturated
aldehydes, and alcohols 3i−k were formed in 67−82% yields.
Reactions with heteroaromatic aldehydes occurred smoothly to
furnish products 3l−n in 67−95% yields. Finally, aliphatic
aldehydes are also suitable reaction partners, and alcohols 3o−
r were obtained in 67−97% yields. It should be noted that the
allylsilane moiety in homoallylic alcohols 3 is sensitive to acidic
a
Allylic acetate 1 (0.15 mmol, 1.5 equiv), Ni(cod) (5 mol %), PPh
2
3
(5 mol %), B pin (0.18 mmol, 1.8 equiv), toluene (0.3 mL), 60 °C, 2
2 2
b
h; then aldehyde (0.1 mmol, 1.0 equiv), rt. Yields of isolated
products are listed.
B
DOI: 10.1021/acs.oprd.9b00168
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
conditions. For instance, homoallylic alcohols 3 were slowly
homoallylic alcohols 3 in good yields. The allylsilane unit
embedded in product 3 serves as a useful handle for additional
functional group transformations, as illustrated by diaster-
eoselective synthesis of cis-2,6-disubstituted tetrahydropyrans.
9
decomposed in deuterated chloroform. However, they are
6
8
perfectly stable in d -acteone or d -toluene.
cis-2,6-Disubstituted tetrahydropyran is a common scaffold
10
in numerous natural products (Figure 1). As many strategies
ASSOCIATED CONTENT
■
*
S
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.9b00168.
Experimental procedures, spectra for all new compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
E-mail: mzc0102@auburn.edu.
■
*
ORCID
Shang Gao: 0000-0001-8166-5503
Ming Chen: 0000-0002-9841-8274
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support provided by Auburn University is gratefully
acknowledged. We thank AllylChem for a generous gift of
B pin .
Figure 1. Selected cis-2,6-disubstituted tetrahydropyran-containing
natural products.
2
2
have been developed to construct such a structural entity,
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DOI: 10.1021/acs.oprd.9b00168
Org. Process Res. Dev. XXXX, XXX, XXX−XXX