Transition-metal-free synthesis of pinacol alkylboronates from tosylhydrazones

Article abstract of DOI:10.1002/anie.201108139

Highly efficient: Pinacol alkylboronates were synthesized by the reaction of tosylhydrazones with bis(pinacolato)diboron or pinacolborane under transition-metal-free conditions. This reaction represents an expeditious conversion of carbonyl functionality into a boronate group. Copyright

Full text of DOI:10.1002/anie.201108139

Angewandte
Chemie
DOI: 10.1002/anie.201108139
Metal-Free Borylation
Transition-Metal-Free Synthesis of Pinacol Alkylboronates from
Tosylhydrazones**
Huan Li, Long Wang, Yan Zhang, and Jianbo Wang*
Organoboron compounds are highly important synthetic
intermediates in transition-metal-catalyzed cross-coupling
reactions[1] and other functional-group transformations.[2] In
this context, arylboron compounds have been extensively
used in organic synthesis, and the corresponding alkylboron
compounds are also useful building blocks. In recent years
great progress has been made in the Suzuki–Miyaura cross-
À
À
Scheme 1. Metal-free C C bond and C B bond formations. pin=pina-
colato, Ts=p-toluenesulfonyl.
coupling reactions involving alkylboron compounds.[1b,h,3,4]
In general, alkylboron compounds can be accessed by four
different methods: 1) nucleophilic reaction by Grignard[5] or
organolithium reagents[6] with suitable boron compounds,
such as BX3 (X = Cl, F) or B(OR)3; 2) hydroboration of
acid, and the 1,2-migration of the aryl or alkyl substituent
from boron to carbon. We have also previously reported the
metal-free arylation of a-diazocarbonyl compounds with
boroxins.[15b] Encouraged by these transformations, we con-
ceived that a transition-metal-free carbon–boron bond-form-
ing reaction may be possible with a similar reaction system.
Research along this line led to the development of a highly
efficient transition-metal-free borylation of tosylhydrazones,
a method which represents novel access to alkylboron
compounds (Scheme 1b).
At the outset, bis(pinacolato)diboron (B2pin2) was used as
a borylating agent and to our delight, the reaction with the
tosylhydrazone derived from benzaldehyde in the presence of
LiOtBu in toluene afforded the expected borylation product
1a in 21% yield (Table 1, entry 1). We then optimized the
reaction conditions by examining the effect of the base and
alkenes;[3,7,8] 3) Miyaura borylation;[9–11] 4) transition-metal-
[12,13]
À
catalyzed borylation of alkanes by C H bond activation.
These powerful methods for the preparation of alkylboron
compounds have been widely practiced in modern organic
synthesis. However, a common requirement is that metals,
either as catalysts or in stoichiometric amounts, have to be
used. This can make these preparative methods environ-
mentally unfriendly and less cost effective. Moreover, heavy
metals may contaminate the final boron products, a problem
which is frequently encountered in the manufacturing pro-
cess.[14]
Recently, significant progress has been made in the
[15]
À
development of metal-free transformations to form C C,
[16]
[17]
[18]
[19]
À
À
C N,
À
C S,
À
C O,
and C B
bonds. Among the
various metal-free transformations that have appeared in
the recent literature, we were particularly attracted by the
metal-free carbon–carbon bond formation between boronic
acids and tosylhydrazones reported by Barluenga and co-
workers (Scheme 1a).[15a] This remarkable transformation
successfully utilizes the combination of three consecutive
steps: the in situ generation a of nonstabilized diazo com-
pound, the coordination of the diazo compound to a boronic
Table 1: Optimization of the reaction of tosylhydrazone with B2pin2.[a]
Entry
Base
Additive
Solvent
T [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
LiOtBu
NaOtBu
NaOEt
NaOMe
NaOH
K2CO3
–
–
–
–
–
–
–
Toluene
Toluene
Toluene
Toluene
Dioxane
Dioxane
Dioxane
Toluene
Dioxane
Toluene
Dioxane
DCE
90
90
90
90
90
90
90
90
90
90
90
90
70
90
21
16
48
43
46
16
30
54
49
63
56
54
39
20
[*] H. Li, L. Wang, Dr. Y. Zhang, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of Ministry of Education, College of Chemistry
Peking University, Beijing 100871 (China)
CsF
E-mail: wangjb@pku.edu.cn
NaOEt
NaOH
NaOMe
NaOMe
NaOMe
NaOMe
NaOMe
EtOH
H2O
MeOH
MeOH
MeOH
MeOH
MeOH
9
Prof. Dr. J. Wang
10
11
12
13
14
The State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
354 Fenglin Lu, Shanghai 200032 (China)
THF
MeCN
[**] The project is supported by National Basic Research Program of
China (973 Program, No. 2012CB821600), Natural Science Foun-
dation of China (Grant No. 21072009, 20902005, 20832002,
20821062).
[a] Reaction conditions: tosylhydrazone (0.5 mmol), B2pin2 (0.6 mmol),
base (1 mmol), additive (1 mmol), solvent (2 mL), 1–12 h. [b] Deter-
mined by GC with dodecane as internal standard. DCE=1,2-dichloro-
ethane.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201108139.
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found that EtONa, NaOMe, and NaOH could give better
results than other bases (Table 1, entries 1–7). In view that the
protonation process is essential for the reaction, we then
introduced two equivalents of an alcohol or H2O, as a proton
source, to the reaction (Table 1, entries 8–11). The yield of 2a
was indeed slightly improved, with MeOH affording the
optimal result. The solvent also affects the reaction and
toluene was found to give the best yield.
borylating agent, as it is less sterically demanding. HBpin is
also a commonly used borylation reagent and it is much
cheaper than B2pin2.
After some initial experiments, we concluded that
a sodium tosylhydrazone salt was better suited for the
borylation with HBpin (Table 2). When a mixture of the
Table 2: Optimization of the reaction of tosylhydrazone salt with
With the optimized reaction conditions (Table 1, entry 10)
in hand, the substrate scope was investigated (Scheme 2). A
series of tosylhydrazones conjugated with aromatic systems
HBpin.[a]
Entry
Solvent
PTC
t [h]
Yield [%][b]
1
2
3
4
5
6
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
–
48
6
16
3
2
3
36
60
53
50
63
74
TBAB
TBAC
15-crown-5
BTEAC
BTMAC
[a] Reaction conditions: tosylhydrazone salt (0.5 mmol), HBpin
(0.75 mmol), PTC (0.05 mmol), toluene (1 mL), 908C. [b] Determined by
GC with dodecane as internal standard. TBAB=tetrabutylammonium
bromide, TBAC=tetrabutylammonium chloride, BTEAC=benzyl-
triethylammonium chloride.
tosylhydrazone salt and HBpin was heated at 908C for
48 hours, 36% yield of the borylation product 4a was
obtained (Table 2, entry 1). In view of the fact that phase-
transfer catalysts (PTC) can facilitate the dissolution and
subsequent conversion of the tosylhydrazone salt into the
corresponding diazo compound,[20] several typical PTC were
tested in the reaction. Benzyltrimethyl ammonium chloride
(BTMAC), a commercially available and cheap PTC, was
found to be the best one for the reaction (Table 2, entry 6).
The optimized reaction conditions (Table 2, entry 6) could
be further simplified by generating the tosylhydrazone salts
in situ. To our delight, in the case of 4a, a slightly higher yield
could be obtained with the in situ tosylhydrazone salt
preparation procedure.
A series of tosylhydrazones were then examined under
the optimized reaction conditions (Scheme 3). This borylation
procedure worked well with a variety of tosylhydrazones
derived from ketones and aldehydes (Scheme 3, types A–D).
For the type A substrates, moderate to high yields of
borylation products could be obtained, no matter whether the
substituents on the aromatic ring are electron-donating
groups (Scheme 3, 4b, c, j, l) or electron-withdrawing
groups (Scheme 3, 4d–h, i, k). It is noteworthy that the
cyclopropyl group remains intact in the reaction (Scheme 3,
4m). This fact suggests that a free carbene species is not
involved in the reaction mechanism, because a carbene
adjacent to a cyclopropyl group would undergo a ring-
expansion rearrangement or the carbene may be protonat-
ed.[21] For type B substrates, the borylation with tosylhydra-
zones derived from aliphatic aldehydes proceeded well.
Compared with the reaction shown in Scheme 2 (type C),
the yield for 3b is now significantly improved. The borylation
Scheme 2. Reaction of tosylhydrazone with B2pin2. Reaction condi-
tions: tosylhydrazone (0.5 mmol), B2pin2 (0.6 mmol), NaOMe
(1 mmol), MeOH (1 mmol), toluene (2 mL), 908C, 3–12 h. Yields were
determined by GC with dodecane as internal standard. [a] Yields were
determined by H NMR spectroscopy with 1,1,2,2-tetrachloroethane as
internal standard. [b] The reactions were carried out at 1108C.
1
could be converted into the corresponding benzylboronates
(Scheme 2, type A). As expected, halides are compatible with
the transition-metal-free reactions (1e–g, j). It is noteworthy
that a boron group is also compatible with the reaction
conditions (1h). With a tosylhydrazone derived from a a,b-
unsaturated aldehyde, the reaction afforded moderate yield
(Scheme 2, type B). For the alkyl-substituted tosylhydra-
zones, the reaction needed a higher temperature and only
gave low to moderate yields (Scheme 2, type C).
However, when tosylhydrazones derived from ketones
were used as reactants, only a trace amount of the desired
borylation products could be detected, even with an elevated
reaction temperature or prolonged reaction time. Moreover,
it was noticed that for the tosylhydrazone with a secondary
alkyl substituent the corresponding borylation only afforded
a very low yield (Scheme 2, 3b). These observations led us to
hypothesize that the diminished reactivity might be due to
steric hindrance between the tosylhydrazone substrate and
the diboron reagent. To circumvent such a problem, we
conceived that pinacolborane (HBpin) might be a suitable
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Scheme 4. Mechanistic rationale.
To verify the mechanistic hypothesis, we carried out an
experiment to isolate the 1,1-diboron intermediate
(Scheme 5). Thus, tosylhydrazone salt 14 was prepared
separately, and was then reacted with B2pin2 at 1108C. The
1,1-diboron compound 15 was detected as the only product by
GC-MS, and it was isolated in 73% yield. A parallel reaction,
in which NaOMe and MeOH were added after 15 was
formed, was then carried out. The corresponding product 3a
was obtained in 26% yield, together with recovery of 26% of
15. A control experiment showed that the base was essential
for the protodeboronation step, because 3a was not formed
when only MeOH was added. The same experiment was
carried out with tosylhydrazone salt 16 and similar results
were obtained.
Scheme 3. Reaction of tosylhydrazone salt with HBpin. Reaction con-
ditions: tosylhydrazone (1 mmol), NaOMe (1 mmol), BTMAC
(0.1 mmol), HBpin (3 mmol), toluene (8 mL), 908C, 1–24 h. The yields
were determined by GC with dodecane as internal standard, and those
in the brackets are yields of the isolated products, purified by silica gel
column chromatography. [a] No BTMAC was added. [b] The reactions
were carried out at 1108C for 12 h. [c] The reactions were carried out
at 1108C for 24 h. [d] Isolated as the corresponding alcohol and the
ratio of cis to trans was based on the analysis of the crude product by
1H NMR spectroscopy (400 MHz).
Scheme 5. Isolation and reaction of 1,1-diboron intermediates.
It is noteworthy that in Scheme 3, the thermodynamically
less-favorable cis isomer 5d is formed as the major borylation
product. The stereoselectivity of boron product 5d can be
interpreted according to the proposed reaction mechanism.[24]
In summary, we have developed a metal-free reaction to
convert tosylhydrazones into pinacol boronates. Both B2pin2
and HBpin can be used as the borylation reagents. The
reaction has wide substrate scope and can be applied to the
synthesis of benzyl-, alkyl-, and allylboronates. Since tosyl-
hydrazones can be easily prepared from aldehydes or ketones,
this novel approach is expected to find wide applications for
the synthesis of boron compounds. Finally, this reaction
represents another important synthetic application of tosyl-
hydrazones, which have recently attracted great attention in
also works well with tosylhydrazones derived from aliphatic
ketones (Scheme 3, type C) and those derived from aromatic
ketones (Scheme 3, type D).
The proposed reaction mechanism for this borylation
reaction is shown in Scheme 4. First, diazo compound 8 is
generated in situ from tosylhydrazone in the presence of base.
The nucleophilic diazo carbon then coordinates to the B2pin2
or HBpin to form boronate intermediate 10 or 13. From
intermediate 10, 1,2-boron migration occurs to form 1,1-
diboron intermediate 11,[22,23] which is further converted into
product 12 after protodeboronation of one boronate group.
From intermediate 13, 1,2-H migration occurs to give the
borylation product 12 directly.
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2945

.
Angewandte
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Received: November 21, 2011
Published online: February 10, 2012
Keywords: boron · diazo compounds · pinacol boronates ·
.
synthetic methods · tosylhydrazone
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