Synthesis of Asymmetrical-Terminally Bifunctionlized Alkanes by Sequential Suzuki–Miyaura Coupling Using B-Thexylboracyclanes

Article abstract of DOI:10.1002/ejoc.201600392

A one-pot, sequential Suzuki–Miyaura coupling (SMC) using B-thexylboracyclanes is reported. We focused on a boracyclane with a bulky B-substituent as an equivalent of a terminal heterobibora-functionalized spacer. The first SMC of the boracyclane proceeded by endocyclic B–C bond cleavage due to the steric hindrance of the exocyclic B-substituent to provide borinic acids. These subsequently underwent the second SMC under harsher conditions by transfer of the less hindered primary alkyl group to provide the asymmetrically bifunctionalized alkyl chain. The seven- to five-membered boracyclanes were adaptable to the sequential SMC reactions to provide terminally bifunctional alkanes, although the efficiency of the transformation of the five-membered boracyclane was poorer than those of the others. To demonstrate the utility of the method, we successfully prepared several terminally heterobifunctional hexanes in a one-pot reaction.

Full text of DOI:10.1002/ejoc.201600392

DOI: 10.1002/ejoc.201600392
Communication
One-Pot Reactions
Synthesis of Asymmetrical-Terminally Bifunctionlized Alkanes
by Sequential Suzuki–Miyaura Coupling Using B-Thexyl-
boracyclanes
Ryota Suzuki,[a] Shinichiro Fuse,[a][‡] and and Hiroshi Tanaka*[a]
Abstract: A one-pot, sequential Suzuki–Miyaura coupling dered primary alkyl group to provide the asymmetrically bifunc-
(SMC) using B-thexylboracyclanes is reported. We focused on a tionalized alkyl chain. The seven- to five-membered boracyc-
boracyclane with a bulky B-substituent as an equivalent of a lanes were adaptable to the sequential SMC reactions to pro-
terminal heterobibora-functionalized spacer. The first SMC of vide terminally bifunctional alkanes, although the efficiency of
the boracyclane proceeded by endocyclic B–C bond cleavage the transformation of the five-membered boracyclane was
due to the steric hindrance of the exocyclic B-substituent to poorer than those of the others. To demonstrate the utility of
provide borinic acids. These subsequently underwent the sec- the method, we successfully prepared several terminally hetero-
ond SMC under harsher conditions by transfer of the less hin- bifunctional hexanes in a one-pot reaction.
Introduction
alkanes allow one to connect two building blocks through alkyl
spacers of various lengths using different conditions. The alkyl
spacer possessing a boronic acid derivative and a dialkylboryl
group can be prepared by hydroboration of an alkenyl-contain-
ing stable boronic acid derivative with dialkylboranes.[6,7] Mo-
lander and co-workers have demonstrated a one-pot hydrobor-
ation and bidirectional SMC of alkenyl-containing organotri-
fluoroborates.[6]
Suzuki–Miyaura cross-coupling (SMC) using organoboron com-
pounds as coupling partners is the most widely applied exam-
ple of transition-metal-catalyzed, carbon–carbon, bond-forming
reactions due to not only their wide functional-group compati-
bilities, but also low toxicity of the reagents.[1] In addition, the
method allows one to transfer alkyl groups to organopalladium
compounds as well as alkenyl and aryl groups.[2,3] Tandem B-
alkyl SMC using alkyl spacers possessing boron functional
groups at each terminal is an effective way for the assembly of
small molecules composed of two different functional groups
through a flexible alkyl spacer. A success of the approach
should depend on the design of the spacers possessing the
reactivity-differentiated boron functional groups; 1,1- or 1,2-di-
boron compounds undergo SMC to selectively provide mono-
boron compounds due to a geminal/vicinal diboron self-activa-
tion.[4] Shibata and co-workers recently reported that 1,1-
bis(pinacolboryl) compounds underwent tandem SMC with dif-
ferent aryl halides to selectively provide diarylmethylene com-
pounds in a one-pot reaction.[5] However, the methodologies
only cover the connection of two building blocks through C1
and C2 spacers. On the other hand, unsymmetrical diboroyl-
Results and Discussion
In this report, we focused on dialkylborinic acids, which are less
reactive than the trialkylboryl group, but retain the potency to
undergo transmetalation.[8–10] We first imagined that the alk-
anes 1 possessing a dialkylboryl group and a boric acid at dif-
ferent terminals would chemoselectively undergo SMC with 2
to provide the borinic acid 3 (Scheme 1). The borinic acid 3
would undergo further SMC with 4 under harsher conditions to
provide the asymmetrically bifunctionalized alkyl compound 5.
However, they would be difficult to prepare by the same proce-
dure for the synthesis of the boronic acid derivatives due to the
instability of both the boron functional groups. We next ex-
pected that boracyclane 6 with a bulky B-substituent would
become an equivalent of the asymmetrially functionalized alk-
ane 1. The first SMC of boracyclanes 6 with 2 would proceed
to provide the borinic acids 3 by endocyclic B–C bond cleavage
since the reactivity depends less on the endocyclic fashion of
coupling but rather on the coupling of a CH2 derivative com-
pared to a tertiary alkyl derivative. The borinic acids subse-
quently undergo the second SMC with 4 by transfer of the less-
hindered primary alkyl group to provide the asymmetrically bi-
functionalized alkyl compound 5. The seven- to five-membered
boracylcanes 6A–C were known to be prepared by tandem
[a] Department of Applied Chemistry, Graduate School of Science and
Engineering
Tokyo Institute of Technology
2-12-1-H101 Ookayama, Meguro Tokyo 152-8552
E-mail: thiroshi@apc.titech.ac.jp
http://www.apc.titech.ac.jp/%7Ehtanaka
[‡] Present address: Laboratory for Chemistry and Life Science, Institute of
Innovative Research, Tokyo Institute of Technology, 4259 Nagatsuta-cho,
Midori-ku, Yokohama 226-8503, Japan
E-mail: sfuse@res.titech.ac.jp
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600392.
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Communication
hydroboration of the corresponding dienes and boron com-
pounds.[11] Brown and co-workers have investigated reactions
of the boracyclanes.[12] However, no application of the reagents
to SMC has been reported. Herein, we report on the synthesis
of asymmetrically bifunctionalized alkyl chains from bora-
cyclanes by a one-pot, tandem Suzuki–Miyaura coupling.
Table 1. One-pot, sequential Suzuki–Miyaura coupling using the cyclic borane
6.
Entry
7
Temperature
[°C]
Time
[h]
Yield of 9
Yield of 10
[%][a]
[%][a]
1
2
3
4
5
7a
7a
7b
7b
7c
0
1.0
1.0
1.0
1.0
24
97
5
98
–
–
86
–
95
–
80
r.t.
80
80
5
[a] The yields of 9 and 10 were determined by 1H NMR spectroscopy of the
crude material based on standard samples.
Scheme 1. One-pot, sequential Suzuki–Miyaura coupling from 1.
membered boracyclanes 6B[10] and 6C[11] prepared from 1,4-
pentadiene and 1,3-butadine, respectively. Boracyclanes 6B and
6C were treated with 11a and 11b under the same reaction
conditions. Borinane 6B was converted into diarylpentane 13ab
in 92 % yield. However, the reaction of borolane 6C provided
diarylbutane 14ab in only 30 % yield. LC-MS analysis of the
reaction mixture indicated that acetophenone (15) was in-
volved in the reaction mixture. These results suggested that
the generated organopalladium complex 16 would undergo ꢀ-
hydride elimination to provide the hydride complex 17 instead
of the desired boronic acid (Scheme 2). The hydride complex
17 would readily undergo reductive elimination to provide 15.
Finally, the synthesis of various 1,6-disubstituted hexanes from
borepane 6 and bromides 13 was examined (Table 2). All aryl
bromides 11a–g were adaptable to the method and provided
the desired 1,6-diarylhexanes 12 in good isolated yields (70–
We first examined the Suzuki–Miyaura coupling of aryl halide
7 with B-thexylborepane (6A), which was prepared from thexyl-
borane and 1,5-hexadiene according to a reported method[12]
(Table 1). Treatment of borepane 6A with 2.5 equiv. of phenyl
iodide (7a) in the presence of PdCl2(dppf) at 0 °C for 1.0 h,
followed by the addition of hydrogen peroxide and aqueous
KOH selectively provided alcohol 9 in 97 % yield. The yield was
1
estimated by H NMR analysis of the crude material based on
hexamethylbenzene as an internal standard. The reaction of
borepane 6A with bromide 7b at room temperature provided
alcohol 9 in 98 % yield. These results indicated that borepane
6A underwent transmetalation in an endocyclic cleavage man-
ner. In addition, the difference in the reactivity of borepane 6A
and the resultant borinic acid 8 towards transmetalation was
sufficient to selectively prepare borinic acid 8. We next exam-
ined a sequential SMC reaction from borepane 6A to 1,6-di-
phenylhexane (10). Treatment of borepane 6A with 2.5 equiv.
of iodide 7a in the presence of PdCl2(dppf) at 80 °C for 1.0 h
provided 1,6-diphenylhexane (10) in 86 % yield accompanied
by alcohol 9 in 5 % yield. On the other hand, bromide 7b was
converted into hexane 10 in 95 % yield under the same reac-
tion conditions. On the other hand, the reaction of phenyl
chloride (7c) at 80 °C for 24 h provided the diphenylhexane 9
in 5 % yield. Based on the results, we concluded that aryl
bromides were suitable building blocks for the sequential one-
pot coupling reactions.
We next examined sequential coupling reactions of bore-
pane 6A with two different aryl bromides (Table 2). Treatment
of borepane 6A with aryl bromide 11a in the presence of a
palladium catalyst at room temperature for 1.0 h, followed by
the addition of 2-naphthyl bromide (11b) at 80 °C for 3.0 h
provided diarylhexane 12ab in 89 % isolated yield. Next, we
examined a sequential coupling reaction of the six- and five-
Scheme 2. Proposed mechanism of a side-reaction of the boracyclane 6C.
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Table 2. Synthesis of asymmetrically terminal-bifunctionalized alkanes 12–14.
Entry
Substrate
First fragment
Second fragment
Product
Isolated yield [%]
1
2
3
4
5
6
7
8
9
6A
6B
6C
6A
6A
6A
6A
6A
6A
6A
6A
6A
11a
11a
11a
11a
11a
11a
11a
11a
11c
11d
11e
11h
11b
11b
11b
11d
11e
11f
11g
11i
11b
11b
11b
11b
12ab
13ab
14ab
12ad
12ae
12af
12ag
12ai
12bc
12bd
12be
12bh
89
92
30
87
86
85
92
62
72
91
83
85
10
11
12
3.0
M solution in water) at 0 °C. After vigorous stirring at room
90 % yield). Vinyl bromide (11i) was used as the second frag-
ment to provide 9-arylnon-2-ene (12ai) in a moderate yield.
temperature for 1 h, 11b (155 mg, 0.750 mmol) was added to the
mixture, and then the tube was sealed. The mixture was stirred
vigorously at 80 °C for 3 h. The mixture was cooled to room temper-
ature, and the residual borane was oxidized with an aqueous solu-
Conclusions
tion of KOH (0.5 mL, 3
M solution)/H2O2 (0.5 mL, 30 % solution) for
1 h. The aqueous layer was extracted with CH2Cl2, and the com-
bined organic layers were washed with brine, dried (MgSO4), con-
centrated, and purified by flash column chromatography to give
12ab (143 mg, 0.433 mol, 89 %).
We described the synthesis of asymmetrically terminal-bifunc-
tionlized alkanes from the B-thexylboracyclanes 6A–C by se-
quential SMC. Boracyclanes 6A–C underwent SMC to selectively
provide terminally functionalized borinic acids. They exhibited
reduced reactivity towards transmetalation in comparison with
B-thexylboracyclanes 6A–C but still reacted with organopalla-
dium under harsher conditions. This method would be effective
for the synthesis of drug-like compounds as well as chemical
probes by conjugating bioactive compounds due to the high
reactivity and wide functional-group compatibility of the cou-
pling reactions.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search on Innovative Areas (No. 26102720).
Keywords: Cyclic compounds · One-pot reactions · Cross-
coupling · Alkanes
Experimental Section
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Received: March 30, 2016
Published Online: June 27, 2016
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim