The second-generation synthesis of BICMAP analogues

Article abstract of DOI:10.1016/j.tet.2018.05.062

We previously reported the synthesis of BICMAP (1a) via 6-diphenylphosphino-2,3-dihydrobenzofuran as a key intermediate. However, we did not successfully synthesize BICMAP analogues via a similar synthetic route. Herein we report the second-generation syn

Full text of DOI:10.1016/j.tet.2018.05.062

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The second-generation synthesis of BICMAP analogues
Takashi Mino, Kohei Watanabe, Takumu Akiyama, Yuki Mizutani, Kazuki Miura,
Masatoshi Hashimoto, Yasushi Yoshida, Masami Sakamoto
PII:
S0040-4020(18)30610-0
10.1016/j.tet.2018.05.062
TET 29569
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 5 March 2018
Revised Date: 19 May 2018
Accepted Date: 22 May 2018
Please cite this article as: Mino T, Watanabe K, Akiyama T, Mizutani Y, Miura K, Hashimoto M, Yoshida
Y, Sakamoto M, The second-generation synthesis of BICMAP analogues, Tetrahedron (2018), doi:
10.1016/j.tet.2018.05.062.
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Graphical Abstract
The second-generation synthesis of BICMAP and its
derivatives
Leave this area blank for abstract info.
Takashi Mino*, Kohei Watanabe, Takumu Akiyama, Yuki Mizutani, Kazuki Miura, Masatoshi Hashimoto,
Yasushi Yoshida, Masami Sakamoto

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The second-generation synthesis of BICMAP analogues
Takashi Minoa,b*, Kohei Watanabea, Takumu Akiyamaa, Yuki Mizutania, Kazuki Miuraa, Masatoshi
Hashimotoa, Yasushi Yoshidaa,b, Masami Sakamotoa,b
aGraduate School of Engineering, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan
bMolecular Chirality Research Center, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522,
Japan
* Corresponding author. Tel.: +81-43-290-3385; fax: +81-43-290-3401; e-mail: tmino@faculty.chiba-u.jp
Abstract: We previously reported the synthesis of BICMAP (1a) via 6-diphenylphosphino-2,3-
dihydrobenzofuran as a key intermediate. However, we did not successfully synthesize BICMAP
analogues via a similar synthetic route. Herein we report the second-generation synthesis of BICMAP
and its derivatives via diethylphosphonate as a key intermediate.
1. Introduction
Chiral bisphosphines are critical molecules that affect asymmetric inductions as chiral ligands for
transition metal catalysts.1 After the discovery of BINAP,2 many atropisomeric chiral bisphosphines
have been reported, including MeO-BIPHEP,3 BIBFUP,4 BIFAP,5 BICAP,6 SEGPHOS,7 and
SYNPHOS.8 We also reported the synthesis of BICMAP,9 such as an atropisomeric bisphosphine with a
dihydrobenzofuran core and its use as a chiral ligand for rhodium-catalyzed asymmetric 1,4-addition9b,10
and copper-catalyzed propargylic amination.11 Dihydrobenzofuran core was easily prepared from 1,4-
dibromo-2-fluorobenzene (2) with ethylene glycol. It seems to be easy to synthesize BICMAP
analogues which have modified dihydrobenzofuran core. On the other hand, chiral bisphosphines with
diarylphosphino groups instead of the diphenylphosphino group were also reported: For example,
1

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BINAP analogues,12 MeO-BIPHEP analogues,13 SEGPHOS analogues,7a,14 and SYNPHOS analogues.15
Here we report the synthesis of BICMAP analogues 1 (Figure 1) and their applications to the palladium-
catalyzed amination reaction.
Figure 1. (R)-BICMAP analogues 1.
2. Results and discussion
2.1. Synthesis of BICMAP analogues 1
We previously reported the synthesis of BICMAP (1a) via 6-diphenylphosphino-2,3-
dihydrobenzofuran as a key intermediate. First, we tried to synthesize such BICMAP analogues as a 3,5-
diMe-BICMAP (1b) via a similar synthetic route (Scheme 1). The reaction of tribromide 29 with
bis(3,5-dimethylphenyl)chlorophosphine using n-butyllithium produced corresponding phosphine 3 in
52%. After oxidation of the phosphine atom by hydrogen peroxide in chloroform, we tried the
ortholithiation of phosphine oxides 4 and further oxidative coupling with anhydrous ferric chloride.
Unfortunately, we failed to obtain the coupling product 5b under this methodology. The 3,5-
dimethylphenyl moiety is more sterically hindered than the phenyl moiety. So, we thought the oxidative
coupling of 5b did not proceed.
2