Stereospecific synthesis of hetero[7]helicenes by Pd-catalyzed double N-arylation and intramolecular O-arylation

Article abstract of DOI:10.1002/anie.200502855

(Chemical Equation Presented) Enantioenriched aza- and oxa[7]helicenes are synthesized from an enantiopure biphenanthryldiol in a highly stereoselective manner. An N-phenylaza[7]helicene is prepared by a palladium-catalyzed double N-arylation of aniline w

Full text of DOI:10.1002/anie.200502855

Communications
Helical Structures
DOI: 10.1002/anie.200502855
Stereospecific Synthesis of Hetero[7]helicenes by
Pd-Catalyzed Double N-Arylation and
Intramolecular O-Arylation**
Scheme 1. Key reactions for the synthesis of heterohelicenes.
Koji Nakano, Yuko Hidehira, Keita Takahashi,
Tamejiro Hiyama, and Kyoko Nozaki*
halides or sulfonates 2 is anticipated to give dibenzofuran,
which we refer to as the palladium-catalyzed intermolecular
diaryl ether synthesis.[9] These reactions of biphenyls were
applied to biphenanthryls to form an efficient synthetic route
to hetero[7]helicenes.
The target aza[7]helicene rac-5 was obtained in 64% yield
by the reaction of aniline with racemic 4,4’-biphenanthryl-
3,3’-ylene ditriflate (rac-4a), which was prepared from
racemic 4,4’-biphenanthryl-3,3’-diol (rac-3; Table 1, run 1).
Oxa[7]helicene rac-6 was produced as a by-product (10%
yield) through the intramolecular O-arylation of 3’-hydroxy-
4,4’-biphenanthryl-3-yl triflate (rac-7a), which was formed by
Helicenes consist of ortho-annulated aromatic and/or hetero-
aromatic rings endowed with a helical chirality.[1] Enantiopure
helicenes can be isolated because of their stable and rigid
helical conformation; furthermore, some of them form
aggregates to give helical supramolecular architectures
potentially applicable to nonlinear optics, electrooptic
switches, and circularly polarized luminescent materials.[2]
To expand the application of helicene molecules as functional
materials, it is important to develop an efficient synthetic
strategy for the production of helicenes with a variety of
frameworks and substituents in enantiopure form. The
classical methodology to synthesize helicenes is an oxidative
photocyclization of stilbene-type precursors.[3] Several non-
photochemical synthetic methods have been reported,[4]
which have been applied to the syntheses of enantioenriched
helicenes.[4a,f,5] Among these previous examples of helicene
synthesis, however, only a few demonstrate the synthesis of
azahelicenes with pyrrole rings or oxahelicenes with furan
rings in spite of their potential to alter molecular proper-
ties,[5g,6,7] which prompted us to develop a new synthetic route
that would produce aza- and oxahelicenes.
Table 1: Syntheses of aza[7]helicene and oxa[7]helicene.
The key reactions in the heterohelicene syntheses are
shown in Scheme 1. Carbazole derivatives can be prepared by
the double N-arylation of primary amines with dihalobiphen-
yls or biphenylylene disulfonate 1, as we reported recently.[8]
The intramolecular O-arylation of 2’-hydroxybiphenyl-2-yl
Run Substrate Conditions[a]
t [h] Product Yield [%]
[*] Dr. K. Nakano, Y. Hidehira, Prof. Dr. K. Nozaki
Department of Chemistry and Biotechnology
Graduate School of Engineering
1
2
3
rac-4a
rac-4b
(S)-4b
A
A
B
141
123
123
rac-5
rac-5
(P)-5
64[b]
88
The University of Tokyo
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656 (Japan)
Fax: ( +81)3-5841-7261
94 (>99% ee)
[a]2D2 =+2310
(c=0.10, CHCl3)
E-mail: nozaki@chembio.t.u-tokyo.ac.jp
4
5
6
7
rac-7a
rac-7b
(S)-7b
(S)-7b
C
C
C
D
18
96
96
13
rac-6
rac-6
(P)-6
(P)-6
45[c]
62
K. Takahashi, Prof. Dr. T. Hiyama
Department of Material Chemistry
Graduate School of Engineering
Kyoto University
60 (20% ee)
49 (94% ee)
[a]2D3 =+1430
(c=0.10, CHCl3)
Nishikyo-ku, Kyoto 615-8510 (Japan)
[**] We are grateful to Prof. Takuzo Aida (The University of Tokyo) for CD
spectroscopic analysis and to Prof. Takayuki Kawashima and Dr.
Makoto Yamashita (The University of Tokyo) for X-ray crystallo-
graphic analysis. We also thank Prof. Koji Araki, Dr. Toshiki Mutai,
and Mr. Isao Yoshikawa (The University of Tokyo) for HRMS
analysis. Financial support from the Yamada Science Foundation to
K. Nozaki and from Konica Minolta Technology Center, Inc. to K.
Nakano are gratefully acknowledged.
[a] Reaction conditions: A: H2NPh (1.2 equiv), [Pd2(dba)3]·CHCl3
(5 mol%), xantphos (10 mol%), K3PO4 (2.8 equiv); B: H2NPh
(1.2 equiv), [Pd2(dba)3]·CHCl3 (10 mol%), xantphos (20 mol%), K3PO4
(2.8 equiv); C: [Pd2(dba)3]·CHCl3 (5 mol%), biphenylphosphine
(20 mol%), K3PO4 (2.0 equiv); D: [Pd2(dba)3]·CHCl3 (10 mol%), biphe-
nylphosphine (40 mol%), K3PO4 (2.0 equiv). [b] A 10% yield of rac-6 as a
by-product was obtained. [c] Consumption of the substrate was
confirmed by TLC; the major by-product was diol rac-3. Cy=cyclohexyl,
dba=dibenzylideneacetone.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Angew. Chem. Int. Ed. 2005, 44, 7136 –7138

Angewandte
Chemie
the partial hydrolysis of rac-4a. The hydrolysis of the
sulfonate functionality was successfully avoided by using a
nonaflate (Nf) group instead of a triflate (Tf).[10] Thus, the
yield was elevated to 88% (run 2) under the optimized
reaction conditions (rac-4b with aniline (1.2 equiv), [Pd2-
(dba)3] (5 mol%), xantphos (10 mol%), K3PO4 (2.8 equiv),
xylene, 1008C, 123 h).
of (P)-6 takes place under the reaction conditions: treatment
of optically active (P)-6 (92% ee) in toluene at 1008C for 88 h
resulted in partial racemization (42% ee). In contrast, none of
(S)-7b (98% ee), (R)-4b (> 99% ee), and (M)-5 (97% ee)
underwent racemization in toluene at 1008C. These results
indicate that the stereospecific intramolecular O-arylation of
(S)-7b gives (P)-6 without any significant loss of enantiopur-
ity, and the racemization takes place after the formation of
(P)-6. The lower tolerance of 6 to racemization relative to 5
may be attributed to the differences in their structure. Indeed,
the single-crystal X-ray analyses suggested that 6 has a less-
distorted structure than 5 (Figure 1), thus indicating that the
terminal two rings in 6 have weaker steric repulsions which
should lead to a lower racemization barrier.[14,15]
The optical resolution of rac-3[11] was investigated for the
preparation of optically active heterohelicenes (Scheme 2).
Figure 1. ORTEP drawings of a) 5 and b) 6, with thermal ellipsoids
shown at the 50% probability level. All hydrogen atoms and the CHCl3
molecule are omitted for clarity.
Scheme 2. Optical resolution of rac-3. a) RSO2Cl (3.0 equiv), 4-(N,N-
dimethylamino)pyridine (5.0 mol%), Et3N, DMF, 08C!RT, 15 h, sepa-
ration by column chromatography on silica gel ((S)-8: 49% yield; (R)-
8: 47% yield); b) THF, MeOH, aq. NaOH (5.0m), reflux, 15 h ((S)-3
and (R)-3: 95% yield; (S)-3: >99% ee; (R)-3: >99% ee). DMF=di-
methylformamide.
The introduction of substituents into aza[7]helicene was
investigated toward the development of hetero[7]helicenes as
functional materials. Regioselective bromination was success-
fully achieved by the treatment of rac-5 with two and four
equivalents of NBS to yield di- and tetrabromoaza[7]heli-
cenes rac-9 and rac-10, respectively (Scheme 3).[16] The
The esterification of rac-3 with the commercially available
(1S)-10-camphorsulfonyl chloride gave diastereomers of
disulfonate 8, which were readily separated by column
chromatography on silica gel. Hydrolysis of the obtained
two single diastereomers gave (S)-3 and (R)-3 in enantiopure
form.
A single enantiomer of 5 was readily prepared from (S)-
4b by a stereospecific double N-arylation reaction; trans-
formation of (S)-4b (> 99% ee) gave (P)-5 in 94% yield with
> 99% ee (Table 1, run 3). The absolute configuration of (P)-
5 was confirmed by its optical rotation ([a]2D2 = + 2310 (c =
0.10, CHCl3)) and CD spectrum,[12] both of which are similar
to those of the known dextrorotatory (P)-heteroheli-
cenes.[5g,6a,13] Thus, the absolute configuration of (S)-4b is
maintained under the reaction conditions (1008C, 123 h) in
contrast to the O-arylation of (S)-7b (see below).
Scheme 3. Functionalization of rac-5. a) NBS (2.0 equiv), SiO2
(2.0 gmmolꢀ1 NBS), CH2Cl2, RT, 31 h (rac-9: 61% yield; b) NBS
(4.0 equiv), SiO2 (2.0 gmmolꢀ1 NBS), CH2Cl2, RT, 43 h (rac-10: 84%
yield ); c) tBuLi (8.4 equiv), THF, ꢀ788C, 4 h, then ClCO2Me
(8.4 equiv), ꢀ788C!RT, 13 h, (rac-11: 44% yield). NBS=N-bromosuc-
cinimide.
Oxa[7]helicene 6 was successfully synthesized through
intramolecular O-arylation. The reaction of triflate rac-7a or
nonaflate rac-7b using a palladium catalyst gave the desired
rac-6 in yields of 45 or 62%, respectively (runs 4 and 5).
Unlike the double N-arylation of (S)-4b (run 3), however, the
reaction of optically active (S)-7b (> 99% ee) gave (P)-6
(20% ee) with significant loss of enantiomeric excess (run 6;
1008C, 96 h). Racemization was suppressed effectively by
shortening the reaction time (13 h) to afford (P)-6 in 49%
yield with high enantiopurity (94% ee; [a]2D3 = + 1430 (c =
0.10, CHCl3); run 7). It should be noted that racemization
substituted positions were determined by single-crystal X-
ray analyses.[17] These brominated aza[7]helicenes should be
useful intermediates for further functionalizations; for exam-
ple, rac-10 was converted into tetraester rac-11 in 44% yield
(Scheme 3).
In conclusion, we have reported an efficient strategy for
the synthesis of aza- and oxa[7]helicenes 5 and 6 from the
same precursor, 4,4’-biphenanthryl-3,3’-diol (3); highly enan-
tioenriched 5 and 6 were successfully obtained in good yields.
In addition, tetrabromoaza[7]helicene 10 was produced by
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Communications
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Received: August 11, 2005
Published online: October 6, 2005
Keywords: arylation · bromination · chirality · helical structures ·
.
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Angew. Chem. Int. Ed. 2005, 44, 7136 –7138