Asymmetric sonogashira coupling with a chiral palladium imidazoindole phosphine complex

Article abstract of DOI:10.1055/s-0033-1339873

The asymmetric Sonogashira coupling of 1-(2,6-di?-bromophenyl) naphthalene or 4,16-dibromo[2,2]paracyclophane with various terminal alkynes was carried out with a palladium complex of a homochiral imidazoindole phosphine, a derivative of a (3R,9aS)-2-aryl-[3-(2-dialkylphosphanyl)phenyl]tetrahydro-1H- imidazo[1,5a]indol-1-one, to give the corresponding axially chiral monoalkynylated biaryl products with up to 72% enantiomeric ?-excess. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1339873

2550▌
LETTER
lAettserymmetric Sonogashira Coupling with a Chiral Palladium Imidazoindole
Phosphine Complex
Asymmetric Sonogashira Coupling
Haifeng Zhou,1 Yasuhiro Uozumi*
Institute for Molecular Science (IMS), Higashiyama 5-1, Myodaiji, Okazaki 444-8787, Japan
Fax +81(564)595574; E-mail: uo@ims.ac.jp
Received: 16.08.2013; Accepted: 18.08.2013
enantioselectivities in palladium-catalyzed asymmetric
Abstract: The asymmetric Sonogashira coupling of 1-(2,6-di-
allylic substitution reactions (also known as Tsuji–Trost
bromophenyl)naphthalene or 4,16-dibromo[2,2]paracyclophane
reactions),8 in Suzuki–Miyaura coupling reactions,5e and
with various terminal alkynes was carried out with a palladium
complex of a homochiral imidazoindole phosphine, a derivative of
in copper-catalyzed asymmetric O–H insertion reactions.9
a (3R,9aS)-2-aryl-[3-(2-dialkylphosphanyl)phenyl]tetrahydro-1H- As a part of our efforts to broaden the utility of these chiral
imidazo[1,5a]indol-1-one, to give the corresponding axially chiral
monoalkynylated biaryl products with up to 72% enantiomeric
excess.
imidazoindole phosphine ligands, we examined their ap-
plication in the asymmetric Sonogashira cross-coupling
reaction. Here we report that a chiral palladium imidaz-
oindole phosphine complex catalyzed the asymmetric
Key words: asymmetric catalysis, coupling, alkynes, chirality,
catalysis, palladium
Sonogashira coupling reaction between dibromoarenes
and terminal alkynes to form enantiomerically enriched
monoalkynylated biaryl products of axial chirality
(Scheme 1, b).
The Sonogashira coupling reaction between an aryl or al-
kenyl halide or triflate and a terminal alkyne has become
one of the most straightforward and powerful methods for
constructing C(sp2)–C(sp) bonds, and it has been exten-
sively used in syntheses of natural products, pharmaceuti-
cals, and other organic materials.2 During the last two
decades, the asymmetrization of various transition-metal-
catalyzed cross-coupling reactions has intrigued many re-
search groups in organic synthetic chemistry. However,
although much work has been devoted to the development
of asymmetric Kumada coupling,3 asymmetric Suzuki–
Miyaura coupling,4,5 and other asymmetric cross-coupling
reactions,6 the development of an asymmetric Sonogashi-
ra coupling remains a major challenge. To the best of our
knowledge, only one pioneering work on this reaction has
been reported;7 in this, the double Sonogashira coupling
of diiodoparacyclophanes with terminal alkynes proceed-
ed in the presence of a chiral palladium ferrocenyl phos-
phine complex to give the corresponding planarly chiral
dialkynylparacyclophanes.
a. previous work: asymmetric Kumada coupling
TfO
OTf
[PdCl2((S)-L*)], LiBr TfO
+
BrMg
R
R
R
R = Me: Alaphos
R = Bn: Phephos
R = i-Pr: Valphos
R = t-Bu: t-Leuphos
(S )-L* =
Ph2P
NMe2
b. this work: asymmetric Sonogashira coupling
Br
Br
Pd/Ln*, CuI, base
Br
*
+
H
R
R
O
H
L1: R = Ph
L2: R = t-Bu
L3: R = Cy
Ln* =
N
N
We have previously reported a chiral palladium β-(amino-
alkyl)phosphine complex-catalyzed asymmetric Kumada
coupling of achiral biaryl ditriflates with alkynyl Grignard
reagents to give the corresponding axially chiral mono-
alkynylated biaryl compounds (Scheme 1, a); however,
attempts to perform the coupling reaction with terminal
alkynes (the so-called asymmetric Sonogashira coupling)
resulted in poor catalytic and stereoselective outcomes.3d
However, we have recently developed (3R,9aS)-2-aryl-
[3-(2-dialkylphosphanyl)phenyl]tetrahydro-1H-imid-
azo[1,5a]indol-1-one derivatives as a series of novel chi-
ral imidazoindole phosphine ligands that provide high
PR2
Scheme 1 Asymmetric monoalkynylation by a desymmetrization
strategy
When we examined the Sonogashira coupling reaction of
1-(2,6-dibromophenyl)naphthalene (1) with ethynylben-
zene (2a) in the presence of 5 mol% tris(dibenzylidene-
acetone)dipalladium [Pd2(dba)3], 12 mol% chiral
imidazoindole phosphine L3, 10 mol% copper(I) iodide,
and 2.5 equivalents of triethylamine in toluene at 110 °C,
the axially chiral monoalkynylated product 3a was ob-
tained in 48% yield and 18% ee (Table 1, entries 1–3).10
Thorough screening of bases and solvents showed that tri-
SYNLETT 2013, 24, 2550–2554
Advanced online publication: 16.10.2013
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1339873; Art ID: ST-2013-D0789-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Sonogashira Coupling
2551
Table 1 Optimization of the Reaction Conditionsa (continued)
ethylamine in acetonitrile was an effective base/solvent
combination, giving 3a in 57% yield and 29% ee
(entries 4–12). We also examined other palladium sources
under similar conditions and achieved a slightly higher
enantioselectivity (32% ee) with dichlorobis(π-allyl)di-
palladium {[PdCl(π-allyl)]2} (entries 13–15). No signifi-
cant enhancement in enantioselectivity was observed
when the molar ratio of L3 to palladium was increased to
2.4 (entry 16). Interestingly, when 3.0 equivalents of 2a
were used, the enantiomeric excess of 3a increased to
63% at the expense of its chemical yield (entry 17). Thus,
in entry 16, 3a was obtained in 61% yield and 35% ee, ac-
companied by trace amounts of the dialkynylated product
4, whereas, when 3 equivalents of ethynylbenzene (2a)
were used (entry 17), a considerable amount of the di-
alkynylated product 4 was formed, reducing the yield of
3a to 52% but increasing the enantiomeric excess to
63%.11
Br
Br
Br
[Pd] (10 mol%)
*
+
H
Ph
Ph
CuI (10 mol%)
base, solvent, 24 h
1
2a
3
Entry Pd source/ligand
Solvent
Temp Yield ee
(°C)
(%)b (%)c
19i
20i
21i
[PdCl(π-allyl)]2/L4
[PdCl(π-allyl)]2/L5
[PdCl(π-allyl)]2/L6
MeCN
MeCN
MeCN
80
80
80
12
25
<5
42
12
k
–
P
P
PAr2
PAr2
OMe
PPh2
Table 1 Optimization of the Reaction Conditionsa
L4: Ar = 3,5-(CH3)2C6H3
L5: MeO-MOP
L6: Me-Duphos
Br
Br
a Reaction conditions: 1 (0.1 mmol), 2a (0.15 mmol), Pd source (10
mol%), ligand (12 mol%), CuI (10 mol%), Et3N (0.25 mmol), under
N2, 24 h.
Br
[Pd] (10 mol%)
*
+
H
Ph
Ph
CuI (10 mol%)
base, solvent, 24 h
b Isolated yield.
c Determined by chiral HPLC analysis with a Chiralpac AD-H col-
umn.
1
2a
3
d Pyrrolidine (0.25 mmol) was used as the base instead of Et3N.
e Morpholine (0.25 mmol) was used as the base instead of Et3N.
f TBAF (0.25 mmol) was used as the base instead of Et3N.
g K2CO3 (0.25 mmol) was used as the base instead of Et3N.
h 24 mol% L3 was used.
Entry Pd source/ligand
Solvent
Temp Yield ee
(°C)
(%)b (%)c
1
2
3
4
5
6
7
8
Pd2(dba)3/L1
Pd2(dba)3/L2
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd2(dba)3/L3
Pd2(dba)3/L3
toluene
toluene
toluene
1,4-dioxane
DMF
110
110
110
100
100
100
100
80
26
33
48
44
43
52
43
57
26
35
30
40
49
53
53
61
52
34
3
14
18
21
26
23
25
29
27
29
16
29
24
27
32
35
63
72
i Alkyne 2a (0.3 mmol) and Et3N (0.35 mmol) were used.
j IL = ionic liquid (1-butyl-3-methylimidazolium tetrafluoroborate).
k Not determined.
As shown in Scheme 2, the results show that the second
Sonogashira coupling of 3a occurred successively, ac-
companied by a kinetic resolution process. The minor en-
antiomer (+)-3a that formed in the first asymmetric
Sonogashira coupling was consumed preferentially in the
second Sonogashira coupling, increasing the enantiomer-
ic purity of 3a as the amount of dialkynylated product 4
increased. Hayashi and co-workers have previously re-
ported a similar kinetic resolution that led to an improve-
ment in enantiomeric purity.3d An even higher
enantiomeric excess (72%), coupled with an even lower
yield of 3a (34%), was observed when an ionic liquid was
used as the reaction medium instead of acetonitrile under
otherwise identical conditions (Table 1, entry 18), show-
ing that the minor enantiomer (+)-3a was consumed faster
in the ionic liquid than in acetonitrile. We also examined
the use of the classical chiral ligands (R)-3,5-Xyl-BINAP
(L4), (R)-MOP (L5), and (R,R)-Me-Duphos (L6) in the
asymmetric Sonogashira coupling under the optimized
conditions, but these gave results that were inferior to
those obtained with chiral imidazoindole phosphine L3
(Table 1, entries 19–21).
DMSO
NMP
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
ILj
9d Pd2(dba)3/L3
10e Pd2(dba)3/L3
11f Pd2(dba)3/L3
12g Pd2(dba)3/L3
80
80
80
80
13
14
15
Pd2(OAc)2/L3
Pd2(TFA)2/L3
80
80
[PdCl(π-allyl)]2/L3
80
16h [PdCl(π-allyl)]2/L3
80
17i
18i
[PdCl(π-allyl)]2/L3
[PdCl(π-allyl)]2/L3
80
80
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2550–2554

2552
H. Zhou, Y. Uozumi
LETTER
In addition to generating axial chirality, this asymmetric
Sonogashira coupling can also be used to generate planar
chirality. Thus, the reaction of 4,16-dibromo paracyclo-
phane (5) with ethynylbenzene (2a) under the optimized
reaction conditions gave the monoalkynylated paracyclo-
phane 6 with planar chirality in 56% yield and 44% ee
(Scheme 3).
Br
*
Ph
slow
fast
3
main enantiomer
Br
Br
Ph
Ph
Br
Br
Br
slow
fast
1
4
*
Ph
[PdCl(π-allyl)]2 (5 mol%)
L3 (12 mol%)
+
2a
CuI (10 mol%)
Et3N (3.5 equiv)
MeCN, 80 °C, 24 h
ent-3
Scheme 2 Kinetic resolution in the second asymmetric Sonogashira
Br
coupling
56% yield, 44% ee
5
6
Ph
We then examined the scope of the reaction with various
terminal alkynes under the optimized reaction conditions
(Table 2). Treatment of 1 with a series of terminal alkynes
2a–i gave the corresponding products 3a–i in moderate
yields and moderate enantioselectivities. The reaction was
not significantly influenced by the presence of substitu-
ents on the aromatic ring of the alkyne. Both electron-rich
(entries 2 and 3) and electron-deficient (entries 4–8) aryl-
substituted alkynes were effective in giving the desired
products. Furthermore, the reaction also proceeded well
with oct-1-yne, with an enantioselectivity comparable to
those obtained with the various arylalkynes (entry 9).
Scheme 3 Asymmetric Sonogashira coupling used to generate pla-
nar chirality in a paracyclophane
In conclusion, we have developed an asymmetric Sono-
gashira coupling with a chiral palladium catalyst. The pal-
ladium complex of imidazoindole phosphine L3
catalyzed the asymmetric Sonogashira coupling of 1-(2,6-
dibromophenyl)naphthalene or 4,16-dibromo[2,2]paracy-
clophane with various terminal alkynes to give the corre-
sponding axially or planarly chiral monoalkynylated
products, respectively, in up to 61% yield and up to 72%
ee.
Table 2 Substrate Scope with Terminal Alkynesa
Acknowledgment
[PdCl(π-allyl)]2 (5 mol%)
We acknowledge the partial financial support extended by MEXT
(Science Research on Priority Areas, no. 460) and JST (CREST
Projects).
Br
Br
L3 (12 mol%)
Br
+
H
R
*
R
CuI (10 mol%)
Et3N (3.5 equiv)
MeCN, 80 °C, 24 h
1
2
3
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlettSnugIiofop
r
imnatrtSufpnogrmIpintart
Entry
2
R
Product Yield ee
(%)b
(%)c
References
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
Ph
3a
3b
3c
3d
3e
3f
52
47
42
47
50
45
46
38
38
63
39
36
31
53
43
50
45
42
(1) Present address: China Three Gorges University (CTGU);
haifeng-zhou@hotmail.com.
4-MeC6H4
4-MeOC6H4
2-F3CC6H4
2-FC6H4
3-FC6H4
4-FC6H4
2,4-F2C6H3
(CH2)5Me
(2) For recent selected reviews, see: (a) Chinchilla, R.; Nájera,
C. Chem. Soc. Rev. 2011, 40, 5084. (b) Chinchilla, R.;
Nájera, C. Chem. Rev. 2007, 107, 874. (c) Doucet, H.;
Hierso, J.-C. Angew. Chem. Int. Ed. 2007, 46, 834.
(3) For asymmetric Kumada coupling reactions, see:
(a) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J. Am.
Chem. Soc. 1988, 110, 8153. (b) Hayashi, T.; Hayashizaki,
K.; Ito, Y. Tetrahedron Lett. 1989, 30, 215. (c) Hayashi, T.;
Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi, Y. J. Am.
Chem. Soc. 1995, 117, 9101. (d) Kamikawa, T.; Uozumi, Y.;
Hayashi, T. Tetrahedron Lett. 1996, 37, 3161.
(e) Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55, 3455.
(4) For pioneering work on the asymmetric Suzuki–Miyaura
coupling, see: (a) Uemura, M.; Nishimura, H.; Hayashi, T.
Tetrahedron Lett. 1993, 34, 107. (b) Cho, S. Y.; Shibasaki,
M. Tetrahedron: Asymmetry 1998, 9, 3751. (c) Cammidge,
A. N.; Crépy, K. V. L. Chem. Commun. (Cambridge) 2000,
1723.
2g
2h
2i
3g
3h
3i
a Reaction conditions: 1 (0.1 mmol), 2 (0.3 mmol), [PdCl(π-allyl)]2 (5
mol%), L3 (12 mol%), CuI (10 mol%), Et3N (0.35 mmol), MeCN (1.0
mL), under N2, 80 °C, 24 h. See refs. 12 and 13.
b Isolated yield.
c Determined by chiral HPLC analysis with a Chiralpac AD-H or
OD-H column.
Synlett 2013, 24, 2550–2554
© Georg Thieme Verlag Stuttgart · New York

LETTER
Asymmetric Sonogashira Coupling
2553
(5) To the best of our knowledge, the reported asymmetric
Suzuki–Miyaura coupling involves a combination of Ar1X
and Ar2B(OH)2, giving >90% ee, see: (a) Yin, J.; Buchwald,
S. L. J. Am. Chem. Soc. 2000, 122, 12051. (b) Genov, M.;
Almorín, A.; Espinet, P. Chem. Eur. J. 2006, 12, 9346.
(c) Bermejo, A.; Ros, A.; Fernández, R.; Lassaletta, J. M. J.
Am. Chem. Soc. 2008, 130, 15798. (d) Sawai, K.; Tatumi,
R.; Nakahodo, T.; Fujihara, H. Angew. Chem. Int. Ed. 2008,
47, 6917. (e) Uozumi, Y.; Matsuura, Y.; Arakawa, T.;
Yamada, Y. M. A. Angew. Chem. Int. Ed. 2009, 48, 2708.
(f) Shen, X.; Jones, G. O.; Watson, D. A.; Bhayana, B.;
Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 11278.
(g) Zhang, S. S.; Wang, Z. Q.; Xu, M. H.; Lin, G. Q. Org.
Lett. 2010, 12, 5546. (h) Yamamoto, T.; Akai, Y.; Nagata,
Y.; Suginome, M. Angew. Chem. Int. Ed. 2011, 50, 8844.
(6) For asymmetric Negishi coupling reactions, see: (a) Genov,
M.; Fuentes, B.; Espinet, P.; Pelaz, B. Tetrahedron:
Asymmetry 2006, 17, 2593. (b) Genov, M.; Almorín, A.;
Espinet, P. Tetrahedron: Asymmetry 2007, 18, 625. For
selected Ni-catalyzed asymmetric cross-coupling reactions,
see: (c) Negishi coupling: Fischer, C.; Fu, G. C. J. Am.
Chem. Soc. 2005, 127, 4594. (d) Negishi coupling: Arp, F.
O.; Fu, G. C. J. Am. Chem. Soc. 2005, 127, 10482.
(e) Negishi coupling: Son, S.; Fu, G. C. J. Am. Chem. Soc.
2008, 130, 2756. (f) Csp2–Csp3 coupling: Smith, S. W.; Fu,
G. C. J. Am. Chem. Soc. 2008, 130, 12645. (g) Csp–Csp3
coupling: Caeiro, J. P.; Sestelo, J. P.; Sarandeses, L. A.
Chem. Eur. J. 2008, 14, 741. (h) Kumada coupling: Lou, S.;
Fu, G. C. J. Am. Chem. Soc. 2010, 132, 1264. (i) Csp2–Csp3
coupling: Lou, S.; Fu, G. C. J. Am. Chem. Soc. 2010, 132,
5010. (j) Csp3–Csp3 coupling: Owston, N. A.; Fu, G. C. J.
Am. Chem. Soc. 2010, 132, 11908.
(13) Analytical Data of Selected Compounds
1-[2-Bromo-6-(phenylethynyl)phenyl]naphthalene (3a):
[α]25D −78.6 (c 1.0, CHCl3); 63% ee (HPLC conditions:
Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate =
0.5 mL/min; wavelength = 254 nm; tR = 13.68 (major isomer),
14.93 (minor isomer) min; 1H NMR (500 MHz, CDCl3): δ =
7.95 (t, J = 7.5 Hz, 2 H), 7.73–7.72 (m, 1 H), 7.64–7.57 (m,
2 H), 7.50–7.39 (m, 4 H), 7.30 (t, J = 7.5 Hz, 1 H), 7.16–7.07
(m, 3 H), 6.70–6.69 (m, 2 H); 13C NMR (125 MHz, CDCl3): δ
= 143.4, 138.1, 133.5, 132.5, 131.4, 131.2, 130.7, 128.8,
128.3, 128.2, 128.0, 127.3, 126.2, 125.8, 125.5, 125.2, 124.7,
122.5, 93.9, 88.1; HRMS (EI-TOF): m/z calcd for C24H15Br:
382.0357; found: 382.0348.
1-[2-Bromo-6-(p-tolylethynyl)phenyl]naphthalene (3b):
[α]25D −69.6 (c 0.9, CHCl3); 39% ee (HPLC conditions:
Chiralpac AD-H column; hexane–i-PrOH, 200:1; flow rate =
0.5 mL/min; wavelength = 254 nm; tR = 12.84 (major isomer),
14.16 (minor isomer) min; 1H NMR (500 MHz, CDCl3): δ =
7.94 (t, J = 7.5 Hz, 2 H), 7.71 (d, J = 8.0 Hz, 1 H), 7.62–7.57
(m, 2 H), 7.49–7.38 (m, 4 H), 7.29 (t, J = 8.0 Hz, 1 H), 6.90 (d,
J = 8.0 Hz, 2 H), 6.58 (d, J = 8.0 Hz, 2 H), 2.23 (s, 3 H); 13
C
NMR (125 MHz, CDCl3): δ 143.3, 138.4, 138.1, 133.5, 132.4,
131.5, 131.3, 131.1, 130.5, 129.2, 128.9, 128.8, 128.2, 127.4,
126.4, 126.2, 125.8, 125.6, 125.2, 124.7, 119.5, 94.2, 87.5,
21.4; HRMS (EI-TOF): m/z calcd for C25H17Br: 396.0514;
found: 396.0506.
1-{2-Bromo-6-[(4-methoxyphenyl)ethynyl]phenyl}-
naphthalene (3c): [α]25D = −62.4 (c 0.5, CHCl3); 36% ee
(HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH,
200:1; flow rate = 0.8 mL/min; wavelength = 254 nm; tR =
13.05 (major isomer), 14.00 (minor isomer) min; 1H NMR
(500 MHz, CDCl3): δ = 7.94 (t, J = 7.0 Hz, 2 H), 7.70–7.69
(m, 1 H), 7.61–7.57 (m, 2 H), 7.50–7.39 (m, 4 H), 7.28 (t,
J = 8.0 Hz, 1 H), 6.62 (s, 4 H), 3.71 (s, 3 H); 13C NMR (125
MHz, CDCl3): δ = 159.5, 143.1, 138.2, 133.4, 132.7, 132.2,
131.5, 130.4, 128.8, 128.2, 127.4, 126.5, 126.1, 125.8, 125.6,
125.2, 124.7, 114.7, 113.7, 94.1, 86.9, 55.2; HRMS (EI-TOF):
m/z calcd for C25H17BrO: 412.0463; found: 412.0477.
1-(2-Bromo-6-{[2-(trifluoromethyl)phenyl]ethynyl}-
phenyl)naphthalene (3d): [α]25D = −47.7 (c 0.9, CHCl3);
31% ee (HPLC conditions: Chiralpac OD-H column; hexane–
i-PrOH, 200:1; flow rate = 0.5 mL/min; wavelength =
254 nm; tR = 12.18 (major isomer), 14.48 (minor isomer) min;
1H NMR (500 MHz, CDCl3): δ = 7.87 (t, J = 8.5 Hz, 2 H),
7.69–7.67 (m, 1 H), 7.60 (dd, J = 7.5, 1.5 Hz, 1 H), 7.53–7.50
(m, 1 H), 7.43–7.32 (m, 5 H), 7.24 (t, J = 8.0 Hz, 1 H), 7.18–
7.12 (m, 2 H), 6.47–6.45 (m, 1 H); 13C NMR (125 MHz,
CDCl3): δ = 143.3, 137.7, 133.9, 133.5, 133.1, 131.4, 131.0,
130.7, 128.9, 128.3, 128.2, 127.8, 127.4, 126.2, 125.8, 125.6,
125.5, 125.4, 125.2, 124.9, 122.0, 120.8, 93.2, 89.3; HRMS
(EI-TOF): m/z calcd for C25H14BrF3: 450.0231; found:
450.0235.
1-{2-Bromo-6-[(2-fluorophenyl)ethynyl]phenyl}-
naphthalene (3e): [α]25D −84.4 (c 0.5, CHCl3); 3% ee (HPLC
conditions: Chiralpac AD-H column; hexane–i-PrOH, 200:1;
flow rate = 0.5 mL/min; wavelength = 254 nm; tR = 12.21
(major isomer), 13.21 (minor isomer) min; 1H NMR (500
MHz, CDCl3): δ = 7.94 (t, J = 8.0 Hz, 2 H), 7.74 (dd, J1=
8.0 Hz, J2 = 1.5 Hz, 1 H), 7.68–7.67 (m, 1 H), 7.60 7.57 (m,
1 H), 7.50–7.40 (m, 4 H), 7.31 (t, J = 8.0 Hz, 1 H), 7.13–7.11
(m, 1 H), 6.88–6.83 (m, 2 H), 6.53–6.50 (m, 1 H); 13C NMR
(125 MHz, CDCl3): δ = 163.1, 143.4, 137.8, 133.5, 133.3,
132.9, 131.4, 131.0, 129.9, 128.8, 128.3, 128.2, 127.3, 126.2,
125.8, 125.5, 124.8, 123.6, 115.3, 115.1, 92.8, 87.0; HRMS
(EI-TOF): m/z calcd for C24H14BrF: 400.0263; found:
400.0251.
(7) Kanda, K.; Koike, T.; Edno, K.; Shibata, T. Chem. Commun.
(Cambridge) 2009, 1870.
(8) (a) Alkylation: Uozumi, Y.; Shibatomi, K. J. Am. Chem.
Soc. 2001, 123, 2919. (b) Amination: Uozumi, Y.; Tanaka,
H.; Shibatomi, K. Org. Lett. 2004, 6, 281. (c) Cyclization:
Nakai, Y.; Uozumi, Y. Org. Lett. 2005, 7, 291.
(d) Nitromethylation: Uozumi, Y.; Suzuka, T. J. Org. Chem.
2006, 71, 8644. (e) Etherification: Uozumi, Y.; Kimura, M.
Tetrahedron: Asymmetry 2006, 17, 161. (f) Uozumi, Y.;
Takenaka, H.; Suzuka, T. Synlett 2008, 1557.
(g) Sulfonylation: Uozumi, Y.; Suzuka, T. Synthesis 2008,
1960.
(9) Osako, T.; Panichakul, D.; Uozumi, Y. Org. Lett. 2012, 14,
194.
(10) The starting material 1, dialkynylated product 4, and
homocoupling product of 2a were also detected by GC/MS,
but were inseparable by column chromatography.
(11) The amount of dialkynylated product 4 was assessed on the
basis of the peak area determined by GC/MS analysis.
(12) General Procedure: [PdCl(π-allyl)]2 (0.005 mmol), chiral
imidazoindole phosphine ligand L3 (0.012 mmol), and
toluene (0.5 mL, degassed) were charged into a Schlenk tube
under N2, and the mixture was stirred at room temperature
for 15 min. After removal of the solvent, 1-(2,6-
dibromophenyl)naphthalene (1; 0.1 mmol), CuI (0.01
mmol), acetonitrile (2 mL, degassed), alkyne (2; 0.3 mmol)
and Et3N (0.35 mmol) were charged into the Schlenk tube.
The mixture was stirred at 80 °C under a nitrogen
atmosphere for 24 h. After cooling to room temperature, the
reaction mixture was passed through a short pad of silica gel
to remove the catalyst, and the filtrate was concentrated
under reduced pressure. The residue was purified by
chromatography with silica gel to give the mono- and
dialkynylated products 3 and 4. The enantiomeric excess of
3 was determined by HPLC analysis with a chiral stationary
phase column (Chiralcel AD-H, Chiralpak OD-H).
1-{2-Bromo-6-[(3-fluorophenyl)ethynyl]phenyl}-
naphthalene (3f): [α]25D −77.6 (c 0.5, CHCl3); 43% ee
© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 2550–2554

2554
H. Zhou, Y. Uozumi
LETTER
1-{2-Bromo-6-[(2,4-difluorophenyl)ethynyl]phenyl}-
(HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH,
200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; tR =
15.07 (major isomer), 17.13 (minor isomer) min; 1H NMR
(500 MHz, CDCl3): δ = 7.96 (t, J = 8.0 Hz, 2 H), 7.74 (d, J =
7.0 Hz, 1 H), 7.63–7.58 (m, 2 H), 7.51–7.39 (m, 4 H), 7.30 (t,
J = 8.0 Hz, 1 H), 7.06–7.02 (m, 1 H), 6.86–6.82 (m, 1 H), 6.47
(d, J = 7.5 Hz, 1 H), 6.35–6.32 (m, 1 H); 13C NMR (125 MHz,
CDCl3): δ = 163.0, 143.6, 137.9, 133.5, 132.9, 131.4, 130.7,
129.6, 128.9, 128.4, 127.3, 127.0, 126.2, 125.9, 125.7, 125.2,
124.8, 124.4, 118.0, 117.9, 115.6, 115.4, 92.5, 88.9; HRMS
(EI-TOF): m/z calcd for C24H14BrF: 400.0263; found:
400.0241.
1-{2-Bromo-6-[(4-fluorophenyl)ethynyl]phenyl}-
naphthalene (3g): [α]25D −71.3 (c 0.9, CHCl3); 50% ee
(HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH,
200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; tR =
10.84 (major isomer), 12.27 (minor isomer) min; 1H NMR
(500 MHz, CDCl3): δ = 7.87 (t, J = 7.5 Hz, 2 H), 7.65 (dd, J1
= 8.0, J2 = 1.0 Hz, 1 H), 7.54–7.49 (m, 2 H), 7.43–7.31 (m,
4 H), 7.21 (t, J = 8.0 Hz, 1 H), 6.72–6.68 (m, 2 H), 6.59–6.55
(m, 2 H); 13C NMR (125 MHz, CDCl3): δ = 161.3, 143.4,
138.0, 133.4, 133.1, 133.0, 132.6, 131.4, 130.5, 128.8, 128.2,
127.3, 126.2, 126.0, 125.8, 125.5, 125.2, 124.7, 118.6, 115.4,
115.2, 92.8, 87.8; HRMS (EI-TOF): m/zcalcd for C24H14BrF:
400.0263; found: 400.0241.
naphthalene (3h): [α]25D −74.0 (c 0.7, CHCl3); 45% ee
(HPLC conditions: Chiralpac AD-H column; hexane–i-PrOH,
200:1; flow rate = 0.5 mL/min; wavelength = 254 nm; tR =
12.22 (major isomer), 13.01 (minor isomer) min; 1H NMR
(500 MHz, CDCl3): δ = 7.94 (t, J = 7.5 Hz, 2 H), 7.74 (d, J =
8.0 Hz, 1 H), 7.65 (d, J = 7.5 Hz, 1 H), 7.58 (t, J = 7.5 Hz,
1 H), 7.50–7.39 (m, 4 H), 7.31 (t, J = 8.0 Hz, 1 H), 6.65–6.58
(m, 2 H), 6.47 (q, J = 7.5 Hz, 1 H); 13C NMR (125 MHz,
CDCl3): δ = 163.5, 161.4, 143.4, 137.8, 134.2, 133.5, 132.9,
131.4, 130.8, 128.8, 128.3, 127.3, 126.2, 125.8, 125.6, 125.4,
125.2, 124.8, 111.3, 111.1, 107.6, 103.9, 92.6, 86.0; HRMS
(EI-TOF): m/z calcd for C24H13BrF2: 418.0169; found:
418.0157.
1-[2-Bromo-6-(pent-1-ynyl)phenyl]naphthalene (3i):
[α]25D −10.2 (c 0.8, CHCl3); 42% ee (HPLC conditions:
Chiralpac OD-H column; hexane–i-PrOH, 200:1; flow rate =
0.3 mL/min; wavelength = 254 nm; tR = 14.70 (major isomer),
16.08 (minor isomer) min; 1H NMR (500 MHz, CDCl3): δ =
7.88 (d, J = 8.0 Hz, 2 H), 7.66–7.64 (m, 1 H), 7.55–7.45 (m,
3 H), 7.39–7.34 (m, 3 H), 7.22 (t, J = 8.0 Hz, 1 H), 1.92–1.89
(m, 2 H), 1.32–1.25 (m, 2 H), 1.14–1.06 (m, 2 H), 0.96–0.70
(m, 7 H); 13C NMR (125 MHz, CDCl3): δ = 143.3, 138.4,
133.4, 131.8, 131.5, 130.8, 128.6, 128.1, 128.0, 127.1, 126.9,
126.0, 125.6, 125.5, 125.2, 124.7, 95.3, 79.1, 31.2, 27.9, 27.8,
22.3, 19.0, 14.1; HRMS (EI-TOF): m/z calcd for C24H23Br:
390.0983; found: 390.0994
Synlett 2013, 24, 2550–2554
© Georg Thieme Verlag Stuttgart · New York

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