Enantioselective ring-opening reactions of racemic ethynyl epoxides via copper-allenylidene intermediates: Efficient approach to chiral β-amino alcohols

Article abstract of DOI:10.1021/jo901064n

(Chemical Equation Presented) Enantioselective copper-catalyzed ring-opening reactions of racemic ethynyl epoxides with amines using (R)-DTBM-MeO-BIPHEP as a chiral ligand have been found to give the corresponding amino alcohols in high yields with up to

Full text of DOI:10.1021/jo901064n

pubs.acs.org/joc
Enantioselective Ring-Opening Reactions of Racemic Ethynyl Epoxides
via Copper-Allenylidene Intermediates: Efficient Approach to Chiral
β-Amino Alcohols
Gaku Hattori, Akiko Yoshida, Yoshihiro Miyake, and
Yoshiaki Nishibayashi*
Institute of Engineering Innovation, School of Engineering, The University of Tokyo, Yayoi, Bunkyo-ku,
Tokyo 113-8656, Japan
ynishiba@sogo.t.u-tokyo.ac.jp
Received May 22, 2009
Enantioselective copper-catalyzed ring-opening reactions of racemic ethynyl epoxides with amines
using (R)-DTBM-MeO-BIPHEP as a chiral ligand have been found to give the corresponding amino
alcohols in high yields with up to 94% ee. The reaction is considered to proceed via copper-
allenylidene complexes as key intermediates. This methodology may provide a novel synthetic
approach to optically active amino alcohols, the structures of which are widely found in many natural
products, biologically active compounds, and chiral ligands.
Introduction
amines with up to 89% enantiomeric excess (ee).4 It is
noteworthy that these reactions are considered to proceed
via copper-allenylidene5 complexes as key intermediates
(Scheme 1).4 Although the copper-allenylidene complexes
have not yet been isolated, the possibility of the presence of
these reactive intermediates prompted us to develop other
novel catalytic reactions. We have now envisaged that
ethynyl epoxides may also be used as precursors to generate
similar complexes, leading to chiral β-ethynyl-β-amino alco-
hols as products (Scheme 2). Optically active β-amino alco-
hols have been found in a large number of natural products
and biologically active compounds and often used as chiral
ligands.6 Results are described here.
Since the first discovery of enantioselective ruthenium-
catalyzed propargylic substitution reactions of propargylic
alcohols with acetone as a carbon-centered nucleophile,1
much attention has been paid to develop transition-metal-
catalyzed propargylic substitution reactions with nucleo-
philes because enantioselective bond-forming reactions at
the propargylic position provide a highly useful synthetic
method for constructing a chiral carbon center with an
alkyne moiety.2,3 Quite recently, copper-catalyzed pro-
pargylic substitution reactions of propargylic acetates with
amines were reported to give the corresponding propargylic
Results and Discussion
(1) Inada, Y.; Nishibayashi, Y.; Uemura, S. Angew. Chem., Int. Ed. 2005,
44, 7715.
Treatment of 2-ethynyl-2-phenyloxirane (1a) with aniline
(1.2 equiv) in the presence of a catalytic amount of Cu(OTf)2
(2 mol %), (R)-DTBM-MeO-BIPHEP7 (5 mol %), and
iPr2NEt (10 mol %) in acetone at -20 °C for 1 h gave
β-ethynyl-β-amino alcohol (2a) in 95% yield with 79% ee
(2) (a) Matsuzawa, H.; Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed.
2007, 46, 6488. (b) Matsuzawa, H.; Kanao, K.; Miyake, Y.; Nishibayashi, Y.
Org. Lett. 2007, 9, 5561. (c) Fukamizu, K.; Miyake, Y.; Nishibayashi, Y. J. Am.
Chem. Soc. 2008, 130, 10498. (d) Kanao, K.; Matsuzawa, H.; Miyake, Y.;
Nishibayashi, Y. Synthesis2008, 3869. (e) Kanao, K.; Miyake, Y.; Nishibayashi,
Y. Organometallics 2009, 28, 2920.
(3) Smith, S. W.; Fu, G. C. J. Am. Chem. Soc. 2008, 130, 12645.
(4) (a) Detz, R. J.; Delville, M. M. E.; Hiemstra, H.; van Maarseveen,
J. H. Angew. Chem., Int. Ed. 2008, 47, 3777. (b) Hattori, G.; Matsuzawa, H.;
Miyake, Y.; Nishibayashi, Y. Angew. Chem., Int. Ed. 2008, 47, 3781.
(5) For recent reviews, see: (a) Metal Vinylidenes and Allenylidenes in
Catalysis: From Reactivity to Applications in Synthesis; Bruneau, C., Dixneuf,
P. H., Eds.; Wiley-VCH: Weinheim, Germany, 2008. (b) Bruneau, C.; Dixneuf,
P. H. Angew. Chem., Int. Ed. 2006, 45, 2176.
(6) For reviews, see: (a) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. Rev.
1996, 96, 835. (b) Fache, F.; Schulz, E.; Tommasino, M. L.; Lamaire, M.
Chem. Rev. 2000, 100, 2159. (c) McManus, H. A.; Guiry, P. J. Chem. Rev.
2004, 104, 4151. (d) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. Rev. 2007,
107, 767.
(7) BIPHEP=2,20-Bis(diphenylphosphino)-1,10-biphenyl.
DOI: 10.1021/jo901064n
r
Published on Web 07/06/2009
J. Org. Chem. 2009, 74, 7603–7607 7603
2009 American Chemical Society

Hattori et al.
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SCHEME 1. Enantioselective Copper-Catalyzed Propargylic
Amination from Propargylic Acetate
TABLE 1. Enantioselective Ring-Opening Reactions of 1a with Aniline
by Using Optically Active Diphosphines
SCHEME 2. This Work
run
ligand
time (h) yield of 2a (%) ee of 2a (%)
1
2
3
4
(R)-DTBM-MeO-BIPHEP
(R)-DTB-MeO-BIPHEP
(R)-DTBM-SEGPHOS
(R)-SEGPHOS
1
1
1
20
95
95
95
79
78
76
0a
(Table 1, run 1).8 When other diphosphine ligands such as
(R)-DTB-MeO-BIPHEP and (R)-DTBM-SEGPHOS9 were
used in place of (R)-DTBM-MeO-BIPHEP, almost the
same enantioselectivity was observed in both cases
(Table 1, runs 2 and 3), while no reaction occurred at all
when (R)-SEGPHOS9 was used as a chiral ligand (Table 1,
run 4).
a1a was recovered in 83%.
TABLE 2. Enantioselective Copper-Catalyzed Ring-Opening Reac-
tions of 1a with Aminesa
Enantioselective ring-opening reactions of 1a with other
amines were investigated using (R)-DTBM-MeO-BIPHEP
as a chiral ligand. Typical results are shown in Table 2. The
presence of methyl, methoxy, chloro, bromo, trifluoromethyl,
and methoxycarbonyl groups at para, meta, and ortho posi-
tions of the benzene ring of aniline did not much affect the
reactivity (Table 2, runs 2-9), while in the case of 4-cyanoani-
line and 4-nitroaniline, a longer reaction time was necessary to
complete the reaction (Table 2, runs 10 and 11). On the other
hand, the enantioselectivity of 2 depended on the nature of
functional groups. The introduction of substituents in the
benzene ring of aniline substantially affected the enantioselec-
tivity. The highest enantioselectivity (93-94% ee) was ob-
served when 4-trifluoromethylaniline and 4-methoxy-
carbonylaniline were used (Table 2, runs 6 and 8). Unfortu-
nately, only the moderate enantioselectivity was observed
when alkylamines such as tert-butylamine and 1-adamantyl-
amine were used as amines (Table 2, runs 12 and 13). The use
of secondary amines such as N-methylaniline and piperidine
resulted with only moderate enantioselectivities, although the
reaction proceeded smoothly (Table 2, runs 14 and 15). It is
considered that classical SN2-type ring-opening reaction inthe
copper-acetylide complex (complex B in Scheme 3, vide
infra) may partly occur to give the racemic ring-opening
products when monoalkyl- and diakylamines were used as
nucleophiles. As a result, only amines bearing an electron-
withdrawing group are available to achieve the high enantio-
selectivity.
run
R1
R2 time (h) yield of 2 (%) ee of 2 (%)b
1
2
3
4
5
6
7
8
9
Ph
4-MeC6H4
4-MeOC6H4
4-ClC6H4
4-BrC6H4
4-CF3C6H4
3-CF3C6H4
4-MeOC(O)C6H4
2-MeOC(O)C6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
1
3
2
3
2
3
2
2
2
46
18
18d
24
1
95 (2a)
96 (2b)
85 (2c)
94 (2d)
95 (2e)
93 (2f)
94 (2g)
95 (2h)
97 (2i)
96 (2j)
94 (2k)
87 (2l)
83 (2m)
91 (2n)
93 (2o)
79
75
57
87
89
94
86
93
79
88
85
55
55
52
26
10 4-CNC6H4
11 4-NO2C6H4
12c tBu
13c 1-adamantyl
14 Ph
15
-(CH2)5-e
4
aAll reactions of 1a (0.20 mmol) with amines (0.24 mmol) were carried
out in the presence of Cu(OTf)2 (0.004 mmol), (R)-DTBM-MeO-BI-
PHEP (0.01 mmol), and Pr2NEt (0.02 mmol) in acetone (2.0 mL) at
i
-20 °C. bDetermined by HPLC. ciPr2NEt (0.24 mmol) was used. dAt
-40 °C. ePiperidine was used.
Next, we carried out enantioselective ring-opening reac-
tions of other 2-aryl-2-ethynyloxiranes (1) with 4-methoxy-
carbonylaniline and 4-trifluoromethylaniline (Table 3, runs
1-12). On the other hand, the reaction of 2-alkyl-2-ethynyl-
oxiranes (1) such as 2-ethynyl-2-methyloxirane (1h) and 2-
tert-butyl-2-ethynyloxirane (1i) proceeded well with a
slightly lower enantioselectivity (Table 3, runs 13-16).
As shown in Tables 2 and 3, the ring-opening products
were obtained in more than 90% yield based on the starting
racemic ethynyl epoxides with up to 94% ee. In addition, we
separately confirmed that no reaction occurred at all when
ethynyl epoxides bearing an internal alkyne moiety such as 2-
phenyl-2-(2-phenylethynyl)oxirane and 2-phenyl-2-(1-pro-
pynyl)oxirane were used as substrates. These results indicate
(8) (a) An excess amount of diphosphine to the copper complex to
Cu(OTf)2 was added in the catalytic ring-opening reaction. We consider that
an equivalent amount of diphosphine is used to reduce Cu(II) complex to the
active species Cu(I) complex: Nieto, S.; Metola, P.; Lynch, V. M.; Anslyn,
E. V. Organometallics 2008, 27, 3608. (b) Cu(II)-catalyzed reactions of
epoxides with carbonyl compounds such as acetone gave the corresponding
1,3-dioxolanes: Krasik, P.; Bohemier-Bernard, M.; Yu, Q. Synlett 2005, 854.
(c) Separately, we confirmed that the ring-opening reaction proceeded smoothly in
the presence of a catalytic amount of Cu(OTf), but the catalytic use of Cu(OTf)2
promoted the ring-opening reaction more smoothly under the same reaction
conditions.
(9) For a recent review, see: Shimizu, H.; Nagasaki, I.; Matsumura, K.;
Sayo, N.; Saito, T. Acc. Chem. Res. 2007, 40, 1385.
7604 J. Org. Chem. Vol. 74, No. 20, 2009

Hattori et al.
JOCFeatured Article
SCHEME 3. Proposed Reaction Pathway for Ring-Opening Reaction of Ethynyl Epoxide
TABLE 3. Enantioselective Copper-Catalyzed Ring-Opening Reacti-
ons of 1 with Anilinesa
Preliminary results of a theoretical study on the copper-
catalyzed propargylic amination4 of propargylic acetates with
amines indicate that copper-allenylidene complexes may be
formed as key intermediates.11 Similarly, we consider that the
copper-allenylidene complex (E) might be formed by the
ring-opening reaction in the copper-acetylide complex (C),
which is formed from the copper-π-alkyne complex (A)
between 1a and copper complex bearing (R)-DTBM-MeO-
BIPHEP, via the copper-acetylide complex (B) (Scheme 3).
iPr2NEt promotes this deprotonation and protonation pro-
cesses from A to the copper-acetylide complex bearing a
carbocation at the γ-carbon (D: a resonance structure of E)
smoothly. Theinteraction between a phenyl group inacetylide
and a bulky aryl group in BIPHEP favors the formation of the
copper-acetylide complex (D0). Then, aniline attacks the γ-
carbon of D0 from si face,12 where the hydrogen bonding
between the oxygen of the hydroxyl group and hydrogen of
aniline is considered to play an important role to achieve the
high enantioselectivity (F). Finally, the higher acidity of the
proton of conjugate aniline in G promotes a hydrogen atom
shift to the R-carbon on the ligand to give another copper-π-
alkyne complex (H).
run
R
R0
time (h) yield of 2 (%) ee of 2 (%)b
1
2
3
4
5
6
7
8
9
4-ClC6H4 (1b) MeOC(O)
4-ClC6H4 (1b) CF3
4-BrC6H4 (1c) MeOC(O)
4-BrC6H4 (1c) CF3
4-MeC6H4 (1d) MeOC(O)
4-MeC6H4 (1d) CF3
4-PhC6H4 (1e) MeOC(O)
4-PhC6H4 (1e) CF3
3
3
3
3
6
6
3
3
3
3
2
2
12
12
48
48
98 (2p)
95 (2q)
96 (2r)
93 (2s)
96 (2t)
97 (2u)
97 (2v)
95 (2w)
95 (2x)
97 (2y)
95 (2z)
92 (2aa)
87 (2ab)
84 (2ac)
81 (2ad)
80 (2ae)
91
91
92
91
94
93
91
91
92
93
90
87
77
54
65
69
4-FC6H4 (1f)
MeOC(O)
CF3
10 4-FC6H4 (1f)
11 2-naphthyl (1g) MeOC(O)
12 2-naphthyl (1g) CF3
13 Me (1h)
14 Me (1h)
15 tBu (1i)
16 tBu (1i)
MeOC(O)
CF3
MeOC(O)
CF3
aAll reactions of 1 (0.20 mmol) with anilines (0.24 mmol) were carried
out in the presence of Cu(OTf)2 (0.004 mmol), (R)-DTBM-MeO-BI-
PHEP (0.01 mmol), and Pr2NEt (0.02 mmol) in acetone (2.0 mL) at
This proposed reaction pathway is supported by the deuterium
incorporation at the C-1 position in the ring-opening product (2a-
d1), which is due to the proton transfer in the proposed reaction
pathway, when 1a was treated with aniline-d7 (Scheme 4). At
present, we cannot exclude other reaction pathways,13 where
i
-20 °C. bDetermined by HPLC.
that this catalytic reaction proceeds not via classical SN2-
type ring-opening reaction at the oxirane moiety10 but via the
formation of copper-allenylidene complexes.4
(11) We will report more detailed results in due course. Hattori, G.;
Matsuzawa, H.;Sakata, K.; Miyake, Y.; Nishibayashi, Y. Unpublishedresults.
(12) The X-ray analysis of a major enantiomer of the tosylated compound
of 2f indicates that the absolute configuration of 2f is R. The molecular
structure of the tosylated compound of 2f was confirmed by X-ray analysis.
See the Supporting Information for experimental details.
(13) Murahashi and his co-workers proposed a free copper allenylidene as
an intermediate in the copper-catalyzed propargylic amination of pro-
pargylic esters with amines. However, no experimental evidence of this
intermediate appeared: Imada, Y.; Yuasa, M.; Nakamura, I.; Murahashi,
S.-I. J. Org. Chem. 1994, 59, 2282.
(10) For reviews of the classical SN2 type of ring-opening reactions of
racemic epoxides with nucleophiles, see: (a) Jacobsen, E. N. Acc. Chem. Res.
2000, 33, 421. (b) Schneider, C. Synthesis 2006, 3919. For recent examples of
the classical SN2 type of ring-opening reactions of optically active epoxides
with nucleophiles, see: (c) Taber, D. F.; He, Y.; Xu, M. J. Am. Chem. Soc.
2004, 126, 13900. (d) Lim, S. M.; Hill, N.; Myers, A. G. J. Am. Chem. Soc.
2009, 131, 5763.
J. Org. Chem. Vol. 74, No. 20, 2009 7605

Hattori et al.
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copper-allenylidene complexes may be formed via copper-
vinylidene complexes.14 Separately, we carried out the reaction
of 1a in the absence of aniline under the same reaction conditions,
where only a complex mixture was formed. This result is in sharp
contrast to the result of the molybdenum-catalyzed intramole-
cular cyclization of 2-ethynyloxiranes to afford the corresponding
furans via molybdenum-vinylidene intermediates.15
crude chlorohydrin. The resulting crude material was used for
the next step without further purification. In a 100 mL round-
bottomed flask were placed the crude chlorohydrin and anhy-
drous diethyl ether (10 mL). Powdered NaOH (2.0 g, 50.0 mmol)
was added to the solution slowly, and the mixture was stirred at
room temperature for 12 h. The reaction mixture was filtered,
and the solvent was concentrated under reduced pressure by an
aspirator, and the residue was purified by column chromato-
graphy (SiO2 supported by amino group) with hexane and ethyl
acetate (9:1) as an eluent to give 2-ethynyl-2-phenyloxirane
(1a)16 as a colorless oil (634 mg, 4.4 mmol; 44% yield).
SCHEME 4. Ring-Opening Reaction with Aniline-d7
Preparation of other ethynyl epoxides (1b, 1c, 1d, 1e, 1f, 1g,
1h,17 1i, 2-phenyl-2-(2-phenylethynyl)oxirane, and 2-phenyl-
2-(1-propynyl)oxirane) was carried out according to this method.
In the case of 2-phenyl-2-(2-phenylethynyl)oxirane or 2-phenyl-
2-(1-propynyl)oxirane, lithium phenylactylide or lithium 1-propy-
nyllithium18 was used instead of ethynylmagnesium bromide.
Spectroscopic data of some ethynyl epoxides are as follows.
2-(4-Chlorophenyl)-2-ethynyloxirane (1b): A pale yellow oil;
TLC (SiO2 supported by amino group) Rf (hexane/EtOAc 9:1)
0.45; 1H NMR δ 2.54 (s, 1H), 2.97 (d, J=5.9 Hz, 1H), 3.44 (d, J=
Finally, we carried out the ring-opening reaction of 1a
with 4-trifluoromethylaniline in the presence of 0.1 mol % of
Cu(OTf)2 and 0.25 mol % of (R)-DTBM-MeO-BIPHEP
(Scheme 5). Interestingly, the reaction proceeded effectively
to give 2f in 84% yield (TON=840) with 94% ee (R).
5.9 Hz, 1H), 7.33 (d, J=8.9 Hz, 2H), 7.43 (d, J=8.9 Hz, 2H); 13
C
NMR δ 50.3 (C), 58.9 (CH2), 73.0 (CH), 80.8 (C), 126.9 (CH),
128.6 (CH), 134.5 (C), 135.1 (C); HRMS calcd for C10H7ClO
[M] 178.0185, found 178.0178.
SCHEME 5. Ring-Opening Reaction in the Presence of 0.1 mol %
of Copper Catalyst
2-(4-Bromophenyl)-2-ethynyloxirane (1c): A colorless solid,
41.4-43.4 °C; TLC (SiO2 supported by amino group) Rf
(hexane/EtOAc 9:1) 0.45; 1H NMR δ 2.54 (s, 1H), 2.97 (d, J=
5.9 Hz, 1H), 3.44 (d, J=5.9 Hz, 1H), 7.36 (d, J=8.6 Hz, 2H), 7.49
(d, J=8.6 Hz, 2H); 13C NMR δ 50.3 (C), 58.9 (CH2), 73.0 (CH),
80.7 (C), 122.6 (C), 127.2 (CH), 131.6 (CH), 135.7 (C). Anal.
Calcd for C10H7BrO: C, 53.84; H, 3.16. Found: C, 54.20; H,
3.18.
Copper-Catalyzed Asymmetric Ring-Opening Reactions of
Racemic Ethynyl Epoxides with Amines. A typical experimental
procedure for the reaction of 2-ethynyl-2-phenyloxirane (1a)
with aniline is described below. In a 20 mL round-bottomed
flask were placed Cu(OTf)2 (1.5 mg, 0.004 mmol) and (R)-
DTBM-MeO-BIPHEP (12.1 mg, 0.010 mmol) under N2. Anhy-
drous acetone (1.0 mL) was added, and then the mixture was
magnetically stirred at 60 °C for 1 h. Then, 1a (29.8 mg,
0.20 mmol), aniline (23.5 mg, 0.24 mmol), and diisopropylethyl-
amine (2.6 mg, 0.020 mmol) in anhydrous acetone (1.0 mL) were
added under N2, and the reaction flask was kept at -20 °C for
1 h. The solvent was concentrated under reduced pressure by an
aspirator, and the residue was purified by column chromato-
graphy (SiO2) with hexane and ethyl acetate (90:10 to 70:30) as
eluents to give 2-phenyl-2-(phenylamino)-3-butyn-1-ol (2a) as a
pale yellow oil (46.7 mg, 0.19 mmol; 95% yield).
Conclusion
We have found enantioselective copper-catalyzed ring-
opening reactions of racemic ethynyl epoxides with amines
to give the corresponding amino alcohols in high yields with
up to 94% ee. The reaction is considered to proceed via
copper-allenylidene complexes as key intermediates. This
methodology may provide a novel synthetic approach to
optically active amino alcohols, the structures of which are
widely found in many natural products, biologically active
compounds, and chiral ligands. Further work is currently in
progress to broaden its synthetic applicability to natural
products and pharmaceuticals.
Experimental Section
2-Phenyl-2-(phenylamino)-3-butyn-1-ol (2a): Yield 95%; a
pale yellow oil; TLC (SiO2) Rf (hexane/EtOAc 7:3) 0.33;
1H NMR δ 2.24 (br, 1H), 2.54 (s, 1H), 3.64 (br d, 1H), 3.77 (d,
J=11.0 Hz, 1H), 5.01 (br, 1H), 6.56 (d, J=7.6 Hz, 2H), 6.73 (t,
J=7.6 Hz, 1H), 7.07 (dd, J=7.6, 7.6 Hz, 2H), 7.32-7.41 (m, 3H),
7.69 (d, J = 7.6 Hz, 2H); 13C NMR δ 61.5 (CH3), 72.9 (C),
74.6 (CH), 83.3 (CH2), 116.1 (CH), 118.8 (CH), 126.5 (CH),
128.1 (CH), 128.6 (CH), 128.8 (CH), 139.0 (C), 144.9 (C);
HRMS calcd for C16H15NO [M] 237.1154, found 237.1147;
[R]25D=þ144 (c=1.21, CHCl3); the optical purity was deter-
mined by HPLC analysis; Daicel Chiralcel AD, hexane/iPrOH=
90/10, flow rate =1.0 mL/min, λ =254 nm, retention time =
8.5 min (minor) and 13.3 min (major), 79% ee.
Preparation of Ethynyl Epoxides. A typical experimental
procedure for the preparation of 2-ethynyl-2-phenyloxirane
(1a) is described below. In a 100 mL round-bottomed flask were
placed phenacyl chloride (1.54 g, 10.0 mmol) and anhydrous
tetrahydrofuran (10 mL). Ethynylmagnesium bromide (0.5 M in
tetrahydrofuran; 22.0 mL, 11.0 mmol) was added to the solu-
tion, and the mixture was stirred at room temperature for 2 h.
The reaction was quenched by saturated NH4Cl aqueous solu-
tion (20 mL), and organic materials were extracted with diethyl
ether (20 mL ꢀ 2). The combined extracts were washed with
brine and dried over anhydrous MgSO4. The solvent was
concentrated under reduced pressure by an aspirator to give
Spectroscopic data of some products are as follows.
(14) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.; Noodleman,
L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem. Soc. 2005, 127, 210.
(16) Miller, D. J. Chem. Soc. (C) 1969, 12.
(17) Minami, I.; Yuhara, M.; Watanabe, H.; Tsuji, J. J. Organomet.
Chem. 1987, 334, 225.
€
(b) Furstner, A.; Stimson, C. C. Angew. Chem., Int. Ed. 2007, 46, 8845.
(c) Dıez-Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2008, 47, 8881.
ꢀ
(15) McDonald, F. E.; Schultz, C. C. J. Am. Chem. Soc. 1994, 116, 9363.
(18) Toussaint, D.; Suffert, J. Org. Synth. 1999, 76, 214.
7606 J. Org. Chem. Vol. 74, No. 20, 2009

Hattori et al.
JOCFeatured Article
2-Phenyl-2-[4-(trifluoromethyl)phenylamino]-3-butyn-1-
ol (2f): Yield 93%; a colorless solid, 88.1-89.0 °C; TLC (SiO2)
Rf (hexane/EtOAc 7:3) 0.35; 1H NMR δ 2.25 (br, 1H), 2.57 (s,
1H), 3.64 (d, J=11.3 Hz, 1H), 3.80 (d, J=11.3 Hz, 1H), 5.24
(br, 1H), 6.58 (d, J=8.6 Hz, 2H), 7.29-7.39 (m, 5H), 7.65 (d,
J=7.6 Hz, 2H); 13C NMR δ 61.1 (C), 72.8 (CH), 74.8 (CH2),
82.6 (C), 115.3 (CH), 120.3 (C, q, J=32 Hz), 124.8 (C, q, J=270
Hz), 125.9 (CH, q, J=3.9 Hz), 126.3 (CH), 128.4 (CH), 129.0
(CH), 138.2 (C), 147.7 (C); [R]25D =þ250 (c=0.61, CHCl3).
Anal. Calcd for C17H14F3NO: C, 66.88; H, 4.62; N, 4.59.
Found: C, 66.99; H, 4.80; N, 4.35. The optical purity was
determined by HPLC analysis; Daicel Chiralcel AD, hexane/
iPrOH=90/10, flow rate=1.0 mL/min, λ=254 nm, retention
time=8.3 min (minor) and 10.8 min (major), 94% ee.
min, λ=254 nm, retention time=9.3 min (minor) and 16.6 min
(major), 93% ee.
2-(4-Fluorophenyl)-2-[4-(trifluoromethyl)phenylamino]-3-
butyn-1-ol (2y): Yield 97%; a colorless amorphous; TLC (SiO2)
Rf (hexane/EtOAc 7:3) 0.30; 1H NMR δ 2.27 (br, 1H), 2.58 (s,
1H), 3.60 (d, J=11.1 Hz, 1H), 3.77 (d, J=11.1 Hz, 1H), 5.20 (br,
1H), 6.57 (d, J=8.4 Hz, 2H), 7.07 (dd, J=8.4, 8.4 Hz, 2H), 7.31
(d, J=8.4 Hz, 2H), 7.63 (dd, J=8.4, 5.4 Hz, 2H); 13C NMR δ
60.6 (C), 72.8 (CH), 75.0 (CH2), 82.4 (C), 115.3 (CH), 115.9 (CH,
d, J=21 Hz), 120.5 (C, q, J=32 Hz), 124.7 (C, q, J=270 Hz),
126.0 (CH, q, J=3.9 Hz), 128.1 (CH, d, J=8.3 Hz), 134.0 (C, d, J
=2.8 Hz), 147.6 (C), 162.7 (C, d, J=247 Hz); HRMS calcd for
C17H13F4NO [M] 323.0933, found 323.0926; [R]24D=þ215 (c=
0.80, CHCl3). The optical purity was determined by HPLC
analysis; Daicel Chiralcel AD, hexane/iPrOH=90/10, flow rate
=1.0 mL/min, λ=254 nm, retention time=9.4 min (minor) and
13.6 min (major), 93% ee.
Tosylation of 2f. In a 20 mL round-bottomed flask were
placed 2f (85.0 mg, 0.28 mmol) and anhydrous dichloroethane
(1.0 mL). p-Toluenesulfonyl chloride (58.3 mg, 0.31 mmol) and
triethylamine (34.0 mg, 0.34 mmol) were added to the solution,
and the mixture was stirred at room temperature for 6 h. The
reaction was quenched by water, and organic materials were
extracted with dichloroethane (20 mL ꢀ 2). The combined
extracts were washed with brine and dried over anhydrous
MgSO4. The solvent was concentrated under reduced pressure
by an aspirator, and the residue was purified by column
chromatography (SiO2) with hexane and ethyl acetate (85:15)
as an eluent to give tosylated 2f as a white solid (97.8 mg,
0.21 mmol; 76% yield).
Methyl 4-[N-(1-hydroxymethyl-1-phenyl-2-propynyl)amino]-
benzoate (2h): Yield 95%; a white solid, 132.2-134.8 °C; TLC
(SiO2) Rf (hexane/EtOAc 7:3) 0.21; 1H NMR δ 2.57 (s, 1H), 3.64
(d, J=11.3 Hz, 1H), 3.81 (d, J=11.3 Hz, 1H), 3.81 (s, 3H), 6.54
(d, J=8.9 Hz, 2H), 7.33-7.42 (m, 3H), 7.65 (d, J=8.9 Hz, 2H),
7.76 (d, J=8.9 Hz, 2H); 13C NMR δ 51.5 (CH3), 61.0 (C), 72.8
(CH), 74.2 (CH2), 82.6 (C), 115.0 (CH), 120.0 (C), 126.3 (CH),
128.4 (CH), 128.9 (CH), 130.7 (CH), 138.2 (C), 149.0 (C), 167.2
(C); [R]24 = þ269 (c = 0.82, CHCl3). Anal. Calcd for
D
C18H17NO3: C, 73.20; H, 5.80; N, 4.74. Found: C, 73.10; H,
6.01; N, 4.58. The optical purity was determined by HPLC
analysis; Daicel Chiralcel AD, hexane/iPrOH = 90/10, flow
rate = 1.0 mL/min, λ = 254 nm, retention time = 21.5 min
(minor) and 26.3 min (major), 93% ee.
Methyl 4-[N-[1-hydroxymethyl-1-(p-tolyl)-2-propynyl]amino]-
benzoate (2t): Yield 96%; a white solid, mp decompose; TLC
(SiO2) Rf (hexane/EtOAc 7:3) 0.26; 1H NMR δ 2.33 (s, 3H), 2.53
(s, 1H), 3.61 (d, J=11.2 Hz, 1H), 3.77 (d, J=11.2 Hz, 1H), 3.79
(s, 3H), 6.52 (d, J=8.9 Hz, 2H), 7.16 (d, J=8.9 Hz, 2H), 7.49 (d,
J=8.9 Hz, 2H), 7.74 (d, J=8.9 Hz, 2H); 13C NMR δ 21.0 (CH3),
51.5 (CH3), 60.8 (C), 72.8 (CH), 74.5 (CH2), 82.7 (C), 114.9
(CH), 119.8 (C), 126.2 (CH), 129.6 (CH), 130.7 (CH), 135.2 (C),
138.2 (C), 149.1 (C), 167.2 (C); HRMS calcd for C19H19NO3 [M]
309.1365, found 309.1355; [R]25D = þ192 (c = 0.88, CHCl3).
Anal. Calcd for C19H19NO3: C, 73.77; H, 6.19; N, 4.53. Found:
C, 73.31; H, 6.30; N, 4.55. The optical purity was determined by
HPLC analysis; Daicel Chiralcel AD, hexane/iPrOH=90/10,
flow rate=1.0 mL/min, λ=254 nm, retention time=20.8 min
(minor) and 28.0 min (major), 94% ee.
2-Phenyl-2-[4-(trifluoromethyl)phenylamino]-3-butynyl p-to-
luenesulfonate: A white solid, mp decompose; TLC (SiO2) Rf
(hexane/EtOAc 7:3) 0.50; 1H NMR δ 2.46 (s, 3H), 2.49
(s, 1H), 4.12 (s, 2H), 6.54 (d, J=8.4 Hz, 2H), 7.23-7.36 (m,
7H), 7.60-7.63 (m, 2H), 7.77 (d, J=8.4 Hz, 2H); 13C NMR δ
21.6 (CH3), 58.5 (C), 75.2 (CH), 75.8 (CH2), 80.5 (C), 115.5
(CH), 120.6 (C, q, J=32 Hz), 124.7 (C, q, J=270 Hz), 125.8 (CH,
q, J=3.9 Hz), 126.7 (CH), 128.0 (CH), 128.9 (CH), 129.0 (CH),
130.0 (CH), 132.2 (C), 136.7 (C), 145.4 (C), 146.8 (C); [R]25
=
D
þ176 (c = 0.84, CHCl3). Anal. Calcd for C24H20F3NO3S: C,
62.74; H, 4.39; N, 3.05. Found: C, 62.64; H, 4.60; N, 2.80.
Acknowledgment. This work was supported by Grants-in-
Aid from the Ministry of Education, Culture, Sports, Science
and Technology, Japan. We thank Solvias AG and Takasago
International Corporation for the gifts of BIPHEP and
SEGPHOS, respectively. Y.N. thanks the Asahi Glass Foun-
dation. G.H. is a recipient of the JSPS Predoctoral Fellow-
ships for Young Scientists. We also thank Todai-ji for
permission and Mr. Hiromichi Inoue for a photograph of
the cover art.
2-(p-Tolyl)-2-[4-(trifluoromethyl)phenylamino]-3-butyn-1-ol
(2u): Yield 97%; a white solid, 142.1-144.7 °C; TLC (SiO2) Rf
1
(hexane/EtOAc 7:3) 0.35; H NMR δ 2.17 (br, 1H), 2.36 (s,
3H), 2.56 (s, 1H), 3.62 (d, J=11.1 Hz, 1H), 3.77 (d, J=11.1 Hz,
1H), 6.59 (d, J=8.9 Hz, 2H), 7.18 (d, J=8.9 Hz, 2H), 7.30 (d, J=
8.9 Hz, 2H), 7.52 (d, J=8.9 Hz, 2H); 13C NMR δ 21.0 (CH3),
60.8 (C), 72.9 (CH), 74.6 (CH2), 82.8 (C), 115.2 (CH), 120.2 (C,
q, J=32 Hz), 124.8 (C, q, J=270 Hz), 125.9 (CH, q, J=3.9 Hz),
126.2 (CH), 129.7 (CH), 135.2 (C), 138.2 (C), 147.8 (C); [R]24
=
D
þ210 (c = 1.12, CHCl3). Anal. Calcd for C18H16F3NO: C,
67.70; H, 5.05; N, 4.39. Found: C, 67.93; H, 5.10; N, 4.44. The
optical purity was determined by HPLC analysis; Daicel
Chiralcel AD, hexane/iPrOH = 90/10, flow rate = 1.0 mL/
Supporting Information Available: Spectroscopic data and
X-ray data. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 20, 2009 7607