Ruthenium-catalyzed enantioselective propargylation of aromatic compounds with propargylic alcohols via allenylidene intermediates

Article abstract of DOI:10.1002/anie.200701261

(Chemical Equation Presented) High enantioselectivity was achieved in the Ru-catalyzed propargylation of furans and N,N-dimethylaniline derivatives to afford the propargylated aromatic compounds. This first asymmetric propargylation of aromatic compounds

Full text of DOI:10.1002/anie.200701261

Communications
DOI: 10.1002/anie.200701261
Asymmetric Catalysis
Ruthenium-Catalyzed Enantioselective Propargylation of Aromatic
Compounds with Propargylic Alcohols via Allenylidene
Intermediates**
Hiroshi Matsuzawa, Yoshihiro Miyake, and Yoshiaki Nishibayashi*
The Friedel–Crafts reaction is one of the most reliable and
temperature for 12 h), and NH4BF4 at 608C for 3 h afforded 2-
methyl-5-(1-phenyl-2-propynyl)furan (3a), which was iso-
lated in 75% yield with 77% ee (Table 1, entry 1). A decrease
[1]
À
powerful C C bond forming tools in organic synthesis.
Recently, the development of an asymmetric Friedel–Crafts
alkylation of aromatic compounds has received a great deal of
attention. This reaction introduces chiral centers at the
benzylic position of aromatic compounds,[2] and a variety of
Lewis acids and organocatalysts are available to promote the
reaction.[2,3] However, the successful examples of asymmetric
Friedel–Crafts alkylation are still limited to reactions with
three types of electrophiles such as epoxides, carbonyl
compounds, activated alkenes, and their analogues.[2,3]
Table 1: Ruthenium-catalyzed enantioselective propargylation of 2-meth-
ylfuran with propargylic alcohol 1a.[a]
We have recently disclosed the novel catalytic activity[4] of
chalcogenolate-bridged diruthenium complexes[5] such as
[{Cp*RuCl(m2-YR)}2] (Cp* = h5-C5Me5; Y= S, Se, Te; R =
Me, nPr, iPr) and [Cp*RuCl(m2-YR)2RuCp*(OH2)]OTf
(Tf = trifluoromethanesulfonyl) for many organic transfor-
mations via ruthenium–allenylidene intermediates.[6] One of
these transformations is the propargylation of aromatic
compounds with propargylic alcohols.[7–9] We envisaged the
development of a catalytic enantioselective propargylation of
aromatic compounds as a new type of asymmetric Friedel–
Crafts alkylation of aromatic compounds by taking account of
our previous development of the ruthenium-catalyzed enan-
tioselective propargylic substitution reactions of propargylic
alcohols with acetone (up to 82% ee).[10] We report here a
successful example of an asymmetric Friedel–Crafts alkyla-
tion by using propargylic alcohols as electrophiles.
Entry
Equiv
T [8C]
t [h]
Yield [%][c]
ee [%][d]
of furan[b]
1
2
3
4
5
6
10
10
10
10
5
60
80
40
RT
60
60
3
2
6
9
3
6
75
37
63
66
61
47
77
79
75
72
81
82
3
[a] All reactions of 1a (0.20 mmol) with 2-methylfuran were carried out in
the presence of a Ru complex (0.010 mmol, generated in situ from
[{Cp*RuCl}4] and 2a) and NH4BF4 (0.020 mmol) in ClCH2CH2Cl (5 mL).
[b] Equivalent of furan with respect to 1a. [c] Yield of isolated 3a.
[d] Determined by HPLC (see the SupportingInformation for details).
Treatment of 1-phenyl-2-propyn-1-ol (1a) with 2-methyl-
furan (10 equiv) in ClCH2CH2Cl in the presence of a catalytic
amount of a chiral thiolate-bridged diruthenium complex 2a,
(prepared in situ from the tetranuclear ruthenium(II) com-
plex [Cp*RuCl]4 and a chiral disulfide[10b] in THF at room
in yield of 3a was observed at slightly higher temperatures,
such as 808C (Table 1, entry 2). The formation of the
corresponding oligomers was observed as side products in
all cases, especially when the reaction was carried out at high
temperature. On the other hand, the reaction at lower
temperatures, such as 408C and at room temperature,
proceeded similarly with a slight decrease in the yield of 3a
(Table 1, entries 3 and 4). Even without the use of excess 2-
methylfuran, the reaction proceeded, but the yield of 3a
decreased (Table 1, entries 5 and 6). In all cases, the
enantioselectivity was not greatly affected.
[*] Dr. H. Matsuzawa, Dr. Y. Miyake, Prof. Dr. Y. Nishibayashi
Institute of Engineering Innovation
School of Engineering, The University of Tokyo
Yayoi, Bunkyo-ku, Tokyo, 113-8656 (Japan)
Fax: (+81)3-5841-1175
E-mail: ynishiba@sogo.t.u-tokyo.ac.jp
Homepage: http://park.itc.u-tokyo.ac.jp/nishiba/
Avariety of optically active disulfides were investigated as
chiral ligands in the reaction of 1a with 2-methylfuran as
shown in Scheme 1. The presence of three aryl groups in the
2-, 3-, and 5-positions of the benzene ring of the chiral
disulfide was necessary to achieve the high enantioselectivity.
In fact, the use of chiral disulfides (2b–2 f) with one or two
phenyl groups on the benzene ring apparently decreased the
enantioselectivity. A similar tendency has been observed in
the catalytic propargylation of acetone with propargylic
alcohols.[10b]
[**] This work was supported by Grant-in-Aids for Scientific Research on
Priority Areas (18037012 and 18066003) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan, and the
Industrial Technology Research Grant Program in 2005 from the
New Energy and Industrial Technology Development Organization
(NEDO) of Japan. Y.N. thanks the Nagase and Tokuyama Science
and Technology Foundation.
Supportinginformation for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Table 2: Ruthenium-catalyzed enantioselective propargylation of 2-
methylfuran with propargylic alcohols 1.[a]
Entry
Ar
t [h]
Yield of 3 [%][b]
ee of 3 [%][c]
1
2
3
4
5
6
7
8
1a, Ph
3
3
3
6
3
6
3
3
6
3
2
3a, 75
3b, 67
3c, 44
3d, 40
3e, 63
3 f, 52
3g, 77
3h, 83
3i, 59
3j, 67
3k, 59
77
82
86
81
68
94
89
76
86
83
79
1b, p-MeC6H4
1c, o-MeC6H4
1d, p-MeOC6H4
1e, p-ClC6H4
1 f, o-PhC6H4
1g, p-PhC6H4
1h, 3,5-Ph2C6H3
1i, 1-napthyl
1j, 2-naphthyl
1a, Ph
9
10
11[d]
[a] All reactions of 1 (0.20 mmol) with 2-methylfuran (2.00 mmol) were
carried out in the presence of a Ru complex (0.010 mmol, generated
in situ from [{Cp*RuCl}4] and 2a) and NH4BF4 (0.020 mmol) in
ClCH2CH2Cl (5 mL) at 608C. [b] Yield of isolated product. [c] Determined
by HPLC (see the SupportingInformation for details). [d] 2-Ethylfuran
(2.00 mmol; 10 equiv) was used in place of 2-methylfuran at 808C.
under the same reaction conditions, the reactions of prop-
argylic alcohols 1 with N,N-dimethylaniline (10 equiv) gave
the corresponding N,N-dimethyl-4-(1-aryl-2-propynyl)ani-
lines 4 in high enantioselectivity (Scheme 2). In all cases,
only moderate yields of the isolated products were obtained
because of formation of the corresponding oligomers as side-
products and/or loss of the product on purification.
Scheme 1. Reactions of 1-phenyl-2-propyn-1-ol (1a) with 2-methylfuran
in the presence of chiral thiolate-bridged diruthenium complexes,
generated in situ from [{Cp*RuCl}4] and chiral disulfides 2.
Next, the catalytic propargylation of 2-methylfuran with
other propargylic alcohols was investigated by using 2a as a
chiral ligand. Typical results are shown in Table 2. The
presence of a substituent in the benzene ring of the
propargylic alcohols greatly affected the enantioselectivity.
The introduction of a methyl or methoxy moiety in the para or
ortho position of the benzene ring of 1a slightly improved the
enantioselectivity (Table 2, entries 2–4), while introduction of
a chlorine moiety decreased the enantioselectivity (Table 2,
entry 5). The introduction of one or two phenyl groups on the
benzene ring of the propargylic alcohols, as well as the use of
1-naphthyl-2-propyn-1-ols, increased the enantioselectivity
(Table 2, entries 6–10). For example, the reaction with a
propargylic alcohol with a phenyl group on the ortho position
of the benzene ring gave the highest enantioselectivity
(94% ee; Table 2, entry 6). The use of 2-ethylfuran
(10 equiv) in place of 2-methylfuran gave the corresponding
propargylated furan 3k in 59% yield and 79% ee (Table 2,
entry 11). After one recrystallization, an optically pure
propargylated aromatic compound was obtained in some
cases.
To obtain more information about the enantioselective
propargylation of aromatic compounds, the stereochemistry
of the propargylated product 4a was determined. Hydro-
genation of the propargylated product 4a in the presence of a
catalytic amount of Pd/C under one atmosphere of H2 at room
temperature for 12 h gave 1-[4-(N,N-dimethylamino)phenyl]-
1-phenylpropane (5) in quantitative yield (Scheme 3). The
absolute configuration of 5 thus obtained was in accord with
(R)-5 obtained by the reported method[11] (Scheme 3), which
shows that the original propargylated product 4a has an
R absolute configuration. These results support our previ-
ously proposed reaction pathway for the propargylation of
acetone,[10] in which the p–p interaction of phenyl rings
between the chiral ligand and allenylidene moieties plays an
important role in the achievement of high enantioselectivity
(Figure 1). Here, N,N-dimethylaniline should attackthe
alkynyl complex 7’ with a cationic g-carbon atom, which is a
resonance structure of the allenylidene complex (7) prepared
from a propargylic alcohol and the diruthenium complex,
from the Si face (Scheme 4).[4,7] Thus, this asymmetric Frie-
del–Crafts alkylation reaction offers a rare example of a
stereoselective reaction via carbocations as reactive inter-
mediates.
As reported from our previous studies,[7] N,N-dimethyl-
aniline is less reactive than 2-alkylfuran in the propargylation
of aromatic compounds with propargylic alcohols catalyzed
by the methanethiolate-bridged diruthenium complex.
Although a large excess of N,N-dimethylaniline was necessary
to fully convert the starting propargylic alcohols into product
Finally, we carried out the reactions of optically active
propargylic alcohols (R)- and (S)-1a with 2-methylfuran using
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Figure 1. Transition state of the reaction of an allenylidene intermedi-
ate with 2-methylfuran.
Scheme 4. Attack of the aromatic compound on the Si face at the Cg
atom of the allenylidene complex.
By considering the above experimental results, a reaction
pathway of this enantioselective propargylation of aromatic
compounds is proposed in Scheme 6 for the propargylation of
2-methylfuran as a representative example. Initially, a vinyl-
idene complex is formed in the reaction of a chiral diruthe-
nium complex with 1a in the presence of NH4BF4. Dehy-
dration of the vinylidene complex leads to an allenylidene
complex, in which the racemization of the allenylidene moiety
rapidly occurs via the corresponding alkynyl complex when
an optically active propargylic alcohol is used as a substrate.
Scheme 2. Reactions of 1-aryl-2-propyn-1-ols 1 with N,N-dimethylani-
line in the presence of chiral thiolate-bridged diruthenium complex,
generated in situ from [{Cp*RuCl}4] and chiral disulfide 2a. All yields
are of the isolated product.
2a as a chiral ligand. In both cases, the propargylated product
3a was obtained in almost the same yield with a similar
enantioselectivity and the same absolute configuration
(Scheme 5). As expected, no optical activity was observed
in 1a recovered from the reaction carried out under the
conditions shown in Scheme 5a. Thus, there is no substantial
reactivity difference between (R)-1a and (S)-1a, which
indicates that the isomerization occurs easily at the chiral
allenylidene intermediates before the attackof 2-methyl-
furan.
Scheme 5. Reactions of optically active 1-phenyl-2-propyn-1-ols (1a)
with 2-methylfuran in the presence of chiral thiolate-bridged diruthe-
nium complex, generated in situ from [{Cp*RuCl}4] and 2a.
Scheme 3. Determination of the absolute configuration of the propar-
gylated aromatic compound 4a. AIBN=2,2’-azobisisobutyronitrile.
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Uemura, Organometallics 2004, 23, 5100, and references therein.
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Eur. J. Org. Chem. 2006, 881.
[8] E. Bustelo, P. H. Dixneuf, Adv. Synth. Catal. 2005, 347, 393.
[9] Some metal salts and Brønsted acid have been reported to
function as catalysts for the propargylation of aromatic com-
pounds; see: a) M. Georgy, V. Boucard, J.-M. Campagne, J. Am.
Chem. Soc. 2005, 127, 14180; b) Z. Zhan, J. Yu, H. Liu, Y. Cui, R.
Yang, W. Yang, J. Li, J. Org. Chem. 2006, 71, 8298; c) R. Sanz, A.
Martꢀnez, J. M. ꢁlvarez-Gutiꢂrrez, F. Rodrꢀguez, Eur. J. Org.
Chem. 2006, 1383; d) Z.-P. Zhan, W.-Z. Yang, R.-F. Yang, J.-L.
Yu, J.-P. Li, H.-J. Liu, Chem. Commun. 2006, 3352.
Scheme 6. Proposed reaction pathway.
Subsequent nucleophilic attackof 2-methylfuran on the C
g
atom of the allenylidene ligand results in the formation of
another vinylidene complex. This vinylidene complex is then
transformed into a h2-coordinated alkyne complex, which
liberates the propargylated furan 3a by reaction with a
propargylic alcohol 1a, and regenerates the starting complex.
We proposed a similar catalytic cycle for the sulfur-bridged
diruthenium-catalyzed propargylic substitution reactions of
propargylic alcohols with nucleophiles in our previous studies,
along with a DFT calculation.[4a,c] It has already been
proposed that the synergistic effect in the diruthenium
complex is quite important for the promotion of the catalytic
reaction.[4a,c]
In summary, we have found that the ruthenium-catalyzed
enantioselective propargylation of aromatic compounds such
as 2-alkylfurans and N,N-dimethylaniline with propargylic
alcohols affords the corresponding propargylated aromatic
compounds selectively in good yields with high enantioselec-
tivity (up to 94% ee). This is the first example of asymmetric
propargylation of aromatic compounds. The synthetic method
described in this article provides a novel protocol for the
catalytic asymmetric Friedel–Crafts alkylation of aromatic
compounds, by using propargylic alcohols as a new type of
electrophiles, because, to date, the selective propargylation of
aromatic compounds is known to be quite difficult.[12]
[10] a) Y. Nishibayashi, G. Onodera, Y. Inada, M. Hidai, S. Uemura,
Organometallics 2003, 22, 873; b) Y. Inada, Y. Nishibayashi, S.
Uemura, Angew. Chem. 2005, 117, 7823; Angew. Chem. Int. Ed.
2005, 44, 7715.
[11] K. Okamoto, Y. Nishibayashi, S. Uemura, A. Toshimitsu, Angew.
Chem. 2005, 117, 3654; Angew. Chem. Int. Ed. 2005, 44, 3588.
[12] The Nicholas reaction has been known to be effective for the
propargylation of aromatic compounds by use of a stoichiomet-
ric amount of [Co2(CO)8], in which several steps are necessary to
obtain propargylated products from propargylic alcohols via the
cationic propargyl complexes [(propargyl)Co2(CO)6]+; a) K. M.
Nicholas, Acc. Chem. Res. 1987, 20, 207, and references therein;
b) A. J. M. Caffyn, K. M. Nicholas, Comprehensive Organome-
tallic Chemistry II, Vol. 12 (Eds.: E. W. Abel, F. G. A. Stone, G.
Wilkinson), Pergamon, New York, 1995, chap. 7.1; c) J. R.
Green, Curr. Org. Chem. 2001, 5, 809; d) B. J. Teobald,
Tetrahedron 2002, 58, 4133.
Received: March 22, 2007
Revised: April 27, 2007
Published online: June 5, 2007
Keywords: alkylation · asymmetric catalysis ·
.
propargylic alcohols · ruthenium · S ligands
[1] G. A. Olah, R. Krishnamurti, G. K. S. Prakash, Friedel–Crafts
Alkylation in Comprehensive Organic Synthesis, Vol. 3 (Eds.:
B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, p. 293.
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