[Ir(cod)Cl]2/FDPPE-catalyzed chemo- and regioselective cyclotrimerization of two different terminal alkynes to give 1,3,5-trisubstituted benzenes

Article abstract of DOI:10.1055/s-2008-1042810

[Ir(cod)Cl]₂ in combination with 1,2- bis(dipentafluorophenylphosphino)ethane catalyzes chemo- and regioselective cyclotrimerization of two different alkynes. The reaction of methyl propiolate with 1-hexyne gave methyl 3,5-di(n-butyl)benzoate a

Full text of DOI:10.1055/s-2008-1042810

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755
[Ir(cod)Cl]2/FDPPE-Catalyzed Chemo- and Regioselective Cyclotrimerization
of Two Different Terminal Alkynes To Give 1,3,5-Trisubstituted Benzenes
[
Ir(cod)Cl] /FDPP
e
E
-Catalyze
d
Chemo- and
Regi
O
oselective
C
yclotr
n
imerization odera, Masayoshi Matsuzawa, Takahiro Aizawa, Takeshi Kitahara, Yoshihisa Shimizu, Satoko Kezuka,1
2
Ryo Takeuchi*
Department of Chemistry and Biological Science, Aoyama Gakuin University, Fuchinobe, Sagamihara 229-8558, Japan
Fax +81(42)7596493; E-mail: takeuchi@chem.aoyama.ac.jp
Received 29 November 2007
er, the reaction of 1a with 2a catalyzed by [Ir(cod)Cl]2/
Abstract: [Ir(cod)Cl]2 in combination with 1,2-bis(dipentafluo-
rophenylphosphino)ethane catalyzes chemo- and regioselective cy-
clotrimerization of two different alkynes. The reaction of methyl
propiolate with 1-hexyne gave methyl 3,5-di(n-butyl)benzoate as a
single product in 88% yield.
DPPE gave no product (3aa); [Ir(cod)Cl]2/PPh3 and
[Ir(cod)Cl]2 alone were examined as catalysts. Only
[Ir(cod)Cl]2/FDPPE gave 3aa. Other transition-metal
complexes combined with FDPPE were also examined for
the reaction of 1a with 2a; [Rh(cod)Cl]2/FDPPE,
Pd(dba)2/FDPPE and Ni(cod)2/FDPPE were inert as cata-
lysts. The molar ratio of 1a to 2a affected the yield of 3aa.
The results are summarized in Table 1. The use of an ex-
cess amount of 2a to 1a is needed to give 3aa in good
yield. The reaction using 3 equivalents of 2a gave 3aa in
88% yield (Table 1, entry 2). The use of 4 equivalents or
2.1 equivalents of 2a to 1a slightly decreased the yield of
3aa (Table 1, entries 1 and 3). On the other hand, the use
of 1 or 2 equivalents of 1a to 2a gave 3aa in poor yields
(Table 1, entries 4 and 5).
Key words: iridium, cyclotrimerization, regioselectivity, alkynes,
catalysis
Polysubstituted benzenes are a common structural com-
ponent of naturally occurring biologically active mole-
cules. The traditional synthesis of polysubstituted
benzene is based on the stepwise introduction of substitu-
ents via electrophilic substitution.2 This process is not
atom-economical or environmentally benign, since a stoi-
chiometric amount of waste is produced as a byproduct.
To overcome these drawbacks, transition-metal-catalyzed
cyclotrimerization to give benzene derivatives has been
studied extensively.3 The regioselective cyclotrimeriza-
tion of two or three different monoynes is a new and effi-
cient route to polysubstituted benzenes. However, it can
be difficult to control the regioselectivity. There are limit-
ed examples of the successful regioselective cyclotrimer-
ization of two or three different monoynes.4 In the course
of our study on iridium-catalyzed cycloaddition of
alkynes,5 we have previously reported the [Ir(cod)Cl]2-
catalyzed highly selective cycloaddition of dimethyl acet-
ylenedicarboxylate (DMAD) with monoynes.5d In that
study, we observed the unique reactivity of
(C6F5)2PCH2CH2P(C6F5)2 (FDPPE) as a ligand. We found
that [Ir(cod)Cl]2/DPPE catalyzed the 2:1 coupling of
DMAD with a monoyne, whereas [Ir(cod)Cl]2/FDPPE
catalyzed the 1:2 coupling of DMAD with a monoyne. In
this communication, we wish to report the [Ir(cod)Cl]2/
FDPPE-catalyzed chemo- and regioselective cyclotrimer-
ization of two different terminal alkynes to give 1,3,5-
trisubstituted benzenes.
Table 1 Effect of Molar Ratio on the Reaction of 1a with 2aa
CO2Me
CO2Me
n-Bu
[Ir(cod)Cl]2/FDPPE
THF, reflux
+
n-Bu
n-Bu
1a
2a
3aa
Entry
1a (mmol)
2a (mmol)
Yield of 3aa (%)b
1
2
3
4
5
1
1
1
2
4
4
83
3
88
2.1
2
71
34c
14c
2
a A mixture of 1a, 2a, [Ir(cod)Cl]2 (0.02 mmol), FDPPE (0.04 mmol),
and THF (5 mL) was stirred under refluxing THF for 2 h.
b Yields were isolated yields based on 1a.
c Yields were isolated yields based on 2a.
We examined the scope of the cross-cyclotrimerization.6
All of the reactions listed in Table 2 gave a single prod-
uct.7 Methyl propiolate (1a) smoothly reacted with vari-
ous 1-alkynes (2b–h) to give 3 in high yields. The results
are summarized in Table 2. The reactions with 1-octyne
(2b) and 1-decyne (2c) gave the corresponding products
in high yields (Table 2, entries 1 and 2). Conjugated
enynes could be used for the reaction. The reaction with
phenylacetylene (2d) required a longer reaction time than
that with ethynylcyclohexene (2e). Teraryl 3ad was ob-
Methyl propiolate (1a) reacted with two molecules of 1-
hexyne (2a) to give 3aa in the presence of a catalytic
amount of [Ir(cod)Cl]2 and FDPPE. Previously, we re-
ported that DPPE was an efficient ligand for the
[Ir(cod)Cl]2-catalyzed cycloaddition of alkynes. Howev-
SYNLETT 2008, No. 5, pp 0755–0758
x
x.
x
x.
2
0
0
8
Advanced online publication: 26.02.2008
DOI: 10.1055/s-2008-1042810; Art ID: Y01807ST
© Georg Thieme Verlag Stuttgart · New York

756
G. Onodera et al.
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tained in 85% yield (Table 2, entry 3). This reaction is used in numerous carbon–carbon and carbon–nitrogen
useful for the synthesis of teraryl compounds. The reac- bond-forming reactions as well as other transformations.
tion of 1a with 2e gave 3ae in 72% yield (Table 2, entry We first attempted to carefully reduce 3aa to 4aa with
4). Methyl propiolate reacted smoothly with 2f, in which DIBAL-H, but instead obtained a mixture of alcohol and
the phenyl group is away from a triple bond, as in 2a or aldehyde 4aa. We then tried reduction–in situ manganese
2b, to give 3af in 88% yield (Table 2, entry 5). The reac- dioxide alcohol oxidation (Table 3).7,10 Various 3,5-di-
tion with monoynes bearing a functional group, such as a substituted benzaldehydes 4 were obtained from 3,5-di-
chloro or cyano group, gave 3ag and 3ah in high yields substituted benzoates by this procedure without isolation
(Table 2, entries 6 and 7). The reaction of ethynyl p-tolyl of the intermediate alcohols.
sulfone (1b) with various 1-alkynes (2a,c,d,g) gave the
corresponding products in high yields (Table 2, entries 8–
Table 3 Reduction–in Situ Manganese Dioxide Alcohol Oxidationa
11).
CHO
CO2Me
reduction
CH2OH
MnO2
Table 2 Reaction of 1 with 2a
CH2Cl2, r.t.
E
R
R
R
R
R
R
E
R
3
4
[Ir(cod)Cl]2/FDPPE
THF, reflux
+
Entry
R
Time (h) Time (h) Product Yield
reduction oxidation 4
(%)b
R
R
1
2
3
1
2
3
4
5
6
7c
n-Bu (3aa)
n-Hex (3ab)
Ph (3ad)
4
5
30
31
41
24
34
31
9
4aa
4ab
4ad
4ae
4af
88
Entry E
R
Time Prod. Yield
(h)
16
5
3
(%)b
96
84
85
72
88
82
90
66
90
58
95
80
1
2
CO2Me (1a)
CO2Me (1a)
n-Hex (2b)
n-Oct (2c)
Ph (2d)
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ba
3bc
3bd
3bg
4
83
1-cyclohexenyl (3ae)
Ph(CH2)3 (3af)
8
68
3c CO2Me (1a)
CO2Me (1a)
5c CO2Me (1a)
14
6
14
6
85
4
1-cyclohexenyl (2e)
Ph(CH2)3 (2f)
Cl(CH2)3 (2g)
NC(CH2)3 (2h)
n-Bu (2a)
Cl(CH2)3 (3ag)
4ag
4ah
82
4
NC(CH2)3 (3ah)
8
58
a A mixture of 3 (1 mmol), LiAlH4 (1.5 mmol), and Et2O (5 mL) was
stirred at r.t. Then, a mixture of crude alcohol, MnO2 (10 mmol), and
CH2Cl2 (5 mL) was stirred.
6
7
8
9
CO2Me (1a)
CO2Me (1a)
SO2p-Tol (1b)
SO2p-Tol (1b)
5
4
b Yields were isolated yields based on 3.
24
5
c A mixture of 3ah (1 mmol), DIBAL-H (3 mmol), and THF (5 mL)
was stirred at –78 °C. Then, a mixture of crude alcohol, MnO2 (10
mmol), and CH2Cl2 (5 mL) was stirred.
n-Oct (2c)
10 SO2p-Tol (1b)
11 SO2p-Tol (1b)
Ph (2d)
2
Cl(CH2)3 (2g)
5
It is reasonable to consider that the reaction proceeds via
iridacyclopentadiene11 as an intermediate. Iridacyclopen-
tadiene can be produced as an intermediate either from
two molecules of 2 or from 1 and 2. To obtain additional
mechanistic information, we examined the cyclotrimer-
ization of 1-hexyne. The cyclotrimerization of 1-hexyne
under refluxing toluene in the presence of [Ir(cod)Cl]2 (Ir
atom 4 mol%) and FDPPE gave no benzene derivative.
The formation of an iridacyclopentadiene from two mole-
cules of 1-hexyne is unlikely. The regioselectivity of the
reaction can be explained by the selective formation of an
iridacyclopentadiene from 1 and 2. The reaction of 1 with
2 can give iridacyclopentadiene 5 and 6 (Scheme 1). The
second molecule of 2 reacts with 5 or 6 to give 3 as a final
product. Due to steric considerations, the more hindered
a-carbon of 5 and 6 smoothly couples with unsubstituted
alkyne carbon to give 3. The regioselectivity of the forma-
tion of metallacyclopentadiene has been reported. The re-
action of diphenylacetylene cobalt Cp complex with
methyl propiolate gave a cobaltacyclopentadiene com-
plex, in which a carbomethoxy group occupied the a-po-
sition.12 On this basis, an iridacyclopentadiene 5 is a more
a A mixture of 1 (1 mmol), 2 (3 mmol), [Ir(cod)Cl]2 (0.02 mmol), FD-
PPE (0.04 mmol), and THF (5 mL) was stirred under refluxing THF.
b Yields were isolated yields based on 1.
c Conditions: 1a (2 mmol), 2 (6 mmol), [Ir(cod)Cl]2 (0.04 mmol), FD-
PPE (0.08 mmol), THF (10 mL).
1,3,5-Trisubstituted benzenes have attracted considerable
attention as basic components in dendrimers.8 The central
core, the surface unit and the branching propagating unit
need this structure. The synthetic approach to 1,3,5-trisub-
stituted benzene via traditional electrophilic substitution
requires long synthetic sequences. For example, 3,5-di-
alkyl benzoate, which is the surface unit of dendrimer, can
be prepared in three steps from benzoate: meta-selective
bromination of benzoate, Sonogashira coupling with 1-
alkyne and hydrogenation of a carbon–carbon triple
bond.9 Our cyclotrimerization provides the most efficient
route to 3,5-disubstituted benzoate.
Aromatic aldehydes are a very useful class of products,
since the highly reactive aldehyde group can be readily
Synlett 2008, No. 5, 755–758 © Thieme Stuttgart · New York

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[Ir(cod)Cl]2/FDPPE-Catalyzed Chemo- and Regioselective Cyclotrimerization
757
Chemistry II, Vol. 12; Abel, E. W.; Stone, F. G. A.;
Wilkinson, W., Eds.; Pergamon: Oxford, 1995, 741.
(i) Schore, N. E. In Comprehensive Organic Synthesis, Vol.
5; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford, 1991,
1129.
likely intermediate. [Ir(cod)Cl]2/FDPPE gave no cyclotri-
merization of two molecules of 1 with one molecule of 2.
The coordination of two molecules of methyl propiolate
(1a) or ethynyl p-tolyl sulfone (1b) to Ir(FDPPE)Cl spe-
cies gives an electron-deficient species. Since an electron-
rich species is more favorable for oxidative addition, the
oxidative cyclization of 1 and 2 to give an iridacyclopen-
tadiene is preferred over that of two molecules of 1 to give
an iridacyclopentadiene.
(4) (a) Tanaka, K.; Toyoda, K.; Wada, A.; Shirasaki, K.; Hirano,
M. Chem. Eur. J. 2005, 1145. (b) Chang, H.-T.;
Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2005,
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Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005,
127, 9625. (e) Chouraqui, G.; Petit, M.; Aubert, C.;
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Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2004,
126, 3712. (g) Ura, Y.; Sato, Y.; Shiotsuki, M.; Kondo, T.;
Mitsudo, T. J. Mol. Catal. A: Chem. 2004, 209, 35.
(h) Tanaka, K.; Shirasaka, K. Org. Lett. 2003, 5, 4697.
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R
E
E
R
Ir
Ir
6
Ln
5
Ln
+
+
R
R
(5) (a) Takeuchi, R.; Kezuka, S. Synthesis 2006, 3349.
(b) Kezuka, S.; Tanaka, S.; Ohe, T.; Nakaya, Y.; Takeuchi,
R. J. Org. Chem. 2006, 71, 543. (c) Kezuka, S.; Okado, T.;
Niou, E.; Takeuchi, R. Org. Lett. 2005, 7, 1711.
E
(d) Takeuchi, R.; Nakaya, Y. Org. Lett. 2003, 5, 3659.
(e) Takeuchi, R. Synlett 2002, 1954. (f) Takeuchi, R.;
Tanaka, S.; Nakaya, Y. Tetrahedron Lett. 2001, 42, 2991.
(6) Typical Experimental Procedure for the Reaction of
Methyl Propiolate (1a) with 1-Hexyne (2a) Catalyzed by
[Ir(cod)Cl]2/FDPPE and Spectral Data of Methyl 3,5-
Di(n-butyl)benzoate (3aa)
E = CO2Me or SO2(p-Tol)
R
R
3
R = alkyl, aryl or alkenyl
Scheme 1 Formation of iridacyclopentadiene
In conclusion, we have found chemo- and regioselective
cyclotrimerization of one molecule of 1 with two mole-
cules of 2. This reaction provides a practical synthesis of
3,5-disubstituted benzoates and 3,5-disubstituted phenyl
p-tolyl sulfone. These 1,3,5-trisubstituted benzenes have
various synthetic applications and should be useful build-
ing blocks. For example, such structural units are needed
in the synthesis of dendrimer. We are currently extending
the scope of the reaction and performing mechanistic
studies.
Into a two-necked flask with a stirring bar were placed [IR
(cod)Cl]2 (13.6 mg, 0.02 mmol) and FDPPE (30.9 mg, 0.040
mmol). The flask was evacuated and filled with Ar. Then,
anhydrous THF (5.0 mL) was added to the flask. To the
stirred solution was added 1-hexyne (2a, 243 mg, 3.0 mmol).
Methyl propiolate (1a, 83.3 mg, 1.0 mmol) was then added
dropwise to the reaction mixture. The reactor was immersed
in an oil bath, which was kept at 75 °C. The reaction mixture
was heated under reflux for 1 h. The progress of the reaction
was monitored by GLC. After the reaction was completed,
the solvent was concentrated in vacuo. Column
chromatography of the residue gave 3aa as a colorless oil (n-
hexane–EtOAc = 99:1, 219 mg, yield 88%). 1H NMR (500
MHz, CDCl3): d = 0.93 (t, J = 7.3 Hz, 6 H), 1.35 (sext,
J = 7.3 Hz, 4 H), 1.58–1.64 (m, 4 H), 2.62 (t, J = 7.8 Hz, 4
Acknowledgment
This research was supported financially by a Grant-in-Aid for Sci-
entific Research (18550098) from the Ministry of Education, Cul-
ture, Sports, Science and Technology of Japan.
H), 3.90 (s, 3 H), 7.18 (s, 1 H), 7.68 (d, J = 1.8 Hz, 2 H). 13
C
NMR (125 MHz, CDCl3): d = 13.9 (2 C), 22.3 (2 C), 33.6 (2
C), 35.4 (2 C), 51.9, 126.9 (2 C), 130.1, 133.4, 143.1 (2 C),
167.6. Anal. Calcd for C16H24O2: C, 77.38; H, 9.74; O,
12.88. Found: C, 77.49; H, 9.74.
References and Notes
(7) All new compounds were fully characterized.
(8) Yamaguchi, Y.; Ochi, T.; Miyamura, S.; Tanaka, T.;
Kobayashi, S.; Wakamiya, T.; Matsubara, Y.; Yoshida, Z.
J. Am. Chem. Soc. 2006, 128, 4504.
(9) Chow, H.-F.; Ng, M.-K.; Leung, C.-W.; Wang, G.-X. J. Am.
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(1) Present address: Department of Applied Chemistry, Tokai
University, Hiratsuka, 259-1292, Japan.
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(3) (a) Agent, N.; Buisine, O.; Slowinski, F.; Gandon, V.;
Aubert, C.; Malacria, M. Org. React. 2007, 68, 1.
(10) Typical Procedure for the Reaction of 3aa To Give 3,5-
Di(n-butyl)benzaldehyde (4aa) and Spectral Data of 4aa
A flask was charged with LiAlH4 (57 mg, 1.5 mmol). The
flask was evacuated and filled with argon. To the flask was
added Et2O (3 mL). An ether solution (3.0 mL) of benzoate
3aa (248 mg, 1 mmol) was added dropwise to the reaction
mixture. The mixture was stirred at r.t. for 4 h. The progress
of the reaction was monitored by TLC. After the reaction
was complete, the mixture was poured into 2 M HCl, and the
(b) Gandon, V.; Aubert, C.; Malacria, M. Chem. Commun.
2006, 2209. (c) Chopade, P. R.; Louie, J. Adv. Synth. Catal.
2006, 348, 2307. (d) Kotha, S.; Brahmachary, E.; Lahiri, K.
Eur. J. Org. Chem. 2005, 4741. (e) Yamamoto, Y. Curr.
Org. Chem. 2005, 9, 503. (f) Saito, S.; Yamamoto, Y.
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Metals in the Synthesis of Complex Organic Molecules, 2nd
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(h) Grotjahan, D. B. In Comprehensive Organometallic
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758
G. Onodera et al.
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aqueous layer was extracted with Et2O. The combined
organic layers were washed with a solution of sat. aq
NaHCO3 and dried with Mg2SO4. The solvent was
4 H), 2.66 (t, J = 7.8 Hz, 4 H), 7.26 (s, 1 H), 7.51 (d, J = 1.4
Hz, 2 H), 9.97 (s, 1 H). 13C NMR (125 MHz, CDCl3): d =
13.9 (2 C), 22.3 (2 C), 33.4 (2 C), 35.3 (2 C), 127.1 (2 C),
135.0, 136.6, 143.8 (2 C), 192.8. HRMS: m/z calcd for
C15H22O [M+]: 218.1671; found: 218.1651.
evaporated in vacuo. Another flask was charged with MnO2
(869 mg, 10 mmol). The flask was evacuated and filled with
argon. Then, CH2Cl2 (2 mL) was added to the flask. The
CH2Cl2 solution (3 mL) of the residue was then added to the
stirred reaction mixture. The reaction mixture was stirred at
r.t. for 30 h. The progress of the reaction was monitored by
GLC and TLC. After the reaction was complete, the mixture
was filtered through a Celite pad. The solution was
evaporated in vacuo. Column chromatography of the residue
gave 4aa as a colorless oil (n-hexane–EtOAc = 99:1, 192
mg, yield 88%). 1H NMR (500 MHz, CDCl3): d = 0.94 (t,
J = 7.3 Hz, 6 H), 1.36 (sext, J = 7.3 Hz, 4 H), 1.59–1.65 (m,
(11) (a) O’Connor, J. M.; Closson, A.; Hiibner, K.; Merwin, R.;
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(12) Wakatsuki, Y.; Nomura, O.; Kitamura, K.; Morokuma, K.;
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