Chemo- and regioselective intermolecular cyclotrimerization of terminal alkynes catalyzed by cationic rhodium(I)/modified BINAP complexes: Application to one-step synthesis of paracyclophanes

Article abstract of DOI:10.1002/chem.200401017

A highly regioselective intermolecular cyclotrimerization of terminal alkynes has been developed based on the use of the cationic rhodium(I)/DTBM- Segphos complex. This method can be applied to a variety of terminal alkynes to provide 1,2,4-trisubstituted benzenes in high yield and with high regioselectivity. A chemo- and regioselective intermolecular crossed-cyclotrimerization of dialkyl acetylenedicarboxylates with a variety of terminal alkynes has also been developed based on the use of the cationic rhodium(I)/H8-BINAP complex, furnishing 3,6-disubstituted phthalates in high yields. It constitutes a highly efficient new method for intermolecular crossed-cyclotrimerization of two different monoynes in terms of catalytic activity, chemo- and regioselectivity, scope of substrates, and ease of operation. The versatility of this new crossed-alkyne cyclotrimerization procedure is demonstrated through its application to one-step synthesis of a [6]metacyclophane and [7]-[12]paracyclophanes from the corresponding terminal α,ω-diynes. Mechanistic studies have revealed that the chemo- and regioselectivity of this crossed-alkyne cyclotrimerization are determined by the preferential formation of a specific rhodium metallacycle derived from a terminal alkyne and a dialkyl acetylenedicarboxylate.

Full text of DOI:10.1002/chem.200401017

FULL PAPER
Chemo- and Regioselective Intermolecular Cyclotrimerization of Terminal
Alkynes Catalyzed by Cationic Rhodium(i)/Modified BINAP Complexes:
Application to One-Step Synthesis of Paracyclophanes
Ken Tanaka,* Kazuki Toyoda, Azusa Wada, Kaori Shirasaka, and Masao Hirano[a]
Abstract: A highly regioselective inter-
molecular cyclotrimerization of termi-
nal alkynes has been developed based
on the use of the cationic rhodium(i)/
DTBM-Segphos complex. This method
can be applied to a variety of terminal
alkynes to provide 1,2,4-trisubstituted
benzenes in high yield and with high
regioselectivity. A chemo- and regiose-
lective intermolecular crossed-cyclotri-
merization of dialkyl acetylenedicar-
boxylates with a variety of terminal al-
kynes has also been developed based
on the use of the cationic rhodium(i)/
H8-BINAP complex, furnishing 3,6-dis-
ubstituted phthalates in high yields. It
cyclotrimerization procedure is demon-
strated through its application to one-
step synthesis of a [6]metacyclophane
and [7]–[12]paracyclophanes from the
corresponding terminal a,w-diynes.
Mechanistic studies have revealed that
the chemo- and regioselectivity of this
crossed-alkyne cyclotrimerization are
determined by the preferential forma-
tion of a specific rhodium metallacycle
derived from a terminal alkyne and a
dialkyl acetylenedicarboxylate.
constitutes
a
highly efficient new
method for intermolecular crossed-cy-
clotrimerization of two different mono-
ynes in terms of catalytic activity,
chemo- and regioselectivity, scope of
substrates, and ease of operation. The
versatility of this new crossed-alkyne
Keywords: alkynes · cyclotrimeriza-
tion · N ligands · paracyclophane ·
rhodium
Introduction
The transition-metal-catalyzed cyclotrimerization of alkynes
has received much attention as a useful method for the con-
struction of substituted benzenes.[1] Compared with conven-
tional substitution methods of benzenes, the alkyne cyclotri-
merization strategy is considerably advantageous for the
synthesis of substituted benzenes due to its high atom econ-
omy and convergent nature.[2] Although various transition
metals catalyze alkyne cyclotrimerization, it has been diffi-
cult to carry out intermolecular reactions in a highly regiose-
lective manner.[3,4] In particular, intermolecular crossed-cy-
clotrimerization of two or three different alkynes leads to
complex mixtures of products, which severely limits its ap-
plication to organic synthesis (Scheme 1). In general, either
Scheme 1. Intermolecular crossed-cyclotrimerization of three different al-
kynes.
a partially intramolecular reaction between an a,w-diyne
and an excess of a monoyne, or a completely intramolecular
reaction of a triyne, has been employed to overcome this
problem.[5,6] Recently, a strategy of temporarily connecting
monoynes by means of a cleavable tether group, such as a
boron[7] or silyl[8] group, was employed to allow highly
chemo- and regioselective crossed-cyclotrimerization of
three different alkynes. However, without the use of such
tether groups, simultaneous control of both chemo- and re-
gioselectivity in wholly intermolecular crossed-cyclotrimeri-
zations of two or three different alkynes has not yet been
accomplished.[9,10]
[a] Prof. Dr. K. Tanaka, K. Toyoda, A. Wada, K. Shirasaka,
Dr. M. Hirano
Department of Applied Chemistry, Graduate School of Engineering
Tokyo University of Agriculture and Technology
Koganei, Tokyo 184–8588 (Japan)
Fax : (+81)42-388-7037
E-mail: tanaka-k@cc.tuat.ac.jp
Herein, we describe regioselective intermolecular cyclotri-
merization of terminal alkynes, as well as chemo- and regio-
selective intermolecular crossed-cyclotrimerization of termi-
nal alkynes and dialkyl acetylenedicarboxylates, as catalyzed
Supporting information for this article is available on the WWW
under http://www.chemeurj.org/ or from the author.
Chem. Eur. J. 2005, 11, 1145 – 1156
DOI: 10.1002/chem.200401017
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1145

by cationic rhodium(i)/modified BINAP complexes.[11] Fur-
thermore, we also describe application of this new crossed-
alkyne cyclotrimerization procedure to a one-step synthesis
of a [6]metacyclophane and [7]–[12]paracyclophanes from
the corresponding a,w-diynes (Scheme 2).
Scheme 4. [RhCl(PPh3)3]-catalyzed dimerization of terminal monoynes.
in transition metal catalyzed intermolecular cycloaddition
processes involving alkynes.[16] However, the application of a
cationic rhodium(i) complex to the cyclotrimerization of ter-
minal alkynes remains unexplored.[17]
With this background in mind, we began to explore the
application of a cationic rhodium(i) complex to the cyclotri-
merization of terminal alkynes. We first examined the reac-
tion of 1-dodecyne (1a) using 5 mol% of [Rh(PPh3)2]BF4 at
room temperature. The reaction was sluggish, but a small
amount of cyclotrimerization products was detected
(Table 1, entry 1). Although the catalytic activities were low,
Scheme 2. Cationic rhodium(i)/H8-BINAP complex catalyzed chemo-
and regioselective intermolecular crossed-cyclotrimerization of terminal
alkynes and dialkyl acetylenedicarboxylates.
Results and Discussion
Intermolecular cyclotrimerization of terminal alkynes: Vari-
ous transition metals have been found to catalyze intermo-
lecular cyclotrimerization of terminal alkynes.[1] There have
been several reports of highly regioselective cyclotrimeriza-
tion of terminal alkynes, but a general protocol applicable
to a wide variety of terminal alkynes is still lacking.[4] Be-
sides the problem of regioselectivity, intermolecular reac-
tions of terminal alkynes are also prone to a competition be-
Table 1. Screening of catalysts for intermolecular cyclotrimerization of 1-
dodecyne (1a).[a]
tween dimerization through C H activation and cyclotrime-
Entry
Catalyst
Yield [%][b]
Ratio of
À
2a+3a
2a:3a[b]
rization through a metallacyclopentadiene (Scheme 3).[12,13]
1[c]
2[c]
3[c]
4[c]
5[c]
6[c]
7[c]
8[c]
9[c]
10
[Rh(Ph3P)2]BF4
[Rh(nBu3P)2]BF4
[Rh(dppe)]BF4
[Rh(dcpe)]BF4
[Rh(dppf)]BF4
[Rh(Tol-BINAP)]BF4
[Rh(Tol-BINAP)Cl]
[Ir(Tol-BINAP)]BF4
[Ir(Tol-BINAP)Cl]
[Rh(cod)(Tol-BINAP)]BF4
3
5
<2
3
<2
>95
<2
<2
0
–
–
–
–
–
64:36
–
–
–
–
3
[a] Catalyst (0.0050 mmol), 1a (0.10 mmol), and CH2Cl2 (1.0 mL) were
employed. [b] Determined by 1H NMR spectroscopy. [c] The active cata-
lysts were prepared by hydrogenation (1 atm, RT, 0.5 h).
the use of cationic rhodium(i) complexes with various mono-
dentate or bidentate phosphine ligands (Ph3P, nBu3P, dppe,
dcpe, dppf) furnished cyclotrimerization products (rather
than dimerization products) as major products (Table 1, en-
tries 1–5). Surprisingly, the use of Tol-BINAP dramatically
improved the catalytic activity and cyclotrimerization prod-
ucts were obtained in almost quantitative yield with moder-
ate regioselectivity (entry 6). The use of a cationic rhodiu-
m(i) complex is essential for this reaction. The neutral rho-
dium(i)/Tol-BINAP complex and both cationic and neutral
iridium(i)/Tol-BINAP complexes did not show any catalytic
activity (Table 1, entries 7–9). Treatment of the catalyst with
hydrogen (removal of the cod ligand) proved to be effective
for this reaction. The catalytic activity of [Rh(cod)(Tol-BI-
NAP)]BF4 (without treatment with hydrogen) was very low
(Table 1, entry 10).
Scheme 3. Transition metal catalyzed dimerization and cyclotrimerization
of terminal alkynes.
Indeed, although a neutral rhodium(i) complex, such as
[RhCl(PPh3)3], is an effective catalyst for partially or com-
pletely intramolecular cyclotrimerization of diynes or
triynes,[14] it generally reacts with terminal monoynes to give
linear dimers (Scheme 4).[15] It has been well documented
that cationic rhodium(i) complexes are the effective catalysts
1146
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1145 – 1156

Chemo- and Regioselective Intermolecular Cyclotrimerization of Terminal Alkynes
FULL PAPER
Table 3. Cationic rhodium(i)/DTBM-Segphos complex catalyzed inter-
molecular cyclotrimerization of terminal alkynes.[a]
Scheme 5. Structures of modified BINAP ligands.
Entry
R
Temp.
[8C]
Major
product
Yield [%][b] Ratio of
2a+3a
2a:3a[b]
1
2
3
4
5
6
nC10H21 (1a)
nC6H13 (1b)
Bn (1c)
(CH2)3Cl (1d)
1-cyclohexenyl (1e)
Ph (1 f)
30
30
30
30
30
2a
2b
2c
2d
2e
2 f
2 f
2g
2h
2i
91
81
94
90
89
93
94[e]
94
90
99
74
84
83:17[e]
82:18[e]
82:18[f]
86:14[e]
97:3[e]
Table 2. Screening of modified BINAP ligands for intermolecular cyclo-
trimerization of 1-dodecyne (1a).[a]
30
83:17[f]
97:3[f]
7[c,d]
8
9
10
11
12[c]
Ph (1 f)
RT
RT
RT
RT
30
CH2OMe (1g)
CH2OAc (1h)
CO2Et (1i)
Me3Si (1j)
86:14[f]
100:0[e]
93:7[e]
Entry
Ligand
Temp.
[8C]
Yield [%][b]
2a+3a
Ratio of
2a:3a[b]
2j
2j
70:30[f]
83:17[f]
Me3Si (1j)
RT
1
2
3
4
5
6
Tol-BINAP
BINAP
DM-BINAP
H8-BINAP
Segphos
RT
RT
RT
30
30
30
>95
>95
90
88
>95
>95
64:36
52:48
51:49
76:24
80:20
83:17
[a] [Rh(cod)2]BF4 (0.050 mmol), DTBM-Segphos (0.050 mmol), terminal
alkyne (1.0 mmol), and CH2Cl2 (3.0 mL) were employed. The active cata-
lyst was prepared by mixing [Rh(cod)2]BF4 and DTBM-Segphos in
CH2Cl2 followed by hydrogenation (1 atm, RT, 0.5 h). [b] Yield of isolat-
ed product. [c] H8-BINAP was used. [d] Catalyst (1.5%) was used.
DTBM-Segphos
1
[e] Determined by H NMR spectroscopy. [f] Determined by GC.
[a] [Rh(cod)2]BF4 (0.0050 mmol), modified BINAP (0.0050 mmol), 1-do-
decyne (1a, 0.10 mmol), and CH2Cl2 (1.0 mL) were employed. The active
catalysts were prepared by mixing [Rh(cod)2]BF4 and phosphines in
CH2Cl2 followed by hydrogenation (1 atm, RT, 0.5 h). [b] Determined by
1H NMR spectroscopy.
(1i, Table 3, entry 10) substituted terminal alkynes proved
to be highly reactive substrates, yielding 1,2,4-trisubstituted
benzenes 2g–i in high yield and with high regioselectivity at
room temperature (20–258C). In particular, alkyne 1h fur-
nished 2h with complete regioselectivity (Table 3, entry 9).
The reaction of sterically demanding trimethylsilyl acetylene
(1j) also proceeded to give 2j in good yield and with moder-
ate regioselectivity (Table 3, entry 11). Higher regioselectivi-
ty was obtained by the use of H8-BINAP as a ligand
(Table 3, entry 12). To the best of our knowledge, the use of
this catalyst system constitutes one of the most general
methods for the regioselective cyclotrimerization of terminal
alkynes.[10]
To improve regioselectivity, a variety of cationic rhodi-
um(i) complexes having modified BINAP ligands (Scheme 5)
were screened, as shown in Table 2. The use of BINAP and
DM-BINAP did not improve the regioselectivity significant-
ly (Table 2, entries 2 and 3). Although the catalytic activity
was slightly lower than that seen with Tol-BINAP, the use of
H8-BINAP[18] showed good regioselectivity (Table 2,
entry 4). Both high catalytic activity and regioselectivity
were achieved using cationic rhodium(i)/Segphos[19] or
DTBM-Segphos[19] complexes (Table 2, entries 5 and 6). In
particular, the use of the cationic rhodium(i)/DTBM-Seg-
phos complex at 308C showed the highest regioselectivity
(Table 2, entry 6).
A series of terminal alkynes was subjected to the above
optimal reaction conditions, as summarized in Table 3.
Alkyl- (1a and 1b, Table 3, entries 1 and 2), benzyl- (1c,
Table 3, entry 3), and chloroalkyl- (1d, Table 3, entry 4) sub-
stituted terminal alkynes cleanly furnished the correspond-
ing 1,2,4-trisubstituted benzenes 2a–d in high yield and with
high regioselectivity. Not only alkyl-substituted terminal al-
kynes but also alkenyl- and aryl-substituted terminal alkynes
proved to be suitable substrates, yielding 1,2,4-trisubstituted
benzenes 2e and 2 f in high yield and with high regioselec-
tivity (Table 3, entries 5 and 6). For the reaction of 1 f, excel-
lent regioselectivity was obtained by the use of H8-BINAP
as a ligand (Table 3, entry 7). Methoxymethyl- (1g, entry 8),
acetoxymethyl- (1h, Table 3, entry 9), and ethoxycarbonyl-
Intermolecular crossed-cyclotrimerization of terminal al-
kynes and dialkyl acetylenedicarboxylates: Encouraged by
the above results, we subsequently investigated rhodium-cat-
alyzed intermolecular crossed-cyclotrimerization of two dif-
ferent alkynes. After screening combinations of 1-dodecyne
(1a) and various terminal or internal alkynes in the pres-
ence of the cationic rhodium(i)/Tol-BINAP complex, we
were pleased to discover that this complex catalyzes chemo-
selective intermolecular crossed-cyclotrimerization of 1a
and diethyl acetylenedicarboxylate (DEAD, 4b) furnishing
a mixture of disubstituted phthalates 5b/6b/7b with moder-
ate regioselectivity (Table 4, entry 1). To improve the regio-
selectivity, a variety of cationic rhodium(i) complexes having
modified BINAP ligands (Scheme 5) were screened, as
shown in Table 4. The use of BINAP and DM-BINAP did
not improve the regioselectivity significantly (Table 4, en-
Chem. Eur. J. 2005, 11, 1145 – 1156
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1147

K. Tanaka et al.
Table 4. Screening of modified BINAP ligands for intermolecular
crossed-cyclotrimerization of 1-dodecyne (1a) and diethyl acetylenedicar-
boxylate (4b).[a]
Table 5. Cationic rhodium(i)/H8-BINAP complex-catalyzed intermolecu-
lar crossed-cyclotrimerization of terminal alkynes and dialkyl acetylene-
dicarboxylates.[a]
Entry
Ligand
Yield [%][b]
5+6+7
Ratio of
5:6:7[b]
1
2
3
4
5
6
Tol-BINAP
BINAP
DM-BINAP
Segphos
DTBM-Segphos
H8-BINAP
82
84
80
82
69
93
46:22:32
54:26:20
49:19:32
81:17:2
32:62:6
92:6:2
Entry
R
4
Major
product
Yield [%][b]
5+6+7
Ratio of
5:6:7[c]
1
2
3
nC10H21 (1a)
nC10H21 (1a)
nC10H21 (1a)
nC10H21 (1a)
(CH2)3Cl (1d)
(CH2)3Cl (1d)
1-cyclohexenyl (1e)
1-cyclohexenyl (1e)
Ph (1 f)
Ph (1 f)
o-Tol (1k)
o-Tol (1k)
MeOCH2 (1g)
AcOCH2 (1h)
Me3Si (1j)
4a
4b
4c
4c
4b
4c
4b
4c
4b
4c
4b
4c
4b
4b
4b
5a
5b
5c
5c
5d
5e
5 f
5g
5h
5i
5j
5k
5l
5m
5n
78
88
94
93
92
95
90
92
90
90
77
90
91:8:1
92:6:2
94:4:2
93:4:3
91:8:1
95:4:1
91:4:5
94:4:2
89:9:2
90:10:0
89:9:2
88:12:0
86:10:4
87:10:3
99:1:0
4[d]
5
[a] [Rh(cod)2]BF4 (0.005 mmol), modified BINAP (0.005 mmol), 1a
(0.2 mmol), 4b (0.1 mmol), and CH2Cl2 (1.0 mL) were employed. The
active catalysts were prepared by mixing [Rh(cod)2]BF4 and modified
BINAP in CH2Cl2, followed by hydrogenation (1 atm, RT, 0.5 h). [b] De-
6
7
8
9
10
11
12
13
14
15
1
termined by H NMR spectroscopy.
tries 2 and 3). Although the overall yield of phthalates was
slightly lower than that obtained using Tol-BINAP, the use
of Segphos[19] showed good regioselectivity and gave 3,6-di-
substituted phthalate 5b as the major isomer (Table 4,
61(30[e]
)
[f]
63(28[e]
57(33[g]
)
)
[a] [Rh(cod)2]BF4 (0.0090 mmol), H8-BINAP (0.0090 mmol), terminal
alkyne (0.60 mmol), dialkyl acetylenedicarboxylate (0.30 mmol), and
CH2Cl2 (3.0 mL) were employed. The catalyst was prepared by mixing
[Rh(cod)2]BF4 and H8-BINAP in CH2Cl2 followed by hydrogenation
(1 atm, RT, 0.5 h). [b] Yield of isolated product. [c] Determined by 1H
NMR spectroscopy. [d] Catalyst (0.005 equiv) was used. Reaction time
was 19 h. [e] Yield of homo-cyclotrimerization products. [f] Isolated as a
mixture with homo-cyclotrimerization products. [g] Yield of 1:2 (=
1j:4b) crossed-cyclotrimerization product 8 based on 4b.
entry 4).
A
sterically demanding Segphos derivative,
DTBM-Segphos,[19] was not so effective, leading to de-
creased yield and regioselectivity (Table 4, entry 5). Both
high yield and regioselectivity were achieved by using the
cationic rhodium(i)/H8-BINAP[18] complex, which yielded
5b with 92% regioselectivity and an overall phthalate yield
of 93% (Table 4, entry 6).
Two molecules of a wide variety of terminal alkynes 1a–k
cleanly reacted with one molecule of DEAD (4b) to give
3,6-disubstituted diethyl phthalates 5 in high yield and with
high regioselectivity upon treatment with a catalytic amount
(3%) of the cationic rhodium(i)/H8-BINAP complex
(Table 5). Alkyl- (1a, Table 5, entry 2), chloroalkyl- (1d,
Table 5, entry 5), alkenyl- (1e, Table 5, entry 7), and aryl-
(1 f, Table 5, entry 9; 1k, Table 5, entry 11) substituted ter-
minal alkynes proved to be suitable substrates for this reac-
tion. The respective reactions of methyl propargyl ether
(1g) and propargyl acetate (1h) furnished 5l and 5m in
moderate yields due to homo-cyclotrimerization of these al-
kynes yielding 2g and 2h as by-products (Table 5, entries 13
and 14). Though the reaction of sterically demanding trime-
thylsilyl acetylene (1j) furnished 5n in only moderate yield
due to the formation of a 1:2 (= 1j:4b) crossed-cyclotrime-
rization product 8, excellent regioselectivity was observed
(Table 5, entry 15). Interestingly, the ester group of 4 affect-
ed the yield and regioselectivity of phthalates 5–7. The use
of dimethyl acetylenedicarboxylate (DMAD, 4a) led to a
lower yield of 5a (entry 1). On the other hand, the use of
sterically demanding di-tert-butyl acetylenedicarboxylate
(4c) improved both the yield and regioselectivity of 5c
(Table 5, entry 3). By employing 4c with alkynes 1d, 1e, 1 f,
and 1k, the corresponding 3,6-disubstituted phthalates 5e,
5g, 5i, and 5k were obtained in higher yields and with
higher regioselectivities than the phthalates 5d, 5 f, 5h, and
5j obtained from 4a (Table 5, entries 6, 8, 10, and 12 vs. en-
tries 5, 7, 9, and 11). To demonstrate the practical utility of
this reaction, the use of a lower catalyst loading was investi-
gated. The reaction of 1a and 4c could be carried out in the
1148
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1145 – 1156

Chemo- and Regioselective Intermolecular Cyclotrimerization of Terminal Alkynes
FULL PAPER
Table 6. Cationic rhodium(i)/H8-BINAP complex catalyzed crossed-cy-
clotrimerization of terminal a,w-diynes and dialkyl acetylenedicarboxyla-
tes.[a]
presence of 0.005 equivalent of the catalyst without erosion
of the yield or regioselectivity (Table 5, entry 4).
Intermolecular crossed-cyclotrimerization of terminal a,w-
diynes and dialkyl acetylenedicarboxylates: Application to
one-step synthesis of paracyclophanes: The successful
crossed-cyclotrimerization of two molecules of a terminal
alkyne and one molecule of a dialkyl acetylenedicarboxylate
to yield a 3,6-disubstituted phthalate prompted us to investi-
gate the synthesis of paracyclophanes using terminal a,w-
diynes instead of two molecules of a terminal alkyne.[20]
Maryanoff et al. reported cobalt-catalyzed macrocyclizations
to form pyridinophanes through [2+2+2] cycloaddition of
a,w-diynes with nitriles[21] or isocyanates.[22] Yamamoto et al.
reported palladium-catalyzed macrocyclizations to form exo-
methylene paracyclophanes based on intramolecular ben-
zannulation of conjugated enynes.[23] Wullf et al. reported
benzannulation reactions of Fischer carbene complexes with
alkynes to form meta- and paracyclophanes.[24] Shinokubo
and Oshima et al. reported [RhCl(PPh3)3]-catalyzed macro-
cyclizations to form ortho- and metacyclophanes by intra-
molecular [2+2+2] cycloaddition of triynes in an aqueous/
organic biphasic system.[14n] On the other hand, the forma-
tion of cyclophanes by intermolecular crossed-cyclotrimeri-
zation of a,w-diynes and alkynes has not hitherto been re-
ported. For the test reaction, commercially available 1,9-dec-
adiyne (9a) was chosen as an a,w-diyne. In this case, a
[6]metacyclophane would be obtained due to the instability
of a [6]paracyclophane at room temperature.[25] We were
pleased to find that the reaction of 9a and 4b under dilute
conditions (0.005m) furnished [6]metacyclophane 10a in
50% yield (Scheme 6). This is the shortest (one-step) syn-
thesis of a [6]metacyclophane starting from commercially
available reagents.[25]
Entry
n
4
Conc. [m]
Paracyclophane
Yield [%][b]
1
2
3
4
5
6
7
8
7 (9b)
7 (9b)
7 (9b)
7 (9b)
7 (9b)
8 (9c)
9 (9d)
10 (9e)
11 (9 f)
12 (9g)
4a
4a
4a
4b
4c
4a
4a
4a
4a
4a
0.01
0.02[e]
0.10[f]
0.01
0.01
0.01
0.01
0.01
0.01
0.01
11a
11a
11a
11b
11c
11d
11e
11 f
11g
11h
23[c](1:0.8[d]
)
14[c](1:0.9[d]
)
0
20[c](1:0.8[d]
)
)
17[c](1:0.8[d]
46
53
36
45
35
9
10
[a] [Rh(cod)2]BF4 (0.0125 mmol), H8-BINAP (0.0125 mmol), a,w-diyne
(0.25 mmol), dialkyl acetylenedicarboxylate (0.25 mmol), and CH2Cl2
(25 mL) were employed. A mixture of the a,w-diyne and the dialkyl ace-
tylenedicarboxylate was added dropwise over 10 min. The active catalyst
was prepared by mixing [Rh(cod)2]BF4 and H8-BINAP in CH2Cl2 fol-
lowed by hydrogenation (1 atm, RT, 0.5 h). [b] Yield of isolated product.
[c] Isolated as a mixture of meta- and paracyclophanes. [d] Ratio of para-
cyclophane:metacyclophane. [e] CH2Cl2 (12.5 mL) was used. [f] CH2Cl2
(2.5 mL) was used.
The reactions of 4a with a,w-diynes 9c–g having different
lengths of the carbon chain furnished the corresponding [8]–
[12]paracyclophanes in fair to good yields (Table 6, en-
tries 6–10). Importantly, the formation of [8]–[12]paracyclo-
phanes predominated and the corresponding [8]–[12]meta-
or orthocyclophanes were generated either in very low yield
(<5%) or not at all.
Table 7. 1H NMR chemical shifts of methylene protons of paracyclo-
phanes at highest field.
Scheme 6. Synthesis of a [6]metacyclophane by intermolecular crossed-
cyclotrimerization of 1,9-decadiyne and DEAD.
Compound
Chemical shift [ppm]
11a (n = 7)
11d (n = 8)
11e (n = 9)
11 f (n = 10)
11g (n = 11)
11h (n = 12)
À1.88 (1H)
À0.10 (2H)
0.10 (2H)
0.30 (2H)
0.90 (10H)
1.00 (4H)
Next, we investigated the reaction of 1,10-undecadiyne
(9b), which was synthesized in one step from the corre-
sponding dibromide and lithium acetylide.[26] The effect of
concentration on the yield of [7]cyclophane was investigated
(Table 6, entries 1–3). The highest yield of [7]cyclophane
was obtained at a concentration of 0.01m (Table 6, entry 2).
The reactions of 9b with various dialkyl acetylenedicarboxy-
lates 4a–c were investigated at concentrations of 0.01m,
which revealed that the desired highly strained [7]paracyclo-
phanes were obtained along with [7]metacyclophanes
(Table 6, entries 1, 4, and 5).[27] The highest yield of [7]para-
cyclophane was obtained by the use of 4a (Table 6, entry 1).
The chemical shifts of the methylene protons appearing at
highest field for each paracyclophane are shown in Table 7.
The higher field shift of the methylene protons clearly sup-
ports the formation of paracyclophanes.
Mechanistic consideration regarding the intermolecular
crossed-cyclotrimerization of terminal alkynes and dialkyl
Chem. Eur. J. 2005, 11, 1145 – 1156
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1149

K. Tanaka et al.
acetylenedicarboxylates: It is difficult to achieve sufficient
control to ensure both high chemo- and regioselectivity in
the intermolecular cyclotrimerization of alkynes, and suc-
cessful examples are quite limited. Our study realized a suc-
cessful control of both high chemo- and regioselectivity in
the intermolecular crossed-cyclotrimerization of alkynes.
The high chemo- and regioselectivity observed in this
crossed-cyclotrimerization indicate that the intermediate, a
rhodium metallacycle, was formed in a highly chemo- and
regioselective manner from two different alkynes. Scheme 7
depicts the possible formation of rhodium metallacycles
crossed-cyclotrimerization product is 5, metallacycle 12a or
13a should be a major intermediate. On the other hand,
homo-cyclotrimerization product 2 could be obtained from
metallacycle 13a, 13b, or 13c, and homo-cyclotrimerization
product
3 could be obtained from metallacycle 13b
(Scheme 8). Because the 3a:2a ratio using RhI+/H8-BINAP
was 24:76 (Table 2, entry 4), the ratio of 13b to 13a+13c
should be >24:76. However, crossed-cyclotrimerization
product 6b, which would be derived from metallacycle 13b,
only constituted 6% of the total product (Table 5, entry 2).
Thus, the formation of 5b from metallacycle 13a is at least a
minor pathway, and the major intermediate should be metal-
lacycle 12a.
To confirm the formation of metallacycle 12a as the
major intermediate of this crossed-cyclotrimerization, homo-
cyclotrimerization of various alkynes in the presence of
RhI+/H8-BINAP was investigated at room temperature for
1 h, as summarized in Table 8. Though it takes less than 1 h
Table 8. Reactivity of various alkynes in the presence of the cationic rho-
dium(i)/H8-BINAP complex.[a]
Scheme 7. Possible formation of rhodium metallacycles from 1 and 4.
from terminal alkyne 1 and dialkyl acetylenedicarboxylate
4. The crossed-cyclotrimerization products 5–7 may be ob-
tained from metallacycles 12 or 13. Metallacycle 12a could
produce isomers 5 and 6, while metallacycle 12b could pro-
duce isomers 6 and 7 (Scheme 8). Alternatively, metallacy-
cles 13a, 13b, and 13c could produce isomers 5, 6, and 7, re-
spectively (Scheme 9). Because the major isomer of the
Entry
R1
R2
Cat.
[%]
Yield [%][b]
2+3
Ratio of
2:3[c]
1
2
3
4
n-C10H21
Me3Si
Ph
CH2OMe
CO2Me
CO2Et
CO2tBu
H
H
H
H
(1a)
(1j)
(1 f)
(1g)
(4a)
(4b)
(4c)
1.5
1.5
1.5
1.5
3.0
3.0
3.0
6
36
94
95
68
78[e]
0
–
83:17
97:3
85:15
–
–
–
5[d]
6[d]
7[d]
CO2Me
CO2Et
CO2tBu
[a] [Rh(cod)2]BF4 (0.0090 mmol), H8-BINAP (0.0090 mmol), alkyne
(0.60 mmol), and CH2Cl2 (3.0 mL) were employed. The active catalyst
was prepared by mixing [Rh(cod)2]BF4 and H8-BINAP in CH2Cl2 fol-
lowed by hydrogenation (1 atm, RT, 0.5 h). [b] Determined by 1H NMR
spectroscopy. [c] Determined by GC. [d] Alkyne (0.30 mmol) was used.
[e] Yield of isolated product.
Scheme 8. Correlation of cyclotrimerization products with rhodium met-
allacycles 12a and 12b.
for the RhI+/H8-BINAP-catalyzed crossed-cyclotrimeriza-
tion of 1a and 4 to proceed to completion at room tempera-
ture, the reactions of terminal alkynes 1a and 1j were slow
(Table 8, entries 1 and 2). On the other hand, the reactions
of DMAD (4a) and DEAD (4b) furnished the correspond-
ing cyclotrimerization products in good yields (Table 8, en-
tries 5 and 6). Thus, the formation of 5 from metallacycle
13a is unlikely. The homo-cyclotrimerization of di-tert-butyl
acetylenedicarboxylate 4c in the presence of RhI+/H8-
BINAP did not proceed at all, which accounts for the high
yield of crossed-cyclotrimerization products 5c.
The reactions of terminal alkynes 1 f and 1g bearing aryl
and oxymethylene substituents furnished the corresponding
cyclotrimerization products in good yields at room tempera-
ture (Table 8, entries 3 and 4). The reaction of 1 f and 4b
Scheme 9. Correlation of cyclotrimerization products with rhodium met-
allacycles 13a–c.
1150
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1145 – 1156

Chemo- and Regioselective Intermolecular Cyclotrimerization of Terminal Alkynes
FULL PAPER
furnished the crossed-cyclotrimerization product 5h in high
yield and did not furnish the homo-cyclotrimerization prod-
ucts (Table 5, entry 9). Thus, the major intermediate would
be 12a. On the other hand, the reaction of 1g and 4b fur-
nished the corresponding homo-cyclotrimerization products
as by-products due to competitive formation of metallacycle
13 rather than 12. A slightly lower regioselectivity was also
observed in this reaction (Table 5, entry 14). We assume that
5l–7l were partially derived from metallacycle 13. To con-
firm this hypothesis, we carried out the reaction using excess
4b (Scheme 10). The yield and regioselectivity were im-
1j with 4b also furnished the sterically unfavorable product
5n with excellent regioselectivity due to the carbon atom a
to the silicon atom being highly electronegative as a result
of the polarization of the silicon–carbon bond.[28] The effect
of modified BINAP ligands on the regioselectivity is not
clearly understood, although their electronic character
would seem to be more important than their steric character
(Table 4). The use of more electron-rich BINAP ligands,
such as H8-BINAP and Segphos, significantly improved the
regioselectivity in favor of 5 compared with the use of
BINAP itself (Table 4, entries 4 and 6 versus entry 2). On
the other hand, no correlation was observed between the di-
hedral angles of the ligands and the regioselectivity of the
cyclotrimerization products (dihedral angle: H8-BINAP >
BINAP
Segphos @ BINAP).
> >
Segphos,[19b,29] regioselectivity: H8-BINAP
Conclusion
In conclusion, we have discovered that the cationic rhodiu-
m(i)/DTBM-Segphos complex is a widely applicable catalyst
for highly regioselective intermolecular cyclotrimerization of
terminal alkynes, providing 1,2,4-trisubstituted benzenes in
high yield and with high regioselectivity. A chemo- and re-
gioselective intermolecular crossed-cyclotrimerization of di-
alkyl acetylenedicarboxylates with a variety of terminal al-
kynes has also been developed based on the use of the cat-
ionic rhodium(i)/H8-BINAP complex, providing 3,6-disubsti-
tuted phthalates in high yields. This catalytic process is a
noteworthy example of intermolecular crossed-cyclotrimeri-
zation of two different alkynes in terms of catalytic activity,
chemo- and regioselectivity, scope of substrates, and ease of
operation. This versatile new crossed-alkyne cyclotrimeriza-
tion procedure has been successfully applied to a one-step
synthesis of a [6]metacyclophane and [7]–[12]paracyclo-
phanes from the corresponding terminal a,w-diynes. Be-
cause 1,10- to 1,15-diynes can be synthesized in one-step
from the commercially available corresponding dibromides,
the present method allows a two-step synthesis of [7]–
[12]paracyclophanes starting from commercially available
reagents. The successful application to the synthesis of the
highly strained [6]metacyclophane and [7]paracyclophane is
particularly noteworthy. Mechanistic studies have revealed
that the chemo- and regioselectivity of this crossed-alkyne
cyclotrimerization are determined by preferential formation
of the rhodium metallacycle 12a derived from terminal
alkyne 1 and dialkyl acetylenedicarboxylate 4.
Scheme 10. Crossed-cyclotrimerization of 1g with excess 4b.
proved, presumably due to the formation of metallacycle 12
being favored by the use of excess 4b.
Thus, a plausible mechanism for the cationic rhodium(i)/
H8-BINAP complex-catalyzed intermolecular crossed-cyclo-
trimerization of 1 and 4 is illustrated in Scheme 11. Chemo-
Scheme 11. Plausible mechanism for intermolecular crossed-cyclotrimeri-
zation of 1 and 4 catalyzed by the cationic rhodium(i)/H8-BINAP com-
plex.
and regioselectivity are determined by the preferential for-
mation of metallacycle 12a rather than 13 and 14, followed
by the coordination of terminal alkynes 1 to form complex
15. Reductive elimination of rhodium gives 5 and regener-
ates the rhodium catalyst. The formation of metallacycle
12a clearly accounts for the selective generation of a [6]meta-
cyclophane 10a and [7]–[12]paracyclophanes 11 when a,w-
diynes 9 are used instead of two molecules of 1.
Experimental Section
The sterically unfavorable coordination of terminal mono-
ynes to form complex 15 occurs under electronic control.
The electronegative carbon atom in the 2-position of 1 coor-
dinates to the carbon atom a to the carbonyl and rhodium
of 12a, giving rise to the observed regioselectivity. Indeed,
the reaction of sterically demanding trimethylsilyl acetylene
General methods: 1H NMR spectra were recorded at 300 MHz (JEOL
AL 300). 13C NMR spectra were obtained with complete proton decou-
pling at 75 MHz (JEOL AL 300). Product isomer distributions were de-
termined by H NMR or GC (HP5890A). HRMS data were obtained on
a JEOL JMS-700. Infrared spectra were obtained on a JASCO A-302.
Anhydrous CH2Cl2 was obtained from Aldrich (No. 27,099–7) and was
1
Chem. Eur. J. 2005, 11, 1145 – 1156
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1151

K. Tanaka et al.
used as received. Tol-BINAP, DM-BINAP, H8-BINAP, Segphos, and
DTBM-Segphos were obtained from Takasago International Corpora-
tion. All other reagents were obtained from commercial sources and
were used as received. All reactions were carried out under an atmos-
phere of argon in oven-dried glassware with magnetic stirring, unless oth-
erwise indicated. a,w-Diynes 9b, 9c, 9d, 9e, 9 f, and 9g were prepared
according to the literature.[26]
1,2,4-Tris(methoxymethyl)benzene (2g, 86% regioselectivity):[4e] Reac-
tion time: 15 h. Yellow oil; 1H NMR (CDCl3, 300 MHz): d = 7.19–7.43
(m, 3H), 4.52 (s, 2H), 4.51 (s, 2H), 4.45 (s, 2H), 3.39 (s, 3H), 3.373 (s,
3H), 3.366 ppm (s, 3H); methylene protons of minor isomer 3g: d =
4.45 ppm (s, 6H); methyl protons of minor isomer 3g: d = 3.38 ppm (s,
9H); 13C NMR (CDCl3, 75 MHz): d = 138.5, 137.7, 136.4, 135.6, 128.8,
127.9, 126.9, 126.1, 74.4, 74.3, 72.0, 71.9, 58.2, 58.13, 58.05, 57.99 ppm.
Acetic acid 2,4-bis(acetoxymethyl)benzyl ester (2h, 100% regioselectivi-
General procedure for intermolecular cyclotrimerization of terminal
monoynes (Table 3, entry 1): Under an argon atmosphere, a solution of
DTBM-Segphos (59.0 mg, 0.050 mmol) in CH2Cl2 (1.0 mL) was added to
a solution of [Rh(cod)2]BF4 (20.3 mg, 0.050 mmol) in CH2Cl2 (1.0 mL) at
room temperature. The mixture was stirred at room temperature for
5 min, and then H2 was introduced into the resulting solution in a
Schlenk tube. After stirring at room temperature for 0.5 h, the resulting
solution was concentrated to dryness and the residue was redissolved in
CH2Cl2 (2.0 mL). A solution of 1-dodecyne (1a) (166.4 mg, 1.00 mmol) in
CH2Cl2 (0.5 mL) was then added dropwise to this solution over 1 min,
and any substrate remaining in the syringe was rinsed into the reaction
mixture with further CH2Cl2 (0.5 mL). The mixture was stirred at room
temperature (20–258C) for 24 h. The resulting solution was concentrated
and the residue was purified by preparative TLC (hexane), which fur-
nished a mixture of 1,2,4-tridecylbenzene (2a) and 1,3,5-tridecylbenzene
(3a) (151.9 mg, 0.913 mmol, 91%, 2a:3a = 83:17).
1
ty):[32] Reaction time: 24 h. Colorless oil; H NMR (CDCl3, 300 MHz); d
= 7.28–7.46 (m, 3H), 5.20 (s, 2H), 5.19 (s, 2H), 5.11 (s, 2H), 2.11 (s, 3H),
2.10 (s, 3H), 2.09 ppm (s, 3H); 13C NMR (CDCl3, 75 MHz): d = 170.7,
170.5, 136.5, 134.8, 134.4, 130.0, 129.4, 128.3, 65.6, 65.5, 63.5, 63.4, 31.9,
20.9, 20.8 ppm.
Benzene 1,2,4-tricarboxylic acid triethyl ester (2i, 93% regioselectivi-
ty):[33] Reaction time: 16 h. Yellow oil; 1H NMR (CDCl3, 300 MHz): d =
8.41 (dd, J = 1.8, 0.3 Hz, 1H), 8.20 (dd, J = 7.8, 1.8 Hz, 1H), 7.76 (dd, J
= 7.8, 0.3 Hz, 1H), 4.31–4.52 (m, 6H), 1.30–1.50 ppm (m, 9H); aryl pro-
tons of minor isomer 3i: d
=
8.85 ppm (s, 3H); 13C NMR (CDCl3,
75 MHz): d = 167.0, 166.5, 164.9, 164.8, 136.1, 134.3, 132.5, 131.9, 131.8,
131.3, 129.9, 128.7, 61.9, 61.8, 61.5, 14.2, 14.1, 14.0, 13.9 ppm.
1,2,4-Tris(trimethylsilyl)benzene (2j, 70% regioselectivity):[33] Reaction
time: 24 h (24 h using H8-BINAP). Colorless oil; 1H NMR (CDCl3,
300 MHz): d = 7.84 (s, 1H), 7.66 (d, J = 7.5 Hz, 1H), 7.49 (d, J =
7.5 Hz, 1H), 0.37 (s, 9H), 0.36 (s, 9H), 0.27 ppm (s, 9H); aryl protons of
minor isomer 3j: d = 7.69 ppm (s, 3H); trimethylsilyl protons of minor
isomer 3j: d = 0.28 ppm (s, 27H); 13C NMR (CDCl3, 75 MHz): d =
146.6, 144.8, 140.0, 139.3, 138.8, 138.3, 134.3, 132.8, 1.96, 1.86, À1.06,
À1.22 ppm.
General procedure for the intermolecular crossed-cyclotrimerization of
dialkyl acetylenedicarboxylates and terminal monoynes (Table 5,
entry 2): Under an Ar atmosphere, H8-BINAP (5.7 mg, 0.009 mmol) and
[Rh(cod)2]BF4 (3.7 mg, 0.009 mmol) were dissolved in CH2Cl2 (1.0 mL)
and the mixture was stirred for 5 min. H2 was then introduced into the
resulting solution in a Schlenk tube. After stirring for 0.5 h at room tem-
perature, the resulting solution was concentrated to dryness and the resi-
due was redissolved in CH2Cl2 (2.0 mL). A solution of 1-dodecyne (1a)
(99.8 mg, 0.60 mmol) and diethyl acetylenedicarboxylate (4b) (51.0 mg,
0.30 mmol) in CH2Cl2 (0.5 mL) was then added dropwise to this solution
over 1 min, and any substrates remaining in the syringe were rinsed into
the reaction mixture with further CH2Cl2 (0.5 mL). The mixture was stir-
red at room temperature (20–258C) for 1 h. The resulting solution was
then concentrated and the residue was purified by preparative TLC
(hexane/ethyl acetate, 10:1), which furnished a mixture of diethyl 3,6-di-
decylphthalate (5b), diethyl 3,5-didecylphthalate (6b), and diethyl 4,5-di-
1,2,4-Tridecylbenzene (2a, 83% regioselectivity):[4f] Colorless oil; 1H
NMR (CDCl3, 300 MHz): d = 7.04 (d, J = 7.5 Hz, 1H), 6.94 (s, 1H),
6.92 (d, J = 7.5 Hz, 1H), 2.48–2.61 (m, 6H), 1.45–1.65 (m, 6H), 1.20–
1.43 (m, 42H), 0.88 ppm (t, J
= 6.6 Hz, 9H); aryl protons of minor
isomer 3a: d = 6.80 ppm (s, 3H); 13C NMR (CDCl3, 75 MHz): d =
142.7, 140.3, 140.2, 137.7, 129.2, 128.9, 125.8, 125.7, 36.0, 35.6, 32.8, 32.4,
31.9, 31.63, 31.62, 31.4, 29.9, 29.7, 29.65, 29.59, 29.56, 29.49, 29.38, 22.7,
14.1 ppm.
1,2,4-Trihexylbenzene (2b, 82% regioselectivity):[30] Reaction time: 18 h.
Colorless oil; 1H NMR (CDCl3, 300 MHz): d = 7.03 (d, J = 7.5 Hz,
1H), 6.94 (s, 1H), 6.92 (d, J = 7.5 Hz, 1H), 2.43–2.63 (m, 6H), 1.45–1.70
(m, 6H), 1.20–1.45 (m, 18H), 0.78–0.98 ppm (m, 9H); aryl protons of
minor isomer 3b: d = 6.80 ppm (s, 3H); 13C NMR (CDCl3, 75 MHz): d
= 142.7, 140.3, 140.1, 137.7, 129.2, 128.9, 125.8, 125.7, 36.0, 35.6, 32.8,
32.4, 31.8, 31.59, 31.57, 31.4, 29.5, 29.1, 22.7, 22.6, 14.1 ppm.
1,2,4-Tribenzylbenzene (2c, 82% regioselectivity):[10a] Reaction time:
16 h. Colorless oil; 1H NMR (CDCl3, 300 MHz): d
= 6.94–7.34 (m,
18H), 3.92 (s, 2H), 3.90 (s, 2H), 3.88 ppm (s, 2H), aryl protons of minor
isomer 3c: d = 6.86 ppm (s, 3H), benzyl protons of minor isomer 3c: d
= 3.88 ppm (s, 6H); 13C NMR (CDCl3, 75 MHz): d = 141.3, 141.2, 141.1,
140.6, 140.5, 139.3, 138.9, 136.8, 131.3, 130.7, 128.9, 128.8, 128.7, 128.6,
128.39, 128.35, 128.34, 127.5, 127.1, 125.96, 125.94, 125.90, 41.8, 41.5, 39.0,
38.6 ppm.
1,2,4-Tris(3-chloropropyl)benzene (2d, 86% regioselectivity):[4f] Reaction
time: 16 h. Colorless oil; 1H NMR (CDCl3, 300 MHz): d = 7.09 (d, J =
6.9 Hz, 1H), 7.00 (s, 1H), 6.98 (d, J = 6.9 Hz, 1H), 3.44–3.65 (m, 6H),
2.64–2.85 (m, 6H), 1.96–2.16 ppm (m, 6H); aryl protons of minor isomer
3d: d = 6.87 ppm (s, 3H); 13C NMR (CDCl3, 75 MHz): d = 141.1, 138.7,
136.3, 129.65, 129.56, 126.5, 44.5, 44.2, 34.00, 33.95, 33.82, 33.79, 32.6,
32.3, 29.5, 29.1 ppm.
decylphthalate (7b) (133 mg, 0.264 mmol, 88%, 5b:6b:7b
= 92:6:2).
This mixture could be purified by preparative TLC (hexane/ethyl acetate,
10:1), which furnished pure 3,6-didecylphthalic acid diethyl ester (5b)
(120 mg, 0.238 mmol, 79%).
Diethyl 3,6-didecylphthalate (5b): Colorless solid; m.p. 42–448C; 1H
NMR (CDCl3, 300 MHz): d = 7.20 (s, 2H), 4.32 (q, J = 7.2 Hz, 4H),
2.67 (t, J = 7.8 Hz, 4H), 1.50–1.62 (m, 4H), 1.36 (t, J = 7.2 Hz, 6H),
1.18–1.40 (m, 28H), 0.88 ppm (t, J = 6.6 Hz, 6H); 13C NMR (CDCl3,
75 MHz): d = 168.6, 139.0, 131.8, 131.6, 61.3, 33.5, 31.9, 31.6, 29.6, 29.63,
29.60, 29.5, 29.3, 22.7, 14.12, 14.10 ppm; IR (neat): n˜ = 2750, 1670, 1230,
1160, 1060 cmÀ1; elemental analysis calcd (%) for C32H54O4: C 76.45, H
10.83; found: C 76.73, H 11.09.
Dimethyl 3,6-didecylphthalate (5a, 91% regioselectivity): Yellow oil; 1H
NMR (CDCl3, 300 MHz): d = 7.21 (s, 2H), 3.85 (s, 6H), 2.67 (t, J =
7.5 Hz, 4H), 1.50–1.62 (m, 4H), 1.20–1.37 (m, 28H), 0.88 ppm (t, J =
6.6 Hz, 6H); aryl protons of minor isomer 6a: d = 7.63 (d, J = 1.8 Hz,
1H), 7.20 ppm (d, J = 1.8 Hz, 1H); aryl protons of minor isomer 7a: d
= 7.49 ppm (s, 2H); 13C NMR (CDCl3, 75 MHz): d = 168.9, 139.1, 131.7,
131.5, 52.2, 33.4, 31.8, 31.4, 29.6, 29.5, 29.45, 29.36, 29.3, 22.6, 14.0 ppm;
IR (neat): n˜ = 2900, 1820, 1720, 1420, 1260, 1190 cmÀ1; elemental analy-
sis calcd (%) for C30H50O4: C 75.90, H 10.62; found: C 75.59, H 10.68.
1,2,4-Tris(1-cyclohexenyl)benzene (2e, 97% regioselectivity):[31] Reaction
time: 18 h. Yellow oil; 1H NMR (CDCl3, 300 MHz): d = 7.19 (dd, J =
8.1, 2.1 Hz, 1H), 7.13 (d, J = 2.1 Hz, 1H), 7.04 (d, J = 8.1 Hz, 1H),
6.06–6.14 (m, 1H), 5.64–5.72 (m, 2H), 2.04–2.48 (m, 12H), 1.51–1.82 ppm
(m, 12H); aryl protons of minor isomer 3e: d = 7.23 ppm (s, 3H); 13C
NMR (CDCl3, 75 MHz): d
= 142.5, 141.0, 140.6, 139.8, 139.1, 136.3,
128.4, 126.2, 125.3, 124.1, 123.4, 122.9, 29.59, 29.54, 29.48, 27.4, 25.88,
25.77, 25.76, 25.73, 23.3, 23.1, 22.2 ppm.
1,2,4-Triphenylbenzene (2 f, 83% regioselectivities):[4e] Reaction time:
16 h (1 h using H8-BINAP). Colorless oil; 1H NMR (CDCl3, 300 MHz):
d = 7.11–7.80 ppm (m, 18H); 13C NMR (CDCl3, 75 MHz): d = 142.3,
141.5, 141.11, 141.07, 140.95, 140.55, 140.3, 139.5, 131.1, 129.89, 129.85,
129.4, 128.83, 128.81, 127.92, 127.89, 127.5, 127.4, 127.3, 127.1, 126.6,
126.5, 126.1, 125.2 ppm.
Di-tert-butyl 3,6-didecylphthalate (5c, 94% regioselectivity): Colorless
oil; 1H NMR (CDCl3, 300 MHz): d = 7.12 (s, 2H), 2.64 (t, J = 7.8 Hz,
4H), 1.46–1.68 (m, 18H), 1.18–1.60 (m, 32H), 0.88 ppm (t, J = 6.6 Hz,
1152
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1145 – 1156

Chemo- and Regioselective Intermolecular Cyclotrimerization of Terminal Alkynes
FULL PAPER
6H); aryl protons of minor isomer 6c: d = 7.41 (d, J = 1.8 Hz, 1H),
7.12 ppm (d, J = 1.8 Hz, 1H); aryl protons of minor isomer 7c: d =
7.38 ppm (s, 2H); 13C NMR (CDCl3, 75 MHz): d = 168.3, 137.7, 133.1,
130.7, 82.1, 33.7, 31.9, 31.7, 29.9, 29.6, 29.5, 29.3, 28.1, 22.7, 14.1 ppm; IR
(neat): n˜ = 2910, 1850, 1710, 1450, 1360, 1290, 1150, 1125 cmÀ1; elemen-
tal analysis calcd (%) for C36H62O4: C 77.37, H 11.18; found: C 77.11, H
11.25.
Di-tert-butyl 3,6-di-o-tolylphthalate (5k, 88% regioselectivity): Yellow
solid; m.p. 50.0–52.58C; 1H NMR (CDCl3, 300 MHz): d = 7.16–7.30 (m,
10H), 2.21 (s, 3.5H), 2.17 (s, 2.5H), 1.15 (s, 7.5H), 1.14 ppm (s, 10.5H);
methyl protons of minor isomer 6k: d = 2.29 (s, 3.5H), 2.16 ppm (s,
2.5H); 13C NMR (CDCl3, 75 MHz): d = 167.3, 167.2, 165.4, 141.9, 140.2,
139.93, 139.89, 139.88, 139.0, 138.9, 136.5, 136.4, 136.3, 135.3, 134.3, 133.8,
133.7, 133.6, 130.7, 130.5, 130.3, 129.8, 129.63, 129.62, 129.60, 129.55,
129.45, 128.9, 127.85, 127.83, 127.6, 125.9, 125.1, 125.0, 81.8, 81.74, 81.70,
81.6, 60.3, 28.09, 28.05, 27.5, 27.2, 21.0, 20.4, 20.3, 20.2, 20.1, 14.2 ppm; IR
(neat): n˜ = 2850, 1700, 1360, 1300, 1240, 1140 cmÀ1; elemental analysis
calcd (%) for C30H34O4: C 78.57, H 7.47; found: C 78.83, H 7.57.
Diethyl 3,6-bis(3-chloropropyl)phthalate (5d, 91% regioselectivity): Col-
orless oil; 1H NMR (CDCl3, 300 MHz): d = 7.28 (s, 2H), 4.34 (q, J =
7.2 Hz, 4H), 3.54 (t, J = 6.3 Hz, 4H), 2.86 (t, J = 7.5 Hz, 4H), 2.02–2.11
(m, 4H), 1.37 ppm (t, J = 7.2 Hz, 6H); aryl protons of minor isomer 6d:
d = 7.68 (d, J = 1.5 Hz, 1H), 7.28 ppm (d, J = 1.5 Hz, 1H); aryl pro-
Diethyl 3,6-bis(methoxymethyl)phthalate (5l, 86% regioselectivity): Col-
orless oil; 1H NMR (CDCl3, 300 MHz): d = 7.54 (s, 2H), 4.59 (s, 4H),
4.33 (q, J = 7.2 Hz, 4H), 3.35 (s, 6H), 1.36 ppm (t, J = 7.2 Hz, 6H); aryl
protons of minor isomer 6l: d = 7.85–7.87 (m, 1H), 7.61–7.63 ppm (m,
1H); aryl protons of minor isomer 7l: d = 7.77 ppm (s, 2H); 13C NMR
tons of minor isomer 7d: d
=
7.53 ppm (s, 2H); 13C NMR (CDCl3,
75 MHz): d = 168.1, 137.6, 132.4, 132.0, 61.7, 44.3, 34.0, 30.6, 14.1 ppm;
IR (neat): n˜ = 2800, 1680, 1230, 1150, 990 cmÀ1; elemental analysis calcd
(%) for C18H24Cl2O4: C 57.61, H 6.45; found: C 57.89, H 6.51.
(CDCl3, 75 MHz):
d = 167.5, 136.6, 131.2, 129.8, 71.8, 61.5, 58.5,
Di-tert-butyl 3,6-bis(3-chloropropyl)phthalate (5e, 95% regioselectivity):
13.9 ppm; IR (neat): n˜ = 2750, 1660, 1220, 1070, 990 cmÀ1; elemental
1
Colorless oil; H NMR (CDCl3, 300 MHz): d = 7.19 (s, 2H), 3.55 (t, J =
analysis calcd (%) for C16H22O4: C 61.92, H 7.15; found: C 61.60, H 6.95.
6.9 Hz, 4H), 2.83 (t, J = 6.9 Hz, 4H), 2.08 (m, 4H), 1.60 ppm (s, 18H);
aryl protons of minor isomer 6e: d = 7.42 (s, 1H), 7.25 ppm (s, 1H); aryl
protons of minor isomer 7e: d = 7.56 ppm (s, 2H); 13C NMR (CDCl3,
75 MHz): d = 168.1, 136.5, 133.9, 131.3, 82.9, 44.5, 33.9, 30.7, 28.2 ppm;
IR (neat): n˜ = 2950, 1710, 1370, 1290, 1160, 1120 cmÀ1; elemental analy-
sis calcd (%) for C22H32Cl2O4: C 61.25, H 7.48; found: C 60.89, H 7.49.
Diethyl 3,6-bis(acetoxymethyl)phthalate (5m, 87% regioselectivity): Iso-
lated as a mixture of 5m (63% yield) and 2h/3h (28% yield), these
yields being determined on the basis of 1H NMR integrals. Colorless oil;
1H NMR (CDCl3, 300 MHz): d = 7.52 (s, 2H), 5.26 (s, 4H), 4.37 (q, J =
7.2 Hz, 4H), 2.07 (s, 6H), 1.37 ppm (t, J = 7.2 Hz, 6H); aryl protons of
minor isomer 6m: d = 7.92 (d, J = 1.5 Hz, 1H), 7.60 ppm (d, J =
1.5 Hz, 1H); aryl protons of minor isomer 7m: d = 7.76 ppm (s, 2H);
13C NMR (CDCl3, 75 MHz): d = 170.3, 167.0, 134.8, 132.2, 130.9, 63.6,
Diethyl 3,6-bis(1-cyclohexenyl)phthalate (5 f, 91% regioselectivity): Col-
orless oil; 1H NMR (CDCl3, 300 MHz): d = 7.18 (s, 2H), 5.57–5.62 (m,
2H), 4.26 (q, J = 7.2 Hz, 4H), 2.03–2.33 (m, 8H), 1.55–1.80 (m, 8H),
1.33 ppm (t, J = 7.2 Hz, 6H); aryl protons of minor isomer 6 f: d = 7.83
(d, J = 1.8 Hz, 1H), 7.33 ppm (d, J = 1.8 Hz, 1H); aryl protons of
minor isomer 7 f: d = 7.46 ppm (s, 2H); 13C NMR (CDCl3, 75 MHz): d
61.9, 20.7, 13.9 ppm; IR (neat): n˜ = 2900, 1700 (br), 1360, 1050 cmÀ1
;
HRMS (EI): calcd for C16H19O6: 307.1181, found: 307.1133 [MÀOAc]+.
Diethyl 3,6-bis(trimethylsilyl)phthalate (5n, 99% regioselectivity): Color-
less solid; m.p. 65–688C; 1H NMR (CDCl3, 300 MHz): d = 7.65 (s, 2H),
4.32 (q, J = 7.2 Hz, 4H), 1.37 (t, J = 7.2 Hz, 6H), 0.30 ppm (s, 18H);
aryl protons of minor 6n: d = 8.00 (d, J = 1.2 Hz, 1H), 7.87 ppm (d, J
= 1.2 Hz, 1H); 13C NMR (CDCl3, 75 MHz): d = 170.3, 140.4, 137.7,
135.8, 61.9, 14.3, 0.3 ppm; IR (neat): n˜ = 2770, 1660, 1200, 1130, 1070,
790 cmÀ1; elemental analysis calcd (%) for C18H30O4Si2: C 58.97, H 8.25;
found: C 59.10, H 8.36.
=
168.7, 141.7, 137.3, 131.3, 129.5, 126.7, 61.4, 29.8, 25.5, 23.1, 21.9,
14.1 ppm; IR (neat): n˜ = 3200, 2750, 1660, 1180, 770 cmÀ1; elemental
analysis calcd (%) for C24H30O4: C 75.36, H 7.91; found: C 75.07, H 7.97.
Di-tert-butyl 3,6-bis(1-cyclohexenyl)phthalate (5g, 94% regioselectivity):
Colorless solid; m.p. 138.5–143.08C; 1H NMR (CDCl3, 300 MHz): d =
7.10 (s, 2H), 5.55–5.65 (m, 2H), 2.22–2.32 (m, 4H), 2.04–2.14 (m, 4H),
1.60–1.80 (m, 8H), 1.53 ppm (s, 18H); aryl protons of minor isomer 6g:
d = 7.61 (m, 1H), 7.24 ppm (m, 1H); aryl protons of minor isomer 7g: d
= 7.35 ppm (s, 2H); 13C NMR (CDCl3, 75 MHz): d = 168.0, 140.7, 137.3,
132.4, 128.6, 126.3, 81.6, 36.7, 28.0, 25.3, 22.9, 21.8 ppm; IR (neat): n˜ =
2850 (br), 1700, 1290, 1220, 1120 cmÀ1; elemental analysis calcd (%) for
C28H38O4: C 76.68, H 8.73; found: C 76.46, H 8.98.
Tetraethyl 5-(trimethylsilyl)benzene-1,2,3,4-tetracarboxylate (8): Color-
less oil; 1H NMR (CDCl3, 300 MHz): d = 8.20 (s, 1H), 4.25–4.44 (m,
8H), 1.29–1.43 (m, 12H), 0.34 ppm (s, 9H); 13C NMR (CDCl3, 75 MHz):
d = 168.7, 167.5, 166.9, 165.9, 142.7, 141.9, 138.3, 135.2, 131.4, 130.4, 62.8,
62.62, 62.55, 62.53, 14.6, 14.5, 14.42, 14.41, 0.0 ppm; IR (neat): n˜ = 3000,
1740, 1390, 1240 (br), 1040, 860 cmÀ1; elemental analysis calcd (%) for
C21H30O8Si: C 57.51, H 6.90; found: C 57.46, H 6.91.
Diethyl 3,6-diphenylphthalate (5h, 89% regioselectivity): Colorless solid;
1
General procedure for the intermolecular crossed-cyclotrimerization of
dialkyl acetylenedicarboxylates and terminal a,w-diynes (Table 6,
entry 6): Under an argon atmosphere, H8-BINAP (5.1 mg, 0.0125 mmol)
and [Rh(cod)2]BF4 (7.9 mg, 0.0125 mmol) were dissolved in CH2Cl2
(1.0 mL) and the mixture was stirred for 5 min. H2 was then introduced
into the resulting solution in a Schlenk tube. After stirring for 0.5 h at
room temperature, the resulting solution was concentrated to dryness
and the residue was redissolved in CH2Cl2 (20 mL). A solution of 1,11-
dodecadiyne (9c) (40.6 mg, 0.25 mmol) and dimethyl acetylenedicarboxy-
late (4a; 35.5 mg, 0.25 mmol) in CH2Cl2 (3.0 mL) was then added drop-
wise to this solution over 1 min, and any substrates remaining in the sy-
ringe were rinsed into the reaction mixture with further CH2Cl2 (2.0 mL).
The mixture was stirred at room temperature for 1 h. The resulting so-
lution was concentrated and the residue was purified by preparative TLC
(hexane/ethyl acetate, 6:1), which furnished [8]paracyclophane 11d
(34.8 mg, 0.114 mmol, 46%).
Dimethyl [8]paracyclophane-10,11-dicarboxylate (11d):[35] Colorless oil;
1H NMR (CDCl3, 300 MHz): d = 7.28 (s, 2H), 3.86 (s, 6H), 3.15 (dt, J =
13.0, 5.3 Hz, 2H), 2.51 (ddd, J = 14.1, 9.0, 5.1 Hz, 2H), 1.57–1.70 (m,
2H), 1.38–1.49 (m, 2H), 1.00–1.15 (m, 2H), 0.75–0.90 (m, 2H), 0.40–0.60
(m, 2H), À0.15–0.10 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d =
168.4, 140.6, 132.8, 132.1, 52.3, 33.9, 30.3, 29.2, 25.4 ppm; IR (neat): n˜ =
2880, 2820, 1705, 1420, 1280, 1190, 1100 cmÀ1; HRMS (EI): calcd for
C18H24O4: 273.1491, found: 273.1469 [MÀOMe]+.
m.p. 99–1058C; H NMR (CDCl3, 300 MHz): d = 7.47 (s, 2H), 7.32–7.66
(m, 10H), 4.07 (q, J = 7.2 Hz, 4H), 0.97 ppm (t, J = 6.9 Hz, 6H); aryl
protons of minor isomer 6h: d = 8.21 (d, J = 2.1 Hz, 1H), 7.74 ppm (d,
J = 2.1 Hz, 1H); aryl protons of minor isomer 7h: d = 7.79 ppm (s,
2H); 13C NMR (CDCl3, 75 MHz): d = 168.3, 139.9, 132.3, 131.5, 129.0,
128.4, 128.3, 127.7, 61.5, 13.5 ppm; IR (neat): n˜ = 1680, 1200, 1110, 1040,
740, 670 cmÀ1; elemental analysis calcd (%) for C24H22O4: C 76.99, H
5.92; found: C 76.82, H 6.01.
Di-tert-butyl 3,6-diphenylphthalate (5i, 90% regioselectivity):[34] Color-
less solid; m.p. 183.5–185.58C; 1H NMR (CDCl3, 300 MHz): d = 7.34–
7.44 (m, 12H), 1.24 ppm (s, 18H); tert-butyl protons of minor isomer 6i:
d = 1.31 (s, 9H), 1.24 ppm (s, 9H); 13C NMR (CDCl3, 75 MHz): d =
167.4, 140.3, 139.4, 133.3, 130.8, 128.9, 128.1, 127.4, 82.3, 27.5 ppm.
Diethyl 3,6-di-o-tolylphthalate (5j, 89% regioselectivity): Colorless solid;
m.p. 103–1088C; 1H NMR (CDCl3, 300 MHz): d = 7.33 (s, 2H), 7.07–
7.29 (m, 8H), 3.98 (q, J = 7.2 Hz, 1.6H), 3.97 (q, J = 7.2 Hz, 2.4H), 2.21
(s, 3.5H), 2.17 (s, 2.5H), 0.88 (t, J = 7.2 Hz, 2.5H), 0.87 ppm (t, J =
7.2 Hz, 3.5H); aryl protons of minor isomer 6j: d = 7.99 (d, J = 2.1 Hz,
1H), 7.38 ppm (d, J = 2.1 Hz, 1H); aryl protons of minor isomer 7j: d
= 7.69 ppm (s, 2H); 13C NMR (CDCl3, 75 MHz): d = 167.9, 139.9, 139.8,
139.5, 136.2, 135.9, 132.6, 129.3, 127.9, 125.2, 61.2, 20.4, 13.4 ppm; IR
(neat): n˜ = 2800, 1680, 1380, 1200, 1100, 730 cmÀ1; elemental analysis
calcd (%) for C26H26O4: C 77.59, H 6.51; found: C 77.41, H 6.47.
Chem. Eur. J. 2005, 11, 1145 – 1156
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1153

K. Tanaka et al.
Diethyl [6]metacyclophane-8,9-dicarboxylate (10a): Colorless oil; 1H
NMR (CDCl3, 300 MHz): d = 7.50 (d, J = 1.2 Hz, 1H), 7.45 (d, J =
1.2 Hz, 1H), 4.29–4.43 (m, 4H), 2.54–2.84 (m, 4H), 1.72–1.91 (m, 2H),
1.16–1.48 (m, 4H), 1.36 (t, J = 7.2 Hz, 6H), 0.20–0.65 ppm (m, 2H); 13C
25.6 ppm; IR (neat): n˜ = 2870, 1710, 1420, 1260, 1090 cmÀ1; HRMS (EI):
calcd for C21H30O4: 346.2144, found: 346.2147 [M]+.
Dimethyl [12]paracyclophane-14,15-dicarboxylate (11h): Colorless oil;
1H NMR (CDCl3, 300 MHz): d = 7.24 (s, 2H), 3.85 (s, 6H), 2.95–3.15
(m, 2H), 2.45–2.65 (m, 2H), 1.52–1.72 (m, 4H), 0.90–1.20 (m, 12H),
0.75–0.90 ppm (m, 4H); 13C NMR (CDCl3, 75 MHz): d = 168.8, 139.4,
NMR (CDCl3, 75 MHz): d
= 168.9, 166.7, 144.2, 141.1, 139.3, 130.6,
129.5, 125.6, 61.3, 61.2, 34.3, 32.6, 32.4, 32.3, 27.8, 27.5, 14.13, 14.11 ppm;
IR (neat): n˜ = 2800, 1670, 1420, 1230, 750 cmÀ1; HRMS (FAB): calcd for
C18H24O4: 305.1753, found 305.1779 [M+H]+; elemental analysis calcd
(%) for C18H24O4: C 71.03, H 7.95; found: C 71.29, H 7.96.
132.1, 131.9, 52.2, 32.7, 29.3, 27.4, 27.3, 26.4, 25.2 ppm; IR (neat): n˜
=
2870, 2820, 1710, 1420, 1260, 1190 cmÀ1; HRMS (EI): calcd for C22H32O4:
360.2301, found: 360.2306 [M]+.
Dimethyl [7]paracyclophane-9,10-dicarboxylate (11a) and dimethyl[7]-
metacyclophane-9,10-dicarboxylate (10b) (11a:10b = 1:0.8):[27] Colorless
solid; m.p. 60–638C; 1H NMR (CDCl3, 300 MHz): d = 7.67 (d, J
=
1.5 Hz, 1H; 10b), 7.62 (d, J = 1.5 Hz, 1H; 10b), 7.23 (s, 2H; 11a), 3.92
(s, 3H; 10b), 3.88 (s, 3H; 10b), 3.87 (s, 6H; 11a), 3.34 (ddd, J = 12.9,
6.3, 1.8 Hz, 2H), 2.70–2.76 (m, 4H), 2.40 (ddd, J = 18.0, 11.4, 6.6 Hz,
2H), 1.26–1.70 (m, 13H), 0.93–1.07 (m, 2H), 0.48–0.67 (m, 1H), 0.21–
0.33 (m, 2H), À0.15–0.15 (m, 1H), À1.99 to À1.77 ppm (m, 1H); 13C
Acknowledgements
This work was supported by the Mitsubishi Chemical Corporation Fund
and a Grant-in-Aid for Scientific Research (No. 16750072) from the Min-
istry of Education, Culture, Sports, Science and Technology, Japan. We
thank Takasago International Corporation for the gift of modified
BINAP ligands.
NMR (CDCl3, 75 MHz): d
= 170.0, 168.2, 166.6, 143.8, 141.1, 140.1,
136.3, 132.8, 132.3, 131.7, 128.9, 126.8, 52.4, 52.34, 52.30, 37.0, 34.9, 30.4,
30.0, 29.5, 29.2, 29.0, 28.8, 28.5, 27.3, 26.9 ppm; IR (neat): n˜ = 2900,
1710, 1420, 1260, 1190 cmÀ1; HRMS (EI): calcd for C17H22O4: 290.1518,
found: 290.1526 [M]+.
[1] For reviews, see: a) S. Saito, Y. Yamamoto, Chem. Rev. 2000, 100,
2901–2915; b) H.-W. Frꢁhauf, Chem. Rev. 1997, 97, 523–596; c) I.
Ojima, M. Tzamarioudaki, Z. Li, R. J. Donovan, Chem. Rev. 1996,
96, 635–662; d) M. Lautens, W. Klute, W. Tam, Chem. Rev. 1996, 96,
46–92; e) R. Boese, A. P. V. Sickle, K. P. C. Vollhardt, Synthesis
1994, 1374–1382; f) N. E. Schore, Chem. Rev. 1988, 88, 1081–1119;
g) K. P. C. Vollhardt, Angew. Chem. 1984, 96, 525–541; Angew.
Chem. Int. Ed. Engl. 1984, 23, 539–556; h) D. B. Grotjahn, in Com-
prehensive Organometallic Chemistry II, Vol. 12, (Eds.: E. W. Abel,
F. G. A. Stone, G. Wilkinson, L. Hegedus), Pergamon, Oxford, 1995,
741–770; i) N. E. Shore, in Comprehensive Organic Synthesis, Vol. 5
(Ed.: B. M. Trost, I. Fleming), Pergamon, Oxford, 1991, 1129–1162.
[2] a) B. M. Trost, Science 1991, 254, 1471–1477; b) B. M. Trost, Angew.
Chem. 1995, 107, 285–307; Angew. Chem. Int. Ed. Engl. 1995, 34,
259–281; c) B. M. Trost, Acc. Chem. Res. 2002, 35, 695–705.
Diethyl [7]paracyclophane-9,10-dicarboxylate (11b) and diethyl [7]meta-
cyclophane-9,10-dicarboxylate (10c) (11b:10c = 1:1.2): Colorless oil; 1H
NMR (CDCl3, 300 MHz): d = 7.67 (d, J = 1.5 Hz, 1H; 10c), 7.62 (d, J
= 1.5 Hz, 1H; 10c), 7.21 (s, 2H; 11a), 4.28–4.43 (m, 8H), 3.36 (ddd, J =
12.9, 6.3, 1.8 Hz, 2H), 2.65–2.82 (m, 4H), 2.39 (ddd, J
= 17.7, 11.4,
6.3 Hz, 2H), 1.26–1.70 (m, 19H), 0.95–1.10 (m, 2H), 0.48–0.68 (m, 1H),
0.20–0.35 (m, 2H), À0.15–0.15 (m, 1H), À1.98 to À1.72 ppm (m, 1H);
13C NMR (CDCl3, 75 MHz): d = 169.3, 167.8, 166.2, 143.6, 140.9, 138.8,
136.2, 132.7, 132.6, 131.9, 131.5, 126.7, 61.3, 42.3, 37.0, 34.9, 31.4, 30.5,
30.0, 29.4, 29.1, 28.9, 28.6, 28.4, 27.4, 26.6, 14.2, 14.14, 14.08 ppm; IR
(neat): n˜
=
2870, 1700 (br), 1260, 1190 cmÀ1; HRMS (EI): calcd for
C19H26O4: 318.1831, found: 318.1783 [M]+.
Di-tert-butyl [7]paracyclophane-9,10-dicarboxylate (11c) and di-tert-
butyl [7]metacyclophane-9,10-dicarboxylate (10d) (11c:10d
= 1:0.8):
1
[3] For the first discovery of metal-catalyzed cyclotrimerization, see: W.
Reppe, W. J. Schweckendick, Justus Liebigs Ann. Chem. 1948, 560,
104–116.
Colorless solid; m.p. 90–938C; H NMR (CDCl3, 300 MHz): d = 7.58 (d,
J = 1.5 Hz, 1H; 10d), 7.41 (d, J = 1.5 Hz, 1H; 10d), 7.26 (s, 2H; 11c),
3.35 (ddd, J = 12.6, 6.3, 1.8 Hz, 2H), 2.66–2.85 (m, 4H), 2.36 (ddd, J =
18.0, 11.4, 6.6 Hz, 2H), 1.59 (s, 18H; 11c), 1.58 (s, 18H; 10d), 1.25–1.70
(m, 13H), 0.95–1.30 (m, 2H), 0.48–0.67 (m, 1H), 0.19–0.34 (m, 2H),
À0.15–0.15 (m, 1H), À1.95 to À1.70 ppm (m, 1H); 13C NMR (CDCl3,
75 MHz): d = 167.3, 165.5, 142.3, 140.0, 139.7, 135.5, 134.1, 132.9, 132.1,
131.3, 126.1, 81.7, 81.6, 81.2, 65.8, 37.0, 35.0, 34.8, 30.0, 29.5, 29.3, 28.2,
28.14, 28.09, 27.9, 27.4, 26.7, 15.2 ppm; IR (neat): n˜ = 2900, 1695, 1360,
[4] For recent papers on catalytic, completely intermolecular cyclotri-
merization of alkynes, see: a) E. S. Johnson, G. J. Balaich, P. E. Fan-
wick, I. P. Rothwell, J. Am. Chem. Soc. 1997, 119, 11086–11087;
b) M. S. Sigman, A. W. Fatland, B. E. Eaton, J. Am. Chem. Soc.
1998, 120, 5130–5131; c) J. Yang, J. G. Verkade, J. Am. Chem. Soc.
1998, 120, 6834–6835; d) O. V. Ozerov, F. T. Ladipo, B. O. Patrick, J.
Am. Chem. Soc. 1999, 121, 7941–7942; e) O. V. Ozerov, B. O. Pat-
rick, F. T. Ladipo, J. Am. Chem. Soc. 2000, 122, 6423–6431; f) S.
Saito, T. Kawasaki, N. Tsuboya, Y. Yamamoto, J. Org. Chem. 2001,
66, 796–802; g) L. Yong, H. Butenschoen, Chem. Commun. 2002,
2852–2853; h) T. Sugihara, A. Wakabayashi, Y. Nagai, H. Takao, H.
Imagawa, M. Nishizawa, Chem. Commun. 2002, 576–577; i) E.
Rꢁba, R. Schmid, K. Kirchner, M. J. Calhorda, J. Organomet. Chem.
2003, 682, 204–211; j) S. Reinhard, K. D. Behringer, J. Bluemel,
New J. Chem. 2003, 27, 776–778; k) F. T. Ladipo, V. Sarveswaran,
J. V. Kingston, R. A. Huyck, S. Y. Bylikin, S. D. Carr, R. Watts, S.
Parkin, J. Organomet. Chem. 2004, 689, 502–514; l) E. Farnetti, N.
Marsich, J. Organomet. Chem. 2004, 689, 14–17.
[5] For stoichiometric intramolecular cyclotrimerization of alkynes, see:
a) E. Mꢁller, R. Thomas, M. Sauerbier, E. Langer, D. Streichfuss,
Tetrahedron Lett. 1971, 12, 521–524; b) E. Mꢁller, Synthesis 1974,
761–774; c) P. Bhatarah, E. H. Smith, J. Chem. Soc. Perkin Trans. 1
1990, 2603–2606; d) P. Bhatarah, E. H. Smith, J. Chem. Soc. Chem.
Commun. 1991, 277–278; e) P. Bhatarah, E. H. Smith, J. Chem. Soc.
Perkin Trans. 1 1992, 2163–2168; f) D. M. Duckworth, S. Lee-Wong,
A. M. Z. Slawin, E. H. Smith, D. J. Williams, J. Chem. Soc. Perkin
Trans. 1 1996, 815–821; g) R. Hara, Q. Guo, T. Takahashi, Chem.
Lett. 2000, 140–141.
1270, 1140 cmÀ1
; HRMS (EI): calcd for C23H34O4: 244.1099, found:
244.1086 [MÀtBu2O]+.
Dimethyl [9]paracyclophane-11,12-dicarboxylate (11e): Colorless oil; 1H
NMR (CDCl3, 300 MHz): d = 7.27 (s, 2H), 3.86 (s, 6H), 3.00 (ddd, J =
12.7, 7.7, 4.6 Hz, 2H), 2.37 (ddd, J = 12.8, 7.9, 5.1 Hz, 2H), 1.50–1.65 (m,
2H), 1.35–1.50 (m, 2H), 0.75–1.15 (m, 4H), 0.48–0.68 (m, 4H), À0.05–
0.17 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d = 168.5, 139.9, 132.8,
131.9, 52.2, 33.1, 28.4, 27.4, 25.7, 23.0 ppm; IR (neat): n˜ = 2880, 2820,
1710, 1420, 1260, 1190, 1140 cmÀ1; HRMS (EI): calcd for C19H26O4:
318.1832, found: 318.1830 [M]+.
Dimethyl [10]paracyclophane-12,13-dicarboxylate (11 f):[36] Colorless oil;
1H NMR (CDCl3, 300 MHz): d = 7.25 (s, 2H), 3.86 (s, 6H), 3.16 (dt, J =
13.2, 5.0 Hz, 2H), 2.47 (ddd, J = 15.8, 10.5, 5.3 Hz, 2H), 1.67–1.80 (m,
2H), 1.42–1.57 (m, 2H), 1.17–1.37 (m, 2H), 0.95–1.08 (m, 2H), 0.65–0.90
(m, 6H), 0.20–0.37 ppm (m, 2H); 13C NMR (CDCl3, 75 MHz): d
=
168.6, 139.2, 132.9, 132.1, 52.2, 33.4, 28.0, 27.9, 26.8, 24.9 ppm; IR (neat):
n˜ = 2880, 2820, 1710, 1420, 1260, 1190, 1150 cmÀ1; HRMS (EI): calcd for
C20H28O4: 332.1988, found: 332.1968 [M]+.
Dimethyl [11]paracyclophane-13,14-dicarboxylate (11g): Colorless oil;
1H NMR (CDCl3, 300 MHz): d = 7.28 (s, 2H), 3.85 (s, 6H), 3.00 (ddd, J
= 13.8, 7.2, 4.8 Hz, 2H), 2.52 (ddd, J = 12.3, 7.8, 4.8 Hz, 2H), 1.55–1.70
(m, 4H), 1.15–1.35 (m, 4H), 0.65–0.95 ppm (m, 10H); 13C NMR (CDCl3,
75 MHz): d = 168.7, 139.7, 132.4, 132.0, 52.2, 33.2, 28.5, 28.0, 27.4, 26.6,
[6] For catalytic intramolecular cyclotrimerization of alkynes, see:
a) K. P. C. Vollhardt, R. G. Bergman, J. Am. Chem. Soc. 1974, 96,
1154
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1145 – 1156

Chemo- and Regioselective Intermolecular Cyclotrimerization of Terminal Alkynes
FULL PAPER
4996–4998; b) R. L. Hillard III, K. P. C. Vollhardt, Angew. Chem.
1975, 87, 744–745; Angew. Chem. Int. Ed. Engl. 1975, 14, 712–713;
c) R. L. Hillard III, K. P. C. Vollhardt, J. Am. Chem. Soc. 1977, 99,
4058–4069; d) K. P. C. Vollhardt, Acc. Chem. Res. 1977, 10, 1–8;
e) G. P. Chiusoli, L. Pallini, G. Terenghi, Transition Met. Chem.
1983, 8, 189–190; f) A. C. Williams, P. Scheffels, D. Sheehan, T. Liv-
inghouse, Organometallics 1989, 8, 1566–1567; g) C. J. Du Toit,
J. A. K. Du Plessis, G. Lachmann, J. Mol. Catal. 1989, 53, 67–78;
h) Y. Badrich, J. Blum, I. Amer, K. P. C. Vollhardt, J. Mol. Catal.
1991, 66, 295–312; i) Y. Sato, T. Nishiyama, M. Mori, Heterocycles
1997, 44, 443–457; j) Y. Sato, T. Nishimata, M. Mori, J. Org. Chem.
1994, 59, 6133–6135; k) M. Nishida, H. Shiga, M. Mori, J. Org.
Chem. 1998, 63, 8606–8608; l) Y. Yamamoto, A. Nagata, K. Itoh,
Tetrahedron Lett. 1999, 40, 5035–5038; m) Y. Yamamoto, R. Ogawa,
K. Itoh, Chem. Commun. 2000, 549–550; n) Y. Yamamoto, A.
Nagata, Y. Arikawa, K. Tatsumi, K. Itoh, Organometallics 2000, 19,
2403–2405; o) R. Takeuchi, S. Tanaka, Y. Nakata, Tetrahedron Lett.
2001, 42, 2991–2994; p) F. Slowinski, C. Aubert, M. Malacria, Adv.
Synth. Catal. 2001, 343, 64–67; q) A. Jeevanandam, R. P. Korivi, I.
Huang, C.-H. Cheng, Org. Lett. 2002, 4, 807–810; r) T. Sugihara, A.
Wakabayashi, Y. Nagai, H. Takao, H. Imagawa, M. Nishizawa,
Chem. Commun. 2002, 9, 576–577; s) Y. Yamamoto, A. Nagata, H.
Nagata, Y. Ando, Y. Arikawa, K. Tatsumi, K. Itoh, Chem. Eur. J.
2003, 9, 2469–2483; t) Y. Yamamoto, K. Hata, T. Arakawa, K. Itoh,
Chem. Commun. 2003, 1290–1291; u) Y. Yamamoto, T. Arakawa, R.
Ogawa, K. Itoh, J. Am. Chem. Soc. 2003, 125, 12143–12160; v) T.
Shibata, T. Fujimoto, K. Yokota, K. Takagi, J. Am. Chem. Soc. 2004,
126, 8382–8383.
Am. Chem. Soc. 2001, 123, 11107–11108; h) W. A. Herrmann,
V. P. W. Bçhm, C. W. K. Gstçttmayr, M. Grosche, C.-P. Reisinger, T.
Weskamp, J. Organomet. Chem. 2001, 617–618, 616–628; i) T.
Ohmura, S. Yorozuya, Y. Yamamoto, N. Miyaura, Organometallics
2000, 19, 365–367; j) Y. Nishibayashi, M. Yamanashi, I. Wakiji, M.
Hidai, Angew. Chem. 2000, 112, 3031–3033; Angew. Chem. Int. Ed.
2000, 39, 2909–2911; k) J.-P. Qꢁ, D. Masui, Y. Ishii, M. Hidai, Chem.
Lett. 1998, 1003–1004; l) B. M. Trost, M. T. Sorum, C. Chan, A. E.
Harms, G. Ruhter, J. Am. Chem. Soc. 1997, 119, 698–708; m) C. S.
Yi, N. Liu, Organometallics 1996, 15, 3968–3971; n) C. Bianchini, P.
Frediani, D. Masi, M. Peruzzini, F. Zanobini, Organometallics 1994,
13, 4616–4632; o) C.-H. Jun, Z. Lu, R. H. Crabtree, Tetrahedron
Lett. 1992, 33, 7119–7120.
[14] For rhodium-catalyzed intramolecular cyclotrimerization of alkynes,
see: a) E. Mꢁller, Synthesis 1974, 761–774; b) R. Grigg, R. Scott, P.
Stevenson Tetrahedron Lett. 1982, 23, 2691–2692; c) R. Grigg, R.
Scott, P. Stevenson, J. Chem. Soc. Perkin Trans. 1 1988, 1357–1364;
d) P. Magnus, D. Witty, A. Stamford, Tetrahedron Lett. 1993, 34, 23–
26; e) F. E. McDonald, H. Y. H. Zhu, C. R. Holmquist, J. Am.
Chem. Soc. 1995, 117, 6605–6606; f) S. Kotha, E. Brahmachary, Tet-
rahedron Lett. 1997, 38, 3561–3564; g) B. Witulski, T. Stengel,
Angew. Chem. 1999, 111, 2521–2525; Angew. Chem. Int. Ed. 1999,
38, 2426–2430; h) R. Grigg, V. Sridharan, J. Wang, J. Xu, Tetrahe-
dron 2000, 56, 8967–8976; i) B. Witulski, T. Stengel, J. M. Fernan-
dez-Hernandez, Chem. Commun. 2000, 1965–1966; j) F. E. McDo-
nald, V. Smolentsev, Org. Lett. 2002, 4, 745–748; k) B. Witulski, A.
Zimmermann, Synlett 2002, 1855–1859; l) B. Witulski, C. Alayrac,
Angew. Chem. 2002, 114, 3415–3418; Angew. Chem. Int. Ed. 2002,
41, 3281–3284; m) H. Nishiyama, E. Niwa, T. Inoue, Y. Ishima, K.
Aoki, Organometallics 2002, 21, 2572–2574; n) H. Kinoshita, H. Shi-
nokubo, K. Oshima, J. Am. Chem. Soc. 2003, 125, 7784–7785.
[15] a) J. Ohshita, K. Furumori, A. Matsuguchi, M. Ishikawa, J. Org.
Chem. 1990, 55, 3277–3280; b) L. D. Field, A. J. Ward, P. Turner,
Aust. J. Chem. 1999, 52, 1085–1092.
[16] For recent examples of rhodium-catalyzed intermolecular cycloaddi-
tions involving an alkyne, see: a) K. H. Park, I. G. Jung, Y. K.
Chung, Org. Lett. 2004, 6, 1183–1186; b) S. Nakamura, Y. Hirata, T.
Kurosaki, M. Anada, O. Kataoka, S. Kitagaki, S. Hashimoto, Angew.
Chem. 2003, 115, 5509–5513; Angew. Chem. Int. Ed. 2003, 42, 5351–
5355; c) D. M. Hodson, R. Glen, G. H. Grant, A. J. Redgrave, J.
Org. Chem. 2003, 68, 581–586; d) P. A. Wender, T. M. Pedersen,
M. J. C. Scanio, J. Am. Chem. Soc. 2002, 124, 15154–15155; e) S. R.
Gilbertson, B. DeBoef, J. Am. Chem. Soc. 2002, 124, 8784–8785.
[17] For rhodium-catalyzed intermolecular cyclotrimerization of alkynes
with rhodium clusters, see: a) W. Baidossi, N. Goren, J. Blum, J.
Mol. Catal. 1993, 85, 153–162; with dirhodium(ii) perfluorobutyrate,
see: b) M. P. Doyle, M. S. Shanklin, Organometallics 1994, 13, 1081–
1088; with dirhodaboranes, see: c) H. Yan, A. M. Beatty, T. P. Fehl-
ner, Organometallics 2002, 21, 5029–5037.
[7] Y. Yamamoto, J. Ishii, H. Nishiyama, K. Itoh, J. Am. Chem. Soc.
2004, 126, 3712–3713.
[8] G. Chouraqui, M. Petit, C. Aubert, M. Malacria, Org. Lett. 2004, 6,
1519–1521.
[9] For stoichiometric intermolecular crossed-cyclotrimerization of al-
kynes, see: a) Y. Wakatsuki, T. Kuramitsu, H. Yamazaki, Tetrahe-
dron Lett. 1974, 15, 4549–4552; b) H. Yamazaki, Y. Wakatsuki, J.
Organomet. Chem. 1977, 139, 157–167; c) T. Takahashi, Z. Xi, A.
Yamazaki, Y. Liu, K. Nakajima, M. Kotora, J. Am. Chem. Soc. 1998,
120, 1672–1680; d) T. Takahashi, F.-Y. Tsai, Y. Li, K. Nakajima, M.
Kotora, J. Am. Chem. Soc. 1999, 121, 11093–11100; e) D. Suzuki,
H. Urabe, F. Sato, J. Am. Chem. Soc. 2001, 123, 7925–7926; f) R.
Tanaka, Y. Nakano, D. Suzuki, H. Urabe, F. Sato, J. Am. Chem. Soc.
2002, 124, 9682–9683.
[10] For catalytic intermolecular crossed-cyclotrimerization of alkynes
with Ni, see: a) N. Mori, S.-I. Ikeda, K. Odashima, Chem. Commun.
2001, 181–182; b) Y. Sato, K. Ohashi, M. Mori, Tetrahedron Lett.
1999, 40, 5231–5234; with Pd, see: c) H. T. Dieck, C. Munz, C.
Mꢁller, J. Organomet. Chem. 1990, 384, 243–255; with Ir, see: d) R.
Takeuchi, Y. Nakaya, Org. Lett. 2003, 5, 3659–3662; with Rh, see:
e) K. Abdulla, B. L. Booth, C. Stacey, J. Organomet. Chem. 1985,
293, 103–114.
[18] X. Zhang, K. Mashima, K. Koyano, N. Sayo, H. Kumobayashi, S.
Akutagawa, H. Takaya, Tetrahedron Lett. 1991, 32, 7283–7286.
[19] a) T. Saito, T. Yokozawa, X. Zhang, N. Sayo, EP 850945 A, 1998,
US 5872273, 1999; b) T. Saito, T. Yokozawa, T. Ishizaki, T. Moroi,
N. Sayo, T. Miura, H. Kumobayashi, Adv. Synth. Catal. 2001, 343,
264–267.
[20] For a review of cyclophane chemistry, see: J. P. Fçgtle, Cyclophane
Chemistry, Wiley. Chichester, England, 1993.
[21] A. F. Moretto, H.-C. Zhang, B. E. Maryanoff, J. Am. Chem. Soc.
2001, 123, 3157–3158.
[11] For a preliminary communication, see: K. Tanaka, K. Shirasaka,
Org. Lett. 2003, 5, 4697–4699.
[12] Cyclotrimerization by an alternative cascade carbometalation route
has also been reported; see: a) I. Ojima, A. T. Vu, J. V. McCullagh,
A. Kinoshita, J. Am. Chem. Soc. 1999, 121, 3230–3231; b) J.-U.
Peters, S. Blechert, Chem. Commun. 1997, 1983–1984; c) S. K. Das,
R. Roy, Tetrahedron Lett. 1999, 40, 4015–4018; d) G. B. Hçven, J.
Efskind, C. Rømming, K. Undheim, J. Org. Chem. 2002, 67, 2459–
2463.
[13] For the transition-metal-catalyzed dimerization of terminal alkynes,
see: a) R. U. Kirss, R. D. Ernst, A. M. Arif, J. Organomet. Chem.
2004, 689, 419–428; b) Y. Gao, R. J. Puddephatt, Inorg. Chim. Acta
2003, 350, 101–106; c) T. Opstal, F. Verpoort, Synlett 2003, 314–320;
d) J. Navarro, M. Sagi, E. Sola, F. J. Lahoz, I. T. Dobrinovitch, A.
Katho, F. Joo, L. A. Oro, Adv. Synth. Catal. 2003, 345, 280–288;
e) K. Melis, D. De Vos, P. Jacobs, F. Verpoort, J. Organomet. Chem.
2002, 659, 159–164; f) E. Ruba, K. Mereiter, R. Schmid, V. N. Sapu-
nov, K. Kirchner, H. Schottenberger, M. J. Calhorda, L. F. Veiros,
Chem. Eur. J. 2002, 8, 3948–3961; g) M. Rubina, V. Gevorgyan, J.
[22] L. V. R. Bonaga, H.-C. Zhang, D. A. Gauthier, I. Reddy, B. E. Mar-
yanoff, Org. Lett. 2003, 5, 4537–4540.
[23] a) S. Saito, M. M. Salter, V. Gevorgyan, N. Tsuboya, K. Tando, Y.
Yamamoto, J. Am. Chem. Soc. 1996, 118, 3970–3971; b) S. Saito, N.
Tsuboya, Y. Yamamoto, J. Org. Chem. 1997, 62, 5042–5047; c) D.
Weibel, V. Gevorgyan, Y. Yamamoto, J. Org. Chem. 1998, 63, 1217–
1220.
[24] a) K. H. Dçtz, A. Gerhardt, J. Organomet. Chem. 1999, 578, 223–
228; b) H. Wang, W. D. Wulff, A. L. Rheingold, J. Am. Chem. Soc.
Chem. Eur. J. 2005, 11, 1145 – 1156
www.chemeurj.org
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1155

K. Tanaka et al.
2000, 122, 9862–9863; c) H. Wang, W. D. Wulff, A. L. Rheingold, J.
Am. Chem. Soc. 2003, 125, 8980–8981.
[30] K. S. Choi, M. K. Park, B. H. Han, Bull. Korean Chem. Soc. 1998,
19, 1257–1261.
[31] S. Dꢂrien, J.-C. Clinet, E. DuÇach, J. Pꢂrichon, J. Organomet. Chem.
1992, 424, 213–224.
[32] S. K. Das, R. Roy, Tetrahedron Lett. 1999, 40, 4015–4018.
[33] L. Yong, H. Butenschçn, Chem. Commun. 2002, 23, 2852–2853.
[34] K. Matsumoto, S. Hashimoto, S. Otani, T. Uchida, Heterocycles
1984, 22, 2713–2717.
[35] K. Satake, I. Umemoto, K. Usumoto, M. Kimura, S. Morosawa, T.
Kumagai, T. Mukai, Heterocycles 1990, 31, 163–172.
[36] W. Tochtermann, M. Haase, Chem. Ber. 1984, 117, 2293–2299.
[25] For the synthesis of [6]metacyclophanes, see: G. W. Wijsman, F. J. J.
de Kanter, W. H. de Wolf, F. Bickelhaupt, Eur. J. Org. Chem. 2001,
2743–2748.
[26] B. Hellbach, R. Gleiter, F. Rominger, Synthesis 2003, 2535–2541.
[27] For the synthesis of [7]paracyclophanes, see: J. Hunger, C. Wolff, W.
Tochtermann, E. M. Peters, K. Peters, H. G. Von Schnering, Chem.
Ber. 1986, 119, 2698–2722.
[28] E. W. Colvin, Silicon Reagents in Organic Synthesis, Academic Press,
London, England, 1988, 1–4.
[29] T. T.-L. Au-Yeung, S.-S. Chan, A. S. C. Chan, Adv. Synth. Catal.
2003, 345, 537–555.
Received: October 8, 2004
Published online: December 27, 2004
1156
ꢀ 2005 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
Chem. Eur. J. 2005, 11, 1145 – 1156