Rhodium-catalyzed [2 + 2 + 2] cyclotrimerization in an aqueous-organic biphasic system

Article abstract of DOI:10.1021/ja035438o

Macrocyclization via rhodium-catalyzed intramolecular [2 + 2 + 2] annulation of triynes has been explored in an aqueous-organic biphasic system. The biphasic system controls the concentration of hydrophobic substrates in the aqueous reaction phase and offers diluted reaction conditions without the use of a slow addition technique. The system also achieves selective cross-annulation between hydrophobic diynes and hydrophilic alkynes. Copyright

Full text of DOI:10.1021/ja035438o

Published on Web 06/04/2003
Rhodium-Catalyzed [2 + 2 + 2] Cyclotrimerization in an Aqueous-Organic
Biphasic System
Hidenori Kinoshita, Hiroshi Shinokubo,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity, Kyoto 606-8501, Japan
Received April 3, 2003; E-mail: shino@fm1.kuic.kyoto-u.ac.jp; oshima@fm1.kuic.kyoto-u.ac.jp
The synthesis of medium- and large-sized ring systems via
intramolecular cyclization often requires highly diluted reaction
conditions or the use of a slow addition technique to prevent
intermolecular reactions.1 However, the use of large quantities of
solvent is uneconomical and inconvenient, and the process of slow
addition requires a special apparatus and is a laborious operation.
Figure 1. Control of concentration in the biphasic reaction system.
In addition, using highly diluted reaction conditions often retards
the reaction rate and results in lower efficiency. It is highly desirable
Scheme 1
to develop a new tactic to circumvent these drawbacks.
We anticipated that a biphasic system could control the concen-
tration of an organic hydrophobic substrate in the aqueous phase
(Figure 1).2,3 Distribution of substrate would keep the concentration
of substrate in the reaction phase low. If the reaction proceeds in
Scheme 2
the aqueous phase, the system would achieve diluted reaction
conditions without the use of a large amount of solvents.
We examined a rhodium-catalyzed [2 + 2 + 2] cyclotrimeriza-
tion of alkynes as a test case for our biphasic system.4,5 A Diels-
Alder type mechanism involving the intermediacy of metallacy-
Table 1. Cyclization of Triynes in a H2O-Et2O Biphasic Systema
clopentadiene complexes has been postulated for the cyclotrimeri-
zation of alkynes (Scheme 1).6 Rate enhancement of the Diels-
Alder reaction in aqueous media is well-recognized.7 We hoped
that water might also accelerate this metal-mediated cycloaddition,
compensating for the sacrificed efficiency due to high dilution.
A water-soluble rhodium catalyst was prepared in situ from
[RhCl(cod)]2 and the trisodium salt of tris(m-sulfonatophenyl)-
phosphine (tppts) in water at 75 °C. The ability of this catalyst to
promote cyclotrimerization in the biphasic system was examined
with 4,9-dioxadodeca-1,6,11-triyne 1a. A solution of triyne 1a in
ether was introduced to the catalyst at room temperature, and
tricyclic compound 2a was obtained in good yield after stirring for
3 h (Scheme 2).
entry
triyne
n
R
time (h)
product
yield (%)
1
2
3
4
5
6
1b
1c
1d
1e
1f
1
2
3
4
5
2
H
H
H
H
H
CH3
10
19
19
19
22
19
2b
2c
2d
2e
2f
93
84
88
91
89
85
1g
2g
We then focused on the synthesis of medium and large rings in
the water-ether biphasic system.8 The reaction of triynes with
Wilkinson’s catalyst generally induces polymerization of alkynes
except in cases where 5-6-5 tricyclic systems are formed.9 To
our delight, we found that medium and large rings can be obtained
in excellent yields with only trace amounts of polymeric com-
pounds. In addition, no dimerization products were detected in the
reaction mixture.10 Table 1 summarizes the results of the cyclo-
trimerization of a series of triynes. It is noteworthy that 4,15-
dioxaoctadeca-1,6,17-triyne (1h) furnished 12-membered methacy-
clophane 3h in 32% yield along with the normal cyclized product
2h (57%) (Scheme 3). Macrocyclization of 1i to provide 12- and
13-membered ring systems was also successful.11
We also examined the cross-annulation of dipropargyl ether with
alkynols (Scheme 4). The [2 + 2 + 2] annulation between a 1,6-
diyne and an alkyne often suffers from dimerization and trimer-
ization of the diyne. In particular, dipropargyl ether is a highly
reactive substrate and provides the dimerized product, propargyl
ether 5, and the trimerized product, benzyl ether 6, very rapidly.
Grigg has already reported that reacting a large excess (5 equiv)
a Reaction conditions: [RhCl(cod)]2 (0.0125 mmol), tppts (0.08 mmol),
triyne (0.5 mmol), H2O (50 mL), ether (10 mL), room temperature.
of propargyl alcohol with dipropargyl ether yields the desired
product 4a in 44% yield along with 5 and 6.12 We anticipated that
the formation of dimer 5 and trimer 6 would be suppressed in a
biphasic system due to the limited concentration of the hydrophobic
diyne in the aqueous phase. Propargyl, homopropargyl, and
bishomopropargyl alcohol, which are completely soluble in water,
were selected as hydrophilic alkyne partners.13 We were pleased
to find that the reaction in the biphasic system cleanly provided
the desired cross-annulation products 4 in good yields even with
1.5 equiv of alkynols. The use of hydrochloric acid and sodium
chloride improved selectivity and conversion of the reaction,
although the reason is not yet clear at this stage. In addition, the
cross-annulation of N-tosyl-N,N-dipropargylamine with propargyl
alcohol furnished isoindoline 4d in 84% yield. Diethyl 2,2-
dipropargylmalonate, which is completely insoluble in water,
yielded none of the annulation product. This result indicates that,
9
7784
J. AM. CHEM. SOC. 2003, 125, 7784-7785
10.1021/ja035438o CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3
Further research on the water-organic biphasic system is currently
underway in our laboratory.
Acknowledgment. This work was supported by a Grant-in-Aid
for Scientific Research (No. 14703026) from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan. H.K.
acknowledges the Research Fellowships of the Japan Society for
the Promotion of Science for Young Scientists for financial support.
Supporting Information Available: General procedures and
spectral data for compounds (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
References
(1) Dietrich, B.; Viout, P.; Lehn, J.-M. Macrocyclic Chemistry; Wiley-VCH:
Weinheim, 1993.
(2) For control of concentration in multiphase, see: (a) Ryu, I.; Matsubara,
H.; Yasuda, S.; Nakamura, H.; Curran, D. P. J. Am. Chem. Soc. 2002,
124, 12946. (b) Xiang, J.; Orita, A.; Otera, J. Angew. Chem., Int. Ed.
2002, 41, 4117.
(3) For transition metal catalysis in an aqueous biphasic system, see: (a) Sinou,
D. In Modern SolVent in Organic Synthesis; Knochel, P. Ed.; Springer-
Verlag: Berlin, 1999; p 41. (b) Cornils, B.; Herrmann, W. A. Aqueous-
Phase Organometallic Chemistry; Wiley-VCH: Weinheim, 1998. (c) Li,
C.-J.; Chan, T.-H. Organic Reactions in Aqueous Media; John Wiley:
New York, 1997. (d) Yonehara, K.; Hashizume, T.; Mori, K.; Ohe, K.;
Uemura, S. J. Org. Chem. 1999, 64, 5593.
Scheme 4
(4) (a) Vollhardt, K. P. C. Angew. Chem., Int. Ed. Engl. 1984, 23, 539. (b)
Lautens, M.; Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (c) Schore,
N. E. In ComprehensiVe Organic Synthesis; Trost, B. M., Fleming, I.,
Eds.; Pergamon Press: New York, 1991; Vol. 5, p 1129.
(5) For cobalt-catalyzed cyclotrimerization of alkynes in aqueous media,
see: (a) Sigman, M. S.; Fatland, A. W.; Eaton, B. E. J. Am. Chem. Soc.
1998, 120, 5130. (b) Yong, L.; Butenscho¨n, H. Chem. Commun. 2002,
2852.
(6) (a) Diercks, R.; Eaton, B. E.; Gurtzgen, S.; Jalisatgi, S.; Matzger, A. J.;
Radde, R. H.; Vollhardt, K. P. C. J. Am. Chem. Soc. 1998, 120, 8247. (b)
Hardesty, J. H.; Koerner, J. B.; Albright, T. A.; Lee, G.-Y. J. Am. Chem.
Soc. 1999, 121, 6055. (c) Takahashi, T.; Xi, Z.; Yamazaki, A.; Liu, Y.;
Nakajima, K.; Kotora, M. J. Am. Chem. Soc. 1998, 120, 1672. (d) Baxter,
R. J.; Knox, G. R.; Pauson, P. L.; Spicer, M. D. Organometallics 1999,
18, 197. (e) O’Connor, J. M.; Closson, A.; Hiibner, K.; Merwin, R.;
Gantzel, P.; Roddick, D. M. Organometallics 2001, 20, 3710. (f) Collman,
J. P.; Kang, J. W.; Little, W. F.; Sullivan, M. F. Inorg. Chem. 1968, 7,
1298.
(7) (a) Breslow, R. Acc. Chem. Res. 1991, 24, 159. (b) Organic Synthesis in
Water; Grieco, P. A., Ed.; Blackie Academic & Professional: London,
1998. (c) Grieco, P. A. Aldrichimica Acta 1991, 24, 59. (d) Lubineau,
A.; Auge´, J. In Modern SolVent in Organic Synthesis; Knochel, P., Ed.;
Springer-Verlag: Berlin, 1999; p 1.
(8) Ruthenium-catalyzed cyclization of 1b and 1c in high dilution conditions
has been recently reported at the 49th Symposium on Organometallic
Chemistry, Japan, 2002. Yamamoto, Y.; Arakawa, T.; Itoh, K. Abstracts
of the 49th Symposium on Organometallic Chemistry; Japan, 2002; p 246.
(9) The reaction of 1c (0.5 mmol) with RhCl(PPh3)3 (5 mol %) in ethanol
(50 mL) at room temperature resulted in formation of 2c in only 20%
yield along with unidentified oligomeric products.
for the reaction to proceed, some of the diyne partner must be
present in the aqueous phase.
(10) The reaction without the ether phase resulted in extensive formation of
polymeric products.
To date, transition metal catalysis in biphasic systems has been
developed mainly for the purpose of easy separation and for the
efficient recycling of catalysts. Here, we expand the utility of the
biphasic system by demonstrating its ability to control substrate
concentration.14 A rhodium-catalyzed [2 + 2 + 2] cyclotrimerization
of triynes in a water-organic biphasic system has been explored.
The biphasic system offers diluted reaction conditions for macro-
cyclization reactions. Selective cross-annulation between hydro-
phobic diynes and hydrophilic alkynes has also been achieved.
(11) The existence of oxygen at the 9-position is crucial: the reaction of 4,10-
dioxanonadeca-1,6,18-triyne afforded 12-membered cyclized product in
16% yield along with 13-membered methacyclophane in 14% yield.
(12) (a) Grigg, R.; Scott, R.; Stevenson, P. J. Chem. Soc., Perkin Trans. 1
1988, 1357. (b) Grigg, R.; Scott, R.; Stevenson, P. Tetrahedron Lett. 1982,
23, 2691.
(13) We could detected none of the tri(hydroxymethyl)benzenes. A rhodium-
catalyzed cyclotrimerization of monoalkyne is generally slow.
(14) The concentration of 1c in the aqueous phase was roughly measured to
be 1.3 × 10-4 mol/L.
JA035438O
9
J. AM. CHEM. SOC. VOL. 125, NO. 26, 2003 7785