Efficient synthesis of macrocyclic paracyclophanes by ring-closing metathesis dimerization and trimerization reactions

Article abstract of DOI:10.1021/ol027557z

(Matrix presented) Ring-closing metathesis reactions of para-disubstituted aromatic substrates produced macrocyclic [n.n]-, and [n.n.n]paracyclophanes efficiently through dimerization and trimerization reactions. Sufficiently long alkyl chains allowed direct monocyclizations to yield [n]paracyclophanes. A small library of paracyclophanes were generated by the combinatorial cross-metathesis approach.

Full text of DOI:10.1021/ol027557z

ORGANIC
LETTERS
2003
Vol. 5, No. 5
741-744
Efficient Synthesis of Macrocyclic
Paracyclophanes by Ring-Closing
Metathesis Dimerization and
Trimerization Reactions
Jinsung Tae* and Young-Keun Yang
Department of Chemistry, Yonsei UniVersity, Seoul, 120-749, Korea
jstae@yonsei.ac.kr
Received December 26, 2002
ABSTRACT
Ring-closing metathesis reactions of para-disubstituted aromatic substrates produced macrocyclic [n.n]-, and [n.n.n]paracyclophanes efficiently
through dimerization and trimerization reactions. Sufficiently long alkyl chains allowed direct monocyclizations to yield [n]paracyclophanes.
A small library of paracyclophanes were generated by the combinatorial cross-metathesis approach.
Cyclophanes are unique in their structures and have interest-
ing electronic properties. Recently, the functional properties
of cyclophanes have drawn great attention.1 Large cyclo-
phanes can form inclusion complexes with metal ions, and
small cyclophanes can make charge-transfer complexes. The
[2.2]paracyclophanes have served as building blocks for
many functional devices.1b Although much synthetic effort
has been given toward the synthesis of paracyclophanes, the
efficient synthesis of various sizes of macrocyclic paracy-
clophanes is still challenging. Typically, [2.2]paracyclo-
phanes have been studied most extensively.
(1), [n.n]paracyclophane (2), and [n.n.n]paracyclophane (3)
(Figure 1). One of the special attractive features of ring-
Ring-closing metathesis (RCM) reaction2 is an attractive
method for the synthesis of macrocyclic [n]paracyclophane
Figure 1. [n], [n.n], and [n.n.n]paracyclophanes.
(1) For reviews on paracyclophanes, see: (a) Vo¨gtle, F.; Seel, C.;
Windscheif, P.-M. ComprehensiVe Supramolecular Chemistry; Atwood, J.
L., Davies, J. E. D., MacNicol, D. D., Vo¨gtle, F., Eds.; Pergamon: Oxford,
1996; Vol. 2, Chapters 1 and 6. (b) Tsuji, T.; Ohkita, M.; Kawai, H. Bull.
Chem. Soc. Jpn. 2002, 75, 415-433. (c) De Meijere, A.; Koenig, B. Synlett
1997, 1221-1232. (d) Tochtermann, W.; Kraft, P. Synlett 1996, 1029-
1035. (e) Kane, V. V.; De Wolf, W. H.; Bickelhaupt, F. Tetrahedron 1994,
50, 4575-4622.
closing olefin metathesis is macrocyclic dimerization (or
trimerization) reaction, which operates when two reacting
alkene termini are conformationally inaccessible for simple
10.1021/ol027557z CCC: $25.00 © 2003 American Chemical Society
Published on Web 02/06/2003

cyclization to monomers. However, this type of macro-
cyclization reaction is not well studied in the literature.3-6
Up to now, only a few olefin metathesis macrocyclizations
have been applied for the synthesis of natural paracyclophane
compounds.3,7 Herein we report an efficient synthesis of
ether-linked [n]-, [n.n]-, and [n.n.n]paracyclophanes by ring-
closing metathesis reactions.
Scheme 2. Ring-Closing Metathesis Macrocyclizationsa
The para-disubstituted substrates 5a-d and 7a-b were
prepared by alkylation reactions of the corresponding diols
4 and 6 with suitable ω-alkenyl bromides (Scheme 1).
Scheme 1. Synthesis of Substrate Dienesa
a Conditions: (a) 10 mol % 10 (or 11), CH2Cl2, 45 °C, 0.005
M.
a Conditions: (a) NaH (2.4 equiv), n-Bu4NI (cat.), DMF, Br-
(CH2)nCHdCH2 (3 equiv), 25 °C; (b) Et3N, CH2Cl2, HOCH2-
CHdCH2, from 0 to 25 °C.
as in 7a (X ) CH2O, n ) 1), dimer 13e (72%) and trimer
14e (23%) were obtained (Table 1, entry 5). Substrate 9,
which is less reactive due to ester linkage, required more
reactive catalyst 1110 to produce trimer 14g (60%) (Table 1,
entry 7). Use of catalyst 10 with (or without) Ti(OiPr)4 failed
to give any desired products.11
Substrates with longer chains provided monomers in the
metathesis macrocyclizations. Metathesis of 5d (X ) O, n
) 9) furnished monomer 12d (33%) along with dimer 13d
(47%) (Table 1, entry 4). Interestingly, 7b (X ) CH2O, n )
3) transformed exclusively into the monomer 12f (70%) with
no dimer or trimer formation observed (Table 1, entry 6).
The monomer 12f was clearly distinguishable from the dimer
by NMR data. The vinyl protons (δ 4.41) of 12f shifted
upfield due to aromatic ring current effects. However, those
of larger ring monomer 13d (δ 5.34) and dimer 13a (δ 5.81)
experience little or no such effects (Figure 2).
Compound 9 was prepared from the terephthaloyl chloride
(8) and allyl alcohol in the presence of triethylamine.
All substrates were reacted under the identical reaction
conditions to compare product distributions for each substrate
(Scheme 2). The results of the metathesis reactions were
summarized in Table 1.8 Reaction of 5a (the substrate with
the smallest alkyl chain) with 10 mol % Grubbs’ catalyst
(10) under refluxing dichloromethane solution (0.005 M
concentration) furnished a single dimeric product 13a in 74%
isolated yield (Table 1, entry 1).9 The next homologue 5b
(X ) O, n ) 2) cyclized into the dimer 13b and trimer 14b
in 42 and 35% yields, respectively (Table 1, entry 2).
Compound 5c (X ) O, n ) 3) provided dimer 13c in 81%
yield (Table 1, entry 3). When benzyl ether was employed
(2) For reviews on metathesis, see: (a) Fu¨rstner, A. Angew. Chem., Int.
Ed. 2000, 39, 3012-3043. (b) Chang, S.; Grubbs, R. H. Tetrahedron 1998,
54, 4413-4450.
(3) (a) Smith, A. B., III; Adams, C. M.; Kozmin, S. A.; Paone, D. V. J.
Am. Chem. Soc. 2001, 123, 5925-5937. (b) Smith, A. B., III; Kozmin, S.
A.; Adams, C. M.; Paone, D. V. J. Am. Chem. Soc. 2000, 122, 4984-
4985. (c) Smith, A. B., III; Adams, C. M.; Kozmin, S. A. J. Am. Chem.
Soc. 2001, 123, 990-991.
(4) (a) Paquette, L. A.; Jose´, M.-A. Tetrahedron Lett. 2001, 42, 967-
970. (b) Paquette, L. A.; Fabris, F.; Tae, J.; Gallucci, J. C.; Hofferberth, J.
E. J. Am. Chem. Soc. 2000, 122, 3391-3398.
1
(5) Chen, G.-W.; Kirschning, A. Chem. Eur. J. 2002, 8, 2717-2729.
(6) Lee, C. W.; Grubbs, R. H. J. Org. Chem. 2001, 66, 7155-7158.
(7) Layton, M. E.; Morales, C. A.; Shair, M. D. J. Am. Chem. Soc. 2002,
124, 773-775.
Figure 2. Selected H NMR chemical shift of vinyl protons.
(8) All new compounds were characterized by FAB-MS and other
spectroscopic data.
At this point, we were curious about the result of cross-
metathesis ring closure of two different alkenes. This type
(9) (E,E)-Stereochemistry of 13a was confirmed by an alternative
synthesis from hydroquinone, trans-1,4-dichloro-2-butene, and K2CO3 under
refluxing acetonitrile according to the modified literature procedure (Vart-
anyan, S. A.; Akopyan, T. R.; Paronikyan, E. G.; Darbinyan, G. A. Arm.
Khim. Zh. 1980, 33, 308-310).
(10) Scholl, M.; Ding, S.; Grubbs, R. H. Org. Lett. 1999, 1, 953-956.
(11) Fu¨rstner, A.; Langemann, K. J. Am. Chem. Soc. 1997, 119, 9130-
9136.
742
Org. Lett., Vol. 5, No. 5, 2003

Table 1. Metathesis of Alkene Substratesa
products (% yield)b
dimer
reaction time
(h)
total yield
(%)
entry
starting diene
monomer
trimer
1
2
3
4
5
6
7
5a X ) O, n ) 1
5b X ) O, n ) 2
5c X ) O, n ) 3
5d X ) O, n ) 9
7a X ) CH2O, n ) 1
7b X ) CH2O, n ) 3
9 X ) CO2, n ) 1
14
32
20
21
21
21
22
13a (74)
13b (42)c
13c (81)c
13d (47)
13e (72)
74
77
81
80
95
70
60d
14b (35)
12d (33)
12f (70)
14e (23)
14g (60)
a Conditions: 10 mol % 10, CH2Cl2, 45 °C, 0.005 M. b Isolated yields. Single isomers, (E,E) or (Z,Z), were obtained for most cases except 13b and 13c.
c (E,Z)-Isomers were obtained. The (E,Z) double bonds in 13b and 13c were reduced to the corresponding alkanes (Scheme 3). Full characterizations of
(E,Z)-products were performed at this stage. d Catalyst 11 (7 mol %) was used.
of mixed ring closure could create compound libraries of
macrocyclic paracyclophanes (Table 2). To minimize prob-
lems anticipated from the heterocoupling reactions, we first
carefully selected substrates that cyclized into dimers only
from Table 1. Substrates 5a and 5c were clearly the best
combination. When substrates 5a and 5c were mixed together
and treated with Grubbs’ catalyst 10 under standard cycliza-
tion conditions, heterodimer 17 (25%) was formed in addition
to homodimers 13a (30%) and 13c (34%) (Table 2, entry
2). Double bonds of compound 17 were reduced to give the
known compound 15, which was synthesized previously from
dimerization of 5b (Scheme 3).
It is noteworthy that the reaction rates were significantly
slowed for the cyclization of heteromixtures (required 30 h
for the mixture of 5a and 5c) compared to those of the
homocoupling reactions (required 14 h for 5a and 20 h for
5c). The pairs of 5a/5d and 5c/7a produced heterodimers
18 (40%) and 19 (25%), respectively, along with homodimers
(Table 2, entries 3 and 5). On the other hand, the pairs of
5a/5b, 5a/7a, and 5c/7b yielded no heterodimers (Table 2,
entries 1, 4, and 6). The product distributions observed in
the homocoupling reactions (see Table 1) were reserved in
the heterocoupling reactions with only minor deviations.
Scheme 3. Reduction of Double Bondsa
a Conditions: (a) 10% Pd-C, H2 (1 atm), CH2Cl2, 25 °C.
Controlled experiments revealed the order of reactivity of
substrates with different chain lengths in the metathesis
macrocyclizations. The relative rates of substrate consump-
tions and product appearances monitored by TLC analysis
can be summarized as follows: 5c > 5a, 5a > 5d, 5c > 5d,
5a > 5b, 5a > 7a, 5c > 7b, and 5c > 7a. Therefore, the
Table 2. Cross-Metathesis of Alkene Mixturesa
product distribution (%)b
total yield
reaction time
entry
starting dienes
(h)
monomer
homodimers
homotrimer
heterodimer
(%)
1
2
3
4
5
6
7
8
5a + 5b
5a + 5c
5a + 5d
5a + 7a
5c + 7a
5c + 7b
5c + 5d
5a + 5c + 7a
33
30
36
35
37
36
35
44
13a (41) + 13b (17)
13a (30) + 13c (34)
13a (24) + 13d (9)
13a (38) + 13e (25)
13c (30) + 13e (21)
13c (31)
14b (6)
64
89
84
74
85
53
85
81
17 (25)c
12d (11)
18 (40)c
19 (25)
14e (11)
14e (9)
12f (22)
12d (20)
13c (19) + 13d (25)
13a (13) + 13c (16) + 13e (14)
20 (21)c
17 (20) + 19 (18)
a Conditions: 10 mol % 10, CH2Cl2, 45 °C, 0.005 M. b Isolated yields. c (E,Z)-Heterodimers were obtained.
Org. Lett., Vol. 5, No. 5, 2003
743

relative rate order is 5c (X ) O, n ) 3) > 5a (X ) O, n )
1) > 5b (X ) O, n ) 2), 7a (X ) CH2O, n ) 1), 5d (X )
O, n ) 9). The substrate 5c with the medium chain length
(X ) O, n ) 3) cyclized faster than the shorter or the longer
ones in the macrocyclization reactions.
Finally, we tried cross-metathesis with three different
alkene substrates to generate higher diversity. The combina-
tion of 5a, 5c, and 7a produced five different dimers in 81%
combined total yield (Table 2, entry 8). Products include two
heterodimers [17 (20%), 19 (18%)] and three homodimers
[13a (13%), 13c (16%), 13e (14%)].
The observed efficient metathesis macrodimerization and
-trimerization are noteworthy because only a few productive
metathesis dimerizations are known in the literature3-6 and
efficient metathesis trimerizations are unknown to the best
of our knowledge except for minor side product formations
in the course of macrocyclizations.5
ring-closing metathesis reactions. The cyclization modes
depend on the chain lengths of alkenyl ethers. Short chains
produced mainly [n.n]- and [n.n.n]paracyclophanes through
dimerization and trimerization reactions. Sufficiently long
alkyl chains allowed direct monocyclization to yield [n]-
paracyclophanes. In addition, we were able to generate a
small library of paracyclophanes in a highly efficient way
by the cross-metathesis of different alkene substrates.
Acknowledgment. This work was supported by a Korea
Research Foundation Grant (KRF-2002-003-C00080).
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H NMR and 13
C
NMR for all new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
In conclusion, we have demonstrated efficient synthesis
of macrocyclic [n]-, [n.n]-, and [n.n.n]paracyclophanes by
OL027557Z
744
Org. Lett., Vol. 5, No. 5, 2003