A new way to generate functionalized bridges in [2,2]cyclophanes

Article abstract of DOI:10.1055/s-0029-1218286

The synthesis of valuable precursors of cyclic endiynes has been accomplished by base-catalyzed intramolecular cyclization of pinacolone-type compounds. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218286

3000
LETTER
A New Way to Generate Functionalized Bridges in [2,2]Cyclophanes
F
unctionalized
B
ridges
.
in [2.2]Cyc
L
a
b
Received 29 July 2009
quired for cyclization of conjugated endiynes (Bergman
cyclization; related to calicheamicins and esperamicins at
a measurable rate at room temperature) to be 3.2–3.3 Å.13
Later, Gleiter et al. extended these studies to nonconjugat-
ed cyclic diynes of medium ring size.14,15
Abstract: The synthesis of valuable precursors of cyclic endiynes
has been accomplished by base-catalyzed intramolecular cycliza-
tion of pinacolone-type compounds.
Key words: [2,2]paracyclophanes, hydrogen transfer,
In a previous paper we presented a vinylogous pinacol–
pinacolone rearrangement that takes place despite the fact
that the two hydroxyl groups are formally separated by
seven bonds.16 The reaction involved a transannular hy-
dride shift that occurs between the benzylic positions of
the various pseudo-geminally substituted [2,2]paracyclo-
phanes (e.g. Scheme 1, 1b → 2b).
[2,2]Paracyclophanes constitute an intriguing class of
compounds that have attracted a constantly growing inter-
est since their first appearance in the chemical literature
exactly 60 years ago.1–3 Most studies so far concern the
structural characteristics of [2,2]paracyclophanes, partic-
ularly its geometry and its steric properties, transanular in-
teractions, and ring-strain; the electronic interaction
between the aromatic rings having a sandwich form, their
influence on reactivity in electrophilic aromatic substitu-
tion reactions, and their implications for charge-transfer
complex formation have also been investigated.4–6 As far
as the chemical behavior is concerned, the vast majority of
the reported reactions have been carried out at the benzene
rings. However, the chemistry of the molecular bridges of
these molecules should also be interesting, especially
when the bridges carry important functional groups.
Whereas we have previously described the introduction of
various functional groups into the ethano bridges of
[2,2]paracyclophanes7 and the generation of new types of
unsaturation by isomerization,8 we now report on a novel
process which not only generates a new bridge in a pseu-
do-geminally substituted [2,2]paracyclophane, but also
produces new, and possibly widely usable functionality in
this new bridge simultaneously. In pseudo-geminally sub-
stituted [2,2]paracyclophanes the functional groups are
often held in such a position as to allow highly specific
reactions to take place between them in near quantitative
yield. In one such application, unsaturated cyclophane
bis-esters undergo intramolecular photocyclization to the
corresponding ladderane isomers.9
R
R
H2SO4, 0 °C
OH
R
R
OH
O
1a,b
a: R = Me; b: R = Ph
2a,b
Scheme 1
Pinacolone type compounds 2 are versatile starting mate-
rials for the investigation of intramolecular interactions
between propargylic/allenic moieties. The treatment of 2
with an appropriate base should trigger the isomerization
of a propargylic into an allenic substituent. We wish to re-
port here on base-induced intramolecular interactions in
pinacolone type compounds 2.
Pinacolone 2a was synthesized from the corresponding
pseudo-geminal bispropargylic alcohol 1a in 83% yield.
The latter was obtained by treatment of 4,13-bis-
formyl[2,2]paracyclophane with 1-propynyl magnesium
bromide.17 The influence of a variety of bases on 2 has
been investigated. In the presence of n-BuLi or LDA, de-
composition of the substrate occurs even below –40 °C.
DBU was eventually found to be the base of choice; its re-
action in DMSO at ambient temperature occurred smooth-
ly and could easily be monitored by NMR spectroscopy
(Scheme 2). Thus, reaction of 2b with one equivalent of
DBU in DMSO was complete in four hours at room tem-
perature. Usual work-up with dichloromethane extraction
followed by fractional precipitation with ether and pen-
tane leaves a solution of pure 3b in 42% isolated yield.
The structure of compounds 3 have been unambiguously
determined by 2D NMR spectroscopy.18
Rather interesting chemical behavior has arisen from the
combination of [2,2]paracyclophane structures with
bispropargylic or bisallenic systems.10,11 It is known that
in a crystal of [2,2]paracyclophane, the distance between
the pseudo-geminal carbon atoms is only 3.09 Å.12 On the
other hand, Nicolaou postulated the critical upper limit for
the distance between the terminal acetylenic carbons re-
SYNLETT 2009, No. 18, pp 3000–3002
x
x
.x
x
.2
0
0
9
Advanced online publication: 08.10.2009
DOI: 10.1055/s-0029-1218286; Art ID: G25509ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Functionalized Bridges in [2,2]Cyclophanes
3001
with more than 95% relative intensity. In contrast, the
mass spectrum of 4 revealed very small peaks for the cor-
responding molecular units (relative intensity <5%). Most
likely, the third phenanthrenic bridge inhibits the cleavage
of the phane into two similar halves.
R
DBU (1 equiv)
DMSO, r.t., 4 h
R
R
R
C
H2
O
O
2a,b
a: R = Me; b: R = Ph
3a,b
hν
Scheme 2
Ph
r.t., 8 h
For the mechanism of this surprising cyclization, we pro-
pose that, under the reaction conditions, the first step in-
volves the isomerization of the propargylic group into an
allenic substituent. However, although the reaction in
CDCl3 is considerably slower than in DMSO (days),
NMR monitoring in the former solvent does not reveal the
characteristic patterns of this functional group. The in-
tramolecular interaction between the two parallel pseudo-
geminal substituents appears to be a fast process, which is
followed by a 1,5-hydrogen shift, as shown in Scheme 3.
This symmetry-allowed process finds an analogy in the
thermal isomerization of 1,2,4-pentatriene (vinylallene) to
(Z)-pent-1-yn-3-ene.19
C
Ph
C
H2
H2
O
O
3b
4
Scheme 4
In conclusion, we have synthesized valuable precursors
for cyclic endiynes by a new intramolecular base-induced
1,5-hydrogen shift of a readily available pseudo-geminally
substituted [2,2]paracyclophane. Investigations into the
synthesis and stability of the cyclic endiynes, as well as
the alternative synthesis of orthogonal p-systems with
fixed double bonds, are underway.
This unexpected rearrangement has provided a valuable
starting material for cyclic endiynes. Under appropriate
conditions, water elimination from compound 3 should
provide, at least as an intermediate, a cyclic endiyne
where the distance between terminal acetylenic carbon at-
oms is below the critical limit postulated by Nicolaou.
Acknowledgment
The authors would like to thank Prof. L. Ernst for helpful discussi-
ons concerning NMR spectra. M.L.B. is indebted to the Alexander
von Humboldt Foundation for a short stay at Braunschweig. Part of
this work was supported by the Romanian PN II (IDEI 2095) pro-
gram.
Moreover, the particular structure of 3b can also serve as
precursor for generating novel polycyclic hydrocarbons.
The use of the stilbene-phenanthrene photocyclization20
will create a novel bridge consisting of a condensed aro-
matic system. This photocyclization step has been carried
out by irradiating 3b (10–3 M in toluene) in the presence
of iodine (0.1 equiv) and biacetyl (2.5 equiv) with a TQ
150 high-pressure mercury lamp (Scheme 4).21,22 The
structure of compound 4, which was isolated in 23%
yield, has again been unambiguously proven by 2D NMR
analysis.23 After photolysis, the overlapping aromatic sig-
nals of the phenyl substituents of 3b were replaced by the
References and Notes
(1) Brown, C. J.; Farthing, A. C. Nature (London) 1949, 164,
915.
(2) Cram, D. J.; Steinberg, H. J. Am. Chem. Soc. 1951, 73, 5691.
(3) Vögtle, F.; Neumann, P. Synthesis 1973, 85.
(4) Staab, H. A.; Knaus, G. H.; Henke, H.-E.; Krieger, C. Chem.
Ber. 1983, 116, 2785.
(5) Boekelheide, V. Top. Curr. Chem. 1983, 113, 87.
(6) Hopf, H.; Marquard, C. In Strain and its Implications in
Organic Chemistry; de Meijere, A.; Blechert, S.; Eds, , Eds.;
Kluwer: Dordrech, 1983, 297.
(7) Hopf, H.; Psiorz, M. Chem. Ber. 1986, 119, 1836.
(8) Werner, C.; Hopf, H.; Grunenberg, J.; Ernst, L.; Jones, P. G.;
Köhler, F.; Herges, R. Eur. J. Org. Chem. 2009, 2621.
(9) For reviews, see: (a) Hopf, H. Angew. Chem. Int. Ed. 2003,
42, 2822; Angew. Chem. 2003, 115, 2928. (b) Hopf, H.;
Bondarenko, L.; Ernst, L.; Jones, P. G.; Grunenberg, J.;
Hentschel, S.; Dix, I.; Greiving, H. Chem. Eur. J. 2007, 13,
3950.
1
characteristic H NMR spectrum of a 9,10-disubstituted
phenanthrene (d = 7.5–8.85 ppm, 8 H). The mass spec-
trum of 4 also confirmed the presence of the new phenan-
threne bridge. Normally, in [2.2]paracyclophanes the base
peaks correspond to the half molecular mass. In the case
of 3b (m/z [M+] calcd for C34H26O = 450), the two frag-
ments resulting from separation of the two ethano bridges
and the double bond, provide peaks at m/z = 217 and 233,
R
R
R
DBU
R
H
R
R
R
C
R
H2
O
O
O
O
Scheme 3
Synlett 2009, No. 18, 3000–3002 © Thieme Stuttgart · New York

3002
M. L. Birsa, H. Hopf
LETTER
(10) Birsa, M. L.; Jones, P. G.; Braverman, S.; Hopf, H. Synlett
2005, 640.
(11) Birsa, M. L.; Hopf, H. Synlett 2007, 2753.
(12) Brown, C. J. J. Chem. Soc. 1953, 3278.
(13) Nicolau, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E. J.;
Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866.
(14) Gleiter, R.; Ritter, J. Angew. Chem. Int. Ed. 1994, 33, 2470;
Angew. Chem. 1994, 106, 2550.
48.7 (t), 99.4 (s), 101.0 (s), 122.2 (s), 126.2 (s), 127.5 (d),
127.6 (d), 128.2 (d, 2 C), 128.6 (d, 2 C), 129.3 (d, 2 C), 129.9
(d, 2 C), 131.1 (d), 132.9 (d), 133.4 (d), 135.2 (d), 137.0 (s),
138.0 (d), 138.3 (d), 139.1 (s), 139.5 (s), 139.9 (s), 140.1 (s),
142.4 (s), 142.5 (s), 150.6 (s), 201.5 (s). MS (EI): m/z
(%) = 450 (100)[M+], 317 (32), 303 (35), 233 (98), 217 (95),
191 (18), 131 (28). Anal. Calcd for C34H26O: C, 90.63; H,
5.82. Found: C, 90.79; H, 5.75.
(15) Haberhauer, G.; Gleiter, R. J. Am. Chem. Soc. 1999, 121,
(19) Hopf, H.; Wachholz, G. Chem. Ber. 1987, 120, 1259.
(20) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30, 1.
(21) Hopf, H.; Mlynek, C.; El-Tamany, S.; Ernst, L. J. Am. Chem.
Soc. 1985, 107, 6620.
4664.
(16) Birsa, M. L.; Jones, P. G.; Hopf, H. Eur. J. Org. Chem. 2005,
3263.
(17) Compound 1a: Yield: 1.2 g (83%); mp 210–211 °C. IR
(ATR): 3240, 2922, 2223, 1482, 1261, 1005, 719 cm–1. 1H
NMR (200 MHz, CDCl3, TMS): d = 1.71 (d, 5J = 3.4 Hz, 6
H, 2 × Me), 3.02 (m, 2 H, CH2), 3.09 (s, 4 H, 2 × CH2), 3.45
(m, 2 H, CH2), 4.05 (br s, 2 H, 2 × OH), 5.65 (q, 5J = 3.4 Hz,
2 H, 2 × CH), 6.52 (m, 4 H, 4 × CHAr), 6.81 (m, 2 H,
2 × CHAr). 13C NMR (50 MHz, CDCl3, TMS): d = 3.7 (q),
31.4 (t), 35.1 (t), 61.5 (d), 79.2 (s), 82.1 (s), 127.4 (d), 132.9
(d), 134.6 (s), 135.1 (d), 139.4 (s), 140.1 (s). MS (EI): m/z
(%) = 326 (22)[M+ – H2O], 171 (15), 155 (100), 141 (38),
128 (35), 115 (30). Anal. Calcd for C24H24O2: C, 83.69; H,
7.02. Found: C, 83.76; H, 6.95.
(18) Compound 3b: Yield: 0.26 g (42%); mp 228–229 °C. IR
(ATR): 2925, 1665, 1480, 1314, 1229, 1005, 767, 698 cm–1.
1H NMR (400 MHz, CD2Cl2, TMS): d = 2.75 (m, 1 H, CH2),
2.95 (m, 1 H, CH2), 2.98–3.30 (m, 4 H, 2 × CH2), 3.40 (m, 1
H, CH2), 3.95 (m, 1 H, CH2), 3.47 and 5.09 (ABq, 2J = 14.7
Hz, 2 H, CH2CO), 6.46 (d, 3J = 7.7 Hz, 1 H, CHAr), 6.55 (d,
4J = 2.0 Hz, 1 H, CHAr), 6.64 (d, 3J = 7.9 Hz, 1 H, CHAr),
6.65 (dd, 3J = 7.7 Hz, 4J = 1.9 Hz, 1 H, CHAr), 6.80 (dd,
3J = 7.9 Hz, 4J = 2.0 Hz, 1 H, CHAr), 7.06 (d, 4J = 1.9 Hz, 1
H, CHAr), 7.15–7.34 (m, 10 H, 10 × CHAr). 13C NMR (100
MHz, CD2Cl2, TMS): d = 32.4 (t), 34.0 (t), 34.9 (t), 35.2 (t),
(22) Hopf, H.; Mlynek, C. J. Org. Chem. 1990, 55, 1361.
(23) Compound 4: Yield: 0.1 g (23%); mp 142–143 °C. IR
(ATR): 2927, 1663, 1485, 1434, 762, 730 cm–1. 1H NMR
(400 MHz, CDCl3, TMS): d = 2.77–3.15 (m, 4 H, 2 × CH2),
3.32 (m, 2 H, CH2), 3.55 (m, 1 H, CH2), 3.93 (m, 1 H, CH2),
4.57 and 5.26 (ABq, 2J = 15.6 Hz, 2 H, CH2CO), 6.48 (d,
3J = 8.0 Hz, 1 H, CHAr), 6.65 (d, 4J = 2.0 Hz, 1 H, CHAr),
6.68 (dd, 3J = 8.2 Hz, 4J = 1.9 Hz, 1 H, CHAr), 6.70 (d,
3J = 8.2 Hz, 1 H, CHAr), 6.83 (dd, 3J = 8.0 Hz, 4J = 2.0 Hz,
1 H, CHAr), 7.26 (d, 4J = 1.9 Hz, 1 H, CHAr), 7.7 (m, 4 H,
4 × CHAr), 8.22 (dd, 3J = 7.6 Hz, 4J = 2.0 Hz, 1 H, CHAr),
8.39 (dd, 3J = 7.6 Hz, 4J = 1.9 Hz, 1 H, CHAr), 8.72 (dd,
3J = 8.0 Hz, 4J = 1.9 Hz, 1 H, CHAr), 8.78 (dd, 3J = 8.0 Hz,
4J = 2.0 Hz, 1 H, CHAr). 13C NMR (100 MHz, CD2Cl2,
TMS): d = 32.5 (t), 33.74 (t), 33.75 (t), 35.1 (t), 40.5 (t), 97.6
(s), 103.4 (s), 119.7 (s), 122.6 (d), 123.3 (d), 125.1 (d), 126.0
(s), 126.9 (d), 127.1 (d), 127.2 (d), 127.3 (d, 2 C), 129.5 (s),
130.1 (s), 130.6 (s), 131.1 (d), 132.0 (s), 132.9 (d), 133.1 (d),
135.0 (d), 137.8 (d), 137.9 (d), 138.9 (s), 139.0 (s), 139.4 (s),
140.2 (s), 142.1 (s), 142.4 (s), 200.9 (s). MS (EI): m/z
(%) = 448 (100)[M+], 405 (24), 315 (43), 302 (25), 131 (18).
Anal. Calcd for C34H24O: C, 91.04; H, 5.39. Found: C, 91.22;
H, 5.27.
Synlett 2009, No. 18, 3000–3002 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.