Photoinduced Bergman cycloaromatization of imidazole-fused enediynes

Article abstract of DOI:10.1016/j.tetlet.2004.12.136

A series of 4,5-bis-(alkyn-1-yl)imidazoles-'imidazole-fused' enediynes-were synthesized and their reactivities in photoinduced Bergman cycloaromatization reactions were determined. The more conformationally rigid analogues gave cycloaromatized products in good yields upon irradiation (450 W low-pressure mercury lamp, ambient temperature). A bicyclic analogue (3) was shown to cleave supercoiled plasmid DNA.

Full text of DOI:10.1016/j.tetlet.2004.12.136

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 1373–1375
Photoinduced Bergman cycloaromatization of
imidazole-fused enediynes
Zhengrong Zhao, Justin G. Peacock, Daniel A. Gubler and Matt A. Peterson*
Department of Chemistry and Biochemistry, Brigham Young University, Provo, UT 84602-5700, USA
Received 19 November 2004; revised 10 December 2004; accepted 10 December 2004
Abstract—A series of 4,5-bis-(alkyn-1-yl)imidazoles—Ôimidazole-fusedÕ enediynes—were synthesized and their reactivities in photo-
induced Bergman cycloaromatization reactions were determined. The more conformationally rigid analogues gave cycloaromatized
products in good yields upon irradiation (450 W low-pressure mercury lamp, ambient temperature). A bicyclic analogue (3) was
shown to cleave supercoiled plasmid DNA.
ꢀ
2005 Published by Elsevier Ltd.
1
Over the past several decades, the thermal Bergman
of compounds have apparently not been previously
investigated. Here, we report the efficient photochemical
Bergman cyclization of imidazole-fused enediynes and
their photoinduced reactivities with supercoiled plasmid
DNA. The potential for facile conjugation (via coupling
chemistries at either N-1 or C-2) to biologically impor-
tant delivery molecules makes imidazole-fused enediynes
exceptionally versatile as new reagents for targeted
delivery of photoreactive enediynes.
cycloaromatization reaction has been the subject of
extensive theoretical and experimental investigation
owing to its relevance to the biological activities of
enediyne antitumor antibiotics, and also because of
its considerable potential for synthetic methods for poly-
2
3
meric materials and/or polycyclic aromatic com-
4
pounds. Parameters affecting energy barriers involved
5
in the thermal reaction have been thoroughly studied.
However, only a limited number of reports dealing with
6
the photochemical reaction have appeared, and com-
The synthesis of imidazole-fused enediynes proceeded as
9
b
10
paratively little is understood about the photoinduced
reaction. As part of research directed toward synthesis
of photoinducible Ôtargeted enediynesÕ (photoreactive
enediynes conjugated to biologically important delivery
molecules such as enzyme substrates or receptor
depicted (Scheme 1). Sonogashira coupling of 1-
methyl-4,5-diiodoimidazole with the corresponding
alkynes gave imidazole-fused enediynes 2a–c in excellent
7
ligands, etc.), we became interested in 4,5-bis-(alkyn-
1
CH3
N
CH3
N
R
-yl)imidazoles, or Ôimidazole-fusedÕ enediynes. The
I
I
R
H
imidazole nucleus possesses two sites (N-1 and C-2),
which could be exploited for simple, straightforward,
conjugation of photoreactive imidazole-fused enediynes
to biologically relevant delivery molecules. The avail-
ability of these sites makes the imidazole scaffold a more
versatile platformthan others previously investigated
Pd(0)/Cu(I)
DMF/Et N
N
N
3
R
1
2a R = CH
3
83%
R = C H9 84%
R = Ph
2
b
c
4
2
85%
(
nes), which cannot be simply or directly conjugated.
including benzannelated and/or heteroaromatic enediy-
7
CH3
CH3
b,8
I
N
N
a–c
Of the heteroaromatic enediynes reported to date, imid-
9
azole-fused enediynes have received limited attention
and the photochemical Bergman reactivities of this class
N
N
I
1
3
*
Corresponding author. Tel.: +1 801 422 6843; fax: +1 801 422
153; e-mail: matt_peterson@byu.edu
Scheme 1. Reagents: (a) TMSC„CH, (Ph P)Pd/CuI, DMF/Et N; (b)
3
3
0
NH
4
F/MeOH; (c) i. BuLi, HMPA, THF, À78 ꢁC; ii. I(CH
2 5
) I.
0
040-4039/$ - see front matter ꢀ 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.12.136

1374
Z. Zhao et al. / Tetrahedron Letters 46 (2005) 1373–1375
1
1
yields. Compound 3 was prepared via a three-step pro-
9
tionally more rigid enediynes (such as 1,2-bis-(phenyl-
ethyn-1-yl)benzene) are less prone to undergo
intersystemcrossing fromthe initial singlet excited state
to the triplet state than less rigid analogues (e.g., 1,2-bis-
(pentyn-1-yl)benzene), and correspondingly higher
cycloaromatization yields are observed for the more
a
cedure, as described previously. Irradiation of com-
1
2
pounds 2a–c and 3 (450 W low-pressure Hg) gave
benzimidazole derivatives 4a–c and 5, respectively
1
1
(
Table 1 and Scheme 2). The cycloaromatized product
c was obtained in highest yields (26–64%), with the best
yield obtained using THF as solvent. The enhanced
yield for compound 5 relative to 4a–b may be due to
the increased conformational rigidity of 3 relative to
4
6
c
rigid system.
Imidazole-fused enediyne 3 was also examined for its
ability to promote photochemical cleavage of DNA.
Accordingly, compound 3 was irradiated (450 W low-
pressure Hg, Pyrex filter, ambient temperature) with
2
a–b. Evenzahav and Turro have shown that conforma-
1
3
supercoiled plasmid DNA (Fig. 1). Significant non-
background cleavage was observed within 60 min at
Table 1.
R
R
CH3
N
14
CH3
N
concentrations as low as 15 lM.
hν
R
R
In summary, imidazole-fused enediynes 2a–c and 3
underwent efficient photoinduced Bergman cycloaroma-
tization. The conformationally more rigid enediynes 2c
and 3 gave higher yields than the less rigid congeners
N
N
2
2
2
a
b
c
R = CH
3
4a R = CH
3
4
R = C H9
R = Ph
4b R = C H9
4
4c R = Ph
2
a–b, in harmony with observed reactivities for the re-
lated benzannelated enediynes studied by Evenzahav
Solvent
4a
4b
4c
6
c
THF
i-PrOH
Hexane
6%
31%
24%
64%
58%
47%
51%
46%
44%
40%
26%
and Turro. Imidazole-fused enediyne 3 cleaved super-
coiled plasmid DNA when irradiated (450 W low-pres-
sure Hg). The imidazole scaffold provides two sites for
potential conjugation to biologically important delivery
molecules, and thus represents an improvement over
known photoreactive benzannelated or heteroaromatic
enediynes, which cannot be simply or directly conju-
gated. An additional benefit provided by the imidazole
scaffold is its potential to undergo hydrogen bonding
Trace
7%
6%
22%
16%
Cyclohexane
CH CN
n-Hexane/1,4-cyclohexadiene
CH Cl
tert-Butanol
3
6%
6%
Trace
15%
2
2
Trace
Trace
Trace
Trace
Yield given as percent conversion.
1
5
with the heterocyclic bases of DNA. This could be
exploited to develop sequence-selective DNA cleaving
agents, and this is an application we are currently
exploring.
CH3
CH3
N
N
hν
N
3
N
Acknowledgements
5
45%
We thank the Elsa Pardee Foundation, the BYU Cancer
Center, and BYU development funds for support of this
work.
Scheme 2.
13
Figure 1. Cleavage of supercoiled plasmid DNA: (1) DNA basepair ladder; (2) dark DNA control; (3) 1500 lM of 3, 30 min; (4) 1500 lM of 3,
14
60 min; (5) 150 lM of 3, 60 min; (6) 15 lM of 3, 60 min; (7) 1.5 lM of 3, 60 min; (8) light DNA control.

Z. Zhao et al. / Tetrahedron Letters 46 (2005) 1373–1375
1375
References and notes
J = 7.2 Hz, 2H), 2.38 (t, J = 7.2 Hz, 2H), 1.61–1.38 (m,
8
1
H), 0.91 (t, J = 7.4 Hz, 6H); C NMR (CDCl
3
3
, 75 MHz):
d 136.8, 128.6, 119.7, 100.4, 92.8, 73.8, 68.2, 32.3, 30.7,
1
2
3
. (a) Bergman, R. G. Acc. Chem. Res. 1973, 6, 25; (b) Jones,
R. R.; Bergman, R. G. J. Am. Chem. Soc. 1972, 94, 660.
. Enediyne Antibiotics as Antitumor Agents; Borders, D. B.,
Doyle, T. W., Eds.; Marcel Dekker: New York, 1995.
. (a) Chen, S.; Tolbert, L. M.; Hess, D. W.; Henderson, C.
Macromolecules 2001, 34, 4104; (b) John, J. A.; Tour, J.
M. J. Am. Chem. Soc. 1994, 116, 5011; For a recent
discussion concerning the corrected structure for Ôpoly-
naphthaleneÕ polymers obtained via Bergman cyclization
of 1,2-diethynylbenzene, see: (c) Johnson, J. P.; Bringley,
D. A.; Wilson, E. E.; Lewis, K. D.; Beck, L. W.; Matzger,
A. J. J. Am. Chem. Soc. 2003, 125, 14708.
+
2
[C H N ] = 242.1783); UV (MeOH) max: 219, 264 nm,
2.0, 19.5, 19.3, 13.7, 13.6; MS (EI) m/z 242.1783 (M
16 22 2
1
min: 212, 230 nm; (2c): H NMR (CDCl
3
, 300 MHz):
d 7.60–7.55 (m, 5H), 7.46 (br s, 1H), 7.40–7.33 (m, 5H),
1
3
3
1
9
3
.74 (s, 3H); C NMR (CDCl , 75 MHz): d 138.3, 131.8,
31.6, 129.2, 129.1, 128.7, 128.4, 123.3, 122.4, 99.9,
2.6, 82.8, 76.7, 32.8; MS (EI) m/z 282.1147 (M
+
[
2
(
1
1
2
(
1
0
20 14 2
C H N ] = 282.1157); UV (MeOH) max: 224, 252,
1
66, 322 nm, min: 241, 260, 279 nm; (4a): H NMR
, 300 MHz): d 8.25 (s, 1H), 7.78 (s, 1H), 7.35 (s,
H), 4.16 (s, 3H), 2.45 (s, 3H), 2.42 (s, 3H); MS (EI) m/z
CDCl
3
+
60.1013 (M [C10
50, 278, 285 nm, min: 263, 282 nm; (4b): H NMR
, 300 MHz): d 8.10 (br s, 1H), 7.61 (s, 1H), 7.19 (s,
H), 3.87 (s, 3H), 2.79–2.71 (m, 4H), 1.66–1.40 (m, 8H),
12 2
H N ] = 160.1001); UV (MeOH) max:
4
5
. (a) Bowles, D. M.; Anthony, J. E. Org. Lett. 2000, 2, 85;
1
(b) Grissom, J. W.; Calkins, T. L.; McMillen, H. A.; Jiang,
Y. J. Org. Chem. 1994, 59, 5833.
CDCl
3
. (a) Schreiner, P. R. J. Am. Chem. Soc. 1998, 120, 4184; (b)
Nicolaou, K. C.; Zuccarello, G.; Ogawa, Y.; Schweiger, E.
J.; Kumazawa, T. J. Am. Chem. Soc. 1988, 110, 4866; (c)
Nicolaou, K. C.; Ogawa, Y.; Zuccarello, G.; Kataoka, H.
J. Am. Chem. Soc. 1988, 110, 7247; (d) Alabugin, I. V.;
Manahoran, M.; Kovalenko, S. V. Org. Lett. 2002, 4,
1
3
3
.97 (q, J = 6.8 Hz, 6H); C NMR (CDCl , 75 MHz):
d 142.5, 139.9, 137.4, 136.5, 132.5, 119.3, 109.4, 34.1, 34.0,
3.2, 32.8, 31.6, 23.1, 22.9, 14.3; MS (EI) m/z 244.1949
3
+
(
M
[C H N ] = 244.1939); UV (MeOH) max: 251,
16 24 2
1
81, 291 nm, min: 269, 288 nm; (4c): H NMR (CDCl
2
3
1
7
1
1
3
,
00 MHz): d 7.96 (br s, 1H), 7.87 (br s, 1H), 7.44 (br s,
1
2
119; (e) Jones, G. B.; Warner, P. M. J. Am. Chem. Soc.
001, 123, 2134; (f) Jones, G. B.; Plourde, G. W., II. Org.
1
3
H), 7.27–7.19 (m, 10H), 3.90 (s, 3H); C NMR (CDCl3,
5 MHz): d 142.3, 142.2, 136.9, 136.1, 132.4, 132.2,
30.5, 130.4, 128.8, 128.6, 128.03, 127.97, 126.6+,
26.3, 122.0, 111.3, 31.4; MS (EI) m/z 284.1307 (M
Lett. 2000, 4, 1119; (g) Choy, N.; Kim, C.-S.; Ballestero,
C.; Artigas, L.; Diez, C.; Lichtenberger, F.; Shapiro, J.;
Russell, K. C. Tetrahedron Lett. 2000, 41, 6955; (h)
Magnus, P.; Fortt, S.; Pitterna, T.; Snyder, J. P. J. Am.
Chem. Soc. 1990, 112, 4986.
[C H N ] = 284.1314); UV (MeOH) max: 241 nm, min:
20 16 2
2
27 nm.
2. The general procedure for the photoreaction is illustrated
1
6
7
. (a) Choy, N.; Blanco, B.; Wen, J.; Krishan, A.; Russell, K.
C. Org. Lett. 2000, 2, 3761; (b) Kaneko, T.; Takahashi,
M.; Hirama, M. Angew. Chem., Int. Ed. 1999, 38, 1267; (c)
Evenzahav, A.; Turro, N. J. J. Am. Chem. Soc. 1998, 120,
835; (d) Funk, R. L.; Young, E. R. R.; Williams, R. M.;
Flanagan, M. F.; Cecil, T. L. J. Am. Chem. Soc. 1996, 118,
291.
. (a) Jones, G. B.; Foud, F. S. Curr. Pharm. Des. 2002, 8,
415; (b) Purohit, A.; Wyatt, J.; Hynd, G.; Wright, J.; El-
for the conversion of 3 to 5. A degassed solution of 3
(20 mg, 0.10 mmol) in solvents (20 mL) (i. hexanes; ii. i-
PrOH) was irradiated in a quartz flask under N at room
2
temperature with a low-pressure mercury lamp (450 W)
for 16 h. Volatiles were evaporated in vacuo, and the
1
residue was purified by preparative TLC (MeOH/CH
5:95) to give 5 (9 mg, 45% in hexane; 9 mg, 45% in i-
PrOH) with H NMR (CDCl
2 2
Cl ,
3
1
, 300 MHz): d 8.0 (s, 1H),
.55 (s, 1H), 7.15 (s, 1H), 3.84 (s, 3H), 2.96–2.91 (m, 4H),
2
3
7
1
Shafey, A.; Swamy, N.; Ray, R.; Jones, G. B. Tetrahedron
Lett. 2001, 42, 8579; (c) Jones, G. B.; Wright, J. M.; Hynd,
G.; Wyatt, J. K.; Yancisin, M.; Brown, M. A. Org. Lett.
1
6
.90–1.78 (m, 2H), 1.75–1.65 (m, 4H); H NMR (d –
benzene, 300 MHz): d 7.84 (s, 1H), 7.26 (s, 1H), 6.79 (s,
1
1
1
3
H), 2.84–2.76 (m, 4H), 2.68 (s, 3H), 1.70–1.62 (m, 4H),
2
000, 2, 1863.
1
3
.59–1.50 (m, 2H); C NMR (CDCl , 75 MHz): d 142.7,
8
9
. (a) Fouad, F. S.; Crasto, C. F.; Lin, Y.; Jones, G. B.
Tetrahedron Lett. 2004, 45, 7753; (b) Plourde, G., II; El-
Shafey, A.; Fouad, F. S.; Purohit, A. S.; Jones, G. B.
Bioorg. Med. Chem. Lett. 2002, 12, 2985.
. (a) Zhao, Z.; Peng, Y.; Dalley, N. K.; Cannon, J. F.;
Peterson, M. A. Tetrahedron Lett. 2004, 45, 3621; (b)
Zhao Z. Masters Thesis, BrighamYoung University,
Provo, UT, 2003; (c) Kim, G.; Kang, S.; Ryu, Y.; Keum,
G.; JoonSeo, M. Synth. Commun. 1999, 29, 507.
3
41.0, 140.0, 139.0, 132.9, 119.5, 109.4, 37.3, 37.0, 32.7,
1.4, 29.3, 29.2; MS (EI) m/z 200.1302 (M
+
[C H N ] = 200.1314); UV (MeOH) max: 251, 258,
13 16 2
280, 290 nm, min: 234, 255, 267, 287 nm.
3. Reaction mixtures were prepared by addition of super-
1
coiled plasmid pGL3con DNA (2 lL of 1 lg/lL solution;
2
appropriate stock solutions of compound 3 (20.5 lL of
lg DNA), and TBE buffer (2.5 lL of 0.5· buffer), to
1
2
830, 183, 18.3, and 1.83 lM) to give a total volume of
5 lL. Samples were irradiated at room temperature with
1
1
0. Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron
Lett. 1975, 4467.
1
13
a 450 W mercury light source equipped with a Pyrex filter.
The mixtures were analyzed on a 1.0% agarose gel at 80 V
for 2 h.
1. All compounds gave clean H and C NMR spectra that
were consistent with the assigned structures. Molecular
formulas were confirmed by high resolution mass spec-
+
1
1
4. Densitometer readings showed non-background cleavage
in lanes 2–6: lane 2 (upper/lower) = 0.3005; lane 3 (upper/
trometry (M within ±10 ppmof theory). Characteriza-
tion data were as follows: (2a): H NMR (CDCl
1
3
,
lower) = 4.588; lane
upper/lower) = 1.707; lane
lane 7 (upper/lower) = 0.5983; lane 8 (upper/lower) =
.5729.
5. Purwanto, M. G. M.; Weisz, K. J. Org. Chem. 2004, 69,
95.
4
(upper/lower) = 13.64; lane
5
3
00 MHz): d 7.39 (s, 1H), 3.61 (s, 3H), 2.16 (s, 3H), 2.08
13
(
6
(upper/lower) = 0.74011;
(
s, 3H); C NMR (CDCl , 75 MHz): d 137.0, 128.2, 96.3,
3
8
8.9, 79.8, 72.7, 32.6, 5.13, 4.90; MS (EI) m/z 158.0830
+
0
(
M
10 2
[C10H N ] = 158.0844); UV (MeOH) max: 217,
1
61 nm, min: 213, 228 nm; (2b): H NMR (CDCl
2
3
,
1
3
00 MHz): d 7.23 (s, 1H), 3.54 (s, 3H), 2.45 (t,