Cyclization of enediyne radical cations through chemical, photochemical, and electrochemical oxidation: The role of state symmetry

Full text of DOI:10.1021/jo951524y

J . Org. Chem. 1996, 61, 2247-2250
2247
Cycliza tion of En ed iyn e Ra d ica l Ca tion s
th r ou gh Ch em ica l, P h otoch em ica l, a n d
Electr och em ica l Oxid a tion : Th e Role of
Sta te Sym m etr y
†
†
Dhruva Ramkumar, Mahadevan Kalpana,
‡
,†
Babu Varghese, and Sethuraman Sankararaman*
Department of Chemistry and Regional Sophisticated
Instrumentation Centre, Indian Institute of Technology,
Madras - 600 036, India
Mavinahalli N. J agadeesh and
J ayaraman Chandrasekhar*
Department of Organic Chemistry, Indian Institute of
Science, Bangalore - 560 012, India
Received August 17, 1995
F igu r e 1. ORTEP diagram of the molecular structure of 6a
in the crystal.
Enediyne chemistry has gained prominence in recent
years in view of the presence of the moiety in several
naturally occurring antitumor antibiotics.1 Thermally
activated cycloaromatization to form 1,4-dehydrobenzene
diradical (Bergman cyclization) is of special interest as
the process has been implicated in the DNA-cleaving
ability of many natural products and synthetic ana-
logues.2 Photoinduced dimerization, cis-trans isomer-
Sch em e 1
3
4
5
ization, and cycloaromatization as well as photochem-
6
ically triggered cyclization of enediynes have also been
studied. Recently, 1,5-cyclizations have been reported in
7
a cyclic, dimeric derivative of 1,2-diethynylbenzene and
in tetrabenzocyclyne,8 induced by iodine and lithium,
respectively. The former presumably proceeds through
a radical cyclization pathway, while the latter involves
a radical anion. We now report electron transfer-medi-
ated cyclization of aromatic enediynes. Of the three
possible modes of cyclization (Scheme 1), the radical
cations of aryl derivatives generated through chemical,
photochemical, and electrochemical oxidation are shown
not to follow the Bergman cyclization mode. The ob-
served 1,5-cyclization process has been interpreted in
terms of the symmetry of electronic states of the species
involved.
Sch em e 2
Resu lts a n d Discu ssion
Photooxidation of enediynes 4a ,b in acetonitrile in the
presence of oxygen using 2,4,6-triphenylpyrilium tet-
+
-
9
rafluoroborate (TPP BF
4
) as the sensitizer yielded the
corresponding indenone derivatives 5a ,b, respectively
(Scheme 2).
Sch em e 3
†
Department of Chemistry.
Regional Sophisticated Instrumentation Centre.
‡
(
1) Nicolaou, K. C.; Dai, W.-M. Angew. Chem., Int. Ed. Engl. 1991,
0, 1387. Nicolaou, K. C.; Smith, A. L. Acc. Chem. Res. 1992, 25, 497.
2) Nicolaou, K. C.; Dai, W.-M.; Tsay, S.-C.; Estevez, V. A.; Wrasidlo,
3
(
W. Science 1992, 256, 1172. Nicolaou, K. C.; Zuccarello, G.; Riemer,
C.; Estevez, V. A.; Dai, W.-M. J . Am. Chem. Soc. 1992, 114, 7360.
Nicolaou, K. C.; Liu, A.; Zeng, Z.; McComb, S. J . Am. Chem. Soc. 1992,
1
14, 9276.
(3) Muller, E.; Zountsas, G. Tetrahedron Lett. 1970, 52, 4531.
4) Konig, B.; Schofield, E.; Bubenitschek, P.; J ones, P. G. J . Org.
Photonitration of 4a with tetranitromethane (TNM) in
dichloromethane using a Pyrex filter yielded red orange
crystals after column chromatographic purification of the
crude material.10 The product was identified as 3,8-
dinitro-2,8-diphenylbenzofulvene (6a ) from the X-ray
(
Chem. 1994, 59, 7142.
5) Turro, N. J .; Evenzahav, A.; Nicolaou, K. C. Tetrahedron Lett.
994, 35, 8089.
6) Wender, P. A.; Zercher, C. K.; Beckham, S.; Haubold, E.-M. J .
Org. Chem. 1993, 58, 5867.
7) Zhou, Q.; Carroll, P. J .; Swager, T. M. J . Org. Chem. 1994, 59,
294.
8) Bradshaw, J . D.; Solooki, D.; Tessier, C. A.; Youngs, W. J . J .
Am. Chem. Soc. 1994, 116, 3177.
(
1
(
(
19
crystal structure shown in Figure 1 (Scheme 3). The
1
(
(10) For the mechanism of photonitration of arenes with TNM see
Sankararaman, S.; Kochi, J . K. J . Chem. Soc., Perkin Trans. 2 1991,
1, 165 and references cited therein. Further details of the photochem-
istry of enediyne-TNM system will be published separately.
+
-
(
9) For TPP BF : E1/2 (red) ) -0.29 V vs SCE in CH CN, E(S) )
4
3
2
1
.8 eV, t(S) ) 2.9 ns. Miranda, M. A.; Garcia, H. Chem. Rev. 1994, 94,
063.
0
022-3263/96/1961-2247$12.00/0 © 1996 American Chemical Society

2
248 J . Org. Chem., Vol. 61, No. 6, 1996
Notes
Sch em e 4
F igu r e 2. ESR spectrum of the adduct of the radical formed
during photolysis of 4a with N-tert-butyl-R-phenylnitrone in
CH CN at rt.
3
Sch em e 5
crystal structure of 6a unequivocally establishes that the
product arises from the 1,5-cyclization mode to yield the
benzofulvene structure.
Chemical oxidation of 4a ,b, by Barton’s procedure,11
+
-
from the photolysis of 4a in the presence of TPP BF
4
when carried out in acetonitrile-isopropyl alcohol (IPA)
mixture under nitrogen atmosphere (eq 12, Scheme 5).
Formation of 7a can only be explained by invoking the
diradical III which undergoes hydrogen abstraction with
IPA (eq 11). The lack of formation of products arising
from the addition of IPA as a nucleophile to I and II
suggests that the cyclization and the subsequent electron
transfer processes (eqs 7 and 8) are very rapid. This also
explains the absence of products arising from the addition
of trinitromethide anion to I and II in the TNM reaction
using tris(p-bromophenyl)aminium hexachloroantimonate
+
-
(
6
TBPA SbCl ) as the catalytic oxidizing agent in the
presence of oxygen yielded 5a ,b, respectively (Scheme 2)
in 60-70% isolated yields.
Electrochemical oxidation of 4a ,b was examined by
cyclic voltammetry in acetonitrile which showed a single
irreversible anodic peak at +1.49 V for 4a and +1.31 V
-
1
for 4b, vs SCE, at 100 mV s scan rate. The bulk
electrolysis of 4a ,b at a constant potential corresponding
to the anodic peak potential under oxygen atmosphere
yielded 5a ,b, respectively, in good yields. Coulometric
studies revealed that the reaction was a catalytic one-
electron transfer process. Thus, for the electrolysis of 0.3
mmol of 4b, only 4 C of current was consumed to yield
(
eq 5), which is in sharp contrast to the previously
reported photochemistry of arene-TNM complexes.
Furthermore, the ESR spectrum shown in Figure 2 arises
from the trapping of a radical intermediate from the
1
0
+
-
photolysis of 4a with TPP BF
4
3
in CH CN under argon
atmosphere, by N-tert-butyl-R-phenylnitrone as the spin
trap. Even though the ESR spectrum does not provide
any structural information on the radical intermediate,
it clearly demonstrates the formation of such an inter-
mediate from the enediyne in the photochemical reaction.
A control experiment under identical conditions but
without the enediyne 4a did not show any ESR signal,
thus clearly demonstrating that the observed ESR signal
in the presence of 4a is only due to a free radical
intermediate formed by the oxidation of 4a (Scheme 4,
eq 8).
Similar steps (Scheme 4, eqs 6-9) are likely in the
chemical and electrochemical oxidation reactions too after
the initial generation of the enediyne radical cation. On
the basis of these studies, we conclude that the radical
cations of 4a ,b, irrespective of the mode of generation,
show preponderant tendency to undergo 1,5-mode of
cyclization, rather than Bergman cyclization.
0
.27 mmol of 5b.
We propose a common pathway involving the enediyne
radical cation in all the cases. Photoinduced electron
+
transfer from 4a ,b to the singlet excited state of TPP is
feasible since the latter is a powerful oxidant.9 This is
further supported by the diffusion-controlled quenching
+
of the fluorescence of TPP by 4a ,b and also by the
calculated ∆G 1e t values based on the redox potentials of
the reactants. 2 The radical cation of the enediyne (I)
cyclizes to the fulvenyl form (II) which further reacts with
the neutral enediyne to yield the fulvenyl diradical (III)
and the enediyne radical cation (I) (eqs 6-8, Scheme 4).
Thus, the radical cation of the enediyne is the chain
carrier. Such a mechanism is akin to the photoinduced
electron transfer-mediated valence isomerization of hex-
amethyldewarbenzene radical cation.13 Evidence for the
formation of the fulvenyl diradical (III) comes from the
isolation of cis- and trans-2,8-diphenylbenzofulvene (7a )
The preferred 1,5-mode of cyclization of the radical
cation is in sharp contrast to 1,6-Bergman cycloaroma-
(11) Barton, D. H. R.; Leclerc, G.; Magnus, P. D.; Menzies, I. D. J .
Chem. Soc., Chem. Commun. 1972, 447.
+
(
12) For fluorescence quenching of TPP by 4a and 4b, k
q
) 3.39 ×
(13) J ones, G. II; Becker, W. G. J . Am. Chem. Soc. 1983, 105, 1276.
Peacock, N. J .; Schuster G. B. J . Am. Chem. Soc. 1983, 105, 3632.
Takahashi, Y; Sankararaman, S; Kochi, J . K. J . Am. Chem. Soc. 1989,
111, 2954.
01 and 4.38 × 10
0
10
M
-1 -1
s , respectively. Since TPP is used as the
+
1
sensitizer, formation of singlet oxygen and superoxide anion radical
as intermediates in the photooxygenation can be ruled out.9

Notes
J . Org. Chem., Vol. 61, No. 6, 1996 2249
tization found in neutral enediynes. Semiempirical
oxidation of 4b was also carried out by the same procedure to
yield 5b in 78% yield.
UHF/AM1)14 and ab initio calculations (PMP2/6-31G*
(
1
5,16
•+
Ch em ical Oxidation . A blue-colored solution of TBPA
0.006 g, 7.4 × 10 mol) in dry CH
+ -
SbCl6
using 3-21G optimized geometries)
on C
6
H
4
isomers
-6
(
-
2 2
Cl (15 mL) was cooled to
78 °C, and then 4b (0.025 g, 0.075 mmol) was added. The
mixture was stirred at -78 °C with continuous bubbling of
oxygen for 3 h to yield 5b in 60% yield.
suggest a deeper electronic origin. To ionize the ene-
diyne, it is preferable to remove an electron from a π MO
of the hexatriene moiety rather than from an in-plane π
orbital of the triple bonds. Thus the ground electronic
state is derived from a 5 π configuration. The radical
cation of 1,4-dehydrobenzene prefers to retain an aro-
matic π sextet. The SOMO of the system is the anti-
symmetric combination of the hybrid orbitals at the 1-
and 4- carbon centers. Hence cycloaromatization of the
enediyne radical cation to 1,4-dehydrobenzene radical
cation is an electronically forbidden process. On the
other hand, formation of the 1,5-cyclization product, viz.,
Electr och em ica l Oxid a tion . Cyclic voltammetry and bulk
electrolysis of 4a ,b were studied on a BAS 100A Electrochemical
Analyzer using platinum electrodes and SCE as reference
electrode. In a divided cell a solution containing 4b (0.1 g, 0.3
mmol) and tetraethylammonium perchlorate (TEAP) (0.7 g) in
3
CH CN (30 mL) was electrolyzed with continuous bubbling of
oxygen at a constant potential of +1.5 V vs SCE until the current
dropped to a low constant value (1 h). During electrolysis, the
yellow solution turned dark red. Usual workup followed by
purification by preparative TLC on silica gel yielded 5b (0.098
g, 0.26 mmol, 88%) as dark red gummy solid. From the
coulometry the actual current consumed was found to be 4 C.
Similarly, the oxidation of 4a was carried out at a constant
potential of +1.8 V vs SCE.
3
,6-dehydrofulvene radical cation is predicted to be
allowed. The ground state of the latter is computed to
have 5 π electrons. An alternative 6 π state was
computed to be consistently higher in energy at all
theoretical levels used (∆E AM1: 25.4, PUHF/6-31G*:
3
-Ben zoyl-2-p h en ylin d en on e (5a ): IR (CCl
4
) 1715, 1669
-
1
cm ; UV-vis (CHCl
31769), 235 nm (sh, 21660); H NMR (CDCl
.8-7.6 (m, 12H); C NMR (CDCl
(s), 144.0 (s), 134.4 (d), 131.2 (d), 130.3 (s), 130.2 (d), 129.7 (s),
129.5 (s), 129.3 (d), 128.9 (d), 128.8 (d), 128.7 (s), 128.3 (d), 127.9
3
) λmax(ꢀ) ) 435 (585), 330 (sh, 1800), 260
3
6.8, PMP2/6-31G*: 20.7 kcal/mol).17 The reduced aro-
1
(
6
3
) δ ) 7.9 (m, 2H),
maticity in the 6 π form of fulvene as well as the
possibility of reduced electron repulsion due to more
effective Fermi correlation in the 5 π state probably
contribute to the preferred electronic configuration.
Consistent with the above electronic structures, attempts
to locate a transition state for the 1,6-cyclization mode
led to discontinuous surfaces and convergence difficulties,
while a smooth energy surface with a productlike transi-
tion state could be located at both AM1 and 3-21G levels
for the allowed 1,5-cyclization process.17
13
3
) δ ) 196 (s), 194.6 (s), 150.4
•+
(
2
d), 123.9 (d), 121.8 (d); MS (70 eV) m/z 310 (100) [M ], 282 (56),
53 (24), 205 (72), 177 (65), 151 (45), 125 (38), 105 (63), 77 (61);
HRMS calcd for C22 310.09938, found 310.09948.
-(4-Met h oxyb en zoyl)-2-p h en ylin d en on e (5b ):
) λmax (ꢀ) ) 465 (1899),
) δ ) 7.92 (d, 2H,
14 2
H O
3
IR
-1
(
2
4 3
CCl ): 1712, 1654 cm ; UV-vis (CHCl
1
70 (33636), 235 nm (15037); H NMR (CDCl
3
J ) 9.3 Hz), 7.57 (d, 1H, J ) 6.9 Hz), 7.43 (d, 2H, J ) 9.0 Hz),
7.34 (apparent t, 1H, J ) 8.0 Hz), 7.25 (apparent t, 1H, J ) 7.3
Hz), 6.97 (d, 1H, J ) 7.3 Hz), 6.83 (d, 2H, J ) 9.3 Hz), 6.77 (d,
2
)
1
H, J ) 9.3 Hz), 3.82 (s, 3H), 3.75 (s, 3H); 13C NMR (CDCl
3
) δ
196.7 (s), 193.2 (s), 164.6 (s), 160.1 (s), 149.1 (s), 144.6 (s),
34.4 (d), 133.4 (s), 131.9 (d), 130.8 (d), 129.5 (s), 128.9 (d), 128.2
(s), 123.7 (d), 122.4 (s), 121.4 (d), 114.2 (d), 113.9 (d), 55.5 (q),
Con clu sion s
The radical cations of aryl-substituted enediynes 4a ,b
generated by a variety of methods prefer to undergo 1,5-
cyclization unlike their neutral counterparts. The 1,5-
cyclization mode of the radical cation is suggested to be
determined by electronic state symmetry.
•
+
55.2 (q); MS (70 eV) m/z 370 (6.5) [M ], 194 (16), 163 (100), 149
24), 135 (15), 85 (18), 83 (29), 77 (16); HRMS calcd for C24
70.12054, found 370.11976.
P h otor ed u ction of 4a to 2,8-Dip h en ylben zofu lven e (7a ).
(
3
18 4
H O
+
-
A mixture of 4a (0.2 g, 0.72 mmol) and TPP BF
mmol) in CH CN (10 mL) and isopropyl alcohol (5 mL) was
photolyzed in a Pyrex tube for 26 h under N atmosphere.
4
(0.02 g, 0.05
3
Exp er im en ta l Section
2
During the photolysis, the solution turned dark yellow. After
removal of the solvent, the crude product was purified by column
chromatography on silica gel using hexane as the eluant to yield
unreacted 4a (0.075 g), cis-2,8-diphenylbenzofulvene (cis-7a )
(0.02 g) as a yellow solid [mp 129 °C (lit.18 129-131 °C)] and
trans-2,8-diphenylbenzofulvene (trans-7a ) (0.04 g) as a yellow
liquid. The products were characterized by the comparison of
P h otooxid a tion . A solution of 4a (0.2 g, 0.72 mmol) and
+
-
TPP BF
4
3
(0.028 g, 0.072 mmol) in CH CN (10 mL) was
photolyzed in a Pyrex tube using the output from a 450 W
Hanovia lamp with continuous bubbling of oxygen. During
photolysis, the solution turned from yellow to dark red. After
3
0 h, solvent was evaporated and the crude was separated by
1
18
column chromatography on silica gel (60-120 mesh). Elution
with hexane yielded the unreacted 4a (0.12 g, 0.43 mmol)
followed by elution with hexane-ethyl acetate (95:5 v/v) gave
the IR, UV, H-NMR spectral data with the literature and also
by mass spectral data.
Sp in Tr a p p in g Exp er im en t. A solution of 4a (0.01 g, 0.035
5
a (0.067 g, 0.22 mmol, 76% based on unrecovered 4a ). Photo-
+
-
mmol), TPP BF
4
(1 mg, 0.0026 mmol), and N-tert-butyl-R-
phenylnitrone (0.05 g, 0.28 mmol) in CH
3
CN (5 mL) was
photolyzed for 1 h in a Pyrex tube under Ar atmosphere, and
the ESR spectrum of the photolysate was recorded at rt. From
the ESR spectrum of the radical adduct (Figure 2) the g value
(
14) Stewart, J . J . P. J . Comput. Aided Des. 1990, 4, 1.
(15) Spin-projected Moller-Plesset theory is known to be more
reliable in estimating energetics of species with varying degrees of
contamination; see, Schlegel, H. B. J . Phys. Chem. 1988, 92, 3075. Sosa,
C.; Schlegel, H. B. J . Am. Chem. Soc. 1987, 109, 4193.
and a
N
were calculated as 2.00416 and 12.0 G, respectively. A
control experiment was carried out under identical conditions
as above but without the enediyne 4a . The photolysate under
this condition did not show the ESR spectrum.
(16) Calculations were carried out using the Gaussian 92 series of
programs (Revision E.3): Frisch, M. J .; Trucks, G. W.; Head-Gordon,
M; Gill, P. M. W.; Wong, M. W.; Foresman, J . B.; J ohnson, B. G.;
Schlegel, H. B.; Robb, M. A.; Replogle, E. S.; Gomperts, R.; Andres, J .
L.; Raghavachari, K.; Binkley, J . S.; Gonzalez, C.; Martin, R. L.; Fox,
D. J .; Defrees, D. J .; Baker, J .; Stewart, J , J . P.; Pople, J . A., Gaussian,
Inc., Pittsburgh, PA, 1992.
Ack n ow led gm en t. Financial support from DST,
New Delhi, is gratefully acknowledged. We thank
(17) The computed AM1 heats of formation (kcal/mol) and ab initio
(18) Whitlock, H. W. J r; Sandvick, P. E; Overman, L. E; Reichardt,
P. B. J . Org. Chem. 1969, 34, 879.
(19) The author has deposited atomic coordinates for this structure
with the Cambridge Crystallographic Data Centre. The coordinates
can be obtained, on request, from the Director, Cambridge Crystal-
lographic Data Centre, 12 Union Road, Cambridge, CB2 1EZ, UK.

2
250 J . Org. Chem., Vol. 61, No. 6, 1996
Additions and Corrections
Regional Sophisticated Instrumentation Centre, IIT,
Madras for spectroscopic and X-ray crystallographic
data. We gratefully acknowledge help from Dr. P.
Ramamurthy, Department of Inorganic Chemistry,
University of Madras, with the ESR experiments.
cations of enediyne, 1,4-dehydrobenzene, 3,6-dehydrofulvene
(5π and 6π configurations) and transition state between
enediyne and 3,6-dehydrofulvene (4 pages). This material is
contained in libraries on microfiche, immediately follows this
article in this article in the microfilm version of the journal,
and can be ordered from the ACS; see any current masthead
page for ordering information.
Su p p or tin g In for m a tion Ava ila ble: The UHF/AM1 and
UHF/3-21G optimized geometries and energies of radical
J O951524Y
Additions and Corrections
Vol. 60, 1995
Ca r los Alva r ez-Iba r r a ,* Au r elio G. Cs a´ k y1 , Mer ced es
Ma r oto, a n d M. Lu z Qu ir oga . Diastereoselective Synthesis
of Substituted Glutamic Acid Derivatives via Michael Additions
of N-[Bis(methylthio)methylene]glycinates under Solid-Liquid
Phase Transfer Catalysis.
Page 6700. We failed to include the work of Hoppe
and co-workers on the first utilizations of N-[bis(meth-
ylthio)methylene]glycine ester enolate for glycine anion
reagents. They reported the deprotonation of 1a by
t
means of KO Bu, its (()-mono- and (()-dialkylation, and,
2 2 2
as well, a deprotection procedure (HCO H/H O ). The
representative articles are as follows: (1) Hoppe, D.
Angew. Chem., Int. Ed. Engl. 1975, 14, 426. (2) Hoppe,
D.; Beckmann, L. Liebigs Ann. Chem. 1979, 2066.
J O9649611
Ca r los Alva r ez-Iba r r a ,* Au r elio G. Cs a´ k y1 , Ra qu el
Ma r oto, a n d M. Lu z Qu ir oga . Asymmetric Alkylation of
8
-Phenylmenthyl N-[Bis(methylthio)methylene]glycinate Eno-
lates. Synthesis of D- and L-R-Amino Acids from a Single Chiral
Precursor.
Page 7934. We failed to include the work of Hoppe
and co-workers on the first utilizations of N-[bis(meth-
ylthio)methylene]glycine ester enolate for glycine anion
reagents. They reported the deprotonation of 1a by
t
means of KO Bu, its (()-mono- and (()-dialkylation, and,
2 2 2
as well, a deprotection procedure (HCO H/H O ). The
representative articles are as follows: (1) Hoppe, D.
Angew. Chem., Int. Ed. Engl. 1975, 14, 426. (2) Hoppe,
D.; Beckmann, L. Liebigs Ann. Chem. 1979, 2066.
J O954034E