Some reactions of persistent benzofuranone radicals related to the 'old' diazonamide structure

Article abstract of DOI:10.1016/j.tetlet.2004.11.103

The benzofuranone dimers 9 and 10/11 readily (ca. 75°C) dissociate to the persistent radicals 16 and 17 respectively, which are stable to, dioxygen. The OMe analog 25 dissociates to form the radical 24, which reacts with dioxygen of TEMPO to give 26.

Full text of DOI:10.1016/j.tetlet.2004.11.103

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 707–710
Some reactions of persistent benzofuranone radicals
related to the ÔoldÕ diazonamide structure
Philip Magnus,* Jennifer D. Venable (nee Kreisberg), Lan Shen and Vince Lynch
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 9November 2004; accepted 17 November 2004
Abstract—The benzofuranone dimers 9 and 10/11 readily (ca. 75 °C) dissociate to the persistent radicals 16 and 17 respectively,
which are stable to, dioxygen. The OMe analog 25 dissociates to form the radical 24, which reacts with dioxygen of TEMPO to
give 26.
Ó 2004 Published by Elsevier Ltd.
The original structure of diazonamide A, 11 was cor-
rected to 2 by Harran and co-workers,2 and the total
synthesis of 1 and 2 has been reported, Scheme 1.3 Prior
to the structural correction we had been interested in the
formation of the central C30–C10 bond of 1 from inter-
mediates such as 3, 4, and 5. Since there have been a
recent resurgence of interest in benzofuranyl radicals
and their exceptional stability even toward dioxygen,4
we report in this letter some of our own observations.
The X-ray crystallographic analysis shows that the C3–
0
˚
C3 bond length in 9 is 1.60 A.
An alternative dimerization route involved reaction of 7
with 4-N,N-dimethylaminopyridine (DMAP)/CH2Cl2
and TiCl4,10 to produce a titanium enolate complex
and further oxidation with TiCl4 gave the dimers
10 and 11 (57% yield, mp 185–195 °C, ratio 6.8:1, or vice
1
versa by H NMR d 2.24 (s) and 2.31 (s) ratio).
The 2-deoxy version of 3, namely 16 is a known radical,
and the precursor 6 (Scheme 2) is readily made in 27%
yield by heating mandelic acid with phenol.5 Most inter-
estingly, it has been reported that treatment of 6 with
Na/Et2O followed by iodine gave the dimer 8/9, which
on heating at 70–75 °C dissociates to the radical 16
(blue).6 The persistent radical7 16 will oxidize thiols to
disulfides,8 and exposure of 6 to sunlight and air gives
the dimer 8/9 rather than peroxides.9
A dichlorobenzene solution of 10/11 became blue when
it was heated to 75 °C. The blue color did not disappear
when the solution was exposed to air, but vanished when
the solution was cooled to room temperature. This sug-
gests that the radical 17 exists in an equilibrium with the
dimers 10/11. Interestingly, after the solution was cooled
to room temperature, the ratio of the dl:meso (or vice
versa) of the recovered dimer 10/11 changed to 5:1.
The low dissociation energy11 of the C3–C30 bond is
attributed to the steric compression in the structure of
17. The repulsive interactions between groups are re-
lieved when the central carbon atom passes from tetra-
hedral bonding to the trigonal bonding. Such steric
compression induced bond weakening has been exten-
sively observed in thermolysis reactions leading to free
radicals.12
2-Oxo-2,3-dihydro-3-phenylbenzo[b]furan 6 and its 5-
methyl analog 7 were synthesized by condensation of
mandelic acid with phenol and p-cresol, respectively.
Deprotonation of 6 with LDA/THF or sodium/Et2O,
and subsequent single electron transfer reaction (SET)
with iodine produced the radical 16, which dimerizes
to give 9 (84%, mp 110–113 °C, meso by X-ray, Fig.
1), Scheme 2. The dl-form, namely 8 was not detected.4a
Treatment of 7 with sodium and PhSSO2Ph gave the sul-
fide 13 (87%). A dichlorobenzene solution of 13
(0.25 mol/L) started turning blue when the temper-
ature reached 125 °C. The solution turned light yellow
upon cooling, and both sulfide 13, dimers 10/11 and
Keywords: Diazonamide; Benzofuranyl radicals; Pummerer reaction.
*
Corresponding author. Tel.: +1 512 471 3966; fax: +1 512 471
7839; e-mail: p.magnus@mail.utexas.edu
Author for inquiries concerning the X-ray data.
0040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.11.103

708
P. Magnus et al. / Tetrahedron Letters 46 (2005) 707–710
Me
H
Me
Me
H
Me
Me
Me
O
Me
Me
O
Cl
Cl
N
A
N
A
N
N
HN
HN
H
H
B
O
B
O
Cl
Cl
O
N
N
O
HO
O
G
H2N
O
G
30
30
10
E
10
HO
OH
1, Old diazonamide A structure
E
C
C
NH
NH
F
F
H
NH
O
D
D
O
2, New diazonamide A structure
N
A
N
N
N
B
N
A
N
B
A
B
O
O
2
O
O
O
O
+
-H
-H
E
E
E
F
F
F
O
G
O
G
O
G
O
O
O
OH
OH
O
3
4
5
Scheme 1. Structures of Diazoamides.
O
O
H
O
O
R
3'
3
3'
3
a). Na/I /Et O/25˚C
2
2
R
R
R
R
+
O
i
b). LiNPr /I /THF -70˚C
2
2
O
6 (R = H, 27%)
7 (R = Me, 63%)
c). DMAP/TiCl /
CH Cl 0˚C
4
O
O
2
2
O
O
meso-
(dl-)
8 (R = H)
9 (R = H)
11 (R = Me)
Na/Et O/reflux
2
10 (R = Me)
PhSO SPh
2
Cl
Cl
75˚C
SPh
Me
R
125˚C
O
O
Cl
O
O
Cl
16 (R = H)/17 (R = Me)
13 (R = Me, 87%)
MCPBA/CH Cl
2
2
85˚C
23˚C
-70˚ to 23˚C
Cl
Cl
O
SO2Ph
SPh
Me
Me
MCPBA/CH Cl
2
2
O
O
O
O
0˚ to 23˚C
14 (88%)
15 (not observed)
Scheme 2.
was observed when 14 was heated to 85 °C in dichloro-
benzene. Upon cooling the solution again became light
yellow, and both 14 and 10/11 were isolated. Oxidation
of the sulfide 13 with 2.5 equiv of m-CPBA or sulfoxide
14 with 1.2 equiv of m-CPBA (from ꢀ70 to 23 °C) gave
only the dimers 10/11, and none of the sulfone 15 was
observed.
3'
3
To examine the 2-oxy version of Scheme 2 we treated 18
with N-chlorosuccinimide (NCS) at 0 °C in CCl4 to give
19, which was treated with p-methylanisole and SnCl4 to
give 20 in 98% yield, Scheme 3. It was notable that the
intermolecular Pummerer reaction took place preferen-
tially to the intramolecular reaction.13 After treatment
of 20 with NCS/PhCl for 2 h the mixture was filtered,
Figure 1. Chem 3D representation of 9 from X-ray coordinates.
diphenyldisulfide were present. Oxidation of the sulfide
13 with 1.1 equiv of m-CPBA produced the sulfoxide
14 in 88% yield. Formation of the radical 17 (blue color)

P. Magnus et al. / Tetrahedron Letters 46 (2005) 707–710
709
MeO
SMe
O
MeO
SMe
SMe
O
Cl
O
Me
Me
Me
NCS/CCl
Me
4
O
O
0˚C
O
SnCl /CH Cl /23˚C
4
2
2
18
19 (90%)
20 (98%)
Me
OM e
O
1. NCS (1.1eq)/PhCl
2. SnCl (0.1 eq)/100˚C
O
4
3'
3
Me
Me
Me
Me
MeO
SMe
Me
Me
Me
180˚C
O
O
O
Cl
O
OM e
O
OM e
O
Cl
Me 21 (78%)
NCS/PhCl
MeO
25 (60%, only dl)
24
Me
Me
Me
MeO
OM e
Cl
Me
Me
MeO
OM e
SnCl /CH Cl
2
Me
O
O
O
4
2
O
O
O
24a
Me 23 (97%)
Me 22 (78%)
or O
X
2
N
O
O
O
Me
Me
H
MeO
MeO
Me
Me
-HX
O
O
O
O
24b (X =
or OH
26
N
Scheme 3.
and a catalytic amount of SnCl4 was added and the
solution was heated to 100 °C. After 10 min the lactone
21 (IR 1798 cmꢀ1) was isolated in 78% yield. Treating
the ester 20 with 2 equiv of N-chlorosuccinimide, fol-
lowed by heating at 100 °C, gave the chlorolactone 22
(IR 1814 cmꢀ1) in 78% yield. It was possible to generate
the chlorolactone 22 directly from the lactone 21 by
heating it with NCS in chlorobenzene.
green color would re-appear at 80 °C. From this reac-
tion the dimer 25 was isolated in 40–60% yields. While
the radical 24 can dimerize in two forms, meso and dl,
only the dl-dimer was detected, and its structure was
determined by X-ray, Figure 2 (C3–C30 bond is
˚
1.622 A).
When the dimer 25 (20 mg) was heated in chlorobenzene
at 120 °C in the presence of TEMPO the orange oxida-
tion product 26 (7 mg) was isolated. Heating 25 in the
presence of air also produced small amounts (<5%) of
26. Presumably, the resonance form 24a intercepts
TEMPO or dioxygen to give 24b, which leads to 26.
The benzofuran-2-one 21 was heated in degassed dichlo-
robenzene, and at 160 °C (internal temperature) a slight
blue-green color appeared, which intensified when the
temperature reached 180 °C. The solution of the bis-benz-
ylic radical 24 remained green upon cooling to about
80 °C, then turned pale yellow below this temperature.
The pale yellow solution could be re-heated and the
Finally, to examine the cationic pathway in Scheme 1,
we treated 22 in CH2Cl2 with SnCl4 in the presence of
p-methylanisole to give the lactone 23 (97%). All
attempts to trap either the radicals 16, 17, and 24, or
cation (from 22) with simple oxazoles failed.
3'
3
Acknowledgements
The National Institutes of Health (CA 50512), Robert
A. Welch Foundation, Merck Research Laboratories
and Novartis are thanked for their support of this
research.
Figure 2. Chem 3D representation of 25 from X-ray coordinates.

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P. Magnus et al. / Tetrahedron Letters 46 (2005) 707–710
1851–1861; Wasserman, H. H.; Liu, T.; Wasserman, E. R.
J. Am. Chem. Soc. 1953, 75, 2056–2058.
References and notes
6. Karafiloglou, P.; Catteau, J.; Lablache-Combier, A.;
Ofenberg, H. J. Chem. Soc., Perkin Trans. 2 1977, 1545–
1548; Pandev, B.; Tikare, R. K.; Muneer, M.; Kamat, P.;
George, M. V. Chem. Ber. 1986, 119, 917–928; Lohray, B.
B.; Kumar, C. V.; Das, P. K.; George, M. V. J. Am. Chem.
Soc. 1984, 106, 7352–7359.
1. Lindquist, N.; Fenical, W.; Van Duyne, G. D.; Clardy, J.
J. Am. Chem. Soc. 1991, 113, 2303–2304.
2. Li, Jing; Jeong, S.; Esser, L.; Harran, P. G. Angew. Chem.,
Int. Ed. 2001, 40, 4765–4770; Li, Jing; Burgett, A. W. G.;
Esser, L.; Amezcua, C.; Harran, P. G. Angew. Chem., Int.
Ed. 2001, 40, 4770–4773.
7. Griller, D.; Ingold, K. U. Acc. Chem. Res. 1976, 9, 9–14.
8. Schonberg, A.; Aziz, G. J. Org. Chem. 1957, 22, 1697–
1698; Schonberg, A.; Mustafa, A. J. Am. Chem. Soc. 1951,
73, 2401–2401.
9. Schoenberg, A.; Mustafa, A. J. Chem. Soc. 1945, 657–660.
10. Kise, N.; Kumada, K.; Terao, Y.; Ueda, N. Tetrahedron
1998, 54, 2697–2708.
3. Burgett, A. W. G.; Li, Q.; Wei, Q.; Harran, P. G. Angew.
Chem., Int. Ed. 2003, 42, 4961–4966; Nicolaou, K. C.;
Chen, D. Y.-K.; Huang, X.; Ling, T.; Bella, M.; Snyder, S.
A. J. Am. Chem. Soc. 2004, 126, 12888–12896; Nicolaou,
K. C.; Hao, J.; Reddy, M. V.; Rao, P. B.; Rassias, G.;
Snyder, S. A.; Huang, X.; Chen, D. Y.-K.; Brenzovich, W.
E.; Giuseppone, N.; Giannakakou, P.; OÕBrate, A. J. Am.
Chem. Soc. 2004, 126, 12897–12906.
11. Szwarc, M. Quart. Rev. 1951, 5, 22–43.
12. Duismann, W.; Ruchardt, C. Tetrahedron Lett. 1974, 51,
4517–4520; Beckhaus, H.-D.; Ruchardt, C. Tetrahedron
Lett. 1973, 22, 1971–1974; Dubois, J.-E.; Lomas, J. S.
Tetrahedron Lett. 1973, 21, 1791–1794; Peters, E. N.;
Brown, H. C. J. Am. Chem. Soc. 1974, 96, 263–266;
Bartlett, P. D.; Tidwell, T. T. J. Am. Chem. Soc. 1968, 90,
4421–4428; Slutsky, J.; Bingham, R. C.; Scheyer, P. v. R.
J. Am. Chem. Soc. 1974, 96, 1969–1970.
4. (a) Frenette, M.; Aliaga, C.; Font-Sanchis, E.; Scaiano, J.
C. Org. Lett. 2004, 6, 2579–2582; (b) Font-Sanchis, E.;
Aliaga, C.; Cornejo, R.; Scaiano, J. C. Org. Lett. 2003, 5,
1515–1518; (c) Bejan, E. V.; Font-Sanchis, E.; Scaiano, J.
C. Org. Lett. 2001, 3, 4059–4062; (d) Scaiano, J. C.;
Martin, A.; Yap, G. P. A.; Ingold, K. U. Org. Lett. 2000,
2, 899–901.
5. Lo¨wenbein, A.; Simonis, H. Chem. Ber. 1924, 57, 2040–
2051; Lo¨wenbein, A.; Folberth, W. Chem. Ber. 1925, 58,
601–612; Lo¨wenbein, A.; Schmidt, H. Chem. Ber. 1927, 60,
13. Magnus, P.; Kreisberg, J. D. Tetrahedron Lett. 1999, 40,
451–454.