Novel features of iron-mediated radical reactions: An unusual mode of silyloxycyclopropane fission, and a new method for radical chain termination using CH2I2

Article abstract of DOI:10.1016/j.tetlet.2004.06.115

Fe(NO₃)₃ mediated radical reactions of silyloxycyclopropanes derived from a range of bicyclic ketones are described, and include examples that undergo an unexpected regiochemical mode of cyclopropane cleavage. The inclusion of CH

Full text of DOI:10.1016/j.tetlet.2004.06.115

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 6679–6683
Novel features of iron-mediated radical reactions: an unusual
mode of silyloxycyclopropane fission, and a new method for
radical chain termination using CH2I2
Adrian Highton, Raffaella Volpicelli and Nigel S. Simpkins*
School of Chemistry, The University of Nottingham, University Park, Nottingham NG7 2RD, UK
Received 10 May 2004; revised 11 June 2004; accepted 18 June 2004
Available online 24 July 2004
Abstract—Fe(NO3)3 mediated radical reactions of silyloxycyclopropanes derived from a range of bicyclic ketones are described, and
include examples that undergo an unexpected regiochemical mode of cyclopropane cleavage. The inclusion of CH2I2 in such reac-
tions allows the synthesis of iodinated products.
ꢀ 2004 Elsevier Ltd. All rights reserved.
The Booker-Milburn research group has described a
substantial body of work involving the use of various
iron salts to mediate synthetically useful radical reac-
tions involving the cleavage of cyclopropane deriva-
tives.1–3 Early work involved treatment of appropriate
silyloxycyclopropanes with FeCl3,1 but the power and
versatility of the method was subsequently extended by
reactions involving additional types of cyclopropane
and by use of alternative iron salts.2,3 In a typical reac-
tion sequence, a silyloxycyclopropane or cyclopropa-
none silyl ketene acetal bearing an unsaturated
appendage is reacted with Fe(NO3)3 and a suitable rad-
ical trap, resulting in the formation of cyclised products,
for example, conversion of 1 into sulfide 2, Eq. 1.
We became interested in this chemistry as a means to
generate moderately complex polycyclic systems that
might allow access to natural products having the fused
[5.8.5] ring system characteristic of the ophiobolin
and fusicoccin families. As shown (Eq. 2) we used the
O
Me3SiO
SPh
Fe(NO3)3, DMF
EtO
(Eq. 1)
EtO
0 oC PhSSPh
1
2 66% (mainly cis)
Me3SiO
SPh
H
O
H
Fe(NO3)3, DMF
O
O
(Eq. 2)
0 oC PhSSPh
3
4 65%
Scheme 1.
Keywords: Cyclopropane; Iodination; Radical cyclisation; Iron salts.
*
Corresponding author. Fax: +44-(0)115-9513564; e-mail: nigel. simpkins@nottingham.ac.uk
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.06.115

6680
A. Highton et al. / Tetrahedron Letters 45 (2004) 6679–6683
Cl
Me3SiO
O
Me3SiO
Cl
3
2
CCl3
1
FeCl3, DMF
5
6
7 major product
Scheme 2.
Me3SiO
O
O
O
Me
Me
Fe(NO3)3, DMF
O
O
+
Me
Me
H
Me
Me
Me
-5 oC cyclohexadiene
(71%)
H
H
H
H
H
O
O
O
O
O
O
8
9
8 : 1
10
O
Me3SiO
O
O
Me
Fe(NO3)3, DMF
O
O
+
0 oC cyclohexadiene
(72%)
Me
Me
Me
Me
Me
Me
Me
Me
Me
11
12
1 : 3.3
13
O
Me3SiO
O
O
Me
Me
Fe(NO3)3, DMF
O
O
+
-5 oC cyclohexadiene
(57%)
Me
Me
14
15
1.3 : 1
16
Scheme 3.
Booker-Milburn method to good effect, starting with si-
lyloxycyclopropanes derived from various substituted
oxa-bridged ketones, such as 3.4 During the course of
this work we have uncovered two novel aspects of the
iron chemistry, which have some significance, and may
have further synthetic utility, and which are described
below.
The reactions were carried out using 1,4-cyclohexadiene
as additive, which is the established method for obtain-
ing clean hydrogen atom quenching of the product radi-
cals.2,3 The formation of a-methyl ketones 9, 12 and 15
in these reactions, as single diastereoisomers, was very
1
clear from the H NMR spectra, which showed a diag-
nostic high-field doublet for the new methyl substituent
in each case.9 The variation in the ratio of ꢀnormalꢁ, ring-
expanded product, to the unexpected product, was
rather intriguing, as the part of the oxabicyclic system
quite remote from the reacting cyclopropane seemed
to be having a pronounced effect.
An important aspect of the iron method is the highly
regiocontrolled nature of the cyclopropane opening,
which inevitably furnishes products arising from the
more substituted of the two possible intermediate radi-
cals.5 This feature ensures that ring-fused silyloxycyclo-
propanes, such as 3, undergo ring-expansion,6 rather
than the alternative mode of reaction that would give
an a-methyl substituted ketone––i.e. as shown in 5 it is
C(1)–C(2) that cleaves, not C(1)–C(3).
Since we expected that the bridging oxygen, and perhaps
the nature of the bridgehead substituents (i.e., methyl
groups in Scheme 3), might also influence the reaction
outcome we tested further substrates, as shown in
Scheme 4.
Only in the biased case of dichlorocyclopropane 6 has
the alternative mode of ring cleavage been seen to pre-
dominate using iron salts, giving mainly 7 (Scheme
2).7,8 Therefore we were very surprised to find that some
of the iron-mediated reactions of silyloxycyclopropanes
related to 3 gave non ring-expanded products, some-
times as the major component, as shown in Scheme 3.
Compound 17 is closely related to 8, but lacks the
bridgehead methyl groups, whereas in 20 the bridging
oxygen is replaced by a methylene. Somewhat surpris-
ingly, we obtained the same distribution of products,
in similar yield, for each of these two compounds. Com-
parison of the result for 8 with that obtained with 17

A. Highton et al. / Tetrahedron Letters 45 (2004) 6679–6683
6681
Me3SiO
X
O
O
Me
Fe(NO3)3, DMF
X
X
+
0 oC cyclohexadiene
H
H
H
O
H
H
H
O
O
O
O
O
17 X = O
18 X = O
1 : 3
19 X = O
83%
20 X = CH2
21 X = CH2 1 : 3
22 X = CH2 88%
Scheme 4.
O
O
O
O
SPh
SPh
Me
SPh
SPh
O
O
O
Me
Me
Me
H
H
H
H
H
H
O
O
O
O
O
O
23 (48%)
+
24 (51%)
25 (40%)
26 (71%)
(+ 22 see text)
9 (26%)
indicates an important effect of the bridgehead substitu-
ents. Presumably the bridgehead methyl groups in 8 in-
hibit radical termination at the adjacent position by a
steric effect, whereas in 17 quenching at that position,
leading to ketone 19, is much easier. The close similarity
of the results in Scheme 4 for 17 and 20 seems to rule out
an influence of the bridging oxygen on the outcome, at
least for reactions involving iron salts.10
cleavage to give the two unexpected products 9 and
23. During further exploration of the reactions of this
compound we found that Fe(NO3)3 reactions under typ-
ical conditions, but with the inclusion of CH2I2, gave
rise to efficient iodine atom incorporation (Scheme 5).
Me3SiO
O
O
O
As illustrated in Scheme 1, PhSSPh can be employed as
an additive in the Fe(NO3)3 reactions, which allows use-
ful functionalisation of the product radicals, leading to
sulfide products. Reactions run in this way, using the si-
lyloxycyclopropanes 8, 11, 17 and 20, gave the products
23–26.11
I
Fe(NO3)3, DMF
0 oC CH2I2
Me
Me
H
Me
Me
H
H
H
O
O
O
O
8
27 (71%)
The formation of phenylthiomethylene derivative 23,
accompanied by small amounts of 9, confirms the unu-
sual regiochemistry seen earlier for reaction of starting
cyclopropane 8. Somewhat surprisingly, the other sys-
tems, which had each provided products from both
modes of cyclopropane cleavage in the cyclohexadiene
reactions, gave only the ring expanded products 24–26
(in the case of 26 ca. 15% of 22 was also observed in the
crude mixture). Also, in the case of 24 and 26 substantial
amounts of endo-sulfide were obtained (in fact the endo
product was predominant for 24), indicating a loss
of facial selectivity for radical quenching in these
systems.
Scheme 5.
As far as we are aware, this type of reaction, leading to
rather versatile iodides, has not been reported previ-
ously. The b-iodoketone 27 was fully characterised and
showed a particularly diagnostic high-field signal in
the 13C NMR (À1.5ppm) corresponding to the CH2I
group.12,13
We also tested this new method in reactions utilising cy-
clopropanes 3 and 11, and isolated the iodoketones 28
and 29 in good yield.
These results point to a finely-balanced situation, where-
by the regiochemical outcome of the iron-mediated reac-
tion depends upon local steric effects, somewhat remote
electronic effects, and also the nature of the radical trap-
ping agent.
I
H
O
O
H
I
O
O
Me
Me
Only in the case of the acetonide-containing substrate 8
had we observed reproducible ꢀabnormalꢁ cyclopropane
29 (58%)
28 (64%)

6682
A. Highton et al. / Tetrahedron Letters 45 (2004) 6679–6683
formed, see: Booker-Milburn, K. I.; Cox, B.; Grady, M.;
I
H
HO
HO
Halley, F.; Marrison, S. Tetrahedron Lett. 2000, 41, 4651.
9. Typical experimental for cyclopropane cleavage: In a
typical procedure 1,4-cyclohexadiene (3equiv) was added
to a solution of Fe(NO3)3Æ9H2O (3equiv) in DMF (dried
and degassed according to the procedure of Booker-
Milburn) and this stirred mixture cooled to 0ꢁC before
addition of the silyloxycyclopropane (1equiv) over 5min.
The solution was stirred for a further 1h at À5ꢁC before
pouring into water, and product extraction using EtOAc.
In some cases product yields and ratios were enhanced by
conducting slow addition of the cyclopropane.
H
H
DBU
O
O
toluene, reflux
SO2Tol
30
Scheme 6.
SO2Tol
H
H
31 (89%)
1
Product ratios were estimated from H NMR spectra of
the crude product mixtures, and pure products were
isolated following flash column chromatography on silica
gel using Et2O–petroleum ether mixtures as eluant.
Ketone 9 was isolated as the less polar component as a
white solid mp 85–86ꢁC; (found C, 64.71; H, 8.50.
C13H20O4 requires C, 64.98; H, 8.39). mmax (CHCl3)/cmÀ1
2936, 1713, 1458, 1375; dH (500MHz, CDCl3) 4.27 (2H, s,
2-H, 6-H), 2.58 (1H, d, J 15, exo 10-H), 2.17 (1H, q, J 7, 8-
H), 2.18 (1H, d, J 15, endo 10-H), 1.52 (3H, s, CH3), 1.40
(3H, s, CH3), 1.31 (3H, s, CH3), 1.30 (3H, s, CH3), 1.20
(3H, d, J 7, CH3); dC (67.8MHz, CDCl3) 211.2 (C), 112.3
(C), 85.8 (CH), 84.7 (CH), 84.2 (C), 82.4 (C), 52.9 (CH),
48.5 (CH2), 26.0 (CH3), 24.9 (CH3), 19.9 (CH3), 16.1
(CH3), 12.7 (CH3); m/z (EI) 240 (M+, 16%), 99 (45), 98
(100). (Found M+ 240.1360. C13H20O4 requires M,
240.1362).
The formation of iodoketones, rather than chloro ana-
logues, available using Fe(NO3)3–NCS,2 may offer dis-
tinct advantages in certain cases. For example, we
found that elimination of HI from complex iodide 30
(prepared in a few steps from 29) to generate exometh-
ylene compound 31 was particularly facile under mild
conditions (Scheme 6).
In conclusion, we have established that the Fe(NO3)3
mediated radical reactions of silyloxycyclopropanes
can occur with either regiochemical mode of cyclopro-
pane fission. The observance of the ꢀabnormalꢁ mode
of reaction, especially for substrate 8, illustrates that
the behaviour of polyoxygenated systems may not al-
ways be predictable. The use of the Fe(NO3)3–CH2I2
combination for radical cyclisation–iodination se-
quences should add further to the utility of the
Booker-Milburn method.
Ring expanded ketone 10 was the polar product, also as a
white solid mp 49–52ꢁC. mmax (CHCl3)/cmÀ1 2921, 2872,
1698, 1456 and 1373; dH (500MHz, CDCl3) 4.65 (1H, d, J
6, CH), 4.58 (1H, d, J 6, CH), 2.76 (1H, d, J 16, exo 8-H),
2.69 (1H, d, J 16, endo 8-H), 2.56 (1H, ddd, J 15, 7, 5, 10-
H), 2.44 (1H, ddd, J 15, 11, 5, 10-H), 1.90 (1H, ddd, J 15,
11, 5, 11-H), 1.80 (1H, ddd, J 15, 7, 5, 11-H), 1.53 (3H, s,
CH3), 1.35 (3H, s, CH3), 1.34 (3H, s, CH3), 1.32 (3H, s,
CH3); dC (125.8MHz, CDCl3) 209.1 (C), 112.3 (C), 87.4
(CH), 86.9 (CH), 83.8 (C), 81.3 (C), 57.0 (CH2), 39.2
(CH2), 35.1 (CH2), 25.9 (CH3), 24.5 (CH3), 23.9 (CH3),
23.0 (CH3); m/z (EI) 240 (M+ 3%), 225 (57), 99 (100).
(Found M+ 240.1361.C13H20O4 requires M, 240.1362).
10. This type of reaction can also be carried out using
manganese salts, see for example Ref. 5b, but using the
hydroxycyclopropane, obtained by treatment of the silyl
derivatives with K2CO3 in methanol. In most cases such
reactions give similar product yields and ratios to the iron-
mediated reactions.
11. A solution of dried ferric nitrate was prepared by stirring a
solution of Fe(NO3)3Æ9H2O (194mg, 0.48mmol) in dry
DMF (6mL) over molecular sieves under an atmosphere
of argon for 2h. This solution was then added over a
period of 1h to a solution of silyloxycyclopropane 8
(50mg, 0.16mmol) and PhSSPh (105mg, 0.48mmol) in
dry degassed DMF (7mL) at 0ꢁC under nitrogen.The
mixture was left to stir for 1.5h and then partitioned
between water (100mL) and ethyl acetate (50mL). The
organic layer was separated and the aqueous was extracted
with further ethyl acetate (2·80mL). The combined
organic extracts were washed with water (3·50mL), dried
over magnesium sulfate, filtered and concentrated under
reduced pressure. The crude material was purified by
column chromatography on silica (eluent petroleum ether/
diethyl ether 4/1) to give phenylsulfanyl ketone 23 as a
white solid (27mg, 48%) and methyl ketone 9 (10mg, 26%)
as a colourless oil.
Acknowledgements
We thank the University of Nottingham for support of
this project.
References and notes
1. (a) Booker-Milburn, K. I. Synlett 1992, 809; (b) Booker-
Milburn, K. I.; Thompson, D. F. Synlett 1993, 592.
2. (a) Booker-Milburn, K. I.; Thompson, D. F. J. Chem.
Soc., Perkin Trans. 1 1995, 2315; (b) Booker-Milburn, K.
I.; Barker, A.; Brailsford, W.; Cox, B.; Mansley, T. E.
Tetrahedron 1998, 64, 15321.
3. For the most recent methodology developments, see: (a)
Booker-Milburn, K. I.; Jones, J. L.; Sibley, G. E. M.; Cox,
R.; Meadows J. Org. Lett. 2003, 5, 1107; For a recent
target application, see: (b) Booker-Milburn, K. I.; Jenkins,
H.; Charmant, J. P. H.; Mohr, P. Org. Lett. 2003, 5, 3309.
4. Blake, A. J.; Highton, A. J.; Majid, T. N.; Simpkins, N. S.
Org. Lett. 1999, 1, 1787.
5. Other closely related methods can lead to the alternative
mode of cleavage, but usually as a minor pathway see: (a)
Rinderhagen, H.; Mattay, J. Chem. Eur. J. 2004, 10, 851;
(b) Iwasawa, N.; Funahashi, M.; Hayakawa, S.; Ikeno, T.;
Narasaka, K. Bull. Chem. Soc. Jpn. 1999, 72, 85.
6. For the origins of this method see: Ito, Y.; Fujii, S.;
Saegusa, T. J. Org. Chem. 1976, 41, 2073.
7. Blanco, L.; Mansouri, A. Tetrahedron Lett. 1988, 29,
3239.
8. Booker-Milburn and co-workers have also observed this
type of cleavage in reactions involving both Fe(NO3)3 and
Cu(OAc)2, but in this case exo-methylene products are
Data for phenylsulfanyl ketone 23, mp 67–69ꢁC; mmax
(CDCl3)/cmÀ1 3982, 2936, 1713, 1382, 1083 and 877; dH
(400MHz; CDCl3) 7.39–7.37 (2H, m, H–Ar), 7.33–7.21

A. Highton et al. / Tetrahedron Letters 45 (2004) 6679–6683
6683
(3H, m, H–Ar), 4.27 (1H, d, J 6, 2-H), 4.24 (1H, d, J 6, 6-H),
3.38 (1H, dd, J 12 and 5, CH2SPh), 3.19 (1H, dd, J 12 and
10, CH2SPh), 2.58 (1H, d, J 15, exo 10-H), 2.41 (1H, dd,
J 10 and 5, 8-H), 2.25 (1H, d, J 15, endo 10-H), 1.51 (3H, s,
CH3), 1.41 (3H, s, CH3), 1.37 (3H, s, CH3), 1.28 (3H, s,
CH3); dC (100MHz; CDCl3) 207.4 (C), 135.1 (C), 130.5
(CH), 129.0 (CH), 126.9 (CH), 112.5 (C), 85.3 (CH), 85.1
(C), 84.6 (CH), 83.4 (C), 58.1 (CH), 49.7 (CH2), 31.6 (CH2),
26.0 (CH3), 24.9 (CH3), 19.8 (CH3) and 16.6 (CH3); m/z (EI)
Found 348.1389 (M+ C19H24O4S requires 348.1395).
and 11, CH2I), 2.56 (1H, d, J 14.5, exo 10-H), 2.48 (1H,
dd, J 11 and 5, 8-H), 2.24 (1H, d, J 14.5, endo 10-H), 1.49
(3H, s, CH3), 1.40 (3H, s, CH3), 1.35 (3H, s, CH3), 1.27
(3H, s, CH3); dC (125MHz; CDCl3) 206.8 (C), 112.7 (C),
85.8 (C), 85.1 (CH), 84.4 (CH), 83.6 (C), 60.6 (CH), 48.9
(CH2), 26.0 (CH3), 25.0 (CH3), 19.8 (CH3), 16.5 (CH3) and
À1.5 (CH2); m/z (CI) Found 367.0413 ((M+1)+.
C13H20O4I requires 367.0406).
13. The isolation of the iodoketone 27 gave us the opportunity
to conduct a free radical reaction using alternative
Bu3SnH conditions, which gave products 9 and 10
in similar yields and ratios to the iron (and manga-
nese) mediated reactions. This outcome lends support
to the proposal that carbon-centred free radical
intermediates are involved in the iron-mediated
reactions.
12. Data for iodoketone 27 (42mg, 71%) isolated as a white
solid; mp 127–128ꢁC; (Found C, 42.63; H, 5.19.
C13H19O4I requires C, 42.64; H, 5.23%); mmax (CHCl3)/
cmÀ1 3002, 2937, 1716, 1254, 1208, 1131 and 1054; dH
(500MHz; CDCl3) 4.29 (1H, d, J 6, 2-H), 4.24 (1H, d, J 6,
6-H), 3.53 (1H, dd, J 11 and 5, CH2I), 3.35 (1H, dd, J 11