A new photochemical route to cyclopropanes

Article abstract of DOI:10.1002/1521-3773(20010316)40:6<1064::AID-ANIE10640>3.0.CO;2-5

Especially highly substituted cyclopropanes can be produced with a new photochemical approach. Starting with aromatic ketones that bear a leaving group adjacent to the carbonyl carbon atom, photolysis leads to the formation of 1,3-diradicals, which efficiently cyclize to cyclopropanes (see scheme; Ms=MeSO₂).

Full text of DOI:10.1002/1521-3773(20010316)40:6<1064::AID-ANIE10640>3.0.CO;2-5

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were particularly interested in the latter case because a-
hydroxy radicals are intermediates in the Norrish ± Yang
reaction. It is noteworthy that the spin density in the formed
enolate radical 3 is shifted to the adjacent atom. The question
is whether the elimination of the acid HX is fast enough to
proceed within the very short lifetime (approximately 10 ns)
of the triplet diradicals produced in the Norrish ± Yang
reaction.
A New Photochemical Route to
Cyclopropanes**
Pablo Wessig* and Olaf Mühling
Cyclopropanes have always fascinated organic chemists.
Due to their considerable ring strain they are very versatile
synthetic building blocks and many interesting applications
are published every year. Furthermore, the cyclopropane ring
is found in many natural products[1] and has been used to
restrict the conformational flexibility of molecules (for
example, peptides[2]). There are many valuable methods for
the preparation of cyclopropanes,[3] but nevertheless, there is
still a great need for new methods. Herein, we wish to report
on a new photochemical route to cyclopropanes.
We first optimized the reaction conditions with the model
reactant 2-X-butyrophenone 4 where X represents a leaving
group (Scheme 2). We found that the most suitable solvent is
The Norrish ± Yang reaction, one of the best investigated
photochemical reactions,[4] was used to synthesize many
homo- and heterocyclic molecules. Among these cyclizations
the formation of cyclopropanes is conspicuous in that it was
very rarely observed. Obviously, the considerable ring strain
of the five-membered transition state accounts for this. In
almost all cases of cyclopropane synthesis using the Norrish ±
Yang reaction an initial photoelectron transfer process (PET)
has been proven or seems very likely.[5]
As expected, the intramolecular hydrogen abstraction in
the course of the Norrish ± Yang reaction takes place prefer-
entially at the g-position to form 1,4-diradicals, unless this
position is blocked. (For exceptions, see ref. [6].) Based on
this fact we developed a method that makes use of a well-
known property of monoradicals, namely that they are
excellent neighbors for the displacement of leaving groups.[7]
Particularly when the radical center is stabilized by an oxygen
atom elimination occurs very fast. Two cases must be
distinguished that differ crucially from each other in their
reaction mechanisms. While a-alkoxy radicals 1 are cleaved
heterolytically to give free ions, a-hydroxy radicals 2 undergo
a concerted elimination of the acid HX (Scheme 1).[8] We
Scheme 2. Photochemical behavior of 2-substituted butyrophenones 4.
ISC ˆ intersystem crossing, Ms ˆ mesyl ˆ methanesulfonyl.
dichloromethane because in some other solvents, such as
diethyl ether, the Norrish Type II cleavage of the triplet 1,4-
diradicals 5 predominates. The leaving group X must be the
counterion of a strong acid. Amongst carboxylates only
trifluoroacetate can be used. Sulfonates are preferable, partly
due to their straightforward introduction, although in one
case (12, see Scheme 3) we used the nitrooxy group. Naturally,
the elimination 5 !6 produces a strong sulfonic acid and we
found that this acid is a serious problem in our reaction. While
benzoylcyclopropane 7 by itself is stable under the irradiation
conditions (lirr ꢀ 300 nm), the cyclopropane ring is rapidly
opened if the irradiation is performed in the presence of the
OR3
OR3
-
- X
R2
R2
R1
R1
X
1
H
X
O
OH
O
-HX
R2
R2
R1
R1
R1
R2
X
3
2
Scheme 1. Cleavage mechanisms for a-alkoxy radicals 1 and a-hydroxy
radicals 2.
[*] Priv.-Doz. Dr. P. Wessig, O. Mühling
Institut für Chemie
Humboldt-Universität zu Berlin
Hessische Strasse 1 ± 2, 10115 Berlin (Germany)
Fax : (‡49)30-2093-6940
E-mail: pabloˆwessig@chemie.hu-berlin.de
[**] We gratefully thank the Deutsche Forschungsgemeinschaft
for financial support (grant no.: We1850/3-1).
Scheme 3. Photochemical behavior of di- and trisubstituted butyrophe-
nones 8.
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Angew. Chem. Int. Ed. 2001, 40, No. 6

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acid. Therefore, the addition of an acid scavenger, which must
be compatible with the photochemistry, is necessary. Amongst
several tested scavengers N-methylimidazole proved to be
most suitable. After these optimizations we obtained benz-
with commercially available hydroxymethylcycloalkanes
14a ± c we prepared the benzoyl[n.1.0]alkanes 15a ± c in few
steps and with good to excellent yields (Scheme 4). Further-
more, the cyclization proceeds in a fully diastereoselective
manner to the exo compounds, as proven by NOE NMR
experiments and in the case 15b also by a crystal structure
analysis.
oylcyclopropane
(Scheme 2).
7 with a remarkable yield of 87%
We introduced various substituents to investigate their
influence on the chemo- and stereoselectivity of the cyclo-
propane formation. The reaction outcome substantially
depends on the position of the substituents. Whereas 2-mes-
yloxyvalerophenone 8a gave a mixture of the desired cyclo-
propane 9a (63%) and the unsaturated ketone 11a (16%, a
product of the well-known ring opening of cis-1-benzoyl-2-
alkylcyclopropanes;[9] Scheme 3, Table 1), the branched iso-
valero-phenone 8b provided exclusively the trans-1-benzoyl-
2-methylcyclopropane 9b.
O
Ph
O
1)–3)
4)
HO
n
n
n
Ph
OMs
15a 61%
15b 80%
15c 86%
14a n=1
14b n=2
14c n=3
Scheme 4. Preparation of [n,1,0]bicycloalkanes 15. 1) pyridinium chloro-
chromate; 2) PhC(OSiMe3)(CN)Li; 3) Ms2O/pyridine, 4) CH2Cl2, hn (l ꢀ
300 nm), N-methylimidazole (2 equiv).
Table 1. Photochemical synthesis of cyclopropanes 9 and 10.
After exploring the synthetic scope of this very efficient
method, whose most important results are described herein,
for the diastereoselective preparation of highly substituted
cyclopropanes, we hope to soon report on applications for the
synthesis of more complex target molecules.
Reactant
R1
R2
R3
Yields [%]
9
10
11
8a
8b
8c
Me
H
Ph
H
H
OBn
H
Me
H
Ph
COOMe
H
Me
Me
Ph
Ph
COOMe
OBn
63
90
47
26
59
46
0
0
31
18
0
16
0
±
±
±
8d
8e
Received: November 6, 2000 [Z16044]
8 f[a]
0
±
[a] Bn ˆ benzyl.
[1] S. Beckmann, H. Geiger, Methoden Org. Chem. (Houben-Weyl) 4th
ed. 1952 ± , Vol. IV/4, 1971, p. 445.
[2] S. Abele, P. Seiler, D. Seebach, Helv. Chim. Acta 1999, 82, 1559.
[3] Methods Org. Chem. (Houben-Weyl), Vol. E17a,b, 1997.
[4] a) P. J. Wagner, Acc. Chem. Res. 1971, 4, 168; b) P. J. Wagner, Top.
Curr. Chem. 1976, 66, 1; c) P. J. Wagner, Acc. Chem. Res. 1989, 22, 83;
d) P. J. Wagner, B. Park in Organic Photochemistry (Ed.: A. Padwa),
Marcel Dekker, New York, 1991, p. 227; e) P. J. Wagner in CRC
Handbook of Organic Photochemistry and Photobiology (Eds.: W. M.
Horspool, P.-S. Song), CRC Press, Boca Raton, 1995, p. 449.
[5] A previously reported formation of cyclopropanes by irradiation of g-
ketoamides (H.-G. Henning, R. Berlinghoff, A. Mahlow, H. Köppel,
K.-D. Schleinitz, J. Prakt. Chem. 1981, 323, 914) seems to be based on a
mistake in the interpretation of the spectral data (compare with U.
Lindemann, M. Neuburger, M. Neuburger-Zehnder, D. Wulff-Molder,
P. Wessig, J. Chem. Soc. Perkin Trans. 2 1999, 2029).
The photochemical behavior of b- and g-phenyl-substituted
butyrophenones 8c, d was surprising at first. No matter at
which position the phenyl group was placed we always
obtained a 60:40 mixture of cis- and trans-1-benzoyl-2-
phenylcyclopropane isomers 9c, 10c, despite the fact that
the yields differed significantly. The same product ratio was
obtained by irradiation of each of the pure isomers 9c and 10c
respectively. Obviously, aryl-substituted benzoylcyclopro-
panes undergo photochemical cis ± trans isomerization, prob-
ably through an intramolecular charge transfer.[10]
The stereochemical course of the cyclization of alkyl- and
aryl-substituted reactants should mainly be controlled by
steric interactions. In contrast to this, 8e, which bears an ester
group in b-position, gave only the trans-configured ketoester
9e in good yield. A photochemical behavior similar to that of
the ester 8e is shown by the ether 8 f. Upon irradiation, only
the trans-cyclopropane 9 f is formed. The stereoselective ring
closure of 8e, f clearly indicates the importance of dipole ±
dipole interactions for the stereocontrol.
[6] U. Lindemann, D. Wulff-Molder, P. Wessig, J. Photochem. Photobiol.
A 1998, 119, 73.
[7] a) G. Koltzenburg, G. Behrens, D. Schulte-Frohlinde, J. Am. Chem.
Soc. 1982, 104, 7311; b) G. Koltzenburg, D. Schulte-Frohlinde, Z.
Naturforsch. C 1982, 37, 1205.
[8] H. Zipse, J. Am. Chem. Soc. 1995, 117, 11798.
[9] a) L. J. Johnston, J. C. Scaiano, J. W. Sheppard, J. P. Bays, Chem. Phys.
Lett. 1986, 124, 193; b) R. A. Caldwell, S. C. Gupta, J. Am. Chem. Soc.
1989, 111, 740.
[10] The photochemical isomerization of 12 has already been observed but
no mechanistic proposal was given: G. W. Griffin, J. Covell, R. C.
Petterson, R. M. Dodson, G. Klose, J. Am. Chem. Soc. 1965, 87, 1410.
[11] a) J.Adams, L. Hoffmann, B. M. Trost, J. Org. Chem. 1970, 35, 1600;
b) B. Alcaide, L. Casarrubios, G. Dominguez, A. Retamosa, M. Sierra,
Tetrahedron 1996, 52, 13215.
The photochemical behavior of the 2,3,4-trisubstituted
butyrophenone 12 (Scheme 3) illustrates the efficiency of
our method. Despite the moderate yield, we obtained only
one diastereomer of the trisubstituted cyclopropane 13 while
the known thermal synthesis provided either a 1:1 mixture of
two diastereomers[11a] or a mixture of 13 and an isomeric furan
derivative.[11b] It is noteworthy that the expected cis ± trans
isomerization was not observed.
Our method is not only suited for the preparation of
monocyclic cyclopropanes. Thus, we also developed a straight-
forward route to highly strained bicyclic molecules. Starting
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