Facile ring opening of tertiary aminocyclopropanes by photooxidation

Full text of DOI:10.1021/ja972115h

J. Am. Chem. Soc. 1997, 119, 10241-10242
10241
tertiary amines have been widely utilized as efficient electron
donors in electron transfer processes with excited states of
various organic substrates. The photoinduced one-electron
oxidation thus allows a convenient method for generating an
amine radical cation. In a typical experiment, the 1,4-di-
cyanobenzene (DCB) photosensitized oxidation of the cyclo-
propylamine 33 was performed in a deaerated solution in MeCN
or 10:1 MeCN/MeOH containing K2CO3 by irradiation (254 or
300 nm), and ketone 4 was isolated in 85% yield as the sole
product after aqueous workup (eq 2).13,14 Similarly, the
diastereomeric cyclopropylamine 5 also afforded the ketone 4
under identical conditions, but the reaction rate was considerably
slower. As can be seen from additional examples in eq 3, ring
Facile Ring Opening of Tertiary
Aminocyclopropanes by Photooxidation
Jinhwa Lee, Jong Sun U, Silas C. Blackstock, and
Jin Kun Cha*
Department of Chemistry, UniVersity of Alabama
Tuscaloosa, Alabama 35487
ReceiVed June 26, 1997
Tertiary aminocyclopropanes, which were prepared in good
yield by the Simmons-Smith cyclopropanation of enamines,
have been shown to resist ring cleavage by acids, bases, or
electrophiles. Accordingly, ring opening was reported to require
high-temperature (150-170 °C) thermolysis.1 A new, efficient
synthesis of tertiary aminocyclopropanes,2,3 as well as other
electron-donor substituted cyclopropanes,4 prompted us to search
for a facile ring cleavage under neutral conditions. Herein we
report a convenient solution by employing the photosenzitized
oxidative ring opening of tertiary aminocyclopropanes.
Our choice of a cyclopropylamine cation radical (1a)-based
approach was initially made by analogy to the well-known, rapid
rearrangement of cyclopropylcarbinyl radical 1b to homoallyl
radical 2b (eq 1).5 An isoelectronic cyclopropoxy radical 1c,
which is conveniently generated by one-electron oxidation (with
oxidants such as Fe+3, Mn+3, or Cu+2) of cyclopropanol, is also
known to readily afford the ring-opened, carbon-centered radical
2c.6 In addition, related ring cleavage of cyclopropyl sulfide
cation radical 1d has been reported.7 Furthermore, analogous
ring opening of the cyclopropylamine radical cation 1a has been
implicated in the inactivation by cyclopropylamines of cyto-
chrome P-450 and monoamine oxidase8 and was subsequently
generated by radiolysis of the parent aminocyclopropane.9,10
Despite the well-established synthetic potential of aminium
radicals,11 little work appeared on ring cleavage initiated by
nonenzymic oxidation at nitrogen of aminocyclopropanes.12
As a result of their low ionization and oxidation potentials,
opening of the tertiary aminocyclopropanes initiated by the
photosensitized oxidation appears to be general. However,
identical application to dialkylamino[4.1.0]bicycloheptanes was
unsuccessful. For example, most of 12 was recovered un-
changed under the same conditions. Although the addition of
Cu(OAc)2 provides a ring-opened product, 2-cycloheptenone
(13), at present this reaction suffers from low conversion [53%
yield based on the recovered (68%) starting material], and an
improvement in yield requires additional studies.
(1) Kuehne, M. E.; King, J. C. J. Org. Chem. 1973, 38, 304.
(2) Chaplinski, V.; de Meijere, A. Angew. Chem., Int. Ed. Engl. 1996,
35, 413.
(3) Lee, J.; Cha, J. K. J. Org. Chem. 1997, 62, 1584.
(4) (a) Lee, J.; Kang, C. H.; Kim, H.; Cha, J. K. J. Am. Chem. Soc.
1996, 118, 291. (b) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996,
118, 4198. (c) Lee, J.; Kim, Y. G.; Bae, J.; Cha, J. K. J. Org. Chem. 1996,
61, 4878 and references cited therein. See also: (d) Lee, J.; Kim, H.; Cha,
J. K. J. Am. Chem. Soc. 1995, 117, 9919. (e) Lee, J.; Cha, J. K. Tetrahedron
Lett. 1996, 37, 3663. (f) U, J. S.; Lee, J.; Cha, J. K. Tetrahedron Lett.
1997, 38, 5233.
Mechanistically, the overall transformation can best be
rationalized by initial formation of the tertiary aminium radical
(11) (a) Nelsen, S. F. In Free Radicals; Kochi, J. K., Ed.; Wiley: New
York, 1973; Vol. 2, Chapter 21. (b) Chow, Y. L.; Danen, W. C.; Nelsen,
S. F.; Rosenblatt, D. H. Chem. ReV. 1978, 78, 243. (c) Stella, L. Angew.
Chem., Int. Ed. Engl. 1983, 22, 337. (d) Newcomb, M.; Deeb, T. M. J.
Am. Chem. Soc. 1987, 109, 3163. (e) Zhang, X.; Yeh, S.-R.; Hong, S.;
Freccero, M.; Albini, A.; Falvey, D. E.; Mariano, P. S. J. Am. Chem. Soc.
1994, 116, 4211 and references cited therein.
(12) To the best of our knowledge, to date only a single report has
appeared on oxidation of cyclopropylamines (CuCl2-catalyzed, with O2) in
modest yields: Itoh, T.; Kaneda, K.; Teranishi, S. Tetrahedron Lett. 1975,
2801.
(5) (a) Maillard, B.; Forrest, D.; Ingold, K. U. J. Am. Chem. Soc. 1976,
98, 7024. (b) Kochi, J. K.; Krusic, P. J.; Eaton, D. R. J. Am. Chem. Soc.
1969, 91, 1877.
(6) (a) For a general review of cyclopropanol, see: Gibson, D. H.; DePuy,
C. H. Chem. ReV. 1974, 74, 605. See also: (b) Schaafsma, S. E.; Molenaar,
E. J. F.; Steinberg, H.; de Boer, Th. J. Recl. TraV. Chim. 1967, 86, 1301.
(c) Ito, Y.; Fujii, S.; Saegusa, T. J. Org. Chem. 1976, 41, 2073.
(7) Takemoto, Y.; Ohra, T.; Koike, H.; Furuse, S.; Iwata, C.; Ohishi, H.
J. Org. Chem. 1994, 59, 4727.
(8) See, inter alia: (a) Bondon, A.; Macdonald, T. L.; Harris, T. M.;
Guengerich, F. P. J. Biol. Chem. 1989, 264, 1988. (b) Hanzlik, R. P.;
Tullman, R. H. J. Am. Chem. Soc. 1982, 104, 2048. (c) Silverman, R. B. J.
Biol. Chem. 1983, 258, 14766. (d) Pirrung, M. C. J. Am. Chem. Soc. 1983,
105, 7207.
(9) Qin, X.-Z.; Williams, F. J. Am. Chem. Soc. 1987, 109, 595.
(10) Cyclopropylaminyl radical is also shown to undergo rapid ring
opening: Maeda, Y.; Ingold, K. U. J. Am. Chem.Soc. 1980, 102, 328. See
also: Sutcliffe, R.; Ingold, K. U. J. Am. Chem.Soc. 1982, 104, 6071.
(13) Aryl-substituted and strained cyclopropanes have been shown to
undergo similar photosensitized ring opening reactions via the corresponding
cyclopropane radical cations: (a) Rao, V. R.; Hixson, S. S. J. Am. Chem.
Soc. 1979, 101, 6458. (b) Dinnocenzo, J. P.; Simpson, T. R.; Zuilhof, H.;
Todd, W. P.; Heinrich, T. J. Am. Chem. Soc. 1997, 119, 987 and references
cited therein. (c) Gassman, P. G.; Olson, K. D.; Walter, L.; Yamaguchi, R.
J. Am. Chem. Soc. 1981, 103, 4977.
(14) While the presence of K2CO3 was unnecessary, it was added to
scavenge any adventitious acidic impurities.
S0002-7863(97)02115-X CCC: $14.00 © 1997 American Chemical Society

10242 J. Am. Chem. Soc., Vol. 119, No. 42, 1997
Communications to the Editor
(3•+ or 5•+) and DCB•- by photoinduced electron transfer from
3 or 5 to DCB (eq 4). The amine radical cation undergoes either
NMR spectrum of the products contains triplets at δ 28.6 (J )
2
19.9 Hz) and 20.0 ppm (J ) 19.8 Hz); the H NMR spectrum
shows two peaks at 1.72 and 1.66 ppm [reference CDCl3 (7.26
ppm)]; satisfactory nominal [m/z 284 for C16H30DO2Si (M+ -
i-Pr)] and high-resolution mass spectra (calcd for C16H30DO2-
Si 284.2156, found 284.2135) were also obtained. Formation
of these two products can easily be explained by initial
production of 17, which undergoes the 1,5-hydrogen transfer
to afford 18.15,16 Subsequent 1,5-deuterium shift would take
place readily in these radical intermediates due to the greater
stability of the resulting R-iminium radicals 19 and 20. Finally,
reduction by DCB•- (see also 15 f 16) accounts for another
experimental finding that the sensitizer operates catalytically
and can be recovered in excellent yield.
With regard to the reaction of the bicyclic cyclopropane 12,
it would be more susceptible than monocyclic compounds (e.g.,
3, 5, 6, 8, and 10) to ring opening, since this process should be
facilitated by relief of the additional ring strain. The surprising
lack of the ring-opened product can best be attributed to fast
re-closure (see, for example, 14 f 3•+ or 5•+), where the 1,5-
hydrogen transfer is inoperative, rather than potential poor
overlap between the amine radical cation and the C-C bond
of the cyclopropane ring. Similarly, a low level of conversion
in the presence of Cu(OAc)2 is likely due to inefficient trapping
of the â-iminium carbon radical by Cu(II), compared to fast
ring closure.17 The reversible nature of 3•+ or 5•+ a 14 is
confirmed by the oxidation experiment of 10, where isomer-
ization took place concomitantly.
In summary, cyclopropylamine cation radicals, which are
readily prepared by photooxidation of tertiary aminocyclopro-
panes, undergo facile ring opening, followed by 1,5-hydrogen
shift(s), to afford the ring-opened ketones after hydrolysis. This
overall transformation allows utilization of aminocyclopropanes
as synthetic equivalents of homologous enamines. Moreover,
the present work might suggest a significant difference in
inhibition of cytochrome P-450 and monoamine oxidase by
primary and tertiary aminocyclopropanes, because internal
hydrogen transfer would accompany ring opening of the radical
cations derived from the latter compounds, but not from the
former. Search for a more efficient method for opening tertiary
amino[n.1.0]bicycloalkanes is currently under way,17b along with
applications to natural product synthesis.
decay by back electron transfer or ring opening to generate the
â-iminium carbon radical 14. Apparently, ring opening of the
cyclopropane in 3•+ or 5•+ takes place faster than R-CH
deprotonation, a well-documented alternate reaction pathway
for tertiary aminium radicals.11 Subsequent hydrogen atom
abstraction, followed by aqueous workup, would furnish the
observed ring-opened ketone 4. To probe the source of the
H-atom, experiments with 6 were undertaken in the presence
of deuterated solvent(s), i.e., CD3OD and/or CD3CN: no
deuterium incorporation was found in the product 7. This result
indicated that an intramolecular hydrogen transfer occurred to
produce a new iminium carbon radical, such as 15, which would
readily undergo reduction by DCB•- to afford the dipole 16
and DCB. Direct evidence for a 1,5-hydrogen transfer was
obtained from the isotopically labeled 6 (6-d10) (eq 5). Thus,
Acknowledgment. This work is dedicated to Professor Frederick
Greene on the occasion of his 70th birthday. We are grateful to the
National Institutes of Health (GM35956) for generous financial support
and an NIH Research Career Development Award (GM00575 to
J.K.C.). We thank Professor Drury S. Caine III for allowing us to use
the photolysis apparatus.
Supporting Information Available: A representative photoinduced
ring-opening procedure and characterization/spectral data (20 pages).
See any current masthead page for ordering and Internet access
instructions.
JA972115H
(15) Weaker bond strength of the C-H bond R to the iminium function
notwithstanding, 17 f 18 is thought to occur faster than 17 f 19 due to
a large primary isotope (kH/kD) effect.
(16) For recent examples of intramolecular hydrogen atom transfer, see
inter alia: (a) Beckwith, A. L. J.; Ingold, K. U. In Rearrangements in the
Ground and Excited States; de Mayo, P., Ed.; Academic: New York, 1980;
Vol. 1, p 161. (b) Baldwin, J. E.; Adlington, R. M.; Robertson, J.
Tetrahedron 1989, 45, 909. (c) Snieckus, V.; Cuevas, J.-C.; Sloan, C. P.;
Liu, H.; Curran, D. P. J. Am. Chem. Soc. 1990, 112, 896.
(17) (a) Attempts to trap the â-iminium carbon radical by an external
H-atom donor or a halogen source have been uniformly unsuccessful. (b)
Subsequently we discovered that the ring-opened, â-iminium carbon radical
can be trapped effectively by a tethered olefin by means of 5-exo cyclization,
affording an efficient bicyclic annulation: Lee, J.; Cha, J. K. Unpublished
results.
photolysis under the identical conditions resulted in a ∼1.1:1
mixture of 21 and 22, monodeuterated products of 7: the 13C