Highly enantiospecific oxyfunctionalization of nonactivated hydrocarbon sites by perfluoro-cis-2-n-butyl-3-n-propyloxaziridine

Article abstract of DOI:10.1021/ol990594e

(equation presented) Nonactivated hydrocarbon sites of enantiopure compounds are oxyfunclionalized enantiospecifically by perfluoro-cis-2-n-butyl-3-n-propyloxaziridine under remarkably mild reaction conditions. The reaction occurs with retention of configuration at the oxidized stereogenic center, and the enantiospecificity is highly independent from both the carbon framework of the substrate and the presence of functional groups.

Full text of DOI:10.1021/ol990594e

ORGANIC
LETTERS
1999
Vol. 1, No. 2
281-284
Highly Enantiospecific
Oxyfunctionalization of Nonactivated
Hydrocarbon Sites by
Perfluoro-cis-2-n-butyl-3-n-propyloxaziridine
Alberto Arnone,† Stefania Foletto,† Pierangelo Metrangolo,†
,†
Massimo Pregnolato,‡ and Giuseppe Resnati*
Department Chemistry, Polytechnic, 7, Via Mancinelli, I-20131 Milano, Italy, and
Department Pharmaceutical Chemistry, UniVersity, 12, Via Taramelli,
I-27100 PaVia, Italy
resnati@dept.chem.polimi.it
Received April 15, 1999
ABSTRACT
Nonactivated hydrocarbon sites of enantiopure compounds are oxyfunctionalized enantiospecifically by perfluoro-cis-2-n-butyl-3-n-
propyloxaziridine under remarkably mild reaction conditions. The reaction occurs with retention of configuration at the oxidized stereogenic
center, and the enantiospecificity is highly independent from both the carbon framework of the substrate and the presence of functional
groups.
Oxyfunctionalized molecules are principal building blocks
in organic synthesis.1 The most straightforward approach to
these compounds is the direct hydroxylation of corresponding
hydrocarbons.
However, saturated hydrocarbons possess neither an
unbounded electron pair or low-lying empty orbitals2 and
as a consequence the selective oxyfunctionalization of
nonactivated C-H bonds under homogeneous and mild
conditions is recognized as an important and challenging
objective.3
A survey of the literature revealed that different approaches
have been employed spanning from the catalytic methods
(microorganisms,4 enzymes,5 and transition metals6) to the
stoichiometric reagents (ozone,7 fluorine,8 peroxides and
peroxy acids9). However, to the best of our knowledge only
very limited examples of stereospecific oxyfunctionalizations
at nonactivated hydrocarbon sites have been described.
Efficient regio- and diastereoselective oxidations of hydro-
carbons have been achieved with dimethyldioxirane10 and
its methyltrifluoromethyl analogue while a single example
(1) Chirality in Industry/II; Collins, A. N., Crosby, J., Sheldrake, G. N.,
Eds.; Wiley: New York, 1997. The Logic of Chemical Synthesis; Corey,
E. J., Cheng, X.-M., Eds.; Wiley: New York, 1989. Heathcock, C. H. In
Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: Orlando, 1984.
(2) Elementary Quantum Chemistry/II; Pilar, F. L., Ed.; McGraw-Hill
Publishing Company: Singapore, 1990.
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Wiley: New York, 1989. Metal-Catalyzed Oxidations of Organic Com-
pounds; Sheldon, R. A., Kochi, J. K., Eds.; Academic Press: New York,
1981. Barton, D. H. R.; Doller, D. Acc. Chem. Res. 1992, 25, 504. Olah,
G. A.; Parker, D. G.; Yoneda, N. Angew. Chem., Int. Ed. Engl. 1978, 17,
909.
(4) Davis, C. R.; Johnson, R. A.; Cialdella, J. I.; Liggett, W. F.; Mizsak,
S. A.; Marshall, V. P. J. Org. Chem. 1997, 62, 2244. Davis, C. R.; Johnson,
R. A.; Cialdella, J. I.; Liggett, W. F.; Mizsak, S. A.; Han, F.; Marshall, V.
P. J. Org. Chem. 1997, 62, 2252. Fantin, G.; Ferrarini, S.; Medicin, A.;
Pedrini, P.; Poli, S. Tetrahedron 1998, 54, 1937. Nozaki, Y. Agric. Biol.
Chem. 1961, 25, 884. Holland, H. L.; Brown, F. M.; Chenchaiah, P. C.;
Chernishenko, M. J.; Khan, S. H.; Rao, J. A. Can. J. Chem. 1989, 67, 268.
(5) Cytochrome P-450. Structure, Mechanism, and Biochemistry; de
Montellano O., Ed.; Plenum: New York, 1986. Van Deurzen, M. P. J.;
van Rantwijk, F.; Sheldon, R. A. Tetrahedron 1997, 53, 13183. Organic
Synthesis with OxidatiVe Enzymes; Holland H. L., Ed.; VCH: New York,
1991.
10.1021/ol990594e CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/16/1999

of oxidation at purely aliphatic sites with 70-85% retention
of configuration has been reported by action of chromic
acid.11
The enantiospecificity of the reaction changed from high
to moderate on prolonging the reaction time. Assuming that
this decrease in the enantiospecificity was due to in situ
racemization of the formed alcohol 3a under catalysis by
traces of hydrofluoric acid (generated by the hydrolytic
decomposition of azaalkene 4 or present in oxaziridine 1),
we performed the oxyfunctionalization reaction in the
presence of metal fluorides which are known to work as
effective scavengers of HF.18 Indeed, the decrease of optical
purity at long reaction times was definitively retarded and
potassium fluoride was slightly more effective than cesium
fluoride.
On treatment of the two citronellyl derivatives 2b,c19 with
oxaziridine 1, almost complete retention of configuration20
has been observed, thus confirming the enantiospecific
character of the hydroxylation reaction performed by the
oxaziridine. Oxyfunctionalization reactions in general21 and
those performed by oxaziridines too13 are retarded by the
presence of electron-withdrawing functional groups near the
reaction center. This is consistent with the fact that oxidation
reactions are electrophilic in nature and the presence of
functionalities decreases the electron density at the reaction
Perfluoro-cis-2,3-dialkyloxaziridines are powerful yet se-
lective oxidizing reagents12 and have already proven their
efficiency also in the regioselectiVe, site-selectiVe, and
diastereoselectiVe hydroxylation of Various hydrocarbon
substrates.13 Herein we describe the effectiveness of per-
fluoro-cis-2-n-butyl-3-n-propyloxaziridine (1) in the enan-
tiospecific oxyfunctionalization of nonactiVated hydrocarbons
under remarkably mild reaction conditions.
Treatment of (R)-2,6-dimethyloctane (2a) with oxaziridine
1 at room temperature cleanly furnished 3-octanol 3a having
the (S) absolute configuration (Table 1).14,15 The reaction did
Table 1. Enantiospecific Oxyfunctionalization of Citronellyl
Derivatives 2a-c
(9) Deno, N. C.; Messer, L. A. J. Chem. Soc., Chem. Commun. 1976,
1051. Muller, W.; Schneider, H.-J. Angew. Chem., Int. Ed. Engl. 1979, 18,
407. Barton, D. H. R.; Chabot, B. M. Tetrahedron 1997, 53, 511.
(10) Bargues, V.; Blay, G.; Cardona, L.; Garcia, B.; Pedro, J. R.
Tetrahedron 1998, 54, 1845. Bernini, R.; Mincione, E.; Sanetti, A.
Tetrahedron Lett. 1997, 38, 4651. Cerre`, C.; Hofmann, A. F.; Schteingart,
C. D. Tetrahedron 1997, 53, 435. Bovicelli, P.; Lupattelli, P.; Mincione,
E. J. Org. Chem. 1992, 57, 5052. Bovicelli, P.; Gambacorta, P.; Lupattelli,
P. Tetrahedron Lett. 1992, 48, 7411. Asensio, G.; Mello, R.; Gonzalez-
Nunez, M. E.; Boix, C.; Royo, J. Tetrahedron Lett. 1997, 38, 2373. Brown,
D. S.; Marples, B. A.; Muxworthy, J. P.; Baggaley, K. H. J. Chem. Res.,
Synop. 1992, 28. Marples, B. A.; Muxworthy, J. P.; Baggaley, K. H.
Tetrahedron Lett. 1991, 32, 533.
(11) Wiberg, K. B.; Foster, G. J. Am. Chem. Soc. 1961, 83, 423.
(12) Petrov, V. A.; Resnati, G. Chem. ReV. 1996, 96, 1809. Bernardi,
R.; Novo, B.; Resnati, G. J. Chem. Soc., Perkin Trans. 1 1996, 2517. Farina,
A.; Meille, S. V.; Resnati, G. J. Fluorine Chem. 1996, 80, 47. Arnone, A.;
DesMarteau, D. D.; Novo, B.; Petrov, V. A.; Pregnolato, M.; Resnati, G.
J. Org. Chem. 1996, 61, 8805. Sorochinsky, A. A.; Petrenko, A. E.; Kukhar,
V. P.; Soloshonok, V. A.; Resnati, G. Tetrahedron 1997, 53, 5995. Arnone,
A.; Novo, B.; Pregnolato, M.; Resnati, G.; Terreni, M. J. Org. Chem. 1997,
62, 6401. Arnone, A.; Metrangolo, P.; Novo, B.; Resnati, G. Tetrahedron
1998, 54, 7831. Resnati, G.; Temperini, A.; Testaferri, L.; Tiecco, M.;
Tingoli, M. Carbohydr. Lett. 1998, 3, 39.
% ee
reactn
time (h) added salta
configuration
retention %
substr
X
Y
2
3
(R)-2a
(R)-2a
(R)-2a
(R)-2a
(R)-2a
(R)-2a
H
H
1
9
1
9
9
9
81 78
81 48
96
59
97
96
89
88
98
97
H
H
H
H
H
H
H
H
H
H
KF (1 equiv) 81 79
KF (1 equiv) 81 78
CsF (1 equiv) 81 72
CsF (2 equiv) 81 71
99 97
(S)-2b Cl Br
(S)-2c OH Br
30
21
99 96
a Equivalents of added salt with respect to 1 equiv of substrate 2.
(13) DesMarteau, D. D.; Donadelli, A.; Montanari, V.; Petrov, V.;
Resnati, G. J. Am. Chem. Soc. 1993, 115, 4897. Arnone, A.; Cavicchioli,
M.; Montanari, V.; Resnati, G. J. Org. Chem. 1994, 59, 5511. Arnone, A.;
Bernardi, R.; Cavicchioli, M.; Resnati, G. J. Org. Chem. 1995, 60, 2314.
(14) All the reactions here described have been performed on both
racemic and nonracemic substrates 2, 5, and 7. The optical purity of any
substrate and product (but 2a) was established unequivocally through GLC
analyses on chiral columns (see Supporting Information), and the stereo-
specificity of the process was thus established. The optical purity of 2a
could not be established by chiral GLC and was determined through the
optical purity of (R)-2,6-dimethyl-2-octanol (3d, ref 15) whose signals in
the 1H NMR spectrum showed a clear splitting in the presence of Eu(hfc)3
(see Supporting Information).
(15) Oxyfunctionalization by oxaziridine 1 is known to occur selectively
at tertiary sites (ref 13). Consistent with this regioselectivity (R)-2a was
attacked by the oxaziridine 1 at both C-6 and C-2 to give (S)-3,7-dimethyl-
3-octanol (3a) and (R)-2,6-dimethyl-2-octanol (3d), respectively, in an
approximate 1:1 ratio.
(16) Substrates 2, 5, and 7 and corresponding oxyfunctionalized products
3, 6, and 8 which have the same geometry at the stereogenic center are
assigned to the opposite absolute configuration due to the CIP rules.
(17) Schneider, H. J.; Muller, W. J. Org. Chem. 1985, 50, 4609. Kirmse,
W.; Rauleder, G.; Ratajczak, H.-J. J. Am. Chem. Soc. 1975, 97, 4142.
(18) This hypothesis was also supported by control experiments where
HF was bubbled in the solution of 3a prior to the addition of 1. The formed
alcohol 3a was nearly racemic.
occur with retention of configuration16 as demonstrated by
chemical correlation with 3-octanol 3a obtained from the
oxidation of (R)-2a with peracids which are known to work
with preferential retention of configuration.17
(6) Crabtree, R. H. Chem. ReV. 1985, 85, 245. Launay, F.; Roucoux, A.;
Patin, H. Tetrahedron Lett. 1998, 39, 1353. Marko′, I. E.; Giles, P. R.;
Tsukazaki, M.; Chelle´-Regnaut, I.; Urch, C. J.; Brown, S. M. J. Am. Chem.
Soc. 1997, 119, 12661. Tenaglia, A.; Terranova, E.; Waegell, B. J. Org.
Chem. 1992, 57, 5523. Newcomb, M.; Simakov, P. A. Tetrahedron Lett.
1998, 39, 965. Barton, D. H. R. Synlett. 1997, 229. Schroder, D.; Schwarz,
H. J. Am. Chem. Soc. 1993, 115, 8818. Fish, R. H.; Fong, R. H.; Vincent,
J. B.; Christou, G. J. Chem. Soc., Chem. Commun. 1988, 1504. Mimoun,
H.; Saussine, L.; Daire, E.; Postel, M.; Fischer, J.; Weiss, Raymond J. Am.
Chem. Soc. 1983, 105, 3101. Smegal, J. A.; Hill, C. L. J. Am. Chem. Soc.
1983, 105, 3515.
(7) Cohen, Z.; Keinan, E.; Mazur, Y.; Varkony, T. H. J. Org. Chem.
1975, 40, 2141. Olah, G. A.; Yoneda, N.; Parker, D. G. J. Am. Chem. Soc.
1976, 98, 5261. Giamalva, D. H.; Church, D. F.; Pryor, W. A. J. Org. Chem.
1988, 53, 3429. Hellman, T. M.; Hamilton, G. A. J. Am. Chem. Soc. 1974,
96, 1530.
(8) Rozen, S.; Brand, M.; Kol, M. J. Am. Chem. Soc. 1989, 45, 8325.
282
Org. Lett., Vol. 1, No. 2, 1999

center. The reduced in situ racemization of 3b,c compared
to 3a can also be ascribed to the decreased electron density
at the oxyfunctionalized center due to the presence of
functional groups.
Table 3. Enantiospecific Oxyfunctionalization of Isoamyl
Alcohol Derivatives 7
To show that the enantiospecificity in the oxyfunctional-
ization is highly independent of both the carbon framework
of the substrate and the presence of functional groups,
3-methyladipic acid derivative 522 (Table 2) and isoamyl
% ee
reactn
configuration
substr
R
time (h)
7
8
retention %
Table 2. Enantiospecific Oxyfunctionalization of
3-Methyladipic Acid Derivative 5
(S)-7a
(S)-7a
(S)-7b
(S)-7b
CH3
CH3
24
31
22
72
99
99
99
99
95
93
93
82
96
94
94
83
(CH3)2CBr
(CH3)2CBr
withdrawing functionalities in the substrate molecules, reac-
tion times were quite long. As expected, the in situ
racemization of 6 was slow and it was retarded by the
presence of alkaline fluorides. The ee of the alcohol (S)-6
was as high as 89% even after a reaction time of 31 days
when cesium fluoride was used as hydrofluoric acid scav-
enger during the reaction.
% ee
configuration
reactn time (h)
added salta
5
6
retention %
In general the oxidative properties of oxaziridine 1 recall
those of dioxiranes10,25 which also have been successfully
employed in the oxyfunctionalization of various hydrocar-
bons. Perfluoro-cis-2-n-butyl-3-n-propyloxaziridine (1) is
confirmed to be an interesting alternative to these reagents.
While the enantiospecificity in the oxidation by dioxiranes
has been tested only on benzylic positions,26 oxaziridine 1
performs the oxyfunctionalization reaction with very high
enantiospecificity on quite different trialkyl-substituted hy-
drocarbon sites and the presence of various functional groups
(carbalkoxy, chloro, bromo, hydroxyl residues) is tolerated.
Useful aspects of the employment of 1 are the mild
reaction conditions, the simple reaction workup procedure,
and the indefinite storage stability of the oxaziridine. The
reactions here described thus represent a general procedure
for the chemical generation of aliphatic chirons possessing
a tertiary carbinol site on quite different carbon skeletons
and in the presence of various functional groups.
24
38
72
48
99
99
99
99
99
93
89
47
94
88
94
90
48
95
89
NaF (1 equiv)
CsF (1 equiv)
31 (days)
a Equivalents of added salt with respect to 1 equiv of substrate 5.
alcohol derivatives 7a,b23,24 (Table 3) have been reacted with
oxaziridine 1 under standard reaction conditions.
In all cases the oxidation did occur with very high retention
of configuration. Consistent with the presence of electron-
(19) Substrates 2b,c have been obtained starting from (S)-citronellyl
bromide (Aldrich) by addition of hydrochloric acid (HCl, n-pentane, rt)
and water (H2O, H2SO4, THF, rt), respectively. Selected spectral and
physical properties of (S)-2b: [R]20D ) -5.30 (c ) 0.5, CHCl3); 1H NMR
(250 MHz, CDCl3) δ 3.47-3.43 (m, 2H), 1.58 (s, 6H), 2.00-1.20 (m, 9H),
0.91 (d, J ) 7.0 Hz, 3H). Selected spectral and physical properties of (R)-
3b: [R]20D ) +2.41 (c ) 0.3, CHCl3); 1H NMR (250 MHz,CDCl3) δ 3.49
(m, 2H), 2.10 (m, 2H), 2.03 (brs, 1H), 1.59 (s, 6H), 1.80-1.30 (m, 6H),
1.22 (s, 3H); 13C NMR (62.9 MHz, CDCl3) δ 73.02 (o), 70.87 (o), 46.29
(o), 45.00 (o), 42.33 (o), 32.52 (e), 32.44 (e), 28.08 (o), 26.61 (e), 19.50
(o); GC-MS (CI) 273 (M+ + 2), 255 (M+ - H2O), 219 (M+ - HCl).
(20) The oxyfunctionalization of substrates 2, 5, and 7 has been assumed
to occur with preferential retention of configuration for analogy with the
proven stereochemical course in the oxidation of 2a.
(21) Asensio, G.; Castellano, G.; Mello, R.; Nunez, M. E. G. J. Org.
Chem. 1996, 61, 5564. Dixon, J. T.; Holzapfel, C. W.; van Heerden, F. R.
Synth. Commun. 1993, 23, 135. Beckwith, A. L. J.; Bodkin, C. L.; Duong,
T. Chem. Lett. 1977, 425.
(22) (R)-3-Methyl-1,6-diacetyloxyhexane (5) has been prepared from (R)-
3-methyladipic acid through esterification (methanol, H2SO4, reflux),
reduction (LiAlH4, ethyl ether, rt), and acetylation (Ac2O, pyridine, rt).
(23) Esters (R)-7a,b have been obtained by acylation of (R)-2-methyl-
1-buthanol (Aldrich) with Ac2O/pyridine and with 2-bromo-2-methylpro-
pionic acid/DCC/4-DMAP/CH2Cl2, respectively.
As far as mechanistic considerations are concerned, the
observed retarding effect of electron-withdrawing substituents
is consistent with an electrophilic process having an ionic
or concerted or radical nature. Among others,27 high enan-
tiospecificity has been used as a proof of a concerted
mechamism in oxyfunctionalization reactions.28 However,
(25) Curci, R.; Dinoi, A.; Rubino, M. F. Pure Appl. Chem. 1995, 67,
811. Murray, R. W. Chem. ReV. 1989, 89, 1187. Adam, W.; Curci, R.;
Edwards, J. O. Acc. Chem. Res. 1989, 22, 205. Murray, R. W.; Jeyaraman,
R.; Mohan, L. J. Am. Chem. Soc. 1986, 108, 2470. Mello, R.; Fiorentino,
M.; Fusco, C.; Curci, R. J. Am. Chem. Soc. 1989, 111, 6749.
(26) Adam , W.; Asensio, G.; Curci, R.; Gonzales-Nunez, M. E.; Mello,
R. J. Org. Chem. 1992, 57, 953.
(24) The presence of the ester residue strongly deactivates the nearby
tertiary site. As a consequence, the oxaziridine 1 attacked also the less
deactivated secondary position (C-3). Indeed, alcohols 8a,b and 3-methyl-
4-carbalkoxy-2-butanones (generated through in situ further oxidation of
the initially formed 3-methyl-4-carbalkoxy-2-butanols) were formed in
nearly equimolar amounts.
(27) Horner, J. H.; Tanaka, N.; Newcomb, M. J. Am. Chem. Soc. 1998,
120, 10379. Simakov, P. A.; Choi, S. Y.; Newcomb, M. Tetrahedron Lett.
1998, 39, 8187.
(28) Adam, W.; Curci, R.; D′accolti, L.; Dinoi, A.; Fusco, C.; Gasparini,
F.; Kluge, R.; Paredes, R.; Schulz, M.; Smerz, A. K.; Veloza, L. A.;
Weinkotz, S.; Winde, R. Chem. Eur. J. 1997, 3, 105.
Org. Lett., Vol. 1, No. 2, 1999
283

radical reactions can occur enantiospecifically;29 therefore,
in our opinion the results here reported do not allow us to
make any definitive statement on the mechanism of the
described process.
Supporting Information Available: General procedure
for the oxyfunctionalization reaction; tecniques (1H NMR,
chiral GC) and conditions for enantiomer separation of
compounds 2, 3, 5, 6, 7, and 8; spectral data (1H and 13C
NMR) for the products 3, 6, and 8. This material is available
free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. Financial support from the European
Union (network INTAS-Ukraine 95-0095) is gratefully
acknowledged.
(29) Minisci, F.; Zhao, L.; Fontana, F.; Bravo, A. Tetrahedron Lett. 1995,
36, 1697. Sibi, M. P.; Porter, N. A. Acc. Chem. Res. 1999, 32, 163.
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