Thermal rearrangement of 2-bromooxazolines to 2-bromoisocyanates

Article abstract of DOI:10.1021/ol7027509

(Chemical Equation Presented) A unprecedented thermally induced rearrangement of 2-bromo-4-substituted oxazolines into 2-bromoisocyanates with high selectivity has been observed. Isolated yields of 85-90% were obtained with 2-bromo-4-phenyloxazoline, 2-br

Full text of DOI:10.1021/ol7027509

ORGANIC
LETTERS
2008
Vol. 10, No. 2
305-308
Thermal Rearrangement of
2-Bromooxazolines to
2-Bromoisocyanates
Carole Foltz,† Ste´phane Bellemin-Laponnaz,*,‡ Markus Enders,†
Hubert Wadepohl,† and Lutz H. Gade*,†
Anorganisch-Chemisches Institut, UniVersita¨t Heidelberg, Im Neuenheimer Feld 270,
69120 Heidelberg, Germany, and Institut de Chimie, UMR CNRS 7177, UniVersite´
Louis Pasteur, 4 rue Blaise Pascal, 67000 Strasbourg, France
lutz.gade@uni-hd.de; bellemin@chimie.u-strasbg.fr
Received November 18, 2007
ABSTRACT
A unprecedented thermally induced rearrangement of 2-bromo-4-substituted oxazolines into 2-bromoisocyanates with high selectivity has
been observed. Isolated yields of 85 90% were obtained with 2-bromo-4-phenyloxazoline, 2-bromo-4-isopropyloxazoline, or 2-bromo-4,4-
−
dimethyloxazoline. In addition, chiral aziridinecarboxamides or 2-aminooxazolines could be selectively obtained from the corresponding 2-bromo
isocyanate depending on reaction conditions.
General interest in the synthesis and reactivity of oxazolines
is reflected in the extensive work published on the subject
matter during past decades.1 Oxazolines are useful intermedi-
ates in the synthesis of many classes of compounds;2 in
particular, they can be used as protecting or activating groups.
Oxazoline units can ring-open under certain conditions, by
way of electrophilic attack,3 acidolysis,4 glycolysis,5 Wittig
rearrangement,6 or transition-metal-promoted rearrangement.7
Ring-opening polymerization of 2-oxazolines is also the
focus of current interest.8 The introduction of a chiral center
within the oxazoline ring leads to versatile synthons for
asymmetric synthesis and for the development of ligands in
catalysis.9,10 These chiral enantiopure materials are readily
accessible in a few steps from R-amino acids.
(7) (a) Kazi, A. B.; Jones, G. D.; Vicic, D. A. Organometallics 2005,
24, 6051. (b) Ward, B. D.; Risler, H.; Weitershaus, K.; Bellemin-Laponnaz,
S.; Wadepohl, H.; Gade, L. H. Inorg. Chem. 2006, 45, 7777. (c) Gott, A.
L.; Coles, S. R.; Clarke, A. J.; Clarkson, G. J.; Scott, P. Organometallics
2007, 26, 136.
(8) See, for example: (a) Hrkach, J. S.; Matyjaszewski, K. Macromol-
ecules 1992, 25, 2070. (b) Jordan, R.; Ulman, A. J. Am. Chem. Soc. 1998,
120, 243. (c) Wiesbrock, F.; Hoogenboom, R.; Leenen, M. A. M.; Meier,
M. A. R.; Schubert, U. S. Macromolecules 2005, 38, 5025. (d) Hoogenboom,
R.; Wiesbrock, F.; Huang, H.; Leenen, M. A. M.; Thijs, H. M. L.; van
Nispen, S. F. G. M.; van der Loop, M.; Fustin, C.-A.; Jonas, A. M.; Alain,
M.; Gohy, J.-F.; Schubert, U. S. Macromolecules 2006, 39, 4719. (e)
Guerrero-Sanchez, C.; Hoogenboom, R.; Schubert, U. S. Chem. Commun.
2006, 3797.
(9) (a) Lowenthal, R. E.; Abiko, A.; Masamune, S. Tetrahedron Lett.
1990, 31, 6005. (b) Evans, D. A.; Woerpel, K. A.; Hinman, M. M.; Faul,
M. M. J. Am. Chem. Soc. 1991, 113, 726. (c) Corey, E. J.; Imai, N.; Zhang,
H. Y. J. Am. Chem. Soc. 1991, 113, 728. (d) Mu¨ller, D.; Umbricht, G.;
Weber, B.; Pfaltz, A. HelV. Chim. Acta 1991, 74, 232.
(10) Reviews: (a) Johnson, J. S.; Evans, D. A. Acc. Chem. Res. 2000,
33, 325. (b) Desimoni, G.; Faita, G.; Jørgensen, K. A. Chem. ReV. 2006,
106, 3561. (c) Dagorne, S.; Bellemin-Laponnaz, S.; Maisse-Franc¸ois, A.
Eur. J. Inorg. Chem. 2007, 913. (d) Gade, L. H.; Bellemin-Laponnaz, S.
Coord. Chem. ReV. 2007, 251, 718.
† Universita¨t Heidelberg.
‡ Universite´ Louis Pasteur.
(1) Ager, D. J.; Prakash, I.; Schaad, D. R. Chem. ReV. 1996, 96, 835.
(2) Gant, T. G.; Meyers, A. I. Tetrahedron 1994, 50, 2297.
(3) (a) Frump, J. A. Chem. ReV. 1971, 71, 483. (b) Laaziri, A.; Uziel, J.;
Juge´, S. Tetrahedron: Asymmetry 1998, 437. (c) Lee, S.-H.; Yoon, J.;
Nakamura, K.; Lee, Y.-S. Org. Lett. 2000, 2, 1243.
(4) (a) Elliott, D. F. J. Chem. Soc. 1950, 62. (b) Fry, E. M. J. Org. Chem.
1950, 15, 802. (c) Fritz, M.; Ko¨chling, H. Chem. Ber. 1958, 673. (d)
Lindberg, B.; Agback, H. Acta Chem. Scand. 1964, 18, 185.
(5) Fritz, M.; Drescher, E. Chem. Ber. 1958, 670.
(6) Mikami, K.; Kasuga, T.; Fujimoto, K.; Nakai, T. Tetrahedron Lett.
1986, 27, 4185.
10.1021/ol7027509 CCC: $40.75
© 2008 American Chemical Society
Published on Web 12/23/2007

In the course of the development of new ligands for
asymmetric catalysis, we have shown that 2-bromooxazolines
may be used as key reagents in the synthesis of 1,1,1-tris-
(oxazolinyl)ethane (“trisox”) ligands11 as well as oxazolinyl-
N-heterocyclic carbenes.12 2-Bromooxazolines, which were
first reported by Meyers and Novachek,13 are readily prepared
by direct lithiation of the 2H-oxazoline14 followed by reaction
with 1,2-dibromo-1,1,2,2-tetrafluoroethane as electrophilic
brominating agent. Upon investigating the reactivity of these
heterocycles (1a-d), we have discovered that they are
thermally sensitive and that a rearrangement occurs to the
respective 2-bromoisocyanates (2a-d) (Scheme 1). This has
Scheme 1. Thermal Rearrangement of 2-Bromooxazolines to
Figure 1. 1H NMR spectra (CDCl3, 300 MHz) of (a) (4R)-2-
bromo-4-phenyloxazoline 1c; (b) after heating 90 °C for 2 days.
2-Bromoisocyanates (Yields in Parentheses)
The same behavior was observed with the 2-bromo-4-
substituted oxazolines 1a-c. Among all substrates studied,
the (4R,5S)-2-bromo-4,5-indanediyloxazoline (1d) was found
to be the least stable derivative,15 and suitable crystals of
the product 2d for an X-ray diffraction study were obtained
(Scheme 2 and Figure 2), thus establishing the details of the
Scheme 2. Diastereoselective Conversion of the
(4R,5S)-2-Bromo-4,5-indandiyloxazoline 1d into
2-Bromo-1-isocyanato-2,3-dihydro-1H-indene 2d
(Neat, 25 °C, 5 min)
prompted a more detailed study of this unprecedented
rearrangement which we report in this work along with the
use of these compounds as synthons for the preparation of
chiral aziridines or 2-aminooxazolines.
The 2-bromooxazoline derivatives can be kept in THF
solution at -30 °C for a few days. However, over time the
formation of a new product is observed, a process which
1
can be monitored by H NMR spectroscopy. As shown in
the proton NMR spectra displayed in Figure 1, 2-bromo-4-
phenyloxazoline (1c, top) is selectively and completely
converted into a new product (2c, bottom) by heating the
solution at 90 °C for 2 days. A GC-MS analysis of the
reaction mixture confirmed the high selectivity of the reaction
and revealed that the molecular weight of the new product
is unchanged with respect to the reactant, suggesting that a
rearrangement had occurred. In the IR spectrum, the char-
acteristic stretching band of an isocyanate (νCdN ) 2265
molecular structure of the compound.16
The X-ray analysis confirmed the ring-opening of the
oxazoline and the formation of a 2-bromoisocyanate. In this
particular case, the rearrangement of the heterocycle induces
the inversion of the absolute configuration of the carbon C(2),
and only one diastereomeric form was observed in the crystal.
1
Moreover, the H NMR spectrum of the crude product
1
cm-1) is observed. The H, 13C, and 15N NMR as well as
established a dr of 95:5 and, thus, the high stereoselectivity
of the rearrangement (Scheme 2).
the analytical data confirmed the formation of a 2-bromoiso-
cyanate.
(15) A low yield was obtained in the synthesis of the trisoxazoline ligand
1,1,1-tris[(4R, 5S)-4,5-indandiyloxazolin-2-yl]ethane; see: Foltz, C.; Enders,
M.; Bellemin-Laponnaz, M.; Wadepohl, H.; Gade, L. H. Chem. Eur. J.
2007, 13, 5961. The fast rearrangement of the bromooxazoline would explain
this result. For the other bromooxazolines, which require higher temperatures
to form the respective â-bromo isocyanates higher yields were consequently
obtained in the coupling reaction.
(16) Crystal data: (1R,2R)-2-bromo-1-isocyanato-2,3-dihydro-1H-indene
C10H8BrNO, orthorhombic, space group P212121, a ) 7.8071(10) Å, b )
8.0417(10) Å, c ) 14.2852(18) Å, V ) 896.9(2) Å3, Z ) 4, µ ) 4.537
mm-1, tmax/tmin ) 0.5494/0.3967, F000 ) 472. Reflections measured: 7904,
independent: 3010 [Rint ) 0.034], index ranges -11 e h e 11, 0 e k e
11, 0 e l e 21, θ range 2.9-32°. Final R values [I > 2σ(I)]: R1 ) 0.0314,
wR2 ) 0.0681, GoF ) 1.015.
(11) (a) Bellemin-Laponnaz, S.; Gade, L. H. Chem. Commun. 2002, 1286.
(b) Bellemin-Laponnaz, S.; Gade, L. H. Angew. Chem., Int. Ed. 2002, 41,
3473.
(12) (a) Ce´sar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Organometallics
2002, 21, 5204. (b) Gade, L. H.; Ce´sar, V.; Bellemin-Laponnaz, S. Angew.
Chem., Int. Ed. 2004, 43, 1014. (c) Ce´sar, V.; Bellemin-Laponnaz, S.;
Wadepohl, H.; Gade, L. H. Chem. Eur. J. 2005, 11, 2862. (d) Schneider,
N.; Ce´sar, V.; Bellemin-Laponnaz, S.; Gade, L. H. Organometallics 2005,
24, 4886.
(13) Meyers, A. I.; Novachek, K. A. Tetrahedron Lett. 1996, 37, 1747.
(14) (a) Leonard, W. R.; Romine, J. L.; Meyers, A. I. J. Org. Chem.
1991, 56, 1961. (b) Kamata, K.; Agata, I.; Meyers, A. I. J. Org. Chem.
1998, 63, 3113.
306
Org. Lett., Vol. 10, No. 2, 2008

considerably accelerates the reaction (t1/2 ) 0.5 h vs t1/2
)
4.5 h at 60 °C and C ) 0.57 mol‚L-1, see the Supporting
Information).
In view of the selectivity of the rearrangements, we
prepared the 2-bromoisocyanates on a millimolar scale for
a first study into their reactivity.17 Various applications of
R-functionalized isocyanates in the synthesis of new com-
pounds are reported in the literature, such as benzimidazole
derivatives,18 oxazolinylpyperazine derivatives,19 oxazolo-
quinazolines,20 2-amino-2-oxazolines,21 fullerene deriva-
tives,22 and 1-amidino-2-imidazolidinones.23 Since the ste-
reogenic center in the 4 position is not affected by the
rearrangement of the bromooxazoline, an interesting applica-
tion appeared to be their use for the determination of the
enantiomeric excess of primary or secondary amines. To
probe this, the enantiomerically pure isocyanates 2a-c were
reacted with (S)-1-phenylethylamine or rac-phenylethy-
lamine.24
Figure 2. Molecular structure of (1R,2R)-2-bromo-1-isocyanato-
2,3-dihydro-1H-indene 2d.16 Selected bond lengths (Å) and angles
(deg): C(1)-C(2) 1.537(3), C(1)-N(1) 1.446(3), N(1)-C(10)
1.183(4), C(10)-O(1) 1.182(3), C(2)-Br(1) 1.949(2), N(1)-C(1)-
C(2) 112.0(2), C(1)-N(1)-C(10) 140.5(3), N(1)-C(10)-O(1)
172.5(3). Torsion angle Br(1)-C(2)-C(1)-N(1) -79.7(2).
Depending on experimental conditions, the reaction of the
2-bromo isocyanate with phenylethylamine and a base led
selectively to aziridinecarboxamides 3a-c or the O-cyclized
2-aminooxazolines 5a-c (Scheme 3). The first reaction
The rate of the rearrangement depends on the substitution
pattern of the oxazoline with the stability decreasing in the
order iPr . Bn ≈ Me2 . Ph > Ind. No conversion was
observed upon exposure of the 2-bromooxazolines to radical
initiators such as 2,2′-azobis(4-methoxy-2,4-dimethylvale-
ronitrile) (V70) and 2,2′-azobis(isobutyronitrile) (AIBN) or
to UV radiation, ruling out a radical mechanism. Monitoring
the conversion of the 2-bromo-4,4-dimethyloxazoline by 1H
NMR spectroscopy at 60 °C at different concentrations gave
the sequence of conversion curves displayed in Figure 3.
Scheme 3. Formation of Aziridinecarboxamide 3, Protonated
Aminooxazoline 4, and Aminooxazoline 5 (Yields in
Parentheses)
Figure 3. Conversion of 2-bromo-4,4′-dimethyloxazoline 1a in
1-bromo-2-isocyanato-2-methylpropane 2a as a function of time
1
at different concentrations (followed by H NMR in THF-d8 at
60 °C).
Their sigmoidal shape suggests autocatalysis by the product,
and the concentration dependence indicates that overall
reaction is not of first order with respect to the concentration
of bromooxazoline. A detailed mechanistic study is underway
and will be reported elsewhere. However, the involvement
of bromide ions liberated in the course of the transformation
is suggested by the observation that the addition of 1 equiv
of Bu4NBr into a solution of 2-bromo-4,4′-dimethyloxazoline
intermediates in these transformations are â-bromourea
derivatives, which are formed by nucleophilic attack of the
amine and which may be detected at low temperature by
NMR spectroscopy (see the Supporting Information). Adding
the base t-BuOK at low temperature (-20 °C) led selectively
to the aziridinecarboxamides 3a-c.25 On the other hand,
carrying out the reaction at room temperature gave the
protonated aminooxazolines 4a-c which were converted to
Org. Lett., Vol. 10, No. 2, 2008
307

the corresponding amino-oxazolines 5a-c by subsequent
addition of the base.
The formation of the aziridines 3a-c was confirmed by
an X-ray diffraction analysis of the (S)-2-isopropyl-N-((S)-
1-phenylethyl)aziridine-1-carboxamide (3b).26 Its molecular
structure is depicted in Figure 4 along with selected bond
NMR chemical shifts.27 Several isomers of the parent
compound 5 (R1 ) R2 ) H) have been calculated. As
expected, the 2-imidazolidinone is the thermodynamically
favored isomer. However, its calculated 15N chemical shifts
(δ 88 and 118 ppm) do not match with the experminental
shifts for 5a-c (δ 77.6-79.8 and 160.0-176.7 ppm). The
latter values are in agreement with the data calculated for
the aminooxazoline isomers (δ 76-95 and 156-179 ppm).
In addition, the infrared data confirm the formation the
aminooxazoline. The infrared spectra of the three derivatives
of 5a-c show a strong absorption between 1672 and 1687
cm-1 which is assigned to the νCdN stretching mode of the
oxazoline.28 Addition of HCl (2 M solution in diethylether)
to 5a-c in chloroform-d1 led to the reformation of 4a-c
and confirmed their fomulation as protonated aminooxazo-
lines.
The potential of using the transformations described above
for the determination of the enantiomeric excess of chiral
amines was probed by reaction 2b with rac-phenylethy-
lamine. The formation of either the 2-aminooxazoline (5b)
or the carbamoyl-aziridine (3b) enabled the determination
of the enantiomeric excess of the amine by 1H NMR
spectroscopy by integration of the completely assigned and
the well-separated signals of the two diastereoisomers.
In conclusion, we have found that 2-bromo-4-substituted
oxazolines, which are readily prepared from 2H-oxazolines,
undergo an unprecedented thermal rearrangement to their
corresponding 2-bromoisocyanates with high selectivity.
Their availablity in good yields may render them key
synthetic intermediates in a variety of organic transforma-
tions.
Figure 4. Molecular structure of (S)-2-isopropyl-N-((S)-1-phenyl-
ethyl)aziridine-1-carboxamide 3b. Selected bond lengths (Å) and
angles (deg): C(1)-O(1) 1.228(3), C(1)-N(2) 1.342(3), C(1)-
N(1) 1.408(3), C(2)-N(1) 1.456(3), C(2)-C(3) 1.485(3), C(3)-
N(1) 1.469(3), N(2)-C(1)-N(1) 113.25(18), N(1)-C(2)-C(3)
59.94(15), N(1)-C(3)-C(2) 59.06(15), C(2)-N(1)-C(3) 61.00-
(15), C(1)-N(1)-C(2) 118.87(18), C(1)-N(1)-C(3) 119.14(19).
lengths and angles. Identification of products 4a-c and 5a-c
1
proved to be not trivial since the H and 13C {1H} NMR
spectroscopic data did not allow the distinction between the
possible formation of imidazolidinones or aminooxazolines.
An unambiguous assignment has been achieved by 15N NMR
spectroscopy along with a theoretical modeling of the 15N
Acknowledgment. We thank the Deutsche Forschungs-
gemeinschaft (SFB 623, Project B6), the Deutsch-Franzo¨-
sische Hochschule (DFH), and the CNRS (France) for
funding and Prof. D. G. Blackmond for helpful comments.
(17) Alternatively, such 2-bromo isocyanates can be obtained from the
rearrangement of N-halogenated â-lactams in the presence of olefins or
alkynes or from the dehydrochlorination of compounds such as RNHCOCl
in the presence of H2O and HCl. See, for example: (a) Kampe, K. D.
Tetrahedron Lett. 1969, 2, 117. (b) Farbwerke Hoechst A.-G. Patent FR
1565226, 1969. (c) Kampe, K. D. Patent DE 1930329, 1970. (d) Kampe,
K. D. Justus Liebigs Ann. Chem. 1971, 752, 142. (e) Koenig, K. H.; Rohr,
W.; Fischer, A. Patent DE 2045907, 1972. (f) Koenig, K. H.; Zanker, F.;
Mangold, D. Fischer, A. Patent DE 2045906, 1972. (g) Zanker, F. Patent
DE 2156761, 1972.
Supporting Information Available: Experimental details
and spectroscopic/analytical data for all new compounds and
crystal data. This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Hoerlein, G.; Mildenberger, H.; Kroeniger, A.; Haertel, K. Patent
DE 2125815, 1972.
OL7027509
(19) (a) Gobel, A.; Schmitt, K.; Linde-Ranke, I. Patent DE 2205814,
1973. (b) Gobel, A.; Schmitt, K.; Linde-Ranke, I. Patent DE 2205815, 1973.
(20) Kampe, K. D. Patent DE 2252122, 1973.
(21) (a) Kampe, K. D. Justus Liebigs Ann. Chem. 1974, 4, 593. (b)
Kampe, K. D.; Babej, M.; Kaiser, J. Patent DE 2253554, 1974.
(22) Kampe, K. D. Patent EP 653424, 1995.
(26) (S)-2-Isopropyl-N-((S)-1-phenylethyl)aziridine-1-carboxamide C14-
H20N2O, orthorhombic, space group P212121, a ) 5.1912(7) Å, b ) 11.6401-
(15) Å, c ) 21.277(3) Å, V ) 285.7(3) Å3, Z ) 4, µ ) 0.076 mm-1, tmax
/
tmin ) 0.8624/0.7746, F000 ) 504. Reflections measured: 10195, indepen-
dent: 1931 [Rint ) 0.067], index ranges 0 e h e 7, 0 e k e 15, 0 e l e
28, θ range 1.9-29°. Final R values [I > 2σ(I)]: R1 ) 0.0429, wR2 )
0.0961, GoF ) 1.015.
(27) Three isomers of 5 and the corresponding 2-imidazolidinone
derivative were calculated. For details of the computational study, see the
Supporting Information.
(28) Aminooxazolines display a vibrational band between 1655 and 1687
cm-1 depending on the substituents, whereas those of imidazolidinones are
observed between 1684 and 1716 cm-1; see ref 24 and: Kim, T. H.; Lee,
N.; Lee, G.-J.; Kim, J. N. Tetrahedron 2001, 57, 7137.
(23) Kulitzscher, B.; Sommer, C.; Kammermeier, B. Patent DE 19502790,
1996.
(24) Kim, T. H.; Lee, G.-J. J. Org. Chem. 1999, 64, 2941.
(25) In a more classical way, such compounds may be obtained by direct
reaction of the aziridine with the isocyanate; see, for examples: (a)
Kostyanovskii, R. G.; Zakharov, K. S.; Zarinova, M.; Rudchenko, V. F.
IzVest. Akad., Nauk SSSR, Ser. Khim. 1975, 4, 875. (b) Araki, T.; Nagata,
K.; Tsukube, H. J. Polym. Sci. Polym. Chem. Ed. 1979, 17, 731. (c) Fishbein,
P. L.; Harold, K. J. Med. Chem. 1987, 30, 1767.
308
Org. Lett., Vol. 10, No. 2, 2008