Comparison of electrophilic amination reagents for N-amination of 2-oxazolidinones and application to synthesis of chiral hydrazones.

Article abstract of DOI:10.1021/jo0259663

Comparison of several hydroxylamine-based electrophilic ammonia equivalents in the N-amination of 2-oxazolidinones revealed that O-(p-nitrobenzoyl)hydroxylamine (NbzONH(2)) and sodium hydride in dioxane is a superior reagent combination for this purpose. Practical preparations of a variety of chiral N-acylhydrazones by this method gave yields ranging from 45 to 95%. Methods for exchange or removal of the aldehyde component have been developed, making this a general route to chiral N-acylhydrazones of interest for asymmetric synthesis applications.

Full text of DOI:10.1021/jo0259663

Hydrazones for the foregoing synthetic methods are
generally derived by condensation of the appropriate
hydrazine with an aldehyde or ketone. These hydrazines
in turn are often prepared by N-amination of the corre-
sponding amine or amide.10 Amination of chiral amines
Com p a r ison of Electr op h ilic Am in a tion
Rea gen ts for N-Am in a tion of
2-Oxa zolid in on es a n d Ap p lica tion to
Syn th esis of Ch ir a l Hyd r a zon es
is usually achieved via nitrosation and reduction,11
a
Yuehai Shen and Gregory K. Friestad*
procedure accompanied by significant toxicity concerns,
or by a multistep procedure involving the Shestakov
rearrangement of N-substituted ureas (a type of Hofmann
degradation).12 To our knowledge, the latter procedure
has not been successful for preparation of N-acylhydra-
zines (i.e., hydrazides).
An attractive possibility for synthesis of N-acylhydra-
zones is the direct transfer of the unprotected amino
group. A number of hydroxylamine derivatives (see Chart
1) are competent electrophilic NH2+ equivalents that have
been shown to transfer the amino group to various oxygen
or nitrogen nucleophiles, including deprotonated amides.13
Among these, O-(mesitylenesulfonyl)hydroxylamine (Mt-
sONH2) was successfully adopted for our initial prepara-
tions of (S)-2-amino-4-benzyl-2-oxazolidinone (1a )8a by
N-amination according to the precedent of White and
Kim.14a,15 However, the instability of MtsONH2 proved
troublesome, as forewarned by the original literature
Department of Chemistry, Cook Physical Science Building,
University of Vermont, Burlington, Vermont 05405
gregory.friestad@uvm.edu
Received May 24, 2002
Abstr a ct: Comparison of several hydroxylamine-based
electrophilic ammonia equivalents in the N-amination of
2-oxazolidinones revealed that O-(p-nitrobenzoyl)hydroxy-
lamine (NbzONH2) and sodium hydride in dioxane is a
superior reagent combination for this purpose. Practical
preparations of a variety of chiral N-acylhydrazones by this
method gave yields ranging from 45 to 95%. Methods for
exchange or removal of the aldehyde component have been
developed, making this a general route to chiral N-acylhy-
drazones of interest for asymmetric synthesis applications.
(8) (a) Friestad, G. K.; Qin, J . J . Am. Chem. Soc. 2000, 122, 8329-
8330. (b) Friestad, G. K.; Qin, J . J . Am. Chem. Soc. 2001, 123, 9922-
9923.
(9) Friestad, G. K.; Ding, H. Angew. Chem., Int. Ed. 2001, 40, 4491-
4493.
(10) General reviews of hydrazine synthesis: Ragnarsson, U. Chem.
Soc. Rev. 2001, 30, 205-213. J ensen-Korte, U.; Mueller, N. In
Methoden der Organische Chemie (Houben-Weyl), 4th ed.; Klamann,
D., Ed.; Thieme: Stuttgart, 1990; Vol. 16a, pp 425-648. Huddleston,
P. R.; Coutts, I. G. C. In Comprehensive Organic Functional Group
Transformations; Katritzky, A. R., Meth-Cohn, O., Rees, C. W., Eds.;
Elsevier: Oxford, 1995; Vol. 2, pp 371-383.
(11) For examples, see refs 1 and 2. See also: Kim, Y. H.; Choi, J .
Y. Tetrahedron Lett. 1996, 37, 5543-5546.
(12) Viret, J .; Gabard, J .; Collet, A. Tetrahedron 1987, 43, 891-894.
Enders, D.; Fey, P.; Kipphardt, H. Organic Syntheses; Wiley & Sons:
New York, 1993; Collect Vol. VIII, pp 26-31.
(13) (a) Hydroxylamine-O-sulfonic acid: Erdik, E. In Encyclopedia
of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New
York, 1995; Vol. 4, pp 2764-2767. (b) O-(Mesitylenesulfonyl)hydroxy-
lamine: CAUTION: This reagent and its synthetic precursor, ethyl
O-(mesitylenesulfonyl)hydroxylacetimidate, may decompose spontane-
ously during drying of the solids. Boche, G. In Encyclopedia of Reagents
for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995;
Vol. 5, pp 3277-3281. Carpino, L. A. J . Am. Chem. Soc. 1960, 82,
3133-3135. Tamura, Y.; Minakawa, J .; Sumoto, K.; Fujii, S.; Ikeda,
M. J . Org. Chem. 1973, 38, 1239-1241. (c) O-Acylhydroxylamines:
Boche, G. In Encyclopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; Wiley: New York, 1995; Vol. 5, pp 3270-3271. (d)
O-(Diphenylphosphinyl)hydroxylamine: Boche, G. In Encyclopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: New York,
1995; Vol. 4, pp 2240-2242. Klotzer, W.; Stadlwieser, J .; Raneburger,
J . Organic Syntheses; Wiley & Sons: New York, 1986; Vol. 64, pp 96-
103. (e) O-(2,4-Dinitrophenyl)hydroxylamine: Bellettini, J . R.; Olson,
E. R.; Teng, M.; Miller, M. J . In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 3, pp
2189-2190. (f) Oxaziridines: Andreae, S.; Schmitz, E. Synthesis 1991,
327-341. Vidal, J .; Guy, L.; Sterin, S.; Collet, A. J . Org. Chem. 1993,
58, 4791-4793. Vidal, J .; Damestoy, S.; Guy, L.; Hannachi, J .-C.;
Aubry, A.; Collet, A. Chem. Eur. J . 1997, 3, 1691-1709. Choong, I. C.;
Ellman, J . A. J . Org. Chem. 1999, 64, 6528-6529.
Chiral hydrazones have served prominent roles in the
early development of asymmetric synthesis, most notably
as chiral auxiliaries for enantioselective R-alkylation of
carbonyl compounds1 and as chiral nitrogen donor aux-
iliaries for asymmetric amine synthesis via reductive
amination2 or addition of organometallic reagents to the
CdN bond.3 Applications of chiral hydrazones have
broadened in recent years; new developments include
allene anion additions to SAMP hydrazones,4 chiral
umpolung reactivity5 and [2 + 2] cycloadditions6 employ-
ing formaldehyde hydrazones, and asymmetric catalysis
with phosphine-hydrazone P,N-chelate complexes.7 In
our own studies, we have designed chelating chiral
N-acylhydrazones for applications in asymmetric amine
synthesis including radical addition8 and allylsilane
addition.9
(1) Enders, D.; Eichenauer, H. Chem. Ber. 1979, 112, 2933-2960.
Review: Enders, D. In Asymmetric Synthesis; Morrison, J . D., Ed.;
Academic Press: New York, 1984; pp 275-339.
(2) (a) Corey, E. J .; McCaully, R. J .; Sachdev, H. S. J . Am. Chem.
Soc. 1970, 92, 2476-2488. Corey, E. J .; Sachdev, H. S.; Gougoutas, J .
Z.; Saenger, W. J . Am. Chem. Soc. 1970, 92, 2488-2501.
(3) (a) Ephedrine-derived hydrazone: Takahashi, H.; Tomita, K.;
Otomasu, H. J . Chem. Soc., Chem. Commun. 1979, 668-669. (b)
Valine-derived hydrazone: Takahashi, H.; Suzuki, Y. Chem. Pharm.
Bull. 1983, 31, 4295-4299. (c) Proline-derived hydrazone: Enders, D.;
Schubert, H.; Nubling, C. Angew. Chem., Int. Ed. Engl. 1986, 25, 1109-
1110. Denmark, S. E.; Weber, T.; Piotrowski, D. W. J . Am. Chem. Soc.
1987, 109, 2224-2225. (d) Reviews: Enders, D.; Reinhold: U. Tetra-
hedron: Asymmetry 1997, 8, 1895-1946. Bloch, R. Chem. Rev. 1998,
98, 1407-1438.
(4) Breuil-Desvergnes, V.; Compain, P.; Vate`le, J .-M.; Gore´, J .
Tetrahedron Lett. 1999, 40, 5009-5012.
(5) (a) Fernandez, R.; Martin-Zamora, E.; Pareja, C.; Alcarazo, M.;
Martin, J .; Lassaletta, J . M. Synlett 2001, 1158-1160. (b) Fernandez,
R.; Martin-Zamora, E.; Pareja, C.; Lassaletta, J . M. J . Org. Chem. 2001,
66, 5201-5207.
(6) Fernandez, R.; Ferrete, A.; Lassaletta, J . M.; Llera, J . M.; Monge,
A. Angew. Chem., Int. Ed. 2000, 39, 2893-2897.
(7) Mino, T.; Shiotsuki, M.; Yamamoto, N.; Suenaga, T.; Sakamoto,
M.; Fujita, T.; Yamashita, M. J . Org. Chem. 2001, 66, 1795-1797.
(14) (a) Kim, M.; White, J . D. J . Am. Chem. Soc. 1977, 99, 1172-
1180. (b) Ciufolini, M. A.; Shimizu, T.; Swaminathan, S.; Xi, N.
Tetrahedron Lett. 1997, 38, 4947-4950.
(15) A chiral N-amino-2-oxazolidinone has been prepared by an
alternate route as reported by two other groups: Evans, D. A.; J ohnson,
J . S. Org. Lett. 1999, 1, 595-598. Yamashita, Y.; Ishitani, H.;
Kobayashi, S. Can. J . Chem. 2000, 78, 666-672.
10.1021/jo0259663 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/19/2002
6236
J . Org. Chem. 2002, 67, 6236-6239

TABLE 1. Com p a r ison of Rea gen ts RONH 2 a n d Ba ses
for N-Am in a tion of Oxa zolid in on e 1a
CHART 1
yield of 3a a (%)
entry
RONH2
n-BuLib
NaHc
1
2
3
4
5
MtsONH2
MtONH2
DppONH2
DnpONH2
NbzONH2
75d,e
22
52
73
54
80
41e
66
0f
a
b
Yield of benzaldehyde hydrazone unless noted. Conditions
A: (1) n-BuLi (1.1 equiv), THF, -78 °C, 1 h then add RONH2; (2)
PhCHO (1.0-2.5 equiv), cat. p-TsOH, toluene, reflux. c Conditions
B: (1) NaH (1.1 equiv), dioxane, 60 °C, 1 h, then cool to 25 °C and
add RONH2; (2) same as A. Reference 8a. e Yield of 2a (step 2
d
SCHEME 1
omitted). f Decomposition occurred.
SCHEME 2
reports of its preparation,13b so we sought more reliable
protocols. Here, we report a study comparing several
hydroxylamine-based electrophilic NH2+ equivalents for
the N-amination of oxazolidinones, revealing O-(p-ni-
trobenzoyl)hydroxylamine (NbzONH2) and sodium hy-
dride as a superior reagent combination for this purpose
and culminating in practical preparations of a variety of
chiral N-acylhydrazones.
A survey of amination reagents was carried out first
for the N-amination of oxazolidinone 1a (Scheme 1) in
the presence of a base. In all cases, amination of 1a gave
a mixture of N-amino-2-oxazolidinone 2a and small
amounts of unreacted 1a , separable with difficulty.
Instead of separating at this stage, the mixture was
submitted to condensation with benzaldehyde (toluene,
catalytic amount of p-toluenesulfonic acid) followed by
chromatography to afford the pure hydrazone 3a . A
comparison of MtsONH2 (see Chart 1) with O-mesitoyl-
hydroxylamine13c (MtONH2), O-(diphenylphosphinyl)-
hydroxylamine13d (DppONH2), O-(2,4-dinitrophenyl)-
hydroxylamine13e (DnpONH2), and O-(p-nitrobenzoyl)-
hydroxylamine16 (NbzONH2) showed significant differences
among these reagents. Because yields in the condensation
step are reliably >90% for benzaldehyde,8,9 the yield of
3a in each run is indicative of the effectiveness of the
amination conditions.
Aminations of 1a with DnpONH2 were effective using
the previously described n-BuLi deprotonation conditions
(THF, -78 °C),8a affording yields slightly inferior to the
original report with MtsONH2 (Table 1, entries 1 and 4),
while MtONH2, DppONH2, and NbzONH2 exhibited
better reactivity with NaH (dioxane, 60 °C) as the base
(Table 1, entries 2, 3, and 5). Although NbzONH2 failed
to undergo the desired reaction when employing n-BuLi
(Table 1, entry 5), in conjunction with NaH this reagent
gave the best results among all variations attempted in
this study. Furthermore, neither DppONH2 nor Nb-
zONH2 has yet shown any tendency to decompose upon
storage as dry solids at ca. 0-5 °C, a welcome and
practical improvement over MtsONH2 for application to
TABLE 2. P r ep a r a tion of Va r iou s Ch ir a l Ben za ld eh yd e
N-Acylh yd r a zon es
entry
RONH2
substrate
product, yield (%)
1
2
3
4
5
6
7
8
9
DppONH2
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
3a , 73
3b, 68
3c, 56
3d , 74
3e, 59
3a , 80
3b, 68
3c, 45
3d , 95
3e, 92
NbzONH2
10
anhydrous reactions. These observations led to our
optimized procedure in which deprotonation (NaH), ami-
nation (either DppONH2 or NbzONH2), and condensation
with an aldehyde were applied in sequence.
Several commercially available chiral 2-oxazolidinones
(Scheme 2) bearing alkyl (1c), benzyl (1a , 1b), or aryl
(1d , 1e) substituents were next employed to test the scope
of these amination conditions (Table 2). Amination with
DppONH2 proceeded in moderate to good yields (56-74%
after condensation with benzaldehyde). Amination of
valine-derived oxazolidinone 1c was least efficient among
these, and the use of NbzONH2 offered no improvement.
In contrast, the oxazolidinones with benzylic substituents
(1a , 1b) were aminated by NbzONH2 in good yields (68-
80%). Interestingly, a dramatic improvement was ob-
served in the cases of aryl oxazolidinones (1d , 1e);
hydrazones 3d and 3e were obtained in excellent yields
(95% and 92%).
The optimized amination procedure also proved reli-
able for synthesis of other aldehyde hydrazones from 1a
by three strategies (Scheme 3). First, crude amination
product 2a obtained as above was divided into two
portions and then condensed with propionaldehyde and
cyclohexanecarboxaldehyde to give hydrazones 4 and 5
in very good yields (73% and 77%, respectively, from 1a ).
Second, hydrazones readily undergo exchange with al-
(16) Marmer, W. N.; Maeker, G. J . Org. Chem. 1972, 37, 3520-
3523.
J . Org. Chem, Vol. 67, No. 17, 2002 6237

slurry in hexane. Gradient flash chromatography was conducted
by adsorption of product mixtures on silica gel, packing over a
short pad of clean silica gel as a slurry in hexane, and eluting
with a continuous gradient from hexane to the indicated solvent.
Melting points are uncorrected. Combustion analyses were
performed by Atlantic Microlab (Norcross, GA).
SCHEME 3
Gen er a l P r oced u r e A: Am in a tion of 2-Oxa zolid in on es.
To a solution of 2-oxazolidinone 1 in dioxane (0.2 M) was added
NaH (1.0-1.10 equiv). The mixture was stirred at 60 °C for 1 h
and then cooled to room temperature. p-Nitrobenzoylhydroxy-
lamine (NbzONH2, 1.00-1.05 equiv) was added. After 24 h, the
reaction mixture was filtered through Celite and concentrated
to afford N-amino-2-oxazolidinone 2 as a brown oil. Without
purification, 2 was dissolved in toluene (0.5 M), and aldehyde
(1.0-2.5 equiv) and TsOH‚H2O (0.02 equiv) were added. The
mixture was stirred under reflux. When the reaction was
complete (TLC), the mixture was concentrated and purified by
gradient flash chromatography (hexane f 2:1 hexane/EtOAc)
or recrystallization from ethanol to furnish pure hydrazone.
(S)-3-(Ben zylid en e)a m in o-4-p h en ylm eth yl-2-oxa zolid i-
n on e (3a ). From 1a (200 mg, 1.13 mmol), NaH (60%) (47 mg,
1.18 mmol), NbzONH2 (216 mg, 1.19 mmol), and benzaldehyde
(0.15 mL, 1.48 mmol) by general procedure A with chromatog-
raphy was obtained 3a 8a (253 mg, 80% yield) as a colorless solid.
Mu ltigr a m Sca le. From 1a (8.00 g, 45.1 mmol), NaH (60%)
(1.81 g, 45.2 mmol), NbzONH2 (8.22 g, 45.1 mmol), and benzal-
dehyde (4.60 mL, 45.1 mmol) by general procedure A with
recrystallization was obtained 3a (7.40 g) as colorless needlelike
crystals. From the mother liquor, additional 3a 8a (2.03 g) was
obtained by chromatography (total 9.43 g, 74% yield).
dehydes. Thus, 4 was converted to 3a in 90% yield by
reaction with PhCHO (3 equiv, cat. TsOH, toluene,
reflux), although 3a could not be converted to 4 in the
same way.17 A third stepwise strategy extends access to
an even wider variety of hydrazones. After preparation
of 3a -e, these hydrazones were easily converted to 2a -e
in 92-98% yield by treatment with MeONH2‚HCl in
pyridine (Scheme 3). By this route, 2a -e are available
in pure form for subsequent condensation with aldehydes
of interest. Thus, it is possible to prepare and store one
initial hydrazone in large scale, then exchange or remove
the aldehyde component as needed. Considering the
documented utility of hydrazones derived from 2a ,8,9 one
can expect new N-amino-2-oxazolidinones 2b-e to also
be useful for a variety of asymmetric synthesis objectives.
In conclusion, a highly reliable and efficient method
was developed to prepare chiral N-acylhydrazones from
various commercially available 4-substituted 2-oxazoli-
dinones. Among hydroxylamine-based amination re-
agents, O-(p-nitrobenzoyl)hydroxylamine (NbzONH2) was
found to be most effective for N-amination of 2-oxazoli-
dinones. This optimized procedure facilitates continuing
applications of chiral N-acylhydrazones in various asym-
metric synthesis objectives.
(S)-3-(Ben zylid en e)a m in o-4-d ip h en ylm eth yl-2-oxa zoli-
d in on e (3b). From 1b (100 mg, 0.395 mmol), NaH (60%) (17
mg, 0.425 mmol), NbzONH2 (76 mg, 0.417 mmol), and benzal-
dehyde (0.10 mL, 0.984 mmol) by general procedure A with
chromatography was obtained 3b (96 mg, 68% yield) as a
colorless solid. Recrystallization from 2-propanol afforded color-
less needles: mp 119.5-120 °C; [R]2D5 -189.6 (c 0.35, CHCl3);
IR (film) 3061, 3028, 2914, 1750, 1717, 1598, 1449, 1235, 1214,
1094, 1030, 744, 693 cm-1 1H NMR (500 MHz, CDCl3) δ 8.91
;
(s, 1H), 7.50 (m, 2H), 7.34 (m, 7H), 7.25 (m, 4H), 7.16 (m, 2H),
5.07 (ddd, J ) 8.6, 5.9, 5.5 Hz, 1H), 4.65 (d, J ) 5.9 Hz, 1H),
4.54 (dd, J ) 9.1, 8.6 Hz, 1H), 4.27 (dd, J ) 9.1, 5.7 Hz, 1H); 13
C
NMR (125 MHz, CDCl3) δ 153.7, 151.3, 140.4, 139.0, 134.5, 130.3,
128.9, 128.8, 128.6, 127.5, 127.4, 127.1, 64.7, 60.5, 53.0; MS (CI)
m/z (relative intensity) 357 ([M + H]+, 25). Anal. Calcd for
C
23H20N2O2: C, 77.51; H, 5.66; N, 7.86. Found: C, 77.34; H, 5.65;
N, 7.80.
(S)-3-(Ben zylid en e)a m in o-4-isop r op yl-2-oxa zolid in on e
(3c). From 1c (100 mg, 0.774 mmol), NaH (60%) (33 mg, 0.825
mmol), NbzONH2 (148 mg, 0.813 mmol), and benzaldehyde (0.10
mL, 0.984 mmol) by general procedure A with chromatography
was obtained 3c (81 mg, 45% yield) as
a colorless solid.
Recrystallization from ethanol afforded squarelike crystals: mp
92.5-93 °C; [R]2D5 -94.8 (c 0.31, CHCl3); IR (film) 3062, 3035,
2965, 2916, 1752, 1491, 1413, 1221, 1087, 962, 884 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 8.92 (s, 1H), 7.72 (m, 2H), 7.40 (m,
3H), 4.39 (m, 1H), 4.21 (dd, J ) 10.6, 5.5 Hz, 1H), 4.20 (dd, J )
10.9, 5.5 Hz, 1H), 2.36 (m, 1H), 0.99 (d, J ) 7.0 Hz, 3H), 0.94 (d,
J ) 6.9 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.2, 150.8,
134.5, 130.3, 128.6, 127.3, 62.8, 61.7, 28.5, 17.7, 15.1; MS (CI)
m/z (relative intensity) 233 ([M + H]+, 100). Anal. Calcd for
C13H16N2O2: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.01; H,
6.96; N, 11.95.
Exp er im en ta l Section
Ma ter ia ls a n d Meth od s. Reactions employed oven-dried
glassware under nitrogen unless otherwise noted. Dioxane and
toluene were dried over activated molecular sieves (4 Å). All
other materials were used as received or purified by standard
procedures. Thin-layer chromatography (TLC) employed glass
0.25 mm silica gel plates with UV indicator. Flash chromatog-
raphy columns were packed with 230-400 mesh silica gel as
(S)-3-(Ben zyliden e)am in o-4-ph en yl-2-oxazolidin on e (3d).
From 1d (100 mg, 0.613 mmol), NaH (60%) (25 mg, 0.625 mmol),
NbzONH2 (117 mg, 0.643 mmol), and benzaldehyde (0.10 mL,
0.984 mmol) by general procedure A with chromatography was
obtained 3d (155 mg, 95% yield) as a colorless solid. Recrystal-
lization from 2-propanol afforded colorless needles: mp 157-
158 °C; [R]2D5 -128.3 (c 0.32, CHCl3); IR (film) 3032, 2920, 1770,
(17) (a) Exchange with excess propionaldehyde (cat. p-TsOH) gave
in 70% yield from the corresponding formaldehyde hydrazone.
4
Unfortunately, the latter was obtained in only 32% yield from 1a . (b)
For a related example of the exchange reaction of aldehydes with a
hydrazone, see: Figueiredo, J . M.; Caˆmara, C. de A.; Amarante, E.
G.; Miranda, A. L. P.; Santos, F. M.; Rodrigues, C. R.; Fraga, C. A. M.;
Barreiro, E. J . Bioorg. Med. Chem. 2000, 8, 2243-2248. (c) For an
example of an exchange reaction involving transoximation, see: Clark,
M. A.; Wang, Q.; Ganem, B. Tetrahedron Lett. 2002, 43, 347-349.
1717, 1652, 1588, 1507, 1457, 1404, 1231, 1026, 751 cm-1 1H
;
NMR (500 MHz, CDCl3) δ 7.94 (s, 1H), 7.57 (m, 2H), 7.42 (m,
2H), 7.33 (m, 6H), 5.32 (dd, J ) 9.0, 5.9 Hz, 1H), 4.80 (dd, J )
9.0, 8.5 Hz, 1H), 4.21 (dd, J ) 8.5, 5.9 Hz, 1H); 13C NMR (125
6238 J . Org. Chem., Vol. 67, No. 17, 2002

MHz, CDCl3) δ 154.5, 147.3, 137.1, 133.8, 130.2, 129.6, 129.0,
128.5, 127.4, 125.9, 69.6, 59.4; MS (CI) m/z (relative intensity)
267 ([M + H]+, 100). Anal. Calcd for C16H14N2O2: C, 72.16; H,
5.30; N, 10.52. Found: C, 71.93; H, 5.29; N, 10.42.
(S)-3-Am in o-4-isop r op yl-2-oxa zolid in on e (2c). From 3c
(70 mg, 0.301 mmol) by general procedure B was obtained 2c
(39 mg, 90%) as a colorless oil: [R]2D5 +10.5 (c 0.62, CHCl3); IR
(film) 3336, 3215, 2919, 2849, 1751, 1650, 1559, 1458, 1419,
1
1221, 1118, 1043 cm-1; H NMR (500 MHz, CDCl3) δ 4.24 (dd,
(Ben zylid en e)a m in o-2-oxa zolid in on e 3e. From 1e (100
mg, 0.517 mmol), dioxane (15 mL), NaH (60%) (25 mg, 0.625
mmol), NbzONH2 (110 mg, 0.604 mmol), and benzaldehyde (0.10
mL, 0.984 mmol) by general procedure A with chromatography
was obtained 3e (146 mg, 92% yield) as a colorless solid.
Recrystallization from ethanol afforded colorless needles: mp
160-161 °C; [R]2D5 +405.1 (c 0.32, CHCl3); IR (film) 3065, 3033,
2926, 1773, 1719, 1590, 1459, 1398, 1363, 1200, 1040, 755, 687
J ) 8.9, 8.6 Hz, 1H), 4.01 (dd, J ) 8.9, 7.0 Hz, 1H), 3.96 (broad
s, 2H), 3.69 (ddd, J ) 8.6, 7.0, 4.1 Hz, 1H), 2.20 (m, 1H), 0.93 (d,
J ) 7.0 Hz, 3H), 0.89 (d, J ) 7.0 Hz, 3H); 13C NMR (125 MHz,
CDCl3) δ 159.6, 63.1, 62.6, 28.1, 17.6, 15.4; MS (CI) m/z (relative
intensity) 145 ([M + H]+, 100); high-resolution mass spectrum
(FAB) m/z 145.0984 ([M + H]+), calcd for C6H13N2O2 145.0978.
(S)-3-Am in o-4-p h en yl-2-oxa zolid in on e (2d ). From 3d (79
mg, 0.297 mmol) by general procedure B was obtained 2d (50
mg, 95%) as a colorless solid: [R]2D5 +87.5 (c 1.6, CHCl3); IR
(film) 3343, 3215, 3188, 2915, 1756, 1627, 1458, 1414, 1215,
1
cm-1; H NMR (500 MHz, CDCl3) δ 9.07 (s, 1H), 7.78 (m, 2H),
7.63 (d, J ) 7.8 Hz, 1H), 7.44 (m, 3H), 7.40-7.25 (m, 3H), 5.64
(d, J ) 7.4 Hz, 1H), 5.40 (ddd, J ) 7.4, 6.0, 1.5 Hz, 1H), 3.48
(dd, J ) 16.0, 6.0 Hz, 1H), 3.41 (dd, J ) 16.0, 1.5 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 152.8, 149.6, 140.1, 138.5, 134.6, 130.3,
129.8, 128.7, 127.7, 127.3, 126.1, 125.5, 77.1, 65.6, 38.7; MS (CI)
m/z (relative intensity) 279 ([M + H]+, 100). Anal. Calcd for
C17H14N2O2: C, 73.37; H, 5.07; N, 10.07. Found: C, 73.41; H,
5.07; N, 10.05.
1
1108, 1026, 959 cm-1; H NMR (500 MHz, CDCl3) δ 7.44-7.36
(m, 3H), 7.33-7.30 (m, 2H), 4.76 (dd, J ) 8.5, 7.7 Hz, 1H), 4.58
(dd, J ) 9.2, 8.5 Hz, 1H), 4.09 (dd, J ) 9.2, 7.7 Hz, 1H), 3.82 (s,
broad, 2H); 13C NMR (125 MHz, CDCl3) δ 159.0, 137.0, 129.2,
129.0, 126.9, 68.7, 63.4; MS (CI) m/z (relative intensity) 179 ([M
+ H]+, 100). Anal. Calcd for C9H10N2O2: C, 60.66; H, 5.66; N,
15.72. Found: C, 60.50; H, 5.70; N, 15.84.
(S)-3-(1-P r op ylid en e)a m in o-4-p h en ylm eth yl-2-oxa zolid i-
n on e (4) a n d (S)-3-(Cycloh exylm eth ylid en e)a m in o-4-p h e-
n ylm eth yl-2-oxa zolid in on e (5). From 1a (200 mg, 1.13 mmol),
NaH (60%) (47 mg, 1.17 mmol), and NbzONH2 (216 mg, 1.19
mmol) was obtained crude 2a (257 mg) as described in general
procedure A. This sample was divided into two parts for
condensation with two different aldehydes as described below.
A mixture of crude 2a (126 mg), propionaldehyde (0.04 mL,
0.55 mmol), and TsOH‚H2O (2 mg) in toluene (0.5 M) was stirred
at reflux. Upon completion (TLC), concentration and gradient
flash chromatography (hexane f 2:1 hexane/EtOAc) furnished
48a (93 mg, 73% yield from 1a ) as a colorless oil.
A mixture of crude 2a (131 mg), cyclohexane carboxaldehyde
(0.07 mL, 0.58 mmol), and TsOH‚H2O (2 mg) in toluene (0.5 M)
was stirred at reflux. Upon completion (TLC), concentration and
gradient flash chromatography (hexane f 2:1 hexane/EtOAc)
furnished 58a (120 mg, 77% yield from 1a ) as a colorless oil.
Gen er a l P r oced u r e B: N-Am in o-2-oxa zolid in on es fr om
Hyd r a zon es. To a solution of hydrazone 3 in pyridine (0.1-0.3
M) was added methoxylamine hydrochloride (3.0-3.5 equiv).
After 2 d at room temperature, concentration and gradient flash
chromatography (hexane f 1:2 hexane/EtOAc) afforded hydra-
zine 2.
3-Am in o-2-oxa zolid in on e 2e. From 3e (102 mg, 0.366
mmol) by general procedure B was obtained 2e (65 mg, 93%) as
a colorless solid: [R]2D5 -78.5 (c 0.85, CHCl3); IR (film) 3330,
3218, 3043, 2924, 1751, 1635, 1461, 1405, 1329, 1205, 1108, 1033
cm-1 1H NMR (500 MHz, CDCl3) δ 7.64 (d, J ) 7.7 Hz, 1H),
;
7.34 (dd, J ) 7.7, 7.7 Hz, 1H), 7.29-7.26 (m, 2H), 5.26 (ddd, J
) 7.3, 6.9, 1.5 Hz, 1H), 5.12 (d, J ) 7.5 Hz, 1H), 4.03 (broad s,
2H), 3.41 (dd, J ) 17.9, 6.9 Hz, 1H), 3.29 (dd, J ) 17.9, 1.5 Hz,
1H); 13C NMR (125 MHz, CDCl3) δ 157.9, 140.2, 138.2, 129.6,
127.4, 125.7, 125.5, 76.6, 65.9, 39.1; MS (CI) m/z (relative
intensity) 191 ([M + H]+, 100). Anal. Calcd for C10H10N2O2: C,
63.14; H, 5.30; N, 14.73. Found: C, 62.93; H, 5.37; N, 14.74.
Hyd r a zon e In ter con ver sion by Exch a n ge of th e Ald e-
h yd e Com p on en t: (S)-3-(1-Ben zylid en e)a m in o-4-p h en yl-
m eth yl-2-oxa zolid in on e (3a ). A mixture of 4 (52 mg, 0.240
mmol), benzaldehyde (0.08 mL, 0.79 mmol), and TsOH‚H2O (3
mg) in toluene was heated at reflux for 1 h. Concentration and
gradient flash chromatography (hexane f 2:1 hexane/EtOAc)
afforded hydrazone 3a 8a (61 mg, 90%) as a colorless solid.
Ack n ow led gm en t. Initial studies of some amina-
tion reactions by Mr. J un Qin and Mr. Hui Ding are
gratefully acknowledged. High-resolution mass spec-
trometry was provided by the Washington University
Mass Spectrometry Resource, an NIH Research Re-
source (Grant No. P41RR00954). We thank the NSF
(CHE-0096803), Research Corporation, Petroleum Re-
search Fund, Vermont EPSCoR, and the University of
Vermont for generous support.
(S)-3-Am in o-4-p h en ylm eth yl-2-oxa zolid in on e (2a ). From
3a (30 mg, 0.106 mmol) by general procedure B was obtained
2a 8a (20 mg, 98%) as a colorless oil.
(S)-3-Am in o-4-diph en ylm eth yl-2-oxazolidin on e (2b). From
3b (30 mg, 0.084 mmol) by general procedure B was obtained
2b (21 mg, 93%) as a colorless solid; [R]2D5 +42.0 (c 0.75, CHCl3);
IR (film) 3338, 3215, 3028, 2918, 1762, 1617, 1496, 1419, 1222,
1093, 1031 cm-1 1H NMR (500 MHz, CDCl3) δ 7.35-7.30 (m,
;
4H), 7.28-7.20 (m, 6H), 4.58 (dd, J ) 15.1, 6.9 Hz, 1H), 4.40-
4.35 (m, 2H), 4.08 (dd, J ) 9.1, 6.9 Hz, 1H), 3.70 (broad s, 2H);
13C NMR (125 MHz, CDCl3) δ 158.9, 140.7, 139.3, 129.0, 128.9,
128.5, 128.3, 127.5, 127.3, 65.5, 61.7, 54.3; MS (CI) m/z (relative
intensity) 269 ([M + H]+, 100); high-resolution mass spectrum
(FAB) m/z 269.1283 ([M + H]+), calcd for C16H17N2O2 269.1291.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 2b-e and 3b-e. This material is available free of
charge via the Internet at http://pubs.acs.org.
J O0259663
J . Org. Chem, Vol. 67, No. 17, 2002 6239