1712
M. Mąkosza et al.
LETTER
3 with propylene oxide in ethanol at room temperature.14
Yields are presented in Table 1.
H
NO2
O
O
t-Bu
H
In summary, we have developed a new method for the
synthesis of optically pure (R)-a-(p-nitroaryl)prolines via
oxidative nucleophilic substitution of hydrogen in nitro-
arenes with carbanion of protected proline 1.
N
H
Figure 2 The NOE experiment of 2a, irradiation of protons of t-Bu
group
Acknowledgment
Table 1 Reaction of Compound 1 with Various Nitroarenes
This work was partially supported by Ministerium of Science and
Higher Education, Grant N204 0304 33
Nitroarene Product
Yield (%)
Product
Yield (%)
H
2a
2b
2c
2d
2e
2f
72
29
37
31
43
15
3a
3b
–
77
85
–
References and Notes
3-F
(1) Summer Trainee from Higher Chemical College, Moscow.
(2) Magaard, V. W.; Sanches, S. R.; Bean, J. W.; Moore, M. L.
Tetrahedron Lett. 1993, 34, 381.
(3) (a) Madger, A. B.; Witkop, B. Chem. Rev. 1966, 66, 47.
(b) Harrison, T.; Williams, B. J.; Swain, C. J. Bioorg. Med.
Chem. Lett. 1994, 4, 2733.
(4) (a) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2004, 53,
5183. (b) Vingola, N.; List, B. J. J. Am. Chem. Soc. 2003,
125, 450.
(5) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J. Am.
Chem. Soc. 1983, 105, 5390.
2-F
2-Cl
2-MeO
2-Me
–
–
3ea
–
55
–
a The product contains 4-nitro-3-hydroxyphenyl group due to O-de-
methylation.
(6) Tayama, E.; Kimura, H. Angew. Chem. Int. Ed. 2007, 46,
886.
(7) Bajgrowicz, J.; Achquar, A. E.; Roumestant, M.-L.; Pigiere,
C.; Viallefont, P. Heterocycles 1986, 24, 2165.
(8) Van Betsbrugge, J.; Tourwe, D.; Kaptein, D.; Kierkels, H.;
Broxterman, R. Tetrahedron 1997, 52, 9233.
took place selectively in the position para to the nitro
group.
On the basis of NMR spectra, particularly NOE experi-
ment of product 2a, it was found that tert-butyl and p-ni-
trophenyl groups are in cis relation to each other
(Figure 2). This means that the nucleophilic center is at-
tacked by nitroarene from the Re face, giving product pos-
sessing R-configuration at the a-position.
(9) Mąkosza, M.; Surowiec, M.; Szczepańska, A.; Sulikowski,
D.; Maltsev, O. Synlett 2007, 470.
(10) (a) Synthesis of 1 was carried out according a literature
procedure (see ref. 10b) with slight modification.
Preparation of Compound 1
To a solution of trimethylsilyl ester of N-trimethylsilyl-L-
proline (28.8 g, 0.111 mol) in dry n-pentane (23 mL) under
argon, pivalaldehyde (12.1 mL, 0.111 mol) was added very
slowly. During the addition temperature must be kept below
20 °C cooling in water bath with ice, reaction is exothermic.
Overheating the reaction mass above 30 °C cause partial
decomposition of the product. After 1 h, the resulting
solution was cooled to –70 °C and the crystalline product
was filtered and dried; yield 20.3 g, 82%. (a) Annunziata,
R.; Ferrari, M.; Papeo, G.; Resmini, M. Synth. Commun.
1997, 27, 23.
Unfortunately the reaction of 1– with other nitroarenes un-
der identical conditions gave products 2 only in moderate
yields (Table 1).
Attempting to improve yields, we have checked the possi-
bility to optimize the reaction conditions between 1– and
m-fluoronitrobenzene. Thus, changing of the reaction
time (addition and oxidation step), temperature (–40 °C
and –60 °C instead of –78 °C), base (KOt-Bu, NaHMDS),
and oxidant (p-chloranil, tetracyanoethylene, KMnO4 in
liquid ammonia, 1,1-dimethyldioxirane) does not improve
the results. It should be noted that there is no correlation
between electrophilic activity of nitroarenes and yields of
the ONSH products. Thus, strongly deactivated and mod-
erately activated 2-methoxy and 2-fluoronitrobenzene
gave ONSH products in moderate yields, whereas the re-
action with highly activated 2- and 3-nitrobenzonitrile
failed. It was difficult to clarify which step – addition or
oxidation – was responsible for the failure. One could sup-
pose that an alternative process between 1– and nitro-
arenes takes place so that sH-adducts are not formed.
(11) (a) Usse, S.; Guillaumet, G.; Viaud, M.-C. J. Org. Chem.
2000, 914. (b) Papillon, J. P. N.; Taylor, R. J. K. Org. Lett.
2000, 2, 1987.
(12) (a) Mąkosza, M.; Winiarski, J. Acc. Chem. Res. 1987, 20,
282. (b) Mąkosza, M.; Surowiec, M. Tetrahedron 2003, 59,
6261.
(13) General Procedure
To a solution of 1 (1 mmol), nitroarene (2 mmol) in THF (10
mL), and DMF (2 mL), cooled to –78 °C, 0.5 M solution of
KHMDS in toluene (3 mL, 1.5 mmol) was added dropwise
during 10 min. The resulting dark-colored mixture was
stirred for 30 min at the same temperature and then treated
with a solution of DDQ (1.2 mmol) in THF (1 mL). After
stirring for further 5 min at –78 °C, a brown slurry was
slowly allowed to reach r.t. Aqueous workup gave crude
product, which was purified by column chromatography.
Selected Analytical Data
Final products 3, free a-(p-nitroaryl)prolines, were ob-
tained via hydrolysis of 2 according to the literature pro-
cedure using aqueous HBr,5 followed by precipitation of
Compound 2a: mp 88–90 °C (MeOH); [a]D22 +0.8 (c 1.000,
Synlett 2008, No. 11, 1711–1713 © Thieme Stuttgart · New York