Stereoselective dimerization of chiral α-bromoamides promoted by Fe(Co)5

Article abstract of DOI:10.1023/A:1011398215836

Organic α-bromocarboxylates react with aldehydes and ketones in the presence of Fe(CO)₅ (the Reformatsky-type reactions). Unlike them, N-oxazolidinone derivatives of the same acids undergo diastereoselective reductive dimerization to give (2S,3S)-dimers, regardless of the configuration of the α-chiral center in the starting reagent.

Full text of DOI:10.1023/A:1011398215836

548
Russian Chemical Bulletin, International Edition, Vol. 50, No. 3, pp. 548—550, March, 2001
Stereoselective dimerization of chiral α-bromoamides promoted by Fe(CO)5
N. Yu. Kuznetsov, V. N. Khrustalev, A. B. Terentiev, and Yu. N. Belokon´«
A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences,
28 ul. Vavilova, 117813 Moscow, Russian Federation.
Fax: +7 (095) 135 5085. E-mail: belokon@ineos.ac.ru
Organic α-bromocarboxylates react with aldehydes and ketones in the presence of
Fe(CO)5 (the Reformatsky-type reactions). Unlike them, N-oxazolidinone derivatives of the
same acids undergo diastereoselective reductive dimerization to give (2S,3S)-dimers, regard-
less of the configuration of the α-chiral center in the starting reagent.
Key words: N-(α-bromoacyl)oxazolidinones, iron pentacarbonyl, diastereoselective dimer-
ization.
Earlier, it was shown that Fe(CO)5 effectively pro-
motes the Reformatsky-type reactions.1,2 Thus, methyl
α-bromopropionate adds to benzaldehyde in boiling
benzene in the presence of Fe(CO)5 to give hydroxyester.
Moreover, we have recently found that methyl dibromo-
acetate and methyl trichloroacetate in an HMPA solu-
tion add to benzaldehyde at room temperature.3 For the
purpose of synthesizing the desired stereoisomers of
β-hydroxyesters or their derivatives, we tried to in-
volve (4R)-N-(α-bromoacyl)-4-phenyloxazolidin-2-ones
(1à—c) in this reaction. Starting reagents were prepared
by acylating (R)-4-phenyloxazolidin-2-one (2) with the
corresponding α-bromine-containing acid bromides.
However, it turned out that amides 1a—c form no
adducts with aldehydes either in boiling benzene or in
an HMPA solution at room temperature. At the same
time, refluxing bromides 1a—c with an equimolar amount
of Fe(CO)5 results in diastereoselective reductive dimer-
ization of the amides (Scheme 1).
Although 2,3-dialkylsuccinamides (3a—c) can form
three isomers, the reaction affords only the (2S,3S)-iso-
mer. The structure of dimers 3a—c and their absolute
configuration were determined by X-ray diffraction analy-
sis. The structure of the dimer with R = Et is shown in
Fig. 1. Its molecule contains four chiral atoms (C(4),
C(7), C(8), and C(14)). The C(4) and C(14) atoms
originally possess (R)-configuration, while the new
chiral centers (C(7) and C(8)) have inverse, (S)-con-
figuration. Amides 1a,b containing a linear alkyl
R (Me and Et) afford dimers in virtually quantitative
yield.
The same dimer is formed from the (4R,α-S)- and
(4R,α-R)-isomers, i.e., independently of the configura-
tion of the α-chiral center in starting compounds 1a—c.
The dimerization conditions suggest that a high
C(24)
C(21)
C(7)
C(22)
O(2)
C(2)
C(23)
Scheme 1
C(8)
R
R
O(11)
C(11)
O
O
S
S
C(6)
O(6)
C(9)
O(9)
O(12)
O(1)
O
N
N
O
R
N(3)
C(4)
Br
O
O
N(10)
C(14)
R
R
N
O
C(13)
R
C(5)
C(15)
O
O
C(25)
C(16)
C(17)
C(30)
1a—c
3a—c
Com-
R
Yield
de
C(20)
C(19)
C(26)
C(27)
C(29)
C(28)
pound
%
a
b
c
Me
Et
Pri
96
95
30
>99
>99
>99
C(18)
Reagents and conditions: Fe(CO)5, PhH—THF (10 : 1), reflux-
ing for 4 h.
Fig. 1. Crystal structure of dimer 3b (R = Et).
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 525—527, March, 2001.
1066-5285/01/5003-548 $25.00 © 2001 Plenum Publishing Corporation

Stereoselective dimerization of chiral α-bromoamides Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
549
(2.5½26 cm) in CHCl3—EtOAc—C6H14 (8 : 1 : 5). The isomer
diastereoselectivity of radical dimerization is due to the
formation of an intermediate chelate with iron ions.
25
with Rfmax, m.p. 89—90 °C (hexane—EtOAc), [α]D –108.9
(c 1, CHCl3). Found (%): C, 50.14; H, 4.60; Br, 25.56; N, 4.45.
C13H14NO3Br. Calculated (%): C, 50.02; H, 4.52; Br, 25.60;
N, 4.49. The isomer with Rfmin, m.p. 81—82 °C (hexane),
Experimental
25
[α]D –52.8 (c 1, CHCl3). Found (%): C, 49.98; H, 4.60;
Br, 25.64; N, 4.36. C13H14BrNO3. Calculated (%): C, 50.02;
1
H and 13C NMR spectra were recorded on Bruker WP-
H, 4.52; Br, 25.60; N, 4.49.
200-SY and Bruker AMX-400 spectrometers (200.13 and
400.13 MHz, respectively). Chemical shifts (CDCl3) are re-
ferred to HMDS or Me4Si as the internal standards. Optical
rotation was measured on a Perkin—Elmer M-241 polarimeter
in a thermostatically controlled cell at 25 °C. GLC analysis was
carried out on an LKhM-80 chromatograph using a steel column
(1300½3 mm) with 15% SKTFT-50Kh and a Carbowax-20000
column with Chromaton-N-AW (helium was used as the carrier
gas (40—60 cm3 min–1), katharometer as a detector). Prepara-
tive GLC was performed on a steel column (1300½9 mm) with
20% SKTFT-50Kh using the same stationary phase and helium
as the carrier gas (120 cm3 min–1). Enantiomeric analysis was
carried out on a 3700-00 gas chromatograph equipped with a
flame ionization detector; columns (32 000 ½ 0.20 mm)
were filled with a DP-TFA-γ-cD chiral phase. In the case
of methyl derivatives, an SE-54 capillary quartz column
(25 000 ½ 0.20 mm) was used. Column chromatography used
Kieselgel 60 silica gel (Merck). TLC was performed on 60 F254
glass or aluminum plates coated with SiO2 or Al2O3 (Merck).
Preparative TLC was carried out on glass plates with LSL254 5/40
silica gel (Chemapol).
(4´R,2R)- and (4´R,2S)-2-Bromo-3-methyl-1-(2´-oxo-4´-
phenyloxazolidin-3´-yl)-butan-1-one (1c). The reaction mixture
was concentrated to an oil, which was crystallized by trituration
with hexane for a long time. The hexane was decanted, and
another portion of hexane was added. The precipitate was left
for 12 h, then filtered off, and dried. The yield of 1c was 78%.
Found (%): C, 50.97; H, 4.82; Br, 24.55. C14H16BrNO3. Cal-
culated (%): C, 51.55; H, 4.95; Br, 24.49. 1H NMR,
δ: 7.35—7.32 (m, 5 H); 5.51—5.40 (m, 2 H); 4.70 (m, 1 H);
4.27 (m, 1 H); 2.03 (m, 1 H); 1.06 (d, relates to one of the
diastereoisomers, 1.5 H, J = 6.4 Hz); 0.97 (inequivalent triplet,
3 H); 0.82 (d, 1.5 H, J = 6.6 Hz). The diastereoisomers with
Rfmax (m.p. 110—111 °C) and Rfmin (m.p. 89—90 °C) were
separated as described above.
Asymmetric dimerization promoted by Fe(CO)5. 2,3-Di-
methyl-1,4-bis(2´-oxo-4´-phenyloxazolidin-3´-yl)butane-1,4-
dione (3à). A mixture of diastereoisomers 1à (3 g, 10 mmol)
was dissolved in a mixture of PhH (15 mL) and THF (5 mL).
Iron pentacarbonyl (1.4 mL, 10 mmol) was added, and the
solution was degassed by three cycles of evacuating—freez-
ing—pumping with argon and refluxed until the evolution of CO
ceased (∼1.5 h). The yield of dimer 3à was 90%, m.p.
Preparation of chiral amides of α-bromo acids. (4´R,2R)-
and (4´R,2S)-2-bromo-1-(2´-oxo-4´-phenyloxazolidin-3´-yl)pro-
pan-1-ones (1a). A 60% suspension of NaH (0.52 g, 13 mmol)
in oil was added to a solution of (R)-4-phenyloxazolidin-2-one
(2) (1.6 g, 10 mmol) in 25 mL of anhydrous THF (Àr). Stirring
was continued until gas evolution ceased. The resulting thick
suspension was cooled to –78 °C with an acetone—solid CO2
mixture, and a solution of α-bromopropanoyl bromide (2.38 g,
1.16 mL, 11 mmol) in 5 mL of THF was added dropwise. The
reaction mixture was stirred for 1.5 h until the starting com-
pound 2 disappeared completely (monitoring by TLC in hex-
ane—THF (1.5 : 1)), filtered through a thin layer of silica gel on
a glass filter, and additionally washed with THF. The filtrate
was concentrated in vacuo to give a yellow oil, which solidified
upon adding hexane. The solid product was crushed, washed
with hexane, filtered off, and dried in vacuo. The yield of the
mixture of diastereoisomers was 2.56 g (86%). Found (%):
C, 47.97; H, 3.82; Br, 25.95. C12H12BrNO3. Calculated (%):
C, 48.34; H, 4.06; Br, 26.80. Diastereoisomers 1a were sepa-
rated by column chromatography on SiO2 in THF—hexane
(1 : 1.5). Recrystallization of each isomer from a hexane—EtOAc
mixture gave the isomers with Rfmax (m.p. 134—135 °C) and
Rfmin (m.p. 149—152 °C) (cf. Ref. 4: m.p. 136—137 °C (Rfmax);
m.p. 151—154 °C (Rfmin)). Found (%): C, 48.72; H, 4.26;
Br, 26.05. C12H12BrNO3. Calculated (%): C, 48.34; H, 4.06;
Br, 26.80. 1H NMR (for the diastereoisomer with Rfmax),
δ: 7.38—7.33 (m, 5 H); 5.72 (q, 1 Hα, J = 6.7 Hz); 5.43 (br.d,
1 H, J = 8.3 Hz); 4.77 (t, 1 H, J = 8.5 Hz); 4.35 (d, 1 H,
25
220—222 °C, [α]D –209 (c 1, acetone). Found (%): C, 66.10;
H, 5.66; N, 6.35. C24H24NO6. Calculated (%): C, 66.04; H, 5.54;
N, 6.42. 1H NMR, δ: 7.04 (m, 5 H); 5.32 (dd, 1 H, J = 3.1 and
8.4 Hz); 4.58 (t, 1 H, J = 8.6 Hz); 4.11—4.05 (m, 2 H); 1.14 (d,
3 H, J = 6.0 Hz). 13C NMR, δ: 175.97 (C(1)=O); 153.67
(C(2)=O); 138.89 (C(1), Ar); 129.29 (C(2) and C(6), Ar);
128.61 (C(4), Ar); 125.31 (C(5) and C(3), Ar); 70.60 (C—N);
57.95 (C—O); 40.50 (Cα); 14.57 (Me).
2,3-Diethyl-1,4-bis(2´-oxo-4´-phenyloxazolidin-3´-yl)-
butane-1,4-dione (3b). Dimerization of 1b was carried out
analogously for 1 h. The yield of dimer 3b was 95%, m.p.
25
215—216 °C, [α]D
–128.3 (c 0.3, CHCl3). Found (%):
C, 67.41; H, 6.36; N, 6.05. C26H28N2O6. Calculated (%):
C, 67.23; H, 6.08; N, 6.03. 1H NMR, δ: 7.29—7.25 (m, 5 H);
5.42 (dd, 1 H, J = 4.3 and 8.5 Hz); 4.65 (t, 1 H, J = 8.6 Hz);
4.18 (m, 2 H).
2,3-Diisopropyl-1,4-bis(2´-oxo-4´-phenyloxazolidin-3´-
yl)butane-1,4-dione (3c). A mixture of diastereoisomers 1c
(0.49 g, 1.5 mmol) was dissolved in 4 mL of PhH containing a
small amount of THF (0.4 mL). Iron pentacarbonyl was added
(0.21 mL, 1.5 mmol), and the reaction mixture was refluxed for
2 h until the evolution of CO ceased. The above workup gave a
mixture of dimer (2S,3S)-3c (the yield of the recrystallized
product was 30%), 4-phenyloxazolidin-2-one (15%, identified
by TLC with an authentic sample), and the reduction product
of 1c, namely, (4´R)-3-methyl-1-(2´-oxo-4´-phenyloxazolidin-
3´-yl)butan-1-one (4) (yield 40%, for 1H NMR data, see
below). Dimer (2S,3S)-3c crystallizes from a CHCl3—C6H14
mixture, m.p. 223—225 °C. Found (%): C, 68.10; H, 6.46;
N, 5.60. C14H16NO3. Calculated (%): C, 68.27; H, 6.55; N, 5.69.
1H NMR, δ: 6.99 (m, 5 H); 5.34 (dd, 1 H, J = 1.8 and 7.7 Hz);
4.48 (m, 2 H); 4.02 (dd, 1 H, J = 1.8 and 8.6 Hz); 2.08 (m,
1 H); 1.03 (d, 6 H, J = 6.8 Hz). The mother liquor was
separated by preparative TLC on SiO2. The fraction with Rfmax
was found to be a derivative of 1c, in which the Br atom is
replaced by the H atom (4). 1H NMR, δ: 7.31 (m, 5 H); 5.39
1
J = 8.8 Hz); 1.77 (d, 3 H, J = 6.7 Hz). H NMR (for the
diastereoisomer with Rfmin), δ: 7.41—7.38 (m, 5 H); 5.76 (q,
1 Hα, J = 6.7 Hz); 5.45 (dd, 1 H, J = 8.8 and 5.1 Hz); 4.74 (t,
1 H, J = 8.9 Hz); 4.28 (dd, 1 H, J = 9.0 and 5.1 Hz); 1.77 (d,
3 H, J = 6.7 Hz).
An analogous procedure was used to prepare (4´R,2R)- and
(4´R,2S)-2-bromo-1-(2´-oxo-4´-phenyloxazolidin-3´-yl)butan-1-
ones (1b). A mixture of diastereoisomers 1b (1 : 1) was obtained
in 95% yield and separated as described above on a column

550
Russ.Chem.Bull., Int.Ed., Vol. 50, No. 3, March, 2001
Kuznetsov et al.
(dd, 1 H, J = 4.4 and 8.4 Hz); 4.62 (t, 1 H, J = 8.4 Hz); 4.20
(dd, 1 H, J = 4.7 and 8.4 Hz); 2.85 (dd, 1 CHaHb, J = 6.4 and
15.7 Hz); 2.68 (dd, 1 CHaHb, J = 7.0 and 15.7 Hz); 2.08 (m,
1 H); 0.85 (dd, 6 H, J = 6.4 and 3.0 Hz). According to the
1H NMR data, the fraction with Rfmin includes dimer
(2S,3S)-3c, 4-phenyloxazolidin-2-one (2), and an unidentified
product. The mixture was separated by preparative TLC on
glass plates covered with Al2O3 (Merck, 60254 Type E) in
CCl4—CHCl3—C6H14 (1 : 2 : 3).
2. A. B. Terentiev, T. T. Vasilieva, N. A. Kuz´mina, E. I.
Mysov, N. Yu. Kuznetzov, and Yu. N. Belokon´, Izv. Akad.
Nauk, Ser. Khim., 1999, 1132 [Russ. Chem. Bull., 1999, 48,
1121 (Engl. Transl.)].
3. A. B. Terentiev, T. T. Vasilieva, N. A. Kuz´mina, O. V.
Chakhovskaya, E. S. Brodskii, and Yu. N. Belokon´, Izv.
Akad. Nauk, Ser. Khim., 2000, 718 [Russ. Chem. Bull., Int.
Ed., 2000, 49, 722].
4. I. Ito, A. Sasaki, K. Tamoto, M. Sunagava, and S. Terashima,
Tetrahedron, 1991, 47, 2801.
References
1. A. B. Terentiev, T. T. Vasilieva, N. A. Kuz´mina, E. I.
Mysov, N. Yu. Kuznetzov, and Yu. N. Belokon´, J. Chem.
Res., 1998, (S) 306, (M) 1281.
Received June 7, 2000;
in revised form October 19, 2000