Synthesis of N,N-dimethylpropanediamide and its utility for the preparation of 2-(acetamidomethyl)-4-aryloxazoles

Article abstract of DOI:10.1055/s-2004-825607

A practical, readily scaleable synthesis of N,N-dimethylpropanediamide (1) is reported. The utility of this bis-amide is demonstrated in the preparation of several 2,4-disubstituted oxazoles from α-bromoketones.

Full text of DOI:10.1055/s-2004-825607

1334
LETTER
Synthesis of N,N-Dimethylpropanediamide and its Utility for the Preparation
of 2-(Acetamidomethyl)-4-aryloxazoles
P
reparatio
o
n of 4-Arylo
h
xazole
s
n A. Ragan,* Michael Burmaster, Paul D. Hill
Chemical Research & Development, Pfizer Global Research & Development, Groton, Connecticut, 06340, USA
Fax +1(860)7159469; E-mail: john_a_ragan@groton.pfizer.com
Received 9 February 2004
Dedicated to Professor Clayton Heathcock in honor of his stewardship of the College of Chemistry at the University of California,
Berkeley, and in recognition of his seminal contributions to organic synthesis, particularly in the areas of biomimetic alkaloid synthesis
and acyclic stereocontrol
prone to trans-amination, we treated 4 (or 5) with 2 M
Abstract: A practical, readily scaleable synthesis of N,N-dimethyl-
Me2NH in MeOH. After three days at room temperature,
concentration and trituration with isopropanol provided 1
propanediamide (1) is reported. The utility of this bis-amide is
demonstrated in the preparation of several 2,4-disubstituted ox-
as a white solid, which was isolated by filtration in 87%
yield on 50 g scale. We suspect that this remarkably facile
ester-amide exchange is due to the intermediacy of ketene
6.4,5
azoles from a-bromoketones.
Key words: oxazole, bromo-ketone, annulation, N,N-dimethylpro-
panediamide, heterocycle
O
HO
O
DCC
HOBT;
Oxazoles are an important class of heterocycles, due to
their ubiquity as both secondary metabolites and pharma-
cologically active agents.1 We recently required a method
for preparing 2-(acetamidomethyl)-4-aryl-oxazoles such
as 2 (Figure 1). Preparation of 2-alkyl-substituted ox-
azoles from primary amides and a-bromoketones is
known,2 suggesting that direct access to oxazole 2 could
be realized from bis-amide 1 and the appropriate bro-
moketone. While bis-amides similar to 1 have been re-
ported, we were surprised to find no experimental data
describing the synthesis of 1.3 Herein we describe a
practical synthesis of 1 and demonstrate its utility in the
preparation of a variety of 2,4-disubstituted oxazoles 2.
H2N
O
Me2NH
MeOH
O
N
N
aq NH3
O
O
O
O
3
1
Scheme 1
On larger scale, it was more convenient to use gaseous
Me2NH. A methanol solution of 4 and 5 was treated with
three equivalents of gaseous Me2NH, added portionwise
over the course of 3–4 days. The reaction was monitored
1
by concentration of an aliquot and analysis by H NMR.
When >90% conversion was reached, the methanol was
displaced with isopropanol, and the product collected by
filtration. This procedure provided an 86% yield on 1 kg
scale.
R
R
H2N
O
O
N
O
+
N
N
Br
O
O
H2N
H2N
O
H2N
O
Me2NH
MeOH
2
1
O
OR
C
O
N
O
Figure 1
O
4 (R = Me)
5 (R = Et)
1
6
Our first synthesis of bis-amide 1 utilized a strategy de-
scribed by Gellman to prepare a variety of unsymmetrical
malonamides from Meldrum’s acid (Scheme 1).3 Amide-
acid 3 was prepared by condensation of dimethylamine
with Meldrum’s acid, as described by Gellman. Activa-
tion with DCC and HOBT, followed by condensation with
aqueous ammonia, provided bis-amide 1, albeit in modest
yield and contaminated with residual HOBT-derived
impurities.
Scheme 2
With access to bis-amide 1, we examined its condensation
with a range of a-bromoketones (Table 1). It was found to
be an effective reagent for formation of 2,4-disubstituted
oxazoles by simply combining with the requisite bro-
moketone and warming to 100 °C in the polar, aprotic
solvent N-methylpyrrolidinone (NMP). Following an
aqueous workup, products were isolated by either tritura-
tion with isopropyl ether (IPE) (entries 1, 2), or by flash
chromatography (entries 3–9). Most of the products were
solids, and could be further purified by recrystallization
from ethyl acetate–hexane.
We next turned to commercially available methyl malona-
mide 4 (Scheme 2). Reasoning that the increased acidity
of the central methylene might render this ester more
SYNLETT 2004, No. 8, pp 1334–1338
0
1.
0
7.
2
0
0
4
Advanced online publication: 18.05.2004
DOI: 10.1055/s-2004-825607; Art ID: Y00504ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Preparation of 4-Aryloxazoles
1335
H2N
O
Table 1 Data for the Condensation of Bis-amide 1 with
Bromoketones to Provide Oxazole 2
N
Entry Bromoketone
Product
Yield (mp, °C) a
O
R
R
1
O
N
O
O
O
N
1
58%
(103.4–107.1)
Br
NMP
100 °C
Br
N
N
O
O
O
2
O
Scheme 3 Condensation of bis-amide 1 with bromoketones to
provide oxazole 2 (see data in Table 1)
2a
2
59%
O
O
Br
(135.1–138.0)
N
The majority of examples provided moderate to good
yields (57–68%, entries 1–4, 7, 8). In these examples, the
desired oxazole was the major product observed by TLC
and 1H NMR analysis. Silica gel chromatography retained
a fair amount of colored impurities at the baseline, sug-
gesting that the remaining mass balance was accounted
for by competing processes that generated significantly
more polar materials.
N
O
Br
Br
Br
2b
3
4
5
57%
(110.8–112.0)
O
O
N
Br
N
O
Br
Electron deficient arenes were less efficient (entries 5 and
6), particularly the 4-nitro case (entry 5, 27% yield). One
reason for this was competitive formation of the bromo-
reduction product 4-nitroacetophenone, which was isolat-
ed in 11% yield. The remaining mass balance was prima-
rily in highly colored, polar impurities which remained at
the baseline on silica gel, and which were not character-
ized. Interestingly, the meta-substituted nitro analogue
suffers less severely from this effect (entry 6, 46% yield).
2c
63%
(107.9–108.0)
O
O
Br
N
N
O
2d
27%
O
O
(197.1–197.2)b
Br
N
N
O
O2N
Entry 9 represents the only example in which there is an
enolizable position a to the ketone on the other side of the
a-bromo substituent. This substrate was also less efficient
(39% yield), although apparently not due to enolization
away from the a-bromoketone, as the optical purity was
retained (as described below).
O2N
2e
6
7
46%
O
O
N
(147.7–149.2)c
O2N
Br
N
O
O2N
For entry 9, the question arises as to whether racemization
of the phenylalanine-derived chiral center occurs under
the reaction conditions. This was investigated by cleavage
of the CBZ group and acylation of primary amine 9 with
each enantiomer of Mosher’s acid chloride (Scheme 4);
three equivalents of the acid chloride were utilized to min-
imize potential kinetic resolution of amine enantiomers.
The resulting diastereomeric amides (10 and 11) were
readily separable by HPLC, and each diastereomer was
formed as a single isomer within the limits of HPLC de-
tection. Had racemization occurred, a mixture of diastere-
omers would be observed, in a ratio corresponding to the
ratio of enantiomers in amine 9.6 Thus, oxazole 8 was
formed as a single enantiomer within the limits of detec-
tion, retaining the optical purity of the precursor a-bro-
moketone.
2f
59%
(130.1–131.6)
O
N
O
O
O
Br
O
N
O
O
2g
8
9
68%
(62.8–63.9)
O
O
Br
N
N
O
7
39% (oil)
O
O
N
H
BnO
N
Br
N
O
The literature precedent for the indicated oxazole regio-
isomer is compelling, and is accounted for by the mecha-
nism shown in Scheme 5 (O-alkylation of the bromide
followed by cyclization). Because this outcome is not nec-
essarily predictable a priori (e.g. N-alkylation of the bro-
mide would lead to the 2,5-regioisomer), we subjected
one of the product oxazoles (2f) to single-crystal X-ray
H
O
BnO
N
O
8
a Average of two or more runs.
b 4-Nitroacetophenone was also isolated in 11% yield.
c Structure confirmed by single crystal X-ray analysis (see Scheme 5).
Synlett 2004, No. 8, 1334–1338 © Thieme Stuttgart · New York

1336
J. A. Ragan et al.
LETTER
meter (atmospheric pressure chemical ionization). Combustion
analyses were performed by Schwarzkopf Microanalytical Labora-
tory (Woodside, NY) or Quantitative Technologies, Inc. (White-
house, NJ). All melting points are uncorrected.
O
N
N
F3C
O
O
H
(R)-acid chloride
N
O
N
O
N,N-Dimethylpropanediamide (1):
Method A (50 g scale): Methyl malonamide 4 (50 g, 0.427 mol)
was treated with 500 mL of 2 M Me2NH in MeOH (1 mol) at r.t. Re-
action progress was monitored by concentration of an aliquot and
analysis by 1H NMR. After 4 days, the reaction mixture was heated
to distill MeOH, with portionwise addition of i-PrOH until the reac-
tion volume was ca. 150 mL, and no more MeOH was present in the
distillate. Upon cooling, solids formed, and the slurry was stirred
overnight. Filtration, rinsing with isopropyl ether, provided 48.3 g
of product (87% yield) as a white solid.
10
(2S)-diastereomer
N
O
H2N
Ph(CF3)(OMe)CCOCl
No cross-contamination
of diastereomers
Et3N
CH2Cl2
O
N
9
N
F3C
O
O
H
Method B (1 kg scale): A mixture of methyl malonamide 4 (450 g,
3.85 mol) and ethyl malonamide 5 (620 g, 4.73 mol) were charged
to a 22 L round bottom flask equipped with an overhead mechanical
stirrer, gas inlet tube, and a gas scrubber line through a trap charged
with 1 N HCl. MeOH (10 L) was then charged, leading to a homo-
geneous solution.The Me2NH gas (890 g, 20 mol, 2.3 equiv) was
added over the course of 8 h via the gas inlet tube, which was sub-
merged in the solution (the cylinder was weighed continuously dur-
ing the addition to monitor stoichiometry). Periodic monitoring of
the HCl trap indicated that the majority of the Me2NH was retained
in solution. The resulting solution was stirred for another 48 h, at
which point NMR analysis indicated 71% conversion. An addition-
al portion of Me2NH (490 g, 11 mol, 1.3 equiv) was then added over
2 h, and the solution stirred for another 18 h. NMR analysis indicat-
ed >90% conversion. The reaction mixture was then placed under
partial vacuum and heated on a steam bath to remove methanol
through an efficient coiled condenser. When a volume of ca. 3 L
was obtained, i-PrOH (4 L) was added (solids began to form at this
point), and distillation was resumed until a final volume of ca. 5 L
was reached. The solution was then cooled to r.t. and stirred over-
night. After cooling for 2 h in an ice bath, solids were collected,
rinsing with 400 mL cold i-PrOH and 1 L of isopropyl ether. The
air-dried solids weighed 960 g (86% yield).
N
O
(S)-acid chloride
11
(2R)-diastereomer
Scheme 4
analysis. This analysis confirmed the indicated regio-
chemistry about the oxazole ring, as shown in the ORTEP
representation in Scheme 5.
In conclusion, a practical synthesis of N,N-dimethylpro-
panediamide 1 has been identified starting from esters 4 or
5, and demonstrated on both laboratory and pilot plant
(50–1000 g) scales. This bis-amide is useful for the prep-
aration of a range of aryl- and alkyl-2,4-disubstituted ox-
azoles from a-bromoketones.
Reagents were purchased from commercial suppliers and used as
received unless otherwise noted. N-Methylpyrrolidinone (NMP)
was purchased in anhydrous form from Aldrich in ‘Sure-Seal’ glass
bottles; all other solvents were reagent grade. Reactions were run
under a positive pressure of nitrogen in flame-dried glassware. Re-
action progress was monitored by TLC, on precoated sheets of 60
F254 (Merck Art. 5719), and visualized by UV, and/or staining with
iodine, phosphomolybdic acid, ceric ammonium molybdate, or
para-anisaldehyde solutions and heating. Mass spectral data were
collected on either a Hewlett-Packard 5890 GC/MS (electron im-
pact ionization), or a Micromass (Fisons) Platform II mas spectro-
Mp 118.7–120.5 °C.
IR (thin film): 3400–3250 (br), 3203, 2949, 1721, 1669, 1616, 1406,
1257, 1216, 1058, 954 cm–1.
1H NMR (CDCl3): d = 7.65–7.75 (br s, 1 H), 5.78–5.85 (br s, 1 H),
3.31 (s, 2 H), 3.05 (s, 3 H), 2.96 (s, 3 H).
13C NMR (CDCl3): d = 169.3, 168.3, 40.2, 38.0, 35.9.
MS (EI): m/z (%) = 130 (100).
Anal. Calcd for C5H10N2O2: C, 46.14; H, 7.74; N, 21.52. Found: C,
45.99; H, 7.62; N, 21.10.
General Procedure for Oxazole Annulation (2a–g, 7, 8):
The a-bromoketone (4–15 mmol) and bis-amide 1 (2.5 equiv) were
combined in 2–3 volumes (mL/g of ketone) of NMP. The mixture
was placed in a 100 °C oil bath for 4–24 h, until TLC or GC/MS
analysis showed complete consumption of the ketone. The mixture
was cooled, diluted with EtOAc, and washed with two portions of
H2O and two portions of brine. The organic phase was dried over
MgSO4, filtered, and concentrated to provide the crude product,
which was purified by chromatography (20–30 g SiO2 per g of prod-
uct), granulation in IPE (entries 2a and 2b), and/or crystallization
from hexane-EtOAc. The yields in Table 1 represent the average of
two or more runs.
2-[4-(4-Methoxy-phenyl)-oxazol-2-yl]-N,N-dimethylacetamide
(2a):
Mp 103.4–107.1 °C.
Scheme 5
Synlett 2004, No. 8, 1334–1338 © Thieme Stuttgart · New York

LETTER
Preparation of 4-Aryloxazoles
1337
IR (thin film): 3127, 2939, 1647, 1591, 1578, 1484, 1401, 1105,
1073, 980, 842 cm–1.
13C NMR (CDCl3): d = 166.5, 160.0, 147.4, 139.4, 137.5, 136.5,
126.2, 124.4, 37.9, 36.0, 34.6.
1H NMR (CDCl3): d = 7.92 (s, 1 H), 7.53 (d, J = 9 Hz, 2 H), 6.80 (d,
MS (APCI): m/z (%) = 276 (100) [M + H].
J = 9 Hz, 2 H), 3.82 (s, 2 H), 3.71 (s, 3 H), 2.87 (s, 3 H), 2.72 (s, 3
Anal. Calcd for C13H13N3O4: C, 56.72; H, 4.76; N, 15.27. Found: C,
56.54; H, 4.61; N, 15.09.
H).
13C NMR (CDCl3): d = 166.8, 159.6, 158.9, 140.8, 133.2, 126.9,
126.7, 123.8, 114.2, 37.9, 35.8, 34.7.
2-[4-(3-Nitro-phenyl)-oxazol-2-yl]-N,N-dimethylacetamide
(2f):
MS (EI): m/z (%) = 260 (100).
Off-white solid, mp 147.7–149.2 °C.
Anal. Calcd for C14H16N2O3: C, 64.60; H, 6.20; N, 10.76. Found: C,
64.49; H, 5.89; N, 10.73.
IR (thin film): 3125, 3097, 2957, 1646, 1591, 1525, 1496, 1417,
1400, 1345, 1145, 1098, 731 cm–1.
2-[4-(4-Bromo-phenyl)-oxazol-2-yl]-N,N-dimethylacetamide
(2b):
Off-white solid, mp 135.1–138.0 °C.
1H NMR (CDCl3): d = 8.53–8.52 (m, 1 H), 8.13–8.10 (m, 1 H), 8.01
(s, 1 H), 8.02–8.00 (m, 1 H), 7.53 (t, J = 8 Hz, 1 H), 3.95 (s, 2 H),
3.12 (s, 3 H), 2.99 (s, 3 H).
IR (thin film): 3126, 2993, 2937, 2840, 1643, 1618, 1587, 1505,
1399, 1304, 1176, 1103, 1070, 1034, 846 cm–1.
13C NMR (CDCl3): d = 166.6, 159.8, 148.8, 139.3, 135.6, 133.0,
131.5, 129.9, 122.8, 120.6, 38.0, 36.0, 34.6.
1H NMR (CDCl3): d = 7.88 (s, 1 H), 7.56 (d, J = 8 Hz, 2 H), 7.49 (d,
J = 8 Hz, 2 H), 3.93 (s, 2 H), 3.10 (s, 3 H), 2.98 (s, 3 H).
MS (APCI): m/z = 309, 311 [M + H] (for 79Br and 81Br, 100%).
MS (APCI): m/z (%) = 276 (100) [M + H].
Anal. Calcd for C13H13N3O4: C, 56.72; H, 4.76; N, 15.27. Found: C,
56.74; H, 4.59; N, 15.24.
Anal. Calcd for C13H13N2O2Br: C, 50.50; H, 4.24; N, 9.06. Found:
C, 50.45; H, 3.88; N, 8.23.
2-[4-(2,5-Dimethoxy-phenyl)-oxazol-2-yl-N,N-dimethylaceta-
mide (2g):
Off-white solid, mp 130.1–131.6 °C.
2-[4-(3-Bromo-phenyl)-oxazol-2-yl]-N,N-dimethylacetamide
(2c):
IR (thin film): 3156, 2951, 2936, 2835, 1642, 1467, 1278, 1255,
1179, 1158, 1089, 1057, 1041, 855 cm–1.
Off-white solid, mp 110.8–112.0 °C.
IR (thin film): 3123, 2929, 1645, 1609, 1592, 1497, 1471, 1418,
1137, 1108, 1082, 727 cm–1.
1H NMR (CDCl3): d = 7.88 (s, 1 H), 7.87 (t, J = 2 Hz, 1 H), 7.60 (dt,
J = 1, 7 Hz, 1 H), 7.40 (ddd, J = 1, 2, 8 Hz, 1 H), 7.23 (t, J = 7 Hz,
1 H), 3.93 (s, 2 H), 3.10 (s, 3 H), 2.98 (s, 3 H).
1H NMR (CDCl3): d = 8.13 (s, 1 H), 7.67 (d, J = 3 Hz, 1 H), 6.87 (d,
J = 9 Hz, 1 H), 6.81 (dd, J = 3, 9 Hz, 1 H), 3.96 (s, 2 H), 3.89 (s, 3
H), 3.83 (s, 3 H), 3.11 (s, 3 H), 2.99 (s, 3 H).
13C NMR (CDCl3): d = 166.9, 157.6, 154.0, 151.0, 138.3, 136.3,
120.8, 114.3, 112.9, 111.9, 56.1, 56.0, 38.0, 36.0, 34.9.
13C NMR (CDCl3): d = 166.6, 159.4, 139.9, 134.9, 133.2, 131.2,
MS (EI): m/z (%) = 290 (100) [M].
130.5, 128.7, 124.3, 123.1, 38.0, 36.0, 34.8.
Anal. Calcd for C15H18N2O4: C, 62.06; H, 6.25; N, 9.65. Found: C,
61.94; H, 5.92; N, 9.61.
MS (EI): m/z = 308, 310 [M] (for 79Br and 81Br, 100%).
Anal. Calcd for C13H13N2O2Br: C, 50.50; H, 4.24; N, 9.06. Found:
C, 50.58; H, 4.16; N, 8.98.
2-[4-tert-Butyl-oxazol-2-yl]-N,N-dimethyl-acetamide (7):
Off-white solid, mp 62.8–63.9 °C.
N,N-Dimethyl-2-(4-naphthalen-2-yl-oxazol-2-yl)-acetamide
(2d):
IR (thin film): 3104, 2965, 2903, 2868, 1643, 1585, 1408, 1359,
1146, 1082, 843 cm–1.
Off-white solid, mp 107.9–108.0 °C.
1H NMR (CDCl3): d = 7.26 (s, 1 H), 3.85 (s, 2 H), 3.04 (s, 3 H), 2.95
IR (thin film): 3128, 3111, 3061, 2926, 1659, 1641, 1581, 1491,
1416, 1397, 1141, 1104, 1063, 821 cm–1.
1H NMR (CDCl3): d = 8.25 (br s, 1 H), 7.98 (s, 1 H), 7.86–7.79 (m,
3 H), 7.72 (dd, J = 2, 8 Hz, 1 H), 7.48–7.42 (m, 2 H), 3.97 (s, 2 H),
3.10 (s, 3 H), 2.98 (s, 3 H).
13C NMR (CDCl3) one of the 14 sp2 carbons not resolved: d = 166.7,
159.3, 141.3, 134.8, 133.8, 133.3, 128.6, 128.4, 127.9, 126.6, 126.3,
124.6, 123.7, 38.0, 36.0, 34.9.
(s, 3 H), 1.22 (s, 9 H).
13C NMR (CDCl3): d = 167.1, 158.2, 150.8, 132.6, 37.8, 35.9, 35.0,
31.0, 29.4.
MS (EI): m/z (%) = 210 (80), 139 (60), 72 (100).
Anal. Calcd for C11H18N2O2: C, 62.83; H, 8.63; N, 13.32. Found: C,
63.01; H, 8.59; N, 13.29.
(S)-[1-(2-Dimethylcarbamoylmethyl-oxazol-4-yl)-2-phenyl-eth-
yl]-carbamic acid benzyl ester (8):
Pale yellow oil.
MS (APCI): m/z (%) = 281 (100) [M + H].
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C,
72.78; H, 5.65; N, 10.0.
IR (thin film): 3296, 2933, 1720, 1650, 1454, 1402, 1256, 1140,
1046, 741, 700 cm–1.
2-[4-(4-Nitro-phenyl)-oxazol-2-yl]-N,N-dimethylacetamide
(2e):
White solid, mp 197.1–197.2 °C.
1H NMR (CDCl3): d = 7.33–7.16 (m, 9 H), 7.07–7.05 (m, 2 H), 5.48
(br d, J = 8 Hz, 1 H), 5.05 (d, J = 12 Hz, 1 H), 5.01 (d, J = 12 Hz, 1
H), 4.96–4.92 (m, 1 H), 3.83 (s, 2 H), 3.16–3.04 (m, 2 H), 3.01 (s, 3
H), 2.95 (s, 3 H).
13C NMR (CDCl3): d = 166.7, 159.1, 155.8, 140.4, 137.3, 136.7,
135.7, 129.l6, 128.7, 128.6, 128.3, 128.2, 126.8, 66.9, 49.4, 40.9,
37.9, 35.9, 34.8.
IR (thin film): 3126, 2935, 1645, 1608, 1512, 1398, 1317, 1107,
1072 cm–1.
1H NMR (CDCl3): d = 8.23 (d, J = 9 Hz, 2 H), 8.04 (s, 1 H), 7.86 (d,
J = 9 Hz, 2 H), 3.96 (s, 2 H), 3.12 (s, 3 H), 2.99 (s, 3 H).
MS (APCI): m/z (%) = 408 (100) [M + H].
Synlett 2004, No. 8, 1334–1338 © Thieme Stuttgart · New York

1338
J. A. Ragan et al.
LETTER
(1¢S,2S)-N-[1¢-(2-Dimethylcarbamoylmethyl-oxazol-4-yl)-2¢-
phenyl-ethyl]-3,3,3-trifluoro-2-methoxy-2-phenyl-propiona-
mide (10):
Acknowledgment
The authors would like to acknowledge Dr. Jon Bordner for deter-
mining the X-ray crystal structure of 2f, and Mr. Dennis Bourassa
for assistance in the scale-up of the synthesis of bis-amide 1.
CBZ-oxazole 8 (556 mg, 1.37 mmol) was dissolved in 15 mL
EtOAc, and added to a pressure bottle containing a slurry of 10%
Pd/C (50% H2O wet, 203 mg) in 5 mL EtOH. The mixture was sub-
jected to 45 psi hydrogen on a Parr shaker for 16 h. After purging
with N2, the slurry was filtered through celite, rinsing with EtOAc.
Concentration provided the desired amine as a pale yellow oil (652
mg) contaminated with some unconsumed starting material (ca.
5%) and residual NMP. This material was dissolved in 30 mL of 0.1
N HCl, and extracted with three 5 mL portions of EtOAc. The aque-
ous phase was made basic with 15% NaOH, and extracted with four
10 mL portions of CH2Cl2. The organic extracts were dried over
K2CO3, filtered, and concentrated to provide the desired amine 9 as
a pale yellow oil (223 mg, 60% yield). This material was used with-
out further purification in the next two reactions.
References
(1) Hartner, F. W. In Comprehensive Heterocyclic Chemistry II,
Vol. 3; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996, 262–318; and references therein.
(2) (a) Friedman, B. S.; Sparks, M.; Adams, R. J. Am. Chem.
Soc. 1937, 59, 2262. (b) Panek, J. S.; Beresis, R. T. J. Org.
Chem. 1996, 61, 6496. (c) Takechi, H.; Oda, Y.; Hishizono,
N.; Oda, K.; Machida, M. Chem. Pharm. Bull. 2000, 48,
1702.
(3) (a) Gellman, S. H.; Dado, G. P.; Liang, G.-B.; Adams, B. R.
J. Am. Chem. Soc. 1991, 113, 1164. (b) Interestingly, both
Beilstein and Sci-Finder searches for bis-amide 1 gave the
preceding reference for its synthesis. We suspect that this
was a typographical error upon entry in these databases, as
there is no description of compound 1 in the Gellman paper.
The Beilstein reference gives a reaction time of 63 h and
81% yield, values which are identical to the first
experimental procedure in the paper, in which the mono-
N,N-dimethylamide of malonic acid (3) is prepared en route
to N,N,N¢-trimethylpropanediamide.
Amine 9 (61 mg, 0.23 mmol) was dissolved in 1 mL CH2Cl2 and
treated with Et3N (0.16 mL, 1.15 mmol, 5 equiv) and (R)-(–)-Mosh-
er’s acid chloride (0.13 mL, 0.69 mmol, 3 equiv). After stirring at
r.t. for 16 h, 20% aq Na2CO3 (2 mL) was added, and the mixture
stirred vigorously for 30 min. Extraction with two 5 mL portions of
CH2Cl2, drying over MgSO4, filtration, and concentration provided
a clear, orange oil. This material was purified on 6 g silica gel, elut-
ing with 1:2 to 1:4 hexane–EtOAc. Product-containing fractions
were combined and concentrated to provide amide 10 as a pale yel-
low oil (79 mg, 71% yield).
(4) This effect has recently been noted in the esterification of
carboxylic acids activated at the a-carbon with
1H NMR (CDCl3): d = 7.34–7.07 (m, 11 H), 5.31 (dd, J = 8, 15 Hz,
1 H), 3.87 (s, 2 H), 3.23 (s, 3 H), 3.11 (ddd, J = 8, 15, 22 Hz, 2 H),
3.02 (s, 3 H), 2.96 (s, 3 H).
phosphonates, esters, sulfones, and nitriles. A mechanism
proceeding through an acyl ketene was supported by
trapping of the ketene with DCC in a [4+2] cycloaddition:
Shelkov, R.; Nahmanh, M.; Melman, A. J. Org. Chem. 2002,
67, 8975.
HPLC retention time: 9.89 min (reverse phase column, 60:40 aq
phosphate buffer/MeCN).
(1¢S,2R)-N-[1¢-(2-Dimethylcarbamoylmethyl-oxazol-4-yl)-2¢-
phenyl-ethyl]-3,3,3-trifluoro-2-methoxy-2-phenyl-propiona-
mide (11):
The same procedure described for amide 10 was repeated, using (S)-
(+)-Mosher’s acid chloride, to provide amide 11 as a waxy, color-
less solid (95 mg, 78% yield). Comparison of the crude NMR spec-
tra and HPLC traces of 10 and 11 prior to chromatography showed
no detectable cross-contamination.
1H NMR (CDCl3): d = 7.41–7.09 (m, 11 H), 5.24 (dd, J = 8, 16 Hz,
1 H), 3.82 (s, 2 H), 3.19 (s, 3 H), 3.14 (apparent d, J = 8 Hz, 2 H),
2.99 (s, 3 H), 2.94 (s, 3 H).
(5) Intermediacy of a ketene is also supported by the following
experiment: exposure of ethyl benzoate to the same reaction
conditions (2 N Me2NH in MeOH) for several days showed
no detectable formation of N,N-dimethylbenzamide by 1H
NMR or GC/MS.
(6) Actually, the opposite enantiomer of the other diastereomer
would be formed. For example, in the condensation of the R-
acid chloride with racemic amine, the products are amide 10
and (ent)-11. This has no impact on the achiral HPLC and
NMR analyses, however.
HPLC retention time: 10.87 min.
Synlett 2004, No. 8, 1334–1338 © Thieme Stuttgart · New York