Mendeleev
Communications
Mendeleev Commun., 2014, 24, 176–177
a-Hydroxy amides from carbamoylsilane and aldehydes
Yuan Yao,a,b Wenting Tonga and Jianxin Chen*a
a College of Chemistry and Materials Science, Shanxi Normal University, Linfen 041004,
P. R. China. E-mail: jjxxcc2002@yahoo.com
b The First Experimental Middle School of Linfen City, Linfen 041000, P. R. China.
E-mail: yao_yuan_2012@163.com
DOI: 10.1016/j.mencom.2014.04.018
Reaction between N,N-dimethylcarbamoyl(trimethyl)silane and aldehydes affords a-hydroxy amides in good yields.
a-Hydroxy amides are important substances in organic synthesis
O
O
O
and valuable agents in medicinal chemistry.1,2 Commonly, they
are accessed by addition of carbamoyllithium reagents onto
carbonyl compounds. However, this approach can be complicated
by thermal instability,3–5 self-condensation6 and potential problems
arising from the high basicity of these reagents. Multi-component
reactions using isonitriles and aldehydes such as the Passerini or
Ugi reactions7–9 generally require strong protic acids or Lewis
acids to catalyze.10–13 Previously, it was reported that N-methoxy-
methyl-N-methylcarbamoyl(trimethyl)silane adds at the C=O
bond of carbonyl compounds to furnish the O-silylated a-hydroxy
amides.14 Carbamoylsilane can also react with a-keto amides,15,16
aldehyde imines,17 imidoyl chlorides,18 alkenes19 and acid chlo-
rides20 to give a-hydroxy-a-carbamoyl amides, a-imino amides,
b-functionalized tertiary amides and a-keto amides.
R
+
NMe2
THF, 60 °C
Me3Si
NMe2
R
H
OH
2
1
3
Scheme 1
Table 1 Synthesis of a-hydroxy amides 3 from aldehydes 2 and carbamoyl-
silane 1.
Entry Aldehyde Product
R
Timea/h
Yieldb,c (%)
1
2a
2b
2c
2d
2e
2f
2g
2h
2i
3a
3b
3c
3d
3e
3f
3g
3h
3i
Pr
Pri
4.5d
6.5d
350
16
78
75
0
2
3
4-Me2NC6H4
4-MeOC6H4
4-MeC6H4
Ph
4
76
78
81
85
86
71
73
90
91
5
14
Herein we report that reaction of N,N-dimethylcarbamoyl-
(trimethyl)silane 1 with aldehydes directly affords a-hydroxy
amides 3 (Scheme 1).†
6
7.5
7
7
4-ClC6H4
4-NO2C6H4
CH2=CH
PhCH=CH
2-Furyl
When 1.2 equiv. of carbamoylsilane 121 was allowed to react
with aldehydes 2 in THF solution under anhydrous conditions,
good yields of a-hydroxy amides 3 were achieved, generally
8
6
7e
9
10
11
12
2j
2k
2l
3j
10
3k
3l
14.5
17
† a-Hydroxy amides 3 (general procedure). A Schlenk tube fitted with a
Teflon vacuum stopcock and a micro stirbar was flame-heated in vacuo
and refilled with argon. Aldehyde (1 mmol), THF (1 ml) and N,N-di-
methylcarbamoyl(trimethyl)silane 1 (1.2 mmol) were then added. The
tube was sealed and the mixture was stirred at 60°C until carbamoyl-
silane was fully consumed (TLC). Volatiles were removed in vacuo,
adducts 3 were isolated by Kugelrohr distillation, or recrystallization from
anhydrous ethanol, or chromatography using 30–50% light petroleum–
EtOAc as eluent.
2-Thienyl
a To complete consumption of carbamoylsilane 1 at 60°C in THF. b Isolated
yield based on aldehyde. c 1:1.2 molar ratio of aldehyde and carbamoylsilane.
d Reaction at 40°C. e Reaction at ~20°C.
within 4.5–17 h at 25–60°C (Table 1). Apparently, primarily
formed silyl ethers undergo transformation into final a-hydroxy
amides 3 by seizing the hydrogen from the medium. This occurred
even in the case of products 3a,b,i which were isolated by
Kugelrohr distillation avoiding protic workup. Initial experiments
were carried out using equimolar amounts of aldehydes and 1.
However, in the case of the enolizable aldehydes (see Table 1,
entries 1 and 2), the higher yields were obtained on using an
excess of carbamoylsilane. This may reflect competitive protono-
lysis of the latter. Similar phenomenon was previously observed
when carbamoylsilane was completely destroyed if iminium
salts with enolizable a-hydrogens were applied.22 Substrate 2a
containing linear propyl substituent reacted essentially quicker
than others with more bulky ones. To explore the scope of this
reaction, we tested the representative series of benzaldehydes
(entries 3–8). Electronic effect plays a significant role: the stronger
electron-donating ability of the substituent, the slower the process
and/or the lower the yield. No product was obtained from aldehyde
2c even after 350 h at 60°C. a,b-Unsaturated aldehydes 2i,j were
investigated to estimate whether 1,2- or 1,4-addition would occur
in a conjugated system (entries 9 and 10). At 60°C, acrolein 2i
1
For 3a: colourless liquid, yield 78%. H NMR (600 MHz, CDCl3) d:
4.37 (t, 1H, J 4.2 Hz), 3.71 (br.s, 1H), 3.02 (s, 3H), 2.99 (s, 3H), 1.60 (m,
2H), 1.49 (m, 2H), 0.96 (t, 3H, J 7.2 Hz). 13C NMR (151 MHz, CDCl3)
d: 174.4, 67.6, 36.7, 36.3, 35.8, 18.2, 13.7. IR (KBr, n/cm–1): 3409, 1645,
1520, 1430. Found (%): C, 57.65; H, 10.63; N, 9.45. Calc. for C7H15NO2
(%): C, 57.90; H, 10.41; N, 9.65.
For 3f: yellowish crystals, yield 81%, mp 105–107°C. 1H NMR (600 MHz,
CDCl3) d: 7.38–7.34 (m, 5H), 5.23 (s, 1H), 4.77 (br.s, 1H), 3.06 (s, 3H),
2.80 (s, 3H). 13C NMR (151 MHz, CDCl3) d: 172.4, 139.2, 129.0, 128.5,
127.5, 71.6, 36.4, 36.3. IR (KBr, n/cm–1): 3387, 1636, 1397, 1278, 1135.
Found (%): C, 67.00; H, 7.20; N, 7.79. Calc. for C10H13NO2 (%): C, 67.02;
H, 7.31; N, 7.82.
For 3k: colourless crystals, yield 90%, mp 138–139°C. 1H NMR (600 MHz,
CDCl3) d: 7.41 (m, 1H), 6.38–6.37 (m, 1H), 6.34 (d, 1H, J 3.6 Hz), 5.34
(s, 1H), 4.61 (br.s, 1H), 3.08 (s, 3H), 2.88 (s, 3H). 13C NMR (151 MHz,
CDCl3) d: 170.1, 152.1, 142.8, 110.6, 108.1, 64.7, 36.4, 36.2. IR (KBr,
n/cm–1): 3377, 1647, 1492, 1241, 1186. Found (%): C, 56.75; H, 6.56;
N, 8.31. Calc. for C8H11NO3 (%): C, 56.80; H, 6.55; N, 8.28.
For characteristics of compounds 3b,d,e,g–j,l, see Online Supplementary
Materials.
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Yao, Yuan
