# An Efficient Method for Synthesis ofN-tert-Butyl Amides Using Oxalic Acid Dihydrate in Solvent-Free Condition

Authors: Masoud Mokhtary; Seyedeh Khadijeh Nasernezhad
Journal: Organic Chemistry International
 (2014)

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## Abstract

An efficient method for the synthesis ofN-tert-butyl amides by reaction of nitriles with tert-butyl acetate or tert-butanol is described using oxalic acid dihydrate in solvent-free condition. The result showed that tert-butyl acetate served as a relatively better source of tert-butyl carbocation than tert-butanol.


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## Body

## 1. Introduction

Solvent-free reactions obviously reduce pollution and bring down handling costs due to simplification of experimental procedure, work-up technique, and saving energy. These would be especially important during industrial production [1]. The Ritter reaction makes possible the conversion of a group, capable of giving a relatively stable carbonium ion, to a substituted amide by reaction with a nitrile in the presence of a strong acid [2]. The classical Ritter reaction is the reaction of alkenes and tertiary or benzylic alcohols with nitriles in the presence of concentrated sulfuric acid [3–5]. Several modifications have been attempted to improve Ritter reaction conditions. However, as an alternative to sulfuric acid, other acid catalysts such as (CF3SO2)2O [6], BF3-Et2O [7], Fe3+-Montmorillonite [8], Mg(HSO4)2 [9], Bi(OTf)3 [10], CeCl3
·7H2O/AcCl [11], P2O5/SiO2 [12], and Nafion [13] are employed in the classical Ritter reaction. Ritter reaction usingtert-butyl acetate instead of alcohol was also reported to be catalyzed by sulfuric acid [14, 15], FeCl3
·6H2O [16], ZnCl2-SiO2 [17], and I2 [18]. However, most of these methods suffer from at least one of the following disadvantages such as vigorous reaction conditions, high cost and toxicity of the reagent, tedious work-up procedures, and instability and hygroscopic nature of the reagent. Also, the use oftert-butanol can be complicated by the melting point (26°C) leading to a semisolid at room temperature. An attractive alternative istert-butyl acetate due to its ease of handling (bp 97-98°C), availability as a common solvent, and low cost [15]. Recently, oxalic acid was efficiently used as catalyst in variety of chemical reactions like imino Diels-Alder reaction [19], Beckmann rearrangement [20], protection of carbonyl to thioacetal, and deprotection of thioacetal to carbonyl as well [21]. The conversion of a nitrile to the correspondingN-tert-butyl amide is a very important transformation in organic synthesis. TheN-tert-butyl amides are pharmaceutically useful [22] and also serve as precursors to the corresponding amines. In connection of our research to develop application of oxalic acid dihydrate for oxygenation of sulfides to sufoxides in the presence of H2O2 [23], herein, we found thatoxalic acid dihydrate can be used for preparation ofN-tert-butyl amide derivatives in good yields. This method often leads to the development of simple and ecofriendly protocols for preparation ofN-tert-butyl amides via modified Ritter reaction. Amidation of tert-butyl acetate or tert-butanol with nitriles using oxalic acid dihydrate. 						(1)
R–CN
+
(
C
H
3
)
3
C–O
R
′
HOOC–COOH
·
2
H
2
O
→
70
°
C
,
2
–
9
h
R–CONHC
(
C
H
3
)
3
,
where R
=
alkyl
,
aryl, R
′
=
-
COC
H
3
,
H.


## 2. Materials and Measurements

All chemicals were purchased from Merck chemical company. Melting points were recorded on an electrothermal melting point apparatus. The NMR spectra were recorded in CDCl3 with TMS as an internal standard on a Bruker advance DRX 400 MHz spectrometer. IR spectra were determined on a SP-1100, P-UV-Com instrument. Elemental analyses were performed using a CHN-O Rapid Heraeus elemental analyser (Wellesley, MA). Purity determination of the products was accomplished by TLC on silica gel polygram SIL G/UV 254 plates. Products were identified by comparison of the obtained FT-IR and 1H NMR spectra with those reported for authentic samples.


## 3. Experimental

### 3.1. General Procedure for the Amidation Reaction

A solution of 5 mmol nitrile in 5 mmoltert-butyl acetate ortert-butanol was prepared. 2.5 mmol oxalic acid dihydrate was added to the solution and the reaction mixture was stirred for 2–9 h under 70°C until TLC analysis showed that no nitrile remained. The solid residue was recrystallized from water to afford pure crystals of the proper amides in 42–94% yields.


### 3.2. Characterization Data

#### 3.2.1.N-tert-Butyl-3-methylbenzamide (d)

M.p.: 96-97°C. IR (KBr)υ: 3382, 2962, 1643, 1529, 1447, 748 cm−1. 1H NMR (400 MHz CDCl3) δ = 1.49 (s, 9H), 2.4 (s, 3H), 5.95 (br s, 1H), 7.28–7.56 (m, 4H) ppm. Anal. Calcd. For C12H17NO: C, 75.35; H, 8.91; N, 7.32. Found: C, 75.15; H, 8.71; N, 7.22.


#### 3.2.2.N-tert-Butyl-4-hydroxybenzamide (e)

M.p.: 189–192°C. FT- IR (KBr):υ = 3274, 3068, 2969, 1639, 1548, 1307, 935 cm−1. 1H NMR (400 MHz, CDCl3) δ = 1.49 (s, 9H), 5.97 (br s, 1H), 6.84 (d, 2H), 7.59 (d, 2H) ppm. Anal. Calcd. For C11H15NO2: C, 68.36; H, 7.82; N, 7.25. Found: C, 67.85; H, 7.37; N, 6.92.


#### 3.2.3.N
1
,N
4-di-tert-Butylterephthalamide (f)

M.p.: 272–276°C. FT-IR (KBr):υ = 3301, 2969, 1639, 1546, 1324, 864 cm−1. 1H NMR (400 MHz, CDCl3) δ = 1.50 (s, 18H), 5.97 (br s, 2H), 7.77 (s, 4H) ppm. Anal. Calcd. For C16H24N2O2: C, 69.52; H, 10.13; N, 8.75. Found: C, 68.95; H, 9.47; N, 7.98.


#### 3.2.4.N
1
,N
3-di-tert-Butylisophthalamide (g)

M.p.: 204–207°C. IR (KBr)υ: 3272, 3068, 2969, 1639, 1548, 1307, 680 cm−1. 1H NMR (400 MHz CDCl3) δ = 1.49 (s, 18H), 6 (br s, 2H), 7.28–8.11 (m, 4H) ppm. Anal. Calcd. For C16H24N2O2: C, 69.52; H, 10.13; N, 8.75. Found: C, 68.87; H, 9.67; N, 8.18.


## 3.1. General Procedure for the Amidation Reaction

A solution of 5 mmol nitrile in 5 mmoltert-butyl acetate ortert-butanol was prepared. 2.5 mmol oxalic acid dihydrate was added to the solution and the reaction mixture was stirred for 2–9 h under 70°C until TLC analysis showed that no nitrile remained. The solid residue was recrystallized from water to afford pure crystals of the proper amides in 42–94% yields.


## 3.2. Characterization Data

### 3.2.1.N-tert-Butyl-3-methylbenzamide (d)

M.p.: 96-97°C. IR (KBr)υ: 3382, 2962, 1643, 1529, 1447, 748 cm−1. 1H NMR (400 MHz CDCl3) δ = 1.49 (s, 9H), 2.4 (s, 3H), 5.95 (br s, 1H), 7.28–7.56 (m, 4H) ppm. Anal. Calcd. For C12H17NO: C, 75.35; H, 8.91; N, 7.32. Found: C, 75.15; H, 8.71; N, 7.22.


### 3.2.2.N-tert-Butyl-4-hydroxybenzamide (e)

M.p.: 189–192°C. FT- IR (KBr):υ = 3274, 3068, 2969, 1639, 1548, 1307, 935 cm−1. 1H NMR (400 MHz, CDCl3) δ = 1.49 (s, 9H), 5.97 (br s, 1H), 6.84 (d, 2H), 7.59 (d, 2H) ppm. Anal. Calcd. For C11H15NO2: C, 68.36; H, 7.82; N, 7.25. Found: C, 67.85; H, 7.37; N, 6.92.


### 3.2.3.N
1
,N
4-di-tert-Butylterephthalamide (f)

M.p.: 272–276°C. FT-IR (KBr):υ = 3301, 2969, 1639, 1546, 1324, 864 cm−1. 1H NMR (400 MHz, CDCl3) δ = 1.50 (s, 18H), 5.97 (br s, 2H), 7.77 (s, 4H) ppm. Anal. Calcd. For C16H24N2O2: C, 69.52; H, 10.13; N, 8.75. Found: C, 68.95; H, 9.47; N, 7.98.


### 3.2.4.N
1
,N
3-di-tert-Butylisophthalamide (g)

M.p.: 204–207°C. IR (KBr)υ: 3272, 3068, 2969, 1639, 1548, 1307, 680 cm−1. 1H NMR (400 MHz CDCl3) δ = 1.49 (s, 18H), 6 (br s, 2H), 7.28–8.11 (m, 4H) ppm. Anal. Calcd. For C16H24N2O2: C, 69.52; H, 10.13; N, 8.75. Found: C, 68.87; H, 9.67; N, 8.18.


## 3.2.1.N-tert-Butyl-3-methylbenzamide (d)

M.p.: 96-97°C. IR (KBr)υ: 3382, 2962, 1643, 1529, 1447, 748 cm−1. 1H NMR (400 MHz CDCl3) δ = 1.49 (s, 9H), 2.4 (s, 3H), 5.95 (br s, 1H), 7.28–7.56 (m, 4H) ppm. Anal. Calcd. For C12H17NO: C, 75.35; H, 8.91; N, 7.32. Found: C, 75.15; H, 8.71; N, 7.22.


## 3.2.2.N-tert-Butyl-4-hydroxybenzamide (e)

M.p.: 189–192°C. FT- IR (KBr):υ = 3274, 3068, 2969, 1639, 1548, 1307, 935 cm−1. 1H NMR (400 MHz, CDCl3) δ = 1.49 (s, 9H), 5.97 (br s, 1H), 6.84 (d, 2H), 7.59 (d, 2H) ppm. Anal. Calcd. For C11H15NO2: C, 68.36; H, 7.82; N, 7.25. Found: C, 67.85; H, 7.37; N, 6.92.


## 3.2.3.N
1
,N
4-di-tert-Butylterephthalamide (f)

M.p.: 272–276°C. FT-IR (KBr):υ = 3301, 2969, 1639, 1546, 1324, 864 cm−1. 1H NMR (400 MHz, CDCl3) δ = 1.50 (s, 18H), 5.97 (br s, 2H), 7.77 (s, 4H) ppm. Anal. Calcd. For C16H24N2O2: C, 69.52; H, 10.13; N, 8.75. Found: C, 68.95; H, 9.47; N, 7.98.


## 3.2.4.N
1
,N
3-di-tert-Butylisophthalamide (g)

M.p.: 204–207°C. IR (KBr)υ: 3272, 3068, 2969, 1639, 1548, 1307, 680 cm−1. 1H NMR (400 MHz CDCl3) δ = 1.49 (s, 18H), 6 (br s, 2H), 7.28–8.11 (m, 4H) ppm. Anal. Calcd. For C16H24N2O2: C, 69.52; H, 10.13; N, 8.75. Found: C, 68.87; H, 9.67; N, 8.18.


## 4. Results and Discussion

A variety ofN-tert-butyl amides were prepared fromtert-butyl acetate with nitriles in the presence of oxalic acid dihydrate in good yields. In order to show the merit of the catalyst for Ritter reactions, we have also studied the reaction of several aromatic nitriles witht-BuOH. The results were satisfactory and the aromatic nitriles proceeded well in good yields (Table 1, entries a–g′). Acrylonitrile and aliphatic nitriles were converted to the corresponding amides in moderate yields in both reaction conditions (Table 1, entries h–k′). It is worth mentioning that the corresponding amide in each case was isolated by simple crystallization from the crude product.Table 1
Amidation oftert-butylacetate or tert-butanol with nitriles using oxalic acid dehydrate.
Entry
Substrate
Nitrile
Amidea
Time/h
Yield  %b
a
(CH3)3COAc
C6H5CN
C6H5CONHtBu
2
90
a
′
(CH3)3COH
C6H5CN
C6H5CONHtBu
2.30
88
b
(CH3)3COAc
p-Cl-C6H4CN
p-Cl-C6H4CONHtBu
2
92
b
′
(CH3)3COH
p-Cl-C6H4CN
p-Cl-C6H4CONHtBu
3
90
c
(CH3)3COAc
p-Me-C6H4CN
p-Me-C6H4CONHtBu
2
88
c
′
(CH3)3COH
p-Me-C6H4CN
p-Me-C6H4CONHtBu
2.30
85
d
(CH3)3COAc
m-Me-C6H4CN
m-Me-C6H4CONHtBu
2
94
d
′
(CH3)3COH
m-Me-C6H4CN
m-Me-C6H4CONHtBu
2
92
e
(CH3)3COAc
p-HO-C6H4CN
p-HO-C6H4CONHtBu
4
76
e
′
(CH3)3COH
p-HO-C6H4CN
p-HO-C6H4CONHtBu
4
70
f
(CH3)3COAc
p-NC-C6H4-CN
p-tBuNHOC-C6H4CONHtBu
4.30
92c
f
′
(CH3)3COH
p-NC-C6H4-CN
p-tBuNHOC-C6H4CONHtBu
5
90c
g
(CH3)3COAc
m-NC-C6H4-CN
m-tBuNHOC-C6H4CONHtBu
4.30
88c
g
′
(CH3)3COH
m-NC-C6H4-CN
m-tBuNHOC-C6H4CONHtBu
5
86c
h
(CH3)3COAc
CH2=CHCN
CH2=CHCONHtBu
3
66
h
′
(CH3)3COH
CH2=CHCN
CH2=CHCONHtBu
4
60
i
(CH3)3COAc
ClCH2CN
ClCH2CONHtBu
3.5
45
i
′
(CH3)3COH
ClCH2CN
ClCH2CONHtBu
4
42
j
(CH3)3COAc
NCCH2COOEt
tBuNHCOCH2COOEt
3.5
54
j
′
(CH3)3COH
NCCH2COOEt
tBuNHCOCH2COOEt
4
48
k
(CH3)3COAc
CH3CN
CH3CONHtBu
8
48
k
′
(CH3)3COH
CH3CN
CH3CONHtBu
9
45
aAll entries were carried on nitrile (5 mmol), oxalic acid dehydrate (2.5 mmol) and t-BuOAc or t-BuOH (5 mmol) at 70°C. bAll yields refer to isolated products. cNitrile (2.5 mmol) is used.The formation oftert-butyl amides in good yields and shorter time as seen from Table 1 shows thattert-butyl acetate served as a relatively better source oftert-butyl carbocation. Greatly facilitated heterolytic cleavage of C–O bond oftert-butyl acetate by oxalic acid dihydrate is rationalized by the leaving group superiority of acetate over OH group.


## 5. Conclusions

In conclusion, we have developed a simple, inexpensive, and ecofriendly methodology for modified Ritter reaction that represents effective activity for the amidation oftert-butyl acetate andtert-butanol with nitriles. This method provides an easy access to a variety oftert-butyl amides.



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*Source: 617153-2014-04-08.xml*