Development of variously functionalized nitrile oxides

Article abstract of DOI:10.3762/bjoc.11.138

N-Methylated amides (N,4-dimethylbenzamide and N-methylcyclohexanecarboxamide) were systematically subjected to chemical transformations, namely, N-tosylation followed by nucleophilic substitution. The amide function was converted to the corresponding carboxylic acid, esters, amides, aldehyde, and ketone upon treatment with hydroxide, alkoxide, amine, diisobutylaluminium hydride and Grignard reagent, respectively. In these transformations, N-methyl-N-tosylcarboxamides behave like a Weinreb amide. Similarly, N-methyl-5-phenylisoxazole-3-carboxamide was converted into 3-functionalized isoxazole derivatives. Since the amide was prepared by the cycloaddition reaction of ethynylbenzene and N-methylcarbamoylnitrile oxide, the nitrile oxide served as the equivalent of the nitrile oxides bearing a variety of functional groups such as carboxy, alkoxycarbonyl, carbamoyl, acyl and formyl moieties.

Full text of DOI:10.3762/bjoc.11.138

Development of variously functionalized nitrile oxides
Haruyasu Asahara*1,2, Keita Arikiyo1 and Nagatoshi Nishiwaki*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1241–1245.
1School of Environmental Science and Engineering, Kochi University
of Technology, Tosayamada, Kami, Kochi 782-8502, Japan and
2Research Center for Material Science and Engineering, Kochi
University of Technology, Tosayamada, Kami, Kochi 782-8502, Japan
doi:10.3762/bjoc.11.138
Received: 13 May 2015
Accepted: 16 July 2015
Published: 23 July 2015
Email:
Haruyasu Asahara* - asahara.haruyasu@kochi-tech.ac.jp;
Nagatoshi Nishiwaki* - nishiwaki.nagatoshi@kochi-tech.ac.jp
Associate Editor: R. Sarpong
© 2015 Asahara et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
acylnitrile oxide; amide; formylnitrile oxide; functionalized nitrile oxide;
Weinreb amide
Abstract
N-Methylated amides (N,4-dimethylbenzamide and N-methylcyclohexanecarboxamide) were systematically subjected to chemical
transformations, namely, N-tosylation followed by nucleophilic substitution. The amide function was converted to the corres-
ponding carboxylic acid, esters, amides, aldehyde, and ketone upon treatment with hydroxide, alkoxide, amine, diisobutylalu-
minium hydride and Grignard reagent, respectively. In these transformations, N-methyl-N-tosylcarboxamides behave like a
Weinreb amide. Similarly, N-methyl-5-phenylisoxazole-3-carboxamide was converted into 3-functionalized isoxazole derivatives.
Since the amide was prepared by the cycloaddition reaction of ethynylbenzene and N-methylcarbamoylnitrile oxide, the nitrile
oxide served as the equivalent of the nitrile oxides bearing a variety of functional groups such as carboxy, alkoxycarbonyl,
carbamoyl, acyl and formyl moieties.
Introduction
Nitrile oxides are valuable synthetic synthons for the construc- desirable to develop methodologies for the facile generation of
tion of heterocyclic compounds by cycloaddition reactions, functionalized nitrile oxides.
which lead to the formation of two bonds in a single experi-
mental step [1,2]. In addition, cycloadducts serve as precursors In our previous work, we reported the preparation of nitrile
of polyfunctionalized compounds by ring opening reaction fol- oxide 2 bearing an N-methylcarbamoyl group by treatment of
lowed by N–O bond fission [2,3]. Hence, functionalized nitrile 2-methyl-4-nitroisoxazolin-5(2H)-one (1) only with water at
oxides are clearly useful for the preparation of more complex room temperature. Nitrile oxide 2 undergoes cycloaddition reac-
systems. However, because the precursors of the functionalized tions with alkenes [4,5], alkynes (Scheme 1) [4,5], nitriles [6],
nitrile oxides are not always easily available, there are only a and 1,3-dicarbonyl compounds [7] to afford the corresponding
few reports that deal with these compounds compared to those polyfunctionalized heterocyclic compounds, which are not
on alkylated and arylated nitrile oxides [1]. Thus, it is highly easily obtained by other approaches. Although this protocol is
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Beilstein J. Org. Chem. 2015, 11, 1241–1245.
Scheme 1: A strategy for developing functionalized nitrile oxides.
expected to be useful for synthesizing polyfunctionalized com- already reported by Itoh and coworkers [10]. However, a
pounds, it is limited by the need of a N-methylcarbamoyl func- systematic study using simple amides has not yet been
tional group. The synthetic utility of nitrile oxide 2 will be performed. In this context, we examined the sulfonylation and
indeed improved by converting the N-methylcarbamoyl group chemical conversion of N-methylated aromatic and aliphatic
into other functionalities, i.e., nitrile oxide 2 may serve as an amides, and a similar conversion of N-methyl-5-phenylisoxa-
equivalent of nitrile oxides 4 having versatile functional groups zole-3-carboxamide (3), which is equal to the generation of
(Scheme 1).
variously functionalized nitrile oxides.
Weinreb amide (N-methoxy-N-methylamide) is widely used for Results and Discussion
the conversion of less reactive amide moieties into other car- At the outset, methanesulfonylation (mesylation) of amides was
bonyl functionalities [8,9]. The two oxygen atoms of the studied. To a suspension of N,4-dimethylbenzamide (6A) and
methoxy and carbonyl groups coordinate to the organometallic sodium hydride (2 equiv) in THF, mesyl chloride (7a,
reagents, thereby suppressing further reaction with the obtained 1.3 equiv) was added, and the resultant mixture was stirred at
aldehyde or ketone. However, this protocol cannot be applied to room temperature for 9 h. After acidification, the reaction mix-
the conversion of N-methylamides because methoxylation of ture was extracted with diethyl ether to afford the crude ma-
N-methylamides is hitherto unknown. Thus, we speculated that terial, from which 32% of N-mesylated product 8Aa [11] was
the introduction of a sulfonyl group would be effective because isolated and 61% of 6A was recovered. Thus, the conversion
of its high electron-withdrawing and coordinating abilities, yield of 8Aa was 82% (Table 1, entry 1). On the other hand, the
serving as an equivalent of the Weinreb amide. Indeed, the use yield of 8Aa was considerably increased (up to 70%) when
of N-methyl-3-phenyl-N-tosylbutanamide for this purpose was ethylmagnesium bromide was employed as a base instead of
Table 1: Sulfonylation of N-methylamides.
entry
R1
R2
Base (equiv)
Temp./°C
Time/h
Product
Yield/%
1
4-MeC6H4
4-MeC6H4
4-MeC6H4
c-Hexyl
Me
NaH (2)
rt
0
0
0
0
9
8Aa
8Aa
8Ab
8Bb
8Bb
32 (82)a
70
2
Me
EtMgBr (1.1)
NaH (2)
1
3
4-MeC6H4
4-MeC6H4
4-MeC6H4
24
12
12
60 (92)a
38
4
NaH (2)
5b
c-Hexyl
NaH (2)
60 (85)a
aConversion yields were shown in parentheses; b5 equivalents of 7b were used.
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Beilstein J. Org. Chem. 2015, 11, 1241–1245.
sodium hydride (Table 1, entry 2). However, the instability and respectively (Table 2, entries 1–4). In addition, the nucleophilic
gradual decomposition of mesylated product 8Aa by ambient substitution also proceeded by employing neutral amines. The
moisture impedes its storage and use as a synthetic reagent. reaction of 8 with propylamine proceed smoothly, leading to
Hence, in the place of the mesyl group, the 4-methylbenzene- N-propylamides 9c and 10c (Table 2, entries 5 and 6). The
sulfonyl (tosyl) moiety was employed as the activating group of substitution reaction was influenced by the bulkiness of the
the amide function. Indeed, tosylated product 8Ab [11] proved amines. Heating at 120 °C was required for the substitution
to be sufficiently stable under ambient conditions. Despite the reaction by sec-butylamine. However, in the case of tert-butyl-
considerable efforts for optimizing the reaction conditions, the amine, even when the reaction was conducted in a sealed tube at
highest yield obtained for 8Ab was 60%; however, 35% of 120 °C, only a small amount of amide was observed (Table 2,
starting material 6A was recovered, and the conversion yield entries 7–10). On the other hand, a cyclic secondary amine,
was 92%. This tosylation method was applied to the aliphatic pyrrolidine, afforded amides 9f and 10f quantitatively at room
amide N-methylcyclohexanecarboxamide (6B) to afford 8Bb temperature (Table 2, entries 11 and 12).
upon treatment with tosyl chloride (7b) using sodium hydride as
a base (Table 1, entry 4). In this case, the use of an excess of 7b When more reactive butyllithium or isopropylmagnesium
increased the yield of 8Bb up to 60% (85% of conversion yield, bromide was used as the nucleophile, the corresponding tertiary
Table 1, entry 5).
alcohols 11g and 11h were obtained in 51% and 58% yields,
respectively, whereas ketones 9g and 9h were not detected
Next, nucleophilic substitutions of tosylated amides 8Ab and (Table 2, entries 13 and 14). In the case of an aromatic Grig-
8Bb were investigated (Table 2). Whereas water and methanol nard reagent, the undesired reaction was suppressed. Although
did not alter the amide moieties, hydroxide and methoxide the reaction did not occur at −78 °C, the substitution proceeded
converted amides 8Ab and 8Bb into the corresponding successfully at −40 °C, affording ketones 9i and 10i (Table 2,
carboxylic acids (9a and 10a) and methyl esters (9b and 10b), entries 15 and 16). Sodium borohydride also proved to be
Table 2: Chemical conversions of N-methylamide to other functions.
entry
Amide
Nucleophile
Solvent
Temp./°C
Product
Yield/%
1
8Ab
8Bb
8Ab
8Bb
8Ab
8Bb
8Ab
8Bb
8Ab
8Bb
8Ab
8Bb
8Ab
8Ab
8Ab
8Bb
8Ab
8Ab
8Bb
NaOH
H2O
H2O
MeOH
MeOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
85
9a
quant.
94
2
NaOH
85
10a
3
NaOMe
60
9b
62
4
NaOMe
60
10b
73
5
PrNH2
rt
9c [12]
10c
quant.
82
6
PrNH2
rt
7
sec-BuNH2
sec-BuNH2
tert-BuNH2
tert-BuNH2
pyrrolidine
pyrrolidine
BuLi
120
120
120
120
rt
9d [13]
10d
72
8
79
9
9e [14]
10e [15]
9f [16]
10f [17]
9g
19
10
11
12
13
14
15
16
17
18
19
3
quant.
quant.
0 (51)a
0 (58)a
59
rt
−78
−40
−40
−40
−78
−78
−78
iPrMgBr
9h
4-MeOC6H4MgBr
4-MeOC6H4MgBr
NaBH4
9i [18]
10i [19]
9j
33
0 (64)a
77 (12)a
39
iBu2AlH
9j
iBu2AlH
10j
aIntermediately produced 9 or 10 underwent the excess reactions to afford alcohols 11.
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Beilstein J. Org. Chem. 2015, 11, 1241–1245.
highly reactive, causing a further addition reaction even at
−78 °C to generate the corresponding alcohol 11j (Table 2,
entry 17). This disadvantage was overcome by using bulkier
diisobutylaluminium hydride (DIBAL) to furnish aldehydes 9j
and 10j, although small amounts of alcohol 11j were also
detected (Table 2, entries 18 and 19).
Table 3: Chemical conversion of N-methylisoxazole-3-carboxamide 3.
In contrast to tosylated amides 8Ab and 8Bb, tosylated
N-methyl-5-phenylisoxazole-3-carboxamide 12 exhibited
higher reactivity. Upon tosylation under similar conditions 3 did
not afford product 12, and isoxazole-3-carboxylic acid 5a, a
hydrolyzed product of 12, was observed. This problem was
solved by quenching the reaction mixture with ice water instead
of just water; yet, 12 was afforded in only 10% yield, and 5a
was the main product in 38% yield. These findings imply that
during the work-up procedure, further decomposition of 12 by
water occurred even at low temperatures because of the higher
electron deficiency of the isoxazole ring compared with carbo-
cyclic rings. When, instead of water, less nucleophilic acetic
acid was employed for the quench, 12 was isolated in 74% yield
and the competitive hydrolysis of 12 was suppressed (6% of
5a).
entry
Nu-H
Yield/%
1
OH2
5a [21]
5k [22]
5c [23]
5d [22]
5e [24]
5f [23]
5i [25]
81
59
74
59
30
42
45
2
iPrOH
3
PrNH2
4
sec-BuNH2
tert-BuNH2
pyrrolidine
5
6
7a,b
4-MeOC6H4
MgBr
8a,c
iBu2AlH
5j [26]
40
a2 Equiv of nucleophiles were used. bAt −40 °C. cAt −78°C.
Although tosylated amide 12 could be isolated, it gradually
decomposed under ambient conditions. Hence, the chemical
conversion was performed by adding a nucleophile to the mix-
ture of the tosylation reaction, without the isolation of 12
(Table 3). As mentioned above, the use of a hydroxide anion for
the hydrolysis was not required, and carboxylic acid 5a was
obtained in 81% yield by the addition of only water (Table 3,
entry 1). This protocol was applicable to a relatively bulky
alcohol to afford isopropyl ester 5k in moderate yield (Table 3,
entry 2). Similarly, primary and secondary amines underwent
the substitution reaction, leading to 5c–f in good to moderate
yields (Table 3, entries 3–6). It was noteworthy that, because of
high reactivity of 12 caused by the isoxazole ring [20], the
methylamino group could be replaced by a bulky tert-butyl-
amino moiety. Conversion of the N-methylcarbamoyl
group to an acyl or formyl group was achieved upon treatment
with a Grignard reagent or with DIBAL (Table 3, entries 7
and 8).
Figure 1: Versatile functionalized nitrile oxides.
Experimental
Conversion of isoxazolecarboxamide 3 to 5c
The chemical conversion of N-methylamides to versatile car- via tosyl derivative 12
bonyl functions was systematically studied. In this protocol, the To a solution of amide 3 (101 mg, 0.5 mmol) in THF (1 mL), a
tosyl group was found to be effective for the activation of the suspension of 60 wt % sodium hydride (100 mg, 2.5 mmol) in
carbamoyl group and for preventing over-addition by THF (3 mL) was added under argon. After the mixture was
organometallic reagents. Isoxazole-3-carboxamide 3 was stirred vigorously for 10 min, the mixture was cooled to 0 °C
successfully converted in a similar fashion. Thus, as shown in and then a solution of tosyl chloride (191 mg, 1 mmol) in THF
Figure 1, nitrile oxide 2 serves as an equivalent of functional- (1 mL) was slowly added. After the mixture was stirred for 3 h
ized nitrile oxides 4, thereby improving the synthetic utility of at 0 °C, propylamine (164 μL, 2 mmol) was added, and then the
carbamoylnitrile oxide 2.
mixture was stirred at room temperature for 12 h. After evapor-
1244

Beilstein J. Org. Chem. 2015, 11, 1241–1245.
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