One-pot sequential Schmidt and Ritter reactions for the synthesis of N-tert-butyl amides

Article abstract of DOI:10.1002/ejoc.201402662

The first example of the direct conversion of benzaldehydes into their corresponding N-tert-butyl amides through a Schmidt reaction/Ritter reaction sequence is described. A reagent mixture consisting of NaN₃ and HBF₄?OEt₂ in acetic acid efficiently reacts with aromatic and conjugated (α,β-unsaturated) aldehydes to produce nitrile derivatives, which in situ undergo a Ritter reaction with tert-butyl acetate to afford the corresponding N-tert-butyl amides in almost quantitative yields. The method needs no column chromatography purification. The wide substrate scope as well as the ready availability of the reagent system also make this protocol convenient.

Full text of DOI:10.1002/ejoc.201402662

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SHORT COMMUNICATION
DOI: 10.1002/ejoc.201402662
One-Pot Sequential Schmidt and Ritter Reactions for the Synthesis of
N-tert-Butyl Amides
[a]
[a]
Nabajyoti Hazarika and Gakul Baishya*
Keywords: Amides / Aldehydes / Schmidt reaction / Ritter reaction
The first example of the direct conversion of benzaldehydes
into their corresponding N-tert-butyl amides through a
Schmidt reaction/Ritter reaction sequence is described. A
reagent mixture consisting of NaN and HBF ·OEt in acetic
3 4 2
acid efficiently reacts with aromatic and conjugated (α,β-un-
situ undergo a Ritter reaction with tert-butyl acetate to afford
the corresponding N-tert-butyl amides in almost quantitative
yields. The method needs no column chromatography purifi-
cation. The wide substrate scope as well as the ready avail-
ability of the reagent system also make this protocol conve-
nient.
saturated) aldehydes to produce nitrile derivatives, which in
Introduction
The N-tert-Butyl amide moiety is an important function-
ality that is present in a variety of drug molecules such as
finasteride and nelfinavir.[
1,2]
Finasteride is known for the
treatment of benign prostatic hyperplasia (BPH), whereas
nelfinavir works as a protease inhibitor for the treatment of
human immunodeficiency virus (HIV). Similarly, saquina-
vir, the first HIV protease inhibitor, is currently undergoing
clinical evaluation and contains the N-tert-butyl amide moi-
ety.[ Moreover, Agouron Pharmaceuticals has recently
3]
synthesized some diarylbutanols[
4,5]
that also bear the N-
tert-butyl amide moiety. These molecules are known to ex-
hibit potent anti-HIV protease activities as well.
The well-known Schmidt reaction[ has been used for the
6]
direct conversion of ketones and acids into their corre-
[
7]
[8]
sponding amide and amine analogues. However, the
successful execution of the Schmidt reaction of aldehydes is
limited because of the formation of other products such as
formanilides along with nitriles.[ Recently, Prabhu and co-
workers established an efficient chemoselective Schmidt re-
action for the synthesis of nitriles from aldehydes by using
sodium azide and an excess amount of triflic acid at room
tert-butyl acetate is used as the source of the tert-butyl
carbocation for the synthesis of N-tert-butyl amides
[13]
through the Ritter reaction.
Recently, Milne’s research
9]
group developed a scalable method for the synthesis of N-
tert-butyl amides directly from nitriles by employing tert-
butyl acetate in acetic acid along with an excess amount of
[14]
corrosive H SO .
Hence, the need for the development
2
4
[
10]
temperature.
It has also been established that nitrile
of a novel synthetic method for the synthesis of N-tert-butyl
amides is in demand. Usually, N-tert-butyl amides are pre-
pared directly from aldehydes through an oxidative amid-
ation process in the presence of a tert-butylamine salt by
groups undergo the Ritter reaction with tert-butyl carbo-
cation species to produce the corresponding N-tert-butyl
[
11]
amides.
Generally, researchers have used either methyl-
[12g,12h]
propene gas or tBuOH
as the source of the tert-butyl
[15]
using an oxidizing agent and a base. However, the yields
cation in the presence of an acid promoter[ for this pur-
12]
of the N-tert-butyl amide derivatives are not satisfactory,
and yields of only 40–50% have been obtained in most of
these methods. Nowadays, one-pot multicomponent reac-
tions are becoming synthetically and environmentally more
attractive than traditional reactions for carrying out
multistep processes in a single operation because of the re-
duction in the reaction time and also the minimization of
pose. Moreover, only a few reports are available in which
[
a] Natural Products Chemistry Division,
CSIR – North East Institute of Science and Technology,
Jorhat 785006, Assam, India
E-mail: b.gakul@gmail.com
http://www.rrljorhat.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201402662.
[
16]
costs and undesired wastes. In our efforts toward the de-
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N. Hazarika, G. Baishya
SHORT COMMUNICATION
velopment of one-pot synthetic approaches,[17] we present reaction of 1h in solvents such as THF, CH Cl , DMF, and
2
2
herein a one-pot novel synthetic method for the conversion toluene, the reaction did not yield 2h (Table 1, Entries 4–7).
of aryl and conjugated (α,β-unsaturated) aldehydes into Similarly, the reaction in CHCl and EtOAc did not pro-
3
their corresponding N-tert-butyl amides by using NaN3/ ceed to completion and gave a low yield of 2h (Table 1,
HBF ·OEt /tBuOAc in acetic acid through sequential Entries 8 and 9).
4
2
Schmidt and Ritter reactions. To the best of our knowledge,
this is the first example of sequential Schmidt/Ritter reac-
tions in one pot for the synthesis of N-tert-butylbenzamides
directly from aryl aldehydes (Scheme 1).
Table 1. Optimization studies for the synthesis of piperonitrile (2h)
from piperonal (1h).[
a]
4 2
Entry HBF ·OEt
[equiv.] Solvent Time [h] Yield [%][b,c]
1
2
3
4
5
6
7
8
9
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
CH
CH
CH
THF
CH Cl
DMF
toluene
CHCl
3
3
3
CN
CN
CN
1
1
1
3
4
4
4
4
3
1
65
77
95
n.r.
n.r.
n.r.
n.r.
46
2
2
3
EtOAc
AcOH
53
95
10
[
a] Reaction conditions: Reaction performed with 1h (1.0 mmol),
NaN (1.5 mmol), and HBF ·OEt (2.0 mmol) in solvent (2 mL).
b] The yield of product 2h was obtained by H NMR spectroscopy.
c] n.r. = no reaction.
3
4
2
1
[
[
Thus, we performed the Schmidt reaction in acetic acid
to give 2h in 95% yield (Table 1, Entry 10). Repeating the
same reaction in acetic acid followed by the Ritter reaction
with tert-butyl acetate (2.0 mmol) by adding further 2 equiv.
of HBF ·OEt in one pot afforded N-tert-butyl amide deriv-
4
2
ative 3h in almost quantitative yield (Table 2, Entry 8).
Thus, the optimal reaction conditions involve the use of 1h
(
1 mmol), NaN (1.5 mmol), HBF ·OEt (4.0 mmol), and
Scheme 1. Synthesis of N-tert-butylbenzamide directly from benzal-
3 4 2
dehyde. T-HYDRO = 69–70% TBHP in water. TBHP = tert-butyl tBuOAc (2.0 mmol) at room temperature (Scheme 2).
hydroperoxide.
To generate a clear picture of the scopes and limitations
of this novel protocol, we tried to explore the protocol with
various aromatic and conjugated aldehydes (Table 2, En-
tries 1–20). Unsubstituted aryl aldehydes such as benzalde-
hyde (1a) and 2-naphthaldehyde (1b) smoothly underwent
Results and Discussion
Initially, we attempted the Schmidt reaction of piperonal the sequential Schmidt and Ritter reactions to give their
1h; 1.0 mmol) with NaN (1.5 mmol) by using HBF ·OEt corresponding N-tert-butyl amide derivatives 3a and 3b in
1 equiv.) in acetonitrile (Table 1, Entry 1). As expected, 91 and 93% yield, respectively (Table 2, Entries 1 and 2).
(
(
3
4
2
piperonitrile (2h) was formed in 65% yield. To enhance the In contrast to the above unsubstituted aryl aldehydes, the
yield of 2h we used an excess amount of HBF ·OEt . Upon Schmidt and Ritter sequence of reactions of sterically hin-
4
2
using 2 equiv. of HBF ·OEt , product 2h was obtained in dered 9-anthracenecarbaldehyde (1c) was not successful; an
4
2
95% yield (Table 1, Entry 3). Then, we decided to convert unidentified mixture of compounds was obtained instead of
2h directly into N-tert-butyl amide derivative 3h in one pot the corresponding N-tert-butyl amide 3c (Table 2, Entry 3).
through sequential Schmidt and Ritter reactions. Given It was already confirmed from the optimized reaction con-
that acetonitrile was used as the solvent in the above ditions with 1h that this protocol was very much effective
Schmidt reaction, we changed the medium of the reaction, with aryl aldehydes bearing electron-donating substituents.
as both product and medium contained the nitrile group. Actually, p-anisaldehyde (1d), p-(benzyloxy)benzaldehyde
Thus, the reaction was performed in solvents other than (1e), p-tolualdehyde (1f), p-isopropylbenzaldehyde (1g), and
acetonitrile to avoid the competitive formation of two N- 3,4-dimethoxybenzaldehyde (1j) also underwent the reac-
tert-butyl amide derivatives. Upon performing the Schmidt tion to give 3d, 3e, 3f, 3g, and 3j in almost quantitative
2
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One-Pot Sequential Schmidt and Ritter Reactions
Table 2. Scope of the sequential Schmidt and Ritter reactions in one pot.
[a] Yield of isolated product. [b] n.r. = no reaction.
yields (Table 2, Entries 4–7 and 10). Similarly, an aryl alde- hydes with electron-withdrawing substituents also under-
hyde with a free hydroxy substituent [p-hydroxybenzalde- went the Schmidt and Ritter reactions, but their N-tert-
hyde (1i)] also afforded its respective N-tert-butyl amide de- butyl amide derivatives were obtained in slightly lower
rivative 3i in very good yield (Table 2, Entry 9). Aryl alde- yields relative to those offered by substrates with electron-
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N. Hazarika, G. Baishya
SHORT COMMUNICATION
Scheme 2. One-pot sequential Schmidt and Ritter reactions of
piperonal.
donating substituents (Table 2, Entries 11–14; used 3 equiv.
of HBF ·OEt in each step of the sequence).
4
2
Interestingly, the reaction of heteroaromatic aldehydes,
that is, 2-furfuraldehye (1o) and 2-thiophenecarbaldehyde
(1p) also afforded their corresponding N-tert-butyl amide
derivatives 3o and 3p, respectively, in very good yields Scheme 5. Proposed mechanism for the sequential Schmidt and
Ritter reactions.[
10,14]
(Table 2, Entries 15 and 16). This methodology was equally
effective with conjugated (α,β-unsaturated) aldehydes and
worked well with (E)-cinnamaldehyde (1q) to afford N-tert- Conclusions
butyl amide derivative 3q in excellent yield (Table 2, en-
A novel one-pot sequence involving Schmidt and Ritter
try 17).
reactions was developed for the first time for the synthesis
of N-tert-butyl amide derivatives in very good to excellent
yields directly from aldehydes by using NaN /HBF ·OEt /
Reactions with p-cyanobenzaldehyde (1r) and 4-(dimeth-
ylamino)benzaldehyde (1s) did not yield the desired N-tert-
butylbenzamides 3r and 3s; instead, we obtained an un-
identified mixture of products in each case (Table 2, En-
tries 18 and 19). Similarly, pyridine-2-carbaldehyde (1t) did
not undergo the reaction to afford 3t after a reaction time
of 12 h (Table 2, Entry 20).
Furthermore, we also performed the reaction with β-
bromo-α,β-unsaturated aldehyde 4 to give 6, but the reac-
tion produced the corresponding β-bromo-α,β-unsaturated
nitrile 5 as the Schmidt product in 82% yield (Scheme 3).
3
4
2
tBuOAc in acetic acid at ambient temperature. Different
unsubstituted and substituted aromatic aldehydes bearing
both electron-donating and electron-withdrawing substitu-
ents underwent the sequence. This methodology was also
found to be equally effective with conjugated (α,β-unsatu-
rated) aldehydes. The main advantage of this methodology
is that it does not require column chromatography for puri-
fication of the products. This novel protocol for sequential
Schmidt and Ritter reactions is a new entry in the area of
synthetic organic chemistry for the synthesis of N-tert-butyl
amide derivatives directly from aldehydes in a one-pot oper-
ation.
Experimental Section
Scheme 3. Sequential Schmidt and Ritter reactions with β-bromo-
α,β-unsaturated aldehyde 4.
General Methods: Melting points were measured with a Büchi B-
5
40 melting point apparatus. IR spectra were recorded with a Shim-
Finally, we also explored the tolerance of other func-
tional groups such as ketones under the reaction conditions.
adzu FTIR-8400 spectrometer. NMR spectra were recorded with
Bruker DPX 300 MHz and AV500 Avance-III 500 MHz FT-NMR
Thus, treatment of an equimolar mixture of p-anisaldehyde spectrometers by using tetramethylsilane as an internal standard.
(
1d) and acetophenone (7) with NaN /HBF ·OEt /tBuOAc All commercially available regents were used without further purifi-
3 4 2
in acetic acid delivered N-tert-butyl amide 3d as the sole cation. All experiments were monitored by thin-layer chromatog-
raphy by using aluminum precoated silica gel TLC plates (Merck).
After elution, the plates were visualized under UV illumination at
and was recovered in almost quantitative yield (Scheme 4).
product. Acetophenone (7) remained intact in the reaction
254 nm for UV-active materials. Further visualization was achieved
by staining with anisaldehyde charring solution.
General Experimental Procedure for the Schmidt–Ritter Reaction:
HBF
hyde (1 mmol, 1 equiv.) and NaN
acid (2 mL), and the mixture was stirred for 1 h. tert-Butyl acetate
2.0 mmol, 2.0 equiv.) was added, followed by HBF ·OEt (2 mmol,
equiv.). The mixture was stirred for further 2–4 h. Upon comple-
tion of the reaction (TLC), a saturated aqueous solution of
NaHCO (20 mL) was added. The solid product that precipitated
4
·OEt
2
(2 mmol, 2 equiv.) was added to a solution of aryl alde-
3
(1.5 mmol, 1.5 equiv.) in acetic
(
2
4
2
Scheme 4. Chemoselective synthesis of N-tert-butyl amide.
3
The mechanism for this sequential reaction can be ex-
plained by the already established mechanisms of each step,
from the mixture was filtered and washed thoroughly with distilled
water (50 mL). The solid was dried under vacuum to give the pure
that is, the Schmidt[10] and Ritter[14] reactions, involved in product. Further purification was not necessary in most cases.
this novel method (Scheme 5).
Compounds 3g, 3k, 3m, and 3n were additionally purified by
4
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One-Pot Sequential Schmidt and Ritter Reactions
recrystallization from hexane. Compounds 3a, 3d, 3f, 3k, 3n, 3p,
[9] W. E. McEwen, W. E. Conrad, C. A. Vanderwerf, J. Am. Chem.
Soc. 1952, 74, 1168.
and 3q are known in the literature;[
14,15]
their structures were con-
[
10] B. V. Rokade, K. R. Prabhu, J. Org. Chem. 2012, 77, 5364–
370.
11] a) J. J. Ritter, P. P. Minieri, J. Am. Chem. Soc. 1948, 70, 4045–
firmed by comparison of their analytical data with the reported
data. Full characteristic data of all new compounds are given in
the Supporting Information.
5
[
4
4
048; b) F. R. Benson, J. J. Ritter, J. Am. Chem. Soc. 1949, 71,
128–129; c) H. Plaut, J. J. Ritter, J. Am. Chem. Soc. 1951, 73,
Supporting Information (see footnote on the first page of this arti-
1
13
4076–4077; d) J. J. Ritter, N. Y. Yonkers, U. S. Patent 2,573,673,
cle): Spectral data and copies of the H NMR and C NMR spec-
tra for all final products.
1
951; e) L. I. Krimen, D. L. Cota, Org. React. 1969, 17, 213–
3
25.
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Acknowledgments
We acknowledge the Council of Scientific and Industrial Research
(CSIR), New Delhi for financial support. The authors are also
grateful to Dr. N. C. Barua, HOD, Natural Products Chemistry
Division, and Dr. D. Ramaiah, Director, CSIR-NEIST, Jorhat, for
their support and keen interest.
1
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Received: May 30, 2014
Published Online: ᭿
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N. Hazarika, G. Baishya
SHORT COMMUNICATION
Sequential Reactions
N. Hazarika, G. Baishya* ................. 1–6
One-Pot Sequential Schmidt and Ritter Re-
actions for the Synthesis of N-tert-Butyl
Amides
A mixture of NaN
3
/HBF
4
·OEt
2
in AcOH
acetate to afford the corresponding N-tert-
butyl amides. The method needs no column
chromatography purification, has a wide
substrate scope, and uses readily available
reagents.
reacts efficiently with aromatic and con-
jugated (α,β-unsaturated) aldehydes to
produce nitrile derivatives, which in situ
undergo a Ritter reaction with tert-butyl
Keywords: Amides / Aldehydes / Schmidt
reaction / Ritter reaction
6
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