Exploiting the Nucleophilicity of N-H Imines: Synthesis of Enamides from Alkyl Azides and Acid Anhydrides

Article abstract of DOI:10.1002/adsc.201400584

The nucleophilicity of N-unsubstituted imines, which were generated from alkyl azides by a ruthenium-catalyzed reaction, was investigated in the reaction with acid anhydrides. The initial products were N-acylimines, which isomerized to the corresponding e

Full text of DOI:10.1002/adsc.201400584

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DOI: 10.1002/adsc.201400584
À
Exploiting the Nucleophilicity of N H Imines: Synthesis of
Enamides from Alkyl Azides and Acid Anhydrides
Junghoon Han,a Mina Jeon,a Han Kyu Pak,a Young Ho Rhee,a,*
and Jaiwook Parka,*
a
Department of Chemisty, POSTECH (Pohang University of Science and Technology), Pohang, 790-784, Korea
Fax : (+82)-54-279-0654; e-mail: yhrhee@postech.ac.kr (homepage: http://yhrhee.postech.ac.kr) or pjw@postech.ac.kr
(homepage: http://oml.postech.ac.kr)
Received: June 16, 2014; Revised: July 15, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400584.
Abstract: The nucleophilicity of N-unsubstituted
imines, which were generated from alkyl azides by
a ruthenium-catalyzed reaction, was investigated in
the reaction with acid anhydrides. The initial prod-
ucts were N-acylimines, which isomerized to the
corresponding enamides. Heating or triethylamine
facilitated the isomerization of N-acylimines that
are stable at room temperature. A wide range of
acyclic and cyclic enamides containing various func-
tional groups was successfully synthesized under
mild conditions. In addition to acetic anhydride,
various acid anhydrides were applicable. From the
reaction with cyclic anhydrides, enamides contain-
ing carboxylic acid group were obtained.
ies coordinated to gold reacted as electrophiles.[5]
À
However, it is rare that N-unsubstituted (N H)
imines are employed as nucleophiles:[6] only benzo-
phenone imine has been used in the nucleophilic ad-
dition to coordinated nitriles and isonitriles in plati-
À
num complexes. A reason for the lack of work on N
H imines is the preconception about their limited ac-
À
cessibility and instability. In fact, N H imines have
been proposed just as intermediates without isolation
(or detection) in most cases.[7] Recently, however, we
found an efficient catalytic method to transform alkyl
À
azides into their corresponding N H imines under
mild and neutral conditions: a wide range of aldi-
mines and ketimines have been produced and ana-
lyzed successfully at room temperature.[8a] This find-
À
À
Keywords: enamides; isomerization; N H imines;
ing led us to investigate applications of N H imi-
ruthenium catalyst; synthetic method
nes,[8b] and herein we wish to report an application of
À
the nucleophilicity of N H imines to provide useful
N-acylimines and enamides in the reaction with acid
anhydrides (Scheme 1).
Enamides are versatile precursors in organic syn-
Imines have been recognized as important intermedi- thesis.[9] They have been employed in C C and C N
ates in organic synthesis, particularly for the prepara- bond forming reactions such as aza-ene,[10] Michael,[11]
tion of nitrogen-containing bioactive natural products Friedel–Crafts,[12] cycloaddition,[13] and arylation reac-
and pharmaceuticals.[1] Because of the electronegativi- tions.[14] In particular, they are important precursors
ty of the nitrogen atom of imines, research projects of optically active amines in enantioselective hydroge-
have been focused primarily on the nucleophillic ad- nation.[15] For these extensive applications, numerous
dition to C=N bonds.[2] In contrast, there are few re- synthetic methods have been developed, including the
ports on the use of imines as N-nucleophiles. Most of representative ones such as the addition of Grignard
them are about the reactions involving imines sug- reagents (or alkyllithium) to nitriles followed by the
gested as transient intermediates.[3] Acylation of
À
À
stable N-substituted imines has been adopted by
Funk et al. for preparing a dienophile and the precur-
sors of heterocyclic ring systems.[3f,g] For the prepara-
tion of b-lactams, N-substituted imines have been
used as N-nucleophiles in the Staudinger synthesis.[4]
Recently, N-substituted imines have been utilized as
nucleophiles in Au-catalyzed reactions, where a-car-
bonyl gold carbenoid intermediates and alkyne moiet- for the synthesis N-acyl enamides.
À
Scheme 1. Application of the nucleophilicity of N H imines
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Junghoon Han et al.
Table 1. Synthesis of enamides under various conditions.[a]
Entry Solvent[b] Base[c]
Amount of Ac2O
(equiv.)
Yield
[%][d]
1
2
3
4
5
6
7
8
9
THF
THF
THF
THF
none
none
none
none
none
none
none
none
1.2
1.5
2.0
3.0
2.0
2.0
2.0
2.0
2.0
67
75
85 (81)[e]
75
75
70
42
49
49
toluene
CH2Cl2
CH3CN
acetone
ethyl ace- none
tate
THF
THF
THF
THF
10
11
12
13
Et3N
2.0
87 (85)[e]
79
80
81
pyridine 2.0
DBU 2.0
DABCO 2.0
[a]
Typical reaction conditions:
a
solution of an azide
(0.25 mmol) and 1 (2.0 mol%) in a solvent (0.50 mL) was
illuminated with a 30 W fluorescent light. After the for-
mation of imine, Ac2O was added. The resulting mixture
was stirred for 12 h at room temperature.
THF=tetrahydrofuran.
2.0 equiv. of base were used. DBU=1,8-diazabicycloun-
Scheme 2. Synthetic methods for enamides.
reaction with acetic anhydride (or acyl chloride) [Eq.
(1)],[16] transition metal-catalyzed cross-coupling reac-
tion of vinyl electrophiles with amides [Eq. (2)],[17]
direct condensation of amides with ketones [Eq.
(3)],[18] reductive acylation of ketoximes [Eq. (4)],[19]
and direct titanium-mediated reaction of ketones with
ammonia and acetic anhydride [Eq. (5), Scheme 2].[20]
However, these methods frequently suffer from poor
[b]
[c]
dec-7-ene, DABCO=1,4-diazabicycloACTHNUGRTENUNG[2.2.2]octane.
[d]
[e]
1
Estimated by H NMR using nitromethane as an internal
standard.
Isolated yield.
functional group tolerance, difficulty in preparing sub- thane were better than acetonitrile, acetone, and ethyl
strates, low yield, and/or requirement of stoichiomet- acetate (entries 5–9). Interestingly, in contrast to the
ric reductants or additives. For example, the reductive previous reports in which triethylamine is used for the
acylation of ketoximes, which is known as the most isomerization of acetimides into enamides,[20] a base
common procedure, needs the reduction of ketoximes was not necessary for the formation of 3a in our
at high temperatures. A noticeable recent method to method. In fact, the use of triethylamine (Et3N)
avoid the reduction is that of Eq. (5), which is a one- slightly increased the yield of 3a (entry 10), while that
pot synthesis under mild conditions.[20] However, it re- of pyridine, DBU, or DABCO did not give any posi-
quires an excess amount of Ti
ACHTUNGTRENNUNG
cated work-up procedure is needed to remove titani-
um waste. Herein we wish to report a new method plored with benzylic azides (Table 2). A wide range of
not requiring additives for the synthesis of enamides enamides was produced successfully from the corre-
using alkyl azides and acid anhydrides under mild sponding benzylic azides by the one-pot two-step re-
À
conditions: N H imines are generated from alkyl actions. Acyclic enamides (3–9) as well as cyclic ones
azides through a ruthenium catalysis, followed by acy- (12–15) were obtained in good to high yields. The ad-
lation of the imines and the isomerization of the re- dition of Et3N increased the yield of enamides in
sulting acyl imines into enamides.
To optimize the reaction conditions, the transforma- that were not affected significantly. The a,a-di-
tion of (1-azidoethyl)benzene to N-(1-phenylvinyl)- substituted enamides (10 and 11) were exceptionally
acetamide (3a) was tested under various conditions opposite cases, which were formed favourably in the
(Table 1). The use of two equivalents of acetic anhy- absence of triethylamine.
most of the reactions, although there were many cases
AHCTUNGTRENNUNG
ACHTUNGTRENNUNG
dride (Ac2O) was optimum for the yield of 3a (en-
Various functional groups (3e–3m) such as halides,
tries 1–4). Among the solvents tested, relatively non- alkoxy groups, thioethers, esters, amides, and nitriles
polar solvents such as THF, toluene, and dichlorome- were compatible with the reaction conditions. Naph-
2
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Exploiting the Nucleophilicity of N H Imines: Synthesis of Enamides
Table 2. Synthesis of enamides from benzylic azides.[a,b]
Table 3. Synthesis of enamides from aliphatic azides.[a,b]
[a]
Typical reaction conditions:
a solution of an azide
(0.25 mmol) and 1 (2.0 mol%) in THF (0.50 mL) was il-
luminated with a 30 W fluorescent light. After the forma-
tion of imine, Ac2O (0.50 mmol) and Et3N (0.50 mmol)
were added. The resulting mixture was stirred for 12 h at
room temperature.
[b]
[c]
Isolated yield.
The reaction temperature was 708C.
isomers (20 and 23) was favoured by heating (19 vs.
20 and 22 vs. 23) and conjugation with a phenyl group
(20 vs. 23). Geometric selectivity was not high for the
internal isomers. Azidocyclohexane was transformed
to the corresponding cyclic enamide 24 in moderate
yield.
In addition to Ac2O, several acid anhydrides were
employed to vary the N-acyl group of the enamides
(Table 4). The reaction with propionic anhydride pro-
ceeded well at room temperature, while that of ben-
zoic anhydride required heating. Interestingly, the re-
action with di-tert-butyl dicarbonate at room tempera-
ture gave the corresponding N-Boc imine 27 selective-
ly in high yield, while the enamide 28 was formed at
708C. The yield of N-trifluoroacetyl enamide 29 was
higher in the absence of Et3N in the reaction with
triflic anhydride; unknown side products were formed
in the presence of Et3N. Enamides (30 and 31) con-
taining carboxylic acid groups were obtained in the
reaction with cyclic anhydrides such as malonic anhy-
[a]
Typical reaction conditions:
a solution of an azide
(0.25 mmol) and 1 (2.0 mol%) in THF (0.50 mL) was il-
luminated with a 30 W fluorescent light. After the forma-
tion of imine, Ac2O (0.50 mmol) and Et3N (0.50 mmol)
were added. The resulting mixture was stirred for 12 h at
room temperature.
Isolated yield. The value in parenthesis is the yield ob-
tained from the reaction without Et3N.
The reaction temperature was 708C.
[b]
[c]
thyl (4) and heterocyclic enamides (5–7) were also ob- dride and diacetyl-l-tartaric anhydride. Another inter-
tained in good yields. a-Substituted enamides (8 and esting product is an N-formyl enamide (32),[21] which
9) were produced as mixtures of geometric isomers, in was selectively formed in high yield in the reaction
which the major products were (Z)-isomers. The with acetic formic anhydride.
cyclic enamides (12–15) were obtained in good yields
To probe the intermediacy of N-acetylimine for the
À
from indanyl, tetralonyl, chromanonyl, and subernoyl formation of enamides, a solution of N H imine 2k
azides. The acetal group (16) which is labile in acidic and Ac2O in [D8]THF was analyzed by 1H NMR
conditions was well tolerated in this transformation. under various conditions (Table 5).[22] The N H imine
À
The enamides (17 and 18) containing carbonyl groups 2k was readily reacted with Ac2O at room tempera-
are notable, which cannot be made from ketones or ture in the absence of base to give a 96:4 mixture of
aldehydes by conventional methods.
the N-acetylimine 33 and the enamide 3k in 6 h
Then, the transformation of aliphatic azides to the (entry 1). The conversion of 33 to 3k did not proceed
corresponding enamides was investigated (Table 3). further at room temperature (entry 2). In contrast,
At room temperature terminal enamides (19 and 22) the addition of Ac2O and triethylamine (Et3N) led to
were formed selectively. The formation of internal the formation of an 8:92 mixture of 33 and 3k in 6 h
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Table 4. Synthesis of various enamides.[a,b]
Scheme 3. Reaction pathway for the formation of enamides
from alkyl azides.
[a]
À
Typical reaction conditions:
a
solution of an azide Scheme 3. The N H imines generated by the Ru-cata-
(0.25 mmol) and 1 (2.0 mol%) in THF (0.50 mL) was il-
luminated with a 30 W fluorescent light. After the forma-
tion of imine, acid anhydride (0.50 mmol) and Et3N
(0.50 mmol) were added. The resulting mixture was
stirred for 12 h at room temperature.
Isolated yield.
The reaction temperature was 708C.
The reaction was performed without Et3N.
The yields of enamides were estimated by H NMR using
lyzed transformation of alkyl azides are acylated by
the reaction with acid anhydride to give N-acylimines.
Then the N-acylimines are isomerized to the thermo-
dynamically more stable enamides with or without
the aid of Et3N.[12c,23]
[b]
[c]
[d]
[e]
In conclusion, we developed a simple and efficient
one-pot synthesis of enamides from alkyl azides and
acid anhydrides under mild conditions. A wide range
of acyclic and cyclic enamides containing various
functional groups were successfully synthesized. We
1
nitromethane as an internal standard.
À
showed for the first time that N H imines react with
Table 5. Reaction of N-unsubstituted imine with acetic anhy-
dride under various conditions.
acid anhydrides to give N-acylimines under neutral
conditions and that the N-acylimines can be isomer-
ized into the corresponding enamides without the aid
of base.
Experimental Section
General Procedure[24]
The ruthenium catalyst 1 was introduced to a flame-dried J-
Young flask filled with argon gas. The dry THF (0.50 mL)
was added to the flask under a stream of argon. The solution
was stirred for 10 min at room temperature without light to
dissolve the catalyst. Then azide (0.25 mmol) was added to
the solution under argon at room temperature. The reaction
mixture was stirred for 3 h at room temperature with a 30 W
Entry
Base
T [oC]
Time [h]
33:3k
1
2
3
4
5
6
7
none
none
Et3N (2.0 equiv.)
Et3N (2.0 equiv.)
none
25
25
25
25
70
70
70
6
12
6
12
6
12
6
96:4
96:4
8:92
0:100
38:62
8:92
À
household fluorescent light. After accumulation of N H
ket
A
none
Et3N (2.0 equiv.)
2.0 equivalents of acid anhydride (and triethylamine) was
(were) added. The reaction mixture was stirred for 12 h at
room temperature. After completion of the reaction, vola-
tiles were removed under vacuum. The product was purified
by flash column chromatography to afford the respective en-
amides.
0:100
(entry 3), and the conversion to 3k was completed in
12 h (entry 4). The conversion was facilitated by heat-
ing (entries 5 and 6); it was completed in 6 h at 708C
in the presence of Et3N (entry 7).
The results of Table 5 support that Et3N is not nec-
À
essary for the N-acetylation of N H imine. However,
Acknowledgements
Et3N is needed for the isomerization of N-acetyli-
mines that are stable at room temperature. Thus the
reaction pathway for the formation of enamides from
This work was supported by the National Research Founda-
tion of Korea (No. 2012R1A2A1A01007235 and No. 2008-
alkyl azides can be summarized as shown in 0061892).
4
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Exploiting the Nucleophilicity of N H Imines: Synthesis of Enamides
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[24] Caution: We have not observed any explosion during
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6
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ÝÝ
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À
Exploiting the Nucleophilicity of N H Imines: Synthesis of
Enamides from Alkyl Azides and Acid Anhydrides
7
Adv. Synth. Catal. 2014, 356, 1 – 7
Junghoon Han, Mina Jeon, Han Kyu Pak, Young Ho Rhee,*
Jaiwook Park*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!