A direct entry to substituted n-methoxyamines from n-methoxyamides via n-oxyiminium ions

Article abstract of DOI:10.1002/anie.201001127

Take the direct path: Sequential nucleophilic addition of N-methoxyamides using DIBAL and organometallic reagents provided substituted N-methoxyamines in one pot via five-membered chelated intermediates (see scheme, DIBAL=diisobutylaluminum hydride). The reaction allows functionalization of acyclic amides and macrolactams without a preactivation step, which is generally required for inert amide carbonyl groups. Copyright

Full text of DOI:10.1002/anie.201001127

Angewandte
Chemie
DOI: 10.1002/anie.201001127
Synthetic Methods
A Direct Entry to Substituted N-Methoxyamines from
N-Methoxyamides via N-Oxyiminium Ions**
Kenji Shirokane, Yusuke Kurosaki, Takaaki Sato,* and Noritaka Chida*
Amide functional groups play a significant role in a variety of
areas such as medicinal drugs and chemical fibers. Therefore,
the efficient synthesis of amide bonds has received much
attention by organic chemists, making this one of the most
reliable reactions in synthetic organic chemistry.[1] On the
other hand, functionalization of the generated amide carbon-
yl groups is less explored than their construction. Amide
carbonyl groups could potentially accept two organometallic
reagents to furnish multisubstituted amines. However, direct
nucleophilic addition requires harsh reaction conditions
because of the high stability of amide carbonyl units.[2–6] The
substrate scope is limited, and it is especially challenging to
functionalize acyclic amides and macrolactams because of the
instability of intermediates, which readily undergo hydrolysis.
To overcome their inertness and poor substrate scope,
preactivation of amides has been employed prior to nucleo-
philic addition (Scheme 1). The research groups of
DeNinno[7] and Suh[8] independently reported efficient strat-
egies that install acyl groups to give acyclic imides (1!2). In
Suhꢀs method, formation of an N,O-acetal TMS ether, and
subsequent Lewis acid promoted nucleophilic addition gave 3
via acyclic N-acyliminium ions. Thionation of amide carbonyl
groups is another practical approach (1!4).[9,10] Murai et al.
demonstrated sequential reactions of acyclic thionium salts
Scheme 1. Selected examples of the nucleophilic addition to amide
carbonyl groups with the preactivation step. DIBAL=diisobutylalumi-
num hydride, py=pyridine, Tf=trifluoromethanesulfonyl, TMS=trime-
thylsilyl.
with organolithium and Grignard reagents (1!4!5).[10]
A
classical method, involving activation of acyclic amides with
dehydrating reagents (Tf2O, P2O5, etc.), has been widely used
such as in the Bischler–Napieralski and Vilsmeier–Haack
reactions (1!6!7).[11] Very recently, Huang and co-workers
reported sequential addition to amides via iminium triflate
intermediate 6.[11d]
Scheme 2. Synthesis of substituted N-methoxyamines by the sequen-
tial nucleophilic addition of N-methoxyamides without the preactiva-
tion step. LA=Lewis acid.
In the hopes of discovering practical transformations of
amides, we initiated a program aimed at developing a novel
one-pot transformation of acyclic N-methoxyamides to give
substituted N-methoxyamines without the preactivation step.
The realization of this process is outlined in Scheme 2.
Treatment of N-methoxyamide 8 with DIBAL is known to
produce the chelated five-membered intermediate 9. In the
well-known Weinreb ketone synthesis, hydrolysis of chelated
intermediate 9 gives aldehyde 10 without extra nucleophilic
addition to the aldehyde carbonyl group.[12] On the other
hand, our reaction would require the capture of intermediate
9 with a Lewis acid, thus generating N-oxyiminium ion 12 via
hemiaminal 11. The resulting N-oxyiminium ion 12 would
undergo a nucleophilic addition to give N-methoxyamine
13.[13–15] N-Methoxyamine 13 could undergo further unique
transformations such as direct oxidation to nitrons.[16] Salient
features of this process are: 1) high yielding synthesis of N-
methoxyamides by condensation between a carboxylic acid
and a N-methoxyamine;[17] 2) exclusion of the preactivation
step as a result of the higher electrophilicity of N-methoxy-
amides compared to ordinary amides; 3) one-pot installation
[*] K. Shirokane, Y. Kurosaki, Dr. T. Sato, Prof. Dr. N. Chida
Department of Applied Chemistry
Faculty of Science and Technology, Keio University
3-14-1, Hiyoshi, Kohoku-ku, Yokohama 223-8522 (Japan)
Fax: (+81)45-566-1551
E-mail: takaakis@applc.keio.ac.jp
chida@applc.keio.ac.jp
Homepage: http://www.applc.keio.ac.jp/~chida/index.html
[**] This research was supported by a Grant-in-Aid for Young Scientists
(B) from MEXT (21750049) and the Otsuka Pharmaceutical Co.
Award in Synthetic Organic Chemistry (Japan).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201001127.
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Table 2: Substrate scope in intermolecular allylation and cyanation.[a]
of a carbon nucleophile to amides; and 4) wide substrate
scope including acyclic and macrocyclic systems.
Our investigations began by examining the reaction of N-
benzyl-N-methoxyoctanamide 14a with DIBAL and allyltri-
methylsilane (Table 1).[18] Treatment of 14a with DIBAL at
Table 1: Optimization of the reaction conditions in the intermolecular
allylation of 14a.[a]
Entry 14
R3M
Lewis acid Yield [%][b]
d.r.[c]
=
1
2
3
4
5
6
7
8
14a
14b
14c
CH2 CHCH2SnBu3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
none
none
none
none
SnCl4
92
91
72
72
48
55
69
53
83
70
79
65
–
–
=
CH2 CHCH2SnBu3
=
CH2 CHCH2SnBu3
1.6:1
1.4:1
–
=
14d CH2 CHCH2SnBu3
ꢀ
14a
14b
14c
NC TMS
Entry
Lewis acid
M
Yield [%][b]
ꢀ
NC TMS
–
ꢀ
NC TMS
1:1
1.4:1
–
1
2
3
4
5
6
7
8
none
TMS
TMS
TMS
TMS
TMS
TMS
TMS
SnBu3
0
0
ꢀ
14d NC TMS
Ac2O, DMAP[c]
BF3·OEt2
SnCl4
ꢀ
9
14a
14b
14c
NC TMS
32
60
70
71
11
92
ꢀ
10
11
12
NC TMS
SnCl4
SnCl4
SnCl4
–
ꢀ
NC TMS
4.2:1
4.1:1
TMSOTf
Sc(OTf)3
Sc(OTf)3
ꢀ
14d NC TMS
[d]
[a] Reaction conditions: 14 (0.11 mmol), DIBAL in toluene
(1.01m,1.3 equiv), CH2Cl2, ꢀ788C, 0.5 h, then Sc(OTf)3 (1.3 equiv) or
SnCl4 (3 equiv), R3M (3 equiv), RT, 1.5 h. [b] Yield of isolated product
after purification by column chromatography on silica gel. [c] The
diastereomeric ratios were determined by 1H NMR analysis.
Sc(OTf)3
[a] Reaction conditions: 14a (0.11 mmol), DIBAL in toluene
(1.01m,1.1 equiv), CH2Cl2, ꢀ788C, 0.5 h, then Lewis acid (1.1 equiv),
CH2 =CHCH2M (3 equiv), RT, 1.5 h. [b] Yield of isolated product after
purification by column chromatography on silica gel. [c] Ac2O (1.3 equiv)
and DMAP (1.3 equiv) were used instead of a Lewis acid. [d] Sc(OTf)3
(0.3 equiv) was used. DMAP=N,N-4-dimethylaminopyridine.
three equivalents of SnCl4 was used (Table 2, entries 9–12).
Use of SnCl4 had some effects on the diastereoselectivity with
branched N-methoxyamides. While cyanation of 14c and 14d
without Lewis acid showed poor diastereoselectivity (Table 2,
entries 7 and 8), the reaction with SnCl4 led to an increase in
diastereoselectivity (Table 2, entries 11 and 12).
One of the conspicuous advantages of utilizing amidation
is a reliable preparation of macrocyclic compounds. By
combining macrolactamization[1] with our process, we could
access macrocyclic amines like the ones embedded in natural
products such as manzamine A[23] and madangamine A.[24,25]
As a demonstration of this concept, we synthesized macro-
cyclic amines 18 and 19 (Scheme 3). A solution of N-
methoxyamino acid 16 in CH2Cl2 was added over 15 hours
(using a syringe pump) to a solution of HATU and iPr2NEt,
and gave 15-membered macrolactam 17 in 80% yield, along
with 8% yield of the dimer. Reduction with DIBAL, and
subsequent Lewis acid promoted allylation and cyanation
gave 18 and 19 in 90% and 76% yield, respectively.
We then turned our attention to intramolecular reactions
to generate substituted azacycles from acyclic N-methoxya-
mides (Table 3).[26] Reduction of 20 (bearing an (E)-allylsilane
group) with DIBAL at ꢀ788C and subsequent addition of
SnCl4 at room temperature induced the diastereoselective
intramolecular allylation, thus favoring the unusual cis ar-
rangement (21/22 = 2.9:1).[27–29] The nature of the Lewis acid
had some effect on reaction efficiency (Table 3, entries 1–3).
The best results in terms of both yield and diastereoselectivity
were obtained with Sc(OTf)3 (Table 3, entry 3). The reaction
proceeded even at ꢀ408C, albeit with a prolonged reaction
time (12 h; Table 3, entry 4). The replacement of CH2Cl2 with
THF had a detrimental effect on diastereoselectivity (Table 3,
entry 5). Although the factors controlling the cis preference
ꢀ788C, and subsequent addition of allyltrimethylsilane with-
out Lewis acid provided octanal and N-benzyl-N-methoxy-
amine, because the corresponding N-oxyiminium ion was not
formed and the chelated five-membered intermediate was
simply hydrolyzed (Table 1, entry 1). Next, we attempted to
trap the chelated intermediate with acetic anhydride under
Rychnovskyꢀs conditions,[6] which gave octanal in addition to
N-benzyl-N-methoxyamine (Table 1, entry 2).[19] However,
when 1.1 equivalents of BF3·Et2O was used instead of acetic
anhydride and DMAP, the desired amine 15a was isolated in
32% yield (Table 1, entry 3). Of the Lewis acids screened,
TMSOTf[8,20] and Sc(OTf)3 proved to be the most effective,
and provided 15a in 70% and 71% yield, respectively
(Table 1, entries 5 and 6). A catalytic amount of Sc(OTf)3
(0.3 equiv) led to a significant decrease in yield (Table 1,
entry 7). The best result was obtained when allyltributylstan-
nane was employed as a stronger nucleophile, and gave 15a in
92% yield (Table 1, entry 8).[21]
With the optimized reaction conditions in hand, the scope
of the sequential nucleophilic addition of various acyclic N-
methoxyamides was surveyed (Table 2). The intermolecular
allylation of the linear substrates 14a and 14b with allyltri-
butylstannane gave the products in high yields (Table 2,
entries 1 and 2). The reaction with branched substrates 14c
and 14d proceeded in slightly lower yields than the linear
ones probably owing to steric hindrance, and exhibited low
diastereoselectivity (Table 2, entries 3 and 4). The method
was also applicable to cyanation of N-methoxyamides with
TMSCN, and proceeded without Lewis acid (Table 2,
entries 5–8).[22] However, higher yields were observed when
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Scheme 3. Approach to macrocyclic azacycles through macrolactamiza-
tion and sequential nucleophilic addition. HATU=O-(7-azabenzotria-
zol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate.
[4] Related nucleophilic additions of esters with higher electro-
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Entry
Lewis acid
Solvent
T [8C]
Yield of
21/22
21+22 [%][b]
1
2
3
4
5
SnCl4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
RT
RT
RT
-40
RT
69
77
88
72
91
2.9:1
3.5:1
5.0:1
5.3:1
1.8:1
TMSOTf
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
[a] 20 (60 mmol), DIBAL in toluene (1.01m, 1.3 equiv), CH2Cl2, ꢀ788C,
0.5 h, then Lewis acid (1.3 equiv), 1.5 h. [b] Combined yield of isolated
products after purification by column chromatography on silica gel.
THF=tetrahydrofuran.
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are yet to be clarified, we have developed this novel
cyclization to give cis-2,3-disubstituted piperidines from
acyclic N-methoxyamides.
In summary, we have developed a useful sequential
nucleophilic addition to N-alkoxyamides with DIBAL and a
variety of organometallic reagents in one-pot. The method
eliminates the preactivation step, which is usually a requisite
for the functionalization of amide carbonyl groups. The
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Received: February 24, 2010
Revised: June 9, 2010
Published online: July 29, 2010
Keywords: allylation · amides · cyanation · cyclization ·
.
macrocycles
Angew. Chem. Int. Ed. 2010, 49, 6369 –6372
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6371

Communications
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[21] As a control experiment, tertiary amide A was reduced with
DIBAL (1.3 equiv) at ꢀ508C, and subsequent treatment with
6372
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