Direct nucleophilic addition to N-alkoxyamides

Article abstract of DOI:10.1002/chem.201202639

While the synthesis of amide bonds is now one of the most reliable organic reactions, functionalization of amide carbonyl groups has been a long-standing issue due to their high stability. As an ongoing program aimed at practical transformation of amides, we developed a direct nucleophilic addition to N-alkoxyamides to access multisubstituted amines. The reaction enabled installation of two different functional groups to amide carbonyl groups in one pot. The N-alkoxy group played important roles in this reaction. First, it removed the requirement for an extra preactivation step prior to nucleophilic addition to activate inert amide carbonyl groups. Second, the N-alkoxy group formed a five-membered chelated complex after the first nucleophilic addition, resulting in suppression of an extra addition of the first nucleophile. While diisobutylaluminum hydride (DIBAL-H) and organolithium reagents were suitable as the first nucleophile, allylation, cyanation, and vinylation were possible in the second addition including inter- and intramolecular reactions. The yields were generally high, even in the synthesis of sterically hindered α-trisubstituted amines. The reaction exhibited wide substrate scope, including acyclic amides, five- and six-membered lactams, and macrolactams. Copyright

Full text of DOI:10.1002/chem.201202639

DOI: 10.1002/chem.201202639
Direct Nucleophilic Addition to N-Alkoxyamides
Yuta Yanagita, Hugh Nakamura, Kenji Shirokane, Yusuke Kurosaki, Takaaki Sato,* and
Noritaka Chida*[a]
Abstract: While the synthesis of amide
bonds is now one of the most reliable
organic reactions, functionalization of
amide carbonyl groups has been a
long-standing issue due to their high
stability. As an ongoing program aimed
at practical transformation of amides,
we developed a direct nucleophilic ad-
dition to N-alkoxyamides to access
multisubstituted amines. The reaction
enabled installation of two different
functional groups to amide carbonyl
groups in one pot. The N-alkoxy group
played important roles in this reaction.
First, it removed the requirement for
an extra preactivation step prior to nu-
cleophilic addition to activate inert
amide carbonyl groups. Second, the N-
alkoxy group formed a five-membered
chelated complex after the first nucleo-
philic addition, resulting in suppression
of an extra addition of the first nucleo-
phile. While diisobutylaluminum hy-
dride (DIBAL-H) and organolithium
reagents were suitable as the first nu-
cleophile, allylation, cyanation, and vi-
nylation were possible in the second
addition including inter- and intramo-
lecular reactions. The yields were gen-
erally high, even in the synthesis of
sterically hindered a-trisubstituted
amines. The reaction exhibited wide
substrate scope, including acyclic
amides, five- and six-membered lac-
tams, and macrolactams.
Keywords: allylation · amides · cy-
anation · nucleophilic addition ·
synthetic methods
Introduction
Amide functional groups are found in a wide variety of or-
ganic molecules including pharmaceuticals and functional
materials. Therefore, the efficient synthesis of amide bonds
has been extensively studied and is now one of the most
promising reactions in modern organic synthesis.[1] On the
other hand, transformation of the generated amide groups is
less explored than their construction. Although amide car-
bonyl groups can potentially accept two organometallic re-
agents through nucleophilic addition to give multisubstituted
amines, this transformation is far more challenging than
with ketones and esters (Scheme 1, 1!2!3!4).[2–5] The
first nucleophilic addition to an amide carbonyl group (1!
2) requires harsh reaction conditions because of the high
stability of amide carbonyl moieties, caused by the reso-
nance effect of the nitrogen atom. Even when the first addi-
tion is achieved, the generation of iminium ion 3 is not trivi-
Scheme 1. Nucleophilic addition to amide carbonyl groups and its inher-
ent problems.
al due to the instability of N,O-acetal 2, resulting in the for-
mation of ketone 5 and amine 6. In addition, the generated
iminium ion 3 readily reacts with the remaining first nucleo-
phile, again to afford 7 because iminium ion 3 is more elec-
trophilic than the amide carbonyl itself.
The development of practical nucleophilic addition reac-
tions to amides must address two key issues. The first is en-
hancement of the poor electrophilicity of the amide carbon-
yl group. The second is sequential installation of two differ-
ent nucleophiles by preventing multiple addition of the first
nucleophile. To overcome these issues, most practical nucle-
ophilic additions so far have utilized a preactivation step.
This extra step renders the amide carbonyl group more reac-
tive and suppresses extra addition of the first nucleophile
(Scheme 2A). One of the more useful examples is preactiva-
tion of the acyclic amide to an imide (DeNinno,[6] Suh,[7] 8!
9!10). In Suhꢀs methodology,[7] reduction of 9 with diisobu-
tylaluminum hydride (DIBAL-H), followed by trapping
with TMSOTf and pyridine in situ gave an N,O-acetal TMS
[a] Y. Yanagita, H. Nakamura, K. Shirokane, Y. Kurosaki, Dr. T. Sato,
Prof. 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
Fax: (+81)45-566-1551
E-mail: takaakis@applc.keio.ac.jp
chida@applc.keio.ac.jp
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201202639.
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FULL PAPER
to exhibit low yields and could only install two identical
functional groups except in the approach developed by
Schiess.[11b]
In this paper, we disclose full details of our investigations
on the direct nucleophilic addition to N-alkoxyamides with-
out an extra preactivation step.[12] The reaction allowed two
different organometallic reagents to be used in one pot. In
many cases, these nucleophilic addition reactions proceeded
in high yields and showed a wide substrate scope including
acyclic amides, five- or six-membered lactams, and macro-
lactams.
Results and Discussion
Our laboratory has been exploring practical transformations
of amide groups and, in this context, initiated a program to
develop a direct nucleophilic addition to amide carbonyl
groups. As noted earlier, the reaction requires a new ap-
proach to enhance the electrophilicity of amide carbonyl
groups without a preactivation step and to install two differ-
ent nucleophiles in one pot. Our fundamental idea to solve
these issues is the utilization of N-alkoxyamides 16, which
are readily prepared by condensation between a carboxylic
acid and an N-methoxyamine (Scheme 3). Treatment of 16
Scheme 2. Selected examples of nucleophilic addition to amide carbonyl
groups: A) Use of a preactivation step, B) in situ activation, and C)
direct nucleophilic addition. DIBAL-H = diisobutylaluminum hydride,
TMS = trimethylsilyl, Tf = trifluoromethanesulfonyl.
ether, which underwent Lewis acid promoted nucleophilic
addition to provide 10. Although only a hydride (DIBAL-
H) could be used as the first nucleophile and a three-step
procedure was required, significant improvement of the sub-
strate scope including acyclic amides[7a] and macrolactams[7b]
was realized. Thionation of the amide carbonyl groups is an-
other practical preactivation strategy (1!11!4).[8] Murai
reported sequential nucleophilic additions of acyclic thioni-
um salts with two different carbon nucleophiles involving or-
ganolithium and Grignard reagents.[8f,g] To circumvent the
extra preactivation step, “in situ activation” was devel-
oped by using Tf2O/2,6-di-tert-butyl-4-methylpyridine
(Scheme 2B).[9] This approach dramatically expanded the
nucleophilic addition to amides. Bꢂlanger[9c,f] and Huang[9d,e]
independently reported sequential nucleophilic additions via
iminium triflate (1!12!4). Two different carbon nucleo-
philes were installed in one pot, resulting in the formation
of sterically hindered a-trisubstituted amines.[10] On the
other hand, some direct nucleophilic additions to amide car-
bonyl groups without a preactivation step have been report-
ed (Scheme 2C).[11] The key to success was utilization of ox-
ophilic Lewis acids such as TiCl4 (Schiess: 1!4[11b]), ZrCl4
Scheme 3. Direct nucleophilic addition to N-alkoxyamides.
with an organometallic reagent is known to produce the
five-membered chelated intermediate 17. Whereas the well-
known Weinreb ketone synthesis[13] provides ketone 20 after
hydrolysis of 17 without extra addition of the nucleophile,
our approach requires the capture of intermediate 17 with
acid. The resulting N-oxyiminium ion 18[14,15] would then un-
dergo a second nucleophilic addition to give multisubstitut-
ed N-alkoxyamines 19. The N-alkoxy group would play im-
portant roles in this reaction. First, it enhances the electro-
philicity of the amide carbonyl (inherent activation), result-
ing in elimination of the extra preactivation step. Second,
the N-alkoxy group possesses chelation ability and is able to
form the relatively stable intermediate 17, which would sup-
press the extra addition of the first nucleophile. Moreover,
the N-alkoxy group in the resulting multisubstituted amine
19 could enable further unique transformations such as re-
(Denton: 1!13[11d]) and Ti
(OiPr)4/TMSCl (de Meijere: 14!
N
15[11e]). Unfortunately, direct nucleophilic additions tended
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679

T. Sato, N. Chida et al.
ductive cleavage of the N-alkoxy group to give secondary
amines, and direct oxidation to nitrones.[16]
Direct nucleophilic addition to N-alkoxyamides was first
realized by using N-benzyl-N-methoxyoctanamide with
DIBAL-H and allyltributylstannane (Scheme 4).[17] Treat-
leading to the highest level of diastereoselectivities. The
most conspicuous example of our methodology was applica-
tion to a macrocyclic lactam.[20] It is known that nucleophilic
addition to macrolactams is highly challenging because the
iminium intermediate is unstable, and readily undergoes hy-
drolysis to give the corresponding amino aldehyde. Howev-
er, the developed conditions allowed the reductive allylation
to furnish 15-membered macrocyclic amine 28 in 90% yield.
The method was applicable to the Strecker type reaction
with TMSCN (Scheme 5).[21] In contrast to reductive allyla-
Scheme 4. Substrate scope for the direct reductive allylation. Reagents
and conditions: 16 (0.11 mmol), DIBAL-H (1.01m in toluene, 1.3 equiv),
CH2Cl2 (0.1m), ꢀ788C, 0.5 h, then CH2=CHCH2SnBu3 (3 equiv),
ScACHTUNGTRENNUNG(OTf)3 (1.3 equiv), RT, 1.5 h. [a] The diastereomeric ratios were deter-
mined by 1H NMR spectroscopic analysis. [b] The reaction was per-
formed in THF (0.1m) instead of CH2Cl2. [c] CH3CN (0.3m) was added
prior to addition of CH2=CHCH2SnBu3.
Scheme 5. Substrate scope for the direct reductive cyanation. Reagents
and conditions: 16 (0.11 mmol), DIBAL-H (1.01m in toluene, 1.3 equiv),
CH2Cl2 (0.1m), ꢀ788C, 0.5 h, then TMSCN (3 equiv), SnCl4 (3 equiv),
RT, 1.5 h. [a] The diastereomeric ratios were determined by 1H NMR
spectroscopic analysis. [b] The reaction was performed in THF (0.1m) in-
stead of CH2Cl2. [c] CH3CN (0.3m) was added prior to addition of
TMSCN.
ment of a solution of N-methoxyamide in CH2Cl2 with
DIBAL-H at ꢀ788C and subsequent addition of allyltribu-
tylstannane in the presence of ScACHTNUTRGNEUNG(OTf)3 afforded N-meth-
ACHTUNGTRENNUNG
A
tion, the cyanation proceeded without Lewis acid (29:
48%). However, addition of three equivalents of SnCl4 sig-
nificantly improved the yield to afford 29 in 83% yield. The
substrate scope of the reductive cyanation was then sur-
veyed under the optimized conditions. Acyclic amides un-
derwent the cyanation in good yields (30–32: 65–79%). In
contrast to allylation, the reaction of branched amides pro-
ceeded with moderate diastereoselectivities (31: d.r.=4.2:1,
32: d.r.=4.1:1). N-Benzyloxylactams were also viable sub-
strates for the cyanation (33–35: 58–99%). Interestingly,
while the five-membered lactam led to poor diastereoselec-
tivity (35: d.r.=2.5:1), the six-membered lactam proceeded
in a completely diastereoselective manner (34: single dia-
stereoisomer). The reaction of the challenging 15-membered
macrolactam gave 36 in reasonable yield.
chelated intermediate, leading to the recovery of octanal
and N-benzyl-N-methoxyamine. This result indicated that
assistance of ScACHTUNGTRENNUNG(OTf)3 was essential to form the correspond-
ing N-oxyiminium ion from the five-membered chelated in-
termediate. The direct reductive allylation was found to be
highly general with respect to the structure of the N-alkoxy-
ACHTUNGTRENNUNGamides. Reaction of the linear substrate derived from benzo-
ic acid gave product 22 in 91% yield. Sterically hindered
branched amides showed slightly lower yields than the
linear amides (23: 72%, 24: 72%). Unfortunately, poor dia-
stereoselectivities were observed in both cases. This method-
ology enabled the one-pot synthesis of substituted piperi-
dines and pyrrolidines from the corresponding N-benzyloxy-
lactams[18] (25–27: 83–93%). In the case of a-phenyl-substi-
tuted lactams, acetonitrile as an additional solvent was nec-
essary in the allylation step to provide 26 and 27 in 83 and
91% yields, respectively.[19] The second allylating reagent
approached from the opposite side of the phenyl group,
The stereochemical outcomes of the reductive allylation
and cyanation of a-phenyl-substituted lactams 37 and 39
were rationalized on the basis of transient N-oxyiminium
ions (Scheme 6). DIBAL-H mediated reduction of six-mem-
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Direct Nucleophilic Addition to N-Alkoxyamides
FULL PAPER
Scheme 7. Intramolecular cyclization of N-methoxyamides.
To confirm the beneficial effects of the N-alkoxy group, a
control experiment with N-benzyl-N-methyloctanamide (46)
was attempted under the optimized conditions (Scheme 8).
Scheme 6. Possible rationale for the stereochemical outcomes in the re-
ductive nucleophilic additions of a-phenyl-substituted lactams 37 and 39.
bered lactam 37 and subsequent addition of Lewis acid
formed N-oxyiminium ion 38, in which the large phenyl
group adopted the pseudoequatorial position (Scheme 6A).
The second nucleophile then approached from the opposite
side of the phenyl group through a stereoelectronically pre-
ferred axial attack.[22] In the case of five-membered lactam
39, the inside-attack model reported by Woerpel would ac-
count for the stereoselectivity (Scheme 6B).[23] When a large
nucleophile such as allyltributylstannane was employed, the
steric interaction between the nucleophile and the phenyl
group in transition state 40’ would dominate, leading to the
formation of 27 in high diastereoselectivity via transition
state 40 (27/27’=12:1). On the other hand, the steric inter-
action in 40’ would be suppressed when smaller TMSCN
was employed. The generation of 35’ via transition state 40’
could then compete due to the relatively increased 1,3-di-
Scheme 8. Control experiment without the N-methoxy group.
First, it was observed that the DIBAL-H-mediated reduc-
tion was not complete at ꢀ788C without the N-alkoxy
group, and the reaction needed to be performed at ꢀ508C.
The resulting solution was then treated with allyltributyl-
stannane and ScACTHNUTRGNEUNG(OTf)3 at room temperature, providing the
desired amine 49 in 20% yield, along with the over-reduced
byproduct 50 in 41% yield. In other words, N,O-acetal 47
did not form a tightly chelated complex and was quickly
converted into iminium ion 48, which underwent further
DIBAL-H-mediated reduction to give 50. These two obser-
vations clearly indicated that the N-alkoxy group enhanced
the electrophilicity of the amide carbonyl and suppressed
the extra addition of DIBAL-H through the tight chelation,
resulting in successful installation of two different functional
groups in one pot.
a-Trisubstituted amines are among the most important
structural motifs embedded in a number of biologically
active natural products. Despite their ubiquity, their efficient
synthesis is not trivial because of the steric congestion im-
posed by the three attached carbon atoms and the one nitro-
gen atom. Our nucleophilic addition to N-alkoxyamides has
the potential to solve this challenging task by employing a
carbon nucleophile in the first addition. If successful, a-tri-
substituted amines could be constructed from easily accessi-
ble N-alkoxyamides in one pot. To test the feasibility of the
reaction, six-membered N-benzyloxylactam 51[30] was ex-
ACHTUNGTRENNUNGaxial-like steric interaction in transition state 40, resulting in
the poor diastereoselectivity (35/35’=2.5:1).
We then turned our attention to an intramolecular version
to generate substituted azacycles from acyclic N-alkoxy-
A
bearing an (E)-allylsilane group[27] with DIBAL-H, followed
by subsequent addition of Sc(OTf)3, promoted the cycliza-
tion to give 2,3-disubstituted piperidines 42 and 43 in 88%
combined yield. Interestingly, the reaction proceeded in a
diastereoselective fashion, favoring the unusual cis arrange-
ment (42/43=5:1). We then found that the methodology al-
lowed the use of not only allylsilane but also (Z)-vinylsi-
lane.[28] Treatment of 44 with DIBAL-H, followed by subse-
quent addition of Sc
ACHTUNGRTENN(UNG OTf)3, initiated the intramolecular re-
ductive vinylation to provide 45 in quantitative yield.[29]
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681

T. Sato, N. Chida et al.
posed to a variety of methylmetallic reagents (Table 1). The
resulting chelated intermediate was then treated with Sc-
ACHTUNGTRENNUNG(OTf)3 and allyltributylstannane at room temperature. After
extensive investigation, an organolithium reagent proved to
be the best nucleophile in the first addition, providing 52 in
47% yield (Table 1, entries 1–3). Addition of acetonitrile
prior to the second allylation dramatically improved the
yield of 52 (Table 1, entries 3 and 4).
fairly congested steric environments, affording 56 and 57 in
90 and 72% yields, respectively. It is noteworthy that the re-
actions proceeded with complete diastereoselectivity
through a transition state similar to that depicted in
Scheme 6 to give multisubstituted piperidines as a single dia-
stereoisomer. The reaction with the five-membered lactam
occurred without loss of diastereoselectivity (58: 63%).
We then turned our attention to the Strecker type reac-
tion with TMSCN (Scheme 10). Use of methyl lithium and
n-butyl lithium gave the products in high yields (59: 85%,
60: 89%). Lithium acetylide led to a low yield because ex-
posure of the chelated intermediate to SnCl4 formed a
Table 1. Optimization of the synthesis of a-trisubstituted amine 52 from
N-benzyloxylactam 51 in one pot.[a]
Entry
MeM
Temp. [8C]
Additional solvent
Yield [%][b]
1
2
3
4
Me3Al
MeMgBr
MeLi
ꢀ20
ꢀ78
ꢀ78
ꢀ78
none
none
none
CH3CN (0.3 M)
5
12
47
92
MeLi
[a] Reaction conditions: 51 (0.15 mmol), MeM (1.3 equiv), THF (0.1m),
10 min, then additive, CH2=CHCH2SnBu3 (3 equiv), Sc(OTf)3 (1.3 equiv),
AHCTUNGTRENNUNG
RT, overnight. [b] Yield of isolated product after purification by column
chromatography.
With optimized conditions in hand, the scope of the reac-
tion was investigated (Scheme 9). Variation in the organo-
lithium reagent was possible, and suitable reagents included
methyl lithium, n-butyl lithium, and lithium acetylide (52:
92%, 53: 86%, 54: 81%), but not phenyl lithium (55: 0%).
N-Benzyloxylactams with an a-phenyl-substituent also
proved to be viable substrates. The reactions with methyl
lithium and n-butyl lithium smoothly took place in spite of
Scheme 10. Substrate scope for the synthesis of a-trisubstituted amines
from N-benzyloxylactams through cyanation in one pot. Reagents and
conditions: lactam (0.15 mmol), R3Li (1.3 equiv), THF (0.1m), ꢀ788C,
10 min, then CH3CN (0.3m), TMSCN (3 equiv), SnCl4 (1.3 equiv), RT,
overnight. [a] The diastereomeric ratios were determined by 1H NMR
spectroscopic analysis.
stable conjugated enamine that prevented the second cyana-
tion (61: 34%). In contrast to the allylation, phenyl lithium
was a viable organolithium reagent, giving 62 in 73% yield.
The reaction was also tolerant towards N-benzyloxylactams
bearing an a-phenyl substituent. While a five-membered
lactam exhibited poor diastereoselectivity, slightly favoring
the b-cyanide (65: 84%, d.r.=1.3:1), six-membered lactams
provided a-cyanides as single diastereoisomers (63: 86%,
64: 62%). Thus, our methodology enabled the installation
of two different carbon nucleophiles to an amide carbonyl
group in one pot. The yield of the nucleophilic addition was
generally high in spite of significant steric hindrance.
Conclusion
We have developed a practical, direct nucleophilic addition
to N-alkoxyamides. Salient features of our methodology are:
1) high yielding synthesis of N-alkoxyamides, 2) exclusion of
the extra preactivation step prior to nucleophilic addition,
3) installation of two different organometallic reagents in
one pot, and 4) generally high yields and a wide substrate
Scheme 9. Substrate scope for the synthesis of a-trisubstituted amines
from N-benzyloxylactams through allylation in one pot. Reagents and
conditions: lactam (0.15 mmol), R3Li (1.3 equiv), THF (0.1m), 10 min,
then CH3CN (0.3m), CH2=CHCH2SnBu3 (3 equiv), ScACTHUNTRGNEU(GN OTf)3 (1.3 equiv),
RT, overnight.
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Direct Nucleophilic Addition to N-Alkoxyamides
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Acknowledgements
This research was supported by a Grant-in-Aid for Young Scientists (B)
from MEXT (24750045), the Otsuka Pharmaceutical Co. Award in Syn-
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thank Professor Takeshi Noda and Ms. Yuka Shibaoka, Kanagawa Insti-
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lylation or cyanation was not observed.
Received: July 25, 2012
Revised: October 2, 2012
Published online: November 14, 2012
684
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