Nucleophilic Arylation of N,O-Ketene Acetals with Triaryl Aluminum Reagents: Access to α-Aryl Amides through an Umpolung Process

Article abstract of DOI:10.1002/anie.201708665

A novel approach for the umpolung α-arylation of amides is presented. By the nucleophilic phenylation of O-silyl N,O-ketene acetals, generated in situ from N-alkoxy amides, a phenyl group can be introduced onto the α-carbon atom of amides through N?O bond cleavage in a two-step, one-pot process. The asymmetric synthesis of α-aryl amides through the diastereoselective arylation of a chiral N,O-ketene acetal is also described.

Full text of DOI:10.1002/anie.201708665

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Nucleophilic Arylation of N,O-Ketene Acetals with
Triarylaluminums: Access to alpha-Aryl Amides through an
Umpolung Process
Authors: Okiko Miyata, Norihiko Takeda, Erika Futaki, Yukiko Kobori,
and Masafumi Ueda
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708665
Angew. Chem. 10.1002/ange.201708665
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10.1002/anie.201708665
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COMMUNICATION
Nucleophilic Arylation of N,O-Ketene Acetals with Triaryl-
aluminums: Access to -Aryl Amides through an Umpolung
Process
Norihiko Takeda, Erika Futaki, Yukiko Kobori, Masafumi Ueda, Okiko Miyata*
Abstract: A novel approach for the umpolung -arylation of amides
is presented. By means of nucleophilic phenylation of O-silyl N,O-
ketene acetals, generated in situ from N-alkoxyamides, a phenyl
group can be introduced onto the -carbon of amides via N–O bond
cleavage through a two-step, one-pot process. The asymmetric
synthesis of -aryl amides through the diastereoselective arylation of
a chiral N,O-ketene acetal is also described.
suppress this undesired retro-ene reaction and introduce the desired
nucleophile at the C-position, we decided to use isoxazolidine
amide 7 owing to the restricted rotation of the N–O bond (Table 1).[11]
We intended to use N-alkoxyamide 7a to investigate the possibility of
the nucleophilic arylation of N,O-ketene acetal 9. Furthermore, an
organoaluminum reagent with Lewis acidic characteristics was
selected as the nucleophile because it would trigger the desired
sequential coordination, N–O bond cleavage, as well as the
nucleophilic addition.[12]
Amides are ubiquitous building blocks and synthetically versatile
intermediates for various chemicals and pharmaceuticals, and are
also common subunits in natural products.[1,2] Therefore, the -
functionalization of amides is an attractive strategy to access a
diverse array of amides.[3,4] The intermolecular -arylation of amides
is one of the most straightforward approaches for functionalization,
and it typically relies on the transition-metal-catalyzed coupling of
enolates or their equivalents with aryl halides or pseudohalides.[5]
Although these reactions can be used to introduce a variety of aryl
groups into the -position of amides in good yields, the substrates
are limited to unsubstituted acetamide, propionamide, and -
arylacetamide derivatives. Therefore, arylation at the -position of
amides remains a major synthetic challenge.[6] Herein, a novel
intermolecular approach towards the nucleophilic arylation of N,O-
ketene acetals, which are generated in situ from N-alkoxyamides, for
the preparation of -aryl amides is presented. Furthermore, the
asymmetric synthesis of -arylcarboxylic acids by the
diastereoselective -arylation of an N-alkoxyamide bearing a chiral
auxiliary is also reported.
Figure 1. N,O-ketene acetals 1 and 2.
In general, O-silyl N,O-ketene acetal 1 has been used as a
nucleophile for Mukaiyama-type reactions, and it reacts with various
electrophiles at the C-position (Figure 1).[7] However, the
nucleophilic addition to N,O-ketene acetals at the C-position is still
extremely scarce.[8] We envisioned that N,O-ketene acetal 2, bearing
an alkoxy group on the nitrogen atom, would act as a formal
electrophile. The umpolung reaction[9] of N,O-ketene acetals A could
thus be triggered by coordination with a Lewis acidic nucleophile
(Scheme 1). Subsequent N–O bond cleavage and nucleophilic
addition at the C-position would form imidate C via B. Hydrolysis of
imidate C by workup would afford -substituted amide 4, with the
nucleophile at the -position via an umpolung process. However, the
Keck group reported that a simple N,O-ketene acetal, generated in
situ from N-methoxy-N-methyl amide 5 (Weinreb amide), undergoes
a retro-ene reaction involving the facile cleavage of the N–O bond
and elimination of formaldehyde to give N-methyl amide 6.[10] To
Scheme 1. Reactivity of N,O-ketene acetals generated from 3 and 5.
We initially investigated the phenylation of O-silyl N,O-ketene
acetal 9, which was generated in situ by the reaction of N-
alkoxyamide 7a with a silylating agent and an amine base through a
two-step, one-pot process (Table 1).[13] The nucleophilic phenylation
of 7a was performed in CH2Cl2 at ambient temperature with
trimethylsilyl triflate (TMSOTf), iPr2NEt, and triphenylaluminum. As
expected, the arylation took place at the -position of 9 (Si = TMS)
to give -phenylated product 8aA and TMS-protected product 8aB,
albeit in low yields (entry 1). This is the first example of an
intermolecular nucleophilic phenylation to an O-silyl N,O-ketene
acetal at the -position. This result encouraged us to optimize the
reaction conditions for the nucleophilic phenylation of 9. To increase
the stability of the O-silyl N,O-ketene acetal, triethylsilyl triflate
(TESOTf) was used and led to improved yields of 8aA and 8aC
(entry 2). Pleasingly, the umpolung phenylation of 7a proceeded
smoothly to afford desired 8aA and 8aD in good yields, when tert-
butyldimethylsilyl triflate (TBSOTf) was used (entry 3). When
sterically bulky triisopropylsilyl triflate (TIPSOTf) was used, the yields
of 8aA and 8aE decreased slightly (entry 4). Increasing the amount
of triphenylaluminum did not influence the yields of 8aA and 8aD
(entry 5). We next examined the effect of the base on the generation
[*]
Dr. N. Takeda, E. Futaki, Y. Kobori, Dr. M. Ueda, Prof. Dr. O. Miyata
Kobe Pharmaceutical University
Motoyamakita, Higashinada, Kobe 658-8558, (Japan)
E-mail: miyata@kobepharma-u.ac.jp
Supporting information for this article is given via a link at the end of
the document
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10.1002/anie.201708665
Angewandte Chemie International Edition
COMMUNICATION
of 9. Et3N was found to be suitable, whereas 2,6-lutidine was not
suitable for this sequential reaction (entries 6 and 7). Reducing the
amount of the base was not effective, but increasing the amount of
iPr2NEt led to slightly improved yields of 8aA and 8aD (entries 8 and
9). Therefore, in order to achieve good conversions and yields, 2.1
eq. of TBSOTf, 4 eq. of iPr2NEt, and 1 eq. of triphenylaluminum
were considered to be optimal for this reaction.[14] When the reaction
was conducted with triphenylaluminum in the absence of TBSOTf
and iPr2NEt, the desired product was not formed, indicating that the
generation of N,O-ketene acetal 9 was critical for the success of the
reaction (entry 10). Furthermore, the sequential reaction of 7a
followed by the removal of the TBS group with TBAF afforded 8aA in
74% overall yield from 7a (entry 11).
acid 10 in good yield. Moreover, the amide moiety of 8aA could be
used for the construction of 5,6-dihydro-4H-1,3-oxazine 11.
Scheme 2. Transformations of 8aA.
With the optimal conditions for the umpolung reaction in hand, we
investigated the nucleophilic phenylation of N,O-ketene acetals
generated in situ by treatment of the corresponding N-alkoxyamides
7b–l with TBSOTf and iPr2NEt, followed by the deprotection of the
TBS group with TBAF (Table 2). The umpolung phenylation of 7b–f
with p-bromo, p-trifluoromethyl, p-methyl, p-methoxy, or
methylenedioxy groups on the benzene ring proceeded smoothly at
ambient temperature to give desired products 8bA–fA in good to
high yields (entries 1–5). The reaction could also be applied to N-
alkoxyamides bearing heteroaromatic rings. For example, the
umpolung phenylation of 7g and 7h proceeded under the optimized
conditions to give corresponding products 8gA and 8hA in moderate
yields (entries 6 and 7). In addition, reactions of one-carbon
dehomologated N-alkoxyamide 7i and homologated substrate 7j, as
well as phenyl ether, alkyl- or olefin-bearing substrates 7k, 7l, and
7m, were also successful (entries 8–12). In contrast, the use of
alkyne-, phthalimide- or tosylamine-bearing substrates 7n, 7o, and
7p in our sequential reaction led to afford -phenylated products
8nA, 8oA, and 8pA in lower yields (entries 13-15).[15]
Table 1. Optimization of the reaction conditions for nucleophilic
phenylation of the N,O-ketene acetal generated in situ from 7a.
a
a
]
Yield[
Yield[ ] (%)
Silylating
agent
Base
(eq.)
Ph3Al
(eq.)
Time
(h)
Entry
(%)
8aB-aE
(eq.)
8aA
TMSOTf
(2.1)
iPr2NEt
(2)
1
2
1
1
1
1
2
1
1
15
12
4
8
8aB: 11
8aC: 30
8aD: 67
8aE: 58
8aD: 59
8aD: 48
8aD: 19
Table 2. Substrate scope for nucleophilic phenylation of N,O-ketene
acetals generated in situ from 7b–p.[a]
TESOTf
(2.1)
iPr2NEt
(2)
18
10
11
11
20
ND
TBSOTf
(2.1)
iPr2NEt
(2)
3
TIPSOTf
(2.1)
iPr2NEt
(2)
4
19
4
Entry
R1
Product
8bA
Yield[b] (%)
TBSOTf
(2.1)
iPr2NEt
(2)
5
1
2
3
4
5
p-BrC6H4CH2
p-CF3C6H4CH2
p-MeC6H4CH2
p-MeOC6H4CH2
80
76
80
63
61
8cA
TBSOTf
(2.1)
Et3N
(2)
6
2.5
24
8dA
7[b]
TBSOTf
(2.1)
2,6-
lutidine
(2)
8eA
8fA
8[c]
1
1
12
4
8
8aD: 36
8aD: 68
TBSOTf
(2.1)
iPr2NEt
(1)
6
7
8gA
8hA
65
62
TBSOTf
(2.1)
iPr2NEt
(4)
9
13
10
none
none
1
1
24
4
ND[d]
74
ND[d]
11[e]
8aD: ND[d]
TBSOTf
(2.1)
iPr2NEt
(4)
8
9
Ph
8iA
8jA
81
57
[a] Yields of the chromatographically pure product. [b] 7a was recovered
in 47% yield. [c] 7a was recovered in 23% yield. [d] Not detected. [e] The
-phenylation of 7a followed by deprotection with TBAF-AcOH were
carried out.
10
8kA
74
11
12
8lA
68
76
To demonstrate the utility of-phenylated amide 8aA, several
transformations were examined (Scheme 2). Removal of the 3-
hydroxypropylamine moiety by acidic hydrolysis afforded carboxylic
8mA
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10.1002/anie.201708665
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13
16 bearing (+)-benzopyranoisoxazolidine[17] as the chiral auxiliary
(Scheme 4). The sequential reaction of 16 with TBSOTf, iPr2NEt,
and triphenylaluminum gave -phenylated product 18a in 10% yield
with dr = 1:1,[18] and TBS-protected product 19aD in 40% yield with
dr = 2:1.[18] Interestingly, the use of TESOTf in the diastereoselective
-phenylation led to the -phenylated product 18a in 39% yield with
8nA
8oA
39
17
14
slightly higher diastereoselctivity (dr = 6:1)[18]
. To confirm the
15
8pA
19
formation of N,O-ketene acetal 17C, the reaction of N-alkoxyamide
16 with TESOTf and iPr2NEt was carried out in CDCl3. However, the
formation of 17C were not observed by 1H NMR, indicating that 17C
was relatively unstable in the presence of iPr2NEt·TfOH. In order to
prepare N,O-ketene acetal 17C in the absence of iPr2NEt·TfOH, we
further investigated the diastereoselective nucleophilic phenylation of
N,O-ketene acetal 17C which was prepared by an alternative
method. Pleasingly, we found that triethylsilylation of the lithium
enolate resulted in the formation of (Z)-N,O-ketene acetal 17C
(Scheme 5).[19] Subsequent nucleophilic phenylation of 17C with
triphenylaluminum proceeded effectively to give -phenylated
product 18a and triethylsilylated product 19aC, each as single
diastereomers (>95% de). The conversion of 19aC to 18a was easily
achieved without racemization by addition of 4M HCl.[20] The chiral
amino alcohol moiety of 18a was easily removed by hydrolysis under
acidic conditions to afford enantioenriched (R)-2,3-diphenylpropionic
acid (10).[21]
[a] 7 (0.25 mmol), TBSOTf (0.525 mmol), iPr2NEt (1.0 mmol), Ph3Al (0.25
mmol) for 1.5-6 h, then TBAF (0.75 mmol), AcOH (0.17 mmol) for 16 h. [b]
Yield of the chromatographically pure product.
To elucidate the reaction pathway, we confirmed the formation of
N,O-ketene acetal 9D under the optimized conditions (Scheme 3).
When the reaction of N-alkoxyamide 7a with TBSOTf and iPr2NEt
1
was carried out in CDCl3, the olefinic proton signal of 9D in the H
NMR spectrum at  = 4.49 (t, J = 7.0 Hz, 1H) was indicative of a
single regioisomer [Eq. (1)].[16] Subsequent nucleophilic phenylation
of 9D with triphenylaluminum proceeded smoothly, and gave -
phenylated product 8aA in 54% yield following the deprotection of
the TBS group, indicating that the umpolung reaction proceeded via
the in situ formation of N,O-ketene acetal 9D [Eq. (1)]. To
demonstrate the effect of isoxazolidine, we examined the sequential
reaction using various amides under the optimized conditions. The
use of N-alkoxyamide 12, which bears a tetrahydro-2H-1,2-oxazine
instead of isoxazolidine, gave -phenylated product 13 and TBS
derivative 14 in 54% combined yield, along with recovered 12 [Eq.
(2)], indicating that the isoxazolidine moiety was more suitable for
nucleophilic phenylation than tetrahydro-2H-1,2-oxazine. Notably,
the sequential reaction of pyrrolidine amide 15 did not occur [Eq.
(3)], indicating that the adjacent nitrogen and oxygen atoms were
critical for this umpolung reaction.
Scheme 5. Diastereoselective nucleophilicphenylation of N,O-ketene acetal
17C.
Next, we examined the scope of the reaction with a variety of
triarylaluminum reagents (Table 3). The introduction of various aryl
groups, including p-methoxy, p-methyl, and m,p-dimethoxy phenyls,
and 2-methyl furan, onto N,O-ketene acetal 17C were achieved in a
similar manner, albeit in moderate yields, with the exception of the
introduction of
a
p-chlorophenyl group (entries 1–5). The
diastereomeric purities of 18b–f were not less than 95% de, as
determined by 1H NMR analysis.
Scheme 3. Control experiments.
Table 3. Diastereoselective nucleophilicarylation of N,O-ketene acetal 17C.
Yield[a] (%)
Selectivity of
18[b]
Entry
Ar
Product
1
2
p-MeOC6H4
p-MeC6H4
p-ClC6H4
18b
18c
18d
40
51
13
>95% de
>95% de
>95% de
Scheme 4. Diastereoselective nucleophilic arylation of N,O-ketene acetals
17D, 17C under TBSOTf- or TESOTf-iPr2NEt-Ph3Al systems.
We next focused on the diastereoselective nucleophilic
phenylation of N,O-ketene acetal 17D, derived from N-alkoxyamide
3[c]
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COMMUNICATION
[5]
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4
18e
18f
41
34
>95% de
>95% de
5
[a] Yield of the chromatographically pure product. [b] Determined by 1H NMR
analysis of the crude products. [c] 16 was recovered in 23% yield.
In summary, we have successfully developed the umpolung -
phenylation of various N,O-ketene acetals, which were generated in
situ from isoxazolidine amides. The reaction proceeds smoothly
under mild conditions at ambient temperature. Furthermore, the
highly diastereoselective arylation of a chiral N,O-ketene acetal gave
the optically pure -aryl carboxylic acid. The development of a novel
nucleophilic arylation reaction using an umpolung strategy clearly
offers new perspectives in the chemistry of N,O-ketene acetals.
Although an effective chiral auxiliary was identified, the transition
state in the diastereoselective arylation remains unclear. Further
studies to clarify the mechanism and demonstrate the synthetic utility
of the developed methodology, including in the synthesis of
biologically active compounds, are now in progress.
[6]
[7]
For an elegant two-step, one-pot procedure for the -arylation of
amides without using
a strong base and involving sequential
electrophilic activation and [3,3]-sigmatropic rearrangement, see: a) B.
Peng, D. Geerdink, C. Farès, N. Maulide, Angew. Chem. Int. Ed. 2014,
53, 5462; Angew. Chem. 2014, 126, 5566; b) S. Shaaban, V. Tona, B.
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G. Myers, K. L. Widdowson, J. Am. Chem. Soc. 1990, 112, 9672.
For an intramolecular nucleophilic addition to N,O-ketene acetals at the
C-position, see D. Kaiser, A. de la Torre, S. Shaaban, N. Maulide,
Angew. Chem. Int. Ed. 2017, 56, 5921; Angew. Chem. 2017, 129, 6015.
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2269.
[8]
[9]
Acknowledgments
This work was supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science, and Technology of Japan
(MEXT).
[10] G. E. Keck, S. F. McHardy, J. A. Murry, Tetrahedron Lett. 1993, 34,
6215.
Keywords: aluminum • amides • ketene acetals • nucleophilic
addition • umpolung
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[2]
[3]
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[13] For examples of the in situ generation of N,O-ketene acetals from
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Kiyohara, M. Yamaguchi, J. Am. Chem. Soc. 2011, 133, 1708; b) C. W.
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[14] When other organometallic reagents (PhLi, PhMgBr, PhZnI, and Ph2Zn)
were used in the umpolung -phenylation of 7a, none of -phenylated
amides 8aA and 8aD were obtained and 7a was recovered in moderate
to good yields in all cases. In particular, the use of PhLi and PhMgBr
led to give 3-phenylpropiophenone in low to moderate yields. Therefore,
Ph3Al plays important roles in the cleavage of N–O bond of 9D and
sequential nucleophilic -phenylation: see the Supporting Information.
[15] The umpolung phenylation of
For recent reviews on amide activation, see a) D. Kaiser, N. Maulide, J.
Org. Chem. 2016, 81, 4421; b) J. Dander, N. Garg, ACS Catal. 2017, 7,
1413; c) S. A. Ruider, N. Maulide, Angew. Chem. Int. Ed. 2015, 54,
13856; Angew. Chem. 2015, 127, 14062; For selected recent examples
of amide activation, see d) L. Hie, N. F. Nathel, T. Shah, E. Baker, X.
Hong, Y. Yang, P. Liu, K. Houk, N. Garg, Nature 2015, 524, 79; e) Á. F.
de Arriba, E. Lenci, M. Sonawane, O. Formery, D. Dixon, Angew. Chem.
Int. Ed. 2017, 56, 3655; Angew. Chem. 2017, 129, 3709.
-substituted amide 7q did
not proceed at all.
[4]
For selected recent examples in the -functionalization of amides, see
a) M. R. Morales, K. T. Mellem, A. G. Myers, Angew. Chem. Int. Ed.
2012, 51, 4568; Angew. Chem. 2012, 124, 4646; b) L. Guo, Y. Liu, W.
Yao, X. Leng, Z. Huang, Org. Lett. 2013, 15, 1144; c) V. Tona, A. Torre,
M. Padmanaban, S. Ruider, L. González, N. Maulide, J. Am. Chem.
Soc. 2016, 138, 8348; d) H. Lubin, A. Tessier, G. Chaume, J. Pytkowicz,
T. Brigaud, Org. Lett. 2010, 12, 1496; e) H. Lubin, C. Dupuis, J.
Pytkowicz, T. Brigaud, J. Org. Chem. 2013, 78, 3487; f) Y. Kim, S.
Chang, Angew. Chem. Int. Ed. 2016, 55, 218; Angew. Chem. 2016, 128,
226.
[16] The geometry of 9D (Si = TBS) was deduced to be a (Z)-configuration
of the C=C group by comparing with 1H NMR of N,O-ketene acetal 20,
which was prepared by triethylsilylation of lithium enolate from one-
carbon homologated substrate 7j. This structure confirmed by 1H NMR
(olefinic-H:  = 4.49 (t, J = 7.0 Hz, 1H)) and NOESY (olefinic-H: = 4.30
and 3-H2:  = 3.24): see the Supporting Information.
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[17] a) A. Abiko, O. Moriya, S. A. Filla, S. Masamune, Angew. Chem. Int. Ed.
1995, 34, 793; Angew. Chem. 1995, 107, 869; b) H. Nemoto, R. Ma, T.
Kawamura, M. Kamiya, M. Shibuya, J. Org. Chem. 2006, 71, 6038; c) A.
C. Evans, D. A. Longbottom, M. Matsuoka, J. E. Davis, R. Turner, V.
Franckevičius, S. V. Ley, Org. Biomol. Chem. 2009, 7, 747; d) A. C.
Evans, D. A. Longbottom, M. Matsuoka, S. V. Ley, Synlett, 2005, 646;
e) A. Abiko, S. Masamune, Tetrahedron Lett. 1996, 37, 1077.
[18] Diastereomeric ratio (dr) was determined from the 1H NMR of the
diastereomixture.
[19] NOE correlation was observed between olefinic-H (δ: 4.79) and 9b-H
(δ: 4.62) in NOESY: see the Supporting Information.
[20] Desilylation of 19aC with TBAF-AcOH gave 18a in lower yield than
desilylation with 4M HCl.
[21] (‒)-10, see a) S.-F. Zhu, Y.-B. Yu, S. Li, L.-X. Wang, Q.-L. Zhou, Angew.
Chem. Int. Ed. 2012, 51, 8872; Angew. Chem. 2012, 124, 9002; b) S.
Yang, S.-F. Zhu, C.-M. Zhang, S. Song, Y.-B. Yu, S. Li, Q.-L. Zhou,
Tetrahedron 2012, 68, 5172; c) Y. Zhang, Z. Han, F. Li, K. Ding, A.
Zhang, Chem. Commun. 2010, 46, 156; d) S. Li, S.-F. Zhu, C.-M.
Zhang, S. Song, Q.-L. Zhou, J. Am. Chem. Soc. 2008, 130, 8584; (+)-
10, see e) C. E. Stivala, A. Zakarian, J. Am. Chem. Soc. 2011, 133,
11936.
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Dr. Norihiko Takeda, Erika Futaki,
Yukiko Kobori, Dr. Masafumi Ueda, Prof.
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NucleophilicArylation of N,O-Ketene
Acetals with Triarylaluminums:
Access to -Aryl Amides through an
Umpolung Process
A new aspect of N,O-ketene acetal chemistry: A novel approach for the umpolung -arylation of
amides is presented. By means of nucleophilic phenylation of O-silyl N,O-ketene acetals, generated
in situ from N-alkoxyamides, a phenyl group can be introduced onto the -carbon center of amides
via N–O bond cleavage through a two-step, one-pot process. The asymmetric synthesis of -aryl
amides through the diastereoselective arylation of a chiral N,O-ketene acetal is also described.
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