Direct Synthesis of N-Acyl-N,O-hemiacetals via Nucleophilic Addition of Unactivated Amides and Their O-Acetylation: Access to α,α-Difunctionalized N-Acylimines

Article abstract of DOI:10.1002/adsc.201600436

A mild, metal-free synthesis of polyfunctionalized N-acyl-N,O-hemiacetals was developed via the nucleophilic addition of unactivated amides to ketones. The protocol demonstrated a wide substrate scope, with good isolated yields. Additionally, their O-acetylated products serve as a precursor of α,α-difunctionalized N-acylimines. An addition reaction of broad scope of nucleophiles to generate N-acylimines is also reported. (Figure presented.).

Full text of DOI:10.1002/adsc.201600436

UPDATES
DOI: 10.1002/adsc.201600436
Direct Synthesis of N-Acyl-N,O-hemiacetals via Nucleophilic
Addition of Unactivated Amides and Their O-Acetylation:
Access to a,a-Difunctionalized N-Acylimines
Haruyasu Asahara,a,b,* Kanami Inoue,a Shinki Tani,c Kazuto Umezu,c
and Nagatoshi Nishiwakia,b,*
a
School of Environmental Science and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
Fax : (+81)-887-57-2520; e-mail: asahara.haruyasu@kochi-tech.ac.jp or nishiwaki.nagatoshi@kochi-tech.ac.jp
Research Center for Material Science and Engineering, Kochi University of Technology, Kami, Kochi 782-8502, Japan
Marketing & Development Department, Ihara Chemical Industry Co., Ltd., Fujikawa-cho, Ihara-gun, Shizuoka 421-3306,
b
c
Japan
Received: April 24, 2016; Revised: June 9, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600436.
Abstract: A mild, metal-free synthesis of polyfunc-
tionalized N-acyl-N,O-hemiacetals was developed
via the nucleophilic addition of unactivated amides
to ketones. The protocol demonstrated a wide sub-
strate scope, with good isolated yields. Additionally,
their O-acetylated products serve as a precursor of
a,a-difunctionalized N-acylimines. An addition re-
action of broad scope of nucleophiles to generate
N-acylimines is also reported.
Highly and densely functionalized N-acylimines have
broad potential in organic synthesis because they
serve as a building block for polyfunctionalized com-
pounds, such as quaternary amines and amino acids.
Therefore, an efficient method for the generation of
a,a-difunctionalized N-acylimines is still desired.
On the other hand, given the importance of N-acyl-
N,O-hemiacetals and acetals, which are one of the
precursors of N-acylimines as well as a structural
motif found in bioactive natural products, a number
of efforts have been made toward their synthesis.[7,8]
Within their synthetic methods, the addition of an
amide to a carbonyl function is a simpler, direct, and
efficient route [Scheme 2, (a)]. This route, however,
requires activation of the amide by costly metals and
shows limited functional group tolerance because of
the harsh reaction conditions (e.g., strongly basic con-
ditions). In addition, the carbonyls usable for this ap-
proach are limited to aldehydes. With regard to ke-
Keywords: N-acylimines; amidoalkylation; N,O-
hemiacetals; unactivated amides; vicinal tricarbonyl
compounds
Introduction
Highly electrophilic N-acylimines are multifunctional tones, only highly electrophilic 3,3,3-trihalo-2-oxopro-
precursors that facilitate the synthesis of functional- panoates,[9] hexafluoroacetone,[10] and vicinal tricar-
ized amines, amino acid derivatives, and oxaziri- bonyl compounds (VTC)[11] are used as electrophiles
dines.[1,2] N-Acylimines are widely used as reactive for the direct construction of N-acyl-N,O-hemiacetals,
building blocks, as heterodienes[3] or as dienophiles[4] among which the former two substrates are most
in Diels–Alder reactions and as enophiles in ene-reac-
tions.[5] Most importantly, N-acylimines serve as active
amidoalkylating reagents in the reactions with various
nucleophiles.[6] Because of their overall high reactivi-
ty, N-acylimines are generally generated in situ from
N-acylamines having a leaving group at the a-position
of the nitrogen atom (Scheme 1).
Although numerous precursors for N-acylimines
have been developed, the methods leading to the a,a-
difunctionalized N-acylimines (R1, R2 =functional
group) are rather limited. This maybe due to the diffi-
culty in the synthesis of corresponding precursors. Scheme 1. Generation and reaction of N-acylimines.
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Table 1. Optimization of the reaction conditions.[a]
Entry
Solvent
Yield of 3a[b] [%]
1
hexane
60
2
3
4
5
toluene
THF
chloroform
acetonitrile
acetonitrile
88
ND[c]
99
99 (98)
(97)
6[d]
[a]
Reaction conditions: unless otherwise noted, all reactions
were performed with 1 (0.5 mmol), 2a (0.6 mmol) in sol-
vent (2.5 mL) at 608C under air for 18 h.
Scheme 2. Direct construction of N-acyl-N,O-hemiacetals
and generation of N-acylimines.
[b]
1
Determined by H NMR using 1,1,2,2-tetrachloroethane
as the internal standard. Numbers in parentheses are
yields of isolated product.
Not detected.
[c]
[d]
often found in the literature. In contrast, there are
limited examples of the use of VTCs and amides for
this reaction, with no systematic study into their reac-
tivity. This observation prompted us to study the reac-
10 mmol (1.8 g) of 1 were used.
tion of VTCs and amides to form a,a-difunctionalized conditions to afford the corresponding N-acyl-N,O-
N-acyl-N,O-hemiacetals [Scheme 2, (b)], which are hemiacetals 3b–g in excellent yields. Importantly, this
useful building blocks for the construction of a,a-di- reaction could be applied to amides having versatile
functionalized N-acylimines. In fact, we successfully functional groups such as cyclopropyl, vinyl, cyano,
generated highly reactive a,a-difunctionalized N-acyl- and carbamate. In addition, the highly electron-defi-
ACHTUNGTRENNUNGimines in situ and trapped them with versatile nucleo- cient trifluoroacetamide 2l and diethyl phosphorami-
philes.
date 2m were converted into N,O-hemiacetals in mod-
erate yields, although a higher reaction temperature
was required. Disappointingly, only a trace amount of
the product was obtained when an acyclic secondary
amide, N-methylacetamide 2n, was used as a substrate.
Results and Discussion
Initially, diethyl mesoxalate 1 and benzamide 2a were Contrary to this, a less sterically hindered cyclic sec-
chosen as model substrates for the synthesis of N- ondary amide, 2-pyrrolidone 2o, afforded the corre-
acyl-N,O-hemiacetals via direct nucleophilic addition sponding N,O-hemiacetal in 90% yield.
of unactivated amides. The desired product 3a was
Subsequently, we studied the reaction of amides
obtained in 60% NMR yield when a mixture of 1 and with various VTCs such as a,b-dioxo esters,[12] 1,2,3-
2a in hexane was heated at 608C in a sealed tube for triketones,[13] tert-butyl ethyl mesoxalate, and a,b-
20 h, without any additive (Table 1, entry 1). We then dioxo amide[12] (Table 3). In the case of the reaction
optimized the reaction conditions by changing the sol- of aryl-substituted dioxo ester 4 with butyramide 2g,
vents and found that polar aprotic solvents, such as the corresponding product 10g was isolated in 63%
chloroform and acetonitrile, were suitable for this re- yield. However, the reaction of bulkier tert-butyl-sub-
action, affording 3a in almost quantitative yields (en- stituted dioxo ester 5 with 2g, resulted in a lower
tries 4 and 5). Unless otherwise specified, acetonitrile yield. In addition, from the reaction of the bulkier
was primarily used in the following reactions. To eval- and less nucleophilic benzamide 2a, only trace
uate the practicality of this method, the reaction of amounts of hemiacetal 11a were obtained, with
1 on a 10 mmol (1.8 g) scale was conducted under the almost complete recovery of 5 and 2a. 1,2,3-Trike-
optimized conditions, which afforded 2.9 g of the tones show a similar tendency, which is to say that
product, in 97% isolated yield (entry 6).
sterically hindered 1,3-diphenyl-substituted substrate
Next, the scope and limitations of this reaction 6 gives the corresponding hemiacetals 12a, g in low
were studied using various amides 2b–o (Table 2). Ar- yield, whereas somewhat less hindered methyl
omatic amides 2b–d and aliphatic amides 2e–g under- phenyl-substituted triketone 7 gives hemiacetals 13a,
went nucleophilic addition to 1 under the optimized g in better isolated yield. These results indicate that
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Table 2. Substrate scope for the synthesis of N-acyl-N,O-
Table 3. Synthesis of N-acyl-N,O-hemiacetals using various
hemiacetals.[a]
VTCs.[a]
[a]
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol) in aceto-
nitrile (2.5 mL) at 608C under air for 18 h. Yields refer
to the isolated yield unless otherwise noted.
In chloroform.
[b]
[c]
At 1208C in a sealed tube.
[d]
1
Determined by H NMR using 1,1,2,2-tetrachloroethane
as the internal standard.
[a]
Reaction conditions: VTCs (0.5 mmol), 2 (0.6 mmol) in
acetonitrile (2.5 mL) at 608C under air for 18 h. Yields
the reactivity is strongly affected by the steric hin-
drance of the center carbonyl carbon of the substrate.
Indeed, from the reaction of tert-butyl-substituted
mesoxalate 8, which is much less hindered than dioxo
esters and triketones, both 14a and 14g were obtained
refer to the isolated yield unless otherwise noted.
Determined by 1H NMR and mass spectra of the reaction
[b]
mixture.
in 97% and 98% yield, respectively. In the case of ing and addition of acids, bases, and molecular sieves,
keto amide-derived tricarbonyl 9, although only low failed.[14] It is noted that the whole amount of hemia-
yields of hemiacetals 15a, g were obtained under cetal 3a was decomposed to 1 and amide 2a when po-
these reaction conditions, a more thorough investiga- tassium tert-butoxide was used as a base. This is pre-
tion could increase the yield.
sumably due to the relatively high acidity of the hy-
After successful establishment of the synthetic droxy group of 3a. We then postulated that O-acetyla-
method for a,a-difunctionalized N-acyl-N,O-hemiace- tion could protect the hydroxy group and increase the
tals 3, we studied the generation of a,a-difunctional- leaving ability.
ized N-acylimines 16 in situ via dehydration of the ob-
As presented in Scheme 3 (b), the O-acetylation of
tained hemiacetals and trapping of 16 with methanol several hemiacetals 3a, f, i proceeded smoothly to
17A to give acetal 18aA [Scheme 3 (a)]. Unfortunate- afford the desired products 19a,[15] 19f, and 19i in
ly, all of our attempts at this reaction, including heat- 96%, 77%, and 85% isolated yields, respectively.
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Scheme 3. Generation and reaction of N-acylimines with alcohols.
Upon treatment with an excess amount of triethyla- omatics reacted well and produced the desired ad-
mine, the desired a,a-difunctionalized N-acylimine 16 ducts in good yields (18aF, 18fF, 18iF, 18aG). More-
was generated in situ. The generation of N-acylimine over, both a silyl enol ether and an enamine also re-
16 was confirmed by 13C NMR spectroscopy in the acted smoothly to give the products in moderate
case of 16f: the signal corresponding to the sp3 qua- yields (18aH and 18aI). These results suggest the
ternary carbon at 81.7 ppm (C-2) disappeared, and broad applicability of our technique.
a new signal from the imine sp2 carbon appeared at
146.9 ppm (C-2’, Figure 1). N-Acylimine 16 was then
trapped by methanol 17A to obtain a,a-difunctional-
ized N-acyl-N,O-acetals 18 in excellent yield.
Table 4. The reaction of N-acylimine intermediate with vari-
ous nucleophiles.[a]
We then applied this method to other nucleophiles
in order to examine the substrate scope (Table 4).
Both N,O-acetals 18aB and 18fB were obtained in
high yields. When the less nucleophilic p-methoxyphe-
nol was used as the substrate, the corresponding
adduct 18aC can also be obtained in good yield. Fur-
thermore, anilines 17D and 17E were also compatible
in this reaction, providing 18aD and 18aE in good
yields.
In order to further extend the substrate scope, we
also investigated the reaction of generated imines
with C-nucleophiles (Table 5). Electron-rich heteroar-
[a]
Reaction conditions: step 1, 19 (0.5 mmol), NEt3
(0.75 mmol), chloroform (5 mL), room temperature
under argon for 10 min; step 2, nucleophile (0.75 mmol)
at 608C under argon for 3 h. Yields refer to the isolated
yield.
Figure 1. 13C NMR monitoring of the generation of N-acyl-
ACHTUNGTRENNUNGimine 16f.
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Table 5. The reaction of N-acylimine intermediate with vari-
ous C-nucleophiles.[a]
Scheme 5. Synthetic transformations of N-acyl-N,O-acetals
18.
[a]
The reactions were performed on a 0.5 mmol scale in
5 mL of chloroform under argon. The amount of nucleo-
phile, reaction temperature, and reaction time required
for each substrate are given. Yields refer to the isolated
yield.
ver(I) oxide afforded N-methylated product 20 in
81% isolated yield. It is noteworthy that this transfor-
mation is the formal introduction of an acyclic secon-
dary amide into the VTC skeleton. The decarboxylat-
ed product 21, which is regarded as an amino acid de-
As a preliminary result, we performed the one-pot rivative, was obtained in moderate yield by the selec-
synthesis of O-acetylated N,O-acetal 19 from diethyl tive monohydrolysis and heating under toluene reflux
mesoxalate 1 with amide 2 to improve the practical conditions. The transformation of ester 18aA into
utility. Based on the electrophilicities of VTC and amide 22 was successfully achieved with 65% yield by
acetic anhydride, we assumed that the amide will se- selective saponification followed by condensation
lectively react with VTC even in the presence of with propylamine via the acid anhydride. The intra-
acetic anhydride. As expected, the desired product molecular cyclization of 3-chloropropoxy-substituted
19a was obtained in 88% yield by the reaction of N,O-acetals 18aB and 18fB with a base in acetonitrile
1 with benzamide 2a in acetic anhydride at 1008C led to N-acyl-1,3-oxazinanes 23a[15] and 23f in good
(Scheme 4). Most importantly, the low nucleophilic yields. 1,3-Oxazinane skeletons are present in
trifluoroacetamide 2l, which afford the poor yield in a number of biologically active compounds.[16] The
the reaction with 1, gave the O-acetylated product 19l present method enabled us to access the polyfunc-
in 93% isolated yield.
tionalized 1,3-oxazinane structure; thereby, it should
Finally, the synthetic application of the obtained find broad applications in organic synthesis.
N,O-acetal 18aA is shown in Scheme 5. The reaction
of 18aA with methyl iodide in the presence of sil-
Conclusions
In conclusion, we have developed an efficient one-
pot, metal-free method for the construction of a,a-di-
functionalized N-acyl-N,O-hemiacetals 3 based on the
nucleophilic addition of unactivated amides 2 to ke-
tones. The hemiacetals could be easily synthesized by
a simple procedure and were shelf-stable for extended
Scheme 4. One-pot synthesis of O-acetyl-N,O-acetals 19.
periods under anhydrous conditions. The obtained N-
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acyl-N,O-hemiacetals could be converted into a,a-di- General Experimental Procedure for the O-
functionalized N-acylimines 16 under mild reaction Acetylation of 3: Method A [Scheme 3 (b)]
conditions by acetylation of the hydroxy group. In ad-
dition, a one-pot synthesis of O-acetyl-N-acyl-N,O-
N,O-Hemiacetal 3 (1.0 mmol) was dissolved in 5 mL of dry
acetonitrile, and the solution was cooled to 08C. Triethyl-
acetals 19 was also acheived. O-Acetylated com-
pounds 19 showed quite good stability and were stor-
able even under air. These results represent the high
value of O-acetylated acetals 19 as precursors for syn-
thetically useful and highly functionalized N-acyli-
mines. The utility of the generated a,a-difunctional-
ized N-acylimine was successfully demonstrated by
examples of the addition of various nucleophiles.
AHCTUNGTREGaNNUN mine (1.2 mmol) and acetyl chloride (1.2 mmol) were
added, and the reaction mixture was stirred at ambient tem-
perature for 1 h. Then 50 mL of water were added to the
mixture, which was extracted with chloroform (3ꢁ20 mL).
The extract was dried over magnesium sulfate and concen-
trated under reduced pressure. The crude product was puri-
fied by silica gel column chromatography (eluent: dichloro-
methane/ethyl acetate=9/1) to afford the O-acetylated
product 19.
General Experimental Procedure for the Generation
and Reaction of N-Acylimine 16 [Scheme 3 (b) and
Table 4]
Experimental Section
General Information
1H and 13C NMR spectra were recorded on a Bruker DPX-
400 spectrometer (400 MHz and 100 MHz, respectively) in
CDCl3 using TMS as an internal standard. H NMR data are
A flame-dried test tube was charged with the corresponding
N,O-acetal 19 (0.5 mmol), molecular sieve 3ꢂ and anhy-
drous acetonitrile or chloroform (5 mL). Triethylamine
(1.5 equiv., 0.75 mmol) was added and the solution was
stirred at room temperature for 10 min. After the nucleo-
phile (1.5 equiv., 0.75 mmol) was added, the reaction mix-
ture was stirred at 608C for 3 h. Upon completion, the reac-
tion mixture was evaporated and the residue was purified by
silica gel column chromatography (eluent: hexane/ethyl ace-
tate) to afford the corresponding pure compound 12.
1
reported as follows: chemical shift (d, ppm), (chemical shift
mutiplicities: s=singlet, d=doublet, t=triplet, q=quartet,
m=multiplet, br s=broad singlet), coupling constant (Hz),
integration. 13C NMR data were reported in terms of chemi-
cal shift (d, ppm). NMR signal assignments were based on
additional 2D-NMR spectroscopy (e.g., COSY, NOESY,
HSQC, and HMBC). A Shimadtu IR Spectrometer was
used to record infrared spectra which are reported in fre-
quency of absorption. Mass spectra were recorded on
a JEOL JMS-Q1050GC. High-resolution mass spectra were
obtained on an AB SCEIX Triplet TOF 4600 mass spec-
trometer. Melting points were recorded with a Yanaco
micro-melting-points apparatus and were uncorrected. Prod-
ucts were purified by chromatography on silica gel.
General Experimental Procedure for the Reaction of
N-acylimine 16 with C-Nucleophiles (Table 5)
To a flame-dried test tube, the corresponding acetal 19
(0.5 mmol), molecular sieve 3ꢂ, nucleophile, and 2 mL of
chloroform were added under argon. Then triethylamine
(1.5 equiv., 0.75 mmol) was successively added and the mix-
ture was stirred and heated. After completion of the reac-
tion, water was added to the reaction mixture. The mixture
was extracted with dichloromethane (2ꢁ5 mL), the com-
bined organic phases were dried over anhydrous MgSO4.
Then, the solvent was removed under vacuum, and the resi-
due was purified by silica gel column chromatography
(eluent: hexane/ethyl acetate) to afford the product 18.
Materials
Unless otherwise noted, all reagents were purchased from
commercial sources and used without further purification.
VTCs 4–9 were prepared according to the reported proce-
dure.[12,13] The hydrate forms of VTCs were transformed to
keto forms by azeotropic distillation with toluene just
before use.
Typical Experimental Procedure for the Synthesis of
N,O-Acetals 19: Method B (Scheme 4)
Typical Experimental Procedure for the Reaction of
VTCs with Amides (Table 1. Entry 5, Table 2 and
Table 3)
To a solution of diethyl mesoxalate (1, 174 mg, 1 mmol) in
acetic anhydride (2 mL), amide (1.2 mmol) was added under
air. The resulting mixture was stirred at 1008C for 18 h.
After completion of the reaction, acetic anhydride was azeo-
tropically removed with toluene. The residue was purified
by recrystallization (hexane/chloroform) to afford the prod-
uct 19.
To an acetonitrile solution (3.0 mL) of VTC (0.5 mmol) in
a
round-bottom flask (10 mL), amide
2
(1.2 equiv.,
0.6 mmol) was added, and the resultant mixture was heated
at 608C for 18 h. Upon completion, the reaction mixture
was concentrated under vacuum to give a residue, which
was subjected to silica gel column chromatography using
hexane/ethyl acetate=1/1 as eluent affording the N,O-hemi-
acetals.
Experimental Procedure for the N-Methylation of
Amide 18aA (Scheme 5)
N-Methylation of amide 18aA (0.2 mmol scale) was per-
formed according to the procedure described by Nair
et al.[17] The crude product was purified by silica gel column
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chromatography (hexane/ethyl acetate=7/3) to afford 20 as
yellow viscous liquid; yield: 52.3 mg (81%).
Diethyl 2-hydroxy-2-(nicotinamido)malonate (3d): yield:
133.1 mg (90%); white solid; mp 129.0–129.88C; 1H NMR
(400 MHz, CDCl3): d=1.31 (t, J=7.2 Hz, 6H), 4.37 (q, J=
7.2 Hz, 4H), 5.21 (s, 1H), 7.42 (dd, J=4.8, 8.0 Hz, 1H), 8.01
(br s, 1H), 8.14 (dd, J=1.6, 8.0 Hz, 1H), 8.79 (dd, J=1.6,
4.8 Hz, 1H), 9.07 (s, 1H); 13C NMR (100 MHz, CDCl3): d=
13.9 (CH3), 63.9 (CH2), 80.1 (C), 123.6 (CH), 128.4 (C),
135.2 (CH), 148.5 (CH), 153.2 (CH), 165.0 (C), 166.9 (C);
IR (ATR): n=1672, 1742, 3310 cmÀ1; HR-MS (ESI-TOF):
m/z=297.1082, calcd. for C13H17N2O6 [M+H]+; 297.1081.
Diethyl 2-hydroxy-2-(2-phenylacetamido)malonate (3e):
yield: 123.5 mg (80%); colorless oil; 1H NMR (400 MHz,
CDCl3): d=1.24 (t, J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H),
3.61 (s, 2H), 4.25 (q, J=7.2 Hz, 2H), 4.28 (q, J=7.2 Hz,
2H), 5.06 (s, 1H), 7.38–7.26 (m, 5H); 13C NMR (100 MHz,
CDCl3): d=13.8 (CH3), 43.2 (CH2), 63.6 (CH2), 79.9 (C),
127.5 (CH), 129.0 (CH), 129.3 (CH), 133.8 (C), 166.8 (C),
171.0 (C); IR (NaCl): n=1656, 1747, 3303 cmÀ1; HR-MS
(ESI-TOF): m/z=310.1298, calcd. for C15H20NO6 [M+H]+;
310.1291.
Experimental Procedure for the Decarboxylation of
18 (Scheme 5)
After selective monosaponification of compound 18aA
(0.2 mmol scale) according to the reported procedure by
Koch et al.,[18] the decarboxylation proceeded under reflux
in toluene for 1 h and gave the desired product 21 without
any further purification as a yellow oil; yield: 27.5 mg
(58%).
Experimental Procedure for the Transformation of
Esters into Amide 22 (Scheme 5)
The compound 22 (0.2 mmol scale) was synthesized accord-
ing to the reported procedure by Koch et al.[18] The crude
product was purified by silica gel column chromatography
(hexane/ethyl acetate=1/1) to furnish a yellow viscous
liquid; yield: 41.8 mg (65%).
Diethyl 2-acetamido-2-hydroxymalonate (3f): yield:
115.4 mg (>99%); white solid; mp 61.3–62.28C; 1H NMR
(400 MHz, CDCl3): d=1.29 (t, J=7.1 Hz, 6H), 2.06 (s, 3H),
4.32 (q, J=7.1 Hz, 4H), 5.07 (s, 1H), 7.31 (br s, 1H);
13C NMR (100 MHz, CDCl3): d=13.9 (CH3), 22.8 (CH3),
63.6 (CH2), 79.9 (C), 166.9 (C), 170.1 (C); IR (NaCl): n=
1673, 1748, 3369 cmÀ1; HR-MS (ESI-TOF): m/z=256.0799,
calcd. for C9H15NNaO6 [M+Na]+; 256.0792.
Experimental Procedure for the Construction of
Oxazinane 23 (Scheme 5)
A magnetic stirring bar, and anhydrous acetonitrile (2 mL)
were placed in the test tube under argon. Then, 1 equivalent
of base (potassium tert-butoxide for 18aB, CsCO3 for 18fB:
each reaction was performed on a 0.2 mmol scale) was
added. The mixture was stirred at 608C for 6 h. The crude
product was purified by silica gel column chromatography
(hexane/ethyl acetate=9/1).
Diethyl 2-butyramido-2-hydroxymalonate (3g): yield:
127.8 mg (98%); white solid; mp 81.0–81.48C; 1H NMR
(400 MHz, CDCl3): d=0.96 (t, J=7.2 Hz, 3H), 1.29 (t, J=
7.2 Hz, 3H), 1.29 (t, J=7.2 Hz, 3H), 1.67 (tq, J=7.2, 7.2 Hz,
2H), 2.23 (t, J=7.2 Hz, 2H), 4.31 (q, J=7.2 Hz, 2H), 4.32
(q, J=7.2 Hz, 2H), 5.06 (s, 1H), 7.27 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=13.5 (CH3), 13.9 (CH3), 18.6 (CH2),
37.9 (CH2), 63.6 (CH2), 79.9 (C), 167.1 (C), 173.1 (C); IR
(NaCl): n=1670, 1748, 3372 cmÀ1; HR-MS (EI): m/z=
284.1111, calcd. for C11H19NNaO6 [M+Na]+: 284.1105.
Diethyl (R)-2-(2,2-dimethylcyclopropane-1-carboxamido)-
2-hydroxymalonate (3h): yield: 139.0 mg (97%); colorless
oil; 1H NMR (400 MHz, CDCl3): d=0.80 (dd, J=4.8,
8.0 Hz, 1H), 1.11 (dd, J=4.8, 4.8 Hz, 1H), 1.15 (s, 3H), 1.17
(s, 3H), 1.29 (t, J=7.2 Hz, 6H), 1.36 (dd, J=4.8, 8.0 Hz,
1H), 4.30 (t, J=7.2 Hz, 4H), 5.07 (s, 1H), 7.39 (br s, 1H);
13C NMR (100 MHz, CDCl3): d=13.9 (CH3), 18.5 (CH),
20.9 (CH2), 23.2 (C), 27.0 (CH3), 28.4 (CH3), 63.5 (CH2),
79.9 (C), 167.1 (C), 167.3 (C), 171.7 (C); IR: n=1670, 1742,
3337; HR-MS (ESI-TOF): m/z=288.1433, calcd. for
C13H22NO6 [M+H]+; 288.1447.
Diethyl 2-acrylamido-2-hydroxymalonate (3i): yield:
110.1 mg (90%); white solid; mp 61.2–61.78C; 1H NMR
(400 MHz, CDCl3): d=1.29 (t, J=7.1 Hz, 6H), 4.33 (q, J=
7.1 Hz, 4H), 5.12 (s, 1H), 5.77 (d, J=10.3 Hz, 1.1 Hz, 1H),
6.16 (dd, J=17.0 Hz, 10.3 Hz, 1H), 6.34 (d, J=17.0 Hz,
1.1 Hz, 1H), 7.38 (br s, 1H); 13C NMR (100 MHz, CDCl3):
d=13.9 (CH3), 63.7 (CH2), 80.0 (C), 128.8 (CH), 129.4
(CH2), 165.0 (C), 166.9 (C); IR (ATR): n=1628, 1661, 1736,
3345 cmÀ1; HR-MS (ESI-TOF): m/z=268.0784, calcd. for
C10H15NNaO6 [M+Na]+: 268.0791.
Diethyl 2-benzamido-2-hydroxymalonate (3a): yield:
144.5 mg (98%); white solid; mp 50.5–51.28C; 1H NMR
(400 MHz, CDCl3): d=1.30 (t, J=7.2 Hz, 3H), 1.30 (t, J=
7.2 Hz, 3H), 4.34 (q, J=7.2 Hz, 2H), 4.34 (q, J=7.2 Hz,
2H), 5.22 (s, 1H), 7.45–7.49 (m, 2H), 7.54–5.58 (m, 1H),
7.83–7.85 (m, 2H), 7.99 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d=13.9 (CH3), 63.7 (CH2), 80.2 (C), 127.3 (CH),
128.7 (CH), 132.5 (C), 132.5 (CH), 166.8 (C), 167.1 (C); IR
(ATR): n=1651, 1744, 3327 cmÀ1
; HR-MS (ESI-TOF):
m/z=318.0962, calcd. for C14H17NNaO6 [M+Na]+: 318.0948.
Diethyl 2-hydroxy-2-(4-methylbenzamido)malonate (3b):
1
yield: 142.1 mg (92%); pale yellow oil; H NMR (400 MHz,
CDCl3): d=1.23 (t, J=7.2 Hz, 6H), 2.41 (s, 3H), 4.35 (q, J=
7.2 Hz, 4H), 5.21 (s, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.73 (d,
J=8.0 Hz, 2H) 7.94 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d=13.9 (CH3), 21.5 (CH3), 63.6 (CH2), 80.3 (C),
127.4 (CH), 129.4 (CH), 129.7 (C), 143.2 (C), 166.8 (C),
167.2 (C); IR (ATR): n=1640, 1740, 3341 cmÀ1; HR-MS
(ESI-TOF): m/z=337.1560, calcd. for C15H23N2O6 [M+
NH4]+; 327.1556.
Diethyl 2-hydroxy-2-(4-bromobenzamido)malonate (3c):
yield: 175.3 mg (94%); white solid; mp 36.5–37.28C;
1H NMR (400 MHz, CDCl3): d=1.30 (t, J=7.2 Hz, 3H),
1.30 (t, J=7.2 Hz, 3H), 4.33 (q, J=7.2 Hz, 2H), 4.34 (q, J=
7.2 Hz, 2H), 5.21 (s, 1H), 7.60 (d, J=8.4 Hz, 2H), 7.70 (d,
J=8.4 Hz, 2H), 7.95 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d=13.9 (CH3), 63.8 (CH2), 80.2 (C),127.4 (C), 129.0
(CH), 131.4 (C), 132.1 (CH), 165.9 (C), 167.0 (C); IR
(ATR): n=1639, 1732, 1755, 3350 cmÀ1; HR-MS (ESI-TOF):
m/z=324.0240, calcd. for C14H17BrNO6 [M+H]+; 374.0239.
Diethyl 2-(2-cyanoacetamido)-2-hydroxymalonate (3j):
yield: 95.5 mg (74%); white solid; mp 102.5–103.08C;
1H NMR (CDCl3): d=1.31 (t, J=7.2 Hz, 6H), 3.43 (s, 2H),
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4.34 (q, J=7.2 Hz, 4H), 5.05 (s, 1H), 7.82 (br s, 1H);
13C NMR (100 MHz, CDCl3): d=13.9 (CH3), 25.9 (CH2),
64.1 (CH2), 79.8 (C), 113.3 (C), 160.9 (C), 166.3 (C); IR
Methyl 2-benzamido-2-hydroxy-4,4-dimethyl-3-oxopenta-
noate (11a): H NMR (400 MHz, CDCl3): d=1.25 (s, 9H),
3.84 (s, 3H), 5.11–5.27 (br, 1H), 7.20–7.42 (m, 2H), 7.42 (br
s, 1H), 7.45–7.47 (m, 1H), 7.81–7.85 (m, 2H); MS: m/z=
293. Satisfactory analytical data were not obtained because
of the instability of 11a.
1
(ATR): n=1674, 1751, 3356 cmÀ1
; HR-MS (ESI-TOF):
m/z=281.0742, calcd. for C10H14N2NaO6 [M+Na]+:
281.0744.
Methyl 2-butyramido-2-hydroxy-4,4-dimethyl-3-oxopenta-
noate (11g): yield: 51.8 mg (40%); white solid; mp 81.0–
81.48C; H NMR (400 MHz, CDCl3): d=0.95 (t, J=7.2 Hz,
Diethyl 2-[(tert-butoxycarbonyl)amino]-2-hydroxymalo-
nate (3k): yield: 118.9 mg (82%); colorless oil; 1H NMR
(400 MHz, CDCl3): d=1.29 (t, J=7.2 Hz, 6H), 1.44 (s, 9H),
4.26–4.37 (m, 4H), 4.95 (br s, 1H), 6.42 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=13.9 (CH3), 28.2 (CH3), 63.5 (CH2),
80.4 (C), 81.3 (C), 167.0 (C), 167.2 (C); IR (ATR); n=1717,
1744, 3439 cmÀ1; HR-MS (ESI-TOF): m/z=309.1676, calcd.
for C12H25N2O7 [M+NH4]+; 309.1662.
Diethyl 2-hydroxy-2-(2,2,2-trifluoroacetamido)malonate
(3l): During isolation by silica gel column chromatography,
the product was easily decomposed to starting materials;
yellow oil; 1H NMR (400 MHz, CDCl3): d=1.30 (t, J=
7.2 Hz, 6H), 4.34 (q, J=7.2 Hz, 4H), 5.12 (br s, 1H), 8.09
(br s, 1H); MS: m/z=287. Satisfactory analytical data were
not obtained because of the instability of 3l.
1
3H), 1.24 (s, 9H), 1.61–1.70 (m, 2H), 2.22 (t, J=7.2 Hz,
2H), 3.81 (s, 3H), 5.68 (br s, 1H), 7.50 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=13.6 (CH3), 18.6 (CH2), 27.7 (CH3),
38.1 (CH2), 44.5 (C), 53.6 (CH3), 83.7 (C), 168.3 (C), 173.5
(C), 205.4 (C); IR (ATR): n=1649, 1719, 1744, 3329 cmÀ1
;
HR-MS (ESI-TOF): m/z=282.1314, calcd. for C12H21NNaO5
[M+Na]+: 282.1312.
2-Butyramido-1,3-diphenyl-2-hydroxypropane-1,3-dione
(12g): yield: 51.8 mg (32%); white solid; mp 121.1–121.98C;
1H NMR (400 MHz, CDCl3): d=0.76 (t, J=7.2 Hz, 3H),
1.52 (tq, J=7.2, 7.2 Hz, 2H), 2.17 (t, J=7.2 Hz, 2H), 6.23
(br s, 1H), 7.35 (dd, J=7.2, 7.2 Hz, 4H), 7.50 (t, J=7.2 Hz,
2H), 7.99 (d, J=7.2 Hz, 4H), 8.09 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=13.4 (CH3), 18.5 (CH2), 38.1 (CH2),
86.8 (C), 128.6 (CH), 130.0 (CH), 132.9 (C), 134.2 (CH),
Diethyl 2-[(diethoxyphosphoryl)amino]-2-hydroxymalo-
nate (3m): yield: 89.7 mg (55%); colorless oil; 1H NMR
(400 MHz, CDCl3): d=1.31 (t, J=7.2 Hz, 6H), 1.32 (t, J=
7.2 Hz, 3H), 1.33 (t, J=7.2 Hz, 3H), 4.09 (q, J=7.2 Hz,
2H), 4.11 (q, J=7.2 Hz, 2H), 4.32 (q, J=7.2 Hz, 4H), 4.76
(JHÀP =9.6 Hz, 1H), 5.04 (s, 1H); 13C NMR (100MHz,
CDCl3): d=13.9 (CH3), 16.0 (CH3, d, JC,P =7.0 Hz), 62.8
(CH2 d, JC,P =5.0 Hz), 63.5 (CH2), 81.5 (C, d, JC,P =3.0 Hz),
172.6 (C), 192.3 (C); IR (NaCl): n=1683, 1732, 3392 cmÀ1
;
HR-MS (ESI-TOF): m/z=345.1211, calcd. for C19H19NNaO4
[M+Na]+: 348.1206.
2-Benzamido-2-hydroxy-1-methyl-3-phenylpropane-1,3-
dione (13a): yield: 56.4 mg (38%); white solid; mp 117.5–
1
118.48C; H NMR (400 MHz, CDCl3): d=2.21 (s, 3H), 6.14
168.0 (C, d, JC,P =9.0 Hz); IR (ATR): n=1742, 3337 cmÀ1
HR-MS (ESI-TOF): m/z=350.0975, calcd. for
C11H22NNaO8P [M+Na]+: 350.0975.
;
(brs, 1H), 7.40–7.47 (m, 4H), 7.52–7.60 (m, 2H), 7.80 (d, J=
7.2 Hz, 2H), 8.07 (d, J=7.2 Hz, 2H), 8.44 (br s, 1H);
13C NMR (100 MHz, CDCl3): d=23.7 (CH3), 87.5 (C), 127.3
(CH), 128.4 (CH), 128.8 (CH), 129.7 (CH), 132.2 (C), 132.5
(CH), 132.5 (C), 166.4 (C), 191.8 (C), 200.7 (C); IR (NaCl):
Diethyl 2-hydroxy-2-(N-methylacetamido)malonate (3n):
1
yield: 5.0 mg (4%); yellow oil; H NMR (400 MHz, CDCl3):
d=1.30–1.40 (m, 6H), 2.35 (s, 1H), 3.26 (s, 1H), 4.31–4.39
(m, 4H), 4.74 (s, 1H); MS: m/z=247. Satisfactory analytical
data were not obtained because of the instability of 3n.
Diethyl 2-hydroxy-2-(2-oxopyrrolidin-1-yl)malonate (3o):
yield: 116.6 mg (90%); mixture of two conformers; yellow
n=1683, 1732, 3392 cmÀ1
; HR-MS (ESI-TOF): m/z=
320.0892, calcd. for C17H15NNaO4 [M+Na]+: 320.0893.
2-Butyramido-2-hydroxy-1-methyl-3-phenylpropane-1,3-
dione (13g): yield: 68.4 mg (52%); yellow oil; 1H NMR
(400 MHz, CDCl3): d=0.81 (t, J=7.4 Hz, 3H), 1.55 (tq, J=
7.2, 7.4 Hz, 2H), 2.15 (s, 3H), 2.18 (t, J=7.2 Hz, 2H), 6.07
(brs, 1H), 7.41 (dd, J=7.2, 7.2 Hz, 2H), 7.58 (t, J=7.2 Hz,
1H), 8.00 (d, J=7.2 Hz, 2H), 8.09 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=13.4 (CH3), 18.5 (CH3), 23.7 (CH2),
37.8 (CH2), 87.2 (C), 128.7 (CH), 129.6 (CH), 132.3 (C),
134.4 (CH), 172.9 (C), 191.9 (C); IR (NaCl): n=1652, 1680,
3292 cmÀ1; HR-MS (ESI-TOF): m/z=286.1056, calcd. for
C14H17NNaO4 [M+Na]+: 286.1050.
1
oil; H NMR (400 MHz, CDCl3): d=1.32 (t, J=7.2 Hz, 6H),
2.10 (tt, J=7.6, 7.6 Hz, 2H), 2.41 (t, J=7.6 Hz, 2H), 3.62 (t,
J=7.6 Hz, 2H), 4.33 (q, J=7.2 Hz, 4H), 5.04 (s, 1H);
13C NMR (100 MHz, CDCl3): major: d=13.9 (CH3), 18.5
(CH2), 30.9 (CH2), 45.2 (CH2), 63.4 (CH2), 83.4 (C), 166.8
(C), 176.9 (C); minor d=13.9 (CH3), 20.9 (CH2), 29.8
(CH2), 42.1 (CH2), 63.5 (CH2), 90.2 (C), 168.5 (C), 179.0
(C); IR (NaCl): n=1684, 1749, 3367 cmÀ1; HR-MS (ESI-
TOF): m/z=282.0936, calcd. for C11H17NNaO6 [M+Na]+:
282.0948.
Ethyl 2-butyramido-2-hydroxy-3-(4-methoxyphenyl)-3-ox-
opropanoate (10g): yield: 101.8 mg (63%); white solid; mp
65.4–66.28C; 1H NMR (400 MHz, CDCl3): d=0.91 (t, J=
7.2 Hz, 3H), 1.12 (t, J=7.2 Hz, 3H), 1.60–1.68 (m, 2H), 2.23
(t, J=7.2 Hz, 2H), 3.88 (s, 3H), 4.15–4.25 (m, 2H), 5.80 (s,
1H), 6.91 (d, J=8.8 Hz, 2H), 7.77 (br s, 1H), 8.15 (d, J=
8.8 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=13.6 (CH3),
13.8 (CH3), 18.6 (CH2), 38.0 (CH2), 55.6 (CH3), 63.3 (CH2),
83.0 (C), 113.9 (CH), 124.8 (C), 132.6 (CH), 164.5 (C), 168.8
(C), 173.2 (C), 187.8 (C); IR (ATR): n=1647, 1717,
3329 cmÀ1; HR-MS (ESI-TOF): m/z=346.1246, calcd. for
C16H21NNaO6 [M+Na]+; 346.1261.
1-(tert-Butyl)-3-ethyl
2-benzamido-2-hydroxymalonate
(14a): yield: 156.8 mg (97%); colorless oil; 1H NMR
(400 MHz, CDCl3): d=1.31 (t, J=7.2 Hz, 3H), 1.50 (s, 9H),
4.32–4.38 (m, 2H), 5.16 (s, 1H), 7.46 (dd, J=7.2, 7.2 Hz,
2H), 7.55 (t, J=7.2 Hz, 1H), 7.83 (d, J=7.2 Hz, 2H), 7.95
(br s, 1H); 13C NMR (100 MHz, CDCl3): d=14.0 (CH3),
27.7 (CH3), 63.4 (CH2), 80.3 (C), 84.9 (C), 127.3 (CH), 128.7
(CH), 132.3 (CH), 132.8 (C), 165.9 (C), 166.6 (C), 167.5 (C);
IR (NaCl): n=1681, 1747, 3425 cmÀ1; HR-MS (ESI-TOF):
m/z=346.1254. calcd. for C16H21NNaO6 [M+Na]+: 346.1261.
1-(tert-Butyl)-3-ethyl
2-butyramido-2-hydroxymalonate
(14g): yield: 141.7 mg (98%); colorless oil; 1H NMR
(400 MHz, CDCl3): d=0.96 (t, J=7.2 Hz, 3H), 1.29 (t, J=
7.2 Hz, 3H), 1.48 (s, 9H), 1.64–1.70 (m, 2H), 2.22 (t, J=
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7.2 Hz, 2H), 4.29–4.35 (m, 2H), 5.05 (br s, 1H), 7.25 (br s,
1H); 13C NMR (100 MHz, CDCl3): d=13.5 (CH3), 13.9
(CH3), 18.7 (CH2), 27.6 (CH3), 37.9 (CH2), 63.2 (CH2), 79.9
(C), 84.6 (C), 165.8 (C), 167.4 (C), 172.7 (C); IR (NaCl): n=
1673, 1743, 3374 cmÀ1; HR-MS (ESI-TOF): m/z=312.1408,
calcd. for C13H23NNaO6 [M+Na]+: 312.1418.
2-Benzamide-2-hydroxy-1-pyrrolidinopropane-1,3-dione
(15a): yield: 21.1 mg (12%); white solid; mp 135.9–136.58C;
1H NMR (400 MHz, CDCl3): d=1.68–1.72 (m, 1H), 1.77–
1.84 (m, 3H), 3.06–3.11 (m, 1H), 3.54–3.60 (m, 2H), 3.64–
3.67 (m, 1H), 3.12 (br s, 1H), 7.39–7.45 (m, 4H), 7.50 (t, J=
7.3 Hz, 1H), 7.55 (t, J=7.4 Hz, 1H), 7.79 (d, J=7.2 Hz,
2H), 8.16 (d, J=7.2 Hz, 2H), 9.00 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=23.2 (CH2), 26.4 (CH2), 46.8 (CH2),
48.5 (CH2), 83.5 (C), 127.3 (CH), 128.7 (CH), 128.8 (CH),
129.7 (CH), 132.2 (CH), 132.4 (C), 133.1 (C), 134.3 (CH),
164.3 (C), 165.9 (C), 192.1 (C); IR (NaCl): n=1636,
3376 cmÀ1; HR-MS (ESI-TOF): m/z=375.1320, calcd. for
C20H20N2NaO4 [M+Na]+: 375.1315.
(400 MHz, CDCl3): d=1.31 (t, J=7.2 Hz, 6H), 2.08 (tt, J=
6.0, 6.0 Hz, 2H), 3.68 (t, J=6.0 Hz, 2H), 3.75 (t, J=6.0 Hz,
2H), 4.31–4.38 (m, 4H), 7.48 (dd, J=7.2, 7.2 Hz, 2H), 7.56
(t, J=7.2 Hz, 1H), 7.85 (d, J=7.2 Hz, 2H); 13C NMR
(100 MHz, CDCl3): d=14.0 (CH3), 32.4 (CH2), 41.7 (CH2),
61.2 (CH2), 63.2 (CH2), 84.2 (C), 127.4 (CH), 128.8 (CH),
132.4 (CH), 132.8 (C), 165.7 (C), 166.4 (C); IR (ATR): n=
1682, 1746 cmÀ1; HR-MS (ESI-TOF): m/z=394.1032, calcd.
for C17H22ClNNaO6 [M+Na]+: 394.1028.
Diethyl 2-acetamido-2-(3-chloropropoxy)malonate (18fB):
yield: 125.4 mg (81%); colorless viscous liquid; 1H NMR
(400 MHz, CDCl3): d=1.29 (t, J=6.8 Hz, 6H), 2.03–2.09
(m, 2H), 2.10 (s, 3H), 3.65–3.68 (m, 4H), 4.26–4.33 (m, 4H),
7.14 (br s, 1H); 13C NMR (100 MHz, CDCl3): d=13.9
(CH3), 23.0 (CH3), 32.3 (CH2), 41.8 (CH2), 60.8 (CH2), 63.1
(CH2), 83.9 (C), 165.6 (C), 169.5 (C); IR (NaCl): n=1684,
1749, 3318 cmÀ1; HR-MS (ESI-TOF): m/z=332.0873, calcd.
for C12H20ClNNaO6 [M+Na]+: 332.0871.
Diethyl
2-benzamido-2-(4-methoxyphenoxy)malonate
2-Butyramide-2-hydroxy-1-pyrrolidinopropane-1,3-dione
(15g): yield: 44.5 mg (28%); white solid; mp 102.0–103.08C;
1H NMR (400 MHz, CDCl3): d=0.77 (t, J=7.4 Hz, 3H),
1.51 (tq, J=7.2, 7.4 Hz, 2H), 1.61–1.90 (m, 4H), 2.08–2.19
(m, 2H), 3.01–3.09 (m, 1H), 3.50–3.54 (m, 2H), 3.55–3.68
(m, 1H), 5.96 (brs, 1H), 7.42 (dd, J=7.2, 7.3 Hz, 4H), 7.57
(t, J=7.3 Hz, 2H), 8.10 (d, J=7.2 Hz, 4H), 8.24 (br s, 1H);
13C NMR (100 MHz, CDCl3): d=13.4 (CH3), 18.5 (CH2),
23.1 (CH2), 26.4 (CH2), 38.1 (CH2), 46.7 (CH2), 48.4 (CH2),
83.3 (C), 128.6 (CH), 129.5 (CH), 132.5 (C), 134.1 (CH),
164.1 (C), 172.3 (C), 192.2 (C); IR (NaCl): n=1637, 2876,
2965, 3336 cmÀ1; HR-MS (ESI-TOF): m/z=341.1480, calcd.
for C17H22N2NaO4 [M+Na]+: 341.1472.
(18aC): yield: 156.6 mg (78%); pale yellow oil; 1H NMR
(400 MHz, CDCl3): d=1.32–1.36 (m, 6H), 3.72 (s, 3H),
4.31–4.48 (m, 2H), 6.74 (d, J=6.8 Hz, 2H), 6.93 (d, J=
6.8 Hz, 2H), 7.43 (dd, J=7.2, 7.2 Hz, 2H), 7.54 (t, J=
7.2 Hz, 1H), 7.74 (d, J=7.2 Hz, 2H), 7.75 (br s, 1H);
13C NMR (100 MHz, CDCl3): d=13.9 (CH3), 55.4 (CH3),
63.3 (CH2), 85.7 (C), 114.3 (CH), 123.9 (CH), 127.3 (CH),
128.8 (CH), 132.5 (CH), 132.7 (C), 146.2 (C), 156.9 (C),
165.3 (C), 166.1 (C); IR (NaCl): n=1682, 1747, 3416 cmÀ1
;
HR-MS (ESI-TOF): m/z=424.1375, calcd. for C21H23NNaO7
[M+Na]+: 424.1367.
Diethyl 2-benzamido-2-(phenylamino)malonate (18aD):
1
yield: 139.6 mg (76%); pale yellow oil; H NMR (400 MHz,
Diethyl 2-benzamido-2-methoxymalonate (18aA): yield:
154.7 mg (>99%); yellow oil; H NMR (400 MHz, CDCl3):
CDCl3): d=1.21 (t, J=7.2 Hz, 6H), 4.25–4.36 (m, 4H), 5.91
(br s, 1H), 6.73 (d, J=7.4 Hz, 2H), 6.78 (t, J=7.4 Hz, 1H),
7.14 (dd, J=7.4, 7.4 Hz, 2H), 7.42 (dd, J=7.2, 7.2 Hz, 2H),
7.50 (t, J=7.2 Hz, 1H), 7.76 (d, J=7.2 Hz, 2H), 8.05 (br s,
1H); 13C NMR (100 MHz, CDCl3): d=13.9 (CH3), 63.7
(CH2), 72.7 (C), 115.7 (CH), 119.9 (CH), 127.2 (CH), 128.6
(CH), 129.1 (CH), 132.1 (CH), 133.2 (C), 143.0 (C), 166.2
(C), 167.3 (C); IR (NaCl): n=1672, 1739, 3409 cmÀ1; HR-
MS (ESI-TOF): m/z=393.1402, calcd. for C20H22N2NaO5
[M+Na]+: 393.1421.
1
d =.32 (t, J=7.2 Hz, 6H), 3.42 (s, 3H), 4.33–4.39 (m, 4H),
7.48 (dd, J=7.2, 7.2 Hz, 2H), 7.55 (t, J=7.2 Hz, 1H), 7.82
(br s, 1H), 7.87 (d, J=7.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=14.0 (CH3), 52.4 (CH3), 63.2 (CH2), 84.7 (C),
127.4 (CH), 128.8 (CH), 132.5 (CH), 132.8 (C), 165.7 (C),
166.3 (C); IR (NaCl): n=1683, 1747, 1775, 3411 cmÀ1; HR-
MS (ESI-TOF): m/z=332.1097, calcd. for C15H19NNaO6
[M+Na]+: 332.1105.
Diethyl 2-acetamido-2-methoxymalonate (18fA): yield:
113.7 mg (92%); yellow viscous liquid; H NMR (400 MHz,
Diethyl 2-Benzamido-2-[methyl(phenyl)amino]malonate
(18aE): yield: 130.9 mg (70%); pale yellow oil; 1H NMR
(400 MHz, CDCl3): d=1.19 (t, J=7.2 Hz, 6H), 3.16 (s, 3H),
4.12–4.38 (m, 4H), 7.11–7.17 (m, 1H), 7.20–7.29 (m, 4H),
7.47 (dd, J=7.2, 7.2 Hz, 2H), 7.55 (t, J=7.2 Hz, 1H), 7.74
(br s, 1H), 7.84 (d, J=7.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=13.8 (CH3), 40.3 (CH3), 62.8 (CH2), 79.1 (C),
125.9 (CH), 126.7 (CH), 127.1 (CH), 128.7 (CH), 128.9
(CH), 132.0 (CH), 133.7 (C), 148.8 (C), 166.2 (C), 166.8 (C);
IR (NaCl): n=1681, 1741, 1771, 3407 cmÀ1; HR-MS (ESI-
TOF): m/z=407.1571, calcd. for C21H24N2NaO5 [M+Na]+:
407.1577.
Diethyl 2-benzamido-2-(1H-pyrrol-2-yl)malonate (18aF):
yield: 148.1 mg (86%); colorless crystals; mp 104.8–105.08C;
1H NMR (400 MHz, CDCl3): d=1.29 (t, J=7.2 Hz, 6H),
4.31–4.39 (m, 4H), 6.01–6.03 (m, 1H), 6.09–6.12 (m, 1H),
6.78–6.80 (m, 1H), 7.45 (dd, J=7.2, 7.2 Hz, 2H), 7.54 (t, J=
7.2 Hz, 1H), 7.83 (d, J=7.2 Hz, 2H), 7.96 (br s, 1H), 9.75
(br s, 1H); 13C NMR (100 MHz, CDCl3): d=13.9 (CH3),
63.2 (CH2), 64.9 (C), 107.3 (CH), 107.3 (CH), 118.9 (CH),
1
CDCl3): d=1.30 (t, J=7.2 Hz, 6H), 2.12 (s, 3H), 3.35 (s,
3H), 4.31 (q, J=7.2 Hz, 4H), 7.24 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=13.8 (CH3), 22.8 (CH3), 52.0 (CH3),
62.9 (CH2), 84.3 (C), 165.5 (C), 169.6 (C); IR (NaCl): n=
1682, 1750, 3353 cmÀ1; HR-MS (ESI-TOF): m/z=270.0942,
calcd. for C10H17NNaO6 [M+Na]+: 270.0948.
Diethyl 2-acrylamido-2-methoxymalonate (18iA): yield:
125.8 mg (98%); pale yellow oil; 1H NMR (400 MHz,
CDCl3): d=1.30 (t, J=7.2 Hz, 6H), 3.34 (s, 3H), 4.33 (q, J=
7.2 Hz, 4H), 5.78 (dd, J=1.2, 10.4 Hz, 1H), 6.23 (dd, J=
10.4, 17.2 Hz, 1H), 6.38 (d, J=17.2 Hz, 2H), 7.21 (br s, 1H);
13C NMR (100 MHz, CDCl3): d=13.9 (CH3), 52.3 (CH3),
63.1 (CH2), 84.4 (C), 128.8 (CH2), 129.5 (C), 164.5 (C), 165.5
(C); IR (NaCl): n=1632, 1692, 1748, 3347 cmÀ1; HR-MS
(ESI-TOF): m/z=282.0944, calcd. for C11H17NNaO6 [M+
Na]+: 282.0948.
Diethyl
2-benzamido-2-(3-chloropropoxy)malonate
(18aB): yield: 161.7 mg (87%); colorless oil; 1H NMR
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126.8 (C), 127.2 (CH), 128.7 (CH), 132.2 (CH), 133.0 (C),
166.9 (C), 166.9 (C); IR (ATR): n=1651, 1728, 3411 cmÀ1
HR-MS (ESI-TOF): m/z=367.1265, calcd. for
C18H20N2NaO5 [M+Na]+: 367.1264.
55.7 (CH), 62.4 (CH2), 63.2 (CH2), 66.0 (C), 127.2 (CH),
128.7 (CH), 132.1 (CH), 133.4 (C), 166.5 (C), 166.8 (C),
168.1 (C), 217.4 (C); IR (NaCl): n=1679, 1745 cmÀ1; HR-
MS (ESI-TOF): m/z=384.1399, calcd. for C19H23NNaO6
[M+Na]+: 384.1418.
;
Diethyl 2-acetamido-2-(1H-pyrrol-2-yl)malonate (18fF):
1
yield: 128.5 mg (91%); pale yellow oil; H NMR (400 MHz,
Diethyl 2-acetoxy-2-benzamidomalonate (19a): yield
(Method A): 161.7 mg (96%), (Method B): 148.1 mg (88%);
CDCl3): d=1.28 (t, J=7.0 Hz, 6H), 2.04 (s, 3H), 4.31 (q, J=
7.0 Hz, 4H), 5.96 (dd, J=1.2, 2.0 Hz, 1H), 6.09 (dd, J=2.0,
2.8 Hz, 1H), 6.76 (dd, J=1.2, 2.8 Hz, 1H), 7.29 (br s, 1H),
9.60 (br s, 1H); 13C NMR (400 MHz, CDCl3): d=13.9
(CH3), 22.9 (CH3), 63.1 (CH2), 64.8 (C), 107.1 (CH), 107.2
(CH), 118.9 (CH), 127.0 (C), 166.8 (C), 170.1 (C); IR
1
white solid; mp 74.0–74.98C; H NMR (400 MHz, CDCl3):
d=1.29 (t, J=7.2 Hz, 6H), 2.20 (s, 3H), 4.34 (q, J=7.2 Hz,
4H), 7.47 (dd, J=7.2, 7.2 Hz, 2H), 7.56 (t, J=7.2 Hz, 1H),
7.84 (d, J=7.2 Hz, 2H), 8.11 (br s, 1H); 13C NMR
(100 MHz, CDCl3): d=13.9 (CH3), 20.9 (CH3), 63.7 (CH2),
82.1 (C), 127.5 (C), 128.8 (C), 132.3 (C), 132.6 (C), 163.6
(C), 165.9 (C), 170.2 (C); IR (ATR): n=1672, 1744,
3318 cmÀ1; HR-MS (ESI-TOF): m/z=360.1059, calcd. for
C16H19NNaO7 [M+Na]+: 360.1054.
(NaCl): n=1668, 1740, 3398 cmÀ1
; HR-MS (ESI-TOF):
m/z=305.1110, calcd. for C13H18N2NaO5 [M+Na]+:
305.1108.
Diethyl 2-acrylamido-2-(1H-pyrrol-2-yl)malonate (18iF):
yield: 105.9 mg (72%); brown solid; mp 60.2–61.08C;
1H NMR (400 MHz, CDCl3): d=1.29 (t, J=7.2 Hz, 6H),
4.33 (q, J=7.2 Hz, 4H), 5.73 (dd, J=1.6, 10.0 Hz, 1H),
5.95–5.97 (m, 1H), 6.09 (dd, J=2.8, 6.4 Hz, 1H), 6.19 (dd,
J=10.0, 17.2 Hz, 1H), 6.31 (dd, J=1.6, 17.2 Hz, 1H), 6.76–
6.78 (m, 1H), 7.36 (s, 1H), 9.65 (s, 1H); 13C NMR
(400 MHz, CDCl3): d=13.9 (CH3), 63.3 (CH2), 64.8 (C),
107.3 (CH), 107.3 (CH), 119.0 (CH), 126.7 (C), 128.1 (CH2),
129.7 (CH), 165.1 (C), 166.8 (C); IR (ATR): n=1627, 1662,
1734, 3392 cmÀ1; HR-MS (ESI-TOF): m/z=317.1096. calcd.
for C13H18N2NaO5 [M+Na]+: 305.1108.
Diethyl 2-benzamido-2-(1H-indol-3-yl)malonate (18aG):
yield: 120.3 mg (61%); white solid: mp 174.0–174.68C;
1H NMR (400 MHz, CDCl3): d=1.22 (dd, J=7.1, 7.1 Hz,
6H), 4.25 (dq, J=7.1, 10.7 Hz, 2H), 4.33 (dq, J=7.1,
10.7 Hz, 2H), 6.99–7.05 (m, 2H), 7.16–7.18 (m, 1H), 7.42
(dd, J=7.2, 7.2 Hz, 2H), 7.50 (t, J=7.2 Hz, 1H), 7.63–7.67
(m, 1H),7.69 (d, J=2.4 Hz, 1H), 7.84 (d, J=7.2 Hz, 2H),
8.07 (br s, 1H), 8.64 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d=14.0 (CH3), 62.8 (CH2), 65.3 (C), 109.2 (C),
111.7, (CH), 119.7 (CH), 119.7 (CH), 121.7 (CH), 125.1 (C),
126.3 (CH), 127.2 (CH), 128.6 (CH), 131.9 (CH), 133.6 (C)
136.3 (C), 165.9 (C), 167.7 (C); IR (NaCl): n=1653, 1733,
3391 cmÀ1; HR-MS (ESI-TOF): m/z=417.1402, calcd. for
C22H22N2NaO5 [M+Na]+: 417.1421.
Diethyl 2-benzamido-2-(2-oxoethyl)malonate (18aH):
yield: 96.4 mg (60%); colorless oil; 1H NMR (400 MHz,
CDCl3): d=1.25 (dd, J=7.2, 7.2 Hz, 6H), 3.82 (s, 2H), 4.28
(dq, J=1.2, 7.2 Hz, 2H), 4.29 (dq, J=1.2, 7.2 Hz, 2H), 7.45
(dd, J=7.2, 7.2 Hz, 2H), 7.54 (t, J=7.2 Hz, 1H), 7.70 (br s,
1H), 7.80 (d, J=7.2 Hz, 2H), 9.70 (s, 1H); 13C NMR
(100 MHz, CDCl3): d=14.0 (CH3), 47.3 (CH2), 63.2 (C),
63.3 (CH2), 127.3 (CH), 128.8 (CH), 132.3, (CH), 133.3 (C),
166.6 (C), 167.0 (C), 198.5 (C); IR (NaCl): n=1667, 1725,
1746, 3418 cmÀ1; HR-MS (ESI-TOF): m/z=344.1105, calcd.
for C16H19NNaO6 [M+Na]+: 344.1105.
Diethyl 2-acetamido-2-acetoxymalonate (19f): yield
(Method A): 211.9 mg (77%); white solid; mp 111.5–
1
113.38C; H NMR (400 MHz, CDCl3): d=1.27 (t, J=7.2 Hz,
6H), 2.06 (s, 3H), 2.18 (s, 3H), 4.30 (q, J=7.2H, 4H), 7.43
(br s, 1H); 13C NMR (100 MHz, CDCl3): d=13.8 (CH3),
20.8 (CH3), 22.8 (CH3), 63.6 (CH2), 81.7 (C), 163.5 (C),
169.1 (C), 170.1 (C); IR (KBr): n=1699, 1763, 3364 cmÀ1
;
HR-MS (ESI-TOF): m/z=298.0888, calcd. for C11H17NNaO7
[M+Na]+: 298.0897.
Diethyl 2-acetoxy-2-acrylamidomalonate (19i): yield
(Method A): 244.2 mg (85%); white solid; mp 104.5–
1
105.68C; H NMR (400 MHz, CDCl3): d=1.27 (t, J=7.2 Hz,
6H), 2.18 (s, 3H), 4.31 (q, J=7.2 Hz, 4H), 5.78 (dd, J=3.6,
10.4 Hz, 1H), 6.17 (dd, J=17.2, 10.4 Hz, 1H), 6.36 (dd, J=
17.2, 3.6 Hz, 1H), 7.53 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d=13.8 (CH3), 20.8 (CH3), 63.6 (CH2), 81.8 (C),
129.2 (CH), 129.2 (CH2), 163.4 (C), 164.1 (C), 170.1 (C); IR
(KBr): n=1695, 1761, 3356 cmÀ1; HR-MS (ESI-TOF): m/z=
288.1064, calcd. for C12H18NO7 [M+H]+: 288.1078.
Diethyl 2-acetoxy-2-(trifluoroacetamido)malonate (19l):
yield (Method B): 305.0 mg (93%); white solid; mp 69.3–
70.18C; 1H NMR (400 MHz, CDCl3): d=1.29 (dd, J=7.2,
7.2 Hz, 6H), 2.22 (s, 3H), 4.27–4.34 (m, 4H), 8.26 (br s,
1H); 13C NMR (100 MHz, CDCl3): d=13.8 (CH3), 20.6
(CH3), 64.3 (CH2), 81.1 (C), 114.0 (CF3, q, JC,F =286.0 Hz),
156.0 (C, q, JC,F =156.0 Hz), 162.2 (C), 169.6 (C); 13F NMR
(376 MHz, CDCl3): d=À75.9; IR (NaCl): n=1667, 1748,
3147 cmÀ1; MS: m/z=329.
Diethyl 2-methoxy-2-(N-methylbenzamido)malonate (20):
yield: 52.3 mg (81%); yellow viscous liquid; 1H NMR
(400 MHz, CDCl3): d=1.31 (t, J=7.2 Hz, 6H), 2.95 (s, 3H),
3.65 (s, 3H), 4.31 (q, J=7.2 Hz, 4H), 7.41–7.50 (m, 3H),
7.59 (d, J=7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
13.9 (CH3), 35.1 (CH3), 53.5 (CH3), 62.5 (CH2), 90.0 (C),
127.7 (CH), 128.5 (CH), 130.9 (CH), 135.0 (C), 164.8 (C),
173.7 (C); IR (NaCl): n=1660, 1754 cmÀ1; HR-MS (ESI-
TOF): m/z=346.1269, calcd. for C16H21NNaO6 [M+Na]+:
346.1261.
Ethyl 2-benzamido-2-methoxyacetate (21): yield: 27.5 mg
(58%); white solid; mp 76.2–77.08C; 1H NMR (400 MHz,
CDCl3): d=1.33 (t, J=7.1 Hz, 3H), 3.52 (s, 3H), 4.28 (q, J=
7.1 Hz, 2H), 5.75 (d, J=9.1 Hz, 1H), 7.36 (d, J=9.1 Hz,
1H) 7.45 (dd, J=7.2, 7.2 Hz, 2H), 7.54 (t, J=7.2 Hz, 1H),
7.86 (d, J=7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
14.0 (CH3), 56.7 (CH3), 62.2 (CH2), 78.8 (CH), 127.3 (CH),
128.7 (CH), 132.2 (CH), 133.2 (C), 167.5 (C), 168.2 (C); IR
Diethyl
2-benzamido-2-(2-oxocyclopentyl)malonate
(18aI): yield: 86.7 mg (48%); colorless crystals; mp 98.9–
1
99.48C; H NMR (400 MHz, CDCl3): d=1.21 (t, J=7.2 Hz,
3H), 1.30 (dd, J=7.3, 7.3 Hz, 3H), 1.75–1.90 (m. 1H), 1.93–
2.12 (m, 3H), 2.27–2.38 (m, 1H), 2.65–2.78 (m, 1H), 3.40
(dd, J=8.9, 11.8 Hz, 1H), 4.23 (q, J=7.2 Hz, 2H), 4.34 (dq,
J=2.4, 7.3 Hz, 2H), 4.35 (dq, J=2.4, 7.3 Hz, 2H), 7.44 (dd,
J=7.2, 7.2 Hz, 1H), 7.53 (t, J=7.2 Hz, 1H), 7.57 (br s, 1H),
7.81 (d, J=7.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=
13.9 (CH3), 14.0 (CH3), 20.5 (CH2), 26.9 (CH2), 38.0 (CH2),
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(NaCl): n=1660, 1748, 2834, 2984, 3335 cmÀ1; HR-MS (ESI-
TOF): m/z=260.0900, calcd. for C12H15NNaO4 [M+Na]+:
260.0893.
Gao, R. P. Singh, E. J. Corey, Org. Lett. 2010, 12, 1812–
1814.
[5] a) D. M. Tschaen, E. Turos, S. M. Weinreb, J. Org.
Chem. 1984, 49, 5058–5064; b) Y. Tohyama, K. Tanino,
I. Kuwajima, J. Org. Chem. 1994, 59, 518–519.
[6] Recent examples, see: a) S. Schunk, D. Enders, Org.
Lett. 2001, 3, 3177–3180; b) J. Adamek, R. Mazurkie-
wicz, A. Pazdzierniok-Holewa, M. Grymel, A. Kuznik,
K. Zielinska, J. Org. Chem. 2014, 79, 2765–2770; c) R.
Ethyl 2-benzamido-2-methoxy-3-oxo-3-(propylamino)pro-
panoate (22): yield: 41.8 mg (65%); yellow viscous liquid;
1H NMR (400 MHz, CDCl3): d=0.95 (t, J=7.6 Hz, 3H),
1.28 (t, J=7.2 Hz, 3H), 1.56–1.63 (m, 2H), 3.29–3.36 (m,
2H), 3.33 (s, 3H), 4.26–4.35 (m, 2H), 6.71–6.90 (m, 1H),
7.46 (dd, J=8.4, 8.4 Hz, 2H), 7.55 (t, J=8.4 Hz, 1H), 7.88
(d, J=8.4 Hz, 2H), 8.00 (br s, 1H); 13C NMR (100 MHz,
CDCl3): d=10.2 (CH3), 12.9 (CH3), 21.6 (CH2), 40.7 (CH2),
50.8 (CH3), 62.1 (CH2), 84.8 (C), 126.4 (CH), 127.7 (CH),
131.3 (CH), 132.1 (C), 164.3 (C), 165.6 (C), 166.0 (C); IR
(NaCl): n=1640, 1683, 1749, 3358 cmÀ1; HR-MS (ESI):
m/z=343.1417, calcd. for C16H22N2NaO5 [M+Na+]:
345.1421.
Diethyl 3-benzoyl-1,3-oxazinane-2,2-dicarboxylate (23a):
yield: 55.0 mg (82%); yellow solid; mp 60.0–61.08C;
1H NMR (400 MHz, CDCl3): d=1.35 (t, J=7.2 Hz, 6H),
1.82 (tt, J=5.6, 6.0 Hz, 2H), 3.56 (t, J=6.0 Hz, 2H), 3.96 (t,
J=5.6 Hz, 2H), 4.37 (q, J=7.2 Hz, 6H), 7.41–7.46 (m, 3H),
7.50–7.53 (m, 2H); 13C NMR (100 MHz, CDCl3): d=14.0
(CH3), 23.9 (CH2), 44.6 (CH2), 62.7 (CH2), 64.3 (CH2), 88.8
(C), 127.3 (CH), 128.6 (CH), 130.5 (CH), 134.7 (C), 165.2
(C), 172.0 (C); IR (NaCl): n=1659, 1747 cmÀ1; HR-MS
(ESI-TOF): m/z=336.1458, calcd. for C17H22NO6 [M+H]+:
336.1442.
Diethyl 3-acetyl-1,3-oxazinane-2,2-dicarboxylate (23f):
yield: 42.6 mg (78%); yellow viscous liquid; 1H NMR
(400 MHz, CDCl3): d=1.33 (t, J=7.2 Hz, 3H), 1.33 (t, J=
7.2 Hz, 3H), 1.91 (tt, J=5.6, 6.0 Hz, 2H), 2.14 (s, 3H), 3.57
(t, J=6.0 Hz, 2H), 3.87 (t, J=5.6 Hz, 2H), 4.31 (q, J=
7.2 Hz, 2H), 4.32 (q, J=7.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=14.0 (CH3), 21.9 (CH3), 23.4 (CH2), 42.6 (CH2),
62.6 (CH2), 63.7 (CH2), 88.6 (C), 165.3 (C), 171.5 (C); IR
(NaCl): n=1647, 1747 cmÀ1; HR-MS (ESI-TOF): m/z=
274.1277, calcd. for C12H20NO6 [M+H]+: 274.1285.
´
Mazurkiewicz, A. Pazdzierniok-Holewa, J. Adamek, K.
´
Zielinska, Adv. Heterocycl. Chem. 2014, 111, 43–94;
d) A. E. Schneider, G. Manolikakes, J. Org. Chem.
À
2015, 80, 6193–6212. One-pot amidoalkylation with C
C bond formation via N-acylimies as intermediate, see:
e) Q. Xiao, P. E. Floreancig, Org. Lett. 2008, 10, 1139–
1142; f) M. V. DeBenedetto, M. E. Green, S. Wan, J.-H.
Park, P. E. Floreancig, Org. Lett. 2009, 11, 835–838;
g) C. Lu, Q. Xiao, P. E. Floreancig, Org. Lett. 2010, 12,
5112–5115.
[7] Recent examples of the synthesis of N,O-acetals, see:
a) S. Wan, M. E. Green, J.-H. Park, P. E. Floreancig,
Org. Lett. 2007, 9, 5385–5388; b) M. Li, B. Luo, Q. Liu,
Y. Hu, A. Ganesan, P. Huang, S. Wen, Org. Lett. 2014,
16, 10–13; c) J. Halli, K. Hofman, T. Beisel, G. Manoli-
kakes, Eur. J. Org. Chem. 2015, 4624–4627.
[8] Recent examples of N,O-acetals as a precursor of N-
acylimines, see: a) Z.-R. Li, Y.-X. Zhang, W.-P. Tu, B.-
L. Yin, Synlett 2011, 2977–2980; b) Y.-Y. Huang, A.
Chakrabarti, N. Morita, U. Schneider, S. Kobayashi,
Angew. Chem. 2011, 123, 11317–11320; Angew. Chem.
Int. Ed. 2011, 50, 11121–11124; c) K. Komeyama, T.
Yamada, R. Igawa, K. Takaki, Chem. Commun. 2012,
48, 6372–6374; d) M. Hamon, N. Dickinson, A. Devi-
neau, D. Bolien, M.-J. Tranchant, C. Taillier, I. Jabin,
D. C. Harrowven, R. J. Whitby, A. Ganesan, V. Dalla,
J. Org. Chem. 2014, 79, 1900–1912; e) M. Michalska, O.
Songis, C. Taillier, S. P. Bew, V. Dalla, Adv. Synth.
Catal. 2014, 356, 2040–2050.
[9] For 3,3,3-trifluoro-2-oxopropanoates, see: a) E. Dessi-
pri, D. A. Tirrell, Macromolecules 1994, 27, 5463–5470;
b) A. Y. Aksinenko, N. Pushin, A. V. B. Sokolov, Russ.
Chem. Bull. 2002, 51, 2136–2138; c) H. Skarpos, D. V.
Vorob’eva, S. N. Osipov, I. L. Odinets, E. Breuer, G.-V.
Rçschenthaler, Org. Biomol. Chem. 2006, 4, 3669–
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propanoates, see: e) D. Matthies, I. Malassa, Synthesis
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[10] a) W. Steglich, K. Burger, M. Durr, E. Burgis, Chem.
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Gertitschke, J. Fluorine Chem. 1985, 27, 327–332.
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111, 247–248; b) B. H. Lee, A. Biswas, M. J. Miller, J.
Org. Chem. 1986, 51, 106–109.
References
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[15] CCDC 1446784 and CCDC 1446786 (13a and 16a) con-
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Direct Synthesis of N-Acyl-N,O-hemiacetals via
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Nucleophilic Addition of Unactivated Amides and Their O-
Acetylation: Access to a,a-Difunctionalized N-Acylimines
Adv. Synth. Catal. 2016, 358, 1 – 13
Haruyasu Asahara,* Kanami Inoue, Shinki Tani,
Kazuto Umezu, Nagatoshi Nishiwaki*
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