An Unconventional Reaction of 2,2-Diazido Acylacetates with Amines

Article abstract of DOI:10.1002/ejoc.201601625

We have discovered that 2,2-diazido acylacetates, a class of compounds with essentially unknown reactivity, can be coupled to amines through a new strategy that does not involve any reagents. 2,2-Diazido acetate is the unconventional leaving group under carbon–carbon bond cleavage. This reaction leads to the construction of amide bonds, tolerates various functionalities and is performed equally well in numerous solvents under experimentally simple conditions. We also demonstrate that the isolation of the 2,2-diazido acylacetate compounds can be circumvented: Acylacetates were easily fragmented when treated with (Bu₄N)N₃ and iodine in the presence of an amine at room temperature. By using this method, a broad range of acylacetates with various structural motifs were directly transformed into amides.

Full text of DOI:10.1002/ejoc.201601625

DOI: 10.1002/ejoc.201601625
Full Paper
Diazide Chemistry
An Unconventional Reaction of 2,2-Diazido Acylacetates with
Amines
Andreas P. Häring,[a] Phillip Biallas,[a] and Stefan F. Kirsch*[a]
Abstract: We have discovered that 2,2-diazido acylacetates, a vents under experimentally simple conditions. We also demon-
class of compounds with essentially unknown reactivity, can be strate that the isolation of the 2,2-diazido acylacetate com-
coupled to amines through a new strategy that does not in- pounds can be circumvented: Acylacetates were easily frag-
volve any reagents. 2,2-Diazido acetate is the unconventional mented when treated with (Bu4N)N3 and iodine in the presence
leaving group under carbon–carbon bond cleavage. This reac- of an amine at room temperature. By using this method, a
tion leads to the construction of amide bonds, tolerates various broad range of acylacetates with various structural motifs were
functionalities and is performed equally well in numerous sol- directly transformed into amides.
Introduction
tion conditions does not require the isolation of organic diazide
compounds and maintains its compatibility with a diverse array
of dicarbonyl substrates.
Geminal diazides have received very little attention in chemical
sciences:[1,2] Only a small number of synthesis methods have
been described since their first appearance in 1908,[3,4] and ap-
plications remain rare.[5] The thermal[6] and photochemical[7]
degradation of this functionality was studied, and the omni-
present cycloaddition with alkynes was also attempted.[8,4c–4e]
Based on our recent studies with geminal diazides,[4c,4d,8b,49] we
now report the general fragmentation shown in Scheme 1a.
The method uses 2,2-diazido acylacetates 1 as unconventional
acyl donors and leads to the direct formation of amides 3
through reaction with amines 2. The unprecedented activating
influence of azido groups on adjacent carbonyl moieties leads
to cleavage of the carbon–carbon bond between C2 and C3
in the course of the amide bond formation, and 2,2-diazido
acetate[3,10] becomes a unique leaving group. This reactivity
was not described before; it loosely resembles a retro-Claisen
reaction wherein typically harsh reaction conditions with strong
Lewis-acid additives and high temperatures are required.[11] Our
acyl transfer, however, occurs at room temperature under ex-
perimentally simple conditions in a great range of solvents and,
in most cases, without the need for additional reagents. Prelimi-
nary studies suggest an excellent chemoselectivity, and numer-
ous coexisting functional groups are tolerated, thus expanding
the potential utility of this transformation tremendously. We
also report a convenient variant that facilitates the direct reac-
tion of acylacetates 4 with primary amines (Scheme 1b). This
straightforward formation of amide bonds through the oxid-
ative in situ diazidation of acylacetates under metal-free reac-
Scheme 1. Concept: fragmentation of 2,2-diazido acylacetates 1 and acyl-
acetates 4 with amines 2.
The ability to create amide bonds is an area of ongoing im-
portance in synthetic chemistry and chemical biology with ap-
plications that span proteins, pharmaceuticals and functional
materials.[12,13] The standard way to approach amide bond for-
mation in the laboratory is the condensation of an amine with
a carboxylic acid via an active ester.[14] Despite the omnipres-
ence of this strategy, chemists have, in the context of pursuing
new amide bond-forming methods, compiled a great reaction
compendium of amide bond-forming methods.[15] Unlike the
many existing reactions, we now add acylacetates (or rather
their diazidated congeners) to the broad group of reliable pre-
cursors for the construction of amides, a strategy that may find
considerable use as a tool for the fragmentation of small mol-
ecules.[16,17] Our new bond fission methodology is a somewhat
rare but powerful synthetic option to afford the controlled
breakdown of acylacetates into acylamides through aminolysis
and carbon–carbon bond cleavage.[18,19]
[a] Organic Chemistry, Bergische Universität Wuppertal,
Gaußstraße 20, 42119 Wuppertal, Germany
E-mail: sfkirsch@uni-wuppertal.de
http://www.oc.uni-wuppertal.de/prof-dr-stefan-f-kirsch.html
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under http://dx.doi.org/10.1002/ejoc.201601625.
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Results and Discussion
96:4, and the isolated chemical yield of 3aa was high. The acyl-
ation of amines with diazido acylacetates appears to be a sub-
stitution in which attack of the substituting amine at the carb-
onyl carbon is followed by elimination of the diazido acetate.
In the case of the formation of 3aa from 1a, we unequivocally
observed the stoichiometric evolution of tert-butyl 2,2-diazido-
The Fragmentation of 2,2-Diazido Acylacetates with
Amines
Our studies began with the observation that treatment of ethyl
2,2-diazidoacetoacetate (1a;[1] R3 = OEt) with benzylamine (2a)
in benzene at 23 °C provided both N-acetyl benzylamine (3aa)
and ethyl N-benzyl carbamate in a 89:11 ratio, with 3aa being
the major product, as indicated by the 1H NMR spectrum of the
crude mixture (Scheme 2a). By simply switching to sterically
more demanding tert-butyl 2,2-diazidoacetoacetate (1a), the ra-
tio between amide and carbamate formation was improved to
1
acetate (6) based on H NMR spectroscopic analysis, and this
compound was also isolated in 70 % yield in pure form
(Scheme 2b).[3,10] Given that azido groups are known for their
electron-withdrawing character,[20] we also assessed whether
the acylation could be rendered possible by the choice of other
electronegative substituents. Through the use of ethyl 2,2-di-
fluorobenzoylacetate (7), for example, the direct benzoylation
of benzylamine was not observed (Scheme 2c). Instead of C–C
bond cleavage, C–O bond cleavage was favoured, providing
amide 8, as reported before,[21] which underlines the unique
reactivity of 2,2-diazido acylacetates with amines.
Encouraged by the ability of 2,2-diazido acetoacetates to
transfer the acetyl group onto amines, we studied this reaction
using various solvents, and the reaction of 1a was selected as
a model (Table 1). Almost equimolar amounts of diazide 1a and
benzylamine (2a) produced the desired product 3aa in good
yields in an attractive collection of standard solvents including
benzene, tetrahydrofuran (THF), isopropanol (iPrOH), dimethyl
sulfoxide (DMSO) and N-methyl-2-pyrrolidinone (NMP) (entries
1–6). Branched amines gave similar reactivity profiles with some
reduction in yield. For example, reaction of 1a with 1-cyclo-
hexylethylamine (2b; 1.1 equiv.) in benzene gave amide 3ab in
a yield of 56 % (entry 7). We were pleased to find, however, that
coupling of substrate 1a with 2b (2 equiv.) gave a high yield
(entry 8), and further tests showed that even in THF, DMA,
DMSO, N,N-dimethylformamide (DMF), MeCN, and EtOAc, prod-
Scheme 2. Initial experiments on the reaction of 2,2-diazido 1,3-dicarbonyl
compounds with primary amines: (a) Influence of the substituents. Ratio 3aa/
5 determined by 1H NMR spectroscopic analysis of the crude mixture; yields
of the isolated compounds after column chromatography. (b) Proposed
mechanism. (c) Reaction of ethyl 2,2-difluorobenzoylacetate with benzyl-
amine.
Table 1. Reaction optimization and robustness toward solvent effects.[a]
No.
Substrate 2
#
Solvent
Additive
Product 3
Yield [%][b]
R2
Equiv.
1
2
3
4
5
6
2a
CH2Ph
1.1
1.1
1.1
1.1
1.1
1.1
THF
3aa
71
74
64
71
58
71
iPrOH
CHCl3
DMSO
DMF
NMP
7
8
9
10
11
12
13
14
2b
CH(Me)(Cy)
1.1
2.0
2.0
2.0
2.0
2.0
2.0
2.0
benzene
benzene
THF
DMSO
DMF
MeCN
EtOAc
DMA
3ab
56
84
87
71
79
76
86
81
15
2c
Cy
1.1
1.1
1.1
THF
THF
THF
3ac
54
75
82
16
Cs2CO3
DBU
17[c]
[a] Reaction conditions: 1a, 2, room temp., solvent (0.5
M), 4–12 h. [b] Isolated yield after column chromatography. [c] Reaction at 50 °C.
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uct formation occurred smoothly (entries 9–14). Our tests also
showed that, with no more than 1.1 equiv. of amine, the desired
amide was more cleanly formed by using base additives. As
exemplified for the acetylation of cyclohexylamine (2c), the
yield of the reaction in THF was markedly improved when the
reaction was conducted in the presence of Cs2CO3 or 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) (entries 16 and 17). We
conclude that the acylation of amines with 2,2-diazido acyl-
acetates is rather robust toward variations in solvent polarity,
and the addition of bases has further potential to create high
yields, even when using the more sterically demanding amines.
Having determined the possible reaction conditions, we be-
gan to examine the scope of the transformation with respect
to the diazide substrate (Scheme 3). For this study, we chose to
utilise 2.0 equiv. of 1-phenylethylamine (2d) as the nucleophile
without further additives; this amine was one of the lowest
yielding under the reaction conditions, and we felt it could
serve as a convenient benchmark to demonstrate the capability
of the amide bond-forming reaction. In addition to the acetyl
donor 1a, a range of benzoyl donor substrates containing the
electron-donating methoxy or methyl substituents or the chlor-
ide substituent gave excellent yields. Beyond the use of phenyl
substrates, furan compound 1f readily coupled with 2d. Fur-
thermore, the reaction tolerated the presence of olefins (3id),
ethers (3jd), esters (3kd), silylethers (3ld), alkyl azides (3md),
and unprotected alcohols (3nd and 3ne). We found that the
hindered amine 2d was a poor partner for diazides with bulky
alkyl groups, thus resulting in rather low yields for the amides
3od, 3pd and 3qd. In contrast, incorporation of n-octylamine
(2e) was no problem under the standard conditions, converting
the challenging diazides into their amides 3oe–qe in good
yields.
Scheme 3. The scope of the reaction leading to amide formation was evalu-
ated with respect to the diazide substrate. Reagents and conditions: 1, 2d or
2e (2.0 equiv.), room temp., THF (0.5 M), 12 h.
THF whereby only 1.1 equiv. of amine 2 was used, without any
additives (method A), or with Cs2CO3 (method B) or DBU
(method C). Synthetically useful yields of product were typically
A variety of amines were also surveyed, as shown in obtained with each of the three methods. In most cases, the
Scheme 4. To this end, we examined the reaction conditions in benzoylation of amines with diazide 1b gave somewhat higher
Scheme 4. The scope of the amide formation was evaluated with respect to the amine substrate.[a] Reagents and conditions: (Method A) 1, 2 (1.1 equiv.),
room temp., THF (0.5 M); (Method B) 1, 2 (1.1 equiv.), Cs2CO3 (2.0 equiv.), room temp., THF (0.5 M); (Method C) 1, 2 (1.1 equiv.), DBU (1.0 equiv.), 50 °C, THF
[b]
[c]
[d]
[e]
(0.5
M
). Isolated yield after column chromatography. Reaction was performed in DMF. Experiment was not performed. Compound 2 (3 equiv.) was
used.
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yields than the acetylation with diazide 1a, and we could not tests on how our protocols[4c,9] for diazidation can be combined
identify any major limitations. Primary amines, such as benzylic with the acylation of amines. To this end, acylacetate 4a was
amines (3aa–bh) and aliphatic amines (3ae–bb) coupled oxidised first in the presence of IBX-SO3K,[27] sodium iodide,
smoothly to produce the corresponding amides. Compatibility sodium azide, and benzylamine (2a). However, amide formation
of the reaction with olefins, alkynes, acetals, and carbamate- was not detected under various reaction conditions, and further
protected amines was demonstrated by the reactions of amines experiments were performed with iodine as the oxidative
2k–n. 1-Amino-2-indanol could be used with no need to block agent,[9] instead of the IBX-SO3K/NaI couple. We then realised
the free hydroxyl (3ao and 3bo). We found that phenol was that the reaction required water-free conditions because all at-
tolerated in the methodology (3ap and 3bp), in addition to an tempts using aqueous DMSO failed. Gratifyingly, THF was found
indole-containing moiety (3aq and 3bq). The amide products to be the solvent of choice, and it became mandatory to em-
were also formed with more hindered secondary amines (3ar– ploy tetrabutylammonium azide as the azide source instead of
bs), albeit with markedly reduced yields when using method A sodium azide, which did not dissolve in pure THF and remained
(i.e., no base additives). As expected, aniline (and various deriva- unreactive. It was also possible to run the reaction in DMSO,
tives thereof) did not undergo the amide formation in the ab- benzene, or dichloromethane. Amide 3aa was formed in 71 %
sence of bases (method A), and yields were low even in the yield by using the optimal conditions: acetylacetate 1a
presence of bases (3bt), a feature that allows for selective amide (1.0 equiv.), (nBu4N)N3 (4.0 equiv.), Et3N (4.0 equiv.), I2
bond formation with aliphatic amines in the presence of aro- (2.2 equiv.), benzylamine (2.0 equiv.), room temp., THF (0.15 M).
matic amines. As demonstrated for amides 3du and 3tv, a com-
plex cinchona alkaloid-derived primary amine 2u with two nu-
cleophilic nitrogen atoms and glucosamine (2v), respectively,
also underwent the desired amide bond formation in good
yields without protecting group chemistry; in the latter case,
DMF was the solvent of choice.
With the optimised conditions in hand, we briefly examined
the scope of the direct acylation of amines with acylacetates.
First, the reaction of tert-butyl acetylacetate (4a) with several
amines was tested, as summarised in Scheme 5. A range of
primary amines gave the corresponding acetyl amides 3, and
the reaction was compatible with various functional groups.
Next, the methodology was evaluated with respect to the scope
of the acylacetate partner. Scheme 6 shows that aliphatic and
aromatic compounds could be used as substrates to generate
the expected amides with benzylamine in 18–74 % yield
through acylacetate fragmentation. Also in these cases, the
functional group tolerance was promising because acylacetates
having, for example, pyridine units and tertiary hydroxyls were
smoothly converted.
The Oxidative Carbon–Carbon Bond Cleavage of
Acylacetates with Amines
All 2,2-diazido acylacetates 1 were generated through the ex-
perimentally simple diazidation of the acylacetates with iodine
and sodium azide in aqueous DMSO, as previously reported by
us.[9] We point out that diazide compounds of type 1 were
shown to be reasonably stable at room temperature (up to
150 °C in most cases), and gram-scale quantities were readily
accessible. Nevertheless, diazides should be considered poten-
tially hazardous and handled accordingly due to their high nitro-
gen content.[22,23]
Given the safety issues, we felt that this new amide-forming
method will appear less attractive to synthetic chemists. One
might hesitate to isolate and employ the diazides 1 although
they represent a powerful alternative to the existing acylation
agents, as discussed above. With these considerations in mind,
we aimed to develop an advantageous protocol that allows for
the direct conversion of acylacetates 4 into amides 3, without
the need to isolate the diazide intermediates (Scheme 1b).
The controlled degradation of the acylacetate core providing
synthetically useful building blocks is surprisingly underdevel-
oped. The retro-Claisen reaction is the textbook fragmentation
of acylacetates, typically involving alcohol nucleophiles under
strongly basic conditions to trigger the desired carbon–carbon
bond cleavage, and several synthetic applications can be
found.[24] Alternative methods were reported that make use of
Lewis acid catalysts and high temperatures.[10,25] However, only
a small number of examples describe retro-Claisen variants in
which amine nucleophiles were employed, most of which rely
on arguably harsh reaction conditions.[26]
To develop a mild method for the direct fragmentation of
acylacetates with primary amines, we started our study with
Scheme 5. Fragmentation of tert-butyl acetylacetate with amines.
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retro-Claisen reaction became possible through the combina-
tion of the aminolysis of 2,2-diazido acylacetates with the
oxidative diazidation of acylacetates, in a straightforward one-
step manner. Of paramount importance, the controlled disinte-
gration of the acylacetate system with primary amines does not
require the isolation of any diazido compounds. We expect to
expand this concept to additional reactions in which the gener-
ation of diazido compounds in situ is used to trigger a nucleo-
philic bond cleavage, in the near future. Studies on the mecha-
nism of fragmentation are ongoing.
Experimental Section
General Remarks: Caution: We underline that geminal diazides 1
are potentially hazardous chemicals that should be handled with
care. Diazido acetates (e.g., 6), with their high nitrogen content,
although not studied in detail, are also potentially hazardous com-
pounds, especially when accumulated during the work-up of large-
scale experiments. To this end, we carefully examined a range of
work-up conditions with the goal to completely remove the di-
azido-containing side products from the organic phases to be con-
centrated and purified. It was found that upon simple stirring of
the reaction mixture with a saturated solution of Na2S2O3 in water
at room temperature for 30 min, no trace of the 2,2-diazidoacetate
6 could be detected in the organic phase. These practical work-
up conditions were applied to all the experiments with more than
0.25 mmol of diazido acylacetates. In the case of the smaller scale
reactions, the crude mixtures were, upon complete conversion of
Scheme 6. Fragmentation of tert-butyl acylacetates with benzylamine.
When the reaction conditions were applied to cyclic acyl-
acetates, new possibilities opened up. For example, dihydro-2H-
pyran-2,4(3H)dione 9 was smoothly transformed into acryl-
amide 10 through treatment with benzylamine in the presence
of iodine and azide anions (Scheme 7). This high-yielding de-
gradation of 4-oxovalerolactones is unique; we are not aware
of related one-step reactions for synthesis on a laboratory scale.
We assume that the initial diazidation (→A) results in the
carbon–carbon bond cleavage (→B) and subsequent elimina-
tion. Further ring-opening applications are under investigation diazides 1, directly submitted to purification through column chro-
matography, and the fractions containing 6 were combined,
and will be reported in due course.
brought to pH 14 with aqueous NaOH (1
N) and discarded without
concentration.
General Procedures
Synthesis of 2,2-Diazido Acylacetates 1: The synthesis of 2,2-di-
azido acylacetates 1a–s was published recently.[9]
General Procedure A for the Synthesis of Amides 3 from 2,2-
Diazido Acylacetates 1: A solution of the corresponding amine 2
(1.10 equiv.) in THF (0.50
M) was added to the 2,2-diazido acyl-
acetate 1 and the mixture was stirred overnight at room tempera-
ture. The mixture was purified by chromatography over silica.
General Procedure B for the Synthesis of Amides 3 from 2,2-
Diazido Acylacetates 1: Cs2CO3 (2.00 equiv.), followed immediately
by a solution of the corresponding amine 2 (1.10 equiv.) in THF
Scheme 7. Conversion of 4-oxovalerolactone 5. 4-PPY = 4-pyrrolidinopyridine.
(0.50 ), were added to the 2,2-diazido acylacetate 1 and the mix-
M
ture was stirred overnight at room temperature. The mixture was
purified by chromatography over silica.
General Procedure C for the Synthesis of Amides 3 from 2,2-
Diazido Acylacetates 1: A solution of the corresponding amine 2
Conclusions
We have discovered a new reactivity between 2,2-diazido
acylacetates and primary amines that results in a nonconven-
tional amide synthesis. The reagent-free conditions are opera-
tionally simple (i.e., open flask, room temperature) and have
been shown to accommodate a range of diazides and amines.
This use of 2,2-diazido acylacetates shows potential for future
exploration and may ultimately find new applications for azide-
containing small molecules, apart from the ubiquitous cyclo-
addition with alkynes.
(1.10 equiv.) and DBU (1.00 equiv.) in THF (0.50
M) was added at
50 °C to the 2,2-diazido acylacetate 1, and the mixture was stirred
at 50 °C overnight. The mixture was purified by chromatography
over silica.
General Procedure D for the Synthesis of Amides 3 from 2,2-
Diazido Acylacetates 1: A solution of the corresponding amine 2
(2.00 equiv.) in THF (0.50 M) was added to the 2,2-diazido acylace-
tate 1 and the mixture was stirred overnight at room temperature.
The mixture was purified by chromatography over silica.
We also described a powerful synthetic application of this
General Procedure E for the Synthesis of Amides 3 from Acyl-
carbon–carbon bond cleavage reaction. A mild version of the acetates 4: Acylacetate (4; 1.00 equiv.), tetrabutylammonium azide
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(4.00 equiv.), triethylamine (4.00 equiv.) and amine (2; 4.00 equiv.)
were dissolved in THF (0.15 ), and iodine (2.20 equiv.) was added
at room temperature. The reaction mixture was stirred overnight at
room temperature. Flash-chromatography furnished the corre-
sponding amides 3.
(0.008 g, 0.03 mmol, 0.20 equiv.) and phenylacetylene (0.04 mL,
0.035 g, 0.33 mmol, 2.20 equiv.) were added. The suspension was
stirred for 5 h. Water was added, and the mixture was extracted
with MTBE. The organic phase was dried with MgSO4 and evapo-
rated in vacuo. The residue was purified by chromatography over
silica (PE/EtOAc, 95:5 → 1:1) to give tert-butyl 2,2-bis(4-phenyl-1H-
1,2,3-triazol-1-yl)acetate (6′; 0.053 g, 87 %) as a white solid. Rf (PE/
M
Experimental Details
tert-Butyl 2,2-Diazido-3-[3-(octyloxy)phenyl]-3-oxopropanoate
(1t): To tert-butyl 3-[3-(octyloxy)phenyl]-3-oxopropanoate (0.959 g,
EtOAc, 8:2) = 0.19 [UV]. IR: ν = 3128, 3097, 3063, 3051, 3035, 2975,
˜
2953, 2928, 2872, 2853, 1751, 1650, 1612, 1557, 1484, 1454, 1428,
1393, 1369, 1355, 1324, 1304, 1289, 1260, 1244, 1235, 1213, 1194,
1178, 1151, 1077, 1069, 1038, 1023, 973, 957, 920, 911, 863, 847,
2.75 mmol, 1.00 equiv.) in DMSO (18.3 mL, 0.15
M) and H2O (9.2 mL,
0.30 ), NaN3 (1.073 g, 16.51 mmol, 6.00 equiv.) and I2 (1.537 g,
M
1
819, 794, 765, 725, 707, 693, 598, 522, 506, 468, 434, 421 cm–1. H
6.05 mmol, 2.20 equiv.) were added. The solution was stirred for
3.5 h. Further NaN3 (1.073 g, 16.51 mmol, 6.00 equiv.) was added
and the solution was stirred for 3 h. A saturated aqueous solution
of Na2S2O3 was added and the solution was diluted with H2O. The
mixture was extracted with EtOAc. The organic phase was dried
with MgSO4 and evaporated in vacuo. The residue was purified by
chromatography over silica (PE → PE/EtOAc, 95:5) to give a mixture
of starting material and 1t. The mixture was once again dissolved
NMR (400 MHz, CDCl3): δ = 8.27 (s, 2 H), 7.88–7.82 (m, 4 H), 7.65 (s,
1 H), 7.46–7.39 (m, 4 H), 7.38–7.32 (m, 2 H), 1.53 (s, 9 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 160.9, 148.8, 129.7, 129.1, 128.9, 126.1,
120.5, 87.1, 71.4, 27.9 ppm. LRMS (ESI): m/z = 425 (20) [M + Na+],
403 (100) [M + H+]. HRMS (ESI): m/z calcd. for C22H23N6O2
:
+
403.1877; found 403.1872.
N-Benzyl-2,2-Difluoro-3-oxo-3-phenylpropanamide (8): To ethyl
2,2-difluoro-3-oxo-3-phenylpropanoate (7; 0.030 g, 0.13 mmol,
1.00 equiv.), a solution of benzylamine (2a; 0.028 g, 0.26 mmol,
in DMSO (18.3 mL, 0.15
M) and H2O (9.2 mL, 0.30 M) and NaN3
(1.073 g, 16.51 mmol, 6.00 equiv.), I2 (1.537 g, 6.05 mmol,
2.20 equiv.) and TBAI (0.051 g, 0.14 mmol, 0.05 equiv.) were added.
The solution was stirred for 9 h. A saturated aqueous solution of
Na2S2O3 was added and the solution was diluted with H2O. The
mixture was extracted with EtOAc. The organic phase was dried
with MgSO4 and evaporated in vacuo. The residue was purified by
chromatography over silica (PE → PE/EtOAc, 95:5) to give tert-butyl
2,2-diazido-3-[3-(octyloxy)phenyl]-3-oxopropanoate (1t; 0.712 g,
60 %) as a colourless liquid. Rf (PE/EtOAc, 95:5) = 0.45 [KMnO4]. IR:
2.00 equiv.) in THF (0.26 mL, 0.50
M) was added. The solution was
stirred for 3 d. The solution was purified by chromatography over
silica (PE/EtOAc, 9:1 → 1:1) to give N-benzyl-2,2-difluoro-3-oxo-3-
phenylpropanamide (8; 0.036 g, 95 %) as a white solid. Rf (PE/EtOAc,
8:2) = 0.39 [KMnO4]. IR: ν = 3313, 3068, 3036, 2951, 2927, 2856,
˜
1708, 1682, 1596, 1580, 1543, 1495, 1451, 1435, 1395, 1357, 1324,
1310, 1273, 1239, 1204, 1155, 1133, 1102, 1041, 1029, 1011, 975,
935, 922, 902, 822, 805, 753, 729, 705, 683, 667, 606, 580, 526, 489,
ν = 3077, 2928, 2857, 2124, 1751, 1705, 1597, 1580, 1487, 1470,
˜
449, 423 cm–1 1H NMR (400 MHz, CDCl3): δ = 8.17–8.09 (m, 2 H),
.
1458, 1438, 1396, 1372, 1290, 1257, 1237, 1201, 1147, 1049, 998,
7.69–7.62 (m, 1 H), 7.54–7.46 (m, 2 H), 7.39–7.23 (m, 6 H), 6.86 (s, 1
H), 4.53 (d, J = 6.1 Hz, 2 H) ppm. 13C NMR: δ = 187.4 (t, J = 27.2 Hz),
161.6 (t, J = 27.5 Hz), 136.5, 135.0, 131.8 (t, J = 1.6 Hz), 130.5 (t, J =
2.9 Hz), 129.0, 128.9, 128.2, 128.0, 111.0 (t, J = 265.7 Hz), 44.0 ppm.
LRMS (EI): m/z = 289 (2) [M+], 105 (100) [PhCO+], 91 (54) [C7H7+], 77
(85) [Ph+]. HRMS (ESI): m/z calcd. for C16H13F2NO2Na+: 312.0807;
found 312.0803.
1
945, 899, 830, 773, 751, 723, 682, 618, 547, 481, 468, 443 cm–1. H
NMR (400 MHz, CDCl3): δ = 7.59 (ddd, J = 7.7, 1.7, 0.9 Hz, 1 H), 7.54–
7.52 (m, 1 H), 7.38–7.32 (m, 1 H), 7.14 (ddd, J = 8.3, 2.6, 1.0 Hz, 1
H), 3.99 (t, J = 6.5 Hz, 2 H), 1.84–1.74 (m, 2 H), 1.51–1.41 (m, 2 H),
1.38 (s, 9 H), 1.37–1.24 (m, 8 H), 0.89 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 186.8, 163.8, 159.5, 133.5, 129.8, 122.2,
121.8, 114.5, 86.7, 83.2, 68.5, 32.0, 29.5, 29.4, 29.3, 27.7, 26.1, 22.8,
14.2 ppm. LRMS (ESI): m/z = 397 (80) [M – tBu + Na+], 289 (85)
N-Benzylacetamide (3aa): By following general procedure A
[M – CO2tBu-N3 + H+], 266 (100). HRMS (ESI) m/z calcd. for (0.022 g, 71 %), B (0.027 g, 87 %), C (0.027 g, 87 %) or E (0.033 g,
C21H30N6O4Na+: 453.2221; found 453.2222.
71 % starting from 0.050 g of tert-butyl acetoacetate 4a), N-benzyl-
acetamide (3aa) was obtained as a white solid after chromatogra-
phy (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/MeOH, 95:5) =
0.31 [KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 7.39–7.16 (m, 5 H),
6.20 (s, 1 H), 4.37 (d, J = 5.7 Hz, 2 H), 1.97 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 170.1, 138.4, 128.7, 127.9, 127.5, 43.7,
23.2 ppm. The analytical data are in agreement with previously re-
ported data.[28]
tert-Butyl 2,2-Diazidoacetate (6): To tert-butyl 2,2-diazido-3-oxo-
butanoate (1a; 0.500 g, 2.08 mmol) in benzene (5.4 mL, 0.20
M), a
solution of benzylamine (2a; 0.270 g, 2.50 mmol, 1.20 equiv.) in
benzene (5.0 mL) was added. The resulting suspension was stirred
for 23 h. Further benzylamine (2a; 0.270 g, 2.50 mmol, 1.20 equiv.)
was added and the suspension was stirred for 3 h. The suspension
was evaporated in vacuo and the residue was purified by chroma-
tography over silica (PE → EtOAc/iPrOH, 8:2) to give tert-butyl 2,2-
diazidoacetate (6; 0.290 g, 70 %) as a colourless liquid and N-benz-
ylacetamide (3aa; vide infra, 0.278 g, 90 %) as a white solid. Rf (PE/
N-(1-Cyclohexylethyl)acetamide (3ab): By following general pro-
cedure A (0.019 g, 54 %), B (0.022 g, 62 %) or C (0.026 g, 74 %), N-
(1-cyclohexylethyl)acetamide (3ab) was obtained as a white solid
after chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/
MeOH, 95:5) = 0.43 [KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 5.40 (s,
1 H), 3.83 (dp, J = 9.1, 6.7 Hz, 1 H), 1.95 (s, 3 H), 1.78–1.58 (m, 5 H),
1.34–1.07 (m, 4 H), 1.05 (d, J = 6.8 Hz, 3 H), 1.04–0.87 (m, 2 H) ppm.
EtOAc, 9:1) = 0.60 [KMnO ]. IR: ν = 2983, 2932, 2873, 2857, 2103,
˜
4
1746, 1478, 1458, 1396, 1371, 1351, 1293, 1211, 1147, 978, 918, 838,
807, 763, 736, 557, 468, 435 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
4.71 (s, 1 H), 1.54 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 164.0,
85.1, 73.9, 27.9 ppm. LRMS (EI): m/z = 155 (1) [(M – HN3)+], 97 (20) 13C NMR (101 MHz, CDCl3): δ = 169.4, 49.5, 43.2, 29.2, 29.1, 26.5,
[CHN6+], 57 (100) [tBu+].
26.3, 26.3, 23.7, 18.0 ppm. The analytical data are in agreement with
previously reported data.[29]
As direct HRMS was not possible, tert-butyl 2,2-diazidoacetate (6)
was converted into its bistriazole derivative 6′: To tert-butyl 2,2-
diazidoacetate (6; 0.030 g, 0.15 mmol) in a 2:1 mixture of tBuOH
N-Cyclohexylacetamide (3ac): By following general procedure A
(0.016 g, 54 %), B (0.022 g, 75 %), C (0.024 g, 82 %) or E (0.022 g,
(0.6 mL, 0.25
(0.012 g, 0.06 mmol, 0.40 equiv.), tris[(1-benzyl-1H-1,2,3-triazol-4- amide (3ac) was obtained as a white solid after chromatography
yl)methyl]amine (0.001 g, 1.5 μmol, 0.01 equiv.), CuSO4·5H2O (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/MeOH, 95:5) = 0.27
M) and H2O (0.3 mL, 0.5 M), (+)-sodium L-ascorbate 49 % using 0.050 g of tert-butyl acetoacetate 4a), N-cyclohexylacet-
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1
[KMnO4]. H NMR (400 MHz, CDCl3): δ = 5.40 (s, 1 H), 3.81–3.67 (m,
21.7 ppm. The analytical data are in agreement with previously re-
ported data.[32]
1 H), 1.94 (s, 3 H), 1.93–1.86 (m, 2 H), 1.74–1.65 (m, 2 H), 1.65–1.55
(m, 1 H), 1.43–1.28 (m, 2 H), 1.21–1.03 (m, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 169.2, 48.4, 33.4, 25.7, 25.0, 23.7 ppm. The
analytical data are in agreement with previously reported data.[30]
N-(4-Phenylbutyl)acetamide (3ai): By following general procedure
A (0.028 g, 70 %), B (0.033 g, 83 %), C (0.032 g, 80 %) or E (0.034 g,
57 % using 0.050 g of tert-butyl acetoacetate 4a), N-(4-phenyl-
butyl)acetamide (3ai) was obtained as a white solid after chroma-
tography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/MeOH,
N-(1-Phenylethyl)acetamide (3ad): By following general proce-
dure A (0.021 g, 62 %), B (0.022 g, 65 %), C (0.027 g, 79 %), D
(0.030 g, 88 %) or E (0.036 g, 70 % using 0.050 g of tert-butyl aceto-
acetate 4a), N-(1-phenylethyl)acetamide (3ad) was obtained as a
white solid after chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH,
8:2). Rf (DCM/MeOH, 95:5) = 0.42 [KMnO4]. 1H NMR (400 MHz,
CDCl3): δ = 7.37–7.28 (m, 4 H), 7.28–7.22 (m, 1 H), 5.95 (s, 1 H), 5.16–
5.06 (m, 1 H), 1.96 (s, 3 H), 1.47 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 169.2, 143.3, 128.8, 127.4, 126.3, 48.9, 23.5,
21.8 ppm. The analytical data are in agreement with previously re-
ported data.[29]
95:5) = 0.38 [KMnO4]. IR: ν = 3291, 3084, 3064, 3026, 2932, 2859,
˜
1637, 1552, 1495, 1453, 1437, 1368, 1292, 1176, 1104, 1030, 1001,
909, 745, 697, 602, 570, 479, 437 cm–1 1H NMR (400 MHz, CDCl3):
.
δ = 7.31–7.23 (m, 2 H), 7.21–7.13 (m, 3 H), 5.70 (s, 1 H), 3.24 (td, J =
7.2, 5.8 Hz, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 1.94 (s, 3 H), 1.69–1.59 (m,
2 H), 1.57–1.46 (m, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.2,
142.2, 128.5, 128.4, 125.9, 39.6, 35.6, 29.3, 28.8, 23.4 ppm. LRMS (EI):
m/z = 191 (15) [M+], 100 (41) [(M – Bn)+], 91 (100) [Bn+], 87 (77), 73
(50). HRMS (ESI): m/z calcd. for C12H18NO+: 192.1383; found
192.1378.
N-Octylacetamide (3ae): By following general procedure
A
(Z)-N-(Octadec-9-en-1-yl)acetamide (3aj): By following general
procedure A (0.055 g, 85 %), B (0.056 g, 87 %) or C (0.056 g, 87 %),
(Z)-N-(octadec-9-en-1-yl)acetamide (3aj) was obtained as a white
solid after chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf
(0.027 g, 76 %), B (0.031 g, 87 %), C (0.027 g, 76 %) or E (0.033 g,
59 % using 0.050 g of tert-butyl acetoacetate 4a), N-octylacetamide
(3ae) was obtained as a colourless liquid after chromatography (PE/
EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/MeOH, 95:5) = 0.32
(DCM/MeOH, 95:5) = 0.46 [KMnO4]. IR: ν = 3292, 3089, 3003, 2922,
1
˜
[KMnO4]. H NMR (400 MHz, CDCl3): δ = 5.75 (s, 1 H), 3.24–3.16 (m,
2853, 1650, 1556, 1463, 1438, 1369, 1293, 1107, 1039, 967, 722, 603,
486 cm–1. 1H NMR (400 MHz, CDCl3): δ = 5.78 (s, 1 H), 5.39–5.26 (m,
2 H), 3.19 (dd, J = 13.2, 7.0 Hz, 2 H), 2.03–1.91 (m, 4 H), 1.94 (s, 3
H), 1.45 (dd, J = 14.2, 7.0 Hz, 2 H), 1.37–1.17 (m, 22 H), 0.85 (t, J =
6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.1, 130.0, 129.8,
39.8, 32.0, 29.8, 29.8, 29.7, 29.7, 29.6, 29.5, 29.4, 29.4, 29.3, 27.3, 27.3,
27.0, 23.3, 22.8, 14.2 ppm. LRMS (EI): m/z = 309 (15) [M+], 86 (56),
73 (97), 72 (80), 60 (77), 55 (100). HRMS (ESI): m/z calcd. for
C20H39NONa+: 332.2924; found 332.2926.
2 H), 1.94 (s, 3 H), 1.53–1.40 (m, 2 H), 1.33–1.17 (m, 10 H), 0.85 (t,
J = 6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.1, 39.8,
31.9, 29.7, 29.4, 29.3, 27.0, 23.4, 22.7, 14.1 ppm. The analytical data
are in agreement with previously reported data.[31]
N-(4-Methoxybenzyl)acetamide (3af): By following general proce-
dure A (0.025 g, 67 %), B (0.033 g, 88 %), C (0.031 g, 83 %) or E
(0.039 g, 69 % using 0.050 g of tert-butyl acetoacetate 4a), N-(4-
methoxybenzyl)acetamide (3af) was obtained as a white solid after
chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/
N-Allylacetamide (3ak): By following general procedure A (0.016 g,
79 %), B (0.018 g, 87 %) or C (0.017 g, 82 %), N-allylacetamide (3ak)
was obtained as a colourless liquid after chromatography (PE/
EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/MeOH, 95:5) = 0.43
[KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 5.81 (ddt, J = 17.1, 10.2,
5.7 Hz, 1 H), 5.16 (dq, J = 17.2, 1.7 Hz, 1 H), 5.10 (dq, J = 10.2, 1.4 Hz,
1 H), 3.84 (tt, J = 5.7, 1.5 Hz, 2 H), 1.98 (s, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 170.1, 134.3, 116.4, 42.1, 23.3 ppm. The ana-
lytical data are in agreement with previously reported data.[33]
1
MeOH, 95:5) = 0.31 [KMnO4]. H NMR (400 MHz, CDCl3): δ = 7.23–
7.15 (m, 2 H), 6.88–6.81 (m, 2 H), 5.93 (s, 1 H), 4.32 (d, J = 5.6 Hz, 2
H), 3.78 (s, 3 H), 1.97 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
169.9, 159.1, 130.5, 129.3, 114.2, 55.4, 43.3, 23.3 ppm. The analytical
data are in agreement with previously reported data.[31]
N-[4-(Trifluoromethyl)benzyl]acetamide (3ag): By following gen-
eral procedure A (0.029 g, 64 %), B (0.036 g, 80 %), C (0.038 g, 84 %)
or E (0.047 g, 69 % using 0.050 g of tert-butyl acetoacetate 4a), N-
[4-(trifluoromethyl)benzyl]acetamide (3ag) was obtained as a white
solid after chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf
N-(Prop-2-yn-1-yl)acetamide (3al): By following general proce-
dure A (0.013 g, 64 %), B (0.016 g, 79 %) or C (0.018 g, 89 %), N-
(prop-2-yn-1-yl)acetamide (3al) was obtained as a white solid after
chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/
MeOH, 95:5) = 0.38 [KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 6.12 (s,
1 H), 4.02 (d, J = 2.6 Hz, 1 H), 4.01 (d, J = 2.6 Hz, 1 H), 2.21 (t, J =
2.6 Hz, 1 H), 1.99 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.0,
79.7, 71.5, 29.3, 23.0 ppm. The analytical data are in agreement with
previously reported data.[34]
(DCM/MeOH, 95:5) = 0.40 [KMnO4]. IR: ν = 3283, 3079, 2937, 2831,
˜
1649, 1620, 1587, 1548, 1454, 1420, 1377, 1324, 1300, 1282, 1229,
1188, 1155, 1109, 1065, 1021, 958, 922, 840, 834, 820, 739, 727, 646,
637, 614, 594, 514, 475, 406 cm–1 1H NMR (400 MHz, CDCl3): δ =
.
7.56 (d, J = 8.0 Hz, 2 H), 7.39–7.33 (m, 2 H), 6.20 (s, 1 H), 4.44 (d, J =
6.0 Hz, 2 H), 2.01 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.3,
142.6 (d, J = 1.3 Hz), 129.9 (q, J = 32.5 Hz), 128.0, 125.7 (q, J =
3.8 Hz), 124.2 (q, J = 272.0 Hz), 43.2, 23.2 ppm. LRMS (EI): m/z = 217
(33) [M+], 174 (38) [(M – Ac)+], 159 (22) [(M – AcNH)+], 109 (19),
106 (100). HRMS (ESI): m/z calcd. for C10H11F3NO+: 218.0787; found
218.0788.
N-(3,3-Diethoxypropyl)acetamide (3am): By following general
procedure A (0.027 g, 69 %), B (0.032 g, 81 %), C (0.032 g, 81 %) or
E (0.035 g, 58 % using 0.050 g of tert-butyl acetoacetate 4a), N-
(3,3-diethoxypropyl)acetamide (3am) was obtained as a colourless
N-[1-(Naphthalen-2-yl)ethyl]acetamide (3ah): By following gen- liquid after chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf
1
eral procedure A (0.032 g, 72 %), B (0.034 g, 77 %) or C (0.039 g, (DCM/MeOH, 95:5) = 0.38 [KMnO4]. H NMR (400 MHz, CDCl3): δ =
88 %), N-[1-(naphthalen-2-yl)ethyl]acetamide (3ah) was obtained as
a white solid after chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH,
8:2). Rf (DCM/MeOH, 95:5) = 0.36 [KMnO4]. 1H NMR (400 MHz,
CDCl3): δ = 7.84–7.77 (m, 3 H), 7.76–7.71 (m, 1 H), 7.52–7.38 (m, 3
H), 6.07 (d, J = 8.0 Hz, 1 H), 5.33–5.22 (m, 1 H), 1.98 (s, 3 H), 1.55 (d,
J = 6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 169.3, 140.7,
6.19 (s, 1 H), 4.53 (t, J = 5.2 Hz, 1 H), 3.66 (q, J = 7.1 Hz, 1 H), 3.64
(q, J = 7.1 Hz, 1 H), 3.49 (q, J = 7.0 Hz, 1 H), 3.46 (q, J = 7.0 Hz, 1
H), 3.32 (dd, J = 12.6, 5.5 Hz, 2 H), 1.91 (s, J = 2.5 Hz, 3 H), 1.79 (ddd,
J = 7.4, 6.3, 5.2 Hz, 2 H), 1.19 (t, J = 7.1 Hz, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 169.9, 102.6, 62.1, 35.7, 33.0, 23.4, 15.4 ppm.
The analytical data are in agreement with previously reported
133.4, 132.8, 128.6, 128.0, 127.7, 126.3, 126.0, 124.9, 124.6, 48.9, 23.5, data.[35]
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tert-Butyl (2-Acetamidoethyl)carbamate (3an): By following gen-
21.6 ppm. The analytical data are in agreement with previously re-
eral procedure A (0.028 g, 67 %), B (0.032 g, 76 %) or C (0.035 g, ported data.[38]
83 %), tert-butyl (2-acetamidoethyl)carbamate (3an) was obtained
N-Benzylbenzamide (3ba): By following general procedure A
as a white solid after chromatography (PE/EtOAc, 1:1 → EtOAc/
iPrOH, 8:2). Rf (DCM/MeOH, 95:5) = 0.22 [KMnO4]. 1H NMR (400 MHz,
CDCl3): δ = 6.47 (s, 1 H), 5.14 (s, 1 H), 3.36–3.28 (m, 2 H), 3.28–3.14
(m, 2 H), 1.95 (s, 3 H), 1.41 (s, 9 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 171.0, 157.1, 79.7, 40.8, 40.4, 28.5, 23.3 ppm. The analytical data
are in agreement with previously reported data.[36]
(0.026 g, 74 %), B (0.030 g, 86 %) or C (0.029 g, 83 %), N-benzyl-
benzamide (3ba) was obtained as a white solid after chromatogra-
phy (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) = 0.63 [KMnO4]. 1H
NMR (400 MHz, CDCl3): δ = 7.82–7.77 (m, 2 H), 7.52–7.46 (m, 1 H),
7.44–7.38 (m, 2 H), 7.36–7.34 (m, 4 H), 7.34–7.27 (m, 1 H), 6.56 (s, 1
H), 4.63 (d, J = 5.7 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
167.5, 138.4, 134.5, 131.6, 128.9, 128.7, 128.0, 127.7, 127.1, 44.2 ppm.
The analytical data are in agreement with previously reported
data.[15b]
N-[(1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide (3ao):
By following general procedure A (0.028 g, 70 %) or E (0.045 g, 75 %
using 50 mg, 0.32 mmol tert-butyl acetoacetate 4a), N-[(1R,2S)-2-
hydroxy-2,3-dihydro-1H-inden-1-yl]acetamide (3ao) was obtained
as a white solid after chromatography (PE/EtOAc, 1:1 → EtOAc/
N-(1-Cyclohexylethyl)benzamide (3bb): By following general pro-
cedure A (0.026 g, 68 %), B (0.035 g, 91 %) or C (0.035 g, 91 %), N-
(1-cyclohexylethyl)benzamide (3bb) was obtained as a white solid
after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) =
0.71 [KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 7.79–7.72 (m, 2 H),
7.51–7.45 (m, 1 H), 7.45–7.37 (m, 2 H), 6.02 (d, J = 8.5 Hz, 1 H), 4.13–
4.01 (m, 1 H), 1.86–1.61 (m, 5 H), 1.48–1.37 (m, 1 H), 1.29–1.20 (m,
2 H), 1.18 (d, J = 6.8 Hz, 3 H), 1.16–0.96 (m, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 167.0, 135.3, 131.3, 128.6, 126.9, 50.0, 43.4,
29.3, 29.3, 26.5, 26.3, 26.3, 18.1 ppm. The analytical data are in
agreement with previously reported data.[39]
iPrOH, 8:2). Rf (DCM/MeOH, 95:5) = 0.16 [KMnO4]. IR: ν = 3443, 3295,
˜
3074, 3045, 3020, 2972, 2932, 2837, 1636, 1616, 1538, 1478, 1457,
1426, 1372, 1324, 1281, 1247, 1182, 1156, 1136, 1083, 1050, 1020,
999, 977, 885, 862, 817, 753, 733, 648, 591, 565, 534, 505, 476,
421 cm–1 1H NMR (600 MHz, CDCl3): δ = 7.28–7.20 (m, 4 H), 6.20
.
(d, J = 7.9 Hz, 1 H), 5.35 (ddd, J = 8.3, 5.2, 1.1 Hz, 1 H), 4.61 (td, J =
5.2, 2.4 Hz, 1 H), 3.16 (dd, J = 16.4, 5.3 Hz, 1 H), 2.93 (dd, J = 16.5,
2.4 Hz, 1 H), 2.41 (s, 1 H), 2.09 (s, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 171.0, 140.7, 140.1, 128.4, 127.4, 125.5, 124.7, 73.8, 57.8,
39.9, 23.5 ppm. LRMS (EI): m/z = 173 (35) [(M – H2O)+], 131 (100)
[(M – AcOH)+], 103 (45), 77 (41). HRMS (ESI): m/z calcd. for
N-Cyclohexylbenzamide (3bc): By following general procedure A
(0.024 g, 71 %), B (0.031 g, 92 %) or C (0.031 g, 92 %), N-cyclohexyl-
benzamide (3bc) was obtained as a white solid after chromatogra-
phy (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) = 0.66 [KMnO4]. 1H
C
11H13NO2Na+: 214.0838; found 214.0838.
N-(4-Hydroxyphenethyl)acetamide (3ap): By following general
procedure A (0.028 g, 75 %) or E (0.040 g, 71 % using 0.050 g of NMR (400 MHz, CDCl3): δ = 7.79–7.71 (m, 2 H), 7.51–7.43 (m, 1 H),
tert-butyl acetoacetate 4a), N-(4-hydroxyphenethyl)acetamide (3ap)
was obtained as a white solid after chromatography (PE/EtOAc, 1:1
7.43–7.36 (m, 2 H), 6.06 (s, 1 H), 4.04–3.90 (m, 1 H), 2.07–1.97 (m, 2
H), 1.80–1.69 (m, 2 H), 1.69–1.59 (m, 1 H), 1.48–1.34 (m, 2 H), 1.30–
1.13 (m, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.8, 135.2,
131.3, 128.6, 127.0, 48.8, 33.3, 25.7, 25.0 ppm. The analytical data
are in agreement with previously reported data.[39]
→ EtOAc/iPrOH, 8:2). Rf (DCM/MeOH, 95:5) = 0.14 [KMnO4]. IR: ν =
˜
3330, 3099, 3043, 3012, 2971, 2934, 2855, 2805, 2754, 2693, 2622,
2511, 1628, 1593, 1565, 1514, 1459, 1434, 1377, 1360, 1307, 1245,
1172, 1104, 1040, 1016, 994, 963, 932, 910, 855, 838, 810, 726, 711,
N-(1-Phenylethyl)benzamide (3bd): By following general proce-
dure A (0.025 g, 67 %), B (0.033 g, 89 %), C (0.032 g, 86 %) or D
(0.034 g, 90 %), N-(1-phenylethyl)benzamide (3bd) was obtained as
a white solid after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/
EtOAc, 1:1) = 0.69 [KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 7.80–
7.75 (m, 2 H), 7.51–7.45 (m, 1 H), 7.44–7.32 (m, 6 H), 7.30–7.25 (m,
1 H), 6.47 (d, J = 6.8 Hz, 1 H), 5.34 (p, J = 7.0 Hz, 1 H), 1.60 (d, J =
6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.7, 143.3,
134.7, 131.5, 128.8, 128.6, 127.5, 127.1, 126.4, 49.3, 21.8 ppm. The
analytical data are in agreement with previously reported data.[40]
647, 637, 600, 552, 493, 460, 422 cm–1 1H NMR (400 MHz,
.
[D6]DMSO): δ = 9.15 (s, 1 H), 7.90–7.77 (m, 1 H), 7.02–6.92 (m, 2 H),
6.72–6.61 (m, 2 H), 3.23–3.12 (m, 2 H), 2.61–2.53 (m, 2 H), 1.78 (s, 3
H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ = 169.0, 155.6, 129.5,
129.4, 115.1, 40.6, 34.4, 22.6 ppm. LRMS (EI): m/z = 179 (2) [M+], 120
(100) [(M – AcNH2)+], 107 (44), 91 (9), 77 (28). HRMS (ESI): m/z calcd.
for C10H13NO2Na+: 202.0838; found 202.0835.
N-[2-(1H-Indol-3-yl)ethyl]acetamide (3aq): By following general
procedure A (0.026 g, 62 %) or C (0.032 g, 76 %), N-[2-(1H-indol-3-
yl)ethyl]acetamide (3aq) was obtained as a yellow solid after chro-
matography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/MeOH,
N-Octylbenzamide (3be): By following general procedure
A
(0.033 g, 86 %), B (0.034 g, 88 %) or C (0.034 g, 88 %), N-octyl-
benzamide (3be) was obtained as a white solid after chromatogra-
phy (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) = 0.68 [KMnO4]. 1H
NMR (400 MHz, CDCl3): δ = 7.79–7.72 (m, 2 H), 7.50–7.43 (m, 1 H),
7.43–7.36 (m, 2 H), 6.33 (s, 1 H), 3.46–3.38 (m, 2 H), 1.65–1.55 (m, 2
H), 1.40–1.21 (m, 10 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 167.7, 135.0, 131.4, 128.6, 127.0, 40.3, 31.9,
29.8, 29.4, 29.3, 27.1, 22.7, 14.2 ppm. The analytical data are in
agreement with previously reported data.[41]
1
95:5) = 0.27 [KMnO4]. H NMR (400 MHz, CDCl3): δ = 8.50 (s, 1 H),
7.63–7.55 (m, 1 H), 7.36 (dt, J = 8.1, 0.9 Hz, 1 H), 7.23–7.17 (m, 1 H),
7.12 (ddd, J = 8.0, 7.0, 1.0 Hz, 1 H), 6.99 (d, J = 2.3 Hz, 1 H), 5.70 (s,
1 H), 3.58 (td, J = 6.8, 5.7 Hz, 2 H), 2.96 (td, J = 6.8, 0.9 Hz, 2 H), 1.91
(s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.4, 136.6, 127.5,
122.2, 122.2, 119.5, 118.7, 112.9, 111.5, 40.0, 25.4, 23.4 ppm. The
analytical data are in agreement with previously reported data.[37]
N-Benzyl-N-methylacetamide (3ar): By following general proce-
dure A (0.019 g, 56 %), B (0.017 g, 50 %) or C (0.019 g, 56 %), N-
benzyl-N-methylacetamide (3ar) was obtained as a colourless liquid
after chromatography (PE/EtOAc, 1:1 → EtOAc/iPrOH, 8:2). Rf (DCM/
N-(4-Methoxybenzyl)benzamide (3bf): By following general pro-
cedure A (0.030 g, 75 %), B (0.035 g, 88 %) or C (0.034 g, 85 %), N-
(4-methoxybenzyl)benzamide (3bf) was obtained as a yellowish
MeOH, 95:5) = 0.51 [KMnO4]. 1H NMR (400 MHz, CDCl3, two solid after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc,
1
rotamers): δ = 7.40–7.21 (m, 8 H), 7.21–7.13 (m, 2 H), 4.58 (s, 2 H),
4.52 (s, 2 H), 2.94 (s, 3 H), 2.91 (s, 3 H), 2.18–2.12 (m, 6 H) ppm. 13C
NMR (101 MHz, CDCl3, two rotamers): δ = 171.1, 170.8, 137.5, 136.7,
129.1, 128.7, 128.1, 127.7, 127.4, 126.4, 54.4, 50.7, 35.6, 33.8, 21.9,
1:1) = 0.51 [KMnO4]. H NMR (400 MHz, CDCl3): δ = 7.81–7.74 (m, 2
H), 7.51–7.44 (m, 1 H), 7.44–7.36 (m, 2 H), 7.30–7.23 (m, 2 H), 6.90–
6.83 (m, 2 H), 6.55 (s, 1 H), 4.55 (d, J = 5.6 Hz, 2 H), 3.79 (s, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 167.4, 159.2, 134.6, 131.6, 130.4,
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129.4, 128.6, 127.1, 114.3, 55.4, 43.7 ppm. The analytical data are in [KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 7.81–7.75 (m, 2 H), 7.53–
agreement with previously reported data.[42]
7.47 (m, 1 H), 7.46–7.39 (m, 2 H), 6.48 (s, 1 H), 4.25 (dd, J = 5.2,
2.6 Hz, 2 H), 2.27 (t, J = 2.6 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 167.3, 133.9, 131.9, 128.7, 127.2, 79.6, 72.0, 29.9 ppm. The ana-
lytical data are in agreement with previously reported data.[47]
N-[4-(Trifluoromethyl)benzyl]benzamide (3bg): By following
general procedure A (0.034 g, 74 %), B (0.043 g, 93 %) or C (0.040 g,
87 %), N-[4-(trifluoromethyl)benzyl]benzamide (3bg) was obtained
as a white solid after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/
EtOAc, 1:1) = 0.58 [KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 7.84–
7.75 (m, 2 H), 7.56 (d, J = 8.1 Hz, 2 H), 7.54–7.47 (m, 1 H), 7.45–7.37
(m, 4 H), 6.84 (s, 1 H), 4.65 (d, J = 6.0 Hz, 2 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 167.6, 142.6 (d, J = 1.4 Hz), 134.0, 131.7, 129.9
(q, J = 32.5 Hz), 128.8, 128.0, 127.1, 125.8 (q, J = 3.8 Hz), 124.2 (q,
J = 272.0 Hz), 43.4 ppm. The analytical data are in agreement with
previously reported data.[43]
N-(3,3-Diethoxypropyl)benzamide (3bm): By following general
procedure A (0.033 g, 79 %), B (0.039 g, 94 %) or C (0.039 g, 94 %),
N-(3,3-diethoxypropyl)benzamide (3bm) was obtained as a white
solid after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc,
1:1) = 0.36 [KMnO4]. IR: ν = 3325, 3065, 3032, 2974, 2930, 2878,
˜
1637, 1603, 1578, 1536, 1489, 1445, 1373, 1344, 1307, 1294, 1222,
1122, 1055, 973, 890, 846, 803, 693, 669, 615, 508 cm–1 1H NMR
.
(400 MHz, CDCl3): δ = 7.78–7.72 (m, 2 H), 7.48–7.42 (m, 1 H), 7.42–
7.35 (m, 2 H), 7.07 (s, 1 H), 4.63 (t, J = 5.0 Hz, 1 H), 3.71 (q, J =
7.1 Hz, 1 H), 3.69 (q, J = 7.1 Hz, 1 H), 3.56 (ddd, J = 7.6, 6.0, 5.3 Hz,
2 H), 3.53 (q, J = 7.1 Hz, 1 H), 3.50 (q, J = 7.0 Hz, 1 H), 1.92 (ddd,
J = 7.7, 6.1, 4.9 Hz, 2 H), 1.21 (t, J = 7.0 Hz, 6 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 167.2, 134.9, 131.3, 128.5, 126.9, 103.1, 62.3,
36.1, 32.9, 15.5 ppm. LRMS (EI): m/z = 222 (2) [(M – Et)+], 205 (5)
[(M – EtOH)+], 176 (8) [(M – EtOH – Et)+], 160 (10) [(M – EtOH –
EtO)+], 105 (100) [PhCO+], 77 (49) [Ph+]. HRMS (ESI): m/z calcd. for
C14H21NO3Na+: 274.1414; found 274.1419.
N-[1-(Naphthalen-2-yl)ethyl]benzamide (3bh): By following gen-
eral procedure A (0.030 g, 66 %), B (0.037 g, 81 %) or C (0.037 g,
81 %), N-[1-(naphthalen-2-yl)ethyl]benzamide (3bh) was obtained
as a white solid after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/
EtOAc, 1:1) = 0.67 [KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 7.85–
7.77 (m, 6 H), 7.53–7.44 (m, 4 H), 7.44–7.37 (m, 2 H), 6.59 (d, J =
7.9 Hz, 1 H), 5.50 (p, J = 7.0 Hz, 1 H), 1.68 (d, J = 6.9 Hz, 3 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 166.8, 140.6, 134.7, 133.5, 132.9,
131.6, 128.7, 128.6, 128.0, 127.7, 127.1, 126.3, 126.0, 124.9, 124.7,
49.4, 21.7 ppm. The analytical data are in agreement with previously
reported data.[44]
tert-Butyl (2-Benzamidoethyl)carbamate (3bn): By following
general procedure A (0.029 g, 66 %), B (0.037 g, 85 %) or C (0.037 g,
85 %), tert-butyl (2-benzamidoethyl)carbamate (3bn) was obtained
as a white solid after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/
N-(4-Phenylbutyl)benzamide (3bi): By following general proce-
dure A (0.036 g, 86 %), B (0.036 g, 86 %) or C (0.039 g, 93 %), N-(4-
phenylbutyl)benzamide (3bi) was obtained as a white solid after
chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) = 0.60
[KMnO4]. 1H NMR (400 MHz, CDCl3): δ = 7.79–7.71 (m, 2 H), 7.52–
7.44 (m, 1 H), 7.45–7.36 (m, 2 H), 7.32–7.23 (m, 2 H), 7.23–7.13 (m,
3 H), 6.32 (s, 1 H), 3.46 (q, J = 6.7 Hz, 2 H), 2.66 (t, J = 7.3 Hz, 2 H),
1.77–1.59 (m, 4 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 167.7,
142.2, 134.9, 131.4, 128.6, 128.5, 128.4, 127.0, 125.9, 40.0, 35.6, 29.4,
28.8 ppm. The analytical data are in agreement with previously re-
ported data.[45]
EtOAc, 1:1) = 0.24 [KMnO4]. IR: ν = 3354, 3322, 3083, 3066, 2990,
˜
2970, 2935, 2872, 1685, 1636, 1603, 1579, 1525, 1490, 1447, 1390,
1367, 1327, 1276, 1250, 1234, 1152, 1075, 1035, 974, 922, 878, 855,
800, 783, 764, 691, 642, 583, 519, 467 cm–1 1H NMR (400 MHz,
.
CDCl3): δ = 7.81 (d, J = 7.2 Hz, 2 H), 7.50–7.43 (m, 1 H), 7.43–7.36
(m, 2 H), 7.26 (s, 1 H), 5.14 (s, 1 H), 3.54 (dd, J = 11.0, 5.2 Hz, 2 H),
3.38 (dd, J = 11.1, 5.7 Hz, 2 H), 1.41 (s, 9 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 168.0, 157.6, 134.3, 131.5, 128.6, 127.1, 80.0, 42.1, 40.1,
28.5 ppm. LRMS (EI): m/z = 208 (3) [(M – tBu + H)+], 134 (47)
[PhCONHCH2+], 105 (100) [PhCO+], 77 (50) [Ph+], 57 (51) [tBu+].
HRMS (ESI): m/z calcd. for C14H20N2O3Na+: 287.1366; found
287.1365.
(Z)-N-(Octadec-9-en-1-yl)benzamide (3bj): By following general
procedure A (0.056 g, 91 %), B (0.062 g, 100 %) or C (0.053 g, 86 %),
(Z)-N-(octadec-9-en-1-yl)benzamide (3bj) was obtained as a white
solid after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc,
N-[(1R,2S)-2-Hydroxy-2,3-dihydro-1H-inden-1-yl]benzamide
(3bo): By following general procedure A, N-[(1R,2S)-2-hydroxy-2,3-
dihydro-1H-inden-1-yl]benzamide (3bo; 0.030 g, 72 %) was ob-
tained as a white solid after chromatography (PE/EtOAc, 9:1 →
1
1:1) = 0.83 [KMnO4]. H NMR (400 MHz, CDCl3): δ = 7.78–7.73 (m, 2
H), 7.49–7.43 (m, 1 H), 7.42–7.36 (m, 2 H), 6.33 (s, 1 H), 5.40–5.29
(m, 2 H), 3.42 (dd, J = 13.3, 6.9 Hz, 2 H), 2.08–1.90 (m, 4 H), 1.64–
1.55 (m, 2 H), 1.41–1.21 (m, 22 H), 0.87 (t, J = 6.9 Hz, 3 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 167.6, 135.0, 131.3, 130.1, 129.9, 128.6,
127.0, 40.2, 32.7, 32.0, 29.9, 29.8, 29.8, 29.8, 29.7, 29.6, 29.6, 29.4,
29.4, 29.3, 27.3, 27.3, 27.1, 22.8, 14.2 ppm. The analytical data are
in agreement with previously reported data.[46]
EtOAc). Rf (PE/EtOAc, 1:1) = 0.38 [KMnO4]. IR: ν = 3295, 3065, 3052,
˜
3021, 2935, 2918, 1637, 1602, 1577, 1525, 1480, 1456, 1345, 1279,
1207, 1184, 1172, 1155, 1110, 1080, 1056, 1023, 1005, 953, 925, 905,
1
847, 835, 797, 748, 695, 665, 621, 582, 559, 514, 445, 429 cm–1. H
NMR (400 MHz, CDCl3): δ = 7.86–7.80 (m, 2 H), 7.55–7.47 (m, 1 H),
7.46–7.39 (m, 2 H), 7.37–7.31 (m, 1 H), 7.30–7.18 (m, 4 H), 6.88 (d,
J = 8.3 Hz, 1 H), 5.58 (ddd, J = 8.4, 5.1, 1.1 Hz, 1 H), 4.72 (td, J = 5.2,
2.2 Hz, 1 H), 3.23 (dd, J = 16.3, 5.0 Hz, 1 H), 2.99 (dd, J = 16.6, 2.0 Hz,
1 H), 2.43 (s, 1 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 168.2, 140.9,
140.1, 134.3, 131.8, 128.7, 128.5, 127.4, 127.3, 125.5, 124.8, 73.9, 58.1,
40.1 ppm. LRMS (EI): m/z = 235 (12) [(M – H2O)+], 105 (100) [PhCO+],
77 (54) [Ph+]. HRMS (ESI): m/z calcd. for C16H15NO2Na+: 276.0995;
found 276.0994.
N-Allylbenzamide (3bk): By following general procedure
A
(0.021 g, 79 %), B (0.023 g, 86 %) or C (0.024 g, 90 %), N-allylbenz-
amide (3bk) was obtained as a colourless liquid after chromatogra-
phy (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) = 0.56 [KMnO4]. 1H
NMR (400 MHz, CDCl3): δ = 7.81–7.75 (m, 2 H), 7.52–7.45 (m, 1 H),
7.45–7.37 (m, 2 H), 6.40 (s, 1 H), 5.93 (ddt, J = 17.1, 10.2, 5.7 Hz, 1
H), 5.25 (ddd, J = 17.1, 3.1, 1.6 Hz, 1 H), 5.17 (dq, J = 10.2, 1.4 Hz, 1
H), 4.07 (tt, J = 5.7, 1.6 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 167.5, 134.6, 134.3, 131.6, 128.7, 127.1, 116.7, 42.5 ppm. The
analytical data are in agreement with previously reported data.[33]
N-(4-Hydroxyphenethyl)benzamide (3bp): By following general
procedure A, N-(4-hydroxyphenethyl)benzamide (3bp; 0.032 g,
80 %) was obtained as a white solid after chromatography (PE/
EtOAc, 9:1 → 3:7). Rf (PE/EtOAc, 1:1) = 0.29 [KMnO4]. 1H NMR
(400 MHz, [D6]DMSO): δ = 9.17 (s, 1 H), 8.50 (t, J = 5.6 Hz, 1 H),
7.87–7.77 (m, 2 H), 7.55–7.40 (m, 3 H), 7.08–6.97 (m, 2 H), 6.73–6.64
(m, 2 H), 3.47–3.39 (m, 2 H), 2.77–2.69 (m, 2 H) ppm. 13C NMR
N-(Prop-2-yn-1-yl)benzamide (3bl): By following general proce-
dure A (0.021 g, 80 %), B (0.024 g, 91 %) or C (0.021 g, 80 %), N-
(prop-2-yn-1-yl)benzamide (3bl) was obtained as a white solid after
chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) = 0.61
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(101 MHz, [D6]DMSO): δ = 166.1, 155.6, 134.7, 131.0, 129.6, 129.5, 21.5 ppm. The analytical data are in agreement with previously re-
128.2, 127.1, 115.1, 41.2, 34.3 ppm. The analytical data are in agree- ported data.[53]
ment with previously reported data.[48]
N-Benzyl-4-methoxybenzamide (3da): By following general pro-
cedure E using tert-butyl 5-methyl-3-oxohexanoate (4c; 50 mg,
0.20 mmol), N-benzyl-4-methoxybenzamide (3da; 0.034 g, 70 %)
was obtained as a yellow solid after chromatography (EA/PE, 2:8 →
6:4). Rf = 0.68 (EA/PE, 6:4) [Cl2]. 1H NMR (600 MHz, CDCl3): δ = 7.80–
7.70 (m, 2 H), 7.40–7.20 (m, 5 H), 6.96–6.83 (m, 2 H), 6.45 (br. s., 1
H), 4.62 (d, J = 5.6 Hz, 2 H), 3.83 (s, 3 H) ppm. 13C NMR (151 MHz,
CDCl3): δ = 167.0, 162.4, 138.6, 128.9, 128.9, 128.0, 127.6, 126.9,
113.9, 55.5, 44.2 ppm. The analytical data are in agreement with
previously reported data.[54]
N-[2-(1H-Indol-3-yl)ethyl]benzamide (3bq): By following general
procedure A (0.032 g, 73 %) or C (0.032 g, 73 %), N-[2-(1H-indol-3-
yl)ethyl]benzamide (3bq) was obtained as a brown solid after chro-
matography (PE/EtOAc, 8:2 → EtOAc). Rf (DCM/MeOH, 95:5) = 0.33
1
[KMnO4]. H NMR (600 MHz, CDCl3): δ = 8.43 (s, 1 H), 7.76–7.60 (m,
3 H), 7.50–7.43 (m, 1 H), 7.43–7.31 (m, 3 H), 7.24–7.17 (m, 1 H), 7.16–
7.09 (m, 1 H), 7.02 (d, J = 2.4 Hz, 1 H), 6.37 (s, 1 H), 3.86–3.73 (m, 2
H), 3.17–3.02 (m, 2 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 167.7,
136.6, 134.8, 131.5, 128.6, 127.4, 127.0, 122.3, 122.3, 119.6, 118.8,
112.9, 111.5, 40.5, 25.4 ppm. The analytical data are in agreement
with previously reported data.[46]
4-Methoxy-N-(1-phenylethyl)benzamide (3dd): By following gen-
eral procedure D, 4-methoxy-N-(1-phenylethyl)benzamide (3dd;
0.037 g, 96 %) was obtained as a white solid after chromatography
N-Benzyl-N-methylbenzamide (3br): By following general proce-
dure A (0.017 g, 46 %), B (0.033 g, 89 %) or C (0.032 g, 86 %), N-
benzyl-N-methylbenzamide (3br) was obtained as a white solid
after chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) =
0.53 [KMnO4]. 1H NMR (400 MHz, CDCl3, two rotamers): δ = 7.49–
7.43 (m, 4 H), 7.43–7.24 (m, 14 H), 7.17 (s, 2 H), 4.76 (s, 2 H), 4.51 (s,
2 H), 3.03 (s, 3 H), 2.86 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3, two
1
(PE/EtOAc, 3:7 → EtOAc). H NMR (400 MHz, CDCl3): δ = 7.79–7.71
(m, 2 H), 7.41–7.30 (m, 4 H), 7.30–7.23 (m, 1 H), 6.93–6.85 (m, 2 H),
6.40 (d, J = 7.2 Hz, 1 H), 5.37–5.27 (m, 1 H), 3.82 (s, 3 H), 1.59 (d, J =
6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.2, 162.3, 143.5,
128.9, 128.8, 127.4, 127.0, 126.4, 113.8, 55.5, 49.2, 21.9 ppm. The
analytical data are in agreement with previously reported data.[55]
rotamers): δ = 172.3, 171.6, 137.1, 136.7, 136.3, 129.7, 128.9, 128.8, 4-Methoxy-N-{(S)-(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-
128.5, 128.3, 127.6, 127.4, 127.0, 126.9, 122.9, 120.0, 55.2, 50.9, 37.1, vinylquinuclidin-2-yl]methyl}benzamide (3du): (1S,2S,4S,5R)-2-
33.2 ppm. The analytical data are in agreement with previously re- [(S)-Ammonio(6-methoxyquinolin-1-ium-4-yl)methyl]-5-vinyl-
ported data.[49]
quinuclidin-1-ium chloride (0.060 g) was dissolved in saturated
aqueous NaHCO3 and the solution was extracted with DCM. The
organic phase was dried with MgSO4 and evaporated to obtain (S)-
(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]meth-
anamine (0.043 g, 0.13 mmol, 1.00 equiv.), which was dissolved in
Morpholino(phenyl)methanone (3bs): By following general pro-
cedure A (0.015 g, 47 %), B (0.022 g, 70 %) or C (0.024 g, 76 %),
morpholino(phenyl)methanone (3bs) was obtained as a colourless
liquid after chromatography (PE/EtOAc, 9:1 → EtOAc). Rf (PE/EtOAc,
THF (0.27 mL, 0.50 M). tert-Butyl 2,2-diazido-3-(4-methoxyphenyl)-3-
1
1:1) = 0.23 [KMnO4]. H NMR (400 MHz, CDCl3): δ = 7.43–7.37 (m, 5
oxopropanoate (1d; 0.044 g, 0.13 mmol, 1.00 equiv.) and cesium
carbonate (0.044 g, 0.13 mmol, 1.00 equiv.) were added to the solu-
tion. The resulting suspension was stirred for 20 h. The suspension
was purified by chromatography over silica (PE/EtOAc/NEt3, 50:45:5
→ EtOAc/iPrOH/MeOH/NEt3, 70:15:10:5) to give 4-methoxy-N-{(S)-
(6-methoxyquinolin-4-yl)[(1S,2S,4S,5R)-5-vinylquinuclidin-2-yl]-
methyl}benzamide (3du; 0.047 g, 77 %). Rf (DCM/MeOH, 9:1) = 0.32
H), 3.90–3.24 (m, 8 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.5,
135.4, 130.0, 128.7, 127.2, 67.0, 48.3, 42.6 ppm. The analytical data
are in agreement with previously reported data.[50]
N-Phenylbenzamide (3bt): By following general procedure B
(0.007 g, 21 %) or C (0.020 g, 61 %), N-phenylbenzamide (3bt) was
obtained as a white solid after chromatography (PE/EtOAc, 9:1 →
1:1). Rf (PE/EtOAc, 1:1) = 0.66 [KMnO4]. 1H NMR (400 MHz, CDCl3):
δ = 7.96–7.83 (m, 3 H), 7.68–7.61 (m, 2 H), 7.58–7.51 (m, 1 H), 7.51–
7.44 (m, 2 H), 7.40–7.33 (m, 2 H), 7.20–7.12 (m, 1 H) ppm. 13C NMR
(101 MHz, CDCl3): δ = 165.9, 138.1, 135.2, 132.0, 129.2, 128.9, 127.2,
124.7, 120.4 ppm. The analytical data are in agreement with previ-
ously reported data.[51]
[KMnO4]. IR: ν = 3294, 3075, 2931, 2862, 2838, 1621, 1606, 1574,
˜
1541, 1504, 1474, 1434, 1362, 1323, 1305, 1251, 1228, 1175, 1108,
1083, 1028, 991, 908, 844, 827, 790, 766, 727, 686, 668, 644, 611,
592, 522, 494, 444 cm–1. 1H NMR (400 MHz, [D6]DMSO): δ = 8.75 (d,
J = 4.5 Hz, 1 H), 8.57 (d, J = 7.6 Hz, 1 H), 7.94 (d, J = 9.2 Hz, 1 H),
7.89 (d, J = 2.8 Hz, 1 H), 7.85–7.78 (m, 2 H), 7.64 (d, J = 4.6 Hz, 1 H),
7.42 (dd, J = 9.0, 2.6 Hz, 1 H), 6.99–6.93 (m, 2 H), 5.92 (ddd, J = 17.5,
10.3, 7.5 Hz, 1 H), 5.81 (s, 1 H), 5.04 (ddd, J = 17.2, 1.9, 1.3 Hz, 1 H),
4.99 (ddd, J = 10.3, 2.0, 1.1 Hz, 1 H), 3.95 (s, 3 H), 3.77 (s, 3 H), 3.59–
3.46 (m, 1 H), 3.35–3.22 (m, 1 H), 3.16 (dd, J = 13.6, 10.0 Hz, 1 H),
2.79–2.69 (m, 1 H), 2.68–2.55 (m, 1 H), 2.31–2.19 (m, 1 H), 1.62–1.40
(m, 4 H), 0.72 (m, 1 H) ppm. 13C NMR (101 MHz, [D6]DMSO): δ =
165.1, 161.6, 157.3, 147.6, 145.2, 144.0, 142.1, 131.2, 129.2, 128.3,
126.4, 121.2, 120.3, 114.2, 113.4, 102.6, 57.8, 55.6, 55.3, 49.6, 40.7,
39.1, 27.3, 27.2, 26.3 ppm. LRMS (ESI): m/z = 458 (100) [M + H+].
HRMS (ESI): m/z calcd. for C28H32N3O3+: 458.2438; found 458.2439.
N-Benzyl-4-methylbenzamide (3ca): By following general proce-
dure E using tert-butyl 3-oxo-3-(p-tolyl)propanoate (4d; 50 mg,
0.21 mmol), N-benzyl-4-methylbenzamide (3ca, 0.036 g, 74 %) was
obtained as a yellow solid after chromatography (EA/PE, 1:9 → 6:4).
1
Rf = 0.93 (EA/PE, 6:4) [Cl2]. H NMR (400 MHz, CDCl3): δ = 7.79–7.66
(m, 2 H), 7.40–7.25 (m, 5 H), 7.26–7.21 (m, 2 H), 6.52 (br. s., 1 H),
4.62 (d, J = 5.6 Hz, 2 H), 2.39 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 167.4, 142.0, 138.5, 131.7, 129.3, 128.9, 128.0, 127.7,
127.1, 44.2, 21.5 ppm. The analytical data are in agreement with
previously reported data.[52]
N-Benzyl-4-chlorobenzamide (3ea): By following general proce-
dure E using tert-butyl 3-(4-chlorophenyl)-3-oxopropanoate (4h;
50 mg, 0.23 mmol), N-benzyl-4-chlorobenzamide (3ea; 0.035 g,
73 %) was obtained as a yellow solid after chromatography (EA/PE,
3:7 → EA). Rf = 0.95 (EA/PE, 6:4) [Cl2]. 1H NMR (400 MHz, CDCl3):
4-Methyl-N-(1-phenylethyl)benzamide (3cd): By following gen-
eral procedure D, 4-methyl-N-(1-phenylethyl)benzamide (3cd;
0.038 g, 99 %) was obtained as a white solid after chromatography
(PE/EtOAc, 3:7 → EtOAc). 1H NMR (400 MHz, CDCl3): δ = 7.68 (d, J =
8.2 Hz, 2 H), 7.42–7.31 (m, 4 H), 7.30–7.24 (m, 1 H), 7.23–7.17 (m, 2 δ = 7.78–7.66 (m, 2 H), 7.44–7.27 (m, 7 H), 6.58 (br. s., 1 H), 4.61 (d,
H), 6.43 (d, J = 7.9 Hz, 1 H), 5.33 (p, J = 7.1 Hz, 1 H), 2.38 (s, 3 H),
J = 5.8 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.5, 138.1,
1.59 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 166.6, 137.9, 132.9, 128.9, 128.6, 128.0, 127.8, 44.3 ppm. The analytical data
143.4, 141.9, 131.9, 129.3, 128.8, 127.5, 127.1, 126.4, 49.2, 21.9, are in agreement with previously reported data.[54]
Eur. J. Org. Chem. 2017, 1526–1539
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4-Chloro-N-(1-phenylethyl)benzamide (3ed): By following gen-
eral procedure D, 4-chloro-N-(1-phenylethyl)benzamide (3ed;
0.038 g, 98 %) was obtained as a white solid after chromatography
N-Benzyl-5-(benzyloxy)pentanamide (3ja): By following general
procedure E using tert-butyl 7-(benzyloxy)-3-oxoheptanoate (4j;
50 mg, 0.16 mmol), N-benzyl-5-(benzyloxy)pentanamide (3ja;
0.019 g, 40 %) was obtained as a yellow oil after chromatography
1
(PE/EtOAc, 3:7 → EtOAc). H NMR (600 MHz, CDCl3): δ = 7.71–7.66
(m, 2 H), 7.39–7.32 (m, 6 H), 7.30–7.25 (m, 1 H), 6.55 (d, J = 6.8 Hz,
1 H), 5.29 (p, J = 7.0 Hz, 1 H), 1.58 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 165.7, 143.1, 137.8, 133.1, 128.9, 128.8, 128.5,
127.6, 126.3, 49.5, 21.8 ppm. The analytical data are in agreement
with previously reported data.[55]
(EA/PE, 3:7 → EA). Rf = 0.41 (EA/PE, 6:4) [Cl2]. IR: ν = 3293, 3086,
˜
3064, 3030, 2929, 2858, 1643, 1541, 1454, 1098, 909, 729, 695 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.44–7.18 (m, 10 H), 5.90 (br. s., 1 H),
4.47 (s, 2 H), 4.40 (d, J = 5.8 Hz, 2 H), 3.49 (t, J = 6.2 Hz, 2 H), 2.24
(t, J = 7.5 Hz, 2 H), 1.86–1.70 (m, 2 H), 1.70–1.58 (m, 2 H) ppm. 13C
NMR (101 MHz, CDCl3): δ = 172.8, 138.6, 138.5, 128.8, 128.5, 128.0,
127.8, 127.7, 127.6, 73.1, 70.2, 43.7, 36.5, 29.2, 22.9 ppm. LRMS (ESI):
m/z = 190.1 (23) [(M – C7H7O)+], 298.2 (100) [M + H+], 299.2 (18) [M
+ 2H+], 300.2 (1) [M + 2H+], 320.2 (2) [M + Na+]. HRMS (ESI): m/z
calcd. for C19H23NO2Na+: 320.1621; found 320.1618.
N-(1-Phenylethyl)furan-2-carboxamide (3fd): By following gen-
eral procedure D, N-(1-phenylethyl)furan-2-carboxamide (3fd;
0.039 g, 99 %) was obtained as a white solid after chromatography
1
(PE/EtOAc, 3:7 → EtOAc). H NMR (400 MHz, CDCl3): δ = 7.43–7.31
(m, 5 H), 7.30–7.23 (m, 1 H), 7.10 (dd, J = 3.5, 0.7 Hz, 1 H), 6.67–6.54
(m, 1 H), 6.47 (dd, J = 3.5, 1.8 Hz, 1 H), 5.36–5.25 (m, 1 H), 1.59 (d,
J = 6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 157.6, 148.1,
143.8, 143.0, 128.8, 127.6, 126.4, 114.4, 112.2, 48.5, 21.9 ppm. The
analytical data are in agreement with previously reported data.[56]
5-(Benzyloxy)-N-(1-phenylethyl)pentanamide (3jd): By following
general procedure D, 5-(benzyloxy)-N-(1-phenylethyl)pentanamide
(3jd; 0.029 g, 73 %) was obtained as a colourless liquid after chro-
matography (PE/EtOAc, 4:6). Rf (PE/EtOAc, 3:7) = 0.54 [Cl2]. IR: ν =
˜
3285, 3063, 3030, 2930, 2862, 1639, 1538, 1452, 1101, 734, 696,
N-Benzyl-3-phenylpropanamide (3ga): By following general pro-
cedure E using tert-butyl 3-oxo-5-phenylpentanoate (4b; 50 mg,
0.20 mmol), N-benzyl-3-phenylpropanamide (3ga; 0.026 g, 53 %)
was obtained as a yellow solid after chromatography (EA/PE, 6:4).
1
540 cm–1. H NMR (600 MHz, CDCl3): δ = 7.36–7.30 (m, 6 H), 7.30–
7.22 (m, 4 H), 5.81 (d, J = 8.0 Hz, 1 H), 5.12 (p, J = 7.1 Hz, 1 H), 4.48
(s, 2 H), 3.49 (td, J = 6.2, 1.1 Hz, 2 H), 2.21 (t, J = 7.4 Hz, 2 H), 1.77–
1.71 (m, 2 H), 1.68–1.61 (m, 2 H), 1.44 (d, J = 7.0 Hz, 3 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 172.0, 143.5, 138.6, 128.7, 128.5, 127.9,
127.7, 127.4, 126.3, 73.2, 70.3, 48.7, 36.6, 29.1, 23.0, 21.9 ppm. LRMS
(ESI): m/z = 312 (100) [M + H+], 204 (16) [(M – BnO)+]. HRMS (ESI):
m/z calcd. for C20H25NO2Na+: 334.1778; found 334.1763.
1
Rf = 0.53 (EA/PE, 6:4) [Cl2]. H NMR (400 MHz, CDCl3): δ = 7.34–7.12
(m, 10 H), 5.71 (br. s., 1 H), 4.39 (d, J = 5.8 Hz, 2 H), 2.99 (t, J =
7.7 Hz, 2 H), 2.51 (t, J = 7.6 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl3):
δ = 172.0, 140.9, 138.3, 128.8, 128.7, 128.5, 127.9, 127.6, 126.4, 43.7,
38.6, 31.8 ppm. The analytical data are in agreement with previously
reported data.[52]
5-Oxo-5-[(1-phenylethyl)amino]pentyl Acetate (3kd): By follow-
ing general procedure D, 5-oxo-5-[(1-phenylethyl)amino]pentyl
acetate (3kd; 0.030 g, 78 %) was obtained as a yellowish liquid after
chromatography (PE/EtOAc, 4:6). Rf (PE/EtOAc, 3:7) = 0.54 [Cl2]. IR:
3-Phenyl-N-(1-phenylethyl)propanamide (3gd): By following
general procedure D, 3-phenyl-N-(1-phenylethyl)propanamide (3gd;
0.035 g, 90 %) was obtained as a white solid after chromatography
(PE/EtOAc, 1:1 → 3:7). Rf (PE/EtOAc, 3:7) = 0.85 [Cl2]. 1H NMR
(600 MHz, CDCl3): δ = 7.32–7.22 (m, 5 H), 7.22–7.15 (m, 5 H), 5.66
(d, J = 7.6 Hz, 1 H), 5.10 (p, J = 7.1 Hz, 1 H), 2.96 (t, J = 7.6 Hz, 2 H),
2.48 (td, J = 7.5, 2.2 Hz, 2 H), 1.41 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR
(151 MHz, CDCl3): δ = 171.2, 143.2, 140.9, 128.7, 128.6, 128.5, 127.4,
126.3, 126.3, 48.7, 38.7, 31.8, 21.7 ppm. The analytical data are in
agreement with previously reported data.[57]
ν = 3294, 3064, 3031, 2960, 2930, 2871, 1721, 1642, 1536, 1451,
˜
1366, 1237, 1041, 912, 731, 699 cm–1
.
1H NMR (600 MHz, CDCl3):
δ = 7.37–7.27 (m, 4 H), 7.27–7.22 (m, 1 H), 5.81 (d, J = 8.4 Hz, 1 H),
5.12 (p, J = 7.0 Hz, 1 H), 4.05 (t, J = 6.4 Hz, 2 H), 2.22–2.16 (m, 2 H),
2.02 (s, 3 H), 1.74–1.67 (m, 2 H), 1.67–1.60 (m, 2 H), 1.48 (d, J =
6.9 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 171.6, 171.3, 143.4,
128.8, 127.5, 126.3, 64.1, 48.8, 36.2, 28.3, 22.2, 21.8, 21.1 ppm. LRMS
(ESI): m/z = 264 (100) [M + H+], 204 (93) [(M – AcO)+]. HRMS (ESI):
m/z calcd. for C15H21NO3Na+: 286.1414; 286.1408.
3-Methyl-N-(1-phenylethyl)butanamide (3hd): By following gen-
eral procedure D (2.50 equiv. amine 2d), 3-methyl-N-(1-phenyl-
ethyl)butanamide (3hd; 0.029 g, 79 %) was obtained as a yellowish
solid after chromatography (PE/EtOAc, 4:6 → 1:9). Rf (PE/EtOAc,
4-[(tert-Butyldimethylsilyl)oxy]-N-(1-phenylethyl)butanamide
(3ld): By following general procedure D, 4-[(tert-butyldimethyl-
silyl)oxy]-N-(1-phenylethyl)butanamide (3ld; 0.030 g, 73 %) was ob-
tained as a yellowish solid after chromatography (PE/EtOAc, 1:1 →
3:7) = 0.73 [Cl2]. IR: ν = 3279, 3064, 3031, 2957, 2930, 2870, 1637,
˜
1539, 1450, 1368, 1215, 1135, 910, 732, 697, 540 cm–1
.
1H NMR
EtOAc). Rf (PE/EtOAc, 1:1) = 0.81 [Cl2]. IR: ν = 3283, 3064, 3031, 2954,
(400 MHz, CDCl3): δ = 7.36–7.29 (m, 4 H), 7.28–7.22 (m, 1 H), 5.77
(d, J = 7.6 Hz, 1 H), 5.21–5.09 (m, 1 H), 2.17–2.06 (m, 1 H), 2.05–2.01
(m, 2 H), 1.48 (d, J = 6.9 Hz, 3 H), 0.94 (d, J = 6.5 Hz, 3 H), 0.92 (d,
J = 6.5 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.6, 143.4,
128.7, 127.4, 126.3, 48.6, 46.3, 26.3, 22.6, 22.5, 21.8 ppm. LRMS (ESI):
m/z = 206 (100) [M + H+]. HRMS (ESI): m/z calcd. for C13H19NONa+:
228.1359; found 228.1359.
˜
2928, 2856, 1640, 1542, 1450, 1254, 1100, 834, 775, 697 cm–1
.
1H
NMR (400 MHz, CDCl3): δ = 7.36–7.28 (m, 4 H), 7.28–7.22 (m, 1 H),
5.88 (d, J = 8.0 Hz, 1 H), 5.20–5.08 (m, 1 H), 3.70–3.56 (m, 2 H), 2.27
(td, J = 7.1, 0.9 Hz, 2 H), 1.89–1.78 (m, 2 H), 1.48 (d, J = 6.9 Hz, 3 H),
0.88 (s, 9 H), 0.03 (s, 3 H), 0.02 (s, 3 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 172.1, 143.4, 128.8, 127.4, 126.3, 62.2, 48.7, 33.3, 28.7,
26.1, 21.9, 18.4, –5.2 ppm. LRMS (ESI): m/z = 322 (100) [M + H+],
190 (17) [(M – TBSO)+]. HRMS (ESI): m/z calcd. for C18H31NO2SiNa+:
344.2016; found 344.2010.
N-(1-Phenylethyl)pent-4-enamide (3id): By following general pro-
cedure D, N-(1-phenylethyl)pent-4-enamide (3id; 0.028 g, 78 %) was
obtained as a yellowish liquid after chromatography (PE/EtOAc, 3:7
→ EtOAc). Rf (PE/EtOAc, 3:7) = 0.71 [Cl2]. 1H NMR (400 MHz, CDCl3):
4-Azido-N-(1-phenylethyl)butanamide (3md): By following gen-
δ = 7.36–7.28 (m, 4 H), 7.28–7.23 (m, 1 H), 5.81 (ddt, J = 16.8, 10.2, eral procedure D, 4-azido-N-(1-phenylethyl)butanamide (3md;
6.5 Hz, 2 H), 5.18–5.09 (m, 1 H), 5.05 (dq, J = 17.1, 1.6 Hz, 1 H), 5.00 0.029 g, 77 %) was obtained as a colourless liquid after chromatog-
(ddd, J = 10.2, 2.2, 0.8 Hz, 1 H), 2.43–2.35 (m, 2 H), 2.29–2.23 (m, 2
H), 1.48 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
171.4, 143.3, 137.2, 128.8, 127.5, 126.3, 115.7, 48.8, 36.1, 29.8,
raphy (PE/EtOAc, 3:7 → EtOAc). Rf (PE/EtOAc, 3:7) = 0.71 [Cl2]. IR:
ν = 3292, 3064, 3031, 2971, 2929, 2872, 2093, 1639, 1539, 1449,
˜
1249, 909, 732, 698, 540 cm–1. 1H NMR (600 MHz, CDCl3): δ = 7.37–
21.9 ppm. The analytical data are in agreement with previously re- 7.28 (m, 4 H), 7.28–7.23 (m, 1 H), 5.83 (d, J = 7.8 Hz, 1 H), 5.12 (p,
ported data.[58]
J = 7.1 Hz, 1 H), 3.38–3.27 (m, 2 H), 2.31–2.20 (m, 2 H), 1.96–1.86
1536 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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(m, 2 H), 1.49 (d, J = 7.0 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 170.8, 143.3, 128.8, 127.5, 126.3, 50.9, 49.0, 33.4, 24.9, 21.9 ppm.
LRMS (ESI): m/z = 233 (100) [M + H+]. HRMS (ESI): m/z calcd. for
C12H16N4ONa+: 255.1216; found 255.1212.
0.85 (t, J = 7.0 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.1,
45.8, 39.5, 31.9, 29.9, 29.8, 29.4, 29.3, 27.0, 25.9, 22.7, 14.2 ppm. The
analytical data are in agreement with previously reported data.[60]
N-Benzylpivalamide (3pa): By following general procedure E using
tert-butyl 4,4-dimethyl-3-oxopentanoate (4f; 25 mg, 0.12 mmol), N-
benzylpivalamide (3pa; 0.007 g, 27 %) was obtained as a yellow oil
after chromatography (EA/PE, 1:9 → 6:4). Rf = 0.73 (EA/PE, 1:1) [Cl2].
1H NMR (400 MHz, CDCl3): δ = 7.38–7.23 (m, 5 H), 5.89 (br. s., 1 H),
4.44 (d, J = 5.8 Hz, 2 H), 1.23 (s, 9 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 178.4, 138.8, 128.9, 127.8, 127.6, 43.8, 38.9, 27.8 ppm.
The analytical data are in agreement with previously reported
data.[61]
N-Benzyl-3-hydroxy-3-methylbutanamide (3na): By following
general procedure E using tert-butyl 5-hydroxy-5-methyl-3-oxo-
hexanoate (4g; 50 mg, 0.23 mmol), N-benzyl-3-hydroxy-3-methyl-
butanamide (3na; 0.030 g, 62 %) was obtained as a brown liquid
after chromatography (EA/PE, 3:7 → EA). Rf = 0.41 (EA/PE, 6:4) [Cl2].
IR: ν = 3294, 3088, 3066, 3032, 2971, 2927, 2855, 1634, 1542, 1364,
˜
1
1236, 909, 687, 608, 481, 458 cm–1. H NMR (400 MHz, CDCl3): δ =
7.41–7.22 (m, 5 H), 6.40 (br. s., 1 H), 4.44 (d, J = 5.6 Hz, 2 H), 4.26
(br. s., 1 H), 2.35 (s, 2 H), 1.26 (s, 6 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = [ppm] = 172.4, 138.1, 128.9, 127.9, 127.7, 69.7, 47.8, 43.5,
29.5 ppm. LRMS (ESI): m/z = 190.1 (100) [(M – HO)+], 208.1 (64) [M
+ H+], 209.1 (7) [M + 2H+], 230.1 (8) [M + Na+]. HRMS (ESI): m/z
calcd. for C12H17NO2Na+: 230.1151; found 230.1150.
N-(1-Phenylethyl)pivalamide (3pd): By following general proce-
dure D, N-(1-phenylethyl)pivalamide (3pd; 0.003 g, 8 %) was ob-
tained as a white solid after chromatography (PE/EtOAc, 9:1 → 1:1).
Rf (PE/EtOAc, 1:1) = 0.71 [KMnO4]. 1H NMR (600 MHz, CDCl3): δ =
7.37–7.23 (m, 5 H), 5.79 (s, 1 H), 5.11 (p, J = 7.1 Hz, 1 H), 1.48 (d, J =
6.9 Hz, 3 H), 1.20 (s, 9 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 177.6,
143.7, 128.8, 127.4, 126.2, 48.6, 38.8, 27.7, 21.9 ppm. The analytical
data are in agreement with previously reported data.[62]
3-Hydroxy-3-methyl-N-(1-phenylethyl)butanamide (3nd): By fol-
lowing general procedure D, 3-hydroxy-3-methyl-N-(1-phenyl-
ethyl)butanamide (3nd; 0.025 g, 67 %) was obtained as a white
solid after chromatography (PE/EtOAc, 8:2 → EtOAc/iPrOH/MeOH,
N-Octylpivalamide (3pe): By following general procedure D,
N-octylpivalamide (3pe; 0.035 g, 93 %) was obtained as a colourless
liquid after chromatography (PE/EtOAc, 9:1 → 3:7). 1H NMR
(600 MHz, CDCl3): δ = 5.63 (s, 1 H), 3.23–3.17 (m, 2 H), 1.50–1.43 (m,
2 H), 1.31–1.21 (m, 10 H), 1.17 (s, 9 H), 0.86 (t, J = 7.0 Hz, 3 H) ppm.
13C NMR (151 MHz, CDCl3): δ = 178.4, 39.7, 38.7, 31.9, 29.7, 29.4,
29.3, 27.7, 27.0, 22.7, 14.2 ppm. The analytical data are in agreement
with previously reported data.[60]
7:2:1). Rf (DCM/MeOH, 95:5) = 0.20 [KMnO4]. IR: ν = 3440, 3276,
˜
3087, 3033, 2980, 2967, 2930, 2876, 1616, 1558, 1493, 1449, 1420,
1398, 1377, 1362, 1344, 1312, 1274, 1246, 1211, 1182, 1154, 1136,
1104, 1076, 1023, 1003, 988, 960, 928, 911, 877, 849, 803, 777, 756,
736, 701, 637, 619, 590, 555, 529, 469, 456 cm–1. 1H NMR (400 MHz,
CDCl3): δ = 7.36–7.22 (m, 5 H), 6.43 (d, J = 7.9 Hz, 1 H), 5.13 (p, J =
7.1 Hz, 1 H), 4.33 (s, 1 H), 2.31 (s, 2 H), 1.48 (d, J = 6.9 Hz, 3 H), 1.24
(s, 3 H), 1.23 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 171.6,
143.1, 128.8, 127.5, 126.2, 69.7, 48.8, 47.9, 29.5, 29.4, 21.9 ppm. LRMS
(EI): m/z = 221 (3) [M+], 203 (5) [(M – H2O)+], 120 (55) [PhCHNHCH3+],
105 (100) [PhCHCH3+], 77 (45) [Ph+]. HRMS (ESI): m/z calcd. for
C13H19NO2Na+: 244.1308; found 244.1307.
N-Benzyladamantane-1-carboxamide (3qa): By following general
procedure E using 4e (27 mg, 0.10 mmol), N-benzyladamantane-1-
carboxamide (3qa, 0.005 g, 18 %) was obtained as a colourless solid
after chromatography (EA/PE, 1:9 → 6:4). Rf = 0.98 (EA/PE, 6:4) [Cl2].
1H NMR (400 MHz, CDCl3): δ = 7.38–7.24 (m, 4 H), 7.25–7.23 (m, 1
H), 5.85 (br. s., 1 H), 4.44 (d, J = 5.6 Hz, 2 H), 2.11–1.97 (m, 4 H), 1.89
(d, J = 2.5 Hz, 6 H), 1.79–1.64 (m, 8 H) ppm. 13C NMR (101 MHz,
CDCl3): δ = 178.0, 138.8, 128.9, 127.8, 127.6, 43.5, 40.8, 39.5, 36.7,
28.3 ppm. The analytical data are in agreement with previously re-
ported data.[63]
3-Hydroxy-3-methyl-N-octylbutanamide (3ne): By following gen-
eral procedure D, 3-hydroxy-3-methyl-N-octylbutanamide (3ne;
0.029 g, 76 %) was obtained as a colourless liquid after chromatog-
raphy (PE/EtOAc, 9:1 → 3:7). IR: ν = 3305, 3098, 2958, 2925, 2855,
˜
1630, 1550, 1465, 1365, 1239, 1152, 908, 603 cm–1 1H NMR
.
(600 MHz, CDCl3): δ = 5.83 (s, 1 H), 4.36 (s, 1 H), 3.30–3.22 (m, 2 H),
2.30 (s, 2 H), 1.54–1.46 (m, 2 H), 1.32–1.23 (m, 16 H), 0.91–0.83 (m,
3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 172.5, 69.6, 47.8, 39.5,
31.9, 29.7, 29.5, 29.3, 29.3, 27.0, 22.7, 14.2 ppm. LRMS (ESI): m/z =
230 (100) [M + H+], 212 (83) [(M – OH)+]. HRMS (ESI): m/z calcd. for
C13H27NO2Na+: 252.1934; found 252.1935.
N-(1-Phenylethyl)adamantane-1-carboxamide (3qd): By follow-
ing general procedure D, N-(1-phenylethyl)adamantane-1-carbox-
amide (3qd; 0.004 g, 10 %) was obtained as a white solid after
chromatography (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) = 0.74
[KMnO4]. 1H NMR (600 MHz, CDCl3): δ = 7.36–7.31 (m, 2 H), 7.31–
7.27 (m, 2 H), 7.25–7.23 (m, 1 H), 5.76 (d, J = 7.3 Hz, 1 H), 5.12 (p,
J = 7.1 Hz, 1 H), 2.06–2.03 (m, 3 H), 1.96–1.94 (m, 2 H), 1.86–1.85
(m, 4 H), 1.75–1.72 (m, 2 H), 1.71–1.69 (m, 2 H), 1.67–1.65 (m, 2 H),
1.47 (d, J = 6.9 Hz, 3 H) ppm. 13C NMR (151 MHz, CDCl3): δ = 176.9,
143.6, 128.6, 127.2, 126.0, 48.2, 42.6, 39.3, 36.5, 36.5, 29.6, 28.2,
21.8 ppm. LRMS (EI): m/z = 283 (14) [M+], 135 (100) [adamantyl+],
104 (43), 79 (50).
N-(1-Phenylethyl)cyclohexanecarboxamide (3od): By following
general procedure D, N-(1-phenylethyl)cyclohexanecarboxamide
(3od; 0.016 g, 43 %) was obtained as a white solid after chromatog-
raphy (PE/EtOAc, 9:1 → 1:1). Rf (PE/EtOAc, 1:1) = 0.70 [KMnO4]. 1H
NMR (600 MHz, CDCl3): δ = 7.36–7.27 (m, 4 H), 7.27–7.22 (m, 1 H),
5.68 (d, J = 7.5 Hz, 1 H), 5.16–5.09 (m, 1 H), 2.07 (tt, J = 11.8, 3.5 Hz,
1 H), 1.90–1.81 (m, 2 H), 1.81–1.74 (m, 2 H), 1.69–1.63 (m, 1 H), 1.47
(d, J = 6.9 Hz, 3 H), 1.46–1.38 (m, 2 H), 1.30–1.20 (m, 3 H) ppm. 13C
NMR (151 MHz, CDCl3): δ = 175.2, 143.6, 128.8, 127.4, 126.2, 48.4,
45.7, 29.9, 29.8, 25.9, 25.9, 21.9 ppm. The analytical data are in
agreement with previously reported data.[59]
N-Octyladamantane-1-carboxamide (3qe): By following general
procedure D, N-octyladamantane-1-carboxamide (3qe; 0.020 g,
50 %) was obtained as a colourless liquid after chromatography (PE/
EtOAc, 9:1 → 3:7). Rf (PE/EtOAc, 8:2) = 0.47 [UV]. IR: ν = 3341, 2904,
˜
1
2851, 1633, 1530, 1452, 1281 cm–1. H NMR (600 MHz, CDCl3): δ =
N-Octylcyclohexanecarboxamide (3oe): By following general pro-
cedure D, N-octylcyclohexanecarboxamide (3oe; 0.030 g, 78 %) was
5.56 (s, 1 H), 3.24–3.19 (m, 2 H), 2.03 (s, 3 H), 1.86–1.82 (m, 6 H),
1.76–1.66 (m, 6 H), 1.50–1.43 (m, 2 H), 1.32–1.23 (m, 10 H), 0.87 (t,
obtained as a colourless liquid after chromatography (PE/EtOAc, 9:1 J = 7.0 Hz, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 177.9, 40.7,
1
→ 3:7). H NMR (600 MHz, CDCl3): δ = 5.55 (s, 1 H), 3.24–3.15 (m, 2
H), 2.04 (tt, J = 11.8, 3.5 Hz, 1 H), 1.87–1.79 (m, 2 H), 1.79–1.72 (m,
2 H), 1.68–1.61 (m, 1 H), 1.50–1.34 (m, 4 H), 1.31–1.18 (m, 13 H),
39.5, 39.5, 36.7, 31.9, 29.8, 29.4, 29.3, 28.3, 27.0, 22.8, 14.2 ppm.
LRMS (ESI): m/z = 292 (100) [M + H+]. HRMS (ESI): m/z calcd. for
C19H34NO+: 292.2635; found 292.2625.
Eur. J. Org. Chem. 2017, 1526–1539
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1
N-Benzylnicotinamide (3ra): By following general procedure E
using tert-butyl 3-oxo-3-(pyridin-3-yl)propanoate (4i; 50 mg,
0.23 mmol), N-benzylnicotinamide (3ra; 0.036 g, 74 %) was ob-
tained as a yellow oil after chromatography (EA/PE, 3:7 → EA). Rf =
Rf = 0.32 (EA/PE, 9:1) [Cl2]. H NMR (400 MHz, CDCl3): δ = 8.00–7.86
(m, 2 H), 7.31–7.26 (m, 2 H), 6.33 (br. s., 1 H), 4.42 (d, J = 5.8 Hz, 2
H), 3.87 (s, 3 H), 2.00 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ =
170.3, 166.9, 143.7, 130.0, 129.3, 127.6, 52.2, 43.3, 23.2 ppm. The
analytical data are in agreement with previously reported data.[65]
1
0.22 (EA/PE, 6:4) [Cl2]. H NMR (400 MHz, CDCl3): δ = 8.93 (dd, J =
2.3, 0.8 Hz, 1 H), 8.65 (dd, J = 4.8, 1.8 Hz, 1 H), 8.20–8.02 (m, 1 H),
7.37–7.26 (m, 6 H), 6.87 (br. s., 1 H), 4.62 (d, J = 5.8 Hz, 2 H) ppm.
13C NMR (101 MHz, CDCl3): δ = 165.6, 152.3, 148.0, 137.9, 135.3,
130.3, 129.0, 128.1, 127.9, 123.6, 44.3 ppm. The analytical data are
in agreement with previously reported data.[46]
N-Benzylcinnamamide (10): 6-Phenyldihydro-2H-pyran-2,4(3H)-di-
one (9; 20 mg, 0.11 mmol, 1.00 equiv.), tetrabutylammonium azide
(120 mg, 0.42 mmol, 4.00 equiv.), 4-PPY (62 mg, 0.42 mmol,
4.00 equiv.) and benzylamine (2a; 23 mg, 0.11 mmol, 2.00 equiv.)
were dissolved in THF (1.7 mL; 0.15
M), and iodine (59 mg,
3-(Octyloxy)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-(hydroxy-
0.23 mmol, 2.20 equiv.) was added. The reaction mixture was stirred
overnight at room temperature. Flash chromatography (EA/PE,
2:8 → 3:7) furnished N-benzylcinnamamide (10; 0.022 mg, 86 %) as
a yellow oil. Rf = 0.73 (EA/PE, 1:1) [Cl2]. 1H NMR (600 MHz, CDCl3):
δ = 7.67 (d, J = 15.8 Hz, 1 H), 7.53–7.46 (m, 2 H), 7.41–7.27 (m, 8 H),
6.42 (d, J = 15.8 Hz, 1 H), 6.00 (br. s., 1 H), 4.57 (d, J = 5.6 Hz, 2
H) ppm. 13C NMR (151 MHz, CDCl3): δ = 165.9, 141.6, 138.3, 134.9,
129.9, 129.0, 128.9, 128.1, 128.0, 127.7, 120.6, 44.0 ppm. The analyti-
cal data are in agreement with previously reported data.[66]
methyl)tetrahydro-2H-pyran-3-yl]benzamide (3tv):
amine hydrochloride (0.038 g, 0.17 mmol, 1.50 equiv.) was sus-
pended in DMF (0.7 mL, 0.10 ) and NaH (60 % dispersion in min-
D-(+)-Glucos-
M
eral oil, 0.007 g, 0.16 mmol, 1.40 equiv.) was added. The suspension
was stirred for 30 min. tert-Butyl 2,2-diazido-3-[3-(octyloxy)phenyl]-
3-oxopropanoate (1t; 0.050 g, 0.12 mmol, 1.00 equiv.) in DMF
(0.5 mL) was added and the suspension was stirred for 2.5 d. The
suspension was purified by chromatography over silica (PE/EtOAc,
1:1 → EtOAc/iPrOH/MeOH, 50:40:10) to give a 68:32 mixture of dia-
stereomers (NMR) of 3-(octyloxy)-N-[(3R,4R,5S,6R)-2,4,5-trihydroxy-6-
(hydroxymethyl)tetrahydro-2H-pyran-3-yl]benzamide (3tv; 0.030 g,
Acknowledgments
63 %) as a white solid. Rf (DCM/MeOH, 9:1) = 0.37 [CAM]. IR: ν =
˜
Supporting works by My Linh Tong and Martin Jübermann are
gratefully acknowledged.
3287, 2953, 2921, 2849, 1640, 1608, 1579, 1538, 1485, 1466, 1440,
1387, 1367, 1324, 1296, 1263, 1229, 1153, 1129, 1108, 1088, 1055,
1017, 953, 921, 886, 864, 795, 776, 754, 705, 686, 667, 647, 626, 583,
564, 510, 489, 448, 409 cm–1 1H NMR (400 MHz, [D6]DMSO, two
.
Keywords: Azides · Fragmentation reactions · Acylation ·
diastereomers): δ = 8.14 (d, J = 8.8 Hz, 1 H), 8.00 (d, J = 7.0 Hz, 1
H), 7.49–7.38 (m, 4 H), 7.38–7.30 (m, 2 H), 7.07 (dd, J = 2.6, 1.0 Hz,
1 H), 7.05 (dd, J = 2.4, 1.1 Hz, 1 H), 6.52 (d, J = 6.3 Hz, 1 H), 6.42 (d,
J = 4.3 Hz, 1 H), 5.11–4.86 (m, 4 H), 4.71 (s, 1 H), 4.62 (dd, J = 8.2,
6.1 Hz, 1 H), 4.52 (t, J = 5.8 Hz, 1 H), 4.43 (t, J = 5.8 Hz, 1 H), 4.05–
3.96 (m, 4 H), 3.81–3.58 (m, 7 H), 3.56–3.39 (m, 3 H), 3.24–3.15 (m,
1 H), 3.12–3.09 (m, 1 H), 1.78–1.66 (m, 4 H), 1.46–1.39 (m, 4 H), 1.35–
1.23 (m, 16 H), 0.86 (t, J = 6.9 Hz, 6 H) ppm. 13C NMR (101 MHz,
[D6]DMSO, two diastereomers): δ = 166.1, 166.1, 158.5, 158.4, 136.5,
135.9, 129.2, 129.1, 119.6, 119.5, 117.3, 116.9, 113.2, 113.2, 95.4, 90.4,
76.9, 74.1, 72.1, 71.0, 70.9, 70.0, 67.6, 61.3, 61.2, 57.5, 55.4, 31.2, 28.7,
28.7, 28.7, 25.5, 22.1, 13.9 ppm. LRMS (ESI): m/z = 412 (100) [M
+ H+]. HRMS (ESI): m/z calcd. for C21H33NO7Na+: 434.2149; found
434.2148.
Amides · Amines
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general procedure E using tert-butyl acetoacetate (4a; 50 mg,
0.32 mmol), N-(benzo[d][1,3]dioxol-5-ylmethyl)acetamide (3aw;
0.036 g, 58 %) was obtained as a yellow solid after chromatography
(EA). Rf = 0.30 (EA/PE, 8:2) [Cl2]. 1H NMR (400 MHz, CDCl3): δ = 6.78–
6.67 (m, 3 H), 6.06 (br. s., 1 H), 5.91 (s, 2 H), 4.28 (d, J = 5.8 Hz, 2 H),
1.97 (s, 3 H) ppm. 13C NMR (101 MHz, CDCl3): δ = 170.0, 148.0, 147.0,
132.3, 121.2, 108.5, 108.4, 101.1, 43.6, 23.3 ppm. The analytical data
are in agreement with previously reported data.[61]
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N-Phenethylacetamide (3ax): By following general procedure E us-
ing tert-butyl acetoacetate (4a; 50 mg, 0.32 mmol), N-phenethyl-
acetamide (3ax; 0.031 g, 61 %) was obtained as a yellow solid after
chromatography (EA). Rf = 0.24 (EA/PE, 8:2) [Cl2]. 1H NMR (600 MHz,
CDCl3): δ = 7.34–7.15 (m, 5 H), 5.63 (br. s., 1 H), 3.60–3.41 (m, 2 H),
2.81 (t, J = 7.0 Hz, 2 H), 1.93 (s, 3 H) ppm. 13C NMR (151 MHz, CDCl3):
δ = 170.1, 139.0, 128.8, 128.7, 126.6, 40.8, 35.8, 23.4 ppm. The ana-
lytical data are in agreement with previously reported data.[64]
Methyl 4-(Acetamidomethyl)benzoate (3ay): By following general
procedure E using tert-butyl acetoacetate (4a; 50 mg, 0.32 mmol),
methyl 4-(acetamidomethyl)benzoate (3ay; 0.049 g, 75 %) was ob-
tained as a colourless solid after chromatography (EA/PE, 9:1 → EA).
Eur. J. Org. Chem. 2017, 1526–1539
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Received: December 21, 2016
Eur. J. Org. Chem. 2017, 1526–1539
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1539
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