Synthesis of Amides from Alcohols and Amines Through a Domino Oxidative Amidation and Telescoped Transamidation Process

Article abstract of DOI:10.1002/ejoc.201800378

The amide bond formation is of paramount importance in organic synthesis, both within academic research and industrial development and manufacturing of pharmaceutical chemicals and other biologically active compounds. Despite this fact, as well as the ever-increasing treatment costs of side streams and other environmental concerns regarding handling and transportation of hazardous reagents, contemporary synthesis has elicited few new reactions and methods for the preparation of amides. Herein, we reveal a high yielding and expedite two-step telescoped synthetic process that comprises a domino oxidative amidation and transamidation for the creation of amides. The process utilizes alcohols and amines as reaction pairs with TEMPO and Fe ions as catalytic system and 1,3-dichloro-5,5-dimethyl hydantoin as a terminal oxidant. The oxidative amidation and transamidation process is conducted under benign reaction conditions and short reaction time (≈ 30 min.) in a two-step telescoped fashion by means of a multi-jet oscillating disk (MJOD) continuous-flow reactor platform. The disclosed process integrates alcohol oxidation and amide formation to afford target amide in yields up to 90 %. The method operates with both primary and secondary amines together, but was hampered when bulky amines and/or alcohols were used as reagent/substrate.

Full text of DOI:10.1002/ejoc.201800378

A Journal of
Accepted Article
Title: Synthesis of amides from alcohols and amines thru a domino
oxidative amidation and telescoped transamidation process
Authors: Audun Drageset and Hans-René Bjørsvik
This manuscript has been accepted after peer review and appears as an
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of the final Version of Record (VoR). This work is currently citable by
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201800378
Link to VoR: http://dx.doi.org/10.1002/ejoc.201800378
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10.1002/ejoc.201800378
European Journal of Organic Chemistry
Accepted Article
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European Journal of Organic Chemistry - ejoc.201800378
Synthesis of amides from alcohols and amines thru a
domino oxidative amidation and telescoped transamidation process
Audun Drageset and Hans-René Bjørsvik*
Department of Chemistry, University of Bergen, Allégaten 41, N-5007 Bergen, Norway
eMail: hans.bjorsvik@kj.uib.no, telphone: +47 55 58 34 52, web: http://folk.uib.no/nkjhn/
Graphical abstract
Cl
N
2
R1
N
1
O
HO
O
O
O
H
O
R2
N
O
N
Cl
N
N
R1
FeCl3
R2
NH
50 oC, 1 h
NaHCO3, CH3CN
35 oC, 20 min.
O
Text for the table of content
Amides are synthesised from alcohols and amines by means of a domino oxidative amidation and
transamidation process. The process is catalysed by TEMPO with iron ions as co-catalyst and 1,3-
dichloro-5,5-dimethylhydantoin as the terminal oxidant. The process is conducted under benign
reaction conditions using a multi-jet oscillating disk (MJOD) continuous flow reactor platform or
using the classical batch approach. Target amides were achieved in yields of up to 90%. The method
operates with both primary and secondary amines with benzyl and alkyl alcohols.
Key Topic
Synthetic method – amidation.
Abstract: The amide bond formation constitute a reaction of paramount importance in organic
synthesis, both within academic research and industrial development and manufacturing of
pharmaceutical chemicals and other biologically active compounds. Despite this fact, as well as the
ever-increasing treatment costs of side streams and other environmental concerns regarding
handling and transportation of hazardous reagents, contemporary synthesis has elicited few new
reactions and methods for the preparation of amides. Herein, it is revealed a high yielding and
expedite two-steps telescoped synthetic process that comprises a domino oxidative amidation and
transamidation for the creation of amides. The process utilizes alcohols and amines as reaction
pairs with TEMPO and Fe ions as catalytic system and 1,3-dichloro-5,5-dimethyl hydantoin as a
terminal oxidant. The oxidative amidation and transamidation process is conducted under benign
reaction conditions and short reaction time (≈30 min.) in a two-step telescoped fashion by means
of a multi-jet oscillating disk (MJOD) continuous flow reactor platform. The disclosed process
integrates alcohol oxidation and amide formation to afford target amide in yields up to 90%. The
method operates with both primary and secondary amines together, but was hampered when bulky
amine and/or alcohol were used as reagent/substrate.
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Introduction
Numerous compounds and advanced materials comprise the amide group, whereof countless of
pivotal importance in society and industry. Amides can be synthesized by means of a number of
classical synthetic methods including the Schotten-Baumann reaction,[1] the Schmidt reaction,[2]
the Beckmann rearrangement,[ 3 ] the Ritter reaction,[ 4 ] the Staudinger reaction,[ 5 ] the multi-
component based Ugi reaction,[6] and some more contemporary methods including aminolysis of
esters,[7] transamidation of primary amides,[8] amino carbonylation of haloarenes,[9] oxidative
amidation of aldehydes,[ 10 ] oxidative amidation of alcohols,[ 11 ] and metal catalysed N-C bond
formation.[12] Renewed interests were lately devoted towards the amide bond synthesis[13] due to
steady emerging requirements and legislation for more environmentally benign production
processes and cost control in the industry as well as necessities in de novo synthesis and
modifications of highly complex proteins, peptides, and small molecules for pharmaceuticals and
other fine chemical applications.
A long-standing project in our laboratory is devoted to the design, implementation, and
development of new continuous flow processes. Within this research activity, we investigated the
two-steps Togo nitrile synthesis[ 14 ] as a model system for continuous flow synthesis of
benzonitriles from benzyl alcohols, Scheme 1.
The Togo nitrile synthesis might utilize 1,3-diiodo-5,5-dimethylhydantoin (DIH) as a terminal
oxidant in a Montanari type oxidation (that is a catalytic oxidation process that involves TEMPO
free radical and a terminal oxidant, which originally was sodium hypochlorite, see Scheme 5).[15] In
a following step, oxidation with iodine or DIH in the presence of aqueous ammonia affords target
nitrile.
1
2
H3C
H3C
CH3
CH3
(5%)
N
O
I2 (1.5 equiv.)
NH3 (aq)
20 oC, 2 h
R
N
R
OH
R
O
Oxidant,
CH2Cl2 , 20 o
C
Scheme 1. Togo two-step nitrile synthesis starting from alcohol.[14]
Results and Discussion
For our outlined continuous flow process, we wanted to examine whether the DIH oxidant could be
replaced with the readily available and low-cost chlorinating / oxidising reagent 1,3-dichloro-5,5-
dimethylhydantoin (DCH), and whether this oxidant could be utilized for both of the two steps of
the process.
Our outline for a continuous flow process for the preparation of nitrile from its corresponding
alcohol was constituted by a two-steps telescoped process (1 ® 2 ® 3): (i) oxidation of alcohol 1
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to aldehyde 2 by means of Montanari type oxidation,[15] and then (ii) an oxidative conversion of 2
to the target nitrile 3, Scheme 2.
We started investigating each of the two distinct steps separately using a continuous flow multi-jet
oscillating disk (MJOD) reactor platform previously designed and developed by our group.[16] The
MJOD continuous flow reactor is realized in stainless steel and TeflonTM and operates with a total
reactor volume on a multi-mL scale, although the MJOD reactor was designed to possess a
favourable ratio between the reactor surface area (A) and the reactor volume (V) to achieve a ratio
! ≈ 10, when V=50 mL. The continuous flow reactor platform we used in this study is shown in
"
Figure 1. Nevertheless, the expected product benzonitrile 3 was not obtained, but benzylamide 5
in good yield (66%). Samples collected during the course of the reaction revealed that the aldehyde
2 was absent, although 3-benzoyl-5,5-dimethylimidazolidine-2,4-dione 4 (that is the intermediate
amide IA) was observed. In fact, after a reactor residence time of 20 min., a quantitative yield of 4
was observed, Scheme 2.
Cl
CN
N
O
O
HO
N
N
Cl
O
O
2
3
NH4OH
50 oC, 60 min.
TEMPO (10%)
DCH (2 equiv.)
2
1 M NaHCO3 (2.5 equiv.)
CH3CN, 35 oC, 20 min.
1
O
NH2
O
O
1
N
HN
O
4 (IA)
5
Scheme 2. Introductory experiment conducted on a MJOD flow reactor platform. Expected reaction path did not take
place as anticipated (1 ® 2) that comprise a Montanari oxidation that affords the intermediate aldehyde 2. In
subsequent step, an oxidative conversion (2 ® 3) was expected to take place to afford the corresponding nitrile 3.
Altogether, a domino oxidative amidation and transamidation process (1 ® 4 ® 5) occured.
Figure 1. Processflow diagramfor the MJODflow reactor platform adaptedand utilized for the continuous flow domino
oxidative amidation and transamidation process. R1-R3 and R5 are reagent / substrate solution reservoirs, R4-STR:
hold-up reservoir (stirred reactor), R6: post-reaction mixture reservoir P1-P5: pumps, MJOD1-2: multi-jet oscillating
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disk (MJOD) reactor body, M1-2: electrical motor for oscillator (cam mechanism), O1-2: oscillator - cam mechanism,
M4: electrical motor, C/HE1-2: Cooler/heater (heat exchanger).
These initial results spurred us to undertake further investigations of the influence of the various
process variables on the outcome and course of the reaction. When one equivalent base was used,
the aldehyde 2 was produced in excellent yield (entry #2, Table 1), which correspond to a quantity
demanded for one cycle of the Montanari oxidation (Scheme 5).[15]
Table 1. Screening experiments
Cl
N
O
O
OH
O
O
N
Cl
N
O
NH
+
Catalyst
NaHCO3 , CH3CN
T oC, t [ min.]
O
1
2
4 (IA)
Catalyst
Qnty [%]
Oxidant
t
Base
y2
[%]
nd
y4
[%]
66[b]
<5%
0
#
[min.]
[equiv.]
Type
Type
DCH
DCH
DCH
DCH
DCH
DCH
DCH
DCH
DCH
DCH
DCH
[equiv.]
1.3
1[a]
20 TEMPO
20 TEMPO
60 TEMPO
60 TEMPO
60 TEMPO
10
10
5
2.47
1
2[a]
3
1.3
>95
0.7
1
>98
>98
>98
93
4
5
1.4
1
0
5
5
1.4
2
0
6
60 TEMPO / FeCl3 5 / 1
60 TEMPO / FeCl3 5 / 1
60 TEMPO / FeCl3 5 / 1
90 TEMPO / FeCl3 5 / 1
90 TEMPO / FeCl3 5 / 1
150 TEMPO / FeCl3 5 / 1
90 TEMPO / FeCl3 5 / 1
150 TEMPO / FeCl3 5 / 1
90 TEMPO / FeCl2 5 / 1
1.4
1
5
7
1.4
2
52
44
62
96
8
1.4
3
35
9
1.4
3
nd
10[d]
11
12[c]
13
14
15[d]
16[d]
17[d]
0.68
0.99
2
24[e] 70
3
3
>98
nd
93
0
Ca(OCl)2 2.0
3
DCH
DCH
DCH
DCH
DCH
1.4
2
>96
86
0
1.4
2
9
90 FeCl3
1
5
0.68
0.68
0.68
2
>96
>98
93
90 TEMPO
2
0
90 t-BuOOH / FeCl3 75 / 1
2
5
[a] Experiment was conducted in a MJOD reactor manufactured of Stainless steel. Iron ion thus present.
[b] Isolated yield of amide after transamidation (NH4OH was added). The amide 4 was not isolated.
[c] 5,5-dimethylhydantoin was present i the reaction mixture (1 equivalent).
[d] Benzaldehyde was used as starting material.
[e] Aldehyde was not determined (nd). Another side product was observed in a quantity of ≈30% formed from
oxidation of the aldehyde.
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Cl
N
O
R1
N
N
H
N
HO
O
N
O
TEMPO (5%)
FeCl3 (1%)
O
R2
O
Cl
R1
R2
O
DCH (2 equiv.)
(1.5 equiv.)
50 oC, 1 h
2
N
1 M NaHCO3 (3.0 equiv.)
CH3CN, 35 oC, 90 min
1
HN
O
1
4 (IA)
TM
Scheme 3. Domino oxidative amidation of benzyl alcohol 1 and transamidation involving an amine NHR1R2 producing
amide TM
When a base excess (≈2.5 equiv.) was used, the amide 3-benzoyl-5,5-dimethylimidazolidine-2,4-
dione 4 was formed in good yield (entry #1, Table 1). Attempts to reproduce these experiments
(entries #3–5) in a laboratory glass flask failed. It is known that transition metal ions might act as
a co-catalyst with TEMPO in oxidation processes.[17] When our experiments were performed using
our MJOD continuous flow reactor rig (Figure 1), the source for the metal ions (iron) could be the
reactor body itself, as the reactor tube that is in direct contact with the reaction mixture is
manufactured of stainless steel. Thus, it was reasonable to assume that iron ions operated as co-
catalyst with TEMPO. Additional experiments performed in the laboratory glass flask were
conducted with the presence of iron ions (entries #6-9), which resulted in outcomes in line with
the results obtained using the continuous flow MJOD reactor. The telescoped domino oxidative
amidation and transamidation process alongside the optimized reaction conditions is provided in
Scheme 3.
Reaction mechanism.
After a brief assessment of potential reaction pathways, we realized that a number of mechanistic
reaction steps might be involved. Some might include radical reaction steps, since TEMPO free
radical was imperative in order to operate the process. An intermediate amide (IA) and final
product amid (TM) were observed, transformation that also might involve an in-situ formed acid
chloride. A third possibility was a Montanari type oxidation (Scheme 5) as an integral part of the
overall process.
Radical reaction steps. With the goal to elucidate whether radical reaction pathways were involved
in the oxidative amidation, two distinct reaction experiments were carried out: (i) TEMPO free
radical that might operate as an free radical initiator was replaced by an alternative radical species;
tert-butyl hydroperoxide (entry #17, Table 1). The outcome of this experiment revealed trace
amounts only of the intermediate amide (IA) 4, which suggest that TEMPO is a key component,
which do not operates as an radical initiator only. (ii) Attempts to trap an expected acyl radical did
not afford the anticipated piperidin-1-yl benzoate product [Scheme 4(a)], which further on indicate
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that free radicals are not involved in the reaction pathway[18] other that the oxidation of the TEMPO
free radical.
In-situ formation of an acid chloride. Another potential reaction pathway involves an acid chloride,
which can be formed from aldehyde [18,19] by reaction with the N-formylformamide (N–Cl) moiety
of 5,5-dimethyl-hydantoin. This hypothesis was verified by a reaction experiment involving
benzoyl chloride 7 and 5,5-dimethylhydantoin (DMH), Scheme 4 (b). The expected product 3-
benzoyl-5,5-dimethylhydantoin 4 was achieved in low yield only (12%), which suggest that the
reaction essentially take place following some different mechanistic steps that not involves an acid
chloride.
(a)
N
O
O
O
(1 equiv.)
FeCl2
or FeCl3
N
O
NaHCO3, 35 oC, 2 h
6 (nd)
H
N
O
Cl
O
(b)
O
N
O
N
O
H
FeCl3
NaHCO3 , CH3CN
35 oC, 24h
HN
O
7
IA (12%)
Scheme 4. (a) Attempts to trap a potential free radical (acyl). (b) Attempt to couple (thought produced in-situ)
benzoic acid chloride 7 with 5,5-dimethylhydantion (DMH).
Selective oxidation of the alcohol into aldehyde. The Montanari type oxidation[15] of alcohols entails
a mechanisms that involves TEMPO free radical as a pre-catalyst that together with a terminal
oxidant, which here is 1,3-dichloro-5,5-hydantoin (DCH), can perform selective oxidation of the
alcohol substrate to the corresponding carbonyl compound. As outlined in Scheme 5, the
stoichiometry of this reaction request 1 mole of the oxidant (the N–Cl moieties are consumed in
two steps) per mole of produced carbonyl compound (aldehyde). Since DCH is used as the terminal
oxidant, one mole of 5,5-dimethylhydantoin (DMH) is produced as a by-product per mole of
produced carbonyl compound, which also implies that both of the N-Cl moieties of DCH are
involved in the catalytic cycle, see entries #1-5 of Table 1. Oxidation of alcohol was successfully
completed following the stoichiometry proposed in Scheme 5.
Reaction pathways involving TEMPO with Fe ions as co-catalyst have previously been described,[20]
but iron can also form complexes with aldehydes,[21] and amides,[22] which make the moiety more
reactive.
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H
H
R1
R1
H
H
O
O
OH
Cl
Cl
N
N
O
DCH
O
N
O
HN
Cl
N
N
TEMPO
O
O
O
N
O
R1
H
O
HN
O
NH
H
N
H
OH
R1
DMH
H
O
Scheme 5. Montanari type oxidation using 1,3-dichloro-5,5-dimethylhydantoin (DCH) as the terminal oxidant. The
stoichiometry for the reaction is 1 mole terminal oxidant DCH (two N-Cl moieties) per 1 mole of alcohol substrate
producing 1 mole of aldehyde and 1 mole of by-produduct DMH (5,5-dimeyhylhydantoin).
Our initial idea was evaluated by replacing the alcohol substrate with the corresponding aldehyde
that subsequently reacted with Fe ions and further on attempted reacted with 5,5-
dimethylhydantoin (DMH, the side product fromthe Monanari oxidation), however this experiment
did not afford the amide intermediate IA. However, in an experiment (entry #10) using an
increased quantity of DCH present, the intermediate amide IA was formed in a yield of 70%. This
reaction suggest that the alcohol to carbonyl conversion is not an integral part of the overall process
of the observed process.
An experiment (entry #11) using the alcohol as substrate with only one mole equivalent of the
terminal oxidant DCH, revealed a quantitative yield of expected amide, from which we advise that
the alcohol react with the iron/TEMPO complex[23] that acts as the catalyst for the generation of
the proposed iron complex R1–CHO-Fe.III 2,2,6,6-tetramethylpiperidin-1-ol is then oxidized by DCH
that produce TEMPO and finally the Iron/TEMPO complex.
In order to evaluate whether 1-chloro-5,5-dimethylimidazolidine-2,4-dione or 5,5-dimethyl-
imidazolidine-2,4-dione (DMH) reacted with the Fe-complex (R1–CHO-FeIII), an experiment was
conducted where DCH was replaced with Ca(OCl)2 as the terminal oxidant (entry #12), but with the
presence of 5,5-dimethylimidazolidine-2,4-dione. This experiment reveal that the Montanari
oxidation type oxidation (Scheme 5) was the only operating one as no amide was produced. This
suggests that the N–Cl moiety[24] react with the R1-CHO-FeIII complex. On the basis on this we
suggest an reaction mechanism as outlined in Scheme 6.
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Amine
NH2
H
R2
O
O
N
H
FeII
HO
N
R2
N
N
O
O
R1
R1
R1-CHO-FeIII
O
N
O
N
O
N
H
N
H
N
O
Cl
TEMPO
O
IA
FeIII
O
Cl
O
N
O
H
H
Base
R2
R1
R1
H
H
NH
O
R1
TM
O
N
N
H
N
H
O
HN
Cl DCH
OH
OH
Alcohol
Amide
DMH
Scheme 6. Proposed reaction mechanisms for the TEMPO/Fe ion catalysed domino oxidative amidation (producing
intermediate amide IA) followed by a transamidation reaction that produce target amide TM.
Some addition questions that were raised: (i) the importance of the quantity of base, and (ii) the
redox state of the iron ions.[18] Experiments using reduced base quantity (entry #13) and replacing
FeCl3 with FeCl2 (entry #14), respectively, afforded both similar high outcome of the amide.
The ultimate step of the process (frame VI) comprise a reaction between the amide intermediate
IA and an amine under the formation of the target amide TM. The electron withdrawing carbonyls
in the 5,5-dimethyl hydantoin moiety facilitate the reaction by weakening the amide C−N bond
allowing the reaction to proceed under exceptionally benign reaction conditions and without the
involvement of any transition metal catalyst.
Scope and limitation of the process. Variation of the amine in the trans amidation step was
investigated by a series of assorted amines that were reacted with two various intermediate amides
IA, Table 2.
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Table 2. Scope of reaction – a selection of various primary and secondary amines that are reacted with benzyl alcohol
and the aliphatic alcohol 2-methylpropan-1-ol.[a,b]
H
O
O
O
N
R2
R2
R1
R
R
N
R
N
EtOAc
50 oC, 60 min
R1
NH
4
O
5
H
N
H
N
NH
-2.40
-1.87
3.89
4.61
NH2
S
H
N
H
N
NH
3 9.21
8.97
NH
NH 10.45
9.02
7.18
O
N
NH2
H
N
10.76
10.76
O
10.69
NH2
NH2
10.58
O
O
O
O
N
NH
N
NH2
N
H
5a (>99%)
5b (93%)
5c (72%)
5d (73%)
O
5e (56%)
O
N
O
N
O
N
O
N
H
N
H
O
N
5f (38%)
5g (79%)
5h (80%)
O
5i (52%)
O
5j (95%)
O
O
N
O
N
N
H
N
N
H
5m (90%)
5n (88%)
5o (34%)
5k (<1%)
O
5l (nd)
O
N
O
N
N
H
5p (51%)
5q (12%)
S
5r (nd)
[a]
[b]
The pKa values given next to the amines were estimated by means of the Advanced Chemistry Development
(ACD/Labs) Software V11.02 (© 1994-2017 ACD/Labs). Data were retrived from SciFinder 12.12.2017.
nd = not detected.
In addition, a series of alcohols were submitted for the domino oxidative amidation and trans
amidation process using N,N-diethylamine in the transamidation step, Table 3. The expriments
reveals that the reaction proceed to afford high yield of the target amide TM, when non bulky
alcohols were used.
Table 3. Scope of reaction – a selection of various alcohols were submitted for the domino oxidative amidation and
trans amidation process using the N,N-diethylamine in the trans amidation step.
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1
Cl
N
O
N
N
O
HO
O
O
Cl
O
TEMPO (5%)
R
1
FeCl3 (1%)
N
R
DCH (2 equiv.)
1 M NaHCO3 (2.0 equiv.)
CH3CN, 35 oC, 90 min.
HN
O
4
2
(1.5 equiv.)
NH
N
5
60 oC, 60 min.
O
R
HO
HO
HO
Cl
OH
N
OH
OH
N
N
N
O
O
O
5c (72%)
5n (88%)
5s (nd)[a]
N
O
N
N
O
Cl
O
N
5t (<1%)
5u (90%)
5v (83%)
[a] The substrate naphthalen-1-ylmethanol was oxidized
selectively to 1-naphthaldehyde probably via Montanari
type oxidation
The results from the scope of the method suggest that steric effects and the basicity of the amine
influence the reaction. In general, good to excellent yields were achieved when small primary and
secondary amines were submitted for the process conditions. Amines with low pKa values afforded
low yields only or no product at all. Likewise, bulky amines resulted in lowered yields of target
amides 5.
A selection of amines were reacted with 3-methylbutanol in order to determine if the reaction
operated with aliphatic alcohols, that all afforded expected amides 5m-q (Table 2) in moderate to
high yields. However, in the cases when 3-methylbutanol was used, the corresponding amide 4 was
readily oxidised to the corresponding carboxylic acid, and was thus not isolated before the
subsequent transamidation reaction. The achieved results from the scope and limitation study
suggest that the reaction follows similar trends as benzyl alcohol.
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An prospective industrial applications of the new amidation process.
N,N-diethyl-meta-toluamide (DEET) 9 is the active ingredient of more than 200 various
commercially available insect repellent formulations for the application on the human body and
clothing’s. The insect repellents containing DEET 9 are used to control biting flies, mosquitoes, and
numerous other insects.[25] DEET 9 is synthesised using a multistep synthesis, Scheme 7, whereof
the last step involves the formation of the amide bond of the N,N-diethylamide moiety. Our new
amidation method was tailored for a telescoped continuous flow process for the amidation step for
the synthesis of DEET 9. The two-steps telescoped process was implemented on a MJOD continuous
flow reactor rig[16] that possessed a configuration as sketched in Figure 1. The reagents of the
reservoirs R1 (3-methylbenzyl alcohol, neat), R2 (DCH, TEMPO and FeCl3 dissolved in CH3CN), and
R3 (aqueous NaHCO3) were pumped into the input section of the MJOD1 continuous flow reactor
-
1
-
1
-
1
using the pumps P1 (0.105 mL min. ), P2 (1.74 mL min. ), and P3 (2.36 mL min. ), Figure 1.
The post reaction mixture containing compound 7 was collected at the output section of the
continuous flow reactor and transferred to a stirred hold-up tank (R4-STR). Reservoir R5 was
charged with diethylamine 8. The intermediate 7 and the amine 8 were pumped (P4 and P5) at
adjusted rates and combined at the input section of the continuous flow reactor MJOD2. The overall
telescoped continuous flow process afforded an isolated yield of 79% (2.11 g, 11 mmol, run time of
»15 min.) of target N,N-diethyl-3-methylbenzamide 9 at an overall mass flow rate 11.2 g h-1 over
the developed two-steps telescoped synthetic process.
Cl
O
N
O
NH
N
O
O
N
HO
N
HN
N
Cl
8
O
O
O
(1.2 equiv.)
TEMPO (5%)
DCH (2 eqvn.)
FeCl3 (1%)
1 M NaHCO3 (3 equiv.)
CH3CN, 35 oC, 15 min
50 oC, 15 min
2
1
6
7
9 DEET 79%
Scheme 7. Oxidative amidation  of 3-methylbenzyl alcohol 6 succeeded by transamidation ‚ of the amide
intermediate 5,5-dimethyl-3-(3-methyl-benzoyl)imidazolidine-2,4-dione 7 with diethylamine 8 to achieve target
product N,N-diethyl-3-methylbenzamide 9 (DEET).
Conclusions
In summary, we have developed a novel expedite two-step telescoped continuous flow process for
the synthesis of amides using alcohols and amines as substrate and reagent pairs.
The unprecedented process emerges as a domino oxidative amidation followed by a
transamidation. The established process was successfully used for the production of a series of
amides and the commercial insect repellent DEET (N,N-diethyl-3-methylbenzamide) both on a
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10.1002/ejoc.201800378
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milli-gram scale batch approach and on a multi-gram scale continuous flow approach that was
implemented on a MJOD continuous flow reactor platform.
Experimental Section
Chemical analysis. The GC–MS analyses were conducted using a capillary gas chromatograph
furnished with a fused silica column (L 25 m, 0.20 mm i.d., 0.33 μm film thickness) with a helium
pressure of 200 kPa, splitless /split injector and flame ionization detector. 1H NMR spectra were
recorded on a NMR spectrometer that operating at 500 MHz. 13C NMR spectra were recorded with
a NMR spectrometer operating at 125 MHz. Chemical shifts were referenced to the deuterated
solvent used for the NMR experiment.
The continuous flow MJOD reactor. The Multi-Jet Oscillating Disk (MJOD) flow reactor platform have
previously been described in detail.16 A short account follows herein. The MJOD flow reactor
platform configuration is outlined in Figure 1. The continuous flow MJOD reactor is a tubular
reactor with an internal oscillating shaft. The internal shaft is fitted with multiple (N) multi-jet disks
and the oscillating motion (A, f) is delivered by a electrical motor. Each multi-jet disk has four (4)
jets and every disk is separated by a fixed length (hcavity). The whole length of the reactor tube is
encapsulated by a heating/cooling jacket. The reagents and substrate solutions are transferred to
supply reservoirs that is connected to their corresponding pumps. The pump rate is adjusted to
give the desired residence time and mole equivalents. Every reactor inlet is fatted with a one-way
valve in order to prevent “kick-back” created by the oscillator (the multi headed piston shaft). The
line connecting P2 to MJOD1 was fitted with an extra T-connector for the removal of build-up of
precipitate in the inlet. Pressurised solvent was flushed through the line in order to remove
precipitated and thus assure free tuning for accurate reagent supply to the flow reactor tube.
MJOD flow synthesis procedure to of benzylamide. A multi-jet oscillating disk flow reactor
platform16 MJOD1 (Vtot 65 mL, L = 150 cm, rosc = 1.5 s-1) was pre-heated at heated at 35 oC. Benzyl
alcohol (6.0 mL, 57.8 mmol) was transferred to the reagent reservoir R1 (Vtot 6.0 mL). NaHCO3
(12.034 g, 143 mmol) was dissolved in water (140 mL) and transferred to the reagent reservoir R2
(Vtot 140 mL). 1,3-dichloro-5,5-hydantoin (22.00 g, 111 mmol) and (2,2,6,6-tetramethylpiperidin-
1-yl)oxyl (0.898 g, 5.75 mmol) were dissolved in acetonitrile (total volume 90 mL) and transferred
to the reservoir R3 (Vtot 90 mL). The reagents (R1–R3) were introduced into to the MJOD1 reactor
using pumps P1 – P3 at feeding rates that afforded a residence time of t = 20 min. The actual feeding
rates were: P1: 0.083 mL min-1, P2: 1.928 mL min,-1 and P3: 1.239 mL min.-1 The crude output
product from MJOD1 was collected in a stirred hold-up tank HT1-R4 (Vtot 236 mL). NH4OH (28%)
was transferred to reservoir R5 (Vtot 100 mL). The MJOD flow reactor MJOD2 (Vtot 96 mL, L = 265
cm, rosc = 1.5 s-1) was cooled at 0 oC. The intermediate product of the hold-up tank HT1 and NH4OH
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of reservoir R5 were pumped into MJOD flow reactor MJOD2 at rates (P4: 1.09 mL min-1, P5: 0.46
mL min-1) to afford a residence time of t = 60 min. The crude reaction mixture was collected in
reservoir R6 (Vtot 336 mL). The reaction mixture was extracted with ethyl acetate (5 × 30 mL). The
organic layers were combined and washed with brine (3 × 15 mL), dried over anhydrous sodium
sulfate, and filtrated. The solvent was removed under reduced pressure on a rotary evaporator to
afford benzylamide in a yield of 66% (4.61 g, 38.14 mmol).
3-benzoyl-5,5-dimethylimidazolidine-2,4-dione. A magnet stirrer bar was placed in the
reaction tube (10 mL) that was capped and flushed with argon. Benzyl alcohol (0.1 mL, 0.9 mmol),
acetonitrile (1 mL) and 1 M NaHCO3 (3 mL, 3 mmol) were transferred to the reaction tube and
heated (35 oC) and stirred. An aqueous solution of FeCl3 (8.1 mg mL-1, 0.2 mL, 0.01 mmol) was then
added to the reaction vial, whereupon a solution of 1,3-dichloro-5,5-hydantoin (0.394 g, 2.0 mmol)
and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (0,007 g, 0.045 mmol) in acetonitrile (2 mL) was added
over a period of 10 min. This reaction mixture was stirred for 80 min. The post reaction mixture
was extracted with ethyl acetate (4 × 5 mL), washed with brine (3 × 3 mL), dried over anhydrous
sodium sulfate, and then filtered. The solvents were removed under reduced pressure on a rotary
evaporator. Crude yield of target product 3-benzoyl-5,5-dimethylimidazolidine-2,4-dione was
determined to 96 % (GC). The post reaction mixture was purified by means of flash
chromatography (EtOAc : Hx)(1 : 9 → 4 : 6) and analyzed by means of 1H-NMR (500MHz, CDCl3) δ:
13
8.15 (dd, 2H), 7.67 (t, 1H), 7.52 (t, 2H), 1.52 (s, 6H). C-NMR (125 MHz) δ: 174.7, 166.1, 153.1,
134.7, 132.0, 130.4, 128.7, 59.2, 25.4. m/z HRMS (EI+): Found: [M]232.08433, Calculated:
232.08479.
General method, benzyl amide synthesis procedure: A magnet stirrer bar was transferred to a
reaction vial (8 mL). 3-Benzoyl-5,5-dimethylimidazolidine-2,4-dione (0.194 g, 0.6 mmol) was
transferred the reaction vial and dissolved in ethyl acetate (2 mL) and then sealed with a septum.
The reaction vial was immersed into an oil bath an heated at 50 oC. Then N-butyl amine (0.12 mL,
1.2 mmol) was added and the reaction mixture was continuous stirred for another 60 min. The
reaction mixture was filtered to remove precipitated the 5,5-dimethylhydantoine. The filtrate was
the extracted with ethyl acetate (3 × 5 mL). The organic layers were combined and washed with
brine (3 × 3 mL), dried over anhydrous sodium sulphate, and filtered. The organic solvents wre
removed under reduced pressure on a rotary evaporator. The obtained solid crude was further
purified by means of flash chromatography (EtOAc : Hx)(2 : 8) to afford N-butylbenzamide in a yield
of 93 % (0.099 g, 0.56 mmol).
General method, alcohol screening. A magnetic stirrer bar was transferred to a reaction tube (10
mL), sealed with a septum and flushed with argon. Benzylalcohol (0.12 mL, 0.12 g, 0.99 mmol),
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acetonitrile (1 mL) and 1M NaHCO3 (2 mmol, 2 mL) were transferred to the reactor tube, which was
then placed in an oil bath and warmed at 35 oC and stirred while solutions of FeCl3 in H2O (8.1 mg
mL-1, 0.2 mL, 0.01 mmol) and 1,3-dichloro-5,5-hydantoin (0.197 g, 1.0 mmol) and (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (0,007 g, 0.045 mmol) in acetonitrile (2 mL) were added. The
reaction mixture was stirred for 90 min., then the reaction temperature was increased to 60 °C and
diethylamine (0.15 mL, 0.11 g, 15 mmol) was added. The reaction was left for another 60 min. under
stirring. The post-reaction mixture was extracted with ethyl acetate (4 × 5 mL) and the organics
was combined and washed with brine (3 × 5 mL) and dried over anhydrous sodium sulphate and
filtered. Solvents were removed under reduced pressure on a rotary evaporator. The isolated crude
prosuct was purified by means of flash chromatography (EtOAc : Hx)(2 : 8) affording N,N-diethyl-
benzamide in a yield of 72%.
Radical trapping experiment.[18] A magnet stirrer bar was transferred to a reaction vial (8 mL),
which then was capped and flushed with argon. Benzyl alcohol (0.1 mL, 0.9 mmol), acetonitrile (1
mL), and aqueous NaHCO3 (1 M, 3 mL, 3 mmol) were transferred to the vial, whereupon the vial
was immersed into an oil bath at a temperature of 35 oC under vigorous stirring. An aqueous
solution of an iron salt (FeCl2 1%, FeCl3 1%, FeCl3 0.5 eqiuv.) was then added. Then a solution of
(2,2,6,6-tetramethylpiperidin-1-yl)oxyl (0.9 mmol) in acetonitrile (2 mL) was added over a period
of 10 min. The reaction mixture was leaved under stirring for 120 min. The reaction mixture was
then extracted with ethyl acetate (4 × 5 mL). The crude isolated solid was analysed by means of a
GC-MS. 2,2,6,6-Tetramethylpiperidin-1-yl benzoate was not observed, which demonstrate absence
of free radicals in the reaction mixture.
Experiment: alternative radical initiator. A magnetic stirrer bar was transferred to a reaction
vial (8 mL), which then was capped and flushed with argon. Benzaldehyde (0.1 mL, 0.9 mmol),
acetonitrile (1 mL) and 1M NaHCO3 (3 mL, 3 mmol) were then transferred to the vial, that was
immersed into an oil bath (35 oC) under vigorous stirring. An aquatic solution of an iron salt (FeCl3
1%) and a solution of 1,3-dichloro-5,5-dimethylhydantoin (1.1 mmol) in acetonitrile (2 mL) were
added, which was followed by a solution of tert-Butyl hydroperoxide (0.6 mmol in water, 0.072 mL).
The reaction was then stirred for 90 min. The post reaction mixture was then extracted with ethyl
acetate (4 × 5 mL), and the crude was analyzed on GC-MS, that revealed a 4 in low yield < 5%.
Experiment: investigate of the reaction mechanism that involves the formation and reaction
with acid chloride. 5,5-dimethylhydantoin (0.2 mmol), NaHCO3 (1 mmol), FeCl3 (0.01 mmol), and
a magnetic stirrer bar were transferred to a reactor vial (2 mL) that was sealed and flushed with
argon. Acetonitrile-d3 (0.7 mL) and benzoyl chloride (0.4 mmol) was added via syringe. The
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o
reaction mixture was immersed in an oil bath (35 C) and stirred vigorously for 24 h. The post
reaction mixture was analyzed by 1H NMR, which revealed a yield of 12% of 4.
3-Methylbutanamide procedure: A magnetic stirrer bar was transferred to a reaction vial (8 mL),
which was capped and flushed with argon. 3-Methylbutan-1-ol (0.1 mL, 0.081 g, 0.9 mmol),
acetonitrile (1 mL) and 1 M NaHCO3 (3 mL, 3 mmol) were transferred to the vial whereupon the
o
vial was immersed into an oil bath (35 C) under vigorous stirring. An aqueous solution of FeCl3
(8.1 mg mL-1, 0.2 mL, 0.01 mmol) was then added to the vial followed by a solution of 1,3-dichloro-
5,5-hydantoin (0.394 g, 2.0 mmol) and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (0,007 g, 0.045
mmol) in acetonitrile (2 mL), which was added over a period of 10 min. The reaction was then
stirred for 80 minutes. Reaction mixture was then extracted with ethyl acetate (4 × 5 mL) and
washed with brine (3 × 3 mL). The organic phase was transferred to reaction flak together with a
magnet. The flask was capped with a septum and heated to 50 °C. n-butylamine (0.12 mL, 0.089 g,
1.21 mmol) was added via syringe and reaction was stirred for 60 min. Reaction mixture was cooled
to room temperature and extracted with Ethyl acetate (3 × 5 mL) organics was combined and
washed with brine (3 × 3 mL) and dried over anhydrous sodium thiosulfate and filtered. Solvents
were removed under reduced pressure on a rotary evaporator. Crude was further purified by
means of flash chromatography (EtOAc : Hx)(2 : 8) affording N-butyl-3-methylbutanamide in a
yield of 90 % (0.81 g, 0.127 mmol).
Syntheis of N,N-diethyl-3-methylbenzamide (DEET), one-pot batch procedure. A magnetic
stirrer bar was transferred to a reaction vial (8 mL) and sealed with a septum. 3-
Methylbenzylalcohol (0.12 mL, 0.12 g, 0.99 mmol), acetonitrile (1 mL) and 1M NaHCO3 (3 mmol, 3
mL) was then added to the vial. The vial was head in an oil bath (35 °C) under vigorous stirring
while An aquatic solution of FeCl3 (8.1 mg mL-1, 0.2 mL, 0.01 mmol) was then added, followed by a
solution of 1,3-dichloro-5,5-hydantoin (0.394 g, 2.0 mmol) and (2,2,6,6-tetramethylpiperidin-1-
yl)oxyl (0,007 g, 0.045 mmol) in acetonitrile (2 mL). The reaction mixture was stirred for 90 min,
afterwards the temperature was increased to 50 °C and Diethylamine (0.12 mL, 0.088 g, 12 mmol)
was added and stirred for 60 min. Reaction mixture was then extracted with Ethyl acetate (4 × 5
mL) and organics was combined and washed with brine (3 × 5 mL) and dried over anhydrous
sodium thiosulfate and filtered. Solvents were removed under reduced pressure on a rotary
evaporator. Crude was further purified by means of flash chromatography (EtOAc : Hx)(2 : 8)
affording N,N-Diethyl-3-methylbenzamide in a yield of >95% (isolated yield of 0.18 g, 0.94 mmol).
Telescoped continuous flow synthesis leading to N,N-diethyl-3-methylbenzamide (DEET).
The MJOD reactor (MJOD1) was prefilled with the reaction solvent (MeCN / H2O). The heat-
exchanger (HE-1) was adjusted at a temperature of 35 °C and the oscillator (O1) was adjusted to a
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frequency f=2.5 Hz. The reservoir R1 was filled with 3-methylbenzylalcohol (1.7 mL, 1.68 g, 14.0
mmol) (R1, Vtot =1.7 mL). Reservoir R2 was filled with a solution of 1,3-dichloro-5,5-hydantoin
(5.924 g, 30.0 mmol), (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (0,218 g, 1.40 mmol) and FeCl3
(0.023 g, 0.14 mmol) in acetonitrile (R2, Vtot = 28 mL). Reservoir R3 was filled with a solution of
NaHCO3 (3.444 g, 42 mmol, 38 mL, 1.1 M) (R3, Vtot = 38 mL). The reagents (R1 – R3) were then
pumped (using pumps P1 – P3) into the MJOD flow reactor MJOD1 at feeding rates to approach a
residence time of t = 15 min. The feeding rates of the various pumps were: P1: 0.105 mL min-1, P2:
1.74 mL min-1, and P3: 2.36 mL min.-1 Anti-clogging pulse in line 2 (between P2 and MJOD1) was
set to inject 0.2 mL acetonitrile every 5 min. The crude product from MJOD1 was collected in a
stirred hold-up tank (HT1-R4) (Vtot = 67.7 mL). The second MJOD reactor (MJOD2) was prefilled
with solvent, heat-exchanger (HE-2) set to 50 °C and oscillation (O2) set to 2.0 Hz. Diethylamine
(1.68 mL, 1.17 g, 16 mmol) was added to reservoir 5 (R5)(R5, Vtot = 1.68 mL). The contents of
reservoir 4 and 5 was pumped (using P4 and P5) into the MJOD reactor (MJOD2) at feeding rates
to approach a residence time of 15 min. The utilized feeding rates were: P4: 6.0 mL min-1, and P5:
0.15 mL min-1. The crude product from MJOD2 was collected in a hold-up tank (HT2-R6). Reaction
mixture was then extracted with Ethyl acetate (4 × 20 mL) and organics was combined and washed
with brine (3 × 15 mL) and dried over anhydrous sodium thiosulfate and filtered. Solvents were
removed under reduced pressure on a rotary evaporator. Reaction gave N,N-Diethyl-3-
methylbenzamide in a crude yield (2.11 g, 11.0 mmol) of 78 % determined by NMR.
N-butylbenzamide (5b).[26] Yield 93 %, 1H-NMR (500 MHz) δ: 7.73 - 7.72 (m, 2H), 7.45 - 7.42 (m,
1H), 7.38 - 7.35 (m, 2H), 6.33 (br, 1H), 3.42 - 3.38 (m, 2H), 1.40 - 1.32 (m, 2H), 0.90 (t, J = 7.26 Hz,
3H). 13C-NMR (125 MHz) δ: 167.6, 134.9, 131.2, 128.5, 126.9, 39.8, 31.7, 20.2, 13.8. GC-MS (EI) m/z
(%): 177.1 (5.5), 134 (16.7), 105.0 (100), 77.0 (46.2).
N,N-diethylbenzylamine (5c).[27] Yield 72 %, 1H-NMR (500 MHz) δ: 7.35 - 7.28 (m, 5H), 3.48 (br,
2H), 3.18 (br, 2H), 1.17 (br, 3H), 1.04 (br, 3H) 13C-NMR (125 MHz) δ: 171.3, 137.3, 129.1, 128.4,
126.3, 43.3, 39.2, 14.2, 12.9. GC-MS (EI) m/z (%): 176.1 (25), 105.0 (100), 77.0 (41.8).
N-(tert-butyl)benzylamine (5d).[28] Yield 73 %, 1H-NMR (500 MHz) δ: 7.70 - 7.69 (m, 2H), 7.47 -
7.43 (m, 1H), 7.41 - 7.37 (m, 2H), 1.46 (s, 9H). 13C-NMR (125 MHz) δ: 166.9, 136.0, 131.1, 128.5,
126.7, 51.6, 28.9. GC-MS (EI) m/z (%):177.1 (9.5), 162.0 (13.3), 105.0 (100), 77.0 (30.2).
N,N-diallylbenzylamine (5e).[29] Yield 56 %, 1H-NMR (500 MHz) δ: 7.42 - 7.34 (m, 5H), 5.86(m,
1H), 5.70 (m, 1H), 5.22 - 5.15 (m, 5H), 4.11 (m, 2H), 3.81 (m, 2H), 13C-NMR (125 MHz) δ: 171.8,
136.3, 133.3, 133.2, 132.8, 130.1, 129.6, 128.4, 126.6, 117.6, 50.8, 47.0. GC-MS (EI) m/z (%): 200.1
(4.0), 160.1 (5.9), 113.0 (7.1), 105.0 (100), 77.0 (51.0).
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(1H-imidazol-1-yl)(phenyl)methanone (5f).[30] Yield 38 %, 1H-NMR (500 MHz) δ: 8.08 (m, 1H)
7.80 - 7.77 (m, 2H), 7.69 - 7-65 (m, 1H), 7.57 - 7.53 (m, 3H), 7.17 - 7.16 (m, 1 H) 13C-NMR (125 MHz)
δ: 166.2, 138.2, 133.6, 131.9, 130.9, 129.8, 129.0, 118.1. GC-MS (EI) m/z (%): 172.0 (3.8), 105,0
(100), 77.1 (88.9).
morpholino(phenyl)methanone (5g).[31] Yield 79 %, 1H-NMR (500 MHz) δ: 7.43 - 7.34 (m, 5H),
3.85 - 3.35 (m, 8H), 13C-NMR (125 MHz) δ: 170.5, 135.4, 129.9, 128.6, 127.1, 66.9. GC-MS (EI) m/z
(%): 190.1 (18.0), 105.1 (100), 77.0 (48.9).
phenyl(piperidin-1-yl)methanone (5h).[32] Yield 80 %, 1H-NMR (500 MHz) δ: 7.39 - 7.34 (m, 5H),
3.69 (m, 2H), 3.32 (m, 2H), 1.69 - 1.63 (m, 4H) 1.54 - 1.46 (m, 2H), 13C-NMR (125 MHz) δ: 170.5,
136.5, 130.1, 129.4, 128.5, 128.4, 126.8, 30.9, 24.6. GC-MS (EI) m/z (%): 188.1 (48.4) 105.0 (100),
77.1 (70.6).
N-(adamantan-1-yl)benzamide (5i).[33] Yield 52 %, 1H-NMR (500 MHz) δ: 7.73 - 7.70 (m, 2H), 7.48
- 7.45 (m, 1H), 7.43 - 7.39 (m,2H), 2.13 (s, 9H), 1.77 - 1.70 (m, 6H) 13C-NMR (125 MHz) δ: 166.6,
136.1 131.0, 128.5, 126.7, 52.3, 41.7, 36.4, 29.5. GC – MS (EI) m/z (%): 255.1 (13), 198.0 (38), 135.1
(5), 105.0 (100), 77.0 (67).
N-phenylbenzylamide (5j).[32] Yield 95 %, 1H-NMR (500 MHz) δ: 7.87 - 7.84 (m, 2H), 7.76 (br, 1H)
7.64 - 7.61 (m, 2H), 7.56 - 7.52 (m, 1H), 7.50 - 7.46 (m, 2H) 7.38 - 7.34 (m, 2H), 7.16 - 7.12 (m, 1H),
13C-NMR (125 MHz). GC – MS (EI) m/z (%): 197.0 (11), 105.0 (100), 77.0 (81). GC-MS (EI) m/z (%):
197.0 (11.0), 105.0 (100), 77.0 (80.6).
1
N-butyl-3-methylbutanamide (5m).[34] Yield 90 %, H-NMR (500 MHz) δ: 5.53 - 5.35 (w, N-H)
3.30 - 3.24 (m, 2H) 2.07 - 2.01 (m, 3H) 1.53 - 1.46 (quintet, 2H) 1.41 - 1.31 (sextet, 2H) 0.99 - 0.91
(m, 9H), 13C-NMR (125 MHz) δ: 172.4, 46.3, 39.1, 31.8, 30.9, 26.2, 22.5, 20.1, 13.7. GC-MS (EI) m/z
(%): 157.1 (6.9), 142.0 (13.0), 115.1 (55.1), 73.0 (66.4) 57.1 (100).
N,N-diethyl-3-methylbutanamide (5n). Yield 88 %, 1H-NMR (500 MHz) δ: 3.38 - 3.33 (q, J = 7.12
Hz, 2H) 3.31 - 3.26 (q, J = 7.12 Hz, 2H) 2.16 - 2.13 (m, 3H) 1.16 - 1.12 (t, J = 7.16, 3H) 1.11 - 1.07 (t, J
= 7.12 Hz) 0.95 - 0.92 (m, 6H), 13C-NMR (125 MHz) δ: 171.2, 42.4, 42.0, 41.9, 40.1, 25.9, 22.7, 14.5,
13.2. GC-MS (EI) m/z (%): 157.1 (5.5), 142.1 (10.0), 115.1 (14.5), 100.1 (24.1), 72.1 (29.0), 58.1
(100).
N-(tert-butyl)-3-methylbutanamide (5o). Yield 34 %, 1H-NMR (500 MHz) δ: 5.34 - 5.10 (w, N-H)
2.09 - 2.01 (m, 1H) 1.91 - 1.89 (d, J = 7.21 Hz, 2H) 1.32 - 1.30 (s, 9H) 0.91 - 0.89 (m, 6H) 13C-NMR
(125 MHz) δ: 171.9, 51.06, 47.2, 28.8, 26.2, 22.4. FT-IR, ν (cm-1): 3309, 3073, 2954, 2868, 1720,
1666, 1641, 1547, 1452, 1391, 1358, 1310, 1260, 1227, 1213, 1170, 931, 679, 603. GC-MS (EI) m/z
(%): 157.1 (3.9), 115.1 (10.2), 58.1 (100).
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N,N-diallyl-3-methylbutanamide (5p). Yield 51 %, 1H-NMR (500 MHz) δ: 5.78 - 5.70 (m, 2H) 5.20
- 5.07 (m, 4H) 3.98 -3.95 (m, 2H) 3.87 - 3.84 (m, 2H) 2.21 - 2.14 (m, 3H) 0.95 - 0.92 (m, 6H) 13C-NMR
(125 MHz) δ: 172.5, 133.6, 133.1, 117.0, 116.5, 49.2, 47.8, 41.8, 25.7, 22.7. GC-MS (EI) m/z (%):
181.1 (2.8), 166.0 (11.9), 124.0 (12.8), 82.4 (27.9),57.1 (74), 56.0 (100).
N-phenyl-3-methylbutanamide (5q).[35] Yield 12 %, H-NMR (500 MHz) δ: 7.52 - 7.48 (m, 2H)
1
7.32 - 7.28 (m, 2H) 7.10 - 7.05 (m, 1H) 2.23 - 2.18 (m, 3H) 1.03 - 0.97 (m, 6H). FT-IR, ν (cm-1): 3282,
3243, 3192, 3131, 3073, 2964, 2964, 1655, 1596,1547, 1488, 1441, 1368, 1318, 1257, 1203, 964,
902, 758, 693, 557, 509. GC-MS (EI) m/z (%): 177.1 (6.6), 93.1 (100).
2-chloro-N,N-diethylnicotinamide (5t): Yield: <1%, GC-MS (EI) m/z (%): 213.9 (2.9), 212.0 (8.3),
196.9 (6.7), 183.0 (6.14), 177.1 (29.4), 141.9 (30.9), 140.0 (100), 114.0 (8.5), 111.9 (27.5).
N,N-diethylhexanamide (5u): Yield 90 %, 1H-NMR (500 MHz) δ: 3.40 – 3.35 (q, J = 7.09 Hz, 2H),
3.33 – 3.29 (q, J = 7.09 Hz, 2H), 2.31 – 2.28 (t, J = 7.64 Hz, 2H), 1.68 – 1.62 (m, 2H), 1.37 – 1.29 (m,
4H), 1.19 – 1.16 (t, J = 6.61 Hz, 3H), 1.12 – 1.09 (t, J = 7.04 Hz, 3H), 0.91 – 0.89 (t, J = 6.65 Hz, 3H).
13C-NMR (125 MHz) δ: 172.4, 42.0, 40.1, 33.1, 31.7, 25.2, 22.5, 14.8, 13.9, 13.1. Cosy spectra in
supporting information.
N,N-diethyldec-9-enamide (5v): Yield 83 %, 1H-NMR (500 MHz) δ: 5.86 – 5.76 (m, 1H), 5.04 – 4.91
(m, 2H), 3.39 – 3.27 (m, 4H), 2.36 – 2.27 (m, 2H), 2.08 – 2.00 (m, 2H), 1.44 – 1.26 (m, 10H), 1.20 –
1.08 (m, 6H). 13C-NMR (125 MHz) δ: 172.6, 139.2, 114.2, 42.1, 40.2, 33.8, 33.2, 29.5, 29.3, 29.0, 28.9,
25.5, 24.9, 14.4, 13.1. Cosy spectra in supporting information. GC-MS (EI) m/z (%): 225.2 (7.4),
184.2 (10.3), 170.2 (4.7), 156.2 (2.8), 142.2 (9.4), 128.2 (58.3), 115.2 (100), 100.2 (64.2), 86.1
(14.1), 72.1 (34.3).
Acknowledgements
A. D. gratefully acknowledges the Department of Chemistry at University of Bergen for funding his
research fellowships. Dr. Bjarte Holmelid is acknowledged for excellent technical assistance with
the HRMS analyses.
Supporting information
Supplementary information and chemical compound information are available in the online
version of the paper.
Conflict of interest
The authors declare no conflict of interest.
Keywords: Oxidative amidation • transamidation • TEMPO • 1,3-dichloro-5,5-dimethylhydantoin •
flow chemistry
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