Mild Access to N-Formylation of Primary Amines using Ethers as C1 Synthons under Metal-Free Conditions

Article abstract of DOI:10.1002/adsc.201800783

A new synthetic protocol has been developed for the synthesis of N-formamide derivatives using ethers as a C1 synthon under metal-free reaction conditions. The reaction is proposed to proceed through C?H functionalization, C?O cleavage, and C?N bond formation. This protocol is applicable to a variety of primary amines resulting in N-formamides in moderate to good yields. 1,4-dioxane was chosen as best C1 synthon after screening with various ethers. Mechanistic studies disclosed that the reaction proceeds through a radical pathway. While using α-amino ketones a α-alkylation product was formed rather than formylation. By replacing dioxane with Tetramethylethylenediamine (TMEDA) under standard conditions also gave the N-formamide derivatives in moderate yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201800783

Title: Mild Access to N-Formylation of Primary Amines using Ethers as
C1 Synthons under Metal-Free Conditions
Authors: Mohana Reddy Mutra, Ganesh Kumar Dhandabani, and Jeh-
Jeng Wang
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800783
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10.1002/adsc.201800783
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Mild Access to N-Formylation of Primary Amines using Ethers
as C1 Synthons under Metal-Free Conditions
Mohana Reddy Mutra,a Ganesh Kumar Dhandabani,a and Jeh-Jeng Wanga,b*
a
Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, No. 100, Shih-Chuan 1st Rd, Sanmin
District, Kaohsiung City, 807 (Taiwan). Tel: (+886)-7-3121101, Fax: (+886)-7-3125339, email: jjwang@kmu.edu.tw
b
Department of Medical Research, Kaohsiung Medical University Hospital, No. 100, Tzyou 1st Rd, Sanmin District,
Kaohsiung City, 807 (Taiwan).
Received:((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A new synthetic protocol has been developed for reaction proceeds through a radical pathway. While using
the synthesis of N-formamide derivatives using ethers as a α-amino ketones a -alkylation product was formed
C1 synthon under metal-free reaction conditions. The rather than formylation. By replacing dioxane with
reaction is proposed to proceed through C-H Tetramethylethylenediamine (TMEDA) under standard
functionalization, C-O cleavage, and C-N bond formation. conditions also gave the N-formamide derivatives in
This protocol is applicable to a variety of primary amines moderate yields.
resulting in N- formamides in moderate to good yields. 1,4-
dioxane was chosen as best C1 synthon after screening with
various ethers. Mechanistic studies disclosed that the
Keywords: Ethers, C1 synthon, Amines, 1,4-Dioxane;
70% TBHP; Formamides; α-amino ketones.
formic acid and acetic anhydride.[8] In the past years,
several other non-conventional protocols were
identified for N-formylation reactions. For examples,
utilization of DMF with metal[18a] or under metal-free
conditions,[18b] MeOH in the presence of Ru,[19a] or
Mn.[19b] Milstein et al[20a] and Li et al[20b]
independently developed N-formylation with CO2 as
formyl precursor. Song et al, observed N-formamide
as a side product while synthesizing, 3-formyl
imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine
under Cu-catalyzed aerobic oxidative coupling with
ethyl tertiary amines as carbon source.[21] Bull et al,
utilized FAPM as a formylating agent in the synthesis
of N-formamides.[22]
Introduction
Ethers are one of the vital chemical feedstocks
because of their widespread use as solvents in
academic and industrial purposes. In recent years, the
importance of ethers as substrates in organic reactions
is increasing gradually because of their significant
reactivity
towards
several
oxidants
based
conditions.[1] In this regard, several researchers
utilized ethers as a -alkyating agent with various
carbon nucleophiles to construct a variety of C-C
bonds depending on the choice of starting materials.[2]
However, there are no other reports on harnessing the
activity of ethers into bioactive molecules,[3]
valuable intermediate[4] and heterocycles.[5]
A
Scheme 1. Synthesis of formamides and alkylation of α-
aminoketones.
probable reason could be the lack of suitable reaction
conditions and coupling partners.
In this work, we were interested to identify suitable
reaction parameters for utilizing ethers as C1
synthons[6] and imply this strategy for the
construction of the N-formyl group for the first time.
The key aspects of this hypothesis would be
classified as (i) ethers are abundant in nature; (ii)
inexpensive; (iii) environmentally benign; (iv) can
avoid conventional toxic formylation protocols such
as chloral,[7] acetic/formic anhydride,[8] cyanide,[9]
formyl fluoride,[10] and formic acid.[11]
N-Formylation of amines is prominent in organic
synthesis to construct valuable reaction intermediates
such as isocyanides,[12] carbamates,[13] isocyanates,[14]
nitriles,[15] aryl amides,[16] and ureas.[17] The classical
method of N-formylation is the combination of
Until recently a variety of reagents or solvents
were used as C1 synthons for the synthesis of N-
[20a-
formamides, such as DMF,[18a-b] MeOH,[19a-c] CO2,
CO,[23] and DMSO.[24] However, the reported
j]
protocols required expensive metals, hazardous
reagents, and harsh reaction conditions and in some
cases, formylating precursor should be synthesized in
advances such as methyl formate and FAPM. In
continuation of our interest in the oxidation reactions
1
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10.1002/adsc.201800783
Advanced Synthesis & Catalysis
with TBHP as an oxidant and C1 synthons.[25] Herein,
we have utilized 1,4-dioxane as a C1 synthon for N-
formylation with amines in presence of the aq. TBHP
(Scheme 1a). Interestingly, by replacing simple
amines with α-amino ketones under the same
conditions afforded a -alkylation product rather than
formylation (Scheme 1b). In this regard, Li et al, also
observed the same alkylation of α-amino ketones in
the presence of metal catalyst.[26] To the best of our
knowledge, this will be the first report on utilizing
ethers as a C1 synthon in the N-formylation of
amines.
entry 1). Interestingly, the desired product was
formed into a trace amount when the reaction was
heated to 50 °C for 20 h (Table 1, entry 2). The
reaction yield of 3c was improved to 63% by heating
at 90 °C for 20 h (Table 1, entry 3). Subsequent
reactions with other oxidants such as DTBP, CHP,
K2S2O8, 36% H2O2 and TBHP in decane (5.5 M)
(Table 1, entries 4-8) also failed to improve the
reaction yield of 3c. Next the effect of solvents was
tested with Toluene, MeOH, DCM, DMSO and DMF
(Table 1, entries 9-12). However, none of them gave
the desired compound in better yields. By changing
the solvent from dioxane to THF gave the expected
N-formylated product 3c albeit in low yield (Table 1,
entry 13). This results confirmed that the ether
solvent is crucial to this transformation. Further
studies on aq. TBHP equivalents revealed that 3.0
equiv of TBHP is necessary to get a maximum yield
of 65% of 3c. (Table 1, entries 14-16). Changing
from 1.0 M solution of dioxane to equivalents led to a
lower reaction yields (Table 1, entries 17-18). Thus,
of the reaction conditions screened in Table 1, entry
14 was chosen as the best conditions for further
screening of ethers.
Results and Discussion
Our investigation started using p-toluidine 1c as a
model substrate in the presence of 70% aq TBHP and
1,4-dioxane as a solvent at RT for 20 h. But, the
desired product was not formed as expected (Table 1,
Table 1. Optimization conditionsa)
To find the best ether as C1 synthon, we tried
with several ether molecules other than 1,4-dioxane
and THF under the optimized conditions to get
desired N-formylation product with 1c as presented in
Scheme 2. Various ether derivatives (2c-2f) gave the
desired product 3c in lower yields as compared with
1,4-dioxane. Whereas, using diethyl ether (2e) as a
solvent didn’t create the desired formylation product.
A probable reason could be the low boiling point of
ether. Thus, 1,4-dioxane was chosen as the best C1
synthon among the others.
Oxidant
(X mmol)
t oC Yield
(%)b)
Entry
Solvent
1
2
TBHP (2) 1,4-Dioxane RT
NR
TBHP (2) 1,4-Dioxane 50 trace
3
TBHP (2) 1,4-Dioxane 90
DTBP (2) 1,4-Dioxane 90
63
26
31
-
4
5
CHP (2)
K2S2O8 (2) 1,4-Dioxane 90
H2O2 (2) 1,4-Dioxane 90
TBHP (2) 1,4-Dioxane 90
1,4-Dioxane 90
Scheme 2. Different types of ethers utilized for N-
formamide products
6c)
7
60
58
NR
NR
NR
NR
47
65
62
64
20
25
8d)
9e)
10e)
11e)
12e)
13
14
15
16
17f)
18g)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
MeOH
DCM
DMSO
DMF
90
90
90
90
90
THF
TBHP (3) 1,4-Dioxane 90
TBHP (4) 1,4-Dioxane 90
TBHP (5) 1,4-Dioxane 90
TBHP (3) 1,4-Dioxane 90
TBHP (3) 1,4-Dioxane 90
With the optimized reaction conditions in the hand,
the scope of amines with various R1 functional groups
(1a-1z) were investigated as shown in Table 2.
Electron donating aromatic amines such as m-Me-Ph
(1b), p-Me-Ph (1c), p-Et-Ph (1d), o-OMe-Ph (1e),
2,4-di-Me-Ph (1f), and 3,4-diMe-Ph (1g) derivatives
afforded the desired compounds (3b-g) in 45-65%
yields respectively. The reaction also underwent
smooth conversion with halogen, and electron-
withdrawing aromatic amines substituents like p-F-Ph
(1h), m-Cl-Ph (1i), p-Cl-Ph (1j), p-Br-Ph (1k), o-I-Ph
a) Reaction conditions: 1a (1.0 mmol), Oxidant (3.0 mmol),
and solvent (1 M) stirred for 20 h at 90 oC unless otherwise
noted. b) Isolated yield. c) Multiple spots observed. d) TBHP
5-6 M in decane was used. Major starting material 1c
observed. 3 equiv of 1,4-dioxane was used. 5 equiv of
1,4-dioxane was used.
e)
f)
g)
2
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10.1002/adsc.201800783
Advanced Synthesis & Catalysis
(1l), o-CF3-Ph (1m), 2-I,4-CF3-Ph (1n), o-acetyl-Ph
(1o), m-NO2-Ph (1p), 3,4-di-Cl-Ph (1q), 2-benzoyl-4-
Cl-Ph (1r) and o-Ph-Ph (1s) to afford the desired
compounds (3h-3s) in 30-75% yields. To our surprise,
the reaction gave the desired compounds 3t-u in 25-
55% yields using allylamine (1t) and o-alkynyl
aniline (1u) without affecting the double or triple
bond which is sensitive to oxidants. The reaction also
gave desired compounds 3v in 35% when aliphatic
amine like n-butyl amine (1v) was used.
Unfortunately, this method was not successful in the
N-formylation of heterocyclic amines and secondary
amines.
ether (2e) was used as a solvent. A probable reason
could be the low boiling point of ether.
Table 3. Scope of α-amino ketones with 1,4-dioxane or
THF a),b)
Table 2. Scope of amines with 1,4-dioxanea),b)
a) Reaction conditions: Compounds 3a-d (0.5 mmol), 2a-c
(1 M), 70% aqueous TBHP (1.5 mmol) at 90 °C for the
indicated time. b) Isolated yields
Table 4. Scope of amines with TMEDAa),b)
a) Reaction conditions: Compounds 1a-z (1.0 mmol), 1,4-
Dioxane (1 M), 70% aqueous TBHP (3.0 mmol) at 90 °C
for the indicated time. b) Isolated yields.
a) Reaction conditions: Compounds 1 (1.0 mmol), TMEDA
(0.5 M), 70% aqueous TBHP (3.0 mmol) at 90 °C for the
indicated time. b) Isolated yields.
In light of the success with amine derivatives, the
scope of α-amino ketones under the optimized
reaction conditions were explored as presented in
Table 3. To our surprise, the reaction underwent
smooth conversion to afford alkylation product of α-
amino ketones rather than the expected N-
formylation product. The probable reason could be
the enolization ability of the acidic -carbon
followed by the attack of oxonium formed by the
ether derivatives. Next, we elucidated the substrate
scope of various substituted α-amino ketones such as
Ph (3a), o-Me-Ph (3b) and p-Br-Ph (3d). The
reaction proceeded smoothly to obtain the desired
alkylated products (5aa-5ab) using 1,4-dioxane and
THF in 45-71% yields. Unfortunately, the reaction
failed to give the desired product 5ac when diethyl
On the other hand, Tetramethylethylenediamine
(TMEDA) is known to act as a formyl precursor with
indoles and imidazopyridines.[27] In this regards, we
also investigated the feasibility of N-formylation by
replacing ethers with TMEDA as C1 synthons to
expanding our scope of methodology in Table 4.
Initially, we have chosen electron-donating aromatic
amines such as p-Me-Ph (1c), 2,4-di-Me-Ph (1f), and
3,4-di-Me-Ph (1g) derivatives as our desired
substrates. To our surprise, the reaction underwent
smooth conversion by affording compounds 3c, f & g
in 51-58% yields respectively. With this positive
outcome, we next extended the scope of the reaction
3
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10.1002/adsc.201800783
Advanced Synthesis & Catalysis
with halogen and electron-withdrawing aromatic
amines substituents like p-Br-Ph (1k) and 3,4-di-Cl-
Ph (1q). As expected, the reactions proceeded well to
beget compounds (3k & q) in 45-46% yields.
However, the reaction gave trace product formation
with o-acetyl-Ph (1o). The reaction also succeeded
with o-alkynyl aniline (1u) without affecting the
triple bond which is sensitive to oxidants. The
mechanism will initiate into oxidative imination
followed by the nucleophilic attack of amine
followed by second oxidative imination and
hydrolysis. [27c]
temperature. To our surprise, the required product
was obtained in 58% (scheme 3d). With the help of
literature precedence, we hypothesized that the
possible intermediate could be 1,4-dioxane-2,5-
dione.[28] In this context, a control reaction was
carried out using 1,4-dioxane-2,5-dione as a substrate
under the standard condition and we observed three
different
reaction
intermediates
2-oxo-2-
(phenylamino)ethyl 2-hydroxyacetate (8), 2-hydroxy-
N-phenylacetamide (9), and N-formylation product
(3a) in 15-56% yields (Scheme 3e). These results
conclude that 1,4-dioxane-2,5-dione (2a’) could be
the key intermediate. However, under the standard
condition, the expected intermediate could not be
isolated. A probable reason may be attributed to the
less stability of the lactone ring under thermal
conditions. Then, the reaction was performed with
1,4-dioxane-2,5-dione with aniline without TBHP.
Surprisingly the formation of the 2-oxo-2-
(phenylamino)ethyl 2-hydroxyacetate (8), 2-hydroxy-
N-phenylacetamide (9), and a trace amount of N-
formylation (3a) were obtained in 5-35% yields
(Scheme 3f) suggesting that the lactone ring can be
cleaved under thermal condition. Next, the reaction
solvent was changed from 1,4-dioxane to ACN to
avoid the interference with 1,4-dioxane in the
reaction and also to identify the exact yields of
intermediates. Under acetonitrile as a solvent, the
desired intermediates were observed in 19-45%
yields (Scheme 3g). Increasing the reaction time from
18 h to 24 h under standard condition resulted in N-
formylation (3a) product along with 2-hydroxy-N-
phenylacetamide (9) in 15-50% (Scheme 3h). Next 2-
oxo-2-(phenylamino)ethyl 2-hydroxyacetate (8) as
starting material in presence of aniline under heating
condition gave 2-hydroxy-N-phenylacetamide (9) and
a trace amount of N-formylation product (3a) in 5-
48% (Scheme 3i). The reaction of 2-hydroxy-N-
phenylacetamide (9) as starting material yielded the
N-formylation (3a) via in situ generation of 2-oxo-2-
(phenylamino)acetic acid (Scheme 3j). Further, to
elucidate the reaction mechanism, we prepared 2-oxo-
2-(p-tolylamino)acetic acid 9a’ according to the
literature protocol[29] and investigated in the presence
of 1,4-dioxane at 90 °C. The desired compound 3a
was isolated in 52% yield via decarboxylation
(Scheme 3k). From these observations, we believe
To understand the reaction mechanism,
preliminary control experiments were carried out as
shown in Scheme 3. Radical inhibition studies of 1a
with TEMPO and 1,4-cyclohexadiene under the
optimized condition gave 3a in 9% and 8% yields
(scheme 3, a & b). These results suggest that the
reaction proceeds with a radical pathway. Further
investigation of the reaction with toluene as a solvent
was unsuccessful (scheme 3c). This confirms that the
carbon source is from ethers and not from the TBHP.
Moreover, the results obtained from H2O2 (Table 1,
entry 7) is also a strong evidence to rule out TBHP as
C1 synthon.
Scheme 3. Control Studies
that
1,4-dioxane-2,5-dione(2a’),
2-oxo-2-
(phenylamino)ethyl 2-hydroxyacetate(8), and 2-
hydroxy-N-phenylacetamide(9) could be the potential
intermediates in the reaction.
On the basis of above control studies and previous
literature reports[6b,28,30] a tentative mechanism was
proposed as depicted in Scheme 4. Under thermal
condition, TBHP tends to cleave homolytically to
generate t-butoxyl radical and hydroxyl radical.[30a]
Subsequent elimination of α-C-H from ethers in the
presence of t-butoxyl radical gave intermediate A.
Then attack of hydroxy radical to the intermediate A
and simultaneously oxidation afforded intermediate
2a’.[28] Then the reaction of amine with 2a’ ended in
stable intermediates 9 via intermediate 8 or direct
To determine the key intermediate in the reaction,
1,4-dioxane was reacted with TBHP for 12 h at 90 oC
followed by the addition of aniline and continued the
reaction for an additional 12 h at the same
4
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10.1002/adsc.201800783
Advanced Synthesis & Catalysis
N-m-tolylformamide (3b):[33] Brown liquid; Yield: 54%
cleavage of lactone ring with nucleophilic amines.[31]
Further in situ oxidation[30b] followed by
decarboxylation[30c] produced the desired N-
formylation product. Whereas, in the case of
alkylation, the starting material can undergo oxidative
dehydrogenation to beget intermediated B. Then the
radical addition of A to the imine would get an amino
radical intermediate C. Finally, hydrogen atom
transfer (HAT) from ether to N-centre radical would
afford the product.
1
(73 mg); (The compound having mixture of rotamers): H
NMR (400 MHz, CDCl3): δ 8.70 (d, J = 10.0 Hz, 2H), 8.35
(d, J = 2.0 Hz, 1H), 7.64 (s, 1H), 7.41 (s, 1H), 7.32 (d, J =
8.2 Hz, 1H), 7.22 (m, 2H), 7.00 (d, J = 7.6 Hz, 1H), 6.95 (d,
J = 7.6 Hz, 1H), 6.91-6.69 (m, 3H), 2.35 (s, 4H), 2.33 (s,
3H); 13C NMR (101 MHz, CDCl3): δ 162.85, 159.12,
139.78, 139.00, 136.75, 136.61, 129.46, 128.83, 125.97,
125.52, 120.57, 119.40, 116.99, 115.64, 21.40, 21.33.
N-p-tolylformamide (3c):[34] White solid; Yield: 55% (74
mg); Mp. 48.7-49.5 °C; (The compound having mixture of
rotamers): 1H NMR (400 MHz, CDCl3): δ 8.63 (d, J =
11.6 Hz, 1H), 8.34 (d, J = 1.6 Hz, 1H), 8.33-8.27 (m, 1H),
7.47 (bs, 1H), 7.44-7.40 (m, 2H), 7.14 (dd, J = 10.4, 8.1 Hz,
4H), 7.00-6.97 (m, 2H), 2.33-2.31 (m, 6H); 13C NMR (101
MHz, CDCl3): δ 162.78, 158.93, 135.09, 134.43, 134.23,
134.01, 130.17, 129.51, 119.96, 119.08, 20.84, 20.76.
Scheme 4. Plausible reaction mechanism
N-(4-ethylphenyl)formamide (3d):[35] White solid; Yield:
53% (79 mg); Mp. 43.1-44.2 (The compound having
mixture of rotamers): 1H NMR (400 MHz, CDCl3): δ 8.65-
8.62 (m, 1H), 8.59 (bs, 1H), 8.32 (d, J = 2.0 Hz, 1H), 7.75
(bs, 1H), 7.46-7.43 (m, 2H), 7.18-7.13 (m, 4H), 7.03-6.99
(m, 2H), 2.61 (q, J = 11.2, 4H), 1.21 (m, 6H); 13C NMR
(101 MHz, CDCl3): δ 162.93, 159.12, 141.46, 140.81,
134.48, 134.26, 128.97, 128.30, 120.12, 119.11, 28.24,
28.15, 15.53.
N-(2-methoxyphenyl)formamide (3e):[36] Brown solid;
Yield: 45% (68 mg); Mp. 78.3-79.5 °C; (The compound
1
having mixture of rotamers); H NMR (400 MHz, CDCl3):
δ 8.74 (d, J = 11.6 Hz, 1H), 8.46 (d, J = 2.0 Hz, 2H), 8.36
(dd, J = 8.0, 1.6 Hz, 2H), 7.80 (s, 2H), 7.70-7.59 (m, 1H),
7.21-7.19 (m, 1H), 7.15-7.05 (m, 4H), 6.99-6.88 (m, 7H),
3.89 (s, 7H), 3.87 (s, 4H); 13C NMR (101 MHz, CDCl3): δ
161.36, 158.64, 147.72, 147.39, 125.16, 124.25, 121.11,
121.04, 120.43, 116.52, 111.23, 109.99, 55.70.
Conclusion
N-(2,4-dimethylphenyl)formamide (3f):[18] yellow solid;
In conclusions, we have utilized ethers as a C1
synthon for the N-formylation of primary amines via
C-H functionalization, C-O bond cleavage, and C-N
bond formation. In addition, alkylation of α-amino
ketones was also achieved under metal-free
conditions. Mechanistic studies presented in Scheme
3 unambiguously confirmed ethers as C1 source. The
key advantages are (i) environmentally benign; (ii)
moderate to good yields and; (iii) can override the
usage of harmful reagents.
Yield: 53% (79 mg); Mp. 112-114 °C; ( The compound
1
having mixture of rotamers) H NMR (400 MHz, CDCl3):
δ 8.45-8.42 (m, 2H), 8.39 (bs, 1H), 8.35 (d, J = 2.0 Hz, 1H),
7.63 (d, J = 8.8 Hz, 1H), 7.51 (bs, 1H), 7.036.032- (m, 2H),
6.99-6.96 (m, 6H), 2.30 (s, 6H), 2.27-2.26 (m, 9H), 2.21 (s,
3H); 13C NMR (101 MHz, CDCl3): δ 163.77, 159.43,
135.83, 135.20, 132.39, 131.86, 131.74, 131.08, 130.09,
129.22, 127.39, 127.09, 123.37, 121.27, 20.74, 20.67,
17.59, 17.55.
N-(3,4-dimethylphenyl)formamide (3g):[37] Brown solid;
Yield: 58% (86 mg); Mp. 60.3-61.4 °C; (The compound
1
having mixture of rotamers) H NMR (400 MHz, CDCl3):
δ 8.62 (d, J = 11.6 Hz, 1H), 8.33 (d, J = 2.0 Hz, 1H), 8.14
Experimental Section
(bs, 1H), 7.338-7.333 (m, 1H), 7.26-7.23 (m, 1H), 7.08 (t,
J=8.4 Hz, 2H), 6.87-6.81 (m, 2H), 2.25-2.22 (m, 12H); 13
C
NMR (101 MHz, CDCl3): δ 162.71, 158.88, 138.16,
137.35, 134.47, 134.24, 133.77, 133.17, 130.59, 129.97,
121.25, 120.47, 117.42, 116.38, 19.82, 19.11.
General procedure (A) for the Synthesis of N-
formamide and α-alkylation of α-amino ketones (3a-3z
& 5aa-5ab). To a stirred solution of amines (1.0 equiv) in
1,4-dioxane or TMEDA was added 70% TBHP in water
(3.0 equiv). The resultant mixture was heated at 90 °C for
1-30 h. After the completion of reaction by TLC, the
reaction mixture was cooled to rt, diluted with water and
extracted with ethyl acetate. The combined organic layer
was dried over Na2SO4, filtered and concentrated to give
crude material. The crude material was purified by column
chromatography using hexane-ethyl acetate as the eluent to
afford the pure product 3a-3z & 5a-5f.
N-(4-fluorophenyl)formamide (3h):[38] Brown solid;
Yield: 60% (84 mg); Mp. 64.3-65.8 °C; (The compound
having mixture of rotamers): 1H NMR (400 MHz, CDCl3):
δ 8.58 (d, J = 11.2 Hz, 1H), 8.45 (bs, 1H), 8.34 (s, 1H),
7.61 (bs, 1H), 7.52-7.49 (m, 3H), 7.09-6.99 (m, 7H); 13C
NMR (101 MHz, CDCl3): δ 162.88, 161.20 (d, JC-F = 84.9
Hz), 158.99, 158.77(d, JC-F = 84.3 Hz), 158.35, 132.76,
121.78 (d, JC-F = 8.1 Hz), 121.15 (d, JC-F = 8.2 Hz), 116.51
(d, JC-F = 22.6 Hz), 115.73 (d, JC-F = 22.3 Hz).
N-phenylformamide (3a):[32] White solid; Yield: 65% (78
mg); Mp. 46.2-47.1 (The compound having mixture of
rotamers): 1H NMR (400 MHz, CDCl3): δ 8.70 (d, J = 11.2
Hz, 1H), 8.51 (bs, 1H), 8.36 (d, J = 1.6 Hz, 1H), 7.68-7.59
(m, 1H), 7.54 (dd, J = 8.0, 1.2 Hz, 2H), 7.39-7.30 (m, 4H),
7.21-7.08 (m, 4H); 13C NMR (101 MHz, CDCl3): δ 162.72,
159.11, 136.83, 136.66, 129.70, 129.04, 125.25, 124.76,
119.96, 118.77.
N-(3-chlorophenyl)formamide (3i):[36] Brown solid;
Yield: 60% (93 mg); Mp. 55.5-56.4 °C; (The compound
1
having mixture of rotamers): H NMR (400 MHz, CDCl3):
δ 9.12 (d, J = 10.4 Hz, 1H), 8.69 (d, J = 11.2 Hz, 1H), 8.47
(s, 1H), 8.34 (d, J = 1.6 Hz, 1H), 7.66 (t, J = 1.6 Hz, 1H),
7.39-7.37 (m, 2H), 7.23 (dt, J = 18.4, 8.0 Hz, 3H), 7.15-
7.06 (m, 4H), 7.00-6.97 (m, 1H); 13C NMR (101 MHz,
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800783
Advanced Synthesis & Catalysis
CDCl3): δ 162.71, 159.65, 137.95, 135.22, 134.46, 130.66,
N-(3,4-dichlorophenyl)formamide (3q):[36] white solid;
Yield: 58% (107 mg); Mp. 92.2-93.2 °C; (The compound
having mixture of rotamers): 1H NMR (400 MHz, CDCl3):
δ 8.67 (d, J = 11.2 Hz, 1H), 8.53 (bs, 1H), 8.37 (d, J = 1.6
Hz, 2H), 7.78-7.77 (m, 2H), 7.70 (s, 2H), 7.42 (d, J = 8.8
Hz, 1H), 7.37-7.36 (m, 3H), 7.22 (d, J = 2.4 Hz, 1H), 6.96
(dd, J = 8.8, 2.8 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ
162.17, 159.05, 136.16, 132.87, 131.34, 130.60, 128.12,
121.67, 120.38, 119.13, 117.89.
129.95, 125.16, 124.72, 120.12, 118.59, 118.00, 116.54.
N-(4-chlorophenyl)formamide (3j):[38] White solid;
Yield: 55% (88 mg); Mp. 94.5-96.0 °C; (The compound
having mixture of rotamers): 1H NMR (400 MHz, CDCl3):
δ 8.66-8.63 (m, 1H), 8.36 (d, J = 1.6 Hz, 1H), 7.79 (bs, 1H),
7.49 (dt, J = 10.0 Hz, 3.2 Hz, 1H), 7.34-7.26 (m, 2H), 7.04
(dt, J = 8.8 Hz, 2.8 Hz, 1H); 13C NMR (101 MHz, CDCl3):
δ 162.57, 159.10, 135.37, 135.28, 130.69, 129.77, 129.06,
121.21, 120.01.
N-(2-benzoyl-4-chlorophenyl)formamide (3r):[42] Yellow
solid; Yield: 75% (195 mg); Mp. 73.0-74.0 °C; (The
1
N-(4-bromophenyl)formamide (3k):[38] Brown solid;
compound having mixture of rotamers): H NMR (400
MHz, CDCl3): δ 10.52 (s, 1H), 8.64 (d, J = 9.6 Hz, 1H),
8.47 (d, J = 1.6 Hz, 1H), 7.72-7.70 (m, 2H), 7.64 (tt, J =
7.2 Hz, 1.2 Hz, 1H), 7.55-7.50 (m, 5H); 13C NMR (101
MHz, CDCl3): δ 198.07, 159.47, 137.61, 133.89, 133.07,
132.63, 129.87, 128.56, 127.94, 124.78, 123.57.
Yield: 68% (135 mg); Mp. 110.2-111.5 °C; (The
1
compound having mixture of rotamers): H NMR (400
MHz, CDCl3): δ 8.66 (d, J = 11.2 Hz, 1H), 8.44 (bs, 1H),
8.37 (d, J = 1.6 Hz, 1H), 7.56-7.54 (m, 1H), 7.47 (dt, J =
6.8 Hz, 2.8 Hz, 2H), 7.44 (s, 5H), 6.98 (dt, J = 6.8 Hz, 2.8
Hz, 2H); 13C NMR (101 MHz, CDCl3): δ 162.33, 158.95,
135.85, 135.76, 132.75, 132.05, 121.48, 120.28, 118.23,
117.44.
N-([1,1'-biphenyl]-2-yl)formamide (3s):[43] White solid;
Yield: 48% (95 mg); Mp. 64.4-65.5 °C; (The compound
having mixture of rotamers): 1H NMR (400 MHz, CDCl3):
δ 8.68 (d, J = 11.2 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.28
(d, J = 1.6 Hz, 1H), 7.51-7.30 (m, 15H), 7.27-7.24 (m, 3H),
7.19 (td, J = 7.6 Hz, 1.2 Hz, 2H); 13C NMR (101 MHz,
CDCl3): δ 161.89, 158.85, 137.69, 137.43, 137.23, 133.75,
132.85, 131.86, 131.13, 130.11, 129.27, 129.16, 129.13,
128.70, 128.48, 128.12, 128.10, 125.27, 124.59, 121.42,
118.09.
N-(2-iodophenyl)formamide (3l):[32] White solid; Yield:
43% (108 mg); Mp. 112.5-113.5 °C; (The compound
having mixture of rotamers): 1H NMR (400 MHz, CDCl3):
δ 8.65 (d, J = 10.8 Hz, 1H), 8.49 (d, J = 0.8 Hz, 1H), 8.27
(dd, J = 8.2, 1.1 Hz, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.79 (dd,
J = 8.0, 1.1 Hz, 1H), 7.56 (bs, 2H), 7.36-7.33 (m, 2H), 7.21
(d, J = 7.6 Hz, 1H), 6.94-6.91 (m, 1H), 6.87 (td, J = 8.0,
1.6 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 161.91,
158.92, 139.84, 138.88, 137.67, 137.19, 129.53, 129.23,
126.99, 126.33, 122.22, 119.33, 90.70, 89.26.
N-allylformamide (3t):[44] Brown liquid; Yield: 25% (21
1
mg); (The compound having mixture of rotamers): H
NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 8.05 (d, J = 11.6
Hz, 1H), 6.11 (bs, 1H), 5.88-5.80 (m, 1H), 5.24-5.12 (m,
2H), 3.93 (t, J = 6.0 Hz, 1H), 3.87 (tt, J = 7.2, 1.6 Hz, 1H);
13C NMR (101 MHz, CDCl3): δ 164.78, 161.08, 134.07,
133.44, 116.59, 116.27, 41.95, 40.37, 23.12.
N-(2-(trifluoromethyl)phenyl)formamide (3m):[39] White
solid; Yield: 50% (94 mg); Mp. 78.2-79.4 °C; (The
1
compound having mixture of rotamers): H NMR (400
MHz, CDCl3): δ 8.56 (d, J = 10.4 Hz, 1H), 8.43-8.42 (m,
1H), 8.20 (d, J = 8.4 Hz, 1H), 8.00-7.93 (m, 2H), 7.65 (d, J
= 8.0 Hz, 1H), 7.60-7.49 (m, 3H), 7.32 (t, J = 8.8 Hz, 1H),
7.22 (t, J = 8.0 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ
162.50, 159.54, 134.29, 133.93, 133.25, 132.75, 127.79,
126.98 (q, J = 5.1 Hz), 126.03 (q, J = 5.2 Hz), 125.08,
124.73, 124.69 (d, J = 27 Hz), , 122.37, 122.20.
N-(2-(phenylethynyl)phenyl)formamide (3u):[45] Yellow
solid; Yield: 55% (121 mg); Mp. 94.2-95.3 °C; (The
1
compound having mixture of rotamers): H NMR (400
MHz, CDCl3): δ 8.85 (d, J = 11.6 Hz, 1H), 8.52 (d, J = 1.6
Hz, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.95 (bs, 1H), 7.57-7.51
(m, 3H), 7.40-7.36 (m, 4H), 7.27-7.25 (m, 1H), 7.18-7.09
(m, 1H): 13C NMR (101 MHz, CDCl3): δ 161.24, 158.83,
137.77, 132.95, 131.88, 131.64, 131.60, 129.75, 129.66,
129.02, 128.53, 128.48, 124.51, 123.95, 122.11, 119.96,
116.01, 111.97, 109.95, 96.54, 83.81.
N-(2-iodo-4-(trifluoromethyl)phenyl)formamide (3n):[40]
White solid; Yield: 61% (192 mg); Mp. 118.0-119.0 °C;
1
(The compound having mixture of rotamers): H NMR
(400 MHz, CDCl3): δ 8.51 (d, J = 11.0 Hz, 1H), 8.47 (d, J
= 1.3 Hz, 2H), 8.21 (dd, J = 9.1, 5.4 Hz, 2H), 7.59 (dd, J =
7.6, 2.7 Hz, 1H), 7.52 (dd, J = 7.7, 2.9 Hz, 2H), 7.41 (s,
N-butylformamide (3v):[46] Brown liquid; Yield:
35%
1
3H), 7.18 (dd, J = 8.8, 5.0 Hz, 1H), 7.13-7.07 (m, 3H); 13
C
(35 mg); (The compound having mixture of rotamers): H
NMR (400 MHz, CDCl3): δ 8.05 (s, 1H), 7.95 (d, J = 12.0
Hz, 1H), 6.77 (bs, 1H), 6.52 (bs, 1H), 3.19 (q, J = 6.4 Hz,
2H), 3.14-3.11 (m, 1H), 1.47-1.40 (m, 2H), 1.30-1.23 (m,
3H), 0.87-0.83 (m, 4H): 13C NMR (101 MHz, CDCl3): δ
164.69, 161.40, 41.37, 37.61, 32.94, 31.20, 19.75, 19.26,
13.42, 13.31.
NMR (101 MHz, CDCl3): δ 162.08, 161.03, 158.77,
158.70 (d, JC-F = 248.1 Hz), 134.36, 133.76, 126.64 (d, JC-F
= 24.6 Hz), 125.57 (d, JC-F = 24.8 Hz), 125.70, 123.14 (d,
JC-F = 7.8 Hz), 121.18 (d, JC-F = 8.3 Hz), 116.50 (d, JC-F
22.3 Hz), 116.08 (d, JC-F = 21.6 Hz), 91.38, 88.90, 88.82.
=
N-(2-acetylphenyl)formamide (3o):[41] White solid;
Yield: 55% (90 mg); Mp. 70.2-71.5 °C; (The compound
having mixture of rotamers): 1H NMR (400 MHz, CDCl3):
2-(1,4-dioxan-2-yl)-1-phenyl-2-(phenylamino)ethan-1-
one (5aa):[26a] Yellow solid; Yield: 71% (105 mg); Mp.
δ 11.62 (bs, 1H), 8.74 (d, J = 8.8 1H), 8.497-8.493 (m, 1H), 90.1-91.0 °C; (The compound having mixture of
1
7.92 (dd, J = 8.0, 1.6 Hz, 1H), 7.56 (t, J = 8.8, 1H), 7.10 (t, diastereomers): H NMR (400 MHz, CDCl3): δ 8.04-7.978
J = 8.0, 4.3 Hz, 1H), 2.67 (s, 3H); 13C NMR (101 MHz,
CDCl3): δ 202.66, 159.81, 139.70, 135.05, 131.58, 122.95,
121.80, 121.40, 28.48.
(m, 2H), 7.60-7.56 (m, 1H), 7.51-7.45 (m, 2H), 7.16-7.12
(m, 2H), 6.74-6.71 (m, 2H), 6.64 (dd, J = 8.8, 1.2 Hz, 1H),
5.06 (d, J = 6.8 Hz, 1H), 4.99 (d, J = 2.8 Hz, 1H), 4.10 (dt,
J = 10.4, 7.6 Hz, 1H), 3.96-3.87 (m, 2H), 3.76-3.70 (m,
1H), 3.67-3.53 (m, 4H); 13C NMR (101 MHz, CDCl3): δ
199.82, 198.13, 147.00, 146.88, 136.01, 135.26, 133.67,
133.59, 129.30, 129.29, 128.99, 128.57, 128.68, 128.55,
128.43, 118.63, 118.40, 114.08, 113.65, 77.31, 77.09,
76.99, 76.67, 75.51, 68.73, 68.35, 67.18, 67.03, 66.35,
66.14, 59.32, 59.26.
N-(3-nitrophenyl)formamide (3p):[18] Yellow solid;
Yield: 30% (65 mg); Mp. 129.0-130.0 °C; (The compound
1
having mixture of rotamers): H NMR (400 MHz, CDCl3)
δ 8.82 (d, J = 11.2 Hz, 1H), 8.47 (s, 1H), 8.41 (t, J = 2 Hz,
1H), 8.15 (bs, 1H), 8.05 (d, J = 8.0 Hz, 1H), 8.01-7.97 (m,
2H), 7.59-7.57 (m, 1H), 7.53 (t, J = 8.4 Hz, 1H), 7.43 (d, J
= 8.0 Hz, 1H); 13C NMR (101 MHz, CDCl3): δ 161.57,
158.99, 137.84, 130.82, 130.06, 125.55, 124.03, 119.80,
119.44, 114.60, 113.01.
2-(-1,4-dioxan-2-yl)-1-phenyl-2-(m-tolylamino)ethan-1-
one (5ba): Yellow liquid; Yield: 52% (81 mg); (The
compound having mixture of diastereomers): 1H NMR
(400 MHz, CDCl3): δ 8.01-7.98 (m, 2H), 7.62-7.56 (m,
1H), 7.52-7.45 (m, 2H), 7.04 (t, J = 8.0 Hz, 1H), 6.56-6.43
6
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800783
Advanced Synthesis & Catalysis
(m, 3H), 5.04 (bs, 1H), 4.99 (dd, J = 8.0, 2.8 Hz, 1H), 4.84
(d, J = 8.4 Hz, 1H), 4.57 (s, 1H), 4.10 (dt, J = 10.0, 2.8 Hz,
1H), 3.95-3.87 (m, 2H), 3.76-3.54 (m, 5H), 2.24 (m, 3H);
13C NMR (101 MHz, CDCl3): δ 199.97, 198.21, 147.03,
146.89, 139.12, 136.06, 135.25, 133.65, 133.57, 129.17,
128.75, 128.67, 128.57, 128.45, 119.60, 119.37, 115.08,
114.64, 111.00, 110.56, 77.31, 77.14, 76.99, 76.67, 75.54,
68.79, 68.37, 67.18, 67.03, 66.37, 66.15, 59.27, 21.54,
21.51; ; HRMS (ESI): Calc’d for [C19H21NNaO3]- [M+Na]-
334.14138, found 334.14136.
Research and Development of Kaohsiung Medical University for
400 MHz NMR, LC-MS and GC-MS analyses. The authors also
thank Dr. Gopal Chandru Senadi for proof reading the
manuscript and for technical discussions.
References
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1
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(m, 1H), 7.53-7.48 (m, 2H), 7.26-7.21 (m, 2H), 6.63 (dt, J
= 6.8Hz, 3.2 Hz, 1H), 6.52 (dt, J = 6.8 Hz, 3.2 Hz, 1H),
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(dt, J = 7.6, 2.4 Hz, 1H), 3.96-3.92 (m, 1H), 3.89-3.75 (m,
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yl)ethan-1-one (5ab):[26a] Yellow solid; Yield: 69% (102
mg); Mp. 81.2-82.3 °C; (The compound having mixture of
diastereomers): 1H NMR (400 MHz, CDCl3) δ 8.04-8.00
(m, 2H), 7.62-7.56 (m, 1H), 7.51-7.46 (m, 2H), 7.18-7.13
(m, 2H), 6.85-6.82 (m, 1H), 6.74-6.69 (m, 2H), 5.21 (d, J =
4.4 Hz, 1H), 5.11 (d, J = 2.8 Hz, 1H), 4.86 (bs, 1H), 4.39-
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1H), 3.75-3.64 (m, 1H), 2.03-1.97 (m, 1H), 1.94-1.77 (m,
2H); 13C NMR (101 MHz, CDCl3): δ 199.57, 199.29,
147.71, 147.51, 135.55, 133.70, 133.43, 129.30, 129.19,
128.78, 128.66, 128.60, 118.18, 114.19, 113.72, 80.54,
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1
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brown gummy; Yield: 35% (75 mg): H NMR (400 MHz,
CDCl3) δ 7.76 (s, 1H), 7.52 (d, J = 7.9 Hz, 2H), 7.35 (t, J =
7.9 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 4.81 (s, 2H), 4.37 (d,
J = 4.8 Hz, 2H), 2.59 (s, 1H); 13C NMR (101 MHz, CDCl3)
δ 171.81, 164.30, 136.40, 129.13, 125.21, 120.30, 63.56,
60.65; HRMS (ESI): Calc’d for [C10H11NNaO4]+ [M+H]+
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1
48% (70 mg); Mp. 91-92 °C; H NMR (400 MHz, CDCl3)
2380.
δ 8.59 (s, 1H), 7.49 (d, J = 7.7 Hz, 2H), 7.30 (t, J = 7.9 Hz,
2H), 7.12 (t, J = 7.4 Hz, 1H), 4.25 (s, 1H), 4.13 (d, J = 5.2
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1
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MHz, CDCl3) δ 9.09 (s, 1H), 7.67 (dd, J = 8.6, 1.1 Hz, 2H),
7.43 – 7.23 (m, 2H), 7.16 (t, J = 7.4 Hz, 1H), 4.36 (q, J =
7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz,
CDCl3) δ 160.77, 153.87, 136.25, 128.90, 125.21, 119.73,
63.40, 13.73.
2-oxo-2-(phenylamino)acetic acid(9a’):[49] White solid;
1
[14] P. P. Fu, J. H. Boyer, J. Chem. Soc. Perkin Trans.
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Yield: 79% (200 mg); Mp. 149-150.5 °C; H NMR (400
MHz, CDCl3+DMSO-d6) δ 9.44 (s, 1H), 7.70 (d, J = 7.5
Hz, 2H), 7.36 (t, J = 7.7 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H);
13C NMR (101 MHz, CDCl3) δ 161.77, 155.20, 136.43,
128.72, 124.89, 119.67.
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Acknowledgements
The authors gratefully acknowledge funding from the Ministry of
Science and Technology (MOST), Taiwan, and the Centre for
7
This article is protected by copyright. All rights reserved.

10.1002/adsc.201800783
Advanced Synthesis & Catalysis
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Mild Access to N-Formylation of Primary Amines
using Ethers as C1 Synthons under Metal-Free
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