DMF·HCl as a versatile and straightforward N- and O-formylating agent

Article abstract of DOI:10.1080/00397911.2020.1844901

Inspired by the serendipitous isolation of N-formylpiperazines when we attempted the synthesis of a series of piperazines, we have developed a straightforward methodology for the N- and O- formylation of secondary cyclic amines, anilines and steroids, respectively. Such approach is based on the hitherto non-reported use of DMF·HCl complex, as a versatile and easily-available formylating system that can be stored without apparent loss of activity.

Full text of DOI:10.1080/00397911.2020.1844901

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: (Print) (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
DMF·HCl as a versatile and straightforward N- and
O-formylating agent
Dulce G. Ramírez-Vázquez , Omar Viñas-Bravo , Roxana Martínez-Pascual ,
Lemuel Pérez-Picaso & Karla Viridiana Castro-Cerritos
To cite this article: Dulce G. Ramírez-Vázquez , Omar Viñas-Bravo , Roxana Martínez-
Pascual , Lemuel Pérez-Picaso & Karla Viridiana Castro-Cerritos (2020): DMF·HCl as a
versatile and straightforward N- and O-formylating agent, Synthetic Communications, DOI:
10.1080/00397911.2020.1844901
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https://doi.org/10.1080/00397911.2020.1844901
DMFꢀHCl as a versatile and straightforward N- and O-
formylating agent
ꢀ
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Dulce G. Ramırez-Vazquez, Omar Vinas-Bravo, Roxana Martınez-Pascual, Lemuel
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Perez-Picaso, and Karla Viridiana Castro-Cerritos
ꢀ
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Instituto de Quımica Aplicada, Universidad del Papaloapan, Tuxtepec, Mexico
ABSTRACT
ARTICLE HISTORY
Received 30 August 2020
Inspired by the serendipitous isolation of N-formylpiperazines when
we attempted the synthesis of a series of piperazines, we have
developed a straightforward methodology for the N- and O- formyla-
tion of secondary cyclic amines, anilines and steroids, respectively.
Such approach is based on the hitherto non-reported use of
DMFꢀHCl complex, as a versatile and easily-available formylating sys-
tem that can be stored without apparent loss of activity.
KEYWORDS
N-Formylation; DMFꢀHCl
complex; O-Formylation;
cyclic amines; anilines
GRAPHICAL ABSTRACT
Introduction
N,N-Dimethylformamide (DMF), is an organic compound widely used in Organic
Chemistry as a versatile solvent with polar aprotic and hydrophilic properties, for
example with great efficiency in SN2 reactions.[1] Furthermore, this compound has
found many other applications such as stabilizer of metal nanoclusters and nanopar-
ticles,[2] ligand[3], catalyst,[4] or as a reagent in organic synthesis,[5] among other uses.
As a reagent, DMF is well known as a source of the formyl moiety to obtain forma-
mides in aromatic, heteroaromatic and non-aromatic systems in the Vilsmeier-Haack
reaction.[6] The Vilsmeier-Haack reagent (POCl3-DMF) has also been used to convert
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CONTACT Roxana Martınez-Pascual
rpascual@unpa.edu.mx; Omar Vinas-Bravo
obravo@unpa.edu.mx
Instituto
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de Quımica Aplicada, Universidad del Papaloapan, Tuxtepec 68345, Mexico
Supplemental data for this article can be accessed on the publisher’s website
ß 2020 Taylor & Francis Group, LLC

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D. G. RAMÍREZ-VÁZQUEZ ET AL.
Scheme 1. Obtention of phenylpiperazine and phenylformamide from aniline.
O-silyl protected carbohydrates[7] and phenol into their corresponding formats.[8] More
recently, formylation of the hydroxyl group at C-3 and C-17 positions of some sterols
was achieved using a combination of POCl3-DMF.[9] Formylation reactions frequently
include transition metals or complex reagents to catalyze the reaction.[10] Most of these
protocols are expensive and sometimes require long reaction times and high tempera-
tures. Protic acids and DMF have been used to a lesser extent for N-formylation and to
our knowledge, there are no reports for O-formylation. In 1973, Kraus reported the
slow formylation of alkyl amines with refluxing DMF and showed that the addition of
concentrated sulfuric acid greatly enhanced the rate of the reaction and improved the
yields.[11] Later, Takahashi et al., reported[12] a protocol of transamidation of carboxa-
mides using catalytic amounts of silica-supported H2SO4 under solvent-free conditions
which was applied to the formylation of aromatic/heteroaromatic amines and some alkyl
amines, as well. Chen and co-workers[13] described the preparation of some formamides
including a two-step route, first, a C–N bond formation of b-keto amides and then a
different C–N cleavage in the presence of a HCl (0.2 equiv)-DMF solution in a Schlenk
tube at 120ꢁ C; similar conditions were used by Zhang (36.5% HCl solution/DMF at
100 ꢁC) for the synthesis of aryl formamides.[14] More recently, acid-promoted N-formy-
lation of 2-aminophenol was studied with different acids, camphorsulfonic acid being
found to be the best catalyst for this purpose.[15]
We herein report a new methodology for the N or O-formylation of aromatic or alkyl
amines and two sterols (diosgenin and cholesterol), respectively, using a stable
DMFꢀHCl complex as a versatile formylating agent under metal-free conditions. This
method is inexpensive and the complex can be prepared and stored under no spe-
cial conditions.
Results and discussion
Access to the DMFꢀHCl complex as a formylating agent occurred in a total serendipit-
ous fashion. We attempted to prepare a phenylpiperazine derivative from aniline in the
presence of bis(2-chloroethyl)amine hydrochloride, and a base (K2CO3) in refluxing
ethylene glycol. However, we did not obtain the expected compound. In order to favor
the nucleophilic reaction with a polar non-protic solvent, we used DMF instead of
ethylene glycol. After the work-up and the chromatographic purification, we isolated 4-
phenylpiperazine-1-carboxaldehyde (2) and N-phenylformamide (3) (Scheme 1). The
same result was observed in the absence of K2CO3 what can be explained by the low
solubility of K2CO3 in DMF. In previous reports, this protocol was carried out to obtain
phenylpiperazine derivatives; however, the yields were poor and the formylated products
were not detected.[16]

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Table 1. Synthesis of N-formyl piperazines.
Ar–NH2
Entry
1
Product
Yield (%)
58
2
71
3
4
62
48
5
48
On the basis that DMF can be a source of the formyl moiety in presence of protic or
Lewis acids, we deduced that the HCl formed during the SN2 reaction between the anil-
ine and bis(2-chloroethyl)amine hydrochloride could catalyze the formylation of the
aniline and phenyl piperazine initially obtained in the reaction. In order to analyze the
scope and limitations of this approach, different anilines bearing both, electron-with-
drawing and electron-donating groups were studied (Table 1, entries 1–5). In general,
moderate yields were obtained; the highest yield was observed in the reaction of p-
methoxyaniline (entry 2, 71%). It is worth mentioning that N-formylpiperazines are
important scaffolds for the synthesis of more complex compounds such as explosives[17]
and bioactive derivatives.[18,19]
To confirm the hypothesis that HCl formed during the reaction could be catalyz-
ing the formylation, HCl (g) was produced by the reaction of H2SO4 and NaCl and
then it was bubbled into a flask containing DMF during 3 h. The HCl concentration
was determined by titration using a 0.1 M NaOH solution, and it turned out to be

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D. G. RAMÍREZ-VÁZQUEZ ET AL.
Scheme 2. DMFꢀHCl resonance hybrids
3.2 M. It is known that when an amide is treated with an acid, the protonation
occurs more easily at the carbonyl oxygen rather than at the nitrogen, because of
the resonance stabilization of the corresponding cation (Scheme 2). The DMFꢀHCl
1
system was characterized by NMR. Concerning the H-NMR spectrum, an additional
signal at 15.10 ppm was observed, attributed to the proton of the oxonium ion in
the resonance hybrid DMFHþ (Scheme 2). The same peak was detected by Deng
et al.,[20] in the complex prepared with DMF and trifluoroacetic or tetrafluoroboric
acids (15.39 ppm in DMSO-d6). A small change of 2.2 ppm was observed in the 13C-
NMR spectrum (160.8 ppm vs 163.0 ppm). It is worthy to mention that the system
HClꢀDMF was stored and after a month it was titrated, exhibiting the same
concentration.
The DMFꢀHCl was used without further purification to formylate a series of anilines
and secondary amines (Table 2, entries 1–5). The methodology consisted of the addition
of DMFꢀHCl solution (5 mL) to the corresponding amine (4.5 mmol) and refluxing with
continuous stirring for 3 h. After work-up and chromatographic purification, a series of
formyl derivatives were obtained in good yields. The anilines tested contained either no
substitution on the aromatic ring (entry 1), electron-donating groups (entries 2–4), or a
strong electron-withdrawing group (entry 5); in all cases, the yields ranged from good
to excellent (70–84%). This protocol showed to be efficient also for cyclic secondary
amines (entries 6–8) and for the O-formylation of two steroids, cholesterol and dios-
genin (entries 9–10), in the latter example, the reaction proceeded at 50–55 ꢁC. Formate
esters are used as intermediates in organic synthesis,[21] mainly as protecting groups of
alcohols.[22] Several methodologies for formylation reported in the literature involve
strong reaction conditions[23] and can affect other functional groups. In this regard, the
protocol depicted herein represents an alternative and inexpensive method with
good yields.
Experimental
Reagents were used as received from Sigma-Aldrich without further purification. NMR
spectra were recorded on a VARIAN Mercury spectrometer (400 MHz for 1H,
1
100.6 MHz for 13C) or on a 80 MHz Spinsolve 80 NMR spectrometer (80 MHz for H,
20 MHz for 13C). IR spectra were acquired on FTIR Perkin Elmer Spectrum 100 (range:
4000–600 cmꢂ1). High resolution mass spectra (HRMS) were obtained by direct infusion
in a Synapt G2-Si Q-TOF system (Waters) equipped with an electrospray (ESI) probe,
and the following parameters were used: flow rate, 10 mL/min; ionization mode, positive;
capillary voltage, 3000 V; cone voltage, 40 V; capillary temperature, 100 ꢁC; nitrogen was
used as desolvation gas at 200 ꢁC; and a flow rate of 800 L/h, cone gas, 50 L/h;

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Table 2. N-formylation of anilines, secondary amines and sterols using the system HClꢀDMF.
Ar–NH2
Entry
Product
Yield (%)
1
71
2
3
75
84
4
70
5
6
73
50
7
8
60
75
9
Cholesterol
Diosgenin
48
48
10

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D. G. RAMÍREZ-VÁZQUEZ ET AL.
Nebulizer pressure; 6 bar. Mass spectrometer was calibrated with sodium formate and
spectra were corrected by simultaneous infusion of the compound Leucine Enkephaline
(556.2771). Data analysis was conducted using MassLynx software version 4.1 (Waters).
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Analytical TLC was performed on silica gel ALUGRAM SIL G/UV254 plates, and
chromatographic columns were carried out on DavisilTM grade 633 silica gel
(200–425 mesh).
Typical experimental procedure for preparation of the DMFꢀHCl complex
H2SO4 (10 mL) was slowly dropped into a stirred flask containing NaCl (10 g,
171.11 mmol) in order to produce HCl(g). The liberated HCl(g) was bubbled into a two-
neck flask containing DMF (50 mL) during 3 h. A 10% NaOH solution trap was
attached to the second neck. The concentration of HCl of the complex was determined
1
by titration with a 0.1 M NaOH solution, being 3.2 M. H NMR (80 MHz, DMSO-d6) d
15.10 (s, 0.3H), 8.00 (s, 1H), 2.89 (s, 3H), 2.70 (s, 3H).
Typical experimental procedure for the preparation of N-formylanilines
The DMFꢀHCl solution (5 mL) was added to the corresponding aniline (4.5 mmol) and
refluxed for 3 h. Then, a saturated aqueous NaHCO3 solution (10 mL) was added and
the resulting mixture was extracted with EtOAc (3 ꢃ 20 mL) and washed with brine
(3 ꢃ 20 mL). The organic layer was dried over Na2SO4, filtrated, and the filtrate was
removed under reduced pressure. The residue was purified as indicated in each case.
Typical experimental procedure for the synthesis of O-formylated species
DMFꢀHCl complex (10 mL) was added to the corresponding alcohol (1.20 mmol) keep-
ing the temperature between 50 and 55 ꢁC for 2 h. Then, an aqueous NaHCO3 solution
(10 mL) was added and the resulting mixture was extracted with AcOEt (3 ꢃ 20 mL)
and washed with brine (3 ꢃ 20 mL). The solvent was removed under reduced pressure.
The residue was purified as indicated below.
Full experimental details, characterization data and isolated yields for N-formyl-4-
arylpiperazines, N-formylanilines, cyclic amides and O-formylated species can be found
through the “Supplementary Content” section of this article’s webpage.
Conclusions
In conclusion, based on the results obtained in the reaction between aniline and bis(2-
chloroethyl)amine hydrochloride, we envisioned the possibility that HCl(g) could cata-
lyze the formylation of aniline and phenyl piperazine. These observations let us to
develop a new straightforward methodology for the simple N-formylation of aniline
derivatives using a stable DMFꢀHCl complex as an easily-handled catalyst, and extended
the scope of this process to secondary cyclic amines and to the O-formylation of two
steroids (diosgenin and cholesterol). DMFꢀHCl complex is easy to prepare and that can
be stored for more than one month without the apparent loss of activity.

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Funding
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The authors thank Consejo Nacional de Ciencia y Tecnologıa (CONACYT) of Mexico for the
award of fellowship to DGRV, and financial grants [INFRA-2015-01-252013 and INFRA-
2019-301144].
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