Metal-free N-formylation of 2-aminophenols using dimethylformamide and CSA

Article abstract of DOI:10.1080/00397911.2019.1584319

DMF has been proved to be an efficient formylation reagent for 2-aminophenols in the presence of (±) camphorsulfonic acid (CSA) in this work. CSA works as an acid catalyst and a neutralizer of dimethyl amine which is kicked off from DMF. Both electron-wit

Full text of DOI:10.1080/00397911.2019.1584319

Synthetic Communications
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Metal-free N-formylation of 2-aminophenols using
dimethylformamide and CSA
Yuanyong Yang, Yingxian Li, Zhenhua Zhang, Yonglong Zhao & Wei Feng
To cite this article: Yuanyong Yang, Yingxian Li, Zhenhua Zhang, Yonglong Zhao & Wei Feng
(2019): Metal-free N-formylation of 2-aminophenols using dimethylformamide and CSA, Synthetic
Communications
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https://doi.org/10.1080/00397911.2019.1584319
Metal-free N-formylation of 2-aminophenols using
dimethylformamide and CSA
Yuanyong Yanga, Yingxian Lia, Zhenhua Zhangb, Yonglong Zhaoa, and Wei Fengb
b
aSchool of Pharmacy, Guizhou Medical University, Guiyang, China; BGI-Shenzhen, Shenzhen, China
ABSTRACT
ARTICLE HISTORY
Received 4 December 2018
Accepted 13 February 2019
DMF has been proved to be an efficient formylation reagent for
2-aminophenols in the presence of ( ) camphorsulfonic acid (CSA) in
this work. CSA works as an acid catalyst and a neutralizer of
dimethyl amine which is kicked off from DMF. Both electron-
withdrawing and electron-donating groups are tolerated. More
importantly, the product could be achieved in gram scale with the
possibility of further diversifying into biologically interesting struc-
tures.
KEYWORDS
2-aminophenols; camphor-
sulfonic acid; formylation;
N,N-dimethylformamide
GRAPHICAL ABSTRACT
Introduction
Formamides are important intermediates and precursors for the preparation of formami-
dine,[1] isocyanides and many other pharmaceutically important heterocycles, such as flour-
oquinolines,[2] oxazolidinones,[3] 1,2-dihydroquinolines,[4] substituted arylimidazoles[5] and
other chemotherapeutic compounds.[6] In addition, formyl group has also been widely
used as amino protecting group throughout peptide synthesis.[7] Furthermore, formamides
have also been used as Lewis base catalysts in organic synthesis.[8]
Numerous formylating methods have been reported in recent years using acetic for-
mic anhydride,[9] chloral,[10] carbodiimides activated formic acid,[11] activated formic
esters[12,13] and ammonium formate.[14] However, some limiting factors such as large
number of byproducts and toxicity of formylating reagents are restricting the applica-
tion of these methods.
N,N-dimethylformamide (DMF) is a cheap and abundantly available organic solvent
which is commonly used in organic synthesis. DMF is well known in the Vilsemiere-
Haak formylation[15] for the synthesis of aromatic aldehyde. In addition, DMF has also
been used as carbonyl source,[16] amide source,[17] oxygen source,[18] carbon source[19]
CONTACT Wei Feng
fengweinku@sina.com
BGI-Shenzhen, Shenzhen, 518083, China.
Supplemental data for this article is available online at on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

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Y. YANG ET AL.
Previous work:
a
b
c
This work:
d
Scheme 1. N-formylation of 2-aminophenols with DMF.
and dimethyl amine source[20] in the synthesis of myriads of heteroatom containing
compounds. Transition metal or harsh condition is always required during these trans-
formations. However, formylation of amine with DMF has been less investigated.
Recently, it was reported that aliphatic amines and anilines were converted to forma-
mides efficiently in the presence of Cu (II) catalyst and 1,2,4-triazole (Scheme 1a).[21]
Metal-free N-formylation with DMF was achieved in the presence of methyl benzoate
[22]
under MW for aliphatic amines (Scheme 1b)
and HCl for aryl amines respectively
(Scheme 1c).[23] However, 2-aminophenol is always missing in the substrate scope prob-
ably due to the steric hindrance of the ortho hydroxyl group. In our continuous effort
in developing environmentally benign chemical reactions, we discovered a metal free
condition for the N-formylation of 2-aminophenol with DMF as shown in Scheme 1d.
Results and discussion
In our preliminary studies, poor conversion along with poor yield was obtained from
the reaction between 2-aminophenol 1a and DMF in the presence of acetic acid
(Table 1, entry 1). As this reaction is acid promoted, we proposed that a stronger acid
may facilitate this reaction, so different acids with different pKa were screened. The

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Table 1. Reaction optimization for the formylation with DMF.
Entry
Acid
AcOH
Benzoic acid
TFA
p-TSA
MSA
CSA
CSA
CSA
CSA
Conversion (%)a
Yieldb
1
2
3
4
5
6
50
70
80
100
100
100
100
70
35%
51%
68%
78%
76%
82%
67%
51%
63%
nd
7c
8d
9e
10f
80
10
CSA
Conditions: 0.2 mmol 2-aminophenol and 0.3 mmol acid in 1 ml DMF was heated to 100 ꢀC for 24 h unless otherwise
c
stated. aConversion was determined by crude 1 H NMR analysis. bIsolated yield. Reaction was conducted at 130 ꢀC.
e
f
dReaction was conducted at 70 ꢀC. 0.2 mmol CSA was used. 0.04 mmol CSA was used.
conversion and yield seem strongly correlated to the acidity of the catalyst. Among
these initially screened catalysts (Table 1, entry 2–4), p-Toluenesulfonic acid with a
lower pKa was found to be the best. Two more sulfonic acids were then tested and
comparable results were obtained. ( ) Camphorsulfonic acid (CSA) resulted in a
slightly better yield (Table 1, entry 4–6). Therefore, reaction catalyzed by CSA was
used as a model to study the temperature effect on this reaction. At a higher reaction
temperature, the reaction mixture became messy on TLC and the yield was slightly
lower. On the other hand, a lower temperature failed to drive the reaction to full
conversion hence reducing the chemical yield (Table 1, entry 7, 8). We also tried to
reduce the amount of the promoter, both stoichiometric and substoichiometric
amount CSA were used to test the efficacy. However, poorer conversions were
observed (Table 1, entry 9, 10). Other than facilitate the amide formation through
hydrogen bonding with the carbonyl group of DMF, CSA may also play an important
role in neutralizing the dimethyl amine formed in situ. Therefore, more than stoichio-
metric amount of CSA is required.
With this established procedure, we carried on to test the substrate scope of this reac-
tion. Electron withdrawing groups like bromo and nitro are good for this reaction and
excellent yields can be achieved (Table 2, entry 2 b, 2c). On the other hand, electron
donating groups slightly reduce the chemical yields (Table 2, entry 2d–2f). Electron rich
aromatic substrate also works well under this condition (Table 2, entry 2g). However,
group like methyl that is adjacent to the amino group will retard the reaction, which is
believed to be due to the steric hindrance of the methyl group (Table 2, entry 2h).
Surprisingly, aniline is unreactive under this condition, which provides an insight into
the reaction mechanism (Figure 1). It is proposed that the ortho-hydroxyl group inter-
acts with DMF through hydrogen bonding. When activated by acid, the carbonyl group
is attacked by the free amine. The product is formed after releasing acid and
dimethylamine.

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Y. YANG ET AL.
Table 2. Substrate scope for the formylation with DMF.
Conditions: 0.2 mmol aminophenol and 0.3 mmol CSA in 1 ml DMF was heated to 100 ꢀC for 24 h.
Figure 1. Proposed mechanism for the formylation of 2-aminophenols.
Scheme 2. Gram scale synthesis of 2a and its diversification.
Moreover, this formylation reaction can also be performed on a gram scale under the
optimized conditions with a slightly better yield (Scheme 2). The product could be fur-
ther diversified to interesting scaffold according to the reported procedure.[24]
Conclusion
In summary, we have demonstrated a ( ) camphorsulfonic acid promoted formylation
reaction of 2-aminophenols with DMF in high yields. The reaction conditions tolerant
various 2-aminophenols bearing both electron-withdrawing and electron-donating
groups. More importantly, gram scale of the product could be achieved with the possi-
bility of further diversifying into biologically interesting structures.

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Experimental section
Procedure for the synthesis of N-(2-hydroxyphenyl)formamides (2a)
0.2 mmol 2-aminophenol and 0.3 mmol Camphorsulfonic acid were mixed in 1 mL
DMF, the mixture was heated to 100 ꢀC under stirring. After two hours, the mixture
was cooled to room temperature and diluted with 10 mL water. The mixture was then
extracted with diethyl ether for 3 times (3X10mL). The combined organic layer was
washed with brine, dried over Na2SO4 and concentrated. The product was purified by
flashing silca gel column chromatography (Eluent: Hexane:EA = 1:1) and characterized
with a 400 MHz Bruker Ultra Shield NMR spectrometer. The NMR data (1 H and 13C)
is consistent with what is reported.[25]
NMR data
1H NMR (400 MHz, Acetone) d 9.18 (brs, 2H), 8.40 (s, 1H), 7.86 (dd, J ¼ 8.0, 1.5 Hz,
1H), 6.99 (ddd, J ¼ 8.1, 7.3, 1.6 Hz, 1H), 6.92 (dd, J ¼ 8.1, 1.5 Hz, 1H), 6.83 (ddd, J ¼ 8.0,
7.3, 1.5 Hz, 1H). 13C NMR (101 MHz, Acetone) d 160.89, 147.95, 127.20, 125.93, 122.13,
120.62, 117.33. HRMS (ESI): m/z, [M þ H]þ for C7H8NO2, calculated: 138.0555, found:
138.0554. Eluent: Hexane/EA = 1/1.
Acknowledgment
We thank BGI-Shenzhen for the support in publishing this work.
Funding
The work was financially supported by the National Natural Science Foundation of China
[21807120, 81660348, 21502030], Office of Science and Technology of Guiyang ([20151001]06).
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