Dichloromeldrum's acid (DiCMA): A practical and green amine dichloroacetylation reagent

Article abstract of DOI:10.1021/acs.orglett.1c00850

Dichloromeldrum's acid is introduced as a bench-stable, nonvolatile reagent for the dichloroacetylation of anilines and alkyl amines to produce α,α-dichloroacetamides, which are important motifs for medicinal chemistry. Products are formed in good to excellent yields with reagent grade solvents, and, as the only byproducts are acetone and CO2, no column chromatography is required. Thus, this reagent is practical, efficient, and green for the dichloroacetylation of primary amines.

Full text of DOI:10.1021/acs.orglett.1c00850

pubs.acs.org/OrgLett
Letter
Dichloromeldrum’s Acid (DiCMA): A Practical and Green Amine
Dichloroacetylation Reagent
David M. Heard and Alastair J. J. Lennox*
Cite This: Org. Lett. 2021, 23, 3368−3372
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Dichloromeldrum’s acid is introduced as a bench-stable, nonvolatile reagent for the dichloroacetylation of anilines
and alkyl amines to produce α,α-dichloroacetamides, which are important motifs for medicinal chemistry. Products are formed in
good to excellent yields with reagent grade solvents, and, as the only byproducts are acetone and CO2, no column chromatography is
required. Thus, this reagent is practical, efficient, and green for the dichloroacetylation of primary amines.
The ideal approach for this transformation should be a
simple functionalization of the parent amine, which is readily
available and the most atom economic starting material.
Hence, we focused on the discovery of a safer and more benign
dichloroacetylation reagent than those previously used in the
traditional approaches. While Meldrum’s acid itself reacts
readily with electrophiles to produce alkylated or acylated
scaffolds,14 we hypothesized that the dichlorinated derivative
should accept nucleophiles now that the α-protons have been
removed and the electrophilicity of the carbonyl has been
enhanced.15 The subsequent loss of acetone and CO2 would
not only provide easily separable byproducts, but provide a
driving force that should facilitate rapid and room temperature
reactivity.
A high yielding, rapid, and procedurally simple synthesis of
dichloroMeldrum’s acid (DiCMA) was developed from
Meldrum’s acid itself (Scheme 1). Meldrum’s acid is very
inexpensive and is prepared from acetone and malonic acid,
which can be produced industrially by fermentation.16 We
employed trichloroisocyanuric acid (TCCA) in acetonitrile, as
it is an inexpensive (<10 cents/g) chlorinating source that has
previously been used for the dichlorination of β-diketones.17
The transformation was achieved without the need for base,
owing to the unusually low pKa of Meldrum’s acid (7.3 in
DMSO at 25 °C).18,19 An excellent yield of 91% was attained
for this transformation, which we scaled up to 65 mmol.
α,α-Dichloroacetamides are a structural feature found in a
variety of medicinally relevant compounds, including in
antibiotic, antiamoebic, and antiprotozoal drugs, Figure 1,
and have been investigated as anticancer agents.1−3 The group
contains two hydrogen-bond donors (N−H and C−H), which
have been exploited to catalytically activate carbonyl
compounds.4 Traditional methods for their synthesis apply a
dichloroacetylation approach of the readily available parent
amine, with either dichloroacetic acid and stoichiometric
coupling reagent, or dichloroacetyl chloride.5,6 Both ap-
proaches use reagents that pose a significant threat to health
and require the use of added base, and the coupling strategy
generates stoichiometric waste that must be separated from the
product. Methyl dichloroacetate is another option, but its
decreased reactivity results in low to moderate yields and
requires prolonged heating.6,7 Thus, more recent approaches
to this reaction have focused on oxidative chlorination
approaches. Unfortunately, the direct dichlorination of an
acetamide is difficult to control, with overhalogenation to the
trichloroacetamide dominating.8 Hence, the use of a 1,3-
dicarbonyl (β-ketoamide) compound has been adopted in
recent developments of this transformation, Figure 1,9−12 as
the α-position is further activated but overchlorination is
prevented. This two-step deacylative dichlorination approach
has been successfully applied with a variety of oxidative
chlorine sources, and most recently with a very specific
zwitterionic catalyst. The homologation of isocyanates using
organolithium reagents is another strategy that has been
demonstrated, but low temperatures and highly reactive
reagents are required.13 We, therefore, sought to develop a
room temperature, single-step methodology with high atom
economy, no additional reagents, minimal purification, and
applicable to various types of primary amines.
Received: March 11, 2021
Published: April 12, 2021
https://doi.org/10.1021/acs.orglett.1c00850
© 2021 American Chemical Society
Org. Lett. 2021, 23, 3368−3372
3368

Organic Letters
pubs.acs.org/OrgLett
Letter
Table 1. Optimization of the Dichloroacetylation of 1a
a
Entry
Solvent
PhMe
Chloroform
THF
Deviation
Yield (%)
1
2
3
4
5
6
7
8
−
−
−
−
−
−
−
50
63
83
95
97
17
14
7
98
96
42
84
99
99
Ether
EtOAc
Acetone
Methanol
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
K2CO3 (1.5 equiv)
HCO2H (1.5 equiv)
H2O (2.5 equiv)
H2O (60 equiv)
DiCMA (1.1 equiv)
DiCMA (2.0 equiv)
400 mM
9
10
11
12
13
14
a
19F NMR yields.
form, THF, and diethyl ether, but the highest yields were
achieved with ethyl acetate. The use of methanol or acetone
resulted in lower yields, and a complex mixture of products
were formed. We explored the effect of either acid or base on
the conditions to test the sensitivity of the reaction to these
conditions. While the addition of K2CO3 destroyed the
reactivity, the addition of formic acid had no effect, thus
demonstrating its stability toward acids (entries 8 and 9). A
small amount of water also had a very minor effect, whereas
larger quantities were shown to reduce yields more
considerably (entries 10 and 11). When varying the quantity
of DiCMA (2), a marginal loss in yield was observed with 1.1
equiv (entry 12) as opposed to 1.2 equiv, and a marginal
improvement was observed with 2.0 equiv of the reagent
(entry 13). Kinetic analysis of the reaction showed good
second-order behavior; hence the reaction becomes extremely
slow at high conversions with the use of lower concentrations
of 2 (see Supporting Information (SI) for data). Thus, using a
higher reaction concentration of 400 mM and 1.2 equiv of 2
led to quantitative yields of 3a in 16 h at room temperature.
With the optimized conditions in hand, we proceeded to
explore the substrate scope, Figure 2. Emboldened by the
insensitivity toward small quantities of water, we used reagent
grade EtOAc with no further purification or degassing. When
testing anilines, we found that the highest yields were obtained
from substrates containing electron-donating substituents
(3b−d), although moderate to good yields were still obtained
with electron-withdrawing groups (3e−f). The conditions
tolerated ortho substitution well, including various groups of
different electronics and sterics (3g−n). However, with
diortho-substitution, the reaction was greatly retarded and a
decrease in yield is observed (3o). Anilines bearing carboxylic
acid substituents (1p and 1q) gave excellent yields of the
dichloroacetamide product, which is of significant interest
because carboxylic acids are less compatible with dichlor-
oacetylation coupling methods (Figure 1) as they may undergo
homocoupling.
Figure 1. Previous syntheses of dichloroacetamides.
Scheme 1. Preparation of Dichloromeldrum’s Acid
(DiCMA)
Although DiCMA was found to be slightly hygroscopic upon
exposure to air for prolonged periods, we found it to be a
bench stable solid that can be stored at room temperature for
several months.
Reaction optimization studies were conducted with 4-
fluoroaniline 1a and initiated in toluene with 1.2 equiv of
DiCMA (2). These conditions immediately gave 50% of
dichloroacetamide product 3a at room temperature in 16 h
(entry 1, Table 1), thus supporting our hypothesis that
DiCMA (2) is an effective and reactive dichloroacetylation
reagent. While acetylation reactions using alkylated Meldrum’s
acid derivatives require elevated reaction temperatures to drive
the decarboxylation step,20 the reaction using 2 proceeds
readily at room temperature. This is likely due to the increased
electrophilicity of the carbonyl groups and the inability to
enolize.
The influence of solvent was examined on the reaction
(entries 2−7). Improved yields were observed with chloro-
Benzylamines were then tested in the reaction and were
shown to react readily with DiCMA (2). However, unlike
3369
https://doi.org/10.1021/acs.orglett.1c00850
Org. Lett. 2021, 23, 3368−3372

Organic Letters
pubs.acs.org/OrgLett
Letter
Figure 2. Isolated yields are shown with 19F NMR yields in parentheses.
anilines, an additional product was formed alongside the
dichloroacetylation product 3, which was found to be
trichloroacetamide 4. The enhanced nucleophilicity of this
class of substrate presumably renders the enol intermediate (5)
more susceptible toward further reaction with 2, as opposed to
tautomerization or protonation to 3 (Figure 3). This
However, superior selectivities were obtained by the slow,
syringe-pump addition of DiCMA (2) to a solution of amine
1s (0.2 mmol/h), which gave a >30:1 selectivity. This strategy
was therefore adopted for all alkyl and benzylamine substrates.
With this improved protocol established, a range of
benzylamines were tested in the reaction. Consistently good
to excellent yields were observed (3r−y) with no clear
correlation to electronic effects. The reaction was then tested
on a variety of alkyl amines. Amines with cyclic substitution
and linear amines, including phenethylamines (3a−ah), were
well tolerated, with no trichlorinated 4 observed in the isolated
material. The esters of two amino acids converted cleanly
(3ai−aj), with no erosion of the ee observed. Esterification of
the amino acids was required for solubility purposes. Finally, a
secondary amine, piperidine, was tested and gave a moderate
yield of dichloroacetylated product (3ak).
The atom economy and the complete E-factor were
calculated for the reaction of 1d to 3d25 and used to
benchmark against other procedures for this transformation
(Table 2).26 As the use of DiCMA (2) does not require the use
of base, coupling agent, or any other reagents to proceed, the
atom economy of 66.7% for the reaction was found to be
superior to all other methods analyzed.27 Equally, as the
substrate does not require preactivation, and the reaction
provides excellent yields of product 3, generates only acetone
and CO2 as byproducts, and does not require a catalyst, the
complete E-factor of 12 demonstrates this method to be the
greenest reported to date.28
Figure 3. Proposed mechanism for the formation of 3 and 4, and
selectivity achieved under different conditions.
chlorination process demonstrates that DiCMA (2) is a rare
example of a C−Cl bond containing chlorinating reagent,21−24
which may be important for other applications. Evidence to
support chlorination of enol 5 rather than product 3 was
attained by resubjecting 3s to the reaction conditions, with and
without added base or acid, but no 4s was observed. To solve
the problem, we explored the use of formic acid to promote
protonation, which did improve the product ratio to 12:1.
In summary, we have discovered that dichloromeldrum’s
acid is an easily prepared, bench stable reagent capable of the
3370
https://doi.org/10.1021/acs.orglett.1c00850
Org. Lett. 2021, 23, 3368−3372

Organic Letters
pubs.acs.org/OrgLett
Letter
Table 2. Green Chemistry Metric Analysis of
Dichloroacetamide Synthesis
REFERENCES
■
(1) Fereidoonnezhad, M.; Tabaei, S. M. H.; Sakhteman, A.; Seradj,
H.; Faghih, Z.; Faghih, Z.; Mojaddami, A.; Sadeghian, B.; Rezaei, Z.
Design, Synthesis, Molecular Docking, Biological Evaluations and
QSAR Studies of Novel Dichloroacetate Analogues as Anticancer
Agent. J. Mol. Struct. 2020, 1221, 128689.
(2) Zhang, S. L.; Yang, Z.; Hu, X.; Tam, K. Y. Dichloroacetophe-
nones Targeting at Pyruvate Dehydrogenase Kinase 1 with Improved
Selectivity and Antiproliferative Activity: Synthesis and Structure-
Activity Relationships. Bioorg. Med. Chem. Lett. 2018, 28 (21), 3441−
3445.
(3) Yang, Y.; Shang, P.; Cheng, C.; Wang, D.; Yang, P.; Zhang, F.;
Li, T.; Lu, A.; Zhao, Y. Novel N-Phenyl Dichloroacetamide
Derivatives as Anticancer Reagents: Design, Synthesis and Biological
Evaluation. Eur. J. Med. Chem. 2010, 45 (9), 4300−4306.
(4) Koeller, S.; Thomas, C.; Peruch, F.; Deffieux, A.; Massip, S.;
Léger, J. M.; Desvergne, J. P.; Milet, A.; Bibal, B. α-Halogenoaceta-
nilides as Hydrogen-Bonding Organocatalysts That Activate Carbonyl
Bonds: Fluorine versus Chlorine and Bromine. Chem. - Eur. J. 2014,
20 (10), 2849−2859.
(5) Swensen, A. D.; Weaver, W. E. Organic Fungicides. III. The
Preparation of Some α,α-Dichloroacetamides. J. Am. Chem. Soc. 1948,
70 (12), 4060−4061.
(6) Hazra, B. G.; Pore, V. S.; Maybhate, S. P. An Improved
Procedure for the Dichloroacetylation of Primary and Secondary
Amines. Org. Prep. Proced. Int. 1989, 21 (3), 355−358.
(7) Controulis, J.; Rebstock, M. C.; Crooks, H. M. Chloramphenicol
(Chloromycetin). 1 V. Synthesis. J. Am. Chem. Soc. 1949, 71 (7),
2463−2468.
(8) Dempsey, A. M.; Hough, L. The Reaction of Phosphorus
Pentachloride with Amides, in Particular 2-Acetamido-2-Deoxyaldo-
hexopyranoses. Carbohydr. Res. 1975, 41 (1), 63−76.
(9) Ke, Z.; Lam, Y. P.; Chan, K. S.; Yeung, Y. Y. Zwitterion-
Catalyzed Deacylative Dihalogenation of β-Oxo Amides. Org. Lett.
2020, 22 (18), 7353−7357.
(10) Liu, W.-B.; Chen, C.; Zhang, Q.; Zhu, Z.-B. Organic Synthesis
Using (Diacetoxyiodo)Benzene (DIB): Unexpected and Novel
Oxidation of 3-Oxo-Butanamides to 2,2-Dihalo- N -Phenylacetamides.
Beilstein J. Org. Chem. 2012, 8, 344−348.
(11) Zhang, Q.; Liu, W.; Chen, C.; Tan, L. Approach for the Direct
Synthesis of β -Dichlorosubstituted Acetanilides Using Iodine
Trichloride (ICl 3) as the Oxidant and Catalyst. Chin. J. Chem.
2013, 31 (4), 453−455.
Atom
Yield
(%)
economy
(%)
Complete
E-factor
a
Entry
Conditions
1
2
DiCMA (2), EtOAc
Dichloroacetic acid, DMAP,
DCC, DCM
Dichloroacetyl chloride, NEt3,
DCM
99
95
66.7
47.6
12
138
32,29
86
69
75
70
72
59.7
53.0
53.0
28.8
42.1
16
97
90
18
18
412,30 (i) t-BuOAcAc, Xylene;
(ii) NCS, EtOH
59,30
(i) t-BuOAcAc, Xylene;
(ii) NCS, Catalyst, MeOH
610,30 (i) t-BuOAcAc, Xylene;
(ii) DIB, ZnCl2, Dioxane
711,30 (i) t-BuOAcAc, Xylene;
(ii) ICl3, DCE
a
Values in entries 1−3 derive from experimentation, whereas values in
entries 4−7 are calculated from literature values.
dichloroacetylation of several amine classes. The reaction
proceeds in good to excellent yields, under ambient conditions
and without the need for column chromatography. This
protocol does not require prefunctionalization of the amine, or
the use of unstable reagents or oxidants, and is more
sustainable than existing approaches.
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c00850.
(12) Wang, J.; Li, H.; Zhang, D.; Huang, P.; Wang, Z.; Zhang, R.;
Liang, Y.; Dong, D. Divergent Synthesis of α,α-Dihaloamides through
α,α-Dihalogenation of β-Oxo Amides by Using N -Halosuccinimides.
Eur. J. Org. Chem. 2013, 2013 (24), 5376−5380.
Experimental procedures and characterization data for
known and new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
(13) Pace, V.; Castoldi, L.; Mamuye, A.; Holzer, W. Homologation
of Isocyanates with Lithium Carbenoids: A Straightforward Access to
α-Halomethyl- and α,α-Dihalomethylamides. Synthesis 2014, 46 (21),
2897−2909.
■
Alastair J. J. Lennox − School of Chemistry, University of
Bristol, Bristol BS8 1TS, U.K.; orcid.org/0000-0003-
2019-7421; Email: a.lennox@bristol.ac.uk
(14) McNab, H. Chem. Soc. Rev. 1978, 7 (3), 345.
(15) Engl, O. D.; Saadi, J.; Cosimi, E.; Wennemers, H. Synthesis of
Monothiomalonates − Versatile Thioester Enolate Equivalents for
C−C Bond Formations. Helv. Chim. Acta 2017, 100 (11), e1700196.
(16) Bureau, I. (12) International Application Published under the
Patent Cooperation Treaty (PCT) (19) World Intellectual Property
Organization, November 14, 2018.
Author
David M. Heard − School of Chemistry, University of Bristol,
Bristol BS8 1TS, U.K.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00850
(17) Mendonca̧ , G. F.; Sindra, H. C.; de Almeida, L. S.; Esteves, P.
M.; de Mattos, M. C. S. Trihaloisocyanuric Acids as Convenient
Reagents for Regioselective Halogenation of β-Dicarbonyl Com-
pounds. Tetrahedron Lett. 2009, 50 (4), 473−475.
Notes
(18) Bordwell, F. G. Equilibrium Acidities in Dimethyl Sulfoxide
Solution. Acc. Chem. Res. 1988, 21 (12), 456−463.
The authors declare no competing financial interest.
(19) Ivanov, A. S. Meldrum’s Acid and Related Compounds in the
Synthesis of Natural Products and Analogs. Chem. Soc. Rev. 2008, 37
(4), 789−811.
ACKNOWLEDGMENTS
■
We would like to thank the Royal Society (University Research
Fellowship and Enhancement award to A.J.J.L.) and EPSRC
(EP/T001631/1) for funding.
(20) Li, J.-S.; Da, Y.-D.; Chen, G.-Q.; Yang, Q.; Li, Z.-W.; Yang, F.;
Huang, P.-M. Solvent-, and Catalyst-Free Acylation of Anilines with
3371
https://doi.org/10.1021/acs.orglett.1c00850
Org. Lett. 2021, 23, 3368−3372

Organic Letters
pubs.acs.org/OrgLett
Letter
Meldrum’s Acids: ANeat Access to Anilides. ChemistrySelect 2017, 2
(5), 1770−1773.
(21) Douglas, J. J.; Churchill, G.; Slawin, A. M. Z.; Fox, D. J.; Smith,
A. D. Stereo- and Chemodivergent NHC-Promoted Functionalisation
of Arylalkylketenes with Chloral. Chem. - Eur. J. 2015, 21 (46),
16354−16358.
(22) Douglas, J.; Ling, K. B.; Concellón, C.; Churchill, G.; Slawin, A.
M. Z.; Smith, A. D. NHC-Mediated Chlorination of Unsymmetrical
Ketenes: Catalysis and Asymmetry. Eur. J. Org. Chem. 2010, 2010
(30), 5863−5869.
(23) Lee, E. C.; McCauley, K. M.; Fu, G. C. Catalytic Asymmetric
Synthesis of Tertiary Alkyl Chlorides. Angew. Chem. 2007, 119 (6),
995−997.
(24) Bernstein, D.; France, S.; Wolfer, J.; Lectka, T. A Column-
Based ‘Flush and Flow’ System for the Asymmetric α-Chlorination of
Acid Halides. Tetrahedron: Asymmetry 2005, 16 (21), 3481−3483.
(25) Sheldon, R. A. Metrics of Green Chemistry and Sustainability:
Past, Present, and Future. ACS Sustainable Chem. Eng. 2018, 6, 32−
48.
(26) For all methods, the analysis has been conducted from the
reagents quoted, as opposed to including their origins from feedstock
chemicals. See SI for analysis that includes the synthesis of 2.
(27) The use of methyl dichloroacetate was also examined for this
analysis; however, only starting material was returned when stirring
overnight in EtOAc.31
(28) Sheldon, R. A. The: E Factor 25 Years on: The Rise of Green
Chemistry and Sustainability. Green Chem. 2017, 19 (1), 18−43.
(29) Hazra, B. G.; Pore, V. S.; Maybhate, S. P. An Improved
Procedure for the Dichloroacetylation of Primary and Secondary
Amines. Org. Prep. Proced. Int. 1989, 21 (3), 355−358.
(30) Witzeman, J. S.; Nottingham, W. D. Transacetoacetylation with
Tert-Butyl Acetoacetate: Synthetic Applications. J. Org. Chem. 1991,
56 (5), 1713−1718.
(31) Macarthur, N. S.; Wang, L.; Mccarthy, B. G.; Jakobsche, C. E.
Using N-Nitrosodichloroacetamides to Conveniently Convert Linear
Primary Amines into Alcohols. Synth. Commun. 2015, 45 (17), 2014−
2021.
3372
https://doi.org/10.1021/acs.orglett.1c00850
Org. Lett. 2021, 23, 3368−3372