Formamide catalyzed activation of carboxylic acids-versatile and cost-efficient amidation and esterification

Article abstract of DOI:10.1039/c9sc02126d

A novel, broadly applicable method for amide C-N and ester C-O bond formation is presented based on formylpyrrolidine (FPyr) as a Lewis base catalyst. Herein, trichlorotriazine (TCT), which is the most cost-efficient reagent for OH-group activation, was employed in amounts of ≤40 mol% with respect to the starting material (100 mol%). The new approach is distinguished by excellent cost-efficiency, waste-balance (E-factor down to 3) and scalability (up to >80 g). Moreover, high levels of functional group compatibility, which includes acid-labile acetals and silyl ethers, are demonstrated and even peptide C-N bonds can be formed. In comparison to reported amidation procedures using TCT, yields are considerably improved (for instance from 26 to 91%) and esterification is facilitated for the first time in synthetically useful yields. These significant enhancements are rationalized by activation by means of acid chlorides instead of less electrophilic acid anhydride intermediates.

Full text of DOI:10.1039/c9sc02126d

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DOI: 10.1039/C9SC02126D
ARTICLE
Formamide Catalyzed Activation of Carboxylic Acids – Versatile
and Cost-Efficient Amidations and Esterifications
Peter H. Huy,*a and Christelle Mbouhomb
Received 00th January 20xx,
Accepted 00th January 20xx
A novel, broadly applicable method for the amide C-N and ester C-O bond formation is presented based on formylpyrrolidine
(FPyr) as Lewis base catalyst. Thereby, trichlorotriazine (TCT), which is the most cost-efficient reagent for OH-group
activations, was employed in amounts of ≤40 mol% with respect to the starting material (100 mol%). The new approach is
distinguished by an excellent cost-efficiency, waste-balance (E-factor down to 3) and scalability (up to >80 g). Moreover,
high levels of functional group combatibility, which includes acid-labile acetals and silyl ethers, are demonstrated and even
peptide C-N bonds can be formed. In comparison to reported amidation procedures using TCT yields are considerably
improved (for instance from 26 to 91%) and esterifications are facilitated for the first time in synthetically useful yields.
These significant enhancements are rationalized by the activation by means of acid chlorides instead of less electrophilic
acid anhydride intermediates.
DOI: 10.1039/x0xx00000x
Intriguing protocols for amidations without the necessity of
reagents have been recently established based on boron,4-7
Hafnium and Zirconium8 Lewis acid catalysts, for example.2e,g-k,m
The latest generation of catalyst such as the remarkable
dioxoazatriborinane of Shibasaki and Kumagai, which is
prepared in five steps, allow even for the synthesis of amides
derived from challenging aromatic and sterically encumbered
aliphatic carboxylic acids.6,7
Introduction
Amide and ester C-N and C-O bond formations account to the
most important and frequently performed transformations in
chemistry.1-2 Both functional groups are ubiquitous as in
peptides and proteins, synthetic polymers and pharmaceuticals,
for instance. The majority of all amides 2 and esters 3 are
synthesized by the straightforward condensation of carboxylic
acids 1 with N- and O-nucleophiles (Scheme 1 A), which is
referred to as amidation and esterification, respectively.1-2
Thereby, conventionally reagents are employed to convert the
hydroxy group of 1 into a decent leaving group, which facilitates
subsequent nucleophilic substitution. As the consequence,
waste by-products are formed, which typically results in a poor
sustainability and cost-efficiency.3
Despite the significant progress accomplished in regard to
catalytic C-N and C-O2e,g bond formation, not all esters and
amides are accessible by means of catalysis in high levels of
efficiency. In fact,
pharmaceutical companies evidences a highly urgent demand
for the development of novel methods for amidations.9
a united appeal of several leading
A
comparison of some of the most common reagents for
stoichiometric OH group activation of carboxylic acids and
NMe2
Costs [€/mol]
O
DCC
>150 €/mol
A
O
O
reagent
base
N
<5
5-20
>20
cHex
cHex
Cl
Cl
O
O
+ HNu
N
Cl
R1
OH
R1
Nu
Ghosez´s
reagent
O
25
1
2 (Nu = NR2)
3 (Nu = OR)
tBuO
OMe
O
Boc2O
OtBu
nPr
O
23
IBCF
O
O
O
Cl
O
B
P
P
19
nPr
O
N
N
O
O
O
this work
P
O
Cl
Cl
N
OMe
MeO
Cl
nPr
O
TCT
(33 mol%)
Cl
S
CDMT
T3P
13
MocCl
11
Cl
Cl
N
10
PF6
N
NMe2
N
N
N
Y
N
N
Cl
H
O
Cl
N
3
Cl
P
Cl
N
PyBOP (Y = CH)
PyAOP (Y = N)
Figure 1 A Amidations and esterifications of carboxylic acids and B comparison of costs for various reagents for this transformation in respect to converted substrate (prices were
obtained from Sigma Aldrich, see chapter 1.2 in the ESI for more details.
a. Saarland University, Institute of Organic Chemistry, P. O. Box 151150, D-66041
Saarbruecken; homepage: peterhuylab.de; email: peter.huy@uni-saarland.de.
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
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alcohols, for instance, is compiled in Scheme 1 B.10 Indeed, Furthermore, a substituted cyclopropenone and VtireowpAortinclee ,Ontlhinee
trichlorotriazine (TCT),11 which is also called cyanuric chloride, latter of which even in catalytic quantities, have been employed
DOI: 10.1039/C9SC02126D
emerges as the least expensive reagent besides phosgene as Lewis bases by the groups of Lambert and Nguyen in the
(COCl2).12 When a 3:1 stoichiometry of the hydroxy group production of acid chlorides, amides and esters with C2O2Cl2.20
bearing starting material in regard to TCT is anticipated, levels
Against this background considering the excellent cost-
of costs are even lower than with common coupling reagents efficiency of TCT, we envisioned the opportunity to develop a
such as thionyl chloride (SOCl2), iso-butyl chloroformate (IBCF), novel method for the synthesis of esters and amides via
oxalyl chloride (C2O2Cl2) and dicyclohexylcarbodiimide (DCC). formamide catalyzed acid chloride generation (Scheme 1 C).
Other frequently used coupling reagents like Ghosez´s chloro Since chlorides of type
6 are more reactive towards
enamine13 and T3P14 are associated unavoidably with nucleophiles than anhydrides such as I, we expected a much
significantly higher costs. In contrast to oxalyl and thionyl broader applicability and significantly enhanced yields. Herein,
chloride and phosgene, application of TCT in addition prevents a novel method for the low-cost chlorination, amidation and
formation of HCl as by-product, which should enable an esterification of carboxylic acids based on FPyr and TCT is
enhanced functional group compatibility.
disclosed.
In fact, TCT (33-40 mol%) in conjunction with NMM (N-
methylmorpholine) has been exploited for the synthesis of
secondary amides 2, diazoketones 4, acyl azides 5, and
hydroxamic acids 2 (R2 = OH, Scheme 1 A).15,16 However, yields
are often moderate (e.g. for secondary amides 65-75%)15a and
esterifications have rarely been reported.16 Thereby, activation
of 1 is not realized through conversion to acid chlorides 6,15a,c
which could also be confirmed by own experiments (vide infra).
Instead, mixed anhydrides of type I have been proposed as
intermediates.15
Results and discussion
Optimization of Reaction Conditions
While the full details of the optimization of the reaction
conditions are enclosed in the ESI (chapter 3), only the essential
findings are discussed in the following based on the synthesis of
model amide 21a (Table 1), which is a frequently engaged test
substrate for CH-activations.21 In terms of solvent, MeCN was
identified as optimal (entry 1). Nevertheless, utilization of more
environmental-friendly EtOAc rendered amide 21a in a similar
yield (entry 2). With respect of the transformation of 16,
heating to 80 °C effects conveniently short reaction durations
≤4 h (entries 1+2). However, the reaction temperature can be
decreased to 40 °C, when 20 mol% of FPyr are employed
instead of 10 (entry 3).
As an important finding, activation of aromatic acids 1 can
also be achieved at room temperature, when MeCN is
harnessed as solvent (entry 4). Moreover, the catalyst loading
can be minimized to 5 mol% and instead of FPyr a two-fold
amount of DMF is also feasible (entries 5+6).
Recently, we discovered that N-formylpyrrolidine (FPyr) is a
potent Lewis base catalyst17 for the transformation of alcohols
7 into alkyl chlorides 8, which are mediated by either benzoyl
chloride or TCT (Scheme 1 B).18,19
A Rayle, Forbes, Bandgar und Giacomelli 1999-200315
TCT
O
O
O
HNu
(33-40 mol%)
OH
NMM
[ I ]
R1
R1
Nu
R1
Cl
2 (Nu = NHR2)
4 (Nu = CHN2)
5 (Nu = N3)
6
1
moderate yields for 2
no esters 3
B Our previous Work 2016/201818
Cl
O
O
Table 1 Optimization of reaction conditions for the preparation of amide 21a
.
N
N
H
N
+
Cl
Ph
OH
7
Cl
Cl
N
Cl
Nu
standard conditions
TCT (38 mol%)
R1
R2
R1
O
R2
FPyr
BzCl
TCT
HNu (1.2 equiv)
NMM (1.1 equiv)
FPyr (20 mol%)
MeCN (2 M)
O
O
O
8
(5-20 mol%) (>1 equiv) (34-40 mol%)
C This Work
oTol
OH
oTol
N
oTol
Cl
one-pot
MeCN (1 M)
0 °C to rt, 2 h
T = 80 °C
t = 2 h
H
FPyr (5-20 mol%)
O
N
O
11
61
21a
TCT (38-40 mol%)
HNu
R1
OH
R1
Cl
R1
Nu
rt-80 °C
base
Entry Deviation from standard conditionsa yield 21ab (%)
1
6
2 (Nu = NR2)
3 (Nu = OR)
9 (Nu = SR)
46 examples
4 examples isolated
1
2
/
90
85
84
78
90
83
88
91
11c
solvent = MeCN, EtOAc
base = NMM, NEt3, K2CO3, DMAP
in EtOAc instead of MeCN
T = 40 °C, 20 mol% FPyr in EtOAc
T = rt, 20 mol% FPyr
3d
4d
5d
6d
7e
8
O
N
good to excellent yields
cost-efficient
R1
O
5 mol% FPyr
scalable (up to > 80 g)
good waste balance
(E-factor down to 3)
good FG tolerance
operationally simple
T = 40 °C, 40 mol% DMF in EtOAc
K2CO3 instead of NMM in EtOAc
NEt3 instead of NMM
no catalyst
O
N
O
R1
O
N
O
R1
proposed intermediate I
9
Scheme 1 Preceding and own work.
a. For detailed reaction conditions see Table S12, ESI. b. Yields refer to isolated
material after chromatography if not otherwise mentioned. c. t = 8-10 h. d. Yield
determined by means of an internal NMR standard. e. Substrate concentration 61
0.5 M).
2 | J. Name., 2012, 00, 1-3
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In general, aliphatic acids are more reactive than aromatic, codistillation with the product. During the reacVtiieownAsrticale Osonllinide
DOI: 10.1039/C9SC02126D
which enables lower reaction temperatures in the former case precipitates. Isolation through filtration and drying delivered a
(rt to 40 °C). Indeed, a low TCT amount around 40 mol% is residue with the mass of ca. 80% of the theoretical yield of
pivotal for one-pot condensations in high yield. For instance, an cyanuric acid (CA). Indeed, 13C-NMR confirmed CA as the major
increase to 60 mol% resulted in a depletion of the yield in the component, which proves its role as main by-product. In
preparation of 2-naphthyl phenyl acetate from 93 to 68%.
A screening of manifold Lewis bases for the transformation precipitation with hydrochloric acid from a basic solution.
of acids 1 into acid chlorides 6 including OPPh3, DMSO, tropone As an important aspect, a good waste balance is attested
Scheme 2 yields for CA are stated after purification by means of
and cyclopropenone derivatives revealed FPyr as by far most through E-factors as low as 2.8, which is the ratio of mass of
effective catalyst (Table S5, ESI). This is surprising, because waste with respect to the mass of isolated products according
some of the probed Lewis bases have been employed in related to Sheldon.3 Remarkably, this beneficial E-factor is in a range
chlorinations of carboxylic acids with oxalyl chloride.20 In typical for the production of bulk chemicals (1.5-5),3 which is
comparison to alcohols,18b the conversion of carboxylic acids explained through the low solvent and reagent amounts
requires higher TCT amounts and increased reaction times. This necessary. Noteworthy, in the absence of FPyr even heating to
is rationalized probably by a lower thermodynamic driving 80 °C did basically not effect formation of acid chlorides, which
force, because the conjugation energy between the hydroxyl emphasises the importance of formamide catalysis. The
substituent and the carbonyl group in 1 is lost.
addition of Brønsted bases has a deteriorative impact on the
Pleasingly, for the formation of amides 2 and esters 3 from yield, in particular when acids bearing -H-atoms are engaged
acid chloride intermediates 6 one equivalent of base is (see Table S7, ESI.)
adequate, albeit in some cases yields are improved by using
Synthesis of Amides
two. Even inexpensive K2CO3 is suitable for the synthesis of
amides (entry 7), although utilization of NMM or NEt3 Initially, we investigated the substrate scope in terms of the
sometimes causes enhanced yields (entries 1+8). For the synthesis of amides 2 (Scheme 3). A variety of aliphatic
synthesis of esters 3 derived from aromatic alcohols the carboxylic acids bearing a primary (1°), secondary (2°) and
aforementioned amine bases are recommended (Table S13 to tertiary (3°) -carbon atom were transformed into the
16, ESI). For condensation of weakly nucleophilic aliphatic respective amides (Scheme
3 B). Among them even
alcohols with substrates 1 in good yields, addition of catalytic dimethylmalonic acid could be coupled with two equivalents of
amounts of DMAP22 proved to be crucial (4- phenyl glycinol to afford diamide 29i. In addition, amides
dimethylaminopyridine, Table S17 to 18, ESI). Finally, in the deduced from electron-rich and poor (hetero)aromatic
absence of FPyr the product 21a was obtained in a very low yield carboxylic acids are accessible in good to excellent yields
of 11%, which proves the crucial role of FPyr as catalyst (entry (Scheme 3 C). The method is also applicable to ,-unsaturated
9).
substrates, whereby in example 216b only little isomerisation
In fact, the solvent volume has a major impact on both, occurred (dr = 97:3, Scheme 3 D). In cases, where the
scalability and sustainability.3 Fortunately, chlorinations 16 nucleophile is considered as the more valuable building block,
can be performed utilizing very low solvent amounts ([1] = 2- the carboxylic acid 1 can be applied in excess. For instance, the
4 M), which also procures shorter reaction durations. Due to the amide 216b was synthesized from 1.3 equiv of crotonic acid and
successive addition of nucleophile and base, the solvent 1.0 equiv of ephedrine.
amount has to be increased. However, in most cases a
Of particular significance is the functional group
concentration of 1 M with respect to the starting material 1 is compatibility in the initiating transformation of acids 1 into
sufficient to ensure stir-ability. Recommendations for reaction chlorides 6 (Scheme 3 F). Since HCl in not released in
conditions in dependence on the starting materials are stoichiometric quantities, even acid sensitive cyclic acetal and
concluded in Scheme 3 A for the chlorination step 16 and in silyl ether functions are tolerated (examples 220t and 221f).
Scheme 5 A for the subsequent condensation 62/3. As a Moreover, cyano and ester groups, ketones, aldehydes and
support for the practitioner, we also included a more detailed chloro alkanes (example 210j) are compatible. Examples for the
reaction conditions guide in chapter 5.2 in the ESI.
production of esters also include carbamates (Scheme 5 D).
Synthesis of Acid Chlorides
24-63 g
CA
OH
In clear contrast to preceding literature protocols,15 carboxylic
acid chlorides of type 6 are generated as intermediates, which
can be monitored by NMR spectroscopy (chapter 3.1.6, ESI).
Simultaneously, reversible formation of the respective acid
anhydride was observed. In order to unambiguously verify that
activation of 1 is accomplished by means of chlorination, four
different acid chlorides were synthesized on a multigram scale
and isolated after distillation in 79-90% yield (Scheme 2).
Thereby, it is important to heat the reaction mixture to 80 °C
in order to decompose FPyr entirely, which prevents
E-factor down to 2.8
w/o FPyr <7%
TCT (40 mol%)
FPyr (10-15 mol%)
O
O
N
N
+
R1
OH
R1
Cl
MeCN (3-4 M)
40-80 °C, 4-5 h
HO
N
OH
12 (R1 = Ph)
13 (R1 = mTol)
11 (R1 = oTol)
14 (R1 = Bn)
62, 90%
11 59%
11 59%
11 48%
11 63%
63, 90%
61, 88%
64, 79%
Scheme 2 Synthesis of carboxylic acid chlorides 6.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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DOI: 10.1039/C9SC02126D
A Reaction Conditions
O
O
1. TCT (38-40 mol%)
Ph
NR2R3
NR2R3
Ph
FPyr (10-20 mol%)
solvent (2 M), T t
O
O
R1 FPyr (mol%) T [°C] t [h]
2
4b, 90% (Pyr)
2
2
5b, 91% (Pyr)
R2
5f, 80% (NHBn)
1o
2o+3o 20-10
20-10
rt-40 20-4
40-80 8-4
2
4c, 75% (NMeOMe)
R1
OH
R1
N
2. HNR2R3 (1.05-1.5 equiv)
K2CO3 or NMM (1.3 equiv)
solvent (0.5 - 1 M)
O
24d, 75% (N Pr )
i
2
R3
1
2
2
4e, 68% (NPh2)
Cl
2
N
(solvent = MeCN, EtOAc)
0 °C to rt, <20 h
10j, 52%
76%b
O
B Aliphatic Acids
CF3
iPr
O
HO
Ph
OH
Ph
O
O
O
O
O
Ph
Ph
N
N
Ph
N
N
N
H
H
N
CF3
TsN
H
H
MeO
iPr
H
2
6f, 78%
2
7g, 92%
2
8h, 81%
2
9i, 66%
2
11k, 89%
C Aromatic Acids
O
O
Ph
S
O
O
Br
O
F
O
NH2
N
Ph
H
N
N
N
Ph
H
H
H
H
MeO
N
2
12l, 89%
2
12m, 87%
2
14o, 87% (2.2 g)
2
15f,86%
2
13n, 83%b
Ph
D ,-Unsaturated Acids
F Pharmaceuticals
O
O
O
O
O
MeO
MeO
OH
Ph
Y
N
N
Ph
NH2
N
H
N
H
Ph
OH
Cl
16p, 82%b
(
dr
= 97:3)
2
17q, 79%
(2 )
18r
2
19m, 85% (Y = S)
Modafinil, 70% (Y = SO)
Moclobemide
90%
2
MeO
MCPBA
O
E Functional Group Tolerance
O
G Scalability
O
O
O
O
NEt2
N
TBDMSO
H
H
N
N
Ph
O
2
3y) 92% (87 g)
DEET (
O
2
14s, 87%
2
20t, 87%
221u
,
75%
OH
O
NH
O
S
O
N
N
O
O
N
N
H
HO
OH
N
H
Ph
N
Ph
+ CA 78% (20 g)
H
N
O
E-factor = 3.5
2
22v, 73%
2
23w, 72%
2
24x, 88%
Scheme 3 Synthesis of amides of type 2. a. Isolated yield after chromatography or distillation if not otherwise mentioned. b. Yield determined by means of an internal NMR-Standard.
c. With 1.3 equiv 1, 49 mol% TCT, 1.7 equiv NMM and 1.0 equiv nucleophile. Pyr = N-pyrrolidyl, Ts = para-tolylsulfonyl, TBDMS = tert-butyldimethylsilyl.
To point out the synthetic value of our approach, the drugs amide 24c, hydrochloride salts of amines can be engaged as
Moclobemide and Modafinil have been prepared (Scheme 3 F). nucleophiles, which requires one additional equivalent of base.
Eventually, significant scalability is proven by the synthesis of
Although -amino acids are suitable starting materials
the insect repellent DEET on a 500 mmol scale, for which (Scheme 5 D, example 324j), reaction of carbamate protected -
standard glass ware ≤1 L is sufficient (Scheme 3 G). An E-factor amino acid derivative 125 with TCT in the presence of FPyr
of 3.5 showcases
determination of which also isolated cyanuric acid was likely reasoned by formation of the cyclic intermediate II25 after
considered. In fact, in all other examples (214a, 330c and 331d activation of the acid function and subsequent nucleophilic
prepared on a multigram scale, environmentally benign EtOAc substitution in benzylic position through the chloride
a reasonable waste balance, in the yielded carboxamide 1025 (Scheme 4 A). This outcome is most
)
was employed as solvent, too.
counterion.
An amide protected alanine derivative was converted into
The scope with respect to the amine nucleophile is divers,
as well. Scheme 3 includes examples derived from various the dipeptide 226z in moderate yield and under epimerization
primary and secondary amines, electron poor and sterically (Scheme 4 B). Variation of the reaction conditions could neither
encumbered, weakly nucleophilic aniline derivatives (examples enhance the yield nor the dr to a significant extent (see ESI).
27g and 28h). In addition, application of plain aqueous ammonia Gratifyingly, the dipeptide 227z emerged from condensation
solution enabled the synthesis of primary amides (examples with phthaloyl protected alanine 126 in an excellent yield as a
212m and 219m). As documented by the synthesis of Weinreb virtually pure diastereomer.
4 | J. Name., 2012, 00, 1-3
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literature conditions thoroughly in order to allow Vaiemw AeraticnleinOgnflinuel
comparison (see Table S19 to S22, ESI). The significantly
improved yields testify our concept that acid chloride activation
is superior to anhydride formation.
O
O
Cl
A
TCT (38 mol%)
O
DOI: 10.1039/C9SC02126D
O
O
Ph
FPyr (10 mol%)
CbzHN
HN
HN
OH
O
O
-BnCl
MeCN, 8 h rt
Ph
125
Ph
Ph
1025, 69%
1. TCT (40 mol%)
FPyr (20 mol%)
MeCN, 15-23 h rt
II25
B
All text and images must be placed within the frame.
A Reaction Conditions
O
O
O
O
1. see Scheme 3 A
Y
Y
HYR2 Base DMAP (mol%)
OH
N
CO2Me
R1
OH
R1
YR2
2. L-Val-OMe-HCl (1.1 equiv)
NMM (2.3 equiv)
H
HOAryl NMM
HOAlkyl NMM
HSAryl K2CO3
0
10
0
2. HYR2(1.05-1.2 equiv)
Base (1.3 equiv)
1
3(Y = O)
9 (Y = S)
1
26 (Y = NHBz)
27 (Y = NPhth)
226z, 39% ( = 68:32)
dr
15 min 0 °C, 4-6 h rt
DMAP (0-20 mol%)
Solvens (0.5 - 1 M)
0 °C to rt, <20 h
1
227z, 83% ( > 97:3)
dr
(solvent = MeCN, EtOAc)
Scheme 4 -Amino acid derivatives. Phth = Phthaloyl
B Aromatic Alcohols + Thiols
O
Thus, the present protocol even allows for peptide C-N bond
formation, when phthaloyl protected amino acids are
employed. In comparison to other amino acid chlorides,1 the
phthaloyl protected analogues are less prone towards
racemisation.24 Against this background, we would also like to
highlight recent contributions about the boron Lewis acid
catalyzed synthesis of peptides.5-7
H
O
O
H
H
Ph
O
D3C
O
3
4a 89%
3
28b 88%b
O
I
O
O
S
O
O
Synthesis of Esters
9
29a 84%
3
30c 88% (4.7 g)
H
Due to the lower nucleophilicity of alcohols, the synthesis of
esters of type 3 is more challenging. This is most probably also
the reason, why esters have been rarely prepared by means of
TCT.16 Fortunately, the present catalytic method facilitates the
synthesis of esters derived from both, aromatic and aliphatic
alcohols, in yields of 73-89% yield (Scheme 5 B to D).
C Aliphatic Alcohols
O
O
NHBoc
S
O
nPendec
O
O
O
CO2Me
3
32e 88%b
3
31d 86%c (3.2 g)
This also includes two examples on a 3-5 g scale, which
certifies a high degree of practicability (examples 330c and 331d).
Since acid chlorides are not isolated, estrone derivative 328b
could be accessed via volatile trideutero acetoyl chloride.
Reasoned by a higher nucleophilicity, 2-naphthalene thiol could
be condensed with 2-iodobenzoic acid using K2CO3 instead of
NMM (example 929a). Esterifications of sterically demanding
alcohols with acid chlorides are usually accomplished using
strong bases such as nBuLi.25 Hence, the current method
provides esters derived from sterically encumbered alcohols in
moderate yields of 47-60% (Scheme 5 D).
O
O
Ph
O
R1
O
3
3
2g 88% (R1 = Ph)
33g 78%b (R1 = Ac)
tBu
3
2f 88%
D Functional Group Tolerance
O
O
O
O
O
Ph
O
AllocN
O
3
34h 89%b
3
20i 73%
O
E Sterically Encumbered Nucleophiles
nBu
CbzHN
O
Comparison Experiments
O
O
Et
3
35j 75%b
O
In order to compare our approach with a literature protocol
harnessing TCT and NMM (Scheme 1 A),15a several amides and
esters were prepared accordingly (see also chapter 4, ESI).
Remarkably, in the event of four exemplary amides the
differences in terms of yield between the reported protocol and
the current catalytic method are in the range of 21 and 65%
(Scheme 6 A). When K2CO3 was applied as base instead of NMM,
the amides 24b and 21a were obtained in even more deteriorated
yields ≤17% (this method 88-90%).
O
MeO
tBu
O
H
O
O
O
MeO
H
O
O
MeO
tBu
3
17k 50%
O
3
14l 46%c
O
H
N
N
3
24n 60%
H
F
O
H
The yields for the preparation of esters of 8-58% according
to ordinary TCT/NMM-activation15a must be classified as
synthetically non-useful (current method 86-89%, Scheme 6 B).
Utilization of DMAP, which has not been described in the
literature, allows to improve the yield of ester 331d (850%),
whereas in example 330c a slightly depleted yield was attained
(4236%). It should be emphasized that we optimized the
O Bu
t
H
3
15m 47%
H
O
O
Scheme 5 Synthesis of Esters. a. isolated yield after chromatography. b. With 1.3 equiv
1, 49 mol% TCT, 1.7 equiv NMM and 1.0 equiv nucleophile. c. With 1.1 equiv 1, 44 mol%
TCT, 2.3 equiv NMM and 1.0 equiv nucleophile.
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respective acid chloride 64 (Scheme 7 C, see also Table S8, ESI).
Thus, the reason for the replacement of the chlorine atom in V
is currently unclear (Scheme 7 D).
View Article Online
DOI: 10.1039/C9SC02126D
A Amides
yields
this worka
literature protocolb,[15a]
O
O
O
N
oTol
NEt2
mTol
Bn
Pyr
H
N
* with K2CO3
instead of NMM
+ with 10 mol% DMAP
A
2
4b, 90%
2
3y, 89%
O
O
X
,
21a 91%
69%
<2%*
50%
SNAr
26%
17%*
R1
Cl
R2N
FPyr
H
N
N
6
O
Ph
Ph
X
or DMF
Cl
N
X
O
B Esters
TCT (X = Cl)
SN
N
N
N
O
H
O
O
N
O
H
O
X
N
2
13n, 83%
2 x
330c, 88%
42%
Cl
R2N
54%
R1
O
NR2
H
H
36%+,
X
IV
III
O
Cl
N
N
BzO
O
n
Pendec
O
O
O
HO
N
X
O
tBu
Bn
O
3
31d, 86%
8%
50%+
V (X = Cl, OH)
3
4a, 89%
3
12f, 88%
R1
OH
1
58%
24%
B
O
O
<2%
TCT (40 mol%)
Scheme 6 Comparison of the present with the literature method16a employing TCT and
NMM. a. For reaction conditions see Scheme 3 and Scheme 5; yields refer to isolated
material after chromatographic purification or distillation. b. For reaction conditions see
Scheme 1 A and chapter 4, ESI; yield determined with internal NMR-standard.
Ph
Ph
<2% (with 10 mol% pTsOH)
90% (with 10 mol% FPyr)
OH
Cl
MeCN (2 M)
4 h 40 °C
14
64
(base)
C
O
base (1.0 equiv)
O
84% (/)
TCT (40 mol%)
FPyr (10 mol%)
MeCN (2 M)
4 h 40 °C
Ph
OH
Ph
Cl 82% (NEt3)
Proposed Mechanism
12
62
77% (2,6-tBu2Py)
In alignment to our previous work on the catalytic chlorination
of alcohols,18 the related transformation of carboxylic acids 1
into acid chlorides 6 is most likely commenced by nucleophilic
aromatic substitution (SNAr) engaging TCT and FPyr (Scheme 7
A). That chloride substitution on a triazine scaffold proceeds via
D
OMe
N
O
CDMT (120 mol%)
O
Ph
Ph
N
O
FPyr (10 mol%)
MeCN (2 M)
4 h 40 °C
OH
Cl
14
64
Cl
N
OMe
<2%
CDMT
<2% (with 10 mol% pTsOH)
a
stepwise SNAr mechanism has been demonstrated
previously.26,27 Next, the plausible intermediate III, which shows
structurally similarities to the Vilsmeier Haack reagent, should
undergo replacement of the triazine moiety through the
substrate 1. In the following, the resulting Intermediate IV
would surpass substitution with the chloride counter ion to
afford the product 6 and regenerate FPyr. Dichlorohydroxy-
TCT (33 mol%)
NMM (1.3 equiv)
E
O
O
O
Ph
Ph
+
Ph
Ph
OH
Cl
O
CDCl3 (1 M)
rt 1 h
14
24
124
26%
<2%
triazine (V with X = Cl) results from the conversion of III with 1 Scheme 7 A Proposed mechanism and B-E comparison experiments. Yields were
determined by internal NMR standard.
to IV. As verified through the formation of CA and the low
stoichiometry of TCT (40 mol%  1.2 equiv, vide supra), V (X =
That activation of carboxylic acids with NMM and TCT does not
yield acid chlorides of type 615a,c was confirmed experimentally
(Scheme 7 E, see Table S23, ESI). The proposed intermediate I
(see Scheme 1), which might be insoluble in CDCl3, was also not
observed. Instead anhydride 124 was encountered in 26% yield,
which provides an additional explanation for the low yields in
the comparison experiments (vide supra).
Cl) undergoes two consecutive reactions with FPyr until all
chlorine atoms are replaced.
Alkoxy iminium salts derived from alcohols, have been
previously proven by us,18a which supports carboxyl iminium
salts of type IV as key intermediates. Preliminary mechanistic
elucidations according to the normalized time scale method of
Burés,28 revealed a reaction order of 1 in FPyr (chp. 3.1.6, ESI),
which is in agreement with the proposed mechanism.
Remarkably, in the absence of FPyr no phenylacetoyl
chloride (64) is formed at all (Scheme 7 B). As an important
finding, para-tolylsulfonic acid (pTsOH) does not promote
production of 64, which rules out Brønsted acid catalysis.
Furthermore, also Brønsted acid cocatalysis can be excluded,
since the conversion of benzoic acid into benzoyl chloride is
virtually not inhibited by bases such as NEt3 and 2,6-bis-tert-
butylpyridine (Scheme 7 C, Table S7, ESI).
Conclusions
In summary, a versatile formamide catalyzed method for the
transformation of carboxylic acids into acid chlorides, amides,
esters and thioesters has been developed. Thereby, cyanuric
chloride (TCT), which is the cheapest reagent for OH group
activation (alongside phosgene), is engaged as promotor in
quantities ≤40 mol%. As the consequence, the presented
protocol exhibits (1) an exceptional cost-efficiency. Additional
important features are high levels of (2) scalability (>80 g) and
Reaction of phenyl acetic acid (14) with CDMT, which is
closely related to intermediate V, does not give rise of the
6 | J. Name., 2012, 00, 1-3
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S. Baran and R. W. Hoffmann, Chem. Soc. Rev., 2009, 38, 3010;
(3) functional group compatibility including acid labile acetals
and silyl ethers; (4) a reasonable waste-balance (E-factor down
to 3) and (5) operational simplicity, since non-dry reaction
conditions are viable. Remarkably, the formation of peptidic C-
N bonds is possible, when phthaloyl protected amino acids are
employed.
In comparison to ordinary protocols using TCT, not only the
yields of amidations are significantly improved (e.g. 91% instead
of 26%), but also esterifications are enabled in synthetically
useful yields for the first time. The significant advancements are
explained by the formation of carboxylic acid chlorides as
intermediates instead of less electrophilic anhydrides. Finally,
high levels of applicability were testified by the preparation of
the pharmaceuticals Moclobemide and Modafinil and the
insecticide DEET. Under consideration of the manifold
enhancements a rapid application of the current method in
academic and industrial laboratories is to be expected.
View Article Online
(d) P. Anastas and N. Eghbali, Chem. SDocO.I:R1e0v.1.02309/1C09,S3C90,2132061D;
(e) R. A. Sheldon, Chem. Soc. Rev., 2012, 41, 1437; (f) P. J.
Dunn, Chem. Soc. Rev., 2012, 41, 1452; (g) R. A. Sheldon,
Green Chem. 2017, 19, 18.
4
5
Reviews on boron Lewis acid catalysis: (a) H. Charville, D.
Jackson, G. Hodgesc, A. Whiting, Chem. Commun., 2010, 46,
1813; (b) H. Zheng and D. G. Hall, Aldrichim. Acta, 2014, 47,
41; (c) P. Huy and B. Zoller, Nachr. Chem. 2019, 67, 51.
Seminal Publications: (a) K. Ishihara, S. Ohara and H.
Yamamoto, J. Org. Chem., 1996, 61, 4196; (b) K. Arnold, B.
Davies, R. L. Giles, C. Grosjean, G. E. Smith, A. Whiting, Adv.
Synth. Catal., 2006, 348, 813; (c) R. M. Al-Zoubi, O. Marion and
D. G. Hall, Angew. Chem. Int. Ed., 2008, 47, 2876; (d) N.
Gernigon, R. M. Al-Zoubi and D. G. Hall, J. Org. Chem., 2012,
77, 8386; (e) M. T. Sabatini, L. T. Boulton and T. D. Sheppard,
Sci. Adv., 2017, 3, e1701028; (f) S. Arkhipenko, M. T. Sabatini,
A. S. Batsanov, V. Karaluka, T. D. Sheppard, H. S. Rzepa and A.
Whiting, Chem. Sci., 2018, 9, 1058.
(a) H. Noda, M. Furutachi, Y. Asada, M. Shibasaki and N.
Kumagai, Nature Chem., 2017, 9, 471; (b) Z. Liu, H. Noda, M.
Shibasaki and N. Kumagai, Org. Lett., 2018, 20, 612; (c) H.
Noda, Y. Asada, M. Shibasaki and N. Kumagai, J. Am. Chem.
Soc. 2019, 141, 1546; (d) C. R. Opie, H. Noda, M. Shibasaki,
and N. Kumagai, Chem. Eur. J., 2019, 25, 4648.
6
Conflicts of interest
There are no conflicts to declare.
7
8
9
For other leading boron Lewis acid catalyzed methods for the
synthesis of challenging amides see: (a) K. Ishihara and Y. Lu,
Chem. Sci., 2016, 7, 1276; (b) K. Wang, Y. Lu and K. Ishihara,
Chem. Commun., 2018, 54, 5410; (c) D. N. Sawant, D. B. Bagal,
S. Ogawa, K. Selvam and S. Saito, Org. Lett., 2018, 20, 4397.
For example see: (a) H. Lundberg, F. Tinnis, H. Adolfsson,
Chem. Eur. J. 2012, 18, 3822; (b) H. Lundberg, H. Adolfsson,
ACS Catal. 2015, 5, 3271, (c) H. Lundberg, F. Tinnis, J. Zhang,
A. G. Algarra, F. Himo, H. Adolfsson, J. Am. Chem. Soc. 2017,
139, 2286.
A round-table of representatives of several pharmaceuticals
companies repeatedly requested more efficient methods for
amidations as primary target: (a) D. J. C. Constable, P. J. Dunn,
J. D. Hayler, G. R. Humphrey, J. L. Leazer, Jr., R. J. Linderman,
K. Lorenz, J. Manley, B. A. Pearlman, A. Wells, A. Zaksh and T.
Y. Zhang, Green Chem., 2007, 9, 411; (b) M. C. Bryan, P. J.
Dunn, D. Entwistle, F. Gallou, S. G. Koenig, J. D. Hayler, M. R.
Hickey, S. Hughes, M. E. Kopach, G. Moine, P. Richardson, F.
Roschangar, A. Steven and F. J. Weibert, Green Chem., 2018,
20, 5082.
Acknowledgements
We want to thank the German research foundation (DFG) and
the Fonds of the Chemical Industry (Liebig fellowship for P. H.)
for generous support. In addition, we would like to thank Rudolf
Thomes and Dr. Klaus Hollemeyer for measuring HR-MS and Dr.
Josef Zapp for the measurement of high temperature NMR
spectra.
Notes and references
1
Reviews on amidations: (a) T. Ziegler in Science of Synthesis,
Vol. 21 (Ed. S. M. Weinreb), Georg Thieme: Stuttgart, 2005,
pp. 43-77; (b) E. Haslam, Tetrahedron, 1980, 36, 2409; (c) C.
A. G. N. Montalbetti and V. Falque Tetrahedron, 2005, 61,
10827; (d) E. Valeur and Mark Bradley, Chem. Soc. Rev., 2009,
38, 606; (e) K. Ishihara, Tetrahedron, 2009, 65, 1085; (f) A. El-
Faham and F. Albericio, Chem. Rev. 2011, 111, 6557; (g) V. R.
Pattabiraman and J. W. Bode, Nature, 2011, 480, 471; (h) R.
M. Lanigan and T. D. Sheppard, Eur. J. Org. Chem. 2013, 7453;
(i) H. Lundberg, F. Tinnis, N. Selander and H. Adolfsson, Chem.
Soc. Rev., 2014, 43, 2714; (j) R. M. de Figueiredo, J.-S. Suppo
and J. M. Campagne, Chem. Rev., 2016, 116, 12029; (k) A.
Ojeda-Porras and D. Gamba-Sanchez, J. Org. Chem., 2016, 81,
11548; (l) J. R. Dunetz, J. Magano and G. A. Weisenburger,
Org. Process Res. Dev., 2016, 20, 140; (m) M.T. Sabatini, L. T.
Boulton, H. F. Sneddon and T. D. Sheppard, Nature Catal.,
2019, 2, 10.
10 For the cost assessment for each reagent the lowest price at
Sigma-Aldrich was selected. We are fully aware that the costs
would drop significantly on an industrial scale. Nevertheless,
we are convinced that current study allows for a relative
ranking with respect to cost-efficiency. For more details, see
chapter 1.2 in the ESI.
11 Reviews on TCT: (a) S. S. Voyutskii, V. L. Vakula, Russ. Chem.
Rev. 1964, 92-103; (b) N. Kriebitzsch and H. Klenk in Ullmann´s
Encyclopedia of Industrial Chemistry, vol. A8 (Eds. W. Gerhartz
et al.), VCH, Weinheim, 1987, pp. 191-200; (c) Z. J. Kaminsky,
Biopolymers, 2000, 55, 140; (d) G. Blotny, Tetrahedron, 2006,
62, 9507.
12 At Sigma-Aldrich phosgene is only available as a relatively
costly solution and is therefore not included in Figure 1. As
carbonyl dichloride is readily prepared from CO and Cl2, the
real costs are likely to be significantly lower.
2
3
Reviews about esterifications: (a) E. Haslam, Tetrahedron,
1980, 36, 2409; (b) R. C. Larock, Comprehensive Organic
Transformations, John Wiley & Sons, New York, 2nd edn,
1999, p. 1932; (c) A. C. Spivey and S. Arseniyadis Angew.
Chem. Int. Ed., 2004, 43, 5436; (d) R. Shelkov, M. Nahmany
and A. Melman, Org. Biomol. Chem., 2004, 2, 397; (e) N. F. Jain
and C. E. Masse in Science of Synthesis, Vol. 20b (Ed. J. S.
Panek), Georg Thieme: Stuttgart, 2006, pp. 711-715.
13 (a) A. Devos, J. Remion, A. M. Frisque-Hesbain, A. Colens, and
L. Ghosez, J. Chem. Soc., Chem. Commun., 1979, 1180; (b) B.
Haveaux, A. Dekoker, M. Rens, A. R. Sidani, J. Toye, L. Ghosez,
M. Murakami, M. Yoshioka and W. Nagata, Org. Synth., 1979,
59, 26.
Selected reviews regarding sustainability: (a) R. A. Sheldon,
Green Chem., 2007, 9, 1273; (b) C. J. Li and B. M. Trost, Proc.
Natl. Acad. Sci. U.S.A., 2008, 105, 13197; (c) T. Newhouse, P.
14 (a) H. Wissmann and H.-J. Kleiner, Angew. Chem., Int. Ed.
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Engl., 1980, 19, 133; (b) R. Escher und P. Bünning, Angew.
entries 1+2+12, ESI). Since 40 mol% of TCT (= 1.V2ieewqAurtiicvl)e Ohnalvinee
been applied, even the 3rd chlorine aDtoOmI: 1o0f.10T3C9T/Cm9SuCs0t2h12a6vDe
been partially replaced.
Chem., Int. Ed. Engl. 1986, 25, 277.
15 (a) H. L. Rayle and L. Fellmeth, Org. Process Res. Dev., 1999, 3,
172; (b) D. C. Forbes, E. J. Barrett, D. L. Lewis and M. C. Smith, 28 J. Burés, Angew. Chem. Int. Ed. 2016, 55, 2028.
Tetrahedron Lett., 2000, 41, 9943; (c) B. P. Bandgar and S. S.
Pandit, Tetrahedron Lett., 2002, 43, 3413; (d) G. Giacomelli, A.
Porcheddu and M. Salaris, Org. Lett., 2003, 5, 2715.
16 Acid chlorides, amides and esters have been prepared using
TCT (50 mol%) and NEt3: K. Venkataraman, D. R. Wagle,
Tetrahedron Lett., 1979, 20, 3037. Therein, the preparation of
two acid chlorides (aromatic) and two esters (with MeOH) has
been described. Own comparison experiments showed that
aromatic benzoyl chloride can be accessed in poorly
reproducible yields of 63-78%, while aliphatic phenylacetyl
chloride was mainly converted into the respective anhydride
(yield phenyl ethanoyl chloride 6-10%; see chapter 4.2, ESI).
17 Reviews on Lewis base catalysis in nucleophilic substitutions:
(a) J. An, R. M. Denton, T. H. Lambert and E. D. Nacsa, Org.
Biomol. Chem., 2014, 12, 2993; (b) P. H. Huy, T. Hauch and I.
Filbrich, Synlett, 2016, 27, 2631.
18 (a) P. H. Huy, S. Motsch and S. M. Kappler, Angew. Chem. Int.
Ed., 2016, 55, 10145; Angew. Chem., 2016, 128, 10300; (b) P.
H. Huy and I. Filbrich, Chem. Eur. J., 2018, 24, 7410.
19 In addition, formamides such as dimethylformamide (DMF)
are known to catalyse the chlorination of carboxylic acids
using thionyl and oxalyl chloride, respectively: (a) R. Richter
and B. Tucker, Helv. Chim. Acta, 1959, 1653; (b) H. Eilingsfeld,
M. Seefelder and H. Weidinger, Angew. Chem., 1960, 72, 836.
20 (a) D. J. Hardee, L. Kovalchuke and T. H. Lambert, J. Am. Chem.
Soc., 2010, 132, 5002; (b) T. V. Nguyen and A. Bekensir, Org.
Lett., 2014, 16, 1720; (c) T. V. Nguyen, D. J. M. Lyons, Chem.
Commun., 2015, 51, 3131.
21 See for instance: (a) Y. Ano, M. Tobisu and N. Chatani, Org.
Lett., 2012, 14, 354; (b) L. D. Tran, I. Popov and O. Daugulis, J.
Am. Chem. Soc., 2012, 134, 18237; (c) Y. Aihara and N Chatani,
Chem. Sci., 2013, 4, 664.
22 For DMAP catalyzed amidations and esterifications using DCC
and Boc2O, respectively, see: (a) B. Neises and W. Steglich,
Angew. Chem., Int. Ed. Engl., 1978, 17, 522; (b) D. K.
Mohapatra and A. Datta, J. Org. Chem., 1999, 64, 6879; (c) K.
Takeda, A. Akiyama, H. Nakamura, S.-i. Takizawa, Y. Mizuno,
H. Takayanagi and Y. Harigaya, Synthesis, 1994, 1063; (d) L. J.
Gooßen, A. Döhring, Synlett, 2004, 263; (e) S. Xu, I. Held, B.
Kempf, H. Mayr, W. Steglich and H. Zipse, Chem. Eur. J., 2005,
11, 4751; (f) I. Held, P. von den Hoff, D. S. Stephenson, H.
Zipse, Adv. Synth. Catal., 2008, 350, 1891.
23 N-Boc- amino acids have been converted to carboxamides
upon activation of the C-Terminus: (a) S. Mobashery, M.
Johnston, J. Org. Chem. 1985, 50, 2200; (b) R. Wilder, S.
Mobashery, J. Org. Chem. 1992, 57, 2755.
24 J. C. Sheehan, D. W. Chapman, R. W. Roth, J. Am. Chem. Soc.
1952, 71, 3823.
25 (a) E. M. Kaiser, R. A. Woodruff, J. Org. Chem., 1970, 35, 1198;
(b) G. P. Crowther, E. M. Kaiser, R. A. Woodruff, C. R. Hauser,
A. Brossi, R. A. LeMahieu and P. LaSalle, Org. Synth., 1971, 51,
96.
26 Z. J. Kamiki, P. Paneth, J. Rudzinski, J. Org. Chem. 1998, 63,
4248.
27 For the substitution of all chlorine atoms on the triazine core
of TCT through O- and N-nucleophiles, respectively, the
reaction temperature has to be gradually raised from 0 to
60 °C (see ref. 11). This experimental observation is most
probably rationalized by a decreasing reaction rate for the
consecutive SNAr-substitutions in the order 1st > 2nd > 3rd Cl-
atom. since each replacement introduces a new electron
donating substituent. In contrast, the present method allows
quantitative conversion of sterically unbiased acids such as
dodecanoic acid already at room temperature (see Table S3,
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DOI: 10.1039/C9SC02126D
O
O
O
one-pot
Nu
FPyr (5-20 mol%)
OH
Cl
Nu
TCT (<40 mol%)
H
(100 mol%)
46 examples
Nu = NR2, OR, SR
cost-efficient
Cl
O
scalable (> 80 g)
good waste balance
good FG tolerance
operationally simple
N
N
H
N
Cl
N
TCT
Cl
FPyr
Formamide catalysis enables highly cost-efficient amide C-N and ester C-O bond formation through
carboxylic acid chlorides as essential intermediates.