A protocol for amide bond formation with electron deficient amines and sterically hindered substrates

Article abstract of DOI:10.1039/c5ob02129d

A protocol for amide coupling by in situ formation of acyl fluorides and reaction with amines at elevated temperature has been developed and found to be efficient for coupling of sterically hindered substrates and electron deficient amines where standard methods failed.

Full text of DOI:10.1039/c5ob02129d

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A protocol for amide bond formation with
electron deficient amines and sterically
hindered substrates†
Cite this: DOI: 10.1039/c5ob02129d
Received 14th October 2015,
Accepted 5th November 2015
Maria E. Due-Hansen, Sunil K. Pandey, Elisabeth Christiansen, Rikke Andersen,
DOI: 10.1039/c5ob02129d
Steffen V. F. Hansen and Trond Ulven*
www.rsc.org/obc
A protocol for amide coupling by in situ formation of acyl fluorides
and reaction with amines at elevated temperature has been deve-
loped and found to be efficient for coupling of sterically hindered
substrates and electron deficient amines where standard methods
failed.
Table 1 Initial attempts at coupling of 1a with 1b
Amide coupling reactions are common in organic synthesis
and the most frequent reaction used in medicinal chemistry.1
The reaction is typically performed by combining an activated
carboxylic acid with an amine and a substantial number of
highly efficient amide coupling protocols have been developed,
especially for peptide synthesis.2 Although often considered to
be a solved problem in organic synthesis, amide couplings
that perform poorly with established protocols are relatively
frequently encountered, in particular with sterically hindered
substrates and electron deficient amines, and alternative strat-
egies for synthesis of such amides have been developed.3 We
here report a protocol for coupling of carboxylic acids with
amines that has proven efficient where other methods have
failed.
Entry Coupling agent(s)
Temp.
Time Conv.a (%) Ref.
1
2
3
4
5
HATU/DIPEA
EDC/HOBt
DCC/DMAP
Ghosez’s reagent
Acid chloride/AgCN rt
rt
rt
4 d
24 h
17
0
4b
7
40 °C (refl.) 5 d
rt
0
9
dec.
8
5,9
6
4 d
24 h
a Determined by HPLC.
of these provided the desired product in significant amounts
(Table 1, entries 2–5).
In our project directed towards the free fatty acid receptor 2
(FFA2/GPR43), we wished to synthesize a compound disclosed
in the patent literature via intermediate 1 (Table 1).4 The litera-
ture indicated that the central coupling between carboxylic
acid 1a and the N-cyclopropyl-2-aminothiazole 1b had been
performed with HATU and DIPEA in anhydrous DMF over four
days.4b However, this method produced unsatisfactory results
in our hands (Table 1, entry 1), especially in light of the labo-
rious multistep sequences required for the production of both
1a and 1b. We proceeded by exploring other conventional
amide coupling methods, such as, EDC/HOBt, DCC/DMAP,
coupling via the acid chloride using Ghosez’s reagent,5 and by
Ag(I)-promoted activation of the acid chloride,6 however, none
The difficulties observed with this coupling were linked to
the electron poor and sterically hindered amine in combi-
nation with a hindered carboxylic acid containing a tert-butyl
ester that is sensitive to forcing conditions.10 We reasoned that
a coupling strategy that minimized steric hindrance between
the coupling partners would be more likely to succeed. Acyl
fluorides are ideal in this respect and are well established as
relatively stable and easily handled substrates that nevertheless
exhibit high reactivity towards amines in amide couplings of
for example sterically hindered amino acids.2c–e One-pot amide
coupling reactions via acyl fluorides have been developed with
the fluorination reagents DAST and Deoxo-Fluor, but these
may give rise to side products from coupling with the released
diethylamine or bis(methoxyethyl)amine.2d,11 XtalFluor-E is a
related reagent that also efficiently promote amide coupling
under mild conditions, but release of diethylamine and side
product formation is a concern also for this reagent.12
Department of Physics, Chemistry and Pharmacy, University of Southern Denmark,
Campusvej 55, DK-5230 Odense M, Denmark. E-mail: ulven@sdu.dk;
Fax: +45 6615 8780; Tel: +45 6550 2568
We decided to explore fluorouronium reagents such as
TFFH13 and BTFFH,14 that have given excellent results in
†Electronic supplementary information (ESI) available: Synthetic procedures,
compound characterization, NMR spectra. See DOI: 10.1039/c5ob02129d
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solid-phase coupling of sterically hindered amino acids.13–15
Using conditions inspired from solid-phase peptide synthesis,13
a conversion of only 8% was obtained after 24 hours (Table 2,
entry 1). Despite the modest success, the reaction was repeated
with heating to 80 °C in a microwave reactor, resulting in an
encouraging 43% conversion and 20% isolated yield of 1
(entry 2). By HPLC monitoring, formation of the acid fluoride
in CH2Cl2 was found to be significantly faster and less prone
to hydrolysis than in DMF. CH2Cl2 as solvent gave a conversion
of 23% after 24 h at room temperature (entry 3). As expected,
TFFH gave a similar conversion (entry 4). BTFFH is preferred
over TFFH as the latter is reported to form toxic by-
products.2b,16 A conversion of 85% and an isolated yield of 61%
after 4 h at 80 °C was observed with BTFFH in the microwave
reactor (entry 5). In contrast, only 50% conversion was
observed in refluxing 1,2-dichloroethane (entry 6). DMAP has
been reported to catalyse the coupling of acyl fluorides with
alcohols and thiols.17 In our system, the addition of 0.2 equiv.
DMAP rather had a detrimental effect on the yield (entry 7),
possibly due to the higher steric demand of the N-acyl DMAP
intermediate. Increasing the temperature above 80 °C did not
result in significant improvements (entries 8–10), whereas
extending the reaction time to 24 hours using conventional
heating in a sealed vial eventually resulted in complete conver-
sion and 85% isolated yield of the desired product (entry 11).
By increasing the concentration of the reaction mixture, the
reaction time could be reduced to 12 hours (Table 3). The
challenging nature of this reaction is illustrated by the
unusual instability of the amide of 1, for which prolonged
exposure to even weak acids such as acetic acid leads to clean
hydrolysis back to 1a and 1b. Deprotection of the tert-butyl
ester by treatment with TFA under anhydrous conditions is
Table 3 Scope of BTFFH promoted couplinga
Table 2 Optimization of BTFFH promoted couplinga
a Reaction conditions: (i) carboxylic acid (1.3 equiv.), BTFFH (1.5
equiv.), DIPEA (4.5 equiv.), CH2Cl2 (2 mL mmol−1), rt, 30 min; (ii)
amine (0.5 mmol, 1 equiv.), 80 °C, 12–24 h. Isolated yields are shown.
b Coupling with 1.3 equiv. amine or oxazolidinone.
Temp.
(°C)
Time
(h)
Conv.b
(%)
Yieldc
(%)
Entry
Solvent (cat.)
tolerated, but the carboxylic acid product must be stored in
solution or on salt form to avoid self-catalysed hydrolysis.
Pleased with the results from the optimized BTFFH pro-
moted coupling of 1a with 1b, we wished to explore the scope
of the reaction for coupling of other sterically hindered sub-
strates and electron deficient amines (Table 3). Thus, a selec-
tion of analogous substrates all provided the desired amide in
good to excellent yield (2–4). 1a was coupled with poor nucleo-
philes such as 2-amino-5-nitropyridine and 2-amino-4,6-di-
methylpyrimidine, resulting in complete conversion, preserved
e
1d
2
DMF
DMF
rt
80
rt
rt
24
2.5
24
24
4
24
4
7
7
3
24
8
43
23
21
85
50
63
94
96
87
100
—
20
e
3d
4f
5g
6g
7g
8j
9j
10j
11
CH2Cl2
CH2Cl2
CH2Cl2
DCE
CH2Cl2 (DMAP)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
—
e
—
80h
84i
80h
80h
100h
140h
80k
61
e
—
35
e
—
78
75
85
a Reaction conditions: 1a (1.3 equiv.), BTFFH (1.5 equiv.), DIPEA
(4.5 equiv.) in 4 mL mmol−1 solvent, 30 min at rt; then 1b (0.25 mmol, tert-butyl esters, and good isolated yields of 5 and 6. The same
1 equiv.). b Determined by HPLC. c Isolated yields. d 1a (1 equiv.),
electron deficient amines were also coupled with other hin-
dered carboxylic acids such as 2-(4-chlorophenyl)-3-methyl-
butanoic acid and diphenylacetic acid, giving rise to moderate
BTFFH (1.2 equiv.). e Not determined. f As entry 3 but with TFFH. g 1a
(1.1 equiv.) h Microwave heating. i Reflux. j 1a (1.2 equiv.)
k Conventional heating in sealed vial.
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to high isolated yields of 7–10. To estimate the degree of chal- thus represents a more practical one-pot route to these
lenge represented by these amide coupling reactions, they structures.
were also attempted using a standard EDC/HOBt method,
resulting in 38% conversion for 7 and only trace of products thesis of a wide variety of challenging amide bonds, the
8–10 by HPLC. method generally failed with arylacetic acid substrates lacking
Although the BTFFH protocol proved successful in the syn-
The method was further tested on other amide coupling a second α-substituent such as phenylacetic acid, indole-3-
reactions reported with low yields in the literature. The coup- acetic acid and benzothiophene-3-acetic acid. The cause for
ling of diphenylacetic acid with diisopropylamine has been this has not been investigated but might be related to
reported in 20% yield by a TaCl5-based method especially deve- decomposition via ketene formation. Also, coupling partners
loped for coupling of hindered substrates, whereas no product with further increased steric hindrance, such as 2,2,6,6-tetra-
was observed by DCC-mediated coupling.18 Since the diphenyl- methylpiperidine or coupling of the hindered and electron
acetyl fluoride intermediate and the product co-eluted on deficient 2,5-dichloroaniline with mesitylcarboxylic acid, failed
silica, an excess of the amine was used in this case, giving full to provide the desired amide product and generally resulted in
conversion to 11 and 71% isolated yield. Coupling of the hin- recovery of the acyl fluoride. The product from the latter coup-
dered triphenylacetic acid with propargylamine, 4-aminopyri- ling can be accessed by Bode’s Grignard procedure,3b demon-
dine and tert-butylamine, by DCC or TaCl5 or via the acid strating that the two methods have complementary scopes.
chloride catalysed by DMAP are reported with low to moderate
yields in the literature.18,19 In all cases, coupling by the opti-
mized BTFFH method resulted in significantly improved yields Conclusions
of 12–14. Coupling of octanoic acid with tert-pentylamine by
We have developed a method for efficient coupling of sterically
XtalFluor-E was reported in only 8% yield due to reaction with
hindered carboxylic acids with hindered or electron deficient
the released diethylamine.12 Using the optimized BTFFH
amines and oxazolidinones via the acyl fluoride at elevated
method, 15 was isolated in 91% yield. Acyl fluorides are
temperature. No α-racemization was observed in the coupling
reported to be less prone to α-racemization than acyl chlo-
of Boc-proline and the method was found to be efficient for a
diverse variety of sterically hindered substrates and electron
deficient amines, frequently providing the desired product in
good to excellent isolated yield where other methods have
rides.13,16 To investigate our method in this respect, we coupled
N-Boc-L-proline with both enantiomers of 1-phenethylamine,
giving 16 and 17 in excellent yields and with no sign of
epimerization as determined after deprotection due to rotameric
failed to give satisfactory results.
forms of the Boc group.
To access some of the most challenging extremely hindered
amides, Bode and co-workers have devised a method involving
addition of Grignard reagents to isocyanates.3b For example,
the very hindered 18, previously synthesized in 19% via ada-
mantanecarbonyl chloride,20 was obtained in 75% by addition
of adamantylmagnesium bromide to adamantyl isocyanate.3b
The BTFFH protocol provided 18 in a highly satisfactory 78%
isolated yield. The sterically hindered amide 19, synthesized in
87% yield by addition of mesityl magnesium bromide to ada-
mantyl isocyanate,3b was subjected to the BTFFH protocol,
resulting in a satisfactory 50% isolated yield. Thus, the BTFFH
protocol can also give access to some of the extremely hindered
amides that has previously required Grignard addition to iso-
cyanates for efficient synthesis. The advantage of the BTFFH
protocol in this respect is a wider general scope that also
includes tertiary amides and sensitive functional groups,
although it is notable that methyl esters and ketones also can
be accommodated in the isocyanate fragment with Grignard
addition at low temperature.3b
Acknowledgements
We thank Assoc. Prof. Paul C. Stein for NMR assistance, Lone
Overgaard Storm for technical support and the Danish Council
for Independent Research
| Technology and Production
Sciences (grant 09-070364) and the Danish Council for Stra-
tegic Research (grant 11-116196) for financial support.
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