The: Ortho -substituent on 2,4-bis(trifluoromethyl)phenylboronic acid catalyzed dehydrative condensation between carboxylic acids and amines

Article abstract of DOI:10.1039/c8cc02558d

2,4-Bis(trifluoromethyl)phenylboronic acid is a highly effective catalyst for dehydrative amidation between carboxylic acids and amines. Mechanistic studies suggest that a 2:2 mixed anhydride is expected to be the only active species, and the ortho-substituent of boronic acid plays a key role in preventing the coordination of amines to the boron atom of the active species, thus accelerating the amidation. This catalyst works for α-dipeptide synthesis.

Full text of DOI:10.1039/c8cc02558d

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ortho‐Substituent on 2,4‐Bis(trifluoromethyl)phenylboronic Acid‐
Catalyzed Dehydrative Condensation between Carboxylic Acids
and Amines†
Received 00th January 20xx,
Accepted 00th January 20xx
Ke Wang,‡ Yanhui Lu‡ and Kazuaki Ishihara*
DOI: 10.1039/x0xx00000x
www.rsc.org/
2,4‐Bis(trifluoromethyl)phenylboronic acid is a highly effective
catalyst for dehydrative amidation between carboxylic acids and
amines. Mechanistic studies suggest that a 2:2 mixed anhydride is
expected to be the only active species and the ortho‐substituent
of boronic acid plays a key role in preventing the coordination of
amines to the boron atom of the active species, thus accelerating
the amidation. This catalyst works for‐dipeptide synthesis.
The organoboron‐catalyzed dehydrative condensation reaction
between carboxylic acids and amines is one of the most ideal
methods for synthesizing the corresponding amides.1,2 In
1996, Yamamoto and Ishihara et al. reported the first example
of the dehydrative amide condensation reaction catalyzed by
meta‐
phenylboronic acids such as 3,4,5‐trifluorophenylboronic acid
1a) and 3,5‐bis(trifluoromethyl)phenylboronic acid (1b) under
azeotropic reflux conditions (Scheme 1a).2a Over the past
decade, the application of arylboronic acids bearing ortho‐
basic groups3 has made it possible to more practical and mild
conditions. However, the substrate scope is limited to simple
or
para‐electron‐deficient
group‐substituted
Scheme 1 Amidation catalysis of 1 based on Whiting’s proposed mechanism.7
(
substrate amine
corresponding amide
intermediate . However,
to give more stable tetrasubstituted boronate
and . We anticipated that suppression of their
3
directly attacks the acyl group of
should be obtained through desired
can also coordinate to the boron
6, the
5
7
3
center of
complexes
6
8
9
ones, and especially the application of this reaction to
dipeptide synthesis2m,3g,h remains a major issue.
‐
generation might increase the chance for amide formation.
Here, we report 2,4‐bis(trifluoromethyl)phenylboronic acid
Recently, other types of boron compounds like a DATB
complex4 and a borate ester5 have been reported to be
alternative powerful catalysts for direct amidations.6 Although
these new catalysts work fairly well on a broad range of
(
1c) as an extremely effective catalyst for direct amidation.
This commercially available 1c worked well for a wide range of
substrates including amino acid substrates to construct
dipeptides in higher yields with almost no epimerization. We
propose that the ortho‐monosubstituent of sterically
prevents the coordination of amine to the boron atom of
dimeric anhydride to give and
To clarify the importance of ortho‐monosubstituent on
arylboronic acid we initiated catalyst screening by
considering amidation between ibuprofen 2a and
benzylamine (3a) in the presence of various arylboronic acid
catalysts and molecular sieves(MS) at ambient

‐
substrates including for
the design of boron catalysts for direct amidation is still
unclear. We previously reported that carboxylic acid might
be activated through the generation of a 1:1 mixed anhydride
4 2a
In contrast, Whiting et al. more recently reported dimeric
mixed anhydride
‐peptide formation, the key point in
1
3
2
6
8
9.
.
1
,
6
might be more preferable as a real active
(
)
species based on their mechanistic study (Scheme 1).7 If
1
3 Å
temperature (Table 1). To our surprise, 1b was totally
ineffective (entry 1), while 1c was quite powerful, and
provided the desired amide product 5aa in 64% yield (entry 2).
On the other hand, 2,6‐bis(trifluoromethyl)phenylboronic acid
Graduate School of Engineering, Nagoya University, B2‐3(611), Furo‐cho, Chikusa,
Nagoya 464‐8603, Japan. E‐mail: ishihara@cc.nagoya‐u.ac.jp.
† Electronic supplementary Information (ESI) available: Details of mechanistic
studies, experimental procedures and analytical data of all new compounds. See
DOI: 10.1039/x0xx00000x
(
1d) was useless in this transformation (entry 4). A lower
‡ These authors contributed equally to this work.
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Table 1 Arylboronic acid 1‐catalyzed direct amidation between 2a and 3aa
Scheme 2 Inactive complex formation on 1c‐catalyzed ‐amino acid activation.
En‐
try
1
2
3
4
5
6
7
ArB(OH)2 (1)
Ar, 1
3,5‐(CF3)2‐C6H3, 1b
2,4‐(CF3)2‐C6H3, 1c 64 (97c)
2,4‐(CF3)2‐C6H3, 1c
2,6‐(CF3)2‐C6H3, 1d
2‐CF3‐C6H4, 1e
2‐Me‐C6H4, 1f
2‐NO2‐C6H4, 1g
Yield (%)
of 5aa
<5
En‐
try
8
ArB(OH)2 (1)
Ar, 1
2‐SF5‐C6H4, 1h
2‐Me‐4‐NO2‐C6H3, 1i
Yield (%)
of 5aa
<5
31
39
amines
ambient temperature or acceptable elevated temperatures.
Moreover, the condensation of pyrazinecarboxylic acid (2f
3 to deliver the corresponding amides 5 in high yield at
9
93d
<5
42
<5
9
10 2‐Et‐4‐NO2‐C6H3, 1j
11 2‐i‐Pr‐4‐NO2‐C6H3, 1k 56
12 2‐(i‐Pr2NCH2)‐C6H4, 1l <5
13 2‐I‐5‐MeO‐C6H3, 1m
14 2‐I‐5‐MeO‐C6H3, 1m
)
and
L‐phenylalanine methyl ester (3f) provided a key
intermediate 5ff for the synthesis of Bortezomib (Velcade®)10
46
69d
without any epimerization.
We then turned our attention to
Although several boronic acids have been reported to be
applicable to ‐ or ‐peptide synthesis, there is still room for
‐peptide synthesis.
a Reaction conditions: 2a (0.5 mmol), 3a (0.5 mmol) and 1 (10 mol %) were stirred
at 25 °C for 12 h in dry dichloromethane containing powdered activated MS 3Å (1
g). b Yields of 5aa were determined by 1H‐NMR. c Isolated yield of 5aa after 18
h. d MS 4Å was used in place of MS 3Å. Reaction time was 20 h.
1


improvement because of remaining problems, like low
yield2n,3g,h and high catalyst loading.2n Similar to Hall’s
catalyst,3h 1c was not effective with coordinatable N‐Boc‐, N‐
Cbz‐ or N‐Fmoc‐protected amino acids because of the
possibility of generating stable inactive complex 10 or 11
(Scheme 2).11 Recently, Shibasaki and Kumagai reported
conventional N‐protective groups (N‐Fmoc and N‐Boc) can be
used in the DATB‐catalyzed peptide synthesis at higher
temperature.4b To inhibit catalyst complexation alternatively,
we introduced more electron‐deficient N‐protecting groups to
weaken the nucleophilicity of the amino moiety of amino
acids. Due to its high reactivity, easy preparation and selective
removability, an N‐trifluoroacetyl moiety was found to be the
most suitable. Notably, the catalytic activity of 1c was superior
electron‐deficiency of
and 6, 1c versus 1e, 1e versus 1f). Interestingly, other ortho‐
electron‐deficient substituents like a nitro group (entry 7, 1g
and pentafluorosulfanyl group (entry 8, 1h) did not work,
perhaps because coordination to boron8 might decrease the
activity or the ortho‐substituents might be too sterically
1 reduced the yield of 5aa (entries 2, 5
)
hindered. Next, the catalytic activities of 1i, 1j and 1k with
simple alkyl groups at othro‐position were examined (entries
9–11). Surprisingly, catalytic activity improved as the size of
the substituent increased. Nevertheless, 1c was still more
powerful than 1k (entry 2 versus entry 11). Furthermore, 1c
showed superior catalytic activity to known boronic acids 1l3a
and 1m3d regardless of the type of molecular sieves (3Å and
4Å) (entry 2 versus entries 12 and 13; entry 3 versus entry 14).9
Subsequently, we explored the substrate scope of direct
amidation using 1c as a catalyst (Table 2). The results showed
to those of 1b and 1m even for
Through further screening, we found that 1,2‐dichloroethane
was optimal solvent in ‐dipeptide synthesis. As similar as

‐dipeptide synthesis.9,12

Shibasaki and Kumagai et al.’s report,4b amino ester
hydrochlorides were also proved to be more efficient than the
amino esters in our catalysis. With regard to the substrate
that 1c was effective for linear,
heteroaromatic carboxylic acids with aliphatic or aromatic
‐branched, aromatic or
2
Table 3 Direct amidations between N‐trifluoromethyl protected L‐amino acids and L‐
amino ester hydrochlorides catalyzed by 1ca
Table 2 Substrate scope for 1c‐catalyzed direct amidationa,b
a Method A: 2 (0.5 mmol), 3 (0.5 mmol) and 1c were stirred at 25 °C for 12 h in
dry toluene containing powdered activated molecular sieves 3 Å (1 g). b Method
B: A solution of 2 (0.5 mmol), 3 (0.5 mmol), 1c in fluorobenzene (bp. 85 °C) was
a Unless otherwise noted: 2 (0.5 mmol), 3•HCl (0.5 mmol) and 1c were stirred at
60 °C for 48 h in 1,2‐dichloroethane containing powdered activated MS 3Å (1 g).
b Isolated yield. c Diastereomeric ratio (dr) was determined by 1H NMR.
c
heated to reflux with the removal of water by 1 g of activated MS 3Å (pellet).
Toluene (bp. 110.6 °C) was used instead of fluorobenzene.
2 | J. Name., 2012, 00, 1‐3
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Table 4 Generation of dimeric anhydride 6 and activities for amidation
Scheme 3 Deprotection of ‐dipeptides 5.
Entry
1
Yield
Yield (%)
Entry
1
Yield (%) Yield (%)
(%) of 6a of 5aaa,b
of 6a
of 5aaa,b
scope, 1c worked fairly well with N‐trifluoroacetyl(A)‐
L
‐glycine
‐phenylalanine (2i), N‐A‐ ‐valine
‐methionine (2k) to deliver ‐dipeptides in high
(
(
2g), N‐A‐
2j), N‐A‐
L
‐alanine (2h), N‐A‐
L
L
1
2
3
1b
1c
1d
6ab, 88
6ac, 85
6ad, 9
<5
41
–
4
5
6
1f
1l
1m
6af, 13
6al, 84
6am, 82
–
<5
16
L

5
yields with almost no epimerization (Table 3). However,
extensive epimerization occurred with N‐A‐ ‐methylcysteine
2l) to produce 5lf as a diastereomer mixture (78/22). The
L
a Determined based on 1H NMR analysis. b Purities of 6 used in the amidation
step were >95%.
(
‐
steric bulkiness of
and the bulky alkoxy groups of
L
‐valine methyl ester hydrochloride (3d•HCl)
‐phenylalanine ester
hydrochlorides 3g•HCl and 3h•HCl slightly decreased the yield
of products 5id 5hg, and 5hh. This protocol is practical and
scalable, and ‐dipeptides 5hf and 5kf could be synthesized on
L
According to Marcelli’s theoretical calculations, the high
catalytic activity of 2‐iodophenylboronic acid can be attributed
to the electronic effect in which an “I•••H–O” hydrogen bond
,
stabilizes monoacyl boronate 4 14
Hall et al. have proposed a
.

similar mechanism.3h On the other hand, Guo et al. proposed
that the orbital overlap between a sp2 orbital of the iodine
atom and the p orbital of the boron atom may stabilize the
complex after amine addition.15 Our experimental results
show that not only these electronic effects but also the steric
effect of an ortho‐substituent should be important for
enhancing the catalytic activities.
a gram scale. Furthermore, the masked dipeptides were
selectively deprotected under mild conditions (Scheme 3).
Recently, Whiting successfully obtained the crystal structures
of dimeric anhydride
halophenylboronic acids (Scheme 4).7 Based on this report,7
we also detected from a reaction mixture of 1c and
ibuprofen 2a by electrospray ionisation mass spectrometry
(ESI‐MS). In contrast, monomeric anhydride was not
detected by ESI‐MS. Although these ESI‐MS experiments are
not enough as evidence for generation of , it is expected that
an active species of 1c‐catalysis as well as those of 2‐
halophenylboronic acid‐catalysis are which may be
generated via
6 between 2‐phenylacetic acid and 2‐
6
4
To clarify the possibility that the ortho‐substituent of boronic
acid
amines to the boron atom of dimeric anhydride
examined the coordination effect between and pyridine by in
1
plays a key role in preventing the coordination of
6
6
, we
6
6,
situ IR through observation of the stretching vibration of the
carbonyl groups (Scheme 5a). As a consequence, 74% of 6ab
(1589 cm‐1) turned to a new peak at 1693 cm‐1 within 3
minutes after pyridine was added. Since the new peak is
different from any reference peaks,16 we proposed that it
should be the coordinate complex 12ab. On the other hand,
only 36% of 6ac changed to the chelate complex (1697 cm‐1).
Similar results were observed in the catalytic amidation
between 2a and benzyl amine 3a (Scheme 5b). Through pre‐
mixing, 6ab was formed quickly, while no amide (also
4
.
To better understand the problems with each catalyst, we
examined the reaction rates of the generation of active species
6
from ibuprofen 2a with
the active species with benzylamine 3a to give amide 5aa
(Table 4). To our surprise, representative 1b 1l and 1m
demonstrated similar activities for the generation of , while
1, and the reaction rates between
,
6
showing lower or no activities for amidations. Furthermore,
1d and 1f failed to provide active species under the same
conditions, perhaps because of steric hindrance or low Lewis
acidity. Moreover, boroxine (cyclic trimer) of 1c also provided
1
confirmed by H NMR) but a new coordinate complex 13ab at
1678 cm‐1 was observed.
comparable result in formation of
also found that formation of boroxine under dehydrative
conditions was quite fast (<5 min), so that not only but also
6 as the single form. We
In the 1c‐catalyzed amidation reaction, amide 5aa was
gradually generated instead of an ate‐complex 13ac
.
We
1
anticipated that the coordination of 3a to 6ab increases its
its boroxine should be effective as catalysts.13 These results
reveal that the activation step and the amidation step are both
crucial for the overall reaction, and 1c is superior in the
amidation step.
Scheme 4 Analysis of active species 6 by X‐ray diffraction7 and ESI‐MS.
Scheme 5 In situ IR analyses
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stability and lowers its reactivity, thus suppressing
amidation.2q
To obtain more mechanistic insights, we
conducted the initial rate kinetic experiments to determine
rate orders in 1c‐catalyzed amidation between 2a and 3a 17
.
Although the formation of ammonium carboxylate salt slightly
complicated this system, we obtained approximate first orders
for 1c and 3a, and a zero order for 2a
.
Moreover, as Hall’s previous report,3d we also found the pre‐
mixing of 1c and 2a in the presence of molecular sieves for
several minutes is indispensable. Control reactions with a
simultaneous addition of both substrates with the catalyst
provided less than 5% yield of amide product after several
Yamashita, A. Sakakura and K. Ishihara, Org. Lett., 2013, 15
3654; (p) K. Ishihara and Y. Lu, Chem. Sci., 2016, , 1276.
,
7
3
For ortho‐basic group‐substituted phenylboronic acid‐
catalysed amidations: (a) K. Arnold, A. S. Batsanov, B. Davies
and A. Whiting, Green Chem., 2008, 10, 124; (b) R. M. Al‐
Zoubi, O. Marion and D. G. Hall, Angew. Chem. Int. Ed., 2008,
47, 2876; (c) I. Georgiou, G. Ilyashenko and A. Whiting, Acc.
Chem. Res., 2009, 42, 756; (d) N. Gernigon, R. M. Al‐Zoubi
and D. G. Hall, J. Org. Chem., 2012, 77, 8386; (e) L. Gu, J. Lim,
J. L. Cheong and S. S. Lee, Chem. Commun., 2014, 50, 7017;
(f) T. Mohy El Dine, W. Erb, Y. Berhault, J. Rouden and J.
Blanchet, J. Org. Chem., 2015, 80, 4532; (g) E. K. W. Tam,
hours. A coherent explanation for this initiation step asserts
as the actual catalytic species (Scheme 1).12 Once formed,
can react with the added amine to give active intermediate
6
6
7
,
which gives amide
5 quickly. The formation of 7 should be the
rate‐determining step according to the kinetics studies.
Moreover, steric effect of 1c helped to suppress the formation
of inactive complexes 8 and 9.
In summary, 2,4‐bis(trifluoromethyl)phenylboronic acid 1c
Rita, L. Y. Liu and A. Chen, Eur. J. Org. Chem., 2015, 2015,
1100; (h) S. Fatemi, N. Gernigon and D. G. Hall, Green Chem.,
2015, 17, 4016.
serves as a highly effective catalyst for direct amidation under
mild conditions. A variety of amides including
‐dipeptides
4
(a) H. Noda, M. Furutachi, Y. Asada, M. Shibasaki and N.
can be successfully constructed through this catalysis.
Moreover, the in situ IR experiments proved that the ortho‐
Kumagai, Nature Chem. 2017, 9, 57; (b) Z. Liu, H. Noda, M.
Shibasaki and N. Kumagai, Org. Lett., 2018, 20, 612.
M. T. Sabatini, L. T. Boulton and T. D. Sheppard, Sci. Adv.
2017, 3:e1701028.
substituent of boronic acid
coordination of amines to the boron atom of 2:2 mixed
anhydride , thus accelerating the amidation.
1 plays a key role in preventing the
5
6
For borinic acid catalysts, see: (a) T. Mohy El Dine, J. Rouden
and J. Blanchet, Chem. Commun., 2015, 51, 16084; (b) T.
Mohy El Dine, D. Evans, J. Rouden and J. Blanchet, Chem.
Eur. J., 2016, 22, 5894. However, Whiting et al. recently
reported that borinic acids do not catalyze amidation
without prior protodeboronation to give boronic acids in
situ, which are active.7
6
This work was financially supported by JSPS KAKENHI Grant
Numbers JP15H05755 and JP15H05810 in Precisely Designed
Catalysts with Customized Scaffolding, and the Program for
Leading Graduate Schools: IGER Program (MEXT).
7
S. Arkhipenko, M. T. Sabatini, A. S. Batsanov, V. Karaluka, T.
D. Sheppard, H. S. Rzepa and A. Whiting, Chem, Sci., 2018, 9,
Conflicts of interest
1058.
8
9
S. Soundararajan, E. N. Duesler and H. Hageman, J. Acta
Crystallogr. C, 1993, 49, 690.
There are no conflicts to declare.
According to ref. 3d, it is noted that the catalytic activity of
1m with MS 3Å is much lower than with MS 4Å. In sharp
contrast, MS 3Å was much more effective than MS 4Å for the
Notes and references
1c‐catalyzed synthesis of ‐peptides.
1
For selected reviews, see: (a) I. Georgiou, G. Ilyashenko and
A. Whiting, Acc. Chem. Res., 2009, 42, 756; (b) K. Ishihara,
Tetrahedron, 2009, 65, 1085; (c) H. Charville, D. Jackson, G.
Hodges and A. Whiting, Chem. Commun., 2010, 46, 1813; (d)
10 Bortezomib is the first FDA‐approved proteasome inhibitor
drug for the treatment of multiple myeloma and mantle cell
lymphoma. (a) For a recent review of proteasome inhibitors,
see: L. Borissenko and M. Groll, Chem. Rev., 2007, 107, 687;
(b) M. A. Beenen, C. An and J. A. Ellman, J. Am. Chem. Soc.,
2008, 130, 6910.
11 (a) C. W. Gray, Jr. and T. A. Houston, J. Org. Chem. 2002, 67
5426; (b) T. Harada and T. Kusukawa, Synlett, 2007, 2007
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E. Dimitrijevi´c and M. S. Taylor, ACS Catal., 2013, 3, 945; (e)
H. Zheng and D. G. Hall, Aldrichmica Acta, 2014, 47, 41; (f) K.
Ishihara, in Synthesis and Application of Organoboron
Compounds, Topics in Organometallic Chemistry, Vol. 49
(Eds.: E. Ferna´ndez and A. Whiting), Springer, Heidelberg,
2015, pp. 243; (g) R. M. de Figueiredo, J.‐S. Suppo and J.‐M.
Campagne, Chem. Rev., 2016, 116, 12029; (h) A. O. Porras
,
,
12 See details for screening of protective groups in ESI.
13 According to ref. 7, it was proposed that destabilizeation of
and D. G. Sanchez, J. Org. Chem., 2016, 81, 11548.
́
boroxines is a key effect of ortho‐group of
significant difference on the stability of boroxines was not
observed between 1b and 1c
1. However, the
2
For selected reports of boronic acid‐catalysed amide
condensations, see: (a) K. Ishihara, S. Ohara and H.
Yamamoto, J. Org. Chem., 1996, 61, 4196; (b) K. Ishihara, S.
Ohara and H. Yamamoto, Macromolecules, 2000, 33, 3511;
(c) K. Ishihara, S. Ohara and H. Yamamoto, Org. Synth., 2002,
79, 176; (d) T. Maki, K. Ishihara and H. Yamamoto, Synlett,
2004, 2004, 1355; (e) P. Tang, Org. Synth., 2005, 81, 262; (f)
.
14 T. Marcelli, Angew. Chem. Int. Ed., 2010, 49, 6840.
15 C. Wang, H.‐Z. Yu, Y. Fu and Q‐X. Guo, Org. Biomol. Chem.,
2013, 11, 2140.
16 See reference peaks of in situ IR in ESI.
17 See details of IRKE in ESI.
T. Maki, K. Ishihara and H. Yamamoto, Org. Lett., 2006, 8,
1431; (g) K. Arnold, B. Davies, R. L. Giles, C. Grosjean, G. E.
Smith and A. Whiting, Adv. Synth. Catal., 2006, 348, 813; (h)
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