Boron-Catalyzed α-Amination of Carboxylic Acids

Article abstract of DOI:10.1021/acs.orglett.9b02769

A boron-catalyzed α-amination of simple carboxylic acids was developed. Catalytically generated boron enolates of carboxylic acids reacted with an electrophilic aminating reagent, diisopropylazodicarboxylate, to provide amino acid derivatives. The catalysis afforded not only α-monosubstituted glycine derivatives but also α,α-disubstituted derivatives. The resulting α-aminocarboxylic acid was easily converted to carboxylic acid derivatives. Extension to a catalytic asymmetric variant was possible by introducing a chiral ligand on the boron catalyst.

Full text of DOI:10.1021/acs.orglett.9b02769

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Boron-Catalyzed α‑Amination of Carboxylic Acids
Takuto Morisawa,‡ Masaya Sawamura,*,†,‡ and Yohei Shimizu*,†,‡
†Institute for Chemical Reaction Design and Discovery (WPI-ICReDD), Hokkaido University, Kita 21 Nishi 10, Kita-ku, Sapporo,
Hokkaido 001-0021, Japan
‡Department of Chemistry, Faculty of Science, Hokkaido University, Kita 10 Nishi 8, Kita-ku, Sapporo, Hokkaido 060-0810, Japan
S
* Supporting Information
ABSTRACT: A boron-catalyzed α-amination of simple carboxylic acids
was developed. Catalytically generated boron enolates of carboxylic acids
reacted with an electrophilic aminating reagent, diisopropylazodicarbox-
ylate, to provide amino acid derivatives. The catalysis afforded not only α-
monosubstituted glycine derivatives but also α,α-disubstituted derivatives.
The resulting α-aminocarboxylic acid was easily converted to carboxylic
acid derivatives. Extension to a catalytic asymmetric variant was possible
by introducing a chiral ligand on the boron catalyst.
Scheme 1. Catalytic α-Amination of Carboxylic Acid
Derivatives
α-Amino acids are attractive synthetic targets due to their
versatile applicability as building blocks of biologically active
molecules and functional molecules. One of the most efficient
and straightforward synthetic methods to construct α-amino
acids is the catalytic α-amination1 of readily available carboxylic
acids. However, this method is less developed compared to
those with other carbonyl congeners, e.g., aldehydes,2 ketones,3
1,3-dicarbonyl compounds,4 and oxyindoles.5 The high pKa
value of the α-proton of carboxylic acid derivatives causes a
major hurdle to realize the catalytic reaction. Preformation of
active surrogates, such as ketenesilylacetals6 or α-bromoesters,7
is an alternative approach toward the α-amination of carboxylic
acid derivatives. However, the direct catalytic α-amination via
deprotonation of the α-proton has been limited to α-arylacetic
acid derivatives,8 in which the enolate formation is relatively easy
due to anion stabilization by conjugation. Hence, the utilization
of α-alkyl-substituted acetic acid derivatives has been challeng-
ing. Smith reported one entry of a catalytic enantioselective α-
amination of 3-phenylpropionic acid through in situ preforma-
tion of an acid anhydride intermediate (Scheme 1a).9 The acid
anhydride is further activated by a chiral isothiourea catalyst for
α-amination via a C1-ammonium enolate. Yazaki and Ohshima
recently reported a copper-catalyzed α-amination of acylpyr-
azoles (Scheme 1b).10 Wasa employed a frustrated Lewis pair
(FLP) system comprised of B(C6F5)3 and a bulky base
(pentamethylpiperidine or Barton’s base) for α-amination of
simple esters (Scheme 1c).11Despite these reports, construction
of tetra-substituted carbon centers α to the carboxy group
remains elusive.
We previously reported the chemoselective enolate formation
of carboxylic acids using a boron activator.12 The reversible
covalent bond formation between the carboxylic acid and the
Lewis acidic boron activator increases the acidity of the α-
proton, thus enabling enolate formation of the carboxylic acid
under mild basic conditions. We envisaged that this method
could be extended to the direct α-amination of carboxylic acids,
leading to α,α-disubstituted glycine derivatives (Scheme 1d).
Herein, we report a boron-catalyzed direct α-amination of
carboxylic acids, which is applicable to the synthesis of α,α-
disubstituted glycine derivatives.
Received: August 6, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02769
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
To assess the feasibility of the proposed reaction, p-
methoxyphenylacetic acid (1a) was selected as a substrate.
Based on the results from previous studies of the boron-
catalyzed Mannich-type reaction, conditions with BH3·SMe2
(20 mol %), 1,8-diazabicyclo[5.4.0]-7-undecene (DBU) (2
equiv), and toluene as a solvent were applied for the carboxylic
acid enolate formation, and diethylazodicarboxylate (DEAD)
was used as the electrophilic aminating reagent (Table 1, entry
Table 2. Boron-Catalyzed α-Amination of α-Monoalkylacetic
Acid
a
Table 1. Boron-Catalyzed α-Amination of α-Monoarylacetic
Acid
a
entry
(AcO)4B2O (x mol %)
DIAD (y equiv)
yield (%)
b
1
2.5
10
10
1
1
2
27
66
84
2
3
a
1b (0.1 mmol), DIAD (0.1−0.2 mmol), (AcO)4B2O (0.0025−0.01
mmol), DBU (0.2 mmol), and toluene (0.15 M), room temperature,
3 h. Crude mixture was treated with TMSCHN2 (0.6 mmol) in
MeOH (0.1 M). Isolated yield. The reaction was conducted in a 0.2
b
mmol scale.
entry
boron source (x mol %)
R
yield (%)
The scope of the carboxylic acids was examined using 10 mol
% of (AcO)4B2O. An amount of 1 equiv of DIAD was used for
the reaction of phenylacetic acid derivatives (Scheme 2). Both
electron-withdrawing and -donating substituents on the α-aryl
group afforded the corresponding amino acid derivatives in good
yields (2a: 96%; 2c: 72%; 2d: 72%; 2e: 77%). A 1 mmol scale
reaction using 1a afforded 2a in 90% yield. On the other hand, 2
equiv of DIAD was used for hydrocinnamic acid derivatives.
Although an electron-donating methoxy substituent at the para-
position of the aryl group decreased the yield (2f: 58%), the
electron-withdrawing p-chloro substituent did not affect the
reactivity (2g: 83%). o-Bromo substitution slightly decreased
the yield probably due to increased steric bulk (2h: 70%). α-
Monoalkylacetic acids other than hydrocinnamic acid deriva-
tives, propionic acid (1i) and valeric acid (1j), were also
competent to afford 2i (91% yield) and 2j (84% yield).
Next, we attempted to use the catalyst for the synthesis of α,α-
disubstituted glycine derivatives. Gratifyingly, α-methylhydro-
cinnamic acid (1k) was converted to the product 2k in 88% yield
with 10 mol % of (AcO)4B2O and 2 equiv of DIAD (Scheme 3).
The yield was low with 1 equiv of DIAD (28% yield). Both
electron-donating and electron-withdrawing substituents were
tolerated on the aryl group of α-methylhydrocinnamic acid (2l:
57%; 2m: 67%). The sterically demanding o-bromo substituent
on the aryl group of α-methylhydrocinnamic acid was also
tolerated, albeit with a lower yield (2n: 47%). Since there is a
member of nonsteroidal anti-inflammatory drugs (NSAIDs)
which possesses the α-methyl-α-aryl carboxylic acid core
structure, such as ibuprofen and naproxen, we examined 2-
phenylpropionic acid (1o) as a simple model. The reaction
proceeded well, and the product 2o was obtained in 81% yield,
indicating that the present reaction would be applicable to α-
amination of NSAIDs. Slightly bulkier 2-phenylbutyric acid (1p)
was also competent to provide 2p in 70% yield.
1
2
3
4
5
6
BH3·SMe2 (20 mol %)
BBr3 (20 mol %)
Et
Et
Et
Et
iPr
tBu
iPr
40
79
89
0
96
86
91
(AcO)4B2O (10 mol %)
B(OEt)3 (20 mol %)
(AcO)4B2O (10 mol %)
(AcO)4B2O (10 mol %)
(AcO)4B2O (2.5 mol %)
b
7
a
1a (0.1 mmol), azodicarboxylate (0.1 mmol), boron catalyst, DBU
(0.2 mmol), and toluene (0.15 M), room temperature, 3 h. A crude
mixture was treated with TMSCHN2 (0.6 mmol) in MeOH (0.1 M).
b
Isolated yield. The reaction was conducted in 0.2 mmol scale.
1). The isolated yield was determined after converting the
product to the corresponding methyl ester by treating the crude
mixture with TMSCHN2. The initial conditions gave the α-
amination product 2a in 40% yield. Changing the boron catalyst
to BBr3, which has a better leaving group (Br−) on the boron
atom, significantly increased the reactivity (entry 2, 79% yield).
Further improvement was made with (AcO)4B2O, giving 2a in
89% yield (entry 3). On the other hand, B(OEt)3 was not
effective at all. Next, we surveyed electrophilic aminating
reagents to avoid the formation of DEAD-derived hydrazine as a
byproduct.13 Increasing the steric bulk of the aminating reagent
by changing DEAD to diisopropylazodicarboxylate (DIAD) was
effective to suppress undesired hydrazine formation, promoting
the α-amination reaction to produce 2a in excellent yield (entry
5, 96% yield). Bulkier di-tert-butylazodicarboxylate did not
improve the product yield (entry 6, 86% yield). The catalyst
loading could be reduced to 2.5 mol % without significant loss of
catalytic activity (entry 7, 91% yield). Nitrosobenzene was not
reactive as an electrophile.
The conditions optimized for the reaction of 1a did not give
satisfactory results for the reaction of α-monoalkylacetic acid 1b
(Table 2, entry 1). The product 2b was obtained in only 27%
yield under the same conditions as in Table 1 (entry 7). This was
likely due to the lower acidity of 1b at the α-methylene group
compared to that of 1a. The yield could be improved to 66% by
increasing the boron catalyst loading to 10 mol % (entry 2).
Since a significant amount of hydrazine was observed as a side
product even with DIAD, the amount of DIAD was increased to
2 equiv. This resulted in a marked increase in the yield to 84%
(entry 3).
Transformation of the carboxy group was examined next
(Scheme 4). After the catalytic amination of 1k, the crude
material was purified by silica gel column chromatography and
subjected to condensation reactions (Scheme 4a). Condensa-
tion with benzylamine using hexafluorophosphate azabenzo-
triazole tetramethyl uronium (HATU) gave amide 4 in 81%
yield over two steps. When glycine was used as a coupling
partner, dipeptide analogue 5 was obtained in 78% yield.
Intramolecular self-condensation provided diazetidinone 6 in
B
DOI: 10.1021/acs.orglett.9b02769
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Substrate Scope for α-Monosubstituted Acetic
Acids
Scheme 3. Substrate Scope for α,α-Disubstituted Acetic
a
a
Acids
a
1 (0.1 mmol), DIAD (0.2 mmol), (AcO)4B2O (0.01 mmol), DBU
(0.2 mmol), and toluene (0.15 M), room temperature, 3 h. Crude
mixture was treated with TMSCHN2 (0.6 mmol) in MeOH (0.1 M).
Isolated yield.
Scheme 4. Transformation of the α,α-Disubstituted Glycine
Derivative
a
1 (0.1 mmol), DIAD (0.1 mmol), (AcO)4B2O (0.01 mmol), DBU
(0.2 mmol), and toluene (0.15 M), room temperature, 3 h. Crude
mixture was treated with TMSCHN2 (0.6 mmol) in MeOH (0.1 M).
b
Isolated yield. The reaction was conducted on a 1 mmol scale. The
c
yield is shown in parentheses. DIAD (0.2 mmol) was used.
51% yield. Although several attempts to cleave the N−N bond of
2a resulted in failure,14 an N-tert-butoxy carbonyl analogue 2atBu
was successfully transformed to α-amino acid methyl ester 7 in
two steps: TFA-mediated cleavage of tert-butoxy carbonyl
groups followed by N−N bond scission by hydrogenolysis using
Raney-Ni (Scheme 4b).
Preliminary results of our investigation on the catalytic
enantioselective α-amination of 1o by introducing a chiral ligand
on the boron catalyst are shown in Scheme 5. Valine-derived L1
and 3,3′-I2−BINOL L2, which were effective chiral ligands for
the previous study of the boron-catalyzed asymmetric C−C
bond-forming reactions of carboxylic acids,12a,d were selected for
initial investigations. Although L2 did not induce meaningful
stereoselectivity, L1 provided 2o in decent enantioselectivity,
45% ee. This result suggests that the boron-catalyzed α-
amination of carboxylic acids may provide a useful method for
the asymmetric synthesis of α,α-disubstituted glycine derivatives
through proper chiral modification of the boron catalyst.
In summary, we have developed the first boron-catalyzed
direct α-amination of carboxylic acids. The reaction provided a
variety of α-amino acid derivatives including α,α-disubstituted
glycine derivatives. Preliminary investigations revealed that the
C
DOI: 10.1021/acs.orglett.9b02769
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
K. A. J. Am. Chem. Soc. 2002, 124, 6254. (b) List, B. J. Am. Chem. Soc.
Scheme 5. Catalytic Enantioselective α-Amination of a
Carboxylic Acid
̈
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present method can be extended to an asymmetric variant by
introducing a chiral ligand on the boron catalyst. Modification of
the chiral ligand to improve the enantioselectivity is ongoing in
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b02769.
C. F., III Org. Lett. 2010, 12, 5696. (c) Mouri, S.; Chen, Z.; Mitsunuma,
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■
S
Detailed experimental procedures, characterization data,
NMR spectra, and HPLC chart (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: sawamura@sci.hokudai.ac.jp.
*E-mail: shimizu-y@sci.hokudai.ac.jp.
ORCID
(7) (a) Fisher, D. J.; Burnett, G. L.; Velasco, R.; Read de Alaniz, J. J.
Am. Chem. Soc. 2015, 137, 11614. (b) Ishida, S.; Takeuchi, K.;
Taniyama, N.; Sunada, Y.; Nishikata, T. Angew. Chem., Int. Ed. 2017, 56,
11610.
Masaya Sawamura: 0000-0002-8770-2982
Yohei Shimizu: 0000-0001-8797-9757
Notes
(8) (a) Zhao, B.; Du, H.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 7220.
(b) Evans, R. W.; Zbieg, J. R.; Zhu, S.; Li, W.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2013, 135, 16074. (c) Evans, D. A.; Nelson, S. G. J. Am.
Chem. Soc. 1997, 119, 6452. (d) Smulik, J. A.; Vedejs, E. Org. Lett. 2003,
5, 4187.
(9) Morrill, L. C.; Lebl, T.; Slawin, A. M. Z.; Smith, A. D. Chem. Sci.
2012, 3, 2088.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Institute for Chemical Reaction Design and Discovery
(ICReDD) was established by the World Premier International
Research Initiative (WPI), MEXT, Japan. This work was
supported by the JSPS KAKENHI grant-in-aid for Scientific
Research (A) to M.S. (No. JP18H03906), JSPS KAKENHI
grant-in-aid for Early-Career Scientists (No. 18K14207), and
grants-in-aid from the Fugaku Trust for Medicinal Research to
Y.S.
(10) Tokumasu, K.; Yazaki, R.; Ohshima, T. J. Am. Chem. Soc. 2016,
138, 2664.
(11) Shang, M.; Wang, X.; Koo, S. M.; Youn, J.; Chan, J. Z.; Yao, W.;
Hastings, B. T.; Wasa, M. J. Am. Chem. Soc. 2017, 139, 95.
(12) (a) Morita, Y.; Yamamoto, T.; Nagai, H.; Shimizu, Y.; Kanai, M. J.
Am. Chem. Soc. 2015, 137, 7075. (b) Nagai, H.; Morita, Y.; Shimizu, Y.;
Kanai, M. Org. Lett. 2016, 18, 2276. (c) Ishizawa, K.; Nagai, H.;
Shimizu, Y.; Kanai, M. Chem. Pharm. Bull. 2018, 66, 231. (d) Fujita, T.;
Yamamoto, T.; Morita, Y.; Chen, H.; Shimizu, Y.; Kanai, M. J. Am.
Chem. Soc. 2018, 140, 5899.
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(14) See Supporting Information for details.
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D
DOI: 10.1021/acs.orglett.9b02769
Org. Lett. XXXX, XXX, XXX−XXX