One-pot synthesis of primary amines from carboxylic acids through rearrangement of in situ generated hydroxamic acid derivatives

Article abstract of DOI:10.1016/j.tetlet.2016.10.037

A one-pot synthesis of primary amines from carboxylic acids through a Lossen rearrangement of hydroxamic acid derivatives, which were in situ generated by the reaction of carboxylic acids with O-trimethylsilylhydroxylamine (NH₂OTMS) and carbonyl diimidazole (CDI, 1.5 equiv) in dimethyl sulfoxide at room temperature, has been achieved. This one-pot method could be applied to various carboxylic acids such as aromatic, heteroaromatic, aliphatic, and optically active substrates.

Full text of DOI:10.1016/j.tetlet.2016.10.037

Accepted Manuscript
One-pot synthesis of primary amines from carboxylic acids through rearrange-
ment of in situ generated hydroxamic acid derivatives
Yujiro Hoshino, Naoya Ohtsuka, Takuya Okada, Kiyoshi Honda
PII:
S0040-4039(16)31351-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.10.037
TETL 48207
Reference:
Tetrahedron Letters
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4 October 2016
12 October 2016
Please cite this article as: Hoshino, Y., Ohtsuka, N., Okada, T., Honda, K., One-pot synthesis of primary amines
from carboxylic acids through rearrangement of in situ generated hydroxamic acid derivatives, Tetrahedron
Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.10.037
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One-pot synthesis of primary amines from
carboxylic acids through rearrangement of
in situ generated hydroxamic acid
derivatives
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Yujiro Hoshino,* Naoya Ohtsuka, Takuya Okada, and Kiyoshi Honda*

1
Tetrahedron Letters
One-pot synthesis of primary amines from carboxylic acids through rearrangement of
in situ generated hydroxamic acid derivatives
Yujiro Hoshino, Naoya Ohtsuka, Takuya Okada, and Kiyoshi Honda*
Graduate School of Environment and Information Sciences, Yokohama National University, Tokiwadai, Hodogaya-ku, Yokohama 240-8501, Japan
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A one-pot synthesis of primary amines from carboxylic acids through a Lossen rearrangement of
hydroxamic acid derivatives, which were in situ generated by the reaction of carboxylic acids
with O-trimethylsilylhydroxylamine (NH2OTMS) and carbonyl diimidazole (CDI, 1.5 equiv) in
dimethyl sulfoxide at room temperature, has been achieved. This one-pot method could be
applied to various carboxylic acids such as aromatic, heteroaromatic, aliphatic, and optically
active substrates.
Available online
Keywords:
2009 Elsevier Ltd. All rights reserved.
One-pot synthesis
Primary amines
Lossen rearrangement
Carboxylic acids
Primary amines constitute the structural basis of various
pharmaceuticals, agrochemicals, and functionalized materials.
Consequently, the direct synthesis of primary amines from
carboxylic acids is more attractive. The Lossen rearrangement is
a synthetic method for primary amines via nucleophilic migration
from a carbonyl carbon of a hydroxamic acid derivative to an
electron-deficient nitrogen center.1 Although many studies have
focused on the development of activation methods to promote the
Lossen rearrangement using an external stoichiometric activating
agent,2 efforts for directly obtaining primary amines from
carboxylic acids in one pot via this rearrangement are rare.
Methods using nitromethane or hydroxylamine in excess
polyphosphoric acid were reported in the literature, but a limited
scope of aromatic carboxylic acids was described primarily
because of the harsh reaction conditions required.3,4 Moderate
yields of aromatic amines were obtained via the Lossen
without an additional activating agent. The present direct
synthesis of primary amines could also apply to various
substrates including aromatic, heteroaromatic, aliphatic, and
chiral carboxylic acids.
Scheme 1. A one-pot synthesis of primary amines from
carboxylic acids through self-propagative Lossen
rearrangement.
Our preliminary experiments were initiated by investigating
the reaction of 2-iodobenzoate with hydroxylamine
hydrochloride in dimethyl sulfoxide (DMSO) in the presence of
various bases (Scheme 2).8 A brief survey of bases resulted in
little or no formation of the desired aniline and led to substantial
decomposition of the ester to the corresponding carboxylic acid
(up to 52% yield). When the reaction was quenched before
warming to 90 °C in order to confirm the in situ generation of
hydroxamic acid, the desired product was isolated in 92% yield.
Thus, we postulated that the remaining proton source such as
hydroxylamine hydrochloride would inhibit the rearrangement
primarily owing to trapping of the isocyanate intermediate.9
Therefore, we turned our attention to the use of O-
rearrangement
of
in
situ
generated
N-acyl-N,O-
bis(ethoxycarbonyl)hydroxylamine.5,6
Recently, we reported a base-mediated rearrangement of free
hydroxamic acids (unsubstituted hydroxamic acids, also called
primary hydroxamic acids) at 90 °C in the presence of a catalytic
or equimolar amount of base, leading exclusively to the desired
amines in high yields.7 We then speculated that if hydroxamic
acids could be synthesized from easily available carboxylic acids
under neutral or basic conditions in good yields, a one-pot
synthesis of primary amines via self-propagative Lossen
rearrangement would be achieved without an additional
activating agent (Scheme 1). Herein, we disclose a one-pot
synthesis of primary amines from carboxylic acids through
trimethylsilylhydroxylamine (NH2OTMS)10 as
a
synthetic
equivalent of hydroxylamine, and carbonyl diimidazole (CDI) as
a dehydrating agent in DMSO. Potassium carbonate was selected
rearrangement of in situ generated hydroxamic acid derivatives
———
 Corresponding author. Tel.: +81-45-339-4434; fax: +81-45-339-4434; e-mail: yhoshino@ynu.ac.jp

2
Tetrahedron
as a base in the second step and added to the reaction mixture
hydroxamic acids from the parent carboxylic acids due to the
steric hindrance.
before the reaction temperature was increased to 90 °C. As
shown in Table 1, a small amount of the desired product,
toluidine (2a), was obtained (entry 1). Because the yield of 2a
was not dramatically increased when the reaction was conducted
using double the amount of K2CO3, the effect of Base A in the
first step was examined (entries 3–8). While the reaction using a
weak base, N-methylimidazole (NMI), resulted in a slight
increase in the yield, several moderately or strongly basic amines
improved the yields approximately two fold. Interestingly, the
addition of CsF, in order to promote desilylation to generate the
alkoxides or amides after exchange of the anion, smoothly
induced the rearrangement to give the symmetrical urea (46%
yield) and pseudodimer (35% yield) (entry 9).11 With treatment
of the same base in both the first and second steps, moderate to
poor yields were obtained (entries 10–11). Note that in contrast
to our previous results of base-mediated rearrangement of
hydroxamic acids,7 the reaction conducted in N,N-
dimethylformamide (DMF) afforded a lower yield, but the one in
acetonitrile (CH3CN) afforded a comparable yield (entries 12–14).
The reduction in the amount of reagents (1 equiv of CDI and 1.5
equiv of NH2OTMS) resulted in a slightly lower yield (entry 15).
Table 1
Optimization of conditions for one-pot synthesis of amines
from carboxylic acids via rearrangement of in situ generated
hydroxamic acids
Entry
1
Base A (equiv)
–
K2CO3 (equiv)
Yield (%)
1
2
2
2
2
2
2
2
2
–
–
2
2
2
2
17
37
37
42
70
75
65
79
2
–
3
DABCO (0.5)
NMI (0.5)
NEt3 (0.5)
iPr2NEt (0.5)
DBU (0.5)
DMAP (0.5)
CsF (1)
4
5
6
7
8
e
9
–
10
11
12a
13b
14c
15d
K2CO3 (2)
DMAP (1)
DMAP (0.5)
DMAP (0.5)
DMAP (0.5)
DMAP (0.5)
48
11
55
79
42
61
Scheme 2. The reaction of 2-iodobenzoate with
hydroxylamine hydrochloride in DMSO in the presence of
base.
We then focused on briefly examining the scope of
dehydrating agents. Although no desired product was obtained in
the reaction using N,N′-dicyclohexylcarbodiimide (DCC) and no
reaction was observed in the case of diphenyl carbonate, the one-
pot synthesis of p-toluidine was successfully conducted using
carbonate dehydrating agents, i.e., N,N′-disuccinimidyl carbonate
and bis(p-nitrophenyl) carbonate, under standard conditions to
afford the desired product 2a in 40% and 45% yields,
respectively. The subtle difference in the reactivity of
dehydrating agents with between p-toluic acid and NH2OTMS is
likely to control the first step of the reaction in the one-pot
synthesis.
a The reaction was performed in DMF. b The reaction was performed in
CH3CN. c The reaction was performed in toluene. d Reaction conditions: CDI
(1 equiv), NH2OTMS (1.5 equiv). e Symmetrical urea (46% yield) and
pseudodimer (35% yield) were obtained.
With the optimized conditions in hand, the scope of substrates
was examined.12 As shown in Table 2, various aromatic
carboxylic acids afford the desired anilines in moderate to good
yields, for example, carboxylic acids having electron
withdrawing groups (2g–i, 63% to 43% yields). Note that the
reaction of o-substituted benzoic acids such as o-toluic acid and
o-bromobenzoic acid afforded the desired o-substituted anilines
in low yields (2c: 38%, 2f: 10%, and 2k: 49% yields). These
results seem to be inconsistent with the ortho effect of the Lossen
rearrangement, in which the existence of an o-substituent, even
an electron-withdrawing group, accelerates the rate of
migration.13 To elucidate this puzzle, the isolation of the
hydroxamic acid intermediate generated in the first step was
examined (Scheme 3). After stirring the reaction mixture for 18 h,
5% aq KHSO4 was added and the reaction was worked up
according to the literature procedure.14 Consequently, the desired
4-methylbenzohydroxamic acid was isolated in high yield (86%).
Conversely, the same reaction conditions using o-bromobenzoic
acid as substrate afforded the desired hydroxamic acid in poor
yield. It is suggested that the low yields of o-substituted anilines
are primarily the result of the difficulty of in situ generation of
Scheme 3. Isolation of hydroxamic acids.
a determined by 1H NMR.
Aliphatic carboxylic acids were also subjected to the present
one-pot synthetic method, and in some cases, the amino group in
the product was protected in order to simplify the purification
and isolation of the product (Table 3). Primary, secondary, and
tertiary aliphatic carboxylic acids afforded the desired amines in
moderate yields (3a–e). For triphenylacetic acid, no reaction was
observed primarily because of the difficulty of in situ formation
of the corresponding hydroxamic acid owing to the high level of
steric hindrance around the carboxylic acid functionality (vide
supra). Heteroaromatic amines were also obtained in good to
moderate yields (3g–i). In particular, o-carboxy pyridine and

3
quinoline were good substrates for this reaction, affording the o-
amino products in good yields, which constitute an important
class of compounds in synthetic organic chemistry and drug
discovery.15
Table 3
One-pot synthesis of primary amines from aliphatic and
heteroaromatic carboxylic acidsa
Table 2
One-pot synthesis of primary anilines from aromatic
carboxylic acidsa
a Reaction Conditions: 1 (2.0 mmol), CDI (3.0 mmol), NH2OTMS (4.0 mmol),
DMAP (1.0 mmol), DMSO (2.0 mL), rt, 18 h, under air; K2CO3 (4.0 mmol),
90 °C, 3 h; 2 M HCl aq. (2 mL) then 2 M NaOH (3 mL), Boc2O (8.0 mmol),
rt, 16 h.
a Reaction Conditions: 1 (2.0 mmol), CDI (3.0 mmol), NH2OTMS (4.0 mmol),
DMAP (1.0 mmol), DMSO (2.0 mL), rt, 18 h, under argon; K2CO3 (4.0
mmol), 90 °C, 3 h.
In conclusion, we have demonstrated a one-pot synthesis of
primary amines from carboxylic acids through the Lossen
rearrangement of hydroxamic acid derivatives, which were in situ
generated by the reaction of carboxylic acids with NH2OTMS
and CDI (1.5 equiv) in DMSO at room temperature, without
using an external activating agent. This one-pot method could be
applied to various carboxylic acids such as aromatic,
heteroaromatic, aliphatic, and optically active substrates. The
present method provides a facile and promising route to primary
amines from carboxylic acids in one pot.
We focused on the application of this one-pot synthetic
method to optically active carboxylic acids as substrates.
Previous studies have shown that the Lossen rearrangement
proceeds in a stereospecific manner with the retention of
configuration of the migrating group.16 (S)-6-Methoxy--methyl-
2-naphthaleneacetic acid was subjected to the present one-pot
conditions to afford a moderate yield of the desired Cbz-
protected amine,17 which was further transformed to the amine
hydrogen chloride 4 in order to confirm the optical purity.
Unfortunately, a lower value of the specific rotation was
observed compared with the literature one. This decrease in
optical purity may be attributed to racemization in the formation
of acyl imidazole from carboxylic acid.18
Acknowledgments
We gratefully acknowledge General Sekiyu Research &
Development Encouragement & Assistance Foundation for
financial support. We would like to thank Enago (www.enago.jp)
for the English language review.
Although the mechanism of the present reaction was not
studied, a plausible proposal could include the generation of
intermediates O-trimethylsilyl hydroxamates by reaction between
NH2OTMS and N-acylimidazoles, which were derived from
carboxylic acids and CDI, followed by production of a small
amount of O-acyl hydroxamates by dimerization of
hydroxamates in the presence of a base. O-Acyl hydroxamates
thus formed would be subject to rearrangement under thermal
conditions, affording intermediate isocyanates, which induce the
self-propagative Lossen rearrangement.
Supplementary Data
Supplementary data
(experimental procedures
and
characterization data for 2a–k, 3a–c,e,g–j, and 4) associated with
this article can be found, in the online version, at
http://dx.doi.org/xxxxx.
Notes and references
1.
(a) Pereira, M. M. A.; Santos, P. P. In The Chemistry of
Hydroxylamines, Oximes and Hydroxamic Acids; Rappoport, Z.,
Liebman, J. F., Eds.; John Wiley & Sons Ltd: Chichester, 2009;
pp. 480–498; (b) Lossen, W. Liebigs Ann. Chem. 1872, 161, 347;
(c) Bauer, L.; Exner, O. Angew. Chem. Int. Ed. Engl. 1974, 13,
376; (d) Yale, H. L. Chem. Rev. 1943, 33, 209; (e) Shioiri, T. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.;
Pergamon Press: Oxford, 1991; Vol. 6, pp. 795–828; (f) Sandler, S.

4
Tetrahedron
R.; Karo, W. Organic Functional Group Preparations, 2nd ed.;
18. Chen, L.; Dovalsantos, E.; Yu, J.; Lee, S.; O’Neill-Slawecki, S.;
Mitchell, M.; Sakata, S.; Borer, B. Org. Process Res. Develop.
2006, 10, 838.
Academic Press: New York, 1983; Vol. 1, pp. 378–433.
For recent publication regarding the Lossen rearrangement, see:
(a) Yadav, A. K.; Srivastava, V. P.; Yadav, L. D. S. RSC Adv.
2014, 4, 24498; (b) Kreye, O.; Wald, S.; Meier, M. A. R. Adv.
Synth. Catal. 2013, 355, 81; (c) Yoganathan, S.; Miller, S. J. Org.
Lett. 2013, 15, 602; (d) Sulzer-Mosse, S.; Cederbaum, F.;
Lamberth, C.; Berthon, G.; Umarye, J.; Grasso, V.; Schlereth, A.;
Blum, M.; Waldmeier, R. Bioorg. Med. Chem. 2015, 23, 2129; (e)
Yadav, D. K.; Yadav, A. K.; Srivastava, V. P.; Watal, G. W.;
Yadav, L. D. S. Tetrahedron Lett. 2012, 53, 2890; (f) Hamon, F.;
Prié, G.; Lecornué, F.; Papot, S. Tetrahedron Lett. 2009, 50, 6800.
Snyder, H. R.; Elston, C. T.; Kellom, D. B. J. Am. Chem. Soc.
1953, 75, 2014.
2.
3.
4.
5.
Bachman, G. B.; Goldmacher, J. E. J. Org. Chem. 1964, 29, 2576.
Anilkumar, R.; Chandrasekhar, S.; Sridhar, M. Tetrahedron Lett.
2000, 41, 5291.
6.
Recently, two research groups reported the one-pot synthesis of
ureas, which are hardly hydrolyzed to the corresponding amines,
from carboxylic acids via Lossen rearrangement. See: (a) Thalluri,
K.; Manne, S. R.; Dev, D.; Mandal, B. J. Org. Chem. 2014, 79,
3765; (b) Dubé, P.; Nathel, N. F. F.; Vetelino, M.; Couturier, M.;
Aboussafy, C. L.; Pichette, S.; Jorgensen, M. L.; Hardink, M. Org.
Lett. 2009, 11, 5622.
7.
(a) Hoshino, Y.; Okuno, M.; Kawamura, E.; Honda, K.; Inoue, S.
Chem. Commun. 2009, 2281; (b) Ohtsuka, N.; Okuno, M.;
Hoshino, Y.; Honda, K. Org. Biomol. Chem. 2016, 14, in press;
(c) Hoshino, Y.; Shinbo, Y.; Ohtsuka, N.; Honda, K. Tetrahedron
Lett. 2015, 56, 710.
8.
9.
The synthesis of hydroxamic acids from esters and hydroxylamine
hydrochloride under basic conditions is well known, for instance:
Hauser, C. R.; Renfrow, Jr., W. B. Org. Synth. 1943, Coll. Vol. 2,
336.
(a) Williams, A.; Jencks, W. P. J. Chem. Soc. Perkin Trans 2 1974,
1760; (b) Castro, E. A.; Moodie, R. B.; Sansom, P. J. J. Chem. Soc.
Perkin Trans. 2 1985, 737.
10. (a) Bottaro J. C.; Bedford C. D.; Dodge, A. Syn. Commun. 1985,
15, 1333; (b) West, R.; Boudjouk, P. J. Am. Chem. Soc. 1973, 95,
3987.
11. See Supporting Information.
12. General Procedure for the one-pot synthesis of primary amines
from carboxylic acids through rearrangement of in situ generated
hydroxamic acid derivatives: CDI (0.486 g, 3.0 mmol) was added
to a solution of p-toluic acid (0.272 g, 2.0 mmol) in dry DMSO (2
mL), then stirring for 1h. DMAP (0.122 g, 1.0 mmol) and
NH2OTMS (0.420 g, 4.0 mmol) were added to the reaction
mixture and stirred at room temperature for 18 h. K2CO3 (0.552 g,
4.0 mmol) was added and the resulting mixture was heated to 90
°C. After stirring at that temperature for 3 h, the reaction mixture
was cooled to 0 °C and then was treated with 2 M HCl (ca. 2 mL).
After the mixture became the clear solution, 2 M NaOH (ca. 3
mL) was added and extracted with CH2Cl2 (15 mL x 3). The
combined organic layer was dried over anhydrous Na2SO4, filtered
and evaporated under reduced pressure. The residue was purified
by silica gel column chromatography (hexane/Et2O, 1:1) to yield
p-toluidine (2a) (0.180 g, 79%) as a yellow crystalline solid. IR
(KBr)  3418, 3337, 3222, 3010, 2914, 2859, 1622, 1514, 1280,
1268, 810, 508 cm-1; 1H NMR (400 MHz, CDCl3)  2.24 (s, 3H),
3.51 (s, 2H), 6.60 (d, J = 7.8 Hz, 2H), 6.96 (d, J = 7.8 Hz, 2H).
13. (a) Bright, R. D.; Hauser, C. R. J. Am. Chem. Soc. 1939, 61, 618;
(b) Berndt, D. C.; Shechter, H. J. Org. Chem. 1964, 29, 916.
14. Usachova, N.; Leitis, G.; Jirgensons, A.; Kalvinsh, I. Synth.
Commun. 2010, 40, 927.
15. (a) Yin, J.; Xiang, B.; Huffman, M. A.; Raab, C. E.; Davies, I. W.
J. Org. Chem. 2007, 72, 4554; (b) Tomioka, T.; Takahashi, Y.;
Maejima, T. Org. Biomol. Chem. 2012, 10, 5113; (c) Cinelli, M.
A.; Li, H.; Chreifi, G.; Martásek, P.; Roman, L. J.; Poulos, T. L.;
Silverman, R. B. J. Med. Chem. 2014, 57, 1513; (d) Leffler, M. T.
Org. React. 1942, 1, 91.
16. (a) Campbell, A.; Kenyon, J. J. Chem. Soc. 1946, 25; (b) Wallis,
E. S.; Dripps, R. D. J. Am. Chem. Soc. 1933, 55, 1701; (c) Hamon,
F.; Prié, G.; Lecornué, F.; Papot, S. Tetrahedron Lett. 2009, 50,
6800; (d) Stafford, S. A.; Gonzales, S. S.; Barrett, D. G.; Suh, E.
M.; Feldman, P. L. J. Org. Chem. 1998, 63, 10040.
17. Optically active naproxen amine (1-(6-methoxynaphth-2-
yl)ethylamine), which has stronger fluorescence, was examined as
a chiral derivatizing agent for the liquid chromatographic
fluorescence assay of chiral carboxylic acids, see: Spahn, H.;
Langguth, P. Pharm. Res. 1990, 7, 1262.

*Highlights
Highlights
·A one-pot synthesis of amines from carboxylic acids via Lossen reaction is achieved.
·Lossen reaction was achieved by in situ generated hydroxamic acid derivatives.
·Hydroxamic acids were generated from acids with NH2OTMS and CDI in DMSO.
·(Hetero)aromatic, aliphatic, and optically active acids can be used as substrates.