Oxidative Rearrangement of Primary Amines Using PhI(OAc)2 and Cs2CO3

Article abstract of DOI:10.1021/acs.orglett.9b00559

An oxidative rearrangement of primary amines mediated by a hypervalent iodine(III) reagent is herein reported. The combination of PhI(OAc)₂ and Cs₂CO₃ proves highly efficient at inducing the direct 1,2-C to N migration of primary amines, which can be applied to the preparation of both acyclic and cyclic amines. A mechanistic study shows that the rearrangement proceeds via a concerted mechanism.

Full text of DOI:10.1021/acs.orglett.9b00559

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Oxidative Rearrangement of Primary Amines Using PhI(OAc)2 and
Cs2CO3
Wataru Yamakoshi, Mitsuhiro Arisawa, and Kenichi Murai*
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
S
* Supporting Information
ABSTRACT: An oxidative rearrangement of primary amines mediated by a hypervalent iodine(III) reagent is herein reported.
The combination of PhI(OAc)2 and Cs2CO3 proves highly efficient at inducing the direct 1,2-C to N migration of primary
amines, which can be applied to the preparation of both acyclic and cyclic amines. A mechanistic study shows that the
rearrangement proceeds via a concerted mechanism.
Scheme 1. Rearrangement Reaction with Hypervalent
Iodine Reagent
mong the transformations of nitrogen-containing com-
Apounds, processes involving 1,2-C to N migration are
useful tools for organic synthesis because they fundamentally
alter the molecular skeletons.1 For example, the Hofmann,
Schmidt, Beckmann, Curtius, and Stieglitz rearrangements are
all well-known reactions whose utility has been proved by their
application to the synthesis of various molecules.2 Considering
the usefulness of these transformations, the development of
new methods for 1,2-C to N migration is still an important
source of new options in organic synthesis. Recently,
hypervalent iodine(III) reagents3 have proven useful for
various oxidative rearrangements because of their electro-
philicity and ability to act as leaving groups as well as their
environmentally friendly behavior.4−6 In regard to 1,2-C to N
migration, the reaction of amides with hypervalent iodine(III)
reagents, that is, Hofmann rearrangement, is established as an
important synthetic tool for converting amides into the
corresponding amines and their derivatives (Scheme 1a).7
Catalytic versions of hypervalent iodine(III) reagent-induced
Hofmann rearrangements have also been developed in the past
decade.8 However, until recently the applications of these
reagents in 1,2-C to N migration have been limited to amides,
and the analogous rearrangements employing other nitrogen-
containing functional groups have not been well explored.
Recently, Beckmann rearrangement of a ketoxime using
PhI(OAc)2 combined with BF3·Et2O was reported by
Maegawa and Miki.9 Alternatively, we have recently reported
the 1,2-C to N migration of secondary amines (Stieglitz
rearrangement) (Scheme 1b).10 By using PhI(OAc)2 in
CF3CH2OH, the oxidative rearrangements directly proceeded
with a range of amine compounds. Compared with the classic
Stieglitz rearrangement, which employs azides, hydroxylamine
derivatives, and N-chloroamines,2,11 this method could provide
a more straightforward synthetic strategy in which amines can
be used directly as substrates.
During our ongoing study of the hypervalent iodine(III)
reagent-mediated oxidative rearrangement of amines, we
Received: February 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
noticed that secondary and primary amines showed a quite
different reactivity: Although tritylamine was applicable in our
previously reported reaction, the conditions used for secondary
amines were not very effective for rearrangement of other
primary amines (Table 1, entry 1). Taking note of this, we then
CF3CH2OH, EtOH, CH3CN, and CH2Cl2 (entries 2−6).
Furthermore, a survey of various base additives revealed that
the use of Cs2CO3 gave a superior result (entry 8). The
efficiency observed with Cs2CO3 can probably be attributed to
its complete solubility in MeOH, in contrast to the partial
solubility of K2CO3 and Na2CO3. The use of organic bases
such as pyridine or triethylamine decreased the yield (entries
9,10). Regarding the amount of Cs2CO3, 2.6 equiv relative to
the substrate was needed to obtain good results (entry 12).
Therefore, the optimal reaction conditions found for the
rearrangement of primary amines involved treatment with
PhI(OAc)2 (1.3 equiv) in MeOH in the presence of Cs2CO3
(2.6 equiv).15
a
Table 1. Study of Reaction Conditions
b
entry
solvent
additive (equiv)
yield (%)
With the optimized conditions established, we proceeded to
investigate the scope of the reaction (Table 2). As shown in
c
1
2
3
4
5
6
7
8
9
10
11
12
CF3CH2OH
CF3CH2OH
MeOH
none
33
41
69
61
35
N.D.
74
82
trace
20
79
90
65
c
K2CO3 (5.2)
K2CO3 (5.2)
K2CO3 (5.2)
K2CO3 (5.2)
K2CO3 (5.2)
Na2CO3 (5.2)
Cs2CO3 (5.2)
pyridine (5.2)
Et3N (5.2)
a
d
Table 2. Generality of Rearrangement Reaction
d
EtOH
d
CH3CN
CH2Cl2
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
d
e
d
d
d
d
d
Cs2CO3 (3.9)
Cs2CO3 (2.6)
Cs2CO3 (1.3)
d
d
13
a
Reaction conditions: PhI(OAc)2 (1.3 equiv) and additive in solvent
(0.05 M) at 0 °C to rt then NaCNBH3 or NaBH4 (5.0 equiv) at 0 °C
b
c
d
to rt. Isolated yield. Reductant: NaCNBH3 Reductant: NaBH4.
e
Not detected on TLC.
re-investigated the reaction of primary amines.12 Herein, we
report our recent success in finding that the combined use of
PhI(OAc)2 with Cs2CO3 efficiently induces the rearrangement
of primary amines (Scheme 1c). Because of the easy handling
and environmentally benign nature of hypervalent iodine
reagents, the method is more practical than the previously
reported 4-nitrobenzenesulfonyl peroxide- or Pb(OAc)4-
mediated Stiegliz rearrangements, which also use amines
directly.13
We began our study on the rearrangement of primary
amines using 1-phenylcyclohexylamine (1a) as a model
substrate (Table 1). As described above, the use of PhI(OAc)2
in CF3CH2OH was not effective for 1a and only afforded 33%
yield of corresponding amine 2a (entry 1). Varying the
reaction conditions by using different solvents, such as MeOH,
CH3CN, CH2Cl2, and DMF as well as hypervalent iodine
reagents such as 4-FC6H4(OAc)2, 4-NO2C6H4(OAc)2, PhI-
(OCOCF3)2, Koser’s reagents,14 and 1-acetoxy-1,2-benziodox-
ol-3-(1H)-one, failed to improve the efficiency of the reaction
(for details see Supporting Information (SI)). However, we
found that the yield was slightly improved by adding K2CO3
(entry 2). Moreover, the use of K2CO3 in MeOH greatly
improved the yield (69%, entry 3). It should be noted that in
this work, the products were typically obtained as the amine
form via a one-pot reduction of the imine generated by
rearrangement reaction with NaCNBH3 or NaBH4 (for details
see footnote of Table 1). Encouraged by these results, we
further investigated the effects of base and solvent used for the
reaction. A survey of several solvents revealed that, when
adding a base, MeOH was a better solvent choice than
a
Reaction conditions: 1 (0.15−0.2 mmol), PhI(OAc)2 (1.3 equiv),
and Cs2CO3 (2.6 equiv) in MeOH (0.05 M) at 0 °C to rt (12 h) then
b
c
NaBH4 (5.0 equiv) at 0 °C to rt (1−7 h, see SI). Isolated yield. 1.0
d
mmol of 1f was used. Reaction time for rearrangement: 24 h.
B
DOI: 10.1021/acs.orglett.9b00559
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Table 2, several electronically different 1-arylcyclohexylamines
underwent the rearrangement efficiently, including those
bearing 4-MeC6H4, 4-ClC6H4, and 4-MeOC6H4 (entries 2−
4).16 It should be noted that despite the risk of electron-rich
aromatic groups such as methoxybenzene being oxidized by
hypervalent iodine reagents, compound 1d successfully
proceeded in the reaction. Cyclopentylamine 1e and cyclo-
heptylamine 1f also gave phenyl group-migrated products 2e
and 2f ,respectively, while cyclobutylamine 1g gave ring-
expanded pyrrolidine 2g, probably because of the ring strain of
the cyclobutane ring (entries 5−7). Acyclic compounds were
tolerant, and compound 2h was obtained selectively from 1,1-
diphenylethylamine (1h) (entry 8).17 Finally, we applied the
method to the synthesis of cyclic amines via a ring expansion
reaction. By using tetraline 1i as a substrate, benzoazepine 2i
was obtained in good yield (entry 9). The method was also
well applicable to the substrates 1j and 1k with a chloro or a
methoxy group on the benzene ring (entries 10 and 11). The
substrates 1l and 1m having an electron-withdrawing group
such as an ester or a trifluoromethyl group also gave the
corresponding benzoazepine 2l and 2m (entries 12 and 13).18
Furthermore, eight-membered ring benzoazocine 2n was
obtained in high yield from benzosuberan 1n (entry 14).
The reaction mechanism was then studied. We first
conducted the reaction of the secondary amine 3 to investigate
the reactivity difference between primary and secondary
amines (Scheme 2, (i). The secondary amine 3 was found
Cs2CO3 was also excluded. Lastly, a series of reactions using
monosubstituted tritylamines 4a−e were conducted to
investigate the migratory aptitude (M.A.) of the rearrangement
(Table 3).20 We reacted 4 under the rearrangement conditions,
Table 3. Study on Migratory Aptitude of Substituted Phenyl
a
Groups Using Monosubstituted Tritylamines
b
entry
Ar
Ph (4a)
4-MeOC6H4 (4b)
4-MeC6H4 (4c)
4-FC6H4 (4d)
combined yield (%) (7 + 8)
M.A.
1
2
3
4
5
82
80
91
96
92
1
>100
8.2
1.36
0.72
4-ClC6H4 (4e)
a
Reaction conditions: reagent (1.3 equiv) in solvent (0.05 M) at 0 °C
b
to rt then NaCNBH3 (5.0 equiv) at 0 °C to rt. M.A. (migratory
aptitude) = 2(% benzophenone (7))/% substituted benzophenone 8
c
Conditions for hydrolysis: HCl aq., DMSO.
Scheme 2. Control Experiments
producing a crude mixture of 5 and 6, then subjected this
mixture to acid hydrolysis and analyzed the ratio of
benzophenone 7 and substituted benzophenone 8 in the
product. This approach was chosen as the product ratio was
easier to analyze than that of the rearrangement itself. The
migratory aptitudes of the substituted phenyl groups (labeled
Ar in Table 3), relative to a migratory aptitude of 1 for the
phenyl group, were calculated by the following formula: M.A. =
2(% benzophenone (7))/% substituted benzophenone 8. As
shown in Table 3, the migratory aptitudes obtained were as
follows: 4-MeOC6H4, >100; 4-MeC6H4, 8.2; 4-FC6H4, 1.36; 4-
ClC6H4, 0.72, showing a strong effect of the electron-rich/-
deficient nature of the substituted phenyl groups. This
tendency is similar to the common trend observed in the
related rearrangements such as Pinacol rearrangement.1 These
results argued against either a free radical mechanism or a
nitrene mechanism.13b
not to undergo rearrangement under the standard conditions
using PhI(OAc)2 and Cs2CO3 in MeOH, suggesting that a
primary amine structure was essential for the rearrangement.
The reactions were also conducted in the presence of radical
scavengers, because in our previous report on the oxidative
rearrangement of secondary amines with PhI(OAc)2 and
CF3CH2OH, we observed that the reaction proceeded via a
radical mechanism. We therefore explored the effect of adding
9,10-dihydroanthracene and galvinoxyl to the reaction of 1a. In
each case, the rearrangement proceeded without significant
decrease in efficiency, and the desired products were obtained
in good yields (Scheme 2, (ii)). From these results, a radical
mechanism could be excluded. We also studied the reaction of
compound 1a treated with only Cs2CO3 in MeOH, because
solely base-induced rearrangement of tritylamines to imines
has been reported by Theodorou.19 However, in our case, the
rearrangement did not proceed at all. Therefore, the possibility
that the rearrangement could have been mediated solely by
On the basis of these observations, a possible pathway for
the rearrangement is proposed in Scheme 3. Initially, the
reaction of amine 1 with PhI(OAc)2 gave intermediate i.
Under basic reaction conditions using Cs2CO3, the N−H of i
was deprotonated to form anion ii. Since the generation of
imino iodanes (PhI = NR) from sulfonamides under basic
conditions is known,21 an analogous imino iodane might be
possible as an alternative intermediate for the current structure
of intermediate ii. The intermediate ii then underwent
rearrangement in a concerted manner to give imine iii. Finally,
reduction of iii by NaBH4 afforded amine 2. In other words,
we can say that the hypervalent iodine(III) reagent-mediated
rearrangement is an analogue of the reaction using N-
haloamines and strong bases,2 but allows the use of primary
amines directly without prefunctionalization and proceeds
under mild conditions near room temperature.
In summary, we have presented the hypervalent iodine-
mediated oxidative rearrangement reaction of primary amines.
C
DOI: 10.1021/acs.orglett.9b00559
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Group (www.edanzediting.com/ac) for editing a draft of this
manuscript.
Scheme 3. Possible Reaction Mechanism
REFERENCES
■
(1) Molecular Rearrangements in Organic Synthesis; Rojas, C. M., Ed.;
John Wiley & Sons, Inc: Hoboken, NJ, 2015.
(2) Wang, Z. Comprehensive Organic Name Reactions and Reagents;
John Wiley & Sons, Inc: Hoboken, NJ, 2010.
(3) (a) Hypervalent Iodine Chemistry (Topics in Current Chemistry;
Wirth, T., Ed.; Springer: Berlin, 2003; Vol. 224. (b) Zhdankin, V. V.
Hypervalent Iodine Chemistry; Wiley: Chichester, 2014. (c) Yoshimura,
A.; Zhdankin, V. V. Advances in Synthetic Applications of
Hypervalent Iodine Compounds. Chem. Rev. 2016, 116, 3328.
(4) For a review, see: Singh, F. V.; Wirth, T. Oxidative
Rearrangements with Hypervalent Iodine Reagents. Synthesis 2013,
45, 2499.
(5) For recent examples, see: (a) Ahmad, A.; Scarassati, P.; Jalalian,
N.; Olofsson, B.; Silva, L. F. Oxidative rearrangement of alkenes using
in situ generated hypervalent iodine(III). Tetrahedron Lett. 2013, 54,
5818. (b) Liu, L.; Du, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Metal-
Free Tandem Oxidative Aryl Migration and C−C Bond Cleavage:
Synthesis of α-Ketoamides and Esters from Acrylic Derivatives. Org.
Lett. 2014, 16, 5772. (c) Liu, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
Hypervalent Iodine Mediated C−C Double Bond Activation: A
Cascade Access to α-Keto Diacetates from Readily Available
Cinnamic Acids. Synthesis 2015, 47, 2924. (d) Yadagiri, D.;
Anbarasan, P. An iodine (III) mediated oxidative rearrangement of
enamines: efficient synthesis of α-amino ketones. Chem. Commun.
2015, 51, 14203. (e) Liu, L.; Zhang, T.; Yang, Y.-F.; Zhang-Negrerie,
D.; Zhang, X.; Du, Y.; Wu, Y.-D.; Zhao, K. Metal-Free Synthesis of 3-
Arylquinolin-2-ones from Acrylic Amides via a Highly Regioselective
1,2-Aryl Migration: An Experimental and Computational Study. J.
Org. Chem. 2016, 81, 4058.
(6) 1,2-C to O migration reactions mediated by hypervalent iodine
(III) reagents were recently reported by Wengryniuk, see: (a) Kelley,
B. T.; Walters, J. C.; Wengryniuk, S. E. Access to Diverse Oxygen
Heterocycles via Oxidative Rearrangement of Benzylic Tertiary
Alcohols. Org. Lett. 2016, 18, 1896. (b) Walters, J. C.; Tierno, A.
F.; Dubin, A. H.; Wengryniuk, S. E. Poly)cationic λ3-Iodane-Mediated
Oxidative Ring Expansion of Secondary Alcohols. Eur. J. Org. Chem.
2018, 2018, 1460.
(7) (a) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.;
Blodgett, J. K.; Boutin, R. H. Conversion of aliphatic amides into
amines with [I,I-bis(trifluoroacetoxy)iodo]benzene. 1. Scope of the
reaction. J. Org. Chem. 1984, 49, 4272. (b) Boutin, R. H.; Loudon, G.
M. Conversion of aliphatic amides into amines with [I,I-bis-
(trifluoroacetoxy)iodo]benzene. 2. Kinetics and mechanism. J. Org.
Chem. 1984, 49, 4277.
(8) (a) Miyamoto, K.; Sakai, Y.; Goda, S.; Ochiai, M. A catalytic
version of hypervalent aryl-λ3-iodane-induced Hofmann rearrange-
ment of primary carboxamides: iodobenzene as an organocatalyst and
m-chloroperbenzoic acid as a terminal oxidant. Chem. Commun. 2012,
48, 982. (b) Yoshimura, A.; Middleton, K. R.; Luedtke, M. W.; Zhu,
C.; Zhdankin, V. V. Hypervalent Iodine Catalyzed Hofmann
Rearrangement of Carboxamides Using Oxone as Terminal Oxidant.
J. Org. Chem. 2012, 77, 11399.
Different from the reaction of secondary amines, the combined
usage of PhI(OAc)2 and Cs2CO3 is revealed to be the key for
the reaction of primary amines. The method can be applied to
the preparation of both acyclic and cyclic amines including an
eight-membered ring compound. Several mechanistic inves-
tigations show that the reaction likely proceeded via a
concerted mechanism rather than a radical or a nitrene
mechanism. This method is practical and can be easily carried
out using commercially available hypervalent iodine reagents.
Further investigation of these transformations is underway in
our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00559.
Full experimental details and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: murai@phs.osaka-u.ac.jp.
ORCID
Mitsuhiro Arisawa: 0000-0002-7937-670X
Kenichi Murai: 0000-0002-1689-6492
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by a Grant-in-Aid for
Scientific Research (C) (T17K082100) from JSPS, from
Platform Project for Supporting Drug Discovery and Life
Science Research (Basis for Supporting Innovative Drug
Discovery and Life Science Research (BINDS)), AMED
under grant number JP18am0101084, and from “Dynamic
Alliance for Open Innovation Bridging Human, Environment
and Materials” from the Ministry of Education, Culture, Sports,
Science, and Technology of Japan under grant number
17am0101084j0001. K.M. acknowledges the research fund
from the Society of Iodine Science (SIS). We thank Mr.
Ahmed A. B. Mohamed and Mr. Ramon Francisco Bernardino
Avena (Osaka University) for their assistance of a draft of this
manuscript. We also thank Leo Holroyd, PhD, from Edanz
(9) Oishi, R.; Segi, K.; Hamamoto, H.; Nakamura, A.; Maegawa, T.;
Miki, Y. Hypervalent Iodine-Mediated Beckmann Rearrangement of
Ketoximes. Synlett 2018, 29, 1465.
(10) Murai, K.; Kobayashi, T.; Miyoshi, M.; Fujioka, H. Oxidative
Rearrangement of Secondary Amines Using Hypervalent Iodine(III)
Reagent. Org. Lett. 2018, 20, 2333.
(11) For selected examples, see: (a) Gassman, P. G.; Fox, B. L. Alkyl
Migration to Electron-Deficient Nitrogen. J. Am. Chem. Soc. 1967, 89,
338. (b) Schell, F. M.; Ganguly, R. N. Silver ion induced
rearrangement of N-chloramines. Isolation of an ionic product in
high yield. J. Org. Chem. 1980, 45, 4069 and references therein .
Synthetic application, see: (c) Grieco, P. A.; Dai, Y. Carbocyclic Ring
Construction via an Intramolecular Diels-Alder Reaction of an in Situ-
D
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Generated, Heteroatom-Stabilized Allyl Cation: Total Synthesis of
( )-Lycopodine. J. Am. Chem. Soc. 1998, 120, 5128.
(12) 1-Arylcyclobutan-1-amines were only reported substrates for
PhI(OCOCF3)2-mediated rearrangement; see: Huang, H.; Yang, Q.;
Zhang, Q.; Wu, J.; Liu, Y.; Song, C.; Chang, J. A Hofmann
Rearrangement−Ring Expansion Cascade for the Synthesis of 1-
Pyrrolines: Application to the Synthesis of 2,3-Dihydro-1H-pyrrolo-
[2,1-a]isoquinolinium Salts. Adv. Synth. Catal. 2016, 358, 1130.
(13) Direct usage of amines in Stiegliz rearrangement were only
reported with p-nitrobenzenesulfonyl peroxide or Pb(OAc)4. For the
reaction of p-nitrobenzenesulfonyl peroxide, see: (a) Hoffman, R. V.;
Poelker, D. J. Oxidation of amines with sulfonyl peroxides. 4. The
Stieglitz rearrangement of tritylamines, benzhydrylamines, and
benzylamines induced by p-nitrobenzenesulfonyl peroxide. J. Org.
Chem. 1979, 44, 2364. For the reaction of Pb(OAc)4, see: (b) Sisti,
A. J.; Milstein, S. R. Stieglitz rearrangement with lead tetraacetate and
triarylmethylamines. J. Org. Chem. 1974, 39, 3932.
(14) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. [Hydroxy-
(organosulfonyloxy)iodo]arenes in Organic Synthesis. Synlett 1990,
1990, 365.
(15) The reactions of 1a using Koser’s reagents or iodosobenzen in
the presence of Cs2CO3 were also examined. However, decrease of
the yield were observed: with Koser’s reagents, 58%; with
iodosobenzen, 31% (details see, SI).
(16) A substrate having 2-thiophene as an aryl group gave complex
mixtures.
(17) We tried the reactions of trialkyl methyl amines, such as 1,1-
dibenzylethylamine and 1-adamantylamine, but the method was not
applicable for these substrates.
(18) The remaining of starting material was observed with 1l and
1m.
(19) (a) Theodorou, V.; Skobridis, K.; Karkatsoulis, A. Base-induced
rearrangement of tritylamines to imines: discovery and investigation
of the mechanism. Tetrahedron 2007, 63, 4284. (b) Theodorou, V.;
Skobridis, K. An unexpected base-induced rearrangement of trityl-
amine. Tetrahedron Lett. 2005, 46, 5021.
(20) (a) Saunders, W. H.; Caress, W. A. A Comparison of Thermal
and Photochemical Rearrangements of Triarylmethyl and Related
Azides. J. Am. Chem. Soc. 1964, 86, 861. (b) Newman, M. S.; Hay, P.
M. Migration Aptitudes in Stieglitz Rearrangement. J. Am. Chem. Soc.
1953, 75, 2322. Also see refs 13a and b.
(21) Dauban, P.; Dodd, R. H. Iminoiodanes and C−N Bond
Formation in Organic Synthesis. Synlett 2003, 11, 1571.
E
DOI: 10.1021/acs.orglett.9b00559
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