Full text of DOI:10.1021/acs.orglett.8b00675

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
Oxidative Rearrangement of Secondary Amines Using Hypervalent
Iodine(III) Reagent
Kenichi Murai,* Tetsuya Kobayashi, Makoto Miyoshi, and Hiromichi Fujioka
Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka 565-0871, Japan
*
S Supporting Information
ABSTRACT: A hypervalent iodine(III) reagent mediated
oxidative skeletal rearrangement reaction of secondary amines
is reported. The transformation, which uses PhI(OAc) in
2
CF CH OH, was found to be highly efficient at inducing the
3
2
direct 1,2-C-to-N migration of secondary amines. This method
offers facile and divergent access to polycyclic and macrocyclic
indole-fused compounds. The synthetic potential of the
method is also demonstrated through its application to several
substrates, including secondary as well as primary amines.
ue to the significance of 1,2-rearrangement reactions in
Scheme 1. 1,2-C-to-N Rearrangements
1
D
organic chemistry, the development of new method-
ologies remains an important challenge. Recently, hypervalent
iodine reagents have been employed in various oxidative
2
rearrangement reactions, owing to their electrophilic proper-
3
ties and leaving group capabilities. C-to-C and C-to-N (amide
nitrogen) migration reactions are particularly common. For C-
to-C migrations, various alkenes have been employed for 1,2-
4
,5
aryl group migrations, ring expansions, and ring contractions.
For C-to-N (amide nitrogen) migrations, the Hofmann
rearrangement is an important synthetic approach for
converting amides into the corresponding amines and their
6
derivatives. In contrast to these established transformations,
migration reactions to heteroatoms other than the amide
nitrogen have been under-explored. Among these reactions, a
C-to-O migration using hypervalent iodine reagents was only
reported for the first time by Wengryniuk in 2016, who
demonstrated the facile synthesis of medium-sized cyclic ethers
by the oxidative rearrangement of benzylic tertiary alcohols
7
using a poly(cationic) hypervalent iodine reagent. However, to
our knowledge, C-to-N migration using amines has yet to be
reported.
We envisioned that the treatment of secondary amines with a
hypervalent iodine(III) reagent could result in in situ
generation of a N−I (III) active species (Scheme 1, (i)) that
could undergo 1,2-C-to-N migration. The incipient iminium
intermediate could be trapped by the appropriate nucleophiles
to afford tertiary amines with significantly different skeletons
compared to the starting materials. The 1,2-rearrangement
reactions of nitrogen atoms bearing leaving groups, such as
azides, hydroxylamine derivatives, and N-chloroamines, are
1
0
chloroamines. In contrast, the direct use of secondary amines
as substrates in 1,2-C-to-N migration reactions has been much
11,12
less explored,
despite the potential of these transformations
in offering an efficient and straightforward strategy for the
synthesis of saturated nitrogen heterocycles, which are
ubiquitous structural motifs in bioactive molecules, including
alkaloid natural products and pharmaceuticals.
8
−10
well-known transformations (Scheme 1, (ii).
In these
transformations, the use of azides or the prior introduction of
leaving groups on the nitrogen atoms is necessary.
Furthermore, a stoichiometric amount of a silver salt is
generally required to induce rearrangement reactions of N-
Received: February 26, 2018
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00675
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Herein, we describe the oxidative skeletal rearrangement of
secondary amines mediated by hypervalent iodine reagents. We
found that the reaction system, which utilizes phenyliodine(III)
diacetate (PhI(OAc) ) in CF CH OH, enables the direct 1,2-
the conditions shown in entry 1 have been identified as
optimal.
With the optimized conditions in hand, the substrate scope
of this transformation was explored (Table 2). The effect of
17
2
3
2
C-to-N migration of secondary amines. This metal-free method
provides facile and divergent access to polycyclic or macrocyclic
indole-fused compounds via a one-pot transformation. The use
of different types of secondary, as well as primary amines
demonstrate the versatility of this method for the synthesis of a
wide range of amine compounds. A radical pathway is
suggested to be involved in these transformations based on
mechanistic investigation using radical scavengers.
a
Table 2. Generality of Rearrangement Reaction
13
The rearrangement reaction of spiro-indole compound 1a
was initially investigated because of the biologically importance
14
of indole-fused compounds and our continued interest in
12c
heterocycle synthesis
(Table 1). After optimizing various
a
Table 1. Study of Reaction Conditions
entry
reagent
PIDA
solvent
yield (%)
1
2
3
4
5
6
7
CF CH OH
89
31
7
3
2
PhIO
PhI(OH)OTs
PIFA
CF CH OH
3 2
CF CH OH
3
2
CF CH OH
54
3
2
b
NIS
CF CH OH
ND
3
2
b
IBX
CF CH OH
ND
3
2
PIDA
MeOH
12
c
b
8
PIDA
CH CN
ND
3
9
PIDA
(CF ) CHOH
12
3
2
a
Reaction conditions: reagent (1.3 equiv) in solvent (0.05 M) at 0 °C
b
to rt then NaCNBH (5.0 equiv) at 0 °C to rt. Not detected on TLC.
3
c
Reaction conditions: reagent (1.3 equiv) in solvent (0.05 M) at 0 °C
to rt; evaporation; NaBH (5.0 equiv) in MeOH at 0 °C to rt.
4
a
reaction conditions, we found that 1,2-C-to-N migration
occurred smoothly using hypervalent iodine reagents, such as
PhI(OAc) in CF CH OH, and that subsequent treatment with
Reaction conditions: PIDA (1.3 equiv) in CF
CH OH (0.05 M) at 0
3 2
°C to rt then NaCNBH
(5.0 equiv) at 0 °C to rt.
3
2
3
2
NaCNBH led to the formation of rearranged product 2a in
ring size on the rearrangement was first investigated.
Compounds 1b−d bearing cyclohexane, cycloheptane, and
cyclododecane rings, respectively, gave the corresponding 7-, 8-,
and 13-membered fused ring products (2b−d), respectively, in
good yields. Pleasingly, substrate 1b bearing a cyclohexane ring,
which has the smallest ring strain among cycloalkanes,
smoothly underwent rearrangement, showing the efficiency of
PhI(OAc)2 as an activator of an oxidative rearrangement
reaction of amines. Substrates 1e and 1f bearing methyl and
chloride substituents at the indole 5-position, respectively, were
well tolerated under the reaction conditions. Furthermore, 1,4-
oxazepine-fused compound 2g was obtained from substrate 1g.
Benzo-fused substrates 1h and 1i also gave satisfactory results.
Notably, aromatic-ring-migration product 2i was selectively
obtained from substrate 1i. The observed migratory tendency
(aryl group over alkyl group) was consistent with that observed
in the standard rearrangement reactions. To our knowledge,
these results are the first examples of the 1,2-C-to-N migration
of secondary amines using hypervalent iodine reagents.
3
high yield (89%, entry 1). NaCNBH showed better efficiency
3
as a reductant in CF CH OH, compared to NaBH and
3
2
4
NaBH(OAc) (see the Supporting Information (SI)). Interest-
3
ingly, possible side reactions, such as imine formation via
secondary amine oxidation, were not observed under these
conditions. Examination of other commercially available
iodine(III) reagents showed that PhI(OAc) was optimal for
2
18
this transformation, while iodosobenzene and Koser’s reagent,
15
hydroxy(tosyloxy)iodobenzene, gave decreased yields (entries
and 3). Interestingly, phenyliodine bis(trifluoroacetate)
PIFA) also showed lower efficiency (entry 4). The lower
2
(
conversion was probably due to the strong acidity of
trifluoroacetic acid generated in situ, which likely inhibits the
reaction between the amine and iodine reagent. N-Iodosucci-
nimide (NIS) or o-iodoxybenzoic acid (IBX) also failed to
promote the rearrangement reaction (entries 5 and 6).
Furthermore, the effect of solvent proved to be crucial in
these transformations. In contrast to CF CH OH, very poor
3
2
results were obtained when reactions were conducted in
Although mechanistic details remain unclear, the following
features are noteworthy. First, to confirm generation of an
16
MeOH, CH CN, or (CF ) CHOH (entries 7−9). As a result,
3
3 2
B
DOI: 10.1021/acs.orglett.8b00675
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
iminium ion intermediate, we obtained H and 13C NMR
1
The development of new methods for the synthesis of
macrocyclic and medium-sized ring compounds is important
because of the significant increase in interest in the medicinal
spectra (in CDCl ) of the reaction mixture prepared from the
reaction of 1a with PhI(OAc) in CF CH OH after solvent
3
2
3
2
22
removal. The iminium ion was observed in the spectra, while
formation of the N,O-acetal was not (see the SI). Second, we
conducted the reaction of 1a in the presence of various radical
scavengers, including galvinoxyl, TEMPO (2,2,6,6-tetramethyl-
piperidine 1-oxyl), BHT (2,6-di-tert-butyl-p-cresol), 1,1-diphe-
nylethylene, and 9,10-dihydroanthracene (Scheme 2). This
applications of larger ring compounds. After investigating
reaction conditions for transformation of the iminium ion
intermediate, we found that ring-expanded compounds were
obtained via hydrolysis under basic conditions and subsequent
trapping of the generated secondary amine with appropriate
electrophiles in a one-pot operation. As shown in Scheme 3, 13-
membered macrocycles 3a−d bearing various substituents, such
as tosyl, benzyl, benzyloxycarbonyl, and ethoxycarbonyl groups,
respectively, on the secondary amino nitrogen were obtained
from 1a and the corresponding electrophiles. The ketone
functionality of these compounds could be useful as a
functional handle for further derivatization. Synthetically
challenging medium-sized ring compounds 3e and 3f were
also obtained from 1b and 1g, respectively, though in lower
yields, compared to the reaction of 1a. As described above, the
rearrangement reaction of indole 1 provided divergent access to
indole-fused compounds with polycyclic or macrocyclic
structures.
Scheme 2. Reactions with Radical Scavengers
Finally, we conducted several experiments to assess whether
the PhI(OAc) -mediated oxidative rearrangement was compat-
2
ible with different types of substrates (Scheme 4). First, we
resulted in a moderate to significant decrease in the yield of
compound 2a in all cases. It should be noted that in the
1
9
Scheme 4. Reaction of Different Types of Amines
reaction with 9,10-dihydroanthracene we detected the
1
generation of anthracene by H NMR analysis (see the SI).
On the basis of these observations, a radical pathway, such as
the generation of a nitrogen-centered radical, might be involved
20,21
in these transformations.
Having demonstrated the generality of the PhI(OAc)2-
mediated rearrangement reaction for the synthesis of polycyclic
compounds, we turned our attention to its application in the
synthesis of macrocyclic and medium-sized ring compounds by
using an iminium ion as the common intermediate (Scheme 3).
Scheme 3. Synthesis of Macrocyclic and Medium-Sized Ring
Compounds
examined the reaction of non-spiro indole compounds 4a and
4b (Scheme 4, (i). The rearrangement reaction of 4a proceeded
smoothly to give phenyl-migrated product 5a in good yield.
However, a lower yield was observed for diethyl substrate 4b,
showing that further improvement is necessary for substrates
with substituents that have relatively poor migratory aptitude.
Next, the reaction of nonindole substrate 2,2-diphenyl
pyrrolidine (6) was investigated. 1,2-Diphenylpyrrolidine (7)
was obtained in 46% yield via migration of the phenyl group,
a
Reaction conditions, for 3a: TsCl (1.2 equiv), Na CO aq, CH Cl .
2
3
2
2
For 3b: BnBr (1.1 equiv), Na CO aq, CH Cl , reflux. For 3c, CbzCl
2
3
2
2
(
1.2 equiv), Na CO3 aq, toluene, 0 °C to rt. For 3d−f: ethyl
2
chloroformate (4.4 equiv), (iPr) NEt (10 equiv), 1,4-dioxane−H O.
2
2
C
DOI: 10.1021/acs.orglett.8b00675
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
showing the feasibility of this method for the synthesis of aryl-
substituted amines. In addition to secondary amines, primary
amine tritylamine (8) also gave a satisfactory result. Finally, we
examined substrate 10 bearing no indolyl amine or benzyl
amine structure (Scheme 4, (ii). Pleasingly, spiro-compound 10
gave a satisfactory result, affording fused compound 11a
bearing a 1-azabicyclo[5.3.0]decane structure, which is found in
biologically active natural products. Notably, a carbon
nucleophile was successfully introduced into the iminium ion
intermediate by reacting with Grignard reagent EtMgBr to
afford 11b bearing a quaternary-substituted carbon center. The
above results suggest that a broad array of substrates are
compatible with these hypervalent iodine mediated oxidative
rearrangement reactions.
M.; Wo
̈
ste, T. H.; Mun
̃
iz, K. Chem. - Asian J. 2014, 9, 972.
(
d) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328.
4) See ref 2, and for recent examples, see: (a) Ahmad, A.; Scarassati,
P.; Jalalian, N.; Olofsson, B.; Silva, L. F. Tetrahedron Lett. 2013, 54,
818. (b) Liu, L.; Du, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. Org.
(
5
Lett. 2014, 16, 5772. (c) Liu, L.; Zhang-Negrerie, D.; Du, Y.; Zhao, K.
Synthesis 2015, 47, 2924. (d) Yadagiri, D.; Anbarasan, P. Chem.
Commun. 2015, 51, 14203. (e) Venkatesan Balaji, P.; Chandrasekaran,
S. Tetrahedron 2016, 72, 1095. (f) Liu, L.; Zhang, T.; Yang, Y.-F.;
Zhang-Negrerie, D.; Zhang, X.; Du, Y.; Wu, Y.-D.; Zhao, K. J. Org.
Chem. 2016, 81, 4058. (g) Nakamura, A.; Tanaka, S.; Imamiya, A.;
Takane, R.; Ohta, C.; Fujimura, K.; Maegawa, T.; Miki, Y. Org. Biomol.
Chem. 2017, 15, 6702.
2
3
(5) The development of enantioselective reactions has also been
actively studied in recent years, see: (a) Farid, U.; Malmedy, F.;
Claveau, R.; Albers, L.; Wirth, T. Angew. Chem., Int. Ed. 2013, 52,
In summary, we present the first hypervalent iodine mediated
oxidative rearrangement reaction of secondary amines. The
transformation, which employs PhI(OAc) in CF CH OH,
7
(
2
(
018. (b) Malmedy, F.; Wirth, T. Chem. - Eur. J. 2016, 22, 16072.
c) Brown, M.; Kumar, R.; Rehbein, J.; Wirth, T. Chem. - Eur. J. 2016,
2, 4030. (d) Ahmad, A.; Silva, L. F., Jr J. Org. Chem. 2016, 81, 2174.
e) Qurban, J.; Elsherbini, M.; Wirth, T. J. Org. Chem. 2017, 82, 11872.
6) (a) Loudon, G. M.; Radhakrishna, A. S.; Almond, M. R.;
2
3
2
allows the direct use of secondary amines as substrates for 1,2-
C-to-N migration reactions. The versatility of this method for
the synthesis of a wide range of amines was demonstrated by its
application to the divergent synthesis of polycyclic and
macrocyclic indole-fused compounds and the reaction of
compounds 4, 6, 8, and 10, including a primary amine, as
shown in Scheme 4. This protocol is also attractive because it
can be readily carried out using a commercially available
hypervalent iodine reagent. Further investigations of these
transformations, including mechanistic studies, are underway in
our laboratory.
(
Blodgett, J. K.; Boutin, R. H. J. Org. Chem. 1984, 49, 4272. (b) Boutin,
R. H.; Loudon, G. M. J. Org. Chem. 1984, 49, 4277. For catalytic
processes, see: (c) Miyamoto, K.; Sakai, Y.; Goda, S.; Ochiai, M. Chem.
Commun. 2012, 48, 982. (d) Yoshimura, A.; Middleton, K. R.;
Luedtke, M. W.; Zhu, C.; Zhdankin, V. V. J. Org. Chem. 2012, 77,
1
1399.
(7) Kelley, B. T.; Walters, J. C.; Wengryniuk, S. E. Org. Lett. 2016, 18,
1896.
(8) For references of Schmidt reactions, see: (a) Wrobleski, A.;
Coombs, T. C.; Huh, C. W.; Li, S.-W.; Aube,
́
J. Org. React. 2012, 78, 1.
ASSOCIATED CONTENT
Supporting Information
(b) Grecian, S.; Aube, J. Organic Azides: Syntheses and Applications;
́
■
John Wiley and Sons: New York, 2010; p 191. (c) Lang, S.; Murphy, J.
A. Chem. Soc. Rev. 2006, 35, 146. (d) Pearson, W. H.; Fang, W.-k. J.
Org. Chem. 2000, 65, 7158. (e) Pearson, W. H.; Walavalkar, R.;
Schkeryantz, J. M.; Fang, W.-k.; Blickensdorf, J. D. J. Am. Chem. Soc.
1993, 115, 10183. (f) Kapat, A.; Nyfeler, E.; Giuffredi, G. T.; Renaud,
P. J. Am. Chem. Soc. 2009, 131, 17746.
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00675.
Full experimental details and characterization data (PDF)
(9) Wang, Z. Comprehensive Organic Name Reactions and Reagents;
John Wiley & Sons, Inc, 2010.
AUTHOR INFORMATION
Corresponding Author
■
*
(10) (a) Gassman, P. G.; Fox, B. L. J. Am. Chem. Soc. 1967, 89, 338.
(b) Schell, F. M.; Ganguly, R. N. J. Org. Chem. 1980, 45, 4069 and
references cited therein. For synthetic applications, see: (c) Grieco, P.
A.; Dai, Y. J. Am. Chem. Soc. 1998, 120, 5128.
E-mail: murai@phs.osaka-u.ac.jp.
ORCID
(
11) For reactions with p-nitrobenzenesulfonyl peroxide, see:
Kenichi Murai: 0000-0002-1689-6492
Notes
(a) Hoffman, R. V.; Poelker, D. J. J. Org. Chem. 1979, 44, 2364.
For reactions with a heavy metal oxidant such as lead tetraacetate, see:
(b) Sisti, A. J.; Milstein, S. R. J. Org. Chem. 1974, 39, 3932.
The authors declare no competing financial interest.
(12) For our recent reports on the oxidative rearrangement reaction
with NXS (X = Cl, Br) with the substrates having a large ring strain
such as a cyclobutane ring, see: (a) Murai, K.; Komatsu, H.; Nagao, R.;
Fujioka, H. Org. Lett. 2012, 14, 772. (b) Murai, K.; Shimura, M.;
Nagao, R.; Endo, D.; Fujioka, H. Org. Biomol. Chem. 2013, 11, 2648.
ACKNOWLEDGMENTS
■
This work was financially supported by the Japan Society for
the Promotion of Science (JSPS) KAKENHI Grant Nos.
T17K082100 (K.M.) and A15H046320 (H.F.) and the
Platform for Drug Discovery, Informatics, and Structural Life
Science from MEXT. K.M. acknowledges the research fund
from the Society of Iodine Science (SIS). We are grateful to
Prof. Richmond Sarpong (University of California, Berkeley)
for useful discussions.
(c) Murai, K.; Endo, D.; Kawashita, N.; Takagi, T.; Fujioka, H. Chem.
Pharm. Bull. 2015, 63, 245. (d) Murai, K.; Matsuura, K.; Aoyama, H.;
Fujioka, H. Org. Lett. 2016, 18, 1314.
(13) 8-Membered ring compound 1a was used instead of 6-
membered ring compound 1b because the purification of 2a by SiO2
column chromatography was easier than that of 2b.
(14) For examples, see: (a) Omoyeni, O. A.; Hussein, A. A.; Iwuoha,
E.; Green, I. R. Phytochem. Rev. 2017, 16, 97. (b) Stempel, E.; Gaich,
T. Acc. Chem. Res. 2016, 49, 2390.
(15) Moriarty, R. M.; Vaid, R. K.; Koser, G. F. Synlett 1990, 1990,
REFERENCES
■
(
1) Molecular Rearrangements in Organic Synthesis; Rojas, C. M., Ed.;
John Wiley & Sons, Inc., 2015.
2) Singh, F. V.; Wirth, T. Synthesis 2013, 45, 2499.
365.
(
(16) Higher acidity of (CF
) CHOH (pK of 9.3) might reduce the
3 2 a
(
3) (a) Hypervalent Iodine Chemistry (Topics in Current Chemistry;
electron donating ability of amines.
Wirth, T., Ed.; Springer: Berlin, 2003; Vol. 224. (b) Zhdankin, V. V.
Hypervalent Iodine Chemistry; Wiley: Chichester, 2014. (c) Romero, R.
(17) The reaction of the nonprotected spiro indole did not give the
rearranged product.
D
DOI: 10.1021/acs.orglett.8b00675
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
18) Compounds 1a and 1b did not undergo the rearrangement
reaction with NCS.
19) (a) Hogg, J. S.; Lohmann, D. H.; Russell, K. E. Can. J. Chem.
961, 39, 1394. For a recent example of mechanistic study with 9,10-
(
1
dihydroanthracene, see: (b) Masumoto, Y.; Miyamoto, K.; Iuchi, T.;
Ochiai, M.; Hirano, K.; Saito, T.; Wang, C.; Uchiyama, M. J. Org.
Chem. 2018, 83, 289.
(
20) For generation of the nitrogen-centered radical using
PhI(OAc) , see: Mondal, S.; Samanta, S.; Jana, S.; Hajra, A. J. Org.
2
Chem. 2017, 82, 4504.
(
21) A nitrogen-centered radical might be generated via the single-
electron transfer (SET) of amines to hypervalent iodine(III) reagents,
and this process could be accelerated by CF CH OH. For an example
3
2
of a SET process from electron-rich π-nucleophiles to hypervalent
iodine(III) species accelerated by CF CH OH, see: Kita, Y.; Tohma,
3
2
H.; Inagaki, M.; Hatanaka, K.; Yakura, T. J. Am. Chem. Soc. 1992, 114,
175.
22) For examples, see: (a) Bauer, R. T.; Wenderski, T. A.; Tan, D. S.
2
(
Nat. Chem. Biol. 2013, 9, 21. (b) Kopp, F.; Stratton, C. F.; Akella, L.
B.; Tan, D. S. Nat. Chem. Biol. 2012, 8, 358 and references cited
therein.
(
23) (a) Greger, H. Planta Med. 2006, 72, 99. (b) Garraffo, H. M.;
Jain, P.; Spande, T. F.; Daly, J. W.; Jones, T. H.; Smith, L. J.; Zottig, V.
E. J. Nat. Prod. 2001, 64, 421.
E
DOI: 10.1021/acs.orglett.8b00675
Org. Lett. XXXX, XXX, XXX−XXX