An iodine(iii) mediated oxidative rearrangement of enamines: efficient synthesis of α-amino ketones

Article abstract of DOI:10.1039/c5cc04265h

An iodine(iii)-mediated, group-selective oxidative rearrangement of β,β-diarylenamines to α-amino ketones has been accomplished with excellent yield. The developed reaction involves the initial oxidation of enamine to an α-acyloxyimine intermediate and concomitant semipinacol rearrangement.

Full text of DOI:10.1039/c5cc04265h

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DOI: 10.1039/C5CC04265H
COMMUNICATION
Iodine(III) Mediated Oxidative Rearrangement of
Enamines: Efficient Synthesis of α-Amino Ketones
Cite this: DOI:
10.1039/x0xx00000x
Dongari Yadagiria and Pazhamalai Anbarasan*a
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
and natural products.10 They exhibit a wide range of biological
An
iodine(III)-mediated,
group-selective
oxidative
activities, such as anti-depressant, appetite suppressant, and
anti-platelet properties. Some of the representative examples
are shown in Figure 1. Most of the strategies developed to date
for the synthesis of α-amino ketones utilize either metal
catalysed11 or metal free12 amination of ketone or its
derivatives. However, development of new strategies for the
synthesis of these biologically important scaffolds from
complementary substrates12a, 13 is in high demand. Herein, we
reveal an efficient chemoselective oxidative rearrangement of
enamines for the synthesis of α-amino ketones.
rearrangement of β,β-diarylenamines to α-amino ketones has
been accomplished with excellent yield. The developed
reaction involves the initial oxidation of enamine to α-
acyloxyimine intermediate and concomitant semipinacol
rearrangement.
Hypervalent iodine compounds, both iodine(III) and iodine(V)
species, have been established as highly valuable reagents in
organic synthesis.1 These reagents are mainly employed as mild
and environmentally benign oxidizing reagents that replace the
use of toxic heavy metal oxidants.2 In addition to the simple
oxidation,3 α-functionalization of carbonyl compounds,4
cyclization,5 atom-transfer6 and oxidative rearrangements7 were
also successfully accomplished using iodine(III) reagents.
Among them, cyclization through C-heteroatom bond
formation is well documented for the synthesis of various
heterocyclic compounds.5 A representative example includes
the synthesis of indole derivatives from electron deficient
enamines via iodine(III) mediated C-N bond formation
(Scheme 1a).8 In contrast, cyclization of electron rich enamines
did not afford the expected indole derivative; instead an
unusual oxidative rearrangement9 to α-amino ketones was
observed, which is the subject of this communication (Scheme
1b).
S
O
O
CH3
CH3
H
OAc
O
N
CH3
CH3
N
N
CH3 CH3
F
CH3
Cl
amfepramone
(appetite suppressant)
bupropion
(antidepressant agent)
prasugrel
(antiplatelet agent)
Figure 1. Examples of therapeutically important α-amino ketones.
At the outset, we synthesized β,β-diarylenamine 1a as model
substrate from 1,2,3-triazole and N,N-diethylaniline under
rhodium catalysis.14 Reaction of equimolar mixture of 1a and
[bis(trifluoroacetoxy)iodo]benzene (PIFA) in dichloromethane
(DCM) afforded 2a in 61% yield through oxidative
rearrangement, with a remarkable reaction time of 5 min (Table
1, entry 1). The structure of α-amino ketone 2a was
unambiguously confirmed by X-ray analysis (Table 1).15
Further to improve the yield, various solvents were screened,
such as toluene, tetrahydrofuran (THF) and chloroform. All of
them gave the product 2a with decrease in yield (Table 1,
entries 2-4). Next, increasing the equivalents of PIFA to 1.2 in
DCM furnished the α-amino ketone 2a in 81% yield (Table 1,
entry 5). No improvement in yield of 2a was observed with
portionwise addition of PIFA over 5 min interval. Changing
PIFA to diacetoxyiodobenzene (PIDA) and diphenyliodonium
triflate gave inferior results compared to PIFA, even after
prolonged reaction time (Table 1, entries 6-7).
a) previous work: Oxidative C-N bond formation
X
X
O
R2
NHR
IIII reagent
CN
X =
R1
R2
R3 ,
N
R1
R
b) present work: Oxidative rearrangement
X
O
IIII reagent
H
NHR
EDG
X =
NHR
X
R1
R1
(EDG = Electron donating group)
Scheme 1. Reaction of substituted enamine with hypervalent iodine reagent.
α-Amino ketone motifs are frequently encountered as an
integral part of many pharmaceutically important molecules
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Table 1. Oxidative rearrangement of enamines: Optimization.[a]
Similar chemoselectivity for the electron rich arene was
observed with enamine 1h, which has electronically different
NEt2
O
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aryl groups, (4-fluorophenyl and 4-(N,N-diethylamino)phenyl).
DOI: 10.1039/C5CC04265H
NHTs
More interestingly, a competition between 4-anisyl and 4-(N,N-
IIII reagent
diethylamino)phenyl substituents also afforded product 2i,
rt, solvent, time
H
N
where
4-(N,N-diethylamino)phenyl
group
selectively
Ts
underwent the migration. Furthermore, heteroaryl, thiophen-3-
yl substituted α-amino ketone 2j was also synthesized in 68%
yield from corresponding enamine.
2a
2a[d]
1a
NEt2
Entry
IIII reagent (X equiv)
PIFA (1)
Solvent
DCM
Toluene
THF
CHCl3
DCM
DCM
Time
5 min
5 min
5 min
5 min
5 min
0.5 h
48 h
Yield (%)[b]
Consequently, we studied the effect of the electronic nature of
the substitutions in the oxidative rearrangement (Scheme 3). In
all the cases we have examined, the more electron rich aryl
moiety (a symmetrically and unsymmetrically-substituted 4-
(N,N-dialkylamino)phenyl group) selectively migrated to afford
α-amino ketones (2k-2n) in good yield. Presence of alkene
functionality in the substrates was well tolerated under the
optimized conditions to afford the corresponding products 2m
and 2n in ~68% yield. Iminodibenzyl, an electron rich
heteroarene substituted enamine furnished the α-amino ketone
2o in 48% yield. Similar to aniline based enamines, anisole
based enamine derivatives also selectively underwent oxidative
rearrangement to give products 2p, 2q and 2r in moderate to
good yield. Interestingly, oxidative rearrangement of
electronically neutral β,β-diphenylenamine 1s was sluggish and
on prolonged reaction time (12 h) gave the product 2s in 47%
yield. However, the electron poor enamine 1t and the α-
disubstituted enamine 1u did not furnish the expected
rearrangement products. Instead, oxidative cleavage to the
ketone and decomposition of the enamine were observed,
respectively (see supporting information).
1
2
3
4
5
6
7
61
40
42
PIFA (1)
PIFA (1)
PIFA (1)
PIFA (1.2)
PIDA (1.2)
Ph2IOTf (1.2)
39
81 (76)[c]
26
DCM
20
[a] enamine 1a (0.12 mmol, 1 equiv), IIII reagent (X equiv), solvent (1 mL),
rt; [b] All are isolated yield; [c] 20 min and portionwise addition of PIFA.
Having shown an efficient oxidative rearrangement of enamine
1a to α-amino ketone 2a, we were interested in exploring the
generality of the reaction with respect to various substitutions
on nitrogen and one of the aryl groups. As shown in Scheme 2,
reaction of enamines having tosyl, mesyl and ethanesulfonyl
substitutions on the nitrogen group gave the corresponding α-
amino ketones (2a-2c) in 81, 75 and 77% yield, respectively.
Reaction also tolerates diverse substitution such as 4-methyl, 4-
tert-butyl, 3-methyl and 3-fluoro on the aromatic ring and led to
the synthesis of corresponding α-amino ketones (2d, 2e, 2f and
2g) through chemoselective oxidative rearrangement of the
electron-rich aryl group.
Z
O
H
N
NEt2
O
H
Ts
N
R1
R
PIFA (1.2 equiv)
S
R
PIFA (1.2 equiv)
DCM, rt, 5 min
O
O
H
N
DCM, rt, 5 min
H
N
Ts
R1
2
R
S
1
Z = NR2, OMe, H
Z
R
2
O
O
1
NEt2
O
O
H
N
O
H
N
H
N
O
O
H
N
O
H
N
H
N
Ts
Ts
Ts
p-Tolyl
Me
Et
S
S
S
O
O
O
O
O O
2l: 65%
2k: 72%
2m: 68%
N
N
N
O
nPr
nBu
nPr
Ts
nBu
2a: 81%
2b: 75%
p-Tolyl
2c: 77%
NEt2
NEt2
NEt2
O
Ts
O
O
H
N
HN
H
N
H
N
H
N
p-Tolyl
O
Ts
S
S
O
O
O O
tBu
MeO
N
O
Et
2n: 64%
2p: 63%
N
2d: 63%
2e: 61%
2o: 48%
OMe
NEt2
NEt2
Et
O
O
O
O
O
H
H
N
S
H
O
H
N
H
N
N
p-Tolyl
p-Tolyl
N
p-Tolyl
H
N
S
S
Ts
Ts
Ts
O
O
O
O
O O
F
F
2q: 34%
2r: 61%
2s: 47%†
2h: 67%
2f: 80%
2g: 74%
NEt2
NEt2
NEt2
OMe
OMe
O
O
F3C
F
H
N
S
H
N
HN Ts
p-Tolyl
p-Tolyl
S
O
O
O O
NEt2
S
MeO
1t
NH
Ts
1u
2i: 65%
2j: 68%
NEt2
NEt2
Scheme 3. Synthesis of functionalized α-amino ketones. † 12 h
Scheme 2. Synthesis of α-amino ketones.
2 | J. Name., 2012, 00, 1-3
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After the successful identification and demonstration of unusual To prove the proposed mechanism, we envisioned the synthesis
oxidative rearrangement of β,β-diarylenamine 1, we were of α-acyloxyimine intermediate C. Thus, we synthesized the α-
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interested in probing its possible mechanism. Initially, we hydroxy aldehydes 4a/4b from 2-hydroxyacetophenone (see
studied the role of the free NH in the enamine. Unsuccessful supporting information). Various atteDmOpI:ts10.1t0o39c/Co5nCvCe0r4t 26t5hHe
rearrangement of N,N-disubstituted enamines 3a/3b under the aldehydes 4a/4b to corresponding imines with tosylamide were
optimized reaction conditions revealed the critical nature of a unsuccessful, which is possibly due to the instability of the
free ‘NH’ group in oxidative rearrangement of enamine imines under the reaction conditions. Interestingly, the reaction
(Scheme 4a). Subsequently, we performed the oxidative of 4a/4b with tosylamide and trifluoroacetic anhydride in DCM
rearrangement of enamine 1a in the presence of radical at room temperature furnished the product 2v and 2s,
scavengers like TEMPO, BHT and BnOH. In all the three respectively in moderate to good yield (Scheme 6). These
reactions, the product 2a was isolated in excellent yield, which studies favoured the formation of α-acyloxyimine intermediate
rules out the formation of radicals and favors the ionic pathway C from 1 and PIFA followed by subsequent acid promoted
(Scheme 4b).
semipinacol rearrangement to the target α-amino ketones 2.
NEt2
Ph
O
R
a)
OH
TsNH2 (1.1 equiv)
TFAA (1.1 equiv)
DCM, rt, 8 h
2v; R = NMe2; 56%
2s; R = H; 38%
Ph
HN
PIFA (1.2 equiv)
DCM, rt
No reaction
R
N
Ts
4a/4b
O
R
Ts
R = Et, Allyl
Scheme 6. Synthesis of α-amino ketones from α-hydroxy aldehydes.
3a/3b
NEt2
O
b)
H
N
Conclusions
additive yield
Ts
PIFA (1.2 equiv)
DCM, rt
TEMPO 70%
We have demonstrated a new oxidative rearrangement of β,β-
diarylenamine with hypervalent iodine reagent. The reaction
enabled the synthesis of various α-amino ketones in good to
excellent yield. During the oxidative rearrangement, electron
rich aryl groups migrate with remarkably high
chemoselectivity. Mechanistic investigation revealed the initial
hypervalent iodine mediated oxidation of β,β-diarylenamine to
α-acyloxyimine intermediate and subsequent acid promoted
semipinacol rearrangement.
BHT
72%
75%
H
N
BnOH
Ts
additive
2a
1a
NEt2
Scheme 4. a) Oxidative rearrangement of N,N-disubstituted enamines; b)
oxidative rearrangement of enamine 1a in presence of radical scavengers.
Based on these studies, we proposed a plausible mechanism for
the oxidative rearrangement of β,β-diarylenamine 1 (Scheme 5).
The reaction of 1 with PhI(OCOCF3)2 (PIFA) would give the
iodonium intermediate A through substitution of ‘CF3COO-’
with enamine 1. Next, enamine assisted reduction of iodonium
A to phenyl iodide and cationic imine B followed by
intermolecular trapping of B with ‘CF3COO-’ anion would
furnish the α-acyloxyimine intermediate C. Alternatively, the
formation of α-acyloxyimine C can also be envisaged from A
through intramolecular rearrangement. Next, α-acyloxyimine C
to product 2 could be visualized via the acid promoted
semipinacol rearrangement.16 Thus, electrophilic activation of
C with TFA and subsequent stabilization by electron-rich aryl
group would generate the intermediate phenonium ion D.
Finally, oxygen lone pair assisted 1,2-migration of electron rich
aryl group in D would generate the oxonium ion E, which on
hydrolysis would furnish the α-amino ketones 2.
Acknowledgments
We thank Department of Science and Technology (DST), New
Delhi (Project No. SR/S1/OC-48/2012), and Board of Research
in Nuclear Sciences (BRNS) through DAE Young Scientist
Award (Project No. 2012/20/37C/14/BRNS) for funding this
work. DY thanks IITM for HTRA fellowship. We also thank
Mr. Ramkumar for single crystal analysis support.
Notes and references
a
Department of Chemistry, Indian Institute of Technology Madras,
Chennai – 600036, India.
Electronic Supplementary Information (ESI) available: General
experimental, reaction optimization data, and spectral copies of all the
new compounds. See DOI: 10.1039/c000000x/
NR2
NR2
CF3COO
Ar
NR2
Ar
Ar
PhI(OCOCF3)2
1. (a) T. Wirth, Top. Curr. Chem., 2003, 224, 1; (b) V. V. Zhdankin and
P. J. Stang, Chem. Rev., 2008, 108, 5299; (c) M. S. Yusubov, A. V.
Maskaev and V. V. Zhdankin, ARKIVOC, 2011, 370; (d) V. V.
Zhdankin, J. Org. Chem., 2011, 76, 1185; (e) E. A. Merritt and B.
Olofsson, Angew. Chem., Int. Ed., 2009, 48, 9052.
OCOCF3
− CF3COOH
I
− PhI
NH
Ts
N
N
Ph
A
1
B
Ts
Ts
− PhI
2
intramolecular
rearrangement
− (CF3CO)2O
CF3
2. (a) M. Uyanik and K. Ishihara, Chem. Commun., 2009, 2086; (b) R.
M. Moriarty, J. Org. Chem., 2005, 70, 2893.
NR2
O
O
F3C
Ar
O
F3C
O
O
OOCCF3
Ar
O
CF3COOH
3. For review see: F. V. Singh and T. Wirth, Chem. Asian J., 2014, 9,
950.
Ar
NR2
N
HN
Ts
HN
C
Ts
4. For review see: E. Merritt and B. Olofsson, Synthesis, 2011, 517.
5. For review see: R. Samanta, K. Matcha and A. P. Antonchick, Eur. J.
Org. Chem., 2013, 5769.
D
CF3COO
Ts
E
NR2
Scheme 5. Plausible mechanism for the oxidative rearrangement of enamine 1.
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6. For review see: J. P. Brand, D. F. Gonzalez, S. Nicolai and J. Waser,
Chem. Commun., 2011, 47, 102.
View Article Online
7. For review see: (a) F. Singh and T. Wirth, Synthesis, 2013, 45, 2499;
For selected recent references see: (b) S. Shang, D. Zhang-Negrerie,
Y. Du and K. Zhao, Angew. Chem., Int. Ed., 2014, 53, 6216; (c) X.
Zhang, R. Huang, J. Marrot, V. Coeffard and Y. Xiong, Tetrahedron,
2015, 71, 700; (d) A. Ahmad, P. Scarassati, N. Jalalian, B. Olofsson
and J. L. F. Silva, Tetrahedron Lett., 2013, 54, 5818; (e) F. V. Singh,
J. Rehbein and T. Wirth, ChemistryOpen, 2012, 1, 245; (f) G.
Jacquemot and S. Canesi, J. Org. Chem., 2012, 77, 7588; (g) U.
Farid, F. Malmedy, R. Claveau, L. Albers and T. Wirth, Angew.
Chem., Int. Ed., 2013, 52, 7018; (h) L. Liu, H. Lu, H. Wang, C.
Yang, X. Zhang, D. Zhang-Negrerie, Y. Du and K. Zhao, Org. Lett.,
2013, 15, 2906.
DOI: 10.1039/C5CC04265H
8. (a) Y. Du, R. Liu, G. Linn and K. Zhao, Org. Lett., 2006, 8, 5919; (b)
X. Ban, Y. Pan, Y. Lin, S. Wang, Y. Du and K. Zhao, Org. Biomol.
Chem., 2012, 10, 3606.
9. M. F. Schlecht, Comprehensive Organic Synthesis, 2004, 7, 815.
10. (a) F. I. Carroll, B. E. Blough, P. Abraham, A. C. Mills, J. A.
Holleman, S. A. Wolckenhauer, A. M. Decker, A. Landavazo, K. T.
McElroy, H. A. Navarro, M. B. Gatch and M. J. Forster, J. Med.
Chem., 2009, 52, 6768; (b) P. C. Meltzer, D. Butler, J. R. Deschamps
and B. K. Madras, J. Med. Chem., 2006, 49, 1420; (c) M. C. Myers,
J. Wang, J. A. Iera, J.-K. Bang, T. Hara, S. Saito, G. P. Zambetti and
D. H. Appella, J. Am. Chem. Soc., 2005, 127, 6152.
11. (a) R. W. Evans, J. R. Zbieg, S. Zhu, W. Li and D. W. C. MacMillan,
J. Am. Chem. Soc., 2013, 135, 16074; (b) N. Matsuda, K. Hirano, T.
Satoh and M. Miura, Angew. Chem., Int. Ed., 2012, 51, 11827; (c) T.
Miura, M. Morimoto and M. Murakami, Org. Lett., 2012, 14, 5214;
(d) J.-S. Tian and T.-P. Loh, Chem. Commun., 2011, 47, 5458.
12. (a) S. Guha, V. Rajeshkumar, S. S. Kotha and G. Sekar, Org. Lett.,
2015, 17, 406; (b) Q. Jiang, B. Xu, A. Zhao, J. Jia, T. Liu and C.
Guo, J. Org. Chem., 2014, 79, 8750; (c) M. Lamani and K. R.
Prabhu, Chem. –Eur. J., 2012, 18, 14638; (d) Y. Wei, S. Lin and F.
Liang, Org. Lett., 2012, 14, 4202; (e) J.-S. Tian, K. W. J. Ng, J.-R.
Wong and T.-P. Loh, Angew. Chem., Int. Ed., 2012, 51, 9105.
13. (a) T. Miura, T. Biyajima, T. Fujii and M. Murakami, J. Am. Chem.
Soc., 2012, 134, 194; (b) T. Miura, T. Tanaka, T. Biyajima, A. Yada
and M. Murakami, Angew. Chem., Int. Ed., 2013, 52, 3883.
14. D. Yadagiri and P. Anbarasan, Org. Lett., 2014, 16, 2510.
15. CCDC 1030816 contains the supplementary crystallographic data for
the compound 2a. The data can be obtained free of charge from The
Cambridge
Crystallographic
Data
.
Centre
via
http://www.ccdc.cam.ac.uk/data_request/cif
16. (a) Z.-L. Song, C.-A. Fan and Y. Q. Tu, Chem. Rev., 2011, 111,
7523; (b) T. J. Snape, Chem. Soc. Rev., 2007, 36, 1823; (c) B. Wang
and Y. Q. Tu, Acc. Chem. Res., 2011, 44, 1207.
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