Concurrent α-iodination and N-arylation of cyclic β-enaminones

Article abstract of DOI:10.1055/s-0029-1219164

A variety of N-substituted 3-aminocyclohex-2-enones were converted into the corresponding N-arylated α-iodo enaminones in high yields via concurrent N-iodination and N-arylation mediated by ArI(OAc)₂. A mechanism is postulated to account for the reaction differences between the cyclic and the acyclic -enaminones, which undergo predominant β-acetoxylation under the same reaction conditions.

Full text of DOI:10.1055/s-0029-1219164

LETTER
231
Concurrent a-Iodination and N-Arylation of Cyclic b-Enaminones
N
-Arylation of Cy
a
clic b-Enam
n
inones Chen, Tong Ju, Junwei Wang, Wenquan Yu, Yunfei Du,* Kang Zhao*
Tianjin Key Laboratory for Modern Drug Delivery & High Efficiency, School of Pharmaceutical Science and Technology,
Tianjin University, Tianjin 300072, P. R. of China
Fax +86(22)27890968; E-mail: duyunfeier@tju.edu.cn; E-mail: kangzhao@tju.edu.cn
Received 28 October 2009
teresting class of reaction and an exceptional case that
supplements our preliminary findings,2c we wish to report
herein this unexpected one-pot a-iodination and N-aryla-
tion process of 3-aminocyclohex-2-enones mediated by
Abstract: A variety of N-substituted 3-aminocyclohex-2-enones
were converted into the corresponding N-arylated a-iodo enamino-
nes in high yields via concurrent a-iodination and N-arylation me-
diated by ArI(OAc)2. A mechanism is postulated to account for the
reaction differences between the cyclic and the acyclic b-enamin- ArI(OAc)2.
ones, which undergo predominant a-acetoxylation under the same
reaction conditions.
EWG
R1
EWG
R1
Key words: polyvalent iodine compounds, a-iodination, PIDA,
a-iodo enaminones, 3-aminocyclohex-2-enones
PhI(OAc)2
R2
R2
DCE
60 °C
N
N
H
H
Scheme 1
The organic chemistry of polyvalent iodine compounds
has experienced an unprecedented explosive development
since the early 1990s. This surging interest in organic io-
dine reagents is mainly due to the fact that the chemical
properties and the reactivity of the iodine species are sim-
ilar to heavy-metal congeners, such as Hg(II), Tl(III),
Pd(IV), but without the toxic and environmental problems
associated with these metal reagents.1
O
O
O
PhI(OAc)2
I
2a
DCE
60 °C
N
N
H
N
H
Ph
3a'
3a
1a
Scheme 2
Among the many polyvalent iodine reagents, phenylio-
dine bis(trifluoroacetate) (PIFA) and phenyliodine(III) di-
acetate (PIDA) have been applied extensively to construct
C–N or C–C bonds leading to heterocyclic compounds.2
Recently, we reported a novel C–C bond formation strat-
egy for indole synthesis via PIDA-mediated oxidation of
the N-aryl enamines (Scheme 1).2c In order to enlarge the
substrate scope and generality of the method, we applied
the reaction conditions (PIDA, 60 °C, DCE) to the similar
N-substituted cyclic enaminone 1a in hopes of achieving
the desired cyclized product 3a¢. However, an unexpected
N-arylated a-iodo enaminone 3a (confirmed by X-ray
crystal analysis,3 Figure 1) was achieved in 85% yield,
with no formation of the desired cyclized 3a¢ (Scheme 2).
One feature of the reaction is that both the aryl and iodo
moiety in ArI(OAc)2 are incorporated into the final prod-
uct, while for most oxidative reactions mediated by
PhI(OAc)2, phenyl iodide is always released as a byprod-
uct.
A variety of 3-arylaminocyclohex-2-enone derivatives,
which were readily prepared via the condensation of cy-
clohexane-1,3-dione and the corresponding anilines,7
were firstly treated with PIDA under optimal conditions8
to investigate the scope and generality of the reaction. The
results listed in Table 1 indicated that both electron-donat-
ing and electron-withdrawing aromatic substituents could
be tolerated in the process. For the substrates with elec-
tron-withdrawing groups, the reaction yields achieved
were relatively higher (entries 2–6, Table 1). Further-
more, five-membered b-enaminone 1n could also be
transferred into the corresponding N-arylated a-iodo
enaminone 3v in good yield by using the method
(Scheme 3).
Numerous methods have been described for the prepara-
tion of a-iodo enaminone compounds,4 which can be
readily converted to a range of a-functionalized enamino-
nes via a transition-metal-catalyzed cross-coupling reac-
tion.5 However, a literature survey indicated that there are
few examples of a general, one-pot a-iodination and N-
arylation of secondary enaminones mediated by
ArI(OAc)2, although a similar two-step chemical process
has already been observed for 2-amin-o-1,4-naphtho-
quinone compounds and 4-aminocoumarin derivatives by
Varvoglis’s group.6 As a complementary work to this in-
I
OAc
OAc
O
DCE
Ph
N
O
+
PhHN
I
60 °C
Ph
75%
1n
2a
3v
SYNLETT 2010, No. 2, pp 0231–0234
Advanced online publication: 22.12.2009
x
x.
x
x.
2
0
1
0
Scheme 3
DOI: 10.1055/s-0029-1219164; Art ID: W17009ST
© Georg Thieme Verlag Stuttgart · New York

232
Y. Chen et al.
LETTER
a
Table 1 a-Iodination and N-Arylation of Cyclic 3-Aminocyclohex-2-enones 1 Mediated by ArI(OAc)2
R1
R1HN
R2
OAc
OAc
N
I
DCE
+
I
O
R2
60 °C
O
1
2
3
Entry
1
R1 in 1
R2 in 2
3
Yields (%)b
Ph
1a
1b
1c
1d
1e
1f
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2b
2d
2e
2e
2b
2b
2c
2f
3a
3b
3c
3d
3e
3f
3g
3h
3i
85
2
4-F3CC6H4
4-BrC6H4
H
74
3
H
75
4
4-O2NC6H4
2,4-F2C6H3
2-ClC6H4
3,4-Me2C6H3
4-MeOC6H4
4-MeC6H4
4-MeOC6H4
4-BrC6H4
4-O2NC6H4
2,4-F2C6H3
2-ClC6H4
Ph
H
89
5
H
85
6
H
72
7
1g
1h
1i
H
77
8
H
60
9
H
85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
1h
1c
1d
1e
1f
4-O2N
4-Br
3-O2N
4-O2N
3-O2N
4-Me
4-Me
4-O2N
4-O2N
4-Br
2-Cl
4-MeO2C
4-O2N
4-O2N
H
3j
3k
3l
57
71
57
3m
3n
–
63
85
1a
1d
1j
n.d.c
n.d.c
84
4-O2NC6H4
Bn
–
3o
3p
3q
3r
3s
3t
3u
–
Bn
1j
91
Bn
1j
57
Bn
1j
62
Bn
1j
2g
2b
2b
2a
65
Ph(CH2)2
c-C6H11
H
1k
1l
86
35d
n.d.c
1m
a Conditions: all reactions were carried out by adding dropwise 1.3 equiv of ArI(OAc)2 in DCE to a 60 °C solution of 1.0 equiv of substrate 1
in DCE under N2 protection.
b Isolated yields after silica gel chromatography.
c n.d. = not detected.
d With concomitant formation of other unidentified byproducts.
In order to realize a versatile N-arylation of the a-iodo Surprisingly, when substrate 1a and 1d were treated with
enaminones, a series of aryliodine diacetates were PIDA analogue 2e, differing from PIDA by only one
prepared9 and applied to the method. It was found that para-methyl group, no expected N-arylated and a-iodo-
when the PIDA derivatives bear aromatic electron-with- nated products were achieved in either case. This result
drawing substituents, the reactions went smoothly to af- might indicate that an aromatic electron-rich polyvalent
ford the corresponding products (entries 10–14, Table 1). iodine(III) reagent is ineffective for this transformation.
Synlett 2010, No. 2, 231–234 © Thieme Stuttgart · New York

LETTER
N-Arylation of Cyclic b-Enaminones
233
R1
R
H
H-bond
R1
NH
O
N+
O
OAc
OAc
PhI(OAc)2
DCE
NH
O
H
R
sp3
I
2a
+
N
O
60 °C
– AcO–
–OAc
OAc
I
H
AcO
Ph
A (stable)
4a R1 = Ph
4b R1 = H
4c R1 = Bn
4d R1 = Me
5a R1 = Ph (85%)
5b R1 = H (73%)
5c R1 = Bn (58%)
5d R1 = Me (72%)
2a
4
– AcO–
– PhI
H
R
H
O
R
– H+
N
O
N+
Scheme 4
Encouraged by the above results, we decided to study
whether N-alkylated 3-aminocyclohex-2-enones could be
applied to this a-iodination and N-arylation process. The
results in Table 1 (entries 17–23) demonstrated that the N-
alkylated and N-arylated a-iodocyclohex-2-enones 3o–u
could also be successively obtained via this a-iodination
and N-arylation approach. However, when nonsubstituted
primary enaminone 1m was subjected to the same reac-
tion conditions, a complex mixture was obtained and no
desired N-arylated a-iodo enaminone was separated.
OAc
5
H
OAc
B
Scheme 5
ecule of phenyl iodide and acetate anion.12 Finally,
capture of the acidic proton by the acetate anion would
transform B into the a-acetoxylated b-enaminone 5
(Scheme 5). While for the cyclic b-enaminones, the C=N
double bond would undoubtedly adopt the E-configura-
tion, and the H-bond cannot be formed between the N–H
and the carbonyl group because of the spatial distance.
Similarly, a-iodo iminium salt C would firstly be formed
from 1 and 2. However, intermediate C is greatly unstable
because of the presence of a ring system and the lack of
H-bond; it would deprotonated instantly to give the stabi-
lized cyclic a-iodo enaminone D. Due to the fact that sub-
stitution of an acetate anion (if formed) cannot occur at a
sp2-carbon center, intermediate D would be converted to
iodine-nitrogen 1,4-dipoles E.6 Finally, the ipso attack of
the negative nitrogen on the phenyl ring, through a five-
membered cyclic intermediate F,13 would afford the cy-
clic N-arylated a-iodo enaminone 3 (Scheme 6). The for-
mation of the cyclic intermediate F seemingly accounts
for the experimental fact that an electron-withdrawing R2
substituent was beneficial while an electron-donating R2
group was ineffective for the reaction (entries 10–16,
Table 1), since the stability of intermediate F would be
greatly deactivated in the latter case.
Figure 1 X-ray crystallography of 3a
O
O
AcO
Interestingly, exceptional results were obtained for the
cases when acyclic b-enaminones were used as substrates.
Under the exact same reaction conditions, acyclic b-
enaminone 4a–c afforded a-acetoxylated10 product 5a–c
in 73–85% yields, with no detection of the desired N-ary-
lated a-enaminones in each case (Scheme 4).
O
AcO
H
ArI(OAc)2
fast
I
I
sp2
2
– H+
Ar
R1
Ar
R1
– AcO–
R1
– AcOH
••
N
H
N
N
H
H
1
C
D
(unstable)
O
O
O
Ar
I+
A plausible mechanism is proposed to explain why the
acyclic b-enaminone 4 and cyclic b-enaminone 1 would
afford different products under the same ArI(OAc)2 con-
ditions. Due to the existence of an H-bond, the acyclic b-
enaminone with the Z-configuration would exist as the
sole isomer.11 Firstly, the reaction of acyclic b-enaminone
with PhI(OAc)2 would give an a-iodo iminium salt A,
which is proposed to be a stable intermediate for the exist-
ence of an intramolecular H-bond. Next, one possible
pathway is that the generated acetate anion would nucleo-
philically attack the sp3-carbon center, releasing one mol-
I
I+
3
R2
–
N–
R1
N
R1
N
R1
R2
E
F
Scheme 6
In conclusion, we have described that when the cyclic N-
substituted 3-aminocyclohex-2-enones were treated with
ArI(OAc)2, both the aryl and iodo moiety of ArI(OAc)2
would be incorporated into the product.14 The cyclic N-
arylated a-iodo b-enaminones could be obtained in high
Synlett 2010, No. 2, 231–234 © Thieme Stuttgart · New York

234
Y. Chen et al.
LETTER
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ones, one acetoxy group of ArI(OAc)2 was transferred to
the product to give selectively the acyclic a-acetoxylated
b-enaminones in good yields.
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Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We acknowledge the National Natural Science Foundation of China
(#20802048) and Cultivation Foundation (B) for New Faculty of
Tianjin University (TJU-YFF-08B68) for financial support. We
also thank Miss Xiling Zhao, University of California, San Diego,
for revising our English text.
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To a solution of substrate 1 (1.0 mmol) in dried DCE (10
mL) was added dropwise a solution of aryliodine diacetate 2
(1.3 mmol) in dried DCE (10 mL) at 60 °C under nitrogen
atmosphere. After the addition, the reaction mixture was
stirred at this temperature until the conversion was complete
as indicated by TLC. Then the mixture was cooled to r.t.,
treated with sat. aq NaHCO3 (40 mL) and extracted with
CH2Cl2 (3 × 20 mL). The combined organic layer was dried
over Na2SO4 and evaporated under reduced pressure to
remove the solvent. The residue was purified by column
chromatography using a mixture of PE and EtOAc as eluent
to afford the product.
Compound 3a: yellow solid, mp 106–108 °C. 1H NMR (500
MHz, CDCl3): d = 7.32 (t, J = 7.9 Hz, 4 H), 7.14 (t, J = 7.4
Hz, 2 H), 7.02 (d, J = 7.7 Hz, 4 H), 2.75–2.65 (m, 2 H), 2.58
(t, J = 6.0 Hz, 2 H), 2.04–1.91 (m, 2 H). 13C NMR (100
MHz, CDCl3): d = 193.09, 166.95, 145.20, 129.52, 125.45,
125.22, 95.80, 37.54, 34.04, 21.38. ESI-LRMS: m/z = 390.2
[M + H+].
(3) Compound 3a
Crystallized in the monoclinic space group P2 (1)/c with cell
dimensions: a = 10.497 (2) Å, b = 13.607 (3) Å, c = 11.987
(2) Å, a = 90°, b = 114.36 (3)°, g = 90°, V = 1559.9 (5) Å3,
Dc = 1.657 g/cm3, Z = 4. CCDC: 753753.
Compound 5a: yellow solid, mp 102–104 °C. 1H NMR (400
MHz, DMSO): d = 7.51 (dd, J = 4.8, 2.5 Hz, 3 H), 7.35 (dd,
J = 7.7, 1.9 Hz, 2 H), 2.43 (s, 3 H), 2.35 (s, 3 H), 2.22 (s, 3
H). ESI-LRMS: m/z = 271.9 [M + K+]. The spectroscopic
data for all the new compounds could be found in the
Supporting Information.
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Synlett 2010, No. 2, 231–234 © Thieme Stuttgart · New York

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