Stereoselective synthesis of trans-α-ketohydrazones from silyl enol ethers mediated by iodobenzene diacetate

Article abstract of DOI:10.1016/j.tetlet.2007.03.164

Stereoselective synthesis of a variety of trans-α-ketohydrazones from silyl enol ethers in the presence of iodobenzene diacetate [PhI(OAc)₂] as oxidant with N-aminophthalimide (PthNH₂) as the nitrogen source in CH₂Cl₂

Full text of DOI:10.1016/j.tetlet.2007.03.164

Tetrahedron Letters 48 (2007) 3789–3792
Stereoselective synthesis of trans-a-ketohydrazones from silyl
enol ethers mediated by iodobenzene diacetate
Weidong Rao and Philip Wai Hong Chan*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637616, Singapore
Received 26 February 2007; revised 19 March 2007; accepted 30 March 2007
Available online 5 April 2007
Abstract—Stereoselective synthesis of a variety of trans-a-ketohydrazones from silyl enol ethers in the presence of iodobenzene
diacetate [PhI(OAc)2] as oxidant with N-aminophthalimide (PthNH2) as the nitrogen source in CH2Cl2 at room temperature was
accomplished in good yields (up to 75%) with exclusive trans-selectivity.
ꢀ 2007 Elsevier Ltd. All rights reserved.
The carbon–nitrogen bond is ubiquitous in organic syn-
thesis and is an important structural feature found in a
myriad of compounds of biological, pharmaceutical,
and materials interest. Among the various methods
developed to date, aryl-k3-iodane-mediated nitrogen
atom transfer reactions without the participation of a
metal catalyst have become increasingly attractive for
carbon–nitrogen bond formation.1–9 Indeed, the
development of PhI(OAc)22,3- and ‘ArI + mCPBA’4-
mediated versions of the lead(IV) acetate5 catalyzed
intermolecular aziridination of alkenes using PthNH2
as the nitrogen source reported by Che and Yudin serve
as excellent examples of what can be accomplished. Fol-
lowing these seminal works, the same PhI(OAc)2-medi-
ated protocol was recently described to be useful for
ring expansions of alkylidenecyclopropanes and an alky-
lidenecyclobutane with PthNH2.6 Azidations7 and ami-
dations8 have also been developed, with the respective
azides and N-substituted acetamides as excellent nitro-
gen sources for these transformations. However, while
the amidation of silyl enol ethers with preformed
PhI@NTs has been previously reported by Lim and
Ahn,9 to our knowledge, there are no known examples
on the analogous nitrogen atom transfer reactions to
silyl enol ethers that make use of hydrazine-based com-
pounds such as PthNH2 as the nitrogen source. In this
context and as part of an ongoing program in our group
on carbon–nitrogen bond formation,2,4,10 we thus chose
the ‘PhI(OAc)2 + PthNH2’ system to examine its reac-
tions with silyl enol ethers. Herein we describe our pre-
liminary findings and a novel synthetic route that is
useful for the construction of a-ketohydrazones11 in
yields up to 75% and with exclusive trans-selectivity in
all but one case (Scheme 1).
O
O
O
PhI(OAc)2
OTMS
R''
N
R'
N
+
H2N
N
R'
R''
O
O
1
2
R', R'' = H, alkyl, aryl, acyl
Scheme 1.
At the outset of this study, we found that treatment of
1a (1 equiv) with PthNH2 (1.5 equiv) and PhI(OAc)2
(3 equiv) in CH2Cl2 at room temperature for 4 h gave
the best result, furnishing 2a in 75% yield (Table 1, entry
1) and with exclusive trans-selectivity.12 The stereo-
1
chemistry of the trans-product was based on H NMR
analysis and an X-ray crystal structure determination
of a closely related structure (see later). Lower product
yields were obtained on either increasing the PhI(OAc)2
loading or introducing 3 equiv of K2CO3 base to the
reaction (entries 2 and 3). In contrast, a 1:1 mixture of
2a and 3a was obtained in yields of 35% upon lowering
the PhI(OAc)2 loading from 3 to 1.5 equiv (entry 4).
Inspection of entries 5–8 revealed that the PhI(OAc)2
mediated reactions of PthNH2 with 1a in other solvents
were less effective. Changing the solvent from CH2Cl2 to
*
Corresponding author. Tel.: +65 6316 8760; fax: +65 6791 1961;
e-mail: waihong@ntu.edu.sg
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.164

3790
W. Rao, P. W. H. Chan / Tetrahedron Letters 48 (2007) 3789–3792
Table 1. Optimization of reaction conditionsa
toluene, CH3CN, THF, or H2O was found to give lower
product yields of 40–65%. The analogous reaction con-
ducted in acetone is the only instance where a markedly
lower product yield of 23% was obtained (entry 9).
PthNH2, PhI(OAc)2
solvent, rt, 4 h
OTMS
O
O
+
NPth
NHPth
Ph
Ph
Ph
1a
2a
3a
To define the scope of the PhI(OAc)2-mediated reac-
tions, we applied this process to a series of internal
and terminal silyl enol ethers 1b–k (Table 2). These reac-
tions afforded the corresponding a-ketohydrazone
adducts 2b–k in yields up to 73% (entries 1–10). The
electronic nature of the C@C bond was found to have
no effect on the reaction yield (cf. entries 1, 2 and 3–5)
and the reaction conditions employed were found to tol-
erate an alkoxycarbonyl functional group (entry 10).
Furthermore, in instances where it was initially envis-
aged that the presence of a sterically demanding func-
tional group in close spatial proximity to the OTMS
group on the C@C bond of the silyl enol ether would re-
tard or prevent the C–N bond forming process, the cor-
responding adducts were obtained in comparable yields
Entry
PhI(OAc)2 (equiv)
Solvent
Yieldb (%)
1
2c
3
4
5
6
7
8
9
3
3
5
1.5
3
3
3
3
3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
PhMe
CH3CN
THF
H2O
75
48
50
35d
47
65
40
45
23
Acetone
a All reactions were performed for 4 h with 1a: PthNH2 molar
ratio = 1:1.5, and PhI(OAc)2 in solvent as stated in the table at room
temperature.
b Isolated yield.
c Reaction carried out with 3 equiv of K2CO3.
d Compound 3a isolated in 35% yield.
a
Table 2. PhI(OAc)2-mediated reactions of silyl enol ethers 1b–k with PthNH2
Entry
Substrate
Product
Yieldb (%)
71
OTMS
O
NPth
1
H3C
H3C
OTMS
O
1b
2b
NPth
2
53
H3CO
H3CO
O
OTMS
2c
1c
NPth
NPth
3
4
73
68
Cl
Cl
O
OTMS
OTMS
1d
2d
Br
Br
O
1e
2e
NPth
5
6
65
66
F
F
OTMS
O
2f
1f
NPth
H3C
CH3
H3C
CH3
2g
1g
O
OTMS
NPth
7
55
Cl
Cl
1h
1i
2h
OTMS
OTMS
O
NPth
NPth
8
9
63
65
2i
O
CH3
CH3
Br
Br
2j
1j
OTMS
O
COOEt
NPth
Ph
Ph
10
66
COOEt
2k
1k
a All reactions were performed for 4 h with 1: PthNH2:PhI(OAc)2 molar ratio = 1:1.5:3 in CH2Cl2 at room temperature.
b Isolated yield.

W. Rao, P. W. H. Chan / Tetrahedron Letters 48 (2007) 3789–3792
3791
O
PhI(OAc)2
O
NPth
NHPth
Ph
CH2Cl2
rt, 4 h
Ph
3a
2a
85%
Scheme 3.
carbonyl compounds with PhI(OH)(OR) (R = Ms,
Ts).15 Subsequent nucleophilic attack by PthNH2 fol-
lowed by reductive elimination of iodobenzene would
afford 3. In the presence of excess PhI(OAc)2, this com-
mon intermediate would be further oxidized to give the
final trans-a-ketohydrazone product 2.
Although the mechanism of the present procedure is
currently unclear, we surmise that the formation of 3
as a common intermediate is likely irrespective of
whether the reaction follows routes a or b in Scheme
2. This is supported by the isolation of 3a in 35% yield
on reducing the oxidant loading from 3 to 1.5 equiv
under the conditions mentioned earlier in entry 4 of Table
1. The origin of the exclusive trans-stereoselectivity in 2
could be due to a discrete oxidation of 3 by excess
PhI(OAc)2. Indeed, this is supported by the fact that
when a solution of CH2Cl2 containing 3a was treated
with 1.2 equiv of PhI(OAc)2 at room temperature for
4 h, 2a was formed exclusively as the trans-product in
85% yield (Scheme 3). The 3:2 trans:cis mixture of iso-
mers obtained in the case of 2k could be due to the benz-
oyl and ethoxycarbonyl groups in this compound
exhibiting similar steric properties.
Figure 1. ORTEP drawing of trans-2k with thermal ellipsoids at 50%
probability levels.13
(entries 6–10). In all except one case, product formation
was found to occur with exclusive trans-selectivity based
on 1H NMR analysis (entries 1–9). The PhI(OAc)2-med-
iated reaction of PthNH2 with trans-1k was the only
instance where the product was obtained in a trans:cis
ratio of 3:2 based on 1H NMR analysis (entry 10).
The trans-stereochemistry of the major isomer of 2k
was further confirmed by X-ray crystal structure mea-
surements, as shown in Figure 1.13
On the basis of the above results, we tentatively propose
two plausible mechanisms for these a-ketohydrazone
forming reactions (Scheme 2). One possible pathway
could involve formation of N-(acetoxyamino)phthal-
imide 4 from reaction of PhI(OAc)2 with PthNH2, which
is the active species that undergoes C@C bond addition
or nucleophilic attack by silyl enol ether 1 and cycliza-
tion to give the aziridine 5. Under slightly acidic oxida-
tive conditions, easy desilylative ring-opening of this
newly formed intermediate would result in the genera-
tion of a-ketohydrazine 3 (route a in Scheme 2).14 It is
possible that steric crowding in 5 also contributes to
an easy ring-opening process. Alternatively, as shown
in route b in Scheme 2, silyl enol ether 1 could react
directly with PhI(OAc)2 to give (substituted-ethan-2-
onyl(acetoxy)iodo)benzene 6 in a manner similar to that
proposed by Moriarty et al. for a-sulfonyloxylation of
In summary, we have demonstrated the ‘PhI(OAc)2 +
PthNH2’ combination to be the method of choice for
transforming silyl enol ethers into the corresponding
trans-a-ketohydrazones in good yields. The present pro-
tocol is applicable to a variety of terminal and internal
silyl enol ethers containing electron-donating and elec-
tron-withdrawing, and sterically demanding substrate
combinations under mild conditions. Efforts are cur-
rently underway to examine the scope and mechanism
of this practical and straightforward reaction and will
be reported in due course as part of a full paper.
Acknowledgements
This work was supported by a College of Science
Start-up Grant, University Research Committee Grant
(RG55/06) and Supplementary Equipment Purchase
Grant (RG134/06) from Nanyang Technological Uni-
versity. The authors would like to thank Professor
Kum Fun Mok for assistance in solving the X-ray crys-
tal structure reported in this work.
AcO
OAc
route a
route b
I
OTMS 1
Ph
PthNH2
R'
R''
OTMS 1
R'
R''
R"
Pth
N
H
N
R'
OAc
TMSO
R'
H
I
OAc
Pth
R''
O
Ph
4
5
6
References and notes
PthNH2
O
O
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Pth
Pth
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R''
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Scheme 2.

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CH2Cl2 (2 mL). The reaction mixture was stirred at room
temperature for 4 h and monitored by TLC analysis using
a 3:2 or 2:1 n-hexane/EtOAc solvent system. Upon
completion, the reaction mixture was quenched with
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(2 · 10 mL). The combined organic layers were washed
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