Intramolecular oxidative diamination and aminohydroxylation of olefins under metal-free conditions

Article abstract of DOI:10.1021/ol300166q

A metal-free procedure that is simple to operate and convenient to handle was developed for the facile intramolecular oxidative diamination of olefins using an iodobenzene diacetate oxidant and a halide additive to furnish bisindolines at room temperature. The present reaction is featured by mild conditions, a broad substrate scope, and excellent functional group tolerance. The same protocol was successfully extended to the aminohydroxylation.

Full text of DOI:10.1021/ol300166q

ORGANIC
LETTERS
2012
Vol. 14, No. 6
1424–1427
Intramolecular Oxidative Diamination and
Aminohydroxylation of Olefins under
Metal-Free Conditions
Hyun Jin Kim, Seung Hwan Cho, and Sukbok Chang*
Department of Chemistry and Molecular-Level Interface Research Center, Korea
Advanced Institute of Science & Technology (KAIST), Daejeon 305-701, Korea
sbchang@kaist.ac.kr
Received January 20, 2012
ABSTRACT
A metal-free procedure that is simple to operate and convenient to handle was developed for the facile intramolecular oxidative diamination of
olefins using an iodobenzene diacetate oxidant and a halide additive to furnish bisindolines at room temperature. The present reaction is featured
by mild conditions, a broad substrate scope, and excellent functional group tolerance. The same protocol was successfully extended to the
aminohydroxylation.
Preparative route to compounds having a diamino- or
aminohydroxy unit from readily available reactants is of
high importance since it constitutes a key component of
Scheme 1. Bioactive Compounds Bearing Diamino- or Amino-
hydroxy Units
natural products, bioactive pharmaceuticals, and electron-
ic materials (Scheme 1).1 Over the past decade, various
metal-mediated approaches have been developed to afford
vicinal diamines in either an intra- or intermolecular
~
manner. For instance, Muniz et al. reported the Pd(II)-
catalyzed intramolecular oxidative diamination of ω-alke-
nyl-substituted ureas.2 They used a hypervalent iodine(III)
reagent such as PhI(OAc)2 as the efficient terminal oxidant
to operate the postulated the Pd(II)/Pd(IV) catalytic cycle
under mild conditions. The bisindolines, annelated in-
doles, and bipyrrolidines were also prepared by the same
(1) (a) Gacheru, S. N.; Trackman, P. C.; Calaman, S. D.; Greenaway,
F. T.; Kagan, H. M. J. Biol. Chem. 1989, 264, 12963. (b) Lucet, D.; Le
Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed. 1998, 37, 2580. (c) Notz,
W.; Tanaka, F.; Barbas, C. F., III. Acc. Chem. Res. 2004, 37, 580. (d)
Kotti, S. R. S. S.; Timmons, C.; Li, G. Chem. Biol. Drug Des. 2006, 67,
101. (e) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13.
catalytic system via the sequential transfer of two sulfona-
mido groups into bridging internal olefins.2b
Lloyd-Jones and Booker-Milburn developed the Pd(II)-
catalyzed intermolecular 1,2-diamination of conjugated
dienes with ureas using oxygen or benzoquinone as the
terminal oxidant.3 The reaction proceeded with excellent
€
~
(2) (a) Streuff, J.; Hovelmann, C. H.; Nieger, M.; Muniz, K. J. Am.
~
Chem. Soc. 2005, 127, 14586. (b) Muniz, K. J. Am. Chem. Soc. 2007, 129,
ꢀ~
~
€
14542. (c) Muniz, K.; Streuff, J.; Hovelmann, C. H.; Nunez, A. Angew.
~
€
Chem., Int. Ed. 2007, 46, 7125. (d) Muniz, K.; Hovelmann, C. H.;
ꢀ
Streuff, J. J. Am. Chem. Soc. 2008, 130, 763. (e) Iglesias, A.; Perez,
E. G.; Muniz, K. Angew. Chem., Int. Ed. 2010, 49, 8109. (f) Muniz, K.;
Streuff, J.; Chavez, P.; Hovelmann, C. H. Chem.;Asian J. 2010, 3, 1248.
~
~
(3) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am.
Chem. Soc. 2005, 127, 7308.
ꢀ
€
r
10.1021/ol300166q
Published on Web 02/24/2012
2012 American Chemical Society

3
~
regioselectivity under mild conditions (60 °C). The Muniz
group also reported the Pd(II)-catalyzed intermolecular
diamination of nonactivated terminal olefins to react with
two different nitrogen sources such as saccharin and di-
benzenesulfonamides using the iodobenzene dipivalate
oxidant.2e Shi et al. elegantly demonstrated that Cu(I)
species can catalyze highly regio- and stereoselective diami-
nations of conjugated dienes or terminal olefins with a
diaziridinone derivative.4 In addition, Chemler et al. showed
that copper(II) acetate promotes the intramolecular diami-
nation of unactivated alkenes to furnish a number of cyclic
sulfamides.5
Table 1. Optimization of the Reaction Conditionsa
entry
oxidant
additive
t (h)
yield(%)b
1
PhI(OAc)2
PhI(OTFA)2
PhI(OH)(OTs)
PhI(OPiv)2
m-CPBA
none
12
12
12
12
12
12
12
12
12
12
12
6
32
<1
5
2
none
3
none
Despite the significant advances made in the metal-
catalyzed synthesis of vicinal diamines, only a few exam-
ples of the corresponding metal-free procedures have been
4
none
<1
NR
30
15
54
57
24
25
80
78
NR
5
none
6
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
none
Cu(OTf)2
TMSOTf
NaCl
6
~
7
revealed. For instance, Muniz et al. reported iodonuim
8
IPy2BF4 (Py = pyridine)-mediated diamination of alkenes
with tethered ureas to afford cyclic ureas at relatively high
temperatures (120 °C).6a Widenhoefer et al. showed that
N-iodosuccinimide (NIS) works as an efficient reagent for
the intramolecular difunctionalization of N-alkenyl ureas.6b
It is noteworthy that a high level of chemoselectivity was
attained by the choice of additives: diamination was opera-
tive in the presence of sodium bicarbonate while a AgOTf
additive led to alkoxyamination to provide isoureas.
In our continuing efforts to develop efficient, selective
CꢀN bond-forming reactions,7 we recently investigated
the synthetic utility of hypervalent iodine(III) species in the
oxidative amination reactions.8
In those studies, we found that the reactivity of iodine-
(III) oxidants was significantly increased by the action of
additives such as Cu(II) species in the intramolecular
synthesis of carbazoles starting from N-amidobiphenyls.8b
We also developed intermolecular chemoselective imida-
tion of aryl sp2 or benzylic sp3 CꢀH bonds using the
PhI(OAc)2 oxidant.8a In this context, we describe herein
a new advance in the oxidative diamination and aminohy-
droxylation of the alkenes tethered with disulfonamides,
ureas, or hydroxysulfonamides using hypervalent iodine
and a halide additive under ambient metal-free conditions.
Optimal diamination conditions were sought using 1a,
stilbene bearing two sulfonamido groups at the ortho-position,
9
NaI
10
11
12
13
14
NaF
NaOAc
n-Bu4NCl
KI
6
n-Bu4NCl
12
a Reaction conditions: 1a (0.1 mmol), iodine(III) oxidant (1.5 equiv),
and additive (1.0 equiv) in DMF (1.0 mL) at rt. b 1H NMR yield (internal
standard: 1,1,2,2-tetrachloroethane).
as a model substrate (Table 1). When 1.5 equiv of PhI-
(OAc)2 was added alone in DMF, the desired bisindoline
product (2a) was observed to form in 32% NMR yield at rt
(entry 1) tosuggest thatametal-freepathway wouldindeed
be possible. This result was surprising in that the role of
iodobenzene diacetate (IBDA) was hypothesized to operate
in only the Pd(II)/Pd(IV) cycle in the diamination method
~
2
developed by Muniz et al. Therefore, this result lead us to
postulate a different role of IBDA in the present case.
We tried to search for a more satisfactory diamination
procedure, especially under metal-free conditions. Unlike
our previous studies wherein electronically more electro-
philic bis(trifluoroacetoxy)iodobenzene (PIFA) displayed
higher reactivity compared to IBDA in the cabazole
synthesis,8b PIFA was ineffective in the present reaction
(entry 2). Different sources of iodine oxidants or m-CPBA
resulted in lower efficiency (entries 2ꢀ5).
(4) (a) Du, H.; Zhao, B.; Yuan, W.; Shi, Y. Org. Lett. 2008, 10, 4231.
(b) Wen, Y.; Zhao, B.; Shi, Y. Org. Lett. 2009, 11, 2365. (c) Zhao, B.; Du,
H.; Shi, Y. J. Org. Chem. 2009, 74, 8392. (d) Cornwall, R. G.; Zhao, B.;
Shi, Y. Org. Lett. 2011, 13, 434. (e) Zhao, B.; Peng, X.; Cui, S.; Shi, Y.
J. Am. Chem. Soc. 2010, 132, 11009.
To improve the reaction efficiency, we subsequently
investigated the additive effects of Lewis acids or other
plausible promotors. Although certain Lewis acids were
previously known to increase the reactivity of hypervalent
iodine(III) oxidants,9 metallic or nonmetallic Lewis acids
were almost ineffective in our case (entries 6ꢀ7). In con-
trast, the addition of NaCl or NaI resulted in a notable
enhancement of the reaction efficiency (entries 8ꢀ9)
(5) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem. Soc. 2005,
127, 11250.
~
€
ꢀ
(6) (a) Muniz, K.; Hovelmann, C. H.; Campos-Gomez, E.; Barluenga,
ꢀ
J.; Gonzalez, J. M.; Streuff, J.; Nieger, M. Chem.;Asian J. 2008, 3, 776.
(b) Li, H.; Widenhoefer, R. A. Tetrahedron 2010, 66, 4827.
(7) (a) Lee, J. M.; Ahn, D.-S.; Jung, D. Y.; Lee, J.; Do, Y.; Kim, S. K.;
Chang, S. J. Am. Chem. Soc. 2006, 128, 12954. (b) Kim, J.; Chang, S.
J. Am. Chem. Soc. 2010, 132, 10272. (c) Kim, J.; Chang, S. Chem.
Commun. 2008, 26, 3052. (d) Cho, S. H.; Kim, J. Y.; Lee, S. Y.; Chang, S.
Angew. Chem., Int. Ed. 2009, 48, 9127. (e) Kim, J. Y.; Cho, S. H.; Joseph,
J.; Chang, S. Angew. Chem., Int. Ed. 2010, 49, 9899. (f) Kim, M.; Chang,
S. Org. Lett. 2010, 12, 1640. (g) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang,
S. Chem. Soc. Rev. 2011, 40, 5068.
(8) (a) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc.
2011, 133, 16382. (b) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc.
2011, 133, 5996. (c) Joseph, J.; Kim, J. Y.; Chang, S. Chem.;Eur. J.
2011, 6, 2040.
(9) (a) Hashem, Md. A.; Jung, A.; Ries, M.; Kirschning, A. Synlett
1998, 195. (b) Kirschning, A.; Hashem, Md. A.; Monenschein, H.; Rose,
€
L.; Schoning, K.-U. J. Org. Chem. 1999, 64, 6522.
(10) It has been known that certain halide additives improved reac-
tion efficiency especially in olefin-containging reactions and cycliza-
tions: (a) Fan, R.; Ye, Y. Adv. Synth. Catal. 2008, 350, 1526. (b) Fan, R.;
Ye, Y.; Li, W.; Wang, L. Adv. Synth. Catal. 2008, 350, 2488. (c) Ye, Y.;
Zheng, C.; Fan, R. Org. Lett. 2009, 11, 3156. (d) Ye, Y.; Wang, H.; Fan,
R. Org. Lett. 2010, 12, 2802.
Org. Lett., Vol. 14, No. 6, 2012
1425

whereas the effectofNaF orNaOAcwasnegligible(entries
10ꢀ11).10 The highest additive effect was observed with
tetrabutylammonium chloride (entry 12) or KI (entry 13).
No conversion was achieved with n-Bu4NCl alone in the
absence of the iodine(III) oxidant (entry 14).
Table 2. Diamination and Aminohydroxylation of Alkenesa,b
Scheme 2. Reactivity Dependence on the N-Substituent Groups
As anticipated, it was observed that the choice of
N-substituents of substrates dramatically influenced the
reaction efficiency (Scheme 2). While unsubstituted 2,20-
diamino-(E)-stilbene was totally inert, substrates bearing
N-acetyl or N-(tert-butyloxycarbonyl) (Boc) groups were
partially decomposed under the employed conditions. In
contrast, N-sulfonamido stilbenes were readily cyclized to
afford the corresponding bisindolines, and the reactivity
was dependent on the type of sulfonamides. Among those
examined, the highest product yield was obtained with a
substratebearing aN-benzenesulfonamidogroup followed
by N-Ts and N-Ns compounds.
Stereochemical assignment of the obtained compounds
was based on the 1H NMR coupling constants. The coupl-
ing constants of the isolated bisindoline products (2aꢀ2c)
were measured to be 6.9ꢀ8.5 Hz, matching the values of
known syn-isomers (J = 7ꢀ10 Hz). In the case of the
corresponding trans-isomers, J-values are known to be in
the range 0ꢀ2 Hz.12 In addition, other spectroscopic data
of the isolated bisindolines and ureas completely matched
those previously reported.2a,b
Under the above optimized conditions using the PhI-
(OAc)2 oxidant (1.5 equiv) and n-Bu4NCl additive (1.0
equiv), a range of substrates were subsequently examined
to study the feasibility of the present reaction (Table 2).
The position of substituents in the arene part did not
significantly influence the reaction efficiency as demonstrated
by entries 2 and 3. The bisindoline products were isolated in
high yields regardless of the electronic variation on substrates
employed. Indeed, the introduction of electron-withdrawing
substituents such as fluoro or ester groups did not diminish
the reaction efficiency (entries 4 and 5, respectively). With the
use of a naphthalene-derived substrate, the cyclization took
place smoothly to furnish the corresponding product in good
yield (entry 6). An unsymmetrical bisindoline skeleton having
a Reaction conditions: substrate (0.1 mmol), PhI(OAc)2 (0.15 mmol),
and n-Bu4NCl (0.1 mmol) in DMF (1.0 mL) at rt for 6 h. b Isolated yield.
c CH2Cl2 (1.0 mL) was used as solvent. d KI (1.0 equiv) was used instead
of ammonium salt.
(11) Cochran, B. M.; Michael, F. E. Org. Lett. 2008, 10, 5039.
(12) Silverstein, R. M.; Webster, F. X.; Kiemle, D. J. Spectrometric
Identification of Organic Compounds; John Wiley & Sons: New York-
London, 2005.
two different aryl parts was obtained without difficulty in
high yield (entry 7).
1426
Org. Lett., Vol. 14, No. 6, 2012

A urea functional group was widely used as a nitrogen
source in the intra- or intermolecualr olefin diamination
reactions under Pd catalysis3,6a or Lewis acid mediated
conditions.11 We, therefore, prepared several alkenyl ureas,
and those substrates were subjected to the optimized con-
ditions. We were pleased to observe that the desired diami-
nation reactions occurred readily to afford 5,5- and 5,6-
fused bicyclic urea products in satisfactory yields (entries
8ꢀ11). Not only terminal olefins but also internal double
bonds particiapted in the oxidative cyclization with similar
efficiency (entry 11).
Scheme 4. Proposed Mechanistic Pathway
With our great delight, the above diamination protocol
was successfully applied to the aminohydroxylation reac-
tion of stilbenes substituted with a hydroxyl and sulfon-
amide group at the ortho-position. Under identical reac-
tion conditions, saturated benzofuroindole products were
obtained in moderate to high yields (entries 12ꢀ14). To the
best of our knowledge, this example represents the first
aminohydroxylation reaction of those substrates under
metal-free conditions.13
assumed that PhI(OAc)2 initially reacts with a halide to
give a halide-exchanged halonium species A which is
subsequently converted to active acetyl hypohalite B.14 It
is postulated that olefin is halogenated upon electrophilic
addition of the double bond by B to afford a halonium
intermediate C. However, instead of forming the hypoha-
lite species B, the possibility that Ph-I-OAc generated by
IBDA can react with olefin to afford the halonium inter-
mediate C cannot be completely ruled out at this stage.16
An intramolecular addition of a sulfonamido group into
the halonium carbon center yields an aminohalogenated
intermediate D which subsequently undergoes an SN2
replacement reaction finally leading to syn-products with
complete selectivity.
Scheme 3. In Situ IOAc Generation Test
In conclusion, we have developed a facile procedure for
intramolecular oxidative diamination of olefins. The reac-
tion proceeds at ambient temperature under metal-free
conditions. For the first time, aminohydroxylation was
also achieved using alkenes tethered with nitrogen and
oxygen atom sources. The halide additive was crucial for
exerting the high reactivity of the iodobenzene diacetate
oxidant to generate an active hypohalite species.
In the oxidative olefin aziridination using the iodine(III)
oxidant and halide additives, it was postulated that acetyl
hypohalite was generated under in situ conditions and the
species was assumed to activate the substrate’s double
bonds more efficiently.10,14 To examine the validity of this
mode of activation in our present reactions, preliminary
studies were next performed (Scheme 3).15 While no con-
version was observed by the single action of I2 (conditions A),
the addition of PhI(OAc)2 resulted in significantly increased
reactivity (conditions B) which was much higher than that
obtained from conditions C using PhI(OAc)2 alone.
Acknowledgment. This work was supported by the
National Research Foundation (KRF-2008-C00024) and
MIRC (NRF-2011-0001322). We acknowledge the Korea
Basic Science Institute for the mass analysis.
Supporting Information Available. Experimental de-
tails, and 1H and 13C NMR spectra of new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
A proposed pathway of the present diamination and
aminohydroxylation reactions is shown in Scheme 4. It is
(13) Widenhoefer reported an intramolecular alkoxyamination of
alkenes with N-sulfonylureas by employing NIS (ref 6b).
(14) Doleschall, G. Tetrahedron 1980, 36, 1649.
(15) (a) Courtneidge, J. L.; Lusztyk, J.; Page, D. Tetrahedron Lett.
1994, 35, 1003. (b) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2008, 47, 5215. (c) Mei, T.-S.; Wang, D.-H.; Yu, J.-Q.
Org. Lett. 2010, 12, 3140.
(16) Boye, A. C.; Meyer, D.; Ingison, C. K.; French, A. N.; Wirth, T.
Org. Lett. 2003, 5, 2157.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 6, 2012
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