Iodine(III)-mediated intermolecular allylic amination under metal-free conditions

Article abstract of DOI:10.1021/ja3013193

A new approach to direct intermolecular allylic amination has been developed using metal-free conditions at room temperature. The reaction employs a hypervalent iodine(III) reagent as an oxidant and bistosylimide as a nitrogen source. A series of different allylic aminations are presented with up to a 99% yield. Mechanistic studies including isotope labeling and Hammett correlation suggest that depending on the substrate structure two different mechanisms can be operating.

Full text of DOI:10.1021/ja3013193

Communication
pubs.acs.org/JACS
Iodine(III)-Mediated Intermolecular Allylic Amination under
Metal-Free Conditions
Jose A. Souto,† Debora Zian,† and Kilian Muniz*,†,‡
́
̃
†Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
‡Catalan Institution for Research and Advanced Studies (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain
S
* Supporting Information
amination employing a hypervalent iodine(III) reagent that falls
into this category (right pathway).
ABSTRACT: A new approach to direct intermolecular
allylic amination has been developed using metal-free
conditions at room temperature. The reaction employs a
hypervalent iodine(III) reagent as an oxidant and
bistosylimide as a nitrogen source. A series of different
allylic aminations are presented with up to a 99% yield.
Mechanistic studies including isotope labeling and
Hammett correlation suggest that depending on the
substrate structure two different mechanisms can be
operating.
A study on the oxidation of α-methyl styrene 2a with
iodosobenzene diacetate and bistosylimide did not undergo the
expected diamination, but gave rise to an unexpected oxidation
product, which was identified as the allylic amination product
3a. Optimization of the reaction was straightforward and
provided conditions that enable the selective oxidation of 2a to
3a in high yield (Table 1). Coinciding with an earlier
Table 1. Discovery and Optimization of Metal-Free Allylic
Amination
llylic amines represent versatile building blocks for the
A
synthesis of organic molecules of higher complexity.
Direct allylic amination reactions functionalizing C−H bonds
constitute an attractive single-step approach to this compound
class. Such C−H activation processes traditionally require the
use of metal promoters.1,2 Reactions of this type have been
developed using the powerful methodology of metal catalyzed
nitrenoid insertion into allylic C−H bonds,3 metal catalyzed
C−H activation followed by nucleophilic additions of anionic
nitrogen sources,4 or application of aza-Wacker reactions.5 Both
intra- and intermolecular reaction pathways have become
available for these elegant metal-mediated allylic amination
reactions.
a
entry
conditions
yield [%]
1
2
3
4
5
Phl(OAc)2 (1.2 equiv), HNTs2 (2.4 equiv), 25 °C
1 (1.1 equiv), 25 °C
1 (1.1 equiv), HNTs2 (0.2 equiv), 25 °C
1 (1.1 equiv), HNTs2 (1.2 equiv), 25 °C
1 (1.4 equiv), HNTs2 (1.5 equiv), 25 °C
45
50
54
62
87
a
Isolated yield after purification.
observation,13 dichloromethane represents the best solvent
for oxidation with 1 and reactions proceed readily at room
temperature. Most importantly, use of the preformed reagent 1
alone was not sufficient (entry 2). Addition of a catalytic
amount of additional imide showed an effect (entry 3), and an
equimolar combination of 1 and bistosylimide significantly
enhanced the yield (entry 4). Finally, in the presence of 1.4
equiv of oxidant 1 complete conversion took place leading to
an isolated yield of 87% for 3a (entry 5). The reaction is very
robust and was routinely conducted on a 5-mmol scale. It adds
to the recent development of metal-free amination reactions of
C−H bonds.9−12
Under the optimized conditions a series of different α-methyl
styrenes 2 were submitted to provide the corresponding allylic
amination products 3 in good to excellent yields. These
reactions proceed readily at room temperature, and quantitative
conversion is obtained in less than 24 h. Common substituents
are all tolerated by the procedure. Different substitution
patterns include para-substitution (Table 2, entries 2−8),
With the introduction of a selenium reagent, an early
exception was described by Sharpless.6 In addition, other metal-
free amination processes involving formal C−H activation have
recently evolved as an attractive synthetic alternative to metal-
mediated reactions.7 These reactions proceed under mild
conditions, are safe to handle, and do not pose major toxicity
problems. In particular, hypervalent iodine(III) reagents8 have
enabled the development of unique amination reactions such
as carbazole synthesis9,10 and direct aromatic and benzylic
amination,11,12 respectively.
We have recently introduced the mixed hypervalent iodine
reagent PhI(OAc)NTs2 (1) and described its use in unpre-
cedented intermolecular diamination reactions (Scheme 1, left
pathway).13,14 We herein describe a new metal-free allylic
Scheme 1. Alkene Oxidation with 1: Diversification
Received: February 9, 2012
Published: April 16, 2012
© 2012 American Chemical Society
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Communication
methylene position. Protonolysis of the iodine-acetate bond
in B from free bistosylimide generates an intermediate C with
pronounced electrophilicity at iodine. At this stage, the
presence of the tertiary carbon center prevents diamination
through nucleophilic substitution. Instead, subsequent elimi-
nation gives rise to the final product 3a-d2 with correct
deuterium labeling (Figure 1). Making use of deuterium
labeling, two competition experiments were employed to
further elucidate the mechanistic context (Scheme 2). First, a
Table 2. Metal-Free Allylic Amination of α-Methyl Styrenes
Scheme 2. Competition Experiments
1:1 mixture of α-methyl styrene 2a and its terminally
bisdeuterated derivative 2a-d2 were submitted to allylic
amination. No secondary kinetic isotope effect was observed
indicating that alkene coordination to the iodine reagent is
rather fast and probably of a reversible nature. In contrast, for
competition between 2a and its deuterated methyl derivative
2a-d3 a strong primary isotope effect kH/kD = 5 was observed,
which is in agreement with expected values for a rate-
determining elimination step,17 and with the established leaving
group character of the electrophilic iodine(III).18 Such a
postulated mechanism is in further agreement with a Hammett
correlation study15 employing α-methyl styrenes 2a,d−g, which
shows a moderate ρ-value of −1.5 and hence demonstrates
enhanced reactivity for electron-rich arenes over the ones
bearing electron-demanding substituents in the formation of
the cationic intermediate arising from C.19
In addition to α-methyl styrenes the new allylic amination
reaction proceeds readily with a series of other alkenes 4a−k as
well (Table 3). For example, cyclohexane 4a gives rise to the
selective formation of the corresponding allylic amine 5a (entry 1).
Exocyclic alkenes 4b and 4c undergo selective allylic amination
to the corresponding products 5b,c, the latter one with an
exceptional rate (entries 2,3). The migration of the double
bond into the ring is in agreement with the mechanistic
proposal from Figure 1. For substrate 4d, the existence of two
different allylic C−H groups for elimination results in the
formation of regioisomers 5d/5f and 5d′ in a 3:2 ratio
suggesting a preference for the benzylic position and therefore
for products 5d/5f with its conjugated double bond (entry 4).
Related product mixtures of up to 3:1 were observed for gem-
disubstituted alkenes 4e−g (entries 5−7) demonstrating the
requirement for regioselective opening of the initial iodocyclo-
propane. Even a tert-butyl-substituted alkene 4h underwent
clean amination (entry 8), although at a reduced rate due to
steric congestion. As the only exception to the broad substrate
scope so far, 2-methyl-2-hexene did only react at a low rate to
give two isomeric allylic amides in an ∼10% yield.15 Gratifyingly,
for substrate 4i, an exclusive preference for allylic amination over
the potential formation of a propargylic amine was observed and
amine 5i was the only obtained oxidation product (entry 9). The
trisubstituted styrene 4j led exclusively to allylic amination
a
Isolated yield after purification.
meta-substitution (entries 9,10), and a naphthyl derivative
(entry 11). Attempts to carry out the corresponding allylic
amination of 2-bromo α-methyl styrene led to less than 10%
conversion over a period of 48 h. Electron-donating
substituents were found to proceed at a higher rate, and in
the case of 4-methoxy α-methyl styrene, complete conversion
was obtained after 15 min. Unfortunately, product 3h was
found to be rather unstable leading to significant degradation
during isolation and purification, which resulted in a low
isolated yield (entry 8). In all other cases, the obtained products
3 are stable compounds, which due to the bissulfonimide group
display high crystallinity.
For related iodine(III)-mediated C−H amination reactions,
radical pathways were postulated.9−12 In our case, a control
experiment showed that the presence of N-tert-butyl-α-
phenylnitrone, a radical trap compatible with iodine(III)
reagents,9 does not affect the conversion of 2a to 3a.15 Another
experiment with selectively deuterated 2a-d3 gave rise to the
corresponding bisdeuterated product 3a-d2 (Figure 1). The
Figure 1. Mechanistic proposal.
observation of a selectively deuterated product excludes a
potential radical abstraction mechanism. Instead, the present
allylic oxidation of compounds 2 proceeds under double bond
isomerization. We postulate a mechanism that starts with the
formation of a iodo(III)cyclopropane A14g,16 followed by
regioselective opening at the more accessible terminal
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Journal of the American Chemical Society
Communication
oxidant 1, bisaminated product 5m was obtained as the only
product in 60% yield according to the H NMR spectrum of
Table 3. Metal-Free Allylic Amination: Substrate Scope
1
the crude reaction mixture. This observation suggests that the
second allylic amination on 5l is faster than the initial one with
4l. Purification of product 5m was found to be difficult due to
instability; however, a reasonable yield of 31% could be isolated
(entry 13).
The latter examples show that, under certain conditions,
allylic amination proceeds without double bond migration. For
product 5j, structural assignment was further assured through
an X-ray crystallographic analysis.15 The operating mechanism
for this reaction is suggested to start from an interaction
between the iodine(III) reagent 1 and the alkene in 4j (Figure 2).
Figure 2. Mechanistic proposal for amination of 4f.
For the resulting intermediate D, nucleophilic ring opening
would require SN2 reactions at a neopentylic or a quaternary
position, respectively. As a consequence, elimination to E is
believed to take place at this stage followed by either direct SN2′
reaction or via an allylic cationic intermediate F to give the
thermodynamic product 5j.
These latter results prove that reactions without double bond
migration are equally feasible under the conditions of this new
metal-free allylic amination. Hence, depending on the substrate
structure, the reaction provides remarkable mechanistic flexibility.
To demonstrate the successful posterior manipulation of the
sulfonyl groups at nitrogen, product 3a was submitted to
deprotection with Red-Al in toluene. Clean removal of one
tosyl group to monosulfonylated 6 was observed, and upon
methylation under standard conditions, quantitative formation
of 7 was obtained (Scheme 3). This compound has been
reported as a precursor to several potent herbicides.20
Scheme 3. Deprotection sequence
a
b
c
Isolated yield after purification. 5 min reaction time. Ratio 5d/5f =
1/2; ratio 5e/5e′ = 2/1; ratio 5f/5f′ = 1/1; ratio 5g/5g′ = 3/1.
d
e
f
Combined yield of isomers. 14 h reaction time. 10 h reaction time.
g
h
In summary, we have described conditions for new metal-free
direct allylic amination reactions. The reaction is operationally
simple using only the defined hypervalent iodine(III) 1 as a
reagent and bistosylimide as a nitrogen source. It proceeds
under mild conditions, and a range of substituents and
functional groups are tolerated. Two mechanistically different
pathways have been identified to operate within this new
transformation, enabling an attractive allylic amination of a
series of substrates.
3 equiv of alkene, 12 h reaction time. Yield from crude reaction
mixture in brackets.
product 5j. This outcome is particularly interesting in view of
the earlier observation of selective diamination for the related
case of β-methyl styrene.13 Methylated stilbene 4k under-
went allylic amination as well. Here, the reaction gives rise to
selective allylic amination in 77% yield, but proceeds with
formation of two isomeric double bonds of the final stilbene 5k
[(Z)/(E) = 1/2.5] (entry 11). 1,3-Diene 4l undergoes rapid
allylic amination. In order to achieve monoamination to 5l, an
excess of the substrate was employed and the expected product
was isolated in 92% yield (entry 12). Using a 1:3 ratio of 5l and
ASSOCIATED CONTENT
* Supporting Information
Complete experimental details and characterization data for new
■
S
compounds, including CIF file on the X-ray crystallographic
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Journal of the American Chemical Society
Communication
W. Aust. J. Chem. 2010, 63, 653. (g) Zhdankin, V. V. ARKIVOC 2009,
1, 1. (h) Hypervalent Iodine in Organic Chemistry: Chemical
Transformations; Moriarty, R. M., Prakash, O., Eds.; Wiley-
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(j) Ochiai, M. Chem. Rec. 2007, 7, 12. (k) Topics in Current Chemistry;
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analysis of 5j. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
kmuniz@iciq.es
■
Notes
(9) Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J. Angew.
Chem., Int. Ed. 2011, 50, 8605.
The authors declare no competing financial interest.
(10) Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133,
5996.
(11) (a) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem. Soc.
2011, 133, 16382. (b) Samanta, R.; Lategahn, J.; Antonchick, A. P.
Chem. Commun. 2012, 48, 3194.
ACKNOWLEDGMENTS
This work was supported by the ICIQ Foundation and by the
Spanish Ministerio de Economıa y Competitividad (CTQ2011-
25027).
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(12) Kantak, A. A.; Potavathri, S.; Barham, R. A.; Romano, K. M.; de-
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