Autoinductive conversion of α,α-diiodonitroalkanes to amides and esters catalysed by iodine byproducts under O2

Article abstract of DOI:10.1039/c8cc03191f

Studies to convert nitroalkanes into amides and esters using I₂ and O₂ revealed in situ-generated iodine species facilitate the homolytic C-I bond cleavage of α,α-diiodonitroalkanes, arguably in an autoinductive or autocatalytic manner. Consequently, we devised a rapid and economical I₂/O₂-based method to synthesise sterically hindered esters directly from primary nitroalkanes.

Full text of DOI:10.1039/c8cc03191f

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DOI: 10.1039/C8CC03191F
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Autoinductive Conversion of ,-Diiodonitroalkanes to Amides
and Esters Catalysed by Iodine Byproducts under O2
Jing Li, a Martin J. Lear* b and Yujiro Hayashi* a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
Studies to convert nitroalkanes into amides and esters using I2 and
O2 revealed in situ-generated iodine species facilitate the homolytic
C–I bond cleavage of ,-diiodonitroalkanes, arguably in an
autoinductive or autocatalytic manner. Consequently, we devised
a rapid and economical I2/O2-based method to synthesise sterically
hindered esters directly from primary nitroalkanes.
It is not trivial to decipher the most meaningful and productive
pathway within a multistep reaction process.1 A case in point
comes from our studies to transform primary nitroalkanes
directly into amides in the presence of I2, O2, bases, and
nucleophilic amines (Figure 1a; HNu = HNR’R’’).2–4 From these
studies, we found the doubly -iodinated derivative of the
nitroalkane
to be key to the oxidative process.2b In contrast to
mechanisms involving the -amination of -bromonitroalkanes
with electrophilic N-iodinated amines,5 we have proposed the
amide product is generated by nucleophilic amine attack on
the acyl derivative , as derived by addition of O2 onto through
the homolytic cleavage of C–I bonds.2b
Clearly the acyl derivative can also react with other
1
4
Fig. 1 Proposed oxidative conversion of (a) nitroalkanes 1 to acyl derivatives 3 and 4 via
the (b) autoinductive reaction of the nitro-diiodide intermediate 2 with increasing
concentrations of catalytically-active iodide byproducts derived from 2 and I2.2,7

2
1


Most strikingly, the reactions from 2a to
6 (Eq. (1)) with
relatively weak nucleophiles (CH3OH, CF3CH2NH2) displayed
clear sigmoidal kinetic profiles at room temperature on the
NMR timescale (Fig. 2, red and black curves). In contrast, the
initial reaction between 2a and benzylamine proceeded
exponentially with no slow induction period at room
temperature, whereas an uncommon sigmoidal profile was
observed at –10 °C (Fig. 2, cyan and blue curves). Several
mechanistic reasons can be attributed to causing such sigmoidal
4
3
2
3
nucleophiles, such as residual water to form carboxylic acids
and alcohols to form esters. Indeed, we have previously isolated
carboxylic acids
4
(HNu = HOH) as side-products.2 If made
synthetically useful under mild conditions with less nucleophilic
amines or alcohols, we could expand the one-pot
transformation of nitroalkanes into other useful
functionalities.6 Herein, we detail our mechanistic development
kinetic profiles: For instance, the final product,
an
intermediate-product, a byproduct or a side-product of the
reaction could be accelerating a rate-determining step in a
chain-like, cross-catalytic, autoinductive or autocatalytic
fashion.7 We thus decided to study the oxidative conversion of
of oxidatively converting primary nitroalkanes
diiodonitroalkanes under O2, into sterically congested esters
(HNu = HOR’). This method was achieved by realising that the
rate-limiting step during the conversion of to is autoinduced
by the iodine byproducts derived from
itself (Fig. 1(b)).7
1, via ,-
2
the ,-diiodonitroalkane 2a to the carboxylic derivatives 7/8
4
systematically and quantify the kinetic effects of adding each
2
3
1
identifiable reaction product at 20 mol% by H NMR analysis
2
(Eq. (2), Figure 3).
In the first instance, without any additives, the methyl ester
7
and carboxylic acid 8 were isolated in 75% and 25% yield,
a.Department of Chemistry, Graduate School of Science, Tohoku University, Aza
Aramaki, Aoba-ku, Sendai 980-8578, Japan. E-mail: yhayashi@m.tohoku.ac.jp
b.School of Chemistry, Brayford Pool, University of Lincoln, Lincoln LN6 7TS, United
Kingdom. E-mail: mlear@lincoln.ac.uk
respectively, and characterized by 1H NMR (Eq. (2)). This
reaction under standard conditions also produced nitrite salts
(KNO2)2b and I2 crystals as byproducts, as detected by ion
chromatography and observed after solvent removal. Next, we
†
Electronic
DOI: 10.1039/x0xx00000x
Supplementary
Information
(ESI)
available.
See
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monitored the effect of adding each reaction product at the observable induction period (Fig. 3(b), blue curve).
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start of the reaction, including the ester
and hydrogen carbonate salts (Fig. 3(a)). All these cases observed in the case of CF3CH2NH2 reacting with 2a to form the
7, carboxylate 8
, nitrite Furthermore, a similar iodide-mediated aDccOeI:le10ra.1t0i3o9n/Ce8fCfeCc0t3w19a1Fs
displayed sigmoidal kinetic profiles similar to the reaction with amide
no additives, although small variations in initial induction times support iodide byproducts (In ) as the principal species which
6
(XR’ = NHCH2CF3; see ESI†). Collectively, these data
–
were observed.
catalyse the oxidative conversion of the diiodide 2a to the ester
7
under O2.
90
80
70
60
50
40
30
20
10
0
90
80
(a)
70
60
50
40
30
20
10
0
additive:
MeOH (r.t.)
CF3CH2NH2 (r.t.)
none
Ph(CH2)2COOMe
Benzylamine (r.t.)
Benzylamine (-10 °C)
KHCO3
KNO2
Ph(CH2)2COOK
I2
0
20
40
60
80
100
120
140
160
Time (minutes)
0
20
40
60
80
100
120
Fig.2 1H NMR profiles of -diiodonitroalkane 2a reacting with MeOH (5 equiv.) or an
amine (1.5 equiv.) to form product 6 according to Eq. (1).
Time (minutes)
90
80
(b)
Eventually, I2 was selected as an additive to the reaction (Eq.
(2); Fig. 3(b)). This gave a dramatic improvement in the initial
reaction rate, similar to conventional pseudo-first-order kinetic
profiles (Fig. 3(a), red curve). Here the addition of I2 gave a
sustained purple-red colour throughout the course of the
reaction. In comparison, without pre-adding I2, the reaction
turned from yellow to a similar purple-red colour after 30
minutes, at which time the rapid formation of the ester product
70
60
50
40
30
20
10
0
NEt4I
I2
7
was clearly observed (Fig. 3(a), black curve). The effect of I2
was therefore studied in more detail by monitoring the in situ
consumption of the -diidonitroalkane 2a and the in situ
formation of ester by React-IR (Fig. 3(b)). Again, we followed
None
NIS
,
7
0
20
40
60
80
100
120
the standard reaction without any additives (Eq. (2)) and,
although the IR-data were consistent with our initial H NMR
Time (minutes)
1
analysis, the 0–40 min induction periods were better resolved
(cf. Fig. 3(a), black curve; Fig. 3(b), blue curve). Addition of I2 also
gave a similar conventional kinetic profile to our 1H NMR
Fig. 3 Normalised profiles of,-diiodonitroalkane 2a reacting with MeOH (5 equiv.) to
form methyl ester 7 according to Eq. (2): (a) 1H NMR analysis with various reaction
product additives (20 mol%); (b) React-FT-IR analysis with various iodine sources (20
mol%), except NMR was used for NIS.
analysis, which produced the desired ester
Fig. 3(a) and Fig. 3(b), red curves).
7 within 80 min (cf.
Since I2 can act as a dual source of cationic iodonium species
–
(I+) and anionic iodide species (I3 or I–) in solution,8 we
performed separate reactions either by adding 20 mol% of NIS
as an I+ source or by adding 20 mol% of NEt4I as an I– source.
While NIS demonstrated a slight retardation on the initial
reaction rate (cf. Fig. 3(b), purple and blue curves), NEt4I
dramatically accelerated the overall reaction rate and gave no
The mechanistic implications of these findings are thought
provoking, especially when we take related studies into
account.2,4,5 Several mechanistic observations are worth noting:
(1) From previously reported radical clock experiments, the
2 | J. Name., 2012, 00, 1-3
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radical 10 is an evidenced key intermediate in this process.2b (2) absence of In species thus accounts for the observed 30–40
–
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The direct reaction of O2 to generate the radical 10 from an
iodo, -nitro, -carbanion , which can conceivably be formed generated, however, through alternative reaction pathways, for
by ionic attack of an iodide anion or another nucleophile onto example, through slow C–NO2 C–ONO homogenic
an -diiodonitroalkane , can be ruled out from our previous rearrangement, C–I homolytic bond cleavage, or by nucleophilic
experiments.2b (3) The reaction remains unaffected by light attack on the gem-diiodide 2 2,5
exposure, which indicates that the homolytic cleavage of the To provide evidence of possible nucleophilic attack on
carbon-iodine bond of via photo-activation can be ruled out. releasing iodide, the differing kinetic profiles of benzylamine at
-
minute induction periods (cf. Fig. 2 and DFOigI.: 130).1.0I3o9d/Cid8eCCc0a3n19b1eF


9
a

,

2
.
2
2
(4) Experiments with the addition of relatively non-nucleophilic room temperature and –10 °C were studied in more detail (see
radical initiators (e.g., (PhCO)2O2 or AIBN at 50 °C) or radical Fig. 2). Firstly, the addition of 20 mol% of NEt4I for the reaction
inhibitors (e.g. TEMPO at 25 °C) were found to not alter the at –10 °C (cf. Eq. (1)) exhibited a conventional kinetic profile
induction periods under our reaction conditions and substrates. with no induction period—see ESI† for comparative reaction
Such additive effects would be expected to be significant for profiles of benzylamine in CD3CN by 1H NMR analysis. Secondly,
radical chain reactions, but not for iodine-atom transfer without iodide additives at room temperature, 1H NMR
reactions (see ESI†).7d
experiments showed that benzylamine forms an amine halogen
bonded complex with 2a and a mono-iodinated derivative
9
,
as well as benzaldehyde after work up (see ESI†). Thirdly, the
same amine complex of 2a was also observed at –10 °C, but
deiodinated 2a and benzaldehyde were not detected.
Collectively, this evidence indicates 2a can transfer an iodine to
the amino group of benzylamine at room temperature, which
likely results in imine formation and the release of iodide
catalyst. In further support of the need to release iodide, we
also observed the accelerating effect of adding strong
nucleophiles such as PPh3 and SMe2 (see ESI†). Indeed, under
unfavorable conditions with weak nucelophiles, the
,-
diiodonitroalkane 2a is suggested to produce iodide byproducts
relatively slowly.2b Reactions with methanol at room
temperature or benzylamine at –10 °C thus necessitate the
gradual generation of iodide anions in sufficient concentrations
to catalyse the formation of the radical 10 from 2a, as reflected
in their kinetic profiles (cf. Scheme 1, Fig. 2 and Fig. 3).
On the mechanistic basis of iodide-mediated autoinduction,
we thus decided to explore the direct oxidative esterification
between primary nitroalkanes and primary alcohols with a slight
excess of I2 (1.2 equiv.) under a variety of basic conditions (see
Scheme 2 and ESI† for optimization studies). Compared to
conventional methods, which first convert primary nitroalkanes
to carboxylic acids before ester formation,14 our aim was to
Scheme 1. Proposed autoinduction of -diiodonitroalkanes 2 by virtue of increasing
concentrations of catalytically active iodide species (In–).2,7–13
Based on these results, our autoinductive interpretation
between the

,

-diiodonitroalkane 22b and iodine byproducts
–
(Fig. 1(b)) is presented in Scheme 1. As iodide anions (In ) are
known to be good electron donors and can afford alkyl radicals
from alkyl iodides,9–12 it is reasonable to expect iodine-atom
transfer from the more highly electron deficient
,-
diiodonitroalkane
2
to I–. This process would give a putative
diiodide radical anion (I2•–) and the previously evidenced carbon
radical 102b (Scheme 1). The subsequent reaction of carbon
radical 10 with oxygen would be similar to the mechanism we
established during the oxidative Nef reaction of nitroalkanes
with molecular oxygen.3b That is, the radical 10 reacts with O2
develop
challenging esters via in situ
a
one-pot method to directly make sterically
-diiodonitroalkanes from

,

2
readily prepared, but hindered primary nitroalkanes 12
(Scheme 2).6 Here, 1.2 equivalents of I2 were considered to be
sufficient because I– would oxidise to I+ under O2, as reported
previously.2b Thus I2 was chosen to act as a source of iodonium
to generate the peroxy-adduct 11 12
,
which would provide the
•–
dioxirane 5 2,3b,4
.
The I2
byproduct can then couple
cations to not only form
to facilitate the homolytic cleavage of
carbon-radical 10 (cf. Scheme 1).8 Experimentally, the
-hydroxy, -alkyl, -benzyl or -phenyl functionalized 
trisubstituted methyl esters 13a all formed in good yields in a
direct and rapid manner (Scheme 2). Although an increase in the
bulkiness of the -position of the starting nitroalkane gave
slightly longer reaction times, the yields remained good (cf.
2
, but also to form iodide byproducts
to the O2-reactive
-amino,
homogenically with mono-iodine (I•) to generate I3– as a known
source of I2 and I–.8 Latterly, in addition to our previous
2

proposal,2a dioxiranes
acyl derivative
through the action of I– anions.13
5 can also conceivably transform to the




-
3
–f
Under this mechanistic framework, the observed
autoinduction profiles of Fig. 2 and Fig. 3 would be explained as
follows: As diiodine (I2) is also a source of electrophilic mono-
iodine (I+) and an extra equivalent of anionic mono-iodide (I–),8

13d–f
). Conveniently, the
-chiral trisubstituted esters 13g/h
the iodide byproducts of
2 can increase up to two-equivalents
and
-lactone 15 can be prepared in high enantioslectivity from
during every turn of this cycle, making the reaction
autoinductive (cf. Fig. 1(b) and Scheme 1).7–13 The initial
chiral nitroalkanes via the asymmetric organocatalysed Michael
reaction of nitromethane with -disubstituted -enals.15
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Notes and references
View Article Online
DOI: 10.1039/C8CC03191F
1
Perspectives on deciphering organic reaction mechanisms: (a)
D. G. Blackmond, Angew. Chem. Int. Ed., 2005, 44, 4302–4320;
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Wu, J. Am. Chem. Soc., 2015, 137, 1706–1725.
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(a) J. Li, M. J. Lear, Y. Kawamoto, S. Umemiya, A. Wong, E.
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,
12986–12990; (b) J. Li, M. J. Lear, E. Kwon and Y. Hayashi,
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(a) Y. Hayashi and S. Umemiya, Angew. Chem. Int. Ed., 2013,
52, 3450–3452; (b) S. Umemiya, K. Nishino, I. Sato and Y.
Hayashi, Chem. Eur. J., 2014, 20, 15753–15759.
Challenging O2-mediated amidations of 1,1-dicyanoalkanes
via dioxiranes and acyl cyanides: J. Li, M. J. Lear and Y. Hayashi,
Angew. Chem. Int. Ed., 2016, 55, 9060–9064.
3
4
5
For umpolung amidation mechanisms via putative N-iodo
amines, see: (a) B. Shen, D. M. Makley and J. N. Johnston,
Nature, 2010, 465, 1027–1032; (b) Shackleford, J. P.; Shen, B.;
Johnston, J. N. Proc. Natl. Acad. Sci. USA 2012, 109, 44–46; (c)
K. E. Schwieter, B. Shen, J. P. Shackleford, M. W. Leighty, J. N.
Johnston, Org. Lett., 2014, 16, 4714–4717.
6
Classical and emerging uses of nitroalkanes in synthesis: (a) D.
Seebach, E. W. Colvin, F. Lehr and T. Weller, Chimia, 1979, 33
,
1–18; (b) A. G. M. Barrett, D. Dhanak, G. G. Graboski and S. J.
Taylor, Organic Synthesis, 1989, 68, 8–13; (c) N. Ono, The
Nitro Group in Organic Synthesis, Wiley-VCH, New York, 2001;
(d) R. Ballini and M. Petrini, Tetrahedron, 2004, 60, 1017–
1047; (e) M. W. Leighty, J. P. Shackleford, B. Shen and J. N.
Johnston, Proc. Natl. Acad. Sci. USA, 2012, 109, 44–46.
Scheme 2. Oxidative esterification and lactonisation of readily prepared primary
nitroalkanes into sterically congested methyl or ethyl esters.
7
8
9
Such reactions can be argued to be autoinductive or
autocatalytic. For leading perspectives in catalysis, see: (a) D.
G. Blackmond, Angew. Chem. Int. Ed., 2009, 48, 386–390; (b)
A. J. Bissette and S. P. Fletcher, Angew. Chem. Int. Ed., 2013,
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In summary, the direct aerobic conversion of
,-
diiodonitroalkanes to amides or esters with relatively weak
2
nucleophiles was found to display unusual sigmoidal reaction
profiles, as evidenced by quantitative 1H NMR and React-IR
studies (Fig. 3). Systematic addition of sub-stoichiometric
Extensive equilibria can occur between I2, I– and I3– in solution.
Alternative [In]– species are thus conceivable catalysts: (a) R.
L. Benoit, M. F. Wilson and S.-Y. Lam, Can. J. Chem., 1977, 55
,
amounts of potential products derived from
2 (Eq. (2)) clearly
792–797; (b) J. M. Gardner, M. Abrahamsson, B. H. Farnum
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identified mono-iodide anions to accelerate the reaction. Due
to the increasing generation of up to two-equivalents of iodine
byproducts after each catalytic cycle,8 we herein propose a new
case of autoinduction,7 whereby the iodide-mediated formation
Oxidation of iodide to iodine in the presence of O2: A. B.
Couto, D. Cassoli de Souza, E. R. Sartori, P. Jacob, D. Klockow
and E. A. Neves, Anal. Lett., 2006, 39, 2763–2774.
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2 is reasoned to occur
through an iodine-atom transfer event (Scheme 1).11 Under this
mechanistic framework, we developed a convenient one-pot
10 Iodide catalysed C–I bond cleavage in polymer synthesis: A.
Goto, A. Ohtsuki, H. Ohfuji, M. Tanishima and H. Kaji, J. Am.
Chem. Soc., 2013, 135, 11131–11139.
oxidative transformation of readily prepared 
-
-
trisubstituted nitroalkanes15 into sterically encumbered 
11 N. Zhang, S. R. Samanta, B. M. Rosen and V. Percec, Chem.
Rev., 2014, 114, 5848−5958.
trisubstituted esters, which are difficult to access directly by
conventional methods.14 Application of these fundamental
understandings7–13 to useful metal-free and iodine-based
oxidative transformations are ongoing.2–6
12 Peroxy-adduct generation from dihaloalkanes: (a) J. M.
Beames, F. Liu, L. Lu, M. I. Lester, J. Am. Chem. Soc., 2012, 134
,
20045–20048; (b) X. Ge, K. L. M. Hoang, M. L. Leow and X.-W.
Liu, RSC Adv., 2014, , 45191–45197.
4
13 Iodide and superoxide can reduce dioxiranes to ketones: W.
Adam, G. Asensio, R. Curci, M. E. González-Núñez, R. Mello, J.
Am. Chem. Soc., 1992, 114, 8345–8349.
We thank Mr. Yuki Haro of Mettler-Teledo K.K. for providing
React-IR analysis support and equipment. We also thank
Professor E. Kwon of Tohoku University, Japan, for X-ray data
analysis and support. This work was funded by JSPS KAKENHI
Grant Number JP 16K13942.
14 (a) N. Kornblum and P. A. Wade, J. Org. Chem., 1973, 38
,
1418–1420; (b) C. Matt, A. Wagner and C. Mioskowski, J. Org.
Chem., 1997, 62, 234–235.
15 Y. Hayashi, Y. Kawamoto, M. Honada, D. Okamura, S.
Umemiya, Y. Noguchi, T. Mukaiyama and I. Sato, Chem. Eur.
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Conflicts of interest
There are no conflicts to declare.
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