Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen and Amine Nucleophiles by Using Electrophilic Iodine

Article abstract of DOI:10.1002/chem.201600540

Recently, we developed a direct method to oxidatively convert primary nitroalkanes into amides that entailed mixing an iodonium source with an amine, base, and oxygen. Herein, we systematically investigated the mechanism and likely intermediates of such methods. We conclude that an amine-iodonium complex first forms through N-halogen bonding. This complex reacts with aci-nitronates to give both α-iodo- and α,α-diiodonitroalkanes, which can act as alternative sources of electrophilic iodine and also generate an extra equimolar amount of I⁺ under O₂. In particular, evidence supports α,α-diiodonitroalkane intermediates reacting with molecular oxygen to form a peroxy adduct; alternatively, these tetrahedral intermediates rearrange anaerobically to form a cleavable nitrite ester. In either case, activated esters are proposed to form that eventually reacts with nucleophilic amines in a traditional fashion.

Full text of DOI:10.1002/chem.201600540

DOI: 10.1002/chem.201600540
Communication
&
Synthetic Methods
Mechanism of Oxidative Amidation of Nitroalkanes with Oxygen
and Amine Nucleophiles by Using Electrophilic Iodine
Jing Li,[a] Martin J. Lear,[b] Eunsang Kwon,[c] and Yujiro Hayashi*[a]
Abstract: Recently, we developed a direct method to oxi-
datively convert primary nitroalkanes into amides that en-
tailed mixing an iodonium source with an amine, base,
and oxygen. Herein, we systematically investigated the
mechanism and likely intermediates of such methods. We
conclude that an amine–iodonium complex first forms
through NÀhalogen bonding. This complex reacts with
aci-nitronates to give both a-iodo- and a,a-diiodonitroal-
Figure 1. Oxidative approaches to umpolung amide synthesis (UmAS).[5–7]
kanes, which can act as alternative sources of electrophilic
iodine and also generate an extra equimolar amount of I+
under O2. In particular, evidence supports a,a-diiodoni-
troalkane intermediates reacting with molecular oxygen to
form a peroxy adduct; alternatively, these tetrahedral in-
termediates rearrange anaerobically to form a cleavable
nitrite ester. In either case, activated esters are proposed
to form that eventually reacts with nucleophilic amines in
a traditional fashion.
Later mechanistic studies supported such tetrahedral inter-
mediates 3’ coupling with molecular oxygen in a homogenic
manner to eventually form the amide products 4 (Figure 1a).[6]
Through a systematic study of our recently developed oxida-
tive amidation procedure on unsubstituted nitroalkanes 1,[7]
we now provide evidence that the tetrahedral intermediates
are more likely a,a-dihalogenated nitroalkanes derived from a-
halonitroalkanes like 1’ or 3 (Figure 1b). Under our reaction
conditions, we propose that there is no umpolung of reactivity
in the amine component and an extra equivalent of iodonium
source is generated in the process.
Thus, having discovered[8] and developed[9] a Nef conversion
of nitroalkenes and nitroalkanes into their carbonyl counter-
parts under base and oxygen, we recently extended our mech-
anistic understanding of such oxidative conversions into an
atom-economical and direct amidation of primary nitroalkanes
1 by mixing in I2 or NIS with amines (Figure 1b).[7] During
these amidation studies, we could not confirm the intermedia-
cy of N-iodoamines 2’ or early-stage a-aminonitroalkanes 3’
derived from 1 as anticipated from UmAS rationales (Fig-
ure 1a).[5a,b,6] Instead, we isolated a halogen bonded amine–NIS
complex 2, which was shown to form the a-iodonitroalkane 3
(Figure 1b) through its anion, and realized data that put the
mechanistic basis of UmAS into question (vide infra). We thus
began to discern each step and intermediate of these clearly
interrelated schemes in a systematic and precise fashion
(Scheme 1).
The structural and functional importance of the amide bond to
natural products and bioactive small molecules is clear.[1] Yet,
the efficient synthesis of amides and peptides with simple re-
agents is still a challenge.[2] Several alternative oxidative and
decarboxylative methods to form amides and peptides have
been developed over the last decade.[3] Related interest has
also been in the use of iodine-based reagents to promote or
catalyze CÀN amine bond formations.[4] In 2010, a major ad-
vancement in oxidative amidation was disclosed by the John-
ston group with the use of N-iodosuccinimide (NIS) and is
termed umpolung amide synthesis (UmAS).[5] The method cen-
ters on a-bromo-substituted nitroalkanes 1’ reacting with elec-
trophilic N-iodoamines 2’ (in situ generated with NIS) to form
reactive tetrahedral a-amino-a-bromonitroalkanes 3’ (Figure 1).
[a] J. Li, Prof. Dr. Y. Hayashi
Department of Chemistry, Graduate School of Science, Tohoku University
Aza Aramaki, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: yhayashi@m.tohoku.ac.jp
In particular, we noted the anaerobic reaction of monoio-
dide 3 with allylamine and K2CO3 not only produced the amide
4 (18%), but also a significant amount (40%) of the deiodinat-
ed nitroalkane 1 (Scheme 1a).[7] Without the amine under O2,
carboxylic acid 5 was generated from 3 (Scheme 1b). These re-
sults led to the idea that the monoiodide 3 could act as
a source of electrophilic iodine for a-carbanions, as opposed
to reacting with amines to generate N-haloamines (2’).[6] This
would logically produce a hitherto unobserved diiodide inter-
Homepage: http://www.ykbsc-chem.com/
[b] Dr. M. J. Lear
School of Chemistry, University of Lincoln
Brayford Pool, Lincoln LN6 7TS (UK)
[c] Prof. Dr. E. Kwon
Research and Analytical Center for Giant Molecules
Graduate School of Science, Tohoku University
Sendai 980-8578 (Japan)
Supporting information for this article and ORCID for one of the authors
can be found under http://dx.doi.org/10.1002/chem.201600549.
Chem. Eur. J. 2016, 22, 5538 – 5542
5538
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
Table 1. Direct amidation of dihalogenated nitroalkanes 6.[a]
Entry
X1
X2
Yield under Ar [%][b]
Yield under O2 [%][c]
1
2
3
Cl
Cl
Cl
Br
Br
I
Cl
Br
I
Br
I
trace
35
48
10
55
<5
20
72
31
70
60
4[d]
5
6[e]
I
50
Scheme 1. Control amidation study of protonated nitroalkanes 1 and 3.
[a] Unless noted otherwise, all reactions were conducted with dihalogen-
ated nitroalkanes (0.1 mmol), allyl amine (0.15 mmol), and K2CO3
6
(0.15 mmol) at 08C in CH3CN (1 mL) under O2 or Ar (1 atm); isolated
yields are given. [b] Reactions under Ar were conducted over 48 h, except
entry 6, which was over 1 h. [c] Reactions under O2 were conducted over
24 h, except entry 6, which was over 20 min. [d] Reaction conducted at
room temperature. [e] Diiodide of 6 was unstable and used immediately
after preparation.
mediate (vide infra) and the isolated deiodinated compound 1.
We thus decided to react the starting nitroalkane 1 directly
with the NIS–amine complex 2 under Ar (Scheme 1c). Notably,
about 25% of the starting nitroalkane 1, 50% of the a-iodoni-
troalkane 3, and 25% of the amide product 4 were produced
under Ar with one equivalent of the 1:1 NIS–amine complex 2.
This means that a 25% yield of amide 4 required 50% of the
iodinating reagent 2 under anaerobic conditions (cf. Scheme-
s 1a and 1c).
under both Ar and O2 (Table 1; see the Supporting Information
for X-ray of bromo/iodo 6). The experiments clearly showed
that the amide 4 formed directly from the dihalide intermedi-
ate 6, whereby higher reactivity and yield resulted with the in-
troduction of at least one iodine substituent. Exceptional reac-
tivity, within 20–60 min, was observed with the unstable diio-
dide 6 (X1, X2 =I), which likely accounted for our difficulty in
observing 6 during our initial amidation studies, unlike the di-
choride.[7]
Suspecting the need for iodine transfer by 3, we studied the
reactivity of the pure anion of 3 with one equivalent of the
NIS–amine complex 2 under O2 and under Ar (Scheme 2). The
In combination with Scheme 2, the results in Table 1 are
consistent with the consecutive bis-iodination of the starting
nitroalkane 1 and then monoiodide 3 through their respective
aci-nitronates. However, at this juncture, it was still not clear
whether the anion of 3 first reacted with oxygen, for example,
either directly or through SET and radical coupling (Scheme 3a)
or with an iodonium source, for example, with I2, NIS or the
halogen bonded NIS–complex 2 (Scheme 3b). We thus consid-
Scheme 2. Control amidation study of the pure anion of 3.
aerobic conditions produced the amide 4 in moderate yields in
20 min when conducted at 08C (Scheme 2a). Markedly, the po-
tassium salt of 3 rapidly produced the diiodide 6 at À308C
with the NIS–amine complex 2 when the reaction was stopped
within 1 min (Scheme 2b). Longer reaction times or higher
temperatures produced the expected amide 4, and diiodide 6
was not observed. Although the anion of 3 transformed into
amide 4 with NIS–amine complex 2 under O2 (Scheme 2a), 3
readily oxidized with O2 to carboxylic acid 5 in the absence of
amine and iodonium sources (cf. Scheme 1b). In such cases,
we observed I2 being generated and, among other possibilities,
these control experiments (cf. Schemes 1 and 2) reinforced the
idea that the amide 4 and carboxylic acid 5 can be derived
from the corresponding a,a-diiodonitroalkane 6, which is gen-
erated by sequential bis-iodination of 1 via intermediate 3.
Considering such types of dihalogenated species 6 as reac-
tive tetrahedral intermediates to the amide 4, as alternatives to
a-amino-a-bromonitroalkanes 3’,[6] we prepared and compared
the reactivity of dihalonitroalkanes 6 (X1, X2 =Cl, Br, and/or I)
Scheme 3. Pathway selection and reactivity of anion of 3 with O2 and NIS.
Chem. Eur. J. 2016, 22, 5538 – 5542
www.chemeurj.org
5539
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
ered two pathways for the formation of amide 4 from monoio-
dide 3 and performed another set of control experiments with
the potassium salt of 3 (Schemes 3c and 3d).
Specifically, we measured the resultant concentration of ni-
trate/nitrite salts and the level of 18O incorporation by convert-
ing 1 into 4 under 18O2.[9]
First, with or without amine being present, the experiments
clearly demonstrated that, in the absence of an iodonium
source, molecular oxygen does not react with the aci-nitronate
intermediate of 3 at all (Scheme 3c). Thus, SET transfer mecha-
nisms or immediate anionic attack onto O2 to afford radical[10]
or anionic[9] oxygen adducts directly from 3 do not operate. It
is more likely the case of molecular oxygen reacting with the
diiodinated nitroalkane 6, as first evidenced during the experi-
ments shown in Scheme 2. Second, in the presence of
20 mol% of NIS and absence of amine, carboxylic acid 5 was
isolated in a yield of 40% after aqueous work-up (Scheme 3d).
Here, we suggest the diiodide intermediate 6 can regenerate
an extra equivalent of the iodonium source (vide infra).
In the event, piperidine was chosen as a less volatile amine
reactant than allylamine, which allowed for the anticipated
and known N-nitrosoamine 10[11] to be isolated reliably
(Scheme 4c). Under Ar, 10 was isolated in 25% yield. Under O2,
10 was isolated in 11 % yield. The formed nitrosyl iodide 9
(Nu=I) would be expected to also convert to I2 and NO gas.[12]
The fact that N-nitrosoamines were isolated supports the exis-
tence of nitrite intermediates 7 under the UmAS reaction con-
ditions. Next, isotope labelling experiments with allylamine as
the nucleophile revealed an 87% of 18O incorporation in the
amide product 4, which was isolated in a chemical yield of
55% under 18O2 (Scheme 4d). The resultant nitro-derived salt
À
ratios were calculated to be 36% nitrite (NO2 ) and 4–6% ni-
À
À
À
Such suggestions have clear experimental precedence in
a recent UmAS study.[6] The difference herein is that we pro-
pose tetrahedral a-iodo-a-halonitroalkane 6 instead of a-
amino-a-halonitroalkane 3’ as the key intermediate that reacts
with oxygen. Further evidence presented in the UmAS-labeling
study[6] also showed that the residual H218O and N18O2-labeled
a-halonitroalkanes 3 do not result in significantly 18O-enriched
amides 4 under 16O2. Thus, having the dioxygen directly react-
ing with the anion of 3, two UmAS-like pathways to form the
amide 4 were reasoned to occur by the tetrahedral a,a-diiodo-
nitroalkane 6, and not by its a-amino-a-bromo counterpart
3’[6] (Scheme 4). Both radical and ionic modes were considered
trate (NO3 ) under O2, whereas 3% NO2 and 1–2% NO3 were
detected under anaerobic conditions (see the Supporting Infor-
mation). Although the data supports the nitro–nitrite rear-
rangement (6 to 7; Scheme 4a) as the predominant fate of the
nitro functionality of 1 under anaerobic conditions, it also sug-
gests that both pathways can occur concomitantly under aero-
bic conditions. Presumably, the proximity and local concentra-
tion of solvated O2 gas to diiodide 6 will be a factor in path-
way selection, and NO2/3 salt counts were found to be low due
to N-nitrosoamine formation and loss of NO gas (and I2)
through species like IÀN=O.[12]
Next,
we
performed
radical
clock
experiments
(Scheme 5).[9,13] Thus, the pure cis-cyclopropanes 11 and 12
were prepared and reacted with the allylamine under our oxi-
dative conditions. Starting from cis-11, a 1.3:1 cis/trans ratio of
Scheme 5. Radical clock control experiments of pure cis-11 and cis-12.
12 was generated in 60% yield (Scheme 5a). In order to ex-
clude epimerization occurring after amide formation, the puri-
fied cis-cyclopropyl amide 12 was similarly treated with NIS,
K2CO3 and O2. This gave complete recovery of the cis-cyclo-
propyl amide, even after 12 h (Scheme 5b). These results sup-
port the existence of a cyclopropylcarbinyl radical being gener-
ated and undergoing ring opening/closure.
Scheme 4. Nitroso-trapping and 18O2-labelling studies of 1.
feasible, and the generation of N-nitrosoamines 9 (Nu=
amine)[11] was also deemed possible as products from previous-
ly related[5b] diiodo nitrites 7, the rearranged adducts of 6
(Scheme 4a). The fate of the nitro group was thus uncertain
under anaerobic and aerobic conditions, for example, to form
either nitrate or nitrite salts from the congested peroxynitroal-
kane 8 (Scheme 4b), and a further set of control experiments
were performed to discern such fates (Schemes 4c and 4d).
Lastly, the regeneration and intermediacy of putative iodoni-
um sources need to be considered under our reaction condi-
tions (Figure 2). In other words, presuming that diiodide 6 is
the key intermediate, the oxidative amidation of the mono-io-
donitroalkane 3 (in the absence of additional NIS or I2) is ex-
pected to occur by an initial iodine transfer to its anion to
afford the diiodide 6 and eventually regenerate an equivalent
Chem. Eur. J. 2016, 22, 5538 – 5542
www.chemeurj.org
5540
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
tion for such latter stage is that the peroxy radical 8 cyclizes
and expels either a mono-iodine or nitrite radical to form a re-
active dioxirane intermediate, which can react with the anion
of 3 (Figure 3).[9] The peroxy radical 8 could also couple with
a nearby radical derived from 6 to form homo- or heterodim-
ers.[14] In either case, the dioxygenated intermediates would
fragment to the acylating species 13. Besides other possibili-
ties,[10] the exact mechanistic details of such latter amine addi-
tion stages (through 7/8 and 13) remains to be supported by
further studies. However, we do provide indirect evidence for
the anaerobic formation of the nitrite ester 7 by isolation of
the N-nitrosoamine 10.
Figure 2. Generic process to regenerate an iodonium source.
amount of the iodinating agent. Furthermore, despite observ-
ing the iodo precursor 3 being oxidized to carboxylic acid 5
with oxygen under basic conditions (cf. Scheme 1b), oxygen
does not react with the anion of 3 first (cf. Scheme 3c), but
more likely O2 reacts with the diiodide 6 after it forms through
iodine transfer of 3 to its nitronate anion (cf. Scheme 2b and
Table 1). Moreover, the oxidative amidation of the nitroalkane
starting material 1 only requires one equivalent of NIS in the
presence of O2.[7] In accordance with the latest UmAS report,[6]
we similarly suggest an extra equivalent of I2, IÀN=O[12] and/or
IÀONO species is generated under the reaction conditions
(Figure 2). These iodonium species can thus react under either
radical or ionic reaction modes and allow the amide oxidation
state of 4 to be achieved from monoiodide 3.
In conclusion, our mechanistic rationales, as depicted in
Figure 2 and Figure 3, are consistent with all of the reported
data and observations that have been obtained during previ-
ously published umpolung amide synthesis (UmAS) studies[5,6]
and our recent work.[7] Critically, the key differences in our con-
clusions include: 1) the intermediacy of a reactive tetrahedral
dihalogenated species like 6, and not a-amino halonitroalkane
3’; 2) the halogen bonding of NIS with amines to form iodoni-
um complexes like 2, and not electrophilic N-iodoamine 2’;
and 3) the late-stage nucleophilic addition of amines to oxy-
genated intermediates like 7 or 8, or a subsequently derived
traditional acyl precursor 13, to give the amide products 4.
Keywords: amides · iodine · peroxides · radicals · umpolung
Collectively, our findings are consistent with the mechanism
illustrated in Figure 3. We thus propose the primary nitroalkane
1 first becomes a-iodinated with NIS from the halogen-
bonded amine complex 2 to afford the monoiodide 3 (Fig-
ure 3a). After further deprotonation, the a-iodo aci-nitronate
[1] a) N. Sewald, H. D. Jakubke, in Peptides: Chemistry and Biology, Wiley-
VCH, Weinheim (Germany), 2002; b) The Amide Linkage: Structural Sig-
nificance in Chemistry, Biochemistry and Materials Science (Eds.: A.Green-
berg, C. M. Breneman, J. F. Liebman), Wiley, 2003; c) Peptide Drug Dis-
covery and Development (Eds.: M. Castanho, N. Santos); Wiley-VCH,
Weinheim (Germany), 2011.
[2] a) E. Valeur, M. Bradley, Chem. Soc. Rev. 2009, 38, 606–631, b) A. El-
Faham, F. Albericio, Chem. Rev. 2011, 111, 6557–6602.
[3] For leading, recent literature on oxidative amidations using oxygen
and/or halonium sources as oxidants, see: a) J. Liu, Q. Liu, H. Yi, C. Qin,
R. Bai, X. Qi, Y. Lan, A. Lei, Angew. Chem. Int. Ed. 2014, 53, 502–506;
Angew. Chem. 2014, 126, 512–516; b) D. Leow, Org. Lett. 2014, 16,
5812–5815; c) O. P. S. Patel, D. Anand, R. K. Maurya, P. P. Yadav, Green
Chem. 2015, 17, 3728–3732; d) A. Alanthadka, C. U. Maheswari, Adv.
Synth. Catal. 2015, 357, 1199–1203; e) S. Khamarui, R. Maiti, D. K. Maiti,
Chem. Commun. 2015, 51, 384–387.
[4] For the virtues of iodine-mediated reactions and iodine-based additives
in synthesis, including oxidative aminations, see: a) S. Minakata, Ac-
c.Chem. Res. 2009, 42, 1172–1182; b) M. Uyanik, K. Ishihara, ChemCatCh-
em 2012, 4, 177–185; c) P. Finkbeiner, B. Nachtsheim, Synthesis 2013,
979–999; d) S. Tang, Y. Wu, W. Liao, R. Bai, C. Liu, A. Lei, Chem.
Commun. 2014, 50, 4496–4499; e) C. Martínez, K. Muniz, Angew. Chem.
Int. Ed. 2015, 54, 8287–8291; Angew. Chem. 2015, 127, 8405–8409.
[5] Initial discovery and mechanistic rationale of oxidative umpolung
amide synthesis (UmAS): a) B. Shen, D. M. Makley, J. N. Johnston, Nature
2010, 465, 1027–1032; b) J. P. Shackleford, B. Shen, J. N. Johnston, Proc.
Natl. Acad. Sci. USA 2012, 109, 44–46. Application of UmAS in synthe-
sis: c) M. W. Leighty, B. Shen, J. N. Johnston, J. Am. Chem. Soc. 2012,
134, 15233–15236; d) K. E. Schwieter, J. N. Johnston, Chem. Sci. 2015, 6,
2590–2595; e) K. E. Schwieter, J. N. Johnston, Chem. Commun. 2016, 52,
152–155.
Figure 3. Proposed oxidative amidation of 1 by a-iodide 3 and diiodide 6.
becomes a-iodinated with another iodonium species (I+) to
afford the diiodide 6. We propose it is this congested, tetrahe-
dral diiodinated nitroalkane 6 that can either rearrange in a ho-
mogenic, anaerobic manner to form the nitrite ester 7 (Fig-
ure 3b) or react with the molecular oxygen to afford peroxy
radical adduct 8 (Figure 3c). From these intermediates on-
wards, several additive–eliminative pathways, under either rad-
ical or ionic reaction modes, can be proposed to afford the
amide product 4.[9–11] On the basis of prior studies, one sugges-
[6] Presently accepted mechanism of oxidative umpolung amide synthesis
(UmAS): K. E. Schwieter, B. Shen, J. P. Shackleford, M. W. Leighty, J. N.
Johnston, Org. Lett. 2014, 16, 4714–4717.
[7] J. Li, M. J. Lear, Y. Kawamoto, S. Umemiya, A. Wong, E. Kwon, I. Sato, Y.
Hayashi, Angew. Chem. Int. Ed. 2015, 54, 12986–12990; Angew. Chem.
2015, 127, 13178–13182.
Chem. Eur. J. 2016, 22, 5538 – 5542
www.chemeurj.org
5541
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Communication
[8] Y. Hayashi, S. Umemiya, Angew. Chem. Int. Ed. 2013, 52, 3450–3452;
Angew. Chem. 2013, 125, 3534–3536.
[9] S. Umemiya, K. Nishino, I. Sato, Y. Hayashi, Chem. Eur. J. 2014, 20,
15753–15759.
[10] For peroxy-adduct generation from dihaloalkanes, see: a) X. Ge, K. L. M.
Hoang, M. L. Leow, X.-W. Liu, RSC Adv. 2014, 4, 45191–45197; b) J. M.
Beames, F. Liu, L. Lu, M. I. Lester, J. Am. Chem. Soc. 2012, 134, 20045–
20048.
[13] Radical clock studies: a) E. L. Spence, G. J. Langley, T. D. H. Bugg, J. Am.
Chem. Soc. 1996, 118, 8336–8343; b) T. Benkovics, J. Du, I. A. Guzei, T. P.
Yoon, J. Org. Chem. 2009, 74, 5545–5552; c) J. F. Van Humbeck, S. P. Si-
monovich, R. R. Knowles, D. W. C. MacMillan, J. Am. Chem. Soc. 2010,
132, 10012–10014; d) E. Arceo, I. D. Jurberg, A. Alvarez-Fernandez, P.
Melchiorre, Nature Chem. 2013, 5, 750–756.
[14] H. Shimakoshi, Y. Hisaeda, Angew. Chem. Int. Ed. 2015, 54, 15439–
15443; Angew. Chem. 2015, 127, 15659–15663.
[11] N. Tokitoh, R. J. Okazaki, Bull. Chem. Soc. Jpn. 1987, 60, 3291–3297.
[12] P. W. Atkins, T. L. Overton, J. P. Rourke, M. T. Weller, F. A. Armstrong, In In-
organic Chemistry: The Group 15 Elements, 6th ed., Oxford University
Press, Oxford (UK), 2014, p. 424.
Received: February 2, 2016
Published online on March 3, 2016
Chem. Eur. J. 2016, 22, 5538 – 5542
www.chemeurj.org
5542
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim