Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using Molecular Oxygen and Iodine

Article abstract of DOI:10.1002/anie.201505192

The formation of amides and peptides often necessitates powerful yet mild reagent systems. The reagents used, however, are often expensive and highly elaborate. New atom-economical and practical methods that achieve such goals are highly desirable. Ideally, the methods should start with substrates that are readily available in both chiral and non-chiral forms and utilize cheap reagents that are compatible with a wide variety of functional groups, steric encumberance, and epimerizable stereocenters. A direct oxidative method was developed to form amide and peptide bonds between amines and primary nitroalkanes simply by using I₂ and K₂CO₃ under O₂. Contrary to expectations, a 1:1 halogen-bonded complex forms between the iodonium source and the amine, which reacts with nitronates to form α-iodo nitroalkanes as precursors to the amides.

Full text of DOI:10.1002/anie.201505192

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Communications
International Edition: DOI: 10.1002/anie.201505192
German Edition: DOI: 10.1002/ange.201505192
Peptide Coupling
Oxidative Amidation of Nitroalkanes with Amine Nucleophiles using
Molecular Oxygen and Iodine
Jing Li, Martin J. Lear, Yuya Kawamoto, Shigenobu Umemiya, Alice R. Wong, Eunsang Kwon,
Itaru Sato, and Yujiro Hayashi*
Abstract: The formation of amides and peptides often
necessitates powerful yet mild reagent systems. The reagents
used, however, are often expensive and highly elaborate. New
atom-economical and practical methods that achieve such
goals are highly desirable. Ideally, the methods should start
with substrates that are readily available in both chiral and
non-chiral forms and utilize cheap reagents that are compatible
with a wide variety of functional groups, steric encumberance,
and epimerizable stereocenters. A direct oxidative method was
developed to form amide and peptide bonds between amines
and primary nitroalkanes simply by using I2 and K2CO3 under
O2. Contrary to expectations, a 1:1 halogen-bonded complex
forms between the iodonium source and the amine, which
Figure 1. Traditional versus oxidative approaches to amide formation.
reacts with nitronates to form a-iodo nitroalkanes as precur-
sors to the amides.
T
raditional peptide and amide synthesis involves the electro-
nitroalkanes are relatively limited in substrate scope.[7,8] In
comparison, there are a wide variety of catalytic asymmetric
methods that adopt nitromethane as a simple, cheap pro-
nucleophile to add to both alkyl and aryl aldehydes, imines,
enals, enones, and so forth.[9,10] Herein, our interest was to
exploit these readily available primary nitroalkane substrates
(Eqs. (2) and (3)) and develop a direct oxidative method to
form amide and peptide bonds in a most economical and
practical manner.
Our inspiration for this study started after our 2013 total
synthesis of prostaglandin A1 and E1 methyl esters.[11] Specif-
ically, we discovered the base-promoted Nef conversion of
a key nitroalkene into an enone product under aerobic
conditions. In 2014, we extended this oxidative transforma-
tion to a wide range of nitroalkenes and nitroalkanes to
produce enones and ketones, respectively (Eq. (3); Fg =
alkyl).[12] Mechanistic insights were gained from 18O-labeling,
nitrite/nitrate ion analysis, intramolecular thioether trapping,
and radical clock experiments. In short, the formation of
ketones from secondary a-alkylated nitroalkanes was shown
to be consistent with a single-electron transfer (SET)
mechanism from a charged aci-nitronate electron donor to
a triplet dioxygen molecule to afford an eventual dioxirane
adduct after expelling a nitrite anion. The dioxirane subse-
quently acts as an electrophilic source of mono-oxygen[13] that
can be captured by another nitronate anion in the surround-
ing basic medium.
philic derivatization and activation of a carboxylic acid into an
amine-selective acylating species (Eq. (1), Figure 1; Lg =
leaving group).[1,2] There are, however, a few atypical cases
of forming reactive N-acylating species in an oxidative
manner from alcohols, aldehydes, and alkyne precursors.[3,4]
Notably, pre-synthesized a-bromo substituted nitroalkanes
have been oxidized with N-iodosuccinimide (NIS) and
molecular oxygen in the presence of amines.[5–7] To account
for the apparent umpolung in reactivity of the amine
components, the intermediacy of electrophilic N-iodo
amines and tetrahedral a-amino, a-bromo nitroalkanes were
suggested.[5,6] From a synthetic point of view, however,
methods to achieve direct asymmetric access to a-bromo
[*] J. Li, Prof. Dr. M. J. Lear,[+] Y. Kawamoto, Dr. S. Umemiya, A. R. Wong,
Prof. Dr. I. Sato,[++] Prof. Dr. Y. Hayashi
Department of Chemistry,
Graduate School of Science,
Tohoku University
6-3 Aramaki-Aza, Aoba-ku, Sendai 980-8578 (Japan)
E-mail: yhayashi@m.tohoku.ac.jp
Homepage: http://www.ykbsc.chem.tohoku.ac.jp
Prof. Dr. E. Kwon
Research and Analytical Center for Giant Molecules,
Graduate School of Science,
Tohoku University
Sendai 980-8578 (Japan)
On the basis of these recent mechanistic findings,[12] we
reasoned that secondary a-amino nitroalkanes could be
formed in situ by reacting primary nitronates with electro-
philic N-halo amines (Eq. (3); Hal = halogen, Fg = amine).
These would be similarly oxidized with oxygen to afford
peroxy adducts bearing amine groups and eventually trans-
[+] Present address: School of Chemistry, University of Lincoln
Brayford Pool, Lincoln LN6 7TS (UK)
[
++] Present address: Faculty of Science, Ibaraki University
Ibaraki 310-8512 (Japan)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201505192.
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form into amides. At this juncture, among other mechanistic
concerns, it was not certain whether the formation and
reaction of N-iodo amines could be achieved in situ and
thereby generate the requisite a-amino nitroalkane inter-
mediates. This premise was, however, given credence by the
suggestion of N-iodo amine and a-amino nitroalkane inter-
mediates being reported in a series of oxidative umpolung
amide synthesis (UmAS) studies.[5–7] Herein, during the
course of developing an atom-economical, direct amidation
procedure of readily prepared chiral nitroalkanes,[9,10] we
describe our independent findings and ultimately propose
new mechanistic aspects that have general implications both
in amine/halogen-based chemistry and in UmAS chemistry.
Despite some mechanistic concerns regarding the amine
component and the oxidative steps (Eq. (3)), we first elected
to pursue the base-promoted oxidative coupling of the
racemic nitroalkane 1[9] with the hydrochloride salt of (S)-
phenylalanine methyl ester 2 and NIS in acetonitrile
(Table 1). Thus, the resultant 1:1 diastereomeric mixture of
the dipeptide 3 could be checked for its stereochemical
integrity by NMR and HPLC analysis. In the first instance,
the base was varied (entries 1–7). This quickly demonstrated
K2CO3 (entry 4) to be superior to weaker bases such as
NaOAc, which gave the a-iodo nitroalkane 4 (entry 1).
Stronger bases, such as Cs2CO3 and K3PO4, gave slightly
lower yields of the dipeptide product 3 (entries 5 and 6).
Soluble bases such as DBU were also found inferior to K2CO3
(cf. entries 4 and 7), but both conditions resulted in significant
amounts of the carboxylic acid 5 (30–50% yields). The use of
less electrophilic N-halosuccinamides did not improve the
result (entries 8 and 9), and the a,a-dichloro nitroalkane 6
(X = Cl) was isolated in one case (entry 9). A change in the
solvent system with NIS and adopting two equivalents of the
free amine of 2 proved more successful (entries 10 to 15). In
particular, the use of molecular I2 or NIS at room temperature
afforded optimal yields of dipeptide 3 (67%; entry 15).
Generation of the carboxylic side-product 5 could not be
avoided even under strictly anhydrous conditions.
Next, we investigated the scope of the oxidative amidation
method with the use of NIS (Scheme 1) and I2 (Scheme 2).
The optimal solvent for primary and secondary alkyl amines
was determined to be acetonitrile (Eq. (5)). Unsaturated
functional groups, such as benzyl, allyl, and alkynyl groups,
remained unreacted, and the amidation method also tolerated
unprotected hydroxy groups (9, 11g). Extension of the
method to amino acid esters with (R)-1[14] was optimally
performed with I2 in 1:1 THF/toluene (Eq. (6)). Importantly,
the dipeptide products (3, 12) were produced with complete
stereochemical integrity. No epimerization of potentially
labile a-stereocenters was observed (Supporting Informa-
tion). The same tolerances were found for readily prepared,
chiral nitroalkyl Michael adducts[15] (13!14, Eq. (7)) and
standard protecting groups (for example, O-tBu, N-Tr, N-Cbz,
N-Boc; Tr= trityl = triphenymethyl, Cbz = benzyloxycar-
bonyl, Boc = tert-butyloxycarbonyl) were also found to be
compatible.
Table 1: Optimization of oxidative peptide formation.[a]
To evaluate whether our initial mechanistic idea was in
keeping with prior studies,[12] we began to explore the first a-
amination step of our proposal (Eq. (3)). In short, all attempts
to prepare, infer, or observe the anticipated N-iodo
amines,[5–7] were not confirmed in our hands. Instead, we
interpret our NMR data to show that amines like allylamine
and a-methyl benzyl amine form a complex readily with NIS
and precipitate, and these precipitates behave chemically as
sources of electrophilic iodine and nucleophilic amine. For
Entry
Base
X+
Solvent (t [h])
3
4
5
1
2
3
4
5
6
7
8
NaOAc
KOAc
Na2CO3
K2CO3
Cs2CO3
K3PO4
DBU
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NBS
NCS
NIS
NIS
NIS
NIS
NIS
I2
CH3CN (5)
CH3CN (5)
CH3CN (15)
CH3CN (3)
CH3CN (2)
CH3CN (3)
CH3CN (12)
CH3CN (12)
CH3CN (12)
CH3CN (2.5)
THF (7.5)
–
20
5
49
30
42
30
20
–
51
51
15
15
59
67
5
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
30
–
–
50
–
–
–
–
[b]
9
10[c]
11[c]
12[c]
13[c]
14[c,d]
15[c,e]
PhCH3 (48)
DMSO (48)
1:1 media (12)
1:1 media (4)
60
30
30
25
[a] Unless noted otherwise, all reactions were conducted with nitroalkane
1 [0.2 mmol], amine·HCl salt 2 [0.2 mmol], base [0.6 mmol], halonium
(X+) source [0.2 mmol] at 08C in solvent [2 mL] under O2 [1 atmosphere]
and yields of isolated products (%) are given. [b] Dichlorinated nitro-
alkane 6 (X=Cl) was isolated in 10% yield. [c] For entries 10 to 15, two
equivalents of the free amine 2 [0.4 mmol] and base [0.4 mmol] were
used. [d] 1:1 toluene/THF mixture was used. [e] Reaction performed at
room temperature with free amine 2 [0.4 mmol] and base [0.4 mmol];
a similar result was obtained with NIS [0.2 mmol] over 12 h.
Scheme 1. Oxidative amidation using NIS/O2.
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Scheme 3. Formation and oxidative amidation of a-iodo nitroalkane 4.
75% yield, pre-prepared 4 was tested for its ability to form
amides directly. Electrophilic halogen sources were omitted
and 4 was reacted in the presence of K2CO3, O2, and a slight
excess of allylamine or phenylalanine methyl ester 2. The
anticipated amides were isolated in good yields at 08C within
30 min. The iodo nitroalkane 4 was even reactive enough to
couple with the methyl ester of l-proline, a secondary amino
ester often displaying unique reactivity, giving its respective
dipeptide 16 in 51% yield.
Notably, we did not observe the intermediacy or isolate
any a-amino nitroalkane product, as either we proposed in
Equation (3)[12] or as reported in umpolung amide synthesis
(UmAS) studies.[5–7] This was the case even by directly
reacting pre-formed N-bromo amines (or 15, see above) with
the aci-nitronate of 1; in fact, this generated the a-bromo
analogue of 4 in good yields.[16] Having confirmed the a-
iodide 4 as the primary intermediate, two possible pathways
to form the amide product 7 were considered; one pathway
being where an oxygen molecule first reacts with 4 before the
amine component, and in the other pathway the amine reacts
with 4 first. Thus, the relative reactivities of the amine and
oxygen components were investigated through a set of control
experiments (Scheme 4). Here, we found the a-iodide 4
reacted readily with O2 within 15–20 min, giving good yields
of the oxidized products 5 or 7 (cf. Eq. (8) and (9)). In the
absence of O2, the amine reacts with 4 relatively slowly and
inefficiently over 3 h (cf. Eq. (10)). These results support the
Scheme 2. Oxidative peptide formation using I2/O2.
example, these 1:1 NIS/amine precipitates can be employed
directly in our base-promoted nitroalkane amidation proce-
dure with similar success (cf. Eq. (4)), and they also react with
electrophilic Boc2O to form standard NH-Boc amides slowly
(Supporting Information). Eventually, we were able to obtain
a single-crystal X-ray crystallographic structure for the allyl-
amine/NIS complex 15 (Figure 2).
This evidence of a halogen bonded amine complex 15 and
isolating an a-iodo nitroalkane 4 (Table 1, entry 1) clearly
puts our proposed a-amination (Eq. (3), Fg = NHR) into
question. Suspecting a-iodination was occurring first, and
thus the mono-iodide 4 as an early intermediate, we first
checked for its formation by reacting the aci-nitronate anion
of 1 with 15 or NIS alone (Scheme 3). This being the case in
Figure 2. ORTEP X-ray crystal structure of 1:1 NIS·allylamine (15) with
Scheme 4. Control experiments to discern relative reactivity of 4 to O2
ellipsoids set at 30% probability level.
and amine components.
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initial reaction of O2 with 4, as opposed to the a-iodide 4 first
reacting with the amine component.[17]
Collectively, our findings are consistent with the reaction
sequence as illustrated in Figure 3. We thus propose an aci-
nitronate anion, once formed under the basic conditions from
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Figure 3. Proposed oxidative conversion of nitroalkanes 1 into amide
products 7 by a-iodinated intermediates 4.
the primary nitroalkane 1, will first become a-iodinated with
NIS from the halogen bonded amine complex 15 or I2, to
afford the mono-iodide 4. From this intermediate onwards,
several addition-elimination pathways, under either radical or
ionic reaction modes, can be proposed to afford the amide
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[12] S. Umemiya, K. Nishino, I. Sato, Y. Hayashi, Chem. Eur. J. 2014,
20, 15753 – 15759.
In closing, several synthetic virtues of this oxidative
amidation method are noteworthy (Schemes 1, 2, and 3). The
method is straightforward in operation, chemoselective in
functional group tolerance, and stereochemically robust to
potentially epimerizable substrates and products. Impor-
tantly, a whole range of primary nitroalkane starting materials
for our reaction method can be readily prepared in chiral
form through a plethora of asymmetric methods.[9,10,14,15]
Further improvements and extension of the mechanistic
rationales presented herein to construct more challenging
amide bonds are ongoing in our laboratories.[17,19] The
implications of amine-complexed, halogen bonded, electro-
philic iodine species to our understanding of amine-based,
asymmetric catalytic events will be published in due
course.[20,21]
[13] W. Adam, M. Makosza, C. R. Saha-Moller, C. G. Zhao, Synlett
1998, 1335 – 1336.
[14] Organocatalytic enantioselective formation of 1: C. Palomo, M.
Oiarbide, A. Laso, R. Lopez, J. Am. Chem. Soc. 2005, 127,
17622 – 17623.
[15] Organocatalytic enantioselective formation of 13: H. Gotoh, H.
Ishikawa, Y. Hayashi, Org. Lett. 2007, 9, 5307 – 5309.
[16] For the synthesis of N-bromo amines, see: a) J. E. M. N. Klein,
H. Müller-Bunz, P. Evans, Org. Biomol. Chem. 2009, 7, 986 – 995;
b) E. J. Corey, C.-P. Chen, G. A. Reichard, Tetrahedron Lett.
1989, 30, 5547 – 5550.
[17] As insightfully suggested by the reviewers, additional halogen-
ation could be occurring on 4 (cf. Eqs. (9) and (10), Scheme 4)
and extra iodonium sources could be regenerated under the
aerobic conditions. These possibilities, and the potential for
catalysis in the iodine component, are being further explored.
For mechanistically related iodine catalyzed and promoted
coupling reactions, see: a) D. Liu, A. Lei, Chem. Asian J. 2015,
10, 806 – 823; b) S. Tang, K. Liu, Y. Long, X. Qi, Y. Lan, A. Lei,
Chem. Commun. 2015, 51, 8769 – 8772; c) S. Tang, K. Liu, Y.
Long, X. Gao, M. Gao, A. Lei, Org. Lett. 2015, 17, 2404 – 2407;
d) S. Tang, Y. Wu, W. Liao, R. Bai, C. Liu, A. Lei, Chem.
Commun. 2014, 50, 4496 – 4499.
[18] For a related mechanistic rationale and peroxy adduct gener-
ation from haloalkanes, 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.
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific
Research on Innovative Areas “Advanced Molecular Trans-
formations by Organocatalysts” from The Ministry of Edu-
cation, Culture, Sports, Science and Technology, Japan, and
the Multidimensional Materials Science Leaders Program (to
M.J.L.).
Keywords: amidation · halogen bonding · iodination ·
peptide formation · umpolung
How to cite: Angew. Chem. Int. Ed. 2015, 54, 12986–12990
Angew. Chem. 2015, 127, 13178–13182
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[19] Besides
UmAS
and
other
possibilities,
see
[21] For general work and concepts in halogen bonding, see:
“Halogen Bonding: Fundamentals and Applications”: Structure
and Bonding, Vol. 126 (Eds.: D. M. P. Mingos, P. Metrangolo, G.
Resnati), Springer, Berlin, 2008.
Refs. [5,6,7a,12,17,18], the exact mechanistic details and
sequence of events for the addition of dioxygen and the exact
stage of introduction of the amine component to an a-iodo
nitroalkane 4, for example, through a peroxy species like 17,
remains to be elucidated.
[20] Examples of assumed N-halogenated ammonium-based catalytic
intermediates may be found in the following critical review: S. E.
Denmark, W. E. Kuester, M. T. Burk, Angew. Chem. Int. Ed.
2012, 51, 10938 – 10953; Angew. Chem. 2012, 124, 11098 – 11113.
Received: June 7, 2015
Revised: July 18, 2015
Published online: September 9, 2015
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