Umpolung Amide Synthesis using substoichiometric N-iodosuccinimide (NIS) and oxygen AS a terminal oxidant

Article abstract of DOI:10.1021/ol502089v

Umpolung Amide Synthesis (UmAS) provides direct access to amides from an α-bromo nitroalkane and an amine. Based on its mechanistic bifurcation after convergent C-N bond formation, depending on the absence or presence of oxygen, UmAS using substoichiometric N-iodosuccinimide (NIS) under aerobic conditions has been developed. In combination with the enantioselective preparation of α-bromo nitroalkane donors, this protocol realizes the goal of enantioselective α-amino amide and peptide synthesis based solely on catalytic methods.

Full text of DOI:10.1021/ol502089v

Letter
pubs.acs.org/OrgLett
Open Access on 09/08/2015
Umpolung Amide Synthesis Using Substoichiometric
N‑Iodosuccinimide (NIS) and Oxygen as a Terminal Oxidant
Kenneth E. Schwieter, Bo Shen, Jessica P. Shackleford, Matthew W. Leighty, and Jeffrey N. Johnston*
Department of Chemistry and Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37235, United
States
S
* Supporting Information
ABSTRACT: Umpolung Amide Synthesis (UmAS) provides
direct access to amides from an α-bromo nitroalkane and an
amine. Based on its mechanistic bifurcation after convergent
C−N bond formation, depending on the absence or presence
of oxygen, UmAS using substoichiometric N-iodosuccinimide
(NIS) under aerobic conditions has been developed. In
combination with the enantioselective preparation of α-
bromo nitroalkane donors, this protocol realizes the goal of
enantioselective α-amino amide and peptide synthesis based
solely on catalytic methods.
“Amide formation avoiding poor atom economy reagents”1 has
been hailed as a high level challenge and in need of critical
importance in organic chemistry due to the ubiquity of amide
bonds in biologically active molecules.2 Currently, solid-phase
peptide synthesis3 and native chemical ligation4 are the most
used amide forming transformations involving stereochemically
complex products.5−8 Solid-phase peptide synthesis, however,
uses superstoichiometric amounts of coupling reagents and is
thus not economical. Catalytic methods9 based on boronic
acids,10 N-heterocyclic carbenes,11 and transfer hydrogena-
tion12−14 have limited or no adaptation to more complex
targets that present Lewis basic functionality and stereo-
chemical complexity; in cases where turnover is documented,
reagent loadings increase substantially as substrate complexity
increases. Hence, it remains a challenge to prepare complex α-
amino amides relying solely on enantioselective catalysis and
amide formation using substoichiometric promoters.2,5,15
We recently reported a unique method to prepare amides
from an α-bromo nitroalkane and amine using N-iodosuccini-
mide (NIS) under semiaqueous conditions, typically in THF
with 5 equiv of H2O.16 The fact that the α-bromonitroalkane in
these transformations is a functional equivalent of an acyl anion
led us to suggest the term Umpolung Amide Synthesis
(UmAS).17 When the chiral proton catalyzed aza-Henry
reaction is used to prepare the α-bromonitroalkane compo-
nents, chiral α-amino acids, specifically aryl glycines,18 can be
accessed in high enantiomeric excess.16 The Henry reaction was
deployed using a similar strategy to develop an enantioselective
α-oxy amide synthesis.19 Concomitant with the development of
these new reactions, we sought knowledge related to the
mechanism of UmAS. Formation of a tetrahedral intermediate
was posited on evidence for the formation of nucleophilic
nitronate and electrophilic N-halamine. More recently, two
pathways from the putative tetrahedral intermediate to an
amide product were outlined, supported by isotopic labeling
Scheme 1. Umpolung Amide Synthesis (UmAS): Competing
Aerobic and Anaerobic Pathways to Amide from the Putative
Tetrahedral Intermediate
studies (Scheme 1).20 These findings served as the basis for the
studies described here which document the feasibility of UmAS
using substoichiometric NIS. Minimization of the cost and
waste generation associated with amide and peptide synthesis
based solely on enantioselective methods is a widely regarded
goal.1
Our initial studies of amide formation from α-bromoni-
troalkanes uniformly required a full equivalent of N-
iodosuccinimide, or an alternative electrophilic halonium
source, in order to achieve complete conversion and the
highest yields. This finding was more rigorously affirmed
following the discovery of the mechanistic bifurcation outlined
in Scheme 1.21 An experimental protocol was designed to track
Received: July 16, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol502089v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Investigation of NIS Reagent Loading Under
Anaerobic and Aerobic Conditions: Catalyzed Umpolung
Amide Synthesis
Scheme 2. Umpolung Amide Synthesis (UmAS): Competing
Aerobic and Anaerobic Pathways to Amide from the Putative
Tetrahedral Intermediate
a
b
c
entry
O2
NIS amount (mol %)
yield (%)
1
no
no
no
no
no
no
no
100
75
50
30
20
10
0
69
52
36
25
20
20
19
76
73
76
55
51
69
2
3
4
5
6
7
8
yes
yes
yes
yes
yes
yes
20
10
5
9
10
11
1
e
12
0
e
d
was observed in these experiments. In these cases, the substrate
acts competitively as a bromonium source, leading to higher
than expected yields for the 0 and 10 mol % NIS experiments as
well as the nonlinear trend observed below 20 mol % NIS
(Figure 1). At higher NIS loadings (≥30 mol %), 5 was not
observed, signaling that the substrate contributes negligibly as a
bromonium source; in this regime, a linear relationship is
observed between the yield and NIS loading. This behavior
suggests that the substrate only acts as the bromonium source
when the reaction is starved of NIS leading to two different
pathways (iodonium- vs bromonium-mediated) to form the
halamine.
13
5
a
Reactions are 0.2 M in nitroalkane and employ 1.2 equiv of amine
and 5 equiv of H2O and run for 24 h. Under anaerobic conditions
(entries 1−7), NIS was added once the nitroalkane was no longer
visible by TLC, indicating that the nitronate predominated (see
b
Supporting Information). All solutions were first degassed (freeze−
pump−thaw cycles), and entries not using oxygen were performed
under an argon atmosphere (balloon), whereas entries using oxygen
c
were performed under an oxygen atmosphere (balloon). Isolated
yield. Open to air. 48 h reaction time.
d
e
substrate conversion (1H NMR analysis of crude reaction
mixtures) and the isolated yield (to corroborate conversion
estimates), and these two measures tracked closely with one
another at high levels of NIS (Table 1).22 When the reaction
setup rigorously excluded oxygen (i.e., three freeze−pump−
thaw cycles ending with an argon backflush) and maintained an
identical overall reaction time, increasing NIS loadings led to
increasing isolated yields of amide, reflecting the trend normally
observed (Table 1, entries 1−5). The crude reaction mixtures
of an experiment series with low NIS loadings (≤20 mol %,
Table 1, entries 5−7) were suggestive of the sacrificial role that
the substrate might play as an electrophilic halogen
(bromonium ion) source, since debrominated nitroalkane (5)
A separate investigational line was aimed at the effect of an
oxygen atmosphere under carefully controlled conditions, vis-a-
̀
vis, reaction degassing followed by an oxygen atmosphere
(balloon). The use of a 20 mol % NIS loading in an otherwise
identical reaction (cf. Table 1, entry 5) to which a balloon of
oxygen was attached led to complete substrate conversion and
isolation of the amide in 76% yield (Table 1, entry 8). It was
further discovered that the magnitude of turnover under these
conditions can be quite high, as the amide was isolated in 55%
yield when 1 mol % NIS was used (Table 1, entry 11). We
therefore examined, under oxygen-rich conditions, the
possibility that the substrate might substitute for NIS to form
Figure 1. Correlation of electrophilic halogen loading and amide yield under anaerobic conditions.
B
dx.doi.org/10.1021/ol502089v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. NIS-Catalyzed Umpolung Amide Synthesis: Scope
of Bromonitroalkane
Table 3. NIS-Catalyzed Umpolung Amide Synthesis: Scope
of Amine
a
All reactions were conducted using bromonitroalkane (1 equiv, 0.2 M
a
All reactions were conducted using bromonitroalkane (1 equiv, 0.2 M
in DME), amine (1.2 equiv), K2CO3 (2 equiv), and H2O (5 equiv) at
0 °C. Entries 6−8 were >20:1 dr. 5 mol % NIS was used in the
presence of an O2 balloon. 1 equiv of NIS was used. Isolated yields.
in DME), amine (1.2 equiv), K2CO3 (2 equiv), and H2O (5 equiv) at
b
b
0 °C. Entries 5−8 were >20:1 dr. 5 mol % NIS was used in the
c
d
c
d
presence of an O2 balloon. 1 equiv of NIS was used. Isolated yields.
e
10 mol % NIS was used.
however, provide for formation of an alkyl peroxy intermediate
competitive with nitrite formation.23 A straightforward balance
of 7 and ·NO2 with amide products leads to the elements of
bromonium nitrate. Hence, aerobic conditions and NIS lead to
the production of an equivalent of electrophilic bromine (or
iodine), in contrast to anaerobic conditions that lead to an
equivalent each of bromide and iodide. The finer details remain
to be clarified, as several pathways can be drawn from 7 to
amide, consistent with oxidation of bromine, or oxidation of
iodide to iodonium (e.g., I−Br) to form the key electrophilic
halamine in a subsequent cycle.24 Nitrite radicals have been
shown in the literature to react with superoxide,23 and XONO2
(X = Cl, Br, I) compounds are known to form via radical
processes.25 The proposed formation of BrONO2 is of
particular interest, as this species can oxidize iodide to
the necessary halamine intermediate to initiate the reaction.
Indeed, amide was isolated in 51% yield in the absence of a
halonium source (Table 1, entry 12). The rate of amide
production in this reaction was noticeably slower. The role of
oxygen is critical for turnover, as the corresponding experiment
under anaerobic conditions (no NIS) provided a 19% yield of
the amide product (Table 1, entry 7). The reaction also
proceeds with a less oxygen-rich atmosphere, although at a
slower rate (Table 1, entry 13).
The behavior outlined in Table 1 is consistent with the
intermediates and pathways depicted in Scheme 2. Recombi-
nation of the two radicals under anaerobic conditions leads to
an alkyl nitrite that can hydrolyze to amide. The coproducts of
this step are formally nitrite and bromide. Aerobic conditions,
C
dx.doi.org/10.1021/ol502089v | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(5) Wu, J.; Ruiz-Rodriguez, J.; Comstock, J. M.; Dong, J. Z.; Bode, J.
W. Chem. Sci. 2011, 2, 1976−1979. Bode, J. W.; Fox, R. M.; Baucom,
K. D. Angew. Chem., Int. Ed. 2006, 45, 1248−1252.
(6) Zheng, J.-S.; Yu, M.; Qi, Y.-K.; Tang, S.; Shen, F.; Wang, Z.-P.;
Xiao, L.; Zhang, L.; Tian, C.-L.; Liu, L. J. Am. Chem. Soc. 2014, 136,
3695−3704.
iodonium. The uncertainty surrounding the actual redox
pathway leading from 7 to amide may be of more academic
value, and it may be difficult to discern whether iodonium or
bromonium is the actual propagating species (or whether they
are mutually exclusive). However, we have noted that reactions
using NIS exhibit both faster conversion and less complex
crude reaction mixtures than alternatives.26
(7) Zheng, J.-S.; Tang, S.; Huang, Y.-C.; Liu, L. Acc. Chem. Res. 2013,
46, 2475−2484.
Notwithstanding this uncertainty, analysis of the aerobic
UmAS protocol substoichiometrically in NIS was evaluated in
several existing UmAS contexts. A direct comparison of UmAS
couplings of α-bromonitroalkanes and α-methyl benzyl amine
led to comparable yields in most cases (Table 2). Several
examples provided a higher yield of amide using aerobic
conditions and a 5 mol % NIS loading. The yield was
significantly lower (e.g., 66% vs 51% yield) in only two cases
when using substoichiometric NIS (Table 2, entries 5−6). A
similar trend was observed when a range of functionalized
amines were compared using the two protocols (Table 3).
In conclusion, consideration of a mechanistic hypothesis that
Umpolung Amide Synthesis under aerobic conditions provides
a pathway to electrophilic halonium regeneration resulted in
the development of a protocol using substoichiometric N-
iodosuccinimide. The protocol described here does not require
reagent excess and avoids the production of coproducts that
present purification issues. The fact that the overall route from
bromonitromethane to chiral nonracemic α-amino amide is
substoichiometric in all components, except for the base
(K2CO3) and oxygen, provides a two-step solution for a
catalytic, enantioselective synthesis of α-amino amides and
peptides.
(8) Wang, T.; Danishefsky, S. J. Proc. Natl. Acad. Sci. U.S.A. 2013,
110, 11708−11713.
(9) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem. Soc.
Rev. 2014, 43, 2714−2742. Singh, C.; Kumar, V.; Sharma, U.; Kumar,
N.; Singh, B. Curr. Org. Synth. 2013, 10, 241−264.
(10) Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H. J. Org.
Chem. 1996, 61, 4560−4567. Marcelli, T. Angew. Chem., Int. Ed. 2010,
49, 6840−6843. Al-Zoubi, R. M.; Marion, O.; Hall, D. G. Angew.
Chem., Int. Ed. 2008, 47, 2876−2879. Charville, H.; Jackson, D.;
Hodges, G.; Whiting, A. Chem. Commun. (Cambridge, U. K.) 2010, 46,
1813−1823.
(11) Bode, J. W.; Sohn, S. S. J. Am. Chem. Soc. 2007, 129, 13798−
13799. Vora, H. U.; Rovis, T. J. Am. Chem. Soc. 2007, 129, 13796−
13797. De Sarkar, S.; Studer, A. Org. Lett. 2010, 12, 1992−1995.
Chiang, P.-C.; Kim, Y.; Bode, J. W. Chem. Commun. (Cambridge, U. K.)
2009, 4566−4568.
(12) Gunanathan, C.; Ben-David, Y.; Milstein, D. Science 2007, 317,
790−792. Nordstrøm, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc.
2008, 130, 17672−17673. Muthaiah, S.; Ghosh, S. C.; Jee, J.-E.; Chen,
C.; Zhang, J.; Hong, S. H. J. Org. Chem. 2010, 75, 3002−3006. Saha,
B.; Sengupta, G.; Sarbajna, A.; Dutta, I.; Bera, J. K. J. Organomet.
Chem., DOI: 10.1016/j.jorganchem.2013.12.051. Srimani, D.;
Balaraman, E.; Hu, P.; Ben-David, Y.; Milstein, D. Adv. Synth. Catal.
2013, 355, 2525−2530. Cho, D.; Ko, K. C.; Lee, J. Y. Organometallics
2013, 32, 4571−4576.
(13) Kang, B.; Fu, Z.; Hong, S. H. J. Am. Chem. Soc. 2013, 135,
11704−11707.
(14) Gunanathan, C.; Milstein, D. Science 2013, 341, 1229712. Chen,
C.; Hong, S. H. Org. Biomol. Chem. 2011, 9, 20−26.
(15) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J.
Am. Chem. Soc. 2003, 125, 7754−7755.
(16) Shen, B.; Makley, D. M.; Johnston, J. N. Nature 2010, 465,
1027−1032.
(17) For an umpolung N-phenyl hydroxamic acid synthesis, see:
Wong, F. T.; Patra, P. K.; Seayad, J.; Zhang, Y.; Ying, J. Y. Org. Lett.
2008, 10, 2333−2336.
(18) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889−917.
(19) Leighty, M. W.; Shen, B.; Johnston, J. N. J. Am. Chem. Soc. 2012,
134, 15233−15236.
(20) Shackleford, J. P.; Shen, B.; Johnston, J. N. Proc. Natl. Acad. Sci.
U.S.A. 2012, 109, 44−46.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jeffrey.n.johnston@vanderbilt.edu.
Notes
The authors declare no competing financial interest.
(21) Prior to the work reported here, aside from the careful
mechanistic studies (ref 20), a typical reaction setup involved a vial or
flask capped with a septum, creating a static atmosphere. In these
cases, exposure to atmospheric oxygen is best described as variable.
(22) THF was originally used as the solvent, but its oxidation by NIS
to the corresponding lactol and lactone was observed when amide
formation was slow. Dimethoxyethane (DME) was identified as the
optimal solvent for these studies since it did not suffer from detectable
oxidation.
(23) Hodges, G. R.; Ingold, K. U. J. Am. Chem. Soc. 1999, 121,
10695−10701. Goldstein, S.; Czapski, G. J. Am. Chem. Soc. 1998, 120,
3458−3463.
(24) Finkbeiner, P.; Nachtsheim, B. J. Synthesis 2013, 45, 979−999.
(25) Papayannis, D. K.; Kosmas, A. M. Chem. Phys. 2005, 315, 251−
258.
ACKNOWLEDGMENTS
■
Research reported in this publication was supported by the
National Institute of General Medical Sciences of the National
Institutes of Health (GM 063557). Predoctoral fellowship
support by the National Science Foundation (J.P.S.) is
gratefully acknowledged.
REFERENCES
■
(1) Constable, D. J. C.; Dunn, P. J.; Hayler, J. D.; Humphrey, G. R.;
Leazer, J. J. L.; Linderman, R. J.; Lorenz, K.; Manley, J.; Pearlman, B.
A.; Wells, A.; Zaks, A.; Zhang, T. Y. Green Chem. 2007, 9, 411−420.
(2) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471−479.
Nilsson, B. L.; Soellner, M. B.; Raines, R. T. Annu. Rev. Biophys. Biomol.
Struct. 2005, 34, 91−118.
(3) Merrifield, R. B. J. Am. Chem. Soc. 1963, 85, 2149−2154. Valeur,
E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606−631.
(4) Dawson, P. E.; Muir, T. W.; Clarklewis, I.; Kent, S. B. H. Science
1994, 266, 776−779. Haase, C.; Seitz, O. Angew. Chem., Int. Ed. 2008,
47, 1553−1556.
(26) NBS is a competent halonium source for the reaction. However,
the conversion to amide is slower and hindered by the formation of
the dibrominated nitroalkane.
D
dx.doi.org/10.1021/ol502089v | Org. Lett. XXXX, XXX, XXX−XXX