Redox-neutral α-amino C-H functionalization: When the catalyst is also the nucleophile

Article abstract of DOI:10.1021/acs.orglett.5b03431

A redox-neutral functionalization of cyclic amines that leads to acyclic products is presented. The reaction hinges on generation of transient aryl radical intermediates by catalytic activation with a simple hydrazine. Those aryl radicals subsequently und

Full text of DOI:10.1021/acs.orglett.5b03431

Letter
pubs.acs.org/OrgLett
Redox-Neutral α‑Amino C−H Functionalization: When the Catalyst Is
Also the Nucleophile
Saad Shaaban, Joongsuk Oh,† and Nuno Maulide*
University of Vienna, Faculty of Chemistry, Institute of Organic Chemistry, Wahringer Strasse 38, 1090 Vienna, Austria
̈
S
* Supporting Information
ABSTRACT: A redox-neutral functionalization of cyclic amines that leads to acyclic products is presented. The reaction hinges
on generation of transient aryl radical intermediates by catalytic activation with a simple hydrazine. Those aryl radicals
subsequently undergo translocation and further oxidation prior to trapping with the same hydrazine, thus resulting in an overall
process where the catalyst unusually also acts as the nucleophile.
Scheme 1. (a) Previous Work on Hydrazine As a Catalyst for
C−C Bond Formation; (b) Our Hypothesis for Metal-Free
C−N Bond Formation
he reduction of aryldiazonium salts (accompanied by the
Trelease of nitrogen gas) is a well-established route to
access aryl radicals,1 which are useful intermediates in
synthesis.2 An array of inorganic and organic catalysts can be
employed in this reduction process.3 These include organic
dyes,4 tetrathiafulvalene,5 and ascorbic acid.6
On the other hand, the construction of C−N bonds is of
significant importance in organic chemistry,7 given the almost
ubiquitous presence of nitrogen in biologically relevant
synthetic constructs. This is illustrated by the wide range of
amination methods available in the literature.8 In particular,
hydrazines constitute a well-known family of aminating
reagents9 ranging from classical condensation reactions with
carbonyl derivatives10 to transition-metal-catalyzed transforma-
tions.11
We have recently shown that hydrazines are excellent
catalysts for the reduction of aryldiazonium salts with rapid
liberation of nitrogen gas, notably without the requirement for
any UV or visible light.12 The resulting aryl radicals could be
engaged in several C−C bond forming processes (Scheme
1a).12
Given the high synthetic relevance of amination processes,
we speculated that a suitable hydrazine promoter might, if
employed in stoichiometric amounts, additionally serve as a
nucleophile for C−N bond formation thus fulfilling an unusual
dual role. Herein we report a metal-free, mild procedure for
redox-neutral α-amino functionalization13with concomitant C−
N bond formation, where the catalyst and nucleophile are the
same entity (Scheme 1b).
At the outset, we focused on a system typified by diazonium
salt 2a. Herein (Scheme 1b), reduction of the diazonium salt
moiety should trigger a 1,5-hydrogen migration,14 generating an
α-amino radical that might, upon additional oxidation and
nucleophilic capture, generate the product 4a. We thus
hypothesized that the use of 1 equiv of 4-aminomorpholine
3a with diazonium salt 2a in DMSO should lead to product 4a
or its ring-chain isomer. As shown in Table 1, under these
conditions we observed formation of linear product 4a in
moderate yield (entry 1). Screening different solvents (entries
2−5) revealed that acetonitrile is the best medium for this
transformation. Increasing the amount of hydrazine to 1.3 equiv
led to higher yields in a shorter reaction time (entry 6). A
further increase of either parameter (entries 7 and 8) did not
lead to better results.
With suitable reaction conditions in hand, we delineated the
scope of this transformation. As seen in Scheme 2, different
Received: December 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03431
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
Scheme 3. Scope of Hydrazines
bc
,
entry
3a (equiv)
solvent
time (h)
yield (%)
b
1
2
3
4
5
6
7
8
1
DMSO
DMF
2
30
b
1
2
22
b
1
MeCN
dioxane
hexane
MeCN
MeCN
MeCN
2
61
1
2
−
−
1
2
c
1.3
1.3
2
0.5
1
76
b
76
b
0.5
76
a
b
Reactions were performed at rt at 0.1 M concentration. NMR yield.
c
Isolated yield.
Scheme 2. Scope of Substrate on Cyclic Amines
Scheme 4. Scope of Alkynes for C−C Bond Formation
cyclic amines underwent this transformation in moderate to
good yields (4a−4c). Sulfonamides were also suitable coupling
partners, as exemplified by the formation of ω-aminohydrazone
4d in good yield. The presence of functional groups on the
aromatic ring, affording opportunities for further synthetic
elaboration,15 was not detrimental to the overall process (4f−
4g).
Different substituted hydrazines also worked well in this
transformation. As seen in Scheme 3, a range of hydrazines
furnished the C−N coupling products in good to excellent
yield, including sterically demanding cases (4h−4j). Dimethyl
hydrazine and arylated derivatives led to the expected products
in moderate to good yield (4k−4m), and this regardless of the
nature of the aryl diazonium salt partner (4n−4o). Piperidine
moieties in the starting diazonium salt similarly led to the
functionalized hydrazones with comparable efficiency to their
pyrrolidine counterparts (4p−4q).
diamines that are interesting compounds with multiple
biological activities.18
Based on literature precedent,4a,12,14,19 a plausible mecha-
nism for this transformation can be proposed (Scheme 5).
Reaction between hydrazine 3 and diazonium salt 2a
presumably leads to the tetrazene intermediate,12,19a which
spontaneously fragments to generate aryl radical 8 with
extrusion of N2. Aryl radical 8 undergoes 1,5 hydrogen
migration to give α-amino radical intermediate 10. This
undergoes a subsequent oxidation, either by amine radical
carbocation 9 furnishing intermediate 11 and regenerating
hydrazine 3 or by oxidation with diazonium salt 2a releasing
again aryl radical 8. Intermediate 11 will then be trapped by
nucleophilic hydrazine 3 to give 12. Finally, under the slightly
acidic conditions of the reaction medium, intermediate 12 will
rearrange with ring opening to give products 4a.
The presence of a hydrazone moiety in the products of these
reactions16 suggests opportunities for further functionaliza-
tion.17 For instance, alkynylation with lithium (alkynyl)-
trifluoroborate nucleophiles 5a−e led to the nucleophilic
addition products 6a−e. As seen in Scheme 4, different
aliphatic 6a, cyclic 6b, arylated 6c,d, and silylated 6e alkynes
were smoothly introduced. This will furnish masked 1,4
In conclusion, we developed a metal-free, redox neutral
methodology for C−N bond formation that hinges on the use
of a hydrazine promoter that fulfills a dual role. The resulting
ω-aminohydrazones can be further functionalized by nucleo-
philic addition. The concept of a promoter which is also a
stoichiometric reagent, thus obviating the need for additional
catalysts, is an intriguing approach to synthesis.
B
DOI: 10.1021/acs.orglett.5b03431
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03431.
■
S
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: nuno.maulide@univie.ac.at.
Present Address
†Department of Chemistry, University of Texas at San Antonio,
One UTSA Circle, San Antonio, TX 78249. E-mail: oh.
joongsuk@gmail.com.
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
Generous support of this research by the University of Vienna
and Sungkyunkwan University BK21 PLUS (fellowship to J.O.)
is acknowledged. Dr. Hanspeter Kahlig from University of
Vienna is acknowledged for invaluable support with NMR
spectroscopic analysis.
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DOI: 10.1021/acs.orglett.5b03431
Org. Lett. XXXX, XXX, XXX−XXX