Stereospecific intramolecular C-H amination of 1-aza-2-azoniaallene salts

Article abstract of DOI:10.1021/ja303054c

We report that 1-aza-2-azoniaallene salts, generated from α-chloroazo compounds by treatment with halophilic Lewis acids, participate in intramolecular C-H amination reactions to provide pyrazoline products in good to excellent yield. This intramolecular amination occurs readily at both benzylic and tertiary aliphatic positions and proceeds at an enantioenriched chiral center without loss of enantiomeric excess. A competition reaction shows that insertion occurs more readily at an electron-rich benzylic position than an electron-deficient one. These observations are consistent with the 1-aza-2-azoniaallene intermediate reacting as a nitrenium-like ion by a concerted insertion mechanism.

Full text of DOI:10.1021/ja303054c

Communication
pubs.acs.org/JACS
Stereospecific Intramolecular C−H Amination of 1-Aza-2-
azoniaallene Salts
Daniel A. Bercovici and Matthias Brewer*
Department of Chemistry, The University of Vermont, 82 University Place, Burlington, Vermont 05405, United States
S
* Supporting Information
Scheme 1. Preparation of a Pyrazoline from an α-Chloroazo
Compound
ABSTRACT: We report that 1-aza-2-azoniaallene salts,
generated from α-chloroazo compounds by treatment with
halophilic Lewis acids, participate in intramolecular C−H
amination reactions to provide pyrazoline products in
good to excellent yield. This intramolecular amination
occurs readily at both benzylic and tertiary aliphatic
positions and proceeds at an enantioenriched chiral center
without loss of enantiomeric excess. A competition
reaction shows that insertion occurs more readily at an
electron-rich benzylic position than an electron-deficient
one. These observations are consistent with the 1-aza-2-
azoniaallene intermediate reacting as a nitrenium-like ion
by a concerted insertion mechanism.
chloroazo compounds with halophilic Lewis acids,21 produc-
tively react with pendant alkenes to provide bicyclic diazenium
salts via intramolecular 1,3-dipolar cycloaddition reactions
similar to the intermolecular cycloadditions described by
Jochims et al.24,25 The requisite α-chloroazo compounds are
easily prepared by reaction of hydrazones with chlorodime-
thylsulfonium chloride.26 We became interested in exploring
the reactivity of these cationic heteroallenes in systems that
cannot participate in 1,3-dipolar cycloadditions because they
lack a pendant alkene.27 To this end, we prepared heteroallene
2a (Scheme 1) by treating the α-chloroazo compound 1a with
SbCl5, and upon purifying this reaction we were surprised to
isolate pyrazoline 3a in good yield as well as traces of pyrazole
4a. This unexpected result is, to our knowledge, the first
example of heteroallenes such as 2a reacting by a nitrene-like
manifold to provide the product of an intramolecular C−H
amination reaction. Although pyrazolines can be readily
prepared by reaction of hydrazines with α,β-unsaturated
aldehydes and ketones or by 1,3-dipolar cycloaddition of
diazoalkanes with alkenes,28,29 the development of new
methods to prepare these compounds is still of interest30−36
due to their prevalence in biologically active compounds.30,37,38
The novelty of this C−H amination reaction encouraged us to
examine this new reactivity more thoroughly.
eactions that result in direct functionalization of
R
unactivated C−H bonds are powerful transformations
because they provide new synthetic strategies that can be more
efficient and simpler to execute than traditional synthetic
sequences.1 For example, Rh-catalyzed carbene insertion
reactions, wherein Rh complexes selectively functionalize C−
H bonds, have become an important strategy for C−C bond
formation.2 Similarly, since Breslow and Gellman’s3,4 seminal
demonstration that (imidoiodo)benzene derivatives react with
alkanes in the presence of a transition metal to provide amine
products, transition-metal-catalyzed C−H amination reactions
have become important ways to prepare organic amines.5−9
These techniques are powerful because they allow for the
selective installation of N atoms both inter- and intra-
molecularly at a late stage in a synthetic sequence and provide
fundamentally new approaches to the preparation of N
heterocycles, which are prevalent in bioactive molecules.10−12
The significant advances that have been made over the past
decade in transition-metal-mediated amination were made
possible in part by the discoveries by Che13 and Du Bois14 that
metal nitrenoid species could be prepared in situ from amine
derivatives, iodine(III) reagents, and a transition metal catalyst.
Recently, amination reactions have been used elegantly in
natural product synthesis15,16 and have been rendered stereo-
selective.17−20 Here we report our discovery that 1-aza-2-
azoniaallene salts21 (e.g., 2a, Scheme 1) undergo intramolecular
C−H insertion reactions to provide pyrazoline products
without the formation of a metal nitrenoid intermediate.
Recent work in our group has focused on investigating 1-aza-
Upon repeating this transformation several times, we noted
that the ratio of pyrazoline 3a and pyrazole 4a varied
significantly between trials, and we reasoned that the pyrazole
−
likely formed by a precedented SbCl6 -mediated oxidation of
the pyrazoline.39 This secondary oxidation reaction proved
2-azoniaallene salts as reactive intermediates for the synthesis of
N heterocycles.22,23 We have demonstrated that these
heteroallene salts, which can be generated by reaction of α-
Received: April 3, 2012
Published: June 8, 2012
© 2012 American Chemical Society
9890
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Journal of the American Chemical Society
Communication
resulted in an increase in yield of ∼15%. The 3-nitrophenyl
derivative (entry 5), in contrast, returned product in at most
20% yield.40 A moderate increase in steric hindrance adjacent to
the amine was well tolerated; 2-methylphenyl derivative 1f
provided the expected product in 80% yield (entry 6).
Changing the electronics of the pendant aryl ring from
marginally electron-rich (entry 8) to electron-neutral (entry
1) to electron-poor (entries 9 and 10) had surprisingly little
influence on the reaction outcome; in each case a similar
quantity of pyrazoline product was formed (61−65% yield). In
contrast, a strong electron-donating group on the pendant aryl
ring (entry 7) appeared to activate the benzylic C−H bond
toward amination and gave a significantly higher product yield
(79%).
Table 1. Optimization of Reaction Conditions for Pyrazoline
Formation
a
entry
MClX
equiv
solvent
time (h) temp (°C) yield (%)
1
2
3
4
5
6
7
8
9
10
SbCl5
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
AlCl3
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
2.2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
THF
2
2
−60
−60
−60
−60
−60
−60
−40
25
53
51
61
62
59
38
56
49
0
4
6
32
48
34
24
24
24
To test this finding more directly, we devised a competition
experiment in which the heteroallene intermediate has equal
opportunity to react at an electron-rich or -deficient benzylic
position. For this experiment, we prepared α-chloroazo
substrate 1k (Scheme 2), which contains both electron-poor
−60
−60
CH2Cl2
36
a
1
Yields determined by H NMR integration relative to an internal
standard.
Scheme 2. Competition Experiment
difficult to control, but we were pleased to find that changing
the Lewis acid from SbCl5 to AlCl3 eliminated formation of
pyrazole 4a while providing comparable yields of the desired
pyrazoline (Table 1, entry 2).21 We next evaluated the effect of
reaction time on the reaction outcome. Increasing the reaction
time from 2 to 4 h resulted in increased product yield (entries 2
and 3), but further extending the reaction time added no
benefit (entries 4−6). We also evaluated the temperature
dependence of the reaction and observed the best results at
−60 °C; higher temperatures resulted in slightly lower yields
(entries 7 and 8). Changing the solvent from CH2Cl2 to THF
inhibited the reaction altogether (entry 9), and increasing the
equivalents of AlCl3 decreased the pyrazoline yield (entry 10).
To gain insight into the role that electronic effects might play
in this reaction, we prepared a series of substrates having either
electron-donating or -withdrawing groups on the N-aryl or the
pendant aryl ring (Table 2). Electron-rich N-aryl rings
facilitated the reaction, and changing the N-aryl ring from 4-
chlorophenyl to phenyl, 4-methylphenyl, or 4-methoxyphenyl
and -rich pendant aryl rings. The heteroallene generated from
this substrate reacted with complete selectivity at the more
electron-rich benzylic C−H bond to provide pyrazoline 3k as
the only product in 92% yield.41 The high yield obtained for
this reaction is likely due to the electron-rich nature of both the
N-aryl and pendant aryl ring. It is accepted that, over the course
of carbenoid and nitrenoid C−H insertion reactions, positive
charge builds at the C undergoing the C−H insertion, and sites
adjacent to electron-donating groups react more quickly.2,42
The result of the competition study supports the notion that
heteroallene intermediate 2, which could exist in nitrenium ion
form 5 (Figure 1), may be reacting similarly to a nitrenoid via a
Table 2. Effect of Aryl Ring Electronics on the
Intramolecular Amination
Figure 1. Nitrenium ion resonance form.
entry α-chloroazo
R1
R2
Cl
R3
R4
yield (%)
1
2
1a
1b
1c
1d
1e
1f
H
H
H
H
H
H
H
H
61
74
C−H amination reaction. Theoretical studies support the
ability of 1-aza-2-azoniaallene cations to react by a nitrenium
ion manifold.43 Nitrenium ions are isoelectronic with carbenes,
but despite the plethora of research in carbene chemistry,
nitrenium ions have been far less studied,44−46 although
recently aryl nitrenium ions47−49 have received more attention
due to their proposed role in mutagenesis and carcinogenesis.
Additionally, nitrenium ions are known to undergo concerted
addition to alkenes to provide aziridinium products,50−53 and
they can act as hydride acceptors.54 The increased yields of
H
H
H
3
CH3
OCH3
H
H
H
79
4
H
H
76
5
NO2
H
H
<20
80
6
H
CH3
H
7
1g
1h
1i
OCH3
CH3
Cl
Cl
H
79
8
Cl
H
H
65
9
Cl
H
H
62
10
1j
NO2
Cl
H
H
65
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Journal of the American Chemical Society
Communication
pyrazoline we obtained for electron-rich N-aryl substrates
(Table 2, entries 3 and 4, and Table 3, all entries) are also
however, in these cases yields suffered (entries 3 and 4). The
reduction in yield is likely due to an increase in steric
interactions that make pyrazoline formation less facile, and not
a subtle electronic effect imparted by the extra substituent since
adding a group adjacent to the chloroazo center on the side
opposite the aryl ring provided the expected product in good
yield (entry 1). Adding a substituent in the benzylic position
was well tolerated when the N-aryl ring was electron-rich to
provide 5,5-disubstituted pyrazoline 3o (entry 2).57 For reasons
that we do not fully understand, this transformation
consistently failed when the N-aryl ring was electron-deficient
(entry 2, 1n). In this latter case, substantial quantities of the
starting ketone were isolated upon workup.
Table 3. Substrate Scope
Successful insertion into a tertiary benzylic center led us to
examine the potential of the heteroallene to react at a tertiary
non-benzylic site. Importantly, subjecting isopropyl derivative
1t or 1u to the reaction conditions returned pyrazoline 3t or 3u
(Table 3, entry 5) in 59% and 62% isolated yield, respectively.
Unfortunately, attempts to insert into a secondary aliphatic
position were not fruitful; the heteroallene derived from 2-
pentanone returned a complex mixture.
Mechanisms that could account for pyrazoline formation
include the concerted C−H insertion of a singlet-state
nitrenium ion-type intermediate, a radical abstraction of a
benzylic H by a triplet-state nitrenium ion-type intermediate
followed by a radical recombination to form the new C−N
bond, or a 1,5-hydride shift followed by nucleophilic attack of
N onto the newly formed benzylic cation. To give some
indication of which of these mechanisms might be operative, we
prepared substrate 1v (Scheme 3) in enantioenriched form.
Scheme 3. Stereospecific C−H Amination
Subjecting this material to the reaction conditions provided
pyrazoline 3v with complete stereochemical fidelity, as
determined by HPLC analysis on a chiral stationary phase.
This result favors a concerted C−H insertion reaction since the
other two mechanistic possibilities would proceed through
achiral intermediates. However, these latter two mechanisms
cannot be ruled out entirely since the recombination steps
could, in principle, occur faster than bond rotation; further
studies are planned to more fully probe the operative
mechanism.
a
b
c
d
Isolated yield. 1H NMR yield, 40%. 1H NMR yield, 56%. 1H NMR
e
f
yield, 71%. 1H NMR yield, 75%. 1H NMR yield, 66%.
In summary, 1-aza-2-azoniaallene salts have been observed to
participate in unprecedented amination reactions at benzylic
and tertiary aliphatic centers to provide pyrazoline products. A
substrate that contained an enantioenriched tertiary benzylic
center reacted without erosion of stereopurity. The results
gathered thus far support the hypothesis that the amination
reaction occurs via a concerted C−H insertion of a singlet-state
nitrenium ion intermediate. Further studies on the scope and
mechanism of this transformation are underway.
consistent with a nitrenium ion-type reaction intermediate since
electron-rich aryl rings and adjacent heteroatoms are known to
stabilize the nitrenium ion singlet state,55 which should undergo
insertion reactions more readily than the triplet state.
We next examined the effect of adding substituents on the C
chain of the α-chloroazo substrate (Table 3) on the reactions
leading to tri- or tetrasubstituted pyrazolines. Adding a
substituent adjacent to the chloroazo center and between the
reacting centers returned a single diastereomer56 of product;
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Journal of the American Chemical Society
Communication
(27) Recent work by Thomson has demonstrated that allyl-
substituted 1-aza-2-azoniaallene salts can undergo 3,3-sigmatropic
rearrangements: Mundal, D. A.; Lutz, K. E.; Thomson, R. J. Org. Lett.
2009, 11, 465. Mundal, D. A.; Avetta, C. T.; Thomson, R. J. Nat.
Chem. 2010, 2, 294. 1-aza-2-azoniaallene salts derived from aryl
ketones are known to undergo electrophilic aromatic substitution to
provide indazole products: Gladstone, W. A. F.; Norman, R. O. C. J.
Chem. Soc. 1965, 3048. Gladstone, W. A. F.; Norman, R. O. C. J. Chem.
Soc. C 1966, 1527 and ref 21.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, spectral data for all
compounds, and HPLC traces for 3o and 3v. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
matthias.brewer@uvm.edu
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(31) Dang, T.-T.; Abdellah, I.; Canac, Y.; Chauvin, R. ChemCatChem
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Dr. John Greaves (University of California, Irvine)
for obtaining mass spectral data, Dr. Bruce Deker (University of
Vermont) for assistance with NMR characterization, and Prof.
Huw Davies (Emory University) for a helpful discussion. This
material is based upon work supported by the National Science
Foundation under CHE-0748058 and instrumentation grant
CHE-0821501. Financial support from the University of
Vermont is gratefully acknowledged.
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