Transition from π radicals to σ radicals: Substituent-tuned cyclization of hydrazonyl radicals

Article abstract of DOI:10.1002/anie.201309918

Hydrazonyl radicals are known for their π-electronic structures; however, their σ-electronic structures have not been reported as yet. Herein, we show that readily accessible β,γ- and γ,δ- unsaturated N-trichloroacetyl and N-trifluoroacetyl hydrazones can be conveniently converted into hydrazonyl σ radicals, which subsequently undergo 5-exo-trig radical cyclization at the N¹ or N² atom to form pyrazolines and azomethine imines, respectively. Time for a radical career change? Known for their π character, hydrazonyl radicals can be tuned to act as σ radicals with the spin density delocalized on both nitrogen atoms by attaching a trifluoroacetyl or trichloroacetyl group to the N ¹ atom. The hydrazonyl σ radicals derived from the corresponding N-acyl-substituted β,γ- and γ,δ-unsaturated hydrazones underwent Ci-N¹ and Ci-N² bond-forming 5-exo-trig cyclization, respectively (see scheme).

Full text of DOI:10.1002/anie.201309918

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Angewandte
Communications
DOI: 10.1002/anie.201309918
Radical Cyclization
Transition from p Radicals to s Radicals: Substituent-Tuned
Cyclization of Hydrazonyl Radicals**
Xiao-Yong Duan, Neng-Neng Zhou, Ran Fang, Xiu-Long Yang, Wei Yu, and Bing Han*
Abstract: Hydrazonyl radicals are known for their p-elec-
tronic structures; however, their s-electronic structures have
not been reported as yet. Herein, we show that readily
accessible b,g- and g,d-unsaturated N-trichloroacetyl and N-
trifluoroacetyl hydrazones can be conveniently converted into
hydrazonyl s radicals, which subsequently undergo 5-exo-trig
radical cyclization at the N1 or N2 atom to form pyrazolines
and azomethine imines, respectively.
as well as nitrogen-centered radicals. Consequently, 5-exo-trig
radical cyclizations[4] can take place at both the O and the
N atom, depending on the position of the carbon–carbon
double bond (Scheme 1, top left).[3a] On the other hand, the
hydrazonyl radicals derived from N-phenyl-substituted b,g-
and g,d-unsaturated hydrazones under similar conditions only
undergo the respective 5-exo-trig, 6-exo-trig, and (or) tandem
1,5-H shift/5-exo-trig cyclization at the N1 atom, thus indicat-
H
ydrazonyl and iminoxyl radicals have
been known for a long time. Although
they have similar molecular structures,
the electronic properties of these two
kinds of radicals are totally different.
Iminoxyl radicals are s radicals with the
single-electron spin delocalized on both
the O and the N atom.[1] In other words,
two resonance structures I and II can be
drawn for iminoxyl radicals (Scheme 1,
top left). On the other hand, hydrazonyl
radicals are ordinarily referred to as
p radicals, which means that the spin
density is delocalized on the p orbital of
the N1 atom and conjugated C atom, but
not on the N2 atom.[2] Thus, hydrazonyl
radicals are represented with resonance
structures III and IV, different from those
of iminoxyl radicals (Scheme 1, top right).
Recently, we confirmed the electronic
properties of these two kinds of radicals
by computational and experimental stud-
ies.[3] We demonstrated that b,g- and g,d-
unsaturated ketoximes can be converted
into the corresponding iminoxyl radicals,
which behave as oxygen-centered radicals
Scheme 1. Top left: Cyclizations of iminoxyl radicals, and their two resonance structures I and II.
Top, right: Cyclizations of hydrazonyl radicals, and their two resonance structures III and IV.
Bottom: Cyclizations described herein of hydrazonyl s radicals, and their two resonance
structures V and VI. In=initiation, T=radical-trapping moiety.
[*] X.-Y. Duan,[+] N.-N. Zhou,[+] Dr. R. Fang,[+] X.-L. Yang, Prof. Dr. W. Yu,
Prof. Dr. B. Han
ing that these N-phenyl-substituted hydrazonyl radicals are
p radicals (Scheme 1, top right).[3b,5]
State Key Laboratory of Applied Organic Chemistry and College of
Chemistry and Chemical Engineering, Lanzhou University
Lanzhou, 730000 (P. R. China)
As free radicals containing two heteroatoms, iminoxyl
radicals have been studied extensively.[6] However, studies on
hydrazonyl radicals have rarely been reported. Could hydra-
zonyl radicals also behave like iminoxyl radicals? Could the
N2 atom also be tuned as a radical center to undergo radical
cyclizations? To answer these questions, we conducted studies
to further explore the nature and diverse reactivity of
hydrazonyl radicals. We anticipated that the substituent
might affect the delocalization of spin density and thus
change the hydrazonyl radical from a p radical to a s radical.
Indeed, our theoretical and experimental studies both con-
firm that the electronic structure of hydrazonyl radicals can
E-mail: hanb@lzu.edu.cn
[+] These authors contributed equally.
[**] We thank the National Natural Science Foundation of China
(21272106), the Program for New Century Excellent Talents in
University (NCET-13-0258), the Changjiang Scholars and Innovative
Research Team in University (IRT1138), the “111” Project, and the
Fundamental Research Funds for the Central Universities (lzujbky-
2013-ct02) for financial support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201309918.
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be adjusted by varying the substituent on the N1 atom. Thus,
N-trichloroacetyl and N-trifluoroacetyl hydrazonyl radicals
behave as s radicals: for these radicals incorporating b,g-
unsaturation, 5-exo-trig cyclization at the N1 atom was found
to take place, whereas their g,d-unsaturated counterparts
underwent 5-exo-trig cyclization at the N2 atom (Scheme 1,
bottom). These radicals can be conveniently generated from
the corresponding hydrazones by using TEMPO+ BF4À as the
oxidant and Cs2CO3 as the base. Our results demonstrate for
the first time that hydrazonyl radicals can be tuned to behave
as s radicals by changing the substituent at the N1 atom.[7]
At the beginning of this study, variously N-substituted g,d-
unsaturated hydrazones 1 were used as model compounds to
calculate (Gaussian09, DFT calculations at the B3LYP/6-31 +
G(d) level) the spin density delocalized on their correspond-
ing hydrazonyl radicals R1.[8] The results are summarized in
Table 1. It is clear that the phenyl-substituted hydrazonyl
Figure 1. Calculated Mulliken spin-density maps of hydrazonyl p radi-
cal R1a (left) and s radical R1h (right). Blue grid lines indicate regions
of positive spin density, and green grid lines indicate regions of
negative spin density.
oxygen atom and can spread further owing to the inductive
effect of the CX3 group (Scheme 1, bottom). Therefore, on
the basis of the computational studies, hydrazonyl radicals can
be divided into three types: 1) p radicals (R1a–c); 2) s rad-
icals (R1g–i); 3) s + p mixed radicals (R1d–f).
Table 1: Substituent-tuned spin-density delocalization on the N1, N2, and
C atoms of g,d-unsaturated hydrazonyl radicals.[a]
Entry
G
Spin density on R1
N2
Radical
type
N1
C
D[b]
1
2
3
4
5
6
7
8
9
Ph (1a)
0.56 À0.01
0.23 0.57
0.29 0.57
0.20 0.49
0.17 0.46 s+p
0.23 0.38 s+p
0.19 0.38 s+p
0.04 0.24 s[c]
p
p
p
Me (1b)
tBu (1c)
H (1d)
CF3 (1e)
mesyl (1 f)
benzoyl (1g)
0.61
0.59
0.62
0.55
0.56
0.52
0.04
0.10
0.16
0.17
0.18
0.28
trichloroacetyl (1h) 0.44
trifluoroacetyl (1i) 0.41
0.35 À0.04 0.09 s[c]
0.38 À0.05 0.03 s[c]
[a] Calculated Mulliken spin-density values. [b] D is the difference in spin
density between N1 and N2. [c] This denotation indicates that the spin-
=
bearing orbital is orthogonal to the adjacent C N double bond.
radical R1a is a typical p radical (Table 1, entry 1, and
Figure 1), which is consistent with our previous observa-
tion.[3b] However, as the strength of the electron-withdrawing
capacity of the substituent increased, the spin density located
on the C atom decreased dramatically from 0.29 to À0.05; at
the same time, the spin density on the N2 atom increased
significantly from 0.04 to 0.38 (Table 1, entries 2–9). The
mesyl group is an exception, probably as a result of its steric
effect. In particular, when trichloroacetyl and trifluoroacetyl
groups were incorporated in the hydrazone, the correspond-
ing radicals became s radicals because the single-electron
spin density was located on both the N1 atom (0.44; 0.41) and
N2 atom (0.35; 0.38), rather than the C atom (Table 1,
entries 8 and 9, and Figure 1).[9] The observed transition
from p radicals to s radicals might be attributed to the
negative charge on the N1 atom in the resonance structure VI.
This negative charge can be delocalized onto the carbonyl
Scheme 2. Proposed mechanism for 5-exo-trig cyclizations at the
N2 atom of hydrazonyl s radicals
Scheme 3. Hydrazonyl-s-radical-promoted 5-exo-trig cyclizations at the
N2 atom.
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Table 2: Hydrazonyl-s-radical-promoted N2-atom 5-exo-trig cyclization for the synthesis of azomethine
Encouraged by the results of the
theoretical calculations, we pre-
pared compounds 1g–i to see if
they could be converted into the
corresponding s radicals to undergo
5-exo-trig radical cyclization at the
N2 atom. It was expected that if g,d-
unsaturated N-acyl hydrazones
were deprotonated with a base, the
corresponding hydrazonyl anions
would react with TEMPO cation
(2,2,6,6-tetramethyl-1-oxopiperi-
din-1-ium) through a single-elec-
tron-transfer (SET) process to pro-
duce hydrazonyl radicals and
TEMPO.[10] The hydrazonyl radicals
would then undergo a 5-exo-trig
cyclization at the N2 atom to give
carbon-centered radicals, which
could be trapped immediately by
TEMPO to produce azomethine
imines.[a]
Entry
1
Substrate
Products
Yield [%][b]
83
2
3
4
5
6
Ar=Ph 1k
Ar=Ph 2k
88
82
81
85
78
Ar=p-MeOC6H4 1l
Ar=p-MeC6H4 1m
Ar=p-ClC6H4 1n
Ar=m-BrC6H4 1o
Ar=p-MeOC6H4 2l
Ar=p-MeC6H4 2m
Ar=p-ClC6H4 2n
Ar=m-BrC6H4 2o
7
68
imine derivatives
2 (Scheme 2).
Indeed, when N-trichloroacetyl-
and N-trifluoroacetyl-substituted
hydrazones 1h and 1i were treated
with TEMPO+ BF4À (1.5 equiv) and
Cs2CO3 (1.5 equiv) in CH3CN at
308C, the desired 5-exo-trig cycliza-
tion at the N2 atom took place
smoothly to afford 2h and 2i in 68
and 65% yield, respectively
(Scheme 3). The reaction hardly
took place at all in the absence of
Cs2CO3, thus indicating that a base
is necessary for this efficient pro-
cess.[11] The potential 6-exo-trig rad-
ical cyclization at the N1 atom was
not observed, as the 6-exo-trig cyc-
lization is generally much less
favored than its 5-exo-trig counter-
part. Our computational studies
also proved this point.[8] When the
N-benzoyl hydrazone 1g was used
as the substrate under the same
conditions, the reaction did not take
place, and only 1g was recovered.
Apparently, the formation of 2h
and 2i cannot be the result of initial
oxidation of the carbon–carbon
double bond.
8
9
n=1 1q
n=2 1r
n=1 2q
n=2 2r
82
87
10
11
72
91
95:5[c,d]
3 (2u)
>99:1[c,d]
68 (3u)
12[e]
>99:1[c,d]
14 (2v)
>99:1[c,d]
63 (3v)
13[e]
>99:1[c,d]
To examine the scope of the
present reaction, a variety of g,d-
[a] All reactions were carried with a hydrazone 1 (0.5 mmol), TEMPO+ BF4 (0.75 mmol), and Cs2CO3
À
(0.75 mmol) at a 0.5m concentration in MeCN at 308C for 3–6 h. [b] Yield of the isolated product. [c] The unsaturated N-trichloroacetyl and
diastereomeric ratio was determined by 1H NMR spectroscopy of the crude reaction mixture. [d] The
N-trifluoroacetyl hydrazones were
1
configuration of the major diastereomer was confirmed by H NMR spectroscopy on the basis of
subjected to the reaction conditions
coupling constants or by X-ray crystal-structure analysis. [e] The reaction was carried out with
shown in Scheme 3. The results are
TEMPO+ BF4À (3 equiv) and Cs2CO3 (3 equiv).
summarized in Table 2. Compounds
1j–t reacted very well under the
reaction conditions to give the cor-
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responding aminooxygenation products 2 in good-to-excel-
lent yields. Notably, the formation of compounds 2 involves
the aminooxygenation of unactivated alkenes: a type of
reaction of synthetic significance.[12] When a gem-dimethyl
group was present at the a position, as in 1j and 1k, the yields
of products 2j and 2k of 5-exo-trig cyclization at the N2 atom
were increased to 83 and 88% (Table 2, entries 1 and 2). The
structures of compounds 2j and 2k were confirmed by single-
crystal X-ray diffraction studies.[13] On the other hand, the 1,5-
H shift involving the N1 atom, which occurs under other
circumstances,[3b,14] was not observed in the present case,
because it is much less favored than the 5-exo-trig cyclization
at the N2 atom. When hydrazones 1q and 1r were utilized in
the reaction, azomethine imines were formed as spiro
compounds in excellent yields (Table 2, entries 8 and 9).
Hydrazone 1s incorporating a thiophene moiety was also
transformed into the desired product 2s in good yield
(Table 2, entry 10), and the reaction of compound 1t, which
incorporates a styrenyl moiety, afforded 2t in 91% yield with
high trans stereoselectivity (Table 2, entry 11). The configu-
ration of 2t was also identified by a single-crystal X-ray
diffraction study.[13] When the alkene moiety was incorpo-
rated in a ring, as in the case of 1u, the reaction afforded only
a small amount of the expected product 2u; the major product
became the doubly TEMPO trapped azomethine imine 3u as
a single diastereomer. A similar result was obtained for the
reaction of 1v. The structure of 3u was unambiguously
identified by a single-crystal X-ray diffraction study.[13] By the
Scheme 5. Transformation of azomethine imine 2n by a [3+2] cyclo-
addition with methyl propiolate.
In this context, 2n reacted with the dipolarophile methyl
propiolate through [3+2] cycloaddition to form 4 and its
diastereomer 4’ in a combined yield of 92% (Scheme 5).
As revealed by the aforementioned calculations, N-
trifluoroacetyl and N-trichloroacetyl hydrazonyl radicals can
be viewed as s radicals with spin density located on both the
N1 atom and the N2 atom. However, g,d-unsaturated hydra-
zonyl radicals were shown to undergo exclusively 5-exo-trig
cyclization, and 6-exo-trig cyclization at the N1 atom was not
detected. We anticipated that if b,g-unsaturated hydrazones
were used as the radical precursors, 5-exo-trig cyclization at
the N1 atom would take place to form pyrazolines. Indeed,
when we subjected b,g-unsaturated hydrazones 5 to the
present conditions, pyrazolines 6 were formed in excellent
yields (Table 3). Pyrazolines are known to possess diverse
biological activity, including antimicrobial, analgesic, and
anticancer activity.[17] The present protocol provides a con-
venient method for the preparation of these valuable com-
pounds.
use of 3 equivalents of TEMPO+ BF4 and 3 equivalents of
À
Cs2CO3, 3u and 3v were obtained in yields of 68 and 63%,
respectively (Table 2, entries 12 and 13). Evidently, these two
products were generated by the further oxidation of 2u and
2v by TEMPO+ BF4 (Scheme 4). The observed high stereo-
À
Table 3: Hydrazonyl-s-radical-promoted N1-atom 5-exo-trig cyclization
selectivity can be accounted for by the preferential trapping
of the cyclization-derived carbon radicals and the oxidized
carbon radicals from the less-hindered exo side.
for the synthesis of pyrazolines.[a]
Entry
Substrate
Product
Yield [%][b]
Azomethine imines are valuable synthetic intermediates
that have attracted great attention because of their multiple
uses as 1,3-dipoles[15] and electrophiles[16] in organic synthesis.
1
2
3
Ar=Ph 5a
Ar=p-MeC6H4 5b
Ar=p-ClC6H4 5c
Ar=Ph 6a
Ar=p-MeC6H4 6b
Ar=p-ClC6H4 6c
93
85
77
4
5
Ar=Ph 5d
Ar=p-MeC6H4 5e
Ar=Ph 6d
Ar=p-MeC6H4 6e
91
83
6
66
7
75
Scheme 4. Transformation of 2u and 2v into 3u and 3v, respectively.
[a,b] See Table 2. Boc=tert-butoxycarbonyl.
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Angew. Chem. 1981, 93, 400; Angew. Chem. Int. Ed. Engl. 1981,
20, 390; however, no neutral hydrazonyl radicals with a s-
electronic structure have yet been reported.
In conclusion, we have demonstrated for the first time that
hydrazonyl radicals, which generally exhibit p-electronic
structures, can be tuned to s radicals by attaching a trifluoro-
acetyl or trichloroacetyl group to the N1 atom. In this way,
both the N1 and the N2 atom become reactive radical
centers.[18] These hydrazonyl s radicals can be generated
simply from N-trichloroacetyl and N-trifluoroacetyl hydra-
[8] See the Supporting Information for details of the theoretical
study.
[9] s radicals are defined as radicals in which the unpaired electron
resides in an orbital with s character (in R1g, R1h, and R1i, the
sp2 orbital on the N2 atom); see: a) W. C. Danen, C. T. West, J.
Am. Chem. Soc. 1973, 95, 6872; s radicals have also been
described as radicals in which the spin-bearing orbital is
orthogonal to an adjacent p system; see: b) R. O. C. Norman,
B. C. Gilbert, J. Phys. Chem. 1967, 71, 14.
[10] For reviews on TEMPO, see: a) L. Tebben, A. Studer, Angew.
Chem. 2011, 123, 5138; Angew. Chem. Int. Ed. 2011, 50, 5034;
b) C. Galli, P. Gentili, O. Lanzalunga, Angew. Chem. 2008, 120,
4868; Angew. Chem. Int. Ed. 2008, 47, 4790; c) R. A. Sheldon,
I. W. C. E. Arends, G.-J. Brink, A. Dijksman, Acc. Chem. Res.
2002, 35, 774.
zones by using TEMPO+ BF4 as the oxidant and Cs2CO3 as
À
the base. This protocol has great synthetic implications.
Under the indicated reaction conditions, b,g- and g,d-unsatu-
rated N-trifluoroacetyl and N-trichloroacetyl hydrazones
1
2
À
À
readily underwent the corresponding C N and C N bond-
forming 5-exo-trig cyclization to afford structurally important
pyrazolines and azomethine imines in high yields. Further
studies on the hydrazonyl-radical-promoted reactions are in
progress in our laboratory.
[11] See the Supporting Information for details of the control
experiments.
Received: November 14, 2013
Revised: January 14, 2014
Published online: February 14, 2014
[12] For the metal-free vicinal aminooxygenation of olefins, see:
a) V. A. Schmidt, E. J. Alexanian, J. Am. Chem. Soc. 2011, 133,
11402; b) U. Farid, T. Wirth, Angew. Chem. 2012, 124, 3518;
Angew. Chem. Int. Ed. 2012, 51, 3462; for the transition-metal-
catalyzed vicinal aminooxygenation of olefins, see: c) P. H.
Fuller, J.-W. Kim, S. R. Chemler, J. Am. Chem. Soc. 2008, 130,
17638.
[13] CCDC 968882 (2j), 968883 (2k), 968884 (2t), and 968885 (3u)
contain the supplementary crystallographic data for this paper.
These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_
request/cif.
[14] For a 1,5-H shift involving a hydrazonyl radical, see: X. Zhu, Y.-
F. Wang, W. Ren, F.-L. Zhang, S. Chiba, Org. Lett. 2013, 15, 3214.
[15] a) T. Hashimoto, H. Kimura, Y. Kawamata, K. Maruoka, Nat.
Chem. 2011, 3, 642; b) R. Shintani, G. C. Fu, J. Am. Chem. Soc.
2003, 125, 10778; c) R. Shintani, T. Hayashi, J. Am. Chem. Soc.
2006, 128, 6330.
[16] For reviews, see: a) L. L. Rodina, A. Kolberg, B. Schulze,
Heterocycles 1998, 49, 587; b) “Azomethine Imines”: J. G.
Schantl in Science of Synthesis, Vol. 27 (Eds.: A. Padwa, D.
Bellus), Thieme, Stuttgart, 2004, pp. 731 – 824.
[17] A. Marella, M. R. Ali, M. T. Alam, R. Saha, O. Tanwar, M.
Akhter, M. Shaquiquzzaman, M. M. Alam, Mini-Rev. Med.
Chem. 2013, 13, 921.
[18] A similar dichotomy has been reported for the nucleophilic
addition of hydrazides to alkynes; in these reactions, both
nitrogen atoms could be activated in a controllable manner: S. F.
Vasilevsky, T. F. Mikhailovskaya, V. I. Mamatyuk, G. E. Salni-
kov, G. A. Bogdanchikov, M. Manoharan, I. V. Alabugin, J. Org.
Chem. 2009, 74, 8106.
Keywords: alkenes · cyclization · heterocycles · radicals ·
.
synthetic methods
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