Generation of Diazomethyl Radicals by Hydrogen Atom Abstraction and Their Cycloaddition with Alkenes

Article abstract of DOI:10.1002/anie.202105472

A general catalytic methodology for the synthesis of pyrazolines from α-diazo compounds and conjugated alkenes is reported. The direct hydrogen atom transfer (HAT) process of α-diazo compounds promoted by the tert-butylperoxy radical generates electrophilic diazomethyl radicals, thereby reversing the reactivity of the carbon atom attached with the diazo group. The regiocontrolled addition of diazomethyl radicals to carbon-carbon double bonds followed by intramolecular ring closure on the terminal diazo nitrogen and tautomerization affords a diverse set of pyrazolines in good yields with excellent regioselectivity. This strategy overcomes the limitations of electron-deficient alkenes in traditional dipolar [3+2]-cycloaddition of α-diazo compounds with alkenes. Furthermore, the straightforward formation of the diazomethyl radicals provides umpolung reactivity, thus opening new opportunities for the versatile transformations of diazo compounds.

Full text of DOI:10.1002/anie.202105472

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Accepted Article
Title: Generation of Diazomethyl Radicals by Hydrogen Atom
Abstraction and Their Cycloaddition with Alkenes
Authors: Michael P. Doyle, Yong-liang Su, Kuiyong Dong, and Haifeng
Zheng
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Generation of Diazomethyl Radicals by Hydrogen Atom
Abstraction and Their Cycloaddition with Alkenes
Yong-Liang Su, Kuiyong Dong, Haifeng Zheng and Michael P. Doyle*
Abstract: A general catalytic methodology for the synthesis of
pyrazolines from α-diazo compounds and conjugated alkenes is
reported. The direct hydrogen atom transfer (HAT) process of α-diazo
compounds promoted by the tert-butylperoxy radical generates
electrophilic diazomethyl radicals, thereby reversing the reactivity of
the carbon atom attached with the diazo group. The regiocontrolled
addition of diazomethyl radicals to carbon-carbon double bonds
followed by intramolecular ring closure on the terminal diazo nitrogen
and tautomerization affords a diverse set of pyrazolines in good yields
with excellent regioselectivity. This strategy overcomes the limitations
of electron-deficient alkenes in traditional dipolar [3+2]-cycloaddition
of α-diazo compounds with alkenes. Furthermore, the straightforward
formation of the diazomethyl radicals provides umpolung reactivity,
thus opening new opportunities for the versatile transformations of
diazo compounds.
methodology that would provide an alternative strategy for
cycloaddition of alkenes that are unreactive towards dipolar
cycloaddition. Previously, we reported radical-mediated
strategies for the functionalization of alkenes with diazo
compounds.[13] The diazo compounds were transformed to carbon
radical species through proton-coupled electron transfer (PCET)
process in which N2 was released. The formation of the carbon-
centered radicals from diazo compounds have also been reported
by other groups, but in each of these processes dinitrogen is
released.[14] With our continuing research interest in the radical
chemistry of diazo compounds, we designed a novel iron-
catalyzed, diazomethyl radical-mediated umpolung cycloaddition
of diazo compounds with alkenes. Different from the previous
photocatalytic single-electron reduction process,[10] we utilize the
tert-butylperoxy radical, derived from the iron-catalyzed
decomposition of tert-butyl hydroperoxide (TBHP), to directly
abstract one hydrogen atom from the diazo compound to
generate the diazomethyl radical. Regioselective addition of the
diazomethyl radical to the C=C bond and subsequent ring closure
deliver various pyrazoline derivatives in moderate to high yields.
Effective construction of pyrazoline 3a was realized via the
iron-catalyzed formal cycloaddition of styrene 1a with ethyl
diazoacetate 2a in 2-propanol at 50 ºC with TFA and TBHP in
decane (Table 1, entry 1). A series of control experiments verified
the necessity of each reaction component. Cycloaddition adduct
3a was not formed in the absence of TBHP (Table 1, entry 4), and
only a trace amount of 3a was observed when Fe(OAc)2 or TFA
was omitted from the reaction system (Table 1, entries 2, 3). Other
transition metal catalysts that have usually cooperated with TBHP
Diazo compounds hold an important place in organic
synthesis due to their versatile reactivity.[1,2] Their reactions with
alkenes are mainly focused on metal-catalyzed cyclopropanation
reactions through metal carbene intermediates,[3] and 1,3-dipolar
cycloadditions enabled by polarity matching (Scheme 1a).[4]
Indeed, the cycloaddition reaction of diazo compounds with
alkenes provides an economical and useful tool for the
construction of pyrazoles and pyrazolines, which are important
bioactive moieties in drugs and agrochemicals.[5] However, since
Buchner reported the cycloadditions of methyl diazoacetate to
unsaturated carboxylic acid esters for the first time in 1888,[6] 1,3-
dipolar cycloadditions of diazo compounds with alkenes have
been limited to electron-deficient alkenes capable of Michael-type
addition.[7] This restriction is due to the intrinsic nucleophilicity of
the diazo carbon.[8] For example, to date there has not neen a
report of dipolar cycloaddition between diazoacetates and
styrene.[9]
Recently, the Sureo group and the Alcarazo group reported
the generation of a diazomethyl radical through the photoredox
single electron transfer (SET) process (Scheme 1b).[10]The diazo
moiety could be transfered to either aromatic rings or hydrazones
utilizing hypervalent I(III)10a-10d or sulfonium ions10e as the leaving
group. Since the electronic characteristics of the diazo group
could be reversed from nucleophilic to electrophilic through the
formation of the diazomethyl radical,[10a,11] we considered whether
electron-neutral or even electron-rich alkenes could be
incorporated with the diazocarbon radical intermediate utilizing
this umpolung strategy,[12] thereby providing
a
general
[a]
Dr. Y.-L. Su, K. Dong, Dr. H. Zheng. Prof. Dr. M. P. Doyle
Department of Chemistry, The University of Texas at San Antonio
One UTSA Circle, San Antonio, TX 78249 (USA)
E-mail: michael.doyle@utsa.edu
Supporting information for this article is given via a link at the end of
the document.
Scheme 1. Designs for the unconventional cycloaddition reaction of α-diazo
compounds with alkenes.
1
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Table 2. Scope with respect to the alkenes 1.[a]
were also tested, but either no product or only a trace amount of
product 3a was formed (Table 1, entries 5-8).[15] Furthermore, the
yield of 3a was significantly reduced when a weaker Brønsted
acid co-catalyst was used, and only trichloroacetic acid with
comparable acid strength gave this product in moderate yield
(entries 9-11). This observation can be rationalized by the direct
decomposition of diazo substrate 2a when a strong carboxylic
acid was used (bubbles were observed when TfOH was added to
the reaction system suggesting proton-denitrogenation), while low
conversion occurred when other weak acids were used. Moreover,
alternative oxidants such as 70% TBHP in H2O (THYDRO) or
cumyl hydroperoxide led to reduced yield (Table 1, entries 13,14),
while di-tert-butyl peroxide (DTBP) failed to give the desired
product 3a (Table 1, entry 12). It should be mentioned that in
addition to the desired 3a, byproducts 4a, 5 and 6 were also
observed under some of these reaction conditions. Pyrazole 4a
was believed formed by the further oxidation of 3a,[7g,16] while the
cyclopropanation products 5 and 6 were generated from either the
metal carbene intermediate or through a free radical process that
Table 1. Optimization of the reaction conditions.[a]
[a] Reaction conditions: alkene 1 (0.2 mmol, 1.0 equiv.), ethyl diazoacetate 2a
(0.6 mmol, 3.0 equiv.), Fe(OAc)2 (5 mol%), TFA (60 mol%) and TBHP in decane
(0.3 mmol, 1.5 equiv.) in i-PrOH (6.0 mL) at 50 ºC. [b] 2.0 equiv. TBHP in
decane. [c] The dr value was determined by 1H NMR. [d] The dr value was
determined by HPLC. Pyrazoles and cyclopropanation by-products were also
detected with some alkene substrates.
Entry
Variation from the standard conditions
Yield [%][b]
3a/4/5/6
occurred with the release of N2,[14e,17] and this process is inhibited
by the use of TFA.
With these optimized conditions in hand, we evaluated the
scope of olefins appropriate in this protocol. As shown in Table 2,
a diverse array of substituted alkenes bearing electron-donating
(3b and 3c) or electron-withdrawing (3d and 3e) substituents in
the phenyl moiety, performed well in this transformation to deliver
the corresponding adducts in moderate to good yields.
Substituents at either the meta or ortho positions also worked well
to form the pyrazolines in good yields (3f-3i). Additionally, reaction
with 2-vinylnaphthalene smoothly delivered 3j. Moreover, α-
methylstyrene derivatives were also appropriate substrates for
this transformation, and the yields were improved due to the
absence of further oxidized pyrazole by-products (3k-3o). The
substrates bearing the 2-naphthyl or 1,3-benzodioxol group
reacted smoothly to afford the desired products (3p and 3q).
Further variation of the α-alkyl groups, such as α-ethyl for 3r, α-n-
pentyl for 3s, α-isobutyl for 3t and even α-benzyl for 3u, proved to
be feasible, and these products were obtained in good to high
yields. β-Substituted styrene (indene) furnished the desired
product smoothly (3v) with >20:1 diastereoselectivity, while 1,1,2-
trisubstituted styrene failed to give the product 3w, presumably
due to the steric hindrance of the trisubstituted alkene. Notably,
substrates containing exocyclic C=C bonds delivered the
corresponding [5,5]-, [5,6]- and [5,7]-spiropyrazoline products in
modest to good yields (3x−3z). Finally, in order to test the
compatibility of the reaction in more structually complex contexts,
the styrene bearing a intricate estrone moiety was tested. The
adduct 3aa was acquired in good yield, which underscores the
1
none
71 (65)[c]/9/nd/nd
9/1/6/2
2
no Fe(OAc)2
3
no TFA
4/nd/16/8
4
no TBHP in decane
nd/nd/nd/nd
nd/nd/nd/nd
nd/nd/nd/nd
nd/nd/nd/nd
5/nd/2/1
5
Cu(CH3CN)PF6 instead of Fe(OAc)2
NiCl2ꞏ6H2O instead of Fe(OAc)2
Co(OAc)2ꞏ4H2O instead of Fe(OAc)2
Mn(OAc)3 instead of Fe(OAc)2
TfOH instead of TFA
6
7
8
9
nd/nd/nd/nd
45/8/nd/nd
14/6/nd/nd
nd/nd/nd/nd
48/9/10/4
10
11
12
13
14
CCl3COOH instead of TFA
p-TsOHꞏH2O
DTBP instead of TBHP
THYDRO instead of TBHP
Cumyl hydroperoxide instead of TBHP
45/13/nd/nd
[a] Reactions were carried out using styrene 1a (0.2 mmol, 1.0 equiv.), ethyl
diazoacetate 2a (0.6 mmol, 3.0 equiv.), Fe(OAc)2 (5 mol%), TFA (60 mol%) and
TBHP in decane (0.3 mmol, 1.5 equiv.) in i-PrOH (6.0 mL) at 50 ºC for 18 h. [b]
1H NMR yields using CHBr3 as an internal standard. [c] Isolated yield in
parentheses.
2
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synthetic utility of this methodology and its compatibility with
complex molecules.
this method for late-stage functionalization. The reaction was not
limited to α-diazo esters. α-Diazo sulfonate, sulfone, phosphonate
and fluorinated diazoalkanes were also found to be competent
substrates (7n-7r). Interestingly, Δ1-pyrazoline was the major
product while the Δ2-pyrazoline tautomer was the minor product
when trifluorodiazoethane was used. The X-ray structure of
product 7q was obtained for full characterization,[18] and a control
experiment showed that the Δ1-pyrazoline was quantitatively
transformed to the Δ2-pyrazoline under TFA conditions (Scheme
2e).[7b,19]
We further assessed the reaction generality with various α-
diazo compounds (Table 3). The reactions of α-methylstyrene 1k
with different diazo esters furnished products in good to high
yields (7a-7m). Diazo compounds with bulky ester alkyl groups
underwent reaction smoothly to deliver products 7a and 7d. In
addition, other potentially reactive functional groups were
tolerated on the ester groups in diazo substrates, including allyl
(7f), homoallyl (7g), propargyl (7h), homopropargyl (7i) and
pentynyl (7j). Possible intramolecular cyclization products were
not detected when 7f-7j were used, which may be explained by
the tendency to form more stable benzyl radical instead of the
alkyl radical. It is worth noting that this methodology is successful
with various natural alcohol derived diazoacetate esters (7e, 7k-
7m), highlighting the broad applicability and the potential utility of
To gain detailed mechanistic insights into this reaction
Table 3. Scope with respect to the diazo compounds 2.[a]
Scheme 2. Mechanistic studies: a) Reaction in the presence of radical
scavenger TEMPO; b) radical trapping experiment with BHT; c) radical clock
experiment; d) control experiment without styrene; e) isotope-labeling study; f)
tautomerization of 7q to 7q'.
[a] Reaction conditions: 1k (0.2 mmol, 1.0 equiv.), α-diazo compound 2 (0.6
mmol, 3.0 equiv.), Fe(OAc)2 (5 mol%), TFA (60 mol%) and TBHP in decane (0.3
mmol, 1.5 equiv.) in i-PrOH (6.0 mL) at 50 ºC. [b] The dr value was determined
by HPLC. [c] The dr value was determined by analogy with 7k.
3
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10.1002/anie.202105472
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process, a series of control experiments was conducted (Scheme
2, see the Supporting Information for more details). Radical
trapping experiments were performed with TEMPO and BHT
separately. The reaction was completely inhibited in the presence
of TEMPO (Scheme 2a), and the yield of pyrazoline 3a decreased
significantly when BHT was added under standard conditions.
Moreover, several related radical-trapping products were
separated and characterized (Scheme 2b). In the radical clock
experiment substrate 12 with 2a led to the radical addition/ring-
opening products 14-16, indicating the radical nature of the
transformation (Scheme 2c). Consistent with the formation of a
diazomethyl radical, the adduct products 17-Z, 17-E along with
the O-H insertion product 18 were identified in the control
experiment without styrene (Scheme 2d). In addition, isotopic-
labeling studies were performed using trifluoromethyl
diazomethane 2q, and deuterated product 7q-d1 along with the
Δ2-pyrazoline 7q′ were formed when D2O was the additive in THF
system (Scheme 2e). Product 7q-d1 was obtained with 85%
deuterium incorporation when 2-propanol-d8 was used as the
solvent. Furthermore, a control experiment showed that Δ1-
pyrazoline 7q was transformed to its Δ2-pyrazoline tautomer 7q'
in the presence of TFA (Scheme 2f), which indicates that Δ1-
pyrazoline is formed and then transformed to the more stable Δ2-
pyrazoline tautomer during the reaction process.
attached with the diazo group, the formal cycloaddition of α-diazo
compounds with non-activated alkenes, which was previously
limited, has been successfully achieved. This efficient process
provides a direct and novel approach for the construction of highly
valuable pyrazoline products. Further investigations toward
developing novel reactions with diazo compounds using this
diazomethyl radical-mediated umpolung strategy are currently
ongoing in our laboratory.
Acknowledgements
We acknowledge the Welch Foundation (AX-1871) for funding
this research. The x-ray diffractometer used in this research was
supported by a grant from the U.S. National Science Foundation
(CHE−1920057).
Conflict of interest
The authors declare no conflict of interest.
Keywords: pyrazolines • diazo compounds • diazomethyl radical
• umpolung • cycloaddition • radical addition
Taking into account the combined results of our mechanistic
studies and previous reports,[20] a plausible mechanism for this
formal cycloaddition is illustrated in Figure 1. The reaction is
initiated by the iron-catalyzed decomposition of TBHP to form the
tert-butoxy radical III, which undergos hydrogen atom transfer
(HAT) from TBHP to deliver the selective tert-butylperoxy radical
IV. Meanwhile, Fe(II) I is regenerated through reduction by
TBHP.[21] A subsequent HAT of the tert-butylperoxy radical with
the α-diazo compound generates the key intermediate
diazomethyl radical V. Addition of radical V to the C=C produces
benzyl radical VI, which is transformed to VII through
intramolecular ring closure. The Δ1-pyrazoline VIII is generated
either through another HAT process or a concerted proton-
electron transfer process. Due to the higher acidity of the proton
in the α-position of the ester group,[4b] tautomerization of VIII
furnishes the final Δ2-pyrazoline product.
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4
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10.1002/anie.202105472
Angewandte Chemie International Edition
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A new approach for the generation of diazomethyl radicals and their addition to alkenes is described. The direct hydrogen atom
transfer (HAT) from α-diazo compounds generates electrophilic diazomethyl radicals, thereby reversing the reactivity of the diazo
carbon. This umpolung strategy overcomes the limitations of electron-deficient alkenes in traditional dipolar [3+2]-cycloaddition of α-
diazo compounds with alkenes and opens new opportunities for versatile transformations of diazo compounds.
6
This article is protected by copyright. All rights reserved.