Modular Synthesis of Alkylarylazo Compounds via Iron(III)-Catalyzed Olefin Hydroamination

Article abstract of DOI:10.1021/acs.orglett.9b00540

A novel Fe-catalyzed olefin hydroamination with aryldiazo sulfones for accessing alkylarylazo compounds has been successfully developed. Aryldiazo sulfones are used as radical acceptors, and N-N double bonds will be regenerated when an arene sulfonyl grou

Full text of DOI:10.1021/acs.orglett.9b00540

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Modular Synthesis of Alkylarylazo Compounds via Iron(III)-
Catalyzed Olefin Hydroamination
Yan Zhang,* Chenchao Huang, Xinru Lin, Qi Hu, Boyue Hu, Yulu Zhou, and Gangguo Zhu*
Key Laboratory of the Ministry of Education for Advanced Catalysis Materials, Zhejiang Normal University, 688 Yingbin Road,
Jinhua 321004, China
S
* Supporting Information
ABSTRACT: A novel Fe-catalyzed olefin hydroamination with aryldiazo sulfones for accessing alkylarylazo compounds has
been successfully developed. Aryldiazo sulfones are used as radical acceptors, and N−N double bonds will be regenerated when
an arene sulfonyl group leaves. The reaction features mild reaction conditions and a broad substrate scope, allowing access to
many azo compounds that would be difficult or perhaps impossible to access using other methods.
he construction of nitrogen-containing organic com-
pounds has been of intense research interest in organic
the synthesis of this class of azo compounds. Furthermore, the
existing protocols have obvious drawbacks such as limited
functional group compatibility, low yields, narrow substrate
scopes, and Grignards mostly derived from tertiary bromides
(Scheme 1A).
T
chemistry.1 Among these, aromatic azo compounds are
ubiquitous motifs and are widely used as dyes,2 indicators,3
radical reaction initiators,4 directing groups in C−H
activition,5 food additives,6 and even medicines.7 Numerous
important attempts have been made to synthesize aromatic azo
compounds from anilines via diazonium salt8 or nitro-
sobenzene intermediates.9 Recent metal-catalyzed aerobic
oxidative dehydrogenative coupling of aromatic anilines10 is
an elegant example of the synthesis of aromatic azo
compounds.
Scheme 1. Formation of Alkylarylazo Compounds through
Radical Addition
However, there have been few reports on the preparation of
alkylarylazo compounds, because the synthesis of these
compounds still involves significant challenges. (1) Coupling
reactions are limited to alkyl iodide,11 Grignards,12 and
alkenes13 with diazonium, necessitating the development of
novel reaction agents and a mechanism. (2) Alkylarylazo
compounds are usually not as stable as the diarylazo
compounds, particularly for the cases of one hydrogen atom
at the α-position on the alkyl part (Figure 1a), which is found
to be highly sensitive to solvent effects (see the Supporting
Information), suggesting that a suitable solvent is critical for
On the other hand, radical addition reactions serve as an
efficient and practical strategy for the construction of new C−
C, C−O, and C−N bonds.14 However, the scope of
intermolecular radical acceptors is still limited to the most
commonly used C−C double or triple bonds, many C−N
double bonds,15 and few C−O double bonds16 (Figure 1b).
Therefore, exploration of a broader acceptor pool in radical
chemistry remains an ongoing challenge. To the best of our
knowledge, N−N double bonds, and specifically aryl-
substituted azo compounds, have never been reported as
Figure 1. Types of alkylarylazo compounds and radical addition to
unsaturated bonds.
Received: February 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00540
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
intermolecular radical acceptors. It is well-known that, upon
addition of a radical to the carbon atom of a multiple bond
bearing an arene sulfonyl group,17 a (trifluoromethyl)-
sulfonyl,18 bromine,19 or nitro group,20 multiple bonds will
be regenerated after the elimination of the leaving groups.
Most recently, the group of Clayden reported an elegant
radical addition reaction between an alkyl radical and a
diazonium ion, leading to the formation of alkylarylazo
compounds (Scheme 1B).21 However, the alkyl radical must
be tertiary, and more electron-deficient diazonium salts are
needed to successfully carry out this synthesis. As a part of our
ongoing research aimed at expanding the type and scope of
radical addition,22 we sought to develop a more general
method for constructing alkylarylazo compounds through
addition of an alkyl radical to aryldiazo sulfones. The
sequential elimination of this newly formed radical would
furnish the alkylarylazo products and an arene sulfonyl radical
(Scheme 1C). This protocol features two obvious properties.
(a) The first is an example of addition of an alkyl radical to the
N−N double bond and regeneration of a new N−N double
bond. (b) Alkylarylazo compounds containing a α-H on the
alkyl part can also be obtained in this catalytic system.
The catalytic hydrogen atom transfer (HAT) reaction
catalyzed by earth-abundant metals (Fe, Mn, and Co) has
become an increasingly attractive strategy in organic syn-
thesis.23 Generally, HAT is involved in the process in which
silanes were used as reductants and the alkyl radical
intermediates were generated in situ. We began our study by
submitting olefin 2-1 to Baran’s Fe(acac)3 and PhSiH3
conditions23b in ethanol at room temperature in the presence
of aryldiazo sulfone 1a. To our delight, the desired product 3-1
was isolated in 34% yield (Table 1, entry 1). Encouraged by
this preliminary observation, we attempted to improve the
reaction efficiency by screening various solvents and metal salts
(entries 2−5). It was found that THF was the best solvent
while using Fe(acac)3 as the catalyst. Among the screened
additives, KHCO3 afforded the best yield (entry 8). Various
sulfone reagents 1 were screened, and the results showed that
1a was optimal (entries 9−11). We also used a 2:1 molar ratio
of alkenes, but this resulted in a slightly lower yield (entry 12).
With the optimized reaction conditions in hand (Table 1,
entry 8), we first explored the substrate scope of unactivated
alkenes (Scheme 2). A series of alkenes, including mono-, di-,
and trisubstituted alkenes (2-1−2-30), were found to behave
well during this process. In particular, the terminal
disubstituted alkene 2-5 and the internal trisubstituted alkene
2-6 are quite amenable to this protocol and furnish the
Markovnikov product 3-5 in good yields. Notably, styrene 2-
10 is also quite applicable to this process, unlike in other
reports.19,20 Interestingly, the reaction proceeded well for
linear monosubstituted alkenes such as (s)-citronellol 2-7, 2-
15, 2-16, and 2-17 to furnish the expected products in good
yields (3-6 and 3-14−3-16), while 1,5-hydrogen transfer
(HAT) did not occur.24 It should be noted that this reaction
features good functional group tolerance. A variety of
important functional groups such as alcohol, ester, ether,
amino (containing sulfonamide), and acyl could react
smoothly with 1a to afford the corresponding alkylarylazo
compounds in moderate to good yields (3-17−3-29).
Next, we examined the scope of the aryldiazo sulfones, as
shown in Scheme 3. The aryldiazo sulfones were easily
prepared from aryl hydrazine and TsCl (see the Supporting
Information). First, we can see that the position of the
substituent on the benzene plays an important role. Generally,
the 2-substituted aryldiazo sulfones were more compatible in
this transformation (4a−4c). Generally, the electronic effect of
the substituents on the benzene does not clearly influence the
reaction efficiency, and moderate to good yields of products 4
were obtained. Additionally, multisubstituted aryldiazo sul-
fones 1r (2,6-dichloro) were also found to be more suitable for
the reaction under the standard conditions than 1s (3,5-
dichro). A series of 4-substituted aryldiazo sulfones, with
valuable functional groups such as ether, bromo, cyano, and
trifluoromethyl, could engage in this process to provide the
corresponding alkylarylazo compounds in moderate to good
yields (4i−4l). Therefore, this leaving group-assisted strategy
opens a new avenue for the preparation of alkylarylazo
compounds with structural generality.
a
Table 1. Optimization of the Reaction Conditions
A scale-up reaction was conducted to explore the synthetic
potential. A 2 mmol scale reaction was carried out for aryldiazo
sulfones 1n and alkene 2-5, and 4j was isolated in 68% yield
(Scheme 4). Further elaboration of 4j was also conducted. For
example, biphenyl azo compound 5 was obtained in excellent
yield in the presence of Pd(OAc)2. 4j can also be converted to
alkyl-substituted phenylhydrazine 6 in nearly quantitative yield
in the presence of hydrazine hydrate. However, compound 6
can partially be transformed to 4j again in air.
To gain insight into the reaction mechanism, two control
experiments were performed. First, the radical clock reaction
using diallyl sulfonamides 2-31 as the radical-trapping reagent
affords the corresponding alkylarylazo compounds 3-30 in
good yield with a diastereomeric ratio of 2.3:1 (Scheme 5 , eq
1). The reaction presented above was carried out in the
presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO). As
a result, 3-30 was not formed. Consequently, a radical
mechanism is depicted in Scheme 5 based on the literature.25
Initially, Fe(III) A was transferred to Fe hydride species B
upon treatment with phenylsilane and methanol. Then alkyl
radical D and Fe(II) species were formed through hydrogen
entry
metal salt
reagent
additive
solvent
yield (%)
34
50
1
2
3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Co(acac)3
Mn(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
−
−
−
−
EtOH
MeOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
b
52
4
5
6
7
8
not reported
−
25
39
58
68
60
67
35
58
b
Na2CO3
NaHCO3
KHCO3
KHCO3
KHCO3
KHCO3
KHCO3
b
b
b
9
b
10
11
12
b
c
a
Reaction conditions: 1a (0.2 mmol), 2-1 (0.4 mmol), PhSiH3 (0.4
mmol), metal salt (20 mol %), additive (0.2 mmol), solvent (2 mL),
room temperature, 4 h. MeOH (10 equiv) was used. 1a (2.0 equiv),
2-1 (1.0 equiv).
b
c
B
DOI: 10.1021/acs.orglett.9b00540
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 2. Scope of Alkenes
Scheme 3. Scope of Aryldiazo Sulfones
a
Isolated yields are given. Reaction conditions: 1 (0.2 mmol), 2-5
(0.4 mmol), PhSiH3 (0.4 mmol), Fe(acac)3 (20 mol %), KHCO3 (0.2
mmol), MeOH (2 mmol), THF (2 mL), under N2, rt, 5 h.
Scheme 4. Scale-Up Reaction and Synthetic Application
Scheme 5. Proposed Mechanism
a
Isolated yields are given. Reaction conditions: 1a (0.2 mmol), 2 (0.4
mmol), PhSiH3 (0.4 mmol), Fe(acac)3 (20 mol %), KHCO3 (0.2
mmol), MeOH (2 mmol), THF (2 mL), under N2, rt, 5 h.
b
Abbreviations: PMP, p-methoxyphenyl; NPhth, phthalimido. Using
2-6 as the reagent.
atom transfer from C. D will be trapped by aryldiazo sulfones
to generate nitrogen free radical E. The sequential elimination
of E furnishes the alkylarylazo compound (3 or 4) and an
C
DOI: 10.1021/acs.orglett.9b00540
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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arylsulfone radical that reoxidizes Fe(II) to Fe(III) to enable
the catalytic cycle.
In conclusion, a practical method for the preparation of
alkylarylazo compounds that utilized an inexpensive iron
catalyst and a silane reducing agent has been developed. This
represents the first example of the addition of an alkyl radical
to aryl-substituted N−N double bonds that can be used for the
modular synthesis of alkylarylazo compounds that are difficult
to prepare by conventional methods. Good tolerance for many
functional groups and mild reaction conditions make this
strategy a nice choice for preparing other novel azo
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ASSOCIATED CONTENT
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■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00540.
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Detailed experimental procedures and characterization
data for all new compounds 3 and 4 (PDF)
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: zhangyan001@zjnu.edu.cn.
*E-mail: gangguo@zjnu.cn.
ORCID
Yan Zhang: 0000-0002-0694-5131
Gangguo Zhu: 0000-0003-4384-824X
Notes
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(b) Jiang, H.; He, Y.; Cheng, Y.; Yu, S. Org. Lett. 2017, 19, 1240.
(19) (a) Li, Y.; Liu, X.; Jiang, H.; Liu, B.; Chen, Z.; Zhou, P. Angew.
Chem., Int. Ed. 2011, 50, 6341. (b) Feng, Y.-S.; Xu, Z.-Q.; Mao, L.;
Zhang, F.-F.; Xu, H.-J. Org. Lett. 2013, 15, 1472. (c) Shen, Y.; Huang,
B.; Zheng, J.; Lin, C.; Liu, Y.; Cui, S. Org. Lett. 2017, 19, 1744.
(20) (a) Zheng, J.; Wang, D.; Cui, S. Org. Lett. 2015, 17, 4572.
(b) Kumar, S.; Singh, R.; Singh, K. N. Asian J. Org. Chem. 2018, 7,
359.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors are grateful for financial support from the NSFC
(21672191 and 21702188) and the Natural Science
Foundation of Zhejiang Province (LQ17B020001).
(21) Abrams, R.; Lefebvre, Q.; Clayden, J. Angew. Chem., Int. Ed.
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D
DOI: 10.1021/acs.orglett.9b00540
Org. Lett. XXXX, XXX, XXX−XXX