Visible-Light-Induced Aza-Pinacol Rearrangement: Ring Expansion of Alkylidenecyclopropanes

Article abstract of DOI:10.1021/acs.orglett.7b02989

A novel visible-light-induced aza-pinacol rearrangement was developed for the first time. In this approach, the addition of the N-centered radical to the C=C bond of alkylidenecyclopropanes delivers a variety of cyclobutanimines and γ-butyrolactones, with

Full text of DOI:10.1021/acs.orglett.7b02989

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX-XXX
Visible-Light-Induced Aza-Pinacol Rearrangement: Ring Expansion of
Alkylidenecyclopropanes
Wen-Deng Liu, Guo-Qiang Xu, Xiu-Qin Hu, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou
730000, P. R. China
S
* Supporting Information
ABSTRACT: A novel visible-light-induced aza-pinacol rearrangement was developed for the first time. In this approach, the
addition of the N-centered radical to the CC bond of alkylidenecyclopropanes delivers a variety of cyclobutanimines and γ-
butyrolactones, with all-carbon quaternary centers via the ring expansion of the cyclopropyl group, in moderate to good yields
under mild reaction conditions.
Scheme 1. Designed Aza-Pinacol Rearrangement by Visible-
Light Photoredox Catalysis
ery often, modern medicinal molecules contain some new
and unconventional structural motifs such as small
V
strained ring systems.1 However, developing methods to
rapidly and directly construct these valuable scaffolds is still a
big challenge for medicinal chemists. Considering the ubiquity
of nitrogen-containing molecules in pharmaceuticals and
bioactive natural products,2 we herein describe a simple
method to build strained cyclobutanimine skeleton via visible-
light photocatalytic aza-pinacol rearrangement.
Pinacol3 and semipinacol4 rearrangements are among the
most well-known classical reactions in organic synthesis, which
play an important role in the construction of α-quaternary
carbon centers, especially all-carbon quaternary centers. These
rearrangement reactions via transition metal catalysis and
organic catalysis have been extensively investigated and widely
used in the total synthesis of natural products.5 However, the
aza-pinacol rearrangement is rarely reported6 (Scheme 1, eq 1)
due to its weak driving force compared with the pinacol
rearrangement and the relatively high activity of the aza-pinacol
rearrangement productimine. Thus, the development of a
novel, environmentally benign aza-pinacol rearrangement under
mild conditions remains a significant challenge.
Over the past decades, photoredox catalysis has emerged as a
powerful and sustainable synthetic technology for the
generation of various radical intermediates via a single-
electron-transfer pathway, which could participate in many
valuable chemical reactions.7 For example, Frank Glorius and
co-workers have reported a photoredox-catalyzed semipinacol-
type rearrangement with the CF3 radical (Scheme 1, eq 2).8
The N-centered radical, a powerful intermediate in organic
synthesis, could also be readily generated via visible-light
photoredox catalysis, which has been widely employed in
addition reactions and cross-coupling reactions.9 Given that
alkylidenecyclopropanes (ACPs) as versatile synthons have
been broadly used in the synthesis of cyclobutane derivatives
and larger rings,10 we devised a novel aza-pinacol rearrange-
ment, which was initiated by a highly reactive nitrogen radical
generated via visible-light photocatalysis, to construct the
synthetically useful cyclobutanimine scaffold under the mild
conditions. (Scheme 1, eq 3)
To test our hypothesis, the investigation began with the
reaction of diphenylmethylenecyclopropane 1a with N-Ts-
protected 1-aminopyridinium 2a using Ir(ppy)3 as a photo-
catalyst at room temperature under irradiation with a 25 W
blue LED for 36 h (Table 1). To our delight, the rearrangement
Received: September 23, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02989
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of Alkylidenecyclopropanes in the Aza-
Pinacol Rearrangement Reaction
a b
,
b
entry
catalyst
Ir(ppy)3
1a/2a
solvent
yield (%)
1
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:2
MeCN
MeCN
MeCN
DCM
61
54
57
42
50
48
55
30
NR
65
76
85
NR
NR
2
Ir(ppy)2(dtbbpy)PF6
Ru(bpy)3Cl2
Ir(ppy)3
3
4
5
Ir(ppy)3
DCE
6
Ir(ppy)3
CH3OH
acetone
DMSO
THF
7
Ir(ppy)3
8
Ir(ppy)3
9
Ir(ppy)3
10
11
12
13
Ir(ppy)3
MeCN
MeCN
MeCN
MeCN
MeCN
Ir(ppy)3
1:3
Ir(ppy)3
1:4
1:4
c
14
Ir(ppy)3
1:4
a
Reaction conditions: 1a (0.1 mmol), 2a (1.5−4 equiv), photocatalyst
(0.002 mmol), MeCN (4 mL), 25 W blue LED strip, room
b
c
temperature, under a N2 atmosphere. Isolated yield. In the dark.
a
Reaction conditions: substrate 1a−1u (0.1 mmol), substrate 2a (0.4
mmol), Ir(ppy)3 (0.002 mmol) in MeCN (anhydrous, 4 mL) under
irradiation of a 25 W blue LED strip at rt under a N2 atmosphere for
product of N-tosyl-2,2-diphenylcyclobutanimine 3aa was
obtained in a yield of 61% (Table 1, entry 1). When
Ir(ppy)2(dtbbpy)PF6 and Ru(bpy)3Cl2 were used as the
photocatalysts, the yield of 3aa was 54% and 57%, respectively
(Table 1, entries 2 and 3). Solvent screening showed that
MeCN was an optimal solvent for this transformation (Table 1,
entries 4−9). Moreover, increasing the quantity of N-Ts-
protected 1-aminopyridinium 2a could lead to higher yields
(Table 1, entries 10−12). Further control experiments revealed
that both Ir(ppy)3 and visible-light were necessary for this
rearrangement protocol (Table 1, entries 13 and 14).
b
36 h. Isolated yields.
configuration of compound 3aa was determined by X-ray
crystal structure analysis. The data of the X-ray crystal structure
can be found in the Supporting Information.11
We next explored the scope of the nitrogen-centered radical
precursors with 1a as the substrate in Scheme 3. It was found
that the N-protected 1-aminopyridium salts with electron-rich
substituents, such as methoxyl and tert-butyl group, afforded the
desired products in excellent yields (3ac and 3ad, 87% and 91%
yield, respectively). The N-protected 1-aminopyridium salts
With the reaction conditions optimized, the substrate scope
of this aza-pinacol rearrangement was then evaluated.
Generally, good to excellent yields were achieved with a variety
of electron-donating and electron-withdrawing substituents on
one of aromatic rings of ACPs (3aa−3na), which are listed in
Scheme 2. When an electron-donating substituent, such as a
methoxyl group, methyl group, and tertiary butyl group, or an
electron-withdrawing substituent, such as a halogen atom, was
at the para-position of the aromatic ring, the reaction
proceeded smoothly to give the corresponding rearrangement
product in good to excellent yields (3ba−3ga, 83%−94%
yield). Similar results were obtained for substituents at the
meta-position of the aromatic ring (3ha−3ja, 83%−86% yield).
Lower yields of the desired products were seen for the
substrates with the substituents at the ortho-position of the
aromatic ring (3ka−3na, 60%−80% yield). Notably, the
substrate with a naphthyl group also gave the desired product
3oa in a yield of 79%. Furthermore, substrates with two
substituents on the aromatic ring were also studied, and the
corresponding products were formed in good yields (3pa and
3qa, 87% and 77% yield). Two symmetrical ACPs underwent
ring expansion under the optimal conditions to afford 3ra and
3sa in 84% and 80% yields, respectively. In addition, substrates
containing an alkyl group instead of a phenyl group also gave
moderate yields (3ta and 3ua, 68% and 52% yield,
respectively). However, neither pyridyl-substituted ACP nor
dialkyl-substituted ACP afforded the desired product. The
Scheme 3. Scope of The Nitrogen Radical Precursors in the
Aza-Pinacol Rearrangement Reaction
a b
,
a
Reaction conditions: substrate 1a (0.1 mmol), substrate 2b−2g (0.4
mmol), Ir(ppy)3 (0.002 mmol) in MeCN (anhydrous, 4 mL) under
irradiation of a 25 W blue LED strip at rt under a N2 atmosphere for
b
36 h. Isolated yields.
B
DOI: 10.1021/acs.orglett.7b02989
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
with halogen atom substituents reacted smoothly to give the
rearrangement products in good yields (3af and 3ag, 79% and
75% yield, respectively). Trifluoromethylbenzenesulfonyl 1-
aminopyridium salt, which has a powerful electron-withdrawing
group on the aromatic ring, afforded the corresponding product
3ae in 71% yield. Interestingly, when electron-neural
benzenesulfonyl group was used, the yield of the product 3ab
was still 80%.
Scheme 5. Mechanistic Investigations
Notably, the rearrangement product could also be obtained
with good yield when the reaction was carried out under natural
sunlight irradiation (Scheme 4, eq 1). Moreover, when a gram-
Scheme 4. Further Applications
A plausible mechanism is illustrated in Scheme 6 based on
the aforementioned control experiments and our previous work
Scheme 6. A Plausible Mechanism
scale reaction was performed, 1.03 g of diphenylmethylenecy-
clopropane 1a yielded 1.12 g (60% yield) of the N-tosyl-2,2-
diphenylcyclobutanimine product 3aa with a slightly decreased
yield (Scheme 4, eq 2). Furthermore, to demonstrate the
synthetic utility of this rearrangement reaction, N-Ts-protected
cyclobutylamine 4a which is prevalent in bioactive molecules
and natural products was obtained from 3aa (Scheme 4, eq 3),
and product 3aa could also be directly transformed to the γ-
butyrolactone 4b in the presence of m-CPBA12 (Scheme 4, eq
4).
Next, to gain mechanistic insight into this reaction, several
control experiments were conducted as shown in Scheme 5.
Fluorescence quenching techniques (Scheme 5a) and the
Stern−Volmer analysis (Scheme 5d) revealed that the photo-
luminescence of Ir(ppy)3 was quenched by N-Ts-protected 1-
aminopyridinium 2a in acetonitrile. When the reaction mixture
was stirred under the standard conditions in the presence of
TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) (2.0 equiv),
3aa could not be detected (Scheme 5, eq 1). All these results
suggested that this radical reaction was initiated by the N-
centered radical generated from N-Ts-protected 1-amino-
pyridinium. When anhydrous methanol was used as the
solvent, product N-tosyl-2,2-diphenylcyclobutanimine 3aa was
obtained in 58% yield as the major product, and a new species
(found 408.1624) was observed when this reaction was
monitored by ESI-HRMS, which was assigned to species 4c
(cal. 408.1628) (Scheme 5, eq 2). In the same way, a new
species (found 394.1468) was observed, which is assigned to
species 4d (cal. 394.1471) (Scheme 5, eq 3).12
as well as other reported literatures.13 At the beginning,
irradiation of the photoredox catalyst Ir(ppy)3 by blue light at
room temperature generates a photoexcited state *Ir(ppy)3,
which is a strong reductant. This excited state can undergo
single-electron transfer (SET) with oxidative species such as
substrate 2.14 Then, The N-protected 1-aminopyridinium 2
obtains an electron from *Ir(ppy)3 to afford the N-centered
+
radical 5 and the oxidized photocatalyst Ir(ppy)3 . The addition
of the N-centered radical to the CC bond of ACP gives
stabilized radical intermediate 6.15 Radical 6 is then oxidized by
+
the powerful oxidant Ir(ppy)3 to afford tertiary cation 7 while
+
oxidant Ir(ppy)3 returns to its ground state, thereby
accomplishing the photocatalytic cycle. Species 7 undergoes
1,2-alkyl migration to form intermediate 8. Finally, intermediate
8 can form product 3 upon loss of a proton.
In conclusion, we have successfully developed a novel aza-
pinacol rearrangement reaction through the photoredox
catalysis for the first time. In this transformation, a variety of
strained cyclobutanimine derivatives were readily constructed
C
DOI: 10.1021/acs.orglett.7b02989
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b02989.
(8) Sahoo, B.; Li, J.-L.; Glorius, F. Angew. Chem., Int. Ed. 2015, 54,
11577.
General information; preparation of substrates, syntheses
procedures, X-ray crystallographic data of compound
3aa; NMR spectra (PDF)
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AUTHOR INFORMATION
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graphic data for this paper. These data can be obtained free of charge
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Corresponding Author
*E-mail: xupf@lzu.edu.cn.
ORCID
Peng-Fei Xu: 0000-0002-5746-758X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSFC (21632003, 21372105, and
21572087), the “111” program from the MOE of P. R. China,
and Syngenta Company for financial support.
(12) See the Supporting Information.
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