Visible-light-promoted carboimination of unactivated alkenes for the synthesis of densely functionalized pyrroline derivatives

Article abstract of DOI:10.1021/acscatal.6b01230

An efficient strategy which integrates visible-light-induced iminyl-radical formation with carboimination of unactivated alkenes has been developed for the easy access of densely functionalized pyrroline derivatives. With fac-[Ir(ppy)₃] as photoredox catalyst, the acyl oximes were converted into iminyl radical intermediates by one electron reduction, and evolve through a cascade of intramolecular cyclization and intermolecular carbon radical trapping to give the functionalized pyrrolines. The utilization of silyl enol ethers as coupling partners not only allows the introduction of synthetically useful ketone functionalities but also renders catalyst regeneration without any external reductants. This protocol is characterized by its mild reaction conditions and the tolerance of a broad range of functionalities.

Full text of DOI:10.1021/acscatal.6b01230

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Article
Visible-Light-Promoted Carboimination of Unactivated Alkenes
for the Synthesis of Densely Functionalized Pyrroline Derivatives
Sai-Hu Cai, Jia-Hao Xie, Shengjin Song, Lu Ye, Chao Feng, and Teck-Peng Loh
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b01230 • Publication Date (Web): 18 Jul 2016
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ACS Catalysis
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Visible-Light-Promoted Carboimination of Unactivated Alkenes for
the Synthesis of Densely Functionalized Pyrroline Derivatives
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,1,3
Sai-Hu Cai, Jia-Hao Xie, Shengjin Song, Lu Ye, Chao Feng,* and Teck-Peng Loh*
1
Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, 230026, China
2
Institute of Advanced Synthesis, College of Chemistry and Molecular Engineering, Jiangsu National Synergetic
Innovation Center for Advanced Materials, Nanjing Tech University, Nanjing, Jiangsu 210009, P.R. China.
3
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang
Technological University, 637371, Singapore
ABSTRACT: An efficient strategy which integrates visible-light-induced iminyl-radical formation with carboimination of
unactivated alkenes has been developed for the easy access of densely functionalized pyrroline derivatives. With
fac-[Ir(ppy) ] as photoredox catalyst, the acyl oximes were converted into iminyl radical intermediates by one electron
3
reduction, which evolve through a cascade of intramolecular cyclization, intermolecular carbon radical trapping to give
the functionalized pyrrolines. The utilization of silyl enol ethers as coupling partners not only allows the introduction
synthetically useful ketone functionalities but also render catalyst regeneration without any external reductants. This
protocol is characterized by its mild reaction conditions and the tolerance of a broad range of functionalities.
KEYWORDS: N-heterocycles, pyrroline, photoredox catalysis, visible light, iminyl radicals
-
centered radicals (NCRs) have been showing their
from being widely applicable for the construction of
complex molecular skeletons despite the synthetic
potential of NCRs and a mild, selective and general
protocol for the generation of NCRs from readily available
bulk starting materials would unarguably be in high
demand.
N
increasing synthetic potential for the creation of C–N
bonds which represent as the centrality in alkaloids
synthesis, yet they have not received adequate attentions
form the synthetic community as compared with the
1
congener of carbon radicals. Arguably, the frequently
employed methods for NCRs generation often rely on the
deprotonative oxidation of N–H containing motifs using
stoichiometric amount of external strong oxidants; spin
transfer type addition of more easily accessible parent
radicals to unsaturated nitrogen-containing functional
groups and the homolytic scission of a weak N–X bond
1a
containing entities. Among all these strategies, the
homolytic cleavage of N-O bond in hydroxy amine
derivatives enables an efficient and facile generation
2
NCRs from readily available starting materials. Therefore,
Scheme 1. Pyrroline construction employing oxime
derivatives
tremendous efforts from the synthetic chemists have been
directed toward this particular scenario by making use of
diverse initiation mode, including either transition-metal
catalysis , microwave heating or UV irradiation . While
much progress in this vein has been made during the past
decade, there, however, still remained considerable
limitations such as relying on the use of toxic and
hazardous reagents, elevated temperatures as well as
narrow substrate scope. Therefore, it is still a long way
The visible-light promoted organic transformations,
which gain energy from photons and enable reactions to
occur under very mild conditions, have been attracting
increasing attentions from synthetic organic chemists
since the seminal work of MacMillan, Yoon and
3
4
5
6
Stephenson. By resorting to either organic or metallic
photoactive sensitizers, a large variety of intriguing
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transformations, which otherwise would be of formidable Table 1. Optimization of reaction condition
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challenge with traditional synthetic protocols, were
7
successfully accomplished. Beyond all doubt, the boom
of photocatalysis, to some extent, led to a renaissance of
this paticular chemistry respect to NCRs because of the
redox activity of photocatalysts which enable the
production of these active species under very mild
Entry
photocatalyst
solvent
Yield (%)(3aa/3aa’)
8
reaction conditions. To be more specific, elegant works
1
fac-Ir(ppy)3
fac-Ir(ppy)3
DMF
54/24
38/43
trace
11/55
15/9
pertaining to iminyl radical as the pivotal intermediate
generated via photocatalysis have been reported by the
2
3
4
5
DMA
DMPU
NMP
9
10
fac-Ir(ppy)
3
0
1
2
3
4
5
6
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8
9
0
1
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0
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0
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9
0
groups of Leonori and Yu , which enables the ease of
C–N bonds or N-heterocycles construction.
fac-Ir(ppy)3
fac-Ir(ppy)3
fac-Ir(ppy)3
CH CN
3
b
6
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
86/12
62/9
c
7
fac-Ir(ppy)3
b,d
8
e
fac-Ir(ppy)3
85(75) /9
b,d
9
Ru(bpz) (PF )
6 2
14/0
trace
0
3
b,d
0
1
DCA
b,d
11
Cu(dap) Cl
2
b,d,f
2
1
fac-Ir(ppy)3
0
b,d
3
1
－
0
a
Unless otherwise noted, the reactions were carried out at
room temperature under Ar atmosphere using 1a (E/Z
mixture, 0.1 mmol), 2a (0.2 mmol), photocatalyst (0.002
mmol) in solvent (1 mL) for 12 h with yields being determined
Scheme 2. Proposed reaction mechanism
Pyrroline represents as a core structural motif which is
widely present in naturally occurring compounds and
pharmaceuticals. As such, the quest for the development
of effective methods for the synthesis of densely
functionalized pyrroline derivatives is actively pursued in
1
b
by H NMR using mesitylene as internal standard. 2a (0.3
c
d
e
f
mmol). 2a (0.4 mmol). Solvent (0.5 mL). Isolated yield. No
light. DCA = 9,10-dicyanoanthra-cene. DMPU = 1,3-dimethyl
-
3,4,5,6-tetrahydro-2(1H)-pyrimidinone. PG = 4-(trifluorome-
1
1
thyl)benzoyl.
the past several years. Quiet recently, by using O-aryl
oxime as substrate, Leonori developed a photocatalytic
Considering the more oxidizing ability of electron
deficient O-acyl oxime, which was envisioned to furnish
iminyl radical more readily via one electron reduction, the
coupling between 1a and 1-phenyl-1-trimethylsilyloxyeth-
ylene 2a was chosen as the model reaction and the
representative experiment results are summarized in
Table 1. It was pleasing to find that when using
hydroimination protocol for construction of pyrroline
9
skeleton (Scheme 1a).
Despite these significant
developments, there still remain ample room for further
improvement especially in terms of reaction diversity,
applicability and practicality. With our continuing
1
2
interest in C-N bonds and N-heterocycles construction,
we would like to report our recent advancement in
visible-light-promoted carboimination of unactivated
alkenes for the construction of densely functionalized
pyrroline derivatives.
fac-Ir(ppy) as photocatalyst and DMF as solvent, the
expected carboimination product 3aa was obtained in
3
5
4% yield as well as the hydroimination 3aa’, which was
assumed to be produced via hydrogen atom abstraction
form the solvent, in 24% yield (Table 1, entry 1). With the
aim of suppressing such accompanying hydroimination
process, various solvents were examined, which, however,
provided no more positive results than that of DMF
(Table 1, entries 2-5). To our delight, the reaction efficacy
could be further enhanced by using 3 equiv 2a, whereas
3aa’ was still produced in 12% yield (Table 1, entry 6). By
adjusting the concentration of reacation, the yield of
desired product 3aa could be further improved to 85%
yield with minimal amounts of the byproduct 3aa’ being
formed (Table 1, entries 7, 8). Different kinds of
photocatalysts were also examined, which, however,
proved to be not efficacious for such transformation
(Table 1, entries 9-11). Control experiments revealed the
indispensability of both light and photocatalyst in this
transformation, without either, no desired product could
As outlined in Scheme 2, the catalytic cycle is
envisioned to start with the excitation of a photocatalyst
PC to its excited state PC*. Oxidative quenching of PC*
via reduction of oxime derivative I would generate the key
iminyl radical intermediate II, which inclines to undergo
5
-exo-cyclization to produce pyrroline species III contain-
ing a primary carbon-centred radical. At this stage, the
carbon radical III is envisioned to be trapped by silyl enol
ether IV to deliver α-oxygen radical V, which would
ultimately furnish the desired product VI through single
electron transfer and desilylation processes, while
simultaneously regenerating the active catalyst PC. It
should also be pointed out that the premature generation
of hydroimination product VII via hydrogen transfer
between III and reaction media shall never be
overlooked.
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proceeded selectively to afford only one diastereoisomer
be obtained but the recovered starting material (Table 1,
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entries 12, 13).
in acceptable yield. While aromatic ketone derived
substrates worked well, notable limitations with respect
to the substrate scope still remain. For example, alkyl,
alkenyl and alkynyl based substrates as well as
imidothioate derivative were all not appropriate for such
transformation and the exact reason for the incompetence
of these substrates is currently not clear.
Table 2. Reaction scope of acyl oximes
R2 R3
R1
O
OPG
N
R2
fac-Ir(ppy)3 (2 mol%)
R
N
Ph
Visible-Light
R3
R
2a, DMF, 12 h, Ar, rt
R1
1
3
O
O
O
To further probe the reaction generality, the reactions
between oxime derivatives and various silyl enol ethers were
carried out and the examination results were listed in Table
3. With respect to α-aryl silyl enol ether, substrates with both
electron-withdrawing and electron-donating functional
groups on the aryl substituents all worked smoothly to afford
desired products in moderate to good yields. Pleasingly, the
halogen substituents were proved to be well adapted to this
reaction condition, thus furnishing the opportunity of
further synthetic elaboration via traditional cross-coupling
methodologies (3ad-3ag). It is worth mentioning that this
transformation was not restricted to aryl derived silyl enol
ethers. Substrates incorporating alkynyl substituents were
also found to be competent reaction partners as
demonstrated in the case of 3ah. Though somewhat
diminished reactivity was observed in this case, the synthetic
potential of thus incorporated alkynyl moiety in 3ah would
make such transformation very appealing. Furthermore, the
variation of silyl enol ether was also feasible when reacting
with 1v, thus offering an effective synthetic pathway for the
easy access of hexahydro-3H-indole derivatives that
containing three contiguous stereogenic centers (3vd-3vh).
Unfortunately, tri- and tetra-substituted silyl enol ethers
were not suitable for such transformation, with no desired
N
Ph
N
Ph
N
Ph
0
1
2
3
4
5
6
7
8
9
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2
3
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0
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0
3
aa, 75%
N
3ba, 62%
3ca, 66%
N
O
O
O
TBSO
Ph
N
Ph
Ph
MeO
Me2N
3
da, 64%
3ea, 61%
3fa, 54%
O
O
O
Cl
Cl
N
Ph
N
Ph
N
Ph
Cl
3
ga, 74%
3ha, 63%
3ia, 55%
O
O
O
N
Ph
Ph
Br
Ph
N
N
MeOOC
Ph NC
PhHNOC
3ja, 61%
3ka, 75%
N
3la, 70%
O
O
O
N
Ph
N
Ph
BocHN
F3C
3ma, 80%
3na, 70%
oa, 82%a
3
O
O
O
O
F3C
F3C
N
Ph
N
Ph
N
Ph
S
3
pa, 33%
3
qa, 61%b, 66%c
3ra, 78%
O
O
N
Ph
N
Ph
N
Ph
3
sa, 75%
O
3ta, 70%
3ua, 83%
Table 3. Reaction scope of silyl enol ethers
Ph
H
H
O
O
N
N
R
Ph
N
Ph
fac-Ir(ppy)3 (2 mol%)
Visible-Light
OTMS
R
Ph
N
Ph
H
O
+
3
va, 61%
3wa, 9%d
3sa, 0%
PGO
N
DMF, 12 h, Ar, rt
1
2
3
See the Supporting Information for the detailed reaction
a
b
O
O
O
conditions. Run in 24 h. E-configuration substrate.
c
d
1
N
N
N
Z-configuration substrate. Yield determined by H NMR
Ph
Ph
Ph
OMe
using mesitylene as internal standard. PG = 4-(trifluoro
methyl)benzoyl.
3
aa, 75%
3ab, 64%
3ac, 72%
O
O
O
Br
Cl
N
N
N
With the optimized conditions obtained, the reaction
generality with respect to O-acyl oximes
Ph
Ph
Ph
Cl
1
was
3ad, 70%
3ae, 62%
3af, 63%
investigated with 2a as model coupling partner and the
results were summarize in Table 2. It was found that this
reaction shown a nice compatiblity of a large variety of
functionalities and enabled diverse substitution patterns
with respect to the starting oxime derivative to be well
accommodated. Generally, the desired pyrroline products
were obtained in moderate to high yield (33-82%)
irrespective of the position and electronical property of
substituents on the phenyl moiety (3aa-pa) and
heterocyclic substrate was also amenable to this
transformation (3qa). Furthermore, oxime substrates that
contain α-substituents also worked smoothly to deliver
desired products in good yields (3ra, 3sa). As expected,
the cyclization also worked smoothly in the cases of
substrates with either di- or tri-substituted alkene
pendent, affording the desired products in good yields
(3ta, 3ua). Notably, when 1v was employed, the reaction
O
O
O
Cl
H
H
H
N
N
N
Ph
Ph
Ph
Br
Ph
3
ag, 58%
3ah, 31%
3vd, 42%
O
Br
O
O
H
H
H
H
H
H
N
N
Ph
N
Ph
Ph
Ph
Ph
Ph
3
vf, 42%
3vh, 32%
3ai, 0%, 43%a
O
O
O
tBu
N
N
Ph
N
Ph
Ph
Ph
aj, 0%, 72%a
3ak, 0%, 43%a
3al, 0%
3
See the Supporting Information for the detailed reaction
a
conditions. Yield of hydroimination product, determined
1
by H NMR using mesitylene as internal standard. PG =
4
-(trifluoromethyl)benzoyl.
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ACS Catalysis
products but only hydroimination byproducts being
ACKNOWLEDGMENT
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obtained in these cases (3ai, 3aj). In addition, alkyl and
alkenyl derived silyl enol ethers were also proved to be
inappropriate (3ak and 3al).
We gratefully acknowledge the funding support of the State
Key Program of National Natural Science Foundation of
China (21432009). We also thank Nanjing Tech University,
Nanyang Technological University, Singapore Ministry of
Education Academic Research Fund [Tier 1: MOE2015-T1-
In order to assess the practicality of this
transformation, a gram-scale reaction between 1b and 2a
was carried out and the desired product 3ba was obtained
001-070(RG5/15) and MOE2014-T1-001-102(RG9/14)], and Sin-
13
gapore National Research Foundation (NRF2015NRF- POC
001-024) for generous financial support.
in comparable yield to that of small scale version. As a
continuing attempt to further showcase the synthetic
potential of these pyrroline derivatives thus obtained,
synthetic elaboration was carried out with product 3ba.
By making use of imine and ketone functionality
incorporated, the reductive cyclization worked smoothly
to the deliver the hexahydro-1H-pyrrolizine alkaloid 4ba,
which is ubiquit- ous and represents as a core structure
0
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In conclusion, a novel strategy for the expedient synthesis
of pyrroline derivatives was discovered. This reaction cascade
takes place through intramolecular 5-exo-cyclization of
iminyl radical, which is generated by virtue of
visible-light-promoted mesolysis of O-acyl oxime derivatives,
followed by intermolecular interception of thus formed
carbon-centred radical with silyl enol ether derivatives.
Furthermore, this transformation exhibited high reaction
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synthetically useful functionalities, thus providing
a
competent synthetic route for the pyrroline derivative
construction. Further investigation to extend the reaction
scope is ongoing in our laboratory and will be reported in the
due course.
ASSOCIATED CONTENT
Supporting Information.
2014, 53, 11060-11064. (h) Ghosh, I.; Ghosh, T.; Bardagi, J. I.;
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acscatal.xxxxxxxxx.
Experimental procedures and compound characterization
(PDF)
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AUTHOR INFORMATION
Corresponding Author
W.-J. Chem. Soc. Rev. 2016, 45, 2044-2056. For selected recent
article, see: (b) Hu, X.-Q.; Chen, J.-R.; Wei, Q.; Liu, F.-L.; Deng,
Q.-H.; Beauchemin, A. M.; Xiao, W.-J. Angew. Chem. Int. Ed.
*
E-mails: iamcfeng@njtech.edu.cn
E-mails: teckpeng@ntu.edu.sg
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014, 53, 12163-12167. (c) Allen, L. J.; Cabrera, P. J.; Lee, M.;
Sanford, M. S. J. Am. Chem. Soc. 2014, 136, 5607-5610. (d) Kim,
H.; Kim, T.; Lee, D. G.; Roh, S. W.; Lee, C. Chem. Commun. 2014,
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- Eur. J. 2014, 20, 14231-14234. (f) Qin, Q.; Yu, S. Org. Lett. 2014,
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The authors declare no competing financial interest.
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