Visible-light-promoted remote C(sp3)-H amidation and chlorination

Article abstract of DOI:10.1021/acs.orglett.5b00582

A visible-light-promoted C(sp³)-H amidation and chlorination of N-chlorosulfonamides (NCSs) is reported. This remote C(sp³)-H functionalization can be achieved in weak basic solution at room temperature with as little as 0.1 mol % of

Full text of DOI:10.1021/acs.orglett.5b00582

Letter
pubs.acs.org/OrgLett
Visible-Light-Promoted Remote C(sp3)−H Amidation and
Chlorination
Qixue Qin and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University,
Nanjing, 210093, China
S
* Supporting Information
ABSTRACT: A visible-light-promoted C(sp3)−H amidation and chlorination
of N-chlorosulfonamides (NCSs) is reported. This remote C(sp3)−H
functionalization can be achieved in weak basic solution at room temperature
with as little as 0.1 mol % of a photocatalyst. A variety of nitrogen-containing
heterocycles (up to 94% yield) and chlorides (up to 93% yield) are prepared
from NCSs. Late-stage C(sp3)−H functionalization of complex and biologically
important (−)-cis-myrtanylamine and (+)-dehydroabietylamine derivatives can
also be achieved with excellent yields and regioselectivity.
elective and deliberate functionalization of inert C−H
such a goal can be traced back to the historical Hofmann−
S
bonds, which has the potential to revolutionize the
Loffler−Freytag (HLF) reaction in the late 19th century
̈
(Figure 1b).7 Later, numerous improvements were introduced
to make this reaction more synthetically useful.8 However, the
requirement of ultraviolet photolysis, strongly acidic media, or
oxidants restrains its applications in organic synthesis.7−9 Due
to the synthetic importance of remote C(sp3)−H functionaliza-
tion, as well as our research interests on visible-light-mediated
radical chemistry,10 we sought to develop a visible-light-
promoted remote C(sp3)−H functionalization of N-chlorosul-
fonamides (NCSs) that would address the synthetic limitations
described above (Figure 1c).
synthesis of complex molecules dramatically, is a long sought
after goal in organic synthesis.1 Nitrogen-centered radicals,
which can be used directly to enable C−H amination/
amidation, have not received much attention in the synthetic
community.2 The lack of methods for their effective generation
and their high reactivity are possible reasons. Very recently, our
group3a and others3b−f reported visible-light-induced C−H
amidations of arenes and heteroarenes using different nitrogen
sources (Figure 1a). The key step in these transformations is
Our efforts toward this goal initially focused on intra-
1a/1a−•
molecular cyclization of NCS 1a (Ep
= −0.470 V vs
SCE). A solution of 1a in CH3CN was irradiated by white LED
strips in the presence of photocatalyst Ir(ppy)2(dtbbpy)PF6 (I)
and Na2HPO4 for 6 h at room temperature. After 1a was
consumed as monitored by TLC analysis, the reaction mixture
was treated with solid NaOH directly and stirred for another 4
h. The desired pyrrolidine 2a could be obtained in 52% NMR
yield, together with a 40% yield of dechlorination product 3a as
a major byproduct (Table 1, entry 1). This encouraging result
prompted us to improve this reaction further. It was found that
the loading of the photocatalyst had an important impact on
the outcome of this transformation. When more photocatalyst I
(2 mol %) was employed, less desired product 2a was produced
with a comparable yield of side product 3a (entry 2). When 0.5
mol % of I was used, a 79% NMR yield of 2a was given
together with a 13% yield of 3a (entry 3). To our delight, when
the photocatalyst loading was reduced to 0.1 mol %, the NMR
yield of 2a increased to 87% (83% isolated yield, entry 4).
Various solvents, such as toluene, MeOH, EtOAc, DMSO,
Figure 1. C−H amination/amidation.
the formation of nitrogen-centered amidyl radicals from
different precursors under visible light.3,4 Despite significant
advances, all these works focused on the amidation of C(sp2)−
H bonds. These promising results inspired us to exploit the
feasibility of the more challenging C(sp3)−H amidation under
photoredox catalysis.5
C(sp3)−H functionalization is a formidable synthetic
challenge due to activity and selectivity issues.6 Efforts toward
Received: February 25, 2015
Published: April 8, 2015
© 2015 American Chemical Society
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Org. Lett. 2015, 17, 1894−1897

Organic Letters
Letter
a
a
Table 1. Reaction Optimization
Table 2. Scope of Intramolecular C(sp3)−H Amidation
b
b
entry
PC
solvent
2a/%
51
3a/%
1
I (1 mol %)
I (2 mol %)
CH3CN
CH3CN
CH3CN
CH3CN
toluene
CH3OH
EtOAc
40
39
13
9
2
33
79
3
I (0.5 mol %)
I (0.1 mol %)
I (0.1 mol %)
I (0.1 mol %)
I (0.1 mol %)
I (0.1 mol %)
I (0.1 mol %)
I (0.1 mol %)
I (0.1 mol %)
II (0.1 mol %)
III (0.1 mol %)
IV (0.1 mol %)
none
c
4
87(83 )
33
5
37
41
50
30
90
65
28
24
9
6
42
7
trace
63
8
DMF
9
DMSO
THF
trace
28
10
11
12
13
14
15
CH2Cl2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
58
69
79
38
31
NR
38
NR
NR
34
d
16
e
I (0.1 mol %)
I (0.1 mol %)
17
NR
a
Reaction conditions: A solution of 1a (0.2 mmol, 1.0 equiv),
Na2HPO4 (0.24 mmol, 1.2 equiv), and photocatalyst in indicated
solvent (3.0 mL) was irradiated by white LED strips for 6 h, and then
the reaction mixture was treated with solid NaOH (0.24 mmol, 1.2
b
1
equiv) for another 4 h. Yields were determined by H NMR using
c
d
e
CH2Br2 as an internal standard. Isolated yield. No Na2HPO4. No
irradiation. NR = no reaction.
THF, and CH2Cl2, were then examined (entries 5−11).
However, none of them gave improved results. Other
photocatalysts, such as Ir(ppy)3 (II), Ru(phen)3(PF6)2 (III),
and Ru(bpy)3(PF6)2 (IV), were not superior to photocatalyst I
(entries 12−14). Control experiments verified the necessity of
the base, irradiation, and photocatalyst (entries 15−17).
Without visible light irradiation or a photocatalyst, the starting
material 1a was fully recovered. And without Na2HPO4, the
yield of 1a dropped to 34%.
After the optimized conditions were established, we next
sought to explore the substrate scope of this visible-light-
mediated intramolecular C(sp3)−H amidation (Table 2). It was
found that protecting groups on the nitrogen atom had a
significant impact on the outcome of the reactions. Electron-
rich NCS 1b gave a slightly better isolated yield of the desired
pyrrolidine 2b (88%) while electron-deficient NCSs 1c and 1d
gave much worse yields (42% for 2c and 28% for 2d). N-
1e/1e−•
Chlorocarbamate 1e (Ep
= −0.682 V vs SCE) and N-
a
chloroalkyl amine 1f could not go through this transformation,
and the starting materials could be recovered fully due to their
lower oxidative capacity compared to 1a. A variety of 2-
substituted pyrrolidines 2g−2j were prepared in good to
excellent yields (57−94%). 3-Substituted and 2,5-disubstituted
pyrrolidines 2k (86%) and 2l (78%) were also accessible by
means of this method. Notably, optically active isoleucine-
derived 2,3-disubstituted pyrrolidines 2m and 2n could be
provided as a single isomer with 85% and 56% yields,
respectively. To our delight, acid-sensitive oxazolidines 2o
and 2p, which are not accessible under classic HLF conditions,
could be produced under our established conditions with
moderate to good yields. Cyclic benzosulfonamides 2q and 2r
Reaction conditions: A solution of 1 (0.2 mmol, 1.0 equiv),
Na2HPO4 (0.24 mmol, 1.2 equiv), and I (0.1 mol %) in CH3CN
(3.0 mL) was irradiated by white LED strips for 4−18 h, and then the
reaction mixture was treated with solid NaOH (0.24 mmol, 1.2 equiv)
b
for another 4 h. Isolated yield.
could be provided in satisfactory yields. It is worthy of note that
2q is easily overoxidized under Suar
́
ez’s modified conditions of
the HLF reaction.11
Interestingly, when NCSs were subjected to standard
conditions, but without adding solid NaOH, C(sp3)−H
chlorination products could be isolated. As shown in Table 3,
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Letter
a serial of chlorides 4a−4f could be prepared in good yields
(64−93%) with the assistance of this newly developed method.
Scheme 2. Late-Stage Functionalization of 1t and 1u
a
Table 3. Scope of C(sp3)−H Chlorination
To understand the mechanism, a series of control reactions
were conducted, as shown in Scheme 3. The reaction could be
Scheme 3. Control Experiments
a
Reaction conditions: A solution of 1 (0.2 mmol, 1.0 equiv),
Na2HPO4 (0.24 mmol, 1.2 equiv), and I (0.1 mol %) in CH3CN
b
(3.0 mL) was irradiated by white LED strips for 4−12 h. Isolated
yield.
Encouraged by these results, we subsequently conducted the
intramolecular C(sp3)−H amidation on a gram scale,
demonstrating its practicability. As shown in Scheme 1, when
Scheme 1. Gram-Scale Preparation of 2a
terminated completely when TEMPO was introduced to the
reaction mixture, which indicated that this reaction goes
through a one-electron transfer pathway. The radical-based
mechanism could be further supported by a radical clock
experiment.16 When cyclopropane-derived NCS 1v went
through this transformation, the ring-open product 4h was
obtained via the key intermediates 5 and 6 (Scheme 3a). When
NCS 1w was subjected to the standard chlorination conditions,
54% of desired chloride 4i was isolated, together with
rearrangement product 4i′ (43% yield) (Scheme 3b). Given
that a radical 1,6-shift is unfavorable when a 1,5-shift is
available, chloride 4i′ could be generated from carbocation 8,
which was formed from carbocation 7 through the Meerwein-
type rearrangement. This phenomenon suggests that this
reaction goes through a radical-polar crossover mechanism
rather than a chain propagation mechanism. Light off/on and
time profile experiments for 1a and 1g (for details, see
Supporting Information) were also carried out to support this
hypothesis. It was observed that the reaction progressed
smoothly with light irradiation, but little conversion was
observed when the light resource was removed. This experi-
ment suggests that regeneration of the photocatalyst is
necessary for the full consumption of NCSs.
1.69 g of NCS 1a was amidated in the presence of as little as
0.05 mol % of the photocatalyst I, a comparative isolated yield
of 2a (87%, 1.32 g) was achieved with the turnover number
(TON) = 1740.
The mildness of the remote C(sp3)−H functionalization
conditions prompted us to investigate the feasibility of late-
stage modification of complex and biologically important
molecules. For example, matrix-2 protein inhibitor (−)-cis-
myrtanylamine-derived NCS 1t12 was subjected to standard
C(sp3)−H amidation conditions, and piperidine 2s was isolated
in 86% yield as one isomer. A six-membered ring was formed
instead of a five-membered ring due to conformation
restriction.13 When (+)-dehydroabietylamine-derived NCS 1u
went through C(sp3)−H chlorination conditions, C10-chlori-
nation product 4g was produced in 94% yield as a sole product.
Dehydroabietylamine derivatives possess broad interesting
pharmacological activities, such as antitumor and antimalarial
activities.14 The structures and stereochemistry of 2s and 4g
were established unambiguously by single crystal X-ray
diffraction analysis (Scheme 2).15
On the basis of these observations, a plausible mechanism is
proposed (Figure 2). First, the photocatalyst IrIII is irradiated to
the excited state IrIII*, which is then oxidatively quenched by
NCS 1a with generation of IrIV and nitrogen-centered radical 9
respectively. Radical 9 undergoes an intramolecular 1,5-
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Organic Letters
Letter
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remote C(sp3)−H functionalization in the presence of 0.1 mol
% of a photocatalyst. This remote C(sp3)−H amidation and
chlorination from NCSs can be achieved in weak basic solution
at room temperature. The reaction can be scaled up to gram
scale with as litlle as 0.05 mol % of the photocatalyst. A variety
of nitrogen-containing heterocycles and chlorides are prepared
from NCSs in good to excellent yields. Late-stage C(sp3)−H
functionalization of complex and biologically important (−)-cis-
myrtanylamine and (+)-dehydroabietylamine derivatives can
also be achieved. We expect this powerful protocol to be of
broad utility in the synthesis and modification of biologically
important N-containing heterocycles, as well as natural
products, which are not easily accessible by means of a
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ASSOCIATED CONTENT
* Supporting Information
Full experimental, CIF information, and characterization data
for all compounds are provided. This material is available free
of charge via the Internet at http://pubs.acs.org.
■
́
S
AUTHOR INFORMATION
Corresponding Author
(10) (a) Jiang, H.; Cheng, Y.; Zhang, Y.; Yu, S. Org. Lett. 2013, 15,
4884. (b) Jiang, H.; Cheng, Y.; Wang, R.; Zheng, M.; Zhang, Y.; Yu, S.
Angew. Chem., Int. Ed. 2013, 52, 13289.
■
*E-mail: yushouyun@nju.edu.cn.
(11) Katohgi, M.; Togo, H.; Yamaguchi, K.; Yokoyama, M.
Notes
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(12) Hu, W. H.; Zeng, S. G.; Li, C. F.; Jie, Y. L.; Li, Z. Y.; Chen, L. J.
Med. Chem. 2010, 53, 3831.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
Financial support from the 863 program (2013AA092903), the
National Natural Science Foundation of China (21472084 and
81421091), and the Natural Science Foundation of Jiangsu
Province (BK20131266) is acknowledged. We thank Dr. Yue
Zhao for the refinement of the single crystal data.
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