Photoredox-Induced Intramolecular 1,5-H Transfer Reaction of Aryl Iodides for the Synthesis of Spirocyclic γ-Lactams

Article abstract of DOI:10.1021/acs.orglett.8b00731

This work develops a photocatalysis method for the synthesis of γ-spirolactams through a tandem intramolecular 1,5-HAT reaction-cyclization process. A variety of novel γ-spirolactams are prepared in good to excellent yields with this method. This transfor

Full text of DOI:10.1021/acs.orglett.8b00731

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Photoredox-Induced Intramolecular 1,5‑H Transfer Reaction of Aryl
Iodides for the Synthesis of Spirocyclic γ‑Lactams
Jian-Qiang Chen, Rui Chang, Jun-Bing Lin, Yong-Chun Luo, and Peng-Fei Xu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
S
* Supporting Information
ABSTRACT: This work develops a photocatalysis method for
the synthesis of γ-spirolactams through a tandem intra-
molecular 1,5-HAT reaction−cyclization process. A variety of
novel γ-spirolactams are prepared in good to excellent yields
with this method. This transformation features mild reaction
conditions and exceptional functional group tolerance. Additionally, γ-terpinene is applied to this transformation as a hydrogen
atom donor for the first time.
s a conformationally rigid scaffold, N-containing spirocy-
bonds via visible-light photoredox catalysis.7 The heteroatom
radical-based 1,5-H atom transfer reaction has been shown as a
reliable and highly selective process in these reactions, and is
therefore a powerful technique to perform the functionalization
of unactivated C(sp3)−H bonds under mild conditions.
However, compared with heteroatom radicals, carbon radicals
have still remained largely unexplored under the visible-light
photocatalysis. On the basis of our previous work,8 and as
shown in Scheme 1a, we have achieved the intramolecular 1,5-
A
clic compounds play an important role in medicinal and
pharmaceutical sciences.1 In particular, γ-spirolactam and spiro-
pyrrolidine structures have been frequently found in
pharmaceutical products and biologically active molecules.2−6
A few selected examples are shown in Figure 1. Atiprimod
Scheme 1. Different Reactions for the Aryl Halides
Figure 1. Pharmaceuticals and bioactive molecules containing
spiropyrrolidine and spiropyrrolidone scaffolds.
(SK&F-106615), an orally bioavailable cationic amphiphilic
molecule, is an effective anti-inflammatory and anticancer
agent;3 Spirapril is a potent antihypertensive agent that can
significantly reduce blood pressure;4 Spiro-carboxamide com-
pound B has been identified as a powerful and selective
inhibitor of 11β-hydroxysteroid dehydrogenase type 1 (11β-
HSD1);5 Compound D containing the γ-spirolactam scaffold
exhibits HIV-protease inhibitory activity.6 As an essential
structural element, a γ-spirolactam can be easily reduced into
a spiro-pyrrolidine. Therefore, the efficient synthesis of γ-
spirolactams is still highly desirable in contemporary organic
chemistry.
H transfer reaction of o-anilide aryl iodides for the synthesis of
oxindole derivatives. To widen the application of this radical
transformation process further, we applied this strategy to the
synthesis of γ-spirolactams. To achieve this goal, the major
challenge to address is how to avoid the reductive cyclization
process,9 as shown in Scheme 1b.
Inspired by the traditional methods,10 we started to apply
this 1,5-HAT process to synthesize complex molecules via
During the past three years, intramolecular 1,5-H atom
transfer (HAT) processes mediated by O-, and N-centered
radicals have been applied to the functionalization of C−H
Received: March 5, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
visible light photoredox catalysis. To construct the γ-
spirolactam skeleton, we initially examined the reaction of the
N-allyl-N-(2-iodophenyl)cyclohexanecarboxamide (1a) at 25
°C in the presence of 1 mol % of commercially available
photocatalyst Ir(ppy)3; the reductant iPr2NEt,9,11c,20 under
irradiation with blue LEDs, and the desired γ-spirolactam
product 2a was obtained in a yield of 62% (Table 1, entry 1).
required, as demonstrated by the control experiments (entries
16 and 17).
Having identified the optimal reaction conditions for
synthesis of spirocyclic γ-lactams, we next sought to examine
the scope of the aryl iodide precursor. As shown in Scheme 2, a
a b
,
Scheme 2. Scope of the Substrate: 5-exo-trig Cyclization
Table 1. Screening of the Reaction Conditions for the
a b
,
Synthesis of γ-Spirolactams 2a
yield
(%)
entry
photocatalyst
Ir(ppy)3
solvent
reductant
time
1
2
acetone iPr2NEt
acetone iPr2NEt
18 h
36 h
62
58
Ir(ppy)2(dtbbpy)
PF6
3
Ru(bpy)3(PF6)2
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
Ir(ppy)3
acetone iPr2NEt
36 h
12 h
12 h
36 h
7 d
0
4
MeCN
DMF
iPr2NEt
iPr2NEt
46
66
59
62
41
37
65
57
53
70
80
55
5
6
CH2Cl2 iPr2NEt
7
THF
iPr2NEt
iPr2NEt
iPr2NEt
Et3N
8
DMSO
MeOH
DMF
DMF
DMF
DMF
DMF
DMF
12 h
60 h
18 h
90 h
90 h
84 h
90 h
90 h
9
10
11
12
13
14
15
DBU
ascorbic acid
1,4-CHD
γ-terpinene
a
Unless otherwise noted, reaction conditions are as follows: 1 (0.2
mmol), Ir(ppy)3 (0.002 mmol), γ-terpinene (1.0 mmol), DMF (4
mL), blue LEDs, 25 °C, and under a N2 atmosphere with a reaction
γ-terpinene/
iPr2NEt (1/1)
b
c
d
time of 90 h. Isolated yield. Reaction time of 96 h. Reaction time of
108 h.
16
−
DMF
DMF
γ-terpinene
γ-terpinene
90 h
90 h
0
0
c
17
Ir(ppy)3
a
Unless otherwise noted, reaction conditions are as follows: 1a (0.2
mmol), photocatalyst (0.002 mmol), reductant (1.0 mmol), solvent (4
range of substituted o-anilide aryl iodides reacted very well in
this radical transformation protocol. Generally, the o-anilide
aryl iodides with electron-donating groups at the C4 position
gave better results under the conditions than those with the
electron-withdrawing ones (2b−2j). Notably, the substrate
with a methoxyl group in the aromatic ring gave the best yield,
while the substrate with a methyl or methoxy group at the C5
position only gave a 65% or 71% yield (2k−2l). The starting
materials possessing various cycloalkyl groups at the α-position
of the amide also delivered the corresponding γ-spirolactams in
modest to excellent yield (2m−2p). Particularly, N-(o-
iodophenyl)-alkylamides with an oxygen atom, a tert-butylox-
ycarbonyl-protected amine or a double bond in the alkyl group
could also be smoothly converted into the corresponding target
products (2q−2s). The product 2r might be unstable in the
presence of HI. The γ-spirolactam compound 2 resulted from
1,5-HAT followed by the 5-exo-trig radical cyclization onto the
allyl double bond. We next sought to investigate the influence
of the olefin component on the cyclization process of this
reaction. A range of di- and trisubstituted alkenes with different
substitution patterns was found to be tolerated (2t−2v).
However, substrates 1t and 1u required longer reaction times
to be converted into the corresponding products (2t and 2u).
In addition, we also realized the construction of contiguous
quaternary carbon centers through visible light photocatalysis
(2v−2y). Furthermore, an acyclic amide substrate was also
b
mL), blue LEDs, 25 °C, and under a N2 atmosphere. Isolated yield.
c
In the dark. 1,4-CHD: 1,4-cyclohexadiene.
When Ir(ppy)2(dtbbpy)PF6 was used as the photocatalyst, the
yield of the product was decreased to 58% (entry 2). However,
substrate 1a did not react to afford the product when
Ru(bpy)3(PF6)2 was used as the catalyst, which was consistent
+
with literature reports that the reduced species Ru(bpy)3
11
+
(E1/2[Ru(ppy)32+/Ru(ppy)3 ] = −1.33 V vs SCE) could not
reduce the unactivated aryl iodide (E1/2red = −1.59 V vs SCE for
iodobenzene).12 A survey of solvents revealed that DMF was
the optimal reaction medium (entries 4−9). The choice of
reductant was also found to have a significant influence on the
reaction yield. When triethylamine,13 ascorbic acid14a or
DBU14b was selected as the reductant, the yield of the product
2a was decreased (entries 10−12). Fortunately, inspiring
improvement of the reaction yield was observed when 1,4-
cyclohexadiene (1,4-CHD)15 was used, instead of iPr2NEt
(entry 13). Finally, the commercially available reagent γ-
terpinene, which has the similar structure to 1,4-CHD, was
found to provide the best yield (entry 14). When i-Pr2NEt and
γ-terpinene were both used as the reductants, the yield of 2a
was decreased to 55% (entry 15). The desired product 2a was
always accompanied by a trace of the byproduct (entries 1−
15). Lastly, both the light source and the photocatalyst were
B
DOI: 10.1021/acs.orglett.8b00731
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Organic Letters
Letter
transformed into the γ-lactam compound (2z) in an excellent
92% yield.
Scheme 4. Further Applications
Similarly, the 5-exo-dig ring-closing reaction was also
investigated under the same reaction conditions. A series of
4-methylenepyrrolidones (Scheme 3, products 3a−3g, 38−73%
a b
,
Scheme 3. Scope of the Substrate: 5-exo-dig Cyclization
a
Unless otherwise noted, reaction conditions are as follows: 1′ (0.2
mmol), Ir(ppy)3 (0.002 mmol), γ-terpinene (1.0 mmol), DMF (4
mL), blue LEDs, 25 °C, and under a N2 atmosphere with a reaction
b
time of 90 h. Isolated yield.
yield) have been synthesized by using this 5-exo-dig radical
cyclization reaction as the critical step. These products bearing
a double bond could be readily functionalized and applied to
complex molecular synthesis.16
To confirm the practicability of this tandem process, a scale-
up experiment was carried out, which afforded the correspond-
ing γ-spirolactam 2a in good yield (Scheme 4a). As mentioned
before, the spiro-pyrrolidine moiety is also commonly found in
the structures of pharmaceutical products and biologically
active molecules. Treatment of 2a under reducing conditions17
afforded the spiro-pyrrolidine product 4a in 84% yield after 1 h
(Scheme 4b). Under similar reaction conditions, a bridged
compound 4s was synthesized from the reactant 1s with a
modest yield. A similar bridged compound could also be found
in the transformation of 1x. The removal of the p-
methoxyphenyl group was investigated by using ceric
ammonium nitrate (CAN) as the stoichiometric oxidant.
Additional modification of 4i afforded 6i, an analogue of the
11β-HSD1 inhibitor (Scheme 4d).10c,18 Further analysis
demonstrated that the product 6i had an anti/syn rotamer
population of 1:1.
Figure 2. Proposed mechanism.
Control experiments demonstrated that both the visible light
and the photocatalyst were essential components for this
tandem 1,5-H atom abstraction/cyclization process. On the
cyclization occurs to provide the spiro structure 9, which
undergoes H atom abstraction from γ-terpinene to generate the
desired product 2a and the cyclohexadienyl radical 13.15
basis of these results, as well as our previous work,8,19
a
plausible reaction mechanism is depicted in Figure 2.
Irradiation of the photoredox catalyst Ir(ppy)3 (10) with
visible light generates a photoexcited state, *Ir(ppy)3 (11),
which is quenched by the unactivated aryl iodide 1a with
+
Finally, the oxidized Ir(ppy)3 (12) can be reduced to the
ground state by species 13, which completes the photoredox
catalytic cycle. By the way, cyclohexadienyl cation 14 formed in
the process could be easily converted into p-cymeme, which
could be detected by GC-MS. The “I” atom would convert into
HI.
In summary, we have developed a photocatalytic method for
the synthesis of γ-spirolactams through a tandem intra-
molecular 1,5-HAT reaction-cyclization process. A variety of
novel γ-spirolactams were prepared from o-anilide aryl iodides
+
generation of the oxidized Ir(ppy)3 (12) and the highly
activated σ-radical 7.20 The rate constant for 1,5-HAT from a
secondary C−H bond is >5 × 108 s−l which is faster than most
of the radical ring-closure reactions, and the 1,5-HAT becomes
even faster for tertiary C−H bonds.21 Radical 7 undergoes an
intramolecular 1,5-HAT process to produce the stabilized
tertiary carbon radical 8. Then, a 5-exo-trig radical-alkene
C
DOI: 10.1021/acs.orglett.8b00731
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xupf@lzu.edu.cn.
ORCID
Yong-Chun Luo: 0000-0002-9567-7297
Peng-Fei Xu: 0000-0002-5746-758X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSFC (21632003 and 21572087), the
Key program of Gansu province (17ZD2GC011) and the “111”
program from the MOE of PR China for financial support.
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DOI: 10.1021/acs.orglett.8b00731
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