Iron-Catalyzed Oxyalkylation of Terminal Alkynes with Alkyl Iodides

Article abstract of DOI:10.1021/acs.orglett.8b03689

A general oxyalkylation of terminal alkynes enabled by iron catalysis has been developed. Primary and secondary alkyl iodides acted as the alkylating reagents and afforded a range of α-alkylated ketones under mild reaction conditions. Acetyl tert-butyl peroxide (TBPA) was used as the radical relay precursor, providing the initiated methyl radical to start the radical relay process. Preliminary mechanistic studies were conducted, and late-stage functionalizations of natural product derivatives were performed.

Full text of DOI:10.1021/acs.orglett.8b03689

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iron-Catalyzed Oxyalkylation of Terminal Alkynes with Alkyl Iodides
Weili Deng,† Changqing Ye,‡ Yajun Li,‡ Daliang Li,*,† and Hongli Bao*,‡
†Key Laboratory of Innate Immune Biology of Fujian Province, Biomedical Research Center of South China, College of Life
Sciences, Fujian Normal University, 1 Keji Road, Fuzhou 350117, P. R. China
‡Key Laboratory of Coal to Ethylene Glycol and Its Related Technology, State Key Laboratory of Structural Chemistry, Center for
Excellence in Molecular Synthesis, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, 155
Yangqiao Road West, Fuzhou, Fujian 350002, P. R. of China
S
* Supporting Information
ABSTRACT: A general oxyalkylation of terminal alkynes
enabled by iron catalysis has been developed. Primary and
secondary alkyl iodides acted as the alkylating reagents and
afforded a range of α-alkylated ketones under mild reaction
conditions. Acetyl tert-butyl peroxide (TBPA) was used as the
radical relay precursor, providing the initiated methyl radical
to start the radical relay process. Preliminary mechanistic studies were conducted, and late-stage functionalizations of natural
product derivatives were performed.
arnessing free radical as the driving force for chemical
transformations has offered a remarkable alternative
besides classical synthetic methodologies. The formation of
free radical under mild reaction conditions has led to
impressive developments for bond formation, such as C−C
bond, C−O bond, and C−N bond.1
using high-valent iodine reagent NFSI (N-fluorobenzenesul-
fonmide) as an oxidative radical relay precursor.3c
H
Oxyfunctionalization of alkynes is an ideal strategy to
produce α-functionalized ketones, which can serve as core
structures in pharmaceuticals, bioactive natural products, and
functional materials.13 Several successful methods to synthesize
α-functionalized ketones from alkynes in a radical relay fashion
have been developed by Lei, Lipshutz, He, Ni, Maiti, Tang, and
others (Scheme 1a).14 Functionalities such as aryl, trifluor-
Radical relay is a useful strategy that employs a precursor to
generate a new radical species, with more general and useful
functionalities from readily available chemicals via a relay
process.2 Many efforts have been dedicated to developing
methods for new bond formation enabled by radical relay
process.3 To date, two types of radical relay precursors,
nonoxidative4 and oxidative radical relay precursors,5 have
been published. AIBN,6 Bu3SnH, BEt3/O2,7 silylated cyclo-
hexadienes,8 catechol/Et3B,9 and some inorganic compounds
like ZnCl2 and SmI2 are frequently used as nonoxidative radical
relay initiators. These initiators are useful for chain reactions or
reductive reactions, but not for oxidative reactions. Recently, as a
complement to reductive radical relays, oxidative radical relay
processes have been developed with oxygen radicals10 and
nitrogen radicals11 but rarely with carbon radicals. The main
obstacles to utilizing a carbon radical to initiate an oxidative
radical relay include the lack of convenient methods to
generate carbon radicals under mild and oxidative conditions
and the undesirable carbon radical side reactions.12 Despite the
difficulties, a carbon radical-initiated oxidative relay is
potentially useful because carbon radicals are able to break
not only C−H bonds but also C−X (halogen) bonds to
generate more versatile radicals from more broadly varied
substrate types, which would be impossible with an oxygen or
nitrogen radical. Recently, the Studer group discovered that
TBAI (tetra-n-butylammonium iodide) can be used as a
nonoxidative radical relay precursor for electron catalysis.3b
And Liu group reported an elegant method for copper-
catalyzed enantioselective cyanation of benzylic C−H bonds,
Scheme 1. Radical Oxy-functionalization of Terminal
Alkynes
omethyl, sulfonyl, and phosphoryl groups can be incorporated.
However, approaches for the introduction of generic alkyl
functionalities in a radical relay process are still rare.
Recently, we reported an iron-catalyzed oxyalkylation of
terminal alkynes with alkyl peroxides via a radical decarbox-
ylation.15 Alkyl halides are a kind of important chemical
feedstock in organic chemistry in terms of their extensive
application.16 Very recently, in the presence of t-butyl
perbenzoate (TBPB), an oxidative radical relay precursor, an
iron-catalyzed carboazidation of alkenes and alkynes with alkyl
Received: November 19, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03689
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
iodides has been successfully developed by our group.17 Thus,
we wondered whether alkyl iodides could serve as the readily
available alkyl source for the alkylation of alkynes to afford α-
alkylated ketones in the presence of an oxidative radical relay
precursor.18 Herein, we report our latest study on iron-
catalyzed oxyalkylation of terminal alkynes via radical relay
reaction using alkyl iodides as the alkylating reagents (Scheme
1b).
In order to test the activities of different alkyl peroxides and
to find a solution for the above key issue, the initiation reaction
was carried out with commercially available 4-ethynyltoluene
(1a), 2-iodobutane (2a), and different alkyl peroxides (3). As
shown in Table 1, although initiators such as TBHP, DTBP,
yield, TBPA (3g, acetyl tert-butyl peroxide) offered a better
yield as high as 72% (Table 1, entries 6 and 7). The results
implied that the methyl radical generated from the alkyl
perester might be the best initiated radical, which is reactive
enough to abstract the iodine atom from the alkyl iodide and
immune to alkyne. We need to mention that AIBN did not
show performance for this radical relay process (Table 1, entry
8). In addition, the influence of the reaction temperature was
investigated, and 60 °C was proven to be optimal (Table 1,
entries 9 and 10). We speculated that the performance of the
radical relay reaction could be enhanced by raising the loading
of the iron catalyst. But the yield of 4aa dropped to 49% with
15 mol % of Fe(OTf)3 (Table 1, entry 11). A low yield was
obtained with 5 mol % of Fe(OTf)3 and only 18% yield was
obtained when no iron metal was used (Table 1, entries 12 and
13). Without TfOH, the yield of 4aa decreased to 46% (Table
1, entry 14). Delightfully, when the first step for the alkylation
was performed at rt, the highest yield was obtained at 80%.
When the amount of the initiator was reduced, the yield of the
desired product dropped dramatically (Table 1, entries 16 and
17), and the reaction failed to produce 4aa without any
initiator (Table 1, entry 18).
a
Table 1. Optimization of the Reaction Conditions
With the identified reaction conditions in hand, the substrate
scope was screened (Scheme 2). With the assistance of TBPA
and TfOH, various aryl alkynes were able to undergo the
reaction and coupled with 2-iodobutane to afford the
corresponding oxyalkylation products. The aryl alkynes with
an electron-donating group on the benzene ring offered the
b
entry
initiator
yield (%)
1
2
3
4
5
6
7
8
TBHP
DTBP
DCP
BPO
LPO
trace
trace
trace
trace
62
47
72
trace
58
62
a,b
Scheme 2. Substrate Scope of the Aryl Alkynes
TBPB
TBPA
AIBN
TBPA
TBPA
TBPA
TBPA
TBPA
TBPA
TBPA
TBPA
TBPA
none
c
9
d
10
e
11
49
56
18
46
f
12
g
13
h
14
i
15
80
37
k
ij
16 ,
k
il
17 ,
8
0
im
18 ,
a
Reaction conditions: 1a (0.5 mmol), 2a (1.5 mmol), Fe(OTf)3 (10
mol %), and initiator (1.5 mmol) in DME (2 mL) at 60 °C for 2 h
under nitrogen atmosphere. Then TfOH (1.0 mmol) was added and
b
stirred at 60 °C for another 10 h under nitrogen atmosphere. Yield of
c
d
the isolated product. The reaction temperature was 80 °C. The
e
f
reaction temperature was 40 °C. Fe(OTf)3 (15 mol %). Fe(OTf)3
(5 mol %). Without Fe(OTf)3. Without TfOH. 24 h at rt for the
first step. Initiator (0.5 mmol). GC yield. Initiator (0.25 mmol).
g
h
i
j
k
l
m
Without initiator.
and DCP could trigger the reaction, the reaction was messy
and only a trace amount of the desired product was observed
(Table 1, entries 1−3). Then, BPO was examined in the
reaction as the initiator. Almost no desired product 4aa was
observed (Table 1, entry 4). To our delight, LPO (3e, lauroyl
peroxide) afforded the desired product 4aa in 62% yield
(Table 1, entry 5). Other alkyl peroxides were also screened.
While perester 3f delivered the desired product 4aa in 47%
a
Reaction conditions: 1 (0.5 mmol), 2a (1.5 mmol), Fe(OTf)3 (10
mol %), and TBPA (1.5 mmol) in DME (2 mL) at rt for 24 h under
nitrogen atmosphere. Then TfOH (1.0 mmol) was added and stirred
b
c
for another 10 h at 60 °C. Yield of the isolated product. 100 °C
instead of 60 °C. 120 °C instead of 60 °C.
d
B
DOI: 10.1021/acs.orglett.8b03689
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Letter
corresponding products (4aa−4ia) with good to high yields.
Interestingly, the yield slightly decreased when a methoxy was
attached on the benzene ring of the aryl alkynes (4ja−4la).
Reactions of halogen substituent aryl alkynes afforded the
corresponding products (4na−4pa) in relatively low efficiency
with elevated temperature. Furthermore, heteroaryl alkynes
such as thienyl alkynes could survive and offered the
corresponding products 4qa and 4ra in 71% and 57% yields,
respectively. However, terminal alkyl alkynes and internal
alkynes, such as prop-2-yn-1-ylbenzene, oct-1-yne, but-3-yn-2-
one, and non-2-yne, failed to afford the corresponding
products.
Scheme 4. Functionalization of Natural Product Derivatives
Next, we examined the substrate scope for alkyl iodides,
which are commercially available or could be easily synthesized
according to reported methods (see the Supporting
Information for details). Primary alkyl iodides as well as
secondary alkyl iodides provided the corresponding products
in moderate yields (Scheme 3, 4ab−4ah). The chloro
a,b
Scheme 3. Substrate Scope of the Alkyl Iodides
desired product 4aa was detected. The methylated TEMPO
product (5a) and sec-butylated TEMPO product (5b) could be
observed by GC-MS analysis (Scheme 5). This result supports
the proposed radical relay process.
Scheme 5. Fundamental Mechanistic Study
a
Reaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), Fe(OTf)3 (10
mol %), and TBPA (1.5 mmol) in DME (2 mL) at rt for 24 h under
nitrogen atmosphere. Then TfOH (1.0 mmol) was added and stirred
b
c
for another 10 h at 60 °C. Yield of the isolated product. 100 °C
instead of 60 °C.
substituent was tolerated under the reaction conditions, and
corresponding product 4ai was obtained in 64% yield.
Interestingly, fluorinated alkyl iodides could also be used as
the reaction substrates and delivered the corresponding
products 4aj and 4ak in 40% and 55% yields, respectively.
But, tertiary alkyl iodides, such as 2-iodo-2-methylpropane and
1-iodoadamantane, failed to afford the corresponding products.
To highlight the synthetic application, late stage function-
alizations of natural product derivatives were developed
(Scheme 4). Estrone derivative (1s) was smoothly transferred
into functionalized estrone (4sa) in moderate yield under the
standard reaction conditions (Scheme 4a). Catalyzed by
Fe(OTf)3 and with the assistance of TBPA, the coupling of
menthol derivative (2l), norborneol derivative (2m), and
lithocholic acid derivative (2n) with terminal alkyne (1a) gave
the corresponding ketone products 4al, 4am, and 4an,
respectively (Scheme 4b−d).
In view of the results of the mechanistic experiments, a
radical relay-involving catalytic cycle is proposed (Scheme 6).
A single electron transfer between Fe(II) and TBPA initiates
the reaction by generating a tert-butoxyl radical (A) and an
Scheme 6. Proposed Catalytic Cycle
In order to probe the mechanism of this reaction,
preliminary mechanistic study was conducted under the
standard reaction conditions. When radical scavenger
TEMPO was added, the reaction was prevented, and no
C
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Fe(III) species. The tert-butoxyl radical (A) then decomposed
to a methyl radical (B, trapped by TEMPO) and a molecular
of acetone. A radical relay process then occurs between the
methyl radical and alkyl iodide affording a new carbon radical
(C, trapped by TEMPO when C is a sec-butyl group) and
methyl iodide. This carbon radical adds to the terminal alkyne,
generating an internal vinyl radical (D). According to our
previous work,15 the radical D can deliver the final product and
regenerate Fe(II) species.
In conclusion, we have developed an efficient iron-catalyzed
oxyalkylation of terminal alkynes with alkyl iodides enabled by
a radical relay process. Primary and secondary alkyl iodides
could be utilized as alkyl sources to afford a range of α-
alkylated ketones under mild reaction conditions.
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.8b03689.
Typical experimental procedure and characterization of
products (PDF)
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AUTHOR INFORMATION
Corresponding Authors
■
*daliangli@fjnu.edu.cn
*hlbao@fjirsm.ac.cn
ORCID
Yajun Li: 0000-0001-6690-2662
Hongli Bao: 0000-0003-1030-5089
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Innovative Research Teams Program II of Fujian
Normal University in China (IRTL1703), the Natural Science
Foundation of Fujian Province, China (2016J0101), the
National Key R&D Program of China (2017YFA0700103),
the NSFC (Grant Nos. 21502191, 21672213, and 21871258),
the Strategic Priority Research Program of the Chinese
Academy of Sciences (Grant No. XDB20000000), and the
Haixi Institute of CAS (Grant No. CXZX-2017-P01) for
financial support.
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