Fe(III)-Catalyzed Hydroallylation of Unactivated Alkenes with Morita-Baylis-Hillman Adducts

Article abstract of DOI:10.1021/acs.orglett.8b00108

An Fe(III)-catalyzed hydroallylation of unactivated alkenes with Morita-Baylis-Hillman adducts via an Fe-catalyzed process is described. A variety of alkenes, including mono-, di-, and trisubstituted alkenes, could all smoothly convert to structural diver

Full text of DOI:10.1021/acs.orglett.8b00108

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Fe(III)-Catalyzed Hydroallylation of Unactivated Alkenes with
Morita−Baylis−Hillman Adducts
Jifeng Qi,† Jing Zheng,† and Sunliang Cui*,†,‡
†Institute of Drug Discovery and Design, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou
310058, Zhejiang, China
‡State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: An Fe(III)-catalyzed hydroallylation of unacti-
vated alkenes with Morita−Baylis−Hillman adducts via an Fe-
catalyzed process is described. A variety of alkenes, including
mono-, di-, and trisubstituted alkenes, could all smoothly convert
to structural diversified cinnamates in this protocol. Interestingly,
when the hydroxyl-containing alkenes were used, various
lactones could be rapidly assembled. Moreover, this protocol
could be applied to late-stage functionalization of natural
products.
Scheme 1. Hydroallylation of Unactivated Alkenes
lkenes are readily available fundamental feedstock in
Aacademia and industry. Therefore, the functionalization of
alkenes for access to structural differential molecules has
become an interesting and challenging task in organic
synthesis.1 Among these, the transition-metal-catalyzed hydro-
functionalization of unactivated alkenes has grown as a
powerful approach for C−C and C−X (N, O, F, Cl) bond
formation toward the construction of diverse molecules.2 For
example, Halpern first revealed the convincing evidence of
radical mechanism for Mn(III)-catalyzed hydrogenation of α-
methylstyrene and found that hydrogen atom transfer (HAT)
was involved in the process.3 Recently, Shenvi elucidated the
HAT mechanism more clearly and applied this to synergistic
catalysis.4 In addition, Mukaiyama,5 Carreira,6 Baran,7 Boger,8
and Herzon9 have also made great progress in this area with the
achievement of practical and efficient alkene transformation. In
those hydrofunctionalization processes, the silanes were used as
reductants and the alkyl radical intermediates were in situ
generated. On the other hand, Buchwald and co-workers have
established Cu-catalyzed unactivated alkenes hydrofunctional-
ization with good enantioselectivity and regioselectivity.10 In
contrast, these processes invoked alkyl-copper species rather
than the radical intermediates.11 Despite these advances, the
hydrofunctionalization of unactivated alkenes toward C−C
bond formation remains continuous interesting.
Typically, the hydroallylation of unactivated alkenes
represents a carbon chain prolonging approach and demon-
strates valuable synthetic utility. For example, Renaud reported
an anti-Markovnikov hydroallylation of unactivated alkenes
(Scheme 1A).12 In this protocol, the alkenes undergo
hydroboration to be organoboranes and then transfer to alkyl
radicals which are sequentially trapped by allyl sulfones to
constitute hydroallylation process.13 Buchwald established an
elegant work of Cu-catalyzed enantioselective hydroallylation of
vinylarenes with allylic phosphates (Scheme 1B).10d More
recently, Yun also applied this to constitute hydroallylation of
borylalkenes (Scheme 1C).14 By contrast, the hydroallylation
especially the hydro(cinnamyl)methylation of unactivated
Received: January 10, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
alkenes receives much less attention. In the course of our
research on alkene hydrofunctionalization,15 we hypothesized
that this could be realized by combination of HAT with suitable
cinnamylmethylation reagents. Herein, we report an Fe(III)-
catalyzed hydroallylation of unactivated alkenes with Morita−
Baylis−Hillman adducts (Scheme 1D).
Table 2. Scope of Alkenes
We commenced our study by using alkene 1a as a model
substrate and the Morita−Baylis−Hillman adduct 2a as
cinnamylation source.16 Morita−Baylis−Hillman adducts
could be easily accessed by the well-known Morita−Baylis−
Hillman reaction from aldehydes, thus exhibiting sufficient
structural diversity.17 Initially, we tested the reaction using 30
mol % Fe(acac)3 as catalyst and ethanol as solvent (Table 1,
a
Table 1. Reaction Optimization
b
entry
1
catalysis
silanes
solvent
T (°C)
yield (%)
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Fe(acac)3
Mn(acac)3
Co(acac)2
Ni(acac)2
PhSiH3
PhSiH3
PhSiH3
Et3SiH
EtOH
THF
THF
THF
THF
THF
THF
THF
THF
60
60
60
60
60
25
60
60
60
63
80
51
0
b
2
b
b
b
b
b
b
b
,c
3
4
5
6
7
8
9
(EtO)3SiH
PhSiH3
PhSiH3
PhSiH3
PhSiH3
43
19
61
0
0
a
Reaction conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (30 mol
%), silanes (1 equiv), solvent (2 mL), 2 h; yield refers to isolated
b
c
product. EtOH (2 equiv) was used as additive. Fe(acac)3 (10 mol %)
was used.
entry 1). To our delight, a new compound 3a was observed as
the main product. The standard identification showed that 3a
was a cinnamate compound, indicating a hydrocinnamylation
process was occurring. A NOESY experiment was carried out to
confirm that the phenyl ring and the ester group were
substituted as the E-form. When the solvent was changed to
THF and a 2 equiv amount of ethanol was used as additive, the
yield was significantly improved to 80% (entry 2). We also tried
to decrease the amount of Fe(acac)3 to 10 mol % and found the
yield was lower (entry 3). A survey of silanes was also
conducted, and Et3SiH was found to be inferior in shutting
down the reactivity (entry 4), while the utilization of
(EtO)3SiH led to a low yield (entry 5, 43%). In addition,
reducing the temperature to 25 °C also resulted in a lower yield
(entry 6). Moreover, various transition metals such as
Mn(acac)3, Co(acac)2, and Ni(acac)2 were also screened.
When the Mn(acac)3 was used, 3a was formed in 61% yield
(enrty 7). In contrast, the utilization of Co(acac)2 and
Ni(acac)2 did not afford any product (entries 8 and 9).
With the optimized reaction conditions in hand, we next set
out to explore the generality of this method (Table 2).
Therefore, a series of alkenes with significant structural
diversity, including mono-, di-, and trisubstituted alkenes,
were subjected to this process. For example, the 3-methylbut-3-
en-1-ol (1b) participated in the process smoothly to afford
cinnamate 3b in 75% yield. The terminal monosubstituted
alkenes, such as hex-5-en-1-ol (1c), allyl cyanide (1d), allyl
carboxamide (1e), benzyl pent-4-enoate (1f), N-Boc allyamine
(1g), allyl silane (1h), and 1-allyl-4-methoxybenzene (1i),
a
Reaction conditions: 1 (0.3 mmol), 2a (0.2 mmol), Fe(acac)3 (30
mol %), PhSiH3 (0.2 mmol), EtOH (0.4 mmol), THF (2 mL), 60 °C,
2 h; yields refer to isolated products.
engaged in this process to afford the products in moderate to
good yields (3b−i) and therefore offer ample opportunity for
further functionalization. The piperidine-functionalized alkene
1j, a type of disubstituted terminal alkene, proceeded well in
this process to deliver the cinnamyl piperidine 3j in good yield.
With respect to disubstituted internal alkenes, the cyclic N-Boc-
2,5-dihydro-1H-pyrrole 1k and dihydropyran 1l were well
amenable to this protocol to furnish the products in good
yields. Notably, the hydrocinnamylation of dihydropyran 1l
regioselectively occurred at the 2-position. The trisubstituted
alkene-like cyclohexene tethered amine 1m was also applied to
this protocol to furnish the cinnamate 3m in moderate yield.
Furthermore, this protocol could be applied to late-stage
functionalization of natural products and their derivatives. For
example, the (S)-citronellol (1n) could be easily accessed to its
cinnamate derivative 3n upon use of this method. Meanwhile,
the estrone analogue 1o could couple with Morita−Baylis−
Hillman adduct 2a to deliver a single diastereomer 3o, albeit in
a slightly low yield. Therefore, this method provides a simple
B
DOI: 10.1021/acs.orglett.8b00108
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
and distinct approach for alkenes transformation and late-stage
functionalization of natural products.
Table 3. Scope of Lactones
Next, the scope of Morita−Baylis−Hillman adducts was also
investigated. As depicted in Scheme 2, a series of para-
a
Scheme 2. Scope of Morita−Baylis−Hillman Adducts
a
a
Reaction conditions: 1 (0.3 mmol), 2 (0.2 mmol), Fe(acac)3 (30 mol
%), PhSiH3 (0.2 mmol), EtOH (0.4 mmol), THF (2 mL), 60 °C, 6 h;
Reaction conditions: 1a (0.3 mmol), 2 (0.2 mmol), Fe(acac)3 (30
mol %), PhSiH3 (0.2 mmol), EtOH (0.4 mmol), THF (2 mL), 60 °C,
2 h; yields refer to isolated products.
b
yields refer to isolated products. Reaction was conducted for 6 h, then
TsOH−H2O (10 mol %) was added and the mixture refluxed for 1 h.
substituted Morita−Baylis−Hillman adducts 2, regardless of the
electron-donating or electron-withdrawing substitution, were
subjected to this process and found well applicable. For
example, groups like methyl, methoxy, fluoro, chloro, bromo,
trifluoromethyl, and ester were tolerated in this hydro-
cinnamylation process and did not show significant effects in
the yields. The o-chloro-substituted Morita−Baylis−Hillman
adduct 2h was also employed to furnish the product 4g in
moderate yields. On the other hand, the 3-Cl- and 3-CF3-
substituted adducts 2i and 2j could undergo the hydroallylation
smoothly. Moreover, the 2-naphthyl- and the 2-phenylethyl-
substituted adducts were also amenable in this process.
Considering the ready availability of Morita−Baylis−Hillman
adducts 2, this protocol provides a simple and direct access to
functionalized cinnamates with the achievement of structural
diversity and molecule complexity (Scheme 3).18
tion process with various Morita−Baylis−Hillman adducts
upon standard conditions. This lactonization could afford the
styrene-tethered six-membered lactones 5a−e in good yields.
The structure of 5c was unambiguously confirmed by X-ray
analysis. Meanwhile, the allyl alcohol 1q and (Z)-but-2-ene-1,4-
diol 1r were amenable in this process to deliver the
functionalized lactones. Interestingly, when the cyclohex-1-en-
1-ylmethanol 1s was utilized, a spiro lactone 5h could be
formed in 42% yields. Additionally, the 3-methylbut-3-en-1-ol
1t was also found to be well applicable in this lactonization
process to deliver the seven-membered oxepan-2-one 5i in
good yield when treated with 10 mol % of p-TsOH as additive.
Thus, this method could be successfully applied to rapid
assembly of lactones from easily available starting materials in a
one-pot fashion.
On the basis of the results and literature reports,5−9,15,16
a
At this point, we hypothesized that the hydrocinnamylation
could be applied to a cascade lactonization for the hydroxyl-
containing alkenes (Table 3). For example, the 2-methylallyl
alcohol 1p could engage in the hydrocinnamylation/lactoniza-
plausible reaction mechanism is proposed in Scheme 4. At the
beginning, the Fe(III) catalyst is converted to Fe hydride
species A in the presence of phenylsilane and ethanol. Then A
undergoes HAT to alkene 2 to give alkyl radical B and Fe(II)
C, and B was trapped by Morita−Baylis−Hillman adducts 2 to
furnish intermediate D. The next single-electron transfer (SET)
between C and D delivers anionic E, followed by an elimination
to produce the cinnamates 3 or 4. When the alkenes contain a
hydroxyl group, a cascade intramolecular lactonization would
occur to deliver the lactones.
Scheme 3. Representative Pharmaceuticals of Cinnamates
In summary, a general and efficient Fe(III)-catalyzed
hydroallylation of unactivated alkenes has been developed.
The protocol features mild reaction conditions, broad substrate
C
DOI: 10.1021/acs.orglett.8b00108
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.8b00108.
Full experimental procedures and spectra data (PDF)
Accession Codes
CCDC 1582722 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
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13130.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: slcui@zju.edu.cn.
ORCID
Sunliang Cui: 0000-0001-9407-5190
Notes
(14) Han, J. T.; Jang, W. J.; Kim, N.; Yun, J. J. Am. Chem. Soc. 2016,
138, 15146.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We are grateful for the financial support from National Natural
Science Foundation of China (No. 21472163).
■
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DOI: 10.1021/acs.orglett.8b00108
Org. Lett. XXXX, XXX, XXX−XXX