Selective Dehydrogenative Acylation of Enamides with Aldehydes Leading to Valuable β-Ketoenamides

Article abstract of DOI:10.1021/acs.orglett.9b04495

We have presented a unique example of dehydrogenative acylation of enamides with aldehydes enabled by an earth-abundant iron catalyst. The protocol provides the straightforward access to valuable β-ketoenamides with ample substrate scope and excellent functional group tolerance. Notably, distinct C-H acylation of enamide rather than at N-H moiety site occurs with absolute Z-selectivity was observed. Late-stage modifications of complex molecules and versatile synthetic utility of β-ketoenamides further highlight the practicability of this transformation.

Full text of DOI:10.1021/acs.orglett.9b04495

pubs.acs.org/OrgLett
Letter
Selective Dehydrogenative Acylation of Enamides with Aldehydes
Leading to Valuable β‑Ketoenamides
Rui-Hua Liu, Zhen-Yao Shen, Cong Wang, Teck-Peng Loh, and Xu-Hong Hu*
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ABSTRACT: We have presented a unique example of dehydro-
genative acylation of enamides with aldehydes enabled by an earth-
abundant iron catalyst. The protocol provides the straightforward
access to valuable β-ketoenamides with ample substrate scope and
excellent functional group tolerance. Notably, distinct C−H
acylation of enamide rather than at N−H moiety site occurs with absolute Z-selectivity was observed. Late-stage modifications
of complex molecules and versatile synthetic utility of β-ketoenamides further highlight the practicability of this transformation.
riggered by the development of transition metal catalysis,
as well as new technologies emerging, free-radical species
Fortunately, the groups of Glorius8 and Lei9 independently
accomplished the oxidative coupling of two such simple
hydrocarbons to access chalcone derivatives (Scheme 1c).
However, the confined substrate scope of both protocols
largely impeded their synthetic applications. Therefore, the
development of a comparably effective and practical method
for acylation of olefins, which could lead to unsaturated ketone
scaffolds with high structural diversity and complexity together
with the on-demand derivatizations of target molecules, is
highly desirable and yet remains elusive.
Enamides, by incorporating amide functionalities into
olefins, have drawn considerable attention due to their
prominent versatility as synthons for the facile synthesis of
chiral amines and numerous nitrogen-based heterocycles.10
Over the past decade, tremendous efforts have been devoted to
developing direct C−H functionalization reactions of ema-
mides to install different functional groups with high levels of
selectivity control, which mainly relied on the use of
preactivated coupling partners or unsaturated systems to
form the heteroannulation products.11 In this regard, cross-
coupling of enamides with simple hydrocarbons undoubtedly
becomes more advantageous to enrich their molecular
functionalities considering atom economy and substrate
availability. Here, we wish to report a new reaction paradigm
in the coupling of enamides with aldehydes,12 which allows for
a rapid assembly of β-ketoenamides enabled by iron catalyst
(Scheme 1d). The reaction provides a direct and comple-
mentary method to existing methods which lack substrate
generality or require multistep approaches from common
feedstocks.13
T
have been recognized as reliable and controllable intermediates
in contemporary organic synthesis.1 Given that, radical-
mediated cross-coupling reactions have flourished over the
past decades to be a powerful tool for C−C bond formation.2
For instance, pioneered by Kharasch’s work,3 addition of
aldehydes, which behave as ideal acyl radical precursors, across
olefins offers an attractive opportunity for ketone synthesis
from atom-economic and environmental viewpoints.4 Despite
the longstanding investigations in this arena, we note that the
vast majority of these modular transformations often led to
hydroacylation5 (Scheme 1a) or difunctionalization adducts
(Scheme 1b).6 In contrast, dehydrogenative coupling of olefins
with aldehydes to prepare unsaturated ketones, via the cleavage
of 2-fold C(sp2)−H bonds,7 remains underrepresented to date.
Scheme 1. TM-Catalyzed Cross-Couplings of Olefins and
Aldehydes
Received: December 16, 2019
https://dx.doi.org/10.1021/acs.orglett.9b04495
© XXXX American Chemical Society
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A

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However, there are a number of fundamental challenges
associated with the designed transformation: (i) Oxidative
coupling of the aldehydic C−H bond with the N−H bond of
secondary enamides might occur prior to the expected olefinic
C−H bond owing to the intrinsic nucleophilicity of amide, in
which case the unwanted imide might be produced.14 (ii) The
inherent nucleophilic property of enamides would result in an
alternative reaction pattern through the nucleophilic addition
of such electron-rich olefins into carbonyls, thereby resulting in
the formation 1,3-aminoalcohol derivatives.15 (iii) A delete-
rious self-condensation of enamides under acidic conditions
should be circumvented in this event.16 (iv) Stereoselective
control in radical-mediated oxidative C−H functionalization of
acyclic enamides seemingly remains an intractable problem.17
With these considerations in mind, we sought to establish
the feasibility of dehydrogenative coupling between enamides
with aldehydes. Given the extensive utility of iron in C−H
bond oxidation reactions,18 we chose iron salt to realize this
challenging reaction. Both readily accessible coupling partners,
N-(1-phenylvinyl)acetamide 1a and benzaldehyde 2a, were
selected as the model substrates (Table 1). A comprehensive
formation (entry 11). Among a number of common bases
tested (see the Table S1 in the Supporting Information),
KOAc proved to be the optimal choice, though other inorganic
bases, such as K2CO3 and K3PO4, gave comparable results.
Furthermore, screening of the solvents revealed that PhCl was
superior to other mediums including 1,2-dichloroethane,
CH3CN, toluene, etc. (see the Table S2 in the Supporting
Information). When a lesser amount of benzaldehyde 2a was
used or the reaction temperature was lowered to 70 °C, the
acylation product was still produced in 67% and 69% yields,
respectively (entries 12 and 13).
The scope of aldehydes for the coupling with 1a was first
investigated under the optimal reaction conditions. As shown
in Scheme 2, both aromatic and aliphatic aldehydes underwent
C−H acylation smoothly to yield the desired β-ketoenamides
in an exclusive Z-selective fashion. A scale-up synthesis of 3a
was performed with a slightly reduced yield, thus validating the
fidelity of this newly developed protocol. Benzaldehydes
decorated with a wide range of functional groups at the
different positions, such as halides (3b−g), cyano (3h),
trifluoromethyl (3i), ester (3j), methyl (3k and 3l), phenyl
(3m), ether (3n−p), pinacol boronic ester (3q), and alkynyl
(3r), participated in the coupling to afford the products in
moderate to good yields (41−78%). We noticed that p-
anisaldehyde showed lower reactivity even by employing an
increased catalyst loading and extending the reaction time,
compared to electron-deficient substrates (3n). The observa-
tion can be rationalized considering the electrophilic nature of
acyl radicals in the process, which implicates that the
introduction of an electron-donating group onto the phenyl
ring is detrimental for radical species to undergo olefin
addition. In addition, the reaction turned out to be sensitive to
the steric hindrance, for which o-chlorobenzaldehyde gave only
a 41% yield of 3g. Naphthaldehyde is suitable for the coupling,
providing 3s in 63% yield. Analogously, heteroaromatic
aldehydes of biological relevance were then evaluated and, to
our satisfaction, were found to be compatible with this catalytic
system, which allowed for the installation of thienyl, furyl, and
indolyl moieties (3t−v) without difficulty. Remarkably, the
protocol is not restricted to aromatic substrates and the use of
less reactive aliphatic aldehydes also led to the corresponding
products in acceptable yields, further demonstrating the
generality of the transformation. Alternate alkyl substituents
with different chain lengths including n-hexyl, n-pentyl, 2-
phenylethyl, and cyclohexyl groups were readily accommo-
dated (3w−z), where no detectable byproducts coming from
unwanted decarbonylation of the acyl radicals were observ-
ed.4a,19 Similarly, citronellal could also act as a viable acylating
reagent to give the corresponding product 3aa in 44% yield
under a slightly modified reaction conditions. Finally, the
promising functional group tolerance with this protocol
prompts us to apply this methodology to the late-stage
modification of complex molecules. In the cases of natural
product-derived benzoates, derivatives of L-menthol, diac-
etone-D-glucose, pregnenolone, and dehydroepiandrosterone
could be readily accommodated under the standard conditions
to afford the target products (3ab−ae) in moderate yields. In
view of these positive results, we anticipate that our strategy
could expand the synthetic utility in future medicinal studies.
Next, we examined the reactivity of the enamides with
benzaldehyde (2a) as the acylating reagent (Scheme 3). We
were pleased to see that various aromatic enamides possessing
electronically and sterically diverse functionalities reacted well
a
Table 1. Optimization of the Reaction Conditions
b
entry
variation from the standard conditions
yield (%)
1
2
3
4
5
6
7
8
none
76
<5
16
7
12
29
9
n.d.
n.d.
41
57
67
69
FeBr2 instead of FeCl2
Fe(OTf)2 instead of FeCl2
FeCl3 instead of FeCl2
CuCl2 instead of FeCl2
CuCl instead of FeCl2
MnCl2 instead of FeCl2
DDQ instead of DTBP
BPO instead of DTBP
TBHP instead of DTBP
w/o KOAc
9
10
11
12
13
1.5 equiv of 2a
70 °C instead of 80 °C
a
Unless otherwise noted, all reactions were conducted with 1a (0.2
mmol), 2a (2.0 equiv), FeCl2 (15 mol %), DTBP (5.0 equiv), and
KOAc (30 mol %) in PhCl (0.8 mL) under N2 at 80 °C for 8 h.
b
Isolated yield. n.d. = not detected, BPO = dibenzoyl peroxide, TBHP
= tert-butyl hydroperoxide.
survey of the reaction parameters uncovered the following
optimum reaction conditions: a 76% yield of the desired
acylation product 3a could be obtained by using di-tert-butyl
peroxide (DTBP) as the oxidant in the presence of catalytic
amounts of FeCl2 and KOAc in PhCl at 80 °C (entry 1). In
stark contrast to previous work by Huang and Lei,14 it was
interesting to find that no N−H acylation byproduct was
observed in the process. Control experiments indicated that
FeCl2 was the sole effective catalyst to promote this reaction
(entries 2−7). Other typical oxidants were also screened while
only the use of TBHP afforded the diminished yield (entries
8−10). As expected, base was essential for the dehydrogenative
coupling reaction to proceed, which probably played a pivotal
role to facilitate the β-elimination step for C−C double bond
B
https://dx.doi.org/10.1021/acs.orglett.9b04495
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a
Scheme 2. Substrate Scope of Aldehydes
a
b
c
Reactions were conducted on a 0.2 mmol scale and all yields given are isolated after chromatographic purification. With 25 mol % catalyst. For
d
e
12 h. For 5 h. At 70 °C.
under the standard conditions, providing access to the
corresponding products (4a−j) in good yields (50−81%).
Comparable reaction efficiencies in the tested substrates reveal
that there is no apparent substitution effect on the aryl ring.
Also, this protocol can be applied to heteroaromatic enamides,
as exemplified by thiophene and furan substrates (4k and 4l).
Cyclic enamide derived from indanone was successfully
acylated, albeit with moderate yield (4m). With respect to
the variation of the N-acyl moiety to be functionalized,
switching the acetyl group to propionyl and isobutyryl
substituents had a marginal impact on the conversion (4n
and 4o). Furthermore, the methodology was extended to more
challenging and bulky alkyl enamides, as documented by the
synthesis of tert-butyl and adamantyl substituted products 4p
and 4q under slightly modified conditions. Pregnenolone-
derived enamide was transformed into the product 4r in a
synthetically useful yield while keeping the internal alkenyl
group intact.
The synthetic value of the facilely prepared β-ketoenamides
has been demonstrated in the subsequent elaboration toward a
series of biologically important nitrogen-based scaffolds
(Scheme 4). The N,O-functionalities embedded in the product
provide a synthetic handle to enable convenient access to
polysubstituted heterocycles,20 including oxazole 5a, pyridine
5b, and 2-pyridone 5c, all of which are prevalent structural
motifs in agrochemical and pharmaceutical compounds as well
as natural products. The acetyl group could be easily removed
in the presence of ammonium bicarbonate to give enaminone
5d in 84% yield. It is worthy to mention that the resultant
enaminones have emerged as valuable building blocks for the
expedient construction of many useful heterocyclic mani-
folds.21 For example, treatment of 5d with hydrazine hydrate in
acetonitrile gave pyrazole 5e in 92% yield. Hydrogenation of
compound 3a by using Pd/C catalyst smoothly produced the
corresponding 1,3-aminoalcohol 5f.
Having established the iron-catalyzed C−H acylation of
enamides, we carried out several preliminary experiments to
shed light on the reaction mechanism. Interstingly, by
employing tertiary enamide 1s as the substrate, the E
configuration of the product 4s was observed,22 which
indicated that the free amine subunit played a pivotal role to
ensure the stereoselectivity (Scheme 5a). Expectably, an acyl
radical species might be generated in situ for the oxidative
coupling of enamides with aldehydes, which is evidenced by
the following radical inhibition experiments. No coupling
product 3a was observed in the presence of TEMPO;
meanwhile, the addition of 1,1-diphenylethylene to the
standard reaction conditions afforded the acylated product 4t
in 83% yield (Scheme 5b). Moreover, a remarkable kinetic
isotope effect value (kH/kD = 5.1) from two parallel reactions
was observed, thus implying that the cleavage of the aldehydic
C−H bond might be the rate-determining step (Scheme 5c).
On the basis of these experimental results and literature
reports,6a−c,i,11k a plausible mechanism for this Fe-catalyzed
acylation was proposed as outlined in Scheme 6. The reaction
initiates with the decomposition of DTBP by Fe(II) via a
single electron transfer (SET) event to produce a tert-butoxyl
radical and tert-butoxide anion. Then, the tert-butoxyl radical
abstracts a hydrogen atom from the aldehyde to give the key
acyl radical A, which subsequently attacks the enamide at the
β-position providing the intermediate B. It is speculated that
coordination of the iron catalyst with the nitrogen and oxygen
C
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a
Scheme 3. Substrate Scope of Enamides
Scheme 5. Mechanistic Investigation
Scheme 6. Proposed Mechanism for the Acylation Reaction
a
Reactions were conducted on a 0.2 mmol scale and all yields given
b
c
are isolated after chromatographic purification. For 18 h. For 5 h.
d
With 25 mol % catalyst at 90 °C.
Scheme 4. Synthetic Applications for the Coupling Product
3a
intermediate B facilitated by the adjacent carbonyl group prior
to the oxidation step,24 may be less likely.
In summary, a regio- and stereoselective oxidative coupling
of enamides with aldehydes catalyzed by an inexpensive iron
salt with low toxicity has been developed. By merit of the
broad substrate scope, good functional group compatibility,
and exquisite stereoselectivity, the protocol allows for the
convenient preparation of a wide range of β-ketoenamides.
Further, the molecular diversity of this method was reflected by
a set of late-stage modifications of bioactive natural products.
Of note, these obtained products which benefit their distinct
N,O-functionalities allow for rich downstream transformations
for the synthesis of many privileged scaffolds including N-
heterocycles and a 1,3-amino alcohol. A mechanism involving
an acyl radical species is discussed in control experiments. This
method enriches the potential applications of enamides in C−
H functionalization reactions, which may offer a flexible route
to nitrogen-based scaffold synthesis.
atoms may take place, which explains the sole Z-selectivity in
these transformations. The intermediate B undergoes an
oxidation by Fe(III) to afford the tentative cationic species
C, which tends to be isomerized to the iminium intermediate
D. Deprotonation of the cation D with the aid of the tert-
butoxide anion eventually recovers the olefinic functionality to
deliver the dehydrogenative acylation product 3a. Note-
worthily, given the observation that the presence of HOAc
minimally affected the formation of the product,23 an
alternative pathway, which involves deprotonation of the
ASSOCIATED CONTENT
* Supporting Information
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sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04495.
Detailed experimental procedures and characterization
data (PDF)
D
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(6) For recent examples, see: (a) Liu, W.; Li, Y.; Liu, K.; Li, Z. J. Am.
Chem. Soc. 2011, 133, 10756−10759. (b) Lv, L.; Lu, S.; Guo, Q.;
Shen, B.; Li, Z. J. Org. Chem. 2015, 80, 698−704. (c) Lv, L.; Li, Z.
Org. Lett. 2016, 18, 2264−2267. (d) Zhou, M.-B.; Song, R.-J.;
Ouyang, X.-H.; Liu, Y.; Wei, W.-T.; Deng, G.-B.; Li, J.-H. Chem. Sci.
2013, 4, 2690−2694. (e) Wei, W.-T.; Yang, X.-H.; Li, H.-B.; Li, J.-H.
Adv. Synth. Catal. 2015, 357, 59−63. (f) Li, J.; Wang, D. Z. Org. Lett.
2015, 17, 5260−5263. (g) Yang, W.-C.; Weng, S.-S.; Ramasamy, A.;
Rajeshwaren, G.; Liao, Y.-Y.; Chen, C.-T. Org. Biomol. Chem. 2015,
13, 2385−2392. (h) Zhao, J.; Li, P.; Li, X.; Xia, C.; Li, F. Chem.
Commun. 2016, 52, 3661−3664. (i) Ge, L.; Li, Y.; Bao, H. Org. Lett.
2019, 21, 256−260. (j) Jiao, Y.; Chiou, M.-F.; Li, Y.; Bao, H. ACS
Catal. 2019, 9, 5191−5197.
(7) For reviews on C−H bond oxidation for C−C bond formation,
see: (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335−344. (b) Yoo, W.-J.;
Li, C.-J. Top. Curr. Chem. 2009, 292, 281−302. (c) Yeung, C. S.;
Dong, V. M. Chem. Rev. 2011, 111, 1215−1292. (d) Klussmann, M.;
Sureshkumar, D. Synthesis 2011, 2011, 353−369. (e) Cho, S. H.; Kim,
J. Y.; Kwak, J.; Chang, S. Chem. Soc. Rev. 2011, 40, 5068−5083.
(f) Wu, Y.; Wang, J.; Mao, F.; Kwong, F. Y. Chem. - Asian J. 2014, 9,
26−47. (g) Liu, C.; Yuan, J.; Gao, M.; Tang, S.; Li, W.; Shi, R.; Lei, A.
Chem. Rev. 2015, 115, 12138−12204.
AUTHOR INFORMATION
Corresponding Author
■
Xu-Hong Hu − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China; orcid.org/0000-0001-6584-2901;
Email: ias_xhhu@njtech.edu.cn
Authors
Rui-Hua Liu − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Zhen-Yao Shen − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Cong Wang − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China
Teck-Peng Loh − Institute of Advanced Synthesis, School of
Chemistry and Molecular Engineering, Nanjing Tech University,
Nanjing 211816, China; Division of Chemistry and Biological
Chemistry, School of Physical and Mathematical Sciences,
Nanyang Technological University, Singapore 637371;
orcid.org/0000-0002-2936-337X
̈
(8) Shi, Z.; Schroder, N.; Glorius, F. Angew. Chem., Int. Ed. 2012, 51,
8092−8096.
(9) Wang, J.; Liu, C.; Yuan, J.; Lei, A. Angew. Chem., Int. Ed. 2013,
52, 2256−2259.
(10) (a) Carbery, D. R. Org. Biomol. Chem. 2008, 6, 3455−3460.
(b) Gopalaiah, K.; Kagan, H. B. Chem. Rev. 2011, 111, 4599−4657.
(c) Courant, T.; Dagousset, G.; Masson, G. Synthesis 2015, 47, 1799−
1856.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.9b04495
Notes
(11) For a review, see: (a) Gigant, N.; Chausset-Boissarie, L.;
Gillaizeau, I. Chem. - Eur. J. 2014, 20, 7548−7564. For selected
recent examples, see: (b) Zhao, M.-N.; Ren, Z.-H.; Wang, Y.-Y.;
Guan, Z.-H. Org. Lett. 2014, 16, 608−611. (c) Zhao, M.-N.; Yu, L.;
Hui, R.-R.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. ACS Catal. 2016, 6,
3473−3477. (d) Wu, J.; Xu, W.; Yu, Z.-X.; Wang, J. J. Am. Chem. Soc.
2015, 137, 9489−9496. (e) Wu, J.; Lang, M.; Wang, J. Org. Lett.
2017, 19, 5653−5656. (f) Santhini, P. V.; Nimisha, G.; John, J.;
Suresh, E.; Varma, R. L.; Radhakrishnan, K. V. Chem. Commun. 2017,
53, 1848−1851. (g) Yu, W.; Zhang, W.; Liu, Y.; Liu, Z.; Zhang, Y.
Org. Chem. Front. 2017, 4, 77−80. (h) Liu, Y.; Liu, Z.; Zhang, Y.;
Xiong, C. Adv. Synth. Catal. 2018, 360, 3492−3496. (i) Ding, R.;
Huang, Z.-D.; Liu, Z.-L.; Wang, T.-X.; Xu, Y.-H.; Loh, T.-P. Chem.
Commun. 2016, 52, 5617−5620. (j) Shi, P.; Li, S.; Hu, L.-M.; Wang,
C.; Loh, T.-P.; Hu, X.-H. Chem. Commun. 2019, 55, 11115−11118.
(k) Shen, Z.-Y.; Cheng, J.-K.; Wang, C.; Yuan, C.; Loh, T.-P.; Hu, X.-
H. ACS Catal. 2019, 9, 8128−8135.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National NSFC (21702106), the
Natural Science Foundation of Jiangsu Province
(BK20170967), and the Start-up Grant from Nanjing Tech
University (39839101) for financial support.
REFERENCES
■
(1) For recent reviews, see: (a) Yan, M.; Lo, J. C.; Edwards, J. T.;
Baran, P. S. J. Am. Chem. Soc. 2016, 138, 12692−12714. (b) Skubi,
vK. L.; Blum, T. R.; Yoon, T. P. Chem. Rev. 2016, 116, 10035−10074.
(c) Leifert, D.; Studer, A. Angew. Chem., Int. Ed. 2020, 59, 74−108.
(2) For recent reviews, see: (a) Liu, C.; Liu, D.; Lei, A. Acc. Chem.
Res. 2014, 47, 3459−3470. (b) Yi, H.; Zhang, G.; Wang, H.; Huang,
Z.; Wang, J.; Singh, A. K.; Lei, A. Chem. Rev. 2017, 117, 9016−9085.
(c) Xie, J.; Jin, H.; Hashmi, A. S. K. Chem. Soc. Rev. 2017, 46, 5193−
5203. (d) Gao, P.; Gu, Y.-R.; Duan, X.-H. Synthesis 2017, 49, 3407−
3421.
(12) (a) Jousseaume, T.; Wurz, N. E.; Glorius, F. Angew. Chem., Int.
Ed. 2011, 50, 1410−1414. (b) Wu, J.; Zhao, C.; Wang, J. J. Am. Chem.
Soc. 2016, 138, 4706−4709. (c) Zhu, W.; Zhao, L.; Wang, M.-X. J.
Org. Chem. 2015, 80, 12047−12057.
(13) (a) Dash, J.; Reissig, H.-U. Chem. - Eur. J. 2009, 15, 6811−
6814. (b) Lechel, T.; Dash, J.; Eidamshaus, C.; Brudgam, I.; Lentz, D.;
̈
(3) Kharasch, M. S.; Urry, W. H.; Kuderna, B. M. J. Org. Chem.
1949, 14, 248−253.
(4) (a) Chatgilialoglu, C.; Crich, D.; Komatsu, M.; Ryu, I. Chem.
Rev. 1999, 99, 1991−2070. (b) Banerjee, A.; Lei, Z.; Ngai, M.-Y.
Synthesis 2019, 51, 303−333.
Reissig, H.-U. Org. Biomol. Chem. 2010, 8, 3007−3014. (c) Geng, H.;
Zhang, W.; Chen, J.; Hou, G.; Zhou, L.; Zou, Y.; Wu, W.; Zhang, X.
Angew. Chem., Int. Ed. 2009, 48, 6052−6054. (d) Kim, S. M.; Lee, D.;
Hong, S. H. Org. Lett. 2014, 16, 6168−6171. (e) Zhu, Z.; Tang, X.; Li,
J.; Li, X.; Wu, W.; Deng, G.; Jiang, H. Chem. Commun. 2017, 53,
3228−3231. (f) Zhu, X.-Q.; Sun, Q.; Zhang, Z.-X.; Zhou, B.; Xie, P.-
X.; Shen, W.-B.; Lu, X.; Zhou, J.-M.; Ye, L.-W. Chem. Commun. 2018,
54, 7435−7438. (g) Debbarma, S.; Bera, S. S.; Maji, M. S. Org. Lett.
2019, 21, 835−839.
(14) (a) Bian, Y.-J.; Chen, C.-Y.; Huang, Z.-Z. Chem. - Eur. J. 2013,
19, 1129−1133. (b) Wang, J.; Liu, C.; Yuan, J.; Lei, A. Chem.
Commun. 2014, 50, 4736−4739.
(15) (a) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41,
292−301. (b) Yang, L.; Wang, D.-X.; Huang, Z.-T.; Wang, M.-X. J.
Am. Chem. Soc. 2009, 131, 10390−10391. (c) He, L.; Zhao, L.; Wang,
D.-X.; Wang, M.-X. Org. Lett. 2014, 16, 5972−5975. (d) Kramer, P.;
(5) For reviews, see: (a) Willis, M. C. Chem. Rev. 2010, 110, 725−
748. (b) Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3, 2202−2209.
(c) Holmes, M.; Schwartz, L. A.; Krische, M. J. Chem. Rev. 2018, 118,
6026−6052. (d) Crossley, S. W. M.; Obradors, C.; Martinez, R. M.;
Shenvi, R. A. Chem. Rev. 2016, 116, 8912−9000. For selected
examples, see: (e) Tsujimoto, S.; Iwahama, T.; Sakaguchi, S.; Ishii, Y.
Chem. Commun. 2001, 2352−2353. (f) Esposti, S.; Dondi, D.;
Fagnoni, M.; Albini, A. Angew. Chem., Int. Ed. 2007, 46, 2531−2534.
(g) Chudasama, V.; Fitzmaurice, R. J.; Caddick, S. Nat. Chem. 2010,
2, 592−596. (h) Moteki, S. A.; Usui, A.; Selvakumar, S.; Zhang, T.;
Maruoka, K. Angew. Chem., Int. Ed. 2014, 53, 11060−11064.
(i) Zheng, Y.-L.; Liu, Y.-Y.; Wu, Y.-M.; Wang, Y.-X.; Lin, Y.-T.; Ye,
M. Angew. Chem., Int. Ed. 2016, 55, 6315−6318.
E
https://dx.doi.org/10.1021/acs.orglett.9b04495
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Grimmer, J.; Bolte, M.; Manolikakes, G. Angew. Chem., Int. Ed. 2019,
58, 13056−13059.
(16) (a) Kobayashi, S.; Gustafsson, T.; Shimizu, Y.; Kiyohara, H.;
Matsubara, R. Org. Lett. 2006, 8, 4923−4925. (b) Zhao, M.-N.; Du,
W.; Ren, Z.-H.; Wang, Y.-Y.; Guan, Z.-H. Eur. J. Org. Chem. 2013,
2013, 7989−7995.
(17) (a) Jiang, H.; Huang, C.; Guo, J.; Zeng, C.; Zhang, Y.; Yu, S.
Chem. - Eur. J. 2012, 18, 15158−15166. (b) Ding, R.; Zhang, Q.-C.;
Xu, Y.-H.; Loh, T.-P. Chem. Commun. 2014, 50, 11661−11664.
(c) Zhang, D.-L.; Li, C.-K.; Zeng, R.-S.; Shoberu, A.; Zou, J.-P. Org.
Chem. Front. 2019, 6, 236−240.
(18) (a) Sarhan, A. A. O.; Bolm, C. Chem. Soc. Rev. 2009, 38, 2730−
̈
2744. (b) Bauer, I.; Knolker, H.-J. Chem. Rev. 2015, 115, 3170−3387.
(c) Jia, F.; Li, Z. Org. Chem. Front. 2014, 1, 194−214. (d) Lv, L.; Li,
Z. Top. Curr. Chem. 2016, 374, 38. (e) Yang, X.-H.; Song, R.-J.; Xie,
Y.-X.; Li, J.-H. ChemCatChem 2016, 8, 2429−2445.
(19) Zong, Z.; Wang, W.; Bai, X.; Xi, H.; Li, Z. Asian J. Org. Chem.
2015, 4, 622−625.
(20) (a) Yamamoto, S.-i.; Okamoto, K.; Murakoso, M.; Kuninobu,
Y.; Takai, K. Org. Lett. 2012, 14, 3182−3185. (b) Zheng, Y.; Li, X.;
Ren, C.; Zhang-Negrerie, D.; Du, Y.; Zhao, K. J. Org. Chem. 2012, 77,
10353−10361. (c) Amer, A. M.; Attia, I. A. G.; El-Mobayad, M.;
Asker, S. Pol. J. Chem. 2000, 74, 681−686.
(21) (a) Yan, R.-L.; Luo, J.; Wang, C.-X.; Ma, C.-W.; Huang, G.-S.;
Liang, Y.-M. J. Org. Chem. 2010, 75, 5395−5397. (b) Senadi, G. C.;
Hu, W.-P.; Garkhedkar, A. M.; Boominathan, S. S. K.; Wang, J.-J.
Chem. Commun. 2015, 51, 13795−13798. (c) Zhou, S.; Wang, J.;
Wang, L.; Song, C.; Chen, K.; Zhu, J. Angew. Chem., Int. Ed. 2016, 55,
9384−9388. (d) Wan, J.-P.; Jing, Y.; Hu, C.; Sheng, S. J. Org. Chem.
2016, 81, 6826−6831. (e) Zhang, H.; Shen, J.; Cheng, G.; Wu, B.;
Cui, X. Asian J. Org. Chem. 2018, 7, 1089−1092.
(22) The stereochemistry was determined by NOESY analysis; see
the Supporting Information for details.
(23) When a 1.0 equiv amount of acetic acid was added into the
standard reaction conditions, the desired product 3a could be
obtained in 71% isolated yield.
(24) (a) Wertz, S.; Leifert, D.; Studer, A. Org. Lett. 2013, 15, 928−
931. (b) Leifert, D.; Daniliuc, C. G.; Studer, A. Org. Lett. 2013, 15,
6286−6289. (c) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2016,
55, 58−102.
F
https://dx.doi.org/10.1021/acs.orglett.9b04495
Org. Lett. XXXX, XXX, XXX−XXX