Palladium-catalyzed allylic alkylation with internal alkynes to construct C-C and C-N bonds in water

Article abstract of DOI:10.1039/c7gc00666g

A palladium-catalyzed system enabled efficient allylic alkylation with alkynes in water has been developed. This reaction presents an environmentally friendly strategy for constructing lots of allylic compounds with indolinones, ketones, amines as well as electron-rich aromatic compounds as nucleophiles. Moreover, the in situ formed arylallene intermediate adopting alkynes as starting materials omits the need for leaving groups and extra oxidants, showing high atom economy. The versatility of the developed reaction also lends itself to the incorporation of deuteriums by simply replacing H₂O with D₂O.

Full text of DOI:10.1039/c7gc00666g

View Article Online
View Journal
Green
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Yao, S. Gao, H.
Liu, Z. Wu and A. Lin, Green Chem., 2017, DOI: 10.1039/C7GC00666G.
This is an Accepted Manuscript, which has been through the
Volume 18 Number
7 7 April 2016 Pages 1821–2242
Royal Society of Chemistry peer review process and has been
accepted for publication.
Green
Chemistry
Accepted Manuscripts are published online shortly after
Cutting-edge research for a greener sustainable future
www.rsc.org/greenchem
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1463-9262
CRITICAL REVIEW
G. Chatel et al.
Heterogeneous catalytic oxidation for lignin valorization into valuable
chemicals: what results? What limitations? What trends?
rsc.li/green-chem

Please do not adjust margins
Green Chemistry
Page 1 of 5
View Article Online
DOI: 10.1039/C7GC00666G
Journal Name
COMMUNICATION
Palladium-Catalyzed Allylic Alkylation with Internal Alkynes to
Construct C-C and C-N Bonds in Water
Received 00th January 20xx,
Accepted 00th January 20xx
Shang Gao, Hao Liu, Zijun Wu, Hequan Yao* and Aijun Lin*
DOI: 10.1039/x0xx00000x
www.rsc.org/
Previous work:
A palladium-catalyzed system enabled efficient allylic alkylation
with alkynes in water has been developed. This reaction presents
an environmental-friendly strategy for constructing lots of allylic
compounds with indolinones, ketones, amines as well as electron-
rich aromatic compounds as nucleophiles. Moreover, the in situ
formed arylallene intermediate adopting alkynes as starting
materials omits the need of leaving groups and extra oxidants,
showing high atom economy. The versatility of the developed
reaction also lends itself to the incorporation of deuteriums by
simply replacing H2O with D2O.
a) Tsuji-Trost reaction
LG
LG = leaving group
b) Oxidative allylic C-H functionalization
[TM]
LG
R
R
R
Nu
Nu
H
-
[TM]
R
H
Nu
Nu
Nu
Nu
H
extra oxidant
c) Allylic alkylation of allenes in organic solvents
[TM]
R
R
Nu
H
organic solvents
d) Allylic alkylation of alkynes in organic solvents
[TM]
Over the last few decades, transition-metal-catalyzed allylic
alkylation provides a useful method to construct various C-C
and C-X bonds, which has been applied to the preparation of
biologically important natural products and drug molecules.1
Tsuji−Trost reacꢀon, as the most frequently-used method,
suffered from the need of pre-installing a leaving group to the
starting allylic substrates (Scheme 1a).2 As an alternative
method, oxidative allylic C-H functionalization requires
stoichiometric amounts of extra oxidants to achieve the
transformation (Scheme 1b).3 Allenes as another type of allylic
alkyl donors normally need to be timely prepared due to the
instability and all of the reactions are conducted in organic
solvents (Scheme 1c).4
Alkynes, as versatile and readily available building blocks,5
have drawn increasing interest in the field of allylic alkylation.6
Compared with their allylmetal equivalent, alkynes possess
inherent advantages for the redox-netrual process, exhibiting
high atom economy. However, organic solvents were usually
used in these reactions (Scheme 1d). From the perspective of
green chemistry, water (H2O) is an ideal solvent in synthetic
chemistry since it is a non-toxic, abundant, cost-effective and
R
R
Me
Nu H
organic solvents
This work:
e) Redox-netural allylic alkylation on water
Pd(PPh3)4/Ligand
PhCO2H
R
(het)
Ar
(het)
Ar
Nu
Nu
H
H2O
R
Nu = ketone, amine, arene,
without oxidants
and leaving groups
38 examples
up to 99% yield
oxindole et al.
Scheme 1 Transition-metal-catalyzed allylic alkylation
environmental-friendly solvent.7 As we all know, the poor
solubility of mostly organic compounds in water limits the
application of water as solvent in organic synthesis. Since the
concept of “on water organic reaction” was first proposed by
Sharpless in 2005,8 lots of efforts have been devoted to the
development of this kind of synthetic chemistry.9 In view of
our continuous interest in allylic alkylation,10 herein, we report
a palladium-catalyzed allylic alkylation with internal alkynes in
water (Scheme 1e).
We commenced our reaction with 1-methyl-3-
phenylindolin-2-one 1a and 1-phenyl-1-propyne 2a as
substrates, and benzoic acid as an additive in 1.0 mL H2O at
o
100 C under argon for 24 h as shown in Table 1. Gratifyingly,
3aa could be obtained in 25% yield (entry 1). Screening of
ligands revealed that the ligands played significant effects on
this allylic alkylation. Monophosphate ligands such as Ph3P,
Cy3P and Cy-JohnPhos showed better performance than the
bisphosphate ligands such as dppm and dppe (entries 2-6), and
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 2 of 5
View Article Online
DOI: 10.1039/C7GC00666G
COMMUNICATION
Journal Name
Table 1 Condition screeninga,b
Table 2 Substrate scope of alkynesa,b
Entry
1
Ligand
Cat (mol%)
Yield (%)
25
/
10
10
10
10
10
10
10
10
7.5
5
2
PPh3
82
3
PCy3
67
99 (96)c
4
Cy-Johnphos
dppm
5
nr
6
dppe
23
7
P(O)Ph3
50
8
AsPh3
<10
86
9
Cy-Johnphos
Cy-Johnphos
Cy-Johnphos
Cy-Johnphos
10
11
12d
69
/
nr
10
92
a
Reaction conditions: 1a (0.25 mmol), 2a (0.5 mmol), Pd(PPh3)4 (10 mol%),
PhCO2H (10 mol%) and L (20 mol%) in 1.0 mL H2O were stirred at 100 oC (oil-bath
temperature) under argon for 24 h. b The yields were determined by 1H NMR with
CH2Br2 as internal standard. c Isolated yield. d 2a (0.375 mmol) was used.
3aa could be isolated in 96% yield when Cy-Johnphos was used.
Triphenylphosphine oxide delivered 3aa in 50% yield (entry 7),
while triphenylarsine depressed this reaction significantly
(entry 8). Decreasing the amount of Pd(PPh3)4 and 1-phenyl-1-
propyne 2a produced 3aa in slightly lower yields (entries 9, 10
and 12). No reaction could be detected without of the catalyst
(entry 11).
a Reaction conditions: 1 (0.25 mmol), 2 (0.5 mmol), Pd(PPh3)4 (10 mol%), PhCO2H
With the optimized conditions in hand, we then explored
the substrate scope of the alkynes and the results are
summarized in Table 2. Substrates with electron-donating
(10 mol%) and Cy-Johnphos (20 mol%) in 1.0 mL H2O were stirred under argon for
c
24 h with the corresponding oil-bath temperature. b Isolated yields. The dr
values were determined by 1H NMR spectra.
groups such as methoxyl and methyl groups provided the
o
3ae in 83%-96% yields at 120 C.
allylic alkylated products 3ab
-
Moreover, various ketone-, ester-, and amide-containing
compounds were selected as substrates to examine the
practicability of this method. The modification of the drug
molecules edaravone derivative 1i, phenylbutazone 1j and
ortho-Substituted 1-phenyl-1-propyne 2d exhibited lower
reactivity due to the steric hindrance. Alkynes bearing
electron-withdrawing groups (-CO2Me, -F) showed higher
reactivity than electron-donating groups, giving 3af in 98%
yield and 3ag in 97% yield under the standard conditions.
Replacing phenyl group with biphenyl, 1-naphthalenyl or 2-
naphthalenyl groups, the reaction proceeded smoothly,
barbituric acid derivative 1k were tested, providing 3ia, 3ja
and 3ka in good to excellent yields. With 2-
acetylcyclohexanone as substrate, the alkylated product 3la
was prepared in 52% yield. It was noteworthy that 2-tetralone
could be dialkylated in C1-position smoothly in 45% yield
leading to 3ah
-
3aj in 96%-98% yields. Notably, the
were
heterocycles such as thiophene rings (2k and 2l
)
(
3ma). The C-allylic alkylated product 3na was exclusively
compatible with the present catalytic system, affording 3ak
and 3al in 81% and 50% yields. Moreover, 1-phenyl-1-butyne
2m participated well to deliver 3am in 99% yield (dr = 1:1).
Finally, this method allowed the late-stage modification of the
unusual derivative of estrone 2n, affording 3an in 94% yield.
Next, the substrate scope of various nucleophiles were also
tested as shown in Table 3. In evaluating the substrate scope
of the oxindoles, both electron-donating groups (-Me, -OMe)
and electron-withdrawing group (-F) were tolerated, giving
obtained in 62% yield when 1n was used. Phenolic-containing
aromatic nucleophiles proceeded well to furnish the
corresponding products 3oa-3qa in moderate yields. In
addition, electron-rich heterocycle, 1,2-dimethylindole (1r),
could also participate in this reaction, delivering 3ra in 37%
yield.
Besides, this method could also be applied to construct N-
allylic alkylated products. Various cyclic amines such as
indoline, 1,2,3,4-tetrahydroquinoline and benzomorpholine
produced 3sa-3ua in 97%-98% yields. Acyclic amine (Bn2NH)
provided 3va in 96% yield. It was noteworthy that selectively
N-alkylated products 3wa and 3xa were obtained when 2-
hydroxy-3-cyanopyridine and 1-hydroxyisoquinoline were sued.
3ba-3ea in good yields from 81% to 97%. Varying aromatic
phenyl group to alkyl group (-Me), 3fa could also be obtained
in 96% yield. 3-Phenyl oxindole (1g) reacted smoothly to
deliver 3ga in 78% yield and the dialkylated product 3ha was
isolated in 62% yield when the temperature raised to 120 oC.
2 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 3 of 5
View Article Online
DOI: 10.1039/C7GC00666G
Journal Name
COMMUNICATION
Table 3 Substrate scope of nucleophilesa,b
Scheme 2 Further study of allylic alkylation with alkynes in water
in 3.8% yield and 3af in 39.8% yield, suggesting that the
electron-rich arylalkynes exhibited higher reactivities (Scheme
2d).
To gain insight into the mechanism of this reaction, control
experiments were performed as shown in Scheme 3. Unluckily,
we could not detect the possible reaction intermediate, phenyl
allene
conditions. Subsequently, we prepared phenyl allene
5, at the initial stage of model reaction under optimized
5, and
tested its reactivity with 1a under the standard conditions,
which could deliver 3aa in 58% yield (Scheme 3a).6g This result
suggested that phenyl allene could be involved in the reaction
process. Combined with the previous works,6,10,12 a plausible
mechanism was proposed (Scheme 3b). Firstly, ligand
exchange of Pd(PPh3)4 with Cy-Johnphos produces the active
palladium catalyst
delivers the hydridopalladium species
insertion of to 2a affords the adduct , and then β
A
and oxidation of
A
with benzoic acid
syn-Migratory
-hydrogen
B.
B
C
a Reaction conditions: 1 (0.25 mmol), 2a (0.5 mmol), Pd(PPh3)4 (10 mol%), PhCO2H
(10 mol%) and Cy-Johnphos (20 mol%) in 1.0 mL H2O were stirred at 100 oC under
argon for 24 h. b Isolated yields. c 120 oC. d 36 h. e 0.75 mmol 2a was used. f 48 h.
To further test the practicability of our reaction, a gram-
scale experiment was conducted (Scheme 2a). When the
loading amount of Pd(PPh3)4 was decreased to 7.5 mol%, 3aa
could also be isolated in 1.60 g (94% yield) on 5.0 mmol scale
in 20.0 mL H2O. Moreover, non-natural amino acid derivative
4
could be prepared within two steps on gram scale (Scheme
2b). A steady increase in the application of deuterated
compounds in analytics, drugs discovery and material sciences
promotes chemists to develop more concise method to
prepare deuterated compounds.11 Replacing H2O with D2O,
deuterium could be incorporated into 3aa successfully. To
compare the activity of alkynes, a competing experiment was
conducted. Treatment of 1a with the electron-rich 1-phenyl-1-
propyne 2b and the electron-deficient 1-phenyl-1-propyne 2f
afforded 3ab
Scheme 3 Proposed mechanism
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Green Chemistry
Page 4 of 5
View Article Online
DOI: 10.1039/C7GC00666G
COMMUNICATION
Journal Name
6. For review, see: (a) Y. Yamamoto and U. Radhakrishnan,
Chem. Soc. Rev., 1999, 28, 199; For selected examples, see:
elimination of intermediate
regenerates B
produces allylic palladium intermediate
C
(catalytic cycle I). Migratory insertion of
forms the phenyl allene
5
B
and
5
D
to
. The intermediate
(b) F. A. Cruz and V. M. Dong, J. Am. Chem. Soc., 2016, 139
,
D
1029; (c) T. M. Beck and B. Breit, Angew. Chem., Int. Ed.,
2017, 56, 1903; (d) T. M. Beck and B. Breit, Org. Lett., 2016,
18, 124; (e) C. Li, C.P. Grugel and B. Breit, Chem. Commun.,
2016, 52, 5840; (f) A. M. Haydl, L. J. Hilpert and B. Breit,
Chem. Eur. J., 2016, 22, 6547; (g) F. A. Cruz, Z. Chen, S. I.
Kurtoic and V. M. Dong, Chem. Commun., 2016, 52, 5836; (h)
Q.-A. Chen, F. A. Cruz and V. M. Dong, J. Am. Chem. Soc.,
2015, 137, 3157; (i) Q.-A. Chen, Z. Chen and V. M. Dong, J.
Am. Chem. Soc., 2015, 137, 8392; (j) P. Koschker, M. Kähny
and B. Breit, J. Am. Chem. Soc., 2015, 137, 3131; (k) U.
Gellrich, A. Meißner, A. Steffani, M. Kähny, H.-J. Drexler, D.
Heller, D. A. Plattner and B. Breit, J. Am. Chem. Soc., 2014,
136, 1097; (l) K. Xu, V. Khakyzadeh, T. Bury and B. Breit, J.
Am. Chem. Soc., 2014, 136, 16124; (m) L. M. Lutete, I. Kadota
and Y. Yamamoto, J. Am. Chem. Soc., 2004, 126, 1622; (n) I.
Kadota, A. Shibuya, Y. S. Gyoung and Y. Yamamoto, J. Am.
Chem. Soc., 1998, 120, 10262.
could be trapped by 1a’ to deliver 3aa directly and the active
catalyst is regenerated to enter the next catalytic cycle
(catalytic cycle II).
A
In conclusion, we have developed a palladium-catalyzed
allylic alkylation of various nucleophiles with internal alkynes
to construct C-C and C-N bonds employing water as
environmental-friendly solvent. This reaction exhibited good
functional group tolerance and scalability, and high
regioselectivity. Late-stage modification of drugs were
conducted, enabling the construction of bioactive compound
library in high efficiency. With D2O as solvent, deuterium could
be incorporated into the allylic alkylated product conveniently.
Further studies on the application of this method to the
construction of bioactive molecules are currently underway in
our laboratory.
7. For selected reviews and book, see: (a) M. M. Heravi, V.
Zadsirjan and K. Kamjou, Curr. Org. Chem., 2015, 19, 813; (b)
M. O. Simon and C.-J. Li, Chem. Soc. Rev., 2012, 41, 1415; (c)
R. N. Butler and A. G. Coyne, Chem. Rev., 2010, 110, 6302;
(d) A. Chanda and V. V. Fokin, Chem. Rev., 2009, 109, 725; (e)
U. M. Lindström, Organic Reactions in Water: Principles,
Strategies and Applications, Blackwell Publishing, Oxford, 1st
edn, 2007; (f) P. J. Dunn, Chem. Soc. Rev., 2012, 41, 1452; (g)
M. B. Gawande, V. D. Bonifácio, R. Luque, P. S. Branco and R.
S. Varma, Chem. Soc. Rev., 2013, 42, 5522.
Acknowledgements
Generous financial support from the National Natural Science
Foundation of China (NSFC21502232 and NSFC21572272), the
Natural Science Foundation of Jiangsu Province (BK20140655)
and the Foundation of State Key Laboratory of Natural
Medicines (ZZJQ201306) is gratefully acknowledged.
8. S. Narayan, J. Muldoon, M. G. Finn, V. V. Fokin, H. C. Kolb
and K. B. Sharpless, Angew. Chem., Int. Ed., 2005, 44, 3275.
9. For selected examples, see: (a) M. Liu and C.-J. Li, Angew.
Chem., Int. Ed., 2016, 55, 10806; (b) F. Zhou and C.-J. Li, Nat.
Notes and references
1. For selected reviews on the application of allylic alkylation in
total synthesis, see: (a) A. Y. Hong and B. M. Stoltz, Eur. J.
Org. Chem., 2013, 2013, 2745; (b) K. C. Majumdar and B.
Sinha, Synthesis, 2013, 45, 1271; (c) G. Helmchen, M. Ernst
and G. Paradies, Pure Appl. Chem., 2004, 76, 495; (d) S.
Arseniyadis, J. Fournier, S. Thangavelu, O. Lozano, S. Prevost,
Commun., 2014, 5, 4254; (c) S. Xu, Y. Zhou, J. Xu, H. Jiang and
H. Liu, Green Chem., 2013, 15, 718; (d) F.-Q. Shi, X. Li, Y. Xia, L.
Zhang and Z.-X. Yu, J. Am. Chem. Soc., 2007, 129, 15503; (e)
D. Ye, J. Wang, X. Zhang, Y. Zhou, X. Ding, E. Feng, H. Sun, G.
Liu, H. Jiang and H. Liu, Green Chem., 2009, 11, 1201; (f) M. A.
Ali, X. Yao, G. Li and H. Lu, Org. Lett., 2016, 18, 1386; (g) M. A.
Ali, X. Yao, H. Sun and H. Lu, Org. Lett., 2015, 17, 1513; (h) Y.
Yang, Y. Bao, Q. Guan, Q. Sun, Z. Zha and Z. Wang, Green
Chem., 2017, 19, 112; (i) V. Arumugam, W. Kaminsky and D.
Nallasamy, Green Chem., 2016, 18, 3295; (j) Y. Uozumi and K.
Shibatomi, J. Am. Chem. Soc., 2001, 123, 2919; (k) T. P. Clark
and C. R. Landis, J. Am. Chem. Soc., 2003, 125, 11792; (l) Y.
Uozumi and T. Suzuka, J. Org. Chem., 2006, 71, 8644; (m) Y.
Lee, S. Shabbir, S. Lee, H. Ahn and H. Rhee, Green Chem.,
2015, 17, 3579.
A. Archambeau, C. Menozzi and J. Cossy, Synlett, 2013, 24
2350; (e) B. M. Trost and M. L. Crawley, Top. Organomet.
Chem., 2012, 38, 321.
,
2. For selected reviews, see: (a) B. M. Trost and D. L. Van
Vranken, Chem. Rev., 1996, 96, 395; (b) B. M. Trost, Chem.
Pharm. Bull., 2002, 50, 1; (c) B. M. Trost and M. L. Crawley,
Chem. Rev., 2003, 103, 2921; (d) N. A. Butt, W. Zhang, Chem.
Soc. Rev., 2015, 44, 7929; (e) C.-X. Zhuo, C. Zheng and S.-L.
You, Acc. Chem. Res., 2014, 47, 2558; (f) N. Butt, G. Yang and
W. Zhang, Chem. Rec., 2016, 16, 2683.
3. For selected reviews, see: (a) G. Liu and Y. Wu, Top. Curr.
Chem., 2009, 292, 195; (b) T. Jensen and P. Fristrup, Chem.
Eur. J., 2009, 15, 9632; (c) F. Liron, J. Oble, M. M. Lorion and
G. Poli, Eur. J. Org. Chem., 2014, 2014, 5863; (d) H. Tang, X.
10. (a) S. Gao, Z. Wu, X. Fang, A. Lin and H. Yao, Org. Lett., 2016,
18, 3906; (b) C. Yang, K. Zhang, Z. Wu, H. Yao and A. Lin, Org.
Lett., 2016, 18, 5332.
11. For selected reviews and examples, see: (a) G. S. Timmins,
Expert Opin. Ther. Patents, 2014, 24, 1067; (b) T. G. Gant, J.
Med. Chem., 2014, 57, 3595; (c) S. L. Harbeson, R. D. Tung,
Annu. Rep. Med. Chem., 2011, 46, 403; (d) J. Atzrodt, V.
Derdau, T. Fey and J. Zimmermann, Angew. Chem., Int. Ed.,
2007, 46, 7744; (e) W. W. Y. Leong, X. Chen and Y. R. Chi,
Green Chem., 2013, 15, 1505.
Huo, Q. Meng and W. Zhang, Acta. Chimica. Sinica., 2016, 74
219.
,
4. For selected review, see: (a) P. Koschker and B. Breit, Acc.
Chem. Res., 2016, 49, 1524; For selected examples, see: (b) Y.
Yamamoto, M. Al-Masum, N. Asao, J. Am. Chem. Soc., 1994,
116, 6019; (c) M. Al-Masum, Y. Yamamoto, J. Am. Chem. Soc.,
1998, 120, 3809.
12. (a) X. Lu, J. Ji, D. Ma and W. Shen, J. Org. Chem., 1991, 56
,
5774; (b) A. Boucherif, S.-W. Duan, Z.-G. Yuan, L.-Q. Lu and
W.-J. Xiao, Adv. Synth. Catal., 2016, 358, 2594; (c) B. M. Trost,
J. Xie and J. D. Sieber, J. Am. Chem. Soc. 2011, 133, 20611; (d)
H. Zhou, Z. Wei, J. Zhang, H. Yang, C. Xia and G. Jiang, Angew.
Chem., Int. Ed., 2017, 56, 1077.
5. For selected reviews, see: (a) M. Patel, R. K. Saunthwal and A.
K. Verma, Acc. Chem. Res., 2017, 50, 240; (b) V. P. Boyarskiy,
D. S. Ryabukhin, N. A. Bokach and A. V. Vasilyev, Chem. Rev.,
2016, 116, 5894; (c) H. Yoshida, ACS Catal., 2016,
R. K. Kumar and X. Bi, Chem. Commun., 2016, 52, 853; (e) V.
6, 1799; (d)
Ritleng, M. Henrion and M. J. Chetcuti, ACS Catal., 2016, 6,
890, and references cited therein.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Green Chemistry
View Article Online
DOI: 10.1039/C7GC00666G
Palladium-Catalyzed Allylic Alkylation with Internal Alkynes to Construct C-C and C-N
Bonds in Water
(Shang Gao, Hao Liu, Zijun Wu, Hequan Yao* and Aijun Lin*)
E-mail: ajlin@cpu.edu.cn; hyao@cpu.edu.cn; cpuhyao@126.com.
Palladium catalyzed allylic alkylation with alkynes in water, omitting the need of leaving groups
and extra oxidants.