Cationic Pd(II)-catalyzed reductive cyclization of alkyne-tethered ketones or aldehydes using ethanol as hydrogen source

Article abstract of DOI:10.1021/ol400531a

A cationic Pd(II)-catalyzed reductive cyclization of alkyne-tethered ketones or aldehydes using ethanol as hydrogen source under mild conditions was developed. The reaction is an environmentally benign synthetic method and proceeds efficiently to give useful N-heterocycles or carbocycles bearing an exocyclic double bond and a hydroxyl group in high yield.

Full text of DOI:10.1021/ol400531a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Cationic Pd(II)-Catalyzed Reductive
Cyclization of Alkyne-Tethered
Ketones or Aldehydes Using Ethanol
as Hydrogen Source
Kun Shen, Xiuling Han,* and Xiyan Lu*
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences, 345 Lingling Lu, Shanghai 200032, China
xlhan@mail.sioc.ac.cn; xylu@mail.sioc.ac.cn
Received February 25, 2013
ABSTRACT
A cationic Pd(II)-catalyzed reductive cyclization of alkyne-tethered ketones or aldehydes using ethanol as hydrogen source under mild conditions
was developed. The reaction is an environmentally benign synthetic method and proceeds efficiently to give useful N-heterocycles or carbocycles
bearing an exocyclic double bond and a hydroxyl group in high yield.
Carbonꢀcarbon coupling reactions are the most useful
synthetic methods in organic chemistry. Among them,
transition-metal-catalyzed alkyneꢀcarbonyl reductive
coupling has been established for the synthesis of allylic
alcohols. Due to the easy further transformation of func-
tional groups of the products, this reaction becomes a
powerful method in synthetic chemistry. In the early stage,
a stoichiometric amount of organometallic compounds
such as Si, Zn, Sn, Cr, and B were used as the reducing
agents, producing equivalent amounts of byproducts.1
Since the pioneering work by Krische, who developed an
atom-economical alkyneꢀcarbonyl reductive coupling
using the rhodium- and iridium-catalyzed hydrogenation,2,3
reactions using different hydrogen sources were reported.4,5
For example, ruthenium was reported to catalyze reductive
alkyneꢀcarbonyl coupling using formic acid as the hydro-
gen source leading to allylic alcohols.5
(1) (a) Ti-catalyzed alkyneꢀcarbonyl reductive coupling: Crowe,
W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787. (b) A review
of Ni-catalyzed alkyneꢀcarbonyl reductive coupling: Montgomery, J.;
Sormunen, G. J. Top. Curr. Chem. 2007, 279, 1.
(4) Ir-catalyzed reactions of alkynes with carbonyl compounds under
transfer hydrogenation conditions: (a) Obora, Y.; Hatanaka, S.; Ishii, Y.
Org. Lett. 2009, 11, 3510. (b) Hatanaka, S.; Obora, Y.; Ishii, Y. Chem.;
Eur. J. 2010, 16, 1883.
(5) Ru-catalyzed reactions of alkynes with carbonyl compounds
under transfer hydrogenation conditions: (a) Patman, R. L.; Chaula-
gain, M. R.; Williams, V. M.; Krische, M. J. J. Am. Chem. Soc. 2009, 131,
2066. (b) Williams, V. M.; Leung, J. C.; Patman, R. L.; Krische, M. J.
Tetrahedron 2009, 65, 5024. (c) Leung, J. C.; Patman, R. L.; Sam, B.;
Krische, M. J. Chem.;Eur. J. 2011, 17, 12437.
(6) For reviews on CꢀC coupling under transition-metal-catalyzed
transfer hydrogenation conditions, see: (a) Shibahara, F.; Krische, M. J.
Chem. Lett. 2008, 37, 1102. (b) Bower, J. F.; Kim, I. S.; Patman, R. L.;
Krische, M. J. Angew. Chem., Int. Ed. 2009, 48, 34. (c) Patman, R. L.;
Bower, J. F.; Kim, I. S.; Krische, M. J. Aldrichimica Acta 2008, 41, 95. (d)
Han, S. B.; Kim, I. S.; Krische, M. J. Chem. Commun. 2009, 7278. (e)
Bower, J. F.; Krische, M. J. Top. Organomet. Chem. 2011, 34, 107. (f)
Leung, J. C.; Krische, M. J. Chem. Sci. 2012, 3, 2202. (g) Moran, J.;
Krische, M. J. Pure. Appl. Chem. 2012, 84, 1729.
(2) For reviews of hydrogen-mediated CꢀC coupling, see: (a) Jang,
H.-Y.; Krische, M. J. Acc. Chem. Res. 2004, 37, 635. (b) Ngai, M.-Y.;
Kong, J.-R.; Krische, M. J. J. Org. Chem. 2007, 72, 1063. (c) Skucas, E.;
Ngai, M.-Y.; Komanduri, V.; Krische, M. J. Acc. Chem. Res. 2007, 40,
1394. (d) Iida, H.; Krische, M. J. Top. Curr. Chem. 2007, 279, 77.
(3) Hydrogen-mediated alkyneꢀcarbonyl coupling reactions: (a)
Huddleston, R. R.; Jang, H.-Y.; Krische, M. J. J. Am. Chem. Soc.
2003, 125, 11488. (b) Jang, H.-Y.; Huddleston, R. R.; Krische, M. J.
J. Am. Chem. Soc. 2004, 126, 4664. (c) Kong, J.-R.; Ngai, M.-Y.;
Krische, M. J. J. Am. Chem. Soc. 2006, 128, 718. (d) Cho, C.-W.;
Krische, M. J. Org. Lett. 2006, 8, 891. (e) Cho, C.-W.; Krische, M. J.
Org. Lett. 2006, 8, 3873. (f) Rhee, J.-U.; Krische, M. J. J. Am. Chem. Soc.
2006, 128, 10674. (g) Kong, J.-R.; Krische, M. J. J. Am. Chem. Soc. 2006,
128, 16040. (h) Komanduri, V.; Krische, M. J. J. Am. Chem. Soc. 2006,
128, 16448. (i) Hong, Y.-T.; Cho, C.-W.; Skucas, E.; Krische, M. J. Org.
Lett. 2007, 9, 3745. (j) Ngai, M.-Y.; Barchuk, A.; Krische, M. J. J. Am.
Chem. Soc. 2007, 129, 280. (k) Han, S. B.; Kong, J.-R.; Krische, M. J.
Org. Lett. 2008, 10, 4133.
r
10.1021/ol400531a
XXXX American Chemical Society

Table 1. Preliminary Examination of the Reductive Cyclization
Reactiona
Scheme 1. Pd(II)-Catalyzed AlkyneꢀCarbonyl Coupling
entry
substrate
time (h)
product
yieldb (%)
1
2
3
1a, R1 = Me
1b, R1 = Ph
1c, R1 = TMS
24
24
2
2a
2b
2c
39c
47c
65d
a Conditions: Reactions were carried out with 1 (0.10 mmol) and
catalyst (7.5 mol %) in EtOH (1 mL) at 50 °C. b Isolated yield. c A
mixture of dimerized products was observed. d Pyrrole 3c was also
formed without the generation of any dimer (see Table 2, entry 1).
Alcohol is an environmentally benign solvent and hy-
drogen source that has been utilized in many CꢀC bond-
forming reactions via transition-metal-catalyzed transfer
hydrogenation.6,7 However, only limited examples were
reported on alkyneꢀcarbonyl reductive coupling using
alcohol as hydrogen source for the reason of low con-
versions.5a,b Sodeoka recently reported an asymmtric con-
jugate reduction of enones by the PdꢀH species generated
from a cationic palladium complex and ethanol.8 This is
another example of using alcohol as the hydrogen source.
In our previous work, Pd(II)-catalyzed intramolecular
alkyneꢀcarbonyl couplings initiated by acetoxypalladation9
or carbopalladation10 of alkynes were reported (Scheme 1,
eqs 1 and 2). We wondered if the PdꢀH species generated
from Sodeoka’s strategy would be used to accomplish an
intramolecular alkyneꢀcarbonyl reductive coupling reac-
tion initiated by hydropalladation of alkynes (Scheme 1,
eq 3). As far as we know, palladium-catalyzed CꢀC bond-
forming reactions initiated by hydropalladation of alkynes
using alcohol as the hydrogen source have not been
reported in the literature.
In our initial study, the substrate alkyne-tethered ketone
1a was reacted in the presence of 7.5 mol % of
[Pd(dppp)(H2O)2](BF4)2 in ethanol (0.1 M) at 50 °C for
24 h (Table 1, entry 1). The reductive cyclized product 2a
was isolated in 39% yield together with a mixture of
dimerized products, the formation of which could not be
suppressed after screening many reaction conditions. In
order to inhibit the formation of the dimerized products,
substrates with bulky group substituted alkynes were
employed (Table 1, entries 2 and 3). Using phenyl-sub-
stituted alkyne-tethered ketone 1b, a slightly higher yield
was obtained, but a mixture of dimerized products was still
formed in addition to 2b (Table 1, entry 2). To our delight,
the reaction went smoothly without the formation of any
dimerized product for substrate 1c with a trimethylsilyl
substituent, indicating that substrates with sterically hin-
dered alkynes gave much better results for this reaction
(Table 1, entry 3). The stereochemistry of the exocyclic
double bond in the products was assigned as E as con-
firmed by the X-ray crystallography of 2c (see the Support-
ing Information). Owing to the easy further transformation
of the silicon moiety, alkyne-tethered ketone 1c was chosen
as the model substrate for reaction condition screening.
The model substrate alkyne-tethered ketone 1c was
completely consumed within 2 h with 7.5 mol % of
[Pd(dppp)(H2O)2](BF4)2 as the catalyst, affording 2c in
65% yield together with pyrrole 3c in 31% yield (Table 2,
entry 1). This byproductwas formed inalmostquantitative
yield with prolonged reaction time, indicating that 3c
might be generated from 2c (Table 2, entry 2). When 1c
was reacted in the presence of 7.5 mol % of [Pd(rac-
binap)(H2O)2](BF4)2 in ethanol (0.1 M) at 50 °C for 24 h,
the reductive cyclized product 2c was isolated in 54% yield
with a 38% recovery of 1c (Table 2, entry 3). A similar
result was obtained when the reaction was catalyzed by
[Pd(rac-binap)(H2O)2](OTf)2 (52% yield, Table 2, entry 4).
No reaction occurred when Pd(OAc)2 or Pd(CF3COO)2
was used as the catalyst (Table 2, entries 5 and 6). Efforts to
suppress the generation of 3c by using some weak bases as
additives failed (Table 2, entries 7 and 8). Although a trace
amount of 3c was formed when 1 equiv of BaCO3 was
added into the reaction, another byproduct 2c0 was iso-
lated in 30% yield together with 2c in 58% yield (Table 2,
entry 7). Substrate 1c was destroyed after addition of 1
equiv of K3PO4 (Table 2, entry 8). The transfomation of 1c
was much slower when the reaction was performed in
i-PrOH, giving 2c in 50% yield accompanied by 3c in
36% yield after 5 h (Table 2, entry 9). Finally, a good yield
(82%) was achieved when the reaction was carried out at
room temperature for 48 h using 1,2-dichloroethane
(DCE) as a cosolvent, although there was still 15% of 3c
isolated (Table 2, entry 10). On the basis of the above
investigation, the optimal condition for this reductive
(7) Rh-catalyzed reductive cyclization of enyne using ethanol as
hydrogen source: Park, J. H.; Kim, S. M.; Chung, Y. K. Chem.;Eur.
J. 2011, 17, 10852.
(8) (a) Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8,
4851. (b) Monguchi, D.; Beemelmanns, C.; Hashizume, D.; Hamashima,
Y.; Sodeoka, M. J. Organomet. Chem. 2008, 693, 867. (c) Greenaway, R. L.;
Campbell, C. D.; Chapman, H. A.; Anderson, E. A. Adv. Synth. Catal.
2012, 354, 3187.
(9) Zhao, L.; Lu, X. Angew. Chem., Int. Ed. 2002, 41, 4343.
(10) (a) Song, J.; Shen, Q.; Xu, F.; Lu, X. Org. Lett. 2007, 9, 2947. (b)
Han, X.; Lu, X. Org. Lett. 2010, 12, 108. (c) Wang, H.; Han, X.; Lu, X.
Tetrahedron 2010, 66, 9129.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Screening of Reaction Conditionsa
Table 3. Reaction Scope of Alkyne-Tethered Ketones or
Aldehydesa
yieldb (%)
entry
catalyst
time (h)
2c
2c0
3c
1
[Pd(dppp)(H2O)2](BF4)2
[Pd(dppp)(H2O)2](BF4)2
[Pd(rac-binap)(H2O)2](BF4)2
[Pd(rac-binap)(H2O)2](OTf)2
Pd(OAc)2 þ dppp
2
8
65
0
31
94
2
trace
54
52
0
0
0
0
0
0
3
24
24
24
24
2
trace
trace
0
4
5
6
Pd(CF3COO)2 þ dppp
[Pd(dppp)(H2O)2](BF4)2
[Pd(dppp)(H2O)2](BF4)2
[Pd(dppp)(H2O)2](BF4)2
0
0
7c
8d
9e
58
30 trace
2
disordered
5
50
82
0
0
36
15
10f,g [Pd(dppp)(H2O)2](BF4)2
48
a Conditions: Reactions were carried out with 1c (0.10 mmol) and
catalyst (7.5 mol %) in EtOH (1 mL) at 50 °C, unless otherwise noted.
b Isolated yield. c BaCO3 (1 equiv) was added. d K3PO4 (1 equiv) was
added. e i-PrOH was used as solvent. f The reaction was performed at
room temperature. g ClCH2CH2Cl (0.2 mL) was added as a cosolvent to
make 1c soluable.
cyclization reaction was as follows: 1c (0.1 mmol) and
[Pd(dppp)(H2O)2](BF4)2 (7.5 mol %) in EtOH/DCE
(1 mL/0.2 mL) at room temperature.
Withoptimal reactionconditionsinhand, westudiedthe
scope of the reductive cyclization of a variety of alkyne-
tethered ketones or aldehydes (Table 3). Generally, the
reaction worked well with trimethylsilyl-substituted NTs-
tethered substrates to give tetrahydropyrroles bearing
an exocyclic double bond (Table 3, entries 1ꢀ10). Aryl
ketones having electron-donating groupssuchas methylor
methoxy were suitable for the reductive cyclization to give
the corresponding products in good yields (Table 3, entries
2 and 6). Substrates with halogen-substituted aryl ketones,
which offered opportunities for further transformations of
the products, were compatible in this reaction (Table 3,
entries 4 and 5). Alkynyl aldehyde 1j worked well in this
reaction, affording secondary alcohol 2j in moderate yield
(Table 3, entry 8). Alkyl ketones (1k and 1l) could also be
transformed to the desired products without the formation
of pyrroles (Table 3, entries 9 and 10). Substrates bearing
other bulky substituents on alkynes show a similar reactivity
with 1c without the observation of any dimer (Table 3,
entries 11 and 12). Furthermore, five-membered carbo-
cycles and six-membered N-heterocycles could be synthe-
sized using this method successfully (Table 3, entries 13
and 15). However, NBn-tethered substrate 1p did not react
at all in this reductive cyclizations (Table 3, entry 14).
Subsequently, the asymmetric version of this reductive
cyclization reaction was studied (Scheme 2). Our prelimin-
ary results showed that the reaction of 1c in the presence of
a Conditions: The reaction was carried out with 1 (0.1 mmol) and
[Pd(dppp)(H2O)2](BF4)2 (7.5 mol %) in EtOH/ClCH2CH2Cl (1 mL/0.2
mL) at room temperature, unless otherwise noted. b Isolated yield.
c Small amounts of pyrroles were also formed. d 2c was isolated in 71%
yield with a 24% recovery of 1c when the reaction was performed on a
0.5 mmol scale. e The reaction was performed in EtOH (1 mL) at 50 °C.
Scheme 2. Asymmetric Reductive Cyclization of 1c
[Pd(S,S-bdpp)(H2O)2](BF4)2 in EtOH at room tempera-
ture can give 2c in 63% yield with 82% ee.
To gain mechanism insights, the reaction was then
conducted in deuteriated ethanol. Subjecting 1l to the
reductive cyclization reaction conditions in CH3CH2OD
gave 2l in 97% yield with no deuterium incorporation into
the product (Scheme 3, eq 1). However, the use of
CH3CD2OH afforded d-2l with a deuterium at the vinyl
position in 92% yield (Scheme 3, eq 2).
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 3. Deuterium Labeling Studies
Scheme 5. Transformations of Product 2c
A to complete the catalytic cycle. This proposed mechan-
ism is in accordance with the configuration of the exocyclic
double bond of the products and the results of the reaction
with deuteriated ethanol.
Scheme 4. Proposed Mechanism for the Reductive Cyclization
Finally, the transformation of the vinylic silane moiety
in product 2c was studied. Treatment of 2c with TBAF in
THF at 60 °C for 30 h gave rise to the desilated product 4c
in 73% yield. The reaction of 2c with NIS could give 5c in
68% yield, which could be used for Suzuki or Sonogashira
coupling reaction to afford 6c or 2b, respectively (Scheme 5).
In conclusion, a cationic Pd(II)-catalyzed intramolecu-
lar reductive cyclization of alkyne-tethered ketones or
aldehydes using ethanol as the hydrogen source under
mild reaction conditions was developed. The reaction is
environmentally benign and proceeds efficiently to give
synthetically useful hydroxy group substituted N-hetero-
cycles and carbocycles bearing an exocyclic double bond
with E-configuration. Further studies on the mechanism
and an asymmetric version of the reaction are underway in
our laboratory.
On the basis of the above results, a possible mechanism
of this reductive cyclization reaction is shown in Scheme 4.
The Pd hydroxo complex A is presumed to be the active
catalytic species.11 The Pd hydroxo complex A reacts with
ethanol to generate Pd ethoxide complex B, which subse-
quently gives the Pd hydride complex C via β-hydride
elimination. Hydropalladation to the alkyne of the sub-
strate affords a vinylpalladium intermediate D followed by
intramolecular addition to the carbonyl group to give the
intermediate E. The protonolysis of the newly formed
intermediateE generates the product and the Pd(II) species
Acknowledgment. We thank the National Basic Re-
search Program of China (2011CB808706), National Natural
Science Foundation of China (21232006, 21272249), and
Chinese Academy of Sciences for financial support.
Supporting Information Available. Experimental pro-
cedures, characterization data of new compounds, copies
of NMR spectra, HPLC data of optically active products,
and X-ray data of compound 2c (CIF). This material is
available free of charge via the Internet at http://pubs.acs.org.
(11) (a) Fujii, A.; Hagiwara, E.; Sodeoka, M. J. Am. Chem. Soc. 1999,
121, 5450. (b) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457. (c)
Hayashi, T.; Takahashi, M.; Takaya, Y.; Ogasawara, M. J. Am. Chem.
Soc. 2002, 124, 5052. (d) Stang, P. J.; Cao, D. H.; Poulter, G. T.; Arif,
A. M. Organometallics 1995, 14, 1110.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX