Highly stereoselective generation of complex oxy -bicyclic scaffolds via an atom-economic Pd(II)-catalyzed hydroalkynylation, isomerization and diels-alder cycloaddition sequence

Article abstract of DOI:10.1021/ol500101b

An atom-economic tandem Pd(II)-catalyzed hydroalkynylation, alkyne-allene isomerization, and Diels-Alder cycloaddition is reported. The reaction employs readily available starting substrates, proceeds in a highly ordered fashion, features high regio- and

Full text of DOI:10.1021/ol500101b

Letter
pubs.acs.org/OrgLett
Highly Stereoselective Generation of Complex Oxy-Bicyclic Scaffolds
via an Atom-Economic Pd(II)-Catalyzed Hydroalkynylation,
Isomerization and Diels−Alder Cycloaddition Sequence
Ruwei Shen,* Ke Chen, Qiulin Deng, Jianjun Yang, and Lixiong Zhang*
State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemistry and Chemical Engineering, Nanjing Tech
University, Nanjing 210009, P. R. China
S
* Supporting Information
ABSTRACT: An atom-economic tandem Pd(II)-catalyzed
hydroalkynylation, alkyne-allene isomerization, and Diels−
Alder cycloaddition is reported. The reaction employs readily
available starting substrates, proceeds in a highly ordered
fashion, features high regio- and stereoselectivity, and tolerates
a wide range of functionality and structural motifs, thus offering an attractive strategy for producing new molecular complexity
and diversity from easily available starting materials. A mechanistic study with density functional theoretical calculations was
conducted to rationalize the observed stereoselectivity.
reactions rely on the formation of an allene intermediate
from a Pd(0)-catalyzed Sonogashira coupling with an
unexpected yet very facile propargyl-allenyl isomerization.
he fast and concise creation of molecular complexity and
Tdiversity from simple and readily available starting
materials is inarguably of central importance in organic
synthesis.1 In this regard, the transition metal catalyzed tandem
or domino reaction continues to play important roles due to its
powerful capacity to execute multiple bond- and stereocenter-
forming events in a single synthetic operation.2,3 Recently, the
Pd-catalyzed tandem coupling−isomerization reaction (CIR,
Figure 1a)4 has emerged as a powerful method for producing
complex and diversified carbo- and heterocycles, as well as for
finding novel lead structures with applications in medicinal
chemistry and material science.4−7 Mechanistically, these
This allene intermediate,8 as demonstrated by Muller and us,
̈
is of unique reactivity and capable of participating in a wide
range of complexity-generating transformations including [4 +
2] cycloaddition,5a−c,6a−d [3 + 2] azide−olefin cycloaddition,6e
Alder-ene reaction,6f Claisen rearrangement,5d,e,6g and Schmit-
tel cyclization.6h Interception by these transformations thus led
to the establishment of an array of efficient domino reactions.
While the methodology has proven successful to access a
diversity of valuable molecular skeletons not easily fabricated by
other methods, there still exist some inherent defects and
limitations which restrict further applications. For example, the
reactions are generally not atom economical from a modern
synthetic perspective, and tedious procedures are often required
for the preparation or prefunctionalization of the starting
substrates for a successful cascade. In particular, the stereo-
defined vinyl halides are still difficult to access.9
Herein we propose a new paradigm of a tandem reaction
sequence as an evolution of CIR toward an atom-economic
method via the combination of the Trost’s hydroalkynylation
with the alkyne−allene isomerization (Figure 1). Thus, the
Pd(II)-catalyzed cross addition of a terminal alkyne to an
internal C−C triple bond, discovered by Trost in the late
1980s,10a represents one basic, highly effective, and atom-
economic way to access molecules with a conjugated enyne
unit.10 It has been applied to the total synthesis of bryostatin
1611 and several members of naturally occurring polyeny-
nes.10b,c Furthermore, the reaction has also been utilized in
tandem reaction design to build more complex structures.12 For
example, a new strategy based on this addition with sequential
Figure 1. Sonogashira coupling−isomerization sequence vs an atom-
economic addition−isomerization sequence.
Received: January 12, 2014
Published: February 6, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
Pd(II)-catalyzed heterocyclization has been realized recently for
pyrrole and related heterocycle synthesis.12 The versatility of
this reaction led us to hypothesize that the Pd(II)-catalyzed
hydroalkynylation should also be an ideal reaction for the
generation of an enyne-ene I from a simple ynoate 1 and an
alkyne 2, provided that the Pd(II) catalyst would not negatively
interfere with the following steps. Isomerization of I upon
mutually compatible reaction conditions followed by an
intramolecular Diels−Alder reaction (IMDA) may give the
fused 1,6,7,7a-tetrahydroisobenzofuran 3, a structural motif
occurring in many biologically active compounds (Figure 1b).13
While such a strategy would enable two linear starting
materials, which by themselves are very easily accessible, to be
directly converted to two annulated cycles without loss of any
atom, we also anticipated that a high degree of stereoselectivity
could be achieved considering the unusual facilitation of
cycloaddition and unique geometry of the allene intermediate.9
Furthermore, due to the easy availability of the starting
substrates 1 and 2 from a pool of alcohols, propiolic acids, and
allylic compounds, we further anticipated that this methodology
could serve as a promising strategy for generating new
molecular complexity and diversity, which is fundamental for
modern drug discovery and chemical genetics technology.14
We initially chose methyl 3-phenyl propiolate (1a) and (E)-
3-phenylallyl 1′-phenylprop-2′-ynyl ether (2a) as model
substrates to probe the hypothesis. Optimization experiments
demonstrated that the use of Pd(OAc)2 as the catalyst, tris(2,6-
dimethoxyphenyl)phosphine (TDMPP) as the ligand, Et3N as a
base, and dioxane as the solvent is optimal for the reaction,
yielding the targeted product 3a in 68% yield at 100 °C in 1 h
(Table 1, entry 1). The reaction at rt led to a long reaction time
reaction resulted in a mixture of unidentifiable products (entry
8).
Noteworthy, although there were three stereogenic centers
generated in the reaction, we note that 3a was obtained as a
1
single diastereoisomer as identified from H and 13C NMR
spectra, indicative of the high stereoselectivity in the reaction.
This remarkable feature was also observed from the reaction of
1b with (Z)-3-phenylallyl 1′-phenylprop-2′-ynyl ether (2b)
bearing a cis-double bond, which furnished 3b in a 62% yield
(eq 1). Recrystallization of 3a from hexane and CH2Cl2 yielded
crystals suitable for X-ray crystallographic analysis, which
unambiguously confirmed the structure and revealed that the
adjacent carboxyl, phenyl groups and hydrogen atom are in a
cis-configured fashion.
As to the observed stereoselectivity, we reasoned that the in
situ generated ene-vinylallene A from a cis-addition and a
kinetically slow isomerization (KH/KD = 5.25, eq 2; for a
detailed study, see Supporting Information) may favor an anti-
endo transition state TS1 over an anti-exo TS2 to undergo the
IMDA reaction (Scheme 1). We surmised that the nonbonding
Scheme 1. Mechanistic Rationale for the Stereochemistry
Table 1. Compatibility of Bases with the Pd Catalyst To
a
Produce 3a
interactions which influence the relative energies of the
competing transition states may account for the selectivity.
TS1 is lower in energy because of the absence of the
nonbonding interactions between C2−C6, which exist in the
transition state TS2. Further information to support the
speculation was obtained from a computational study. Thus,
density functional theoretical (DFT) calculations indicate that
the formation of 3a/3a′ is exothermic almost equally by ca. 35
kcal/mol whereas the barrier height of the two optimized
transition states corresponds to a 3.6 kcal/mol difference in
favor of TS1, implying a kinetic preference for the formation of
3a (Scheme 1). As shown in Figure 2, the bond-forming bond
lengths are 2.08 and 2.82 Å in TS1 and 2.05 and 3.05 Å in TS2.
Particularly, the atoms C2−C1−O5−C6 in TS2 are much
more planar with a dihedral angel of −5.1° (23.3° for TS1).
The bond angles of C2−C1−O5 and C1−O5−C6 are 116.5°
and 109.3° respectively (119.4° and 110.5° for TS1). Such
geometry may cause considerable repulsive interactions
between C2−C6 thus elevating the energy of TS2. In addition,
the more bent bond angle of the allene moiety (C1−C2−C3)
in TS2 should also contribute to the higher energy (138.6° vs
a
Reaction conditions: 1 (0.2 mmol), 2 (0.25 mmol), Pd(OAc)2 (5
mol %), TDMPP (5 mol %) and base (0.2 mL), dioxane (0.8 mL).
b
c
d
Isolated yields. 1.0 equiv. Cs2CO3 or K2CO3 or K3PO4, 4 equiv.
and lower yield. Performing the reaction in the absence of a
base did not result in the formation of 3a. Investigation into the
compatibility of bases with the Pd catalysts revealed that
i
organic bases such as Pr2NEt, 1,4-diazabicyclo[2.2.2]octane
(DABCO), and N-methylmorpholine(NMM) were also
competent in promoting the reaction (entries 2−4). A clean
reaction was also observed when 1,8-diazabicyclo[5.4.0]undec-
7-ene (DBU) was employed, indicative of the compatibility of
this base with the current Pd catalyst (entry 5). However,
inorganic bases Cs2CO3, K2CO3, and K3PO4 were incapable of
promoting the tandem process despite the high temperature
employed (entry 7), and t-BuOK was incompatible as the
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Organic Letters
Letter
with the current Pd catalysts (entry 7). In the case of using a
substrate bearing a methyl group (R4 = Me) in the olefin
moiety, an all-carbon quaternary center could be incorporated
into the product (entries 12 and 13).
Further investigation into the reaction scope demonstrated
that the use of 3-alkyl substituted allyl propargyl ethers also led
to clean reactions to produce the corresponding bicyclic
compounds (Scheme 2). Thus, the reaction of 1b and 2c which
a
Scheme 2. Efficient Formation of Fused 5,6-Bicycles 4
Figure 2. Calculated transition state structures of TS1 and TS2. Bond
lengths are in Å. Bond and dihedral angles are in degree.
147.8°). Notably, this endo-selectivity is different from a
previous observation.5a
The results compiled in Table 2 show that this operationally
simple tandem reaction indeed represents an efficient and
a
Table 2. Efficient Formation of 5,6-Bicycles 3
1
2
b
entry
R1
R2
R3
R4
Ar
3 yield (%)
1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Ph
H
H
H
H
H
H
H
H
H
H
H
H
Ph
Ph
H
H
H
H
H
H
H
H
H
H
H
Me
Me
H
H
Ph
Ph
Ph
Ph
Ph
3c, 69
3d, 70
3e, 68
3f, 71
3g, 68
3h, 65
3i, 56
3j, 68
3k, 65
2
Et
a
Reactions were conducted on a 0.2 mmol scale following a standard
3
i-Pr
b
c
procedure in 1 h unless otherwise noted. 1.5 h. 8 h.
4
1-napCH2
5
homoallyl
Me
Me
Me
Et
bears an n-butyl group at the 3-position of the olefin moiety
gave 4a in 61% yield as the only product. The exclusive
formation of 4b was also observed from the reaction of 1c and
2c. Furthermore, this tandem reaction is also effective with
substrates 2 that contain heteroatom groups (Scheme 2).
Substrate 2d bearing a free hydroxyl group reacted smoothly
with 1c to give 4c in 69% yield in 1 h. Prolonging the reaction
time did not result in a further lactonization product. Other
substrates bearing alkoxyl, amino (a morpholine motif), and
phthalimido groups also participated effectively and efficiently
in producing the products, except for the reaction of a bis(2-
hydroxyethyl)amino-attached substrate 2h which required a
longer time to deliver the desired product 4g in an acceptable
yield, and a thiocyanate substrate unfortunately failed to give
the expected product probably due to the sulfur poisoning of
the Pd catalyst.
6
m-CIC6H4
7
o-BrC6H4
8
p-t-BuC6H4
9
p-MeOC6H4
c
10
11
12
13
14
15
n-C6H13
Me
Et
Ph
Ph
Ph
Ph
Ph
Ph
3l, 56
c
Et
3m, 41
c
Me
Et
3n, 53
Ph
Me
i-Pr
Et
3o, 69
3p, 67
Ph
c
n-C6H13
3q, 47
a
Reactions were carried out on a 0.2 mmol scale following a standard
b
c
procedure. Isolated yields. 1.5 h.
straightforward method to access fused bicyclic compounds
from simple linear starting materials. Phenylpropiolic acid
esters derived from ethanol, isopropanol, and 1-naphthalenyl-
methanol all can be applied. Particularly, the expected product
3g was also obtained in 68% yield when but-3-enyl 3-
phenylpropiolate was used (entry 5), indicating the tolerance
of the double bond appended in ynoate. In addition to
phenylpropionic acid esters, alkylpropionic acid esters ethyl
but-2-ynoate and ethyl non-2-ynoate can also be used, affording
the desired products highly stereoselectively albeit in relatively
low yields (entries 10−12 and 15). As to allyl propargyl ethers,
Ar could be an orth-, meta-, and para-substituted phenyl group
with either an electron-donating or -withdrawing group (entries
6−9). Thus, the reaction of 1a with allyl 1-(3-chlorophenyl)-
prop-2-ynyl ether (entry 6) and allyl 1-(4-tert-butylphenyl)-
prop-2-ynyl ether (entry 8), for example, proceeded smoothly
to afford 3h and 3j in 65% and 68% yield. Furthermore,
bromide functionality on the aromatic ring is also compatible
In a synthetic application of the present reaction to generate
new molecular complexity and diversity, we finally examined
several naturally occurring alcohol derived ynoates 5a−5e to
produce complex natural-product-like molecules. As demon-
strated in Figure 3, despite the structural complexity, 5a−5e all
could be used to produce the corresponding products in good
yields. The reaction of a (−)-menthol derived ynoate 5a with
2a, for example, gave the expected product 6a in 61% yield.
Similarly, the use of (−)- nopol derivative 5d gave 6d and 6e in
68% and 64% yields. While the diastereoselectivities obtained
from 5a−5d were generally low, interestingly, the use of the
cholesterol derivative 5e afforded the sterol derivatives 6f and
1
6g with excellent diastereoselectivity as identified from H, 13
C
NMR and DEPT spectra. The net result of the asymmetric
induction effect in the reaction is intriguing, considering its
potential use for the synthesis of optically active compounds.
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, DFT calculation data, character-
ization of the products, CIF file. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shenrw@njtech.edu.cn.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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This research was supported by the National Natural Science
Foundation (21302095), Research Fund for the Doctoral
Program of Higher Education (20133221120003), Jiangsu
Provincial NSFC (BK20130924), and Foundation of Jiangsu
Educational Committee (13KJB150019, CXZZ13_0449) of
China. We thank Prof. Jun Ling of Zhejiang University for help
in DFT calculations and Prof. Yi Pan of Nanjing University for
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DEDICATION
■
R.S. would like to dedicate this paper to the memory of his
mentor, Prof. Xian Huang, on the occasion of his 80th birthday.
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