N-Substitution dependent stereoselectivity switch in palladium catalyzed hydroalkynylation of ynamides: A regio and stereoselective synthesis of ynenamides

Article abstract of DOI:10.1039/c5cc06251a

A highly general palladium catalysed regioselective hydroalkynylation of ynamides for versatile enamide building blocks with an alkyne tether is achieved with an N-substitution dependent stereoselectivity switch under very mild reaction conditions.

Full text of DOI:10.1039/c5cc06251a

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DOI: 10.1039/C5CC06251A
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N-Substitution Dependent Stereoselectivity Switch in Palladium
Catalyzed Hydroalkynylation of Ynamides: A Regio and
Stereoselective Synthesis of Ynenamides‡
Received 00th January 20xx,
Accepted 00th January 20xx
Vikas Dwivedi,a† Madala Hari Babu,a† Ruchir Kantb and Maddi Sridhar Reddya,c*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A highly general palladium catalysed regioselective hydroalkynylation of
ynamides for versatile building blocks enamides with alkyne tether is
achieved with an N-substitution dependent stereoselectivity switch under
very mild reaction conditions.
Hydroalkynylation of alkyne (alkyne-alkyne cross dimerization)1-3 is
a remarkably straightforward, simple and atom economical means
for the construction of enyne, a linchpin subunit in many natural
products4 and a useful intermediate for the construction of larger
molecules.5 As a result, there has been a deep search for both
homodimerization and cross dimerization of two different alkynes.
Although a great attention was given for homo dimerization,1 and
cross addition of terminal alkynes to acceptor alkynes,2 the addition
to neutral internal alkynes3 and to electron rich alkynes are yet to be
studied and standardized. On the other hand, enamines/enamides are
equally highly sought after scaffolds because of their significance in
both medicinal and synthetic chemistries, and due to their presence
in various natural products.6 Hence, an enormous effort was made
for their selective synthesis.7 The synthesis of hybrid of these two
intriguing subunits (i.e. enynes and enamides), namely ynenamides
(or enynamides), may pave the way for the synthesis of new class of
molecules with new therapeutic indexes. In this direction, Zhu et al.
recently reported an elegant Pd-catalyzed trans addition of terminal
alkynes to aryl ynamides to achieve selectively α, β-disubstituted
enamides [Scheme 1 (a)].8 As part of our on-going program to
explore the new reactivities of activated alkynes,9-10 we previously
reported a regioselective syn addition of acetylenes to ynol ethers
under very mild conditions [Scheme 1 (b)].9 We herein describe a
regioselective syn addition of acetylenes to ynamides [Scheme 1
(c)]. Incidentally, with the ynamides bearing non cyclic substitution
on nitrogen, we observed a strange but interesting stereoselectivity
switch depending on aryl or alkyl substitution at the C-terminal.
Scheme 1. Cross dimerization of acetylenes and electron rich alkynes.
Initially we synthesized the oxazolidinone based phenyl ynamide 1a
and treated it with 1.2 equivalents of phenyl acetylene 2a, 10 mol%
Pd(PPh3)2Cl2 and 2.5 equivalents of triethylamine in THF at room
temperature (the conditions identified earlier in our laboratory for
the cross addition of acetylenes to ynol ethers).9 The expected
product 3aa was cleanly formed with excellent regio- and
stereoselectivity (Table 1). With this exciting result, we next turned
to evaluate its generality. Initially we verified the scope of the
reaction with respect to acetylenes. Similar to phenyl acetylene,
various halophenyl acetylenes reacted successfully despite the
possibility of Sonogashira coupling. Thus, 2b-e provided the
corresponding products 3ab-ae in 69-76% yields. As is evident
from the table, the yields in case of electron rich phenyl acetylenes
were higher when compared to their electron deficient counterparts.
a.Medicinal & Process Chemistry Division, CSIR-Central Drug Research Institute, BS-
10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India.
b.Molecular & Structural Biology Division, CSIR-CDRI, Lucknow 226031, India.
c. Academy of Scientific and Innovative Research, New Delhi 110001, India.
† Contributed equally.
‡CDRI Communication No: xxxx. Electronic Supplementary Information (ESI)
available: See DOI: 10.1039/x0xx00000x
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Table 1. Addition of acetylenes 2 to oxazolidinone ynamide 1a.a
respectively reacted smoothly (66-68% yields) under standard
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DOI: 10.1039/C5CC06251A
conditions.
With the above encouraging results, we next aimed to evaluate
reaction scope with respect to ynamides. Similar to 1a, halophenyl
ynamides 1b-d were also added by phenyl acetylene with an
excellent yielding (78-84%). In case of electron rich ynamides (1e-f)
the yields were slightly dropped (63-66%). The reaction was not
restricted to aromatic ynamides, the aliphatic substrates (1g-j) also
effectively participated in the reaction although with relatively less
yielding (55-64%). Further, cyclohexenyl ynamide 1k yielded the
desired dienynamide 3ka in 61% yield. Propargyl alcohol based
ynamide 1l was also found to be competent reaction partner to
deliver 3la in 64% yield.
Table 2. Addition of phenyl acetylene to oxazolidinone ynamide 1.a
aReaction conditions: 1 (1.0 mmol), 2a (1.2 mmol), Pd(PPh3)2Cl2 (0.1
mmol), TEA (2.5 equiv), THF (0.5 M), RT, 12 h.
Having successfully tested the newly found method by varying
substitution on C-terminal of ynamides, we set out to unveil that
how the change of substitution on nitrogen would vary the results.
Pleasingly, despite the steric hindrance from closely positioned
phenyl group, enantiopure chiral ynamide 1m (prepared from
commercially available enantiopure phenyl oxazolidinone)
underwent the hydroalkynylation very cleanly to afford 3ma in 78%
aReaction conditions: 1a (1.0 mmol), 2 (1.2 mmol), Pd(PPh3)2Cl2 (0.1
mmol), TEA (2.5 equiv), THF (0.5 M), RT, 12 h.
Thus, alkyl- and methoxyphenyl acetylenes 2f-h produced the yield (Scheme 2). Compared to oxazolidinone ynamides,
corresponding products 3af-ah in 82-86% yields. The unprotected
amino group in 2i survived the reaction very well to produce 3ai in
80% yield. CF3-substituted phenyl acetylenes 2j-k were also added
smoothly to produce the expected products 3aj-ak in 68-71% yields.
The structure of 3aj was unambiguously confirmed by X-ray
crystallography. Nitrophenyl acetylene 2l gave 3al in a moderate
yield of 55%. Incurring a high functional group tolerance to the
reaction, formyl- and cyano-substituted phenyl acetylenes showed a
hassle free reactivity to produce the products 3am-3an albeit in
slightly reduced yields (66-70%). Pyridylacetylene also smoothly
reacted in the reaction to produce heteroaryl adduct 3ao in 66%
yield. In contrast to aromatic acetylenes, although conjugated,
cyclohexenyl acetylene showed a moderate reactivity to yield 3ap in
42%. Aliphatic acetylenes (2q-s) were found to be less productive
(48-51% yields) compared to aromatic counterparts, whereas
Scheme 2. Scope of reaction with various ynamides 1m-p.
trimethylsilyl acetylene, and propargyl derivative 2t and 2u
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Table 4. Trans addition of 2a on N-tosyl aryl ynamides 4.a
pyrrolidinone based ynamide 1n needed slightly elevated
temperature (50 oC) to furnish 3na in moderate yield of 44%.
Delightfully, indole based ynamines 1o and 1p were found to
participate well in the reaction to produce 3oa and 3pa respectively
in good to moderate yields (54-79%). Structure of 3oa was
confirmed by single crystal X-ray diffraction.
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DOI: 10.1039/C5CC06251A
Our attention was next turned to explore the reactivity of N-protected
secondary ynamides. We first chose N-tosyl aliphatic ynamides
which were found by Zhu et al. to be poorly reactive (<35%
conversion) to produce a mixture of isomers (79:21) with a slight
predominance of trans addition product. Surprisingly, when
subjected to our standard conditions (with an elevation of
o
temperature to 50 C), tosyl protected aliphatic ynamide 4a reacted
well and produced selectively the syn addition adduct 5aa in 58%
yield (Table 3). No trans isomer but an unidentified by-product
(15%) was isolated. We immediately verified this contrasting result
for its generality. Pleasingly, similar to 4a, other n-alkyl and
cycloalkyl N-tosyl ynamides 4b-f produced corresponding syn
addition adducts in 48-58% yields. Likewise, propargyl derivative 4g
also gave syn addition adduct 5ga in 51% yield. Structure of 5fa was
confirmed by X-ray crystallography.
aReaction conditions: 4 (1.0 mmol), 2a (1.2 mmol), Pd(PPh3)2Cl2 (0.1
mmol), TEA (2.5 equiv), THF (0.5 M), 50 oC, 2-12 h.
Table 3. Cis addition of 2a to N-tosyl aliphatic ynamides 4.a
Scheme 3. Addition of 2a and 2k to Boc-protected ynamide 6a.
afforded selectively the trans adducts 7aa-ak with both phenyl- and
bis(trifluoromethyl)phenyl acetylenes (Scheme 3).11
From these examples, i.e. aryl ynamides with non-cyclic substition
on nitrogen (Table 4 and Scheme 3), it appears that an increased
bond angle between N-substituents is enhancing the steric hindrance
between ortho-proton of aryl ring and N-substitution. Hence, the
tentative enynyl palladium intermediate formed via syn addition (A,
Figure 1) might have forcibly switched to sterically less hindered
trans isomer before reductive elimination. This happened only with
aryl ynamides because the aryl ring lies in plane with ynenamide
system due to conjugation. Whereas with sulfonyl protected alkyl
ynamides (Table 3), due to free rotation of the alkyl group, there
does not exist any steric repulsion (B, Figure 1) from non-cyclic
substituents on nitrogen and hence they underwent straight syn
addition. However, due to less or no steric hindrance (C-D, Figure
1), the ynamides with N-cyclic substitution (Tables 1-3) uniformly
incurred the syn addition irrespective of aryl or alkyl substitution on
C-terminal.
aReaction conditions: 4 (1.0 mmol), 2a (1.2 mmol), Pd(PPh3)2Cl2 (0.1
mmol), TEA (2.5 equiv), THF (0.5 M), 50 oC, 2-12 h.
We then turned our attention toward the reactivity of N-sulfonyl aryl
ynamides which were the substrates for trans addition by Zhu et al.
Similar to their observation, and unlike in all the above cases (Tables
1-3 and Scheme 2), the addition of 2a to 4h led to the selective
formation of trans adduct 5ha in 61% yield (Table 4). Since our
reaction conditions are slightly better and more convenient (no
additives, non protic solvent and reduced temperature) compared to
those developed by Zhu et al. (Scheme 1A), we wanted to pursue
this trans addition reaction for its scope. In addition, we particularly
wanted to choose the substrates other than methanesulfonamides as
they were not tested in earlier finding. Thus, various N-arylsulfonyl
arylynamides (4i-n) were tested under the standard conditions to
obtain, pleasingly, the expected products (5ia-na) in good to
excellent yields (59-78%).
Figure 1. Steric constraints in various intermediates.
Finally, we verified whether it was possible to selectively modify the
The subsequent feedstock we chose for the reaction was N-Boc-aryl alkyne group of above ynenamides to acquire differently substituted
enamides. Thus, partial syn reduction of 3aa was achieved (8 in
84%) using 10 mol% Pd-BaSO4 under hydrogen atmosphere. Use of
ynamide. Thus, when subjected to the standard conditions, 6a
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higher amounts of catalyst (15 mol% Pd-BaSO4) along with longer
reaction timings (8h) cleanly led to the complete and selective
reduction of alkyne group to afford 9 in 80% yield. However, use of
Pd/C with hydrogen totally reduced the enyne system to afford
saturated adduct 10 (95%).
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Scheme 4. Reductions of ynenamide 3aa.
In conclusion, we demonstrated the selective addition of acetylenes
to ynamides under mild reaction conditions. The addition to
substrates with cyclic substitution on nitrogen was always syn
irrespective of alkyl or aryl substitution at C-terminal, whereas to
substrates with noncyclic substitution (sulfonyl or Boc protected
secondary ynamides), the addition was subjective depending on the
steric constraints: syn with alkyl ynamides and trans with aryl
ynamides. We hope that these highly and selectively
functionalized/substituted subunits will find extensive applications
in both synthetic and medicinal chemistries.
6
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VD and MHB thank CSIR for the fellowships. We thank SAIF
division CSIR-CDRI for the analytical support. We gratefully
acknowledge the financial support by CSIR (SPLENDID, BSC
0104).
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11 See Supporting Information for NOESY spectrum of 7ak
.
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