Palladium- and ruthenium-catalyzed cycloisomerization of enynamides and enynhydrazides: A rapid approach to diverse azacyclic frameworks

Article abstract of DOI:10.1002/anie.201304186

I want to ride my azacycle: The title reaction of enynamides affords a wide diversity of azacycles. The reactions are high-yielding, highly stereoselective, and proceed rapidly under mild reaction conditions. Equivalent transformations using enynhydrazides offer new routes to pyrazole and indazole scaffolds. Boc=tert-butoxycarbonyl, EWG=electron-withdrawing group, Ns=4-nitrobenzenesulfonyl, Ts=4-toluenesulfonyl. Copyright

Full text of DOI:10.1002/anie.201304186

Angewandte
Chemie
Communications
Heterocycles
I want to ride my azacycle: The title
reaction of enynamides affords a wide
diversity of azacycles. The reactions are
high-yielding, highly stereoselective, and
proceed rapidly under mild reaction con-
ditions. Equivalent transformations using
enynhydrazides offer new routes to pyra-
zole and indazole scaffolds. Boc=tert-
butoxycarbonyl, EWG=electron-with-
drawing group, Ns=4-nitrobenzenesul-
fonyl, Ts=4-toluenesulfonyl.
P. R. Walker, C. D. Campbell, A. Suleman,
G. Carr, E. A. Anderson*
&&&& — &&&&
Palladium- and Ruthenium-Catalyzed
Cycloisomerization of Enynamides and
Enynhydrazides: A Rapid Approach to
Diverse Azacyclic Frameworks
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
DOI: 10.1002/anie.201304186
Heterocycles
Palladium- and Ruthenium-Catalyzed Cycloisomerization of
Enynamides and Enynhydrazides: A Rapid Approach to Diverse
Azacyclic Frameworks**
P. Ross Walker, Craig D. Campbell, Abid Suleman, Greg Carr, and Edward A. Anderson*
Cycloisomerizations are amongst the most atom-economical
methods to access valuable organic ring systems from simple
acyclic starting materials.[1] 1,n-Enynes have been particularly
explored as cycloisomerization substrates, thus giving rise to
a broad spectrum of products depending on the choice of
catalyst and substrate. In contrast, reports of 1,n-enynamide
cycloisomerization are limited to p-acid activation of the
ynamide[2] or enynamide ring-closing metathesis.[3] This is
surprising given the importance of azacycles in organic and
medicinal chemistry, to which enynamide cycloisomerization
could provide a unique and sustainable entry.
enynamide cycloisomerization, together with contrasting
ruthenium-catalyzed processes. The structural outcome of
these high yielding reactions depends crucially on both the
catalyst[6] and substrate substitution pattern.
With the elegant studies from Trost et al. on palladium-
catalyzed 1,n-enyne cycloisomerization in mind,[7] we began
by evaluating the cyclization of the enynamide 4a with
various palladium catalysts (Table 1). To our delight, the
Table 1: Optimization of enynamide cycloisomerization.[a]
Our group has established a program of research on the
formation of azacycles from ynamides,[4,5] including palla-
dium-catalyzed cyclization of bromoenynamides to amido-
dienes (1!2; Scheme 1), which are precursors to azabicycles
Entry
Catalyst system
t
5a/4a/6a[b]
1
2
3
4
5
6
7
8
Pd(OAc)2/bbeda
[Pd(OAc)2(PPh3)2]
10 min
10 min
1 h
1 h
1 h
10 min
1 h
1.5 h
100:0:0
98:0:2
31:62:7
66:29:4
50:44:6
99:0:1
[Pd(OAc)2{P(o-tol)3}2]
Pd(OAc)2
[Pd2dba3]·CHCl3/AcOH
[Pd2dba3]·CHCl3/AcOH/bbeda
[Pd2dba3]·CHCl3/AcOH/P(o-tol3)
[Cp*Ru(cod)Cl][c]
19:69:11
100:0:0
[a] Reaction conditions: 5 mol% catalyst system, toluene (0.167m),
1
608C. [b] Measured by H NMR spectroscopic analysis of the crude
reaction mixture. [c] Performed in acetonitrile at 608C. Ts=4-toluene-
sulfonyl; bbeda=N,N’-bis(benzylidene) ethylenediamine, cod=cyclo-
1,5-octadiene, Cp*=C5Me5, dba=dibenzylideneacetone, o-tol=2-
MeC6H4.
Scheme 1. Cyclizations of enynamides to 2-amidodienes. Ts=4-tolue-
nesulfonyl.
3 through Diels–Alder reactions.[4b] We realized that not only
could we improve the atom economy of the synthesis of 2
through cycloisomerization of an enynamide 4, but also that
a far greater diversity of azacyclic products might be obtained.
Here we describe the first examples of palladium-catalyzed
combination of Pd(OAc)2 with either N,N’-bis(benzylidene)
ethylenediamine (bbeda) or triphenylphosphine effected
rapid cycloisomerization to the desired 1,3-dienamide 5a
(entries 1 and 2). In contrast, use of the bulkier ligand, P(o-
tol)3, or phosphine-free conditions, led to sluggish reactions
and the formation of small amounts of the enol acetate 6a
(entries 3 and 4).[5c] Interestingly, the use of Trostꢀs alternative
reaction conditions for the generation of a palladium(II)
hydride species ([Pd2dba3]/AcOH)[7c] proved effective only in
the presence of bbeda (entries 5–7). [Cp*Ru(cod)Cl] has also
been reported to catalyze the formation of 1,3-dienes from
1,n-enynes,[1c,8] and we were pleased to find that this catalyst
was similarly competent in the formation of 5a, albeit
requiring an extended reaction time (entry 8).
[*] P. R. Walker,[+] Dr. C. D. Campbell,[+] Dr. E. A. Anderson
Chemistry Research Laboratory, University of Oxford
12 Mansfield Road, Oxford, OX1 3TA (UK)
E-mail: edward.anderson@chem.ox.ac.uk
Homepage: http://anderson.chem.ox.ac.uk/
A. Suleman, G. Carr
AstraZeneca, Alderley Park, Macclesfield, SK10 4TF (UK)
[+] These authors contributed equally to this work.
[**] We thank the EPSRC for an Advanced Research Fellowship (E.A.A.;
EP/E055273/1) and for further funding (C.D.C.; EP/H025839/1).
We also thank AstraZeneca for a CASE award (P.R.W.).
With optimized reaction conditions in hand for the
formation of cyclic 1,3-dienamides, we set about exploring
the reaction scope (Figure 1). Alkyl-substituted 1,6-enyn-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201304186.
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Alkyl-substituted 1,6-enynamides were also viable sub-
strates under ruthenium catalysis (Figure 1), which afforded
the pyrrolidine enamides 5a and 5b as single isomers in high
yield. However, a remarkable switch in reaction outcome was
seen on examining 1,7-enynamides, with the 6,4-fused cyclo-
butenes 7a–c being formed in excellent yields with only trace
amounts of the corresponding 1,3-dienes (< 5%).[10,11] It is
notable that formal [2+2] cycloadditions of ynamides usually
require either electron-deficient or strained-alkene coupling
partners, whereas in this intramolecular case high efficiency is
observed with unstrained, electron-neutral alkenes.[12] Indeed
for 7c, this cycloisomerization occurred rapidly at room
temperature, presumably due to a beneficial Thorpe–Ingold
effect.
We next turned our attention to enynamides featuring 1,2-
disubstituted alkenes, which have the potential to form either
1,3- or 1,4-dienes (Table 2). The cycloisomerization of enyn-
amides with an ethyl-substituted E alkene (entries 1 and 2)
successfully gave the E-1,4-dienes (E)-8a and (E)-8b as the
major products, along with moderate amounts of the 1,3-
diene. The analogous Z-alkene substrates 4n and 4o proved
more reactive, and also favored formation of (E)-8a and (E)-
8b, now to the exclusion of 1,3-diene, but with minor amounts
of the Z-1,4-diene (entries 3 and 4). The regio- and stereo-
selectivity of these processes likely reflects the relative ease of
b-hydride elimination from probable alkylpalladium(II)
intermediates (see Scheme 3). The styrenyl ynamides 4p
and 4q, which lack the hydrogen atoms required for 1,4-diene
formation, pleasingly afforded the 1,3-dienes (E)-5l and (Z)-
5l, respectively, as single stereoisomers (entries 5 and 6),
further supporting the involvement of a stereospecific b-
hydride elimination step. To enhance selectivity for the
formation of the 1,3-diene from alkyl-substituted alkenes,
we examined the cycloisomerization of allylic silyl ether 4r
(entry 7), a tactic successfully employed by Trost.[13] We found
that this indeed improved selectivity for the 1,3-diene (E)-5m,
which for convenience was isolated as the free alcohol after
treatment with TBAF. A piperidine 1,4-dienamide could also
be prepared by cycloisomerization of the 1,7-enynamide 4s
(entry 8). Finally, we were intrigued to study the potential for
diastereoselective cycloisomerization. To our delight, the
cyclization of the a-branched enynamides 4t and 4u gave the
1,4-dienes (E)-8d and (E)-8e, respectively, as single diaste-
reomers (entries 9 and 10).[9] In the case of (E)-8e, minor
amounts of 1,3-diene and a 1,5-diene arising from palladium-
catalyzed alkene isomerization,[14] were also observed. This
relay of stereochemistry for these substrates represents the
first example of diastereoselective ynamide cycloisomeriza-
tions, and augurs well for the stereocontrolled synthesis of
polysubstituted azacycles such as indolizidine and quinolizi-
dine alkaloids.[15]
Figure 1. Cycloisomerization of monosubstituted enynamides to 1,3-
dienes and bicyclic cyclobutenes. [a] Figures in parentheses indicate
reaction time. Yields are those of isolated products. Products isolated
as a 97:3 Z/E ratio of enamides as determined by 1H NMR spectro-
scopic analysis of the crude reaction mixture.[9] [b] Performed on 1 g
scale with 1 mol% catalyst (2.5 h). [c] Performed using 5 mol%
catalyst. [d] Performed using 10 mol% catalyst. [e] Isolated as a 92:8
Z/E ratio of enamides. [f] Figures in parentheses indicate reaction
temperature/time. Yields are those of isolated products. Ns=4-
O2NC6H4SO2, Boc=tert-butoxycarbonyl, TBS=tert-butyldimethylsilyl.
amides rapidly delivered the pyrrolidine enamides 5a and 5b
in excellent yield with just 2.5 mol% catalyst, whilst aryl- and
silyl-substituted ynamides required a slightly higher catalyst
loading (5 mol%) to achieve complete conversion. Notably,
the formation of 5a could be performed in excellent yield on
gram scale with just 1 mol% of the catalyst (83%), and the
nature of the nitrogen electron-withdrawing group could also
be varied to afford the nosyl- and Boc-protected amidodienes,
5e and 5 f, respectively. The presence of a substituent adjacent
to the sulfonamide was well-tolerated (5g), and high yields
were also obtained for the formation of the piperidine
enamides 5h–k from 1,7-enynamides. In all cases, the
reactions proved highly stereoselective, with only trace
amounts of the isomeric E enamides being observed (Z/E =
97:3).[9]
Subjecting the disubstituted enynamides to ruthenium-
catalyzed cycloisomerization conditions revealed lower reac-
tivity. Of the substrates studied, only 4k underwent successful
cycloisomerization, intriguingly giving the (Z,Z)-1,4-diene
(Z)-8b as the major product (entry 11)—a result that supports
the operation of different reaction pathways for the two
catalyst systems (see below).
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Table 2: Cycloisomerization of disubstituted alkenyl ynamides.[a]
Table 3: Cycloisomerization of cycloalkenyl ynamides to azabicyclic 1,4-
dienes.[a]
Entry Substrate
T [8C] t [h] Major product
Yield
[%][b]
Ratio
1
25
2.5
89
96:4[c]
Entry Subs-
trate
n
R1
R2
R3
T
t
Major product
Yield[b]
5/(E)-8/
(Z)-8[c]
2
3
4
25
60
35
2.5
1
91
82
77
90:10[d]
93:7[e]
91:9[c]
Hex
H
(E)-Et
608C
30 min
80%
22:78:0
1
2
3
4
4l
1
1
1
1
Ph
H
(E)-Et
608C
30 min
83%
27:70:3
4m
4n
4o
5
Hex
H
(Z)-Et
258C
1.5 h
87%
0:86:14
[a] Reaction conditions: Pd(OAc)2 (2.5 mol%), bbeda (2.5 mol%),
0.167m in toluene. [b] Yield of isolated product. [c] Ratio of Z/E
enamides. [d] Ratio of 5,7-cis/5,7-trans fused rings. [e] Ratio of 1,4-diene/
1,5-diene.
Ph
H
(Z)-Et
608C
30 min
81%
0:91:9
Hex
H
(E)-Ph
608C
4 h
82%
–
5
6
4p
4q
1
1
[d]
smoothly at room temperature to give the cis-fused bicycle
10a in high yield (89%). Pleasingly, the cycloheptenyl
analogue 9b also cyclized efficiently at room temperature,
thus giving the 5,7-cis-fused azabicycle 10b (91%), along with
a minor amount of the trans-fused diastereomer. Cyclization
of the cyclohexenyl ynamide 9c was similarly successful,
giving the spirocyclic 1,4-diene 10c (82%).[7c,11] Lastly,
reaction of enynamide 9d led to the bridged azabicycle 10d
(77%), a structure which bears close resemblance to the core
of the alkaloid peduncularine.[16] To the best of our knowl-
edge, this represents the first example of the use of cyclo-
isomerization to access a bridged bicyclic system. It is of some
note that this methodology is able to prepare, with high
efficiency, these three distinct and challenging classes of
azabicycle.
As a final extension, we were attracted to a recent
approach to ynhydrazides,[17] which we found enabled a one-
pot synthesis of enynhydrazides 11a–c (Scheme 2), substrates
which are unexplored in cycloisomerization, through in situ
alkylation. We were delighted to find that these substrates
underwent smooth cyclization at low catalyst loading
(1 mol%), giving the corresponding 1,3- and 1,4-pyrazole
dienes 12a–c in excellent yields, including an attractive
tetrahydroindazole framework (12c). These products offer
many possibilities for the construction of other diazacycles.
For instance, treatment of 12a with dimethylacetylene
dicarboxylate afforded the complementary tetrahydroinda-
zole 13. Notably, this cycloisomerization/cycloaddition
sequence could also be carried out in a single step (56%),
thus affording these synthetically challenging systems in just
two operations from commercial materials.
Hex
H
(Z)-Ph
608C
20 min
84%
[d]
–
Hex
H
(Z)-
CH2OTBS
608C
53%[f]
66:17:17
7
4r
1
20 min[e]
Hex
H
(Z)-Me
608C
72%
9:91
8
9
4s
4t
2
1
20 min[e]
Hex
Ph
(Z)-nPr
258C
3 h
87%
0:100:0
Hex
Bn
(Z)-Et
608C
1.5 h
86%
10
11
4u
2
1
9:77:14[g]
Ph
H
(E)-Et
608C
1 h
84%
4m
33:9:58[h]
[a] Reaction conditions: Pd(OAc)2 (2.5 mol%), bbeda (2.5 mol%),
0.167m in toluene. [b] Yield of isolated product. [c] Ratio of 5/(E)-8/(Z)-8
as determined by 1H NMR spectroscopic analysis of the crude reaction
mixture. [d] Formed as a single stereoisomer. [e] Performed using
5 mol% catalyst. [f] Yield of pure alcohol after treatment of the reaction
mixture with TBAF. [g] 14% (by ratio) of the 1,5-diene arising from
isomerization of (E)-8e. [h] Catalyzed by [Cp*Ru(cod)Cl] (5 mol%).
Having established cycloisomerizations of acyclic enyna-
mides, we next turned to cycloalkenyl ynamides which have
the potential to form a range of interesting azabicycles not
readily accessible through other means (Table 3).[9] In the case
of the cyclohexenyl ynamide 9a, cyclization proceeded
The contrasting outcomes of these palladium- and ruthe-
nium-catalyzed processes can be explained by two mecha-
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allylic strain between the ynamide side chain and tosyl group,
places the phenyl substituent in a pseudo-equatorial position,
and orients the alkenyl side chain pseudo-axial to avoid
unfavorable steric interactions with the bbeda ligand (a
similar model can be used to rationalize the cyclization of 4u).
Under ruthenium catalysis, initial complexation of the
catalyst to both the alkene and ynamide enables ruthenacycle
formation (17). With a six-membered tether, direct reductive
elimination then leads to the 6,4-fused cyclobutene product 7.
However for 5,5-fused ruthenacycles, developing ring strain
presumably prohibits reductive elimination, and instead b-
hydride elimination affords the diene products, albeit in
differing ratios to those obtained under palladium catalysis.
In conclusion, we have demonstrated that alkenyl yna-
mides and ynhydrazides, which are readily prepared from
simple precursors, undergo high yielding cycloisomerizations
under palladium and ruthenium catalysis. These operationally
simple processes occur with high stereo- and regioselectivity,
affording a wide diversity of attractive azacyclic scaffolds. The
reactions are tolerant of a range of substituents on both the
ynamide and alkene, underlining their potential utility as an
atom-economical source of azacycles.
Scheme 2. Synthesis and cycloisomerization of enynhydrazides.
=
a) nBuLi, THF, ꢀ788C; BocN NBoc; allyl bromide, 59%. b) nBuLi,
=
THF, ꢀ788C; BocN NBoc; R-Br, nBu4NI (20 mol%), nBu4NHSO4
=
(20 mol%), NaOH (aq.)/toluene (1:1), 78% (11b, R=(E)-CH2CH
CHPh), 70% (11c, R=3-cyclohexenyl); c) Pd(OAc)2 (1 mol%), bbeda
ꢁ
(1 mol%), toluene 608C, 84%; d) MeO2CC CCO2Me, toluene, 808C,
62%. e) Pd(OAc)2 (1 mol%), bbeda (1 mol%), toluene, 608C; then
ꢁ
add MeO2CC CCO2Me, 808C, 56%.
nistic manifolds (Scheme 3). Under palladium catalysis, an
in situ generated palladium(II) hydride species effects regio-
selective hydropalladation of the ynamide to afford alkenyl-
Received: May 15, 2013
Published online: && &&, &&&&
Keywords: cyclization · heterocycles · homogeneous catalysis ·
.
palladium · ynamide
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Scheme 3. Proposed cycloisomerization mechanisms.
palladium intermediate 14. Ensuing carbopalladation gives
the alkylpalladium species 15, which (depending on the
substrate) has a choice of hydrogen atoms with which to
undergo b-hydride elimination. Loss of Ha delivers the 1,3-
dienes 5, whilst elimination of Hb or Hc leads to the E- or Z-
1,4-dienes 8. The highly stereoselective cyclizations of 4t and
4u suggest that the sulfonamide plays an important role not
only as an ynamide/enamide stabilizing group, but also as
a fluxional stereogenic center. The stereoselectivity (for 4t)
can be explained by conformation 16, which minimizes 1,3-
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could lead to 1,3-dienes by 4p-electrocyclic ring opening, we
have found them to be resistant to this process.
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[14] A minor amount of 1,5-diene was detected. For a similar
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