Gold-catalyzed three-component spirocyclization: A one-pot approach to functionalized pyrazolidines

Article abstract of DOI:10.1039/c5ob02453f

An efficient, highly atom economic synthesis of hitherto unknown spirocyclic pyrazolidines in a one-pot process was developed. The gold-catalyzed three-component coupling of alkynols, hydrazines and aldehydes or ketones likely proceeds via cycloisomerization of the alkynol to an exocyclic enol ether and subsequent [3 + 2]-cycloaddition of an azomethine ylide. A library of 29 derivatives with a wide range of functional groups was synthesized in up to 97% yield. With this new method, every position in the final product can be substituted which renders the method ideal for applications in combinatorial or medicinal chemistry.

Full text of DOI:10.1039/c5ob02453f

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Gold‐catalyzed three‐component spirocyclization: a one‐pot
approach to functionalized pyrazolidines†
Bernd Wagner,a Wolf Hiller,a Hiroaki Ohnob and Norbert Krause*a
Received 00th January 20xx,
Accepted 00th January 20xx
An efficient, highly atom economic synthesis of hitherto unknown spirocyclic pyrazolidines in a one‐pot process was
developed. The gold‐catalyzed three‐component coupling of alkynols, hydrazines and aldehydes or ketones likely proceeds
via cycloisomerization of the alkynol to an exocyclic enol ether and subsequent [3+2]‐cycloaddition of an azomethine ylide.
A library of 29 derivatives with a wide range of functional groups was synthesized in up to 97% yield. With this new
method, every position in the final product can be substituted which renders the method ideal for applications in
combinatorial or medicinal chemistry.
DOI: 10.1039/x0xx00000x
www.rsc.org/
b]indoles.9 We now report a conceptually new gold‐catalyzed
three‐component spirocyclization of acetylenic alcohols,
hydrazines, and aldehydes or ketones which provides a
diversity‐oriented access to previously unknown spirocyclic
Introduction
Heterocycles are a pivotal structural element of a large
number of pharmaceuticals. Hence, in order to tackle new
challenges in medicinal chemistry, there is a growing demand
for novel types of heterocycles with tailored pharmacological
properties.1 From the preparative point of view, extensive
structural variation of the heterocyclic target molecules is
required using the full arsenal of modern synthetic
methodology, e.g., catalytic processes utilizing transition
metals or organocatalysts,2 C‐H activation,3 and multicompo‐
nent reactions (MCRs).4
pyrazolidines (Scheme 1).
A. Three-component Annulation
R3
N
R2
R1
H
O
[Au]
R2
N
R
+
N
+
N
R3
R
R1
H
H
B. This work: Three-component Spirocyclization
R3
N
H
O
R2
R1
[Au]
R2
N
O
HO
N
+
+
N
R3
R1
H
H
The use of homogeneous gold catalysts in multicomponent
reactions holds great promise. Due to their high reactivity
towards ‐systems (in particular alkynes), gold catalysts allow
Scheme 1 Gold‐catalyzed three‐component annulation vs.
spirocyclization.
a distinctive control of selectivity, as well as, wide tolerance
towards reactive functional groups.5 Combining this with the
advantages of MCRs (rapid assembly of complex structural
motifs from small molecules with high atom economy) renders
the method highly valuable in combinatorial and medicinal
chemistry. Since the first publication of a gold‐catalyzed
coupling of aldehydes, secondary amines and alkynes by Li et
al.,6 the number of MCRs catalyzed by gold is continuously
rising.7 Recently, one of us (H.O.) has developed a new
approach to dihydropyrazoles by gold‐catalyzed three‐
component annulation of alkynes with hydrazines and
aldehydes or ketones, a method that was applied to the one‐
pot synthesis of dihydroindazoles,8 as well as, pyrazolo[4,3‐
Many natural products contain spiroacetals as
characteristic scaffold (Fig. 1). Prominent examples are the
marine toxines okadaic acid, isolated from the sponge
Halichondria okadai, and azaspiracid‐1, obtained from blue
mussels (Mytilus edulis).10
HO
O
O
H
O
O
H
O
HO
O
H
O
OH
O
H
H
OH
OH
OH
H
Okadaic acid
H
H
O
OH
HO2C
O
O
O
O
H
H
H
H
NH
O
O
a. Organic Chemistry, Dortmund University of Technology, Otto‐Hahn‐Str. 6, D‐
44227 Dortmund, Germany. E‐mail: norbert.krause@tu‐dortmund.de; Fax: (+)49
231 755 3884.
O
H
b. Kyoto University, Graduate School of Pharmaceutical Sciences
Sakyo‐ku, Kyoto 606‐8501 (Japan).
Azaspiracid-1
Fig. 1 Natural products containing [O,O]‐ and [N,O]‐spiro‐
acetals.
†Electronic Supplementary Information (ESI) available: Experimental procedures
and characterization data for all new compounds. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
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Synthetic approaches to the most common [O,O]‐ Table 1 Optimization of the gold‐catalyzed spirocyVcieliwzaAtrtiioclne .Oanline
DOI: 10.1039/C5OB02453F
spiroacetals are well developed and normally take advantage
of Lewis acid, Brønsted acid, or transition metal catalysts for
the spirocyclization of prefunctionalized substrates.11 Recent
examples involve an efficient gold‐ or palladium‐catalyzed
cyclization of monopropargylic triols or ketoallylic diols
reported by Aponick and co‐workers,12 the first asymmetric
Brønsted acid‐catalyzed cyclization of enol ethers with chiral
phosphoric acids developed by List and Nagorny,13 as well as,
the enantioselective synthesis of spiroacetals in
a
multicomponent approach disclosed by Fañanás, Rodríguez,
and Gong.14 In contrast to this, other heterocyclic spiro‐
compounds have been relegated to a niche existence.15 A rare
exception is the recent report by Xu et al.16 on the synthesis of
spiroaminals and spiroketals by bimetallic relay catalysis
involving a gold‐catalyzed cycloisomerization of a functionali‐
zed alkyne followed by a transition metal‐catalyzed hetero‐
Diels‐Alder reaction.
Entry
Catalyst
Solvent
Timeb
Yieldc
1d
2d
3d
4d
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Ph3PAuCl/AgOTf
Ph3PAuCl/AgBF4
Ph3PAuCl/AgSbF6
AuCl
1,2‐DCE
toluene
DCM
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
22 he
16 he
16 he
16 h
3 h
41%
37%
43%
52%
40%
58%
69%
traces
traces
75%
65%
77%
89%
97%
85%
84%
traces
traces
57%
3 h
3 h
7 he
7 he
4 h
Results and discussion
AuCl3
Ph3PAuNTf2
A
Crucial to our approach towards spirocyclic pyrazolidines is the
use of an acetylenic alcohol instead of a simple alkyne in the
three‐component reaction with a hydrazine and an aldehyde
or ketone. We anticipated that the alkynol would undergo a
facile cyclization in the presence of a gold catalyst17 to afford
the ether ring of the desired spiroacetal. We started our
4 h
4 h
4 h
4 h
B/AgSbF6f
B/AgSbF6g
B/AgSbF6g,h
B/AgSbF6g,i
B/AgSbF6
4 h
6 h
AgSbF6
4 he
14 de
24 h
investigation with pent‐4‐yn‐1‐ol 1, isobutyraldehyde 2 and
CuBrj
the protected hydrazine 38 in 1,2‐dichloroethane with 5 mol%
of Ph3PAuCl/AgOTf as catalyst at room temperature (Table 1,
entry 1). After 22 h, the spiroacetal 4a was isolated with 41%
yield. A brief screening showed THF to be the best solvent
(52% yield after 16 h at rt; entries 2‐4). Increasing the reaction
temperature to 50°C improved the reactivity and afforded 4a
with 40% yield after only 3 h (entry 5). A change of the silver
salt revealed AgSbF6 to the best choice (69% yield; entries 5‐7),
indicating the importance of the counteranion.5h,i
j
PtCl2
THF
a Reactions performed on a 0.45 mmol scale (0.15 M solution) with 1.2
equiv. each of
dr = 58:42 in all cases. b Time required to reach completion. c Isolated
yield. d At rt. e Incomplete conversion. f With 1.5 equiv. each of
and
+ 1.0 equiv. of and + 1.0 equiv. of
g With 2.0 equiv. each of
With 2 mol% catalyst. I With 1 mol% catalyst. j With 10 mol% catalyst.
1 and 2 + 1.0 equiv. of 3. Product 4a was obtained with
1
2
h
3
.
1
2
3.
With the optimized conditions (Table 1, entry 14) in hand,
we investigated the scope of the gold‐catalyzed three‐
component spirocyclization (Scheme 2). A wide variety of
aliphatic
aldehydes (4l
enolization took place, resulting in a diminished yield (46%) of
product 4c. Aromatic aldehydes bearing various substituents
(including nitro groups) afforded the spirocyclic pyrazolidines
The use of neutral gold salts AuCl and AuCl3 resulted in
poor conversion and formation of a gold mirror (entries 8&9).
(
4a
‐
c
), aromatic
(4d‐k), and heteroaromatic
In contrast, cationic gold catalysts Ph3PAuNTf2 and
good yields of 4a (entries 10&11). The best results were
obtained with phosphite gold complex in the presence of
AgSbF6 (entries 12‐16). By increasing the amount of alkyne
and aldehyde from 1.2 to 2.0 equiv., the yield of spiroacetal
A furnished
/
m) is tolerated. With butyraldehyde, extensive
B
1
2
4d
‐
/
k
k
with high yield (71‐89%). Notably, fluorinated aryl groups
), as well as, bromide (4h ) can be introduced without
4a could be raised up to 97% (entries 13&14). Under these
conditions, the catalyst loading could be reduced from 5 to 1
mol%, resulting only in a slight decrease of reactivity and
product yield (entries 15&16). The silver salt alone does not
catalyze the spirocyclization (entry 17); the same is true for
CuBr (entry 18). In contrast, PtCl2 is a competent catalyst,
albeit not as efficient as cationic gold (entry 19).
(
4j
/i
difficulty, the latter offering a handle for further functionaliza‐
tion. Whereas heteroaromatic aldehydes work exceptionally
well (products 4l/m), cinnamic aldehyde afforded product 4n
with only 33% yield. Attempts to extend this method to
ketones revealed a pronounced reactivity issue. With an
excess of cyclohexanone in the presence of 4 Å molecular
sieves, bis‐spirocycle 4o was isolated with only 7% yield. This
could be improved to 35% by adding Yb(OTf)3 as Lewis‐acidic
activator of the ketone.
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spirocycles. For example, hydrogenative debenzylation of 4a
View Article Online
DOI: 10.5103w9/iCt5hOBa0l2m4o53sFt
furnished the monoprotected pyrazolidine
quantitative yield (Scheme 3). In contrast, removal of the Boc
group under acidic conditions led to a mixture containing 50%
of the ring‐opened product 6. Obviously, the presence of a
protecting group at the hemiaminal nitrogen is important for
the stability of the spirocyclic pyrazolidine.
Scheme 3 Deprotection of spiroacetal 4a
In most cases, the spirocyclic pyrazolidines
4 were formed
with diastereomeric ratios between 2:1 and 3:1. Generally,
aromatic and heteroaromatic aldehydes give higher diastero‐
selectivites (up to 4:1) than their aliphatic counterparts
(Scheme 2). The catalyst did not have an impact on the
diastereoselectivity. The relative configuration of the major
diastereomer of product 4h was determined by X‐ray crystal
structure to be (3RS,5SR). The diastereoselectivities and the
configuration of the major isomer are analogous to those
observed previously in the gold‐ and Brønsted acid‐catalyzed
three‐component coupling of alkynols, anilines, and glyoxalic
acid.14a
From the mechanistic point of view, there appear be exist
two possible pathways for the formation of the spirocyclic
Scheme 2 Scope of the gold‐catalyzed three‐component
spirocyclization. Conditions according to Table 1, entry 14.
Diastereomeric ratios determined by 1H‐NMR. Moc
=
pyrazolidines
4 from the components 1‐3 which differ in the
methoxycarbonyl. a With 8 equiv. of cyclohexanone, 10 mol%
of Yb(OTf)3 and 4 Å molecular sieves. b Only two diastereomers
observed.
order of events. Following the proposal made previously by
one of us (H.O.) for the gold‐catalyzed three‐component
annulation to dihydropyrazoles, a Mannich‐type coupling of
the aldehyde with the hydrazine would afford a propargyl
hydrazine; cyclization to a dihydropyrazole would then be
followed by an intramolecular hydroalkoxylation to give the
spiroacetal.8 Alternatively, the reaction might be initiated by
gold‐catalyzed cyclization of the alkynol to an exocyclic enol
ether17 which then undergoes a [3+2]‐cycloaddition with an
azomethine ylide formed from the hydrazine and the
Structural variations of the alkynol
well. Introduction of substituents at the tether connecting
triple bond and hydroxy gave products 4p . Interestingly, only
1 were rewarding as
‐r
two diastereomers were formed in the case of the richly
functionalized 6‐oxa‐1,2‐diazaspiro[4.4]nonane 4r. Extension
of the tether by one carbon atom allowed the smooth
formation of the 6‐oxa‐1,2‐diazaspiro[4.5]decane 4s with good
yield of 75%. Nicely, the spirocyclization is not restricted to
terminal alkynols; use of internal acetylenic alcohols furnished
1
aldehyde. Following the reaction of by H‐NMR spectroscopy
revealed a rapid consumption of the alkynol within 5 min
whereas the hydrazine is consumed at a slower rate (Fig. 2).
Moreover, an intermediate was observed in the 1H‐NMR at  
3.5 which may be attributed to an enol ether.
the products 4t/u with a fully substituted pyrazole ring, albeit
with reduced yield (46/52%). Analogous to 4r, only two of four
possible diastereomers were obtained. Finally, variation of the
protecting groups at the hydrazine
3 is also possible. For a
successful three‐component transformation, the hydrazine has
to bear an electron‐rich and an electron‐deficient group.8,
18
The former can be benzyl or p‐methoxybenzyl (product 4b); for
the latter, various carbamates can be employed: Boc, Cbz
(spirocycles 4u‐v, 4x‐z), or Moc (products 4w, 4aa‐ac). This
opens up different options for further transformation of the
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in a one‐pot fashion based on simple starting materials. The
gold‐catalyzed three‐component coupling of alkynols,
View Article Online
DOI: 10.1039/C5OB02453F
B/
AgSbF6
(5 mol%)
Ph
Bn
a
O
b
Cbz
A
O
H
c
Bn
N
HO
+
+
hydrazines and aldehydes or ketones likely proceeds via
cycloisomerization of the alkynol to an exocyclic enol ether
and subsequent [3+2]‐cycloaddition of an azomethine ylide.
We have synthesized a library of 29 derivatives with a wide
range of functional groups in up to 97% yield. With this new
method, every position in the final product can be substituted
as required for applications in combinatorial or medicinal
chemistry. Further work devoted to a better mechanistic
understanding, as well as, to an improved substrate scope,
reactivity, sustainability, and stereoselectivity of the three‐
component spirocyclization is in progress. Gratifyingly, initial
experiments to perform the reaction in micelles with water as
bulk solvent were successful.20 Reaction of isobutyraldehyde,
pent‐4‐yn‐1‐ol, and benzyl/Cbz‐protected hydrazine with
N
N
N
C6D6, rt
Ph
H
H
C
Cbz
B
Fig. 2 Kinetic 1H‐NMR study of the gold‐catalyzed three‐
cationic gold catalyst
A in an aqueous medium containing 5%
component coupling.
polyoxyethanyl ‐tocopheryl sebacate (PTS) and 3 M NaCl

afforded spiroacetal 4v with 35% yield after 20 h at 50°C
(Scheme 5). Even though further optimization is required, this
result demonstrates that even highly demanding
multicomponent reactions can be carried out under the
challenging conditions of micellar catalysis.
Accordingly, we assume that the transformation starts with
the gold‐catalyzed cycloisomerization of alkynol
1 to enol
ether III via intermediates
I
and II (Scheme 4).14a,17 The
subsequent [3+2]‐cycloaddition with azomethine ylide IV may
follow a stepwise (via intermediate Va) or concerted pathway
(via transition state Vb). There is a limited number of examples
for gold‐catalyzed [3+2]‐cycloadditions involving azomethine
ylides;14a,19 thus, the gold catalyst may be involved also in the
O
H
O
A (5 mol%)
final step towards spirocycles 4. Unfortunately, attempts to
HO
N
5% PTS, 3 M NaCl
H2O, 50°C, 20 h
N
H
perform the [3+2]‐cycloaddition with preformed enol ethers
Bn
Cbz
N
Cbz
4v (35%)
have failed due to the instability of these substrates.17b
Bn
N
H
OH
OH
[Au]
Scheme 5 Gold‐catalyzed three‐component spirocyclization in
1
I
micelles (PTS = polyoxyethanyl ‐tocopheryl sebacate).
H
O
[Au]
[Au]
Notes and references
II
1
(a) S. M. Sondhi, N. Singhl, M. Johar, B. S. N. Reddyb, J. W.
O
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Boc
N
Boc
Bn
R
Bn
R
N
III
N
N
IV
IV
Boc
Boc
Boc
N
Bn
Bn
R
N
N
Bn
R
N
N
N
R
O
O
4
2
3
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O
Va
Vb
Scheme 4 Proposed mechanism for the gold‐catalyzed three‐
component spirocyclization.
Conclusions and outlook
We have developed an efficient, highly atom economic and
general synthesis of hitherto unknown spirocyclic pyrazolidines
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18 With doubly Boc‐protected hydrazine, no reaction took place;
with mono‐Boc‐protected hydrazine, the corresponding hydra‐
zone was formed.
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