Expanding the Scope of the Gold(I)-Catalyzed Rautenstrauch Rearrangement: Protic Additives

Article abstract of DOI:10.1021/acs.orglett.6b02505

The synthesis of substituted 2-cyclopentenones using a commercially available gold(I) catalyst is described under flexible reaction conditions. During the course of our investigations, we discovered that using a proton source as an additive is required to obtain the desired substituted cyclopentenones in good yields.

Full text of DOI:10.1021/acs.orglett.6b02505

Letter
pubs.acs.org/OrgLett
Expanding the Scope of the Gold(I)-Catalyzed Rautenstrauch
Rearrangement: Protic Additives
Cedric Burki,† Andrew Whyte,† Sebastian Arndt,‡ A. Stephen K. Hashmi,‡,§ and Mark Lautens*,†
́
̈
†Davenport Research Laboratories, Department of Chemistry, University of Toronto, Toronto M5S 3H6, Canada
‡Organisch-Chemisches Institut, Ruprecht-Karls-Universitat Heidelberg, Im Neuheimer Feld 270, 69120 Heidelberg, Germany
̈
§Chemistry Department, Faculty of Science, King Abdulaziz University, Jeddah 21589, Saudi Arabia
S
* Supporting Information
ABSTRACT: The synthesis of substituted 2-cyclopentenones using a
commercially available gold(I) catalyst is described under flexible
reaction conditions. During the course of our investigations, we
discovered that using a proton source as an additive is required to
obtain the desired substituted cyclopentenones in good yields.
Scheme 1. Reported Rautenstrauch Rearrangements
n 2013, we reported a tandem Meyer−Schuster rearrange-
ment/enantioselective conjugate addition for the one-pot
I
asymmetric synthesis of β-disubstituted ketones from racemic
propargylic alcohols.1 With these results in hand, we envisioned
extending this concept toward the preparation of enantioen-
riched 2-cyclopentanones using the Rautenstrauch rearrange-
ment followed by a Pd(II)-catalyzed asymmetric conjugate
addition.2−4
Synthesis of cyclopentenones from acyclic precursors has been
achieved through efficient catalytic processes.5 A variety of gold
catalyzed cyclizations have been reported for the synthesis of
cyclopentenones.6−10 For example, Rautenstrauch pioneered the
transformation of 1-ethynyl-2-propargyl acetate derivatives 1
into 2-cyclopentenones 2 mediated by a palladium(II) catalyst in
1984 (Scheme 1a).11 In 2005, Toste (Scheme 1b)12 as well as
Gagosz13 reported that gold(I) can catalyze the transformation
of similar substrates 3 into the related cyclopentenones 4 in a
more efficient manner than when palladium is employed. They
demonstrated the tolerance of this reaction to a diverse
substitution pattern as well as its sensitivity to the reaction
conditions. Indeed, only dilute solutions of substrate in MeCN
afforded the desired cyclopentenone products in good yields,
while dichloromethane, THF, or methanol afforded lower yields.
They also demonstrated that chirality transfer occurred when
enantioenriched 1-ethynyl-2-propenyl pivaloates were employed
as starting materials. In 2015, Toste disclosed an asymmetric
dearomative version of this rearrangement using acetals 5 for the
preparation of indole derivatives 6 (Scheme 1c).14 Very recently,
Occhiato and co-workers reported a gold-catalyzed reaction
similar to the Rautenstrauch rearrangement generating
cyclopenta[b]indol-1-ones.15
rearrangement in order to suit this goal led to the development of
modified conditions for this gold-catalyzed reaction. Herein, we
report a versatile set of reaction conditions for the Rautenstrauch
rearrangement which allow for the straightforward construction
of complex cyclopentenone structures.
To explore a one-pot Rautenstrauch rearrangement−asym-
metric conjugate addition (Scheme 1d), we aimed to use DCE
since Stoltz and co-workers showed it to be the optimal solvent
for the asymmetric conjugate addition.2−4 In this regard, our
investigations in modifying the parameters of the Rautenstrauch
Received: August 21, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02505
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Organic Letters
Letter
To initiate our investigation, we independently attempted the
Rautenstrauch rearrangement under the two sets of conditions
reported by Toste12 and Gagosz13 and co-workers on the
transformation of propargyl pivalate ester 7a into cyclo-
pentenone derivative 8b. Toste’s group reported a 63% yield
with PPh3AuOTf (Table 1, entry 1) and Gagosz’s group reported
Table 2. Reaction Condition Screening
a,b
entry scale (mmol) C (mol/L) proton source (equiv) yield (%)
Table 1. Reproduction of Gagosz’s Results
1
2
3
4
5
6
7
0.25
0.25
0.25
0.25
0.25
0.25
5
0.063
0.063
0.063
0.063
0.25
none
44
83
water (1)
AcOH (1)
AcOH (2)
water (1)
AcOH (2)
AcOH (2)
59
81 (76)
67
0.25
77
0.25
(80)
temp
time
scale
water
yield
(%)
a
1
Yields were determined by H NMR spectroscopy analysis of the
entry
cat. (mol %)
(°C) (min) (mmol) (equiv)
crude reaction mixture using 1,3,5-trimethoxybenzene as internal
standard. Isolated yields in parentheses.
1 (Toste)
PPh3AuOTf (2
mol %)
rt
5
600
75
0.38
1.0
nd
nd
82
81
48
74
b
2 (Gagosz) PPh3AuNTf2 (1
mol %)
highlights the scalability of this reaction under relatively
concentrated conditions.
Having now developed reaction conditions that would be
better suited to the tandem reaction, we investigated the scope
and limitations (Scheme 2). The first set of substrates bears alkyl
3
PPh3AuNTf2 (1
mol %)
rt
rt
60
0.25
0.25
4
PPh3AuNTf2 (1
mol %)
60
1
Scheme 2. Rautenstrauch Rearrangement: Reaction Scope
an 81% yield using PPh3AuNTf2 with a notably shorter reaction
time (75 min, entry 2). During our early efforts, we noted that
previously reported conditions used reagent-grade MeCN. We
found that running the reaction in MeCN distilled over CaH2
afforded 8b in 48% yield (Table 1, entry 3). We were further
inspired by the report of Zhang and Wang which described a
closely related Au-mediated Nazarov-type cyclization of enynyl
acetates in CH2Cl2.16 They observed that wet solvent was critical
to obtain the desired product in good yield. Following this report,
we ran the reaction with dry solvent and purposely added a
known amount of a proton source to examine its influence on the
efficiency. We anticipated that a proton is needed for the
proposed hydrolysis of the enol ester intermediate (Scheme 3,
14).17,18 Upon addition of 1 equiv of water to the reaction
mixture, the product was obtained in 74% yield (Table 1, entry
4).19 We continued our investigation using anhydrous solvent
with a controlled amount of added water in order to quantify the
optimal amount of the moisture for the reaction.
In our work, we decided to test water and acetic acid (used by
Rautenstrauch) as additives in the transformation of enynyl ester
7b into cyclopentenones 8b (Table 2). We optimized these
conditions using CH2Cl2 or DCE, as they would be suited for the
development of the desired tandem reaction involving an
asymmetric conjugate addition.2−4,20 In the absence of water,
product 8b was formed in 44% yield by NMR (Table 2, entry 1),
and we observed formation of products of a polymeric nature.
Upon the addition of 1 equiv of water, the yield increased to 83%
(Table 2, entry 2). We then tested acetic acid as a proton source.
The addition of 1 equiv resulted in 59% yield by NMR (Table 2,
entry 3), but the yield improved when 2 equiv of acetic acid was
added (Table 2, entry 4). In addition, the low concentration
required for the reaction hampered its feasibility on a large scale.
We observed that a higher concentration negatively influenced
the reaction outcome when water was used, giving a 67% NMR
yield (Table 2, entry 5). However, we obtained good yields of the
desired cyclopentenone when AcOH was used as an additive at
0.25 M on a 5 mmol scale (Table 2, entries 6 and 7), which
a
b
See the Supporting Information for reaction details. Yields were
1
determined by H NMR spectroscopy analysis of the crude reaction
mixture using 1,3,5-trimethoxybenzene as internal standard.
groups at R1 and R2. Products 8a and 8b were afforded in good
yields with water (conditions a) or acetic acid (conditions b) as
additives. Employing a cycloheptane ring led to a slight decrease
in yield in product 8c when conditions a were used, and the
reaction became messy under conditions b. When substituents R1
and R2 were linear alkyl chains, yields were generally good as
exemplified with enones 8d and 8e. The yield of 8e was
somewhat lower, potentially due to its high volatility. A halide on
substituent R1 and an aromatic ring as substituent R2 in 8f were
also tolerated in this reaction and afforded a high yield under
conditions a and a moderate yield in the presence of acetic acid
(conditions b). As exemplified by 8g, omission of substituent R1
afforded generally lower yield compared to other products.
Nevertheless, the yield could be increased by employing a higher
catalyst loading in the presence of acetic acid (conditions c).
Interestingly, omission of the substituent R2 did not affect the
B
DOI: 10.1021/acs.orglett.6b02505
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Organic Letters
Letter
reaction outcome. A methyl (8h) or butyl (8i) side chain was
well tolerated and afforded high yields in the presence of added
water (conditions a) or acetic acid (conditions b). Alternatively,
silyl-protected alcohols successfully underwent this trans-
formation under conditions a. The increased stability of the
TIPS-protected alcohol (8j) compared to the TBS protecting
group (8k) might explain the difference in yield between these
reactions.21 Finally, a substituent could be introduced at the R3
position. While a simple alkyl chain (8l) was successful in the
reaction, aromatics (8m,n) and ethyl ester (8o,p) required a
modification of the reaction conditions. Indeed, we observed that
the presence of water in the reaction mixture afforded an
undesired alkyne hydration product (Scheme 3, 12) leading to
Table 3. Solvent Screening
b
conv
product 8i (%
hydration product 9 (%
c
c
entry
solvent
(%)
yield)
yield)
a
1
CH2Cl2
100
100
100
14
96
87
94
9
0
0
a
2
CDCl3
a
3
DCE
0
4
MTBE
Et2O
4
5
38
14
14
0
8
a
6
THF
18
3
a
Scheme 3. Reaction Mechanism
7
dioxane
19
0
a
8
toluene
77
57
43
36
10
11
0
a
9
MeCN
EtOAc
acetone
MeOH
56
10
11
12
52
4
80
64
>99
100
0
a
b
Solvent distilled over drying agent. See the Supporting Information
c
for reaction details. Yields were determined by 1H NMR spectroscopy
analysis of the crude reaction mixture using 1,3,5-trimethoxybenzene
as internal standard.
and the reaction could be run in the absence of water, but a strong
acid was required to liberate the desired cyclopentenones 15 at
the end of the reaction. When R3 was a hydrogen, the enol ester
was less stable, and a proton source like water or a weak acid was
required to afford the cyclopentenones 16 in good yields. The
poor yields at the beginning of our investigations were due to
unknown side products of polymeric nature and could be
avoided by the addition of water from the outset of the reaction.
To demonstrate the usefulness of the revamped conditions for
the Rautenstrauch rearrangement, we prepared an intermediate
in the synthesis of the cyclopentylamine 17, a new antidepressant
exhibiting dual NK1R antagonism and SERT inhibition.25,26 Our
synthesis utilized a palladium-mediated asymmetric conjugate
addition on the substrate 8j, forming the quaternary carbon in
product 18 with the desired configuration (Scheme 4).2−4 The
decreased yields. The reaction was then run under anhydrous
conditions, and formation of an isolable pivalic enol ester was
detected (Scheme 3, 14). Addition of anhydrous HCl (generated
from acetyl chloride and methanol) after consumption of the
starting material unveiled the desired product in good yield. This
product represents an unprecedented substituted cyclopente-
none scaffold.22
We decided to explore the tolerance of this reaction to
different solvents in order to broaden its utility. Generally,
chlorinated solvents (CH2Cl2, CHCl3, and DCE) afforded the
desired product 8i in high yield (Table 3, entries 1−3). In turn,
ethereal solvents (MTBE, Et2O, THF, dioxane) proved
unsuitable for this reaction since the conversion and the yield
were low (entries 4−7). Toluene, acetonitrile, and ethyl acetate
led to a decent conversion and reasonable to low yields of
product 8i (entries 8 and 9). Interestingly, polar solvents such as
acetone and methanol, where the water content was not
controlled, showed good conversion but predominant formation
of the undesired hydration product 9 (entries 10 and 11).
After improvement of the reaction conditions and exploration
of the reaction scope, our developments can be evaluated in light
of the reaction mechanism proposed by Toste and co-workers.12
In this mechanism, the first event is complexation of the alkyne of
10 by the cationic gold catalyst, which triggers an intramolecular
nucleophilic attack of the carbonyl of the pivalic ester to afford
the cationic intermediate 11.23,24 In the cases where R3 was an
electrophilic group, like an ester or an aromatic ring, hydration
afforded the undesired product 12. The intermediate 11 then
undergoes a Nazarov-like rearrangement to form the 5-
membered ring 13 followed by elimination to give the
substituted cyclopentadiene 14. We observed that the sub-
stituent R3 modulated the stability of this cyclopentadiene ring,
and this determines the conditions necessary to successfully run
the Rautenstrauch reaction. When R3 was an electron-with-
drawing group or an aromatic ring, the enol ester 14 was stable
Scheme 4. Formal Synthesis of Cyclopentylamine 17
silyl ether was not isolated, and the TIPS protecting group was
removed using tetrabutylammonium fluoride (TBAF). The
configuration of the quaternary center in 18 was unambiguously
determined by X-ray diffraction analysis. Benzylation with
trichloroacetimidate 1927 yielded the benzyl ether product 20,
which was a known intermediate toward this cyclopentylamine
C
DOI: 10.1021/acs.orglett.6b02505
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Organic Letters
Letter
target.25,26 This reaction sequence would be a novel and flexible
enantioselective entry in to this promising class of API allowing a
convergent strategy.
Finally, we imagined that the Rautenstrauch rearrangement
could be incorporated in a two-step process with a Tsuji−Trost
allylation28,29 to access functionalized chiral cyclopentenones
(Scheme 5). Work by Clark and co-workers30 have already
(NSERC) for financial support. We thank Dr. D. Petrone, Dr.
Z. Qureshi, Alvin Young-Jin Jang (University of Toronto), and
Dr. L. Zhang (Stanford University) for fruitful discussions
throughout the project. C.B. thanks the SNSF (Grant No.
P2BEP2_155570) for financial support. We thank Dr. Alan
Lough (University of Toronto) for single-crystal X-ray structural
analysis of 18.
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Scheme 5. Rautenstrauch−Allylation Method
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b02505.
P.; Cavallo, L. Angew. Chem., Int. Ed. 2008, 47, 718.
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Experimental procedures and full compound character-
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: mlautens@chem.utoronto.ca.
Notes
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The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
We thank the University of Toronto, Alphora Research, Inc., and
the Natural Sciences and Engineering Research Council
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DOI: 10.1021/acs.orglett.6b02505
Org. Lett. XXXX, XXX, XXX−XXX