Neutral nazarov-type cyclization catalyzed by palladium(0)

Article abstract of DOI:10.1002/anie.201201724

Joining the circle: The first Pd⁰ catalyzed Nazarov-type cyclization of diketoesters (see scheme) proceeds in 70 % to 95 % yield under strictly neutral pH conditions. Aryl substitution of the diketoesters is not required, so the reaction shows great versatility and can also proceed with aliphatic substrates. Copyright

Full text of DOI:10.1002/anie.201201724

Angewandte
Chemie
DOI: 10.1002/anie.201201724
Palladium Catalysis
Neutral Nazarov-Type Cyclization Catalyzed by Palladium(0)**
Naoyuki Shimada, Craig Stewart, William F. Bow, Anais Jolit, Kahoano Wong, Zhe Zhou, and
Marcus A. Tius*
The Nazarov cyclization[1] is an attractive process for the
stereocontrolled assembly of five-membered carbocycles that
are a feature of many natural products.[2] The classical
Nazarov reaction conditions require the use of stoichiometric
or superstoichiometric amounts of strong acid that limits
applications to robust and unfunctionalized substrates.[3] In
Scheme 1. Palladium-catalyzed cyclizations. Conditions: A: (4a)
recent work, Trauner and co-workers,[4] Rueping et al.,[5] and
20 mol% [Pd(PPh3)4], 0.1m CH2Cl2, room temperature, <24 h; 80%
yield. B: (4b) 20 mol% [PdCl2(MeCN)2], 0.1m wet acetone, room
others[6] have described very mild conditions for the catalytic
asymmetric Nazarov reaction. Our group developed the
organocatalytic asymmetric Nazarov reaction that is shown
in Equation (1).[7] Exposure of diketoester 1 to organocata-
temperature, approximately 3 d; 65% yield. C : (4b) 20 mol% [Pd-
(OAc)2], 0.1m DMSO, room temperature, approximately 5 d; 80%
yield.
would also undergo cyclization under PdII catalysis. The
complementary polarization of carbon atoms 2 and 6 in 4a
greatly increases the reactivity, so we hoped that cyclization
would not be suppressed in the presence of phosphines. This
would enable the use of chiral phosphine ligands for an
asymmetric catalytic cyclization. The starting materials for
this study were prepared according to our published
method.[7] The Nazarov product 5 was obtained in 65% or
80% yield from the treatment of 4b with PdCl2 or Pd(OAc)2,
respectively. However, this cyclization did not take place in
the presence of [PdCl2(PPh3)2], thereby precluding our
approach to an asymmetric catalytic process. Much to our
surprise, exposure of 4a to 20 mol% [Pd(PPh3)4] in dichloro-
methane at room temperature led to Nazarov product 5 in
80% yield. This Pd0-catalyzed reaction proceeds under
strictly neutral pH conditions and is the first Nazarov-type
cyclization that is catalyzed by a zero-valent metal. The
success of [Pd(PPh3)4] as a catalyst indicates a mechanism that
is distinct from the PdII catalyzed reaction and suggests the
possibility of asymmetric catalysis through the use of chiral
phosphine ligands.
First, we defined the scope of the cyclization leading to
racemic products. The reaction was optimized with respect to
solvent, concentration, temperature, catalyst, and catalyst
load (Table 1). The cyclization was most efficient in DMF and
DMSO. In the absence of added PPh3, no reaction took place.
Our initial experiments utilized a 1:4 ratio of palladium to
phosphine. Decreasing the ratio to 1:2 had no effect on the
yield (entries 6,7 versus 8,9). In DMSO, we were able to
reduce the catalyst load to 0.5 mol% [Pd2(dba)3] (1 mol% Pd
atoms) without an appreciable decrease in the rate or yield
(entry 11). For less reactive substrates that lack a C6 aryl
group, the use of 2 mol% Pd atoms led to a better reaction, so
we settled on the conditions that appear in entry 10 of Table 1.
No reaction took place in the absence of palladium (entry 14)
and only traces of product were observed in the absence of
PPh3 (entry 13).
lyst 2 led to cyclopentenone 3 in 87% yield and in 98.5:1.5 e.r.
as a single diastereomer. The reaction was slow, most likely
because of product inhibition of the catalyst, which can bind
both product and starting material in a similar way through
their respective keto–enol forms. The C6 aryl group in 1 was
required, whereas a branched substituent at C2 was not
tolerated. We sought an alternative catalytic Nazarov cycli-
zation that would not be subject to these limitations.
In earlier work we described PdII-catalyzed Nazarov-type
cyclizations of a-ethoxy dienones, which proceed through
a palladium enolate intermediate.[8] These PdII-catalyzed
cyclization reactions are initiated through an electrophilic
interaction with the metal and are suppressed in the presence
of basic ligands, for example, PPh3. We postulated that silyl
enol ether 4b, which was prepared from 4a (Scheme 1),
[*] Dr. N. Shimada, Dr. C. Stewart, W. F. Bow, A. Jolit, K. Wong, Z. Zhou,
Prof. M. A. Tius
Chemistry Department, University of Hawaii at Manoa
2545 The Mall, Honolulu, HI 96822 (USA)
E-mail: tius@hawaii.edu
Prof. M. A. Tius
The University of Hawaii Cancer Center
677 Ala Moana Blvd, Suite 901, Honolulu, HI 96813 (USA)
[**] We thank the NIH-NIGMS (R01 GM57873) for generous support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201201724.
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Table 1: Optimization of reaction conditions.
process. Diketoester 21 [Eq. (2)] led to the formation of
cyclopentenone 22 as an approximately 1:1 mixture of
diastereomers in 66% yield. Because 16 was formed through
Entry
Solvent
Pd/P
t [h]
Yield [%]
1[a]
2
3
4
5
6
7
8
CH2Cl2
(CH2Cl)2
PhMe
THF
MeCN
DMF
1:4
1:4
1:4
1:4
1:4
1:4
1:4
1:2
1:2
1:2
1:2
1:2
1:0
0:1[d]
0:0[e]
120
16
16
9
9
7
4
7
4
4.5
5
69
82
85
85
86
90
92
91
92
91
91
72
trace
No rxn
No rxn
the expected mode of cyclization, the presence of the C5
phenyl group must be responsible for the unexpected out-
come in the case of 22. The phenyl group may acidify the C7
methyl allowing dienol 23 to form, which can undergo ring
closure to 22 either through an iso-Nazarov process or
through an intramolecular aldol reaction.
DMSO
DMF
9
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
10[b]
11[c]
12[a]
13[b]
14
15
We considered that the first step of the Nazarov-type
cyclization involved formation of a palladium hydride inter-
mediate and tried to find evidence of oxidative addition of Pd0
to the enol form of the diketoester. We first prepared
diketoester 24 [Eq. (3)]. Oxidative addition of Pd0 to the
enol form of 24 might have led to 26 through hydride 25.
However, there was no evidence of the formation of 26, even
40
24
24
24
[a] 188C. [b] 1 mol% [Pd2(dba)3]. [c] 0.5 mol% [Pd2(dba)3]. [d] 4.0 mol%
PPh3. [e] No [Pd2(dba)3], no PPh3. dba=dibenzylideneacetone.
Scheme 2 summarizes the results. All products were
isolated as single diastereomers in 70% to 95% yield. The
formation of 8 in 82% yield is noteworthy because this
product could not be prepared using the organocatalytic
process, which failed for substrates bearing a branched
substituent at C2.[7] The synthesis of cyclopentenones 16–20
in high yield demonstrates that an aryl substituent is not
required for the Pd0-catalyzed process. Cyclopentenones 16–
20 also could not be prepared through the organocatalytic
after heating the solution for 24 h. Instead we detected the
slow formation of tetronic acid 27. After 24 h at 608C 27 was
isolated as the sole reaction product (40%; 73% based on
recovered starting material (brsm)). Reasoning that 25 might
have formed but that its cyclization to 26 was slow, we
prepared diketoester 28 and repeated the experiment
[Eq. (4)]. Once again we observed only the slow formation
of tetronic acid 29 (11%; 32% brsm after 72 h at 608C) with
no evidence for the formation of 30. Control experiments
showed that tetronic acid formation was not palladium
catalyzed. It is plausible that the conversion to tetronic
acids 27 and 29 is initiated by nucleophilic attack of a ketone
carbonyl oxygen atom onto the ester carbonyl carbon atom.
The experiments with 24 and 28 were repeated in the presence
of 10 equiv styrene in an attempt to trap the palladium
hydride through an intermolecular process. Neither experi-
ment provided evidence of an intermolecular reaction with
styrene.
Because our results to date have not provided evidence
for a Pd0–PdII catalytic cycle proceeding by means of a metal
hydride intermediate, the mechanism for the Nazarov-type
cyclization remains unknown. We considered that other zero
Scheme 2. Examples of the Pd0-catalyzed Nazarov cyclization with
yields.
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bis(1,5-cyclooctadiene)nickel(0) [Ni(cod)2] also catalyzes the
conversion of 6 to 7.[9] Unlike the PdII-catalyzed Nazarov
cyclizations that are suppressed by basic phosphine ligands,
the Pd0-catalyzed cyclization is amenable to asymmetric
catalysis by phosphines and phosphoramidites.[10] For exam-
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and a small excess of phosphoramidite 31[11] leads to 7 in
80.5:19.5 e.r. [Eq. 5]. Significantly, the cyclization is complete
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In conclusion, we have described the first Pd0-catalyzed
Nazarov-type cyclization of diketoesters. The reaction pro-
ceeds in good to excellent yields for a variety of substrates
under strictly neutral pH conditions and has a much broader
scope than the organocatalyzed process of Equation (1). Aryl
substitution at C6 is not required, so the reaction succeeds
with aliphatic substrates, including those that fail to cyclize in
the presence of organocatalyst 2 (e.g. 8, and 16–20). The
mechanism may not involve a pentadienyl cation intermedi-
ate, even though the reaction leads to the same products as
a Nazarov cyclization. Early indications suggest that the
asymmetric version of this process will also be successful.
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Experimental Section
A solution of diketoester 6 (58 mg, 0.20 mmol), [Pd2(dba)3]·CHCl3
(2 mg, 2.0 mmol, 1 mol%), and PPh3 (2 mg, 8.0 mmol, 4 mol%) in dry
DMSO (1.0 mL, 0.2m) was stirred at 608C. After 4.5 h, the reaction
mixture was poured into water (5 mL) and extracted with ether (3 ꢀ
10 mL). The combined ether extracts were washed with water, brine,
and dried (anh. Na2SO4). Evaporation and column chromatography
(silica gel, 15% EtOAc in hexanes) produced 7 as a clear oil (53 mg,
91% yield): 1H NMR (300 MHz, CDCl3): d = 7.26–7.27 (m, 3H),
7.08–7.11 (m, 2H), 3.73 (s, 1H), 3.53 (dq, J = 10.8, 7.2 Hz, 1H), 3.42
(dq, J = 10.8, 7.2 Hz, 1H), 2.23 (dq, J = 14.8, 7.4 Hz, 1H), 2.20 (dq, J =
14.8, 7.4 Hz, 1H), 1.90 (s, 3H), 0.92 (t, J = 7.4 Hz, 3H), 0.85 ppm (t,
J = 7.2 Hz, 3H); 13C NMR (75 MHz, CDCl3): d = 199.8, 169.8, 149.6,
142.8, 136.9, 129.3, 128.1, 127.6, 62.4, 60.8, 55.7, 28.4, 13.4, 12.8,
8.3 ppm; IR (neat): n = 3342, 1731, 1713, 1660, 1242, 1079 cmÀ1; MS
˜
(EI+): m/z (%): 288 [M+, 100], 242 (23), 215 (35), 145 (61), 143 (75),
115 (54); HRMS (EI+): m/z calcd for C17H20O4: 288.1362 [M+]; found
288.1364.
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[8] C. Bee, E. Leclerc, M. A. Tius, Org. Lett. 2003, 5, 4927 – 4930.
[9] In the presence of approximately 23 mol% [Ni(cod)2], 6 was
converted into 7 in 58% yield (86% brsm, not optimized) after
24 h at room temperature. See the Supporting Information for
the reaction conditions.
Received: March 3, 2012
Published online: April 26, 2012
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Keywords: diastereoselectivity · homogeneous catalysis ·
Nazarov cyclization · palladium · synthetic methods
.
[1] Reviews of the Nazarov reaction: a) N. Shimada, C. Stewart,
M. A. Tius, Tetrahedron 2011, 67, 5851 – 5870; b) W. Nakanishi,
F. G. West, Curr. Opin. Drug Discovery Dev. 2009, 12, 732 – 751;
c) T. N. Grant, C. J. Rieder, F. G. West, Chem. Commun. 2009,
[12] Efforts to improve the enantioselectivity of this reaction are
underway.
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