Conjugate addition-initiated Nazarov cyclization

Article abstract of DOI:10.1021/ja205440x

A reaction sequence involving the 1,6-conjugate addition of a nucleophile to a dienyl diketone followed by Nazarov cyclization is described. Several nucleophiles are identified as competent initiators for the sequence. A different reaction outcome is observed when catalytic amounts of nucleophile are employed, involving elimination of the nucleophile after the electrocyclization.

Full text of DOI:10.1021/ja205440x

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Conjugate Addition-Initiated Nazarov Cyclization
Joshua L. Brooks, Patrick A. Caruana, and Alison J. Frontier*
Department of Chemistry, University of Rochester, Rochester, New York 14627, United States
S Supporting Information
b
Scheme 1. Two Cyclization Pathways of Unsaturated
r-Diketonesa
ABSTRACT: A reaction sequence involving the 1,6-con-
jugate addition of a nucleophile to a dienyl diketone
followed by Nazarov cyclization is described. Several nu-
cleophiles are identified as competent initiators for the
sequence. A different reaction outcome is observed when
catalytic amounts of nucleophile are employed, involving
elimination of the nucleophile after the electrocyclization.
he classical Nazarov cyclization involves Lewis acid-pro-
T
moted generation of a pentadienyl cation from a divinyl
ketone, which undergoes conrotatory 4π electrocyclization to
deliver cyclopentenone derivatives.1 Recent advances in
catalysis2 and capture of the oxyallyl cation intermediate3 have
increased the synthetic utility of the reaction. It is also possible to
generate the reactive pentadienyl cation using methods other
than Lewis acid activation, including protonation of enol ethers,4
oxidation,5 and cyclopropanation.6 In this communication, the
development of a 4π electrocyclization initiated by 1,6-conjugate
addition of a nucleophile to a dienyl diketone is described. The
two-step sequence is catalyzed by Lewis acids, is stereoselective,
and affords high yields of R-hydroxycyclopentenones.
a Reagents and conditions: a) Yb(OTf)3 (catalytic), pyrrolidine (1 equiv),
DMSO, rt, 63%. b) Yb(OTf)3 (10 mol %), pyrrolidine (1 equiv), DMSO,
rt, 83%.
Tius has described the Nazarov cyclization of diketones of
type 1 using Yb(OTf)3 and pyrrolidine as a base, which gives
diosphenol 3 (Scheme 1).7,8 We found that treatment of dienyl
diketone 4 under similar reaction conditions resulted in a
different cyclization, giving R-hydroxycyclopentenone 6, with
incorporation of the pyrrolidine base (see Figure 1). Further
exploration of this interesting diastereoselective reaction was
warranted.
Studies began with catalyst evaluation (Table 1). Although the
reaction did occur in the absence of an acidic promoter, the rate
was much slower (24 h vs 15 min), and no diastereoselectivity
was observed (entry 1). Using 10 mol % of a protic or Lewis acid,
full conversion was achieved in 15 min with very high diastereos-
electivity (entries 2, 4, 5, and 6). In general, Lewis acidic
transition metal complexes (entries 2À5) gave better chemical
yields than the protic acid (TFA, entry 6).
At lower catalyst loading (2.5 mol %), yields decreased, and
Y(OTf)3 was found to be more effective than Cu(OTf)2 (entries
7 and 8). Experimentation with solvents revealed that CH2Cl2
gave the best selectivity (entry 10), while THF produced the
highest chemical yield (entry 11). The reaction was further
optimized by the addition of Et3N and LiCl (entry 12), which
are thought to improve catalyst solubility.9
Figure 1. ORTEP drawing of 6.
was also effective for these reactions, but yields were lower.
Malonate derivatives also participated as nucleophiles, allow-
ing for the installation of a versatile carbon-based handle
(8fÀ8i). Addition of malonate did not occur when Cu(OTf)2
was used as catalyst. In all of these reactions, only one
diastereoisomer was detected. The more complex diketone
7 also underwent smooth cyclization to give pyrrolidine
adduct 9, as a 1:1 mixture of diastereomers relative to the
remote stereocenter (see Supporting Information [SI]).
The stereochemistry of compounds 6 and 8c was assigned
using X-ray crystallographic data, and in other cases the syn
Efforts were then made to identify other viable nucleophiles
for the reaction. Primary amines and cyclic and acyclic secondary
amines did initiate the cyclization (8aÀ8e; Scheme 2). Cu(OTf)2
Received: June 18, 2011
Published: July 22, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/ja205440x J. Am. Chem. Soc. 2011, 133, 12454–12457
|

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Table 1. Optimization of the Pyrrolidine-Initiated
Cyclizationa
Table 2. Formation of Dienone 10a
product
time
(h)
yield
(%)
baseb
entry
catalyst
solvent
dr
1:1
yield (%)
entry
nucleophile
(ratio 10:11)
1b
2
--
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
68
99
87
83
99
74
54
68
81
71
89
99
1
2
3
4
DMAP (10 mol %)
DMAP (1 equiv)
i-PrMe2N (10 mol %)
N-methyl-morpholine
(10 mol %)
10 only
10 only
1:1
À
48
48
48
48
45
75
45
55
Cu(OTf)2 (10 mol %)
Sc(OTf)3 (10 mol %)
Yb(OTf)3 (10 mol %)
Y(OTf)3 (10 mol %)
TFA (10 mol %)
>20:1
3:1
À
À
À
3
4
>20:1
>20:1
>20:1
4:1
1:1
5
5c,d
6c,d
7
12 (10 mol %)
10 only
10 only
10 only
1:1
t-BuOK
t-BuOK
Et3N
1
1
8
1
1
93
82
64
94
50
6
7
Cu(OTf)2 (2.5 mol %)
Y(OTf)3 (2.5 mol %)
Y(OTf)3 (1 mol %)
Y(OTf)3 (1 mol %)
Y(OTf)3 (1 mol %)
Y(OTf)3 (1 mol %)
13 (10 mol %)
8
15:1
9:1
DMM (1 mol %)
DMM (1 mol %)
DMM (1 mol %)
DMM (1 mol %)
DABCO
9
8
NaH
10
11
12c
CH2Cl2
THF
>20:1
9:1
9
10 only
10 only
1
DBU
10
THF
>20:1
82
a Reaction conditions: 4 (1 equiv), pyrrolidine (1.2 equiv), catalyst as
listed. All reactions were conducted at 0.1 M for 15 min at rt except
where otherwise noted. b The reaction required 24 h for completion.
c With Et3N (1 equiv) and LiCl (2 equiv).
Scheme 2. Scope of the Cyclizationa
a Reaction conditions: 4, Y(OTf)3 (1 mol %), LiCl (2 equiv), THF
(0.1 M), at rt unless otherwise stated. b Ratio of base:nucleophile
c
was 1:1. Thiol premixed with base, À78 °C then 4. d No Lewis acid
present. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene; DABCO = 1,4-
diazabicyclo[2.2.2]octane.
instead of enones 8 (Table 2, entries 1 and 2). A stoichiometric
amount was required for complete conversion (entry 2). Other
nucleophiles known to be effective in the MoritaÀBaylisÀ
Hillman reaction were also tested.10 The tertiary amines N,N-
dimethylisopropylamine and N-methylmorpholine gave a 1:1
mixture of 10 and 11 in moderate yield (entries 3 and 4), while
DBU and DABCO did not catalyze the reaction. Tertiary
phosphines were also ineffective. Thiols 12 and 13, which are
effective in the RauhutÀCurrier reaction,11 did catalyze the
cyclization, allowing complete conversion to 10 in 1 h. Interest-
ingly, we found that catalytic amounts of dimethyl malonate
(DMM) in the presence of base also led to formation of product
10. The most effective base for the DMM-catalyzed process was
DABCO (cf. entries 6À9, Table 2)
A proposed mechanism for the cyclization and subsequent
elimination is presented in Scheme 3. The reaction begins with
Lewis acid-promoted conjugate addition of the nucleophile to
form intermediate 14. Activation of the ketone carbonyl pro-
duces pentadienyl cation 15, which undergoes 4π conrotatory
cyclization to give products of type 8. The high diastereoselec-
tivity is thought to result from the conrotatory electrocyclization
of pentadienyl cation 15.12 Thus, Lewis acidic Y(OTf)3 is
responsible for activation of first one carbonyl (for conjugate
addition) and then the other (for electrocyclization). In the
formation of compound 10, intermediate 8 undergoes elimina-
tion through intermediate 16.
a Reaction conditions: a) 4, Y(OTf)3 (1 mol %), Et3N (1 equiv), LiCl
(2 equiv), amine or malonate nucleophile (1.2 equiv), THF, rt; b) 7,
Cu(OTf)2 (10 mol %), pyrrolidine (1 equiv), DMSO, rt.
relationship between the R-methyl and β-methylene was
detected by measurement of the NOE (see SI).
The reactions with dimethylmalonate (DMM) as nucleophile
warrant further comment. Products 8fÀ8i are obtained using a
By employing DMAP as the nucleophile, it was possible
to achieve a different reaction outcome, obtaining dienone 10
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dx.doi.org/10.1021/ja205440x |J. Am. Chem. Soc. 2011, 133, 12454–12457

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Scheme 3. Proposed Mechanism for Cyclization
In summary, a new method for the initiation of the Nazarov
cyclization via conjugate addition to a dienyl diketone is de-
scribed. The reaction efficiently proceeds to afford either the
nucleophile adducts 8 or the elimination products 10. Further
investigation into substrate scope is underway, as well as the
development of an enantioselective variant of this reaction
sequence.
Scheme 4. Cycloaddition of 10 with Danishefsky’s Diene
Reaction conditions: a) toluene, 180 °C, sealed tube, 24 h, then TFA
(10 mol %) 10 min, rt, 80%.
’ ASSOCIATED CONTENT
S
Supporting Information. Experimental details and char-
b
acterization data for all new compounds, X-ray crystal structures,
and CIF file for 6, 8c, and 17. This material is available free of
charge via the Internet at http://pubs.acs.org
’ AUTHOR INFORMATION
Corresponding Author
frontier@chem.rochester.edu
’ ACKNOWLEDGMENT
We thank the National Institutes of Health (NIGMS R01
GM079364) and ARRA supplement (3R01GM079364-03S2)
for funding this work. We are also grateful to Dr. William
Brennessel for solving X-ray structures of 6, 7c, and 17.
Figure 2. ORTEP drawing of 17.
stoichiometric amount of malonate (Scheme 2), while product
10 is obtained using catalytic DMM (Table 2, entry 9). A series of
experiments were performed to better understand these observa-
tions. Subjection of 10 to DMM under the reaction conditions
used in the Scheme 2 experiments gave 8f as a 1:1 mixture of
diastereomers, presumably via intermediate 16. Also, if the
reaction of 4 with DMM (Scheme 2) was run for a longer period,
8f with dr = 1:1 was isolated. When 8f (dr > 20:1) was
resubjected to the Scheme 2 reaction conditions, complete
epimerization was observed after 2 h (dr = 1:1). Finally, treat-
ment of 8f with 1 equiv of diethylmalonate under the usual
reaction conditions led to a 1:1 mixture of 8f and 8g, as mixtures
of diastereomers. These experiments indicate that, with malonate
derivatives as nucleophiles, the formation of 10 from 8 is
reversible under the reaction conditions, and this equilibrium
between 8 and 10 lies in favor of 8.
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