Enhanced geometrical control in a Ru-catalyzed three component coupling

Article abstract of DOI:10.1016/S0040-4039(00)01735-4

Exclusive Z-selectivity in the Ru-catalyzed bromoalkylation of alkynes with vinyl ketones is observed with aryl and other tertiary substituted acetylenic substrates, a feature that has led to an efficient synthesis of a COX-2 inhibitor. (C) 2000 Elsevier

Full text of DOI:10.1016/S0040-4039(00)01735-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9627–9631
Enhanced geometrical control in a Ru-catalyzed three
component coupling†
Barry M. Trost* and Anthony B. Pinkerton
Department of Chemistry, Stanford University, Stanford, CA 94305-5080 USA
Received 26 July 2000; revised 3 October 2000; accepted 4 October 2000
Abstract
Exclusive Z-selectivity in the Ru-catalyzed bromoalkylation of alkynes with vinyl ketones is observed
with aryl and other tertiary substituted acetylenic substrates, a feature that has led to an efficient synthesis
of a COX-2 inhibitor. © 2000 Elsevier Science Ltd. All rights reserved.
In previous papers, we reported the ruthenium-catalyzed haloalkylation of acetylenes could
occur with either a cis1 or trans2 geometry to form Z-1 or E-1, respectively, as outlined in
Scheme 1.3 The competition of the conversion of 2 to 3 compared to the conversion of 4 to 5
determines the geometric selectivity. Our interest in employing the Z-bromoalkenes (Z-1,
X=Br) in a cyclopentenone synthesis4 stimulated the need to enhance the Z-selectivity of the
bromoalkylation process. Examination of 3 and 5 suggests that the steric interactions between
X
O
R
O
[Ru]
R
R'
X
R'
Z-1
E-1
[Ru+]
R'
R'
O
O
cycle A
R
cycle B
R
X
R
X
R
X
[Ru]
R
[Ru]
[Ru-X]
[Ru+] X
3
5
4
2
Scheme 1. Proposed mechanism of Ru-catalyzed haloalkylation
* Corresponding author.
†
Dedicated with great admiration to Professor Harry H. Wasserman in honor of his 80th birthday and with best
wishes for many more to come.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01735-4

9628
the alkyne substituent R and the metal may affect their ease of formation. In this paper, we
report the results of our investigation of this effect. The success of these studies led to a very
successful synthesis of 2-arylcyclopentenones as demonstrated by the completion of a short
synthesis of a COX-2 inhibitor.
Using a classical t-butyl group as the acetylenic substituent to maximize steric interactions,
t-butylacetylene (6) and methyl vinyl ketone (7b, PVK) were subjected to 10 mol%
−
[CpRu(CH3CN)3]+PF6 (8), 15 mol% stannic bromide and 1.5 equiv. of lithium bromide in
acetone at 60°C (Eq. (1)). Delightfully only a single geometric isomer 95 is observed as product.
Changing the acceptor to phenyl vinyl ketone 7b gave virtually identical results. Replacing the
t-butyl group with trimethylsilyl (e.g. 10) shows no deterioration in the Z-selectivity to produce
exclusively bromide 115 as shown in Eq. (2). The more modest yields may reflect the volatility
of the products upon isolation since the reactions are quite clean.
see text
LiBr
R
R
Br
O
O
(1)
7
6
9
a) R = CH3
b) R = Ph
54%
56%
a) R = CH3
b) R = Ph
as in eq. 1
LiBr
TMS
TMS
(2)
49%
O
Br
O
10
11
Replacing an alkyl group with a hydroxy group as shown with the propargyl alcohol substrate
12 also gave only the Z-alkene 135 with MVK (Eq. (3)). The compatibility of the tertiary
propargylic alcohol is particularly noteworthy because of the well known reactivity of substrates
like 12 to form allenylidene ruthenium complexes.6 Reducing the size of the substituent to an
isopropyl like group as in 14 saw a decrease in Z-selectivity wherein an 8:1 Z:E ratio of
bromoalkenes 155 was obtained (Eq. (4)).
as in eq. 1
LiBr
OH
OH
55%
O
(3)
(4)
Br
O
12
13
as in eq. 1
LiBr
H
H
69%
H
O
H
OH
Br
O
HO
15 Z:E 8:1
14
The steric bulk of an aryl group depends upon its conformation.7 Thus, we were pleased to
observe that phenylacetylene (16a) also shows formation of only the Z-bromoalkene 17a5 (Eq.
(5)) with MVK (7a). As before, replacing MVK (7a) by PVK (7b) showed no deterioration in
Z-alkene selectivity to form 17b.5 Using a more electron rich arylacetylene 16b led to equivalent
results and formed only Z-alkenes 17c5 and 17d5. 3,5-Disubstituted aryl groups are also

9629
tolerated in this reaction as shown in Eq. (6). This equation illustrates the facility of the process
since the starting alkynes 19a,b are easily accessible by a Sonogashira type coupling protocol8
from the bromoarenes 18a,b. Both substrates gave single products 20a and 20b, respectively.
X
as in eq. 1
LiBr
R
R
X
O
Br
O
(5)
16
7
17
53%
55%
c) X = OCH3, R = CH3
a) X = H
a) R = CH3
b) R = Ph
a) X = H, R = CH3
b) X = H, R = Ph
72%
72% d) X = OCH3, R = Ph
b) X = CH3O
R
R
R
R
i) cat. (PhCN)2PdCl2
cat. CuI
as in eq. 1
LiBr
Br
TMS
R
(6)
ii) K2CO3
CH3OH
Br
O
R
18
19
20
a) R = CH3
b) R = F
76%
68%
a) R = CH3
b) R = F
67%
53%
a) R = CH3
b) R = F
One particularly useful application of these adducts of three component coupling is their
application to a synthesis of cyclopentenones as illustrated in the retrosynthetic analysis of Eq.
(7). The sequence is initiated by a Kishi–Nozaki modification9 of the Barbier reaction which
requires the Z-bromoalkene. In the case of aryl substituted substrates, the viability of the initial
adducts of this reaction such as 21 must be questioned since it entails formation of a highly
labile tertiary allylic and benzylic alcohol. Surprisingly, vinylbromide 17b does form 21 which,
upon oxidative rearrangement, provides 2,3-diphenylcyclopentenone 2210 in excellent yield (Eq.
(8)).
O
R
R
R'
(7)
O
R'
O
CrCl2/NiCl2
83%
PDC
83%
17b
(8)
HO
22
21
The success of this cyclopentenone formation led to our exploration of a synthesis of a potent
COX-2 inhibitor 2811 as shown in Scheme 2. The requisite vinyl ketone 24 was formed from the
commercially available carboxylic acid 23 using a Stille coupling with an in situ formed acid
chloride.12 Ruthenium-catalyzed addition of vinyl ketone 24 with acetylene 19b generates a
single vinyl bromide 255. The compatibility with divalent sulfur should be noted. In spite of the
sensitivity of the tertiary alcohol 26, it forms in good yield under the standard conditions.

9630
Oxidative rearrangement produces the previously described cyclopentenone 2711, which was
oxidized as reported using oxone13 to form the desired target 28 in only five linear steps.
Although none of the steps have really been optimized, the overall yield of 28% is quite
reasonable.
F
F
F
O
O
b
Br
O
c
a
F
19b
HO
72%
81%
64%
SCH3
SCH3
O
HO
24
23
SCH3
SCH3
F
F
25
26
O
d
e
F
F
80%
92%
SCH3
SO2CH3
27
28
Scheme 2. A synthesis of a potent cox-2 inhibitor. (a) (COCl)2, cat. DMF, CH2Cl2 then (n-C4H9)3SnCHꢀCH2, 0.01
mol% (Ph3P)2Pd(CH2Ph)Cl, PhCH3, 80°C. (b) 10% [CpRu(NCCH3)3]+PF6−, 15 mol% SnBr4, 1.5 equiv. LiBr,
CH3COCH3, 60°C. (c) CrCl2, NiCl2, DMF, rt. (d) PDC, CH2Cl2, 0°C. (e) Oxone, acetone, H2O, 45°C
The ability to enhance the Z-selectivity by modification of the substrate in the manner
indicated supports the mechanistic rationale as outlined in Scheme 1. The synthetic implications
stem from the ability to use the geometrically pure products directly for further conversions. The
synthesis of the cyclopentenones is but one illustration. Cross-coupling of the vinyl bromides14
is an obvious additional direction that arises.
Acknowledgements
We thank the National Institutes of Health, General Medical Sciences, and the National
Science Foundation for their generous support of our programs. A.B.P. was an ACS Organic
Division Fellow sponsored by Bristol-Myers-Squibb. Mass spectra were obtained from the Mass
Spectrometry Facility, University of San Francisco, supported by the NIH Division of Research
Resources.
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9631
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