Palladium-catalyzed tandem reactions to form 1-vinyl-1H-isochromene derivatives

Article abstract of DOI:10.1021/jo0011991

The palladium-catalyzed reaction of pinacolone with tert-butyldimethyl(3-(2-bromophenyl)allyloxy)-silane results in direct formation of 1-vinyl-3-tert-butyl-1H-isochromene. This is the result of a ketone arylation followed by an intramolecular cyclization of the enolate with the allylic system. The use of a lithium diamide base appears to be essential for success. The tert-butyldimethylsilyl protecting group is also an essential choice as it furnishes the appropriate reactivity to promote allylic substitution after the aryl coupling process. The use of more effective leaving groups, such as acetate, results in reaction of the allylic group, and no aryl coupling is observed. Through the appropriate selection of phosphine ligand and solvent, either the cyclized isochromene product or the noncyclized intermediate may be formed selectively. A short combinatorial study of the scope and limitations of the reaction, involving 24 ketones, is described.

Full text of DOI:10.1021/jo0011991

3284
J . Org. Chem. 2001, 66, 3284-3290
P a lla d iu m -Ca ta lyzed Ta n d em Rea ction s To F or m
1-Vin yl-1H-isoch r om en e Der iva tives1
Roger Mutter,† Ian B. Campbell,‡ Eva M. Martin de la Nava,†,§ Andy T. Merritt,‡ and
Martin Wills*,†
Department of Chemistry, University of Warwick, Coventry CV4 7AL, U.K., and GlaxoSmithKline
Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, SG1 2NY, U.K.
m.wills@warwick.ac.uk
Received August 7, 2000
The palladium-catalyzed reaction of pinacolone with tert-butyldimethyl(3-(2-bromophenyl)allyloxy)-
silane results in direct formation of 1-vinyl-3-tert-butyl-1H-isochromene. This is the result of a
ketone arylation followed by an intramolecular cyclization of the enolate with the allylic system.
The use of a lithium diamide base appears to be essential for success. The tert-butyldimethylsilyl
protecting group is also an essential choice as it furnishes the appropriate reactivity to promote
allylic substitution after the aryl coupling process. The use of more effective leaving groups, such
as acetate, results in reaction of the allylic group, and no aryl coupling is observed. Through the
appropriate selection of phosphine ligand and solvent, either the cyclized isochromene product or
the noncyclized intermediate may be formed selectively. A short combinatorial study of the scope
and limitations of the reaction, involving 24 ketones, is described.
Sch em e 1. In tr a m olecu la r Cycliza tion Rea ction
During the course of a project directed at the synthesis
To F or m 1-Vin yl-1H-isoch r om en esa
of structural analogues of the anti-cancer molecule bryo-
statin,2 we required a method for the synthesis of 1-vinyl-
1H-isochromenes 1. Toward this end, the reaction of a
suitable ketone 2 with a (o-bromophenyl)allylic ether 3
to give 4, followed by a palladium-catalyzed cyclization
appeared to be an attractive approach. For the first step,
we were confident that a palladium-catalyzed ketone
arylation reaction would be effective.3 However, since
such reactions are typically carried out at elevated
temperatures (ca. 80 °C), we anticipated that the protect-
ing group R would be required to not activate the reagent
toward allylic substitution since this would give an
undesired product. Allylic acetates, for example, are
known to react with ketones under palladium-catalyzed
reactions at room temperature.4
a
Reagents and conditions: (i) ligand, base, toluene/THF or
dioxane, [Pd2(dba)3], 85 °C.
alcohol substrate 5 with pinacolone. Our intention at this
point was to replace the silyl group with an acetate
following the arylation and complete the cyclization in a
second step.
Starting material 5 was prepared from readily avail-
able 2-bromobenzaldehyde in three steps in 90% overall
yield.5 Initial attempts to couple 5 to pinacolone following
the procedure of Hartwig et al.3 (NaO-t-Bu, Pd/DPPF,
toluene, 100 °C) led mainly to the debrominated cinnamyl
ether 6, and no coupling product was observed. Investi-
(1) Preliminary report: Mutter, R.; Martin de la Neva, E.; Wills,
M. Chem. Commun. 2000, 1675.
(2) Mutter, R.; Wills, M. Bioorg. Med. Chem. 2000, 8, 1841.
(3) (a) Palucki, M.; Buchwald, S. L. J . Am. Chem. Soc. 1997, 119,
11108. (b) Hamann, B. C.; Hartwig, J . F. J . Am. Chem. Soc. 1997, 119,
12382. (c) Ahman, J .; Wolfe, J . P.; Troutman, M. V.; Palucki, M.;
Buchwald, S. L. J . Am. Chem. Soc. 1998, 120, 1918. (d) Kawatsura,
M.; Hartwig, J . F. J . Am. Chem. Soc. 1999, 121, 1473. (e) Satoh, T.;
Kametani, Y.; Terao, Y.; Miura, M.; Nomura, M. Tetrahedron Lett.
1999, 40, 5345. (f) Muratake, H.; Natsume, M. Tetrahedron Lett. 1997,
38, 7581.
(4) (a) Fiaud, J . C.; Malleron, J . L. J . Chem. Soc., Chem. Commun.
1981, 1159. (b) Negishi, E.; Matsushita, H.; Chatterjee, S.; J ohn, R.
A. J . Org. Chem. 1982, 47, 3190. (c) Trost, B. M.; Radinov, R.; Grenzer,
E. M. J . Am. Chem. Soc. 1997, 119, 7879. (d) Trost, B. M.; Schroeder,
G. M. J . Am. Chem. Soc. 1999, 121, 6759. (e) Trost, B. M.; Ariza, X. J .
Am. Chem. Soc. 1999, 121, 10727. (f) Inoue, Y.; Tofofuku, M.; Taguchi,
M.; Okada, S.-I.; Hashimoto, H. Bull. Chem. Soc. J pn. 1986, 59, 885.
(5) Hammond, M. L.; Zambias, R. A.; Chang, M. N.; J ensen, N. P.;
McDonald, J .; Thompson, K.; Boulton, D. A.; Kopka, I. E.; Hand, K.
M.; Opas, E. E.; Luell, S.; Bach, T.; Davies, P.; MacIntyre, D. E.;
Bonney, R. J .; Humes, J . L. J . Med. Chem. 1990, 33, 908.
For our initial experiments, we chose to investigate the
coupling of the tert-butyldimethylsilyl-protected allylic
* To whom correspondence should be addressed. Tel: (+24) 7652
3260. Fax: (+24) 7652 4112.
† University of Warwick.
‡ GlaxoSmithKline Research and Development.
§ Visitor from the University of Salamanca, Summer 1999. Current
address: Departamento de Quimica Organica, Facultad de Quimica,
Plaza de los Caidos 1-5, 37008-Salamanca, Spain.
10.1021/jo0011991 CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/24/2001

Formation of 1-Vinyl-1H-isochromene Derivatives
J . Org. Chem., Vol. 66, No. 10, 2001 3285
Ta ble 1. P a lla d iu m -Ca ta lyzed Cou p lin g Rea ction s of Keton es w ith [3-(2-Br om op h en yl)a llyloxysila n es]
entry
aryl bromide
ketone
pinacolone
pinacolone
pinacolone
solvent
ligand
DPPF
DPPF
DPPF
product
yield (%)
side products
yield (%)
1
2
3
5
5
5
toluene/THF
dioxane/THF
toluene
8
8
67
71
0
4
5
6
7
8
9
10
11
12
9
10
5
5
5
5
5
5
5
pinacolone
pinacolone
pinacolone
pinacolone
toluene/THF
toluene/THF
dioxane
toluene/THF
toluene/THF
toluene/THF
toluene/THF
toluene/THF
toluene/THF
DPPF
DPPF
ESPHOS
(o-Tol)3P
(t-Bu)3P
DPPF
DPPF
DPPF
DPPF
8
54
0
8
8
8
11
12
13
14
15
61
27
28
36
13
34
7/6
7/6
21/6
30/6
pinacolone
acetophenone
propiophenone
cyclohexanone
3-methyl-2-butanone
15b
6
6
10
Sch em e 2. Com bin a tor ia l Stu d y of
gation of several bases such as NaO-t-Bu, Na2CO3, Cs2-
CO3, and LHMDS gave none of the expected ketone
product 7; however, in the case of LHMDS a new
nonpolar product was formed. This turned out to be the
1H-isochromene 8, one of the desired heterocycles. Op-
timization of this tandem arylation/allylic substitution
reaction led to yields of up to 70%. As far as we are aware,
this represents the first observation of such a cyclization
reaction, which is notable for the involvement of a silyloxy
leaving group in the allylic substrate. In contrast, intra-
molecular reactions of â-keto ester enolates have been
reported to form five-membered rings in palladium-
catalyzed intramolecular cyclizations.6 During this work,
it appeared that not only must a lithium base be used
(NaHMDS and KHMDS failed to give the same product),
but a coordinating solvent must also be present (Table
1, entries 1 and 2 vs 3). Trost has reported a similar
requirement for a lithium base in an allylic alkylation
reaction.4d A series of phosphine ligands and ketones
were also investigated, and we found that a substantial
amount of the intermediate 7 could be isolated when
either tri-tert-butylphosphine or the bis(diazaphospholi-
dine) ligand SEMI-ESPHOS7 was used (Table 1, entries
6 and 8). This intermediate, 7, was then exposed to the
reaction conditions in the absence of palladium and
ligands. No cyclization occurred after several hours,
indicating that the cyclization step was also palladium
catalyzed. Tri(o-tolyl)phosphine also proved to be a good
ligand for 1H-isochromene formation (Table 1, entry 7).
P a lla d iu m -Ca ta lyzed Cycliza tion Rea ction sa
a
Reagents and conditions: (i) ligand, LHMDS, solvent,
[Pd2(dba)3], 85 °C.
ether carbon with a phenyl group led to an unreactive
substrate (Table 1, entry 5). In view of these promising
results, a short study was then carried out using a series
of alternative ketones; acetophenone (entry 9), propio-
phenone (entry 10), cyclohexanone (entry 11), and 3-
methylbutan-2-one (entry 12). In each case, a cyclic
product was formed, although the nonoptimized yields
were low to moderate in most cases, suggesting that the
reaction could be a versatile one.
With these results in hand, we decided to carry out a
wider study to optimize the reaction and to determine
its scope and limitations. This was done through a
parallel synthesis approach in collaboration with Glaxo-
SmithKline (Scheme 2). Four runs of 24 reactions each
were planned. The first two runs were designed to find
the ideal conditions with pinacolone and acetophenone
as test ketones. Four solvents were used (DME, dioxane,
DMSO, and DMF) and six ligands (dppf, tri-tert-butyl-
phosphine, tricyclohexylphosphine, BINAP, SEMI-
ESPHOS,7 and the biarylphosphine 16). Our intention
was to find idealized conditions for the formation of both
the cyclic product 8 or 11 and the intermediate 7 or 15a .
The third and fourth runs were designed to find out more
about the substrate scope; 24 different ketones were
employed under the optimized conditions for the forma-
tion of both the intermediate and the cyclic product.
The reactions were assessed by LC of the crude
reaction mixtures in the optimization work. In the case
of reactions in DME and dioxane, three ratios were
determined from the crude reaction mixtures. The first
ration was that between the remaining starting material
and the products (including debromination, coupling, and
cyclization products) to gain insight into the conversion
and general reactivity. The second ratio was that between
the debromination product and the coupling/cyclization
products to assess the cleanliness of the reaction. The
third ratio was that between the coupling and the
cyclization product to provide a measure of selectivity.
Changing the protecting group on the bromide from
the TBS to the TBDPS ether did not effect the tandem
reaction (Table 1, entry 4). Substitution at the allylic
(6) (a) Hayashi, T.; Yamane, M.; Ohno, A. J . Org. Chem. 1997, 62,
204. (b) Trost, B. M. Angew. Chem., Int. Ed. Engl. 1989, 28, 1173.
(7) Wills, M.; Breeden, S. W. J . Org. Chem. 1999, 64, 9735.

3286 J . Org. Chem., Vol. 66, No. 10, 2001
Mutter et al.
Ta ble 2. Op tim iza tion of P a lla d iu m -Ca ta lyzed Cou p lin g Rea ction s of 5 w ith Acetop h en on e a n d P in a colon ea
entry
ketone
ligand
substrate solvent
dioxane (K)
SM/products
6/products
intermediate/product
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
acetophenone in dioxane (A)
DPPF (E)
P(t-Bu)3 (F)
PCy3 (G)
BINAP (H)
ESPHOS (I)
16 (J )
DPPF (E)
P(t-Bu)3 (F)
PCy3 (G)
BINAP (H)
ESPHOS (I)
16 (J )
DPPF (E)
P(t-Bu)3 (F)
PCy3 (G)
BINAP (H)
ESPHOS (I)
16 (J )
DPPF (E)
P(t-Bu)3 (F)
PCy3 (G)
BINAP (H)
ESPHOS (I)
16 (J )
50:50
2:98
50:50
60:40
75:25
<1:>99
<1:>99
<1:>99
<1:>99
15:85
8:92
<1:>99
traces of 6
10:90
10:90
25:75
43:57
<1:>99
95:5
67:33
40:60
<1:>99
80:20
<1:>99
67:33
40:60
20:80
10:90
10:90
20:80
pinacolone in dioxane (B)
acetophenone in DME (C)
pinacolone in DME (D)
<1:>99
<1:>99
8:92
<1:>99
30:70
traces of 6
DME (L)
<1:>99
25:75
<1:>99
85:15
<1:>99
<1:>99
1:99
<1:>99
<1:>99
<1:>99
<1:>99
15:85
15:85
80:20
70:30
60:40
33:67
<1:>99
2:98
traces of 6
<1:>99
traces of 6
<1:>99
<1:>99
<1:>99
50:50
20:80
<1:>99
50:50
<1:>99
a
Key: (A) 1 mL of a solution of 3 mmol (0.361 g) of acetophenone in 6 mL of dioxane was used; (B) 1 mL of a solution of 3 mmol (0.301
g) of pinacolone in 6 mL of dioxane was used; (C) 1 mL of a solution of 3 mmol (0.361 g) of acetophenone in 6 mL of DME was used; (D)
1 mL of a solution of 3 mmol (0.301 g) of pinacolone in 6 mL of DME was used (1.0-1.5 mL of a 1 M solution of LHMDS in THF was used
in each reaction); (E) 0.5 mL of a solution of 0.025 mmol (0.023 g) of Pd2(dba)3 + 0.05 mmol (0.028 g) of DPPF in 2 mL of THF was used;
(F) 0.5 mL of a solution of 0.025 mmol (0.023 g) of Pd2(dba)3 + 0.1 mmol (0.020 g) of t-Bu3P in 2 mL of THF was used; (G) 0.5 mL of a
solution of 0.025 mmol (0.023 g) of Pd2(dba)3 + 0.1 mmol (0.028 g) of Cy3P in 2 mL of THF was used. (H) 0.5 mL of a solution of 0.025
mmol (0.023 g) of Pd2(dba)3 + 0.05 mmol (0.031 g) of BINAP in 2 mL of THF was used; (I) 0.5 mL of a solution of 0.025 mmol (0.023 g)
of Pd2(dba)3 + 0.1 mmol (0.031 g) of S-ESPHOS in 2 mL of THF was used. (J ) 0.5 mL of a solution of 0.025 mmol (0.023 g) of Pd2(dba)3
+ 0.1 mmol (0.030 g) of Biaryl-P 16 in 2 mL of THF was used. (K) 1 mL of a solution of 3 mmol (1.142 g) of 5 in 12 mL of dioxane was
used; (L) 1 mL of a solution of 3 mmol (1.142 g) of 5 in 12 mL of DME was used.
The results of these reactions are summarized in Table
2 for the reactions involving DME and dioxane as solvent.
The reactions in DMSO and DMF gave only complex
mixtures of products in low conversions.
In the case of the alkyl ketones, only the simplest gave
substantial amounts of cyclized products 17 (Table 3
entries 14, 17, and 18). A larger number of noncyclized
intermediates 18 could be isolated (entries 13, 14, 16-
18, 21, 22), although these were contaminated by 2,2-
biaryl coupling products 19-22. In one example (entry
19), a major side product was a biaryl compound, 23,
arising from a homocouping. These results suggest that
the cyclization reactions of alkyl ketones are rather slow
compared to the rates of the coupling reactions. In the
case of aromatic ketones, a larger proportion of the
experiments gave cyclized products 17 (Table 3, entries
1, 8-12) in good conversions. Under the alternative
conditions, a still larger proportion of acyclic intermedi-
ates 18 could be isolated (Table 3, entries 2, 6-12),
essentially free of side products.
As a result of this study, the best conditions for
formation of the noncyclized intermediates 7 and 15a
from the pinacolone and acetophenone, respectively, were
found to be tri-tert-butylphosphine in dioxane (Table 2;
entries 2 and 8). The best conditions for formation of the
vinyl-1H-isochromenes 11 and 8 were found to be,
respectively, o-biaryldi-tert-butylphosphine 16 as ligand
in DME (Table 2, entry 18) and DPPF as ligand in DME
(Table 2, entry 19). In some cases, these “optimised”
conditions were only marginally better than other condi-
tions; for example, BINAP and o-biaryl-di-tert-butylphos-
phine 16 were also effective in the synthesis of cyclic
In all cases there was no evidence of C-alkylated
products (i.e., cyclic ketones), suggesting a strong prefer-
ence for attack on the allyl cation by the oxygen atom of
the enolate. This observation is in agreement with the
results of related cyclization reactions in which a choice
of O- or C-alkylation was available to the reagents.6
These results clearly demonstrate the difference in
reactivity that can result from the variation of the ligand
and solvent in a simple reaction. This selectivity provides
a means for directing reactions toward specific outcomes.
To demonstrate the value of such selectivity, we prepared
a sample of both the cyclized and uncyclized intermedi-
ates from the reaction of 5 with p-methoxyacetophenone
(Scheme 3). Using the specific conditions for the former
process (o-biaryl-di-tert-butylphosphine as ligand in DME),
the isochromene 17d was formed, while using the specific
conditions for the latter (tri-tert-butylphosphine in diox-
products from alkyl ketones (entries 21 and 24) and the
solvent often had minimal effect (entry 19). Following
these studies, a semiquantitative investigation of 24
ketones (Figure 1; 12 aromatic A1-A12 and 12 aliphatic
B1-B12) was undertaken using both sets of conditions
to create a library of aryl ketones and vinyl-1H-iso-
chromenes (Scheme 2). The results are summarized in
Table 3. The reactions were initially carried out on a 0.25
mmol scale and analyzed for evidence of products. In
cases where substantial amounts of products were formed,
these were isolated and characterized (Figure 2).

Formation of 1-Vinyl-1H-isochromene Derivatives
J . Org. Chem., Vol. 66, No. 10, 2001 3287
F igu r e 1. Ketones used in the combinatorial study (A, aromatic; B, aliphatic).
ane),, the acyclic product 18g was isolated (60% yield
after 2.5 h).
made from 18g via desilylation to the alcohol and
acetylation, could be converted to 17d at room temper-
ature using a combination of SEMI-ESPHOS7 and pal-
ladium (0); however, the yield was low (20%) and the
enantiomeric excess remains to be determined.
Mindful of the synthetic potential of the cyclized
products, we have begun to explore the chemistry of these
novel materials. In an interesting preliminary experi-
ment, hydroboration of 8 with 9-BBN gave the primary
alcohol product 24 in 37% yield together with 28% of the
cyclized product 25, a result of an acid-catalyzed side
reaction in the workup. This was confirmed by a second
experiment where the acid workup was avoided, which
gave only 24 in 72% yield. Presumably, the hydroboration
by the hindered reagent is controlled more significantly
by steric factors rather than electronic. In another
reaction, treatment of 8 with methanolic HCl resulted
in ring-opening to give the methoxy allyl ether 26 in low
yield (25%).
In a final study, we wished to confirm that the choice
of a silyloxyallylic substrate was essential for a successful
reaction. This was achieved through the attempted
reactions of acetate 28 with both pinacolone and aceto-
phenone under our reaction conditions for cyclization. In
the former case, the result was a complex mixture, in
the latter case the deacetylated alcohol was the major
product, together with a small amount of ketone 29. The
latter result serves to confirm the ability of the silyloxy
group to delay the allylc reaction conveniently until after
the arylation process has been completed.
We recognized the potential for the formation of an
enantiomerically enriched product, but were concerned
that this would be difficult to achieve at the high reaction
temperatures involved. Unfortunately all attempts to
achieve the cyclization of ketone 18g under our conditions
failed at room temperature. In contrast, the acetate 27,
Con clu sion
In conclusion, we have demonstrated that the use of a
combinatorial approach to the optimization of a reaction

3288 J . Org. Chem., Vol. 66, No. 10, 2001
Ta ble 3. P a lla d iu m -Ca ta lyzed Cou p lin g Rea ction s of a Ser ies of Keton es (F igu r e 1) w ith 5a
Mutter et al.
isolated product(s)
(ratio cyclic/acyclic)
isolated product(s)
(ratio acyclic/cyclic)
entry
ketone
procedure A, comments
mixture
procedure B, comments
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
A1
A2
A3
A4
A5
A6
A7
A8
17a , 18a
mixture, low conversion
predominantly acyclic product
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture
predominantly acyclic product
predominantly acyclic product
predominantly acyclic product
predominantly acyclic product
predominantly acyclic product
predominantly acyclic product
mixture
predominantly acyclic product
mixture, low conversion
mixture
mixture
predominantly acyclic product
mixture
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture, low conversion
predominantly cyclic product
predominantly cyclic product
predominantly cyclic product
predominantly cyclic product
predominantly cyclic product
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture, low conversion
predominantly cyclic product
mixture
18b
18c
18d
17b (9:1)
17c (9:1)
17d (9:1)
17e (14:1)
17f (6:1)
18e (4:1)
18f (13:1)
18g (26:1)
18h (3:1)
18i (9:1)
18j, 19
A9
A10
A11
A12
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
17g
18k , 18l, 20
18m , 18n , 21
18o (2.2:1), 22
18p
23
17h (9:1)
13
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture, low conversion
mixture
mixture
mixture, low conversion
mixture, low conversion
18q
18r
a
Procedure A: aromatic sustrates; o-biaryl-di-tert-butylphosphine in DME, aliphatic substrates; DPPF in DME. Procedure B (all
substrates): tri-tert-butylphosphine in dioxane. See the Experimental Section for full details. Products were characterized to confirm
identity; however, isolated yields for these unoptimized reactions were not routinely obtained. “Mixture” indicates the formation of three
or more significant (>10%) products by GC analysis. “Low conversion” indicates <10% conversion of substrate, no product being isolated.
F igu r e 2. New compounds prepared and characterized in the combinatorial chemistry.
can permit the rapid determination of substrate scope
and versatility. In addition, the rapid screening process
can assist with the identification of optimum conditions
for the specific formation of intermediates in a reaction

Formation of 1-Vinyl-1H-isochromene Derivatives
J . Org. Chem., Vol. 66, No. 10, 2001 3289
(9H, s), 5.16 (1H, dt, J ) 17.1, 1.3 Hz), 5.23 (1H, dt, J ) 10.4,
1.3 Hz), 5.46 (1H, d, J ) 6.6 Hz), 5.67 (1H, s), 6.15 (1H, ddd,
J ) 17.1, 10.4, 6.6 Hz), 6.90-7.30 (4H, m); 13C NMR (75 MHz,
CDCl3) δ 28.3, 35.5, 79.3, 97.7, 118.2, 123.8, 124.9, 126.2, 128.5,
129.4, 132.0, 136.7, 164.2; MS (EI) m/z 214 [M]+, 187, 129;
HRMS (EI) m/z 214.136173 (calcd for C15H18O 214.135765).
(E:Z)-ter t-Bu tyld ip h en yl[3-(2-br om op h en yl)a llyloxy]-
sila n e 9. A solution of (E:Z)-3-(2-bromophenyl)prop-2-en-1-ol
(1.04 g, 91% in toluene, 4.9 × 10-3mol, 1 equiv) in DCM (10
mL) was added to a solution of tert-butyldiphenylchlorosilane
(1.45 mL, 5.46 × 10-3 mol, 1.1 equiv) in DCM (2 mL), followed
by a solution of triethylamine (2.0 mL, 1.4 × 10-2 mol, 2.5
equiv) in DCM (2 mL) and DMAP (0.065 g, 5.0 × 10-4 mol, 10
mol %) at room temperature. After the mixture was stirred
for 3 h, methanol (0.25 mL) was added and the resulting
mixture was stirred for 1.5 h. The mixture was twice extracted
with 1 M HCl solution (2 × 15 mL). The organic layer was
dried, and the solvent was evaporated under reduced pressure
to yield a mixture of E/Z isomers (1.98 g, E/Z ) 5:1, 4.4 × 10-3
mol, 90%): IR (NaCl) 2967, 2929, 2834, 2366, 1272, 1109, 716
cm-1; 1H NMR (CDCl3, 250 MHz) isomer E δ 1.11 (9H, s), 4.41
(2H, dd, J ) 4.4, 1.9 Hz), 6.22 (1H, dt, J ) 15.6, 4.3 Hz), 7.00-
7.80 (15H, m); isomer Z δ 1.07 (9H, s), 4.34 (2H, dd, J ) 6.4,
1.5 Hz), 6.00 (1H, dt, J ) 11.5, 6.6 Hz), 7.00-7.80 (15H, m);
13C NMR (CDCl3, 60 MHz) δ 19.7, 27.2, 64.6, 124.1, 127.9,
128.1, 128.5, 128.9, 130.0, 130.1, 132.1, 133.3, 133.9, 136.0,
137.5; MS (CI) m/z 470 [M + NH4]+, 468 [M + NH4]+, 453,
451, 412, 410, 395, 393; HRMS (CI) 468.136962 (calcd for
Sch em e 3. Selective F or m a tion of Cyclic or
Acyclic P r od u cta
a
Reagents and conditions: (i) [Pd2(dba)3], LiHMDS, DME, (2-
C6H5)C6H4P(t-Bu)2, (ii) [Pd2(dba)], LiHMDS, dioxane, P(t-Bu)3.
sequence. We are continuing to examine the synthetic
potential and application of both the cyclized and uncyc-
lized products of the palladium-catalyzed coupling reac-
tions. The results of these studies will be disclosed in due
course.
Exp er im en ta l Section
(E:Z)-ter t-Bu tyld im eth yl-[3-(2-br om op h en yl)a llyloxy]-
sila n e 5. A solution of (E:Z)-3-(2-bromophenyl)prop-2-en-1-ol
(4.5 g, 2.1 × 10-2 mol, 1 equiv) in THF (20 mL) was added to
a solution of TBDMSCl (3.3 g, 2.2 × 10-2 mol, 1.05 equiv) in
THF (20 mL), followed by a solution of triethylamine (7.6 mL,
5.3 × 10-2 mol, 2.5 equiv) in THF (8 mL) and DMAP (0.13 g,
1.05 × 10-3 mol, 5 mol %) at room temperature. After the
mixture was stirred for 3 h, methanol (1 mL) was added, and
the resulting mixture was stirred for 1.5 h. The mixture was
diluted with DCM (200 mL) and twice extracted with 1 M HCl
solution (2 × 150 mL). The organic layer was dried, and the
solvent was evaporated under reduced pressure to yield a
mixture of E/Z isomers (6.5 g, E/Z ) 5:1, 2.9 × 10-2 mol,
95%): IR (NaCl) 2929, 1250, 834, 776 cm-1; 1H NMR, (CDCl3,
250 MHz) isomer E δ 0.13 (6H, s), 0.96 (9H, s), 4.38 (2H, dd,
J ) 4.6, 1.8 Hz), 6.23 (1H, dt, J ) 15.9, 4.9 Hz), 6.97 (1H, d,
J ) 15.6 Hz), 7.00-7.60 (4H, m). Isomer Z: δ 0.13 (6H, s),
0.96 (9H, s), 4.29 (2H, dd, J ) 6.4, 1.5 Hz), 5.93 (1H, dt, J )
11.6, 6.4 Hz), 6.58 (1H, d, J ) 11.6 Hz), 7.00-7.60 (4H, m);
13C NMR (CDCl3, 60 MHz) δ -4.3, 19.3, 26.8, 64.5, 124.5,
127.9, 128.3, 128.9, 129.4, 133.0, 133.9, 137.9; MS (CI) m/z 328
[M]+, 326 [M + H]+, 271, 269, 191, 116; HRMS (CI) m/z
326.070358 (calcd for C15H2379BrOSi 326.070155).
Gen er a l P r oced u r e for Syn th esis of Su bstitu ted 1-Vi-
n yl-1H-isoch r om en es. To a solution of LHMDS (1 M in THF,
3 equiv) was slowly added a solution of the ketone (2 equiv)
at 5 °C. A solution of Pd2(dba)3 (5% mol) and ligand (10% mol)
in solvent was added at room temperature, followed by a
solution of (E/Z)-tert-butyldimethyl[3-(2-bromophenyl)allyloxy]-
silane 5 (1 equiv). The reaction mixture was heated to 100 °C
overnight and quenched with 1 M HCl solution at room
temperature. The mixture was twice extracted with DCM, the
combined organic layers were dried, and the solvent was
evaporated under reduced pressure yielding the crude product.
The crude product was purified by flash chromatography or
by preparative TLC. In the case of the parallel synthesis work,
C
25H2779BrOSi‚NH4 468.135829).
(E)-ter t-Bu t yld im et h yl[3-(2-b r om op h en yl)-1-p h en yl-
a llyloxy]sila n e 10. A solution of (E)-3-(2-bromophenyl)-1-
phenylprop-2-en-1-ol (0.30 g, 1.0 × 10-3 mol, 1 equiv) in DCM
(1 mL) was added to a solution of tert-butyldimethylchloro-
silane (0.18 g, 1.14 × 10-3 mol, 1.1 equiv) in DCM (1 mL),
followed by a solution of triethylamine (0.4 mL, 2.8 × 10-3 mol,
2.8 equiv) in DCM (1 mL) and DMAP (0.02 g, 1.6 × 10-4 mol,
15 mol %) at room temperature. After being stirred for 2 days
the solvent was evaporated under reduced pressure to give an
oily residue. The product was isolated by flash column chro-
matography (20 mL silica gel, eluent ether/petroleum ether
1:19) to give the product (yield ) 0.14 g, 3.3 × 10-4 mol, 33%):
1
IR (NaCl) 2973, 2946, 2865, 1492, 1263, 840 cm-1; H NMR
(CDCl3, 250 MHz) δ 0.03 (3H, s), 0.11 (3H, s), 0.94 (9H, s),
5.37 (1H, d, J ) 5.7 Hz), 6.17 (1H, dd, J ) 15.6, 6.0 Hz), 7.03
(1H, d, J ) 15.5 Hz), 6.80-7.60 (9H, m); 13C NMR (CDCl3, 75
MHz) δ -4.4, -4.1, 26.3, 75.7, 120.5, 124.2, 126.5, 127.6, 127.9,
128.7, 129.0, 129.8, 133.2, 136.4, 137.3; MS (EI) m/z 404 [M]+,
402 [M]+, 347, 345, 273, 271, 192; HRMS (CI) m/z 402.101418
(calcd for C21H2779BrOSi 402.101455).
1-Vin yl-3-p h en yl-1H-isoch r om en e 11: IR (NaCl) 2926,
1
1255, 765 cm-1; H NMR (CDCl3, 300 MHz) δ 5.29 (1H, dt, J
) 18.0, 1.2 Hz), 5.30 (1H, dt, J ) 10.0, 1.2 Hz), 5.71 (1H, d, J
) 6.1 Hz), 6.19 (1H, ddd, J ) 17.0, 10.0, 6.1 Hz), 6.43 (1H, s),
7.40-7.45 (7H, m), 7.74-7.78 (2H, m); 13C NMR (CDCl3, 75
MHz) δ 79.4, 101.0, 118.3, 124.3, 124.9, 125.4, 125.4, 126.9,
128.6, 128.7, 128.7, 129.2, 130.0, 131.5, 134.8, 136.1, 163.8;
MS (CI) m/z 235 [M + H]+, 105; HRMS (EI) m/z 234.104176
(calcd for C17H14O 234.104465).
the reactions were carried out on
a 24-position Radleys
greenhouse parallel synthesizer coupled to a robotic system
for analysis by GC.
t er t -B u t y ld im e t h y ls ily l-2-(2-o x o -2-p h e n y le t h y l)-
cin n a m yl eth er 15a : IR (NaCl) 2955, 2930, 2856, 1687, 1266,
837, 738 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.02 (6H, s), 0.84
(9H, s), 4.30 (2H, dd, J ) 4.5, 1.9 Hz), 4.38 (2H, s), 6.17 (1H,
dt, J ) 15.5, 4.5 Hz), 6.71 (1H, d, J ) 15.6 Hz), 7.10-8.10
(9H, m); 13C NMR (CDCl3, 75 MHz) δ -4.9, 26.2, 43.6, 64.1,
126.8, 126.9, 127.8, 128.7, 128.8, 129.0, 130.8,131.0, 132.3,
133.6, 164.0; MS (EI) m/z 385 [M + NH3D]+, 368 [M + D]+,
310, 251, 236; HRMS (CI) m/z 384.1967 (calcd for C23H30O2-
Si‚NH4 384.2017).
ter t-Bu tyld im eth yl(3-p h en yla llyoxy)sila n e 6: 1H NMR
(CDCl3, 250 MHz) δ 0.11 (6H, s), 0.94 (9H, s), 4.35 (2H, dd, J
) 4.9, 1.5 Hz), 6.28 (1H, dt, J ) 15.9, 4.9 Hz), 6.59 (1H, d, J
) 15.6 Hz), 7.10-7.40 (5H, m).
t er t -Bu t yld im e t h ylsilyl-2-(2-oxo-2-t er t -b u t yle t h yl)-
cin n a m yl eth er 7: IR (NaCl) 2956, 2931, 2858, 1712, 836,
777 cm-1; 1H NMR (CDCl3, 300 MHz) δ 0.00 (6H, s), 0.83 (9H,
s), 1.14 (9H, s), 3.80 (2H, s), 4.23 (2H, dd, J ) 4.7, 1.9 Hz),
6.02 (1H, dt, J ) 16.0, 4.7 Hz), 6.54 (1H, d, J ) 16.0 Hz), 6.85-
7.40 (4H, m); 13C NMR (CDCl3, 75 MHz) -5.4, 18.2, 25.8, 26.4,
40.8, 44.3, 63.8, 126.3, 126.5, 126.9, 127.0, 130.3, 131.4, 132.4,
136.9, 212.3; MS (EI) m/z 345[M - H]+, 243, 215; HRMS (EI)
m/z 345.212265 (calcd for C21H33O2Si 345.224984).
1-Vin yl-3-ter t-bu tyl-1H-isoch r om en e 8: IR (NaCl) 2954,
1-Vin yl-3-p h en yl-4-m eth yl-1H-isoch r om en e 12: IR
(NaCl) 2925, 1489, 1244, 1016, 757 cm-1 1H NMR (CDCl3,
;
300 MHz) δ 2.09 (3H, s), 5.25 (1H, dt, J ) 17.0, 1.2 Hz), 5.30
(1H, dt, J ) 10.0, 1.2 Hz), 5.51 (1H, d, J ) 6.6 Hz), 6.23 (1H,
ddd, J ) 17.0, 10.0, 6.8 Hz), 7.00-7.50 (9H, m); 13C NMR
(CDCl3, 75 MHz) δ 14.3, 79.1, 119.1, 122.1, 124.6, 126.9, 128.3,
128.3, 128.5, 128.8, 130.1, 130.1, 131.0, 133.9, 135.8, 136.4,
1
1638, 1085, 914, 750 cm-1; H NMR (CDCl3 300 MHz) δ 1.16

3290 J . Org. Chem., Vol. 66, No. 10, 2001
Mutter et al.
164.2; MS (EI) m/z 249 [M + H]+, 248 [M]+, 221, 191, 143;
HRMS (EI) m/z 248.119930 (calcd for C18H16O 248.120115).
ter t-Bu t yld im et h ylsilyl-2-(2-oxo-2-p h en yl-1-m et h yl-
eth yl)cin n a m yl eth er 15b: IR (NaCl) 2933, 1686, 1258, 837,
779 cm-1; 1H NMR (CDCl3, 250 MHz) δ 0.00 (6H, s), 0.82 (9H,
s), 1.34 (3H, d, J ) 6.7 Hz), 3.73 (1H, q, J ) 6.7 Hz), 4.30 (2H,
dd, J ) 4.6, 1.9 Hz), 6.13 (1H, dt, J ) 15.0, 4.6 Hz), 6.85-7.35
(8H, m), 7.65-7.73 (2H, m); 13C NMR (CDCl3, 75 MHz) δ -5.4,
18.2, 25.7, 43.9, 63.5, 125.7, 126.8, 127.1, 127.8, 128.2, 128.2,
128.5, 128.5, 132.4, 132.6, 135.0, 136.0, 138.8, 200.4; MS (CI)
m/z 380 [M]+, 323, 231, 149, 129, 105; HRMS (EI) m/z
380.216667 (calcd for C24H32O2Si 380.217159).
1-Vin yl-3,4-b icycloh exa n yl-1H -isoch r om en e 13: IR
(NaCl) 2954, 1638, 1085, 914 cm-1; 1H NMR (CDCl3, 300 MHz)
δ 1.64 (4H, m), 2.10 (2H, m), 2.25 (2H, m), 5.16 (1H, dt, J )
17.1, 1.3 Hz), 5.20 (1H, dt, J ) 10.4, 1.3 Hz), 5.31 (1H, d, J )
6.8 Hz), 6.01 (1H, ddd, J ) 17.1, 10.4, 6.6 Hz), 6.80-7.30 (4H,
m); 13C NMR (CDCl3, 75 MHz) δ 28.3, 35.5, 79.3, 97.7, 118.2,
123.8, 124.9, 126.2, 128.5, 129.4, 132.0, 136.7, 164.2; MS (CI)
m/z 213 [M + H]+, 134, 117; HRMS (EI) m/z 212.120811 (calcd
for C15H16O 212.120115).
1-Vin yl-3-(2-pr opyl)-1H-isoch r om en e 14: IR (NaCl) 2974,
804, 750 cm-1; 1H NMR (CDCl3, 300 MHz) δ 1.15 (6H, dd, J )
6.8, 1.8 Hz), 2.41 (1H, sep, J ) 7.0 Hz), 5.16-5.30 (2H, m),
5.50 (1H, d, J ) 6.4 Hz), 5.61 (1H, s), 6.14 (1H, ddd, J ) 17.1,
10.4, 6.4 Hz), 6.90-7.30 (4H, m); 13C NMR (CDCl3, 75 MHz) δ
19.9, 20.0, 32.1, 78.6, 97.8, 117.3, 122.8, 124.3, 125.5, 127.9,
128.7, 131.1, 135.5, 161.5; MS (EI) m/z 200 [M]+, 167, 149;
HRMS (EI) m/z 200.120167 (calcd for C14H16O 200.120115).
ter t-Bu t yld im et h ylsilyl-2-(2-oxo-[4′-m et h oxyp h en yl]-
et h yl)cin n a m yl E t h er 18g. Sca le-u p fr om t h e P a r a llel
Syn th esis. A solution of 4-methoxyacetophenone A10 (0.92
g, 6.13 × 10-3 mol, 2 equiv) in dioxane (5 mL) was added to a
solution of LHMDS (12.5 mL, 1 M in THF, 1.25 × 10-2 mol, 4
equiv) at 0 °C. A solution of tris(dibenzylideneacetone)-
dipalladium (0.070 g, 7.6 × 10-5 mol, 5% mol) and tri-tert-
butylphosphine (0.062 g, 3.1 × 10-4 mol, 10% mol) in dioxane
(5 mL) was added at room temperature followed by 5 (1.00 g,
3.05 × 10-3 mol, 1 equiv) in dioxane (5 mL). The mixture was
then heated to 90 °C. After 3 h, the reaction mixture was
allowed to cool to room temperature and was partitioned
between 1 M HCl solution (100 mL) and DCM (200 mL). The
organic layer was dried, and the solvent was evaporated under
reduced pressure to give an oil. The product was isolated by
flash column chromatography (150 mL silica gel, eluent ethyl
acetate/petroleum ether 1:49) to give the product as a yellow
oil (yield ) 0.41 g, 93% in ethyl acetate, 1.84 × 10-3 mol,
60%): IR (NaCl) 3008, 2932, 2857, 1682, 1601, 1512, 1259,
835 cm-1; 1H NMR (CDCl3, 300 MHz) δ isomer E 0.05 (6H, s),
0.86 (9H, s), 3.88 (3H, s), 4.20-4.40 (4H, m), 6.17 (1H, dt, J )
15.6, 4.7 Hz), 6.73 (1H, dt, J ) 15.6, 1.7 Hz), 7.10-8.10 (8H,
m); 13C NMR (CDCl3, 75 MHz) δ -4.9, 18.7, 22.1, 26.3, 43.4,
64.1, 126.9, 126.9, 127.7, 127.8, 128.9, 129.7, 130.9, 132.2,
132.8, 134.6, 137.3, 144.3, 197.4; MS (EI) m/z 396 [M]+, 380,
265; HRMS (EI) m/z 396.212006 (calcd for
C24H32O3Si
396.212074).
2-(3-ter t-Bu tyl-1H-isoch r om en -1-yl)eth a n ol 24. A solu-
tion of 9-BBN (1.0 mL, 0.5 M in THF, 5.0 × 10-4 mol, 2 equiv)
was added to a solution of 8 (0.05 g, 2.3 × 10-4 mol, 1 equiv)
in THF (1 mL) at room temperature. After the mixture was
stirred for 2 h, methanol (0.5 mL) and H2O2 (30%, 0.25 mL)
were added. After 1.5 h the solvent was evaporated under
reduced pressure. The residue was partitioned between DCM
and 1 M HCl. The organic layer was dried, and the solvent
was removed under reduced pressure. The product was
isolated by flash column chromatography (20 mL silica gel,
eluent ether/petroleum ether 1:99) to give the product (yield
) 0.020 g, 8.6 × 10-5 mol, 37%) and 25 as side product (0.015
g, 6.5 × 10-5 mol, 28%). Avoiding the acidic workup gave 24
in 72% yield. 2-(3-ter t-Bu tyl-1H-isoch r om en -1-yl)eth a n ol
24: IR (NaCl) 3322, 2964, 1642, 1085, 744 cm-1 1H NMR
;
(CDCl3, 300 MHz) δ 1.17 (9H, s), 2.00-2.40 (2H, m), 3.70-
4.00 (2H, m), 5.25 (1H, dd, J ) 8.6, 4.6 Hz) 5.69 (1H, s), 6.90-
7.20 (4H, m); 13C NMR (CDCl3, 75 MHz) δ 28.3, 35.1, 36.0,
60.0, 75.9, 97.8, 123.7, 123.8, 126.3, 128.3, 131.8, 131.8, 164.1;
MS (EI) m/z 232 [M]+, 187, 129; HRMS (CI) m/z 232.146076
(calcd for C15H20O2 232.146330). 25: IR (NaCl) 2957, 1132,
1
1099, 944, 766, 740 cm-1; H NMR (CDCl3, 300 MHz) δ 1.02
(9H, s), 1.20-1.40 (1H, m), 2.44 (1H, tt, J ) 12.0, 5.2 Hz), 2.80
(1H, d, J ) 1.8 Hz), 3.35 (1H, d, J ) 1.8 Hz), 3.65-3.90 (2H,
m), 5.07 (1H, d, J ) 4.6 Hz), 6.95-7.25 (4H, m); 13C NMR
(CDCl3, 75 MHz) δ 24.1, 31.2, 39.0, 57.2, 70.4, 99.8, 124.4,
125.4, 126.6, 127.4, 135.1, 136.7; MS (EI) m/z 232 [M]+, 187,
130; HRMS (CI) 232.146725 (calcd for C15H20O2 232.146330).
Ack n ow led gm en t. We thank the CVCP for an
Overseas Research Studentship (ORS) award (to R.M.)
and Professor D. Games, Dr. J . Ballantine, and Dr. B.
Stein of the EPSRC Mass Spectrometry Service at
Swansea for carrying out analyses of certain compounds.
We particularly thank GlaxoSmithKline for allowing
R.M. to carry out the combinatorial studies at their
laboratory. We wish to acknowledge the use of the
EPSRC’s Chemical Database Service at Daresbury.8
Su p p or tin g In for m a tion Ava ila ble: Detailed experi-
mental procedures, data from the parallel synthesis, and full
characterization of all new compounds not featured in this
paper. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O0011991
(8) Fletcher, D. A., McMeeking, R. F., Parkin, D. J . Chem. Inf.
Comput. Sci. 1996, 36, 746-749.