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Efficient synthesis of carbobicyclic and carbopolycyclic compounds via intramolecular carbopalladation catalyzed by palladium-phosphine complexes1
Tetrahedron Letters,Vol.29,No.24,pp Printed in Great Britain
EFFICI~
2915-2918,1988
0040-4039,'88 $3.00 + .OO Perqamon Press plc
SYNTHESIS OF CAREQBICYCLJC AND CARBopoL;YCYCLIC Cafe
INTl?AWLFCULARCLlWI3OP~ATION
VIA
CATALYZED BY PALLADIUM-PHOSPHINECOMPLEXES1
Ei-ichi Negishi,* Yantao Zhang, Brian O'Connor Department of Chemistry, Purdue University, W. Lafayette, Indiana 47907, U.S.A.
SUMMARY: Intramolecular aryl- and alkenylpalladation reactions of cyclic olefins catalyzed by palladium-phosphinecomplexes, such as Pd(PPh3)4, can produce fused, bridged, and spirofused carbobicyclic and carbopolycyclic compounds in high yields.
Although
intermolecular
addition
of aryl- and alkenyl-palladium bonds to alkenes
followed by dehydropalladation is a well-established formation,2
method
for carbon-carbon
bond
its intrarrolecular(cyclic) version has until recently been limited to the
synthesis of heterocycles.3 In 1983 Heck reported the synthesis of carbccyclic allylamines via c~~~lladation.4
In the following year, intramolecular alkenylation of alkenes to
produce carbocycles containing exccyclic conjugated dienes was reported by Grigge5 the course
of our study of cyclic acylpalladation,6
During
we found that intramolecular
arylpalladatron converted 1 into a 60:40 mixture of 2 and 3 in ca. 90% yield.
These
results prompted us to develop Pd-catalyzed cyclization procedures for preparing fused, bridged, and spirofused carbobicyclic and carbopolycyclic compounds.7
co O/ 3
We now report that treatment of alkenyl or aryl iodides appropriately linked to l-, 2-, and 3-cycloalkenyl groups with a catalytic amount (3-5 mol OS)of a Pd-phosphine catalyst, such as Pd(PPh3)4,
in the presence of a base, such as NEt3 or NaOAc, provides the
corresponding spirofused, fused, and bridged carbobicyclic or carbopclycyclic compounds, respectively, in high yields. The experimental results are shcwn in the equations l-7. Typically, 14 (0.72 g, 2 mnol) was refluxed for 6 h in MeCN (8 mL) and THF (2 mL) in the presence of ?d(PPh3)4 (69 mg, 0.06 n-sol)and NEt3, (0.40 g, 4 mmol). The reaction mixture was extracted with pentane, washed with 3N HCl, saturated NaHC03, and brine, dried over MgSO4, filtered through a plug of silica gel, and concentrated to afford 0.30 g (81%) of 15: IR (neat) 1740 (s), 1245 (s), 1060 (s) cm-l; 1H NMR (ClX13, Me&) 3 H), 1.2-1.55 (m, 4 H), 1.8-2.05 (m, 5 H), 2.05-2.3 (m, 2 H),
6 0.90 (t, J_= 7 Hz,
2.4-2.7 (m, 2 H), 3.71 (S,
3 H), 5.25-5.4 (m, 1 H), 5.6-5.85 (m, 2 H); 13C NMP (cDC13) 6 14.10, 22.60, 29.17, 30.27,
2915
2916
31.73, 31.79, 35.02, 35.45, 42.57, 52.01, 117.73, 126.31, 129.19, 140.86, 177.30. The 13C NMR spectrum lndrcates that the compound 1s contaminated by a small amount (10-158) of the regioisomeric 3,7-dlene. Pd(PPh3)4,
NEt3,
4
3%
F
MeCN, THF reflux, 10 h
-n-B;
OOEt
2 equiv
Pd(PPh3)4,
5 (86%, 4:ld'b)
(1)
7 (80%, l:l=)
(2)
7:3h)
(3)
Bu-n
5%
$OOEt
NET33 1.5 equiv
6
MeCN, THF reflux, 20 h
Pd(PPh3)4,
3%
NEt3, 1 equiv
8 BU-5
Pd(PPh3)4,
QyJQ lo Hex-n_
aBuy,:'"%.
12
_
5%
NEt3, 1.5 equiv :
MeCN, THF reflux, 6 h
Pd(PPh3)4,
CQ-
>
MeCN, THF reflux, 1 h
m
11(80%,
9:lh)
(4)
3%
NEt3, 1 equiv
Hex-n
13(70%, 9:lh)
(5)
MeCN, THF reflux, 2 h
COOMe
Pd(PPh3)4,
3%
COOMe
NEt3, 2 equiv 14 MeCN, THF reflux, 6 h
Bu-IJ
$OOMe
Pd(PPh3)4,
15 (81%, 9:la)
(6)
17 (al%, 7:3d)
(7)
Bu-IJ
5%
NEt3, 1.5 equiv 16
a _. . - 'me ratro reglolsomer posrtion
rn parentneses which
relative
contains to the
Dlastereomeric mixture.
MeCN, THF reflux, 20 h
corresmnds
to that of the indicated regiorsomer to its
the newly formed double bond In the adjacent homoallylrc b ring junction. - 1:l Diastereomeric mixture. c 2:l
2917
The following observations and generalizations are worth noting.
First, under the
conditions employed, all of the reported cases proceded to give the cyclization products in excellent yields (90-100% by GIG).
In general, alkenyl icdides appear to be somewhat more
reactive than similarly structured aryl i&ides.
The presence of an ester group appears to
slow down the reaction rate (eq 5 vs. eg 6).
Secondly, all cyclization products are
identified by IR, 1H and 13C NMR, and high resolution MS. are mixtures of 3-4 isomers.
The spirofused products 5 and 7
For example, the 13C NMR spectrum of 7 shows at least two
major and one minor sets of signals. Catalytic hydrogenation of 7 over Pd/C in EtOH at 2 atm gave isomerically pure 18, indicating that 7 is most likely two double bond regioisomers each of which exists as tm cis.
diastereoners. The fused products 9 and 11 are 90-95%
Whereas 9 is a 70:30 mixture of 2,8- and 2,7-regioisomers, 11 is of ca. 90% regio-
isomeric purity. major products.
Their lH NMR spectra support the assigned cis stereochemistry of the Thus, for example, the coupling constant between the two bridgehead
protons of 11 is 5-6 Hz.
The bridged products 13 and 15 are regiochemically 85-90% pure by
13C NMR, and 17 is of ca. 70% regicchemical purity. Catalytic hydrogenation of 17 as above gives 19 as an isomerically homogeneous species. containing
iodide intermediates
was achieved
Thirdly, the preparation of the esterby allylation
or benzylation of the
corresponding lithium enolates in THF in the presence of l-2 equiv of HMPA8 using 20g or 21,1° respectively. The preparation of 8 and 12 involves carbocupration-iodinolysi& of the corresponding alkynes using 2212 and 23.13 high yields.
All of the above reactions proceeded in
On the other hand, 10 was prepared in law yield by treating a 1:l mixture of
21 and 3-brorro-1-hexene with Mg in THF.
Fourthly, the use of NaOAc(2 eguiv) in place of
NEt3 for the conversion of 12 to 13 gave 13 in 97% GIG yield.
On the other hand, the use
of 3 mol % of Pd(dba)2 in place of Pd(PPh3)4 for the conversion of 8 to 9 resulted in only a
9
COOMe
q@ 18
cr Br 0
fl-BkBr 19
20
22
23
I
21
Further developments of this highly efficient and potentially versatile methodology for construction of cyclic structures are in progress in our laboratories. Aclaww1~t.s.
We thank the National Institutes of Health (GM 36792) and the donors
of the Petroleum Research Fund administered by the American Chemical Society (18710-ACl) for support.
E N is a John Simon Guggenheim Memorial Foundation Fellow(1987). We thank
Professor Richard C. Larock of Iowa State University for informing us of their related study prior to publication.
2918
References andNotes
(1)
Metal-Promoted Cyclization. 18.
Part 17. Negishi, E.; Sawada, H.; Tour, J. M.;
Wei, Y. J. Org. Chem. 1988, 53, 0000. (2)
For reviews,
see (a) Heck, R. F. Org. React. 1982, z,
345.
(b) Heck, R. F.
"Palladium Reagents in Organic Syntheses," Academic Press, New York, 1985. (3)
(a) Mori, M.; Chiba, M.; Ban, Y. Tetrahedron L&t. Tetrahedron Lett. 1979, 1133. 5315.
1977, 1073.
(b) Mori, M.; Ban, Y.
(c) Mori, M.; Ban, Y. Tetrahedron I&t.
(d) Terpko, M. 0.; Heck, R. F. J. Am. Chem. See. 1979, l&,
5281.
1982, 23, (e) Shi,
L.; Narula, C. K.; Mak, K. T.; Kao, L.; Xu, Y.; Heck, R. F. J. Org. Chem. 1983, 48, 3894.
(f) Cdle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S. J. Org. Chem. 1980,
45, 2709.
(g) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980, 5,
Dieck, H. A. J. Org. Chem. 1983, 48, 807. Yanai,
H.; Takatori,
2938.
(h)
(i) Kasahara, A.: Izumi, T.; Murakami, S.;
M. Bull. Chem. Sot. Jpn. 1986, 59, 927.
(j) Grigg, R.;
Sridharan, V.; Stevenson, P.; Worakun, J. J. Chem. See., Chem. Common. 1986, 1697. (4) Narula, C. Km; Mak,K. T.; Heck, R. F. J. Org. Chem. 1983, 48, 2792. (5) Grigg, R.; Stevenson, P.; Worakun, T.; J. Chem. Sot., Chem. Cornmun.1984, 1073. (6) Tour, J. M.; Negishi, E. J. Am. Chem. Sot. 1985, 107, 8289. (7) During
the course
of this study, another
example of carbocycles prepared by
intramolecular arylpalladation appeared [Abelman, M. M.; Oh, T.; Overman, L. E. J1 Org. Chem. 1987, 52, 41331. (8) Herrmann, J. L.; Kieczykowski, G. R-i Schlessinger, R. H. Tetrahedron Lett. 1973, 2433. (9) Prepared by LiAlH4 reduction-iodinolysisfollowed by bromination with NBS-Me2S of 2heptyn-l-01 [Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem. See. 1967, 89, 42451. (IO) Prepared by treating o-iodobenzyl alcohol with PBr3 [Tour, J. M. Ph.D. Dissertation, Purdue University, 19861. (11) Normant, J. F.; Bourgain, M. Tetrahedron I&t.
1971, 2583.
See, also, Iyer, R. S.;
Helguist, P. Org. Synth. 1985, 64, 1. (12) Prepared from the corresponding bromide [Salomon, R. G.; Ghosh, S.; Zagorski, M. G.; Reitz, M. J. Org. Chem. 1982, 47, 8291. (13) Prepared from the corresponding bromide [Klein, J. Israel J. Chem. 1963, 1, 3851. (Received
in USA
13 January
1988)
EFFICI~
2915-2918,1988
0040-4039,'88 $3.00 + .OO Perqamon Press plc
SYNTHESIS OF CAREQBICYCLJC AND CARBopoL;YCYCLIC Cafe
INTl?AWLFCULARCLlWI3OP~ATION
VIA
CATALYZED BY PALLADIUM-PHOSPHINECOMPLEXES1
Ei-ichi Negishi,* Yantao Zhang, Brian O'Connor Department of Chemistry, Purdue University, W. Lafayette, Indiana 47907, U.S.A.
SUMMARY: Intramolecular aryl- and alkenylpalladation reactions of cyclic olefins catalyzed by palladium-phosphinecomplexes, such as Pd(PPh3)4, can produce fused, bridged, and spirofused carbobicyclic and carbopolycyclic compounds in high yields.
Although
intermolecular
addition
of aryl- and alkenyl-palladium bonds to alkenes
followed by dehydropalladation is a well-established formation,2
method
for carbon-carbon
bond
its intrarrolecular(cyclic) version has until recently been limited to the
synthesis of heterocycles.3 In 1983 Heck reported the synthesis of carbccyclic allylamines via c~~~lladation.4
In the following year, intramolecular alkenylation of alkenes to
produce carbocycles containing exccyclic conjugated dienes was reported by Grigge5 the course
of our study of cyclic acylpalladation,6
During
we found that intramolecular
arylpalladatron converted 1 into a 60:40 mixture of 2 and 3 in ca. 90% yield.
These
results prompted us to develop Pd-catalyzed cyclization procedures for preparing fused, bridged, and spirofused carbobicyclic and carbopolycyclic compounds.7
co O/ 3
We now report that treatment of alkenyl or aryl iodides appropriately linked to l-, 2-, and 3-cycloalkenyl groups with a catalytic amount (3-5 mol OS)of a Pd-phosphine catalyst, such as Pd(PPh3)4,
in the presence of a base, such as NEt3 or NaOAc, provides the
corresponding spirofused, fused, and bridged carbobicyclic or carbopclycyclic compounds, respectively, in high yields. The experimental results are shcwn in the equations l-7. Typically, 14 (0.72 g, 2 mnol) was refluxed for 6 h in MeCN (8 mL) and THF (2 mL) in the presence of ?d(PPh3)4 (69 mg, 0.06 n-sol)and NEt3, (0.40 g, 4 mmol). The reaction mixture was extracted with pentane, washed with 3N HCl, saturated NaHC03, and brine, dried over MgSO4, filtered through a plug of silica gel, and concentrated to afford 0.30 g (81%) of 15: IR (neat) 1740 (s), 1245 (s), 1060 (s) cm-l; 1H NMR (ClX13, Me&) 3 H), 1.2-1.55 (m, 4 H), 1.8-2.05 (m, 5 H), 2.05-2.3 (m, 2 H),
6 0.90 (t, J_= 7 Hz,
2.4-2.7 (m, 2 H), 3.71 (S,
3 H), 5.25-5.4 (m, 1 H), 5.6-5.85 (m, 2 H); 13C NMP (cDC13) 6 14.10, 22.60, 29.17, 30.27,
2915
2916
31.73, 31.79, 35.02, 35.45, 42.57, 52.01, 117.73, 126.31, 129.19, 140.86, 177.30. The 13C NMR spectrum lndrcates that the compound 1s contaminated by a small amount (10-158) of the regioisomeric 3,7-dlene. Pd(PPh3)4,
NEt3,
4
3%
F
MeCN, THF reflux, 10 h
-n-B;
OOEt
2 equiv
Pd(PPh3)4,
5 (86%, 4:ld'b)
(1)
7 (80%, l:l=)
(2)
7:3h)
(3)
Bu-n
5%
$OOEt
NET33 1.5 equiv
6
MeCN, THF reflux, 20 h
Pd(PPh3)4,
3%
NEt3, 1 equiv
8 BU-5
Pd(PPh3)4,
QyJQ lo Hex-n_
aBuy,:'"%.
12
_
5%
NEt3, 1.5 equiv :
MeCN, THF reflux, 6 h
Pd(PPh3)4,
CQ-
>
MeCN, THF reflux, 1 h
m
11(80%,
9:lh)
(4)
3%
NEt3, 1 equiv
Hex-n
13(70%, 9:lh)
(5)
MeCN, THF reflux, 2 h
COOMe
Pd(PPh3)4,
3%
COOMe
NEt3, 2 equiv 14 MeCN, THF reflux, 6 h
Bu-IJ
$OOMe
Pd(PPh3)4,
15 (81%, 9:la)
(6)
17 (al%, 7:3d)
(7)
Bu-IJ
5%
NEt3, 1.5 equiv 16
a _. . - 'me ratro reglolsomer posrtion
rn parentneses which
relative
contains to the
Dlastereomeric mixture.
MeCN, THF reflux, 20 h
corresmnds
to that of the indicated regiorsomer to its
the newly formed double bond In the adjacent homoallylrc b ring junction. - 1:l Diastereomeric mixture. c 2:l
2917
The following observations and generalizations are worth noting.
First, under the
conditions employed, all of the reported cases proceded to give the cyclization products in excellent yields (90-100% by GIG).
In general, alkenyl icdides appear to be somewhat more
reactive than similarly structured aryl i&ides.
The presence of an ester group appears to
slow down the reaction rate (eq 5 vs. eg 6).
Secondly, all cyclization products are
identified by IR, 1H and 13C NMR, and high resolution MS. are mixtures of 3-4 isomers.
The spirofused products 5 and 7
For example, the 13C NMR spectrum of 7 shows at least two
major and one minor sets of signals. Catalytic hydrogenation of 7 over Pd/C in EtOH at 2 atm gave isomerically pure 18, indicating that 7 is most likely two double bond regioisomers each of which exists as tm cis.
diastereoners. The fused products 9 and 11 are 90-95%
Whereas 9 is a 70:30 mixture of 2,8- and 2,7-regioisomers, 11 is of ca. 90% regio-
isomeric purity. major products.
Their lH NMR spectra support the assigned cis stereochemistry of the Thus, for example, the coupling constant between the two bridgehead
protons of 11 is 5-6 Hz.
The bridged products 13 and 15 are regiochemically 85-90% pure by
13C NMR, and 17 is of ca. 70% regicchemical purity. Catalytic hydrogenation of 17 as above gives 19 as an isomerically homogeneous species. containing
iodide intermediates
was achieved
Thirdly, the preparation of the esterby allylation
or benzylation of the
corresponding lithium enolates in THF in the presence of l-2 equiv of HMPA8 using 20g or 21,1° respectively. The preparation of 8 and 12 involves carbocupration-iodinolysi& of the corresponding alkynes using 2212 and 23.13 high yields.
All of the above reactions proceeded in
On the other hand, 10 was prepared in law yield by treating a 1:l mixture of
21 and 3-brorro-1-hexene with Mg in THF.
Fourthly, the use of NaOAc(2 eguiv) in place of
NEt3 for the conversion of 12 to 13 gave 13 in 97% GIG yield.
On the other hand, the use
of 3 mol % of Pd(dba)2 in place of Pd(PPh3)4 for the conversion of 8 to 9 resulted in only a
9
COOMe
q@ 18
cr Br 0
fl-BkBr 19
20
22
23
I
21
Further developments of this highly efficient and potentially versatile methodology for construction of cyclic structures are in progress in our laboratories. Aclaww1~t.s.
We thank the National Institutes of Health (GM 36792) and the donors
of the Petroleum Research Fund administered by the American Chemical Society (18710-ACl) for support.
E N is a John Simon Guggenheim Memorial Foundation Fellow(1987). We thank
Professor Richard C. Larock of Iowa State University for informing us of their related study prior to publication.
2918
References andNotes
(1)
Metal-Promoted Cyclization. 18.
Part 17. Negishi, E.; Sawada, H.; Tour, J. M.;
Wei, Y. J. Org. Chem. 1988, 53, 0000. (2)
For reviews,
see (a) Heck, R. F. Org. React. 1982, z,
345.
(b) Heck, R. F.
"Palladium Reagents in Organic Syntheses," Academic Press, New York, 1985. (3)
(a) Mori, M.; Chiba, M.; Ban, Y. Tetrahedron L&t. Tetrahedron Lett. 1979, 1133. 5315.
1977, 1073.
(b) Mori, M.; Ban, Y.
(c) Mori, M.; Ban, Y. Tetrahedron I&t.
(d) Terpko, M. 0.; Heck, R. F. J. Am. Chem. See. 1979, l&,
5281.
1982, 23, (e) Shi,
L.; Narula, C. K.; Mak, K. T.; Kao, L.; Xu, Y.; Heck, R. F. J. Org. Chem. 1983, 48, 3894.
(f) Cdle, R.; Blevins, B.; Ratcliff, M.; Hegedus, L. S. J. Org. Chem. 1980,
45, 2709.
(g) Iida, H.; Yuasa, Y.; Kibayashi, C. J. Org. Chem. 1980, 5,
Dieck, H. A. J. Org. Chem. 1983, 48, 807. Yanai,
H.; Takatori,
2938.
(h)
(i) Kasahara, A.: Izumi, T.; Murakami, S.;
M. Bull. Chem. Sot. Jpn. 1986, 59, 927.
(j) Grigg, R.;
Sridharan, V.; Stevenson, P.; Worakun, J. J. Chem. See., Chem. Common. 1986, 1697. (4) Narula, C. Km; Mak,K. T.; Heck, R. F. J. Org. Chem. 1983, 48, 2792. (5) Grigg, R.; Stevenson, P.; Worakun, T.; J. Chem. Sot., Chem. Cornmun.1984, 1073. (6) Tour, J. M.; Negishi, E. J. Am. Chem. Sot. 1985, 107, 8289. (7) During
the course
of this study, another
example of carbocycles prepared by
intramolecular arylpalladation appeared [Abelman, M. M.; Oh, T.; Overman, L. E. J1 Org. Chem. 1987, 52, 41331. (8) Herrmann, J. L.; Kieczykowski, G. R-i Schlessinger, R. H. Tetrahedron Lett. 1973, 2433. (9) Prepared by LiAlH4 reduction-iodinolysisfollowed by bromination with NBS-Me2S of 2heptyn-l-01 [Corey, E. J.; Katzenellenbogen, J. A.; Posner, G. H. J. Am. Chem. See. 1967, 89, 42451. (IO) Prepared by treating o-iodobenzyl alcohol with PBr3 [Tour, J. M. Ph.D. Dissertation, Purdue University, 19861. (11) Normant, J. F.; Bourgain, M. Tetrahedron I&t.
1971, 2583.
See, also, Iyer, R. S.;
Helguist, P. Org. Synth. 1985, 64, 1. (12) Prepared from the corresponding bromide [Salomon, R. G.; Ghosh, S.; Zagorski, M. G.; Reitz, M. J. Org. Chem. 1982, 47, 8291. (13) Prepared from the corresponding bromide [Klein, J. Israel J. Chem. 1963, 1, 3851. (Received
in USA
13 January
1988)