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Pericyclic umpolung. Reversal of regioselectivity in the diels-alder reaction
oc404039/91$3.00+ .w
Teuahedmn L.enm.Vol.32 No.24,pp US2718.1991 hintedin GreatBritain
Reversal
PC~&3”lOn
Pericyclic of Regioselectivity
Umpolung. in the Diels-Alder
h3.S
&dC
Reaction
K. J. Shea*, Andrew J. Staab, and Kathleen S. Zandi -tit
of Chemistry
University of California, Irvine Irvine, California 927 17
Summary: New methodology is reported which enables reversal of regiochemistry in the Diels-Alder reaction. Esterifcation of 2-(/I-hydroxyethyl)dimethylsilyldienes with common dienophiles followed by type 2 intramokcular Dkis-Alder reaction results information of a single regio- and stereoisomer. Oxtitive ckavage of the cycloadduct produces a cyclohexanone with a substitution pattern opposite of that found in the analogous bimolecular cycloaaUitionreaction. Reversal of the normal patterns of chemical reactivity, i.e., functional
group umpolung,ls4
can
significantly enhance the number of viable approaches to chemical synthesis. In this communication, we report methodology that accomplishes reversal of the intrinsic regiochemicaI preferences of the Diels-Alder reaction. The methodology, which we term pericyclic umpolung5 utilizes a type 2 intramolecular Diels-Alder reaction7-9 and involves temporarily joining diene and dienophile with a disposable tether. The mechanical constraints imposed by type 2 intramolecularity (Scheme 1).
enables reversal of the inherent regiochemical bias of the cycloaddition reaction
n\
x/
n x/
\I ‘(f
Scheme:
1.
-
I
“‘o-, +xy-Jz
2
z-
7
“‘Q,
n +“0”
Schematicre+.msentation of paicyclic wnpcluagresuhingkan type2 inmimo~ular cyclcadditia~. ThegroupsX and Z are usedto designatedonoraadxcqttx gmaps.respectively.
2715
2716
We recently mported a means for temporarily joining diene and dienophile in a type 2 intramolecular DielsAlder reaction.10 The methodology. which employs a silylacetal group as the nexus between reacting groups, achieves stereochemical control in the cycloaddition step. A single (meta) regioisomer is observed in cases where the intrinsic regiochemical bias of the diene and dienophile is not challenged. A limitation to this methodology quickly arose during efforts to override this intrinsic preference. Thus, cycloaddition of siloxydiene 1 gave a 70:30 mixture of 1,4- and 1,3-mgioisomers
(2 and 3). 11 The major product was shown to be the 1,4-
regioisomer, corresponding to the dominant isomer formed in the bimolecular reaction. If the tether is shortened by one atom, i.e., vinyl silyl ether 4,12 a mixture of regioisomers is also formed, but the major product is now the desired 1,3-cycloadduct 5 (equation 2).
(1)
(2)
0 4
.5
6
Complete regio- and stereochemical control is achieved by shortening the tether tofive atoms. The key
linkage utilizes a 2-(P-hydroxyethyl)dimethylsilyl
group as in 7, 15 which is condensed with common dienophiles
to produce the type 2 intramolecular Diels-Alder precursor, 8 (equation 3). 0
+
HO
RI R2
8
7
1) M~H/NzCO3 21 . Ac?O _ 3) (n-J%N+F 4) m-CPBA
(3)
A J
2717
Table Dieaophile (cycloaddition
Cycllmddwt~ conditions)
cycloakanone (yield)
(yield)
0
(1)
(170-C,40 (98%)
0
min)
OzMe (54%)
(18O”C, 1.S) (88%)
(2) H$
0 (185-C, 4.5b) (78%)
(3) H3C
0 (4)
(18O”C, 4h) (93%)
(18O’C, 18h) (65%)
3yj=o 0
(llS”C, 36h) (53%)
ck
H
g+Y-
(7) HF
I
3
(ZOO’C 4h) (71;)
P
’ Cycloadditions were run in 0.1 M toluene solution at the indicated time and temperatures (isolated yield). A single enantiomer of the mcemic compound is drawn in each case.
2718
The cycloaddition
reactions proceed smoothly at elevated temperatures
in toluene.
A summary of the
results and reaction conditions is given in the table. In all cases, a single product was observed. the 1,3-regiochemistry
was secured by spectroscopic
products and in several examples by an X-ray crystal structure. cinnamate
cycloadduct
Confirmation
of
analysis, chemical correlation with bimolecular cycloaddition An ORTEP plot of the X-ray crystal structure of
9 (entry 4) is shown below. 16 Significantly,
the reactions
proceed
well even with
trisubstitutedmonoactivated dienophiles (entry 5) and doubly 1,4-directing dienophiles (entry 6). The tether may be oxidatively removed by the sequence of reactions shown in equation 3.17 The overall transformation a substitution examples
pattern that is reversed
of functional
synthetic strategies
References 1. ::
4. 5.
and
from the normal bimolecular
group umpolung,3s4 pericyclic
for six-membered
Notes
rings.
Applications
Diels-Alder
reaction.
umpolung permits a completely of this new methodology
results in
As with previous revised
analysis of
will be the topic of future
9
Corey, E. J.; Cheng, X. -M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1989. Warren, S. Organic Synthesis: The Disconnection Approach, John Wiley & Sons, New York, 1982. Seebach, D. Angcw. Chem. Int. Ed. Engl. 1919.18,321. Hase, T. A. (Ed.) Urnpoled Synrhons, John Wiley & Sons, 1987. Diels-Alder transition states between donor dienes and acceptor dienophiles have traditionally been analyzed in terms of their dipolar-like character. Theoretical studies indicate the reactions are highly unsymmetrical with substantial charge separation Character.6
6.
:: 9. 10. 11. 12.
(a) Sauer, J.; Sustmann. R. Angew. Chem. Int. Ed. Engl. 1980.19.779. (b) Brown, F. K.: Houk, K. N. Tetrahedron Lett. 1984.25.4609; Brown, F. K.; Houk, K. N. Tetrahedron L&t. 1985.26.2297. Shea, K. J.; Burke, L. D.; England, W. P. J. Am. Chem. Sot. 1988,110, 860. Shea. K. J.; Ftuscella, W. M.; Carr. R. C.: Cooper, D. K.; Burke, L. D. J. Am. Chem. Sot. 1987,109,447. (a) Shea, K. J.; Wise, S.; Burke, L. D.; Davis, P. D.; Gilman, J. W.; Greeley, A. C. J. Am. Chem. Sot. 1982,104, 5708. (b) Shea. K. J.; Wada, E. J. Am. Chem. Sot. 1982,104. 5715. Shea, K. J.: Zandi, K. S.; Staab, A. J.; Carr, R. Tetrahedron Lett. 1990.31.5885. Au new compounds gave spectroscopic and analytical data consistentwith their assigned structures. Regiochemical assignment of the cycloadduct was aided by correlation with poduct mixtures obtained fmn the comsponding bhnolecular reactions. The 2-silyl diene not only serves as an oxygen surrogate, t3 but is also a strong para-directing group in the Diels-Alder
reaction.14 13. 14. 15. 16.
17.
18.
Calvin, E. W. Silicon in Organic Synthesis, Butterworths, London, 1981, revised edition Krieger Press, 1985. Batt, D. G.; Ganem. B. Tetrohedron Lett. 1978,3323. Silyl diene 7 is prepared by reaction of the Grignard reagent derived from chlomprene with chlommethyldimethylchlomsilane. The resulting chlommethylsilykiie is converted to the Grignard nzagent then condensed with famaldeh de. Crystal data for 9: monoclinic, space group P2t/c, a = 12.554(2). b = 18.620(3). c = 6.8561(9) x . p = 94.689’. and V = 1597.2(4) A3.Z = 4. DC = 1.19 Mg/m3, RF = 4.3%. RwF = 5.6% for 1758 reflections with IFd > 3.0 s (IFol). Structural data have been deposited with the Cambridge CrystalData Cenlre. For related oxidative cleavage of vinyl silanes, see (a) Tamao, K.; Akita. M.; Kumada, M. J. Organomet. Chem. 1983,254, 631. (b) Tamao, K.; Kumada, M.; Maeda. K. Tetrahedron Lm. 1984,25,321. (c) Tamao. K.; Maeda, K.; Yamaguchi, T.: Ito, Y. J. Am. Chem. Sot. 1989,111, 4984. Financial support from the National Institutes of Health and the National Science Foundation is greatly appreciated.
(Received in USA 20 February 1991)
Teuahedmn L.enm.Vol.32 No.24,pp US2718.1991 hintedin GreatBritain
Reversal
PC~&3”lOn
Pericyclic of Regioselectivity
Umpolung. in the Diels-Alder
h3.S
&dC
Reaction
K. J. Shea*, Andrew J. Staab, and Kathleen S. Zandi -tit
of Chemistry
University of California, Irvine Irvine, California 927 17
Summary: New methodology is reported which enables reversal of regiochemistry in the Diels-Alder reaction. Esterifcation of 2-(/I-hydroxyethyl)dimethylsilyldienes with common dienophiles followed by type 2 intramokcular Dkis-Alder reaction results information of a single regio- and stereoisomer. Oxtitive ckavage of the cycloadduct produces a cyclohexanone with a substitution pattern opposite of that found in the analogous bimolecular cycloaaUitionreaction. Reversal of the normal patterns of chemical reactivity, i.e., functional
group umpolung,ls4
can
significantly enhance the number of viable approaches to chemical synthesis. In this communication, we report methodology that accomplishes reversal of the intrinsic regiochemicaI preferences of the Diels-Alder reaction. The methodology, which we term pericyclic umpolung5 utilizes a type 2 intramolecular Diels-Alder reaction7-9 and involves temporarily joining diene and dienophile with a disposable tether. The mechanical constraints imposed by type 2 intramolecularity (Scheme 1).
enables reversal of the inherent regiochemical bias of the cycloaddition reaction
n\
x/
n x/
\I ‘(f
Scheme:
1.
-
I
“‘o-, +xy-Jz
2
z-
7
“‘Q,
n +“0”
Schematicre+.msentation of paicyclic wnpcluagresuhingkan type2 inmimo~ular cyclcadditia~. ThegroupsX and Z are usedto designatedonoraadxcqttx gmaps.respectively.
2715
2716
We recently mported a means for temporarily joining diene and dienophile in a type 2 intramolecular DielsAlder reaction.10 The methodology. which employs a silylacetal group as the nexus between reacting groups, achieves stereochemical control in the cycloaddition step. A single (meta) regioisomer is observed in cases where the intrinsic regiochemical bias of the diene and dienophile is not challenged. A limitation to this methodology quickly arose during efforts to override this intrinsic preference. Thus, cycloaddition of siloxydiene 1 gave a 70:30 mixture of 1,4- and 1,3-mgioisomers
(2 and 3). 11 The major product was shown to be the 1,4-
regioisomer, corresponding to the dominant isomer formed in the bimolecular reaction. If the tether is shortened by one atom, i.e., vinyl silyl ether 4,12 a mixture of regioisomers is also formed, but the major product is now the desired 1,3-cycloadduct 5 (equation 2).
(1)
(2)
0 4
.5
6
Complete regio- and stereochemical control is achieved by shortening the tether tofive atoms. The key
linkage utilizes a 2-(P-hydroxyethyl)dimethylsilyl
group as in 7, 15 which is condensed with common dienophiles
to produce the type 2 intramolecular Diels-Alder precursor, 8 (equation 3). 0
+
HO
RI R2
8
7
1) M~H/NzCO3 21 . Ac?O _ 3) (n-J%N+F 4) m-CPBA
(3)
A J
2717
Table Dieaophile (cycloaddition
Cycllmddwt~ conditions)
cycloakanone (yield)
(yield)
0
(1)
(170-C,40 (98%)
0
min)
OzMe (54%)
(18O”C, 1.S) (88%)
(2) H$
0 (185-C, 4.5b) (78%)
(3) H3C
0 (4)
(18O”C, 4h) (93%)
(18O’C, 18h) (65%)
3yj=o 0
(llS”C, 36h) (53%)
ck
H
g+Y-
(7) HF
I
3
(ZOO’C 4h) (71;)
P
’ Cycloadditions were run in 0.1 M toluene solution at the indicated time and temperatures (isolated yield). A single enantiomer of the mcemic compound is drawn in each case.
2718
The cycloaddition
reactions proceed smoothly at elevated temperatures
in toluene.
A summary of the
results and reaction conditions is given in the table. In all cases, a single product was observed. the 1,3-regiochemistry
was secured by spectroscopic
products and in several examples by an X-ray crystal structure. cinnamate
cycloadduct
Confirmation
of
analysis, chemical correlation with bimolecular cycloaddition An ORTEP plot of the X-ray crystal structure of
9 (entry 4) is shown below. 16 Significantly,
the reactions
proceed
well even with
trisubstitutedmonoactivated dienophiles (entry 5) and doubly 1,4-directing dienophiles (entry 6). The tether may be oxidatively removed by the sequence of reactions shown in equation 3.17 The overall transformation a substitution examples
pattern that is reversed
of functional
synthetic strategies
References 1. ::
4. 5.
and
from the normal bimolecular
group umpolung,3s4 pericyclic
for six-membered
Notes
rings.
Applications
Diels-Alder
reaction.
umpolung permits a completely of this new methodology
results in
As with previous revised
analysis of
will be the topic of future
9
Corey, E. J.; Cheng, X. -M. The Logic of Chemical Synthesis, John Wiley & Sons, New York, 1989. Warren, S. Organic Synthesis: The Disconnection Approach, John Wiley & Sons, New York, 1982. Seebach, D. Angcw. Chem. Int. Ed. Engl. 1919.18,321. Hase, T. A. (Ed.) Urnpoled Synrhons, John Wiley & Sons, 1987. Diels-Alder transition states between donor dienes and acceptor dienophiles have traditionally been analyzed in terms of their dipolar-like character. Theoretical studies indicate the reactions are highly unsymmetrical with substantial charge separation Character.6
6.
:: 9. 10. 11. 12.
(a) Sauer, J.; Sustmann. R. Angew. Chem. Int. Ed. Engl. 1980.19.779. (b) Brown, F. K.: Houk, K. N. Tetrahedron Lett. 1984.25.4609; Brown, F. K.; Houk, K. N. Tetrahedron L&t. 1985.26.2297. Shea, K. J.; Burke, L. D.; England, W. P. J. Am. Chem. Sot. 1988,110, 860. Shea. K. J.; Ftuscella, W. M.; Carr. R. C.: Cooper, D. K.; Burke, L. D. J. Am. Chem. Sot. 1987,109,447. (a) Shea, K. J.; Wise, S.; Burke, L. D.; Davis, P. D.; Gilman, J. W.; Greeley, A. C. J. Am. Chem. Sot. 1982,104, 5708. (b) Shea. K. J.; Wada, E. J. Am. Chem. Sot. 1982,104. 5715. Shea, K. J.: Zandi, K. S.; Staab, A. J.; Carr, R. Tetrahedron Lett. 1990.31.5885. Au new compounds gave spectroscopic and analytical data consistentwith their assigned structures. Regiochemical assignment of the cycloadduct was aided by correlation with poduct mixtures obtained fmn the comsponding bhnolecular reactions. The 2-silyl diene not only serves as an oxygen surrogate, t3 but is also a strong para-directing group in the Diels-Alder
reaction.14 13. 14. 15. 16.
17.
18.
Calvin, E. W. Silicon in Organic Synthesis, Butterworths, London, 1981, revised edition Krieger Press, 1985. Batt, D. G.; Ganem. B. Tetrohedron Lett. 1978,3323. Silyl diene 7 is prepared by reaction of the Grignard reagent derived from chlomprene with chlommethyldimethylchlomsilane. The resulting chlommethylsilykiie is converted to the Grignard nzagent then condensed with famaldeh de. Crystal data for 9: monoclinic, space group P2t/c, a = 12.554(2). b = 18.620(3). c = 6.8561(9) x . p = 94.689’. and V = 1597.2(4) A3.Z = 4. DC = 1.19 Mg/m3, RF = 4.3%. RwF = 5.6% for 1758 reflections with IFd > 3.0 s (IFol). Structural data have been deposited with the Cambridge CrystalData Cenlre. For related oxidative cleavage of vinyl silanes, see (a) Tamao, K.; Akita. M.; Kumada, M. J. Organomet. Chem. 1983,254, 631. (b) Tamao, K.; Kumada, M.; Maeda. K. Tetrahedron Lm. 1984,25,321. (c) Tamao. K.; Maeda, K.; Yamaguchi, T.: Ito, Y. J. Am. Chem. Sot. 1989,111, 4984. Financial support from the National Institutes of Health and the National Science Foundation is greatly appreciated.
(Received in USA 20 February 1991)