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Heterocyclic Synthesis
INTRODUCTION
The importance of the Diels-Alder reaction in organic synthesis derives in large part from its ability to generate six-membered rings containing several contiguous stereogenic centers in one synthetic operation. In recent years the Diels-Alder reaction of heterosubstituted 1,3-dienes and dienophiles has emerged as a powerful method for preparing highly functionalized heterocyclic ring systems. The aim of this chapter is to provide an indication of the wide assortment of Diels-Alder chemistry that has been used for heterocyclic synthesis. Although some older references are mentioned, the coverage has been selected from the last fifteen years, including new applications and modifications of older reactions and innovations. The organization of the review is according to structural type and represents an extension of an approach used earlier in Volume 6 of PHC. Each synthetic sequence is accompanied by references to the original literature. We hope that you find this unusual format to be useful. The following reaction sequences provide a sampling of some noteworthy transformations in this area of heterocyclic chemistry.
2.2
Reaction Schemes
I Imino Die/s-Aider Reactions I
Reviews: Boger [87M1001] Weinreb [82TET3087, 79HET949]
H- y
'NCH2Ph ' U. ~.
~ O
IP
21
22
Danishefsky - Application of the aldimine diene-cyclocondensation reaction for total synthesis [86JOC3915] H EtOyOSiEt3 ~ ./',~C02Me
IJ, ,
+
OMe
50 %
ZnCI2
N
OMe
Holmes- Synthesis of piperidine alkaloids using a tosyl imine [87TL813] 0 HyCO2Me ~]1OSiMe3 Lewisacid Tos~N + 1) MeCO3H. I" OH OH ~ 2) LiAIH4 H3 O+ " TosN CO2Me
Grieco - Diels-Alder reaction of iminium salts generated under Mannich conditions in aqueous solution [85JACS1768] 1.3 eq PhCH2NH2-HCI 1.3 eq HCHO H2O, 55 ~ 96 h 62 % ~N CH2Ph
~-
t ~
N CH2Ph
O
+
Me~,,,,H
H2Nq "Ph
HCHO/H20 86 % =
ON
Ph
Me_ H
9 1
Grieco- Cyclocondensation of C-acyl iminium ions with cyclopentadiene [86TL1975] O + Me-NH2 HCI O
H20, rt, 22 h
82 %
Me 4.2 9 1
23
= H H
+ H 3.7 ' 1 H
NH3CI"
HCHO/H20
, v
50 ~ 48 h
95 %
"H
CI
CHO
H sa e
NH
h
"~CHO
MeNH2 HCI
H20/EtOH (1" 1) 70 ~ 66 %
MeN
Dihydrocannivonine
O H Me3Si~.~~
MeaSi~
N'OMe
24
Boger- Vinyl sulfonylimines as azadienes - preparation from the corresponding oximes or unsaturated aldehydes [91JACS1713] OH| M S(O)Ph 25~ S02Ph
Mean
PhSOCI.
-20tO 0 ~
SO2Ph
I
H.~O Ph
PhSO2NH2MgS04
H~ Ph
OCH2Ph
H" Me
L,j
"Me
SO2Ph +
H,,,~OMe C II CH2
CH2CI2 12 kbar 54 %
I =
OMe CH2
25
Weinreb - Intramolecular Die/s-Aider reactions of N-acyl azadienes [85ACR16, 79JACS5073, 81JACS6387, 82JACS7065]
c~
O
650~ ll~s
-HOAc
CH2~,~ I~/N~ O
= 73'0
~N~ O
,c o-- ,co
73 % ~ O 1) H2,Pd 2) B2H8
"~176I Q
6-Coniceine
Weinreb - Acylimines as key intermediates for alkaloid synthesis [83JOC3661]
OBn
o-dichloro- --N H /~ benzene .--i./
,,OH
epi-Lupinine
r'~Y
AcO O
178~
930/.
O
Rigby - [4+2]-Cycloadditions of vinyl isocyanates [84JOC4569, 86JOC1374, 89JOC224, 89JOC4019, 89JOC5852, 89SC2699, 91JACS8975]
[~ ~C~ 0 0
H2/ Pd (C) 73 %
MeO MeO" ~
NCO
~ + ~ 34 % =-
OMe
MeO
MeO" ~
I
v OMe
26
58%
!
NCO
NH2
good synthon for ben~ne
Magnus - Indole 2,3-quinodimethane strategy for synthesis of indole alkaloids [84ACR35] 1'~ ~:~/'~ E"N NI~CH2
R SiMe3
E+
J R
CH2 O
N
R
N
L~
,3,00
~ ~ , ,H,,..~,,,J ~
"''~Et R I(+)- Aspidospermidine ]
I
N~ S P h
O O 33"---~/0
PhS~ N I R
O
f
""Et
R
I Acvlationl
o
CH2
~~
"=
"
~L~~'N ~'~'~'"Et R
Me ~,,.~ CycllzationlI
~ . . . . . . . . . . . . . . . . . . . . . . .
~ . . . . . . . . . . . . . . . .
~N'~
R
I
Ne~ jJl M CI
c,~oCH~OCOC," ~,
PhCI
i-PrNEt,120~
~ ' ~ N J I~ " C I
R
~~'"~
E"N"~'I H,,.
27
R ..R1
R2.~H
heat = 66-100 %
(~+N~~
Br-
CH2=C(OEt)2 .= 25 ~ 1 h 89 %
C104"
Cycloaddition of isoquinolinium salts Franck- Use of vinyl sulfides for synthesis of 1-naphthaldehydes [89JOC1097]
,~ts
R' RtR~ ./~--" H
R 1 = R2= H
.~r R1
1)H+, H20
2) K2CO3, MeOH, H20
CHO
overall 91%
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . o
NHBn COC'
O
O O
exo-adduct
28
80JACS3632, 85JACS5534]
t-BuMe2SiO,,
N r
~ r OMe
83%
_ ,,0..,,,OMe _,,0,..,OMe
70" 13 Kibayashi- Stereospecific total synthesis of GTX 223AB [86TL5513] Pr4N104= CHCI3 O H 1) Zn, HOAc 2) BnOCOCI Na2CO3/CHCI3 MsCI, Et3N 31H2,Pd/C,MeOH
I=, 4" -"
~
several steps
Gephyyrotoxin 223AB
pyridine
0 .,~.x. R
29
Me NHTos "_- Me Me
.o,
~.
o NH2
SOCI2 pyridine"
"15~
N 85 %
r
13H27
'~n .C13(~27
n-C13H27~ ~ O "
i
Ba(OH)2
Ii=
_NH2 n-C13H27~ O H
threo-Sphingosin
OH
O H
E.threo .carbamate
Weinreb - Stereochemica/contro/[84JACS7867] Me +
Me
Me
.oS" II NCO2Bn
PhMe 25 oC95 %
I[~ ~
Me
,oCO2Bn
PhMgBr
H.,,,I~::~ Me 2,3-eigmatropic
Me,~Ix. " "OSPh H NHCO2Bn
Me + . = "1 ~s "r" /
P(OMe)3 85 %
OH NHCO2B n
threo.hydroxy carbamate
MeOH = Mei~~,,,~Me
Me'~NI~I~O2Bn ]
30
[84JACS7867]
S ~'NR II NR
benzene "' 25 oc
i RN
I Me
1) PhMgBr
=
2) P(OMe)3
83-92 %
Me
Me R = Tos, C02Me
PhMgBr Me
2,3-
3-Pyridyne as a dienophile
[88JCS(P1)247]
NH2,,v,,,% N HO2C i ~ / ,
1) HNO2 2) Me2NH
Me2N_N=N~
M6
72%-
H02C ] ~ ~ ''
M6
Me E//ipticine MeCN A
+
Me BF3-Et20 T Ac20 44 %
Me
OH
Me
Me Isoellipticine 40 % (1 91)
KOH, &
N" H
31
MeO2C -
H "C=C(C02Me)2 ~,'
81% MeO2C MeO Me
.OMe 7 steps
10 eq H2C=C(OMe)2
toluene,140 ~ 21 h
~OH
.,, MeO 17%
Me
Me
75 % MeO
Me
Juncusol
xylene ID reflux
93 %
H
~l o
RO
RO
OMe
(:/:)-Reserpine Hetero Die/s-Aider Reactions Reviews: Boger and Weinreb [87MI001, 91MI402, 91MI451] Intramolecular Cycloadditions Involving Oxabutadienes Tietze -in situ generation of heterodiene via Knoevenagel condensation
[87ACIE 1295, 82ACIE221]
o
~CHO
0_.~ O ~
OMe + ~ , . 0
I I
"T
o ~ o ~ io~~.~ o
.
exo.E-anti
(S)-Citronellal
preferential 5,6-cis-fused cycloadduct from endo. E-syn transition state = 52 %
L ~176
endo-E-syn
0~.,,.0,~ H
H .C02Me
6 steps
~,~ 0
O
Osugar
i-de 9 98 %
Deoxyloganin
32
O DMF
w
O (R)-Citronellal R=
C5Hll
100 ~
R
i-de 9 98 %
46 % R
(-)-(9R)-Hexahydrocannabinol
HO CF3CO2H CHCI3 OH Me 87 %
EtO~l
==~CHO 0.05 eq Yb(fod)3, rt, 80 h 60-80 %
33
I"`'`r~176
I
RIJR1 + hv = R R1
Vedejs - Unstable thioaldehydes can be generated and trapped in situ by a photochemical method[80JOC2601, 83JACS6999, 82JACS1445, 83JACS1683, 86JOC1556, 88JOC2226, 88JACS5452]
o ~~
h~
[ o
..~
C
~ Y
H
phi
"
0
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
12" 1)
Ph.~ O
O O
hv =
i,
O
=
89 %
R1
O2Et
F.. R=RI=H 1 R=Me, R =2-methylpropenyl intrarnolecular EtO2C, H ene reaction , eo . ~ S 62 % M retro A Diels-Alder =
. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Baldwin - New thermal method for generating thioaldehydes from alkyl thiosu/finates [82CC 1029]
S.
'40
(1.1)
34
New tactics for effecting Diels-Alder reactions Dauben- Cycloadditions at high pressure [80JACS7126, 85JOC2567] ~CO2Me S~ ~ _j,,~O 1)liq HCN 2) H3PO4 3) HCI, AcOH-H20 = ~ s~.~o O + ~ 7 kbar, i1, 24 h (10 g scale) "
~0
4) SOCI2, A 50 %
O O~o
O ~ ~ O
Canthat~din
MeO2C'~"~
290 ~ 100 %
v
MeO2C'~~'~ 290 ~ 97 %
MeOjC/~/,~
Keay - High pressure intramolecular Diels-Alder reaction of furan as a diene [89TL1045] O 12 kbar R R2 25 ~ R, R1, R2 = H, Me 43-65 % McCulloch - Diels-Alder reactions of pyrroles [70CJC1472] CO2Me C AlCla III = C CH2CI2 i COiMe 75 % N,CO2Me R~~ COiMe R2 \ CO2Me R1 AICI3 ~ CO2Me
R2
R1 + i CO2Me
85 % R2f..,,,~n,~CO2 Me
R 1 = H; R2 = Me
H"N'cojMe
35
,r.CO,Et
+ ~ "COjEt 70 %"
/i~N
CO2Et 75 ~ CO2Et CO2Et
/~=N
O2Et J~"\CO2Et CO2Et
N"~
CO2Et
Murase - Vinyl pyrroles as dienes for Die/s-Aider reactions [91CPB489] SCH2Ph S /JL'Me i Me BnCI
THF I Me
i~ )
Me
A 220 ~
0 Me Me"N~" N"
N - HCN 7O%
Me ,~
O + ---
\ OAc 90 %
= PhC=N + O ~
OAc
Ph
OH MeN ~ ~ O
36
%~
H* ==~ 98% = 0
Gnididione
94
~ ' ~ 0/'~0
Paniculide-A
OMe
OMe
(-) Norsecurinine
Jacobi -Synthesis of furans or functionality derived from a s u ~ u r a n [87TET5475] ~ O~o ~ ,,,,~~N)J~OMe PhEt _ refluxMe
1) NaBH4 ,.
- MeCN
94 %
2) pH5 H
OH..~ O H O
PaniculideA
37
Diels-Alder of Thiazole Derivatives Jacobi - Formation of fused ring thiophenes [84HET281, 88TET3327, 87TL2937] Me~OEt N~ ,S OEt
~
I O
-MeCN 57 %
"
R = CH2OMe
H Me Me
~en~U~ 1'1
Intramolecular Kondrat'eva Pyridine Synthesis [57MI666, 59MI484] Weinreb - Addition of DBN is helpful to intramolecular cycloadditions [89JO05580]
~~1'~ N,,Ac
A o-DCB DBN
.,Ac
[
A -H20 ~NAc
OTBS
OTBS
OTBS
I Heter~
cti~ I
49--*7./o CO2Me
'pyrrolidine CO2Me
38
Boger - Die/s-Aider reactions of heterocyclic azadienes for the total synthesis of complex molecules [87JACS2717] NH CO2Me dioxane 1) H2S,Et2NH ~~~'SMe 80 ~ 22 h NO2 dioxane _- NO2 N + || | 2) Mel, MeCN 82 % MeO" ~'~ 42 % MeO" ~ MeO2C
N)~-N N.,~N
R2N",~M e 4 eq
~OBn
" ~ "OMe
OMe
(2.8" 1)
65 %
10 steps
I=
NH2~Me
Streptonigrin OMe
R R=Bz
COtMe
CO2Me
Neunhoeffer [73LAC1955] R1 R2"~ R21 R i ~ / N I~1 + Me2N~ CH2 1110Me X = NMe2,OMe 57-93 %
91
39
.C02Me
N~"~CO2 Me MeC_=CNEt2 MeO2CN.~ NEt2 N~,,,,'~CO2Me
Me
-N2
R1CH=CHR 1 =
"N2
~RR 1
N .
.,
R
Die/s-Aider reactions of electron deficient heteroaromatic dienes
EtO,,,ll/Ph r
NH CO2Me /
,N I~1/CO2Me
"N2 27 %
LMeO2C Ph
N-J~N N~IN
I II
CO2Me
"'y"
R = alkyl, Ph
=- "
N.=-~N..NMe2 /
~,bCO~M,, " 1
"N2 = 56-81%
N~,,N.NMe2
CO2Me
CO2Me
Taylor - Route to condensed pyrazines via internal cycloadditions using nitriles as dienophiles [89JOC1245, 86JOC1967] CN Ph,,,,,~N,,N L x
225.235oc
Ph,. N,. ~ X
X = O, NCOCF 3
40
2.3 References
55JACS4812 57MI666 58JACS933 59MI484 66TL4979 67TET943 68JOC390 69JHC497 69TL5171 70CJC1472 72TL1517 73CC156 73LAC437 73LAC1955 75TL2897 78JACS7748 78JOC2083 78MI1095 78TL4767 79AP452 79JACS5073 79HET949 80JACS3632 80JACS5245 80JACS7126 80JOC2601 81JACS6387 81JOC2065 82ACIE221 82CC1029 82JACS 1445 82JACS7065 82TET3087 82TL3739 C. K. Bradshaw, L. E. Beavers, J. Am. Chem. Soc. 1955, 77, 4812. G. Y. Kondrat'eva Khim. Prom. (Moscow) 1957, 2, 666. C. K. Bradsher, T. W. G. Solomons, J. Am. Chem. Soc. 1958, 80, 933. G. Y. Kondrat'eva Izv. Akad. Nauk. SSSR, Ser. Khim. 1959, 484. J. Sauer, G. Heinrichs, Tetrahedron Lett. 1966, 4979. R. A. Firestone, E. E. Harris, W. Reuter, Tetrahedron 1967, 23, 943. D. L. Fields, T. H. Regan, J. C. Dignan, J. Org. Chem. 1968, 33, 390. P. Roffey, J. P. Verge, J. Heterocycl. Chem. 1969, 6, 497. W. Dittmar, J. Sauer, A. Steigel Tetrahedron Lett. 1969, 5171. R. C. Bansal, A. W. McCulloch, A. G. McInnes, Can. J. Chem. 1970, 48, 1472. H. Neunhoeffer, G. Werner, Tetrahedron Lett. 1972, 1517. C. K. Bradsher, F. H. Day, A. T. McPhail, P. S. Wong, J. Chem. Soc., Chem. Commun. 1973, 156. H. Neunhoeffer, G. Werner, Liebigs Ann. Chem. 1973, 437. H. Neunhoeffer, G. Werner, Liebigs Ann. Chem. 1973, 1955. . Burg, W. Dittmar, H. Reim, A. Steigel, J. Sauer, Tetrahedron Lett. 1975, 2897. P. A. Jacobi, T. Craig, J. Am. Chem. Soc. 1978, I00, 7748. A. P. Kozikowski, M. P. Kuniak, J. Org. Chem. 1978, 43, 2083. H. Neunhoeffer, Chemistry of Heterocyclic Compounds; Wiley: New York, 1978; Vol. 33 pp 1095-1097. G. E. Keck, Tetrahedron Lett. 1978, 4767. G. Seitz, W. Overheu, Arch. Pharm. 1979, 312, 452. S. M. Weinreb, N. A. Khatri, H. Shringarpure, J. Am. Chem. Soc. 1979, 101, 5073. S. M. Weinreb, J. I. Levin, Heterocycles 1979, 12, 949. G. E. Keck, D. G. Nickell, J. Am. Chem. Soc. 1980, 102, 3632. K. P. C. Vollhardt, R. L. Funk, J. Am. Chem. Soc. 1980, 102, 5245. W. G. Dauben, C. R. Kessel, K. H. Takemura, J. Am. Chem. Soc. 1980, 102, 7126. E. Vedejs, M. J. Amost, M. Dolphin, J. Eustache, J. Org. Chem. 1980, 45, 2601. N. A. Khatri, H. F. Schmitthener, J. Schringarpure, S. M. Weinreb, J. Am. Chem. Soc. 1981, 103, 6387. P. A. Jacobi, D. G. Walker, I. M. A. Odeh, J. Org. Chem. 1981, 46, 2065. L. F. Tietze, G. von Kiedrowski, B. Berger, Angew. Chem. Int. Ed. 1982, 21, 221. J. E. Baldwin, R. C. G. Lopez, J. Chem. Soc., Chem. Commun. 1982, 1029. E. Vedejs, T. H. Eberlein, D. L. Vanle, J. Am. Chem. Soc. 1982, 104, 1445. R. A. Gobao, M. L. Bremmer, S. M. Weinreb, J. Am. Chem. Soc. 1982, 104, 7065. S. M. Weinreb, R. R. Staib, Tetrahedron 1982, 38, 3087. J. F. Kerwin, S. J. Danishefsky Tetrahedron Lett. 1982, 23,
41
83JACS1683 83JACS6999 83JOC3661 83TL987 83TL1481 83TL2473 84ACR35 84HET281 84JACS7861 84JACS7867 84JOC3243 84JOC4045 84JOC4569 84JOC4741 84MI550 84TL721 84TL2541 84TL4859 85ACR16 85JACS1768 85JACS4072 85JACS5534 85JOC1695 85JOC2567 85TET1173 86CR781 86JACS1306 86JOC1374 86JOC1556 86JOC1967 86JOC3553 86JOC3915 86TL1975
3739. E. Vedejs, D. A. Perry, J. Am. Chem. Soc. 1983, 105, 1683. E. Vedejs, D. A. Perry, K. N. Houk, N. G. Rondan, J. Am. Chem. Soc. 1983, 105, 6999. M. L. Bremmer, N. A. Khatri, S. M. Weinreb, J. Org. Chem. 1983, 48, 3661. R. S. Garigipati, J. A. Morton, S. M. Weinreb, Tetrahedron Lett. 1983, 24, 987. J. Balcar, G. Chrismam, F. X. Huber, J. Sauer, Tetrahedron Lett. 1983, 1481. D. Liotta, M. Saindane, W. Ott, Tetrahedron Lett. 1983, 24, 2473. P. Magnus, T. Gallagher, P. Brown, P. Pappalarado, Acc. Chem. Res. 1984, 17, 35. P. A. Jacobi, K. Weiss, M. Egbertson, Heterocycles 1984, 22, 281. R. S. Garigipati, A. J. Freyer, R. R. Whittle, S. M. Weinreb, J. Am. Chem. Soc. 1984, 106, 7861. H. Natsugari, R. R. Whittle, S. M. Weinreb, J. Am. Chem. Soc. 1984, 106, 7867. S. W. Remiszewski, R. R. Whittle, S. M. Weinreb, J. Org. Chem. 1984, 49, 3243. D. L. Bo~er, M. D. Mullican, J. Org. Chem. 1984, 49, 4045. J. H. Rigoy, N. Balasubramanian, J. Org. Chem. 1984, 49, 4569. S. E. Denmark, M. S. Dappen, J. A. Sternberg, J. Org. Chem. 1984, 49, 4741. H. Neunhoeffer, Comprehensive Heterocyclic Chemistry; Pergamon: London, 1984; Vol. 3, p 550. S. Danishefsky, M. Bednarski, Tetrahedron Lett. 1984, 25, 721. K. MUller, J. Sauer, Tetrahedron Lett. 1984, 2541. P. A. Jacobi, C. S. R. Kaczmarek, U. E. Udodong, Tetrahedron Lett. 1984, 4859. S. M. Weinreb, Acc. Chem. Res. 1985, 18, 16. S. D. Larsen, P. A. Grieco, J. Am. Chem. Soc. 1985, 107, 1768. S. F. Martin, S. Grzejszczak, H. Rtieger, S. A. Williamson, J. Am. Chem. Soc. 1985, 107, 4072. H. Iida, Y. Watanabe, C. Kibayashi, J. Am. Chem. Soc. 1985, 107, 5534. J. J. Talley, J. Org. Chem. 1985, 50, 1695. W. G. Dauben, J. M. Gerdes, D. B. Smith, J. Org. Chem. 1985, 50, 2576. S. W. Remiszewski, T. R. Stouch, S. M. Weinreb, Tetrahedron 1985, 41, 1173. D. L. Boger, Chem. Rev. 1986, 86, 781. S. E. Denmark, M. S. Dappen, C. J. Cramer, J. Am. Chem. Soc. 1986, 108, 1306. J. H. Risby, F. Burkhardt, J. Org. Chem. 1986, 51, 1374. E. Vedejs, T. H. Eberlein, D. J. Mazur, C. K. McClure, D. A. Perry, R. Rugged, E. Schwartz, J. S. Stults, D. L. Varie, R. G.Wilde, S. Wittenberger, J. Org. Chem. 1986, 51, 1556. E. C. Taylor, L. G. French, J. Org. Chem. 1986, 51, 1967. P. A. Grieco, S. D. Larsen, J. Org. Chem. 1986, 51, 3553. S. J. Danishefsky, C. Vogel, J. Org. Chem. 1986, 51, 3915. P. A. Grieco, S. D. Larsen, W. F. Fobare, Tetrahedron Lett. 1986, 27, 1975.
42 86TL5513 87ACIE1295 87JACS2717 87MI001 87TET5475 87TL813 87TL2937 88JACS1638 88JACS5452 88JCS(P1)247 88JOC2220 88JOC2226 88TET3327 88TL2107 88TL5855 89JOC224 89JOC1097 89JOC1245 89JOC4019 89JOC5580 89JOC5852 89SC2699 89TL1045 90JOC202 90JOC3257 91CPB489 91JACS1713 91JACS8975 91MI402 91MI451 92MI001 92TL5697