Acc. Chem. Res. 1980, 13, 218-224
218
Scheme VI Reactions of Large Ring Bicyclic Alkenes
0 0 msorb = 12, n.24
B
n
(a) m-C1C6H4C03H
A
(b) B H 3 * T H F ; HZOZ, NaOH
rope” betweenanene, the [22.10] system 54.30 In jump rope systems one of the bridging chains is long enough to swing around the smaller second chain, thus exposing the double bond and making it accessible to external reagents (Figure 4). Since the inner ring cannot pass through the outer chain, the process would not cause racemization of an optically active betweenanene as it does with trans-cycloalkenes (Figure 3). We hope to bracket the jump rope phenomenon by examining a series of [a.lO]betweenanenes (54, a 20-30). Our initial studies on [22.10]betweenanene (54) and its cis isomer 53 indicate that both undergo slow epoxidation (Scheme VI, A, B = 0) and hydroborationoxidation (Scheme VI, A, B = H, OH).30 However, reaction of 54 with isopinocampheylborane could not be effected even with a large excess of the reagent and prolonged reaction times. Furthermore, only the cis isomer 53 afforded a colored charge-transfer complex with TCNE.30 Thus, the double bond of 54 appears to be shielded from sterically demanding reagents.
-
Conclusions In this Account we have described some fundamental characteristics of mono- and bicyclic trans~cycloalkenes, We have pointed out the profound influence of bridging chains on reactions leading to and from these cyclespecial considerations which and the must be accorded to their synthesis. The bicyclics ex-
amined to date show no unusual behavior save for the unreactivity of the encapsulated betweenanene double bond. This is in keeping with expectations based on molecular models and known cycloalkene chemistry. In that context, we might expect betweenanenes with rings of eight or fewer members to be fairly strained and to act accordingly. The synthetic challenges of betweenanenes largely stem from the tetrasubstituted double bond. As noted above, the bridging chains limit the choice of synthetic approach that can be employed. While photoisomerization has proven extremely valuable for generating the betweenanene system from accessible bicyclic olefin precursors, some of the more interesting betweenanenes will require the development of additional new synthetic approaches to tetrasubstituted cycloalkenes. Targets of immediate interest include (1)optically active betweenanenes, (2) ring-chain functionalized betweenanenes, and (3) polycyclic (stacked) betweenanenes. Finally, it should be noted that a number of biologically interesting natural products contain trans-cycloalkene rings.35 The biological activity of such substances is undoubtedly influenced by ring-bridging effects of the type discussed in this Account. In fact, it is possible that in vivo transformations of these natural products may proceed via betweenanene-like intermediates. In this way the double bond would be shielded from external influences and could become more vulnerable to internal attack from groups on the bridging chains or from bridging enzyme functionality. W e are indebted to the National Science Foundation for financial support. Our special thanks go to the “Betweenanene Team”, A1 Runquist, Mary Delton, Morris Lewellyn, Kyoo-Hyun Chung, Larry Karas, Richard Bierenbaum, Tim Konicek, Howard Black, Richard Royce, James Peterson, and K a t h y Flynn. Without their dedicated efforts and team spirit this work could never have been accomplished. (35) E.g., Macrolides: Masamune, S.; Bates, G. S.; Corcoran, J. W. Angew. Chem., Int. Ed. Engl. 1977,16,585-90. Cembranolides: Weinheimer, A. J.; Chang, C. W.J.; Matson, J. A. Fortschr. Chem. Org. Naturst. 1979,36,286-387. Germacranolides: Yoshioka, H.; Mabry, T. J.; Timmerman, B. N. “Sesquiterpene Lactones”; University of Tokyo Press: Tokyo, 1973; pp 7-22. Ansamycin antibiotics: Kupchan, S. M.; et al. J. Am. Chem. SOC.1972,94,1354-5. Rinehart, K. L., Jr.; e t al. Ibid. 1971, 93,6273-4.
Allylic and Propargylic Imidic Esters in Organic Synthesis LARRYE. OVERMAN Department of Chemistry, University of California, Irvine, California 92717 Received January 25, 1980
The imidic acid-amide interconversion (eq 1, R1 =
H)played an important role in the evolution of modern
OI - R ‘ R-C=NR
= *
O R-2-N’
R ( 1 )
‘R‘
Larry E. Overman was born in Chicago, IL, in 1943. He earned a B.A. degree from Eariham Coiiege and completed his doctoral study in 1969 with Howard W. Whitlock, Jr., at the University of Wisconsin. After an NIH postdoctoral fellowship with Ronald Breslow at Columbia University, he joined the facutiy at the University of California, Irvine, in 1971, where he is now Professor of Chemistry. He has been a Fellow of the A. P. Sloan Foundation and a recipient of a Camille and Henry Dreyfus Teacher-Scholar award.
Concepts Of molecular Structure and taUtOmeriZatiOn. Baey& in 1882,1as partof his classic investigations of indigo, was the first’ to correctly formulate the concept (1) Baeyer, A,; Oekonomides, S. Chem. Ber. 1882, 15, 2093.
0001-4842/80/0113-0218$01.00/00 1980 American Chemical Society
Allylic Imidic Esters
Vol. 13, 1980 Scheme I
A
R , R2C=CR-CR3R4-
I OH
R
‘R
C-CR=CR3R4 21 HNCY
R, R2C=CR-CR3R4
I
-
219
Table I Conversion of Allylic Alcohols to Rearranged Trichloroacetamides8 39
OCY
II NH
‘
R R C-CR=CR3R4
2l
NH2
II
0
of tautomerization to describe the imidic acid-amide isomerization of isatin (eq 2).
a H I
(2)
0
0
The conversion of an imidic ester (or imidate) to an amide (eq 1,R’ = alkyl or aryl) is a highly exothermic tran~formation.~Recent quantitative studies of Beak and co-workers3place the enthalpy difference between an unstrained dialkyl amide and a dialkyl imidate at -16 kcal/mol in the gas phase and -17 kcal/mol in the liquid phase. The imidate to amide rearrangement converts a carbon-oxygen to a carbon-nitrogen single bond. Since it is typically easier to introduce oxygen than nitrogen functionality into nonaromatic organic molecules,4 it is not surprising that this conversion has proven useful for the preparation of a variety of nitrogen compound^.^ The purpose of this Account is to summarize our recent work on the development of new methods for preparing nitrogen-containing molecules, which exploit the exothermicity of the imidate to amide isomerization. Our research has been guided by the premise that the imidate-amide conversion would be highest yielding and occur under the mildest conditions when it occurs in an intramolecular fashion (eq 3). The thermal re3,3
-
sigmatropic+ rearrangement
,,Yo x
@%a NHCOCC13 OH
I
(31
Yo X
arrangement of allylic imidates was first described by Mumm and Mo11er6in 1937, and the reader is referred to the comprehensive review by McCarty and Garner5 in which the early work in this area is summarized.
A General Synthesis of Allylic Amines Our initial involvement in the imidate area began several years ago when we attempted to develop a generally useful method for the 1,3 conversion of allylic alcohols to allylic amines (Scheme I). Investigations of various imidic ester derivatives in our laboratory7and (2)A most interesting account of the historical development of the concept of tautomerization is found in: Ingold, C. K. “Structure and Mechanism of Organic Chemistry”, Cornell University Press: Ithaca, NY, 1953;Chapter 10. (3)Beak, P.Acc. Chem. Res. 1977,IO, 186. Beak, P.; Mueller, D. S.; Lee, J. J. Am. Chem. Soc. 1974,96, 3867. Beak, P.; Lee, J.; Zeigler, J. M. J. Org. Chem. 1978,43,1536. (4)Cf.: Buehler, C. A.; Pearson, D. E. “Survey of Organic Synthesis”, Wiley: New York, Vola. I and 11, 1970 and 1976;Chapters 4 and 8. $5) McCarty, C. G.; Garner, L. A. “The Chemistry of Amidines and Imidates”; Patai, S., Ed.; Wiley: New York, 1975;Chapter 4. (6)Mumm, 0.;Moller, F. Chem. Ber. 1937,70, 2214. (7)Marlowe, C. M., and Overman, L. E., unpublished observations.
elsewhere5 indicate that trichloroacetimidic esters (Scheme I, Y = CC13)are the preferredg1’ intermediates for this transformation. Trichloroacetimidates are easily prepared in good yields from primary, secondary, and tertiary alcohols by base-catalyzed condensation with trichloroacetonitrile at 0 0C.8JoJ2 For most synthesis applications, this mild base-catalyzed procedure is clearly preferable to other classical methods of imidate synthesis.13J4 Allylic trichloroacetimidic esters (8) Overman, L. E. J. Am. Chem. Soc. 1974,96,597. 1976,98,2901. (9)Overman, L. E.J. Am. Chem. SOC. (10)Clizbe, L. A.;Overman, L. E. Org. Synth. 1978,58,4. (11)Tsuboi, S.;Stromquist, P.; Overman, L. E. Tetrahedron Lett. 1976,1145. (12)The preparation of trichloroacetimidates by this method was first described by Cramer: Cramer, F.; Pawelzik, K.; Baldauf, H. J. Chem. Ber. 1958,91,1049. Cramer, F.;Baldauf, H. J. Ibid. 1961,94,976. (13)The preparation of imidates has been reviewed Sandler, S. R.; Karo, W. “Organic Functional Group Preparations”, Academic Press: New York, 1972;Val. 3, Chapter 8. Neilson, D. G. In “The Chemistry of Amidines and Imidates”; Patai, S., Ed.; Wiley: New York, 1975;pp 389-412.
220
Overman
undergo clean [3,3]-sigmatropicrearrangement to give the allylically transposed trichloroacetamides when heated at temperatures between 25 and 140 OC.&l0 Some of the allylic trichloroacetamides which have been prepared in this manner are summarized in Table I. In no cases have trichloroacetamides with unrearranged carbon skeletons (i.e., products of formal [ 1,3]-sigmatropic rearrangement) been d e t e ~ t e d .The ~ thermal rearrangement of trichloroacetimidic esters of secondary allylic alcohols gives exclusively (E)-trichloroacetamides,9'16J7and trichloroacetimidates derived from the terpene alcohols, cis- and trans-carveol,17undergo clean suprafacial rearrangement (Table I). Inouye and cow o r k e r ~also ~ ~demonstrated that the rearrangement of (R)-3-phenyl-2(E)-buten-l-yl trichloroacetimidate occurs suprafacially with complete (>97 %) transfer of chirality (eq 4). The only limitation observed to date 0
/NH
74%
Me,&$ph H
+
H
M
O
y
~
&
H
~
~
Accounts of Chemical Research
In some cases, the allylic trichloroacetimidate rearrangement can be accomplished under mild conditions at room temperature by the addition of catalytic amounts of m e r c ~ r y ( I 1or ) ~palladium(I1) ~~ salts.lg For example, the trichloroacetimidic ester of geraniol is converted in good yield to linalyl trichloroacetamide (eq 7) when treated at room temperature for 10 min with 0.2 equiv of mercuric trifluoroacetate. This catalytic transformation also occurs readily at -60 "C, and a catalytic rate enhancement of >10l2 (1 M catalyst concentration) has been e ~ t i m a t e d .A~ cyclization-induced rearrangement mechanism20has been proposed for this reaction (eq 7).
-
~
~
(4)
H
in the thermal rearrangement step is a competing elimination reaction which is pronounced with cyclohexenyl trichloroacetimidatesgJ7and becomes the predominate reaction pathway in the thermolysis of trichloroacetimidic esters of 3-substituted 2-cyclohexenl - o l ~ . ~The J ~ trichloroacetyl group may be removed from the product amide at room temperature by treatment with aqueous base to complete the alcohol to primary amine conversion (eq 5).9J0
The allylic alcohol to amine transformation can also be accomplished in a somewhat different fashion21by the [3,3]-sigmatropicrearrangement22of in situ generated allyl cyanate esters, as illustrated in eq 8. Al-
r
O IH
oI - c = q
3M N a O H ~
C
O
C
C
I
25",
Y-QH,
(5)
R
R
55% o v e r a l l
Utilization of this 1,3-functionality transposition in conjunction with the addition of vinyl organometallics to aldehydes or ketones achieves the general transformation illustrated in eq 6 in overall yields which are
often greater than 50%.9 Although a thorough study of the mechanism of the allylic trichloroacetimidate rearrangement has not been conducted, its formulation as a concerted pericyclic process is consistent with the observed regio~electivity,~ ( E ) stereosele~tivity,~J~J~ chirality transfer,17 and activation parametersg (14) N-Unsubstituted imidates are typically preparedI3 by the Pinner synthesis, which involves treatment of a mixture of an alcohol and nitrile with an equimolar amount of a mineral acid to give the imidate salt, from which the free imidate is obtained upon basification. Although this method succeeds with some propargylic alcohols,'J5 it is of no use for the preparation of allylic imidates since allylic amides (products of the Ritter reaction) are formed under these conditions.' To avoid this limitation and also since few complex molecules can withstand the conditions of Pinner imidate synthesis, we have confined our attention to imidic ester derivations which can be prepared under mildly basic conditions. (15) Yura, Y. Chem. Pharm. Bull. 1962, 10, 1094. (16) Metcalf, B. W.; Bey, P.; Danzin, C.; Jung, M. J.; Casara, P.; Vevert, J. P. J. Am. Chem. Sac. 1978,100, 2551. (17) Yamamoto, Y.; Shimoda, H.; Oda, J.; Inouye, Y. Bull. Chem. SOC. Jpn. 1976,49, 3247. (18) Overman, L. E. Tetrahedron Lett. 1975, 1149.
36% overall
though this process is complicated by addition of the starting alkoxide to the rearranged isocyanate to form a dimeric carbamate, it does allow introduction of nitrogen at the hindered 3-position of 3-substituted 2cyclohexen-l-ols.21 The sequence of Scheme I is also useful for the preparation of N,N,N'-trisubstituted allylic ureas from allylic alcohols.ll For example, condensation of 2methyl-1-hepten-3-01with l-cyanopyrrolidineB followed by rearrangement of the derived pseudourea in refluxing xylene gives the allylically transposed urea 1 in 63% yield (eq 9).
4 0
/ NH
Y
0
137' __t
9hr
4 I
N H C V 3
0 63% o v e r a l l 19)
(19) Keister, R.; unpublished observations. (20) Overman, L. E.; Campbell, C. B.; Knoll, F. M. J. Am. Chem. SOC. 1978, 100,4822. (21) Overman, L. E.; Kakimoto, M. J. Org. Chem. 1978, 43, 4564. (22) Christophersen, C.; Holm, A. Acta Chem. Scand., 1970,24,1512; 1970. 24. 1852. (23) Cf.: Forman, S. E.; Erickson, C. A,; Adelman, H. J. Org. Chem., 1963,28, 2653.
22 1
Allylic Imidic Esters
Vol. 13, 1980
Scheme I1
Table I1 T r i c h l o r o a c e t a m i d o 1 , 3 - D i e n e s Prepared from Thermal R e a r r a n g e m e n t of Propargylic T r i c h l o r ~ a c e t i m i d a t e s ~ ~
C,C'3
3"
1 - T r i c h l o r o a c e t a m i d o 1,3-Dienes (38%)
2
H
c
0
c
c
1
3
(66%)
(51%)
&NHc0cc'3
(27%) dNHC0cC'3
(92%)
3 I J
(68%)
IIHCOCC13
NHCOCCI
(55%)
(86%)
P W - W A P h
6vvccCc3 (83%)
d;a,
(45%)
Scheme I11 !H
2 - T r i c h l o r o a c e t a m i d o 1,3-Dienes
NI-rCCCC',
(14%)
"p""" YHCOCC
(go%, 60%Z,
40% E )
Thermal Rearrangements of Imidic Esters of Propargylic Alcohols To further explore applications of unsaturated imidates for the synthesis of nitrogen compounds, we have examined in some detail the thermal chemistry of imidic ester derivatives of propargylic alcohols. Our initial investigations focused on the preparation of N-acylamino 1,3-dienes, a class of heteroatom-substituted 1,3-dienes whose chemistry and synthesis applications had been little explored at the time our work began.24-27 Synthesis of N-Acylamino 1,3-Dienes. A variety of N -trichloroacetyl- 1-amino 1,3-dienes and N-trichloroacetyl-2-amino 1,3-dienes (Table 11) have been prepared by the thermal rearrangement of propargylic trichlor~acetimidates.~~~~~ The interesting chemistry involved in this diene synthesis is best illustrated with a specific example. Thus, when the trichloroacetimidic ester of 1-pentyn-3-01is heated in refluxing xylene for 5 h in the presence of a free-radical inhibitor, the crystalline (12,3E)-diene 3 is isolated in 51% yield. This transformation occurs with remarkable stereoselectivity, since careful examination of the pyrolyzate by high-performance LC and 13C NMR fails to reveal any trace of the (1E,3E) isomer. The thermodynamically more stable (1E,3E) isomer 4 could be prepared from 3 by base-catalyzed equilibration. When the conversion of 2 3 is monitored by high-performance LC, an intermediate is observed to build up to a maximum of -25% after 1h.28 Termination of the thermolysis at this time allows the crystalline intermediate, l-tri-
-
8
9
IO
II
chloroacetamido-1,2-pentadiene(5), to be isolated.29 When the 1,2-diene 5 is subsequently heated in refluxing xylene for 1 h, the (12,3E)-diene 3 is formed These results (Scheme stereoselectivelyin 70% 11)indicate that the mechanism for this 1,3-dieneamide synthesis involves initial [3,3]-sigmatropic rearrangement of propargylic imidate 2 to give the 1,2-diene 5 , which then undergoes tautomeric reorganization to yield the more stable 1,3-diene 3. The kinetic preference which is observed for forming the l,&diene with the 2 configuration about the 1,2-double bond can be rationalized by invoking the cis-a,&unsaturated N-acylimine 630 as an intermediate in this tautomeric conversion (eq 10). The related tautomerization of cis+ I
wlycNHCOCC13
5
-/r -
c- H
\ NCOCC13
6
L 1,J 1
(IO)
H-migration
NHCOCCl3
3
(24) Overman, L. E.; Clizbe, L. A. J. Am. Chem. SOC.1976,98,2352. (25) Early reports of acyclic N-acylamino 1,3-dienes include the preparation of 2-acetamido-1,3-butadiene from 2-amin0-3-butyne?~~ 1benzyl-3-(1,3-pentadienyl)ureafrom 1 , 3 - b ~ t a d i e n e ,1-(4-nitrobenz~~~ amido)-1,3-butadienefrom 1,3-butadiene,% and N-(l3-butadienyl)-Ntert-butylcarbamoyl chloride from crotonaldehyde.2Bd (26) (a) Dickey, J. B. U.S.Patent 2,446,172,1948; Chem. Abstr. 1948, 42, 82093. (b) Tanimoto, F.; Tanaka, T.; Kitano, H.; Fukui, K. Bull. Chem. SOC. Jpn. 1966,39,1922. ( c ) Heine, H. W.; Mente, P. G. J. Org. Chem. 1971,36,3078. (d) Kiefer, H. Synthesis 1972, 39. (27) While our investigations were in progress, Oppolzer and coworkers reported a general synthetic route to N-acyl-N-alkyl-l-amino1,g-butadienes: Oppolzer, W.; Frostl, W. Helu. Chim. Acta 1975,58,587. Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron Lett. 1979, 981. (28) Clizbe, L. A. Ph.D. Dissertation, University of California, Irvine, 1978. Overman, L. E.; Clizbe, L. A., manuscript in preparation.
l,&hexadiene by a [1,5]-sigmatropichydrogen migration is known31 to afford (22,4E)-2,4-hexadiene stereoselectively. Similar selectivity is observed in the formation of other 1-trichloroacetamido1,3-dienes(see Table 11),and the propargylic trichloroacetimidaterearrangement thus (29) Overman, L. E.; Marlowe, C. M.; Clizbe, L. A. Tetrahedron Lett. 1979,599. (30) The cis-&unsaturated N-acylimine 6 may be either the highly favored kinetic tautomer of 5 (preferential protonation at C-2 cis to the C-3 hydrogen) or may be in rapid equilibrium with the corresponding trans isomer. (31) Frey, H. M.; Pope, B. M. J. Chem. SOC. A 1966, 1701.
Overman
222
constitutes a highly stereoselective method for pre1,3-dienesaa Many paring (lZ,3E)-l-trichloroacetamido of the stereoisomeric (lE,3E)-l-trichloroacetamido 1,3-dienes are also available by this procedure, since (1Z,3E)-l-trichloroacetamido1,3-dienes which have a hydrogen substituent at C-1 may be converted to their more stable (1E,3E) isomers by treatment with triethylamine.2s An interesting situation arises in the thermolysis of an imidate such as 7,where formation of a 1,3-diene with the trichloroacetamido group at either the 1- or 2-position is possible (eq 11). In this and in all related 0
/T3 \NH
Accounts of Chemical Research Table I11 Preparation of Substituted 2-Pyridinones from Propargylic Alcohols33 overall yield, %
R3
R6
Me,C Ph Me n-C,H, H Me Et Ph Et Et
Me,C Me,C n-C,H, n-C;H, 2-C,H, Me Ph Ph H 2,5-dimethoxyphenyl >
I
pyrrol- N-methylidine aniline pseudo- pseudourea urea 68 63 79 64 58 15
46 29 12 16
69 41 46
7 NHCOCCl3
A General Synthesis of Substituted 2/+-+A Pyridinones. The fact that the thermal rearrangement 86 %
0 VC~NHC : C_;
(Ill
~
NHCOCC13
n o t observed
cases, only the (1Z,3E)-l-trichloroacetamido1,3-diene is produced, presumably reflecting the facility of [ 1,5]-sigmatropichydrogen Dienes with the trichloroacetamido substituent at the 2-position can be prepared from trichloroacetimidic esters of 2-alkyn-1-01s only (eq i2).24 cc13 I
f (12) NHCOCC13
NHCOCC13
of propargylic imidates affords the (12,3E)-diene isomers stereoselectively can be further exploited if the X substituent of the starting imidic ester is a potential leaving group (Scheme Thus, thermal elimination of HX from diene 9 would be expected to give the (lZ,3E)-diene isocyanate 10, which is set up to undergo electrocyclic ring c l ~ s u r eto~ yield ~ , ~ ultimately ~ a substituted 2-pyridinone. We have examined this reaction in some detail with pseudourea derivatives (X = NR2) of propargylic alcohols.33 Base-catalyzed condensation of secondary propargylic alcohols with l-cyanop y r r ~ l i d i n e l lfollowed ,~~ by thermal rearrangement of the pyrrolidine pseudourea derivatives in refluxing xylene provides a convenient synthesis of 3,g-disubstituted 2-pyridinones (Table 111). The conversion of pyrrolidine pseudourea 8 (X = N(CH2),) to 2pyridinone 11 in one thermolysis step is noteworthy, since at least six separate steps, three of which are pericyclic reactions, must occur. Since sec-propargylic alcohols are typically formed from the addition of alkyne anions to aldehydes, this reaction allows the 3,6disubstituted 2-pyridinone ring to be easily assembled from aldehyde, alkyne, and cyanamine components (eq 15). Other pseudoureas may be employed also in this
(3:2)
Excellent alternate methods for preparing trans-lacylamino 1,3-dienes from conjugated enals or 1,3dienoic acids have also been recently described €rom Oppolzer'sZ7and laboratories. Typical examples of these two very general procedures are shown in eq 13 and 14. ,
H
2-pyridinone synthesis. The use of the less basic pseudoureas derived from N-cyano-N-methylaniline allow 2-pyridinones,with R6 = H or aryl, to be prepared in higher yields than by the pyrrolidine pseudourea method (Table III).33937
CH2Ph
80% ( f r o m m n e I
I ) C I C0,Et 0
2) Na N 3
~ N H I O C H B P h( 1 4 1 3 2
31 liO',PhCH20H~
53% ( o v e r a l l 1
(32) Overman, L. E.; Taylor, G. F.; Jessup, P. J. Tetrahedron Lett. 1976, 3089. Overman, L. E.; Taylor, G. F.; Petty, C. B.; Jessup, P. J. J . Org. Chem. 1978,43,2164. Jessup, P. J.; Petty, C. B.; Roos, J.; Overman, L. E. Org. Synth. 1979, 59, 1.
(33) Overman, L. E.; Tsuboi, S.; Roos, J. P. J . Am. Chem. SOC. 1980, 102, 747. Overman, L. E.; Tsuboi, S. Ibid. 1977, 99, 2813. (34) Electrocyclic ring closure of 1,3,5-hexatrienes, in which one or more carbon atoms are replaced by heteroatoms, is a general method for forming six-membered heterocycles. For a recent example and leading references, see: Baydar, A. E.; Boyd, G. V. J . Chem. Soc., Chem. Comnun. 1976, 718. (35) The formation of 2-pyridinones from the thermolysis of acyl azide derivatives of (lE,3E)-dienoic acids has been reported.36 This 2pyridinone synthesis requires high temperatures (typically 240 "C) since cis-trans isomerization is required at some point. (36) Eloy, F.; Deryckere, A. J . HeterocycL Chem. 1970, 7, 1191. MacMillan, J. H.; Washburne, S. S. J. Org. Chem. 1973, 38, 2982. (37) Roos, J. P. M. S. Thesis, University of California, Irvine, 1979.
A1ly lic Imidic Esters
Vol. 13, 1980
223 Scheme V
Scheme IV PhCH20
c H3-CH0
4 s1eps
+
CH3
&J.dl-pumiliotoxin C
The mechanism suggested in Scheme I11 for this 2pyridinone synthesis is consistent with the isolation of the intermediate (lZ,SE)-dieneurea 13 from the thermolysis of pseudourea 12 and the demonstration that 13 is subsequently converted in high yield to 3phenyl-6-tert-butyl-2-pyridinone (15) in refluxing xylene.33 Although a diene isocyanate intermediate has not been directly observed in this latter transformation, its intermediacy has been established by demonstrating that the conversion of diene urea 13 to 2-pyridinone 15 is inhibited by added pyrrolidine and is accompanied by amine exchange to give the piperidine diene urea 14 when carried out in the presence of ~ i p e r i d i n e . ~ ~ NH II
h
IS
13, X = N 3 14, X = N 3
Diels-Alder Reactions of Trichloroacetamido 1,3-Dienes Our original interest in the preparation of N-acylamino 1,3-dienes derived from their potential use in synthesis as equivalents for amino 1,3-dienes 17 and 18.24138p39N-Acylamino 1,3-dienes have subsequently proven to have significant utility as reactive dienes for the Diels-Alder synthesis of amino-functionalized carb o ~ y ~ l e s . ~The ~ 7synthetic ~ ~ r ~ ~equivalency ~~ of transl-(acylamino)-1,3-butadienes16 with trans-l-amino1,3-butadiene (17) has recently been exploited in our 0 II W NHCX
q0
&
I0 %
CH3
HOJ
d l -.perhydrogephyroloxin
butadiene-1-carbamate with a trans-enal allowed the three chiral centers of the alkaloid's carbocyclic ring to be established in a single step and in excellent yield. The reader is referred to the elegant work of the Oppolzer s ~ h o o lon~ the ~ , use ~ ~ of N-alkenyl-N-acylamino l,&dienes and intramolecular Diels-Alder strategies in the alkaloid total synthesis area. Trichloroacetamido 1,3-dienes exhibit a rich DielsAlder chemistry. trans-l-(Trichloroacetamido)-1,3butadiene (19) undergoes cycloaddition with maleic anhydride at 80 0C24and reacts with complete regioselectivity with methyl acrylate at 110 "C to give in high yield a 3:l mixture of endo (21) and exo (22) cycloadducts.44 Interestingly, an identical mixture of cy-
flCOOMe IIO", 8 0 h r
1
W ~ NH H C O C C i 3 '
21
20
Y
cr
COOMe
H '* NHCOCC I
N
MNH~ 17
16 0 II
PhCH20
h
18
laboratory to achieve total syntheses of the neurotoxin alkaloids, dl-pumiliotoxin-C38 and dl-perhydrogephyr~toxin~~ (Schemes IV and V). In each synthesis, endo-stereoselective cycloaddition of benzyl trans-1,3(38)Overman, L.E.;Jessup, P. J. J. Am. Chem. SOC.,1978,100,5179. Overman, L. E.; Jessup, P. J. Tetrahedron Lett. 1977,1253. (39)Oppolzer, W.; Bieber, L.; Francotte, E. Tetrahedron Lett. 1979, 4537. (40)Overman, L.E.;Petty, C. B.; Doedens, R. J. J. Org. Chem. 1979, 44, 4183. (41)Overman, L. E.;Fukaya, C. J. Am. Chem. Soc., 1980,102,1454. (42)Danishefsky, S.;Hershenson, F. M. J. Org. Chem. 1979,44,1180. (43)Oppolzer, W.; Frostl, W. Helu. Chim. Acta 1975,58,590. Oppolzer, W.; Frostl, W.; Weber, H. P. Ibid. 1975,58,593. Oppolzer, W.; Flashkamp, E. Ibid. 1977,60,2040.Oppolzer, W. Angew. Chem.,Int. Ed. Engl. 1977,16, 10. (44)Overman, L.E.;Taylor, G . F.; Houk, K. N.; Domelsmith, L. S. J. Am. Chem. SOC.1978,100,3182.
22
cloadducts is formed from cis-1-(trich1oroacetamido)1,3-butadiene (20) when dioxane is used as the cycloaddition solvent, since isomerization of the unreactive cis isomer 20 to 19 occurs slowly under these condit i o n ~ This . ~ ~isomerization ~ ~ ~ can be accelerated by conducting the reaction of 20 with methyl acrylate in the presence of triethylamine, in which case the cycloaddition step can be made rate limiting.46 Similar cis-trans isomerizations are observed in Diels-Alder reactions of other cis-1-trichloroacetamido 1,3-dienes (eq 16). As expected from the electron-withdrawing character of the CC13 group, 1-(trich1oroacetamido)1,3-butadiene (16, X = CC13) reacts with electron-deficient dienophiles somewhat more slowly than the corresponding diene carbamates (16, X = OR) or dienes ureas (16, X = NR2).44 Diels-Alder reactions of 2-trichloroacetamido 1,3dienes provide a convenient synthesis of cyclohexyl (45) Oppolzer, W.; Keller, K. J. Am. Chem. SOC.1971,93,3836. (46)Overman, L.E.;Taylor, G . F., unpublished results.
224
Overman
NHCOCCI3
enamides. For example, diene 23 reacts at 80 "C with methyl acrylate to give the endo cycloadduct 24 as the
Accounts of Chemical Research
acteristic of the chemistry of trichloroacetamido 1,3dienes can be exploited to generate reactive 2-trichloroacetamido 1,3-dienes in situ from unreactive 1alkyl-1-trichloroacetamido 1,3-dienes. For example, when diene 27 was heated with maleic anhydride in dioxane for 36 h, the crystalline cycloadduct 29 was isolated in 73% yield.28 The formation of 29 must involve tautomeric e q ~ i l i b r a t i o n ~with ~ ~ 9the ~~~ 2-trichloroacetamido 1,3-diene 28, as summarized in eq 17.
COOMe
+
+
ntnor adducls (
