J . Am. Chem. SOC.1982, 104, 555-563
555
Dimethylaluminum Chloride Catalyzed Ene Reactions of Aldehydes Barry B. Snider,*' David J. Rodini, Thomas C. Kirk, and Robert Cordova Contributionfrom the Department of Chemistry, Princeton University, Princeton, New Jersey 08544. Received May 21, 1981
Abstract: Dimethylaluminum chloride, which is a mild Lewis acid and a proton scavenger, catalyzes the ene reactions of aliphatic and aromatic aldehydes with alkenes containing a disubstituted vinylic carbon. Proton-initiated rearrangements do not occur, since the alcohol-Lewis acid complex formed in the ene reaction reacts rapidly to give methane and a nonacidic aluminum alkoxide. Formaldehyde and excess Me2A1C1give good yields of ene adducts with all types of alkenes. With 1 equiv of Me2AIC1, formaldehyde and mono- and 1,2-disubstituted alkenes give y-chloro alcohols resulting from cis addition of chlorine and hydroxymethyl groups to the double bond.
The ene reaction of carbonyl compounds with alkenes is a potentially valuable route to homoallylic alcohols.2 With reactive, i.e., electron deficient, aldehydes such as chloral or methyl glyoxylate, these reactions can be carried out thermally at 100-200 0C.394 Formaldehyde reacts with alkenes at 180 "C with optimal yields often being obtained when acetic acid-acetic anhydride is the ~ o l v e n t . ~ In the presence of acid, aldehydes and alkenes undergo the Prim reaction? Stepwise addition of the alkene to the aldehyde gives a carbenium ion intermediate which can lose a proton to give an ene-type product, react with nucleophiles present in solution, or react with another molecule of aldehyde to give a m-dioxane. 1,3-Diols and m-dioxanes are the major product in aqueous acid. Ene-type products have been obtained from Lewis acids, formaldehyde, and alkenes which can give a tertiary carbenium ion.' Methyl glyoxylate3 and chloral4 react with a wide variety of alkenes to give ene adducts in the presence of Lewis acids. Unfortunately, formation of y-chloro alcohols by incorporation of a chlorine from the Lewis acid is a serious problem with alkenes which give a secondary carbenium ion. We have found that dimethylaluminum chloride (Me,AICl), in equivalent or greater amounts, is a useful catalyst for the ene reactions of aliphatic and aromatic aldehydes and leads to improved yields of ene adducts from formaldehyde.* Me2AlCl is a mild Lewis acid and a proton scavenger. A problem with Lewis acid catalyzed ene reactions of aldehydes is that the alcohol-Lewis acid complex produced in the reaction is susceptible to solvolysis and is a strong protic acid capable of protonating the double bond of the ene adduct or alkene. The alcohol-Me2A1C1 complex formed in the reaction decomposes rapidly to give methane and ~~
~~~
Sloan Foundation, 1979-1981. Department of Chemistry, Brandeis University, Waltham, MA 02154. (2) (a) Hoffmann, H. M. R. Angew. Chem., Int. Ed. Engl. 1969, 8, 556. (b) Snider, B. B. Acc. Chem. Res. 1980, 13, 426 and references cited therein. (3) (a) Snider, B. B.; van Straten, J. W. J. Org. Chem. 1979,443567. (b) Klimova, E.I.; Antonova, N. D.; Arbuzov, Y. A. J . Org. Chem. USSR (Engl. Transl.) 1969, 5, 1312 and references cited therein. (c) Achmatowicz, O., Jr.; Szechner, B. J . Org. Chem. 1972, 37,964. (4) (a) Gill, G. B.; Marrison, K.;Parrott, S. J.; Wallace, B. Tetrahedron Lett. 1979, 4867 and references cited therein. (b) Gill, G. B.; Parrott, S. J.; Wallace, B. J. Chem. SOC.,Chem. Commun. 1978, 655. (c) Gill, G. B.; Wallace, B. Ibid. 1977, 380. (5) (a) Blomquist, A. T.; Passer, M.; Schollenberger, C. S.;Wolinsky, J. (1) Fellow of the Alfred P.
J. Am. Chem. SOC.1957, 79,4972. (b) Blomquist, A. T.; Verdol, J.; Adami, C. L.; Wolinsky, J.; Phillips, D. D. Ibid. 1957, 79,4976. (c) Agami, C. Ann. Chim. (Paris) 1965,10,25. (d) Agami, C.; Prevost, C. C. R . Hebd. Seances Acad. Sci., Ser. C 1966, 263, 153. (6) Adams, D. R.; Bhatnagar, S.P. Synthesis 1977, 661 and references cited therein. (7) (a) Blomquist, A. T.; Himics, R. J. J . Org. Chem. 1968,33, 1156. (b) Addy, L.E.;Baker, J. W. J. Chem. Soc. 1953,4111. (c) Yang, N. C.; Yang, D.-D. H.; Ross, C. B. J . Am. Chem. SOC.1959, 81, 133. (8) For a preliminary report of this work see: Snider, B. B.; Rodini, D. J. Tetrahedron Letr. 1980, 21, 1815.
0002-7863/82/1504-0555%01.25/0 , I
,
~
~
Table I. Me,AlCl Catalyzed Ene Reactions of Aldehydes OtheI Than Formaldehydea alkene products yield (5%)
mR 1
2a, R = CH, (65) 2b, R = CH, W C H , 1 (79) 3 (16) 4 (60)
,
2
&
y,
4
3
d
la, R = CH, (91) lb, R = CH,CH(CH,), (74) IC,R = Ph (69) Id, R = H (80) le, R = C(CH,), (93)
5 (43)
5
20.
6a, R = CH, (56) 6b, R = C%CWCH,), (38) 6c, R=n-C,H,, (42)
6
voH 7
8
9a, R = CH, (35) 9b, R = CH,CH(CH,), (16)
9
a 1.5 equiv of Me,AlCl was used in all cases. Pivalaldehyde gives only 3,3-dimethyl-2-butanol. Benzaldehyde gives only 1phenylethanol.
a nonbasic aluminum alkoxide which does not undergo these side reactions. These reactions are Prim reactions. A zwitterionic intermediate is formed which selectively undergoes a 1,s-proton shift to give the ene adduct.Me2A1C1 complex which loses methane (eq 1). Formation of a chloro alcohol as a byproduct is observed when the carbenium ion is secondary. However, in the presence of excess Me2AlCl, the chloro alcohol is unstable, forming ene adduct in the case of acyclic alkenes and a complex mixture from cyclic alkenes. The methyl group of Me2AlCl can also act as a nucleophile. It is remarkable that any alkene is more nucleophilic toward the 0 1982 American Chemical Society
556 J . Am. Chem. SOC.,Vol. 104, No. 2, 1982
R
\
R
P
I
Snider et al.
-
OAIMe2CI R'
R = H, R' = H or alkyl; R = alkyl, R' # H
aldehyde than the methyl group. Addition of the methyl group to the aldehyde occurs in some cases, limiting the scope of the reaction.
Results and Discussion Alkyl- and Aryl-Substituted Aldehydes. The results of the Me2AlCl catalyzed reactions of alkyl- and aryl-substituted aldehydes with alkenes are shown in Table I. Moderate to good yields of ene adducts are obtained from alkenes which can give a tertiary carbenium ion. 1,l-Disubstituted alkenes are the most reactive class of alkenes. Good to excellent yields of ene adduct 1 are obtained from methylenecyclohexane and acetaldehyde (or paraldehyde), isovaleraldehyde, pivalaldehyde, or benzaldehyde as well as formaldehyde (as trioxane or paraformaldehyde). Since methylenecyclohexane is easily isomerized to 1-methylcyclohexene, the success of these reactions indicates the effectiveness of Me2AlCl as a proton scavenger. Ene reactions with tri- and tetrasubstituted double bonds also occur readily. However, due to the slower rates of these reactions, two competing reactions are also observed. Addition of a methyl group to the aldehyde leads to alcohols. This problem becomes more serious as the alkene is made more hindered (compare yields of 2,6, and 9). Hindered and aromatic aldehydes react primarily via methyl group addition. With aliphatic aldehydes, acid-catalyzed aldol reactions also lead to byproducts. The aldol condensation has limited the use of aliphatic aldehydes in the Prins r e a ~ t i o n . ~The byproducts formed in Me2A1C1-catalyzed ene reactions are easily removed by distillation, since the methyl addition product is much more volatile, and the aldol product less volatile, than the ene adduct. Alkenes which would give a secondary carbenium ion do not react with aldehydes other than formaldehyde. The ene reaction of isovaleraldehyde with isoprene provides a one-step synthesis of ipsenol (3), a pheromone of the bark beetle Ips confusus.I0 Treatment of isovaleraldehydewith isoprene gives a 16% yield of ipsenol (3) and a 60% yield of Diels-Alder adduct 4," which is related to nerol oxide and rose oxide.'! The 3/4 ratio does not change during the course of the reaction. The related reaction of chloral with isoprene, catalyzed by A1Cl3, has been studied by Gill." Similar products were obtained in varying ratios, since the ene adduct was converted to the dihydropyran during the reaction by protonation to give an allylic carbenium ion which closes to give the dihydropyran." Use of MezAICl allows the isolation of acid-sensitive ipsenol, since protic acids are not present in the reaction mixture. (9) Safarov, M. G.; Nigmatullin, N. G.; Komissarov, V . D. Izu. Akad. Nauk SSSR, Ser. Khim. 1976,1154; Bull. Acad. Sci. USSR, Diu.Chem. Sci. (Engl. Transl.) 1976, 1123. (10) Brand, J. M.; Young, J. C.; Silverstein, R. M. Prog. Chem. Org.Nat. Prod. 1979, 37, 1. (1 1) Ohloff, G.; Schulte-Elte, K.-H.; Willhalm, B. Helv. Chim. Acra 1964, 47, 602.
The formation of 4 indicates that Me2A1C1is a useful catalyst for the synthesis of dihydropyrans by the Diels-Alder reactions of aldehydes with dienes. The use of formaldehyde or aromatic aldehydes as dienophilesis well-known.I2 The reaction of isoprene with acetaldehyde for 24 h at 150 OC has been reported to give a 4% yield of Diels-Alder adduct.13 The reaction of methylenecyclobutane with isovaleraldehyde gives 5 in 43% yield. Cyclobutene 5 has previously been synthesized by longer routes and converted to ipsenol by pyr01ysis.I~ The reaction of aldehydes with limonene occurs exclusively at the less substituted double bond as reported by Blomquist for the reaction with f ~ r m a l d e h y d e .Lewis ~ ~ acid catalyzed reactions of methyl propiolate with limonene show only slight (X 1.5) preference for the less substituted double bond, presumably due to the smaller steric bulk of the acetylene.ls Isovaleraldehyde and limonene give a 70% yield of 2b, an intermediate in Crawford's synthesis of dihydro-ar-turmerone.I6 Formaldehyde. Formaldehyde is a more versatile enophile, reacting, even with mono- and 1,2-disubstituted alkenes, in the presence of Me2AlC1to give good yields of ene adducts (see Table 11). The 1,2-disubstituted double bonds formed in these reactions are ca. 90% trans. The results with terminal alkenes contrast favorably with Blomquist's report of a 17% yield of 3-octen-1-01 from the reaction of heptene and formaldehyde for 60 h in acetic acid at 190 "C5 When 1 equiv of Me2AlCl was used, chloro alcohols were formed as byproducts. When 1.5-2 equiv of Me2AIC1was used, chloro alcohols were formed as transient intermediates. With acyclic alkenes they are converted to the ene adducts. With cyclopentene and cyclohexene, a mixture of products is formed. The nature of this reaction is discussed in more detail later. The chloro alcohols formed from 1,2-disubstituted alkenes result from the stereospecifically cis addition of the hydroxymethyl group and the chloride to the double bond. Since all previous Prins reactions have been shown to proceed predominantly by trans addition,6 the determination of stereochemistry is discussed in detail. cis- and trans-2-butene each give a single chloro alcohol, 12a and l l a respectively. These compounds have been obtained with the opposite, trans stereoselectivity by Stapp and Weinberg from 2-butene, paraformaldehyde, and hydrogen ch10ride.l~ They assigned stereochemistry based on the coupling constant for the methine protons, which is 6.5 Hz for the 2R*,3S* isomer l l a and 3.0 Hz for the 2R*,3R* isomer 12a. The spectral data and melting points of the dinitrobenzoates leave no doubt that the stereochemistry of addition with Me2A1C1 is opposite to that with hydrogen chloride. The stereochemistry of llb-d and 12b-d is assigned by analogy. In addition, the relative chemical shifts of the methine and methyl protons are consistent with the N M R spectra of l l a and 12a. The stereochemistry of cis-2-chlorocyclohexanemethanol(14b) is assigned from the proton and "C N M R spectrum. The proton a to the chlorine absorbs at 6 4.6 (Wl,2 = 8 Hz). The downfield shift from chlorocyclohexane (6 3.95) is consistent with that expected for a substituent trans to the methine hydrogen and a change in conformation making the hydrogen equatorial. The W,,, is consistent only with an equatorial hydrogen, which would be present in the cis but not the trans isomer. The 13C NMR spectrum shows the upfield y shifts relative to cyclohexane(12) Hamer, J.; Turner, J. A. In 'J,4-CycloaddifionReactions"; Hamer, J., Ed.; Academic Press: New York, 1967; p 205. Ansell, M. G.; Charalambides, A. A. J . Chem. Soc., Chem. Commun. 1972, 739. Griengl, H.; Geppert, K. P. Monarsh. Chem. 1976, 107, 675. Gramenitskaya, V. N.; Vodka,V. S.; Golovkina, L. S.; Vul'fson, N. S.Zh. Org. Khim. 1977, I3, 2329; J . Org.Chem. USSR (Engl. Transl.) 1977, I 3 , 2169. (13) Dale, W. J.; Sisti, A. J. J. Am. Chem. SOC.1954, 76, 81. (14) Wilson, S.R.; Phillips, L. R.; Natalie, K. J., Jr. J . Am. Chem. Soc. 1979 __ . - , -101 _ _1140 , (15) Snider, B. B.; Roush, D. M.; Rcdini, D. J.; Gonzalez, D.; Spindell, D. J. Org.Chem. 1980, 45, 2773. (16) Crawford, R. J.; Erman, W. F.; Broaddus, C. D. J. Am. Chem. SOC. 1972, 94, 4298. (17) Stapp, P. R.; Weinberg, D. S. J . Org.Chem. 1969, 34, 3592.
__
J . Am. Chem. Soc., Vol. 104, No. 2, 1982 551
Me2AlCl- Catalyzed Ene Reactions of Aldehydes
Table 11. Me,AlCl-Catalyzed Ene Reactions of Formaldehyde with Mono- and 1,2-Disubstituted Alkenes alkene
equiv of Me,AlCl
products, % yield
RcHzl CH$
a, R = R' = H b, R = R' = CH,CH, c(d),b R = n-Pr, R' = H
a,R=R'=H b, R = R' = CH,CH, c(d),b R = n-PI, R' = H
1 1 1.5 1 1.5
1 1 1.5 1
10
11
20 5 7" 58a 52 (14) 53 (22)
50 8
10
12
20 5I" 13" 6 2 (16)
39 23 2 8 (5)
1 4 (10) 1(1)
13
14
15
I
17 16 13a (71, 14a (39), 15a (1) 13a ( l o ) , 14a (4), 15a (44), 16a (10) 13b (36), 14b (17) 13b (54), 14b (3), 15b (8): 16b (24) CH3
a,n=2 b,n=3
1 2 1 1.5
COH
0 1
18 (46) H
0
n
c
l
PCH~OH '-T I
19 (37) C 5 H lO -lH
20 (32) +
22
C
5
21 (11) H
,
V
o
H
ti 23
1 2 1.4d le
1
73" 80" 3 0" 90"
0
24 (72)
9: 1 trans cis ratio. &I d and the yields in parentheses refer to the compounds with R and R' switched. during the course of the reaction. Et,AlCl. e EtAlC1,. a
8
This isomer decompcses slowly
methanol1*expected for an axial ch10ride.l~ Reaction of cyclohexene with formaldehyde and hydrogen chloride gave a chloro alcohol, assigned the trans stereochemistry based on mechanistic arguments, whose dinitrobenzoate melted at 86 O C 2 0 The di-
nitrobenzoate of 14b melts at 120 OC. The stereochemistry of 18 is assigned from the coupling constants of
