Intramolecular Diels-Alder Reaction by Self-assembly of the Components on a Lewis Acid Template

Article abstract of DOI:10.1021/ol0067235

equation presented Diels-Alder reactions of 2,4-hexadienol or its O-methyl ether with acrylate derivatives at 120°C give mixtures of the four possible adducts with low selectivity. At ambient temperature and in the presence of Mg(II) or Al(III) Lewis acids, reactions of the dienol (but not the ether) are highly selective. Control experiments suggest that the Lewis acid serves both to tether the diene and dienophile and to induce an intramolecular reaction of the resulting self-assembled intermediate.

Full text of DOI:10.1021/ol0067235

ORGANIC
LETTERS
2000
Vol. 2, No. 24
3937-3940
Intramolecular Diels−Alder Reaction by
Self-Assembly of the Components on a
Lewis Acid Template
Dale E. Ward* and Mohammad Saeed Abaee
Department of Chemistry, UniVersity of Saskatchewan, 110 Science Place,
Saskatoon, SK, S7N 5C9 Canada
dale.ward@usask.ca
Received October 11, 2000
ABSTRACT
Diels−Alder reactions of 2,4-hexadienol or its O-methyl ether with acrylate derivatives at 120 °C give mixtures of the four possible adducts
with low selectivity. At ambient temperature and in the presence of Mg(II) or Al(III) Lewis acids, reactions of the dienol (but not the ether) are
highly selective. Control experiments suggest that the Lewis acid serves both to tether the diene and dienophile and to induce an “intramolecular”
reaction of the resulting “self-assembled” intermediate.
The Diels-Alder (DA) reaction is perhaps the most powerful
and versatile reaction in the synthetic chemist’s arsenal, in
part because of the continuous evolution of strategies to
improve reactivity and selectivity. In this regard, the use of
Lewis acid mediators has been particularly successful in
expanding the scope of the DA reaction.1 Similarly, the many
advantages of the intramolecular Diels-Alder (IMDA)2
reaction have been extended to the intermolecular counterpart
by covalently linking the diene to the dienophile via a
“temporary” tether.3,4 In this paper we report a combination
of these approaches whereby a Lewis acid serves both to
tether the diene and dienophile and to induce an “IMDA”
reaction of the resulting “self-assembled” intermediate.
The DA reaction is often limited by the poor reactivity
associated with cis-substituted dienes.5 We have investigated
the potential of 2H-thiopyrans to act as surrogates for cis-
dienes in a strategy to overcome this limitation.6,7 The facility
of these DA reactions is increased by using Lewis acids8a
and in intramolecular applications;8b however, our attempts
to further extend the scope of the process using a sulfur-
based temporary tether to attach the dienophile were
unsuccessful.8b Subsequently, we considered the feasibility
of using a multivalent Lewis acid to coordinate simulta-
neously to the diene and dienophile and promote an IMDA
reaction of the resulting complex (Figure 1). A search of
(1) Santelli, M.; Pons, J.-M. In Lewis Acids and SelectiVity in Organic
Chemistry; CRC: Boca Raton, 1995.
(2) Reviews: (a) Roush, W. R. In ComprehensiVe Organic Synthesis;
Trost, B. M., Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 5, pp 513-
550. (b) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1977, 16, 10-23. (c)
Brieger, G.; Bennett, J. N. Chem. ReV. 1980, 80, 63-97. (d) Fallis, A. G.
Can. J. Chem. 1983, 62, 183-234. (e) Taber, D. F. In Intramolecular Diels-
Alder and Alder Ene Reactions; Springer-Verlag: New York, 1984. (f) Craig,
D. Chem. Soc. ReV. 1987, 16, 187-238.
(3) Reviews: (a) Gauthier, D. R., Jr.; Zandi, K. S.; Shea, K. J.
Tetrahedron 1998, 54, 2289-2338. (b) Bols, M.; Skrydstrup, T. Chem.
ReV. 1995, 95, 1253-1277. (c) Fensterbank, L.; Malacria, M.; Sieburth, S.
M. Synthesis 1997, 813-854.
(5) (a) Martin, J. C.; Hill, R. K. Chem. ReV. 1961, 61, 537-562. (b)
Roush, W. R.; Barda, D. A. J. Am. Chem. Soc. 1997, 119, 7402-7403.
(6) (a) Ward, D. W.; Zoghaib, W. M.; Rhee, C. K.; Gai, Y. Tetrahedron
Lett. 1990, 31, 845-848. (b) Ward, D. E.; Gai, Y. Can. J. Chem. 1997, 75,
681-693.
(7) Adducts from reactions of 2H-thiopyrans with dienophiles are, after
desulfurization, synthetically equivalent to adducts from cis-dienes.
(8) (a) Ward, D. E.; Gai, Y. Can. J. Chem 1992, 70, 2627-2633. (b)
Ward, D. E.; Nixey, T. E.; Gai, Y.; Hrapchak, M. J.; Abaee, M. S. Can. J.
Chem. 1996, 1418-1436.
(4) Recent examples of Mg, Zn, B, and Al based tethers: (a) Stork, G.;
Chan, T. Y. J. Am. Chem. Soc. 1995, 117, 6595-6596. (b) Batey, R. A.;
Thadani, A. N.; Lough, A. J. J. Am. Chem. Soc. 1999, 121, 450-451. (c)
Bertozzi, F.; Olsson, R.; Frejd, T. Org. Lett. 2000, 2, 1283-1286.
10.1021/ol0067235 CCC: $19.00 © 2000 American Chemical Society
Published on Web 11/03/2000

and, to the best of our knowledge, none provides evidence
for a discrete preorganized intermediate. Thus, we initiated
a study to determine the feasibility of the mechanistic
hypothesis outlined in Figure 1 and, if possible, to develop
conditions to promote such a reaction pathway.
DA reactions of 1a or 1b with 2a or 2b at 120 °C are
unselective, giving nearly equimolar mixtures of the four
possible products 3 (or 7) and 4-6 (Table 1). As a
Figure 1. Diels-Alder reaction where a Lewis acid (LA)
coordinates simultaneously to the diene and dienophile and induces
an “intramolecular” reaction of the resulting complex.
Table 1. Diels-Alder Reactions of 1 with 2
the literature revealed several scattered examples where the
reactivity and/or selectivity observed in Diels-Alder reac-
tions was (or could have been) rationalized by proposing a
favorable noncovalent association of the diene with the
dienophile (e.g., hydrogen bonding9 or coordination to a
Lewis acid10) in the transition state. In particular, two
examples that closely resemble the mechanistic scenario in
Figure 1 were identified: Snider’s “quasi-intramolecular”
hetero-DA reaction (A)11 and Bienayme’s “internally” Lewis
acid-catalyzed DA reaction (B).12 Nonetheless, few if any
of these proposals contemplate an “intramolecular” reaction
diene/
adduct
series 7(or 3):4:5:6b
selectivity
yieldc
(%)
entry dienophile conditionsa
(9) (a) Jones, D. W. J. Chem. Soc., Chem. Commun. 1980, 739-740.
(b) Fisher, M. J.; Hehre, W. J.; Kahn, S. D.; Overman, L. E. J. Am. Chem.
Soc. 1988, 110, 4625-4633. (c) Trost, B. M.; Lee, D. C. J. Org. Chem.
1989, 54, 2271-2274. (d) Macaulay, J. B.; Fallis, A. G. J. Am. Chem. Soc.
1988, 110, 4074-4076. (e) Macaulay, J. B.; Fallis, A. G. J. Am. Chem.
Soc. 1990, 112, 1136-1144. (f) Tripathy, R.; Carrol, P. J.; Thornton, E. R.
J. Am. Chem. Soc. 1990, 112, 6743-6744. (g) Tripathy, R.; Carrol, P. J.;
Thornton, E. R. J. Am. Chem. Soc. 1991, 113, 7630-7640. (h) Hatakeyama,
S.; Sugawara, K.; Takano, S. J. Chem. Soc., Chem. Commun. 1992, 953-
955. (i) Bloch, R.; Chaptal-Gradoz, N. Tetrahedron Lett. 1992, 33, 6147-
6150. (j) Bloch, R.; Chaptal-Gradoz, N. J. Org. Chem. 1994, 59, 4162-
4169. (k) Charlton, J. L.; Maddaford, S. Can. J. Chem. 1993, 71, 827-
833. (l) Kerrigan, J. E.; McDougal, P. G.; VanDerveer, D. Tetrahedron
Lett. 1993, 34, 8055-8058. (m) Greenlee, W. J.; Woodward, R. B.
Tetrahedron 1980, 36, 3367-3375. (n) Schmidlin, T.; Burckhardt, P. E.;
Waespe-Sarcevic, N.; Tamm, C. HelV. Chim. Acta 1983, 66, 450-466. (o)
Schmidlin, T.; Gamboni, R.; Strazewski, P.; Tamm, C. HelV. Chim. Acta
1983, 66, 1796-1805. (p) Strekowski, L.; Kong, S.; Battiste, M. A. J. Org.
Chem. 1988, 53, 901-904. (q) Datta, S. C.; Franck, R. W.; Tripathy, R.;
Quigley, G. J.; Huang, L.; Chen, S.; Sihaed, A. J. Am. Chem. Soc. 1990,
112, 8472-8478.
(10) (a) Metral, J.; Lauterwein, J.; Vogel, P. HelV. Chim. Acta 1986, 69,
1287-1309. (b) Green, R. L.; Nelson, J. H. Organometallics 1987, 6, 2256-
2257. (c) Solujic, Lj.; Milosavljevic, E. B.; Nelson, J. H.; Alcock, N. W.;
Fischer, J. Inorg. Chem. 1989, 28, 3453-3460. (d) Barluenga, J.; Aznar,
F.; Cabal, M.; Cano, F. H.; Concepcion, M.; Foces, F. J. Chem. Soc., Chem.
Commun. 1988, 1247-1249. (e) Barluenga, J.; Aznar, F.; Cabal, M.; Valdes,
C. J. Chem. Soc., Perkin Trans. 1 1990, 633-638. (f) Ward, D. E.; Gai, Y.
Tetrahedron Lett. 1992, 33, 1851-1854. (g) Adams, H.; Jones, D. N.;
Aversa, M. C.; Bonaccorsi, P.; Gianneto, P. Tetrahedron Lett. 1993, 34,
6481-6484. (h) Arce, E.; Carreno, M. C.; Cid, M. B.; Ruano, J. L. C. J.
Org. Chem. 1994, 59, 3421-3426. (i) Renard, P. Y.; Lallemand, J. Y.
Tetrahedron: Asymmetry 1996, 7, 2523-2524. (j) Aversa, M. C.; Barattucci,
A.; Bonaccorsi, P.; Giannetto, P. J. Org. Chem. 1997, 62, 4376-4384. (k)
Aversa, M. C.; Barattucci, A.; Bonaccorsi, P.; Giannetto, P. Tetrahedron:
Asymmetry 1997, 8, 1339-1367.
1
2
3
4
5
6
7
8
1a /2a
1a /2a
1a /2a
1a /2a
1a /2a
1a /2a
1a /2a
1a /2a
120 °C
TiCl4
TiCl2(OiPr)2
SnCl4
EtAlCl2
Et2AlCl
MgBr2‚OEt2
MgBr2‚OEt2,
Et3Ne
MeMgBrf
MeMgBrf,g
MeMgBr,
pentanolf,h
120 °C
a
1.3:1:1.3:1.2
d
d
d
90
d
a
a
a
7 only
7 only
7 only
75
70
75
9
10
11
1a /2a
1a /2a
1a /2a
a
a
a
7 only
7 only
7 only
35
75
95
12
13
14
15
1b/2a
1b/2a
1b/2a
1b/2a
b
b
1:1:1.8:1.4
1:-:2:-
d
d
90
20
Et2AlCl
MgBr2‚OEt2
MgBr2‚OEt2,
Et3Ne
MeMgBr,
pentanolf,h
120 °C
16
1b/2a
d
17
18
19
1a /2b
1a /2b
1a /2b
c
c
c
1.4:1:2:1
3.1:1:6.3:1
7.3:1.4:4.3:1
60
65
25
MgBr2‚OEt2
MeMgBrf,g
a Thermal reactions: a solution of the diene (0.5-2 M) and 2a (2 equiv)
or 2b (1 equiv) in C6D6 was heated for 20-36 h.LA-mediated reactions:
LA (1 equiv) and 2a (2 equiv) or 2b (1 equiv) were sequentially added to
a solution of diene (0.1-0.3 M) in CH2Cl2 at 0 °C and then stirred at ambient
temperature for 10-48 h. b Ratios measured by 1H NMR of the crude
reaction mixture (relative error estimated as (10%). c Isolated. d DA adducts
not detected. e 2 equiv of Et3N. f MeMgBr (3 M in ether) was used; reaction
in toluene. g 0.5 equiv of MeMgBr, reaction for 7 days. h 1 equiv of pentanol
added (cf. note 15); reaction for 2 days.
(11) (a) Snider, B. B.; Phillips, G. B. J. Am. Chem. Soc. 1982, 104, 1113-
1114. (b) Snider, B. B.; Phillips, G. B.; Cordova, R. J. Org. Chem. 1983,
48, 3003-3010.
(12) (a) Bienayme, H.; Longeau, A. Tetrahedron 1997, 53, 9637-9646.
(b) Bienayme, H. Angew. Chem., Int. Ed. Engl. 1997, 36, 2670-2673.
3938
Org. Lett., Vol. 2, No. 24, 2000

consequence, these reactions are useful probes to test the
ability of Lewis acids both to preorganize the components
and to catalyze Diels-Alder cycloaddition according to
Figure 1. High selectivity will occur only if both attributes
act in concert. A variety of Lewis acids were screened for
their ability to promote the reaction between 1a and methyl
acrylate (2a) (Table 1). In most cases, no DA adducts were
detected;13 however, in the presence of Et2AlCl or MgBr2‚
OEt2 a good yield of 74a was obtained as the only DA prod-
uct from 1a and 2a. Similarly, reaction of 2a with the
bromomagnesium alkoxide formed by reaction of 1a either
with MgBr2‚OEt2 in the presence of Et3N14 or with MeMgBr
gave 7 exclusively and in near quantitative yield under
optimized conditions (entry 11).15 In contrast, reaction of
1b with 2a in the presence of MgBr2‚OEt2, MgBr2‚OEt2/
Et3N, or MeMgBr/pentanol failed to give DA adducts (Table
1, entries 14-16), and with Et2AlCl, a 2:1 mixture of 5b
and 3b was obtained in poor yield (entry 13). The 2:1
regioselectivity16 of the latter reaction is similar to that
observed on heating in the absence of a Lewis acid (1.6:1;
cf. entry 12) and is inconsistent with simultaneous coordina-
tion of diene and dienophile with the Lewis acid in the
transition state (TS).17 Although the results of the DA
reaction of 1a and 2a mediated by Et2AlCl, MgBr2‚OEt2,
and MeMgBr are consistent with the mechanistic scenario
outlined in Figure 1, a number of alternative pathways can
be considered (Scheme 1).
when 9 was subjected to the same conditions (i.e., MgBr2‚
OEt2, MgBr2‚OEt2/Et3N, MeMgBr/pentanol, or Et2AlCl) that
gave 7 from 1a and 2a (Scheme 1).
Comparison of the DA reactions of 2a with 1a and with
1b strongly suggest that a coValent interaction between the
diene oxygen and the Lewis acid is an important factor in
the selective formation of 7 from 1a and 2a. Because there
is no background reaction between 1a and 2a at room
temperature, the formation of 7 implies LA activation of 2a;
assuming that MeMgBr is quantitatively converted into 8 in
the presence of excess 1a, one can conclude that the
“complex” 10 is involved (Scheme 1). The possibility that
3a (and thus 7) was formed by a “bimolecular” DA reaction
of 1a with 10 (or other ROMgBr‚2a complex, e.g., 12) was
inconsistent with a number of observations (Scheme 1).
Despite the similar reactivity of 1a and 1b in uncatalyzed
reactions,19 MeMgBr-mediated reaction of 1a with 2a in the
presence of a 10-fold excess of 1b gave 7 as the only DA
product. Similarly, the bromomagnesium alkoxide formed
from pentanol and MeMgBr failed to promote a DA reaction
between 1b and 2a via 12 (Table 1, entry 16). In an effort
to promote a “bimolecular” pathway, we examined dieno-
philes where an “intramolecular” DA reaction upon coordi-
nation with 8 was disfavored. DA adducts were not obtained
from Mg(II)-mediated reactions of 1a with acrylonitrile. As
with 2a, the thermal DA reaction of N-acryloyloxazolidinone
(2b)20 with 1a is slightly regioselective16 in favor of adducts
5c and 6c (Table 1, entry 17). By comparison, in the presence
of MgBr2‚OEt2 a much higher endo stereoselectivity with
only a marginal increase in regioselectivity results (Table 1,
entry 18), as observed in the Et2AlCl-mediated reaction of
1b with 2a (Table 1, entry 13) and consistent with reaction
via 15a. Modest regioselectivity in favor of adducts 7 and
4c was observed in the MeMgBr-mediated reaction of 1a
with 2b (Table 1, entry 19), suggesting reaction via both
15b and 14. The striking contrasts between the LA-mediated
reactions of 2a with 1a and 1b and of 1a with 2a and 2b
militate against a “bimolecular” mechanistic hypothesis for
selective formation of 7.
Scheme 1
The above results strongly indicate that the diene and
dienophile are simultaneously associated with the LA in the
TS leading to 7 (i.e., TS C in Scheme 1). In an effort to
provide evidence for a discrete intermediate (i.e. 10) along
the reaction pathway, we examined the concentration de-
(15) Addition of MeMgBr (1 equiv) to a toluene solution of 1a gave a
clear solution only with a MeMgBr/1a ratio near 0.5; with greater or lesser
amounts of MeMgBr, the mixture was cloudy. With a total ROH:MeMgBr
ratio of 2, the use of pentanol (1 equiv) as a “dummy” alcohol gave a faster
and more efficient reaction. Presumably, the ROH:ROMgBr ratio affects
the speciation of ROMgBr. For an example of a dimeric structure, see:
Moseley, P. T.; Shearer, H. M. M. J. Chem. Soc., Chem. Commun. 1968,
279-280. Reaction is much slower with MeMgCl and faster but less
efficient with MeMgI.
(16) The regioselectivity is the ratio of ([5] + [6]):([3] + [4] + [7]).
(17) A predominance of 5/6 regioisomers is expected on the basis of
greater electron-donating properties of a methyl group vs a hydroxymethyl
or methoxymethyl group. Only 3/4/7 regioisomers can form if diene and
dienophile are tethered by association with a Lewis acid in the TS.
(18) Toyota, M.; Wada, Y.; Fukumoto, K. Heterocycles 1993, 35, 111.
(19) For example, 1a was 1.2 times more reactive than 1b toward 2a in
toluene solution at 120 °C as determined in a competition experiment.
(20) Chelation of 8 by 2b (i.e. 15b) prevents IMDA reaction; IMDA
reaction is feasible with monodentate coordination (e.g., 14).
The possible formation of 7 by IMDA reaction of ester
918 was easily ruled out because adducts were not detected
(13) The dienes are acid sensitive and are consumed by dimerization
and/or polymerization in these cases.
(14) Vedejs, E.; Daugulis, O. J. Org. Chem. 1996, 61, 5702-5703.
Org. Lett., Vol. 2, No. 24, 2000
3939

pendence of the DA chemoselectivity between 1a and
cyclopentadiene competing for a deficient amount of 2a
(Scheme 2). In the absence of Mg(II), only adducts from
reactions of 1a with methyl methacrylate and with dimethyl
fumarate, but attempted reactions with methyl crotonate
failed.13,25 Analogous reactions with the chiral diene 1926
resulted in marked increases in diastereoselectivity compared
to that of uncatalyzed reactions (Scheme 3). For example,
Scheme 2
Scheme 3a
a Conditions: (a) i. MeMgBr (1 equiv) 17 (1 equiv), toluene (0.1
M), rt, 3 h; (b) 17 (1 equiv), CDCl3 (0.1 M), rt, 6 h; (c) 17 (1
equiv), C6D6 (0.1 M), 120 °C, 2 h.
the MeMgBr-mediated reaction of 19 with 17 gave the endo
adduct 2026 with excellent diene diastereotopic face selectiv-
ity (>19:1; cf. 1.7:1 for the uncatalyzed reaction). The adduct
2227 was obtained with similar stereoselectivity from the 2H-
thiopyran diene 21.28
In summary, we have demonstrated the feasibility of a
strategy to control Diels-Alder reactions based on a Lewis
acid-catalyzed reaction of a “self-assembled” complex
(LACASA-DA).29,30 Thus, the benefits of intramolecularity
and Lewis acid catalysis are exploited to enhance reactivity,
regioselectivity, and stereoselectivity of Diels-Alder reac-
tions. In principle, enantioselective reactions should also be
possible by providing an appropriate chiral ligand sphere for
the Lewis acidic metal center.
cyclopentadiene were detected (16;21 3:1, endo:exo)22 In
reactions mediated by MeMgBr, the reactivity of 1a was
dramatically enhanced and 7 was produced competitively
with 16. In these cases, adduct 16 was formed with increased
diastereoselectivity (9:1, endo:exo),22 suggesting a Lewis
acid-mediated reaction (e.g., cyclopentadiene and 10). Sig-
nificantly, otherwise identical experiments conducted with
a 10-fold difference in concentration (0.3 vs 0.03 M in 1a)
showed a >8-fold difference in chemoselectivity (3.5:1 vs
1:2.5)22 but with little change in the amount of 7 formed (%
yield based on 2a).23 These results are most easily rational-
ized by assuming that 16 is formed by intermolecular reaction
of cyclopentadiene with 10, that 7 results from an “intra-
molecular” reaction of 10, and that the equilibrium favors
the formation of 10 from 8 and 2a (Scheme 1). By contrast,
the relative reactivity of 1a is ca. 6 times greater than that
of 1b toward N-phenylmaleimde (17) at room temperature.
Although the higher reactivity of 1a might be attributable
to a favorable H-bond in the TS leading to 18a,24 the
hypothetical “intramolecular” reaction of a H-bonded com-
plex is inconsistent with the observed concentration inde-
pendence of the chemoselectivity.
Acknowledgment. Financial support from the Natural
Sciences and Engineering Research Council of Canada and
the University of Saskatchewan is gratefully acknowledged.
M.S.A. thanks the Ministry of Science, Research, and
Technology of Iran for sponsorship.
OL0067235
(25) Diene 1b did not react under these conditions.
(26) Tripathy, R.; Franck, R. W.; Onan, K. D. J. Am. Chem. Soc. 1988,
110, 3257-3262.
(27) The C-Me configuration of 22 was not rigorously determined.
(28) The preparation and reactions of thiopyran dienes will be described
separately.
Comparable increases in reactivity and selectivity were
also observed on using MeMgBr and/or Et2AlCl to mediate
(29) For similar Mg(II)-mediated [3 + 2] cycloadditions of nitrile oxides
with allylic alcohols, see: (a) Kanemasa, S.; Hidetoshi, Y.; Shinsuke, K.
Tetrahedron Lett. 1997, 38, 4095-4098. (b) Kanemasa, S.; Nishiuchi, M.;
Kamimura, A.; Hori, K. J. Am. Chem. Soc. 1994, 116, 2324-2339.
(30) For other examples of “self-assembled” templates for DA reactions,
see: (a) Walter, C. J.; Anderson, H. L.; Sanders, J. K. M. J. Chem. Soc.,
Chem. Commun. 1993, 458-460. (b) Walter, C. J.; Sanders, J. K. M. Angew.
Chem., Int. Ed. Engl. 1995, 34, 217-219. (c) Wang, B.; Sutherland, I. O.
J. Chem. Soc., Chem. Commun. 1997, 1495-1496.
(21) Kobuke, Y.; Fueno, T.; Furukawa, Y. J. Am. Chem. Soc. 1970, 92,
6548-6553.
(22) Ratios were determined by 1H NMR of the crude reaction mixture;
yields were determined using an internal standard.
(23) Qualitatively similar results were obtained in Et2AlCl-mediated
competition reactions which were faster though less reproducible.
(24) Khandelwal, G. D.; Wedzicha, B. L. Food Chem. 1997, 60, 237-
244.
3940
Org. Lett., Vol. 2, No. 24, 2000