Intramolecular Diels-Alder reactions of ester linked 1,3,9-decatrienes: Cis/trans selectivity in thermal and Lewis acid promoted reactions of ethylene-tethered and benzo-tethered systems

Article abstract of DOI:10.1021/jo0607818

High cis (i.e., endo) diastereoselectivities are witnessed in heat-promoted intramolecular Diels-Alder (IMDA) reactions of ethylene-tethered hexadienyl acrylates. The cis stereoselectivity is improved by promotion with Et ₂AlCl. The first examples of Et₂AlCl catalyzed intramolecular Diels-Alder reactions of ester-activated dienophiles are reported. In contrast, the corresponding benzo-tethered hexadienyl acrylates undergo moderately trans (i.e., exo) selective IMDA reactions. Very high trans stereoselection is obtained upon promotion with ATPH. The outcomes of these reactions are essentially insensitive to dienophile (C10) geometry and substitution. DFT (B3LYP/6-31+G(d)) computed cis/trans product distributions-based on Boltzmann transition structure populations-are in good agreement with the experimental results. These computational investigations provide useful insights into the origins of stereoselection in these systems. The stereoselectivity exhibited by the ethylene-tethered hexadienyl acrylates is ascribed to stabilizing secondary orbital interactions at play in the cis-transition structures (TSs). In the benzo-tethered series, this effect is overridden by stabilizing π-conjugative interactions, between the benzo moiety and the 1,3-diene component, which are stronger in trans TSs, compared to the cis TSs. The computed TS geometries generally exhibit advanced peripheral bond forming asynchronicity, with the tether carbonyl group in conjugation with the dienophile. Such TS features significantly weaken the stereodirecting influence of terminal dienophile substituents.

Full text of DOI:10.1021/jo0607818

Intramolecular Diels-Alder Reactions of Ester Linked
1,3,9-Decatrienes: Cis/Trans Selectivity in Thermal and Lewis Acid
Promoted Reactions of Ethylene-Tethered and Benzo-Tethered
Systems
Emma L. Pearson,† Laurence C. H. Kwan,† Craig I. Turner,† Garth A. Jones,‡
Anthony C. Willis,† Michael N. Paddon-Row,*,‡ and Michael S. Sherburn*,†
Research School of Chemistry, Australian National UniVersity, Canberra, ACT 0200, Australia, and
School of Chemistry, The UniVersity of New South Wales, Sydney, NSW 2052, Australia
sherburn@rsc.anu.edu.au; m.paddonrow@unsw.edu.au
ReceiVed April 13, 2006
High cis (i.e., endo) diastereoselectivities are witnessed in heat-promoted intramolecular Diels-Alder
(IMDA) reactions of ethylene-tethered hexadienyl acrylates. The cis stereoselectivity is improved by
promotion with Et2AlCl. The first examples of Et2AlCl catalyzed intramolecular Diels-Alder reactions
of ester-activated dienophiles are reported. In contrast, the corresponding benzo-tethered hexadienyl
acrylates undergo moderately trans (i.e., exo) selective IMDA reactions. Very high trans stereoselection
is obtained upon promotion with ATPH. The outcomes of these reactions are essentially insensitive to
dienophile (C10) geometry and substitution. DFT (B3LYP/6-31+G(d)) computed cis/trans product
distributionssbased on Boltzmann transition structure populationssare in good agreement with the
experimental results. These computational investigations provide useful insights into the origins of
stereoselection in these systems. The stereoselectivity exhibited by the ethylene-tethered hexadienyl
acrylates is ascribed to stabilizing secondary orbital interactions at play in the cis-transition structures
(TSs). In the benzo-tethered series, this effect is overridden by stabilizing π-conjugative interactions,
between the benzo moiety and the 1,3-diene component, which are stronger in trans TSs, compared to
the cis TSs. The computed TS geometries generally exhibit advanced peripheral bond forming
asynchronicity, with the tether carbonyl group in conjugation with the dienophile. Such TS features
significantly weaken the stereodirecting influence of terminal dienophile substituents.
Introduction
eoisomeric products (P), namely cis-1P and trans-1P, which
differ in the stereochemistry about the ring fusion. Whereas
terminal diene (C1) substituents have little influence upon the
stereochemical outcome of the reaction, there is a marked
stereochemical dependence upon both the nature of the dieno-
phile (C9) substituent and the dienophile geometry. Experiments
show that the C9-unsubstituted acrylate derivative is quite
strongly cis selective (trans/cis ) 25:75).4 The 9-E-CH3
analogue also shows cis-IMDA selectivity whereas the 9-Z-CH3
gives equal amounts of the two isomers. The two 9-CO2Me
derivatives exhibit trans selectivity, the selectivity being marked
in the case of the Z-ester analogue. These intriguing results were
explained in terms of competing conformational, electronic, and
The intramolecular version of the Diels-Alder cycloaddition
(IMDA) is a powerful reaction since two rings, two covalent
bonds, and up to four contiguous stereocenters are generated
in a concerted event.1 We are focusing efforts on the prediction
and rationalization of the stereochemical outcome of this
synthetically important reaction. In recent papers, we presented
experimental and computational studies of the IMDA reactions
of pentadienyl acrylates 1 (Scheme 1) bearing substituents at
C1 and C9.2,3 These reactions can furnish two distinct diaster-
† Australian National University.
‡ University of New South Wales.
10.1021/jo0607818 CCC: $33.50 © 2006 American Chemical Society
Published on Web 07/14/2006
J. Org. Chem. 2006, 71, 6099-6109
6099

Pearson et al.
SCHEME 1. Pentadienyl Acrylate IMDA Reaction Cis and
Trans Transition Structures (TS) and Bicyclic Products (P)
FIGURE 1. The presence of the 9-Z-CO2Me group (right-hand TS)
in pentadienyl acrylate cis TSs is accompanied by increased twist-mode
asynchronicity (blue arrow) and increased out-of-plane twisting of the
tether carbonyl group (blue dashed box).
whose endo selectivities, displayed in intermolecular DA
reactions, are reversed in the IMDA reactions of pentadienyl
acrylates. The origin of this so-called anomalous Z-effect was
ascribed to destabilizing structural changes in the cis TSs
namely, amplification of twist-mode asynchronicity, resulting
from out-of-plane twisting of the tether carbonyl groupscaused
by repulsive interactions between the 9-Z-substituent and the
tether carbonyl group, which lead to diminished SOIs involving
the tether carbonyl and to the 9-Z substituent being driven further
into the endo region of the diene where electrostatic repulsion
prevail over SOIs (Figure 1).
The aims of the present study are to investigate the stereo-
chemical outcomes of IMDA reactions of the higher homologue
of the system depicted in Scheme 1, ethylenoxycarbonyl-tethered
1,3,9-decatrienes 2, along with their benzo-tethered analogues
3 (Scheme 2). A major objective of this work was to develop
an understanding of the origins of stereoselection of these
reactions by the location and examination of computed transition
structures. Would a similar stereochemical dependence upon
dienophile substitution be witnessed in these systems? Penta-
dienyl acrylates 1 suffer decomposition through C5-O6 bond
heterolysis upon treatment with Lewis acids.7 A further goal of
the present study was to investigate both the enhancement and
reversal of inherent thermal stereoselectivities in IMDA reac-
tions of 2 and 3, by way of Lewis acid promotion.
steric effects operating in the two competing diastereomeric TSs.
For example, the cis preference exhibited by C9-unsubstituted
pentadienyl acrylates is the result of two opposing influences
in the cis TS, namely destabilizing torsional strain about the
C4-C5 bond and (slightly stronger) stabilizing attractive
electrostatic and/or Singleton-type [4 + 3] secondary orbital
interactions (SOIs)5,6 between the endo-oriented tether carbonyl
group and atoms C4 and possibly C3 of the diene unit.4
Whereas cis/trans selectivity for IMDA reactions involving
9-E-substituted pentadienyl acrylates generally follows the
normal pattern found for the corresponding intermolecular DA
reactions, the 9-Z-substituted stereoisomers generally displayed
trans selectivity that was much stronger than can be attributed
to effects of the isolated substituent. This is strikingly so with
unsaturated electron withdrawing substituents (e.g., CO2Me)
The importance of IMDA reactions of ester linked decatrienes
2 in total synthesis is well documented. The natural products
(1) (a) Taber, D. F. Intramolecular Diels-Alder and Alder Ene Reactions;
Springer-Verlag: Berlin, 1984. (b) Fallis, A. G. Can. J. Chem. 1984, 62,
183-234. (c) Ciganek, E. Org. React. 1984, 32, 1-374. (d) Craig, D. Chem.
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(f) Roush, W. R. In ComprehensiVe Organic Synthesis; Trost, B. M.,
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pp 513-550. (g) Oh, T.; Reilly, M. Org. Prep. Proced. Int. 1994, 26, 129-
158. (h) Craig, D. In StereoselectiVe Synthesis, 4th ed.; Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schumann, E., Eds.; Methods of Organic
Chemistry (Houben-Weyl) No. E21c; Thieme: Stuttgart, 1995; pp 2872-
2904. (i) Fallis, A. G. Acc. Chem. Res. 1999, 32, 464-474. (j) Bear, B. R.;
Sparks, S. M.; Shea, K. J. Angew. Chem., Int. Ed. 2001, 40, 820-849. (k)
Marsault, E.; Toro´, A.; Nowak, P.; Deslongchamps, P. Tetrahedron 2001,
57, 4243-4260. (l) Takao, K.-i.; Munakata, R.; Tadano, K.-i. Chem. ReV.
2005, 105, 4779-4807.
(5) (a) Alder, K.; Schumacher, M. Liebigs Ann. Chem. 1951, 571, 87-
107. (b) Salem, L. J. Am. Chem. Soc. 1968, 90, 553-566. (c) Woodward,
R. B.; Hoffmann, R. The ConserVation of Orbital Symmetry; Verlag
Chemie: Weinheim, Germany, 1970. (d) Houk, K. N. Tetrahedron Lett.
1970, 2621-2624. (e) Ginsburg, D. Tetrahedron 1983, 39, 2095-2135.
(f) Birney, D. M.; Houk, K. N. J. Am. Chem. Soc. 1990, 112, 4127-4133.
(g) Singleton, D. A. J. Am. Chem. Soc. 1992, 114, 6563-6564. (h) Kong,
S.; Evanseck, J. D. J. Am. Chem. Soc. 2000, 122, 10418-10427. (i) Garcia,
J. I.; Mayoral, J. A.; Salvatella, L. Acc. Chem. Res. 2000, 33, 658-664. (j)
Caramella, P.; Quadrelli, P.; Toma, L. J. Am. Chem. Soc. 2002, 124, 1130-
1131.
(6) Whether SOIs are important in Diels-Alder reactions remains
controversial. For more detailed discussion on this issue, including evidence
suggesting that SOIs are not the origin of endo selectivity in intermolecular
Diels-Alder reactions, see ref 5i and the following: (a) Garc´ıa, J. I.;
Mart´ınez-Merino, M.; Mayoral, J. A.; Salvatella, L. J. Am. Chem. Soc. 1998,
120, 2415-2420. (b) Garc´ıa, J. I.; Mayoral, J. A.; Salvatella, L. Tetrahedron
1997, 53, 6057-6064. (c) Garc´ıa, J. I.; Mayoral, J. A.; Salvatella, L. Eur.
J. Org. Chem. 2005, 85-90.
(2) Paddon-Row, M. N.; Moran, D.; Jones, G. A.; Sherburn, M. S. J.
Org. Chem. 2005, 70, 10841-10853.
(3) Cayzer, T. N.; Paddon-Row, M. N.; Moran, D.; Payne, A. D.;
Sherburn, M. S.; Turner, P. J. Org. Chem. 2005, 70, 5561-5570.
(4) Cayzer, T. N.; Wong, L. S.-M.; Turner, P.; Paddon-Row, M. N.;
Sherburn, M. S. Chem.sEur. J. 2002, 8, 739-750.
(7) Toyota, M.; Wada, Y.; Fukumoto, K. Heterocycles 1993, 35, 111-
114.
6100 J. Org. Chem., Vol. 71, No. 16, 2006

Intramolecular Diels-Alder Reactions
SCHEME 2. IMDA Reactions under Scrutiny
into the IMDA reaction of the 3,5-dimethyl analogue of
E-crotonate 2 (Scheme 2, E ) Me; Z ) H) highlighted the
preference for a boatlike-TS tether conformation22 and identified
its origins but apparently did not offer an explanation of the cis
preference of the reaction. Despite the significant number of
publications describing IMDA reactions of trienes 2, no
investigation into the influence of dienophile substitution has
been reported. Recent findings by Roush in the decatrienone
series demonstrate an intriguing cis-trans stereoselectivity
reversal with E- and Z-dienophile congeners of otherwise
identical triene precursors,23 a result which is similar to that
witnessed with pentadienyl acrylates.2 We felt that a systematic
computational-experimental investigation into compounds of
type 2, carrying representative E- and Z-substituents, was
warranted.
Despite the ease of access to benzo-precursors 3 depicted in
Scheme 2 and the synthetic potential of their cycloadducts, we
have been able to locate only three previous examples of IMDA
reactions of this type in the literature. One describes a trans-
selective double IMDA reaction of a cross-conjugated thia-triene
with acrylate dienophiles,24 and another describes a trans-
selective IMDA reaction of triene 3 (E ) Z ) H).25 The third
paper describes our preliminary investigations with the E-
crotonate 3 (Scheme 2, E ) Me; Z ) H), in which we
erroneously reported a transposed experimental cis 73:27 trans
ratio from the thermal IMDA reaction.16 This experimental error
led us to the incorrect conclusions that DFT is inferior to MP
theory and that DFT failed in this case. Herein we clarify the
experimental selectivities and elucidate their origins with a
detailed computational-experimental investigation into com-
pounds of type 3.
gibberellic acid,8 mellein and ramulosin,9 stenine,10 and lyco-
rine11 have all been prepared using an IMDA reaction of this
class as a key step, and no less than four groups have described
the results of preliminary investigations into the total synthesis
of eleutherobin.12 In agreement with Corey’s observations with
a precursor containing a semicyclic diene and a chloroacrylate
dienophile,8 Martin demonstrated that the parent ester linked
decatriene 2 (Scheme 2, E ) Z ) H) undergoes a strongly (90%)
cis-selective cycloaddition under thermal conditions.13 Subse-
quent investigations with more highly substituted precursors
under both thermal14-16 and Lewis acid-mediated17-19 conditions
have confirmed high cis stereoselectivity as the norm for
substrates 2 where E ) Z ) H and E ) substituent; Z ) H.20
A computational investigation by Tantillo, Houk, and Jung21
(8) Corey, E. J.; Danheiser, R. L.; Chandrasekaran, S.; Keck, G. E.;
Gopalan, B.; Larsen, S. D.; Siret, P.; Gras, J. L. J. Am. Chem. Soc. 1978,
100, 8034-8036.
Results and Discussion
(9) Mori, K.; Gupta, A. K. Tetrahedron 1985, 41, 5295-5299.
(10) (a) Chen, C. Y.; Hart, D. J. J. Org. Chem. 1990, 55, 6236-6240.
(b) Chen, C. Y.; Hart, D. J. J. Org. Chem. 1993, 58, 3840-3849.
(11) (a) Hoshino, O.; Ishizaki, M.; Kamei, K.; Taguchi, M.; Nagao, T.;
Iwaoka, K.; Sawaki, S.; Ymezawa, B.; Iitaka, Y. Chem. Lett. 1991, 1365-
1368. (b) Hoshino, O.; Ishizaki, M.; Kamei, K.; Taguchi, M.; Nagao, T.;
Iwaoka, K.; Sawaki, S.; Umezawa, B.; Iitaka, Y. J. Chem. Soc., Perkin
Trans. 1 1996, 571-580.
Heat-Promoted IMDA Reactions. Triene IMDA precursors
4-13, differing in the nature of the dienophile (C10) substituent
and dienophile geometry, were accessed in two or three
straightforward steps as described in the Supporting Information
(SI). Heat-promoted IMDA reactions were carried out in
common aromatic solvents (Table 1). The order of reactivity
of the five non-benzo substrates toward IMDA reaction is as
follows: fumarate 6 > maleate 8 > acrylate 4 > E-crotonate 5
> Z-crotonate 7. A very similar order of reactivity was witnessed
within the benzo series, with the only difference being that the
acrylate precursor 9 underwent IMDA reaction more readily
than the maleate precursor 13. A substrate containing an
aromatic ring invariably cyclizes more readily than its ethylene
tether analogue. The reactions of the crotonates were consider-
ably slower than those of the other three substrates, with some
decomposition being witnessed under conditions required to
induce thermal cycloaddition of Z-crotonate 7. The reactions
(12) (a) Kim, P.; Nantz, M. H.; Kurth, M. J.; Olmstead, M. M. Org.
Lett. 2000, 2, 1831-1834. (b) Jung, M. E.; Huang, A.; Johnson, T. W.
Org. Lett. 2000, 2, 1835-1837. (c) Ritter, N.; Metz, P. Synlett 2003, 2422-
2424. (d) Bruye`re, H.; Samaritani, S.; Ballereau, S.; Tomas, A.; Royer, J.
Synlett 2005, 1421-1424.
(13) Martin, S. F.; Williamson, S. A.; Gist, R. P.; Smith, K. M. J. Org.
Chem. 1983, 48, 5170-5180.
(14) (a) Nugent, W. A.; Calabrese, J. C. J. Am. Chem. Soc. 1984, 106,
6422-6424. (b) Nugent, W. A.; Thorn, D. L.; Harlow, R. L. J. Am. Chem.
Soc. 1987, 109, 2788-2796.
(15) Lorvelec, G., Vaultier, M. Tetrahedron Lett. 1998, 39, 5185-5188.
(16) (a) Jones, G. A.; Paddon-Row, M. N.; Sherburn, M. S.; Turner, C.
I. Org. Lett. 2002, 4, 3789-3792. Erratum: (b) Jones, G. A.; Paddon-
Row, M. N.; Sherburn, M. S.; Turner, C. I. Org. Lett. 2005, 7, 4547.
(17) Alexakis, A.; Jachiet, D.; Toupet, L. Tetrahedron 1989, 45, 6203-
6210.
(18) (a) Saito, A.; Ito, H.; Taguchi, T. Org. Lett. 2002, 4, 4619-4621.
(b) Saito, A.; Yanai, H.; Taguchi, T. Tetrahedron 2004, 60, 12239-12247.
(c) Saito, A.; Yanai, H.; Sakamoto, W.; Takahashi, K.; Taguchi, T. J.
Fluorine Chem. 2005, 126, 709-714. (d) Yanai, H.; Saito, A.; Taguchi, T.
Tetrahedron 2005, 61, 7087-7093.
(21) Tantillo, D. J.; Houk, K. N.; Jung, M. E. J. Org. Chem. 2001, 66,
1938-1940.
(22) A boatlike TS conformation for the ketone tether analogue of 2
(Scheme 2) was discussed earlier by Roush: (a) Coe, J. W.; Roush, W. R.
J. Org. Chem. 1989, 54, 915-930. (b) Roush, W. R.; Kageyama, M.; Riva,
R.; Brown, B. B.; Warmus, J. S.; Moriarty, K. J. J. Org. Chem. 1991, 56,
1192-1210.
(23) Dineen, T. A.; Roush, W. R. Org. Lett. 2005, 7, 1355-1358.
(24) Saito, T.; Kimura, H.; Sakamaki, K.; Karakasa, T.; Moriyama, S.
Chem. Commun. 1996, 811-812.
(25) Inoue, S.; Kosugi, C.; Lu, Z. G.; Sato, K. Nippon Kagaku Kaishi
1992, 45-52.
(19) Zhou, G.; Hu, Q.-Y.; Corey, E. J. Org. Lett. 2003, 5, 3979-3982.
This paper describes the only example of enantioselective catalysis of an
ester-linked precursor to date.
(20) To our knowledge, only one example of an IMDA reaction of a
Z-substituted precursor 2, the carboxylic acid (E ) H; Z ) CO2H) has
been reported. Cyclization of this substrate was promoted by In(OTf)3 in
an aqueous solvent.18d No thermal cycloaddition results were disclosed.
J. Org. Chem, Vol. 71, No. 16, 2006 6101

Pearson et al.
TABLE 1. Thermal Intramolecular Diels-Alder Reactions
b
c
c
structure
C10-substituent
T (°C)
t (ha)
Y (%)
cis/transexptl
cis/transDFT
Erel
4d
5
H
E-Me
E-CO2Me
Z-Me
Z-CO2Me
H
E-Me
E-CO2Me
Z-Me
132e
180f
110h
180h
132e
110h
180f
110h
180f
110h
47
113
22
120
72
70
76
82
54
90
92
100
96
92
87
92:8
85:15
81:19
79:21
74:26
60:40
13:87
21:79
31:69
9:91
c5.85
c5.54
c4.20
c3.94
c1.38
t5.94
t4.96
t2.51
t8.76
t9.01
88:12
83:17
85:15
70:30
26:74
27:73j
29:71
24:76
22:78
6g
7
8
9i
12
10
11
12
13
2.2
0.5
21
Z-CO2Me
28.5
6:94
a Time taken for >95% conversion of starting triene. b The mean of the ratios measured from HPLC of the crude reaction mixture, 1H NMR of the crude
reaction mixture, and the isolated yields after purification. The difference between the three sets of ratios was at most (5%. c DFT ) B3LYP/6-31+G(d).
Relative energies (kJ mol-1) refer to 0 K and include ZPVE corrections. For 4-8, the boatlike conformation is always more stablesbetween 6 and 20 kJ
mol-1sthan the chairlike conformation and Erel refers only to the boatlike conformations. The cis/transDFT ratios are the Boltzmann populations of the cis
and trans TSs at the experimental temperatures; both chairlike and boatlike TSs were included in the calculations. All 10-CO2Me TSs have the ester group
adopting the cisoid conformation; inclusion of those TSs having the transoid conformation had no effect on the Boltzmann distributions. d Previously reported
to give a 90:10 mixture of cis-4P/trans-4P in 42% yield (sealed tube, 210 °C, 5 h).13 e Chlorobenzene. f 1,2-Dichlorobenzene. g Previously reported to give
a 78:22 mixture of cis-6P/trans-6P in 67% yield (xylene, reflux, 5 h).10 h Toluene. i Previously reported to give a 30:70 mixture of cis-6P/trans-6P (no
yield, experimental details, or characterization data provided).25 j Erroneously reported to give a 73:27 mixture of cis-10P/trans-10P in an earlier
communication.16
FIGURE 2. IMDA product molecular structures from single-crystal X-ray analyses.
of the non-benzo substrates 4-8 exhibit strong cis kinetic26
stereoselectivities, whereas the IMDA reactions of the five
benzo-tethered analogues all exhibit marked trans kinetic26
stereoselectivities. Single-crystal X-ray analyses of cis-8P, trans-
8P, cis-9P, trans-10P, trans-11P, cis-12P, and cis-13P (Figure
2) augmented NMR analyses in securing the stereochemical
assignments of cycloadducts (see SI for full details).
The thermal IMDA reactions of substrates 4-13 were
modeled computationally in order to answer the following
questions: (1) Why are the stereochemical outcomes of these
thermal IMDA reactions not influenced by the dienophile
geometry and the nature of the dienophile terminal substituent?
(cf. pentadienyl acrylates, Scheme 1.) (2) Why do the non-benzo
precursors undergo cis-selective thermal IMDA reactions, and
(3) why do the benzo precursors give trans cycloadducts?
Computational Methods. Gas-phase transition structures
(TSs) for intramolecular Diels-Alder reactions were optimized
using the B3LYP functional27 and the 6-31+G(d) basis set.28
Harmonic vibrational frequencies (at the same level of theory)
were employed to characterize optimized geometries as either
first-order saddle structures (one negative Hessian eigenvalue)
or minima (all frequencies real), and to providesafter scaling
(26) All cycloadducts reported in this study were found to be stable
towards the reaction conditions used to form them.
6102 J. Org. Chem., Vol. 71, No. 16, 2006

Intramolecular Diels-Alder Reactions
SCHEME 3. Schematic of Cis and Trans Boatlike and Chairlike IMDA TSs for the Non-Benzo Hexadienyl Acrylate, Depicting
the Numbering Conventions and Relevant Geometrical Parameters
by 0.961429szero-point vibrational energies (ZPVEs) and
calculated using electronic energies. The single exception is 8,
for which the free energy calculation incorrectly predicts
predominant trans selectivity, whereas both electronic energy
and enthalpy calculations are in agreement with the experimental
finding of predominant cis selectivity. Salient TS ZPVE-
corrected relative energies and cis/trans populations, calculated
using the electronic energies, are presented in Table 1. The
corresponding cis/trans selectivities, based on enthalpy and free
energy calculations, are given in Supporting Information (SI)
(Table S2). Geometrical parameters (Schemes 3 and 4) are
summarized in Tables S3 and S4 (SI). The Gaussian 9830 and
0331 program packages were used throughout. Optimized
geometries (in Cartesian coordinate form) and their energies
are provided as Supporting Information.
Justification of the Theoretical Model. The B3LYP func-
tional, in conjunction with either the 6-31G(d) or 6-31+G(d)
basis sets, is known to give acceptable relative energies and
geometries for a broad variety of Diels-Alder reactions.3-5,21,32,33
Importantly, we have shown that the B3LYP/6-31+G(d) method
correctly predicts cis/trans ratios for the IMDA reactions of
several 9-substituted pentadienyl acrylates, often with an ac-
curacy of 1 kJ/mol.2 This level of theory is, therefore, adequate
for this study. In this work we focus exclusively on the influence
enthalpies and free energies. ZPVE (0 K) corrected TS relative
TS
energies (E ) were calculated using the electronic energies
rel
TS
rel
from optimized cis- and trans-IMDA TS isomers (i.e., E
)
Ecis TS - Etrans TS). The relative enthalpies and free energies of
TS
TS
the cis and trans TSs, H and G , respectively, were calcu-
rel
rel
lated at the experimental temperatures. The cis and trans TS
populations (which are equated to the cis/trans product ratios)
were calculated using three different methods. First, and least
rigorously, TS Boltzmann populations were calculated from the
ZPVE-corrected electronic energies for each IMDA reaction,
using the experimental temperature. Second and third, the TS
populations were calculated from the TS enthalpies and free
energies, respectively, the latter being the most sound procedure
to follow. Interestingly, the cis/trans product ratios, determined
from electronic energies (i.e., the first method) have been shown
to give similar results to those based on enthalpies and free
energies.4 Indeed, both electronic energy and enthalpy calcula-
tions give almost identical cis/trans selectivities for the current
series of systems, 4-13. With one exception, the free energy-
calculated cis/trans selectivities are very similar to those
(27) (a) Lee, C.; Yang, W.; Parr, R. G. Phys. ReV. B 1988, 37, 785-
789. (b) Becke, A. D. J. Chem. Phys. 1993, 98, 5648-5652. For reviews
of density-functional methods see the following: (c) Ziegler, T. Chem. ReV.
1991, 91, 651-667. (d) Density Functional Methods in Chemistry;
Labanowski, J. K., Andzelm, J. W., Eds.; Springer-Verlag: New York, 1991.
(e) Parr, R. G.; Yang, W. Density-Functional Theory of Atoms and
Molecules; Oxford University Press: New York, 1989. (f) Koch, W.;
Holthausen, M. C. A Chemist’s Guide to Density Functional Theory; Wiley-
VCH: Weinheim, Germany, 2000.
(28) (a) Hehre, W. J.; Radom, L.; Schleyer, P. v. R.; Pople, J. A. Ab
Initio Molecular Orbital Theory; John Wiley & Sons: New York, 1986.
(b) The Encyclopedia of Computational Chemistry; Schleyer, P. v. R.,
Allinger, N. L., Clark, T., Gasteiger, J., Kollman, P. A., Schaefer, H. F.,
III, Schreiner, P. R., Eds.; John Wiley & Sons Ltd.: Chichester, U.K., 1998.
(29) Scott, A. P.; Radom, L. J. Phys. Chem. 1996, 100, 16502-16513.
(30) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi,
I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.;
Peng, C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M.
W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.11; Gaussian,
Inc.: Pittsburgh, PA, 2001.
J. Org. Chem, Vol. 71, No. 16, 2006 6103

Pearson et al.
SCHEME 4. Schematic of Cis- and Trans-IMDA TSs for
the Benzo Hexadienyl Acrylate, Depicting the Numbering
Conventions and Relevant Geometrical Parameters
selectivities for the heat-promoted reactions (Table 1) allows
the experimental findings to be explained through interpretation
of the TS geometries. As noted previously by Tantillo, Houk,
and Jung,21 the diene-dienophile linkers of ethylene-tethered
hexadienyl acrylates adopt two distinct conformations in IMDA
TSs, namely the chairlike and boatlike conformations. In the
benzo-analogues, the linker adopts a single flattened boatlike
conformation. The cis and trans cycloaddition modes are feasible
for each tether conformation type. Thus, four discrete TSs are
located for the non-benzo system (Scheme 3) and two for the
benzo system (Scheme 4). Referring to Schemes 3 and 4, there
are eight significant geometrical parameters associated with the
IMDA TS: the peripheral and internal forming bonds, rp and
ri, respectively; the bond forming asynchronicity, ∆ras () rp -
ri); the twist-mode asynchronicity dihedral angle, θas () the
dihedral angle C4-C1-C10-C9); the dihedral angle, θ1, made
between the tether carbonyl group and the dienophile double
bond; the dihedral angle, θ2, made between the C10 carbonyl
group (when present) and the dienophile double bond; the ester
group dihedral angle, θ3, made between the tether carbonyl
group and the alkoxy (aryloxy) substituent; the dihedral angle,
θ4, which gives the degree of conjugation between the diene
and the aromatic ring in benzo-TSs. Values for developing bond
length parameters and dihedral angles for all TSs are given in
Tables S3 and S4, respectively.
Before we offer explanations of stereoselectivities in these
reactions, it should be noted that boatlike TS are more stable
than chairlike TSs in hexadienyl acrylate IMDA reactions.
Consistent with findings on tether-substituted systems by
Tantillo, Houk, and Jung,21 the ester group of the tether exhibits
an energetically costly 55-72° out-of-plane conformation in
chairlike TSs (Table S4, dihedral θ3). In comparison, ester
tethers of boatlike TSs are significantly closer to the preferred
in-plane conformation (154-170°). The preference for boatlike
TSs in IMDA reactions of decatrienone systems was proposed
in earlier studies by Roush and Coe,21 who identified more subtle
conformational influences at play in IMDA TSs. Indeed, such
influences can be seen in hexadienyl acrylate TSs (Scheme 3,
pink hydrogens). The chairlike-cis TS for the IMDA reaction
of 4, for example, contains an unfavorable eclipsed arrangement
about the C4-C5 bond (H4-C4-C5-H5 dihedral angle ) 10°)
which is much weaker in the boatlike-cis TS (H4-C4-C5-
H5 dihedral angle ) 45°). Nevertheless, a comparison of the
trans TSs leads us to believe that the stronger ester overlap in
the boatlike TSs of the ester tethered system is the dominant
TS feature. Thus, the torsional strain associated with the H4-
C4-C5-H5 angle is about the same magnitude in both
chairlike-trans TS and boatlike-trans TS, H4-C4-C5-H5
dihedral angles ) 75° and 41°, respectively, and yet the boatlike-
trans TS is more stable than the chairlike-trans TS (by 7.4 kJ
mole-1), albeit, to a lesser extent than in the corresponding cis
TSs in which the boatlike-cis TS is 9.4 kJ mole-1 more stable
than the chairlike-cis TS.
of electronic, strain, and steric factors on cis/trans selectivities
of IMDA reactions, without considering solvent effects; con-
sequently, we have used gas-phase DFT calculations. The
excellent agreement found between gas-phase B3LYP/6-31+G-
(d) predicted IMDA cis/trans ratios and the experimental ratios,
obtained using toluene, chlorobenzene, or 1,2-dichlorobenzene
as solvent, suggests that weakly polar solvents, which are often
used in IMDA reactions, have no significant influence on cis/
trans selectivities.3
Transition Structure Geometries and Salient Parameters.
The good agreement between synthetic and calculated stereo-
(31) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Montgomery, J. A., Jr.; Vreven, T.; Kudin, K.
N.; Burant, J. C.; Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.;
Mennucci, B.; Cossi, M.; Scalmani, G.; Rega, N.; Petersson, G. A.;
Nakatsuji, H.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Klene, M.; Li,
X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Bakken, V.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.;
Cammi, R.; Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.;
Voth, G. A.; Salvador, P.; Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich,
S.; Daniels, A. D.; Strain, M. C.; Farkas, O.; Malick, D. K.; Rabuck, A.
D.; Raghavachari, K.; Foresman, J. B.; Ortiz, J. V.; Cui, Q.; Baboul, A.
G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.; Liashenko, A.;
Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham,
M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzalez, C.; Pople, J. A. Gaussian
03, version B; Gaussian, Inc.: Pittsburgh, PA, 2003.
(32) Wiest, O.; Montiel, D. C.; Houk, K. N. J. Phys. Chem. A 1997,
101, 8378-8388.
Because we find that the boatlike TS is always significantly
more stable (by 6 to 20 kJ mol-1) than the corresponding
chairlike TS for all IMDA reactions studied, the sections of the
following discussion involving cis/trans stereoselectivities in
hexadienyl acrylates will be restricted to the consideration of
boatlike TSs. The ensuing sections offer possible answers to
the three questions posed earlier.
(33) (a) Lilly, M. J.; Paddon-Row, M. N.; Sherburn, M. S.; Turner, C.
I. Chem. Commun. 2000, 2213-2214. (b) Paddon-Row, M. N.; Sherburn,
M. S. Chem. Commun. 2000, 2215-2216. (c) Turner, C. I.; Williamson,
R. M.; Paddon-Row, M. N.; Sherburn, M. S. J. Org. Chem. 2001, 66, 3963-
3969. (d) Cayzer, T. N.; Paddon-Row, M. N.; Sherburn, M. S. Eur. J. Org.
Chem. 2003, 4059-4068. (e) Lilly, M. J.; Miller, N. A.; Edwards, A. J.;
Willis, A. C.; Turner, P.; Paddon-Row, M. N.; Sherburn, M. S. Chem.s
Eur. J. 2005, 11, 2525-2536. (f) Cayzer, T. N.; Lilly, M. J.; Williamson,
R. M.; Paddon-Row, M. N.; Sherburn, M. S. Org. Biomol. Chem. 2005, 3,
1302-1307.
Why Are the Stereochemical Outcomes of these Thermal
IMDA Reactions Not Influenced by the Dienophile Geometry
6104 J. Org. Chem., Vol. 71, No. 16, 2006

Intramolecular Diels-Alder Reactions
FIGURE 3. Diverging outcomes from related Diels-Alder reactions.
and the Nature of the Dienophile Terminal Substituent
(Figure 3)? In all but 2 of the 28 hexadienyl acrylate TSs
located, the peripheral (C1-C10) bond rp is shorter than the
internal (C4-C9) bond ri. This result contrasts markedly with
the corresponding pentadienyl acrylate system, which exhibits
advanced internal TS bond formation.3 Advanced internal bond
formation is linked to the “Z-effect”,3 whereby Z-substituted
dienophiles exhibit anomalously trans-selective IMDA reactions
(Scheme 1, Figure 1). A significant consequence of advanced
peripheral bond formation in hexadienyl acrylates is the lack
of an anomalous Z-effect, that is, the consistently high cis
stereoselection for 4-8 (Table 1).
FIGURE 4. B3LYP/6-31+G(d) optimized pentadienyl maleate (left)
and hexadienyl maleate (right) TSs. Note the advanced internal bond
formation in the former and the advanced peripheral bond formation
in the latter. Distances are in angstroms.
The anomalous Z-effect is most apparent in the IMDA
reaction of pentadienyl maleate precursor (Scheme 1, 1, E )
H; Z ) CO2Me), which undergoes a trans-selective IMDA
reaction (cis/trans ) 21:79), while the corresponding hexadienyl
maleate 8 shows no such behavior and remains cis selective
(Table 1, cis/trans ) 62:38).34 Not only is twist-mode asyn-
chronicity modest in boatlike cis-8TS, amounting to 5° (Table
S4), but it takes place about the shorter C1-C10 forming bond35
and in the exo direction, away from the diene. Thus, the 10-
Z-CO2Me group in boatlike cis-8TS does not experience the
energetically costly displacement in the endo direction, as
suffered by the 9-Z-substituted pentadienyl acrylates (Figure 1).3
The main reason for the smaller magnitude of twist-mode
asynchronicity in the cis-Z IMDA TSs of the hexadienyl
acrylates, compared to that found in the TSs for the pentadienyl
acrylates is that, in the TSs for the latter systems, the developing
five-membered lactone ring forces the tether carbonyl group
out-of-plane, with respect to the dienophile double bond (Figure
1); the presence of a 9-Z-CO2Me group forces the tether
carbonyl group further out-of-plane which, in the cis TS, results
in driving the 9-Z-CO2Me group further in the endo direction.
Free from any ring-forming constraints, the 9-Z-CO2Me group
is able to remain coplanar with respect to the dienophile CdC
bond, thereby preserving conjugative stabilization. In contrast,
the developing, less strained, six-membered ring in the TSs for
the hexadienyl acrylates allows the tether carbonyl to remain
coplanar with respect to the dienophile double bond, even in
the presence of the 10-Z-CO2Me group. In this case, the
repulsive interaction between the 10-Z-ester substituent and the
tether carbonyl group in the endo TS is ameliorated by the out-
of-plane twisting of the ester substituent by 71° (Figure 4);
because the 10-Z-ester is not part of the tether, out-of-plane
twisting of this group has a negligible effect on the magnitude
of twist-mode asynchronicity. Consequently, no significant
destabilization of the cis-Z TS is to be expected.
FIGURE 5. B3LYP/6-31+G(d) optimized pentadienyl acrylate (left)
and hexadienyl acrylate (right) TSs. Note the essentially coplanar C10d
C9-C8dO arrangement in the latter and the severely twisted C9d
C8-C7dO arrangement in the former. This results in the C3dC4 bond
being much more closely aligned in the right-hand TS. Distances are
in angstroms.
Why Do the Non-Benzo Precursors Undergo Cis-Selective
Thermal IMDA Reactions? It is noteworthy that the favored
conformation of the forming six-membered lactone ring in all
boatlike TSs has the tether carbonyl group nearly coplanar with
the dienophile double bond (Table S4, θ1 ) 4-13°). Coplanarity
between tether carbonyl and dienophile cannot take place in
the pentadienyl acrylate TSs, even in the absence of a 9-Z-
substituent (θ1 ) ca. 30-40° in pentadienyl acrylates3). That
the hexadienyl acrylate TSs (a) tolerate an essentially coplanar
tether carbonyl group, and (b) have a shorter developing internal
C4-C9 bond has a consequence for the cis TSs, namely, that
they bring the tether carbonyl group into better alignment with
C3 and C4 of the diene, perhaps promoting SOIs (Figure 5).
Indeed, C4‚‚‚C8 distances (2.76-2.83 Å) and C3‚‚‚O distances
(3.42-3.68 Å) are remarkably similar throughout the five
boatlike-cis TSs.
It is noteworthy that the cis selectivitysboth experimentally
observed and computationally predictedsis more pronounced
in the hexadienyl acrylates 4-8 than in the pentadienyl acrylates
1. For example, the cis IMDA TS for the 9-unsubstituted
pentadienyl acrylate 1 (Scheme 1; E ) Z ) H) is 1.9 kJ mol-1
more stable than the trans TS,2 whereas, for the 10-unsubstituted
hexadienyl acrylate 4, the cis TS is 5.9 kJ mol-1 more stable
(34) This reaction was erroneously reported to give exclusiVe formation
of the cis product in ref 2.
(35) Brown, F. K.; Houk, K. N. Tetrahedron Lett. 1985, 26, 2297-2300.
J. Org. Chem, Vol. 71, No. 16, 2006 6105

Pearson et al.
Et2AlCl-Promoted and Et2AlCl-Catalyzed IMDA Cyclo-
additions of Esters. The stereoselectivities listed for substrates
4-13 in Table 1 are clearly synthetically useful. Nevertheless,
we were intrigued by the potential for stereoselectivity enhance-
ment or reversal in IMDA reactions by way of Lewis acid
promotion.
It has been known for many years that Lewis acids impact
upon the rate and stereoselectivity of IMDA reactions.38 Simple
Lewis acids generally lead to an improvement in the stereo-
selectivity of an IMDA process in the same manner observed
for intermolecular Diels-Alder reactions, that is, they promote
the formation of the product resulting from an endo disposition
of the coordinating carbonyl group of the dienophile.39 Aluminum-
based compounds are among the most frequently used promot-
ers, and the relatively mild Lewis acid Et2AlCl is a particularly
common reagent. In seminal investigations into IMDA reactions
in the 1980s, Roush observed that stoichiometric quantities of
Et2AlCl and related Lewis acids are required for complete
conversions of ester-substituted trienes.40 This result was
ascribed to the stronger Lewis basicity of the cycloadducts
(saturated esters) than the precursor trienes (R,â-unsaturated
esters), which form more stable complexes. Interestingly,
MeAlCl2 and EtAlCl2 have been shown to catalyze IMDA
reactions of R,â-unsaturated ketones41 and aldehydes,42 and
important competition experiments performed by Keay dem-
onstrated that the unconjugated carbonyl groups of cycloadducts
derived from these functionalities are weaker Lewis bases than
their conjugated counterparts.43 Our own studies (vide infra)
demonstrate that IMDA reactions involving R,â-unsaturated
ester precursors can be catalyzed by Et2AlCl.
Under optimized reaction conditions, Et2AlCl was effective
in enhancing the rate and modifying the stereochemical outcome
of the IMDA reactions of all 10 hexadienyl acrylate precursors
(Table 2).44 Under Et2AlCl promotion, trienes undergo IMDA
reaction at temperatures ca. 100 °C lower than the purely thermal
process. Under high dilution conditions (10 mM triene concen-
trations), stoichiometric amounts of the reagent were needed
for complete conversions; with the fumarate precursors 6 and
11 and maleate precursor 8, 1.9 equiv of Et2AlCl was optimal.
Unexpectedly, benzo maleate precursor 13 suffered decomposi-
tion when exposed to the same reaction conditions. All five
non-benzo precursors 4-8 exhibit stronger cis selectivity under
Et2AlCl promotion than under purely thermal conditions.
Regarding the benzo-tethered precursors, all of which are
inherently trans selective, three substrates display a shift in
stereoselectivity toward the cis cycloadduct on promotion with
FIGURE 6. B3LYP/6-31+G(d) optimized cis- and trans-9TS. Note
the essentially orthogonal diene-arene arrangement in the former. The
latter enjoys significantly more stabilizing π-conjugative interactions.
Distances are in angstroms.
than the trans TS (Table 1). The smaller cis selectivity found
for the pentadienyl acrylates, compared to the hexadienyl
acrylates, is probably due to two effects: (1) there may be
weakened SOIs in the pentadienyl acrylate cis TSs, owing to
the less favorable alignment of the tether carbonyl group with
the diene (the tether carbonyl group is twisted out-of-plane in
the TS (vide supra)) and (2) there is greater torsional strain about
the C4-C5 bond in the pentadienyl acrylate cis TSs (i.e., the
H4-C4-C5-H5 dihedral angle ) 3° for the cis TS of 1 (E, Z
dH)),2,3 compared to that in the hexadienyl acrylate cis TSs
(i.e., the H4-C4-C5-H5 dihedral angle ) 45° for the cis TS
of 4) (Figure 5, eclipsed protons highlighted).
Why Do the Benzo Precursors Give Trans Cycloadducts?
The benzo-tethered trienes 9-13 undergo trans-selective IMDA
reactions. Interestingly, the same stabilizing SOIs seen between
C8dO and C3dC4 are evident here in the cis TSs. The
alignment between these two π-bonds is similar to that witnessed
in the non-benzo cis TSs, with little variation in both C4‚‚‚C8
distances (2.70-2.77 Å) and C3‚‚‚O distances (3.31-3.50 Å).
Evidently, some other factor is operative in the benzo TSs to
override this cis-TS stabilization.
The preference for the trans isomer can be traced to
conjugation effects between the diene and the aromatic ring of
the tether. Values for the dihedral angle, θ4, which gives the
degree of conjugation between the diene and the aromatic ring
in the benzo TSs, for optimized cis and trans TSs for the IMDA
reaction of 3 (Scheme 4) are listed in Table S4. Whereas the
cis TSs suffer roughly perpendicular diene-arene angles of 103-
111°, the trans TSs benefit from substantially more conjugation
between these two groups, with dihedral angles in the 29-33°
range (Figure 6).
The relative energies of the two conformations of 1-phenyl-
1,3-butadiene were calculated to estimate the magnitude of the
stabilization enjoyed by the benzo trans TSs over the cis TSs.
The dihedral angle between the phenyl and diene groups were
set at 30° in one conformation (quasi-trans) and 112° in the
other (quasi-cis). The B3LYP/6-31+G(d) method favors the
quasi-trans conformation of 1-phenyl-1,3-butadiene over the
quasi-cis conformation by 11.7 kJ mol-1. Thus, there is
substantially more conjugative stabilization between the benzene
and diene groups in the trans TS than in the cis TS. The fact
that the calculated trans selectivities for 9-13 are generally
greater than the experimental values suggests that the DFT
calculations may be overestimating the benzo-diene conjugative
interaction energy; indeed, it is known that DFT methods tend
to overestimate the stability of conjugated systems.36,37
(37) Choi, C. H.; Kertesz, M.; Karpfen, A. Chem. Phys. Lett. 1997, 276,
266-268.
(38) (a) First report of significant rate and product selectivity improve-
ment upon the intermolecular Diels-Alder reaction by Lewis acid: Yates,
P.; Eaton, P. J. Am. Chem. Soc. 1960, 82, 4436-4437. (b) First report of
significant rate and product selectivity improvement upon the intramolecular
Diels-Alder reaction by Lewis acid: Roush, W. R.; Gillis, H. R. J. Org.
Chem. 1980, 45, 4267-4268.
(39) For an excellent discussion on Lewis acid promotion of IMDA
reactions, see ref 1f.
(40) Roush, W. R.; Gillis, H. R.; Ko, A. I. J. Am. Chem. Soc. 1982,
104, 2269-2283.
(41) Rogers, C.; Keay, B. A. Tetrahedron Lett. 1991, 32, 6477-6480.
(42) Marshall, J. A.; Audia, J. E.; Grote, J. J. Org. Chem. 1984, 49,
5277-5279.
(43) Hunt, I. R.; Rogers, C.; Woo, S.; Rauk, A.; Keay, B. A. J. Am.
Chem. Soc. 1995, 117, 1049-1056.
(44) The Supporting Information contains the yields and stereoselectivi-
ties of IMDA reactions of acrylate precursor 9 promoted by seven common
Al-based Lewis acid catalysts.
(36) Choi, C. H.; Kertesz, M.; Karpfen, A. J. Chem. Phys. 1997, 107,
6712-6721.
6106 J. Org. Chem., Vol. 71, No. 16, 2006

Intramolecular Diels-Alder Reactions
TABLE 2. Lewis Acid Promoted and Catalyzed Intramolecular Diels-Alder Reactionsa
IMDA reaction cis/trans ratio (isolated yield)
substrate
thermal
Et2AlCl-promoted
Et2AlCl-catalyzed
ATPH-promoted
4
5
6
7
8
92:8 (70%)
>99:1 (72%)
98:2 (86%)
96:4 (79%)
94:6 (50%)
>99:1 (71%)
47:53 (72%)
63:37 (89%)
23:77 (89%)
80:20 (40%)
decomposes
>99:1 (68%)
98:2 (71%)
96:4 (72%)
85:15 (63%)
>99:1 (60%)
60:40 (48%)
52:48 (81%)
22:78 (66%)
88:12 (28%)
79:21 (35%)
77:23 (71%)
58:42 (60%)
54:46 (80%)
77:23 (70%)
93:7 (90%)
3:97 (73%)
4:96 (75%)
5:95 (72%)
62:38 (60%)
78:22 (70%)
88:12 (76%)
83:17 (82%)
85:15 (54%)
70:30 (90%)
26:74 (92%)
27:73 (100%)
29:71 (96%)
24:76 (92%)
22:78 (87%)
9
10
11
12
13
a Reaction conditions: (a) 0.01 M substrate concentration in PhMe, Et2AlCl (0.95 equiv per substrate carbonyl group); (b) 0.5-1.0 M substrate concentration
in PhMe or PhCl, Et2AlCl (0.2 equiv); (c) 0.1-0.5 M substrate concentration in PhMe or PhCl, ATPH (1.5 equiv per substrate carbonyl group). For reaction
temperatures and times, see SI.
SCHEME 5. Cis/Trans IMDA Stereocontrol by Lewis Acid
Et2AlCl. The stereochemical switch is most dramatic in the case
of Z-crotonate 12 (thermal: 76% trans; Et2AlCl-promoted: 80%
Promoters According to Yamamoto47a
cis). Interestingly, fumarate 11 exhibits an essentially unaltered
trans selectivity upon promotion with Et2AlCl.
Attempts to catalyze these IMDA reactions with Et2AlCl at
10 mM initial substrate concentrations were unsuccessful, with
incomplete consumption of starting triene being witnessed.
Consistent with previous findings40 were our observations that
conversion rates of precursors invariably reflected the amount
of reagent added. Complete conversions of precursors can be
realized with substoichiometric amounts of Et2AlCl, however,
if high concentrations are employed. Routinely, 0.5 M substrate
concentrations and temperatures a little higher than those used
for the stoichiometric Et2AlCl-promoted process are necessary.45
Et2AlCl-catalyzed IMDA reactions of esters generally compare
favorably with those from Et2AlCl-promoted runs. Evidently,
a Reaction conditions: (a) Me3Al (unspecified amount), CH2Cl2, -78
to -20 °C, 75%; (b) ATPH (1.1 equiv), CH2Cl2, -78 to -20 °C, 69%.
R,â-unsaturated esters can compete with their saturated coun-
terparts for aluminum-based Lewis acids in concentrated solu-
tions. In the case of the maleate precursor 13, Et2AlCl is
effective in promoting the IMDA reaction when present in
a dramatic switch from cis to trans stereoselectivity with 1,3,9-
decatrienone 14 (Scheme 5). These very unusual outcomes are
catalytic amounts in high concentration solutions, yet the same
rationalized in terms of a destabilization of the endo TS upon
reagent (1.9 equiv) leads to substrate decomposition at high
carbonyl group complexation to Al in the deep binding pocket
of these promoters. The need for a stoichiometric quantity of
these bulky Lewis acid promoters is curious in light of the
relative Lewis base strengths of cycloadducts and precursor (vide
supra).49 To our knowledge, no other reports of ATPH, or MAD-
promoted IMDA reactions are present in the literature.
dilution!46 It is noteworthy that four of the five benzo-tethered
precursors display a shift in stereoselectivity toward the cis
cycloadduct on catalysis of the IMDA process with Et2AlCl,
as compared to the heat-promoted reaction.
ATPH-Promoted IMDA Cycloadditions. Yamamoto and
co-workers have described a very different stereochemical
outcome in the promotion of Diels-Alder reactions by the
sterically hindered Lewis acids methyl aluminum di(2,6-di-tert-
butyl-4-methylphenoxide) (MAD) and aluminum tris(2,6-diphen-
ylphenoxide) (ATPH), which encourage exo-selective intermo-
lecular Diels-Alder reactions.47,48 One example of an IMDA
reaction was also described in this elegant investigation, detailing
As can be seen by inspection of Table 2, with the non-benzo
substrates of common structure 2, ATPH generally causes a
modest shift in stereoselection toward the trans-fused product,
when compared to the thermal process.50 Unfortunately, the
switch to the trans isomer is of insufficient magnitude for the
(48) For reviews, see the following: (a) Saito, S.; Yamamoto, H. Chem.
Commun. 1997, 1585-1592. (b) Saito, S. In Main Group Metals in Organic
Synthesis; Yamamoto, H., Oshima, K., Eds.; Wiley-VCH: Weinheim,
Germany, 2004; Vol. 1, pp 189-306.
(49) We presume that ligand exchange at aluminum is either an
associative or SN2-type process, since neither would be possible with these
complexes.
(45) Control experiments demonstrated that under the conditions em-
ployed, triene conversion by way of the thermal (uncatalyzed) IMDA
reaction is negligible.
(46) These findings are consistent with an unstable 13‚2Et2AlCl complex.
(47) Maruoka, K.; Imoto, H.; Yamamoto, H. J. Am. Chem. Soc. 1994,
116, 12115-12116.
J. Org. Chem, Vol. 71, No. 16, 2006 6107

Pearson et al.
process to be synthetically useful. Non-benzo maleate 8 behaves
differently to the four other substrates in that ATPH inexplicably
promotes a more cis selective reaction of this precursor. With
the benzo substrates of common structure 3, ATPH reinforces
the inherent thermal stereoselectivity to deliver a very strongly
trans-selective IMDA reaction for unsubstituted 9 and E-
substituted trienes 10 and 11. Conversely, Z-substituted trienes
12 and 13 exhibit cis-selective IMDA reactions upon exposure
to ATPH. The results with 8, 12, and 13 are intriguing in that
inherently exo-selective processes are being made endo-selective
by ATPH, i.e., a reversal of its known function.47
Whereas a detailed analysis of the experimental findings from
Lewis acid mediated IMDA reactions are the subject of ongoing
investigations, a brief discussion is offered here. In reactions
employing Et2AlCl as catalyst or promoter, IMDA reaction cis
selectivity is enhanced because of the known endo preference
for a Lewis acid-complexed carbonyl group, in these cases the
carbonyl group of the tether. The Et2AlCl-mediated IMDA
reactions of the two fumarate substrates 6 and 11 are interesting
since the former non-benzo analogue 6 shows enhanced cis
selectivity, whereas the latter benzo analogue 11 exhibits
enhanced trans selectivity. Presumably, productive complexation
of the non-benzo fumarate substrate 6 occurs readily at the tether
carbonyl, thus promoting the formation of the cis isomer, in
line with the other substrates. The enhanced trans selectivity
for benzo substrate 11 can be explained by productive Et2AlCl
complexation at the C10 ester carbonyl group; in this case the
tether carbonyl is less Lewis basic owing to ester conjugation
with the aromatic ring. With ATPH as promoter, Yamamoto’s
steric argument holds for 7 of the 10 substrates. Of the three
exceptions, two (8 and 13) involve the maleate dienophile.
Perhaps the maleates do not follow the standard reactivity pattern
because, owing to repulsions between the C10 and C8 carbonyls,
several different conformations of similar energy are adopted
upon complexation with ATPH. A more detailed analysis of
these intriguing experimental findings will be presented in a
forthcoming report from our group.
3, π-conjugative interactions between the diene and the aromatic
ring of the tether stabilize the transition structure leading to the
trans isomer.
Major reviews of the IMDA reaction explain stereoselectivi-
ties on the basis of the location of dienophile activating groups
and their influence on bond length asynchronicities in TSs: an
activating group at the internal position was thought to give
rise to advanced peripheral bond formation and a cis-selective
IMDA reaction, whereas an activating group at the peripheral
position was thought to give rise to advanced internal bond
formation and a trans-selective IMDA reaction.1e,f In the present
study and in our earlier studies with pentadienyl acrylates3 we
find no such correlation between bond length asynchronicity
and cis/trans stereoselectivity of intramolecular Diels-Alder
reactions.
Experimental Section
General Procedure for Thermal IMDA Reactions. A stirred
5-10 mM concd solution of the triene substrate and BHT (0.05-
0.10 equiv) in PhMe, PhCl, or 1,2-Cl2C6H4 under Ar or N2 was
1
heated to reflux until H NMR analysis of the reaction mixture
indicated >95% conversion of the starting material. The solvent
was removed under reduced pressure, and product ratios were
1
determined by GC and/or H NMR analysis. The products were
separated by flash chromatography or HPLC of the crude reaction
mixture.
General Procedure for Et2AlCl-Promoted IMDA Reactions.
To a stirred 10 mM concd solution of the triene substrate in PhMe
under Ar or N2 at the temperature specified in the SI (range: 0-110
°C) was added Et2AlCl (1.8 M solution in PhMe, 0.95 or 1.90
equiv). Stirring was continued at the same temperature until analysis
indicated >95% conversion of the starting material. Saturated aq
NH4Cl was added, and the organic layer was collected, then washed
with brine, and dried over MgSO4. The solvent was removed under
reduced pressure, and product ratios were determined by GC and/
1
or H NMR analysis. Products were separated by flash chroma-
tography or HPLC of the crude reaction mixture.
General Procedure for Et2AlCl-Catalyzed IMDA Reactions.
To a degassed 0.5 or 1.0 M concd stirred solution of the triene
substrate in PhMe or PhCl under Ar or N2 at the temperature
specified in the SI (range: 80-132 °C) was added Et2AlCl (1.8 M
solution in PhMe, 0.2 equiv). Stirring was continued at the same
temperature until 1H NMR analysis indicated complete consumption
of the starting material. After the mixture was diluted with
CH2Cl2, saturated aq NH4Cl was added, and the organic layer was
collected, then washed with brine, and dried over MgSO4. The
solvent was removed under reduced pressure, and product ratios
Concluding Remarks
The first systematic survey of IMDA reactions of ester linked
decatrienes has demonstrated that substrates of general structure
2 (Scheme 2) undergo cis-selective thermal reactions, while their
benzannulated cousins of general structure 3 undergo trans-
selective thermal reactions. In most cases, the application of
Lewis acid promoters enhance the thermal process to furnish
one diastereomer in g94% stereoselectivity: with substrates of
general structure 2, a suitable Lewis acid is Et2AlCl, whereas
substrates of general structure 3 require ATPH. Under high
concentration conditions, Et2AlCl has been shown to catalyze
intramolecular Diels-Alder reactions of ester-containing sub-
strates for the first time.
The analysis of intramolecular Diels-Alder reaction transition
structures using DFT methods continues to provide important
new insights. We reaffirm the validity of the DFT method in
this paper. With substrates of general structure 2, stabilizing
secondary orbital interactions between the tether carbonyl group
and the diene operate to stabilize the transition structure leading
to the cis isomer. Conversely, with substrates of general structure
1
were determined by GC and/or H NMR analysis. Products were
separated by flash chromatography or HPLC of the crude reaction
mixture.
General Procedure for ATPH Promoted IMDA Reactions.
After Yamamoto et al.,51 to a degassed, stirred solution of 2,6-
diphenylphenol (3.0 equiv) in PhMe or PhCl at room temperature
under Ar or N2 was added dropwise AlMe3 (2.0 M in toluene, 1.0
equiv). Methane gas was immediately evolved. The resulting yellow
solution was stirred at room temperature for 1 h. To this 0.1 -0.5
M solution of ATPH (1.5 or 3.0 equiv) in PhMe or PhCl under Ar
or N2 at the temperature specified in the SI (range: 80-132 °C)
was added dropwise the triene precursor (1.0 equiv). Stirring was
continued at the same temperature until 1H NMR analysis indicated
complete consumption of the starting material. After the mixture
was diluted with CH2Cl2, saturated aq NH4Cl was added. The
organic layer was collected, washed with brine, and dried over
(50) Exposure of fumarate 6 to (PhO)3Al under conditions otherwise
identical to those used for the ATPH mediated reactions delivered a cis
85:15 trans ratio of cycloadducts; i.e., there was essentially no change from
the ratio observed for the thermal IMDA reaction.
(51) Saito, S.; Nagahara, T.; Shiozawa, M.; Nakadai, M.; Yamamoto,
H. J. Am. Chem. Soc. 2003, 125, 6200-6210.
6108 J. Org. Chem., Vol. 71, No. 16, 2006

Intramolecular Diels-Alder Reactions
MgSO4. The solvent was removed under reduced pressure, and
product ratios were determined by GC and/or H NMR analysis.
Products were separated by flash chromatography or HPLC of the
crude reaction mixture.
colorless needles: mp 85-88 °C. 1H NMR (300 MHz, CDCl3): δ
7.25-7.35 (2H, m), 7.08-7.19 (2H, m), 6.25 (1H, ddd, J ) 10.2,
4.2, 1.8 Hz), 5.97-6.04 (1H, m), 3.55 (1H, d, J ) 13.2 Hz), 2.12-
1
2.49 (4H, m) and 1.76 (1H, ddd, J ) 25.2, 12.3, 6.3 Hz) ppm. 13
C
Representative Thermal IMDA Reaction of 2((E)-Buta-1,3-
dienyl)phenyl Acrylate (9). According to the general procedure,
a solution of 9 (176 mg, 0.88 mmol) and BHT (10.0 mg, 0.04 mmol)
in toluene (100 mL) was heated at reflux for 12 h. Flash
chromatography (15 g silica gel, 1:1 CH2Cl2-hexane) gave a mixture
of the two diastereomeric adducts cis-9P and trans-9P as a colorless
oil (162 mg, 0.81 mmol, 92%, cis-9P/trans-9P ) 26:74). Separation
was performed using preparative HPLC (EtOAc-hexane 5:95).
rel 6aR,7,8,10aS-Tetrahydro-6H-dibenzo[b,d]pyran-6-one. Com-
pound cis-9P was recrystallized from CH2Cl2-hexane as colorless
NMR (125 MHz, CDCl3): δ 170.9, 151.5, 129.9, 128.2, 126.9,
124.5, 123.9, 123.0, 117.1, 40.6, 34.9, 24.7 and 22.0 ppm. IR (thin
film): V 1775, 1455, 1221, 1140, 755 cm-1. MS (200 eV, EI) m/z
(%): 200 (100) [M]+, 185 (31), 172 (41), 171 (44), 144 (86), 131
(44). Anal. Calcd for C13H12O2: C, 77.98; H, 6.04. Found: C, 77.84;
H, 6.08.
Acknowledgment. Funding from the Australian Research
Council (ARC) is gratefully acknowledged, as are generous
computing time allocations from the Australian Partnership for
Advanced Computing (APAC) and the Australian Centre for
Advanced Computing and Communications (ac3).
1
rhombs: mp 72-77 °C. H NMR (500 MHz, CDCl3): δ 7.21-
7.26 (2H, m), 7.11-7.16 (1H, m), 7.03 (1H, dd, J ) 8.4, 1.4 Hz),
5.77-5.84 (1H, m), 5.61 (1H, ddd, J ) 10.3, 4.4, 2.2 Hz), 3.68
(1H, ddd, J ) 6.3, 3.2, 3.0 Hz), 3.04-3.09 (1H, m), 2.27-2.41
(2H, m), 2.06-2.17 (1H, m) and 1.75-1.86 (1H, m) ppm. 13C NMR
(125 MHz, CDCl3): δ 170.1, 150.9, 128.9, 128.5, 128.2, 126.4,
125.9, 124.8, 117.0, 37.6, 36.3, 21.9 and 21.6 ppm. IR (thin film):
V 1759, 1230, 1132, 751 cm-1. MS (55 eV, EI) m/z (%): 200 (100)
[M]+, 171 (44), 144 (88), 131 (45). HRMS (200 eV, EI): calcd
for C13H12O2 [M]+, 200.0837; found, 200.0835.
Supporting Information Available: Synthetic procedures and
characterization details, 1H and 13C NMR spectra, thermal ellipsoid
plots for compounds cis-8P, trans-8P, cis-9P, trans-10P, trans-
11P, cis-12P, and cis-13P, the Cartesian coordinates of B3LYP/
6-31+G(d) optimized TS geometries, cis/trans ratios and energy
differences from electronic energies, enthalpies and free energies,
and geometric parameters for transition structures. This material is
available free of charge via the Internet at http://pubs.acs.org.
rel 6aR,7,8,10aR-Tetrahydro-6H-dibenzo[b,d]pyran-6-one.
Compound trans-9P was recrystallized from CH2Cl2-hexane as
JO0607818
J. Org. Chem, Vol. 71, No. 16, 2006 6109