Mechanism leading to the observed product of intramolecular aryl Diels-Alder reaction

Article abstract of DOI:10.1016/S0040-4039(02)01012-2

A mechanistic investigation into the recently reported intramolecular aryl Diels-Alder reaction was carried out using deuterium labeling. These studies led to the conclusion that the initial Diels-Alder adduct is isomerized to a highly conjugated tetra-ene intermediate which undergoes a stereospecific suprafacial 1,5-dienyl hydrogen shift to give the observed product.

Full text of DOI:10.1016/S0040-4039(02)01012-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 5101–5103
Mechanism leading to the observed product of intramolecular
aryl Diels–Alder reaction
Samuel Chackalamannil,* Dar´ıo Doller and Keith Eagen
Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, NJ 07033, USA
Received 25 February 2002; accepted 24 May 2002
Abstract—A mechanistic investigation into the recently reported intramolecular aryl Diels–Alder reaction was carried out using
deuterium labeling. These studies led to the conclusion that the initial Diels–Alder adduct is isomerized to a highly conjugated
tetra-ene intermediate which undergoes a stereospecific suprafacial 1,5-dienyl hydrogen shift to give the observed product. © 2002
Elsevier Science Ltd. All rights reserved.
We have recently reported1 a novel intramolecular aryl
Diels–Alder reaction (IMDA) that leads to the
stereospecific formation of D9,9a dihydronaphthofuran-
one 1a (Scheme 1).2 The reaction is general to a
variety of substrates, proceeds in good yields, and can
be performed on a 100 g scale. In all cases, a single
diastereomer of the product was isolated with exclusive
presence of the double bond at the C9–C9a position.
This remarkable diastereoselectivity evoked our curios-
ity into the mechanism of this reaction. Particularly
noticeable was the absence of any of the isomeric
products corresponding to structures 1b or 1c, although
ab initio calculations3 suggested an order of stability
1b>1c>1a.
ing deuterium labeled precursors. These studies con-
vincingly prove that the initial intramolecular
Diels–Alder adduct 3 undergoes a double bond isomer-
ization to give the intermediate 18 followed by a
stereospecific 1,5-dienyl proton transfer to give the
observed product 1a (Scheme 4).
The deuterium labeled IMDA precursors were synthe-
sized as shown in Scheme 2 in an overall yield ranging
from 50 to 60%. Reaction of commercially available
benzaldehyde-a-d1 (4) with tert-butyl dimethylphospho-
noacetate under basic conditions yielded the tert-butyl
D
O
O
D
D
In this communication, we wish to report the results of
mechanistic studies conducted on the intramolecular
Diels–Alder reactions of propargyl cinnamates employ-
t-BuOOC
b, c
a
O
O
5
CO2Bn
D
4
6
H
H
D
D
O
D
D
t-BuOOC
a
D
D
D
D
b, c
O
O
O
O
H
O
195°C
D
D
H
D
D
D
o-Xylene
D
H
8
CO2Bn
CO2Bn
9
2
7
CO2Bn
O
t-BuOOC
3
b, c
d
O
O
8
O
9
O
O
O
H
D
9a
3a
9a
3a
1
D
O
O
11
3a
10
4
4a
5
4a
CO2Bn
3
12
H
CO2Bn
1a (57%)
CO2Bn
1b (not formed)
CO2Bn
1c (not formed)
Scheme 2. Reagents and conditions: (a) (MeO)2P(O)-
CH2CO2Bu-tert, n-BuLi–hexane, THF, 0°C; (b) (i) TFA,
CH2Cl2; (ii) (COCl)2, DMF (cat.), CH2Cl2, rt; (c) Et3N,
HOCH2CCCO2Bn (13), CH2Cl2, 0°C; (d) (MeO)2P(O)CD2-
CO2Bu-tert (14),5 n-BuLi–hexane, THF, 0°C.
Scheme 1. Intramolecular aryl Diels–Alder reaction.
* Corresponding author.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)01012-2

5102
S. Chackalamannil et al. / Tetrahedron Letters 43 (2002) 5101–5103
cinnamate 5 which was transformed to the Diels–Alder
precursor 6 by acid mediated hydrolysis followed by
esterification with propargylic alcohol 13.1 Similarly,
the precursor 9, labeled with deuterium in the benzene
ring, was prepared from benzaldehyde-2,3,4,5,6-d5 (7).4
Using a similar sequence, the a-deuterated cinnamate
precursor 12 was synthesized from benzaldehyde and
deuterated phosphonate 14.5
O
O
H
O
O
195°C
9a
o-Xylene
4
H
H+
CO2Bn
CO2Bn
2
3
O
O
O
1,5-suprafacial
H shift
O
The results of the intramolecular aryl Diels–Alder reac-
tion studies are shown in Scheme 3. Thermal cyclization
of deuterium-labeled precursor 6 in o-xylene at 195°C
gave tricyclic derivative 15 in 48% yield with complete
retention of deuterium at C9 as indicated by the proton
NMR and mass spectral data. Cyclization of the d5-
labeled precursor 9 under similar conditions gave a
single dihydronaphthofuranone 16 which retained all
five deuterium atoms according to mass spectroscopic
H
H
CO2Bn
CO2Bn
1a
18
O
O
O
O
H
1,3-H shift
3
disallowed
H
H
H+
CO2Bn
CO2Bn
17
1a
1
data and showed a remarkably simple H NMR spec-
Scheme 4. Mechanism of intramolecular aryl Diels–Alder
trum in the aliphatic region with a pair of doublets at
4.04 and 4.64 ppm corresponding to the C3 protons and
a singlet at 3.86 ppm corresponding to the C4 benzylic
methine proton (Scheme 3).6 The multiplet correspond-
ing to the C3a methine proton at 3.60–3.70 ppm, present
in the dihydronaphthofuranone 1a (Scheme 1), was
reaction.
product (16) was isolated and it contained complete
incorporation of deuterium at C3a which suggests a
highly efficient intramolecular transfer of deuterium
from C4a to C3a.
1
totally absent in the H NMR spectrum7 of tricyclic
derivative 16. Under identical conditions, cyclization of
a-deutero-cinnamate 12 gave approximately a 1:1 mix-
ture of tricyclic compounds 1a and 17, indicating par-
tial incorporation of deuterium at C4.
Based on the above observations, we propose the fol-
lowing mechanism outlined in Scheme 4 for the
intramolecular aryl Diels–Alder reaction. The initial
intramolecular Diels–Alder adduct 3 undergoes a dou-
ble bond isomerization7 to give the highly conjugated
tetra-ene derivative 18 which subsequently undergoes a
stereospecific 1,5-dienyl suprafacial proton shift8 to give
the observed product 1a. Under these circumstances,
one would expect a deuterium label at C9a of intermedi-
ate 3 to be completely lost into the reaction medium
and be partially incorporated at C4. In fact, the
intramolecular Diels–Alder cyclization of the a-deuter-
ated cinnamate 12 further lends credence to this mecha-
nism (Scheme 3). When the reaction is carried out in
o-xylene, about 50% of the deuterium that was present
a-to the carbonyl group of cinnamate 12 was incorpo-
rated at C4. An alternative mechanism involving C4a–
C3a suprafacial 1,3-hydrogen shift of intermediate 3
(Scheme 4) is ruled out since it is a symmetry-forbidden
thermal process.9 The highly stereospecific nature of
deuterium transfer from C4a to C3a of intermediate 3
also rules out a diradical mechanism.
The following conclusions can be made based on the
above observations. First, the total lack of deuterium
exchange or scrambling for the cyclization of precursor
6 to the tricyclic product 15 (Scheme 3) rules out a
sequential double bond isomerization of the initial
Diels–Alder adduct 3 to 1a, via the intermediates 1c
and 1b (Scheme 1), that necessarily involves at least
partial loss of deuterium label at C9. The outcome of
the cyclization of the d5-labeled precursor 9 is more
revealing. Only
a
single dihydronaphthofuranone
D
O
O
O
O
D
9
195°C
o-Xylene
H
15
CO2Bn
D
6
COOMe
D
O
O
O
195°C
D
D
Although it is likely that the relative stereochemistry at
C4 of the final product 1a is under thermodynamic
control, C4 axial protonation of the enolate of 3
(Scheme 4) should also yield the thermodynamically
stable, equatorially substituted carboxylic ester.
Cyclization of the unlabeled precursor 2 in the presence
of trace amounts of deuterium oxide in xylene gave
about 50% incorporation of deuterium at C4 suggesting
proton exchange between this center and the solvent
during the reaction (Scheme 5). However, when cyclized
product 1a was subjected to identical reaction condi-
tions in the presence of deuterium oxide, it did not
undergo any deuterium exchange suggesting the ther-
modynamic stability of the equatorial carboxylic ester.
O
3a
4a
4
o-Xylene
D
D
D
3
D
D
D
CO2Bn
CO2Bn
16
9
O
O
O
O
195°C
X
D
o-Xylene
H
COOMe
CO2Bn
17 X = D
1a X = H 1a:17 = ca. 1:1
12
Scheme 3.

S. Chackalamannil et al. / Tetrahedron Letters 43 (2002) 5101–5103
5103
O
O
2. (a) Roush, W. R. In Comprehensive Organic Synthesis;
Trost, B. M.; Fleming, I., Eds.; Pergamon Press: Oxford,
1991; Vol. 4, p. 513; (b) Ciganek, E. In Organic Reac-
tions; Dauben, W. G., Ed.; John Wiley & Sons: New
York, 1984; Vol. 32, p. 1; (c) Craig, D. Chem. Soc. Rev.
1987, 16, 87; (d) Weinreb, S. W. Acc. Chem. Res. 1985,
18, 16.
3. Ab initio calculations using full DF(B3LYP) optimization
were carried out on the tert-butyl esters corresponding to
compounds 1a, 1b and 1c, giving heats of formation of
−601741.55403, −601743.25662 and −601741.66614 kcal/
mol, respectively. According to this calculation, the tert-
butyl ester corresponding to 1b is 1.70259 kcal/mol more
stable than tert-butyl ester corresponding to 1a, and the
tert-butyl ester corresponding to 1c is 0.11211 kcal/mol
more stable than the tert-butyl ester corresponding to 1a.
The choice of tert-butyl ester was made to reduce calcu-
lation time. Similar calculations performed on the corre-
sponding ethyl esters also showed the same trend of
relative stability.
O
O
195°C
X
o-Xylene
D2O
4a
H
CO2Bn
2
CO2Bn
1a X = H
17 X = D
1a:17 = ca 1:1
O
O
195°C
O
O
o-Xylene
D2O
H
H
CO2Bn
CO2Bn
1a
1a
No D incorporation
O
O
O
195°C
D
O
D
o-Xylene,
H2O
H
H
CO2Bn
CO2Bn
17
No change in percent of D
4. Although only the ortho protons of cinnamate 2 (Scheme
1) are of interest from a mechanistic standpoint, we used
2,3,4,5,6-d5 labeled benzaldehyde 7 due to its commercial
availability.
Scheme 5. External deuterium incorporation studies.
Additionally, when the C4 deuterated tricyclic deriva-
tive 17 was subjected to the intramolecular Diels–Alder
reaction conditions in the presence of trace amounts of
water (Scheme 5), no change in the percentage of
deuterium at C4 was noted, which further corroborated
the stability of the equatorially oriented carboxylic ester
at C4.
5. (a) Seguineau, P.; Villieras, J. Tetrahedron Lett. 1998, 29,
477; (b) Bergen, H. R.; Furr, H. C.; Olson, J. A. J.
Labeled Compd. Radiopharm. 1988, 25, 11.
6. Physical data 1a: 1H NMR (400 MHz, CDCl3) l 3.60–
3.70 (m, 1H), 3.86 (d, J=15.0 Hz, 1H), 4.04 (t, J=9.0
Hz, 1H), 4.64 (t, J=9.0 Hz, 1H), 5.28 (d, J=12.0 Hz,
1H), 5.38 (d, J=12.0 Hz, 1H), 7.16–7.21 (m, 2H), 7.29–
7.45 (m, 8H); IR (neat) 1785, 1735 cm−1; MS (ESI) m/e
321 (M+H)+. 9: 1H NMR (400 MHz, CDCl3) l 4.93 (s,
2H), 5.22 (s, 2H), 6.44 (d, J=16.0 Hz, 1H), 7.38 (m, 5H),
7.75 (d, J=16.0 Hz, 1H); HRMS (FAB) calcd for
In summary, we have established a plausible mecha-
nism of the intramolecular aryl Diels–Alder reaction
that accounts for the observed product, using deu-
terium labeling. The initial cycloadduct 3 undergoes a
double bond isomerization to give the tetra-ene inter-
mediate 18 which undergoes a stereospecific 1,5-
suprafacial dienyl hydrogen shift to give dihydro-
naphthofuranone 1a (Scheme 4).
C20H12D5O4 (M+H)+ m/e 326.1441, found m/e 326.1442.
1
16: H NMR (400 MHz, CDCl3) l 3.86 (s, 1H), 4.04 (d,
J=9.0 Hz, 1H), 4.64 (d, J=9.0 Hz, 1H), 5.37 (d, J=12.1
Hz, 1H), 5.43 (d, J=12.1 Hz, 1H), 7.49 (m, 6H). HRMS
(FAB) calcd for C20H12D5O4 (M+H)+ m/e 326.1441,
found m/e 326.1440.
Acknowledgements
7. The double bond isomerization which occurs prior to
aromatization is likely to be facilitated by the high acidity
of C9a proton and the highly conjugated nature of the
resultant tetra-ene intermediate 18.
8. (a) Jiao, H.; Schleyer, P. v. R. J. Chem. Soc., Faraday
Trans. 1994, 90, 1559; (b) Doering, W. v. E.; Roth, W.
R.; Breuckmann, R.; Figge, L.; Lennartz, H.-W.; Fessner,
W. D.; Prinzbach, H. Chem. Ber.-Recueil 1998, 121, 1; (c)
Jensen, F.; Houk, K. N. J. Am. Chem. Soc. 1987, 109,
3139.
The authors would like to thank Drs. Ashit K. Gan-
guly, Michael Czarniecki, and William J. Greenlee for
helpful discussions. We also thank Dr. Vincent
Madison and Dr. Jose Duca for molecular modeling
studies and Dr. Pradip Das for mass spectral data.
References
9. (a) Berson, J. A. Acc. Chem. Res. 1972, 5, 406; (b)
Woodward, R. B.; Hoffman, R. The Conservation of
Orbital Symmetry; Academic Press: New York, NY,
1970.
1. Chackalamannil, S.; Doller, D.; Clasby, M.; Xia, Y.;
Eagen, K.; Lin, Y.; Tsai, H.-A.; McPhail, A. T. Tetra-
hedron Lett. 2000, 41, 4043.