Contrasteric Diels-Alder reactions of 5-methyl-5-phenylcyclopentadiene

Article abstract of DOI:10.1016/j.tetlet.2008.01.045

The frontier molecular orbital of 5-phenylcyclopentadiene was predicted on the basis of the orbital mixing rule to deform to favor the Diels-Alder reaction in a syn contrasteric manner. The prediction was substantiated experimentally by the reactions of 5

Full text of DOI:10.1016/j.tetlet.2008.01.045

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1804–1807
Contrasteric Diels–Alder reactions of 5-methyl-5-
phenylcyclopentadiene
Masaru Ishida *, Makoto Itakura, Hiroshi Tashiro
Department of Chemistry, Faculty of Engineering, Gifu University, Yanagido 1-1, Gifu 501-1193, Japan
Received 10 November 2007; revised 26 December 2007; accepted 10 January 2008
Available online 15 January 2008
Abstract
The frontier molecular orbital of 5-phenylcyclopentadiene was predicted on the basis of the orbital mixing rule to deform to favor the
Diels–Alder reaction in a syn contrasteric manner. The prediction was substantiated experimentally by the reactions of 5-methyl-5-
phenylcyclopentadiene with dienophiles to afford the syn attack products, exclusively.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords: Cyclopentadienes; Diels–Alder reactions; Frontier molecular orbital; Facial selectivities; Substituent effects
Control of the p-facial selectivity in the Diels–Alder
reactions of 5-substituted cyclopentadienes has been one
of the most fundamental subjects of organic chemistry.1
The dienes can react at either face. anti p-Facial selectivity
with respect to the substituents has been attributed to steric
hindrance due to the substituents at the syn attack transi-
tion states. The reactions of 5-alkylcyclopentadienes were
typical examples.2 However, the cyclopentadienes having
smaller heteroatom substituents such as amino,3a acet-
oxy,3b hydroxyl,3a,c methoxy,3a,d fluoro,3e and chloro3a,f–h
moieties at the 5-positions were found to react with dieno-
philes in a syn contrasteric manner (see Scheme 1).
There had been proposed some stereoelectronic pheno-
mena due to heteroatoms in substituents as the origin of
the selectivity. These include beneficial interaction of the
antisymmetric oxygen orbital with the LUMO of dieno-
philes by Anh for 5-acetoxycyclopentadiene,4a electrostatic
interaction of electrophilic dienophiles with the more
nucleophilic diene face, syn to ‘a lone-pair-containing sub-
stituent’, by Kahn and Hehre,4b transition state hypercon-
jugative stabilization (Cieplak-effect) by Macaulay and
Dienophiles
X
H
X
X
X= NH2, OH, OAc, OCH3, F, Cl
syn contrasteric
Scheme 1.
Fallis,3a,5 and the frontier orbital deformation by Inagaki
and Fukui.6 This latter proposed that unsymmetrical
deformation of the frontier molecular orbital (FMO) of
the dienes with respect to the p-plane is the major contri-
butor to the selectivity. The orbital mixing rule can predict
the deformation. On the basis of the orbital mixing rule, we
successfully predicted and designed the p-facial selectivity
in the reactions of various cyclopentadiene having various
substituents such as SR, SeR, TeR, COOR, COOH,
CONH2, CHO, CH@NOH, CH@CH2, and 2-oxazolynyl
moiety at the 5-position.5a,7a–h The next task is to avoid
the factors due to the heteroatoms in the substituents. In
this Letter we will show the extensive application of the
theory by designing a heteroatom-free 5-substituted cyclo-
pentadiene, which reacted in a contrasteric fashion, over-
whelming the steric hindrance due to the substituent.
*
Corresponding author. Tel.: +81 58 293 2613; fax: +81 58 230 1893.
E-mail address: m_ishida@gifu-u.ac.jp (M. Ishida).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.01.045

M. Ishida et al. / Tetrahedron Letters 49 (2008) 1804–1807
1805
H
1
x=0.950Å (inside of C1)
x=1.330Å (outside of C1)
z
y
As the first candidate of such a diene, 5-phenylcyclo-
pentadiene 1 was selected, since the phenyl moiety of diene
1 can mediate orbital mixing through its degenerated
x
C1
p
Ph-HOMO’s almost independently on the conformation
H
around the phenyl moiety. The deformation of the FMO
is predicted as follows. When the phenyl moiety lies in
the plane of symmetry perpendicular to the cyclopentadi-
ene p-plane (hereinafter referred to as a bisected conforma-
tion, 1b), the symmetric pPh-HOMO(S) mediates the mixing.
The pHOMO of the diene combines with the low-lying
1
p
Ph-HOMO(S) out of phase and mixes the low-lying r-orbital
z=-1.020Å (anti-side of Ph) z=1.020Å (syn-side of Ph)
of carbon framework out of phase with the pPh-HOMO(S). As
the result, the mixing of the pHOMO and the r-system of the
diene is perturbed by the low-lying pPh-HOMO(S) in such a
way that both diene orbitals contribute to the FMO in
an out of phase manner relative to mediated orbital
˚
Fig. 2. Contour maps of the sections (x = 0.950,1.330, and z = 1.020 A)
of the FMO of diene 1b at the RHF/6-31G* level (Cs). The Cp ring and the
phenyl moiety are in xy and yz planes, respectively. C1 and C4 carbons are
˚
on the x-axis at the space coordinates (A) of (1.174,00) and (ꢀ1.17400),
respectively. The absolute value of the largest contour line is
5.0 ꢁ 10ꢀ3 AU. The heights of adjacent contours differ by a factor 2.0.
pPh-HOMO(S). The FMO extends and distorts inwardly to
favor the reaction on the syn side of the phenyl moiety
(Fig. 1a: W (FMO) = pHOMO ꢀ pPh-HOMO(S) + r). When
0
the phenyl moiety rotates by 90° around C5–C1 bond from
the bisected conformation (hereinafter referred to a
horizontal conformation 1h), the asymmetric pPh-HOMO(A)
similarly mediates the mixing (Fig. 1b: W(FMO) =
pHOMO ꢀ pPh-HOMO(A) + r).
πHOMO
The prediction was briefly examined by ab initio mole-
cular orbital calculation at the RHF/6-31G* level.8 The
bisected conformer 1b was fully optimized to be a Cs
symmetric structure as the global minimum. The nonequiv-
alency of the FMO was confirmed based on contour maps
(Fig. 2).9 Small contours of the highest absolute value
(-)
πPh-HOMO
A
S
(-)
πPh-HOMO
σ
˚
appeared in the map of the section of x = 0.950 A (inside
of C1) and X = 1.330 A (outside of C1) at syn and anti sides
(-): out of phase
˚
Favor
of phenyl moiety, respectively. The highest contours of the
˚
sections of z = 1.020 A appeared at the syn side of the
H
phenyl moiety but not in the anti side. The FMO of 1b does
distort inwardly and extends at the syn side of the phenyl
moiety.
The molecular geometry of the horizontal conformer 1h
was similarly optimized by fixing the phenyl moiety to lie in
an orthogonal plane with respect to the plane of symmetry
perpendicular to the cyclopentadiene. Conformer 1h is the
transition state for rotation of the phenyl moiety around
≡
H
Ψ(FMO)= πHOMO - πPh-HOMO(S)+ σ
H
1b
(a) Orbital mixing mediated by πPh-HOMO(S)
Favor
0
H
the C5–C1 bond and less stable than 1b by 3.4 kcal/mol.
The contour maps of the FMO showed small contours of
the highest absolute value in the maps of the section of
≡
H
H
˚
˚
x = ꢀ0.905 and 1.420 A and z = 1.121 A at the syn side
of the phenyl moiety, but not in the map of the section
Ψ(FMO)= πHOMO - πPh-HOMO(A)+ σ
1h
˚
of z = ꢀ1.121 A (Fig. 3). The FMO dose extent at the
(b) Orbital mixing mediated by πPh-HOMO(A)
syn side of phenyl moiety, although distortion is not clearly
confirmed.10
Fig. 1. Deformation of the FMO of 5-phenylcyclopentadiene.

1806
M. Ishida et al. / Tetrahedron Letters 49 (2008) 1804–1807
Table 1
Diels–Alder reactions of 2 with dienophiles
Dienophile
CCl4
O
Y
syn attack
2
x=0.905Å (inside of C1)
x=1.420Å (outside of C1)
z
O
y
3a,b
Diene
Dienophile Products
Selectivitya syn/anti
x
2
PMI
MA
3a (Y = NPh)
3b (Y = O)
100:0
100:0
C-1
H
1h
PMI
PMI
30c, 40c (X@CH@CH2) 34:66b,c
40d (X@CH@O) 0:100b,d
X
a
The reactions proceeded quantitatively.
b
X
X
z=-1.121Å (anti-side of Ph) z=1.121Å (syn-side of Ph)
O
O
˚
Fig. 3. Contour maps of the sections (x = 0.905, 1.420, and z = 1.121 A)
of the FMO of the fixed conformer 1h at the RHF/6-31G* level (Cs). The
Cp ring is in xy plane. C1 and C4 carbons are on the x-axis at the space
NPh
NPh
syn attack
˚
anti attack
coordinates (A) of (1.173,0,0) and (ꢀ1.173,0,0), respectively. The
O
O
absolute value of the largest contour line is 5.0 ꢁ 10ꢀ3 AU. The heights
3'c
4'c,d
of adjacent contours differ by a factor 2.0.
c
See Ref. 7f.
See Refs. 7f and 16.
d
O
O
HO
OH
In conclusion, orbital effects designed on the basis of the
orbital mixing rule can overcome the steric effects due to
substituents.17 Further applications of the reactions
designed by this concept are now in progress.
98%
iii
TsO
OTs
ii
Acknowledgments
75%
2: 59%
We thank Professor Satoshi Inagaki for fruitful discus-
sions and helpful suggestions. We also thank Professor
Hiroaki Wasada for helpful suggestions and for providing
the software for drawing contour maps.
Scheme 2. Preparation of 5-methyl-5-phenylcyclopentadiene 2. Reagents:
(i) NaBH4/MeOH; (ii) TsCl, DMAP/pyridine; (iii) DBU/toluene.
Encouraged by these calculations, the prediction was
examined experimentally. To avoid complication due to
[1,5] hydrogen rearrangement, 5-methyl-5-phenylcyclo-
pentadiene 211,12 was prepared from 2-methyl-2-phenyl-
cyclopentane-1,3-dione13 in 43% total yield (Scheme 2).
The reactions of diene 2 with dienophiles N-phenylmale-
imide (PMI) and maleic anhydride (MA) were performed
at 25 °C in carbon tetrachloride (0.5 M) under nitrogen
atmosphere. The reactions were followed by TLC. After
completion of the reactions, the solvent was removed and
References and notes
1. Reviews: (a) Ishida, M.; Inagaki, S. J. Synth. Org. Chem. Jpn. 1994,
52, 649–657; (b) Ohwada, T. Chem. Rev. 1999, 99, 1337–1375; (c)
Cieplak, A. S. Chem. Rev. 1999, 99, 1265–1336; (d) Fallis, A. G.; Lu,
Y.-F. In Advances in Cycloaddition; Curran, D. P., Ed.; JAI Press:
Greenwich, CT, 1993; Vol. 3, pp 1–66.
2. Letourneau, J. E.; Wellman, M. A.; Burnell, D. J. J. Org. Chem. 1997,
62, 7272–7277.
3. (a) Macaulay, J. B.; Fallis, A. G. J. Am. Chem. Soc. 1990, 112, 1136–
1144; (b) Winstein, S.; Shatavsky, M.; Norton, C.; Woodward, A. B.
J. Am. Chem. Soc. 1955, 77, 4183–4184; (c) Jones, D. W. J. Chem.
Soc., Chem. Commun. 1980, 739–740; (d) Burry, L. C.; Bridson, J. N.;
Burnell, D. J. J. Org. Chem. 1995, 60, 5931–5934; (e) McClinton, M.
A.; Sik, V. J. Chem. Soc., Perkin Trans. 1 1992, 1891–1895; (f)
Wellman, M. A.; Burry, L. C.; Letourneau, J. E.; Bridson, J. N.;
Miller, D. O.; Burnell, D. J. J. Org. Chem. 1997, 62, 939–946; (g)
Williamson, K. L.; Hsu, Y.-F. L.; Lacko, R.; Youn, C. H. J. Am.
1
the residues were subjected to H NMR to show exclusive
formation of syn attack products, 3a and 3b, respectively
(Table 1).14,15 These results are in contrast with the anti
p-facial selectivity observed in the reactions of the cyclo-
pentadiene derivatives having smaller substituents such as
vinyl and formyl moieties at the 5-positions.7f,16

M. Ishida et al. / Tetrahedron Letters 49 (2008) 1804–1807
1807
Chem. Soc. 1969, 91, 6129–6138; (h) Williamson, K. L.; Hsu, Y.-F. L.
J. Am. Chem. Soc. 1970, 92, 7385–7389.
the CH@CH protons at d 6.41. No NOE was observed between the
methyl protons at d 1.24 and the methyne protons at d 3.49–3.51. 13
C
4. (a) Anh, N. T. Tetrahedron 1973, 29, 3227–3232; (b) Kahn, S. D.;
Hehre, W. J. J. Am. Chem. Soc. 1987, 109, 663–666.
5. There have been some arguments against the proposal: (a) Ishida, M.;
Aoyama, T.; Beniya, Y.; Yamabe, S.; Kato, S.; Inagaki, S. Bull.
Chem. Soc. Jpn. 1993, 66, 3430–3439; (b) Werstiuk, N. H.; Ma, J.
Can. J. Chem. 1994, 72, 2493–2505.
NMR (100 MHz, CDCl3) d 23.4, 46.5, 52.4, 72.1, 125.3, 127.0, 129.3,
134.6, 144.4, 171.6; HRMS calcd for C16H14O3 254.0943; found
254.0946.
15. Following the suggestion made by one reviewer, the transition states
for the reaction between diene 2 and maleic anhydride were calculated
at the RHF/6-31G* level. The results were confirmed by IRC
calculations at the same level. The syn attack transition states
TSsyn-endo and TSsyn-exo are Cs-symmetric. The phenyl moieties of syn
attack transition states are in horizontal conformation similar to
1h. The anti attack transition states TSanti-endo and TSanti-exo are
C1-symmetric. Relative energies of TSsyn-endo, TSsyn-exo, TSanti-endo, and
TSanti-exo were 0.0, 9.3, 4.2, and 14.4 kcal/mol, respectively. These
results are well consistent with the observation.
6. Inagaki, S.; Fujimoto, H.; Fukui, K. J. Am. Chem. Soc. 1976, 98,
4054–4061.
7. (a) Ishida, M.; Aoyama, T.; Kato, S. Chem. Lett. 1989, 663–666; (b)
Ishida, M.; Beniya, Y.; Inagaki, S.; Kato, S. J. Am. Chem. Soc. 1990,
112, 8980–8982; (c) Ishida, M.; Kakita, S.; Inagaki, S. Chem. Lett.
1995, 469–470; (d) Ishida, M.; Tomohiro, S.; Shimizu, M.; Inagaki, S.
Chem. Lett. 1995, 739–740; (e) Ishida, M.; Kobayashi, H.; Tomohiro,
S.; Wasada, H.; Inagaki, S. Chem. Lett. 1998, 41–42; (f) Ishida, M.;
Kobayashi, H.; Tomohiro, S.; Inagaki, S. J. Chem. Soc., Perkin
Trans. 2 2000, 1625–1630; (g) Ishida, M.; Sakamoto, M.; Hattori, H.;
Shimizu, M.; Inagaki, S. Tetrahedron Lett. 2001, 42, 3471–3474; (h)
Ishida, M.; Hirasawa, S.; Inagaki, S. Tetrahedron Lett. 2003, 44,
2187–2190.
8. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, Jr., J. A.;
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.; Baboul, A. G.; 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.; Challacombe, M.; Gill, P. M. W.; Johnson, B.;
Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez, C.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. GAUSSIAN 98, Revision A.9, Gaussian:
Pittsburgh, PA, 1998.
TSsyn-endo
TSsyn-exo
9. Wasada, H.; Tsutsui, Y. Bull. Fac. Gen. Edu., Gifu Univ. 1996, 33,
145–158.
10. Lack of distortion is probably due to lack of contribution of the p-
component of the r-system of the diene framework to the orbital
mixing. The overlap between pPh-HOMO(A) and the p-component of the
r-system is much less effective than that between pPh-HOMO(A) and the
s-component in 1h.
11. Preparation of 5-methyl-5-phenylcyclopentadiene 2 by other proce-
dures was reported: Eilbracht, P.; Dahler, P. Liebigs Ann. Chem. 1979,
1890–1907.
12. Diels–Alder reactions of 5,5-diarylcyclopentadienes: 5-Aryl-5-phenyl-
cyclopentadienes: (a) Halterman, R. L.; McCarthy, B. A.; McEvoy,
M. A. J. Org. Chem. 1992, 57, 5585–5589; Cyclopentadienes bearing a
benzofluorene in spiro geometry: (b) Tsuji, M.; Ohwada, T.; Shudo,
K. Tetrahedron Lett. 1998, 39, 403–406; Cyclopentadienes bearing a
fluorene in spiro geometry: (c) Igarashi, H.; Sakamoto, S.; Yama-
guchi, K.; Ohwada, T. Tetrahedron Lett. 2001, 42, 5257–5260.
13. Jenkins, T. J.; Burnell, D. J. J. Org. Chem. 1994, 59, 1485–
1491.
TSanti-endo
TSanti-exo
16. Adam, W.; Jacob, U.; Prein, M. J. Chem. Soc., Chem. Commun. 1995,
839–840.
17. p–p Interaction between a dienophile and the phenyl moiety of diene 2
was suggested as a possible explanation for the observed selectivity by
one reviewer. This explanation seemed to be less likely since the
interaction destabilizes syn attack transition states due to the out of
phase relationship between pꢂdienophile and pPh-HOMO(A). The interac-
tion can be the origin of the selectivity of 5-aryl-5-phenylcyclopent-
adiene to favor the reactions on the anti side of more electron rich
aromatic system.12a The selectivity is consistꢂent with the approach of
0
reactants to avoid the interaction between pdienophile and pPh-HOMOðAÞ
of more electron rich aromatic system.
dienophile
dienophile
14. Selected spectroscopic data: Compound 3a: mp 181.3–182.6 °C
(colorless solid from hexane–AcOEt). 1H NMR (400 MHz, CDCl3)
d 1.26 (s, 3H, Me), 3.37–3.39 (m, 2H, CH), 3.74 (s, 2H, CH), 6.36 (t,
J = 2.0 Hz, 2H, CH@CH), 7.08–7.48 (m, 10H, Ph). Compound 3a
displayed 3.3% of NOE between the methyl protons at d 1.26 and the
CH@CH protons at d 6.36. No NOE was observed between the
Ph-HOMO(A)
Ph-HOMO(A)
(-)
methyl protons at d 1.26 and the methyne protons at d 3.37–3.39. 13
C
NMR (100 MHz, CDCl3) d 23.7, 45.1, 51.9, 71.3, 125.6, 126.6, 126.8,
128.6, 129.1, 131.8, 133.6, 145.0, 177.1; HRMS calcd for C22H19NO2
329.1416; found 329.1407. Compound 3b: mp 134.6–135.6 °C
(colorless solid from hexane–AcOEt). 1H NMR (400 MHz, CDCl3)
d 1.24 (s, 3H, Me), 3.49–3.51 (m, 2H, CH), 3.72 (s, 2H, CH), 6.41 (t,
J = 2.0 Hz, 2H, CH), 7.20–7.39 (m, 5H, Ph). Compound 3b
displayed 4.7% of NOE between the methyl protons at d 1.24 and
HOMO
HOMO
Ph-HOMO(A)'
More electron rich
aromatic system
Ph
Ph Ar