Highly diastereoselective tandem photoenolization-hetero-Diels-Alder cycloaddition reactions of o-tolualdehydes in the solid state

Article abstract of DOI:10.1021/jo048482a

The (E)-photoenols generated in situ by photolysis of o-tolualdehydes 1-5 in the solid state react with the precursor aldehydes as dienophiles in a hetero-Diels-Alder cycloaddition fashion to afford trans-3-arylisochromanols in excellent yields and in a h

Full text of DOI:10.1021/jo048482a

Highly Diastereoselective Tandem
Photoenolization-Hetero-Diels-Alder Cycloaddition Reactions of
o-Tolualdehydes in the Solid State
Jarugu Narasimha Moorthy,*,† Prasenjit Mal,† Nidhi Singhal,†
Parthasarathi Venkatakrishnan,† Ravish Malik,† and Paloth Venugopalan*,‡
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India, and Department of
Chemistry, Panjab University, Chandigarh 160 014, India
moorthy@iitk.ac.in
Received August 30, 2004
The (E)-photoenols generated in situ by photolysis of o-tolualdehydes 1-5 in the solid state react
with the precursor aldehydes as dienophiles in a hetero-Diels-Alder cycloaddition fashion to afford
trans-3-arylisochromanols in excellent yields and in a high diastereoselectivity. An examination of
the reactivity of three different classes of rationally designed aldehydes shows that the tandem
enolization-Diels-Alder cycloaddition occurs in the solid state efficiently for aldehydes whose (E)-
photoenols (i) are more stable than their corresponding benzocyclobutenols and (ii) are not sterically
congested. However, rapid cyclization to benzocyclobutenols is found to be the sole pathway for
sterically encumbered (E)-enols derived from aldehydes 6-8. Given that the execution of
heteromolecular reactions in the solid state is a challenge, the results obtained with simple
crystalline o-tolualdehydes are remarkable and the strategy involving in situ generation of a dienol
in the crystal lattice of a dienophile to achieve hetero-Diels-Alder reaction in a highly diastereo-
selective manner is heretofore unprecedented. In the context of enormous interest in tandem/domino
reactions in contemporary synthetic organic chemistry, the results observed with o-tolualdehydes
exemplify successful execution of tandem reactions in the solid state.
Introduction
state.1a,c Insofar as homomolecular dimerizations and/or
polymerization reactions are concerned, some remarkable
strategies have been demonstrated in the literature,
particularly with regard to the photochemical transforma-
tions.1a,c,2d,3-5 However, engineering two dissimilar mol-
ecules into required proximity and orientations to effect
hetero-bi-/polymolecular reactions in the solid state is an
arduous task and is a challenge to chemists. We are
aware of a few strategies, where heteromolecular reac-
tions (thermal/photochemical) between two dissimilar
molecules have been successfully demonstrated in the
solid state. These strategies rely on (i) the use of
container molecules,6 (ii) exploitation of charge-transfer
interactions,7 (iii) formation of mixed crystals,2d and (iv)
Prohibitive motions of the molecules in the crystalline
medium exert a strict control over the reaction coordinate
of a solid-state reaction.1 Consequently, reactions in the
solid state proceed largely with a high degree of regio-
and/or stereoselectivity and also selectivity in terms of
product profile.1,2 In general, the occurrence of unimo-
lecular thermal and photochemical reactions can be
predicted a priori, as the molecules largely crystallize out
in their lowest energy conformations; the knowledge as
to the energies of various conformations can be readily
had from theoretical calculations.1b,3 On the contrary, the
proximity considerations and the relative orientations
between reacting partners hold sway in determining the
occurrence of bi-/polymolecular reactions in the solid
(4) (a) Moorthy, J. N.; Venkatesan, K.; Weiss, R. G. J. Org. Chem.
1992, 57, 3292-3297. (b) Jon, S. Y.; Ko, Y. H.; Park, S. H.; Kim, H.-J.;
Kim, K. Chem. Commun. 2001, 1938-1939. (c) Hamilton, T. D.;
Papaefstathiou, G. S.; MacGillivray, L. R. J. Am. Chem. Soc. 2002,
124, 11606-11607. (d) Friscic, T.; MacGillivray, L. R. Chem. Commun.
2003, 1306-1307. (e) Papaefstathiou, G. S.; Kipp, A. J.; MacGillivray,
L. R. Chem. Commun. 2001, 2462-2463. (f) Amirsakis, D. G.; Garcia-
Garibay, M. A.; Rowan, S. J.; Stoddart, J. F.; White, A. J. P.; Williams,
D. J. Angew. Chem., Int. Ed. 2001, 40, 4256-4261. (g) Gao, X.; Friscic,
T.; MacGillivray, L. R. Angew. Chem., Int. Ed. 2004, 43, 232-236.
(5) For solid-state Diels-Alder cycloadditions, see: (a) Kishan, K.
V. R.; Desiraju, G. R. J. Org. Chem. 1987, 52, 4640-4641. (b) Desiraju,
G. R.; Kishan, K. V. R. J. Am. Chem. Soc. 1989, 111, 4838-4843. (c)
Mikami, K.; Matsumoto, S.; Tonoi, T.; Okubo, Y.; Suenobu, T.;
Fukuzumi, S. Tetrahedron Lett. 1998, 39, 3733-3736.
† Indian Institute of Technology.
‡ Panjab University.
(1) (a) Ramamurthy, V.; Venkatesan, K. Chem. Rev. 1987, 87, 433-
481. (b) Scheffer, J. R.; Garcia-Garibay, M.; Nalamasu, O. Org.
Photochem. 1987, 8, 249-347. (c) Venkatesan, K.; Ramamurthy, V.
In Photochemistry in Organized and Constrained Media; Ramamurthy,
V., Ed.; VCH: New York, 1991; pp 133-182.
(2) (a) Ito, Y. Synthesis 1998, 8, 249-347. (b) Toda, F. Acc. Chem.
Res. 1995, 28, 480-486. (c) Gamlin, J. N.; Jones, R.; Leibovitch, M.;
Patrick, B.; Scheffer, J. R.; Trotter, J. Acc. Chem. Res. 1996, 29, 203-
209. (d) Tanaka, K.; Toda, F. Chem. Rev. 2000, 100, 1025-1074.
(3) For a recent work on unimolecular carbene rearrangements in
the solid state and predictions based on theoretical calculations, see:
(a) Garcia-Garibay, M. A.; Shin, S. H.; Sanrame, C. N. Tetrahedron,
2000, 56, 6729-6737. (b) Garcia-Garibay, M. A. Acc. Chem. Res. 2003,
36, 491-498.
(6) (a) Wernick, D. L.; Yazbek, A.; Levy, J. J. Chem. Soc., Chem.
Commun. 1990, 956-957. (b) Mir, M.; Marquet, J.; Cayon, E. Tetra-
hedron Lett. 1992, 46, 7053-7056.
10.1021/jo048482a CCC: $27.50 © 2004 American Chemical Society
Published on Web 11/04/2004
J. Org. Chem. 2004, 69, 8459-8466
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Moorthy et al.
application of porous organic materials,8 which in analogy
to the inorganic zeolites incorporate two dissimilar
molecules in their cavities and promote reactions between
them. Herein, we report an unprecedented protocol
involving in situ generation of a dienol in the crystal
lattice of a dienophile to achieve hetero-Diels-Alder
reaction in a highly diastereoselective manner; the di-
enophile is a cloaked precursor of the photoenol.
SCHEME 1
Results and Discussion
The photoenolization and photocyclization of o-alkyl-
aromatic carbonyl compounds have been well estab-
lished.9,10 The photocyclization affords benzocyclobutenols,
which serve as excellent synthetic intermediates and also
as masked dienols. The photoenolization leads directly
to 4π-dienols,9b,11 and is undoubtedly one of the syntheti-
cally very useful photoreactions, which continues to be
exploited tremendously as a key step in the total syn-
theses of complex and diverse natural products.12 The
photoenols derived from o-alkylaromatic carbonyl com-
pounds are also known to undergo cycloaddition with
heterodienophiles to afford heterocyclic systems.13 In the
past few years, we have focused our attention on the
solid-state photobehavior of o-alkylaromatic aldehydes,14
which have been explored little as compared to their
ketone counterparts. Our investigations have shown that
the relative energy differences between (E)-enols (Scheme
1) and the corresponding benzocyclobutenols determine
whether one observes the cyclization or the photo-
chromism (due to photoenols) in the solid state; the (Z)-
enols are known to be very short-lived due to rapid
thermal [1,5]-sigmatropic shift, which regenerates the
precursor carbonyl compounds.15 Further, we have found
that cyano-substitution,14b hydrogen bonding,14d and the
presence of heteroatoms as, for example, in pyridine-3-
carboxaldehydes14d stabilize the (E)-enols, while bromo-
substitution and steric crowding favor cyclization. In the
backdrop of this knowledge on the solid-state photobe-
havior of simple o-alkylaromatic aldehydes and on the
propensity of photoenols to undergo cycloadditions, we
rationally designed a set of cyano-substituted aldehydes
1-8 (Chart 1) to explore the possibility of trapping dia-
CHART 1
(7) (a) Suzuki, T.; Fukushima, T.; Yamashita, Y.; Miyashi, T. J. Am.
Chem. Soc. 1994, 116, 2793-2803. (b) Kim, J. H.; Hubig, S. M.;
Lindeman, S. V.; Kochi, J. K. J. Am. Chem. Soc. 2001, 123, 87-95. (c)
Kim, J. H.; Lindeman, S. V.; Kochi, J. K. J. Am. Chem. Soc. 2001,
123, 4951-4959. (d) Kim, J. H.; Jaung, J. Y.; Jeong, S. H. Opt. Mater.
2002, 21, 395-400.
(8) Endo, K.; Koike, T.; Sawaki, T.; Hayashida, O.; Masuda, H.;
Aoyama, Y. J. Am. Chem. Soc. 1997, 119, 4117-4122.
(9) (a) Yang, N. C.; Rivas, C. J. Am. Chem. Soc. 1961, 83, 2213. (b)
Sammes, P. G. Tetrahedron 1976, 32, 405-422. (c) Wagner, P. J.; Zepp,
R. G.; Liu, K.-C.; Thomas, M.; Lee, T.-J.; Turro, N. J. J. Am. Chem.
Soc. 1976, 98, 8125-8134. (d) Das, P. K.; Encinas, M. V.; Small, R.
D., Jr.; Scaiano, J. C. J. Am. Chem. Soc. 1979, 101, 6965-6970.
(10) For recent examples, see: (a) Wagner, P. J.; Subrahmanyam,
D.; Park, B.-S. J. Am. Chem. Soc. 1991, 113, 709-710. (b) Wagner, P.
J.; Sobczak, M.; Park, B.-S. J. Am. Chem. Soc. 1998, 120, 2488-2489.
(c) Gamarnik, A.; Johnson, B. A.; Garcia-Garibay, M. A. J. Phys. Chem.
A 1998, 102, 5491-5498. (d) Johnson, B. A.; Garcia-Garibay, M. A. J.
Am. Chem. Soc. 1999, 121, 8114-8115.
stereoselectively the persistent (E)-photoenols generated
in the solid state by the precursor aldehydes themselves
in a hetero-Diels-Alder cycloaddition fashion;16 our
preference to cyano-derivatives was based on the premise
that the cyano groups stabilize and thus increase the
lifetimes of the dienols to permit bimolecular Diels-Alder
cycloaddition reactions in competition with intramolecu-
lar cyclization to benzocyclobutenols.17 The aldehydes
1-8 may be broadly classified into three categories, viz.,
A, B and C.
Category A is made up of conformationally ill-defined
aldehydes (1-3) with no steric encumbrance to photo-
enolization. The formyl group in these aldehydes may or
may not be oriented toward the o-methyl group in the
(11) For a recent example, see: Grosch, B.; Orlebar, C. N.; Herdtweck,
E.; Massa, W.; Bach, T. Angew. Chem., Int. Ed. 2003, 42, 3693-3696.
(12) For recent examples, see: (a) Nicolaou, K. C.; Snyder, S. A.;
Montagnon, T.; Vassilikogiannakis, G. Angew. Chem., Int. Ed. 2002,
41, 1668-1698. (b) Nicolaou, K. C.; Gray, D. L. F. J. Am. Chem. Soc.
2004, 126, 607-612. (c) Ryu, D. H.; Zhou, G.; Corey, E. J. J. Am. Chem.
Soc. 2004, 126, 4800-4802. (d) Nicolaou, K. C.; Gray, D. L. F.; Tae, J.
J. Am. Chem. Soc. 2004, 126, 613-627.
(13) (a) Griesbeck, A. G.; Stadtmuller, S. Chem. Ber. 1993, 126,
2149-2150. (b) Chino, K.; Takata, T.; Endo, T. Synth. Commun. 1996,
26, 2145-2154.
(14) (a) Moorthy, J. N.; Mal, P.; Natarajan, R.; Venugopalan, P. Org.
Lett. 2001, 3, 1579-1583. (b) Moorthy, J. N.; Mal, P.; Natarajan, R.;
Venugopalan, P. J. Org. Chem. 2001, 66, 7013-7019. (c) Moorthy, J.
N.; Venkatakrishnan, P.; Mal, P.; Venugopalan, P. J. Org. Chem. 2003,
68, 327-331. (d) Mal, P.; Lourderaj, U.; Parveen; Venugopalan, P.;
Moorthy, J. N.; Sathyamurthy, N. J. Org. Chem. 2003, 68, 3446-3453.
(15) Haag, R.; Wirz, J.; Wagner, P. J. Helv. Chim. Acta 1977, 60,
2595-2607.
(16) This investigation was inspired by the observation of the
formation of a Diels-Alder adduct in a very low yield in a preliminary
study on the solid-state photochemistry of 2,6-dichloro-4-methylpyri-
dine-3-carboxaldehyde, see: Sarkar, T. K.; Ghosh, S. K.; Moorthy, J.
N.; Fang, J.-M.; Nandy, S. K.; Sathyamurthy, N.; Chakraborty, D.
Tetrahedron Lett. 2000, 41, 6909-6914.
8460 J. Org. Chem., Vol. 69, No. 24, 2004

Tandem Photoenolization-Hetero-Diels-Alder Cycloaddition
solid state. In the latter event, the γ-hydrogen abstrac-
tion, the primary photochemical event, cannot occur.
dure was employed for the preparation of 4-cyano-2,5-
dimethoxy-3,6-dimethylbenzaldehyde (5) from 1,4-di-
bromo-2,5-dimethoxy-3,6-dimethylbenzene.24 Bromina-
tion of 4-methoxy-2,6-dimethylbenzonitrile25 with 3 equiv
of NBS in acetonitrile for 48 h at room temperature
yielded 3-bromo-4-methoxy-2,6-dimethylbenzonitrile. This
bromo derivative was first reduced with DIBALH and
then subjected to cyanation to isolate 3-cyano-4-methoxy-
2,6-dimethylbenzaldehyde (6). 4-Cyano-2,3,5,6-tetrameth-
ylbenzaldehyde (7) was synthesized from 1,4-dibromo-
2,3,5,6-tetramethylbenzene26 in an analogous manner.
Synthesis of the 3,5-dicyano-2,4,6-trimethylbenzaldehyde
(8) has previously been reported by us.14b
Solid-State Photolysis and Characterization of
Photoproducts. All of the aldehydes 1-5 (categories A
and B) were found to exhibit distinct color changes upon
exposure to UV-vis radiation. While similar changes
were not readily perceptible at room temperature for
aldehydes 6-8, exposure at low temperatures (<0 °C) did
lead to a change in the color for aldehyde 8.14b The UV-
vis absorption spectra that characterize the color changes
are typically exhibited in Figure 1 for aldehydes 1 and 4
as representative cases. Orange-yellow to brick-red color
was readily observed for all of the aldehydes 1-5 upon
brief exposure to UV radiation. The long wavelength
absorption that is responsible for the observed color in
all of the cases is attributed to the formation of (E)-enol
from the respective aldehydes;14a as mentioned earlier,
the (Z)-enols are notoriously labile to permit their
characterization readily. Thus, the observation of (E)-
enols is in line with the expectation that cyano groups
influence their stabilities.
Category B is made up of conformationally predestined
aldehydes (4 and 5), whose (E)-photoenols may derive
additional stabilization via intramolecular O-H‚‚‚O hy-
drogen bonding;14a,d the formyl oxygen in the crystals of
o-anisaldehydes is known to orient away from the meth-
oxy group and toward the o-methyl group so that the
γ-hydrogen abstraction from the methyl group occurs
readily upon photolysis.
Category C is made up of conformationally predestined
and sterically encumbered aldehydes (6-8); in these
aldehydes, the conformational preference is inconsequen-
tial, as the formyl oxygen may abstract the γ-hydrogen
in both of the orientations.
Syntheses of Aldehydes 1-8. Scheme 2 shows
synthetic protocols for the preparation of aldehydes 1-7.
3-Cyano-2,5-dimethylbenzaldehyde (1) was synthesized
from the literature-known 3-bromo-2,5-dimethylbenzal-
dehyde18 by cyanation with CuCN in DMF.19 In a similar
manner, 4-cyano-2,5-dimethylbenzaldehyde (2) was pre-
pared from 4-bromo-2,5-dimethylbenzaldehyde.20 Dibro-
mination21 of m-xylene followed by controlled cyanation
with 1.2 equiv of CuCN led to isolation of 5-bromo-2,4-
dimethylbenzonitrile. This was subjected to reduction
with DIBALH, and the resulting aldehyde was cyanated
to yield 5-cyano-2,4-dimethylbenzaldehyde (3). Dibromi-
nation of 1,3-dimethoxy-2,5-dimethylbenzene22 with NBS
in CH3CN23 followed by cyanation (CuCN-DMF) led to
3-bromo-4,6-dimethoxy-2,5-dimethylbenzonitrile. Reduc-
tion of this cyano compound with DIBALH and subse-
quent cyanation with CuCN-DMF yielded 3-cyano-4,6-
dimethoxy-2,5-dimethylbenzaldehyde (4). A similar proce-
Continued irradiation of the aldehydes 1-5 was found
to result in clean products as monitored by 400-MHz 1H
NMR spectroscopy of the irradiated samples at regular
intervals. Figure 2 shows a typical spectral profile for 2
with increasing duration of irradiation (350 nm, Luzchem
photoreactor) of the crystalline samples dispersed in a
test tube under a N2 gas atmosphere. As can be seen from
1H NMR spectra, the signals corresponding to the formyl
and methyl hydrogens disappear gradually with con-
comitant appearance of the signals due to protons of the
products. Most gratifyingly, the uncomplicated 1H NMR
spectra revealed diagnostic signals in the region of ca. δ
5.0-6.5, which immediately suggested the formation of
the Diels-Alder cycloadducts (DCAs), viz., 1-isochro-
1
manols (eq 4). With the exception of aldehyde 5, the H
(17) Semiempirical AM1 calculations are known to predict reliably
the enthalpy of thermal conversion of (E)-enols to benzocyclobutenols,
see: ref 14b and the references therein. These calculations for
aldehydes 1-3 and 6-8 show that the stability of the (E)-enol in each
case is comparable to the corresponding benzocyclobutenol. In 3 and
5, the (E)-enol is much more stabilized relative to the benzocyclobutenol
due to the intramolecular O-H‚‚‚O hydrogen bond involving the
methoxy oxygen and the hydrogen of the hydroxy group of the dienol
(see category B).
NMR analyses of the irradiated samples of aldehydes
1-4 at different time intervals (at different conversions)
clearly indicated the formation of only one Diels-Alder
(18) Mitchell, R. H.; Zhang, L. J. Org. Chem. 1999, 64, 7140-7152.
(19) Friedman, L.; Shechter, H. J. Org. Chem. 1961, 26, 2522-2524.
(20) Brizius, G.; Pschirer, N. G.; Steffen, W.; Stitzer, K.; zur Loye,
H.-C.; Bunz, U. H. F. J. Am. Chem. Soc. 2000, 122, 12435-12440.
(21) Ashton, P. R.; Girreser, U.; Giuffrida, D.; Kohnke, F. H.;
Mathias, J. P.; Raymo, F. M.; Slawin, A. M. Z.; Stoddart, J. F.;
Williams, D. J. J. Am. Chem. Soc. 1993, 115, 5422-5429.
(22) Azzena, U.; Denurra, T.; Melloni, G.; Piroddi, A. M. J. Org.
Chem. 1990, 55, 5386-5390.
(24) Staab, H. A.; Rebafka, W. Chem. Ber. 1977, 110, 3333-3350.
(25) Dell’Erba, C.; Sancassan, F.; Novi, M.; Petrillo, G.; Mugnoli,
A.; Spinelli, D.; Consigilo, G.; Gatti, P. J. Org. Chem. 1988, 53, 3564-
3568.
(26) Sawatzky, H.; Wright, G. F. Can. J. Chem. 1958, 36, 1555-
1569.
(23) Carreno, M. C.; Ruano, J. L. G.; Sanz, G.; Toledo, M. A.; Urbano,
A. J. Org. Chem. 1995, 60, 5328-5331.
J. Org. Chem, Vol. 69, No. 24, 2004 8461

Moorthy et al.
SCHEME 2. Synthesis of Aldehydes 1-7
cycloadduct.27 In the former though, the Diels-Alder
adduct was found to be accompanied by benzocy-
clobutenol, as monitored by 1H NMR spectroscopy. Most
remarkably, only one of the two diastereomeric lactols
was observed predominantly in all cases, with the pres-
ence of the other diastereomer being hardly traceable.
The trans stereochemistry between the aryl and hydroxyl
groups of the lactols derived from 1 and 2 was established
by NOE experiments and also by comparison of the
spectral characteristics with analogous lactols reported
in the literature.13 A similar stereochemistry was inferred
for the lactols derived from other aldehydes 3-5 by
1
comparison of the H NMR spectral characteristics. In
contrast, all of the three sterically encumbered aldehydes
6-8 were found to undergo efficient cyclization to the
corresponding cyclobutenols (eq 4); we have previously
shown that the latter indeed derive from the precursor
(E)-photoenols via thermal conrotatory closure.14b The
isolated yields of the Diels-Alder cycloadducts from
aldehydes 1-3 (category A) were 70-90% from a pre-
parative photolysis employing ca. 100-150 mg of the
aldehyde in each case (Table 1). While one of the
dimethoxy-cyano aldehydes, i.e., 4, yielded exclusively the
(27) For comparison, the solution-state photolysis of 1 and 2 was
found to yield, as monitored by 1H NMR spectroscopy, the Diels-Alder
adduct with trans stereochemistry as a major product in each case,
which was accompanied by a variety of other products. It has been
shown that solution-state photolysis of o-tolualdehyde leads to products
resulting from intermolecular photoreductions, see: (a) Findlay, D. M.;
Tchir, M. F. J. Chem. Soc., Chem. Commun. 1974, 514-515. (b) Arnold,
B. J.; Mellows, S. M.; Sammes, P. G.; Wallace, T. W. J. Chem. Soc.,
Perkin Trans. 1 1974, 401-409.
1
DCA adduct (from 400-MHz H NMR spectroscopy), 5
was found to afford the cyclobutenol (CB) in addition to
8462 J. Org. Chem., Vol. 69, No. 24, 2004

Tandem Photoenolization-Hetero-Diels-Alder Cycloaddition
FIGURE 1. The solid-state absorption spectra of aldehydes 1 and 4 before (- - -) and after (s) brief exposure to UV radiation (λ
ca. 350 nm).
FIGURE 2. Powder XRD and 1H NMR monitoring of the tandem reaction of aldehyde 2 in the solid state with increasing durations
of irradiation: (a) 0 h; (b) 3.5 h, conversion 33%; (c) 7.0 h, conversion 50%; (d) 12.0 h, conversion 82%; (e) 20.0 h, conversion
∼100%.
TABLE 1. Results of Photolysis of Aldehydes 1-8 in the
SCHEME 3
Solid Statea,b
duration of
hν (h)
aldehyde
convc (%)
DCAd
CBd
1
2
3
4
5
6
7
8
10
10
60
12
60
19
60
24
79
82
71
90
<5
95
82
100e
>80f
85
>90
38
32
88g
89
90
90
100h
a The photolyses were carried out in a Luzchem photoreactor
fitted with UV lamps (λ ) 350 nm). b The irradiations were carried
out on ca. 100 mg scale, unless otherwise mentioned. c Based on
the recovered starting material. d Unless otherwise mentioned,
isolated yields of the products. DCA ) Diels-Alder cycloadducts;
CB ) cyclobutenols (cf. eq 4). e From 400-MHz 1H NMR spectros-
copy. f The DCA and CB were isolated as an inseparable mixture.
The relative ratios of DCA and CB were obtained from the
integrals of the characteristic signals in the 1H NMR spectrum of
the mixture. g Regioisomeric mixture, see text. h From ref 14b.
mixture. All of the sterically hindered aldehydes 6-8
(category C) yielded the benzocyclobutenols in excellent
yields (88-100%). In the case of 6, an inseparable
regioisomeric mixture of benzocyclobutenols was isolated.
Mechanistic Rationalizations. The formation of
bimolecular Diels-Alder adducts (DCAs) may, in prin-
ciple, occur by either of the two following mechanisms:
First, the photoenolization via intramolecular γ-hydrogen
abstraction from the o-methyl group by the triplet-excited
formyl oxygen followed by trapping of the persistent (E)-
enol with the precursor aldehyde in a hetero-Diels-Alder
cycloaddition fashion may lead to DCA (Scheme 3).9,10
Second, the intermolecular hydrogen abstraction by the
the Diels-Alder cycloadduct. The two products were
isolated as an inseparable mixture and their relative ratio
(55:45 for DCA:CB) was deduced from the integrals of
the characteristic signals in the 1H NMR spectrum of the
J. Org. Chem, Vol. 69, No. 24, 2004 8463

Moorthy et al.
SCHEME 4
(Scheme 3). Figure 4 shows the crystal packing diagrams
for aldehydes 2 and 5. Both of the aldehydes crystallize
with about a 4.0 Å short a-axis corresponding to plane-
to-plane aromatic stacking. From the crystal packing
analysis, it is not readily explicable as to how the DCA
adducts with anti stereochemistry may result after
photoenolization. The fact that the Diels-Alder reaction
between translationally related molecules along the
a-axis does not occur is suggested by the anti stereo-
chemistry observed with the bimolecular adducts. The
contact distances between the reaction sites of the
molecules in the bc-plane are very large (>6.0 Å), and
this necessitates large-scale motions in the crystal lattice
to afford the product with anti stereochemistry.
triplet-excited carbonyl from the o-methyl group of a
neighboring aldehyde and subsequent coupling of the
resulting radicals may lead to a hydroxy aldehyde, which
may lactonize (Scheme 4).28
To rationalize the observed photochemical results in
the light of crystal packing, the X-ray crystal structures
of one aldehyde each of the two categories A and B, i.e.,
2 and 5, were determined; the X-ray crystal structure of
8 (category C) has previously been reported.14b In Figure
3 are exhibited the molecular structures of 2 and 5; the
The formation of (E)-enols via the initially generated
triplet-excited twisted biradical10c necessitates a confor-
mational change, which must be permitted in the crystal
lattices of the aldehydes. Besides, the bimolecular trap-
ping of the dienol by a dienophile can result in further
reorganization of atomic positions. As a result, one may
anticipate that the occurrence of a tandem reaction could
disrupt the crystal lattice. Figure 2 shows the powder
XRD profile typically recorded for aldehyde 2 with
increasing conversions. As can be seen from the powder
X-ray diffraction patterns, the crystallinity is conserved
up to ca. 50% conversion of the aldehyde, which suggests
that the crystal lattice in the aldehydes is tolerant to
large-scale motions to afford the adducts with anti
stereochemistry. However, with a further increase in the
conversion, the crystallinity is gradually lost. The sample
becomes entirely amorphous at 100% conversion. The
product formation at low conversions is evidently con-
trolled by crystal lattice forces; indeed, the photolysis of
the amorphous sample of 2 obtained from quenching of
the melt led to observation of a substantial amount of
the acid (ca. 30%) in addition to the DCA adduct under
N2 atmosphere, which suggests that the mobility of O2
in the crystals is restricted for oxidation.30 The efficient
formation selectively of the same product at high conver-
sions, in the absence of any lattice effects, is remarkable
and must be construed as resulting from a highly efficient
reaction proceeding under solvent-free conditions with
astounding selectivity.31 This also suggests that the
longer lifetimes of the (E)-enols cause the bimolecular
reaction to be more efficient, while the thermal intramo-
lecular cyclization to benzocyclobutenols becomes disfa-
vored due to lesser stability of the cyclobutenols relative
to the corresponding (E)-enols.32 A reason for the ob-
served exo selectivity of the Diels-Alder cycloaddition
should be traceable to steric factors in the transition state
for endo cycloaddition. Notably, even the solution-state
FIGURE 3. The X-ray molecular structures of the aldehydes
2 and 5. Note that the oxygen and nitrogen atoms of CHO and
CN groups are disordered in both cases with an occupancy
factor of 0.5 for each. The hydrogens that may be abstracted
by the formyl oxygens after photoexcitation are shown by a
thick broken line.
oxygen and nitrogen atoms of CHO and CN groups are
disordered in both cases with an occupancy factor of 0.5
for each. In both cases, the orientation of the formyl
oxygen is ideally suited for γ-hydrogen abstraction from
the o-methyl groups, a prerequisite for photochemical
reactivity, to afford o-xylylenols.29 Thus, the structural
studies show that the photoenolization may proceed
strictly in a topochemical fashion in both cases; we believe
that the formyl oxygen orients toward the o-methyl group
in the crystals of 1, 3, and 4 as well, otherwise the color
due to the formation of photoenols would not be observed.
The topochemical formation of photoenols (as revealed
by structural analysis) in conjunction with UV-vis
spectral characterization of the (E)-photoenols attest to
the fact that the formation of Diels-Alder cycloadducts
occurs via the trapping of dienols, generated in situ, by
the precursor aldehydes in their respective crystal lattices
(30) In a similar manner, the photolysis of the amorphous powder
of the aldehyde 1 yielded anti DCA adduct together with small amounts
of syn adduct as well as the acid, as monitored by 400-MHz spectros-
copy.
(31) The irradiation carried out typically for aldehydes 1 and 2 in
melt (ca. 130 °C) led predominantly to the corresponding acids even
under O2-excluded conditions. It appears that aldehydes undergo facile
oxidation at high temperatures even with trace amounts of O2 present.
(32) The competitive formation of benzocyclobutenol in the case of
5 may be a result of a smaller reaction cavity (see: Weiss, R. G.;
Ramamurthy, V.; Hammond, G. S. Acc. Chem. Res. 1993, 26, 530-
536) in the crystal lattice, which causes the bimolecular trapping
reaction to occur rather sluggishly. The calculated densities (from X-ray
studies) of the crystals of 2 (1.215 g/cm3) and 5 (1.301 g/cm3) suggest
that the molecules in the latter are more tightly packed.
(28) Intermolecular hydrogen abstractions from the methyl groups
attached to the arene rings are known. For example, the solid-state
photolysis of 4,4′-dimethylbenzophenones is known to yield intermo-
lecular coupling products arising from hydrogen abstraction from the
methyl groups, see: Ito, Y.; Matsuura, T.; Tabata, K.; Ji-Ben, M.;
Fukuyama, K.; Sasaki, M.; Okada, S. Tetrahedron 1987, 43, 1307-
1312.
(29) The calculated geometrical parameters for hydrogen abstraction
in both cases fall in good agreement with the values generally observed,
see: Ihmels, H.; Scheffer, J. R. Tetrahedron 1999, 55, 885-907.
8464 J. Org. Chem., Vol. 69, No. 24, 2004

Tandem Photoenolization-Hetero-Diels-Alder Cycloaddition
FIGURE 4. The crystal packing diagrams of aldehydes 2 (left) and 5 (right) viewed down the short (ca. 4.0 Å) a-axis. The blue
and red atoms correspond to disordered positions of nitrogen and oxygen atoms of the CHO and CN groups with an occupancy
factor of 0.5 for each.
photolysis is found to afford selectively the exo addition
product in addition to a variety of other products.27
Why do aldehydes 6-8 of category C undergo cycliza-
tion efficiently? As mentioned at the outset, the (E)-enols
derived from these aldehydes are highly sterically en-
cumbered. Indeed, it is known that the steric hindrance
in dienols promotes cyclization.33 Evidently, the dienols
do not survive long enough to be trapped intermolecu-
larly. It is noteworthy that even stabilization of the
dienols through dicyano substitution has no effect on
diverting the unimolecular reactivity. As mentioned
earlier, we have previously shown that the dicyano
aldehyde 8 does produce the colored dienols when pho-
tolysis is carried out at low temperature.14b However, the
thermal activation at room temperature is high enough
to enforce cyclization and obviate UV-vis spectral detec-
tion of the former. It is precisely for this reason that
simple o-alkyl aromatic ketones do not readily lend
themselves to the phenomenon of photochromism based
on photoenolization being observed in the solid state. The
fleeting existence of the photoenols in these cases, due
to steric factors that promote cyclization, presumably
prevents any bimolecular chemistry from being competi-
tively observed. This is a clear illustration of how the
photochemistry of o-alkyl aromatic aldehydes can be at
so much of a variance with that of the analogous ketones.
for sterically encumbered (E)-enols derived from alde-
hydes such as 6-8. Given that the execution of hetero-
molecular reactions in the solid state is a challenge, the
strategy involving the in situ generation of a dienol in
the crystal lattice of a dienophile so that the Diels-Alder
reaction occurs readily is conceptually different from
those that rely on host-guest chemistry, charge-transfer
complexation, and mixed crystal formation. Further, from
the point of view of enormous interest in tandem/cascade/
domino34 reactions in the contemporary organic synthe-
sis, the results reported herein exemplify successful
execution of tandem reactions in the solid state.
Experimental Section
The details of synthesis and characterization data for all of
the aldehydes 1-7 and the photoproducts have been provided
in the Supporting Information.
Photolysis Procedure and Characterization of Prod-
ucts. The gently ground crystalline sample of an aldehyde was
dispersed in a Pyrex test tube and subjected to photolysis,
under N2 gas, in a Luzchem reactor fitted with 350-nm lamps.
The sample was kept rotated over a turntable during the
photolysis. The irradiated samples were analyzed at regular
1
intervals by H NMR spectroscopy by dissolving the photoly-
sate in either CDCl3 or DMSO-d6. In preparative scale pho-
tolysis, ca. 100 mg of each of the aldehydes was irradiated for
the durations specified in Table 1, and the reaction mixture
was subjected to column chromatography on neutral alumina
(eluent: 25% EtOAc in petroleum ether) to isolate the pure
products. The characterization data are given below for two
representative cases.
Conclusions
We have shown that the (E)-enols generated in the
solid state by the photolysis of crystalline o-alkyl aro-
matic aldehydes (cloaked dienols) react with the precur-
sor aldehydes within the crystal lattice in a hetero-Diels-
Alder cycloaddition fashion to afford trans-3-aryl-
isochromanols in excellent isolated yields with a high
diastereoselectivity. An examination of the reactivity of
three different classes of aldehydes shows that the
tandem enolization-Diels-Alder cycloaddition occurs
efficiently for aldehydes whose (i) photoenols are more
stable relative to their benzocyclobutenols and (ii) are not
sterically congested. However, rapid cyclization to ben-
zocyclobutenols is found to be the predominant pathway
1-DCA: Colorless powder, mp 210 °C dec; IR (KBr) 3315,
2926, 2226 cm-1 1H NMR (DMSO-d6, 400 MHz) δ 2.340 (s,
;
3H), 2.344 (s, 3H), 2.51 (s, 3H), 2.95-3.05 (m, 2H), 5.37 (dd,
1H, J1 ) 8.5 Hz, J2 ) 5.8 Hz), 5.97 (d, 1H, J ) 6.1 Hz), 7.14
(d, 1H, J ) 5.9 Hz), 7.45 (s, 1H), 7.59 (s, 1H), 7.63 (s, 1H), 7.67
(s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 16.6, 20.3, 20.4, 31.8,
64.2, 90.8, 111.2, 112.7, 117.5, 118.6, 132.2, 132.4, 132.8, 133.1,
134.6, 136.3, 136.8, 137.0, 137.2, 140.5. FAB-MS 319 (M + H),
301, 287, 279, 214, 179, 157.
7-CB: Colorless solid, mp 154-156 °C; IR (KBr) 3263, 2923,
2214 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.19 (s, 3H), 2.29 (s,
3H), 2.40 (s, 3H), 2.89 (d, 1H, J ) 14.2 Hz), 3.48 (dd, 1H, J1 )
14.3 Hz, J2 ) 4.4 Hz), 5.25 (s, 1H); 13C NMR (CDCl3, 100 MHz)
(33) (a) Matsuura, T.; Kitaura, Y. Tetrahedron Lett. 1967, 8, 3309-
3310. (b) Kitaura, Y.; Matsuura, T. Tetrahedron 1971, 27, 1597-1606.
(34) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115-136. (b) Winkler, J.
D. Chem. Rev. 1996, 96, 167-176.
J. Org. Chem, Vol. 69, No. 24, 2004 8465

Moorthy et al.
δ 13.9, 15.7, 17.9, 40.0, 69.6, 113.9, 118.0, 130.1, 134.8, 138.1,
Supporting Information Available: The synthesis of all
aldehydes 1-7, characterization data for all of the (i) inter-
mediates, (ii) aldehydes 1-7, and (iii) photoproducts, and
crystallographic data for aldehydes 2 and 5. This material is
available free of charge via the Internet at http://pubs.acs.org.
140.6, 150.3.
Acknowledgment. We thank the Department of
Science and Technology (DST), India for financial sup-
port. P.M., N.S. and P.V. are grateful to CSIR for
research fellowships. Thanks are also due to anonymous
referees for their invaluable suggestions.
JO048482A
8466 J. Org. Chem., Vol. 69, No. 24, 2004