Concerning the reactivity of ptad with isomeric dienes: The mechanism of the Diels-Alder cycloaddition

Article abstract of DOI:10.1021/ol900363n

Cyclopropyl substituted dienes are employed as mechanistic probes in the triazolinedione Diels-Alder (DA) reaction. In aprotic and protic solvents, apart from the DA adducts that bear an intact cyclopropyl group, complicated and rearranged products are also obtained. These results provide solid evidence for the involvement of an open intermediate with a lifetime greater than 2 x 10 ^-12 s.

Full text of DOI:10.1021/ol900363n

ORGANIC
LETTERS
2009
Vol. 11, No. 7
1659-1662
Concerning the Reactivity of PTAD with
Isomeric Dienes: The Mechanism of the
Diels-Alder Cycloaddition
Mariza N. Alberti and Michael Orfanopoulos*
Department of Chemistry, UniVersity of Crete, 71003 Voutes, Heraklion, Crete, Greece
orfanop@chemistry.uoc.gr
Received February 19, 2009
ABSTRACT
Cyclopropyl substituted dienes are employed as mechanistic probes in the triazolinedione Diels-Alder (DA) reaction. In aprotic and protic
solvents, apart from the DA adducts that bear an intact cyclopropyl group, complicated and rearranged products are also obtained. These
results provide solid evidence for the involvement of an open intermediate with a lifetime greater than 2 × 10-12 s.
Triazolinedione (RTAD, R ) M for methyl and R ) P for
phenyl) is a strong electron acceptor and one of the most
powerful enophiles as well as dienophiles.1 RTADs afford
ene products (N-allylurazoles)2 or [2 + 2] adducts (1,2-
diazetidines)3,4 with alkenes and undergo DA reactions with
conjugated dienes.4,5 The latter class of reactions is useful
in characterizing dienes,6 protecting diene moieties,7 isolating
dienes from complex reaction mixtures,8 and trapping
unstable or volatile intermediates.9
The stereochemistry of the DA adducts from the reaction
of RTAD with substituted 1,3-butadienes10 is consistent with
both concerted and stepwise mechanisms, depending on the
substituents. For example, the addition of PTAD to the (E,E)-
or (Z,E)-2,4-hexadiene was stereospecific according to the
Woodward-Hoffmann rules, whereas reactions of RTAD
with (Z,Z)-2,4-hexadiene and (Z,Z)-1,4-di-tert-butoxy-1,3-
butadiene showed a lack of stereospecificity. Moreover, when
RTAD reactions with the aforementioned substrates were
(1) (a) Moody, C. J. AdV. Heterocycl. Chem. 1982, 30, 1–45. (b) Radl,
S. AdV. Heterocycl. Chem. 1996, 67, 119–205.
(2) Vougioukalakis, G. C.; Orfanopoulos, M. Synlett 2005, 713–731,
and references therein.
(3) (a) Kim, D. K.; O’Shea, K. E. J. Am. Chem. Soc. 2004, 126, 700–
701. (b) Sivaguru, J.; Poon, T.; Hooper, C.; Saito, H.; Solomon, M. R.;
Jockusch, S.; Adam, W.; Inoue, Y.; Turro, N. J. Tetrahedron 2006, 62,
(7) (a) Barton, D. H. R.; Gunatilaka, A. A. L.; Nakanishi, T.; Patin, H.;
Widdowson, D. A.; Worth, B. R. J. Chem. Soc., Perkin Trans. 1 1976,
821–826. (b) Yakhimovich, R. I.; Fursaeva, N. F.; Pashinnik, V. E. Chem.
Nat. Prod. 1985, 21, 98–103.
10647–10659
.
(4) (a) Fischer, T.; Kunz, U.; Lackie, S. E.; Cohrs, C.; Palmer, D. D.;
Christl, M. Angew. Chem., Int. Ed. 2002, 41, 2969–2971. (b) Paquette, L. A.;
Webber, P.; Simpson, I. Org. Lett. 2003, 5, 177–180
.
(8) Poutsma, M. L.; Ibarbia, P. A. J. Am. Chem. Soc. 1971, 93, 440–
450.
(5) (a) Adam, W.; Gla¨ser, J.; Peters, K.; Prein, M. J. Am. Chem. Soc.
1995, 117, 9190–9193. (b) Fujita, M.; Matsushima, H.; Sugimura, T.; Tai,
(9) Henderson, A. P.; Mutlu, E.; Leclercq, A.; Bleasdale, C.; Clegg,
W.; Henderson, R. A.; Golding, B. T. Chem. Commun. 2002, 1956–1957.
(10) (a) Jensen, F.; Foote, C. S. J. Am. Chem. Soc. 1987, 109, 6376–
6385. (b) Clennan, E. L.; Earlywine, A. D. J. Am. Chem. Soc. 1987, 109,
7104–7110.
A.; Okuyama, T. J. Am. Chem. Soc. 2001, 123, 2946–2957
.
(6) (a) Kobal, V. M.; Gibson, D. T.; Davies, R. E.; Garza, A. J. Am.
Chem. Soc. 1973, 95, 4420–4421. (b) Hoffman, K.-L.; Maas, G.; Regitz,
M. J. Org. Chem. 1987, 52, 3851–3857.
10.1021/ol900363n CCC: $40.75
Published on Web 03/12/2009
2009 American Chemical Society

carried out in MeOH or acetone, the proposed aziridinium
imide intermediate (AI; b, Scheme 1) was trappable affording
2,2-diphenylcyclopropylcarbinyl radical (1b) rearranges rap-
idly with experimental rate constant of 5 × 1011 s-1 at rt.16
This probe is often used as a radical clock17 to quantify a
radical lifetime.
Scheme 1
.
Stepwise and Concerted Mechanistic Pathways for
the Triazolinedione DA Reaction
In the present work, the cyclopropyl substituted dienes Z-3
and E/Z-3 were prepared (Scheme 2).18 Notably, we were
Scheme 2
the corresponding MeOH insertion adducts. Generally, it was
concluded that dienes, which cannot easily adopt the s-cis
conformation, react via a stepwise mechanism involving the
formation of an AI intermediate in equilibrium with a 1,4-
biradical or 1,4-dipolar (a or c, Scheme 1).11 On the other
hand, when the s-cis conformation of the diene moiety is not
sterically precluded, a concerted mechanism is favored.10a,12
Likewise, theoretical calculations with RTADs indicated that
both concerted (with a highly asynchronous transition state
d, Scheme 1) and stepwise pathways may occur, depending
on the diene structure.12b,13
Our research aim was to reinvestigate the mechanism of
this classical DA reaction between RTAD and dienes. The
main focus was to ascertain precisely the possible involve-
ment of an open biradical/dipolar intermediate in the title
reaction. For this purpose, we used highly informative
substrates which bear the 2,2-diphenylcyclopropyl group as
a mechanistic probe. It is noteworthy that substituted
cyclopropyl groups have been used as traps for other radical
intermediates,14 since they involve the rapid rearrangement
of the cyclopropylcarbinyl radical (1a) to homoallylcarbinyl
radical (2a) (eq 1).15 Newcomb and co-workers reported that
a Determined by the NMR integration of the proper hydrogen signals
of the crude reaction mixture. b Ratio was found to be temperature
independent. c Mixture of two isomers E/Z ) 30/70. d Yield determined
based on mass isolated product (purified by column chromatography).
Similar results obtained when MTAD was used as dienophile. e Reaction
was performed in the presence of 50 equiv of MeOH. f Unreacted diene
was mainly the Z-isomer.
able to isolate the Z-3 from the E/Z-3 mixture by the
exclusive reaction of tetracyanoethylene (TCNE) with the
E-3 isomer.19 Initially, we carried out the RTAD (1.1 equiv)
reactions with E/Z-3 at 0 °C (or rt). When the reaction solvent
was CHCl3, apart from the formation of unidentified prod-
ucts, the unrearranged DA adduct 4 (R ) Me) or 5 (R )
Ph) was detected (entry 1, Scheme 2). Interestingly, when
the same reaction was conducted in the presence of 50 equiv
of MeOH, compounds 4, E-6a,b, (E,E)-7 and anti-8 were
obtained as the only products (entry 2). The anti-configu-
ration of adduct 8 was confirmed by NOE experiments.18
The above-mentioned four products were also observed when
MeOH was used as a solvent (entry 3). In a similar manner,
(11) For a stepwise mechanism, see also: (a) Yamada, S.; Hamado, K.;
Shimizu, M. Tetrahedron Lett. 1991, 32, 2379–2382. (b) Stratakis, M.;
Hatzimarinaki, M.; Froudakis, G. E.; Orfanopoulos, M. J. Org. Chem. 2001,
66, 3682–3687.
(12) For a concerted mechanism, see also: (a) Laila, A. J. Prakt. Chem.
1995, 655–658. (b) Singleton, D. A.; Schulmeier, B. E.; Hang, C.; Thomas,
A. A.; Leung, S.-W.; Merrigan, S. R. Tetrahedron 2001, 57, 5149–5160.
(c) Roa, R.; O’Shea, K. E. Tetrahedron 2006, 62, 10700–10708
(13) Chen, J. S.; Houk, K. N.; Foote, C. S. J. Am. Chem. Soc. 1998,
120, 12303–12309. (b) Alajar´ın, M.; Cabrera, J.; Pastor, A.; Sa´nchez-
.
Andrada, P.; Bautista, D. J. Org. Chem. 2008, 73, 963–973
.
(14) (a) Hatzimarinaki, M.; Roubelakis, M. M.; Orfanopoulos, M. J. Am.
Chem. Soc. 2005, 127, 14182–14183. (b) Milnes, K. K.; Jennings, M. C.;
Baines, K. M. J. Am. Chem. Soc. 2006, 128, 2491–2501. (c) Alberti, M. N.;
Orfanopoulos, M. Org. Lett. 2008, 10, 2465–2468.
(16) Newcomb, M.; Johnson, C. C.; Manek, M. B.; Varick, T. R. J. Am.
Chem. Soc. 1992, 114, 10915–10921.
(17) Griller, D.; Ingold, K. U. Acc. Chem. Res. 1980, 13, 317–323.
(15) Newcomb, M.; Glenn, A. G. J. Am. Chem. Soc. 1989, 111, 275–
277.
(18) For details, see the Supporting Information.
(19) O’Shea, K. E.; Foote, C. S. Tetrahedron Lett. 1990, 31, 841–844.
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Org. Lett., Vol. 11, No. 7, 2009

the reactions of PTAD with Z-3 in CHCl3 and MeOH were
studied. When the reaction solvent was CHCl3, only uni-
dentified products were formed. Alternatively, when the
reaction was carried out in MeOH, solvent-trapped products
E-6a,b, (E,E)-7 and anti-8 were obtained in almost quantita-
tive yield (entry 5).
bisadduct anti-8 (isolated yield >90%). In case of a concerted
[4 + 2] addition, the syn-8 would have been expected. This
result indicates that the reaction proceeds via an open polarized
biradical or dipolar intermediate I4 as shown in Scheme 3.
Despite these interesting findings, the existence of an
intermediate in the triazolinedione DA reaction in nonpolar
solvents with a diene, which can easily adopt the s-cis
conformation, remains particularly elusive. To shed more light
on this issue, we synthesized and assayed the less-substituted
dienes (Z,E)-9 and (E,E)/(Z,E)-9 (Scheme 4).18 Unlike substrate
Examining the results of the PTAD addition to dienes Z-3
and E/Z-3 in CHCl3, the unidentified products (most probably
polymeric materials) are plausibly formed through an open
polarized biradical/dipolar intermediate. This is evident by the
fact that, in the PTAD reaction with diene E/Z-3, a small amount
of MeOH admixed to CHCl3 intercepted the open intermediate
forming the MeOH-trapped products and minimizing the
amount of polymeric materials (compare entries 1 and 2).
Moreover, because the PTAD reaction with diene Z-3 in CHCl3
furnished only unidentified products (entry 4), it is obvious that
product 4 is exclusively formed from diene E-3 (entry 1).
The formation of MeOH-trapped adducts [E-6a,b, (E,E)-7
and anti-8] doubtlessly points to the existence of an open
polarized biradical or dipolar intermediate. The possible mech-
anism that could account for their formation is outlined in
Scheme 3. There are two distinct possibilities depending on
Scheme 4
Scheme 3. Plausible Mechanism for the Formation of
MeOH-Trapped Products 6, (E,E)-7 and anti-8
a Determined by the NMR integration of the proper hydrogen signals
of the crude reaction mixture. b Ratio was found to be temperature
independent. c Mixture of two isomers (E,E)/(Z,E) ) 35/65. d Unreacted
diene was mainly the (Z,E)-isomer. e Reaction was performed in the presence
of 50 equiv of MeOH. f Only two diastereoisomers were formed.
3, diene 9 bears one alkyl substituent on each double bond
carbon C1 and C4, correspondingly. In the trasition state, both
double bonds are almost electronically equivalent and therefore
equally competitive for the RTAD addition. In the case of an
open biradical/dipolar intermediate, a secondary radical/car-
bocation in both C1 and C4 carbons would be formed. This
intermediate is expected to form products derived from both
sides of the diene moiety.
The reactions of PTAD (1.1 equiv) with (E,E)/(Z,E)-9 at 0
°C (or rt) were initially studied. When CHCl3 was the reaction
solvent, four DA adducts 10 and four rearranged PTAD-
bisadducts 11 were isolated and characterized (entry 1, Scheme
4). Noteworthy, when the same reaction was conducted in the
presence of 50 equiv MeOH in CHCl3, DA adducts 10 (four
stereoisomers) and rearranged MeOH-trapped adducts anti-12
(two stereoisomers) were isolated (entry 2). These six products
were also detected when MeOH was used as a solvent (entry
3). Likewise, the reactions of PTAD with (Z,E)-9 in CHCl3
and MeOH were studied. When the reaction solvent was CHCl3,
two stereoisomers of 10 and four stereoisomers of 11 were
detected (entry 4). According to previous studies,10 we expected
which carbon atom the enophile is added to. The addition of
PTAD at C1 furnishes the open intermediate I1. Subsequently,
the tertiary polarized radical or carbocation (at C4) is trapped
by MeOH affording product 6. An intact cyclopropyl moiety
in the product is expected in this case, as found. Alternatively,
the addition of PTAD at C4 affords the open intermediate I2.
Notably, the lifetime of I2 must be greater than 2 × 10-12 s (at
rt), which is the lifetime of 2,2-diphenylcyclopropylcarbinyl
radical.16 Thus, the initially formed secondary polarized radical
or carbocation (at C1) undergoes ring opening to the more stable
dibenzyl polarized biradical or dipolar intermediate I3. Then,
I3 is trapped by MeOH forming the observed product (E,E)-7.
This diene further reacts with another molecule of PTAD to
form stereospecifically the anti-8 adduct. To confirm the
formation of anti-8 from the precursor (E,E)-7, the reaction of
the isolated (E,E)-7 with PTAD in CHCl3 was studied. Indeed,
compound (E,E)-7 afforded the thermodynamically more stable
Org. Lett., Vol. 11, No. 7, 2009
1661

to observe the exclusive formation of DA adducts 10 with an
anti-configuration. Suprisingly, (Z,E)-9 gave a mixture of two
stereoisomers of 10 (85:15); the major and minor isomers had
the anti- and syn-configuration, respectively. The stereochem-
istry of these products was confirmed by NOE experiments.18
Moreover, when we used 0.8 equiv of PTAD, the same
products, mentioned above, were obtained. Attempts to isolate
any rearranged PTAD-monoadduct were unsuccessful. Ulti-
mately, when the reaction was carried out in MeOH apart from
the formation of DA-adducts 10 (both anti- and syn-stereoiso-
mers), two rearranged MeOH-trapped adducts anti-12 were also
isolated (entry 5). It is noteworthy that in this case no rearranged
PTAD-bisadducts 11 were formed.
Scheme 5
.
Plausible Mechanism for the Formation of Products
10a-d, 11a-d and anti-12a,b
Due to the fact that three stereogenic centers are present in
compound 11, a maximum of eight stereoisomers (four enan-
tiomeric pairs of diastereomers) are expected to be formed.
Gratifyingly, we were able to separate these diastereomers,
namely 11a-d, by flash column chromatography. This separa-
tion was crucial since our goal was to precisely elucidate the
structure of compound 11. The structure was established through
various 1D/2D NMR techniques as well as ESI-MS spectros-
copy.18 Efforts to crystallize compounds 11a-d were unsuc-
cessful.
Since the reaction of PTAD with diene (Z,E)-9 in both CHCl3
and MeOH solvents furnished an anti- and a syn-stereoisomer
of product 10, it is obvious that the other two diastereomers
(an anti and a syn) are exclusively formed from diene (E,E)-9.
Because these reactions proceeded without stereospecificity
(predicted for a concerted DA reaction according to symmetry
orbital rules), we strongly suggest that DA adducts 10a-d are
formed via an open polarized biradical or dipolar intermediate
I5 (Scheme 5). Additionally, cyclopropyl rearranged compounds
11a-d and anti-12a,b are derived from an open polarized
biradical or dipolar intermediate. A plausible mechanism that
could account for the formation of these products is represented
in Scheme 5. In particular, the addition of PTAD at C4 affords
an open intermediate I6, with a lifetime greater than 2 × 10-12
s (at rt).16 As expected, this intermediate rapidly undergoes ring
opening leading to the more stable dibenzyl polarized radical
or cation intermediate I7. At this point, there are two possibilities
depending on the reaction solvent. In CHCl3, this intermediate
can undergo intramolecular cyclization to yield rearranged
PTAD-monoadduct 13. Then, a second molecule of PTAD is
added regioselectively through a [2 + 2] cycloaddition to the
C3-C4 double bond of 13 forming compounds 11a-d. On
the other hand, when the reaction solvent is MeOH, intermediate
I7 is trapped by one molecule of the solvent forming the
rearranged product 14. Ultimately, a second molecule of PTAD
is added stereoselectively through a [4 + 2] cycloaddition
furnishing two anti-stereoisomers anti-12a,b.
ucts.2,20 In our case, due most probably to steric interactions,
no ene adducts were observed. Alternatively, an extended
tandem sequence of 1,4-dipolar cycloaddition of PTAD to
(E,E)/(Z,E)-9, cyclopropyl rearrangement, cyclization and
then [2 + 2] cycloaddition of PTAD to the C3-C4 double
bond of 13 are likely to occur as found.
In conclusion, a hypersensitive mechanistic probe was used
for the investigation of a triazolinedione DA reaction with
simple acyclic dienes in both aprotic and protic solvents. The
lack of [4 + 2] stereoselectivity in nonpolar solvents (for the
diene 9) as well as the formation of cyclopropyl rearranged
PTAD-bisadducts and MeOH-trapped products provide strong
evidence for the involvement of an open polarized biradical or
dipolar intermediate in the aforementioned reaction. The lifetime
of this intermediate is estimated to be greater than 2 × 10-12 s.
Acknowledgment. We thank Mrs. Francesca Sweeney at
University of Crete for valuable comments and discussions.
The project was cofunded by the European Social Fund and
National Resources (Pythagoras II 2005).
Supporting Information Available: Detailed experimen-
tal procedures, spectral data, 1D and 2D NMR spectra. This
material is available free of charge via the Internet at
http://pubs.acs.org.
As already mentioned, compound 13 could not be isolated.
Moreover, due to steric hindrance the C3-C4 double bond of
13 is more accessible than the C5-C6. Two possible pathways
for the PTAD addition to the C3-C4 double bond of 13 could
be considered: (a) through an ene reaction and (b) via a [2 +
2] cycloaddition. It is generally accepted that the RTAD ene
reaction proceeds via the rate-limiting formation of an AI
intermediate (b, Scheme 1) which leads directly to ene prod-
OL900363N
(20) (a) Smonou, I.; Khan, S.; Foote, C. S.; Elemes, Y.; Mavridis, I. M.;
Pantidou, A.; Orfanopoulos, M. J. Am. Chem. Soc. 1995, 117, 7081–7087.
(b) Vougioukalakis, G. C.; Roubelakis, M. M.; Alberti, M. N.; Orfanopoulos,
M. Chem. Eur. J. 2008, 14, 9697–9705
.
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