Cationic iron(III) porphyrin-catalyzed [4 + 2] cycloaddition of unactivated aldehydes with simple dienes

Article abstract of DOI:10.1021/ja300790x

Cationic iron(III) porphyrin was found to be an efficient catalyst for the highly chemoselective hetero-Diels-Alder-type reaction of aldehydes with 1,3-dienes. The catalyzed process did not require the use of electron-deficient aldehydes such as glyoxylic acid derivatives or activated electron-rich 1,3-dienes such as Danishefsky's diene and Rawal's diene. The high functional group tolerance and robustness of the catalyst were demonstrated. Further, the potential utility of the catalyst was demonstrated by performing the cycloaddition in the presence of water and by carrying out cycloaddition of an unactivated ketone such as cyclohexanone with a diene.

Full text of DOI:10.1021/ja300790x

Communication
pubs.acs.org/JACS
Cationic Iron(III) Porphyrin-Catalyzed [4 + 2] Cycloaddition of
Unactivated Aldehydes with Simple Dienes
Kyohei Fujiwara, Takuya Kurahashi,* and Seijiro Matsubara*
Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Kyoto 615-8510, Japan.
S
* Supporting Information
Scheme 1. Synthesis of the [Fe(TPP)(C10H7CHO)2]SbF6
Complex
ABSTRACT: Cationic iron(III) porphyrin was found to
be an efficient catalyst for the highly chemoselective
hetero-Diels−Alder-type reaction of aldehydes with 1,3-
dienes. The catalyzed process did not require the use of
electron-deficient aldehydes such as glyoxylic acid
derivatives or activated electron-rich 1,3-dienes such as
Danishefsky’s diene and Rawal’s diene. The high functional
group tolerance and robustness of the catalyst were
demonstrated. Further, the potential utility of the catalyst
was demonstrated by performing the cycloaddition in the
presence of water and by carrying out cycloaddition of an
unactivated ketone such as cyclohexanone with a diene.
he hetero-Diels−Alder reaction is one of the most
T
powerful synthetic methods for the construction of six-
membered heterocyclic compounds. In particular, the cyclo-
addition of aldehydes to dienes, which affords the pyran
scaffold, has been widely applied in the preparation of natural
products and physiologically active substances.1,2 However, the
majority of these reactions involve the use of activated
aldehydes such as glyoxylates or electron-rich dienes such as
Danishefsky’s diene and Rawal’s diene.3 Only a limited number
of hetero-Diels−Alder reactions in which unactivated aldehydes
and simple dienes are employed have been reported.
Furthermore, the use of a very strong Brønsted acid or Lewis
acid is mandatory to activate the poorly reactive hetero-
dienophile to a sufficient extent in order to compensate for the
low reactivity of simple dienes. These requirements impose
strict limitations on the choice of functional groups that can be
tolerated under the reaction conditions adopted.4 Thus, the
development of an efficient catalyst that overcomes such
drawbacks remains a challenging research topic in organic
synthesis. Herein we report the reaction of unactivated
aldehydes with simple dienes in the presence of a cationic
iron(III) porphyrin catalyst to afford pyrans. This catalyst has
high functional group tolerance, chemoselectivity, and robust-
ness in the reaction.
Figure 1. ORTEP drawing of [Fe(TPP)(C10H7CHO)2]SbF6.
unactivated aldehydes into stronger heterodienophiles for
cycloaddition with simple dienes.
Indeed, the reaction of benzaldehyde (1a) with 2,3-dimethyl-
1,3-butadiene (2a) in the presence of the cationic iron(III)
porphyrin catalyst (5 mol %) in benzene at 80 °C for 12 h
afforded pyran 3aa in 81% isolated yield (Table 1, entry 1). In
other solvents such as toluene, 1,4-dioxane, and MeCN or in
the absence of a reaction medium, the yields were even lower
(entries 2−5). Upon optimization of the counteranion of the
Initially, we prepared the cationic iron(III) porphyrin catalyst
[Fe(TPP)]SbF6 (TPP = meso-tetraphenylporphyrinato) by
treating [Fe(TPP)]Cl with AgSbF6 in CH2Cl2 at ambient
temperature for 12 h (Scheme 1).5,6 Treatment of the resulting
[Fe(TPP)]SbF6 with 2 equiv of 1-naphthaldehyde afforded
[Fe(TPP)(C10H7CHO)2]SbF6, in which two molecules of
naphthaldehyde are coordinated as axial ligands to the iron(III)
center (Figure 1). Therefore, we presumed that [Fe(TPP)]-
SbF6 would be an efficient Lewis acid for converting
Received: January 24, 2012
Published: March 19, 2012
© 2012 American Chemical Society
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a
Table 1. Iron-Catalyzed Cycloaddition of 1a with 2a
Table 2. Iron Porphyrin-Catalyzed Cycloaddition of
a
Aldehydes 1 with 2a
b
entry
catalyst
solvent
yield (%)
1
2
[Fe(TPP)]SbF6
[Fe(TPP)]SbF6
[Fe(TPP)]SbF6
[Fe(TPP)]SbF6
[Fe(TPP)]SbF6
[Fe(TPP)]Cl
[Fe(TPP)]OTf
[Fe(TPP)]BF4
[Fe(TPP)]PF6
FeCl3
benzene
toluene
1,4-dioxane
MeCN
81
66
<1
<1
49
<1
<1
92
<1
38
3
3
4
5

6
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
benzene
7
8
9
10
11
12
13
14
15
16
FeCl3·(tmeda)2
FeCl3·(bpy)2
FeCl3·TPPH2
FeCl2
5
<1
4
FeF3
<1
<1
AgBF4
a
Reactions were carried out using the iron catalyst (5 mol %),
aldehyde 1a (0.5 mmol), and diene 2a (2.0 mmol, 4 equiv) in 2 mL of
b
solvent at 80 °C for 12 h. Isolated yields based on aldehyde 1a.
cationic iron porphyrin complex, 3aa was obtained in excellent
yield. When [Fe(TPP)]BF4 was used, 3aa was obtained in 92%
yield (entry 8). The use of other iron catalysts such as FeCl3,
FeCl3·(tmeda)2, FeCl3·(bpy)2, FeCl2, and FeF3 or the use of
AgBF4 in place of the cationic iron(III) porphyrin complex
resulted in the formation 3aa in trace amounts or much lower
yields (entries 10−16).
With the optimized reaction conditions in hand, we first
evaluated the cationic iron(III) porphyrin-catalyzed hetero-
Diels−Alder-type reaction of various aldehydes 1 with 2a
[Table 2; for details, see the Supporting Information (SI)]. 2-
Naphthaldehyde (1b) participated in the reaction with 2a to
afford 3ba in 88% isolated yield. Benzaldehydes with electron-
withdrawing substituents such as trifluoromethyl, fluoride,
chloride, and bromide afforded pyrans 3 in good yields.
Benzaldehyde 1i, which has an electron-donating methoxy
substituent, reacted with 2a to furnish 3ia in excellent yield
(99%). Nitro and nitrile substituents on benzaldehyde were
well-tolerated under the present reaction conditions, and the
corresponding cycloaddition products (3ja and 3ka, respec-
tively) were isolated in excellent yields. Furthermore, the
reaction of p-acetylbenzaldehyde (1l) with 2a gave 3la in 98%
yield, but a considerably long reaction time (5 days) was
required. The cationic iron(III) porphyrin complex was also
found to be effective for the reaction of aliphatic aldehydes with
2a. Notably, phenylacetaldehyde (1p), a highly enolizable
aldehyde, also underwent cycloaddition with 2a to afford pyran
3pa in 72% yield. Cyclopropanecarboxaldehyde (1r) reacted
with 2a to afford the corresponding substituted pyran 3ra in
84% yield. Aldehydes with unsaturated moieties such as a
double bond, triple bond, or even a conjugated diene also
furnished cycloadducts 3 in moderate to excellent yields (3sa,
92%; 3ta, 99%; 3ua, 73%; 3va, 73%). Moreover, various
functional groups such as bromide, nitro, ether, and imide on
aliphatic aldehydes were tolerated under the reaction
conditions, and functionalized pyrans were obtained (3wa,
76%; 3xa, 73%; 3ya, 73%; 3za, 92%).
a
Reactions were carried out using [Fe(TPP)]BF4 (5 mol %), aldehyde
1 (0.5 mmol), and diene 2a (2.0 mmol, 4 equiv.) in 2 mL of benzene
at 80 °C for 12 h, unless otherwise noted. Isolated yields based on
aldehyde 1 are shown. A diastereomeric ratio of 1/1 was observed.
b
c
To demonstrate the scope of this cycloaddition, we next
examined the reaction of aldehyde 1a with various conjugated
dienes 2 (Table 3; for details, see the SI). Under the optimized
reaction conditions, 2-aryl-1,3-butadienes having an electron-
withdrawing substituent on the phenyl moiety reacted with 1a
to afford the corresponding substituted pyrans regioselectively
in good yields. On the other hand, when the butadiene had an
electron-donating methoxy substituent on the phenyl moiety, as
in 2f, cycloaddition with 1a was retarded, and oligomerization
of 2f proceeded predominantly. Oligomerization was prevented
by slow addition of 2f to the reaction mixture over 3 h, and as a
result, the desired cycloadduct 3af was obtained, but in a very
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and 1,2-bis(methylene)cyclooctane (2k) reacted with 1a to
furnish polycyclic cycloadducts 3aj and 3ak, respectively, in
excellent yields. Furthermore, cycloadditions of 1a with 1,4-
disubstituted-1,3-dienes proceeded with high regio- and
stereoselectivity. 2-Phenyl-1,3-pentadiene (2l) reacted with 1a
to afford cis-3al in 99% yield in a regioselective manner, with a
stereoisomer ratio of 92/8. Cycloaddition of 2m with 1a gave
3am as the single isomer in 88% yield (for details of X-ray
crystal structure analysis, see the SI).8 Acid-sensitive functional
groups such as acetal, acetoxy, and siloxy groups were also
tolerated under the reaction conditions, giving the correspond-
ing substituted pyrans (3an, 83%; 3ao, 72%; 3ap, 82%). These
results clearly highlighted the excellent chemoselectivity of the
[Fe(TPP)]BF4-catalyzed cycloaddition of aldehydes with
dienes.
Table 3. Iron Porphyrin-Catalyzed Cycloaddition of 1a with
Dienes 2
a
Notably, the [Fe(TPP)]BF4-catalyzed [4 + 2] cycloaddition
was feasible in the presence of water. An aqueous solution of
formaldehyde (4a) could be made to react with 2l to obtain
pyran 5al in 98% yield (Scheme 2). It is also noteworthy that
the α,β-unsaturated aldehyde 6a behaved as a heterodienophile
but not as a heterodiene, reacting with 2l to afford 7al in 72%
yield with a diastereomeric ratio of 75/25. Moreover,
unactivated ketones, which are much poorer heterodienophiles
than are aldehydes as a result of steric and electronic effects,
also participated in the cycloaddition with the diene; cyclo-
hexanone (8a) reacted with 2l to afford oxaspiro compound 9al
in 97% isolated yield.9
In summary, we have developed an unprecedented catalyst
for the hetero-Diels−Alder-type [4 + 2] cycloaddition of
unactivated aldehydes with simple dienes. The readily available
cationic iron(III) porphyrin effectively catalyzes the cyclo-
addition with high functional group tolerance and robustness.
Furthermore, the use of this catalyst in the cycloaddition of an
unactivated ketone and a simple diene has been demonstrated
for the first time. Efforts directed toward the development of an
asymmetric variant of the reaction and detailed studies to
elucidate the mechanism underlying the unique reactivity of the
cationic iron(III) porphyrin complex are underway.10,11
a
Reactions were carried out using [Fe(TPP)]BF4 (5 mol %), aldehyde
1a (0.5 mmol), and diene 2 (2.0 mmol, 4 equiv) in 2 mL of benzene at
80 °C for 12 h, unless otherwise noted. Isolated yields based on
aldehyde 1 are shown. Diene 2f was added to the reaction mixture
b
c
d
over 3 h. Ratio of diastereomers (cis/trans).
Scheme 2. Effects of the Cationic Iron(III) Porphyrin
Catalyst
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, spectroscopic and analytical data for
new compounds, and crystallographic data (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
tkuraha@orgrxn.mbox.media.kyoto-u.ac.jp; matsubar@orgrxn.
mbox.media.kyoto-u.ac.jp
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Grants-in-Aid from the Ministry of
Education, Culture, Sports, Science, and Technology, Japan.
T.K. acknowledges Tokuyama Science Foundation, Kurata
Memorial Hitachi Science and Technology Foundation, and
Toyota Physical and Chemical Research Institute. We thank Dr.
Kenji Yoza (Bruker AXS) for valuable help in X-ray crystal
structure analysis.
low yield (44%).7 A 1,3-butadiene possessing a highly
polymerizable styryl moiety also reacted with 1a to give 3ag
in 83% yield. Cycloaddition of conformationally fixed s-cis-
dienes such as 1,2-bis(methylene)cyclohexane (2i) with 1a also
proceeded successfully to give hexahydro-1H-isochromene 3ai
in 99% yield. Likewise, 1,2-bis(methylene)cycloheptane (2j)
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(11) Cationic iron porphyrins may undergo spin-state transition and/
or mixing, which contributes to an increase in the catalytic activity for
the cycloaddition. For the spin state of cationic iron porphyrins, see:
(a) Dolphin, D. H.; Sams, J. R.; Tsin, T. B. Inorg. Chem. 1977, 16, 711.
(b) Shelly, K.; Bartczak, T.; Robertscheidt, W.; Reed, C. A. Inorg.
Chem. 1985, 24, 4325. (c) Reed, C. A.; Guiset, F. J. Am. Chem. Soc.
1996, 118, 3281. (d) Ikeue, T.; Ohgo, Y.; Yamaguchi, T.; Takahashi,
M.; Takeda, M.; Nakamura, M. Angew. Chem., Int. Ed. 2001, 40, 2617.
For a study of spin-state mixing of cytochromes, see: (f) Maltempo, M.
M. J. Chem. Phys. 1974, 61, 2540. For a related theoretical study of a
spin-state transition that enhances the reactivity of cobalt catalysts for
the hetero-Diels−Alder reaction, see: (e) Iwakura, I.; Ikeno, T.;
Yamada, T. Angew. Chem., Int. Ed. 2005, 44, 2524.
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