Taming the friedel-crafts reaction: Organocatalytic approach to optically active 2,3-dihydrobenzofurans

Article abstract of DOI:10.1002/anie.201105819

Fine-tuning: Three types of optically active trans-2,3-disubstituted-2,3- dihydrobenzofurans having three contiguous stereogenic centers can be efficiently accessed by one-pot reaction cascades (see scheme; TMS=trimethylsilyl). High substitution diversity of the final products can be achieved from the same common precursors by fine-tuning of their reactivity through simple structural modifications. Copyright

Full text of DOI:10.1002/anie.201105819

Communications
DOI: 10.1002/anie.201105819
Asymmetric Catalysis
Taming the Friedel–Crafts Reaction: Organocatalytic Approach to
Optically Active 2,3-Dihydrobenzofurans**
Łukasz Albrecht, Lars Krogager Ransborg, Vibeke Lauridsen, Mette Overgaard, Theo Zweifel,
and Karl Anker Jørgensen*
The Friedel–Crafts reaction constitutes one of the fundamen-
tal reactions in organic chemistry and allows facile function-
alization of aromatics and heteroaromatics.[1] Asymmetric
variants of this reaction that enable the introduction of
benzylic stereocenters are well recognized.[2] Whereas imines
constitute a particularly attractive group of electrophilic
reagents commonly employed in the Friedel–Crafts reaction,
the application of epoxides as electrophiles has been much
less studied.[2a,3,4] Intramolecular epoxide openings have been
successfully applied to the construction of heterocyclic
systems.[3a–c,4] However, since epoxide opening can proceed
through two different pathways (Scheme 1a), regioselectivity
of the reaction is an important issue. Whereas 6-endo
cyclizations were shown to be a reliable tool for the
construction of chroman derivatives,[4] the application of 5-
exo cyclizations for the synthesis of 2,3-dihydrobenzofurans is,
to the best of our knowledge, unprecedented.
The trans-2,3-disubstituted-2,3-dihydrobenzofuran is a
moiety often encountered in nature.[5,6] Compounds incorpo-
rating this structural motif have been isolated from different
species of higher plants for example, Asteraceae.[5a,b] Toxol,[5a]
a natural product of Encelia californica and lawsonicin,[5d] as
well as other structurally related neolignans[5e–h,7b] constitute
Scheme 1. a) Synthesis of heterocycles through the regioselective intra-
molecular Friedel-Crafts reaction with epoxides. b) Structures contain-
ing the 2,3-dihydrobenzofuran motif.
representative examples of such naturally occurring 2,3-
dihydrobenzofurans (Scheme 1b). The biological activity of
these systems is also well recognized.[5a] For example, the
furaquinocins are a family of cytotoxic antibiotics.[6] Intrigu-
ing biological properties combined with wide occurrence in
nature has become a driving force for the development of
synthetic methods leading to these structural motifs.[7] How-
ever, methods for their preparation in an asymmetric fashion
are limited and rely mainly on the application of kinetic
resolution,[8] chiral auxilliaries,[9] or chiral starting materi-
als.[10] Enantioselective, catalytic methods are also known,[11]
although, drawbacks related to low efficiency or scope
restrictions occur in most cases.
Given the importance of optically active trans-2,3-disub-
stituted-2,3-dihydrobenzofurans, studies on a synthetic meth-
odology offering general and enantioselective access to these
compounds were initiated. Our plan was focused on the
development of one-pot reaction cascades that enable
efficient control of the regio- and chemoselectivity of the
overall reaction sequence through structural modifications of
the intermediates involved. Such strategies, if successful,
would offer an easy entry to diversely substituted products
starting from common precursors. The approach is depicted in
Scheme 2. It was envisioned that diversity-oriented
approaches to the differently substituted 2,3-dihydrobenzo-
furans 7 and 9 could rely on the application of 2,3-epoxy
aldehydes 3 as common intermediates. These interesting 1,2-
di-electrophilic species are easily available by asymmetric
organocatalytic[12] epoxidation of the a,b-unsaturated alde-
hydes 1.[13] It was expected that initial imine formation from 3
should enable Friedel–Crafts reaction with the electron-rich
hydroxyarenes 5 to occur at the imine group of 4. Subsequent
5-exo-tet epoxide opening of 6 through the hydroxyarenic
oxygen atom should result in formation of the 2,3-dihydro-
benzofurans 7. Alternatively, it was anticipated that direct
[*] Dr. Ł. Albrecht, L. K. Ransborg, V. Lauridsen, M. Overgaard,
Dr. T. Zweifel, Prof. Dr. K. A. Jørgensen
Center for Catalysis, Department of Chemistry
Aarhus University, 8000 Aarhus C (Denmark)
E-mail: kaj@chem.au.dk
[**] This work was made possible by grants from the OChemSchool,
Carlsberg Foundation, and FNU, as well as scholarships from the
Foundation for Polish Science (Kolumb Programme–Ł.A.) and the
Swiss National Science Foundation (T.Z.). We thank Dr. Jacob
Overgaard for performing X-ray analysis.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201105819.
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conditions epoxide opening proceeded by a 5-exo pathway to
give the 2,3-dihydrobenzofuane 7a through a TypeA-4-1C3X
one-pot reaction sequence[12f] (Table 1, entry 1). Gratifyingly,
applying these optimized reaction conditions to various linear
Table 1: Enantioselective synthesis of trans-3-(benzylamino)-2-(hydrox-
yalkyl)-2,3-dihydrobenzofurans 7: Aldehyde scope.[a]
Entry
1 (R1)
Yield
[%][b]
d.r.[c]
ee
[%][d]
Scheme 2. Asymmetric organocatalytic approach to optically active 2,3-
dihydrobenzofurans. TMS=trimethylsilyl.
1
2
3
4
1a (Hex)
1b (Pentyl)
1c (nPr)
1d (iPr)
1e (Me)
1 f (CH2CH2Ph)
1g (CH2OTBS)
1h (CO2Et)
1i (E-Hex-3-enyl)
7a: 70
7b: 52
7c: 62
7d: 60
7e: 56
7 f: 69
7g: 45
7h: 44
7i: 60
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
96
92
95
97
94
97
95
95
97
5[e]
6
reaction of the 2,3-epoxy aldehydes 3 with hydroxyarenes 5
might proceed in the following sequence: 1,2-addition of
hydroxyarenic hydroxy group to the carbonyl group of 3 to
give intermediate 8 with subsequent 5-exo-tet epoxide open-
ing to afford 9. In such a manner molecular complexity and
diversity should be attainable from easily available starting
materials by simple modification of the structure of the key
intermediates, thus resulting in a different reactivity pattern.
However, at the outset of our studies the concept seemed
particularly challenging since issues regarding regioselectivity
(alkylation of the electron-rich hydroxyarenes 5 at different
positions or epoxide opening 5-exo versus 6-endo), chemo-
selectivity (arylation of 1,2-di-electrophilic species 3 or 4 at
different positions; carbonyl or imine moiety versus epoxide
carbon atoms), and diastereoselectivity (new stereogenic
center formed) of the Friedel–Crafts step needed to be
taken into considaration.
Herein we report on the efficient asymmetric diversity-
oriented access to optically active trans-2,3-disubstituted-2,3-
dihydrobenzofurans based on organocatalytic one-pot reac-
tion cascades.[12f] The diversity of the methodology is addi-
tionally expanded by application of the resulting 2,3-dihy-
drobenzofurans for the construction of more elaborate
derivatives.
We initiated our studies with the goal of finding optimal
reaction conditions for the synthesis of trans-3-(benzyla-
mino)-2-(hydroxyalkyl)-2,3-dihydrobenzofurans 7 (Scheme 2,
Path A). Optimization studies using trans-2-nonenal (1a;
R1 = n-hexyl) and 3,5-dimethoxyphenol (5a) as model sub-
strates (for detailed results see the Supporting Information)
revealed that the reaction sequence involving epoxidation/
imine formation/Friedel–Crafts reaction/epoxide opening is
possible. To our delight, the Friedel–Crafts reaction pro-
ceeded with complete regio- and chemoselectivity, thus
affording 6a exclusively. Moreover, remarkably high diaste-
reoselectivity (> 20:1 d.r.) was obtained both at À208C and at
room temperature. Further screening revealed that a base
must be employed to accomplish the epoxide opening, with
DBU proving to be the most effective. Under these reaction
7
8
9
[a] Reactions performed on 0.2 mmol scale in 0.4 mL CH2Cl2 (see the
Supporting Information for details). [b] Overall yield given. [c] Deter-
mined by 1H NMR spectroscopy. [d] Determined by HPLC analysis using
a chiral stationary phase. [e] Epoxidation performed using 10 mol% of 2.
Nomenclature legend: Type A refers to the position of the enantiodif-
ferentiating manual operation (at the start); 4 refers to the number of
manual operations; 1C3X refers to the number of C C bonds (mC) and
C X bonds (nX) formed in the one-pot reaction cascade. ADN=addition
reaction, AOC=asymmetric organocatalysis, Bn=benzyl, CDN=con-
densation, DBU=1,8-diazabicyclo[5-4-0]undec-7-ene, SBN=substitu-
tion reaction.
À
À
and g-branched aliphatic aldehydes (1b–e) proved successful
and afforded the highly enantiomerically enriched 2,3-dihy-
drobenzofurans 7b–e in good overall yields as single regio-
and diastereoisomers (Table 1, entries 2–5). Furthermore, the
functional-group tolerance of the developed TypeA-4-1C3X
cascade was high as various functional groups could be
present in the side chain of the starting a,b-unsaturated
aldehydes 1 f–i (Table 1, entries 6–9). However, the use of
aromatic enals, for example, cinamaldehyde, did not give
satisfactory results, presumably because of the lack of
regioselectivity in the epoxide opening reaction.
In the course of further studies, the possibility to employ
various electron-rich hydroxyarenes in the TypeA-4-1C3X
one-pot reaction sequence was evaluated (Scheme 3).
Delightfully, the developed cascade proved to be general as
various electron-rich phenols and the naphthols 5b–g reacted
smoothly to afford the target products 7j–o in moderate to
good overall yields (55–83%) and excellent enantioselectiv-
ities (93–97% ee). Moreover, complete regio- and diastereo-
selectivity was observed in all cases.
With the goal of achieving high control of the regio- and
chemoselectivity in the Friedel–Crafts reaction utilizing 2,3-
epoxy imines as 1,2-di-electrophilic species being accom-
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Communications
Table 2: Enantioselective synthesis of the trans-3-(hydroxyalkyl)-2,3-
dihydrobenzofuran-2-ols 9.[a]
Entry
5
1 (R1)
Yield
[%][b]
d.r.[c]
ee [%][d]
1
5a
5a
5a
5a
5a
5a
5a
1a (Hex)
1a (Hex)
1c (Pr)
1d (iPr)
1e (Me)
9a: 57 >20:1 96
9a: 52 >20:1 96
9c: 52 >20:1 96
9d: 51 >20:1 95
9e: 47 >20:1 95
2[e]
3
4
5[e]
6
1 f (CH2CH2Ph) 9 f: 46 >20:1 96
1g (CH2OTBS) 9g: 62 >20:1 95
7
8[f]
5d
1a (Hex)
1a (Hex)
9h: 39 >20:1 96
9i: 47 >20:1 97
Scheme 3. Enantioselective synthesis of trans-3-(benzylamino)-2-
(hydroxyalkyl)-2,3-dihydrobenzofurans 7: Hydroxyarene scope (see the
Supporting Information for details).
9[g]
5 f
plished, we turned our attention to the 2,3-epoxy aldehyde
counterparts. We were aware of an earlier report showing that
under basic conditions similar 2,3-epoxy aldehydes react with
electron-rich hydroxyarenes leading to the formation of 3-
hydroxy-2,3-dihydrobenzofurans in a non-diastereoselective
manner,[14] and we therefore focused on the development of a
complementary route that would allow stereoselective prep-
[a] Reactions performed on 0.2 mmol scale in 0.4 mL CH2Cl2 (see the
Supporting Information for details). [b] Overall yield given. [c] Deter-
mined by 1H NMR spectroscopy. [d] Determined by HPLC analysis using
a chiral stationary phase. [e] Reaction performed in the absence of 2-
NO2C6H4CO2H. [f] 2nd step run for 8 days. [g] 2nd step run for 3 days.
ANN=annulation, TBS=tert-butyldimethylsilyl.
aration of the 2-hydroxy-2,3-dihydrobenzofurans
9
(Scheme 2, Path B). In such a manner formal a-arylation-b-
hydroxylation of a,b-unsaturated aldehydes would be accom-
plished since the aldehyde moiety in 9 is masked as the
corresponding cyclic hemiacetal.[15] To our delight initial
experiments showed that in the absence of base the desired
reaction pathway was accessible (Table 2). It was found that
elevated temperature (408C) as well as the presence of an
acidic cocatalyst (Table 2, compare entries 1 and 2) are
beneficial for the TypeA-2-1C2X reaction cascade. Under
these reaction conditions various a,b-unsaturated aldehydes 1
were effectively reacted with 3,5-dimethoxyphenol (5a), thus
offering an enantio-, diastereo-, and regioselective entry to
the 3-(hydroxyalkyl)-2,3-dihydrobenzofuran-2-ols 9 (Table 2,
entries 1 and 3–7). Furthermore, other electron-rich hydrox-
yarenes were successfully employed in the developed reaction
cascades as demonstrated for the b-naphthol (5d; Table 2,
entry 8) and the 2,7-dihydroxynaphthalene (5 f; Table 2,
entry 9). However, longer reaction times were required to
achieve full conversion in the annulation step for these
substrates.
Scheme 4. Enantioselective synthesis of trans-2-aryl-3-(hydroxyalkyl)-
2,3-dihydrobenzofuran 11.
Interestingly, when 3-dimethylaminophenol (5h) was
subjected to the optimized reaction conditions the unex-
pected formation of the dihydrobenzofuran 11 was observed
(twofold excess of the starting 5h was required to accomplish
full conversion of 1a; Scheme 4). We assume that as a result
of the strong electron-donating ability of the dimethylamino
substituent, the reaction sequence is not terminated at the
stage of the corresponding 2-hydroxy-2,3-dihydrobenzofuran
9j. Instead the corresponding oxocarbenium ion 10 is formed,
which undergoes a second, fully diastereoselective Friedel–
Crafts reaction, thus resulting in the introduction of an aryl
moiety at the 2-position of the target 2,3-dihydrobenzofuran
11.
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Angew. Chem. Int. Ed. 2011, 50, 12496 –12500

Taking advantage of the aldehyde moiety, protected as the
corresponding cyclic hemiacetal, in 9 we devised an alter-
native approach for the formation of trans-2,3-disubstituted-
2,3-dihydrobenzofurans, thus further expanding the diversity
obtained by the synthetic strategy. Merging the developed
TypeA-2-1C2X reaction cascade (see Table 2) with a subse-
quent Wittig reaction, using the stabilized phosphorus ylides
12, and subsequent base-induced oxa-Michael addition
proved successful, thus affording access to the dihydrobenzo-
furans 14 (Scheme 5). In the case of the Wittig reagent 12b
the olefination reaction had to be performed at 408C.
Notably, cyclization then proceeded spontaneously in the
absence of base affording 14c through a TypeA-3-2C2X one-
pot reaction cascade.
Scheme 6. a) Configurational assignments of the trans-2,3-dihydroben-
zofurans 7, 9, 11, and 14. b) Rationalization for the diastereoselectivity
of the Friedel–Crafts reaction leading to 7.
data[16] (Scheme 6a). Based on the presented configurational
assignments, a transition-state model explaining the high
diastereoselectivity observed in the Friedel–Crafts reaction of
the 2,3-epoxy imines 4 with hydroxyarenes 5 was proposed
(Scheme 6b). This experimental result can be rationalized by
the Felkin–Anh model in which the imine moiety of 4
(Scheme 2) is approached by the electron-rich aromatic
system from the side opposite to the largest substituent. We
postulate that hydrogen bonding between the phenolic or
naphtholic hydroxy group and the epoxide oxygen atom is
crucial for the high control of the diastereoselectivity in the
formation of the C3 stereogenic center in 7.[16a,b] In this
context it is worth mentioning that the C2 stereogenic center
in dihydrobenzofurans 9 is probably thermodynamically
controlled. Furthermore, the formation of the C2 stereocen-
ters in the products 11 and 14 can easily be rationalized by
nucleophilic attack occurring from the least hindered faces of
the electrophilic sites in 10 (Scheme 4) and 13 (Scheme 5),
respectively; that is opposite to the large hydroxyalkyl moiety.
In summary, diversity-oriented one-pot reaction cascades
for the preparation of optically active trans-2,3-disubstituted-
2,3-dihydrobenzofurans having three contiguous stereogenic
centers have been developed. Highly diverse substitution
patterns of the final products could be achieved by simple
modification of the structure of the key intermediates which
resulted in different chemoselectivity of the particular
reaction cascades.
Scheme 5. Enantioselective synthesis of the trans-2,3-dihydrobenzofur-
ans 14 by a TypeA-4-2C2X one-pot reaction cascade. CEN=chain-
elongation.
The absolute stereochemistry of the C2 and C1’ stereo-
genic centers in the dihydrobenzofurans 7 as well as that of
the C3 and C1’ stereocenters in the products 9, 11, and 14
were assigned on the basis of our earlier results regarding 2,3-
epoxy aldehydes and their applications in target-oriented
syntheses.[16a–d] These assignments were additionally con-
firmed by single-crystal X-ray analysis (see the Supporting
Information for details). This result also allowed assignment
of the trans relationship between the H2 and H3 protons in 7.
Relative stereochemistry at the C2 and C3 stereogenic centers
of the 2,3-dihydrobenzofuran ring in the products 7, 9, 11, and
14 was further elucidated on the basis of the 1H NMR data. In
Received: August 17, 2011
Published online: November 7, 2011
Keywords: asymmetric catalysis · diversity oriented synthesis ·
.
heterocycles · organocatalysis · synthetic methods
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