Syntheses of Polycyclic Tetrahydrofurans by Cascade Reactions Consisting of Five-Membered Ring Selective Prins Cyclization and Friedel-Crafts Cyclization

Article abstract of DOI:10.1021/acs.joc.8b01195

A novel cascade reaction consisting of a five-membered ring selective Prins cyclization and a subsequent Friedel-Crafts cyclization is reported. Treatment of homocinnamyl alcohols and aromatic aldehydes with BF₃·OEt₂ in CH₂

Full text of DOI:10.1021/acs.joc.8b01195

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Article
Syntheses of Polycyclic Tetrahydrofurans by Cascade
Reactions Consisting of Five-membered Ring Selective
Prins Cyclization and Friedel-Crafts Cyclization
Yuki Sakata, Eiko Yasui, Kazuhiko Takatori, Yuji Suzuki, Megumi Mizukami, and Shinji Nagumo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01195 • Publication Date (Web): 04 Jul 2018
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Syntheses of Polycyclic Tetrahydrofurans by Cascade Reactions
Consisting of Five-membered Ring Selective Prins Cyclization and
Friedel-Crafts Cyclization
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Yuki Sakata,a Eiko Yasui,a Kazuhiko Takatori,b Yuji Suzuki,a,c Megumi
Mizukami,c and Shinji Nagumoa*
a) Department of Applied Chemistry, Kogakuin University, Nakano 2665ꢀ1, Hachioji, Tokyo
192ꢀ0015, Japan.
b) Department of Synthetic Organic Chemistry, Meiji Pharmaceutical University, Noshio 2ꢀ522ꢀ1,
Kiyose, Tokyo 204ꢀ8588, Japan.
c) Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Hokkaido University of
Science, Maeda 15ꢀ4ꢀ1, Teine, Sapporo, Hokkaido 006ꢀ8585, Japan.
bt13071@ns.kogakuin.ac.jp
The First Cascade Reaction
The Second Cascade Reaction
MeO
Ph
O
H
CHO
N
MeO
CHO
Ts
NTs
MeO
MeO
H
MeO
H
HO
BF3 OEt2
0 o
BF3 OEt2
MeO
rt
C
H
O
ABSTRACT: A novel cascade reaction consisting of a fiveꢀmembered ring selective
Prins cyclization and a subsequent FriedelꢀCrafts cyclization is reported. Treatment of
homocinnamyl alcohols and aromatic aldehydes with BF3･OEt2 in CH2Cl2 afforded
hydrocyclopentafurans. Also hydrocyclopentafurans underwent the same cascade
reaction after its furan ring cleavage upon treatment with BF3･OEt2 at room temperature.
Various combinations of hydropentafurans and aromatic aldehydes or indole aldehydes
permitted divergent synthesis of diquinaneꢀfurans stuck in aromatic rings.
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INTRODUCTION
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A cascade reaction by which complex molecules are formed in a single operation
from relatively simple substrates continues to be an attractive field of synthetic organic
chemistry.1 Various types of reaction have been utilized as elements of cascade reactions.
Prins cyclization, inter alia, is an important method for directly synthesizing oxygenated
heterocycles from homoallylic alcohols and aldehydes.2 The reaction mechanism
consists of three successive steps: (1) an acidꢀpromoted condensation of a homoallylic
alcohol and an aldehyde, (2) cyclization of the resultant oxocarbenium ion with an
alkene, and (3) capture of the generated carbocation by some kind of nucleophile. In the
second step, a 6ꢀmembered ring is generally favored over a 5ꢀmembered ring for
cyclization to generate multisubstituted tetrahydropyrans with excellent regioselectivity.
Possible nucleophiles in the third step include carboxylic acid,3 halogen ion,4 nitrile (i.e.,
Ritter reaction),5 and aromatic ring (i.e., FriedelꢀCrafts reaction).6 The combination of
Prins cyclization with an intramolecular reaction constitutes a practical cascade reaction
for generating complicated polycyclic frameworks in a single operation.7 Reddy and
Yadav et al. reported a cascade reaction consisting of Prins cyclization and a subsequent
intramolecular Friedel–Crafts cyclization that afforded tetrahydropyran fused with
tetrahydronaphthalene.8 On the other hand, the presence of naturally occurring
tetrahydrofurans with multiple substituents and/or fused with other ring systems has
directed our attention to a 5ꢀmemberedꢀselective Prins cyclization and its cascade
cyclization. The unusual regioselectivity leading to tetrahydrofuran necessitates some
kind of advantage that is superior to the stability of the chair form transition state in
6ꢀmembered ring closure. The number of substituents on alkene of a homoallylic
alcohol affects the size selectivity of ring closure. Prins cyclization of monoꢀ and
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(E)ꢀdiꢀsubstituted homoallylic alcohols show preferential formation of a 6ꢀmembered
ring, whereas a (Z)ꢀdiꢀsubstituted homoallylic alcohol affords a mixture of
tetrahydropyran and tetrahydrofuran.9 A chair form transition state for ring closure of
tetrahydropyran from a (Z)ꢀhomoallylic alcohol and an aldehyde should be less stable
than that from an (E)ꢀhomoallylic alcohol because the structure has an axial substituent.
The regiochemistry is also affected by the stability of intermediary carbenium ions.
Prins cyclization of a trisubstituted homoallylic alcohol favors a 5ꢀexo cyclization over a
6ꢀendo one because the 5ꢀexo cyclization generates a more stable tertial carbenium ion
(Scheme 1, eq. 1).10 Device of the neighboring group is also known to change the ring
selectivity of an (E)ꢀdiꢀsubstituted homoallylic alcohol to 5ꢀexo mode. Homoallylic
alcohols fused with allylsilane (eq. 2),11 propargylsilane (eq. 3)12 and allenylsilane (eq.
4)13 react with aldehydes and ketones to give tetrahydrofuran derivatives, reactions that
are frequently referred to as silylꢀPrins reactions. The regioselectivity correlates with the
formation of stabilized βꢀsilylethyl and βꢀsilylvinyl cation intermediates. However,
these cations are immediately converted into the corresponding alkene and alkyne
through the elimination of silyl groups and it is therefore difficult to apply them to a
cascade reaction for affording tetrahydrofurans fused with other ring systems. As
another neighboring group of a homoallylic alcohol directing ring selectivity to 5ꢀexo,
we have had a strong interest in a phenyl group. Namely, a homocinnamyl alcohol
would undertake 5ꢀringꢀselective Prins cyclization with an aldehyde to generate a
benzyl cation. Furthermore, if an aromatic aldehyde is selected as a coupling partner,
the benzyl cation would give rise to further cyclization.14 We wish to report syntheses of
various polycyclic tetrahydrofurans based on a novel cascade reaction consisting of
5ꢀringꢀselective Prins cyclization and intramolecular FriedelꢀCrafts cyclization.15
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Scheme 1 5ꢀRing membered selective Prins cyclizations
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RESULTS AND DISCUSSION
We initially examined the reaction of transꢀhomocinnamyl alcohol 2A with several
kinds of benzaldehydes 1AꢀG (Scheme 2). Treatment of 2A with 1A and/or 1C (1.3
equiv.) in the presence of BF3･OEt2 (3 equiv.) in CH2Cl2 at 0 °C (Method A) resulted in
decomposition, whereas the reaction of 1B under the same conditions proceeded facilely
to generate tetrahydroindenofuran 3BAꢀp (91%) and its regioisomer 3BAꢀo (6%) after
15 min. The relative configuration of 3BAꢀp was determined by NOE correlation as
shown in Scheme 2. The reactive difference between 1B and 1C suggested that an
electron releasing group at the meta position in benzaldehydes is crucial for this cascade
reaction. We thus investigated the cascade cyclization of other aldehydes 1DꢀG having
at least one metaꢀalkoxy group. As anticipated, aldehydes 1DꢀE bearing two
metaꢀalkoxy groups reacted with 2A to give 3DA and 3EA in excellent yields after 15
min. Also, the reaction of 1FꢀG having a 4ꢀalkoxy group afforded 3FA and 3GA in
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good yields, but it took a few hours to consume substrates. Furthermore, a slight amount
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of diquinaneꢀfuran 4FAF and 4GAG were simultaneously formed.
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Scheme 2 Cascade reactions of 1 (1.3 eq.) and 2 (1 eq.) (Method A)
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The number with symbols for each compound is systematically marked. The
numbers represent types of compound: 1 is aromatic aldehyde, 2 is
homocinnamyl alcohol, 3 is tetrahydroindenofuran, and 4 is diquinaneꢀfuran. The
symbols represent substituent patterns on benzene rings of 1 and 2: A is
nonꢀsubstituted, B is 3ꢀmethoxy, C is 4ꢀmethoxy, D is 3,5ꢀdimethoxy, E is
3,4,5ꢀtrimethoxy, F is 3,4ꢀdimethoxy, and G is 3,4ꢀdiethoxy. For example, 3DA
means that the compound is obtained by the coupling of 1D and 2A, and 4FAF
means that the compound is obtained by further coupling of 3FA and 1F. Symbol
“α” or “β” means the configuration of the branched aromatic ring, and “o” or “p”
means the reacting site when using aldehyde 1B.
Scheme 3 shows the formation mechanism of 3FA and 4FAF as typical examples.
The cascade reaction starts with 5ꢀmembered ringꢀselective Prins cyclization of the
oxonium ion (I) derived from benzaldehyde 1F and homocinnamyl alcohol 2A. The
cyclization might proceed nonꢀstereoselectively to form both cisꢀbenzyl cation (II) and
transꢀbenzyl cation (III), which can be transformed to each other. However, only (II)
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should bring about the next 5ꢀmembered FriedelꢀCrafts cyclization to give 3FA because
of the great ring strain of a transꢀfused bicyclo[3.3.0] system. Compound 4FAF should
be derived from 3FA by the second cascade cyclization, which is commenced with a
BF3ꢀpromoted cleavage of the furan ring. The CꢀO bond cleavage necessitates the
assistance of an electronꢀreleasing group at the C6 position of hydroindenofuran. The
resulting intermediate (IVꢀPh) is converted to (V) by rearomatization concomitant with
deprotonation. Intermediate (V) notably contains a homoallylic alcohol neighboring to
the aryl group as well as 2A. Therefore, excess 1F couples with (V) to form oxonium
ion (VI), which is further converted to 4FAF by the sequence of Prins cyclization and
FriedelꢀCrafts cyclization.
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Scheme 3 Formation mechanism of 3FA and 4FAF.
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Scheme 4 Cascade reaction of transꢀhomocinnamyl alcohols having a 3ꢀ or 4ꢀmethoxy
group (Method A).
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OMe
OMe
OMe
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HO
H
trans-2B
MeO
1D
(1)
BF3 OEt2
H
O
-3DB (90%)
OMe
MeO
MeO
H
trans-2B
1F
(2)
BF3 OEt2
H
O
-3FB (72%)
OMe
OMe
OMe
H
HO
OMe
H
trans-2C
+
1B
(3)
MeO
BF3 OEt2
H
O
H O
-3BC-p (72%)
-3BC-o (14%)
OMe
OMe
H
2C
trans-
1D
(4)
MeO
BF3 OEt2
H
O
OMe
-3DC (93%)
OMe
MeO
MeO
OH
MeO
MeO
H
H
trans-2C
H
+
1F
(5)
MeO
BF3 OEt2
H
O
O
5FC (11%)
-3FC (77%)
Next, we surveyed the scope limitation of this cascade reaction using various
homocinnamyl alcohols bearing a methoxy group on the benzene ring. Scheme 4
summarizes the reactions of transꢀ2B and transꢀ2C having a 3ꢀ or 4ꢀmethoxy group.
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Reactions of transꢀ2B with 1D and 1F proceeded stereoselectively to give βꢀ3DB and
βꢀ3FB in 90% and 72% yields, respectively (eq. 1ꢀ2). The reaction of transꢀ2C with
aldehyde 1B proceeded stereoselectively to afford regional isomers βꢀ3BCꢀp (72%) and
βꢀ3BCꢀo (14%) (eq. 3). Likewise, transꢀ2C reacted with 1D to give βꢀ3DC in an
excellent yield (eq. 4). Interestingly, only the combination of transꢀ2C with 1F
generated 5FC (11%) in addition to βꢀ3FC (eq. 5). The structure was unambiguously
determined by Xꢀray crystallographic analysis. As with the formation of
diquinaneꢀfuran 4FAF and 4GAG (Scheme 2, eq. 4), the formation of 5FC should start
with furan ring cleavage of βꢀ3FC accelerated by the 6ꢀmethoxy group (Scheme 5). The
resulting intermediate (IVꢀpꢀMeOPh) is converted to 5FC by coupling with alkene 2C,
which is more reactive than 2A and 2B, concomitant with furan ring formation.
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Scheme 5 Formation mechanism of 5FC.
Subsequently, we examined the reaction using cisꢀhomocinnamyl alcohols
(Scheme 6). Their stereochemical results were found to depend on the position of the
methoxy group in homocinnamyl alcohols. Whereas transꢀ2B reacted with 1D to give
only βꢀ3DB (Scheme 4, eq. 1), the reaction of cisꢀ2B with 1D gave αꢀ3DB almost
exclusively (α : β = 14 : 1) (Scheme 6, eq. 1). The reaction of 1F and cisꢀ2B lost near
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stereospecificity to form βꢀ3FB and αꢀ3FB as a mixture with a ratio of 1 : 2 (eq. 2). On
the other hand, the reaction of homocinnamyl alcohols having a 4ꢀmethoxy group
generated βꢀisomers regardless of their alkene geometry (trans/cis). Namely, cisꢀ2C
reacted with aldehydes 1D and 1F to generate βꢀ3DC and βꢀ3FC as with the reaction of
transꢀ2C (eq. 3ꢀ4). In the case of 1F, a trace amount of 5FC was also obtained.
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Scheme 6 Cascade reaction by the use of cisꢀhomocinnamyl alcohols (Method A).
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The α/βꢀselectivity for the branched aryl group in hydroindenofurans seems to correlate
with two factors in the intermediates (II-A) and (II-B) (Scheme 7): reactivity of the
nucleophilic benzene ring and life time of a benzyl cation. These factors are affected by
the respective ring substituent style. It should be noted that 3,5ꢀdimethoxyphenyl (from
1D) is more nucleophilic than 3,4ꢀdimethoxyphenyl (from 1F). On the other hand, the
4ꢀmethoxy group presented in transꢀ and cisꢀ2c should stabilize the benzyl cation
intermediates by the resonance effect to prolong their life time. Considering these
factors, stereoselective formation of βꢀarylated hydroindenofurans in the cascade
reaction using cisꢀ2C can be explained as follows (Scheme 7 (a)). The life time of a
benzyl cation derived from cisꢀ2C is long enough to complete conformational change
from (II-B), which would be initially formed after Prins cyclization, to a more stable
form (II-A). On the other hand, the life time of a benzyl cation derived from cisꢀ2B is
not so long. In the cascade reaction of 1D and cisꢀ2B, the second cyclization is
completed prior to the conformational change to generate αꢀ3DB selectively (Scheme 7
(b)). In the cascade reaction of 1F and cisꢀ2B, the second cyclization proceeds from
both (II-A) and (II-B) after partial conformational change, resulting in the formation of
a mixture of αꢀ and βꢀ3FB (Scheme 7 (c)).
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Scheme 7 Stereochemical insight of the cascade reaction using cisꢀhomocinnamyl
alcohol.
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Since indole and pyrrole rings fused with cyclopentane are present in natural products
such as bruceolline,16 paspaline,17 yuehchukene,18 and roseophilin19 and in
pharmaceutical drugs such as laropiprant (MKꢀ0524),20 we tried to apply the cascade
reaction to the construction of these frameworks (Scheme 8).21,22 The trial began with
the cascade reaction of pyrroleꢀ2ꢀcarboxaldehyde 1H and indoleꢀ2ꢀcarboxaldehyde 1I,
of which nitrogen was not protected. However, treatment of 1H by method A resulted in
gradual decomposition and recovery of phenyl homoallylic alcohol. On the other hand,
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1
1I did not react with 2A at all. Interestingly, a H NMR spectrum of an equimolar
mixture of 1H and BF3ꢁOEt2 in CD2Cl2 showed that the peak corresponding to aldehyde
appeared to shift to a higher magnetic field than that of only 1H. This finding indicated
that BF3 coordinated with aldehyde to form an enol structure. The structure was also
confirmed by Xꢀray structural analysis. The facile enol formation should correlate with
strong electron donation by nitrogen. In order to prevent electron donation, we carried
out the cascade reaction of Nꢀtosyl pyrrole 1J with 2A under the same conditions. As
expected, pyrroleꢀfused hydrocyclopentafuran 3JA was obtained in 76% yield along
with skeletal isomer 6JA, which would be generated by a furan ring transfer from 3JA
via a CꢀO bond cleavage of the furan ring giving (VIII), two 1,2ꢀhydride shifts giving
(IX), and recyclization. The relative configuration of 3JA was determined by NOE
experiments. The reaction of Nꢀtosyl indole aldehyde 1K also proceeded well to
produce 3KA (91%) and also 6KA (4%),23 the structure of which was confirmed by
Xꢀray crystallography. Interestingly, when the cascade reaction of 1K was carried out at
room temperature, formation of 6KA increased to yield of 31%.
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Scheme 8 Cascade reaction by the use of pyrrole aldehyde and 2ꢀindole aldehyde
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(Method A).
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Indoleꢀ3ꢀcarboxyaldehyde 1L coupled with 2A to give 3LA (70%), 6LA (9%), 3KA
(2%) and 6KA (6%) (Scheme 9). The formation of 3KA in this reaction can be
explained as follows. The intermediate (X) derived from 1L and 2A mainly causes
5ꢀmembered ring closure (route a) to afford 3LA as a major product. However, also
4ꢀmembered ring closure (route b) partially occurs to give a spiro intermediate (XI),
which is converted into an oxonium ion (XII) by Grob type fragmentation.24 Finally,
5ꢀmembered ring closure of (XII) generates 3KA. Compounds 6KA and 6LA are
generated by furan ring transfer of 3LA and 3KA, respectively.
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Scheme 9 Cascade reaction of 3ꢀindole aldehyde.
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Other positional isomers of indole aldehydes 1MꢀO were next subjected to the
cascade reaction (Scheme 10). In the case of using indoleꢀ4ꢀcarboxyaldehyde 1M,
annulations proceeded in two ways to give hydrobenzoindole 3MAꢀ3 and
cyclopentafuran 3MAꢀ5 in moderate combined yields. The reaction of
indoleꢀ5ꢀcarboxyaldehyde 1N afforded two regional isomeric cyclopentafurans 3NAꢀ4
and 3NAꢀ6. Likewise, 1O coupled with 2A at two positions to give 3OAꢀ5 and 3OAꢀ7.
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Scheme 10 Cascade reaction by the use of various indole aldehydes.
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O
O
CHO
Ph
2A (1 eq.)
Ph
+
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BF3 OEt2
CH2Cl2
rt
N
Ts
N
N
Ts
Ts
3MA-3 (33%)
3MA-5 (22%)
1M (1.3 eq.)
O
Ph
O
OHC
2A (1 eq.)
+
N
BF3 OEt2
CH2Cl2
rt
Ts
Ph
N
N
Ts
Ts
1N (1.3 eq.)
3NA-4 (30%)
3NA-6 (19%)
Ph
2A (1 eq.)
O
+
N
N
OHC
Ts
O
Ts
BF3 OEt2
CH2Cl2
rt
N
Ph
Ts
3OA-5 (28%)
3OA-7 (17%)
1O (1.3 eq.)
Unexpected formation of the diquinanes 4FAF and 4GAG observed in the reactions
of 1FꢀG and 2A (Scheme 2) attracted our interest because complex and polycyclic
compounds are obtained by a single operation. We thus improved the reaction
conditions as follows. Treatment of a 3 : 1 molar mixture of 1FꢀG and 2A with BF3･
OEt2 (3 equiv.) in CH2Cl2 at room temperature afforded diquinanes 4FAF and 4GAG in
excellent yields (method B, Table 1). Also 1E reacted with 2A under the conditions to
give diquinane 4EAE in 26% yield along with 3EA (66%), but the reaction rate was
slower than that of 1FꢀG. Compound 4EAE was obtained in 91% yield when the
reaction was carried out in 1,2ꢀdichloroethane at 50 oC. Interestingly, the reaction of 1D
with 2A stopped at indenofuran 3DA and did not give 4DAD even by method B.
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Table 1 Cascade reaction of 1 (3 eq.) and 2A (1 eq.) at room temperature (Method B)
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Scheme 11 Cascade reaction of pyrroleꢀ and/or indoleꢀfused cyclopentafuran
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We next examined whether 3JA and 3KA reacted with another molecule of heterocyclic
aldehydes (Scheme 11). Treatment of 3JA and 1J having a pyrrole ring with BF3ꢁOEt2
in CH2Cl2 at room temperature showed many spots on TLC. Interestingly, the main
product of them was 7JAJ rather than 4JAJ that we anticipated. Furthermore, cascade
reaction of 3KA and aldehyde 1K resulted in a similar cyclization mode to generate
7KAK in high yield, the structure of which was unambiguously identified by Xꢀray
crystallography. The formation of diquinanes 7JAJ and 7KAK seems to include the
migration step of an alkene bond (from (XIV) to (XVII)) (Scheme 12). Complete
migration might be correlated with strong steric repulsion between the tosyl group and
the indole skeleton. If (XIV) proceeds on the regular pathway (i.e. Prins cyclization as it
is), a spirocyclic intermediate (XVI) would be formed. However, it should be difficult
for FriedelꢀCrafts cyclization of (XVI) to proceed due to the steric repulsion.
Intermediate (XIV) is inevitably isomerized to (XVII), which then undergoes Prins
cyclization with aldehyde 1K. FriedelꢀCrafts reaction of (XIX) has less steric repulsion
and thus proceeds smoothly to produce 7KAK.
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Scheme 12 Formation mechanism of 7KAK
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With anticipation for preparing more divergent polycyclic frameworks, the coupling
between hydrocyclopentafurans and aromatic aldehydes was applied to the combination
of two substrates having different aromatic rings as shown in Table 2 (cross cascade
reaction). Hydroindenofuran 3EA reacted with mꢀanisaldehyde 1B to generate
polycyclic diquinanes 4EABꢀp (66%) and 4EABꢀo (9%) upon treatment with BF3ꢁOEt2
o
in 1,2ꢀdichloroethane at 50 C. Similarly, 3EA reacted with 1F to give 4EAF in 76%
yield. Also, 3FA coupled with 1B and 1E to afford 4FABꢀp, 4FABꢀo and 4FAE. We
also examined the cross cascade reaction using indole aldehyde 1K or indoleꢀfused
cyclopentafuran 3KA. As we expected, coupling of 1K and 3FA afforded 4FAK in 90%
yield. However, coupling of 1F and 3KA afforded 7KAF rather than 4KAF.
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Table 2 Cross cascade reactions of various cyclopentafurans and aromatic aldehydes
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R6
R3
R5
R4
R2
R1
H
CHO
H
O
1B (R4=OMe, R5=R6=H)
1E
3EA (R1=R2=R3=OMe)
3FA (R1=R2=OMe, R3=H)
BF3 OEt2
(R4=R5=R6=OMe)
4 or 7KAF
1F (R4=R5=OMe, R6=H)
rt, CH2Cl2 (Method B)
or
Ph
H
50 oC, ClCH2CH2Cl (Method C)
H
N
N
Ts
O
Ts
H
O
1K
3KA
MeO
MeO
MeO
MeO
MeO
MeO
MeO
MeO
O
O
H
O
H
H
MeO
H
H
H
MeO
OMe
OMe
MeO
4EAB-o (9% from 3EA + 1B)
by Method C
4EAF (76% from 3EA + 1F)
by Method C
4EAB
-p (66% from
by Method C
3EA 1B
+
)
MeO
MeO
MeO
MeO
MeO
O
H
O
O
H
H
MeO
H
H
H
OMe
MeO
OMe
OMe
MeO
4FAB
-p (79% from
by Method B
3FA 1B
)
4FAB
-o (20% from
by Method B
3FA 1B
4FAE
3FA 1E
+
+
)
(98% from
+
)
by Method B
MeO
Ph
OMe
Ph
O
O
H
Ph
N
NTs
MeO
MeO
Ts
H
O
OMe
N
Ts
MeO
4FAK (90% from 3FA + 1K)
by Method B
7KAF (94% from 3KA + 1F)
by Method B
4KAF (not obtained)
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CONCLUSION
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We have reported a novel cascade reaction of homoallylic alcohols linked to
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various aryl groups and aromatic aldehydes. Treatment of a homocinnamyl alcohol 2
and benzaldehydes, pyrrole aldehyde or indole aldehydes with BF3 generates
cyclopentafurans 3 fused with various aromatic rings through 5ꢀringꢀselective Prins
cyclization and subsequent FriedelꢀCrafts cyclization. In some cases, the resulting 3 was
found to be further converted into diquinanes 4 stuck in two aromatic rings upon
treatment with another molecule of aromatic aldehyde in the presence of BF3 at room
temperature. The reaction mechanism of the second cascade reaction also consists of
Prins cyclization and subsequent FriedelꢀCrafts cycliczation. These cascade reactions
can be applied to the divergent synthesis of complex polycyclic compounds containing a
diquinane skeleton in the central part.
EXPERIMENTAL SECTION
General. Melting points were determined on a Yanagimoto MPꢀS3 micro melting point
1
apparatus and were uncorrected. IR spectra were recorded on a JASCO FT/IRꢀ4100. H
and 13C NMR spectra were recorded on a JEOL JNNꢀECXꢀ400 spectrometer at 400 and
100 MHz, respectively. Chemical shifts were expressed in δ parts per million with
1
tetramethylsilane as internal standard (δ = 0 ppm) for H NMR. Chemical shifts of
carbon signals were referenced to CDCl3 (δC = 77.0 ppm), Benzeneꢀd6 (δC = 128.0 ppm).
The following abbreviations are used: s = singlet, d = doublet, t = triplet, q = quartet, m
= multiplet, and br = broad. EIꢀmass spectra were recorded on a JEOL JMSꢀGCmate II.
FABꢀmass spectra were recorded on a JEOL JMSꢀ700. Column chromatography was
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carried out on Merck’s Silica gel 60 (70ꢀ230 mesh ASTM). Dehydrated
Dichloromethane (CH2Cl2) was purchased from Kanto Chemical and used without
further purification.
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Synthesis of Nꢀtosyl pyrrole aldehyde (1J). To a solution of 1H (0.208 g, 2.19
mmol) in CH2Cl2 (22 mL) was added TsCl (0.836 g, 4.38 mmol), Et3N (0.9 mL, 6.42
o
mmol), N,Nꢀdimethylꢀ4ꢀaminopyridine (53.5 mg, 0.438 mmol) at 0 C under an argon
atmosphere. After being stirred for 25 hours at room temperature, the reaction mixture
was quenched with saturated aqueous NH4Cl and extracted with CH2Cl2. The combined
organic phase was dried over Na2SO4 and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel eluted with hexaneꢀAcOEt
(3: 1) to give 1J (0.531 mg, 97%) as pale yellow crystal. The spectral data showed good
agreement with the reported data.25
Typical synthetic procedure of Nꢀtosyl indole aldehydes (1KꢀO). To a solution
o
of indole aldehyde (1 eq.) in DMF was added NaH (1.5 eq.) and TsCl (2 eq.) at 0 C
under an argon atmosphere. After being stirred for 1.5ꢀ2.5 hours at room temperature,
the reaction mixture was quenched with water and extracted with Et2O. The organic
layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography on silica gel to give 1KꢀO as pale yellow crystal.
1ꢀTosylꢀ1Hꢀindoleꢀ2ꢀcarbaldehyde (1K): 0.388 g, 88%; The spectral data
showed good agreement with the reported data.26
1ꢀTosylꢀ1Hꢀindoleꢀ3ꢀcarbaldehyde (1L): 0.215 g, 92%; The spectral data
showed good agreement with the reported data.25
1ꢀTosylꢀ1Hꢀindoleꢀ4ꢀcarbaldehyde (1M): 0.204 g, 96%; mp 143.7ꢀ144.5 oC; 1H
NMR (CDCl3, 400 MHz) δ 10.17 (1H, s), 8.27 (1H, d, J = 8.4 Hz), 7.78ꢀ7.75 (3H, m),
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7.71 (1H, d, J = 6.8 Hz), 7.49ꢀ7.45 (2H, m), 7.23 (2H, d, J = 8.8 Hz), 2.33 (3H, s); 13C
NMR (CDCl3, 100 MHz) δ 192.2 (CH), 145.5 (C), 135.5 (C), 135.1 (C), 130.1 (2C,
CH), 129.5 (2C, CH), 129.0 (C), 128.9 (C), 126.9 (2C, CH), 124.3 (CH), 119.3 (CH),
108.5 (CH), 21.6 (CH3); IR (KBr) 3117, 2801, 2731, 1697, 1581, 1366, 1180, 1142,
1119, 1088, 671 cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for C16H13NO3S [M]+ 299.0616,
found 299.0590.
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1ꢀTosylꢀ1Hꢀindoleꢀ5ꢀcarbaldehyde (1N): 0.248 g, 93%; mp 134.6ꢀ135.4 oC; 1H
NMR (CDCl3, 400 MHz) δ 10.03 (1H, s), 8.11 (1H, d, J = 8.8 Hz), 8.06 (1H, d, J = 0.8
Hz), 7.85 (1H, dd, J = 8.8 1.2 Hz), 7.79 (2H, d, J = 8.4 Hz), 7.67 (1H, d, J = 3.6 Hz),
7.25 (2H, d, J = 8.4 Hz), 6.77 (1H, d, J = 3.2 Hz), 2.34 (3H, s); 13C NMR (CDCl3, 100
MHz) δ 191.8 (CH), 145.6 (C), 138.1 (C), 135.0 (C), 132.3 (C), 130.9 (C), 130.1 (2C,
CH), 128.1 (CH), 126.9 (2C, CH), 125.3 (CH), 124.8 (CH), 114.0 (CH), 109.4 (CH),
21.6 (CH3); IR (KBr) 3132, 3109, 2816, 1690, 1597, 1366, 1273, 1165, 1150, 1111,
1088 cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for C16H13NO3S [M]+ 299.0616, found
299.0625.
1ꢀTosylꢀ1Hꢀindoleꢀ6ꢀcarbaldehyde (1O): 0.208 g, 95%; mp 155.4ꢀ157.1 oC; 1H
NMR (CDCl3, 400 MHz) δ 10.08 (1H, s), 8.49 (1H, s), 7.80 (2H, d, J = 8.4 Hz),
7.78ꢀ7.76 (2H, m), 7.25 (2H, d, J = 8.8 Hz), 6.73 (1H, d, J = 3.6 Hz), 2.34 (3H, s); 13C
NMR (CDCl3, 100 MHz) δ 191.9 (CH), 145.6 (C), 135.7 (C), 135.0 (C), 134.6 (C),
130.3 (C), 130.2 (3C, CH), 126.9 (2C, CH), 123.8 (CH), 122.0 (CH), 116.4 (CH), 109.0
(CH), 21.6 (CH3); IR (KBr) 3132, 3109, 2816, 2731, 1690, 1597, 1427, 1366, 1273,
1173, 1126, 1088, 1003 cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for C16H13NO3S [M]+
299.0616, found 299.0601.
Typical procedure of the cascade reaction (Method A). To a solution of 1 (1.3
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eq.) and 2 (1 eq.) in CH2Cl2 was added borontrifluoride diethylether complex (3 eq.) at
0 oC or room temperature under an argon atmosphere. After being stirred for minutes or
hours, the reaction mixture was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel to give 3. If polarities of product and aromatic aldehyde 1
are close, the crude was subjected to column chromatography on silica gel after
treatment with NaBH4 in MeOH.
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Typical procedure of the cascade reaction (Method B). To a solution of 2 (or 3)
and three equivalents of 1 in CH2Cl2 was added borontrifluoride diethylether complex
(3 eq.) at room temperature under an argon atmosphere. After being stirred for hours,
the reaction mixture was quenched with saturated aqueous NaHCO3 and extracted with
CH2Cl2. The organic layer was dried over anhydrous MgSO4 and concentrated under
reduced pressure. The residue was purified by column chromatography on silica gel to
give 4 or 7.
Typical procedure of the cascade reaction (Method C). To a solution of 2 (or 3)
and three equivalents of 1 in 1,2ꢀdichloroethane was added borontrifluoride diethylether
complex (3 eq.) at room temperature under an argon atmosphere. After being stirred for
hours at 50 oC, the reaction mixture was quenched with saturated aqueous NaHCO3 and
extracted with CH2Cl2. The organic layer was dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was purified by column
chromatography on silica gel to give 4.
(3aS,4R,8bS)ꢀrelꢀ7ꢀMethoxyꢀ4ꢀphenylꢀ3,3a,4,8bꢀtetrahydroꢀ2Hꢀindeno[1,2ꢀb]f
uran (3BAꢀp): 0.246 g, 91%; 1H NMR (CDCl3, 400 MHz) δ 7.29 (2H, m), 7.21 (1H, m),
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7.08 (2H, m), 7.00 (1H, d, J = 2.0 Hz), 6.88 (1H, d, J = 8.0 Hz), 6.83 (1H, dd, J = 8.0,
2.0 Hz), 5.57 (1H, d, J = 6.8 Hz), 4.16 (1H, d, J = 3.6 Hz), 3.94 (1H, m), 3.82 (3H, s),
3.78 (1H, dt, J = 8.0, 6.4 Hz), 3.08 (1H, m), 2.24 (1H, m), 1.94 (1H, m); 13C NMR
(CDCl3, 100 MHz) δ 159.6 (C), 145.9 (C), 143.4 (C), 138.1 (C), 128.5 (2C, CH), 127.5
(2C, CH), 126.3 (CH), 126.0 (CH), 116.5 (CH), 109.0 (CH), 86.6 (CH), 67.6 (CH2),
56.7 (CH), 55.3 (CH3), 53.5 (CH), 33.8 (CH2); IR (film) 2941, 2864, 1609, 1491, 1254
cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for C18H18O2 [M]+ 266.1307, found 266.1287.
(3aS,4R,8bS)ꢀrelꢀ5ꢀMethoxyꢀ4ꢀphenylꢀ3,3a,4,8bꢀtetrahydroꢀ2Hꢀindeno[1,2ꢀb]f
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uran (3BAꢀo): 16.7 mg, 6%; mp 128.3ꢀ129.0 C; H NMR (CDCl3, 400 MHz) δ 7.31
(1H, t, J = 7.6 Hz), 7.24 (2H, t, J = 7.6 Hz), 7.20ꢀ7.13 (1H, m), 7.09 (1H, d, J = 7.2 Hz),
7.07ꢀ7.01 (2H, m), 6.75 (1H, d, J = 8.0 Hz), 5.70 (1H, d, J = 7.6 Hz), 4.33 (1H, d, J =
2.0 Hz), 3.84 (1H, ddd, J = 8.0, 6.8, 5.2 Hz), 3.69ꢀ3.63 (4H, m), 3.01ꢀ2.95 (1H, m),
2.32ꢀ2.23 (1H, m), 1.88ꢀ1.80 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 156.2 (C), 145.4
(C), 144.3 (C), 132.8 (C), 129.7 (CH), 128.2 (2C, CH), 127.1 (2C, CH), 125.9 (CH),
117.4 (CH), 110.3 (CH), 86.8 (CH), 67.2 (CH2), 55.2 (CH3), 54.5 (CH), 52.5 (CH), 34.3
(CH2); IR (KBr) 2965, 2938, 2891, 2855, 1591, 1481, 1269, 1055, 760 cmꢀ1; HRMS (EI
doubleꢀfocusing) calcd for C18H18O2 [M]+266.1307, found 266.1305.
,
(3aS,4R,8bS)ꢀrelꢀ5,7ꢀDimethoxyꢀ4ꢀphenylꢀ3,3a,4,8bꢀtetrahydroꢀ2Hꢀindeno[1,2
o
ꢀb]furan (3DA): 0.163 g, 92%; mp 167.0ꢀ167.5 C; 1H NMR (CDCl3, 400 MHz) δ 7.24
(2H, m), 7.16 (1H, m), 7.03 (2H, m), 6.60 (1H, d, J = 2.0 Hz), 6.34 (1H, d, J = 2.4 Hz),
5.64 (1H, d, J = 7.2 Hz), 4.25 (1H, d, J = 2.0 Hz), 3.84 (1H, m), 3.83 (3H, s), 3.68 (1H,
m), 3.60 (3H, s), 2.96 (1H, m), 2.27 (1H, m), 1.85 (1H, m); 13C NMR (CDCl3, 100
MHz) δ 161.6 (C), 156.8 (C), 145.7 (C), 144.8 (C), 128.2 (2C, CH), 127.0 (2C, CH),
125.8 (CH), 125.2 (C), 99.6 (CH), 99.4 (CH), 86.8 (CH), 67.3 (CH2), 55.4 (CH3), 55.1
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(CH3), 53.9 (CH), 52.8 (CH), 34.2 (CH2); IR (KBr) 2938, 2886, 1459, 1340, 1117 cmꢀ1;
HRMS (EI, doubleꢀfocusing) calcd for C19H20O3 [M]+ 296.1412, found 296.1424.
(3aS,4R,8bS)ꢀrelꢀ5,6,7ꢀTrimethoxyꢀ4ꢀphenylꢀ3,3a,4,8bꢀtetrahydroꢀ2Hꢀindeno[1
,2ꢀb]furan (3EA): 0.176g, 90%; 1H NMR (CDCl3, 400 MHz) δ 7.27 (2H, m), 7.18 (1H,
m), 7.07 (2H, m), 6.79 (1H, s), 5.64 (1H, d, J = 6.8 Hz), 4.27 (1H, d, J = 2.4 Hz), 3.89
(3H, s), 3.86 (1H, m), 3.80 (3H, s), 3.72 (1H, m), 3.32 (3H, s), 3.00 (1H, m), 2.25 (1H,
m), 1.88 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 154.4 (C), 149.6 (C), 146.1 (C), 142.7
(C), 137.7 (C), 131.0 (C), 128.3 (2C, CH), 127.2 (2C, CH), 126.1 (CH), 103.1 (CH),
87.1 (CH), 67.3 (CH2), 60.6 (CH3), 59.9 (CH3), 55.9 (CH3), 55.1 (CH), 52.9 (CH), 34.3
(CH2); IR (film) 2972, 2938, 1458, 1215 cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for
C20H22O4 [M]+ 326.1518, found 326.1488.
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(3aS,4R,8bS)ꢀrelꢀ6,7ꢀDimethoxyꢀ4ꢀphenylꢀ3,3a,4,8bꢀtetrahydroꢀ2Hꢀindeno[1,2
o
1
ꢀb]furan (3FA): 0.146 g, 82%; mp 91.0ꢀ92.5 C; H NMR (CDCl3, 400 MHz) δ 7.29
(2H, m), 7.22 (1H, m), 7.09 (2H, m), 6.98 (1H, s), 6.44 (1H, s), 5.57 (1H, d, J = 6.8 Hz),
4.16 (1H, d, J = 3.6 Hz), 3.91 (1H, m), 3.91 (3H, s), 3.91 (1H, m), 3.74 (3H, s), 3.73
(1H, m), 3.04 (1H, m), 2.21 (1H, m), 1.94 (1H, m); 13C NMR (CDCl3, 100 MHz) δ
150.3 (C); 149.2 (C), 145.9 (C), 138.0 (C), 133.9 (C), 128.6 (2C, CH), 127.5 (2C, CH),
126.4 (CH), 107.2 (2C, CH), 86.8 (CH), 67.3 (CH2), 57.6 (CH), 55.8 (2C, CH3), 53.6
(CH), 33.9 (CH2); IR (KBr) 2961, 2851, 1655 cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd
for C19H20O3 [M]+ 296.1412, found 296.1427.
(3aS,4R,8bS)ꢀrelꢀ6,7ꢀDiethoxyꢀ4ꢀphenylꢀ3,3a,4,8bꢀtetrahydroꢀ2Hꢀindeno[1,2ꢀb
]furan (3GA): 0.160 g, 82%; 1H NMR (CDCl3, 400 MHz) δ 7.29 (2H, m), 7.21 (1H, m),
7.07 (2H, m), 6.97 (1H, s), 6.44 (1H, s), 5.53 (1H, d, J = 6.8 Hz), 4.12 (3H, m), 3.93
(2H, q, J = 6.8 Hz), 3.91 (1H, m), 3.75 (1H, dt, J = 8.8, 6.0 Hz), 3.02 (1H, m), 2.19 (1H,
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m), 1.94 (1H, m), 1.46 (3H, t, J = 6.8 Hz), 1.36 (3H, t, J = 6.8 Hz); 13C NMR (CDCl3,
100 MHz) δ 150.0 (C), 148.9 (C), 145.9 (C), 138.1 (C), 134.0 (C), 128.5 (2C, CH),
127.5 (2C, CH), 126.3 (CH), 109.4 (CH), 109.2 (CH), 86.8 (CH), 67.3 (CH2), 64.4 (2C,
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)
CH2), 57.5 (CH), 53.7 (CH), 33.8 (CH2 , 14.8 (CH3), 14.6 (CH3); IR (film) 2976, 2932,
2870, 1740, 1605, 1506 cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for C21H24O3 [M]+
324.1725, found 324.1706.
(3aS,4R,8bS)ꢀrelꢀ5,7ꢀDimethoxyꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ3,3a,4,8bꢀtetrahydroꢀ2H
ꢀindeno[1,2ꢀb]furan (βꢀ3DB): 30.4 mg, 90%; mp 94.8ꢀ95.3 C; 1H NMR (CDCl3, 400
o
MHz) δ 7.16 (1H, t, J = 8.4 Hz), 6.70 (1H, dd, J = 8.4, 2.4 Hz), 6.63 (1H, d, J = 8.0 Hz),
6.60ꢀ6.58 (2H, m), 6.34 (1H, d, J = 2.4 Hz), 5.63 (1H, d, J = 7.2 Hz), 4.23 (1H, d, J =
1.6 Hz), 3.86ꢀ3.81 (4H, m), 3.76 (3H, s), 3.67 (1H, q, J = 7.6 Hz), 3.62 (3H, s),
13
2.98ꢀ2.92 (1H, m), 2.31ꢀ2.22 (1H, m), 1.87ꢀ1.79 (1H, m); C NMR (CDCl3, 100 MHz)
δ 161.6 (C), 159.5 (C), 156.8 (C), 147.5 (C), 144.8 (C), 129.1 (CH), 125.0 (C), 119.4
(CH), 113.1 (CH), 110.7 (CH), 99.7 (CH), 99.4 (CH), 86.8 (CH), 67.3 (CH2), 55.4
(CH3), 55.2 (CH3), 55.0 (CH3), 53.9 (CH), 52.7 (CH), 34.2 (CH2); IR (KBr) 2961, 2897,
2845, 1608, 1487, 1261, 1204, 1139, 1051 cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for
C20H22O4 [M]+ 326.1518, found 326.1503.
(3aS,4R,8bS)ꢀrelꢀ6,7ꢀDimethoxyꢀ4ꢀ(3ꢀmethoxyphenyl)ꢀ3,3a,4,8bꢀtetrahydroꢀ2H
ꢀindeno[1,2ꢀb]furan (βꢀ3FB): 73.9 mg, 72%; 1H NMR (CDCl3, 400 MHz) δ 7.22 (1H, t,
J = 8.0 Hz), 6.97 (1H, s), 6.77 (1H, dd, J = 8.4, 0.8 Hz), 6.68 (1H, d, J = 7.6 Hz), 6.62
(1H, dd, J = 2.4, 2.0 Hz), 6.46 (1H, s), 5.57 (1H, d, J = 6.8 Hz), 4.13 (1H, d, J = 4.0 Hz),
3.94ꢀ3.89 (4H, m), 3.77 (3H, s), 3.76ꢀ3.70 (4H, m), 3.07ꢀ3.01 (1H, m), 2.26ꢀ2.16 (1H,
m), 1.96ꢀ1.89 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 159.7 (C), 150.2 (C), 149.1 (C),
147.5 (C), 137.7 (C), 133.8 (C), 129.5 (CH), 119.9 (CH), 113.5 (CH), 111.2 (CH), 107.2
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(CH), 107.1 (CH), 86.7 (CH), 67.2 (CH2), 57.6 (CH), 55.8 (2C, CH3), 55.0 (CH3), 53.4
(CH), 33.9 (CH2); IR (film) 3001, 2955, 2864, 2833, 1607, 1584, 1504, 1265, 1225,
1103, 1049, 756 cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for C20H22O4 [M]+ 326.1518,
found 326.1522.
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(3aS,4R,8bS)ꢀrelꢀ7ꢀMethoxyꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ3,3a,4,8bꢀtetrahydroꢀ2Hꢀind
1
eno[1,2ꢀb]furan (βꢀ3BCꢀp): 72.2 mg, 72%; H NMR (CDCl3, 400 MHz) δ 7.02ꢀ6.99
(3H, m), 6.88ꢀ6.81 (4H, m), 5.55 (1H, d, J = 6.8 Hz), 4.11 (1H, d, J = 4.4 Hz), 3.93 (1H,
ddd, J = 8.0, 7.2, 4.0 Hz), 3.82 (3H, s), 3.80ꢀ3.74 (4H, m), 3.06ꢀ3.01 (1H, m), 2.26ꢀ2.17
(1H, m), 1.96ꢀ1.89 (1H, m); 13C NMR (CDCl3, 100 MHz) δ 159.5 (C), 158.1 (C), 143.3
(C), 138.5 (C), 138.0 (C), 128.4 (2C, CH), 126.0 (CH), 116.5 (CH), 113.9 (2C, CH),
109.0 (CH), 86.6 (CH), 67.7 (CH2), 55.9 (CH), 55.3 (CH3), 55.2 (CH3), 53.7 (CH), 33.7
(CH2); IR (film) 2999, 2953, 2864, 2835, 1609, 1510, 1493, 1252, 1178, 1034, 824, 756
cmꢀ1; HRMS (EI, doubleꢀfocusing) calcd for C19H20O3 [M]+ 296.1413, found 296.1411.
(3aS,4R,8bS)ꢀrelꢀ5ꢀMethoxyꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ3,3a,4,8bꢀtetrahydroꢀ2Hꢀind
eno[1,2ꢀb]furan (βꢀ3BCꢀo): 13.8 mg, 14%; 1H NMR (CDCl3, 400 MHz) δ 7.30 (1H, t, J
= 7.6 Hz), 7.08 (1H, d, J = 8.0 Hz), 6.98ꢀ6.94 (2H, m), 6.80ꢀ6.74 (2H, m), 6.75 (1H, d, J
= 8.4 Hz), 5.69 (1H, d, J = 7.6 Hz), 4.29 (1H, d, J = 1.2 Hz), 3.86ꢀ3.81 (1H, m), 3.77
(3H, s), 3.68ꢀ3.62 (4H, m), 2.97ꢀ2.91 (1H, m), 2.31ꢀ2.22 (1H, m), 1.86ꢀ1.78 (1H, m);
13C NMR (CDCl3, 100 MHz) δ 157.7 (C), 156.2 (C), 144.2 (C), 137.6 (C), 133.1 (C),
129.6 (CH), 128.0 (2C, CH), 117.3 (CH), 113.5 (2C, CH), 110.3 (CH), 86.7 (CH), 67.3
(CH2), 55.2 (CH3), 55.1 (CH3), 53.6 (CH), 52.7 (CH), 34.2 (CH2); IR (film) 3005, 2938,
2864, 2835, 1593, 1510, 1479, 1265, 1252, 1057, 1038, 758 cmꢀ1; HRMS (EI
doubleꢀfocusing) calcd for C19H20O3 [M]+ 296.1413, found 296.1393.
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(3aS,4R,8bS)ꢀrelꢀ5,7ꢀDimethoxyꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ3,3a,4,8bꢀtetrahydroꢀ2H
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