Bidentate Lewis acids for the activation of 1,2-diazines - A new mode of catalysis

Article abstract of DOI:10.1002/ejoc.201100335

Bidentate Lewis acids were applied as catalysts for the inverse-electron-demand Diels-Alder (IEDDA) reaction of 1,2-diazines. The concept of catalysis is based on the coordination of the bidentate Lewis acid to both nitrogen atoms of the 1,2-diazine moiety, thereby reducing the electron density and lowering the energy of the LUMO. This should, according to frontier molecular orbital (FMO) theory, facilitate the cycloaddition step. This new concept was successfully applied to a variety of dienophiles and substituted phthalazine substrates. Careful investigations of the mechanism led to the isolation and characterization of key intermediates; all of which support the presented catalytic cycle. Copyright

Full text of DOI:10.1002/ejoc.201100335

FULL PAPER
DOI: 10.1002/ejoc.201100335
Bidentate Lewis Acids for the Activation of 1,2-Diazines – A New Mode of
Catalysis
[a]
[a]
[a]
Simon N. Kessler, Markus Neuburger, and Hermann A. Wegner*
Keywords: Cycloaddition / Lewis acids / Naphthalenes / Boranes
Bidentate Lewis acids were applied as catalysts for the in-
verse-electron-demand Diels–Alder (IEDDA) reaction of 1,2-
diazines. The concept of catalysis is based on the coordina-
tion of the bidentate Lewis acid to both nitrogen atoms of the
ing to frontier molecular orbital (FMO) theory, facilitate the
cycloaddition step. This new concept was successfully ap-
plied to a variety of dienophiles and substituted phthalazine
substrates. Careful investigations of the mechanism led to
the isolation and characterization of key intermediates; all of
which support the presented catalytic cycle.
1,2-diazine moiety, thereby reducing the electron density
and lowering the energy of the LUMO. This should, accord-
Introduction
Results and Discussion
Synthesis of the Bidentate Lewis Acid
One of the most important goals in catalysis is to develop
new modes of activation. In this context, Lewis acids play
an important role in promoting a plethora of chemical
Initially, the bidentate Lewis acid 4 based on the bor-
anthrene scaffold was prepared by a four-step sequence, ac-
cording to literature procedures, with an overall yield of less
transformations.[1] The majority of reactions, though, are
initiated by a monodentate Lewis acid catalyst, which can
[
7]
than 5%. Therefore, we optimized the synthesis to provide
a very robust route that yielded the desired bidentate Lewis
acid in only three steps (Scheme 1). In doing so, simple,
cheap, starting materials were used, and the reactions could
be carried out on a multi-millimol scale. The preparation
started with an iron-catalyzed Grignard reaction of 1,2-di
only coordinate at one site. Although there are examples of
bidentate Lewis acids in catalysis,[2] in nearly all of these
cases the catalysts bind only to one atom of the substrate.
There have been reports on the simultaneous binding of
bidentate Lewis acids to 1,2-dinitrogen compounds, such as
[
3]
1
,2-diazines, but never in the context of catalysis. Re-
cently, we reported the proof of concept for the catalysis of
an inverse-electron-demand Diels–Alder (IEDDA) reaction
of 1,2-diazines, using a bidentate Lewis acid.[ The IEDDA
4]
[
5,6]
of 1,2-diazines was initially described over 25 years ago.
However, due to the relatively high energy of the LUMO of
,2-diazines, the reaction requires harsh conditions that li-
1
mit the utility of this valuable transformation. With the aid
of a bidentate Lewis acid, the reaction can now be con-
ducted under milder conditions at lower temperatures,
which also allows for considerable broadening of the sub-
strate scope.
Herein, we investigate the scope as well as the mechanism
of the catalyzed IEDDA reaction and provide experimental
data to support the mechanistic rationale for this new mode
of catalysis.
[
a] Department of Chemistry, University of Basel
St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax: +41-61-267-09-76
Scheme 1. Three-step preparation of the bidentate Lewis acid 4.
TMEDA = N,N,NЈNЈ-tetramethylethylenediamine, DIBALH = di-
isobutylaluminum hydride, TMSCl = trimethylsilyl chloride, 1,2-
DCE = 1,2-dichloroethane.
E-mail: Hermann.wegner@unibas.ch
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100335.
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Bidentate Lewis Acids for the Activation of 1,2-Diazines
bromobenzene (1), which was developed in our group.[8,9] Table 1. Different enamines in the Lewis acid catalyzed IEDDA
with phthalazine.[
a]
Although this new protocol gives 1,2-bis(TMS)aryl com-
pounds only in moderate yields, it allows for the multigram
preparation of the desired intermediate 2. Next, the original
two-step process to access the dichloroboranthrene 3 was
shortened to one step. For this transformation, it is critical
to use 1,2-DCE as the solvent at high temperatures in a
sealed pressure tube. After the reaction was complete and
the mixture had cooled to room temperature, the air- and
moisture-sensitive product was obtained as white needles,
which after washing with hexanes could be used without
further purification. The final attachment of the Me group
was achieved by using AlMe to yield the desired bidentate
3
Lewis acid 4.
Scope of the Reaction
The use of bidentate Lewis acid catalysis allows for a
wide range of dienophiles to be employed in the IEDDA
reaction with phthalazines. The order of reactivity corre-
sponds nicely to the study by Sauer et al., in which the
IEDDA of 1,2,4,5-tetrazine with various dienophiles was
[
10]
investigated. One of the best classes of substrates in this
report were enamines. Accordingly, these compounds also
performed very well in our catalyzed IEDDA. By em-
ploying a bidentate Lewis acid catalyst, the reaction tem-
perature could be decreased to as low as 55 °C in some
cases (Table 1, Entry 1). The enamine can also be prepared
in situ from the corresponding ketone and a secondary
amine (in this case pyrrolidine).[ It is noteworthy that the
[
%
a] Phthalazine (1.00 equiv.), enamine (3.00 equiv.), catalyst (5 mol-
), diglyme; workup with m-chloroperbenzoic acid (mCPBA). [b]
All enamines were prepared in situ from the corresponding ketone
11]
activity of the catalyst is not disturbed by the presence of and pyrrolidine, unless stated otherwise. [c] The enamine was pre-
pared separately prior to use.
the free amine or the water formed during this process. In
fact, the addition of molecular sieves or MgSO to remove
4
the water actually had adverse effects and inhibited the re-
action. Enamines that are difficult to isolate, such as en-
amine 7d, can still be used in this catalytic IEDDA reaction
by preparing them in situ.[ Thus, enamine 7d provided
12]
3
the corresponding 2,3-substituted naphthalene 6d (Table 1, 2.2ϫ10 times less reactive than N,N-dimethylcyclopent-1-
Entry 4). With this procedure, essentially any ketone that is enamine (7a). Although the temperature had to be raised
able to form an enamine can be incorporated into an aro- to 170 °C, we found that dihydrofurans smoothly under-
matic structure. For example, the catalyzed IEDDA reac- went an IEDDA with phthalazines in the presence of the
tion of enamines 7e and 7f derived from 1- and 2-indanone bidentate Lewis acid catalyst 4 (Table 2, Entry 1). In most
gave, in one step, access to tetracyclic ring structures cases, Hünig’s base was added to suppress polymerization
[
15]
(
Table 1, Entries 5 and 6) that display the core of the natu- of the dienophiles. The use of substituted dihydrofurans
[13]
ral product Kinafluorenone.
In addition to enamines, in the reaction provides access to 2,3-disubstituted naphthal-
N,O-substituted alkene 7g also served as an excellent sub- enes, which are otherwise difficult to prepare. The resulting
strate for the catalyzed IEDDA (Table 1, Entry 7). Al- regioisomeric products can be explained by an endo/exo
though elimination of either the N or the O residue is feas- isomerization of the double bond during the reaction. The
ible, only the extrusion of OEt is observed, giving rise to free alcohol formed during re-aromatization in the reaction
the annulated tetrahydroquinoline 6g in quantitative yield. did not seem to influence the activity of the bidentate Lewis
This structural theme is also present in compounds such as acid. Importantly, in the absence of catalyst, no reaction
Kalasinamide, which was isolated in 2000 from the acetone was observed for any of the cases. In contrast to dihydro-
extract of Polyalthia suberosa.[
14]
furan substrates, 2,3-dihydropyran (10) did not react
In contrast to enamines, enols, such as dihydrofurans, are (Table 2, Entry 5). This was not surprising, because the
much less activated for the IEDDA reaction. For example, study by Sauer et al. demonstrated that the pyran derivative
Sauer et al. reported that 2,3-dihydrofuran (8a) was is 250 times less reactive than furan.
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S. N. Kessler, M. Neuburger, H. A. Wegner
FULL PAPER
Table 2. Different dienophiles in the Lewis acid catalyzed IEDDA
with phthalazine (5).
Table 3. Lewis acid catalyzed IEDDA of substituted 1,2-diazines.
[
a]
[
(
a] Phthalazine (1.00 equiv.), dienophile (2.00–3.00 equiv.), catalyst
5 mol-%), diglyme/Hünigs base (3:1); workup included UV irradi-
ation.
In addition to exploring the scope of the dienophiles, dif-
ferent 1,2-diazines were also investigated. Besides the parent
phthalazine (5), substituted derivatives were screened. For
example, substitution with chlorine was found to facilitate
the process (Table 3, Entry 1). The electron-withdrawing
properties of chlorine cause a reduction of electron density
at the phthalazine moiety, leading to a decreased LUMO
energy, which is beneficial for its part as a diene in the
Mechanistic Investigations
A proposal for the mechanism of the uncatalyzed
IEDDA reaction. Surprisingly, groups that are also able to IEDDA reaction of 1,2-diazines has been put forward by
[
16]
coordinate to the bidentate Lewis acid gave moderate yields Heuschmann and co-workers (Scheme 2).
After the ini-
of the desired naphthalene derivative. For example, 5-nitro- tial cycloaddition step of the diazine A with the dienophile
phthalazine (11b) can be treated with various dihydrofurans B to adduct C, N is spontaneously expelled to form inter-
2
to give the substituted products 12. It is noteworthy that mediate D. The resulting diene then undergoes aromatiza-
the reaction can even be performed at room temperature, tion to give product E.
albeit with lower yield (Table 3, Entry 4). In this case, the
Our initial proposal for the mode of action of the biden-
high tendency of the dienophile to polymerize might cause tate Lewis acid was based on the following thought: the
the reduction of product formation. Pyridazine (14a), how- Lewis acid will coordinate to the diazine and, therefore,
ever, did not show any reaction in the bidentate Lewis acid lower the energy of its LUMO. This should facilitate the
catalyzed IEDDA reaction (Table 3, Entry 5). Attachment critical step: the cycloaddition. Expulsion of N will elimin-
2
of an electron-withdrawing group (Cl) also did not facilitate ate the coordinating group and free the catalyst, thereby
the transformation (Table 3, Entry 6). Although in this case, closing the catalytic cycle. At the outset, we verified the
1
turnover was observed in the crude H NMR spectrum, no concept by DFT calculations, which predicted a lowering
product could be isolated. This observation can be rational- of the LUMO energy of the phthalazine by 1.29 eV upon
ized by the loss of aromaticity during the initial cycload- complexation with the bidentate Lewis acid 4. Furthermore,
1
dition step. In contrast, when phthalazine is used, aromatic- in the H NMR spectrum, a downfield shift of the phthalaz-
ity is broken in only one of the rings during the course of ine signals was observed, which corresponds to a with-
the reaction.
drawal of electrons from the ring and, therefore, a deshield-
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Bidentate Lewis Acids for the Activation of 1,2-Diazines
Scheme 2. Reaction mechanism proposed by Heuschmann and co-workers.[16]
ing of the protons.[4] Another mechanistic possibility could
be the complexation of the catalyst with the dienophile in-
stead. All of the dienophiles discussed are also electron-rich
and usually have heteroatoms that can form Lewis acid–
Lewis base pairs. Indeed, if an oxazolidine was treated with
1
equiv. of Lewis acid 4, a complexation of the nitrogen
atom with the Lewis acidic centers could be observed in the
1
H NMR spectrum. However, after addition of phthalazine
to the mixture, only complexation with the 1,2-diazine
could be observed. This proves the strong cooperativity of
the bidentate nature of substrate and catalyst. It has to be
emphasized that the reaction is not promoted in the pres-
ence of a monodentate Lewis acid, such as BF . If a mono-
3
dentate Lewis acid is employed, none of the desired cy-
cloadducts could be observed. Instead, all data suggest a
nucleophilic addition pathway to the phthalazine, similar to
the reported addition of BuLi to phthalazine catalyzed by
the monodentate Lewis acid.[ Furthermore, the complex
17]
of phthalazine with the bidentate Lewis acid was success-
fully crystallized and studied by X-ray analysis (Fig- Figure 1. Solid-state structure of the bidentate Lewis acid/phthal-
[
18]
azine complex.
ure 1).
While this does not definitively prove the biden-
tate nature of coordination during the crucial cycloaddition
step, these data are consistent with such a mechanism.
nation of N and loss of a leaving group, re-aromatization
2
After the activation of the 1,2-diazine, cycloaddition is occurs. Although the elimination of N is a thermodynami-
2
the proposed next step. In this process, the aromaticity of cally favored process and is observed in all cases, the follow-
the N-containing ring is lost. However, following elimi- ing elimination to install aromaticity does not always spon-
Scheme 3. Isomerization of 2,3-dihydrofurans 8d during the reaction and re-aromatization to give product 9d.
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S. N. Kessler, M. Neuburger, H. A. Wegner
FULL PAPER
Scheme 4. Re-aromatization to the cycloaddition product 19 by Cope elimination in the Lewis acid catalyzed IEDDA of enamines with
phthalazine.
taneously occur under the reaction conditions (Scheme 3). case of enamines, the elimination is induced by Cope re-
For example, in the case of 2-nBu-dihydrofuran 8d as the arrangement, whereas enol ethers undergo elimination
dienophile, intermediate 16 was isolated and characterized through UV irradiation.
by NMR spectroscopy, GC–MS, and elemental analysis.
Also, if the 2-Me derivative 8b was allowed to react, charac-
teristic signals in the H NMR spectrum of intermediate
1
Conclusions
species were observed. Treatment of the crude sample 16
with light (Rayonet reactor, 300 nm) induced the elimi-
nation process to cleanly form the desired naphthalene
product 9db. However, only intermediate 16 resulting from
reaction with the endo isomer of the starting material is
observed. In the cases in which the starting material under-
went isomerization of the double bond to the exo position,
the corresponding intermediate 18 could not be isolated.
Also, in some of the enamine studies, products were iso-
lated before re-aromatization occurred.[19] For example, the
reaction of 5 and 7a gave adduct 19 in 86% yield
A new mode of catalysis is presented by applying a bi-
dentate Lewis acid for the activation of 1,2-diazine for the
IEDDA reaction. Different dienophiles, such as enamines
and enols, can undergo IEDDA reactions with substituted
phthalazines in this powerful transformation. The mecha-
nism was thoroughly investigated, and key intermediates
were isolated and characterized. In the future, this concept
of catalysis will be extended to other cycloaddition reac-
tions. Additionally, the catalyst will be optimized to pro-
mote the reaction of even less activated substrates.
(Scheme 4). Similar results were reported by Boger and co-
workers in the IEDDA reaction of 1,2,4-triazine with en-
Experimental Section
[
11]
amines. Treatment of the crude mixture with mCPBA in-
duced a Cope elimination to produce the desired product.
Based on the observations described above, the following
catalytic cycle is proposed (Figure 2): Bidentate Lewis acid
5,10-Dichloro-5,10-dihydroboranthrene (3): 1,2-Dichloroethane
(10 mL), and 2 (2.85 g, 12.8 mmol, 1.00 equiv.) were added to BCl
3
(
26.3 mL, 26.3 mmol, 1 m in heptanes, 2.05 equiv.), and the mixture
was stirred at 140 °C for 3 d. The reaction mixture was then cooled
to 0 °C and decanted, washed twice with hexane (5 mL and
4
coordinates to the 1,2-diazine, forming complex F. Then,
the cycloaddition step occurs to form intermediate H. De-
2.5 mL), and the precipitate was dried at high vacuum to yield
pending on the dienophile, the cycloadduct can eliminate white needles (944 mg, 60%). By additionally concentrating and
1
spontaneously to the 2,3-substituted naphthalene J. In the subliming the filtrate, a total yield of 70% could be achieved. H
6 6
NMR (400 MHz, C D ): δ = 8.20 (m, 4 H, 1-H, 4-H, 6-H, 9-H),
1
7
.17 (m, 4 H, 2-H, 3-H, 7-H, 8-H) ppm. H NMR (400 MHz,
1
3
CDCl
(
3
): δ = 8.35–8.28 (m, 4 H), 7.73–7.67 (m, 4 H) ppm. C NMR
): δ = 136.6, 134.1 ppm; C-4a, C-5a, C-9a, C-10a
101 MHz, C
signals not visible due to coupling with B). C NMR (101 MHz,
CDCl ): δ = 136.7, 134.4 ppm (C-4a, C-5a, C-9a, C-10a signals not
visible due to coupling with B). B NMR (CDCl
6 6
D
1
3
3
1
1
3
, 57 MHz): δ =
5
8.50 ppm.
,10-Dimethyl-5,10-dihydroboranthrene (4): AlMe
.11 mmol, 2 m in heptane, 1.00 equiv.) was added within 5 min to
5
2
3
(1.06 mL,
a suspension of 3 (516 mg, 2.11 mmol, 1.00 equiv.) in hexane
15 mL) at –40 °C and stirred for 1 h before being allowed to warm
to room temp. and stirred for 19 h. Sublimation at 120 °C/0.2 mbar
(
1
6 6
yielded white crystals (394 mg, 92%). H NMR (400 MHz, C D ):
δ = 8.01 (m, 4 H, 1-H, 4-H, 6-H, 9-H), 7.34 (m, 4 H, 2-H, 3-H, 7-
H, 8-H), 1.32 (s, 6 H, 1Ј-H, 1ЈЈ-H) ppm. The analytical data are in
accordance with the literature.[
7]
General Procedure for Enamines and Ketones: Diglyme (0.45 mL),
enamine (3.00 equiv.) or ketone, and pyrrolidine (2.00 equiv.) were
added to 5 (57.2 mg, 0.440 mmol, 1.00 equiv.) and catalyst 4
(
4.5 mg, 22.0 μmol, 5 mol-%). The mixture was stirred at the given
Figure 2. Proposed catalytic cycle for the IEDDA of 1,2-diazines
catalyzed by a bidentate Lewis acid.
temperature for the given time. mCPBA (1.50–5.00 equiv.) was
added to the mixture at –78 °C and then left at room temperature
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Bidentate Lewis Acids for the Activation of 1,2-Diazines
overnight. After the addition of H
was extracted with cyclohexane (3ϫ 5 mL), re-extracted with 1 m
2
O (5 mL), the reaction mixture
(117 mg, 882 μmol, 2.00 equiv.), and pyrrolidine (94.2 mg,
1.32 mmol, 3.00 equiv.) were stirred at 110 °C for 2.5 d and treated
with mCPBA (297 mg, 1.32 mmol, 77%, 3.00 equiv.). After
workup, the residue was purified by column chromatography on
NaOH, dried with Na
chromatography.
2 4
SO , concentrated, and purified by column
1
silica (15 g; cyclohexane) to yield white crystals (25.9 mg, 26%). H
2,3-Dihydro-1H-cyclopenta[b]naphthalene (6a): According to the ge-
NMR (400 MHz, CDCl
3
): δ = 8.21 (s, 1 H, 5-H), 8.03–7.85 (m, 4
neral procedure, catalyst 4 (4.5 mg, 22.0 μmol, 5.00 mol-%), 5
H), 7.85 (d, J = 7.4 Hz, 1 H), 7.51–7.33 (m, 4 H), 4.09 (s, 2 H, 11-H)
(
(
57.5 mg, 441 μmol, 1.00 equiv.), solvent (450 μL), cyclopentanone
61.9 mg, 736 μmol, 1.67 equiv.), and pyrrolidine (62.8 mg,
[
23]
ppm. The analytical data are in accordance with the literature.
8
83 μmol, 2.00 equiv.) were stirred at 55 °C for 2.5 d and treated
1-Methyl-1,2,3,4-tetrahydrobenzo[g]quinoline (6g): Phthalazine (5;
57.5 mg, 0.441 mmol), catalyst 4 (4.5 mg, 22.0 μmol, 5.00 mol-%),
and 7g (125 mg, 0.883 mmol) were stirred in diglyme (0.50 mL) at
80 °C for 14 h. The reaction mixture was purified by column
with mCPBA (495 mg, 2.21 mmol, 77%, 5.00 equiv.). After
workup, the residue was purified by column chromatography on
silica (10 g; cyclohexane) to yield white crystals (38.5 mg, 52%). H
1
NMR (400 MHz, CDCl
3
): δ = 7.81–7.76 (m, 2 H, 5-H, 8-H), 7.68 chromatography on silica (EtOAc/cyclohexane, 1:19, +1% NEt ) to
3
1
(s, 2 H, 4-H, 9-H), 7.44–7.37 (m, 2 H, 6-H, 7-H), 3.13–3.03 (m, 4 obtain the product (87 mg, quant.). H NMR (400 MHz, CDCl ): δ
3
H, 1-H, 3-H), 2.22–2.12 (m, 2 H, 2-H) ppm. The analytical data
= 7.69–7.61 (m, 2 H, 6-H, 9-H), 7.44 (s, 1 H, 10-H), 7.38–7.32 (m,
1 H, 8-H), 7.23–7.17 (m, 1 H, 7-H), 6.82 (s, 1 H, 5-H), 3.37 (t, J =
are in accordance with the literature.[
20]
5
.9 Hz, 2 H, 2-H), 3.05 (s, 3 H, 1Ј-H), 2.98 (t, J = 6.3 Hz, 2 H, 4-
1
,2,3,4-Tetrahydroanthracene (6b): According to the general pro-
1
3
H), 2.11–2.02 (m, 2 H, 3-H) ppm. C NMR (101 MHz, CDCl
δ = 145.71, 134.84, 127.24 (2 C), 127.03, 126.79, 126.01, 125.76,
21.98, 104.29, 51.66, 39.59, 28.94, 23.05 ppm. MS (70 eV): m/z
3
):
cedure, catalyst 4 (4.5 mg, 22.0 μmol, 5.00 mol-%), 5 (57.5 mg,
4
1
41 μmol, 1.00 equiv.), solvent (450 μL), and 7b (200 mg,
1
.32 mmol, 3.00 equiv.) were stirred at 90 °C for 2.5 d and treated
+
+
+
(
1
%) = 197 (100) [M ]. HRMS (ESI): calcd. for C14
98.1277; found 198.1276.
H16N [M + H ]
with mCPBA (297 mg, 1.32 mmol, 77%, 3.00 equiv.). After
workup, the residue was purified by column chromatography on
1
silica (10 g; hexane) to yield white crystals (64.5 mg, 80%).
NMR (400 MHz, CDCl
s, 2 H, 5-H, 10-H), 7.41–7.33 (m, 2 H, 7-H, 8-H), 2.98 (s, 4 H, 1-
H
General Procedure for Furanes and Dioxolanes: Diglyme (0.45 mL),
N,N-diisopropylethylamine (75–150 μL), and the dienophile (2.00–
3
3
): δ = 7.76–7.68 (m, 2 H, 6-H, 9-H), 7.55
(
.00 equiv.) were added to 5 (0.441 mmol, 1.00 equiv.) and catalyst
(4.5 mg, 22.1 μmol, 5.00 mol-%) or as a complex with 5. The
H, 4-H), 1.96–1.81 (m, 4 H, 2-H, 3-H) ppm. The analytical data
4
are in accordance with the literature.[
20]
mixture was stirred at the given temperature for the given time.
After the addition of 1 m HCl (5 mL), the reaction mixture was
7
,8,9,10-Tetrahydro-6H-cyclohepta[b]naphthalene (6c): According
to the general procedure, catalyst 4 (4.5 mg, 22.0 μmol, 5.00 mol-
), 5 (57.5 mg, 441 μmol, 1.00 equiv.), solvent (450 μL), cyclohep-
tanone (99.0 mg, 883 μmol, 2.00 equiv.), and pyrrolidine (47.1 mg,
62 μmol, 1.50 equiv.) were stirred at 80 °C for 2.5 d and treated
extracted (3ϫ 5 mL), dried with Na
with CDCl (0.75–1 mL), irradiated with UV light, and distilled or
purified by column chromatography.
2 4
SO , concentrated, diluted
%
3
6
2
-(Naphthalen-2-yl)ethanol (9a): According to the general pro-
cedure, the phthalazine complex of catalyst 4 (7.3 mg, 21.8 μmol,
.00 mol-%), (56.7 mg, 0.436 mmol, 1.00 equiv.), diglyme
450 μL), N,N-diisopropylethylamine (150 μL), and 8a (61.1 mg,
.871 mmol, 1.98 equiv.) were stirred at 170 °C for 3 d. After evapo-
with mCPBA (297 mg, 1.32 mmol, 77%, 3.00 equiv.). After
workup, the residue was purified by column chromatography on
silica (10 g; cyclohexane) to yield white crystals (73.9 mg, 85%). H
5
(
0
5
1
NMR (400 MHz, CDCl
s, 2 H, 5-H, 11-H), 7.50–7.39 (m, 2 H, 2-H, 3-H), 3.08–2.94 (m, 4
H, 6-H, 10-H), 2.00–1.85 (m, 2 H, 8-H), 1.85–1.68 (m, 4 H, 7-H,
3
): δ = 7.84–7.74 (m, 2 H, 1-H, 4-H), 7.63
(
ration of the diglyme at 80 °C/10 mbar, the residue was purified by
column chromatography on silica gel (20 g; EtOAc/hexanes, 1:4) to
9-H) ppm. The analytical data are in accordance with the litera-
1
obtain 9a (32.6 mg, 43%). H NMR (400 MHz, CDCl
3
): δ = 7.86–
[
21]
ture.
7.76 (m, 3 H, 4-H, 5-H, 8-H), 7.70 (s, 1 H, 1-H), 7.52–7.40 (m, 2
2
-Ethyl-3-methylnaphthalene (6d): According to the general pro-
H, 6-H, 7-H), 7.40–7.32 (dd, J = 8.3, 1.4 Hz, 1 H, 3-H), 3.95 (t, J
= 6.0 Hz, 2 H, 3Ј-H), 3.04 (t, J = 6.4 Hz, 2 H, 2Ј-H), 1.68 (s, 1 H,
OH) ppm. The analytical data are in accordance with the litera-
ture.[
cedure, catalyst 4 (4.5 mg, 22.0 μmol, 5.00 mol-%), 5 (57.5 mg,
441 μmol, 1.00 equiv.), solvent (450 μL), 3-pentanone (97 mg,
1.10 mmol, 2.50 equiv.), and pyrrolidine (62.8 mg, 883 μmol,
2.00 equiv.) were stirred at 130 °C for 2.5 d and treated with
24]
3-(Naphthalen-2-yl)propan-1-ol (9ba) and 2-(3-Methylnaphthalen-2-
mCPBA (198 mg, 882 μmol, 77%, 2.00 equiv.). After workup, the
residue was purified by column chromatography on silica (10 g;
cyclohexane) to yield white crystals (19.1 mg, 25%). 1H NMR
yl)ethanol (9bb). From 8b: According to the general procedure, the
phthalazine complex of catalyst 4 (7.3 mg, 21.8 μmol, 5.00 mol-%),
5
(56.7 mg, 0.436 mmol, 1.00 equiv.), diglyme (450 μL), N,N-diiso-
propylethylamine (150 μL), and 8b (73.3 mg, 0.872 mmol,
.00 equiv.) were stirred at 160 °C for 2 d to obtain 9ba and 9bb
63.9 mg, 75%) in a 3:1 ratio after workup with hexane, 2.5 h of
(400 MHz, CDCl
3
): δ = 7.81–7.70 (m, 2 H, 5-H, 8-H), 7.61 (s, 2 H,
-H, 4-H), 7.43–7.36 (m, 2 H, 6-H, 7-H), 2.80 (q, J = 7.5 Hz, 2 H,
Ј-H), 2.48 (s, 3 H, 1ЈЈ-H), 1.33 (t, J = 7.5 Hz, 3 H, 2Ј-H) ppm.
1
1
2
(
[
22]
The analytical data are in accordance with the literature.
irradiation, and distillation at 190 °C/0.5 mbar. From 8c: According
to the general procedure, the phthalazine complex of catalyst 4
11H-Benzo[b]fluorene (6e). From 7e: According to the general pro-
cedure, catalyst 4 (4.5 mg, 22.0 μmol, 5.00 mol-%), 5 (57.5 mg,
(7.3 mg, 21.8 μmol, 5.00 mol-%),
1.00 equiv.), diglyme (450 μL),
(150 μL), and 8c (73.3 mg, 0.872 mmol, 2.00 equiv.) were stirred at
160 °C for 2 d. After workup with CH Cl , the residue was purified
5
(56.7 mg, 0.436 mmol,
441 μmol, 1.00 equiv.), solvent (450 μL), 1-indanone (117 mg,
882 μmol, 2.00 equiv.), and pyrrolidine (62.8 mg, 882 μmol,
2.00 equiv.) were stirred at 100 °C for 14 h and treated with
N,N-diisopropylethylamine
2
2
mCPBA (198 mg, 882 μmol, 77%, 2.00 equiv.). After workup, the
residue was purified by chromatography on silica (15 g; cyclohex-
ane) to yield white crystals (37 mg, 39%). From 7f: According to
the general procedure, catalyst 4 (4.5 mg, 22.0 μmol, 5.00 mol-%),
by chromatography on silica (15 g; EtOAc/hexane, 1:4) to yield 9ba
and 9bb in a 4.5:1 ratio (55.5 mg, 65%). H NMR (400 MHz,
CDCl ): δ = 7.88–7.75 (m, 2 H, 9ba: 5-H, 8-H), 7.88–7.75 (m, 2 H,
3
9bb: 5-H, 8-H), 7.66 (s, 2 H, 9ba: 1-H, 4-H), 7.66 (s, 2 H, 9bb: 1-
H, 4-H), 7.53–7.43 (m, 2 H, 9ba: 6-H, 7-H), 7.53–7.43 (m, 2 H,
1
5
(57.5 mg, 441 μmol, 1.00 equiv.), solvent (450 μL), 2-indanone
Eur. J. Org. Chem. 2011, 3238–3245
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3243

S. N. Kessler, M. Neuburger, H. A. Wegner
FULL PAPER
9
bb: 6-H, 7-H), 7.37 (dd, J = 8.4, 1.6 Hz, 1 H, 9ba: 3-H), 3.94 (t, (74.0 mg, 0.880 mmol, 2.00 equiv.) were stirred at 100 °C for 2 d.
J = 6.8 Hz, 2 H, 9bb: 2Ј-H), 3.70 (t, J = 6.4 Hz, 2 H, 9ba: 3Ј-H), After workup with TBME/hexane (1:1), distillation at 200 °C/
.06 (t, J = 6.8 Hz, 2 H, 9bb: 1Ј-H), 2.89 (t, J = 8.0 Hz, 2 H, 9ba: 0.5 mbar gave a mixture of regioisomers 12ba and 12bb (34.0 mg,
3
1
2
1
Ј-H), 2.51 (s, 3 H, 9bb: 1ЈЈ-H), 1.99 (tt, J = 13.0, 6.5 Hz, 2 H, 9ba:
41%) in a 1.5:1 ratio. H NMR (400 MHz, CDCl
= 8.9 Hz, 1 H, 12bb: 4-H), 8.36 (s, 1 H, 12ba: 1-H), 8.19 (dd, J =
): δ = 139.80, 135.82, 135.42, 134.08, 7.6, 1.0 Hz, 1 H, 12ba: 4-H), 8.16 (dd, J = 7.7, 1.2 Hz, 1 H, 12bb:
3
): δ = 8.49 (d, J
1
3
Ј-H), 1.92 (s, 1 H, 9ba: OH), 1.92 (s, 1 H, 9bb: OH) ppm.
C
NMR (101 MHz, CDCl
3
1
33.04, 132.69, 132.47, 128.80, 128.41, 128.35, 128.07, 127.87,
6-H), 8.06 (d, J = 8.2 Hz, 1 H, 12ba: 5-H), 8.03 (d, J = 8.4 Hz, 1
H, 12bb: 8-H), 7.87 (d, J = 8.4 Hz, 1 H, 12ba: 7-H), 7.74 (s, 1 H,
12bb: 1-H), 7.57 (dd, J = 8.9, 1.7 Hz, 1 H, 12bb: 7-H), 7.51–7.44
(m, 2 H, 12ba: 3-H, 6-H), 7.51–7.44 (m, 1 H, 12bb: 3-H), 3.77–3.67
(m, 2 H, 12ba: 1Ј-H), 3.77–3.67 (m, J = 6.4 Hz, 2 H, 12bb: 1Ј-H),
2.99–2.85 (m, 2 H, 12ba: 3Ј-H), 2.99–2.85 (m, 2 H, 12bb: 3Ј-H),
127.74, 127.56, 127.32, 126.88, 126.40, 125.96, 125.70, 125.64,
62.95, 62.61, 36.99, 34.50, 32.64, 20.39 ppm. MS (70 eV): m/z (%)
+
+
=
+
186 (33) [M ], 142 (100). HRMS (ESI): calcd. for C13
H
15
O
[M
+
H ] 187.1117; found 187.1124. The analytical data of 9ba are in
[24]
accordance with the literature.
2
.05–1.93 (m, 2 H, 12ba: 2Ј-H), 2.05–1.93 (m, 2 H, 12bb: 2Ј-H)
2
2
-(3-Butylnaphthalen-2-yl)ethanol (9da) and 3-(3-Propylnaphthalen-
-yl)propan-1-ol (9db): According to the general procedure, the
13
ppm. C NMR (101 MHz, CDCl
3
): δ = 146.91, 146.62, 144.19,
1
1
1
41.63, 135.11, 134.81, 134.63, 133.47, 131.36, 129.22, 129.10,
27.52, 125.78, 124.64, 124.57, 124.12, 123.80, 123.76, 123.68,
phthalazine complex of catalyst 4 (7.3 mg, 21.8 μmol, 5.00 mol-%),
phthalazine (5) (56.7 mg, 0.436 mmol, 1.00 equiv.), diglyme
22.07, 62.49, 62.38, 34.38, 34.13, 33.19, 32.27 ppm. MS (70 eV):
(
450 μL), N,N-diisopropylethylamine (75 μL) and 8d (111 mg,
.880 mmol, 2.02 equiv.) were stirred at 160 °C for 2 d to obtain
72.7 mg, 73%) of the naphthalenes 9da and 9db in a 1.5:1 ratio
after workup, 3.5 h of irradiation and distillation at 200 °C/
+
m/z (%) = 231 (9) [M ], 139 (100). HRMS (ESI): calcd. for
0
(
+
+
C
13
H
14
O
3
N
[M + H ] 232.0968; found 232.0976.
-(8-Nitronaphthalen-2-yloxy)ethanol (12c): The phthalazine com-
plex of catalyst 4 (3.7 mg, 12 μmol, 5.0 mol-%), 11b (41.9 mg,
39 μmol, 1.00 equiv.), diglyme (300 μL), N,N-diisopropylethyl-
2
.5 mbar. 1H NMR (400 MHz, CDCl
3
): δ = 7.84–7.72 (m, 2 H,
0
9
9
1
9
6
2
9
2
db: 5-H, 8-H), 7.78–7.71 (m, 2 H, 9da: 5-H, 8-H), 7.68 (s, 1 H,
da: 1-H*, 4-H*), 7.67 (s, 1 H, 9da: 1-H*, 4-H*), 7.65 (s, 2 H, 9db:
-H, 4-H), 7.49–7.37 (m, 2 H, 9db: 6-H, 7-H), 7.43–7.35 (m, 2 H,
da: 6-H, 7-H), 3.94 (t, J = 6.8 Hz, 2 H, 9db: 2Ј-H), 3.77 (t, J =
.4 Hz, 2 H, 9da: 3Ј-H), 3.08 (t, J = 6.8 Hz, 2 H, 9db: 1Ј-H), 2.94–
.83 (t, J = 7.7 Hz, 2 H, 9da: 1Ј-H), 2.85–2.75 (t, J = 6.6 Hz, 2 H,
db: 1ЈЈ-H), 2.81–2.72 (t, J = 7.7 Hz, 2 H, 9da: 1ЈЈ-H), 1.97 (dq, J
amine (100 μL), and 13 (41.2 mg, 479 μmol, 2.00 equiv.) were
stirred at room temp. for 12 h. After evaporation of the diglyme, the
residue was purified by preparative TLC chromatography (silica;
1
hexane/EtOAc, 2:3) to yield a solid (5.6 mg, 10%). H NMR
(400 MHz, CDCl
3
): δ = 8.35–8.29 (m, 1 H), 8.11–8.02 (m, 2 H),
7
4
.92–7.83 (m, 1 H), 7.46–7.39 (m, 1 H), 7.36–7.30 (m, 1 H), 4.33–
1
3
.22 (m, 2 H, 1Ј-H), 4.13–4.02 (m, 2 H, 2Ј-H) ppm. C NMR
): δ = 160.10, 135.15, 133.76, 130.86, 130.72,
27.27, 125.69, 122.35, 120.78, 102.92, 69.90, 61.69 ppm. HRMS
=
14.2, 6.4 Hz, 2 H, 9da: 2Ј-H), 1.76–1.66 (m, 2 H, 9db: 2ЈЈ-H),
.73 (dd, J = 15.3, 7.6 Hz, 2 H, 9da: 2ЈЈ-H), 1.55–1.44 (m, 2 H,
(101 MHz, CDCl
3
1
9
3
1
1
1
2
1
db: 3ЈЈ-H), 1.04 (t, J = 7.3 Hz, 3 H, 9da: 3ЈЈ-H), 0.98 (t, J = 7.3 Hz,
+
+
H, 9db: 4ЈЈ-H) ppm. 1 C NMR (101 MHz, CDCl
3
12 12 4
(ESI): calcd. for C H NO [M + H ] 234.0761; found 234.0767.
3
): δ = 140.04,
39.66, 138.94, 135.21, 132.99, 132.69, 132.59, 132.46, 128.53,
27.90, 127.60, 127.47, 127.45, 127.43 (2 C), 127.40, 125.87, 125.67,
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental data for 7g, 8c, 8d, 16, 19 and H and
25.55, 125.51, 63.59, 63.00, 36.34, 35.31, 34.20, 33.71, 33.12, NMR spectra for 3, 7g, 11g, 9ba/b, 9da/b, 12a, 12ba/b, 12c, 16, 19;
1
13
C
9.36, 24.53, 23.21, 14.64, 14.46 ppm. MS (70 eV): m/z (%) = 228
crystal data for the complex of 5 with Lewis acid 4.
+
+
+
21
(54) [M ], 155 (100). HRMS (ESI): calcd. for C16H O [M + H ]
2
29.1587; found 229.1592.
Acknowledgments
4,9-Dichloro-2,3-dihydro-1H-cyclopenta[b]naphthalene (12a): Ac-
cording to the general procedure, catalyst 4 (3.00 mg, 14.7 μmol,
.00 mol-%), 11a (58.6 mg, 294 μmol, 1.00 equiv.), diglyme
450 μL), and 7a (80.8 mg, 589 μmol, 2.00 equiv.) were stirred at
0 °C for 2.5 d. After workup, the residue was purified by column
chromatography on silica (15 g; cyclohexane) to yield white crystals
We thank the Swiss National Science Foundation for financial sup-
port. The award of a Novartis fellowship in Organic Chemistry to
S. N. K. is gratefully acknowledged, and H. A. W. is indebted to
the Fonds der Chemischen Industrie for a Liebig Fellowship.
5
(
4
1
3
(43.3 mg, 62%). H NMR (400 MHz, CDCl ): δ = 8.29–8.20 (m, 2
[
[
1] Lewis Acids in Organic Synthesis (Ed.: H. Yamamoto), Wiley-
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): δ = 142.02, 131.51, 126.99, 125.91, 124.53, 34.05,
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24.51 ppm. MS (70 eV): m/z (%) = 236 (85) [M ], 165 (100). The
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aphthalen-2-yl)propan-1-ol (12bb). From 8b: According to the gene-
ral procedure, the phthalazine complex of catalyst 4 (7.3 mg,
2
1.8 μmol, 5.00 mol-%), 11b (76.3 mg, 0.437 mmol, 1.00 equiv.), di-
glyme (450 μL), N,N-diisopropylethylamine (75 μL), and 8b
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(
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distillation at 210 °C/0.4 mbar gave a mixture of regioisomers 12ba
and 12bb (44.3 mg, 44%) in a 1.5:1 ratio. From 8c: According to the
general procedure, the phthalazine complex of catalyst 4 (7.3 mg,
21.8 μmol, 5.00 mol-%), 11b (76.3 mg, 0.437 mmol, 1.00 equiv.), di-
glyme (450 μL), N,N-diisopropylethylamine (75 μL), and 8c
3244
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3238–3245

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Published Online: May 4, 2011
Eur. J. Org. Chem. 2011, 3238–3245
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3245