Bidentate Lewis acid catalyzed inverse-electron-demand Diels-Alder reaction for the selective functionalization of aldehydes

Article abstract of DOI:10.1055/s-0031-1291127

The inverse-electron-demand Diels-Alder (IEDDA) reaction catalyzed by a bidentate Lewis acid was applied to enamines generated in situ from aldehydes. In general, a high functional group tolerance has been observed. Side reactions during the enamine forming step can limit the yield of the desired naphthalene. For citronellal as substrate, the initial intermediate after the catalyzed IEDDA reaction was trapped by an intramolecular Diels-Alder reaction to furnish a tricyclic compound. This scaffold represents the framework of natural products such as valerianoids A-C or the patchouli alcohol. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1291127

SPECIAL TOPIC
▌2195
special topic
Bidentate Lewis Acid Catalyzed Inverse-Electron-Demand Diels–Alder
Reaction for the Selective Functionalization of Aldehydes
Lewis Acid Catalyzed IEDDA of Phthalazine with Aldehydes
Luca Schweighauser, Ina Bodoky, Simon N. Kessler, Daniel Häussinger, Hermann A. Wegner*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2670976; E-mail: hermann.wegner@unibas.ch
Received: 03.04.2012; Accepted: 10.04.2012
of the lowest unoccupied molecular orbital (LUMO) is de-
creased facilitating the critical step, the cycloaddition. Af-
ter that N2 is released, which produces the product after
aromatization and expels the coordinating groups regen-
Abstract: The inverse-electron-demand Diels–Alder (IEDDA) re-
action catalyzed by a bidentate Lewis acid was applied to enamines
generated in situ from aldehydes. In general, a high functional
group tolerance has been observed. Side reactions during the en-
amine forming step can limit the yield of the desired naphthalene. erating the catalyst. This way a variety of dienophiles can
For citronellal as substrate, the initial intermediate after the cata-
lyzed IEDDA reaction was trapped by an intramolecular Diels–
Alder reaction to furnish a tricyclic compound. This scaffold repre-
means. Especially intriguing is the fact that the activation
sents the framework of natural products such as valerianoids A–C
or the patchouli alcohol.
be reacted with phthalazines producing 2,3-substituted
naphthalenes, which are difficult to synthesize by other
due to the bidentate binding is highly specific for the dia-
zene moiety. As a result, a broad range of functional
Key words: aldehydes, catalysis, Diels–Alder reaction, fused-ring
groups, such as alcohols, amines, ketones, esters, nitro
systems, Lewis acids
compounds, and halides are tolerated. Especially, the use
of enamines, generated in situ from the corresponding ke-
tone, provide an extremely powerful tool to introduce an
The chemical space is as vast as the universe. Most of its
aromatic unit in a very complex environment (Scheme 1).
regions are still unexplored and promise gold mine-like
It has to be pointed out that the initial keto group and the
discoveries of structures with the ultimate properties as
free amine, as well as the water created during the en-
drugs or functional materials.1 One source of inspiration
amine formation do not disturb the catalytic process. Cy-
for the exploration of the new worlds of chemical struc-
clic ketones have been transformed to the corresponding
tures are natural products.2 However, the isolation and
enamines in good to excellent yields. Linear ketones,
characterization of new compounds is laborious and pro-
however, gave only low yields. Pentan-3-one, for in-
vides usually only minute amounts of material. Synthetic
stance, gave only 25% of the desired naphthalene. Alde-
efforts can be a solution, but can expand quickly to an in-
hydes have so far not been investigated in the bidentate
tellectual adventure itself leading to multistep protocols.3
Lewis acid catalyzed IEDDA reaction as substrates, al-
A different approach relies on the synthetic elaboration of
though this transformation should be perfectly suitable for
complex molecules to further diversify their structural
the attachment of an aromatic unit to an aldehyde, even in
complexity.4 As those starting materials are, ideally, al-
the presence of other multiple functional groups.
ready highly functionalized, there is a high demand for
synthetic transformations that would allow the conversion
O
of those feedstocks, in the presence of all these functional
groups, in a selective manner.5
The Diels–Alder reaction6 and in particular the inverse-
electron-demand Diels–Alder (IEDDA) reaction of 1,2-
n
2
diazines represents a powerful instrument to assemble
Me
B
N
H
3
H2O
1,2-substituted aromatics and has been featured in spec-
tacular examples of complex molecule synthesis tolerat-
ing in principle a wide range of functionalities.7 However,
the reaction suffers from harsh conditions and a narrow
substrate scope.8 Therefore, we recently presented a new
catalytic principle for the IEDDA reaction of 1,2-diazine
based on bidentate Lewis acid catalysts.9 The underlying
concept of catalysis is based on the simultaneous coordi-
nation of the bidentate Lewis acid to the two vicinal N-
atoms of the 1,2-diazine. Upon coordination, the energy
B
Me
5
N
N
N
(2.5–5 mol%)
workup with
m-CPBA
n
6
1
n
4
Scheme 1 IEDDA reaction of phthalazine with enamines, generated
in situ
SYNTHESIS 2012, 44, 2195–2199
Advanced online publication: 25.05.2012
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
In order to verify the utility of aldehydes, different substi-
tution patterns were chosen and submitted to the catalyzed
DOI: 10.1055/s-0031-1291127; Art ID: SS-2012-C0325-ST
© Georg Thieme Verlag Stuttgart · New York

2196
L. Schweighauser et al.
SPECIAL TOPIC
Table 2 Bidentate Lewis Acid Catalyzed IEDDA Reaction of β-
Branched Aldehydes
IEDDA reaction. Besides alkyl chains also aromatic
groups were introduced. All aldehydes were transformed
to the corresponding naphthalenes (Table 1). Interesting-
ly, n-alkyl aldehydes gave the desired products only in
low yields. The phthalazine (1) starting material, howev-
er, was consumed. Additionally, considerable gas evolu-
tion was observed, which hints to a successful IEDDA
reaction. Therefore, the explanation for the low yield
seems not to be the catalyzed IEDDA but rather due to
side reaction in the enamine formation or with subsequent
stable intermediates.9b A slightly improved outcome
could be observed for substrate 8d, which is distinguished
by a methyl substituent in the β-position. The additional
steric hindrance might slow down the side reaction and fa-
vor the desired IEDDA transformation. For heptanal (8c),
only traces of product were found by GCMS, if the stan-
dard pyrrolidine (3) was used for the enamine formation.
The use of N-methylethylenediamine,10 however, gave the
desired 2-n-pentylnaphthalene (7c) in an improved yield
of 30% as the required elimination is accelerated due to an
intramolecular pathway.
Me
B
B
Me
5
R1
(2.5–5 mol%)
N
N
dienophile
+
1
7
Entry Aldehyde
R1
Yield
(%)a
O
H
1
64
8f
O
OH
OH
2
3
59
H
Table 1 Aldehydes as Substrates for the Bidentate Lewis Acid Cat-
alyzed IEDDA Reaction
8g
O
Me
B
OEt
OEt
H
41b
O
O
B
8h
Me
O
O
5
R
O
(2.5 mol%)
N
N
H
O
dienophile
+
4
5
11
–
1
7
8i
H
Entry
Aldehyde
R
Yield (%)
R2
O
H
R2
8j R2 = SMe
8k R2 = OH
1
Me
30
a Amount of catalyst used: 5.0 mol%, if not stated otherwise.
b Amount of catalyst used: 2.5 mol%.
8a
O
2
3
4
n-Pr
12
30a
43
H
Therefore, other aldehydes were assayed in the bidentate
Lewis acid catalyzed IEDDA reaction, which contained a
methyl substituent in β-position. With this arrangement,
elimination to the corresponding naphthalene skeleton is
still possible. However, the corresponding enamine will
contain an isopropyl-type substitution, increasing the ste-
ric demand considerably. In the case of the methyl ana-
logue of 8e the desired naphthalene derivative could be
isolated in 64% (Table 2, entry 1). Additionally, other
functional groups have been introduced, which also bear
the potential of interaction with the Lewis acid catalyst.
The tertiary alcohol can be problematic in Lewis acid ca-
talysis as it could eliminate. However, in the presence of
the bidentate Lewis acid the substrate derived from 8g
was converted in good yield to the desired product (Table
2, entry 2). Also an ester group was included in the side
chain (Table 2, entry 3). Such a substrate also has the po-
8b
O
n-C5H11
H
8c
O
H
8d
O
H
5
9
8e
a The enamine was derived from N-methylethylenediamine.
Synthesis 2012, 44, 2195–2199
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Lewis Acid Catalyzed IEDDA of Phthalazine with Aldehydes
2197
tential to coordinate with its two oxygen atoms to the bi- maining fraction being amine products. Increasing the re-
dentate Lewis acid. Nevertheless, the product was isolated action temperature did favor the elimination to the
in 41%, supporting the high specificity of the bidentate expected naphthalene 7l resulting in a yield of 37%. Inter-
binding event of the catalyst with the 1,2-diazine moiety. estingly, the by-product mixture was not composed main-
A more challenging starting material is the furan ana- ly of the usual noneliminated amine 13. Careful 2D-NMR
logue, which itself is a good diene in the normal Diels– analysis (i.e., HSQC-TOCSY) revealed a complex tricy-
Alder reaction. Although the product is observed, the clic structure 12 (2:2.5 ratio of endo/exo isomer of the
yield is rather low (Table 2, entry 4). The reason for that amine) as the major component (>50% of the aromatic
can be found in side reactions of the aldehyde as for in- fraction).12 Such a scaffold can be readily explained by the
stance to the aldol condensation product. Also, thioether following rational: elimination of N2 leads to the tetraene
8j was treated under standard conditions. Although the intermediate 11, which can now undergo a normal Diels–
mass of the amino derivative was observed by GC/MS no Alder reaction with the olefin appendix. Such an interme-
specific product could be isolated. Interestingly, all diate has been isolated and characterized in the catalyzed
phthalazine starting material was consumed. Similar at- IEDDA reaction with 2-n-butyl-4,5-dihydrofuran.9b
tempts to promote the IEDDA with β-hydroxyaldehyde
8k also failed. As mentioned above, the reason is not the
reactivity in the IEDDA reaction; but the aldehyde itself
undergoes a variety of transformations, which proceed be-
fore the cycloaddition event. All these side products are
now themselves substrates for the IEDDA reaction.
Therefore, although phthalzine 1 was consumed no prod-
uct could be isolated.
The interesting tricycle 12 is featured in a number of nat-
ural products (Figure 1). For instance, valerianoids A–C
[e.g., valerianoid A (14)],13 constituents of folk medicine
for sedative and antispasmodic purposes, as well as pa-
tchouli alcohol (15),14 used in fragrances, map the com-
plete saturated carbon framework of 12 without the
additional aromatic ring.
Furthermore, terpene-based structures have been chosen
HO
HO
O
as substrates for the catalyzed IEDDA reaction. Such di-
enophiles should give access to an interesting alkenyl-aryl
motive, which has been prepared before in multiple
steps.11 Citronellal has been tested in the bidentate Lewis
acid catalyzed IEDDA reaction with phthalazine (Scheme
2). The reaction proceeded smoothly and after one day no
starting materials were observed. The product showed in
this case a mixture of the aromatized naphthalene deriva-
tive 7l and products, which still contain the amine func-
tionality (by GC/MS). After column chromatography, the
desired product 7l could be isolated in 27% yield, the re-
N
12
14
15
Figure 1 Product of the catalyzed IEDDA reaction of citronellal 12;
valerianoid A (14), and patchouli alcohol 15
The examples presented above illustrate the utility of the
bidentate Lewis acid catalyzed IEDDA reaction to intro-
duce aromatic scaffolds into highly complex and func-
tionalized molecules. Especially hydroxy as well as ester
+
N
N
H
O
9
8l
3
Me
B
N
N
B
1
Me
5
(2.5–5 mol%)
N
N
– N2
– N2
N
N
N
11
10
13
N
27% (60 ºC)
37% (100 ºC)
12
7l
Scheme 2 Catalyzed IEDDA reaction of citronellal
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2195–2199

2198
L. Schweighauser et al.
SPECIAL TOPIC
2-Isopropylnaphthalene (7d)17
substitution in the substrates do not disturb the reaction
and furnish cleanly the desired cycloadducts. Linear alde-
hydes suffer from side reactions during the enamine-
forming step limiting its applicability. Usage of N-methyl-
ethylenediamine can partially circumvent this difficulty
allowing access to the desired naphthalenes in moderate
yield. When citronellal was employed in the catalyzed
IEDDA reaction an interesting tricyclic compound was
observed besides the expected naphthalene derivative.
Therefore, this cascade of transformation will offer an ef-
ficient access to complex frameworks, which are found in
natural products, for example, valerianoids A–C or pa-
tchouli alcohol.
Yield: 22.8 mg (44%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 1.36 (d, J = 7.0 Hz, 6 H), 3.13–
3.04 (m, 1 H), 7.48–7.38 (m, 3 H), 7.66 (s, 1 H), 7.84–7.77 (m, 3 H).
13C NMR (126 MHz, CDCl3): δ = 24.1 (2 C), 34.4, 124.2, 125.2,
125.89, 125.94, 127.69, 127.70, 128.0, 132.2, 133.8, 146.5.
MS (EI, 70 eV): m/z (%) = 170 (31, [M]+), 155 (100).
2-Benzylnaphthalene (7e)18
Yield: 6.2 mg (9%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 4.16 (s, 2 H), 7.25–7.20 (m, 3 H),
7.34–7.28 (m, 3 H), 7.48–7.40 (m, 2 H), 7.64 (s, 1 H), 7.86–7.70 (m,
3 H).
13C NMR (126 MHz, CDCl3): δ = 42.3, 125.5 (2 C), 126.1, 126.3,
127.2, 127.7, 127.76, 127.78, 128.2, 128.6 (2 C), 129.2, 132.2,
133.7, 138.7, 141.1.
All chemicals were used as received from commercial sources with-
out any prior purification. Technical grade solvents for extractions
MS (EI, 70 eV) m/z = 218 (100%, [M]+).
1
and chromatography were distilled once before usage. H and 13C
2-(1-Phenylethyl)naphthalene (7f)19
Yield: 45.9 mg (64%); yellow oil.
1H NMR (400 MHz, CDCl3): δ = 1.75 (d, J = 7.2 Hz, 3 H), 4.33 (q,
J = 7.2 Hz, 1 H), 7.24–7.16 (m, 1 H), 7.36–7.26 (m, 5 H), 7.50–7.40
(m, 2 H), 7.71 (s, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.86–7.78 (m, 2 H).
NMR spectra were recorded on a Bruker DPX-NMR 400 MHz and
Bruker Avance 500 MHz spectrometer, respectively, in CDCl3 with
TMS as an internal standard. Mass spectra were performed on
Hewlett Packard 5890 Series II GC/MS spectrometer by EI ioniza-
tion at 70 eV. Catalyst 5 was prepared according to the literature.9b
13C NMR (101 MHz, CDCl3): δ = 21.9, 45.0, 125.5 (2 C), 126.1,
126.2, 127.0, 127.7, 127.86, 127.90 (2 C), 128.1, 128.5 (2 C), 132.3,
133.7, 143.9, 146.4.
Bidentate Lewis Acid Catalyzed IEDDA Reaction of Phthala-
zine (1) with Aldehydes; General Procedure
Phthalazine (1; 40.0 mg, 0.307 mmol, 1.00 equiv) with catalyst 5
(3.13 mg, 0.0154 mmol, 5.00 mol%/1.57 mg, 0.0077 mmol, 2.50
mol%) was dissolved in THF (0.5 mL) and stirred. The aldehyde
(0.768 mmol, 2.50 equiv) and pyrrolidine (26.2 mg, 0.369 mmol,
1.20 equiv) were added. In most cases immediate N2 formation at
r.t. was observed. The reaction mixture was stirred at 60 °C for 20
h; the NMR showed total conversion of the phthalazine. The solvent
was removed under reduced pressure. The crude was purified by
flash column chromatography (eluent: cyclohexane, cyclohexane–
CH2Cl2 or cyclohexane–EtOAc) to give the pure product.
MS (EI, 70 eV): m/z (%) = 232 (49, [M]+), 217 (100).
2-Methyl-6-(naphthalen-2-yl)heptan-2-ol (7g)
Yield: 46.3 mg (59%); colorless oil.
1H NMR (400 MHz, CDCl3): δ = 1.15 (s, 6 H), 1.33–1.21 (m, 6 H),
1.54–1.40 (m, 2 H), 1.76–1.60 (m, 2 H), 2.94–2.83 (m, 1 H), 7.35
(dd, J = 8.5, 1.8 Hz, 1 H), 7.48–7.40 (m, 2 H), 7.61 (d, J = 0.8 Hz,
1 H), 7.80 (t, J = 8.8 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 22.5, 22.6, 29.3, 29.4, 38.9, 40.2,
44.1, 71.1, 125.2, 125.3, 125.89, 125.93, 127.68, 127.71, 128.1,
132.3, 133.8, 145.2.
2-Methylnaphthalene (7a)15
Yield: 13.1 mg (30%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 2.55 (s, 3 H), 7.35 (dd, J = 8.3, 0.9
Hz, 1 H), 7.52–7.40 (m, 2 H), 7.81–7.75 (m, 2 H), 7.65 (s, 1 H), 7.83
(d, J = 8.0 Hz, 1 H).
MS (EI, 70 eV): m/z (%) = 256 (14, [M]+), 155 (100).
HRMS-EI: m/z [M]+ calcd for C18H24O: 256.1827; found: 256.1823.
13C NMR (126 MHz, CDCl3): δ = 21.8, 125.0, 125.9, 126.9, 127.2,
127.6, 127.7, 128.1, 131.7, 133.7, 135.5.
Ethyl 2-(Naphthalen-2-yl)propanoate (7h)
Yield: 29.0 mg (41%); yellow oil.
1H NMR (500 MHz, CDCl3): δ = 7.89–7.81 (m, 3 H), 7.77 (s, 1 H),
7.54–7.44 (m, 3 H), 4.24–4.09 (m, 2 H), 3.91 (q, J = 7.1 Hz, 1 H),
1.62 (d, J = 7.2 Hz, 3 H), 1.23 (t, J = 7.1 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 174.6, 138.2, 133.5, 132.6, 128.3,
127.8, 127.6, 126.1, 126.1, 125.8 (2 C), 60.8, 45.7, 18.6, 14.2.
MS (EI, 70 eV): m/z (%) = 228 (22, [M]+), 155 (100).
HRMS-ESI: m/z [M + H]+ calcd for C15H16O2: 229.1223; found:
MS (EI, 70 eV): m/z = 142 (100, [M]+).
2-n-Propylnaphthalene (7b)16
Yield: 6.0 mg (12%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 0.98 (t, J = 7.3 Hz, 3 H), 1.89–1.65
(m, 2 H), 2.87–2.63 (m, 2 H), 7.36–7.32 (m, 1 H), 7.49–7.38 (m, 2
H), 7.61(s, 1 H), 7.84–7.75 (m, 3 H).
13C NMR (126 MHz, CDCl3): δ = 14.0, 24.6, 38.3, 125.1, 125.9,
126.5, 127.5, 127.6, 127.7, 127.8, 132.1, 133.8, 140.3.
229.1224.
MS (EI, 70 eV): m/z (%) = 170 (30, [M]+), 141 (100).
2-Methyl-5-(1-(naphthalen-2-yl)ethyl)furan (7i)
Yield: 7.8 mg (11%); yellow oil.
2-Pentylnaphthalene (7c)
Reaction carried out with N-methylethylenediamine; yield: 18.0 mg
(30%); colorless oil.
1H NMR (500 MHz, CDCl3): δ = 0.95–0.87 (m, 3 H), 1.42–1.34 (m,
4 H), 1.79–1.64 (m, 2 H), 2.78 (t, J = 7.5 Hz, 2 H), 7.35 (dd, J = 8.4,
1.7 Hz, 1 H), 7.51–7.38 (m, 2 H), 7.62 (s, 1 H), 7.85–7.73 (m, 3 H).
13C NMR (126 MHz, CDCl3): δ = 14.1, 22.6, 31.1, 31.6, 36.1, 125.0,
125.8, 126.3, 127.4, 127.5, 127.6, 127.7, 131.9, 133.7, 140.5.
MS (EI, 70 eV): m/z (%) = 198 (26, [M]+), 141 (100).
1H NMR (500 MHz, CDCl3): δ = 1.67 (d, J = 7.2 Hz, 3 H), 2.25 (s,
3 H), 4.26 (q, J = 7.2 Hz, 1 H), 5.92–5.89 (m, 1 H), 5.98 (dd, J = 3.0,
0.5 Hz, 1 H), 7.39 (dd, J = 8.4, 1.8 Hz, 1 H), 7.51–7.41 (m, 2 H),
7.68 (d, J = 0.9 Hz, 1 H), 7.86–7.77 (m, 3 H).
13C NMR (126 MHz, CDCl3): δ = 13.7, 20.7, 39.5, 105.9, 105.9,
125.5, 125.7, 126.0, 126.2, 127.7, 127.9, 128.2, 132.5, 133.7, 142.1,
151.1, 157.2.
MS (EI, 70 eV): m/z (%) = 236 (28, [M]+), 221 (100).
HRMS-EI: m/z [M]+ calcd for C17H16O: 236.1201; found: 236.1198.
Synthesis 2012, 44, 2195–2199
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Lewis Acid Catalyzed IEDDA of Phthalazine with Aldehydes
2199
2-(6-Methylhept-5-en-2-yl)naphthalene (7l)
Yield: 19.7 mg (27%); colorless oil.
2005, 105, 4779. (d) Juhl, M.; Tanner, D. Chem. Soc. Rev.
2009, 38, 2983.
1H NMR (400 MHz, CDCl3): δ = 1.34 (d, J = 6.9 Hz, 3 H), 1.52 (s,
3 H), 1.82–1.64 (m, 5 H), 2.07–1.82 (m, 2 H), 2.96–2.81 (m, 1 H),
5.18–5.08 (m, 1 H), 7.37 (dd, J = 8.5, 1.5 Hz, 1 H), 7.52–7.39 (m, 2
H), 7.62 (s, 1 H), 7.86–7.74 (m, 3 H).
(7) For selected examples, see: (a) Boger, D. L.; Coleman, R. S.
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also: Boger, D. L.; Sakya, S. M. J. Org. Chem. 1988, 53,
1415. (d) For examples with phthalazines, see: Oishi, E.;
Taido, N.; Iwamoto, K.; Miyashita, A.; Higashino, T. Chem.
Pharm. Bull. 1990, 38, 3268.
13C NMR (101 MHz, CDCl3): δ = 17.8, 22.5, 25.9, 26.4, 38.4, 39.7,
124.6, 125.2, 125.4, 125.9, 126.0, 127.68, 127.72, 128.0, 131.7,
132.3, 133.8, 145.3.
MS (EI, 70 eV): m/z (%) = 238 (28, [M]+), 156 (100).
HRMS-EI: m/z [M]+ calcd for C18H22: 238.1722; found: 238.1720.
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Acknowledgment
Financial support by the Swiss National Science Foundation is
gratefully acknowledged. S.N.K. thanks Novartis for a fellowship
and H.A.W. is indebted to the Fonds der Chemischen Industrie for
a Liebig’s Fellowship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2195–2199