A Photocatalytic Meerwein Approach to the Synthesis of Isochromanones and Isochromenones

Article abstract of DOI:10.1002/ejoc.201601458

A visible-light Ru^II photoredox Meerwein synthesis of isochromanones and isochromenones is described starting from diazonium salts of differently substituted anthranilic acids and various alkenes. This approach has allowed the reliable and effi

Full text of DOI:10.1002/ejoc.201601458

A Journal of
Accepted Article
Title: A Photocatalytic Meerwein Approach for the Synthesis of
Isochromanones and Isochromenones
Authors: Stefano Crespi, Stefanie Jäger, Burkhard Koenig, and
Maurizio Fagnoni
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601458
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10.1002/ejoc.201601458
European Journal of Organic Chemistry
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A Photocatalytic Meerwein Approach for the Synthesis of
Isochromanones and Isochromenones
Stefano Crespi,[a] Stefanie Jäger,[b] Burkhard König*[b] and Maurizio Fagnoni*[a]
Abstract: A visible light Ru(II) photoredox Meerwein synthesis of
isochromanones and isochromenones is described starting from
diazonium salts of different substituted anthranilic acids. This
approach allows the reliable and efficient preparation of structures
found in many biologically active molecules or used in material
chemistry.
chemistry, in liquid crystals and the construction of molecular
machines.[7] In particular, heterosubstitued derivatives C,
(Scheme 1) emerged as a class of iridium ligands in strongly
emitting organometallic complexes, that could find application in
the development of tunable OLEDs.[8]
Introduction
The isochromanone moiety (A, Scheme 1) is a recurrent
structure in a huge number of molecules recognized to have
biological
and
pharmacological
activity.[1]
3,4–
Dihydroisocoumarins are commonly isolated from a wide variety
of natural sources such as plants, insects and microbes and
their activity spans from antifungal to cytotoxic, antimalarial and
antiallergical properties.[2] The interest on these molecules is
clearly witnessed by the recent isolation of icumazole A and by
the total synthesis of noricumazole A (Scheme 1), two molecules
characterised by a marked activity against various fungi and
yeasts.[2a]
Moreover,
(S)–4–(1H-imidazol–1–yl)–3,3–
dimethylisochroman–1–one was discovered as a significant
aldosterone inhibitor.[3] Noteworthy, amicoumacins (Scheme 1)
belong to an interesting family of antibiotics bearing the
isochromanone core that are currently under study for their
antibacterial antinflammatory, antiulcer and antineoplastic
action.[4] An interesting case is phyllodulcin (Scheme 1), a
principal constituent of Hydrangeae Dulcis Folium, a natural
medicine belonging to the Japanese heritage and its traditional
pharmacopoeia. Phyllodulcin not only possesses antimicrobial
activity, but has a well-known sweetening effect, 600–800 times
as sweet as sucrose.[2b,5]
Scheme 1. Examples of molecules possessing the isochromanone and
isochromenone core.
A structurally related class of compounds is represented by
molecules possessing the isochromenone moiety (B, Scheme 1)
that, as the isochromanones, belongs to the bigger
isocoumarin–like product family.[6] Molecules bearing an
isochromenone functionality possess various biological
activities.[6] and they have found application in material
The large number of applications triggered the development of
various synthetic routes to compounds A–C. The synthesis of
dihydroisocoumarins comprises ortho–lithiation of aromatic
compounds,[9a] oxidation of the isochromane moiety,[9b,c] NHC,[9d]
rhodium[9e–g] or palladium[9h] catalysed reactions, or procedures
based either on rearrangements of isobenzofurans,[9i] or
Passerini–aldol sequence.[3] Besides, isochromenone tricyclics
are synthesized by metal–catalysed and metal free classic
oxidative lactonization.[10] On the other hand, derivatives C can
be prepared following a free radical pathway starting from ortho–
[a]
[b]
Mr. S. Crespi, Prof. M. Fagnoni
PhotoGreen Lab, Department of Chemistry
University of Pavia
V.le Taramelli 10 27100 Pavia (Italy)
E-mail: fagnoni@unipv.it
Mrs. S. Jäger. Prof. Dr. B. König
Institut für Organische Chemie
bromobenzoic
acids,[11] through
a
rearrangement
of
isoindolones[12] or by treating the diazonium salt of the
anthranilic acid in the presence of TiCl3 and 3–hydroxypyridines
in aqueous hydrochloric acid.[13]
Universität Regensburg
Universitätstraße 31, D-93053 Regensburg, Germany
E-mail: burkhard.koenig@chemie.uni-regensburg.de
Herein we report the preparation of isochromanones and
isochromenones by the photo–Meerwein reaction using the
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201601458
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diazonium salts of different substituted anthranilic acids as the
source of aryl radicals.[14]
of different solvents was tested using Ru(bpy)3Cl2•6H2O (2 mol%,
entries 1–5 Table 1) as the photocatalyst, and a ratio of 2/1a of 5.
Solvents spanning from MeCN and MeCN/water (9:1, volume
ratio), to the protic (EtOH), polar aprotic (dry dimethylsulfoxide,
DMSO) and non–polar (dichloromethane, DCM) were tested.
Table 1. Optimization of the reaction between diazonium salt 1a and styrene
2.[a]
1a[b]
2[b]
3 [%][c]
Entry
Solvent
Catalyst (mol%)
40
1
Dry MeCN
[Ru(bpy)3]2+ (2)
[Ru(bpy)3]2+ (2)
[Ru(bpy)3]2+ (2)
[Ru(bpy)3]2+ (2)
[Ru(bpy)3]2+ (2)
Eosin Y (5)
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
5 equiv.
2 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
1 equiv.
5 equiv.
5 equiv.
5 equiv.
5 equiv.
5 equiv.
5 equiv.
1 equiv.
1 equiv.
1 equiv.
3 equiv.
3 equiv.
3 equiv.
3 equiv.
3 equiv.
(37)[d]
MeCN/water
9:1
2
17
35
10
21
34
54
30
61
3
Dry DMSO
DCM
4
5
EtOH
6
Dry MeCN
Dry MeCN
Dry MeCN
Dry MeCN
Dry MeCN
Dry MeCN
Dry MeCN
Dry MeCN
Dry MeCN
7
[Ru(bpy)3]2 (2)+
[Ru(bpy)3]2+ (2)
[Ru(bpy)3]2+ (2)
[Ru(bpy)3]2+ (2)
[Ru(bpy)3]2+ (1)
[Ru(bpy)3]2+ (3)
–
8
9
90
10
11
12
13
14[e]
(86)[d]
78
87
6
Scheme 2. a) Classic Meerwein reaction, b) the photoredox catalytic variation
of the Meerwein reaction and c) our reaction proposal.
The classic Meerwein arylation scheme reported by Hans
Meerwein in 1939 involves the copper catalysed addition of an
aryl diazonium salt to an electron–poor alkene,[15] but the yields
are rather poor (only around 20–40%) with high catalyst loadings
(Scheme 2a).[16] The use of an organometallic ([Ru(bpy)3]2+) or
an organic (Eosin Y) photocatalyst allows the generation of aryl
radicals from aryl diazonium salts under visible light irradiation
by loss of molecular nitrogen. The radicals thus generated can
be trapped by a suitable unsaturated compound forming a
styrene in good yields (37–94%) by an addition–elimination
reaction making use of low catalyst loadings (Scheme 2b).[16] We
reasoned that the presence of an acidic moiety in the starting
diazonium salt may drive a cyclization step to form the desired
bi(tri)cyclic compound (Scheme 2c).[17]
[Ru(bpy)3]2+ (2)
55
[a] Reactions are carried out under inert atmosphere (N2) for 2 h at 23°C. [b]
The limiting reagent concentration is 0.25M. [c] GC yields. [d] Isolated yields.
[e] Reaction performed under aerated conditions.
Irradiations were carried out by using 455 nm blue LEDs under
inert atmosphere at 23 °C for 2 h. Dry MeCN (entry 1) was
identified as the best reaction medium and isochomanone 3 was
obtained in 40% GC yield (37% isolated yield). The same
reaction in dry MeCN when replacing the metal complex
photocatalyst by Eosin Y (7.5 mol%, Entry 6) gave a lower yield
of 3. Next, the reaction was further optimized using dry MeCN as
the solvent and Ru(bpy)3Cl2•6H2O as the catalyst, varying the
proportion of the diazonium salt and the olefin. We observed that
a combination of 1a and 2 in a 1:3 ratio gave a significant
increase in the yield of the reaction (Entry 10, Table 1), giving up
to 90% of compound 3 (GC yield). Interestingly, higher amounts
of 2 were found to be detrimental for the overall yield, probably
due to polymerization reactions as indicated by the presence of
a thick insoluble precipitate. The catalyst loading was tested and
further experiments confirmed that the maximum conversion is
Results and Discussion
In order to develop
a
photo–Meerwein arylation for
isochoma(e)none synthesis, we first investigated a series of
different reaction conditions. The model reaction chosen for the
optimization was the one between diazonium salt 1a, thoroughly
studied in the past as aryne source,[18] and styrene 2. First, a set
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10.1002/ejoc.201601458
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obtained with 2 mol% of Ru(bpy)3Cl2•6 H2O (Entries 10–12,
Table 1). Two control experiments were also carried out in order
to assess the role of the catalyst and the effect of air on the
reaction. Thus, irradiating the diazonium salt and the olefin
under uncatalyzed conditions led only to a small amount of 3
(6% yield, entry 13, Table 1).
reaction parameters, the optimum conditions were those
reported in Table 1, entry 10.
Having optimized the reaction conditions, we decided to
investigate the reaction scope by using a series of diazonium
salts of different benzoic acids and different substituted styrenes
(Table 2). The photo–Meerwein reaction was found to occur in
moderate to good yields (23–95%) affording a small library of
3,4–dihydroisocoumarins. Both the presence of different
substituents on the ring of the diazonium salt and modifications
of the electron demanding nature of the substituents on styrenes
do not affect the reaction outcome. Both electron withdrawing
and electron donating groups on the aromatic ring give
acceptable yields of compounds 3-14. To extend the scope of
the reaction methyl methacrylate was used as olefin giving
product 15 in 64% yield. The formation of quaternary carbons is
possible by the transformation and illustrated by the synthesis of
compounds 13–15 that were obtained in good yields.
Table 2. Photo-Meerwein synthesis of isochromanones 3-15.
In order to broaden the scope of the reaction, (hetero)aromatic
compounds were tested as trapping agents of the aryl radicals
extending our protocol to isochromenones (Table 3).
Table 3 Photocatalyzed synthesis of isochromenones 16-19.
Hydroxy-substituted (hetero)aromatics were chosen due to the
known ortho directing effect of the hydroxyl group on the
regioselectivity of the radical attack.[13,19] Moreover, the presence
of the hydroxy group allows the one–pot condensation of the
carboxy group with the alcohol, affording the tricyclic compounds
16–19 in yields comparable with those achievable with thermal
methods.[13]
A plausible mechanism of the reaction is shown in Scheme 3 for
the reaction of 1a and styrene. Experiments in the presence of
TEMPO support a photo–Meerwein radical reaction pathway
(see Supporting Information).[20] Oxidative quenching of the
photoexcited Ru catalyst by the diazonium salt 1 followed by
loss of N2 leads to the aryl radical I that in the presence of
styrene gives radical II. The catalytic cycle is closed by the
electron transfer from II to the oxidized form of the catalyst
generating the benzyl cation III.
Furthermore, degassing was proven to be necessary for the
outcome of the reaction since the irradiation in the presence of
air leads to a significant yield drop (55% yield, entry 14). The
reaction time was optmized and 2 h are sufficient to obtain a
complete conversion of the diazonium salt (see Supporting
Information, Table S1). Therefore, after the evaluation of various
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10.1002/ejoc.201601458
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Scheme 3. Proposed mechanism for the reaction of 1a with styrenes. The intermediates trapped by TEMPO are highlighted.
A radical chain process can also be envisaged, in which
intermediate II reduces the diazonium salt 1 directly. Such smart
initiations of radical reactions have been reported for other
photo-Meerwein reactions.[20] Branched -nucleophiles like
diphenylethylene or methyl methacrylate promote a better
stabilization of the cationic intermediate allowing the formation of
quaternary carbon centres in high yield, as demonstrated by
products 13-15. The final product 3 is obtained from ring closure
and subsequent proton loss of the cation III (Scheme 3). Both
radical intermediates I and II were trapped by TEMPO to give Iʹ
(MH+ (ESI–MS): 278.1792) and IIʹ (MH+ (ESI–MS): 382.2381),
respectively.
the hydroxypyridine reaction we propose the intermediacy of the
3–hydroxypyridinium cation IV, generated in situ from the
interaction of the heterocyclic nitrogen and the carboxylic acid
proton (Scheme 4).[13,19, 22]
Conclusions
In conclusion, we optimized and developed a photo-Meerwein
procedure giving access to structurally diverse isochromanone
derivatives bearing the dihydroisocoumarin core and to the
(hetero)biaryl tricyclic isochromenones. The reported method is
reliable and affords the desired products in good yields with high
selectivity under mild conditions.
Experimental Section
Preparation of Aryldiazonium Tetrafluoroborates 1a-1d: Compounds
1a-1d were prepared according to
a
modification of
a
literature
procedure.[22] In a mixture of 2 mL of EtOH and
5
mL of 50%
hydrofluoroboric acid, 15 mmol of the appropriate aniline were dissolved,
assisting at the precipitation of a thick salt. The reaction mixture was then
cooled to 0 °C using an ice bath, consequently a solution of 20 mmol of
sodium nitrite in distilled water (1.35 g in 2 mL, 1.5 equiv.) was added
dropwise in 5 minutes. The suspension was stirred for an additional 20
min at 0 °C and then the temperature was allowed to raise to RT, while
the reaction was stirred for 30 min. The mixture was filtered and the
recovered solid was washed with cold methanol, rinsed several times
with diethyl ether and dried under vacuum.
Scheme 4. Proposed mechanism for the reaction of 1a with hydroxypyridines.
On the other hand, the selectivity of the attack in position 2 of
the pyridine and phenolic ring can be explained on the basis of
cases previously reported in the literature.[13,19] In particular for
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Photocatalytic Synthesis of Isochromanones and Isochromenones:
In a 5 mL snap vial 0.25 mmol of the appropriate aryl diazonium
tetrafluoroborate, 0.75 mmol (3 equiv.) of the olefin or aromatic, and 3.7
mg (0.02 equiv.) [Ru(bpy)3]Cl2•6H2O were dissolved in 1 mL of dry MeCN.
The vial was sealed with a septum and degassed via the “freeze-pump-
method” (3×). The reaction mixture was stirred at 23 °C and irradiated
from the bottom side of the vial for 2 h using blue LEDs (455 nm). After
the irradiation time the mixture was diluted with water and washed three
times with diethyl ether. The combined organic layers were dried over
Na2SO4, filtered, and concentrated in vacuum. The resulting crude
product was further purified by column chromatography using a petrol
ether/ethyl acetate as eluent. For GC analysis, the samples were taken
directly after irradiation, 20 L of isochroman were added as internal
standard, and the mixture submitted to GC without further purification.
8.14 (dd, J = 7.8, 1.3 Hz, 1H), 7.56 (td, J = 7.5, 1.5 Hz, 1H), 7.43 (d, J =
7.8 Hz, 1H), 7.40 (d, J = 8.6 Hz, 2H), 7.28 (d, J = 7.8 Hz, 1H), 6.93 (d, J =
8.8 Hz, 2H), 5.50 (dd, J = 12.0, 3.1 Hz, 1H), 3.82 (s, 3H), 3.34 (dd, J =
16.5, 12.1 Hz, 1H), 3.09 (dd, J = 16.5, 3.2 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 165.5, 159.8, 139.1, 133.9, 130.6, 130.4, 127.8, 127.7, 127.4,
125.1, 114.0, 79.9, 55.4, 35.5. IR (neat, cm-1) 3071, 2959, 2926, 2855,
1707, 1606, 1513, 1457, 1245, 1025, 831, 734. HRMS (EI) calcd. m/z for
C16H14O3 [M•+] 254.09375; found 254.09331. The spectroscopic data of 7
are in accordance with previous data reported in the literature.[25]
3-(4-Fluorophenyl)isochroman-1-one (8): Pale yellow solid (47.8 mg,
yield 79%), m.p. 84–85 °C. 1H NMR (300 MHz, CDCl3): δ 8.15 (dd, J =
7.8, 1.4 Hz, 1H), 7.58 (td, J = 7.5, 1.4 Hz, 1H), 7.52–7.39 (m, 3H), 7.29 (d,
J = 7.6 Hz, 1H), 7.18–7.05 (m, 2H), 5.54 (dd, J = 12.1, 3.2 Hz, 1H), 3.32
(dd, J = 16.5, 12.1 Hz, 1H), 3.11 (dd, J = 16.4, 3.2 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 165.2, 162.8 (d, J = 247.4 Hz), 138.7, 134.4 , 134.0 ,
130.5 , 128.1 , 128.0 , 127.4 , 125.0 , 115.7 (d, J = 21.6 Hz), 79.3 , 35.6.
IR (neat, cm-1) 3067, 3019, 2922, 2855, 1718, 1603, 1510, 1271, 1222,
1061, 831, 738 HRMS (EI) calcd. m/z for C15H11FO2 [M•+] 242.07376;
found 242.07305 The spectroscopic data of 8 are in accordance with
previous data reported in the literature.[26]
3-Phenylisochroman-1-one (3): Colourless solid (48.2 mg, yield 86%),
m.p. 89–90°C (lit. 90–91°C[23]). 1H NMR (300 MHz, CDCl3): δ 8.16 (dd, J
= 7.5, 1.5 Hz, 1H), 7.57 (td, J = 7.5, 1.5 Hz, 1H), 7.52–7.36 (m, 6H), 7.29
(d, J = 7.5 Hz, 1H), 5.56 (dd, J = 12.0, 3.3 Hz, 1H), 3.34 (dd, J = 16.5,
12.0 Hz, 1H), 3.13 (dd, J = 16.5, 3.3 Hz, 1H). 13C NMR (75 MHz, CDCl3):
δ 165.4, 139.0, 138.6, 134.0, 130.4, 128.7, 128.7, 127.9, 127.4, 126.1,
125.1, 80.0, 35.6. IR (neat, cm-1) 3071, 2922, 2855, 1715, 1603, 1457,
1267, 1222, 991, 909, 764, 693. HRMS (EI) calcd. m/z for C15H12O2 [M•+]
3-(4-Chlorophenyl)isochroman-1-one (9): White solid (14.9 mg, yield
23%), m.p. 82–83 °C (lit. 81–83 °C[25]). 1H NMR (300 MHz, CDCl3): δ
8.14 (dd, J = 7.8, 1.5 Hz, 1H), 7.58 (td, J = 7.5, 1.5 Hz, 1H), 7.49–7.36 (m,
5H), 7.28 (d, J = 7.6 Hz, 1H), 5.54 (dd, J = 11.9, 3.3 Hz, 1H), 3.30 (dd, J
= 16.4, 11.9 Hz, 1H), 3.12 (dd, J = 16.4, 3.3 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 165.1, 138.6, 137.1, 134.5, 134.1, 130.5, 128.9, 128.0, 127.5,
127.4, 125.0, 79.2, 35.6. IR (neat, cm-1) 3067, 2918, 1722, 1603, 1413,
1271, 1114, 831, 746, 705. HRMS (EI) calcd. m/z for C15H11FO2 [M•+]
224.08318; found 224.08275. The spectroscopic data of
accordance with previous data reported in the literature.[23]
3 are in
8-Methyl-3-phenylisochroman-1-one (4): Colourless solid (51.8 mg,
yield 87%), m.p. 147–148 °C. 1H NMR (300 MHz, CDCl3): δ 7.53–7.33 (m,
6H), 7.26–7.21 (m, 1H), 7.11 (d, J = 7.4 Hz, 1H), 5.46 (dd, J = 12.0, 2.9
Hz, 1H), 3.32 (dd, J = 16.2, 12.0 Hz, 1H), 3.08 (dd, J = 16.2, 2.9 Hz, 1H),
2.72 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 164.7, 143.1, 140.0, 138.6,
132.8, 131.3, 128.7, 128.6, 126.2, 125.2, 123.7, 79.3, 36.8, 22.3. IR (neat,
cm-1) 3075, 3019, 2952, 2922, 2855, 1707, 1595, 1461, 1282, 1126,
1066, 753, 704. HRMS (EI) calcd. m/z for C16H14O2 [M•+] 238.09883;
found 238.09805.
258.04421; found 258.04377. The spectroscopic data of
accordance with previous data reported in the literature.[25]
9 are in
3-(4-Bromophenyl)isochroman-1-one (10): White solid (37.9 mg, yield
50%), m.p. 106–107 °C. 1H NMR (300 MHz, CDCl3): δ 8.14 (dd, J = 7.8,
1.3 Hz, 1H), 7.62–7.51 (m, 3H), 7.49–7.40 (m, 1H), 7.39–7.33 (m, 2H),
7.28 (d, J = 7.5 Hz, 1H), 5.52 (dd, J = 11.8, 3.3 Hz, 1H), 3.28 (dd, J =
16.4, 11.9 Hz, 1H), 3.11 (dd, J = 16.5, 3.3 Hz, 1H). 13C NMR (75 MHz,
CDCl3): δ 165.1, 138.6, 137.6, 134.1, 131.9, 130.5, 128.0, 127.8, 127.4,
125.0, 122.6, 79.2, 35.5. IR (neat, cm-1) 3067, 2915, 1722, 1599, 1487,
1271, 1066, 1006, 839, 738, 693. HRMS (EI) calcd. m/z for C15H11BrO2
[M•+] 301.99220; found 301.99270.
5-Methyl-3-phenylisochroman-1-one (5): Colourless solid (15.0 mg,
yield 25%), m.p. 90–91 °C. 1H NMR (300 MHz, CDCl3): δ 8.08–7.96 (m,
1H), 7.56–7.30 (m, 8H), 5.52 (dd, J = 10.0, 5.4 Hz, 1H), 3.25–3.04 (m,
2H), 2.33 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 165.8, 138.8, 137.6,
135.3, 135.2, 128.7, 128.7, 128.3, 127.3, 126.2, 125.1, 79.4, 32.9, 18.9.
IR (neat, cm-1) 3067, 2963, 2922, 1707, 1595, 1469, 1245, 1107, 999,
741, 697. HRMS (EI) calcd. m/z for C16H14O2 [M•+] 238.09883; found
238.09821.
3-(4-Cyanophenyl)isochroman-1-one (11): White solid (59.2 mg, yield
95%), m.p. 152–153 °C. 1H NMR (300 MHz, CDCl3): δ 8.12 (dd, J = 7.8,
1.3 Hz, 1H), 7.74–7.58 (AA’BB’, 4H), 7.57 (dd, J = 7.5, 1.4 Hz, 1H), 7.43
(tt, J = 7.6, 1.0 Hz, 1H), 7.29 (d, J = 7.6 Hz, 1H), 5.61 (dd, J = 11.4, 3.8
Hz, 1H), 3.27 (dd, J = 16.4, 11.5 Hz, 1H), 3.16 (dd, J = 16.4, 3.8 Hz, 1H).
13C NMR (75 MHz, CDCl3): δ 164.7, 143.7, 138.2, 134.3, 132.6, 130.5,
128.2, 127.4, 126.7, 124.7, 118.4, 112.5, 78.8, 35.4. IR (neat, cm-1) 3056,
2930, 2229, 1707, 1607, 1458, 1274, 1062, 839, 749, 690. HRMS (EI)
calcd. m/z for C16H11NO2 [M•+] 249.07843; found 249.07729.
7-Nitro-3-phenylisochroman-1-one (6): Pale yellow solid (47.1 mg,
yield 70%), m.p. 172–173 °C. 1H NMR (300 MHz, CDCl3): δ 8.14 (dd, J =
7.7, 1.5 Hz, 1H), 7.62–7.51 (m, 3H), 7.44 (tt, J = 7.7, 1.1 Hz, 1H), 7.39–
7.33 (m, 2H), 7.28 (d, J = 7.7 Hz, 1H), 5.52 (dd, J = 11.9, 3.3 Hz, 1H),
3.29 (dd, J = 16.4, 11.9 Hz, 1H), 3.12 (dd, J = 16.4, 3.3 Hz, 1H). 13C
NMR (75 MHz, CDCl3): δ 165.1, 138.6, 137.6, 134.1, 131.9, 130.5, 128.0,
127.8, 127.4, 125.0, 122.6, 79.2, 35.5. IR (neat, cm-1) 3082, 3037, 2926,
2855, 1726, 1614, 152, 1424, 1346, 1260, 1137, 1066, 998, 760, 693.
HRMS (EI) calcd. m/z for C15H11NO4 [M•+] 269.06826; found 269.06724.
3-(4-Methylphenyl)isochroman-1-one (12): White solid (45.3 mg, yield
76%), m.p. 96–97 °C (lit. 92–94 °C[25]). 1H NMR (300 MHz, CDCl3): δ
8.15 (dd, J = 7.8, 1.4 Hz, 1H), 7.57 (td, J = 7.5, 1.5 Hz, 1H), 7.42 (tt, J =
7.6, 1.1 Hz, 1H), 7.39–7.19 (AA’BB’, 4H), 7.28 (d, J = 7.8 Hz, 1H), 5.51
3-(4-Methoxyphenyl)isochroman-1-one (7): White solid (29.9 mg, yield
47%), m.p. 109–110°C. (lit. 108-109 °C[24]). 1H NMR (300 MHz, CDCl3): δ
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(dd, J = 12.0, 3.3 Hz, 1H), 3.33 (dd, J = 16.5, 12.0 Hz, 1H), 3.10 (dd, J =
16.5, 3.3 Hz, 1H), 2.37 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 165.5,
139.1, 138.5, 135.6, 133.9, 130.4, 129.3, 127.8, 127.4, 126.1, 125.2,
80.0, 35.6, 21.2. IR (neat, cm-1) 3034, 2918, 1718, 1606, 1461, 1267,
1118, 812, 738, 689. HRMS (EI) calcd. m/z for C16H14O2 [M•+] 238.09883;
found 238.09868.
spectroscopic data of 17 are in accordance with previous data reported in
the literature.[33]
2-Methyl-6H-isochromeno[4,3-b]pyridin-6-one (18): White solid (29.0
mg, yield 55%), m.p. 139–140 °C (lit. 138–139 °C [32]). 1H NMR (300 MHz,
CDCl3): δ 8.71–8.67 (m, 1H), 8.36 (dt, J = 7.8, 0.9 Hz, 1H), 7.93–7.84 (m,
1H), 7.67 (ddd, J = 8.0, 7.3, 1.3 Hz, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.26 (d,
J = 8.5 Hz, 1H), 2.66 (s, 3H). 13C NMR (75 MHz, CDCl3): δ 160.5, 155.0,
145.9, 135.7, 135.5, 135.0, 135.0, 130.3, 130.0, 125.1, 124.8, 123.4,
122.4, 24.2. IR (neat, cm-1) 3078, 2952, 2855, 1730, 1573, 1435, 1267,
824, 743 HRMS (ESI) calcd. m/z for C13H9NO2H+ [(M + H)]+ 212.0712;
found 212.0719.
3-Methyl-3-phenylisochroman-1-one (13): White solid (45.9 mg, yield
77%), m.p. 50–52 °C 1H NMR (300 MHz, CDCl3): δ 8.01 (dd, J = 7.6, 1.3
Hz, 1H), 7.50–7.39 (m, 3H), 7.32–7.15 (m, 5H), 3.52 (d, J = 16.4 Hz, 1H),
3.40 (d, J = 16.3 Hz, 1H), 1.75 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
165.3, 143.6, 137.9, 133.9, 130.0, 128.5, 127.7, 127.6, 127.5, 125.2,
124.7, 83.7, 39.1, 30.2. IR (neat, cm-1) 3064, 2982, 2930, 1707, 1603,
1286, 1114, 760, 697. HRMS (EI) calcd. m/z for C16H14O2 [M•+]
238.09883 found 238.09827. The spectroscopic data of 13 are in
accordance with previous data reported in the literature.[27]
2,7-Dimethyl-6H-isochromeno[4,3-b]pyridin-6-one (19): White solid
(24.8 mg, yield 44%) m.p. 150–152 °C. 1H NMR (300 MHz, CDCl3): δ
8.68–8.56 (m, 1H), 7.71 (t, J = 7.7 Hz, 1H), 7.54–7.40 (m, 2H), 7.22 (d, J
= 8.4 Hz, 1H), 2.85 (s, 3H), 2.64 (s, 3H). 13C NMR (75 MHz, CDCl3): δ
159.8, 154.6, 145.7, 143.7, 137.0, 135.7, 134.2, 133.5, 124.6, 124.5,
121.5, 120.6, 24.2, 23.5. IR (neat, cm-1) 3086, 2922, 2851, 1730, 1584,
1469, 1245, 1211, 1036, 828, 753. HRMS (ESI) calcd. m/z for
C14H11NO2H+ [(M + H)]+ 226.0870; found 226.0885.
3,3-Diphenylisochroman-1-one (14): White solid (66.1 mg, yield 88%),
1
m.p. 148–149 °C (lit. 148–149 °C[28]). H NMR (300 MHz, CDCl3): δ 7.98
(dd, J = 7.8, 1.3 Hz, 1H), 7.50 (td, J = 7.5, 1.4 Hz, 1H), 7.47–7.39 (m, 4H),
7.36–7.16 (m, 9H), 3.82 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 165.1,
143.0, 138.2, 134.1, 130.2, 128.5, 127.7, 127.6, 127.5, 126.2, 125.7,
86.6, 39.1. IR (neat, cm-1) 3030, 3067, 2922, 2855, 1718, 1603, 1446,
1282, 1237, 760, 701. HRMS (EI) calcd. m/z for C21H16O2 [M•+]
300.11448; found 300.11383. The 1H NMR and IR data of 14 are in
accordance with previous data reported in the literature.[29]
Acknowledgements
S. C. gratefully thanks A. Eisenhofer, A. Kralik, M. Obst, K.
Rustler and N. A. Simeth for fruitful discussions. We thank the
Deutsche Forschungsgemeinschaft (GRK 1626) for financial
support.
Methyl 3-methyl-1-oxoisochromane-3-carboxylate (15): White solid
(35.2 mg, yield 64%), m.p. 105–107 °C (lit. 104–105 °C[30]). 1H NMR (300
MHz, CDCl3): δ 8.06 (dd, J = 7.7, 1.3 Hz, 1H), 7.51 (td, J = 7.5, 1.5 Hz,
1H), 7.42–7.33 (m, 1H), 7.20 (dt, J = 7.6, 0.6 Hz, 1H), 3.59 (s, 3H), 3.39
(d, J = 16.3 Hz, 1H), 3.29–3.14 (m, 1H), 1.75 (s, 3H). 13C NMR (75 MHz,
CDCl3): δ 172.2, 164.3, 136.3, 134.0, 130.1, 128.1, 127.5, 124.5, 82.0,
53.1, 37.0, 25.0. IR (neat, cm-1) 3030, 2967, 2922, 2855, 1750, 1722,
1606, 1454, 1208, 1081, 738, 685. HRMS (ESI) calcd. m/z for
C21H16O2H+ [(M + H)]+ 221.0814; found 221.0818.
Keywords: Visible Light • Photoredox Catalysis • Aryl Radicals •
Diazonium Salts • Cyclization
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Entry for the Table of Contents
FULL PAPER
Photoredox Catalysis
Stefano Crespi, Stefanie Jäger,
Burkhard König* and Maurizio Fagnoni*
Page No. – Page No.
A Photocatalytic Meerwein Approach
for the Synthesis of Isochromanones
and Isochromenones
A
mild and facile photoredox approach towards synthetically interesting
isochromanones and isochromenones is presented. Diazonium salts of various
functionalized anthranilic acids are converted to the desired bi– and tricyclic
compounds in good to excellent yields.
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