Furan Ring Opening – Pyridine Ring Closure: An Efficient Approach towards 6H-Isochromeno[4,3-b]pyridin-6-ones from Readily Available Furans and Phthalaldehydic Acid Methyl Esters

Article abstract of DOI:10.1002/ejoc.201701355

An efficient iodine-catalyzed three-component Mannich-type reaction of various 2-alkylfurans, methyl 2-formylbenzoates and carbamates under mild reaction conditions was realized. Synthetic utility of the resulting N-Boc-1-[2-(carbomethoxy)aryl]furfurylami

Full text of DOI:10.1002/ejoc.201701355

A Journal of
Accepted Article
Title: Furan ring opening − pyridine ring closure: an efficient approach
towards 6H-isochromeno[4,3-b]pyridin-6-ones from readily
available furans and phthalaldehydic acid methyl esters
Authors: Pavel Shpuntov, Alexandra Kolodina, Maxim Uchuskin, and
Vladimir Abaev
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201701355
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10.1002/ejoc.201701355
European Journal of Organic Chemistry
FULL PAPER
Furan ring opening − pyridine ring closure: an efficient approach
towards 6H-isochromeno[4,3-b]pyridin-6-ones from readily
available furans and phthalaldehydic acid methyl esters
Pavel M. Shpuntov,[a] Alexandra A. Kolodina,[b] Maxim G. Uchuskin[c] and Vladimir T. Abaev*[d]
Abstract: An efficient iodine-catalyzed three-component Mannich-
type reaction of various 2-alkylfurans, methyl 2-formylbenzoates and
carbamates under mild reaction conditions was realized. Synthetic
utility of the resulting N-Boc-1-[2-(carbomethoxy)aryl]furfuryl amines
was demonstrated by their facile two-step transformation into 2-
methyl-6H-isochromeno[4,3-b]pyridin-6-ones employed in high-
performance cyclometalated OLEDs.
furan and thiophene derivatives.[7b],[7c] Eventually this
transformation was shown to proceed in the presence of
FeCl3·6H2O as a cheap and green alternative.[7a]
However, despite the broad substrate scope and overall
utility of the existing methods, the potential of exploiting this
remarkable reaction for amidoalkylation of furans with ortho-
functionalized benzaldehydes and carbamates yet remains
completely unexplored. Meanwhile, the target products of such
transformation, namely, N-substituted α-arylfurfuryl amines have
been solidly established as promising objects for a variety of
subsequent structural modifications, thereby opening up new
opportunities in the synthesis of complex natural products and
drug molecules. Furfuryl amines of this type are well recognized
to undergo a number of furan ring transforming processes such
as aza-Achmatowicz,[12] aza-Piancatelli[13] rearrangements, intra-
Introduction
In the last decades multicomponent reactions (MCRs) have
gained ever increasing attention from the synthetic community,
due to serving as an exceptionally efficient and powerful tool for
one-pot transformation of simple and readily available starting
materials into relatively complex molecules representing
valuable intermediates in the synthesis of various natural
products and pharmaceuticals.[1] In particular, the Mannich-type
three-component condensation reaction of diverse electron-rich
arenes and heteroarenes with aldehydes and various nitrogen
[14]
and intermolecular Diels-Alder reactions[15] and protolytic
furan recyclizations[16] leading to an array of diverse carbo- and
heterocycles. Moreover, the presence of an ortho-substituent in
the aryl ring renders the target ortho-functionalized N-
alkoxycarbonyl α-(α-furyl)benzylamines appropriate substrates
for the Butin reaction[17] providing access to a variety of
benzannelated polyheterocyclic compounds.
nucleophiles has emerged as
a versatile and therewith
straightforward approach to C-C bond formation which is of
current importance in modern organic synthesis. Thus far,
transformations of this type featuring aromatic aldehydes as
electrophilic components have been extensively applied to
functionalization of phenols,[2] α-naphthols,[3] β-naphthols (Betti
reaction),[4] hydroxyquinolines[3a],[5] and other heteroannelated
phenols,[6] some electron-rich benzenes,[7] naphthylamines,[8]
indoles,[9] 7-azaindoles[10] and indolizines[11] while examples of
employing other heterocycles, particularly, pyrrole, thiophene
and furan derivatives, are scarcely encountered in literature. J.
Jaratjaroonphong and co-workers reported a versatile iodine-
catalyzed carbamoalkylation procedure utilizing benzyl- and tert-
butyl carbamates with a variety of aldehydes which was
successfully applied to 2-alkylfurans and 2-methylthiophene.[7d]
Later on their group and the group of Manolikakes virtually
simultaneously introduced Bi(OTf)3 to promote carbamo- and
amidoalkylation of various (hetero)aromatic substrates including
Hence, herein we report an efficient iodine-catalyzed three-
component Mannich-type condensation of 2-alkylfurans, various
phthalaldehydic acid methyl esters and carbamates as well as
the novel transformation of the resulting N-Boc-arylfurfuryl
amines into 2-methyl-6H-isochromeno[4,3-b]pyridin-6-ones via a
straightforward two-step procedure.
Results and Discussion
In order to avoid potential complications that could arise from the
intrinsic ring-chain tautomerism of phthalaldehydic acid and its
active proton or from its relatively poor solubility in common
weak polar organic solvents the corresponding methyl 2-
formylbenzoate (1a), 2-methylfuran (2a) and ethyl carbamate
(3a) were chosen as model substrates for initial optimization of
the reaction conditions (Table 1). Molecular iodine was chosen
as an inexpensive and eco-friendly catalyst to start with in a
series of solvent screening experiments. Employing toluene as
the reaction medium gave only moderate yield of the target
product 4a (entry 1). Bis(furyl)arylmethane 5a resulting from the
competing 2-methylfuran double addition reaction was also
isolated from the reaction mixture.[18] It should be noted that
bis(furyl)arylmethane 5a was observed as the minor product in
each case the reaction took place. Lowering temperature of the
reaction to 0 °C resulted in a slightly increased yield of the
desired product (entry 2). Switching the reaction solvent to DCM
[a]
[b]
P. M. Shpuntov
Institute of Food and Processing Industry, Kuban State
Technological University, 2 Moskovskaya St., Krasnodar 350072,
Russian Federation.
A. A. Kolodina
Institute of Physical and Organic Chemistry, Southern Federal
University, 194/2 Stachka St., Rostov on Don 344090, Russian
Federation.
[c]
[d]
M. G. Uchuskin
Department of Chemistry, Perm State University, 15 Bukireva St.,
Perm 614990, Russian Federation.
Dr. V. T. Abaev
Department of Chemistry, North-Ossetian State University, 43-46
Vatutina St., Vladikavkaz 362025, Russian Federation.
E-mail: hampazero@mail.ru
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201701355
European Journal of Organic Chemistry
FULL PAPER
promoting this transformation (entries 9-12). However, iodine
appeared to be the catalyst of choice in terms of cost, ease of
handling, non-hydrophobicity and relative non-toxicity.
Table 1 Optimization of the reaction conditions[a]
With the optimized reaction conditions in hand (CH3CN, 10%
I2, 0 °C, 2h, stirring) the scope of the reaction was investigated
by testing an array of substituted methyl 2-formylbenzoates, 2-
alkylfurans and carbamates. The experimental results are
summarized in Table 2. When urethane 3a was replaced by tert-
butyl carbamate 3b, a slightly better yield of carbamoalkylation
product 4b was obtained. This fact along with the more feasible
cleavage of the N-Boc protecting group encouraged us to
employ tert-butyl carbamate as the amine component in further
examinations. The reaction proceeded smoothly with 2-methyl-,
2-ethyl- and 2-tert-butylfurans 2a-c furnishing the corresponding
N-Boc-arylfurfuryl amines 4b, 4c, 4d in high yields.
Unfortunately, no carbamoalkylation product was detected in the
reaction with unsubstituted furan 2d under the optimized
conditions, probably, due to its substantially lower nucleophilicity.
At the same time, when a series of phthalaldehydic acid
methyl esters were subjected to this transformation, the outcome
appeared to be dependent upon the nature of substituents.
Methyl 2-formylbenzoates 1b-d, 1f, 1i-k bearing halogen
substituents at C4 and C5 positions of the ring generally
afforded high yields of the desired products albeit 5-iodo
derivative 4g was isolated with a somewhat lower yield. Methyl
2-formylbenzoate 1e containing strongly electron-withdrawing
nitro group gave equally good results whereas the trisubstituted
benzaldehyde 1l displayed low conversion, probably, because of
the undesirable steric and electronic effects interplay, and only
moderate product yield was obtained in this case even after a
prolonged period of time. The reaction proved less efficient with
methyl 2-formylbenzoates 1g and 1h possessing electron-
donating (OMe) substituents. In these cases the desired N-Boc-
1-[2-(carbomethoxy)aryl]furfuryl amines 4k and 4l were obtained
in lower yields along with sufficient amounts of the
corresponding bis(furyl)arylmethanes 5b and 5c (25% and 23%,
respectively).
Yield (%)[b]
Catalyst
(mol %)
Time
(h)
Entry
Solvent
t (°C)
4a
53
5a
1
toluene
toluene
DCM
I2 (10)
2
2
rt
0
rt
0
0
0
0
rt
0
0
0
14
9
2
I2 (10)
67
3
I2 (10)
0.25
0.5
1
53
24
12
9
4
DCM
I2 (10)
75
5
DCM
I2 (5)
68
6
DCM
I2 (10)
1.17
24
1
77[c]
61[d]
45
14
19
19
7
7
THF
I2 (10)
8
CH3CN
CH3CN
CH3CN
CH3CN
I2 (10)
9
I2 (10)
2
81
10
11
Bi(OTf)3 (5)
CuBr2 (10)
0.75
1
78
5
80
7
BF3·Et2O
(10)
12
CH3CN
2
0
78
7
13
14
15
16
CH3CN
CH3CN
CH3CN
CH3CN
Cu(OTf)2 (5)
ZnCl2 (10)
TiCl4 (10)
I2 (10)
24
3.5
1.5
4
0
72
traces
76
12
−
rt
-15
-15
16
5
74
It is also worth mentioning that accordingly to our initial
assumption, free phthalaldehydic acid 6 appeared not suitable
for this transformation as after 2 hours diminished conversion
was observed by TLC, and after 12 hours at room temperature
[a] Reaction conditions: methyl 2-formylbenzoate 1a (2.4 mmol), 2-methylfuran
2a (2.66 mmol), ethyl carbamate 3a (2.7 mmol) and solvent (3 ml), stirring.
[b] Isolated yield. [c] To a cooled solution of 1a, 3a and I2 in 2 ml of DCM a
solution of 2a in 1 ml of DCM was added dropwise over a period of 30 min with
stirring and then stirred for another 40 min. [d] The reaction mixture was stirred
at 0 °C for 7 h and left overnight at rt for another 17 h.
the
corresponding
3-(2-furyl)phthalide
7
and
bis(furyl)arylmethane 8 were isolated from the reaction mixture
in 23% and 38% yield, respectively, along with 30% of recovered
phthalaldehydic acid (Scheme 1). Formation of the same
products was reported earlier in the acid-catalyzed condensation
of phthalaldehydic acids with furans.[19]
Next, aiming to get a deeper insight into the pathway of this
three-component coupling reaction, we turned our attention to a
series of mechanistic experiments (for details, see ESI). When
the reaction was performed in the absence of carbamate with
excess of 2-methylfuran 2a, bis(furyl)arylmethane 5a was
formed in 69% yield. Interestingly, the carbamoalkylation product
4b could barely be converted to the corresponding
bis(furyl)arylmethane 5a via a Friedel-Crafts-type reaction with
2-methylfuran 2a under the optimized conditions even after
increasing the reaction temperature to 60 °C providing only 21%
yield of the product along with 63% of recovered starting
material. The latter observation allows us to assume that the
accelerated the transformation significantly without any relevant
improvement in the reaction outcome (entry 3). However, in this
case cooling of the reaction mixture also proved beneficial (entry
4). Decreasing the catalyst loading to 5% mol led to a somewhat
lower yield of the carbamoalkylation product (entry 5) while slow
dropwise addition of a 2-methylfuran 2a solution in DCM to the
reaction mixture over 30 minutes did not significantly improve
the yield (entry 6). Finally, CH3CN was found to be the most
suitable solvent for this one-pot three-component coupling
reaction (entry 9). Despite the fact that cooling of the reaction
mixture to 0 °C appeared crucial for obtaining high yields of the
target product, further lowering of temperature to -15 °C was not
advantageous due to a considerable decrease in the reaction
rate (entry 16). After identifying the optimal solvent and
temperature we focused on establishing the most efficient
catalyst. Among a series of Lewis acids tested (entries 9-15) I2,
Bi(OTf)3, CuBr2 and BF3·Et2O proved almost equally potent at
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10.1002/ejoc.201701355
European Journal of Organic Chemistry
FULL PAPER
Table 2 Substrate scope of phthalaldehydic acid methyl esters, furans and carbamates[a],[b]
[a] Reaction conditions: methyl 2-formylbenzoate (2.4 mmol), furan (2.66 mmol), carbamate (2.7 mmol), I2 (0.24 mmol), CH3CN (3 ml for 1a; 5 ml for 1b-1l), 0 °C,
stirring. [b] Isolated yields. [c] Target product not detected by TLC. [d] 25% of the corresponding bis(furyl)arylmethane 5b and 13% of unreacted methyl 2-
formylbenzoate 1g were also isolated from the reaction mixture. [e] 23% of the corresponding bis(furyl)arylmethane 5c and 9% of unreacted methyl 2-
formylbenzoate
1h
were
also
isolated
from
the
reaction
mixture.
[f]
Time
of
the
reaction
was
increased
to
24
h.
desired carbamoalkylation reaction and inevitable formation of
minor quantities of bis(furyl)arylmethanes proceed in parallel
rather than in sequential fashion. However, in the case of
substrates with electron-donating substituents such as 1g and
1h which can form stabilized carbocations it can not be ruled out
that the formation of bis(furyl)arylmethanes by interaction of the
generated N-Boc-arylfurfuryl amines with the second molecule
of furan becomes more significant and is responsible for the
decreased yields of the desired products 4k and 4l. Expectedly,
subjecting bis(furyl)arylmethane 5a to the reaction with tert-butyl
carbamate 3b proved unsuccessful. Condensation of methyl 2-
formylbenzoate 1a and tert-butyl carbamate 3b without addition
of furan component furnished the corresponding N-Boc-aminal 9
(Scheme 2) in only 37% yield, probably, due to unfavorable
equilibrium constant. However, under the optimized reaction
conditions the latter rapidly interacted with 2-methylfuran 2a
providing 84% yield of N-Boc-arylfurfuryl amine 4b as well as
4% of bis(furyl)arylmethane 5a as by-product. Hence, N-Boc-
aminal 9 might well act as an alternative source of the
intermediate protonated N-Boc-imine II in this three-component
transformation despite we were never able to observe it in the
reaction mixture by TLC. Examples of employing such aminals
as precursors to the corresponding N-Boc-imines are
precedented earlier.[20]
Based on these results, the plausible mechanism for this
three-component coupling reaction is shown in Scheme 2. It
should be noted that the nature of the actual catalytic species
under molecular iodine catalysis is still under debate. One
possible mechanism includes protic catalysis with HI that can be
reversibly generated in minor quantities in the reaction of iodine
with water or protic solvents. An alternative point of view was
disclosed in the recent work by Breugst and colleagues[21]
providing evidence for halogen-bond based activation of the
Michael acceptors in reactions catalyzed by molecular iodine
rather than Brønsted-acidity mode. In particular, they showed
that the conjugate addition of indole to α,β-unsaturated ketones
is efficiently promoted by iodine whereas the same reaction
under HI catalysis leads to significantly lower yields of the
corresponding product. To shed light on the mode of action of
iodine we performed a control experiment with methyl 2-
Scheme 1 Reaction with phthalaldehydic acid under the optimized reaction
conditions
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10.1002/ejoc.201701355
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Scheme 3 Plausible mechanism
formylbenzoate 1a, 2-methylfuran 2a and tert-butyl carbamate
3b in the presence of 5% mol HI (57% aq.) under the optimized
reaction conditions. To our surprise in this case the reaction
proceeded smoothly providing the target carbamoalkylation
product 4b in 88% yield. Moreover, the reaction with 5% mol HCl
(37% aq.) proceeded equally well leading to the formation of
product 4b in 89% isolated yield. In contrast, the same reaction
with iodine (10% mol) was completely retarded when performed
in the presence of proton scavenger 2,6-lutidine (10% mol).
Keeping in mind that this lack of reactivity could be caused by
the formation of iodine-pyridine complex another portion of
iodine (10% mol) was added to the reaction mixture but only
trace amounts of the desired carbamoalkylation product 4b were
observed by TLC after 4 hours of the reaction providing an
argument in favour of proton catalysis.
complexes acting as highly efficient and stable emitters in
organic light-emitting diodes (OLEDs).[28]
However, despite the apparent potential, the number of
reported methods providing access to this pyridine-fused
isocoumarin ring system is thus far rather limited.[29] The
classical Hantzsch pyridine synthesis was found to be
inapplicable for the preparation of compounds incorporating this
structural moiety.[30] Synthesis of various annelated 6H-
isochromeno[4,3-b]pyridin-6-ones was accomplished via an
unusual rearrangement of indolizinediones under acidic
conditions.[29e] However, this method appears to be of limited
use due to poor availability of substrates needed. Likewise, most
of other reported procedures build upon the preformed
functionalized pyridine synthons which are obviously much less
accessible than the benzene-based substrates, and furthermore,
suffer from some other substantial drawbacks such as
unsatisfactory product yields, use of expensive reagents and
harsh reaction conditions operating at temperatures up to
300 °C. Hence, new synthetic approaches towards 6H-
isochromeno[4,3-b]pyridin-6-ones employing readily available
substrates and reagents are highly desirable.
In order to demonstrate the synthetic utility of the resulting
N-Boc-1-[2-(carbomethoxy)aryl]furfuryl amines 4 we envisaged
an oxidative furan ring opening
/ recyclization sequence
providing access to the corresponding 6H-isochromeno[4,3-
b]pyridin-6-ones 11. Both isocoumarin[22] and pyridine[23]
frameworks are well recognized as privileged scaffolds widely
represented in a great number of natural products possessing
versatile biological activities. Considering this fact, 6H-
isochromeno[4,3-b]pyridin-6-ones 11 containing both of these
moieties fused together emerge as perspective polyheterocycles
with potentially attractive biological properties.
To prove the concept N-Boc-arylfurfuryl amine 4b was
subjected to oxidative furan ring cleavage[31] in DCM in the
presence of m-CPBA providing the expected ene-dione 10 in
At the same time, 2-arylpyridine skeleton is present in
organoplatinum (II) complexes exhibiting potent antitumor
activities,[24] in luminescent iridium (III) complexes suitable for
living cells imaging[25] and in a number of compounds with
fluorescence properties capable of acting as metal ion binding
chemosensors with readily tunable emission wavelengths.[26]
Similarly, some [4,3-b]-annelated isocoumarins are also reported
to be potentially useful fluorophores for development of new
photochromic systems owing to their inherent fluorescence
“turn-off” sensing of Cu2+ and Fe3+ ions under visible and UV
light.[27] Eventually it should be noted that 6H-isochromeno[4,3-
b]pyridin-6-ones comprised of these two substructures were
successfully applied as cyclometalating ligands for Ir(III)
Scheme 2 Two-step synthesis of 6H-isochromeno[4,3-b]pyridin-6-one 11a
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10.1002/ejoc.201701355
European Journal of Organic Chemistry
FULL PAPER
(2.4 mmol) and carbamate (2.7 mmol) in acetonitrile (3 ml for 1a; 5 ml for
1b-l) at 0 ºC (ice/water bath). The mixture was allowed to stir for 5
minutes. Then furan (2.66 mmol) was slowly added and the reaction
mixture was stirred for 2 h at 0 ºC. After completion of the reaction
monitored by TLC (in some cases traces of unreacted methyl 2-
formylbenzoate could be observed) the reaction mixture was poured into
saturated aqueous Na2S2O3 (15 ml), extracted with CH2Cl2 (3 × 10 ml),
washed with water (4 ml) and brine (4 ml), dried with anhydrous Na2SO4,
filtered and organic solvents were removed in vacuo. The residue was
purified by flash column chromatography on silica gel (petroleum
ether/EtOAc as eluent) to afford the desired products 4a-p. Analytical
samples of solid compounds were obtained by recrystallization from
CH2Cl2/petroleum ether mixture.
Table 3 Substrate scope for the two-step preparation of 6H-isochromeno-[4,3-
b]pyridin-6-ones[a]
Entry
4
R1
R2
H
11, (Yield, %)[b]
11a (65)
Methyl
2-{[(ethoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
benzoate (4a): pale yellow oil (0.61 g, 81%). 1H NMR (400 MHz, DMSO-
d6) δ = 8.18 (d, 3J = 8.9 Hz, 1H, NH), 7.79 (d, 3J = 7.7 Hz, 1H, HAr), 7.65-
1
2
3
4
5
4b
4f
4i
4l
4n
H
3
7.56 (m, 2H, HAr), 7.46-7.37 (m, 1H, HAr), 6.72 (d, J = 8.9 Hz, 1H, CH),
Br
H
11b (61)
5.92 (d, 3J = 3.1 Hz, 1H, HFur), 5.69 (d, 3J = 3.1 Hz, 1H, HFur), 3.98 (q, 3J
= 7.1 Hz, 2H, CH2), 3.77 (s, 3H, OCH3), 2.20 (s, 3H, CH3), 1.15 (t, 3J =
7.1 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 167.1, 155.6,
152.7, 151.0, 141.0, 132.2, 129.8, 129.1, 127.9, 127.5, 107.9, 106.3,
60.0, 52.1, 49.0, 14.6, 13.3 ppm; IR (neat) νmax = 3341, 2982, 2953, 1713,
1503, 1433, 1271, 1125, 1038, 964, 785, 750, 719 cm-1; HRMS (EI) m/z
calcd for C17H20NO5 [M+H]+ = 318.1336, found = 318.1326.
NO2
OMe
H
H
11c (61)
OMe
Br
11d (62)
11e (68)
[a] Reaction conditions: 1) N-Boc-1-[2-(carbomethoxy)aryl]furfuryl amine 4 (1.0
mmol), m-CPBA (1.56 mmol), CH2Cl2 (3 ml), 0 °C, stirring; 2) 4.0 M HCl in 1,4-
dioxane (1 ml), CH2Cl2 (2 ml), rt, stirring. [b] Isolated yield.
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
benzoate (4b): pale yellow oil (0.70 g, 85%). 1H NMR (400 MHz, DMSO-
d6) δ = 7.87 (d, 3J = 9.0 Hz, 1H, NH), 7.78 (d, 3J = 7.7 Hz, 1H, HAr), 7.64-
3
7.56 (m, 2H, HAr), 7.45-7.36 (m, 1H, HAr), 6.66 (d, J = 9.0 Hz, 1H, CH),
81% yield (Scheme 3). The latter under the action of 4 N HCl in
dioxane smoothly underwent N-Boc deprotection with
subsequent pyridine ring formation / lactonization furnishing the
desired isochromenopyridinone 11a in 76% yield.
Then a number of substituted N-Boc-arylfurfuryl amines
were tested in this transformation to examine the scope of the
reaction (Table 3). Gratifyingly, the procedure proved successful
with both electron-withdrawing (Br, NO2) and electron-donating
(OMe) substituents leading to 61-68% overall yields of the
corresponding isochromenopyridinones 11a-e after two steps
with no need for isolation of the intermediate ene-diones.
5.91 (d, 3J = 3.1 Hz, 1H, HFur), 5.68 (d, 3J = 3.1 Hz, 1H, HFur), 3.77 (s, 3H,
OCH3), 2.19 (s, 3H, CH3), 1.37 (s, 9H, t-Bu) ppm; 13C NMR (100 MHz,
DMSO-d6) δ = 167.2, 154.8, 152.9, 150.8, 141.2, 132.1, 129.7, 129.1,
127.9, 127.4, 107.8, 106.2, 78.2, 52.1, 48.7, 28.2 (3C), 13.3 ppm; IR
(neat) νmax = 3386, 2977, 2925, 1715, 1487, 1366, 1248, 1163, 1076,
1020, 784, 755, 719 cm-1; HRMS (EI) m/z calcd for C19H24NO5 [M+H]+ =
346.1649, found = 346.1653.
Methyl
2-{[(tert-butoxycarbonyl)amino](5-ethylfuran-2-yl)methyl}-
benzoate (4c): colorless solid (0.75 g, 88%), mp 74−75 ºC
(CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 7.89 (d, 3J =
9.0 Hz, 1H, NH), 7.78 (d, 3J = 7.7 Hz, 1H, HAr), 7.66-7.55 (m, 2H, HAr),
7.45-7.35 (m, 1H, HAr), 6.67 (d, 3J = 9.0 Hz, 1H, CH), 5.91 (d, 3J = 3.1 Hz,
1H, HFur), 5.70 (d, 3J = 3.1 Hz, 1H, HFur), 3.77 (s, 3H, OCH3), 2.54 (q, 3J =
3
7.5 Hz, 2H, CH2), 1.37 (s, 9H, t-Bu), 1.12 (t, J = 7.5 Hz, 3H, CH3) ppm;
Conclusions
13C NMR (100 MHz, DMSO-d6) δ = 167.2, 156.4, 154.9, 152.8, 141.2,
132.2, 129.8, 129.2, 127.9, 127.4, 107.6, 104.7, 78.3, 52.1, 48.7, 28.2
(3C), 20.8, 12.0 ppm; IR (neat) νmax = 3358, 2970, 2934, 1732, 1721,
1677, 1520, 1249, 1167, 1014, 877, 757, 720 cm-1; HRMS (EI) m/z calcd
for C20H26NO5 [M+H]+ = 360.1805, found = 360.1803.
In conclusion, we have demonstrated a facile and efficient one-
pot three-component procedure for α-carbamoalkylation of
furans with various phthalaldehydic acid methyl esters and
carbamates. The reaction proceeds under mild conditions
employing I2 as an inexpensive, non-hydrophobic and
operationally simple catalyst. Scope and limitations of the
devised method as well as mechanistic aspects were
investigated. Moreover, a powerful and straightforward two-step
reaction sequence for transformation of the resulting N-Boc-1-[2-
(carbomethoxy)aryl]furfuryl amines into 6H-isochromeno[4,3-
b]pyridin-6-ones was developed. Further investigation of the
iodine catalyzed amidoalkylation of furans employing other
ortho-functionalized benzaldehydes is currently underway.
Methyl
2-{[(tert-butoxycarbonyl)amino](5-(tert-butyl)furan-2-
yl)methyl}benzoate (4d): pale yellow oil (0.80 g, 87%). 1H NMR (400
MHz, DMSO-d6) δ = 7.90 (d, J = 9.1 Hz, 1H, NH), 7.77 (d, 3J = 7.8 Hz,
3
1H, HAr), 7.63-7.53 (m, 2H, HAr), 7.44-7.35 (m, 1H, HAr), 6.70 (d, 3J = 9.1
Hz, 1H, CH), 5.87 (d, 3J = 3.2 Hz, 1H, HFur), 5.72 (d, 3J = 3.2 Hz, 1H,
HFur), 3.77 (s, 3H, OCH3), 1.38 (s, 9H, t-Bu), 1.17 (s, 9H, t-Bu) ppm; 13C
NMR (100 MHz, DMSO-d6) δ = 167.3, 162.6, 154.9, 152.6, 141.2, 132.0,
129.7, 129.2, 127.7, 127.3, 106.9, 102.5, 78.3, 52.1, 48.8, 32.1, 28.8
(3C), 28.2 (3C) ppm; IR (neat) νmax = 3384, 2967, 2870, 1717, 1487,
1365, 1248, 1165, 1124, 1077, 1014, 785, 720 cm-1; HRMS (EI) m/z
calcd for C22H30NO5 [M+H]+ = 388.2118, found = 388.2130.
Experimental Section
Methyl
5-bromo-2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-
yl)methyl}benzoate (4f): colorless crystals (0.89 g, 88%), mp 101−102
ºC (CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 7.93 (d,
3J = 8.8 Hz, 1H, NH), 7.91 (d, 4J = 2.3 Hz, 1H, HAr), 7.84 (dd, 3J = 8.5 Hz,
General procedure for the preparation of 4a-p: Molecular iodine (0.06
g, 0.24 mmol) was added to a stirred solution of methyl 2-formylbenzoate
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701355
European Journal of Organic Chemistry
FULL PAPER
4J = 2.3 Hz, 1H, HAr), 7.54 (d, 3J = 8.5 Hz, 1H, HAr), 6.59 (d, 3J = 8.8 Hz,
3.79 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 2.19 (s, 3H, CH3), 1.37 (s, 9H, t-
Bu) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 167.0, 158.0, 154.8, 153.3,
150.7, 133.2, 130.2, 129.5, 117.8, 114.5, 107.6, 106.2, 78.2, 55.4, 52.2,
48.3, 28.2 (3C), 13.3 ppm; IR (neat) νmax = 3357, 2983, 2950, 1725, 1708,
1511, 1258, 1210, 1164, 1070, 1044, 1021, 792 cm-1; HRMS (EI) m/z
calcd for C20H26NO6 [M+H]+ = 376.1755, found = 376.1769.
3
3
1H, CH), 5.92 (d, J = 3.1 Hz, 1H, HFur), 5.72 (d, J = 3.1 Hz, 1H, HFur),
3.78 (s, 3H, OCH3), 2.19 (s, 3H, CH3), 1.37 (s, 9H, t-Bu) ppm; 13C NMR
(100 MHz, DMSO-d6) δ = 165.8, 154.8, 152.1, 151.0, 140.6, 134.9, 132.1,
131.1, 130.2, 120.3, 108.0, 106.3, 78.4, 52.5, 48.4, 28.2 (3C), 13.3 ppm;
IR (neat) νmax = 3277, 2969, 1723, 1696, 1370, 1352, 1291, 1252, 1163,
1023, 784 cm-1; HRMS (EI) m/z calcd for C19H23BrNO5 [M+H]+
=
424.0754, found = 424.0770.
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
4,5-dimethoxybenzoate (4l): colorless prisms (0.52 g, 54%), mp 98−99
1
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
5-iodobenzoate (4g): colorless solid (0.86 g, 77%), mp 78−79 ºC
(CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 8.07 (d, 4J =
1.9 Hz, 1H, HAr), 7.98 (dd, 3J = 8.3 Hz, 4J = 1.9 Hz, 1H, HAr), 7.90 (d, 3J =
ºC (CH2Cl2/petroleum ether). H NMR (400 MHz, DMSO-d6) δ = 7.81 (d,
3J = 9.3 Hz, 1H, NH), 7.35 (s, 1H, HAr), 7.27 (s, 1H, HAr), 6.78 (d, 3J = 9.3
Hz, 1H, CH), 5.89 (d, 3J = 3.0 Hz, 1H, HFur), 5.67 (d, 3J = 3.0 Hz, 1H,
HFur), 3.81 (s, 3H, OCH3), 3.79 (s, 3H, OCH3), 3.76 (s, 3H, OCH3), 2.20 (s,
3H, CH3), 1.38 (s, 9H, t-Bu) ppm; 13C NMR (100 MHz, DMSO-d6) δ =
166.4, 154.9, 153.5, 151.9, 150.6, 147.1, 135.9, 120.2, 112.7, 111.5,
107.4, 106.2, 78.2, 55.8, 55.6, 51.9, 48.3, 28.2 (3C), 13.3 ppm; IR (neat)
νmax = 3272, 3002, 2946, 1715, 1697, 1523, 1351, 1253, 1211, 1157,
3
3
8.8 Hz, 1H, NH), 7.38 (d, J = 8.3 Hz, 1H, HAr), 6.57 (d, J = 8.8 Hz, 1H,
3
3
CH), 5.91 (d, J = 3.1 Hz, 1H, HFur), 5.72 (d, J = 3.1 Hz, 1H, HFur), 3.77
(s, 3H, OCH3), 2.19 (s, 3H, CH3), 1.36 (s, 9H, t-Bu) ppm; 13C NMR (100
MHz, DMSO-d6) δ = 165.7, 154.8, 152.1, 151.0, 141.0, 140.7, 137.8,
131.0, 130.1, 108.0, 106.3, 93.0, 78.4, 52.4, 48.4, 28.2 (3C), 13.3 ppm;
IR (neat) νmax = 3343, 2943, 1737, 1670, 1519, 1241, 1154, 1079, 1023,
849, 784 cm-1; HRMS (EI) m/z calcd for C19H23INO5 [M+H]+ = 472.0615,
found = 472.0600.
1018, 1003, 784 cm-1; HRMS (EI) m/z calcd for C21H28NO7 [M+H]+
=
406.1860, found = 406.1852.
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
4-chlorobenzoate (4m): colorless crystals (0.79 g, 88%), mp 92−93 ºC
(CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 7.97 (d, 3J =
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
5-chlorobenzoate (4h): colorless solid (0.78 g, 87%), mp 93.5−94.5 ºC
(CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 7.93 (d, 3J =
8.9 Hz, 1H, NH), 7.78 (d, 4J = 2.3 Hz, 1H, HAr), 7.71 (dd, 3J = 8.5 Hz, 4J =
3
4
9.0 Hz, 1H, NH), 7.82 (d, J = 8.4 Hz, 1H, HAr), 7.68 (d, J = 2.2 Hz, 1H,
HAr), 7.50 (dd, 3J = 8.4 Hz, 4J = 2.2 Hz, 1H, HAr), 6.70 (d, 3J = 9.0 Hz, 1H,
3
3
CH), 5.92 (d, J = 3.1 Hz, 1H, HFur), 5.72 (d, J = 3.1 Hz, 1H, HFur), 3.78
(s, 3H, OCH3), 2.19 (s, 3H, CH3), 1.38 (s, 9H, t-Bu) ppm; 13C NMR (100
MHz, DMSO-d6) δ = 166.2, 154.8, 152.1, 151.1, 143.8, 137.2, 131.9,
127.8, 127.7, 127.6, 108.1, 106.3, 78.5, 52.3, 48.4, 28.2 (3C), 13.3 ppm;
IR (neat) νmax = 3239, 3127, 2951, 1719, 1703, 1362, 1261, 1238, 1170,
1102, 1071, 1020, 789 cm-1; HRMS (EI) m/z calcd for C19H23ClNO5
[M+H]+ = 380.1259, found = 380.1256.
3
3
2.3 Hz, 1H, HAr), 7.61 (d, J = 8.5 Hz, 1H, HAr), 6.61 (d, J = 8.9 Hz, 1H,
CH), 5.92 (d, 3J = 3.1 Hz, 1H, HFur), 5.72 (d, 3J = 3.1 Hz, 1H, HFur), 3.79 (s,
3H, OCH3), 2.19 (s, 3H, CH3), 1.37 (s, 9H, t-Bu) ppm; 13C NMR (100 MHz,
DMSO-d6) δ = 165.9, 154.8, 152.2, 151.0, 140.2, 132.0 (2C), 130.9,
129.9, 129.2, 108.0, 106.3, 78.4, 52.5, 48.3, 28.2 (3C), 13.3 ppm; IR
(neat) νmax = 3279, 2970, 1724, 1696, 1370, 1351, 1294, 1253, 1166,
1023, 965, 784 cm-1; HRMS (EI) m/z calcd for C19H23ClNO5 [M+H]+
=
380.1259, found = 380.1266.
Methyl
4-bromo-2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-
yl)methyl}benzoate (4n): colorless solid (0.90 g, 89%), mp 109−110 ºC
(CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 7.98 (d, 3J =
9.0 Hz, 1H, NH), 7.82 (br s, 1H, HAr), 7.73 (d, 3J = 8.4 Hz, 1H, HAr), 7.63
(dd, 3J = 8.4 Hz, 4J = 2.0 Hz, 1H, HAr), 6.69 (d, 3J = 9.0 Hz, 1H, CH), 5.92
(d, 3J = 3.1 Hz, 1H, HFur), 5.71 (d, 3J = 3.1 Hz, 1H, HFur), 3.77 (s, 3H,
OCH3), 2.19 (s, 3H, CH3), 1.38 (s, 9H, t-Bu) ppm; 13C NMR (100 MHz,
DMSO-d6) δ = 166.4, 154.8, 152.2, 151.1, 143.8, 132.0, 130.7, 130.6,
128.1, 126.2, 108.1, 106.4, 78.6, 52.4, 48.4, 28.2 (3C), 13.3 ppm; IR
(neat) νmax = 3239, 3125, 2980, 1720, 1702, 1361, 1260, 1237, 1171,
1091, 1070, 1021, 790 cm-1; HRMS (EI) m/z calcd for C19H23BrNO5
[M+H]+ = 424.0754, found = 424.0746.
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
5-nitrobenzoate (4i): colorless solid (0.77 g, 82%), mp 112−113 ºC
(CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 8.54 (d, 4J =
2.5 Hz, 1H, HAr), 8.49 (dd, 3J = 8.7 Hz, 4J = 2.5 Hz, 1H, HAr), 8.11 (d, 3J =
3
8.6 Hz, 1H, NH), 7.89 (d, 3J = 8.7 Hz, 1H, HAr), 6.75 (d, J = 8.6 Hz, 1H,
3
3
CH), 5.94 (d, J = 3.1 Hz, 1H, HFur), 5.78 (d, J = 3.1 Hz, 1H, HFur), 3.85
(s, 3H, OCH3), 2.20 (s, 3H, CH3), 1.37 (s, 9H, t-Bu) ppm; 13C NMR (100
MHz, DMSO-d6) δ = 165.3, 154.8, 151.4, 151.2, 148.3, 146.5, 130.2,
129.5, 126.8, 124.7, 108.5, 106.4, 78.6, 52.8, 48.7, 28.2 (3C), 13.3 ppm;
IR (neat) νmax = 3276, 3132, 2971, 1731, 1699, 1526, 1343, 1311, 1260,
1168, 787, 739 cm-1; HRMS (EI) m/z calcd for C19H23N2O7 [M+H]+
=
391.1500, found = 391.1508.
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
4-iodobenzoate (4o): colorless crystals (0.95 g, 85%), mp 117−118 ºC
(CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 7.99 (br s,
1H, HAr), 7.94 (d, 3J = 9.0 Hz, 1H, NH), 7.80 (dd, 3J = 8.2 Hz, 4J = 1.7 Hz,
1H, HAr), 7.54 (d, 3J = 8.2 Hz, 1H, HAr), 6.65 (d, 3J = 9.0 Hz, 1H, CH),
5.91 (d, 3J = 3.1 Hz, 1H, HFur), 5.70 (d, 3J = 3.1 Hz, 1H, HFur), 3.76 (s, 3H,
OCH3), 2.19 (s, 3H, CH3), 1.38 (s, 9H, t-Bu) ppm; 13C NMR (100 MHz,
DMSO-d6) δ = 166.6, 154.8, 152.3, 151.1, 143.1, 136.5, 136.4, 131.5,
128.5, 108.0, 106.3, 100.3, 78.5, 52.3, 48.3, 28.2 (3C), 13.3 ppm; IR
(neat) νmax = 3242, 3123, 2980, 1721, 1699, 1360, 1262, 1237, 1170,
1084, 1070, 1021, 791 cm-1; HRMS (EI) m/z calcd for C19H23INO5 [M+H]+
= 472.0615, found = 472.0626.
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
5-fluorobenzoate (4j): colorless solid (0.75 g, 87%), mp 70−71 ºC
(CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ = 7.91 (d, 3J =
9.0 Hz, 1H, NH), 7.70-7.59 (m, 1H, HAr), 7.59-7.52 (m, 1H, HAr), 7.52-
7.43 (m, 1H, HAr), 6.62 (d, 3J = 9.0 Hz, 1H, CH), 5.91 (br s, 1H, HFur),
5.70 (br s, 1H, HFur), 3.79 (s, 3H, OCH3), 2.19 (s, 3H, CH3), 1.37 (s, 9H, t-
Bu) ppm; 13C NMR (100 MHz, DMSO-d6) δ = 166.0, 160.6 (d, JCF
1
=
3
244.8 Hz), 154.8, 152.6, 151.0, 137.5, 131.0 (d, JCF = 7.0 Hz), 130.3 (d,
3JCF = 8.1 Hz), 119.1 (d, 2JCF = 20.9 Hz), 116.3 (d, 2JCF = 23.0 Hz), 107.9,
106.3, 78.3, 52.4, 48.2, 28.2 (3C), 13.3 ppm; IR (neat) νmax = 3354, 2985,
1735, 1674, 1520, 1496, 1299, 1252, 1204, 1164, 1021, 781 cm-1; HRMS
(EI) m/z calcd for C19H23FNO5 [M+H]+ = 364.1555, found = 364.1545.
Methyl 6-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
3-chloro-2-nitrobenzoate (4p): colorless solid (0.55 g, 54%), mp
145−146 ºC (CH2Cl2/petroleum ether). 1H NMR (400 MHz, DMSO-d6) δ =
8.13 (d, 3J = 8.6 Hz, 1H, NH), 8.01 (d, 3J = 8.5 Hz, 1H, HAr), 7.69 (d, 3J =
8.5 Hz, 1H, HAr), 6.20 (d, 3J = 8.6 Hz, 1H, CH), 5.99 (br s, 2H, HFur), 3.77
(s, 3H, OCH3), 2.20 (s, 3H, CH3), 1.37 (s, 9H, t-Bu) ppm; 13C NMR (100
MHz, DMSO-d6) δ = 163.5, 154.8, 151.8, 150.5, 147.0, 140.2, 133.4,
131.6, 126.6, 123.9, 109.0, 106.6, 78.9, 53.7, 48.7, 28.1 (3C), 13.3 ppm;
Methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
5-methoxybenzoate (4k): colorless crystals (0.45 g, 51%), mp 124−125
ºC (CH2Cl2/petroleum ether). H NMR (400 MHz, DMSO-d6) δ = 7.78 (d,
1
3J = 9.1 Hz, 1H, NH), 7.49 (d, J = 8.7 Hz, 1H, HAr), 7.27 (d, 4J = 2.8 Hz,
3
1H, HAr), 7.18 (dd, 3J = 8.7 Hz, 4J = 2.8 Hz, 1H, HAr), 6.55 (d, 3J = 9.1 Hz,
3
3
1H, CH), 5.90 (d, J = 3.0 Hz, 1H, HFur), 5.68 (d, J = 3.0 Hz, 1H, HFur),
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201701355
European Journal of Organic Chemistry
FULL PAPER
IR (neat) νmax = 3321, 2982, 1746, 1685, 1545, 1523, 1367, 1298, 1242,
3J = 8.4 Hz, 1H, HPyr), 7.15 (d, 3J = 8.4 Hz, 1H, HPyr), 4.09 (s, 3H, OCH3),
3.98 (s, 3H, OCH3), 2.61 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3) δ
= 160.3, 155.3, 154.7, 151.2, 145.5, 135.5, 131.1, 124.8, 123.9, 115.7,
110.0, 104.0, 56.6, 56.4, 24.2 ppm; IR (neat) νmax = 3087, 2972, 1714,
1595, 1504, 1463, 1447, 1398, 1304, 1257, 1242, 1222, 1153, 1044,
1029, 876, 821, 787, 751 cm-1; HRMS (EI) m/z calcd for C15H14NO4
[M+H]+ = 272.0917, found = 272.0926.
1217, 1160, 790 cm-1; HRMS (EI) m/z calcd for C19H22ClN2O7 [M+H]+
=
425.1110, found = 425.1121.
General two-step procedure for the preparation of 11a-e: m-CPBA
(77% w/w, 0.35 g, 1.56 mmol) was added to a stirred and cooled solution
of methyl 2-{[(tert-butoxycarbonyl)amino](5-methylfuran-2-yl)methyl}-
benzoate 4 (1.0 mmol) in CH2Cl2 (3 ml) at 0 ºC (ice/water bath). The
reaction mixture was stirred at the same temperature for 2 h until
disappearance of the starting material (TLC control). Then the reaction
mixture was filtered from the precipitated m-chlorobenzoic acid and filter
pad was washed with cooled CH2Cl2 (2 × 1 ml). The combined filtrates
were diluted with more CH2Cl2 (5 ml), cooled to 0 ºC, washed with
saturated aqueous NaHCO3 (2 × 3 ml), water (2 ml) and brine (2 ml),
dried with anhydrous Na2SO4, filtered and concentrated in vacuo. The
residue was redissolved in CH2Cl2 (2 ml) and 4.0 M HCl in 1,4-dioxane (1
ml) was added at room temperature. The reaction mixture was allowed to
stir for 3 h. After completion of the reaction (TLC control) the volatiles
were removed by evaporation in vacuo. The residue was suspended in
CH2Cl2 (15 ml) and the resulting pyridine hydrochloride was neutralized
by washing with saturated aqueous NaHCO3 (2 × 5 ml), water (3 ml) and
brine (3 ml). The organic extract was dried with anhydrous Na2SO4,
filtered and evaporated to dryness in vacuo. The residue was purified by
flash column chromatography on silica gel (petroleum ether/EtOAc as
eluent) to afford the corresponding 2-methyl-6H-isochromeno[4,3-
b]pyridin-6-ones 11a-e (compound 11c was purified by passing through a
thin layer of silica gel with petroleum ether/EtOAc and subsequent
recrystallization from CH2Cl2/petroleum ether mixture). Analytical
samples were obtained by recrystallization from CH2Cl2/petroleum ether
mixture.
9-Bromo-2-methyl-6H-isochromeno[4,3-b]pyridin-6-one
(11e):
colorless solid (0.20 g, 68%), mp 238−239 ºC (CH2Cl2/petroleum ether).
4
3
1H NMR (400 MHz, CDCl3) δ = 8.80 (d, J = 2.0 Hz, 1H, HAr), 8.18 (d, J
= 8.5 Hz, 1H, HAr), 7.76 (dd, 3J = 8.5 Hz, 4J = 2.0 Hz, 1H, HAr), 7.53 (d, 3J
= 8.4 Hz, 1H, HPyr), 7.28 (d, 3J = 8.4 Hz, 1H, HPyr), 2.66 (s, 3H, CH3) ppm;
13C NMR (100 MHz, CDCl3) δ = 160.0, 155.5, 146.5, 137.2, 134.3, 133.7,
131.7, 131.1, 126.5, 125.6, 125.3, 121.1, 24.3 ppm; IR (neat) νmax = 3080,
2922, 1750, 1584, 1560, 1479, 1264, 1224, 1076, 1040, 871, 831, 749
cm-1; HRMS (EI) m/z calcd for C13H9BrNO2 [M+H]+ = 289.9811, found =
289.9814.
Acknowledgements
Financial support of this work by the Russian Foundation for
Basic Research (Grant
№
16-03-00807) is gratefully
acknowledged. This work was accomplished with the use of
scientific equipment of the Collective Employment Centre
«Ecoanalytical
Centre»,
Kuban
State
University
(RFMEFI59317Х0008).
Keywords: Sustainable chemistry • Iodine • Multicomponent
reactions • Fused-ring systems • 6H-Isochromeno[4,3-b]pyridine-
6-ones
2-Methyl-6H-isochromeno[4,3-b]pyridin-6-one
(11a):
colorless
needles (0.14 g, 65%), mp 139−140 ºC (CH2Cl2/petroleum ether) (lit.:
139−140 ºC).[29a] 1H NMR (400 MHz, CDCl3) δ = 8.70-8.62 (m, 1H, HAr),
8.38-8.30 (m, 1H, HAr), 7.90-7.83 (m, 1H, HAr), 7.69-7.61 (m, 1H, HAr),
7.51 (d, 3J = 8.4 Hz, 1H, HPyr), 7.24 (d, 3J = 8.4 Hz, 1H, HPyr), 2.65 (s, 3H,
CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 160.6, 155.1, 146.0, 135.9,
135.6, 135.1, 130.3, 130.1, 125.1, 124.8, 123.5, 122.5, 24.3 ppm; IR
(neat) νmax = 3080, 2924, 1728, 1574, 1481, 1436, 1270, 1244, 1226,
[1]
For selected reviews on MCRs, see: a) T. Zarganes-Tzitzikas, A.
Domling, Org. Chem. Front. 2014, 1, 834; b) R. C. Cioc, E. Ruijter, R. V.
A. Orru, Green Chem. 2014, 16, 2958; c) Y.-M. Ren, C. Cai, R.-C. Yang,
RSC Adv. 2013, 3, 7182; d) R. Orru, E. Ruijter, G. van der Heijden,
Synlett 2013, 24, 666; e) P. Slobbe, E. Ruijter, R. V. A. Orru, Med.
Chem. Commun. 2012, 3, 1189; f) M. S. Singh, S. Chowdhury, RSC
Adv. 2012, 2, 4547; g) B. B. Toure, D. G. Hall, Chem. Rev. 2009, 109,
4439.
1049, 825, 734 cm-1; HRMS (EI) m/z calcd for C13H10NO2 [M+H]+
212.0706, found = 212.0712.
=
8-Bromo-2-methyl-6H-isochromeno[4,3-b]pyridin-6-one
(11b):
colorless needles (0.18 g, 61%), mp 191−192 ºC (CH2Cl2/petroleum
ether). 1H NMR (400 MHz, CDCl3) δ = 8.50 (d, 3J = 8.5 Hz, 1H, HAr), 8.43
(d, 4J = 2.1 Hz, 1H, HAr), 7.93 (dd, 3J = 8.5 Hz, 4J = 2.1 Hz, 1H, HAr), 7.50
(d, 3J = 8.4 Hz, 1H, HPyr), 7.26 (d, 3J = 8.4 Hz, 1H, HPyr), 2.64 (s, 3H,
CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 159.2, 155.5, 145.9, 138.2,
134.9, 134.6, 132.6, 125.3, 125.22, 125.17, 124.6, 123.8, 24.3 ppm; IR
(neat) νmax = 3086, 2921, 1728, 1585, 1466, 1308, 1254, 1219, 1196, 841,
[2]
For selected articles, see: a) B. Priya, V. Cherkadu, P. Kalavagunta, N.
Ravirala, N. Shivananju, Synlett 2016, 27, 2795; b) O. Salgado-Escobar,
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830, 772, 750 cm-1; HRMS (EI) m/z calcd for C13H9BrNO2 [M+H]+
=
289.9811, found = 289.9815.
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2-Methyl-8-nitro-6H-isochromeno[4,3-b]pyridin-6-one (11c): yellow
crystals (0.16 g, 61%), mp 223−224 ºC (CH2Cl2/petroleum ether). 1H
4
5
NMR (400 MHz, CDCl3) δ = 9.15 (dd, J = 2.4 Hz, J = 0.6 Hz, 1H, HAr),
8.86 (dd, 3J = 8.8 Hz, 5J = 0.6 Hz, 1H, HAr), 8.64 (dd, 3J = 8.8 Hz, 4J = 2.4
Hz, 1H, HAr), 7.60 (d, 3J = 8.5 Hz, 1H, HPyr), 7.39 (d, 3J = 8.5 Hz, 1H, HPyr),
2.69 (s, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3) δ = 158.8, 156.3,
148.7, 147.3, 140.6, 133.7, 129.1, 126.9, 125.9, 125.6, 125.5, 123.2,
24.3 ppm; IR (neat) νmax = 3092, 2928, 1748, 1732, 1583, 1525, 1469,
1342, 1255, 1216, 1097, 876, 837, 762, 736 cm-1; HRMS (EI) m/z calcd
for C13H9N2O4 [M+H]+ = 257.0557, found = 257.0564.
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colorless solid (0.17 g, 62%), mp 217−219 ºC (CH2Cl2/petroleum ether).
1H NMR (400 MHz, CDCl3) δ = 7.96 (s, 1H, HAr), 7.62 (s, 1H, HAr), 7,44 (d,
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10.1002/ejoc.201701355
European Journal of Organic Chemistry
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10.1002/ejoc.201701355
European Journal of Organic Chemistry
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Entry for the Table of Contents
Layout 2:
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Furan Recyclizations
Pavel M. Shpuntov, Alexandra A.
Kolodina, Maxim G. Uchuskin and
Vladimir T. Abaev*
Page No. – Page No.
Straightforward functionalization of furans via a three-component Mannich-type
condensation reaction with methyl 2-formylbenzoates and carbamates was
accomplished. The synthetic utility of the resulting N-Boc arylfurfuryl amines was
Furan ring opening − pyridine ring
closure: an efficient approach
towards 6H-isochromeno[4,3-
b]pyridin-6-ones from readily
available furans and phthalaldehydic
acid methyl esters
demonstrated by
a
practically useful two-step strategy leading to 6H-
isochromeno[4,3-b]pyridin-6-ones finding application as perspective cyclometalating
ligands for OLEDs.
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