Pyridazine N-Oxides as Precursors to 2-Aminofurans: Scope and Limitations in Complexity Building Cascade Reactions

Article abstract of DOI:10.1021/acs.orglett.9b00682

A method to transform pyridazine N-oxides into 2-aminofurans using a combination of UV light and transition metal catalysis has been developed. These electron-rich species exhibit a surprising range of useful reactivity, including the ability to participate in complexity building cascade processes when reacted with dienophiles. This study also establishes 2-aminofurans as valuable synthons that support modular synthetic entry to the shared heterocyclic core of certain aspidosperma and amaryllidaceae alkaloids.

Full text of DOI:10.1021/acs.orglett.9b00682

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Pyridazine N‑Oxides as Precursors to 2‑Aminofurans: Scope and
Limitations in Complexity Building Cascade Reactions
Maribel Borger and James H. Frederich*
Department of Chemistry and Biochemistry, Florida State University, 95 Chieftan Way, Tallahassee, Florida 32306, United States
S
* Supporting Information
ABSTRACT: A method to transform pyridazine N-oxides
into 2-aminofurans using a combination of UV light and
transition metal catalysis has been developed. These electron-
rich species exhibit a surprising range of useful reactivity,
including the ability to participate in complexity building
cascade processes when reacted with dienophiles. This study
also establishes 2-aminofurans as valuable synthons that
support modular synthetic entry to the shared heterocyclic
core of certain aspidosperma and amaryllidaceae alkaloids.
Scheme 1. Photoinduced Cascade Reaction To Access
Functionalized Variants of Scaffold 1
urans harbor considerable utility as dienes in Diels−Alder
1
Freactions despite their aromatic electronic configuration. A
powerful variant of this chemistry involves the introduction of an
amine at the 2-position of the furan nucleus.2 Padwa established
that this modification increases the HOMO energy relative to
that of furan and, therefore, facilitates [4 + 2] cycloadditions
with a range of dienophiles.3 However, in many cases, these
electron-rich furans are difficult to isolate or even trap as
intermediates in situ.4 As a result, intramolecular reactions of
deactivated 2-amidofuran derivatives5,6 are required for most
synthetic applications,7,8 leaving the intrinsic reactivity of the
parent furan underexplored.9 This limitation became apparent
to us during a campaign to develop generalized synthetic entry
to the shared heterocyclic nucleus of certain aspidosperma and
amaryllidaceae alkaloids (1, Figure 1), wherein an intermo-
lecular 2-aminofuran Diels−Alder reaction was chosen as a part
of our strategy.10
With assembly of scaffold 1 as our goal, we considered that the
requisite 2-aminofurans might be prepared from pyridazine N-
oxides 2 using photochemistry.11 As shown in Scheme 1, we
previously reported that exposure of 3-aryl-6-aminopyridazine
N-oxides (e.g., 2a) to UV light generates (Z)-diazoalkenes A,
which isomerize to pyrazoles (e.g., 3a) at 65 °C.12 Notably,
incorporation of an electron-donating amine substituent to C6 of
the pyridazine nucleus was found to be critical for suppressing
photodeoxygenation of 2.13 This key feature also slowed
competitive decomposition of A to the free carbene, which
Received: February 22, 2019
Figure 1. Selected alkaloids containing target substructure 1.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00682
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Letter
a
Table 1. Summary of Catalyst Optimization Studies
Table 2. Control Experiments Establishing an Acid-Catalyzed
Mechanism for the Rearrangement of Furan 5b to Indole 6
a
b
entry
modification
time
NMR yield of 6 (%)
1
2
3
4
5
6
none
hν = 350 nm
no light
0.5 equiv of K2CO3
no light, 3 mol % of Rh2(esp)2
no light, 10 mol % of TsOH
6 h
5 min
6 h
6 h
6 h
86
84
trace
trace
27
product
g
de
,
f
entry
2
catalyst (mol %) additive
3/5/6
(% yield)
b
b
b
b
b
b
c
1
2
3
4
5
6
7
8
9
10
11
12
13
2a
2a
2a
2a
2a
2a
none
none
none
none
none
none
none
none
none
≥95% 3a
1:3:0
3a (93)
5a (nd)
5a (nd)
5a (nd)
5a (91)
5a (62)
3b (46)
6 (92)
Rh2(OAc)4 (2)
Rh2(TFA)4 (2)
Rh2(cap)4 (2)
Rh2(esp)2 (2)
Rh2(esp)2 (1)
none
Rh2(esp)2 (1)
Rh2(esp)2 (3)
none
1 h
89
1:12:0
1:4:0
1:18:0
1:15:0
2:0:1
a
b
No light = protected from light with aluminum foil. Yields
determined by H NMR (400 MHz) using bibenzyl as an internal
standard.
1
2b
2b
2b
2b
2b
2b
2b
c
c
c
c
c
c
≥95% 6
≥95% 5b
1.3:1:0
1:10:0
1:12:4
2:4:1
nm) of 2a at 35 °C in THF (0.3 M) for 2 h afforded pyrazole 3a
in 93% yield in the absence of a catalyst (entry 1).17 After an
extensive catalyst screen, we found that catalyst systems based
on copper or iron exhibited virtually no improvement over the
background reaction. In contrast, dirhodium(II) complexes gave
furan 5a as the major product under otherwise identical
conditions (entries 2−5).18,19 Notably, Rh2(esp)2 emerged as
the top performing catalyst from our study, providing furan 5a in
91% yield (entry 5). We also determined that 1 mol % of
Rh2(esp)2 was necessary to suppress formation of 3a and give
synthetically useful yields of 5a (entry 6).
Our next experiments targeted the corresponding reaction of
N-oxide 2b (X = NH2). This substrate was notably less soluble
than 2a. As such, we found that a useful rate of photochemical
ring opening was achieved in THF (0.1 M) at 65 °C. Under
these modified conditions, irradiation of 2b in the absence of a
catalyst afforded pyrazole 3b; however, indole-2-acetamide 6
was observed as an unexpected side product (entry 7). To our
surprise, 6 was isolated in 92% yield when 2b was irradiated in
the presence of 1 mol % of Rh2(esp)2 (entry 8). We reasoned
that 6 might be generated from initially formed furan 5b via acid-
catalyzed isomerization. As a result, we examined the utility of
bases as additives to suppress this rearrangement. Extensive
experimentation revealed that addition of powdered K2CO3 (0.5
equiv) to the reaction media fully inhibited formation of 6 and
furnished 5b as the exclusive product when 3 mol % of Rh2(esp)2
was included to suppress the background formation of 3b (entry
9).20,21 Notably, photolysis of 2b in the presence of 0.5 equiv of
K2CO3 but without Rh2(esp)2 afforded a 1.3:1 mixture of 3b and
5b (entry 10). The potassium ion also proved to be optimal as
evidenced by the inferior results obtained with Na2CO3 and
Cs2CO3 (entries 11 and 12). In addition, organic bases such as
Et3N afforded complex mixtures of 3b, 5b, and 6 (entry 13).
As summarized in Table 2, we carried out a series of
experiments to confirm the origin of indole 6. A key observation
h
K2CO3
K2CO3
Na2CO3
Cs2CO3
Et3N
5b (88)
3b (nd)
5b (nd)
5b (nd)
5b (nd)
Rh2(esp)2 (3)
Rh2(esp)2 (3)
Rh2(esp)2 (3)
a
Reactions were carried out on 0.1 mmol scale in a Rayonet using 24
W UV lamps (see the Supporting Information for a description of the
b
reaction setup). Reaction carried out at 35 °C in THF (0.3 M).
c
d
Reaction carried out at 65 °C in THF (0.1 M). 0.5 equiv of additive
e
was used. Reactions containing inorganic bases were heterogeneous.
f
1
The ratio of products was determined by H NMR spectroscopy at
400 MHz from unpurified reaction mixtures. Isolated yield of the
indicated major product (nd = not determined). Compound 5b is
g
h
reactive; isolated yields varied from 62 to 88%.
reportedly generates furan side products (e.g., 5a).14 On the
basis of these results, we reasoned that a transition metal catalyst
could be used to fully divert intermediate A to 2-aminofuran B
via the corresponding metallocarbene.15,16 Once formed, we
expected to trap B via cycloaddition with an electron-deficient
alkene to afford a reactive oxabicyclo[2.2.1]heptene intermedi-
ate.3 Spontaneous ring opening of this species would unveil
vinylogous iminium C, allowing cyclization of a pendent
nucleophile (X = NH2, OH) to terminate the reaction en
route to heterocycles 4. Herein, we report the systematic
development of this photoinduced cascade reaction and evaluate
its scope and limitations as a modular entry point to substructure
1.
At the outset, we realized that successful implementation of
the strategy outlined in Scheme 1 required a catalyst capable of
intercepting A faster than it could isomerize to pyrazole 3. Along
these lines, experiments to identify an effective catalyst focused
on substrates 2a (X = H) and 2b (X = NH2), which were
prepared on gram-scale via a modification of our reported two-
step synthesis.12 As outlined in Table 1, photolysis (hν = 350
B
DOI: 10.1021/acs.orglett.9b00682
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
Scheme 2. Scope of Complexity Building Cascade Reactions Triggered by Photochemical Ring Opening of Pyridazine N-Oxides 2
a
The corresponding pyrazole (3) was isolated in 43% yield.
was that purified samples of 5b in CDCl3 (0.1 M) isomerized to
6 under ambient laboratory conditions over 6 h (entry 1). The
rate of isomerization was unchanged by the presence and
rigorous exclusion of oxygen; however, UV light (hν = 350 nm)
greatly accelerated the reaction (entry 2).22 In contrast,
protecting 5b from light slowed the rearrangement to the extent
that only trace amounts of 6 were detected after 6 h (entry 3).
The same result was achieved in ambient light when 0.5 equiv of
K2CO3 was added to the solution (entry 4). Notably, when a
mixture of 5b and 3 mol % of Rh2(esp)2 in CDCl3 was protected
from light, we found that indole 6 was formed in 27% yield after
6 h (entry 5). Alternatively, when a solution of 5b was protected
from light and then treated with TsOH (10 mol %), we observed
rapid formation of indole 6 (entry 6). Taken together, these
results are consistent with the scenario wherein 6 arises from 5b
via an acid-catalyzed mechanism.
trapping these reactive heterocycles via a Diels−Alder reaction
with acrylonitrile. As shown in Scheme 2, our initial experiments
focused on N-oxide 2a (X = H). Thus, exposure of a solution of
2a and 1.5 mol % of Rh2(esp)2 in THF (0.3 M) to UV light (hν =
350 nm) at 35 °C (method A) cleanly generated 5a after 3 h.
The unpurified reaction mixture was then removed from UV
light, treated with acrylonitrile (1.5 equiv), and heated to 80 °C
for 10 h. This two-stage procedure afforded dihydrobiaryl 7 in
82% yield.23 In contrast, no reaction occurred when 2a and
acrylonitrile (5 equiv) were heated to 80 °C in THF (0.3 M).
This control experiment confirms that 2a is not a substrate for
Diels−Alder chemistry under the reaction conditions described
here.24 Importantly, variants of 2a bearing functionalized arenes
were viable substrates (Scheme 2a). Accordingly, cycloadducts
containing substituted aryl groups (i.e., 8−11) were formed in
good yield. The lone exception was product 12, which was
isolated in 30% yield alongside 43% of the corresponding
Having established conditions to transform pyridazine N-
oxides 2 into 2-aminofurans 5, we turned our attention toward
C
DOI: 10.1021/acs.orglett.9b00682
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ketone 26 in 68% yield (Scheme 3a). Electron-deficient
dienophiles such as (E)-fumaronitrile and dimethyl acetylene-
dicarboxylate were also productive cycloaddition partners,
affording carbazole derivatives 27 and 28 in good yield. In
contrast, more reactive dienophiles gave alternative products.
For example, 5b reacted rapidly with N-methylmaleimide at 23
°C to give biaryl 29 in 79% yield. Alternatively, a Diels−Alder
reaction was not observed when 5b was treated with 2-
propylidenemalonitrile. Instead, alkylated furan 30 was
generated as the exclusive product in 60% yield. Taken together,
these results highlight the complex reactivity profile of electron-
rich heterocycle 5b.
Scheme 3. Diels−Alder Reactions between 2-Aminofurans 5a
and 5b with Alternative Dienophiles: Scope and Limitations
In further support of this point, we found that acrolein and
acrylates gave complex, intractable mixtures of products when
reacted with 5b. Moreover, we could not identify any products
reminiscent of a carbazole from these reactions. To probe this
limitation further, we explored the reactivity of furan 5a with this
subclass of dienophiles. To our surprise, exposure of 5a to either
acrolein or methyl acrylate afforded aniline derivative 31,
wherein the carbonyl group was lost altogether. We probed the
mechanism of this unexpected transformation by reacting 5a
with benzyl acrylate (5 equiv) in THF at 120 °C. This reaction
cleanly afforded an equimolar mixture of 31 and benzyl alcohol
(see the Supporting Information for details). As shown in
Scheme 3b, we propose a mechanism to rationalize this result
wherein the initial Diels−Alder reaction gives rise to an
equilibrium of intermediates D and E. Intramolecular capture
of the ester within E by the pendent alkoxide gives rise to
intermediate F, which collapses to afford tertiary carbonate G.
Subsequent elimination of benzyl hydrogen carbonate25 then
restores aromaticity en route to arene 31.
In summary, we have developed a new method to convert
pyridazine N-oxides 2 to 2-aminofurans 5 using a combination
of UV light and rhodium catalysis. These electron-rich
heterocycles exhibit a surprising range of synthetically useful
reactivity. Importantly, our work highlights the utility of elusive
2-aminofurans in intermolecular Diels−Alder reactions with
simple alkenes. Moreover, when designed appropriately, this
reaction manifold can be leveraged to provide practical entry to
functionalized carbazole and dibenzofuran motifs that would be
difficult or impossible to prepare by other means. Efforts to
adapt and extend this methodology to the total syntheses of the
aspidosperma and amaryllidaceae alkaloids described in Figure 1
are ongoing in our laboratory.
pyrazole (3). This result indicates that the basic pyridine group
slows Rh-catalyzed formation of the required 2-aminofuran.
Next, we explored the reactivity of N-oxide 2b (X = NH2)
harboring an amine nucleophile on the arene ring. In this case, 2-
aminofuran 5b was generated in situ using K2CO3 as an additive
as previously described (method B). This species was then
reacted with 5 equiv of acrylonitrile at 80 °C to furnish cis-
tetrahydrocarbazole 13 in 75% yield. To our delight, this
procedure enabled access to variants of 13 harboring a range of
functionality around the aromatic periphery of the tetrahy-
drocarbazole framework (Scheme 2b). Importantly, the
chemistry is tolerant of systems with electron-donating groups
(14), electron-withdrawing groups (16 and 17), and nitrogen
heterocycles (20). Notably, this method was also compatible
with variants of N-oxide 3b (X = OH), which afforded valuable
cis-tetrahydrodibenzofuran derivatives 23−25 in good to
excellent yield (Scheme 2c).
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.9b00682.
Experimental details and NMR spectra (PDF)
Accession Codes
CCDC 1895817 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge via
www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; fax: +44 1223 336033.
As shown in Scheme 3, intermolecular Diels−Alder reactions
of photochemically generated 2-aminofuran 5b were explored
using other dienophiles. Thus, we found that purified 5b could
be reacted with phenyl vinyl sulfone in THF at 80 °C to furnish
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: frederich@chem.fsu.edu.
D
DOI: 10.1021/acs.orglett.9b00682
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(17) Photoreactions were carried out in a Rayonet chamber reactor
equipped with 24 W UV lamps wherein ∼90% of emission is 350 nm.
Reactions were conducted in 1-dram borosilicate vials using untreated
THF under ambient atmosphere. See the Supporting Information for
details regarding the reaction setup.
(18) As expected, furans 5a and 5b were labile. However, they could
be purified using silica gel and stored at −20 °C for 24−48 h. The half-
lives of these species at rt and 80 °C are reported in the Supporting
Information.
(19) Consistent with ref 12, secondary amines such as morpholine are
tolerated in this chemistry; however, pyrrolidine gave the best results in
our experiments. A complete report on the scope and limitations of
electron-donating groups at C6 of the pyridazine nucleus is forth-
coming.
James H. Frederich: 0000-0003-2077-4436
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Florida State University (FSU). We
thank Michael Maxwell (FSU), Daniel Callen (FSU), and Elena
Paola (FSU) for assistance with substrate synthesis. Mass
spectra were collected, in part, at the University of Florida (UF)
using NIH-sponsored equipment (S10-OD021751-A1).
(20) Lower catalyst loadings (1−2.5 mol %) gave mixtures of 5b and
pyrazole 3b. See the Supporting Information for details on optimization
of catalyst loading.
(21) Powered KOH and K3PO4 gave results comparable to those of
K2CO3. A comprehensive screen of inorganic bases is reported in the
Supporting Information.
(22) No photochemical rate acceleration was observed when the
reaction was performed in THF-d6. We suspect this rate acceleration is
the result of trace HCl generated by photodecomposition of
chloroform: Hill, D. G. J. Am. Chem. Soc. 1932, 54, 32.
(23) Product 7 was isolated in identical yield when acrylonitrile (1.5
equiv) was included in the photochemical step; however, this
modification resulted in a prolonged photoirradiation time of 9 h.
(24) Pyridazines have been used as 4π-diene components in Diels−
Alder reactions; however, these cycloadditions require increased
temperature or catalytic activation of the diazine. For examples, see:
(a) Boger, D. L.; Coleman, R. S. J. Org. Chem. 1984, 49, 2240.
(b) Kessler, S. N.; Wegner, H. A. Org. Lett. 2010, 12, 4062.
(25) Benzyl hydrogen carbonate was not detected by 1H NMR
spectroscopy (400 MHz) of the unpurified reaction mixture. Instead,
this species undergoes decarboxylation to give benzyl alcohol: Pocker,
Y.; Davison, B. L.; Deits, T. L. J. Am. Chem. Soc. 1978, 100, 3564.
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DOI: 10.1021/acs.orglett.9b00682
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