Transition Metal-Free Intermolecular C(sp2)-H Direct Amination of Furanones via a Redox Pathway

Article abstract of DOI:10.1021/acs.joc.8b02760

A direct C(sp²)-H amination of 2-furanones under metal-free conditions was realized. This unprecedented intermolecular C-H to C-N conversion provides rapid access to 4-amino-furanone derivatives and novel aza-heterocycle fused furanone skeleton

Full text of DOI:10.1021/acs.joc.8b02760

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Article
Transition Metal-free Intermolecular C(sp2)-H Direct
Amination of Furanones via a Redox Pathway
Qiang Wei, Junfeng Wang, Eman A Akam, Dawei Yin, Zemei Ge,
Tieming Cheng, Xin Wang, Anna-Liisa Brownell, and Runtao Li
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02760 • Publication Date (Web): 04 Jan 2019
Downloaded from http://pubs.acs.org on January 4, 2019
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Transition Metal-free Intermolecular C(sp2)–H Direct
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Amination of Furanones via a Redox Pathway
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Qiang Wei,† Junfeng Wang,*‡,§ Eman A. Akam,§ Dawei Yin,† Zemei Ge,† Tieming Cheng,†
Xin Wang,*† Anna-Liisa, Brownell,*‡ Runtao Li*†
†State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences,
Peking University, Beijing 100191, China.
§
‡Gordon Center for Medical Imaging, Martinos Center for Biomedical Imaging, Department of
Radiology, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129,
USA.
Supporting Information Placeholder
R
O
Het
X
R
O
R
R'NH2
R
O
NH2
O
O
O
R
R
Transition metal-free
Simple base, no extra oxidation
Excellent functional group tolerance
23 example, 52-93% yield
N
O
One step
20 example, 59-94% yield
X
R''
HN
R'
R''
H
Het
Redox of Furanone
ABSTRACT:
A direct C(sp2)–H amination of 2-furanones under metal-free conditions has
been realized. This unprecedented intermolecular C–H to C–N conversion provides
rapid access to 4-amino-furanone derivatives and noval aza-heterocycle fused
furanones skeletons. A redox mechanism based on a double-Michael-addition
intermediate INT2 is proposed and detected by spectrometry.
INTRODUCTION
New methods for C–N bond formation are of constant interest due to the
wide-spread presence of nitrogen-rich heterocyclic motifs in drugs used to combat a
broad range of diseases and pathophysiological conditions.1 Accessing these
compounds directly, without pre-functionalization is a highly attractive synthetic
strategy since it would be atom-economic and environmentally benign.2
Transition-metal catalysts have made C–H activation accessible and have allowed
many carbon functionalizations, especially aromatic C–H functionalizations.3 More
recently, aliphatic amination4 using metal complexes as catalysts has become a
prevalent research area. Despite advancements in carbon functionalization, the
vinylation of amines has remained an almost unexplored area of synthetic chemistry
until the beginning of the 21st century5 in large part due to the general inertness of
olefins toward amines.6 In addition, methods for activating sp2-hybridized alkene C–H
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bonds in the absence of a directing group still remain sparse.7 Moreover, current C–H
bond functionalization protocols often require substrate preoxidation, directing
groups, or strong chemical oxidants with transition metal catalysts,8 and all these
factors limit the general utility of these methods. Herein, we report an unprecedented
intermolecular C(sp2)–H direct amination that leads to 4-enamine and enamide
2-furanone derivatives, which can be performed under mild metal-free conditions.
Recent years have seen rising interest in the preparation of various substituted
2-furanones,9 which are the common structural subunits in over 13,000 natural
products9a,9f,10 that have biological activity ranging from antifungal and antibacterial
activity to anti-inflammatory and tumoricidal actions.11 These 2-furanone structural
motifs have also been incorporated into a wide variety of therapeutically interesting
drug candidates that include Penicillic acid, Basidalin, Eucilat, and L-784512.12
Compared with 3- or 5-substituted 2-furanones, the synthesis of 4-substituted
2-furanones has been particularly problematic,13 and transition metal-catalyzed
coupling methodologies are employed in the overwhelming majority of synthetic
reports.14 However, there has hitherto been no report on the synthesis of
4-N-substituted 2-furanones via direct C–H amination to the best of our knowledge.
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Results and Discussion
Our continuous interest in 2-furanones15 prompted us to investigate new
methodologies for accessing 4-N-substituted 2-furanone derivatives. We examined the
intermolecular Michael addition reaction of 2-furanone 1a with benzylamine 2a in
ethanol. This reaction is sluggish at room temperature, and no significant change in
rate of product formation was observed upon heating to 50 ˚С for 60 hours (Table 1,
entry 1). To our delight, however, the addition of base (K2CO3) resulted in a rapid
consumption of the starting material 1a within 16 h at 50 ˚С but with 41% of amine
recovered unreacted; the amination product 3a was identified as the major product
(Table 1, entry 2, yield 30%) while the N-Michael addition product 3a'' was not
detected. This unexpected amination reaction was further explored under different
reaction conditions [Table 1 and Supporting Information(SI), Table S1]. Interestingly,
organic bases such as DBU and Et3N did not contribute to formation of the desired
product (Table 1, entries 3 and 4). Although strong inorganic bases such as NaOt-Bu
or LiOt-Bu could facilitate formation of product 3a, the yield was significantly
decreased (Table 1, entries 5 and 6). K2CO3 appeared to be the most efficient base for
this reaction and the yield was greatly improved to 91% in dry THF within 10 h (mole
ratio of 1a:2a: K2CO3 = 2:1:2).
Table 1. Optimization of reaction conditionsa, b
O
O
O
O
conditions
O
O
+
Ph
NH2
Ph
N
Ph
N
CO2Et
H
H
CO2Et
CO2Et
3a''
1a
2a
3a
Entry
1a:2a
Conditions
Yield(%)
1
2
1
1
no additive, EtOH, 60 h
0
K2CO3 (1 equiv), EtOH, 16 h
30
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1
1
1
1
2
2
2
DBU (1 equiv), EtOH, 60 h
Et3N (1 equiv), EtOH, 60 h
NaOt-Bu (1 equiv), EtOH, 16 h
LiOt-Bu (1 equiv), EtOH, 16 h
K2CO3 (2 equiv), EtOH, 16 h
K2CO3 (2 equiv), THF, 16 h
K2CO3 (2 equiv), THF(dry), 10 h
0
0
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aReaction conditions: 2a (0.25 mmol), solvent (3 mL) at 50 ˚C. bisolated yields.
Much to our delight, the reaction could be applied to a wide range of substrates
including aliphatic amines, arylamines and amides under the optimized reaction
conditions (Scheme 1). Aromatic methanamines (2a–2f), heterocycles (2g–2i), vinyl
(2j–2l) and alkyl group (2m) all gave quite satisfactory yields (80–92%). Aniline
substrates (2n–2p) gave moderate yields with the recovery of unreacted 2 probably
due to their low nucleophilicity and big hindrance of these substrates. Attractively,
amides (2q–2t) also reacted efficiently with 2-furanone 1a to give the corresponding
products in high yields (77–93%), although it took 7 days to complete the conversion
of 1a because of the low nucleophilicity of amide and low stabilization (high Gribs
energy) of its enamide product. In addition, the electron withdrawing substituent in R
of 2-furanone 1a containing either esters (3u–3v) or benzoyl (3w) was necessary for
the amination reaction (as discussed in mechanism part below) and the weaker
electron withdrawing inductive effect and high steric hindrance of benzoyl group
resulted in its lower yield (52%, 3w) compared with esters (89%–91%, 3u–3v). These
remarkable yields and the wide-range of tolerable substrates prompted us to further
explore the reactions of 2-furanones with bifunctional substituents to access
interesting heterocycles.
Scheme 1. Substrate scopea, b
O
O
O
1
K2CO3
NH2
O
+
R'
R'
N
THF 50 o
C
R''
H
R''
2
3
O
O
O
O
O
O
O
O
CO2Et
CO2Et
CO2Et
CO2Et
NH
R1
NH
NH
NH
N
X
R2
R1
R2
3a, R1 = R2 = H, 91%
3b, R1 = R2 = Me, 92%
3c, R1 = OMe,R2 = H, 89%
3d, R1 = R2 = F, 88%
3e, R1 = R2 = Cl, 89%
3f, R1 = H, R2 = Cl, 87%
3h, X = O, 91%
3i, X = S, 76%
3g, 81%
O
O
O
O
O
O
O
Ph
O
N
H
N
HN
NH
CO2Et
CO2Et
CO2Et
H
CO2Et
3m, 87%
3j, 89%
3l, 91%
3k, 81%
O
O
O
O
O
O
R1
O
X
N
CO2Et
NH
R''
H
NH
CO2Et
R
Ph
R2
3qe, X = CH,R = H, 92%
3re, X = CH,R = OMe, 93%
3se, X = CH,R = NO2, 77%
3te, X = N,R = H, 79%
3u, R'' = CO2Me, 91%
3nd, R1 = R2 = H, 58% (26%)c
3od, R1 = H,R2 = OMe, 61% (32%)c
3pd, R1 = Br,R2 = H, 62% (12%)c
3v, R'' = CO2Bu-t, 89%
3wd, R'' = COPh, 52% (40%)c
aReaction condition: 1 (0.5 mmol), 2 (0.25 mmol), K2CO3 (0.5 mmol), THF (3 mL), 10 h.
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bisolated yields. crecovery of unreacted 2. dt = 3 d. et = 7 d.
With our expertise in heterocycles,16 we envisioned that heterocyclic compounds
might be synthetically accessible using this new methodology via participation of a
functional group R'' with another suitable adjacent functional group in the amine
substrate. (Scheme 2) Excitingly, we found that the amidines and guanidines
employed in this reaction resulted in the corresponding pyrimidine-4-one derivatives
fused with 2-furanones in high yield (80–94%, 4a–4n), and the high stabilization (low
Gribs energy) of the fused pyrimidine-4-one also resulted the rapid conversion of 1a
in 10 h compared with enamide products of amides (7 days, 3q–3t) in Scheme 1.
Similarly, 2-aminopyridines and 2-aminoimidazoles respectively produced the
pyrido[1,2-a]pyrimidine-4-ones and imidazo[1,2-a]pyrimidine-4-ones derivatives
fused with 2-furanones in moderate yield (62–81%, 5a–5e), as the substrates 2n–2p in
Scheme 1 above, the low activity of aromatic amines was the main reason for the
variation in yield and the driving force of cyclization similarly leads to a shorter
reaction time (10 h) compared with the arylamine substrates 2n–2p (3 days). It was
worth noting that the activation of phenolic hydroxyl group of para-position in
3-aminophenols further realized an intramolecular Friedel-Crafts acylation after its
amination process and resulted construction of quinoline-4-one fused with 2-furanone
in moderate yield (59%, 5f). This discovery may act as a new kind of skeleton
modification strategy for the existed dominant aza-heterocycle skeletons in drug or
bioactive molecules to achieve novel lead compounds containing 2-furanones.
Scheme 2. Further application of the C(sp2)–H aminationa, b
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R
O
R
O
H2N
NH
HCl
R
R
O
Het
X
O
O
O
R
2'
R
R
NH2
N
O
2''
X
N
R
O
K2CO3, THF 50 o
C
K2CO3, THF 50oC
CO2Et
NH
Het
1
4
5
R
O
O
O
O
O
O
O
R
O
O
O
N
N
O
HN
HO
O
N
O
N
O
N
O
N
NH
NH
R2
HN
R
4a, R = n-propyl, 83%
4b, R = cyclopropyl, 84%
4c, R = t-butyl, 92%
R1
5e,75%
5a, R1, R2 = H, 78%
5b, R2 = H, R1 = F, 73%
5c, R2 = H, R1 = Me, 81%
5d, R1 = H, R2 = NH2, 62%
5f,59%
4d, R = ethyl, 80%
4e, R, R =
4f, R = phenyl, 90%;
,86%
4g, R = 4-F-phenyl, 94%
4h, R = 4-Br-phenyl, 84%;
4i, R = 4-NO2-phenyl, 93%
4j, R = pyridin-2-yl, 84%
4k, R = pyrimidin-2-yl, 92%
4l, R = pyridin-3-yl, 93%
4m, R = morpholinyl, 94%
4n, R = pyrimidinyl, 85%
aReaction condition: 1 (0.5 mmol), 2 (0.25 mmol), K2CO3 (0.75 mmol), THF (3 mL), 10 h.
bisolated yields.
These interesting transformations compelled us to study the possible reaction
mechanism. Three separate reactions of 1a and 2a were conducted involving
stoichiometric addition of an electron-transfer scavenger (1, 4-dinitrobenzene), a
radical clock (diallyl ether) and a radical inhibitor (hydroquinone) to the model
reaction. Under all three reaction conditions, the reaction still proceeded smoothly to
afford the desired product 3a. The observed results suggest that a radical process may
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not be involved in this transformation. The reaction also proceeds smoothly in the
absence of O2, which rules out the participation of external O2 as the oxidant.
To shed new light on the mechanism, the in-situ 1H NMR experiments combined
with the mass experiments were carefully carried out (Scheme 3, Figure 1 and SI,
Figure S1–5). We intentionally chose pyridin-2-ylmethanamine (PIM-amine) 2g in
1
the reaction due to its easily identifiable aromatic protons in H NMR spectra. At
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room temperature, the reaction of 2-furanone 1a and 2g appeared to reach a quick
equilibrium (2 mins), which was not affected by addition of the base K2CO3 (SI,
Figure S1a), but no clear product 3g was observed. The appearance of the resonances
ranging from δ 3.3 to δ 4.3 (Ha and Hb in Figure 1 and S1a) could be attributed to the
Michael addition intermediate INT1. Upon heating the reaction to 50 ˚C, we observed
the clear formation of compound 3g accompanied by the formation of a by-product 3'
(Figure 1and S1b). However, the reaction of the secondary amine
bis(pyridin-2-ylmethyl)amine (DPA) with 2-furanone 1a did not proceed at all under
these conditions (SI, Figure S3) with both starting materials remaining intact. In
ESI-MS experiments, a key intermediate from the reaction of 1a and 2g was
fortunately captured with its mass peak at m/z = 499.0, which matched the isotope
patterns for [1a + 1a + 2g + Na+]+ = 499.2 (C24H32N2O8Na) (SI, Figure S4). In
addition, the sodiated peak of the key intermediate INT2 (m/z 499.0) was fragmented
by CAD in the QIT mass spectrometer (SI, Figure S5), which led to the formation of
product 3g and the by-product 3'. This indicates that the reaction may proceed via the
key intermediate INT1 and INT2 through a redox mechanism, which involves C–N
bond cleavage and proton transfer.
Scheme 3. Possible reaction intermediates monitored by in-situ 1H NMR and ESI-MS
experiments
O
O
O
O
O
O
O
O
CO2Et
3g
Ha
HN
CO2Et
EtO2C
EtO2C
N
PIM
1a
+
PIM
+
CO2Et
Hb
HN
O
O
PIM
O
O
PIM-NH2
2g
CO2Et
3'
products
INT1
INT2
[INT4 + Na+]+ signal
in ESI-MS
Ha,Hb signal
in 1HNMR
start materials
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Figure 1. The in-situ 1H NMR experiments: the amination reaction of 1a and 2g was carried out at
room temperature (orange line) and 50⁰C (green line).
To further confirm the hypothesis, compound 3tx was prepared, which reacted
readily with 1a smoothly to give enamine product 3t and the reduced product 3’.
However, there was no clear change when 1a was absent in this reaction. This clearly
gave us the hint that 3tx may be used for the reduction of certain double bond.
(Scheme 4A) Besides, the reaction of 3nx (its 3-carboxylic acid ester group was
absent) and 1a proved quite difficult. With a stronger base (NaOt-Bu) and a higher
temperature, INTn2 was acquired with 8% yield after 2 days and further confirmed in
the transformation to the exclusive product 3n (not 3n′) with 12% yield after 1 week.
(Scheme 4B) Collectively, all these phenomena indicated the probability of a redox
mechanism involving INT1 and INT2 in this reaction. For the redox process from
INT2 to product 3g, as inorganic base K2CO3 previously thought to promote the
oxidative process17, we further speculated that this process may involves a
[1,2]-proton transfer assisted by the in-situ-generated base KHCO3 via the
six-membered ring transition state18 of INT3 to form 3g and by-product 3’ (Scheme
5). The 3-carboxylic acid ester is beneficial to the reaction, which may lead to new
design of substrates for the redox transformation under mild reaction conditions for a
wide range of substrates.
Scheme 4 The experiment involving the analogues of INT1 and INT2.
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(A)
K2CO3
80%
1a
THF, 50 o
C
1
O
O
1
O
O
week
O
O
N
N
+
N
N
H
CO2Et
H
CO2Et
week
reac
on
3t
ti
K2CO3
THF, 50 o
3tx
no 1a
PhN
no
C
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(B)
O
O
O
O
O
O
NaOt-Bu
NaOt-Bu
CO2Et
1a
3n
+
THF, reflux
2 day, 8%
THF, reflux
1 week, 12%
PhHN
PhHN
O
O
3nx
not 3n'
INTn2
Scheme 5. Proposed mechanism of the redox reaction
O
O
O
O
H2
O
O
CO2Et
O
1a
O
H2N PIM
K2CO3
Redox
K2CO3
CO2Et
3'
CO2Et
N
MIP
H
H
K2CO3
NH
CO2Et
MIP
CO2Et
CO2Et
NH
MIP
H1
O
3g
O
INT2
O
1a
INT1
O
O
O
O
O
CO2Et
H2
CO2Et
H2
3g
H
K
O
H
N
K2CO3
O
N
MIP
H1
O
MIP
+
H
INT2
EtO2C
EtO2C
H
H
H1
EtO2C
O
O
KHCO3
K2CO3
K
O
K
3'
O
O
O
K+
+KH1CO3
INT3a
INT3b
Redox via possible KHCO3/K2CO3-assisted proton transfer pathways
Conclusion
In summary, we demonstrated in this work the unprecedented intermolecular
direct C(sp2)–H amination reaction of 2-furanones. The reactions proceeded smoothly
under metal-free conditions in the absence of external oxidants. The reaction has been
applied to a wide range of substrates, including aliphatic amines, amides and
substituted anilines to afford the corresponding 4-enamine/4-enamide 2-furanone
derivatives. Further rational design led to a variety of 2-furanone fused heterocycle
compounds in high yields. Mechanistic studies have revealed that the reaction may
involve the redox capability of 2-furanones, which was demonstrated by 1H NMR and
mass experiments. This discovery and mechanistic insight may complement
traditional amination reactions used to prepare enamine/enamide compounds from
other suitable substrates in the near future, and provide a pathway for the reduction of
double bonds in different substrates.
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Experimental Section
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General information. All reagents were purchased from commercial sources
7
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and used without treatment, unless otherwise indicated. The products were purified by
1
column chromatography over silica gel. H NMR and 13C{1H} NMR spectra were
recorded at 25 ºC on Bruker AVANCE III 400MHz and 100 MHz, respectively, and
TMS as internal standard. The proton spectra are reported as follows: δ (position of
proton, multiplicity, coupling constant J, number of protons). Multiplicities are
indicated by s (singlet), d (doublet), t (triplet), q (quartet), h (septet), m (multiplet) and
br (broad). High-resolution mass spectra (HRMS) were obtained using a Bruker Apex
IV FTMS. Melting points were collected on an X-4 micromelting point apparatus
uncorrected. The furanone substrates were prepared according to the reported
method.15b Electrospray ionization (ESI) mass spectra were acquired with a Waters
Synapt HDMS quadrupole/time-of-flight (Q/ToF) mass spectrometer. This instrument
contains a triwave device located between Q and ToF mass analyzers and the device
consists of three components: a trap cell, an ion mobility cell, and a transfer cell. Dry
THF was obtained by distillation over sodium/benzophenone.
Experimental procedure for the synthesis and analytical data of 3a–w.
Ethyl 4-(benzylamino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate (3a).
To the mixture of 1a (92 mg, 0.5 mmol) and 2a (26 mg, 0.25 mmol) in dry THF (3
mL) was added dry K2CO3 powder (69 mg, 0.5 mmol) in one portion at room
temperature. The reaction mixture was heated to 50 ºC and stirred for 10 h until
substrate 1a was consumed monitored by TLC. THF was removed under reduced
pressure and the precipitated solid was washed with saturated NH4Cl aq. (3 mL) and
extracted with EtOAc (3 mL  3). The combined organic layers were dried over
Na2SO4 and the solvent was removed under reduced pressure. The residue was
purified by flash chromatography (silica gel, petroleum ether : ethyl acetate = 2: 1,
V/V) to give 3a (66 mg, 91 %) as colorless crystals, m.p. 90–92 ºC. 1H NMR (400
MHz, CDCl3) δ 9.02 (s, 1H), 7.45 – 7.38 (m, 2H), 7.38 – 7.33 (m, 1H), 7.31 – 7.26
(m, 3H), 4.67 (d, J = 6.6 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.68 (s, 6H), 1.35 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 179.3, 167.2, 166.6, 135.8, 129.3,
128.5, 126.8, 86.1, 79.3, 60.3, 48.2, 25.2, 14.4. HRMS (ESI) m/z calcd. for
C16H20NO4 [M+H]+ 290.1387, found 290.1391.
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Ethyl
4-((2,3-dimethylbenzyl)amino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3b). Following the same experimental procedure of 3a with 2b (34 mg, 0.25 mmol),
3b (73 mg, 92%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained
as brown solid, m.p. 141–143 ºC. 1H NMR (400 MHz, CDCl3) δ 8.86 (s, 1H), 7.17 (d,
J = 7.1 Hz, 1H), 7.13 (t, J = 7.5 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 4.63 (d, J = 6.1 Hz,
2H), 4.29 (q, J = 7.1 Hz, 2H), 2.32 (s, 3H), 2.25 (s, 3H), 1.69 (s, 6H), 1.33 (t, J = 7.1
Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 179.3, 167.2, 166.6, 137.8, 134.1,
133.6, 130.4, 126.3, 125.5, 86.0, 79.3, 60.3, 47.0, 24.9, 20.5, 14.9, 14.4. HRMS (ESI)
m/z calcd. for C18H24NO4 [M+H]+ 318.1700, found 318.1701.
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Ethyl
4-((2-methoxybenzyl)amino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate (3c).
Following the same experimental procedure of 3a with 2c (34 mg, 0.25 mmol), 3c (71
mg, 89%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained as white
solid, m.p. 158–159 ºC. 1H NMR (400 MHz, CDCl3) δ 9.13 (s, 1H), 7.36 (t, J = 7.8
Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 7.04 – 6.90 (m, 2H), 4.63 (d, J = 6.5 Hz, 2H), 4.32
(q, J = 7.1 Hz, 2H), 3.92 (s, 3H), 1.71 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H). 13C{1H} NMR
(101 MHz, CDCl3) δ 179.0, 167.4, 166.6, 157.1, 130.0, 128.4, 124.0, 121.0, 110.8,
85.6, 79.2, 60.1, 55.4, 44.5, 25.1, 14.5. HRMS (ESI) m/z calcd. for C17H22NO5
[M+H]+ 320.1493, found 320.1495.
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Ethyl
4-((3,4-difluorobenzyl)amino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3d). Following the same experimental procedure of 3a with 2d (36 mg, 0.25 mmol),
3d (72 mg, 88%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained
as white solid, m.p.79–81 ºC. 1H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.20 (dd, J
= 17.5, 8.7 Hz, 1H), 7.15 – 7.08 (m, 1H), 7.04 (br, 1H), 4.64 (d, J = 6.4 Hz, 2H), 4.29
(dd, J = 13.9, 6.9 Hz, 2H), 1.64 (s, 6H), 1.33 (t, J = 7.0 Hz, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ 179.3, 166.9, 166.6, 151.7 (dd, J = 86.0, 12.5 Hz), 149.2 (dd, J =
84.8, 12.9 Hz), 133.0 (dd, J = 4.6, 3.7 Hz), 122.9 (dd, J = 6.3, 3.7 Hz), 118.2 (d, J =
17.1 Hz), 116.0 (d, J = 17.7 Hz), 86.6, 79.2, 60.5, 47.2, 25.1, 14.4. HRMS (ESI) m/z
calcd. for C16H18F2NO4 [M+H]+ 326.1198, found 326.1203.
Ethyl
4-((3,4-dichlorobenzyl)amino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3e). Following the same experimental procedure of 3a with 2e (44 mg, 0.25 mmol),
3e (79 mg, 89%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained
as brown solid, m.p. 147–148 ºC. 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.49 (d,
J = 8.3 Hz, 1H), 7.38 (d, J = 2.0 Hz, 1H), 7.14 (dd, J = 8.3, 2.1 Hz, 1H), 4.64 (d, J =
6.6 Hz, 2H), 4.31 (q, J = 7.1 Hz, 2H), 1.65 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 179.3, 166.8, 166.6, 136.2, 133.5, 132.8, 131.3, 128.8,
126.0, 86.8, 79.1, 60.5, 47.1, 25.2, 14.4. HRMS (ESI) m/z calcd. for C16H18Cl2NO4
[M+H]+ 358.0607, found 358.0614.
Ethyl
4-((3-chlorobenzyl)amino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate (3f).
Following the same experimental procedure of 3a with 2f (35 mg, 0.25 mmol), 3f (70
mg, 87%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained as
brown solid, m.p. 129–130 ºC. 1H NMR (400 MHz, CDCl3) δ 9.03 (s, 1H), 7.39 –
7.31 (m, 2H), 7.27 (s, 1H), 7.20 – 7.15 (m, 1H), 4.66 (d, J = 6.7 Hz, 2H), 4.32 (q, J =
7.1 Hz, 2H), 1.67 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 179.4, 167.0, 166.6, 137.9, 135.2, 130.6, 128.8, 127.0, 124.8, 86.6, 79.2, 60.5, 47.6,
25.2, 14.4. HRMS (ESI) m/z calcd. for C16H19ClNO4 [M+H]+ 324.0997, found
324.1003.
Ethyl
5,5-dimethyl-2-oxo-4-((pyridin-2-ylmethyl)amino)-2,5-dihydrofuran-3-carboxylate
(3g). Following the same experimental procedure of 3a with 2g (27 mg, 0.25 mmol),
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3g (59 mg, 81%, silica gel, petroleum ether : ethyl acetate = 1: 1, V/V) was obtained
as yellow crystals, m.p. 122–125 ºC. 1H NMR (400 MHz, CDCl3) δ 9.63 (s, 1H), 8.67
(d, J = 4.6 Hz, 1H), 7.75 (td, J = 7.7, 1.7 Hz, 1H), 7.37 – 7.19 (m, 2H), 4.79 (d, J =
6.0 Hz, 2H), 4.36 (q, J = 7.1 Hz, 2H), 1.69 (s, 6H), 1.38 (t, J = 7.1 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 179.0, 167.3, 166.3, 154.4, 149.8, 137.3, 123.2, 121.1,
86.5, 79.3, 60.3, 48.6, 24.9, 14.5. HRMS (ESI) m/z calcd. for C15H19N2O4 [M+H]+
291.1339, found 291.1340.
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Ethyl
4-((furan-2-ylmethyl)amino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3h). Following the same experimental procedure of 3a with 2h (24 mg, 0.25 mmol),
3h (63 mg, 91%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained
as brown crystals, m.p. 141–142 ºC. 1H NMR (400 MHz, CDCl3) δ 8.93 (s, 1H), 7.42
(d, J = 0.7 Hz, 1H), 6.38 – 6.35 (m, 1H), 6.32 (d, J = 3.0 Hz, 1H), 4.62 (d, J = 6.5 Hz,
2H), 4.29 (q, J = 7.1 Hz, 2H), 1.70 (s, 6H), 1.34 (t, J = 7.1 Hz, 3H). C{1H} NMR
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(101 MHz, CDCl3) δ 179.0, 167.1, 166.5, 148.6, 143.4, 110.7, 108.7, 86.4, 79.2, 60.4,
41.5, 25.2, 14.4. HRMS (ESI) m/z calcd. for C14H18NO5 [M+H]+ 280.1180, found
280.1181.
Ethyl
5,5-dimethyl-2-oxo-4-((thiophen-2-ylmethyl)amino)-2,5-dihydrofuran-3-carboxylate
(3i). Following the same experimental procedure of 3a with 2i (28 mg, 0.25 mmol), 3i
(56 mg, 76%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained as
yellow crystals, m.p. 107–110 ºC. 1H NMR (400 MHz, CDCl3) δ 9.01 (s, 1H), 7.33
(dd, J = 4.9, 1.2 Hz, 1H), 7.06 – 7.00 (m, 2H), 4.83 (d, J = 6.4 Hz, 2H), 4.31 (q, J =
7.1 Hz, 2H), 1.71 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ 178.7, 167.0, 166.5, 138.2, 127.4, 126.4, 126.2, 86.4, 79.2, 60.4, 43.5, 25.3, 14.4.
HRMS (ESI) m/z calcd. for C14H18NO4S [M+H]+ 296.0951, found 296.0951.
Ethyl
4-(but-3-en-1-ylamino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3j).
Following the same experimental procedure of 3a with 2i (14 mg, 0.25 mmol), 3j (53
mg, 89%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained as
yellow solid, m.p. 69–71 ºC. 1H NMR (400 MHz, CDCl3) δ 8.82 (s, 1H), 6.06 – 5.78
(m, 1H), 5.34 (s, 1H), 5.31 (d, J = 6.1 Hz, 1H), 4.33 (q, J = 7.1 Hz, 2H), 4.13 – 4.06
(m, 2H), 1.64 (s, 6H), 1.37 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (101 MHz, CDCl3) δ
179.5, 167.2, 166.7, 132.5, 118.1, 86.0, 79.2, 60.3, 46.5, 25.1, 14.4. HRMS (ESI) m/z
calcd. for C12H18NO4 [M+H]+ 240.1230, found 240.1226.
Ethyl
4-(but-3-en-1-ylamino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
Following the same experimental procedure of 3a with 2k (18 mg, 0.25 mmol), 3k
(51 mg, 81%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained as
colourless crystals, m.p. 70–72 ºC. H NMR (400 MHz, CDCl3) δ 8.72 (s, 1H),
5.87-5.71 (m, 1H), 5.26 (s, 1H), 5.25-5.21 (m, 1H), 4.31 (q, J = 7.1 Hz, 2H), 3.52 (q,
J = 6.6 Hz, 2H), 2.44 (q, J = 6.8 Hz, 2H), 1.64 (s, 6H), 1.36 (t, J = 7.1 Hz, 3H);
13C{1H} NMR (101 MHz, CDCl3) δ 179.2, 167.2, 166.6, 132.9, 119.3, 85.6, 79.1,
(3k).
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60.2, 43.6, 34.4, 24.9, 14.5. HRMS (ESI) m/z calcd. for C13H20NO4 [M+H]+
254.1387, found 254.1384.
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5,5-dimethyl-2-oxo-4-(phenethylamino)-2,5-dihydrofuran-3-carboxylate
(3l). Following the same experimental procedure of 3a with 2l (28 mg, 0.25 mmol),
3c (69 mg, 91%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained
as yellow liquid. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 7.34 (t, J = 7.2 Hz, 2H),
7.30 – 7.25 (m, 1H), 7.20 (d, J = 7.0 Hz, 2H), 4.30 (q, J = 7.1 Hz, 2H), 3.68 (q, J =
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6.8 Hz, 2H), 2.96 (t, J = 7.0 Hz, 2H), 1.51 (s, 6H), 1.35 (t, J = 7.1 Hz, 3H). C{1H}
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NMR (101 MHz, CDCl3) δ 179.2, 167.2, 166.5, 136.8, 129.0, 128.8, 127.3, 85.6,
79.1, 60.2, 46.1, 36.9, 24.8, 14.4. HRMS (ESI) m/z calcd. for C17H22NO4 [M+H]+
304.1543, found 304.1546.
Ethyl
4-(isobutylamino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3m). Following the same experimental procedure of 3a with 2m (18 mg, 0.25 mmol),
3m (55 mg, 87%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained
as brown solid, m.p. 128–130 ºC. 1H NMR (400 MHz, CDCl3) δ 8.77 (s, 1H), 4.25 (q,
J = 7.1 Hz, 2H), 3.19 (t, J = 6.5 Hz, 2H), 1.85 (h, 1H), 1.56 (s, 6H), 1.30 (t, J = 7.1
Hz, 3H), 0.98 (d, J = 6.7 Hz, 6H); 13C{1H} NMR (101 MHz, CDCl3) δ 179.5, 167.3,
166.9, 85.3, 79.1, 60.2, 51.8, 29.3, 25.0, 19.8, 14.5. HRMS (ESI) m/z calcd. for
C13H22NO4 [M+H]+ 256.1543, found 256.1541.
Ethyl 5,5-dimethyl-2-oxo-4-(phenylamino)-2,5-dihydrofuran-3-carboxylate (3n).
Following the same experimental procedure of 3a with 2n (23 mg, 0.25 mmol) in 3
day reaction time, 3n (40 mg, 58%, silica gel, petroleum ether : ethyl acetate = 4: 1,
V/V) was obtained as brown solid, m.p. 119–121 ºC. 1H NMR (400 MHz, CDCl3) δ
10.26 (s, 1H), 7.47 – 7.43 (m, 3H), 7.32 – 7.29 (m, 2H), 4.37 (q, J = 7.1 Hz, 2H), 1.40
(t, J = 7.1 Hz, 3H), 1.36 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 179.2, 167.1,
166.7, 135.8, 87.2, 80.4, 60.6, 26.0, 14.5. HRMS (ESI) m/z calcd. for C15H18NO4
[M+H]+ 276.1230, found 276.1232.
Ethyl
4-((4-methoxyphenyl)amino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-
Carboxylate (3o). Following the same experimental procedure of 3a with 2o (31 mg,
0.25 mmol) in 3 day reaction time, 3o (47 mg, 61%, silica gel, petroleum ether : ethyl
acetate = 4: 1, V/V) was obtained as brown solid, m.p. 156–158 ºC. 1H NMR (400
MHz, CDCl3) δ 10.10 (s, 1H), 7.21 (d, J = 8.7 Hz, 2H), 6.92 (d, J = 8.9 Hz, 2H), 4.36
(q, J = 7.1 Hz, 2H), 3.85 (s, 3H), 1.39 (t, J = 7.1 Hz, 3H), 1.36 (s, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ 179.7, 167.1, 166.7, 159.9, 130.1, 128.1, 114.3, 87.0, 80.4, 60.5,
55.6, 26.0, 14.5. HRMS (ESI) m/z calcd. for C16H20NO5 [M+H]+ 306.1336, found
306.1336.
Ethyl
4-((2-bromophenyl)amino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate (3p).
Following the same experimental procedure of 3a with 2p (43 mg, 0.25 mmol) in 3
day reaction time, 3p (55 mg, 62%, silica gel, petroleum ether : ethyl acetate = 4: 1,
V/V) was obtained as yellow solid, m.p. 118–120 ºC. H NMR (400 MHz, CDCl3) δ
10.12 (s, 1H), 7.71 (d, J = 7.8 Hz, 1H), 7.43 (d, J = 4.1 Hz, 2H), 7.37 – 7.30 (m, 1H),
4.39 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H), 1.37 (s, 6H). C{1H} NMR (101
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80.4, 60.7, 25.5, 14.4. HRMS (ESI) m/z calcd. for C15H17BrNO4 [M+H]+ 354.0336
and 356.0315, found 354.0338 and 356.0322.
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Ethyl 4-benzamido-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate (3q).
Following the same experimental procedure of 3a with 2q (30 mg, 0.25 mmol) in 7
day reaction time, 3q (70 mg, 92%, silica gel, petroleum ether : ethyl acetate = 1: 1,
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V/V) was obtained as colorless crystals, m.p. 142–144 ºC. H NMR (400 MHz,
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CDCl3) δ 12.26 (s, 1H), 8.08 – 8.01 (m, 2H), 7.69 (t, J = 7.4 Hz, 1H), 7.60 (t, J = 7.6
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Hz, 2H), 4.47 (q, J = 7.1 Hz, 2H), 1.92 (s, 6H), 1.45 (t, J = 7.1 Hz, 3H). C{1H}
NMR (101 MHz, CDCl3) δ 175.7, 166.0, 162.9, 133.8, 131.9, 129.3, 128.2, 96.9,
84.2, 61.9, 24.3, 14.3. HRMS (ESI) m/z calcd. for C16H18NO5 [M+H]+ 304.1180,
found 304.1181.
Ethyl
4-(4-methoxybenzamido)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3r).
Following the same experimental procedure of 3a with 2r (38 mg, 0.25 mmol) in 7
day reaction time, 3r (77 mg, 93%, silica gel, petroleum ether : ethyl acetate = 1: 1,
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V/V) was obtained as white solid, m.p. 159–161 ºC. H NMR (400 MHz, CDCl3) δ
12.18 (s, 1H), 8.00 (d, J = 8.9 Hz, 2H), 7.05 (d, J = 8.9 Hz, 2H), 4.45 (q, J = 7.1 Hz,
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2H), 3.91 (s, 3H), 1.89 (s, 6H), 1.44 (t, J = 7.1 Hz, 3H). C{1H} NMR (101 MHz,
CDCl3) δ 176.0, 166.1, 165.9, 164.1, 162.2, 130.4, 124.1, 114.5, 96.2, 84.2, 61.8,
55.6, 24.3, 14.2. HRMS (ESI) m/z calcd. for C17H20NO6 [M+H]+ 334.1291, found
334.1292.
Ethyl 5,5-dimethyl-4-(4-nitrobenzamido)-2-oxo-2,5-dihydrofuran-3-carboxylate
(3s). Following the same experimental procedure of 3a with 2s (42 mg, 0.25 mmol) in
7 day reaction time, 3s (67 mg, 77%, silica gel, petroleum ether : ethyl acetate = 1: 1,
V/V) was obtained as white solid, m.p. 172–174 ºC. 1H NMR (400 MHz, CDCl3) δ
12.42 (s, 1H), 8.44 (d, J = 8.8 Hz, 2H), 8.23 (d, J = 8.8 Hz, 2H), 4.47 (q, J = 7.1 Hz,
2H), 1.91 (s, 6H), 1.46 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 175.2,
166.0, 165.3, 161.0, 150.8, 137.2, 129.4, 124.4, 98.1, 84.2, 62.3, 24.2, 14.2. HRMS
(ESI) m/z calcd. for C16H17N2O7 [M+H]+ 349.1036, found 349.1033.
Ethyl 5,5-dimethyl-2-oxo-4-(picolinamido)-2,5-dihydrofuran-3-carboxylate (3t).
Following the same experimental procedure of 3a with 2t (31 mg, 0.25 mmol) in 7
day reaction time, 3t (60 mg, 79%, silica gel, petroleum ether : ethyl acetate = 1: 1,
V/V) was obtained as white solid, m.p. 141–143 ºC. 1H NMR (400 MHz, CDCl3) δ
12.33 (s, 1H), 9.29 (d, J = 2.2 Hz, 1H), 8.89 (dd, J = 4.8, 1.5 Hz, 1H), 8.33 – 8.28 (m,
1H), 7.53 (dd, J = 8.0, 4.8 Hz, 1H), 4.45 (q, J = 7.1 Hz, 2H), 1.89 (s, 6H), 1.43 (t, J =
7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 175.3, 174.4, 166.0, 165.4, 162.9,
161.4, 154.2, 149.5, 135.6, 127.8, 123.8, 97.7, 84.2, 62.1, 24.2, 14.2. HRMS (ESI)
m/z calcd. for C15H17N2O5 [M+H]+ 305.1129, found 305.1132.
Methyl
4-(benzylamino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3u). Following the same experimental procedure of 3a with 1u (85 mg, 0.5 mmol),
3u (63 mg, 91%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained
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as yellow solid, m.p. 87–90 ºC. H NMR (400 MHz, CDCl3) δ 9.00 (s, 1H), 7.44 –
7.38 (m, 2H), 7.38 – 7.33 (m, 1H), 7.30 – 7.26 (m, 2H), 4.67 (d, J = 6.6 Hz, 2H), 3.83
(s, 3H), 1.68 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 179.4, 167.2, 167.0, 135.8,
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129.3, 128.5, 126.8, 85.9, 79.4, 51.4, 48.3, 25.2. HRMS (ESI) m/z calcd. for
C15H18NO4 [M+H]+ 276.1229, found 276.1230.
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Tert-butyl 4-(benzylamino)-5,5-dimethyl-2-oxo-2,5-dihydrofuran-3-carboxylate
(3v). Following the same experimental procedure of 3a with 1v (106 mg, 0.5 mmol),
3v (71 mg, 89%, silica gel, petroleum ether : ethyl acetate = 2: 1, V/V) was obtained
as yellow solid, m.p. 112–115ºC. 1H NMR (400 MHz, CDCl3) δ 8.94 (s, 1H), 7.44 –
7.39 (m, 2H), 7.38 – 7.33 (m, 1H), 7.31 – 7.27 (m, 2H), 4.65 (d, J = 6.6 Hz, 2H), 1.66
(s, 6H), 1.54 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 178.9, 167.2, 166.0, 136.1,
129.2, 128.5, 126.9, 87.2, 81.3, 78.8, 48.2, 28.4, 25.2. HRMS (ESI) m/z calcd. for
C18H24NO4 [M+H]+ 318.1700, found 318.1698.
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3-Benzoyl-4-(benzylamino)-5,5-dimethylfuran-2(5H)-one (3w). Following the
same experimental procedure of 3a with 1w (108 mg, 0.5 mmol), 3w (41 mg, 52%,
silica gel, petroleum ether : ethyl acetate = 4: 1, V/V) was obtained as yellow solid,
m.p. 110–112ºC. 1H NMR (400 MHz, CDCl3) δ 10.82 (s, 1H), 7.77 (d, J = 7.3 Hz,
2H), 7.55 – 7.48 (m, 1H), 7.48 – 7.37 (m, 5H), 7.34 (d, J = 7.2 Hz, 2H), 4.76 (d, J =
13
6.6 Hz, 2H), 1.78 (s, 6H). C{1H} NMR (101 MHz, CDCl3) δ 193.5, 180.6, 168.1,
138.2, 135.4, 131.7, 129.4, 128.8, 128.6, 127.6, 126.9, 94.4, 78.8, 48.4, 25.4. HRMS
(ESI) m/z calcd. for C20H20NO3 [M+H]+ 322.1438, found 322.1442.
Representative Synthesis of 3a on a 1 mmol Scale
To the mixture of 1a (184 mg, 1 mmol) and 2a (52 mg, 0.5 mmol) in dry THF (6
mL) was added dry K2CO3 powder (138 mg, 1 mmol) in one portion at room
temperature. The reaction mixture was heated to 50 ºC and stirred for 10 h until
substrate 1a was consumed monitored by TLC. THF was removed under reduced
pressure and the precipitated solid was washed with saturated NH4Cl aq. (6 mL) and
extracted with EtOAc (6 mL  3). The combined organic layers were dried over
Na2SO4 and the solvent was removed under reduced pressure. The residue was
purified by flash chromatography (silica gel, petroleum ether : ethyl acetate = 2: 1,
V/V) to give 3a (127 mg, 88 %)
Experimental procedure for the synthesis and analytical data of 4a–n, 5a–f
7,7-dimethyl-2-propylfuro[3,4-d]pyrimidine-4,5(3H,7H)-dione (4a). To the
mixture of 1a (92 mg, 0.5 mmol) and butyramidine hydrochloride 2a’ (26 mg, 0.25
mmol) in dry THF (3 mL) was added dry K2CO3 powder (103 mg, 0.75 mmol) in one
portion at room temperature. The reaction mixture was heated to 50 ºC and stirred for
10 h until substrate 1a was consumed indicated by TLC. Glacial acetic acid (1 ml)
was added to neutralize the K2CO3 powder. Solvent was removed under reduced
pressure. The residue was purified by flash chromatography directly (silica gel,
petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02, V/V) to give
7,7-dimethyl-2-propylfuro[3,4-d]pyrimidine-4,5(3H,7H)-dione 4a (46 mg, 83%) as
white solid, m.p. 112–115 ºC. 1H NMR (400 MHz, CDCl3) δ 2.87 (t, J = 7.5 Hz, 2H),
1.95 – 1.84 (m, 2H), 1.63 (s, 6H), 1.04 (t, J = 7.4 Hz, 3H). 13C{1H} NMR (101 MHz,
CDCl3) δ 185.9, 170.9, 165.7, 159.6, 105.3, 84.3, 37.6, 24.5, 20.7, 13.5. HRMS (ESI)
m/z calcd. for C11H14N2NaO3 [M+Na]+ 245.0897, found 245.0898.
2-cyclopropyl-7,7-dimethylfuro[3,4-d]pyrimidine-4,5(3H,7H)-dione
(4b).
Following the same experimental procedure of 4a with 2’b (30 mg, 0.25 mmol), 4b
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(46 mg, 84%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
V/V) was obtained as white solid, m.p. 168–170 ºC. H NMR (400 MHz, CDCl3) δ
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2.32 – 2.23 (br, 1H), 1.56 (s, 6H), 1.41 – 1.36 (m, 2H), 1.36 – 1.29 (m, 2H). 13C{1H}
NMR (101 MHz, CDCl3) δ 186.1, 181.2, 173.4, 169.6, 166.2, 160.0, 103.9, 84.2,
24.5, 15.5, 13.3. HRMS (ESI) m/z calcd. for C11H12N2NaO3 [M+Na]+ 243.0740,
found 243.0740.
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2-(tert-butyl)-7,7-dimethylfuro[3,4-d]pyrimidine-4,5(3H,7H)-dione
(4c).
Following the same experimental procedure of 4a with 2’c (34 mg, 0.25 mmol), 4c
(54 mg, 92%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
V/V) was obtained white solid, m.p. 190–193 ºC. 1H NMR (400 MHz, CDCl3) δ 1.60
(s, 6H), 1.46 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ 185.1, 176.7, 165.9, 158.9,
105.2, 84.3, 38.8, 28.3, 24.6. HRMS (ESI) m/z calcd. for C12H17N2O3 [M+H]+
237.1234, found 237.1233.
2-(tert-butyl)-7,7-diethylfuro[3,4-d]pyrimidine-4,5(3H,7H)-dione
Following the same experimental procedure of 4c with 1d (106 mg, 0.5 mmol), 4d
(4d).
(52 mg, 80%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
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V/V) was obtained as colorless crystals, m.p. 165–167 ºC. H NMR (400 MHz,
CDCl3) δ 2.14 – 1.83 (m, 4H), 1.45 (s, 9H), 0.79 (t, J = 7.0 Hz, 6H). 13C{1H} NMR
(101 MHz, CDCl3) δ 183.6, 176.2, 166.3, 158.4, 107.5, 89.5, 38.7, 29.1, 28.3, 7.3.
HRMS (ESI) m/z calcd. for C14H21N2O3 [M+H]+ 265.1547, found 265.1546.
2'-(tert-butyl)-3'H-spiro[cyclohexane-1,7'-furo[3,4-d]pyrimidine]-4',5'-dione
(4e). Following the same experimental procedure of 4c with 1e (112 mg, 0.5 mmol),
4e (59 mg, 86%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1:
1
0.02, V/V) was obtained as white solid, m.p. 196–198 ºC. H NMR (400 MHz,
CDCl3) δ 2.01 – 1.89 (m, 1H), 1.89 – 1.73 (m, 5H), 1.71 – 1.62 (m, 1H), 1.45 (s, 9H),
1.26 (br, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ 185.0, 176.1, 166.1, 158.7, 105.6,
85.8, 38.7, 33.3, 28.3, 24.5, 21.6. HRMS (ESI) m/z calcd. for C15H21N2O3 [M+H]+
277.1547, found 277.1545.
7-methyl-2-phenylfuro[3,4-d]pyrimidine-4,5(3H,7H)-dione (4f). Following the
same experimental procedure of 4a with 2’f (39 mg, 0.25 mmol), 4f (58 mg, 90%,
silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02, V/V) was
obtained as white solid, m.p. 230–233 ºC. 1H NMR (400 MHz, CDCl3) δ 8.34 (d, J =
7.3 Hz, 2H), 7.76 – 7.61 (m, 3H), 1.71 (s, 6H). 13C{1H} NMR (101 MHz, DMSO-d6)
δ 184.8, 165.9, 164.2, 158.1, 133.7, 131.6, 129.4, 129.3, 105.1, 83.8, 24.8. HRMS
(ESI) m/z calcd. for C14H12N2NaO3 [M+Na]+ 279.0740, found 279.0743.
2-(4-fluorophenyl)-7,7-dimethylfuro[3,4-d]pyrimidine-4,5(3H,7H)-dione
(4g).
Following the same experimental procedure of 4a with 2’g (44 mg, 0.25 mmol), 4g
(64 mg, 94%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
V/V) was obtained as white solid, m.p. 232–235 ºC. 1H NMR (400 MHz, DMSO-d6) δ
8.57 – 8.14 (m, 2H), 7.43 (t, J = 8.8 Hz, 2H), 1.58 (s, 6H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 184.7, 165.5 (d, J = 252.2 Hz), 166.0, 163.3, 158.41, 132.2 (d, J = 9.5
Hz), 128.4 (d, J = 3.7 Hz), 116.4 (d, J = 22.1 Hz). 104.8, 83.7, 24.8. HRMS (ESI) m/z
calcd. for C14H12FN2O3 [M+H]+ 275.0827, found 275.0825.
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2-(4-bromophenyl)-7,7-dimethylfuro[3,4-d]pyrimidine-4,5(3H,7H)-dione (4h).
Following the same experimental procedure of 4a with 2’h (34 mg, 0.25 mmol), 4h
(70 mg, 84%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
V/V) was obtained as white solid, m.p. 236–238 ºC. 1H NMR (400 MHz, DMSO-d6) δ
8.15 (d, J = 7.8 Hz, 2H), 7.80 (d, J = 7.7 Hz, 2H), 1.57 (s, 6H). 13C{1H} NMR (101
MHz, DMSO-d6) δ 184.6, 166.2, 163.7, 159.6, 132.3, 131.6, 131.3, 127.4, 104.8,
83.7, 24.9. HRMS (ESI) m/z calcd. for C14H11BrN2NaO3 [M+Na]+ 356.9845 and
358.9824, found 356.9844 and 358.9826.
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7,7-dimethyl-2-(4-nitrophenyl)furo[3,4-d]pyrimidine-4,5(3H,7H)-dione
(4i).
Following the same experimental procedure of 4a with 2’i (50 mg, 0.25 mmol), 4i (70
mg, 93%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
V/V) was obtained as brown solid, m.p. 255–258 ºC (decomposition temperature). 1H
NMR (400 MHz, DMSO-d6) δ 8.41 (t, 4H), 1.60 (s, 6H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 184.5, 165.9, 162.9, 158.9, 150.2, 138.1, 130.9, 124.2, 105.6, 83.8, 24.8.
HRMS (ESI) m/z calcd. for C14H12N3O5 [M+H]+ 302.0772, found 302.0770.
7,7-dimethyl-2-(pyridin-2-yl)furo[3,4-d]pyrimidine-4,5(3H,7H)-dione
(4j).
Following the same experimental procedure of 4a with 2’j (39 mg, 0.25 mmol), 4j (54
mg, 84%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
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V/V) was obtained as white solid, m.p. 208–210 ºC. H NMR (400 MHz, DMSO-d6)
δ 8.80 (d, J = 4.2 Hz, 1H), 8.44 (d, J = 7.8 Hz, 1H), 8.11 (t, J = 7.7 Hz, 1H), 7.72 (dd,
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J = 7.2, 4.9 Hz, 1H), 1.60 (s, 6H). C{1H} NMR (101 MHz, DMSO-d6) δ 184.7,
166.0, 162.0, 157.7, 150.0, 148.6, 138.7, 128.1, 124.5, 106.5, 83.6, 24.8. HRMS (ESI)
m/z calcd. for C13H12N3O3 [M+H]+ 258.0873, found 258.0873.
7,7-dimethyl-2-(pyrimidin-2-yl)furo[3,4-d]pyrimidine-4,5(3H,7H)-dione
(4k).
Following the same experimental procedure of 4a with 2’k (40 mg, 0.25 mmol), 4k
(59 mg, 92%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
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V/V) was obtained as white solid, m.p. 263–265 ºC (decomposition temperature). H
NMR (400 MHz, DMSO-d6) δ 9.10 (d, J = 4.9 Hz, 2H), 7.80 (t, J = 4.9 Hz, 1H), 1.59
(s, 6H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 184.8, 165.8, 160.9, 158.7, 157.5,
157.4, 124.0, 107.8, 84.0, 24.7. HRMS (ESI) m/z calcd. for C12H11N4O3 [M+H]+
259.0826, found 259.0824.
7,7-dimethyl-2-(pyridin-3-yl)furo[3,4-d]pyrimidine-4,5(3H,7H)-dione
(4l).
Following the same experimental procedure of 4a with 2’l (39 mg, 0.25 mmol), 4l (60
mg, 93%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
V/V) was obtained as yellow solid, m.p. 188–190 ºC. 1H NMR (400 MHz, DMSO-d6)
δ 9.33 (d, J = 1.6 Hz, 1H), 8.87 – 8.74 (m, 1H), 8.59 – 8.47 (m, 1H), 7.60 (dd, J = 8.0,
4.8 Hz, 1H), 1.58 (s, 6H). 13C{1H} NMR (101 MHz, DMSO-d6) δ 184.5, 166.6, 163.4,
153.2, 150.1, 136.8, 129.2, 124.1, 104.5, 83.6, 25.0. HRMS (ESI) m/z calcd. for
C13H12N3O3 [M+H]+ 258.0873, found 258.0873.
7,7-dimethyl-2-morpholinofuro[3,4-d]pyrimidine-4,5(3H,7H)-dione
(4m).
Following the same experimental procedure of 4a with 2’m (41 mg, 0.25 mmol), 4m
(62 mg, 94%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
V/V) was obtained as white solid, m.p. 247–249 ºC. 1H NMR (400 MHz, CDCl3) δ
3.91 (br, 4H), 3.80 (br, 4H), 1.51 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3) δ 186.4,
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167.5, 161.8, 157.8, 95.3, 83.7, 66.3, 45.4, 24.8. HRMS (ESI) m/z calcd. for
C12H16N3O4 [M+H]+ 266.1135, found 266.1135.
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7,7-dimethyl-2-(1H-pyrazol-1-yl)furo[3,4-d]pyrimidine-4,5(3H,7H)-dione (4n).
Following the same experimental procedure of 4a with 2’n (37 mg, 0.25 mmol), 4n
(57 mg, 85%, silica gel, petroleum ether: ethyl acetate: glacial acetic acid = 1: 1: 0.02,
V/V) was obtained as yellow solid, m.p. 278–280 ºC. 1H NMR (400 MHz, DMSO-d6)
δ 8.53 (d, J = 2.4 Hz, 1H), 7.71 (br, 1H), 6.48 (br, 1H), 1.48 (s, 6H). 13C{1H} NMR
(101 MHz, DMSO-d6) δ 185.6, 169.2, 168.9, 159.3, 142.5, 129.9, 108.0, 100.3, 82.3,
25.5. HRMS (ESI) m/z calcd. for C11H10N4NaO3 [M+H]+ 269.0645, found 269.0645.
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3,3-Dimethyl-1H-furo[3,4-d]pyrido[1,2-a]pyrimidine-1,10(3H)-dione
(5a).
Following the same experimental procedure of 4a with 2’aa (24 mg, 0.25 mmol) and
K2CO3 (138mg. 1 mmol), 5a (45 mg, 78%, silica gel, petroleum ether: ethyl acetate =
1: 4, V/V) was obtained as light yellow solid, m.p. 204–207 ºC (decomposition
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temperature). H NMR (400 MHz, CDCl3) δ 9.31 (dd, J = 7.0, 0.9 Hz, 1H), 8.13 –
8.04 (m, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.49 – 7.38 (m, 1H), 1.69 (s, 6H). 13C{1H}
NMR (101 MHz, CDCl3) δ 181.1, 166.4, 154.9, 152.8, 140.4, 129.4, 126.9, 117.3,
+
96.6, 83.9, 25.1. HRMS (ESI) m/z calcd. for C12H10N2NaO3 [M+Na]+ 253.0584,
found 253.0584.
7-Fluoro-3,3-dimethyl-1H-furo[3,4-d]pyrido[1,2-a]pyrimidine-1,10(3H)-dione
(5b). Following the same experimental procedure of 4a with 2’bb (28 mg, 0.25 mmol)
and K2CO3 (138mg. 1 mmol), 5b (45 mg, 73%, silica gel, petroleum ether: ethyl
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acetate = 1: 4, V/V) was obtained as white solid, m.p. 210–214 ºC. H NMR (400
MHz, CDCl3) δ 9.21 (s, 1H), 8.02-7.95 (m, 1H), 7.94 – 7.84 (m, 1H), 1.69 (s, 6H).
13C{1H} NMR (101 MHz, CDCl3) δ 180.8, 166.0, 154.9 (d, J = 249.3 Hz), 152.4 (d, J
= 55.9 Hz), 132.0 (d, J = 24.5 Hz), 128.6 (d, J = 7.2 Hz), 116.1 (d, J = 40.9 Hz), 96.5,
+
84.0, 25.0. HRMS (ESI) m/z calcd. for C12H10FN2O3 [M+H]+ 249.0670, found
249.0668.
3,3,7-Trimethyl-1H-furo[3,4-d]pyrido[1,2-a]pyrimidine-1,10(3H)-dione
(5c).
Following the same experimental procedure of 4a with 2’cc (27 mg, 0.25 mmol) and
K2CO3 (138mg. 1 mmol), 5c (49 mg, 81%, silica gel, petroleum ether: ethyl acetate =
1: 4, V/V) was obtained as light yellow solid, m.p. 270–273 ºC(decomposition
1
temperature). H NMR (400 MHz, CDCl3) δ 9.10 (s, 1H), 7.94 (dd, J = 8.9, 2.0 Hz,
13
1H), 7.78 (d, J = 8.9 Hz, 1H), 2.54 (s, 3H), 1.67 (s, 6H). C{1H} NMR (101 MHz,
CDCl3) δ 180.4, 166.6, 153.5, 152.8, 143.1, 128.1, 127.1, 126.2, 96.2, 83.8, 25.1,
+
18.4. HRMS (ESI) m/z calcd. for C13H13N2O3 [M+H]+ 245.0920, found 245.0918.
5-Amino-3,3-dimethyl-1H-furo[3,4-d]pyrido[1,2-a]pyrimidine-1,10(3H)-dione
(5d). Following the same experimental procedure of 4a with 2’dd (27 mg, 0.25 mmol)
and K2CO3 (138mg. 1 mmol), 5d (40 mg, 62%, silica gel, petroleum ether: ethyl
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acetate = 1: 2, V/V) was obtained as brown solid, m.p. 243–246 ºC. H NMR (400
MHz, DMSO-d6) δ 8.42 (dd, J = 6.6, 1.2 Hz, 1H), 7.37-7.32 (m, 1H), 7.28 (dd, J =
13
7.7, 1.2 Hz, 1H), 6.45 (s, 2H), 1.61 (s, 6H). C{1H} NMR (101 MHz, DMSO-d6) δ
177.7, 166.8, 153.4, 144.7, 143.5, 119.3, 116.9, 115.7, 94.7, 83.4, 25.5. HRMS (ESI)
+
m/z calcd. for C13H13N2O4 [M+H]+ 261.0870, found 261.0868.
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3,3-Dimethylbenzo[4,5]imidazo[1,2-a]furo[3,4-d]pyrimidine-1,11(3H,5H)-dione
(5e). Following the same experimental procedure of 4a with 2’ee (33 mg, 0.25 mmol)
and K2CO3 (138mg. 1 mmol), 5e (50 mg, 75%, petroleum ether: ethyl acetate: glacial
acetic acid = 2: 1: 0.02, V/V) was obtained as white solid, m.p. 280–283 ºC. 1H NMR
(400 MHz, DMSO-d6) δ 7.91 (d, J = 8.1 Hz, 1H), 7.62 (d, J = 7.7 Hz, 1H), 7.44 (t, J =
13
7.5 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 1.95 (s, 3H), 1.90 (s, 1H). C{1H} NMR (101
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MHz, DMSO-d6) δ 167.7, 164.6, 157.5, 149.6, 142.9, 127.1, 126.2, 122.7, 118.4,
+
113.6, 101.4, 81.4, 23.9. HRMS (ESI) m/z calcd. for C14H12N3O3 [M+H]+ 270.0873,
found 270.0872.
6-Hydroxy-3,3-dimethylfuro[3,4-b]quinoline-1,9(3H,4H)-dione (5f). Following
the same experimental procedure of 4a with 2’ff (27 mg, 0.25 mmol) and K2CO3
(138mg. 1 mmol), 5f (39mg, 59%, petroleum ether: ethyl acetate: glacial acetic acid =
4: 1: 0.02, V/V) was obtained as brown solid, m.p. 318–320 ºC (decomposition
temperature). 1H NMR (400 MHz, DMSO-d6) δ 7.68 (d, J = 8.8 Hz, 1H), 6.99 (s, 1H),
6.70 (d, J = 8.6 Hz, 1H), 6.52 (s, 1H), 1.71 (s, 6H). 13C{1H} NMR (101 MHz,
DMSO-d6) δ 173.5, 166.0, 159.6, 157.2, 155.8, 128.6, 113.1, 102.6, 101.6, 99.0, 83.3,
+
26.3. HRMS (ESI) m/z calcd. for C13H11NNaO4 [M+Na]+ 268.0580, found 268.0577.
Analytical data of the corresponding by-product 3′, intermediate 3qx and
INTn2.
Ethyl 5,5-dimethyl-2-oxotetrahydrofuran-3-carboxylate (3′). Following the same
experimental procedure of 3a, the by-product 3’ (42 mg, 89%, silica gel, petroleum
ether: ethyl acetate = 2 : 1, V/V) was obtained as colorless liquid. 1H NMR (400 MHz,
CDCl3) δ 4.19 (q, J = 7.2 Hz, 2H), 3.68 (t, J = 9.7 Hz, 1H), 2.44 (dd, J = 13.0, 9.7 Hz,
1H), 2.26 (dd, J = 13.0, 9.6 Hz, 1H), 1.46 (s, 3H), 1.35 (s, 3H), 1.25 (t, J = 7.1 Hz,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ 171.3, 168.0, 83.7, 77.4, 77.1, 76.8, 62.2,
47.7, 38.4, 28.4, 27.7, 14.1.
Ethyl 5,5-dimethyl-4-(nicotinamido)-2-oxotetrahydrofuran-3-carboxylate (3tx).
Following the same experimental procedure of 3t in 3 day reaction time, 3tx (40 mg,
52%, silica gel, petroleum ether: ethyl acetate = 1: 1, V/V) was obtained as colorless
liquid. 1H NMR (400 MHz, CDCl3) δ 9.04 (d, J = 1.7 Hz, 1H), 8.66 (dd, J = 4.8, 1.6
Hz, 1H), 8.19 (dt, J = 7.9, 1.9 Hz, 1H), 7.90 (d, J = 8.5 Hz, 1H), 7.41 – 7.38 (m, 1H),
5.23 (t, J = 8.7 Hz, 1H), 4.24 (q, J = 7.0 Hz, 2H), 3.99 (d, J = 8.8 Hz, 1H), 1.64 (s,
3H), 1.43 (s, 3H), 1.26 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ 169.3,
166.5, 165.7, 152.4, 148.1, 135.8, 129.4, 123.7, 86.8, 62.8, 57.2, 52.6, 27.5, 22.3,
+
13.9. HRMS (ESI) m/z calcd. for C15H19N2O5 [M+H]+ 307.1294, found 307.1292.
Ethyl 4-((2,2-dimethyl-5-oxotetrahydrofuran-3-yl)(phenyl)amino)-5,5-dimethyl-
2-oxotetrahydrofuran-3-carboxylate (INTn2). To the mixture of 3nx (205 mg, 1
mmol) and 1a (184 mg, 1 mmol) in dry THF (5 mL) was added dry NaOt-Bu powder
(192 mg, 2 mmol) in one portion at room temperature. The reaction mixture was
heated to reflux and stirred for 2 day. THF was removed underreduced pressure and
the precipitated solid was washed with saturated NH4Cl aq. (5 mL) and extracted with
EtOAc (5 mL  3). The combined organic layers were dried over Na2SO4 and the
solvent was removed under reduced pressure. The residue was purified by flash
chromatography (silica gel, petroleum ether : ethyl acetate = 8: 1, V/V) to give INTn2
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(31 mg, 8%), white solid, m.p. 81–83 ºC. H NMR (400 MHz, CDCl3) δ 7.24 (t, J =
7.9 Hz, 2H), 6.83 (t, J = 7.3 Hz, 1H), 6.74 (t, J = 9.1 Hz, 2H), 4.36-4.23 (m, 4H), 3.73
(d, J = 11.5 Hz, 1H), 3.09 (dd, J = 12.0, 4.7 Hz, 1H), 2.61 (dd, J = 10.5, 4.8 Hz, 1H),
1.51 (s, 3H), 1.48 (s, 3H), 1.46 (s, 3H), 1.38 (s, 3H), 1.36 (t, J = 7.2 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ 172.4, 169.7, 167.9, 146.0, 129.8, 119.6, 114.0, 85.2,
85.1, 63.6, 62.4, 49.2, 48.3, 44.2, 28.5, 27.5, 23.3, 21.6, 14.1. HRMS (ESI) m/z calcd.
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for C21H28N1O6 [M+H]+ 390.1917, found 390.1913.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications
website.
1. Optimization of the amination reaction.
2. The in-situ 1H NMR and Mass data and Analysis.
3. Spectral copies of 1H and 13C NMR of compounds obtained in this study.
AUTHOR INFORMATION
Corresponding Author
*Email: lirt@bjmu.edu.cn.
*Email: xinwang@bjmu.edu.cn
*Email: jwang83@mgh.harvard.edu
*Email: abrownell@mgh.harvard.edu.
Acknowledgment
Financial support of this research is provided by the NNSFC (No.81673287) and
the NIH (R01NS100164 and R01EB021708) to ALB at MGH.
Reference
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