Copper Salt Catalyzed Synthesis of Functionalized 2H-Pyranes

Article abstract of DOI:10.1002/jhet.3570

A copper-catalyzed reaction between terminal alkynes, oxiranes, and malonitrile has been described. In this transformation, copper acetylide was attacked on oxiranes to form homopropargyl alkoxy-copper intermediate that was further transferred to 2H-pyrane skeletons by reaction with malonitrile. We found that the reaction was not productive without hexafluoroisopropanol.

Full text of DOI:10.1002/jhet.3570

Month 2019
Copper Salt Catalyzed Synthesis of Functionalized 2H-Pyranes
a
a
a,b
c
Alireza Varmazyar, Sajjad Sedaghat, Ahmad Nozad Goli-Kand, Mehdi Khalaj,
and Samira Arab-Salmanabadia
*
*
aDepartment of Chemistry, Shahr-e-Qods Branch, Islamic Azad University, Tehran, Iran
bMaterial and Nuclear Fuel Cyclic Research School, NSTRI, Tehran, Iran
cDepartment of Chemistry, Buinzahra Branch, Islamic Azad University, Buinzahra, Iran
*E-mail: sajjadsedaghat@yahoo.com; khalaj_mehdi@yahoo.com
Received December 16, 2018
DOI 10.1002/jhet.3570
Published online 00 Month 2019 in Wiley Online Library (wileyonlinelibrary.com).
A copper-catalyzed reaction between terminal alkynes, oxiranes, and malonitrile has been described. In
this transformation, copper acetylide was attacked on oxiranes to form homopropargyl alkoxy-copper inter-
mediate that was further transferred to 2H-pyrane skeletons by reaction with malonitrile. We found that the
reaction was not productive without hexafluoroisopropanol.
J. Heterocyclic Chem., 00, 00 (2019).
INTRODUCTION
acetylides reacted with the intermediate to give the ring-
opened product. Whereas when the activated three-
membered heterocycle is relatively unstable, Meinwald
rearrangement occurred instantaneously to give the
corresponding product, which reacted with the metal
acetylides to give the product. While the importance of
such reports cannot be overstated, the transformation
suffered from the limitations such as low yields and
regioselectivity. Recently, regioselective ring opening of
oxiranes with lithium alkynyl ate complex has been
reported [26]. Based on these finding, we decided to
examine the feasibility of the oxiranes alkynylation
strategy for the synthesis of 2H-pyrane motif.
Terminal alkynes exhibited good reactivity both as
nucleophiles and as electrophiles using appropriate
catalytic systems [1–3]. Moreover, conversion of terminal
alkynes to the corresponding acetylides and subsequent
reactions with C-electrophiles is an important carbon–
carbon bond-forming reaction. Accordingly, there are
many reports in literature featuring the additions of metal-
alkynylides to Michael acceptors [4–9]. In most of these
transformations, metal acetylides formation occurred
using equimolar amounts of pre-catalyst sources. During
the last decade, in situ formations of metal acetylides
offered an opportunity for the catalytic reactions of
metal acetylides in C─C bond formations [10–12].
Additionally, there are many reports in literature featuring
synthesis of heterocycle compounds catalysis in coinage
metals [13]. Due to the high activity of Cu, metal
acetylides synthesis has been extensively studied on
Cu-based catalysts [14–17]. Since the pioneering work of
Knöpfel and Carreira in catalytic conjugate addition
reaction of terminal alkynes [18], the additions of metal
acetylides on carbonyl, imine, and α-imino ester moieties
for the construction of C─C bonds have been well
explored [19–21]. Importantly, alkynylation of oxiranes
with ring opening with metal acetylides is among
the most versatile methods for the C─C bond formation
[22–24]. As far as we could ascertain, the regioselectivity
in the ring opening reactions of three-membered
heterocycles depends on electronic and steric parameters
on the substrates structures [25]. When the activated
three-membered heterocycle is stable enough, metal
RESULTS AND DISCUSSION
To examine the efficiency of the proposed reaction,
phenyl acetylene (1a), 2-methyloxirane (2a), and
malonitrile (3) were selected as reaction partners using
AgOAc and (i-Pr)2EtN in hexafluoroisopropanol (HFIP)
at 85°C. Our optimization results are shown in Table 1.
The targeted product 4a was achieved only in 25% yield
together with the direct coupling by-product 5 in 42% yield
(Table 1, entry 1). This compound must be generated by
the direct attack of the silver acetylide to 2a. It could be
deduced that the reaction did not proceed through
the SN1-like pathway as no products arising from the
Meinwald rearrangement are detected in crude reaction
mixture analysis. The examination of other silver pre-
catalysts showed that silver salts were inefficient in these
transformations (Table 1, entries 2–7). Pd(OAc)2 resulted
© 2019 Wiley Periodicals, Inc.

A. Varmazyar, S. Sedaghat, A. N. Goli-Kand, M. Khalaj, and S. Arab-Salmanabadi
Vol 000
Table 1
Optimization of the reaction conditionsa.
Entry
Catalyst
Base
Solvent
Yield (%)
1
2
3
4
5
6
7
8
AgOAc
AgI
AgCl
AgNO3
AgF
AgBF4
Ag2CO3
Pd(OAc)2
AuCl3
(IPr)CuCl
CuOTf
Cu2O
CuBr
CuCl
CuI
Cu(OTf)2
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
Et3N
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
HFIP
MeCN
DMF
PEG 200
PEG 400
HFIP
25 (42)b
19 (53)
31 (29)
38 (25)
50 (34)
13 (22)
24 (16)
46 (25)
70
68
80
85
65
73
80
55
68
16
38
13
21
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
K2CO3
Cs2CO3
LiOtBu
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
(i-Pr)2EtN
—
Cu2O
Cu2O
Cu2O
Cu2O
26
40
70
31
DMF, dimethylformamide; HFIP, hexafluoroisopropanol; PEG, polyethylene glycol.
aReaction conditions: 1a (1.2 mmol), 2 (1.0 mL), 3a (1.0 mmol), catalyst (0.1 mmol), base (1.2 mmol), and Linde-type 3-Å molecular sieves (250 mg) in
solvent (3 mL) at 85°C for 14 h.
bThe digit in parentheses refer to the yield of 5.
in a moderate yield of the targeted product, which might
arise from the protonolysis of palladium acetylide, while
the reaction conducted with AuCl3 proceeded with good
successes (Table 1, entries 8 and 9). It was delightedly
found that 10 mol % loading of N-heterocyclic carbene
dimethylformamide resulted in inferior yields of 4a
(Table 1, entries 21 and 22). Polyethylene glycol 200 and
400 (known solvents for activating oxiranes and
aziridines) resulted lower productivity (Table 1, entries 23
and 24). The control experiment showed that extremely
low yield of 4a was obtained in the absence of (i-Pr)2EtN,
testifying the vital roles of base in this catalytic system
(Table 1, entry 25).
Afterwards, we examined the scope of the transformation
with different terminal alkynes and oxiranes (Table 2).
Methyl oxirane 3a afforded the corresponding 2H-pyrane
motif 4a with good success (Table 2, entry 1). It was
delightedly found that oxiranes with longer chains gave
the products in diminished yields, which might arise
from the steric hindrance of alkyl branches (Table 2,
entries 2 and 3). The reaction proceeded smoothly with
phenoxy methyl-substituted oxirane (Table 2, entry 4).
Oxirane possessing an ester motif was also tolerated
(Table 2, entries 5 and 6). The transformation is sensitive
copper(I) catalyst (IPr)CuCl (IPr
=
1,3-bis(2,6-
diisopropylphenyl)imidazol-2-ylidene) was turned out to
effectively suppress the direct coupling by-product
formation (Table 1, entry 10). The yield was highly
improved upon using of CuOTf as the catalyst source
(Table 1, entry 11). A copper pre-catalyst screen showed
that Cu2O gave superior yield in comparison with other
copper catalysts (Table 1, entries 11–16). The superior
catalytic activity of Cu2O is likely due to its good
solubility in HFIP. Importantly, no direct coupling by-
product 5 was formed when the reaction was conducted
with copper salts. The reactions conducted with Et3N or
inorganic bases formed lower yields than (i-Pr)2EtN
(Table 1, entries 17–20). Replacing HFIP with MeCN or
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Copper Salt Catalyzed Synthesis of Functionalized 2H-Pyranes
Table 2
Scope of terminal alkynes and oxiranesa.
Entry
Alkyne
R1
Epoxide
R2, R3, R4
4, Yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2d
2d
CH3, H, H
n-Pr, H, H
n-Pr, H, CH3
4a, 85
4b, 80
4c, 71
4d, 84
4e, 69
4f, 88
4g, 60
4h, 95
4i, 47
PhOCH2, H, H
CH3, H, CH3OCO
CH2CMeCO2CH2, H, H
(CH3)3, H, H
─(CH2)4─, H
─(CH2)5─, H
Me2CHOCH2, H, H
H, Ph, H
9
10
11
12
13
14
15
4j, 78
4k, 90b
4l, 94
Ph, Ph, H (trans 2S, 3S)
4-NO2-C6H4, H, H
H, Ph, H
4m, 58
4n, 63b
4o, 60b
CH3OCH2
TMS
H, Ph, H
aFor all entries except stated otherwise: 1 (1.2 mmol), 2 (1.0 mmol), 3 (1.0 mmol), Cu2O (0.1 mmol), (i-Pr)2EtN (1.2 mmol), and 250 mg of Linde-type 3-
Å molecular sieves, in hexafluoroisopropanol (HFIP) (3 mL) at 85°C for 14 h.
bThe yield of internal-attacked product.
to steric hindrance of substrate as 2-(tert-butyl)oxirane (2g)
yielded the targeted product in 60% yield (Table 2, entry 7).
The meso oxirane derived from cyclohexene furnished the
trans-configuration product 4h in excellent yield (Table 2,
entry 8). Cycloheptene oxide (2i) was less reactive in
this developed transformation (Table 2, entry 9). This
coupling reaction was also extended to phenyl-substituted
oxiranes. As expected, 2-phenyloxirane (2k) was attacked
by silver acetylide at the internal carbon (Table 2, entry
11). 2,3-Diphenyloxirane (2l) also afforded a good yield
(Table 2, entry 12). Oxirane bearing 4-nitrophenyl 2m
underwent the transformation in different manners and
give the terminal-attacked product exclusively (Table 2,
entry 13). An obvious decrease in reaction outcome was
observed when aliphatic terminal alkyne (1b) was used as
the substrate, likely due to the lower acidity of aliphatic
alkyne than that of phenyl acetylene (Table 2, entry 14).
Trimethylsilylacetylene provided the 2H-pyrane skeleton
in 60% yield, which could participate in organosilicon
chemistry (Table 2, entry 15).
tautomerization, affording 2H-pyrane derivatives 4. The
investigation indicated that HFIP is necessary to furnish
the reaction in acceptable yields (Scheme 1).
In this report, we attempt to develop a novel catalytic
one-pot reaction involving in situ generated copper
acetylides, oxiranes, and malonitrile. The control
experiments showed that the choice of catalyst and the
reaction medium had great impact in furnishing the
desired transformation. Copper salts exhibited unique
reactivity and selectivity in this transformation. We found
that the efficiency and regioselectivity of the ring opening
reaction of oxiranes depend on electronic and steric
properties of substrates. Alkyl terminal alkynes required
longer reaction times to furnish the reaction with good
success. Gratifyingly, the reaction was proved to be
general under the optimized conditions, performing well
in most of the cases examined.
EXPERIMENTAL
Mechanistically, copper(I) coordinates with the phenyl
acetylene activating the alkyne carbon–hydrogen bond.
The abstraction of the terminal proton easily by (i-Pr)2EtN
leads to the formation of copper acetylide nucleophile 6.
Copper acetylide was attacked on oxiranes to form
homopropargyl alkoxy-copper intermediates 7, which
were further attacked by dicyanocarbanion 8, generated
from malinitrile and DIEPA, followed by cyclization and
Substrates and metal salts were purchased from
commercial sources. All the solvents were purchased
from PALACHEM Chemical Industries. Solvents were
dried over molecular sieves before the use. Molecular
sieves were activated at 260°C for 6 h and stored in
desiccator in the presence of P2O5. The copper(I) salts
were typically weighted in a glovebox and were stored in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Varmazyar, S. Sedaghat, A. N. Goli-Kand, M. Khalaj, and S. Arab-Salmanabadi
Vol 000
Scheme 1. Proposed reaction progress path for the synthesis 2H-pyranes.
a desiccator while being utilized. All reactions were carried
out in Schlenk tube (25 mL) using oven-dried glassware
under a dry Ar atmosphere. All reactions were monitored
by TLC analyses that were performed on silica gel 60
(Merck, item number 116835). Column chromatography
was performed on silica gel 60 (particle size 63–200 μm)
(Merck, item number 7734-3) on a glass column.
Melting points (mp) were recorded with Electrothermal-
9100 apparatus and are uncorrected. 1H NMR spectra
were recorded with Bruker DRX-500 AVANCE
instrument, at 500 MHz (using TMS, as a reference),
and 13C NMR spectra were recorded at 125 MHz (using
the CDCl3 triplet as reference) in CDCl3 as solvent at
ambient temperature. Chemical shifts were reported as δ
in parts per million (ppm), and coupling constant (J)
values are given in Hertz. Mass data were recorded with
EIMS (70 eV): Finnigan-MAT-8430 mass spectrometer,
in m/z. IR spectra were recorded with Shimadzu IR-460
FTIR spectrometer as KBr pellets. Elemental analyses
(C, H, N) were performed with a Heraeus CHN-O-Rapid
analyzer. The results agreed favorably with the
calculated values.
General procedure for the preparation of 4. A Schlenk
tube (25 mL) was charged with Cu2O (0.1 mmol,
14 mg), (i-Pr)2EtN (1.2 mmol), alkyne (1.2 mmol), and
HFIP (3.0 mL). The mixture was stirred for 30 min at
ambient conditions and then warmed up to 85°C. Oxirane
(1.0 mmol) was then injected to the reaction vessel. The
reaction mixture was then stirred for an additional 30 min
at 85°C, followed by addition of a solution of malonitrile
(1.0 mmol, 66 mg) in HFIP (1.0 mL). After consuming
the starting material (TLC monitoring, 14 h), the resulting
slurry was quenched with saturated aqueous NH4Cl
(5 mL) and extracted with EtOAc (3 × 10 mL). The
organic layers were dried over MgSO4, filtered, and
concentrated in vacuo. The residue was subjected to flash
chromatography (silica gel, hexane:EtOAc) to give the
pure targeted product 4.
6-Amino-4-benzylidene-2-methyl-3,4-dihydro-2H-pyran-5-
carbonitrile (4a, C14H14N2O).
The crude product was
purified
by
column
chromatography (SiO2;
hexane/EtOAc 3/1, Rf: 0.52) affording 0.19 g (85%) of
4a. Colorless oil. IR (KBr): V = 3441, 3427, 3074, 2934,
1
2236, 1615, 1440, 1120. H NMR (500.1 MHz, CDCl3):
δH = 1.23 (3H, d, 3J = 5.9 Hz, Me), 2.31 (1H, dd,
3
2
2J = 11.4, J = 8.8 Hz, CH), 2.49 (1H, dd, J = 11.4,
3J = 5.1 Hz, CH), 4.01–4.14 (1H, m, CH), 6.44 (1H, t,
4J = 2.0 Hz, CH), 7.01 (2H, br s, NH2), 7.29 (1H, t,
3J = 6.5 Hz, CH), 7.42 (2H, t, J = 6.5 Hz, 2CH), 7.65
3
(2H, d, 3J = 6.6 Hz, 2CH). 13C NMR (125.7 MHz,
CDCl3): δC = 19.8 (Me), 46.8 (CH2), 76.5 (C), 79.6
(CH), 114.2 (CN), 125.1 (CH), 126.8 (CH), 128.2 (2CH),
130.0 (2CH), 137.6 (C), 143.4 (C), 184.1 (C). EI-MS
(70 eV): m/z (%) = 226 (M+, 2), 210 (15), 136 (34), 121
(56), 77 (100). Anal. Calcd (%) for (226.28): C, 74.31;
H, 6.24; N, 12.38. Found: C, 74.66; H, 6.45; N, 12.61.
6-Amino-4-benzylidene-2-propyl-3,4-dihydro-2H-pyran-5-
carbonitrile (4b, C16H18N2O).
The crude product was
purified
by
column
chromatography (SiO2;
hexane/EtOAc 4/1, Rf: 0.34) affording 0.20 g (80%) 4b.
Colorless oil. IR (KBr): V = 3422, 3411, 3043, 2966,
1
2273, 1611, 1376, 1052. H NMR (500.1 MHz, CDCl3):
3
δH = 0.92 (3H, t, J = 6.2 Hz, Me), 1.36–1.57 (4H, m,
2
3
2CH2), 2.24 (1H, dd, J = 12.0, J = 4.9 Hz, CH), 2.47
2
3
(1H, dd, J = 12.0, J = 10.1 Hz, CH), 3.96–4.08 (1H, m,
CH), 6.48 (1H, t, J = 1.8 Hz, CH), 7.03 (2H, br s, NH2),
4
3
3
7.28 (1H, t, J = 6.6 Hz, CH), 7.41 (2H, t, J = 6.6 Hz,
2CH), 7.63 (2H, d, 3J = 6.6 Hz, 2CH). 13C NMR
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Copper Salt Catalyzed Synthesis of Functionalized 2H-Pyranes
4
(125.7 MHz, CDCl3): 13.1 (Me), 23.4 (CH2), 40.14 (CH2),
43.8 (CH2), 76.1 (CH), 79.5 (C), 114.1 (CN), 126.3 (CH),
128.1 (CH), 129.5 (2CH), 130.8 (2CH), 136.1 (C), 144.8
(C), 182.2 (C). EI-MS (70 eV): m/z (%) = 254 (M+, 7),
211 (12), 164 (40), 121 (67), 91 (38), 77 (100). Anal.
Calcd (%) for (254.33): C, 75.56; H, 7.13; N, 11.01.
Found: C, 75.88; H, 7.45; N, 11.14.
6-Amino-4-benzylidene-2-methyl-2-propyl-3,4-dihydro-2H-
pyran-5-carbonitrile (4c, C17H20N2O). The crude product
2J = 10.9 Hz, J = 1.9 Hz, CH), 3.71 (3H, s, OCH3),
4
6.70 (1H, t, J = 1.9 Hz, CH), 6.94 (2H, br s, NH2), 7.35
3
3
(1H, t, J = 6.8 Hz, CH), 7.44 (2H, t, J = 6.8 Hz, 2CH),
7.67 (2H, d, J = 6.7 Hz, 2CH). 13C NMR (125.7 MHz,
3
CDCl3): 23.5 (CH3), 44.1 (CH2), 57.2 (OCH3), 79.5 (C),
84.1 (C), 114.1 (CN), 126.1 (CH), 127.1 (CH), 128.8
(2CH), 130.4 (2CH), 136.5 (C), 143.2 (C), 174.5 (C),
183.1 (C). EI-MS (70 eV): m/z (%) = 284 (M+, 4), 269
(14), 210 (33), 121 (76), 91 (44), 77 (100) 54 (38). Anal.
Calcd (%) for (284.32): C, 67.59; H, 5.67; N, 9.85.
Found: C, 67.93; H, 5.96; N, 9.94.
6-Amino-4-benzylidene-5-cyano-3,4-dihydro-2H-pyran-2-yl-
methyl methacrylate (4f, C18H18N2O3). The crude product
was purified by column chromatography (SiO2;
hexane/EtOAc 4/1, Rf: 0.49) affording 0.19 g (71%) 4c.
Yellow oil. IR (KBr): V = 3420, 3411, 2936, 2182, 1609,
1
1448, 1222. H NMR (500.1 MHz, CDCl3): δH = 0.95
3
was purified by column chromatography (SiO2;
hexane/EtOAc 4/1, Rf: 0.30) affording 0.25 g (81%) 4f.
Yellow oil. IR (KBr): V = 3408, 3385, 2934, 2181, 1713,
(3H, t, J = 6.6 Hz, Me), 1.30–1.48 (7H, m, 2CH2, Me),
2
3
2.26 (1H, dd, J = 11.7, J = 9.2 Hz, CH), 2.45 (1H, dd,
2J = 11.7, J = 5.1 Hz, CH), 6.40 (1H, t, J = 1.8 Hz,
CH), 6.98 (2H, br s, NH2), 7.31 (1H, t, J = 6.9 Hz, CH),
3
4
3
1
1415, 1167. H NMR (500.1 MHz, CDCl3): δH = 2.17
3
3
3
2
7.45 (2H, t, J = 6.7 Hz, 2CH), 7.66 (2H, d, J = 6.7 Hz,
2CH). 13C NMR (125.7 MHz, CDCl3): 13.93 (Me), 19.7
(CH2), 27.2 (CH3), 45.7 (CH2), 49.1 (CH2), 78.2 (C),
89.7 (C), 114.3 (CN), 125.3 (CH), 128.2 (CH), 130.0
(2CH), 132.6 (2CH), 136.8 (C), 145.02 (C), 183.6 (C).
EI-MS (70 eV): m/z (%) = 268 (M+, 4), 225 (11), 134
(38), 135 (68), 77 (100). Anal. Calcd (%) for (268.36): C,
76.09; H, 7.51; N, 10.44. Found: C, 76.36; H, 7.83; N,
(3H, t, J = 1.7 Hz, CH3), 2.39 (1H, d, J = 11.1 Hz,
3J = 9.5 Hz, CH), 2.62 (1H, d, J = 11.1 Hz, J = 4.9 Hz,
2
3
CH), 4.35–4.46 (1H, m, CH), 4.59–4.76 (2H, m, 2CH),
4
2
6.40 (1H, t, J = 1.7 Hz, CH), 6.52 (1H, d, J = 4.5 Hz,
CH), 6.68 (1H, d, 2J = 4.5 Hz, CH), 6.89 (2H, br s,
NH2), 7.38 (1H, t, 3J = 6.7 Hz, CH), 7.42 (2H, t,
2J = 6.6 Hz, 2CH), 7.68 (2H, d, J = 6.7 Hz, 2CH). 13C
2
NMR (125.7 MHz, CDCl3): 18.6 (CH3), 38.3 (CH2),
73.3 (CH2), 79.2 (C), 86.1 (CH), 114.3 (CN), 125.9
(CH), 126.9 (CH2), 126.5 (CH), 129.2 (2CH), 131.5
(2CH), 136.2 (C), 138.0 (C), 143.1 (C), 169.2 (C), 182.8
(C). EI-MS (70 eV): m/z (%) = 310 (M+, 8), 269 (14),
212 (34), 121 (69), 91 (45), 77 (100). Anal. Calcd (%)
for (310.35): C, 69.66; H, 5.85; N, 9.03. Found: C,
10.54.
6-Amino-4-benzylidene-2-(phenoxymethyl)-3,4-dihydro-2H-
pyran-5-carbonitrile (4d, C20H18N2O2). The crude product
was purified by column chromatography (SiO2;
hexane/EtOAc 4/1, Rf: 0.31) affording 0.27 g (84%) 4d.
Pale yellow oil. IR (KBr): V = 3384, 3362, 2949, 2172,
1617, 1466, 1046. 1H NMR (500.1 MHz, CDCl3):
69.87; H, 6.07; N, 9.24.
6-Amino-4-benzylidene-2-(tert-butyl)-3,4-dihydro-2H-pyran-
5-carbonitrile (4g, C17H20N2O).
2
3
δH = 2.22 (1H, dd, J = 10.5, J = 8.9 Hz, CH), 2.45
2
3
The crude product was
(1H, dd, J = 10.5, J = 5.0 Hz, CH), 3.93–4.12 (2H, m,
2CH), 4.56–4.67 (1H, m, CH), 6.51 (1H, t, J = 1.9 Hz,
4
purified by column chromatography (SiO2; hexane/EtOAc
4/1, Rf: 0.49) affording 0.16 g (60%) 4g. Yellow oil. IR
(KBr): V = 3415, 3398, 2975, 2186, 1610, 1427, 1118. 1H
NMR (500.1 MHz, CDCl3): δH = 0.92 (9H, s, 3CH3),
2.42–2.60 (2H, m, 2CH), 3.78–3.89 (1H, m, CH), 6.56
(1H, t, 4J = 1.7 Hz, CH), 6.89 (2H, br s, NH2), 7.35 (1H, t,
CH), 6.85 (2H, br s, NH2), 6.90–7.05 (3H, m, 3CH), 7.29
3
3
(2H, t, J = 6.3 Hz, 2CH), 7.35 (1H, t, J = 6.4 Hz, CH),
3
3
7.43 (2H, t, J = 6.4 Hz, 2CH), 7.65 (2H, d, J = 6.3 Hz,
2CH). 13C NMR (125.7 MHz, CDCl3): 40.1 (CH2), 76.0
(CH2), 79.2 (C), 85.2 (CH), 114.1 (CN), 114.9 (2CH),
121.3 (CH), 125.2 (CH), 128.3 (CH), 129.2 (2CH), 130.2
(2CH), 132.73 (2CH), 137.2 (C), 144.1 (C), 159.2 (C),
184.2 (C). EI-MS (70 eV): m/z (%) = 318 (M+, 6), 211
(14), 217 (17), 121 (82), 107 (68), 77 (100), 54 (46).
Anal. Calcd (%) for (318.38): C, 75.45; H, 5.70; N, 8.80.
3J = 6.7 Hz, CH), 7.46 (2H, t, J = 6.8 Hz, 2CH), 7.62
3
(2H, d, 3J = 6.7 Hz, 2CH). 13C NMR (125.7 MHz,
CDCl3): 27.3 (3CH3), 36.9 (CH2), 38.1 (C), 78.1 (C), 84.9
(CH), 114.5 (CN), 126.7 (CH), 127.6 (CH), 129.9 (2CH),
131.2 (2CH), 136.1 (C), 145.2 (C), 181.9 (C). EI-MS
(70 eV): m/z (%) = 268 (M+, 4), 211 (17), 196 (34), 121
(67), 77 (100), 57 (89). Anal. Calcd (%) for (268.36):
C, 76.09; H, 7.51; N, 10.44. Found: C, 76.31; H, 67.83;
Found: C, 75.71; H, 75.98; N, 8.93.
Methyl-6-amino-4-benzylidene-5-cyano-2-methyl-3,4-
dihydro-2H-pyran-2-carboxylate (4e, C16H16N2O3).
The
crude product was purified by column chromatography
(SiO2; hexane/EtOAc 6/1, Rf: 0.30) affording 0.20 g
(69%) 4e. Yellow oil. IR (KBr): V = 3432, 3421, 3006,
2968, 2244, 1731, 1611, 1415, 1016. 1H NMR
(500.1 MHz, CDCl3): δH = 1.53 (3H, s, CH3), 2.70 (1H,
dd, 2J = 10.9 Hz, 4J = 1.9 Hz, CH), 2.96 (1H, dd,
N, 10.62.
2-Amino-4-benzylidene-4a,5,6,7,8,8a-hexahydro-4H-
chromene-3-carbonitrile (4h, C17H18N2O).
The crude
product was purified by column chromatography (SiO2;
hexane/EtOAc 3/1, Rf: 0.44) affording 0.25 g (95%) 4h.
Yellow oil. IR (KBr): V = 3433, 3346, 2896, 2181, 1622,
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

A. Varmazyar, S. Sedaghat, A. N. Goli-Kand, M. Khalaj, and S. Arab-Salmanabadi
Vol 000
1
1460, 1115. H NMR (500.1 MHz, CDCl3): δH = 1.31–
1.97 (8H, m, 4CH2), 2.62–2.74 (1H, m, CH), 3.48–3.60
solid, mp: 76–78°C. IR (KBr): V = 3412, 3400, 2948,
2189, 1613, 1382, 1022. H NMR (500.1 MHz, CDCl3):
1
4
3
3
(1H, m, CH), 6.72 (1H, d, J = 1.9 Hz, CH), 7.04 (2H, br
δH = 3.81 (1H, dd, J = 10.0 Hz, J = 7.1 Hz, CH), 4.40
s, NH2), 7.33 (1H, t, 3J = 6.8 Hz, CH), 7.42 (2H, t,
2
3
(1H, dd, J = 12.0 Hz, J = 10.0 Hz, CH), 4.69 (1H, dd,
3J = 6.8 Hz, 2CH), 7.65 (2H, d, J = 6.8 Hz, 2CH). 13C
3
2J = 12.0 Hz, J = 7.1 Hz, CH), 6.59 (1H, t, J = 1.8 Hz,
CH), 6.89 (2H, br s, NH2), 7.32–7.50 (8H, m, 8CH), 7.65
(2H, d, 3J = 6.5 Hz, 2CH). 13C NMR (125.7 MHz,
CDCl3): 47.1 (CH), 71.3 (CH2), 78.2 (C), 114.3 (CN),
125.1 (CH), 126.1 (CH), 127.4 (CH), 127.9 (2CH), 129.8
(2CH), 130.7 (2CH), 132.5 (2CH), 135.1 (C), 140.1 (C),
142.7 (C), 181.9 (C). EI-MS (70 eV): m/z (%) = 288 (M+,
3), 211 (24), 196 (36), 171 (50), 121 (74), 77 (100), 54
(36). Anal. Calcd (%) for (288.35): C, 79.14; H, 5.59; N,
3
3
NMR (125.7 MHz, CDCl3): 26.7 (CH2), 28.1 (CH2),
32.6 (CH2), 35.4 (CH2), 47.6 (CH), 79.5 (C), 83.4 (CH),
114.1 (CN), 125.9 (CH), 126.4 (CH), 128.9 (2CH), 131.2
(2CH), 136.1 (C), 144.3 (C), 182.7 (C). EI-MS (70 eV):
m/z (%) = 266 (M+, 7), 210 (14), 184 (35), 96 (80), 91
(44), 77 (100). Anal. Calcd (%) for (266.34): C, 76.66;
H, 6.81; N, 10.52. Found: C, 76.95; H, 7.04; N, 10.73.
2-Amino-4-benzylidene-4,4a,5,6,7,8,9,9a-
octahydrocyclohepta[b]pyran-3-carbonitrile
(4i,
9.72. Found: C, 79.42; H, 5.85; N, 9.94.
6-Amino-4-benzylidene-2,3-diphenyl-3,4-dihydro-2H-pyran-
C18H20N2O). The crude product was purified by column
chromatography (SiO2; hexane/EtOAc 4/1, Rf: 0.21)
affording 0.13 g (47%) 4i. Pale yellow solid, mp: 57–
59°C. IR (KBr): V = 3419, 3403, 2930, 2216, 1611,
5-carbonitrile (4l, C25H20N2O).
The crude product was
purified
by
column
chromatography (SiO2;
hexane/EtOAc 2/1, Rf: 0.44) affording 0.34 g (94%) 4l.
Yellow solid, mp: 127–129°C. IR (KBr): V = 3376,
3348, 2962, 2235, 1643, 1432, 1176, 1007. 1H NMR
1
1445, 1029. H NMR (500.1 MHz, CDCl3): δH = 1.31–
1.97 (10H, m, 5CH2), 2.45–2.56 (1H, m, CH), 3.37–3.48
4
3
(1H, m, CH), 6.68 (1H, d, J = 1.8 Hz, CH), 7.01 (2H, br
(500.1 MHz, CDCl3): δH = 4.49 (1H, d, J = 9.1 Hz,
s, NH2), 7.32 (1H, t, 3J = 6.8 Hz, CH), 7.40 (2H, t,
CH), 5.23 (1H, d, 3J = 9.1 Hz, CH), 6.55 (1H, d,
3J = 1.8 Hz, CH), 6.88 (2H, br s, NH2), 7.21–7.49 (13H,
3J = 6.8 Hz, 2CH), 7.51 (2H, d, J = 6.8 Hz, 2CH). 13C
3
3
m, 13CH), 7.63 (2H, d, J = 6.8 Hz, 2CH). 13C NMR
NMR (125.7 MHz, CDCl3): 26.7 (CH2), 27.5 (CH2),
29.2 (CH2), 31.4 (CH2), 35.2 (CH2), 37.1 (CH), 71.1
(CH), 79.4 (C), 114.2 (CN), 125.2 (CH), 127.1 (CH),
129.4 (2CH), 130.8 (2CH), 136.5 (C), 143.7 (C), 181.6
(C). EI-MS (70 eV): m/z (%) = 280 (M+, 12), 210 (15),
195 (29), 170 (44), 81 (76), 91 (43), 77 (100). Anal.
Calcd (%) for (280.37): C, 77.11; H, 7.19; N, 9.99.
Found: C, 77.32; H, 7.38; N, 10.16.
6-Amino-4-benzylidene-2-(isopropoxymethyl)-3,4-dihydro-
2H-pyran-5-carbonitrile (4j, C17H20N2O2).
product was purified by column chromatography (SiO2;
hexane/EtOAc 4/1, Rf: 0.53) affording 0.22 g (78%) 4j.
Colorless solid, mp: 82–84°C. IR (KBr): V = 3362, 3339,
(125.7 MHz, CDCl3): 49.1 (CH), 78.1 (C), 83.9 (CH),
114.0 (CN), 126.1 (CH), 126.1 (CH), 127.0 (CH), 127.8
(2CH), 128.2 (2CH), 128.7 (CH), 129.0 (2CH), 129.4
(2CH), 130.1 (2CH), 132.6 (2CH), 136.1 (C), 139.1 (C),
142.5 (C), 144.1 (C), 183.2 (C). EI-MS (70 eV): m/z
(%) = 364 (M+, 5), 287 (14), 210 (34), 185 (41), 170
(43), 121 (83), 77 (100). Anal. Calcd (%) for (364.45): C,
82.39; H, 5.53; N, 7.69. Found: C, 82.64; H, 5.86; N, 7.81.
6-Amino-4-benzylidene-2-(4-nitrophenyl)-3,4-dihydro-2H-
pyran-5-carbonitrile (4m, C19H15N3O3). The crude product
The crude
was purified by column chromatography (SiO2;
hexane/EtOAc 1/1, Rf: 0.58) affording 0.19 g (58%) 4m.
Yellow solid, mp: 153–155°C. IR (KBr): V = 3447,
3411, 2963, 2191, 1605, 1594, 1368, 1221, 1080. 1H
NMR (500.1 MHz, CDCl3): δH = 2.650–2.85 (2H, m,
1
3001, 2206, 1603, 1428, 1123. H NMR (500.1 MHz,
3
CDCl3): δH = 1.23 (6H, d, J = 6.1 Hz, 2CH3), 2.37 (1H,
dd, 2J = 11.2 Hz, 3J = 9.5 Hz, CH), 2.62 (1H, dd,
2J = 11.2 Hz, 3J = 5.1 Hz, CH), 4.11–4.66 (4H, m,
4
2CH), 4.78–4.89 (21H, m, CH), 6.62 (1H, t, J = 1.8 Hz,
4
4CH), 6.47 (1H, J = 1.8 Hz, CH), 6.89 (2H, br s, NH2),
CH), 6.81 (2H, br s, NH2), 7.31–7.43 (3H, m, 3CH), 7.61
3
3
3
3
7.35 (1H, t, J = 6.5 Hz, CH), 7.44 (2H, t, J = 6.6 Hz,
2CH), 7.64 (2H, d, 3J = 6.6 Hz, 2CH). 13C NMR
(125.7 MHz, CDCl3): 24.7 (2CH3), 39.1 (CH2), 69.1
(CH2), 74.6 (CH), 79.1 (C), 86.1 (CH), 115.1 (CN),
126.1 (CH), 127.1 (CH), 129.3 (2CH), 130.8 (2CH),
137.1 (C), 143.5 (C), 181.9 (C). EI-MS (70 eV): m/z
(%) = 284 (M+, 5), 211 (15), 196 (41), 121 (78), 77
(100), 73 (64). Anal. Calcd (%) for (284.36): C, 71.81;
(2H, d, J = 6.7 Hz, 2CH), 7.70 (2H, d, J = 6.9 Hz,
2CH), 8.21 (2H, d, 3J = 6.9 Hz, 2CH). 13C NMR
(125.7 MHz, CDCl3): 45.1 (CH2), 79.1 (C), 89.2 (CH),
114.5 (CN), 126.0 (CH), 126.7 (2CH), 127.1 (CH), 128.8
(2CH), 129.2 (2CH), 129.9 (2CH), 136.3 (C), 140.5 (C),
146.1 (C), 147.3 (C), 183.7 (C). EI-MS (70 eV): m/z
(%) = 333 (M+, 11), 211 (18), 196 (25), 171 (34), 121
(78), 77 (100). Anal. Calcd (%) for (333.35): C, 68.46;
H, 7.09; N, 9.85. Found: C, 72.06; H, 7.38; N, 9.98.
6-Amino-4-benzylidene-3-phenyl-3,4-dihydro-2H-pyran-5-
carbonitrile (4k, C19H16N2O).
purified by column chromatography (SiO2; hexane/EtOAc
3/1, Rf: 0.27) affording 0.26 g (90%) 4k. Pale yellow
H, 4.54; N, 12.61. Found: C, 68.69; H, 4.82; N, 12.80.
6-Amino-4-(2-methoxyethylidene)-3-phenyl-3,4-dihydro-2H-
pyran-5-carbonitrile (4n, C15H16N2O2). The crude product
was purified by column chromatography (SiO2;
hexane/EtOAc 4/1, Rf: 0.39) affording 0.16 g (63%) 4n.
The crude product was
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

Month 2019
Copper Salt Catalyzed Synthesis of Functionalized 2H-Pyranes
[4] Pappo, R.; Collins, P. W. Tetrahedron Lett 1972, 13, 2627.
[5] Bruhn, M.; Brown, C. H.; Collins, P. W.; Palmer, J. R.; Dajani,
E. Z.; Pappo, R. Tetrahedron Lett 1976, 17, 235.
[6] Schwartz, J.; Carr, D. B.; Hansen, R. T.; Dayrit, F. M. J Org
Chem 1980, 45, 3053.
[7] Sinclair, J. A.; Molander, G. A.; Brown, H. C. J Am Chem Soc
1977, 99, 954.
[8] Kim, S.; Lee, J. M. Tetrahedron Lett 1990, 31, 7627.
[9] Hooz, J.; Layton, R. B. J Am Chem Soc 1971, 93, 7320.
[10] Zhang, X.; Zhang, W. Z.; Shi, L. L.; Zhu, C.; Jiang, J. L.; Lu,
X. Tetrahedron 2012, 68, 9085.
Colorless solid, mp: 78–80°C. IR (KBr): V = 3413, 3400,
2924, 2211, 1611, 1459, 1381, 1250, 1103. 1H NMR
(500.1 MHz, CDCl3): δH = 3.48 (3H, s, OMe), 4.03–4.25
(3H, m, 3CH), 4.45–4.61 (2H, m, 2CH), 5.81 (1H, t,
3J = 6.7 Hz, CH), 6.87 (2H, br s, NH2), 7.310 (1H, t,
3J = 6.7 Hz, CH), 7.35–7.42 (4H, m, 4CH). 13C NMR
(125.7 MHz, CDCl3): 40.3 (CH), 57.4 (OMe), 69.1
(CH2), 76.4 (CH2), 79.1 (C), 114.2 (CN), 126.5 (CH),
128.5 (2CH), 129.1 (CH), 130.5 (2CH), 141.3 (C), 144.7
(C), 182.5 (C). EI-MS (70 eV): m/z (%) = 256 (M+, 2),
179 (15), 164 (28), 139 (40), 121 (79), 77 (100). Anal.
Calcd (%) for (256.21): C, 70.29; H, 6.29; N, 10.93.
[11] Ranjan, A.; Mandal, A.; Yerande, S. G.; Dethe, D. H. J Name
2012, 16, 1.
[12] Guo, M.; Li, D.; Zhang, Z. J Org Chem 2003, 68, 10172.
[13] For selected examples of coinage metals-catalyzed synthesis of
heterocycles, see; (a) Patil, N. T.; Yamamoto, Y. Chem Rev 2008, 14,
3395; (b) Echavarren, A. M.; Jiaoc, N.; Gevorgyand, V. Chem Soc Rev
2016, 45, 4445; (c) Carabineiro, S. A. C. Molecules 2016, 21, 746.
[14] Meldal, M.; Tornøe, C. W. Chem Rev 2008, 108, 2952.
[15] Hein, J. E.; Tripp, J. C.; Krasnova, L. B.; Sharpless, K. B.;
Fokin, V. V. Angew Chem Int Ed 2009, 48, 1.
[16] Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew Chem Int Ed
2001, 40, 2004.
[17] Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J Am Chem Soc 2005,
127, 210.
Found: C, 70.48; H, 6.46; N, 11.16.
6-Amino-3-phenyl-4-((trimethylsilyl)methylene)-3,4-dihydro-
2H-pyran-5-carbonitrile (4o, C16H20N2OSi).
The crude
product was purified by column chromatography (SiO2;
hexane/EtOAc 5/1, Rf: 0.28) affording 0.17 g (60%) 4o.
Colorless solid, mp: 60–62°C. IR (KBr): V = 3345, 3303,
3066, 2924, 2260, 1613, 1539, 1447, 1331, 1083. 1H
NMR (500.1 MHz, CDCl3): δH = 0.11 (9H, s, 3 Me),
3.90–3.98 (1H, m, CH), 4.41 (1H, dd, 2J = 12.0 Hz,
3J = 5.9 Hz, CH), 4.63 (1H, dd, 2J = 12.0 Hz,
[18] Knöpfel, T. F.; Carreira, E. M. J Am Chem Soc 2003, 125,
6054.
[19] Fischer, C.; Carreira, E. M. Org Lett 2001, 3, 4319.
[20] Frantz, D. E.; Fassler, R.; Carreira, E. M. J Am Chem Soc
2000, 122, 1806.
4
3J = 9.1 Hz, CH), 5.95 (1H, d, J = 1.7 Hz, CH), 6.87
3
(2H, br s, NH2), 7.30 (1H, t, J = 6.4 Hz, CH), 7.35–7.44
(4H, m, 4CH). 13C NMR (125.7 MHz, CDCl3): 1.9
(3CH3), 49.5 (CH), 74.7 (C), 76.19 (CH2), 114.6 (CN),
125.1 (CH), 127.9 (2CH), 128.9 (2CH), 129.8 (CH),
142.7 (C), 160.1 (C), 183.7 (C). EI-MS (70 eV): m/z
(%) = 284 (M+, 7), 207 (15), 192 (27), 167 (41), 121
(73), 77 (100). Anal. Calcd (%) for (284.43): C, 67.56;
H, 7.09; N, 9.85. Found: C, 67.82; H, 7.33; N, 10.04.
[21] Lu, Y.; Johnstone, T. C.; Arndtsen, B. A. J Am Chem Soc
2009, 131, 11284.
[22] Lee, K. Y.; Park, D. Y.; Kim, T. H.; Kim, J. N. Bull Korean
Chem Soc 2005, 26, 1617.
[23] Dávila, W.; Torres, W.; Prieto, J. A. Tetrahedron 2007, 63,
8218.
[24] Hanazawa, T.; Sasaki, K.; Takayama, Y.; Sato, F. J Org Chem
2003, 68, 4980.
[25] For the regioselectivity in ring opening of oxiranes and related
three-membered heterocycles, see; (a) Zhou, C.; Xu, J. X. Prog Chem
2011, 23, 174; (b) Yub, H.; Caob, S.; Zhangc, L.; Liuc, G.; Xu, J. Synthe-
sis 2009, 2009, 2205; (c) Gálvez, J. A.; de Villegas, M. D. D.; Badorreya,
R.; López-Ram-de-Víua, P. Org Biomol Chem 2011, 9, 8155; (d) Li, X.;
Xu, J. Tetrahedron 2011, 67, 1681; (e) Cossy, J.; Bellosta, V.; Hamoir,
C.; Desmurs, J. R. Tetrahedron 2002, 43, 7083; (f) Hu, L.; Zhu, H.;
Du, D.; Xu, J. J Org Chem 2007, 72, 4543.
REFERENCES AND NOTES
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[2] Yoo, W. J.; Lia, C. J. Adv Synth Catal 2008, 350, 1503.
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Journal of Heterocyclic Chemistry
DOI 10.1002/jhet