Intramolecular iminium ene reaction with Cu(I) catalysts: Facile formation of 4-amino-3-methylenechromans from O-propargyl salicylaldehydes and dialkylamines

Article abstract of DOI:10.1016/j.tet.2011.01.007

Reaction of O-propargyl salicylaldehyde and related compounds with dialkylamines in the presence of copper(I) iodide gave 4-(alkylamino)-3- methylenechroman derivatives in good yields through the loss of one alkyl group of the dialkylamine. The reaction a

Full text of DOI:10.1016/j.tet.2011.01.007

Tetrahedron 67 (2011) 1617e1622
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Intramolecular iminium ene reaction with Cu(I) catalysts: facile formation
of 4-amino-3-methylenechromans from O-propargyl salicylaldehydes and
dialkylamines
*
*
Noriyoshi Arai , Takeshi Ohkuma
Division of Chemical Process Engineering, Faculty of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Reaction of O-propargyl salicylaldehyde and related compounds with dialkylamines in the presence of
copper(I) iodide gave 4-(alkylamino)-3-methylenechroman derivatives in good yields through the loss of
one alkyl group of the dialkylamine. The reaction also worked well by employing 2-amino benzaldehyde
derivatives to afford 4-(alkylamino)-3-methylene-1,2,3,4-tetrahydroquinolines. A deuterium-labeling
Received 2 December 2010
Accepted 5 January 2011
Available online 12 January 2011
experiment suggested that the a-hydrogen of the dialkylamine was transferred intramolecularly into the
Keywords:
Iminium
Aldehyde
Alkyne
Ene reaction
Cyclization
terminal methylene. This result indicated the reaction mechanism, which involved the formation of
iminium ion between the aldehyde and the dialkylamine followed by ene-type CeC bond formation with
inverse electron demand and hydrolysis.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
The ene reaction of imines (imino ene reaction) is one of the
important transformations for preparing a wide range of amine
derivatives, and much effort has been devoted to its investigation
so far.1e5 In most of the imino ene reactions, the imine moiety
behaves as an ‘enophile.’ That is, carbonecarbon bond formation
occurs with hydrogen transfer from the allylic position to the
nitrogen to give the homoallylic amine (Scheme 1, a), while in the
other case a carbonenitrogen bond is formed through hydrogen
transfer to the imino carbon affording the allylic amine (Scheme 1,
b).6 The type (a) is often regarded as involving a stepwise Mannich-
type reaction, although the intrinsic imino ene reaction should
occur via a concerted pathway.7e10
To the best of our knowledge, the only example of the neutral
imino ene reaction in which the imine moiety reacts as an ‘ene’
(inverse electron demand reaction) is involved in a complex series of
transformations in the pyrolysis of methyl-deuterated cocaine at
600 ꢀC.11 An intramolecular ene reaction in which an enamine gen-
erated by tautomerizationofimine actsasanene has beenreported.12
Mayr and Ofial reported that isolated dialkylmethyleneammonium
hexachloroantimonate reacted with a series of alkynes to give an
Scheme 1. Typical ene-type reactions of imines.
ene-type adduct through an inverse electron demand reaction.13,14
The iminium salt can be prepared in situ from dialkylmethoxy-
methylamine (formaldehyde N,O-acetal) and SnCl4.15 Herein, we
would like to report our findings on the copper(I)-catalyzed intra-
molecular ene-type reaction with inverse electron demand between
alkynes and iminium salts (ene), which were generated in situ from
aldehydes to give the cyclized products in good yields. The reaction
proceeds via a completely mechanism from that in Mayr’s system.
2. Results and discussion
2.1. Reaction of O-propargyl salicylaldehyde with
dialkylamines
* Corresponding authors. Tel.: þ81 11 706 6600; fax: þ81 11 706 6598 (N.A.); tel.:
þ81 11 706 6599; fax: þ81 11 706 6598 (T.O.); e-mail addresses: n-arai@eng.ho-
kudai.ac.jp (N. Arai), ohkuma@eng.hokudai.ac.jp (T. Ohkuma).
We found that treatment of O-propargyl salicylaldehyde (1a)
with neat diethylamine in the presence of catalytic amounts of CuI
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.01.007

1618
N. Arai, T. Ohkuma / Tetrahedron 67 (2011) 1617e1622
(typically 10 mol %) at room temperature gave the product 2a in
moderate yield with a loss of one ethyl group of diethylamine
(Scheme 2).
employable, but gave a poor material balance (entry 6). Metal salts
that are known to exhibit high affinity to the alkynes18 turned out
to be completely ineffective in this reaction (entries 7e11).
Having fixed the metal salts, we investigated the effect of
ligands on the catalyst performance (Table 3).
Table 3
Screening of ligandsa
Entry
Ligand
Yield of 2a (%)b
Recovery of 1a (%)b
1
2
3
4
5
6
7
8
none
PPh3
PPh3
PBu3
PCy3
P(OPh)3
DPPE
DPPP
DPPB
DPPF
65
54
38
38
67
57
40
42
34
24
20
56
48
6
28
44
39
20
11
40
38
47
60
63
19
18
c
Scheme 2.
Although it has been reported the oximes derived from 1a were
transformed to the dihydrochroman-4-amine derivative via radical
cyclization,16 the radical cyclization process is not plausible in the
above reaction. Intramolecular cyclization of benzylic imine with
prenyl moiety via carbocation intermediates has also been repor-
ted,17 but the reaction shown in Scheme 2 proceeded in a quite
distinct manner. This unusual reaction prompted us to investigate it
in greater detail. The screening of solvents and the amounts of
amine are summarized in Table 1.
9
10
11
12
13
(ꢁ)-BINAP
TMEDA
2,20-bipyridine
a
All reactions were carried out with 1a (0.20 mmol), CuI (0.02 mmol), ligand
(0.02 mmol), and Et2NH (2.0 mmol) in DMF (0.6 mL) at room temperature under an
argon atmosphere for 2 h unless otherwise stated.
b
Estimated by 1H NMR integral.
c
Catalyst (20 mol %).
Table 1
Screening of solvents and the amounts of aminea
Addition of an equimolar amount of PPh3 to CuI was effective in
inhibiting the formation of undesired tarry materials to improve the
total material balance, though itslightlyslowed the reaction (entry 2).
Two molar amounts of PPh3 versus copper(I) resulted in a slowdown
of the reaction rate without improvement of the total recovery (entry
3). Employment of PBu3 instead of PPh3 did not have a desirable effect
on the reaction, but the reaction with PCy3 showed a better yield and
better material balance than that with PPh3 (entries 4 and 5). Phos-
phite ligand (entry 6), bidentate phosphine (entries 7e11) or amine
ligands (entries 12 and 13) gave disappointing results.
Entry
Solvent
Amine equiv
Yield of 2a (%)b
Recovery of 1a (%)b
1
2
3
4
5
6
7
8
9
None
CH2Cl2
CH2Cl2
CH2Cl2
THF
THF
Toluene
DMF
40
10
5
1.1
10
5
10
10
10
10
44
41
26
11
45
29
36
65
44
38
0
0
0
6
2
7
trace
6
30
16
DMSO
EtOH
10
Consequently, we set the standard reaction conditions to be
0.1 equiv CuI, 0.1 equiv PCy3, 10 equiv amine, in DMF at room
temperature, and then investigated the reaction by using several
secondary amines other than diethylamine (Table 4). We confirmed
a
All reactions were carried out with 1a (0.20 mmol), CuI (0.02 mmol), and Et2NH
(2.0 mmol) in 0.6 mL solvent at room temperature under an argon atmosphere for 2 h.
b
Estimated by 1H NMR integral.
The reactions were discontinued in 2 h to compare the yield of
2a and the recovery of 1a. Use of dichloromethane as a solvent had
little effect on the yield of 2a (entry 2). The yield of 2a decreased as
the amounts of amine were lowered (entries 2e4). Polar solvent
seemed to be suitable for this reaction (entries 2, 5, 7e10), and DMF
gave the best result (entry 8). The incomplete material balances
were due to the formation of unidentified brown tarry materials.
With these results in hand, we next turned our attention to the
choice of the catalyst (Table 2).
Table 4
Reactions with various aminesa
Several copper(I) salts showed some catalytic activity, although
they were no match for CuI (entries 1e5). Copper(II) was also
Entry
Amine
x
Time (h)
Product (R)
Yield (%)b
Table 2
1c
2c,d
3d
4
Et2NH
10
10
10
9
6
7
7
2a (Et)
3 (Allyl)
3 (Allyl)
4 (Bu)
5 (Ph(CH2)2)
ef
70
76
65
78
59
0
Screening of catalystsa
Allyl2NH
Allyl2NH
Bu2NH
[Ph(CH2)2]NH
PrNH2
Entry
Catalyst
Yield of 2a (%)b
Recovery of 1a (%)b
8
1
2
3
4
5
6
7
8
CuI
CuBr
CuCl
(CuOTf)2$C6H6
CuCN
65
39
22
42
24
26
0
0
0
0
0
6
13
38
22
73
15
98
88
99
5e
6
7
5
24
11
6.5
10
10
Et3N
eg
0
a
All reactions were carried out with 1a (0.20 mmol), CuI (0.02 mmol), PCy3
(0.02 mmol), and amine (2.0 mmol) in DMF (0.6 mL) at room temperature under an
argon atmosphere until the starting material had been consumed, unless otherwise
stated.
CuBr2
AgOAc
AgOCOCF3
Pd(OAc)2
PdCl2
b
9
10
11
Isolated yield.
Wet DMF (1% H2O (v/v)) was used.
c
100
100
d
PtCl2
Without PCy3.
Catalyst (25 mol %).
e
a
All reactions were carried out with 1a (0.20 mmol), CuI (0.02 mmol), and Et2NH
f
Formation of imine was surmised from the 1H NMR spectra of crude materials.
(2.0 mmol) in DMF (0.6 mL) at room temperature under an argon atmosphere for 2 h.
g
Recovery (86%) of 1a.
b
Estimated by 1H NMR integral.

N. Arai, T. Ohkuma / Tetrahedron 67 (2011) 1617e1622
1619
that dibutyl, diallyl, and di(2-phenylethyl)amine gave the corre-
sponding products 3e5 in comparable yield to diethylamine (en-
tries 2e5), whereas both propylamine (primary) and triethylamine
(tertiary) were not suitable for the reaction (entries 6 and 7). In
some cases, addition of a small amount of water turned out to be
effective in improving the yield (entries 2 and 3).
Scheme 3.
2.2. Substrates scope
completely deuterated. The other methylene hydrogen was not
deuterated at all. This result indicates that one of the methylene
hydrogens comes from the a-hydrogen of the secondary amine via
After establishing the suitable reaction conditions as described
above, we turned our attention to the applicability of the reaction to
various aldehydes with a propargyl moiety. The results are sum-
marized in Table 5.
an intramolecular transfer process.
We also confirmed that the aldehyde with a phenylpropynyl
group 6 did not give the cyclized product, resulting in incomplete
recovery of the starting material with the formation of unidentified
materials (Scheme 4). The drastic change of the substrate reactivity
by substitution at the alkyne terminal suggests that the formation
of copper acetylide is necessary for the cyclization reaction, though
the possibility of a simple steric effect cannot be ruled out. The
formation of copper acetylide under similar reaction conditions has
been described in the literature.20e23
Table 5
Reactions with various substratesa
Entry
Substrate
R
Z
Time (h)
Yield of 2 (%)b
1c
2
3
1a
1b
1c
1d
1e
1f
1g
1h
1a
1a
H
O
O
O
O
O
O
NBoc
NTs
O
6
8
3
7
6
70
74
81
74
60
65
72
68
79
67
3-MeO
5-CO2Me
5-Br
5-NO2
5-Ph
H
H
H
H
4
Scheme 4.
5d
6
6
7
8
11
11
11
32
As shown in Table 2, this cyclization reaction was not promoted
at all by Ag, Pd, or Pt, which are well known to activate alkynes by
9e
10f
-complexation.24,25 These results also indicate the formation of
O
p
a
acetylide rather than simple
cyclization.
p-complex activation for the
All reactions were carried out with 1 (0.20 mmol), CuI (0.02 mmol), PCy3
(0.02 mmol), and Et2NH (2.0 mmol) in DMF (0.6 mL) at room temperature under an
argon atmosphere until the starting material had been consumed, unless otherwise
stated.
Based on these experimental results and considerations, we
propose a plausible reaction mechanism as illustrated in Scheme 5.
Initially, copper(I) acetylide 7 is formed by mixing a terminal alkyne,
CuI, and a base.20e23 The acetylide is considered to be in equilibrium
with iminium ion 8, which is immediately converted to a cyclized
intermediate 9 through an iminiumealkyne ene-type reaction.
Then, hydrolysis of 9 by quenching or water contained in the solvent
gives the product 2a. Promotion of an ene reaction through metal
acetylide was reported in the Au catalytic system.26 Hydrogen
transfer from the position adjacent to the nitrogen of a propargylic
amine to the carbonecarbon triple bond is known to afford an allene
compound accompanied by concomitant elimination of the amine
moiety.27e30 Previous reports have shown that configuration of the
b
Isolated yield.
Wet DMF (1% H2O (v/v)) was used.
Without PCy3.
Catalyst (5 mol %).
c
d
e
f
Catalyst (1 mol %).
The substrates with a methoxy group (1b) or with a methoxy-
carbonyl group (1c) on the aromatic ring gave the corresponding
cyclized products in good yields (entries 2 and 3). This result shows
that the electronic features of the aromatic moiety had little effecton
the product yields, while the electron-donating substituent some-
what slowed the reaction. Other substituents on the aromatic ring,
such as bromo, nitro, and phenyl, were well-tolerated, and afforded
the corresponding products, 4-(alkylamino)-3-methylenechroman
derivatives 2def, in moderate to good yields (entries 4e6). The
reaction can also be applied to the O-(propargylamino)benzalde-
hyde derivatives (1g and 1h) to give 4-(alkylamino)-3-methylene-
1,2,3,4-tetrahydroquinolines that are structurally related to the
synthetic intermediate of martinelline, a pyrroloquinoline alkaloid
(entries 7 and 8).19 Concerning 1a, the amounts of CuIePCy3 can be
reduced to 1 mol % without decrease of the yield by prolonging the
reaction time (entries 9 and 10).
2.3. Mechanistic considerations
To obtain some insight into the reaction mechanism, we carried
out a deuterium-labeling experiment (Scheme 3). When the re-
action was carried out by using
amine, the methylene hydrogen of 5 close to the amino group was
a-deuterated bis(2-phenyethyl)
Scheme 5. Plausible reaction mechanism.

1620
N. Arai, T. Ohkuma / Tetrahedron 67 (2011) 1617e1622
non-functionalized alkenyl copper(I) species (corresponding to 9)
does not change at ambient temperature.31,32 This property is also
consistent with our labeling experiment (Scheme 3).
(C), 159.0 (C), 189.4 (CH). HRMS (ESIþ) m/z 237.0915 (MþHþ), calcd
for C16H13O2: 237.0916.
4.2.3. tert-Butyl N-(2-formylphenyl)-N-(2-propynyl)carbamate (1g).
Yellow powder. Mp 85.0e87.0 ꢀC (hexaneeethyl acetate). IR (KBr-
disk) 3260, 2981, 2865, 2117, 1701, 1691, 1600, 1460, 1379, 1371, 1291,
3. Conclusion
1161, 1148, 1014, 761 cmꢂ1. 1H NMR (400 MHz, CDCl3, 50 ꢀC)
d 1.37
We found that the treatment of O-propargyl salicylaldehyde and
related compounds with secondary amines in the presence of CuI
gave cyclized products, 3,4-dihydro-3-methylene-2H-chroman-4-
amines, in moderate to good yields accompanied by removal of one
alkyl group of the secondary amine. Addition of PCy3 to the reaction
system gave better results in some cases. A deuterium-labeling
experiment revealed that the methylene hydrogen close to the
(9H, br s, t-Bu), 2.23 (1H, t, J¼2.5 Hz, C^CH), 4.43 (2H, br s, CH2), 7.37
(1H, br d, J¼8.1 Hz, AreH), 7.41e7.45 (1H, m, AreH), 7.62 (1H, dt,
Jd¼1.4, Jt¼7.7 Hz, AreH), 7.92 (1H, dd, J¼7.7, 1.9 Hz, AreH), 10.14 (1H,
s, CHO). 13C NMR (100 MHz, CDCl3)
d 28.0 (CH3), 39.7 (CH2), 73.1 (CH),
78.5 (C), 81.9 (C), 127.9 (CH, probably overlapping), 128.4 (CH), 133.1
(C), 134.8 (CH), 143.5 (C), 153.8 (C), 190.2 (CH). HRMS (ESIþ) m/z
260.1286 (MþHþ), calcd for C15H18NO3: 260.1287.
amino group came from amine a-hydrogen. This reaction is con-
sidered to proceed through the intramolecular inverse electron
demand ene-type reaction, in which the in situ-formed iminium
moiety behaves as a hydrogen donor (ene).
4.2.4. N-(2-Formylphenyl)-N-(2-propynyl)-p-toluenesulfonamide
(1h). Colorless crystals. Mp 81.0e82.0 ꢀC (heptaneeethyl acetate). IR
(KBr-disk) 3280, 2892, 2124, 1690, 1596, 1484, 1451, 1350, 1167, 1092,
1065, 864, 822, 725, 665, 577 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d 2.20
(1H, t, J¼2.5 Hz, C^CH), 2.45 (3H, s, CH3), 4.48 (2H, br s, CH2),
6.92e6.95 (1H, m, AreH), 7.29 (2H, d, J¼8.0 Hz, AreH), 7.48e7.54 (4H,
m, AreH), 8.00e8.03 (1H, m, AreH), 10.39 (1H, s, CHO). 13C NMR
4. Experimental section
4.1. General
(100MHz,CDCl3)d21.6 (CH3), 41.7 (CH2),74.7(CH),76.8(C),128.0(CH),
128.4 (CH), 128.5 (CH), 129.2 (CH), 129.6 (CH), 134.2 (CH), 134.4 (C),
135.8 (C), 140.9 (C), 144.5 (C), 190.1 (CH). HRMS (ESIþ) m/z 314.0845
(MþHþ), calcd for C17H16NO3S: 314.0851. Anal. Found: C, 65.19%; H,
4.69%; N, 4.42%. Calcd for C17H15NO3S: C, 65.16%; H, 4.82%; N, 4.47%.
NMR spectra were obtained on JEOL JNM-ECX400P and ECS-400
spectrometers. Carbon multiplicity was assigned by a DEPT experi-
ment. IR spectra were recorded on a JASCO FT/IR-4100 spectropho-
tometer. Silica gel column chromatography was performed with
Kanto Chemical Co., Inc. Silica Gel 60 N (63e210
mm) or Fuji Silisia
4.3. Typical procedure for the Cu(I) catalyzed cyclization
FL60D. Preparative thin layer chromatography was carried out with
Wako Gel B-5F (Wako Pure Chemical Industries, Ltd.). Solvents and
reagents were used after appropriate purification, if necessary.33
Mass spectrometry and elemental analyses were carried out at the
Instrumental Analysis Division, Equipment Management Center,
Creative Research Institution, Hokkaido University.
To
a 30 mL two-necked flask was added CuI (3.8 mg,
0.020 mmol), PCy3 (6.1 mg, 0.022 mmol), 1 (0.200 mmol), and DMF
(0.6 mL). The mixture was stirred at room temperature under an
argon atmosphere, and Et2NH (0.21 mL, 2.0 mmol) was added. After
stirring for the indicated period, all volatile materials were re-
moved under reduced pressure. The residue was purified by silica
gel column chromatography (eluent, hexaneeethyl acetate; typi-
cally 30:1 gradually to 2:1).
4.2. Preparation of starting materials
Compounds 1a,34,35 1b,34 1d,34,35 1e,34 and 636 were prepared
according to the methods described in the literature. The other
related compounds, 1c and 1feh, were prepared by the same
method. The physical properties of the new compounds were as
follows.
4.3.1. 4-Ethylamino-3,4-dihydro-3-methylene-2H-1-benzopyran
(2a). Yellow oil (70%). IR (KBr, neat) 3320, 2966, 1607, 1583, 1487,
1241, 1216, 1038, 1007, 753 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d 1.13
(3H, t, J¼7 Hz, CH2CH3), 1.27 (1H, br s, NH), 2.65e2.69 (2H, br m,
CH2CH3), 4.08 (1H, br s, CHNHEt), 4.46 (1H, d, J¼11.8 Hz, OCH2), 4.78
(1H, dd, J¼11.8, 1.4 Hz, OCH2), 5.19 (1H, br s, ]CH2), 5.24 (1H, br s,
]CH2), 6.83 (1H, dd, J¼7.7, 0.9 Hz, AreH), 6.91 (1H, dt, Jd¼0.9 Hz,
Jt¼7.7 Hz, AreH), 7.16 (1H, dt, Jd¼1.8 Hz, Jt¼7.7 Hz, AreH), 7.22 (1H,
4.2.1. Methyl 3-formyl-4-(2-propynyloxy)benzoate (1c). Faintly yel-
low crystals. Mp 92.0e92.5 ꢀC (heptaneeethyl acetate). IR (KBr-
disk) 3229, 2952, 2880, 2128, 1708, 1682, 1610, 1496, 1266, 1014,
dd, J¼7.7,1.8 Hz, AreH). 13C NMR (100 MHz, CDCl3)
d 15.2 (CH3), 41.1
767 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
2.61 (1H, t, J¼2.2 Hz, C^CH),
(CH2), 57.9 (CH), 67.0 (CH2),114.0 (CH2),116.8 (CH),120.6 (CH),124.9
(C), 128.7 (CH), 129.6 (CH), 140.6 (C), 154.3 (C). HRMS (ESIþ) m/z
212.1045 (MþNaþ), calcd for C12H15NONa: 212.1046.
3.92 (3H, s, CH3), 4.91 (2H, d, J¼2.2 Hz, CH2), 7.19 (1H, d, J¼8.6 Hz,
AreH), 8.26 (1H, dd, J¼8.6, 2.2 Hz, AreH), 8.54 (1H, d, J¼2.2 Hz,
AreH), 10.47 (1H, s, CHO). 13C NMR (100 MHz, CDCl3)
d 52.2 (CH3),
56.5 (CH2), 76.9 (C), 77.1 (CH), 112.9 (CH), 123.7 (C), 124.9 (C), 130.6
(CH), 135.5 (CH), 136.8 (CH), 163.5 (C), 165.8 (C), 188.5 (CH). HRMS
(ESIþ) m/z 219.0653 (MþHþ), calcd for C12H11O4: 219.0657. Anal.
Found: C, 66.03%; H, 4.60%. Calcd for C12H10O4: C, 66.05%; H, 4.62%.
4.3.2. 4-Ethylamino-3,4-dihydro-8-methoxy-3-methylene-2H-1-
benzopyran (2b). Yellow oil (74%). IR (KBr, neat) 3317, 2965, 1585,
1486, 1264, 1213, 1091, 1010, 737 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
1.13 (3H, t, J¼7 Hz, CH2CH3), 1.34 (1H, br s, NH), 2.60e2.74 (2H, m,
CH2CH3), 3.86 (3H, s), 4.08 (1H, br s, CHNHEt), 4.58 (1H, d, J¼11.8 Hz,
OCH2), 4.82 (1H, dd, J¼11.8, 1.4 Hz, OCH2), 5.19 (1H, br s, ]CH2),
5.24 (1H, br s, ]CH2), 6.83 (1H, dd, J¼7.7, 0.9 Hz, AreH), 6.76e6.89
4.2.2. 5-Phenyl-2-(2-propynyloxy)benzaldehyde (1f). Pale yellow
oil. IR (KBr, neat) 3290, 3033, 2868, 2122, 1682, 1607, 1481, 1274,
1224, 1018, 762, 697 cmꢂ1. 1H NMR (400 MHz, CDCl3)
d
2.60 (1H, d,
(3H, m, AreH). 13C NMR (100 MHz, CDCl3)
d 15.2 (CH3), 41.1 (CH2),
J¼2.3 Hz, C^CH), 4.88 (2H, d, J¼2.3 Hz, CH2), 7.21 (1H, d, J¼8.7 Hz,
AreH), 7.34e7.37 (1H, m, AreH), 7.42e7.46 (2H, m, AreH),
7.56e7.59 (2H, m, AreH), 7.81 (1H, dd, J¼8.7, 2.7 Hz, AreH), 8.11
(1H, d, J¼2.7 Hz, AreH), 10.53 (1H, s, CHO). 13C NMR (100 MHz,
55.8 (CH3), 57.7 (CH), 67.3 (CH2), 110.2 (CH), 114.2 (CH2), 120.3 (CH),
121.2 (CH), 125.5 (C), 140.2 (C), 143.7 (C), 148.2 (C). HRMS (ESIþ) m/z
220.1335 (MþHþ), calcd for C13H18NO2: 220.1332.
CDCl3)
d
56.4 (CH2), 76.6 (CH), 77.6 (C), 113.6 (CH), 125.4 (C), 126.65
4.3.3. Methyl 4-ethylamino-3,4-dihydro-3-methylene-2H-1-benzo-
(CH), 126.71 (CH), 127.4 (CH), 128.8 (CH), 134.0 (CH), 134.7 (C), 139.2
pyran-6-carboxylate (2c). Orange-yellow oil (81%). IR (KBr, neat)

N. Arai, T. Ohkuma / Tetrahedron 67 (2011) 1617e1622
1621
3323, 2967,1716,1613,1580,1497,1438,1240,1193,1173,1119,1002,
917, 769 cmꢂ1 1H NMR (400 MHz, CDCl3)37
1H NMR (400 MHz, CDCl3)37
d
0.89 (3H, t, J¼7 Hz, CH2CH3),
.
d
1.14 (3H, t, J¼7 Hz,
2.22e2.39 (5H, m including s at 2.34, CH2CH3 and CH3C6H4), 3.71
(1H, br s, CHNHEt), 4.30 (1H, d, J¼15 Hz, OCH2), 4.43 (1H, d, J¼15 Hz,
OCH2), 4.89 (1H, br s, ]CH2), 4.99 (1H, br s, ]CH2), 7.12e7.30 (5H,
m, AreH), 7.42 (2H, d, J¼8.1 Hz, AreH), 7.85 (1H, d, J¼8.1 Hz, AreH).
CH2CH3), 2.61e2.74 (2H, br m, CH2CH3), 3.88 (3H, s), 4.11 (1H, br s,
CHNHEt), 4.51 (1H, d, J¼11.8 Hz, OCH2), 4.87 (1H, d, J¼11.8 Hz,
OCH2), 5.23 (1H, br s, ]CH2), 5.26 (1H, br s, ]CH2), 6.84 (1H, d,
J¼8.6 Hz, AreH), 7.84 (1H, dd, J¼8.6, 1.8 Hz, AreH), 7.92 (1H, d,
13C NMR (100 MHz, CDCl3)
d 15.0 (CH3), 21.4 (CH3), 40.5 (CH2), 49.8
J¼1.8 Hz, AreH). 13C NMR (100 MHz, CDCl3)
d
15.2 (CH3), 41.2 (CH2),
(CH2), 59.5 (CH), 112.4 (CH2), 125.2 (CH), 125.6 (CH), 127.5 (CH),
127.9 (CH), 128.3 (CH), 129.2 (CH), 133.3 (C), 135.4 (C), 136.2 (C),
140.4 (C), 143.5 (C). HRMS (ESIþ) m/z 365.1294 (MþNaþ), calcd for
C19H22N2O2SNa: 365.1294.
51.8 (CH3), 58.0 (CH), 67.4 (CH2), 114.8 (CH2), 116.8 (CH), 122.3 (C),
124.7 (C),130.5 (CH),131.7 (CH),139.6 (C),158.4 (C),166.7 (C). HRMS
(ESIþ) m/z 270.1098 (MþNaþ), calcd for C14H17NO3Na: 270.1101.
4.3.4. 6-Bromo-4-ethylamino-3,4-dihydro-3-methylene-2H-1-ben-
4.3.9. 3,4-Dihydro-3-methylene-4-(2-propenyl)amino-2H-1-benzo-
zopyran (2d). Orange oil (74%). IR (KBr, neat) 3323, 2967,1576, 1241,
pyran (3). Yellow oil (76%). IR (KBr, neat) 3328, 3075, 2979, 1607,
1218, 1124, 1007, 921, 816 cmꢂ1. 1H NMR (400 MHz, CDCl3)37
d
1.13
1583, 1487, 1464, 1241, 1214, 1038, 1008, 918, 754 cmꢂ1 1H NMR
.
(3H, t, J¼7.2 Hz, CH2CH3), 2.58e2.73 (2H, br m, CH2CH3), 4.04 (1H,
br s, CHNHEt), 4.45 (1H, d, J¼11.8 Hz, OCH2), 4.75 (1H, d, J¼11.8 Hz,
OCH2), 5.19 (1H, br s, ]CH2), 5.25 (1H, br s, ]CH2), 6.71 (1H, d,
J¼8.6 Hz, AreH), 7.24 (1H, dd, J¼8.6, 2.7 Hz, AreH), 7.35 (1H, d,
(400 MHz, CDCl3)37
d
3.24 (1H, dd, J¼14.0, 6.5 Hz, CH2), 3.32 (1H, dd,
J¼14.0, 5.5 Hz, CH2CH]CH2), 4.11 (1H, br s, CHNHallyl), 4.46 (1H, d,
J¼11.7 Hz, OCH2), 4.78 (1H, d, J¼11.7 Hz, OCH2), 5.13 (1H, br d,
J¼9.9 Hz, CH]CH2), 5.18 (1H, br s, ]CH2), 5.22 (1H, dd, J¼17.2,
1.8 Hz, CH]CH2), 5.26 (1H, br s, ]CH2), 5.88e5.98 (1H, m, CH]
CH2), 6.83 (1H, d, J¼8.2 Hz, AreH), 6.89e6.93 (1H, m, AreH),
7.15e7.19 (1H, m, AreH), 7.22 (1H, d, J¼7.7 Hz, AreH). 13C NMR
J¼2.7 Hz, AreH). 13C NMR (100 MHz, CDCl3)
d 15.2 (CH3), 41.1 (CH2),
57.6 (CH), 67.2 (CH2), 112.4 (C), 114.7 (CH2), 118.6 (CH), 126.9 (C),
131.6 (CH), 132.0 (CH), 139.6 (C), 153.5 (C). HRMS (ESIþ) m/z
268.0333 (MþHþ), calcd for C12H1579BrNO: 268.0332.
(100 MHz, CDCl3)
d 49.1 (CH2), 56.8 (CH), 67.0 (CH2), 114.5 (CH2),
116.2 (CH2), 116.8 (CH), 120.6 (CH), 124.6 (C), 128.8 (CH), 129.7 (CH),
136.7 (CH), 140.1 (C), 154.4 (C). HRMS (ESIþ) m/z 202.1227 (MþHþ),
calcd for C13H16NO: 202.1226.
4.3.5. 4-Ethylamino-3,4-dihydro-3-methylene-6-nitro-2H-1-benzo-
pyran (2e). Yellow oil (60%). IR (KBr, neat) 3325, 2968, 1615, 1584,
1517, 1486, 1340, 1242, 1090, 997, 920, 832, 751 cmꢂ1 1H NMR
.
(400 MHz, CDCl3)
d
1.15 (3H, t, J¼7 Hz, CH2CH3), 1.56 (1H, br s, NH),
4.3.10. 4-Butylamino-3,4-dihydro-3-methylene-2H-1-benzopyran
2.62e2.76 (2H, br m, CH2CH3), 4.15 (1H, br s, CHNHEt), 4.58 (1H, d,
J¼11.8 Hz, OCH2), 4.91 (1H, dd, J¼11.8, 0.9 Hz, OCH2), 5.28 (1H, br s,
]CH2), 5.31 (1H, br s, ]CH2), 6.89 (1H, d, J¼9.0 Hz, AreH), 8.06
(1H, dd, J¼9.0, 2.7 Hz, AreH), 8.18 (1H, d, J¼7.7, 2.7 Hz, AreH). 13C
(4). Yellow oil (78%). IR (KBr, neat) 3326, 2957, 2927, 1607, 1583,
1487, 1465, 1241, 1219, 1039, 1008, 753 cmꢂ1 1H NMR (400 MHz,
.
CDCl3)37
d
0.91 (3H, t, J¼7.3 Hz, (CH2)3CH3), 1.29e1.54 (4H, m,
(CH2)2CH3), 2.62 (2H, br t, J¼7 Hz, NHCH2), 4.05 (1H, br s, CHNHBu),
4.45 (1H, d, J¼11.8 Hz, OCH2), 4.78 (1H, dd, J¼11.8, 1.4 Hz, OCH2),
5.18 (1H, br s, ]CH2), 5.23 (1H, br s, ]CH2), 6.83 (1H, dd, J¼8.1,
0.9 Hz, AreH), 6.88e6.92 (1H, m, AreH), 7.14e7.18 (1H, m, AreH),
NMR (100 MHz, CDCl3)
d 15.2 (CH3), 41.2 (CH2), 57.8 (CH), 67.9
(CH2), 115.6 (CH2), 117.4 (CH), 124.8 (CH), 125.3 (C), 126.0 (CH), 138.5
(C),141.1 (C), 159.9 (C). HRMS (ESIþ) m/z 235.1079 (MþHþ), calcd for
C12H15N2O3: 235.1077.
7.21 (1H, dd, J¼7.5, 1.6 Hz, AreH). 13C NMR (100 MHz, CDCl3)
d 14.0
(CH3), 20.5 (CH2), 32.1 (CH2), 46.5 (CH2), 58.1 (CH), 67.0 (CH2), 114.1
(CH2), 116.7 (CH), 120.6 (CH), 124.9 (C), 128.7 (CH), 129.6 (CH), 140.6
(C), 154.3 (C). HRMS (ESIþ) m/z 218.1538 (MþHþ), calcd for
C14H20NO: 218.1539.
4.3.6. 4-Ethylamino-3,4-dihydro-3-methylene-6-phenyl-2H-1-ben-
zopyran (2f). Yellow oil (65%). IR (KBr, neat) 3323, 2967, 1614, 1508,
1482, 1453, 1241, 1224, 1129, 1008, 918, 826, 764, 698 cmꢂ1. 1H NMR
(400 MHz, CDCl3)
d
1.14 (3H, t, J¼7.2 Hz, CH2CH3),1.36 (1H, br s, NH),
2.63e2.76 (2H, br m, CH2CH3), 4.15 (1H, br s, CHNHEt), 4.49 (1H, d,
J¼11.8 Hz, OCH2), 4.83 (1H, dd, J¼11.8, 1.4 Hz, OCH2), 5.22 (1H, br s,
]CH2), 5.26 (1H, br s, ]CH2), 6.90 (1H, d, J¼8.6 Hz, AreH),
7.27e7.32 (1H, m, AreH), 7.39e7.44 (4H, m, AreH), 7.53e7.56 (2H,
4.3.11. 3,4-Dihydro-3-methylene-4-(2-phenylethyl)amino-2H-1-ben-
zopyran (5). Yellow oil (59%). IR (KBr, neat) 3322, 3026, 2922, 2850,
1605, 1582, 1487, 1454, 1241, 1216, 1038, 1006, 753, 699 cmꢂ1 1H
.
NMR (400 MHz, CDCl3)
d 1.87 (1H, br s, NH), 2.78e2.97 (4H, m,
m, AreH). 13C NMR (100 MHz, CDCl3)
d
15.3 (CH3), 41.2 (CH2), 58.2
(CH2)2Ph), 4.11 (1H, br s, CHNHphenethyl), 4.42 (1H, d, J¼11.4 Hz,
OCH2), 4.69 (1H, dd, J¼11.4, 1 Hz, OCH2), 5.19 (1H, br s, ]CH2), 5.24
(1H, br s, ]CH2), 6.81 (1H, br d, J¼8.2 Hz, AreH), 6.86e6.90 (1H, m,
AreH), 7.12e7.17 (2H, m, AreH), 7.20e7.23 (3H, m, AreH),
(CH), 67.2 (CH2), 114.3 (CH2), 117.2 (CH), 125.0 (C), 126.60 (CH),
126.65 (CH), 127.6 (CH), 128.2 (CH), 128.6 (CH), 133.7 (C), 140.4 (C),
140.7 (C), 153.9 (C). HRMS (ESIþ) m/z 288.1357 (MþNaþ), calcd for
C18H19NONa: 288.1359.
7.28e7.32 (2H, m, AreH). 13C NMR (100 MHz, CDCl3)
d 36.1 (CH2),
47.9 (CH2), 57.8 (CH), 67.0 (CH2), 114.5 (CH2), 116.8 (CH), 120.7 (CH),
124.4 (C), 126.2 (CH), 128.5 (CH), 128.7 (CH), 128.9 (CH), 129.6 (CH),
139.9 (C), 140.2 (C), 154.3 (C). HRMS (ESIþ) m/z 288.1357 (MþNaþ),
calcd for C18H19NONa: 288.1359.
4.3.7. tert-Butyl 4-ethylamino-3,4-dihydro-3-methylene-1(2H)-qui-
nolinecarboxylate (2g). Yellow-brown oil (72%). IR (KBr, neat) 3323,
2973, 1700, 1490, 1367, 1167, 756 cmꢂ1. 1H NMR (400 MHz, CDCl3)37
d
1.11 (3H, t, J¼7 Hz, CH2CH3), 1.52 (9H, s, t-Bu), 2.58e2.74 (2H, br m,
CH2CH3), 4.12 (1H, br s, CHNHEt), 4.25 (1H, d, J¼11.8 Hz, OCH2), 4.42
(1H, dt, Jd¼11.8 Hz, Jt¼1.5 Hz, OCH2), 4.99 (1H, br s, ]CH2), 5.01 (1H,
br s, ]CH2), 7.04e7.08 (1H, m, AreH), 7.20e7.25 (2H, m, AreH),
4.4. Deuterium-labeling experiments
4.4.1. Bis(1,1-dideuterio-2-phenylethyl)amine. This compound was
prepared by LiAlD4/AlCl3 reduction of phenylacetonitrile,38 fol-
lowed by amidation with phenylacetyl chloride and LiAlD4
reduction.39
7.60 (1H, br d, J¼8.2 Hz, AreH). 13C NMR (100 MHz, CDCl3)
d 15.3
(CH3), 28.3 (CH3), 41.4 (CH2), 48.3 (CH2), 61.5 (CH), 80.9 (C), 110.0
(CH2), 124.0 (CH), 124.4 (CH), 127.1 (CH), 127.3 (CH), 132.6 (C), 137.8
(C), 143.4 (C), 153.6 (C). HRMS (ESIþ) m/z 311.1728 (MþNaþ), calcd
for C17H24N2O2Na: 311.1730.
Colorless oil. IR (KBr, neat) 3312, 3026, 2922, 2172, 2057, 1673,
1603, 1496, 1453, 1155, 744, 698 cmꢂ1. 1H NMR (400 MHz, CDCl3)37
d
2.77 (4H, s, CH2Ph), 7.16e7.21 (6H, m, AreH), 7.26e7.29 (4H, m,
4.3.8. 4-Ethylamino-1,2,3,4-tetrahydro-3-methylene-1-(4-methyl-
AreH). 13C NMR (100 MHz, CDCl3)
d 36.1 (CH2), 50.1 (C, quint,
phenylsulfonyl)quinoline (2h). Orange brown oil (68%). IR (KBr,
1JCeD¼20 Hz), 126.0 (CH), 128.4 (CH), 128.6 (CH), 139.9 (C). HRMS
neat) 3326, 2966, 1599, 1485, 1456, 1351, 1165, 1091, 668, 578 cmꢂ1
.
(ESIþ) m/z 230.1843 (MþHþ), calcd for C16H16D4N: 230.1841.

1622
N. Arai, T. Ohkuma / Tetrahedron 67 (2011) 1617e1622
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4.4.2. (E)-3-deuteriomethylene-4-(1,1-dideuterio-2-phenylethyl)
amino-3,4-dihydro-2H-1-benzopyran (5-d3). The reaction was car-
ried out according to the typical procedure described above (Sec-
tion 4.3). The configuration of 5-d3 was determined by comparison
of the 1H NMR spectrum with that of non-deuterated 5. The NMR
signals of terminal methylene protons of 5 were assigned by NOE
experiments (see Supplementary data).
8. Tanner, D.; Hagberg, L. Tetrahedron 1998, 54, 7907e7918.
9. Sakane, S.; Maruoka, K.; Yamamoto, H. Tetrahedron 1986, 42, 2203e2209.
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14. Ofial, A. R.; Mayr, H. Angew. Chem., Int. Ed. 1997, 36, 143e145.
15. Rehn, S.; Ofial, A. R.; Mayr, H. Synthesis 2003, 1790e1796.
16. Booth, S. E.; Jenkins, P. R.; Swain, C. J.; Sweeney, J. B. J. Chem. Soc., Perkin Trans. 1
1994, 3499e3508.
Yellowoil. IR (KBr, neat) 3322, 3026, 2922, 2852, 2174, 2071,1605,
1582, 1487, 1462, 1453, 1236, 1038, 1006, 751, 699 cmꢂ1 1H NMR
.
(400 MHz, CDCl3)
d
1.79 (1H, br s, NH), 2.80 (1H, d, J¼13.6 Hz, CH2Ph),
2.84 (1H, d, J¼13.6 Hz, CH2Ph), 4.11 (1H, br s, CHNHphenethyl), 4.42
(1H, d, J¼11.7 Hz, OCH2), 4.69 (1H, dd, J¼11.7,1.3 Hz, OCH2), 5.23 (1H,
br s, ]CHD), 6.81 (1H, dd, J¼7.5, 1.6 Hz, AreH), 6.86e6.90 (1H, m,
AreH), 7.12e7.20 (2H, m, AreH), 7.21e7.23 (3H, m, AreH), 7.28e7.32
17. Laschat, S.; Grehl, M. Angew. Chem., Int. Ed. Engl. 1994, 33, 458e461.
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11568e11579.
(2H, m, AreH).13C NMR (100 MHz, CDCl3)
d 36.0 (CH2), 47.1 (C, quint,
ꢀ
20. Chinchilla, R.; Najera, C. Chem. Rev. 2007, 107, 874e922.
1JCeD¼20 Hz), 57.7 (CH), 67.0 (CH2), 114.1 (CH, t, 1JCeD¼24 Hz), 116.8
(CH), 120.7 (CH), 124.5 (C), 126.2 (CH), 128.5 (CH), 128.7 (CH), 128.8
(CH), 129.6 (CH), 139.9 (C), 140.2 (C), 154.3 (C). HRMS (ESIþ) m/z
291.1546 (MþNaþ), calcd for C18H16D3NONa: 291.1547.
21. Okuro, K.; Furuune, M.; Enna, M.; Miura, M.; Nomura, M. J. Org. Chem. 1993, 58,
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25. Formation of amino benzofurans via
p-complex between Cu(I) and in situ-
Acknowledgements
generated propargyl amine followed by nucleophilic addition of oxygen:
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This work was supported by a Grant-in-Aid from the Japan
Society for the Promotion of Science (JSPS) (No. 21350048).
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Supplementary data
1H NMR spectra of (PhCH2CH2)2NH, (PhCH2CD2)2NH, compound
5 and compound 5-d3, and the NOE experiment on 5 are included in
the Supplementary data. Supplementary data related to this article
can be found online at doi:10.1016/j.tet.2011.01.007.
References and notes
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37. The signal of the NH proton was not clearly observed.
38. Frejd, T.; Klingstedt, T. Synthesis 1987, 40e42.
39. Trost, B. M.; Yeh, V. S. C.; Ito, H.; Bremeyer, N. Org. Lett. 2002, 4, 2621e2623.