Copper-Catalyzed Regioselective Ring-Opening Hydroamination of Methylenecyclopropanes

Article abstract of DOI:10.1021/acs.joc.6b02483

A copper-catalyzed ring-opening hydroamination of methylenecyclopropanes with polymethylhydrosiloxane and O-benzoylhydroxylamines has been developed. The cyclopropane C-C bond cleavage occurs selectively at the more congested proximal position, and the corresponding homoallylamines are obtained in good to excellent yields. The umpolung electrophilic amination strategy with the hydroxylamine derivatives can provide a new reaction mode of methylenecyclopropanes in the catalytic hydroamination reaction.

Full text of DOI:10.1021/acs.joc.6b02483

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Featured Article
Copper-Catalyzed Regioselective Ring-Opening
Hydroamination of Methylenecyclopropanes
Daiki Nishikawa, Ryosuke Sakae, Yuya Miki, Koji Hirano, and Masahiro Miura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02483 • Publication Date (Web): 02 Dec 2016
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CopperꢀCatalyzed Regioselective RingꢀOpening
Hydroamination of Methylenecyclopropanes
Daiki Nishikawa, Ryosuke Sakae, Yuya Miki, Koji Hirano,* and Masahiro Miura*
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka
565ꢀ0871, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
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k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
A
copperꢀcatalyzed
ringꢀopening
hydroamination
of
methylenecyclopropanes
with
The
polymethylhydrosiloxane (PMHS) and Oꢀbenzoylhydroxylamines has been developed.
cyclopropane C–C bond cleavage occurs selectively at the more congested proximal position, and the
corresponding homoallylamines are obtained in good to excellent yields. The umpolung electrophilic
amination strategy with the hydroxylamine derivatives can provide a new reaction mode of
methylenecyclopropanes in the catalytic hydroamination reaction.
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Introduction
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Methylenecyclopropanes (MCPs) are useful C4 building blocks in synthetic organic chemistry
because of their uniquely high reactivity associated with the large ring strain.1 Therefore, there are
many reports of synthetic applications with use of MCPs, particularly, transitionꢀmetalꢀcatalyzed
coupling reactions with various nucleophiles and π components.2 Among them, the catalytic
ringꢀopening hydroamination can provide a unique approach to alkylamines of high value in fine
chemical industries. To date, three reaction modes of MCPs have been reported (Scheme 1). In
1998, Yamamoto developed a palladiumꢀcatalyzed ringꢀopening hydroamination of MCPs with
secondary amines and imides (mode a).3 The cyclopropane ring cleavage occurs at the distal position,
and subsequent isomerization forms a πꢀallylpalladium intermediate, thus leading to the corresponding
allylamine products. Afterward, Shi reported a similar palladium catalysis with sulfonamide nitrogen
nucleophiles.4 Titanium and zirconium amide complexes are also known to catalyze the ringꢀopening
hydroamination of MCPs with primary amines, in which a unique azametallacyclobutane intermediate is
generated and the corresponding imines are finally obtained (mode b).5 The regioselectivity in the
ringꢀopening step is highly dependent on the metal center: the titanium catalyst delivers the linear
imines as the major products while the branched isomers are preferably formed under the zirconium
catalysis. Organolanthanide catalysts also promoted the formation of the same imines from MCPs and
primary amines but through the completely different intermediates (mode c).6 Additionally, a
goldꢀcatalyzed ringꢀopening process has been recently reported by Widenhoefer (mode d).7 In this
case, the reactivity of MCPs is controlled by the substituent on the cyclopropane ring: only when R is an
aryl group, the goldꢀpromoted ringꢀopening reaction proceeds to form the allylamine derivative. On
the other hand, a 2ꢀalkylꢀsubstituent on methylenecyclopropane leads to the ringꢀretaining
cyclopropylmethylamine selectively. Subsequent computational studies have suggested an allyl cation
intermediate in the ringꢀopening hydroamination.8
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Meanwhile, our research group9 and Buchwald group10 recently focused on the unique electrophilic
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nature of hydroxylamine derivatives11 and independently developed the copperꢀcatalyzed formal
hydroamination reaction of various alkenes with hydrosilanes and hydroxylamines. In these reactions,
the silanes and the amines work as the nucleophilic hydride and electrophilic nitrogen functions,
respectively, and the corresponding hydroaminated products are produced via a completely distinct
mechanism from that of the conventional hydroamination reactions with simple NH compounds.12
During our continuous interest in the umpolung electrophilic aminationꢀenabled hydroamination of
alkenes, we then paid our attention into MCPs.13 Herein, we report a copperꢀcatalyzed highly
regioselective ringꢀopening hydroamination of 2ꢀsubstituted 1ꢀmethylenecyclopropanes with a
hydrosilane such as polymethylhydrosiloxane (PMHS) and Oꢀbenzoylhydroxylamines (mode e): the
cyclopropanes undergo ringꢀopening reaction exclusively at the more congested proximal position, and
the corresponding homoallylamines are produced in good to excellent yields. To the best of our
knowledge, this is the first example of the homoallylamine product selectivity in the catalytic
ringꢀopening hydroamination of MCPs.
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Scheme 1. Reaction Modes of Methylenecyclopropanes in Catalytic Ring-Opening
Hydroamination
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Results and Discussion
On the basis of our previous work on the formal alkene hydroamination,8 we chose
2ꢀphenylꢀ1ꢀmethylenecyclopropane (1a; 0.38 mmol), morpholino benzoate (2a; 0.25 mmol), and
polymethylhydrosiloxane (PMHS; 0.75 mmol based on the SiꢀH moiety) as model substrates and started
the optimization studies by screening a number of phosphorous ligands in the presence of a Cu(OAc)2
catalyst (10 mol %) and a LiOꢀtꢀBu base (4.0 equiv).
Pleasingly, we found that a
Cu(OAc)2/CF3ꢀdppbz (dppbz = 1,2ꢀbis(diphenylphosphino)benzene) catalyst system promoted the
ringꢀopening hydroamination smoothly at room temperature in DCE, and the corresponding
homoallylamine 3aa was obtained in 94% yield (Scheme 2). Notably, the alkylamine 3aa could be
easily isolated by the simple acid/base extraction without chromatographic purification (see the
Experimental Section for details). The remarkable ligand effects were observed: the parent dppbz and
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electronꢀrich MeOꢀdppbz showed the sluggish reactivity. On the other hand, the bulky DTBMꢀdppbz
and relatively electronꢀdeficient F3ꢀdppbz gave the product in moderate yields. The use of 20 mol %
(to Cu) of the monodentate variant of CF3ꢀdppbz, namely P[3,5ꢀ(CF3)2C6H3]3, also promoted the
reaction to some extent. On the basis of the above phenomena, the rigid chelating nature as well as
steric bulkiness and electron deficiency of CF3ꢀdppbz could be all essential for the high reaction
efficiency. Additionally, as far as we tested, no other regioꢀ and constitutional isomers of 3aa were
detected.
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Scheme 2. Optimal Conditions for Copper-Catalyzed Regioselective Ring-Opening
Hydroamination of Methylenecyclopropane 1a with Hydroxylamine 2a and Remarkable Ligand
Effects
With the optimal conditions in hand, we initially investigated the scope of the hydroxylamine
derivatives 2 (Table 1). In addition to the morpholine 2a, the copper catalyst accommodated other
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sixꢀmembered cyclic amines including piperidine 2b and NꢀBoc piperazine 2c (entries 2 and 3). In the
1
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latter case, the Boc protection was spontaneously removed in the acid/base extraction step to form the
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NHꢀfree piperazine 3ac.
sevenꢀmembered azepane 2f could also be employed, and the corresponding homoallylamines 3ad–3af
in good yields (entries 4–6). Additionally, the acyclic amines coupled with the
The bicyclic tetrahydroisoquinoline 2d, thienopiperidine 2e, and
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methylenecyclopropane 1a without any difficulties: N,Nꢀdiethylꢀ, N,Nꢀdibenzylꢀ, N,Nꢀdiallylꢀ, and
NꢀbenzylꢀNꢀmethylamines 2g–2j were well tolerated under the standard reaction conditions (entries 7–
10). Particularly, the benzyl and allyl moieties in 3ah–3aj can be easily deprotected under appropriate
conditions14 to furnish the NH2 amines, which are useful synthetic handles for further manipulations.
Particularly notable is the successful ringꢀopening hydroamination with the somewhat challenging
secondary hydroxylamine 2k (entry 11). Again, each of the products was readily obtained in high
purity form by the simple acid/base extraction technique. Moreover, regardless of the steric and
electronic nature of the hydroxylamines, the homoallylamines 3 were exclusively formed.
Table
1.
Copper-Catalyzed
Regioselective
Ring-Opening
Hydroamination
of
2-Phenyl-1-methylenecyclopropane (1) with Various Hydroxylamines 2a
entry
1
yield (%)
94
2
3
2
99
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a
Reaction conditions: 1a (0.38 mmol), 2 (0.25 mmol), PMHS (0.75 mmol based on SiꢀH), Cu(OAc)2
1
2
3
(0.025 mmol), CF3ꢀdppbz (0.025 mmol), LiOꢀtꢀBu (1.0 mmol), DCE (1.5 mL), rt, N2, 4 h. b Isolated as
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the NHꢀfree piperazine.
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The copper catalysis was compatible with several 2ꢀsubstituted methylenecyclopropanes 1 (Scheme
3a). The substrates that bear the aromatic substituents underwent the ringꢀopening hydroamination
with 2a efficiently to deliver the homoallylamines 3ba–3da in good yields. The reaction of the
alkylꢀsubstituted methylenecyclopropane also proceeded well, and the ring cleavage occurred at the
same more congested proximal position (3ea). However, the 2,2ꢀdisubstituted system 1f gave a 37:63
mixture of 3fa and 3fa’ (Scheme 3b). Apparently, the C–C cleavage around the highly sterically
demanding quaternary carbon center was unfavored, thus mainly leading to the less congested isomer
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3fa’
(vide
infra).
Additionally notable
is
the
reaction
of
2,3ꢀdisubstituted
9ꢀmethylenebicyclo[6.1.0]nonane (1g): the ringꢀopening hydroamination did not occur at all, and the
ringꢀretaining cyclopropylmethylamine 4ga was instead formed7 with 61:39 dr15 (Scheme 3c). These
outcomes indicate that the C–C bond cleavage process is highly sensitive to both steric and electronic
factors around the breaking carbonꢀcarbon bond.16
Scheme 3. Scope of Methylenecyclopropanes 1
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Based on our findings and literature information,10f we are tempted to assume the hydroamination
mechanism as follows (Scheme 4). An initial reduction17 and salt metathesis of Cu(OAc)2 with
LiOꢀtꢀBu and ligand coordination forms the starting LnCuOꢀtꢀBu species 5. Subsequent σꢀbond
metathesis with PMHS generates a copper hydride key intermediate 6. In the insertion step of the
methylenecyclopropane 1, the bulkier copper center is located at the less congested terminal carbon to
afford the cyclopropylmethylcopper 7, from which the substrateꢀdependent three distinct pathways are
available. In the case of the monoꢀsubstituted methylenecyclopropanes 1a–1e, the
βꢀcarbon
elimination occurs selectively at the more congested proximal position, probably because of electronic
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factors, to produce the secondary alkylcopper 8 (path a). However, when the 2,2ꢀdisubstituted
methylenecyclopropane 1f is applied, the alkylcopper 8 derived from the ꢀcarbon elimination at the
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β
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8
more crowded position is the highly sterically demanding tertiary alkylmetal. Thus, the C–C bond
cleavage at the less congested position competitively occurs, leading to a regiomixture of 8 and 8’ (path
a and path b). After these ringꢀopening events, the alkylcoppers 8 and 8’ react with the hydroxylamine
218 to furnish the ringꢀopening hydroaminated products 3 and 3’, respectively. A similar ringꢀopening
mechanism has been proposed in the palladiumꢀcatalyzed hydrostannylation19 and rhodiumꢀcatalyzed
hydrosilylation.20 On the other hand, if the cyclopropane ring has substituents at both 2 and 3
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positions, the βꢀcarbon elimination of the alkylcopper 7 can be relatively slow, and direct coupling with
the hydroxylamine 2 predominantly proceeds to deliver the ringꢀretaining hydroaminated product 4
(path c). Irrespective of the reaction course, the copper benzoate 9 is generated after the C–N bond
formation and finally transformed to the starting copper alkoxide 5 by the ligand exchange with
LiOꢀtꢀBu.21 The result of the following deuteriumꢀlabeling experiment with Ph2SiD2 is also consistent
with the proposed mechanism (Scheme 5): the hydride was derived from the hydrosilane and selectively
incorporated to the internal position of the methylene moiety of 1a.
Scheme 4. Plausible Mechanism. L = CF3-dppbz.
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Scheme 5. Deuterium-Labeling Experiment with Ph2SiD2
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Conclusion
We have developed a copperꢀcatalyzed highly regioselective ringꢀopening hydroamination of
2ꢀsubstituted 1ꢀmethylenecyclopropanes with hydrosilanes and hydroxylamines.
The formal
hydroamination strategy is based on the umpolung electrophilic amination and provides the first access
to the homoallylamine products in the catalytic ringꢀopening hydroamination of the
methylenecyclopropanes, to the best of our knowledge. The present electrophilic amination catalysis
can open the door to a new reaction mode of MCPs in the ringꢀopening hydroamination reaction.
Further studies on clarification of the detailed mechanism and catalytic asymmetric induction are
ongoing in our laboratory.
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Experimental Section
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Instrumentation and Chemicals 1H, 13C, and 2H NMR spectra were recorded at 400, 100, 60 MHz,
respectively, for CDCl3 solutions. HRMS data were obtained by CI or APCI using a doubleꢀfocusing
mass spectrometer or TOF, respectively. TLC analyses were performed on commercial glass plates
bearing a 0.25 mm layer of Wako NH2 Silica gel 60F254. DCE was freshly distilled from CaH2 prior to
use. Methylenecyclopropanes 122, Oꢀbenzoylhydroxylamines 211b,c, and CF3ꢀdppbz23 are prepared
according to the literature.
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Typical
Methylenecyclopropanes 1 with PMHS and Hydroxylamines 2. The synthesis of 3aa is
representative (Scheme 1). Cu(OAc)2 (4.5 mg, 0.025 mmol),
Procedure
for
Copper-Catalyzed
Ring-Opening
Hydroamination
of
1,2ꢀbis[bis{3,5ꢀdi(trifluromethyl)phynyl}phosphino]benzene (CF3ꢀdppbz; 25 mg, 0.025 mmol), and
LiOꢀtꢀBu (80 mg, 1.0 mmol) were placed in a 20 mL twoꢀnecked reaction flask, which was filled with
nitrogen by using the Schlenk technique. 1,2ꢀDichloroethane (DCE; 0.50 mL) was then added to the
flask, and the suspension was stirred for 15 min at ambient temperature. Polymethylhydrosiloxane
(PMHS; 50 µL, 0.75 mmol based on SiꢀH) and a solution of 2ꢀphenylꢀ1ꢀmethylenecyclopropane (1a; 49
mg, 0.38 mmol) and morpholino benzoate (2a; 52 mg, 0.25 mmol) in DCE (1.0 mL) were sequentially
added dropwise. After stirring was continued at ambient temperature for additional 4 h, the resulting
mixture was quenched with water. An aqueous solution of 6 M HCl (30 mL) was added to the
mixture. The aqueous layer was washed three times with Et2O, neutralizes with 6 M NaOH aq. (30
mL), and then extracted three times with Et2O. The combined organic layer was dried over
magnesium sulfate and filtered through a pad of Celite.
Concentration in vacuo gave
4ꢀ(1ꢀphenylbutꢀ3ꢀenꢀ1ꢀyl)morpholine (3aa; 51 mg, 0.24 mmol) in 94% yield in high purity.
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4-(1-Phenylbut-3-en-1-yl)morpholine (3aa). yellow oil, 51 mg (94%); H NMR (400 MHz, CDCl3) δ
2.36ꢀ2.41 (m, 2H), 2.44ꢀ2.53 (m, 3H), 2.62ꢀ2.69 (m, 1H), 3.30 (dd, J = 5.2, 8.8 Hz, 1H), 3.67 (t, J = 4.8
Hz, 4H), 4.91 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H), 4.95 (dddd, J = 1.6, 1.6, 2.0, 17.2 Hz, 1H), 5.59
(dddd, J = 6.8, 6.8, 10.2, 17.2 Hz, 1H), 7.22ꢀ7.26 (m, 3H), 7.29ꢀ7.33 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 37.3, 51.2, 67.4, 70.3, 116.6, 127.3, 128.2, 128.8, 135.5, 140.3; HRMS (CI) m/z ([M+H]+)
calcd for C14H20NO: 218.1539, found: 218.1544.
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1
1-(1-Phenylbut-3-en-1-yl)piperidine (3ab). yellow oil, 53 mg (99%); H NMR (400 MHz, CDCl3) δ
1.31ꢀ1.37 (m, 2H), 1.47ꢀ1.60 (m, 4H), 2.36 (t, J = 4.8 Hz, 4H), 2.53ꢀ2.61 (m, 1H), 2.62ꢀ2.70 (m, 1H),
3.39 (dd, J = 5.2, 9.2 Hz, 1H), 4.89 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H), 4.96 (dddd, J = 1.6, 1.6, 2.0,
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17.2 Hz, 1H), 5.63 (dddd, J = 6.8, 6.8, 10.2, 17.2 Hz, 1H), 7.19ꢀ7.25 (m, 3H), 7.28ꢀ7.32 (m, 2H); C
NMR (100 MHz, CDCl3) δ 24.7, 26.4, 37.2, 51.3, 70.3, 116.1, 126.9, 127.8, 128.8, 136.2, 139.9; HRMS
(CI) m/z ([M+H]+) calcd for C15H22N: 216.1747, found: 216.1750.
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1-(1-Phenylbut-3-en-1-yl)piperazine (3ac). yellow oil, 36 mg (66%); H NMR (400 MHz, CDCl3) δ
1.53 (bs, 1H), 2.35ꢀ2.44 (m, 4H), 2.49ꢀ2.57 (m, 1H), 2.63ꢀ2.70 (m, 1H), 2.83ꢀ2.86 (m, 4H), 3.34 (dd, J =
5.2, 8.8 Hz, 1H), 4.90 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H), 4.96 (dddd, J = 1.6, 1.6, 2.0, 17.2 Hz, 1H),
5.61 (dddd, J = 6.8, 6.8, 10.2, 17.2 Hz, 1H), 7.20ꢀ7.26 (m, 3H), 7.28ꢀ7.33 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ 37.2, 46.6, 51.8, 70.4, 116.4, 127.2, 128.1, 128.9, 135.9, 140.1; HRMS (APCI) m/z ([M+H]+)
calcd for C14H21N2: 217.1699, found: 217.1690.
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2-(1-Phenylbut-3-en-1-yl)-1,2,3,4-tetrahydroisoquinoline (3ad). yellow oil, 53 mg (81%); H NMR
(400 MHz, CDCl3) δ 2.56ꢀ2.67 (m, 2H), 2.74ꢀ2.91 (m, 4H), 3.56 (dd, J = 5.2, 8.8 Hz, 1H), 3.59 (d, J =
14.4 Hz, 1H), 3.76 (d, J = 14.4 Hz, 1H), 4.90ꢀ4.94 (m, 1H), 4.96ꢀ5.02 (m, 1H), 5.65 (dddd, J = 7.2, 7.2,
13
10.2, 17.2 Hz, 1H), 6.96ꢀ6.99 (m, 1H), 7.04ꢀ7.11 (m, 3H), 7.23ꢀ7.27 (m, 1H), 7.29ꢀ7.34 (m, 4H); C
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NMR (100 MHz, CDCl3) δ 29.5, 37.8, 47.8, 53.5, 69.5, 116.6, 125.6, 126.1, 126.8, 127.3, 128.2, 128.7,
128.8, 134.7, 135.3, 135.8, 140.5; HRMS (APCI) m/z ([M+H]+) calcd for C19H22N: 264.1747, found:
264.1744.
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5-(1-Phenylbut-3-en-1-yl)-4,5,6,7-tetrahydrothieno[3,2-c]pyridine (3ae). yellow oil, 60 mg (89%); 1H
NMR (400 MHz, CDCl3) δ 2.60ꢀ2.67 (m, 2H), 2.73ꢀ2.83 (m, 3H), 2.87ꢀ2.93 (m, 1H), 3.51 (d, J = 14.4
Hz, 1H), 3.60 (dd, J = 5.2, 8.8 Hz, 1H), 3.71 (d, J = 14.4 Hz, 1H), 4.90ꢀ4.94 (m, 1H), 4.96ꢀ5.02 (m, 1H),
5.64 (dddd, J = 6.8, 6.8, 10.2, 17.2 Hz, 1H), 6.68 (d, J = 5.2 Hz, 1H), 7.03 (d, J = 5.2 Hz, 1H), 7.24ꢀ7.34
(m, 5H); 13C NMR (100 MHz, CDCl3) δ 25.9, 37.8, 47.9, 50.5, 69.2, 116.7, 122.7, 125.5, 127.3, 128.2,
128.7, 133.6, 134.2, 135.7, 140.5; HRMS (APCI) m/z ([M+H]+) calcd for C17H20NS: 270.1311, found:
270.1306.
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1-(1-Phenylbut-3-en-1-yl)azepane (3af). yellow oil, 50 mg (88%); H NMR (400 MHz, CDCl3) δ
1.52ꢀ1.61 (m, 8H), 2.48ꢀ2.58 (m, 3H), 2.62ꢀ2.70 (m, 3H), 3.66 (dd, J = 6.0, 8.4 Hz, 1H), 4.92 (dddd, J =
1.2, 1.2, 2.0, 10.2 Hz, 1H), 5.01 (dddd, J = 1.6, 1.6, 2.0, 17.2 Hz, 1H), 5.72 (dddd, J = 6.8, 6.8, 10.2,
17.2 Hz, 1H), 7.20ꢀ7.32 (m, 5H); 13C NMR (100 MHz, CDCl3) δ 27.1, 29.3, 37.5, 52.0, 69.0, 116.0,
126.8, 127.9, 128.6, 136.8, 141.5; HRMS (CI) m/z ([M+H]+) calcd for C16H24N: 230.1903, found:
230.1910.
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N,N-Diethyl-1-phenylbut-3-en-1-amine (3ag). yellow oil, 27 mg (53%); H NMR (400 MHz, CDCl3)
δ 1.00 (t, J = 7.2 Hz, 6H), 2.38 (dq, J = 7.2, 14.4 Hz, 2H), 2.47ꢀ2.55 (m, 1H), 2.60ꢀ2.68 (m, 1H), 2.64
(dq, J = 7.2, 14.4 Hz, 2H), 3.71 (dd, J = 5.6, 9.2 Hz, 1H), 4.90 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H),
4.97 (dddd, J = 1.6, 1.6, 2.0, 17.2 Hz, 1H), 5.65 (dddd, J = 6.8, 6.8, 10.2, 17.2 Hz, 1H), 7.20ꢀ7.32 (m,
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5H); C NMR (100 MHz, CDCl3) δ 12.8, 37.2, 43.2, 64.6, 116.1, 126.9, 128.0, 128.8, 136.7, 141.5;
HRMS (CI) m/z ([M+H]+) calcd for C14H22N: 204.1747, found: 204.1751.
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N,N-Dibenzyl-1-phenylbut-3-en-1-amine (3ah). yellow oil, 65 mg (79%); H NMR (400 MHz,
CDCl3) δ 2.53ꢀ2.60 (m, 1H), 2.81ꢀ2.89 (m, 1H), 3.19 (d, J = 13.6 Hz, 2H), 3.77ꢀ3.83 (m, 1H), 3.80 (d, J
= 13.6 Hz, 2H), 5.00 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H), 5.04 (dddd, J = 1.6, 1.6, 2.0, 17.2 Hz, 1H),
5.79 (dddd, J = 6.4, 7.2, 10.2, 17.2 Hz, 1H), 7.19ꢀ7.24 (m, 4H), 7.26ꢀ7.33 (m, 5H), 7.34ꢀ7.40 (m, 6H);
13C NMR (100 MHz, CDCl3) δ 35.4, 53.6, 61.6, 116.1, 126.8, 127.1, 128.0, 128.2, 128.8, 129.0, 136.7,
138.6, 140.3; HRMS (CI) m/z ([M+H]+) calcd for C24H26N: 328.2060, found: 328.2064.
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N,N-Diallyl-1-phenylbut-3-en-1-amine (3ai). yellow oil, 54 mg (95%); 1H NMR (400 MHz, CDCl3) δ
2.48ꢀ2.56 (m, 1H), 2.64ꢀ2.72 (m, 1H), 2.83 (dd, J = 7.2, 14.4 Hz, 2H), 3.26 (dddd, J = 1.6, 1.6, 5.2, 14.4
Hz, 2H), 3.82 (dd, J = 6.4, 8.4 Hz, 1H), 4.93 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H), 4.99 (dddd, J = 1.6,
1.6, 2.0, 17.2 Hz, 1H), 5.09ꢀ5.12 (m, 2H), 5.13ꢀ5.18 (m, 2H), 5.70 (dddd, J = 6.8, 6.8, 10.2, 17.2 Hz,
1H), 5.82 (dddd, J = 5.2, 7.2, 10.2, 17.2 Hz, 2H), 7.21ꢀ7.26 (m, 3H), 7.29ꢀ7.33 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 36.5, 52.7, 63.4, 116.0, 116.8, 126.9, 127.9, 128.7, 136.4, 136.9, 139.9; HRMS (CI) m/z
([M+H]+) calcd for C16H22N: 228.1747, found: 228.1753.
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N-Benzyl-N-methyl-1-phenylbut-3-en-1-amine (3aj). yellow oil, 57 mg (91%); H NMR (400 MHz,
CDCl3) δ 2.12 (s, 3H), 2.54ꢀ2.62 (m, 1H), 2.72ꢀ2.80 (m, 1H), 3.26 (d, J = 13.6 Hz, 1H), 3.59ꢀ3.63 (m,
1H), 3.60 (d, J = 13.6 Hz, 1H), 4.96 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H), 5.02 (dddd, J = 1.6, 1.6, 2.0,
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17.2 Hz, 1H), 5.74 (dddd, J = 6.8, 6.8, 10.2, 17.2 Hz, 1H), 7.19ꢀ7.36 (m, 10H); C NMR (100 MHz,
CDCl3) δ 37.1, 38.3, 58.6, 68.2, 116.3, 126.9, 127.2, 128.1, 128.3, 128.9 (2C), 136.4, 140.0, 140.1;
HRMS (CI) m/z ([M+H]+) calcd for C18H22N: 252.1747, found: 252.1753.
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N-Butyl-1-phenylbut-3-en-1-amine (3ak). colorless oil, 32 mg (63%); H NMR (400 MHz, CDCl3) δ
0.86 (t, J = 7.2 Hz, 3H), 1.12ꢀ1.33 (m, 2H), 1.38ꢀ1.46 (m, 3H), 2.37ꢀ2.44 (m, 4H), 3.64 (dd, J = 6.0, 7.6
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Hz, 1H), 5.05 (dddd, J = 1.2, 1.2, 2.0, 10.0 Hz, 1H), 5.09 (dddd, J = 1.6, 1.6, 2.0, 17.2 Hz, 1H), 5.67
(dddd, J = 6.4, 6.4, 10.0, 17.2 Hz, 1H), 7.21ꢀ7.27 (m, 1H), 7.30ꢀ7.35 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 14.1, 20.6, 32.5, 43.2, 47.6, 62.8, 117.6, 127.0, 127.3, 128.4, 135.8, 144.4; HRMS (APCI) m/z
([M+H]+) calcd for C14H22N: 204.1747, found: 204.1751.
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4-(1-(4-Methoxyphenyl)but-3-en-1-yl)morpholine (3ba). colorless oil, 60 mg (97%); H NMR (400
MHz, CDCl3) δ 2.35ꢀ2.51 (m, 5H), 2.60ꢀ2.67 (m, 1H), 3.26 (dd, J = 5.2, 9.2 Hz, 1H), 3.67 (t, J = 4.8
Hz, 4H), 3.79 (s, 3H), 4.91 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H), 4.92ꢀ4.98 (m, 1H), 5.59 (dddd, J =
13
6.8, 6.8, 10.2, 17.2 Hz, 1H), 6.85 (d, J = 8.8 Hz, 2H), 7.14 (d, J = 8.8 Hz, 2H); C NMR (100 MHz,
CDCl3) δ 37.3, 51.1, 55.3, 67.3, 69.7, 113.5, 116.5, 129.7, 132.2, 135.7, 158.8; HRMS (APCI) m/z
([M+H]+) calcd for C15H22NO2: 248.1645, found: 248.1646.
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4-(1-(4-Chlorophenyl)but-3-en-1-yl)morpholine (3ca). colorless oil, 41 mg (65%); H NMR (400
MHz, CDCl3) δ 2.34ꢀ2.40 (m, 2H), 2.43ꢀ2.49 (m, 3H), 2.59ꢀ2.66 (m, 1H), 3.27 (dd, J = 4.8, 8.8 Hz, 1H),
3.67 (t, J = 4.8 Hz, 4H), 4.91ꢀ4.96 (m, 2H), 5.55 (dddd, J = 6.8, 6.8, 10.2, 17.2 Hz, 1H), 7.18 (d, J = 8.4
13
Hz, 2H), 7.28 (d, J = 8.4 Hz, 2H); C NMR (100 MHz, CDCl3) δ 37.3, 51.2, 67.3, 69.7, 117.1, 128.4,
130.0, 132.9, 135.0, 139.1; HRMS (APCI) m/z ([M+H]+) calcd for C14H19ClNO: 252.1150, found:
252.1151.
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4-(1-(Naphthalen-2-yl)but-3-en-1-yl)morpholine (3da). colorless oil, 62 mg (93%); H NMR (400
MHz, CDCl3) δ 2.39ꢀ2.45 (m, 2H), 2.52ꢀ2.62 (m, 3H), 2.70ꢀ2.77 (m, 1H), 3.43 (dd, J = 4.8, 9.2 Hz, 1H),
3.65ꢀ3.71 (m, 4H), 4.88 (dddd, J = 1.2, 1.2, 2.0, 10.2 Hz, 1H), 4.93ꢀ4.98 (m, 1H), 5.58 (dddd, J = 6.8,
6.8, 10.2, 17.2 Hz, 1H), 7.40ꢀ7.48 (m, 3H), 7.64ꢀ7.65 (m, 1H), 7.79ꢀ7.82 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 37.3, 51.5, 67.3, 70.6, 116.8, 125.8, 126.1, 126.6, 127.7 (2C), 127.9, 128.0, 133.0, 133.3,
135.4, 138.3; HRMS (APCI) m/z ([M+H]+) calcd for C18H22NO: 268.1696, found: 268.1693.
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4-(1-Phenylhex-5-en-3-yl)morpholine (3ea). colorless oil, 61 mg (99%); 1H NMR (400 MHz, CDCl3)
δ 1.46ꢀ1.55 (m, 1H), 1.82ꢀ1.91 (m, 1H), 2.25ꢀ2.29 (m, 3H), 2.36 (t, J = 4.4 Hz, 4H), 2.51 (ddd, J = 7.2,
10.0, 14.0 Hz, 1H), 2.70 (ddd, J = 5.2, 10.0, 14.0 Hz, 1H), 3.66 (t, J = 4.8 Hz, 2H), 3.67 (t, J = 4.8 Hz,
2H), 5.05 (dd, J = 2.0, 17.2 Hz, 1H), 5.10 (dd, J = 2.0, 10.4 Hz, 1H), 5.61ꢀ5.70 (m, 1H), 7.14ꢀ7.18 (m,
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3H), 7.24ꢀ7.28 (m, 2H); C NMR (100 MHz, CDCl3) δ 33.2, 34.3, 40.7, 54.0, 63.9, 67.0, 115.5, 125.8,
128.4, 128.5, 141.5, 142.7; HRMS (APCI) m/z ([M+H]+) calcd for C16H24NO: 246.1852, found:
246.1840.
A
37:63
mixture
of
4-(2-phenylpent-4-en-2-yl)morpholine
(3fa)
and
4-(2-phenylbut-3-en-1-yl)morpholine (3fa’). colorless oil, 58 mg (99%); 1H NMR (400 MHz, CDCl3) δ
1.33 (s, 0.37×3H for 3fa), 1.44 (s, 0.63×3H for 3fa’), 2.18ꢀ2.23 (m, 0.63×2H for 3fa’), 2.30ꢀ2.35 (m,
0.63×2H for 3fa’), 2.38ꢀ2.44 (m, 0.37×3H for 3fa), 2.50ꢀ2.58 (m, 0.37×3H for 3fa), 2.62 (d, J = 2.8 Hz,
0.63×2H for 3fa’), 3.54 (t, J = 4.8 Hz, 0.63×4H for 3fa’), 3.65ꢀ3.68 (m, 0.37×4H for 3fa), 4.86ꢀ4.90 (m,
0.37×2H for 3fa), 5.03 (dd, J = 1.2, 17.6 Hz, 0.63×1H for 3fa’), 5.11 (dd, J = 1.2, 10.8 Hz, 0.63×1H for
3fa’), 5.33ꢀ5.43 (m, 0.37×1H for 3fa), 6.20 (dd, J = 10.8, 17.6 Hz, 0.63×1H for 3fa’), 7.15ꢀ7.22 (m,
1H), 7.24ꢀ7.31 (m, 2H), 7.37 (d, J = 8.4 Hz, 0.63×2H for 3fa’),7.46 (d, J = 8.4 Hz, 0.37×2H for 3fa);
13C NMR (100 MHz, CDCl3) for mixture: δ 16.2, 23.6, 45.7, 45.8, 46.9, 55.7, 62.5, 67.4, 68.0, 69.3,
112.5, 117.2, 126.0, 126.5, 127.1, 127.3, 127.9, 128.0, 135.0, 145.8, 146.2, 146.6; HRMS (APCI) m/z
([M+H]+) calcd for C15H22NO: 232.1696, found: 232.1695.
A 61:39 diastereomixture of 4-(bicyclo[6.1.0]nonan-9-ylmethyl)morpholine (4ga). colorless oil, 38
1
mg (68%); H NMR (400 MHz, CDCl3) δ 0.24ꢀ0.29 (m, 0.61×1H), 0.41ꢀ0.44 (m, 0.61×2H), 0.69 (m,
0.39×2H), 0.81ꢀ0.89 (m, 0.39×1H), 0.91ꢀ1.01 (m, 0.61×2H), 1.04ꢀ1.10 (m, 0.39×2H), 1.26ꢀ1.43 (m,
0.39×5H and 0.61×4H), 1.52ꢀ1.67 (m, 0.39×3H and 0.61×4H), 1.72ꢀ1.76 (m, 0.39×2H), 1.98ꢀ2.02 (m,
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0.61×2H), 2.30 (d, J = 6.4 Hz, 0.61×2H), 2.39 (d, J = 6.0 Hz, 0.39×2H), 2.46ꢀ2.52 (m, 4H), 3.72ꢀ3.75
(m, 4H); 13C NMR (100 MHz, CDCl3) for major diastereomer δ 21.2, 22.4, 26.6, 26.7, 29.8, 53.7, 63.6,
67.2; HRMS (APCI) m/z ([M+H]+) calcd for C14H26NO: 224.2009, found: 224.2010.
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4-(1-Phenyl-3-deuteriobut-3-en-1-yl)morpholine (3aa-d1). pale yellow oil, 42 mg (77%); H NMR
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(400 MHz, CDCl3) δ 2.36ꢀ2.42 (m, 2H), 2.44ꢀ2.52 (m, 3H), 2.65 (dd, J = 5.2, 14.0 Hz, 1H), 3.29 (dd, J
= 5.2, 8.8 Hz, 1H), 3.67 (t, J = 4.8 Hz, 4H), 4.90 (bs, 1H), 4.94 (d, J = 2.0 Hz, 1H), 7.22ꢀ7.25 (m, 3H),
13
7.29ꢀ7.33 (m, 2H); C NMR (100 MHz, CDCl3) δ 37.2, 51.2, 67.3, 70.4, 116.5, 127.3, 128.2, 128.8,
135.2 (t, J = 23.4 Hz), 140.3; 2H NMR (60 MHz, CDCl3) δ 5.62 (s); HRMS (APCI) m/z ([M+H]+) calcd
for C14H19DNO: 219.1608, found: 219.1599.
Associated Content
Author Information
Corresponding Authors
*Eꢀmail: k_hirano@chem.eng.osakaꢀu.ac.jp.
*Eꢀmail: miura@chem.eng.osakaꢀu.ac.jp.
Notes
The authors declare no competing financial interest.
Acknowledgment. This work was supported by JSPS KAKENHI Grant Nos. JP 15K13696
(GrantꢀinꢀAid for Exploratory Research), and JP 15H05485 (GrantꢀinꢀAid for Young Scientists (A)) to
K.H. and JP 24225002 (GrantꢀinꢀAid for Scientific Research (S)) to M.M.
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Supporting Information: H, C{1H}, and H NMR spectra for products. This material is available
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free of charge via the Internet at http://pubs.acs.org.
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References
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