Copper/bisphosphine catalysts in the internally borylative aminoboration of unactivated terminal alkenes with bis(pinacolato)diboron

Article abstract of DOI:10.1021/acs.joc.7b01874

Cu(I)/modified dppbz catalyst systems for the regioselective aminoboration of unactivated terminal alkenes have been developed. The bisphosphine-based Cu catalysis enables the introduction of the readily transformable Bpin group at the more congested inte

Full text of DOI:10.1021/acs.joc.7b01874

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Article
Copper/Bisphosphine Catalysts in Internally Borylative Aminoboration
of Unactivated Terminal Alkenes with Bis(pinacolato)diboron
Kodai Kato, Koji Hirano, and Masahiro Miura
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01874 • Publication Date (Web): 29 Aug 2017
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The Journal of Organic Chemistry
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Copper/Bisphosphine Catalysts in Internally Borylative
Aminoboration of Unactivated Terminal Alkenes with
Bis(pinacolato)diboron
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Kodai Kato, 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)
k_hirano@chem.eng.osaka-u.ac.jp; miura@chem.eng.osaka-u.ac.jp
Abstract: Cu(I)/modified dppbz catalyst systems for the regioselective aminoboration of unactivated
terminal alkenes have been developed. The bisphosphineꢀbased Cu catalysis enables the introduction
of readily transformable Bpin group at the more congested internal position and shows better
regioselectivity for broader terminal alkenes involving sterically demanding allylbenzenes, which are
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relatively challenging substrates in the previous IPrCuBr catalysis. Additionally, the second
generation catalyst systems accommodate the exoꢀmethyleneꢀtype disubstituted alkenes to deliver the
corresponding aminoborated products in good yield with high regioselectivity.
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Introduction
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The catalytic difunctionalization of simple and abundant terminal alkenes is highly attractive from the
synthetic point of view because both positions of the π bond are simultaneously functionalized in a
single synthetic operation. Particularly, the aminative difunctionalization can readily transform the
olefinic feedstock materials into the functionalized alkylamines of great interest in both bulk and fine
chemical syntheses.1 In this context, we reported the Cuꢀcatalyzed aminoboration of unactivated
terminal alkenes with hydroxylamines and diboron reagents as the amino electrophiles2 and boryl
nucleophiles,3 respectively. Additionally, the ligandꢀcontrolled regiodivergency was achieved: the
CuCl(xantphos) complex guided the boron and amino groups to the terminal and internal positions,
respectively, whereas the opposite regioisomers were selectively obtained under the IPrCuBr (IPr =
1,3ꢀbis(2,6ꢀdiisopropylphenyl)imidazolꢀ2ꢀylidene) catalysis.4 However, the latter has two drawbacks
(Scheme 1a). One is the use of pinBꢀBdan (pin = pinacolato, dan = 1,8ꢀdiamiononaphthyl) as the boryl
source, in which the Bdan group is selectively introduced to the product. The Bdan is more stable and
easyꢀtoꢀhandle boron masking group but sometimes needs tedious deprotection steps for the latent boron
functionalization. Another is lower regioselectivity for relatively sterically hindered terminal alkenes
such as allylbenzene and vinylcyclohexene.
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On the other hand, the research groups of Ito,5a Xiao and Fu,5b and Montgomery,5c independently,
recently developed Cuꢀcatalyzed highly regioselective hydroboration and alkylboration of unactivated
terminal alkenes, in which the readily transformable Bpin group was selectively incorporated at the
internal carbon with pinB–Bpin as the boryl source. Inspired by these works, we reinvestigated the
catalytic system, particularly, ancillary ligand to overcome the above limitations of the IPrCuBrꢀbased
first generation catalyst system.
Here, we report Cu/modified dppbz (dppbz
=
1,2ꢀbis(diphenylphosphino)benzene) catalysis for highly regioselective aminoboration of terminal
alkenes (Scheme 1b). The second generation catalysts enable the use of pinBꢀBpin and give better
regioselectivity for broader terminal alkenes.
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Scheme 1. Copper-Catalyzed Internally Borylative Aminoboration of Unactivated Terminal
Alkenes with Bis(pinacolato)diboron
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Results and Discussion
Table 1 summarizes ligand optimization studies, in conjunction with a CuCl catalyst and a LiOꢀtꢀBu
base, using 1ꢀoctene (1a), OꢀbenzoylꢀN,Nꢀdibenzylhydroxylamine (2a), and pinB–Bpin as model
substrates. Entries 1 and 2 show our previous results in THF solvent: the use of IPr ligand gave high
1
regioselectivity of 3aa:4aa = 96:4 albeit with low yield (24% judged by H NMR), whereas dppbz
showed moderate regioselectivity (3aa:4aa = 69:31) and reaction efficiency (31% H NMR yield).4a
1
According to the works by Montgomery5c and Xiao and Fu,5b we initially tested IPr in CH3CN solvent6
and CyꢀXantphos in DMAc or THF solvent, but the satisfactory yield was not obtained (entries 3–5).
On the other hand, the oꢀMeꢀdppbz ligand originally developed by Ito5a increased the yield to 55% with
maintenance of good 3aa:4aa selectivity (92:8; entry 6). Thus, we extensively investigated modified
dppbz ligands.7 While the introduction of electronꢀwithdrawing F or CF3 group resulted in lower
regioselectivity and/or yield (entries 7–9), electronꢀdonating groups generally improved the ratio of
3aa:4aa (entries 10–12). Particularly, the substituents at the meta position dramatically increased the
regioselectivity (entries 13–15), finally with electronꢀrich and bulky DTBMꢀdppbz proving to be
optimal in view of both regioselectivtiy and yield (entry 16). The reaction under the previous optimal
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conditions using the preꢀformed IPrCuBr was unsuccessful, thus confirming the advantage of newly
developed Cu(I)/DTBMꢀdppbz system (entry 17).
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Table 1. Optimization for Copper-Catalyzed Internally Borylative Aminoboration of 1-Octene
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(1a) with O-Benzoyl-N,N-dibenzylhydroxylamine (2a) and Bis(pinacolato)diborona
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entry
1
ligand
IPr
solvent
THF
yield (%)b
24
3aa:4aac
96:4
2
dppbz
THF
CH3CN
DMAc
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
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18
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69:31
64:37
84:16
82:18
92:8
3
IPr
4
CyꢀXantphos
CyꢀXantphos
oꢀMeꢀdppbz
pꢀCF3ꢀdppbz
F3ꢀdppbz
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6d
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66:34
78:22
50:50
73:27
77:23
81:19
87:13
91:9
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9
CF3ꢀdppbz
pꢀtꢀBuꢀdppbz
MeOꢀdppbz
Me2Nꢀdppbz
TMSꢀdppbz
tꢀBuꢀdppbz
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DTBMꢀdppbz
DTBMꢀdppbz
IPrCuBr
THF
THF
THF
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93:7
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16d
17e
76 (60)
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91:9 (92:8)
ca. 90:10
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a
Reaction conditions: 1a (0.25 mmol), 2a (0.38 mmol), pinB–Bpin (0.38 mmol), CuCl (0.025 mmol),
ligand (0.025 mmol), LiOꢀtꢀBu (0.75 mmol), solvent (1.5 mL), 4 h, rt, N2. b 1H NMR yield. Isolated
yield is in parentheses. c Determined by 1H NMR of the crude mixture. The ratio of isolated product
d
e
in parentheses.
With 2a (0.75 mmol), pinB–Bpin (0.75 mmol), and LiOꢀtꢀBu (1.0 mmol).
With
the preꢀformed IPrCuBr instead of CuCl and ligand.
We next examined the scope of unactivated terminal alkenes with the hydroxylamine 2a (Table 2).
The CuCl/DTBMꢀdppbz catalysis could be applied to not only the simple terminal alkene 1a (entry 1)
but also functionalized alkenes including silyl ether 1b, acetal 1c, and pivaloyl ester 1d, and the desired
internally borylated products 3ba–3da were formed with >90:10 regioselectivity (entries 2–4). In the
cases of 1c and 1d, the aminoborated products 3ca and 3da were somewhat unstable for
chromatographic purification and thus isolated as the corresponding aminoalcohols after oxidation with
H2O2/NaOH aq. The reaction of 1a could also be conducted on a 1.0 mmol scale with acceptable yield
and regioselectivity, thus indicating the good reproducibility of this process (entry 1). Allylsilane 1e
and allylic alcohol derivative (1f) also provided high regioselectivity (>99:1) albeit with lower yields
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(entries 5 and 6). On the other hand, the relatively sterically demanding allylbenzene (1g) decreased
the 3ga:4ga ratio to 71:29 (entry 7). However, to our delight, the use of oꢀMeꢀdppbz improved the
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regioselectivity to 92:8 (entry 8).
The oꢀMeꢀdppbz ligand also accommodated
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3,4ꢀdimethoxyallylbenzene (1h) and 2ꢀallylnaphthalene (1i) (entries 9 and 10). Additionally, much
bulkier vinylcyclohexene (1j) also underwent the aminoboration with 91:9 regioselectivity (entry 11).
The observed high regioselectivity toward allylbenzenes and vinylcyclohexene deserves significant
attention because the previous IPrCuBr catalysis only showed 83:17–87:13 regioselectivity.4a
Particularly notable is the successful regioselective aminoboration of 1,1ꢀdisubstituted alkenes 1k and 1l
by using the DTBMꢀdppbz ligand (entries 12 and 13): such exoꢀmethyleneꢀtype substrates did not
provide any aminoborated products at all under the first generation IPrCuBr catalysis.4a
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Table 2. Copper-Catalyzed Internally Borylative Aminoboration of Various Unactivated
Terminal Alkenes 1 with O-Benzoyl-N,N-dibenzylhydroxylamine (2a) and Bis(pinacolato)diborona
entry
1
ligand
3 or 3-O, yield (%)b, 3:4c
1
DTBMꢀdppbz
2
DTBMꢀdppbz
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1
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DTBMꢀdppbz
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DTBMꢀdppbz
DTBMꢀdppbz
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DTBMꢀdppbz
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DTBMꢀdppbz
oꢀMeꢀdppbz
1g
9
oꢀMeꢀdppbz
oꢀMeꢀdppbz
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11
oꢀMeꢀdppbz
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DTBMꢀdppbz
DTBMꢀdppbz
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a
13
Reaction conditions: 1 (0.25 mmol), 2a (0.75 mmol), pinB–Bpin (0.75 mmol), CuCl (0.025 mmol),
ligand (0.025 mmol), LiOꢀtꢀBu (1.0 mmol), THF (1.5 mL), 4 h, rt, N2. b 1H NMR yield of 3 (Bpin
form). Isolated yields (3 or 3-O) are in parentheses. c The regioisomeric ratio of 3:4 was determined
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1
d
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by H NMR of the crude mixture.
1.0 mmol scale.
92:8 diastereomeric ratio. The relative
stereochemistry was not determined.
The generality of hydroxylamines 2 was also briefly investigated with 1ꢀoctene (1a) (Scheme 2).
The CuCl/DTBMꢀdppbz catalysis was compatible with other acyclic amines such as
NꢀbenzylꢀNꢀmethylamine (3ab-O) and N,Nꢀdiethylamine (3ac-O).
The cyclic piperizine and
morpholine were also viable substrates, and the desired aminoalcohol derivatives 3ad-O and 3ae-O
were obtained in synthetically acceptable yield. Also in these cases, the regioselectivity was
substantially high (3:4 >91:9).
Scheme 2. Cu/DTBM-dppbz-Catalyzed Internally Borylative Aminoboration of 1-Octene (1a)
with Several Hydroxylamines 2 and Bis(pinacolato)diborona
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a
Reaction conditions: see footnote of Table 2. 1H NMR yields of 3 (Bpin form) are given. Isolated
yields of 3-O are in parentheses. The regioisomeric ratio of 3:4 was determined by 1H NMR.
The Bpin moiety of 3aa can be a useful synthetic handle (Scheme 3). Upon treatment with
MeOꢀNHLi followed by (Boc)2O,8 3aa could be directly converted into the corresponding 1,2ꢀdiamine
5 without any additional deprotection of the boryl group. Additionally, the reaction of crude 3aa with
KHF2 afforded the more stable internal ammonium borate salt 6 in 48% overall yield from 1ꢀoctene
(1a).9 This protocol is beneficial from the technical point of view because the borate 6 was readily
purified by simple filtration without column chromatography. Furthermore, the Mn(III)ꢀmediated
oxidative radical cyclization of 6 proceeded to afford the tetrahydroisoquinoline framework 7 in 71%
yield.10
Scheme 3. Transformation of Bpin moiety of 3aa
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Although the mechanistic detail is unclear at present, the overall regioselectivity of aminoboration
reaction can be determined in the insertion step of alkene 1 into the pinB–CuLn intermediate 8,11 in
which the more congested copper center is located at the terminal carbon (9; Scheme 4).5,12
Subsequent C–N forming process13 with the hydroxylamine 2 occurs to form the observed internally
borylative aminoborated product 3. The formed Cu(OBz)Ln is again converted to 8 via Cu(OꢀtꢀBu)Ln.
The above assumption is consistent with the trend observed in Table 1: the ratio of 3:4 increased with
increasing the size of ligand substituent. However, it cannot completely explain the decreased
regioselectivity when the bulky metaꢀCF3ꢀsubstituted ligand (CF3ꢀdppbz) is employed (Table 1, entry
9). Thus, electronic effects11b are not negligible. Further studies are essential for the clarification of
the mechanism.
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Scheme 4. Plausible Mechanism
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Conclusion
We have developed two Cu(I)/modified dppbz catalyst systems for regioselective aminoboration of
unactivated terminal alkenes with bis(pinacolato)diboron. The bisphosphineꢀbased catalysis allows the
introduction of readily transformable Bpin group and shows better internally borylation regioselectivity
for broader terminal alkenes. Moreover, the second generation catalyst is compatible with
1,1ꢀdisubstituted alkenes, which are inaccessible substrates under the IPrCuBrꢀbased first generation
catalysis. Further development of related electrophilic amination as well as alkene difunctionalization
reactions is ongoing in our laboratory and will be reported in due course.
Experimental Section
Instrumentation and Chemicals 1H, 13C{1H}, 11B, and 19F{1H} NMR spectra were recorded at 400
MHz, 100 MHz, 128 MHz, and 376 MHz, respectively, for CDCl solutions. HRMS data were
3
obtained by APCI or ESI using TOF. TLC analyses were performed on commercial glass plates
bearing 0.25ꢀmm layer of Wako NH2 Silica gel 60F254 or Merck silica gel 60F254. Silica gel (Wakogel
50NH2 or Wakosil Cꢀ200) was used for column chromatography. Gel permeation chromatography
(GPC) was performed by by LCꢀ20AR (pump, SHIMADZU, 7.5 mL/min EtOAc) and SPDꢀ20A (UV
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detector, SHIMADZU, 254 nm) with two inꢀline YMCꢀGPC T2000 (20 x 600 mm, particle size: 10 ꢀm)
(preparative columns, YMC, EtOAc eluent). Unless otherwise noted, materials obtained from
commercial suppliers were used as received. Anhydrous THF was purchased and used out of the
bottle without further purification. CuCl was washed sequentially with 1 M HCl aq., EtOH, and Et2O
three times at each step and dried under high vacuum for 6 h before use. Modified dppbz ligands were
synthesized according to the literature.7a,b,14 OꢀBenzoylꢀN,Nꢀdiethylhydroxylamine 2c was prepared
by the condensation of diethylhydroxylamine and benzoyl chloride. Others were readily accessible
through the nucleophilic substitution of the corresponding secondary amines with benzoyl peroxide.15a,b
All reactions were carried out under nitrogen atmosphere unless otherwise noted.
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The regiochemistry of 3aa was determined by derivatization into the known diamine 5.4a The
isomers 4aa, 4ba, and 4ha were already prepared and reported in our previous work.4a The
regiochemistry of other aminoborated products was assigned by analogy.
Typical Procedure for Cu/DTBM-dppbz-Catalyzed Regioselective Aminoboration of
Unactivated Terminal Alkenes with Bis(pinacolato)diboron. The synthesis of 3aa is representative
(Table
2,
entry
1).
CuCl
(2.5
mg,
0.025
mmol),
1,2ꢀbis(bis(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀmethoxyphenyl)phosphino)benzene (DTBMꢀdppbz, 25 mg, 0.025 mmol),
and LiOtBu (80 mg, 1.0 mmol) were placed in a 20 mL twoꢀnecked reaction flask, which was filled
with nitrogen by using the Schlenk technique. THF (0.75 mL) was then added to the flask, and the
suspension was stirred for 15 min at ambient temperature. A solution of 1ꢀoctene (1a, 28 mg, 0.25
mmol), bis(pinacolato)diboron (0.19 g, 0.75 mmol), and OꢀbenzoylꢀN,Nꢀdibenzylhydroxylamine (2a,
0.24 g, 0.75 mmol) in THF (0.75 mL) were added dropwise. The solution was stirred at ambient
temperature for additional 4 h. The resulting mixture was filtered through a short pad of sodium
sulfate and neutral alumina. After evaporation of the volatile materials, the residue was purified by gel
permeation chromatography (GPC) with ethyl acetate to yield
a
91:9 mixture of
N,Nꢀdibenzylꢀ2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)octanꢀ1ꢀamine
(3aa)
and
13
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N,Nꢀdibenzylꢀ1ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)octanꢀ2ꢀamine (4aa) in 60% combined
1
2
3
yield (65 mg, 0.15 mmol).
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5
6
7
8
A
91:9
Regiomixture
of
9
N,N-Dibenzyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octan-1-amine
(3aa)
and
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60
N,N-Dibenzyl-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)octan-2-amine (4aa): oil; 65 mg, 60%;
1H NMR (400 MHz, CDCl3) for mixture δ 0.76ꢀ0.81 (m, 0.09 x 1H for 4aa), 0.87 (t, J = 6.8 Hz, 0.91 x
3H for 3aa), 0.84ꢀ0.89 (m, 0.09 x 3H for 4aa), 1.24 (s, 0.91 x 6H for 3aa), 1.26 (s, 0.91 x 6H for 3aa),
1.23ꢀ1.30 (m, 0.91 x 8H for 3aa), 1.23ꢀ1.30 (m, 0.09 x 21H for 4aa), 1.35ꢀ1.49 (m, 0.91 x 3H for 3aa),
1.54ꢀ1.68 (m, 0.09 x 2H for 4aa), 2.39 (dd, J = 7.0, 12.1 Hz, 0.91 x 1H for 3aa), 2.58 (dd, J = 8.2, 12.1
Hz, 0.91 x 1H for 3aa), 2.83ꢀ2.90 (m, 0.09 x 1H for 4aa), 3.38 (d, J = 13.8 Hz, 0.09 x 2H for 4aa), 3.45
(d, J = 13.7 Hz, 0.91 x 2H for 3aa), 3.56 (d, J = 13.7 Hz, 0.91 x 2H for 3aa), 3.64 (d, J = 13.8 Hz, 0.09
x 2H for 4aa), 7.18ꢀ7.22 (m, 0.09 x 2H for 4aa), 7.20 (d, J = 7.1 Hz, 0.91 x 2H for 3aa), 7.25ꢀ7.30 (m,
0.09 x 4H for 4aa), 7.28 (t, J = 7.1 Hz, 0.91 x 4H for 3aa), 7.34 (d, J = 7.1 Hz, 0.91 x 4H for 3aa),
7.32ꢀ7.38 (m, 0.09 x 4H for 4aa); 13C{1H} NMR (100 MHz, CDCl3) for mixture δ 15.7, 22.8, 24.7,
24.85, 24.89, 25.1, 29.1, 29.3, 29.4, 29.7, 29.8, 33.4, 56.1, 58.2, 82.9, 83.0, 126.6, 126.7, 128.1, 129.1,
129.2, 139.8 (All observed signals were shown because of the complexity associated with the
11
regioisomer. The carbon signal bound to boron was not observed due to quadrupolar relaxation.); B
NMR (128 MHz, CDCl3) for mixture δ 33.99; HRMS (APCI) m/z (M+H)+ Calcd for C28H43BNO2,
436.3386. Found 436.3379.
A
90:10
N,N-Dibenzyl-5-((tert-butyldimethylsilyl)oxy)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)penta
n-1-amine (3ba) and
Regiomixture
of
N,N-Dibenzyl-5-((tert-butyldimethylsilyl)oxy)-1-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)penta
1
n-2-amine (4ba): oil; 91 mg, 70%; H NMR (400 MHz, CDCl3) for mixture δ 0.01 (s, 0.10 x 6H for
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4ba), 0.08 (s, 0.90 x 6H for 3ba), 0.77ꢀ0.82 (m, 0.10 x 1H for 4ba), 0.87 (s, 0.10 x 9H for 4ba), 0.89 (s,
0.90 x 9H for 3ba), 1.21ꢀ1.23 (m, 0.10 x 1H for 4ba)1.23 (s, 0.10 x 6H for 4ba), 1.24 (s, 0.90 x 6H for
3ba), 1.25 (s, 0.90 x 6H for 3ba), 1.26 (s, 0.10 x 6H for 4ba), 1.33ꢀ1.51 (m, 0.90 x 5H for 3ba),
1.33ꢀ1.51 (m, 0.10 x 3H for 4ba), 1.69ꢀ1.79 (m, 0.10 x 1H for 4ba), 2.40 (dd, J = 7.4, 12.2 Hz, 0.90 x
1H for 3ba), 2.58 (dd, J = 8.2, 12.2 Hz, 0.90 x 1H for 3ba), 2.82ꢀ2.89 (m, 0.10 x 1H for 4ba), 3.38 (d, J
= 13.7 Hz, 0.10 x 2H for 4ba), 3.47 (d, J = 13.8 Hz, 0.90 x 2H for 3ba), 3.55ꢀ3.58 (m, 0.10 x 2H for
4ba), 3.55 (d, J = 13.8 Hz, 0.90 x 2H for 3ba), 3.56 (t, J = 6.2 Hz, 0.90 x 2H for 3ba), 3.65 (d, J = 13.7
Hz, 0.10 x 2H for 4ba), 7.16ꢀ7.24 (m, 0.10 x 2H for 4ba), 7.21 (d, J = 7.0 Hz, 0.90 x 2H for 3ba),
7.23ꢀ7.30 (m, 0.10 x 4H for 4ba), 7.27 (d, J = 7.0 Hz, 0.90 x 4H for 3ba), 7.32ꢀ7.37 (m, 0.10 x 4H for
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13
4ba), 7.33 (d, J = 7.0 Hz, 0.90 x 4H for 3ba); C{1H} NMR (100 MHz, CDCl3) for mixture δ ꢀ5.09,
ꢀ5.08, 14.3, 18.5, 21.2, 24.7, 24.9, 25.05, 25.08, 25.6, 25.7, 26.2, 32.1, 32.6, 56.1, 58.2, 60.5, 63.7, 83.1,
126.65, 126.74, 128.1, 129.16, 129.20, 139.8 (All observed signals were shown because of the
complexity associated with the regioisomer. The carbon signal bound to boron was not observed due to
quadrupolar relaxation.); 11B NMR (128 MHz, CDCl3) for mixture δ 34.99; HRMS (APCI) m/z (M+H)+
Calcd for C31H51BNO3Si, 524.3731. Found 524.3738.
Typical Procedure for Cu/o-Me-dppbz-Catalyzed Regioselective Aminoboration of Unactivated
Terminal Alkenes with Bis(pinacolato)diboron. The synthesis of 3ha is representative (Table 2,
entry 7). CuCl (2.5 mg, 0.025 mmol), 1,2ꢀbis(diꢀoꢀtolylphosphino)benzene (oꢀMeꢀdppbz, 13 mg,
0.025 mmol), and LiOtBu (80 mg, 1.0 mmol) were placed in a 20 mL twoꢀnecked reaction flask, which
was filled with nitrogen by using the Schlenk technique. THF (0.75 mL) was then added to the flask,
and the suspension was stirred for 15 min at ambient temperature.
A solution of
4ꢀallylꢀ1,2ꢀdimethoxybenzene (1h, 45 mg, 0.25 mmol), bis(pinacolato)diboron (0.19 g, 0.75 mmol), and
OꢀbenzoylꢀN,Nꢀdibenzylhydroxylamine (2a, 0.24 g, 0.75 mmol) in THF (0.75 mL) were added
dropwise. The solution was stirred at ambient temperature for additional 4 h. The resulting mixture
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was filtered through a short pad of sodium sulfate and neutral alumina. After evaporation of the
volatile materials, the residue was purified by gel permeation chromatography (GPC) with ethyl acetate
1
2
3
4
5
6
to
yield
a
93:7
mixture
of
7
8
N,N-dibenzylꢀ3ꢀ(3,4ꢀdimethoxyphenyl)ꢀ2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)propanꢀ1ꢀamine
9
(3ha)
and
10
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N,Nꢀdibenzylꢀ1ꢀ(3,4ꢀdimethoxyphenyl)ꢀ3ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)propanꢀ2ꢀamine
(4ha) in 52% combined yield (65 mg, 0.13 mmol).
A
93:7
N,N-Dibenzyl-3-(3,4-dimethoxyphenyl)-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-1-a
mine (3ha) and
Regiomixture
of
N,N-Dibenzyl-1-(3,4-dimethoxyphenyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)propan-2-a
1
mine (4ha): oil; 65 mg, 52%; H NMR (400 MHz, CDCl3) for mixture δ 0.88ꢀ0.92 (m, 0.07 x 1H for
4ha), 1.11 (s, 0.93 x 6H for 3ha), 1.17 (s, 0.93 x 6H for 3ha), 1.22 (s, 0.07 x 6H for 4ha), 1.23 (s, 0.07 x
6H for 4ha), 1.20ꢀ1.25 (m, 0.07 x 1H for 4ha), 1.78ꢀ1.86 (m, 0.93 x 1H for 3ha), 2.45 (dd, J = 7.5, 12.2
Hz, 0.93 x 1H for 3ha), 2.50ꢀ2.60 (m, 0.07 x 1H for 4ha), 2.52 (dd, J = 9.9, 13.7 Hz, 0.93 x 1H for
3ha), 2.65 (dd, J = 8.8, 12.2 Hz, 0.93 x 1H for 3ha), 2.79 (dd, J = 6.2, 13.7 Hz, 0.93 x 1H for 3ha),
2.83ꢀ3.20 (m, 0.07 x 2H for 4ha), 3.47 (d, J = 13.7 Hz, 0.93 x 2H for 3ha), 3.52 (d, J = 14.2 Hz, 0.07 x
2H for 4ha), 3.61 (d, J = 13.7 Hz, 0.93 x 2H for 3ha), 3.66 (d, J = 14.2 Hz, 0.07 x 2H for 4ha), 3.72 (s,
0.07 x 3H for 4ha), 3.82 (s, 0.93 x 3H for 3ha), 3.83 (s, 0.93 x 3H for 3ha), 3.88 (s, 0.07 x 3H for 4ha),
6.69ꢀ6.75 (m, 0.93 x 3H for 3ha), 6.51ꢀ6.75 (m, 0.07 x 3H for 4ha), 7.20 (d, J = 7.0 Hz, 0.93 x 2H for
3ha), 7.18ꢀ7.23 (m, 0.07 x 6H for 4ha), 7.28 (t, J = 7.0 Hz, 0.93 x 4H for 3ha), 7.34 (d, J = 7.0 Hz, 0.93
x 4H for 3ha), 7.24ꢀ7.30 (m, 0.07 x 4H for 4ha); 13C{1H} NMR (100 MHz, CDCl3) for mixture δ 25.0,
25.1, 53.5, 55.8, 56.1, 58.3, 77.4, 83.2, 111.1, 112.2, 120.8, 126.8, 128.1, 129.2, 134.9, 139.6, 147.1,
148.6 (All observed signals were shown because of the complexity associated with the regioisomer. The
11
carbon signal bound to boron was not observed due to quadrupolar relaxation.); B NMR (128 MHz,
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CDCl3) for mixture δ 34.81; HRMS (APCI) m/z (M+H)+ Calcd for C31H41BNO4, 502.3129. Found
1
2
3
502.3122.
4
5
6
7
8
9
Typical Procedure for Cu/Bisphosphine-Catalyzed Regioselective Aminoboration of
Unactivated Terminal Alkenes with Bis(pinacolato)diboron followed by Oxidation with H2O2.
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The synthesis of 3ad-O is representative (Scheme 2).
CuCl (2.5 mg, 0.025 mmol),
1,2ꢀbis(bis(3,5ꢀdiꢀtertꢀbutylꢀ4ꢀmethoxyphenyl)phosphino)benzene (DTBMꢀdppbz, 25 mg, 0.025 mmol),
and LiOtBu (80 mg, 1.0 mmol) were placed in a 20 mL twoꢀnecked reaction flask, which was filled
with nitrogen by using the Schlenk technique. THF (0.75 mL) was then added to the flask, and the
suspension was stirred for 15 min at ambient temperature. A solution of 1ꢀoctene (1a, 28 mg, 0.25
mmol), bis(pinacolato)diboron (0.19 g, 0.75 mmol), and piperidinꢀ1ꢀyl benzoate (2d, 0.15 g, 0.75 mmol)
in THF (0.75 mL) were added dropwise. The solution was stirred at ambient temperature for
additional 4 h. The resulting mixture was quenched with water and then extracted with ethyl acetate
three times. The combined organic layer was dried over sodium sulfate and concentrated in vacuo.
The residual materials were dissolved in THF/EtOH (1.0 mL/0.5 mL), and NaOH aq. (3.0 M, 0.50 mL)
and H2O2 aq. (30%, 0.50 mL) were added in one portion. The resulting mixture was stirred for 30 min
under air. The reaction was quenched with sat. Na2S2O3 aq. The mixture was extracted with Et2O three
times. The combined organic layer was dried over sodium sulfate and concentrated in vacuo. The
residue was purified by NH2 silica gel column chromatography with hexane/ethyl acetate (5:1, v/v) as
an eluent to give
a
91:9 mixture of 1ꢀ(piperidinꢀ1ꢀyl)octanꢀ2ꢀol (3ad-O) and
2ꢀ(piperidinꢀ1ꢀyl)octanꢀ1ꢀol (4ad-O) in 50% overall yield (31 mg, 0.13 mmol).
A 91:9 Regiomixture of 1-(Piperidin-1-yl)octan-2-ol (3ad-O) and 2-(Piperidin-1-yl)octan-1-ol
(4ad-O): oil; 27 mg, 50%; 1H NMR (400 MHz, CDCl3) for mixture δ 0.88 (t, J = 6.9 Hz, 0.91 x 3H for
3ad-O), 0.86ꢀ0.90 (m, 0.09 x 3H for 4ad-O), 1.26ꢀ1.36 (m, 0.91 x 10H for 3ad-O), 1.26ꢀ1.36 (m, 0.09 x
10H for 4ad-O), 1.39ꢀ1.48 (m, 0.91 x 4H for 3ad-O), 1.39ꢀ1.48 (m, 0.09 x 4H for 4ad-O), 1.51ꢀ1.64
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(m, 0.91 x 4H for 3ad-O), 1.51ꢀ1.64 (m, 0.09 x 4H for 4ad-O), 2.17 (dd, J = 10.6, 12.2 Hz, 0.91 x 1H
for 3ad-O), 2.27 (dd, J = 3.1, 12.2 Hz, 0.91 x 1H for 3ad-O), 2.27ꢀ2.36 (m, 0.09 x 2H for 4ad-O),
2.53ꢀ2.66 (m, 0.91 x 2H for 3ad-O), 2.53ꢀ2.66 (m, 0.09 x 1H for 4ad-O), 3.19 (dd, J = 10.2, 10.7 Hz,
0.09 x 1H for 4ad-O), 3.48 (dd, J = 5.3, 10.2 Hz, 0.09 x 1H for 4ad-O), 3.64 (m, 0.91 x 1H for 3ad-O);
13C{1H} NMR (100 MHz, CDCl3) for mixture δ 14.2, 22.8, 24.5, 25.8, 26.3, 29.6, 32.0, 35.2, 54.8, 65.0,
66.2 (All observed signals were shown because of the complexity associated with the regioisomer.);
HRMS (APCI) m/z (M+H)+ Calcd for C13H28NO, 214.2165. Found 214.2165.
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A 90:10 Regiomixture of 1-(Dibenzylamino)-4-(1,3-dioxan-2-yl)butan-2-ol (3ca-O) and
1
2-(Dibenzylamino)-4-(1,3-dioxan-2-yl)butan-1-ol (4ca-O): oil; 54 mg, 61%; H NMR (400 MHz,
CDCl3) for mixture δ 1.28ꢀ1.34 (m, 0.90 x 1H for 3ca-O), 1.28ꢀ1.34 (m, 0.10 x 1H for 4ca-O),
1.34ꢀ1.51 (m, 0.90 x 2H for 3ca-O), 1.34ꢀ1.51 (m, 0.10 x 2H for 4ca-O), 1.55ꢀ1.67 (m, 0.90 x 1H for
3ca-O), 1.55ꢀ1.67 (m, 0.10 x 1H for 4ca-O), 1.69ꢀ1.78 (m, 0.90 x 1H for 3ca-O), 1.69ꢀ1.78 (m, 0.10 x
1H for 4ca-O), 1.83ꢀ1.94 (m, 0.10 x 1H for 4ca-O), 1.98ꢀ2.16 (m, 0.90 x 1H for 3ca-O), 2.43 (dd, J =
5.6, 8.8 Hz, 0.90 x 2H for 3ca-O), 2.79ꢀ2.82 (m, 0.10 x 1H for 4ca-O), 3.39 (d, J = 13.4 Hz, 0.90 x 2H
for 3ca-O), 3.41ꢀ3.54 (m, 0.10 x 4H for 4ca-O), 3.66ꢀ3.77 (m, 0.90 x 3H for 3ca-O), 3.66 ꢀ3.77 (m,
0.10 x 3H for 4ca-O), 3.82 (d, J = 13.4 Hz, 0.90 x 2H for 3ca-O), 3.79ꢀ3.86 (m, 0.10 x 2H for 4ca-O),
4.08 (dd, J = 1.0, 5.0 Hz, 0.90 x 2H for 3ca-O), 4.04ꢀ4.15 (m, 0.10 x 2H for 4ca-O), 4.49 (t, J = 5.0 Hz,
0.90 x 1H for 3ca-O), 7.23ꢀ7.36 (m, 0.90 x 10H for 3ca-O), 7.23ꢀ.7.36 (m, 0.10 x 10H for 4ca-O);
13C{1H} NMR (100 MHz, CDCl3) for mixture δ 19.4, 25.9, 29.1, 31.3, 31.4, 32.6, 53.2, 58.5, 59.7, 60.9,
61.2, 66.8, 67.0, 101.9, 102.2, 127.4, 128.5, 128.6, 129.2, 138.5, 139.4 (All observed signals were
shown because of the complexity associated with the regioisomer.); HRMS (APCI) m/z (M+H)+ Calcd
for C22H30NO3, 356.2220. Found 356.2213.
1
5-(Dibenzylamino)-4-hydroxypentyl pivalate (3da-O): oil; 49 mg, 51%; H NMR (400 MHz,
CDCl3) δ 1.18 (s, 9H), 1.29–1.41 (m, 2H), 1.59–1.68 (m, 1H), 1.68–1.82 (m, 1H), 2.43 (dd, J = 3.8, 7.1
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Hz, 2H), 3.34 (bs, 1H), 3.34 (d, J = 13.4 Hz, 2H), 3.67ꢀ3.73 (m, 1H), 3.84 (d, J = 13.4 Hz, 2H),
3.98ꢀ4.08 (m, 2H), 7.24ꢀ7.35 (m, 10H); 13C{1H} NMR (100 MHz, CDCl3) δ 25.0, 27.3, 31.1, 38.8, 58.5,
59.8, 64.4, 66.6, 127.4, 128.6, 129.1, 138.5, 178.7; HRMS (APCI) m/z (M+H)+ Calcd for C24H34NO3,
384.2533. Found 384.2527.
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1
1-(Dibenzylamino)-3-(trimethylsilyl)propan-2-ol (3ea-O): oil; 25 mg, 31%; H NMR (400 MHz,
CDCl3) δ 0.01 (s, 9H), 0.57 (dd, J = 6.1, 14.5 Hz, 1H), 0.74 (dd, J = 7.6, 14.5 Hz, 1H), 2.41 (d, J = 5.8
Hz, 2H), 3.40 (d, J = 13.5 Hz, 2H), 3.77ꢀ3.83 (m, 1H), 3.83 (d, J = 13.5 Hz, 2H), 7.24ꢀ7.35 (m, 10H);
13C{1H} NMR (100 MHz, CDCl3) δ ꢀ0.5, 23.0, 58.7, 63.0, 65.2, 127.4, 128.6, 129.2, 138.7; HRMS
(APCI) m/z (M+H)+ Calcd for C29H30NOSi, 328.2091. Found 328.2086.
1-(Dibenzylamino)-3-((triisopropylsilyl)oxy)butan-2-ol (3fa-O): An amount of minor diastereomer
1
was quite small, and thus we could not assign all H NMR signals because of low intensity; oil; 25 mg,
31%; 1H NMR (400 MHz, CDCl3) δ 0.01 (s, 9H), 0.57 (dd, J = 6.1, 14.5 Hz, 1H), 0.74 (dd, J = 7.6, 14.5
Hz, 1H), 2.41 (d, J = 5.8 Hz, 2H), 3.40 (d, J = 13.5 Hz, 2H), 3.77ꢀ3.83 (m, 1H), 3.83 (d, J = 13.5 Hz,
2H), 7.24ꢀ7.35 (m, 10H); 13C{1H} NMR (100 MHz, CDCl3) δ ꢀ0.5, 23.0, 58.7, 63.0, 65.2, 127.4, 128.6,
129.2, 138.7; HRMS (APCI) m/z (M+H)+ Calcd for C29H30NOSi, 328.2091. Found 328.2086.
1
1-(Dibenzylamino)-3-phenylpropan-2-ol (3ga-O): oil; 32 mg, 39%; H NMR (400 MHz, CDCl3) δ
2.45 (dd, J = 4.4, 12.6 Hz, 1H), 2.50 (dd, J = 8.8, 12.6 Hz, 1H), 2.58 (dd, J = 5.7, 13.6 Hz, 1H), 2.73
(dd, J = 7.2, 13.6 Hz, 1H), 3.31 (bs, 1H), 3.37 (d, J = 13.4 Hz, 2H), 3.80 (d, J = 13.4 Hz, 2H), 3.90ꢀ3.97
(m, 1H), 7.16ꢀ7.34 (m, 15H); C{1H} NMR (100 MHz, CDCl3) δ 41.4, 58.5, 59.3, 68.4, 126.4, 127.4,
13
128.5, 128.6, 129.1, 129.2, 129.4, 138.6; HRMS (APCI) m/z (M+H)+ Calcd for C23H26NO, 332.2009.
Found 332.1998.
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1-(Dibenzylamino)-3-(naphthalen-2-yl)propan-2-ol (3ia-O): oil; 32 mg, 37%; 1H NMR (400 MHz,
CDCl3) δ 2.47ꢀ2.57 (m, 2H), 2.75 (dd, J = 7.0, 13.7 Hz, 1H), 2.89 (dd, J = 7.0, 13.7 Hz, 1H), 3.39 (d, J
= 13.4 Hz, 2H), 3.80 (d, J = 13.4 Hz, 2H), 3.99ꢀ4.06 (m, 1H), 7.24ꢀ7.32 (m, 12H), 7.41ꢀ7.45 (m, 2H),
7.47 (s, 1H), 7.60ꢀ7.81 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 41.5, 58.3, 59.2, 68.1, 125.4,
126.0, 127.4, 127.66, 127.71, 127.9, 128.0, 128.6, 128.8, 129.2, 132.3, 133.6, 136.1, 138.5.; HRMS
(APCI) m/z (M+H)+ Calcd for C27H28NO, 382.2165. Found 382.2160.
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1
1-Cyclohexyl-2-(dibenzylamino)ethan-1-ol (3ja-O): oil; 30 mg, 37%; H NMR (400 MHz, CDCl3)
δ 0.88ꢀ1.02 (m, 2H), 1.07ꢀ1.27 (m, 4H), 1.55 (d, J = 12.9 Hz, 1H), 1.06ꢀ1.64 (m, 1H), 1.67ꢀ1.73 (m,
2H), 1.83 (d, J = 12.9 Hz, 1H), 2.47 (m, 2H), 3.35 (d, J = 13.4 Hz, 2H), 3.46 (ddd, J = 2.1, 6.6, 11.7 Hz,
13
1H), 3.53 (bs, 1H), 3.87 (d, J = 13.4 Hz, 2H), 7.24ꢀ7.35 (m, 10H); C{1H} NMR (100 MHz, CDCl3) δ
26.1, 26.2, 26.7, 28.7, 29.0, 42.3, 57.3, 58.3, 70.7, 127.4, 128.6, 129.2, 138.5; HRMS (APCI) m/z
(M+H)+ Calcd for C22H30NO, 324.2322. Found 324.2325.
1
1-(Dibenzylamino)-2-methylhexan-2-ol (3ka-O): oil; 47 mg, 60%; H NMR (400 MHz, CDCl3) δ
0.84 (t, J = 7.3 Hz, 3H), 1.06 (s, 3H), 1.10ꢀ1.25 (m, 4H), 1.33ꢀ1.38 (m, 2H), 2.51 (d, J = 13.8 Hz, 1H),
2.51 (bs, 1H), 2.60 (d, J = 13.8 Hz, 1H), 3.66 (d, J = 13.6 Hz, 2H), 3.70 (d, J = 13.6 Hz, 2H), 7.23ꢀ7.28
(m, 2H), 7.30ꢀ7.34 (m, 8H); 13C{1H} NMR (100 MHz, CDCl3) δ 14.2, 23.5, 26.0, 26.1, 41.0, 60.6, 63.0,
72.2, 127.3, 128.5, 129.2, 139.5; HRMS (APCI) m/z (M+H)+ Calcd for C21H30NO, 312.2322. Found
312.2323.
1-((Dibenzylamino)methyl)cyclohexan-1-ol (3la-O): oil; 42 mg, 54%; 1H NMR (400 MHz, CDCl3)
δ 1.28–1.29 (m, 3H), 1.33–1.39 (m, 2H), 1.46–1.61 (m, 5H), 2.55 (s, 2H), 2.66 (bs, 1H), 3.68 (s, 4H),
13
7.23ꢀ7.28 (m, 2H), 7.30ꢀ7.34 (m, 8H); C{1H} NMR (100 MHz, CDCl3) δ 22.3, 26.0, 37.1, 60.7, 63.6,
70.7, 127.3, 128.5, 129.2, 139.4; HRMS (APCI) m/z (M+H)+ Calcd for C21H28NO, 310.2165. Found
310.2159.
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1
2
3
A
92:8
Regiomixture
of
1-(Benzyl(methyl)amino)octan-2-ol
(3ab-O)
and
4
5
1
2-(Denzyl(methyl)amino)octan-1-ol (4ab-O): oil; 36 mg, 58%; H NMR (400 MHz, CDCl3) for
mixture δ 0. 87 (t, J = 7.0 Hz, 0.92 x 3H for 3ab-O), 0.86ꢀ0.90 (m, 0.08 x 3H for 4ab-O), 1.28ꢀ1.40 (m,
0.92 x 8H for 3ab-O), 1.28ꢀ1.40 (m, 0.08 x 8H for 4ab-O), 1.42ꢀ1.47 (m, 0.92 x 2H for 3ab-O),
1.42ꢀ1.47 (m, 0.08 x 2H for 4ab-O), 2.18 (s, 0.08 x 3H for 4ab-O), 2.24 (s, 0.92 x 3H for 3ab-O), 2.34
(dd, J = 3.3, 12.3 Hz, 0.92 x 1H for 3ab-O), 2.41 (dd, J = 10.2, 12.3 Hz, 0.92 x 1H for 3ab-O),
2.77ꢀ2.83 (m, 0.08 x 1H for 4ab-O), 3.31ꢀ3.37 (m, 0.08 x 2H for 4ab-O), 3.46 (d, J = 13.1 Hz, 0.92 x
1H for 3ab-O), 3.57 (dd, J = 4.9, 10.6 Hz, 0.08 x 1H for 4ab-O), 3.70 (d, J = 13.1 Hz, 0.92 x 1H for
3ab-O), 3.67ꢀ3.74 (m, 0.92 x 1H for 3ab-O), 3.67ꢀ3.74 (m, 0.08 x 2H for 4ab-O), 7.25ꢀ7.35 (m, 0.92 x
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60
13
5H for 3ab-O), 7.25ꢀ7.35 (m, 0.08 x 5H for 4ab-O); C{1H} NMR (100 MHz, CDCl3) for mixture δ
11.1, 14.2, 22.7, 23.9, 25.8, 28.5, 29.6, 31.9, 33.4, 35.0, 38.9, 42.1, 51.0, 62.6, 63.6, 66.9, 127.2, 127.3,
127.7, 128.3, 128.5, 129.0, 129.1, 129.8 (All observed signals were shown because of the complexity
associated with the regioisomer.); HRMS (APCI) m/z (M+H)+ Calcd for C16H28NO, 250.2165. Found
250.2162.
A 92:8 Regiomixture of 1-(Diethylamino)octan-2-ol (3ac-O) and 2-(Diethylamino)octan-1-ol
(4ac-O): oil; 21 mg, 42%; 1H NMR (400 MHz, CDCl3) for mixture δ 0.88 (t, J = 7.0 Hz, 0.92 x 3H for
3ac-O), 1.02ꢀ1.04 (m, 0.08 x 3H for 4ac-O), 1.02 (t, J = 7.1 Hz, 0.92 x 6H for 3ac-O), 1.04 (t, J = 7.0
Hz, 0.08 x 6H for 4ac-O), 1.25ꢀ1.37 (m, 0.92 x 8H for 3ac-O), 1.25ꢀ1.37 (m, 0.08 x 8H for 4ac-O),
1.39ꢀ1.55 (m, 0.92 x 2H for 3ac-O), 1.39ꢀ1.55 (m, 0.08 x 2H for 4ac-O), 2.20 (dd, J = 10.6, 12.5 Hz,
0.92 x 1H for 3ac-O), 2.40 (dd, J = 3.1, 12.5 Hz, 0.92 x 1H for 3ac-O), 2.39ꢀ2.42 (m, 0.08 x 2H for
4ac-O), 2.42ꢀ2.51 (m, 0.92 x 2H for 3ac-O), 2.57ꢀ2.68 (m, 0.08 x 2H for 4ac-O), 2.57ꢀ2.68 (m, 0.92 x
2H for 3ac-O), 2.73ꢀ2.80 (m, 0.08 x 1H for 4ac-O), 3.15 (dd, J = 10.1, 10.6 Hz, 0.08 x 1H for 4ac-O),
3.49 (dd, J = 5.2, 10.1 Hz, 0.08 x 1H for 4ac-O), 3.53ꢀ3.59 (m, 0.92 x 1H for 3ac-O), 3.82 (bs, 0.92 x
1H for 3ac-O); 13C{1H} NMR (100 MHz, CDCl3) for mixture δ 12.2, 14.2, 14.9, 22.8, 25.9, 29.7, 29.8,
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32.0, 35.2, 43.2, 47.1, 59.7, 66.9 (All observed signals were shown because of the complexity associated
1
2
3
with the regioisomer.); HRMS (APCI) m/z (M+H)+ Calcd for C12H28NO, 202.2165. Found 202.2167.
4
5
6
7
8
A 91:9 Regiomixture of 1-Morpholinooctan-2-ol (3ae-O) and 2-Morpholinooctan-1-ol (4ae-O):
9
1
oil; 20 mg, 37%; H NMR (400 MHz, CDCl3) for mixture δ 0.88 (t, J = 6.8 Hz, 0.91 x 3H for 3ae-O),
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0.86ꢀ0.91 (m, 0.09 x 3H for 4ae-O), 1.26ꢀ1.40 (m, 0.91 x 8H for 3ae-O), 1.26ꢀ1.40 (m, 0.09 x 8H for
4ae-O), 1.41ꢀ1.51 (m, 0.09 x 2H for 4ae-O), 1.41ꢀ1.51 (m, 0.91 x 2H for 3ae-O), 2.25 (dd, J = 10.5,
12.3 Hz, 0.91 x 1H for 3ae-O), 2.22ꢀ2.78 (m, 0.09 x 1H for 4ae-O), 2.34 (dd, J = 3.0, 12.3 Hz, 0.91 x
1H for 3ae-O), 2.30ꢀ2.35 (m, 0.09 x 1H for 4ae-O), 2.36ꢀ2.42 (m, 0.09 x 2H for 4ae-O), 2.38 (d, J = 6.6
Hz, 0.91 x 2H for 3ae-O), 2.65 (d, J = 6.6 Hz, 0.91 x 2H for 3ae-O), 2.63ꢀ2.76 (m, 0.09 x 2H for
4ae-O), 2.74ꢀ2.77 (m, 0.09 x 1H for 4ae-O), 3.39 (bs, 0.91 x 1H for 3ae-O), 3.66ꢀ3.76 (m, 0.91 x 5H
for 3ae-O), 3.66ꢀ3.76 (m, 0.09 x 4H for 4ae-O); 13C{1H} NMR (100 MHz, CDCl3) for mixture δ 14.21,
14.24, 22.7, 22.8, 24.5, 25.7, 29.6, 31.7, 31.9, 35.0, 53.8, 64.9, 66.1, 67.2 (All observed signals were
shown because of the complexity associated with the regioisomer.); HRMS (APCI) m/z (M+H)+ Calcd
for C12H26NO2, 216.1958. Found 216.1956.
Procedure for Amination of 3aa (Scheme 3). OꢀMethylhydroxylamine (1.2 M THF solution, 0.5
mL, 0.6 mmol) in THF (1.3 mL) was placed in a 20 mL twoꢀnecked reaction flask, which was flushed
o
with nitrogen. BuLi (1.6 M hexane solution, 0.4 mL, 0.6 mmol) was added to the flask at –78 C, and
the suspension was stirred for 30 min at the same temperature. A THF (0.8 mL) solution of a 98:2
regiomixture of N,Nꢀdibenzylꢀ2ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)octanꢀ1ꢀamine (3aa) and
N,Nꢀdibenzylꢀ1ꢀ(4,4,5,5ꢀtetramethylꢀ1,3,2ꢀdioxaborolanꢀ2ꢀyl)octanꢀ2ꢀamine (4aa) (44 mg, 0.1 mmol)
o
was then added dropwise to the solution, and the solution was then stirred at 60 C for 24 h. The
resulting mixture was allowed to cool to room temperature, and Boc2O (0.13 g, 0.6 mmol) was then
added dropwise via a syringe. After being stirred at room temperature for additional 2 h, the resulting
mixture was quenched with water. The mixture was extracted with ethyl acetate, and the combined
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organic layer was dried over sodium sulfate. Concentration in vacuo and purification by silica gel
column chromatography with hexane/ethyl acetate (10:1, v/v) gave tertꢀbutyl
(1ꢀ(dibenzylamino)octanꢀ2ꢀyl)carbamate (5, 29 mg, 0.07 mmol) in 68% yield.
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3
4
5
6
7
8
9
1
tert-Butyl (1-(dibenzylamino)octan-2-yl)carbamate (5): oil; 29 mg, 68%; H NMR (400 MHz,
CDCl3) δ 0.87 (t, J = 6.7 Hz, 3H), 1.22ꢀ1.27 (m, 10H), 1.48 (s, 9H), 2.30ꢀ2.39 (m, 2H), 3.47 (d, J = 13.4
Hz, 2H), 3.63 (d, J = 13.4 Hz, 2H), 3.76ꢀ3.79 (m, 1H), 4.25 (bs, 1H), 7.21ꢀ7.35 (m, 10H); 13C{1H}
NMR (100 MHz, CDCl3) δ 14.2, 22.7, 25.6, 28.6, 29.4, 31.9, 33.8, 48.7, 57.9, 58.7, 78.9, 127.1, 128.3,
129.2, 139.6, 156.1; HRMS (APCI) m/z (M+H)+ Calcd for C27H41N2O2, 425.3163. Found 425.3165.
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Procedure for Synthesis of Internal Ammonium Borate Salt 6 (Scheme 3). The catalytic
aminoboration
was
conducted
with
1ꢀoctene
(1a,
28
mg,
0.25
mmol)
and
OꢀbenzoylꢀN,Nꢀdibenzylhydroxylamine (2a, 0.24 g, 0.75 mmol) under the above standard conditions.
The crude aminoborated product was dissolved in THF/H2O (1.3/0.3 mL), and KHF2 (156 mg, 2.0
mmol) was added. After the resulting mixture was stirred at ambient temperature for 2 h, the mixture
was concentrated in vacuo. The dried solids were triturated with acetone and filtered to remove
inorganic salts. The resulting filtrate was concentrated, and the residual solids was collected and
rinsed with Et2O to give a 96:4 mixture of (1ꢀ(dibenzylammonio)octyl)trifluoroborate (6) and
(2ꢀ(dibenzylammonio)octyl)trifluoroborate (6’) in 48% overall yield (45 mg, 0.12 mmol).
A
96:4 Regiomixture of (1-(Dibenzylammonio)octan-2-yl)trifluoroborate (6) and
o
(2-(Dibenzylammonio)octyl)trifluoroborate (6’): light yellow solid; 126ꢀ129 C; 45 mg, 48% overall
1
yield; H NMR (400 MHz, CDCl3) for major isomer 6 δ 0.86 (t, J = 7.0 Hz, 3H), 0.89ꢀ0.96 (m, 1H),
1.02ꢀ1.11 (m, 1H), 1.19ꢀ1.31 (m, 8H), 1.55ꢀ1.63 (m, 1H), 3.01ꢀ3.06 (m, 1H), 3.20 (dd, J = 11.5, 13.0
Hz, 1H), 3.96 (d, J = 13.3 Hz, 1H), 3.99 (d, J = 13.3 Hz, 1H), 4.22 (d, J = 13.2 Hz, 1H), 4.57 (d, J =
13.2 Hz, 1H), 7.29ꢀ7.34 (m, 2H), 7.44ꢀ7.47 (m, 3H), 7.47ꢀ7.51 (m, 5H), 8.19 (bs, 1H) (An amount of
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1
minor regioisomer 6’ was quite small, and thus we could not assign all H NMR signals because of low
intensity); 13C{1H} NMR (100 MHz, CDCl3) for mixture δ 14.3, 22.9, 28.9, 29.9, 32.0, 56.7, 58.6, 60.0,
129.0, 129.8, 129.9, 130.0, 130.47, 130.52, 130.6 (All observed signals were shown because of the
complexity associated with the regioisomer. The carbon signal bound to boron was not observed due to
quadrupolar relaxation.); 11B NMR (128 MHz, CDCl3) δ 3.92.; 19F{1H} NMR (376 MHz, CDCl3) δ
ꢀ141.58, ꢀ135.77; HRMS (ESI) m/z ([MꢀF]+) calcd for C22H31BF2N, 358.2516. found 358.2512.
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Procedure for Mn(III)-Mediated Oxidative Radical Cyclization of 6 to 7 (Scheme 3). A 96:4
mixture
of
(1ꢀ(dibenzylammonio)octyl)trifluoroborate
(6)
and
(2ꢀ(dibenzylammonio)octyl)trifluoroborate (6’) (38 mg, 0.1 mmol) was placed in a 20 mL twoꢀnecked
reaction flask, which was filled with nitrogen by using the Schlenk technique. AcOH (1.0 ml), water
(1.0 mL), 4ꢀmethylquinoline (14 mg, 0.1 mmol), and trifluoroacetic acid (0.1 mmol, 7.7 ꢀL) were then
added to the flask, and the resulting mixture was stirred at room temperature until complete dissolution
then manganese(III) acetate (0.3 mmol, 58 mg) was added in one portion. The mixture was stirred at
50 °C for 18 h. After cooling to room temperature, the mixture was slowly added to a saturated
Na2CO3 aq. (20 mL). The aqueous layer was then extracted with EtOAc three times. The organic
layers were washed with water then dried (Na2SO4), filtered, and concentrated in vacuo, and purification
by NH2 silica gel column chromatography with hexane/ethyl acetate (20:1, v/v) gave
2ꢀbenzylꢀ4ꢀhexylꢀ1,2,3,4ꢀtetrahydroisoquinoline (7, 22 mg, 0.07 mmol) in 71% yield.
2-Benzyl-4-hexyl-1,2,3,4-tetrahydroisoquinoline (7): oil; 22 mg, 71%; 1H NMR (400 MHz, CDCl3)
δ 0.87 (t, J = 7.1 Hz, 3H), 1.20ꢀ1.32 (m, 8H), 1.63ꢀ1.68 (m, 1H), 1.72ꢀ1.82 (m, 1H), 2.57 (dd, J = 4.1,
11.6 Hz, 1H), 2.68 (dd, J = 4.1, 11.6 Hz, 1H), 2.73ꢀ2.79 (m, 1H), 3.48 (d, J = 14.7 Hz, 1H), 3.55 (d, J =
12.8 Hz, 1H), 3.73 (d, J = 12.8 Hz, 1H), 3.74 (d, J = 14.7 Hz, 1H), 6.97 (d, J = 7.5 Hz, 1H), 7.07ꢀ7.12
(m, 1H), 7.14ꢀ7.18 (m, 2H), 7.26 (d, J = 7.0 Hz, 1H), 7.33 (t, J = 7.0 Hz, 2H), 7.39 (d, J = 7.0 Hz, 2H);
13C{1H} NMR (100 MHz, CDCl3) δ 14.3, 22.8, 27.6, 29.7, 32.0, 36.2, 38.9, 54.4, 57.0, 63.0, 125.6,
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126.2, 126.5, 127.1, 128.35, 128.41, 129.1, 135.0, 138.9, 139.7; HRMS (APCI) m/z (M+H)+ Calcd for
1
2
3
C22H30N, 308.2373. Found 308.2375.
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ASSOCIATED CONTENT
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Supporting Information
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The Supporting Information is available free of charge on the ACS Publication website at DOI:
10.1021/acs.joc.xxxx.
1H, 13C{1H}, 11B, and 19F{1H} NMR spectra for products and kinetic profiles (PDF)
AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: k_hirano@chem.eng.osakaꢀu.ac.jp.
*Eꢀmail: miura@chem.eng.osakaꢀu.ac.jp.
ORCID
Koji Hirano: 0000ꢀ0001ꢀ9752ꢀ1985
Masahiro Miura: 0000ꢀ0001ꢀ8288ꢀ6439
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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 17H01202
(GrantꢀinꢀAid for Scientific Research (A)) and JP 17H06092 (GrantꢀinꢀAid for Specially Promoted
Research) to M.M.
References
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(1) Reviews: (a) Müller, T. E.; Hultz, K. C.; Yus, M.; Foubelo, F.; Tada, M. Chem. Rev. 2008, 108,
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8
(2) For selected recent reviews on the electrophilic amination, see: (a) Barker, T. J.; Jarvo, E. R.
Synthesis 2011, 2011, 3954. (b) Pirnot, M. T.; Wang, Y.ꢀM.; Buchwald, S. L. Angew. Chem., Int. Ed.
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