A mild one-pot conversion of alkenes into amines through tandem ozonolysis and reductive amination

Article abstract of DOI:10.1055/s-0030-1260244

The selective reduction of hydroperoxyacetals to aldehydes by sodium triacetoxyborohydride provides the basis for a mild one-pot synthesis of amines from alkenes. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1260244

PAPER
3475
A Mild One-Pot Conversion of Alkenes into Amines through Tandem
Ozonolysis and Reductive Amination
Tandem
Ozon
h
olysis and Re
i
ductiv
v
e
A
minationaKumar Kyasa,1 Thomas J. Fisher,1 Patrick H. Dussault*
Department of Chemistry, University of Nebraska–Lincoln, Lincoln, NE 68588-0304, USA
Fax +1(402)4729402; E-mail: pdussault1@unl.edu
Received 30 June 2011; revised 27 August 2011
Table 1 Preparation of Hydroperoxyacetals
Abstract: The selective reduction of hydroperoxyacetals to alde-
hydes by sodium triacetoxyborohydride provides the basis for a
mild one-pot synthesis of amines from alkenes.
O3/O2
hydroperoxyacetal
alkene
MeOH–CH2Cl2
Key words: ozonolysis, hydroperoxyacetal, reductive amination,
amine, sodium triacetoxyborohydride
Alkene
Hydroperoxyacetal
Yield
OOH
C8H17
1b (70%)
2b (67%)
3b (69%)
C8H17
OMe
OOH
1a
Reductive amination is a widely used transformation in
organic synthesis.2 The carbonyl precursors are often pre-
pared from alkenes through ozonolysis followed by re-
duction of the ozonide or peroxide intermediates.3,4 In the
course of investigations into new transformations based
upon fragmentation of ozonolysis intermediates,5 we be-
came interested in the development of a mild method for
a one-pot conversion of alkenes to amines. Reductive am-
ination is frequently achieved through the reaction of car-
bonyls and amines in the presence of deactivated boron
hydrides,2b,6,7and NaCNBH3-promoted reductive amina-
tion has been applied in tandem with ozonolysis.8 Howev-
er, NaCNBH3 reduces ozonides (1,2,4-trioxolanes) very
slowly,9 and some of the reported transformations may ac-
tually involve amine-promoted E1cb fragmentation of ter-
minal ozonides.10,11 We investigated the reaction of
NaCNBH3 with more reactive hydroperoxyacetals, but
observed significant formation of alcohols. Our attention
was therefore turned to the less reactive triacetoxyborohy-
dride, which has been investigated little in ozonolysis/
amination sequences.12,13 We now report that NaBH(OAc)3
allows rapid and efficient reduction of ozonolysis-derived
hydroperoxyacetals to aldehydes, enabling a mild and
convenient one-pot synthesis of amines from alkenes
based upon ozonolysis and reductive amination.
AcO(CH2)8
AcO(CH2)8
OMe
OOH
2a
BnO(CH2)3
BnO(CH2)3
OMe
3a
OMe
4b (38%)a
5b (74%)
6b (63%)
MeO OOH
Ph
Ph
4a
OMe
OOH
t-Bu
t-Bu
5a
OMe
OMe
OOH
6a
a Partial decomposition upon chromatography.
equivalent of NaBH(OAc)3 proved optimal; and excess of
reducing reagent (1.5–3 equiv) led to slow overreduction
of the aldehyde. In contrast, the use of the more reactive
NaCNBH3 in stoichiometric amounts cleanly generated
alcohol, while a mixture of alcohol and starting material
was observed even with only 0.33 equivalent of reagent.
Reduction with NaBH(OAc)3 was next applied to a wider
group of hydroperoxyacetals (Table 2). Hydroperoxyace-
tals reacted faster (2 h) than hydroperoxyketals (5–8 h). In
both cases, a high yield of the carbonyl was obtained with
little or no overreduction.
The starting hydroperoxyacetals were readily available
through ozonolysis of precursor alkenes or enol ethers in
3% MeOH–CH2Cl2 (Table 1).14,15
Reduction conditions were initially screened on hydroper-
oxyacetal 1b using 1H NMR of crude reaction mixtures to
monitor the ratio of starting hydroperoxyacetal, aldehyde
(nonanal), and the alcohol (nonanol) derived from overre-
duction. It was found that NaBH(OAc)3 offered high se-
lectivity for aldehyde formation in several different
solvent systems (CH2Cl2, DCE, THF) and under several
sets of conditions. Performing the reduction with one
Reductive amination was easily conducted through reduc-
tion of the hydroperoxyacetal with NaBH(OAc)3 (1
equiv), followed by addition of amine and additional hy-
dride (Scheme 1). The reactions were found to give good
yields of monoalkylated amines. For the amination of al-
dehyde 2b with benzylamine, 8% of the tertiary amine de-
rived from overalkylation was isolated, in addition to the
expected secondary amine 2f.
SYNTHESIS 2011, No. 21, pp 3475–3481
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x.
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x
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2
0
1
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Advanced online publication: 27.09.2011
DOI: 10.1055/s-0030-1260244; Art ID: M64811SS
© Georg Thieme Verlag Stuttgart · New York
Finally, it was found that ozonolysis and reductive amina-
tion could be easily combined into a one-pot transforma-

3476
S. Kyasa et al.
PAPER
Table 2 Reduction of Hydroperoxyacetals with NaBH(OAc)3
Table 3 Stepwise versus One-Pot Reductive Amination
O3, CH2Cl2–MeOH; then:
A) NaBH(OAc)3; then reactant
amine, additional NaBH(OAc)3
alkene
NaBH(OAc)3 (1 equiv)
carbonyl
Yield (time)
1c (63%, 2 h)
hydroperoxyacetal
DCE, r.t.
product
Hydroperoxy acetal Carbonyl
B) NaBH(OAc)3 (3 equiv) plus
reactant amine
O
1b
Alkene
Reactant amine Method (yield) Product amine
C8H17
H
O
PhCH2NH2
A (57%)
A (63%)
N
Ph
2b
2c (85%, 2 h)
3c (91%, 2 h)
AcO(CH2)8
H
7
O
3b
Ph(CH2)2NH2
BnO(CH2)3
H
N
Ph
O
4b
4c (70%, 5 h)
5c (68%, 5 h)
8
3d
Ph
3a
morpholine
PhCH2NH2
A (64%)
A (65%)
5b
t-Bu
O
N
Ph
6b
6c (68%, 8 h)a
O
9
Ph(CH2)2NH2
A (72%)
B (62%)
Ph
N
a Based upon 15% recovered starting material.
10
2d
a. NaBH(OAc)3 (1 equiv)
DCE, 1 h; then
2a
morpholine
PhCH2NH2
B (66%)
B (60%)
H
N
MeO
R1
OOH
R2
R1
R2
NR
b. amine
NaBH(OAc)3 (2 equiv)
2b, 3b, or 4b
amine
Ph
11a R = H 50%
11b R = Me 10%
O
Ph
H
NHBn
Ph(CH2)2NH2
A (65%)
B (65%)
H
NHPh
R2
H
NH
R2
H
N
R1
R2
R1
R1
R1
R2
67%a
63%
75%
63%
65%
52%
Ph
85%
89%
45%
75%
69%
60%
:
:
2d:
3d:
4d:
2e:
3e:
4e:
2f
3f
4f:
2g:
3g:
4g:
N
12
2d–g: R1 = AcO(CH2)8: R2 = H
3d–g: R1 = BnO(CH2)3; R2 = H
4d–g: R1 = Ph(CH2)2; R2 = Me
idation/reduction amination sequence to provide a variety
of heterocyclic amines with an average yield of ~90% per
reaction. In some cases, condensation of the product sec-
ondary amine with residual formaldehyde, a by-product of
the ozonolysis of terminal olefins, gave rise to a tertiary
amine (e.g., 11b).
a 8% of 3° amine was also isolated.
Scheme 1 Stepwise reduction–reductive amination
tion (Table 3). Ozonolysis of an alkene substrate was
conducted in methanol–CH2Cl2 until the alkene could no
longer be detected (TLC). The crude reaction mixture was
then submitted to one of two protocols. In the first (meth-
od A), addition of acetoxyborohydride (1 equiv) was fol-
lowed, after 45 minutes to 1 hour, by addition of amine
and additional acetoxyborohydride. More conveniently
(method B), the crude ozonolysis product was treated with
acetoxyborohydride (3 equiv) and amine (1–2 equiv).
Similar yields were obtained from the two sequences. Un-
der these conditions, cyclic alkenes undergo a tandem ox-
A very similar protocol can be applied to the synthesis of
hydrazones, hydrazines, and diazenes. Ozonolysis of 4a,
followed by treatment of the crude hydroperoxyacetal
with phenylhydrazine and NaBH(OAc)3, cleanly fur-
nished a phenylhydrazone (TLC). Addition of NaCNBH3
resulted in the formation of the phenylhydrazide, which
underwent rapid air oxidation during isolation to furnish
the diazene as the isolated material in 57% yield
(Scheme 2).
Synthesis 2011, No. 21, 3475–3481 © Thieme Stuttgart · New York

PAPER
Tandem Ozonolysis and Reductive Amination
3477
Carbonyl Compounds from Hydroperoxyacetals; General Pro-
cedure 2 (GP 2)
a. O3, MeOH, then
NaBH(OAc)3, PhNHNH2
H
OMe
N
N
Ph
To a r.t. solution of hydroperoxyacetal (~0.5 mmol) in DCE (10
mL) was added NaBH(OAc)3 (0.5 mmol). After product formation
was complete (TLC, eluent: EtOAc–hexanes), the reaction was di-
luted with CH2Cl2 (~40 mL) and washed sequentially with sat. aq
NaHCO3 (~30 mL) and brine (~30 mL). The organic layer was dried
(Na2SO4) and the residue obtained upon concentration in vacuo was
purified by flash chromatography using EtOAc–hexanes.
b. NaCNBH3
R
R
4a
Ph
air
N
R = PhCH2CH2
NHPh
HN
N
R
R
Amines from Hydroperoxyacetals; General Procedure 3 (GP 3)
To a solution of hydroperoxyacetal (~0.5 mmol) in DCE (10 mL)
was added NaBH(OAc)3 (0.5 mmol). The reaction mixture was
stirred for an hour at r.t., after which additional NaBH(OAc)3 (1
mmol) was added followed by amine (0.5 mmol). After the reaction
appeared complete (TLC, eluent: EtOAc–hexanes), the solution
was diluted with CH2Cl2 (40 mL), and washed sequentially with sat.
aq NaHCO3 (30 mL) andbrine (30 mL). The organic layer was dried
(Na2SO4) and the residue obtained upon concentration was purified
by flash chromatography with CH2Cl2–MeOH (1–2%) containing a
few drops of Et3N.
13
Scheme 2
While there are many procedures for conversion of alk-
enes to amines, most require separate oxidation and ami-
nation steps, each involving isolation and purification.
The procedure reported here, which allows a one-pot con-
version of alkenes to a variety of amines while avoiding
any accumulation of peroxide intermediates, may be of
particular use for preparation of an array of amines from a
common precursor, or in procedures limited by concerns
with isolation or handling of peroxide intermediates. Uti-
lization of NaBH(OAc)3 in place of NaCNBH3 provides a
more economical, safe, and selective protocol for the one-
pot tandem ozonolysis/reductive amination sequence for
the conversion of alkenes to amines. The speed and selec-
tivity of the reduction of the hydroperoxyacetals suggests
the formation and decomposition of a peroxyborate,
ROOBH(OAc)2.
Direct Synthesis of Amines from Alkenes; General Procedure 4
(GP 4)
Stepwise (Method A): A solution of alkene (~1 mmol) and MeOH
(0.3 mL) in CH2Cl2 (10 mL) in a round-bottomed flask was ozo-
nized as in GP 1. Following removal of free ozone, the cooling bath
was removed and NaBH(OAc)3 (1 mmol) was added. The reaction
mixture was stirred at r.t. for 45 min, after which amine (~1 mmol)
and NaBH(OAc)3 (2 mmol) were sequentially added. The mixture
was stirred at r.t. for 1–2 h and then filtered through Celite and the
pad washed with CH2Cl2 (20 mL). The filtrate was concentrated on
a rotary evaporator, and the residue was purified as in GP 3.
One Step (Method B): A solution of alkene (~1 mmol) and MeOH
(0.3 mL) in CH2Cl2 (10 mL) in a round-bottomed flask was ozo-
nized as in GP 1. Following removal of free ozone, the cooling bath
was removed and NaBH(OAc)3 (3 mmol) and the amine (1–2
mmol) were sequentially added. The reaction mixture was stirred at
r.t. for 1–2 h and then filtered through Celite and the pad washed
with CH2Cl2 (20 mL). The filtrate was concentrated on a rotary
evaporator, and the residue was purified as in GP 3.
All reagents were used as received from commercial vendors, with
the exception of CH2Cl2, which was distilled from CaH2, and THF,
which was distilled from Na/benzophenone. TLC was performed on
0.25 mm hard-layer silica G plates; developed plates were visual-
ized with a hand-held UV lamp or by staining: 1% Ce(SO4)2 and
10% (NH4)2MoO4 in 10% H2SO4 (general stain, after charring); 1%
N,N¢-dimethyl-p-phenylenediamine solution in 1:20:100 AcOH–
H2O–MeOH (specific for peroxides);16 1% aq KMnO4 (for unsatur-
ated compounds); 3% vanillin in 3% H2SO4 in EtOH (general stain
after charring). NMR spectra were recorded at 400 MHz (1H) or 100
MHz (13C) and in CDCl3 unless otherwise indicated; peaks are re-
ported as: chemical shift (multiplicity, J couplings in Hz, number of
protons). IR spectra were recorded as neat films (ZnSe, ATR mode)
with selected absorbances reported in wavenumbers (cm–1). Melt-
ing points were collected using a melting point apparatus and all
values are uncorrected unless otherwise noted.
Hydroperoxyacetals from Alkenes
1-Methoxynonyl Hydroperoxide (1b) [20525-41-1]
Prepared from 1a (1.40 g, 10 mmol) by GP 1; yield: 1.33 g (70%);
Rf = 0.22 (10% EtOAc–hexanes).
1H NMR: d = 8.19 (s, 1 H), 4.76 (t, J = 5.6 Hz, 1 H), 3.52 (s, 3 H),
1.60–1.80 (m, 2 H), 1.20–1.50 (m, 12 H), 0.90 (t, J = 6.8 Hz, 3 H).
13C NMR: d = 108.8, 55.8, 31.9, 31.3, 29.43, 29.38, 29.3, 24.6, 22.7,
14.1.
Hydroperoxyacetals from Alkenes; General Procedure 1 (GP 1)
A solution of alkene (~1 mmol) and MeOH (0.3 mL) in CH2Cl2 (10
mL) in a round-bottomed flask was cooled to –78 °C and a gaseous
stream of 2% O3/O2 (approximately 1 mmol O3/min) was bubbled
through the solution. Once the pale blue color of ozone appeared,
the ozonizer voltage was set to zero and the reaction was sparged
with O2 until the blue color dissipated. The reaction was quenched
with sat. aq NaHCO3 (15 mL) and the resulting mixture was allowed
to warm to r.t. The separated aqueous layer was extracted with
CH2Cl2 (2 × 25 mL) and the combined organic layers were dried
(Na2SO4). The residue obtained upon concentration in vacuo was
purified by flash chromatography using EtOAc–hexanes.
9-Hydroperoxy-9-methoxynonanol Acetate Ester (2b)
[1255126-65-8]
Prepared from 2a (2.0 g, 10 mmol) by GP 1; yield: 1.66 g (67%);
Rf = 0.33 (25% EtOAc–hexanes).
1H NMR (300 MHz): d = 9.46 (s, 1 H), 4.66 (t, J = 5.8 Hz, 1 H), 3.97
(t, J = 6.7 Hz, 2 H), 3.43 (s, 3 H), 1.98 (s, 3 H), 1.66–1.48 (m, 4 H),
1.33–1.23 (m, 10 H).
13C NMR (75 MHz): d = 171.6, 108.5, 64.7, 55.7, 31.3, 29.2, 29.1,
28.9, 28.4, 25.7, 24.5, 20.9.
4-Benzyloxy-1-methoxybutyl Hydroperoxide (3b) [1255126-67-
0]
Prepared from 3a (1.76 g, 10 mmol) by GP 1; yield: 1.56 g (69%);
Rf = 0.37 (25% EtOAc–hexanes).
Synthesis 2011, No. 21, 3475–3481 © Thieme Stuttgart · New York

3478
S. Kyasa et al.
PAPER
1H NMR: d = 8.93 (s, 1 H), 7.39–7.29 (m, 5 H), 4.77–4.74 (m, 1 H),
4.54 (s, 2 H), 3.58–3.50 (s, 5 H), 1.93–1.71 (m, 4 H).
1H NMR: d = 7.33–7.29 (m, 2 H), 7.24–7.20 (m, 3 H), 2.92 (t,
J = 7.6 Hz, 2 H), 2.79 (t, J = 7.6 Hz, 2 H), 2.16 (s, 3 H).
13C NMR: d = 138.1, 128.4, 127.8, 127.7, 108.4, 72.9, 69.8, 55.9,
28.0, 24.6.
13C NMR: d = 207.9, 141.0, 128.5, 128.3, 126.1, 45.2, 30.1, 29.7.
4-(tert-Butyl)cyclohexanone (5c) [98-53-3]
Prepared from 5b (0.101 g, 0.5 mmol) by GP 2; reaction time: 5 h;
yield: 0.053 g (68%); Rf = 0.50 (25% EtOAc–hexanes).
1H NMR: d = 2.40–2.26 (m, 4 H), 2.09–2.06 (m, 2 H), 1.52–1.38 (m,
3 H), 0.91 (s, 9 H).
(3-Hydroperoxy-3-methoxybutyl)benzene (4b)
Prepared from 4a (1.0 g, 5.6 mmol) by GP 1; yield: 0.427 g (38%);
Rf = 0.36 (25% EtOAc–hexanes).
IR (neat): 3345, 2943, 1102, 1069, 697 cm–1.
1H NMR: d = 7.49 (s, 1 H), 7.31–7.22 (m, 5 H), 3.37 (s, 3 H), 2.76–
2.69 (m, 2 H), 2.08–2.02 (m, 2 H), 1.45 (s, 3 H).
13C NMR: d = 212.5, 46.7, 41.3, 32.4, 27.6.
Adamantan-2-one (6c) [700-58-3]
13C NMR: d = 141.7, 128.5, 128.3, 126.0, 106.9, 49.1, 36.9, 30.5,
Prepared from 6b (0.099 g, 0.5 mmol) by GP 2; reaction time: 8 h;
yield: 0.044 g [68% based on 0.015 g (15%) starting material recov-
ery]; Rf = 0.47 (25% EtOAc–hexanes).
1H NMR: d = 2.54 (m, 2 H), 2.09–1.92 (m, 12 H).
13C NMR: d = 218.4, 46.9, 39.2, 36.3, 27.4.
19.1.
HRMS-ESI: m/z calcd for C11H16O3 + Na (M + Na)+: 219.0997;
found: 219.1007.
4-(t-Butyl)-1-hydroperoxy-1-methoxycyclohexane (5b)
[169294-55-7]
Prepared as a mixture of diastereomers from 5a (1.52 g, 10 mmol)
by GP 1; yield: 1.49 g (74%); Rf = 0.41 (20% EtOAc–hexanes).
1H NMR: d = 7.50 (s, 0.25 H), 7.48 (s, 0.68 H), 3.34 (s, 0.79 H), 3.31
(s, 2.18 H), 2.20–2.28 (m, 0.54 H), 2.09–2.19 (m, 1.52 H), 1.66–177
(m, 2 H), 1.33–1.46 (m, 2 H), 1.12–1.32 (m, 2 H), 1.00–1.11 (m, 1
H), 0.89 (s, 9 H).
Amines from Hydroperoxyacetals
9-Morpholinononanol Acetate Ester (2d)
Prepared from 2b (0.124 g, 0.5 mmol) with morpholine (0.5 mmol)
by GP 3; reaction time: 5 h; yield: 0.115 g (85%); Rf = 0.32 (10%
MeOH–CH2Cl2).
IR (neat): 2927, 2853, 1738, 1118 cm–1.
13C NMR: d = 105.7, 105.4, 48.5, 48.3, 47.6, 47.5, 32.3, 31.5, 30.9,
27.6, 23.6, 23.4.
1H NMR: d = 4.05 (t, J = 6.8 Hz, 2 H), 3.72 (t, J = 4.4 Hz, 4 H), 2.44
(m, 4 H), 2.32 (t, J = 7.4 Hz, 2 H), 2.04 (s, 3 H), 1.65–1.57 (m, 2 H),
1.48 (m, 2 H), 1.35–1.29 (m, 10 H).
2-Hydroperoxy-2-methoxyadamantane (6b) [55975-21-8]
Prepared from 6a (1.0 g, 5.61 mmol) by GP 1; yield: 0.700 g (63%);
Rf = 0.50 (25% EtOAc–hexanes).
1H NMR: d = 7.34 (s, 1 H), 3.32 (s, 3 H), 2.23 (m, 2 H), 2.01–1.86
(m, 6 H), 1.70–1.66 (m, 6 H).
13C NMR: d = 171.2, 66.9, 64.6, 59.2, 53.8, 29.42, 29.38, 29.1, 28.5,
27.4, 26.5, 25.8, 20.9.
HRMS-FAB: m/z calcd for C15H30NO3 (M + H)+: 272.2226; found:
272.2213.
13C NMR: d = 107.5, 47.4, 37.1, 33.71, 33.68, 31.9, 27.0, 26.9.
N-Phenyl-9-aminononanol Acetate Ester (2e)
Prepared from 2b (0.124 g, 0.5 mmol) with aniline (0.5 mmol) by
GP 3; reaction time: 5 h; yield: 0.104 g (75%); Rf = 0.50 (10%
EtOAc–hexanes).
Carbonyls from Hydroperoxyacetals
Nonanal (1c) [124-19-6]
Prepared from 1b (0.095 g, 0.5 mmol) by GP 2; reaction time: 2 h;
yield: 0.045 g (63%); Rf = 0.66 (10% EtOAc–hexanes).
1H NMR: d = 9.78 (t, J = 1.8 Hz, 1 H), 2.43 (dt, J = 1.8, 7.3 Hz, 2
H), 1.64 (m, 2 H), 1.31–1.28 (m, 10 H), 0.89 (t, J = 6.9 Hz, 3 H).
13C NMR: d = 203.0, 43.9, 31.8, 29.3, 29.2, 29.1, 22.6, 22.0, 14.0.
IR (neat): 3401, 2926, 2854, 1734, 1236 cm–1.
1H NMR: d = 7.22–7.18 (m, 2 H), 6.74–6.62 (m, 3 H), 4.09 (t,
J = 6.76 Hz, 2 H), 3.66 (s, 1 H), 3.13 (t, J = 7.16 Hz, 2 H), 2.08 (s,
3 H), 1.68–1.63 (m, 4 H), 1.43–1.36 (m, 10 H).
13C NMR: d = 171.3, 148.6, 129.2, 117.0, 112.7, 64.6, 43.9, 29.6,
29.5, 29.4, 29.2, 28.6, 27.2, 25.9, 21.1.
HRMS-FAB: m/z calcd for C17H28NO2 (M + H)+: 278.2115; found:
278.2123.
9-Hydroxynonanal Acetate Ester (2c) [29541-97-7]
Prepared from 2b (0.496 g, 2 mmol) by GP 2; reaction time: 2 h;
yield: 0.341 g (85%); Rf = 0.44 (25% EtOAc–hexanes).
1H NMR: d = 9.78 (t, J = 1.8 Hz, 1 H), 4.07 (t, J = 6.8 Hz, 2 H), 2.45
(dt, J = 1.8, 7.3 Hz, 2 H), 2.07 (s, 3 H), 1.64 (m, 4 H), 1.34 (m, 8 H).
13C NMR: d = 202.7, 171.1, 64.5, 43.8, 29.1, 28.97, 28.95, 28.5,
25.8, 21.9, 20.9.
N-Benzyl-9-aminononanol Acetate Ester (2f)
Prepared from 2b (0.124 g, 0.5 mmol) with benzylamine (2.5
mmol) by GP 3; reaction time: 5 h; yield: 0.098 g (67%); Rf = 0.42
(10% MeOH–CH2Cl2).
IR (neat): 2923, 2856, 1737, 1236 cm–1.
4-(Benzyloxy)butanal (3c) [5470-84-8]
Prepared from 3b (0.107 g, 0.47 mmol) by GP 2; reaction time: 2 h;
yield: 0.076 g (91%); Rf = 0.33 (25% EtOAc–hexanes).
1H NMR: d = 9.79 (t, J = 1.5 Hz, 1 H), 7.39–7.27 (m, 5 H), 4.51 (s,
2 H), 3.53 (t, J = 6.0 Hz, 2 H), 2.58 (dt, J = 1.32, 7.1 Hz, 2 H), 1.98
(quint, J = 6.5 Hz, 2 H).
13C NMR: d = 202.3, 138.3, 128.4, 127.6, 72.9, 69.1, 40.9, 22.6.
1H NMR: d = 7.39–7.25 (m, 5 H), 4.21 (s, 1 H), 4.04 (t, J = 6.8 Hz,
2 H), 3.84 (s, 2 H), 2.65 (t, J = 7.5 Hz, 2 H), 2.04 (s, 3 H), 1.62–1.59
(m, 4 H), 1.28 (m, 10 H).
13C NMR: d = 171.2, 138.2, 128.6, 128.5, 127.4, 64.6, 53.3, 48.7,
29.4, 29.3, 29.1, 29.1, 28.6, 27.2, 25.9, 21.0.
HRMS-ESI: m/z calcd for C15H29NO2 + Na (M + Na)+: 314.2091;
found: 314.2110.
4-Phenylbutan-2-one (4c) [2550-26-7]
Prepared from 4b (0.098 g, 0.5 mmol) by GP 2; reaction time: 5 h;
yield: 0.052 g (70%); Rf = 0.37 (25% EtOAc–hexanes).
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Tandem Ozonolysis and Reductive Amination
3479
N,N¢-(Bis-9-acetoxynonyl)benzylamine
13C NMR: d = 140.5, 138.6, 128.4, 128.3, 128.1, 127.6, 127.5,
The tertiary amine, N,N¢-(bis-9-acetoxynonyl)benzylamine, result-
ing from the reductive amination of 2f by 2b was also isolated in 8%
yield; Rf = 0.65 (10% MeOH–CH2Cl2).
126.9, 72.9, 70.3, 54.0, 49.2, 27.6, 26.8.
N-[4-(Benzyloxy)butyl)]-2-phenethylamine (3g)
Prepared from 3b (0.107 g, 0.47 mmol) with phenethylamine (2.5
mmol) by GP 3; reaction time: 4 h; yield: 0.087 g (65%); Rf = 0.22
(5% MeOH–CH2Cl2).
IR (neat): 2925, 2855, 1738, 1232, 1043 cm–1.
1H NMR: d = 7.35–7.22 (m, 5 H), 4.06 (t, J = 6.8 Hz, 4 H), 3.56 (s,
2 H), 2.40 (t, J = 7.2 Hz, 4 H), 2.06 (s, 6 H), 1.66–1.59 (m, 4 H),
1.47–1.45 (m, 4 H), 1.34–1.27 (20 H).
13C NMR: d = 171.2, 140.5, 128.8, 128.0, 126.6, 64.6, 58.6, 53.8,
29.5, 29.4, 29.2, 28.6, 27.4, 27.0, 25.9, 21.0.
HRMS-FAB Calcd for C29H50NO4 (M + H)+: 476.3740; found:
476.3725.
IR (neat): 3026, 2932, 2854, 1097, 696 cm–1.
1H NMR: d = 7.37–7.22 (m, 10 H), 4.52 (s, 2 H), 3.50 (t, J = 6.2 Hz,
2 H), 2.92–2.88 (m, 2 H), 2.84–2.80 (m, 2 H), 2.68–2.65 (t, J = 7.1
Hz, 2 H), 1.69–1.55 (m, 4 H), 1.37 (s, 1 H).
13C NMR: d = 140.1, 138.6, 128.7, 128.5, 128.4, 127.6, 127.5,
126.1, 72.9, 70.3, 51.2, 49.7, 36.5, 27.6, 26.9.
N-Phenethyl-9-aminononanol Acetate Ester (2g)
Prepared from 2b (0.124 g, 0.5 mmol) with phenethylamine (2
mmol) by GP 3; reaction time: 5 h; yield: 0.096 g (63%); Rf = 0.60
(10% MeOH–CH2Cl2).
HRMS-FAB: m/z calcd for C19H26NO (M + H)+: 284.2009; found:
284.2018.
4-(4-Phenylbutan-2-yl)morpholine (4d) [2832-95-3]
Prepared from 4b (0.098 g, 0.5 mmol) with morpholine (0.5 mmol)
by GP 3; reaction time: 24 h; yield: 0.049 g (45%); Rf = 0.37 (5%
MeOH–CH2Cl2).
1H NMR: d = 7.32–7.18 (m, 5 H), 3.75–3.72 (m, 4 H), 2.75–2.62 (m,
2 H), 2.60–2.52–2.44 (m, 5 H), 1.90–1.83 (m, 1 H), 1.66 (m, 1 H),
1.64–1.54 (m, 1 H), 1.03 (d, J = 6.7 Hz, 2 H).
IR (neat): 3676, 2988, 2901, 1736 cm–1.
1H NMR: d = 7.32–7.19 (m, 5 H), 4.06 (t, J = 6.7 Hz, 2 H), 2.91–
2.87 (m, 2 H), 2.84–2.80 (m, 2 H), 2.62 (t, J = 7.3 Hz, 2 H), 2.06 (s,
3 H), 1.62 (q, J = 7.2 Hz, 2 H), 1.47 (m, 2 H), 1.29 (m, 10 H).
13C NMR: d = 171.3, 140.2, 128.7, 128.4, 126.1, 64.6, 51.3, 49.9,
36.5, 30.1, 29.5, 29.4, 29.2, 28.6, 27.3, 25.9, 21.0.
HRMS-FAB: m/z calcd for C19H32NO2 (M + H)+: 306.2428; found:
306.2439.
13C NMR: d = 142.6, 128.4, 128.3, 125.7, 67.5, 58.4, 48.7, 35.3,
32.8, 13.9.
N-(4-Phenylbutan-2-yl)aniline (4e) [72641-00-0]
Prepared from 4b (0.098 g, 0.5 mmol) with aniline (0.5 mmol) by
GP 3; reaction time: 36 h; yield: 0.068 g (60%); Rf = 0.51 (10%
EtOAc–hexanes).
1H NMR: d = 7.33–7.28 (m, 2 H), 7.23–7.15 (m, 5 H), 6.69 (t,
J = 7.3 Hz, 1 H), 6.56 (d, J = 8.2 Hz, 2 H), 3.52 (m, 1 H), 3.45 (s, 1
H), 2.75 (t, J = 7.8 Hz, 2 H), 1.95–1.86 (m, 1 H), 1.84–1.75 (m, 1
H), 1.24 (d, J = 6.3 Hz, 3 H).
4-[4-(Benzyloxy)butyl]morpholine (3d)
Prepared from 3b (0.107 g, 0.47 mmol) with morpholine (0.5
mmol) by GP 3; reaction time: 5 h; yield: 0.104 g (89%); Rf = 0.33
(5% MeOH–CH2Cl2).
IR (neat): 2942, 2853, 2806, 1116 cm–1.
1H NMR: d = 7.34–7.27 (m, 5 H), 4.50 (s, 2 H), 3.72 (t, J = 4.7 Hz,
4 H), 3.49 (t, J = 6.1 Hz, 2 H), 2.44 (m, 4 H), 2.35 (t, J = 7.2 Hz, 2
H), 1.66–1.56 (m, 4 H).
13C NMR: d = 147.6, 142.0, 129.3, 128.5, 128.4, 125.9, 116.9,
113.2, 47.9, 38.8, 32.5, 20.9.
13C NMR: d = 138.6, 128.4, 127.6, 127.5, 72.9, 70.1, 66.9, 58.8,
53.7, 27.7, 23.2.
N-Benzyl-4-phenylbutan-2-amine (4f) [68164-04-5]
Prepared from 4b (0.098 g, 0.5 mmol) with benzylamine (0.5
mmol) by GP 3; reaction time: 36 h; yield: 0.089 g (75%); Rf = 0.25
(5% MeOH–CH2Cl2).
1H NMR: d = 7.36–7.20 (m, 10 H), 3.87 (d, J = 13.0 Hz, 1 H), 3.77
(d, J = 13.0 Hz, 1 H), 2.82–2.64 (m, 3 H), 1.90–1.81 (m, 1 H), 1.76–
1.66 (m, 1 H), 1.41 (s, 1 H), 1.19 (d, J = 6.4 Hz, 3 H).
HRMS-FAB: m/z calcd for C15H24NO2 (M + H)+: 250.1802; found:
250.1812.
N-[4-(Benzyloxy)butyl]aniline (3e)
Prepared from 3b (0.107 g, 0.47 mmol) with aniline (0.5 mmol) by
GP 3; reaction time: 4 h; yield: 0.083 g (69%); Rf = 0.51 (20%
EtOAc–hexanes).
13C NMR: d = 142.5, 140.7, 128.44, 128.39, 128.2, 127.9, 126.9,
IR (neat): 3403, 3026, 2935, 2858, 1601, 1505 cm–1.
125.7, 52.0, 51.3, 38.7, 32.3, 20.4.
1H NMR: d = 7.38–7.30 (m, 5 H), 7.21–7.17 (m, 2 H), 6.71 (t,
J = 7.3 Hz, 1 H), 6.61–6.59 (m, 2 H), 4.54 (s, 2 H), 3.73 (s, 1 H),
3.55 (t, J = 5.9 Hz, 2 H), 3.18–3.15 (m, 2 H), 1.79–1.57 (m, 4 H).
13C NMR: d = 148.6, 138.6, 129.3, 128.5, 127.8, 127.7, 117.2,
112.8, 73.1, 70.2, 43.8, 27.5, 26.5.
N-Phenethyl-4-phenylbutan-2-amine (4g) [161012-69-7]
Prepared from 4b (0.138 g, 0.7 mmol) with phenethylamine by GP
3; reaction time: 30 h; yield: 0.092 g (52%); Rf = 0.30 (10% MeOH–
CH2Cl2).
HRMS-FAB: m/z calcd for C17H22NO (M + H)+: 256.1696; found:
256.1692.
1H NMR: d = 7.36–7.15 (m, 10 H), 2.99–2.91 (m, 1 H), 2.88–2.79
(m, 3 H), 2.72–2.66 (m, 1 H), 2.64–2.57 (m, 2 H), 1.84–1.75 (m, 1
H), 1.68–1.59 (m, 1 H), 1.30 (s, 1 H), 1.13 (d, J = 6.3 Hz, 3 H).
N-[4-(Benzyloxy)butyl]benzylamine (3f) [60058-23-3]
Prepared from 3b (0.107 g, 0.47 mmol) with benzylamine (2.5
mmol) by GP 3; reaction time: 5 h; yield: 0.079 g (63%); Rf = 0.51
(10% MeOH–CH2Cl2).
1H NMR: d = 7.39–7.24 (m, 10 H), 4.52 (s, 2 H), 3.80 (s, 2 H), 3.50
(t, J = 6.2 Hz, 2 H), 2.67 (t, J = 6.9 Hz, 2 H), 1.73–1.59 (m, 4 H),
1.55 (s, 1 H).
13C NMR: d = 142.3, 140.1, 128.7, 128.5, 128.4, 128.3, 126.2,
125.7, 55.4, 48.5, 38.7, 36.6, 32.3, 20.3.
Amines from Alkenes
1-Benzylazapine (7) [20422-13-3]
Prepared by reacting cyclohexene (0.082 g, 1 mmol) with benzyl-
amine (1 mmol) according to GP 4A; reaction time: 2 h; yield: 0.107
g (57%); Rf = 0.57 (10% MeOH–CH2Cl2).
Synthesis 2011, No. 21, 3475–3481 © Thieme Stuttgart · New York

3480
S. Kyasa et al.
PAPER
1H NMR: d = 7.40–7.27 (m, 5 H), 3.69 (s, 2 H), 2.67–2.66 (m, 4 H),
1.67 (m, 8 H).
13C NMR (150 MHz): d = 139.8, 128.9, 128.0, 126.7, 64.7, 62.7,
42.9, 35.8, 31.8, 26.9, 26.2.
13C NMR: d = 140.1, 128.8, 128.1, 126.7, 62.7, 55.6, 28.2, 27.0.
3-Phenethyl-3-azabicyclo[3.2.1]octane (12)
Prepared by reacting norbornene (0.094 g, 1 mmol) with phenethyl-
amine (1 mmol) according to GP 4A; reaction time: 2 h; yield: 0.139
g (65%); Rf = 0.63 (10% MeOH–CH2Cl2).
IR (neat): 2931, 2757, 1496, 1406 cm–1.
1-Phenethylazapine (8) [65530-43-0]
Prepared by reacting cyclohexene (0.082 g, 1 mmol) with pheneth-
ylamine (1 mmol) according to GP 4A; reaction time: 2 h; yield:
0.127 g (63%); Rf = 0.57 (10% MeOH–CH2Cl2).
1H NMR: d = 7.32–7.21 (m, 5 H), 2.83–2.80 (m, 8 H), 1.72 (m, 4
1H NMR: d = 7.37–7.24 (m, 5 H), 2.84–2.80 (m, 4 H), 2.64–2.60 (m,
2 H), 2.20–2.14 (m, 4 H), 1.76–1.63 (m, 4 H), 1.56–1.53 (m, 1 H),
1.44–1.42 (m, 1 H).
13C NMR: d = 140.9, 128.8, 128.2, 125.8, 60.2, 60.1, 37.7, 35.2,
33.3, 28.6.
H), 1.64 (m, 4 H).
13C NMR: d = 140.2, 128.8, 128.4, 126.0, 59.9, 55.1, 33.6, 27.2,
27.1.
4-[4-(Benzyloxy)butyl]morpholine (3d)
HRMS-FAB: m/z calcd for C15H22N (M + H)+: 216.1747; found:
216.1748.
Prepared from 3a (0.176 g, 1.0 mmol) with morpholine (1 mmol) by
GP 4A; reaction time: 2 h; yield: 0.159 g (64%). Spectral data were
identical with those of compound 3d described above.
This product was also prepared by reacting norbornene (0.041 g,
0.43 mmol) with phenethylamine (0.43 mmol) according to GP 4B;
yield: 0.062 g (65%).
1-Benzylpiperidine (9) [2905-56-8]
Prepared by reacting cyclopentene (0.068 g, 1 mmol) with benzyl-
amine (1 mmol) according to GP 4A; reaction time: 2 h; yield: 0.113
g (65%); Rf = 0.50 (10% MeOH–CH2Cl2).
1H NMR: d = 7.35–7.24 (m, 5 H), 3.50 (s, 2 H), 2.40–2.39 (m, 4 H),
1.64–1.57 (m, 4 H), 1.49–1.46 (m, 2 H).
1-Phenyl-2-(4-phenylbutan-2-yl)diazene (13) [343222-12-8]
A solution of alkene 4a (0.176 g, 1 mmol) and MeOH (0.3 mL) in
CH2Cl2 (10 mL) in a round-bottomed flask was cooled to –40 °C
and a stream of 2% O3/O2 (approximately 1 mmol O3/min) was bub-
bled through the reaction solution. Once the pale blue color of ozone
was observed, the ozonizer voltage was set to zero and the reaction
was sparged for 1 min with N2. The resulting solution was removed
from dry ice/acetone bath, whereupon NaBH(OAc)3 (2 mmol) and
phenylhydrazine (1 mmol) were sequentially added. The reaction
was stirred for 2 h at r.t. and then treated with NaCNBH3 (1 mmol).
After stirring for another 30 min, the reaction was filtered though
neutral alumina with CH2Cl2, and the residue obtained upon con-
centration was purified by chromatography (alumina) using 10%
EtOAc–hexanes to furnish a light yellow oil, which darkened very
rapidly. Air was passed over the oil for 2 h to furnish diazene 13 as
a yellow oil; yield: 0.135 g (57%); Rf = 0.50 (10% EtOAc–hexanes).
13C NMR: d = 138.7, 129.2, 128.0, 126.8, 63.9, 54.5, 26.0, 24.4.
1-Phenethylpiperidine (10) [332-14-9]
Prepared by reacting cyclopentene (0.068 g, 1 mmol) with pheneth-
ylamine (1 mmol) according to GP 4A; reaction time: 2 h; yield:
0.136 g (72%); Rf = 0.55 (10% MeOH–CH2Cl2).
1H NMR: d = 7.32–7.20 (m, 5 H), 2.86–2.82 (m, 2 H), 2.60–2.50 (m,
2 H), 2.40 (m, 4 H), 1.68–1.62 (m, 4 H), 1.51–1.48 (m, 2 H).
13C NMR: d = 140.7, 128.7, 128.3, 125.9, 61.5, 54.6, 33.7, 26.1,
24.5.
1H NMR: d = 7.73–7.70 (m, 2 H), 7.53–7.46 (m, 3 H), 7.33–7.28 (m,
2 H), 7.24–7.20 (m, 3 H), 3.90–3.81 (m, 1 H), 2.66 (t, J = 8.1 Hz, 2
H), 2.41–2.32 (m, 1 H), 2.13–2.04 (m, 1 H), 1.42 (d, J = 6.6 Hz, 3
H).
13C NMR: d = 152.1, 141.9, 130.3, 129.0, 128.5, 128.4, 125.8,
122.2, 72.7, 36.9, 32.6, 19.0.
Compound 10 was also prepared by reacting cyclopentene (0.068 g,
1 mmol) with phenethylamine (1 mmol) according to GP 4B; yield:
0.117 g (62%).
9-(N-Morpholino)nonyl Acetate Ester (2d)
Prepared from 2a (0.099 g, 0.5 mmol) with morpholine (1 mmol) by
GP 4B; reaction time: 6 h. The product was identical to 2d obtained
as above; yield: 0.089 g (66%).
Supporting Information for this article is available online at
N-Benzylcyclohexylmethanamine (11a) [4352-47-0] and N-ben-
zyl-N-methylcyclohexylmethanamine (11b) [79952-95-7]
Prepared from the reaction of vinylcyclohexane (0.11 g, 1 mmol)
with benzylamine (2 mmol) by GP 4B; reaction time: 6 h; yield:
0.102 g (50%); Rf = 0.50 (10% MeOH–CH2Cl2).
http://www.thieme-connect.com/ejournals/toc/synthesis.
Acknowledgment
Research was conducted with NSF funding (CHE-0749916,
-1057982) in facilities remodeled with NIH support (RR016544).
NMR spectra were acquired, in part, on instruments purchased with
NSF support (MRI 0079750 and CHE 0091975).
1H NMR: d = 7.36–7.26 (m, 5 H), 3.80 (s, 2 H), 2.49 (d, J = 6.7 Hz,
2 H), 1.84–1.68 (m, 5 H), 1.57–1.46 (m, 1 H), 1.32–1.13 (m, 4 H),
0.99–0.90 (m, 2 H).
13C NMR: d = 140.6, 128.4, 128.0, 126.8, 56.2, 54.1, 37.9, 31.5,
26.7, 26.1.
References
The reaction also yielded 10% of 11b.
(1) These authors contributed equally to this manuscript.
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2.16 (m, 5 H), 1.84 (d, J = 12.4 Hz, 2 H), 1.74–1.67 (m, 3 H), 1.57–
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Synthesis 2011, No. 21, 3475–3481 © Thieme Stuttgart · New York

PAPER
(4) Although a variety of reagents have been applied for post-
Tandem Ozonolysis and Reductive Amination
3481
(10) Ozonides derived from mono- and 1,1-disubstituted alkenes
can react with secondary amines to form tertiary amines
through base-promoted E1cb fragmentation to form an
aldehyde, which undergoes reductive amination in the
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Synthesis 2011, No. 21, 3475–3481 © Thieme Stuttgart · New York