Expedient reductive animation of aldehyde bisulfite adducts

Article abstract of DOI:10.1055/s-0029-1217050

A novel, one-pot protocol for the direct reductive animation of aldehyde bisulfite adducts is reported. Bisulfite adducts of aliphatic and aromatic aldehydes, on treatment with an organic base under non-aqueous conditions liberate the aldehyde in situ, which then undergoes efficient reductive amination with amines in the presence of sodium triacetoxyborohydride.

Full text of DOI:10.1055/s-0029-1217050

4032
PAPER
Expedient Reductive Amination of Aldehyde Bisulfite Adducts
E
xpedient Reduc
h
A
minati
e
on of
A
ldeh
n
yde Bisulfite
n
A
dducts agiri R. Pandit, Neelakandha S. Mani*
Department of Drug Discovery, Johnson & Johnson Pharmaceuticals Research and Development, L.L.C.,
3210 Merryfield Row, San Diego, CA 92121, USA
Fax +1(858)3203354; E-mail: nmani@its.jnj.com
Received 29 May 2009; revised 22 July 2009
As part of a medicinal chemistry program, a series of pip-
eridinylindoline cinnamides was prepared, the representa-
tives of which were identified as the first potent, non-
peptide, low molecular weight selective neuropeptide Y
Abstract: A novel, one-pot protocol for the direct reductive amina-
tion of aldehyde bisulfite adducts is reported. Bisulfite adducts of
aliphatic and aromatic aldehydes, on treatment with an organic base
under non-aqueous conditions liberate the aldehyde in situ, which
then undergoes efficient reductive amination with amines in the Y2 antagonists.6,7 One of the compounds in the series,
presence of sodium triacetoxyborohydride.
trans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyano-
phenyl)-N-[1-(2-cyclopentylethyl)piperidin-4-yl]acryla-
mide (4) was selected for a detailed in vivo pharma-
cological evaluation of the role of Y2 receptors in a variety
of physiological conditions and thus, multi-gram quanti-
ties of 4 were required.
Key words: Bisulfite adducts, reductive amination, sodium triace-
toxyborohydride
Bisulfite adducts provide a means for the isolation and or
separation of carbonyl compounds from compounds not
having this functional group. These adducts are generally
crystalline solids that are easy to handle and are stable for
prolonged periods of time. However, reports of their use
in synthetic applications are sparse. This may be due to
the fact that regeneration of aldehydes from their bisulfite
adducts is typically carried out by treatment with aqueous
acid1 or base,2 conditions which may not be tolerated by
many aldehydes or other functional groups present. To
solve this problem, a novel method for the regeneration of
aldehydes from bisulfite adducts using chlorotrimethylsi-
lane was reported by Kjell et al.3 This suggests that alde-
hydes can be regenerated in situ in organic solvents under
non-aqueous conditions, and that the bisulfite adducts
themselves can presumably be used as an aldehyde surro-
gate in synthetic applications. Reductive amination reac-
tions are well precedented in synthetic organic chemistry
due to their versatility.4 It is a process by which aldehydes
or ketones are transformed into amines, which are useful
intermediates for the synthesis of agrochemicals and phar-
maceuticals. A variety of aldehydes have been used in re-
ductive aminations. More recently, the utility of an
aldehyde bisulfite adduct in a reductive amination reac-
tion was disclosed, albeit in lower yield than the compara-
ble reductive amination with the free aldehyde.5 In this
report, one equivalent of the trifluoroacetate salt of an
amine was reacted with a bisulfite adduct (1.5 equiva-
lents) with azeotropic removal of water and subsequent
reduction of the iminium intermediate with sodium tri-
acetoxyborohydride. Herein, we report a simple, high-
yielding one-pot protocol for the direct reductive amina-
tion of aldehyde bisulfite adducts.
In the drug discovery synthesis of 4, the key step
(Scheme 1) was reductive amination of 2-cyclopentyl-
acetaldehyde (2) with the functionalized indoline 3. Alde-
hyde 2 was obtained by oxidation of commercially
available 2-cyclopentylethanol (1). However, due to its
volatility, isolation of 2 proved to be problematic as prod-
uct loss was encountered upon extractive workup and ro-
tary evaporation of the solvent. Thus, subsequent
reductive amination with 3 was carried out with the organ-
ic extract of the reaction mixture containing crude 2, to af-
ford piperidinylindoline cinnamide 4 in ca. 50% yield.
For the scale-up synthesis, we sought to explore a practi-
cal process for the isolation of aldehyde 2. As bisulfite ad-
ducts of aldehydes are known to be stable, crystalline
OH
PCC (1.2 equiv)
CH2Cl2, r.t.
1
O
N
2
O
DCE, AcOH
NaBH(OAc)3
50%
N
CN
HN
O
3
N
O
N
CN
N
O
SYNTHESIS 2009, No. 23, pp 4032–4036
x
x.
x
x
.
2
0
0
9
4
Advanced online publication: 03.11.2009
DOI: 10.1055/s-0029-1217050; Art ID: M03009SS
Scheme 1 Preparation of piperidinylindoline cinnamide 4
© Georg Thieme Verlag Stuttgart · New York

PAPER
Expedient Reductive Amination of Aldehyde Bisulfite Adducts
4033
solids, isolation and storage of 2 in this form appeared at- bisulfite adduct8in situ, and the second equivalent partici-
tractive. Thus, after oxidation of 1 with pyridinium chlo- pates in the amination reaction.
rochromate, the reaction mixture was decanted. The
In fact, while the 1H NMR spectrum of the benzaldehyde
organic layer was diluted with ethanol and treated with an
aqueous solution of sodium bisulfite (1.05 equivalents).
bisulfite adduct (Table 1, entry 1) in dichloromethane-d2
did not show a resonance due to the aldehyde proton,
Partial concentration of the reaction mixture resulted in
within five minutes of the addition of one equivalent of
precipitation of the bisulfite adduct 2a in 81% yield
triethyl-d15-amine, liberation of the aldehyde was com-
(Scheme 2).
plete, as was evident by the appearance of an aldehyde
proton signal in the 1H NMR spectrum. Although the re-
1) PCC, CH2Cl2
0 °C to r.t.
action proceeds in solvents typically used for reductive
aminations such as dichloromethane, dichloroethane and
SO3Na
OH
tetrahydrofuran, we preferred dichloroethane, as reactions
2) NaHSO3, EtOH, r.t.
81%
HO
in this solvent are reported to be faster.9
1
2a
In order to extend the scope of the reaction, we explored
the use of a tertiary amine (e.g., triethylamine) to liberate
the aldehyde from its bisulfite adduct. Thus, the bisulfite
adduct was first treated with triethylamine (1.1 equiva-
lents), followed by piperidine (1.1 equivalents) and sodi-
um triacetoxyborohydride (Table 2, entry 1c). Extractive
workup followed by purification afforded the desired
product in 94% yield. The generality of the method was
evaluated by subjecting the bisulfite adducts to reductive
amination conditions with various amines. In all cases, the
reactions proceeded smoothly to afford, after purification,
excellent isolated yields of the desired products (Table 2).
While the yields of products from both methods are com-
parable, the latter method is particularly useful if the re-
acting amine is expensive or a product of a multi-step
synthesis, and hence deemed non-expendable. Thus, the
reductive amination in the synthesis of 4 was accom-
plished by treatment of the bisulfite adduct 2a with trieth-
ylamine (one equivalent) followed by the amine 3 (0.9
equivalents). The reaction proceeded smoothly to produce
the desired product in 71% isolated yield (Scheme 4).
Scheme 2 Synthesis of bisulfite adduct 2a
In order to investigate the potential of bisulfite adducts in
direct reductive amination, a number of aldehyde bisulfite
adducts were prepared in a similar manner by treating an
ethanolic solution of the aldehyde with aqueous sodium
bisulfite (Table 1). These adducts were obtained with
good purity (>95%) and were used directly in our reduc-
tive amination experiments. Recrystallization from etha-
nol–water mixtures afforded analytically pure material.
Table 1 Preparation of Aldehyde Bisulfite Adducts
NaHSO3 (1.05 equiv)
HO
H
SO3Na
O
H2O, EtOH, r.t.
R
R
Entry
R
Yield (%) of product
1
2
3
4
5
Ph
92
97
94
89
90
4-EtC6H4
4-MeOC6H4
PhCH2CH2
cyclohexyl
In conclusion, we have demonstrated the utility of alde-
hyde bisulfite adducts in direct reductive amination reac-
tions. This method is particularly attractive in cases where
HO
Exploratory reductive amination reactions were carried
out on five millimole scale at a concentration of 20 mL/g.
Treatment of the bisulfite adduct of benzaldehyde with
one equivalent of piperidine followed by sodium triacet-
oxyborohydride afforded, after workup, the correspond-
ing tertiary amine product in 42% yield (Scheme 3 and
Table 2, entry 1a).
SO3Na
N
2a
O
DCE, Et3N
NaBH(OAc)3, 4A MS
N
CN
71%
HN
O
R2
3
N
1) R2R3NH, DCE
HO
SO3Na
N
R3
O
R1
R1
2) NaBH(OAc)3, r.t., 16 h
N
O
Scheme 3 Reductive amination of bisulfite adducts with various
amines
CN
N
We discovered that the use of two equivalents of piperi-
dine (Table 2, entry 1b) resulted in a good yield of the cor-
responding tertiary amine product. Presumably, the first
equivalent of piperidine liberates the aldehyde from the
4
Scheme 4 One-step synthesis of 4 via reductive amination
Synthesis 2009, No. 23, 4032–4036 © Thieme Stuttgart · New York

4034
C. R. Pandit, N. S. Mani
PAPER
Table 2 Reductive Amination of Bisulfite Adducts with Various Amines
Entry
Bisulfite Adduct (R1)
Amine (equiv)
Producta
Yield (%)
42
85
94
87
N
N
1a
1b
1c
1d
Ph
Ph
Ph
Ph
piperidine (1.0)
piperidine (2.0)
Et3N (1.1), piperidine (1.1)
morpholine (2.0)
O
2a
2b
4-EtC6H4
4-EtC6H4
pyrrolidine (2.0)
Et3N (1.1), pyrrolidine (1.1)
84
80
N
Et
N
N
N
N
3a
3b
4-MeOC6H4
4-MeOC6H4
Et3N (1.1), pyrrolidine (1.1)
Et3N (1.1), diethylamine (1.1)
85
88
MeO
MeO
4a
4b
PhCH2CH2
PhCH2CH2
Et3N (1.1), pyrrolidine (1.1)
Et3N (1.1), morpholine (1.1)
80
83
O
N
5
cyclohexyl
Et3N (1.1), N-methylbenzylamine (1.1)
79
a All products were purified using a general acid–base workup procedure and the purity was determined to be >98% by HPLC.
1
(OptiMelt, Stanford Research Systems). H and 13C NMR spectra
were recorded using either a Bruker DPX 400 or a Bruker DRX 500
spectrometer (1H at 400 or 500 MHz and 13C at 100 MHz) in the sol-
vents noted. HRMS for accurate mass analysis were performed us-
ing a Bruker micro TOF instrument (TOF ESI).
the aldehyde to be used in a reductive amination step is not
easy to isolate or purify, or cannot be stored as such due
to stability issues. Preparation of the aldehyde bisulfite
adduct alleviates these problems and in addition, this
derivative proves to be an excellent aldehyde surrogate in
direct reductive amination reactions. A second distinct ad-
vantage with this method is the use of an organic base un-
der non-aqueous conditions to liberate the aldehyde in
situ. Thus, aldehyde bisulfite adducts with functional
groups that may not withstand standard protocols of
strong aqueous base or acid treatment for aldehyde regen-
eration can be handled with relative ease. The methodolo-
gy has been applied to the synthesis of compound 4
Aldehyde Bisulfite Adducts; General Procedure
To a stirred soln of the aldehyde (0.1 mol) in EtOH (200 mL) was
added dropwise a soln of anhyd NaHSO3 (10.6 g, 102.0 mmol) in
H2O (20 mL) over 0.5 h. The resulting suspension was stirred at am-
bient temperature for 16 h and subsequently at 0 °C for 4 h, follow-
ing which the product was collected by filtration. The filter-cake
was broken, washed with hexanes (3 × 100 mL) and dried in vacuo
to afford the bisulfite adduct as a white powder. Recrystallization of
a small sample from EtOH–H2O furnished an analytically pure sam-
resulting in improved yields in the isolation of an alde- ple.
hyde intermediate as well as in the key reductive amina-
tion step. In addition to demonstrating the generality of
this method, we have also applied this procedure for the
synthesis of multi-gram quantities of other pharmaceuti-
cal intermediates.
Sodium Hydroxy(phenyl)methanesulfonate (Table 1, Entry 1)
Yield: 92%; white plates; mp 153–156 °C (dec.).
1H NMR (500 MHz, DMSO-d6): d = 7.50–7.38 (m, 2 H), 7.23–7.18
(m, 3 H), 5.81 (d, J = 5.2 Hz, 1 H), 4.96 (d, J = 5.2 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 140.5, 128.8, 127.8, 127.6,
85.9.
All reactions were carried out under a positive pressure of N2. 1,2-
Dichloroethane (DCE) was dried by passing through activated alu-
mina cylinders under Ar. Glassware was oven-dried and cooled to
r.t. prior to use. Reaction mixtures and products were analyzed by
reverse phase HPLC according to the following conditions: column,
Zorbax Eclipse XBD-C8, 5 m, 4.6 × 1.50 mm; gradient, 1%–99%
MeCN–H2O containing 0.1 v/v TFA, 8 min; 99% MeCN–H2O con-
taining 0.1 v/v TFA, 2 min. Column chromatography was carried
out on EMD Chemicals silica gel (230–400 mesh). Melting points
were determined using an automated electrothermal instrument
HRMS (TOF ESI): m/z [M – Na]– calcd for C7H7O4S: 187.0071;
found: 187.0076.
Sodium (4-Ethylphenyl)(hydroxy)methanesulfonate (Table 1,
Entry 2)
Yield: 97%; white plates; mp 136–138 °C.
1H NMR (500 MHz, DMSO-d6): d = 7.33 (d, J = 6.1 Hz, 2 H), 7.06
(d, J = 6.1 Hz, 2 H), 5.68 (d, J = 5.1 Hz, 1 H), 4.90 (d, J = 5.1 Hz,
1 H), 2.59 (q, J = 7.5 Hz, 2 H), 1.18 (t, J = 7.5 Hz, 3 H).
Synthesis 2009, No. 23, 4032–4036 © Thieme Stuttgart · New York

PAPER
Expedient Reductive Amination of Aldehyde Bisulfite Adducts
4035
13C NMR (100 MHz, DMSO-d6): d = 142.9, 137.9, 128.7, 127.2,
Method B: Using Triethylamine and the Reacting Amine
85.8, 28.9, 16.8.
A suspension of aldehyde bisulfite adduct (5.0 mmol) and Et3N
(0.76 g, 5.5 mmol) in anhyd DCE (20 mL) was stirred at ambient
temperature under an N2 atm for 15 min. The amine (5.5 mmol) was
added and the reaction mixture was stirred for 45 min following
which NaBH(OAc)3 (1.5 g, 7.0 mmol) was added in small portions
over ca. 30 min and stirring was continued. After 16 h, the reaction
mixture was diluted with EtOAc (80 mL), and washed with 1 N
NaOH (25 mL) followed by brine (25 mL). The organic layer was
dried over anhyd MgSO4, filtered and concd. The crude material
was purified using the general acid–base purification procedure de-
scribed above.
HRMS (TOF ESI): m/z [M – Na]– calcd for C9H11O4S: 215.0384;
found: 215.0381.
Anal. Calcd for C9H11O4NaS: C, 45.37; H, 4.65; S, 13.46. Found: C,
45.10; H, 4.84; S, 13.89.
Sodium Hydroxy(4-methoxyphenyl)methanesulfonate (Table 1,
Entry 3)
Yield: 94%; white plates; mp 155–157 °C (dec.).
1H NMR (500 MHz, DMSO-d6): d = 7.35 (d, J = 8.5 Hz, 2 H), 6.80
(d, J = 8.8 Hz, 2 H), 5.69 (d, J = 5.1 Hz, 1 H), 4.90 (d, J = 5.2 Hz,
1 H), 3.73 (s, 3 H).
1-Benzylpiperidine (Table 2, Entry 1b)
Yield: 85%; oil.
13C NMR (100 MHz, DMSO-d6): d = 159.2, 132.7, 129.8, 113.2,
1H NMR (400 MHz, CDCl3): d = 7.32–7.20 (m, 5 H), 3.49 (s, 2 H),
2.39 (br s, 4 H), 1.60–1.54 (m, 4 H), 1.42 (br s, 2 H).
HRMS (TOF ESI): m/z [M + H]+ calcd for C12H18N: 176.1434;
85.5, 55.9.
HRMS (TOF ESI): m/z [M – Na]– calcd for C8H9O5S: 217.0176;
found: 217.0167.
found: 176.1426.
Anal. Calcd for C8H9O5NaS: C, 40.00; H, 3.78; S, 13.35. Found: C,
39.64; H, 3.82; S, 12.97.
4-Benzylmorpholine (Table 2, Entry 1d)
Yield: 87%; oil.
1H NMR (CDCl3, 400 MHz): d = 7.36–7.21 (m, 5 H), 3.70 (t, J = 4.7
Hz, 4 H), 3.50 (s, 2 H), 2.44 (t, J = 4.4 Hz, 4 H).
Sodium 1-Hydroxy-3-phenylpropane-1-sulfonate (Table 1, En-
try 4)
Yield: 89%; white plates; mp 193–210 °C (dec.).
1H NMR (500 MHz, DMSO-d6): d = 7.30–7.24 (m, 2 H), 7.20–7.14
(m, 3 H), 5.32 (d, J = 5.9 Hz, 1 H), 3.79 (ddd, J = 9.5, 6.0, 3.1 Hz,
1 H), 2.79–2.71 (m, 1 H), 2.63–2.55 (m, 1 H), 2.06–1.97 (m, 1 H),
1.74 (dtd, J = 14.4, 9.5, 9.5, 5.0 Hz, 1 H).
13C NMR (100 MHz, DMSO-d6): d = 142.7, 128.7, 128.5, 125.9,
82.2, 34.2, 31.9.
HRMS (TOF ESI): m/z [M + H]+ calcd for C11H16NO: 178.1226;
found: 178.1219.
1-(4-Ethylbenzyl)pyrrolidine (Table 2, Entry 2a)
Yield: 84%; oil.
1H NMR (400 MHz, CDCl3): d = 7.24 (d, J = 8.0 Hz, 2 H), 7.14 (d,
J = 8.0 Hz, 2 H), 3.59 (s, 2 H), 2.63 (q, J = 7.6 Hz, 2 H), 2.55–2.46
(m, 4 H), 1.81–1.74 (m, 4 H), 1.23 (t, J = 7.6 Hz, 3 H).
HRMS (TOF ESI): m/z [M – Na]– calcd for C9H11O4S: 215.0384;
found: 215.0382.
HRMS (TOF ESI): m/z [M + H]+ calcd for C13H20N: 190.1590;
found: 190.1590.
Anal. Calcd for C9H11O4NaS: C, 45.37; H, 4.65; S, 13.46. Found: C,
45.06; H, 4.77; S, 13.57.
Sodium Hydroxy(cyclohexyl)methanesulfonate (Table 1, Entry 5)
Yield 90%; white plates; mp 179–185 C (dec).
1-(4-Methoxybenzyl)pyrrolidine (Table 2, Entry 3a)
Yield: 85%; oil.
1H NMR (DMSO-d6, 500 MHz = 4.75 (d, J = 5.3 Hz, 1 H), 3.62 (t,
J = 5.2 Hz, 1 H), 2.08–1.96 (m, 1 H), 1.82–1.50 (m, 5 H), 1.20–0.98
(m, 5 H).
1H NMR (400 MHz, CDCl3): d = 7.30–7.25 (m, 2 H), 6.88–6.83 (m,
2 H), 3.80 (s, 3 H), 3.62 (br s, 2 H), 2.60–2.54 (m, 4 H), 1.84–1.78
(m, 4 H).
13C NMR (DMSO-d6, 100 MHz): = 87.8, 31.5, 27.8, 27.1, 27.0,
26.7.
HRMS (TOF ESI): m/z [M + H]+ calcd for C12H18NO: 192.1383;
found: 192.1391.
HRMS (TOF ESI): m/z [M – Na]– calcd for C7H13O4S: 193.0540;
found 193.0537.
N-Ethyl-N-(4-methoxybenzyl)ethanamine (Table 2, Entry 3b)
Yield: 88%; oil.
1H NMR (400 MHz, CDCl3): d = 7.23 (d, J = 8.6 Hz, 2 H), 6.85 (dd,
J = 8.7, 2.1 Hz, 2 H), 3.78 (s, 3 H), 3.50 (s, 2 H), 2.50 (q, J = 7.1
Hz, 4 H), 1.03 (t, J = 7.1 Hz, 6 H).
HRMS (TOF ESI): m/z [M + H]+ calcd for C12H20NO: 194.1539;
found: 194.1531.
Reductive Amination of Bisulfite Adducts; General Procedures
Method A: Using Two Equivalents of the Reacting Amine
A suspension of aldehyde bisulfite adduct (5.0 mmol) and amine
(10.0 mmol) in anhyd DCE (20 mL) was stirred at ambient temper-
ature under an N2 atm for 45 min. NaBH(OAc)3 (1.5 g, 7.0 mmol)
was added in small portions over ca. 30 min and stirring was con-
tinued. After 4 h, the reaction mixture was diluted with EtOAc (80
mL), filtered, and washed with 1 N NaOH (25 mL) followed by
brine (25 mL). The organic layer was dried over anhyd MgSO4, fil-
tered, and concd. The residue was purified using a general acid–
base purification procedure as follows: the crude product was dis-
solved in EtOAc (50 mL) and the organic layer was extracted with
1.5 N HCl (25 mL). The aq layer was basified to ca. pH 12 with 1
N NaOH and extracted with EtOAc (3 × 50 mL). The combined or-
ganic layer was dried over anhyd MgSO4, filtered and concd to af-
ford the desired product (HPLC purity >98%).
1-(3-Phenylpropyl)pyrrolidine (Table 2, Entry 4a)
Yield: 80%; oil.
1H NMR (400 MHz, CDCl3): d = 7.29–7.25 (m, 2 H), 7.20–7.15 (m,
3 H), 2.65 (t, J = 7.7 Hz, 2 H), 2.55–2.43 (m, 6 H), 1.90–1.73 (m, 6
H).
HRMS (TOF ESI): m/z [M + H]+ calcd for C13H20N: 190.1590;
found: 190.1581.
4-(3-Phenylpropyl)morpholine (Table 2, Entry 4b)
Yield: 83%; oil.
Synthesis 2009, No. 23, 4032–4036 © Thieme Stuttgart · New York

4036
C. R. Pandit, N. S. Mani
PAPER
1H NMR (400 MHz, CDCl3): d = 7.29–7.26 (m, 2 H), 7.19–7.17 (m,
3 H), 3.71 (t, J = 4.6 Hz, 4 H), 2.64 (t, J = 7.6 Hz, 2 H), 2.45–2.32
(m, 6 H), 1.87–1.77 (m, 2 H).
HRMS (TOF ESI): m/z [M + H]+ calcd for C13H20NO: 206.1539;
found: 206.1544.
at ambient temperature for 40 min, following which NaBH(OAc)3
(7.4 g, 34.9 mmol) was added in small portions over 0.5 h. The re-
action was stirred at ambient temperature overnight. Celite (50.0 g)
and EtOAc (200 mL) were added and the reaction was stirred for 10
min and filtered. The filtrate was washed with 0.5 N NaOH (200
mL) and brine (250 mL). The organic layer was dried over anhyd
Na2SO4, filtered and concd to give a pale-yellow semi-solid. The
crude product was purified by silica gel column chromatography
(MeOH–CH2Cl2, 1%–4%) to afford the title compound as a pale-
yellow foam; yield: 9.0 g (71%).
1H NMR (500 MHz, CDCl3): d = 8.04 (s, 1 H), 7.59 (d, J = 15.5 Hz,
1 H), 7.53–7.49 (m, 3 H), 7.40–7.37 (m, 1 H), 7.20–7.19 (m, 1 H),
6.78–6.73 (m, 1 H), 6.22 (d, J = 15.5 Hz, 1 H), 4.72 (br s, 1 H),
4.22–4.11 (m, 2 H), 3.34–3.24 (m, 2 H), 2.96 (br s, 1 H), 2.30–2.24
(m, 5 H), 2.08–1.86 (m, 6 H), 1.71–1.44 (m, 10 H), 1.07–1.03 (m, 2
H).
13C NMR (100 MHz, CDCl3): d = 168.9, 164.8, 144.0, 138.8, 137.1,
136.7, 132.8, 132.1, 131.7, 130.2, 129.4, 125.6, 124.8, 122.2, 118.9,
118.5, 112.7, 77.3, 76.7, 57.8, 53.1, 52.9, 49.2, 45.9, 38.3, 33.3,
32.6, 30.2, 27.7, 25.0, 24.1, 9.5.
HRMS (TOF ESI): m/z [M + H]+ calcd for C32H39N4O2: 511.2995;
found: 511.2921.
N-Benzyl-1-cyclohexyl-N-methylmethanamine (Table 2, Entry
5)
Yield: 79%; oil.
1H NMR (400 MHz, CDCl3): d = 7.31–7.22 (m, 5 H), 3.44 (s, 2 H),
2.15 (s, 3 H), 2.13 (s, 2 H), 1.84–1.80 (m, 2 H), 1.72–1.64 (m, 3 H),
1.54–1.48 (m, 1 H), 1.28–1.12 (m, 3 H), 0.88–0.78 (m, 2 H).
HRMS (TOF ESI): m/z [M + H]+ calcd for C15H24N: 218.1903;
found: 218.1912.
Sodium 2-Cyclopentyl-1-hydroxyethanesulfonate (2a)
A 500 mL round-bottomed flask was charged with anhyd CH2Cl2
(90 mL) and PCC (20.4 g, 94.6 mmol), and the reaction mixture was
cooled to 0 °C. A soln of 2-cyclopentylethanol 1 (9.0 g, 78.9 mmol)
in anhyd CH2Cl2 (10 mL) was added dropwise over 20 min and the
reaction was removed from the cooling bath and stirred at ambient
temperature for 2 h. The reaction mixture was diluted with Et2O
(100 mL) with stirring, cooled to 0 °C and decanted. The residue
was triturated with Et2O (3 × 75 mL) followed by decanting. The or-
ganic layers were pooled and diluted with EtOH (50 mL). A soln of
NaHSO3 (9.0 g, 86.5 mmol) in H2O (30 mL) was added dropwise
over 0.5 h with vigorous stirring and the resulting suspension was
stirred at ambient temperature overnight. The reaction mixture was
partially concd to remove lower boiling volatiles and the resulting
suspension was diluted with EtOH (50 mL) and stirred at 0 °C for 2
h. The precipitate was collected by suction filtration. The filter-cake
was washed with hexanes (2 × 50 mL) and dried in vacuo to afford
the title compound as a pale-blue powder; yield: 13.7 g (81%). Re-
crystallization of a small sample from EtOH–H2O furnished white
crystalline plates; mp 168–172 °C (dec.).
Acknowledgment
The authors would like to thank Dr. Jiejun Wu and Ms. Heather
McAllister for mass spectral data.
References
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1H NMR (500 MHz, D2O): d = 4.31 (dd, J = 9.2, 3.4 Hz, 1 H), 2.00–
1.84 (m, 1 H), 1.80–1.63 (m, 4 H), 1.60–1.37 (m, 4 H), 1.15–0.98
(m, 2 H).
13C NMR (100 MHz, D2O): d = 83.8, 37.0, 35.9, 32.8, 31.2, 24.6,
24.5.
HRMS (TOF ESI): m/z [M – Na]– calcd for C7H13O4S: 193.0540;
found: 193.0551.
(5) Ragan, J. A.; am Ende, D. J.; Brenek, S. J.; Eisenbeis, S. A.;
Singer, R. A.; Tickner, D. L.; Teixeira, J. J. Jr.; Vanderplas,
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Anal. Calcd for C7H13O4SNa·0.5H2O: C, 37.35; H, 6.28; S, 14.25.
Found: C, 37.07; H, 6.16; S, 14.43.
trans-N-(1-Acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cyanophe-
nyl)-N-[1-(2-cyclopentylethyl)piperidin-4-yl]acrylamide (4)
A 500 mL round-bottomed flask was charged with anhyd DCE (100
mL), sodium 2-cyclopentyl-1-hydroxyethanesulfonate (2a) (6.5 g,
30.0 mmol), powdered 4 Å MS (3.0 g) and Et3N (3.0 g, 30.0 mmol)
and the resulting suspension was stirred at ambient temperature for
10 min. trans-N-(1-acetyl-2,3-dihydro-1H-indol-6-yl)-3-(3-cy-
anophenyl)-N-piperidin-4-yl-acrylamide (3)7 (10.3 g, 24.9 mmol)
was added in one portion and the reaction mixture was maintained
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Maryanoff, C. A.; Shah, R. D. J. Org. Chem. 1996, 61, 3849.
Synthesis 2009, No. 23, 4032–4036 © Thieme Stuttgart · New York