Rh-catalyzed addition of arylboroxines to cyclic N -(Isopropanesulfinyl) ketimines

Article abstract of DOI:10.1021/jo301634y

Arylboroxines, which are easily accessed by drying commercially available arylboronic acids, are added to N-(isopropanesulfinyl)ketimines derived from cyclohexanone, N-Boc-piperidin-4-one, and tetrahydropyran-4-one in high yields and with excellent functional group compatibility via rhodium catalysis. These results contrast with additions to the corresponding ketimines incorporating the larger N-tert-butanesulfinyl group, which give considerably lower yields. Efficient two-step preparation of racemic isopropanesulfinamide from inexpensive isopropyl disulfide and recycling of the isopropanesulfinyl group from the addition products are also described.

Full text of DOI:10.1021/jo301634y

Article
pubs.acs.org/joc
Rh-Catalyzed Addition of Arylboroxines to Cyclic
N‑(Isopropanesulfinyl)ketimines
Hyung Hoon Jung, Andrew W. Buesking, and Jonathan A. Ellman*
Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: Arylboroxines, which are easily accessed by
drying commercially available arylboronic acids, are added to
N-(isopropanesulfinyl)ketimines derived from cyclohexanone,
N-Boc-piperidin-4-one, and tetrahydropyran-4-one in high
yields and with excellent functional group compatibility via
rhodium catalysis. These results contrast with additions to the
corresponding ketimines incorporating the larger N-tert-
butanesulfinyl group, which give considerably lower yields. Efficient two-step preparation of racemic isopropanesulfinamide
from inexpensive isopropyl disulfide and recycling of the isopropanesulfinyl group from the addition products are also described.
Scheme 2. Previously Reported Additions of Organoboron
INTRODUCTION
■
Reagents to Activated N-(tert-Butanesulfinyl)ketimines5
Nucleophilic additions to N-(tert-butanesulfinyl)imines are
among the most extensively used approaches for the synthesis
of amines.1 Transition-metal-catalyzed additions of organoboron
reagents to N-(tert-butanesulfinyl)imines are particularly attrac-
tive due to the large number of commercially available, air-stable
organoboron reagents and the high functional group compati-
bility of these transformations.1,2 While a broad range of amines
have been prepared by the addition of aryl- and alkenylboron
reagents to N-(tert-butanesulfinyl)aldimines (Scheme 1),3,4 only
Scheme 1. Previously Reported Additions of Organoboron
Reagents to N-(tert-Butanesulfinyl)aldimines3,4
RESULTS AND DISCUSSION
■
We initiated our study by performing additions to N-(tert-
butanesulfinyl)ketimine 1 under conditions that had previously
been determined to be optimal for additions to activated
N-sulfinyl ketimines, namely, 1.5 equiv of 4-methoxyphenylbor-
oxine with 2.5 mol % of [RhCl(cod)]2 as catalyst, NaOEt as
base, and 4:1 dioxane/EtOH as solvent.5 Unfortunately, product
3 was obtained in a disappointing 36% yield (Table 1, entry 1).
Variation of reaction parameters, including boron reagent, base,
solvent, temperature, concentration, Rh-precatalyst, and ligands
was explored, but a higher yield could not be achieved. Indeed,
even the 1,2-diphenylphosphinobenzene (dppbenz) ligand that
we had previously identified as an optimal ligand for Rh-
catalyzed organoboron reagent additions to N-sulfinyl aldimines
and ketimines completely abolished reactivity (entries 2 and 3).
Fernandez, Khiar, and co-workers have previously demonstrated
that for N-sulfinyl imines derived from sterically encumbered
recently have the addition of these reagents to N-(tert-
butanesulfinyl)ketimines been described (Scheme 2).5,6 How-
ever, only N-sulfinyl ketimines activated through ring strain
and/or electron-withdrawing substituents were reported.
In an effort to broaden the scope of Rh-catalyzed organo-
boron reagent additions to N-sulfinyl ketimines, we sought
substrates that were less activated toward nucleophilic attack.
Because of increased ring size, imines derived from cyclo-
hexanone, N-Boc-piperidin-4-one, and tetrahydropyran-4-one
are less electrophilic than previously described N-sulfinyl
ketimine substrates. Additionally, carbon nucleophile addition
products of each of these imines have been extensively used
in medicinal chemistry endeavors.7−9 As a result, we focused
on expanding the scope of Rh-catalyzed organoboron reagent
additions to racemic imines derived from cyclohexanone,
N-Boc-piperidin-4-one, and tetrahydropyran-4-one.
Received: August 1, 2012
Published: October 24, 2012
© 2012 American Chemical Society
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a
Table 1. Optimization of Reaction Conditions
b
entry
imine
[Rh] catalyst
[RhCl(cod)]2
Ar[B] (equiv)
additive (equiv)
solvent (ratio)
temp (°C)
yield (%)
1
2
1
1
1
2
2
2
2
2
2
2
2
2
2
2
(4-OMePhBO)3 (1.5)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
MeOH (3.0)
MeOH (3.0)
MeOH (3.0)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
NaOEt (1.2)
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
dioxane
rt
rt
36
0
[RhCl(cod)]2, dppbenz
[RhCl(cod)]2, dppbenz
[RhCl(cod)]2
3
60
rt
<5
99
<5
<5
<5
78
81
0
4
5
[RhCl(cod)]2
(4-OMePh)BF3K (3.0)
(PhBO)3 (1.5)
rt
6
[RhCl(cod)]2
dioxane
80
80
rt
7
[RhCl(cod)]2, dppbenz
[RhCl(cod)]2
dioxane
8
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
dioxane/EtOH (4:1)
9
[RhCl(cod)]2
60
rt
10
11
12
13
14
[RhCl(cod)]2, dppbenz
[RhCl(cod)]2, dppbenz
[RhCl(cod)]2, dppbenz
[RhCl(cod)]2, dppbenz
[RhCl(cod)]2, dppbenz
60
60
60
60
90
65
91
70
(PhBO)3 (1.0)
(PhBO)3 (2.0)
c
PhB(OH)2 (4.5)
a
b
Reactions were performed with 2.5 mol % of rhodium catalyst and when relevant 5 mol % of ligand. The reaction time was 18 h. Yields were
c
1
determined by H NMR analysis of the crude material relative to 1,3,5-trimethoxybenzene as an external standard. The commercial source of
PhB(OH)2 contained 34% w/w boroxine.
carbonyl compounds, additions to N-(isopropanesulfinyl)imines
can proceed in significiantly higher yields relative to the cor-
responding more hindered N-(tert-butanesulfinyl) derivatives.10
For this reason, we next explored additions to N-(isopropane-
sulfinyl)ketimine 2. A pronounced increase in reactivity was
observed with the addition product 4 obtained in an almost
quantitative yield (entry 4).11 Aryltrifluoroborates were also
investigated based upon Hayashi’s recent report on their
asymmetric addition to sulfonyl ketimines;6 however, under
the reported reaction conditions less than 5% yield was observed
(entries 5−7).
give methyl isopropylsulfinate followed by addition of lithium
bistrimethylsilylamide.12 By instead oxidizing isopropyl disulfide
with sulfuryl chloride to give sulfinyl choride 5, inexpensive
ammonium hydroxide could be used as the amine source to
give racemic isopropanesulfinamide (6), which was isolated by
extraction in 91% overall yield over the two steps (Scheme 3).
Scheme 3. Synthesis of Racemic Isopropanesulfinamide
With optimal conditions established for the addition of
4-methoxyphenylboroxine, the less reactive phenylboroxine was
next investigated. Addition proceeded in 78% yield at rt (entry 8)
with heating resulting in miminal improvement (entry 9).
The reaction did not proceed at rt in the presence of dppbenz
(entry 10), although an excellent yield was obtained upon
heating (entry 11). The room temperature results are consistent
with previous work on isatin-derived imines that suggests the
sterics of dppbenz can actually diminish catalyst reactivity in the
case of less reactive substrates;5 however, for the current class of
substrates, this limitation can apparently be overcome upon
heating. The number of equivalents of phenylboroxine was also
explored. Reactions with just a single equivalent proved detri-
mental (entry 12), while both 1.5 and 2.0 equiv of phenyl-
boroxine provided similar yields (entries 11 and 13). Finally,
using commerical phenylboronic acid under the optimal condi-
tions resulted in a diminished yield (entry 14), a result consistent
with previous work with activated N-(tert-butanesulfinyl)-
ketimines.5
The subsequent preparation of N-isopropanesulfinyl ketimines 2,
7, and 9 proceeded in moderate to good yields by condensing
6 with the appropriate ketone using Ti(O-i-Pr)4 in CH2Cl2
(Scheme 4).
Scheme 4. Preparation of N-(Isopropanesulfinyl)ketimines
Before evaluating the scope of Rh-catalyzed arylboroxine
additions to N-(isopropanesulfinyl)ketimines, we sought to more
fully explore their preparation. Ruano has previously reported a
two step process for the synthesis of racemic isopropanesulfina-
mide via NBS oxidation of isopropyl disulfide in MeOH to
The addition of a wide variety of arylboroxines to sulfinyl
ketimines 2, 7, and 9 was next investigated (Scheme 5). While
phenylboroxine showed comparable results whether 1.5 or 2.0
equiv were used, initial investigation of the scope demonstrated
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a
Scheme 5. N-(Isopropanesulfinyl)ketimine Addition Reaction Scope
a
b
c
d
Isolated yields after chromatography. Reaction were performed without added dppbenz. Reaction was performed at 80 °C. Reaction was
performed at room temperature in the absence of dppbenz.
that 2.0 equiv of arylboroxine resulted in improved yields for a
number of products including 4f and 4g. As a result, the reaction
scope was evaluated utilizing 2.0 equiv of arylboroxine to
provide more general reaction parameters. Electron-neutral and
electron-rich aryl boroxines added in good to high yields (e.g.,
4a−d, 8a−b, and 10a−b). In contrast, the addition of electron-
deficient arylboroxines was less efficient resulting in low (4j) to
moderate (10e) yields. While meta and para substitution was
well tolerated (e.g., 4c and 4d), ortho-substituted arylboroxines
were evaluated but these coupled with poor efficiency (4e). The
functional group compatibility of the reaction was high with
effective couple being observed for arylboroxines incorporating
phenyl esters (4l), primary alcohols (4k), ketones (10e), chlorides
(4g, 4h, 8c, and 10d), fluorides (4f), and bromides (4i and 8d).
However, for bromo-substituted arylboroxines, coupling was
performed without the dppbenz ligand to prevent competitive
Rh insertion into the C−Br bond.
The practicality of the addition products was demonstrated
by selective cleavage of the isopropanesulfinyl group in 4g with
HCl treatment (Scheme 6). Not only is the desired product 11
readily isolated in almost quantitative yield, but straightforward
operations also enable the efficient recovery of the isopropane-
sulfinyl group via its reconversion to isopropanesulfinamide
(6).13 Specifically, treatment of 4g with greater than 2 equiv of
HCl in the acid stable and increasingly popular industrial
solvent, cyclopentyl methyl ether (CPME),14 led to precip-
itation of the amine hydrochloride 11, which was isolated in
near-quantitative yield and with high purity by simple filtration.
The filtrate containing the sulfinyl chloride was then added to
ammonium hydroxide to provide sulfinamide 6, which was also
obtained with high purity and excellent yield after straightfor-
ward extraction.
Scheme 6. Cleavage and Recycling of Isopropanesulfinyl
Group
CONCLUSION
■
In conclusion, the rhodium-catalyzed additions of arylboroxines
to N-(isopropanesulfinyl)ketimines derived from cyclohexa-
none, N-Boc-piperidin-4-one, and tetrahydropyran-4-one pro-
ceed in high yields with excellent functional group compatibility
to provide privileged classes of tertiary carbinamine products.
The isopropanesulfinamide is readily prepared using inexpensive
starting materials and reagents. Moreover, the isopropanesulfinyl
group can be recycled, which adds to the overall efficiency of
this tertiary carbinamine synthesis process.
EXPERIMENTAL SECTION
General Experimental Methods. Methylene chloride (CH2Cl2),
1,4-dioxane, and cyclopentyl methyl ether (CPME) were dried by
passing through an aluminum drying column. Ethanol (EtOH) was
■
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refluxed with activated magnesium for several hours, distilled under
nitrogen gas, and stored over MS 3 Å in a nitrogen filled glovebox.
Arylboroxines (anhydrous trimers) were readily prepared by heating
commercially available arylboronic acids up to 110−130 °C under high
vacuum (approximately 0.3 Torr) for 12−18 h; complete conversion
upon which 1.0−1.5 cm (depth) of Celite was added. Additional
CH2Cl2 (2 × 40 mL) was used to rinse the flask and the pad of Celite.
The organic layer of the filtrate was separated, washed with brine, dried
over MgSO4, filtered, and concentrated under a reduced pressure. The
crude product was purified via flash chromatography on silica gel.
Although the imine product did not readily hydrolyze during aqueous
workup, imine hydrolysis does occur during purification via
chromatography on silica gel. To minimize hydrolysis a short plug of
silica gel column (3.0 cm (d) × 10 cm (l)) with constant air-pressure
was therefore used.
N-(N-Boc-4-piperidylidene)isopropanesulfinamide (2). From
1-Boc-4-piperidone (1.00 g, 5.02 mmol), ( )-isopropanesulfinamide
(538 mg, 5.02 mmol), and Ti(OiPr)4 (3.0 mL, 10 mmol) was obtained
ketimine 2 as a slightly yellow solid (1.08 g, 75% yield). Rf = 0.25 (1:1
hexanes/EtOAc). Mp: 63.7−64.3 °C. 1H NMR (500 MHz, CDCl3): δ
3.71 (dt, J = 13.2, 6.0, 1H), 3.67−3.53 (m, 3H), 3.09 (ddd, J = 14.9,
6.9, 4.9 Hz, 1H), 2.89 (sept, J = 6.9 Hz, 1H), 2.82 (ddd, J = 14.9, 7.4,
4.9 Hz, 1H), 2.52 (app t, J = 5.3 Hz, 2H), 1.48 (s, 9H), 1.28 (d, J = 6.9
Hz, 3H), 1.27 (d, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ
183.1, 154.4, 80.3, 54.1, 39.3, 33.5, 28.3, 14.6, 13.9. IR: 2973, 2930,
1691, 1624, 1416, 1236, 1162, 1075 cm−1. HRMS (ESI): m/z calcd for
C13H25N2O3S (M + H)+ 289.1580, found 289.1576.
N-(4-Tetrahydropyranylidene)isopropanesulfinamide (7).
From tetrahydro-4H-pyran-4-one (923 μL, 9.99 mmol), ( )-iso-
propanesulfinamide (1.28 mg, 12.0 mmol), and Ti(OiPr)4 (6.0 mL,
20 mmol) was obtained ketimine 7 as a slightly yellow oil (1.18 g, 62%
yield). Rf = 0.30 (EtOAc). 1H NMR (500 MHz, CDCl3): δ 3.95−3.85
(m, 2H), 3.86−3.80 (m, 2H), 3.16−3.09 (m, 1H), 2.91−2.83 (m, 2H),
2.53 (app td, J = 5.7, 2.0 Hz, 2H), 1.27 (d, J = 6.9 Hz, 3H), 1.25 (d, J =
6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 182.1, 68.6, 67.5, 54.1,
40.7, 35.1, 14.6, 13.9. IR (thin film): 2966, 2854, 1620, 1381, 1223,
1071, 1030 cm−1. HRMS (ESI): m/z calcd for C8H16NO2S (M + H)+
190.0896, found 190.0894.
1
to arylboroxine was confirmed by H NMR with deuterated dimethyl
sulfoxide (DMSO-d6) as solvent. Powdered molecular sieves (pore
size 3 Å) were preheated to 300−350 °C under high vacuum overnight
and cooled under dry nitrogen atmosphere. All glassware and magnetic
stir bars were dried at 150 °C overnight or flame-dried prior to use.
All reagents necessary for addition reactions were stored in a nitrogen-
filled glovebox. Reactions were conducted under nitrogen atmosphere
unless otherwise specified. Melting points are reported uncorrected.
Proton (1H NMR), carbon (13C NMR), and fluorine (19F NMR)
nuclear magnetic resonance spectra were recorded on 400 and 500 MHz
spectrometers. All 19F NMR experiments utilized proton decoupling.
The chemical shifts are given in parts per million (ppm) on the delta (δ)
scale. The solvent peak or the internal standard tetramethylsilane
(TMS) was used as reference values. For 1H NMR: CDCl3 = 7.26 ppm,
CD3OD = 3.31 ppm, TMS = 0.00 ppm. For 13C NMR: CDCl3 =
77.0 ppm, CD3OD = 49.0 ppm, TMS = 0.00 ppm. Infrared (IR) spectra
were collected on a FT-IR spectrometer possessing an ATR attachment
with anvil; only partial data are provided. High resolution mass spectra
(HRMS) were obtained on a Fourier transform ion cyclotron resonance
(FT-ICR) mass spectrometer except in the case of ketimine 9, which
was obtained on a time-of-flight (TOF) mass spectrometer.
Isopropanesulfinamide (6). In a 100 mL, three-neck flask with
a magnetic stirring bar were placed isopropyl disulfide (8.00 mL,
50.0 mmol, 1.0 equiv) and acetic acid (5.72 mL, 100 mmol, 2.0 equiv).
The solution was cooled to −20 °C with stirring; solids formed due
to the low melting point of acetic acid. Sulfuryl chloride (12.5 mL,
155 mmol, 3.1 equiv) was slowly added by a syringe over a period of
30 min resulting in slow melting of the solids. The mixture was stirred
at −20 °C for 3 h and was allowed to warm to room temperature over
a period of 2 h during which evolution of SO2 (g) and HCl (g) was
observed. The reaction mixture was stirred at 35 °C for an additional
1 h and then cooled to 0 °C. Acetyl chloride was removed under a
reduced pressure (approximately 0.5 Torr); a vacuum trap was
required. The remaining sulfinyl chloride was then dissolved in 80 mL
of anhydrous CH2Cl2, and the solution was slowly transferred by a
cannula to 600 mL of cold 28−30% aqueous NH4OH solution at 0 °C
with vigorous stirring over a period of 1 h. An additional 20 mL of
CH2Cl2 was added to the reaction flask and then was transferred by
cannula to the NH4OH solution to ensure complete transfer of the
sufinyl chloride solution. After the addition was complete, the reaction
mixture was stirred overnight open to air during which time much of
the ammonia evaporated. The reaction mixture was transferred to a
1 L separatory funnel, the aqueous phase was saturated with NaCl, and
then extraction was performed with a solution of 10:1 CHCl3/EtOH
(4 × 250 mL). Concentration of the combined organic layers under
reduced pressure afforded ( )-isopropanesulfinamide (9.78 g, 91.3
mmol, 91% yield) as a pale yellow solid. 1H NMR (500 MHz, CDCl3):
δ 3.99 (br s, NH2), 2.73 (sept, J = 6.9 Hz, 1H), 1.28 (d, J = 6.9 Hz,
3H), 1.27 (d, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 54.5,
14.8, 14.7.12
N-Cyclohexylideneisopropanesulfinamide (9). From cyclo-
hexanone (1.24 mL, 11.9 mmol), ( )-isopropanesulfinamide (720 mg,
6.72 mmol), and Ti(OiPr)4 (6.0 mL, 20 mmol) was obtained ketimine 9
as a slightly yellow oil (700 mg, 56% yield). Rf = 0.30 (1:1 hexanes/
1
EtOAc). H NMR (500 MHz, CDCl3): δ 2.86−2.78 (m, 1H), 2.79
(sept, J = 6.9 Hz, 1H), 2.72−2.64 (m, 1H), 2.39 (app t, J = 6.4 Hz, 2H),
1.82−1.60 (m, 6H), 1.27 (d, J = 6.9 Hz, 3H), 1.23 (d, J = 6.9 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 188.4, 54.0, 40.5, 34.3, 27.8, 27.4, 25.2,
14.6, 14.0. IR: 2932, 2860, 1610, 1448, 1068, 1029 cm−1. HRMS (ESI):
m/z calcd for C9H18NOS (M + H)+ 188.1104, found 188.1133.
General Procedure for the Addition of Arylboroxines to
Ketimines 2, 7, and 9. Reactions were set up in a nitrogen-filled
glovebox. To a vial (2 dram) containing an N-(isopropanesulfinyl)-
ketimine substrate (0.20 mmol) and a magnetic stirring bar was
transferred a mixture of NaOEt (16 mg, 0.24 mmol), arylboroxine (0.40
mmol), and MS 3 Å powder (200% mass to boroxine) in a solvent
mixture of dioxane (0.4 mL) and EtOH (0.2 mL). Subsequently,
a heterogeneous orange-colored mixture of [RhCl(cod)]2 (2.5 mg,
5.0 μmol) and dppbenz (4.5 mg, 10 μmol) in dioxane (0.4 mL), which
had been initially stirred for 10 min (approx), was added to the reaction
vial. The vial was capped, removed from the box, sealed with Parafilm,
and placed on a magnetic stir plate. The reaction mixture was stirred at
60 °C for 12−18 h unless otherwise noted. The reaction mixture was
then filtered through a short pad of silica gel, which was washed with
EtOAc. The filtrate was concentrated under a reduced pressure. The
crude product was purified via chromatography on silica gel (hexanes/
EtOAc mixture or EtOAc/EtOH mixture).
General Procedure for the Synthesis of Sulfinyl Ketimines.
In a 50 mL, round-bottom flask with a magnetic stirring bar were
placed the appropriate ketone and ( )-isopropanesulfinamide. CH2Cl2
(10 mL) and then Ti(OiPr)4 were added at room temperature. The
reaction mixture was refluxed (at 45 °C) overnight (ca. 16 h) under a
nitrogen atmosphere and then was cooled to room temperature.
N-4-(N-Boc-4-phenylpiperidinyl)isopropanesulfinylamine
(4a). From 58.0 mg (0.201 mmol) of imine 2 and 125 mg (0.401 mmol)
of phenylboroxine was obtained 62.5 mg (85% yield) of sulfinylamine 4a
as an off-white solid after purification by silica gel chromatography eluting
with 1:1 hexanes/EtOAc followed by 100% EtOAc. Rf = 0.50 (EtOAc).
Mp = 120−121 °C. 1H NMR (500 MHz, CDCl3): δ 7.47 (d, J = 7.5 Hz,
2H), 7.38 (t, J = 7.5 Hz, 2H), 7.29 (t, J = 7.5 Hz, 1H), 3.81 (s, NH),
3.63−3.54 (m, 2H), 3.54−3.43 (m, 2H), 2.67 (sept, J = 6.9 Hz, 1H),
2.40−2.32 (m, 1H), 2.24−2.08 (m, 3H), 1.45 (s, 9H), 1.19 (d, J = 6.9
Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 154.7, 143.3, 128.6, 127.7,
1
Conversion was monitored by H NMR analysis of aliquots of the
reaction mixture diluted with CDCl3. The mixture was poured into a
125 mL Erlenmeyer flask, which contained 50 mL (approx) of satd
NaHCO3 (aq) and a long magnetic stirring bar (length = 6.0 cm). The
reaction flask was rinsed with 10 mL of CH2Cl2, and the rinse was
poured into the Erlenmeyer flask. The resulting mixture was vigorously
stirred for 20 min (approx) during which time white solids precipitated.
The solids were removed by filtration under a reduced pressure through
a 60 mL fritted filter funnel (pore size = 20−30 μm and disk size = 6.5 cm)
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126.5, 79.7, 58.3, 55.1, 37.2, 36.9, 28.4, 15.4, 15.3. IR: 3485, 3201, 2973,
2930, 1693, 1424, 1248, 1168, 1031 cm−1. HRMS (ESI): m/z calcd for
C19H31N2O3S (M + H)+ 367.2050, found 367.2041.
(125 MHz, CDCl3): δ 154.7, 142.1, 133.6, 128.7, 128.0, 79.8, 58.0,
55.2, 37.1, 37.0, 28.4, 15.4. IR: 3480, 3190, 2929, 1687, 1423, 1246,
1163, 1029 cm−1. HRMS (ESI): m/z calcd for C19H30ClN2O3S
(M + H)+ 401.1660, found 401.1665.
N-4-(N-Boc-4-(4-methoxyphenyl)piperidinyl)isopropanesulfinyl-
amine (4b). From 58.0 mg (0.201 mmol) of imine 2 and 161 mg
(0.401 mmol) of 4-methoxyphenylboroxine was obtained 73.3 mg
(92% yield) of sulfinylamine 4b as an off-white solid after purification
by silica gel chromatography eluting with 1:1 hexanes/EtOAc followed
N-4-(N-Boc-4-(3-chlorophenyl)piperidinyl)isopropanesulfinyl-
amine (4h). From 58.0 mg (0.201 mmol) of imine 2 and 167 mg
(0.402 mmol) of 3-chlorophenylboroxine was obtained 49.8 mg (62%
yield) of sulfinylamine 4h as an off-white solid after purification by
silica gel chromatography eluting with 1:1 hexanes/EtOAc followd
1
by 100% EtOAc. Rf = 0.40 (EtOAc). Mp =100−101 °C. H NMR
1
(500 MHz, CDCl3): δ 7.38 (d, J = 8.8 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H),
3.81 (s, 3H), 3.71 (s, NH), 3.65−3.58 (m, 1H), 3.54−3.46 (m, 2H),
3.45−3.37 (m, 1H), 2.65 (sept, J = 6.9 Hz, 1H), 2.40−2.32 (m, 1H),
2.20−2.05 (m, 3H), 1.45 (s, 9H), 1.18 (d, J = 6.9 Hz, 6H). 13C NMR
(125 MHz, CDCl3): δ 158.9, 154.7, 134.9, 127.9, 113.9, 79.7, 58.0, 55.2,
55.0, 37.5, 37.2, 28.4, 15.4, 15.3. IR: 3483, 3185, 2930, 1688, 1423, 1246,
1165, 1030 cm−1. HRMS (ESI): m/z calcd for C20H33N2O4S (M + H)+
397.2155, found 397.2160.
by 100% EtOAc. Rf = 0.45 (EtOAc). Mp = 147−148 °C. H NMR
(500 MHz, CDCl3): δ 7.44 (s, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.31
(t, J = 7.8 Hz, 1H), 7.27 (d, J = 7.8 Hz, 1H), 3.80 (s, NH), 3.65 (dt, J =
13.6, 5.0 Hz, 1H), 3.61−3.50 (m, 2H), 3.45−3.35 (m, 1H), 2.69 (sept,
J = 6.9 Hz, 1H), 2.34−2.26 (m, 1H), 2.20−2.05 (m, 3H), 1.46 (s, 9H),
1.21 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 154.7,
145.9, 134.6, 129.8, 127.9, 126.9, 124.7, 79.8, 58.2, 55.2, 37.2,
36.8, 28.4, 15.3. IR: 3488, 3206, 2973, 2929, 1690, 1421, 1247, 1165,
1034 cm−1. HRMS (ESI): m/z calcd for C19H30ClN2O3S (M + H)+
401.1660, found 401.1663.
N-4-(N-Boc-4-(4-methylphenyl)piperidinyl)isopropanesulfinyl-
amine (4c). From 58.0 mg (0.201 mmol) of imine 2 and 161 mg
(0.401 mmol) of 4-methylphenylboroxine was obtained 73.1 mg (96%
yield) of sulfinylamine 4c as an off-white solid after purification by silica
gel chromatography eluting with 1:1 hexanes/EtOAc followed by 100%
N-4-(N-Boc-4-(4-bromophenyl)piperidinyl)isopropanesulfinyl-
amine (4i). The general reaction procedure was employed except that
the dppbenz ligand was not added. From 58.0 mg (0.201 mmol) of
imine 2 and 220 mg (0.401 mmol) of 4-bromophenylboroxine was
obtained 78.2 mg (88% yield) of sulfinylamine 4i as an off-white
solid after purification by silica gel chromatography eluting with 1:1
hexanes/EtOAc followed by 100% EtOAc. Rf = 0.50 (EtOAc). Mp =
1
EtOAc. Rf = 0.55 (EtOAc). Mp = 132−133 °C. H NMR (500 MHz,
CDCl3): δ 7.35 (d, J = 8.2 Hz, 2H), 6.18 (d, J = 8.2 Hz, 2H), 3.72
(s, NH), 3.63−3.57 (m, 1H), 3.57−3.40 (m, 3H), 2.65 (sept, J = 6.9
Hz, 1H), 2.38−2.32 (m, 1H), 2.34 (s, 3H), 2.22−2.06 (m, 3H), 1.45
(s, 9H), 1.19 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ
154.8, 140.1, 137.4, 129.3, 126.4, 79.7, 58.1, 55.0, 37.3, 37.0, 28.4, 21.0,
15.4, 15.3. IR: 3488, 3202, 2973, 2928, 1692, 1424, 1247, 1166, 1032 cm−1.
HRMS (ESI): m/z calcd for C20H33N2O3S (M + H)+ 381.2206, found
381.2207.
1
114−115 °C. H NMR (500 MHz, CDCl3): δ 7.49 (d, J = 8.6 Hz,
2H), 7.34 (d, J = 8.6 Hz, 2H), 3.77 (s, NH), 3.64−3.58 (m, 1H),
3.57−3.48 (m, 2H), 3.45−3.38 (m, 1H), 2.68 (sept, J = 6.9 Hz, 1H),
2.32−2.25 (m, 1H), 2.20−2.05 (m, 3H), 1.45 (s, 9H), 1.20 (d, J = 6.9
Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 154.7, 142.7, 131.7, 128.3,
121.8, 79.9, 58.1, 55.2, 37.0, 36.9, 28.4, 15.4. IR: 3484, 3206, 2974,
1684, 1424, 1247, 1163, 1028 cm−1. HRMS (ESI): m/z calcd for
C19H30BrN2O3S (M + H)+ 447.1136, found 447.1139.
N-4-(N-Boc-4-(3-methylphenyl)piperidinyl)isopropanesulfiny-
lamine (4d). From 58.0 mg (0.201 mmol) of imine 2 and 161 mg
(0.401 mmol) of 3-methylphenylboroxine was obtained 70.8 mg (93%
yield) of sulfinylamine 4d as an off-white solid after purification by
silica gel chromatography eluting with 1:1 hexanes/EtOAc followed
N-4-(N-Boc-4-(4-(trifluoromethyl)phenyl)piperidinyl)-
isopropanesulfinylamine (4j). The general reaction procedure was
employed except that the reaction mixture was stirred at 80 °C. From
58.0 mg (0.201 mmol) of imine 2 and 207 mg (0.401 mmol) of
4-(trifluoromethyl)phenylboroxine was obtained 15.6 mg (18% yield)
of sulfinylamine 4j as an off-white solid after purification by silica gel
chromatography eluting with 1:1 hexanes/EtOAc followed by 100%
1
by 100% EtOAc. Rf = 0.55 (EtOAc). Mp = 123−124 °C. H NMR
(500 MHz, CDCl3): δ 7.27−7.25 (m, 3H), 7.12−7.09 (m, 1H), 3.74
(s, NH), 3.63−3.53 (m, 2H), 3.53−3.42 (m, 2H), 2.66 (sept, J = 6.9
Hz, 1H), 2.39−2.33 (m, 1H), 2.36 (s, 3H), 2.21−2.08 (m, 3H), 1.45
(s, 9H), 1.19 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ
154.8, 143.2, 138.1, 128.5, 128.4, 127.3, 123.6, 79.7, 58.3, 55.1, 37.4,
36.9, 28.4, 21.7, 15.4, 15.3. IR: 3483, 3200, 2928, 1688, 1422, 1238,
1159, 1034 cm−1. HRMS (ESI): m/z calcd for C20H33N2O3S (M +
H)+ 381.2206, found 381.2203.
1
EtOAc. Rf = 0.55 (EtOAc). Mp: 90−92 °C. H NMR (500 MHz,
CDCl3): δ 7.65−7.58 (m, 4H), 3.87 (s, NH), 3.71 (dt, J = 13.8, 4.6
Hz, 1H), 3.62 (app d, J = 12.6 Hz, 1H), 3.52 (app t, J = 13.8 Hz, 1H),
3.39 (m, 1H), 2.71 (sept, J = 6.9 Hz, 1H), 2.34−2.26 (m, 1H), 2.23−
2.08 (m, 3H), 1.46 (s, 9H), 1.22 (d, J = 6.9 Hz, 6H). 13C NMR (125
MHz, CDCl3): δ 154.7, 148.0, 130 (q, J = 32 Hz), 126.9, 125.5 (q, J =
4 Hz), 123.9 (q, J = 270 Hz), 79.9, 58.3, 55.3, 37.0, 36.8, 28.4, 15.4,
15.3. 19F NMR (376 MHz, CDCl3): δ −62.62. IR: 3485, 3191, 2974,
1690, 1424, 1326, 1248, 1164, 1122, 1031 cm−1. HRMS (ESI): m/z
calcd for C20H29F3N2O3SNa (M + Na)+ 457.1743, found 457.1728.
N-4-(N-Boc-4-(4-(hydroxymethyl)phenyl)piperidinyl)-
isopropanesulfinylamine (4k). From 58.0 mg (0.201 mmol) of
imine 2 and 161 mg (0.401 mmol) of 4-(hydroxymethyl)phenylboroxine
was obtained 65.0 mg (82% yield) of sulfinylamine 4k as an off-white
solid after purification by silica gel chromatography eluting with 100%
EtOAc followed by 20:1 EtOAc/EtOH. Rf = 0.30 (20:1 EtOAc/EtOH).
N-4-(N-Boc-4-(4-fluorophenyl)piperidinyl)isopropanesulfinyl-
amine (4f). From 58.0 mg (0.201 mmol) of imine 2 and 147 mg
(0.402 mmol) of 4-fluorophenylboroxine was obtained 68.2 mg (89%
yield) of sulfinylamine 4f as an off-white solid after purification by
silica gel chromatography eluting with 1:1 hexanes/EtOAc followed
1
by 100% EtOAc. Rf = 0.40 (EtOAc). Mp = 119−121 °C. H NMR
(500 MHz, CDCl3): δ 7.46−7.43 (m, 2H), 7.07−7.04 (m, 2H), 3.76
(s, NH), 3.63−3.47 (m, 3H), 3.57−3.40 (m, 1H), 2.68 (sept, J = 6.9
Hz, 1H), 2.36−2.28 (m, 1H), 2.20−2.08 (m, 3H), 1.45 (s, 9H), 1.20
(d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 162.0 (d, J = 246
Hz), 154.7, 139.2 (d, J = 2 Hz), 128.3 (d, J = 9 Hz), 115.4 (d, J = 20
Hz), 79.8, 58.0, 55.1, 37.3, 37.2, 28.4, 15.4, 15.3. 19F NMR (376 MHz,
CDCl3): δ −114.56. IR: 3482, 3191, 2972, 1693, 1426, 1248, 1166,
1033 cm−1. HRMS (ESI): m/z calcd for C19H30FN2O3S (M + H)+
385.19557, found 385.19563.
1
Mp = 94−95 °C. H NMR (500 MHz, CDCl3): δ 7.45 (d, J = 8.2 Hz,
2H), 7.36 (d, J = 8.2 Hz, 2H), 4.67 (d, J = 5.5 Hz, 2H), 3.82 (s, NH),
3.56 (app s, 2H), 3.47 (app s, 2H), 2.66 (sept, J = 6.9 Hz, 1H), 2.37−
2.22 (m, 2H), 2.22−2.08 (m, 3H), 1.45 (s, 9H), 1.18 (d, J = 6.9 Hz, 6H).
13C NMR (125 MHz, CDCl3): δ 154.7, 142.5, 140.6, 127.1, 126.6, 79.7,
N-4-(N-Boc-4-(4-chlorophenyl)piperidinyl)isopropanesulfinyl-
amine (4g). From 58.0 mg (0.201 mmol) of imine 2 and 167 mg
(0.402 mmol) of 4-chlorophenylboroxine was obtained 69.3 mg (86%
yield) of sulfinylamine 4g as an off-white solid after purification by
silica gel chromatography eluting with 1:1 hexanes/EtOAc followed
64.6, 58.1, 55.1, 37.1, 37.0, 28.4, 15.4. IR: 3478, 3222, 2972, 2929, 2870,
1669, 1425, 1248, 1164, 1031 cm−1. HRMS (ESI): m/z calcd for
C20H33N2O4S (M + H)+ 397.2155, found 397.2160.
N-4-(N-Boc-4-(4-acetoxyphenyl)piperidinyl)isopropanesulfinyl-
amine (4l). The general reaction procedure was employed except
that the dppbenz ligand was not added and the reaction mixture was
stirred at room temperature. From 58.0 mg (0.201 mmol) of imine 2
and 195 mg (0.401 mmol) of 4-acetoxyphenylboroxine was obtained
1
by 100% EtOAc. Rf = 0.45 (EtOAc). Mp = 102−103 °C. H NMR
(500 MHz, CDCl3): δ 7.40 (d, J = 8.6 Hz, 2H), 7.34 (d, J = 8.6 Hz,
2H), 3.79 (s, NH), 3.60 (dt, J = 13.7, 3.2 Hz, 1H), 3.57−3.49 (m, 2H),
3.45−3.37 (m, 1H), 2.68 (sept, J = 6.9 Hz, 1H), 2.33−2.25 (m, 1H),
2.18−2.05 (m, 3H), 1.45 (s, 9H), 1.20 (d, J = 6.9 Hz, 6H). 13C NMR
9597
dx.doi.org/10.1021/jo301634y | J. Org. Chem. 2012, 77, 9593−9600

The Journal of Organic Chemistry
Article
41.7 mg (49% yield) of sulfinylamine 4l as an off-white solid after
purification by silica gel chromatography eluting with 1:1 hexanes/
EtOAc followed by 100% EtOAc. Rf = 0.45 (EtOAc). Mp = 104−
105 °C. 1H NMR (500 MHz, CDCl3): δ 7.48 (d, J = 8.7 Hz, 2H), 7.10
(d, J = 8.7 Hz, 2H), 3.79 (s, NH), 3.64−3.47 (m, 3H), 3.47−3.39 (m,
1H), 2.68 (sept, J = 6.9 Hz, 1H), 2.35−2.28 (m, 1H), 2.29 (s, 3H),
2.18−2.09 (m, 3H), 1.45 (s, 9H), 1.20 (d, J = 6.9 Hz, 6H). 13C NMR
(125 MHz, CDCl3): δ 169.2, 154.7, 150.0, 141.0, 127.7, 121.5, 79.8,
58.2, 55.1, 37.3, 37.0, 28.4, 21.1, 15.4, 15.3. IR: 3484, 3220, 2973,
1758, 1686, 1424, 1365, 1199, 1164, 1030 cm−1. HRMS (ESI): m/z
calcd for C21H32N2O5SNa (M + Na)+ 447.1924, found 447.1902.
N-4-(4-Phenyltetrahydropyranyl)isopropanesulfinylamine
(8a). From 38.0 mg (0.201 mmol) of imine 7 and 125 mg (0.401 mmol)
of phenylboroxine was obtained 45.5 mg (85% yield) of sulfinylamine 8a
as an off-white solid after purification by silica gel chromatography eluting
with 100% EtOAc followed by 20:1 EtOAc/EtOH. Rf = 0.30 (20:1
EtOAc/EtOH). Mp = 64−65 °C. 1H NMR (500 MHz, CDCl3): δ 7.47
(d, J = 7.5 Hz, 2H), 7.39 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.5 Hz, 1H),
3.94 (ddd, J = 11.9, 8.1, 3.1 Hz, 1H), 3.83 (ddd, J = 12.0, 8.1, 3.1 Hz,
1H), 3.82 (s, NH), 3.77 (ddd, J = 11.9, 6.3, 3.7 Hz, 1H), 3.67 (ddd, J =
12.0, 6.3, 3.7 Hz, 1H), 2.68 (sept, J = 6.9 Hz, 1H), 2.50−2.43 (m, 1H),
2.29−2.15 (m, 3H), 1.19 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz,
CDCl3): δ 143.6, 128.6, 127.7, 126.5, 64.1, 64.0, 57.5, 55.1, 38.2, 37.7,
15.4, 15.3. IR: 3447, 3204, 2960, 2929, 2868, 1447, 1420, 1160, 1030
cm−1. HRMS (ESI): m/z calcd for C14H22NO2S (M + H)+ 268.1366,
found 268.1361.
N-4-(4-(4-Methoxyphenyl)tetrahydropyranyl)isopropane-
sulfinylamine (8b). From 38.0 mg (0.201 mmol) of imine 7 and
161 mg (0.401 mmol) of 4-methoxyphenylboroxine was obtained
52.4 mg (88% yield) of sulfinylamine 8b as an off-white solid after
purification by silica gel chromatography eluting with 100% EtOAc
followed by 10:1 EtOAc/EtOH. Rf = 0.25 (20:1 EtOAc/EtOH). Mp =
dec over 150 °C. 1H NMR (500 MHz, CDCl3): δ 7.38 (d, J = 8.9 Hz,
2H), 6.90 (d, J = 8.9 Hz, 2H), 3.92 (ddd, J = 11.3, 7.6, 1.4 Hz, 1H),
3.86 (s, NH), 3.84−3.78 (m, 1H), 3.81 (s, 3H), 3.78−3.72 (m, 1H),
3.67−3.62 (m, 1H), 2.67 (sept, J = 6.9 Hz, 1H), 2.47−2.41 (m, 1H),
2.25−2.13 (m, 3H), 1.19 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz,
CDCl3): δ 158.9, 135.3, 127.9, 113.8, 64.2, 64.0, 57.1, 55.2, 55.0, 38.4,
38.0, 15.6, 15.4. IR: 3445, 3203, 2965, 1464, 1189, 1101, 1028 cm−1.
HRMS (ESI): m/z calcd for C15H24NO3S (M + H)+ 298.14714, found
298.14713.
HRMS (ESI): m/z calcd for C14H21BrNO2S (M + H)+ 348.0451,
found 348.0452.
N-(1-Phenylcyclohexyl)isopropanesulfinylamine (10a). From
38.5 mg (0.200 mmol) of imine 9 and 125 mg (0.401 mmol) of
phenylboroxine was obtained 35.8 mg (67% yield) of sulfinylamine
10a as an off-white solid after purification by silica gel chromatography
eluting with 1:1 hexanes/EtOAc followed by 100% EtOAc. Rf = 0.20
1
(1:1 hexanes/EtOAc). Mp: = 99.6−100.2 °C. H NMR (500 MHz,
CDCl3): δ 7.50 (d, J = 8.2 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.26 (t,
J = 8.2 Hz, 1H), 3.76 (s, NH), 2.63 (sept, J = 6.9 Hz, 1H), 2.36−2.29
(m, 1H), 2.16−2.06 (m, 2H), 2.04−1.97 (m, 1H), 1.78−1.72 (m, 1H),
1.65−1.38 (m, 5H), 1.17 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz,
CDCl3): δ 144.6, 128.3, 127.1, 126.8, 59.8, 55.0, 38.9, 37.4, 25.4, 22.6,
22.3, 15.5, 15.2. IR: 3445, 3186, 2929, 2859, 1448, 1035 cm−1. HRMS
(ESI): m/z calcd for C15H24NOS (M + H)+ 266.1573, found 266.1568.
N-(1-(4-Methoxyphenyl)cyclohexyl)isopropanesulfinylamine
(10b). From 38.5 mg (0.200 mmol) of imine 9 and 161 mg (0.401
mmol) of 4-methoxyphenylboroxine was obtained 50.2 mg (85% yield)
of sulfinylamine 10b as an off-white solid after purification by silica gel
chromatography eluting with 1:1 hexanes/EtOAc followed by 100%
EtOAc. Rf = 0.45 (EtOAc). Mp = 88.6−89.4 °C. 1H NMR (500 MHz,
CDCl3): δ 7.41 (d, J = 8.8 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 3.81 (s,
3H), 3.71 (s, NH), 2.61 (sept, J = 6.9 Hz, 1H), 2.34−2.28 (m, 1H),
2.13−2.06 (m, 2H), 2.00−1.93 (m, 1H), 1.78−1.72 (m, 1H), 1.63−
1.38 (m, 5H), 1.17 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3):
δ 158.5, 136.4, 128.1, 113.5, 59.4, 55.1, 54.9, 39.1, 37.7, 25.4, 22.6, 22.4,
15.5, 15.2. IR: 3448, 3185, 2931, 2860, 1452, 1248, 1182, 1034 cm−1.
HRMS (ESI): m/z calcd for C16H26NO2S (M + H)+ 296.1679, found
296.1669.
N-(1-(3-Methoxyphenyl)cyclohexyl)isopropanesulfinylamine
(10c). From 38.5 mg (0.200 mmol) of imine 9 and 161 mg (0.401
mmol) of 4-methoxyphenylboroxine was obtained 43.7 mg (74%
yield) of sulfinylamine 10c as an off-white solid after purification by
silica gel chromatography eluting with 1:1 hexanes/EtOAc followed
1
by 100% EtOAc. Rf = 0.45 (EtOAc). Mp = 113−114 °C. H NMR
(500 MHz, CDCl3): δ 7.27 (t, J = 8.2 Hz, 1H), 7.09 (d, J = 8.2 Hz,
1H), 7.06 (s, 1H), 6.80 (dd, J = 8.2, 2.4 Hz, 1H), 3.81 (s, 3H), 3.76 (s,
NH), 2.61 (sept, J = 6.9 Hz, 1H), 2.32−2.25 (m, 1H), 2.15−2.03 (m,
2H), 2.03−1.97 (m, 1H), 1.80−1.73 (m, 1H), 1.65−1.36 (m, 5H),
1.18 (d, J = 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 159.5,
146.5, 129.2, 119.1, 113.3, 111.9, 59.8, 55.1, 54.9, 39.0, 37.4, 25.4, 22.6,
22.2, 15.4, 15.3. IR: 3455, 3188, 2931, 2859, 1451, 1243, 1037 cm−1.
HRMS (ESI): m/z calcd for C16H26NO2S (M + H)+ 296.1679, found
296.1668.
N-4-(4-(4-Chlorophenyl)tetrahydropyranyl)isopropanesulfinyl-
amine (8c). From 38.0 mg (0.201 mmol) of imine 7 and 167 mg
(0.402 mmol) of 4-chlorophenylboroxine was obtained 41.6 mg (69%
yield) of sulfinylamine 8c as an off-white solid after purification by
silica gel chromatography eluting with 100% EtOAc followed by 20:1
EtOAc/EtOH. Rf = 0.35 (20:1 EtOAc/EtOH). Mp =103.6−104.4 °C.
1H NMR (500 MHz, CDCl3): δ 7.41 (d, J = 8.7 Hz, 2H), 7.35 (d, J =
8.7 Hz, 2H), 3.92 (ddd, J = 11.9, 8.3, 3.0 Hz, 1H), 3.84−3.75 (m, 2H),
3.81 (s, NH), 3.70−3.66 (m, 1H), 2.68 (sept, J = 6.9 Hz, 1H),
2.41(ddd, J = 13.9, 8.3, 3.5 Hz, 1H), 2.23−2.14 (m, 3H), 1.20 (d, J =
6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 142.4, 133.6, 128.7,
128.0, 63.9, 63.7, 57.2, 55.2, 38.0, 37.8, 15.4, 15.3. IR: 3446, 3192,
2957, 2867, 1493, 1095, 1035, 1014 cm−1. HRMS (ESI): m/z calcd for
C14H21ClNO2S (M + H)+ 302.0976, found 302.0977.
N-(1-(4-Chlorophenyl)cyclohexyl)isopropanesulfinylamine
(10d). From 38.5 mg (0.200 mmol) of imine 9 and 167 mg (0.402
mmol) of 4-chlorophenylboroxine was obtained 29.4 mg (49% yield)
of sulfinylamine 10d as an off-white solid after purification by silica gel
chromatography eluting with 1:1 hexanes/EtOAc. Rf = 0.60 (EtOAc).
1
Mp = 128−129 °C. H NMR (500 MHz, CDCl3): δ 7.43 (d, J = 8.7
Hz, 2H), 7.31 (d, J = 8.7 Hz, 2H), 3.75 (s, NH), 2.63 (sept, J = 6.9 Hz,
1H), 2.28−2.22 (m, 1H), 2.14−2.07 (m, 1H), 2.06−1.95 (m, 2H),
1.79−1.72 (m, 1H), 1.65−1.52 (m, 3H), 1.52−1.36 (m, 2H), 1.18 (d,
J = 6.9 Hz, 6H). 13C NMR (125 MHz, CDCl3): δ 143.3, 133.0, 128.4,
128.3, 59.4, 55.0, 38.8, 37.5, 25.3, 22.5, 22.2, 15.4, 15.3. IR: 3460, 3200,
2928, 2859, 1494, 1451, 1033, 1010 cm−1. HRMS (ESI): m/z calcd for
C15H23ClNOS (M + H)+ 300.1183, found 300.1176.
N-4-(4-(3-Bromophenyl)tetrahydropyranyl)isopropanesulfinyl-
amine (8d). The general reaction procedure was employed except
that the dppbenz ligand was not added. From 38.0 mg (0.201 mmol)
of imine 7 and 220 mg (0.401 mmol) of 3-bromophenylboroxine was
obtained 41.2 mg (59% yield) of sulfinylamine 8d as an off-white solid
after purification by silica gel chromatography eluting with 20:1
CH2Cl2/EtOH. Rf = 0.25 (20:1 EtOAc/EtOH). Mp: = 107.8−
N-(1-(3-Acetylphenyl)cyclohexyl)isopropanesulfinylamine
(10e). From 38.5 mg (0.200 mmol) of imine 9 and 176 mg (0.402
mmol) of 3-acetylphenylboroxine was obtained 30.2 mg (49% yield)
of sulfinylamine 10e as an off-white solid after purification by silica gel
chromatography eluting with 1:1 hexanes/EtOAc followed by 100%
1
1
EtOAc. Rf = 0.30 (EtOAc). Mp = 97−98 °C. H NMR (500 MHz,
108.4 °C. H NMR (500 MHz, CDCl3): δ 7.59 (t, J = 1.8 Hz, 1H),
CDCl3): δ 8.13 (s, 1H), 7.85 (d, J = 7.7 Hz, 1H), 7.73 (d, J = 7.7 Hz,
1H), 7.46 (t, J = 7.7 Hz, 1H), 3.88 (s, NH), 2.67 (sept, J = 6.9 Hz,
1H), 2.61 (s, 3H), 2.34−2.27 (m, 1H), 2.22−2.15 (m, 1H), 2.08−2.03
(m, 2H), 1.83−1.75 (m, 1H), 1.67−1.55 (m, 3H), 1.55−1.45 (m, 1H),
1.45−1.37 (m, 1H), 1.20 (d, J = 6.9 Hz, 3H), 1.19 (d, J = 6.9 Hz, 3H).
13C NMR (125 MHz, CDCl3): δ 198.1, 145.9, 137.1, 131.6, 128.5,
127.3, 126.6, 59.7, 55.1, 38.6, 37.5, 26.7, 25.2, 22.3, 22.1, 15.4, 15.3.
7.44 (d, J = 8.0 Hz, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 8.0 Hz,
1H), 3.93 (ddd, J = 11.9, 8.6, 3.0 Hz, 1H), 3.84 (s, NH), 3.83−3.77
(m, 2H), 3.72−3.67 (m, 1H), 2.70 (sept, J = 6.9 Hz, 1H), 2.41 (ddd,
J = 13.9, 8.6, 3.8 Hz, 1H), 2.25−2.12 (m, 3H), 1.22 (d, J = 6.9 Hz,
3H), 1.21 (d, J = 6.9 Hz, 3H). 13C NMR (125 MHz, CDCl3): δ 146.5,
130.8, 130.1, 129.9, 125.2, 122.8, 63.9, 63.7, 57.3, 55.2, 38.1, 37.5, 15.4,
15.3. IR: 3450, 3200, 2959, 2868, 1466, 1241, 1207, 1103, 1026 cm−1.
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IR: 3457, 3184, 2931, 2860, 1681, 1450, 1257, 1036 cm−1. HRMS
(ESI): m/z calcd for C17H26NO2S (M + H)+ 308.1679, found 308.1672.
4-(N-Boc-4-(4-chlorophenyl)piperidinyl)amine Hydrochloride
(11). To a cooled solution of sulfinyl amide 3g (401.0 mg, 1.00 mmol)
in CPME (10 mL) at 0 °C was slowly added a 3 M HCl solution in
CPME (1.0 mL, 3.00 mmol) over 10 min under a dry nitrogen
atmosphere. The reaction mixture was stirred at the same temperature
for 30 min, allowed to warm to room temperature, and then stirred for
an additional 1−2 h. While no solid was formed at 0 °C, a white solid
precipitated at room temperature. Complete consumption of the
starting material was monitored by TLC analysis. The white solid was
filtered through a finely fritted filter funnel with a moderate positive
pressure of nitrogen gas. The solid was then washed with CPME
(10 mL). The filter funnel was directly placed under reduced pressure
for 1 h. The disk of white solid on the filter funnel was transferred to
a preweighed vial and was placed under a high vacuum (ca. 0.5 Torr)
overnight to afford the amine hydrochloride 11 (340.5 mg, 98% yield)
as a white powder. Mp = 212.8−213.4 °C. 1H NMR (500 MHz, D2O):
δ 7.60 (d, J = 9.0 Hz, 2H), 7.57 (d, J = 9.0 Hz, 2H), 4.00−3.88 (m,
2H), 3.02−2.92 (m, 2H), 2.65 (dm, J = 13.7 Hz, 2H), 2.08 (ddd, J =
13.7, 11.1, 4.1 Hz, 2H), 1.45 (s, 9H). 13C NMR (125 MHz, D2O): δ
156.1, 135.0, 133.8, 129.5, 128.4, 82.1, 56.0, 40.0 (br), 32.9, 27.5. IR:
2867, 1696, 1514, 1405, 1392, 1166 cm−1. HRMS (ESI): m/z calcd for
C32H47Cl2N4O4 (2M − HCl2)+ 621.2969, found 621.2957.
Recycling of Sulfinyl Moiety To Yield Isopropansulfinamide
(6). The filtered CPME solution from above was slowly transferred into
a 28−30% aqueous ammonium hydroxide solution (approximately
4.0 N) (5 mL) at 0 °C with rapid stirring over 30 min. The mixture
was stirred for 30 min at 0 °C and then was allowed to warm to
room temperature with stirring for an additional 1 h. The mixture was
concentrated by rotary evaporation at 40 °C (water bath temperature).
Residual CPME and water were then removed under a high vacuum
(approximately 0.5 Torr) to afford a crude N-isopropanesulfinamide as
a yellow solid. The crude sulfinamide was redissolved with 10 mL of
CH2Cl2, filtered through a finely fritted filter funnel, and washed with
CH2Cl2 (2 × 10 mL). The filtrate was concentrated under a reduced
pressure to afford a pale white solid, which was further purified by
washing with a cold solution of hexanes/EtOAc (10:1) (2 × 2 mL) to
regenerate analytically pure N-isopropanesulfinamide (98 mg, 91%
yield).12
(b) Suzuki, A. Angew. Chem., Int. Ed. 2011, 50, 6723. (c) Marques, C.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Spectroscopic data of all new compounds shown in Schemes
3−6. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the NSF (CHE-1049571). We also
thank Dr. T. T. Lam and Edward Voss from the FT-ICR Mass
Spectrometry Resource of the Keck Biotechnology Resource
Laboratory for the HRMS data/results obtained.
(9) For additions to N-(tert-butanesulfinyl)imines derived from
tetrahydropyran-4-one, see: (a) John, V.; Maillard, M.; Tucker, J. WO
2005087752, 2005; Chem. Abstr., 2005, 2005:1021744. (b) John, V.;
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Fujii, H.; Sakami, S.; Nishimura, Y.; Ohyama, T.; Satoh, M.; Nakaki, J.;
Satoh, S.; Inada, C.; Kozono, H.; Kumagai, H.; Shimamura, M.;
Fukazawa, T.; Kawai, H. Bioorg. Med. Chem. Lett. 2008, 18, 5435.
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(11) The corresponding N-(propanesulfinyl)imine was also initially
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