Intramolecular olefin diamination for the stereoselective synthesis of 3-aminopiperidines

Article abstract of DOI:10.1055/s-0031-1290591

A general method for the direct intramolecular diamination of terminal olefins is presented. The reaction, mediated by hypervalent iodine oxidants, produces substituted 3-aminopiperidine scaffolds with high regio- and stereoselectivity, rendering this process relevant to both medicinal chemistry and natural products synthesis. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1290591

1190▌
SPECIAL TOPIC
special topic
Intramolecular Olefin Diamination for the Stereoselective Synthesis of
3-Aminopiperidines
Piperidine Synthesis by Olefin Diamination
Aidi Kong, Simon B. Blakey*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA
Fax +1(404)7276586; E-Mail: sblakey@emory.edu
Received: 15.02.2012; Accepted: 24.02.2012
conjugated dienes were required as substrates.7 Recent ad-
Abstract: A general method for the direct intramolecular diamina-
vances now allow for both intermolecular diamination of
tion of terminal olefins is presented. The reaction, mediated by hy-
terminal olefins and 5-exo-selective cyclization reactions
pervalent iodine oxidants, produces substituted 3-aminopiperidine
scaffolds with high regio- and stereoselectivity, rendering this pro-
for the synthesis of 2-(aminomethyl)pyrrolidines.8,9 Al-
cess relevant to both medicinal chemistry and natural products syn- though a select group of substrates can be cyclized to yield
piperidine products in a gold-catalyzed process,10 a gener-
thesis.
al procedure for 6-endo-selective olefin diamination has
remained elusive. Inspired by the exquisite regiocontrol
that can be garnered through subtle changes in reaction
conditions utilizing hypervalent iodine oxidants for
amino-oxygenation reactions (Figure 2),11,12 we sought to
develop conditions for a general 6-endo-oxidative cycli-
zation for the synthesis of 3-aminopiperidines.
Key words: diamination, hypervalent iodine, oxidation, catalysis,
piperidine
The 3-aminopiperidine motif is found in both naturally
occurring alkaloids, such as slaframine (1, Figure 1),1,2
and molecules of pharmaceutical relevance including
NK1 receptor antagonists [e.g., CP-99,994 (2)]3 and inte-
grin αvβ3 antagonists (e.g., 3).4 These molecules have the
potential to impact osteoporosis, rheumatoid arthritis, re-
stenosis, and acute ischemic disease.
amino-oxygenation
diamination
R1
R1
5-exo (ref. 9)
5-exo (ref. 11)
N
NR2
N
2
OR2
R1
AcO
H
NH
N
OMe
NH2
R1
N
R1
N
N
slaframine (1)
HN
NHSO2Ph
CO2H
H
6-endo (ref. 12)
6-endo
(ref. 10, this work)
N
N
NH
NR2
OR2
H
N
O
2
integrin αvβ3 antagonist (3)
Figure 2 Intramolecular oxidative amino functionalization of ole-
OMe
fins for the selective formation of pyrrolidines and piperidines.
N
H
Our early efforts, based on the discovery that
Cu(MeCN)4PF6 catalyzed 6-endo-selective olefin amino-
acetoxylation reactions,12d focused on the identification of
an appropriate nitrogen nucleophile that would participate
in the reaction, but would not bind to and inhibit the cop-
per catalyst. However, after an extensive survey of nitro-
gen nucleophiles, copper salts, oxidants, and solvents, we
were unable to realize an effective 6-endo-selective di-
amination reaction. In fact, the most promising conditions
for the cyclization of the simple 5-aminopentene deriva-
tive 4 led primarily to the undesired 5-exo cyclization
product 5 in 21% yield (Equation 1).
(+)-CP-99,994 (2)
Figure 1 3-Aminopiperidines are common in naturally occurring
alkaloids and medicinally important molecules.
In considering possible approaches to these molecules, an
intramolecular oxidative olefin diamination emerges as a
particularly direct strategy. In this context, we note that al-
though the oxidative addition of heteroatoms across ole-
fins has received considerable attention, and general
methods for dihydroxylation and amino-oxygenation are
particularly well developed,5 the addition of two nitrogen
atoms across a C–C π-bond has proven to be a more chal-
lenging problem.6 The first transition-metal-catalyzed
olefin diamination reactions were disclosed in 2005, and
Further analysis of known 6-endo amino-oxygenation re-
actions revealed that a variety of oxygen nucleophiles
could be incorporated into the products. In particular, we
noted that mixing the bis(acetoxy)iodobenzene oxidant
with either trifluoroacetic acid or 4-toluenesulfonic acid
resulted in incorporation of either trifluoroacetate12b or
tosylate12d into the 3-oxypiperidine product, respectively.
SYNTHESIS 42170012, 44,81190–1198
Advanced online publication: 28.03.2012
DOI: 10.1055/s-0031-1290591; Art ID: SS-2012-C0156-ST
© Georg Thieme Verlag Stuttgart · New York
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SPECIAL TOPIC
Piperidine Synthesis by Olefin Diamination
1191
4-Ns
NH
4-Ns
4-Ns
Cu(MeCN)4PF6 (10 mol%)
NH
PhI(OAc)2 (1.5 equiv), K2CO3 (1.2 equiv)
N3
N
OH
+
Bu4NClO4 (5.0 equiv), NaN3 (5.0 equiv)
PhMe–H2O (3:2)
N3
21%
9%
5, 5-exo
6
4
Equation 1
The observation that the conjugate base of the most acidic In order to assess the generality of the reaction, we first in-
oxygenated species was incorporated into the product vestigated the effect of various electron-withdrawing
prompted us to consider nitrogen sources with particularly groups used to activate the internal nitrogen (Table 2). Al-
acidic N–H bonds as potential partners in 6-endo-selec- ternative sulfonyl groups 2-nitrophenylsulfonyl (2-Ns)
tive olefin diamination reactions.
and tosyl (Ts) (entries 1–3) were equally as effective as
the 4-nitrophenylsulfonyl (4-Ns) group, but a carbamate
(Cbz) was not tolerated (not shown). Alternative external
nitrogen nucleophiles, such as phthalamide and saccha-
rin,8e were also found to be ineffective. We selected the 2-
nitrophenylsulfonyl group for use in the remainder of our
study, due to the mild conditions required for its subse-
quent removal.
When 5-[(4-nitrophenylsulfonyl)amino]pent-1-ene (4)
was treated with Cu(MeCN)4PF6 (10 mol%), bis(acet-
oxy)iodobenzene (1.5 equiv), and trifluoromethanesul-
fonimide (2.0 equiv) in dichloromethane at room
temperature, we observed rapid intramolecular diamina-
tion, with the desired 6-endo product 7 formed in 53%
yield (Table 1). The regioisomeric 5-exo diamine 8 (28%)
and the 3-acetoxypiperidine 9 (19%) were both observed With respect to substrate scope, geminal alkyl substitution
as byproducts of the reaction. A control experiment re- at the 4-position of the 5-aminopentene completely sup-
vealed that the Cu(I) salt was not required as a catalyst and pressed the 5-exo pathway, leading to excellent yields of
did not significantly influence the outcome of the reaction the 3-aminopiperidine products (entries 1–4). However,
(entry 2). During a brief optimization study, we observed reaction of 5-[(2-nitrophenylsulfonyl)amino]-4,4-diphe-
that formation of the amino-oxygenation byproduct 9 nylpent-1-ene (18) gave the diamination product 19 in
could be suppressed by premixing the bis(acetoxy)iodo- only 35% yield under the standard conditions (entry 5),
benzene and trifluoromethanesulfonimide and that selec- with the majority of the material undergoing transforma-
tivity for the 6-endo regioisomer 7 could be substantially tion to the tricyclic olefin aminoarylation product 20 (50%
improved by conducting the reaction at –78 °C (entries 3 yield). Intriguingly, use of iodosobenzene in place of the
and 4). Under the optimal conditions, reactions were com- bis(acetoxy)iodobenzene rescued the reaction, and the ex-
plete in five minutes with the desired product 7 formed in pected product 19 was produced cleanly in 88% yield (en-
81% yield and the two minor components 8 and 9 pro- try 6). Although aniline-based substrate 21 could be
duced in 15% and 4% yields, respectively.
cyclized, the yield was moderate (66%), and the regiose-
lectivity was particularly poor (1.3:1 6-endo/5-exo, entry
7), consistent with previous observations in intramolecu-
lar olefin amino-oxygenation.12b–e
A survey of solvents indicated that in addition to dichlo-
romethane, the reaction proceeded equally well in dichlo-
roethane and α,α,α-trifluorotoluene, but that toluene, N,N-
dimethylformamide, and ethereal solvents were not com- When the carbon tether between the amine and olefin was
patible with the reaction conditions. shortened, the diamination reaction proceeded to generate
Table 1 Optimization of the 6-endo-Selective Intramolecular Diamination Protocol
4-Ns
NH
4-Ns
N
4-Ns
N
PhI(OAc)2 (1.5 equiv)
N(SO2CF3)2
HN(SO2CF3)2 (2.0 equiv)
+
CH2Cl2, temp
R
4
7, R = N(SO2CF3)2
9, R = OAc
8
Yield (%) of 7/8/9a
Entry
Conditions
Temp (°C)
1
2
3
4
Cu(MeCN)PF6 (10 mol%) added
22
53:28:19
56:26:18
64:30:5
81:15:4
–
22
PhI(OAc)2, HN(SO2CF3)2, premixed
22
PhI(OAc)2, HN(SO2CF3)2, premixed (–78 °C)
–78
a Yield based on 1H NMR of the crude reaction mixture.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1190–1198

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A. Kong, S. B. Blakey
SPECIAL TOPIC
Table 2 Substrate Scope for Intramolecular Diamination Reaction
R1
R1
N
PhI(OAc)2 (1.5 equiv)
R2
NH
R2
R3
HN(SO2CF3)2 (2.0 equiv)
R3
R3
CH2Cl2, –78 °Ca
N(SO2CF3)2
R3
n
n
Yieldb (%)
Entry
Alkene
Product(s)
R1
R1
N
NH
N(SO2CF3)2
10, R1 = Ts
1
2
3
11
13
15
88
90
96
12, R1 = 4-Ns
14, R1 = 2-Ns
2-Ns
N
2-Ns
NH
4
94
N(SO2CF3)2
16
17
2-Ns
NH
2-Ns
N
Ph
N
2-Ns
Ph
Ph
Ph
Ph
N(SO2CF3)2
5
6
18
19
20
19: 35; 20: 50
19: 88; 20: 6c
2-Ns
N
2-Ns
NH
66
7
8
(1.3:1)d
N(SO2CF3)2
21
22
2-Ns
N
2-Ns
NH
61
N(SO2CF3)2
23
24
a PhI(OAc)2 and HN(SO2CF3)2 were premixed in CH2Cl2 at 22 °C, then cooled to –78 °C before addition to the substrate.
b Isolated yield after purification by chromatography.
c PhI=O was used in place of PhI(OAc)2; reaction conducted at 22 °C [19 (67%) and 20 (9%) were obtained with PhI=O at –78 °C].
d Ratio of 6-endo (22)/5-exo (not shown) isomers isolated by chromatography.
the expected 3-aminopyrrolidine 24 in 61% yield (entry
8). Unexpectedly, when the carbon chain was extended
(25, Equation 2), an allylic amination took place to give 2-
vinylpyrroline 26 in 50% yield. This result is particularly
surprising, as the related hypervalent iodine mediated
amino-oxygenation reaction proceeds smoothly to give
the expected seven-membered nitrogen heterocycle.12b
2-Ns
2-Ns
PhI(OAc)2 (1.5 equiv)
NH
N
HN(SO2CF3)2 (2.0 equiv)
CH2Cl2, –78 °C, 1 h
25
26, 50%
Equation 2
Synthesis 2012, 44, 1190–1198
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Piperidine Synthesis by Olefin Diamination
1193
Additionally, monosubstituted 5-aminopent-1-enes were When 1,2-disubstituted olefins were utilized as substrates,
investigated, and in all cases the expected 3-aminopiperi- reactions conducted at both –78 °C and 22 °C produced
dines were formed in high yields with good to excellent complex mixtures of products.
diastereoselectivity (Table 3). When substituents were
present in the homoallylic position (both phenyl 27 and
methyl 29 were examined), the reaction proceeded with
exquisite regioselectivity (>20:1 6-endo/5-exo) and good
From a practical perspective, we found that the 6-endo-se-
lective cyclization reactions could be conducted at room
temperature using catalytic iodobenzene and 3-chloroper-
oxybenzoic acid as the terminal oxidant (Equation 3). Un-
diastereoselectivity (4.2:1 and 4.3:1 syn/anti, respective-
der these conditions, the cyclized product 15 was obtained
ly). Placing a methyl substituent in the allylic position in
in 85% yield. In the absence of iodobenzene, a control re-
31 negatively impacted the regioselectivity of the reaction
action produced a complex mixture that did not contain
(1.9:1 6-endo/5-exo), but the 3-aminopiperidine product
any of the desired 3-aminopiperidine 15.
32 was formed with excellent diastereoselectivity (>20:1
Additionally, we have shown that both amines can be or-
thogonally deprotected. Although traditional methods for
trifluoromethanesulfonamide removal (e.g., LiAlH4) are
not compatible with the 2-nitrophenylsulfonyl group, the
anti/syn).
We observed a similar outcome for the cyclization of
5-[(2-nitrophenylsulfonyl)amino]hex-1-ene (33), which
underwent the diamination reaction to give the expected
trifluoromethanesulfonyl groups can be removed in excel-
piperidine product 34 with moderate regioselectivity (3:1
lent overall yield (91%) (Scheme 1). Treatment of 19 with
6-endo/5-exo) and excellent stereoinduction (>20:1
cesium carbonate in acetonitrile facilitates removal of the
first trifluoromethanesulfonamide to give 35 in 98% yield.
anti/syn).
A subsequent alkylation–elimination–hydrolysis proce-
Table 3 Diastereoselectivity in 6-endo Intramolecular Diamination Reactions
2-Ns
NH
2-Ns
PhI(OAc)2 (1.5 equiv)
N
HN(SO2CF3)2 (2.0 equiv)
CH2Cl2, –78 °Ca
N(SO2CF3)2
R
R
Yieldb (%)
r.s.c
Entry
Alkene
Product
d.r.
2-Ns
N
2-Ns
NH
1
89
>20:1
4.2:1
Ph
N(SO2CF3)2
Ph
27
28
2-Ns
N
2-Ns
NH
2
3
4
96
86
71
>20:1
1.9:1
3.0:1
4.3:1
N(SO2CF3)2
29
30
2-Ns
NH
2-Ns
N
>20:1
>20:1
N(SO2CF3)2
31
32
2-Ns
N
2-Ns
NH
N(SO2CF3)2
33
34
a PhI(OAc)2 and HN(SO2CF3)2 were premixed in CH2Cl2 at 22 °C, then cooled to –78 °C before addition to the substrate.
b Isolated combined yield of both diamination regioisomers.
c r.s. = regioselectivity; ratio of 6-endo (shown)/5-exo (not shown) regioisomers.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1190–1198

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A. Kong, S. B. Blakey
SPECIAL TOPIC
dure completed the deprotection of the exocyclic amine 1H and 13C NMR spectra were recorded on a Varian Inova 400 spec-
trometer (400 MHz 1H, 100 MHz, 13C), VNMR400 (400 MHz 1H,
100 MHz, 13C), a Varian Inova 600 spectrometer (600 MHz 1H, 150
MHz 13C), a Varian Unity plus 600 spectrometer (600 MHz 1H, 150
MHz 13C) at r.t. in CDCl3 with internal CHCl3 as the reference (δ =
7.27 for 1H and δ = 77.23 for 13C) unless otherwise stated. Infrared
spectra were recorded using an ASI ReactIR 1000 spectrophotome-
ter or using Thermo Electron Corporation Nicolet 380 FT-IR spec-
trophotometer. HRMS were obtained using a Thermo Electron
Corporation Finnigan LTQFTMS (at the Mass Spectrometry Facil-
ity, Emory University). Melting points were taken using a Thomas-
Hoover melting point apparatus in open capillary tubes and are un-
calibrated. Analytical TLC was performed on precoated glass-
backed EMD 0.25-mm silica gel 60 plates. Visualization was ac-
complished with UV light, ethanolic anisaldehyde followed by
heating. Flash column chromatography was carried out using EMD
Geduran® silica gel 60 (40–63 μm) or Fluka® aluminum oxide
(0.05–0.15 mm); pH 7.0. All reactions were conducted with anhyd
solvents in oven dried or flame-dried and argon-charged glassware.
Anhyd solvents were purified by passage through activated alumina
using a Glass Contours solvent purification system unless otherwise
noted. Solvents used in workup, extraction and column chromatog-
raphy were used as received from commercial suppliers without pri-
or purification. All reagents were purchased from Sigma-Aldrich or
Acros and used as received unless otherwise noted.
giving 36 in 93% yield.13
2-Ns
N
2-Ns
PhI (20 mol%)
m-CPBA (2.0 equiv)
NH
HN(SO2CF3)2 (2.0 equiv)
CH2Cl2, r.t., 4 h
N(SO2CF3)2
85%
14
15
Equation 3
2-Ns
2-Ns
N
N
Cs2CO3 (3.0 equiv)
MeCN, r.t., 4 h
Ph
Ph
35, 98%
Ph
Ph
19
NHSO2CF3
N(SO2CF3)2
O
1.
(1.5 equiv)
Br
K2CO3 (4.0 equiv), MeCOMe
Br
2-Ns
N
Ph
2. 2 N HCl, MeOH, then 6 N NaOH
NH2
Ph
Intramolecular Olefin Diamination Reaction; General Proce-
dure
36, 93%
An oven-dried flask with a stirring bar was cooled to r.t. under argon
and then charged with HN(SO2CF3)2 (2.0 equiv) in the glove box.
After flushing with argon, CH2Cl2 (0.04 M) and PhI(OAc)2 (1.5
equiv) were added and the soln was stirred at r.t. for 1 h. During this
time a soln of the alkene substrate (1.0 equiv) in CH2Cl2 (0.04 M)
was prepared in a separate flask. Both solns were then separately
cooled to –78 °C. The cold substrate soln was transferred into the
cold reagent soln by cannulation under a slight vacuum. The mix-
ture was stirred at –78 °C for 1 h, and then it was diluted with EtOAc
Scheme 1 Deprotection of the trifluoromethanesulfonyl groups.
Alternatively, the 2-nitrophenylsulfonyl protecting group
can be removed under standard conditions (19 → 37,
Equation 4). Although treatment with thiophenol concom-
itantly removes one of the trifluoromethanesulfonamide
groups on the exocyclic amine, the second remains intact,
differentiating the exocyclic amine from the deprotected (20.0 mL per 0.1 mmol substrate). The organic layer was washed
with NaHCO3 (2 × 10.0 mL per 0.1 mmol substrate), brine (2 × 10.0
piperidine nitrogen.
mL per 0.1 mmol substrate), and dried (anhyd Na2SO4). Filtration
and concentration in vacuo provided crude product; a 1H NMR ex-
H
N
2-Ns
N
periment was conducted to obtain the ratio of the products. Then the
crude was purified via flash column chromatography (silica gel) or
by preparative TLC.
PhSH (4.0 equiv)
Cs2CO3 (6.0 equiv)
Ph
Ph
Ph
Ph
MeCN, r.t., 16 h
NHSO2CF3
N(SO2CF3)2
1,1,1-Trifluoro-N-[1-(4-nitrophenylsulfonyl)piperidin-3-yl]-N-
(trifluoromethylsulfonyl)methanesulfonamide (7)
37, 80%
19
Prepared according to the general procedure using 4-nitro-N-(pent-
4-enyl)benzenesulfonamide (4, 100.8 mg, 0.4 mmol),
HN(SO2CF3)2 (209.7 mg, 0.8 mmol), and PhI(OAc)2 (180.3 mg, 0.6
mmol) in CH2Cl2 (20.0 mL). Purification by flash column chroma-
tography (silica gel, 5% → 20% EtOAc–hexanes) afforded sulfon-
amide 7 (178.5 mg, 81%) as a white solid; mp 112–114 °C;
Rf = 0.65 (hexanes–EtOAc, 2:1).
Equation 4
In conclusion, we have developed a general protocol for
the oxidative cyclization of 5-aminopent-1-ene deriva-
tives for the synthesis 3-aminopiperidines. The reaction
tolerates substitution along the pentene side chain and
generally proceeds with good to excellent regio- and dia-
stereoselectivity. In the case where an aryl substituent in-
terfered with the reaction, subtle changes in reaction
conditions restored clean diamination chemistry. During
the course of this study, Muñiz and co-workers outlined a
chiral hypervalent iodine oxidant capable of promoting
intermolecular enantioselective diamination of terminal
olefins under similar conditions to the reactions described
here.14 The combination of this chiral catalyst with the
catalytic conditions outlined in Equation 3 offers exciting
possibilities for the future in the field of hypervalent io-
dine mediated amination chemistry.
IR (thin film): 1608, 1535, 1415, 1349, 1208, 1092, 955, 856, 702,
595 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.43–8.40 (m, 2 H), 8.00–7.89 (m,
2 H), 4.58–4.38 (m, 1 H), 4.08–4.04 (m, 1 H), 3.85 (t, J = 10.8 Hz,
1 H), 3.06 (t, J = 11.6 Hz, 1 H), 2.37 (td, J = 12.4, 2.8 Hz, 1 H),
2.15–1.74 (m, 4 H).
13C NMR (100 MHz, CDCl3): δ = 150.7, 143.0, 128.7, 124.9, 119.0
(q, J = 323.6 Hz), 64.7, 49.2, 45.6, 29.2, 25.6.
HRMS [+APCI]: m/z [M + H]+ calcd for C13H14O8N3F6S3:
549.9842; found: 549.9843.
N-(5,5-Dimethyl-1-tosylpiperidin-3-yl)-1,1,1-trifluoro-N-(tri-
fluoromethylsulfonyl)methanesulfonamide (11)
Prepared according the general procedure using N-(2,2-dimethyl-
pent-4-enyl)-4-methylbenzenesulfonamide (10, 32.8 mg, 0.1
Synthesis 2012, 44, 1190–1198
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Piperidine Synthesis by Olefin Diamination
1195
mmol), HN(SO2CF3)2 (69.0 mg, 0.2 mmol), and PhI(OAc)2 (59.3
mg, 0.2 mmol) in CH2Cl2 (5.0 mL). Purification by preparative TLC
(20% EtOAc–hexanes) gave 11 (59.2 mg, 88%) as a thick oil;
Rf = 0.75 (hexanes–EtOAc, 2:1).
mmol), HN(SO2CF3)2 (66.0 mg, 0.2 mmol), and PhI(OAc)2 (56.0
mg, 0.2 mmol) in CH2Cl2 (5.0 mL). Purification by flash column
chromatography (silica gel, 5% → 20% EtOAc–hexanes) gave 17
(69.2 mg, 94%) as a thick oil that turned into a solid upon standing
in the fridge; mp 48–50 °C; Rf = 0.62 (hexanes–EtOAc, 2:1).
IR (thin film): 2968, 1741, 1598, 1440, 1355, 1220, 1166, 1096,
1004, 741 cm–1.
IR (thin film): 3103, 2930, 2856, 1590, 1544, 1440, 1328, 1227,
1019, 702 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.63 (d, J = 8.4 Hz, 2 H), 7.36 (d,
J = 8.4 Hz, 2 H), 4.68 (tt, J = 11.6, 4.0 Hz, 1 H), 4.06–3.74 (m, 1 H),
3.38 (d, J = 12.0 Hz, 1 H), 2.81 (t, J = 11.2 Hz, 1 H), 2.46 (s, 3 H),
2.02 (d, J = 11.6 Hz, 1 H), 1.89 (t, J = 12.4 Hz, 1 H), 1.76 (d,
J = 11.2 Hz, 1 H), 1.16 (s, 3 H), 1.00 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 144.4, 133.6, 130.2, 127.5, 119.0
(q, J = 323.7 Hz), 63.0, 56.3, 49.2, 42.3, 33.5, 28.6, 23.8, 21.8.
1H NMR (400 MHz, CDCl3): δ = 8.06–7.93 (m, 1 H), 7.80–7.71 (m,
2 H), 7.71–7.65 (m, 1 H), 4.72 (tt, J = 12.0, 3.6 Hz, 1 H), 4.12–3.97
(m, 1 H), 3.84 (d, J = 13.6 Hz, 1 H), 3.36 (t, J = 11.6 Hz, 1 H), 2.47
(d, J = 13.2 Hz, 1 H), 2.05–2.02 (m, 1 H), 1.92 (t, J = 12.8 Hz, 1 H),
1.76–1.64 (m, 1 H), 1.54–1.40 (m, 7 H), 1.40–1.30 (m, 2 H).
13C NMR (100 MHz, CDCl3): δ = 148.3, 134.3, 132.14, 132.07,
131.1, 124.7, 119.0 (q, J = 323.7 Hz), 62.2, 53.7, 49.0, 40.7, 37.5,
36.5, 31.0, 26.2, 21.6, 21.2.
HRMS [+ESI]: m/z [M + H]+ calcd for C16H21O6N2F6S3: 547.0461;
found: 547.0460.
HRMS [+APCI]: m/z [M + H]+ calcd for C18H22O8N3F6S3:
618.0468; found: 618.0480.
N-[5,5-Dimethyl-1-(4-nitrophenylsulfonyl)piperidin-3-yl]-
1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfon-
amide (13)
Prepared according the general procedure using N-(2,2-dimethyl-
pent-4-enyl)-4-nitrobenzenesulfonamide (12, 46.0 mg, 0.15 mmol),
HN(SO2CF3)2 (86.6 mg, 0.3 mmol), and PhI(OAc)2 (74.4 mg, 0.2
mmol) in CH2Cl2 (10.0 mL). Purification by flash column chroma-
tography (silica gel, 5% → 20% EtOAc–hexanes) gave 13 (78.9
mg, 90%) as a thick oil; Rf = 0.75 (hexanes–EtOAc, 2:1).
1,1,1-Trifluoro-N-[1-(2-nitrophenylsulfonyl)-5,5-diphenylpi-
peridin-3-yl]-N-(trifluoromethylsulfonyl)methanesulfonamide
(19) and 3-(2-Nitrophenylsulfonyl)-1-phenyl-2,3,4,5-tetra-
hydro-1H-1,4-methanobenzo[d]azepine (20)
Prepared according the general procedure using N-(2,2-diphenyl-
pent-4-enyl)-2-nitrobenzenesulfonamide (18, 125.1 mg, 0.3 mmol),
HN(SO2CF3)2 (166.6 mg, 0.6 mmol), and PhI(OAc)2 (143.1 mg,
0.45 mmol) in CH2Cl2 (14.8 mL). Purification by flash column
chromatography (silica gel, 5% → 20% EtOAc–hexanes) afforded
19 (73.7 mg, 35%) as a white solid and 20 (63.0 mg, 50%) as a thick
oil.
IR (thin film): 3107, 2968, 2876, 1610, 1536, 1440, 1351, 1227,
1004, 706 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.52–8.34 (m, 2 H), 8.02–7.79 (m,
2 H), 4.67 (tt, J = 11.6, 4.0 Hz, 1 H), 4.08–4.05 (m, 1 H), 3.45 (d,
J = 12.0 Hz, 1 H), 2.94 (t, J = 11.2 Hz, 1 H), 2.16 (d, J = 11.6 Hz, 1
H), 1.94 (t, J = 12.8 Hz, 1 H), 1.81 (d, J = 10.8 Hz, 1 H), 1.17 (s, 3
H), 1.03 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 150.6, 143.0, 128.6, 124.9, 119.0
(q, J = 322.9 Hz), 62.4, 56.2, 49.0, 42.2, 33.7, 28.5, 23.6.
Sulfonamide 19
Mp 150–151 °C; Rf = 0.60 (hexanes–EtOAc, 2:1).
IR (thin film): 3065, 3030, 2922, 1590, 1544, 1440, 1374, 1231,
1007, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.91 (dd, J = 7.6, 1.2 Hz, 1 H),
7.77–7.64 (m, 2 H), 7.59 (dd, J = 7.6, 1.2 Hz, 1 H), 7.37 (d, J = 7.6
Hz, 2 H), 7.35–7.22 (m, 6 H), 7.15–7.12 (m, 2 H), 4.75 (d, J = 13.2
Hz, 1 H), 4.62–4.45 (m, 1 H), 4.13 (dd, J = 10.8, 4.0 Hz, 1 H), 3.43
(t, J = 11.2 Hz, 1 H), 2.98–2.94 (m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.9, 144.7, 140.9, 134.7, 132.0,
131.3, 130.0, 129.14, 129.11, 127.7, 127.6, 127.4, 126.3, 124.6,
119.0 (q, J = 323.7 Hz), 62.1, 53.8, 48.8, 48.3, 40.1.
HRMS [+ESI]: m/z [M + Na]+ calcd for C15H17O8N3F6NaS3:
599.9974; found: 599.9975.
N-[5,5-Dimethyl-1-(2-nitrophenylsulfonyl)piperidin-3-yl]-
1,1,1-trifluoro-N-(trifluoromethylsulfonyl)methanesulfon-
amide (15)
Prepared according the general procedure using N-(2,2-dimethyl-
pent-4-enyl)-2-nitrobenzenesulfonamide (14, 58.8 mg, 0.2 mmol),
HN(SO2CF3)2 (117.6 mg, 0.4 mmol), and PhI(OAc)2 (101.0 mg, 0.3
mmol) in CH2Cl2 (10.0 mL). Purification by flash column chroma-
tography (silica gel, 5% → 20% EtOAc–hexanes) gave 15 (110.8
mg, 96%) as a thick oil that turned into a solid upon standing in the
fridge; mp 104–105 °C; Rf = 0.62 (hexanes–EtOAc, 2:1).
HRMS [+APCI]: m/z [M + H]+ calcd for C25H22O8N3F6S3:
702.0468; found: 702.0492.
Methanobenzo[d]azepine 20
Rf = 0.55 (hexanes–EtOAc, 2:1).
IR (thin film): 3065, 2968, 1729, 1540, 1486, 1451, 1347, 1173,
1034, 953 cm–1.
IR (thin film): 2968, 1544, 1440, 1370, 1231, 1170, 1127, 1004,
984, 706 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.97 (dd, J = 7.6, 1.6 Hz, 1 H),
7.70–7.58 (m, 3 H), 7.41–7.24 (m, 5 H), 7.18–7.12 (m, 2 H), 7.01–
6.96 (m, 1 H), 6.52 (d, J = 8.0 Hz, 1 H), 4.79 (dt, J = 7.2, 2.8 Hz, 1
H), 4.06 (dd, J = 8.4, 1.2 Hz, 1 H), 3.83 (d, J = 8.0 Hz, 1 H), 3.35
(d, J = 17.2 Hz, 1 H), 3.20 (dd, J = 17.2, 2.4 Hz, 1 H), 2.59 (d,
J = 10.8 Hz, 1 H), 2.24 (ddd, J = 7.6, 6.4, 1.2 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 148.5, 143.8, 142.4, 133.7, 133.0,
132.7, 131.7, 130.7, 129.8, 129.1 (br), 127.8, 127.5, 126.9, 126.4,
124.2, 60.9, 58.3, 51.4, 40.8, 39.1.
1H NMR (400 MHz, CDCl3): δ = 8.02–7.96 (m, 1 H), 7.80–7.72 (m,
2 H), 7.70–7.67 (m, 1 H), 4.72 (tt, J = 11.2, 4.0 Hz, 1 H), 4.08–4.04
(m, 1 H), 3.50 (d, J = 12.8 Hz, 1 H), 3.35 (t, J = 11.6 Hz, 1 H), 2.60
(d, J = 13.2 Hz, 1 H), 2.07 (t, J = 12.8 Hz, 1 H), 1.84 (d, J = 11.6 Hz,
1 H), 1.11 (s, 3 H), 1.06 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.2, 134.3, 132.15, 132.11,
131.1, 124.7, 119.0 (q, J = 323.7 Hz), 62.6, 56.1, 48.5, 42.4, 34.0,
28.4, 23.4.
HRMS [+ESI]: m/z [M + H]+ calcd for C15H18O8N3F6S3: 578.0155;
found: 578.0156.
HRMS [+APCI]: m/z [M + H]+ calcd for C23H21O4N2S: 421.1212;
found: 421.1218.
1,1,1-Trifluoro-N-[2-(2-nitrophenylsulfonyl)-2-azaspi-
ro[5.5]undecan-4-yl]-N-(trifluoromethylsulfonyl)methane-
sulfonamide (17)
Prepared according the general procedure using N-[(1-allylcyclo-
hexyl)methyl]-2-nitrobenzenesulfonamide (16, 39.6 mg, 0.1
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1190–1198

1196
A. Kong, S. B. Blakey
SPECIAL TOPIC
1,1,1-Trifluoro-N-[1-(2-nitrophenylsulfonyl)-1,2,3,4-tetrahy-
droquinolin-3-yl]-N-(trifluoromethylsulfonyl)methanesulfon-
amide (22) and 1,1,1-Trifluoro-N-{[1-(2-nitrophenylsulfon-
yl)indolin-2-yl]methyl}-N-(trifluoromethylsulfonyl)methane-
sulfonamide (22′)
Prepared according the general procedure using N-(2-allylphenyl)-
2-nitrobenzenesulfonamide (21, 95.5 mg, 0.3 mmol), HN(SO2CF3)2
(168.7 mg, 0.6 mmol), and PhI(OAc)2 (144.9 mg, 0.45 mmol) in
CH2Cl2 (15.0 mL). Purification by flash column chromatography
(silica gel, 10% → 20% EtOAc–hexanes) gave 22 and 22′ (118.9
mg, 66%, 22/22′ 1.3:1) as a colourless oil.
(silica gel, 10% → 25% EtOAc–hexanes) gave 26 (42.3 mg, 50%)
as a thick oil; Rf = 0.45 (hexanes–EtOAc, 2:1).
IR (thin film): 3096, 2953, 1544, 1440, 1355, 1204, 1166, 1127,
930, 710 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.03–8.01 (m, 1 H), 7.69–7.59 (m,
3 H), 5.67 (ddd, J = 17.2, 10.0, 6.8 Hz, 1 H), 5.19 (dt, J = 16.8, 1.2
Hz, 1 H), 5.02 (dt, J = 10.0, 1.2 Hz, 1 H), 4.47–4.42 (m, 1 H), 3.60–
3.50 (m, 2 H), 2.12–2.03 (m, 1 H), 2.01–1.82 (m, 2 H), 1.80–1.73
(m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.4, 137.8, 133.53, 133.47,
131.53, 131.49, 124.1, 116.5, 62.8, 49.1, 33.1, 24.3.
HRMS [+APCI]: m/z [M + H]+ calcd for C12H15O4N2S: 283.0747;
Quinolinyl-methanesulfonamide 22
Rf = 0.50 (hexanes–EtOAc, 2:1).
IR (thin film): 3100, 2961, 1733, 1544, 1440, 1366, 1227, 1007,
853, 687 cm–1.
found: 283.0750.
1,1,1-Trifluoro-N-[cis-1-(2-nitrophenylsulfonyl)-5-phenylpi-
peridin-3-yl]-N-(trifluoromethylsulfonyl)methanesulfonamide
(28)
Prepared according the general procedure using 2-nitro-N-(2-
phenylpent-4-enyl)benzenesulfonamide (27, 103.9 mg, 0.3 mmol),
HN(SO2CF3)2 (168.7 mg, 0.6 mmol), and PhI(OAc)2 (144.9 mg,
0.45 mmol) in CH2Cl2 (15.0 mL). Purification by flash column
chromatography (silica gel, 10% → 40% EtOAc–hexanes) afforded
28 (167.0 mg, 89%) as a thick oil; Rf = 0.50 (hexanes–EtOAc, 2:1).
1H NMR (400 MHz, CDCl3): δ = 8.00 (d, J = 7.6 Hz, 1 H), 7.87–
7.67 (m, 3 H), 7.36–7.33 (m, 1 H), 7.25–7.16 (m, 3 H), 4.86–4.81
(m, 1 H), 4.52 (dd, J = 12.8, 4.0 Hz, 1 H), 3.95 (dd, J = 13.2, 11.2
Hz, 1 H), 3.43 (dd, J = 16.0, 11.2 Hz, 1 H), 3.27 (dd, J = 16.0, 7.2
Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.1, 135.3, 134.9, 132.6, 131.0,
129.8, 127.9, 127.1, 126.7, 125.3, 124.0, 119.1 (q, J = 323.7 Hz),
61.5, 48.2, 32.8.
HRMS [+APCI]: m/z [M + H]+ calcd for C17H14O8N3F6S3:
597.9842; found: 597.9838.
IR (thin film): 3057, 2930, 1729, 1548, 1440, 1266, 1224, 1127,
1004, 706 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.03 (dd, J = 7.6, 2.0 Hz, 1 H),
7.79–7.69 (m, 3 H), 7.40–7.30 (m, 3 H), 7.24–7.22 (m, 2 H), 4.68
(tt, J = 11.6, 3.6 Hz, 1 H), 4.17–4.13 (m, 1 H), 3.97 (dd, J = 12.8,
4.0 Hz, 1 H), 3.60 (t, J = 11.6 Hz, 1 H), 3.10 (tt, J = 12.0, 3.6 Hz, 1
H), 2.84 (dd, J = 13.2, 11.6 Hz, 1 H), 2.53 (q, J = 12.4 Hz, 1 H), 2.39
(d, J = 12.4 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 148.1, 139.3, 134.5, 132.3, 132.1,
131.2, 129.3, 128.1, 127.2, 124.8, 119.1 (q, J = 324.0 Hz), 64.7,
51.3, 48.4, 43.8, 36.2.
Indolinyl-methanesulfonamide 22′
Rf = 0.40 (hexanes–EtOAc, 2:1).
IR (thin film): 3088, 2934, 1733, 1544, 1451, 1227, 1019, 914, 838,
699 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.89 (dd, J = 8.0, 1.6 Hz, 1 H),
7.72–7.68 (m, 1 H), 7.63–7.56 (m, 3 H), 7.29 (t, J = 8.0 Hz, 1 H),
7.22 (d, J = 7.6 Hz, 1 H), 7.17–7.13 (m, 1 H), 5.07–5.01 (m, 1 H),
4.33 (dd, J = 14.8, 5.2 Hz, 1 H), 3.83 (dd, J = 14.4, 10.0 Hz, 1 H),
3.21 (dd, J = 16.4, 8.8 Hz, 1 H), 2.96 (d, J = 16.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 148.3, 139.1, 134.8, 131.8, 131.7,
130.9, 130.2, 128.7, 126.3, 124.6, 119.2 (q, J = 323.7 Hz), 117.0,
60.0, 53.9, 31.0.
HRMS [+APCI]: m/z [M + H]+ calcd for C19H18O8N3F6S3:
626.0155; found: 626.0167.
1,1,1-Trifluoro-N-[cis-5-methyl-1-(2-nitrophenylsulfonyl)pi-
peridin-3-yl]-N-(trifluoromethylsulfonyl)methanesulfonamide
(30) and 1,1,1-Trifluoro-N-[trans-5-methyl-1-(2-nitrophenyl-
sulfonyl)piperidin-3-yl]-N-(trifluoromethylsulfonyl)methane-
sulfonamide (30′)
Prepared according the general procedure using N-(2-methylpent-4-
enyl)-2-nitrobenzenesulfonamide (29, 85.3 mg, 0.3 mmol),
HN(SO2CF3)2 (168.7 mg, 0.6 mmol), and PhI(OAc)2 (144.9 mg,
0.45 mmol) in CH2Cl2 (15.0 mL). Purification by flash column
chromatography (silica gel, 10% → 40% EtOAc–hexanes) afforded
30 and its trans isomer 30′ (167.7 mg, 96%, 30/30′ 4.3:1) as thick
oils.
HRMS [+APCI]: m/z [M + H]+ calcd for C17H14O8N3F6S3:
597.9842; found: 597.9837.
1,1,1-Trifluoro-N-[1-(2-nitrophenylsulfonyl)pyrrolidin-3-yl]-
N-(trifluoromethylsulfonyl)methanesulfonamide (24)
Prepared according the general procedure using 2-nitro-N-(but-3-
enyl)benzenesulfonamide (23, 76.9 mg, 0.3 mmol), HN(SO2CF3)2
(168.7 mg, 0.6 mmol), and PhI(OAc)2 (144.9 mg, 0.45 mmol) in
CH2Cl2 (15.0 mL). Purification by flash column chromatography
(silica gel, 5% → 20% EtOAc–hexanes) gave 24 (98.0 mg, 61%) as
a thick oil; Rf = 0.40 (hexanes–EtOAc, 2:1).
cis-Isomer 30
Rf = 0.45 (hexanes–EtOAc, 2:1).
IR (thin film): 3107, 2918, 1544, 1440, 1370, 1216, 1173, 1046,
903, 706 cm–1.
IR (thin film): 3107, 2964, 1733, 1544, 1440, 1363, 1243, 1131,
1015, 842 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.10–7.96 (m, 1 H), 7.80–7.72 (m,
2 H), 7.70–7.67 (m, 1 H), 4.98 (p, J = 8.8 Hz, 1 H), 3.99 (dd,
J = 10.0, 8.4 Hz, 1 H), 3.71 (t, J = 8.8 Hz, 1 H), 3.70–3.65 (m, 1 H),
3.55 (dt, J = 10.0, 7.2 Hz, 1 H), 2.61–2.37 (m, 2 H).
13C NMR (150 MHz, CDCl3): δ = 148.5, 134.4, 132.1, 131.3, 131.1,
124.6, 119.0 (q, J = 324.0 Hz), 63.1, 49.6, 46.0, 30.0.
1H NMR (400 MHz, CDCl3): δ = 8.05–7.98 (m, 1 H), 7.79–7.71 (m,
2 H), 7.68 (dd, J = 7.6, 1.6 Hz, 1 H), 4.51 (tt, J = 11.6, 4.0 Hz, 1 H),
4.07–3.96 (m, 1 H), 3.86–3.70 (m, 1 H), 3.40 (t, J = 11.6 Hz, 1 H),
2.38 (dd, J = 12.8, 11.2 Hz, 1 H), 2.15 (d, J = 10.0 Hz, 1 H), 2.00–
1.79 (m, 2 H), 1.00 (t, J = 6.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.1, 134.4, 132.2, 132.0, 131.0,
124.7, 119.0 (q, J = 323.6 Hz), 64.7, 51.7, 48.3, 37.6, 32.9, 18.3.
HRMS [+APCI]: m/z [M + H]+ calcd for C12H12O8N3F6S3:
535.9685; found: 535.9683.
HRMS [+ESI]: m/z [M + H]+ calcd for C14H16O8N3F6S3: 564.0004;
found: 564.0006.
1-(2-Nitrophenylsulfonyl)-2-vinylpyrrolidine (26)
Prepared according the general procedure using 2-nitro-N-(hex-5-
enyl)benzenesulfonamide (25, 85.3 mg, 0.3 mmol), HN(SO2CF3)2
(168.7 mg, 0.6 mmol), and PhI(OAc)2 (144.9 mg, 0.45 mmol) in
CH2Cl2 (15.0 mL). Purification by flash column chromatography
trans-Isomer 30′
Rf = 0.43 (hexanes–EtOAc, 2:1).
Synthesis 2012, 44, 1190–1198
© Georg Thieme Verlag Stuttgart · New York

SPECIAL TOPIC
Piperidine Synthesis by Olefin Diamination
1197
IR (thin film): 3107, 2926, 1733, 1544, 1440, 1370, 1227, 1015,
938, 703 cm–1.
(m, 1 H), 2.19 (d, J = 12.0 Hz, 1 H), 1.86–1.81 (m, 2 H), 1.17 (d,
J = 6.8 Hz, 3 H).
1H NMR (400 MHz, CDCl3): δ = 8.00 (dd, J = 7.6, 2.0 Hz, 1 H),
7.78–7.71 (m, 2 H), 7.68 (dd, J = 7.6, 1.6 Hz, 1 H), 4.76 (tt,
J = 12.0, 4.0 Hz, 1 H), 4.13–3.99 (m, 1 H), 3.64 (dd, J = 13.2, 1.2
Hz, 1 H), 3.41 (t, J = 12.0 Hz, 1 H), 2.97 (dd, J = 13.2, 3.2 Hz, 1 H),
2.41 (td, J = 12.4, 5.2 Hz, 1 H), 2.35–2.23 (m, 1 H), 1.94 (d, J = 12.0
Hz, 1 H), 1.15 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 147.8, 135.3, 134.2, 132.4, 130.4,
124.6, 119.1 (q, J = 323.6 Hz), 65.1, 56.6, 51.2, 34.0, 29.7, 18.9.
HRMS [+ESI]: m/z [M + H]+ calcd for C14H16O8N3F6S3: 563.9998;
found: 564.0001.
1,1,1-Trifluoro-N-[1-(2-nitrophenylsulfonyl)-5,5-diphenylpi-
peridin-3-yl]methanesulfonamide (35) and 1-(2-Nitrophenyl-
sulfonyl)-5,5-diphenylpiperidin-3-amine (36)
13C NMR (100 MHz, CDCl3): δ = 148.3, 134.3, 132.1, 131.2, 124.7,
119.0 (q, J = 322.9 Hz), 61.6, 50.7, 49.1, 35.3, 29.5, 16.4.
Monotrifluoromethylsulfonyl group deprotected product 37 can be
obtained in excellent yield. 3-gem-Diphenyl-substituted cyclization
product 19 (266.6 mg, 0.4 mmol, 1.0 equiv) was dissolved in MeCN
(30.0 mL) at r.t.; Cs2CO3 (371.4 mg, 1.14 mmol, 3.0 equiv) was
added and the soln was stirred at r.t. overnight. The suspension was
cooled to 0 °C with ice-water bath and 2 M HCl (20.0 mL) was add-
ed. The mixture was extracted with EtOAc (2 × 30.0 mL). The com-
bined organic extracts were washed H2O (10.0 mL) and brine
(2 × 10.0 mL) and dried (anhyd Na2SO4). Filtration and concentra-
tion in vacuo provided a crude product that was purified by flash
chromatography (silica gel, 20–50% EtOAc–hexanes) to give 35
(220.7 mg, 98%) as a white solid; mp 206–208 °C; Rf = 0.20 (hex-
anes–EtOAc, 2:1).
HRMS [+ESI]: m/z [M + H]+ calcd for C14H16O8N3F6S3: 563.9998;
found: 564.0004.
1,1,1-Trifluoro-N-[trans-4-methyl-1-(2-nitrophenylsulfonyl)pi-
peridin-3-yl]-N-(trifluoromethylsulfonyl)methanesulfonamide
(32) and 1,1,1-Trifluoro-N-{[3-methyl-1-(2-nitrophenylsulfo-
nyl)pyrrolidin-2-yl]methyl}-N-(trifluoromethylsulfonyl)meth-
anesulfonamide (32′)
Prepared according the general procedure using N-(3-methylpent-4-
enyl)-2-nitrobenzenesulfonamide (31, 85.3 mg, 0.3 mmol),
HN(SO2CF3)2 (168.7 mg, 0.6 mmol), and PhI(OAc)2 (144.9 mg,
0.45 mmol) in CH2Cl2 (15.0 mL). Purification by flash column
chromatography (silica gel, 10% → 40% EtOAc–hexanes) afforded
32 and its regioisomer 32′ (145.4 mg, 86%, 32/32′ 1.9:1) as thick
oils.
IR (thin film): 3237, 1591, 1538, 1375, 1344, 1232, 1202, 1168,
1151, 1091 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 8.16–8.14 (m, 1 H), 7.98–
7.94 (m, 1 H), 7.91–7.87 (m, 2 H), 7.55 (d, J = 8.4 Hz, 2 H), 7.36 (t,
J = 7.6 Hz, 2 H), 7.32–7.18 (m, 6 H), 4.82 (d, J = 12.8 Hz, 1 H),
4.11 (dd, J = 10.8, 4.4 Hz, 1 H), 3.67 (tt, J = 12.0, 4.0 Hz, 1 H), 3.15
(d, J = 13.2 Hz, 1 H), 3.05 (d, J = 12.8 Hz, 1 H), 2.88 (t, J = 10.8 Hz,
1 H), 2.40 (t, J = 12.8 Hz, 1 H).
13C NMR (100 MHz, CD3COCD3): δ = 149.8, 146.6, 143.4, 135.9,
133.0, 132.1, 129.8, 129.63, 129.56, 128.5, 127.8, 127.6, 127.2,
125.2, 120.8 (q, J = 318.4 Hz), 54.0, 51.8, 50.4, 47.7, 42.0.
Piperidinyl-methanesulfonamide 32
Rf = 0.50 (hexanes–EtOAc, 2:1).
IR (thin film): 3100, 2941, 1590, 1544, 1436, 1370, 1227, 1127,
1004, 703 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.06–7.94 (m, 1 H), 7.80–7.70 (m,
2 H), 7.70–7.65 (m, 1 H), 4.12 (td, J = 11.2, 4.0 Hz, 1 H), 4.06–3.98
(m, 1 H), 3.92–3.77 (m, 1 H), 3.45 (t, J = 11.6 Hz, 1 H), 2.81 (td,
J = 13.2, 2.8 Hz, 1 H), 2.43–2.25 (m, 1 H), 2.03–1.91 (m, 1 H), 1.53
(ddd, J = 17.2, 13.2, 4.0 Hz, 1 H), 1.14 (d, J = 6.8 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.3, 134.4, 132.1, 131.8, 131.2,
124.7, 119.1 (q, J = 325.2 Hz), 71.8, 48.9, 45.9, 35.0, 34.2, 18.3.
HRMS [+APCI]: m/z [M + H]+ calcd for C24H23O6N3F3S2:
570.0975; found: 570.0986.
The monotrifluoromethylsulfonyl group deprotected product 35
was further deprotected according to a literature procedure for sim-
ilar substrates.8 1,1,1-Trifluoro-N-[1-(2-nitrophenylsulfonyl)-5,5-
diphenylpiperidin-3-yl]methanesulfonamide (35, 79.8 mg, 0.14
mmol, 1.0 equiv) was dissolved in acetone (6.0 mL) at r.t. 2-Bromo-
1-(4-bromophenyl)ethanone (58.5 mg, 0.21 mmol, 1.5 equiv) and
K2CO3 (77.4 mg, 0.56 mmol, 4.0 equiv) were added. The mixture
was stirred at r.t. and tracked by TLC for completion. The acetone
was evaporated in vacuo and the residue was cooled to 0 °C with
ice-water bath. 2 M HCl (8.0 mL) and MeOH (8.0 mL) were then
added, and the suspension was stirred at r.t. overnight. MeOH was
evaporated in vacuo and the residue was cooled to 0 °C with ice-
water bath. 6 M NaOH was added until the mixture became basic.
It was then extracted with Et2O (3 × 30.0 mL). The combined or-
ganic extracts were washed with brine (20.0 mL) and dried (anhyd
Na2SO4). Filtration and concentration in vacuo provided a crude
product that was purified by flash column chromatography (silica
gel, 2–10% MeOH–CHCl3) to give 36 (57.0 mg, 93%) as a light-
yellow solid; mp 76–78 °C; Rf = 0.45 (CHCl3–MeOH, 10:1).
HRMS [+APCI]: m/z [M + H]+ calcd for C14H16O8N3F6S3:
563.9998; found: 563.9989.
Pyrrolidinyl-methanesulfonamide 32′
Rf = 0.40 (hexanes–EtOAc, 2:1).
IR (thin film): 3100, 2972, 1544, 1451, 1374, 1224, 1042, 1004,
838, 706 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.17–7.99 (m, 1 H), 7.80–7.66 (m,
2 H), 7.66–7.56 (m, 1 H), 4.43 (dd, J = 13.6, 6.8 Hz, 1 H), 4.01–3.88
(m, 2 H), 3.64–3.52 (m, 2 H), 2.20–2.01 (m, 2 H), 1.72–1.61 (m, 1
H), 1.07 (d, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 148.7, 134.2, 132.1, 131.8, 131.4,
124.3, 119.3 (q, J = 323.6 Hz), 61.7, 52.6, 47.1, 37.3, 31.2, 13.7.
HRMS [+APCI]: m/z [M + H]+ calcd for C14H16O8N3F6S3:
563.9998; found: 563.9993.
1,1,1-Trifluoro-N-[6-methyl-1-(2-nitrophenylsulfonyl)piperi-
din-3-yl]-N-(trifluoromethylsulfonyl)methanesulfonamide (34)
Prepared according the general procedure using N-(hex-5-en-2-yl)-
2-nitrobenzenesulfonamide (33, 85.3 mg, 0.3 mmol), HN(SO2CF3)2
(168.7 mg, 0.6 mmol), and PhI(OAc)2 (144.9 mg, 0.45 mmol) in
CH2Cl2 (15.0 mL). Purification by flash column chromatography
(silica gel, 10% → 40% EtOAc–hexanes) afforded 34 (120.0 mg,
71%) as a thick oil; Rf = 0.45 (hexanes–EtOAc, 2:1).
IR (thin film): 1589, 1542, 1372, 1350, 1162, 991, 851, 793, 698,
582 cm–1.
1H NMR (400 MHz, CDCl3): δ = 7.87 (dd, J = 7.6, 1.6 Hz, 1 H),
7.70–7.61 (m, 2 H), 7.54 (dd, J = 7.6, 1.6 Hz, 1 H), 7.43–7.40 (m, 2
H), 7.29–7.23 (m, 4 H), 7.19–7.14 (m, 4 H), 4.66 (d, J = 12.4 Hz, 2
H), 3.91 (dd, J = 11.2, 4.8 Hz, 1 H), 2.97 (tt, J = 10.8, 4.0 Hz, 1 H),
2.81 (d, J = 12.8 Hz, 1 H), 2.77 (d, J = 12.8 Hz, 1 H), 2.36 (t,
J = 10.8 Hz, 1 H), 1.90 (dd, J = 12.8, 11.2 Hz, 1 H).
IR (thin film): 2953, 2926, 1731, 1544, 1440, 1370, 1220, 1123,
1023, 896 cm–1.
1H NMR (400 MHz, CDCl3): δ = 8.14–7.91 (m, 1 H), 7.79–7.53 (m,
3 H), 4.55 (tt, J = 11.6, 4.0 Hz, 1 H), 4.45–4.34 (m, 1 H), 3.57 (dd,
J = 12.8, 11.6 Hz, 1 H), 3.26 (dq, J = 13.6, 6.8 Hz, 1 H), 2.36–2.28
13C NMR (100 MHz, CDCl3): δ = 149.0, 146.2, 143.8, 134.1, 131.6,
131.1, 129.9, 128.81, 128.76, 127.8, 126.9, 126.6, 126.5, 124.1,
54.0, 53.9, 46.7, 44.9, 44.3.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1190–1198

1198
A. Kong, S. B. Blakey
SPECIAL TOPIC
HRMS [+APCI]: m/z [M + H]+ calcd for C23H24O4N3S: 438.1482;
found: 438.1470.
G. Synlett 1999, 49. (o) Comins, D. L.; Fulp, A. B. Org. Lett.
1999, 1, 1941. (p) Sibi, M. P.; Christensen, J. W. J. Org.
Chem. 1999, 64, 6434. (q) Pourashraf, M.; Delair, P.;
Rasmussen, M. O.; Greene, A. E. J. Org. Chem. 2000, 65,
6966. (r) Cossy, J.; Willis, C.; Bellosta, V.; Saint-Jalmes, L.
Synthesis 2002, 951.
N-(5,5-Diphenylpiperidin-3-yl)-1,1,1-trifluoromethanesulfon-
amide (37)
3-gem-Diphenyl-substituted cyclization product 19 was trans-
formed into N-(5,5-diphenylpiperidin-3-yl)-1,1,1-trifluorometh-
anesulfonamide (37) via the modification of the standard 2-nosyl
deprotection literature procedure.9 3-gem-Diphenyl-substituted cy-
clization product 19 (45.0 mg, 1.0 equiv) was dissolved in MeCN
(5.0 mL) at r.t.; Cs2CO3 (140.0 mg, 6.0 equiv) and PhSH (28.2 mg,
4.0 equiv) were added and the soln was stirred at r.t. overnight. The
suspension was filtered to remove the solid which was washed with
CHCl3. The soln was concentrated to remove the solvent providing
a crude product, which was then purified by preparative TLC
(CHCl3–MeOH, 5:1) to give 37 (9.7 mg, 80%) as a colourless oil;
Rf = 0.70 (CHCl3–MeOH, 5:1).
(3) Tattersall, F. D.; Rycroft, W.; Hill, R. G.; Hargreaves, R. J.
Neuropharmacology 1994, 33, 259.
(4) (a) Ishikawa, M.; Kubota, D.; Yamamoto, M.; Kuroda, C.;
Iguchi, M.; Koyanagi, A.; Murakami, S.; Ajito, K. Bioorg.
Med. Chem. 2006, 14, 2109. (b) Ishikawa, M.; Hiraiwa, Y.;
Kubota, D.; Tsushima, M.; Watanabe, T.; Murakami, S.;
Ouchi, S.; Ajito, K. Bioorg. Med. Chem. 2006, 14, 2131.
(5) (a) Johnson, R. A.; Sharpless, K. B. Catalytic Asymmetric
Synthesis, 2nd ed. Ojima, I., Ed.; Wiley-VCH: New York,
2005, 357. (b) Lutz, J.-F. Angew. Chem. Int. Ed. 2007, 46,
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Int. Ed. 1998, 37, 2580. (b) Muñiz, K. New J. Chem. 2005,
29, 1371. (c) de Figueiredo, R. M. Angew. Chem. Int. Ed.
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IR (thin film): 3401, 3366, 3061, 2918, 1698, 1602, 1471, 1378,
1204, 699 cm–1.
1H NMR (400 MHz, CD3COCD3): δ = 7.51 (d, J = 7.2 Hz, 2 H),
7.36 (t, J = 8.0 Hz, 2 H), 7.28–7.19 (m, 5 H), 7.16–7.12 (m, 1 H),
7.96 (dd, J = 13.6, 2.8 Hz, 1 H), 3.55–3.47 (m, 1 H), 3.24–3.20 (m,
1 H), 3.09–3.06 (m, 1 H), 2.86 (br s, 1 H), 2.85 (d, J = 13.6 Hz, 1
H), 2.66 (t, J = 11.2 Hz, 1 H), 2.27 (t, J = 12.4 Hz, 1 H).
(7) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I.
J. Am. Chem. Soc. 2005, 127, 7308.
13C NMR (100 MHz, CD3COCD3): δ = 148.6, 144.9, 129.6, 129.3,
128.8, 127.0, 120.9 (q, J = 319.2 Hz), 55.3, 53.4, 51.8, 48.7, 43.8.
HRMS [+APCI]: m/z [M + H]+ calcd for C18H20O2N2F3S: 385.1192;
(8) (a) Li, G.; Kim, S. H.; Wei, H. Tetrahedron Lett. 2000, 41,
8699. (b) Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz,
K. J. Am. Chem. Soc. 2005, 127, 14586. (c) Du, H.; Zhao, B.;
Shi, Y. J. Am. Chem. Soc. 2007, 129, 762. (d) Du, H.; Yuan,
W.; Zhao, B.; Shi, Y. J. Am. Chem. Soc. 2007, 129, 11688.
(e) Iglesias, Á.; Pérez, E. G.; Muñiz, K. Angew. Chem. Int.
Ed. 2010, 49, 8109.
(9) (a) Zabawa, T. P.; Kasi, D.; Chemler, S. R. J. Am. Chem.
Soc. 2005, 127, 11250. (b) Zabawa, T. P.; Chemler, S. R.
Org. Lett. 2007, 9, 2035. (c) Sibbald, P. A.; Michael, F. E.
Org. Lett. 2009, 11, 1147. (d) Sequeira, F. C.; Turnpenny, B.
W.; Chemler, S. R. Angew. Chem. Int. Ed. 2010, 49, 6365.
(e) Sibbald, P. A.; Rosewall, C. F.; Swartz, R.; Michael, F.
E. J. Am. Chem. Soc. 2009, 131, 15945.
found: 385.1193.
Acknowledgment
This research was supported by the NSF (NSF CHE 0847258). We
thank Kenneth Hardcastle and Chongchao Zhao for assistance with
X-ray crystallography and Fred Strobel for assistance with HRMS.
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Synthesis 2012, 44, 1190–1198
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