Asymmetric Synthesis of amines through rhodium-catalyzed C-H amination with sulfonimidoylnitrenes

Article abstract of DOI:10.1055/s-0033-1339280

An efficient asymmetric C-H amination of benzylic and allylic substrates, as well as of adamantane derivatives, through catalytic C-H insertion of a chiral nitrene is reported. The reaction involves a chiral rhodium(II) complex, an iodine(III) oxidant, an

Full text of DOI:10.1055/s-0033-1339280

PRACTICAL SYNTHETIC PROCEDURES
▌2079
pArasctyicaml symntheetticrpircoceSduyrens thesis of Amines through Rhodium-Catalyzed C–H
Amination with Sulfonimidoylnitrenes
Catalytic C–H Amination
Benjamin Darses,1,a Amanda G. Jarvis,1,a Abdel-Kader Mafroud,a,b Geneviève Estenne-Bouhtou,b Gihad Dargazanli,b
Philippe Dauban*a
a
Institut de Chimie des Substances Naturelles, UPR 2301 CNRS, Centre de Recherche de Gif,
Avenue de la Terrasse, 91198 Gif-sur-Yvette, France
Fax +33(1)69077247; E-mail: philippe.dauban@cnrs.fr
PSP
b
Sanofi-Aventis Recherche et Développement, Unité Exploratoire, 1 Avenue Pierre Brossolette,
91385 Chilly-Mazarin, France
No252
Received: 05.04.2013; Accepted after revision: 27.05.2013
Abstract: An efficient asymmetric C–H amination of benzylic and allylic substrates, as well as of adamantane derivatives, through catalytic
C–H insertion of a chiral nitrene is reported. The reaction involves a chiral rhodium(II) complex, an iodine(III) oxidant, and a sulfonimid-
amide as a nitrene precursor. Experimental protocols for the preparation of the reagents and the catalytic nitrene are provided. The C–H
amination can provide the corresponding amino derivatives on a gram scale. Various methods for the cleavage of the sulfonimidoyl group
to give the corresponding tert-butoxycarbonyl- or acetyl-protected optically pure amines are also described.
Key words: rhodium, amines, nitrene, asymmetric catalysis, C–H amination
Procedure 1
O
S
O
S
1. SOCl2, CH2Cl2, r.t.
2. chloramine-T, toluene, 80 °C
ONa
NH2
N
Ts
1 (S)-S*NH2
28–32% (25 g)
Ph
NH
2 , NaHCO3, CH Cl2/H2O
3.
4. TfOH, CH2Cl2, 0 °C to r.t. 2
Procedure 2
Procedure 3
1. 1,8-naphthalic anhydride
KOH, H2O–EtOH, reflux, 6 h
O
H2N
N
2. 1 M HCl
CO2H
L-alanine
O
CO2H
2 78–88% (10 g)
O
O
Rh2(OAc)4, PhCl, reflux, 20 h
N
N
O
O
O
4
3 Rh2(S-nta)4
88–95% (2.5 g)
O
2
CO2H
Rh
Rh
Procedure 4
NHS*
(S)-S*NH2 1 (1.2 equiv)
Rh2(S-nta)4
3
PhI(OCOt-Bu)2 (1.4 equiv)
Cl2CHCHCl2–MeOH (3:1), –35 °C
4a (1 equiv)
5a 94%, dr >20:1
*S
Procedure 5a or 5b
Boc
N
NHS*
Boc2O (3 equiv), DMAP (0.5 equiv)
CH2Cl2, r.t., 18 h
8a 97%, 5 g
5a
8a
NHBoc
Method A: Mg (10 equiv), I2 (20 mol%)
MeOH, sonication, 1 h
Method B: KPPh2 (1.5 equiv), THF
–78 °C then 1 M HCl
9a
A: 93%, 1 g - B: 70%
Procedure 6
NHAc
NHS*
Na (6 equiv), naphthalene (3 equiv)
THF, r.t., 2 h
then 10 M aq NaOH, AcCl (3 equiv), 16 h
5a
10a 74%
Scheme 1 Procedures for the practical preparation of optically pure protected amines through catalytic C–H amination
SYNTHESIS 2013, 45, 2079–2087
Advanced online publication: 27.06.2013
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DOI: 10.1055/s-0033-1339280; Art ID: SS-2013-Z0271-PSP
© Georg Thieme Verlag Stuttgart · New York

2080
B. Darses et al.
PRACTICAL SYNTHETIC PROCEDURES
mixture of ethanol and water11 allowed the isolation of the
Introduction
optically pure protected alanine derivative 2 in 88% yield
The development of C–N bond-forming reactions is a re- on a 50 mmol scale (Scheme 1, procedure 2).
search area of longstanding interest that has fundamental
Rhodium-catalyzed C–H amination proceeded efficiently
applications in natural-product synthesis, the life scienc-
at low temperature in a 3:1 mixture of 1,1,2,2-tetrachloro-
es, and materials science.2 The field has been revolution-
ethane and methanol with a hydrocarbon as the limiting
ized by the recent discovery of efficient protocols for the
agent, as exemplified in Scheme 1, procedure 4.12 Second-
direct conversion of C–H bonds into C–N bonds, which
ary benzylic and allylic positions were functionalized un-
has streamlined the preparation of nitrogen-containing
der these conditions in very good yields and excellent
compounds. The most significant achievements, exempli-
diastereomeric ratios (Table 1).13 With regard to the abso-
fied by a total synthesis of tetrodotoxin,3 involve the use
lute configuration of the product, a combination of (S)-1
and (S)-3 generally gives the (R)-benzylic or (R)-allylic
amine, whereas the S-isomer is isolated with the corre-
sponding enantiomeric pair of matched R-configured re-
of metal-catalyzed nitrene transfers.4 These reactions
have been improved through the design of a wide range of
transition-metal-complex catalysts, of which dirhodi-
um(II) compounds are the most efficient.5 The use of io-
agents; this has been confirmed by various X-ray crystal-
dine(III) oxidants permits the generation of nitrenes from
structure determinations.7 The amination of indan (4a;
various nitrogen functionalities.6 In this context, we re-
Scheme 1, procedure 4 and Table 1, entry 1) illustrates the
cently reported a catalytic stereoselective intermolecular
efficiency of the process, which gives a yield of 90% and
C–H amination based on a chiral nitrene generated from a
a dr of >20:1 when the reaction is carried out on a 20
matched combination of a sulfonimidamide 1 and a chiral
mmol scale in the presence of only 0.3 mol% of rhodium
catalyst 3. The results obtained with various indan deriv-
atives 4b–d (entries 2–4) show that the nitrene addition
rhodium(II) catalyst 3 (Scheme 1).7 Starting from a sub-
strates used as the limiting agent, benzylic or allylic C–H
aminations can be performed in high yields and with ex-
process tolerates a range of useful functional groups. The
cellent levels of regio-, chemo-, and stereoselectivity to
moderate to good regioselectivities observed with the
give optically pure amines. Alkanes can also be function-
nonsymmetrical 1,2-diphenylethanes 4e and 4f demon-
strate that electron-deficient nitrenes react preferentially
alized efficiently under these conditions. Here, we de-
scribe some practical protocols for the preparation of the
with electron-rich C–H bonds (entries 5 and 6).
necessary reagents on a gram scale, for the subsequent
catalytic C–H amination reaction, and for the removal of
the sulfonimidoyl moiety (Scheme 1).
Table 1 Benzylic and Allylic C–H Aminations in the Presence of
(S)-S*NH2 (1)
(S)-S*NH2 1 (1.2 equiv)
Rh2(S-nta)4 3 (3 mol%)
H
NHS*
R3
H
H
R1
R1
R3
PhI(OCOt-Bu)2 (1.4 equiv)
Cl2CHCHCl2–MeOH (3:1)
–35 °C, 72 h
Scope and Limitation
R2
R2
4 (1 equiv)
5
The optically pure (S)-sulfonimidamide 1 can be prepared
on a multigram scale in four steps, starting from 50 grams
of commercially available sodium 4-toluenesulfinate
(Scheme 1, procedure 1), according to a strategy adapted
from a previously published procedure.8 The overall yield
of 28–32% includes the resolution of the diastereomeric
mixture obtained by condensation of N-tosyl-4-toluene-
sulfonimidoyl chloride with [(1R)-1-phenylethyl]amine,
which involves precipitation in a mixture of dichloro-
methane and methyl tert-butyl ether, followed by recrys-
tallization from ethanol. Treatment with 1.5 equivalents
of triflic acid in dichloromethane then results in the cleav-
age of the chiral auxiliary with a 93% yield.
Entrya Substrate
Productb
Yieldc drd
(%)
(%)
NHS*
NHS*
1e
90
>20:1
4a
5a
OMe
OMe
2
94
70
97
>20:1
>20:1
>20:1
4b
6b
NHS*
Br
The chiral rhodium(II) complex 3 can be obtained on a
multigram scale from commercially available dirhodium
tetraacetate by simple ligand exchange with the protected
L-alanine derivative 2 in refluxing chlorobenzene
(Scheme 1, procedure 3).9 The large-scale preparation of
L-alanine derivative 2, however, proved troublesome, be-
cause application of the classical conditions for its forma-
tion (heating L-alanine in the presence of 1,8-naphthalic
anhydride in N,N-dimethylformamide or dimethyl sulfox-
ide)10 induced partial racemization of the chiral center.
Fortunately, the use of potassium hydroxide in a refluxing
Br
3f
5c
5c
NHS*
N3
N3
4
4d
5d
Synthesis 2013, 45, 2079–2087
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Catalytic C–H Amination
2081
Table 1 Benzylic and Allylic C–H Aminations in the Presence of
(S)-S*NH2 (1) (continued)
Steric factors might be responsible for discrimination be-
tween various benzylic sites within a substrate, as illus-
trated by the regioselective amination of 10,11-dihydro-
5H-dibenzo[a,d][7]annulene (4g; entry 7). The amination
of 1-acetyl-1,2,3,4-tetrahydroquinoline (4h; entry 8)
proves that the reaction can be efficiently applied to nitro-
gen heterocycles; however, the ring size and the position
of the nitrogen atom are critical, because neither N-pro-
tected indolines nor tetrahydroisoquinolines gave satis-
factory yields of the expected amines (data not shown).
(S)-S*NH2 1 (1.2 equiv)
H
NHS*
R3
H
H
Rh2(S-nta)4 3 (3 mol%)
R1
R1
R3
PhI(OCOt-Bu)2 (1.4 equiv)
Cl2CHCHCl2–MeOH (3:1)
–35 °C, 72 h
R2
R2
4 (1 equiv)
5
Entrya Substrate
Productb
Yieldc drd
(%)
(%)
NHS*
Ph
In the case of allylic substrates (entries 9–12), the reaction
proceeds successfully with either linear or cyclic alkenes,
although lower diastereoselectivities are observed in
some cases. More importantly, the absence of products
arising from classical alkene aziridination6 emphasizes
the excellent chemoselectivity observed in the catalytic
C–H insertion of sulfonimidoylnitrenes. Interestingly, the
reaction with (+)-α-pinene (4j) allowed us to recover and
recycle the rhodium catalyst 3; the recycled catalyst gave
compound 5j with comparable yield and dr. In addition,
C–H amination of geranyl trichloroacetate (4l) clearly
demonstrated that the amount of rhodium complex cata-
lyst can be reduced by an order of magnitude without di-
minishing the yield. Indeed, the use of as little as 0.03
mol% of catalyst 3 led to clean formation of the expected
product 5l in 65% yield.
>20:1
Ph
5
83g
(6.5:1)h
MeO
MeO
4e
5e
NHS*
C6H4-4-F
MeO
>20:1
(9:1)h
6i
96g
99
MeO
C6H4-4-F
4f
5f
NHS*
7
>20:1
4g
5g
NHS*
N
8
70
97
>20:1
14:1
Ac
N
The reaction conditions reported in procedure 4 also per-
mit efficient C–H functionalization of nonactivated al-
kanes selectively at tertiary positions. The reaction of
adamantyl derivatives (Table 2) illustrates the high reac-
tivity of cyclic substrates with sulfonimidoylnitrenes.14
1,3-Dimethyladamantane (6a) was efficiently converted
into a protected analogue of the NMDA antagonist me-
mantine, useful for the treatment of moderate to severe
Alzheimer’s disease (Table 2, entry 1). Once again, the
transformation tolerates the presence of an electron-with-
drawing group such as a bromo or carboxylic acid group
(entries 2 and 3), whereas the result observed for ketal 6d
(entry 4) demonstrates the possibility of overriding the
lack of reactivity of the corresponding ketone.
Ac
4h
5h
5i
NHS*
9
4i
NHS*
10
89
95
13:1
12:1
4j
5j
NHS*
11
Finally, the sulfonimidoyl moiety can be cleaved without
loss of enantioselectivity. Three methods have been
shown to be effective in this transformation of benzylic
substrates. The first two strategies rely on the activation of
the N–S bond by the addition of a tert-butyloxycarbonyl
group onto the nitrogen atom. With product 5a this can be
achieved in high yields (97%) for 10 mmol amounts of
substrate. Once activated, the N–S bond can be cleaved by
either the magnesium, methanol and catalytic iodine sys-
tem under sonication (Scheme 1, procedure 5, method A)
or by nucleophilic displacement by the diphenyl phos-
phide anion followed by acid workup15 (procedure 5,
method B). These methods allowed us to isolate the pro-
tected amine 9a in 93% and 70% yield, respectively, start-
ing from 2.5 grams of sulfonimidamide 8a. The overall
yield for the conversion of 5a into 9a was 68–90%, de-
pending on the method used.16
4k
5k
NHS*
88
>20:1
>20:1
>20:1
O
87j
65k
O
12
Cl3C
O
Cl3C
O
4l
5l
a The reaction was performed on a 2 mmol scale unless otherwise stated.
b S* = (S)-NHS(=O)(=NTs)4-Tol
c Isolated yield.
d Determined by 1H NMR spectroscopy.
e Reaction performed on a 20 mmol scale using 0.3 mol% of Rh catalyst 3.
f Reaction performed on a 1.8 mmol scale.
g The regioisomers were not separated.
h Regioisomer ratio determined by 1H NMR spectroscopy.
i Reaction performed on a 0.75 mmol scale.
j Reaction performed with 0.3 mol% of Rh catalyst 3.
k Reaction performed with 0.03 mol% of Rh catalyst 3.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2079–2087

2082
B. Darses et al.
PRACTICAL SYNTHETIC PROCEDURES
mass spectra were obtained by using a Kratos MS-80 spectrometer.
Optical rotations were determined with a JASCO P-1010 polarime-
ter. Chiral HPLC was performed by using a ChiralPack IA column
(5 μm, 250 × 4.6 mm) in a Waters 2695 Separations Module cou-
pled to a Waters 996 Photodiode Array Detector. All solvents were
stored over 3 Å MS and purged with argon. All commercial reagents
were purchased from the Aldrich Chemical Co. or Alfa Aesar, and
were used without further purification.
Table 2 Catalytic C–H Amination Reactions of Adamantyl Deriva-
tives
R1
R1
(S)-S*NH2 1 (1.2 equiv)
Rh2(S-nta)4 3 (3 mol%)
R2
R3
H
R2
NHS*
R3
PhI(OCOt-Bu)2 (1.4 equiv)
Cl2CHCHCl2–MeOH (3:1)
–35 °C, 72 h
7
6 (1 equiv)
Entrya
Substrate
Product
Yieldb (%)
N-[(1S)-Amino(4-tolyl)oxido-λ4-sulfanylidene]tosylamide (1);
Procedure 1
Sodium p-toluenesulfinate (50.0 g, 0.281 mol) was dried by heating
under vacuum and then suspended in anhyd toluene (500 mL) at
0 °C under argon. Freshly distilled SOCl2 (102 mL, 1.40 mol) was
added over 5 min from an equilibrating addition funnel. After 10
min, the ice bath was removed and the mixture was stirred for 16 h
at r.t. It was then concentrated under vacuum at 40 °C to give the
crude 4-toluenesulfinyl chloride as a yellow slurry that was used in
the next step without further purification.
1
2
94
76
NHS*
6a
6b
7a
7b
Br
Br
NHS*
Chloramine-T trihydrate was freshly dried by heating in a drying
pistol at 80 °C under vacuum for 8 h. [Caution! This is liable to ex-
plode if heated to a higher temperature.] The dried chloramine-T
(64.0 g, 0.281 mol) was added to a solution of the crude 4-toluene-
sulfinyl chloride in anhyd toluene (600 mL). The mixture was
heated at 80 °C for 4 h then concentrated under vacuum at 40 °C to
afford the crude 4-toluenesulfonimidoyl chloride as a yellow slurry,
which was used in the next step without further purification.
CO2H
CO2H
3
84
54
NHS*
7c
6c
A solution of the crude 4-toluenesulfonimidoyl chloride in CH2Cl2
(300 mL) at 0 °C was treated with [(1R)-1-phenylethyl]amine (42.9
mL, 0.337 mol), followed immediately by a solution of NaHCO3
(28.3 g, 0.337 mol) in H2O (300 mL). The mixture was stirred vig-
orously overnight while slowly warming to r.t. After 16 h, the mix-
ture was diluted with H2O (200 mL) and the organic phase was
decanted. The aqueous phase was extracted with CH2Cl2 (2 × 150
mL) and the organic layers were combined, washed with 0.1 M aq
HCl (250 mL), dried (Na2SO4), and filtered. The filtrate was con-
centrated under vacuum at 40 °C to give a yellow viscous oil that
was directly dissolved in CH2Cl2 (50 mL). t-BuOMe (400 mL) was
immediately added and white needles began to form rapidly. After
NHS*
O
O
4
O
O
6d
7d
a Reaction performed on a 2 mmol scale.
b Isolated yield.
On moving to the allylic or adamantyl derivatives, protec-
tion of the nitrogen with the tert-butyloxycarbonyl group 2 h, the mixture was cooled to 0 °C for 2 h and then to –30 °C for
15 h. The white needles were collected by filtration to give the re-
quired protected sulfonimidamide; yield: 49.5 g (17:1 mixture of
diastereoisomers). Recrystallization from boiling EtOH (225 mL)
gave the diastereoisomerically pure protected sulfonimidamide as
white needles; yield: 43.4 g (36%); mp 160–161 °C.
1H NMR (300 MHz, CDCl3): δ = 1.33 (dd, J = 6.6, 0.9 Hz, 3 H),
2.39 (s, 3 H), 2.37 (s, 3 H), 4.48 (q, J = 6.6 Hz, 1 H), 6.26 (s, 1 H),
failed to give the desired product or gave it in low yield,
possibly due to steric hindrance. This led us to revisit an
earlier removal method based on reduction with sodium
naphthalenide.7a Treatment of 5a (2.5 mmol) with sodium
naphthalenide followed by addition of 10 M sodium hy-
droxide and acetyl chloride to aid isolation of the product
gave the N-acetyl amine 10a in one step and 74% yield.
We assume that the protection of the free amine is quanti-
tative and, therefore, the yield that was obtained corre-
sponds to the yield for the removal of the sulfonimidoyl
moiety.
7.31–7.10 (m, 9 H), 7.85–7.68 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 21.74, 21.77, 23.1, 54.1, 126.5,
127.0, 127.9, 128.0, 128.8, 129.4, 129.9, 136.2, 140.5, 141.8, 143.0,
144.8.
From an equilibrating funnel with a greased glass tap, TfOH (5.33
mL, 60.2 mmol) was added dropwise over 1 min to a solution of the
protected sulfonimidamide (17.2 g, 40.1 mmol) in CH2Cl2 (55 mL)
at 0 °C. After 5 min, the ice bath was removed and the orange solu-
tion was stirred at r.t. After 1 h a precipitate began to form. When
the starting material had been consumed [2 h; TLC (EtOAc–
In summary, the use of sulfonimidamides as nitrene pre-
cursors in combination with a chiral dirhodium(II) cata-
lyst permits the direct C–H amination of hydrocarbons on
a gram scale with high efficiency and selectivity. The re-
action provides access to optically pure protected amines, CH2Cl2, 1:9)], the mixture was poured into PE (250 mL) to
precipitate a product. The orange solid was collected by filtration
and washed with H2O (250 mL). The resulting white solid was dried
under vacuum for 20 h then dissolved in boiling MeOH (100 mL).
The vigorously stirred refluxing solution was treated with H2O (300
the protecting groups of which can be replaced by a sim-
ple tert-butoxycarbonyl or acetyl group.
mL) previously heated at 65 °C. The mixture was then cooled to r.t.
and the resulting precipitate was collected by filtration and dried un-
der vacuum to afford the pure sulfonimidamide 1 as an off-white
solid; yield: 12.1 g (93%); mp 159–160 °C; [α]D –106 (c 0.19,
acetone).
Melting points were measured in capillary tubes on a Büchi B-540
apparatus and are uncorrected. IR spectra were recorded with a
1
PerkinElmer Spectrum BX FTIR spectrometer. H NMR and 13C
22
NMR spectra were recorded at 300 MHz or 75 MHz, respectively,
on a Bruker Aspect 3000 (300 MHz) instrument. High-resolution
Synthesis 2013, 45, 2079–2087
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Catalytic C–H Amination
2083
IR (ATR, neat): 3270, 3182, 3071, 1597, 1560, 1495, 1451, 1405,
1384, 1303, 1288, 1265, 1138, 1098, 1059, 1018, 937, 811, 739,
670, 658 cm–1.
1H NMR (300 MHz, acetone-d6): δ = 2.37 (s, 3 H), 2.41 (s, 3 H),
7.10 (br s, 2 H), 7.20–7.29 (m, 2 H), 7.30–7.37 (m, 2 H), 7.61–7.71
(m, 2 H), 7.73–7.83 (m, 2 H).
13C NMR (75 MHz, acetone-d6): δ = 21.4, 21.5, 127.3, 127.8, 129.8,
130.3, 140.2, 142.5, 143.0, 144.8.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C14H17N2O3S2: 325.0675;
found: 325.0691.
N-[(Substituted Amino)(4-tolyl)oxido-λ4-sulfanylidene]tosyl-
amides; General Procedure (Procedure 4)
The sulfonimidamide 1 (1.2 equiv, 2.4 mmol), Rh2[(S)-nta]4 (3; 3
mol%, 0.06 mmol), 4 Å MS (1 g), and the substrate (1 equiv, 2
mmol, introduced either as a solid or as a solution in the reaction
solvent) were placed in a carousel tube (Radleys Discovery Tech-
nologies) under argon. Cl2CHCHCl2 (7.5 mL) and MeOH (2.5 mL)
were added and the mixture was stirred until everything dissolved.
The mixture was then cooled to –78 °C, and PhI(OPiv)2 (1.4 equiv,
2.8 mmol) was added as a solid. The reaction vessels were placed in
the carousel and stirred at –35 °C for 3 d. The solvent was removed
in vacuo and the products were isolated by column chromatography
(silica gel). Diastereoisomeric ratios of the products were deter-
mined by 1H NMR spectroscopic analysis.
(2S)-2-(1,3-Dioxo-1H-benzo[de]isoquinolin-2(3H)-yl)propano-
ic Acid [(S)-nta]; Procedure 2
Lightly crushed pellets of KOH (2.8 g, 50 mmol) were added to a
solution of L-alanine (4.9 g, 55 mmol) in H2O (63 mL), and the mix-
ture was stirred at r.t. for 20 min. EtOH (188 mL) and 1,8-naphthalic
anhydride (9.9 g, 50 mmol) were added to give a cream-colored sus-
pension. The mixture was refluxed for 6.5 h, and then cooled slight-
ly to about 80 °C. 1 M aq HCl (50 mL) was added and the mixture
was stirred for 10 s and then left to stand for 16–48 h. The beige nee-
dle crystals were collected by filtration, washed sequentially with
H2O (4 × 120 mL) and ice-cold EtOH (120 mL), and dried in vacuo;
yield: 11.7 g [88%, >99% ee (HPLC)]; mp 262–264 °C; [α]D20 –25
(c 0.30, MeOH).
N-[(2,3-Dihydro-1H-inden-1-ylamino)(4-tolyl)oxido-λ4-sulfa-
nylidene]tosylamide (5a)
Prepared by the general procedure from indan (2.45 mL, 20 mmol).
The product was isolated by column chromatography [CH2Cl2 then
EtOAc–CH2Cl2 (1:20)] as a white solid; yield: 7.89 g (90%; dr
>20:1); mp 168–169 °C; [α]D22 +82.5 (c 1.00, CHCl3).
IR (ATR, neat): 3227, 1593, 1478, 1425, 1316, 1304, 1242, 1213,
1183, 1155, 1105, 1066, 1014, 989, 941, 906, 814, 752, 740, 703,
679, 656 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.76–1.60 (m, 1 H), 2.20–2.08 (m,
1 H), 2.41 (s, 3 H), 2.43 (s, 3 H), 2.74–2.64 (m, 1 H), 2.90–2.80 (m,
1 H), 4.80 (app q, J = 7.9 Hz, 1 H), 6.06 (br d, J = 8.7 Hz, 1 H), 7.37–
7.12 (m, 8 H), 7.85 (dd, J = 8.5, 8.2 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ = 21.78, 21.84, 30.2, 33.8, 58.6,
124.8, 124.9, 127.0, 127.3, 128.1, 128.7, 129.4, 130.1, 136.3, 140.6,
141.3, 142.9, 143.1, 145.0.
HPLC: IA column (250 × 4.6 mm, 5 μm), heptane–EtOH (60:40) +
0.1% HCO2H, 35 °C, 0.9 mL/min; Rt = 15.1 min.
IR (ATR, neat): 1715, 1670, 1664, 1623, 1587, 1437, 1367, 1328,
1231, 1189, 1103, 1035, 966, 891, 852, 783, 676, 657 cm–1.
1H NMR (300 MHz, DMSO-d6): δ = 1.56 (d, J = 7.0 Hz, 3 H), 5.60
(q, J = 7.0 Hz, 1 H), 7.82 (dd, J = 7.8, 7.6 Hz, 2 H), 8.40 (d, J = 7.8
Hz, 2 H), 8.45 (d, J = 7.6 Hz, 2 H), 12.73 (s, 1 H).
HRMS [ESI(+)]: m/z [M + H]+ calcd for C23H25N2O3S2: 441.1307;
found: 441.1322.
13C NMR (75 MHz, DMSO-d6): δ = 14.6, 48.5, 121.7, 127.26,
127.29, 131.1, 131.2, 134.7, 162.9, 171.5.
HRMS [ESI(–)]: m/z [M – H]– calcd for C15H10NO4: 268.0610;
N-[(2-Methoxy-2,3-dihydro-1H-inden-1-ylamino)(4-tolyl)oxi-
do-λ4-sulfanylidene]tosylamide (5b)
Prepared by the general procedure from 2-methoxyindan (296 mg).
The product was isolated by column chromatography [CH2Cl2 then
EtOAc–CH2Cl2 (1:20)] as a light-brown solid; yield: 881 mg (94%;
dr >20:1); mp 115–116 °C; [α]D26 +105.0 (c 1.00, CHCl3).
found: 268.0621.
Dirhodium Tetrakis{(2S)-2-(1,3-dioxo-1H-benzo[de]isoquino-
lin-2(3H)-yl)propanoic acid} {Rh2[(S)-nta]4}; Procedure 3
Rh2(OAc)4 (1.00 g, 2.26 mmol) and (S)-nta (2.92 g, 10.8 mmol)
were placed in a 500 mL round-bottomed flask fitted with a con-
denser and a Soxhlet extractor filled with one-third sand and two-
thirds anhyd Na2CO3 by weight (55 g total). PhCl (250 mL) was
added, ensuring that the contents of the Soxhlet extractor were thor-
oughly wetted. The mixture was then heated at 165 °C for 23 h. The
solvent was removed and the product was eluted through a short
column of alumina (200 g) with MeOH–CH2Cl2 (1:20, 500 mL) fol-
lowed by MeOH–CH2Cl2 (1:9, 100 mL). The solvent was removed
and the dark-green solid was washed with CH2Cl2 (20 mL) to re-
move any grease, then dried in vacuo at 150 °C overnight to give an
IR (ATR, neat): 3179, 1594, 1447, 1301, 1256, 1186, 1149, 1124,
1102, 1056, 991, 947, 807, 764, 747, 700, 668 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.41 (s, 3 H), 2.43 (s, 3 H), 2.65
(dd, J = 15.8, 6.4 Hz, 1 H), 3.00 (s, 3 H), 3.18 (dd, J = 15.8, 6.9 Hz,
1 H), 3.81 (app q, J = 6.4 Hz, 1 H), 4.72 (dd, J = 8.1, 5.9 Hz, 1 H),
6.50 (d, J = 8.3 Hz, 1 H), 7.17–7.10 (m, 1 H), 7.28–7.21 (m, 4 H),
7.30 (d, J = 8.4 Hz, 2 H), 7.46–7.39 (m, 1 H), 7.83 (d, J = 8.4 Hz, 2
H), 7.88 (d, J = 8.5 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 21.78, 21.82, 36.0, 57.3, 63.2, 87.7,
125.2, 125.3, 127.0, 127.8, 128.3, 129.2, 129.5, 129.7, 136.7, 138.6,
139.5, 140.6, 143.1, 144.8.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C24H27N2O4S2: 471.1412;
found: 471.1397.
HRMS [ESI(–)]: m/z [M – H]– calcd for C24H25N2O4S2: 469.1256;
found: 469.1245.
26
olive-green solid; yield: 2.55 g (88%); mp 330–331 °C; [α]D
+127.0 [c 0.10, MeOH–CHCl3 (1:9)].
IR (ATR, neat): 2937, 1702, 1660, 1587, 1411, 1377, 1339, 1295,
1239, 1193, 1097, 1034, 969, 889, 845, 777, 683 cm–1.
1H NMR (300 MHz, CDCl3 + 1 drop CD3OD): δ = 1.71 (d, J = 6.9
Hz, 12 H), 5.89 (q, J = 6.9 Hz, 4 H), 7.73 (dd, J = 8.2, 7.3 Hz, 8 H),
8.12 (d, J = 8.2 Hz, 8 H), 8.60 (d, J = 7.3 Hz, 8 H).
13C NMR (75 MHz, CDCl3 + 1 drop CD3OD): δ = 15.2, 50.7, 122.6,
127.0, 128.1, 131.48, 131.53, 133.9, 163.5, 188.5.
N-[(2-Bromo-2,3-dihydro-1H-inden-1-ylamino)(4-tolyl)oxido-
λ4-sulfanylidene]tosylamide (5c)
Prepared by the general procedure from 2-bromoindan (353 mg, 1.8
mmol). The product was isolated by column chromatography
[CH2Cl2 then EtOAc–CH2Cl2 (1:20)] as an off-white solid; yield:
730 mg, (70%; dr >20:1); mp 152–154 °C (dec.); [α]D26 +157.4 (c
0.98, CHCl3).
HRMS [ESI(–)]: m/z [M + HCO2]– calcd for C61H41N4O18Rh2:
1323.0531; found: 1323.0549.
Anal. Calcd for C60H40N4O16Rh2·CH2Cl2: C, 53.72; H, 3.10; N,
4.11. Found: C, 53.80; H, 3.43; N, 4.16.
IR (ATR, neat): 3228, 1598, 1439, 1426, 1324, 1254, 1156, 1126,
1094, 1061, 1017, 939, 878, 805, 756, 741, 699, 657 cm–1.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2079–2087

2084
B. Darses et al.
PRACTICAL SYNTHETIC PROCEDURES
1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H), 2.44 (s, 3 H), 3.10
(dd, J = 16.5, 7.0 Hz, 1 H), 3.48 (dd, J = 16.5, 7.3 Hz, 1 H), 4.12
(app q, J = 6.8 Hz, 1 H), 4.93 (dd, J = 8.5, 6.2 Hz, 1 H), 6.66 (d, J =
8.5 Hz, 1 H), 7.20–7.13 (m, 1 H), 7.28–7.23 (m, 4 H), 7.31 (d, J =
8.4 Hz, 2 H), 7.54–7.42 (m, 1 H), 7.82 (d, J = 8.3 Hz, 2 H), 7.91 (d,
J = 8.4 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 21.8, 21.9, 41.4, 50.7, 67.2, 124.6,
125.4, 127.0, 128.3, 128.6, 129.5 (2 C), 130.0, 136.0, 139.1, 140.1,
140.5, 143.3, 145.4.
J = 8.5 Hz, 2 H), 7.06–6.97 (m, 4 H), 7.19–7.09 (m, 4 H), 7.30 (d,
J = 8.2 Hz, 2 H), 7.45 (d, J = 8.3 Hz, 2 H), 7.67 (d, J = 8.3 Hz, 2 H),
7.74 (d, J = 6.9 Hz, 2 H).* * Independent peaks for the minor regio-
isomer.
13C NMR (75 MHz, CDCl3): δ = 21.6, 21.7, 43.7, 55.5, 59.6, 114.2,
124.4 (q, J = 271 Hz), 125.4 (q, J = 4 Hz), 126.9, 127.7, 128.2, 129.0
(q, J = 33 Hz), 129.4, 129.6, 129.8, 132.6, 135.7, 140.4, 141.2,
143.0, 144.6, 159.4.
HRMS [ESI(–)]: m/z [M – H]– calcd for C30H28F3N2O4S2: 601.1443;
found: 601.1451.
HRMS [ESI(–)]: m/z [M – H]– calcd for C23H22BrN2O3S2: 517.0255
(100), 519.0235 (97); found: 517.0276 (90), 519.0260 (100).
N-[(10,11-Dihydro-5H-dibenzo[a,d][7]annulen-10-ylamino)(4-
tolyl)oxido-λ4-sulfanylidene]tosylamide (5g)
N-[(2-Azido-2,3-dihydro-1H-inden-1-ylamino)(4-tolyl)oxido-
λ4-sulfanylidene]tosylamide (5d)
Prepared by the general procedure from 2-azidoindan (318 mg).
The product was obtained by column chromatography [heptane–
EtOAc (70:30)] as a white foamy solid; yield: 932 mg (97%, dr
>20:1); mp 140–142 °C; [α]D26 + 91.5 (c 1.00, CHCl3).
Prepared by the general procedure from 10,11-dihydro-5H-diben-
zo[a,d][7]annulene (389 mg). The product was obtained by column
chromatography [heptane–EtOAc (70:30)] as an off-white foamy
solid; yield: 1.02 g (99%, dr >20:1); mp 71–73 °C; [α]D26 + 33.9 (c
1.00, CHCl3).
IR (ATR, neat): 3213, 3028, 2922, 2102, 1596, 1444, 1257, 1148,
1104, 1050, 812, 748 cm–1.
IR (ATR, neat): 3227, 3024, 2925, 1596, 1493, 1446, 1302, 1259,
1151, 1107, 1089, 1026, 814, 752 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.42 (s, 3 H), 2.44 (s, 3 H), 2.76
(dd, J = 15.8, 7.6 Hz, 1 H), 3.23 (dd, J = 15.8, 7.5 Hz, 1 H), 3.84–
3.96 (m, 1 H), 4.58–4.68 (m, 1 H), 6.70 (d, J = 9.0 Hz, 1 H), 7.12–
7.19 (m, 1 H), 7.21–7.37 (m, 6 H), 7.44–7.51 (m, 1 H), 7.78–7.86
(m, 2 H), 7.88–7.96 (m, 2 H).
1H NMR (300 MHz, CDCl3): δ = 2.38 (s, 3 H), 2.47 (s, 3 H), 2.72
(dd, J = 14.4, 7.5, Hz, 1 H), 3.14 (dd, J = 14.4, 3.5 Hz, 1 H), 3.86 (d,
J = 15.4 Hz, 1 H), 4.14 (d, J = 15.5 Hz, 1 H), 4.94–5.03 (m, 1 H),
5.63 (d, J = 8.9 Hz, 1 H), 6.67–6.73 (m, 1 H), 7.06–7.23 (m, 8 H),
7.33–7.47 (m, 3 H), 7.70–7.78 (m, 2 H), 7.86–7.94 (m, 2 H).
13C NMR (75 MHz, CDCl3): δ = 21.8, 21.9, 36.1, 63.4, 68.0, 124.9,
125.3, 127.0, 128.23, 128.25, 129.45, 129.50, 130.0, 136.0, 138.4,
138.7, 140.4, 143.3, 145.4.
13C NMR (75 MHz, CDCl3): δ = 21.8, 21.9, 37.7, 41.2, 54.4, 126.9,
127.1, 127.4, 127.5, 128.0, 128.2, 128.6, 129.4, 130.0, 130.2 (2 C),
132.3, 134.6, 136.4, 137.3, 137.7, 140.6, 140.7, 143.0, 145.1.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C23H24N5O3S2: 481.1315;
found: 481.1316.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C29H29N2O3S2: 517.1614;
found: 517.1636.
N-[{[1-(4-Methoxyphenyl)-2-phenylethyl]amino}(4-tolyl)oxido-
λ4-sulfanylidene]tosylamide (5e)
Prepared by the general procedure from 1-methoxy-4-(2-phenyl-
ethyl)benzene (425 mg). The product was obtained by column chro-
matography [heptane–EtOAc (80:20 to 70:30)] as a white foamy
solid; yield: 1.03 g (96%, dr >20:1, 6.5:1 regioisomeric ratio).
N-[[(1-Acetyl-1,2,3,4-tetrahydroquinolin-4-yl)amino](4-tol-
yl)oxido-λ4-sulfanylidene]tosylamide (5h)
Prepared by the general procedure from 1-acetyl-1,2,3,4-tetrahy-
droquinoline (351 mg). The product was obtained by a modified
work-up procedure to remove residual Rh. After removal of the sol-
vent, the residue was dissolved in CH2Cl2 (25 mL) and stirred with
sat. aq thiourea (15 mL) for 1 h. The organic layer washed with
phosphate buffer (pH 7, 0.1 M aq Na2HPO4·KH2PO4, 15 mL), and
the resulting aqueous layer was extracted with CH2Cl2 (3 × 25 mL).
The organic layers were combined, washed with phosphate buffer
(pH 7, 100 mL), dried (MgSO4), filtered, and concentrated. The
crude product was purified by column chromatography [silica gel,
EtOAc–CH2Cl2 (1:9 to 3:9)] to give an off-white solid; yield: 691
IR (ATR, neat): 3235, 3025, 2925, 1612, 1514, 1301, 1247, 1149,
1106, 1090, 1033, 811, 747 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.35 (s, 3 H), 2.36 (s, 3 H), 2.87–
2.96 (m, 2 H), 3.77 (s, 3 H),* 3.78 (s, 3 H), 4.34–4.44 (m, 1 H), 6.37
(d, J = 7.1 Hz, 1 H), 6.41 (d, J = 7.4 Hz, 1 H),* 6.60–6.68 (m, 2 H),*
6.73–6.82 (m, 2 H), 6.83–6.93 (m, 2 H), 7.01–7.22 (m, 9 H), 7.41–
7.49 (m, 2 H), 7.64–7.73 (m, 2 H). * Independent peaks for the mi-
nor regioisomer.
26
mg (70%; dr >1:20);17 mp 173–174 °C; [α]D +110.2 (c 1.00,
CHCl3).
13C NMR (75 MHz, CDCl3): δ = 21.7 (2 C), 43.2,* 44.1, 55.36,
55.44, 59.4, 60.1,* 113.98, 114.04,* 126.89, 126.92, 127.8, 128.2,
128.6,* 128.7, 129.3, 129.5, 129.6,* 129.7, 130.4,* 132.7, 135.5,
136.6, 140.4, 142.9, 144.4, 159.2. * Independent peaks for the mi-
nor regioisomer.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C29H31N2O4S2: 535.1720;
found: 535.1723.
IR (ATR, neat): 3167, 1626, 1580, 1493, 1401, 1304, 1254, 1207,
1153, 1108, 1075, 1042, 1017, 966, 929, 886, 812, 798, 764, 750,
701, 659 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.90–1.72 (m, 2 H), 2.19 (s, 3 H),
2.41 (s, 3 H), 2.44 (s, 3 H), 3.66–3.48 (m, 1 H), 3.83–3.66 (m, 1 H),
4.55–4.43 (m, 1 H), 6.42 (br s, 1 H), 7.41–7.07 (m, 7 H), 7.52 (d, J =
7.1 Hz, 1 H), 7.96–7.67 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 21.7, 21.8, 23.4, 30.9, 40.8, 50.3,
124.6, 125.8, 126.9, 127.8, 128.2, 128.3, 129.4, 130.1, 136.6, 138.4,
140.6, 143.1, 145.0, 170.4; 1 C not observed.
HRMS [ESI(–)]: m/z [M – H]– calcd for C25H26N3O4S2: 496.1365;
found: 496.1368.
N-[({1-(4-Methoxyphenyl)-2-[4-(trifluoromethyl)phenyl]eth-
yl}amino)(4-tolyl)oxido-λ4-sulfanylidene]tosylamide (5f)
Prepared by the general procedure from 1-methoxy-4-{2-[4-(tri-
fluoromethyl)phenyl]ethyl}benzene (210 mg, 0.75 mmol). The
product was obtained by column chromatography [EtOAc–heptane
(2:8 then 3:7)] as a white solid; yield: 436 mg (96%, dr >20:1, 9:1
regioisomeric ratio); mp 67–68 °C; [α]D26 + 108.5 (c 1.00, CHCl3)
N-[[(3-Methylcyclohex-2-en-1-yl)amino](4-tolyl)oxido-λ4-sulfa-
nylidene]tosylamide (5i)
Prepared by the general procedure from 1-methylcyclohexene (0.24
mL). The product was isolated by column chromatography [CH2Cl2
then EtOAc–CH2Cl2 (2:98 to 1:20)] as an off-white solid; yield: 780
mg (97%; dr 14:1); mp 145–148 °C; [α]D26 +113.0 (c 1.00, CHCl3).
IR (ATR, neat): 3213, 2934, 1612, 1514, 1419, 1323, 1301, 1247,
1149, 1106, 1066, 1038, 1016, 810, 760, 702, 669 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.35 (s, 6 H), 3.09–2.87 (m, 2 H),
3.76 (s, 3 H),* 3.79 (s, 3 H), 4.49–4.35 (m, 1 H), 6.47 (d, J = 7.2 Hz,
1 H),* 6.66 (d, J = 8.0 Hz, 2 H),* 6.71 (d, J = 8.0 Hz, 1 H), 6.79 (d,
Synthesis 2013, 45, 2079–2087
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Catalytic C–H Amination
2085
IR (ATR, neat): 3251, 2946, 1597, 1445, 1421, 1377, 1316, 1303,
1286, 1240, 1156, 1103, 1085, 1071, 1043, 1017, 998, 924, 905,
847, 819, 811, 735, 703, 679, 655 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.61–1.28 (m, 4 H), 1.67 (s, 3 H),
1.95–1.78 (m, 2 H), 2.41 (s, 3 H), 2.43 (s, 3 H), 3.70 (s, 1 H),* 3.82
(br s, 1 H), 5.05–4.99 (m, 1 H),* 5.38–5.33 (m, 1 H), 5.84 (d, J = 8.2
Hz, 1 H), 7.33–7.18 (m, 4 H), 7.88–7.76 (m, 4 H). * Independent
peaks for the minor diastereomer.
13C NMR (75 MHz, CDCl3): δ = 19.6, 21.7, 21.8, 23.8, 29.1, 29.6,
49.8, 121.4, 126.9, 128.0, 129.3, 129.9, 136.7, 140.1, 140.7, 142.9,
144.7.
HRMS [ESI(–)]: m/z [M – H]– calcd for C21H25O3N2S2: 417.1307;
found: 417.1331.
(dd, J = 13.4, 7.1 Hz, 1 H), 2.39 (s, 3 H), 2.42 (s, 3 H), 4.13–4.24
(m, 1 H), 4.67–481 (m, 2 H), 4.82–4.89 (m, 1 H), 5.36 (td, J = 7.0,
1.1 Hz, 1 H), 5.67 (d, J = 5.3 Hz, 1 H), 7.21–7.31 (m, 4 H), 7.75–
7.86 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 16.7, 18.4, 21.75, 21.78, 25.7,
46.1, 51.2, 65.7, 120.6, 123.86, 123.90, 126.9, 128.0, 129.4, 129.7,
136.6, 136.7, 140.5, 140.7, 143.0, 144.8, 162.1.
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C26H31Cl3N2NaO5S2:
643.0638; found: 643.0618.
N-[[(3,5-Dimethyl-1-adamantyl)amino](4-tolyl)oxido-λ4-sulfa-
nylidene]tosylamide (7a)
Prepared by the general procedure from 1,3-dimethyladamantane
(371 μL). The product was isolated by column chromatography
(CH2Cl2) as a white solid; yield: 864 mg (94%); mp 124–126 °C;
[α]D20 +14.7 (c 1.00, acetone).
N-{(4-Tolyl)(oxido)[(4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-
yl)amino]-λ4-sulfanylidene}tosylamide (5j)
Prepared by the general procedure from (S)-α-pinene (319 μL). The
product was isolated by chromatography [CH2Cl2–EtOAc (100:0 to
98:2)] as a white foamy solid; yield: 812 mg (89%, dr 13:1); mp 55–
57 °C; [α]D20 –69.5 (c 1.00, acetone).
IR (ATR, neat): 3278, 2902, 1650, 1454, 1317, 1233, 1152, 1107,
1090, 1019, 815, 655 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.767 (s, 3 H), 0.772 (s, 3 H), 1.06
(s, 2 H), 1.15–1.55 (m, 9 H), 1.67 (td, J = 11.7, 2.5 Hz, 1 H), 2.05
(quint, J = 3.1 Hz, 1 H), 2.40 (s, 3 H), 2.42 (s, 3 H), 6.09 (s, 1 H),
7.21–7.30 (m, 4 H), 7.74–7.85 (m, 4 H).
IR (ATR, neat): 3236, 2920, 1596, 1420, 1300, 1245, 1150, 1104,
1088, 1016, 1000, 811 cm–1.
1H NMR (300 MHz, CDCl3): δ = 0.76 (s, 3 H), 1.23–1.28 (m, 1 H),
1.28 (s, 3 H), 1.63 (s, 3 H), 1.95–2.02 (m, 1 H), 2.16–2.25 (m, 1 H),
2.32 (td, J = 9.5, 5.5 Hz, 1 H), 2.38 (s, 3 H), 2.42 (s, 3 H), 3.74–3.84
(m, 1 H), 4.80–4.85 (m, 1 H), 6.03 (d, J = 9.01 Hz, 1 H), 7.17–7.32
(m, 4 H), 7.73–7.85 (m, 4 H).
13C NMR (CDCl3, 75 MHz): δ = 20.5, 21.6, 21.7, 22.8, 26.4, 28.7,
44.5, 46.6, 47.1, 54.2, 115.0, 126.9, 127.8, 129.2, 129.9, 136.5,
140.6, 142.8, 144.6, 150.5.
13C NMR (75 MHz, CDCl3): δ = 21.77, 21.79, 30.0 (2 C), 30.3,
32.88, 32.94, 41.3, 42.2, 42.3, 49.2, 49.3, 50.2, 59.2, 127.0, 127.8,
129.4, 129.7, 139.3, 140.6, 143.0, 144.4.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C26H35N2O3S2: 487.2089;
found: 487.2089.
N-[[(3-Bromo-1-adamantyl)amino](4-tolyl)oxido-λ4-sulfanyli-
dene]tosylamide (7b)
Prepared by the general procedure from 1-bromoadamantane (430
mg). The product was obtained by column chromatography [hep-
tane–EtOAc (80:20 to 70:30)] as an off-white foam; yield: 820 mg
(76%); mp 68–71 °C; [α]D26 +70.4 (c 1.00, CHCl3).
HRMS [ESI(+)]: m/z [M + Na]+ calcd for C24H30N2NaO3S2:
481.1596; found: 481.1588.
N-[[(1,3-Dimethylbut-2-en-1-yl)amino](4-tolyl)oxido-λ4-sulfa-
nylidene]tosylamide (5k)
Prepared by the general procedure from 2-methylpent-2-ene (0.244
mL). The product was isolated by column chromatography [CH2Cl2
then EtOAc–CH2Cl2 (2:98 to 1:20)] as an off-white oil; yield: 774
mg (95%; dr 12:1); [α]D26 +23.5 (c 0.97, CHCl3).
IR (ATR, neat): 3224, 2916, 2860, 1596, 1452, 1300, 1285, 1148,
1102, 1056, 973, 812, 749 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.45–1.64 (m, 2 H), 1.66–1.77 (m,
2 H), 1.79–1.89 (m, 2 H), 2.07–2.24 (m, 6 H), 2.34–2.47 (m, 8 H),
6.33 (s, 1 H), 7.21–7.32 (m, 4 H), 7.74–7.86 (m, 4 H).
IR (ATR, neat): 3239, 2930, 1735, 1596, 1495, 1448, 1375, 1302,
1250, 1149, 1106, 1088, 1059, 1016, 980, 916, 811, 752, 702, 668
cm–1.
13C NMR (75 MHz, CDCl3): δ = 21.7 (2 C), 32.4 (2 C), 33.9, 40.7,
41.1, 47.36, 47.43, 53.9, 59.1, 62.0, 127.0, 127.7, 129.3, 129.8,
138.9, 140.4, 143.0, 144.5.
1H NMR (300 MHz, CDCl3): δ = 1.02 (d, J = 6.6 Hz, 3 H), 1.55 (d,
J = 1.1 Hz, 3 H), 1.59 (d, J = 1.2 Hz, 3 H), 2.39 (s, 3 H), 2.41 (s, 3
H), 4.25–4.05 (m, 1 H), 4.72–4.63 (m, 1 H),* 5.00–4.88 (m, 1 H),
5.76 (d, J = 5.6 Hz, 1 H), 5.98–5.91 (m, 1 H),* 7.23 (d, J = 7.9 Hz,
2 H), 7.26 (d, J = 7.9 Hz, 2 H), 7.87–7.70 (m, 4 H). * Independent
peaks for the minor diastereomer.
13C NMR (75 MHz, CDCl3): δ = 18.3, 21.7, 21.8, 22.1, 25.7, 48.9,
125.6, 127.0, 128.0, 129.4, 129.8, 135.7, 136.9, 140.7, 142.9, 144.7.
HRMS [ESI(–)]: m/z [M – H]– calcd for C20H25N2O3S2: 405.1307;
found: 405.1299.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C24H30BrN2O3S2: 537.0876
(100), 539.0856 (97); found: 537.0880 (90), 539.0872 (100).
(3-{[S-(4-Tolyl)-N-(tosyl)sulfonimidoyl]amino}-1-adaman-
tyl)acetic Acid (7c)
Prepared by the general procedure from 1-adamantanylacetic acid
(389 mg). The product was isolated by using a modified workup.
Purification by column chromatography [silica gel EtOAc–CH2Cl2
(1:9) + 1% HCO2H] gave an off-white solid; 917 mg (89%; 84%
corrected for contamination with the sulfonimidamide). An analyt-
ical sample was obtained by crystallization (i-PrOH–PE); mp 139–
141 °C; [α]D26 +55.9 (c 1.00, CHCl3).
(2E)-3,7-Dimethyl-5-{[S-(4-tolyl)-N-tosylsulfonimidoyl}ami-
no]octa-2,6-dien-1-yl Trichloroacetate (5l)
IR (ATR, neat): 3239, 2909, 2850, 1701, 1598, 1450, 1284, 1237,
1149, 1103, 1083, 1052, 976, 815, 761, 744, 700, 668, 654 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.52 (br m, 6 H), 1.65–1.56 (m, 1
H), 1.88–1.68 (m, 5 H), 2.14–1.99 (m, 4 H), 2.40 (s, 3 H), 2.41 (s, 3
H), 6.38 (s, 1 H), 7.25 (app d, J = 8.5 Hz, 4 H), 7.79 (app t, J = 7.8
Hz, 4 H); the acid proton was not observed.
Prepared by the general procedure from geranyl trichloroacetate
(599 mg). The product was isolated by column chromatography
[heptane–EtOAc (80:20 to 60:40)] as a white crystalline solid;
yield: 1.09 g (88%, dr >20:1); mp 103–106 °C; [α]D20 –18.5 (c 1.00,
acetone).
IR (ATR, neat): 3166, 2974, 2918, 1764, 1597, 1444, 1419, 1378,
1304, 1285, 1221, 1157, 1102, 1065, 1050, 1019, 951, 883, 810,
747, 679 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.53 (d, J = 1.1 Hz, 3 H), 1.56 (d,
J = 1.1 Hz, 3 H), 1.58 (s, 3 H), 2.06 (dd, J = 13.5, 7.1 Hz, 1 H), 2.19
13C NMR (75 MHz, CDCl3): δ = 21.77, 21.79, 29.66, 29.69, 34.9,
35.0, 40.6, 40.8, 42.0, 42.1, 47.4, 47.7, 58.1, 127.0, 127.8, 129.4,
129.8, 139.2, 140.5, 143.0, 144.5, 179.4.
HRMS [ESI(–)]: m/z [M – H]– calcd for C26H31N2O5S2: 515.1674;
found: 515.1678.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2079–2087

2086
B. Darses et al.
PRACTICAL SYNTHETIC PROCEDURES
HRMS [ESI(+)]: m/z [M + NH4]+ calcd for C26H36N3O5S2:
534.2096; found: 534.2102.
to yellow. 1 M aq HCl (23 mL) was then added dropwise at –78 °C
and the mixture was stirred for a further 45 min at r.t. Sat. aq
NaHCO3 solution (100 mL) was added and the mixture was extract-
ed with EtOAc (3 × 100 mL). The organic extracts were combined,
dried (Na2SO4), filtered, and concentrated in vacuo. Automatic col-
umn chromatography [silica gel (120 g, dry loading), heptane then
EtOAc–heptane (1:9)] gave a white solid; yield: 0.74 g (70%); mp
82–83 °C; [α]D26 +40.4 (c 1.00, CHCl3).
N-[(4-Tolyl)(oxido)(5′H-spiro[1,3-dioxolane-2,2′-tricy-
clo[3.3.1.13,7]decan]-5′-ylamino)-λ4-sulfanylidene]tosylamide
(7d)
Prepared by the general procedure from spiro[2,2′-adamantane-1,3-
dioxolane] (388 mg). The product was isolated by column chroma-
tography [CH2Cl2 then EtOAc–CH2Cl2 (1:20)] as a white solid;
yield 557 mg (54%) + 116 mg of recovered starting material (30%);
mp 74–75 °C; [α]D26 +72.9 (c 0.91, CHCl3).
IR (ATR, neat): 3379, 2969, 2931, 1684, 1506, 1484, 1459, 1387,
1360, 1319, 1275, 1237, 1161, 1053, 1028, 942, 895, 870, 837, 780,
766, 753 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.50 (s, 9 H), 1.79 (dddd, J = 12.8,
8.6, 8.3, 8.1 Hz, 1 H), 2.58 (dddd, J = 12.8, 8.2, 8.1, 4.1 Hz, 1 H),
3.04–2.75 (m, 2 H), 4.83–4.40 (br m, 1 H), 5.20 (td, J = 7.4, 7.4 Hz,
1 H), 7.26–7.17 (m, 3 H), 7.37–7.28 (m, 1 H).
IR (ATR, neat): 3229, 2910, 1567, 1447, 1386, 1300, 1286, 1247,
1148, 1089, 1054, 1015, 984, 927, 875, 812, 755, 721, 702, 656
cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.55–1.42 (m, 2 H), 1.89–1.65 (m,
8 H), 2.04–1.90 (m, 2 H), 2.17–2.09 (m, 1 H), 2.41 (s, 3 H), 2.42 (s,
3 H), 3.89 (s, 4 H), 6.15 (s, 1 H), 7.33–7.18 (m, 4 H), 7.79 (d, J =
8.4 Hz, 2 H), 7.82 (d, J = 8.3 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 28.7, 30.3, 34.6, 56.2, 79.6, 124.2,
124.9, 126.9, 128.0, 143.4, 143.8, 155.9.
HRMS [ESI(+)]: m/z [2M + H]+ calcd for C28H39N2O4: 467.2910;
found: 467.2902.
13C NMR (75 MHz, CDCl3): δ = 21.57, 21.58, 28.0, 33.0 (2 C), 37.3,
37.4, 39.8, 40.3, 42.2, 56.5, 64.3, 64.4, 109.4, 126.8, 127.7, 129.2,
129.6, 138.9, 140.4, 142.8, 144.3.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C26H33N2O5S2: 517.1831;
found: 517.1829.
HRMS [ESI(–)]: m/z [M – H]– calcd for C26H31N2O5S2: 515.1674;
found: 515.1678.
N-[(1R)-2,3-Dihydro-1H-inden-1-yl]acetamide (10a); Proce-
dure 6
A flame-dried round-bottomed flask was charged with Na (345 mg,
15 mmol) and naphthalene (961 mg, 7.5 mmol) under argon. De-
gassed anhyd THF (10 mL) was added and the mixture was stirred
at r.t. for 4 h to give a dark-green solution. A solution of substrate
5a (1.10 g, 2.5 mmol) in degassed anhyd THF (15 mL) was added
dropwise, and the color changed from dark-green to dark-brown.
The mixture was stirred for 2 h at r.t. then cooled to 0 °C. H2O (2–
3 drops) was added to give a white suspension, followed by 10 M
aq NaOH (12.5 mL) and AcCl (0.54 mL, 7.5 mmol). The mixture
was allowed to warm to r.t. and after 18 h it was filtered through
Celite. Sat. aq NaCl (10 mL) was added, and the aqueous layer was
extracted with EtOAc (3 × 25 mL). The organic layers were com-
bined, dried (MgSO4), filtered, and concentrated. Automatic col-
umn chromatography [silica gel (120 g, wet loaded with CH2Cl2)
gradient EtOAc–heptane (4:6 to 6:4)] gave a white solid; yield: 324
mg (74%); mp 153–154 °C; [α]D26 +73.3 (c 1.00, CHCl3).
tert-Butyl 2,3-Dihydro-1H-inden-1-yl[S-(4-tolyl)-N-(tosyl)sul-
fonimidoyl]carbamate (8a); Procedure 5 (Part 1)
Anhyd N2-purged CH2Cl2 (100 mL) and Boc2O (6.55 g, 30 mmol)
were added sequentially to a round-bottomed flask containing the
substrate 5a (4.41 g, 10 mmol) and DMAP (0.61 g, 5 mmol) under
argon, and the mixture was stirred for 18 h at r.t. The solvent was
removed in vacuo and the crude product was purified by column
chromatography [silica gel, CH2Cl2 then EtOAc–CH2Cl2 (2:98)] to
give a white solid; yield: 5.23 g (97%); mp 61–63 °C; [α]D26 +101.2
(c 1.00, CHCl3).
IR (ATR, neat): 2980, 1730, 1596, 1460, 1369, 1323, 1247, 1151,
1106, 1078, 1016, 870, 812, 750, 700, 674, 655 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.08 (s, 9 H), 2.39 (s, 3 H), 2.44
(s, 3 H), 2.78–2.63 (m, 1 H), 3.00–2.85 (m, 1 H), 3.08 (ddd, J = 15.8,
10.3, 3.0 Hz, 1 H), 6.21 (dd, J = 9.0, 7.9 Hz, 1 H), 7.39–7.05 [m with
two underlying d; 7.31 (d, J = 8.2 Hz) and 7.26 (d, J = 8.2 Hz), 8 H],
7.92 (d, J = 8.3 Hz, 4 H).
13C NMR (75 MHz, CDCl3): δ = 21.8, 21.9, 27.6, 30.5, 31.0, 64.6,
84.9, 123.9, 124.9, 126.8, 126.96, 127.01, 127.8, 128.3, 129.7,
136.7, 141.1, 141.5, 142.3, 143.1, 145.2, 149.9.
IR (ATR, neat): 3283, 2961, 2930, 1631, 1545, 1480, 1458, 1436,
1370, 1289, 1211, 1151, 1123, 1052, 1039, 1023, 993, 929, 770,
749, 730, 717 cm–1.
1H NMR (300 MHz, CDCl3): δ = 1.80 (dddd, J = 12.9, 8.8, 8.0, 7.1
Hz, 1 H), 2.02 (s, 3 H), 2.58 (dtd, J = 12.9, 7.8, 4.3 Hz, 1 H), 3.05–
2.75 (m, 2 H), 5.46 (dt, J = 8.4, 7.4 Hz, 1 H), 5.78 (br s, 1 H), 7.36–
7.12 (m, 4 H).
13C NMR (75 MHz, CDCl3): δ = 23.6, 30.4, 34.3, 55.0, 124.2, 125.0,
HRMS [ESI(+)]: m/z [M + K]+ calcd for C28H32KN2O5S2: 579.1390;
found: 579.1390.
127.0, 128.2, 143.4, 143.6, 170.0.
HRMS [ESI(+)]: m/z [M + H]+ calcd for C11H14NO: 176.1075;
found: 176.1075.
tert-Butyl (1R)-2,3-Dihydro-1H-inden-1-ylcarbamate (9a); Pro-
cedure 5 (Part 2)
Method A. Mg (1.12 mg, 46.2 mmol) and I2 (243 mg, 20 mol%, 0.92
mmol) were added to a solution of carbamate 8a (2.50 g, 4.62
mmol) in MeOH (46 mL), and the resulting suspension was sonicat-
ed. After 1 h, the mixture was filtered through Celite (~24 g), which
was washed with MeOH (100 mL). Silica gel (20 g) was immedi-
ately added to the mixture for dry loading onto a column. Automatic
column chromatography [silica gel (160 g), EtOAc–heptane (1:9)]
gave a white solid; yield: 1.01 g (93%).
Acknowledgment
We would like to thank the Institut de Chimie des Substances Natu-
relles and ANR-08-BLAN-0013-01 for financial support and fel-
lowships (B.D. and A.J.). Support and sponsorship provided by
SANOFI, LabEx CHARM3AT, and COST Action D40 ‘Innovative
Catalysis: New Processes and Selectivities’ are gratefully acknow-
ledged.
Method B. A 0.5 M solution of KPPh2 in THF (13.9 mL, 6.93 mmol)
was added to a solution of carbamate 8a (2.50 g, 4.62 mmol) in de-
gassed anhyd THF (46 mL) at –78 °C under argon. While the mix-
ture was stirred for 2.5 h at –78 °C, its color changed from orange
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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Synthesis 2013, 45, 2079–2087
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
References
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© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2079–2087