Intermolecular C-H amination of complex molecules: Insights into the factors governing the selectivity

Article abstract of DOI:10.1021/jo301563j

Transition-metal-catalyzed C-H amination via nitrene insertion allows the direct transformation of a C-H into a C-N bond. Given the ubiquity of C-H bonds in organic compounds, such a process raises the problem of regio- and chemoselectivity, a challenging

Full text of DOI:10.1021/jo301563j

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Intermolecular C-H amination of complex molecules:
insights into the factors governing the selectivity
Camille Lescot, Benjamin Darses, Florence Collet, Pascal Retailleau, and Philippe Dauban
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo301563j • Publication Date (Web): 15 Aug 2012
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The Journal of Organic Chemistry
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Intermolecular C-H amination of complex molecules:
insights into the factors governing the selectivity
Camille Lescot, Benjamin Darses, Florence Collet, Pascal Retailleau, and Philippe Dauban*
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, UPR 2301 CNRS
Avenue de la Terrasse, F-91198 Gif-sur-Yvette, France
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RECEIVED DATE
Corresponding Author
E-mail: Philippe.dauban@icsn.cnrs-gif.fr
N
O
O
O
MeO
N
O
O
OMe
89%
d.r. > 20:1
92%
d.r. > 20:1
88%
d.r. 2:1
N
CCl3
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Abstract. Transition metal-catalyzed C-H amination via nitrene insertion allows the direct
transformation of a C-H into a C-N bond. Given the ubiquity of C-H bonds in organic compounds, such
a process raises the problem of regio- and chemoselectivity, a challenging goal even more difficult to
tackle as the complexity of the substrate increases. Whereas excellent regiocontrol can be achieved by
the use of an appropriate tether securing intramolecular addition of the nitrene, the intermolecular C-H
amination remains much less predictable. This study aims at addressing this issue by capitalizing on an
efficient stereoselective nitrene transfer involving the combination of a chiral aminating agent 1 with a
chiral rhodium catalyst 2. Allylic C-H amination of terpenes and enol ethers occurs with excellent yields
as well as with high regio-, chemo-, and diastereoselectivity as a result of the combination of steric and
electronic factors. Conjugation of allylic C-H bonds with the π-bond would explain the chemoselectivity
observed for cyclic substrates. Alkanes used in stoichiometric amounts are also efficiently
functionalized with a net preference for tertiary equatorial C-H bonds. The selectivity, in this case, can
be rationalized by steric and hyperconjugative effects. This study, therefore, provides useful information
to better predict the site of C-H amination of complex molecules.
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Introduction
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The last decade has witnessed considerable interest in the area of catalytic C-H functionalization, a
new class of reactions which provides unprecedented bond disconnections.1 Recent examples of natural
product syntheses perfectly showcase the unique opportunities offered by these transformations.2 In
addition, site-selective C-H functionalization affords the possibility to tailor “a façon” drugs or
materials with the aim of modifying their properties or tackle the issue of diversity-oriented synthesis.3,4
Application of this strategy to incorporate a nitrogen group into a molecule is thus of fundamental
importance.
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Catalytic C-H amination has been extensively investigated in the last decade as shown by the growing
number of reviews devoted to the field.5 The direct introduction of a nitrogen functionality can be
efficiently achieved by catalytic C-H activation6,7 or, more frequently, by C-H insertion of a
metallanitrene that has led to great achievements in synthesis.5 The efficiency and scope of the latter
process have recently been improved by the design of several transition metal complexes,8-12 among
which dirhodium(II) catalysts hold a prominent position,13 or sustainable metal-free conditions.14
However, although catalytic C-H amination is a method of choice to prepare amines, an efficient
chemoselective intermolecular process remains to be developed. Whereas catalytic intramolecular
nitrene C-H insertion occurs with very good levels of regio-, chemo- and stereocontrol, the
intermolecular reaction, by comparison, appears less predictable. The selective amination of a specific
C-H bond in compounds displaying several functional groups, especially alkenes, remains a challenge to
tackle.1d,15
Notwithstanding foreseeable difficulties, it was decided to capitalize on our previous studies with
sulfonimidamides16,17 to address the issue of chemoselectivity in intermolecular C-H amination. The
purpose was to gain helpful information to better predict the site of functionalization of complex
molecules. This was inspired by the observation that, contrary to C-H hydroxylation mediated by
oxidases,18 a chemoselective intermolecular C-H amination is not known in nature. Whereas a lot of
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studies have focused on the search for new efficient catalysts to perform nitrene transfers, we have
recently documented the conception of new types of reagents for a more practical synthetic nitrene
chemistry. This led us to report the use of sulfonimidamides together with chiral rhodium(II) complexes
in the presence of the soluble iodine oxidant PhI(OCOt-Bu)2, in stereoselective intermolecular C-H
amination of various simple hydrocarbons.16 The excellent results obtained by combining the amide 1
with the chiral catalyst Rh2(S-nta)4 2 (Figure 1), then persuaded us to explore the chemoselective
functionalization of more complex molecules with the aim to better predict the selectivity of
intermolecular C-H amination. We therefore wish to describe in this article the site-selective catalytic C-
H amination of substrates of increasing complexity that relies on the influence of several factors.
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O
O
H
S
NH2
N
N
O
Me
O
O
S
O
O
Rh Rh
Rh2(S-nta)4: 2
S*NH2: 1
Figure 1. Sulfonimidamide 1 and the rhodium catalyst Rh2(S-nta)4 2.
Results and Discussion
C-H Amination of terpenes: Attention was first paid to terpenes with initial experiments carried out
on both enantiomers of α-pinene.19 Catalytic C-H amination of substrates used as the limiting reagents
proved highly efficient since the expected C-H aminated products 3a and 3b were isolated in 91% and
71% yields, respectively (Table 1, entries 1 and 2). A single compound is formed in each case as a
consequence of steric and electronic factors. Secondary allylic C-H bonds are thus selectively
functionalized in the presence of primary and tertiary positions. This preference matches that reported
for carbenes, resulting from the best compromise in terms of steric and electronic effects provided by a
methylene group.5a The trans stereochemistry, in addition, was deduced from NOESY experiments run
on compounds 3a and 3b, then corroborated by the X-ray crystal structure of 3a obtained from (R)-α-
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pinene (see the supporting information). Interestingly, our previous studies16 have shown that the
combination of (S)-1 with the (S)-catalyst 2 induces the formation of optically active amine derivatives
with the (R)-configuration. Because either (R)- or (S)-amides are here isolated with the same matched
pair of (S)-reagents, these results suggest that the stereoselectivity of the nitrene C-H insertion is
controlled by the substrate. Steric factors are also responsible for the selective introduction of the amino
group at the less hindered secondary site (“a” vs. “b”) of (S)-limonene, trans to the isopropenyl chain
(entry 3). In this case, the bulky chiral metallanitrene allows the discrimination of only one out of 11
available allylic C-H bonds of limonene, affording enantiopure compound 3c in 73% yield.
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Table 1. Allylic amination of terpenes.a
H
NHS*
1 (1.2 equiv), 2 (3 mol% )
H
PhI(OCOtBu)2 (1.4 equiv)
1.0 equiv
3
Entry
Product
Yield
d.r.b
Entry
Product
Yield
d.r.b
NHS*
NHS*
3a
1
91
39:1
6
3f
85
1.5:1
S*HN
NHS*
NHS*
NHS*
2
3
4
71
73
98
49:1
49:1
7
8
9
3g
34 (63)c
-
3b
NHS*
a
3h: R = Ac
3i: R = COCCl3
90
89
19:1
>20:1
b
3c
OR
RO
R: COCCl3
NHS*
3j: R = 3,5-NO2Bz
3d
>20:1
81
5:1
OR
NHS*
5
3e
27
10:1
a
b
Reaction conditions: Terpene (0.2 mmol) in a 3:1 mixture of 1,1,2,2-Tetrachloroethane:MeOH at -35 °C. The
diastereomeric ratios have been determined by 1H NMR or HPLC. c Yields in parentheses obtained using 5 equiv of substrate.
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Pleasingly, comparable high levels of regio-, chemo- and stereoselectivity were observed with nopol
trichloroacetate that affords exclusively the product 3d in 98% yield (entry 4). In this case, unfavourable
inductive effects from the trichloroacetyl ester deactivate the exocyclic secondary allylic position. A
similar inhibiting effect was observed when the reaction was applied to (R)-(-)-carvone (data not
shown). The presence of a carbonyl deactivates the vinylogous allylic position, thereby leading to the
complete recovery of the starting material. Carene also proved to give a major isomer though with a
lower yield of 27% (entry 5).20 By contrast, both (-)-isolongifolene and (-)-α-cedrene provided
unexpected results (entries 6 and 7). Whereas the former afforded a 60:40 mixture of allylic amines 3f
with a good yield of 85%, the latter led to a rare example of C-H amination at a primary allylic position,
as indicated by the X-ray crystal structure of 3g (see the supporting information). This switch in
regiochemistry can be rationalized by the steric hindrance induced by the neopentyl position.
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An important feature of the amination is the chemoselective formation of compounds 3a-g; the
potentially reactive alkene units proved inert under these conditions since the corresponding aziridines
were not isolated. Based on the X-ray structure obtained for the amino derivatives 3a and 3e (see the
supporting information), we propose to rationalize this observation by the involvement of
stereoelectronic factors resulting from the dihedral angle of 60° between the plane of the olefin and each
allylic C-H bonds. This allows their hyperconjugation with the π-bond thereby increasing their
reactivity. This hypothesis, interestingly, is corroborated by the result observed in the case of β-(-)-
caryophyllene that led us to isolate the aziridine 4 as a single isomer in 28% yield (79% using 5
equivalents of caryophyllene). The structure of compound 4 was confirmed by X-ray crystallography
(see the supporting information). A closer inspection of the product then revealed that allylic C-H
bonds, in this case, nearly lie in the plane of the alkene. Such a conformation would deactivate these
bonds towards C-H amination. Electron density of the olefin, moreover, would be substantially
increased by the hyperconjugation of allylic σC-C orbitals, which are perpendicular to its plane.21
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High efficiency and selectivity, finally, have been observed in the case of geranyl derivatives (entry
1
2
8). A single aminated product was isolated in each case despite the presence of 15 allylic C-H bonds. A
screening of various protecting groups (see the supporting information) then led to find that a
trichloroacetyl substituent was suitable to grow single crystals. This allowed us to confirm
unambiguously the structure of the resulting product 3i (see the supporting information). Once again,
the combination of (S)-1 with the (S)-catalyst 2 induces the formation of optically active (R)-amine
derivatives. Such a high level of regio- and stereoselectivity can be rationalized by a reactive allylic
position that is less hindered and electronically deactivated than both others allylic methylene groups. A
comparable result was obtained starting from neryl 3,5-dinitrobenzoate though with lower yield and
diastereoselectivity (entry 9). From a synthetic point of view, the regioselective C-H amination of
terpenes, ultimately, affords synthetic products displaying structures complementary to those previously
reported by application of different oxidizing conditions.22
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C-H Amination of enol ethers. We next turned our attention to cyclic enol ethers likely to produce
useful intermediates, which could be further functionalized. Fundamentally, these substrates possess an
electron-rich alkene even more prone to react with nitrenes.23 Nevertheless, inspired by the studies of
Hashimoto that describe the enantioselective C-H amination of cyclohexanone-derived enol ethers with
ees of up to 72%,24 we initially investigated the reactivity of silyl enol ethers. We first confirmed that a
triethylsilyl protecting group is the most compatible with the reaction conditions. However, whereas the
6-membered silyl enol ether afforded the expected product 5a though in low yield and moderate
stereoselectivity (Table 2, entry 1), C-H amination of the cyclopentanone-derived analog did not prove
successful (data not shown). In addition, the 7-membered derivative gave a single isomer of a
compound 6 that turned out to be the product of α-amination arising from initial alkene aziridination
followed by hydrolytic ring-opening of the resulting aziridine (entry 2). All these disappointing results
then convinced us to screen other enol ethers and led us to concentrate on allyl enol carbonates.25
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Table 2. Allylic C-H amination of enol ethers.a
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1
2
3
H
RO
RO
NHS*
1 (1.2 equiv), 2 (3 mol% )
PhI(OCOtBu)2 (1.4 equiv)
H
4
5
n
n
6
7
8
9
1.0 equiv
5
Entry
Product
NHS*
Yield
d.r.b
Entry
Product
Yield
d.r.b
NHS*
TESO
O
O
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60
20 (63)c
4:1
5
52
>20:1
>20:1
5:1
5d
1
5a
O
H
S*HN
O
O
O
N
2
30
199:1
6d
98
6
5e
S
NTs
O
O
4-NO2Ph
NHS*
5f
O
O
TfO
NHS*
3
4
92
80
>20:1
9:1
7
8
70
58
5b
O
O
O
NHS*
Ph
NHS*
5g
5c
5:1
O
a
b
Reaction conditions: Enol ether (0.2 mmol) in a 3:1 mixture of 1,1,2,2-Tetrachloroethane:MeOH at -35 °C. The
1
diastereomeric ratios have been determined by H NMR or HPLC. Yields in parentheses obtained using 5 equiv of
c
substrate. d Reaction performed with the (R)-enantiomer of the p-nitro analog of 1 in the presence of catalyst (R)-2.
In our hands, these allyl carbonates proved highly useful since we were able to perform C-H
amination with high levels of regio-, chemo- and stereoselectivity comparable to those recorded with
terpenes despite six available secondary allylic C-H bonds. Thus, the 5-, 6-, and 7-membered cyclic enol
ethers undergo amination at a single methylene group to afford a sole isomer with yields ranging from
52% to 98% (entries 3-6). Based on the previous results, the hypothesis of steric hindrance and
unfavourable inductive effects allows predicting that the reaction occurs at the β-position. This, and the
absolute configuration of the newly created stereocenter, were confirmed by X-ray crystallography of
compound (S)-5e obtained by using the opposite matched pair of reagent, i.e. the (R)-enantiomer of the
(p-nitrobenzene)-sulfonimidamide with the (R)-Rh(II) catalyst 2 (see the supporting information).
A vinyl triflate also efficiently reacts under these conditions as nicely demonstrated by the isolation of
product 5f in 70% yield and with a d.r. of 5:1 (entry 7).26 Application of palladium-cross coupling to the
latter then affords a variety of more complex enantioenriched amino derivatives.27 We have
demonstrated on the other hand that this sequence of reactions can be performed in reversed order with
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equal success as shown by the entry 8. The formation of compound 5g, resulting from the application of
C-H amination to the coupling product with styrene, thus showcases again the high chemoselectivity of
the reaction since aziridination of the electron-rich styrene moiety is not observed. To the best of our
knowledge, this is the first example of a selective C-H amination of a 1,3-diene.
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2
3
4
5
6
7
8
9
C-H Amination of alkanes. We finally focused on the selective C-H amination of alkanes. Despite
recent significant achievements in catalytic C-H hydroxylation,18 examples of efficient selective
functionalization of unactivated Csp3-H bonds are scarce. In the case of amination, they still remain
confined to hydrocarbons used in excessive amount. Our matched pair of reagents, by comparison,
allows the efficient selective functionalization of several cyclic substrates used as the limiting agents
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(Table 3).
Table 3. Catalytic C-H amination of alkanes.a
1 (1.2 equiv), 2 (3 mol% )
H
S*HN
PhI(OCOtBu)2 (1.4 equiv)
1.0 equiv 7
8
Entry
Substrate
Product
Yield
H
NHS*
1
7a
8a 64(91)b
H
H
7b
8b
2
83
48
H
H
H
NHS*
H Hb
H
Hb
H
H
3c
7c
8c
Ha
NHS*
H
NHS*
7d
8d
4
75
H
H
O
O
O
O
OMe
OMe
OMe
OMe
88
7e
8e
5
H
H
d.r. 2:1
H
NHS*
a
Reaction conditions: Alkane (0.2 mmol) in a 3:1 mixture
b
of 1,1,2,2-Tetrachloroethane:MeOH at -35 °C. Yields in
parentheses obtained using 5 equiv of substrate. c Reaction
performed
in
a
3:3:1
mixture
of
1,1,2,2-
Tetrachloroethane:Benzene:MeOH.
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Both isomers of 1,4-dimethylcyclohexane, first, were textbook cases to document the higher reactivity
of tertiary equatorial C-H bonds as a consequence of combined steric and hyperconjugative effects.28
Whereas the trans-isomer with two axial tertiary C-H bonds proved to give minute amounts of a C-H
aminated compound (data not shown), the equatorial C-H bond of the cis-isomer 7a was efficiently
transformed (entry 1). This trend was corroborated by the reaction with dimethyladamantane 7b that
affords a direct precursor of memantine13k in 83% yield (entry 2). That the selective functionalization of
a methine group can be achieved by the introduction of additional steric factors, was then demonstrated
by the C-H amination of diamantane 7c. The latter displays 6 equivalents “internal” tertiary C-Hb bonds
and 2 external identical sites (Ha). Despite an adverse statistical distribution, one of the latter was
exclusively aminated in 48% yield (entry 3) as indicated by the X-ray crystal structure (See the
Supporting Information). This selectivity can be rationalized by 1,3-diaxial interactions disfavouring the
amination of the C-Hb bonds, which are axial with respect to one cyclohexyl ring (contrary to the purely
equatorial C-Ha bonds).29
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Discriminating a tertiary position among several ones can also be envisaged through inductive
effects.30 Whereas 2-adamantanone did not undergo amination either at the α- or γ-tertiary center, it was
found that the inhibiting effect of the ketone is suppressed by its protection as a ketal. Compound 7d
thus reacts selectively at the less deactivated tertiary position to afford product 8d in 75% yield (entry
4). Last but not least, another type of tertiary bridgehead position can be efficiently functionalized with
sulfonimidamide-derived nitrenes. The adamantanone-derived bicyclo[3.3.1]nonane derivative 7e
afforded the expected amine 8e in 88% yield and, more fundamentally, with a diastereomeric ratio of
2:1 (entry 5). Though modest, this diastereoselectivity suggests that desymmetrization of meso
substrates could be achieved using catalytic nitrene transfers.
Conclusion
In conclusion, the use of a sulfonimidoylnitrene species allows the intermolecular chemoselective C-
H amination of various complex molecules used in stoichiometric amounts. This reaction gives access
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to enantiopure aminated derivatives, which are not easily accessible by “classical” organic synthesis.31
Allylic methylene units of terpenes and enol ethers have been efficiently aminated with yields of up to
98% and very high diastereomeric ratios (of up to 199/1). More importantly, the combination of steric,
inductive and conformational factors leads to the chemoselective functionalization of allylic positions
vs. adjacent π-bonds. The site-selective amination of alkanes also proves possible under these conditions
with yields of up to 88%. Steric and stereoelectronic effects, in this case, favour the amination of tertiary
equatorial C-H bonds. This efficient catalytic C-H functionalization therefore provides information on
the inherent reactivity of various substrates. These should serve as a guide to incorporate this
transformation into retrosynthetic analysis. Work is now in progress to apply catalytic C-H amination in
total synthesis as well as to investigate the desymmetrization of meso compounds by C-H oxidation.
Experimental procedure
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General Information. Melting points were measured in capillary tubes and are uncorrected. Infrared
spectra were recorded on a FT-IR spectrometer. Proton (1H) and carbon (13C) NMR spectra were
recorded on 300 MHz and 500 MHz spectrometers. Carbon NMR (13C) spectra were recorded at 125 or
75 MHz, using a broadband decoupled mode with the multiplicities obtained using a JMOD or DEPT
sequence. NMR experiments were carried out in deuterochloroform (CDCl3), methanol (CD3OD),
benzene (C6D6) and dimethylsulfoxide (DMSO). Chemical shifts (δ) are reported in parts per million
(ppm) with reference to tetramethylsilane (TMS) or residual solvent peaks as internal standards.
Coupling constants (J) are reported in Hertz (Hz). Values in italics refer to the minor diastereomer,
where applicable. Mass spectra were obtained either with a LCT instrument using electrospray
ionization (ES), or from a Time of Flight analyzer (ESI-MS) for the high resolution mass spectra
(HRMS). Elemental analyses were performed on an analyzer with a detection by catharometry. All
reagents were obtained from commercial suppliers unless otherwise stated. The rhodium catalyst 2 is
prepared from rhodium(II) acetate which was purchased either from Aldrich Chemical Company or Alfa
Aesar Company. Where necessary, organic solvents were routinely dried and/or distilled prior to use
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and stored over molecular sieves under argon. Organic extracts were dried over magnesium sulfate
(MgSO4) or sodium sulfate (Na2SO4).
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General procedure for catalytic C-H amination. In an oven-dried tube were introduced activated 4
Å molecular sieves (100 mg), Rh2[(S)-nta]4 2 (7.7 mg, 0.006 mmol) and (–)-N-(p-toluenesulfonyl)-p-
toluenesulfonimidamide (–)-(S)-1 (78 mg, 0.24 mmol). The tube was capped with a rubber septum and
purged with argon. Anhydrous and degassed 1,1,2,2-tetrachloroethane (0.75 mL) and methanol (0.25
mL) were added under argon, and the mixture was stirred for 5 min before addition of the substrate (0.2
mmol). The tube was cooled to –78 °C, and bis(tert-butylcarbonyloxy)iodobenzene (115 mg, 0.28
mmol) was added. The mixture was stirred at –35 °C for 3 days. After dilution with dichloromethane (3
mL), the molecular sieves were removed by filtration and the filtrate was evaporated to dryness under
reduced pressure. The oily residue was purified by flash chromatography on silica gel, affording the
following C-H insertion products.
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1R,2S,5R)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-4,6,6-trimethylbicyclo[3.1.1]hept-
3-en-2-amine 3a: Prepared following the typical amination procedure from (R)-α-pinene, the
corresponding amination product was obtained (dichloromethane/ethyl acetate 20/1) as a white
crystalline solid (83 mg, 91%); 39:1 d.r. (HPLC, Hypercarb column, 100 x 4.6 mm, 5 μm, MeCN +
0.1% HCOOH/ H2O + 0.1% HCOOH:80/20, 1 mL min-1, tmaj = 17.25 min). Rf = 0.60 (heptane/ethyl
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acetate 50/50); M.p. 55-57 °C; [α]D = -10.6 (c 1.00 in CHCl3); H NMR (300 MHz, CDCl3) δ = 7.85-
7.75 (m, 4H), 7.30-7.22 (m, 4H), 5.86 (d, J = 8.6 Hz, 1H), 5.21 (qd, J = 1.6, 3.1 Hz, 1H), 3.92-3.84 (m,
1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.20 (td, J = 5.5, 9.5 Hz, 1H), 1.98 (td, J = 1.3, 5.5 Hz, 1H), 1.83-1.76
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(m, 1H), 1.70 (t, J = 1.7 Hz, 3H), 1.19 (s, 3H), 1.25-1.17 (m, 1H), 0.76 (s, 3H); C NMR (CDCl3, 75
MHz) δ= 150.5, 144.6, 142.8, 140.6, 136.5, 129.9, 129.2, 127.8, 126.9, 115.0, 54.2, 47.1, 46.6, 44.5,
28.7, 26.4, 22.8, 21.7, 21.6, 20.5; I.R. (neat, cm-1) ν = 3218, 2925, 1596, 1403, 1301, 1258, 1150, 1105,
1089, 1074, 1016, 1002, 810; HRMS (ESI) Calcd for C24H30N2O3S2Na 481.1596; found 481.1588.
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The Journal of Organic Chemistry
(1S,2R,5S)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-4,6,6-trimethylbicyclo[3.1.1]hept-
3-en-2-amine 3b: Prepared following the typical amination procedure from (S)-α-pinene, the
corresponding amination product was obtained (dichloromethane/ethyl acetate 20/1) as a white
crystalline solid (65 mg, 71%); 49:1 d.r. (HPLC, Hypercarb column, 100 x 4.6 mm, 5 μm, MeCN +
0.1% HCOOH/ H2O + 0.1% HCOOH:90/10, 1 mL min-1, tmaj = 13.08 min). Rf = 0.55 (heptane/ethyl
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acetate 50/50); M.p. 123-125 °C; [α]D = +142 (c 1.00 in CHCl3); 1H NMR (500 MHz, CDCl3) δ = 7.80
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(t, J = 7.7 Hz, 4H), 7.31 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 7.9 Hz, 2H), 5.91 (br s, 1H), 4.85-4.80 (m,
1H), 3.79 (br s, 1H), 2.44 (s, 3H), 2.40 (s, 3H), 2.34 (td, J = 5.5, 9.5 Hz, 1H), 2.25-2.19 (m, 1H), 2.00 (t,
J = 5.5 Hz, 1H), 1.63 (s, 3H), 1.28 (s, 3H), 1.28-1.23 (m, 1H), 0.76 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ = 150.7, 144.8, 143.0, 140.6, 136.6, 130.0, 129.3, 127.9, 127.0, 115.0, 54.3, 47.2, 46.7, 44.6, 28.8,
26.4, 22.9, 21.82, 21.76, 20.6; I.R. (neat, cm-1) ν = 3236, 2920, 1596, 1420, 1300, 1245, 1150, 1104,
1088, 1016, 1000, 811; HRMS (ESI) Calcd for C24H30N2O3S2 Na 481.1596; found 481.1575.
(1S,6R)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-3-methyl-6-(prop-1-en-2-yl)cyclohex-
2-enamine 3c: Prepared following the typical amination procedure from (S)-limonene, the
corresponding amination product was obtained (dichloromethane/ethyl acetate: 20/1) as a white
crystalline solid (67 mg, 73%); 49:1 d.r. (HPLC, Hypercarb column, 100 x 4.6 mm, 5 μm, MeCN+
0.1% HCOOH/H2O + 0.1% HCOOH: 80/20, 1 mL min-1, tmaj = 46.38 min). Rf = 0.54 (heptane/ethyl
acetate 50/50); M.p. 83-85 °C ; [α]D = +105.5 (c 1.00 in CHCl3); 1H NMR (300 MHz, CDCl3) δ = 7.84-
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7.79 (m, 2H), 7.77-7.71 (m, 2H), 7.26-7.20 (m, 4H), 5.72 (d, J = 8.0 Hz, 1H), 5.46 (br s, 1H), 4.59 (s,
1H), 4.56-4.52 (m, 1H), 3.62-3.51 (m, 1H), 2.39 (s, 3H), 2.38 (s, 3H), 2.05-1.93 (m, 2H), 1.90-1.78 (m,
1H), 1.65 (s, 3H), 1.62-1.42 (m, 2H), 1.08 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 145.1, 144.8, 143.0,
140.7, 138.2, 135.6, 129.6, 129.4, 128.6, 127.0, 122.9, 113.6, 53.1, 48.4, 29.6, 27.1, 23.4, 21.79, 21.76,
18.6; I.R. (neat, cm-1) ν = 3190, 1597, 1424, 1299, 1283, 1146, 1109, 1030, 1014, 806; HRMS (ESI)
Calcd for C24H30N2O3S2Na 481.1596; found 481.1608.
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2-((1R,4R,5S)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-4-amino-6,6-
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dimethylbicyclo[3.1.1]hept-2-en-2-yl)ethyl 2,2,2-trichloroacetate 3d: Prepared following the typical
amination procedure from (1R)-(–)-nopol trichloroacetate, the corresponding amination product was
obtained (heptane/ethyl acetate: 80/20 to 70/30) as a white foam (124 mg, 98%); > 20:1 d.r. (1H NMR
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evaluation). Rf = 0.30 (heptane/ethyl acetate 70/30); [α]D = -60.6 (c 1.00 in acetone); H NMR (300
MHz, CDCl3) δ = 7.84-7.76 (m, 4H), 7.34-7.20 (m, 4H), 5.96 (d, J = 9.2 Hz, 1H), 4.99-4.93 (m, 2H),
4.38-4.22 (m, 1H), 3.88-3.80 (m, 1H), 2.44 (s, 3H), 2.44-2.34 (m, 3H), 2.40 (s, 3H), 2.28-2.20 (m, 1H),
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2.18-2.12 (m, 1H), 1.30 (s, 3H), 1.28 (d, J = 9.7 Hz, 1H), 0.78 (s, 3H); C NMR (75 MHz, CDCl3)
δ = 162.0, 152.4, 148.8, 145.0, 143.1, 140.5, 136.5, 130.1, 129.4, 127.9, 127.0, 118.4, 66.8, 54.0, 46.7,
46.0, 44.9, 35.1, 29.1, 26.4, 21.83, 21.75, 20.9; I.R. (neat, cm-1) ν = 3225, 2925, 1764, 1597, 1303,
1241, 1153, 1108, 1092, 1017, 815, 755, 680; HRMS (ESI) Calcd for C27H32Cl3N2O5S2 633.0818; found
633.0804.
(1R,2S,6S)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-4,7,7-trimethylbicyclo[4.1.0]hept-
3-en-2-amine 3e: Prepared following the typical amination procedure from (S)-3-carene, the
corresponding amination product was obtained (dichloromethane/ethyl acetate: 100/0 to 95/5) as a white
crystalline solid (25 mg, 27%); 10:1 d.r. (1H NMR evaluation). Rf = 0.40 (dichloromethane/ethyl acetate
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98/2); M.p. 105-109 °C ; [α]D = +32.6 (c 1.00 in acetone); H NMR (500 MHz, CDCl3) δ = 7.88-7.80
(m, 4H), 7.34-7.21 (m, 4H), 5.87 (d, J = 9.2 Hz, 1H), 5.24-5.17 (m, 1H), 3.75-3.64 (m, 1H), 2.42 (s,
3H), 2.40 (s, 3H), 2.29-2.15 (m, 1H), 1.83-1.70 (m, 1H), 1.60 (s, 3H), 0.76 (s, 3H), 0.75-0.63 (m, 1H),
0.66 (s, 3H), 0.29 (d, J = 8.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ = 144.7, 142.9, 140.7, 137.6, 136.7,
129.9, 129.3, 128.0, 127.0, 120.1, 46.9, 28.0, 25.1, 23.6, 23.3, 21.7, 18.6, 16.1, 13.4; I.R. (neat, cm-1)
ν = 3171, 2943, 1598, 1446, 1427, 1283, 1260, 1300, 1146, 1112, 1016, 995, 806, 766, 743, 704, 666;
HRMS (ESI) Calcd for C24H31N2O3S2 459.1776; found 459.1754.
(2R,4aR)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-1,1,5,5-tetramethyl-2,3,4,5,6,7-
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The Journal of Organic Chemistry
hexahydro-1H-2,4a-methanonaphthalen-7-amine 3f: Prepared following the typical amination
procedure from (-)-isolongifolene, the corresponding amination product was obtained (heptane/ethyl
acetate: 90/10 to 80/20) as a white foam (89 mg, 85%); 1.5:1 d.r. (1H NMR evaluation). Rf = 0.35
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(heptane/ethyl acetate 80/20); diastereomer A 1.5/ diastereomer B 1 H NMR (500 MHz, CDCl3)
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δ = 7.86-7.78 (m, 4H), 7.34-7.22 (m, 4H), 5.79 (d, J = 8.6 Hz, 1H), 5.60 (d, J = 9.1 Hz, 1H), 5.05 (s,
1H), 4.76 (d, J = 4.0 Hz, 1H), 3.83-3.76 (m, 1H), 3.76-3.70 (m, 1H), 2.44 (s, 3H), 2.404 (s, 3H), 2.400
(s, 3H), 1.82-1.76 (m, 1H), 1.74-1.54 (m, 4H), 1.51-1.35 (m, 2H), 1.29-1.22 (m, 2H), 1.21-1.16 (m, 2H),
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(75 MHz, CDCl3) δ = 162.0, 161.2, 144.80, 144.77, 142.92, 142.87, 140.75, 140.66, 136.6, 136.1,
130.0, 129.9, 129.4, 128.2, 128.0, 127.0, 126.9, 112.0, 109.5, 56.4, 56.2, 50.6, 49.0, 46.8, 46.5, 42.7,
42.6, 41.7, 41.0, 37.0, 36.7, 32.9, 31.1, 29.0, 28.8, 28.4, 28.2, 26.6, 26.4, 25.5, 24.8, 24.7, 24.5, 21.79,
21.78, 21.7; I.R. (neat, cm-1) ν = 3224, 2960, 1596, 1403, 1302, 1257, 1150, 1105, 811, 734 ; HRMS
(ESI) Calcd for C29H37N2O3S2 525.2246; found 525.2257.
(3R,3aS,7R,8aS)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-(3,8,8-trimethyl-2,3,4,7,8,8a-
hexahydro-1H-3a,7-methanoazulen-6-yl)methanamine 3g: Prepared following the typical amination
procedure from (–)-cedrene, the corresponding amination product was obtained (dichloromethane
100%) as an orange oil recrystallized in MeOH to afford white crystals (36 mg, 34%). Rf = 0.30
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(dichloromethane); M.p. 159-160 °C ; [α]D = -37.0 (c 1.00 in acetone); H NMR (300 MHz, CDCl3)
δ = 7.88-7.80 (m, 4H), 7.31 (d, J = 8.1 Hz, 2H), 7.25 (d, J = 7.9 Hz, 2H), 5.68 (dd, J = 4.7, 7.9 Hz, 1H),
5.49-5.44 (m, 1H), 3.52 (ddd, J = 0.8, 4.7, 14.2 Hz, 1H), 3.32 (qdd, J = 2.0, 7.9, 14.2 Hz, 1H), 2.43 (s,
3H), 2.40 (s, 3H), 2.20-2.10 (m, 1H), 1.89-1.47 (m, 9H), 1.41-1.27 (m, 2H), 1.23 (d, J = 10.5 Hz, 1H),
0.82 (d, J = 7.0 Hz, 1H), 0.79 (s, 3H), 0.74 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 145.1, 143.0, 140.7,
138.6, 134.9, 130.0, 129.4, 128.3, 126.9, 124.2, 59.1, 54.2, 50.9, 48.7, 48.5, 41.5, 40.5, 38.8, 36.2, 27.5,
25.4, 24.9, 21.79, 21.76, 15.6; I.R. (neat, cm-1) ν = 3224, 2929, 1595, 1458, 1312, 1238, 1149, 1110,
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1091, 1052, 870, 812, 754, 668; HRMS (ESI) Calcd for C29H39N2O3S2 527.2402; found 527.2394.
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acetate 3h: Prepared following the typical amination procedure from geranyl acetate, the corresponding
amination product was obtained (dichloromethane/ethyl acetate: 20/1) as a clear oil (93 mg, 90%); 19:1
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d.r. (1H NMR evaluation). Rf = 0.36 (heptane/ethyl acetate 60/40); [α]D = + 25.4 (c 1.00 in CHCl3); 1H
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(d, J = 5.0 Hz, 1H), 5.29 (t, J = 6.8 Hz, 1H), 4.86 (d, J = 9.0 Hz, 1H), 4.46 (d, J = 7.0 Hz, 2H), 4.05-4.12
(m, 1H), 2.40 (s, 3H), 2.37 (s, 3H), 2.13-2.07 (m, 1H), 2.04 (s, 3H), 2.03-1.98 (m, 1H), 1.56 (s, 3H),
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1.51 (s, 3H), 1.47 (s, 3H); C NMR (75 MHz, CDCl3) δ = 171.3, 144.7, 142.9, 140.7, 137.1, 136.6,
136.0, 129.7, 129.4, 128.1, 126.9, 124.3, 123.3, 61.1, 51.0, 46.1, 25.8, 21.8, 21.7, 21.2, 18.3, 16.4; I.R.
(neat, cm-1) ν = 3229, 1732, 1596, 1443, 1232, 1151, 1105, 1089, 1016, 812; HRMS (ESI) Calcd for
C26H34N2O5S2Na 541.1807; found 541.1779.
(R,E)-5-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]amino-3,7-dimethylocta-2,6-dien-1-yl
2,2,2-trichloroacetate 3i: Prepared following the typical amination procedure from geranyl
trichloroacetate, the corresponding amination product was obtained (heptane/ethyl acetate: 80/20 to
70/30) as white crystalline solid (110 mg, 89%); >20:1 d.r. (1H NMR evaluation). Rf = 0.50
(heptane/ethyl acetate 70/30); M.p. 103-106 °C ; [α]D = -18.6 (c 1.00 in acetone); 1H NMR (300 MHz,
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CDCl3) δ = 7.86-7.75 (m, 4H), 7.31-7.21 (m, 4H), 5.67 (d, J = 5.3 Hz, 1H), 5.36 (td, J = 1.1, 7.0 Hz,
1H), 4.89-4.82 (m, 1H), 4.77 (dd, J = 7.2, 12.1 Hz, 1H), 4.71 (dd, J = 6.6, 12.1 Hz, 1H), 4.24-4.13 (m,
1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.19 (dd, J = 7.1, 13.4 Hz, 1H), 2.06 (dd, J = 7.1, 13.5 Hz, 1H), 1.58 (s,
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3H), 1.57 (d, J = 1.1 Hz, 3H), 1.54 (d, J = 1.1 Hz, 3H); C NMR (75 MHz, CDCl3) δ = 162.1, 144.8,
143.0, 140.7, 140.5, 136.7, 136.6, 129.7, 129.4, 128.0, 126.9, 123.90, 123.86, 120.6, 65.7, 51.2, 46.1,
25.7, 21.78, 21.75, 18.4, 16.7; I.R. (neat, cm-1) ν = 3166, 2974, 2918, 1764, 1597, 1444, 1419, 1378,
1304, 1285, 1221, 1157, 1102, 1065, 1050, 1019, 951, 883, 810, 747, 679; HRMS (ESI) Calcd for
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The Journal of Organic Chemistry
C26H31Cl3N2O5S2Na 643.0638; found 643.0618.
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(R,Z)-5-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]amino-3,7-dimethylocta-2,6-dien-1-yl
3,5-dinitrobenzoate 3j: Prepared following the typical amination procedure from neryl 3,5-
dinitrobenzoate, the corresponding amination product was obtained (dichloromethane/ethyl acetate:
98/2) as pasty solid (108 mg, 81%); 5:1 d.r. (1H NMR evaluation). Rf = 0.30 (dichloromethane/ethyl
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acetate 98/2); Diastereomer A 5/ diastereomer B 1 H NMR (300 MHz, CDCl3) δ = 9.22-9.11 (m, 3H),
7.80-7.64 (m, 4H), 7.32-7.15 (m, 4H), 6.19 (d, J = 5.9 Hz, 1H), 5.78 (d, J = 5.7 Hz, 1H), 5.70 (t, J = 7.8
Hz, 1H), 5.54 (t, J = 7.4 Hz, 1H), 5.14 (dd, J = 8.7, 12.2 Hz, 1H), 5.02-4.87 (m, 2H), 4.80 (dd, J = 6.6,
12.3 Hz, 1H), 4.67-4.60 (m, 1H), 4.32-4.19 (m, 1H), 2.73 (dd, J = 8.6, 13.8 Hz, 1H), 2.50 (dd, J = 7.1,
13.4 Hz, 1H), 2.45-2.35 (m, 1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.38 (s, 3H), 2.37 (s, 3H), 2.17 (dd, J = 7.5,
13.4 Hz, 1H), 1.87 (s, 3H), 1.67 (s, 3H), 1.56 (s, 3H), 1.55 (s, 3H), 1.38 (d, J = 1.1 Hz, 3H), 1.32 (d, J =
1.1 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ = 163.3, 162.8, 148.80, 148.75, 144.8, 144.4, 142.94, 142.86,
140.64, 140.59, 139.8, 139.6, 136.8, 136.6, 136.5, 136.1, 134.1, 129.9, 129.74, 129.70, 129.4, 129.32,
129.25, 128.0, 126.8, 126.7, 124.1, 124.0, 122.5, 122.1, 121.7, 63.3, 63.1, 51.5, 50.4, 38.5, 38.3, 25.7,
25.5, 24.0, 23.6, 21.75, 21.69, 18.4, 18.0; I.R. (neat, cm-1) ν = 3243, 3102, 2924, 1729, 1544, 1344,
1270, 1152, 1090, 813, 720; HRMS (ESI) Calcd for C31H34N4O9S2Na 693.1665; found 693.1685.
(1R,4R,6R,10S)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-4,12,12-trimethyl-9-
methylene-5-azatricyclo[8.2.0.04,6]dodecane 4: Prepared following the typical amination procedure
from β-(-)-caryophyllene, the aziridine 4 was obtained (dichloromethane/ethyl acetate: 100/0 to 98/2) as
a white crystalline solid (29 mg, 28%); >20:1 d.r. (1H NMR evaluation). Rf = 0.30 (dichloromethane);
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M.p. 125-128 °C ; [α]D = -80.1 (c 1.00 in acetone); H NMR (300 MHz, CDCl3) δ = 7.79-7.73 (m,
2H), 7.71-7.64 (m, 2H), 7.23 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 4.93 (d, J = 1.4 Hz, 1H), 4.76
(d, J = 1.4 Hz, 1H), 3.03 (dd, J = 4.0, 11.1 Hz, 1H), 2.58 (dd, J = 9.5, 10.5 Hz, 1H), 2.41 (s, 3H), 2.36
(s, 3H), 2.27-2.17 (m, 2H), 2.06-1.95 (m, 1H), 1.93-1.82 (m, 1H), 1.81-1.52 (m, 4H), 1.51-1.35 (m, 1H),
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1.30 (s, 3H), 1.31-1.18 (m, 1H), 0.99 (s, 3H), 0.97 (s, 3H); 13C NMR (75 MHz, CDCl3) δ = 151.1, 144.5,
142.3, 140.9, 137.6, 129.6, 129.0, 127.8, 126.9, 113.4, 57.7, 51.6, 49.8, 48.9, 39.7, 34.6, 34.3, 30.0,
29.8, 29.7, 27.4, 21.8, 21.6, 18.8; I.R. (neat, cm-1) ν = 2926, 2868, 1596, 1456, 1384, 1316, 1232, 1151,
1090, 1067, 1048, 1014, 974, 915, 890, 811, 763, 709, 650; HRMS (ESI) Calcd for C29H39N2O3S2
527.2402; found 527.2401.
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(R)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-3-((triethylsilyl)oxy)cyclohex-2-enamine
5a: Prepared following the typical amination procedure from (cyclohex-1-en-1-yloxy)triethylsilane, the
corresponding amination product was obtained (dichloromethane/ethyl acetate: 20/1) as a pasty solid
(21 mg, 20%); 4:1 d.r. (1H NMR evaluation); Rf = 0.22 (heptane/ethyl acetate 50/50) diastereomer A 4/
Diastereomer B 1 1H NMR (300 MHz, C6D6) δ = 8.22 (d, J = 8.3 Hz, 2H), 7.93 (d, J = 8.3 Hz, 2H), 7.90
(d, J = 8.3 Hz, 2H), 6.86-6.81 (m, 2H), 6.75 (d, J = 8.3 Hz, 2H), 6.47 (d, J = 8.1 Hz, 1H), 6.43 (d, J =
8.1 Hz, 1H), 5.07 (d, J = 4.1 Hz, 1H), 4.66 (d, J = 4.1 Hz, 1H), 4.20-4.14 (m, 1H), 4.08-4.03 (m, 1H),
1.89 (s, 3H), 1.88 (s, 3H), 1.85 (s, 3H), 1.84 (s, 3H), 1.81-1.46 (m, 2H), 1.44-1.23 (m, 2H), 1.22-1.06
(m, 1H), 1.00 (t, J = 7.9 Hz, 9H), 0.90 (t, J = 7.9 Hz, 9H), 0.67 (q, J = 7.5 Hz, 15.6 Hz, 6H), 0.54 (q, J =
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7.5 Hz, 15.6 Hz, 6H); C NMR (75 MHz, C6D6) δ = 156.0, 155.8, 144.3, 144.2, 142.8, 142.7, 142.60,
142.56, 138.7, 138.6, 130.1, 129.7, 127.74, 127.69, 104.5, 103.5, 50.7, 50.4, 30.6, 30.1, 30.0, 29.5,
21.49, 21.46, 19.7, 19.6, 7.4, 7.3, 5.7, 5.6; I.R. (neat, cm-1) ν = 3233, 2953, 2876, 1660, 1597, 1495,
1457, 1414, 1369, 1314, 1302, 1250, 1199, 1151, 1106, 1090, 1062, 1016, 927, 897, 812, 744, 703, 657;
HRMS (ESI) Calcd for C26H37N2O4S2Si 533.1964; found 533.1959.
2-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]aminocycloheptanone 6: Prepared following
the typical amination procedure from (cyclohept-1-en-1-yloxy)triethylsilane, the corresponding
amination product was obtained (dichloromethane/ethyl acetate: 20/1) as a pasty solid (26 mg, 30%);
199:1 d.r. (HPLC, Hypercarb column, 100 x 4.6 mm, 5 μm, MeCN+ 0.1% HCOOH/H2O + 0.1%
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HCOOH: 80/20, 1 mL min-1, tmaj = 13.52 min); Rf = 0.37 (heptane/ethyl acetate 50/50); H NMR (300
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MHz, C6D6) δ = 8.21 (d, J = 8.5 Hz, 2H), 7.80 (d, J = 8.5 Hz, 2H), 7.08-6.94 (m, 1H), 6.80 (d, J = 7.9
Hz, 2H), 6.71 (d, J = 7.9 Hz, 2H), 4.40-4.35 (m, 1H), 2.09-2.04 (m, 2H), 1.85 (s, 3H), 1.81 (s, 3H),
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1.77-1.70 (m, 1H), 1.43-1.36 (m, 1H), 1.24-1.14 (m, 6H); C NMR (75 MHz, C6D6) δ = 207.8, 144.7,
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142.7, 142.6, 138.1, 130.2, 129.7, 128.1, 127.7, 62.5, 41.0, 32.8, 29.0, 27.1, 23.5, 21.5; I.R. (neat, cm-1)
ν = 3357, 3260, 1597, 1448, 1300, 1154, 1097, 1035, 1009, 902, 812; HRMS (ESI) Calcd for
C21H26N2O4S2Na 457.1232; found 457.1229.
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(R)-allyl
(3-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]aminocyclopent-1-en-1-yl)
carbonate 5b: Prepared following the typical amination procedure from allyl cyclopent-1-en-1-yl
carbonate, the corresponding amination product was obtained (heptane/ethyl acetate: 70/30) as a pasty
solid (90 mg, 92%); >20:1 d.r. (1H NMR evaluation); Rf = 0.47 (heptane/ethyl acetate 50/50); 1H NMR
(500 MHz, C6D6) δ = 8.23 (d, J = 8.2 Hz, 2H), 7.77 (d, J = 8.2 Hz, 2H), 6.82 (d, J = 8.2 Hz, 2H), 6.69
(d, J = 8.2 Hz, 2H), 5.94-5.79 (m, 1H), 5.63-5.53 (m, 2H), 5.06 (d, J = 17.4 Hz, 1H), 4.91 (d, J = 10.4
Hz, 1H), 4.28 (d, J = 5.8 Hz, 2H), 4.27-4.22 (m, 1H), 2.23-2.15 (m, 1H), 1.99-1.90 (m, 1H), 1.86 (s,
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3H), 1.81 (s, 3H), 1.66-1.57 (m, 1H), 1.27-1.18 (m, 1H); C NMR (75 MHz, CDCl3) δ = 154.3, 145.1,
143.1, 136.2, 131.1, 130.1, 129.5, 128.0, 127.0, 119.9, 111.8, 69.4, 57.0, 29.7, 29.3, 21.83, 21.78; I.R.
(neat, cm-1) ν = 3224, 2925, 2856, 1766, 1645, 1596, 1437, 1383, 1313, 1304, 1284, 1220, 1211, 1152,
1108, 1087, 1014, 976, 922, 885, 813, 779, 732, 682; HRMS (ESI) Calcd for C23H26N2O6S2Na
513.1130; found 513.1124.
(R)-allyl
(3-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]aminocyclohex-1-en-1-yl)
carbonate 5c: Prepared following the typical amination procedure from allyl cyclohex-1-en-1-yl
carbonate, the corresponding amination product was obtained (dichloromethane/ethyl acetate: 20/1) as a
pasty solid (81 mg, 80%); 9:1 d.r. (1H NMR evaluation); Rf = 0.40 (heptane/ethyl acetate 50/50);
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Diastereomer A 9/ Diastereomer B 1 H NMR (500 MHz, C6D6) δ = 8.23-8.16 (m, 2H), 7.91-7.84 (m,
2H), 6.88-6.82 (m, 2H), 6.79 (d, J = 8.2 Hz, 1H), 6.75 (d, J = 8.5 Hz, 2H), 5.73-5.69 (m,1H), 5.69-5.55
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(m, 1H), 5.35-5.32 (m, 1H), 5.14-5.05 (m, 1H), 4.98-4.91 (m, 1H), 4.35 (dd, J = 1.2 Hz, 5.5 Hz, 2H),
4.29 (dd, J = 1.2 Hz, 5.5 Hz, 2H), 4.09-4.00 (m, 1H), 3.98-3.91 (m, 1H), 3.46-3.44 (m, 1H), 2.02-1.92
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(m, 2H), 1.90 (s, 3H), 1.89-1.85 (m, 1H), 1.84 (s, 3H), 1.42-1.27 (m, 3H); C NMR (75 MHz, CDCl3)
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27.3, 26.2, 21.83, 21.76, 19.3; I.R. (neat, cm-1) ν = 3232, 2949, 1755, 1596, 1447, 1363, 1210, 1149,
1088, 1056, 1015, 924, 882, 812, 752, 700, 655, 612; HRMS (ESI) Calcd for C24H28N2O6S2Na
527.1287; found 527.1296.
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(R)-allyl
(3-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]aminocyclohept-1-en-1-yl)
carbonate 5d: Prepared following the typical amination procedure from allyl cyclohex-1-en-1-yl
carbonate, the corresponding amination product was obtained (dichloromethane/ethyl acetate: 20/1) as a
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pasty solid (54 mg, 52%); >20:1 d.r. (1H NMR evaluation); Rf = 0.43 (heptane/ethyl acetate 50/50); H
NMR (300 MHz, C6D6) δ = 8.25-8.19 (m, 2H), 7.81-7.75 (m, 2H), 6.81 (d, J = 8.1 Hz, 2H), 6.68 (d, J =
8.1 Hz, 2H), 6.26 (d, J = 8.3 Hz, 1H), 5.71 (d, J = 4.9 Hz, 1H), 5.69-5.57 (m, 1H), 5.14-5.05 (m, 1H),
4.97-4.90 (m, 1H), 4.36-4.32 (m, 2H), 4.06-3.95 (m, 1H), 2.16-2.07 (m, 2H), 1.85 (s, 3H), 1.78 (s, 3H),
1.49-1.20 (m, 6H); 13C NMR (75 MHz, C6D6) δ = 153.8, 153.5, 144.1, 142.1, 141.6, 137.5, 131.8, 129.8,
129.4, 127.9, 127.3, 120.8, 118.5, 68.6, 51.4, 33.2, 32.1, 27.0, 24.7, 21.1; I.R. (neat, cm-1) ν = 3237,
2932, 1749, 1687, 1596, 1440, 1316, 1278, 1237, 1212, 1152, 1150, 1086, 1014, 993, 919, 811, 734,
684, 654; HRMS (ESI) Calcd for C25H30N2O6S2Na 541.1443; found 541.1469.
(S)-allyl
(3-[N-(R)-(p-toluenesulfonyl)-p-nitrobenzenesulfonimidoyl]aminocyclopent-1-en-1-yl)
carbonate 5e: Prepared following the typical amination procedure from allyl cyclopent-1-en-1-yl
carbonate using (R)-p-NO2-1 and (R)-2, the corresponding amination product was obtained
(heptane/ethyl acetate: 50/50) as white needles (102 mg, 98%); >20:1 d.r. (1H NMR evaluation); Rf =
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0.47 (heptane/ethyl acetate 50/50); M.p. 124-126 °C; [α]D = -30.3 (c 0.53 in acetone), H NMR (500
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MHz, CDCl3) δ = 8.35-8.29 (m, 2H), 8.15-8.09 (m, 2H), 7.84-7.77 (m, 2H), 7.30-7.22 (m, 2H), 6.06 (d,
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J = 8.8 Hz, 1H), 6.00-5.85 (m, 1H), 5.49-5.44 (m, 1H), 5.42-5.34 (m, 1H), 5.33-5.28 (m, 1H), 4.65 (dt, J
= 1.3, 5.9 Hz, 2H), 4.51-4.40 (m, 1H), 2.65-2.51 (m, 1H), 2.44-2.31 (m, 1H), 2.40 (s, 3H), 2.25-2.11 (m,
1H), 1.72-1.57 (m, 1H); 13C NMR (75 MHz, CDCl3) δ = 154.7, 151.7, 150.7, 145.8, 143.7, 140.0, 131.0,
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129.6, 129.2, 126.9, 124.6, 120.0, 111.0, 69.4, 57.5, 29.8, 28.9, 21.8; I.R. (neat, cm-1) ν = 3211, 2924,
1767, 1650, 1607, 1531, 1349, 1219, 1154, 1115, 1091, 1039, 1012, 945, 855, 817, 723, 682; HRMS
(ESI) Calcd for C22H22N3O8S2 520.0848; found 520.0855.
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(R)-3-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]aminocyclohex-1-en-1-yl
trifluoromethanesulfonate 5f: Prepared following the typical amination procedure from cyclohexen-1-
yl trifluoromethanesulfonate, the corresponding amination product was obtained (heptane/ethyl acetate:
70/30) as a white solid in 70% yield and 5:1 d.r. (1H NMR evaluation), which can be recrystallized from
diisopropyl oxide leading to white needles and a 13:1 d.r.; Rf = 0.30 (heptane/ethyl acetate 70/30); M.p.
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114-115 °C; Diastereomer A 5/ Diastereomer B 1 H NMR (300 MHz, CDCl3) δ 1.35-1.49 (m, 1H),
1.60-1.81 (m, 3H), 2.21-2.33 (m, 2H), 2.40 (s, 3H), 2.42 (s, 3H), , 3.94-4.04 (m, 1H), 5.30-5.35 (m, 1H),
5.63-5.67 (m, 1H), 6.01 (d, J = 8.9 Hz, 1H), 7.24-7.34 (m, 4H), 7.74-7.86 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 19.4, 21.57, 21.63, 27.1, 28.1, 48.7, 118.8, 120.6, 126.7, 126.8, 127.6, 127.7, 129.3, 129.4,
130.0, 130.1, 135.7, 140.2, 143.2, 145.2, 152.0; I.R. (neat, cm-1) ν 3208, 2925, 1686, 1597, 1417, 1303,
1210, 1143, 1109, 1061, 1017, 897, 815; HRMS (ESI) Calcd for C21H24F3N2O6S3 553.0749, found
553.0757.
(R,E)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-3-styrylcyclohex-2-enamine
5g:
Prepared following the typical amination procedure from (2-(cyclohex-1-en-1-yl)vinyl)benzene, the
corresponding amination product was obtained (heptane/ethyl acetate: 90/10) as a yellow oil in 58%
yield and 5:1 d.r. (1H NMR evaluation); Rf = 0.51 (heptane/ethyl acetate 50/50); Diastereomer A 5/
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Diastereomer B 1 H NMR (500 MHz, CDCl3) δ 1.33-1.43 (m, 1H), 1.58-1.75 (m, 3H), 2.15-2.27 (m,
2H), 2.34 (s, 3H), 2.39 (s, 3H), 2.41 (s, 3H), 2.42 (s, 3H), 3.85-3.93 (m, 1H), 3.93-4.00 (m, 1H), 5.38-
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5.41 (m, 1H), 5.71-5.74 (m, 1H), 5.85 (d, J = 8.2 Hz, 1H), 6.02 (d, J = 8.2 Hz, 1H), 6.34 (d, J = 16.2 Hz,
1H), 6.52 (d, J = 16.2 Hz, 1H), 6.69 (d, J = 16.2 Hz, 1H),7.18-7.23 (m, 2H), 7.27-7.33 (m, 5H), 7.35-
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126.5, 126.6, 126.8, 127.6, 127.8, 128.1, 128.2, 128.3, 128.4, 128.7, 129.0, 129.2, 129.7, 129.8, 130.7,
139.7, 144.8; I.R. (neat, cm-1) ν 3242, 2930, 1709, 1597, 1494, 1449, 1302, 1151, 1106, 1064, 910, 813;
MS m/z 505 [(M-H)-], HRMS (ESI) Calcd for C28H29N2O3S2 505.1620, found 505.1633.
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(1r,4r)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-1,4-dimethylcyclohexanamine
8a:
Prepared following the typical amination procedure from cis-1,4-dimethylcyclohexane, the
corresponding product was obtained (dichloromethane/ethyl acetate 20/1) as a pasty solid (56 mg, 64%).
Rf = 0.53 (heptane/ethyl acetate 50/50); 1H NMR (500 MHz, CDCl3) δ = 7.79 (d, J = 7.9 Hz, 2H), 7.75
(d, J = 8.2 Hz, 2H), 7.25-7.20 (m, 4H), 6.17 (s, 1H), 2.39 (s, 3H), 2.38 (s, 3H), 1.77-1.70 (m, 1H), 1.67-
1.60 (m, 2H), 1.57-1.44 (m, 2H), 1.39 (td, J = 4.1, 12.8 Hz, 1H), 1.35-1.25 (m, 1H), 1.16 (s, 3H), 1.01-
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0.93 (m, 2H), 0.82 (d, J = 6.4 Hz, 3H); C NMR (75 MHz, CDCl3) δ = 144.4, 143.0, 140.6, 139.3,
129.8, 129.4, 127.8, 127.0, 60.0, 38.6, 37.9, 31.6, 31.0, 30.95, 27.9, 23.3, 21.78, 21.75; I.R. (neat, cm-1)
ν = 3235, 2925, 2861, 1597, 1495, 1447, 1380, 1312, 1301, 1277, 1245, 1148, 1089, 1060, 1015, 976,
861, 811, 755, 702, 656.; HRMS (ESI) Calcd for C22H30N2O3S2Na 457.1596; found 457.1611.
(1r,3R,5S,7r)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-3,5-dimethyladamantan-1-
amine 8b: Prepared following the typical amination procedure from dimethyladamantane, the
corresponding product was obtained (dichloromethane 100%) as a white crystalline solid (81 mg, 83%).
Rf = 0.30 (dichloromethane); M.p. 124-126 °C; [α]D = +14.7 (c 1.00 in acetone); 1H NMR (300 MHz,
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CDCl3) δ = 7.85-7.74 (m, 4H), 7.30-7.21 (m, 4H), 6.09 (s, 1H), 2.42 (s, 3H), 2.40 (s, 3H), 2.05 (quint, J
= 3.1 Hz, 1H), 1.67 (td, J = 2.5, 11.7 Hz, 1H), 1.55-1.15 (m, 9H), 1.06 (s, 3H), 0.772 (s, 3H), 0.767 (s,
3H); 13C NMR (75 MHz, CDCl3) δ = 144.4, 143.0, 140.6, 139.3, 129.7, 129.4, 127.8, 127.0, 59.2, 50.2,
49.3, 49.2, 42.3, 42.2, 41.3, 32.94, 32.88, 30.3, 30.0, 21.79, 21.77; I.R. (neat, cm-1) ν = 3278, 2902,
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1650, 1454, 1317, 1233, 1152, 1107, 1090, 1019, 815, 655; HRMS (ESI) Calcd for C26H35N2O3S2
487.2089; found 487.2089.
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(4r,4ar,8r,8ar,9r,10r)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-decahydro-2,8,4,6-
(epibutane[1,2,3,4]tetrayl)naphthalen-2-amine 8c: Prepared following the typical amination
procedure from diamantane, the corresponding product was obtained (dichloromethane 100%) as a
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white crystalline solid (49 mg, 48%). Rf = 0.35 (dichloromethane); M.p. 210-213 °C, [α]D = + 27.0 (c
1
1.00 in acetone); H NMR (300 MHz, CDCl3) δ = 7.86-7.74 (m, 4H), 7.29-7.20 (m, 4H), 6.10 (s, 1H),
13
2.41 (s, 3H), 2.40 (s, 3H), 1.86-1.56 (m, 19H); C NMR (75 MHz, CDCl3) δ = 144.4, 142.9, 140.6,
139.3, 129.7, 129.4, 127.9, 127.0, 56.7, 43.6, 38.7, 37.2, 36.1, 25.5, 21.8; I.R. (neat, cm-1) ν = 3564,
3135, 2917, 1629, 1455, 1297, 1285, 1239, 1150, 1107, 1055, 1043, 1014, 884, 814, 688, 662; HRMS
(ESI) Calcd for C28H34N2O3S2Na 533.1909; found 533.1907.
(1R,3S,5s,7s)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-spiro[adamantane-2,2'-
[1,3]dioxolan]-5-amine 8d: Prepared following the typical amination procedure from dioxolane
adamantane, the corresponding product was obtained (dichloromethane/ethyl acetate 100/0 to 90/10) as
20
a white foam (77 mg, 75%). Rf = 0.50 (dichloromethane/ethyl acetate 90/10); [α]D = +16.9 (c 1.00 in
1
acetone); H NMR (300 MHz, CDCl3) δ =7.84-7.75 (m, 4H), 7.29-7.21 (m, 4H), 6.14 (s, 1H), 3.88 (s,
6H), 2.41 (s, 3H), 2.40 (s, 3H), 2.16-2.08 (m, 1H), 2.03-1.65 (m, 10H), 1.55-1.43 (m, 2H); 13C NMR (75
MHz, CDCl3) δ = 144.5, 143.0, 140.6, 139.1, 129.8, 129.4, 127.9, 127.0, 109.6, 64.6, 64.5, 56.8, 42.5,
40.5, 40.0, 37.6, 37.5, 33.21, 33.19, 28.2, 21.80, 21.78; I.R. (neat, cm-1) ν = 3238, 2921, 2858, 1596,
1448, 1300, 1285, 1258, 1148, 1088, 1055, 1014, 927, 812, 755, 725, 650; HRMS (ESI) Calcd for
C26H34N2O5S2 517.1831; found 517.1843.
(1R,3S,5S,7R)-[N-(S)-(p-toluenesulfonyl)-p-toluenesulfonimidoyl]-3-methoxy-7-(methoxymethyl)-
bicyclo[3.3.1]nonan-1-amine 8e: Prepared following the typical amination procedure from 3-methoxy-
7-(methoxymethyl)bicyclo[3.3.1]nonane, the corresponding product was obtained (heptane/ethyl acetate
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70/30 to 50/50) as a colorless pasty solid (87 mg, 88%); 2:1 d.r. (1H NMR evaluation). Rf = 0.35
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2
3
1
(heptane/ethyl acetate 60/40); diastereomer A 2/ diastereomer B 1: H NMR (500 MHz, CDCl3) δ =
4
5
6
7
8
7.85-7.72 (m, 4H), 7.30-7.19 (m, 4H), 6.18 (s, 1H), 6.16 (s, 1H), 3.55-3.46 (m, 1H), 3.27 (s, 3H), 3.23
(s, 3H), 3.20 (s, 3H), 3.19 (s, 3H), 3.09-2.96 (m, 2H), 2.40 (s, 6H), 2.27-2.09 (m, 2H), 2.07-1.56 (m,
9
13
7H), 1.42-1.15 (m, 3H), 1.06 (dd, J = 2.7, 12.0 Hz, 1H); C NMR (75 MHz, CDCl3) δ = 144.3, 144.2,
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142.9, 142.8, 140.6, 139.38, 139.35, 129.70, 129.68, 129.3, 127.64, 127.57, 126.94, 126.92, 78.3, 78.2,
77.4, 77.2, 77.1, 58.8, 58.7, 57.9, 57.8, 56.03, 56.00, 42.7, 42.6, 37.7, 37.6, 35.04, 35.00, 34.90, 34.88,
30.9, 30.7, 28.4, 28.3, 25.79, 25.76, 21.7; I.R. (neat, cm-1) ν = 3232, 2928, 1597, 1450, 1301, 1286,
1254, 1149, 1102, 1072, 1051, 1016, 1006, 909, 812, 727, 702, 656; HRMS (ESI) Calcd for
C26H35N2O5S2 519.1988; found 519.1978.
Acknowledgements. C.L. and B.D. contributed equally to this work. We wish to thank the Institut de
Chimie des Substances Naturelles for financial support and ANR-08-BLAN-0013-01 for fundings and
fellowships (C. L., B. D., F. C.). Support and sponsorship concerted by COST Action D40 "Innovative
Catalysis: New Processes and Selectivities" are kindly acknowledged.
Supporting Information Available. 1H NMR and 13C NMR spectra of all compounds.
Crystallographic data and X-ray structures of 3a, 3e, 3g, 3i, 4, 5e, and 8c. This material is available free
of charge via the Internet at http://pubs.acs.org.
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epoxidation of α-humulene: Neuenschwander, U.; Czarniecki, B.; Hermans, I. J. Org. Chem. 2012,
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(22)Bulman Page, P. C.; McCarthy, T. J. In Comprehensive Organic Synthesis, Vol. 7, B. M. Trost, I.
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(26)After recrystallization in diisopropyl oxide, compound 5f was isolated with an improved d.r. of
12:1.
(27)Heck-type couplings with styrene or methyl acrylate have been performed using Pd(PPh3)2Cl2.
(28)Orbital overlap of the C-C σ bonding orbital with the C-H σ antibonding orbital is allowed by their
trans antiperiplanar disposition thereby leading to activation of the C-H bond.
(29)It should be pointed out that the aminated product 8c is likely to provide opportunities for the
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