Oxidative interception of the hydroamination pathway: A gold-catalyzed diamination of alkenes

Article abstract of DOI:10.1002/chem.200901199

A complimentary diamination of alkenes by using homogeneous gold catalysts is described. The reaction is one of very few examples of homogeneous gold oxidation catalysis and proceeds with high selectivity under mild conditions. Individual steps of the sug

Full text of DOI:10.1002/chem.200901199

FULL PAPER
DOI: 10.1002/chem.200901199
Oxidative Interception of the Hydro
ACHTUNGTRENNaUNG mination Pathway: A Gold-Catalyzed
Diamination of Alkenes
Alvaro Iglesias and Kilian MuÇiz*[a]
Dedicated to Professor Fernando Aznar on the occasion of his 60th birthday
Abstract: A complimentary diamina-
gated on isolated model gold com-
plexes, and new pathways for gold-cat-
alyzed amination reactions were estab-
lished. The key step is an intramolecu-
lar alkyl–nitrogen bond formation from
a gold(III) intermediate. This process
validates the concept of reductive elim-
ination from high oxidation catalyst
tion of alkenes by using homogeneous
gold catalysts is described. The reaction
is one of very few examples of homo-
geneous gold oxidation catalysis and
proceeds with high selectivity under
mild conditions. Individual steps of the
suggested catalytic cycle were investi-
AHCTUNGTRENNUNG
Keywords: amination · gold · ho-
mogeneous catalysis · oxidation ·
reaction mechanisms
À
states for this type of C N bond form-
ing reactions.
Introduction
ACHTUNGTRENdNUNG ently developed the first protocols for the direct diamina-
tion of simple alkenes under either nickel or palladium cat-
alysis.[10,11] Involvement of a metal catalyst in a high oxida-
tion state was postulated for reactions involving palla-
dium.[11b,12] Thereby, the otherwise difficult formation of the
Fundamental investigations on metal-mediated diamination
of alkenes date back to a seminal report from Barluenga
and Aznar. In their work, diamine formation was enabled
by the use of thallium triacetate, which promotes two con-
À
final Calkyl N bond through reductive elimination benefits
secutive aminations within a sequence of aminothallation
from the inherent stabilization of the metalꢀs energy state
(Scheme 1).
III
À
and reductive C N bond formation from a Tl intermediate
upon elimination of TlI.[1] Similarly, diamination reactions
employing stoichiometric amounts of other metal promoters
such as mercury and copper[2] as well as preformed osmium-
ACHTUNGTRENNUNG
(VIII) reagents[3] were reported. Finally, the observation
that palladium salts are capable of promoting the diamina-
tion of alkenes[4] and butadienes[5] served as inspiration for
the development of a catalytic reactivity. Consequently, pal-
ladium-catalyzed oxidation of alkenes and butadienes has
recently emerged as a versatile entry into vicinal di-
À
Scheme 1. Reductive C N bond formation from a PdIV intermediate.
À
amines.[6,7] One concept to this end consists in a final C N
bond formation through the involvement of established p–
allyl intermediates, as mainly developed by Shi and co-work-
ers.[8,9] Within an alternative approach, we have indepen-
Within a general interest to identify complimentary metal
catalysts undergoing diamination via Mn+/M(n+2)+ catalyst
states,[13] gold complexes emerged as suitable candidates.
Gold catalysis itself has risen over past years as a conse-
quence of this metalꢀs unique capability for electrophilic ac-
tivation of unsaturated carbon entities.[14] Such reactions
entail a variety of different addition reactions to unsaturated
C C bonds and subsequent cascade reactions. Despite this
impressive body of work, gold-catalyzed oxidation reactions
for the construction of C C and C X bonds involving
[a] A. Iglesias, Prof. Dr. K. MuÇiz
Institut de Chimie, UMR 7177, University of Strasbourg,
4 rue Blaise Pascal, F-67000 Strasbourg Cedex (France)
Fax : (+33)390-241521
À
À
À
E-mail: muniz@chimie.u-strasbg.fr
gold(I)/gold
AHCTUNGTRENNUNG
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200901199.
protocol to intercept the common hydroamination path-
Chem. Eur. J. 2009, 15, 10563 – 10569
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10563

way[16] in gold catalysis to generate vicinal diamines. This
work also aims to clarify several mechanistic aspects of the
homogeneous gold catalyst states.
Under the chosen conditions, a variety of diamination re-
actions could readily be realized, including oxidation to the
new compounds 2e, 2 f, 2i, 2l, and 2m (Table 1).
Liberation of the corresponding free diamines from the
urea core has proven somewhat troublesome in the past;
Results and Discussion
Table 1. Gold-catalyzed diamination of alkenes.
Scheme 2 summarizes the initial screening of gold com-
plexes as catalysts for the intramolecular diamination of 1a.
Under optimized conditions, the gold(I) acetate complex 3
Entry[a]
Substrate
Product
Yield[b]
[%]
1
90
85
88
2
3
4
5
90
87
Scheme 2. Development of conditions for the gold-catalyzed diamination
of 1a. NHC=1,2-bis(2,6-diisopropylphenyl)imidazol-2-ylidene. Reported
yields refer to purified and isolated material.
6
7
8
93
92
85
gives complete conversion and high isolated yield under
mild reaction conditions. A related complex bearing a NHC
ligand[17] was less efficient. Less than 5% conversion was ob-
served in the absence of the gold catalyst. The related com-
plex Ph3PAuCl shows slower performance in the presence of
acetate base. Control experiments reveal that under the con-
ditions of the catalysis, it is slowly transformed into the re-
spective acetate complexes over time.[18]
9
82
Abstract in Spanish: Se describe una diaminaciꢀn de alque-
nos complementaria usando catalizadores de oro en fase ho-
mogꢁnea. Esta reacciꢀn constituye uno de los pocos y excep-
cionales ejemplos de oxidaciꢀn en catꢂlisis homogꢁnea con
oro, procediendo con una elevada selectividad en condiciones
moderadas. Investigaciones de cada etapa individual del ciclo
catalꢃtico, llevadas a cabo en complejos de oro aislados, han
permitido establecer nuevas vꢃas hacia reacciones de amina-
10
11
12
87
84
ciꢀn catalizadas por oro. El paso clave de la reacciꢀn es la
3
À
formaciꢀn intramolecular de un enlace Csp N a partir de un
62
intermedio de oro
A
catalizadores en altos estados de oxidaciꢀn para inducir una
eliminaciꢀn reductora en la formaciꢀn de este tipo de enlaces
À
C N.
[a] General reaction conditions: 7.5 mol% gold catalyst
3
(from
Ph3PAuCl and AgOAc), 0.4m solution in dichloroethane, 1.2 equiv iodo-
sobenzene diacetate, 0.5 equiv NaOAc, 558C external bath temperature,
10 h. [b] Isolated yield after purification.
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Gold-Catalyzed Hydroamination
FULL PAPER
however, urea removal has been reported within a recent al-
kaloid synthesis,[13c] and we have now found that for hydro-
carbon substituents diamine liberation can be accomplished
within a two-step sequence as shown for product 2c
(Scheme 3):
Scheme 3. Conditions for tosyl and urea removal.
Two experiments involving oxidation of compounds
[D1]1a and 1m confirmed the overall stereochemical pro-
cess, and that the reaction is indeed diastereoselective
(Scheme 4). This stereochemical outcome is opposite to the
one from our previous palladium catalysis,[11a,b] in which 1m
does not yield a diamination product, and [D1]1a forms the
opposite diastereoisomer. It thus has the potential to im-
prove our understanding of the mechanistic pathways in the
presence of the gold catalyst.
Scheme 5. Proposed catalytic cycle for oxidation with catalyst
(L=PPh3).
3
AHCTUNGTRENNUNG
First, these approaches demonstrated that triphenylphos-
phine gold acetate 3 is inert to oxidation in the presence of
iodosobenzene diacetate as judged from unchanged
31P NMR spectra. This observation provides evidence that
the initial aminometallation step occurs indeed at a metal
oxidation state of +I.
This was further evidenced from the fact that reactions
starting from gold(I) catalysts such as [AuCl
significantly faster than those from the corresponding gold-
(III) catalysts. Figure 1 shows a representative stoichiometric
investigation by using [AuCl(PPh3)] and [AuCl3A(PPh3)], re-
ACHTUNGRTEN(NUNG PPh3)] initiate
AHCTUNGTRENNUNG
A
CHTUNGTRENNUNG
spectively, in the presence of excess acetate. As we have so
far been unable to generate a trisacetate gold species, the
experiment was conducted in the presence of two equiva-
lents of acetate base, to allow putative formation of mixed
Scheme 4. Stereochemical aspects of gold-catalyzed diamination.
The following catalytic cycle is suggested for this new
gold oxidation catalysis on the basis of the observed reac-
tion products and based on relevant control experiments as
discussed in the following (Scheme 5). The reaction initiates
through an anti-aminometallation.[19–21] The resulting alkyl
gold complex A then undergoes irreversible oxidation to the
À
corresponding goldACHTUNGTRENNUNG(III) complex B. At this stage, C N bond
formation with the anion of the tosylamido group (C) gener-
ates the product and closes the catalytic cycle. Because the
acetate base is continuously regenerated during the course
of the reaction, the present protocol readily works in the
presence of substoichiometric amounts of base.
The mechanistic understanding of gold catalysts can con-
stitute a major challenge.[22] With the aim to further under-
stand the individual steps of the catalytic cycle, stoichiomet-
ric control experiments on isolated gold model complexes
were performed and monitored by 31P NMR spectroscopy.[18]
Figure 1. Kinetic profile for initial diamination processing employing a
gold(I) or goldACTHNUTRGNEU(GN III) catalyst source.
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10565

K. MuÇiz and A. Iglesias
acetate species. Product formation over time shows a signifi-
cantly retarded reaction for catalysis that starts from the
gold
ACHTUNGTRENNUNG
tion is also known to proceed with goldAHCUTNGTRENNUNG
present observation suggests that temperature plays an im-
portant role for the initial step of aminometallation in this
case. Attempts to carry out the reaction at elevated temper-
atures of hydroamination conditions above 1008C resulted
in the formation of complex mixtures with little or no diami-
nation product detected.
Alkyl gold species such as the methyl gold complex 5 un-
dergo quantitative oxidation to a clean 90:10 mixture of two
isomeric goldACHTUNGTRENNUNG(III) complexes 6a and 6b (Scheme 6). For
Scheme 6. Stoichiometric control experiments on oxidation of gold com-
plex 5.
equimolar amounts of reactants, this process proceeds
within 40 min at room temperature and within 15 min at
558C and is again selective with respect to the gold center
because no phosphine oxidation was detected during NMR
spectroscopy experiments (Figure 2). When the reaction is
carried out in the presence of approximately ten equivalents
of oxidant, the final ratio of 6a/6b is 58:42. This suggests
that under the actual catalysis conditions both isomers are
present in significant amounts.
Changing the oxidant to phthaloyl based iodosobenzene 7
resulted in the formation of a single isomer 8, formation of
which required a reaction half time of just 18 min at room
temperature.[18] Despite extensive efforts, complexes of the
type 6 and 8 are too reactive and have so far escaped isola-
tion.
Figure 2. Kinetic profile for oxidation of methyl gold complex 3 with 1
(top) and 10 equiv (bottom) of PhIACTHNUTRGENUN(G OAc)2 at T=298 K.
ladium catalysis requires urea deprotonation for palladium
coordination prior to the initial aminopalladation event. For
the case of the present gold catalyst, anti-aminometallation
does not require such a precoordination and hence allows
for a reduction in the amount of base.
However, chemoselectivity is significantly diminished in
the complete absence of base and the 1,2-difunctionalization
then leads to a mixture of diamine 2e and isourea 9
(Scheme 7). Still, no hydroamination product is detected
Among the well-studied gold-catalyzed hydroamination
reactions,[16] Widenhoefer described the application of urea
substrates related to compounds 1.[16e] However, hydroami-
nation does not constitute a competitive event within the
present process. This is based on the fact that under the
chosen conditions, acetic acid is the strongest acid within the
system. Evidently, alkyl–gold bond cleavage at stage A by
acetic acid is slow in comparison to gold oxidation. For hy-
droamination reactions, this observation suggests that apart
from playing a role in aminoauration, the anion nature is de-
cisive to generate strong acid to assure protonolysis of the
rather unpolar alkyl–gold intermediate such as A.
Scheme 7. Gold-catalyzed alkene oxidation under base-free conditions.
and for the overall reaction, this pathway characterizes the
gold-catalyzed diamination reaction as an oxidatively inter-
cepted hydroamination.
It is important to note that unlike palladium catalysts,
complex 3 even works under base-free conditions. This ob-
servation can be rationalized from the observation that pal-
Observation of the putative gold
ACHTUNGERTN(NUNG III) complexes 6a and b
À
allowed us to monitor the final step of C N bond formation
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Gold-Catalyzed Hydroamination
FULL PAPER
by reductive elimination from the goldACTHNUTRGNEUNG
(III) catalyst.[23]
Treatment of this mixture with an equimolar amount of
anionic N-tosyl urea 10 led to almost immediate clean for-
mation of the corresponding N-methylated product 11 to-
phine gold(I) chloride was purchased from ChemPur. [1,3-Bis(2,6-diiso-
propylphenyl)imidazol-2-ylidene]gold(I) chloride was purchased from Al-
drich. Triphenylphosphine methyl gold(I), triphenylphosphine gold(I)
acetate, and triphenylphosphine goldACTHNUTRGNEUGN(III) trichloride were prepared fol-
lowing literature protocols.[25–27] CH2Cl2 was dried over CaCl2, distilled,
and used without further manipulation. Column chromatography was
performed with silica gel (Merck, type 60, 0.063–0.2 mm). NMR spectra
were recorded on a Bruker Avance 400 MHz spectrometer. All chemical
shifts in NMR spectroscopy experiments are reported as ppm downfield
from tetramethylsilane. The following calibrations were used: CD2Cl2 d=
5.30 and 55.00 ppm; CDCl3 d=7.26 and 77.00 ppm. Melting points were
measured on a Bꢂchi Melting Point B-450 apparatus. MS (ESI-LCMS)
experiments were performed using an Agilent 1100 HPLC with a Bruker
micro-TOF instrument (ESI). Unless otherwise stated, a Supelco C8
(5 cm x 4.6 mm, 5 mm particles) column was used with a linear elution
gradient from 100% H2O (0.5% HCO2H) to 100% MeCN in 13 min at a
flow rate of 0.5 mLminÀ1. MS (EI) and HRMS experiments were per-
formed on a Kratos MS 50 within the service centers at ISIS Strasbourg
and the University of Strasbourg (France).
gether with the reduced gold(I) acetate complex
3
(Scheme 8). This process could also be followed by
À
Scheme 8. Reductive C N bond formation from gold
N
Synthesis of gold acetate catalysts: The respective gold chloride precursor
was dissolved in absolute CH2Cl2 under argon. AgOAc (1.0 equiv) was
added in one portion, and the resulting mixture was stirred in the dark at
RT for 1 h before it was left to stand for 1 h under argon. It was filtered
through a pad of Celite, which was washed with small portions of
CH2Cl2. The combined filtrates are reduced to dryness under reduced
pressure to leave the gold(I) acetate complexes as white solids.
Triphenylphosphinegold(I) acetate (3):[26] White solid, 100%; 1H NMR
(400 MHz, CD2Cl2): d=1.96 (s, 3H), 7.46–7.50 (m, 6H), 7.53–7.58 ppm
(m, 9H); 31P NMR (121 MHz, CD2Cl2): d=27.68 ppm (s); 13C NMR
(100 MHz, CD2Cl2): d=26.64, 129.10 (d, J=63.6 Hz), 129.52 (d, J=
12.2 Hz), 132.32 (d, J=3.0 Hz), 134.51 (d, J=13.8 Hz), 176.53 ppm.
31P NMR spectroscopy and the known product 3 was unam-
biguously identified from its NMR spectroscopic data. No
other phosphine–gold complexes could be detected during
the course of the reaction. In agreement with the required
stereochemistry as demanded from the respective product
configurations from Scheme 4, an SN2-type attack on the
methyl carbon in 6a and 6b is proposed (Scheme 5, state
C), which for the intramolecular diamination must result in
inversion of configuration.[24] This is in agreement with a re-
AHCTUNGTERG[NNUN 1,3-Bis(2,6-diisopropylphenyl)imidazol-2-ylidene]gold(I) acetate (4):
White solid, 100%; 1H NMR (400 MHz, CD2Cl2): d=1.22 (d, J=6.7 Hz,
12H), 1.35 (d, J=7.0 Hz, 12H), 1.64 (s, 3H), 2.55 (hp, J=7.0 Hz, 4H),
7.23 (s, 2H), 7.34 (d, J=7.8 Hz, 4H), 7.55 ppm (t, J=7.8 Hz, 2H);
13C NMR (100 MHz,CD2Cl2): d=23.89, 24.13, 24.42, 29.20, 123.75, 124.56,
130.95, 134.50, 146.21, 168.73, 175.73 ppm; HRMS: m/z: calcd for
C17H12AuLiN2O2: 480.0724; found: 480.0756.
lated oxidative methanol synthesis with goldACTHNUTRGNEUNG
(III),[15a] and, in
sharp contrast to palladium,[11a,b] characterizes the overall
gold-catalyzed diamination as an anti-aminometallation/anti-
[24]
À
C N bond formation process.
This diamination procedure on the basis of gold(I)/gold-
Synthesis of alkene starting materials. Alkene starting materials were
ACHTUNGTRENNUNG(III) catalysis is reminiscent of our earlier findings with pal-
prepared as previously described.[11a,b]
ladium catalysts. Although the two protocols are very simi-
lar in nature, and the price for generating the gold(I) cata-
lyst might be an issue when compared to palladium acetate,
they are complimentary in diastereoselectivity due to the
difference in stereochemistry for the initial step of amino-
General procedure for diamination: The urea starting material
(0.2 mmol, 1.0 equiv), iodosobenzene diacetate (0.24 mmol, 1.2 equiv)
and NaOAc (0.08 mmol, 0.4 equiv) were weighed into an oven-dried
Pyrex tube equipped with a magnetic stirrer bar and set under N2 atmos-
phere. Preformed gold acetate catalyst 3 (0.015 mmol, 7.5 mol%) or a
combination of triphenylphosphine gold chloride (0.015 mmol) and
AgOAc (0.015 mmol) were added in one portion, and the combined
solids were dissolved in CH2Cl2 (2 mL). The resulting mixture was stirred
for 12 h at 508C oil bath temperature. The reaction was quenched by ad-
dition of sat. aq Na2S2O3 solution, and a small additional amount of H2O
was added. The organic phase was separated, and the aqueous phase was
extracted with EtOAc several times. The combined organic layers were
dried over MgSO4 and the solvent was removed under reduced pressure.
All products were purified by flash-chromatography.
metallation. In the second step the goldACTHNUTRGNEUNG(III) catalyst state
enables reductive elimination in a similar manner as does
the postulated PdIV intermediate.[11b]
In conclusion, we have broadened the catalyst scope for
the diamination of alkenes by introducing a homogeneous
gold(I) catalyst. The individual steps of the catalytic cycle
were investigated on the basis of model reactions and char-
acterized the overall reaction as an oxidatively intercepted
hydroamination reaction. It also provides evidence that
Compounds 2a–2d, 2g, 2h, 2k, and [D1]2a are known compounds that
were described previously.[11a,b] For the reported reactions, all involved
products matched with authentic compounds as verified by 1H and
13C NMR spectroscopy.
gold(I)/goldACHTUNGTRENNUNG(III) cycles are capable of realizing oxidation
catalysis under homogeneous conditions. The obtained data
render a further development of alkene oxidation based on
gold catalysis promising.
2’-Tosyltetrahydrospiro[cyclopentane-1,6’-pyrroloACHTUNTRGENNUG[1,2-c]imidazol]-3’ACHTUNGTRENNUNG(2’H)-
one (2e): White solid; m.p. 838C; 1H NMR (400 MHz, CDCl3): d=1.36–
1.63 (9H, m), 1.88 (dd, J1 =5.8 Hz, J2 =12.0 Hz 1H), 2.41 (s, 3H), 2.86 (d,
J=11.1 Hz, 1H), 3.38 (d, J=11.1 Hz, 1H), 3.63–3.66 (m, 1H), 3.84–3.90
(m, 1H), 3.99–4.04 (m, 1H), 7.31 (d, J=7.6 Hz, 2H), 7.90 ppm (d, J=
7.6 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.6, 24.1, 24.2, 38.0, 38.2,
43.9, 48.1, 51.7, 54.9, 57.1, 127.9, 129.6, 134.9, 144.7, 156.3 ppm; IR (KBr):
n˜ =2928, 2854, 1729, 1385, 1365, 1266, 1170, 736, 704, 667 cmÀ1; MS (ESI-
LCMS): m/z (%): 335 (100) [M+H]+; HRMS: m/z: calcd for
C17H22Li1N2O3S1: 341.1506; found: 341.1474.
Experimental Section
General. All organic reagents, sodium acetate, iodosobenzene diacetate
and all deuterated solvents were purchased from Aldrich. Triphenylphos-
Chem. Eur. J. 2009, 15, 10563 – 10569
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10567

K. MuÇiz and A. Iglesias
2’-Tosyltetrahydrospiro[cyclopropane-1,6’-pyrrolo
G
E
928C; 1H NMR (400 MHz, CDCl3): d=1.47–1.65 (m, 9H), 1.94 (dd, J1 =
6.1 Hz, J2 =12.3 Hz, 1H), 2.38 (s, 3H), 3.06 (d, J=11.4 Hz, 1H), 3.49 (d,
J=11.4 Hz, 1H), 4.14–4.27 (m, 2H), 4.69 (t, J=8.2 Hz, 1H), 7.22 (d, J=
8.4 Hz, 2H), 7.81 ppm (d, J=8.4 Hz, 2H); 13C NMR (100 MHz, CDCl3):
d=21.4, 24.1, 24.2, 37.7, 38.0, 43.26, 53.2, 58.3, 59.6, 73.7, 126.9, 129.0,
139.8, 142.3, 160.79 ppm; IR (KBr): n˜ =2947, 1589, 1478, 1434, 1301,
1154, 1111, 1083, 895, 873, 824, 734, 692 cmÀ1; MS (ESI-LCMS): m/z (%):
335 (100) [M+H]+; HRMS: m/z: calcd for C17H22Li1N2O3S1: 341.1506;
found: 341.1511.
one (2 f): White solid; m.p. 858C; 1H NMR (400 MHz, CDCl3): 0.51–0.53
(m, 1H), 0.60–0.66 (m, 3H), 1.61 (dd, J1 =5.3 Hz, J2 =12.0 Hz, 1H), 1.77
(dd, J1 =9.6 Hz, J2 =12.0 Hz, 1H), 2.46 (s, 3H), 2.83 (d, J=11.1 Hz, 1H),
3.57 (d, J=11.1 Hz, 1H), 3.79 (d, J=6.4 Hz, 1H), 4.00–4.04 (m, 2H), 7.36
(d, J=8.2 Hz, 2H), 7.95 ppm (d, J=8.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=8.8, 14.1, 21.6, 40.6, 47.0, 53.1, 55.6, 128.0, 129.6, 135.1, 144.8,
156.4 ppm; IR (KBr): n˜ =2927, 2854, 1730, 1676, 1597, 1449, 1366, 1267,
1171, 1120, 1091, 815, 734, 704, 664 cmÀ1; MS (ESI-LCMS): m/z (%): 313
(14) [M+Li]+, 292 (15), 273 (10), 255 (13), 242 (25), 239 (100), 225 (20),
214 (30), 198 (50), 182 (33), 176 (10), 168 (8), 153 (3); HRMS: m/z: calcd
for C15H18N2NaO3S: 329.0900; found: 329.0930.
Exposure of Ph3P-AuMeACHTNUGRTENUNG(OAc)2 to an excess of anionic urea: N-Tosylpyr-
rolidine-1-carboxamide was dissolved in abs THF and NaH was carefully
added under an atmosphere of argon. After 2 h at RT the solvent was re-
moved under reduced pressure, and the remaining white solid was dried
7a’-Methyl-2’-tosyltetrahydrospiro[cyclopentane-1,6’-pyrrolo
(2’H)-one (2i):White solid; m.p. 1148C; 1H NMR (400 MHz,
in vacuo. A solution of the in situ formed goldACTHNUTRGENUG(N III) complexes 6a and 6b
dazol]-3’
was added, and the resulting mixture was stirred at RT. Monitoring by
31P NMR spectroscopy revealed the disappearance of the signals for 6a/
6b in favor of the singlet at 27 ppm; this was indicative of the initial ace-
tate complex 3 within a period of 5 min (See below). When carried out
on a preparative 0.3 mmol scale, the N-methylated product 10 could be
isolated by silica gel chromatography (hexanes/EtOAc, 1:1; v/v) as an
off-white solid (84%). 1H NMR (400 MHz, CDCl3): d=1.96 (m, 2H),
2.44 (s, 3H), 2.83 (s, 3H), 3.64 (m, 2H), 7.34 (d, J=8.1 Hz, 2H),
7.80 ppm (d, J=8.1 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.5, 25.1,
34.5, 48.0, 128.6, 129.4, 133.7, 144.2, 154.5 ppm; LC–MS m/z (%): 283
(100) [M+H]+, 279 (18), 267 (8), 255 (10), 226 (19), 214 (15), 196 (19);
HRMS: m/z: calcd for C13H18N2NaO3S: 305.09; found: 305.0930.
CDCl3): d=0.99–1.04 (m, 1H), 1.07–1.31 (m, 1H), 1.30 (s, 3H), 1.43–1.55
(m, 6H), 1.65–1.77 (m, 2H), 2.41 (s, 3H), 2.76 (d, J=12.0 Hz, 1H), 3.48
(d, J=12.0 Hz, 1H), 3.65–3.70 (m, 2H), 7.31 (d, J=8.2 Hz, 2H),
7.91 ppm (d, J=8.2 Hz, 2H); 13C NMR (100 MHz, CDCl3): d=21.6, 24.1,
24.2, 27.1, 37.7, 39.3, 50.8, 52.2, 56.3, 56.4, 61.8, 128.1, 129.5, 134.7, 144.7,
156.5 ppm; IR (KBr): n˜ =2953, 2872, 1732, 1456, 1365, 1165, 1092, 736,
667 cmÀ1; MS (ESI-LCMS): m/z (%): 349.15 (100) [M+H]+; HRMS:
m/z: calcd for C18H24Na1N2O3S1: 371.1400; found: 371.1353.
6-Phenyl-2-tosyltetrahydro-1H-pyrrolo
G
G
(2l):
White solid; m.p. 1518C; 1H NMR (400 MHz, CDCl3): d=1.49–1.55 (m,
1H), 2.36–2.42 (m, 1H), 2.47 (s, 3H), 3.49–3.59 (m, 3H), 3.86–3.95 (m,
2H), 4.05–4.10 (m, 1H), 7.11–7.13 (m, 2H), 7.24–7.31 (m, 3H), 7.37 (d,
J=8.2 Hz, 2H), 7.98 ppm (d, J=8.2 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=21.6, 40.0, 45.5, 46.9, 51.9, 56.3, 126.9, 127.0, 127.9, 128.7,
129.7, 135.0, 141, 144.8, 156.3 ppm; IR (cmÀ1): n˜ =3062, 2968, 1728, 1597,
1363, 1265, 1166, 1092, 815, 736, 702, 664 cmÀ1; MS (ESI-LCMS): m/z
(%): 357.08 (100) [M+H]+; HRMS: m/z: calcd for C19H20Na1N2O3S1:
379.1087; found: 379.1089.
Acknowledgements
This work was supported by the Fonds der Chemischen Industrie, Ger-
many, the Agence nationale de la recherchꢃ, France, the Centre Interna-
tional de Recherche au Frontiꢄre de la Chimie, France and the Institut
Universitaire de France. A. I. thanks DAAD and Fundaciꢅn La Caixa
for a predoctoral fellowship.
Octahydro-6,6-dimethyl-2-tosylimidazoACTHUNTGRNEUNG[4,5,1-hi]indol-1-one (2m): White
solid; m.p. 1578C; 1H NMR (400 MHz, CDCl3): d=0.75–0.81 (m, 1H),
1.01 (s, 3H), 1.11 (s, 3H), 1.12–1.20 (m, 1H), 1.35–1.45 (m, 1H), 1.58–
1.68 (m, 3H), 2.05–2.13 (m, 1H), 2.42 (s, 3H), 2.91 (d, J=10.5 Hz, 1H),
3.12 (d, J=10.5 Hz, 1H), 4.17–4.21 (m, 1H), 4.47–4.52 (m, 1H), 7.29 (d,
J=8.0 Hz, 2H), 7.96 ppm (d, J=8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl3): d=19.2, 21.6, 22.1, 22.1, 27.8, 28.6, 44.7, 45.4, 54.2, 56.4, 56.9,
128.2, 129.4, 136.9, 144.2, 153.7 ppm; IR (KBr): n˜ =2943, 2872, 1731,
1396, 1358, 1309, 1265, 1168, 1090, 815, 734, 704, 662 cmÀ1; MS (ESI-
LCMS): m/z (%): 349.19 (100) [M+H]+; HRMS: m/z: calcd for
C18H24Li1N2O3S1: 355.1663; found: 355.1619.
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4,4-Diphenylpyrrolidin-2-yl-methylamine (2c’): Urea 2c (433 mg,
1 mmol) was dissolved in abs MeOH and Na2CO3 (1.07 g, 10 mmol) was
added in one portion. Three portions of freshly prepared Na amalgam
(5%-Na, 8.5 g) were added over a period of 3 h to the stirred solution.
The reaction mixture was diluted with EtOAc and extracted with sat.
Na2CO3 solution. After additional washing with EtOAc, the organic
phases were evaporated to dryness and taken up in freshly distilled Et2O
under an atmosphere of argon. LiAlH4 (76 mg, 2 mmol) was added in a
single portion, and the resulting solution was refluxed for 2 h. After cool-
ing to 08C, it was quenched with a minimum amount of 1m NaOH solu-
tion, dried over MgSO4, and filtered through a pad of Celite. Removal of
the solvent under reduced pressure left 2c’ as a colorless oil (227 mg,
0.9 mmol, 90%). 1H NMR (CDCl3, 400 MHz): d=1.92 (dd, J=12.9 Hz,
9.1 Hz, 1H), 2.49 (s, 3H), 2.59 (dd, J=12.3 Hz, 7.9 Hz, 1H), 2.67 (dd, J=
12.3 Hz, 4.4 Hz, 1H), 2.76 (ddd, J=12.9 Hz, 7.0 Hz, 1.6 Hz, 1H), 3.23–
3.30 (m, 2H), 3.61(dd, J=11.7 Hz, 1.7 Hz, 1H), 7.07–7.26 ppm (m, 10H);
13C NMR (CDCl3, 100 MHz): d=42.1, 47.1, 56.8, 57.1, 59.7, 126.1, 126.2,
126.8, 127.0, 128.3, 128.5, 146.1, 147.0 ppm; IR (KBr): n˜ =3390, 3150,
3056, 3025, 2963, 2923, 2878, 1650, 1600, 1494, 1446, 1361, 1262, 1157,
1096, 1031, 757, 699, 586 cmÀ1; MS (ESI-LCMS): m/z (%): 253 (60)
[M+H]+, 236 (100), 198 (10), 158 (10), 141 (6), 95 (25), 79 (15); HRMS:
m/z: calcd for C17H21N2 [M+H]+: 253.1699; found: 253.1704.
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10568
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Chem. Eur. J. 2009, 15, 10563 – 10569

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Received: May 6, 2009
Published online: September 10, 2009
Chem. Eur. J. 2009, 15, 10563 – 10569
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
10569