Enantioselective decarboxylative amination: Synthesis of axially chiral allenyl amines

Article abstract of DOI:10.1002/anie.201204796

Getting axed: Synthesis of the title amines, bearing functionality (R ¹ and R²), involves the enantioselective palladiumcatalyzed decarboxylation of allenyl Ntosylcarbamates. The reaction proceeds smoothly using both the chiral ligan

Full text of DOI:10.1002/anie.201204796

Angewandte
Chemie
DOI: 10.1002/anie.201204796
Synthetic Methods
Enantioselective Decarboxylative Amination: Synthesis of Axially
Chiral Allenyl Amines**
Baoqiang Wan and Shengming Ma*
Naturally occurring biomolecules that display chirality are
enantiomerically enriched and different enantiomers show
different biological activities. Thus, the development of new
enantioselective approaches for chiral compounds are still of
great interest. Allenes are now an important class of
compounds and versatile intermediates in organic synthesis.[1]
Thus, efficient methodologies for synthesizing allenes is of
current interest for organic chemists.[2] The synthesis of axially
chiral allenes are particularly important because of their
efficient chirality transfer[3] and their existence as core
structures in natural products and pharmaceuticals.[4] Typi-
cally, the synthesis of axially chiral allenes relies on the
resolution of racemic allenic precursors[5] and the chirality
transfer of chiral propargyl alcohols[6] or propargyl amine
derivatives.[7] However, most of these procedures require
Scheme 1. Enantioselective synthesis of axially chiral allenes via an
stoichiometric amounts of enantiomerically enriched chiral
a-methylene p-allylpalladium intermediate. Bn=benzyl, Boc=tert-bu-
toxycarbonyl.
compounds, and are thus inefficient. Recently, asymmetric
catalysis for the synthesis of chiral allenes has attracted much
attention.[8–10] Trost et al.[9f] and Imada et al.[10a] have inde-
pendently reported the asymmetric synthesis of allenyl
amines with 76–91% ee by using intermolecular reactions.
Interestingly, in two reported examples, 95 or 97% of ee has
been realized (Scheme 1, top). Herein, we disclose a different
protocol for the construction of axially chiral allenyl amines,
investigated and the results are listed in Table 1. Some issues
should be noted: 1) the yields of these reactions are good to
excellent; 2) functional groups such as alkynyl, allenyl, and
alkenyl, were tolerated in the reaction; 3) when R2 = H, the
reaction afforded the monoallenylation product 2n and the
diallenylation product 2n’ in 73% and 8% yields, respec-
tively, upon isolation.
=
bearing an extra hydroxy group or C C bond, by the
decarboxylative amination[11] of allenyl N-tosylcarbamates;
the products are obtained in 91–99% ee (Scheme 1, bottom).
Initially, we successfully established the palladium-cata-
lyzed decarboxylative amination of N-tosylcarbamates for the
synthesis of racemic allenyl amines. After screening the
reaction conditions, it was observed that the reaction of
1 could proceed smoothly to afford the allenyl amines 2 by
utilizing 5 mol% of [Pd(PPh3)4] in CH2Cl2 at 408C. The scope
of decarboxylative reaction of the N-tosylcarbamates 1 was
With this approach in hand, we envisioned that such
a decarboxylative amination reaction could afford the axially
chiral allenes if a chiral catalyst was used. The N-tosylcarba-
mate 1a was chosen as a model substrate to optimize the
reaction conditions for the enantioselective decarboxylation.
Firstly a variety of chiral phosphine ligands were examined in
THF (Scheme 2). The results with the most commonly used
ligands for enantioselective allylation are disappointing: The
use of (S)-binap [(S)-L1] gave only 22% ee,[12] and the
reaction failed to afford the desired product 2a when using
either the Trost ligand (R,R)-L2 or (R,R)-L3.[13] It is exciting
to observe that the results with biphenyl ligands are much
better. A much higher enantioselectivity was observed in the
reactions using (R)-L4 and (S)-Segphos. Additional screening
based on the results of (S)-Segphos led to the observation that
the reaction with (S)-DTBM-Segphos gave the best enantio-
selectivity (86% ee) albeit with a low yield. Thus, (S)-DTBM-
Segphos was chosen as the ligand for optimization studies for
improving the yield and enantioselectivity.
[*] B. Wan, Prof. Dr. S. Ma
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
345 Lingling Lu, Shanghai 200032 (P.R. China)
E-mail: masm@sioc.ac.cn
Prof. Dr. S. Ma
Shanghai Key Laboratory of Green Chemistry and Chemical Process,
Department of Chemistry, East China Normal University
3663 North Zhongshan Lu, Shanghai 200062 (P.R. China)
[**] Financial support from the National Natural Science Foundation of
China (21232006) and the Major State Basic Research and
Development Program (2011CB808700) is greatly appreciated. We
thank Minyan Wang from our research group for reproducing the
results for compounds 2i, (S)-2d, and (S)-2v.
Next, the effect of solvent (1,4-dioxane, DME, CH2Cl2,
toluene, and DMF) was studied, and DMF resulted in the
complete consumption of 1a and highest enantioselectivity
(Table 2, entries 1–6). By conducting the reaction at 258C, the
enantioselectivity was improved to 91% ee (entry 7). Finally,
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201204796.
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Table 1: [Pd(PPh3)4]-catalyzed decarboxylation of the N-tosylcarbamates
1.
Table 2: Solvent effect on the enantioselective decarboxylative amination
of 1a.[a]
Entry
Solvent
T
[8C]
t
[h]
1a (rec.)
2a
Yield [%][c]
[%][b]
ee [%][d]
1
2
3
4
5
6
THF
1,4-dioxane
DME
CH2Cl2
toluene
DMF
50
50
50
50
50
50
25
25
48
48
48
48
48
48
96
84
52
12
29
67
17
0
33
75
40
20
70
85
79
88
86
82
87
74
84
88
91
92
7[e]
8[e]
DMF
DMF/DME
0
0
[a] Under argon, a mixture of 1a (0.1 mmol), [Pd(dba)2] (5 mmol), and
(S)-DTBM-Segphos (7.5 mmol) was stirred in 1 mL of the indicated
1
solvent. [b] recovered starting compound 1a, determined by H NMR
analysis using 1,3,5-trimethylbenzene as the internal standard. [c] Yield
of isolated product. [d] Determined by HPLC analysis using a chiral
stationary phase. [e] The reaction was carried out on a 0.5 mmol scale in
2 mL of DMF/DME (1:1). DME=dimethoxyethane, DMF=N,N’-dime-
thylformamide, THF=tetrahydrofuran.
it was observed that a combination of DMF and DME led to
a higher yield and enantioselectivity (entry 8).
Substituents on the phenyl ring have a limited influence
on the yields and enantioselectivities (Scheme 3). The 4-Cl
and 2-Cl substituents on the phenyl ring were also suitable in
this reaction, thus providing an opportunity for elaboration of
the product.
TBS=tert-butyldimethylsilyl, Ts=4-toluenesulfonyl.
Scheme 3. The effect of the substituent of the phenyl ring on the reaction.
Notably, the R group on the nitrogen atom greatly
influences the enantioselectivity, and an isopropyl group
gave the best result with a 97% ee (Table 3). The absolute
configuration was assigned by analogy to that of (S)-2t, the
configuration of which was determined by a single-crystal X-
ray diffraction study (Figure 1).[14]
Interestingly, with the synthetically attractive tertiary
alcohol group as R1, the decarboxylative reaction proceeded
smoothly to afford the axially chiral allenyl amines in 93–
97% ee (Table 4). To our delight, the en-allene (S)-2m was
obtained, and can be used for additional cyclization.[15]
To emphasize the practicability of the methodology, the
reactions of 1u and 1m were conducted on a one-gram scale,
thus affording the desired products (S)-2u and (S)-2m,
respectively, in 97% ee (Scheme 4). The reaction of 1w
afforded 2w in 97%ee. After removal of the TBS group from
Scheme 2. Ligand effect on the enantioselective decarboxylative amina-
tion of 1a. dba=dibenzylideneacetone, n.d.=not detected.
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Table 3: Enantioselective decarboxylative amination of the N-tosylcar-
bamates 1. The effect of the R group.
Scheme 4. Synthesis of the 2,5-dihydrofuran derivatives 3 and
4.DMA=diemthylacetamide, TBAF=tetra-n-butylammonium fluoride.
(S)-2u, (S)-2w, and (S)-2m to afford the corresponding
allenols, the palladium(II)-catalyzed cyclization was per-
formed in the presence of allyl bromide, thus providing the
2,5-dihydrofuran derivatives (À)-3a, (À)-3b, and (À)-3c with
complete chirality transfer.[16] The triene (À)-3c with an N-
allylic unit could be transformed into the hetero-bicyclic
diene product 4 in 82% yield and 96% ee using a ring-closing
metathesis reaction at 108C.
Figure 1. ORTEP representation of (S)-2t. Thermal ellipsoids are
shown at 30% probability.
Table 4: Enantioselective decarboxylative amination of 1 bearing a TBS-
protected alcohol unit.[a]
Furthermore, the reaction of 1x, bearing a secondary
alcoholic group, afforded a pair of diastereoisomers (d.r. =
1:1) with high ee values [Scheme 5, Eq. (1)]. When the
optically active substrates having a central chirality such as
(S)-1x and (R)-1x were used, all four isomers (Sa,S)-2x,
(Ra,S)-2x, (Sa,R)-2x, and (Ra,R)-2x were obtained success-
fully with this protocol using either (S)-DTBM-Segphos or
(R)-DTBM-Segphos as the ligand. It is interesting to observe
that there is a case for matched or mismatched pairs between
the chiral substrates and the ligand affording different
diastereoisomeric excess [Scheme 5, Eqs. (2)–(5)].
At this moment we do not have a working model to
predict the absolute configuration of the allene moiety for this
reaction. On the basis of the results presented in Scheme 2, we
reason that the binaphthyl backbone in the L1 and the
biphenyl backbone in L4 and Segphos are responsible for the
high catalytic reactivities since the Trost ligands L2 and L3
demonstrated a very slow reaction. The biphenyl backbone in
[a] The ee value was determined for the corresponding alcohol after
removal of the TBS group; see the Supporting Information.
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Experimental Section
(S)-2u (Scheme 4): [Pd(dba)2] (57.8 mg, 0.1 mmol), (S)-DTBM-
Segphos (178.0 mg, 0.15 mmol), and
a mixed solvent system
(6.0 mL, DMF/DME = 1:1) were added sequentially to a flame-
dried Schlenk tube under argon. The mixture was stirred at 258C with
a preheated oil bath for 30 min. Then 1u (1.0319 g, 2.0 mmol) and the
mixed solvent system (2.0 mL; DMF/DME = 1:1) were added
sequentially to the above solution. The resulting mixture was stirred
at 258C. After completion, as monitored by TLC, the reaction was
quenched with Et2O (30 mL), H2O (30 mL), extracted with Et2O (3 ꢀ
20 mL), and dried over anhydrous Na2SO4. Filtration, evaporation,
and chromatography on silica gel (eluent: petroleum ether/ethyl ether
20:1) afforded (S)-2u (860.8 mg, 91% yield, 97% ee) as a liquid.
HPLC conditions: IA column, rate = 0.7 mLminÀ1, eluent: hexane/
iPrOH 100:1, l = 214 nm, tR(major) = 12.3 min, tR(minor) = 13.9 min.
1H NMR (300 MHz, CDCl3): d = 7.71 (d, J = 8.4 Hz, 2H, Ar-H), 7.28
= =
(d, J = 9.0 Hz, 2H, Ar-H), 5.37–5.24 (m, 2H, HC C CH), 4.13
(heptet, J = 6.6 Hz, 1H, NCH), 3.90 (ddd, J1 = 15.9 Hz, J2 = 5.7 Hz,
J3 = 3.0 Hz, 1H, one proton of NCH2), 3.76 (ddd, J1 = 15.9 Hz, J2 =
6.9 Hz, J3 = 2.7 Hz, 1H, one proton of NCH2), 2.42 (s, 3H, CH3), 1.72–
1.17 (m, 10H, 5 ꢀ CH2), 1.12 (d, J = 6.6 Hz, 3H, CH3), 1.08 (d, J =
6.9 Hz, 3H, CH3), 0.87 (s, 9H, 3 ꢀ CH3), 0.07 ppm (s, 6H, 2 ꢀ CH3);
13C NMR (75.4 MHz, CDCl3): d = 201.6, 142.8, 138.3, 129.5, 126.9,
101.7, 92.7, 73.2, 49.5, 41.8, 39.0, 38.8, 25.8, 25.6, 22.30, 22.27, 21.5,
~
21.4, 20.8, 18.2, À2.1, À2.2 ppm; IR (neat): n = 2934, 2886, 2857, 1963,
1599, 1463, 1444, 1391, 1342, 1252, 1187, 1154, 1091, 1050, 1023,
1004 cmÀ1; MS (70 ev, EI) m/z (%): 477 (M+, 0.07), 420 (M+ÀC4H9,
45.92), 91 (100); HRMS calcd for C26H43NO3SSi (M+): 477.2733,
found: 477.2720.
Scheme 5. Decarboxylation of rac-1x, (S)-1x, and (R)-1x, thus affording
allenes having axial chirality and central chirality.
Received: June 19, 2012
Published online: && &&, &&&&
the L4 and SEGPHOS ligands are responsible for the high
enantioselectivity, and has been additionally fine-tuned by the
steric effect of the 3,5-tBu-4-MeOC6H2 together with the
solvent effect shown in Table 2. A rationale for this reaction is
shown in Scheme 6.
Keywords: allene · amination · chirality · enantioselectivity ·
.
synthetic methods
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Scheme 6. Proposed mechanism.
In conclusion, a novel intramolecular decarboxylative
amination protocol for the synthesis of axially chiral allenes
containing synthetically attractive functionalities has been
developed with excellent enantioselectivities and good yields.
The synthetic utility of optically active allenyl amines involv-
ing axial-to-central chirality transfer and the extra function-
=
alities, such as an alcohol and C C bond, should make this
protocol of particular value in organic and medicinal chemis-
try. Further studies to expand the scope of this reaction and
application of the chiral products are ongoing in our
laboratory.
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Synthetic Methods
B. Wan, S. Ma*
&&&& — &&&&
Enantioselective Decarboxylative
Amination: Synthesis of Axially Chiral
Allenyl Amines
Getting axed: Synthesis of the title
smoothly using both the chiral ligands
(S)- and (R)-DTBM-Segphos (1) to afford
the allenyl amines in good yields and with
high enantioseletivities.
amines, bearing functionality (R1 and R2),
involves the enantioselective palladium-
catalyzed decarboxylation of allenyl N-
tosylcarbamates. The reaction proceeds
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