Pd-catalyzed asymmetric conjugate addition of arylboronic acids to 2-nitroacrylates: A facile route to β2-homophenylglycines

Article abstract of DOI:10.1016/j.tetlet.2013.11.015

Asymmetric conjugate addition of arylboronic acids to 2-nitroacrylamide in the presence of cationic palladium-Chiraphos complex proceeds with high yield and enantioselectivity (73-89% ee) using as low as 0.05-0.25 mol % of the catalyst. The adducts can be smoothly transformed into the corresponding β²-homophenylglycines in two simple steps.

Full text of DOI:10.1016/j.tetlet.2013.11.015

Tetrahedron Letters xxx (2013) xxx–xxx
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Pd-catalyzed asymmetric conjugate addition of arylboronic acids
to 2-nitroacrylates: a facile route to b2-homophenylglycines
Andreas Petri, Oliver Seidelmann, Uwe Eilitz, Frank Leßmann, Stefan Reißmann, Volkmar Wendisch,
⇑
Andrey Gutnov
ChiroBlock GmbH, Andresenstrasse 1a, D-06766 Wolfen, Germany
a r t i c l e i n f o
a b s t r a c t
Article history:
Asymmetric conjugate addition of arylboronic acids to 2-nitroacrylamide in the presence of cationic pal-
ladium–Chiraphos complex proceeds with high yield and enantioselectivity (73–89% ee) using as low as
0.05–0.25 mol % of the catalyst. The adducts can be smoothly transformed into the corresponding
b2-homophenylglycines in two simple steps.
Received 29 September 2013
Revised 2 November 2013
Accepted 5 November 2013
Available online xxxx
Ó 2013 Published by Elsevier Ltd.
Keywords:
b2-Amino acids
Pd-catalysis
Asymmetric Michael addition
Nitroalkenes
Arylboronic acids
Introduction
The preparation of enantiopure b2-amino acids has gained
increasing attention in recent years due to the fact that they are
components of numerous natural products and precursors of active
pharmaceutical ingredients, b-lactams, and b-peptides. Syntheses
and applications of b2-amino acids have already been the subject
of extensive reviews.1
Scheme 1. From nitroacrylates to b2-homophenylglycines.
As a part of an ongoing project concerning the synthesis of
b2-amino acids,2 we set a goal to develop a general catalytic, enan-
tioselective approach to b2-homophenylglycines implementing
nitroacrylate strategy, an addition of metalated aryl species to
nitroacrylate esters, and derivatives followed by uncomplicated
transformation into target compounds (Scheme 1).
Numerous Rh-catalyzed enantioselective addition reactions of
arylboronic acids to nitroalkenes were reported so far,3 some pub-
lications demonstrated utility of the obtained nitro compounds for
transformation into other functional groups and molecular
systems.
Enantioselective Pd-catalyzed addition of arylboronic acids to
common Michael acceptors like enones was first discovered and la-
ter extensively studied by Miyaura and co-workers.4 They showed
that cationic [Pd(Chiraphos)(PhCN)2](SbF6)2 complex exhibits the
highest activity: TONs up to 9900 with 0.01 mol % of catalyst load-
ing at >98% yield and >89% ee. Minnaard and co-workers success-
fully applied Me-DuPHOS/Pd(O2CCF3)2 based catalysts.5 In spite of
this fact only few examples of Pd-catalyzed additions of aryl spe-
cies to nitroalkenes have been known, all of them racemic.6
It should be noted that application of rhodium catalysis to the
studied reaction is hampered by high costs of corresponding pre-
catalysts (1–3 mol % amounts are usually required), and by the fact
that basic reaction conditions used for the addition of organobo-
ronic acids are not generally compatible with active nitroalkene
Discussion
For practical reasons the source of structurally diverse aryl
groups should be readily available commercially, environmentally
benign, cheap, easy to handle, and stable. Arylboronic acids
meet all the requirements and can be used in combination with
those transition metal catalysts (Rh, Pd) which allow facile B-
Rh/Pd transmetalation and aryl group transfer to Michael
acceptors.
⇑
Corresponding author. Tel.: +49 3494 638323; fax: +49 3494 638324.
E-mail address: gutnov@gmail.com (A. Gutnov).
0040-4039/$ - see front matter Ó 2013 Published by Elsevier Ltd.
http://dx.doi.org/10.1016/j.tetlet.2013.11.015
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2
A. Petri et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Table 1
Initial screening of substrates, catalysts, and conditions
Entrya
Alkene
Solvent
Catalyst
Yieldb (%)
eec (%)
Figure 1. Nitroalkene substrates.
1
1
2
3
4
5
6
7
3
3
3
3
4
4
5
6
6
6
6
6
7
7
7
7
aq acetone
aq DMA
aq acetone
aq acetone
aq DMA
aq DMA
aq DMA
aq DMA
aq acetone
aq DMA
aq DMA
aq DMA
aq DMA
aq DMA
aq DMA
aq DMA
aq acetone
aq DMA
aq acetone
aq DMA
8
8
8
8
8
8
8
9
ꢀ5 (GC)d
0 (GC)e
51
33
36
78
94
67
47
42
17
9
15
16
86
36
72
—
—
—
—
—
—
—
83
85
51
38
22
49
58
81
75
70
41
—
2
3f
4
5
6
7
8f
9f
9
10f
11f
12
13
14
15
16
17
18
19
20
21
22
23
10
11
9
10
10
9
10
10
11
12
9
Figure 2. Pd-catalysts employed.
49
0
81
76
68
56
84
85
61
64
aq acetone
aq DMA
aq DMA
9
10
11
substrates, especially 2-nitroacrylates, leading to their reasonable
decomposition. Therefore we decided to explore a more favorable
combination of readily available 2-nitroacrylate derivatives and
their precursors (Fig. 1)7 with ArB(OH)2 and phosphine–Pd cata-
lysts (Fig. 2).
a
The reaction was carried out on a 2 mmol scale with PhB(OH)2 (4 mmol), cat-
alyst (0.04 mmol), AgBF4 (0.2 mmol), 50% aq HBF4 (6 mmol) in 12 ml of solvent–
H2O 2:1 mixture at 20 °C for 18 h.
Furyl derivative 1 appeared to be too unreactive under the reac-
tion conditions, and nitrile 2 underwent complete decomposition.
Dimethylacetal 3 was more promising showing up to 67% yield
and 85% ee (Table 1, entries 8–11), however reasonable amounts
of hydrate (CH3O)2CH(OH)CH2NO2 (up to 20%) were isolated to-
gether with the desired product. The conjugated addition of water
to the C@C bond could be mostly suppressed by addition of HBF4,
but this led in its turn to partial hydrolysis of the acetal group thus
reducing the yield. Nitroacrylates 4 and 5 exhibited high reactivity
but the reaction was accompanied by numerous side reactions: di-
phenyl formation and formation of cinnamic acid esters, which
could result from inverted addition to the C@C bond followed by
NO2-group elimination. The latter substrates brought generally
low yields and moderate ee values (entries 12–14). 2-Nitroacryla-
mides 6 and 7 (entries 15–23) showed most clean reactions almost
without substrate decomposition and substrate derived side prod-
ucts (<5%, GC). Chiraphos catalyst 9 exhibited better activity and
enantioselectivity than that derived from DIPAMP 10. Other cata-
lysts revealed less promising or even no activity. The 2-nitroacryla-
mide 6 was chosen for further optimizations for best stability and
ease of handle.
b
Yield of isolated product if not indicated otherwise.
Determined by chiral HPLC analysis.
Marginal conversion of substrate.
Substrate decomposition.
c
d
e
f
Without HBF4 and AgBF4.
under different conditions. Last but not the least, the conditions al-
lowed to reduce the amount of PhB(OH)2 to 1.5 equiv.
In order to screen more chiral ligands and to check a possibility
to generate the catalysts in situ we tested
(Pd(acac)2, PdCl2, Pd(OAc)2, and Pd(cod)Cl2). It appeared that only
Pd(cod)Cl2 is inactive to catalyze the racemic background reaction
without support of a phosphine ligand. Corresponding in situ gen-
erated catalysts were than tested in the reaction of 2-nitroacryla-
mide 6 and PhB(OH)2 (Table 3).
4 precatalysts:
All precatalysts in combination with Chiraphos demonstrated
comparable results (entries 1–3), and Pd(cod)Cl2 being slightly bet-
Table 2
Influence of solvents on the reaction of 2-nitroacrylamide 6
Extensive solvent screening showed that all tested solvents can
be divided into two parts (Table 2). The first group comprises
mainly of polar aprotic DMF, DMA, tetramethylurea, NMP, DMSO,
acetonitrile, sulfolane, and PEG-400 which caused relatively slow
main reaction, but also very slow protodeboronation of PhB(OH)2.
The second group (acetone, MeOH, EtOH, dioxane, THF, and nitro-
methane) facilitated both reactions. However, as appeared, an
important requirement for organic co-solvents is their miscibility
with water. Solvents which do not form binary aqueous solutions
with high water content (e.g., TBME, toluene) proved to be an inap-
propriate medium for very slow reaction rates.
Entrya
Solvent
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
DMA/water
Acetone/water
MeOH/water
EtOH/water
i-PrOH/water
t-BuOH/water
THF/water
85
72
76
81
84
88
87
81
81
77
81
82
83
84
A minor influence of solvent on enantioselectivity should be
also noted. Finally we chose to use THF as a compromise solution
of several practical factors (protodeboronation, reaction rate, and
toxicity). The ratio THF–H2O 2:1 and substrate concentration
ꢀ1.7 M appeared to be optimal, as the reaction became sluggish
a
The reaction was carried out on a 10 mmol scale with PhB(OH)2 (15 mmol),
[Pd((S,S)-Chiraphos)(PhCN)2](SbF6)2 catalyst (0.02 mmol), AgBF4 (1 mmol), 50% aq
HBF4 (30 mmol) in 60 ml of solvent–H2O 2:1 mixture at 20 °C for 18 h.
b
Isolated yield.
Determined by chiral HPLC analysis.
c
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A. Petri et al. / Tetrahedron Letters xxx (2013) xxx–xxx
3
Table 3
Reaction of 2-nitroacrylamide 6 and PhB(OH)2 with in situ generated catalysts
Entrya
Precatalyst and ligand
T (°C)
Time (h)
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
9
Pd(acac)2 and Chiraphos
Pd(OAc)2 and Chiraphos
Pd(cod)Cl2 and Chiraphos
20
20
20
50
20
20
20
60
60
7
7
7
65
72
48
8
8
4
69
77
80
>2
19
42
83
51
56
83
87
86
—
42
87
63
0
Pd(cod)Cl2 and (R,R)-Norphos
Pd(cod)Cl2 and (R,R)-Ph-BPE
Pd(cod)Cl2 and (R,R)-Catasium D
Pd(cod)Cl2 and (R)-Prophos
Pd(acac)2 and (R)-BINAP
Pd(acac)2 and (R,R,S)-phosphoramidited
0
a
The reaction was carried out on a 4 mmol scale with PhB(OH)2 (6 mmol), precatalyst (0.08 mmol), phosphine ligand (0.084 mmol), AgBF4 (0.4 mmol), 50% aq HBF4
(12 mmol) in 24 ml of THF–H2O 2:1 mixture.
b
Isolated yield.
Determined by chiral HPLC analysis.
0.17 mmol (2 equiv) of the ligand was taken.
c
d
Table 4
Influence of catalyst loading
ter. Most of the tested ligands exhibited lower activity and/or
enantioselectivity than those of Chiraphos. (R)-Binap and (R,R,S)-
phosphoramidite furnished racemic product. This is in accordance
with earlier observations that only P–C–C–P tethered diphosphine
ligands are able to form active and enantioselective Pd-catalysts
for the conjugate addition.
The catalyst loading was then stepwise reduced and the results
are summarized in Table 4.
Entrya
Catalyst loading (mol %)
Timeb (h)
Yieldc (%)
eed (%)
As low as 0.05 mol % of the catalyst was able to bring the reac-
tion to full conversion albeit very slowly after 7 days. The amount
of 0.25 mol % was chosen as optimal for further experiments.
The conditions were further optimized and the amount of AgBF4
was reduced from 10 to 0.4 mol % relative to substrate without
having influence on the reaction rate and enantioselectivity.
Attempts to replace HBF4 with other strong non-nucleophilic
acids (HSbF6, HPF6) did not bring any improvement. Apart from
acceleration of protonolysis of intermediate C-bound palladium
enolates, the addition of acid strongly increases the stability of 2-
nitroacrylamide 6 against polymerization and formation of hydrate
NH2COCH(OH)CH2NO2.
1
2
3
4
5
6
7
8
1.5
1
8
25
25
72
72
72
120
168
81
89
83
79
72
66
61
56
87
86
86
86
85
87
84
86
0.5
0.25
0.2
0.15
0.1
0.05
a
The reaction was carried out on a 10 mmol scale with PhB(OH)2 (15 mmol),
[Pd((S,S)-Chiraphos)(PhCN)2](SbF6)2 catalyst, AgBF4 (1 mmol), 50% aq HBF4
(30 mmol) in 60 ml of THF–H2O 2:1 mixture at 20 °C.
b
The reaction was carried out until full conversion was achieved.
Isolated yield.
Determined by chiral HPLC analysis.
c
d
Table 5
Addition of substituted arylboronic acids
Entrya
Ar
Time
Yieldb (%)
eec (%)
1
2
3
4
5
6
7
8
p-ClPh
p-FPh
48
64
24
64
48
48
24
48
88
67
44
71
79
85
65
84d
88, (R)-(+)
87, (R)-(+)
73, (R)-(+)
82, (R)-(+)
86, (R)-(+)
88, (R)-(+)
82, (R)-(+)
89, (R)-(+)
p-OMePh
p-MePh
m-MePh
m-ClPh
m-OMePh
p-BrPh
a
The reaction was carried out on a 20 mmol scale with ArB(OH)2 (30 mmol), [Pd((R,R)-(+)-Chiraphos)(PhCN)2](SbF6)2 catalyst (0.05 mmol, 0.25 mol %), AgBF4 (0.08 mmol,
0.4 mol %), 50% aq HBF4 (60 mmol) in 130 ml of THF–H2O 2:1 mixture at 20 °C.
b
Isolated yield.
Determined by chiral HPLC analysis.
No Suzuki coupling products were determined.
c
d
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A. Petri et al. / Tetrahedron Letters xxx (2013) xxx–xxx
Scheme 2. From nitroamides to b2-homophenylglycines.
2. (a) Sewald, N.; Wendisch, V. Tetrahedron: Asymmetry 1998, 9, 1341–1344; (b)
Temperature screening showed its little influence on enantiose-
Eilitz, U.; Leßmann, F.; Seidelmann, O.; Wendisch, V. Tetrahedron: Asymmetry
2003, 14, 189–191; (c) Eilitz, U.; Leßmann, F.; Seidelmann, O.; Wendisch, V.
Tetrahedron: Asymmetry 2003, 14, 3095–3097.
lectivity and big influence on the rate of the reaction (i-PrOH/H2O
2:1, 10 mol % catalyst): 0 °C (48 h, 63%, 84% ee), 10 °C (30 h, 76%,
83% ee), 20 °C (16 h, 84%, 82% ee), 30 °C (3 h, 78%, 80% ee), 40 °C
(2.5 h, 86%, 80% ee).
3. (a) Hayashi, T.; Senda, T.; Ogasawara, M. J. Am. Chem. Soc. 2000, 122, 10716–
10717; (b) Duursma, A.; Hoen, R.; Schuppan, J.; Hulst, R.; Minnaard, A. J.;
Feringa, B. L. Org. Lett. 2003, 5, 3111–3113. For addition of ArB(OH)2 to 2-
nitroacrylates, see:; (c) Duursma, A. Asymmetric catalysis with chiral
monodentate phosphoramidite ligands, Ph.D. Dissertation, Rijksuniversiteit
Groningen, 2004.; (d) Wang, Z.-Q.; Feng, C.-G.; Zhang, S.-S.; Xu, M.-H.; Lin, G.-
Q.; Xu, M.-H. Angew. Chem., Int. Ed. 2010, 49, 5780–5783; (e) Xing, J.; Chen, G.;
Cao, P.; Liao, J. Eur. J. Org. Chem. 2012, 1230–1236. For application to the
The optimized conditions were then applied to the addition of
several substituted arylboronic acids to 2-nitroacrylamide
6
(Table 5).8
The results appeared to be similar to those obtained with phenyl-
boronic acid except p-OMePhB(OH)2 which underwent rapid pro-
todeboronation, and the reaction resulted in an incomplete
conversionandloweree-value of corresponding nitroamide (entry 3).
Final transformation of substituted nitroamides to homochiral
b2-homophenylglycines proceeded in two straightforward steps
(reduction of the nitro-group and amide hydrolysis). Recrystalliza-
tion of target amino acids either as free bases or suitable salts fur-
nished the products with >98% ee in ꢀ50% yield over two steps
(Scheme 2).
Comparison of optical rotation angle of unsubstituted-, p-OMe-,
and p-F-b2-homophenylglycines prepared using [Pd((R,R)-(+)-
Chiraphos)(PhCN)2](SbF6)2 catalyst with previously published
values leads to a conclusion that absolute configurations of the
products obtained with this catalyst have to be assigned as (R).9
Assuming an analogous reaction mechanism, the absolute configu-
ration of other products obtained was assigned as indicated in
Table 5.
In summary, a palladium–diphosphine catalyzed asymmetric
conjugate addition of arylboronic acids to 2-nitroacrylate deriva-
tives was developed. The reaction, which can be carried out with-
out inert atmosphere in technical grade THF using up to 0.05% of
catalyst, led to enantiomerically enriched 2-aryl-3-nitropropiona-
mides (73–89% ee). The latter were transformed into enantiopure
b2-homophenylglycines on hundred gram scale with high yields
in two straightforward steps.
synthesis of (+)-c-lycorane, see:; (f) Dong, L.; Xu, Y.-J.; Cun, L.-F.; Cui, X.; Mi, A.-
Q.; Jiang, Y.-Z.; Gong, L.-Z. Org. Lett. 2005, 7, 4285–4288. For a kilogram-scale
industrial synthesis leading to Telcagepant (MK-0974), see:; (g) Burgey, C. S.;
Paone, D. V.; Shaw, A. W.; Deng, J. Z.; Nguyen, D. N.; Potteiger, C. M.; Graham, S.
L.; Vacca, J. P.; Williams, T. M. Org. Lett. 2008, 10, 3235–3238; (h) Lang, F.; Chen,
G.; Li, L.; Xing, J.; Han, F.; Cun, L.; Liao, J. Chem. Eur. J. 2011, 17, 5242–5345; (i)
Xue, F.; Wang, D.; Li, X.; Wan, B. J. Org. Chem. 2012, 77, 3071–3081; (j) Morigaki,
A.; Tanaka, T.; Miyabe, T.; Ishihara, T.; Konno, T. Org. Biomol. Chem. 2013, 11,
586–595; (k) Duursma, A.; Pena, D.; Minnaard, A. J.; Feringa, B. L. Tetrahedron:
Asymmetry 2005, 16, 1901–1904.
4. (a) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Angew. Chem., Int. Ed. 2003, 42,
2768–2770; (b) Nishikata, T.; Yamamoto, Y.; Miyaura, N. Adv. Synth. Catal. 2007,
349, 1759–1764. For recent reviews, see:; (c) Gutnov, A. Eur. J. Org. Chem. 2008,
4547–4554; (d) Miyaura, N. Synlett 2009, 2039–2050.
5. (a) Gini, F.; Hessen, B.; Minnaard, A. J. Org. Lett. 2005, 7, 5309–5312.
6. For PdCl2/LiCl-catalyzed reactions with polyarylmetallics, see: (a) Ohe, T.;
Uemura, S. Tetrahedron Lett. 2002, 43, 1269–1271; (b) Ohe, T.; Uemura, S. Bull.
Chem. Soc. Jpn. 2003, 76, 1423–1431; For addition of ArSi(OEt)3, see: (c)
Denmark, S. E.; Amishiro, N. J. Org. Chem. 2003, 68, 6997–7003; (d) Lerebours, R.;
Wolf, C. Org. Lett. 2007, 9, 2737–2740; For Pd(OAc)2/bipyridine-catalyzed
addition of ArB(OH)2, see: (e) Lu, X.; Lin, S. J. Org. Chem. 2005, 70, 9651–9653;
For Pd/N-heterocyclic carbenes catalyzed reductive Heck reaction with aryl
iodides, see: (f) Gottumukkala, A. L.; de Vries, J. G.; Minnaard, A. J. Chem. Eur. J.
2011, 17, 3091–3095.
7. For preparation of nitroacrylates, see: (a) Shechter, H.; Conrad, F.; Daulton, A. L.;
Kaplan, R. B. J. Am. Chem. Soc. 1952, 74, 3052–3056; (b) Knochel, P.; Seebach, D.
Synthesis 1982, 1017–1018.
8.
A
representative procedure for the asymmetric conjugate addition: 2-
Nitroacrylamide (71.4 g, 615.1 mmol), p-chlorophenylboronic acid (125 g,
6
799.3 mmol), [Pd((R,R)-(+)-Chiraphos)(PhCN)2](SbF6)2 catalyst (1.861 g,
1.54 mmol), and AgBF4 (0.479 g, 2.46 mmol) were dissolved in a mixture of
THF (2.5 L), deionized H2O (1.25 L), and HBF4 (324 g, 1845.3 mmol, 50% in H2O).
The turbid reaction was stirred at 20 °C for ꢀ50 h under TLC control (ethyl
acetate/hexane/MeOH 95:95:10, silica gel) until starting 2-nitroacrylamide 6
disappeared. The reaction was concentrated to remove THF and extracted twice
with CH2Clu (1500 ml and 600 ml). Combined organic phases were dried over
Na2SO4, filtered, and evaporated to give the crude (+)-2-(4-chlorophenyl)-3-
nitropropionamide (133.25 g, 94.7% yield, >90% chemical purity). Chiral HPLC
(Daicel Chiralpak AS, Heptane/Isopropanol 30:70, 0.7 ml/min, UV 254 nm,
Rt = 8.7 min and 14.3 min) showed 88% ee. The product can be used as is in
the next steps. Otherwise twofold recrystallization from ethyl acetate–heptane
(200 ml, 1:1) brings 81.4 g of the analytically pure nitroamide (58% yield, 98.7%
ee). 1H NMR (400 MHz, CDCl3): 7.31 (m, 2H), 7.21 (m, 2H), 5.62 (br s, 1H), 5.47
(br s, 1H), 5.09 (dd, 1H), 4.45 (dd, 1H), 4.25 (dd, 1H); 13C NMR (100 MHz, CDCl3):
Acknowledgment
This research was kindly supported by the German Ministry of
Economy and Technology based on a resolution of the ‘Deutscher
Bundestag’.
References and notes
171.17, 135.06, 132.65, 129.80, 129.38, 75.93, 48.91; mp 109–111 °C; ½a D20
ꢁ
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Please cite this article in press as: Petri, A.; et al. Tetrahedron Lett. (2013), http://dx.doi.org/10.1016/j.tetlet.2013.11.015