Organocatalytic asymmetric hydrophosphination of nitroalkenes

Article abstract of DOI:10.1039/b613477g

The use of a bifunctional Cinchona alkaloid catalyst has provided a new organocatalytic strategy for the enantioselective addition of diphenylphosphine to a range of nitroalkenes, affording optically active β-nitrophosphines (up to 99% ee after crystallization); this organocatalytic approach, providing a direct route to a new class of potentially useful enantiopure P,N-ligands, constitutes a bridge between the two complementary areas of asymmetric catalysis: organo- and metal-catalyzed transformations. The Royal Society of Chemistry.

Full text of DOI:10.1039/b613477g

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Organocatalytic asymmetric hydrophosphination of nitroalkenes{
Giuseppe Bartoli, Marcella Bosco, Armando Carlone, Manuela Locatelli, Andrea Mazzanti, Letizia Sambri
and Paolo Melchiorre*
Received (in Cambridge, UK) 18th September 2006, Accepted 8th November 2006
First published as an Advance Article on the web 29th November 2006
DOI: 10.1039/b613477g
Surprisingly, to date, no effective methods for the conjugate
addition of phosphines to unsaturated nitro compounds are
available.9,10
The use of a bifunctional Cinchona alkaloid catalyst has
provided a new organocatalytic strategy for the enantioselective
addition of diphenylphosphine to a range of nitroalkenes,
affording optically active b-nitrophosphines (up to 99% ee after
crystallization); this organocatalytic approach, providing a
direct route to a new class of potentially useful enantiopure
P,N-ligands, constitutes a bridge between the two complemen-
tary areas of asymmetric catalysis: organo- and metal-catalyzed
transformations.
Herein, we describe a simple, general and efficient protocol for
the hydrophosphination reaction of nitroalkenes to produce
b-nitrophosphines. Additionally, an asymmetric organocatalytic
version of this process, based on the use of a chiral bifunctional
organocatalyst, affording optically active compounds (up to 99% ee
after a single crystallization), has been disclosed.
Recently, it was reported that hydrophosphination reactions of
activated olefins can be carried out under mild basic conditions.11
On this basis, and considering our interest in the development of
new organocatalytic transformations promoted by chiral tertiary
amines,12 we questioned recently whether the stereocontrolled
conjugate addition of secondary phosphines to nitroalkenes might
be accomplished using a chiral organic base-catalyst (Scheme 2).
Specifically, we proposed that exposure of phosphines13 to a chiral
base would result in the formation of an intermediate ionic species
that would undergo an asymmetric addition to nitroalkenes. This
organocatalytic tactic,14 as compared with a metal-catalyzed
process, would prevent product inhibition arising from the
coordination ability of the phosphorus atom.
Chiral phosphines, valuable ligands for metal-catalyzed enantio-
selective transformations,1 are generally prepared by resolution or
by using stoichiometric amounts of chiral auxiliaries.2 Thus, the
development of more efficient catalytic methods for the enantio-
selective synthesis of optically active phosphines is of pressing
current importance.3 Asymmetric hydrophosphination (AHP),4
the stereocontrolled addition of trivalent phosphine compounds,
containing a P–H bond, to electron-deficient olefins, provides
direct, atom-efficient access to potentially useful chiral phosphine
ligands containing different chemical functionalities. These hetero-
functional systems, which enable electronic and steric tuning along
with unique dynamic features such as hemilability,5 facilitate the
optimization of the parameters that engender high stereocontrol in
metal-catalyzed reactions. However, to our knowledge, just one
effective catalytic AHP reaction has been reported recently by the
group of Togni.6
In this context, the direct conjugate additions of secondary
phosphines to nitroalkenes (Scheme 1) would constitute a
particularly attractive strategy for the synthesis of optically active
nitrophosphines, which, due to the synthetic versatility of the nitro
group, can be considered as direct precursors for a wide range of
diverse organic functionalities;7 simple reduction of the nitro
moiety, for example, affords non-proteinogenic amino acid-
derived b-aminophosphines, potentially useful P,N-ligands.8
Scheme 2 Organocatalytic asymmetric hydrophosphination strategy.
To assess the feasibility of such an organocatalytic hydro-
phosphination strategy, we examined the addition of diphenyl-
phosphine 1 to b-nitrostyrene 2 in toluene as the model reaction
(Table 1). The sequential one-pot formation of the air-stable
phosphine–borane complex derivative 3, generated in situ by
employing a trivial procedure,15 facilitates the purification process,
rendering the adduct bench stable for a long time.
Importantly, in the initial studies we noted that, even
performing the model reaction at room temperature (RT) in the
absence of a base-catalyst, complete conversion was achieved after
3 h. This type of uncatalyzed hydrophosphination strategy proved
to be effective for a variety of aromatic and aliphatic nitroalkenes
by using both diphenylphosphine 1 and di-tert-butylphosphine;
detailed results are provided as supporting information{ (yields
ranging from 65% to 94%). Although the intrinsic reactivity of the
process accounts for a direct and operationally simple synthesis of
b-nitrophosphines, this feature constitutes an important hurdle to
overcome in order to accomplish an asymmetric organocatalytic
Scheme 1 Conjugate addition of secondary phosphines to nitroalkenes.
Dipartimento di Chimica Organica ‘‘A. Mangini’’, Alma Mater
Studiorum – Universita` di Bologna, V.le Risorgimento 4 - 40136
Bologna, Italy. E-mail: pm@ms.fci.unibo.it; Fax: +39 051 2093654;
Tel: +39 051 2093624
{ Electronic supplementary information (ESI) available: Catalysts and
conditions screening studies, results for the uncatalyzed hydrophosphina-
tion, experimental procedures and full characterization. See DOI: 10.1039/
b613477g
722 | Chem. Commun., 2007, 722–724
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Table 1 Organocatalytic AHP of 2a
bifunctional organocatalysts in many asymmetric transforma-
tions,16 led to identification of compound D17 as a promising
catalyst (49% ee, entry 7).
Among the standard reaction parameters, solvent choice and
reagent concentration proved particularly important. Examination
of the reaction media with catalyst D revealed that Et2O gave
better selectivity (entry 10). While the use of i-PrOH as the reaction
solvent was less than fruitful, the addition of 10% of i-PrOH as a
cosolvent resulted in improved stereocontrol,{ albeit at the expense
of reactivity (entries 11–12). However, at higher concentration ([2]0
= 1 M) complete conversion was achieved after 16 h (entry 13).
Importantly, under these conditions, lowering the catalyst loading
to 10 mol% did not affect the efficiency of the system (entry 14).18
The synthetic potential of this method was evaluated using a
2 mmol scale reaction (Scheme 3); it is noteworthy that the
possibility to obtain 3 in enantiomerically pure form after a single
crystallization and the reductive manipulation of the nitro group
with concomitant in situ tert-butyloxycarbonyl (Boc) protection,
affording the enantiopure aminophosphine 4, provides a direct
route to a new, potentially useful class of chiral P,N-ligand.8 In a
broader sense, the organocatalytic AHP constitutes a bridge
between the two complementary areas of asymmetric catalysis:
organo- and metal-catalyzed transformations.
Conversion ee (%)
(%)b
Entry Catalyst
Solvent
of 3c
1
2
3
— Toluene
Quinine Toluene
(DHQ)2PHAL Toluene
24
85
—
0
76
92
80
89
93
.95
55
88
.95
80
18
15
27
36
49
34
24
60
13
65
67
66
4
5
A
B
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
Et2O
i-PrOH
Et2O–i-PrOH 9 : 1
6
7
8
9
10
11
12
13d
14d,e
a
C
D
D
D
D
D
D
D
D
Et2O–i-PrOH 9 : 1 .95
Et2O–i-PrOH 9 : 1
92 (86)f
Reactions were carried out at 240 uC under N2 using 20 mol% of
the catalyst on a 0.2 mmol scale (16 h). Determined by 1H NMR
spectroscopy of the crude mixture. ee of 3 was determined by
b
c
d
e
HPLC analysis. [2]0 = 1 M. 10 mol% of the catalyst, 24 h.
f
Number in parentheses indicates yield of the isolated 3.
version as the chiral base-catalyzed reaction of 1 with 2 must
proceed at a higher rate than the relatively fast uncatalyzed
background reaction.
With this in mind, we undertook an extensive screen{ of
Cinchona alkaloids derivatives as potential catalysts (20 mol%) for
the model reaction in toluene (0.5 M, 16 h) at 240 uC; under these
conditions, a minimal rate of background reaction was observed
(entry 1, Table 1).
Scheme 3 Preparation of enantiopure N-protected aminophosphine 4.
Investigation into the reaction scope was carried out under the
optimal reaction conditions (Scheme 4).19 Although the b-nitro-
phosphines 5–8 were obtained in moderate enantioselectivity, the
optical purity can be easily increased (.99% ee) by simple
crystallization, as demonstrated for compounds 6 and 8. The
absolute configuration of compound 8 was established to be (S)20
by X-ray crystallographic analysis.{
The asymmetric induction observed when using (DHQ)2PHAL
as the catalyst (entry 3), albeit not satisfactory, was interpreted as
an encouraging clue for a successful development of our
asymmetric organocatalytic approach. We speculated that the
use of thiourea-based bifunctional catalysts capable of
a
simultaneous activation of both the electrophilic and nucleophilic
components, might lead to higher catalytic activity and, more
importantly, to better stereocontrol. A survey of chiral thiourea
frameworks (Fig. 1), of established ability to act as efficient
Scheme 4 Reaction scope for the AHP.
In summary, we have developed a direct and very simple
methodology for the hydrophosphination of nitroalkenes that
provides access to useful and synthetically challenging b-nitropho-
sphines. Additionally, newly formed stereocenters can be con-
trolled using a chiral thiourea organocatalyst. This organocatalytic
approach, highlighting the potential of a chiral base organocatalyst
to efficiently activate secondary phosphines toward asymmetric
nucleophilic addition, could pave the way for the development of
new, synthetically useful asymmetric hydrophosphination trans-
formations. Current efforts are directed toward application of this
Fig. 1 Thiourea bifunctional organocatalysts.
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Chem. Commun., 2007, 722–724 | 723

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8 For a review on the utility of bidentate P,N-ligands, see: P. J. Guiry and
C. P. Saunders, Adv. Synth. Catal., 2004, 346, 497.
9 For the addition of alkali-phosphorus compounds to nitrostyrene, see:
K. Issleib and P. Von Malotki, J. Prakt. Chem. (Leipzig), 1973, 315,
463.
10 For the asymmetric addition of chiral phosphites to nitroalkenes, see:
D. Enders, L. Tedeschi and J. W. Bats, Angew. Chem., Int. Ed., 2000, 39,
4605.
11 T. Bunlaksananusorn and P. Knochel, J. Org. Chem., 2004, 69, 4595
and references cited therein.
12 (a) G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, P. Melchiorre and
L. Sambri, Angew. Chem., Int. Ed., 2005, 44, 6219; (b) G. Bartoli,
M. Bosco, A. Carlone, A. Cavalli, M. Locatelli, A. Mazzanti, L. Sambri
and P. Melchiorre, Angew. Chem., Int. Ed., 2006, 45, 4966.
13 For studies on the acidity of phosphines, see: (a) A. Streitwieser,
A. E. McKeown, F. Hasanayn and N. R. Davis, Org. Lett., 2005, 7,
1259; (b) W. A. Henderson, Jr. and C. A. Streuli, J. Am. Chem. Soc.,
1960, 82, 5791.
14 For recent studies on organocatalytic addition of pentavalent phos-
phorus compounds to unsaturated substrates, see: (a) D. Pettersen,
M. Marcolini, L. Bernardi, F. Fini, R. P. Herrera, V. Sgarzani and
A. Ricci, J. Org. Chem., 2006, 71, 6269; (b) T. Akiyama, H. Morita,
J. Itoh and K. Fuchibe, Org. Lett., 2005, 7, 2583.
15 (a) J. McNulty and Y. Zhou, Tetrahedron Lett., 2004, 45, 407.
Phosphine–borane deprotection can be easily accomplished under mild
conditions, see: (b) H. Brisset, Y. Gourdel, P. Pellon and M. Le Corre,
Tetrahedron Lett., 1993, 34, 4523.
16 For recent reviews, see: (a) M. S. Taylor and E. N. Jacobsen, Angew.
Chem., Int. Ed., 2006, 45, 1520; (b) S. J. Connon, Chem.–Eur. J., 2006,
12, 5418.
promising organocatalytic AHP strategy to other alkene acceptors
and fully defining its utility as a new synthetic tool for asymmetric
catalysis.
We thank Prof. Pier Giorgio Cozzi and Dr Marzia Mazzacurati
(Bologna University) for fruitful discussions. We are also indebted
to Mr Luca Zuppiroli for his timely assistance in mass spectro-
metry analysis. This research was carried out within the framework
of the National Project ‘‘Stereoselezione in Sintesi Organica’’
supported by MIUR, Rome, and FIRB National Project
‘‘Progettazione, preparazione e valutazione farmacologica di
nuove molecole organiche quali potenziali farmaci innovativi’’.
Notes and references
{ Crystal data for 8. C27H27BNO3P, M = 455.29, monoclinic, a =
˚
9.7738(12), b = 13.1358(16), c = 9.8656(12) A, b = 109.146(2)u,
3
˚
U = 1196.5(3) A , T = 100(2) K, space group P21 (no. 4), Z = 2, m(Mo-
Ka) = 0.144 mm21, 13 673 reflections measured, of which 5605
independent (Rint = 0.0277) and 5533 observed (I . 2s). The final R1
(I . 2s) was 0.0271 and wR2 was 0.0779 (all data). The Flack parameter
was 20.03(4). CCDC 615184. For crystallographic data in CIF or other
electronic format see DOI: 10.1039/b613477g
1 (a) Asymmetric Catalysis on Industrial Scale. Challenges, Approaches,
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18 Other nucleophilic phosphorus reagents examined included di-tert-
butylphosphine (0% ee), 1–borane complex (0% ee) and diphenylpho-
sphine oxide (20% ee, 30% conversion, 24 h).
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19 The organocatalytic AHP of aliphatic nitroalkenes afforded racemic
products (aliphatic substituent: isopropyl: 0% ee; n-pentyl: 0% ee). Other
aromatic nitroalkenes tested gave poor enantioselectivity (aromatic
substituent: p-MeO–C6H4: 25% ee; p-Br–C6H4: 22% ee; 2-furanyl: 11%
ee; p-NO2–C6H4: 0% ee; 2,6-Cl–C6H3: 0% ee).
20 The sense of stereochemical induction is in agreement with a previously
reported selectivity model, in which the selective binding of the
nitroolefin with the thiourea framework of the bifunctional catalyst D
through a double-hydrogen bonding mechanism directs the nucleophilic
attack at the Si-face of the electrophile. See ref. 17b.
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724 | Chem. Commun., 2007, 722–724
This journal is ß The Royal Society of Chemistry 2007