Stereoselective alkylation of [2-(diphenylphosphino)ferrocenyl]acetonitrile

Article abstract of DOI:10.1016/j.inoche.2005.12.003

Deprotonation of racemic [2-(diphenylphosphino)ferrocenyl]acetonitrile (1) with NaN(SiMe₃)₂ in THF followed by reaction with electrophiles MeI and Ph₂PCl affords the substituted nitriles, 2-[2-(diphenylphosphino)ferrocenyl]propionitrile (2a) and 2-(diphenylphosphino)- [2-(diphenylphosphino)ferrocenyl]acetonitrile (2b), respectively. Whereas the former reaction yields a 15:1 mixture of isomers differing in configuration at the alkylated α-carbon from which the major diastereoisomer can be isolated by simple recrystallization, the latter gives 2b as a single diastereoisomer. The dominating product of the methylation reaction was characterized by X-ray diffraction analysis as (S,R_p/R,S _p)-2a, which is in accordance with the possible access of the electrophile towards deprotonated 1.

Full text of DOI:10.1016/j.inoche.2005.12.003

Inorganic Chemistry Communications 9 (2006) 319–321
www.elsevier.com/locate/inoche
Stereoselective alkylation
of [2-(diphenylphosphino)ferrocenyl]acetonitrile
ˇ
*
ˇ
ˇ
ˇ
Martin Lamac, Petr Stepnicka
Department of Inorganic Chemistry, Faculty of Science, Charles University, Hlavova 2030, 12840 Prague, Czech Republic
Received 15 November 2005; accepted 3 December 2005
Available online 24 January 2006
Abstract
Deprotonation of racemic [2-(diphenylphosphino)ferrocenyl]acetonitrile (1) with NaN(SiMe3)2 in THF followed by reaction with
electrophiles MeI and Ph2PCl affords the substituted nitriles, 2-[2-(diphenylphosphino)ferrocenyl]propionitrile (2a) and 2-(diph-
enylphosphino)-[2-(diphenylphosphino)ferrocenyl]acetonitrile (2b), respectively. Whereas the former reaction yields a 15:1 mixture of
isomers differing in configuration at the alkylated a-carbon from which the major diastereoisomer can be isolated by simple recrystal-
lization, the latter gives 2b as a single diastereoisomer. The dominating product of the methylation reaction was characterized by
X-ray diffraction analysis as (S,Rp/R,Sp)-2a, which is in accordance with the possible access of the electrophile towards deprotonated 1.
ꢀ 2006 Elsevier B.V. All rights reserved.
Keywords: Ferrocene; Nitriles; Alkylation; Chiral donors; Structure elucidation
In recent years, there has been much effort devoted to
the preparation of new chiral ferrocene ligands for catalytic
applications. Their synthesis has been accomplished mostly
via metallation/functionalization approach from precur-
sors bearing chiral substitents that are ‘equipped’ with
functional groups capable of promoting ortho-metallation.
An inverse method based on deprotonation of achiral fer-
rocenes with chiral bases has been utilized less frequently
[1,2].
ethyl)phenylsulfone FcCH2SO2Ph [4] and phosphine chalc-
ogenides FcCH2P(E)Ph2 (E = O and S) [5] were shown to
behave similarly. To the best of our knowledge, these reac-
tions were not studied further nor found utilization in the
synthesis of other ferrocene derivatives. This contribution
deals with diastereoselective alkylation of planarly chiral,
but racemic [2-(diphenylphosphino)ferrocenyl]acetonitrile
(1), to give substituted (phosphinoferrocenyl)nitriles 2, that
combine central and planar chirality.
It is well established in organic chemistry that strongly
electron-withdrawing groups activate C–H bonds in adja-
cent positions towards the action of bases. Anions resulting
from deprotonation of polar substrates are valuable syn-
thetic intermediates that bring polar group(s) capable of
further reactions into the molecules of products. In ferro-
cene chemistry, selective a-deprotonation of ferrocenyl-
acetonitrile followed by alkylation (with RX) to give
doubly substituted nitriles FcCR2CN has been reported
as early as in 1973 (Fc = ferrocenyl) [3]. (Ferrocenylm-
We have found that selective deprotonation of nitrile
1 [6] can be accomplished easily by treatment with
NaN(SiMe3)2 in THF at low temperature. Addition of
iodomethane [7] or chloro-diphenylphosphine [8] to the
deprotonated nitrile then furnished good yields of the
respective alkylation products 2a and 2b (Scheme 1),
substituted in a-position to the nitrile group.
Notably, the reactions proceeded with a high stereose-
lectivity: whereas the crude methylation product was
shown by NMR spectroscopy to be a 15:1 mixture of dia-
stereoisomers, the phosphanylated nitrile 2b was obtained
in diastereoisomerically pure form. Pure major isomer of
2a was subsequently isolated by recrystallization of the
mixture of diastereoisomers from aqueous acetic acid and
*
Corresponding author. Fax: +420 221 951 253.
ˇ
E-mail address: stepnic@natur.cuni.cz (P. Steˇpnicˇka).
1387-7003/$ - see front matter ꢀ 2006 Elsevier B.V. All rights reserved.
doi:10.1016/j.inoche.2005.12.003

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M. Lamacˇ, P. Steˇpnicˇka / Inorganic Chemistry Communications 9 (2006) 319–321
320
even lower than in solid 1. The cyano(ethyl) side arm is
PPh
PPh
2
2
rotated with respect to ferrocene unit so that the angles
subtended by the C(11)–C(12) and C(11)–C(13) bond vec-
tors and the Cp(1) plane are, respectively, 68.6(2)ꢁ and
29.7(2)ꢁ. Ferrocene cyclopentadienyl (Cp) planes are
almost perfectly parallel and equally distant from the iron
atom: relative difference of the Fe–Cg(1,2) bond lengths is
lower than 1% (see Fig. 1).
CN
CN
i.NaN(SiMe )
3 2
Fe
Fe
E
ii. EX
1
2a (E = Me; EX= MeI)
2b (E = PPh , EX = Ph PCl)
2
2
Scheme 1.
The course of the deprotonation reaction seems to be
controlled largely by steric properties of the (phos-
phino)ferrocenyl moiety, which provides geometric bias to
the diastereotopic hydrogens in the parent nitrile, and
by steric relation between the formed cyano[2-(diph-
enylphosphino)ferrocenyl]methanide salt and the electro-
phile (cf. different selectivity observed in the reactions
yielding 2a and 2b). On the other hand, the base seems
to play a less important role. For instance, substituting
NaN(SiMe3)2 for LiN(iPr)2 (prepared freshly from butyl
lithium and diisopropylamine) in the preparation of 2a
did not alter the product yield nor the diastereoisomer ratio.
The presented results show that deprotonation/alkyl-
ation of ferrocenylacetonitrile 1 proceeds with very good
stereoselectivity, yielding a-substituted nitriles 2. Extension
of this approach towards other, possibly homochiral
(cyanomethyl)ferrocenes, as well as further synthetic mod-
ification of 2-type products may open an alternative routes
to a variety of new chiral ferrocene donors (a single isomer
from optically pure precursors), e.g., to novel ferrocene
phosphinocarboxylic ligands [12].
structurally characterized (see below). Both alkylation
products 2a [9] and 2b [10] gave correct HR MS analyses
and their formulation is in accordance with spectral data
(IR and NMR).
The structure of the major diastereoisomer, (S,Rp/R,Sp)-
2a, as determined by single-crystal X-ray diffraction [11]
(Fig. 1) clearly shows that the attack of the electrophile
occurs preferably from the exo side with respect to the fer-
rocene unit. The molecular geometry of (S,Rp/R,Sp)-2a is
very much similar to that of the parent nitrile 1 [6]. The
most notable, albeit only a slight difference can be found
in the C(1)–C(11)–C(13) angle being more acute than in 1
(by ca. 4ꢁ), which corresponds with a larger steric demands
of the methyl group. However, the data indicate that no
torsional deformation occurs at the C(1)–C(2) bond; cf.
the torsion angle [C(11)–C(1)–C(2)–P] of 0.5(3)ꢁ, which is
Acknowledgements
´
ˇ
´
The authors thank Dr. Ivana Cısarova from the Centre
of Molecular and Crystal Structures, Faculty of Science,
Charles University for recording the X-ray diffraction data.
This work was financially supported by the Grant Agency
of Charles University (Project No. 318/2005 B-CH/PrF).
C(15)
C(12)
C(14)
C(11)
Appendix A. Supplementary data
P
C(13)
C(2)
C(1)
N
C(21)
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/
j.inoche.2005.12.003.
C(20)
Fe
C(7)
References
C(6)
[1] (a) A. Togni, T. Hayashi (Eds.), Ferrocenes: Homogeneous Catalysis,
Organic Synthesis, Materials Science, VCH, Weinheim, 1995;
(b) A. Togni, in: A. Togni, R.L. Halterman (Eds.), Metallocenes:
Synthesis, Reactivity, Applications, vol. 2, Wiley-VCH, Weinheim,
1998, p. 685 (Chapter 11);
Fig. 1. View of the molecular structure of the major isomer of 2a (the
(S,Rp)-isomer is shown). Displacement parameters enclose 30% probabil-
ity level. Selected geometric parameters [in A and ꢁ]: P–C(2) 1.813(2), P–
˚
(c) T.J. Colacot, Chem. Rev. 103 (2003) 3101;
(d) C.J. Richards, A.J. Locke, Tetrahedron: Asymmetry 9 (1998)
2377.
[2] For a comprehensive review about the utilization of diastereoselective
lithiation in the synthesis of chiral ferrocene compounds, see:
J. Clayden, Top. Organomet. Chem. 5 (2003) 251.
C(14) 1.843(2), P–C(20) 1.832(2), C(1)–C(11) 1.514(3), C(11)–C(12)
1.539(4), C(11)–C(13) 1.475(3), C(13)–N 1.135(3) and C(2)–P–C(14)
101.0(1), C(2)–P–C(20) 101.8(1), C(14)–P–C(20) 101.0(1), C(1)–C(11)–
C(12) 112.1(2), C(1)–C(11)–C(13) 109.6(2), C(12)–C(11)–C(13) 110.5(2),
C(11)–C(13)–N 179.3(3); metallocene geometry: Fe–Cg(1) 1.638(1), Fe–
Cg(2) 1.654(1), \Cp(1), Cp(2) 0.9(2). Definitions of the ring planes:
Cp(1) = C(1–5), Cp(2)@C(6–10); Cg(1,2) are the respective ring centroids.
[3] G. Marr, J. Ronayne, J. Organomet. Chem. 47 (1973) 417.
[4] J.B. Evans, G. Marr, J. Chem. Soc., Perkin Trans. I (1972) 2502.

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M. Lamacˇ, P. Steˇpnicˇka / Inorganic Chemistry Communications 9 (2006) 319–321
321
[5] G. Marr, B.J. Wakefield, T.M. White, J. Organomet. Chem. 88 (1975)
357.
(7), 199 (8), 183 (17), 149 (16), 147 (30), 121 (17), 105 (14), 75 (56), 56
(15). HR MS calcd. for C25H2256FeNP: 423.0839, found 423.0835.
Minor diastereoisomer: 31P{1H} NMR (CDCl3): d À24.6 (s).
ˇ
´
ˇ
´
[6] P. Steˇpnicˇka, I. Cısarova, Organometallics 22 (2003) 1728.
[7] Preparation of 2-[2-(diphenylphosphino)ferrocenyl]propionitrile (2a).
To a stirred solution of nitrile 1 [6] (197 mg, 0.48 mmol) in dry THF
(15 mL) cooled to À78 ꢁC (dry ice/ethanol bath), NaN(SiMe3)2
(0.6 mL of 1.0 M solution in THF, 0.58 mmol; Aldrich) was added
dropwise. The colour of the reaction solution turned from orange to
dark red. The mixture was stirred at À78 ꢁC for 15 min and then
treated with methyl iodide (355 mg, 2.5 mmol), while the colour
changed to brown–yellow. The reaction mixture was stirred for
another 30 min at À78 ꢁC and then at room temperature for 1 h and
then quenched by adding saturated aqueous NH4Cl solution (10 mL).
The organic phase was separated, washed with saturated aqueous
NaCl, dried over MgSO4, and evaporated under reduced pressure.
The crude product was immediately purified by column chromatog-
raphy (silica gel, diethyl ether) to give 2a as an orange oil, that
solidified at 4 ꢁC. Yield: 125 mg (62%). NMR analysis revealed the
product to be a mixture of two diastereoisomers in a molar ratio of
15:1. Recrystallization from aqueous acetic acid afforded pure major
diastereoisomer as an orange crystalline solid.
[10] Analytical data for 2b.1H NMR (CDCl3): d 3.91 (m, 1H, C5H3), 3.98
(C5H5), 4.05 (m, 1H, C5H3), 4.26 (apparent t, J ꢀ 2.6 Hz, 1H, C5H3),
2
4.89 (dd, JPH = 4JPH = 5.3 Hz, 1H, CHPPh2), 7.24–7.67 (m, 10H,
PPh2). 13C{1H} NMR (CDCl3): d 31.19 (dd, 1JPC = 36 Hz, 3JPC = 15
Hz, CHPPh2), 70.01 (CH C5H3), 70.35 (C5H5), 71.00 (CHC5H3),
2
1
72.00 (d, JPC = 4 Hz, CH C5H3), 74.94 (dd, JPC = 10 Hz, C–P
2
3
C5H3), 86.84 (dd, JPC = 28 Hz, JPC = 17 Hz, C–CH C5H3), 118.56
(d, JPC = 2 Hz, C„N), 127.79, 128.75 (2 · CHP PPh2); 127.83,
2
3
128.18 (2 · d, JPC = 6 Hz, CHm PPh2), 128.27, 128.57 (2 · d,
3JPC = 5 Hz, CHm PPh2); 129.40, 130.56 (2 · CHP PPh2); 131.56 (d,
2JPC = 18 Hz, CHo PPh2), 132.61 (dd, 2JPC = 17 Hz, JPC = 2 Hz, CHo
PPh2), 132.66 (d, 1JPC = 21 Hz, Cipso PPh2), 135.18 (d, JPC = 20 Hz,
2
CHo PPh2), 135.40 (d, 2JPC = 21 Hz, CHo PPh2), 135.43 (d, 1JPC = 18
1
Hz, Cipso PPh2), 137.58, 139.62 (2 · d, JPC = 6 Hz, Cipso PPh2).
31P{1H} NMR (CDCl3): d À26.1 (d, JPP = 20 Hz, C5H3PPh2), 2.0
4
(d,4JPP = 20 Hz, CHPPh2). IR (DRIFTS, KBr): m/cmÀ1 2227 w
m(C„N), 1585 w, 1570 w, 1477 m, 1433 s, 1244 w, 1165 w, 1128 w,
1107 w, 1092 m, 1026 w, 999 w, 827 m, 816 m, 748 s, 739 s, 698 vs, 515
s, 503 m, 480 m, 451 w. MS (direct inlet): m/z (relative abundance) 593
(52), 516 (2), 425 (7), 409 (100), 370 (4), 306 (11), 285 (8), 261 (47), 199
(16), 186 (53), 183 (82), 152 (15), 121 (17), 108 (98), 71 (31), 57 (62), 43
(59). HR MS calcd. for C36H2956FeNP2: 593.1125, found 593.1102.
[11] Diffraction data were measured on a Nonius KappaCCD diffractom-
eter at 150(2) K. The structure was solved by direct methods (SIR97
[11a]) and refined by full-matrix least squares on F2 (SHELXL97
[11b]). The non-hydrogen atoms were refined with anisotropic
displacement parameters; all hydrogen atoms were included in
calculated positions (riding model). Crystal data and refinement
[8] Preparation of 2-(diphenylphosphino)-[2-(diphenylphosphino)ferr-
ocenyl]acetonitrile (2b). Similar to the previous procedure, nitrile 1
[6] (205 mg, 0.50 mmol in dry THF (15 mL)) was deprotonated with
NaN(SiMe3)2 (0.8 mL, 1.0 M in THF, 0.80 mmol) at À78 ꢁC for
30 min and then treated with neat chlorodiphenylphosphine (0.2 mL,
1.1 mmol; freshly distilled). The reaction was completed by stirring
for 15 min at À78 ꢁC and then at room temperature for 90 min and
then terminated by addition of saturated aqueous NaCl solution
(10 mL). The organic phase was separated, washed twice with
saturated aqueous NaCl, dried over MgSO4, and pre-adsorbed onto
silica gel by co-evaporation. The solid material was transferred onto
the top of a chromatographic column (silica gel, hexane-ether 10:1)
and eluted with the same solvent mixture. A subsequent evaporation
yielded diphosphine 2b as a single diastereoisomer. Yield: 200 mg
(67%), viscous orange oil.
ꢀ
˚
parameters: triclinic, space group P1 (no. 2), a = 10.1434(2) A,
˚
˚
b = 10.3163(2) A, c = 11.9958(3) A; a = 109.317(2)ꢁ, b = 109.802(1)ꢁ,
3
˚
c = 102.574(2)ꢁ; V = 1034.83(4) A , Z = 2, Dcalc
= ,
1.358 g cmÀ3
l(Mo Ka) = 0.816 mmÀ1, 19040 total (2h 6 55ꢁ), 4759 independent
(Rint = 3.2%) and 4111 observed [Io > 2 (Io)] diffractions. Final
refinement parameters: R = 4.16% (observed data); R = 5.10%,
[9] Analytical data for 2a. Mixture of isomers: IR (Nujol): m/cmÀ1 2239 w
m(C„N), 1584 w, 1434 s, 1305 w, 1246 w, 1166 w, 1097 m, 1066 w,
1038 w, 999 w, 844 w, 819 s, 745 s, 697 s, 553 w, 502 m, 486 m, 455 m.
Major diastereoisomer: M.p. 159–161 ꢁC. 1H NMR (CDCl3): d 1.13
À3
˚
wR = 11.24% (observed data); Dq +2.23, À0.42 e A (The positive
residual electron density is due to the phosphorus lone pair; attempted
refinement of this electron density maximum as a helium atom (2
electrons) lead to a decrease of the R value by 1%. Thus, the second
3
(d, JHH = 7.2 Hz, 3H, CHMe), 3.87 (m, 1H, C5H3), 4.11 (s, 5H,
3
4
C5H5), 4.13 (qd, JHH = 7.2 Hz, JPH = 5.0 Hz, 1H, CHMe), 4.38
(apparent t, J ꢀ 2.6 Hz, 1H, C5H3), 4.65 (m, 1H, C5H3), 7.12–7.58 (m,
10H, P Ph2). 13C{1H} NMR (CDCl3): d 22.47 (CH3), 26.26 (d,
3JPC = 14 Hz, CHCH3), 69.23 (d, JPC = 4 Hz, CH C5H3), 69.91 (CH
C5H3), 70.34 (C5H5), 71.57 (d, JPC = 5 Hz, CH C5H3), 74.90 (d,
largest positive difference electron density peak (+0.37 e AÀ3) should
˚
be regarded as true positive residual electron density). Geometric
calculations were performed with Platon program [11c]. CCDC
Deposition No.: 288346. References: (a) A. Altomare, M.C. Burla, M.
Camalli, G.L. Cascarano, C. Giacovazzo, A. Guagliardi, A.G.G.
Moliterni, G. Polidori, R. Spagna, J. Appl. Crystallogr. 32 (1999) 115;
(b) G.M. Sheldrick, SHELXL97. Program for the Refinement of
Crystal Structures, University of Goettingen, Germany, 1997;
(c) Platon – A Multipurpose Crystallographic Tool. Available from:
http://www.cryst.chem.uu.nl/platon/.
2
1JPC = 9 Hz, C–P C5H3), 90.81 (d, JPC = 27 Hz, C–CH C5H3),
3
122.07 (C„N), 128.21 (CHm PPh2), 128.27 (d, JPC = 2 Hz, CHm
PPh2), 128.29, 129.40 (2 · CHp PPh2); 132.42, 134.87 (2 · d,
1
2JPC = 21 Hz, CHo PPh2); 136.49, 139.26 (2 · d, JPC = 8 Hz, Cipso
PPh2). 31P{1H} NMR (CDCl3): dÀ25.9 (s). EI MS (direct inlet): m/z
ˇ
(relative abundance) 423 (100), 384 (7), 302 (4), 276 (9), 239 (9), 217
[12] P. Steˇpnicˇka, Eur. J. Inorg. Chem. (2005) 3787.