Bis((2-methoxymethyl)pyrrolidine)phosphine as effective chiral auxiliary for the stereoselective synthesis of chiral ferrocenyl diphosphines

Article abstract of DOI:10.1016/j.tetasy.2010.05.028

The bis(2-methoxymethyl pyrrolidine)phosphine moiety is shown to be a very effective chiral auxiliary for the ortho-and diastereoselective lithiation of ferrocene, thereby allowing the highly selective attachment of various electrophiles to the cyclopentadienyl ring of ferrocene. The potential of the methodology is demonstrated by the synthesis of Kephos, a new family of ferrocenyl diphosphines and of OH-Taniaphos derivatives.

Full text of DOI:10.1016/j.tetasy.2010.05.028

Tetrahedron: Asymmetry 21 (2010) 1199–1202
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Tetrahedron: Asymmetry
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Bis((2-methoxymethyl)pyrrolidine)phosphine as effective chiral auxiliary
for the stereoselective synthesis of chiral ferrocenyl diphosphines
a,
a
a
a
Matthias Lotz a, , Benoît Pugin , Martin Kesselgruber , Marc Thommen , Felix Spindler ,
*
*
Hans-Ulrich Blaser a, Andreas Pfaltz b, Marc Schoenleber b
a Solvias AG, PO Box, CH-4022 Basel, Switzerland
b Department of Chemistry, University of Basel, St. Johanns-Ring 19, CH-4056 Basel, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
The bis(2-methoxymethyl pyrrolidine)phosphine moiety is shown to be a very effective chiral auxiliary
for the ortho- and diastereoselective lithiation of ferrocene, thereby allowing the highly selective attach-
ment of various electrophiles to the cyclopentadienyl ring of ferrocene. The potential of the methodology
is demonstrated by the synthesis of Kephos, a new family of ferrocenyl diphosphines and of OH-Tania-
phos derivatives.
Received 31 March 2010
Accepted 14 May 2010
Available online 19 June 2010
Dedicated to Professor Henri Kagan on the
occasion of his 80th birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
O
O
Fe
Ferrocene-based chiral diphosphines are amongst the most ver-
satile ligands for a variety of asymmetric catalytic transforma-
tions.1 In most cases these compounds exhibit planar chirality,
which renders their enantioselective synthesis non-trivial. The
most common approach to solve this problem is the diastereose-
lective functionalization of chiral monosubstituted ferrocene
derivatives via ortho lithiation followed by reaction with an elec-
trophile.2,3a A variety of chiral ortho-directing groups has been re-
ported and some representative examples are depicted in Figure 1.
The majority of these groups are attached to the ferrocene via a
carbon bond, one of the most versatile being the chiral amine
introduced by Ugi in 1970,4 which is now used to produce a num-
ber of commercial ligands.5 Other well-known examples are Rich-
ards’s6 and Uemura’s7 chiral oxazolines or Kagan’s chiral acetal.8
An important property of these C-bound groups is the fact that
they cannot be easily removed or replaced. Kagan9 overcame this
limit by using a chiral sulfoxide. After the stereoselective introduc-
tion of a first electrophile, the sulfoxide can be replaced relatively
easily by another electrophile such as a PR2 group. However, the
yields are usually relatively low and the reaction is not easy to
scale. Our goal was to find a suitable chiral ortho-directing P(III)-
bound auxiliary that could be readily transformed into a phosphine
after introduction of the electrophile. A similar approach had al-
ready been described by Nettekoven et al.10 but the scope of the
phosphine oxide auxiliary is rather narrow and restricted to P-chi-
Fe
O
Fe
N
NMe2
R
MeO
chiral oxazolines
(S)-1,2,4-butanetriol
based acetal
(Kagan)
(R)-Ugiamine
(Uemura, Richards)
Ph
Ph
Ar
O
N
P
p-Tol
O
P
Fe
Fe
S
Fe
O
O
(-)-ephedrine based
oxazaphospholidine oxide
(Xiao et al.)
(R)-sulfoxide
(R)-phosphine oxide
(Kagan)
(Nettekoven et al.)
Figure 1. Chiral ferrocene derivatives used as starting material for various ligand
syntheses.
ral phosphines with bulky groups. When we already had filed our
patents,11–13 Xiao published a method using an ephedrine-based
P(V) auxiliary.14 In both cases, an (often problematic) reduction
is required to obtain the desired PR2 group.
Herein we report a new modular and versatile methodology
based on
a P(III) derivative of the commercially available
(2-methoxymethyl)pyrrolidine auxiliary allowing the highly ortho-
and diastereoselective functionalization of ferrocene with a variety
of electrophiles as depicted in Figure 2. The versatility of this strat-
* Corresponding authors.
E-mail addresses: matthias.lotz@solvias.com (M. Lotz), benoit.pugin@solvias.
com (B. Pugin).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.028

1200
M. Lotz et al. / Tetrahedron: Asymmetry 21 (2010) 1199–1202
[N*]
1) R-Li
2) EX
[N*]
E
P
Fe
PR'2
E
Fe
P
Fe
[N*]
[N*]
ortho- and diastereoselective
Ph
R
N
P
[N*]
N
N
N
OMe
=
P
P
P
[N*]
N
N
MeO
R
Ph
1
2a R = Me
3
chiral, ortho
directing group
2b R = 2-Napthyl
2c R = (CH2)2OMe
Figure 2. General strategy and structures of directing groups used in this work.
egy is demonstrated by the synthesis of Kephos, a new family of 1,2-
substituted ferrocenyl diphosphines 7 (see Fig. 5,8), and of various
Taniaphos12,13,15 derivatives 10 (see Fig. 6).
addition of n-heptane, thoroughly washed with n-heptane, and dis-
solved in THF. Solution A was then added dropwise at ꢀ78 °C and
the reaction mixture stirred overnight at rt. The borane complex
was prepared by the dropwise addition of BH3ꢁMe2S followed by
over night stirring at rt. After hydrolysis with a saturated NH4Cl
solution, extraction with TMBE and chromatography on silica gel
(S,S)-5 was obtained as an orange solid in 70% yield, which showed
a broad multiplet signal at around 81 ppm in the 31P NMR spec-
trum. Obviously, the ortho- and diastereoselective lithiation of
(S,S)-5ꢁBH3 is the key step in our new synthesis of a variety of ferr-
ocenyl diphosphine ligands. As mentioned above, it can be carried
out in >99% selectivity under optimized conditions. The choice of
the Li reagent (optimal s-BuLi), the temperature (ꢀ30 to ꢀ40 °C),
the solvent (TMBE/hexane 1:1), and the absence of any coordinat-
ing agents such as TMEDA are important.
The potential of this methodology is illustrated by the prepara-
tion of a Kephos (Fig. 5) and a Taniaphos (Fig. 6) ligand. It is impor-
tant to note that a variety of different analogues of both ligand
families have been prepared with similar yields and described in
several patent applications in some detail.11–13 Intermediates 6
and 7 (Kephos synthesis), and 9 and 10 (Taniaphos synthesis) were
characterized by 31P NMR spectroscopy and used without further
purification since only one isomer was detected. The lithiation of
(S,S)-5ꢁBH3 and subsequent reaction with ClPR2 took place with
very high selectivity and in good yields to give (SP)-6. Depending
on the choice of the ClPR2 reagent, the next reaction step, that is,
the hydrolysis of the P–N bonds, occurs with different selectivity.
When ClPPh2 is used (as depicted in Fig. 5) the PCl2 moiety ob-
tained by reaction with HCl can be reduced to the desired PH2
group without affecting the stable PPh2 substituent. Reaction with
the corresponding diol sulfates or tosylates allows the synthesis of
mixed phospholane/diarylphosphino Kephos ligands 8, which
would be very difficult to make otherwise. With the appropriate
choice of the absolute configuration of the chiral diol, both diaste-
reomers (SP,S,S and SP,R,R)-8 with R = Me, Et or i-Pr can be prepared
in a controlled manner. Due to the presence of phospholane moie-
ties, most Kephos ligands are relatively air sensitive and should be
stored either in protonated form or as metal complexes.
2. Results and discussion
In order to find effective chiral auxiliaries and suitable reaction
conditions several3b lithiation studies were carried out with vari-
ous ferrocene diazaphospholidine derivatives (auxiliaries 1 and
2) and bis((2-methoxymethyl)pyrrolidine)phosphine 3. It turned
out that the borane protection was required for stability reasons
and that diazaphospholidine 2 moieties without an additional
coordinating group (such as 1 or 2b) did not give any lithiation
of the ferrocene with t-BuLi (ꢀ25 °C in diethyl ether). Auxiliaries
2c and 3 were more successful, allowing very selective ortho lithi-
ation (>99% selectivity) with >98% de, when the corresponding BH3
adducts of 4 and 5 were lithiated and treated with tert-butyllith-
ium under optimized reaction conditions (see Fig. 3). Since both
enantiomers of (2-methoxymethyl)pyrrolidine are commercially
available, we carried out all further investigations with intermedi-
ate 5.
OMe
OMe
H3B
N
N
N
H3B
P
P
Fe
Fe
MeO
Li
Li
N
OMe
(R,R)-4.BH3
(S,S)-5.BH3
(t-BuLi, TBME/hexane, -78ºC to rt)
(s-BuLi, Et2O, -78ºC)
Figure 3. Lithiation of BH3 adducts of 4 and 5.
The synthesis of the key intermediate 5 will be described in de-
tail (Fig. 4,16). In the first step, NEt3 and then (S)-(2-methoxy-
Several synthetic approaches to the various Taniaphos ligand
types with MeO, NR2, or alkyl groups at the stereogenic center have
been described,5 but the corresponding OH derivatives seem not to
be accessible via these routes. The OH derivative is of interest as a
ligand in its own right but also because the OH group can be read-
ily converted to an MeO or NR2 substituent. A first attempt using
Kagan’s sulfoxide route gave the desired ligand but was not scal-
able. As shown in Figure 6, the new methodology gives ready ac-
cess to these derivatives via reaction of the lithiated 5ꢁBH3 with
methyl)pyrrolidine were added dropwise at 0 °C to
a PCl3
solution in THF (since most reagents and intermediates are air
and water sensitive, all manipulations were carried out under ar-
gon). The resulting suspension was stirred overnight at rt. The pre-
cipitated salts were filtered off and solution A was directly used in
the next step. Here, ferrocene and t-BuOK were dissolved in dry
THF and cooled to ꢀ78 °C, followed by the dropwise addition of
t-BuLi in hexane. The lithiated ferrocene was precipitated by the

M. Lotz et al. / Tetrahedron: Asymmetry 21 (2010) 1199–1202
1201
OMe
OMe
Fe
1) s-BuLi, TBME/hexane, -30ºC
2) ClPPh2, -30°C to rt
N
N
H3B
P
P
Fe
PPh2
MeO
MeO
3) NEt3, 50ºC
N
N
(S,S)-5·BH3
(SP,S,S)-6
85% yield
R
1) LiN(i-Pr)2, THF, rt
1) HCl (Et2O)
TBME, 0ºC
P
PPh2
H2P
Fe
PPh2
Fe
(SP, S,S)-6
O
O
O
O
2)
2) LiAlH4, THF, -78ºC
3) NaOH
R
S
7
(RP,S,S)-8
R = Me 45% yield
R
R
Figure 5. Synthesis of Kephos derivatives 8.
OMe
Fe
OMe
1) s-Bu-Li, TBME/hexane, -30ºC
2) 2-BrC6H4CHO
N
OH
N
BH3
BH3
+
Br
P
P
MeO
MeO
Fe
N
(SP, αR)-9·BH3
N
24%
(SP,αS)-9·BH3
61%
(S,S)-5·BH3
1) HCl, TBME/toluene, 0ºC
2) PhMgCl, 0ºC to rt
78%
3) DBU, toluene, 80ºC
1) KH, THF, 0ºC to rt
OH
2) t -BuLi, -78ºC
PPh2
3) ClPPh2, -78ºC to rt
OH
Br
PPh2
Fe
PPh2
Fe
47%
(SP,αS)-11
OH-Taniaphos
Figure 6. Synthesis of OH-Taniaphos derivative 11.
(SP,αS)-10
2-Br-benzaldehyde. The reaction also occurs with this electrophile
with very high ortho- and diastereoselectivity at the cp ring and
high yields of the two diastereomeric adducts can be obtained. A
mixture of (SP,aS)-9 and of (SP,aR)-9 was obtained (ca. 3:1), which
could be readily separated by chromatography on a silica gel
column. The absolute configuration at the stereogenic center for
(SP,
S)-9 was confirmed by X-ray analysis.17 In principle, this pro-
cedure allows the preparation of both diastereomeric ligands,
which might lead to different catalytic properties. Reaction with
HCl gives the PCl2 derivative which can be reacted with Grignard
a
OMe
N
1) NEt3, THF, 0ºC
PCl3
P
solution A
Cl
MeO
OMe
2)
N
NH
OMe
Fe
N
H3B
1) t-BuOK, THF, -78ºC
2) t-BuLi, hexane, -78ºC
P
1) THF, solution A, -78ºC to rt
MeO
Li
Fe
Fe
N
2) BH3·Me2S
3) saturated NH4Cl
(S,S)-5·BH3 70%
Figure 4. Synthesis of key intermediate 5.

1202
M. Lotz et al. / Tetrahedron: Asymmetry 21 (2010) 1199–1202
R= H, Me
COOR
R = Me, Ph
O
COOMe
COOMe
COOR
NHAc
Ph
COOEt
NHAc
R
(RP,S,S)-8
(RP,R,R)-8
96-98%
50-60%
>99,9%
<30-87%
96-98%
70-80%
>99%
(SP,αS)-11
>99%
97-98% (Ru)
Figure 7. Enantioselectivities obtained with Kephos and Taniaphos ligands.
2. Kagan, H. B.; Riant, O.. In Advances in Asymmetric Synthesis; Hassner, A., Ed.; JAI
Press, 1997; Vol. 2, p 189.
reagents in conventional manner to give intermediate (SP,aS)-10.
The introduction of the second phosphino group via lithiation
and reaction with ClPAr2 requires first a deprotonation of the OH
with KH but then proceeds reasonably well under the conditions
originally described by Knochel.5 Several mixed Ar/Ar0 derivatives
have been prepared via this route with non-optimized yields of
45–88%.
3. Schönleber, M. Ph.D. Thesis, University of Basel, 2005. http://pages.unibas.ch/
diss/2005/DissB_7189.pdf; (a) For a literature overview see pp 69–75; (b)
Lithiation studies are described in detail on pp 76–133.
4. Marquarding, D.; Klusacek, H.; Gokel, G.; Hoffmann, P.; Ugi, I. J. Am. Chem. Soc.
1970, 92, 5389.
5. For an overview see: Chen, W.; Blaser, H. U. In Trivalent Phosphorus Compounds
in Asymmetric Catalysis: Synthesis and Applications; Börner, A., Ed.; Wiley-VCH,
2008; p 359.
6. Richards, C. J.; Damalidis, T.; Hibbs, D. E.; Hursthouse, M. B. Synlett 1995, 74.
7. Nishibayashi, Y.; Uemura, S. Synlett 1995, 79.
8. Riant, O.; Samuel, O.; Flessner, T.; Taudien, S.; Kagan, H. B. J. Org. Chem. 1997,
62, 6733.
Starting from (S,S)-5ꢁBH3, further alternative classes of ligands
can be prepared, for example, if (S,S)-5ꢁBH3 is reacted with
ClP(NEt2)2, both P substituents can be converted to the PH2
group.18 This intermediate allows access to ferrocenyl analogues
of the well-known DuPhos diphospholane ligands in (non-opti-
mized) yields of 40–52%. Also, it is possible to prepare 1,2-diphos-
9. Rebiere, F.; Riant, O.; Ricard, L.; Kagan, H. B. Angew. Chem., Int. Ed. Engl. 1993, 32,
568.
10. Nettekoven, U.; Widhalm, M.; Kamer, P. C. J.; van Leeuwen, P. W. N. M.;
Mereiter, K.; Lutz, M.; Spek, A. L. Organometallics 2000, 19, 2299.
11. Pfaltz, A.; Lotz, M.; Schoenleber, M.; Pugin, B.; Kesselgruber, M.; Thommen, M.
PCT Int. Appl. WO 2005/056566, 2005 (assigned to Solvias AG).
12. Lotz, M.; Kesselgruber, M.; Thommen, M.; Pugin, B. PCT Int. Appl. WO 2005/
056568, 2005 (assigned to Solvias AG).
phines with different PR2/PR0 groups with only planar chirality as
2
described by Kagan in his seminal paper19 by reacting the PCl2
intermediate after HCl hydrolysis of 6 with RMgBr as described
for the synthesis of OH-Taniaphos.
13. Lotz, M.; Spindler, F. PCT Int. Appl. WO 2005/108409, 2005 (assigned to Solvias
AG and Umicore AG).
The enantioselectivities for the hydrogenation of several test
substrates using Rh and Ru complexes of various Kephos and
Taniaphos derivatives are shown in Figure 7; more detailed results
will be reported elsewhere. The results clearly demonstrate that
these ligands have considerable potential for the Rh hydrogenation
of activated alkenes and of b-keto esters (Ru complex, only OH-
Taniaphos). As expected, the unsymmetrical Kephos ligands of type
8 exhibit a pronounced ‘matched–mismatched’ effect and interest-
ingly, the optimal ligand for dimethyl itaconate is opposite the one
14. Vinci, D.; Mateus, N.; Wu, X.; Hancock, F.; Steiner, A.; Xiao, J. Org. Lett. 2006, 8,
215.
15. For an overview on Taniaphos derivatives and their synthesis see Ref.5.
16. Synthesis of bis((2-methoxymethyl)pyrrolidine)phosphine chloride.
In a 500 mL-Schlenk flask, PCl3 (7.38 g, 53.75 mmol) was dissolved in dry THF
(150 mL) under argon and the solution was cooled to 0 °C in an ice bath. Next,
NEt3 (11.97 g, 118.25 mmol, 2.20 equiv) was added dropwise, followed by the
dropwise
addition
of
(S)-(2-methoxymethyl)pyrrolidine
(12.69 g,
110.19 mmol, 2.05 equiv). A white precipitate formed during the addition.
The ice bath was removed and the resulting suspension was stirred at rt
overnight (14 h). The precipitated white solid was filtered off under argon and
washed with dry THF (2 ꢂ 25 mL). A 31P NMR (C6D6, 121 MHz) spectrum of the
yellowish filtrate was recorded: 154.3 (s). The obtained solution A was used
without further purification.
for dehydro
a-amino acid derivatives. The Rh catalysts showed
quite good activities, allowing the hydrogenation of DMI with
(RP,S,S)-8 with ee values of 97.8% and full conversion at an s/c ratio
of 10,000 (1 bar, 40 °C, 1 h). With very few exceptions, the OH-
Taniaphos ligands had similar performances as the analogous
MeO derivatives which have been profiled extensively.20
Preparation of (S,S)-5ꢁBH3.
In a 1 L-Schlenk flask, ferrocene (10.00 g, 53.75 mmol) and KOt-Bu (754 mg,
6.72 mmol, 0.125 equiv) were dissolved in dry THF (100 mL) under argon. The
solution was cooled to ꢀ78 °C and t-BuLi (1.5 M in hexane; 71.67 mL,
107.50 mmol, 2.00 equiv) was added within 45 min. After stirring the
resulting solution for 1.5 h at ꢀ78 °C, heptane (75 mL) was added. The
resulting precipitate was filtered off under argon and washed with heptane
(60 mL) at ꢀ78 °C. This procedure was repeated three times. The obtained solid
was dissolved in dry THF (50 mL) and solution A (53.75 mmol, 1.00 equiv) in
THF (200 mL) was added at ꢀ78 °C within 1.5 h. The solution was allowed to
warm to rt overnight (14 h). Borane–dimethylsulfide-complexes (5.10 mL,
53.75 mmol, 1.00 equiv) were added dropwise and the solution was stirred at
rt overnight. The reaction was quenched with satd NH4Cl-solution (50 mL) and
the mixture was extracted with TBME (3 ꢂ 100 mL). The combined org. layers
were dried over Na2SO4 and the solvent was removed under reduced pressure.
The crude product (24.18 g) was purified by column chromatography (200 g
silica gel, n-heptane/TBME 5:1). (S,S)-5ꢁBH3 (17.23 g, 37.60 mmol, 70%) was
isolated as an orange solid. 1H NMR (C6D6), selected characteristic signals: 4.22
(s, 5H cp), 3.11 (s, 3H, OMe), 3.04 (s, 3H, OMe). 31P NMR (C6D6, 121 MHz): 81.7–
80.4 (m, br).
3. Conclusions
The bis((2-methoxymethyl)pyrrolidine)phosphine moiety is
very effective in directing the lithiation of ferrocene. The presence
of the methoxy groups as well as the appropriate lithium reagent is
required to give good selectivity. Electrophiles such as ClPR2 or
aldehydes can be introduced with good yields, allowing the prep-
aration of a variety of 1,2-substituted ferrocene derivatives.
Acknowledgments
17. Bats, J. W.; Doppiu, A.; Rivas Nass, A.; Hashmi, A. S. K. Acta Crystallogr., Sect. E
2008, 64, m1585.
18. The use of a chiral directing group is of course not optimal to make this
symmetrical intermediate and, indeed, 1,2-bis(phosphino)ferrocene can be
prepared using –P(O)(OEt)2 as directing group. These results will be published
elsewhere.
We thank the innovation promotion agency of Switzerland (CTI)
and Umicore for partial financial support, Umicore for allowing
publication of the Taniaphos results, and Reto Kellerhals and Cédric
Raillard for excellent experimental work.
19. Argouarch, G.; Samuel, O.; Riant, O.; Daran, J.-C.; Kagan, H. B. Eur. J. Org. Chem.
2000, 2893.
References
20. Spindler, F.; Malan, C.; Lotz, M.; Kesselgruber, M.; Pittelkow, U.; Rivas-Nass, A.;
Briel, O.; Blaser, H. U. Tetrahedron: Asymmetry 2004, 15, 2299.
1. For a recent monograph see: Chiral Ferrocene Ligands in Asymmetric Catalysis;
Dai, L., Hou, X.-L., Eds.; Wiley-VCH, 2010; For a recent review see: Gomez, A. R.;
Adrio, J.; Carretero, J. C. Angew. Chem., Int. Ed. 2006, 45, 7674.