A C2-symmetric metallocene-pyrrolidinopyridine nucleophilic catalyst for asymmetric synthesis

Article abstract of DOI:10.1055/s-2007-970764

A C₂-symmetric nucleophilic catalyst, (R,R)-3,5-diferrocenyl-4- (2′,5′-dimethylpyrrolidino)pyridine, was synthesised in three steps from commercially available (S,S)-hexane-2,5-diol. Application to the kinetic resolution of secondary alcohols (0.5 mol% loading) resulted in selectivity factors (s) of up to 6. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970764

LETTER
725
A C -Symmetric Metallocene-Pyrrolidinopyridine Nucleophilic Catalyst for
2
Asymmetric Synthesis
A
H
C
-Symmetric
M
u
etallocene-P
y
yrrolidinopyridineV. Nguyen, Majid Motevalli, Christopher J. Richards*
2
School of Biological and Chemical Sciences, Queen Mary, University of London, Mile End Road, London E1 4NS, UK
Fax +44(20)78827794; E-mail: c.j.richards@qmul.ac.uk
Received 12 January 2007
cene, such that the environment about this nitrogen may
be represented by the quadrant model A (Figure 1). A C2-
symmetric variant of the catalyst, as represented by model
Abstract: A C -symmetric nucleophilic catalyst, (R,R)-3,5-diferro-
cenyl-4-(2¢,5¢-dimethylpyrrolidino)pyridine, was synthesised in
three steps from commercially available (S,S)-hexane-2,5-diol.
2
Application to the kinetic resolution of secondary alcohols (0.5 B, may have advantages over a C -system by reducing the
1
mol% loading) resulted in selectivity factors (s) of up to 6.
number of possible transition states in the enantioselective
step of a catalysed reaction. Relatively few of the known
4
Key words: alcohols, asymmetric catalysis, kinetic resolution,
metallocenes, nucleophiles
chiral non-racemic 4-aminopyridine nucleophilic cata-
5
lysts are C -symmetric and the possible advantages of
2
such disymmetry are not clear. In this Letter we report on
the synthesis of 2 containing two smaller ferrocene
moieties in place of the larger metallocene substituent of
4
-Aminopyridine derivatives such as 4-DMAP and 4-
PPY are efficient organocatalysts for a number of reac-
tions, especially those involving acyl transfer. Chiral 4-
aminopyridines have also been applied to asymmetric
transformations, but the widespread use of these method-
1
1. The advantages of the C -symmetry of 2 are explored
2
by application of this catalyst to the kinetic resolution of
secondary alcohols.
2
6
ologies is often hampered by the difficulty of synthesising Commercially available (S,S)-hexane-2,5-diol was first
3
the catalyst itself, and/or the requirement to resolve the converted into the corresponding dimesylate 3 and then
7
catalyst and confirm enantiopurity.
reacted with 3,5-dibromo-4-aminopyridine to give the
new (R,R)-pyrrolidinopyridine 4. A subsequent double
8
small
Me
Stille reaction with ferrocenyltributyltin, using the condi-
9
tions developed by Baldwin et al., led to the formation of
N
N
the required nucleophilic catalyst in excellent yield
(Scheme 1).
Me
N
N
C
N
C
Co
Ph
Ph
Ph
NH2
large
A
Br
Br
Ph
1
OH
OMs
MsCl
N
small
CH2Cl2,
3
NaH, THF
∆
Fe
OH
Et N
3 91% OMs
Me
N
N
Me
SnBu3
N
N
C
N
C
Fe
Me
Br
Me
Br
N
Fe
Me
medium
Fe
B
N
Me
PdCl2, P(t-Bu)3,
N
2
N
72%
CsF, CuI, DMF
∆
4
2 82%
Fe
Figure 1 Comparison of catalysts 1 and 2
We recently reported the synthesis of 1, obtained in three Scheme 1 Synthesis of C -symmetric nucleophililc catalyst 2
2
steps from commercially available (S,S)-hexane-2,5-diol,
and on the application of 1 as a catalyst for the asymmetric
Steglich rearrangement. The stereochemical information
The corresponding C -catalyst 6 containing a single
1
3
ferrocene substituent was similarly synthesised from
in the C -symmetric pyrrolidine substituent of 1 is relayed
R,R)-3-bromo-4-(2¢,5¢-dimethylpyrrolidino)pyridine (5),3
2
(
to the pyridine nitrogen by a bulky cobalt-based metallo-
also in good yield (Scheme 2). We next investigated the
application of these Stille cross-coupling conditions to
the synthesis of 1. This had previously been obtained in
SYNLETT 2007, No. 5, pp 0725–0728
1
6.
0
3.
2
0
0
7
Advanced online publication: 08.03.2007
DOI: 10.1055/s-2007-970764; Art ID: D35506ST
5
0% yield by the palladium-catalysed reaction of 5 with
3
10
organozinc 8. The Stille reaction of 7 gave 1 in only
©
Georg Thieme Verlag Stuttgart · New York

7
26
H. V. Nguyen et al.
LETTER
1
4% yield. Use of the 3,5-dibromo derivative 4 as the cou- creasing temperature, but as the rate of reaction was im-
pling partner in both the Stille and Negishi reactions with practically slow at –78 °C, further optimisation was
and 8, respectively, failed to give the product containing performed at –40 °C. Use of isobutyric anhydride (entry
7
the metallocene at both the 3- and 5-positions.
4) or Hünig’s base (entry 5) increased the selectivity fac-
tor, but combining these together did not give further im-
provement (entry 6). The conditions that gave the highest
SnBu3
Me
Me
Br
selectivity (entry 5, s = 6) were employed with C -cata-
1
N
Fe
lysts 1 (entry 7) and 6 (entry 8). Both of these gave higher
levels of conversion compared to 2 but with little enantio-
mer discrimination.
7
PdCl2, P(t-Bu)3,
PdCl2, P(t-Bu)3,
N
CsF, CuI, DMF
∆
CsF, CuI, DMF
∆
5
O
1
0
.7 equiv (R CO2)2O
Me
1 14%
OH
O
R1
OH
0
.7 equiv R2NEt
N
M
Me
+
Ph
Me
±)-9
PhMe
Ph
Me
Ph
(R)-9
Me
N
(
(S)-10
Co
Ph
Ph
6
76%
Fe
7 M = SnMe3
Scheme 3 Kinetic resolution of 1-phenylethanol
8
M = ZnCl
Ph
Ph
Other aryl-alkyl secondary alcohols were also examined
with catalyst 2 (Scheme 4). The presence of a p-nitro sub-
stituent (Table 2, entry 1) tripled the level of conversion
compared to 1-phenylethanol and gave a comparable val-
ue of s. In contrast the use of p-methoxyphenyl (entry 2)
or 1-naphthyl aryl groups (entry 3) resulted in lower
selectivity, as did the use of a tert-butyl alkyl substituent
Scheme 2 Synthesis of C -symmetric nucleophililc catalysts 1
and 6
1
Slow evaporation of a solution of 2 in CDCl resulted in
3
1
1
crystals suitable for X-ray crystal structure analysis. The
5
resulting structure (Figure 2) revealed that both Fe(h -
C H ) groups lie opposite the pyrrolidine methyl sub-
5
5
(
entry 4).
stituents, thus relaying the pyrrolidine stereochemistry
through to the vicinity of the pyridine nitrogen. The
pyrrolidine ring [as defined by the plane containing
C(10)–N(2)–C(7)] lies at an angle of 53° to the pyridine
ring in order to accommodate the two adjacent ferrocene
O
0
.7 equiv Ac2O
OH
O
Me
OH
R1
0.7 equiv (i-Pr)2NEt
+
R1
Ar
Ar
R1
Ar
0.5 mol% 2, 24 h
substituents. The resulting reduction in n →p*C=C inter-
N
PhMe, –40 °C
action should reduce the activity of 2 as a nucleophilic
1
2
catalyst, and in practice we found 2 to be slightly less
Scheme 4 Kinetic resolution of aryl-alkyl secondary alcohols
active than the C -systems 1 and 6 (vide infra).
1
The relatively much higher value of s obtained with 2
compared to 1 and 6 (6 vs. 1.3) reveals the advantages of
C -symmetry in these relay catalysts when applied to sec-
2
ondary alcohol kinetic resolution. In contrast, application
of 2 to the Steglich rearrangement of 5-benzyloxycarbon-
yloxy-4-methyl-2-(4-methoxyphenyl)oxazole gave the R-
rearranged product with an enantiomeric excess of only
2
2% compared to the value of 76% (S) obtained with
3
catalyst 1. This reveals that 1 and 2 are complementary
with respect to their application in these two different
reactions.
A further consequence of the C -symmetry of 2 is that
2
Figure 2 Representation of the X-ray crystal structure of 2 (CHCl3
of crystallisation removed for clarity). Key bond angles and torsions:
C(7)–N(2)–C(10) = 113.3(2)°, C(7)–N(2)–C(4) = 123.1(2)°, C(4)–
N(2)–C(10) = 123.4(2)°, C(3)–C(4)–N(2)–C(7) = –50.4(3)°, C(5)–
there is only one rotamer for the intermediate N-acetal
pyridinium salt [with respect to rotation about the N–C(O)
bond]. As attack at the carbonyl Si-face is likely blocked
C(4)–N(2)–C(10) = –55.2(3)°, C(4)–C(3)–C(23)–C(27) = 115.5(3)°, by ferrocene, it is possible to propose a model for the
C(4)–C(5)–C(13)–C(14) = 150.5(3)°.
enantioselectivity observed (Figure 3). In this the R-alco-
hol reacts less readily in the enantiomer discriminating
1
4
rate-determining step due to an unfavourable interaction
between the aryl group of the alcohol and the substituted
pyridine ring. For the faster reacting S-alcohol this is
avoided due to projection of the smaller methyl group into
this space.
The application of 2 to the kinetic resolution of 1-phenyl-
ethanol (Scheme 3) was initially performed at 0 °C,
1
3
–
0
40 °C and –78 °C in toluene with catalyst loadings of
.1 mol%, 0.5 mol% and 1 mol%, respectively (Table 1,
entries 1–3). The selectivity factor (s) increased with de-
Synlett 2007, No. 5, 725–728 © Thieme Stuttgart · New York

LETTER
A C -Symmetric Metallocene-Pyrrolidinopyridine
727
2
Table 1 Kinetic Resolution of 1-Phenylethanol 9a,b
Entry
1
Temp (°C)
0
Time (h)
60
Catalyst (mol%) R
Conv. (%)c
ee of 9d
32
se
2 (0.1)
2 (0.5)
2 (1)
Et
52
22
12
8
2.5
4.2
5.3
5.8
6.1
4.1
1.3
1.3
2
–40
24
Et
16
3
–78
72
Et
9
4f
–40
24
2 (0.5)
2 (0.5)
2 (0.5)
1 (0.5)
6 (0.5)
Et
6
5
–40
24
i-Pr
i-Pr
i-Pr
i-Pr
23
32
79
95
20
6f
–40
24
25
7g
8g
–40
24
22
–40
24
43
a
b
c
d
e
f
1
R = Me unless otherwise stated.
.5 M 9 in toluene.
0
1
Determined by H NMR spectroscopy.
Determined by GC, absolute configuration determined by comparison to commercially available (R)-9.
Selectivity factor.
1
R = i-Pr.
g
1
equiv of Ac O and base.
2
O
O
Synthesis of 4
7
To a solution of 4-amino-3,5-dibromopyridine (1.86 g, 7.4 mmol)
in THF (50 mL) was added NaH (60% dispersion in mineral oil,
Fc
Fc
N
Me
Ar
N
Me
Me
Me
N
Me
OH OAc
OH OAc
fast
slow
0
.75 g, 19 mmol) and the resulting solution stirred at r.t. for 3 h. To
N
Me
Ar
this was added a solution of (S,S)-2,5-bis(methylsulfonyloxy)hex-
ane (1.01 g, 3.7 mmol, synthesised in 91% yield using the procedure
previously reported ) in THF (30 mL), and the resulting reaction
H
Fc
Me
H
Fc
Me
(
S)
(R)
6
mixture was heated at reflux for 20 h. After cooling, quenching with
Figure 3 Model of enantioselection
H O (20 mL) and extraction with CH Cl (3 ꢀ 50 mL), the com-
2
2
2
bined organic extracts were dried (MgSO ), filtered and evaporated
4
In summary, we have synthesised a novel enantiopure 4- in vacuo. Column chromatography (SiO , 0.25% Et N/5% MeOH–
2
3
CH Cl ) gave 4 (0.882 g, 72% yield) as an off-white crystalline
aminopyridine nucleophilic catalyst 2, obtained in three
steps from commercially available (S,S)-hexane-2,5-diol
2
2
solid, mp 52–54 °C. Anal. Calcd for C H Br N : C, 39.55; H,
11 14
2
2
2
0
4
0
.22; N, 8.39. Found: C, 39.55; H, 4.28; N, 8.20. [a] +289 (c
D
with an overall yield of 54%. The C -symmetry of this
2
1
.115, MeOH). H NMR (270 MHz, CDCl ): d = 0.86 (6 H, d,
3
catalyst is an advantage when applied to the kinetic reso-
lution of chiral secondary alcohols. Work is currently in
progress to improve the selectivity of this reaction and to
discover further applications of catalysts 1 and 2.
J = 7.6 Hz, 2 ꢀ CH ), 1.47–1.58 (2 H, m, 2 ꢀ CHH), 2.09–2.24 (2 H,
3
m, 2 ꢀ CHH), 4.41–4.49 (2 H, m, 2 ꢀ CH), 8.48 (2 H, s, py).
1
3
1
C{ H} NMR (68 MHz, CDCl ): d = 21.3 (CH ), 34.8 (CH ), 56.9
3
3
2
+
(CH), 122.5 (py), 150.9 (py), 152.3 (py). HRMS (ES ): m/z
C H Br N : 332.9597; found: 332.9598 [MH ].
7
9
+
1
1
15
2
2
Table 2 Kinetic Resolution of Aryl-Alkyl Secondary Alcoholsa
Entry
Ar
R
Conv. (%)
ee (%)b
82c
s
1
2
3
p-NO C H
4
Me
Me
Me
t-Bu
69
35
79
13
5.0
2.4
2.7
2.5
2
6
p-MeOC H
18c
6
4
1-Naph
Ph
71d
4
6c
a
0
.5 M in toluene.
b
c
d
Of recovered alcohol, determined by GC.
Absolute configuration assigned by analogy to entry 3.
Absolute configuration determined by comparison to commercially available (R)-1-naphthylethanol.
Synlett 2007, No. 5, 725–728 © Thieme Stuttgart · New York

7
28
H. V. Nguyen et al.
LETTER
Synthesis of 2
A mixture of ferrocenyltributyltin, (0.440 g, 0.92 mmol) and 4
0.140 g, 0.42 mmol) was dissolved in DMF (4 mL). To this was
added CsF (0.256 g, 1.69 mmol), PdCl (3 mg, 17 mmol), P(t-Bu)
References and Notes
8
(
1) For reviews on achiral 4-aminopyridine nucleophilic
catalysts, see: (a) Scriven, E. F. V. Chem. Soc. Rev. 1983,
2, 129. (b) Grondal, C. Synlett 2003, 1568. (c) Murugan,
(
2
3
1
(
0.32 mL of 0.052 M solution in dioxane, 17 mmol), and CuI (6.4
mg, 34 mmol). The mixture was heated under nitrogen for 15 h at
00 °C. To the cooled reaction mixture was added CH Cl (30 mL)
R.; Scriven, E. F. V. Aldrichimica Acta 2003, 36, 21.
2) For reviews on chiral 4-aminopyridine nucleophilic
catalysts, see: (a) Fu, G. C. Acc. Chem. Res. 2004, 37, 542.
(b) Spivey, A. C.; Maddaford, A.; Redgrave, A. Org. Prep.
Proced. Int. 2000, 32, 331. (c) Connon, S. J. Lett. Org.
Chem. 2006, 3, 333.
(
1
2
2
and H O (10 mL). After vigorous shaking, the mixture was filtered
2
®
through Celite washing with a CH Cl –EtOAc mixture. The or-
2
2
ganic layer was separated, dried (MgSO ) and the solvent removed
4
in vacuo. Column chromatography (SiO , 2% MeOH–CH Cl ) gave
2
2
2
(3) Nguyen, H. V.; Butler, D. C. D.; Richards, C. J. Org. Lett.
2
1
as an orange crystalline solid (0.186 g, 82% yield), mp 193–
96 °C. Anal. Calcd for C H Fe N ·0.25H O: C, 67.85; H, 5.97;
2006, 8, 769.
3
1
32
2
2
2
2
0
(4) (a) Whitesell, J. K. Chem. Rev. 1989, 89, 1581. (b) Najdi,
S.; Kurth, M. J. Tetrahedron Lett. 1990, 31, 3279.
N, 5.10. Found: C, 67.81; H, 5.99; N, 4.86. [a]D –88 (c 0.105,
MeOH). H NMR (270 MHz, CDCl ): d = 0.69 (6 H, d, J = 6.0 Hz,
1
3
(
(
5) (a) Naraku, G.; Shimomoto, N.; Hanamoto, T.; Inanaga, J.
Enantiomer 2000, 5, 135. (b) Spivey, A. C.; Maddaford, A.;
Fekner, T.; Redgrave, A. J.; Frampton, C. S. J. Chem. Soc.,
Perkin Trans. 1 2000, 3460.
2
2
4
ꢀ CH ), 1.13–1.18 (2 H, m, 2 ꢀ CHH), 1.68–1.80 (2 H, m,
3
ꢀ CHH), 3.08–3.14 (2 H, m, 2 ꢀ CH), 4.17 (10 H, s, 2 ꢀ C H ),
5
5
.20 (2 H, s, Fc), 4.27 (2 H, s, Fc), 4.41 (4 H, s, Fc), 8.85 (2 H, br s,
13
1
py). C{ H} NMR (68 MHz, CDCl ): d = 21.4 (CH ), 34.2 (CH ),
3
3
2
6) Lieser, J. K. Synth. Commun. 1983, 13, 765.
5
5.3 (CH), 67.8 (Fc), 67.9 (Fc), 70.0 (Fc), 70.1 (Fc), 71.3 (Fc), 86.6
+
(7) Canibano, V.; Rodríguez, J. F.; Santos, M.; Sanz-Tejedor,
M. A.; Carreno, M. C.; González, G.; García-Ruano, J. L.
Synthesis 2001, 2175.
(py), 129.5 (py), 152.8 (py). HRMS (ES ): m/z C H Fe N :
31 33 2 2
+
5
45.1337; found: 545.1338 [MH ].
(
(
8) Guillaneux, D.; Kagan, H. B. J. Org. Chem. 1995, 60, 2502.
9) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem. Int. Ed.
Representative Method of Alcohol Acetylation
-Phenylethanol 5 (0.148 mL, 1.23 mmol) was dissolved in toluene
2.46 mL), followed by the addition of 2 (3.3 mg, 6 mmol) and
1
(
2004, 43, 1132.
(
(
10) Nguyen, H. V.; Motevalli, M.; Richards, C. J. manuscript in
preparation.
11) Crystal data of 2.
Hünig’s base (0.15 mL, 0.86 mmol). The reaction vessel was cooled
to –40 °C and to this was added Ac O (0.08 mL, 0.85 mmol). The
2
reaction mixture was stirred and maintained at –40 °C for 24 h. Af-
ter quenching with MeOH (10 mL), the solvent was removed in vac-
C H Cl Fe N , M = 663.65, orthorhombic, a = 7.3563(2),
32 33
3
2
2
1
b = 17.9280(6), c = 21.8849(7) Å, a = 90°, b = 90°, g = 90°,
uo and H NMR was used to determine the level of conversion [9:
3
V = 2886.26(15) Å , space group P2 2 2 , Z = 4, D = 1.527
CH(CH )OH = 4.85 ppm, 10: CH(CH )OAc = 5.86 ppm]. The
1
1
1
c
3
3
3
–1
mg/m , m = 1.309 mm , reflections measured 21200,
product 9 was isolated by column chromatography (SiO , 25%
2
reflections unique 6560 with R = 0.0495, T = 120 (2) K,
EtOAc–PE (40–60), changing the solvent mixture to 2% MeOH–
CH Cl led to recovery of the catalyst), and the ee was determined
int
2
2
final R indices [F >2s(F )] R1 = 0.0370, wR2 = 0.0670 and
for all data R1 = 0.0457, wR2 = 0.0701 (CCDC 619938).
12) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron
2
2
by gas chromatography (Chirasil-Dex CB 25 m ꢀ 0.25 mm), start-
ing temperature 80 °C, initial time 1 min, rate 1 °C/min, final tem-
(
(
1978, 34, 2069.
perature 180 °C, final time 10 min;. t = 42.27 min (R)-9 and 44.28
R
13) Toluene has frequently been found to be one of the best
solvents for this reaction, for example see: (a) Ruble, J. C.;
Tweddell, J.; Fu, G. C. J. Org. Chem. 1998, 63, 2794.
(b) Priem, G.; Pelotier, B.; Macdonald, S. J. F.; Anson, M.
S.; Campbell, I. B. J. Org. Chem. 2003, 68, 3844.
min (S)-9.
Acknowledgment
We thank the EPSRC for financial support (HVN) and the EPSRC
National Crystallography Service (Southampton University) for
data collection.
(
14) (a) Spivey, A. C.; Arseniyadis, S. Angew. Chem. Int. Ed.
2004, 43, 5436. (b) Xu, S.; Held, I.; Kempf, B.; Mayr, H.;
Steglich, W.; Zipse, H. Chem. Eur. J. 2005, 11, 4751.
Synlett 2007, No. 5, 725–728 © Thieme Stuttgart · New York

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