Molybdenum-Catalyzed Asymmetric Allylic Alkylation Reactions Using Mo(CO)6 as Precatalyst

Full text of DOI:10.1002/1615-4169(20010129)343:1<46::AID-ADSC46>3.0.CO;2-W

COMMUNICATIONS
Molybdenum-Catalyzed Asymmetric Allylic Alkylation
Reactions Using Mo(CO)6 as Precatalyst
Michael Palucki,* Joann M. Um, David A. Conlon, Nobuyoshi Yasuda,
David L. Hughes, Bing Mao, Jian Wang, Paul J. Reider
Department of Process Research, Merck Research Laboratories, P. O. Box 2000 Rahway,
New Jersey 07065±0900, U.S.A.
Fax: (+1) 7 32-5 94-51 70; e-mail: michael_palucki@merck.com
Received June 29, 2000; Accepted September 21, 2000
The transition metal-cat-
alyzed asymmetric allylic
alkylation of unsymme-
trically substituted allyl
derivatives has recently
emerged as an effective
production would not be
straightforward due to
the limited availability of
the precatalyst (EtCN)3-
Mo(CO)3 and ligand 1,
both of which are not
Keywords: allylic alkylation; asymmetric cataly-
sis; homogeneous catalysis; molybdenum; N li-
gands
method for the preparation of optically active commercially available.[5,6] The synthesis of
branched regioisomers in high enantioselectivity (EtCN)3Mo(CO)3 requires refluxing a solution of
and regioselectivity.[1] Results of these studies are in Mo(CO)6 in a large excess of propionitrile.[7] This
contrast to the traditional palladium-catalyzed reac- procedure represents a potential hazard since pro-
tions that predominantly afford the linear regioiso- pionitrile decomposes upon heating to hydrogen cy-
meric product.[2,3] Particularly interesting is the anide and ethylene.[8]
molybdenum-catalyzed asymmetric allylic alkylation
method developed by Trost, which has emerged as
one of the most promising methods for obtaining
optically active branched regioisomeric products,
Scheme 1.[1c,4] Indeed, high enantio- and regioselec-
tivities have been achieved for a range of allylic sub-
strates with various malonate nucleophiles.
Scheme 2. Synthesis of the desired optically active
branched regioisomeric product
Scheme 1. Trost's asymmetric allylic alkylation reaction
The effectiveness of (EtCN)3Mo(CO)3 as precatalyst
presumably derives from the lability of the propioni-
Our primary interest in the described reaction trile ligand, thus allowing for facile substitution with
arose from our desire to utilize the chiral unsym- the chiral ligand. In addition to (EtCN)3Mo(CO)3,
metrically substituted ªbranchedº allylic derivative Trost has recently disclosed that (C7H8)Mo(CO)3 can
3 as a key intermediate in the synthesis of a lead be used in place of (EtCN)3Mo(CO)3 with comparable
drug candidate (Scheme 2). The results published results.[9,10] Both (EtCN)3Mo(CO)3 and (C7H8)Mo-
by Trost suggest that the molybdenum-catalyzed (CO)3 are air-sensitive and are made from the com-
asymmetric allylic alkylation methodology would mercially available Mo(CO)6. We reasoned that, since
provide the desired product 3 in good enantio- and both molybdenum-precatalysts are derived from
regioselectivities. However, it became clear that di- Mo(CO)6, perhaps the air stable, readily available
rect implementation of the reaction to large-scale Mo(CO)6 could be directly used as a molybdenum-
46
Ó WILEY-VCH Verlag GmbH, 69451 Weinheim, Germany, 2001
1615-4150/01/34301-46±50 $ 17.50-.50/0
Adv. Synth. Catal. 2001, 343, No. 1

COMMUNICATIONS
precatalyst. In this communication we describe our sired product in either lower enantioselectivity,
efforts which have led to the successful and general regioselectivity, or yield. Reactions carried out in to-
use of Mo(CO)6 in asymmetric allylic alkylations.[11]
luene provided higher enantioselectivity and regio-
a molybdenum-catalyzed selectivity than in THF. Activation of the catalyst in
The development of
asymmetric allylic alkylation method employing THF at 65 °C followed by a room temperature alkyla-
Mo(CO)6 as precatalyst would require establishing tion reaction resulted in higher enantioselectivity, but
the necessary activation time and temperature in or- in lower product yield (Table 1, entry 6). Similarly, al-
der to ensure complete catalyst formation between kylation reactions performed in toluene at tempera-
the Mo(CO)6 precatalyst and ligand 1. Complete cata- tures < 65 °C were found to be extremely slow, pre-
lyst formation is necessary in order to avoid undesir- sumably due to the poor solubility of the dimethyl
able catalysis by the Mo(CO)6 precatalyst as well as sodiomalonate in toluene. Other solvents including
other possible molybdenum complexes.[12] Towards DMF, 1,2-dimethoxyethane (DME), and 1,2-dichloro-
this end, in situ IR was used to monitor the activation ethane (DCE) were found to be less effective in either
process. Consumption of Mo(CO)6 [assigned m(CO) enantioselectivity or product yield (Table 1, entries 7±
1984 cm±1 in toluene] and concomitant formation of 9).
the ªactive catalystº [tentatively assigned m(CO) 2011,
A fundamental question which now arises is
1984, 1891, 1818 cm±1 in toluene] was followed by whether the same active catalyst is generated regard-
monitoring the CO region of the IR spectrum.[13] less of the molybdenum precatalyst. To answer this, a
Thus, heating
a toluene solution of Mo(CO)6 comparison study was performed involving three dif-
(0.175 M) and 1.5 equiv of ligand 1 in the presence of ferent molybdenum precatalysts ((EtCN)3Mo(CO)3,
an in situ IR probe showed that 4 h at 85±90 °C was re- (C7H8)Mo(CO)3, Mo(CO)6) in two different solvents
quired to reach the minimum concentration of (THF and toluene).[14] Results of these studies, shown
Mo(CO)6 and maximum concentration of the ªactiveº in Table 2, reveal that the enantioselectivity and re-
catalyst. In THF, this steady state was reached in ap- gioselectivity are similar within each solvent system
proximately 2±3 h at 65 °C using similar concentra- regardless of the molybdenum precatalyst. In addition,
tions of Mo(CO)6 and ligand 1. With these results in the same major product enantiomer was obtained in
hand, initial asymmetric allylic alkylation experi- all cases using the same enantiomeric ligand 1.
ments examined the effect of varying activation time
and temperature of the catalyst/ligand solution, as Mo(CO)6 as precatalyst, with the results shown in Ta-
well as a brief survey of solvents (Table 1). ble 3. The enantioselectivity and regioselectivity ob-
Other substrates were also examined using
Toluene and THF were first examined as solvents tained for entries 1±3 were comparable to those ob-
since they were used in molybdenum-catalyzed tained by Trost using (EtCN)3Mo(CO)3 as
asymmetric allylic alkylation reactions previously re- precatalyst.[1c] The asymmetric allylic alkylation of
ported in the literature.[1c,1e,4] As shown in Table 1, the linear carbonate shown in entry 2 gave slightly
the optimal activation times that were determined by better enantioselectivity and regioselectivity than the
in situ IR proved to be experimentally superlative. branched carbonate shown in entry 1, which also par-
Longer or shorter activation times provided the de- allels the findings of Trost.[1c,15]
Table 1 Asymmetric allylic alkylation reactions of carbonate 2 with sodiodimethyl malonate using catalytic Mo(CO)6/li-
gand 1.[a]
Entry
Solvent
Activation Time (h)
Activation Temp(°C)[c]
% ee of 3[b]
Branched : Linear % Assay Yield[d]
1
2
3
toluene
toluene
toluene
THF
THF
THF
DMF
DME
DCE
0.75
85
85
85
65
95
97
89
92
92
96
87
95
98
95 : 5
95 : 5
92 : 8
92 : 8
89 : 11
84 : 16
86 : 14
85 : 15
96 : 4
77
91(84)
91
86
83
33
55
90
36
4
15
2
4
4
4
4
4
4[e]
5[e]
6
65
65 to rt[f]
7
8
9
85
80
80
[a] Reaction conditions: 10 mol% Mo(CO)6, 15 mol% ligand 1, 2.0 equiv dimethyl sodiomalonate, 0.15 M substrate 2, reaction
time: 8±12 h.
[b] Determined by HPLC using a chiral column (CHIRALPAK AD, 25 cm ´ 4.6 mm, 10 lm particle diameter).
[c] The activation temperature [Mo(CO)6 + ligand 1 in solvent] is also the alkylation reaction temperature.
[d] Yield in parentheses represent isolated product yield with purity > 95% as determined by HPLC and 1H NMR.
[e] Results reported in entries 4 and 5 represent the average of two or more runs.
[f] Activation of the catalyst was performed at 65 °C, and subsequent alkylation reaction performed at room temperature.
Adv. Synth. Catal. 2001, 343, 46±50
47

asc.wiley-vch.de
Table 2 Comparison of different molybdenum-precatalyst for the allylic alkylation of carbonate 2 with sodiodimethyl mal-
onate.[a]
Entry Mo-precatalyst[b]
Solvent
Activation Time (h) Activation Temp(°C)[c] % ee of 3[d] Branched:Linear % Assay Yield of 3
1
2
3
4
5
6
(EtCN)3Mo(CO)3
(C7H8)Mo(CO)3
Mo(CO)6
(EtCN)3Mo(CO)3
(C7H8)Mo(CO)3
Mo(CO)6
toluene
toluene
toluene
THF
THF
THF
0.5
0.5
4
0.5
0.5
4
85
85
85
65
65
65
95
96
97
91
88
91
93 : 7
96 : 4
95 : 5
90 : 10
88 : 12
89 : 11
84
87
91
88
81
83
[a] Results represent the average of two or more runs.
[b] (EtCN)3Mo(CO)3 was prepared using a literature procedure, see reference 7.
[c] The activation temperature [Mo(CO)6 + ligand 1 in solvent] is also the subsequent alkylation reaction temperature.
[d] Determined by HPLC using a chiral column (CHIRALPAK AD, 25 cm  4.6 mm, 10 lm particle diameter).
Table 3 Asymmetric allylic alkylation of various carbonates with sodiodimethyl malonate using catalytic Mo(CO)6/ligand 1.[a]
Entry
1
Substrate
% ee[b]
96
Branched:Linear
93:7
% Isolated Yield[c]
76
2
3
4
99
96
94
95:5
98:2
94:6
80
80
76
[a] Reaction conditions: 10 mol% Mo(CO)6, 15 mol% ligand 1, 2.0 equiv dimethyl sodiomalonate, 0.15 M substrate in toluene,
reaction temperature: 85 °C, reaction time: 8±12 h.
[b] Determined by HPLC using a chiral column (CHIRALPAK AD, 25 cm ´ 4.6 mm, 10 lm particle diameter).
[c] Isolated yields represent the average of two runs with product purity > 95% as determined by HPLC and 1H NMR.
In summary, the molybdenum-catalyzed asym- substrates. Results from comparison studies are con-
metric allylic alkylation reaction originally developed sistent with the notion that the same active catalyst is
by Trost has been modified by using the readily avail- generated regardless of the molybdenum-precatalyst.
able Mo(CO)6 in place of (EtCN)3Mo(CO)3. Using in Current work is focused on determining the structure
situ IR, the proper activation time required to maxi- of the active catalyst and on developing a better un-
mize catalyst formation was determined. The new derstanding of the mechanistic aspects controlling
protocol has been shown to be effective for various the enantio- and regioselectivity.
48
Adv. Synth. Catal. 2001, 343, 46±50

COMMUNICATIONS
Vagg, E. C. Walton, J. Chem. Eng. Data., 1978, 23, 348±
359. We have found that activation of picolinic acid
with 1,1-carbodiimidazole is remarkably effective and
provides crystalline ligand 1 in 86% isolated yield,
D. A. Conlon, N. Yasuda, Adv. Synth. Catal., 2001, 343,
137±138.
Experimental Section
Representative Procedure for the Asymmetric Allylic Al-
kylation Reaction
A 12-L, 3-necked round-bottomed flask was charged with
Mo(CO)6 (219 g, 0.828 mol), ligand 1 (402 g, 1.24 mol), and
evacuated/back filled with argon (3 cycles). To this was
added anhydrous toluene (4.36 L). The flask was evacu-
ated/back filled with argon (3 cycles) and the resulting mix-
ture heated to 85±88 °C for 4 hours. Separately, a 100-L flask
was charged with dimethyl sodiomalonate (2.36 kg,
[6] During the course of manuscript review, ligand 1 be-
came commerically available from Strem Chemical
Company.
[7] G. J. Kubas, L. S. Van Der Sluys, Inorg. Syntheses,
1990, 28, 29±33.
[8] The Merck Index, 11th ed, Merck & Co., Inc. Rahway
N. J. 1989 item 7839, pp 1244.
12.42 mol),
a toluene solution of carbonate 2 (2.0 kg,
8.28 mol, 3 L of anhydrous toluene), and toluene (30.6 L).
The flask was evacuated/back filled with argon and the re-
sulting solution heated to 70 °C followed by the addition of
the catalyst solution via cannula. The resulting mixture was
heated to 85 °C for 15 h and subsequently cooled to room
temperature. Water (36 L) was added and the organic layer
separated and filtered through a small pad of silica gel. Pro-
duct assay yield was 91%, with a 97% ee and a 95 : 5 regio-
selectivity (branched:linear ratio). Rf = 0.35 (hexane: EtOAc =
9 : 1); 1H NMR (400 MHz, CDCl3): d = 7.24±7.52 (m, 2 H), 7.01
(d, J = 7.7 Hz, 1 H), 6.90±6.95 (m, 2 H), 5.96 (ddd, J = 17.0,
10.2, 8.2 Hz, 1 H), 5.11±5.16 (m, 2 H), 4.09±4.14 (m, 1 H),
3.84 (d, J = 10.9 Hz, 1 H), 3.75 (s, 3 H), 3.53 (s, 3 H); 13C NMR
(100 MHz, CDCl3): d = 167.9, 167.6, 162.8 (d, JCF = 241 Hz),
142.6 (d, JCF = 10 Hz), 137.1, 131.0 (d, JCF = 10 Hz), 123.6 (d,
JCF = 10 Hz), 117.2, 114.9 (d, JCF = 20 Hz), 114.1 (d,
J = 10 Hz), 57.1, 52.6, 52.5, 49.3; IR (neat, cm±1): 2955, 1732,
1614, 1590, 1489, 1435, 1268, 1177, 1140, 1026; anal. calcd.
for C14H15O4F: C, 63.15; H, 5.68%; found C, 62.94; H, 5.63%;
HPLC (ChiralPak AD, 4.6 ´ 250 mm, flow rate = 0.8 mL/min,
detection at 210 nm, 2% MeOH in hexane), tR = 9.1 min
(minor), tR = 10.4 min (major).
[9] B. M. Trost, personal communication.
[10] (C7H8)Mo(CO)3 is commercially available in limited
quantities from Strem Chemical Co. For the synthesis
of (C7H8)Mo(CO)3 see: F. A. Cotton, J. A. McCleverty,
J. E. White, Inorg. Syntheses, 1990, 28, 45±47.
[11] Subsequent to manuscript review, a report describing
the asymmetric alkylation of allyl carbonates with so-
diodimethyl malonate using Mo(CO)6 as precatalyst
with ligand 1 appeared. The reaction employs the use
of microwave irradiation resulting in internal reaction
temperatures of 140±180 °C. See: O. Belda, N.-F. Kai-
ser, U. Bremberg, M. Larhed, A. Hallberg, C. Moberg,
J. Org. Chem. 2000, 65, 5868±5870.
[12] The Mo(CO)6-catalyzed alkylation reaction of carbo-
nate 2 performed in the absence of ligand 1 gave, after
15 h at 90 °C, a 42% assay yield of a mixture of regio-
isomeric products in a 1.4 : 1 ratio of branched to line-
ar products. By comparison, alkylations performed
using the chiral catalyst are complete within 8±12 h.
No alkylation product was observed in the absence of
any molybdenum-precatalyst.
[13] A waterfall plot of the CO region of the IR spectra
from our in situ IR studies is included in the support-
ing information.
Reference
[14] Preliminary in situ IR data show that activation of
(C7H8)Mo(CO)3 with ligand
1 was achieved in
[1] (a) G. C. Lloyd-Jones, A. Pflatz, Angew. Chem. Int. Ed.
Engl. 1995, 34, 462±464; (b) J. P. Janssen, G. Helm-
chen, Tetrahedron Lett. 1997, 38, 8025±8026;
(c) B. M. Trost, I. Hachiya, J. Am. Chem. Soc. 1998, 120,
1104±1105; (d) P. A. Evans, J. D. Nelson, J. Am. Chem.
Soc. 1998, 120, 5581±5582; (e) F. Glorius, A. Pfaltz, Or-
ganic Lett. 1999, 1, 141±144.
[2] For reviews on asymmetric transition metal-catalyzed
allylic alkylations, see (a) B. M. Trost, D. L. Van Vran-
ken, Chem. Rev. 1996, 96, 395±422; (b) T. Hayashi, in:
Catalytic Asymmetic Synthesis, (Ed.: I. Ojima), VCH,
New York, 1993, pp 325±365.
[3] For notable exceptions wherein chiral branched pro-
ducts are obtained as the major isomer using palla-
dium-catalyzed systems, see: (a) T. Hayashi, M. Ka-
watsura, Y. Uozumi, J. Chem. Soc., Chem. Commun.
1997, 561±562; (b) R. PreÂtoÃt, A. Pfaltz, Angew. Chem.
Int. Ed. Engl. 1998, 37, 323±325.
< 30 min. Similarly, Trost and Pfaltz used a 30 min ac-
tivation time at 60±65 °C using (EtCN)3Mo(CO)3 as
precatalyst in THF.
[15] Trost has suggested that p-allylmolybdenum com-
plexes A and B are in dynamic equilibrium and that
the enantiodifferentiating step is preferential nucleo-
philic attack of the malonate on either p-allylmolybde-
num complex A or B (ref. [1c]). The small differences
observed in using the prochiral linear carbonate ver-
sus the racemic branched carbonate may arise from
the ability of the prochiral linear carbonate to prefer-
entially produce one p-allylmolybdenum complex
over the other, whereas, ionization/complexation of
the racemic branched carbonate produces a 50:50
mixture of diastereomeric p-allylmolybdenum com-
plexes. This would then suggest that equilibration of
the p-allylmolybdenum complexes A and B, although
rapid, is not fully under Curtin-Hammett conditions.
Our preliminary results show that a kinetic resolution
of the racemic carbonate 4 afforded a 5% ee of start-
ing material at 52% conversion at 90 °C in toluene,
giving a krel of 1.12. Using the opposite enantiomer li-
[4] B. M. Trost, S. Hildbrand, K. Dogra, J. Am. Chem. Soc.
1999, 121, 10416±10417.
[5] The only reported synthesis of ligand 1 yields the de-
sired product in 47% yield from picolinic acid and 1,2-
diaminocyclohexane, via activation with triphenyl
phosphite. See: D. J. Barnes, R. L. Chapman, R. S.
_
gand, a 10% ee at 88% conversion was observed, giv-
ing a krel of 1.10. krel was calculated using the equa-
Adv. Synth. Catal. 2001, 343, 46±50
49

asc.wiley-vch.de
tion krel = ln[(1 ± c)(1 ± ee)]/ln[(1 ± c)(1 + ee)], where
ee is the enantiomeric excess of the starting material
and c the conversion of the starting material. See:
H. B. Kagan, J. C. Fiaud, in: Topics in Stereochemistry
Vol 5 (Eds.: N. L. Allinger, E. L. Eliel), Interscience;
New York 1987, vol 14, pp 249.
50
Adv. Synth. Catal. 2001, 343, 46±50