Concise synthesis of conformationally constrained pybox ligands

Full text of DOI:10.1021/jo9616264

J . Org. Chem. 1996, 61, 9629-9630
9629
Sch em e 1
Con cise Syn th esis of Con for m a tion a lly
Con str a in ed P ybox Liga n d s
Ian W. Davies,* Linda Gerena, Nu Lu,
Robert D. Larsen, and Paul J . Reider
Department of Process Research, Merck & Co., Inc.,
P.O. Box 2000, Rahway, New J ersey 07065
Received August 20, 1996
A key feature of transition metal-catalyzed processes
is the ability to control the regio- and stereochemical
outcome of a reaction by variation of the steric and
electronic nature of the ligand. Some of the most
important examples of “ligand tuning” are evident in
asymmetric catalysis where ligands can have a profound
influence on the enantiomeric excess of the product.1 We
have demonstrated that ligands that contain the amino-
indanol motif provide very high levels of absolute and
relative stereocontrol in Diels-Alder reactions in contrast
to their acyclic counterparts.2 Similar observations have
now been reported by Ghosh.3 Pyridine bis(oxazoline)s
pyboxsligands were first introduced by Nishiyama for
Rh-catalyzed hydrosilylation reactions,4 and Evans has
very recently demonstrated that they are very efficient
ligands for Cu-catalyzed Mukiayama aldol5 and Diels-
Alder6 reactions. Herein, we describe a concise synthesis
of the conformationally constrained pybox ligand 1
derived from (1S,2R)-aminoindanol (2), which is ame-
nable to the synthesis of other important pybox ligands.
tions.9 Addition of 2,6-pyridine dicarbonyl dichloride to
an isopropyl acetate (IPAC) solution of 2 at 65 °C gave
the bis(amide) 3, which precipitated directly from the
reaction mixture in 91% yield (Scheme 1). In order to
induce cyclization, the amide carbonyl would first need
to be activated. Singh has recently reported a MsOH-
promoted dehydration of a bis(amide) to a pybox; a priori,
it is unclear whether this reaction would tolerate a
substrate that is stereogenic at the alcohol-bearing
carbon.10 In our case, reaction of the bis(amide) 3 with
MsOH (toluene, 110 °C) gave 5% of the oxazoline/amide,
and none of the pybox 1 was detected. This low reactivity
is due in part to the insolubility of the bis(amide) 3. The
use of MsOH as solvent only led to hydrolysis affording
2 upon aqueous workup. After examination of a number
of other Bronsted and Lewis acids, BF3‚Et2O was found
to be the best candidate. Reaction of the bis(amide) 3
with 4 equiv of BF3‚Et2O in toluene at 110 °C gave a 10%
yield of the in-pybox 1. However, our best results were
obtained by simply heating a 15% w/v solution of bis-
(amide) 3 in BF3‚Et2O at 120 °C. After 6 h, following an
aqueous workup, the in-pybox 1 was isolated by direct
crystallization in 70-73% yield (Table 1, entry 1).
Significantly, similar yields were obtained when excess
BF3‚Et2O was distilled at 140 mmHg after complete
reaction, making the workup easier and allowing the
recovered BF3‚Et2O to be recycled.
To test the generality of this method for the prepara-
tion of other pybox ligands, we investigated the ligand
derived from 1(R)-amino-2(S)-hydroxytetrahydronaph-
thalene.11 The thn-pybox 5 was obtained in good yield
following crystallization (Table 1, entry 2), and the
expected cis-stereochemistry was confirmed by NOE
studies. The ph-pybox 6 (mp 169-170 °C (lit.4 mp 170-
172 °C)) and tb-pybox 7 (mp 239-241 °C dec) (lit.4 mp
242-243 °C), which are currently the most commonly
used architectural features in pybox ligands, were pre-
pared in 62 and 75% yield, respectively (Table 1, entries
3 and 4). The dm-pybox 8 (mp 139 °C (lit.4 mp 140-141
°C) was also prepared in a similar manner (Table 1, entry
5). A limitation of this method was discovered with the
bis(amide) derived from (1S,2R)-norephedrine (Table 1,
entry 6). In this case, the trans-pybox 9 was formed
exclusively (NOE), indicating that the amide acted as the
Although the Nishiyama synthesis of pybox ligands is
efficient (42-70% overall yield), it involves a four-step
reaction sequence and a 6-day time cycle. In addition,
this approach could not guarantee the stereochemical
integrity of an indan-derived amino alcohol since two
sequential nucleophilic reactions are required to con-
struct the oxazoline.7,8 We therefore decided to prepare
the pybox ligand 1 by dehydration of the bis(amide) 3,
which was prepared using Schotten Baumann condi-
(1) Noyori, R. Asymmetric Catalysis in Organic Synthesis; Wiley:
New York, 1994.
(2) (a) Davies, I. W.; Senanayake, C. H.; Larsen, R. D.; Verhoeven,
T. R.; Reider, P. J . Tetrahedron Lett. 1996, 37, 1725. (b) Davies, I. W.;
Gerena, L.; Castonguay, L.; Senanayake, C. H.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J . J . Chem. Soc., Chem. Commun. 1996,
1753.
(3) Ghosh, A. K.; Mathivanan, P.; Cappiello, J . Tetrahedron Lett.
1996, 37, 3815.
(4) Nishiyama, H.; Kondo, M.; Nakamura, T.; Itoh, K. Organo-
metallics 1991, 10, 500.
(9) Maligres, P. E.; Upadhyay, V.; Rossen, K.; Ciancosi, S. J .; Purick,
R. M.; Eng, K. K.; Reamer, R. A.; Askin, D.; Volante, R. P.; Reider, P.
J . Tetrahedron Lett. 1995, 36, 2195.
(5) Evans, D. A.; Murry, J . A.; Kozlowski, M. C. J . Am. Chem. Soc.
1996, 118, 5814.
(10) Gupta, A. D.; Bhuniya, D.; Singh, V. K. Tetrahedron 1994, 50,
13725.
(6) Evans, D. A.; Murry, J . A.; von Matt, P.; Norcross, R. D.; Miller,
S. J . Angew. Chem., Int. Ed. Engl. 1995, 34, 798.
(7) Meyers, A. I.; Gant, T. G. Tetrahedron 1994, 50, 2297.
(8) Reaction of indan-derived amides with thionyl chloride under
standard conditions leads to a mixture of products including epimeric
chlorides and regioisomeric indenes.
(11) (a) Senanayake, C. H.; Roberts, F. E.; DiMichele, L. M.; Ryan,
K. M.; Liu, J .; Fredenburgh, L. E.; Foster, B. S.; Douglas, A. W.; Larsen,
R. D.; Verhoeven, T. R.; Reider, P. J . Tetrahedron Lett. 1995, 36, 3993.
(b) Senanayake, C. H.; DiMichele, L. M.; Liu, J .; Fredenburgh, L. E.;
Ryan, K. M.; Roberts, F. E.; Larsen, R. D.; Verhoeven, T. R.; Reider,
P. J . Tetrahedron Lett. 1995, 36, 7615.
S0022-3263(96)01626-X CCC: $12.00 © 1996 American Chemical Society

9630 J . Org. Chem., Vol. 61, No. 26, 1996
Notes
Ta ble 1. Deh yd r a tion a t 120 °C Usin g 15% w /v BF 3‚Et2O
Exp er im en ta l Section
The identities of known compounds were confirmed by
comparison of melting points and spectroscopic data with the
published values. All solvents and reagents were used as
received from commercial sources. Melting points were deter-
mined on a Thomas Hoover apparatus and are uncorrected. J
values are given in Hz. Elemental analyses were performed by
Quantitative Technologies, Inc., Whitehouse, NJ . Water content
was determined by Karl Fischer titration on a Metrohm 737 KF
Coulometer.
[3a S-[2(3′a R*,8′a S*),3a r,8a r]]-2,2′-(2,6-P yr id in ed iyl)bis-
[3a ,8a -d ih yd r o-8H-in d en o[1,2-d ]oxa zole] (1). The procedure
for the preparation of 1 is illustrative: A 15% w/v suspension
of the bis(amide) 3 (0.01-0.1 mol) in BF3‚Et2O was heated to
120 °C (the mixture became homogeneous at 75 °C) for 6 h. After
complete reaction (NMR), the solution was allowed to cool,
diluted with dichloromethane (5×), and poured into ice-cold 2
N NaOH (5×). The phases were separated, and the dichloro-
methane layer was diluted with diethyl ether (1×) and treated
with Darco G-60. The suspension was filtered through a pad of
silica gel (1 cm) and washed with dichloromethane:diethyl ether
(1:1, ×2). Concentration of this solution gave pybox 1, which
was collected by filtration and dried in vacuo (70-73%): mp
265-268 °C dec; [R]22 -364.0 (c 1.04, CH2Cl2); IR 1630, 1573
D
cm-1; 1H NMR (CDCl3) 3.47-3.55 (4H, m), 5.60 (2H, dt, J ) 8.3,
4.0), 5.79 (2H, d, J ) 8.3), 7.24-7.30 (6H, m), 7.53-7.59 (2H,
m), 7.78 (1H, t, J ) 7.5), 8.11 (2H, d, J ) 7.5); 13C NMR (CDCl3)
39.7, 77.0, 84.3, 125.4, 125.7, 126.0, 127.5, 128.7, 137.2, 139.9,
141.5, 146.9, 162.9. Anal. Calcd for C25H19N3O2‚0.5(H2O): C,
74.60; H, 5.00; N, 10.44. Found: C, 74.64; H, 5.06; N, 10.30.
[3a S-[2(3a ′R*,9b′S*),3a r,9br]]-2,2′-(2,6-P yr id in ed iyl)bis-
[3a ,4,5,9b-tetr a h yd r on a p h th [1,2-d ]oxa zole] (5): mp 234-235
°C; [R]22 +485.0 (c 1.00, CH2Cl2); IR 1643 cm-1 1H NMR
;
D
(CDCl3) 1.90-2.01 (2H, m), 2.29-2.39 (2H, m), 2.59 (2H, dt, J
) 15.8, 3.8), 2.80 (2H, dt, J ) 15.8, 3.0), 5.33 (2H, dt, 9.8, 3.8),
5.45 (2H, d, J ) 9.8), 7.12 (2H, d, J ) 6.8), 7.20 (2H, t, J ) 6.8),
7.29 (2H, t, J ) 6.8), 7.58 (2H, d, J ) 6.8), 7.78 (1H, t, J ) 7.5),
8.12 (2H, d, J ) 7.5); 13C NMR (CDCl3) 24.6, 28.1, 67.5, 79.6,
126.1, 127.0, 127.4, 128.3, 129.9, 134.3, 137.1, 138.4, 147.0, 162.7.
Anal. Calcd for
C27H23N3O2: C, 76.94; H, 5.50; N, 9.97.
Found: C, 76.75; H, 5.71; N, 9.84.
nucleophile rather than as an electrophile, the benzylic
alcohol being more susceptible to displacement than in
the other examples.12
[4S-[2(4′R*,5′R*),4r,5â]]-2,2′-(2,6-P yr id in ed iyl)bis[4,5-d i-
h yd r o-4-m eth yl-5-p h en yloxa zole] (9): mp 138-139 °C; [R]22
D
-124.0 (c 0.55, CH2Cl2); IR 1638 cm-1
;
1H NMR (CDCl3) 1.50
(6H, d, J ) 6.8), 4.32(2H, dq, J ) 8.2, 6.8), 5.19 (2H, d, J ) 8.2),
7.30 -7.40 (10H, m), 7.92 (1H, t, J ) 8.2), 8.19 (2H, d, J ) 8.2);
13C NMR (CDCl3) 21.2, 71.1, 89.3, 125.9, 126.1, 128.5, 128.8,
The pybox ligands 1, 5, and 6 represent a toolbox of
ligands that can be used to systematically determine the
role of ligand conformation in transition metal-catalyzed
reactions.13 The straightforward method described in
this paper allows for rapid construction of these impor-
tant new pybox ligands in two steps without a need for
chromatographic purification. In addition to the pybox
ligands already in use, they will find application in high-
throughput screening of catalytic reactions.14
137.5, 139.9, 147.2, 161.6. Anal. Calcd for
0.4(H2O): C, 74.21; H, 5.93; N, 10.38. Found: C, 74.62; H, 5.95;
N, 10.23.
C25H23N3O2‚
Ack n ow led gm en t. We thank Robert Reamer and
Lisa DiMichele for key NMR assignments.
Su p p or tin g In for m a tion Ava ila ble: Experimental, spec-
troscopic, and characterization data for amide 3 and interme-
diates to 5 and 9 (2 pages). This material is contained in
libraries on microfiche, immediately follows this article in the
microfilm version of the journal, and can be ordered from the
ACS; see any current masthead page for ordering information.
(12) Meyers, A. I.; Gant, T. G. Tetrahedron 1994, 50, 2297.
(13) For an example of the use of this “toolbox” of auxiliaries see:
Davies, I. W.; Castonguay, L.; Senanayake, C. H.; Larsen, R. D.;
Verhoeven, T. R.; Reider, P. J . Tetrahedron Lett. 1995, 36, 7619.
(14) Burgess, K.; Lim, H.-J .; Porte, A. M.; Sulikowski, G. A. Angew.
Chem., Int. Ed. Engl. 1996, 35, 220.
J O9616264