Axially chiral analogues of 4-(dimethylamino)pyridine: Novel catalysts for nonenzymatic enantioselective acylations

Article abstract of DOI:10.1021/jo0000574

A concise seven-step synthesis of atropisomeric 3-aryl analogues of DMAP from 4-pyridone 8 has been developed. A representative compound of this class, biaryl (±)-15, has been resolved using CSP HPLC and shown to be an efficient nucleophilic catalyst for kinetic resolution of a series of secondary alcohols on both an analytical and preparative scale (stereoselectivity factors, s = 8.9-29).

Full text of DOI:10.1021/jo0000574

3154
J . Org. Chem. 2000, 65, 3154-3159
Axia lly Ch ir a l An a logu es of 4-(Dim eth yla m in o)p yr id in e: Novel
Ca ta lysts for Non en zym a tic En a n tioselective Acyla tion s
Alan C. Spivey,* Tomasz Fekner,† and Sharon E. Spey‡
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, U.K.
Received J anuary 14, 2000
A concise seven-step synthesis of atropisomeric 3-aryl analogues of DMAP from 4-pyridone 8 has
been developed. A representative compound of this class, biaryl (()-15, has been resolved using
CSP HPLC and shown to be an efficient nucleophilic catalyst for kinetic resolution of a series of
secondary alcohols on both an analytical and preparative scale (stereoselectivity factors, s ) 8.9-
29).
In tr od u ction
Previously, we reported on a short synthetic approach
toward a novel class of catalysts such as 3 and 4
incorporating 1-methyl-2-pyrrolino[3,2-c]pyridine 1 as a
nucleophilic core.7 Chirality of such compounds stems
from restricted rotation about an aryl-aryl bond, and
their configurational stability and high nucleophilicity
have been unequivocally demonstrated. We now describe
the results of our initial studies on catalytic kinetic
resolution (CKR) of aryl alkyl carbinols in the presence
of these and related axially chiral analogues of DMAP.8
Recent years have witnessed an explosion of interest
in the development of nonenzymatic nucleophilic cata-
lysts for enantioselective acyl transfer.1 As a result of
these endeavors, a number of families of chiral nucleo-
philic catalysts have been discovered that offer practically
useful levels of stereoselectivity in acylative kinetic
resolution (KR)2,3 and asymmetric desymmetrization4 of
alcohols,5 as well as other transformations.6 In particular,
the results achieved with planar-chiral derivatives of
4-(dimethylamino)pyridine (DMAP) by Fu and co-work-
ers,5c,d,h,j,k with proline-derived diamines by Oriyama and
co-workers,5f,p and with chiral bicyclic phoshines by
Vedejs and Daugulis5m,o represent significant milestones
in the search for low-molecular-weight compounds that
can serve as alternatives to enzymes in transformations
amenable to nucleophilic catalysis.
* Tel: +44(0)114 22-29467. Fax: +44(0)114 27-38673. E-mail:
a.c.spivey@sheffield.ac.uk.
Resu lts a n d Discu ssion
† Present address: Department of Chemistry, The Ohio State
University, 100 West 18th Ave., Columbus, OH 43210.
Substituents ortho to the pyridyl nitrogen in DMAP
derivatives strongly attenuate their catalytic activity in
acyl transfer processes.9 Cognizant of this, we designed
catalysts 3 and 4 with stereogenic axes meta to their
pyridyl nitrogen and lacking ortho substituents such that
they retained the high nucleophilicity of parent amine
1.7b Although this places the stereogenic element distant
from the reactive center, we anticipated that it would
allow rapid acyl transfer even when carrying out CKR
at low temperature and that this, in turn, would be
beneficial for enantiodiscrimination. Disappointingly,
catalyst (+)-3 showed low levels of enantioselectivity
(stereoselectivity factor10 s ) 1.3-1.5 depending on
‡ Single-crystal X-ray analysis.
(1) Somfai, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 2731-2733.
(2) For a review on kinetic resolution, see: Kagan, H. B.; Fiaud, J .
C. Top. Stereochem. 1988, 18, 249-330.
(3) For KR of secondary alcohols with chiral acyl donors, see: Evans,
D. A.; Anderson, J . C.; Taylor, M. K. Tetrahedron Lett. 1993, 34, 5563-
5566 and references therein.
(4) For a review on asymmetric desymmetrization, see: Willis, M.
C. J . Chem. Soc., Perkin Trans. 1 1999, 1765-1784.
(5) For nonenzymatic enantioselective acylation catalysts, see: (a)
Vedejs, E.; Chen, X. J . Am. Chem. Soc. 1996, 118, 1809-1810. (b)
Ruble, J . C.; Fu, G. C. J . Org. Chem. 1996, 61, 7230-7231. (c) Dosa,
P. F.; Ruble, J . C.; Fu, G. C. J . Org. Chem. 1997, 62, 444-445. (d)
Ruble, J . C.; Latham, H. A.; Fu, G. C. J . Am. Chem. Soc. 1997, 119,
1492-1493. (e) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J . Am.
Chem. Soc. 1997, 119, 3169-3170. (f) Oriyama, T.; Imai, K.; Sano, T.;
Hosoya, T. Tetrahedron Lett. 1998, 39, 397-400. (g) Miller, S. J .;
Copeland, G. T.; Papaioannou, N.; Horstmann, T. E.; Ruel, E. M. J .
Am. Chem. Soc. 1998, 120, 1629-1630. (h) Ruble, J . C.; Tweddell, J .;
Fu, G. C. J Org. Chem. 1998, 63, 2794-2795. (i) Copeland, G. T.; J arvo,
E. R.; Miller, S. J . J . Org. Chem. 1998, 63, 6784-6785. (j) Garrett, C.
E.; Fu, G. C. J . Am. Chem. Soc. 1998, 120, 7479-7483 (erratum, see
p 10276). (k) Tao, B.; Ruble, J . C.; Hoic, D. A.; Fu, G. C. J . Am. Chem.
Soc. 1999, 121, 5091-5092 (erratum, see p 10452). (l) Iwasaki, F.;
Maki, T.; Nakashima, W.; Onomura, O.; Matsumura, Y. Org. Lett.
1999, 1, 969-972. (m) Vedejs, E.; Daugulis, O. Latv. Kim. Z. 1999,
31-38. (n) Copeland, G. T.; Miller, S. J . J . Am. Chem. Soc. 1999, 121,
4306-4307. (o) Vedejs, E.; Daugulis, O. J . Am. Chem. Soc. 1999, 121,
5813-5814. (p) Sano, T.; Imai, K.; Ohashi, K.; Oriyama, T. Chem. Lett.
1999, 265-266.
(7) (a) Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998,
39, 8919-8922. (b) Spivey, A. C.; Fekner, T.; Spey, S. E.; Adams, H.
J . Org. Chem. 1999, 64, 9430-9443.
(8) For leading references on DMAP and its congeners, see: (a)
Litvinenko, L. M.; Kirichenko, A. I. Dokl. Chem. (Engl. Transl.) 1967,
763-766 [Dokl. Akad. Nauk. SSSR 1967, 176, 97-100]. (b) Steglich,
W.; Ho¨fle, G. Angew. Chem., Int. Ed. Engl. 1969, 8, 981. (c) Hassner,
A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978, 34, 2069-2076.
(d) Ho¨fle, G.; Steglich, W.; Vorbruggen, H., Angew. Chem., Int. Ed.
Engl. 1978, 17, 569-583. (e) Scriven, E. F. V. Chem. Soc. Rev. 1983,
129-161. (d) Hassner, A. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; pp 2022-2024.
(f) Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1998, 31, 494-501.
(9) Spivey, A. C.; Maddaford, A., unpublished results. See also refs
5a,b.
(6) (a) Liang, J .; Ruble, C.; Fu, G. C. J . Org. Chem. 1998, 63, 3154-
3155. (b) Ruble, J . C.; Fu, G. C. J . Am. Chem. Soc. 1998, 120, 11532-
11533. (c) Hodous, B. L.; Ruble, J . C.; Fu, G. C. J . Am. Chem. Soc.
1999, 121, 2637-2638.
(10) s ) (rate constant of fast-reacting enantiomer)/(rate constant
of slow-reacting enantiomer).
10.1021/jo0000574 CCC: $19.00 © 2000 American Chemical Society
Published on Web 04/18/2000

Chiral Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 65, No. 10, 2000 3155
Sch em e 1a
Sch em e 2a
a
Reagents and conditions: (a) 3,5-di-Me(C6H3)MgBr, THF, rt
f reflux, 17 h; 37%; (b) i. Mg, I2, Et2O, THF, rt f reflux, 30 min;
ii. 3, PdCl2(dppp), Et2O, THF, reflux, 15 h; 19% (69% if based on
recovered 3).
solvent; see Supporting Information) in CKR of 1-phe-
nylethanol. The results indicated, however, that the acyl
transfer is reasonably fast (conversion, C ) 7.6-61.2%
after 2 h, depending on solvent) even at -78 °C. Simi-
larly, catalyst (-)-4 gave unsatisfactory levels of enan-
tioselection (s ) 2.1 at C ) 26.0% in toluene after 2 h) in
CKR of 1-phenylethanol. In an attempt to develop more
selective catalysts it was initially assumed that the low
levels of enantioselection observed for catalysts 3 and 4
could be attributed to insufficient differentiation between
access to the two faces of the pyridine ring. If such
differentiation is not secured, two enantiomeric nucleo-
philes (alcohols) may approach opposite faces of the
acylpyridinium intermediates derived from DMAP-type
catalysts 3 or 4 at comparable rates, thereby rendering
KR ineffective. Molecular modeling studies11 indicated
that analogues of biaryls 3 and 4 incorporating sterically
more demanding substituents at the 2′-position would
provide more effective top-from-bottom differentiation for
the incoming nucleophiles. These considerations led us
to select biaryl 7, possessing no additional stereogenic
axes that would have complicated optical resolution, as
the next catalyst candidate. Thus (Scheme 1), treatment
of 2,4,6-tribromoiodobenzene 512 with the Grignard re-
agent derived from 5-bromo-m-xylene according to the
methodology of Hart et al.13 gave aryl bromide 6, which
underwent Kharash-type cross-coupling via the corre-
sponding arylmagnesium bromide with aryl triflate 27b
to give racemic biaryl 7 in low yield. Optical resolution
of biaryl (()-7 was performed using semipreparative CSP
HPLC. Although biaryl 7 proved a more enantioselective
catalyst than either biaryl 3 or 4, giving s ) 4.7 for CKR
of 1-(1-naphthyl)ethanol, it still was not sufficient for
practical applications (KRs giving s > 7 are regarded as
practically useful because they guarantee at least a 20%
recovery of the less reactive enantiomer with 99% ee).2
Hence, further attempts to optimize the structure of the
catalysts were undertaken.
a
Reagents and conditions: (a) Br2, KOH, H2O, 0 °C, 1 h; (b)
PCl5, 160 °C, 3 h; 72% over two steps; (c) Et2NH, HCONEt2, 170
°C, 20 h; 94% (d) 2-(phenylmethoxy)-1-naphthaleneboronic acid,
NaOH, Pd(PPh3)4, PhMe, H2O, EtOH, reflux, 22 h; 59%; (e) H2 (1
atm), Pd/C, EtOH, rt, 5 h; (f) Tf2O, pyridine, 0 °C, 2 h; 76% over
two steps; (g) PhMgBr, PdCl2(dppp), Et2O, reflux, 22 h; 93%.
nucleophiles (alcohols) may approach the more accessible
face of a derived acylpyridinium intermediate with
similar ease and with inevitable detriment to the outcome
of CKR. As a consequence of this reasoning, we postu-
lated that the substitution pattern in biaryls 3, 4, and 7,
in which both the 3- and 5-positions on the pyridine ring
bear non-hydrogen substituents, did not secure a suf-
ficiently high level of dissymmetry on the more accessible
face of the pyridine ring. The above considerations led
us to select biaryl 15 as the next catalyst candidate,14
which was subsequently prepared in enantiomerically
pure form. Thus (Scheme 2), 4-pyridone 8 was bromi-
nated according to a modified method of Tee and Paven-
ti15 to give dibromide 9, which upon heating with PCl5
was converted to trihalopyrdine 10.16 Heating in a sealed
high-pressure tube with Et2NH in the presence of N,N-
diethylformamide furnished dibromoamine 11 in excel-
lent yield. Suzuki cross-coupling17 with 2-(phenylmethoxy)-
1-naphthaleneboronic acid7b in the presence of NaOH
gave biaryl 12 in moderate yield.18 Catalytic hydro-
genolysis furnished phenol 13, which was treated with
Tf2O/pyridine to give aryl triflate 14. A final Kumada-
Corriu cross-coupling19 with PhMgBr in the presence of
PdCl2(dppp) furnished racemic biaryl 15 in excellent
yield. The synthetic approach described above is highly
flexible, and by varying the secondary amine used in the
(14) Comparative atropisomerization kinetic studies for 3-aryl
analogues of amine 1 and DMAP (ref 7b) indicated that biaryl 15 would
be configurationally sufficiently stable at room temperature, enabling
its optical resolution and convenient use in enantiopure form without
any risk of racemization.
(15) Tee, O. S.; Paventi, M. Can. J . Chem. 1983, 61, 2556-2562.
(16) Clarke, K.; Rothwell, K. J . Chem. Soc. 1960, 1885-1895.
(17) Miyaura, N.; Yanogi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513-519.
(18) An analogous coupling in the presence of Na2CO3 instead of
NaOH as base gives the 5-bromo derivative of biaryl 12 in a 30% yield.
Further functionalization of the 5-position can open access to a variety
of novel catalyst candidates. Suzuki cross-coupling of aryl dibromide
11 with sterically less demanding arylboronic acids (i.e., 1-naphthalene-
or 3-methoxybenzeneboronic acid) affords the products of bis-coupling
in high yield (74% and 97%, respectively).
Having addressed the issue of top-from-bottom dif-
ferentiation in the design of biaryl 7, we turned our
attention to left-from-right differentiation on the more
accessible face of such molecular systems. If the latter
differentiation is not well-pronounced, two enantiomeric
(11) Computer program: CS Chem3D Pro, version 4.0; Cambridge
Soft Corp.: U.S., 1997.
(12) Hodgson, H. H.; Mahadevan, A. P. J . Chem. Soc. 1947, 173-
174.
(13) Du, C.-J ., F.; Hart, H.; Ng, K.-K., D. J . Org. Chem. 1986, 51,
3162-3165.
(19) (a) Kumada, M. Pure Appl. Chem. 1980, 52, 669-679. (b) Ritter,
K. Synthesis 1993, 735-762.

3156 J . Org. Chem., Vol. 65, No. 10, 2000
Ta ble 1. Kin etic Resolu tion of Acoh ols 16 Ca ta lyzed by Bia r yl (-)-15a
Spivey et al.
(()-16b
Ar
(S)-16
(R)-17
entry
1
alcohol, ester
R1
R2 (mmol)c
Me (0.75)
solvent
CH2Cl2
time, h
eeA, %d
eeE, %d
C, %e
sf
16a , 17a 1
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
1-naphthyl
Me
2.0
6.3
2.0
7.6
2.0
10.3
2.0
7.3
2.0
8.4
2.0
8.4
9.0
9.3
7.6
9.7
10.1
10.5
9.5
12.1
8.0
18.6
43.1
5.1
14.6
2.9
69.5
63.7
79.5
77.1
74.9
73.0
80.5
77.4
77.1
69.9
89.3
83.6
84.1
70.9
78.1
79.2
72.7
88.8
86.0
81.5
90.7
21.2
40.3
6.0
15.9
3.7
6.6
6.8
9.2
8.9
7.2
7.1
9.7
9.3
8.9
8.9
2
3
4
5
6
16a , 17a 1
16a , 17a 1
16a , 17a 1
16a , 17a 1
16a , 17a
Me
Me
Me
Me
Me
Me (0.75)
Me (0.75)
Me (0.75)
Me (2.0)
iPr (2.0)
Et2O
THF
10.2
4.9
12.2
5.7
PhMe
PhMe
PhMe
17.5
14.2
46.6
18.6
62.4
69.2
76.1
49.9
43.1
29.8
18.8
60.7
40.2
21.3
18.5
15.5
40.0
17.2
42.7
45.1
51.8
39.0
35.2
29.1
17.5
41.4
33.0
19.0
21
21
24
13
13
13
7
8
9
10
11
12
13
14
15
16a , 17a
16a , 17a
16b, 17b
16c, 17c
16d , 17d
16e, 17e
16f, 17f
16g, 17g
16h , 17h
1-naphthyl
1-naphthyl
Ph
Me
Me
Me
Et
iPr (2.0)
iPr (2.0)
iPr (2.0)
iPr (2.0)
iPr (2.0)
iPr (2.0)
iPr (2.0)
iPr (2.0)
iPr (1.0)
PhMe
EtOAc
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Ph
Ph
Ph
iPr
tBu
Me
Me
Me
8.4g
20
25
15
25
2-Me(C6H4)
2-OMe(C6H4)
2,6-di-Me(C6H3)
a
b
Key: (a) (R2CO)2O, Et3N (0.75 mmol), solvent (2 mL), (-)-15 (10 µmol, >99.9% ee), -78 °C. Reactions were performed using 1.0
mmol of (()-16. c The amount of acylating agent (R2CO)2O used. Established by CSP HPLC. e Conversion C ) 100 × eeA/(eeA + eeE).
d
f See ref 2. s ) 7.6 in a duplicate run.
g
Sch em e 3a
reaction with trihalopyridine 10 and the two organome-
tallic partners used for construction of the 3-substituent
(with or without further functionalization at the 5-posi-
tion), a wide range of modified biaryl catalyst candidates
can be conveniently prepared. The structure of biaryl 15
was confirmed by single-crystal X-ray analysis, and its
optical resolution was performed using semipreparative
CSP HPLC. A series of CKRs in the presence of catalyst
15 were carried out (Table 1). The solvent-effect studies
(entries 1-4) in the CKR of alcohol 16a using Ac2O as
acyl donor demonstrated that carrying out the reaction
in toluene gives the best results (s ) 9.3-9.7 vs 6.6-9.2
for other solvents tested). A 2.5-fold increase in the
a
Reagents and conditions: (a) (iPrCO)2O (3.2 mL, 19 mmol),
amount of Ac2O used (entries 4 and 5) resulted in a ca.
2.5-fold initial acylation rate enhancement with a slight
decrease in the s value observed (from 9.3-9.7 to 8.9). A
remarkable increase in selectivity was observed (entries
5-7) when using (iPrCO)2O in place of Ac2O as acyl donor
(s ) 8.9 and 24, respectively). Using the optimized
conditions, a series of secondary alcohols (entries 9-15)
were subjected to CKR with good levels of selectivity (s
) 8.4-25). Interestingly, in the series of 1-alkylphenyle-
thanols 16b-e (entries 9-12) the stereoselectivity factor
initially decreases (entries 9-11) as the steric demand
of the alkyl group increases, but the order changes
(entries 11 and 12) for the most bulky alkyl group. The
results obtained for a series of 1-arylethanols 16a , 16b,
16f-h (entries 7, 9, and 13-15) indicate that the increase
in ortho-substitution of the aryl group results in a marked
increase in the stereoselectivity factor. Using a more
polar solvent for carrying out CKR (entries 7 and 8),
which widens the range of alcohols soluble at -78 °C,
causes dramatic decrease (from 24 to 13) in the stereo-
selectivity factor.20
Et3N (1.3 mL, 9.6 mmol), PhMe (25 mL), (+)-15 (45 mg, 0.13 mmol,
>99.9% ee), -78 °C, 30 h.
alcohol 16a using the (+)-15/(iPrCO)2O catalytic system
proceeded uneventfully to give optically highly pure
alcohol (R)-16a along with enantiomerically significantly
enriched ester (S)-17a . The process gives a quantitative
overall yield of products and allows almost complete
recovery of the enantiopure catalyst (+)-15. The ease of
preparation of both enantiomers of catalyst 15 makes
further CKR of enantiomerically enriched ester (S)-17a ,
after its saponification, an attractive option (i.e., so-called
“double CKR”).21
Table 2 details the results of comparative studies on
CKR of 1-(1-naphthyl)ethanol via isobutyrylation in the
presence of all four biaryl DMAP analogues. Catalyst 3
is essentially unselective, whereas catalyst 4 confers
selectivity higher than that of catalyst 7.22 The marked
difference in selectivity (s ) 7.6 vs 29) observed for
(20) Low solubility in toluene at -78 °C prevented the use of benzoic
anhydride as an acylating agent. Similarly, some alcohols, such as 16
[Ar ) 2,6-di-OMe(C6H3), R1 ) Me], were not sufficiently soluble at -78
°C for CKR to be carried out.
The catalytic system developed can be conveniently
used for preparative-scale CKR. Thus (Scheme 3), KR of

Chiral Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 65, No. 10, 2000 3157
Ta ble 2. Kin etic Resolu tion of Alcoh ol 16a by
Isobu tyr yla tion in th e P r esen ce of Bia r yl DMAP
Der iva tivesa
CDCl3) δ 21.50, 123.1, 124.9, 125.2, 128.8, 129.7, 138.5, 139.9,
and 143.9; IR (CHCl3) vmax 1593 and 1560 cm-1; MS (EI+) m/z
(rel intensity) 366/364 (100%, M+); HRMS calcd for C22H21Br
(M+) 364.0827, found 364.0817.
(R)-16a
(S)-17a
eeA, %b
eeE, %b
C, %c
sd
7-{2-[3,5-Bis(3,5-d im eth ylp h en yl)p h en yl]n a p h th yl}-1-
m eth yl-2-p yr r olin o-[3,2-c]p yr id in e (7). To a suspension of
aryl bromide 6 (566 mg, 1.55 mmol) and Mg (57 mg, 2.3 mmol)
in Et2O (5 mL) and THF (2 mL) was added a crystal of I2, and
the mixture was gently heated to initiate the reaction. The
resulting arylmagnesium bromide was transferred via syringe
to a solution of aryl triflate 27b (316 mg, 0.78 mmol) and PdCl2-
(dppp) (23 mg, 39 µmol) in Et2O (2 mL). The resulting brown
solution was stirred at room temperature for 1 h and refluxed
for 15 h. After cooling to room temperature, the reaction
mixture was quenched with water (10 mL) and extracted with
CH2Cl2. The combined extracts were dried (MgSO4) and
evaporated in vacuo. The residue was purified by flash
chromatography (EtOAc f EtOAc/Et3N, 98/2) to give the
recovered starting material 2 (183 mg, 58%) along with the
title compound 7 (80 mg, 19%) as a yellow oil. Biaryl 7: Rf )
0.55 (EtOAc/Et3N, 95/5); 1H NMR (250 MHz, CDCl3) δ 2.26
(s, 3H), 2.38 (s, 12H), 2.92-3.18 (m, 2H), 3.44-3.52 (m, 2H),
6.99 (s, 2H), 7.11 (s, 4H), 7.41-7.67 (m, 6H), 7.70 (d, J ) 8.5
Hz, 1H), 7.81 (s, 1H), 7.95 (m, 1H), 7.99 (d, J ) 8.5 Hz, 1H),
and 8.02 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 21.45, 25.69,
34.97, 55.48, 114.4, 124.6, 125.2, 126.0, 126.7, 127.0, 127.5,
128.0, 128.1, 128.5, 129.0, 132.1, 132.5, 133.9, 138.2 (2C?),
139.7, 141.3, 141.5, 142.0, 142.7, 151.7, and 156.6; IR (CHCl3)
entry
catalyst
1
2
3
4
(+)-3
(+)-4
(+)-7
(+)-15
1.9
87.7
37.8
26.3
1.7
48.0
44.3
91.4
53.4e
64.6
46.0
22.3
1.1
7.6
3.7
29
Reaction conditions: (iPrCO)2O (1.0 mmol), Et3N (0.75 mmol),
a
(()-16a (1.0 mmol), PhMe (2 mL), catalyst (10 µmol, >99.9% ee),
-78 °C, 8 h. Established by CSP HPLC. c Conversion C ) 100
b
× eeA/(eeA + eeE). See ref 2. e Established by 1H NMR.
d
catalysts 4 and 15, respectively, probably reflects the
degree of dissymmetry on the more accessible face of the
pyridine ring, with the difference in substitution at the
5-position (ring CH2 vs H) being most crucial.
Con clu sion s
In summary, a short and general synthesis of atropi-
someric 3-aryl analogues of DMAP from commercially
available and inexpensive 4-pyridone 8 has been devel-
oped. A representative compound of this novel class of
nucleophilic catalysts, biaryl 15, has been shown to be
an efficient catalyst in CKR of a series of secondary
alcohols via acylation with achiral anhydrides. The ease
of preparation and both chiral and chemical stability of
biaryl 15 and its congeners render such compounds
attractive catalysts for various nucleophile-catalyzed
transformations. Structure-selectivity optimization stud-
ies aimed at developing yet more effective catalysts and
elucidating the origin of the enantiodiscrimination are
ongoing, and results of these studies will be reported
shortly.
v
max 2922 and 1593 cm-1; MS (EI+) m/z (rel intensity) 544 (60%,
M+) and 277 (100); HRMS calcd for C40H36N2 (M+) 544.2853,
found 544.2878.
Op tica l Resolu tion of Bia r yl (()-7. The enantiomers of
biaryl 7 were separated using semipreparative CSP HPLC
(Chiralcel OD column, 1 cm × 25 cm; hexanes/EtOAc/Et2NH,
75/24/1; 3 mL min-1; 25 °C). UV detection was performed at
250 nm. Injections of ∼2 mg of the racemate in 30 µL of CH2-
Cl2 were made every 11 min. The enantiomer (-)-7 was
collected from 8.3 to 9.5 min, and the enantiomer (+)-7 was
collected from 12.9 to 14.2 min. The enantiomer (+)-7 was
repurified using the same HPLC conditions with the product
collected from 12.6 to 15.1 min. The enantiomers were further
purified by flash chromatography (EtOAc) to give final prod-
ucts as clear oils. Analytical CSP HPLC revealed >99.9% ee
Exp er im en ta l Section
for both the levorotatory {[R]25 -142 (c 0.90 in CHCl3)} and
Gen er a l Meth od s. The methods described previously were
applied.7b CSP HPLC analyses were performed on Diacel
columns: Chiralcel OD (4.6 mm × 25 cm) for alcohols 16a -e,
Chiralcel OB (4.6 mm × 25 cm) for alcohols 16f,g and
Chiralpak AD (4.6 mm × 25 cm) for alcohol 16h using
conditions described elswhere.5o,23
D
the dextrorotatory {[R]25D +141 (c 0.90 in CHCl3)} enantiomer.
3,5-Dibr om o-4-ch lor op yr id in e (10). The dibromination
of 4-pyridone 8 was carried out according to a modified method
of Tee and Paventi.15 Thus, to an ice-cooled and mechanically
stirred solution of 4-pyridone 8 (34.9 g, 0.367 mol) and KOH
(41.2 g, 0.736 mol) in water (700 mL) was added Br2 (37.9 mL,
0.735 mol) dropwise over 30 min. After an additional 30 min,
the white precipitate was filtered off, washed with a copious
amount of water, and dried in vacuo to give the crude
dibromide 9 (79.0 g, 85%), which was used in the next step
without further purification. Thus, a mixture of dibromide 9
(79.0 g, 0.312 mol) and PCl5 (79 g, 0.38 mol) was heated at
160 °C for 3 h.16 The reaction mixture was cooled to 0 °C and
quenched by slow addition of water (200 mL). The resulting
precipitate was crushed, filtered off, washed with water, and
transferred onto the top of a flash silica column, which was
then eluted with CH2Cl2. The crude product thus obtained was
crystallized from EtOH to give the title compound 10 (73.9 g,
72%) as white needles: Rf ) 0.60 (CH2Cl2); mp 95.0-96.5 °C
(EtOH) (lit.16 98.0-98.5 °C); 1H NMR (250 MHz, CDCl3) δ 8.65
(s); 13C NMR (63 MHz, CDCl3) δ 121.8, 144.0, and 150.9; IR
(CHCl3) vmax 1549, 1524, 1410, and 1394 cm-1; MS (EI+) m/z
(rel intensity) 271 (100%, M+) and 192 (30); HRMS calcd for
C5H2Br2ClN (M+) 268.8242, found 268.8231.
1,5-Bis(3,5-d im eth ylp h en yl)-3-br om oben zen e (6). To a
mixture of Mg (4.6 g, 0.19 mol) and a crystal of I2 in THF (250
mL) was added 5-bromo-m-xylene (29.0 g, 0.157 mol) over 40
min. To remove the excess magnesium, the resulting arylmag-
nesium bromide solution was transferred via cannula to
another flask and treated with a solution of 2,4,6-tribro-
moiodobenzene 512 (13.8 g, 31.4 mmol) in THF (100 mL) over
30 min. After 15 h at room temperature, the mixture was
refluxed for 2 h, cooled in an ice bath, and quenched with 1 M
HCl (200 mL). The reaction mixture was then extracted with
CH2Cl2, and the combined extracts were dried (MgSO4) and
evaporated in vacuo to give a white solid. Purification by flash
chromatography (petroleum ether), followed by crystallization
from EtOAc/EtOH, gave the title compound 6 (4.22 g, 37%) as
a white solid: Rf ) 0.30 (petroleum ether); mp 145.0-146.5
°C (EtOAc/EtOH); 1H NMR (250 MHz, CDCl3) δ 2.28 (s, 12H),
6.91 (s, 2H), 7.11 (s, 4H), and 7.56 (s, 3H); 13C NMR (63 MHz,
(21) For KR of partially enriched compounds and “double” KR, see:
(a) Horeau, A. Tetrahedron 1975, 31, 1307-1309. (b) Brandt, J .;
J ochum, C.; Ugi, I.; J ochum, P. Tetrahedron 1977, 33, 1353-1363. (c)
Brown, S. M.; Davies, S. G.; deSousa, J . A. A. Tetrahedron: Asymmetry
1991, 2, 511-514.
(22) This order for catalysts 4 and 7 was reversed in KRs involving
Ac2O as acyl donor.
(23) Toda, F.; Tohi, Y. J . Chem. Soc., Chem. Commun. 1993, 1238-
1240.
(3,5-Dibr om o(4-p yr id yl))d ieth yla m in e (11). A mixture
of trihalopyridine 10 (18.8 g, 70.0 mmol), Et2NH (21.7 mL,
0.210 mol), and N,N-diethylformamide (35 mL) was heated in
a sealed high-pressure tube at 170 °C for 20 h. The reaction
mixture was cooled to room temperature, dissolved in EtOAc
(300 mL), and washed with 1 M K2CO3 (200 mL) and water (8
× 200 mL). The organic layer was dried (MgSO4) and evapo-

3158 J . Org. Chem., Vol. 65, No. 10, 2000
Spivey et al.
rated in vacuo to give a brown oil. Purification by flash
Op tica l Resolu tion of Bia r yl (()-15. The enantiomers of
biaryl 15 were separated using semipreparative CSP HPLC
(Chiralcel OD column, 1 cm × 25 cm; hexanes/EtOAc/Et2NH,
80/19.2/0.8; 4 mL min-1; 30 °C). UV detection was performed
at 250 nm. Injections of ∼7 mg of the racemate in 70 µL of
CH2Cl2 were made every 12 min. The enantiomer (-)-15 was
collected from 8.7 to 10.1 min, and the enantiomer (+)-15 was
collected from 13.3 to 15.9 min. The enantiomer (+)-15 was
repurified using the same column (hexanes/EtOAc/Et2NH, 75/
24/1; 4 mL min-1; 30 °C) with the product collected from 11.2
to 13.8 min. The enantiomers were further purified by flash
chromatography (EtOAc) to give final products as white solids
[mp 105-106 °C (CHCl3)]. Analytical CSP HPLC revealed
chromatography (CH2Cl2) gave the title compound 11 (20.3 g,
1
94%) as a yellow oil: Rf ) 0.45 (CH2Cl2); H NMR (250 MHz,
CDCl3) δ 1.01 (t, J ) 7.0 Hz, 6H), 3.26 (q, J ) 7.0 Hz, 4H),
and 8.49 (s, 2H); 13C NMR (63 MHz, CDCl3) δ 14.10, 46.05,
122.9, 151.9, and 154.1; IR (CHCl3) vmax 2976, 1553, 1457, 1167
cm-1; MS (EI+) m/z (rel intensity) 308 (15%, M+), 193 (100),
and 264 (30); HRMS calcd for C9H12Br2N2 (M+) 305.9367, found
305.9366.
Diet h yl{3-[2-(p h en ylm et h oxy)n a p h t h yl](4-p yr id yl)}-
a m in e (12). To a solution of aryl dibromide 11 (5.13 g, 16.7
mmol) in toluene (100 mL) and ethanol (5 mL) was added 2 M
NaOH (30 mL) followed by Pd(PPh3)4 (965 mg, 0.835 mmol)
and 2-(phenylmethoxy)-1-naphthaleneboronic acid7b (5.56 g,
20.0 mmol). The mixture was refluxed with vigorous stirring
for 22 h, cooled to room temperature, and diluted with water
(100 mL). The phases were separated, and the extraction was
completed with CH2Cl2. The combined organic extracts were
dried (MgSO4) and evaporated in vacuo to give a brown oil.
The residue was purified by flash chromatography (CH2Cl2 f
EtOAc) to give the title compound 12 (3.77 g, 59%) as a yellow
>99.9% ee for both the levorotatory {[R]25 -124 (c 0.58 in
D
CHCl3)} and the dextrorotatory {[R]25D +126 (c 0.57 in CHCl3)}
enantiomer.
1-(2,6-Dim eth ylp h en yl)eth a n -1-ol (16h ). To a mixture of
Mg (875 mg, 36.0 mmol) and a crystal of I2 in THF (40 mL)
was added a solution of 2-bromo-m-xylene (5.13 g, 27.7 mmol)
in THF (10 mL) over 30 min. To initiate the reaction, the
mixture was gently heated during initial stages of the addition.
The resulting arylmagnesium bromide solution was cooled in
an ice bath and treated with acetaldehyde (2.3 mL, 42 mmol).
After 4 h at room temperature and 1 h at reflux, the reaction
mixture was cooled in an ice bath, quenched with 1 M HCl
(50 mL), and extracted with CH2Cl2. The combined extracts
were dried (MgSO4) and evaporated in vacuo to give a brown
oil. Purification by flash chromatography (petroleum ether/
CH2Cl2, 1/1 f CH2Cl2), followed by distillation under reduced
pressure, gave the title compound 16h (2.50 g, 60%) as a pale
1
oil: Rf ) 0.25 (EtOAc); H NMR (250 MHz, CDCl3) δ 0.70 (t,
J ) 7.0 Hz, 6H), 2.85-3.06 (m, 4H), 5.15 (s, 2H), 6.79 (d, J )
6.0 Hz, 1H), 7.20-7.44 (m, 9H), 7.75-8.07 (m, 2H), 8.07 (s,
1H), and 8.31 (d, J ) 6.0 Hz, 1H); 13C NMR (63 MHz, CDCl3)
δ 12.36, 44.83, 70.86, 111.0, 115.0, 120.3, 123.3, 123.9, 125.5,
126.5, 126.8, 127.7, 127.9, 128.4, 129.2, 129.4, 133.2, 137.3,
148.6, 153.1, 153.6, and 155.3; IR (CHCl3) vmax 2979, 1587,
1505, and 1271 cm-1; MS (EI+) m/z (rel intensity) 382 (15%,
M+) and 277 (100); HRMS calcd for C26H26N2O (M+) 382.2045,
found 382.2041.
1
yellow solid: Rf ) 0.30 (CH2Cl2); mp 68-69 °C (hexanes); H
1-[4-(Dieth yla m in o)-3-p yr id yl]-2-n a p h th yl (tr iflu or o-
m eth yl)su lfon a te (14). A solution of benzyl ether 12 (3.48 g,
9.10 mmol) in EtOH (120 mL) was hydrogenated under normal
pressure in the presence of 10% Pd/C (1.0 g) for 9 h (TLC).
The reaction mixture was filtered through a thin pad of Celite
and evaporated in vacuo to give a crude phenol 13 (2.60 g),
which was dissolved in pyridine (30 mL) and treated at 0 °C
with Tf2O (1.70 mL, 10.0 mmol). After 2 h, the solvent was
evaporated in vacuo, and the residue was partitioned between
CH2Cl2 and water. The phases were separated and the
extraction was completed with additional portions of CH2Cl2.
The combined extracts were dried (MgSO4) and evaporated in
vacuo to give a brown oil. Purification by flash chromatography
(CH2Cl2 f EtOAc) gave the title compound 14 (2.94 g, 76%)
as a yellow oil: Rf ) 0.50 (EtOAc); 1H NMR (250 MHz, CDCl3)
δ 0.77 (t, J ) 7.0 Hz, 6H), 2.77-3.02 (m, 4H), 6.85 (d, J ) 6.0
Hz, 1H), 7.45-7.59 (m, 3H), 7.77 (d, J ) 5.5 Hz, 1H), 7.92-
7.95 (m, 2H), 8.14 (s, 1H), and 8.38 (d, J ) 6.0 Hz, 1H); 13C
NMR (63 MHz, CDCl3) δ 12.19, 44.87, 112.1, 117.8, 118.3 (q,
J ) 320 Hz), 119.6, 126.5, 127.2, 127.9, 128.4, 129.4, 130.3,
132.7, 132.8, 144.8, 150.1, 153.6, and 155.6; IR (CHCl3) vmax
2978, 1585, 1500, 1421, and 1142 cm-1; MS (EI+) m/z (rel
intensity) 424 (20%, M+), 291 (100), 259 (90), and 219 (45);
HRMS calcd for C20H19F3N2O3S (M+) 424.1071, found 424.1068.
(()-Dieth yl[3-(2-ph en yln aph th yl)(4-pyr idyl)]am in e (15).
To a solution of triflate 14 (193 mg, 0.45 mmol) in Et2O (3
mL) was added PdCl2(dppp) (13 mg, 22 µmol), followed by
PhMgBr (300 µL, 3.0 M, 0.90 mmol) in Et2O. The mixture was
refluxed for 16 h, cooled to room temperature, quenched with
water (10 mL), and extracted with CH2Cl2. The combined
extracts were dried (MgSO4) and evaporated in vacuo to give
a brown oil. Purification by flash chromatography (CH2Cl2/
EtOAc, 3/1 f EtOAc) gave the title compound 15 (147 mg,
93%) as a white solid: Rf ) 0.25 (EtOAc); mp 124-125 °C
(CHCl3); 1H NMR (250 MHz, CDCl3) δ 0.52 (t, J ) 7.0 Hz, 6H),
2.55-2.88 (m, 4H), 6.50 (d, J ) 6.0 Hz, 1H), 7.09-7.18 (m,
5H), 7.41-7.56 (m, 3H), 7.82-7.94 (m, 3H), 8.18 (s, 1H), and
8.22 (d, J ) 6.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 12.07,
44.56, 111.7, 122.9, 126.0, 126.4, 126.6 (2C), 127.6, 128.1 (2C),
128.6, 129.6, 132.4, 133.1, 134.0, 138.8, 141.7, 148.7, 154.3,
and 155.0; IR (CHCl3) vmax 2976, 1586, and 1496 cm-1; MS
(EI+) m/z (rel intensity) 352 (70%, M+), 337 (100), 231 (65),
and 77 (60); HRMS calcd for C25H24N2 (M+) 352.1930, found
352.1939.
NMR (250 MHz, CDCl3) δ 1.52 (d, J ) 6.5 Hz, 3H), 2.14 (s,
1H), 2.45 (s, 6H), 5.36 (q, J ) 6.5 Hz, 1H), and 6.98-7.09 (m,
3H); 13C NMR (63 MHz, CDCl3) δ 20.68, 21.41, 67.59, 126.9,
129.4, 135.7, and 140.6; IR (CHCl3) vmax 3609, 1470, 1258, and
1066 cm-1; MS (EI+) m/z (rel intensity) 150 (35%, M+), 135
(100), 107 (75), and 91 (65); HRMS calcd for C10H14O (M+)
150.1038, found 150.1045.
Gen er a l P r oced u r e for An a lytica l-Sca le Ca ta lytic Ki-
n etic Resolu tion . CKR of Alcoh ol (()-16a (Ta ble 1, en tr y
6). A solution of (()-1-(1-naphthyl)ethanol 16a (172 mg, 1.00
mmol), Et3N (104 µL, 0.75 mmol), and catalyst (-)-15 (3.5 mg,
10 µmol, >99.9% ee) in toluene (2.0 mL) was cooled to -78
°C. During vigorous stirring, (iPrCO)2O (331 µL, 2.00 mmol)
was added dropwise over 3 min. After 2.0 h at -78 °C, ∼1 mL
of the reaction mixture was removed rapidly via syringe, added
to MeOH (2 mL), and stirred at room temperature for 15 min.
The solvents were then evaporated in vacuo and alcohol 16a
and ester 17a were separated by flash chromatography
(petroleum ether/CH2Cl2, 1/1 f CH2Cl2). After 8.4 h, the
remainder of the reaction was quenched by a dropwise addition
of MeOH (3 mL) over 2 min. After 15 min at -78 °C and 15
min at room temperature, the solvents were evaporated in
vacuo, and alcohol 16a and ester 17a were separated as
described above. The esters 17a obtained from the two aliquots
were hydrolyzed by heating to reflux in 5% NaOH/MeOH (2
mL) for 5 min.5o After evaporation of the solvent, the residue
was passed through a short flash silica column eluted with
EtOAc. The enantiomeric excess for the unreacted alcohols 16a
and the alcohols obtained by the ester saponification (17a f
16a ) was established by analytical CSP HPLC (Chiralcel OD
column, 1 cm × 25 cm; hexanes/2-propanol, 90/10; 1 mL min-1
;
30 °C). The results are given in Table 1.
P r ep a r a tive-Sca le Ca ta lytic Kin etic Resolu tion of
1-(1-Na p h th yl)eth a n ol (()-16a . To a solution of alcohol (()-
16a (2.20 g, 12.8 mmol), triethylamine (1.3 mL, 9.6 mmol),
and catalyst (+)-15 (45 mg, 0.13 mmol) in toluene (25 mL) was
added dropwise isobutyric anhydride (3.2 mL, 19 mmol) at -78
°C. The reaction mixture was stirred at this temperature for
30 h and quenched by a slow addition of methanol (10 mL).
After an additional 15 min at -78 °C, the reaction mixture
was allowed to warm to room temperature, and the solvents
were evaporated in vacuo. The residue was dissolved in CH2-
Cl2 and washed with 1 M K2CO3 and brine. The organic layer
was concentrated in vacuo, and the residue was purified by

Chiral Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 65, No. 10, 2000 3159
flash chromatography (CH2Cl2/petroleum ether, 1/1 f CH2-
Cl2 f EtOAc) to give ester (S)-17a (1.73 g, 56%) as a pale
yellow oil, alcohol (R)-16a (956 mg, 43%) as a colorless oil,
and catalyst (+)-15 (43 mg, 96%) as a colorless oil. Ester (S)-
16a was analyzed by the same method, and its enantiomeric
excess was shown to be 97.0%. This corresponds to stereose-
lectivity factor s ) 26.8 at 56.8% conversion. The recovered
catalyst (+)-15 was shown to retain its optical purity (>99.9%
ee) by CSP HPLC analysis (Chiralcel OD; hexanes/ethyl
acetate/diethylamine 80/19.2/0.8, 1 mL min-1, 20 °C).
17a : Rf ) 0.45 (petroleum ether/CH2Cl2, 1/1); [R]25 -29.3 (c
D
1
1.1 in CHCl3); H NMR (250 MHz, CDCl3) δ 1.22 (d, J ) 7.0
Hz, 3H), 1.26 (d, J ) 7.0 Hz, 3H), 1.74 (d, J ) 6.5 Hz, 3H),
2.67 (dq, J ) 7.0, 7.0 Hz, 1H), 6.70 (q, J ) 6.5 Hz, 1H), 7.47-
7.60 (m, 3H), 7.65 (d, J ) 7.5 Hz, 1H), 7.83 (d, J ) 6.0 Hz,
1H), 7.90 (∼d, J ) 7.5 Hz, 1H), and 8.14 (d, J ) 8.0 Hz, 1H);
13C NMR (63 MHz, CDCl3) δ 19.05, 21.76, 34.30, 69.21, 123.2,
123.3, 125.4, 125.7, 126.3, 128.4, 129.0, 130.4, 133.9, 137.7,
and 176.4; IR (CHCl3) vmax 1725 cm-1; MS (EI+) m/z (rel
intensity) 242 (45%, M+) and 155 (100); HRMS calcd for
Ack n ow led gm en t. The generous financial support
of this work by Leverhulme Trust is gratefully acknowl-
edged. We also thank Mr. Adrian Maddaford for as-
sistance with analytical CSP HPLC.
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for all compounds, single-crystal X-ray data and
ORTEP for compound 15, and selected CKR experimental
data. This material is available free of charge via the Internet
at http://pubs.acs.org.
C
16H18O2 (M+) 242.1317, found 242.1307. Alcohol (R)-16a : Rf
) 0.25 (CH2Cl2); [R]25 +64.5 (c 1.1 in CHCl3), [R]25 +77.2 (c
D
D
1.1 in MeOH) {lit.24 [R]20 +78 ( 2 (c 1.0 in MeOH)}. A small
D
sample of ester (S)-17a was hydrolyzed with 5%NaOH in
MeOH,5o and the resulting alcohol was analyzed by CSP HPLC
(Chiralcel OD; hexanes/2-propanol 90/10, 1 mL min-1, 35 °C),
which showed an enantiomeric excess of 73.7%. Alcohol (R)-
J O0000574
(24) Fluka Laboratory Chemicals and Analytical Reagents catalogue,
1999-2000, p 980, product number 70692.