Configurationally Stable Biaryl Analogues of 4-(Dimethylamino)pyridine: A Novel Class of Chiral Nucleophilic Catalysts

Article abstract of DOI:10.1021/jo991011h

A short synthetic approach toward a novel class of chiral nucleophilic catalysts, the dissymmetry of which stems from restricted rotation about an Ar-Ar bond, has been developed. The key steps of the synthesis include preparation of a nucleophilic 1-methyl-2-pyrrolino[3,2-c]pyridine core 16 by ortho-lithiation and creation of the biaryl axes via Suzuki cross-coupling reactions. Comparative HPLC studies of racemization for configurationally labile biaryls 31, 38, and 43 containing 1-methyl-2-pyrrolino[3,2-c]pyridine, 4-(dimethylamino)pyridine, and 4-(1-pyrrolidino)pyridine cores, respectively, have demonstrated that a pyrrolidino substituent ortho to the biaryl axis is optimal for slowing Ar-Ar rotation. Biaryls containing all three cores have been shown to retain DMAP-like catalytic activity in the acylation of a hindered alcohol. Biaryls 55 and 56, which are configurationally stable at ambient temperature, have also been prepared via modification of configurationally labile derivatives. Compounds 55 and 56 in optically pure form should provide a useful starting point for studies on catalytic asymmetric acyl transfer using atropisomeric analogues of DMAP.

Full text of DOI:10.1021/jo991011h

9430
J . Org. Chem. 1999, 64, 9430-9443
Con figu r a tion a lly Sta ble Bia r yl An a logu es of
4-(Dim eth yla m in o)p yr id in e: A Novel Cla ss of Ch ir a l Nu cleop h ilic
Ca ta lysts
Alan C. Spivey,* Tomasz Fekner, Sharon E. Spey,† and Harry Adams†
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK
Received J une 24, 1999
A short synthetic approach toward a novel class of chiral nucleophilic catalysts, the dissymmetry
of which stems from restricted rotation about an Ar-Ar bond, has been developed. The key steps
of the synthesis include preparation of a nucleophilic 1-methyl-2-pyrrolino[3,2-c]pyridine core 16
by ortho-lithiation and creation of the biaryl axes via Suzuki cross-coupling reactions. Comparative
HPLC studies of racemization for configurationally labile biaryls 31, 38, and 43 containing 1-methyl-
2-pyrrolino[3,2-c]pyridine, 4-(dimethylamino)pyridine, and 4-(1-pyrrolidino)pyridine cores, respec-
tively, have demonstrated that a pyrrolidino substituent ortho to the biaryl axis is optimal for
slowing Ar-Ar rotation. Biaryls containing all three cores have been shown to retain DMAP-like
catalytic activity in the acylation of a hindered alcohol. Biaryls 55 and 56, which are configuration-
ally stable at ambient temperature, have also been prepared via modification of configurationally
labile derivatives. Compounds 55 and 56 in optically pure form should provide a useful starting
point for studies on catalytic asymmetric acyl transfer using atropisomeric analogues of DMAP.
In tr od u ction
wide range of related transformations.7 The first chiral
DMAP-based acyl transfer reagent was reported by
Vedejs and Chen in 1996.8 Although their reagent was
noncatalytic, high levels of chiral discrimination were
obtained in the acylative kinetic resolution of various
secondary alcohols, especially when combined with the
elegant concept of parallel kinetic resolution.9 Shortly
thereafter, Fu and Ruble10 reported on the synthesis and
catalytic activity of a novel class of planar-chiral ana-
logues of DMAP. The MIT group have subsequently
utilized one of their enantiomerically pure catalysts in a
wide range of asymmetric transformations, achieving
impressive levels of enantioselectivity.11 Fuji and co-
workers have also described a chiral derivative of DMAP,
which proved highly effective for the acylative kinetic
resolution of a specific series of secondary alcohols.12
Here we report on the synthesis of a novel family of
chiral DMAP-based nucleophilic catalysts, the dissym-
metry of which stems from restricted rotation about an
aryl-aryl bond.13
The development of chiral catalysts capable of mediat-
ing asymmetric organic transformations is one of the
most challenging and rewarding areas of organic syn-
thesis. Although the design and synthesis of chiral
ligands for metal-based catalytic systems has commanded
particular attention in recent years, there has also been
considerable interest in the development of small, purely
organic catalysts.1 Much of the inspiration behind the
development of synthetic chiral catalysts can be at-
tributed to the desire of chemists to develop systems that
mimic enzymes. In view of the importance of nucleophilic
catalysis in many enzyme-mediated transformations2 it
is, therefore, rather surprising that asymmetric nucleo-
philic catalysis by small organic compounds has, until
very recently, scarcely been addressed.3 However, the last
three years have witnessed an explosion of interest in
this area4 and, in particular, highly effective nucleophilic
catalysts based around 4-(dimethylamino)pyridine (DMAP)
have been discovered.5
The high nucleophilicity of DMAP was first noted over
30 years ago, when it was found to be an excellent cata-
lyst for the acylation of hindered alcohols.6 Subsequently,
DMAP has been employed as a nucleophilic catalyst in a
(7) (a) Hassner, A.; Krepski, L. R.; Alexanian, V. Tetrahedron 1978,
34, 2069-2076. (b) Ho¨fle, G.; Steglich, W.; Vorbruggen, H., Angew.
Chem., Int. Ed. Engl. 1978, 17, 569-583. (c) 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. (e) Ragnarsson, U.; Grehn, L. Acc. Chem. Res. 1998,
31, 494-501.
* To whom correspondence should be addressed. Tel.: +44(0)114
22-29467. Fax: +44(0)114 27-38673. E-mail: a.c.spivey@sheffield.ac.uk.
† Single-crystal X-ray analyses.
(1) (a) Ojima, I. Catalytic Asymmetric Synthesis; Wiley-VCH: New
York, 1993. (b) Asymmetric Catalysis in Organic Synthesis; Noyori,
R., Ed.; Wiley: New York, 1994.
(8) Vedejs, E.; Chen, X. J . Am. Chem. Soc. 1996, 118, 1809-1810.
(9) Vedejs, E.; Chen, X. J . Am. Chem. Soc. 1997, 119, 2584-2585.
(10) Ruble, J . C.; Fu, G. C. J . Org. Chem. 1996, 61, 7230-7231.
(11) (a) Dosa, P. F.; Ruble, J . C.; Fu, G. C. J . Org. Chem. 1997, 62,
444-445. (b) Ruble, J . C.; Latham, H. A.; Fu, G. C. J . Am. Chem. Soc.
1997, 119, 1492-1493. (c) Ruble, J . C.; Tweddell, J .; Fu, G. C. J Org.
Chem. 1998, 63, 2794-2795. (d) Liang, J .; Ruble, C.; Fu, G. C. J . Org.
Chem. 1998, 63, 3154-3155. (e) Garrett, C. E.; Fu, G. C. J . Am. Chem.
Soc. 1998, 120, 7479-7483. (f) Ruble, J . C.; Fu, G. C. J . Am. Chem.
Soc. 1998, 120, 11532-11533. (g) Hodous, B. L.; Ruble, J . C.; Fu, G.
C. J . Am. Chem. Soc. 1999, 121, 2637-2638. (h) Tao, B.; Ruble, J . C.;
Hoic, D. A.; Fu, G. C. J . Am. Chem. Soc. 1999, 121, 5091-5092.
(12) Kawabata, T.; Nagato, M.; Takasu, K.; Fuji, K. J . Am. Chem.
Soc. 1997, 119, 3169-3170.
(2) Bender, M. L. Mechanisms of Homogeneous Catalysis from
Protons to Proteins; Wiley: New York, 1971.
(3) Vedejs, E.; Daugulis, O.; Diver, S. T. J . Org. Chem. 1996, 61,
430-431, and references therein.
(4) (a) Somfai, P. Angew. Chem., Int. Ed. Engl. 1997, 36, 2731-
2733. (b) Copeland, G. T.; J arvo, E R.; Miller, S. J . J . Org. Chem. 1998,
63, 6784-6785, and references therein.
(5) Morken, J . P.; Taylor, S. J . Science 1998, 280, 267-270.
(6) (a) Litvinenko, L. M.; Kirichenko, A. I. Doklady 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.
(13) Spivey, A. C.; Fekner, T.; Adams, H. Tetrahedron Lett. 1998,
39, 8919-8922.
10.1021/jo991011h CCC: $18.00 © 1999 American Chemical Society
Published on Web 12/04/1999

Biaryl Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 64, No. 26, 1999 9431
Sch em e 1
Sch em e 2a
a
Reagents and conditions: (a) Boc2O, DCM, rt, 45 min; >99%;
Resu lts a n d Discu ssion
(b) t-BuLi, THF, -78 °C f -15 °C, 3.5 h; (c) Br(CH2)2Br, -78 °C
f rt, 2 h; 85%; (d) ethylene oxide, -78 °C f rt, 2 h; 75% of 10, or
Br(CH2)2OLi, -78 °C f rt, 2 h; 66% of 10, or propylene oxide,
-78 °C f rt, 2 h; 81% of 11.
A synthetic strategy for the preparation of atropiso-
meric analogues of DMAP 1 (Scheme 1) involves forma-
tion of the Ar-Ar bond via direct coupling of an appro-
priately substituted organometallic partner 2 with an
electrophilic equivalent of bicyclic heterocyle 3. By vary-
ing substituents R1 and R2, satisfactory levels of both the
internal rotational barrier and dissymmetry of the mo-
lecular systems 1 were anticipated to be achieved. In our
initial studies, a substituent R3 was incorporated as a
chiral marker, to enable straightforward observation of
atropisomerism by both 1H and 13C NMR, although in
the synthesis of catalyst candidates, formation of race-
mates (R3 ) H) rather than diastereoisomeric mixtures
would be preferred.
Instead of using DMAP itself as a catalytically active
subunit in biaryls 1, we opted for 1-methyl-2-pyrrolino-
[3,2-c]pyridine 16, as it was anticipated that stopping
rotation about the CAr-N bond would enhance the barrier
to internal rotation about the central biaryl axis. More-
over, it has been recently reported14 that amine 16 shows
catalytic activity comparable to DMAP itself, although
no detail regarding its synthesis was given. Since the
previously reported synthetic routes leading to amine 16
are both multistep and low-yielding,15 it was planned to
prepare bicyclic amine 16 via alkylation of a pyridyl
dianion 5 with a vicinal dielectrophile 4. The choice of R
) Boc would allow the preparation of the dianion 5 using
directed ortho-metalation methodology16 and subsequent
utilization of the carbamate as a latent methyl group.
The synthesis commenced with the conversion of
4-aminopyridine 6 to the known carbamate 717 (Scheme
2). Although amine 6 is not highly soluble in CH2Cl2,
treatment of a suspension thereof with Boc2O resulted
in rapid and quantitative conversion to carbamate 7. The
ortho-lithiation of carbamate 7 to its dianion 8 was
performed as previously reported using t-BuLi in THF.17a,18
Unfortunately, attempts to bis-alkylate dianion 8 in one
step failed. While both 1,2-dibromoethane and 1-bromo-
2-chloroethane reacted with dianion 8 to give a high yield
of aryl bromide 9, the product of halophilic attack, 1,2-
dichloroethane, for which the halophilic attack was not
expected, proved not reactive enough for alkylation to
proceed. In contrast, dianion 8 reacted smoothly with
lithium 2-bromoethanoate to give primary alcohol 10. For
large-scale preparations, it was more convenient to
synthesize alcohol 10 by the alkylation of dianion 8 with
ethylene oxide. Analogously, alkylation of dianion 8 with
propylene oxide gave secondary alcohol 11 as the only
isomer. No product of epoxide ring opening on the more
substituted carbon atom was noted. The expected mode
of epoxide ring opening leading to secondary alcohol 11
was confirmed by single-crystal X-ray analysis of biaryl
22.
Amino alcohols 10 and 11 were cyclized (Scheme 3) by
conversion to the corresponding methanosulfonates 12
and 13, respectively, on treatment with MsCl/Et3N. While
the primary mesylate 12 underwent in situ cyclization
to bicyclic carbamate 14, the intramolecular alkylation
of mesylate 13 leading to carbamate 15 was sluggish.
However, isolation of mesylate 13 and treatment with
LHMDS furnished the cyclized product 15 in high yield.
Subsequent reduction of carbamates 14 and 15 to N-
methylamines 16 and 17, respectively, was accomplished
in moderate yield using either LiAlH4 or DIBAL. Reduc-
tions with LiAlH4 provided substantial amounts of N-
demethylated side-products, although the overall recov-
ery of the material was high.19,20 In contrast, DIBAL gave
almost exclusively (∼ 10:1) the product of the carbamate
reduction without the C-N bond cleavage, although in
(14) Vedejs, E.; Chen X. Abst. Pap.-Am. Chem. Soc. 1995, 210,
ORGN-174.
(15) (a) Yakhantov, L. N.; Azimov, V. A.; Lapan, E. I. Tetrahedron
Lett. 1969, 1909-1912. (b) Kauffmann, T.; Fischer, H. Chem. Ber. 1973,
106, 220. (c) Yakhantov, L. N. Chem. Heterocycl. Compd. (Engl. Transl.)
1983, 19, 873-885.
(18) (a) Muchowski, J . M.; Venuti, M. C. J . Org. Chem. 1980, 45,
4798-4801, (b) Reed, N. J .; Rotchford, J .; Srickland, D. Tetrahedron
Lett. 1988, 29, 5725-5728. (c) Hands, D.; Bishop, B.; Cameron, M.;
Edwards, J . S.; Cottrell, I. F.; Wright, S. H. B. Synthesis 1996, 877-
882.
(19) When the TFA-mediated removal of the Boc group from
carbamate 14 was attempted, only traces of the desired product were
obtained and the overall material recovery was low. Presumably, tert-
butylation of the highly nucleophilic product on the pyridyl nitrogen
interferes. Performing the cleavage in the presence of Et3SiH (ref 20),
however, allowed for a high yield of the deprotected product to be
isolated.
(16) Queguiner, G.; Marsais, F.; Snieckus, V.; Epsztajn, J . In
Advances in Heterocyclic Chemistry; Katritzky, A. R., Ed.; Academic
Press: San Diego, 1991; Vol. 52, pp 187-304.
(17) (a) Fishwick, C. W. G.; Storr, R. C.; Manley, P. W. J . Chem.
Soc., Chem. Commun. 1984, 1304-1305. (b) Kim, S.; Lee, J . I.; Yi, K.
Bull. Chem. Soc. J pn. 1985, 58, 3570-3575. (c) Venuti, M. C.;
Stephenson, R. A.; Alvarez, R.; Bruno, J . J .; Strosberg, A. M. J . Med.
Chem. 1988, 31, 2136-2145. (d) Reed, J . N.; Rotchford, J .; Strickkland,
D. Tetrahedron Lett. 1988, 29, 5725-5728. (e) Kelly, T. A.; McNeil, D.
W. Tetrahedron Lett. 1994, 35, 9003-9006. (f) Rivalle, C.; Bisagni, E.
J . Med. Chem. 1997, 34, 441-444.
(20) Pearson, D. A.; Blanchette, M.; Baker, M. L.; Guindon, C. A.
Tetrahedron Lett. 1989, 30, 2739-2742.

9432 J . Org. Chem., Vol. 64, No. 26, 1999
Spivey et al.
Sch em e 3a
The high cost of the reagent, however, prevented us from
using this route in large-scale preparations of amine 16.
With efficient syntheses of aryl bromides 18 and 19 in
hand, the key biaryl cross-coupling step was investigated.
Gratifyingly, treatment of aryl bromide 19 with a series
of unhindered arylboronic acids under standard Suzuki
cross-coupling conditions [Pd(PPh3)4, Na2CO3 in PhMe/
H2O/EtOH],24 furnished biaryls 21-24 in excellent yield
1
(Scheme 5). Neither the H nor the 13C NMR spectra of
Sch em e 5a
a
Reagents and conditions: (a) MsCl, Et3N, DCM, -10 °C f rt,
2 h for 12 and -20 °C f rt, 80 min for 13; (b) as (a); >99% of 14
or LHMDS, THF, -78 °C f reflux, overnight; 95% of 15; (c)
DIBAL, DCM, 0 °C f reflux, 20 h; 55% of 16 or LiAlH4, THF, 0
°C f reflux, 4 h; 38% of 17; (d) NBS, DMF, 0 °C, 90 min; 81% of
18 or 62% of 19.
a
Reagents and conditions: (a) ArB(OH)2, Na2CO3, Pd(PPh3)4,
PhMe, H2O, EtOH, reflux, 2-24 h.
biaryls 22 and 23 showed any evidence of diasteroisom-
erism due to slow rotation about the biaryl axis (on the
NMR time-scale). By comparison with low-temperature
NMR experiments of closely related compounds (vide
infra), it appears that the similarity in the NMR behavior
between fully symmetrical biaryl 21 and biaryls 22 and
23 reflects the low level of dissymmetry exerted by the
methoxy substituent. In contrast, the naphthyl analogue
24 could be observed as a ∼1:1 mixture of atropisomers
(in CDCl3 at room temperature).
this case the material recovery was lower. Bromination
of amines 16 and 17 under mild conditions using NBS/
DMF21 gave aryl bromides 18 and 19, respectively. The
structure of aryl bromide 18 was confirmed by single-
crystal X-ray analysis.
In contrast to moderate yields observed for reduction
of carbamates 14 and 15 (Scheme 3), reduction of
carbamate 10 with LiAlH4 gave amino alcohol 20 in
excellent yield (99%, Scheme 4). In this case, however,
Sch em e 4a
To explore the formation of racemic biaryls, the Suzuki
cross-coupling of a series of arylboronic acids with aryl
bromide 18 was performed (Scheme 6). As previously,
Sch em e 6a
a
Reagents and conditions: (a) LiAlH4, THF, 0 °C f reflux, 4
h; 99%; (b) NaH, PhN(Me)PIPh3, DMF, 80 °C, 2 h; 63%.
conversion to amine 16 proved difficult. Attempted cy-
clization of alcohol 20 via its mesylate to amine 16, the
method successfully applied to cyclization of carbamates
10 and 11, gave only a small amount (<20%) of the
desired product 16 with a significant loss of material
during workup. Presumably, the increased nucleophilicity
of the pyridyl nitrogen in amine 20, as compared to its
Boc-deactivated analogues 10 and 11, makes quaterniza-
tion of the substrate/product a significant side-reaction.
Since intermolecular alkylations of 4-monoalkylaminopy-
ridine anions are known to proceed selectively on the
exocyclic nitrogen,22 it was anticipated that conversion
of the hydroxyl group in amino alcohol 20 to a good
leaving group with concomitant deprotonation of the
amine would improve the yield of the process. Indeed,
treatment of the alkoxide of aminol 20 with (N-meth-
ylphenylamino)triphenylphosphonium iodide (Mura-
hashi’s reagent),23 gave the desired product in good yield.
a
Reagents and conditions: (a) ArB(OH)2, Na2CO3, Pd(PPh3)4,
PhMe, H2O, EtOH, reflux, 2-24 h.
high yields of biaryls were obtained when unhindered
arylboronic acids were used (25-29, 31, 33, and 34). In
more difficult cases (30, 32, and 3525), the yields of the
cross-coupling were lower and required increased amounts
of both catalyst (5 mol % vs 3 mol %) and arylboronic
acids (2.0 equiv vs 1.2 equiv).
As the result of axial dissymmetry, the protons of each
of the two methylene groups, at C-2 and C-3, in biaryls
26-29 and 31-35 are diastereotopic. H NMR studies
1
(21) Michell, R. M.; Lai, Y.-H.; Williams, R. V. J . Org. Chem. 1979,
44, 4733-4735.
(24) Miyaura, N.; Yanogi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513-519.
(25) The ability of biaryl 35 to induce R-elimination of HCl from
dichloromethane was noted during the growth of a single crystal from
an ether/dichloromethane solution. The crystal grown was demon-
strated to be hydrochloride of biaryl 35 by single-crystal X-ray analysis.
(22) J itao, H.; J ingwu, S.; Zhenghua, L. J . Appl. Polym. Sci. 1995,
56, 1805-1806.
(23) Tanigawa, Y.; Murahashi, S.-I.; Moritani, I. Tetrahedron Lett.
1975, 471-472.

Biaryl Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 64, No. 26, 1999 9433
symmetrically substituted 2′6′-dimethoxy biaryl 30 could
be envisaged to constitute an attractive starting material
(via its 2′,6′-ditriflate) for the asymmetric synthesis of
configurationally stable phenyl-based biaryls by enan-
tioposition-selective couplings.32
At this juncture, having developed an efficient meth-
odology for the preparation of relatively unhindered and
configurationally labile biaryls, the racemization of which
could be conveniently followed by chiral HPLC, we
embarked on the preparation of an analogous set of
compounds containing DMAP itself as a nucleophilic
component. This would enable us to assess the effect of
freezing the rotation about the C-N bond on the barrier
to rotation about the biaryl axis. As in previous cases,
Suzuki cross-coupling of the known aryl bromide 3633
with selected arylboronic acids proceeded uneventfully
(Scheme 7) yielding biaryls 37-39.
Sch em e 7a
F igu r e 1. High-field fragment of the 1H NMR spectrum of
axially chiral biaryl 28 in CDCl3 (250 MHz).
(250 MHz, CDCl3, rt) showed that in biaryls 26, 29, and
35 these protons are isochronous, i.e., appear as a pair
of triplets, as in symmetrical biaryls 25 and 30.26,27 In
contrast, the methylene protons in biaryls 27, 28, and
31-34 are anisochronous and show more complex split-
ting patterns (Figure 1), which unequivocally confirms
slow internal rotation about the central biaryl axis due
to steric hindrance. For naphthyl derivative 31, no
coalescence was observed even at 100 °C. Its racemiza-
tion, however, could be conveniently studied using chiral
HPLC (Figure 2).28 Computer simulation of the plateau-
shaped elution profiles29 allowed calculation of the rota-
tional energy barrier for biaryl 31 which was found to
be 85.9 ( 0.3 kJ /mol (20 °C). This corresponds to a half-
life for racemization of ∼1.9 min at 20 °C which is
significantly shorter than the arbitrarily set threshold
of 1000 s considered the minimum requirement for
chemical separation of optical antipodes.30 Similar HPLC
analysis of methoxynaphthalene biaryls 32-35 enabled
us to study both stereoelectronic (conjugation across the
biaryl system) and steric effects of varying substitution
patterns on the barrier to Ar-Ar rotation.31
a
Reagents and conditions: (a) ArB(OH)2, Na2CO3, Pd(PPh3)4,
PhMe, H2O, EtOH, reflux, 2-24 h.
Here, atropisomerism could not be observed by NMR,
but the rotational behavior of the DMAP analogues 38
and 39 was easily followed by chiral HPLC. Contrary to
our expectations, the barriers to internal rotation ob-
served for naphthyl-substituted biaryls 31 (Figure 2) and
38 (Figure 3) were not significantly different. It could,
therefore, be concluded that the increased conformational
rigidity of the nucleophilic component has no significant
effect on the configurational stability of the biaryls. This
presumably reflects the importance of conjugation across
the 4-aminopyridyl system, for which coplanarity is
optimal, thus restricting rotation about the C-N bond
(Scheme 8).34 In the case of biaryl 31, for which the
Sch em e 8
Although the studies described herein focus on con-
figurationally stable naphthyl-based biaryls (vide infra),
(26) For biaryl 26, the broad 1H NMR signals for methylene protons
gave a more complex splitting pattern at 243 K (similar to that of biaryl
28). For biaryl 29 no decoalescence was observed even at 223 K.
(27) The N-methyl groups in 7-aryl derivatives of azaindoline 16
show a significant ring current upfield shift in 1H NMR (CDCl3). The
effect is more pronounced for naphthyl derivatives 31 and 55 (-0.69
and -0.70 ppm, respectively, relative to 16) than for phenyl analogue
25 (-0.34 ppm).
coplanarity is enforced, the N-methyl group is pulled
away from the biaryl axis due to Baeyer strain imposed
by the five-membered ring. As a result, the N-methyl
group in biaryl 31 plays a lesser role in slowing the Ar-
Ar rotation than the proximal N-methyl group in conju-
gated resonance form 38(b). This effect becomes more
(28) (a) Veciana, J .; Crespo, M. I. Angew. Chem., Int. Ed. Engl. 1991,
30, 74-76. (b) J ung, M.; Schuring, V. J . Am. Chem. Soc. 1992, 114,
529-534. (c) Hochmuth, D. H.; Ko¨nig, W. A. Liebigs Ann. Chem. 1996,
947-951. (d) Cabrera, K.; J ung, M.; Fluck, M.; Schurig, V. J . Chro-
matogr. 1996, A 731, 315-321. (e) Wolf, C.; Pirkle, W. H.; Welch, C.
J .; Hochmuth, D. H.; Ko¨nig, W. A.; Chee, G.-L.; Charlton, J . L. J . Org.
Chem. 1997, 62, 5208-5210. (f) Hochmuth, D. H.; Ko¨nig, W. A.
Tetrahedron: Asymmetry 1999, 10, 1089-1097. (g) Oxelbark, J .;
Allenmark, S. J . Org. Chem. 1999, 64, 1483-1486.
(31) Spivey, A. C.; Hochmuth, D. H.; Fekner, T., unpublished results.
(32) (a) Hayashi, T.; Niizuma, S.; Kamikawa, T.; Suzuki, N.; Uozumi,
Y. J . Am. Chem. Soc. 1995, 117, 9101-9102. (b) Kamikawa, T.;
Uozumi, Y.; Hayashi, T. Tetrahedron Lett. 1996, 37, 3161-3164. (c)
Kamikawa, T.; Hayashi, T. Tetrahedron 1999, 55, 3455-3466.
(33) (a) Essery, J . M.; Schofield, K. J . Chem. Soc. 1960, 4953-4959.
(b) Groziak, M. P.; Melcher, L. M. Heterocycles 1987, 26, 2905-2910.
(c) Paudler, W. W.; J ovanovic, M. V. J . Org. Chem. 1983, 48, 1064-
1069.
(29) Computer program: Hochmuth, D. H. Mimesis 2.0 for Windows
95.
(30) Oˆ ki, M. In Topics in Stereochemistry; Allinger, N. L., Eliel, N.
L., Wilen, S. H., Eds.; J ohn Wiley & Sons: New York, 1983; Vol. 14,
pp 1-81.
(34) X-ray single-crystal structures of biaryl 38 and its N-oxide are
almost superimposable, suggesting a high level of across-ring conjuga-
tion in the parent molecule 38.

9434 J . Org. Chem., Vol. 64, No. 26, 1999
Spivey et al.
F igu r e 2. Interconversion of enantiomers on chiral HPLC
(Chiralcel OD column, 4.6 mm × 25 cm; hexanes/2-propanol/
diethylamine, 79/20/1, 1 mL min-1) for biaryl 31 (7 µg).
F igu r e 3. Interconversion of enantiomers on chiral HPLC
(Chiralcel OD column, 4.6 mm × 25 cm; hexanes/2-propanol/
triethylamine, 79/20/1, 1 mL min-1) for biaryl 38 (5.5 µg).
pronounced for tri-ortho-substituted biaryls for which
DMAP-based analogues seem rotationally much more
restricted than the corresponding analogues of azaindo-
line 16 (vide infra).
If the above reasoning is correct, analogous biaryl
derivatives of yet another highly nucleophilic catalyst,
4-(1-pyrrolidino)pyridine (4-PPY) 40, should show even
higher barriers to Ar-Ar rotation due to prevented
rotation about the N-CH2 bonds. Thus (Scheme 9),
ronic acids under standard Suzuki conditions24 to give
biaryls 42-44 in good yields. For biaryls 43 and 44,
1
atropisomerism could be observed by H NMR owing to
more complex splitting patterns for the methylene groups
as compared with symmetrical phenyl derivative 42. As
anticipated, chiral HPLC studies revealed that the bar-
rier to Ar-Ar rotation in biaryl 43 is significantly higher
than for its closely related analogues 31 and 38 and can
be compared to the levels of steric hindrance observed
in peri-methoxy-substituted naphthalene 35 (Figure 4).
Since aryl bromides 36 and 41 are far more readily
available than aryl bromide 18, their use as templates
on which configurationally stable atropisomeric nucleo-
philic catalysts can be constructed is an attractive option.
Moreover, the use of DMAP and 4-PPY as nucleophilic
components should allow the preparation of their 3,5-
bis(aryl) derivatives possessing C2-symmetry, a feature
that may enhance chiral recognition in acyl transfer as
compared to the corresponding monoaryl analogues. In
our initial studies, however, we utilized aryl bromide 18
as the nucleophilic template.
Sch em e 9a
a
Reagents and conditions: (a) Br2, K2CO3, Bu4NOH, CH2Cl2,
rt, 3 h; 47%; (b) ArB(OH)2, Na2CO3, Pd(PPh3)4, PhMe, H2O, EtOH,
reflux, 2-24 h.
It was anticipated that the attachment of a sterically
more demanding group at the 2′-position in biaryl 31
would be sufficient to increase the barrier to internal
bromination of 4-PPY 40 with Br2 gave aryl bromide 41,
which was subsequently coupled with a series of arylbo-

Biaryl Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 64, No. 26, 1999 9435
Sch em e 11a
a
Reagents and conditions: (a) BnBr, K2CO3, DMF, 60 °C, 5 h;
F igu r e 4. Interconversion of enantiomers on chiral HPLC
(Chiralcel OD column, 4.6 mm × 25 cm; 2-propanol/hexanes/
diethylamine, 78/20/2, 1 mL min-1) for biaryls 43 (2.5 µg) and
35 (4.0 µg).
93%; (b) n-BuLi, Et2O, -78 °C f 0 °C, 1 h followed by B(OMe)3,
-78 °C f rt, overnight; 83%; (c) 18, Na2CO3, Pd(PPh3)4, PhMe,
H2O, EtOH, reflux, 24 h; 82% (based on 18); (d) H2 (1 atm), Pd/C,
EtOH, rt, 5 h; (e) Tf2O, pyridine, 0 °C, 90 min; 93% over two steps;
(f) MeMgBr, NiBr2(PPh3)2, Et2O, reflux, 15 h; 85% of 55 or Me4Sn,
Pd(PPh3)2Cl2, PPh3, LiCl, 2,6-di-tert-butyl-4-methylphenol, DMF,
120 °C, 20 h; 73% of 55 or PhMgBr, PdCl2(dppp), Et2O, reflux, 24
h; 85% of 56.
rotation to such a degree that racemization of the
corresponding biaryls would become negligible at room
temperature. Unfortunately, all attempts to perform
direct Suzuki cross-coupling of 2-methyl-1-naphthalene-
boronic acid/di-n-butyl ester or Kharasch-type cross-
coupling of the corresponding Grignard reagent failed
and, at best, only small amounts of biaryl 55 (<5%) could
AlCl336), the synthesis was modified using benzyl as an
easily removable protecting group (Scheme 11). Thus,
benzylation of phenol 49 with BnBr/K2CO3 furnished
benzyl ether 50 which was converted in a high overall
yield to arylboronic acid 51 upon lithiation with n-BuLi
in Et2O at 0 °C, followed by quenching with B(OMe)3.
The Suzuki cross-coupling of arylboronic acid 51 with aryl
bromide 18 gave biaryl 52 in high yield. Catalytic
hydrogenation of benzyl ether 52 furnished phenol 53,
which was subsequently converted to triflate 54 on
treatment with Tf2O/pyridine. The triflate group in biaryl
54 was substituted by the methyl group using either
Stille cross-coupling37 with Me4Sn or, preferably, Ku-
mada-Corriu cross-coupling with MeMgBr38 to give
biaryl 55 in good yield. A similar Kharasch-type cross-
coupling39 with PhMgBr gave 2′-phenyl derivative 56.
The structure of biaryl 56 was confirmed by single-crystal
X-ray analysis (Figure 5).
1
be detected by H NMR/HPLC. One way to circumvent
this problem would be to carry out the crucial biaryl
coupling in intramolecular fashion using an auxiliary
bridge (Scheme 10), a strategy successfully applied to the
Sch em e 10
At this stage, several of these molecules were tested
as acyl transfer catalysts using Ac2O and 1-methylcyclo-
hexanol 57 (Table 1), the standard test used previously
by others to assess the catalytic activity of DMAP and
its analogues.6b As anticipated, the introduction of the
aryl substituents into either 16 or DMAP does cause a
drop in catalytic activity, but the effect is not dramatic,
especially when compared with the background acylation
level observed in the absence of the catalyst (Table 1,
entry 1).
preparation of a broad range of highly substituted
biaryls.35 Thus, alkylation of amine 48 with naphthalene
derivative 47 would lead to amine 46. A subsequent
intramolecular biaryl coupling would create the central
biaryl axis to give 45, which after benzylamine cleavage
and N-methylation would furnish the desired highly
substituted biaryl 55. Initially, however, we decided to
use a more direct approach. As such, it was anticipated
that 2′-methoxy-substituted biaryl 32 could be conve-
niently converted to the desired 2′-methyl analogue. Since
demethylation of methyl ether 32 proved rather difficult
(at best, a yield of ∼35% could be achieved using EtSH/
The barriers to internal rotation for biaryls 55 and 56,
which were to be used as chiral nucleophilic catalysts,
were then evaluated. Thus, samples of racemic biaryls
(36) Node, M.; Nishide, K.; Fuji, K.; Fujita, E. J . Org. Chem. 1980,
45, 4275-4277.
(37) (a) Echavarren, A. M.; Stille, J . K. J . Am. Chem. Soc. 1987,
109, 5478-5486. (b) Saa´, J . M.; Martorell, G.; Garcia-Raso, A. J . Org.
Chem. 1992, 57, 678-685.
(35) (a) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int.
Ed. Engl. 1990, 29, 977-991. (b) Bringmann, G.; Breuning, M.; Tasler,
S. Synthesis 1999, 4, 525-558.
(38) (a) Kumada, M. Pure Appl. Chem. 1980, 52, 669-679. (b) Ritter,
K. Synthesis 1993, 735-762.
(39) Kamikawa, T.; Hayashi, T. Synlett 1997, 163-164.

9436 J . Org. Chem., Vol. 64, No. 26, 1999
Spivey et al.
Ta ble 3. Ar r h en iu s P a r a m eter s a n d Tr a n sition -Sta te
F u n ction s for Ra cem iza tion of Bia r yls 55, 56, a n d 59 in
Ben zen e
55
56
59
Ea/kJ mol-1
107 (3)
18.8 (1.0)
103 (4)
110 (5)
21.7 (1.4)
106 (5)
124 (5)
23.9 (1.3)
121 (5)
ln(A/s-1
)
∆H‡/kJ mol-1
∆S‡/J mol-1 K-1
-100 (8)
-75 (12)
-57 (11)
F igu r e 5. An ORTEP plot of the molecular structure of biaryl
56. H atoms and a molecule of water are omitted for clarity.
Torsion angle C20-C11-C7-C8 ) 78.7°, torsion angle C11-
C12-C21-C6 ) 74.1°. The bond lengths of the biaryl axes:
C11-C7 ) 1.50 Å and C12-C21 ) 1.49 Å.
F igu r e 6. Eyring plots for the racemization of biaryls 55, 56,
and 59 in benzene.
Ta ble 1. Acyla tion of Alcoh ol 57a
tion of the Eyring plots (Figure 6) indicated that an
enantiomerically homogeneous sample of biaryl 55 would
lose less than 1% of its optical purity over 1 year in
solution at room temperature (298 K). Although, biaryl
56 (t1/2(racem) ) ∼125 years at 298 K) is configurationally
less stable than the methyl analogue 55, its racemization
at room temperature is slow enough for its practical use.
Since barriers to internal rotation in biaryls 31 and
38 had been demonstrated to be similar, it was expected
that the levels of steric hindrance in biaryl 5941 would
57:58 ratiosb
entry
catalyst
after 10 h
after 24 h
1
2
3
4
5
6
7
8
no catalyst
DMAP
16
18
31
38
55
56
99:1
98:2
13:87
21:79
96:4
36:64
63:37
22:78
30:70
5:95
10:90
90:10
18:82
45:55
13:87
14:86
a
Key: (a) Ac2O (2.1 equiv), Et3N (1.5 equiv), catalyst (4 mol
b
%); rt. Established by GC on a DB1701 ISM capillary column
(70 °C).
Ta ble 2. Ra cem iza tion Kin etics of Bia r yls 55, 56, a n d 59
in Ben zen ea
be at least comparable to these observed for biaryl 55.
Indeed, racemization studies for the individual enanti-
omers of biaryl 59 (Tables 2 and 3 and Figure 6) showed
that its configurational stability is far superior (at
ambient temperature) to either biaryl 55 or 56. Extrapo-
lation of the corresponding Eyring plot indicates that the
half-life for racemization for biaryl 59 at 298 K exceeds
5000 years. Interestingly, the racemization of biaryl 55
is slower than the racemization of biaryl 59 at temper-
atures exceeding ∼410 K. This is due to the larger
absolute value of ∆S‡ for biaryl 55 relative to biaryl 59,
which is indicative of a more highly ordered transition
state for rotation (relative to the ground state) for the
former.
55
56
59
T/K
107kracem/s-1
106kracem/s-1
107kracem/s-1
373
383
393
403
413
423
433
443
453
-
1.14 (0.01)
3.35 (0.06)
7.32 (0.18)
16.2 (0.3)
39.5 (0.4)
83.7 (2.8)
153 (28)
-
-
-
-
8.93 (0.22)
-
45.4 (2.0)
-
185 (3)
-
682 (16)
7.6 (0.3)
18.0 (1.2)
45.0 (0.6)
114 (7)
235 (27)
551 (11)
-
-
a
Separation of enantiomers and monitoring of racemization
were performed on chiral HPLC [Chiralcel OD column, 4.6 mm ×
25 cm; hexanes/2-propanol, 96/4; 1 mL min-1; 0 °C (for 55) or hex-
anes/EtOAc/Et2NH, 75/24/1; 1 mL min-1; 25 °C (for 56 and 59)].
Optical resolution of racemic biaryls 55 and 56 was
performed using semipreparative chiral HPLC. The
55 and 56 were separated into enantiomers using ana-
lytical chiral HPLC and the atropisomerization of the
individual enantiomers studied in benzene over a wide
temperature range (sealed-tube experiments, Table 2).
Kinetic parameters for the racemization (Table 3) were
obtained from Arrhenius and Eyring plots.40 Extrapola-
(40) (a) Cagle, F. W., J r.; Eyring, H. J . Am. Chem. Soc. 1951, 73,
5628-5630. (b) Cooke, A. S.; Harris, M. M. J . Chem. Soc. C 1967, 988-
992.
(41) Prepared by an analogous route to that described for the
preparation of biaryl 55 via low-yielding (13%) Suzuki cross-coupling
of aryl bromide 36 with arylboronic acid 51. Various attempts to
accomplish a similar coupling with aryl bromide 41 failed.

Biaryl Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 64, No. 26, 1999 9437
nearest 0.05. All reaction solvents were distilled before use
and stored over activated 4 Å molecular sieves, unless other-
wise indicated. Anhydrous CH2Cl2 was obtained by refluxing
over calcium. Anhydrous THF and Et2O were obtained by
distillation, immediately before use, from sodium/benzophe-
none ketyl under an inert atmosphere of nitrogen. Anhydrous
DMF was obtained by distillation from calcium hydride under
reduced pressure. Petroleum ether refers to the fraction of light
petroleum boiling between 40 and 60 °C. High-resolution mass
spectrometry (HRMS) measurements are valid to (5 ppm ((10
ppm for biaryl 54).
(ter t-Bu toxy)-N-(4-p yr id yl)ca r boxa m id e (7). A solution
of Boc2O (43.6 g, 0.20 mol) in CH2Cl2 (100 mL, not anhydrous)
was added over 20 min to a stirred suspension of 4-aminopy-
ridine 6 (18.8 g, 0.20 mol) in CH2Cl2 (200 mL). The resulting
pale yellow solution was stirred at room temperature for 25
min (TLC) and acidified with 1 M HCl (230 mL, 0.23 mol).
The phases were separated, and the aqueous layer was washed
with CH2Cl2. The aqueous layer was mixed with a fresh portion
of CH2Cl2 (200 mL) and treated during vigorous stirring with
solid K2CO3 (21.1 g, 0.16 mol). The phases were separated,
and the extraction was completed with additional portions of
CH2Cl2. The combined organic extracts were dried (MgSO4)
and evaporated in vacuo to give the title compound 7 as a white
solid (38.6 g, >99%) which was used in the next step without
further purification. For analytical purposes, a small amount
of the product was recrystallized from EtOAc/petroleum
ether: Rf ) 0.30 (EtOAc); mp 151.0-151.5 °C (EtOAc/
petroleum ether) (lit.17c 144-145 °C); 1H NMR (250 MHz,
CDCl3) δ 1.46 (s, 9H), 7.37 (d, J ) 5.5 Hz, 2H), 8.38 (d, J ) 5.5
Hz, 2H), and 8.52 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 28.22,
81.28, 112.5, 146.6, 150.0, and 152.5; IR (CHCl3) vmax 1724,
1598, 1507, and 1260 cm-1; MS (EI+) m/z (rel intensity) 194
(25%, M+), 138 (5), 121 (10), 94 (15), and 57 (100). Anal. Calcd
for C10H14N2O2: C, 61.84; H, 7.27; N, 14.42. Found: C, 61.94;
H, 7.27; N, 14.20.
Th e Gen er a l Meth od for th e Lith ia tion of Ca r ba m a te
(7). (ter t-Bu toxy)-N-[3-(2-h yd r oxyeth yl)(4-p yr id yl)]ca r -
boxa m id e (10). Th e fir st m eth od : To a solution of carbamate
7 (38.8 g, 200 mmol) in THF (500 mL) at -78 °C was added
t-BuLi (282 mL, 1.7 M, 480 mmol) in pentane over 70 min.
The resulting bright yellow suspension was stirred at -78 °C
for 20 min and at -15 °C for 2 h. After recooling to -78 °C,
the pale yellow suspension was treated via cannula with
ethylene oxide (15 mL, 300 mmol) at -78 °C. The reaction
mixture was allowed to warm to room temperature over 2 h
and quenched after cooling to -78 °C with water (80 mL). The
solvents were evaporated in vacuo, and the residue was
partitioned between water (250 mL) and CH2Cl2 (350 mL). The
phases were separated, and the extraction was completed with
additional portions of CH2Cl2. The combined organic extracts
were washed with brine, dried (MgSO4), and evaporated in
vacuo to give a pale yellow solid. The crude product was
dissolved in a small amount of CH2Cl2 and passed through a
short plug of flash silica eluting with EtOAc. Fractions
containing the product were concentrated, and the title
compound 10 as a white crystalline precipitate was removed
by filtration (32.1 g, 67%). The mother liquor was concentrated
and purified by flash chromatography (EtOAc) to afford an
additional amount of the product 10 (3.5 g, 7%; total yield:
75%) along with the starting material 7 (2.5 g, 7%).
F igu r e 7. An ORTEP plot of the molecular structure of biaryl
(+)-55. H atoms are omitted for clarity. Torsion angle C20-
C11-C7-C8 ) 71.9°. The bond length of the biaryl axis: C11-
C7 ) 1.49 Å.
structure of biaryl 55 was confirmed by single-crystal
X-ray analysis of the dextrorotatory enantiomer (+)-55
{[R]25 +107 (c 0.43 in CHCl3)} (Figure 7).
D
Con clu sion s
In summary, a concise synthetic approach toward
axially chiral biaryls incorporating a structural motif of
4-(dimethylamino)pyridine has been developed. This
novel family of chiral DMAP’s have been shown to retain
the high catalytic activity of the parent compound toward
acylation of a hindered alcohol. Biaryls 55, 56, and 59,
for which internal rotation about the chiral axis has been
shown to be sufficiently slow at ambient temperature to
allow for their chiral separation and easy handling
without racemization, are of potential use as chiral
catalysts for resolution of secondary alcohols and for other
asymmetric transformations. Studies in this area are
ongoing, and results will be reported shortly.
Exp er im en ta l Section
Gen er a l Meth od s. All reactions were performed under
anhydrous conditions and an inert atmosphere of argon in the
flame-dried glassware. Yields refer to chromatographically and
spectroscopically (1H NMR) homogeneous materials, unless
otherwise indicated. Reagents were used as obtained from
commercial sources or purified according to known proce-
dures.42 Flash chromatography was carried out using Merck
Kiesegel 60 F254 (230-400 mesh) silica gel. Only distilled
solvents were used as eluents. Thin-layer chromatography
(TLC) was performed on Merck DC-Alufolien or glass plates
precoated with silica gel 60 F254 which were visualized either
by quenching of ultraviolet fluorescence (λmax ) 254 nm) or by
charring with 5% w/v phosphomolybdic acid in 95% EtOH, 10%
w/v ammonium molybdate in 1 M H2SO4, or 10% KMnO4 in 1
M H2SO4. Observed retention factors (Rf) are quoted to the
Th e secon d m eth od : To a solution of 2-bromoethanol (3.2
mL, 45 mmol) in THF (60 mL) at -78 °C was added n-BuLi
(21.6 mL, 2.5 M, 54 mmol) in hexanes. After 10 min, the
mixture was transferred via cannula to a flask containing the
lithiated species 8 prepared from carbamate 7 (5.82 g, 30.0
mmol) according to the general procedure. The reaction and
purification were carried out as in the first method to afford
the title compound 10 (4.73 g, 66%) and the starting material
7 (999 mg, 17%). Alcohol 10: Rf ) 0.15 (EtOAc); mp 138.5-
139.0 °C (EtOAc/petroleum ether); 1H NMR (250 MHz, CDCl3)
δ 1.48 (s, 9H), 2.73 (t, J ) 5.0 Hz, 2H), 3.88 (t, J ) 5.0 Hz,
2H), 4.82 (br s, 1H), 7.89 (d, J ) 6.0 Hz, 1H), 8.03 (s, 1H), 8.16
(d, J ) 6.0 Hz, 1H), and 8.96 (s, 1H); 13C NMR (63 MHz, CDCl3)
δ 28.25, 32.88, 63.34, 80.92, 114.0, 125.1, 146.2, 148.1, 150.5,
(42) Perrin, D. D.; Armarego, W. L. F. Purification of Laboratory
Chemicals; Pergamon Press: New York, 1988.

9438 J . Org. Chem., Vol. 64, No. 26, 1999
Spivey et al.
and 152.8; IR (CHCl3) vmax 1730, 1583, and 1509 cm-1; MS
(EI+) m/z (rel intensity) 238 (15%, M+), 182 (10), 152 (15), 107
(15), and 57 (100). Anal. Calcd for C12H18N2O3: C, 60.49; H,
7.61; N, 11.76. Found: C, 60.41; H, 7.57; N, 11.59.
(44.4 mL, 1.0 M, 44.4 mmol) in THF. After 1 h, the reaction
mixture was allowed to warm to room temperature and was
then refluxed overnight. After cooling to 0 °C, the mixture was
quenched with water (50 mL) and extracted with CH2Cl2. The
combined extracts were dried (MgSO4) and evaporated in
vacuo to give a yellow oil which was purified by flash
chromatography (EtOAc) to afford the title compound 15 (9.00
g, 95%) as a pale yellow solid: Rf ) 0.30 (EtOAc); 1H NMR
(250 MHz, CDCl3) δ 1.11 (d, J ) 6.5 Hz, 3H), 1.38 (s, 9H),
2.47 (dd, J ) 2.5, 16.0 Hz, 1H), 3.15 (dd, J ) 10.0, 16.0 Hz,
1H), 4.33 (ddq, J ) 2.5, 6.5, 10.0 Hz, 1H), 7.33 (br s, 1H), 8.10
(s, 1H), and 8.14 (d, J ) 5.5 Hz, 1H); 13C NMR (63 MHz, CDCl3)
δ 21.00, 28.16, 33.26, 55.72, 81.59, 109.8, 125.6, 145.8, 148.6,
149.1, and 151.6; IR (CHCl3) vmax 1702, 1522, 1485, 1428, 1385,
and 1226 cm-1; MS (EI+) m/z (rel intensity) 234 (25%, M+),
178 (45), 119 (35), and 57 (100); HRMS calcd for C13H18N2O2
(M+) 234.1368, found 234.1369.
1-Met h yl-2-p yr r olin o[3,2-c]p yr id in e (16). Th e fir st
m eth od : To a solution of carbamate 14 (32.8 g, 149 mmol) in
CH2Cl2 (400 mL) at 0 °C was added diisobutylaluminum
hydride (100 g, 700 mmol) in CH2Cl2 (400 mL) over 1 h. The
resulting yellow solution was refluxed for 20 h, recooled to 0
°C, and treated sequentially with solid NaF (118 g, 2.81 mol)
in portions over 30 min and water (39 mL, 2.2 mol) over 90
min. The resulting thick suspension was warmed to room
temperature over 3 h, filtered through a thin pad of Celite,
and evaporated in vacuo to give a brown oil, which was found
to be a ∼10:1 mixture of amine 16 and its N-demethylated
analogue by 1H NMR. The oil was dissolved in CH2Cl2 (200
mL) and treated with Boc2O (6.0 g, 28 mmol). After 3 h at room
temperature, the mixture was concentrated in vacuo and
purified by flash chromatography (EtOAc f EtOAc/Et3N, 95/
5) to give the starting material 14 (1.75 g, 5%) and the title
compound 16 (11.0 g, 55%) as a white solid.
Th e secon d m eth od : A suspension of aminol 20 (76 mg,
0.50 mmol) and NaH (12 mg, 0.50 mmol) in DMF (2 mL) was
heated at 80 °C until a clear solution resulted (∼40 min). After
cooling to 0 °C, the mixture was treated with (N-methylphe-
nylamino)triphenylphosphonium iodide (248 mg, 0.50 mmol)
and heated at 80 °C for 2 h. The mixture was cooled to room
temperature and partitioned between water (5 mL) and CH2-
Cl2 (5 mL). The phases were separated, and extraction was
completed with additional portions of CH2Cl2. The combined
extracts were dried (MgSO4) and evaporated in vacuo. The
residue was purified by flash chromatography (EtOAc f
EtOAc/Et3N, 95/5) to give the title compound 16 (42 mg, 63%)
as a white solid: Rf ) 0.15 (EtOAc/Et3N, 99/5); 1H NMR (250
MHz, CDCl3) δ 2.74 (s, 3H), 2.94 (t, J ) 8.5 Hz, 2H), 3.40 (t,
J ) 8.5 Hz, 2H), 6.21 (d, J ) 5.5 Hz, 1H), 7.99 (s, 1H), and
8.07 (d, J ) 5.5 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 26.03,
33.64, 54.53, 101.3, 125.4, 143.6, 149.1, and 158.4; IR (CHCl3)
vmax 2958, 1605, 1510, and 1305 cm-1; MS (EI+) m/z (rel
intensity) 134 (75%, M+), 133 (100), and 118 (20); HRMS calcd
for C8H10N2 (M+) 134.0844, found 134.0841.
(ter t-Bu toxy)-N-(3-br om o(4-p yr id yl))ca r boxa m id e (9).
The lithiated species 8 prepared from carbamate 7 (469 mg,
2.00 mmol) according to the general procedure was reacted
with 1,2-dibromoethane (250 mL, 2.90 mmol). The reaction was
carried out as described for the preparation of alcohol 10, and
purification by flash chromatography (EtOAc) furnished the
title product 9 (559 mg, 85%) as a white solid, along with the
starting material 7 (40 mg, 9%): Aryl bromide 9: Rf ) 0.60
(CH2Cl2/EtOAc, 3/1); 1H NMR (250 MHz, CDCl3) δ 1.47 (s, 9H),
7.17 (s, 1H), 8.07 (d, J ) 5.5 Hz, 1H), 8.29 (d, J ) 5.5 Hz, 1H),
and 8.50 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 28.15, 82.41,
109.6, 113.1, 143.2, 149.4, 151.4, and 151.5; IR (CHCl3) vmax
1739, 1583, 1569, 1505, 1450, and 1407 cm-1; MS (EI+) m/z
(rel intensity) 272 (10%, M+), 172 (10), and 57 (100); HRMS
calcd for C10H13BrN2O2 (M+) 272.0160, found 272.0167.
(ter t-Bu t oxy)-N-[3-(2-h yd r oxyp r op yl)(4-p yr id yl)]ca r -
boxa m id e (11). The lithiated species 8 prepared from car-
bamate 7 (9.70 g, 50.0 mmol) according to the general
procedure was reacted with propylene oxide (3.8 mL, 55 mmol).
The reaction was carried out as described for the preparation
of alcohol 10, and purification by flash chromatography
(EtOAc) furnished the title product 11 (10.2 g, 81%) as a white
crystalline solid: Rf ) 0.25 (EtOAc); mp 128.5-129.5 °C
1
(EtOAc/petroleum ether); H NMR (250 MHz, CDCl3) δ 1.21
(d, J ) 6.0 Hz, 3H), 1.46 (s, 9H), 2.64 (dd, J ) 7.0, 14.5 Hz,
1H), 2.75 (dd, J ) 2.5, 14.5 Hz, 1H), 4.12 (ddq, J ) 2.5, 6.0,
7.0 Hz, 1H), 5.24 (br s, 1H), 7.90 (d, J ) 5.5 Hz, 1H), 8.02 (s,
1H), 8.17 (d, J ) 5.5 Hz, 1H), and 9.28 (s, 1H); 13C NMR (63
MHz, CDCl3) δ 23.54, 28.28, 38.62, 69.01, 80.83, 114.2, 123.5,
146.2, 148.2, 151.2, and 152.8; IR (CHCl3) vmax 1728, 1583,
1512, 1249, and 1157 cm-1; MS (EI+) m/z (rel intensity) 252
(15%, M+), 208 (10), 152 (55), 108 (35), and 57 (100). Anal.
Calcd for C13H20N2O3: C, 61.88; H, 7.99; N, 11.10. Found: C,
61.86; H, 8.01; N, 10.98.
ter t-Bu tyl 2-P yr r olin o[3,2-c]p yr id in eca r boxyla te (14).
To a stirred solution of alcohol 10 (35.6 g, 150 mmol) and
triethylamine (46.0 mL, 330 mmol) in CH2Cl2 (400 mL) was
added methanesulfonyl chloride (12.8 mL, 165 mmol) over 80
min, while the temperature was maintained between -10 and
-5 °C. After 1 h at room temperature, the reaction mixture
was washed sequentially with satd NaHCO3, water, and brine.
The organic layer was dried (MgSO4) and concentrated in
vacuo to give a brown oil which was purified by flash
chromatography (EtOAc) to afford the title compound 14 (32.8
g, ∼100%) as a white solid: Rf ) 0.15 (EtOAc); 1H NMR (250
MHz, CDCl3) δ 1.43 (s, 9H), 2.96 (t, J ) 9.0 Hz, 2H), 3.84 (t,
J ) 9.0 Hz, 2H), 7.47 (br s, 1H), 8.13 (s, 1H), and 8.17 (d, J )
5.5 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 24.80, 28.19, 47.63,
81.71, 109.3, 126.8, 145.5, 149.1, and 152.0 (one C not
detected); IR (CHCl3) vmax 1703, 1600, 1494, 1389, and 1160
cm-1; MS (EI+) m/z (rel intensity) 220 (35%, M+), 164 (55), 120
(30), and 57 (100); HRMS calcd for C12H16N2O2 (M+) 220.1212,
found 220.1204.
ter t-Bu tyl 2-Meth yl-2-p yr r olin o[3,2-c]p yr id in eca r box-
yla te (15). To a solution of alcohol 11 (10.2 g, 40.4 mmol) and
triethylamine (7.3 mL, 53 mmol) in CH2Cl2 (150 mL) was
added methanesulfonyl chloride (3.4 mL, 44 mmol) over 80 min
at -20 °C. The reaction mixture was warmed to room tem-
perature, washed with satd NaHCO3, dried (MgSO4), and
evaporated in vacuo to give crude mesylate 13 (13.4 g, ∼100%)
as a white solid.
1,2-Dim eth yl-2-p yr r olin o[3,2-c]p yr id in e (17). To a solu-
tion of carbamate 15 (8.89 g, 38.0 mmol) in THF (150 mL) at
0 °C was added lithium aluminum hydride (5.78 g, 152 mmol)
over 30 min, and the reaction mixture was refluxed for 4 h.
After recooling to 0 °C, the mixture was quenched sequentially
with water (5.8 mL), 15% NaOH (5.8 mL), and water (17.4
mL) to give a thick suspension which was filtered through
Celite. The filtrate was evaporated in vacuo to give a white
solid, which was found to be a ∼1:1 mixture of amine 17 and
its N-demethylated analogue by 1H NMR. The solid was
dissolved in THF (100 mL) and treated with Boc2O (5.0 g, 23
mmol). After 24 h at room temperature, the solvent was
evaporated in vacuo and the residue purified by flash chro-
matography (EtOAc f EtOAc/Et3N, 95/5) to give the starting
material 15 (3.48 g, 39%) and the title compound 17 (2.14 g,
38%) as a pale yellow solid. Amine 17: Rf ) 0.15 (EtOAc/Et3N,
2-{4-[(ter t-Bu toxy)ca r bon yla m in o](3-p yr id yl)}isop r o-
p yl m eth ylsu lfon a te (13): 1H NMR (250 MHz, CDCl3) δ 1.43
(d, J ) 6.0 Hz, 3H), 1.51 (s, 9H), 2.86 (s, 3H), 2.89 (dd, J )
6.5, 15.0 Hz, 1H), 3.04 (dd, J ) 6.0, 15.0 Hz, 1H), 4.86 (ddq, J
) 6.0, 6.0, 6.5 Hz, 1H), 7.23 (br s, 1H), 8.02 (d, J ) 5.5 Hz,
1H), 8.24 (s, 1H), and 8.37 (d, J ) 5.5 Hz, 1H); 13C NMR (63
MHz, CDCl3) δ 20.62, 28.16, 36.27, 38.18, 78.51, 81.07, 113.6,
119.1, 144.6, 149.8, 151.9, and 152.2.
1
99/5); H NMR (250 MHz, CDCl3) δ 1.22 (d, J ) 6.0 Hz, 3H),
2.52 (dd, J ) 8.5, 15.5 Hz, 1H), 2.68 (s, 3H), 3.08 (dd, J ) 9.0,
15.5 Hz, 1H), 3.59 (ddq, J ) 6.0, 8.5, 9.0 Hz, 1H), 6.15 (d, J )
5.5 Hz, 1H), 7.93 (s, 1H), and 8.04 (d, J ) 5.5 Hz, 1H); 13C
NMR (63 MHz, CDCl3) δ 19.01, 31.19, 43.43, 61.46, 101.2,
To a solution of mesylate 13 (13.4 g, 40.4 mmol) in THF
(150 mL) at -78 °C was added lithium bis(trimethylsilyl)amide

Biaryl Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 64, No. 26, 1999 9439
124.4, 142.5, 148.6, and 158.3; IR (CHCl3) vmax 2971, 1606,
1504, and 1296 cm-1; MS (EI+) m/z (rel intensity) 148 (55%,
M+), 133 (100), and 118 (20); HRMS calcd for C9H12N2 (M+)
148.1000, found 148.1000.
116.1, 125.2, 125.7, 126.0, 126.3, 126.4, 128.1 (2C?), 128.3,
133.1, 133.2, 135.0, 143.2, 151.3, and 155.9; IR (CHCl3) vmax
2956, 1597, 1497, and 1413 cm-1; MS (EI+) m/z (rel intensity)
260 (100%, M+); HRMS calcd for C18H16N2 (M+) 260.1313,
found 260.1303.
7-Br om o-1-m eth yl-2-p yr r olin o[3,2-c]p yr id in e (18). To
a solution of amine 16 (7.73 g, 57.7 mmol) in DMF (100 mL)
at 0 °C was added a solution of N-bromosuccinimide (11.3 g,
63.5 mmol) in DMF (100 mL). After 90 min (TLC) the solvent
was evaporated in vacuo, and the residue partitioned between
water (100 mL) and CH2Cl2 (100 mL). The phases were
separated, and the extraction completed with additional por-
tions of CH2Cl2. The combined organic extracts were dried
(MgSO4) and evaporated in vacuo. The residue was purified
by flash chromatography (EtOAc) to give the title compound
18 (9.97 g, 81%) as a white solid: Rf ) 0.15 (EtOAc); 1H NMR
(250 MHz, CDCl3) δ 2.92 (t, J ) 9.0 Hz, 2H), 3.16 (s, 3H), 3.46
(t, J ) 9.0 Hz, 2H), 7.85 (s, 1H), and 8.09 (s, 1H); 13C NMR
(63 MHz, CDCl3) δ 25.31, 35.97, 55.91, 97.98, 127.9, 142.3,
152.1, and 153.8; IR (CHCl3) vmax 2960, 1602, 1496, 1416, and
1314 cm-1; MS (EI+) m/z (rel intensity) 214/212 (100%, M+),
132 (70), 118 (20), 105 (20), and 63 (30); HRMS calcd for C8H9-
BrN2 (M+) 211.9949, found 211.9943.
7-Br om o-1,2-d im eth yl-2-p yr r olin o[3,2-c]p yr id in e (19).
As described for the preparation of aryl bromide 18, amine 17
(2.10 g, 14.1 mmol) was reacted with N-bromosuccinimide (2.65
g, 14.9 mmol) to give, after purification by flash chromatog-
raphy (EtOAc), the title compound 19 (1.99 g, 62%) as a pale
yellow solid: Rf ) 0.20-0.45 (EtOAc); 1H NMR (250 MHz,
CDCl3) δ 1.11 (d, J ) 6.0 Hz, 3H), 2.36 (dd, J ) 8.0, 16.0 Hz,
1H), 2.98 (s, 3H), 2.98 (dd, J ) 10.0, 16.0 Hz, 1H), 3.48 (ddq,
J ) 6.0, 8.0, 10.0 Hz, 1H), 7.69 (s, 1H), and 7.96 (s, 1H); 13C
NMR (63 MHz, CDCl3) δ 19.27, 33.75, 33.81, 62.41, 97.94,
126.7, 142.1, 152.2, and 153.5; IR (CHCl3) vmax 2972, 1601,
1488, 1415, and 1305 cm-1; MS (EI+) m/z (rel intensity) 228/
226 (70%, M+), 211/213 (100), and 132 (80); HRMS calcd for
C9H11BrN2 (M+) 226.0106, found 226.0101.
1,2-Dim eth yl-7-p h en yl-2-p yr r olin o[3,2-c]p yr id in e (21).
Following the general procedure, aryl bromide 19 (114 mg, 0.50
mmol) was reacted with phenylboronic acid (73 mg, 0.60 mmol)
to give, after purification by flash chromatography (EtOAc f
EtOAc/Et3N, 98/2), the title compound 21 (110 mg, 98%) as a
1
pale yellow oil: Rf ) 0.35 (EtOAc/Et3N, 99/5); H NMR (250
MHz, CDCl3) δ 1.28 (d, J ) 6.0 Hz, 3H), 2.36 (s, 3H), 2.59 (dd,
J ) 9.0, 16.0 Hz, 1H), 3.19 (dd, J ) 9.0, 16.0 Hz, 1H), 3.54
(ddq, J ) 6.0, 9.0, 9.0 Hz, 1H), 7.34 (s, 5H), 7.98 (s, 1H), and
7.99 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 19.58, 34.19, 35.48,
62.91, 118.4, 124.9, 127.1, 128.0, 129.6, 137.5, 142.6, 150.8,
and 155.3; IR (CHCl3) vmax 2971, 1598, 1482, and 1412 cm-1
;
MS (EI+) m/z (rel intensity) 224 (70%, M+) and 209 (100);
HRMS calcd for C15H16N2 (M+) 224.1313, found 224.1317.
1-(1,2-Dim eth yl(2-pyr r olin o[2,3-d]pyr idin -7-yl))-2-m eth -
oxyben zen e (22). Following the general procedure, aryl
bromide 19 (227 mg, 1.00 mmol) was reacted with 2-methoxy-
benzeneboronic acid (182 mg, 1.20 mmol) to give, after
purification by flash chromatography (EtOAc f EtOAc/Et3N,
98/2), the title compound 22 (222 mg, 87%) as a white solid:
Rf ) 0.35 (EtOAc/Et3N, 99/5); mp 154.0-155.0 °C (EtOAc/
1
petroleum ether); H NMR (250 MHz, CDCl3) δ 1.26 (d, J )
5.5 Hz, 3H), 2.35 (s, 3H), 2.60 (dd, J ) 8.0, 15.5 Hz, 1H), 3.20
(dd, J ) 9.0, 15.5 Hz, 1H), 3.64 (ddq, J ) 5.5, 8.0, 9.0 Hz, 1H),
3.76 (s, 3H), 6.90 (d, J ) 8.0 Hz, 1H), 6.97 (t, J ) 7.5 Hz, 1H),
7.22 (br s, 1H), 7.31 (ddt, J ) 1.5, 7.5, 8.0 Hz, 1H), 7.91 (s,
1H), and 7.97 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 19.44, 33.10,
34.08, 55.31, 62.11, 110.3, 114.1, 120.3, 124.2, 126.6, 129.0,
131.7, 142.6, 151.2, 155.2, and 157.5; IR (CHCl3) vmax 2968,
1599, 1494, 1412, and 1206 cm-1; MS (EI+) m/z (rel intensity)
254 (100%, M+), 239 (100), 223 (15), and 207 (25); HRMS calcd
for C16H18N2O (M+) 254.1419, found 254.1423. Anal. Calcd for
2-[4-(Meth yla m in o)-3-p yr id yl]eth a n -1-ol (20). To a solu-
tion of carbamate 10 (2.38 g, 10.0 mmol) in THF (50 mL) at 0
°C was added lithium aluminum hydride (1.98 g, 52.0 mmol)
over 20 min, and the resulting mixture was refluxed for 4 h.
After recooling to 0 °C, the reaction mixture was quenched
sequentially with water (2.0 mL), 15% NaOH (2 mL), and
water (6.0 mL). The resulting thick suspension was diluted
with EtOH (30 mL) and filtered through a thin pad of Celite.
Evaporation in vacuo gave a crude product, which was purified
by flash chromatography (EtOH/H2O/NH4OH, 95/3/2) to give
the title compound 20 (1.50 g, 99%) as a white solid: Rf )
0.50 (EtOH/Et3N, 10/1); mp 155.0-156.0 °C (MeOH/EtOAc);
1H NMR (250 MHz, d4-MeOH) δ 2.73 (t, J ) 6.5 Hz, 2H), 2.89
(s, 3H), 3.76 (t, J ) 6.5 Hz, 2H), 6.55 (d, J ) 6.0 Hz, 1H), 7.91
(s, 1H), and 8.03 (d, J ) 6.0 Hz, 1H); 13C NMR (63 MHz, d4-
MeOH) δ 29.52, 32.86, 61.75, 105.3, 120.0, 148.7, 149.1, and
155.2; IR (CHCl3) vmax 2976 and 1600 cm-1; MS (EI+) m/z (rel
intensity) 152 (45%, M+), 121 (100), 92 (15), and 65 (15); HRMS
calcd for C8H12N2O (M+) 152.0950, found 152.0946. Anal. Calcd
for C8H12N2O: C, 63.13; H, 7.95; N, 18.41. Found: C, 63.04;
H, 7.92; N, 18.23.
Th e Gen er a l P r oced u r e for th e Su zu k i Cr oss-Cou -
p lin g In volvin g Ster ica lly Un h in d er ed Ar ylbor on ic Ac-
id s. 1-Meth yl-7-n a p h th yl-2-p yr r olin o[3,2-c]p yr id in e (31).
To a solution of aryl bromide 18 (213 mg, 1.00 mmol) in toluene
(2 mL) and ethanol (0.5 mL) was added 2 M Na2CO3 (2 mL)
followed by Pd(PPh3)4 (35 mg, 0.030 mmol) and 1-naphthale-
neboronic acid (206 mg, 1.2 mmol). The mixture was refluxed
for 6 h (TLC), cooled to room temperature, and partitioned
between CH2Cl2 (10 mL) and water (10 mL). The phases were
separated, and the extraction was completed with additional
portions of CH2Cl2. The combined organic extracts were dried
(MgSO4) and evaporated in vacuo. The residue was purified
by flash chromatography (EtOAc f EtOAc/Et3N, 98/2) to give
the title compound 31 (249 mg, 96%) as a white crystalline
solid: Rf ) 0.30 (EtOAc/Et3N, 99/5); 1H NMR (250 MHz,
CDCl3) δ 2.05 (s, 3H), 3.08 (t, J ) 8.5 Hz, 2H), 3.31-3.54 (m,
2H), 7.41-7.63 (m, 5H), 7.85-7.90 (m, 2H), 8.01 (s, 1H), and
8.13 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 25.79, 35.77, 55.77,
C
16H18N2O: C, 75.56; H, 7.13; N, 11.01. Found: C, 75.45; H,
7.11; N, 10.86.
1-(1,2-Dim eth yl(2-pyr r olin o[2,3-d]pyr idin -7-yl))-3-m eth -
oxyben zen e (23). Following the general procedure, aryl
bromide 19 (241 mg, 1.06 mmol) was reacted with 3-methoxy-
benzeneboronic acid (193 mg, 1.27 mmol) to give, after
purification by flash chromatography (EtOAc f EtOAc/Et3N,
98/2), the title compound 23 (242 mg, 90%) as a clear oil: Rf
) 0.35 (EtOAc/Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 1.28
(d, J ) 6.5 Hz, 3H), 2.40 (s, 3H), 2.59 (dd, J ) 9.0, 16.0 Hz,
1H), 3.20 (dd, J ) 9.0, 16.0 Hz, 1H), 3.55 (ddq, J ) 6.5, 9.0,
9.0 Hz, 1H), 3.80 (s, 3H), 6.83-6.93 (m, 3H), 7.27 (ddd, J )
1.0, 7.5, 7.5 Hz, 1H), and 7.99 (s, 2H); 13C NMR (63 MHz,
CDCl3) δ 19.68, 34.31, 35.47, 55.36, 63.01, 112.7, 115.4, 118.3,
122.4, 125.0, 129.1, 139.0, 142.8, 150.9, 155.3, and 159.4; IR
(CHCl3) vmax 2969, 1598, 1486, and 1410 cm-1; MS (EI+) m/z
(rel intensity) 254 (60%, M+), 239 (100), and 195 (35); HRMS
calcd for C16H18N2O (M+) 254.1419, found 254.1430.
1,2-Dim eth yl-7-n aph th yl-2-pyr r olin o[3,2-c]pyr idin e (24).
Following the general procedure, aryl bromide 19 (227 mg, 1.00
mmol) was reacted with 1-naphthaleneboronic acid (206 mg,
1.20 mmol) to give, after purification by flash chromatography
(EtOAc f EtOAc/Et3N, 98/2), the title compound 24 (225 mg,
82%) as a white solid: Rf ) 0.30 (EtOAc/Et3N, 99/5); 1H NMR
(250 MHz, CDCl3) δ 1.21-1.25 (m, 3H), 1.99 [s, 3H (major
atropisomer)], 2.06 [s, 3H (minor atropisomer)], 2.61-2.73 (m,
1H), 3.26 (dd, J ) 9.0, 16.0 Hz, 1H), 3.50-3.69 (m, 1H), and
7.38-8.10 (m, 9H); 13C NMR (63 MHz, CDCl3) δ 19.14, 19.61,
33.25, 33.52, 34.21, 62.02, 62.35, 115.5, 116.0, 124.2, 124.7,
125.1, 125.3, 126.0, 126.2, 126.3, 126.5, 128.0, 128.1, 128.2,
128.3, 132.8, 133.1, 133.4, 133.5, 135.0, 143.0, 143.1, 151.4,
151.5, 155.6, and 155.7; IR (CHCl3) vmax 2970, 1597, 1485, and
1412 cm-1; MS (EI+) m/z (rel intensity) 274 (35%, M+) and 259
(100); HRMS calcd for C19H18N2 (M+) 274.1470, found 274.1484.
1-Meth yl-7-p h en yl-2-p yr r olin o[3,2-c]p yr id in e (25). Fol-
lowing the general procedure, aryl bromide 18 (213 mg, 1.00
mmol) was reacted with phenylboronic acid (146 mg, 1.20
mmol) to give, after purification by flash chromatography

9440 J . Org. Chem., Vol. 64, No. 26, 1999
Spivey et al.
(EtOAc f EtOAc/Et3N, 98/2), the title compound 25 (197 mg,
94%) as a pale yellow oil: Rf ) 0.30 (EtOAc/Et3N, 99/5); H
1-naphthaleneboronic acid44,45 (121 mg, 0.60 mmol) to give,
after purification by flash chromatography (EtOAc f EtOAc/
Et3N, 98/2), the title compound 33 (135 mg, 93%) as a white
crystalline solid: Rf ) 0.35 (EtOAc/Et3N, 99/5); 1H NMR (250
MHz, CDCl3) δ 2.07 (s, 3H), 3.03 (t, J ) 8.5 Hz, 2H), 3.26-
3.51 (m, 2H), 3.89 (s, 3H), 7.10-7.14 (m, 2H), 7.22-7.75 (m,
4H), 7.98 (s, 1H), and 8.09 (s, 1H); 13C NMR (63 MHz, CDCl3)
δ 25.75, 35.71, 55.33, 55.72, 106.0, 115.5, 120.7, 124.0, 125.7,
126.2, 126.6, 127.2, 128.9, 134.5, 136.8, 143.2, 151.1, 155.8,
1
NMR (250 MHz, CDCl3) δ 2.40 (s, 3H), 3.00 (t, J ) 8.5 Hz,
2H), 3.43 (t, J ) 8.5 Hz, 2H), 7.28-7.40 (m, 5H), 7.98 (s, 1H),
and 8.03 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 25.72, 37.42,
56.12, 118.7, 126.0, 127.2, 128.1, 129.6, 137.3, 142.8, 150.7,
and 155.4; IR (CHCl3) vmax 2957, 1597, 1495, and 1412 cm-1
;
MS (EI+) m/z (rel intensity) 210 (90%, M+) and 209 (100);
HRMS calcd for C14H14N2 (M+) 210.1157, found 210.1155.
2-Met h oxy -1-(1-m et h yl(2-p yr r olin o[2,3-d ]p yr id in -7-
yl))ben zen e (26). Following the general procedure, aryl
bromide 18 (213 mg, 1.00 mmol) was reacted with 2-methoxy-
benzeneboronic acid (182 mg, 1.20 mmol) to give, after
purification by flash chromatography (EtOAc f EtOAc/Et3N,
98/2), the title compound 26 (230 mg, 96%) as a white solid:
and 156.7; IR (CHCl3) vmax 2959, 1599, 1412, and 1225 cm-1
;
MS (EI+) m/z (rel intensity) 290 (100%, M+) and 257 (25);
HRMS calcd for C19H18N2O (M+) 290.1419, found 290.1407.
4-Met h oxy -1-(1-m et h yl(2-p yr r olin o[2,3-d ]p yr id in -7-
yl))n a p h th a len e (34). Following the general procedure, aryl
bromide 18 (107 mg, 0.50 mmol) was reacted with 4-methoxy-
1-naphthaleneboronic acid46 (121 mg, 0.60 mmol) to give, after
purification by flash chromatography (EtOAc f EtOAc/Et3N,
98/2), the title compound 34 (135 mg, 93%) as a white
crystalline solid: Rf ) 0.20 (EtOAc/Et3N, 99/5); 1H NMR (250
MHz, CDCl3) δ 2.06 (s, 3H), 3.03 (t, J ) 8.5 Hz, 2H), 3.26-
3.50 (m, 2H), 4.00 (s, 3H), 6.82 (d, J ) 7.5 Hz, 1H), 7.31 (d, J
) 7.5 Hz, 1H), 7.40-7.55 (m, 3H), 7.99 (s, 1H), 8.10 (s, 1H),
and 8.28-8.32 (m, 1H); 13C NMR (63 MHz, CDCl3) δ 25.76,
35.72, 55.54, 55.76, 103.2, 116.2, 122.2, 125.2, 125.3, 125.6,
126.1, 126.8, 127.0, 128.0, 134.0, 143.0, 151.7, 155.3, and 156.2;
IR (CHCl3) vmax 1597, 1465, 1413, and 1293 cm-1; MS (EI+)
m/z (rel intensity) 290 (100%, M+); HRMS calcd for C19H18N2O
(M+) 290.1419, found 290.1425.
1
Rf ) 0.35 (EtOAc/Et3N, 99/5); H NMR (250 MHz, CDCl3) δ
2.37 (s, 3H), 2.99 (t, J ) 8.5 Hz, 2H), 3.43 (br s, 2H), 3.75 (s,
3H), 6.90 (d, J ) 8.0 Hz, 1H), 6.96 (t, J ) 7.5 Hz, 1H), 7.19
(dd, J ) 1.5, 7.5 Hz, 1H), 7.29 (dt, J ) 1.5, 8.0 Hz, 1H), 7.90
(s, 1H), and 8.00 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 25.64,
35.44, 55.46, 55.77, 110.4, 114.4, 120.3, 125.5, 126.4, 129.1,
131.8, 142.8, 151.1, 155.5, and 157.6; IR (CHCl3) vmax 3028,
1598, 1494, and 1413 cm-1; MS (EI+) m/z (rel intensity) 240
(100%, M+), 224 (15), and 209 (20); HRMS calcd for C15H16N2O
(M+) 240.1263, found 240.1258.
1-Met h yl-7-(2-m et h ylp h en yl)-2-p yr r olin o[3,2-c]p yr i-
d in e (27). Following the general procedure, aryl bromide 18
(213 mg, 1.00 mmol) was reacted with 2-methylbenzeneboronic
acid (163 mg, 1.2 mmol) to give, after purification by flash
chromatography (EtOAc f EtOAc/Et3N, 98/2), the title com-
pound 27 (219 mg, 98%) as a white solid: Rf ) 0.35 (EtOAc/
Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 2.09 (s, 3H), 2.23 (s,
3H), 2.97 (t, J ) 8.5 Hz, 2H), 3.22-3.51 (m, 2H), 7.10-7.21
(m, 4H), 7.86 (s, 1H), and 8.01 (s, 1H); 13C NMR (63 MHz,
CDCl3) δ 20.07, 25.72, 35.78, 55.84, 117.8, 125.5, 127.8, 129.5,
130.6, 136.8, 137.6 (2C?), 142.9, 150.5, and 155.1; IR (CHCl3)
vmax 2955, 1597, 1494, 1467, 1413, and 1318 cm-1; MS (EI+)
m/z (rel intensity) 224 (100%, M+); HRMS calcd for C15H16N2
(M+) 224.1313, found 224.1308.
Dim eth yl(3-p h en yl(4-p yr id yl))a m in e (37). Following the
general procedure, aryl bromide 36 (1.21 g, 6.00 mmol) was
reacted with phenylboronic acid (878 mg, 7.20 mmol) to give,
after purification by flash chromatography (EtOAc f EtOAc/
Et3N, 98/2), the title compound 37 (1.09 g, 92%) as a clear oil:
1
Rf ) 0.30 (EtOAc/Et3N, 99/5); H NMR (250 MHz, CDCl3) δ
2.55 (s, 6H), 6.65 (d, J ) 6.0 Hz, 1H), 7.19-7.38 (m, 5H), 8.13
(s, 1H), and 8.21 (d, J ) 6.0 Hz, 1H); 13C NMR (63 MHz, CDCl3)
δ 41.95, 110.5, 126.1, 127.0, 128.5, 128.6, 139.4, 149.1, 151.9,
and 155.8; IR (CHCl3) vmax 2954, 1588, 1506, and 1402 cm-1
;
MS (EI+) m/z (rel intensity) 198 (100%, M+); HRMS calcd for
C
13H14N2 (M+) 198.1157, found 198.1158.
7-(2-E t h ylp h e n yl)-1-m e t h yl-2-p yr r olin o[3,2-c]p yr i-
d in e (28). Following the general procedure, aryl bromide 18
(213 mg, 1.00 mmol) was reacted with 2-ethylbenzeneboronic
acid43 (180 mg, 1.20 mmol) to give, after purification by flash
chromatography (EtOAc f EtOAc/Et3N, 98/2), the title com-
pound 28 (227 mg, 95%) as a white solid: Rf ) 0.35 (EtOAc/
Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 1.03 (t, J ) 7.5 Hz,
3H), 2.24 (s, 3H), 2.37-2.53 (m, 2H), 2.98 (t, J ) 8.5 Hz, 2H),
3.25-3.51 (m, 2H), 7.15-7.30 (m, 4H), 7.88 (s, 1H), and 8.02
(s, 1H); 13C NMR (63 MHz, CDCl3) δ 14.72, 25.69, 26.31, 35.91,
55.76, 117.4, 125.4, 125.5, 127.8, 128.0, 130.9, 136.1, 142.9,
143.5, 150.7, and 155.1; IR (CHCl3) vmax 2968, 1597, 1496,
1466, 1412, and 1207 cm-1; MS (EI+) m/z (rel intensity) 238
(100%, M+), 224 (40), 207 (30), and 194 (30); HRMS calcd for
Dim eth yl(3-n a p h th yl(4-p yr id yl))a m in e (38). Following
the general procedure, aryl bromide 36 (1.01 g, 5.00 mmol)
was reacted with 1-naphthaleneboronic acid (1.03 g, 6.00
mmol) to give, after purification by flash chromatography
(EtOAc f EtOAc/Et3N, 98/2), the title compound 38 (1.24 g,
∼100%) as a white crystalline solid: Rf ) 0.35 (EtOAc/Et3N,
1
99/5); H NMR (250 MHz, CDCl3) δ 2.46 (s, 6H), 6.71 (d, J )
6.0 Hz, 1H), 7.33-7.84 (m, 7H), 8.19 (s, 1H), and 8.33 (d, J )
6.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 41.26, 109.6, 123.11,
125.5, 125.9, 126.1, 127.3, 127.8, 128.2, 131.9, 133.5, 137.5,
149.2, 152.7, and 155.6; IR (CHCl3) vmax 1586 and 1506 cm-1
;
MS (EI+) m/z (rel intensity) 248 (100%, M+) and 233 (75);
HRMS calcd for C17H16N2 (M+) 248.1313, found 248.1305. Anal.
Calcd for C17H16N2: C, 82.22; H, 6.49; N, 11.28. Found: C,
81.99; H, 6.47; N, 11.09.
C
16H18N2 (M+) 238.1470, found 238.1480.
3-Met h oxy -1-(1-m et h yl(2-p yr r olin o[2,3-d ]p yr id in -7-
3-P h en yl-4-p yr r olid in ylp yr id in e (42). Following the gen-
eral procedure, aryl bromide 41 (114 mg, 0.50 mmol) was
reacted with phenylboronic acid (73 mg, 0.60 mmol) to give,
after purification by flash chromatography (EtOAc f EtOAc/
Et3N, 98/2), the title compound 42 (85 mg, 76%) as a clear oil:
yl))ben zen e (29). Following the general procedure, aryl
bromide 18 (213 mg, 1.00 mmol) was reacted with 3-methoxy-
benzeneboronic acid (182 mg, 1.20 mmol) to give, after
purification by flash chromatography (EtOAc f EtOAc/Et3N,
98/2), the title compound 29 (221 mg, 92%) as a clear oil: Rf
) 0.30 (EtOAc/Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 2.45
(s, 3H), 3.01 (t, J ) 8.5 Hz, 2H), 3.44 (t, J ) 8.5 Hz, 2H), 3.81
(s, 3H), 6.84-6.93 (m, 3H), 7.26-7.32 (m, 1H), 7.99 (s, 1H),
and 8.03 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 25.41, 37.01,
55.24, 56.02, 113.1, 115.2, 122.1, 129.2, 137.9, 140.6, 148.8,
155.8, and 159.3; IR (CHCl3) vmax 2959, 1597, 1488, 1466, 1410,
and 1286 cm-1; MS (EI+) m/z (rel intensity) 240 (100%, M+)
and 195 (25); HRMS calcd for C15H16N2O (M+) 240.1263, found
240.1258.
1
Rf ) 0.35 (EtOAc/Et3N, 99/5); H NMR (250 MHz, CDCl3) δ
1.73-1.79 (m, 4H), 2.94-2.99 (m, 4H), 6.55 (d, J ) 6.0 Hz,
1H), 7.26-7.38 (m, 5H), 8.10 (s, 1H), and 8.19 (d, J ) 6.0 Hz,
1H); 13C NMR (63 MHz, CDCl3) δ 25.60, 50.49, 108.2, 123.2,
126.8, 127.8, 129.8, 140.1, 148.4, 151.4, and 152.0; IR (CHCl3)
vmax 2952, 1587, 1501, 1481, 1414, and 1369 cm-1; MS (EI+)
m/z (rel intensity) 290 (100%, M+) and 195 (20); HRMS calcd
for C15H16N2 (M+) 224.1313, found 224.1302.
(44) Prepared from 1-bromo-3-methoxynaphthalene (ref 45) accord-
ing to the procedure described for the preparation of arylboronic acid
3-Meth oxy-1-(1-m eth yl(2-p yr r olin o[2,3-d ]p yr id in -7-yl-
))n a p h th a len e (33). Following the general procedure, aryl
bromide 18 (107 mg, 0.50 mmol) was reacted with 3-methoxy-
51.
(45) Newman, M. S.; Sankaran, V.; Olson, D. R. J . Am. Chem. Soc.
1976, 98, 3237-3242.
(46) Snyder, H. R.; Wyman, F. W. J . Am. Chem. Soc. 1948, 70, 234-
(43) Dale, W. J .; Rush, J . E. J . Org. Chem. 1962, 27, 2598-2603.
237.

Biaryl Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 64, No. 26, 1999 9441
3-Na p h th yl-4-p yr r olid in ylp yr id in e (43). Following the
general procedure, aryl bromide 41 (41 mg, 0.18 mmol) was
reacted with 1-naphthaleneboronic acid (37 mg, 0.22 mmol)
to give, after purification by flash chromatography (EtOAc f
EtOAc/Et3N, 98/2), the title compound 43 (40 mg, 82%) as a
1597, 1472, 1250, and 1114 cm-1; MS (EI+) m/z (rel intensity)
270 (100%, M+) 237 (10), and 223 (15); HRMS calcd for
C16H18N2O2 (M+) 270.1368, found 270.1369.
2-Met h oxy -1-(1-m et h yl(2-p yr r olin o[2,3-d ]p yr id in -7-
yl))n a p h th a len e (32). Following the general procedure, aryl
bromide 18 (213 mg, 1.00 mmol) was reacted with 2-methoxy-
1-naphthaleneboronic acid48 (404 mg, 2.00 mmol) to give, after
purification by flash chromatography (EtOAc f EtOAc/Et3N,
98/2), the title compound 32 (200 mg, 69%) as a white solid:
1
clear oil: Rf ) 0.35 (EtOAc/Et3N, 99/5); H NMR (250 MHz,
CDCl3) δ 1.56-1.64 (m, 4H), 2.60-2.73 (m, 2H), 2.92-3.01 (m,
2H), 6.59 (d, J ) 6.0 Hz, 1H), 7.38-7.51 (m, 4H), 7.54 (d, J )
8.5 Hz, 1H); 7.83-7.89 (m, 2H), 8.10 (s, 1H), and 8.27 (d, J )
6.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 25.41, 49.42, 108.0,
120.5, 125.0, 125.9, 126.2, 126.4, 127.8, 128.2 (2C?), 133.1,
133.2, 137.7, 148.7, 151.7, and 152.4; IR (CHCl3) vmax 2976,
1587, and 1500 cm-1; MS (EI+) m/z (rel intensity) 274 (100%,
M+); HRMS calcd for C19H18N2 (M+) 274.1470, found 274.1459.
1
Rf ) 0.30 (EtOAc/Et3N, 99/5); H NMR (250 MHz, CDCl3) δ
2.12 (s, 3H), 3.05 (t, J ) 8.5 Hz, 2H), 3.41 (t, J ) 8.5 Hz, 2H),
3.85 (s, 3H), 7.29-7.46 (m, 4H), 7.76-7.90 (m, 2H), 7.90 (s,
1H), and 8.10 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 25.72, 34.76,
55.65, 56.58, 111.3, 113.3, 119.8, 123.7, 125.4, 125.8, 126.8,
127.9, 128.7, 129.8, 134.5, 142.9, 151.9, 155.0, and 156.4; IR
(CHCl3) vmax 2940, 1597, 1508, 1467, 1413, 1312, and 1261
cm-1; MS (EI+) m/z (rel intensity) 290 (100%, M+) and 257 (20);
HRMS calcd for C19H18N2O (M+) 290.1419, found 290.1410.
8-Met h oxy -1-(1-m et h yl(2-p yr r olin o[2,3-d ]p yr id in -7-
yl))n a p h th a len e (35). Following the general procedure, aryl
bromide 18 (107 mg, 0.50 mmol) was reacted with 8-methoxy-
1-naphthaleneboronic acid49 (202 mg, 1.00 mmol) to give, after
purification by flash chromatography (EtOAc f EtOAc/Et3N,
98/2), the title compound 35 (131 mg, 90%) as a white solid:
3-Br om o-4-p yr r olid in ylp yr id in e (41). To a solution of
4-(1-pyrrolidino)pyridine 40 (2.20 g, 14.9 mmol) in CH2Cl2 (20
mL) were added satd K2CO3 solution (20 mL) and a drop
tetrabutylammonium hydroxide (40% w/w in water). During
vigorous stirring, bromine (1.15 mL, 22.3 mmol) was added,
and after 3 h (TLC) the reaction mixture was diluted with
water (50 mL). The phases were separated, and the extraction
was completed with additional portions of CH2Cl2. The com-
bined extracts were dried (MgSO4) and evaporated in vacuo
to give a brown oil. Purification by flash chromatography
(EtOAc) furnished the title compound 41 (1.60 g, 47%) as a
low-melting white solid: Rf ) 0.30 (EtOAc); 1H NMR (250
MHz, CDCl3) δ 1.78-1.82 (m, 4H), 3.40-3.45 (m, 4H), 6.30
(d, J ) 6.0 Hz, 1H), 7.92 (d, J ) 6.0 Hz, 1H), and 8.22 (s, 1H);
13C NMR (63 MHz, CDCl3) δ 25.60, 50.74, 104.8, 110.4, 147.8,
151.3, and 153.6; IR (CHCl3) vmax 2977, 1584, 1501, 1482, and
1414 cm-1; MS (EI+) m/z (rel intensity) 227 (100%, M+) and
147 (25); HRMS calcd for C9H11BrN2 (M+) 226.0106, found
226.0098.
Th e Gen er a l P r oced u r e for th e Su zu k i Cr oss-Cou -
p lin g In volvin g Ster ica lly Hin d er ed Ar ylbor on ic Acid s.
1-(1-Met h yl(2-p yr r olin o[2,3-d ]p yr id in -7-yl))-2-(p h en yl-
m eth oxy)n a p h th a len e (52). To a solution of aryl bromide
18 (1.49 g, 7.00 mmol) in toluene (28 mL) and ethanol (5 mL)
was added 2 M Na2CO3 (28 mL) followed by Pd(PPh3)4 (243
mg, 0.210 mmol) and arylboronic acid 51 (2.53 g, 9.1 mmol).
The mixture was refluxed for 24 h while additional portions
of arylboronic acid 51 [(680 mg, 2.44 mmol) after both 90 min
and 4.5 h] and Pd(PPh3)4 [(81 mg, 0.070 mmol) after both 90
min and 4.5 h] were added. The phases were separated, and
the extraction was completed with additional portions of CH2-
Cl2. The combined organic extracts were dried (MgSO4) and
evaporated in vacuo. The residue was purified by flash
chromatography (EtOAc f EtOAc/Et3N, 98/2) to give the title
compound 52 (2.09 g, 82%) as a white crystalline solid: Rf )
0.35 (EtOAc/Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 2.14
(s, 3H), 3.09 (t, J ) 8.5 Hz, 2H), 3.43 (t, J ) 8.5 Hz, 2H), 5.18
(s, 2H), 7.23-7.56 (m, 9H), 7.80-7.88 (m, 2H), 7.96 (s, 1H),
and 8.15 (s, 1H); 13C NMR (63 MHz, CDCl3) d 25.77, 34.87,
55.62, 71.15, 111.4, 115.2, 121.0, 124.0, 125.6, 125.7, 126.8,
127.0, 127.7, 128.0, 128.4, 129.0, 129.6, 134.5, 137.3, 143.0,
151.9, 154.1, and 156.5; IR (CHCl3) vmax 2958, 1597, and 1226
cm-1; MS (EI+) m/z (rel intensity) 366 (90%, M+), 349 (100),
275 (90), 257 (40), and 91 (30); HRMS calcd for C25H22N2O (M+)
366.1732, found 366.1726.
1
Rf ) 0.20 (EtOAc/Et3N, 99/5); H NMR (250 MHz, CDCl3) δ
2.07 (s, 3H), 2.94 (t, J ) 8.5 Hz, 2H), 3.30 (t, J ) 8.5 Hz, 2H),
3.44 (s, 3H), 6.69 (d, J ) 7.5 Hz, 1H), 7.16 (dd, J ) 1.0, 7.0
Hz, 1H), 7.30 (d, J ) 7.5 Hz, 1H), 7.35-7.39 (m, 2H), 7.70 (dd,
J ) 1.0, 8.0 Hz, 1H), 7.79 (s, 1H), and 7.97 (s, 1H); 13C NMR
(63 MHz, CDCl3) δ 25.88, 35.78, 55.53, 55.80, 106.6, 121.1,
121.7, 124.5, 125.4, 125.6, 126.2, 128.1, 129.9, 133.2, 135.4,
142.1, 149.3, 155.0, and 156.9; IR (CHCl3) vmax 2958, 1594,
1498, 1464, 1413, and 1257 cm-1; MS (EI+) m/z (rel intensity)
290 (100%, M+), 259 (30), and 244 (85); HRMS calcd for
C
19H18N2O (M+) 290.1419, found 290.1410.
[3-(8-Meth oxyn aph th yl)(4-pyr idyl)]dim eth ylam in e (39).
Following the general procedure, aryl bromide 36 (101 mg, 0.50
mmol) was reacted with 8-methoxy-1-naphthaleneboronic
acid49 (202 mg, 1.00 mmol) to give, after purification by flash
chromatography (EtOAc f EtOAc/Et3N, 98/2), the title com-
pound 39 (87 mg, 63%) as a white solid: Rf ) 0.35 (EtOAc/
Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 2.56 (s, 6H), 3.51 (s,
3H), 6.66 (d, J ) 6.0 Hz, 1H), 6.76 (dd, J ) 1.0, 7.0 Hz, 1H),
7.25 (dd, J ) 1.0, 7.0 Hz, 1H), 7.38 (dd, J ) 8.0, 8.0 Hz, 1H),
7.44 (dd, J ) 7.0, 7.0 Hz, 1H), 7.46 (dd, J ) 1.0, 8.0 Hz, 1H),
7.78 (dd, J ) 1.0, 8.0 Hz, 1H), 8.01 (s, 1H), and 8.25 (d, J )
6.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 41.57, 55.22, 106.0,
109.2, 121.1, 124.4, 125.6, 126.1, 127.8, 128.8, 129.2, 135.5,
135.8, 147.8, 150.6, 154.7, and 156.7; IR (CHCl3) vmax 1586,
1507, 1463, and 1253 cm-1; MS (EI+) m/z (rel intensity) 278
(100%, M+), 263 (30), 247 (55), 232 (80), and 219 (40); HRMS
calcd for C18H18N2O (M+) 278.1419, found 278.1425.
8-Met h oxy-1-(4-p yr r olid in yl(3-p yr id yl))n a p h t h a len e
(44). Following the general procedure, aryl bromide 41 (114
mg, 0.50 mmol) was reacted with 8-methoxy-1-naphthalenebo-
ronic acid49 (202 mg, 1.00 mmol) to give, after purification by
flash chromatography (EtOAc f EtOAc/Et3N, 98/2), the title
compound 44 (85 mg, 56%) as a white solid: Rf ) 0.20 (EtOAc/
Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 1.61-1.66 (m, 4H),
2.83-3.00 (m, 4H), 3.50 (s, 3H), 6.47 (d, J ) 6.0 Hz, 1H), 6.77
(d, J ) 7.5 Hz, 1H), 7.25 (∼d, J ) 7.0 Hz, 1H), 7.37 (dd, J )
8.0, 8.0 Hz, 1H), 7.40 (dd, J ) 7.0, 7.5 Hz, 1H), 7.46 (d, J )
8.0 Hz, 1H), 7.78 (d, J ) 8.0 Hz, 1H), 7.91 (s, 1H), and 8.16 (d,
J ) 6.0 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 25.58, 49.36,
55.47, 106.5, 107.2, 121.2, 125.1, 125.9, 126.0, 126.2, 127.8,
130.1, 135.3, 136.1, 147.7, 150.3, 150.8, and 157.0; IR (CHCl3)
vmax 2974, 1588, 1505, 1483, 1463, and 1253 cm-1; MS (EI+)
m/z (rel intensity) 304 (90%, M+), 273 (100), 219 (20), and 83
(90); HRMS calcd for C20H20N2O (M+) 304.1576, found 304.1575.
1-Br om o-2-(p h en ylm eth oxy)n a p h th a len e (50). To a sus-
pension of 1-bromo-2-naphthol 49 (15.0 g, 67.3 mmol) and K2-
1,3-Dim eth oxy-2-(1-m eth yl(2-p yr r olin o[2,3-d ]p yr id in -
7-yl))ben zen e (30). Following the general procedure, aryl
bromide 18 (107 mg, 0.50 mmol) was reacted with 2,6-
dimethoxy-1-benzeneboronic acid47 (182 mg, 1.00 mmol) to
give, after purification by flash chromatography (EtOAc f
EtOAc/Et3N, 98/2), the title compound 30 (99 mg, 73%) as a
white solid: Rf ) 0.20 (EtOAc/Et3N, 99/5); 1H NMR (250 MHz,
CDCl3) δ 2.36 (s, 3H), 2.97 (t, J ) 8.5 Hz, 2H), 3.40 (t, J ) 8.5
Hz, 2H), 3.70 (s, 6H), 6.57 (d, J ) 8.5 Hz, 2H), 7.27 (t, J ) 8.5
Hz, 1H), 7.80 (s, 1H), and 7.97 (s, 1H); 13C NMR (63 MHz,
CDCl3) δ 25.61, 34.63, 55.62, 55.84, 103.6, 109.4, 114.5, 125.6,
129.3, 142.5, 151.7, 155.9, and 158.7; IR (CHCl3) vmax 2939,
(48) Lawesson, S.-O. Acta Chem. Scand. 1957, 11, 1075-1076.
(49) Ford, A.; Sinn, E.; Woodward, S. J . Chem. Soc., Perkin Trans.
1 1997, 927-934.
(47) Kuivila, H. G.; Nahabedian, K. V. J . Am. Chem. Soc. 1961, 83,
2159-2163.

9442 J . Org. Chem., Vol. 64, No. 26, 1999
Spivey et al.
CO3 (18.6 g, 135 mmol) in DMF (100 mL) was added benzyl
bromide (9.6 mL, 81 mmol), and the mixture was stirred at
60 °C for 5 h. After cooling to room temperature, the solvent
was evaporated in vacuo and the residue, dissolved in a small
amount of CH2Cl2, passed through a thin pad of flash silica.
Fractions containing the product were evaporated in vacuo to
give an off-white solid. Crystallization from CH2Cl2/petroleum
ether gave the title compound 50 as a white crystalline solid
(16.0 g, 76%). The mother liquor was concentrated and purified
by flash chromatography (petroleum ether/CH2Cl2, 2/1) to give
an additional amount of the product 50 (3.7 g, 17%; total
yield: 93%). Benzyl ether 50: Rf ) 0.50 (petroleum ether/CH2-
(()-1-Meth yl-7-(2-m eth yln a p h th yl)-2-p yr r olin o[3,2-c]-
p yr id in e (55). Th e fir st m eth od : To a vial charged with
triflate 54 (57 mg, 0.14 mmol), LiCl (18 mg, 0.42 mmol), PPh3
(22 mg, 0.084 mmol), Pd(PPh3)2Cl2 (12 mg, 0.017 mmol), and
a crystal of 2,6-di-tert-butyl-4-methylphenol was added DMF
(1 mL) followed by tetramethyltin (25 µL, 0.18 mmol). The vial
was tightly sealed and kept at 120 °C for 20 h. After recooling
to room temperature, the mixture was diluted with EtOAc and
washed with 10% NH4OH. The organic layer was dried
(MgSO4) and evaporated in vacuo. The residue was purified
by flash chromatography (EtOAc f EtOAc/Et3N, 98/2) to give
the title compound 55 as a white solid (28 mg, 73%).
Th e secon d m eth od : To a solution of triflate 54 (1.08 g,
2.65 mmol) in Et2O (17 mL) was added NiBr2(PPh3)2 (59 mg,
0.080 mmol) followed by MeMgBr (2.2 mL, 3.0 M, 6.6 mmol)
in Et2O. The mixture was refluxed for 24 h, quenched with
water (30 mL), and diluted with CH2Cl2 (30 mL). The phases
were separated, and the extraction was completed with ad-
ditional portions of 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 title compound 55 (618 mg, 85%) as a white solid: Rf )
0.30 (EtOAc/Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 2.04
(s, 3H), 2.27 (s, 3H), 3.07 (t, J ) 9.0 Hz, 2H), 3.33-3.51 (m,
2H), 7.33-3.50 (m, 4H), 7.76-7.84 (m, 2H), 7.87 (s, 1H), and
8.13 (s, 1H); 13C NMR (63 MHz, CDCl3) δ 20.95, 25.77, 34.79,
55.65, 114.5, 125.0, 125.8 (2C?), 126.2, 127.9 (2C?), 128.3,
131.8, 132.5, 133.8, 135.3, 143.1, 151.2, and 155.9; IR (CHCl3)
vmax 2955, 1598, 1497, 1468, 1413, and 1311 cm-1; MS (EI+)
m/z (rel intensity) 274 (100%, M+); HRMS calcd for C19H18N2
(M+) 274.1470, found 274.1463.
1
Cl2, 2/1); mp 104-106 °C (CH2Cl2/petroleum ether); H NMR
(250 MHz, CDCl3) δ 5.35 (s, 2H), 7.32 (d, J ) 9.0 Hz, 1H),
7.38-7.50 (m, 4H), 7.57-7.66 (m, 2H), 7.79-7.86 (m, 3H), and
8.31 (d, J ) 8.5 Hz, 1H); 13C NMR (63 MHz, CDCl3) δ 71.81,
110.0, 115.6, 124.6, 126.3, 127.2, 127.8, 128.1 (2C), 128.7,
128.9, 130.1, 133.2, 136.7, and 153.0; IR (CHCl3) vmax 1626,
1596, 1502, 1350, and 1268 cm-1; MS (EI+) m/z (rel intensity)
314/312 (25%, M+) and 91 (100); HRMS calcd for C17H13BrO
(M+) 312.0150, found 312.0150. Anal. Calcd for C17H13BrO: C,
65.19; H, 4.18; Br, 25.51. Found: C, 64.94; H, 4.12; Br, 25.71.
2-(P h en ylm et h oxy)-1-n a p h t h a len eb or on ic Acid (51).
To a suspension of aryl bromide 50 (6.26 g, 20.0 mmol) in Et2O
(75 mL) at -78 °C was added n-BuLi (8.0 mL, 2.5 M, 20 mmol)
in hexanes, and the mixture was stirred at 0 °C for 1 h. After
recooling to -78 °C, the mixture was treated with trimethyl
borate (2.5 mL, 22 mmol) and allowed to warm to room-
temperature overnight. The resulting mixture was quenched
with 1 M HCl (50 mL) and stirred at room temperature for 45
min. The phases were separated, and the extraction was
completed with CH2Cl2. The combined organic extracts were
dried (MgSO4) and evaporated in vacuo to give the title
compound 51 as a white powder (4.62 g, 83%), which was used
in the next step without further purification. For analytical
purposes, a small amount of the product was recrystallized
from MeOH/H2O: mp 133.0-135.0 °C (MeOH/H2O); 1H NMR
(250 MHz, d4-MeOH) δ 5.20 (s, 2H), 7.28-7.60 (m, 9H), and
7.56-7.88 (m, 2H); 13C NMR (63 MHz, d4-MeOH) δ 71.95,
115.4, 124.8, 127.7 (2C), 128.4, 128.9, 129.5, 129.6, 130.7 (2C?),
131.8, 137.2, 139.0, and 159.7;50 IR (CHCl3) vmax 3609, 3490,
1592, 1509, 1386, and 1332 cm-1; MS (EI+) m/z (rel intensity)
(()-1-Meth yl-7-(2-p h en yln a p h th yl)-2-p yr r olin o[3,2-c]-
p yr id in e (56). To a solution of triflate 54 (652 mg, 1.60 mmol)
in Et2O (10 mL) was added PdCl2(dppp) (47 mg, 0.08 mmol)
followed by PhMgBr (1.1 mL, 3.0 M, 3.3 mmol) in Et2O. The
mixture was refluxed for 24 h, 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 title compound 56 (457 mg, 85%) as a white solid: Rf )
0.30 (EtOAc/Et3N, 99/5); 1H NMR (250 MHz, CDCl3) δ 2.16
(s, 3H), 2.82-3.10 (m, 2H), 3.35 (t, J ) 9.0 Hz, 2H), 7.13-7.30
(m, 5H), 7.43-3.64 (m, 4H), 7.79 (s, 1H), and 7.89-7.97 (m,
3H); 13C NMR (63 MHz, CDCl3) δ 25.60, 34.85, 55.35, 114.0,
125.3, 126.0, 126.6, 126.7, 127.0, 127.8, 128.0, 128.1, 129.7,
132.1, 132.4, 133.8, 140.0, 141.6, 142.6, 151.9, and 156.1; IR
(CHCl3) vmax 2955, 1599, 1497, 1413, and 1310 cm-1; MS (EI+)
m/z (rel intensity) 336 (5%, M+), 203 (85), 185 (75), and 82
278 (10%, M+), 234 (10), and 91 (100); HRMS calcd for C17H15
BO3 (M+) 277.1151, found 277.1163. Anal. Calcd for C17H15
BO3: C, 73.42; H, 5.44. Found: C, 73.07; H, 5.33.
-
-
1-(1-Meth yl-2-p yr r olin o[2,3-d ]p yr id in -7-yl)-2-n a p h -
th yl (Tr iflu or om eth yl)su lfon a te (54). A suspension of
benzyl ether 52 (1.83 g, 5.0 mmol) in EtOH (80 mL) was
hydrogenated under normal pressure in the presence of 10%
Pd/C (700 mg) for 5 h (TLC). The reaction mixture was filtered
through a thin pad of Celite and evaporated in vacuo to give
a crude phenol 53 (1.38 g, 5.0 mmol) as a white solid, which
was used in the next step without further purification. Thus,
to a solution of phenol 53 (1.38 g, 5.0 mmol) in pyridine (15
mL) at 0 °C was added trifluoromethanesulfonic anhydride
(925 mL, 5.5 mmol). After 70 min, the solvent was evaporated
in vacuo and the residue partitioned between water (50 mL)
and CH2Cl2 (50 mL). 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 red oil. Purification by flash chromatography
(EtOAc f EtOAc/Et3N, 98/2) afforded the title compound 54
(1.90 g, 93%) as a pale orange solid: Rf ) 0.40 (EtOAc/Et3N,
(100); HRMS calcd for
290.1410.
C
19H18N2O (M+) 290.1419, found
X-r a y Cr ysta l Str u ctu r e An a lyses. The structures were
solved by direct methods (SHELXTL51). For further details of
the crystal structure determination, see: Supporting Informa-
tion.
X-r a y Cr ysta l Str u ctu r e An a lysis of Ar yl Br om id e 18.
C8H9BrN2 (213.08); from CHCl3 as colorless blocks; crystal
dimensions: 0.50 × 0.48 × 0.45 mm; monoclinic; space group:
P21/c (C52h′, No. 14); unit cell dimensions: a ) 7.7576(15), b )
13.231(3), c ) 8.2134(16) Å; â ) 110.010(4)°; U ) 792.1(3) Å3,
Z ) 4, Dc ) 1.787 mg m-3; Mo KR radiation (λ ) 0.71073 Å),
µ(Mo KR) ) 5.119 mm-1, F(000) ) 424. Cell parameters were
refined from the setting angles of 46 reflections (θ range 2.79
< 28.26°); total number of reflections: 4053; number of
independent reflections: 1407 (exceeding the significance level
|F|/σ(|F|) > 4.0); R ) 0.0491 (wR2all ) 0.1270).
1
99/5); H NMR (250 MHz, CDCl3) δ 2.09 (s, 3H), 3.06 (t, J )
8.5 Hz, 2H), 3.46 (t, J ) 8.5 Hz, 2H), 7.43-7.68 (m, 4H), 7.88-
7.95 (m, 3H), and 8.11 (s, 1H); 13C NMR (63 MHz, CDCl3) δ
25.56, 34.66, 55.48, 107.4, 118.3 (q, J ) 320 Hz), 119.4, 126.0,
129.6, 127.2, 127.8, 127.9, 128.3, 130.6, 132.1, 134.1, 143.7,
145.4, 151.5, and 156.0; IR (CHCl3) vmax 2957, 1600, 1507,
1419, 1314, 1218, and 1140 cm-1; MS (FAB+) m/z (rel intensity)
409 (100%, MH+), 275 (15), and 259 (15); HRMS calcd for
X-r ay Cr ystal Str u ctu r e An alysis of Biar yl 22. C16H18N2O
(254.32); from EtOAc as colorless blocks; crystal dimensions:
0.40 × 0.21 × 0.21 mm; orthorhombic; space group: P212121 (
D42, No. 19); unit cell dimensions: a ) 7.461(6), b ) 8.350(8),
c ) 21.315(18) Å; U ) 1328(2) Å3, Z ) 4, Dc ) 1.272 mg m-3
Mo KR radiation (λ ) 0.71073 Å), µ(Mo KR) ) 0.080 mm-1
;
,
C
19H16F3N2O3S (MH+) 409.0834, found 409.0805.
(50) Another set of weak signals could be observed in 13C NMR,
which can be attributed to a small amount of the anhydride formed.
(51) An Integrated System for Solving and Refining Crystal Struc-
tures from Diffraction Data (Revision 5.1); Bruker AXS Ltd.

Biaryl Analogues of 4-(Dimethylamino)pyridine
J . Org. Chem., Vol. 64, No. 26, 1999 9443
F(000) ) 544. Cell parameters were refined from the setting
angles of 45 reflections (θ range 1.91 < 28.72°); total number
of reflections: 8858; number of independent reflections: 1505
(exceeding the significance level |F|/σ(|F|) > 4.0); R ) 0.1018
(wR2all ) 0.2882).
dimensions: 0.24 × 0.12 × 0.12 mm; triclinic; space group:
P1h (C1i , No. 2); unit cell dimensions: a ) 9.977(3), b ) 9.993-
(3), c ) 10.769(3) Å; R ) 107.865(5)°, â ) 113.068(5)°, γ )
93.022(5)°; U ) 921.6(4) Å3, Z ) 2, Dc ) 1.277 mg m-3; Mo KR
radiation (λ ) 0.71073 Å), µ(Mo KR) ) 0.078 mm-1
, F(000) )
X-r a y Cr ysta l Str u ctu r e An a lysis of Bia r yl 35. C19H18
-
376. Cell parameters were refined from the setting angles of
26 reflections (θ range 2.18 < 28.30°); total number of
reflections: 6108; number of independent reflections: 2424
(exceeding the significance level |F|/σ(|F|) > 4.0); R ) 0.0564
(wR2all ) 0.1694).
N2O‚HCl (326.31); from petroleum ether/CH2Cl2 as colorless
blocks; crystal dimensions: 0.32 × 0.16 × 0.15 mm; monoclinic;
space group: P21/n (a nonstandard setting of P21/c C52h′, No.
14); unit cell dimensions: a ) 7.194(3), b ) 23.993(7), c )
9.667(3) Å; â ) 106.41(4)°; U ) 1600.5(9) Å3, Z ) 4, Dc ) 1.356
mg m-3; Mo KR radiation (λ ) 0.71073 Å), µ(Mo KR) ) 0.245
mm-1, F(000) ) 688. Cell parameters were refined from the
setting angles of 45 reflections (θ range 1.70 < 28.31°); total
number of reflections: 10487; number of independent reflec-
tions: 2157 (exceeding the significance level |F|/σ(|F|) > 4.0);
R ) 0.0832 (wR2all ) 0.2675).
Op tica l Resolu tion of th e Ra cem ic Bia r yl (()-55. The
enantiomers of the biaryl 55 were separated using semi-
preparative 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 ∼3.5 mg of
the racemate in 100 mL of dichloromethane were made every
13 min. Enantiomer (+)-55 was collected from 15.6 to 17.4 min,
and the enantiomer (-)-55 was collected from 19.5 to 21.9 min.
The enantiomers were further purified by flash chromatogra-
phy (EtOAc) to give final products as white crystalline solids.
Analytical HPLC revealed the enantiomeric purity of 99.9%
{[R]25D +107 (c 0.43 in CHCl3)} and 99.7% {[R]25D -107 (c 0.45
in CHCl3)} for the two enantiomers, respectively.
X-r a y Cr ysta l Str u ctu r e An a lysis of Bia r yl 38. C17H16N2
(248.32); from petroleum ether/CH2Cl2 as colorless blocks;
crystal dimensions: 0.40 × 0.32 × 0.32 mm; monoclinic; space
group: P21 (C2, No. 4); unit cell dimensions: a ) 7.1351(12),
2
b ) 7.1394(12), c ) 13.279(2) Å; â ) 104.452(3)°; U ) 655.03-
(19) Å3, Z ) 2, Dc ) 1.259 mg m-3; Mo KR radiation (λ )
0.71073 Å), µ(Mo KR) ) 0.075 mm-1, F(000) ) 264. Cell
parameters were refined from the setting angles of 48 reflec-
tions (θ range 1.58 < 28.30°); total number of reflections: 4356;
number of independent reflections: 2403 (exceeding the
significance level |F|/σ(|F|) > 4.0); R ) 0.0651 (wR2all ) 0.2159).
X-r a y Cr ysta l Str u ctu r e An a lysis of N-Oxid e of Bia r yl
38. C17H16N2O‚H2O (282.33); from CH2Cl2/EtOAc as colorless
blocks; crystal dimensions: 0.37 × 0.22 × 0.22 mm; monoclinic;
space group: P21/c (C52h′, No. 14); unit cell dimensions: a )
6.8156(9), b ) 7.6023(10), c ) 27.838(4) Å; â ) 96.509(2)°; U
) 1433.1(3) Å3, Z ) 4, Dc ) 1.309 mg m-3; Mo KR radiation (λ
) 0.71073 Å), µ(Mo KR) ) 0.087 mm-1, F(000) ) 600. Cell
parameters were refined from the setting angles of 66 reflec-
tions (θ range 2.78 < 28.34°); total number of reflections: 9146;
number of independent reflections: 2491 (exceeding the
significance level |F|/σ(|F|) > 4.0); R ) 0.0542 (wR2all ) 0.1716).
X-r a y Cr ysta l Str u ctu r e An a lysis of Bia r yl (+)-55.
Op tica l Resolu tion of th e Ra cem ic Bia r yl (()-56. The
enantiomers of the biaryl 56 were separated using semi-
preparative HPLC (Chiralcel OD column, 1 cm × 25 cm;
hexanes/EtOAc/Et2NH, 75/24/1; 4 mL min-1; 35 °C). UV
detection was performed at 250 nm. Injections of ∼8 mg of
the racemate in 35 mL of dichloromethane were made every
14 min. Enantiomer (-)-56 was collected from 9.7 to 12.4 min,
and the enantiomer (+)-56 was collected from 14.9 to 19.1 min.
The enantiomers were further purified by flash chromatogra-
phy (EtOAc f EtOAc/Et3N, 98/2) to give final products as
white foams. Analytical HPLC revealed the enantiomeric
purity of >99.9% for both the levorotatory {[R]25 -144 (c 1.9
D
in CHCl3)} and the dextrorotatory {[R]25 +151 (c 1.9 in
D
CHCl3)} enantiomer.
Ack n ow led gm en t. The generous support of this
work by Leverhulme Trust is gratefully acknowledged.
We also thank Dr. Detlev H. Hochmuth (University of
Hamburg) for determination of the barrier to rotation
of biaryl 31 by computer simulation of HPLC elution
profiles.
C
19H18N2 (274.35); from EtOAc as colorless blocks; crystal
dimensions: 0.34 × 0.31 × 0.31 mm; orthorhombic; space
group: P212121 (D42, No. 19); unit cell dimensions:
a
)
7.8911(16), b ) 12.503(3), c ) 14.477(3) Å; U ) 1428.4(5) Å3,
Z ) 4, Dc ) 1.276 mg m-3; Mo KR radiation (λ ) 0.71073 Å),
µ(Mo KR) ) 0.075 mm-1, F(000) ) 584. Cell parameters were
refined from the setting angles of 45 reflections (θ range 2.15
< 28.36°); total number of reflections: 9470; number of
independent reflections: 1715 (exceeding the significance level
|F|/σ(|F|) > 4.0); R ) 0.0472 (wR2all ) 0.1326).
Su p p or tin g In for m a tion Ava ila ble: Copies of 1H and 13C
NMR spectra for all compounds and single-crystal X-ray data
for compounds 18, 22, 35, 38, N-oxide of 38, (+)-55, and 56.
This material is available free of charge via the Internet at
http://pubs.acs.org.
X-r a y Cr ysta l Str u ctu r e An a lysis of Bia r yl (()-56.
24H20N2‚H2O (354.44); from EtOAc as colorless blocks; crystal
C
J O991011H