Atropisomeric α-methyl substituted analogues of 4-(dimethylamino)pyridine: Synthesis and evaluation as acyl transfer catalysts

Article abstract of DOI:10.1039/b103385a

The regioselectivity of α-metalation-methylation of N-BF₃ adducts of 4-(dimethylamino)pyridines as a function of β-substitution is examined in attempts to prepare configurationally stable atropisomeric derivatives (I and II) having an α-methyl substituent and a β-biaryl stereogenic axis. The activity of some of these derivatives as catalysts for acyl transfer is examined and the kinetic resolution of 1-(1-naphthyl)ethanol catalysed by α-methyl chiral DMAP (-)-24 is reported. A rationale for the reduced stereoselectivity of this catalyst relative to its non-α-substituted analogue (-)-1 is also proposed.

Full text of DOI:10.1039/b103385a

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Atropisomeric ꢀ-methyl substituted analogues of
4-(dimethylamino)pyridine: synthesis and evaluation as
acyl transfer catalysts
1
Alan C. Spivey,*a Adrian Maddaford,a David P. Leesea and Alison J. Redgraveb
a Department of Chemistry, University of Sheffield, Brook Hill, Sheffïeld, UK S3 7HF
b GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire,
UK SG1 2NY
Received (in Cambridge, UK) 17th April 2001, Accepted 13th June 2001
First published as an Advance Article on the web 13th July 2001
The regioselectivity of α-metalation–methylation of N-BF3 adducts of 4-(dimethylamino)pyridines as a function of
β-substitution is examined in attempts to prepare configurationally stable atropisomeric derivatives (I and II) having
an α-methyl substituent and a β-biaryl stereogenic axis. The activity of some of these derivatives as catalysts for acyl
transfer is examined and the kinetic resolution of 1-(1-naphthyl)ethanol catalysed by α-methyl chiral DMAP (Ϫ)-24
is reported. A rationale for the reduced stereoselectivity of this catalyst relative to its non-α-substituted analogue (Ϫ)-
1 is also proposed.
Introduction
Although it has been known since the 1890’s that pyridine
accelerates the rate of acylation of alcohols with Ac2O
(Einhorn acylation),1 it was not until the 1950’s that this
acceleration was shown to be primarily due to nucleophilic
catalysis.2–6 Subsequently, Litvinenko7 and Steglich8 indepen-
dently discovered that 4-(dimethylamino)pyridine (DMAP) was
a superior nucleophilic catalyst for acyl transfer reactions and
this derivative is now routinely used for this purpose.9–13
Recently, we14–17 and others18–36 have reported chirally modified
Fig. 1 DMAP-based chiral catalyst and proposed catalyst structures.
derivatives of DMAP as catalysts for enantioselective acyl
transfer to secondary alcohols in kinetic resolution (KR)37 and
catalytically active pyridyl nitrogen (the other being the 4-
amino function). This scenario is attractive as it should allow a
mono-ortho substituted aryl group as the axial partner, thereby
ensuring maximum steric differentiation between the faces of
the pyridine ring (which is probably important for enantiodis-
crimination). Additionally, a substituent α to the pyridyl nitro-
gen would be expected to exert a strong influence over the con-
asymmetric desymmetrisation38 protocols. Our efforts have
mainly focused on the development of atropisomeric analogues
of DMAP having a stereogenic biaryl axis β to the pyridine
nitrogen and this work has led to the identification of chiral
DMAP (Ϫ)-1 as an efficient catalyst for the KR of alkylaryl-
carbinols (Fig. 1).14–16,39 The configurational stability of this
derivative accrues from severe steric hindrance to rotation
formation of the carbonyl group in the acylpyridinium inter-
about the key biaryl axis as the result of di-ortho substitution of
mediate during catalysis of acyl transfer. Such control could
the non-pyridyl ring.15 In this paper we describe our attempts to
enhance enantiodiscrimination47 and so, although α substitu-
prepare atropisomeric chiral DMAPs I and II (Fig. 1) having
tion is known to strongly attenuate the nucleophilicity of pyrid-
di-ortho substitution, relative to the biaryl axis, on the pyridyl
ines,‡ we anticipated that α-methyl substituted DMAPs might
ring and evaluate α-methyl chiral DMAP derivative (Ϫ)-24 (see
nevertheless be viable templates for asymmetric catalysts. Our
initial target structures (I, Fig. 1) had α-methyl-N-methyl-5-
azaindoline 4 as their core catalytic unit as the azaindoline
scaffold was anticipated to impart enhanced configurational
Scheme 5) as a catalyst for asymmetric acyl transfer.
The positioning of the stereogenic axis is central to the design
of configurationally stable atropisomeric analogues of DMAP.
As a rule-of-thumb, at least three ortho substituents are
stability relative to the corresponding DMAP.§
required for rotamers (i.e. atropisomers) of a biaryl to be con-
figurationally stable at ambient temperature.40,41 Cognisant of
‡ Following pioneering studies by Gold and Butler,6 Litvinenko and co-
this, and mindful that several biaryls comprising pyridyl rings
workers found that the ratio of rates of catalysis by DMAP, pyridine, 2-
methylpyridine, and 2,6-dimethylpyridine relative to the uncatalysed
display anomalously low barriers to rotation,† we chose to
position the axis β to the pyridyl nitrogen so as to allow di-ortho
substitution on either (or both) of the aryl partners. Di-ortho
substitution on the pyridyl ring requires a substituent α to the
reaction for the benzoylation of benzyl alcohol using BzCl (1 eq.)
in benzene are: 3.45 × 108 : 9.29 × 103 : 435 : 115.48 More recently,
Sammakia and Hurley have shown that the ratio of rates of catalysis
by 4-(pyrrolidino)pyridine (PPY), 2-methyl-PPY, and 2-ethyl-PPY
(1 mol%) (relative to the uncatalysed reaction) for the acetylation of
menthol using Ac2O–Et3N (10 eq.) in CH2Cl2 is 120 : 4.0 : 1.7 and
that 2-isopropyl-PPY and 2-tert-butyl-PPY do not show catalytic
activity above that of the uncatalysed reaction.49
† For example, at ambient temperature 2,2Ј,6,6Ј-tetracarboxy-4,4Ј-
diphenyl-3,3Ј-bipyridyl racemises rapidly whereas biphenyls substituted
with ortho substituents of comparable size are configurationally
stable.42 However, configurationally stable pyridyl-containing biaryls
are known.43–46
§ This turned out not to be the case.15 The results of an investigation
into the reasons for this are the subject of a forthcoming full paper.
DOI: 10.1039/b103385a
J. Chem. Soc., Perkin Trans. 1, 2001, 1785–1794
This journal is © The Royal Society of Chemistry 2001
1785

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could be eliminated by employing BuLi as base to give
exclusively α-methyl-DMAP–BF3 7 in 87% yield in a protocol
similar to one recently developed by Sammakia and Hurley.49
Heating at reflux in MeOH effected quantitative decom-
plexation of the BF3 to give α-methyl-DMAP 9. With an effi-
cient procedure for α-methylation established, we turned our
attention to the α-methylation of N-methyl-5-azaindoline 3.
Methylation of BF3 adduct 10 afforded a 1 : 3 mixture of
regioisomers†† (4 and 11, 73% combined yield, for assignment
see later) favouring the more hindered (and undesired) 4-methyl
isomer 11. These were inseparable by flash chromatography
both before and after BF3 decomplexation but bromination
with NBS15 afforded a separable mixture of regioisomeric
bromides 5 (17%) and 12 (53%) (Scheme 2). Although the
desired bromide 5 was the minor isomer we were able to prepare
ample quantities to explore subsequent Suzuki type cross-
coupling of both isomers with 1-naphthylboronic acid.
Unfortunately, under conditions which we had previously
optimised for analogous couplings in the non α-methyl series,15
bromide 12 coupled to give biaryl 13 in 98% yield but bromide
5 underwent hydrodebromination to regenerate 5-azaindoline
4 in 95% yield. Despite extensive experimentation, we were
unable to effect coupling of bromide 5 [or 3-bromo-2-methyl-4-
(dimethylamino)pyridine (14)]‡‡ with 1-naphthylboronic acid
or other comparably hindered boronic acids.
Results and discussion
Our strategy for the preparation of catalyst candidates of
type I is outlined in Scheme 1. N-Methyl-5-azaindoline 3 was
Scheme 1 A strategy for preparation of atropisomeric α-methyl chiral
DMAPs I. Reagents: i, p-NsCl, Et3N [98%].
prepared from 4-aminopyridine (4 steps, 72% overall yield) by
a modification of our previous method15 now employing
cyclisation of intermediate alcohol 2 using p-nitrobenzene-
sulfonyl chloride (NsCl)–Et3N in CH2Cl2 (99%). We envis-
aged that α-metalation–methylation of an N-BF3 pyridine
adduct50,51 would effect efficient introduction of the α-methyl
group¶ (i.e. 3 → 4, Scheme 1). Thus, metalation of DMAP–
BF3 653 with lithium 2,2,6,6-tetramethylpiperidine (LTMP) in a
modification of a procedure described by Vedejs and Chen,||18
followed by alkylation with MeI afforded α-methyl and α-ethyl
products 7 and 8 in 60 and 17% respectively (Scheme 2).
α-Ethyl-DMAP–BF3 8 presumably results from in situ lateral
deprotonation of α-methyl-DMAP–BF3 7.** This side reaction
We reasoned that cross-coupling prior to α-methylation
might circumvent this impasse and furnish the desired isomer as
the major product, providing that α-methylation once again
occurred at the (presumably) more hindered 6-position ortho to
the biaryl axis. In the event, methylation of the BF3 adduct of
biaryl 1615 gave the undesired 4-methyl product 17 exclusively
(71%) (Scheme 3). A strong NOE to the C-3 methylene protons
Scheme 3 Reagents: i, BF3ؒEt2O; ii, (a) BuLi, (b) MeI [71% overall].
in BF3 adduct 17 confirmed the position of the methyl group.
The decomplexed product was identical to the previously
obtained biaryl 13, thereby confirming our previous assign-
ments. To probe further the factors influencing the regio-
selectivity of metalation, and also in the hope of obtaining a
configurationally stable biaryl derivative for KR studies, we
next studied methylation of the BF3 adduct 18 of 3-(1-
naphthyl)-4-(pyrrolidino)pyridine.15
Disappointingly,
this
derivative also gave the undesired 6-methyl regioisomer 19
exclusively (68%) (Scheme 4), indicating that the regioselectivity
observed with biaryl 16 was a result of additive preferences for
metalation distal to the biaryl axis (strong) and proximal to the
ring junction (weak).
Since the biaryl axis clearly directed metalation to the distal
α-position, our next strategy was to introduce a removable
Scheme 2 Reagents: i, (a) LTMP, (b) MeI {6 → 7 [60%] ϩ 8 [17%];
10 → 4 ϩ 11 [∼1 : 3, 73%]}, or (a) BuLi, tBuOK, (b) MeI {6 → 7
[87%]}; ii, MeOH {7 → 9 [99%]; 4 ϩ 11 → 5 [17%] ϩ 12 [53%]}; iii,
Na2CO3, Pd(PPh3)4 (cat.), 1-naphthylboronic acid [98%].
†† Our observations with N-BF3 complex 10 contrast sharply with those
of Abramovitch and co-workers who have noted that N-oxides of
3-alkyl substituted pyridines tend to metalate at the less hindered
6-position55,56 and undergo nucleophilic addition at the more hindered
2-position.57
‡‡ Pyridine 14 and its regioisomer, 3-bromo-6-methyl-4-(dimethyl-
amino)pyridine (15) were obtained by bromination of α-methyl-DMAP
9. Isomer 14, the product of bromination at the more hindered position,
predominates under our NBS-based conditions whereas it has been
reported that 2-methyl-4-(piperidino)pyridine brominates predomin-
antly at the less hindered position using Br2–K2CO3.58
¶ An alternative approach for the introduction of an α-methyl substitu-
ent into pyridine N-oxides using the Tebbe reagent has recently been
reported by Nicolaou et al.52
|| Vedejs has prepared DMAP–BF3 6 in situ and quenched with pival-
dehyde.18 For methylation, we obtained better results by isolation of N-
BF3 adduct 6 which is stable to flash chromatography on SiO2.53
** Analogous ethylation when quenching α-metalated pyridine with
Me2SO4 has recently been reported by Fort and co-workers.54
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J. Chem. Soc., Perkin Trans. 1, 2001, 1785–1794

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heterocycles (e.g. DMAP, entry 3, Table 1) they all catalyse the
transformation significantly.
To compare the selectivity (s) achieved using α-methyl-
pyridine (Ϫ)-24 with that using non-α-methylpyridine (Ϫ)-1,
parallel KR experiments were performed under identical
conditions employing 1-(1-naphthyl)ethanol and (iPrCO)2O at
0 ЊC in toluene (Table 2). It can be seen that both catalysts have
the same sense of stereoinduction but that catalyst (Ϫ)-24 is
significantly less selective (s = 2.0, entry 4, Table 2) than catalyst
(Ϫ)-1 (s = 5.2, entry 3). Although this decrease in selectivity was
disappointing, we had expected that KR selectivity would be
strongly influenced by the presence of an α-methyl group. We
had reasoned that an α-methyl group would impose a signifi-
cant bias on the conformation of the acyl C᎐O function in the
᎐
Scheme 4 Reagents: i, (a) BuLi, (b) MeI {18 → 19 [68%]; 20 → 21
[72%]}; ii, (a) BuLi, (b) D2O {6 → 20 [97%]; 18 → 22 [61%]}.
key acylpyridinium salt intermediate in the catalytic cycle
favouring the planar conformation in which the acyl oxygen is
positionedclosesttotheα-methylgrouptominimiseA1,3 strain§§
blocking group at this position. We were attracted to the
possibility of using deuterium for this purpose as metalation
processes are known to be subject to significant primary deu-
terium isotope effects (kH/kD > 30).59 Moreover, deuterium
should be readily washed out of the α-position in DMAP-
like systems using dilute alkali.60 Preliminary investigations
into the feasibility of this approach involved the prepar-
ation of 2-deuterio-DMAP–BF3 20 (97%) by quenching
lithiated 6 with D2O. Pleasingly, lithiation of this adduct and
alkylation with MeI as before afforded the desired 2-methyl-
6-deuterio-DMAP–BF3 21 exclusively (72%) (Scheme 4).
To test if this isotope effect was sufficient to overcome the
bias exerted by the biaryl axis, 6-deuteriobiaryl 22 was pre-
pared in 61% yield by quenching the lithiated 18 with D2O
(Scheme 4). However, this molecule resisted metalation–
methylation (or deuteriation) under the optimised conditions
and starting material was recovered almost quantitatively on
each occasion.
(i.e. such that the C᎐O bond is aligned parallel to the biaryl axis
᎐
for catalyst 24). As a consequence of this, the incoming alcohol
nucleophile would have fewer Burgi–Dunitz trajectories
available to it (relative to in the corresponding non-α-methyl
substituted salt for which both planar conformations would
be significantly populated) and this would result in a change
in stereoselectivity.
In order to further understand the effect of α-methyl
substitution on acylpyridinium carbonyl conformation and
corroborate this hypothesis we performed a series of 1H NMR
experiments at 400 MHz on solutions (∼30 mg cmϪ3) of ( )-1,
( )-24, DMAP (30), and α-methyl-DMAP 9 in acid free
CDCl3 at ambient temperature. For each catalyst, AcCl
1
(1 equiv.) was added and H NMR spectra acquired at t = 2
min and regular time intervals thereafter. Each experiment was
performed in duplicate and gave good reproducibility between
runs. Catalysts 1, 30, and 9 were converted to acetylpyridinium
chlorides 26, 31, and 32, respectively, within 2 min (see Table 3
We decided to terminate this line of enquiry and to assess the
impact of α-methyl substitution on both catalytic activity and
KR selectivity by preparing the derivative of chiral catalyst (Ϫ)-
116 having an α-methyl group distal to its biaryl axis using the
BF3 adduct metalation–methylation methodology. Accordingly,
this compound was prepared in racemic form (Scheme 5) and
1
for diagnostic H NMR data) although the half-lives of these
salts with respect to subsequent decomposition to their respec-
tive hydrochlorides 28, 33, and 34, respectively, varied dramat-
1
1
2
1
2
ically [26: t ≈ 12 h; 31: t ≈ 36 h; 32: t ≈ 2.5 h]. With catalyst 24
–
–
–
we were u2nable to observe acetylpyridinium chloride 27 as
quantitative conversion to hydrochloride 29 was complete
1
within 2 min [i.e. presumably 27 has t < 1 min]. Analysis of the
–
2
spectra for acetylpyridinium chlorides 26, 31, and 32 reveals a
number of interesting features. The α protons and the β protons
in DMAP-derived salt 31 appear as two sets of doublets
(Ha/Hb at δ 9.06 ppm, and Hc/Hd at δ 7.19 ppm). Therefore
rotation about the N–Ac bond is rapid on the NMR timescale
at this temperature. Consequently, these chemical shifts are
average values for the individual signals dependent on the
N–Ac bond-rotation. This interpretation is confirmed by com-
1
parison with the H NMR spectrum acquired at Ϫ115 ЊC (at
which temperature N–Ac rotation is ‘frozen-out’)61 on the
acetylpyridinium acetate of 4-(pyrrolidino)pyridine (PPY),
which reveals that protons corresponding to Ha and Hb resonate
at δ 8.7 and 10.1 ppm, and Hc and Hd at δ 6.9 and 7.2 ppm,
respectively.9 It follows that at ambient temperature rotation
about the N–Ac bond will not be resolved in the spectrum of
acetylpyridinium chloride 26 either. However, the fact that the
signal for Ha (which is unambiguously assigned on the basis of
its multiplicity) resonates at δ 8.30 ppm [i.e. ∆δ = ϩ0.12 ppm
cf. 1] and the signal for Hb resonates at δ 9.91 ppm [i.e.
∆δ = ϩ1.69 ppm cf. 1] in the spectrum of acetylpyridinium
chloride 26 strongly suggests that even in the absence of an
Scheme 5 Reagents: i, BF3ؒEt2O [62%]; ii, (a) BuLi, (b) MeI; iii,
MeOH {23 → 24 [25%] ϩ 25 [11%]}; iv, CSP HPLC (for 24 only).
α-methyl group the conformation in which the acetyl C᎐O bond
᎐
resolved by semipreparative chiral stationary phase (CSP)
HPLC to give enantiomerically pure α-methylpyridine (Ϫ)-24.
α-Methylpyridines 4, 9, and 13 were shown to catalyse the
acetylation of 1-phenylethanol with Ac2O under standard con-
ditions at 25 ЊC (Table 1). Although the catalytic activity of
these catalysts is, as expected, reduced relative to the parent
§§ The carbonyl oxygen is smaller than the acyl substituent.47 Fu and co-
workers have obtained an X-ray crystal structure of an acetylpyridin-
ium salt of one of their ferrocenyl DMAPs showing an approximately
planar conformation in which steric interactions with the fused five-
membered ring are minimised.29
J. Chem. Soc., Perkin Trans. 1, 2001, 1785–1794
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Table 1 Catalysis of acylation of 1-phenylethanol with Ac2O–Et3N
Alcohol : acetate ratiosa
After 5 min After 15 min
Entry
Catalyst
After 4 h
After 24 h
c
c
c
1
2
3
4
5
6
No catalystb
No catalyst
DMAP
9
4
13
—
—
—
94 : 6
91 : 9
<1 : 99
15 : 85
16 : 84
14 : 86
>99 : 1
83 : 17
97 : 3
99 : 1
99 : 1
>99 : 1
<1 : 99
92 : 8
97 : 3
96 : 4
98 : 2
<1 : 99
45 : 55
67 : 33
61 : 39
a Determined by HPLC on a Chiralcel OD column. b No Et3N. c Not determined.
Table 2 KR of 1-phenylethanol using C2-symmetric PPYs
Entry
Catalyst
T /ЊC
t/h
C (%)a
(R)-Alcohol eeA (%)b
(S)-Ester eeE (%)b
s
1
2
3
4
No catalyst
(Ϫ)-1
0
Ϫ78
0
0
24.0
9.0
0.08
24.0
3
—
—
—
24
5.2
2.0
45.1
40.8
15.3
69.2
39.1
5.6
84.1
56.6
30.9
(Ϫ)-1
(Ϫ)-24
a Conversion by (HPLC) mass balance. b By HPLC using a Chiralcel OD column.
is aligned parallel to the biaryl axis [i.e. as drawn in the Table 3
graphic)] is significantly favoured.¶¶ We currently have no con-
vincing explanation for this preference, although it may reflect a
stereoelectronic stabilisation dependent on partial conjugation
across the biaryl bond. Our inability to observe acetylpyridin-
ium chloride 27 derived from α-methyl catalyst 24 does not
allow us to corroborate our prediction that an α-methyl group
imposes an additional bias towards this same conformer.
Indeed, the fact that the signal for Ha in the spectrum of α-
methylacetylpyridinium chloride 32 resonates at δ 8.57 ppm [i.e.
acetyl group and pyridine ring to adopt a non-planar conform-
ation in solution. Such an orientation could explain the shorter
half-lives of the α-methylacetylpyridinium chlorides 27 and 32
relative to their non-α-methyl counterparts 26 and 31. The con-
version of an acetylpyridinium chloride to give a hydrochloride
presumably involves elimination of ketene.62 For a non-planar
acetylpyridinium salt in which conjugation between the C᎐O
᎐
function and the aromatic ring is compromised this elimination
should be particularly facile. The generation of ketene under
KR conditions could also account for the reduced selectivity of
α-methyl substituted catalyst (Ϫ)-24 relative to catalyst (Ϫ)-1,
since ketene itself is an achiral acylating agent. Although we
saw no ketene (or diketene) in our NMR spectra, it is volatile
and we did observe the formation of acetic acid which could,
among other pathways, be produced by reaction of ketene with
adventitious water.
In summary, the α-methylation of DMAP derivatives by
metalation–methylation of N-BF3 adducts has been explored
and the regioselectivity of this process has been shown to be
strongly dependent on the substitution pattern at the β-
positions. α-Methyl-DMAPs, as expected, display significantly
reduced catalytic activity in the acylation of secondary alcohols
by Ac2O as the result of decreased nucleophilicity. More-
over, enantiomerically pure DMAP (Ϫ)-24, which contains
an α-methyl group distal to its biaryl axis, displays moderate
selectivity in the KR of 1-(1-naphthyl)ethanol compared to its
b
∆δ = ϩ0.63 ppm cf. 9] and the signal for the α-methyl CH3
resonates at δ 2.69 ppm [i.e. ∆δ = ϩ0.18 ppm cf. 9] does not
appear to support this hypothesis. By analogy with the data for
compounds 1, 26, 30 and 31 the signal for Ha would not be
expected to shift and the signal for CH3b would be expected to
shift to lower field if the planar conformation drawn were to be
significantly populated for pyridinium chloride 32. This sug-
gests that the effect of an α-methyl group may be to force the
¶¶ The complexity of the N-ethyl resonances of acetylpyridinium chlor-
ide 26 reveals that there is restricted rotation about the CAr–N bond at
ambient temperature. This bond rotation is not resolved for the parent
catalyst 1 and confirms the expected increase in conjugation across the
CAr–N bond as the result of N-acetylation. The magnitudes of energy
barriers to rotation about the three rotatable bonds in catalyst 1 are
therefore in the order: biaryl ӷ CAr–N > N–Ac.
1788
J. Chem. Soc., Perkin Trans. 1, 2001, 1785–1794

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Table 3 Comparison of selected 1H NMR signals for free, acylated, and protonated forms of ( )-24,29 (DMAP), and 9 following treatment with
AcCl in CDCl3 at rt
Cat
Ha
Rb
Hc
Hd
Mee
(ϩ)-1
(ϩ)-26
(ϩ)-28
(ϩ)-24
(ϩ)-27
(ϩ)-29
30
8.18 (s)
8.22 (d, 6.0 Hz)
9.91 (d, 8.0, 2.0 Hz)
8.02 (d, 7.0 Hz)
2.49 (s)
N/A
2.69 (s)
6.50 (d, 6.0 Hz)
7.41 (d, 8.0 Hz)
6.60 (d, 7.0 Hz)
6.39 (s)
N/A
6.34 (s)
6.46 (dd, 5.0, 1.5 Hz)
7.19 (d, 8.0 Hz)
6.75 (d, 7.0 Hz)
6.52 (d, 3.0 Hz)
6.72 (d, 3.0 Hz)
6.50 (d, 2.0 Hz)
—
—
—
—
—
—
—
3.05 (s)
—
—
N/A
—
—
2.94 (s)
—
—
2.80 (s)
—
8.30 (d, 2.0 Hz)
8.08 (t, 7.0 Hz)
8.08 (s)
N/A
7.98 (d, 8.5 Hz)
8.19 (dd, 5.0, 1.5 Hz)
9.06 (d, 8.0 Hz)
8.05 (t, 7.0 Hz)
7.94 (d, 7.0 Hz)
8.57 (d, 8.0 Hz)
7.93 (t, 7.0 Hz)
31
33
9
2.51 (s)
2.69 (s)
2.60 (s)
6.62 (dd, 7.0, 3.0 Hz)
6.95 (dd, 8.0, 3.0 Hz)
6.65 (dd, 7.0, 2.0 Hz)
32
34
non-α-methylated analogue (Ϫ)-1 at 0 ЊC. On the basis of
NMR data it is proposed that the α-methyl group may enforce
a non-planar conformation on the derived acylpyridinium
salt, leading to the notion that the reduced stereoselectivity of
α-methyl-DMAP (Ϫ)-24 may reflect an increased susceptibility
to ketene formation.
sodium–benzophenone ketyl under an inert atmosphere of
nitrogen. Anhydrous DMF was obtained by distillation from
CaH2 under reduced pressure. Petrol refers to the fraction of
light petroleum boiling between 40–60 ЊC. High resolution
mass spectrometry (HRMS) measurements are valid to
ppm.
5
1-Methyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 315
Experimental
To a stirred solution of alcohol 215 (0.45 g, 2.9 mmol) in CH2Cl2
(15 cm3) was added Et3N (1.23 cm3, 8.7 mmol) and the mixture
was cooled to 0 ЊC. p-Nitrobenzenesulfonyl chloride (0.98 g,
4.35 mmol) was then added over 10 min and the reaction was
stirred for 1 h. The mixture was then warmed to room tem-
perature, stirred for a further 2 h and then washed with
sat. NaHCO3 (15 cm3). The organic phase was then dried
over MgSO4, concentrated in vacuo and purified by flash chro-
matography (Et3N–EtOAc, 1 : 19) to give pyridine 3 (0.39 g,
98%) as a white solid. Rf 0.15 (EtOAc–Et3N, 19 : 1); δH (CDCl3)
2.74 (3H, s, CH3), 2.92 (2H, t, J = 8.5 Hz, CH2), 3.37 (2H, t,
J = 8.5 Hz, CH2), 6.20 (1H, d, J = 5.5 Hz, CH), 7.95 (1H, s, CH)
and 8.05 (1H, d, J = 5.5 Hz, CH); m/z (EIϩ) (rel. intensity) 134
(75%, Mϩ) and 133 (100).
General
All reactions were performed under anhydrous conditions and
an inert atmosphere of nitrogen in oven-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 procedures.63 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 pre-coated with silica gel 60 F254 which
were visualised 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 fac-
tors (Rf) are quoted to the nearest 0.05. All reaction solvents
were distilled before use and stored over activated 4 Å mole-
cular sieves, unless otherwise indicated. Anhydrous CH2Cl2 was
obtained by refluxing over CaH2. Anhydrous THF and Et2O
were obtained by distillation, immediately before use, from
2-Methyl-4-(dimethylamino)pyridineؒBF3 7 and 2-ethyl-4-
(dimethylamino)pyridineؒBF3 8
Method I. To a stirred solution of DMAPؒBF3 653 (0.10 g,
0.53 mmol) in THF (3 cm3) at Ϫ78 ЊC was added LTMP (0.26
M in THF, 2 cm3, 0.53 mmol). After 30 min MeI (0.75 cm3, 5.3
mmol) was added and the mixture stirred for 30 min. The reac-
J. Chem. Soc., Perkin Trans. 1, 2001, 1785–1794
1789

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tion mixture was then warmed to room temperature, carefully
quenched with water (15 cm3) and extracted with chloroform
(2 × 20 cm3). The organic extracts were combined, dried over
MgSO4 and concentrated in vacuo. The crude mixture was
purified by flash chromatography (EtOAc–petrol, 2 : 3) to give
the following compounds.
δC (CDCl3) 24.78 (CH2), 32.68 (CH3), 54.16 (CH2), 99.23 (CH),
126.14 (Cq), 135.21 (CH), 143.58 (CH) and 160.31 (Cq); m/z
(CIϩ) (rel. intensity) 220 (81%, MNH4ϩ) and 135 (100); HRMS
calcd. for C8H14N3B1F3 (MNH4ϩ) 219.1269, found 219.1278.
1,6-Dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridineؒBF3 4 and
1,4-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridineؒBF3 11
2-MethylpyridineؒBF3 7. White solid (0.065 g, 60%). Mp
143 ЊC; Rf 0.40 (EtOAc–CH2Cl2–petrol, 1 : 3 : 3); νmax/cmϪ1
(CHCl3) 1636, 1548, 1440, 1386, 1290, 1108, 1037 and 912; δH
(CDCl3) 2.60 (3H, s, CH3), 3.12 (6H, s, 2 × CH3), 6.37–6.46
(2H, m, 2 × CH) and 8.17 (1H, br d, J = 5.5 Hz, CH); δC
(CDCl3) 21.31 (CH3), 39.50 (2 × CH3), 104.04 (CH), 107.92
(CH), 142.87 (CH), 154.58 (Cq) and 156.42 (Cq); m/z (CIϩ) (rel.
intensity) 222 (11%, MNH4ϩ), 185 (7) and 137 (100). HRMS
calcd. for C8H16N3B1F3 (MNH4ϩ) 221.1426, found 221.1427.
2-EthylpyridineؒBF3 8. White solid (0.020 g, 17%). Rf 0.50
(EtOAc–CH2Cl2–petrol, 1 : 3 : 3); νmax/cmϪ1 (CHCl3) 1637,
1551, 1535, 1442, 1393, 1109, 1073 and 903; δH (CDCl3) 1.29
(3H, t, J = 7.6 Hz, CH3), 3.05 (2H, q, J = 7.6 Hz, CH2), 3.15
(6H, s, 2 × CH3), 6.42–6.48 (2H, m, 2 × CH) and 8.25 (1H, d,
J = 7.0 Hz, CH); δC (CDCl3) 14.12 (CH3), 31.68 (CH2), 39.12
(2 × CH3), 104.39 (2 × CH), 149.05 (CH), 154.95 (Cq) and
163.35 (Cq); m/z (CIϩ) (rel. intensity) 151 (100%, MHϩ) and 122
(6). Found: C, 49.49; H, 6.44; N, 12.69. Calcd. for C9H14N2B1F3:
C, 49.58; H, 6.47; N, 12.85%.
To a stirred solution of pyridineؒBF3 10 (0.1 g, 0.5 mmol) in
THF (2 cm3) at Ϫ78 ЊC was added LTMP (0.25 M in THF, 2
cm3) and the mixture was stirred vigorously for 1 h. The mixture
was then warmed to Ϫ60 ЊC and MeI (0.3 cm3, 5.0 mmol) was
added dropwise. After 10 min at Ϫ60 ЊC, the mixture was
allowed to warm to room temperature, diluted with water (10
cm3) and then CH2Cl2 (10 cm3). The organic phase was separ-
ated and the aqueous phase was extracted with CH2Cl2 (3 × 10
cm3). The organic layers were combined, dried over MgSO4 and
concentrated in vacuo. The crude mixture was purified by flash
chromatography (CH2Cl2–petrol, 7 : 13) to give a mixture of
pyridines 4 and 11 (∼1 : 3 by 1H NMR) as a white solid (0.078 g,
73%). Rf 0.40 (EtOAc–CH2Cl2–petrol, 1 : 3 : 3); δH (CDCl3)
[pyridine 11] 2.63 (3H, s, CH3), 2.95 (3H, s, CH3), 3.07 (2H, t,
J = 8.9 Hz, CH2), 3.75 (2H, t, J = 8.9 Hz, CH2), 6.10 (1H, s,
CH) and 7.97 (1H, br s, CH); [pyridine 4] 2.47 (3H, s, CH3), 2.95
(3H, s, CH3), 3.05 (2H, t, J = 8.9 Hz, CH2), 3.77 (2H, t, J = 8.9
Hz, CH2), 6.15 (1H, d, J = 9.1 Hz, CH) and 8.13–8.25 (1H, br s,
CH); m/z decomplexed ions found: (EIϩ) (rel. intensity) 148
(74%, Mϩ), 147 (100), 133 (17), 106 (10) and 79 (9).
2-Methyl-4-(dimethylamino)pyridineؒBF3 7
Method II. To a stirred solution of DMAPؒBF3 653 (0.15 g,
0.79 mmol) in THF (4 cm3) was added freshly sublimed t-
BuOK (0.106 g, 0.95 mmol). The mixture was cooled to Ϫ78 ЊC
and n-BuLi (1.63 M in hexanes, 0.58 cm3, 0.95 mmol) was
added dropwise. After 10 min, MeI (0.5 cm3, 7.9 mmol) was
added and stirred for 30 min. The mixture was warmed to
Ϫ40 ЊC, quenched with water (10 cm3) and then warmed to
room temperature. The reaction mixture was extracted with
CH2Cl2 (3 × 10 cm3), the organic extracts were combined
and dried over MgSO4. Evaporation and purification by flash
chromatography (CH2Cl2–petrol, 4 : 1) gave 2-methylpyridineؒ
BF3 7 (0.14 g, 87%) as a white solid. Spectroscopic data as
above.
7-Bromo-1,6-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridine 5
and 7-bromo-1,4-dimethyl-2,3-dihydro-1H-pyrrolo[3,2-c]-
pyridine 12
A mixture of pyridines 4 and 11 (0.093 g, 0.63 mmol) in MeOH
(5 cm3) was heated at reflux for 4 h and then concentrated
in vacuo to give a white solid. The crude mixture was passed
through a short silica column (EtOAc), concentrated in vacuo
and dissolved in DMF (5 cm3). The solution was cooled to 0 ЊC
and NBS (0.117 g, 0.64 mmol) was added slowly. After 2 h the
solvent was concentrated in vacuo and the residue was dissolved
in CH2Cl2 (10 cm3), and washed successively with sat. NaHCO3
(7 cm3) and water (2 × 5 cm3). The organic phase was dried over
MgSO4 and the solvent was removed in vacuo. The residue was
purified by flash chromatography (EtOAc) to give the following
compounds.
2-Methyl-4-(dimethylamino)pyridine 9
A stirred solution of 2-methylpyridineؒBF3 7 (0.14 g, 0.69
mmol) in MeOH (8 cm3) was heated at reflux for 2 h. The
solution was cooled to room temperature and concentrated
in vacuo. The residue was purified by flash chromatography
(EtOAc–MeOH saturated with NH3, 97 : 3) to give 2-
methylpyridine 9 (0.092 g, 99%) as a white solid. Rf 0.40 (NH3
saturated MeOH–CH2Cl2, 7 : 93); νmax/cmϪ1 (Nujol) 1644, 1608,
1560 and 1077; δH (CDCl3) 2.51 (3H, s, CH3), 3.17 (6H, s,
2 × CH3), 6.52 (1H, d, J = 3.0 Hz, CH), 6.62 (1H, dd, J = 7.0,
3.0 Hz, CH) and 7.94 (1H, d, J = 7.0 Hz, CH); δC (CDCl3) 24.70
(CH3), 39.10 (2 × CH3), 104.24 (CH), 105.58 (CH), 148.98
(CH), 154.84 (Cq) and 158.07 (Cq); m/z (EIϩ) (rel. intensity) 136
(83%, Mϩ), 135 (100), 121 (24) and 92 (20); HRMS calcd. for
C8H12N2 (Mϩ) 136.1000, found 136.1002.
Pyridine 5. Brown solid (0.024 g, 17%), Rf 0.15 (EtOAc–
petrol, 1 : 1); νmax/cmϪ1 (CHCl3) 1601, 1492, 1467, 1415, 1311,
1207, 1093 and 906; δH (CDCl3) 2.49 (3H, s, CH3), 2.87 (2H, t,
J = 8.9 Hz, CH2), 3.20 (3H, s, CH3), 3.47 (2H, t, J = 8.9 Hz,
CH2) and 7.75 (1H, s, CH); δC (CDCl3) 24.79 (CH2), 25.47
(CH3), 37.00 (CH3), 56.79 (CH2), 99.59 (Cq), 126.00 (Cq), 140.99
(CH), 154.96 (Cq) and 157.21 (Cq); m/z (EIϩ) (rel. intensity)
226/228 (100%, MHϩ), 146 (38), 132 (8), 118 (9), 77 (12) and 52
(12); HRMS calcd. for C9H11N2Br79 (Mϩ) 226.0106, found
226.0104.
Pyridine 12. Brown solid (0.076 g, 53%), Rf 0.20 (EtOAc–
petrol, 1 : 1); νmax/cmϪ1 (CHCl3) 1596, 1567, 1492, 1463, 1446,
1409, 1288 and 1014; δH (CDCl3) 2.12 (3H, s, CH3), 2.74 (2H, t,
J = 8.9 Hz, CH2), 3.30 (3H, s, CH3), 3.35 (2H, t, J = 8.9 Hz,
CH2) and 7.90 (1H, s, CH); δC (CDCl3) 20.58 (CH3), 25.89
(CH2), 36.06 (CH3), 55.62 (CH2), 96.10 (Cq), 125.27 (Cq), 150.32
(Cq), 151.37 (CH) and 153.57 (Cq); m/z (EIϩ) (rel. intensity)
226/228 (100%, MHϩ), 146 (44), 132 (10) and 77 (9); HRMS
calcd. for C9H11N2Br79 (Mϩ) 226.0106, found 226.0095.
1-Methyl-2,3-dihydro-1H-pyrrolo[3,2-c]pyridineؒBF3 10
To a stirred solution of pyridine 3 (0.1 g, 0.75 mmol) in Et2O
(3 cm3) at 0 ЊC was added BF3ؒEt2O (0.1 cm3, 0.825 mmol).
After 30 min a white precipitate formed which was collected by
filtration, washed with cold Et2O (1 cm3) and the filtrate con-
centrated in vacuo to give pyridineؒBF3 10 (0.12 g, 80%) as a
white amorphous solid. Rf 0.30 (EtOAc–CH2Cl2–petrol,
1 : 3 : 3); νmax/cmϪ1 (CHCl3) 1649, 1596, 1535, 1478, 1430, 1409
and 1085; δH (CDCl3) 3.00 (3H, s, CH3), 3.15 (2H, t, J = 8.5 Hz,
CH2), 3.80 (2H, t, J = 8.5 Hz, CH2), 6.30 (1H, d, J = 6.7 Hz,
CH), 7.85 (1H, br s, CH) and 8.03–8.11 (1H, br s, CH);
1,4-Dimethyl-7-(1-naphthyl)-2,3-dihydro-1H-pyrrolo[3,2-c]-
pyridine 13
To a stirred solution of pyridine 12 (0.27 g, 1.17 mmol) in
ethanol (1 cm3) and toluene (2.5 cm3) was added aqueous
1790
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Na2CO3 (2 M, 2.5 cm3) followed by Pd(PPh3)4 (0.041 g, 0.035
mmol) and 1-naphthylboronic acid (0.24 g, 1.4 mmol). The
mixture was heated at reflux overnight, cooled to room tem-
perature and partitioned between CH2Cl2 (20 cm3) and sat.
NaHCO3 (20 cm3). The phases were separated and the aqueous
phase was extracted with further portions of CH2Cl2 (2 × 20
cm3). The combined organic extracts were dried over MgSO4
and concentrated in vacuo. The residue was purified by flash
chromatography (EtOAc → EtOAc–MeOH saturated with
NH3, 49 : 1) to give pyridine 13 (0.31 g, 98%) as a white solid. Rf
0.45 (NH3 saturated MeOH–CH2Cl2, 7 : 93); νmax/cmϪ1 (CHCl3)
1600, 1576, 1490, 1462, 1405 and 1280; δH (CDCl3) 2.05 (3H, s,
CH3), 2.42 (3H, s, CH3), 2.98 (2H, t, J = 8.3 Hz, CH2), 3.27–
1413, 1355, 1296, 1234 and 1055; δH (CDCl3) 2.12 (3H, s, CH3),
2.41 (3H, s, CH3), 3.07 (2H, t, J = 9.1 Hz, CH2), 3.59–3.84 (2H,
m, CH2), 7.27–7.33 (1Harom, m), 7.40–7.50 (4Harom, m), 7.77
(1H, s, CH) and 7.79–7.89 (2Harom, m); δC (CDCl3) 16.46, 16.97,
24.22, 25.37, 34.40, 34.47, 55.18, 55.54, 113.51, 124.38, 124.98,
125.185, 125.21, 125.36, 126.42, 126.59, 126.97, 127.28, 128.52,
128.64, 128.75, 129.21, 129.66, 130.39, 131.83, 132.57, 132.84,
133.11, 142.72, 143.03, 146.10, 157.47 and 158.54 (more peaks
than expected, presumably due to atropisomerism around the
N–B bond); m/z decomplexed ions found: (EIϩ) (rel. intensity)
274 (100%, Mϩ), 239 (8), 189 (6) and 137 (7); HRMS calcd. for
C19H18N2 (Mϩ) 274.1470, found 274.1474.
3.53 (2H, m, CH2), 7.37–7.52 (4Harom, m), 7.60–7.72 (1Harom
,
3-(1-Naphthyl)-4-pyrrolidinopyridineؒBF3 18
m), 7.70–7.89 (2Harom, m) and 7.95 (1H, s, CH); δC (CDCl3)
21.21 (CH3), 26.23 (CH2), 35.89 (CH3), 55.52 (CH2), 114.55
(Cq), 122.91 (Cq), 125.31 (CH), 125.97 (CH), 126.37 (CH),
128.12 (CH), 128.21 (CH), 128.41 (CH), 132.01 (CH), 132.162
(CH), 133.22 (Cq), 135.20 (Cq), 150.77 (CH), 151.05 (Cq) and
155.93 (Cq); m/z (EIϩ) (rel. intensity) 274 (100%, Mϩ), 259 (7),
and 189 (8); HRMS calcd. for C19H18N2 (Mϩ) 274.1470, found
274.1481.
To a stirred solution of the 3-(1-naphthyl)-4-pyrrolidino-
pyridine15 (1.2 g, 4.38 mmol) in THF (35 cm3) at 0 ЊC was
added BF3ؒTHF (0.58 cm3, 5.26 mmol). After 15 min, the mix-
ture was warmed to room temperature and stirred for a further
25 min. The reaction mixture was concentrated in vacuo and
purified by flash chromatography to give (0.29 g, 24%) as a
white solid and pyridineؒBF3 18 (1.08 g, 72%) as a yellow foam.
Rf 0.25 (EtOAc–CH2Cl2–petrol, 1 : 3 : 3); νmax/cmϪ1 (CHCl3)
1632, 1523, 1454, 1385, 1344, 1308, 1235, 1129, 1105, 1004 and
919; δH (CDCl3) 1.4–2.0 (4H, br s, 2 × CH2), 2.07–3.87 (4H, m,
2 × CH2), 6.74 (1H, d, J = 7.3 Hz, CH), 7.36–7.54 (5Harom, m),
7.87–7.96 (2Harom, m), 8.05 (1H, s, CH) and 8.19 (1H, br d,
J = 6.7 Hz, CH); δC (CDCl3) 24.70 (br, 2 × CH2), 50.19
(2 × CH2), 108.15 (CH), 120.24 (Cq), 124.82 (CH), 125.29 (CH),
126.35 (CH), 127.14 (CH), 128.57 (CH), 128.70 (CH), 129.18
(CH), 132.78 (Cq), 132.93 (Cq), 134.19 (Cq), 140.70 (CH),
144.20 (CH) and 153.80 (Cq). Found: C, 66.54; H, 5.19; N, 8.12.
Calcd. for C19H18N2B1F3: C, 66.70; H, 5.30; N, 8.19%.
3-Bromo-2-methyl-4-dimethylaminopyridine 14 and 3-bromo-6-
methyl-4-dimethylaminopyridine 15
To a stirred solution of 2-methylpyridine 9 (0.3 g, 2.2 mmol) in
DMF (15 cm3) at 0 ЊC was slowly added NBS (0.4 g, 2.3 mmol).
After 2 h, the solvent was evaporated in vacuo and the residue
dissolved in CH2Cl2 (25 cm3), this was then washed successively
with sat. NaHCO3 (20 cm3) and water (2 × 15 cm3). The organic
phase was dried over MgSO4 and concentrated in vacuo. The
residue was purified by flash chromatography (CH2Cl2) to give
the following compounds.
2-Methyl-5-(1-naphthyl)-4-pyrrolidinopyridine–boron trifluoride
complex 19
Bromopyridine 14. Yellow oil (0.2 g, 43%), Rf 0.30 (CH2Cl2–
EtOAc, 3 : 2); νmax/cmϪ1 (CHCl3) 1751, 1719, 1687, 1580, 1481,
1457, 1430, 1342, 1156 and 1029; δH (CDCl3) 2.63 (3H, s, CH3),
2.82 (6H, s, 2 × CH3), 6.66 (1H, d, J = 5.5 Hz, CH) and 8.16
(1H, d, J = 5.5 Hz, CH); δC (CDCl3) 26.09 (CH3), 43.08
(2 × CH3), 112.26 (CH), 114.85 (Cq), 147.39 (CH), 158.37 (Cq)
and 158.82 (Cq); m/z (EIϩ) (rel. intensity) 213/215 (100%, Mϩ),
135 (13) and 55 (15); HRMS calcd. for C8H11N2Br79 (Mϩ)
214.0106, found 214.0111.
To a solution of pyridineؒBF3 18 (0.11 g, 0.32 mmol) in THF
(10 cm3) at Ϫ78 ЊC was added n-BuLi (2.5 M in hexanes, 0.26
cm3, 0.64 mmol). After 30 min, MeI (0.1 cm3, 1.6 mmol) was
added and the mixture was stirred for a further 30 min. The
reaction was quenched with water (10 cm3), allowed to warm to
room temperature and then extracted with CH2Cl2 (3 × 10
cm3). The organic extracts were combined, dried over MgSO4
and concentrated in vacuo. The crude material was purified by
flash chromatography (CH2Cl2–EtOAc–petrol, 3 : 1 : 4) to give
2-methylpyridineؒBF3 19 (0.078 g, 68%) as a yellow foam. Rf
0.35 (EtOAc–CH2Cl2–petrol, 1 : 3 : 3); δH (CDCl3) 1.62–1.79
(4H, m, 2 × CH2), 2.65 (3H, s, CH3), 2.73–2.92 (2H, m, CH2),
3.04–3.22 (2H, m, CH2), 6.56 (1H, s, CH), 7.35–7.55 (5Harom, m)
and 7.85–7.97 (1H ϩ 2Harom, m); δC (CDCl3) 19.61 (CH3), 25.12
(2 × CH2), 50.51 (2 × CH2), 107.86 (CH), 119.07 (Cq), 124.943
(CH), 125.08 (CH), 126.49 (CH), 127.33 (CH), 128.66 (CH),
128.81 (CH), 129.44 (CH), 132.76 (Cq), 132.98 (Cq), 133.19
(Cq), 141.85 (CH), 150.16 (Cq) and 154.59 (Cq); δF (CDCl3)
Ϫ146 (BF3); m/z decomplexed ions found: (EIϩ) (rel. intensity)
288 (15%, Mϩ), 86 (65) and 84 (100); HRMS calcd. for
C20H20N2 (Mϩ) 288.1626, found 288.1620.
Bromopyridine 15. Yellow oil (0.18 g, 38%), Rf 0.25 (CH2Cl2–
EtOAc, 3 : 2); νmax/cmϪ1 (CHCl3) 1707, 1580, 1521, 1485, 1453,
1441, 1386, 1295, 1160 and 1025; δH (CDCl3) 2.37 (3H, s, CH3),
2.85 (6H, s, 2 × CH3), 6.58 (1H, s, CH) and 8.28 (1H, s, CH); δC
(CDCl3) 23.95 (CH3), 42.40 (2 × CH3), 109.85 (Cq), 113.22
(CH), 152.33 (CH), 157.04 (Cq) and 157.71 (Cq); m/z (EIϩ) (rel.
intensity) 213/215 (100%, Mϩ), 135 (16) and 56 (50); HRMS
calcd. for C8H11N2Br79 (Mϩ) 214.0106, found 214.0097.
1,4-Dimethyl-7-(1-naphthyl)-2,3-dihydro-1H-pyrro lo[3,2-c]-
pyridineؒBF3 17
To a stirred solution of 1-methyl-7-(1-naphthyl)-2,3-dihydro-
1H-pyrrolo[3,2-c]pyridine 1615 (0.15 g, 0.58 mmol) in THF (4
cm3) at 0 ЊC was added BF3ؒTHF (0.064 cm3, 0.58 mmol). After
1 h, the mixture was cooled to Ϫ78 ЊC and n-BuLi (2.5 M in
hexanes, 0.46 cm3, 1.16 mmol) was added dropwise. After an
additional 1 h, MeI (0.37 cm3, 5.8 mmol) was added, the mix-
ture was stirred at Ϫ78 ЊC for 30 min, then 0 ЊC for 30 min and
finally warmed to room temperature. The reaction mixture was
carefully diluted with water (10 cm3) and then extracted with
CH2Cl2 (3 × 15 cm3). The organic extracts were combined,
dried over MgSO4 and concentrated in vacuo. The residue was
purified by flash chromatography (EtOAc–petrol, 1 : 1) to give
pyridineؒBF3 17 (0.14 g, 71%) as a pale yellow foam. Rf 0.24
(EtOAc–petrol, 2 : 3); νmax/cmϪ1 (CHCl3) 1658, 1596, 1533,
2-Deuterio-4-dimethylaminopyridineؒBF3 20
To a stirred solution of DMAPؒBF3 653 (0.3 g, 1.58 mmol) in
THF (15 cm3) at Ϫ78 ЊC was added n-BuLi (2.5 M in hexanes,
0.98 cm3, 3.16 mmol). After 1 h, deuterium oxide (0.3 cm3, 15.8
mmol) was added and stirring continued for 30 min. The reac-
tion mixture was warmed to room temperature and extracted
with CH2Cl2 (3 × 20 cm3). The organic extracts were combined,
dried over MgSO4 and concentrated in vacuo. Purification by
flash chromatography (CH2Cl2) gave 2-deuteriopyridineؒBF3 20
(0.29 g, 97%) as a white solid. Rf 0.25 (EtOAc–CH2Cl2–petrol,
1 : 3 : 3); νmax/cmϪ1 (CHCl3) 1621, 1550, 1438, 1388, 1363 and
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1292; δH (CDCl3) 3.31 (6H, s, 2 × CH3), 6.37 (2H, m, 2 × CH)
and 8.21 (1H, br d, CH); δC (CDCl3) 39.63 (2 ×CH3), 106.19
(2 × CH), 141.45 (t, 1JC–D = 27 Hz, Cq), 141.72 (CH) and 156.53
(Cq); m/z decomplexed ions found: (EIϩ) (rel. intensity) 123
(100%, Mϩ), 112 (49) and 83 (19); HRMS calcd. for C7H9D1N2
(Mϩ) 123.0907, found 123.0902.
decomplexed ions found: (CIϩ) (rel. intensity) 353 (MHϩ,
100%), 337 (15); HRMS calcd. for C25H24BF3N2 (NH4 adduct)
438.233, found 438.233.
( )-Diethyl[2-methyl-5-(2-phenyl-1-naphthyl)-4-pyridyl]amine
24 and ( )-diethyl[2-ethyl-5-(2-phenyl-1-naphthyl)-4-pyridyl]-
amine 25
2-Deuterio-6-methyl-4-dimethylaminopyridineؒBF3 21
To a stirred solution of pyridineؒBF3 ( )-23 (185 mg, 0.44
mmol) in THF (7 cm3) at Ϫ78 ЊC was added t-BuLi (0.590 cm3,
1.65 M, 0.97 mmol) dropwise. After 2 h, MeI (0.275 cm3, 626
mg) was added at Ϫ78 ЊC and the reaction mixture was allowed
to warm to room temperature over 18 h. The mixture was then
diluted with water (15 cm3) and extracted with CH2Cl2 (3 × 15
cm3). The organic extracts were combined, dried over MgSO4
and concentrated in vacuo. The residue was then heated at
reflux in MeOH (5 cm3) for 2 h. The resulting solution was
allowed to cool to room temperature and concentrated in
vacuo. Purification by flash chromatography (EtOAc) gave the
following compounds.
To a stirred solution of pyridineؒBF3 20 (0.15 g, 0.81 mmol) in
THF (7 cm3) at Ϫ78 ЊC was added n-BuLi (2.5 M in hexanes,
0.65 cm3, 1.62 mmol). After 1 h, MeI (0.4 cm3, 6.48 mmol) was
added and stirring continued for 1 h. The reaction mixture was
carefully quenched with water (20 cm3), warmed to room tem-
perature and extracted with CH2Cl2 (3 × 20 cm3). The organic
extracts were combined, dried over MgSO4 and concentrated in
vacuo. Purification by flash chromatography (CH2Cl2) gave
6-methylpyridineؒBF3 21 (0.12 g, 72%) as a white solid. Rf 0.40
(EtOAc–CH2Cl2–petrol, 5 : 15 : 15); νmax/cmϪ1 (CHCl3) 1627,
1540, 1444, 1365, 1095 and 904; δH (CDCl3) 2.61 (3H, s, CH3),
3.13 (6H, s, 2 × CH3) and 6.43 (2H, d, J = 5.2 Hz, 2 × CH);
δC (CDCl3) 21.28 (CH3), 39.50 (2 × CH3), 103.90 (CH), 107.91
ꢀ-Methylpyridine ( )-24. Yellow oil (40 mg, 0.11 mmol, 25%),
Rf 0.20 (EtOAc); νmax/cmϪ1 (CHCl3) 2979, 2254, 1593, 1381 and
918; δH (CDCl3) 0.52 (6H, t, J = 7.2, 2 × CH3), 2.49 (3H, s,
CH3), 2.57–2.85 (4H, m, 2 × CH2), 6.39 (1H, s, CH), 7.11–7.19
(5Harom, m), 7.40–7.55 (3Harom, m), 7.81–7.93 (3Harom, m) and
8.08 (1H, s, CH); δC (CDCl3) 12.06 (2 × CH3), 24.36 (CH3),
44.49 (2 × CH2), 110.99 (CH), 120.41 (Cq), 125.90 (CH), 126.34
(CH), 126.47 (CH), 126.66 (CH), 127.56 (2 × CH), 128.02
(2 × CH), 128.58 (CH), 129.56 (2 × CH2), 132.51 (Cq), 133.07
(Cq), 133.97 (Cq), 138.81 (Cq), 141.80 (Cq), 153.32 (CH), 155.52
(Cq) and 156.94 (Cq); m/z (EIϩ) (rel. intensity) 366 (Mϩ, 77%),
351 (100); HRMS calcd. for C26H26N2 366.2096, found
366.2096.
1
(CH), 141 (t, JC–D = 27 Hz, Cq), 154.49 (Cq) and 156.43 (Cq);
m/z decomplexed ions found: (EIϩ) (rel. intensity) 137 (100%,
Mϩ), 122 (18) and 93 (12); HRMS calcd. for C8H11N2D1 (Mϩ)
137.1063, found 137.1065.
2-Deuterio-5-(1-naphthyl)-4-pyrrolidinopyridineؒBF3 22
To a stirred solution of pyridineؒBF3 18 (0.31 g, 0.9 mmol) in
THF (15 cm3) at Ϫ78 ЊC was added n-BuLi (2.5 M in hexanes,
0.72 cm3, 1.8 mmol). After 1 h, deuterium oxide (0.5 cm3, 28
mmol) was added and stirring continued for 30 min. The reac-
tion mixture was warmed to room temperature and extracted
with CH2Cl2 (3 × 20 cm3). The organic extracts were combined,
dried over MgSO4 and concentrated in vacuo. Purification by
flash chromatography (CH2Cl2) gave 1-deuteriopyridineؒBF3 22
(0.19 g, 61%) as a pale yellow foam. Rf 0.25 (EtOAc–CH2Cl2–
petrol, 1 : 3 : 3); νmax/cmϪ1 (CHCl3) 1621, 1529, 1513, 1446,
1355, 1301, 1138, 1105, 1001 and 914; δH (CDCl3) 1.48–1.96
(4H, m, 2 × CH2), 2.63–3.80 (4H, m, 2 × CH2), 6.73 (1H, s,
CH), 7.37–7.60 (5Harom, m), 7.88–7.99 (2Harom, m) and 8.07
(1H, s, CH); δC (CDCl3) 24–26 (br, 2 × CH2), 50.29 (2 × CH2),
108.154 (CH), 120.37 (Cq), 124.93 (CH), 125.38 (CH), 126.45
(CH), 127.23 (CH), 128.67 (CH), 128.79 (CH), 129.28 (CH),
ꢀ-Ethylpyridine ( )-25. Yellow oil (19 mg, 0.05 mmol, 11%),
Rf 0.30 (EtOAc); νmax/cmϪ1 (CHCl3) 2976, 2257, 1591, 1382 and
918; δH (CDCl3) 0.51 (6H, t, J = 7.0, 2 × CH3), 1.31 (3H, t,
J = 7.6, CH3), 2.56–2.84 (6H, m, 3 × CH2), 6.38 (1H, s, CH),
7.08–7.16 (5Harom, m), 7.41–7.56 (3Harom, m), 7.84–7.94 (3Harom
,
m) and 8.10 (1H, s, CH); δC(CDCl3) 12.04 (2 × CH3), 14.09
(CH3), 31.27 (CH2), 44.56 (2 × CH2), 109.77 (CH), 120.61 (Cq),
125.90 (CH), 126.29 (CH), 126.47 (CH), 126.70 (CH), 127.49
(2 × CH), 128.00 (2 × CH), 128.57 (CH), 129.59 (2 × CH),
132.52 (Cq), 133.07 (Cq), 134.05 (Cq), 138.83 (Cq), 141.80 (Cq),
153.37 (CH), 155.65 (Cq), and 162.32 (Cq); m/z (EIϩ) (rel. inten-
sity) 380 (Mϩ, 85%), 365 (100); HRMS calculated for C27H28N2
380.2253, found 380.2260.
1
132.90 (Cq), 133.06 (Cq), 134.32 (Cq), 140.51 (t, JC–D = 27 Hz,
Cq), 144.25 (CH) and 153.95 (Cq). Found: C, 66.08; H,
5.23; N, 8.03. Calcd. for C19H17D1N2B1F3: C, 66.50; H, 4.99;
N, 8.16%.
Optical resolution of biaryl ( )-24
The enantiomers of biaryl 24 were separated using semi-
preparative CSP HPLC (Chiralcel OD column, 1 × 25 cm;
hexanes–EtOAc–Et2NH, 90 : 9.6 : 0.4; 4 cm3 minϪ1; 30 ЊC).
UV detection was performed at 250 nm. Injections of ∼0.5 mg
of the racemate in 5 µL of CH2Cl2 were made every 12 min.
Enantiomer (Ϫ)-24 was collected from 9.0 to 10.5 min, and
enantiomer (ϩ)-24 was collected from 14.0 to 15.5 min. Both
enantiomers were pale yellow oils. Analytical CSP HPLC
revealed >99.9% ee for the levorotatory {[α]2D5 Ϫ107 (c 0.15 in
CHCl3)} and >97.9% for the dextrorotatory {[α]2D5 ϩ100 (c 0.20
in CHCl3)} enantiomer.
( )-Diethyl[3-(2-phenyl-1-naphthyl)-4-pyridyl]amineؒBF3 23
To a stirred solution of pyridine ( )-116 (397 mg, 1.13 mmol) in
THF (10 cm3) at 0 ЊC was added BF3ؒTHF. The resulting solu-
tion was stirred for 1 h at this temperature and then allowed to
warm to room temperature. The solution was then concentrated
in vacuo, and purified by flash chromatography (EtOAc–petrol,
1 : 1) to give the pyridineؒBF3 ( )-23 as a white solid (294 mg,
0.70 mmol, 62%). Rf 0.75 (EtOAc–petrol, 1 : 1); mp 150–152 ЊC;
νmax/cmϪ1 (CHCl3) 2978, 1636, 1526 and 1115; δH (CDCl3) 0.65
(6H, t, J = 7.2 Hz, 2 × CH3), 2.79–2.88 (2H, m, CH2), 3.05–3.10
(2H, m, CH2), 6.54 (1H, d, J = 7.3Hz, CH), 7.03–7.06 (2Harom
,
m), 7.20–7.25 (3Harom, m), 7.51–7.58 (3Harom, m), 7.74 (1H, d,
J = 7.9 Hz, CH), 7.94 (1H, d, J = 7.1 Hz, CH), 7.99 (1H, d,
J = 8.5 Hz, CH), 8.06 (1H, s, CH) and 8.10 (1H, d, J = 7.2 Hz,
CH); δC (CDCl3) 12.22 (2 × CH3), 45.49 (2 × CH2), 109.54
(CH), 120.10 (Cq), 125.85 (CH), 126.57 (CH), 127.17 (CH),
127.58 (CH), 128.16 (3 × CH), 128.53 (CH), 129.28 (2 × CH),
129.49 (CH), 131.51 (Cq), 131.67 (Cq), 133.06 (Cq), 139.46 (Cq),
140.51 (Cq), 140.57 (CH), 146.50 (CH), and 156.59 (Cq); m/z
Representative procedure for rate experiments using 1-
phenylethanol. The experiment employing 2-methyl-DMAP 9
To a stirred solution of 2-methyl-DMAP 9 (0.007 g, 0.05
mmol), 1-phenylethanol (0.122 g, 1.0 mmol) and Et3N (0.209
cm3, 1.5 mmol) in THF (2 cm3) was added Ac2O (0.094 cm3, 1.0
mmol). After 5 min, ∼0.5 cm3 of the reaction mixture was
removed and quickly filtered through a short plug of silica
1792
J. Chem. Soc., Perkin Trans. 1, 2001, 1785–1794

View Article Online
(CH2Cl2–EtOAc, 19 : 1). After 15 min, 4 h and 24 h this
sampling procedure was repeated. After evaporation of the
solvent, the extent of reaction was determined by HPLC
(Chiralcel OD column, 0.46 × 25 cm; hexanes–propan-2-ol,
99 : 1; 1 cm3 minϪ1; 0 ЊC): Rt [(R)- and (S)-acetates] 7.4 and 8.4
min; Rt [(R) and (S)-alcohol] 31 and 49 min.16
2 × CH3), 7.19 (2H, d, J = 8.0 Hz, 2 × CH) and 9.06 (2H, d,
J = 8.0 Hz, 2 × CH).
Dimethyl[pyridin-4(1H)-ylidene]ammonium chloride 33. δH
(CDCl3, 400 MHz) 3.18 (6H, s, 2 × CH3), 6.75 (2H, d, J = 7.0
Hz, 2 × CH) and 8.05 (2H, t, J = 7.0 Hz, 2 × CH).
2-Methyl-4-(dimethylamino)pyridine 9. Data as above.
Representative procedure for catalytic KR of alcohol ( )-1-
(1-naphthyl)ethanol. The experiment employing catalyst (Ϫ)-24
Dimethyl[1-acetyl-2-methylpyridin-4(1H)-ylidene]ammonium
chloride 32. δH (CDCl3, 400 MHz) 2.69 (3H, s, CH3), 2.80 (3H, s,
COCH3), 3.31 (3H, s, CH3), 3.33 (3H, s, CH3), 6.72 (1H, d,
J = 3.0 Hz, CH), 6.95 (1H, dd, J = 3.0, 8.0 Hz, CH) and 8.57
(1H, d, J = 8.0 Hz, CH).
A solution of ( )-1-(1-naphthyl)ethanol (172 mg, 1.00 mmol),
Et3N (104 µL, 0.75 mmol), and catalyst (Ϫ)-24 (3.7 mg, 10
µmol, >99.9% ee) in toluene (2.0 cm3) was cooled to 0 ЊC. Dur-
ing vigorous stirring, (iPrCO)2O (331 µL, 2.00 mmol) was added
dropwise. After 24 h at 0 ЊC, the reaction was quenched by
addition of MeOH (10 cm3) at 0 ЊC. The mixture was allowed to
warm to room temperature over 15 min and the solvents were
evaporated in vacuo. 1-(1-Naphthyl)ethanol and its isobutyric
ester were separated by flash chromatography (petrol–CH2Cl2,
1 : 1 → CH2Cl2). The ester was hydrolyzed by heating to reflux
in 5% NaOH–MeOH (2 cm3) for 5 min.18 After evaporation of
the solvent, the residue was passed through a short flash silica
column eluting with EtOAc. The enantiomeric excess for the
unreacted alcohol and the alcohol obtained by the ester saponi-
fication was established by analytical CSP HPLC (Chiralcel
OD column, 0.46 × 25 cm; hexanes–propan-2-ol, 90 : 10; 1 cm3
minϪ1; 30 ЊC): Rt [(S)-alcohol] 12.4 min; Rt [(R)-alcohol] 21.1
min.16
Dimethyl[2-methylpyridin-4(1H)-ylidene]ammonium chloride
34. δH (CDCl3, 400 MHz) 2.60 (3H, s, CH3), 3.18 (6H, s,
2 × CH3), 6.50 (1H, d, J = 2.0 Hz, CH), 6.65 (1H, dd, J = 7.0,
2.0 Hz, CH) and 7.93 (1H, t, J = 7.0 Hz, CH).
Acknowledgements
Grateful acknowledgement is made to the ESPRC, the BBSRC,
and GlaxoSmithKline for financial support. We thank Mr
Teyrnon Jones and Mr Fujiang Zhu (Sheffield University) for
assistance with NMR experiments.
References
1H NMR data for compounds in Table 3
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,
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(1Harom, d, J = 6.0 Hz), 7.92 (1Harom, d, J = 7.5 Hz) and 7.98
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4-(Dimethylamino)pyridine 30. δH (CDCl3, 400 MHz) 2.96
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J. Chem. Soc., Perkin Trans. 1, 2001, 1785–1794
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