Preparative-Scale Synthesis of Vedejs Chiral DMAP Catalysts

Article abstract of DOI:10.1021/acs.joc.8b01687

A scalable synthesis of chiral Vedejs-type DMAP catalysts is reported. The key step of the synthesis is amination of the enantiomerically pure 4-chloropyridine derivative using well-defined ZnCl₂(amine)₂ complexes. A series of Zn(II)-amine complexes have been synthesized to explore the scope of the ZnCl₂-mediated amination of 4-halopyridines. Mechanistic studies support a Zn(II)-facilitated nucleophilic aromatic substitution as a plausible mechanism for the chlorine-to-amine exchange.

Full text of DOI:10.1021/acs.joc.8b01687

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Article
Preparative Scale Synthesis of Vedejs Chiral DMAP Catalysts
Artis Kinens, Simonas Balkaitis, and Edgars Suna
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01687 • Publication Date (Web): 26 Sep 2018
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Preparative Scale Synthesis of Vedejs Chiral DMAP Catalysts
Artis Kinensa,b, Simonas Balkaitisa,b and Edgars Sunaa,b*
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a Latvian Institute of Organic Synthesis, Aizkraukles 21, LVꢀ1006, Riga, Latvia
b University of Latvia, Department of Chemistry, Jelgavas 1, LVꢀ1004 Riga, Latvia
edgars@osi.lv
TOC Abstract.
Abstract. A scalable synthesis of chiral Vedejsꢀtype DMAP catalysts is reported. The key
step of the synthesis is amination of the enantiomerically pure 4ꢀchloropyridine derivative
using wellꢀdefined ZnCl2(amine)2 complexes. A series of Zn(II)ꢀamine complexes have been
synthesized to explore the scope of the ZnCl2ꢀmediated amination of 4ꢀhalopyridines.
Mechanistic studies support a Zn(II)ꢀfacilitated nucleophilic aromatic substitution as a
plausible mechanism for the chlorineꢀtoꢀamine exchange.
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Introduction
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Chiral DMAPꢀcatalyzed asymmetric acylꢀtransfer reactions are widely used in the
synthesis of enantiomerically pure compounds.1 A variety of chiral DMAP catalysts have
been developed for a range of enantioselective acylation reactions.2 Among them, a family of
tertꢀleucineꢀderived chiral DMAP catalysts (S,S)–1 developed by Vedejs (Figure 1, eq 1)
have provided excellent enantiocontrol in the Steglich rearrangement of indolyl acetates and
carbonates,3a in the kinetic resolution (KR) of secondary alcohols3b as well as in the dynamic
KR of azoleꢀderived hemiaminals.3c The efficiency of Vedejs catalysts in various asymmetric
transformations is attributed to their modular design, which allows for a relatively simple
fineꢀtuning of the chiral DMAP structure for a particular stereoselective reaction.
Unfortunately, the challenges associated with the preparative scale synthesis of chiral DMAP
(S,S)–1 has hampered its wider application in enantioselective synthesis. The difficult step for
the scaleꢀup is attachment of the tertꢀleucine chiral subunit to the DMAP core, a reaction that
requires lithiation of a DMAP derivative with excess tertꢀBuLi. Herein we report a new
approach towards the family of chiral DMAP catalysts (S,S)–1, which is based on a highly
diastereoselective addition of 3ꢀlithioꢀ4ꢀchloropyridine intermediate to (S)–tertꢀleucineꢀ
derived aldehyde (S)–2, followed by ZnCl2ꢀmediated substitution of chlorine for amine as
key steps (Figure 1, eq 2). The new approach is especially suitable for multiꢀgram scale
syntheses of the chiral DMAP catalysts (S,S)–1 since inexpensive starting 4ꢀchloropyridine
and easyꢀtoꢀhandle and safe LDA are used in the orthoꢀlithiation step. Furthermore, the
ZnCl2ꢀpromoted amination step allows for installation of a range of amines in the pyridine
subunit, thus further increasing modularity of the chiral DMAP catalysts (S,S)–1. It should be
also noted that halideꢀtoꢀamine exchange is a frequently used transformation in the synthesis
of chiral DMAP catalysts. For example, Connon and Spivey employed the amination of 4ꢀ
chloropyridines under SNAr conditions2cꢀe to obtain chiral DMAP species. Alternatively, 4ꢀ
amino substituent was also introduced into pyridine core through 3,4ꢀpyridyne intermediate.2f
Finally, Mandai and Suga utilized Pdꢀcatalyzed BuchwaldꢀHartwig amination of 4ꢀ
bromopyridine2b in the synthesis of their C2ꢀsymmetric chiral DMAP catalyst. Application of
the ZnCl2ꢀpromoted amination as inexpensive and relatively mild complementary
methodology to access these catalysts is demonstrated below.
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Figure 1. Synthesis of chiral DMAP catalysts.
Results and Discussion
The requirement for an excess of the highly pyrophoric tꢀBuLi to generate 3ꢀLiꢀ
DMAP from the corresponding bromide (Figure 1, eq 1)3a,c largely constrains multiꢀgram
scale preparation of chiral DMAP (S,S)–1 because of safety reasons. Attempts to replace tꢀ
BuLi with a less hazardous and easierꢀtoꢀhandle lithiation reagent such as nꢀBuLi was not
successful and resulted in decreased yields of the addition product (S,S)–3. We realized that
directed orthoꢀlithiation of a suitably substituted pyridine is the most straightforward
approach for installation of the tertꢀleucine chiral subunit. Unfortunately, a directed orthoꢀ
lithiation4 of DMAP at position 3 with LDA was not successful, apparently because of poor
orthoꢀdirecting ability of the N,Nꢀdimethylamino moiety. The search for a more efficient
orthoꢀdirecting group that could be subsequently transformed into N,Nꢀdimethylamino
moiety led us to the choice of commercially available and inexpensive 4ꢀchloropyridine as a
substrate for the orthoꢀlithiation. Treatment of commercially available 4ꢀchloropyridine
hydrochloride5 with two equivalents of LDA,6 followed by a reaction with enantiomerically
pure aldehyde (S)–2b3c afforded (S,S)–4b in 71% yield (Figure 1, eq 2). Gratifyingly, the
addition of lithiated pyridine to (S)–2b proceeded with excellent diastereoselectivity (98:2
dr). The diastereomeric purity of the crystalline aldol product (S,S)–4b was increased to
>99:1 dr by a single recrystallization of the crude material. Absolute configuration of the
newly created stereogenic center was confirmed to be (S) by comparison of a downstream
synthesis product (S,S)–1b with a batch of a previously synthesized catalyst.3c The lithiationꢀ
addition sequence was easily scaledꢀup to more than 5 g loading of 4ꢀchloropyridine.
Next, substitution of the 4ꢀchloro moiety by the dimethylamino group was
investigated. Attempted reaction of 4ꢀchloropyridine (S,S)–4b with 40% aqueous
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dimethylamine (100 oC, 48 h)7 afforded the desired (S,S)–3b in poor yields along with
multiple decomposition products (entry 1, Table 1). Nucleophilic substitution of chlorine
with liquid HNMe2 in various anhydrous solvents such as methanol, DMSO and DMF
(entries 2ꢀ4) was also unsuccessful. When a 1:1 (v/v) mixture of DMF and water was used as
a solvent, the reaction with HNMe2 resulted in formation of the desired (S,S)–3b without
concomitant decomposition of the starting (S,S)–4b. Although the presence of water
facilitated the formation of chiral DMAP (S,S)–3b, the reaction was very slow, and only 30%
conversion after heating at 100 oC for 20 h could be achieved (entry 5). The use of DMF as a
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source of HNMe2 led to complete decomposition of the starting (S,S)–4b (entry 6).
Disappointingly, the reaction with liquid HNMe2 in the presence of catalytic Cu/CuCl9 did
not afford the desired chiral DMAP (entry 7). In contrast, the reaction of (S,S)–4b with
ZnCl2(NHMe2)2(HCl)2, prepared from ZnCl2 and Me2NH hydrochloride,10 furnished the
desired chiral DMAP (S,S)–3b in 71% yield (entry 8).11 Unfortunately, the success of the
ZnCl2ꢀmediated substitution was counterbalanced by experimental difficulties associated with
handling the thick suspension of inorganic salts (ca. 1.8 g of solid in 1 mL of DMSO) and
with generation of considerable amounts of inorganic waste. Furthermore, ca. 10% of a sideꢀ
product oxazoline (S,S)–5 was also formed, and its separation from the desired (S,S)–3b
required chromatography. To address these shortcomings, the ZnCl2ꢀmediated substitution
reaction was investigated in more detail.
Table 1. Optimization of the amination conditions.
entry conditions
(S,S)–3b, %
20a
<1b
<1b
<1b
30c
<1a
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40% HNMe2 in water, 100 °C, 47 h
HNMe2 (liquid):methanol 1:1 (v/v), 100 °C, 13 h
HNMe2 (liquid):DMF 1:1 (v/v), 100 °C, 13 h
HNMe2 (liquid):DMSO 1:1 (v/v), 100 °C, 13 h
HNMe2 (liquid):DMF:water 2:1:1 (v/v), 100 °C, 20 h
K2CO3, DMF,d 80 °C, 60 h
HNMe2 (liquid), Cu (0.25 equiv), CuI (0.25 equiv) 80 °C, 40 h <1a
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ZnCl2(NHMe2)2(HCl)2 (6; 5 equiv), K2CO3 (1.3 equiv), DMSO, 71e
100 °C, 21 h
ZnCl2(NHMe2)2 (7a; 2 equiv), DMF, 80 °C, 63 h
80
a Accompanied by multiple decomposition products b No conversion of (S,S)–4b. c At 30% conversion of (S,S)–
4b. d DMF served both as a source of HNMe2 and as a solvent. eAccompanied by ca. 10% of oxazoline (S,S)–5.
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We hypothesized that a complex between ZnCl2 and the free base HNMe2 is the
reactive species in the ZnCl2ꢀmediated substitution reaction, and that the role of K2CO3 is
limited to the conversion of complex 610b into the reactive species. To verify this hypothesis,
a new complex ZnCl2(NHMe2)2 (7a) was prepared by mixing equimolar amounts of HNMe2
(2M solution in THF) and ZnCl2 in Et2O.12 Gratifyingly, addition of 7a (2 equiv) to (S,S)–4b
in DMF resulted in a smooth formation of the desired (S,S)–3b in 80% yield (entry 9, Table
1). Furthermore, the excellent solubility of the Zn(II)ꢀamine complex 7a in DMF completely
circumvented difficulties with handling the previously encountered thick suspension of
inorganic salts.
To examine the scope of amines in the Zn(II)–mediated chlorine substitution reaction,
a series of Zn(II)ꢀamine complexes 7b–j have been synthesized (Table 2) from the
corresponding amine and ZnCl2 in Et2O. Products 7a,c–j precipitated from the reaction
mixture and could be recrystallized from EtOH. Complex 7b was obtained as an oil in
moderate yield (entry 2). The structures of Zn complexes 7d,f,h,j have been verified by Xꢀray
crystallographic analysis. Interestingly, the alcohol moiety of 1,2ꢀaminoalcohol 7h is not
involved in the complex formation with Zn(II) species as evidenced by the Xꢀray data (see
Supporting Information). Secondary amineꢀderived complexes 7a,b,d–f readily reacted with
4ꢀchloropyridine and formed the corresponding 4ꢀaminopyridines within 3 h (entries 1,2,4–6,
Table 2). A slower reaction was observed for primary aliphatic and aromatic amineꢀ
containing Zn species 7c,g,j (entries 3,7,10). as well as for sterically hindered secondary
amineꢀderived Zn complexes 7h,k (entries 8,11). It should be mentioned that Zn(II)ꢀamine
complexes could not be obtained in a pure form from sterically highly hindered N,Nꢀ
diisopropylamine and 2,6ꢀdimethylpiperidine. Hence, secondary amines possessing steric
bulk next to the nitrogen atom are not suitable for the Zn(II)ꢀmediated amination reaction.
The Zn(II)ꢀmediated amination reaction conditions are compatible with the alcohol (entry 8)
and the carbamate NꢀH (entry 9) moieties in the amine. Finally, the reaction between 4ꢀ
chloropyridine and Zn complex (R,R)–7k (entry 11, Table 2) is a less expensive alternative to
the Pdꢀcatalyzed BuchwaldꢀHartwig amination for the synthesis of axially chiral DMAP
catalyst (R)–8k, developed by Mandai and Suga.2b
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Table 2. The scope of amines.
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entry R1R2NH
yield of 7
yield of 8 (time)
8a, 82% (3 h)
8b, 68% (3 h)
1
2
Me2NH
Et2NH
7a, 75%
7b, 39%
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5
7c, 64%
7d, 70%a
7e, 85%
8c, 53% (18 h)
8d, 77% (3 h)
8e, 64% (3 h)
6
7f, 80%a
7g, 93%
8f, 73% (3 h)
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8
PhNH2
8g, 86% (18 h)
(S,S)–7h, 76%a (S)–8h, 79% (18 h)
9
7i, 86%
8i, 86% (18 h)
10
(S,S)–7j, 80%a
(S)–8j, 83% (32 h)
11
(R,R)–7k, 68%
(R)–8k, 75% (16 h)
a Structure confirmed by Xꢀray crystallographic analysis.
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Next, the scope of pyridines was examined in the reaction with Zn(II)ꢀamine complex
7d (Table 3). The amination reaction of 4ꢀhalosubstituted pyridines with 7d proceeded
readily (entries 1–4) with 4ꢀfluoropyridine being the most reactive among halides (entry 1).
The reactivity of halides decreased in the order F>Cl>Br>I. In addition, 2ꢀhalosubstituted
pyridines were less reactive than their 4ꢀsubstituted congeners: only 2ꢀfluoropyridine
underwent amination with Zn complex 7d (entry 5), whereas 2ꢀCl and 2ꢀBrꢀpyridines did not
react under standard conditions (entries 6,7). This allowed for selective substitution at the
position 4 in 2,4ꢀdichloropyridine (entry 8),13 whereas 2ꢀfluoroꢀ4ꢀchloropyridine underwent
selective substitution of the more reactive fluoroꢀmoiety (entry 12). Notably, the amination
proceeded considerably faster for 2ꢀunsubstituted pyridine (entry 2) as compared to its 2ꢀCl
and 2ꢀPh substituted analogs (compare reaction halfꢀlives in entries 2, 8 and 9, Table 3). The
presence of a substituent in position 3 has a less pronounced influence on the reactivity with
Zn complex 7d (see reaction halfꢀlives in entries 2, 10 and 11). These observations imply that
the reactivity of the 4ꢀchloro substituent in pyridines is influenced mostly by steric bulk in the
remote meta position, and to a lesser extent by substitution of the proximal orthoꢀposition.
Finally, the Zn(II)–mediated amination of 9 and 10 with 7a (entries 13 and 14, respectively)
provides a convenient access to DMAP species such as rac–8r (precursor of TADMAP
catalyst)14 and the N,Nꢀdimethylamino analogue of Spivey catalyst rac–8s.2e,f
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Table 3. Substrate scope for the amination reaction.a
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9
entry substrate
product, yield
t1/2, h
<0.5
3.6
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4
4ꢀFꢀpyridine
4ꢀClꢀpyridine
4ꢀBrꢀpyridine
4ꢀIꢀpyridine
4.7
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8d, 88ꢀ90%
8l, 83%
19.2
5
2ꢀFꢀpyridine
4.2
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7
2ꢀClꢀpyridine no reactionb
2ꢀBrꢀpyridine no reactionb
ꢀ
ꢀ
8
63.7
75.0
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8m, 78%
9c
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8n, 56%d
8o, 73%
35.9
8p, 67%
8q, 95%
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nd
8r, 83%
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14e
nd
8s, 78%
10
a Reaction conditions: pyridine (1 equiv), Zn complex 7 (2 equiv), DMF (1 mL per 1 mmol of pyridine), 40
oC. b 0% conversion after 24 h. c The reaction was performed at 80 oC; 0% conversion after 75h at 40 oC. d At
50% conversion. e The reaction was performed at 120 oC
The relative reactivity of 4ꢀhalopyridines (F>Cl>Br>I) is characteristic to that
observed in nucleophilic aromatic substitution (SNAr) reactions. Therefore we hypothesized
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that the Zn complex–mediated amination of halopyridines proceeds through the SNAr
pathway. We propose that the Zn(II) species helps to stabilize a transient Meisenheimerꢀtype
anionic intermediate of the nucleophilic aromatic substitution reaction by forming a Lewis
acidꢀLewis base complex with pyridine under equilibrium conditions (Scheme 1).
Experimental evidence for the complex formation between pyridine and ZnCl2 was obtained
from NMR studies. Thus, addition of ZnCl2 (1 equiv) to 4ꢀchloropyridine B resulted in an
upfield shift of pyridine nitrogen (15NꢀNMR)15 and a downfield shift of carbon C4 resonances
(Table 4). Less pronounced changes of 13C signals were observed for other carbon atoms.
Furthermore, substantial decrease of 13C spinꢀlattice relaxation times T1 for all carbon atoms
was observed in pyridine B in the presence of ZnCl2, with the largest decrease of 62% (from
12.6 to 4.8 sec) measured for carbon C4 (Table 4). Even larger shifts of 13C and 15N signals
as well as more pronounced decrease of T1 values were measured for the relatively more
Lewis basic pyridine A in the presence of added ZnCl2.16 In sharp contrast, negligible
changes of the chemical shifts and relaxation times were observed for 2ꢀPh substituted
pyridine C. This suggests a small equilibrium concentration of the Lewis acidꢀLewis base
complex between ZnCl2 and pyridine C, presumably because of a steric shielding of the
nitrogen by 2ꢀphenyl substituent. Such a hypothesis is in agreement with the considerably
longer reaction times required for chlorine to amine exchange at position 4 of 2ꢀPh and 2ꢀCl
pyridines (entries 8,9, Table 3) as opposed to their 3ꢀsubstituted analogues (entries 10,11,
Table 3) or 4ꢀchloropyridine (entry 2, Table 3).
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Kinetic studies were also carried out to establish the kinetic order of Zn(II)ꢀmediated
amination of 4ꢀchloropyridine in each reaction component. The reactions were monitored by
NMR spectroscopy, and the reaction order in Zn(II) complex 7d and 4ꢀchloropyridine was
determined by plotting the reaction halfꢀtime vs. natural logarithm of reactants concentration
(Noyes plot). The amination of 4ꢀchloropyridine in DMF at 40 oC was found to be secondꢀ
order in Zn(II) complex 7d (see SI, Figure S1) and firstꢀorder in 4ꢀchloropyridine (see SI,
Figure S2). These data indicate that two equivalents of Zn(II) complex 7d are involved in a
rateꢀdetermining step of the amination. In fact, a stoichiometry of a classical twoꢀstep baseꢀ
catalyzed SNAr reaction in polar aprotic solvents in the absence of added general base
requires two equivalents of amine, with one acting as a nucleophile, and the other one serving
as a base.17
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Table 4. Percent Change of 13C and 15N chemical shiftsa and spinꢀlattice relaxation time T1.b
4
5
6
7
8
9
Ac
Cd
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B
Atom
ꢀδ (%) ꢀΤ1 (%) ꢀδ (%) ꢀΤ1 (%) ꢀδ (%) ꢀΤ1 (%)
C2
C3
C4
C5
C6
N1
0.51
ꢀ1.03
ꢀ2.06
ꢀ1.03
0.51
ꢀ74.2
ꢀ75.0
ꢀ87.7
ꢀ75.0
ꢀ74.2
ꢀ
0.30
ꢀ0.38
ꢀ0.72
ꢀ0.38
0.30
ꢀ39.1
ꢀ43.1
ꢀ61.9
ꢀ43.1
ꢀ39.1
ꢀ
0.18
0.21
0.19
0.22
0.16
0.05
ꢀ15.7
ꢀ15.0
ꢀ10.6
ꢀ11.6
ꢀ13.4
ꢀ
10.5
4.14
a For chemical shift values see SI. Negative values represent a downfield shift and positive values an upfield
shift of NMR signals. b Negative ꢀΤ1 values represent decrease of relaxation time. c A 1:1 mixture of 4ꢀ
chloropyridine hydrochloride and DIPEA was used. d Determined in DMF–d7.
Consistent with the data above is a plausible pathway for Zn(II)ꢀmediated amination
of 4ꢀchloropyridines, which involves an initial reversible formation of Zn(II)ꢀpyridine
complex IM1 and pyrrolidine (Scheme 1). Subsequent nucleophilic ipsoꢀaddition of
pyrrolidine to the Zn(II)ꢀcoordinated 4ꢀchloropyridine results in the formation of
Meisenheimerꢀtype intermediate IM2. Not only is the electrophilicity of pyridine increased,
but also the intermediate zwitterionic complex IM2 is stabilized by complexation with Lewis
acidic Zn(II) species. Ion pair IM3 is generated after proton transfer from intermediate IM2
to the pyrrolidine ligand of the complex 7d. Finally, departure of the chloride leaving group
provides Zn complex IM4 which hydrolyzes to pyridine 8d during the workup (Scheme 1). It
is conceivable that the departure of the chloride leaving group is facilitated by coordination to
a Zn(II) species, however we do not have sufficient evidence to support this assumption.
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Scheme 1. Working mechanism for Zn(II)ꢀmediated amination reaction.
The proposed mechanism implies that only 3 equivalents of pyrrolidine are available
under equilibrium conditions for the nucleophilic substitution of chlorine, whereas one
equivalent of the amine is involved in the Zn(II)ꢀpyridine complex formation. This scenario
was supported by a control experiment where 4ꢀchloropyridine was reacted with a 2:1
mixture of Zn(II) complex 7a and pyrrolidine under standard conditions (eq 3). In total 5
equivalents of amines of comparable Lewis basicity and nucleophilicity (nucleophilicity
parameter N for Me2NH in MeCN is N=17.9618a and for pyrrolidine N=18.6418b) were present
in the reaction mixture under equlibrium conditions, however chlorine substitution products
DMAP and PPY were formed in 3:1 ratio (1HꢀNMR assay). Comparable reactivity of
pyrrolidine and Znꢀcoordinated Me2NH in the substitution of chlorine also supports exchange
of amine ligands between different Zn(II) complexes.19a Finally, coordination of Zn(II)
species by the solvent and formation of DMFꢀcontaing complexes such as Zn(DMF)2Cl219b or
mixed analogues such as Zn(DMF)(amine)Cl2 under equilibrium conditions cannot be ruled
out. Nevertheless, we regard the aromatic nucleophilic substitution mechanism via IM1
(Scheme 1) to be sufficiently plausible and consistent with the available data for most
experiments.20
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Chiral DMAP derivatives (S,S)–3a,b and (S,S)–11 were obtained in 76ꢀ80% yield
from pyridines (S,S)–4a,b and Zn(II)ꢀamine complexes 7a,d under the optimized conditions
for the aromatic nucleophilic substitution (Scheme 2). Because the amination proceeded
without formation of sideꢀproducts such as (S,S)–5 (see Table 1), a simple extractive workup
was sufficient to obtain targets (S,S)–3a,b and (S,S)–11 in pure form and additional
chromatographic purification was not required. Finally, Oꢀacetylation with Ac2O provided
the corresponding chiral DMAP catalysts (S,S)–1a,b and (S,S)–12 in excellent 91ꢀ95% yield
(Scheme 2). Pure products were obtained by recrystallization of crude solid materials.
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N
N
OR
Cl OH
Me2N
N
OR
7d (2 equiv)
7a (2 equiv)
HN
O
HN
O
HN
O
DMF, 80 °C
DMF, 80 °C
N
Ar
Ar
Ar
Ac2O
NEt3
Ac2O
NEt3
(S,S)-11, R=H
(S,S)-12, R=Ac
(S,S)-4a,b
(S,S)-3a,b, R=H
(S,S)-1a,b, R=Ac
a: Ar = Ph
b: Ar = 3,5-(CF3)2-C6H4-
CH2Cl2
CH2Cl2
Scheme 2. Final stages of chiral DMAP synthesis.
Conclusions
A scalable synthesis of Vedejsꢀtype chiral DMAP catalysts comprising two key steps
has been described. The first key step is orthoꢀlithiation of readily available and inexpensive
4ꢀchloropyridine hydrochloride with LDA, and subsequent highly diastereoselective (98:2 dr)
addition of the lithiated intermediate to (S)–tertꢀleucineꢀderived aldehyde (S)–2. The
diastereomeric purity of the crystalline aldol product (S,S)–4 was increased to >99:1 dr by a
single recrystallization. The second key step of the synthesis is the substitution of the 4ꢀ
chloro moiety in the enantiomerically pure pyridine (S,S)–4 with dimethylamine or
pyrrolidine. The amination employs wellꢀdefined Zn(amine)2Cl2 complexes, which were
prepared from ZnCl2 and the respective amine. Only those amines which form relatively
stable complexes with ZnCl2 can be employed in the amination. Primary and secondary
aliphatic amines as well as aniline readily formed crystalline complexes with ZnCl2, and
structures of Zn(amine)2Cl2 complexes 7d,f,h,j were confirmed by Xꢀray crystallographic
analysis. The reactivity of pyridyl halides with Zn(II)ꢀamine species decreased in the order
F>Cl>Br>I, and selective amination of the more reactive 4ꢀchloro substituent in 2,4ꢀ
dichloropyridine can be achieved. The reactivity of the 4ꢀchloro substituent is reduced
considerably if the heterocycle possesses a substituent next to the pyridine nitrogen.
Mechanistic studies suggest that the pyridine nitrogen forms a complex with Zn(II) species
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under equilibrium conditions. Lewis acidꢀLewis baseꢀtype interactions between Zn(II)
species and 4ꢀhalopyridine increases electrophilicity of the heterocycle and helps to stabilize
the Meisenheimerꢀtype intermediate of the aromatic nucleophilic substitution reaction. The
developed synthetic approach is especially suitable for the multiꢀgram scale synthesis of
chiral DMAP derivatives because it employs safe and inexpensive chemicals and avoids
chromatographic purification. Lateꢀstage introduction of the amine moiety in the pyridine
core helps to fineꢀtune the nucleophilicity of Vedejs chiral DMAP catalysts for given
asymmetric transformations. Efficiency of the Zn(II)–mediated chlorine substitution reaction
in the synthesis of various DMAP catalysts is also demonstrated. Finally, the Zn(II)ꢀmediated
amination may be especially useful for the synthesis of pharmaceutically relevant
aminopyridines in cases where the transition metalꢀcatalyzed amination is not applicable.
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Experimental Section
General Information. Unless otherwise noted, all chemicals were used as obtained from
commercial sources and all reactions were performed under argon atmosphere. Analytical
thinꢀlayer chromatography (TLC) was performed on precoated silica gel Fꢀ254 plates.
Nuclear magnetic resonance spectra were recorded on NMR spectrometers at the following
frequencies: 1H, 400 or 300 MHz; 13C{1H}, 101 or 75 MHz; HCNMBC, 800 MHz. Chemical
shifts are reported in parts per million (ppm) relative to TMS or with the residual solvent
peak as an internal reference. Infrared (IR) spectra were recorded with a KBr pellet, and
wavenumbers are given in cm−1. Highꢀresolution mass spectra (HRMS) were recorded on a
TOF MS instrument using ESI or the APCI techniques.
General procedure A for synthesis of 4-chloropyridines (S,S)–4a,b. nꢀBuLi (2.5 M
solution in hexane, 4.6 equiv) was added to a solution of diisopropylamine (4.6 equiv in
anhydrous THF (1 mL of solvent / 1 mmol of diisopropylamine) at –75 °C (acetone/dry ice
bath) under argon atmosphere. The light yellow solution was stirred at –75 °C for 2 h and
then transferred via cannula to a suspension of 4ꢀchloropyridine hydrochloride (2.2 equiv) in
anhydrous THF (2.4 mL / 1 mmol of 4ꢀchloropyridine hydrochloride) at –75 °C. The
resulting light yellow solution was stirred at –75 °C for 2 h, whereupon a solution of
aldehyde (S)ꢀ2a3c or (S)ꢀ2b3c (1 equiv) in anhydrous THF (0.7 mL/1 mmol of aldehyde) was
added at a rate to maintain the reaction temperature below –73 °C. The light orange solution
was stirred at –75 °C for 2 h, and then quenched with a saturated aqueous solution of NH4Cl
(0.5 mL/1 mmol of LDA). After warming to rt all volatiles were removed under reduced
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pressure. The orange residue was diluted with EtOAc (15 mL/1 mmol of aldehyde) and
washed twice with H2O (15 mL/1 mmol of aldehyde), then with 0.5 M aqueous NaOH
solution (15 mL/1 mmol of aldehyde) and brine (15 mL/1 mmol of aldehyde). The organic
layer was dried over Na2SO4, filtered and concentrated under reduced pressure.
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N-((1S,2S)-1-(4-Chloropyridin-3-yl)-1-hydroxy-3,3-dimethylbutan-2-yl)benzamide
((S,S)–4a). The title compound was obtained as fine sandꢀcolored crystals (4.37 g, 63 %)
from 4ꢀchloropyridine hydrochloride (6.92 g, 46.2 mmol, 2.2 equiv) and aldehyde (S)-2a3c
(4.6 g, 21.0 mmol, 1 equiv) by following general procedure A. Pure material was obtained by
recrystallization from CH2Cl2 (50 mL) and hexane (200 mL); mp 181ꢀ182 °C. Analytical
TLC on silica gel, 1:1 EtOAc/Hexanes, Rf = 0.12. 1H NMR (400 MHz, CDCl3, ppm) δ 8.53
(1H, s), 8.24 (1H, d, J = 5.3 Hz), 7.66–7.60 (2H, m), 7.49–7.43 (1H, m), 7.41–7.34 (2H, m),
7.19 (1H, d, J = 5.3 Hz), 6.79 (1H, d, J = 10.2 Hz), 5.53 (1H, d, J = 3.5 Hz), 4.07 (1H, dd, J =
10.2, 0.9 Hz), 3.69 (1H, d, J = 3.5 Hz), 1.11 (9H, s). 13C NMR (101 MHz, CDCl3, ppm) δ
167.6, 149.1, 148.9, 141.3, 136.7, 134.7, 131.6, 128.8, 126.9, 124.4, 67.5, 59.4, 36.2, 27.7.
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C18H22N2O2Cl 333.1370; Found 333.1376.
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Optical rotation [α]20 +165.8 (c 0.41, CH2Cl2). HPLC/csp assay: Daicel CHIRALPAK IF,
D
25 cm × 4.6 mm i.d., mobile phase 15% IPA/85% Hexanes, flow rate 1 mL/min, detector UV
254 nm, retention time 13.2 min, major and 9.4 min, minor (99% ee).
N-((1S,2S)-1-(4-Chloropyridin-3-yl)-1-hydroxy-3,3-dimethylbutan-2-yl)-3,5-
bis(trifluoromethyl)benzamide ((S,S)–4b). The title compound was obtained as sand color
crystals (5.32 g, 71 %) from 4ꢀchloropyridine hydrochloride (5.3 g, 35.3 mmol, 2.2 equiv)
and aldehyde (S)–2b3c (5.7 g, 16.0 mmol, 1.0 equiv) by following general procedure A. Pure
material was obtained by recrystallization from Et2O (30 mL) and hexane (100 mL); mp 127–
129 °C. Analytical TLC on silica gel, 2:5 EtOAc/Hexanes, Rf = 0.35. 1H NMR (400 MHz,
CDCl3, ppm) δ 8.52 (1H, s), 8.31 (1H, d, J = 5.2 Hz), 8.09 (2H, s), 8.00 (1H, s), 7.39–7.18
(1H, m), 6.84 (1H, d, J = 10.1 Hz), 5.63 (1H, s), 4.17 (1H, d, J = 10.1 Hz), 3.12 (1H, s), 1.17
(9H, s). 13C NMR (100.6 MHz, CDCl3, ppm) δ 164.4, 149.6, 148.4, 141.5, 136.5, 136.2,
132.5 (q, J = 34.0 Hz), 127.1 (m), 125.3 (m), 124.7, 121.6 (q, J = 272.9 Hz), 67.6, 59.9, 36.2,
27.7. 19F NMR (376.5 MHz, CDCl3, ppm) δ –62.9. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd
for C20H20N2O2F6Cl 469.1117; Found 469.1122. Optical rotation [α]20D +116.6 (c 0.56,
CH2Cl2). HPLC/csp assay: Daicel CHIRALPAK IE, 25 cm × 4.6 mm i.d., mobile phase 5%
IPA/95% Hexanes, flow rate 1 mL/min, detector UV 254 nm, retention time 8.0 min, major
and 6.1 min, minor (99% ee).
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General procedure B for synthesis of 4-aminopyridines (S,S)–3a, b and (S,S)–9b.
4ꢀChloropyridine (S,S)–4a or (S,S)–4b (1.0 equiv) and ZnCl2(amine)2 complex 7a or 7d
(2.0 equiv) were dissolved in anhydrous DMF (1 mL/1 mmol of 4ꢀchloropyridine (S,S)–
4a,b), and the resulting yellowꢀbrown solution was stirred at 80 °C. Progress of the reaction
was monitored by 1HꢀNMR spectra. Upon complete conversion of the starting chloropyridine
(S,S)–4a,b, all volatiles were removed under reduced pressure and the brown oil like residue
was suspended in water (60 mL/1 mmol of the starting chloropyridine). The suspension was
acidified to pH 6 using 1 M HCl solution and extracted three times with EtOAc (3x30 mL/1
mmol of the starting chloropyridine). The combined organic extracts were dried over Na2SO4,
filtered and concentrated under reduced pressure.
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N-((1S,2S)-1-(4-(Dimethylamino)pyridin-3-yl)-1-hydroxy-3,3-dimethylbutan-2-
yl)benzamide ((S,S)–3a). The title compound was obtained as a white powder (2.72 g, 78 %)
from chloropyridine (S,S)ꢀ4a (3.4 g, 10.2 mmol, 1.0 equiv) and ZnCl2(NHMe2)2 complex 7a
(4.6 g, 20.4 mmol, 2.0 equiv) by following general procedure B. After removal of EtOAc
pale yellow solid was suspended in Et2O (200 mL) and sonicated in ultrasound bath for 20
min. The resulting white suspension was centrifuged and the supernatant was decanted. The
sonication/centrifugation cycle was repeated to afford (S,S)–3a; mp 225ꢀ226 °C. Analytical
TLC on silica gel, EtOAc, Rf = 0.07. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 8.45 (1H, s),
8.01 (1H, d, J = 5.7 Hz), 7.70–7.62 (2H, m), 7.52–7.45 (2H, m), 7.45–7.38 (2H, m), 6.92
(1H, d, J = 5.7 Hz), 5.56 (1H, d, J = 6.0 Hz), 5.42 (1H, dd, J = 6.0, 1.8 Hz), 4.03 (1H, dd, J =
10.0, 1.8 Hz), 2.82 (6H, s), 1.03 (9H, s). 13C NMR (100.6 MHz, DMSOꢀd6, ppm) δ 166.5,
158.0, 147.8, 147.4, 134.9, 132.1, 130.8, 128.2, 127.1, 113.6, 65.5, 59.0, 43.4, 35.3, 27.6.
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C20H28N3O2 342.2182; Found 342.2175. Optical
rotation [α]20D –31.5 (c 0.45, CH2Cl2).
N-((1S,2S)-1-(4-(Dimethylamino)pyridin-3-yl)-1-hydroxy-3,3-dimethylbutan-2-yl)-3,5-
bis(trifluoromethyl)benzamide ((S,S)–3b). The title compound was obtained as a pale
yellow powder (4.26 g, 80 %) from chloropyridine (S,S)–4b (5.2 g, 11.1 mmol, 1.0 equiv)
and ZnCl2(NHMe2)2 complex 7a (5.0 g, 22.2 mmol, 2.0 equiv) by following general
procedure B. Pure material was obtained by precipitation from CH2Cl2/heptane; mp 99ꢀ
102 °C. Analytical TLC on silica gel, EtOAc, Rf = 0.17. 1H NMR (400 MHz, CDCl3, ppm) δ
8.50 (1H, s), 8.25 (1H, d, J = 5.5 Hz), 8.09 (2H, s), 7.96 (1H, s), 6.93 (1H, d, J = 5.5 Hz),
6.90 (1H, d, J = 10.0 Hz), 5.53 (1H, s), 5.41 (1H, s), 4.29 (1H, d, J = 10.0 Hz), 2.74 (6H, s),
1.12 (9H, s). 13C NMR (100.6 MHz, CDCl3, ppm) δ 164.5, 158.8, 149.7, 148.2, 137.0, 132.3
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(q, J = 33.7 Hz), 127.2 (m), 125.0 (m), 123.1 (q, J = 272.9 Hz), 115.0, 110.2, 67.5, 60.0, 44.3,
35.9, 27.6. 19F NMR (376.5 MHz, CDCl3, ppm) δ –62.9. HRMS (ESIꢀTOF) m/z: Calcd for
C22H26N3O2F6 478.1929; Found 478.1931. Optical rotation [α]20D +49.2 (c 0.95, CH2Cl2).
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N-((1S,2S)-1-Hydroxy-3,3-dimethyl-1-(4-(pyrrolidin-1-yl)pyridin-3-yl)butan-2-yl)-3,5-
bis(trifluoromethyl)benzamide ((S,S)–11). The title compound was obtained as a pale
yellow powder (1.09 g, 76 %) from chloropyridine (S,S)–4b (1.33 g, 2.84 mmol, 1.0 equiv)
and ZnCl2(pyrrolidine)2 complex 7d (1.58 g, 5.67 mmol, 2.0 equiv) by following general
procedure B. Pure material was obtained by precipitation from CH2Cl2/heptane; mp 110–
112 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.38 (1H, s), 8.04 (2H, s), 7.90–7.83 (2H, m),
7.43 (1H, d, J = 10.2 Hz), 6.57 (1H, d, J = 6.2 Hz), 5.57 (1H, d, J = 1.8 Hz), 4.18 (1H, dd, J =
10.2, 1.8 Hz), 3.52–3.34 (4H, m), 2.18–2.04 (2H, m), 2.03–1.90 (2H, m), 1.13 (9H, s). 13C
NMR (100.6 MHz, CDCl3, ppm) δ 165.2, 153.8, 146.2, 144.3, 137.1, 131.9 (q, J = 33.7 Hz),
127.5, 126.1, 124.8, 123.2 (q, J = 273.0 Hz), 110.1, 68.3, 59.5, 51.3, 36.2, 28.1, 25.8. 19F
NMR (376.5 MHz, CDCl3, ppm) δ –62.84. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C24H28N3O2F6 504.2086; Found 504.2087. Optical rotation [α]20D +109.1 (c 0.59, CH2Cl2).
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General procedure C for synthesis of chiral DMAP catalysts (S,S)–1a,b and (S,S)–12.
Triethylamine (2.0 equiv) and acetic anhydride (1.1 equiv) were added to a solution of
alcohol (S,S)–3a,3b or (S,S)–11 (1.0 equiv) in anhydrous CH2Cl2 (1 mL/1 mmol of alcohol).
The colorless solution was stirred at rt, and progress of the reaction was monitored by LCꢀMS
assay. Full conversion of the starting alcohol was observed after 1 h. The colorless solution
was diluted with CH2Cl2 (10 mL/1 mmol of alcohol) and washed sequentially with H2O
(2x15 mL/1 mmol of alcohol) and aqueous saturated NaHCO3 solution (2x15 mL/1 mmol of
alcohol). The organic layer was dried over Na2SO4, filtered and solvent was removed under
reduced pressure.
(1S,2S)-2-Benzamido-1-(4-(dimethylamino)pyridin-3-yl)-3,3-dimethylbutyl acetate
((S,S)–1a). The title compound was obtained as white flakes (3.11 g, 92 %) from alcohol
(S,S)–3a (3 g, 8.79 mmol, 1.0 equiv), acetic anhydride (0.91 mL, 9.67 mmol, 1.1 equiv) and
triethylamine (2.45 mL, 17.57 mmol, 2.0 equiv) by following general procedure C. Pure
material was obtained by recrystallization from Et2O (50 mL) and hexane (250 mL); mp 171–
172 °C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.32 (1H, d, J = 5.5 Hz), 8.25 (1H, s), 7.64–7.58
(2H, m), 7.51–7.45 (1H, m), 7.45–7.37 (2H, m), 6.92 (1H, d, J = 5.5 Hz), 6.57 (1H, d, J = 1.6
Hz), 6.35 (1H, d, J = 10.7 Hz), 4.34 (1H, dd, J = 10.7, 1.6 Hz), 2.87 (6H, s), 2.19 (3H, s),
1.07 (9H, s). The 1H NMR spectra is in full agreement with that reported in the literature.3a
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13C NMR (100.6 MHz, CDCl3, ppm) δ 169.8, 167.5, 158.4, 150.4, 147.4, 135.0, 131.4, 128.8,
128.6, 126.7, 114.6, 70.3, 58.7, 43.9, 35.4, 27.3, 21.4. HRMS (ESIꢀTOF) m/z: [M + H]+
Calcd for C22H30N3O3 384.2287; Found 384.2288. Optical rotation [α]20 –1.0 (c 0.56,
D
CH2Cl2). HPLC/csp assay: Daicel CHIRALPAK IF, 25 cm × 4.6 mm i.d., mobile phase 20%
IPA/80% Hexanes, flow rate 1 mL/min, detector UV 297 nm, retention time 43.6 min, major
and 18.7 min, minor (99% ee).
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(1S,2S)-2-(3,5-Bis(trifluoromethyl)benzamido)-1-(4-(dimethylamino)pyridin-3-yl)-3,3-
dimethylbutyl acetate ((S,S)–1b). The title compound was obtained as a white foam (3.7 g,
95 %) from alcohol (S,S)–3b (3.6 g, 7.54 mmol, 1.0 equiv), acetic anhydride (0.78 mL, 8.30
mmol, 1.1 equiv) and triethylamine (2.10 mL, 15.08 mmol, 2.0 equiv) by following general
procedure C. Analytical TLC on silica gel, 95:5 MeOH/CHCl3, Rf = 0.32. 1H NMR
(400 MHz, CDCl3, ppm) δ 8.34 (1H, d, J = 5.4 Hz), 8.19–8.16 (1H, m), 8.03–7.96 (3H, m),
6.94 (1H, d, J = 5.4 Hz), 6.59 (1H, d, J = 1.6 Hz), 6.35 (1H, d, J = 10.6 Hz), 4.36 (1H, dd, J =
10.6, 1.6 Hz), 2.89 (6H, s), 2.22 (3H, s), 1.09 (9H, s). 13C NMR (100.6 MHz, CDCl3, ppm) δ
169.7, 164.5, 158.5, 150.6, 147.0, 136.8, 132.5 (q, J = 33.9 Hz), 128.2, 127.0, 125.3, 123.0
(q, J = 273.0 Hz), 114.7, 70.2, 59.3, 43.9, 35.3, 27.4, 21.4. 19F NMR (376.5 MHz, CDCl3,
ppm) δ –62.9. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C24H28N3O3F6 520.2035; Found
520.2032. Optical rotation [α]20D –5.0 (c 0.28, CH2Cl2). HPLC/csp assay: Daicel
CHIRALPAK IC, 25 cm × 4.6 mm i.d., mobile phase 10% IPA/90% Hexanes, flow rate 1
mL/min, detector UV 254 nm, retention time 9.8 min, major and 7.6 min, minor (99% ee).
(1S,2S)-2-(3,5-Bis(trifluoromethyl)benzamido)-3,3-dimethyl-1-(4-(pyrrolidin-1-
yl)pyridin-3-yl)butyl acetate ((S,S)–12). The title compound was obtained as a pale yellow
amorphous solid (266 mg, 91 %) from alcohol (S,S)ꢀ11 (270 mg, 0.54 mmol, 1.0 equiv),
acetic anhydride (62 ꢁL, 0.66 mmol, 1.2 equiv) and triethylamine (0.17 mL, 1.19 mmol,
2.2 equiv) by following general procedure C. 1H NMR (400 MHz, CDCl3, ppm) δ 8.17 (1H,
s), 8.11 (1H, d, J = 5.8 Hz), 8.03–7.95 (3H, m), 6.72 (1H, d, J = 2.4 Hz), 6.63 (1H, d, J = 5.8
Hz), 6.27 (1H, d, J = 10.5 Hz), 4.27 (1H, dd, J = 10.5, 2.4 Hz), 3.54 (2H, td, J = 8.9, 6.1 Hz),
3.41 (2H, td, J = 8.2, 7.7, 2.3 Hz), 2.19 (3H, s), 2.15–2.05 (2H, m), 1.99–1.89 (2H, m), 1.07
(9H, s). 13C NMR (100.6 MHz, CDCl3, ppm) δ 169.9, 164.7, 152.7, 149.3, 148.3, 136.8,
132.4 (q, J = 33.9 Hz), 127.1, 125.2, 123.0 (q, J = 273.1 Hz), 121.2, 110.4, 70.4, 59.1, 51.2,
35.7, 27.7, 25.9, 21.5. 19F NMR (376.5 MHz, CDCl3, ppm) δ –62.9. HRMS (ESIꢀTOF) m/z:
[M + H]+ Calcd for C26H30N3O3F6 546.2191; Found 546.2195. Optical rotation [α]20D +80.7
(c 0.53, CH2Cl2).
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3-((4S,5S)-2-(3,5-Bis(trifluoromethyl)phenyl)-4-(tert-butyl)-4,5-dihydrooxazol-5-yl)-
N,N-dimethylpyridin-4-amine ((S,S)–5). A sand colored suspension of finely ground and
oven–dried (120 °C) K2CO3 (1.92 g, 13.86 mmol, 1.3 equiv), chloropyridine (S,S)–4b (5.00
g, 10.67 mmol, 1.0 equiv) and ZnCl2(Me2NH)2(HCl)2 complex 6 (15.96 g, 53.33 mmol, 5.0
equiv) in anhydrous DMF (11 mL) was stirred at 80 °C, and progress of the reaction was
monitored by LCꢀMS assay. Complete conversion of (S,S)–4b was achieved after 63 h,
whereupon a 9:1 mixture of (S,S)–3b and (S,S)–5 was observed. DMF was removed under
reduced pressure, the yellow oily residue was suspended in EtOAc (400 mL), washed with
water (500 mL), saturated aqueous NaHCO3 solution (430 mL) and brine (450 mL). The
organic layer was dried over Na2SO4, filtered and the solvent was removed under reduced
pressure. The light brown oil like residue was split into three batches and each of the batches
was subjected to column chromatography on silica gel (120 g of silica) using gradient elution
from 50% EtOAc in hexanes to 100% EtOAc. In total 3.7 g (73%) of (S,S)–3b was obtained
as a pale yellow amorphous solid together with 400 mg (8%) of (S,S)–5 as yellow oil. 1H
NMR (400 MHz, CDCl3, ppm) δ 8.46 – 8.40 (3H, m), 8.38 (1H, d, J = 5.6 Hz), 7.98 (1H, s),
6.89 (1H, d, J = 5.6 Hz), 5.76 (1H, d, J = 7.4 Hz), 4.16 (1H, d, J = 7.4 Hz), 2.94 (6H, s), 0.96
(9H, s). 13C NMR (101 MHz, CDCl3, ppm) δ 159.8, 159.1, 151.1, 150.6, 132.1 (q, J = 33.7
Hz), 130.2, 128.6, 128.5, 124.8, 123.2 (q, J = 272.9 Hz), 113.2, 85.3, 77.9, 44.4, 35.0, 26.0.
19F NMR (376 MHz, Chloroformꢀd) δ ꢀ62.9. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for
C22H24F6N3O 460.1824; Found 460.1825. Optical rotation [α]20D 213.9 (c 0.32, CH2Cl2).
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Bis(dimethylammonium) zinc(II) chloride (6). The title compound was prepared according
to the literature procedure.10 Thus, a white suspension of anhydrous ZnCl2 (15.00 g, 110.1
mmol, 1 equiv) and dimethylamine hydrochloride (17.95 g, 220.1 mmol, 2 equiv; dried by
repeated vacuum evaporation of a suspension in anhydrous toluene) in EtOH (360 mL) was
stirred at 82 °C. After 10 min the suspension turned to clear colorless solution. The solution
was stirred at 82 °C for 1 h, then all volatiles were removed under reduced pressure to yield
32.16 g (98%) of title compound 6 as white crystals. Anal. Calcd for C4H16Cl4N2Zn: C,
16.05; H, 5.39; N, 9.36. Found: C, 16.26; H, 5.41; N, 9.25.
General procedure D for synthesis of zinc(II)-amine complexes 7a–k. Amine (2.0 equiv)
was added to a wellꢀstirred suspension of anhydrous ZnCl2 (1.0 equiv) in anhydrous Et2O (10
mL/1 mmol of ZnCl2), and the resulting white suspension was stirred at rt for 12 h. The white
precipitates were filtered and the filterꢀcake was washed with Et2O.
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Bis(dimethylamine) zinc(II) chloride (7a). The title compound was obtained as a white
solid (310 mg, 75%) from dimethylamine (2M solution in THF, 1.83 mL, 3.67 mmol,
2.0 equiv) and anhydrous ZnCl2 (250 mg, 1.83 mmol, 1.0 equiv) by following general
procedure D. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 2.45 (12H, s). 13C NMR (100.6 MHz,
DMSOꢀd6, ppm) δ 35.5. 1H NMR spectrum was identical to that from the literature.21
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Bis(diethylamine) zinc(II) chloride (7b). The title compound was obtained as a brown semiꢀ
solid (404 mg, 39%) from neat diethylamine (0.76 mL, 7.34 mmol, 2.0 equiv) and anhydrous
ZnCl2 (500 mg, 3.67 mmol, 1.0 equiv) by following general procedure D. The material is
highly hygroscopic! 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 4.39–4.21 (2H, br s), 2.69 (8H,
q, J = 7.2 Hz), 1.07 (12H, t, J = 7.2 Hz). 13C NMR (100.6 MHz, DMSOꢀd6, ppm) δ 42.4,
13.1. Anal. Calcd for C8H22N2Cl2Znx4H2O: C, 27.10; H, 8.53; N, 7.90. Found: C, 26.74;
H, 8.29; N, 7.77. HRMS (ESIꢀTOF) m/z: [M + HCl + H]+ Calcd for C8H24Cl3N2Zn 317.0297;
Found 317.0307.
Bis(azetidine) zinc(II) chloride (7c). The title compound was obtained as a white powder
(234 mg, 84%) from neat azetidine (0.16 mL, 2.42 mmol, 2.2 equiv) and anhydrous ZnCl2
(150 mg, 1.10 mmol, 1.0 equiv) by following general procedure D. 1H NMR (400 MHz,
DMSOꢀd6, ppm) δ 3.55 (8H, t, J = 7.7 Hz), 2.22 (4H, p, J = 7.7 Hz). 13C NMR (100.6 MHz,
DMSOꢀd6, ppm) δ 47.0, 20.5. Anal. Calcd for C6H14N2Cl2Zn + 2% ZnCl2: C, 28.46; H, 5.57;
N, 11.06. Found: C, 28.14; H, 5.45; N, 10.67.
Bis(pyrrolidine) zinc(II) chloride (7d). The title compound was obtained as a white
crystalline material (7.16 g, 70%) from neat pyrrolidine (6.1 mL, 73.37 mmol, 2.0 equiv) and
anhydrous ZnCl2 (5 g, 36.69 mmol, 1.0 equiv) by following general procedure D. Pure
material was obtained by recrystallization from EtOH (10 mL); mp 179–180 °C, elongated
plates. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 4.89–4.15 (2H, br s), 2.90–2.75 (8H, m),
1.75–1.60 (8H, m). 13C NMR (100.6 MHz, DMSOꢀd6, ppm) δ 47.0, 24.3. Anal. Calcd for
C8H18N2Cl2Zn: C, 34.50; H, 6.51; N, 10.06. Found: C, 34.65; H, 6.43; N, 9.90. HRMS (ESIꢀ
TOF) m/z: [M + HCl + H]+ Calcd for C8H20Cl3N2Zn 312.9984; Found 313.0002.
Bis(piperidine) zinc(II) chloride (7e). The title compound was obtained as an offꢀwhite
powder (480 mg, 85%) from neat piperidine (0.36 mL, 3.67 mmol, 2.0 equiv) and anhydrous
ZnCl2 (250 mg, 1.83 mmol, 1.0 equiv) by following general procedure D. 1H NMR
(400 MHz, DMSOꢀd6, ppm) δ 4.65–4.01 (2H, br s), 2.89–2.68 (8H, m), 1.59–1.43 (12H, m).
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13C NMR (100.6 MHz, DMSOꢀd6, ppm) δ 46.2, 24.8, 23.5. Anal. Calcd for C10H22N2Cl2Zn:
C, 39.18; H, 7.23; N, 9.14. Found: C, 39.18; H, 7.19; N, 8.98.
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Bis(morpholine) zinc(II) chloride (7f). The title compound was obtained as sand color
crystals (458 mg, 80%) from neat morpholine (0.32 mL, 3.67 mmol, 2.0 equiv) and
anhydrous ZnCl2 (250 mg, 1.83 mmol, 1.0 equiv) by following general procedure D. Pure
material was obtained by recrystallization from EtOH (1.5 mL); mp 234–236 °C, block
clusters. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 4.07–3.69 (2H, br s), 3.64–3.51 (8H, m),
2.81–2.70 (8H, m). 13C NMR (100.6 MHz, DMSOꢀd6, ppm) δ 66.2, 45.8. Anal. Calcd for
C8H18N2O2Cl2Zn: C, 30.94; H, 5.84; N, 9.02. Found: C, 31.16; H, 5.82; N, 8.87.
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Bis(aniline) zinc(II) chloride (7g). The title compound was obtained as a white solid (1.32 g,
93%) from neat aniline (0.8 mL, 8.8 mmol, 2.0 equiv) and anhydrous ZnCl2 (600 mg,
4.4 mmol, 1.0 equiv) by following general procedure D. 1H NMR (400 MHz, DMSOꢀd6,
ppm) δ 7.05–6.95 (4H, m), 6.60–6.52 (4H, m), 6.51–6.43 (2H, m), 5.23–4.80 (4H, br s). 13C
NMR (100.6 MHz, DMSOꢀd6, ppm) δ 148.5, 128.8, 115.7, 113.9. Anal. Calcd for
C12H14N2Cl2Zn: C, 44.69; H, 4.37; N, 8.69. Found: C, 44.72; H, 4.31; N, 8.57.
Bis((S)-diphenyl(pyrrolidin-2-yl)methanol) zinc(II) chloride ((S,S)–7h). The title
compound was obtained as a white powder (193 mg, 76%) from (S)ꢀdiphenyl(pyrrolidinꢀ2ꢀ
yl)methanol (201 mg, 0.79 mmol, 2.0 equiv) and anhydrous ZnCl2 (54 mg, 0.40 mmol,
1.0 equiv) by following general procedure D. Pure material was obtained by recrystallization
from EtOH (7 mL); mp 205–207 °C, block clusters. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ
7.61–7.55 (4H, m), 7.51–7.44 (4H, m), 7.32–7.23 (8H, m), 7.20–7.11 (4H, m), 4.44 (2H, t,
J = 7.7 Hz), 3.43–3.26 (4H, br s), 3.01–2.86 (4H, m), 1.74–1.60 (4H, m), 1.60–1.48 (4H, m).
13C NMR (100.6 MHz, DMSOꢀd6, ppm) δ 147.1, 146.3, 127.9, 127.9, 126.3, 126.2, 126.2,
125.4, 77.5, 64.2, 47.0, 26.5, 25.3. Anal. Calcd for C34H38N2O2Cl2Zn: C, 63.51; H, 5.96;
N, 4.36. Found: C, 63.59; H, 5.95; N, 4.18. Optical rotation [α]20D –70.2 (c 1.94, DMSO).
Bis(tert-butyl pyrrolidin-3-ylcarbamate) zinc(II) chloride (7i). The title compound was
obtained as a white powder (1.175 g, 86%) from tertꢀbutyl pyrrolidinꢀ3ꢀylcarbamate (1.0 g,
5.37 mmol, 2.0 equiv) and anhydrous ZnCl2 (366 mg, 2.69 mmol, 1.0 equiv) by following
general procedure D. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 7.22–6.76 (2H, m), 4.78–4.29
(2H, br s), 4.01–3.83 (2H, m), 3.03–2.89 (4H, m), 2.89–2.77 (2H, m), 2.62 (2H, dd, J = 11.7,
5.1 Hz), 2.04–1.89 (2H, m), 1.68–1.52 (2H, m), 1.38 (18H, s). 13C NMR (100.6 MHz,
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DMSOꢀd6, ppm) δ 155.1, 77.8, 53.0, 50.4, 45.7, 31.4, 28.2. Anal. Calcd for
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C18H36N4O4Cl2Zn: C, 42.49; H, 7.13; N, 11.01. Found: C, 42.59; H, 7.09; N, 10.89.
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Bis((S)-1-phenylethan-1-amine) zinc(II) chloride complex ((S,S)–7j). The title compound
was obtained as a white powder (668 mg, 80%) from (S)ꢀphenylethylamine (534 mg,
4.4 mmol, 2.0 equiv) and anhydrous ZnCl2 (300 mg, 2.2 mmol, 1.0 equiv) by following
general procedure D. Pure material was obtained by recrystallization from EtOH (5 mL); mp
165–166 °C, colorless needles. 1H NMR (400 MHz, DMSOꢀd6, ppm) δ 7.41–7.36 (4H, m),
7.35–7.28 (4H, m), 7.25–7.19 (2H, m), 4.03 (2H, q, J = 6.7 Hz), 3.69–3.58 (4H, m), 1.37
(6H, d, J = 6.7 Hz). 13C NMR (100.6 MHz, DMSOꢀd6, ppm) δ 146.2, 128.3, 126.9, 126.0,
51.2, 24.3. Anal. Calcd for C16H22N2Cl2Zn: C, 50.75; H, 5.86; N, 7.40. Found: C, 50.66;
H, 5.90; N, 7.37. Optical rotation [α]20D –22.9 (c 0.23, DMSO).
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Bis((R)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine) zinc(II) chloride ((R,R–7k). The
title compound was obtained as a white solid (152 mg, 68%) from (R)ꢀ4,5ꢀdihydroꢀ3Hꢀ
dinaphtho[2,1ꢀc:1',2'ꢀe]azepine22 (182 mg, 0.62 mmol, 2.0 equiv) and anhydrous ZnCl2
(42 mg, 0.31 mmol, 1.0 equiv) by following general procedure D. 1H NMR (300 MHz,
DMSOꢀd6, ppm) δ 8.07 (8H, dd, J = 8.4 Hz), 7.69 (4H, d, J = 8.4 Hz), 7.56 – 7.46 (4H, m),
7.38 – 7.19 (8H, m), 4.02 – 3.87 (4H, m), 3.33 – 3.25 (4H, m). 13C NMR (75 MHz, DMSOꢀ
d6, ppm) δ 134.3, 133.6, 132.9, 130.6, 128.7, 128.5, 127.9, 126.6, 126.1, 125.8, 47.6. Anal.
Calcd for C44H34N2Cl2Zn: C, 72.69; H, 4.71; N, 3.85. Found: C, 72.83; H, 4.79; N, 3.74.
Optical rotation [α]20D –305.9 (c 0.68, DMSO).
General procedure E for synthesis of 4-aminopyridines 8a–k. To a suspension of 4ꢀ
chloropyridine hydrochloride (1 equiv) and zincꢀamine complex 7a–k (2 equiv) in anhydrous
DMF (1 mL/1 mmol of 4ꢀchloropyridine) was added neat DIPEA (1 equiv), and the resulting
yellowꢀbrown solution was stirred at 40 °C. Progress of the reaction was monitored by 1Hꢀ
NMR spectra. Upon complete conversion of 4ꢀchloropyridine hydrochloride, the reaction
mixture was diluted with Et2O (50 mL) and washed with saturated aqueous NaHCO3 (75
mL), followed by brine (75 mL). The organic layer was dried over Na2SO4 and filtered.
Anhydrous HCl (2M solution in Et2O, 1 equiv) was added to a solution of 4ꢀaminopyridines
8a–k in Et2O. The precipitate that formed was filtered and dried under reduced pressure.
General procedure F for synthesis of 4-aminopyridines 8l–s. A yellowꢀbrown solution of
a halogenꢀsubstituted pyridine (1 equiv) and zincꢀamine complex 7 (2 equiv) in anhydrous
DMF (1 mL/1 mmol of halopyridine) was stirred at 40 °C, and the progress of the reaction
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was monitored by 1HꢀNMR spectra. Upon complete conversion of the pyridine the reaction
mixture was diluted with Et2O (50 mL) and washed with saturated aqueous NaHCO3 (75 mL)
and brine (75 mL). The organic layer was dried over Na2SO4, filtered and concentrated under
reduced pressure. Purification by column chromatography on silica gel (10 g of silica) using
gradient elution from 0% EtOAc in hexanes to 100% EtOAc afforded 4ꢀaminopyridines.
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N,N-Dimethylpyridin-4-amine hydrochloride (8a). The title compound was obtained as a
white powder (48 mg, 82%) from bis(dimethylamine) zinc(II) chloride 8a (166 mg,
0.73 mmol, 2.0 equiv), 4ꢀchloropyridine hydrochloride (55 mg, 0.37 mmol, 1.0 equiv) and
DIPEA (63 ꢁL, 0.37 mmol, 1.0 equiv) by following general procedure E. 1H NMR spectrum
was identical to that from the literature.23
N,N-Diethylpyridin-4-amine hydrochloride (8b). The title compound was obtained as a
white powder (93 mg, 68%) from bis(diethylamine) zinc chloride 7b (414 mg, 1.47 mmol,
2.0 equiv), 4ꢀchloropyridine hydrochloride (110 mg, 0.73 mmol, 1.0 equiv) and DIPEA (127
ꢁL, 0.73 mmol, 1.0 equiv) by following general procedure E. 1H NMR spectrum was
identical to that from the literature.24
4-(Azetidin-1-yl)pyridine hydrochloride (8c). The title compound was obtained as an offꢀ
white powder (30 mg, 53%) from bis(azetidine) zinc chloride 7c (167 mg, 0.67 mmol,
2.0 equiv), 4ꢀchloropyridine hydrochloride (50 mg, 0.33 mmol, 1.0 equiv) and DIPEA
(58 ꢁL, 0.33 mmol, 1.0 equiv) by following general procedure E. 1H NMR (300 MHz,
CDCl3, ppm) δ 15.88–14.98 (1H, br s), 8.27–7.88 (2H, m), 6.53–6.19 (2H, m), 4.26 (4H, t,
J = 7.7 Hz), 2.61 (2H, p, J = 7.7 Hz). 13C NMR (100.6 MHz, CDCl3, ppm) δ 155.9, 138.9,
105.2, 51.2, 15.4. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C8H11N2 135.0922; Found
135.0919.
4-(Pyrrolidin-1-yl)pyridine hydrochloride (8d). The title compound was obtained as a
white powder (48 mg, 77%) from bis(pyrrolidine) zinc chloride 7d (186 mg, 0.67 mmol,
2.0 equiv), 4ꢀchloropyridine hydrochloride (50 mg, 0.33 mmol, 1.0 equiv) and DIPEA (58
ꢁL, 0.33 mmol, 1.0 equiv) by following general procedure E. 1H NMR spectrum was
identical to that from the literature.25
4-(Piperidin-1-yl)pyridine hydrochloride (8e). The title compound was obtained as an offꢀ
white powder (94 mg, 64%) from bis(piperidine) zinc chloride 7e (450 mg, 1.47 mmol,
2.0 equiv), 4ꢀchloropyridine hydrochloride (110 mg, 0.73 mmol, 1.0 equiv) and DIPEA (127
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ꢁL, 0.73 mmol, 1.0 equiv) by following general procedure E. 1H NMR spectrum was
identical to that from the literature.26
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4-(Pyridin-4-yl)morpholine hydrochloride (8f). The title compound was obtained as a
white powder (98 mg, 73%) from bis(morpholine) zinc chloride 8f (414 mg, 1.33 mmol,
2.0 equiv), 4ꢀchloropyridine hydrochloride (100 mg, 0.66 mmol, 1.0 equiv) and DIPEA (115
ꢁL, 0.66 mmol, 1.0 equiv) by following general procedure E. 1H NMR spectrum was
identical to that from the literature.27
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N-Phenylpyridin-4-amine (8g). The title compound was obtained as a pale yellow solid
(117 mg, 86%) from bis(aniline) zinc chloride 7g (516 mg, 1.60 mmol, 2.0 equiv), 4ꢀ
chloropyridine hydrochloride (120 mg, 0.80 mmol, 1.0 equiv) and DIPEA (138 ꢁL, 0.80
mmol, 1.0 equiv) by following general procedure E. Pure pyridine 8g was obtained by
purification on silica gel (10 g) using gradient elution from 10% EtOAc in hexanes to 100%
EtOAc. Analytical TLC on silica gel, EtOAc, Rf = 0.7. 1H NMR spectrum was identical to
that from the literature.28
(S)-Diphenyl(1-(pyridin-4-yl)pyrrolidin-2-yl)methanol ((S)–8h). The title compound was
obtained as an offꢀwhite amorphous solid (33 mg, 79%) from bis((S)ꢀdiphenyl(pyrrolidinꢀ2ꢀ
yl)methanol) zinc chloride 7h (163 mg, 0.25 mmol, 2.0 equiv), 4ꢀchloropyridine
hydrochloride (19 mg, 0.13 mmol, 1.0 equiv) and DIPEA (21 ꢁL, 0.13 mmol, 1.0 equiv) by
following general procedure E. Pure pyridine 8h was obtained by purification on silica gel (5
g) using gradient eluent from 0% MeOH in chloroform to 90% MeOH in chloroform.
Analytical TLC on silica gel, 3:7 MeOH/CHCl3, Rf = 0.17; 1H NMR (400 MHz, CDCl3, ppm)
δ 7.95 (2H, s), 7.45–7.40 (2H, m), 7.40–7.29 (5H, m), 7.24–7.16 (3H, m), 6.36–6.26 (2H, m),
4.88–4.80 (1H, m), 3.48 (1H, td, J = 9.4, 2.7 Hz), 3.24 (1H, q, J = 8.9 Hz), 2.11–2.01 (2H,
m), 1.80–1.66 (1H, m), 1.57–1.38 (1H, m). 13C NMR (100.6 MHz, CDCl3, ppm) δ 154.3,
149.1, 145.3, 144.8, 128.3, 128.1, 127.8, 127.5, 127.5, 108.5, 82.1, 65.6, 50.7, 29.4, 23.1.
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C22H23N2O 331.1810; Found 331.1816. Optical
rotation [α]20D +60.0 (c 0.10, CH2Cl2).
tert-Butyl (1-(pyridin-4-yl)pyrrolidin-3-yl)carbamate (8i). The title compound was
obtained as a white foam (443 mg, 86%) from bis(tertꢀbutyl pyrrolidinꢀ3ꢀylcarbamate) zinc
chloride 7i (1.99 g, 3.92 mmol, 2.0 equiv), 4ꢀchloropyridine hydrochloride (294 mg,
1.96 mmol, 1.0 equiv) and DIPEA (339 ꢁL, 1.96 mmol, 1.0 equiv) by following general
procedure E. Pure pyridine 8i was obtained by purification on silica gel (120 g of RPꢀ18
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silica gel) using gradient eluent from 0% MeCN in water to 100% MeCN in water. 1H NMR
(400 MHz, CDCl3, ppm) δ 8.09–7.94 (2H, m), 6.73–6.51 (2H, m), 5.65 (1H, s), 4.38 (1H, s),
3.84–3.68 (2H, m), 3.63–3.50 (2H, m), 2.42–2.26 (1H, m), 2.26–2.14 (1H, m), 1.41 (9H, s).
13C NMR (100.6 MHz, CDCl3, ppm) δ 155.6, 155.0, 138.9, 107.6, 80.2, 54.0, 50.3, 47.0,
31.1, 28.5. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C14H22N3O2 264.1712; Found
264.1712.
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(S)-N-(1-Phenylethyl)pyridin-4-amine ((S)–8j). The title compound was obtained as a
87:13 mixture of tautomers (54 mg, 83%, colorless oil) from bis((S)ꢀ1ꢀphenylethylamine)
zinc chloride 7j (252 mg, 3.92 mmol, 2.0 equiv), 4ꢀchloropyridine hydrochloride (50 mg,
0.33 mmol, 1.0 equiv) and DIPEA (58 ꢁL, 0.33 mmol, 1.0 equiv) by following general
procedure E. Pure material was obtained by purification on a silica gel (5 g) using gradient
eluent from 0% MeOH in chloroform to 100% MeOH. Analytical TLC on silica gel, MeOH,
Rf = 0.36; 1H NMR (400 MHz, CDCl3, ppm) δ 8.09–7.98 (2H, m), 7.36–7.30 (4.2 H, m),
7.31–7.20 (1.36H, m), 6.50–6.44 (2H, m), 5.67–5.53 (1H, m), 4.60–4.50 (1H, p, J = 6.6 Hz),
4.12 (0.15H, q, J = 6.6 Hz), 3.93 (1H, s), 1.58 (3H, d, J = 6.6 Hz), 1.40 (1.4H, d, J = 6.6 Hz).
13C NMR (100.6 MHz, CDCl3, ppm) δ 153.7, 147.5, 143.4, 129.1, 128.6, 127.6, 127.0, 125.8,
108.4, 53.0, 24.5. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C13H15N2 199.1235; Found
199.1241. Optical rotation [α]20D –152.5 (c 1.09, DMSO).
(R)-4-(Pyridin-4-yl)-4,5-dihydro-3H-dinaphtho[2,1-c:1',2'-e]azepine ((R)–8k).
The title compound was obtained as a white solid (15 mg, 75%) from bis((R)ꢀ4,5ꢀdihydroꢀ
3Hꢀdinaphtho[2,1ꢀc:1',2'ꢀe]azepine) zinc(II) chloride ((R,R)–7k) (75 mg, 0.11 mmol, 2.0
equiv), 4ꢀchloropyridine hydrochloride (8 mg, 0.05 mmol, 1.0 equiv) and DIPEA (9 ꢁL, 0.05
mmol, 1.0 equiv) by following general procedure E. The reaction was stirred at 80 °C for 16
h. 1H NMR spectrum was identical to that from the literature.2d Optical rotation [α]20D +306.6
(c 0.60, DMSO).
2-(Pyrrolidin-1-yl)pyridine (8l). The title compound was obtained as a colorless oil (25 mg,
83%) from bis(pyrrolidine) zinc chloride 7d (113 mg, 0.40 mmol, 2.0 equiv) and
2ꢀfluoropyridine (17 ꢁL, 0.20 mmol, 1.0 equiv) by following general procedure F. 1H NMR
spectrum was identical to that from the literature.29
2-Chloro-4-(pyrrolidin-1-yl)pyridine (8m). The title compound was obtained as a white
solid (29 mg, 78%) from bis(pyrrolidine) zinc chloride 7d (113 mg, 0.40 mmol, 2.0 equiv)
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and 2,4ꢀdichloropyridine (30 mg, 0.20 mmol, 1.0 equiv) by following general procedure F. 1H
NMR spectrum was identical to that from the literature.30
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2-Phenyl-4-(pyrrolidin-1-yl)pyridine (8n). The title compound was obtained as a light
yellow oil (66 mg, 56%) from bis(pyrrolidine) zinc chloride 7d (293 mg, 1.05 mmol,
2.0 equiv) and 4ꢀchloroꢀ2ꢀphenylpyridine (100 mg, 0.53 mmol, 1.0 equiv) by following
general procedure F. 1H NMR (300 MHz, CDCl3, ppm) δ 8.30 (1H, d, J = 5.8 Hz), 8.01–7.88
(2H, m), 7.52–7.33 (3H, m), 6.79 (1H, d, J = 2.4 Hz), 6.36 (1H, dd, J = 5.8, 2.4 Hz), 3.44–
3.28 (4H, m), 2.12–1.96 (4H, m). 13C NMR (75 MHz, CDCl3, ppm) δ 157.9, 152.6, 149.7,
140.9, 128.6, 128.5, 127.1, 105.9, 104.0, 47.2, 25.5. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd
for C15H17N2 225.1392; Found 225.1388.
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3-Chloro-4-(pyrrolidin-1-yl)pyridine (8o). The title compound was obtained as a white
amorphous solid (27 mg, 73%) from bis(pyrrolidine) zinc chloride 7d (113 mg, 0.40 mmol,
2.0 equiv) and 3,4ꢀdichloropyridine (30 mg, 0.20 mmol, 1.0 equiv) by following general
procedure F. 1H NMR (400 MHz, CDCl3, ppm) δ 8.20 (1H, s), 8.05 (1H, d, J = 5.8 Hz), 6.46
(1H, d, J = 5.8 Hz), 3.63–3.53 (4H, m), 2.00–1.89 (4H, m). 13C NMR (100.6 MHz, CDCl3,
ppm) δ 151.1, 150.2, 147.8, 116.4, 110.0, 50.4, 25.7. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd
for C9H12N2Cl 183.0689; Found 183.0692.
3-Phenyl-4-(pyrrolidin-1-yl)pyridine (8p). The title compound was obtained as a light
yellow oil (13 mg, 67%) from bis(pyrrolidine) zinc chloride 7d (49 mg, 0.18 mmol,
2.0 equiv) and 3ꢀphenylꢀ4ꢀchloropyridine (17 mg, 0.09 mmol, 1.0 equiv) by following
general procedure F. 1H NMR (300 MHz, CDCl3, ppm) δ 8.19 (1H, d, J = 6.0 Hz), 8.09 (1H,
s), 7.43–7.27 (5H, m), 6.59 (1H, d, J = 6.0 Hz), 3.05–2.95 (4H, m), 1.87–1.73 (4H, m). 13C
NMR (75 MHz, CDCl3, ppm) δ 151.9, 150.7, 147.1, 139.7, 130.0, 128.0, 127.2, 123.4, 108.4,
50.8, 25.7. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C15H17N2 225.1392; Found 225.1393.
4-Chloro-2-(pyrrolidin-1-yl)pyridine (8q). The title compound was obtained as a colorless
oil (105 mg, 95%) from bis(pyrrolidine) zinc chloride 7d (334 mg, 1.20 mmol, 2.0 equiv) and
4ꢀchloroꢀ2ꢀfluoropyridine (59 ꢁL, 0.60 mmol, 1.0 equiv) by following general procedure F.
1H NMR (300 MHz, CDCl3, ppm) δ 8.02 (1H, d, J = 5.5 Hz), 6.50 (1H, dd, J = 5.5, 1.8 Hz),
6.33 (1H, d, J = 1.8 Hz), 3.52–3.33 (4H, m), 2.08–1.90 (4H, m). 13C NMR (75 MHz, CDCl3,
ppm) δ 158.1, 149.2, 144.3, 111.6, 106.1, 46.9, 25.6. HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd
for C9H12N2Cl 183,0689; Found 183,0691.
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1-(4-(Dimethylamino)pyridin-3-yl)-2,2,2-triphenylethan-1-ol (8r). The title compound
was obtained as a white solid (51 mg, 83%) from bis(dimethylamine) zinc chloride 7a (70
mg, 0.31 mmol, 2.0 equiv) and 1ꢀ(4ꢀchloropyridinꢀ3ꢀyl)ꢀ2,2,2ꢀtriphenylethanꢀ1ꢀol (9) (60 mg,
0.16 mmol, 1.0 equiv) by following general procedure F. The reaction was stirred at 80 °C for
1
48 h. H NMR spectrum was identical to that from the literature.3d
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N,N-Dimethyl-3-(2-phenylnaphthalen-1-yl)pyridin-4-amine (8s). The title compound was
obtained as a yellow oil (17 mg, 78%) from bis(dimethylamine) zinc(II) chloride (7a) (86 mg,
0.38 mmol, 6.0 equiv) and 4ꢀchloroꢀ3ꢀ(2ꢀphenylnaphthalenꢀ1ꢀyl)pyridine (10) (20 mg,
0.06 mmol, 1.0 equiv) by following general procedure F. The reaction was stirred at 120 °C
for 170 h. 1H NMR spectrum was identical to that from the literature.31
1-(4-Chloropyridin-3-yl)-2,2,2-triphenylethan-1-ol (9). nꢀBuLi (2.4 M solution in hexane,
0.42 mL, 1.0 mmol, 2.3 equiv) was added to a solution of diisopropylamine (0.14 mL, 1.0
mmol, 2.3 equiv) in anhydrous THF (1 mL) at –75 °C (acetone/dry ice bath) under argon
atmosphere. The light yellow solution was stirred at –75 °C for 2 h and then transferred via
cannula to a suspension of 4ꢀchloropyridine hydrochloride (72 mg, 0.48 mmol, 1.1 equiv) in
anhydrous THF (1.15 mL) at –75 °C. The resulting light yellow solution was stirred at –75
°C for 2 h, whereupon a solution of 2,2,2 triphenylacetaldehyde (118 mg, 0.43 mmol, 1
equiv) in anhydrous THF (0.3 mL) was added at a rate to maintain the reaction temperature
below –73 °C. The light orange solution was stirred at –75 °C for 2 h, and then quenched
with saturated aqueous solution of NH4Cl (0.5 mL). After warming to room temperature all
volatiles were removed under reduced pressure. The orange residue was diluted with EtOAc
(10 mL) and extracted twice with water (15 mL), then with aqueous 0.5 M NaOH solution
(15 mL) and brine (15 mL). The organic layer was dried over Na2SO4 and concentrated under
reduced pressure. The light orange oily residue was purified by column chromatography on
silica gel (12 g silica gel) using gradient elution from 20% EtOAc in hexanes to 100% EtOAc
to afford 9 as a pale yellow solid (60 mg, 49% yield). Analytical TLC on silica gel, 1:1
EtOAc/Hexanes, Rf = 0.27. 1H NMR (300 MHz, CDCl3, ppm) δ 8.34 – 8.21 (2H, m), 7.31 –
7.22 (15H, m), 7.16 (1H, d, J = 5.3 Hz), 6.45 (1H, s), 2.86 (1H, s). 13C NMR (75 MHz,
CDCl3, ppm) δ 152.3, 149.2, 145.6, 143.4, 134.9, 131.0, 128.1, 127.1, 124.0, 73.9, 63.7.
HRMS (ESIꢀTOF) m/z: [M + H]+ Calcd for C25H21ClNO 386.1312; Found 386.1325.
4-Chloro-3-(2-phenylnaphthalen-1-yl)pyridine (10). White suspension of 4ꢀchloroꢀ
3ꢀiodopyridine (62 mg, 0.26 mmol, 1.0 equiv), 4,4,5,5ꢀtetramethylꢀ2ꢀ(2ꢀphenylnaphthalenꢀ1ꢀ
yl)[1,3,2]dioxaborolane2k (85 mg, 0.26 mmol, 1.0 equiv), Pd(PPh3)4 (12 mg, 0.01 mmol, 0.04
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equiv) and K2CO3 (107 mg, 0.77 mmol, 3.0 equiv) were stirred in anhydrous toluene (1 mL)
under argon atmosphere at 80 °C for 72 h. The resulting brown suspension was diluted with
EtOAc (50 mL) and washed with water (50 mL) and brine (50 mL). Organic layer was dried
over Na2SO4 and concentrated under reduced pressure. Column chromatography (12 g of RPꢀ
18 silica gel) using gradient elution from 10% MeCN in water containing 0.1% HCOOH to
100% MeCN afforded 10 as a white solid (59 mg, 72% yield). 1H NMR spectrum was
identical to that from the literature.31
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Associated Content
The Supporting Information is available free of charge on the ACS Publications website at
DOI: 10.1021/acs.joc.XXXXXX.
Details of the kinetic experiments, 1H and 13C NMR spectra, Xꢀray crystallographic data for
Zn complexes 6,7d,7f,7h,7j (CIF).
Author Information
Corresponding Author
*Eꢀmail: edgars@osi.lv.
ORCID
Edgars Suna: 0000ꢀ0002ꢀ3078ꢀ0576
Artis Kinens: 0000ꢀ0003ꢀ1992ꢀ525X
Notes
The authors declare no competing financial interest.
Acknowledgments
This paper is dedicated to the memory of Professor Edwin Vedejs. We thank Dr. S. Belyakov
from Latvian Institute of Organic Synthesis (LIOS) for Xꢀray crystallographic analysis, Prof.
K. Jaudzems (LIOS) for assistance with NMR experiments and Dr. D. W. Piotrowski
(Worldwide Medicinal Chemistry, Pfizer, Inc) for helpful discussions.
References
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Wurz, R. P. Chiral Dialkylaminopyridine Catalysts in Asymmetric Synthesis.Chem.
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3. (a) Duffey, T. A.; Shaw, S. A.; Vedejs, E. AcOLeDMAP and BnOLeDMAP:
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Rearrangement of Indolyl Acetates and Carbonates. J. Am. Chem. Soc. 2009, 131, 14–
15. (b) Duffey, T. A.; MacKay, J. A.; Vedejs, E. Catalytic Parallel Kinetic Resolution
under Homogeneous Conditions. J. Org. Chem. 2010, 75, 4674–4685. (c) Kinens, A.;
Sejejs, M.; Kamlet, A. S.; Piotrowski, D. W.; Vedejs, E.; Suna, E. Development of a
Chiral DMAP Catalyst for the Dynamic Kinetic Resolution of Azole Hemiaminals. J.
Org. Chem. 2017, 82, 869–886.
4. Snieckus, V. Directed ortho Metalation. Tertiary Amide and OꢀCarbamate Directors in
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933.
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5. The commercially available material was used in the orthoꢀlithiation step as received,
without additional purification or drying.
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9
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Tetrahedron Lett. 1980, 21, 4137–4140. (b) Marsais, F.; Trécourt, F.; Bréant, P.;
Quéguiner, G. Directed Lithiation of 4ꢀHalopyridines: Chemoselectivity,
Regioselectivity and Application to Synthesis. J. Heterocycl. Chem. 1988, 25, 81–87.
7. Busto, E.; GotorꢀFernández, V.; Gotor, V. Enantioselective Synthesis of 4ꢀ
(Dimethylamino)pyridines through a Chemical OxidationꢀEnzymatic Reduction
Sequence. Application in Asymmetric Catalysis. Adv. Synth. Catal. 2006, 348, 2626–
2632.
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8. Agarwal, A.; Chauhan, P. M. S. Convenient Dimethylamino Amination in
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9. Vedejs, E.; Trapencieris, P.; Suna, E. Substituted Isoquinolines by Noyori Transfer
Hydrogenation: Enantioselective Synthesis of Chiral Diamines Containing an Aniline
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and Mechanism. Chin. J. Org. Chem. 2013, 33, 2435. (b) The structure of complex 6
has been determined by Xꢀray crystallographic analysis; see Supporting Information.
11. Other representative Lewis acids such as MgCl2, CuCl2, CuCl, FeCl2 and FeCl3 did
not form stable complexes with Me2NH, which could be isolated in a pure form. In
situ mixing of these salts with Me2NH and 4ꢀClꢀpyridine did not effect the formation
of DMAP.
12. (a) Alexakis, A.; Tomassini, A.; Chouillet, C.; Roland, S.; Mangeney, P.;
Bernardinelli, G. A New Efficient Synthesis of (R,R)ꢀ2,2′ꢀBipyrrolidine: An
Interesting Chiral 1,2ꢀDiamine with C2 Symmetry. Angew. Chem. 2000, 39, 4093–
4095. (b) For synthetic applications of Zn(II)ꢀamine complexes, see: Łowicki, D.;
Baś, S.; Mlynarski, J. Chiral Zinc Catalysts for Asymmetric Synthesis. Tetrahedron
2015, 71, 1339–1394 and references cited therein.
13. Preferential substitution of the 4ꢀposition in 2,4ꢀdihalopyridines has been
demonstrated: (a) Schlosser, M.; Bobbio, C.; Rausis, T. Regiochemically Flexible
Substitutions of Diꢀ, Triꢀ, and Tetrahalopyridines:ꢂ The Trialkylsilyl Trick. J. Org.
Chem. 2005, 70, 2494–2502. (b) Wendt, M. D.; Kunzer, A. R. ortho Selectivity in
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