Scale-up of flow-assisted synthesis of C2-symmetric chiral PyBox ligands

Article abstract of DOI:10.1055/s-0031-1289676

A series of PyBox ligands were prepared from commercially available chelidonic acid by a multistep flow sequence using mesoreactor technology. A chloro group introduced onto the ligand scaffold was subsequently exploited to give amine derivatives ready for immobilization through microencapsulation technologies. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1289676

PAPER
635
Scale-Up of Flow-Assisted Synthesis of C2-Symmetric Chiral PyBox Ligands
Flow Synthesis
o
l
f
PyBo
a
x Ligands udio Battilocchio,a,c Marcus Baumann,a Ian R. Baxendale,a Mariangela Biava,c Matthew O. Kitching,a
Steven V. Ley,a Rainer E. Martin,*b Stephan A. Ohnmacht,b Nicholas D. C. Tappina
a
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK
E-mail: theitc@ch.cam.ac.uk
b
F. Hoffmann-La Roche Ltd., Pharmaceuticals Division, Chemistry Technology and Innovation, 4070 Basel, Switzerland
Department of Pharmaceutical Chemistry and Technology, Sapienza University of Rome, Rome, Italy
c
Received 19 November 2011; revised 13 December 2011
resin, as well as the preparation of monolithic constructs,
Abstract: A series of PyBox ligands were prepared from commer-
both used in flow cyclopropanations.4 In addition, Tilliet
has reported asymmetric silacyanations, epoxide ring
cially available chelidonic acid by a multistep flow sequence using
mesoreactor technology. A chloro group introduced onto the ligand
openings, and imine alkynylations using PyBox ligands
immoblized via a Huisgen cycloaddition reaction to estab-
lish the tether.5 Recently, PyBox systems have also been
immobilized on triiron tetraoxide (Fe3O4) nanoparticles to
create magnetically recoverable catalysts for use in the ad-
dition of terminal alkynes to imines.6 As a general class,
PyBox ligands show excellent utility and continue to gen-
erate significant interest; however, their scalable synthesis
and immobilization is not always straightforward due to
the highly reactive intermediates that are involved in their
preparation.
scaffold was subsequently exploited to give amine derivatives ready
for immobilization through microencapsulation technologies.
Key words: ligands, macrocycles, flow chemistry, solid-supported
reagent, asymmetric synthesis, scale up
Improvements in the understanding and design of asym-
metric syntheses have led to the discovery of a versatile
class of chiral C2-symmetric chelators that are commonly
referred to as PyBox ligands.1 In combination with metals
such as scandium, copper, or ruthenium, these chiral
ligands have been used in various transformations, includ-
ing asymmetric cycloadditions, aldol reactions, hydrocy-
anation, cyclopropanation, and ene-type reactions.2 As the
application of such species is always associated with loss
or incomplete recovery of the precious ligand, chemists
have been attracted to immobilization strategies to miti-
gate this inefficiency.3 For instance, Cornejo demonstrat-
ed the immobilization of PyBox ligands onto Merrifield
As part of our ongoing interest in developing and applying
new encapsulated catalyst systems,7 we decided to study
the immobilization of PyBox ligands within a polyurea
matrix with the ultimate aim of evaluating the capability
of the resulting catalysts in continuous asymmetric flow
synthesis. For this purpose, we wished to achieve the rap-
id preparation of multi-gram quantities of various 4-ami-
no-PyBox ligands 4, ready for encapsulation. The strategy
Cl
O
OH
NH3
O
O
N
HO
OH
HO
OH
O
N
N
N
*
R
*
R
O
O
O
O
1
2
3
NH2
R
NCO
NCO
*
O
N
NH2
O
O
O
N
M
N
N
H2O, CH2Cl2
metal salt
N
N
N
H
*
*
R
N
4
H
R
R
O
*
5
M = Ru, Cu, Sc, etc.
Scheme 1 Strategy for the synthesis and immobilization of Py-Box ligands
SYNTHESIS 2012, 44, 635–647
x
x
.x
x
.2
0
1
2
Advanced online publication: 25.01.2012
DOI: 10.1055/s-0031-1289676; Art ID: N108111SS
© Georg Thieme Verlag Stuttgart · New York

636
C. Battilocchio et al.
PAPER
for this preparation is outlined in Scheme 1 and involves give a residence time of 4.5 hours. The reactor was sub-
the elaboration of commercial chelidonic acid (1; 4-oxo- merged in an ultrasonically agitated water bath held at 45
4H-pyran-2,6-dicarboxylic acid) into the desired 4-chlo- °C, and the system was maintained under a positive pres-
ro-PyBox system 3 in several steps; the presence of the sure by a 75-psi back-pressure regulator at the outlet to the
chloro group permits the subsequent introduction of an first reactor coil. The yellow–orange solution that left the
amine functionality through incorporation and reduction first reactor coil was combined with a second flow stream
of an azide group. The resulting 4-amino-PyBox ligands consisting of 3.5 M aqueous hydrochloric acid. A tube-
could subsequently be encapsulated by intercepting the displaced T-piece connector (see Scheme 2)12 was used to
wall-forming
sequence
during
an
intrafacial add the acid solution (2 mL/min) to the flow stream of the
polymerization8 of a polyfunctional isocyanate residue.
ammonia solution, resulting in neutralization and immedi-
ate formation of a fine white precipitate. The use of a stan-
dard T-union led to blockages as a result of solid buildup
at the joints as a resulting of back-mixing; this was com-
pletely avoided by the use of the modified displacement
T-connector. To maintain a free-flowing slurry, a second
sonicator (isothermal water temperature 15 °C) was used
to break up any aggregate that formed,13 simply by sub-
merging the connecting T-unit and a short length of the
downstream tubing (3.5 m × 3 mm id.) in the water well
of the sonicator.14 A further length of the tube reactor (1.5
m) was used to direct the output onto a sintered filter that
was maintained under vacuum suction to permit isolation
of the product. The resulting white solid was dried under
vacuum at 40 °C to give chelidamic acid (2) as its pure
monohydrate in 81% isolated yield. The identity of the
product was confirmed by 1H NMR spectroscopy and by
elemental analysis, and the compound was used in the
next step without any further purification.
Our route to the PyBox ligands is similar to previously re-
ported procedures,9 but we decided to establish a flow se-
quence, as it was noted that upon scale-up the reported
yields varied dramatically and the potential hazards asso-
ciated with scaling increased significantly. Furthermore,
in addition to gaining benefits through higher reproduc-
ibility due to constant heat and mass transfer provided by
the micro-mixing in flow, we also expected to obtain in-
creased processing efficiencies through automation and to
achieve improved safety profiles in the handling of toxic
or hazardous reagents, as reported in several recent publi-
cations.10,11
Our starting point was commercially available chelidonic
acid (1), which we transformed into the analogous che-
lidamic acid (2; 4-oxo-1,4-dihydropyridine-2,6-dicarbox-
ylic acid) by treatment with 25% aqueous ammonia under
sonication conditions. A 1 M solution of the chelidonic
acid in aqueous ammonia was pumped at 0.5 mL/min
through a 135-mL coil of fluorinated ethylene propylene
copolymer (FEP), with an internal diameter of 3 mm, to
In the next step of the sequence, the acid 2 was polychlo-
rinated to give the diacyl dichloride core building block 6
(Scheme 3). The reported batch conditions15 for this pro-
Scheme 2 Flow synthesis of chelidamic acid (2) by using sonication
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Flow Synthesis of PyBox Ligands
637
cedure involve refluxing the substrate in excess thionyl We found that commercially available Vilsmeier
chloride for several hours. This is an efficient reaction reagent17 (7) dissolved in acetonitrile was capable of con-
when conducted on a small scale, but on scaling up results verting the hydroxy diacid 2 into the trichloride 6 in excel-
in problems of reaction containment and workup (CAU- lent yields in a Vapourtec R2+/R4 flow system.18 A 0.2 M
TION: extremely exothermic/delayed runaway, with the solution of substrate 2 (1 equiv) and triethylamine (2
liberation of large quantities of hydrogen chloride and sul- equiv) in acetonitrile and a 0.45 M solution of Vilsmeier
fur dioxide). Consequently, we performed this crucial reagent (5.625 equiv) in a 9:1 mixture of acetonitrile and
chlorination step as a flow process, preferably by using N,N-dimethylformamide were separately loaded into indi-
stoichiometric amounts of various chlorinating reagents vidual sample loops mounted on the R2+ unit. The solu-
to minimize workup. Our initial attempts using oxalyl tions were combined at a T-piece connector and the
chloride in acetonitrile resulted in incomplete formation resulting mixture was passed through a convection flow
of the chlorinated product 6. Quenching the output stream coil (CFC) heated at 75 °C. We found that a residence
with excess methanol to aid characterization led to the iso- time of 57 minutes was suitable for full chlorination of
lation of a mixture of the 4-hydroxy and the 4-chloro di- chelidamic acid (2) and we isolated product 6b in quanti-
methyl esters 6a and 6b, respectively, as the corresponding tative conversion after quenching the reaction with meth-
monohydrochloride salts, together with the symmetrical anol. In practice, the corresponding acid chloride 6 could
4-chloro anhydride 6c (Scheme 3). Changing the resi- be isolated by collecting the output from the reactor in a
dence time and temperature of the process failed to alter stirred solution of anhydrous diethyl ether to precipitate
the ratio of products significantly, whereas increasing the the triethylammonium salts, which could then be filtered
stoichiometry of the oxalyl chloride led to more of the de- off. This procedure allowed the isolation of the pure
sired product 6b, but also raised new problems with re- trichlorinated product 6 with acceptable recovery simply
gard to quenching and isolation. We therefore evaluated by evaporation of the solvent (Scheme 4).
the use of thionyl chloride, but the results of this process
Alternatively, the output stream could be combined di-
mirrored those achieved with oxalyl chloride, requiring
rectly with a quench stream of methanol with incubation
the use of an excess of the reagent to achieve good conver-
in a second 10-mL flow coil (20 minutes residence time),
sions into 6b. It is well documented in the literature16 that
followed by evaporation of the solvents (NOTE: The use
the addition of catalytic quantities of N,N-dimethylforma-
of a hydrochloric acid trap when evaporating the solvent
is recommended), thereby permitting the isolation of 6b
as its hydrochloride salt in quantitative yield. The free
base from 6b could also be isolated by directing the com-
mide can improve yields from chlorination reactions in-
volving oxalyl chloride or thionyl chloride. Although this
indeed proved to be the case, it also led us to consider the
use of the Vilsmeier’s intermediate (7) as an alternative
bined methanolic stream through a cartridge of a dimeth-
reagent for the reaction.
ylamino-functionalized resin (Quadrapure-DMA;
4
Scheme 3 Chlorination of chelidamic acid (2) in flow
© Thieme Stuttgart · New York
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638
C. Battilocchio et al.
PAPER
Scheme 4 Preparation of diacyl dichloride building block 6 using Vilsmeier’s agent
equivalents) before evaporation of the solvent, although Our previous experience showed that batch procedures20
this process resulted in a slightly lower recovery (91%).19 for the preparation of amido alcohols 8a–e (Scheme 5) –
the next step in the sequence (the amide-forming step) –
Cl
Cl
are troublesome because of the formation of a number of
impurities as a result of the presence of local excesses of
reagents during the coupling process. These impurities
were identified by liquid chromatography/mass spectros-
copy as dimerized or partially dimerized material that
were difficult to separate by column chromatography be-
cause their Rf values were similar to those of the desired
products.
O
O
O
O
N
N
NH
O
HN
O
NH
O
HN
O
N
N
O
O
O
O
However, because macrocycles of the type 10a–f
(Figure 1) represent an interesting new class of structures
with considerable potential for selective chelation of
small molecules or ions,21 we set ourselves the challenge
of deliberately preparing these structures. We felt that this
would not be easily accomplished in a selective and effi-
cient manner by batch-processing techniques for the rea-
sons discussed above. However, because flow
microreactors permit better control over mixing of sub-
strate streams, we were confident that such reactors could
be used to perform the transformation efficiently. Indeed,
when we adjusted the pump delivery speeds to produce a
1:1 stoichiometry of reagent streams (each 0.1 M in ace-
tonitrile) with a 60-minute residence time in a CFC reac-
tor maintained at 80 °C, we obtained the macrocyclic
structures shown in Figure 1 in high yields and high puri-
ties.
Cl
Cl
10a, 90%
10b, 91%
Cl
Cl
O
O
O
O
O
O
O
O
N
N
Ph
NH
HN
Ph
NH
HN
O
O
O
O
N
N
Cl
Cl
10c, 85%
Cl
10d, 65%
Cl
By performing the amide formation from the diacyl
dichloride 6 in a flow process and by using a 1:2 stoichio-
metric ratio of 6 and amino alcohol 9, we succeeded in the
clean formation of the desired bisamides 8a–e through
precise mixing of the starting materials in an exact and
constant ratio (Scheme 5). We also found that the same
amide products could be produced by mixing the corre-
sponding amino alcohols 9a–e with diester 6b (free base
form, previously prepared in flow) in a 2:1 ratio, and melt-
ing the components together for 3.5 h at 120 °C. Tritura-
tion of the resulting light-brown gum with a 10:1 mixture
of diethyl ether and methanol gave the desired amides as
O
O
O
O
O
O
O
O
N
N
NH
NH
HN
NH
O
HN
O
HN
N
N
Cl
Cl
10e, 82%
10f, 70%
Figure 1 Structures of macrocycles 10a–f prepared in flow
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Flow Synthesis of PyBox Ligands
639
Scheme 5 Preparation of chlorobisamides 8a–d
a white solid in >85% isolated yield. The resulting mate- lematic as a result of insufficient solubility, which
rial was of sufficient purity (>90%) for use in the subse- prevented us from progressing through the sequence. The
quent stages of the synthesis.
desired bisoxazoline product tended to precipitate from
solution upon meeting the calcium carbonate quenching
column, making recovery difficult. After considering the
safety aspects of excluding the in-line fluoride scavenge,
we decided not to progress further with this particular sub-
strate.
Next, we turned our attention to the cyclodehydration of
the chiral bis-amides 8a–d (R and S enantiomeric series)
by using a previously described diethylaminosulfur tri-
fluoride (DAST)-promoted flow procedure (Scheme 6).22
The use of this reagent in flow provided rapid and clean
access to the bisoxazolines 3a–c without the need for In the final stage of the sequence, a 0.1 M solution of the
manual handling of large quantities of the hazardous oxazoline starting material 3 in N,N-dimethylformamide
DAST reagent, as would be required in a batch process. was combined in a standard T-mixing piece with a 5.0 M
Additionally, we were able to benefit from the use of an aqueous solution of sodium azide. The resulting mixture
in-line calcium carbonate quench to remove the liberated was then directed through a CFC reactor at 120 °C (resi-
hydrogen fluoride and to trap any inorganic fluoride con- dence time 70 min) to effect an SNAr reaction on the 4-
taminants,23 thereby allowing the isolation of clean 4- chloro substituent (Scheme 7). The desired azide deriva-
chloro-PyBox ligands merely by removing the solvent. tives 11a–c were generated in excellent yields24 and were
This procedure proved high successful in providing the subsequently reduced to the corresponding amines by us-
oxazolines 3a–c in high yields and in permitting ready ing an H-Cube flow hydrogenator.25 Although this reduc-
scale-up to gram quantities with excellent reproducibility tion can be performed under standard batch conditions,
(approximately 1–3 g per aliquot injection). Unfortunate- we found that the use of the H-Cube in combination with
ly, the synthesis of the indane derivative 8d proved prob- catalyst cartridges filled with 10% palladium/carbon was
Scheme 6 Synthesis of 4-chloro-PyBox ligands in flow
© Thieme Stuttgart · New York
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C. Battilocchio et al.
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Scheme 7 Synthesis of 4-amino-PyBox ligands 4a–c in flow
advantageous, as the controlled mode (30 bar, 50 °C, 0.01 capsulating for application in asymmetric flow transfor-
M in MeOH) allowed a complete and clean conversion mations.
into the desired amines within minutes as opposed to the
In summary, we have devised a scalable flow route to a
hours required by the batch method. The desired 4-amino
number of functionalized PyBox ligands. Improvements
PyBox ligands 4a–c were isolated in analytical purity by
to previous syntheses have been achieved through the use
crystallization from diethyl ether. The structure and
of flow techniques that resulted in better reproducibility,
chirality of (S)-4b was confirmed by high-resolution
greater automation, and improved safety standards; more-
single-crystal X-ray analysis (Figure 2). The structures of
over, the flow techniques permit in-line purification, mak-
the other compounds were inferred by analogy.
ing the demonstrated route both rapid and highly efficient.
Unless stated otherwise, reagents were obtained from commercial
sources and used without purification. Laboratory reagent grade
EtOAc, PE 40–60, and CH2Cl2 were obtained from Fischer Scien-
tific and distilled before use. Laboratory reagent-grade toluene was
obtained from Fischer Scientific, azeotropically distilled to remove
H2O, and then distilled from CaH2 before use. Solvent were re-
moved under reduced pressure by using a standard rotary evapora-
tor (Genevac EZ-2 Plus personal evaporator or Vapourtec V-10
evaporator). All column chromatography was carried out by using
silica gel (0.040–0.063 mm), purchased from Breckland Scientific
Supplies. TLC analyses were performed on Merck 60 F254 silica
gel plates, visualized by short- and long-wave UV radiation in com-
bination with standard laboratory stains (acidic potassium perman-
ganate or acidic ammonium molybdate). Preparative TLC was
conducted on PLC 20 × 20 × 1 cm plates impregnated with silica gel
60 F254, purchased from Merck. Melting points were measured on
Figure 2 Single-crystal X-ray diffraction analysis of 4-amino-tert-
butyl-PyBox ligand (S)-4b. The ORTEP drawing shows thermal
ellipsoids at a 30% probability level.
a Stanford Research Systems MPA100 (OptiMelt) automated melt-
ing point system.
IR spectra were recorded neat on a PerkinElmer Spectrum One FT-
IR spectrometer with Universal ATR sampling accessories. Letters
in parentheses refer to the relative absorbance of the peak:
This three-step sequence consisting of DAST-mediated
cyclodehydration, high-temperature azide substitution, w = weak (£40% of the most intense peak); m = medium (41–69%
of the most intense peak); s = strong ( 70% of the most intense
peak).
and hydrogenation shows the advantages of flow tech-
niques over batch processing in a number of powerful yet
1H NMR spectra were recorded on Bruker Avance DPX-400, Bruk-
cumbersome reaction steps (Schemes 5 and 6). Further-
er Avance DRX-600, Avance 400 QNP Cryo, or Avance 500 Cryo
more, all the above steps proved to be readily scalable,
spectrometers with the residual solvent peak as the internal refer-
successfully generating sufficient quantities (10-gram
ence (CDCl3 = 7.26 ppm, DMSO-d6 = 2.50 ppm, CD3OD = 3.31).
amounts) of the final materials, which we are currently en-
1H resonances are reported to the nearest 0.01 ppm. 13C NMR Spec-
tra were recorded on the same spectrometers with the central reso-
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Flow Synthesis of PyBox Ligands
641
nance of the solvent peak as the internal reference (CDCl3 = 77.16
ppm, DMSO-d6 = 39.52 ppm, CD3OD = 49.00). All 13C resonances
are reported to the nearest 0.1 ppm. DEPT 135, COSY, HMQC, and
HMBC experiments were used to aid structural determination and
spectral assignment. Where specified, NOESY and gradient NOE
a sintered filter that was maintained under vacuum suction to permit
isolation of the product. The resulting white solid was dried under
vacuum at 40 °C to give chelidamic acid (2) monohydrate as a white
solid; yield: 41.02 g (81%); molecular formula C7H5NO5.
IR (neat): 3604 (m), 3443 (m), 3122 (w), 2993 (w), 2857 (w), 2455
(br m) 1720 (m), 1608 (s), 1470 (s), 1422 (s), 1393 (s), 1337 (s),
1259 (s), 1132 (s), 1022 (s), 986 (s), 935 (s), 916 (s), 895 (s), 782
(s), 761 (s), 704 (s), 697 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.53 (s, 2 H, Py-CH).
13C NMR (100 MHz, DMSO-d6): d = 167.0 (C), 165.7 (C), 149.6
(C), 115.2 (CH).
1
spectra were used to aid the assignment of H spectra. Coupling
constants (J) are quoted in Hz and reported to the nearest 0.1 Hz.
Where appropriate, averages of the signals from peaks displaying
multiplicity were used to calculate the values of the coupling con-
stants.
High-resolution mass spectra were recorded on a Waters Micro-
mass LCT Premier spectrometer operating in the time-of-flight
mode with a positive ESI; some were recorded by Mr. Paul Skelton
on a Bruker BioApex 47e FTICR spectrometer operating in the pos-
itive ESI or EI mode at 70 eV to within a tolerance of 5 ppm of the
theoretically calculated value.
LC-MS: tR = 0.34 min; m/z = 182.09 [M – H].
HRMS (ESI): m/z calcd for [C7H6NO5]+: 184.0259; found:
184.0257.
LC-MS analyses were performed on an Agilent HP 1100 series
chromatography [Mercury Luna 3u C18 (2) column] attached to a
Waters ZQ2000 mass spectrometer 102 with an ESCi ionization
source operating in the ESI mode. Elution was carried out at a flow
rate of 0.6 mL/min using a reverse-phase gradient of MeCN and
H2O containing 0.1% formic acid. The gradient used is shown in
Table 1. The retention time (tR) is given in minutes to the nearest 0.1
minutes, and the m/z value is reported to the nearest mass unit
(m.u.).
PyBox Cyclization; General Procedure
A 0.24 M soln of Et2NSF3 (DAST) in CH2Cl2 was loaded into a 10-
mL sample loop, and a 0.1 M soln of the appropriate bisamide 8 in
1:1 MeCN–CH2Cl2 was separately loaded into a second 10-mL
sample loop. The solns were injected into the system and combined
at a standard T-piece mixer before flowing through a 10-mL CFC
(0.5 mL/min, 1:1 ratio, residence time: 20 min, system solvent:
CH2Cl2) maintained at 90 °C. The outflow was directed through a
glass column loaded sequentially with a layer of CaCO3 and a layer
of silica gel (2 g each). The soln was collected for 2 h and then the
solvent was removed in vacuo to yield the corresponding cyclized
material 3.
Table 1 Solvent Gradient for HPLC Purification
Time
0.0
1.0
4.0
5.0
7.0
8.0
MeCN (%)
4-Chloro-2,6-bis[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-
yl]pyridine [(S)-3a]27
5
5
Yield: 298 mg (89%); colorless oil; [a]D25 +96.9 (c 1.1, CHCl3).
IR (neat): 3441 (w), 2960 (m), 2916 (m), 2874 (m), 1642 (s), 1562
(s), 1468 (m), 1426 (w), 1382 (s), 1366 (m), 1324 (w), 1270 (m),
1237 (s), 1151 (m), 1020 (w), 975 (s), 937 (m), 887 (m), 788 (s), 731
(s) cm–1.
1H NMR (600 MHz, CDCl3): d = 8.18 (s, 2 H), 4.53 (app. t, J = 8.9
Hz, 2 H), 4.22 (app. t, J = 8.4 Hz, 2 H), 4.12–4.17 (m, 2 H), 1.85
(sext, J = 6.6 Hz, 2 H), 1.03 (d, J = 6.6 Hz, 6 H), 0.93 (d, J = 6.6 Hz,
6 H).
95
95
5
5
1H NMR (400 MHz, CDCl3): d = 8.12 (s, 2 H), 4.48 (dd, J = 8.4, 8.4
Hz, 2 H), 4.18 (dd, J = 8.4, 8.4 Hz, 2 H), 4.13–4.07 (m, 2 H), 1.82
(sext, J = 6.6 Hz, 2 H), 1.00 (d, J = 6.6 Hz, 6 H), 0.89 (d, J = 6.6 Hz,
6 H).
13C NMR (150 MHz, CDCl3): d = 161.4 (C), 148.0 (C), 145.5 (C),
125.8 (CH), 72.8 (CH), 71.3 (CH2), 32.8 (CH), 18.9 (CH3), 18.3
(CH3).
13C NMR (100 MHz, CDCl3): d = 161.4 (C), 148.0 (C), 145.4 (C),
125.8 (CH), 73.0 (CH), 71.3 (CH2), 32.8 (CH), 19.0 (CH3), 18.4
(CH3).
Optical rotations were measured by using a PerkinElmer Model 343
polarimeter equipped with a sodium lamp (l = 589 nm, D-line);
[a]D25 values are reported in 10–1 deg cm2 g–1.
CIF numbers are reported as part of compound characterization. El-
emental analyses within a tolerance of 0.5% of the theoretical val-
ues were performed by Mr. Alan Dickerson and Mrs. Patricia Irele
in the microanalytical laboratories at the Department of Chemistry,
of the University of Cambridge.
4-Hydroxypyridine-2,6-dicarboxylic Acid (2)26
[CAS Reg. No. 499–51–4]
LC-MS: tR = 4.57 min, m/z = 335.9 [M + H]+.
A 1 M soln of chelidonic acid (1) in 25% aq NH3 was pumped at 0.5
mL/min through a 135-mL FEP coil (3 mm i.d.; 4.5 h residence
time). The entire tubular reactor was submerged in an ultrasonic wa-
ter bath (isothermal regulation 45 °C) and the system was main-
tained under positive pressure by using a 75-psi back-pressure
regulator at the outlet of the reactor coil. The yellow/orange soln
that exited the initial reactor coil was combined with a second flow
stream consisting of 3.5 M aq HCl. A tube-displaced T-piece con-
nector (see Scheme 2) was used to mix the acid soln (2 mL/min)
with the flow stream (3.5 m × 3 mm i.d.) of the ammonia soln, re-
sulting in neutralization and immediate formation of a fine white
precipitate. The mixture was maintained as a free-flowing slurry by
using a second sonicator (isothermal water regulation 15 °C). An
additional 1.5-m length of the tube reactor directed the output onto
HRMS (ESI): m/z calcd for C17H23ClN3O2: 336.1479; found:
336.1494.
4-Chloro-2,6-bis[(4R)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-
yl]pyridine [(R)-3a]
Yield: 281 mg (84%); colorless oil; [a]D25 –47.6 (c 0.5, CHCl3).
IR (neat): 2959 (m), 2932 (w), 1666 (m), 1642 (s), 1561 (s), 1529
(m), 1381 (s), 1366 (m), 1147 (m), 1123 (m), 976 (s), 937 (s), 886
(s), 790 (s), 730 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.18 (s, 2 H), 4.49 (dd, J = 8.8 and
8.8 Hz, 2 H), 4.19 (app. t, J = 8.4 Hz, 2 H), 4.13–4.07 (m, 2 H), 1.83
(m, 2 H), 1.01 (d, J = 6.6 Hz, 6 H), 0.88 (d, J = 6.6 Hz, 6 H).
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13C NMR (100 MHz, CDCl3): d = 161.45 (C), 148.12 (C), 145.39
(C), 125.87 (CH), 72.98 (CH), 71.29 (CH2), 32.86 (CH), 19.01
(CH3), 18.36 (CH3).
HRMS (ESI): m/z calcd for C23H18ClN3O2: 404.1088; found:
404.1092.
Anal. Calcd for C23H18ClN3O2: C, 67.4; H, 4.49; N, 10.4. Found: C,
66.95; H, 4.49; N, 10.28.
LC-MS: tR = 4.58 min, m/z = 336.1 [M + H]+.
HRMS (ESI): m/z calcd for C17H23ClN3O2: 336.1479; found:
336.1487.
2,6-Bis[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]pyridin-4-
amine [(S)-4a]:27 Typical Procedure
A 0.1 M soln of chloropyridine (S)-3a in DMF flowing at 0.5 mL/
min was mixed with a stream consisting of a 5.0 M aq soln of NaN3
flowing at 0.1 mL/min. The combined stream was passed through
four 10-mL CFCs heated at 120 °C, giving a residence time of ~67
min. The output stream was diluted 9:1 with MeOH, and the soln
was passed at a flow rate of 2 mL/min through an H-cube hydroge-
nator containing a 10% Pd/C cartridge at 50 °C at 30 bar H2 pres-
sure. The soln was then passed through a short plug of silica gel and
the solvent was evaporated.
2,6-Bis[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]-4-chloro-
pyridine [(S)-3b]20
Yield: 327 mg (90%); off-white solid; mp 177–179 °C; [a]D25 –25.8
(c 1.0, CHCl3).
IR (neat): 3334 (br w), 2932 (br w), 2170 (w), 2158 (w), 1673 (s),
1644 (s), 1550 (s), 1520 (s), 1467 (m), 1397 (m), 1231 (w), 1218
(w), 1205 (w), 1155 (m), 1112 (w), 1044 (m), 1006 (w), 766 (m),
712 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.30 (s, 2 H), 4.52 (dd, J = 10.2
and 9.0 Hz, 2 H), 4.37 (m, 2 H), 4.15 (dd, J = 10.2 and 9.0 Hz, 2 H),
1.01 (br s, 18 H).
13C NMR (100 MHz, CDCl3): d = 162.2 (C), 148.3 (C), 145.6 (C),
126.5 (CH), 75.7 (CH2), 70.2 (CH), 34.6 (C), 26.4 (CH3).
LC-MS: tR = 4.87 min, m/z = 364.2 [M + H]+.
Yield: 10.8 g (84%); mp >230 °C (dec.); [a]D25 –76.1 [c 0.7,
MeOH–CHCl3 (1:1)].
IR (neat): 3290 (br w), 3162 (br s), 2960 (m), 1663 (s), 1588 (s),
1536 (s), 1466 (m), 1349 (m) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.27 (s, 2 H), 6.44 (br s, 2 H,
NH2), 4.40 (t, J = 8.8 Hz, 2 H), 4.02–4.11 (m, 4 H), 1.74 (sext,
J = 6.4 Hz, 2 H), 0.95 (d, J = 6.4 Hz, 6 H), 0.88 (d, J = 6.4 Hz, 6 H).
HRMS (ESI): m/z calcd for C19H26ClN3O2Na: 386.1611; found:
13C NMR (150 MHz, DMSO-d6): d = 162.7 (C), 155.5 (C), 147.1
(C), 110.5 (CH), 72.3 (CH), 70.3 (CH2), 32.7 (CH), 19.0 (CH3),
18.7 (CH3).
386.1628.
4-Chloro-2,6-bis[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]py-
ridine [(S)-3c]
LC-MS: tR = 3.61 min, m/z = 317.2 [M + H]+.
Yield: 353 mg (88%); off-white solid; mp 160–163 °C; [a]D25 –15.6
(c 1.0, CHCl3).
HRMS (ESI): m/z calcd for C17H25N4O2: 317.1978; found:
317.1973.
IR (neat): 3313 (br w), 2930 (br w), 2161 (w), 1671 (s), 1639 (s),
1561 (m), 1518 (s), 1454 (m), 1406 (w), 1380 (m), 1314 (w), 1235
(w), 1189 (w), 1148 (m), 1063 (m), 1029 (m), 914 (w), 755 (m), 700
(s) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.35 (s, 2 H), 7.39–7.31 (m, 10 H),
5.46 (dd, J = 8.8 and 10 Hz, 2 H), 4.93 (dd, J = 8.4 and 10.0 Hz, 2
H), 4.44 (dd, J = 8.4 and 8.8 Hz, 2 H).
Anal. Calcd for C17H25N4O2: C, 64.5; H, 7.65; N, 17.71. Found: C,
64.1; H, 7.57; N, 17.2.
The structure was unambiguously confirmed by X-ray crystallogra-
phy. Molecular formula: C17H24N4O2; space group: orthorhombic
P2(1)2(1)2(1), a = 6.1451(1), b = 13.9669(3), c = 20.2757(5),
b = 90.896°.
1H NMR (600 MHz, CDCl3): d = 8.34 (s, 2 H), 7.36 (t, J = 7.8 Hz,
4 H), 7.28–7.35 (m, 6 H), 5.46 (app. t, J = 9.6 Hz, 2 H), 4.93 (app.
t, J = 9.0 Hz, 2 H), 4.93 (app. t, J = 10.2 Hz, 2 H).
13C NMR (150 MHz, CDCl3): d = 162.8 (C), 148.0 (C), 145.6 (C),
141.3 (C), 128.9 (CH), 127.9 (CH), 126.8 (CH), 126.4 (CH), 75.7
(CH2), 70.3 (CH).
4-Azido-2,6-bis[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-
yl]]pyridine (11a)27
To isolate the intermediate 11a, a small sample (3 mL) of the output
from the reaction of (S)-3a with NaN3 was collected and mixed with
acetone (20 mL) to give an off-white precipitate; yield: 7.4 mg
(72%).
1H NMR (400 MHz, CDCl3): d = 7.82 (s, 2 H), 4.53 (t, J = 8.6 Hz,
2 H), 4.22 (t, J = 8.6 Hz, 2 H), 4.10–4.16 (m, 2 H), 1.86 (sext,
J = 6.8 Hz, 2 H), 1.05 (d, J = 6.8 Hz, 6 H), 0.89 (d, J = 6.8 Hz, 6 H).
LC-MS: tR = 4.74 min, m/z = 404.2 [M + H]+.
HRMS (ESI): m/z calcd for C23H19ClN3O2: 404.1166; found:
404.1169.
13C NMR (100 MHz, CDCl3): d = 162.5 (C), 150.3 (C), 148.6 (C),
115.8 (CH), 73.0 (CH), 71.2 (CH2), 32.8 (CH), 19.0 (CH3), 18.3
(CH3).
4-Chloro-2,6-bis[(4R)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]py-
ridine [(R)-3c]
Yield: 301 mg (75%); white solid; mp 159–161 °C; [a]D25 +12.4 (c
LC-MS: tR = 4.24 min, m/z = 343.2 [M + H]+.
0.9, CHCl3).
IR (neat): 2959 (s), 2932 (w), 1666 (s), 1642 (s), 1561 (m), 1529 (s),
1468 (m), 1424 (w), 1381 (s), 1366 (s), 1235 (m), 1147 (m), 1123
(m), 976 (s), 886 (s), 790 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.36 (s, 2 H), 7.39–7.31 (m, 10 H),
5.45 (dd, J = 9.1 and 11.0 Hz, 2 H), 4.98 (dd, J = 8.4 and 11.0 Hz,
2 H), 4.36 (dd, J = 8.4 and 9.1 Hz, 2 H).
2,6-Bis[(4R)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]pyridin-4-
amine [(R)-4a]26
Yield: 6.89 g (81%); white solid; mp >235 °C (dec.); [a]D25 +62.8
[c 0.45, MeOH–CHCl3 (1:1)].
IR (neat): 3260 (br w), 3165 (br s), 2957 (m), 1666 (s), 1585 (s),
1535 (s), 1470 (m), 1343 (m) cm–1.
13C NMR (100 MHz, CDCl3): d = 163.1 (C), 148.3 (C), 145.8 (C),
141.1 (C), 129.1 (CH), 128.2 (CH), 126.9 (CH), 126.6 (CH), 75.7
(CH2), 70.4 (CH).
1H NMR (400 MHz, DMSO-d6): d = 7.21 (s, 2 H), 6.36 (br s, 2 H,
NH2), 4.37 (t, J = 8.8 Hz, 2 H), 4.11 (t, J = 8.8 Hz, 2 H), 4.01 (m, 2
H), 1.71 (sext, J = 6.0 Hz, 2 H), 0.91 (d, J = 6.0 Hz, 6 H), 0.85 (d,
J = 6.0 Hz, 6 H).
LC-MS: tR = 4.72 min, m/z = 404.1 [M + H]+.
Synthesis 2012, 44, 635–647
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Flow Synthesis of PyBox Ligands
643
13C NMR (100 MHz, CDCl3): d = 162.79 (C), 153.68 (C), 147.51
(C), 111.06 (CH), 72.75 (CH), 70.90 (CH2), 32.89 (CH), 19.11
(CH3), 18.37 (CH3).
4-Chloropyridine-2,6-dicarbonyl Dichloride (6)26: Batch Syn-
thesis
[CAS Reg. No. 71022–75–8]
LC-MS: tR = 3.63 min, m/z = 317.2 [M + H]+.
HRMS (ESI): m/z calcd for [C17H25N4O2]+: 317.1978; found:
DMF (1.75 mL) was added dropwise to a soln of chelidamic acid (2;
10.0 g) in SOCl2 (125 mL). The yellow reaction mixture was stirred
under reflux for 8 h and then excess SOCl2 was removed in vacuo.
The resulting yellow solid was suspended in toluene (15 mL) and
the solvent was removed in vacuo to give an off-white solid; yield:
13.0 g (quant).
317.1973.
Anal. calcd for [C17H24N4O2]: C, 64.5; H, 7.65; N, 17.71. Found: C,
64.3; H, 7.55; N, 17.5.
4-Chloropyridine-2,6-dicarbonyl Dichloride (6)26: Flow Synthe-
sis
2,6-Bis[(4S)-4-tert-butyl-4,5-dihydro-1,3-oxazol-2-yl]pyridin-4-
amine [(S)-4b]
Yield: 9.87 g (82%); white solid; mp: 254.4–257.2 °C; [a]D25 –10.0
[c 0.25, CHCl3–MeOH (1:1)].
A first stock soln was prepared containing Vilsmeier’s reagent
(ClCH=N+Me2 Cl–; 4.5 mmol) in a mixture of MeCN (9 mL) and
DMF (1 mL), and a second stock soln was prepared containing che-
lidamic acid (2; 2 mmol) and Et3N (4 mmol) in MeCN (25 mL).
These solns were pumped at flow rates of 100 mL/min and 250 mL/
min, respectively, to meet at a T-piece. The combined flow stream
was then directed through two 10-mL CFCs linked in series and
heated at 75 °C (residence time ~57 min), followed by a cartridge
containing Quadrapure Dimethylamine resin (QP-DMA; 6 g). The
output stream was collected for 2.5 h and the solvent was evaporat-
ed; yield: 431 mg (91%); white solid; molecular formula:
C7H2Cl3NO2.
IR (neat): 3370 (w), 3285 (w), 3193 (m), 2985 (m), 1629 (m), 1588
(s), 1357 (m), 1304 (m), 1235 (s), 1224 (s), 1164 (s), 983 (s), 967
(m), 881 (m), 868 (m), 695 (m) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.27 (s, 2 H), 6.51 (s, 2 H,
NH2), 4.36 (app. t, J = 9.6 Hz, 2 H), 4.22 (app. t, J = 8.8 Hz, 2 H),
3.99 (dd, J = 8.8 and 9.6 Hz, 2 H), 0.88 (s, 18 H).
13C NMR (100 MHz, DMSO-d6): d = 162.3 (C), 155.3 (C), 146.6
(C-1), 110.0 (CH), 75.4 (CH), 68.4 (CH2), 33.5 (C), 25.7 (3 × CH3).
LC-MS: tR = 2.07 min, m/z = 345.3 [M + H]+.
Alternatively, the QP-DMA column was omitted and the output
stream was collected in a stirred Et2O (100 mL) to precipitate the tri-
ethylammonium salts. After evaporation of the solvent, the product
was isolated in 76% yield.
HRMS (ESI): m/z calcd for C19H28N4O2: 344.2212; found:
344.2205.
The structure was unambiguously confirmed by X-ray crystallogra-
phy. Molecular formula C19H28N2O4; space group: orthorhombic
P2(1)2(1)2(1), a = 6.0689(3), b = 14.2417(6), c = 22.2350(10).
IR (neat): 3082 (w), 1759 (s), 1614 (w), 1584 (m), 1556 (m), 1431
(w), 1416 (w), 1371 (w), 1259 (s), 1190 (m), 1144 (m), 1123 (m),
1101 (m), 1044.5 (w), 1022 (w), 990 (m), 947 (s), 907 (s), 806 (m),
726 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 8.32 (s, 2 H).
1H NMR (400 MHz, DMSO-d6): d = 8.25 (s, 2 H).
13C NMR (150 MHz, CDCl3): d = 168.6 (C), 150.1 (C), 147.9 (CH),
128.9 (C).
13C NMR (100 MHz, DMSO-d6): d = 164.5 (C), 149.9 (C), 145.3
(CH), 127.3 (C).
2,6-Bis[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]pyridin-4-
amine [(S)-4c]
Yield: 5.22 g (88%); white solid; mp >250 °C (dec.); [a]D25 –8.0 (c
0.1, MeOH).
IR (neat): 3290 (w), 3144 (m), 2892 (w), 1665 (m), 1581 (s), 1411
(m), 1233 (s), 1167 (s), 983 (s), 968 (m), 756 (m), 697 (s) cm–1.
1H NMR (400 MHz, DMSO-d6): d = 7.40–7.20 (m, 12 H), 6.64 (br
s, 2 H, NH2), 5.40 (t, J = 8.9 Hz, 2 H), 4.75 (t, J = 8.9 Hz, 2 H), 4.25
(t, J = 8.9 Hz, 2 H).
13C NMR (100 MHz, DMSO-d6): d = 163.4 (C), 162.5 (C), 157.6
(C), 142.6 (C), 128.7 (CH), 127.5 (CH), 126.6 (CH), 117.4 (CH),
75.3 (CH2), 69.2 (CH).
HRMS (ESI): m/z calcd for C7H2Cl3NNaO2: 259.9049; found:
259.9087.
Anal. Calcd for C7H2Cl3NO2: C, 35.26; H, 0.85; Cl, 44.60; N, 5.87.
Found: C, 35.12; H, 0.98; Cl, 43.40; N, 6.00.
LC-MS: tR = 4.60 min, m/z = 385.1 [M + H]+, 407.1 [M + Na]+.
Dimethyl 4-Hydroxypyridine-2,6-dicarboxylate (6a)21b,26,28
[CAS Reg. No. 20443–03–2]
HRMS (ESI): m/z calcd for C23H21N4O2: 385.1665; found:
385.1672.
White solid.
2,6-Bis[(4R)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]pyridin-4-
amine [(R)-4c]
IR (neat): 3346 (w), 3213 (m), 2917 (w), 1723 (s), 1611 (m), 1459
(w), 1419 (m), 1355 (s), 1266 (m), 1207 (s), 1182 (s), 1155 (m), 973
(m), 948 (s), 922 (m), 878 (s), 853 (s), 777 (s) cm–1.
Yield: 7.81 g (80%); white solid; mp >250 °C (dec.); [a]D25 +13.0
(c 0.1, MeOH).
1H NMR (400 MHz, DMSO-d6): d = 11.62 (s, 1 H), 7.59 (s, 2 H),
3.89 (s, 6 H).
IR (neat): 3333 (w), 3205 (m), 2890 (w), 1641 (m), 1583 (s), 1352
(m), 1238 (s), 1044 (m), 984 (m), 926 (m), 756 (m), 698 (s) cm–1.
13C NMR (100 MHz, DMSO-d6): d = 167.2 (C), 165.5 (C), 150.3
1H NMR (400 MHz, DMSO-d6): d = 7.38–7.20 (m, 12 H), 6.60 (br
s, 2 H, NH2), 5.39 (t, J = 8.9 Hz, 2 H), 4.80 (t, J = 8.9 Hz, 2 H), 4.20
(t, J = 8.9 Hz, 2 H).
(CH), 116.8 (C), 54.7 (CH3).
LC-MS: tR = 3.85 min, m/z = 230.11 [M + H]+.
13C NMR (100 MHz, DMSO-d6): d = 163.1 (C), 162.5 (C), 153.6
(C), 141.3 (C), 128.7 (CH), 127.5 (CH), 126.6 (CH), 116.4 (CH),
75.7 (CH2), 70.4 (CH).
HRMS (ESI): m/z calcd for C9H10NO5: 212.0559; found: 212.0574.
Dimethyl 4-Chloropyridine-2,6-dicarboxylate (6b)27–29
[CAS Reg. No. 5371–70–0]
LC-MS: tR = 4.59 min, m/z = 385.1 [M + H]+, 407.1 [M + Na]+.
A soln of Vilsmeier reagent (ClCH=N+Me2 Cl–) (4.5 mmol) in a
mixture of MeCN (8 mL) and DMF (2 mL) flowing at 150 mL/min
was combined at a T-piece with a soln of chelidamic acid (2; 2
HRMS (ESI): m/z calcd for [C23H21N4O2]+: 385.1665; found:
385.1670.
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644
C. Battilocchio et al.
PAPER
mmol) and Et3N (4 mmol) in MeCN (20 mL) flowing at 300 mL/
min. The combined stream was then pumped through two 10-mL
CFCs at 75 °C linked in series. The exiting soln was quenched by
the addition of an auxiliary stream containing distilled MeOH (flow
rate 1 mL/min). The volatile solvent was removed in vacuo to give
an orange soln that was diluted with EtOAc (30 mL). The DMF was
then removed by washing with sat. aq LiCl (3 × 15 mL), and the or-
ganic phase was dried (Na2SO4) and concentrated in vacuo to give
a white solid; yield: 380 mg (83%); mp 140–141 °C (Lit.25 139–
140).
delivered separately, each at a flow rate of 250 mL/min, to a standard
T-piece connector. The combined soln was then passed into a 10-
mL CFC heated at 75 °C (20 min residence time). The exiting soln
was subjected to scavenging by elution through a glass column
packed with polystyrene-bound guanidine base (PS-TBD; 15
mmol), and collected for 2.5 h. The solvent was finally removed in
vacuo to give the required product.
4-Chloro-N,N¢-bis[(1R)-1-(hydroxymethyl)-2-methylpropyl]py-
ridine-2,6-dicarboxamide [(R)-8a]
Yield: 1035 mg (74%); cream solid; mp 127–130 °C; [a]D +41.9 (c
Alternatively, the MeOH-quenched soln was passed through a col-
umn of QP-DMA (4 equiv) and the solvent was evaporated; yield
417 mg (91%).
1.00, CHCl3).
IR (neat): 3500–3200 (br w), 2966 (w), 1684 (m), 1650 (s), 1583
(w), 1536 (s), 1517 (s), 1478 (m), 1390 (m), 1370 (w), 1337 (m),
1294 (w), 1240 (w), 1142 (w), 1092 (w), 1065 (s), 1015 (s), 970 (m),
891 (m), 779 (w), 698 (s), 727 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 8.30 (s, 2 H), 7.97 (d, J = 8.4 Hz,
2 H), 3.96–3.91 (m, 2 H), 3.85 (dd, J = 11.2 and 5.4 Hz, 2 H), 3.81
(dd, J = 11.1 and 3.6 Hz, 2 H), 2.64 (br s, 2 H), 1.05 (d, J = 6.6 Hz,
6 H), 1.01 (d, J = 6.6 Hz, 6 H).
IR (neat): 3085 (m), 2954 (m), 1720 (s), 1574 (m), 1467 (w), 1448
(m), 1438 (s), 1328 (s), 1263 (m), 1249 (s), 1199 (s), 1145 (s), 1105
(m), 986 (m), 971 (s), 911 (m), 889 (s), 842 (s), 783 (s), 762 (s), 739
(s), 692 (s) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.29 (s, 2 H), 4.03 (s, 6 H).
1H NMR (400 MHz, DMSO-d6): d = 8.28 (s, 2 H), 3.92 (s, 6 H).
13C NMR (150 MHz, CDCl3): d = C 164.3 (C), 149.6 (CH), 147.0
(C), 128.4 (C), 53.6 (CH3).
13C NMR (100 MHz, DMSO-d6): d = 164.0 (C), 149.5 (CH), 145.8
(C), 128.2 (C), 53.3 (CH3).
13C NMR (150 MHz, CDCl3): d = 162.9 (C), 150.1 (C), 148.0 (C),
125.4 (CH), 63.6 (CH2), 57.2 (CH), 29.3 (CH), 19.6 (CH3), 18.6
(CH3).
LC-MS: tR = 4.26 min, m/z = 396.1 [M + Na]+, 372.1 [M + H]+,
370.3 [M – H]+.
LC-MS: tR = 3.85 min, m/z = 230.11 [M + H]+.
HRMS (ESI): m/z calcd for C17H27ClN3O4: 372.1690; found:
372.1993.
HRMS (ESI): m/z calcd for C9H9NO4Cl: 230.0220; found:
230.0225.
The structure was unambiguously confirmed by single X-ray crys-
tallography. Molecular formula C9H8NO4Cl; space group: ortho-
rhombic P2(1)2(1)2(1), a = 3.8361(1), b = 13.7763(3), c = 18.2100
(4), b = 91.542°.
4-Chloro-N,N¢-bis[(1S)-1-(hydroxymethyl)-2-methylpropyl]py-
ridine-2,6-dicarboxamide [(S)-8a]20
[CAS Reg. No. 477779–36–5]
Yield: 1141 mg (82%); white solid; mp 130–134 °C; [a]D25 –47.4 (c
1.23, MeOH); [a]D –38.3 (c 0.97, CHCl3).
4-Chloro-6-(methoxycarbonyl)pyridine-2-carboxylic Acid
The anhydride 6c, obtained as a byproduct in the synthesis of 6b,
was isolated and characterized as the corresponding title carboxylic
acid.
IR (neat): 3500–3150 (br m); 2964 (m), 1683 (m), 1649 (s), 1582
(w), 1536.5 (s), 1478 (m), 1391 (m), 1337 (m), 1240 (m), 1132 (w),
1065 (s), 1016 (s), 971 (m), 892 (m), 850 (w), 814 (w), 779 (w), 748
(s), 727 (m) cm–1.
White solid.
1H NMR (400 MHz, CD3OD): d = 8.28 (s, 2 H, Py-H), 3.88–3.93
(m, 2 H), 3.76 (m, 4 H), 2.04 (sext, J = 6.8 Hz, 2 H), 1.04 (d, J = 6.8
Hz, 6 H), 0.98 (d, J = 6.8 Hz, 6 H).
1H NMR (600 MHz, CDCl3): d = 8.32 (d, J = 8.4 Hz, 2 H, 2 × NH),
8.19 (2 s, H, Py-H), 4.66 (br s, 2 H, 2 × OH), 3.75–3.87 (m, 4 H),
3.74 (dd, J = 11.0 and 2.9 Hz, 2 H), 2.02 (sext, J = 6.7 Hz, 2 H), 0.96
(d, J = 6.7 Hz, 6 H, 2 × Me), 0.93 (d, J = 6.7 Hz, 6 H, 2 × Me).
13C NMR (100 MHz, CD3OD): d = 163.9 (C), 151.3 (C), 147.5 (C),
125.1 (CH), 62.1 (CH2), 58.1 (CH), 29.3 (CH), 19.2 (CH3), 18.5
(CH3).
13C NMR (150 MHz, CDCl3): d = 163.1 (C), 150.4 (C), 147.6 (C),
125.2 (CH), 62.9 (CH2), 57.5 (CH), 29.1 (CH), 19.6 (CH3), 18.9
(CH3).
IR (neat): 3371 (w), 3100 (br w), 3080 (w), 1724 (s), 1695 (s), 1650
(s), 1577 (m), 1558 (m), 1434 (s), 1375 (s), 1283 (s), 1201 (w), 1174
(w), 1146 (m), 1101 (w), 976 (m), 893 (m), 839 (s), 782 (s), 748 (s)
cm–1.
1H NMR (400 MHz, DMSO-d6): d = 8.25 (s, 1 H), 7.96 (br s, 1 H),
3.94 (s, 3 H).
1H NMR (400 MHz, CDCl3): d = 8.41 (s, 1 H), 8.23 (s, 1 H), 4.05
(s, 3 H).
13C NMR (100 MHz, DMSO-d6): d = 164.5 (C), 164.0 (C), 152.6
(C), 148.6 (C), 146.1 (C), 127.3 (CH), 125.4 (CH), 53.3 (CH3).
13C NMR (100 MHz, CDCl3): d = 165.0 (C), 164.3 (C), 151.5 (C),
148.4 (C), 147.5 (C), 128.2 (CH), 126.5 (CH), 53.6 (CH3).
LC-MS: tR = 3.50 min, m/z = 214.99 [M + H]+.
LC-MS: tR = 4.27 min, m/z = 372.1 [M + H]+, 394.1 [M + Na]+,
370.1 [M – H]+.
HRMS (ESI): m/z calcd for C8H7ClNO4: 214.9985; found:
214.9991.
HRMS (ESI): m/z calcd for C17H27ClN3O4: 372.1690; found:
The structure was unambiguously confirmed by single X-ray crys-
tallography. Molecular formula C8H6ClNO4; space group: triclinic
P-1, a = 7.3283(2), b = 10.2281(2), c = 12.2785(3), a = 91.641°,
b = 96.796°, g = 95.470°.
372.1707.
Anal. Calcd for C17H26ClN3O4: C, 54.91; H, 7.05; Cl, 9.73; N,
11.30. Found: C, 54.29; H, 6.98; Cl, 9.80; N, 10.95.
4-Chloro-N,N¢-bis[(1S)-1-(hydroxymethyl)-2,2-dimethylpro-
pyl]pyridine-2,6-dicarboxamide [(S)-8b]20
Yield: 1392 mg (93%); white solid; mp 121.5–123.0 °C; [a]D –32.5
(c 0.85, CHCl3).
Bisamides 8: General Procedure
A soln of the appropriate amino alcohol (7.5 mmol) and Et3N (7.5
mmol, 1 equiv) in anhyd MeCN (50 mL) and a soln of dicarbonyl
dichloride 5 (3.75 mmol, 0.5 equiv) in anhyd MeCN (50 mL) were
Synthesis 2012, 44, 635–647
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Flow Synthesis of PyBox Ligands
645
IR (neat): 3378 (w), 3289 (w), 3088 (m), 2966 (m), 1670 (m), 1530
(s), 1483 (m), 1478 (m), 1360 (m), 1284 (s), 1229 (s), 1123 (s), 954
(m), 883 (m), 788 (m), 690 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.31 (s, 2 H), 8.04 (d, J = 10.0 Hz,
2 H), 4.00 (m, 4 H), 3.78 (dd, J = 10.0 and 8.2 Hz, 2 H), 1.06 (s, 18
1H NMR (600 MHz, CDCl3): rotamers of the amide cause degener-
acy of the signals for the amide, pyridine, and chiral protons; Rota-
mer A: d = 8.66 (d, J = 13.2 Hz, 2 H), 8.34 (s, 2 H), 7.30–7.12 (m,
8 H), 5.57 (dd, J = 13.2 and 10.5 Hz, 2 H), 4.63–4.61 (m, 2 H),
3.15–3.05 (m, 2 H). Rotamer B: d = 8.56 (d, J = 12.6 Hz, 2 H), 8.28
(s, 2 H), 7.30–7.12 (m, 8 H), 5.45 (dd, J = 12.6 and 18.1 Hz, 2 H),
4.63–4.61 (m, 2 H), 3.15–3.05 (m, 2 H).
1H NMR (600 MHz, DMSO-d6): d = 8.90 (d, J = 8.4 Hz, 2 H, NH),
8.32 (s, 2 H, Py), 7.19 (m, 8 H, Ar), 5.42 (t, J = 1.8 Hz, 2 H), 5.24
(d, J = 3.6 Hz, 2 H, OH), 4.52 (d, J = 3.6 Hz, 2 H), 3.11 (dd, J = 16.2
and 3.6 Hz, 2 H), 2.82 (d, J = 16.2 Hz, 2 H).
H).
13C NMR (100 MHz, CDCl3): d = 163.2 (C), 150.3 (C), 148.5 (C),
125.7 (CH), 63.2 (CH), 60.2 (CH2), 34.2 (C), 27.2 (CH3).
LC-MS: tR = 4.45 min, m/z = 400.3 [M + H]+.
HRMS (ESI): m/z calcd for C19H31N3O4Cl: 400.2003; found:
13C NMR (150 MHz, DMSO-d6): d = 162.7 (C), 151.3 (C), 146.7
(C), 142.0 (C), 141.3 (C), 128.0 (CH), 126.9 (CH), 125.4 (CH),
125.1 (CH), 124.7 (CH), 72.3 (CH), 57.7 (CH), 40.4 (CH2).
400.2016.
4-Chloro-N,N¢-bis[(1S)-2-hydroxy-1-phenylethyl]pyridine-2,6-
dicarboxamide [(S)-8c]
Yield: 1613 mg (98%); white solid; mp >248 °C (dec.); [a]D +69.5
(c 1.00, CHCl3).
LC-MS: tR = 4.56 min, m/z =486.2 [M + Na]+, 461.99 [M – H]+.
HRMS (ESI): m/z calcd for C25H23ClN3O4: 464.1377; found:
464.1398.
IR (neat): 3291 (w), 3065 (w), 2936 (w), 1655 (s), 1523 (s), 1454
(m), 1407 (m), 1308 (m), 1238 (w), 1070 (m), 1030 (s), 898 (m),
847 (w), 729 (s), 698 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 8.56 (d, J = 7.2 Hz, 2 H), 8.29 (s,
2 H), 7.38–7.31 (m, 10 H), 5.25–5.21 (m, 2 H), 4.00 (app. d, J = 4.5
Hz, 4 H), 2.20 (br s, 2 H).
1H NMR (600 MHz, DMSO-d6): d = 8.74 (d, J = 7.8 Hz, 2 H, 2 ×
NH), 8.18 (s, 2 H, Py), 7.30 (m, 10 H, Ph), 5.21 (app. quin, J = 5.6
Hz, 2 H), 3.95 (d, J = 6.6 Hz, 4 H).
13C NMR (150 MHz, CDCl3): d = 162.4 (C), 150.0 (C), 148.0 (C),
138.5 (C), 129.0 (CH), 128.1 (CH), 126.6 (CH), 125.5 (CH), 66.3
(CH2), 55.8 (CH).
4-Chloro-N,N¢-bis(2-hydroxyethyl)pyridine-2,6-dicarbox-
amide (8e)
Yield: 969 mg (90%); white solid; mp >178 °C (dec.).
IR (neat): 3296 (br m), 3065 (m), 2908 (w), 1649 (s), 1614 (s), 1538
(s), 1495 (m), 1447 (m), 1330 (m), 1223 (w), 1040 (m), 996 (m),
861 (m), 710 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 8.15 (2 H, s), 7.15 (app. t, 2 H),
4.78 (br s, 2 H), 3.53 (m, 4 H), 3.36 (m, 4 H).
13C NMR (150 MHz, CDCl3): d = 162.6 (C), 156.5 (C), 151.1 (C),
126.6 (CH), 60.3 (CH2), 59.7 (CH2).
LC-MS: tR = 3.55 min, m/z = 286.19 [M – H]+.
13C NMR (150 MHz, DMSO-d6): d = 162.7 (C), 150.1 (C), 147.8
(C), 138.6 (C), 128.9 (CH), 127.9 (CH), 126.7 (CH), 125.4 (CH),
65.8 (CH2), 55.8 (CH).
HRMS (ESI): m/z calcd for C11H15ClN3O4: 288.0751; found:
288.0761, calcd for C11H14ClN3NaO4: 310.0571; found: 288.0581.
LC-MS: tR = 4.46, m/z = 440.03 [M + H]+, 437.99 [M – H]+.
Macrocycles 10a–d: General Procedure
HRMS (ESI): m/z calcd for C23H22ClN3NaO4: 462.1197; found:
A soln of the appropriate amino alcohol (5 mmol) and Et3N (10
mmol, 2 equiv) in anhyd MeCN (50 mL) and a soln of dicarbonyl
dichloride 6 (2.5 mmol) in anhyd MeCN (50 mL) were separately
delivered, each at a flow rate of 250 mL/min, to a standard T-piece
connector. The combined fluidic flow was then passed into three
10-mL interlinked CFCs heated to 80 °C (60 min residence time). A
75-psi back-pressure regulator at the exit of the reactor maintained
the system pressure. The exiting soln was concentrated and sus-
pended in EtOAc (50 mL), which was extracted with sat. aq
NaHCO3 (2 × 30 mL). The organic layer was dried (MgSO4) and
concentrated in vacuo to yield the desired product.
462.1201.
4-Chloro-N,N¢-bis[(1R)-2-hydroxy-1-phenylethyl]pyridine-2,6-
dicarboxamide [(R)-8c]
Yield: 1580 mg (96%); off-white solid; mp >250 °C (dec.); [a]D
–63.1 (c 0.97, CHCl3).
IR (neat): 3600–3150 (br w), 1655 (s), 1524 (s), 1453 (m), 1407 (w),
1306 (m), 1239 (w), 1070 (m), 1029 (m), 996 (w), 896 (m), 846 (w),
743 (s), 699 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 8.56 (d, J = 7.2 Hz, 2 H), 8.27 (s,
2 H), 7.38–7.31 (m, 10 H), 5.25–5.21 (m, 2 H), 4.00 (app. d, J = 4.5
Hz, 4 H), 2.20 (br s, 2 H).
13C NMR (150 MHz, CDCl3): d = 162.4 (C), 150.0 (C), 148.0 (C),
138.5 (C), 129.0 (CH), 128.1 (CH), 126.6 (CH), 125.5 (CH), 66.3
(CH), 55.8 (C).
(5S,15S)-10,21-Dichloro-5,15-diisopropyl-3,17-dioxa-
6,14,23,24-tetraazatricyclo[17.3.1.18,12]tetracosa-
1(23),8(24),9,11,19,21-hexaene-2,7,13,18-tetrone (10a)
25
Yield: 1206 mg (90%); white solid; mp >254 °C (dec.); [a]D
–303.2 (c 1.2, CHCl3).
LC-MS: tR = 4.48, m/z = 440.01 [M + H]+, 438.01 [M – H]+.
IR (neat): 3664 (w), 3450 (br w), 2969 (s), 1732 (m), 1676 (s), 1528
(s), 1465 (w), 1383 (m), 1321 (s), 1235 (m), 1163 (w), 1066 (s),
1056 (s), 898 (w), 763 (w) cm–1.
1H NMR (600 MHz, CDCl3): d = 8.43 (s, 2 H), 8.38 (s, 2 H), 8.26
(d, J = 10.2 Hz, 2 H), 5.36 (dd, J = 1.2 and 11.4 Hz, 2 H), 4.30 (app.
t, 2 H), 4.16 (dd, J = 1.8 and 11.4 Hz, 2 H), 1.94–1.89 (m, 2 H), 1.05
(d, J = 6.6 Hz, 6 H), 0.96 (d, J = 6.6 Hz, 6 H).
13C NMR (150 MHz, CDCl3): d = 163.7 (C), 162.2 (C), 150.4 (C),
149.1 (C), 147.8 (C), 146.8 (C), 128.8 (CH), 126.1 (CH), 66.1
(CH2), 54.4 (CH), 29.7 (CH), 19.8 (CH3), 19.7 (CH3).
HRMS (ESI): m/z calcd for C23H22ClN3NaO4: 462.1197; found:
462.1186.
4-Chloro-N,N¢-bis[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-
yl]pyridine-2,6-dicarboxamide [(1S,2R)-8d]
Yield: 1178 mg (68%); white solid; mp 245.3–252.1 °C; [a]D
–21.0 (c 0.25, CHCl3).
25
IR (neat): 3430 (m), 3382 (m), 2941 (w), 1661 (s), 1581 (m), 1518
(s), 1495 (s), 1478 (m), 1328 (w), 1300 (w), 1264 (w), 1173 (w),
1081 (w), 1053 (m), 957 (m), 895 (w), 825 (w), 750 (s), 721 (s)
cm–1.
LC-MS: tR = 5.29, m/z = 536.98 [M + H]+.
© Thieme Stuttgart · New York
Synthesis 2012, 44, 635–647

646
C. Battilocchio et al.
PAPER
HRMS (ESI): m/z calcd for C24H27Cl2N4O6: 537.1308; found:
LC-MS: tR = 5.38, m/z = 629.1 [M + H]+.
537.1332.
HRMS (ESI): m/z calcd for C32H22Cl2N4NaO6: 651.0820; found:
The structure was unambiguously confirmed by X-ray crystallogra-
phy; space group: orthorhombic P2(1)2(1)2(1), a = 12.2197(2),
b = 9.4134(2), c = 12.3527(3), b = 108.897°.
651.0814; calcd for C32H23Cl2N4O6: 629.0995; found: 629.1000.
10,21-Dichloro-3,17-dioxa-6,14,23,24-tetraazatricy-
clo[17.3.1.18,12]tetracosa-1(23),8(24),9,11,19,21-hexaene-
2,7,13,18-tetrone (10e)
(5S,15S)-5,15-Di-tert-butyl-10,21-dichloro-3,17-dioxa-
6,14,23,24-tetraazatricyclo[17.3.1.18,12]tetracosa-
1(23),8(24),9,11,19,21-hexaene-2,7,13,18-tetrone (10b)
Yield: 1283 mg (91%); pale-yellow solid; mp >230 °C (dec.);
[a]D25 –10.0 (c 0.25, CHCl3).
Yield: 927 mg (82%); white solid; mp >190 °C (dec.).
IR (neat): 3380 (br w), 2964 (w), 1715 (m), 1669 (s), 1520 (s), 1234
(s), 1155 (m), 890 (w), 780 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.82 (app. t, 2 H), 8.38 (s, 2 H),
8.29 (s, 2 H), 4.65 (t, J = 8.9 Hz, 4 H), 3.96 (m, 4 H).
13C NMR (100 MHz, CDCl3): d = 164.2 (C), 162.8 (C), 150.3 (C),
149.1 (C), 147.8 (C), 146.7 (C), 129.6 (CH), 126.3 (CH), 67.2
(CH2), 48.5 (CH2).
IR (neat): 3373 (br w), 2964 (w), 1729 (m), 1679 (s), 1520 (s), 1368
(m), 1234 (s), 1155 (m), 895 (m), 780 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.43 (s, 2 H), 8.37 (s, 2 H), 8.32
(d, J = 10.4 Hz, 2 H), 5.54 (d, 2 H, J = 10.4 Hz), 4.43 (dd, J = 1.8
and 10.4 Hz, 2 H), 4.14 (dd, J = 1.8 and 10.4 Hz, 2 H), 0.95 (s, 18
H).
LC-MS: tR = 4.61, m/z = 453.03 [M + H]+, 450.99 [M – H]+.
13C NMR (100 MHz, CDCl3): d = 163.8 (C), 162.5 (C), 150.6 (C),
149.3 (C), 147.8 (C), 146.7 (C), 128.6 (CH), 126.3 (CH), 66.0
(CH2), 55.5 (CH), 35.2 (C), 28.0 (CH3).
HRMS (ESI): m/z calcd for C18H15Cl2N4O6: 453.0369; found:
453.0381; calcd for C18H14Cl2N4NaO6: 475.0183; found: 453.0165.
10,21-Dichloro-3,6,14,17,23,24-hexaazatricyclo[17.3.1.18,12]tet-
racosa-1(23),8(24),9,11,19,21-hexaene-2,7,13,18-tetrone (10f)
Yield: 788 mg (70%); off-white solid; mp >285 °C (dec.).
LC-MS: tR = 5.57, m/z = 565.19 [M + H]+.
HRMS (ESI): m/z calcd for C26H31Cl2N4O6: 565.1621; found:
565.1625.
IR (neat): 3330 (br w), 1655 (s), 1530 (s), 1446 (w), 1306 (w), 896
(w), 787 (m), 737 (m) cm–1.
1H NMR (400 MHz, CDCl3): d = 8.37 (s, 4 H), 8.24 (br s, 2 H), 3.77
(s, 8 H).
13C NMR (100 MHz, CDCl3): d = 164.1 (C), 148.3 (C), 145.0 (C),
126.1 (CH), 49.2 (CH2).
(5S,15S)-10,21-Dichloro-5,15-diphenyl-3,17-dioxa-6,14,23,24-
tetraazatricyclo[17.3.1.18,12]tetracosa-1(23),8(24),9,11,19,21-
hexaene-2,7,13,18-tetrone (10c)
Yield: 1284 mg (85%); white solid; mp 270–273 °C; [a]D25 –16 (c
0.25, CHCl3).
LC-MS: tR = 4.42, m/z = 451.1 [M + H]+, 448.98 [M – H]+.
HRMS (ESI): m/z calcd for [C18H17N6O4Cl2]+: 451.0688; found:
IR (neat): 3400 (w), 3084 (br w), 1728 (s), 1682 (s), 1582 (w), 1560
(w), 1510 (s), 1454 (w), 1415 (m), 1375 (w), 1356 (w), 1300 (m),
1258 (w), 1224 (m), 1149 (s), 1050 (w), 1028 (w), 995 (w), 902 (m),
779 (m), 752 (w), 721 (w), 698 (s) cm–1.
1H NMR (600 MHz, CDCl3): d = 9.02 (d, J = 10.0 Hz, 2 H, NH),
8.41 (s, 2 H), 8.27 (s, 2 H), 7.51 (d, J = 7.0 Hz, 4 H, Ph), 7.25 (m, 6
H), 5.77 (d, J = 9.9 Hz, 2 H), 5.37 (d, J = 11.4 Hz, 2 H), 4.58 (dd,
J = 11.4 and 3.0 Hz, 2 H).
451.0687.
Crystallographic data for compounds (S)-4a, (S)-4b, 6b, 4-chloro-
6-(methoxycarbonyl)pyridine-2-carboxylic acid, and 10a have been
deposited with the accession numbers CCDC 850877, 849198,
850875, 850878, and 850876, respectively, and can be obtained free
of charge from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB2 1EZ, UK; Fax: +44(1223)336033; E-
mail: deposit@ccdc.cam.ac.uk; Web site: www.ccdc.cam.ac.uk/
conts/retrieving.html.
13C NMR (150 MHz, CDCl3): d = 163.4 (C), 161.5 (C), 150.9 (C),
147.6 (C), 146.5 (C), 138.2 (C), 129.0 (CH), 128.1 (CH), 128.05
(CH), 126.7 (CH), 126.3 (CH), 69.3 (CH2), 50.9 (CH).
LC-MS: tR = 5.26, m/z = 605.1 [M + H]+.
HRMS (ESI): m/z calcd for C30H23Cl2N4O6: 605.0995; found:
605.1003.
Acknowledgment
The authors would like to thank the following for their financial
support: the Ralph Raphael studentship award and the Cambridge
European Trust (M.B.); the Royal Society (I.R.B.); the EPSRC
(M.O.K.); F. Hoffmann-La Roche, Basel (R.E.M. and S.A.O.); and
the BP Endowment (S.V.L.). X-ray crystal structures were determi-
ned by Dr John Davies at the Department of Chemistry, of the Uni-
versity of Cambridge and by Dr André Alker, of Parma Research
Basel.
(4R,12S,22S,30R)-17,35-Dichloro-13,21-dioxa-3,31,37,38-tetra-
azaheptacyclo[31.3.1.115,19.04,12.05,10.022,30.024,29]octatriaconta-
1(37),5,7,9,15(38),16,18,24,26,28,33,35-dodecaene-2,14,20,32-
tetrone (10d)
Yield: 1021 mg (65%); white solid; mp >260 °C (dec.); [a]D25 –5.0
(c 0.25, CHCl3).
IR (neat): 2357 (w), 2128 (br w), 1727 (m), 1674 (m), 1512 (s),
1356 (w), 1317 (m), 1241 (m), 1158 (s), 1036 (w), 879 (w), 783 (w),
750 (s), 723 (m) cm–1.
1H NMR (600 MHz, CDCl3): d = 8.76 (d, J = 7.1 Hz, 2 H, NH), 8.44
(s, 2 H), 8.07 (s, 2 H), 7.23 (m, 8 H, Ar), 5.96 (m, 2 H), 5.76 (m, 2
H), 3.44 (m, 2 H), 3.31 (m, 2 H).
13C NMR (150 MHz, CDCl3): d = 164.6 (C), 163.4 (C), 150.0 (C),
147.6 (C), 146.5 (C), 139.6 (C), 139.0 (C), 128.4 (CH), 127.8 (CH),
127.3 (CH), 126.3 (CH), 125.1 (CH), 123.7 (CH), 79.4 (CH), 56.3
(CH), 37.7 (CH2).
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Synthesis 2012, 44, 635–647