Regioselective synthesis of 3-aminoimidazo[1,2- a ]-pyrimidines under continuous flow conditions

Article abstract of DOI:10.1021/jo501861g

Multicomponent synthesis of 3-aminoimidazo[1,2-a]pyrimidines usually affords a product mixture containing varying amounts of the corresponding 2-amino regioisomer. Modified methods, particularly microwave heating, have been employed to suppress formation

Full text of DOI:10.1021/jo501861g

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Article
Regioselective synthesis of 3-aminoimidazo[1,2-
a]pyrimidines under continuous flow conditions
Ashlie J. E. Butler, Mark J. Thompson, Patrick J. Maydom,
James A. Newby, Kai Guo, Harry Adams, and Beining Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo501861g • Publication Date (Web): 13 Oct 2014
Downloaded from http://pubs.acs.org on October 16, 2014
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Regioselective synthesis of 3-aminoimidazo[1,2-a]-
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pyrimidines under continuous flow conditions.
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Ashlie J. E. Butler, Mark J. Thompson, Patrick J. Maydom1, James A. Newby,2 Kai Guo3, Harry
Adams and Beining Chen*
Department of Chemistry, University of Sheffield, Brook Hill, Sheffield, S3 7HF, UK.
b.chen@sheffield.ac.uk
1Present address: Notre Dame High School, Fulwood Road, Sheffield, S10 3BT
2Present address: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK.
3Present address: College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech University, No.30 South
Puzhu Road, Pukou District, Nanjing, Jiangsu Province, P.R. China 211816
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TOC GRAPHIC
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ABSTRACT
Multicomponent synthesis of 3-aminoimidazo[1,2-a]pyrimidines usually affords a product
mixture containing varying amounts of the corresponding 2-amino regioisomer. Modified
methods, particularly microwave heating, have been employed to suppress formation of this
side-product but none of the revised protocols are readily amenable to scale. A continuous
flow adaptation was found to offer improved regioselectivity towards the targeted 3-amino
regioisomer with significantly shorter reaction times, and also widened the scope of the
reaction to permit the use of aliphatic aldehyde building blocks.
INTRODUCTION
Multicomponent reactions (MCRs) have garnered increasing interest during recent years,
most particularly for their utility in rapid synthesis of large chemical libraries for application
in high-throughput screening efforts in drug discovery and related disciplines. One such
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example,1–3 first reported in 1998 by three separate groups and now referred to as the
Groebke–Blackburn reaction,4 involves combination of a 2-aminoazine, aldehyde and
isocyanide to form a fused imidazole ring (Scheme 1).
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Scheme 1. The Groebke–Blackburn three-component approach to fused imidazoles.
This three-component coupling (3-CC) offers excellent atom economy and is readily
applicable to preparation of extensive libraries of drug-like heterocycles. As such, it has been
very widely employed in the context of drug discovery, and reviewed extensively
elsewhere.5–7 The reaction is catalysed by either Brønstead or Lewis acids, but is typically
performed using 2.5 mol% Sc(OTf)3 in an organic solvent (methanol or methanol–
dichloromethane mixtures). Although 2-aminopyridine and aminopyrazine have been
employed most often as the 2-aminoazine building block due to the consistently high yields
obtained, our interest primarily focuses on use of 2-aminopyrimidine as the amine starting
material, yielding imidazo[1,2-a]pyrimidines as products. The imidazo[1,2-a]pyrimidine
substructure is found in many compounds of potential pharmaceutical interest, including
divaplon8 1 (Figure 1) and fasiplon9 2, both being part of a large class of nonbenzodiazepine
agonists of GABAA receptors investigated throughout the 1980s and 1990s as potential
anxiolytic and anticonvulsant agents, albeit without successful translation to clinical use.10 It
is also found in compound 3, a potent androgen receptor antagonist with promising in vivo
efficacy in animal models of castration-resistant prostate cancer,11 which is seemingly under
ongoing preclinical development.12
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Figure 1. Examples of past or present clinical candidates containing the imidazo[1,2-
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a]pyrimidines.
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One unique feature of the Groebke–Blackburn 3-CC approach to imidazo[1,2-a]pyrimidines
(Scheme 2) is that in addition to the expected 3-amino substituted product 4a, the
regioisomeric 2-amino compound 4b is also formed in varying amounts, presumably via
initial imine formation through one of the ring nitrogen atoms as opposed to the exocyclic
amino-group.13,14 Although product distribution varies considerably with the exact nature of
the aldehyde and isocyanide components, the anticipated 3-amino isomer 4a usually
predominates.13,14 Performing the reaction in a nonpolar solvent, toluene, was found to
suppress formation of 4b,15 supporting the assumption that this product is formed via a
charged iminium intermediate as shown in Scheme 2. Alternatively, solvent-free microwave
heating—in the presence of either montmorillonite K-10 clay16 or Zeolite HY14 as a mildly
acidic solid support catalyst —was found to greatly accelerate the reaction and offer
significantly improved regioselectivity for 4a.
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Scheme 2. Mechanistic rationale for the formation of a product mixture in the
multicomponent reaction of 2-aminopyrimidine.
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If required, the pure 2-amino isomer 4b may be accessed by performing a Dimroth
rearrangement of the initial product mixture.17 More recently, Guchhait & Madaan
intriguingly reported exclusive formation of 4b when 10 mol% ZrCl4 is used as catalyst in
poly(ethylene glycol)-400 (PEG-400) at 50 °C.18
In the past two decades continuous flow technology has found many applications in life
science related areas such as academic research laboratories and industrial settings with
distinctive advantages of being green, efficient and selective when compared to traditional
batch processes.19,20 In organic synthesis, it has been utilised to prepare a wide range of
pharmaceutically important heterocyclic compounds.21-23 However, this technique has never
been applied to the synthesis of aminoimidazo[1,2-a]-pyrimidines. In this paper, we would
like firstly to address the issue of stereochemical outcome of the synthesis of this class of
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heterocycles reported by Guchhait & Madaan. Then, the regioselectivity of the reaction will
be explored and optimised using continuous flow techniques and the scope of the reaction
demonstrated by synthesis of a small library of representative compounds.
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RESULTS AND DISCUSSION
The claimed selectivity of the ZrCl4/PEG-400 method for the 2-amino isomer seemed highly
unprecedented, since we previously demonstrated14 preferential or even sole formation of the
3-amino product in the presence of Sc(OTf)3, and would not expect the reaction to behave
profoundly differently under ZrCl4 catalysis, with it simply being another transition metal
based Lewis acid catalyst. After closely following one of the reported examples18 (model
reaction 1, Scheme 3) crystallising the isolated product for X-ray analysis, it was in fact
found to be 3-amino isomer 5a (Figure S1a; see Supporting Information). In the light of this
apparently contradictory result, it quickly became clear that Guchhait and Madaan must have
based their regiochemical assignment on the original work of Mandair et al.13 which
erroneously designated the 3-amino product as the less polar (higher-running on TLC) and
the 2-amino as the more polar—without additional verification, as per our subsequent report14
which corrected this earlier error.
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Scheme 3. Model MCRs used in comparison of Sc3+ and Zr4+ catalyst, and of batch vs.
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continuous flow reaction conditions.
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Since we had only previously presented example X-ray structures of the more crystalline 3-
amino isomers 4a and inferred the identity of 4b by NOE experiments, we endeavoured to
also crystallise a representative 2-amino isomer for the confirmation of its absolute identity.
The same model reaction as used in the earlier study14—between 2-aminopyrimidine,
benzaldehyde and Walborsky’s reagent (1,1,3,3-tetramethylbutyl isocyanide), i.e. model
reaction 2 (Scheme 3)—furnished sufficient quantities of 6b for X-ray crystallography,
clearly establishing this less polar (higher-running) product as the 2-amino isomer (Figure
S1b, Supporting Information). Thus, it is now confirmed beyond doubt that in the Groebke–
Blackburn 3-CC of 2-aminopyrimidine, the expected 3-aminoimidazo[1,2-a]pyrimidine
product 4a is always the more polar (lower-running on TLC), with the corresponding 2-
amino regioisomer 4b always being higher-running.
Both Sc3+ and Zr4+ will complex to the carbonyl oxygen atom of the starting aldehyde and
activate it to be attacked by 2-aminopyrimidine, although the observed product
regioselectivity is unlikely to originate from this original imine formation. It more likely
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stems from complexation of the metal ion to the neutral imine species en route to 4a (Scheme
2), since Zr4+ is a stronger Lewis acid with higher charge density and will more readily
activate the imine to be attacked by the isocyanide carbanion, thus favouring formation of the
3-amino product isomer. It may also be postulated that the charged iminium intermediate
ultimately leading to 4b will not complex with either metal ion due to Coulombic repulsion.
These considerations satisfactorily explain the typical selectivity of the reaction for 4a, and
its enhanced preferential formation in the presence of Zr4+ as opposed to Sc3+. Nonetheless,
with the regioselectivity of the reaction now clearly resolved, the next step was to evaluate an
optimal reaction yield and duration under continuous flow conditions. A coil mesofluidic
reactor (Vapourtec R-series flow chemistry system) was employed for all continuous flow
experiments.
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The residence time optimisation of model reaction 2 (Scheme 2) was carried out using 10
mol% ZrCl4 catalyst at 70 °C and the optimum residence time maintaining a reliable flow rate
was found to be 50 min giving a yield of 37% (Figure 2a). The optimisation reactions to
determine the optimum temperature were carried out using the above determined optimal
residence time of 50 min and a catalyst loading of 10 mol% ZrCl4. At temperatures greater
than 80 °C yields began to decrease again, so it was determined that this was the optimum
temperature for reaction, giving a yield of 6a of 68%. These results are comparable to the
70% yield produced under batch conditions over 48 h (Figure 2b). The yield of 6b was
dramatically reduced in comparison to batch reactions under continuous flow conditions.
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Figure 2. Results for the model reaction 2 under continuous flow conditions by varying
a) residence time (temperature was kept at 70 °C); and b) temperature (residence time
was kept at 50 min) both using 10 mol% ZrCl4 as catalyst.
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During the course of optimisation experiments, it was found that the ratio of regioisomeric
products in the MCR varies over time. The flow reaction to form 6a and 6b (Scheme 3,
model reaction 2), when catalysed by 2.5 mol% Sc(OTf)3 and followed closely over short
residence times, showed predominant formation of the 2-amino product 6b in the early stages
(Figure 3b). However, with a reaction duration of 10 min or above, the 3-amino isomer 6a
increasingly dominated under flow conditions. A similar phenomenon was observed when the
batch synthesis of 5a and 5b (Scheme 3, model reaction 1) was repeated with different
reaction durations, in the presence of 10 mol% ZrCl4. Shorter reactions led to isolation of
relatively more of the 2-amino isomer 5b, whose ratio in the product mixture decreased with
prolonged heating (Figure 3a).
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Figure 3. The 2-amino isomers were formed more rapidly during the initial stages of
reaction. a) Batch synthesis of 5a and 5b promoted by 10 mol% ZrCl4 followed over 24
h; b) continuous flow synthesis of 6a and 6b under Sc(OTf)3 catalysis with varying coil
residence times.
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The foregoing observations indicate that the system is held in dynamic equilibrium, thereby
implying that all steps in the proposed mechanism (Scheme 2) are reversible. These results
also suggest that the 2-amino regioisomers are the kinetic product of the reaction, and 3-
amino regioisomers the thermodynamic product, although further investigation would be
necessary to confirm this supposition.
Additional reactions were performed to investigate the optimal catalyst loading and make
comparisons between Zr4+ and Sc3+ as Lewis acids. The batch reactions were carried out at
the reflux temperature (~ 45 °C) due to the low boiling point of the mixing solvents
(DCM/MeOH 3:1) while under continuous flow conditions the same solvent system can be
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heated to 80 °C using the back pressure regulator. Comparisons with microwave irradiation
were not attempted as the solvent system used is not suitable for microwave conditions and
the advantages of using this technique in synthesising this family of compounds have been
demonstrated in our previous studies.14
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As shown in Figure 4 there is a marked improvement in regioselectivity towards the 3-
aminopyrimidine product for all reactions in continuous flow conditions compared to batch
conditions, with the best yield and regioselectivity found with 10 mol% ZrCl4.
Figure 4. Outcome of model reaction 1 to form 6a and 6b, comparing a range of
catalytic options under both batch conditions and continuous flow conditions.
To demonstrate its general application, the optimal continuous flow protocol (80 °C, 50 min
residence time, 10 mol% ZrCl4) was used to prepare a small library of 3-
aminoimidazo[1,2-a]pyrimidines (Table 1). In line with earlier observations, consistently
high regioselectivity was observed, with the extent of formation of the 2-amino isomer either
small or undetectable. The 2-amino minor products 8b, 9b, 10b, 11b and 13b were detected
by TLC and confirmed by 1H NMR spectroscopy but were not obtained in pure form, so their
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presence in the mixture was confirmed by LC-MS (see Supporting Information).
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Table 1. Library compounds synthesised with the continuous flow adaption of the
Groebke–Blackburn reaction with 2-aminopyrimidine. Isolated yields after column
chromatography.
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Product
R1-CHO
R2-NC
% Yield Isomer A
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% Yield Isomer B
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<1a
<1a
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<1a
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<1a
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<1a
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Pure products not isolated but presence of product shown by LCMS in supporting
information.
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In the case of the reaction to give 11a and 11b, unequivocal assignment of the major product
was not possible based solely on 1H NMR spectra and NOE experiments proved inconclusive.
Subsequent crystallisation and X-ray analysis identified the major product as 11a, as
anticipated (Figure S2, Supporting Information). Successful formation of 14a and 15a is of
particular note since equivalent batch reactions gave no detectable amounts of expected
products, as is typical when employing aliphatic aldehyde components. A continuous flow
approach thus expands the available scope of the reaction, permitting access to a more
diverse array of substituted imidazo[1,2-a]pyrimidines.
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CONCLUSIONS
Continuous flow synthesis has steadily been gaining interest in recent years, particularly
because of its ready amenability to scale-up without modification of reaction parameters, and
its obvious safety advantages on a large scale. For these reasons amongst others, the
pharmaceutical industry has been a key player in advancing its use,24 and continuous flow
approaches to drug-like structures of potential interest are therefore of particular appeal. We
present here an optimised flow protocol to access such a class of compounds; and although a
limited number of related fused imidazoles (primarily imidazo[1,2-a]pyridines rather than
pyrimidines) have previously been prepared via continuous flow methodology,25 this earlier
work was not undertaken using the multicomponent approach outlined here, with its obvious
advantages in flexibility and access to a wider diversity of products.
During the course of developing this flow protocol we confirmed that both Sc3+ and Zr4+
Lewis acid catalysts lead to preferential formation of 3-aminoimidazo[1,2-a]pyrimidines over
the corresponding 2-amino regioisomeric products, with Zr4+ offering significantly enhanced
regioselectivity. Our continuous flow approach offers improved selectivity over conventional
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batch synthesis in considerably shorter reaction times, thus enabling rapid, scalable access to
3-aminoimidazo[1,2-a]pyrimidines, and was demonstrated to be equally as effective over a
range of examples where the aldehyde and isocyanide components of the reaction mixture
were varied.
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EXPERIMENTAL SECTION
General Procedures
All solvents and reagents were obtained from commercial sources and used as supplied.
Walborsky’s reagent and PEG-400 are 1,1,3,3-tetramethylbutyl isocyanide and poly(ethylene
glycol)-400 respectively. p-Chlorobenzyl isocyanide, 2-(2-thienyl)ethyl isocyanide, 1-chloro-
4-(2-isocyanoethyl)benzene and 2-fluoro-4-isocyano-1-methylbenzene were prepared as
described previously.26 1H and F NMR spectra were recorded at 400 MHz and 235 MHz,
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respectively, and C NMR spectra at 100 MHz with complete proton decoupling. J values
are reported in Hz. Electrospray mass spectra were acquired using a Micromass LCT Premier
XE system. HPLC analysis was carried out using a Genesis C18 4 µm column (4.6 ×
150 mm); 5–95% MeCN/water over 20 min, hold 5 min; UV detection at 254 nm; flow rate
1.0 mL min–1. Continuous flow reactions were performed using a Vapourtec R-series flow
chemistry system with two inlet pumps (designated line A and line B) operated with the
supplied Flow Commander™ software package. The samples were injected into 2 mL
injection loops and run through a 10 mL reaction coil. It was found necessary to flush the full
system with solvent between reactions to prevent inconsistent results arising from
cross-contamination between samples. This practice was adopted routinely, and achieved
using a third intake pump charged with the reaction solvent alone (1:3 MeOH–CH2Cl2).
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2-(4-Chlorophenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine 5a.
(Method 1, according to Guchhait & Madaan).18 2-Aminopyrimidine (190 mg, 2 mmol),
p-chlorobenzaldehyde (281 mg, 2 mmol) and Walborsky’s reagent (351 µL, 278 mg,
2 mmol) were combined in PEG-400 (2 mL), then ZrCl4 (47 mg, 0.2 mmol) was added and
the mixture heated at 50 °C for 1 h. Dichloromethane (50 mL) was added, and PEG-400
removed by successive extraction with water (4 × 50 mL). The organic layer was evaporated
and the crude material crystallised from CH2Cl2/hexane giving the title compound as a pale
yellow crystalline solid (396 mg, 56%). A portion of the product was recrystallised from the
same solvent system to provide crystals suitable for structure determination by X-ray
crystallography (Figure S3). mp 205–212 °C; purity (HPLC) 94.2%; max (solid/cm–1) 3295,
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3081, 2946, 1607, 1486, 1370, 839, 792, 763; H (400 MHz, CDCl3) 1.00 (9 H, s), 1.59 (6 H,
s), 1.91 (2H, s), 4.30 (1H, br s), 6.72 (1 H, dd, J 4.5 and 6.5), 7.42 (2 H, d, J 8.5), 7.51 (2 H,
d, J 8.5), 8.24 (1 H, dd, J 4.5 and 2.0), 8.29 (1 H, dd, J 6.5 and 2.0); C (400 MHz, CDCl3)
29.0, 31.6, 31.7, 56.8, 60.7, 107.9, 121.9, 128.2, 129.7, 131.4, 133.2, 133.4, 139.9, 145.0,
149.4; HRMS (ES-TOF) m/z: [M+H]+ calcd. for C20H26ClN4 357.1846, found 357.1862.
2-(4-Chlorophenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine 5a
and 3-(4-chlorophenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-2-amine
5b. (Standard batch synthesis method). 2-Aminopyrimidine (380 mg, 4 mmol),
p-chlorobenzaldehyde (562 mg, 4 mmol) and ZrCl4 (93 mg, 0.4 mmol) were stirred in
MeOH–CH2Cl2 (1:3, 50 mL) for 30 min at room temperature. After this time, Walborsky’s
reagent (702 µL, 556 mg, 4 mmol) was introduced to the reaction flask, and the mixture
heated at 45 °C for 24 h. The solution was evaporated to dryness under reduced pressure and
the crude material purified by column chromatography on basic alumina, eluted with
10→15→20→50% EtOAc/toluene, affording 5a (507 mg, 36%) as a pale yellow solid, with
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analytical data in agreement with those above; and 5b (157 mg, 11%) as a bright yellow
crystalline solid: mp 62–72 °C; max (solid/cm–1) 3244, 2950, 2890, 1567, 1496, 1478, 1188,
751; H (400 MHz, CDCl3) 0.98 (6H, s), 1.05 (9H, s) 1.59 (2 H, s), 3.29 (1 H, s), 6.88 (1 H,
dd, J 4.0 and 7.0), 7.42 (2 H, d, J 8.5), 7.93 (2 H, d, J 8.5), 8.52 (2 H, dd, J 2.0 and 4.0), 8.55
(2H, dd, J 2.0 and 7.0); C (400 MHz, CDCl3) 30.1, 31.7, 31.8, 52.9, 56.2, 101.9, 107.7,
126.7, 127.5,129.1, 130.1, 133.0, 145.0, 146.6, 151.4; HRMS (ES-TOF) m/z: [M+H]+ calcd.
for C20H26ClN4 357.1846, found 357.1868. Repeat reactions, with different durations of
heating in the final stage, were carried out and their results used to compile the graph shown
in Figure 3a.
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2-Phenyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine 6a and 3-
phenyl-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-2-amine 6b.14
2-Aminopyrimidine (951 mg, 10 mmol), benzaldehyde (1.02 mL, 1.06 g, 10 mmol) and
Sc(OTf)3 (123 mg, 0.25 mmol) were stirred in MeOH–CH2Cl2 (1:3, 100 mL) for 30 min at
room temperature. Walborsky’s reagent (1.75 mL, 1.39 g, 10 mmol) was then added, and the
mixture heated at 45 °C for 48 h. The solution was evaporated under reduced pressure and the
residue purified by column chromatography on basic alumina, eluted with 20→30→50%
EtOAc/hexane then CH2Cl2 then 1% MeOH/CH2Cl2, to provide 6b (0.74 g, 23%) as a yellow
crystalline solid: mp 88–94 °C; purity (HPLC) 92.6 %; max (solid/cm–1) 3288, 2948, 2362,
1608, 1561, 1185, 888; H (400 MHz, CDCl3) 1.01 (9 H, s), 1.60 (6 H, s), 1.93 (2 H, s), 4.37
(1 H, br s), 6.71 (1 H, dd, J 6.5 and 4.5), 7.38 (1 H, t, J 7.5), 7.58–7.47 (3H, m), 8.24 (1 H,
dd, J 2.0 and 4.5), 8.36 (1 H, dd, J 2.0 and 6.5); C (400 MHz, CDCl3) 30.2, 31.6, 31.7, 31.8,
53.1, 56.1, 107.5, 126.7, 127.5, 127.8, 128.5, 129.0, 129.8, 144.6, 151.3; m/z (ES) 322
(100%); HRMS (ES-TOF) m/z: [M + H]+ calcd. for C20H27N4 323.2250, found 323.2236); and
6a (0.81 g, 25%) as a pale yellow solid. mp 215–225 °C; purity (HPLC) 98.7 %; max
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(solid/cm–1) 3333, 2949, 1742, 1607, 1498, 1308, 1190, 885; H (400 MHz, CDCl3) 0.96 (6
H, s), 1.03 (9H, s), 1.57 (2H, s), 3.33 (1H, br s), 6.84 (1H, dd, J 4.0 and 7.0), 7.35 (1 H, t, J
7.5), 7.45 (2H, t, J 7.5), 7.92 (2H, t, J 7.5), 8.49 (1H, dd, J 2.0 and 4.0), 8.56 (1H, dd, J 2.0
and 7.0); C (400 MHz, CDCl3) 29.0, 31.7, 31.8, 56.9, 60.9, 107.8, 121.8, 127.9, 128.3,
128.6, 131.2, 134.8, 141.5, 149.3; HRMS (ES-TOF) m/z: [M+H]+ calcd. for C20H27N4
323.2236, found 323.2235. Both products from this reaction were used as HPLC reference
standards for subsequent optimisation experiments. In addition, the sample of 6b prepared
here was crystallised from toluene for use in X-ray structure determination.
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Catalyst Optimisation Experiments (Figure 4; Batch Conditions).
2-Aminopyrimidine (190 mg, 2 mmol), benzaldehyde (203 µL, 212 mg, 2 mmol) and the
appropriate quantity of catalyst [2.5 or 10 mol% Sc(OTf)3 or ZrCl4] were combined in
MeOH–CH2Cl2 (1:3, 20 mL) and stirred at room temperature for 30 min. Walborsky’s
reagent (351 µL, 278 mg, 2 mmol) was then added, and the solution heated at 45 °C for 24 h.
At this point, an aliquot of the reaction mixture was diluted 1:10 with CH2Cl2 then analysed
by HPLC to determine yields of 6a and 6b. Results are graphed in Figure 2.
Catalyst Optimisation Experiments (Figure 4; Flow Conditions).
Intake line A of the flow reactor was charged with a solution of 0.2 M 2-aminopyrimidine,
0.2 M benzaldehyde and the appropriate concentration of catalyst in MeOH–CH2Cl2 (1:3),
which had been premixed at least 30 min prior to use. Line B contained 0.2 M Walborsky’s
reagent in the same solvent system. The reagents were combined in the reactor coil at 80 °C
for a residence time of 50 min. An aliquot of post-reactor product solution from the steady-
state region was drawn and analysed as above, with the results also graphed in Figure 2.
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Continuous Flow Synthesis of Imidazo[1,2-a]pyrimidines (Table 1). General Procedure.
Intake line A was charged with a solution of 0.2 M 2-aminopyrimidine, 0.2 M starting
aldehyde, and 0.02 M ZrCl4 in MeOH–CH2Cl2 (1:3), which had been premixed at least
30 min prior to use. Line B contained 0.2 M isocyanide in the same solvent system. The
solutions were combined and passed through the reactor at 80 °C with a residence time of
50 min (or a flow rate of 0.2 mL/min). The crude product solution was collected, evaporated
under reduced pressure then the residue purified as indicated below for each individual case.
Reactions were each carried out on a 0.4 mmol scale, based on 2-aminopyrimidine, unless
otherwise stated.
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2-(4-Methoxyphenyl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine
7a.14 General procedure followed using p-anisaldehyde and Walborsky’s reagent. Column
chromatography on basic alumina, eluted with 30→50% EtOAc/toluene then 1%
MeOH/CH2Cl2, yielded 7a (0.063 g, 45 %) as a yellow crystalline solid: mp 90–92 °C; purity
(HPLC) 91.2 %; H (400 MHz, CDCl3) 0.94 (6H, s), 1.01 (9H, s), 1.56 (2H, s), 3.27 (1H, s),
3.84 (3H, s), 6.80 (1H, dd, J 4.0 and 7.0), 6.95 (2H, d, J 9.0), 7.86 (2H, d, J 9.0), 8.44 (1H,
dd, J 2.0 and 7.0), 8.50 (1H, dd, J 2.0 and 7.0); C (100 MHz, CDCl3) 29.0, 31.7, 31.8, 55.2,
56.9, 60.8, 107.6, 113.7, 121.1, 127.3, 129.8, 131.0, 141.3, 148.9, 158.3, 159.3; HRMS (ES-
TOF) m/z: [M+H]+ calcd. for C21H29N4O 353.2341, found 353.2350.
2-(Thiophen-2-yl)-N-(2,4,4-trimethylpentan-2-yl)imidazo[1,2-a]pyrimidin-3-amine 8a.
General procedure followed using thiophene-2-carboxaldehyde and Walborsky’s reagent.
Column chromatography was carried out on basic alumina, eluted with 20→30→50%
EtOAc/toluene then 1% MeOH/CH2Cl2, after which the title compound was obtained as a
dark yellow amorphous solid (0.079 g, 60%). max (solid/cm–1) 3433, 3080, 2962, 1984, 1604,
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1221, 1012, 888; H (400 MHz, CDCl3) 1.10 (9 H, s), 1.14 (6 H, s), 1.71 (2 H, s), 3.28 (1 H,
s), 6.83 (1 H, dd, J 4.0 and 7.0), 7.13 (1 H, dd, J 4.0 and 5.0), 7.37 (1 H, dd, J 1.0 and 5.0),
7.66 (1 H, dd, J 1.0 and 4.0), 8.49 (1 H, dd, J 2.0 and 7.0), 8.50 (1 H, dd, J 4.0 and 2.0); C
(100 MHz, CDCl3) 29.3, 31.8, 31.9, 57.1, 61.2, 107.8, 121.0, 125.7, 126.1, 127.3, 131.1,
136.5, 136.7, 149.5, 158.3; HRMS (ES-TOF) m/z: [M+H]+ calcd. for C18H25N4S 329.1800,
found 329.1816.
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2-Phenyl-N-(2-(thiophen-2-yl)ethyl)imidazo[1,2-a]pyrimidin-3-amine 9a. Prepared by the
general procedure, with benzaldehyde and 2-(2-thienyl)ethyl isocyanide. Column
chromatography on basic alumina, using 33→50→80% EtOAc/toluene then 1% MeOH/CH-
2Cl2 as eluent, followed by a further column on silica eluted with 30→50→80%
EtOAc/toluene, afforded the title compound (0.063, 49%) as a yellow amorphous solid.
Purity (HPLC) 99.2%; max (solid/cm–1) 3302, 3076, 2924, 2850, 1610, 1491, 1444, 1213,
1188, 783, 761, 690; H (400 MHz, DMSO-d6) 3.02 (2H, t, J 7.0), 3.23 (2H, q, J 6.0), 5.11
(1H, t, J 6.0), 6.82 (1H, dd, J 7.0 and 4.0), 6.89 (1H, dd, J 3.5 and 1.0), 7.01 (1H, dd, J 5.0
and 3.5), 7.25 (1H, dd, J 5.0 and 1.0), 7.38–7.32 (1H, m), 7.52–7.40 (2H, m), 8.02–7.94 (2H,
m), 8.17 (1H, dd, J 7.0 and 2.0), 8.50 (1H, dd, J 2.0 and 4.0); C (100 MHz, CDCl3) 31.0,
49.3, 108.1, 123.9, 124.1, 125.8, 127.1, 127.3, 127.9, 128.7, 130.1, 133.4, 137.3, 141.4,
144.5, 149.2; HRMS (ES-TOF) m/z: [M+H]+ calcd. for C18H17N4S 321.1174, found
321.1186.
2-(4-(1H-Pyrazol-1-yl)phenyl)-N-(2-(thiophen-2-yl)ethyl)imidazo[1,2-a]pyrimidin-3-
amine 10a. General procedure followed using 4-(1H-pyrazol-1-yl)benzaldehyde and 2-(2-
thienyl)ethyl isocyanide. Flash column chromatography on silica, eluted with 205080%
ethyl acetate/petroleum ether, afforded the title compound (0.085 g, 55%) as a yellow
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amorphous solid. Purity (HPLC) 98.0%; max (solid/cm–1) 3284, 3086, 2924, 2853, 1613,
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1562, 1526, 1394, 1319, 1243, 1216, 1120, 1046, 1030, 935, 847. H (400 MHz, DMSO-d6)
3.05 (2H, t, J 7.0), 3.27 (2H, q, J 7.0), 5.15 (1H, t, J 6.0), 6.58 (1H, t, J 2.0), 6.87 (1H, d, J
3.5), 6.94 (1H, dd, J 3.5 and 5.0), 7.02 (1H, dd, J 4.0 and 7.0), 7.33 (1H, dd, J 1.0 and 5.0),
7.79 (1H, d, J 1.0), 7.92 (2H, d, J 9.0), 8.25 (2H, d, J 9.0), 8.48 (1H, dd, J 2.0 and 4.0), 8.37
(1H, d, J 2.5), 8.63 (1H, dd, J 2.0 and 7.0). C (100 MHz, DMSO-d6) 31.1, 49.7, 108.5 (d, J
16.5), 118.8, 119.5, 124.4, 125.5, 125.8, 127.4, 128.1 (d, J 8.2), 129.1, 131.8, 132.3, 134.7,
139.1, 141.5, 142.2, 144.2, 149.9; HRMS (ES-TOF) m/z: [M+H]+ calcd. for C21H19N6S
387.1392, found 387.1404.
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N-(3-Fluoro-4-methylphenyl)-2-p-tolylimidazo[1,2-a]pyrimidin-3-amine 11a. Prepared by
the general procedure with p-tolualdehyde and 2-fluoro-4-isocyano-1-methylbenzene. The
crude material was subjected to column chromatography on silica, eluted with 0→1→2→4%
MeOH/CH2Cl2, providing the title compound as a yellow solid (0.057 g, 43%) after further
recrystallisation from CH2Cl2/hexane: mp 89–97 °C; Purity (HPLC) 97.6 %; max (solid/cm–1)
3214, 3074, 2912, 1506, 1374, 1317, 1242, 1115, 806, 765, 750; H (400 MHz, DMSO-d6)
2.06 (3H, s), 2.30 (3H, s), 6.22 (1H, d, J 8.5), 6.28 (1H, d, J 12.0), 6.99 (1H, t, J 8.5), 7.03
(1H, dd, J 4.5 and 6.5), 7.22 (2H, d, J 8.0), 7.93 (2H, d, J 8.0), 8.32 (1H, s), 8.39 (1H, d, J
7.0), 8.55–8.57 (1H, m). C (100 MHz, DMSO-d6) 13.3 (d, J 2.5), 20.8, 100.0 (d, J 26.5),
108.8, 113.5 (d, J 17.5), 116.7, 126.6, 129.2, 130.2, 131.26, 132.3 (d, J 7.0), 137.4, 144.9,
145.2 (d, J 10.0), 150.4, 160.5, 162.4; HRMS (ES-TOF) m/z: [M+H]+ calcd. for C20H18N4F
333.1516, found 333.1518.
N-(4-Chlorobenzyl)-2-(thiophen-2-yl)imidazo[1,2-a]pyrimidin-3-amine 12a. General
procedure followed using thiophene-2-carboxaldehyde and p-chlorobenzyl isocyanide.
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Successive recrystallisations from EtOAc/hexane, then CH2Cl2/hexane, provided the title
compound (0.075 g, 55%) as a dark yellow amorphous solid. Purity (HPLC) 98.9%; max
(solid/cm–1) 3275, 3049, 2978, 2856, 1610, 1490, 1198, 790, 767, 695; H (400 MHz,
DMSO-d6) 4.15 (2H, d, J 6.5), 5.46 (1H, t, J 6.5), 6.96 (1H, dd, J 4.0 and 7.0), 7.17 (1H, dd, J
3.5 and 5.0), 7.32–7.39 (4H, m), 7.58 (1H, dd, J 1.0 and 5.0), 7.68 (1H, dd, J 1.0 and 3.5),
8.43 (1H, dd, J 2.0 and 4.0), 8.52 (1H, dd, J 2.0 and 7.0); C (100 MHz, DMSO-d6) 50.0,
108.0, 123.3, 124.5, 126.1, 127.8, 128.2, 130.1, 131.3, 131.7, 132.3, 136.7, 138.7, 143.6,
149.5; HRMS (ES-TOF) m/z: [M+Na]+ calcd. for C17H13ClN4SNa 363.0447, found 363.0446.
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N-(4-Chlorobenzyl)-2-phenylimidazo[1,2-a]pyrimidin-3-amine 13a. Prepared by the
general procedure using benzaldehyde and 4-chlorobenzyl isocyanide. Column
chromatography on basic alumina, eluted with 0→5→10→20→50% EtOAc/toluene,
provided the title compound (0.062 g, 46%) as a yellow amorphous solid. Purity (HPLC)
98.6%; max (solid/cm–1) 3268, 3051, 2973, 2855, 1610, 1492, 793, 766, 713, 693, 662; H
(400 MHz, CDCl3) 4.02 (1H, br s), 4.17 (2H, s), 6.80 (1H, dd, J 4.0 and 7.0), 7.17–7.26 (4H,
m), 7.34–7.40 (1H, m), 7.43–7.49 (2H, m), 8.03 (2H, d, J 7.5), 8.32 (1H, dd, J 2.0 and 7.0),
8.4 (1H, dd, J 2.0 and 4.0); C (100 MHz, CDCl3) 51.7, 108.3, 123.8, 127.4, 128.1, 128.7,
128.8, 129.6, 130.2, 133.1, 133.5, 137.3, 137.4, 144.3, 149.6; HRMS (ES-TOF) m/z: [M+H]+
calcd. for C19H16ClN4 335.1063, found 335.1061.
N-(4-Chlorobenzyl)-2-(2-ethylbutyl)imidazo[1,2-a]pyrimidin-3-amine 14a. Prepared by
the general procedure with 2-ethylbutyraldehyde and 4-chlorobenzyl isocyanide. Flash
column chromatography on silica, eluted with 20335080% ethyl acetate/petroleum
ether provided the title compound as a yellow amorphous solid (0.036 g, 27%). Purity
(HPLC) 92.4 %; max (solid/cm-1) 3228, 3069, 2960, 2929, 2871, 1615, 1492, 1408, 1374,
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1318, 1090, 1014, 781, 732; H (400 MHz, CDCl3) 0.81 (6H, t, J 7.5), 1.72–1.90 (4H, m),
2.55–2.63 (1H, m), 3.45 (1H, s), 4.13 (2H, s), 6.75 (1H, dd, J 4.0 and 7.0), 7.27–7.32 (4H,
m), 8.17 (1H, dd, J 2.0 and 7.0), 8.41 (1H, dd, J 2.0 and 4.0); C (100 MHz, CDCl3) 12.6,
27.9, 41.4, 53.0, 107.7, 124.7, 128.8, 129.6, 129.6, 133.5, 137.6, 143.9, 144.6, 148.4; HRMS
(ES-TOF) m/z: [M+H]+ calcd. for C18H22ClN4 329.1533, found 329.1519.
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N-(4-Chlorobenzyl)-2-propylimidazo[1,2-a]pyrimidin-3-amine 15a.
Prepared by the general procedure with propionaldehyde and 4-chlorobenzyl isocyanide.
Flash column chromatography on silca, eluted with 205080% ethyl acetate/petroleum
ether provided the title compound as a yellow amorphous solid (0.038 g, 32%). Purity
(HPLC) 92.7 %; max (solid/cm–1) 3228, 2932, 2875, 1654, 1614, 1596, 1519, 1491, 1462,
1408, 1340, 1272, 1214, 1175, 1090, 1067, 1014, 800, 767; H (CDCl3, 400 MHz) 1.33 (3H,
t, J 7.5), 2.73 (2H, q, J 7.5), 3.54 (1H, s), 4.14 (2H, s), 6.80 (1H, dd, J 4.0 and 7.0), 7.21–7.31
(4H, m), 8.26 (1H, dd, J 2.0 and 7.0), 8.44 (1H, dd, J 2.0 and 4.0); C (CDCl3, 100 MHz)
13.8, 20.4, 52.7, 108.0, 128.8, 129.2, 129.7, 129.8, 133.6, 137.6, 142.5, 148.7; HRMS (ES-
TOF) m/z: [M+H]+ calcd. for C15H16N4Cl 287.1063, found 287.1058.
ACKNOWLEDGEMENTS
We are grateful for funding from the UK Department of Health, The Home Office (Contract
No. 04-70-174), EPSRC (for a studentship to AJEB) and National Key Basic Research
Program of China (973 Program) 2012CB725204 and 2011CB710803. We would also like to
thank Vapourtec for their continued technical support.
SUPPORTING INFORMATION AVAILABLE
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Supplementary Figures, H NMR and C NMR for all compounds in Table 1, LC-MS data
for 8b, 9b, 10b, 11b and 13b and crystallographic data for compounds 5a, 6b and 11a. This
data is available free of charge via the internet at http://pubs.acs.org.
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