Nucleophilic aromatic substitution of heterocycles using a high-temperature and high-pressure flow reactor

Article abstract of DOI:10.1016/j.tetlet.2016.01.080

We report herein a high-temperature and high-pressure continuous-flow protocol to carry out nucleophilic aromatic substitution (S_NAr) of heterocycles with nitrogen nucleophiles. Utilizing the Phoenix Flow Reactor in parallel with Design-of-Experiment software enabled rapid optimization of the S_NAr protocol. This protocol facilitated efficient synthesis of a broad range of 2-aminoquinazolines, and was extended to 2-aminoquinoxalines and 2-aminobenzimidazoles.

Full text of DOI:10.1016/j.tetlet.2016.01.080

Accepted Manuscript
Nucleophilic Aromatic Substitution of Heterocycles Using a High-Temperature
and High-Pressure Flow Reactor
Manwika Charaschanya, Andrew R. Bogdan, Ying Wang, Stevan W. Djuric
PII:
S0040-4039(16)30079-X
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.01.080
TETL 47244
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
9 December 2015
20 January 2016
21 January 2016
Please cite this article as: Charaschanya, M., Bogdan, A.R., Wang, Y., Djuric, S.W., Nucleophilic Aromatic
Substitution of Heterocycles Using a High-Temperature and High-Pressure Flow Reactor, Tetrahedron Letters
(2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.01.080
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Nucleophilic Aromatic Substitution of Heterocycles Using a High-Temperature and High-
Pressure Flow Reactor
Manwika Charaschanyaa, Andrew R. Bogdanb*, Ying Wangb and Stevan W. Djuricb
aDepartment of Medicinal Chemistry, University of Kansas, Lawrence, Kansas, 66047
bAbbVie Inc. Discovery Chemistry and Technologies, 1 North Waukegan Road, North Chicago,
Illinois, 60064
*andrew.bogdan@abbvie.com
Abstract
We report herein a high-temperature and high-pressure continuous-flow protocol to carry out
nucleophilic aromatic substitution (SNAr) of heterocycles with nitrogen nucleophiles. Utilizing
the Phoenix Flow ReactorTM in parallel with Design-of-Experiment software enabled rapid
optimization of the SNAr protocol. This protocol facilitated efficient synthesis of a broad range of
2-aminoquinazolines, and was extended to 2-aminoquinoxalines and 2-aminobenzimidazoles.
Introduction
Innovations in continuous-flow technology have stimulated both industrial and academic
laboratories to approach organic chemistry with a new level of efficiency.1 Technologies in
continuous-flow synthesis offer opportunities to accelerate chemical transformations, maximize
product outcome, automate synthesis, and scale-up with minimal optimization. Performing
reactions under continuous-flow conditions offer many advantages over batch processes
including increased safety, efficient heat transfer due to high surface-to-volume ratio in
microchannels, and good control of reaction variables such as temperature and residence time. A
particularly impactful feature of continuous-flow chemistry is process intensification, which is
the ability to obtain higher product quality (purity, selectivity, and/or yield) of desired product
rapidly by enhancing reaction parameters such as temperature and pressure.1d
The nucleophilic aromatic substitution (SNAr) of heterocycles is a high-value, synthetically
versatile reaction used widely in both the medicinal and process chemistry communities.
Examples of SNAr being run in flow exist in the literature using activated aryl halides under both
traditional and microwave heating.2 As a starting point towards a general approach for the direct
amination of heterocycles in continuous-flow, we chose to investigate the SNAr reaction of 2-

chloroquinazoline with nitrogen nucleophiles.3 The resulting 2-aminopyrimidine-like structure is
commonly found in pharmaceutical reagents, such as Rosuvastatin and Imatinib. Traditionally,
amination of 2-chloroquinazoline requires conditions such as refluxing in 1-pentanol, isoamyl
alcohol, or isopropyl alcohol between 3-20 hours,4 heating ethanol or isopropyl alcohol in sealed
tubes to 150 ˚C until reaction completion,5heating in N-methyl-2-pyrrolidine (NMP) to 110 ˚C
for 24 hours,6 or microwave-assisted heating in acetonitrile in the range of 120-180 ˚C or neat
within 5-60 minutes.3b, 7 For example, Henriksen and Sørensen reported a microwave-assisted
synthesis of 2-benzylaminoquinazoline by heating a mixture of 2-chloroquinazoline,
benzylamine, and potassium carbonate in acetonitrile to 170 ˚C for 50 minutes to obtain a 50%
yield. Previous examples using flow reactors in SNAr reactions of heterocycles with nitrogen
nucleophiles include the preparation of 2-aminopyridines.8 In this protocol, 2-chloropyridine and
piperidine were optimized in NMP heated to 260 ˚C to afford the desired product in 20
minutes.8a Compared to conventional and microwave-assisted heating, high-temperature and
high-pressure flow reactors significantly extend the spectrum of reaction conditions. It should be
noted that most commercially-available microwave reactors have a temperature maximum of
250˚C, a pressure maximum of 2 MPa, and have scale-up limitations. Unlike microwave
reactors, high-temperature and high-pressure flow reactors can execute synthesis in low-boiling
solvents at temperatures above their boiling points without pressure and solvent limitations.1c, 8b, 9
Adopting this technology into synthesis may minimize reaction time, enhance substrate scope,
maxmize yield, and more importantly, provide a practical platform for reaction telescoping and
automation.
In our investigations, we used a commercially available high-temperature and high-pressure
Phoenix Flow ReactorTM from ThalesNano (Figure 1). This flow reactor was designed to achieve
a temperature maximum of 450 ˚C, and a pressure maximum of 14 MPa when equipped with a
proper back-pressure regulator. The reactor coil consists of a stainless steel tubing (1.0 mm
diameter) of 8 mL volume, which is wrapped around a metallic housing tube and placed inside
the Phoenix. Our flow platform consisted of four components: a JASCO PU-2085 plus HPLC
pump, a JASCO BP-2080 Plus back pressure regulator, a manual injection loop, and the Phoenix
Flow ReactorTM. The HPLC pump allowed for a range of flow rates from 0.01 to 4.0 mL/min,
and along with the variable back pressure regulator, a wide array of residence times, pressures
and temperatures could readily be assessed.
In this report, we disclose a rapid optimization of the SNAr reaction of 2-chloroquinazoline with
benzylamine using the Phoenix Flow ReactorTM and statistical Design-of-Experiment (DoE)
software. A comprehensive optimization of three parameters—temperature, pressure, and flow
rate was executed to achieve a general protocol for the SNAr reaction of 2-chloroquinazoline
with benzylamine in continuous-flow. The optimal conditions were applied to a variety of
nucleophiles such as primary and secondary amines, as well as anilines. Additional electrophilic
heterocycles, such as 2-chloroquinoxaline and benzimidazole, were also investigated.

Figure 1. Schematic of the Phoenix Flow ReactorTM and flow platform.
Results and Discussion
A continuous-flow SNAr of 2-chloroquinazoline with benzylamine was investigated using DoE
(Table 1). Using Stat-Ease Design Expert 7, a series of reactions were designed and subsequently
carried out using the Phoenix. All reactions were analyzed using HPLC/MS, and the resulting
data was input in the DoE software. In this investigation, three parameters were optimized,
which included a range of temperatures, pressures, and flow rates. Ethanol was chosen as the
solvent of choice due to its green chemistry nature and its wide use in SNAr chemistry. Contour
plots were generated using the Design Expert software from the acquired data. These plots
allowed the relationship between temperature, pressure, and flow rate on reaction outcome could
be visualized (Figure 2). In Figure 2a, the results indicated that lower temperatures and higher
pressures gave a higher percent of desired product 3. While conversions were high in all cases,
significant decomposition and side-reactions were observed at temperatures of 325 ˚C and above.
More evident in Table 1, decomposition was observed by LC at 400 ˚C, giving a lower
percentage of product. In comparison, reactions performed at 250 ˚C afforded clean conversions
from 1 to 3.

Table 1. DoE optimization of continuous-flow SNAr between 2-chloroquinazoline and
benzylamine.
product (%UV)a
temperature (˚C)
pressure (MPa)
flow rate (mL/min)
250
250
250
250
325
325
325
325
325
400
400
400
400
8
2.5
4.0
1.0
2.5
1.0
4.0
2.5
1.0
4.0
2.5
1.0
4.0
2.5
46
29
75
42
37
20
34b
62
47
25
37
27
37
10
10
12
8
8
10
12
12
8
10
10
12
a Percent product by analytical HPLC.
b Center point, average of 4 runs.

Figure 2. DoE contour plots for a) the relationship between temperature and pressure at 1.0
mL/min and b) the relationship between flow rate and pressure at 250 ˚C.
a)
b)
Reaction temperatures less than 250 ˚C were deemed optimal for the SNAr. In Figure 2b, the
results depicted higher conversions of 3 when a slower flow rate was employed. Accordingly,
increasing the residence time of the reaction mixture in the flow reactor increased product yield.
Based on data, optimal conditions were predicted to require flow reactor temperature of 225 ˚C
or lower, pressure of 12 MPa, and flow rate of 0.5 mL/min (equivalent to a 16 minute residence
time) as shown in Figure 3. The suggested conditions were used, and a complete conversion
from 1 to 3 was observed by analytical HPLC that led to an isolated yield of 97%. Under these
optimized conditions, a range of nucleophiles was screened to demonstrate the scope of SNAr
(Table 2). The SNAr of 2-chloroquinazoline with primary amines gave desired products in
excellent yields (example 4-8, Table 2), while secondary amines gave desired products in modest
to high yields (examples 10-14). Lower yielding examples such as example 9 are presumably
due to that fact the hydrochloride salt was used as the monomer. Additionally, low molecular
weight amines such as methylamine could readily be used in flow to afford the methylamine
adduct 4 in high yield (Table 2). Monomers such as imidazole and benzyl amines could also be
used, giving the resultant product in modest yields (examples 15-18). We examined several
anilines including both electron-poor and electron-rich substituted anilines and heterocycles, and
unfortunately, only observed modest yield (example 19-21, Table 2). Further optimization using
DoE of weak nucleophiles, as in the case of anilines would be required to increase the yield and
scope. Next, SNAr of related heterocycles such as 2-chloroquinoxaline and benzimidazole were
investigated. In Table 3, SNAr reactions of either 2-chloroquinoxaline or benzimidazole with
primary and secondary amines afforded the desired products in modest yields. Further
optimization could be carried out on these substrates to increase their isolated yields. It is also
worth noting that no ethanol adducts were observed while running these reactions.

Figure 3. DoE-suggested optimal reaction condition and isolated yield of 3.
Table 2. Scope for the continuous-flow SNAr of 1 with nitrogen nucleophiles.a-c
2-aminoquinazoline product
isolated yield (%)
4
5
73
92
6
7
92
82
90
8
9
38
71
10

11
12
79
66
13
64
14
15
73
50
16
17
68
66
18
19
60
63
20
21
39
27
aAll reactions were carried out in ethanol. The reaction stoichiometry was 0.063 mmol of 2-
chloroquinazoline and 0.125 mmol of amines, which were used as 0.25 M solutions. In a 1-dram

vial, 0.25 mL of 2-chloroquinazoline and 0.5 mL of amine were premixed. The reaction mixture
was introduced into the Phoenix Flow ReactorTM via a 1mL injection loop.
bFlow rate of 0.5 mL/min, residence time of 16 min, 225 ˚C, and 12 MPa.
cCompounds were purified by a mass triggered, reverse phase HPLC method.
Table 3. Additional evaluation of reaction scope using 2-chloroquinoxaline and 2-
chlorobenzimidazole.a-c
product
isolated yield (%)
22
42
23
24
59
60
25
78
26
27
73
65
aAll reactions were carried out in ethanol. The reaction stoichiometry was 0.063 mmol of 2-
chloroquinoxaline or benzimidazole and 0.125 mmol of amines, which were used as 0.25 M
solutions. In a 1-dram vial, 0.25 mL of 2-chloroquinoxaline and 0.5 mL of amine were premixed.
The reaction mixture was introduced into the Phoenix Flow ReactorTM via a 1mL injection loop.
bFlow rate of 0.5 mL/min, residence time of 16 min, 225 ˚C, and 12 MPa.
cCompounds were purified by a mass triggered, reverse phase HPLC method.
Conclusion
In summary, we have demonstrated the use of a simple high-temperature and high-pressure flow
reactor to carry out SNAr reactions of heterocycles with a broad range of nitrogen nucleophiles.
This flow platform was used alongside with DoE analysis to establish an optimized synthesis of
amino-substituted heterocycles in an efficient manner. We find that this straightforward and
easily assembled flow platform is amenable for the preparation of libraries, automation, and the
scale-up of compound synthesis. More importantly, this protocol is not only an alternative

method to microwave-assisted heating, but offers the advantages of using green solvents at
elevated temperatures, shortened reaction times, as well as the prospect of continuous-flow scale-
up. Additionally, we are continuing to investigate high-temperature chemistry with the hope of
discovering new, fast and clean methodologies that are enabled by running reactions close to
their transition state temperature.
Disclosures
All authors are employees or former employees of AbbVie. This study was sponsored by
AbbVie. AbbVie contributed to the study design, research, and interpretation of data, writing,
reviewing, and approving the manuscript.
Acknowledgements
The authors wish to thank Rickie Yarbrough, Jan Waters and David Whittern, of AbbVie, for
structural chemistry support.
References
1.
(a) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.; McQuade, D. T. Chem.
Rev. 2007, 107 (6), 2300-2318; (b) Geyer, K.; Gustafsson, T.; Seeberger, P. H. Synlett, 2009
(15), 2382-2391; (c) Razzaq, T.; Kappe, C. O. Chemistry – An Asian Journal 2010, 5 (6), 1274-
1289; (d) Malet-Sanz, L.; Susanne, F. J. Med. Chem. 2012, 55 (9), 4062-4098; (e) McQuade, D.
T.; Seeberger, P. H. J. Org. Chem. 2013, 78 (13), 6384-6389; (f) Ley, S. V.; Fitzpatrick, D. E.;
Ingham, R. J.; Myers, R. M. Angew. Chemie Int. Ed. 2015, 54 (11), 3449-3464. (g) Pastre, J. C.;
Browne, D. L.; Ley, S. V. Chem. Soc. Rev. 2013, 42, 8849–8869. (h) Baxendale, I. R.; Deeley,
J.; Griffiths-Jones, C. M.; Ley, S. V.; Saaby, S.; Tranmer, G. Chem. Commun. 2006, 2566-2568.
(i) Baxendale, I. R. J. Chem. Technol. Biotechnol. 2013; 88: 519–552. (j) Baumann, M.;
Baxendale, I. R.; Ley, S. V. Mol. Divers. 2011, 15, 613-630. (k) Baumann, M.; Baxendale, I. R.
Bielstein J. Org. Chem. 2015, 11, 1149-1219.
2. (a) Chen, M.; Buchwald, S. L. Angew. Chemie Int. Ed. 2013, 52, 4247-4250. (b) Wiles, C.;
Watts, P. Beilstein J. Org. Chem. 2011, 7, 1360-1371. (c) Petersen, T. P.; Larsen, A. F.; Ritzen,
A.; Ulven, T. J. Org. Chem. 2013, 78, 4190. (d) Lengyel, L.; Gyollai, V.; Nagy, T.; Dorman, G.;
Terleczky, P.; Hada, V.; Nogradi, K.; Sebok, F.; Urge, L.; Darvas, F. Mol. Divers. 2011, 15,
631-638.
3.
(a) Connolly, D. J.; Cusack, D.; O'Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61 (43),
10153-10202; (b) Saari, R.; Törmä, J.-C.; Nevalainen, T. Bioorg. Med. Chem. 2011, 19 (2), 939-
950.
4.
(a) Zunszain, P. A.; Federico, C.; Sechi, M.; Al-Damluji, S.; Ganellin, C. R. Bioorg. Med.
Chem. 2005, 13 (11), 3681-3689; (b) Zhu, L.; Jin, J.; Liu, C.; Zhang, C.; Sun, Y.; Guo, Y.; Fu,
D.; Chen, X.; Xu, B. Bioorg. Med. Chem. 2011, 19 (9), 2797-2807.

5.
(a) Odingo, J.; O’Malley, T.; Kesicki, E. A.; Alling, T.; Bailey, M. A.; Early, J.; Ollinger,
J.; Dalai, S.; Kumar, N.; Singh, R. V.; Hipskind, P. A.; Cramer, J. W.; Ioerger, T.; Sacchettini, J.;
Vickers, R.; Parish, T. Bioorg. Med. Chem. 2014, 22 (24), 6965-6979; (b) Van Horn, K. S.; Zhu,
X.; Pandharkar, T.; Yang, S.; Vesely, B.; Vanaerschot, M.; Dujardin, J.-C.; Rijal, S.; Kyle, D. E.;
Wang, M. Z.; Werbovetz, K. A.; Manetsch, R. J. Med. Chem. 2014, 57 (12), 5141-5156; (c) Van
Horn, K. S.; Burda, W. N.; Fleeman, R.; Shaw, L. N.; Manetsch, R. J. Med. Chem. 2014, 57 (7),
3075-3093.
6.
Okano, M.; Mito, J.; Maruyama, Y.; Masuda, H.; Niwa, T.; Nakagawa, S.-i.; Nakamura,
Y.; Matsuura, A. Bioorg. Med. Chem. 2009, 17 (1), 119-132.
7. (a) Henriksen, S. T.; Sørensen, U. S. Tet. Lett. 2006, 47 (47), 8251-8254; (b) Smits, R.
A.; de Esch, I. J. P.; Zuiderveld, O. P.; Broeker, J.; Sansuk, K.; Guaita, E.; Coruzzi, G.; Adami,
M.; Haaksma, E.; Leurs, R. J. Med. Chem. 2008, 51 (24), 7855-7865; (c) LaPorte, M. G.; da Paz
Lima, D. J.; Zhang, F.; Sen, M.; Grandis, J. R.; Camarco, D.; Hua, Y.; Johnston, P. A.; Lazo, J.
S.; Resnick, L. O.; Wipf, P.; Huryn, D. M. Bioorg. Med. Chem. Lett. 2014, 24 (21), 5081-5085;
(d) Chou, T.-F.; Li, K.; Frankowski, K. J.; Schoenen, F. J.; Deshaies, R. J. Chemmedchem 2013,
8 (2), 297-312.
8.
(a) Hamper, B. C.; Tesfu, E. Synlett 2007, (14), 2257-2261; (b) Razzaq, T.; Glasnov, T.
N.; Kappe, C. O. Eur. J. Org. Chem. 2009, (9), 1321-1325.
9. Damm, M.; Glasnov, T. N.; Kappe, C. O. Org. Proc. Res. Dev. 2010, 14 (1), 215-224.

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