Nucleophilic aromatic substitution reactions under aqueous, mild conditions using polymeric additive HPMC

Article abstract of DOI:10.1039/d1gc00128k

The use of the inexpensive, benign, and sustainable polymer, hydroxypropyl methylcellulose (HPMC), in water enables nucleophilic aromatic subsitution (S_NAr) reactions between various nucleophiles and electrophiles. The mild reaction conditions facilitate a broad functional group tolerance that can be utilized for subsequent derivatization for the synthesis of pharmaceutically relevant building blocks. The use of only equimolar amounts of all reagents and water as reaction solvent reveals the greenness and sustainability of the methodology presented herein.

Full text of DOI:10.1039/d1gc00128k

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Nucleophilic aromatic substitution reactions under
aqueous, mild conditions using polymeric additive
HPMC†
Cite this: DOI: 10.1039/d1gc00128k
Niginia Borlinghaus, a Tharique N. Ansari,‡b Leon H. Braje, ‡a Deborah Ogulu,‡b
Sachin Handa, b Valentin Wittmann c and Wilfried M. Braje*a
The use of the inexpensive, benign, and sustainable polymer, hydroxypropyl methylcellulose (HPMC), in
water enables nucleophilic aromatic subsitution (SNAr) reactions between various nucleophiles and elec-
trophiles. The mild reaction conditions facilitate a broad functional group tolerance that can be utilized
for subsequent derivatization for the synthesis of pharmaceutically relevant building blocks. The use of
only equimolar amounts of all reagents and water as reaction solvent reveals the greenness and sustain-
ability of the methodology presented herein.
Received 12th January 2021,
Accepted 15th April 2021
DOI: 10.1039/d1gc00128k
rsc.li/greenchem
the interface of insoluble organic reactants and water, termed
Introduction
“on water”,12,13 to taking place “in water”.14,15 Designer surfac-
The recent interest in using water as a reaction solvent for syn- tants such as PS-750-M,16–18 or TPGS-750-M19,20 have shown to
thetic chemistry is built upon a desire for cheaper, less hazar- be broadly applicable to different types of reactions. Both sur-
dous, and more sustainable production of chemicals. Besides, factants are used for discovery research, i.e., small-scale synthesis
this increasing interest also reflects advantages that aqueous of drug candidates in the pharmaceutical industry.21 Notably,
reaction conditions can offer in terms of selectivity, for TPGS-750-M has proven its generality by enabling syntheses of
example, due to the unique physical and chemical properties active pharmaceutical ingredients (APIs) also on industrial
of water.1 Pioneering work from Breslow and Grieco in the scale.22,23 However, some of the designer surfactants are relatively
1980s presented the starting point for an ever since broaden- expensive, and their synthesis requires several steps.20 Besides,
ing application of water as reaction medium for chemical their shelf-life in aqueous solution can be diminished by the
reactions.2,3 As solubility of organic compounds in this highly presence of labile ester groups, which are prone to hydrolysis.24
polar solvent remains the main obstacle, a variety of different Furthermore, co-solvents, such as THF, acetone, DMF, etc.,25 are
methods to enhance aqueous solubility have been investi- often required to achieve high reaction yields. The presence of
gated.4 The most promising approach so far relies on the use these co-solvents generally ensures homogeneous reaction mix-
of non-ionic surfactants in water that form dynamic micelles tures and uniform mixing, which is particularly necessary in
of different sizes and shapes.5–7 In these micelles, organic scaled-up reactions.26–28 The outcome of reactions depends on
compounds can be solubilized, thereby allowing chemical physical properties of the micelles, such as size, shape, critical
reactions to proceed under mild reaction conditions.8–10 The micelle concentration (CMC), and their relative stability which
formation of these “nanoreactors”11 copes not only with the can complicate the application of micellar catalysis.11
low solubility of organic reactants in water, but also with the
An alternative method for conducting chemical reactions in
water sensitivity and associated decomposition of reactive water using catalytic amounts of the inexpensive, benign, and
intermediates, i.e. by hydrolysis. By employing micellar cataly- sustainable polymer hydroxypropyl methylcellulose (HPMC,
sis, chemical reactions have evolved from being conducted at see Fig. 1), could be a solution to aforementioned issues. In
contrast to micelle-forming non-ionic surfactants, the solubi-
lity enhancing properties of HPMC are hypothesized to orig-
aNeuroscience Discovery Research, AbbVie Deutschland GmbH & Co. KG, 67061
Ludwigshafen, Germany. E-mail: wilfried.braje@abbvie.com
bDepartment of Chemistry, University of Louisville, Louisville, Kentucky 40292, USA
cDepartment of Chemistry, University of Konstanz, 78457 Konstanz, Germany
†Electronic supplementary information (ESI) available: Reaction optimization,
reaction procedures, analytical data of products. See DOI: 10.1039/d1gc00128k
‡These authors contributed equally.
inate from the formation of hydrophobic pockets.29 This three-
dimensional structure of HPMC enables amide couplings and
Buchwald–Hartwig aminations without the need of organic co-
solvents in unprecedented short reaction times.29 However,
the application of aqueous HPMC solution as solvent to other
important reaction types remained unaddressed so far.
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Table 1 Optimization of the SNAr reaction in HPMC/H2O
Fig. 1 Structure of hydroxypropyl methylcellulose (HPMC), originating
from renewable cellulose, and its plausible mode of action (schematic).
HPMC
[wt%]
Time
[min]
Conv.
[%]
Ratio
3 : 4
Entry
Base (pKa)
To further demonstrate the generality of this approach,
nucleophilic aromatic substitution (SNAr) reactions were inves-
tigated. SNAr reactions are the second most frequently used
reaction type in medicinal chemistry,30 as evidenced by the
high abundance of drugs that require at least one SNAr reac-
tion for their assembly.31 Besides, SNAr reactions possess a
huge potential to be conducted under sustainable reaction
conditions as they are not metal-catalyzed, and have an appeal-
ing atom-economy. Despite these advantages, they are com-
monly conducted in dipolar-aprotic solvents, such as, DMSO,
DMF, DMAc, 1,4-dioxane, and NMP. These solvents account
for a significant amount of waste produced by the pharma-
ceutical industry.32 Likewise, some of these solvents, such as
NMP, 1,4-dioxane, and DMF, present a significant health risk,
and their increasing regulation and restriction of use point to
the need for feasible alternatives.33,34 From an energy and
safety standpoint, the requirement of high temperatures
(80–130 °C) at which SNAr reactions are conducted is also a
concern. Moreover, these harsh reaction conditions generally
cause a reduced functional group tolerance due to unwanted
side reactions. As a consequence, a protecting group strategy is
often required, which can further complicate synthetic routes
and is not desirable from an economic point of view due to an
increased use of organic solvents and potentially toxic chemi-
cals. Herein, we disclose a general, efficient, and sustainable
methodology that addresses aforementioned challenges and
meets the standards set by ACS Pharmaceutical Green
Chemistry Institute for SNAr reactions.35 Our technology
involves safe, mild, and environmentally benign reaction con-
ditions leading to a striking functional group tolerance.
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
1
0.1
0
0.1
0.1
NaHCO3 (6.0)36
2,6-Lutidine (6.8)37
K2CO3 (9.1)36
DIPEA (10.8)38
DBU (11.9)39
30
30
30
30
10 s
10 s
10 s
10 s
10 s
30
70
80
99
99
99
99
99
99
99
53
99
90b
n.d.
n.d.
>99 : 1
n.d.
n.d.
KOH (15.7)40
>99 : 1
>99 : 1
>99 : 1
>99 : 1
1 : 1
NaOtBu (17.0)40
NaOtBu (17.0)
NaOtBu (17.0)
NaOtBu (17.0)
NaOtBu (17.0)
KOH (15.7)
9
10
11
12
10 s
10 s
4 : 1a
>99 : 1
Order of addition: 1. electrophile (1), 2. nucleophile (2), 3. base.
Conversion of electrophile 1 and ratio of 3 : 4 determined by LC/MS.
n.d.: not determined, s: seconds. a Changed order of addition: 1. elec-
trophile (1), 2. base, 3. nucleophile (2). b Isolated yield.
was the minimal time detectable using LC/MS. From several
organic and inorganic bases, DBU, KOH, and NaOtBu were
found to be equally effective in terms of yield and reaction
time. However, due to cost, atom-economy, and superior safety
profile, KOH was selected as the base of choice for further
investigation of the substrate scope. Besides, we were also
interested to explore whether different counterions of the
hydroxide ion would be influenced differently by the surround-
ing free hydroxy groups of HPMC, e.g. by complexation. We
hypothesized that this could result in altered distances between
the ion pairs, and therefore, lead to modified base strengths of
the corresponding hydroxide ion, affecting conversions as well
as reaction kinetics. Moreover, the solubility of the inorganic
salt, e.g. CaF2, which is formed during the course of the reaction
could have an impact on the reaction kinetics. To investigate
these hypotheses, seven different hydroxides were examined
(see ESI, Fig. S1†). This study revealed only minor effects on the
reaction kinetics which could not be correlated to the ion associ-
ation of the different ion pairs. A variety of lipophilic auxiliary
Results and discussion
Reaction optimization
Our investigation of the SNAr reaction in aqueous medium bases were explored to examine if a beneficial impact on the
using the polymer HPMC as an additive started by optimizing reaction could be observed due to their ability to enter hydro-
the reaction of 2,4,5-trichloropyrimidine (1) with pyrrolidine phobic pockets formed by HPMC. For this purpose, different
(2). As shown in Table 1, all reagents can be used in equimolar lipophilic silanols and phenols were screened, but no positive
amounts (1 : 1), which significantly eases the purification of impact on the product formation or the reaction kinetics was
the resulting products, avoids using any excess of expensive or observed (see ESI, Table S1†).
toxic chemicals, and thereby minimizes waste production.
Next, we evaluated the minimally required amount of the
Several bases with different pKa values were screened (see solubilizing additive HPMC, and found that it is possible to
Table 1, entries 1–7). The formation of 3 increased when bases reduce it from commonly employed 2 wt% surfactant for
with higher pKa values were used. Accordingly, reaction times micellar catalysis41 to 0.1 wt% (see Table 1, entries 7–9). A
decreased significantly from 30 minutes to 10 seconds, which control reaction in pure water was conducted (see Table 1,
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entry 10) and the conversion dropped to 53%. Additionally,
side-product 4 resulting from the hydrolysis of 2,4,5-trichloro-
pyrimidine (1) was formed in equal amounts as the desired
product
3 when using sole water as reaction solvent.
Interestingly, the remarkable regioselectivity for the 4-position
was not affected (for further discussion see section Scope and
limitations). Moreover, the order of addition of the reactants
plays an important role in the side product formation. Altering
the order of addition of reactants from 1. electrophile, 2.
nucleophile, 3. base to 1. electrophile, 2. base, 3. nucleophile
also led to an increased formation of the side-product 4 (see
Table 1, entry 11).
Fig. 3 Comparison of isolated yields on small scale (0.1 g) and large
scale (20–50 g) for compounds 8 and 9. PMI: process mass intensity.
Picture: reaction mixture of compound 9 on 50 g scale.
Under the optimized reaction conditions, we finally obtained
product 3 in 90% isolated yield (see Table 1, entry 12).
factor of 200–500 nor a possible side-reaction of the hydroxy
group of 8 were observed. These remarkable aspects of the
scale-up reactions are indicating an unproblematic transfer of
our HPMC technology to process chemistry. To enable direct
comparison of the methodology presented herein with other
approaches, the process mass intensity (PMI), a metric to
evaluate the sustainability of a process,44 was calculated for
both reactions on-scale and was found to be remarkably low
(see ESI, Table S5†). Next, recycling of the aqueous reaction
solvent containing HPMC was evaluated. In a recycle study, we
performed three consecutive SNAr reactions in the same reac-
tion medium. Desired products 3 and 10 were obtained in
good yields regardless of the reaction cycle (see Scheme 1).
Subsequently, we compared our approach with different
known methodologies for the SNAr reaction of 2-fluoronitro-
benzene (5) with benzylamine (6). We found that our method-
ology was as equally effective as the reaction in organic media
(92%), and better than micellar technology (74%),41 or “on
water” (64%) (see Fig. 2). As DCM is not an environmentally
friendly solvent,42,43 its replacement for extraction of the SNAr
products was investigated. Notably, product extraction with
minimal amounts of EtOAc results in comparable isolated
yields (see ESI, Table S3†). Additionally, HPMC is not soluble
in EtOAc leading to high purity of final products (see ESI,
Table S4 and Fig. S3, S4†). On a small scale (0.5 mmol), pro-
ducts were mainly purified by column chromatography.
However, on a large scale (20–50 g) compounds 8 and 9 were
isolated by simple filtration, which completely circumvented
the use of organic solvents (see Fig. 3). Besides, neither a
reduction in isolated yield upon scaling the reaction up by a
Fig. 2 Comparison of different methodologies for the SNAr reaction of
2-fluoronitrobenzene (5) with benzylamine (6). The following bases
were used for the reactions: 0.1 wt% HPMC/water: KOH (90%); 2 wt%
TPGS-750-M/water: K3PO4 (74%); DMF: K2CO3 (92%); water: KOH (64%).
Isolated yields are reported in brackets.
Scheme 1 Recycle study of the aqueous reaction solvent. Products
were extracted from the reaction mixture using EtOAc and the aqueous
layer was reused for the next reaction cycle (see ESI, page S9† for
details). Reactions were performed on 1.0 mmol scale.
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Scope and limitations
Sprycel®), a tyrosinkinase inhibitor, without the formation of
O-substituted or N,O-disubstituted by-products. Notably, the
same clean reaction profile was observed for symmetrical
4-aminobutanol (24). For this reaction we were able to show
that our methodology stands out from the classical reaction
set-up in organic media where approx. 60% of the N,O-di-
substituted product was observed (in contrast to 5% for the
reaction in HPMC/water, see ESI, Fig. S7 and S8†). This cir-
cumvents the usage of protecting groups in several cases and
thus leads to shortened reaction sequences and reduced use of
potentially toxic chemicals required for introduction of these
groups. Moreover, these functionalities enable consecutive
modifications and reactions such as amide or Sonogashira
couplings which can also be conducted in aqueous
medium.29,46 In addition to this excellent chemoselectivity, a
remarkable regioselectivity was observed for the conversion of
2,4,5-trichloropyrimidine (1) as the 4-position was highly
favoured (94 : 6 over the 2-position). This type of chemo-
selectivity cannot be achieved in organic solvents where a
mixture of both regioisomers (69 : 31 over the 2-position, see
ESI, Fig. S9 and S10†) is obtained.
Despite the superior selectivity and stability observed
herein, general reactivity trends remained similar when using
optimized reaction conditions in HPMC/water compared to
organic solvents. For instance, reactions of electron deficient
and therefore less nucleophilic amines resulted in low to mod-
erate yields of the desired products (e.g. morpholine deriva-
tives 17 and 22, ketone 34) and non-nucleophilic nitrogen
groups such as carbamates, ureas, or amides showed no con-
version (see ESI, Scheme S1†). This is also true for the reactiv-
ity of different electrophiles where we observed that either
chloride or fluoride can be employed as leaving groups, with
fluorides being more reactive. Moreover, substituent effects of
electron withdrawing groups such as –CF3, –CN, –CO2R, –Cl,
–Br, and –NO2 were also comparable to those observed in
organic solvents. However, suppression of hydrolysis for highly
activated electrophiles such as 2-chloro-5-nitropyrimidine
under aqueous basic reaction conditions remains an obstacle
and resulted in low isolated yields of the desired products (see
ESI, Scheme S2†). For less activated substrates it was observed
that isolated yields increased upon heating to 50–60 °C (e.g.
15: rt: 52%, 50 °C: 82%). This temperature dependency is also
comparable to the behaviour in organic solvents; however, our
method uses mild temperatures when compared to the ones
that promote reactions in organic solvents (80–130 °C). These
similarities in reactivities and operational principles will hope-
fully ease the transfer from organic solvents to reactions in an
aqueous medium and reduce the reluctance of chemists to
employ this more environmentally friendly methodology.
To further highlight the applicability of our methodology in
medicinal chemistry, we reacted different five-membered het-
erocycles like oxazoles (37) and thiazoles (38) using our opti-
mized conditions. The resulting products can be easily further
derivatized by either ester hydrolysis or nitro group reduction
followed by e.g. amide coupling. Therefore, these substituted
five-membered heterocycles represent a valuable substance
We applied the optimized reaction conditions to a large library
of diverse substrates and reacted multiple electrophiles with a
variety of different nitrogen-based nucleophiles at mild temp-
eratures using a 1 : 1 ratio of the reactants along with the
cheap, benign, inorganic base KOH (see Scheme 2). Within
this substrate scope, we noted that several products were
formed after unprecedented short reaction times (e.g. 14,
40–46, 10–25 min). We found that it is not only possible to
react free amine moieties but also the corresponding HCl- or
HBr-salts of the amines (11, 17, 18, 22, 25–34) by employing an
additional equivalent of base. Benzylic (7, 35, 40), primary (9,
24, 44), and secondary amines (e.g. 14–23) were reacted suc-
cessfully including highly sterically hindered amines (44).
Different cyclic secondary amines were reacted spanning ring
sizes from four- to seven-membered rings. Remarkably, aniline
derivative 13 which is significantly less nucleophilic than ali-
phatic amines was also reactive using our reaction conditions.
Several functional groups showed surprisingly good stabi-
lities under aqueous basic reaction conditions including
strained systems like oxetanes (14–16), which are prone to ring
opening,45 and different types of esters. Carboxylic esters (25,
37) showed only a minimal amount of hydrolysis and were iso-
lated in excellent yields if a weaker base such as K2CO3 was
employed (e.g., 25, 54% (KOH), 86% (K2CO3)). Vinyl boronic
ester (31) as well as alkyl boronic esters (32–33) were not only
tolerated under our reaction conditions but showed superior
stability towards decomposition than in classical organic sol-
vents (decomposition of 33: 25% (DMF), 5% (HPMC/water),
see ESI, Fig. S5 and S6†). Furthermore, the synthesized
boronic esters can be reacted in subsequent Suzuki–Miyaura
couplings which enables easy derivatization necessary for
example in medicinal chemistry for rapid structure–activity-
relationship (SAR) generation. To showcase that this consecu-
tive derivatization is possible using an aqueous reaction
medium, we performed a two-steps one-pot synthesis by react-
ing 2-fluoro-5-cyanopyridine (47) with boronate 48 (see
Scheme 3A). The resulting vinyl pinacol boronate 31 was used
directly in a Suzuki–Miyaura coupling with bromobenzene and
final product 50 was obtained in 77% yield over two steps.
To investigate other valuable precursors for subsequent
modifications, brominated derivates 29 and 30 were syn-
thesized. Remarkably, no elimination was observed for the ali-
phatic bromide 29. Vinyl bromide 30 was further derivatized in
a tandem Suzuki–Miyaura coupling, again, by reacting it in a
one-pot procedure with phenylboronic acid to obtain coupling
product 50 via this alternative route in 90% yield over two
steps (see Scheme 3B).
Further on, we discovered such functional groups as alco-
hols (8, 19–24), carboxylic acids (26), or alkynes (27) which
often require protecting groups to ensure chemoselectivity and
prevent side reactions are well tolerated using HPMC/water as
reaction medium. For instance, we observed a very high N-
over O-selectivity for various aminoalcohols. In this course, we
were able to synthesize
a precursor for Dasatinib (20,
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Scheme 2 Substrate scope of the SNAr reaction in HPMC/water using N-nucleophiles. All yields are reported as isolated yields. a HCl-salt of the
corresponding amine was used, 2.0 equiv. base; b K2CO3 was used, c at 50 °C; d at 60 °C, 0.5 M; e 2.0 equiv. of the corresponding electrophile, 2.0
equiv. KOH.
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Scheme 3 Tandem reactions of a one-pot SNAr reaction followed by a
Suzuki–Miyaura coupling starting either from the corresponding vinyl
pinacol boronate 48 (A) or vinyl bromide 49 (B). Conditions: (a)
PdCl2(dtbpf) (0.02 equiv.), NEt3 (3.0 equiv.), rt, 1 h. a K2CO3 was used to
ensure stability of boronic ester moiety.
Scheme 5 Substrate scope of the SNAr reaction in HPMC/water using
S- and O-nucleophiles. a 60 °C, 0.5 M.
oped herein. Conversion of benzylic alcohol (59) was possible
but interestingly, other O-nucleophiles were difficult to react
under our standardized reaction conditions and need individ-
ual optimization in contrast to the other types of nucleophiles.
class for the pharmaceutical industry, which is not well
covered in literature by now.
In addition, we were able to synthesize two distinct repre-
sentatives of anxiolytic psychotropic drugs, Buspirone (54,
Buspar®) by Bristol-Myers Squibb and Ipsapirone (55, see
Scheme 4). Both products were obtained in good yields after
only 30 min reaction time. Notably, the sensitive sulfonamide
moiety of Ipsapirone was stable under aqueous basic reaction
conditions. These reactions demonstrate the possibility to
react more complex building blocks indicating the value of our
methodology to the pharmaceutical industry.
To broaden the generality of our methodology we explored
not only nitrogen-based nucleophiles but also S-nucleophiles
and O-nucleophiles (see Scheme 5). Different thiols (56–58)
were reacted successfully using the reaction procedure devel-
Conclusions
We employed catalytic amounts of the benign polymer hydro-
xypropyl methylcellulose (HPMC) to enable nucleophilic aro-
matic substitution reactions in water using equimolar
amounts of all reagents at mild temperatures. We applied
these reaction conditions to the synthesis of a diverse substrate
scope in which short reaction times, excellent chemo- and
regioselectivities, as well as a broad functional group tolerance
were observed. The latter allows further derivatization of the
reaction products for the synthesis of biologically active com-
pounds which are of interest to the pharmaceutical industry.
We demonstrated scalability in which the usage of organic sol-
vents was completely avoided throughout the whole reaction
process as well as the application to the synthesis of APIs.
Overall, we developed a general, efficient, and sustainable
methodology that addresses several drawbacks associated with
SNAr reactions under classical reaction conditions.
Author contributions
All authors have given approval to the final version of the
manuscript. Niginia Borlinghaus and Wilfried M. Braje are
employees of AbbVie. Leon H. Braje was employee of AbbVie at
the time of the study. Tharique N. Ansari, Deborah Ogulu,
Sachin Handa, and Valentin Wittmann have nothing to dis-
close. The design, study conduct, and financial support for
this research were provided by AbbVie. AbbVie participated in
the interpretation of data, review, and approval of the
publication.
Scheme 4 SNAr reaction towards two anxiolytic psychotropic drugs 54
and 55 in HPMC/water. a K2CO3 was used ensure stability of sulfonamide
moiety of 53 and 55.
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Conflicts of interest
There are no conflicts to declare.
21 S. Sharma, J. Das, W. M. Braje, A. K. Dash and S. Handa,
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for HRMS measurements, Dr Oliver Callies from our NMR
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from the University of Louisville for technical assistance. No
funding to disclose.
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