Highly regioselective 4-hydroxy-1-methylpiperidine mediated aromatic nucleophilic substitution on a perfluorinated phthalimide core

Article abstract of DOI:10.1016/j.jfluchem.2018.05.011

A tertiary amine-mediated highly regioselective aromatic nucleophilic substitution (S_NAr) protocol was developed in the assemblies of perfluorinated phtalimide with primary or secondary amines as inputs. Application of 1-methyl-4-hydroxypiperidine as additive, formation of the less favoured, bioactive regioisomer was facilitated, modifying their ratios from the initial 8–36% to 81–91%. After optimization, a facile gram scale syntheses were accomplished and isolated the desired analogues in up to 63% yield.

Full text of DOI:10.1016/j.jfluchem.2018.05.011

Accepted Manuscript
Title: Highly regioselective 4-hydroxy-1-methylpiperidine
mediated aromatic nucleophilic substitution on a
perfluorinated phthalimide core
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Authors: Ramona Madacsi, Mario Gyuris, Janos Wo¨lfling,
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Laszlo G. Puskas, Ivan Kanizsai
PII:
S0022-1139(18)30139-8
DOI:
Reference:
https://doi.org/10.1016/j.jfluchem.2018.05.011
FLUOR 9174
To appear in:
FLUOR
Received date:
Revised date:
Accepted date:
29-3-2018
23-5-2018
26-5-2018
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Please cite this article as: Madacsi R, Gyuris M, Wo¨lfling J, Puskas LG, Kanizsai
I, Highly regioselective 4-hydroxy-1-methylpiperidine mediated aromatic nucleophilic
substitution on a perfluorinated phthalimide core, Journal of Fluorine Chemistry (2018),
https://doi.org/10.1016/j.jfluchem.2018.05.011
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Highly regioselective 4-hydroxy-1-methylpiperidine mediated aromatic
nucleophilic substitution on a perfluorinated phthalimide core
Ramóna Madácsia,b, Márió Gyurisa, János Wölflingb, László G. Puskása, Iván Kanizsaia,*
aAVIDIN Ltd. – Alsó Kikötő sor 11/D, H-6726, Szeged, Hungary
bDepartment of Organic Chemistry, Faculty of Science and Informatics, University of Szeged, Dóm tér 8,
H-6720, Szeged, Hungary
Graphical asbtract
Highlights
 1-methyl-4-hydroxypiperidine mediated highly regioselective SNAr protocol was
developed.
 The inherent regioselectivities were modified towards the less favoured bioactive
regioisomer.
 The optimal condition could be utilized for gram scale synthesis.
1

Abstract
A tertiary amine-mediated highly regioselective aromatic nucleophilic substitution (SNAr)
protocol was developed in the assemblies of perfluorinated phtalimide with primary or secondary
amines as inputs. Application of 1-methyl-4-hydroxypiperidine as additive, formation of the less
favoured, bioactive regioisomer was facilitated, modifying their ratios from the initial 8-36% to
81-91%. After optimization, a facile gram scale syntheses were accomplished and isolated the
desired analogues in up to 63% yield.
Keywords: aromatic nucleophilic substitution, SNAr, phtalimide, regioselective, tertiary amine
1. Introduction
The selective decoration of (hetero)aromatic scaffolds is an undoubtedly essential synthetic tool
in medicinal chemistry in order to generate a diverse set of compounds having the best balance of
pharmacological properties. The most commonly used techniques for this purpose include either
the transition metal-catalyzed, or the aromatic nucleophilic substitution (SNAr) reactions [1,2].
The outcome of SNAr transformations strongly depends on the simultaneous interplay between
several parameters, such as, for instance, the overall electronics of the (hetero)arene affected by
the substitution pattern, the influence and mobility of the leaving group, the nature of the
nucleophile applied, solvent and medium effects, stability of the intermediate σ-complex, etc [3].
It should be emphasized, that hydrogen bonding between an SNAr donor and acceptor may
account for specific solvent effect on the regioselectivity [3,4]. For instance, ortho selectivity was
observed in the reaction of 2,4-difluoroacetophenone with secondary amines in non-polar solvents
(toluene, dioxane, etc.) [5]. In this case, precoordination of the amine to the carbonyl function via
H-bond formation may occur, and intramolecular hydrogen bond stabilization (inverted built-in
solvation) may operate in the transition state, preferring the ortho-displacement supported by the
solvent. In contrast, solvents having high solvent hydrogen bond basicity (SHBB) (e.g. DMSO)
result in para-displacement. The reversed selectivity can be interpreted by the lack of a transition
2

state stabilized by H-bond and a relatively strong H-bond interaction between the polar solvent
and the nucleophile applied.
There are certain SNAr synthetic ‘tricks’ described in the literature, which, in contrast to the
general considerations, led to either improved conversion or regioselectivity [6-8]. For instance, a
regioselective DABCO-catalyzed two-stage sequential SNAr reaction of methyl 2,6-
dichloronicotinate with phenols was first introduced by Merck Research Laboratories [6]. Besides
the remarkable solvent effect observed, the reaction proceeds through the regioselective generation
of an unprecedented DABCO–pyridine reactive intermediate. As disclosed by Amgen Inc., certain
ortho-heteroaryl substituents, relative to the leaving group, exert moderate electron-withdrawing
effects. As a result, they are able to facilitate the SNAr reactions via preferential hydrogen bond
formation between the directing group and the amine nucleophile, thereby stabilizing the transition
state [7]. Furthermore, O’Reilly and co-workers have demonstrated the potential of metal ions
such as Rh3+ to increase the electrophilicity of electron-rich fluoroarenes and allow the initiation
SNAr for even weak nucleophiles [8]. The nucleophile and ‘host’ fluoroarene are coordinated to
the metal prior to nucleophilic attack.
In a recent medicinal chemistry program, we have synthesized and evaluated a large set of 4- and
5-amino-substituted perfluorophthalimide derivatives via SNAr reactions [9-11]. In most cases,
regioisomer a exerted excellent cytotoxicity in different cell lines including melanoma, leukemia,
hepatocellular carcinoma, glioblastoma at micromolar concentrations. Unfortunately, the reaction
mixtures contained predominantly the less or non-active isomer b. This required a relatively
expensive, difficult and long isolation process resulting in low isolated yields. Therefore, our goal
was to develop a regioselective and cost-efficient SNAr reaction between the privileged C4-C7
perfluorinated phatlimide core and various amines towards the active C-4 (ortho) substituted
isomers (Figure 1).
2. Results and discussion
Selected primary and secondary amines were reacted with 1 under general conditions we applied
earlier. That is, two equivalents of the corresponding amine in DCM at room temperature were
reacted to obtain preliminary data in terms of yields and isomer ratios (Scheme 1 and Table 1).
3

As expected, the desired analogues 2a–8a were detected as minor components (up to 39%
conversion by HPLC), and poor HPLC yields (6–34%) were obtained.
1
19
13
Compounds were characterized by means of H- F- C-NMR and mass-spectrometry. In
addition, the exact structures of regioisomers 4a and 4b were defined by XRD analysis (See
detailed X-Ray crystallographic data and molecular structure in the Supporting Information).
In order to investigate the effect of additives on the regioselectivity, first the possible role of
Lewis acid activators was tested. For this purpose, several salts were examined in a model SNAr
reaction between 1 and morpholine in DCM (see Supplementary Information, Table S1, Entries
1–39). Unfortunately, most of the additives did not lead to either improved isomer ratios or yields
in favour of isomer 2b. However, using iron(III)-based Lewis acids, such as FeCl3·6H2O or
Fe(NO3)3·6H2O, moderately altered ratios (2a:2b= 30:70 to 53:47) were observed. Therefore,
FeCl3·6H2O was selected for further investigations in the Lewis acid-mediated SNAr optimization
phase.
As a continuation of our study, the optimal equivalent of amine and FeCl3·6H2O were identified
(see Supplementary Information, Table S2 and S3, Entries 40–48). Employing one equivalent of
morpholine along with 50 mol% of FeCl3·6H2O in DCM gave improved selectivity for isomer 2a
(2a:2b= 68:32%). Next, we investigated the solvent effects in the model reaction in terms of
selectivity and conversion (see Supplementary Information, Table S4). Some polar-aprotic
solvents (DMSO, CH3CN and THF) and non-polar–aprotic toluene were tested besides DCM. To
our delight, toluene as solvent was proved to be an excellent reaction medium to gain good ortho
selectivity (2a:2b = 84:16%) and high conversion in favour of isomer 2a.
Then we attempted to extend these conditions by means of different amine sources (Scheme2
and Table 2). For N-methylethanolamine, a rather meager regioselectivity was detected (6a:6b=
48:52%). Moreover, no conversions were observed using 4-piperidinol (3) and thiomorpholine (7).
Presumably, the formation of 3a,3b or 7a,7b is hindered due to a unsoluble metal salt–amine
complex formed in the reaction, since the addition of few drops of water into the reaction mixture
induced the reactions (data not shown). Hence, further experiments were focused on reactions
performed in toluene–water reaction medium.
4

The synthesis of 3, 6, 7 and 8 were repeated in a toluene-water (1:1) solvent mixture without
using any additives in the first instance (Scheme 3 and Table 3). Interestingly, the toluene–water
system increased the conversion in cases of 3, 6 and 7. Surprisingly and more importantly, the
reaction of 4-piperidinol and 1 led to the exclusive formation of isomer 3a. Presumably, a hydrogen
bond is formed between the host (–C=O) and the guest (–OH), resulting in a sort of kinetic control
favouring the ortho SNAr selectivity. This observation gave a completely new direction for the
synthetic development of regioselective SNAr reactions in our model system. We hypothesized,
that if the tertiary 1,3-aminoalcohol, which is converted to a quaternary ammonium cation after
the first displacement, can serve as the leaving group, we might have control over the selectivity
through a two-stage sequential SNAr. Therefore, we turned our attention to select suitable tertiary
amines as potential leaving groups. Besides, further studies for revealing the synthetic and
theoretical aspects and background of a regioselective Fe(III)-mediated SNAr reactions are
ongoing in our laboratory.
As regards the tertiary amine-promoted selective SNAr strategy, we assumed that 1-methyl-4-
piperidinol as an 1,3-aminoalcohol promoter might be a suitable additive for influencing the
favourable regioselectivity based on our observation described earlier. Other 1,2- and 1,3-
aminoalcohols with tertiary amine moieties were also tested besides DABCO and DBU for having
a full scope. In addition, the less selective SNAr reaction, namely, the reaction of N-
ethylaminoethanol and phthalimide derivative 1 was selected for these studies (Scheme 4 and
Table 4).
The reaction of 1 with 1-methyl-4-hydroxypiperidine followed by subsequent treatment with N-
ethylethanolamine gave regioisomer 8a with 88% conversion (total conversion: 95% by HPLC).
Based on these findings, additional amines have been applied without any further optimization in
the presence of 1-methyl-4-hydroxy piperidine, and in all cases the desired 2a–8a isomers were
detected as major components with excellent regioselectivity up to 91% (Scheme 5 and Table 5).
Finally, the well-established regioselective SNAr protocol was repeated on a gram scale,
affording the desired isomers 2a–8a with isolated yields up to 63% (Figure 2).
3. Conclusion
5

In this study we presented a novel, tertiary amine-mediated highly regioselective SNAr method.
The formation of the less favoured regioisomer was facilitated in the presence of equimolar tert-
1,3-aminoalcohol. This facile protocol gave a simple and selective access to pharmacologically
relevant compounds even on a gram scale.
4. Experimental section
1H-NMR spectra were recorded on a Bruker Spectrospin 500 spectrometer. Chemical shifts (in
ppm) were referenced to tetramethylsilane (δ = 0 ppm) in CDCl3-d1 as an internal standard. 13C-
NMR spectra were obtained by using the same NMR spectrometer and were calibrated with
CDCl3-d1 (δ = 76.6 ppm). 19F-NMRspectra were obtained by using the same NMR spectrometer.
Mass spectra were recorded by Micromass ZMD spectrometer. IR spectra were recorded by Jasco
FT/IR-4700 spectrometer (ATR PRO ONE; ZnSe). Elemental analyses were performed using a
Perkin Elmer 2400 elementary analyzer. Melting points were determined by a Stuart SMP10
device, and they are uncorrected. All chemicals and solvents were of commercial grade and used
without further purification. For X-ray diffraction measurement see Supplementary Information
CCDC 1843621-1843622.
4.1. General procedure for the syntheses of compounds 2–8 for HPLC:
To a solution of 50 mg (0.13 mmol) 1 in toluene–water (1:1) (0.5 mL) was added 15 mg (0.13
mmol, 1 equiv) 1-methyl-4-hydroxypiperidine, and the reaction mixture was stirred at room
temperature for 36 hours. Then one equivalent of the corresponding amine was added, and the
reaction mixture was stirred for an additional 24 hours at room temperature. The reaction was
monitored by TLC (eluent: n-hexane:EtOAc). The mixture after complete reaction was evaporated
to dryness and prepared for the HPLC measurements for detecting regioisomeric ratios.
4.2. Gram-scale synthetic procedure for compounds 2a-8a:
To a solution of 3.0g (7.8 mmol) 1 in toluene–water mixture (1:1) (30 mL) was added 911 mg
(7.8 mmol, 1 equiv) 1-methyl-4-hydroxypiperidine, and the reaction mixture was stirred at room
temperature for 36 hours. Then one equivalent amine was added slowly, and the reaction mixture
was stirred for an additional 24 hours at room temperature. The reaction was monitored by TLC
6

(eluent: n-hexane:EtOAc 6:1). Once the reaction was completed, the mixture was diluted with
ethyl acetate (100 mL), and the organic phase was extracted with water (2 x 100 mL). The organic
phase was dried over Na2SO4, filtered and evaporated. The crude products were purified by flash
chromatography (CombiFlash, Rf Gold column).
4.2.1. 2-(2,6-Diisopropylphenyl)-4,5,6-trifluoro-7-morpholinoisoindoline-1,3-dione (2a)
Yellow solid. m.p.: 146–148°C. TLC: Rf=0.31 (hexane:EtOAc=6:1). C24H25F3N2O3. Elemental
analysis: Calcd.: C 64.56, H 5.64, N 6.27. Found: C 67.56, H 5.64, N 6.28. IR (ATR PRO ONE;
-1
ZnSe) ν = 1401, 1499, 1503, 1630, 1723, 1778, 2878, 2932, 2972 cm ; 1H NMR (500 MHz, CDCl3
with 0.03 % TMS) δ 1.17 (t, J = 6.9 Hz, 4 CH3), 2.67 (h, J = 7.3 Hz, 2 CH), 3.39–3.48 (m, 2 CH2),
3.80–3.88 (m, 2 CH2), 7.28 (d, J = 7.4 Hz, 2 ArH), 7.44 (t, J = 7.8 Hz, ArH). 13C-NMR(126 MHz,
CDCl3) δ (ppm): 23.5, 23.6, 29.0, 51.7, 51.8, 66.9, 114.2–114.4 (m), 114.6–114.9 (m), 123.7,
126.0, 130.0, 135.9 (d, J = 8.0 Hz), 140.2 (d, J = 11.6 Hz), 142.3 (d, J = 11.0 Hz), 143.3–143.7
(m), 145.4–145.8 (m), 146.2, 148.5 (dd, J = 261.1 Hz, 10.7 Hz), 162.8, 164.3. 19FNMR (471 MHz,
DMSO) δ (ppm): -133.00 (d, J = 14.1 Hz), -143.81 (dd, J = 22.6, 6.1 Hz), -147.75 (dd, J = 22.1,
16.8 Hz). MS (ESI) m/z =447 [(M+H)+].
4.2.2. 2-(2,6-Diisopropylphenyl)-4,5,7-trifluoro-6-morpholinoisoindoline-1,3-dione (2b)
Yellow solid. m.p.: 105–107°C. TLC: Rf=0.22 (hexane:EtOAc=6:1). C24H25F3N2O3. Elemental
analysis: Calcd.: C 64.56, H 5.64, N 6.27. Found: C 67.57, H 5.66, N 6.26. IR (ATR PRO ONE;
-1
ZnSe) ν = 1361, 1407, 1486, 1498, 1628, 1716, 1770, 2845, 2867, 2920, 2963 cm ; 1H NMR (500
MHz, CDCl3 with 0.03 % TMS) δ 1.17 (t, J = 6.5 Hz, 4 CH3), 2.68 (h, J = 7.2 Hz, 2 CH), 3.42–
13
3.48 (m, 2 CH2), 3.81–3.88 (m, 2 CH2), 7.28 (d, J = 7.8 Hz, 2 ArH), 7.46 (t, J = 7.6 Hz, ArH). C-
NMR (126 MHz, CDCl3) δ (ppm): 23.6, 29.0, 29.3, 50.6, 66.7, 112.9–113.3 (m), 123.6, 125.7,
130.0, 135.4–135.6 (m), 144.6–145.0 (m), 146.8, 162.7, 163.7. 19F NMR (471 MHz, DMSO) δ
(ppm): -124.12 (t, J = 14.9 Hz), -135.15–-135.88 (m), -139.79 (dd, J = 20.5, 16.1 Hz). MS (ESI)
m/z =447 [(M+H)+].
4.2.3.
2-(2,6-Diisopropylphenyl)-4,5,6-trifluoro-7-(4-hydroxypiperidin-1-yl)isoindoline-1,3-
dione (3a)
7

Yelllow solid. m.p.: 153–155°C. TLC: Rf=0.10 (hexane:EtOAc=4:1). C25H27F3N2O3. Elemental
analysis: Calcd.: C 65.21, H 5.91, N 6.08. Found: C 65.22, H 5.90, N 6.08. IR (ATR PRO ONE;
-1
ZnSe) ν = 1456, 1504, 1713, 1766, 2870, 2928, 2960, 3268 cm ; 1H NMR (500 MHz, CDCl3 with
0.03 % TMS) δ 1.17 (t, J = 7.1 Hz, 4 CH3), 1.70–1.82 (m, CH2), 1.98–2.08 (m, CH2), 2.67 (h, 2
CH), 3.31 (t, J = 10.9 Hz, CH2), 3.49–3.60 (m, CH2), 3.85–3.94 (m, CH), 7.28 (d, J = 9.7 Hz, 2
ArH), 7.44 (t, J = 7.8 Hz, ArH). 13C-NMR (126 MHz, CDCl3) δ (ppm): 23.5, 23.6, 28.9, 34.4,
49.2, 49.3, 66.7, 114.1, 114.6 (d, J = 8.0 Hz), 123.6, 126.1, 129.9, 136.6 (d, J = 8.0 Hz), 141.1 (dd,
J = 265.4 Hz, 12.5 Hz), 143.2–145.8 (m), 146.8, 149.7 (dd, J = 259.2 Hz, 10.7 Hz), 162.9, 164.4.
19F NMR (471 MHz, DMSO) δ(ppm): -132.65 (d, J = 14.5 Hz), -144.55 (dd, J = 22.6, 5.6 Hz), -
148.03 (dd, J = 22.1, 17.1 Hz). MS (ESI) m/z =461 [(M+H)+].
4.2.4.
2-(2,6-Diisopropylphenyl)-4,5,7-trifluoro-6-(4-hydroxypiperidin-1-yl)isoindoline-1,3-
dione (3b)
Pale yellow solid. m.p.: 177–179°C. TLC: Rf=0.06 (hexane:EtOAc=4:1). C25H27F3N2O3.
Elemental analysis: Calcd.: C 65.21, H 5.91, N 6.08. Found: C 65.23, H 5.90, N 6.08. IR (ATR
-1
PRO ONE; ZnSe) ν = 1483, 1701, 1758, 2853, 2910, 2960, 3236 cm ; 1H NMR (500 MHz, CDCl3
with 0.03 % TMS) δ 1.16 (d, J = 6.9 Hz, 4 CH3), 1.66–1.75 (m, CH2), 1.98–2.05 (m, CH2), 2.68
(h, 2 CH), 3.28 (t, J = 10.6 Hz, CH2), 3.57–3.65 (m, CH2), 3.89–3.98 (m, CH), 7.27 (d, J = 7.9 Hz,
2 ArH), 7.45 (t, J = 7.8 Hz, ArH). 13C-NMR(126 MHz, CDCl3) δ (ppm): 23.6, 28.9, 34.3, 48.0,
66.4, 108.4 (d, J = 10.7 Hz), 112.9 (d, J = 11.8 Hz), 123.6, 125.8, 130.0, 136.3–136.8 (m), 143.8
(dd, J = 266.4 Hz, 5.9 Hz), 146.6–146.8 (m), 146.9, 147.0–147.4 (m), 148.7–148.9 (m), 149.0–
149.9 (m), 162.9, 163.4. 19F NMR (471 MHz, DMSO) δ(ppm): -124.18 (t, J = 15.2 Hz), -136.05
(dd, J = 18.6, 17.6 Hz), -139.82 (dd, J = 20.6, 15.9 Hz). MS (ESI) m/z =461 [(M+H)+].
4.2.5. 2-(2,6-Diisopropylphenyl)-4-(ethylamino)-5,6,7-trifluoroisoindoline-1,3-dione (4a)
Orange solid. m.p.: 147–149°C. TLC: Rf=0.57 (hexane:EtOAc=6:1). C22H23F3N2O2. Elemental
analysis: Calcd.: C 65.34, H 5.73, N 6.93. Found: C 65.35, H 5.72, N 6.92. IR (ATR PRO ONE;
-1
ZnSe) ν = 1460, 1496, 1512, 1702, 1720, 1766, 1779, 2872, 2932, 2971, 3370 cm ; 1H NMR (500
MHz, CDCl3 with 0.03 % TMS) δ 1.17 (d, J = 6.8 Hz, 4 CH3), 1.32 (t, J = 7.2 Hz, CH3), 2.69 (h,
J = 6.8 Hz, 2 CH), 3.55–3.63 (m, CH2), 6.35–6.40 (m, NH), 7.28 (d, J = 7.8 Hz, 2 ArH), 7.45 (t, J
= 7.8 Hz, ArH). 13C-NMR(126 MHz, CDCl3) δ (ppm): 15.7, 23.5, 23.6, 28.9, 39.4, 39.5, 104.9 (d,
8

J = 10.0 Hz), 112.7–113.0 (m), 123.6, 125.7, 129.9, 134.9 (d, J = 10.0 Hz), 137.9 (dd, J = 263.0
Hz, 15.0 Hz), 142.6–142.9 (m), 144.2–145.0 (m), 146.3–146.8 (m), 147.0, 163.1, 168.0. 19F NMR
(471 MHz, DMSO) δ (ppm): -142.16 (d, J = 15.1 Hz), -148.55 (dd, J = 22.0, 15.7 Hz), -149.74 (t,
J = 30.6 Hz). MS (ESI) m/z =405 [(M+H)+]. The structure of the molecule was verified using
single crystal X-ray diffraction measurement.
4.2.6. 2-(2,6-Diisopropylphenyl)-5-(ethylamino)-4,6,7-trifluoroisoindoline-1,3-dione (4b)
Pale yellow solid. m.p.: 169–171°C. TLC: Rf=0.33 (hexane:EtOAc=6:1). C22H23F3N2O2.
Elemental analysis: Calcd.: C 65.34, H 5.73, N 6.93. Found: C 65.34, H 5.71, N 6.92. IR (ATR
-1
PRO ONE; ZnSe) ν = 1501, 1701, 1753, 2836, 2930, 2972, 3368 cm ; 1H NMR (500 MHz, CDCl3
with 0.03 % TMS) δ 1.17 (d, J = 6.8 Hz, 4 CH3), 1.32 (t, J = 7.2 Hz, CH3), 2.71 (m, 2 CH), 3.48–
3.83 (m, CH2), 4.39–4.58 (m, NH), 7.27 (d, J = 7.8 Hz, 2 ArH), 7.45 (t, J = 7.8 Hz, ArH). 13C-
NMR (126 MHz, CDCl3) δ (ppm): 15.8, 23.6, 28.9, 39.9, 103.4 (d, J = 11.0 Hz), 113.0 (d, J = 12.0
Hz), 123.5, 125.9, 129.9, 133.7–134.1 (m), 141.2–141.8 (m), 143.8 (dd, J = 264.0 Hz, 13.5 Hz),
19
143.3–143.8 (m), 146.9, 163.2, 163.5. F NMR (471 MHz, DMSO) δ (ppm): -133.29 (dd, J =
18.7, 15.1 Hz), -141.01 (dd, J = 20.2, 14.0 Hz), -148.82 (t, J = 20.3 Hz). MS (ESI) m/z =405
[(M+H)+]. The structure of the molecule was verified using single crystal X-ray diffraction
measurement.
4.2.7. 4-(Cyclopentylamino)-2-(2,6-diisopropylphenyl)-5,6,7-trifluoroisoindoline-1,3-dione (5a)
Yellow solid. m.p.: 118–120°C. TLC: Rf=0.69 (hexane:EtOAc=6:1). C25H27F3N2O2. Elemental
analysis: Calcd.: C 67.55, H 6.12, N 6.30. Found: C 67.52, H 6.12, N 6.31. IR (ATR PRO ONE;
ZnSe) ν= 1467, 1483, 1504, 1613, 1650, 1700, 1768, 2870, 2929, 2962, 3350 cm-1; 1H NMR (500
MHz, CDCl3 with 0.03 % TMS) δ1.17 (dd, J = 6.8 Hz, 2.2 Hz, 4 CH3), 1.54–1.71 (m, 2 CH2),
1.72–1.83 (m, CH2), 1.98–2.10 (m, CH2), 2.69 (h, 2 CH), 4.23–4.34 (m, CH), 6.43 (d, J = 7.4 Hz,
NH), 7.27 (d, J = 7.9 Hz, 2 ArH), 7.45 (t, J = 7.8 Hz, ArH). 13C-NMR (126 MHz, CDCl3) δ(ppm):
23.0, 23.5, 23.6, 28.9, 34.2, 55.9, 56.0, 105.1 (d, J = 8.0 Hz), 112.7–113.1 (m), 123.6, 125.7, 129.9,
134.5 (d, J = 9.0 Hz), 137.9 (dd, J = 263.0 Hz, 15.0 Hz), 142.3–142.8 (m), 144.1–144.8 (m), 146.2–
146.7 (m), 146.9, 163.1, 168.0. 19F NMR (471 MHz, DMSO) δ(ppm): -140.64 (d, J = 15.3 Hz), -
148.18 (dd, J = 22.0, 16.0 Hz), -148.59 (d, J = 22.2 Hz). MS (ESI) m/z =445 [(M+H)+].
4.2.8. 5-(Cyclopentylamino)-2-(2,6-diisopropylphenyl)-4,6,7-trifluoroisoindoline-1,3-dione (5b)
9

Pale yellow solid. m.p.: 164–167°C. TLC: Rf=0.45 (hexane:EtOAc=6:1). C25H27F3N2O2.
Elemental analysis: Calcd.: C 67.55, H 6.12, N 6.30. Found: C 67.54, H 6.11, N 6.29. IR (ATR
PRO ONE; ZnSe) ν= 1432, 1474, 1630, 1689, 2868, 2912, 2953, 3420 cm-1; 1H NMR (500 MHz,
CDCl3 with 0.03 % TMS) δ1.17 (d, J = 6.8 Hz, 4 CH3), 1.51–1.63(m, CH2), 1.64–1.85 (m, 2 CH2),
2.04–2.15 (m, CH2), 2.71 (h, 2 CH), 4.30–4.43 (m, NH, CH), 7.27 (d, J = 7.8 Hz, 2 ArH), 7.45 (t,
J = 7.8 Hz, ArH). 13C-NMR (126 MHz, CDCl3) δ(ppm): 23.2, 23.6, 28.9, 34.3, 56.2, 113.1 (d, J =
12.0 Hz), 123.5, 126.0, 133.4–133.7 (m), 141.1–141.4 (m), 143.1–143.5 (m), 144.7–145.0 (m),
146.9, 163.2, 163.5. 19FNMR (471 MHz, DMSO) δ(ppm): -131.74 (dd, J = 17.2, 16.2 Hz), -140.87
(dd, J = 20.4, 14.0 Hz), -147.02 (t, J = 20.2 Hz).MS (ESI) m/z =445 [(M+H)+].
4.2.9. 2-(2,6-Diisopropylphenyl)-4,5,6-trifluoro-7-((2-hydroxyethyl)(methyl)amino)isoindoline-
1,3-dione (6a)
Yelllow solid. m.p.: 127-130°C. TLC: Rf=0.18 (hexane:EtOAc=4:1). C23H25F3N2O3. Elemental
analysis: Calcd.: C 63.59, H 5.80, N 6.45. Found: C 63.57, H 5.81, N 6.46. IR (ATR PRO ONE;
-1
ZnSe) ν = 1465, 1490, 1632, 1643, 1698, 1722, 1758, 1782, 2871, 2929, 2972, 3360 cm ; 1H NMR
(500 MHz, CDCl3 with 0.03 % TMS) δ 1.15 (d, J = 6.8 Hz, 2 CH3), 1.18 (d, J = 6.8 Hz, 2 CH3),
2.65 (h, J = 6.7 Hz, 2 CH), 2.71–2.79 (m, OH), 3.06 (d, J = 1.6 Hz, CH3), 3.47 (t, J = 4.8 Hz, CH2),
3.72–3.79 (m, CH2), 7.29 (d, J = 7.7 Hz, 2 ArH), 7.46 (t, J = 7.9 Hz, ArH), 13C-NMR(126 MHz,
CDCl3) δ (ppm): 23.5, 29.0, 40.2, 40.9, 56.9, 57.0, 58.6, 123.7, 125.8, 130.1, 142.4 (dd, J = 264.0
Hz, 15.0 Hz), 144.5 (dd, J = 261.0 Hz, 15.0 Hz), 146.7, 151.4 (dd, J = 264.0 Hz, 11.0 Hz), 162.7,
165.3. MS (ESI) m/z =435 [(M+H)+].
4.2.10. 2-(2,6-Diisopropylphenyl)-4,5,7-trifluoro-6-((2-hydroxyethyl)(methyl)amino)isoindoline-
1,3-dione (6b)
Pale yellow solid. m.p.: 80-83°C. TLC: Rf=0.08 (hexane:EtOAc=4:1). C23H25F3N2O3.Elemental
analysis: Calcd.: C 63.59, H 5.80, N 6.45. Found: C 63.56, H 5.80, N 6.43. IR (ATR PRO ONE;
-1
ZnSe) ν = 1450, 1462, 1620, 1713, 1765, 2870, 2925, 2968, 3349 cm ; 1H NMR (500 MHz, CDCl3
with 0.03 % TMS) δ 1.17 (d, J = 6.9 Hz, 4 CH3), 2.22–2.51 (m, OH), 2.69 (h, J = 6.8 Hz, 2 CH),
3.13–3.16 (m, CH3), 3.51 (t, J = 5.3 Hz, CH2), 3.86 (t, J = 5.3 Hz, CH2), 7.28 (d, J = 7.8 Hz, 2
ArH), 7.46 (t, J = 7.5 Hz, ArH). 13C-NMR (126 MHz, CDCl3) δ (ppm): 23.6, 28.9, 40.4, 56.6,
59.7, 109.1 (d, J = 10.9 Hz), 112.9 (d, J = 13.2 Hz), 115.5, 123.1, 123.6, 125.6, 130.0, 136.9 (t, J
10

= 11.3 Hz), 143.7 (dd, J = 267.4 Hz, 14.7 Hz), 146.9, 148.2 (dd, J = 263.8 Hz, 5.0 Hz), 148.8 (ddd,
J = 255.2 Hz, 13.6 Hz, 5.4 Hz), 162.8, 163.4. 19F NMR (471 MHz, DMSO) δ(ppm): -123.30 (t, J
= 15.0 Hz), -135.91 (t, J = 17.8 Hz), -140.18 (dd, J = 20.0, 15.6 Hz). MS (ESI) m/z =435 [(M+H)+].
4.2.11. 2-(2,6-Diisopropylphenyl)-4,5,6-trifluoro-7-thiomorpholinoisoindoline-1,3-dione (7a)
Yellow solid. m.p.: 181–183°C. TLC: Rf=0.55 (hexane:EtOAc=6:1). C24H25F3N2O2S.Elemental
analysis: Calcd.: C 62.32, H 5.45, N 6.06. Found: C 62.34, H 5.44, N 6.08. IR (ATR PRO ONE;
-1
ZnSe) ν = 1478, 1495, 1630, 1722, 1781, 2880, 2940, 2973 cm ; 1H NMR (500 MHz, CDCl3 with
0.03 % TMS) δ 1.17 (t, J = 6.2 Hz, 4 CH3), 2.66 (h, J = 6.7 Hz, 2 CH), 2.78–2.84 (m, 2 CH2),
3.60–3.66 (m, 2 CH2), 7.28 (d, J = 7.9 Hz, 2 ArH), 7.46 (t, J = 7.6 Hz, ArH). 13C-NMR(126 MHz,
CDCl3) δ (ppm): 23.5, 23.6, 27.6, 29.0, 53.9, 54.0, 114.7 (d, J = 6.2 Hz), 115.1, 123.7, 126.0,
126.8, 129.7, 130.0, 136.7 (d, J = 6.7 Hz), 141.6 (dd, J = 265.7 Hz, 12.9 Hz), 144.5 (dt, J = 262.7
Hz, 15.6 Hz), 146.7, 150.0 (dd, J = 259.2 Hz, 10.8 Hz), 162.7, 164.2. 19FNMR (471 MHz, DMSO)
δ(ppm): -131.50 (d, J = 12.4 Hz), -143.16 (dd, J = 22.6, 7.0 Hz), -147.80 (dd, J = 21.9, 18.0 Hz).
MS (ESI) m/z =463 [(M+H)+].
4.2.12. 2-(2,6-Diisopropylphenyl)-4,5,7-trifluoro-6-thiomorpholinoisoindoline-1,3-dione (7b)
Pale yellow solid. m.p.: 145–147°C. TLC: Rf=0.43 (hexane:EtOAc=6:1). C24H25F3N2O2S.
Elemental analysis: Calcd.: C 62.32, H 5.45, N 6.06. Found: C 62.33, H 5.43, N 6.07. IR (ATR
-1
PRO ONE; ZnSe) ν = 1467, 1486, 1628, 1716, 1771, 2870, 2918, 2963 cm ; 1H NMR (500 MHz,
CDCl3 with 0.03 % TMS) δ 1.17 (t, J = 7.4 Hz, 4 CH3), 2.67 (h, J = 7.1 Hz, 2 CH), 2.75–2.82 (m,
2 CH2), 3.60–3.66 (m, 2 CH2), 7.28 (d, J = 8.2 Hz, 2 ArH), 7.45 (t, J = 7.5 Hz, ArH). 13C-NMR
(126 MHz, CDCl3) δ (ppm): 23.6, 27.6, 29.0, 29.2, 29.3, 52.7, 109.2–109.9 (m), 112.5–114.4 (m),
116.4–117.7 (m), 123.6, 125.7, 130.0, 136.0–136.6 (m), 142.6 (d, J = 12.7 Hz), 144.6–144.9 (m),
146.8, 147.1–147.7 (m), 148.8–149.1 (m), 149.4–149.8 (m), 162.6, 163.1. 19F NMR (471 MHz,
DMSO) δ(ppm): -123.49 (t, J = 14.6 Hz), -134.54 (dd, J = 20.6, 14.3 Hz), -139.68 (dd, J = 20.8,
16.5 Hz). MS (ESI) m/z =463 [(M+H)+].
4.2.13. 2-(2,6-Diisopropylphenyl)-4-(ethyl(2-hydroxyethyl)amino)-5,6,7-trifluoroisoindoline-1,3-
dione (8a)
11

Yellow semisolid. TLC: Rf=0.36 (hexane:EtOAc=4:1). C24H27F3N2O3. Elemental analysis:
Calcd.: C 64.27, H 6.07, N 6.25. Found: C 64.30, H 6.08, N 6.25. IR (ATR PRO ONE; ZnSe) ν =
-1
1460, 1496, 1512, 1641, 1655, 1703, 1720, 1766, 1780, 2852, 2872, 2930, 2971, 3369 cm ; 1H
NMR (500 MHz, CDCl3 with 0.03 % TMS) δ 1.09 (t, J = 7.1 Hz, CH3), 1.14 (d, J = 6.8 Hz, 2CH3),
1.18 (d, J = 6.8 Hz, 2 CH3), 2.58–2.69 (m, 2 CH), 2.92 (t, J = 6.4 Hz, OH), 3.34 (q, J = 7.1 Hz,
CH2), 3.45 (t, J = 4.7, CH2), 3.59–3.69 (m, CH2), 7.28 (d, J = 7.8 Hz, 2 ArH), 7.46 (t, J = 7.8 Hz,
13
ArH). C-NMR(126 MHz, CDCl3) δ (ppm): 12.8, 23.4, 23.5, 29.1, 47.3, 54.3, 58.8, 114.1, 119.6,
123.7, 125.7, 130.1, 135.6 (d, J = 8.3 Hz), 143.2 (dd, J = 270.0 Hz, 12.3 Hz), 144.4 (d, J = 264.1
Hz), 146.7, 153.0 (dd, J = 261.4 Hz, 8.6 Hz), 162.6, 165.4. MS (ESI) m/z =449 [(M+H)+].
4.2.14. 2-(2,6-Diisopropylphenyl)-5-(ethyl(2-hydroxyethyl)amino)-4,6,7-trifluoroisoindoline-1,3-
dione (8b)
Pale yellow semisolid. TLC: Rf=0.20 (hexane:EtOAc=4:1). C24H27F3N2O3. Elemental analysis:
Calcd.: C 64.27, H 6.07, N 6.25. Found: C 64.29, H 6.07, N 6.22. IR (ATR PRO ONE; ZnSe) ν =
-1
1
1466, 1487, 1620, 1714, 1768, 2870, 2928, 2963, 3348 cm ; H NMR (500 MHz, CDCl3 with
0.03 % TMS) δ 1.17 (d, J = 6.9 Hz, 4 CH3), 1.20 (t, J = 7.1 Hz, CH3), 1.78–1.98 (m, OH), 2.61–
2.76 (m, 2 CH), 3.38–3.45 (m, CH2), 3.51 (t, J = 5.1, CH2), 3.76 (t, J = 5.1 Hz, CH2), 7.28 (d, J =
7.8 Hz, 2 ArH), 7.46 (t, J = 7.8 Hz, ArH). 13C-NMR(126 MHz, CDCl3) δ (ppm): 13.0, 23.6, 28.9,
47.5, 53.8, 59.9, 110.4 (d, J = 10.6 Hz), 112.8 (d, J = 13.7 Hz), 123.6, 125.7, 130.0, 135.4 (t, J =
11.7 Hz), 143.5 (dd, J = 266.1 Hz, 15.8 Hz), 146.8, 149.5 (dd, J = 264.3 Hz, 4.3 Hz), 150.2 (ddd,
J = 257.1 Hz, 12.8 Hz, 5.5 Hz), 162.7, 163.3. 19F NMR (471 MHz, DMSO) δ(ppm): -122.59 (t, J
= 14.8 Hz), -134.58 (dd, J = 19.3, 15.7 Hz), -140.16 (dd, J = 20.2, 16.0 Hz). MS (ESI) m/z =449
[(M+H)+].
4.3. Representative gram-scale isolation method for compound 7a:
To a solution of 5.0g (13.2 mmol) 1 in toluene–water mixture (1:1) (50 mL) was added 1.52 g
(13.2 mmol, 1 equiv) 1-methyl-4-hydroxypiperidine, and the reaction mixture was stirred at room
temperature for 36 hours. Then one equivalent amine was added slowly, and the reaction mixture
was stirred for an additional 24 hours at room temperature. The reaction was monitored by TLC
(eluent: n-hexane:EtOAc 6:1). Once the reaction was completed, the mixture was diluted with
ethyl acetate (100 mL), and the organic phase was extracted with water (2 x 100 mL). The organic
12

phase was dried over Na2SO4, filtered and evaporated. The crude products were isolated by
crystallization with heptane:EtOAc mixture (5:1) to yield pure compound 7a (2.31 g, 38%)
13

References
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activated 'polar' nucleophilic aromatic substitution. A new mechanism in aromatic chemistry?,
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Kumar, C. H. Pundlik, R. Bhagat, Nonpolar Solvent a Key for Highly Regioselective SNAr
Reaction in the Case of 2,4-Difluoronitrobenzene, Org. Process Res. Dev. 18 (2014) 912-918;
c) L. Politanskaya, E. Malykhin, V. Shteingarts, The Influence of Nucleophile Substituents on
the Orientation in the Reaction between 2,4-Difluoronitrobenzene and Lithium Phenoxides in
Liquid Ammonia, Eur. J. Org. Chem. (2001) 405-411; perfluorinated system: d) G. M.
Brooke, The preparation and properties of polyfluoro aromatic and heteroaromatic
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Polyfluoroheteroaromatic Compounds, Adv. Heterocycl. Chem. 28 (1981) 1-71.
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Phosphane Ligands in Palladium-Catalyzed Amination, Angew. Chem. Int. Ed. 47 (2008)
6338-6361; b) S. L. Buchwald, C.Mauger, G. Mignani, U. Scholz, Industrial-Scale Palladium-
Catalyzed Coupling of Aryl Halides and Amines –A Personal Account, Adv. Synth. Catal.
348 (2006) 23-39; Ullman type reactions: c) F. Monnier, M. Taillefer, Catalytic C-C, C-N,
and C-O Ullmann-Type Coupling Reactions, Angew. Chem. Int. Ed. 48 (2009) 6954-6971; d)
F. Monnier, M. Taillefer, Katalytische C-C-, C-N- und C-O-Ullmann-Kupplungen, Angew.
Chem. 121 (2009) 7088-7105; e) Q. Yang, Y. Wang, L. Yang, M. Zhang, N-Arylation of
heterocycles promoted by tetraethylenepentamine in water, Tetrahedron 69 (2013) 6230-
6233; Lewis acids (nickel and zinc salts) f) S. Ge, R. A. Green, J. F. Hartwig, Controlling
First-Row Catalysts: Amination of Aryl and Heteroaryl Chlorides and Bromides with Primary
Aliphatic Amines Catalyzed by a BINAP-Ligated Single-Component Ni(0) Complex, J. Am.
Chem. Soc. 136 (2014) 1617-1627; g) L. B. Delvos, J.-M. Begouin, C. Gosmini, Zinc Base
Assisted Amination of 2-Chloropyrimidines by Aniline Derivatives at Room Temperature,
Synlett 16 (2011) 2325-2328; Z.-J. Liu, J.-P. Vors, E. R. F. Gesing, C. Bolm, Ligand-Free
Copper-Catalyzed Amination of Heteroaryl Halides with Alkyl- and Arylamines, Adv. Synth.
Catal. 352 (2010) 3158-3162; Z.-J. Liu, J.-P. Vors, E. R. F. Gesing, C. Bolm, Microwave-
assisted solvent- and ligand-free copper-catalysed cross-coupling between halopyridines and
nitrogen nucleophiles, Green Chem. 13 (2011) 42-45; h) K. Walsh, H. F. Sneddon, C. J.
14

Moody, Amination of Heteroaryl Chlorides: Palladium Catalysis or SNAr in Green Solvents?,
ChemSusChem 6 (2013) 1455-1460; i) S. Abou-Shehada, M. C. Teasdale, S. D. Bull, C. E.
Wade, J. M. J. Williams, Lewis Acid Activation of Pyridines for Nucleophilic Aromatic
Substitution and Conjugate Addition, ChemSusChem 8 (2015) 1083-1087.
[3] F. Terrier, Modern Nucleophilic Aromatic Substitution, Wiley-VCH Verlag GmbH & Co.
KGaA, DOI: 10.1002/9783527656141, ISBN: 9783527318612, 2013.
[4] selected papers for solvent effects on regioselective SNAr: (a) S. G. Ouellet, A. Bernardi, R.
Angelaud, P. D. O’Shea, Regioselective SNAr reactions of substituted difluorobenzene
derivatives: practical synthesis of fluoroaryl ethers and substituted resorcinols, Tetrahedron
Lett. 50 (2009) 3776-3779; (b) A. D. Miller, V. I. Krasnov, D. Peters, V. E. Platonov, R.
Miethchen, Perfluorozinc aromatics by direct insertion of zinc into C–F or C–Cl bonds,
Tetrahedron Lett. 41 (2000) 3817-3819; (c) M. Schlosser, T. Rausis, C. Bobbio, Rerouting
Nucleophilic Substitution from the 4-Position to the 2- or 6-Position of 2,4-Dihalopyridines
and 2,4,6-Trihalopyridines: The Solution to a Long-Standing Problem, Org. Lett. 7 (2005)
127-129.
[5] X. Wang, E. J. Salaski, D. M. Berger, D. Powell, Dramatic Effect of Solvent Hydrogen Bond
Basicity on the Regiochemistry of SNAr Reactions of Electron-Deficient Polyfluoroarenes,
Org. Lett. 11 (2009) 5662-5664.
[6] Y.-J. Shi, G. Humphrey, P. E. Maligres, R. A. Reamer, J. M. Williams, Highly Regioselective
DABCO-Catalyzed Nucleophilic Aromatic Substitution (SNAr) Reaction of Methyl 2,6-
Dichloronicotinate with Phenols, Adv. Synth. Catal. 348 (2006) 309-312.
[7] W. Qian, H. Wang, M. D. Bartberger, Accelerating Effect of Triazolyl and Related Heteroaryl
Substituents on SNAr Reactions: Evidence of Hydrogen-Bond Stabilized Transition States, J.
Am. Chem. Soc. 137 (2015) 12261-12268.
[8] M. E. O’Reilly, S. I. Johnson, R. J. Nielsen, W. A. Goddard III, T. B. Gunnoe, Transition-
Metal-Mediated Nucleophilic Aromatic Substitution with Acids, Organometallics 35 (2016)
2053-2056.
[9] L. G. Puskás, L. Z. Fehér, C. Vizler, F. Ayaydin, E. Rásó, E. Molnár, I. Magyary, I. Kanizsai,
M. Gyuris, R. Madácsi, G. Fábián, K. Farkas, P. Hegyi, F. Baska, B. Ózsvári, K. Kitajka,
Polyunsaturated fatty acids synergize with lipid droplet binding thalidomide analogs to induce
oxidative stress in cancer cells, Lipids in health and disease 9 (2010) 56.
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[10.] (a) Avicor Ltd., Compounds and composition for labeling lipid droplets, and a method for
visualization of cells and/or cellular organelles, WO2008155593A2, 24 December, 2008; (b)
Avidin Ltd., Phthalimide derivatives that influence cellular vesicular systems, pharmaceutical
compositions, and use thereof, US20100184762A1, 22 July, 2010; (c) I. S. Kaisha, H. Yuichi,
Phthalimide derivative or its salt, their production and pharmaceutical composition containing
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[11.] Avidin Ltd. Use of trifluoro phthalimides for the treatment of cancerous diseases,
WO2012085608A2, 28 June, 2012.
16

Figure 1. The regioselective outcomes of the SNAr transformation of the perfluorinated
phthalimide
17

Figure 2. The isolated bioactive ortho substituted regioisomers 2a–8a.
18

Scheme 1. The initial regioselective SNAr outcomes of 1 with primary and secondary amines
19

20

Scheme 2. Regioselective SNAr efforts with application of 50 mol% FeCl3·6H2O as catalyst
Scheme 3. SNAr study in toluene/water mixture with the unsoluble/unreactive amines
21

Scheme 4. The SNAr outcomes of 1 with N-ethylethanolamine in the presence of additives
22

Scheme 5. Utilization of 1-methyl-4-hydroxypiperidine additive in the SNAr treatments of 1
23

Table 1. SNAr transformations of 1
Isomer ratioc (%)
Compounda Amine
Conversionb (%)
a
b
2
3
4
5
6
7
8
morpholine
98
87
95
93
100
85
30
34
39
17
33
8
70
66
61
83
67
92
72
4-piperidinol
ethylamine
cyclopentylamine
N-methylethanolamine
thiomorpholine
N-ethylethanolamine
99
28
a: reaction conditions: amine (2 equiv), CH2Cl2, 24 h, r.t.; : total conversion calculated by HPLC; c: calculated by
b
HPLC.
24

Table 2. The influence of 50 mol% FeCl3·6H2O for the SNAr outcomes
Isomer ratiob (%)
Compounds
Amine
Conversiona (%)
a
b
2
3
4
5
6
7
8
morpholine
83
0
84
16
4-piperidinol
0
0
ethylamine
65
75
64
0
80
71
48
0
20
29
52
0
cyclopentylamine
N-methylethanolamine
thiomorpholine
N-ethylethanolamine
54
66
34
b
a: reaction conditions: amine (1 equiv), 50 mol% FeCl3·6H2O, toluene, 24 h, r.t.; : total conversion calculated by
c
HPLC; : calculated by HPLC
25

Table 3. The solvent effect ( toluene/water mixture) for the SNAr outcomes; without additive
Isomer ratiob (%)
Compounds
Amine
Conversiona (%)
a
b
3
6
7
8
4-piperidinol
77
68
72
91
100
0
N-methylethanolamine
thiomorpholine
81
80
51
19
20
49
N-ethylethanolamine
c
a: reaction conditions: amine (1 equiv), toluene:water 1:1, 24 h, r.t.; b: total conversion calculated by HPLC;
:
calculated by HPLC
26

Table 4. The effect of tertiary 1,2- and 1,3-aminoalcohols on the ratios of 8a and 8b
Isomer ratioc (%)
Additivea
Conversionb (%)
8a
8b
-
90
95
82
63
51
49
1-methyl-4-hydroxypiperidine
2-diethylaminoethanol
2-dimethylaminoethanol
88
58
67
12
42
33
N,N-dimethylethylamine
4-methylmorpholin
DABCO
66
65
71
95
65
72
45
33
35
28
55
67
DBU
61
61
39
b
a: using one equivalent of the corresponding additive; : total conversion calculated by HPLC; c: calculated by HPLC
27

Table 5. SNAr outcomes in the presence of 1-methyl-4-hydroxypiperidine
Conversiona
(%)
Isomer ratiosb (%)
Compounds
Amine
a
b
2
3
4
5
6
7
8
morpholine
86
81
19
4-piperidinol
100
100
89
83
79
80
89
91
88
17
21
20
11
9
ethylamine
cyclopentylamine
N-methylethanolamine
thiomorpholine
N-ethylethanolamine
91
87
91
12
b
a: reaction conditions:1-methyl-4-hydroxypiperidine (1 equiv), amine (1 equiv), toluene:water1:1, 60 h, r.t.; : total
c
conversion calculated by HPLC; : calculated by HPLC
28