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SUPPORTING INFORMATION
Design and Development of 3D Printed Catalytically-Active Stirrers for Chemical Synthesis
Matthew R. Penny[a] and Stephen T. Hilton*[a]
Abstract: In this present study, we describe the novel design, preparation and evaluation of catalyst-impregnated stirrer beads for chemical synthesis. Using a low-cost SLA 3D printer and freeware design software, a high surface area holder for a magnetic stirrer bead was developed and 3D printed containing p-toluenesulfonic acid. The devices were used to efficiently catalyze Mannich reactions in excellent yields and it was demonstrated that the devices can be re-used up to 5-times with excellent reproducibility.
[a] Dr M.R. Penny, Dr S.T. HiltonUCL School of PharmacyUniversity College London29-39 Brunswick Square, London, WC1N 1AX, United KingdomE-mail: [email protected]
Supporting information for this article is given via a link at the end of the document.
Electronic Supplementary Material (ESI) for Reaction Chemistry & Engineering.This journal is © The Royal Society of Chemistry 2020
2
Table of Contents
S1. Design and Development of Stirrer Device S2
S1.1. Design Software S2
S1.2. Device Design S2
S2. Preparation of Photopolymerisable Resin S4
S2.1. Preparation of catalyst-loaded photopolymerizable resin S4
S2.3. Device Printing and Fabrication S4
S2.4. Estimation of the amount of pTsOH content per device S4
S3.1. General Procedure for Mannich Reactions S5
S4. References S22
S1. Design and Development of Stirrer DeviceS1.1. Design Software
The stirrer bar holders and other objects were designed using the web-based freeware design program
- Tinkercad (www.tinkercad.com) which is able to export models in .STL file format for use with a 3D
printer.
S1.2. Device Design
The stirrer bar holder design was based upon a commercial overhead stirrer
(www.silverson.com/us/products/ultramix-mixers) with a large surface area which, when spun at high
speeds, would cause 1) a high flow of liquid over the surface of the stirrer and 2) high turbulence to
ensure efficient mixing. A slot to hold a 10 mm x 3 mm magnetic flea was added to the design in order
to use it with batch reactions. Stirrers were designed via combining and subtracting a range of shapes
in Tinkercad in order to create vertical columns and horizontal channels to increase mixing of the reaction
with the final design being 15 mm x 15 mm around and 9 mm high. Once combined, the shape was
exported as an STL file ready for printing.
Supplementary Figure 1. Development of Stirrer Device.
3
Initial prototypes were designed around a single stirrer bead which could be housed in the centre as
shown below (Supplementary Figure 2). Following iterative development, it was clear that in order to
catalyse a reaction, the stirrer device needed a larger surface area. The third row clearly highlights the
difference that an increased size of device can bring (Supplementary Figure 2).
Supplementary Figure 1. Development of Stirrer Device.
4
2. Preparation of Photopolymerisable Resin
S2.1. Preparation of catalyst-loaded photopolymerizable resin
Freshly ground p-toluene sulfonic acid monohydrate (5% w/v) and diphenyl(2,4,6-
trimethylbenzoyl)phosphine oxide (2% w/w) were dissolved in isobornyl acrylate (33% w/w) in the
absence of light with the aid of sonication. Trimethylolpropane triacrylate (15% w/w) and bisphenol A
ethoxylate diacrylate (50% w/w) were added and the mixture stirred for 15 hours. The
photopolymerizable resin thus prepared was then poured into the tray of a Formlabs Form 1+ SLA 3D
printer prior to printing.
S2.3. Device Printing and Fabrication
The photopolymerizable resin was poured into the tray of the Formlabs Form 1+ SLA 3D printer. The
.STL file of the model was loaded using the PreForm software for use with a Formlabs 3D printer. The
stirrer bar holders were printed with a layer height of 0.1 mm using the Clear02 resin setting. After
printing, objects were removed, soaked in isopropanol for 10 minutes and left to dry and finish curing in
natural light for 24 hours. A magnetic flea (10 mm x 3 mm) was added and to secure it, additional catalyst-
doped photopolymerizable resin added and the objects placed in natural sunlight for 24 hours to cure.
The objects were finally rinsed with isopropanol, dried and stored at room temperature prior to use.
S2.4. Estimation of the amount of pTsOH content per device
Following the printing of the stirrer bead devices, each device was weighed and the average weight
obtained, providing a total mass of 1.31 g per device. Therefore, each device can be expected to contain
0.065 g/ 0.34 mmol of pTsOH. Whilst it is difficult to estimate or quantify the amount of catalyst at the
surface, from the literature, it has been reported that the amount of surface that is exposed in a reaction
is 70 microns.1 However, this is based on a very different system, meaning that these two results are not
directly comparable. The surface area of the 3D printed stirrer device is approximately 1380 mm2 with
an overall volume of 815 mm3 before reaction and on exposure to solvent, if we assume the loss/
reactivity of the first 100 microns of the surface, this leads to an overall reduction in volume of the device
of approximately 8%. Using the w/w calculation, this equates to an overall amount of 0.005 g/ 0.027 mmol
of pTsOH available per reaction.
5
S3.1. General Procedure for Mannich Reactions
The catalytically active stirrer bar holder containing a magnetic flea was added to a 25 mL round bottom
flask along with ethanol (4 mL) and placed above a stirrer hotplate. With the stirrer at maximum speed,
benaldehyde (2 mmol), aniline (2 mmol) and ketone (3 mmol) were added successively and the reaction
was monitored by thin layer chromatography. Upon completion, the reaction was concentrated in vacuo
and the crude material purified by flash column chromatography (hexane/EtOAc) to afford the Mannich
adduct. In the case of compound 6 deionised water (8 mL) was added and the precipitate filtered off
under vacuum, washed with EtOH/H2O (2:1) and dried.
2-(Phenyl(phenylamino)methyl)cyclohexan-1-one2
According to the general procedure compound 6 was obtained as a colourless
solid (508 mg, 91%); m.p. 107-109 ºC; syn/anti 33:67; IR (thin film) max 3379, 2943,
1692, 1601, 1510, 1492 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.60-2.06 (m, 6H),
2.31-2.36 (m, 1H), 2.42-2.46 (m, 1H), 2.74-2.79 (m, 1H), 4.63 (d, J = 7.1 Hz,
0.67H), 4.69 (brs, 1H), 4.81 (d, J = 4.3 Hz 0.33H), 6.52-6.57 (m, 2H), 6.61-6.67 (m,
1H), 7.05-7.10 (m, 2H), 7.20-7.24 (m, 1H), 7.28-7.33 (m, 2H). 7.35-7.39 (m, 2H); 13C NMR (100 MHz,
CDCl3) δ (anti) 23.7, 27.9, 31.3, 41.8, 57.5, 58.0, 113.6, 117.5, 127.2, 127.3, 128.5, 129.1, 141.6, 147.2,
212.9; (syn) 24.9, 27.0, 26.7, 42.4, 56.6, 57.2, 114.1, 117.7, 127.0, 127.5, 128.4, 129.0, 141.5, 147.5,
211.3; HRMS (ESI) m/z calc for C19H22NO [M+H]+ 280.1696, found: 280.1695.
2-((4-Nitrophenyl)(phenylamino)methyl)cyclohexan-1-one3
According to the general procedure compound 18 was obtained as an orange
gum (579 mg, 89%); syn/anti 36:64; IR (thin film) max 3387, 2936, 1703,
1598, 1511, 1340 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.58-1.84 (m, 3H), 1.94-
2.04 (m, 3H), 2.30-2.48 (m, 2H), 2.84-2.88 (m, 1H), 4.59 (br. s, 0.7 H), 4.72
(d, J = 5.3 Hz, 0.3H), 4.86 (br. s, 1H), 6.50-6.52 (m, 2H), 6.86-6.71 (m, 1H),
7.07-7.11 (m, 2H), 7.53-7.60 (m, 2H), 8.14-8.18 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (anti) 25.0, 27.0,
29.1, 42.5, 56.2, 57.3, 114.1, 118.4, 123.6, 128.6, 129.2, 146.6, 149.5, 210.6; (syn) 24.5, 27.8, 32.0,
42.3, 57.1, 57.8, 113.5, 118.2, 123.7, 128.2, 129.3, 147.1, 149.8, 211.7; HRMS (ESI) m/z calc for
C19H21N2O3 [M+H]+ 325.1547, found: 325.1548.
ONH
6
ONH
O2N 18
6
2-((4-Methoxyphenyl)(phenylamino)methyl)cyclohexan-1-one4
According to the general procedure compound 19 was obtained as a
colourless solid (440 mg, 71%); syn/anti 31:69; IR (thin film) max 3359, 2935,
1658, 1591, 1555, 1505, 1247 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.55-2.09
(m, 6H), 2.27-2.48 (m, 2H), 2.69-2.80 (m, 1H), 3.78 (s, 3H), 4.60 (d, J = 7.3
Hz, 1.5H), 4.73 (d, J = 4.5 Hz, 0.5H), 6.53-6.57 (m, 2H), 6.61-6.67 (m, 1H),
6.81-6.86 (m, 2H), 7.04-7.10 (m, 2H), 7.26-7.31 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (anti) 23.5, 27.9,
31.1, 41.7, 55.2, 56.9, 57.6, 113.7, 113.9, 117.5, 128.27, 129.0, 133.6, 147.3, 158.7, 213.0; (syn) 24.8,
27.0, 29.0, 42.4, 55.2, 56.6, 57.4, 113.7, 114.1, 117.6, 128.6, 129.0, 133.4, 147.5, 158.5, 211.6; HRMS
(ASAP) m/z calc for C2-H22NO2 [M-H]- 308.1651, found: 308.1647.
2-((4-Fluorophenyl)(phenylamino)methyl)cyclohexan-1-one3
According to the general procedure compound 20 was obtained as a colourless
solid (508 mg, 85%); m.p. 111-113 ºC; syn/anti 32:68; IR (thin film) max 3376,
2951, 1690, 1602, 1506, 1224 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.57-2.08 (m,
6H), 2.31-2.45 (m, 1H), 2.40-2.45 (m, 1H), 2.71-2.81 (m, 1H), 4.61-4.76 (m,
2H), 6.50-6.55 (m, 2H), 6.63-6.69 (m, 1H), 6.96-7.02 (m, 2H), 7.06-7.11 (m,
2H), 7.32-7.37 (m, 2H); 13C NMR (100 MHz, CDCl3) δ (anti) 23.9, 27.8, 31.4, 42.0, 57.4, 57.5, 113.6,
115.3 (d, J = 21.2 Hz), 117.7, 128.8 (d, J = 8.0 Hz), 129.1, 137.4 (d, J = 2.9 Hz), 147.1, 161.9 (d, J =
245.2 Hz), 212.5; (syn) 24.9, 27.0, 29.0, 42.5, 56.5, 56.9, 114.1, 115.2 (d, J = 21.2 Hz), 117.9, 129.1,
129.1 (d, J = 8.1 Hz), 137.1 (d, J = 3.7 Hz), 147.2, 161.9 (d, J = 245.2 Hz), 211.3; HRMS (ESI) m/z calc
for C19H21FNO [M+H]+ 298.1602, found: 298.1602.
2-((4-Chlorophenyl)(phenylamino)methyl)cyclohexan-1-one5
According to the general procedure compound 21 was obtained as a
colourless oil (440 mg, 70%); syn/anti 40:60; IR (thin film) max 3398, 2938,
1704, 1602, 1502, 1316 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.58-2.06 (m, 6H),
2.25-2.35 (m, 1H), 2.37-2.43 (m, 1H), 2.70-2.79 (m, 1 H), 4.53 (brs, 0.3 H),
4.58 (d, J = 6.3 Hz, 0.7 H), 4.7 (brs, 1H), 6.48-6.52 (m, 2H), 6.61-6.67 (m, 1H),
7.04-7.09 (m, 2H), 7.23-7.26 (m, 2 H), 7.28-7.32 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 24.9, 27.0, 29.0,
29.7, 42.4, 56.4, 57.0, 114.1, 118.0, 128.5, 129.0, 132.7, 140.0, 147.1, 211.1; HRMS (ESI) m/z calc for
C19H21ClNO [M+H]+ 314.1306, found: 314.1306.
ONH
MeO 19
ONH
F 20
ONH
Cl 21
7
2-(((4-Fluorophenyl)amino)(phenyl)methyl)cyclohexan-1-one6
According to the general procedure compound 22 was obtained as a
colourless solid (502 mg, 84%); m.p. 92-94 ºC; syn/anti 29:71; IR (thin film)
max 3402, 2932, 1698, 1509, 1448, 1210 cm-1; 1H NMR (400 MHz, CDCl3) δ
1.56-2.06 (m, 6H), 2.32-2.37 (m, 1H), 2.42-2.48 (m, 1H), 2.72-2.82 (m, 1H),
4.55 (d, J = 7.3 Hz, 0.7H), 4.59 (br. s, 1H), 4.76 (d, J = 4 Hz, 0.3 H), 6.45-6.51
(m, 2H), 6.74-6.81 (m, 2H), 7.21-7.25 (m, 1H), 7.29-7.38 (m, 4H); 13C NMR (100 MHz, CHCl3) δ (syn)
24.9, 27.0, 28.4, 42.4, 56.0, 57.9, 115.1 (d, J = 8.1 Hz), 115.4 (d, J = 22.7 Hz), 127.1, 127.5, 128.5,
141.3, 143.9 (d, J = 2.2 Hz), 157.2 (d, J = 235.7 Hz), 211.5; (anti) 23.8, 28.0, 31.5, 41.9, 57.5, 58.8,
114.7 (d, J = 7.3 Hz), 115.4 (d, J = 22.7 Hz), 127.3, 127.3, 128.5, 141.5, 143.6 (d, J = 1.5 Hz), 155.5 (d,
J = 234.9 Hz), 212.9; HRMS (ESI) m/z calc for C19H21FNO [M+H]+ 298.1602, found: 298.1602.
2-(Phenyl((4-(trifluoromethyl)phenyl)amino)methyl)cyclohexan-1-one7
According to the general procedure compound 23 was obtained as a
colourless solid (415 mg, 60%); m.p. 141-142 ºC; syn/anti 53:47; IR (thin
film) max 3397, 2950, 1700, 1615, 1538, 1516, 1325 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.57-1.69 (m, 3H), 1.91-1.93 (m, 1H), 2.03-2.09 (m, 2 H), 2.29-2.37
(m, 1H), 2.42-2.47 (m, 1H), 2.80-2.85 (m, 1H), 4.83 (m, 1H), 4.92 (br. s,
0.5H), 4.94 (br. s, 0.4H), 6.56 (d, J = 8.6 Hz, 2H), 7.22-7.26 (m, 1H), 7.30-7.36 (m, 6H); 13C NMR (100
MHz, CDCl3) δ 24.8, 26.8, 28.6, 42.4, 56.2, 57.0, 113.1, 126.4, 126.4, 127.3, 127.5, 128.7, 140.6, 149.9,
211.2; HRMS (ESI) m/z calc for C20H21F3NO [M+H]+ 348.1570, found: 348.1567.
2-(Phenyl((4-(trifluoromethoxy)phenyl)amino)methyl)cyclohexan-1-one7
According to the general procedure compound 24 was obtained as a
colourless solid (632 mg, 87%); m.p. 96-97 ºC; syn/anti 53:47; IR (thin film)
max 3390, 2937, 1699, 1608, 1517, 1225, 1125 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.59-2.07 (m, 6H), 2.32-2.39 (m, 1H), 2.41-2.47 (m, 1H), 2.74-
2.81 (m, 1H), 4.56 (d, J = 7.1 Hz, 0.6H), 4.63 (br. s, 0.3H), 4.78 (d, J = 3.8
Hz, 0.4H), 4.86 (br. s, 0.6H), 6.48-6.53 (m, 2H), 1.94 (m, 2H), 7.23-7.27
(m, 1H), 7.31-7.39 (m, 4H); 13C NMR (100 MHz, CDCl3) δ (major) 23.9, 28.0, 31.6, 42.0, 57.4, 58.5,
113.9, 121.1 (q, J = 255.4 Hz), 122.2, 127.2, 127.4, 128.6, 140.5 (q, J = 2.2), 141.3, 146.1, 212.8; δ
(minor) 24.9, 27.0, 28.4, 42.4, 56.5, 57.6, 114.3, 121.1 (q, J = 255.4 Hz), 112.13, 127.22, 127.4, 128.5,
140.7 (q, J = 2.2 Hz), 141.0, 146.3, 211.3; HRMS (ESI) m/z calc for C20H21F3NO2 [M+H]+ 364.1519,
found: 364.1517.
ONH
F
22
ONH
F3C
23
ONH
F3CO
24
8
2-(((4-Chlorophenyl)amino)(phenyl)methyl)cyclohexan-1-one7
According to general procedure compound 25 was obtained as a colourless
solid (450 mg, 72%); m.p. 113-115 ºC; syn/anti 38:62; IR (thin film) max 3410,
2957, 1698, 1598, 1496, 1448 cm-1; 1H NMR (400 MHz, CDCl3) δ 1.58-2.07
(m, 6H), 2.31-2.38 (m, 1H), 2.41-2.46 (m, 1H), 2.74-2.82 (m, 1H), 4.57 (d, J =
6.7 Hz, 0.7H), 4.76 (m, 1.2H), 6.45-6.50 (m, 2H), 6.99-7.04 (m, 2H), 7.21-7.26
(m, 1H), 7.29-7.37 (m, 4H); 13C NMR (100 MHz, CDCl3) δ (syn) 24.9, 26.9, 28.5, 42.4, 56.4, 57.5, 115.2,
122.3, 127.2, 127.5, 128.5, 128.8, 141.0, 146.1, 211.3; (anti) 23.9, 27.9, 31.6, 42.0, 57.4, 58.4, 114.8,
122.1, 127.2, 127.3, 128.6, 128.9, 141.3, 145.9, 212.7; HRMS (ESI) m/z calc for C19H21ClNO [M+H]+
314.1306, found: 314.1308.
2-((4-Nitrophenyl)((4-(trifluoromethoxy)phenyl)amino)methyl)cyclohexan-1-oneAccording to the general procedure compound 26 was obtained as an orange
solid (740 mg, 91%); m.p. 125-127 ºC; syn/anti 52:48; IR (thin film) max 3422,
2944, 1710, 1608, 1512, 1345, 1250, 1200 cm-1; 1H NMR (400 MHz, CDCl3)
δ 1.59-1.81 (m, 3H), 1.94-2.09 (m, 3H), 2.30-2.49 (m, 2H), 2.84-2.88 (m, 1H),
4.65 (br.d, J = 5.1 Hz, 1H), 4.83 (br.s, 0.5H), 4.99 (br. s, 0.5 H), 6.44-6.48
(m, 2H), 6.93-6.96 (m, 2H), 7.54-7.59 (m, 2H), 8.15-8.19 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 24.6,
24.9, 27.0, 27.9, 28.8, 32.3, 42.4, 42.6, 57.0, 57.4, 58.2, 113.8, 114.4, 122.3, 122.4, 123.8, 123.8, 128.2,
128.5, 141.1, 140.9, 145.4, 145.5, 147.2, 147.2, 148.9, 149.3, 211.8, 210.6; HRMS (ESI) m/z calc for
C20H22F3N2O4 [M+H]+ 409.1370, found: 409.1367.
1,3-Diphenyl-3-(phenylamino)propan-1-one4
According to the general procedure compound 27 was obtained as a
colourless solid (314 mg, 52%); m.p. 168-170 ºC; IR (thin film) max 3; IR (thin
film) max 3383, 3023, 1668, 1596, 1509, 1492, 1288 cm-1; 1H NMR (400 MHz,
CDCl3) δ 3.48 (ddd, J = 15.1, 7.8, 5.1 Hz, 2 H), 4.56 (br. s, 1H), 5.02 (dd, J =
7.3, 5.6 Hz, 1H), 6.55-6.58 (m, 2H), 7.08-7.12 (m, 2H), 7.22-7.26 (m, 1H),
7.32-7.35 (m, 2H), 7.44-7.48 (m, 4H), 7.55-7.60 (m, 1H), 7.91-7.94 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 46.3, 54.8, 113.8, 117.8, 126.4, 127.4, 128.2, 128.7, 128.8, 129.1, 133.4, 136.7, 143.1, 147.0, 198.3;
HRMS (ESI) m/z calc for C21H20NO [M+H]+ 302.1539, found: 302.1538.
ONH
Cl
25
ONH
O2N
F3CO
26
ONH
27
9
4-Phenyl-4-(phenylamino)butan-2-one8
According to the general procedure compound 4 was obtained as a colourless solid
(310 mg, 65%); m.p. 88-89 ºC; IR (thin film) max 3368, 2934, 1706, 1602, 1511,
1493, 1280 cm-1; 1H NMR (400 MHz, CDCl3) δ 2.12 (s, 3H), 2.94 (d, J = 6.3 Hz, 2H),
4.46 (br. s, 1H), 4.86 (t, J = 6.3 Hz, 1H), 6.55-6.58 (m, 2H), 6.67-6.71 (m, 1H), 7.09-
7.13 (m, 2H), 7.23-7.27 (m, 1H), 7.32-7.40 (m, 4H); 13C NMR (100 MHz, CDCl3) δ
30.8, 51.3, 54.4, 113.8, 117.9, 126.3, 127.4, 128.8, 129.2, 142.5, 146.8, 207.2; HRMS (ESI) m/z calc for
C16H18NO [M+H]+ 240.1383, found: 240.1383.
ONH
4
10
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-2.0×106
0.0
2.0×106
4.0×106
6.0×106
8.0×106
1.0×107
1.2×107
1.4×107
1.6×107
1.8×107
2.0×107
2.2×107
2.4×107
2.6×107
2.8×107
3.0×107mp2-12-082015-5.10.1.1rSample Ref 1MRP069
6.44
1.00
1.00
1.00
1.57
0.33
1.96
0.98
1.96
0.97
1.98
2.00
1.62
1.68
1.69
1.69
1.71
1.71
1.72
1.85
1.86
1.86
1.87
1.87
1.88
1.89
1.89
1.90
1.90
1.90
1.91
1.92
1.93
2.33
2.40
2.41
2.42
2.42
4.61
4.63
4.80
4.81
6.52
6.52
6.52
6.53
6.53
6.54
6.54
6.54
6.56
6.56
6.60
6.62
6.62
6.62
6.64
6.64
6.64
7.04
7.05
7.05
7.06
7.06
7.07
7.07
7.08
7.09
7.19
7.21
7.22
7.23
7.23
7.27
7.27
7.28
7.29
7.29
7.30
7.30
7.31
7.31
7.31
7.32
7.34
7.34
7.35
7.35
7.36
7.36
7.38
7.38
7.38
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-2.0×107
0.0
2.0×107
4.0×107
6.0×107
8.0×107
1.0×108
1.2×108
1.4×108
1.6×108
1.8×108
2.0×108
2.2×108
2.4×108
2.6×108
2.8×108
3.0×108
3.2×108
mp2-12-082015-5.11.1.1rSample Ref 1MRP069
23.6
624
.87
27.0
327
.91
28.6
831
.31
41.7
942
.43
56.6
357
.25
57.5
157
.97
76.7
277
.03
77.3
5
113.
6011
4.07
117.
5111
7.69
127.
0112
7.18
127.
2612
7.53
128.
3812
8.48
129.
0212
9.07
141.
5414
1.72
147.
2214
7.48
211.
3421
2.88
ONH
6
ONH
6
11
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
-2.0×106
0.0
2.0×106
4.0×106
6.0×106
8.0×106
1.0×107
1.2×107
1.4×107
1.6×107
1.8×107
2.0×107
2.2×107
2.4×107
2.6×107
2.8×107
3.0×107mp2-11-022016-24.10.1.1rSample Ref 1MRP073
3.07
3.04
2.06
1.00
0.70
0.29
0.95
2.01
1.02
2.02
2.03
1.97
1.59
1.60
1.61
1.61
1.62
1.62
1.63
1.63
1.64
1.64
1.65
1.65
1.66
1.74
1.93
1.93
1.93
1.94
1.94
1.95
1.95
2.05
2.06
2.06
2.07
2.08
2.09
2.09
2.32
2.33
2.34
2.36
2.36
2.42
2.43
2.43
2.83
2.84
2.85
2.86
4.85
6.48
6.49
6.49
6.49
6.49
6.50
6.51
6.51
6.51
6.66
6.67
6.67
6.68
6.68
6.69
6.70
6.70
6.71
7.06
7.07
7.08
7.08
7.08
7.10
7.10
7.26
7.54
7.55
7.55
7.56
7.57
7.57
7.58
7.59
8.13
8.14
8.14
8.16
8.16
8.17
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-2.0×107
-1.0×107
0.0
1.0×107
2.0×107
3.0×107
4.0×107
5.0×107
6.0×107
7.0×107
8.0×107
9.0×107
1.0×108
1.1×108
1.2×108
1.3×108
1.4×108
1.5×108
1.6×108
1.7×108
1.8×108
1.9×108
2.0×108
2.1×108mp2-11-022016-43.10.1.1rSample Ref 1MRP073
24.5
124
.96
27.0
427
.77
29.1
332
.04
42.4
342
.47
56.2
257
.07
57.2
957
.83
76.7
0 CD
Cl3
77.0
2 CD
Cl3
77.3
4 CD
Cl3
113.
5111
4.07
118.
1511
8.43
123.
6412
3.69
128.
2512
8.62
129.
1912
9.29
146.
6414
7.13
149.
5214
9.84
210.
5821
1.72
ONH
O2N 18
ONH
O2N 18
12
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-5.0×106
0.0
5.0×106
1.0×107
1.5×107
2.0×107
2.5×107
3.0×107
3.5×107
4.0×107
4.5×107
5.0×107
5.5×107
6.0×107
6.5×107mp2-19-022016-51.10.1.1rSample Ref 1MRP080
6.16
2.01
1.00
3.00
1.50
0.46
1.96
1.00
1.98
1.99
2.87
1.61
1.61
1.62
1.64
1.65
1.66
1.67
1.68
1.68
1.69
1.70
1.72
1.83
1.84
1.84
1.85
1.86
1.86
1.87
1.88
1.88
1.89
1.90
1.90
1.91
1.92
2.29
2.32
2.32
2.34
2.39
2.41
2.42
2.43
2.69
3.77
4.58
4.60
4.72
4.73
6.51
6.52
6.52
6.52
6.53
6.54
6.54
6.54
6.55
6.56
6.56
6.60
6.62
6.62
6.62
6.64
6.64
6.64
6.66
6.81
6.82
6.83
6.83
6.84
6.85
7.04
7.04
7.05
7.06
7.06
7.07
7.07
7.07
7.08
7.09
7.25
7.26
7.27
7.28
7.29
7.29
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-1.0×107
0.0
1.0×107
2.0×107
3.0×107
4.0×107
5.0×107
6.0×107
7.0×107
8.0×107
9.0×107
1.0×108
1.1×108
1.2×108
1.3×108
1.4×108
1.5×108
1.6×108
1.7×108
1.8×108mp2-19-022016-52.10.1.1rSample Ref 1MRP080
23.5
424
.81
27.0
027
.86
29.0
131
.09
41.6
942
.44
55.1
855
.20
56.6
256
.91
57.3
957
.65
76.7
077
.02
77.3
4
113.
6711
3.74
113.
8811
4.06
117.
4811
7.61
128.
2812
8.62
129.
0012
9.03
133.
4013
3.63
147.
2614
7.51
158.
5415
8.66
211.
6021
2.99
ONH
MeO 19
ONH
O2N 18
13
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-5.0×106
0.0
5.0×106
1.0×107
1.5×107
2.0×107
2.5×107
3.0×107
3.5×107
4.0×107
4.5×107
5.0×107
5.5×107
6.0×107
mp2-21-082015-46.10.1.1rSample Ref 1MRP091
6.21
1.01
0.99
1.00
1.98
1.98
1.00
1.95
2.01
1.99
1.59
1.60
1.61
1.62
1.67
1.69
1.69
1.69
1.70
1.70
1.71
1.72
1.72
1.88
1.89
1.89
1.90
1.91
1.92
1.93
1.93
2.33
2.33
2.34
2.34
2.39
2.40
2.40
2.41
2.42
4.60
4.62
4.74
4.75
6.50
6.50
6.50
6.51
6.51
6.52
6.52
6.52
6.53
6.54
6.62
6.64
6.64
6.64
6.66
6.66
6.95
6.96
6.97
6.97
6.98
6.98
6.99
6.99
7.00
7.01
7.05
7.06
7.06
7.06
7.07
7.07
7.08
7.08
7.09
7.09
7.10
7.10
7.31
7.32
7.33
7.33
7.34
7.34
7.35
7.36
7.36
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-2.00×107
-1.00×107
0.00
1.00×107
2.00×107
3.00×107
4.00×107
5.00×107
6.00×107
7.00×107
8.00×107
9.00×107
1.00×108
1.10×108
1.20×108
1.30×108
1.40×108
1.50×108
1.60×108
1.70×108
1.80×108
1.90×108
2.00×108
2.10×108
2.20×108
2.30×108
2.40×108mp2-12-022016-39.10.1.1rSample Ref 1MRP091
23.8
924
.87
27.0
227
.85
29.0
131
.39
41.9
742
.46
56.5
056
.93
57.4
257
.49
113.
6411
4.07
115.
1011
5.21
115.
3111
5.42
117.
7011
7.87
128.
7612
8.84
129.
0612
9.11
129.
2013
7.09
137.
1313
7.43
137.
4614
7.09
147.
24
160.
6516
3.09
211.
3121
2.54
ONH
F 20
ONH
F 20
14
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-2000000
-1000000
0
1000000
2000000
3000000
4000000
5000000
6000000
7000000
8000000
9000000
10000000
11000000
12000000
13000000
14000000
15000000
16000000
17000000
18000000
19000000
20000000
21000000
22000000
23000000
24000000mp2-27-042017-3.10.1.1rSample Ref 1MRP097
6.19
1.01
1.00
1.00
0.28
0.71
0.95
1.99
1.03
2.00
1.83
2.00
1.58
1.60
1.60
1.66
1.67
1.68
1.69
1.69
1.70
1.71
1.71
1.72
1.87
1.89
1.89
1.90
1.91
1.91
1.93
1.94
2.03
2.29
2.31
2.31
2.32
2.32
2.33
2.34
2.35
2.37
2.39
2.40
2.42
2.71
2.72
2.72
2.73
2.73
4.58
4.59
4.70
6.48
6.48
6.49
6.49
6.50
6.50
6.51
6.51
6.52
6.61
6.63
6.63
6.65
6.67
7.04
7.04
7.05
7.06
7.06
7.06
7.07
7.07
7.08
7.08
7.23
7.23
7.24
7.25
7.25
7.26
7.26
7.27
7.27
7.28
7.28
7.29
7.29
7.30
7.31
7.32
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-2.0×107
-1.0×107
0.0
1.0×107
2.0×107
3.0×107
4.0×107
5.0×107
6.0×107
7.0×107
8.0×107
9.0×107
1.0×108
1.1×108
1.2×108
1.3×108
1.4×108
1.5×108
1.6×108
1.7×108
1.8×108
1.9×108mp2-01-022016-44.10.1.1rSample Ref 1MRP097
24.8
927
.00
28.9
529
.71
42.4
5
56.4
057
.00
76.7
177
.02
77.3
4
114.
09
117.
97
128.
5312
9.04
129.
0713
2.70
140.
05
147.
14
211.
14
ONH
Cl 21
ONH
Cl 21
15
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
0.0
5.0×106
1.0×107
1.5×107
2.0×107
2.5×107
mp2-12-082015-8.10.1.1rSample Ref 1MRP077
6.13
0.95
1.00
1.00
1.65
0.32
1.99
1.97
0.98
3.97
1.61
1.65
1.65
1.65
1.66
1.67
1.67
1.67
1.68
1.68
1.69
1.69
1.70
1.70
1.82
1.82
1.83
1.84
1.84
1.85
1.86
1.87
1.88
1.91
1.91
2.34
2.35
2.35
2.41
2.41
2.42
2.42
2.43
2.44
2.74
4.53
4.55
4.74
4.75
6.45
6.45
6.46
6.46
6.47
6.47
6.48
6.48
6.49
6.50
6.74
6.75
6.76
6.76
6.77
6.77
6.77
6.78
6.79
6.80
7.21
7.22
7.23
7.24
7.24
7.25
7.28
7.29
7.30
7.30
7.31
7.31
7.32
7.32
7.33
7.34
7.34
7.35
7.35
7.36
7.36
7.37
ONH
F
22
16
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-2.0×106
0.0
2.0×106
4.0×106
6.0×106
8.0×106
1.0×107
1.2×107
1.4×107
1.6×107
1.8×107
2.0×107
2.2×107
2.4×107
2.6×107
2.8×107
3.0×107
3.2×107
3.4×107mp2-12-082015-9.10.1.1rSample Ref 1MRP078
2.98
1.06
1.90
1.01
1.00
1.00
0.96
0.91
2.03
1.06
5.89
1.57
1.58
1.59
1.59
1.59
1.60
1.60
1.61
1.62
1.62
1.63
1.64
1.64
1.65
1.89
1.89
1.90
1.90
1.91
1.91
1.92
1.92
2.02
2.02
2.03
2.04
2.05
2.06
2.06
2.07
2.07
2.08
2.31
2.31
2.32
2.33
2.33
2.34
2.35
2.36
2.40
2.41
2.41
2.42
2.42
2.43
2.45
2.46
2.80
2.82
2.82
2.82
2.83
2.83
4.80
4.81
4.82
4.83
4.91
4.93
6.54
6.56
7.22
7.22
7.23
7.23
7.24
7.24
7.25
7.25
7.26
7.29
7.30
7.31
7.31
7.32
7.33
7.33
7.34
7.34
7.35
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-5.0×107
0.0
5.0×107
1.0×108
1.5×108
2.0×108
2.5×108
3.0×108
3.5×108
4.0×108
4.5×108
5.0×108
5.5×108
6.0×108
6.5×108
mp2-12-082015-9.11.1.1rSample Ref 1MRP078
24.8
326
.84
28.5
9
42.3
8
56.1
956
.99
76.7
177
.03
77.3
5
113.
07
126.
3812
6.42
127.
3512
7.45
128.
56
140.
58
149.
93
211.
19
ONH
F3C
23
ONH
F3C
23
17
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-2.0×106
0.0
2.0×106
4.0×106
6.0×106
8.0×106
1.0×107
1.2×107
1.4×107
1.6×107
1.8×107
2.0×107
2.2×107
2.4×107
2.6×107
2.8×107
3.0×107
3.2×107
3.4×107mp2-25-082015-1.10.1.1rSample Ref 1MRP092
6.19
1.01
1.00
1.00
0.67
0.29
0.38
0.58
1.97
1.95
0.96
3.96
1.60
1.61
1.66
1.67
1.68
1.69
1.69
1.70
1.71
1.72
1.84
1.85
1.85
1.86
1.86
1.87
1.88
1.88
1.89
1.89
1.90
1.90
1.91
1.91
1.92
2.34
2.34
2.35
2.35
2.36
2.36
2.40
2.41
2.41
2.42
2.43
2.43
2.43
2.45
2.75
2.75
2.76
2.76
2.77
2.77
4.54
4.56
4.77
4.78
6.47
6.48
6.49
6.50
6.51
6.51
6.91
6.92
6.93
6.94
7.22
7.23
7.24
7.24
7.25
7.26
7.30
7.30
7.30
7.31
7.31
7.32
7.32
7.33
7.34
7.34
7.35
7.36
7.36
7.37
7.38
7.38
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
-1.0×108
0.0
1.0×108
2.0×108
3.0×108
4.0×108
5.0×108
6.0×108
7.0×108
8.0×108
9.0×108
1.0×109
mp2-25-082015-34.10.1.1rSample Ref 1MRP092
23.8
824
.87
26.9
627
.96
28.3
831
.60
42.0
242
.41
56.5
357
.43
57.4
758
.45
76.7
577
.07
77.3
8
113.
8711
4.33
116.
8611
9.40
121.
9412
2.13
122.
2112
4.47
127.
2312
7.40
127.
4412
8.52
128.
6114
0.50
140.
5314
0.66
140.
6814
1.03
141.
2914
6.11
146.
31
211.
3321
2.83
ONH
F3CO
24
ONH
F3CO
24
18
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.5f1 (ppm)
-2.0×106
0.0
2.0×106
4.0×106
6.0×106
8.0×106
1.0×107
1.2×107
1.4×107
1.6×107
1.8×107
2.0×107
2.2×107
2.4×107
2.6×107
2.8×107
mp2-25-012016-2.10.1.1rSample Ref 1MRP099
6.21
1.03
0.99
1.00
0.69
1.26
1.99
1.95
0.98
3.95
1.59
1.60
1.67
1.67
1.68
1.69
1.69
1.70
1.71
1.72
1.84
1.85
1.85
1.86
1.87
1.87
1.88
1.88
1.89
1.90
1.90
1.90
1.91
1.92
1.92
1.95
2.33
2.33
2.34
2.35
2.35
2.40
2.41
2.42
2.42
2.44
2.74
2.74
2.75
2.76
2.76
4.55
4.57
4.75
4.76
6.45
6.45
6.46
6.47
6.48
6.48
6.48
6.99
7.00
7.00
7.01
7.01
7.02
7.03
7.21
7.22
7.22
7.23
7.24
7.24
7.25
7.28
7.29
7.29
7.30
7.30
7.31
7.32
7.32
7.33
7.33
7.34
7.34
7.35
7.36
7.36
-100102030405060708090100110120130140150160170180190200210f1 (ppm)
0.0
5.0×107
1.0×108
1.5×108
2.0×108
2.5×108
3.0×108
3.5×108mp2-25-012016-3.10.1.1rSample Ref 1MRP099
23.8
724
.86
26.9
327
.94
28.5
331
.55
41.9
842
.39
56.4
357
.39
57.4
858
.35
76.7
577
.07
77.3
9
114.
8011
5.23
122.
1312
2.31
127.
1912
7.23
127.
3412
7.49
128.
4712
8.57
128.
8512
8.89
141.
0314
1.30
145.
9214
6.11
211.
2821
2.71
ONH
Cl
25
ONH
Cl
25
19
0.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.59.0f1 (ppm)
0.0
5.0×106
1.0×107
1.5×107
2.0×107
2.5×107
3.0×107
3.5×107
4.0×107
4.5×107mp2-12-022016-38.10.1.1rSample Ref 1MRP094
3.23
3.04
2.01
1.00
0.98
0.45
0.56
2.00
1.98
2.00
1.97
1.59
1.60
1.61
1.62
1.62
1.63
1.72
1.73
1.73
1.74
1.74
1.75
1.76
1.76
1.93
1.94
1.94
1.94
1.95
1.99
2.00
2.02
2.03
2.03
2.04
2.04
2.05
2.05
2.06
2.06
2.07
2.08
2.33
2.33
2.35
2.36
2.38
2.39
2.39
2.42
2.43
2.44
2.83
2.84
2.86
2.87
4.63
4.65
4.81
4.82
6.43
6.44
6.45
6.46
6.46
6.47
6.91
6.92
6.92
6.93
6.93
6.94
6.94
6.95
6.95
7.26
7.53
7.54
7.54
7.55
7.55
7.56
7.57
7.57
8.14
8.15
8.15
8.16
8.17
8.17
8.18
102030405060708090100110120130140150160170180190200210f1 (ppm)
-5.0×107
0.0
5.0×107
1.0×108
1.5×108
2.0×108
2.5×108
3.0×108
3.5×108
4.0×108
4.5×108
5.0×108
5.5×108
6.0×108
mp2-25-082015-35.10.1.1rSample Ref 1MRP094
24.6
424
.94
26.9
827
.85
28.8
232
.31
42.4
442
.59
56.1
256
.99
57.4
458
.24
76.7
277
.03
77.3
5
113.
7911
4.37
116.
7911
9.33
121.
8712
2.32
122.
4412
3.79
123.
8212
4.41
128.
2112
8.55
140.
8914
0.91
141.
1314
1.15
145.
4414
5.50
147.
1814
7.25
148.
9214
9.29
210.
6121
1.82
ONH
O2N
F3CO
26
ONH
O2N
F3CO
26
20
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.08.5f1 (ppm)
0.0
5.0×106
1.0×107
1.5×107
2.0×107
2.5×107
3.0×107
3.5×107
4.0×107
mp2-12-082015-44.10.1.1rSample Ref 1MRP079
1.01
1.03
0.96
1.00
1.96
1.00
1.97
1.09
1.98
3.94
0.99
1.97
1.55
3.39
3.41
3.43
3.45
3.49
3.50
3.53
3.54
4.55
4.99
5.00
5.01
5.02
6.55
6.55
6.55
6.56
6.57
6.57
6.57
6.58
6.64
6.64
6.65
6.66
6.66
6.66
6.68
6.68
6.68
7.07
7.07
7.08
7.09
7.09
7.10
7.10
7.11
7.22
7.23
7.23
7.24
7.25
7.25
7.26
7.26
7.31
7.31
7.32
7.33
7.33
7.34
7.34
7.35
7.42
7.43
7.43
7.44
7.44
7.45
7.45
7.45
7.46
7.46
7.47
7.54
7.55
7.55
7.56
7.56
7.57
7.58
7.58
7.59
7.90
7.90
7.91
7.92
7.92
7.92
102030405060708090100110120130140150160170180190200210f1 (ppm)
-2.0×107
0.0
2.0×107
4.0×107
6.0×107
8.0×107
1.0×108
1.2×108
1.4×108
1.6×108
1.8×108
2.0×108
2.2×108
2.4×108
2.6×108
2.8×108
3.0×108
3.2×108
3.4×108mp2-12-082015-44.11.1.1rSample Ref 1MRP079
46.3
2
54.8
0
76.7
177
.03
77.3
5
113.
81
117.
78
126.
3812
7.37
128.
2212
8.71
128.
8412
9.11
133.
4513
6.68
142.
98
146.
98
198.
27
ONH
27
ONH
27
21
0.00.51.01.52.02.53.03.54.04.55.05.56.06.57.07.58.0f1 (ppm)
-1.0×107
0.0
1.0×107
2.0×107
3.0×107
4.0×107
5.0×107
6.0×107
7.0×107
8.0×107
9.0×107
1.0×108
1.1×108
1.2×108
1.3×108mp2-12-082015-43.10.1.1rSample Ref 1MRP075
2.83
1.91
0.94
1.00
1.90
0.99
1.94
1.33
3.82
2.11
2.92
2.94
4.44
4.84
4.85
4.87
6.54
6.54
6.55
6.55
6.56
6.56
6.57
6.57
6.65
6.66
6.66
6.67
6.67
6.68
6.69
6.69
6.70
7.08
7.08
7.09
7.09
7.10
7.10
7.11
7.12
7.12
7.13
7.22
7.22
7.23
7.24
7.24
7.25
7.26
7.26
7.26
7.28
7.31
7.31
7.32
7.33
7.33
7.34
7.34
7.35
7.36
7.36
7.36
7.37
7.38
7.38
7.38
102030405060708090100110120130140150160170180190200210f1 (ppm)
-2.0×107
0.0
2.0×107
4.0×107
6.0×107
8.0×107
1.0×108
1.2×108
1.4×108
1.6×108
1.8×108
2.0×108
2.2×108
2.4×108
2.6×108
2.8×108
3.0×108
3.2×108
mp2-12-082015-43.11.1.1rSample Ref 1MRP075
30.7
7
51.2
5
54.3
7
76.7
377
.05
77.3
7
113.
75
117.
86
126.
2812
7.39
128.
8312
9.16
142.
49
146.
78
207.
18
ONH
4
ONH
4
22
S4. References
[1] J. S. Manzano, Z. B. Weinstien, A. S. Sadow, I. I. Slowing, ACS Catal. 2017, 7, 7567-7577.[2] M. Bandini, P. G. Cozzi, M. Giacomini, P. Melchiorre, S. Selva, A. Umani-Ronchi, J. Org. Chem. 2002, 67, 3700-3704[3] A. Pettignano, L. Bernardi, M. Fochi, L. Geraci, M. Robitzer, N. Tanchoux, F. Quignard, New. J. Chem. 2015, 39, 4222-4226[4] N. Tanaka, Y. Masaki, Synlett 2000, 406-408[5] B. C. Ranu, S. Samanta, S. K. Guchhait, Tetrahedron, 2002, 58, 983-988[6] S. Sukumari, I. A. Azath, K. Pitchumani, Synlett 2012, 23, 2328-2332[7] A. Yanagisawa, Y. Lin, R. Miyake, K. Yoshida, Org. Lett. 2014, 16, 86-89[8] X-D. Jia, X-E. Wang, C-X. Yang, C-D. Huo, W-J. Wang, Y. Ren, X-C. Wang, Org. Lett. 2010, 12, 732-735
Author Contributions
Dr Matthew R. Penny – Device design and chemical reactions, Dr Stephen T. Hilton - funding acquisition, project administration, writing of original draft with equal contribution.
