Accessing simply-substituted 4-hydroxytetrahydroisoquinolines via Pomeranz-Fritsch-Bobbitt reaction with non-activated and moderately-activated systems

Article abstract of DOI:10.3762/bjoc.13.182

Background: 1,2,3,4-Tetrahydroisoquinolines (THIQs) are common motifs in alkaloids and in medicinal chemistry. Synthetic access to THIQs via the Pomeranz-Fritsch-Bobbit (PFB) methodology using mineral acids for deactivated, electron-poor aromatic systems, is scarcely represented in the literature. Here, the factors controlling the regiochemical outcome of cyclization are evaluated. Results: A double reductive alkylation was telescoped into a one-pot reaction delivering good to excellent yields of desired aminoacetals for cyclization. Cyclization of activated systems proceeded smoothly under standard PFB conditions, but for non-activated systems the use of HClO₄ alone was effective. When cyclization was possible in both para- and ortho-positions to the substituent, 7-substituted derivatives were formed with significant amounts of 5-substituted byproduct. The formation of the 4-hydroxy-THIQs vs the 4-methoxy-THIQ products could be controlled through modification of the reaction concentration. In addition, while a highly-activated system exclusively cyclized to the indole, this seems generally highly disfavored. When competition between 6-and 7-ring formation was investigated in non-activated systems, 5,7,8,13-tetrahydro-6,13-methanodibenzo[c,f]azonine was exclusively obtained. Furthermore, selective ring closure in the para-position could be achieved under standard PFB conditions, while a double ring closure could be obtained utilizing HClO₄. Conclusion: Reactivity differences in aminoacetal precursors can be employed to control cyclization using the PFB methodology. It is now possible to select confidently the right conditions for the synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.

Full text of DOI:10.3762/bjoc.13.182

Accessing simply-substituted 4-hydroxytetrahydroisoquino-
lines via Pomeranz–Fritsch–Bobbitt reaction with
non-activated and moderately-activated systems
Marco Mottinelli1,§, Mathew P. Leese1 and Barry V. L. Potter*1,2
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1871–1878.
1Wolfson Laboratory of Medicinal Chemistry, Department of
Pharmacy and Pharmacology, University of Bath, Claverton Down,
BA2 7AY Bath, UK and 2Drug Discovery & Medicinal Chemistry,
Department of Pharmacology, University of Oxford, Mansfield Road,
Oxford, OX1 3QT, UK
doi:10.3762/bjoc.13.182
Received: 09 June 2017
Accepted: 17 August 2017
Published: 06 September 2017
Email:
Associate Editor: I. R. Baxendale
Barry V. L. Potter* - barry.potter@pharm.ox.ac.uk
© 2017 Mottinelli et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
§ Present affiliation: Department of Medicinal Chemistry, School of
Pharmacy, University of Florida, 1345 Center Drive, Gainesville,
Florida, 32611, USA
Keywords:
cyclization; Pomeranz–Fritsch; steroidomimetic; synthesis;
tetrahydroisoquinoline
Abstract
Background: 1,2,3,4-Tetrahydroisoquinolines (THIQs) are common motifs in alkaloids and in medicinal chemistry. Synthetic
access to THIQs via the Pomeranz–Fritsch–Bobbit (PFB) methodology using mineral acids for deactivated, electron-poor aromatic
systems, is scarcely represented in the literature. Here, the factors controlling the regiochemical outcome of cyclization are evalu-
ated.
Results: A double reductive alkylation was telescoped into a one-pot reaction delivering good to excellent yields of desired
aminoacetals for cyclization. Cyclization of activated systems proceeded smoothly under standard PFB conditions, but for non-acti-
vated systems the use of HClO4 alone was effective. When cyclization was possible in both para- and ortho-positions to the substit-
uent, 7-substituted derivatives were formed with significant amounts of 5-substituted byproduct. The formation of the 4-hydroxy-
THIQs vs the 4-methoxy-THIQ products could be controlled through modification of the reaction concentration. In addition, while
a highly-activated system exclusively cyclized to the indole, this seems generally highly disfavored. When competition between 6-
and 7-ring formation was investigated in non-activated systems, 5,7,8,13-tetrahydro-6,13-methanodibenzo[c,f]azonine was exclu-
sively obtained. Furthermore, selective ring closure in the para-position could be achieved under standard PFB conditions, while a
double ring closure could be obtained utilizing HClO4.
Conclusion: Reactivity differences in aminoacetal precursors can be employed to control cyclization using the PFB methodology.
It is now possible to select confidently the right conditions for the synthesis of N-aryl-4-hydroxy-1,2,3,4-tetrahydroisoquinolines.
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Introduction
1,2,3,4-Tetrahydroisoquinoline (THIQ) motifs are present in
many natural alkaloids [1]. THIQ derivatives have also been in-
vestigated as potential therapeutics in a wide range of diseases
and recent studies have explored their potential as steroido-
mimetics [2-5]. Given the success of these authors in designing
highly potent non-steroidal chimeric microtubule disruptors
based upon decorated THIQ-based mimics of the steroidal AB
ring system that possess pendant N-substituents [2], robust
routes to direct N-aryl substituted THIQs were targeted for
related activities (Figure 1).
Isoquinolines can be obtained from benzaldehyde and 2,2-
diethoxyethylamine under Pomeranz–Fritsch (PF) reaction
conditions (Scheme 1), as first reported in 1893 [6,7]. A modifi-
cation of the classic reaction reported by Bobbitt allows access
to THIQ analogues (Scheme 1) [8-10]. Later, research has prin-
Scheme 1: Pomeranz–Fritsch and Pomeranz–Fritsch–Bobbitt reac-
tions. Conditions: (a) conc. H2SO4; (b) benzene, ∆, Dean–Stark then
Raney Ni, H2, 50 psi, EtOH; (c) conc. HCl, Δ.
cipally focused on the asymmetric THIQ synthesis and a sub- effects of the substituents on the electron density of the aromat-
stantial number of approaches to this end have been reported in ic ring in intermediate 4.
the literature [1,11-14]. Notwithstanding this, application of the
Bobbitt modification of the Pomeranz–Fritsch reaction, or Given our established interest in exploring structural mimetics
Pomeranz–Fritsch–Bobbit (PFB), as an approach to simply- for the steroid nucleus we were drawn to explore whether the
substituted THIQs has been somewhat neglected. In fact, most PFB reaction could be used to access libraries of regioisomeric
literature reports of cyclization under PFB conditions have N-aryl-1,2,3,4-tetrahydroisoquinoline derivatives that might
concerned strongly-activated aromatic systems [8-12,15-18] facilitate the design of new structural templates for steroid-
with a few examples of cyclization of deactivated, electron-defi- binding receptors. We thus evaluated the robustness and flexi-
cient, aromatic systems [19] in the presence of mineral acids. bility of this approach to the THIQ system and considered, in
Synthetic approaches to electron poor systems more often particular, the factors controlling the regiochemical outcome of
involve different chemistries [20].
the reaction to direct synthetic design. Reaction conditions of
the PFB methodology and opportune modifications necessary to
The PFB reaction proceeds via reduction of an intermediate direct such reactions towards the synthesis of the desired THIQ
iminoacetal to provide an aminoacetal that is then cyclized derivatives are reported here.
and reduced to deliver the 1,2,3,4-tetrahydroisoquinoline
product. Relative to the original Pomeranz–Fritsch conditions, Results and Discussion
the Bobbitt modification features a reduced acid concentration To address aforementioned aims, we envisaged that the synthe-
that advantageously reduces the formation of side products sis set out in Scheme 2 could deliver access to substrates for the
[8-10].
PFB reaction such as 9. After an initial, unfruitful, attempt to
obtain the aminoacetals 9 from sequential condensation of
The key cyclization in the PFB synthesis reaction is an electro- aniline and alkyl and aryl halides, a double reductive alkylation
philic aromatic substitution that is strongly impacted by the that could be telescoped into a one-pot reaction was investigat-
Figure 1: Non-steroidal templates from estradiol.
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Beilstein J. Org. Chem. 2017, 13, 1871–1878.
Scheme 2: Designed synthesis of THIQ. Conditions: (a) NaBH(OAc)3, CHCl3, rt; (b) 6 M HCl or 70% HClO4 (see Table 1), rt.
ed. This reaction proceeded to deliver good to excellent yields
of the desired aminoacetals 9a–g,i–p accompanied by only a
small amount of side products (Table 1).
As an exception to the above, the acetal 9h did not form, which
could be attributed to the poor solubility of the intermediate
benzylated aniline. In addition, the reaction of 3,4-dimethoxy-
aniline under the same conditions did not afford 9q and instead
11 was the sole isolable reaction product (62% yield
(Scheme 3)). The reaction was reproducible and proceeded even
in the absence of a reducing agent (NaBH(OAc)3). The prefer-
ential formation of 11 relative to imine reduction, even in the
presence of an excess of reducing agent, suggests a rapid intra-
molecular rearrangement of an iminium derivative 12 to the
highly activated ortho-position of the aromatic ring. The
possible rearrangement product 13 would then lead to the isolat-
ed compound 11 upon hydration, either during the reaction or
the work-up. However, the precise mechanism for the forma-
tion of 11 has yet to be explored and efforts to unravel it lay
outside the scope of this work.
Scheme 3: Side reaction during the double alkylation of 7 and possible
reaction mechanism for the formation of 11. Conditions: (a)
NaBH(OAc)3, CHCl3, rt; (b) 2,2-dimethoxyacetaldehyde, NaBH(OAc)3,
rt.
The addition of 6 M HCl led to the cyclization of the 3-MeO
compound 9f, that bears an electron-donating group in a posi- As previously mentioned, cyclization with activated systems,
tion para- to the cyclization point. However, the same condi- such as the one for compound 9f, proceeds smoothly with 6 M
tions were unable to catalyze the cyclization of 4-MeO com- HCl, whereas the stronger acids H2SO4 and HClO4 triggered
pound 9b. We thus decided to proceed with an initial screen of the degradation of the starting material (Table 2). In contrast,
acids for cyclization of non-activated compounds (Table 2).
for a non-activated system, e.g., 9b, HClO4 was the only acid
Table 1: Double reductive alkylation.
Cmpd
R1
R2
Yield (%)
Cmpd
R1
R2
Yield (%)
9a
9b
9c
9d
9e
9f
H
H
99
69
88
90
54
79
90
–
9j
4-OH
4-OMe
4-Cl
90
66
91
98
96
73
85
–
4-OMe
4-Cl
H
9k
9l
4-OH
H
3,4-(OMe)2
4-OMe
4-OMe
4-Cl
4-OH
3-Br
H
9m
9n
9o
9p
9q
3,4,5-(OMe)3
H
2-OMe
3-OMe
3-OMe
4-OH
4-OH
H
H
H
H
3-OMe
3,4,5-(OMe)3
3,5-(OMe)2
9g
9h
9i
4-Cl
4-OH
4-Me
94
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Beilstein J. Org. Chem. 2017, 13, 1871–1878.
THIQs (e.g., 10e–g, Scheme 4) were obtained as the major
product. Nevertheless, it was possible to isolate a usable amount
of the 5-substituted THIQ 14e. The ratio of the two regio-
isomers proved to be fairly constant, ranging from 5:1 to 4:1 for
the three compounds considered. However, when more than one
substituent was present, i.e., 9l, only compound 10l formed and
the alternative product 14l was not observed.
Table 2: Screening of the acidic catalyst for the PFB reaction.
SM
Acid (conc.)
pKaa
SMb (%)
P (%)
9f
HCl (6 M)
HCl (36%)
H2SO4 (97%)
TFA
−8.0c
−8.0c
−3.0c
−0.25c
−10.0c
−8.0c
−8.0c
−8.0c
−3.0c
−0.25c
−10.0c
0
Q
9f
0
Q
9f
0
0d
0
9f
100
0
9f
HClO4 (70%)
HCl (6 M)
HCl (6 M)
HCl (36%)
H2SO4 (97%)
TFA
0d
0e
0g
0g
0d
0
9b
9bf
9b
9b
9b
9b
0
A kinetic NMR study was performed by running a sample reac-
tion directly in an NMR tube. However, the strongly ionic envi-
ronment did not allow for a sufficient resolution of the NMR
spectra and instead only extremely broad and convoluted peaks
were observed. The kinetic study was then repeated by
sampling the reaction at regular intervals, showing an almost
instant hydrolysis of the acetal 9l to give the corresponding
aldehyde followed by its rapid conversion into THIQ 10l within
the first ten minutes of the reaction.
0
0
0
100
0
HClO4 (70%)
Q
SM (starting material), P (product), Q (quantitative); apKa refers to the
acid catalyst used in the reaction; bThe reaction was monitored by
LC–MS and the same method was used to calculate the percentage of
conversion. cpKa measured in water [21]. dDegraded to unknown com-
pound. eHemiacetal formed. fReaction was performed in a microwave
at 100 °C for 30 min. gThe was aldehyde formed.
Despite the indication that the reaction proceeded through an
initial complete conversion of the acetal to the aldehyde, in
able to deliver the desired THIQ 10b. However, in the presence certain cases the formation of the ethers 15 was identified
of a deactivating, ortho/para-directing group, such as chlorine (Scheme 5). The formation of the two derivatives could be con-
(9c) or bromine (9e), HClO4 afforded the desired cyclized prod- trolled through changes in the reaction concentration (Table 3).
uct only in the position directed by the substituent. In addition, When 9f was dissolved in sufficient 6 M HCl necessary to
even HClO4 failed to catalyze the cyclization of 2-MeO com- provide a 1 M solution of the acetal, the main product obtained
pound 9n, rendering the target THIQ 10n inaccessible by this was the 4-hydroxy-THIQ. However, when 70% HClO4 was
approach.
used, the ratio between the 4-hydroxy and 4-methoxy-THIQs
varied from ca. 1:1 to approaching 1:0, depending on the con-
In certain cases, during scale-up of the reaction to a gram scale, centration of starting material in the reaction mixture. Ulti-
a minor product became clearly identifiable and could some- mately, it was postulated that the ratio between formation of the
times be isolated. Whenever the cyclization was possible in ether and the alcohol is most likely a function of the water
both the para- and the ortho-position to the substituent, as ex- content of the reaction mixture. An acetal concentration of
pected, the para-position predominated and the 7-substituted 0.3 M proved optimal to minimize the ether formation.
Scheme 4: Competition between the formation of 5- and 7-substituted THIQs. Conditions: (a) 6 M HCl, rt.
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Beilstein J. Org. Chem. 2017, 13, 1871–1878.
Scheme 5: Formation of the 4-hydroxy and 4-methoxy-THIQs. Conditions: (a) 6 M HCl or 70% HClO4, rt (see Table 3).
We then decided to expand our analysis to include competition
between 6- and 7-membered ring formation. Compound 18
(Scheme 7) was generated via a double reductive amination, in
analogy to the syntheses of compounds 9a–q. Because none of
the aromatic rings contained any activating group, the cycliza-
tion was performed with 70% HClO4 as catalyst. However, in
the experimental conditions used it was not possible to isolate
either compound 19 or 20 (Scheme 7). Instead, the reaction
proceeded to give complete conversion of 18 into the doubly-
cyclized 21. Hence, the experimental conditions used did not
allow to discriminate between 6- and 7-membered ring forma-
tion.
Table 3: Ratio between the formation of 10d,f,i,j,k and 15d,f,i,j,k at
different reaction concentrations.
SM
Conc. (M)
Products
Ratioa
9db
9db
9fc
0.9
0.3
1.0
0.7
0.8
0.9
10d + 15d
10d + 15d
10f + 15f
10i + 15i
10j + 15j
10k + 15k
2:1
1:0
5:1
1:1
1:1
1:1
9ib
9jb
9kb
aMolar ratios 10d,f,i–k vs 15d,f,i–k were calculated by 1H NMR spec-
troscopy of the crude reaction mixtures. bReaction was performed with
70% HClO4. cReaction was performed with 6 M HCl.
Lastly, we investigated potential competition between ring for-
mation in para- or meta-position to an activating group such as
The PF reaction conditions could possibly lead to a competition a methoxy group, when both were possible. For this, compound
between 6-membered and 5-membered ring formation in 22 (Scheme 8) was synthesized via a double reductive amina-
systems such as 9a,o,p (Scheme 6). For this study, compounds tion, as per synthesis of 9a–q. As expected, when the precursor
bearing a different number of methoxy groups were selected in was treated with 6 M HCl, the cyclization occurred only in the
order to understand the electronic constrains that might render para-position. However, when 70% HClO4 was used, com-
indole formation competitive. Upon treatment with 70% pound 22 afforded exclusively the double ring-closed product
HClO4, acetals 9a and 9o yielded the respective THIQs 10a and 25 (Scheme 8), analogous to 21. Presumably, in this case the
10o. However, the highly-activated acetal 9p exclusively six-membered ring para-cyclization may occur first followed
cyclized into the indole 16p. It is thus possible to infer that by that directed by the six ring meta-position. Therefore, under
indole formation is highly disfavored and only the presence of a our experimental conditions it was possible to obtain selec-
great number of activating groups can make this outcome tively the desired mono-cyclized product solely when this
competitive.
contained the activating group in the para-position.
Scheme 6: Competition between the formation of THIQs 10a,o,p and indoles 16a,o,p. Conditions: (a) 70% HClO4, rt.
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Beilstein J. Org. Chem. 2017, 13, 1871–1878.
Scheme 7: Competition between 6- and 7-membered ring formation. Conditions: (a) NaBH(OAc)3, CHCl3, rt; (b) 2,2-dimethoxyacetaldehyde,
NaBH(OAc)3, rt; (c) 70% HClO4, rt.
Scheme 8: Competition between ring formation para- or meta- to an activating group. Conditions: (a) NaBH(OAc)3, CHCl3, rt; (b) 4-methoxybenzalde-
hyde, NaBH(OAc)3, rt; (c) 70% HClO4, rt; (d) 6 M HCl, rt.
Conclusion
uct may be identified and its formation could be controlled by
The classical PFB conditions could be used successfully when modifying the concentration of the starting material in the reac-
at least one activating group was present in a position para to tion media. In summary, the reported findings reveal the possi-
the cyclization point. When the substitution position was not bility to select confidently the appropriate conditions to synthe-
para or the group was not an electron-donating group, the PFB size the desired N-aryl-4-hydroxy-1,2,3,4-tetrahydroiso-
conditions were not successful and the target THIQ could be quinolines and derivatives to be explored as steroidomimetics in
obtained only with the use of 70% HClO4 as a catalyst. This medicinal chemistry. Further investigation is currently being
difference in reactivity could be exploited to control the cycliza- conducted and the findings will be reported upon their availabil-
tion point when both conditions were present, e.g., compound ity.
22. In addition, in more simply substituted substrates, e.g.,
Experimental
9e–g, the formation of both 5- and 7-THIQs was observed in a
somewhat constant ratio. This was not observed for compounds Materials and methods
bearing more than one substituent. We noticed a strong prefer- All chemicals were purchased from Aldrich Chemical Co. or
ence for the 6-membered ring formation over the 5-membered Alfa Aesar. Organic solvents of A. R. grade were supplied by
ring, and the latter formed only in a greatly activated system. Fisher Scientific. Thin-layer chromatography (TLC) was per-
Conversely, no preference between 6- and 7-membered ring formed on precoated plates (Merck TLC aluminum sheets silica
formation was observed. In addition, a 4-MeO-THIQ side prod- gel 60 F254). Product(s) and starting material(s) were detected
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Beilstein J. Org. Chem. 2017, 13, 1871–1878.
by either TLC and/or LC–MS. Flash column chromatography 1.81 min (87%), m/z 226.0 (M + H)+; HRMS (ES+): (M + H)+
was performed on RediSep® prepacked columns (normal phase calcd. for C17H22NO2, 272.1645; found, 272.1651.
and reversed phase) with an Isco CombiFlash® Rf. NMR
General method for the PF cyclization with
(400 MHz or 500 MHz) spectra were recorded with Bruker
AMX systems and chemical shifts are reported in parts per HClO4 (method A)
million (ppm). HPLC and low-resolution mass spectra analyses Compound 9a (3.0 g, 11.1 mmol) was dissolved in 70% HClO4
were obtained on a Waters Micromass ZQ equipped with a (33 mL) and stirred for 1 h at rt. The mixture was then diluted
Waters 996 PDA detector using either a Waters Radialpack C18 with water (30 mL) and basified by carefully pouring the
reversed-phase column (8 × 100 mm), or a Symmetry C18 mixture over Na2CO3. The aq layer was then extracted with
reversed-phase column (4.6 × 150 mm) eluting with the solvent EtOAc (3 × 30 mL) and the combined organic layers were dried
system specified at 1.0 mL/min. High-resolution mass spectra with MgSO4, filtered and evaporated to give a brown foam
(HRMS) were recorded at the Mass Spectrometry Service (2.97 g).
Centre, University of Bath, on a Bruker microTOF. Melting
General method for the PF cyclization with
HCl (method B)
points were determined using an Optimelt block and are uncor-
rected.
Compound 9f (500 mg, 1.66 mmol) was dissolved in 6 M HCl
2,2-Dimethoxyacetaldehyde was purchased as an aqueous solu- (2 mL) and stirred at rt for 1 h during which time the mixture
tion and was extracted in CHCl3 before use. Petroleum ether turned red. The reaction mixture was cooled to 0 °C and then
(pet. ether) used for chromatography was the 40–60 °C distil- quenched by the slow addition of aq 3 M NaOH (10 mL) (a
late. The general procedures were followed unless indicated white suspension with a yellow precipitate formed). The mix-
otherwise. Some representative examples of spectroscopic data ture was then extracted with EtOAc (3 × 20 mL). The organic
are reported below. The complete sets of data are reported in layer was dried with MgSO4, filtered and evaporated to give a
Supporting Information File 1.
yellow-brown oil (445 mg).
General method for the double reductive
amination reaction
2-Phenyl-1,2,3,4-tetrahydroisoquinolin-4-ol (10a). The com-
pound was synthesized according to method A. A sample of the
NaBH(OAc)3 (3.3 g, 15 mmol) was added to a stirring solution crude compound was purified by column chromatography
of benzaldehyde (1.0 mL, 10 mmol) and aniline (1.1 mL, (eluent: from 0% to 10% EtOAc in pet. ether) to give a yellow
12 mmol) in CHCl3 (60 mL) and the mixture was stirred at oil which showed: 1H NMR (500 MHz, CDCl3) δ 2.65 (bs, 1H,
room temperature (rt) for one hour (h). 2,2-Dimethoxyacetalde- OH), 3.39 (dd, J = 2.6, 12.6 Hz, 1H, H3-THIQ), 3.86 (ddd, J =
hyde (30 mmol) was then introduced into the reaction mixture 1.1, 3.8, 12.6 Hz, 1H, H3-THIQ), 4.20 (d, J = 15.4 Hz, 1H,
followed by NaBH(OAc)3 (3.3 g, 15.0 mmol) and the resultant H1-THIQ), 4.49 (d, J = 15.4 Hz, 1H, H1-THIQ), 4.79 (bs, 1H,
mixture was stirred at rt for further 8 h. The mixture was then H4-THIQ), 6.94 (tt, J = 1.1, 7.4 Hz, 1H, ArH, phenyl), 7.09 (dd,
quenched with saturated aqueous solution of K2CO3 (60 mL) J = 1.0, 8.8 Hz, 2H, ArH, phenyl), 7.17–7.23 (m, 1H),
and the aqueous (aq) layer was extracted with CHCl3 7.29–7.32 (m, 2H, H6,H7-THIQ ), 7.34 (dd, J = 7.3, 8.8 Hz, 2H,
(2 × 30 mL). The combined organic layers were dried with ArH, phenyl), 7.47–7.51 (m, 1H) ppm; 13C NMR (126 MHz,
MgSO4, filtered and evaporated to give the crude compound 9a CDCl3) δ 51.4 (C1-THIQ), 55.6 (C3-THIQ), 67.3 (C4-THIQ),
as a pale yellow oil (3.87 g).
116.6 (ArCH, phenyl), 120.2 (ArCH, phenyl), 126.5, 127.2,
128.2, 129.3, 129.4 (ArCH, phenyl), 136.7, 134.3 and 151.1
N-Benzyl-N-(2,2-dimethoxyethyl)aniline (9a). The crude (ArCN) ppm; LC/MS (ES+) tR = 1.75 min (66 %), m/z 226.0
compound was purified by column chromatography (eluent: (M+ + H)+; (RP, isocratic, 90% MeOH); HRMS (ES+): (M +
from 0–30% EtOAc in pet. ether) to give 9a as a colorless oil H)+ calcd. for C15H16NO, 226.1226; found, 226.1234.
(2.92 g, 99%) which showed: 1H NMR (500 MHz, CDCl3) δ
3.41 (s, 6H, OCH3), 3.58 (d, J = 5.1 Hz, 2H, NCH2CH), 4.63 (t,
Supporting Information
J = 5.1 Hz, 1H, CH(OR)2), 4.67 (s, 2H, CH2Ar), 6.70 (tt, J =
0.9, 7.4 Hz, 1H, ArH), 6.74 (dd, J = 0.9, 8.9 Hz, 2H, ArH),
Supporting Information File 1
7.16–7.25 (5H, m, ArH), 7.27–7.34 (m, 2H, ArH) ppm;
13C NMR (126 MHz, CDCl3) δ 53.9 (CH2CH), 54.6 (CH3),
54.9 (ArCH2), 103.5 (CH(OR)2), 112.3 (ArCH), 116.7 (ArCH),
126.6 (ArCH), 126.8 (ArCH), 128.7 (ArCH), 129.4 (ArCH),
138.9 (ArCCH2) and 148.7 (ArCN) ppm; LC–MS (ES+) tR =
Synthetic and purification methodologies and spectroscopic
data.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-13-182-S1.pdf]
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Beilstein J. Org. Chem. 2017, 13, 1871–1878.
Acknowledgements
We thank Ipsen for Research Studentship support.
License and Terms
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Creative Commons Attribution License
ORCID® iDs
Barry V. L. Potter - https://orcid.org/0000-0003-3255-9135
(http://creativecommons.org/licenses/by/4.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
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