Synthesis of Tetrahydroquinolines via Borrowing Hydrogen Methodology Using a Manganese PN3Pincer Catalyst

Article abstract of DOI:10.1021/acs.orglett.0c02905

A straightforward and selective synthesis of 1,2,3,4-tetrahydroquinolines starting from 2-aminobenzyl alcohols and simple secondary alcohols is reported. This one-pot cascade reaction is based on the borrowing hydrogen methodology promoted by a manganese(I) PN3 pincer complex. The reaction selectively leads to 1,2,3,4-tetrahydroquinolines thanks to a targeted choice of base. This strategy provides an atom-efficient pathway with water as the only byproduct. In addition, no further reducing agents are required.

Full text of DOI:10.1021/acs.orglett.0c02905

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Letter
Synthesis of Tetrahydroquinolines via Borrowing Hydrogen
Methodology Using a Manganese PN3 Pincer Catalyst
Natalie Hofmann, Leonard Homberg, and Kai C. Hultzsch*
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ABSTRACT: A straightforward and selective synthesis of 1,2,3,4-
tetrahydroquinolines starting from 2-aminobenzyl alcohols and
simple secondary alcohols is reported. This one-pot cascade
reaction is based on the borrowing hydrogen methodology
promoted by a manganese(I) PN3 pincer complex. The reaction
selectively leads to 1,2,3,4-tetrahydroquinolines thanks to a
targeted choice of base. This strategy provides an atom-efficient
pathway with water as the only byproduct. In addition, no further reducing agents are required.
Scheme 1. Proposed Borrowing Hydrogen (BH) Cycle for
the Synthesis of Tetrahydroquinolines (3)
itrogen-containing heterocycles are indispensable sub-
structures of important pharmaceuticals and agro-
N
chemicals.1 Within this important substance class, the
1,2,3,4-tetrahydroquinoline2 scaffold represents a particularly
relevant building block for various natural products and
pharmacologic active substances. While a number of synthetic
approaches to tetrahydroquinolines exist,2 the development of
new catalytic processes that provide a faster and more (atom-)
efficient access are highly desirable to reach the goals of a
sustainable development.3 The borrowing hydrogen (BH)
methodology4 offers an atom-economical pathway for the
formation of carbon−carbon and carbon−nitrogen bonds
utilizing inexpensive, abundant, and renewable starting
materials.5 Key to many BH processes is the catalytic
acceptorless dehydrogenation6,7 of an alcohol to form a
carbonyl compound that can subsequently undergo further
transformations, such as imine formation or aldol condensa-
tion. Finally, the catalyst returns the hydrogen to the
condensation product to complete the BH cycle. While most
catalyst systems have relied on precious metals, such as Ru and
Ir,4c more abundant and less expensive base metal catalysts,
including Mn, Fe, Co, and Ni, have received significant
attention recently.4d,7,8
The BH methodology offers a simple opportunity to
construct tetrahydroquinolines in an atom- and step-econom-
ical manner starting from 2-aminobenzyl alcohols and a second
alcohol (Scheme 1, steps a−c) with water as the only
byproduct.
However, previous attempts in the condensation of 2-
aminobenzyl alcohols and alcohols have produced only
quinolines via an acceptorless dehydrogenative coupling
(corresponding to Scheme 1, steps a and b) utilizing
precious9−11 and recently also base metal12−16 catalysts, thus
falling short of completing the whole BH cycle. Quinolines can
be reduced to tetrahydroquinolines via catalytic hydro-
genation;10d,17−19 however, the additional reduction step
Received: August 29, 2020
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© XXXX American Chemical Society
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reduces the efficiency of the overall process and reactions with
molecular hydrogen often depend on higher pressure
(≥15 atm) for catalytic turnover.17a,d,f−i
A screening was conducted in order to identify the most
suitable conditions for the selective formation of the
hydrogenated product (Table 1, see also Tables S1−S5).
The influence of different solvents (Table S1) revealed that
DME combined the highest activity with good selectivity for
3a.
Curiously, efforts to combine the dehydrogenative coupling
with catalytic hydrogenation to a full BH cycle are scarce and
limited in scope to primary alcohols using a heterogeneous Ni
catalyst20 or the Ru-catalyzed synthesis of tetrahydronaphthyr-
idines.21 Tetrahydroquinolines have been prepared in an
intramolecular N-alkylation reaction via BH,22 but the
necessary amino alcohols have to be prepared in a multistep
reaction sequence.
Among the tested bases (Table 1, entries 1−5), KH led to
the highest selectivity for 3a. The application of 150 mol % of
KH is the best choice (Table 1, entry 7), while lower amounts
of base decrease the reactivity (Table 1, entries 5 and 6) and
higher amounts (Table 1, entry 8) hamper the selectivity of the
system for 3a. The concentration as well as the ratio between
reaction volume and headspace have an additional impact on
the success of the system (Table 1, entry 7 vs entry 10; Table
S3). A substrate concentration of 1.0 M and a 1:5 ratio
between volume of reaction mixture and headspace led to the
best results. Increasing the catalyst loading to 3.0 mol % only
led to a minor improvement in conversion (Table 1, entry 11),
whereas a reduction to 1.5 mol % impairs the outcome more
clearly (Table 1, entry 9). Attempts to increase the conversion
to 3a further by extending the reaction time had only a minor
effect (Table S2).
A challenging problem is the suppression of the self-
condensation of 2-aminobenzyl alcohol,10b which led to the
formation of oligomeric products. In our case, the additional
application of KOH (30 mol %) and the order of addition
seem to be crucial to minimize this competing side reaction
(Table 1, entry 12 and Table S4). No conversion was observed
with Mn(CO)5Br in the absence of the pincer ligand (Table 1,
entry 13).
Herein, we disclose the direct synthesis of 1,2,3,4-
tetrahydroquinolines starting from 2-aminobenzyl alcohols
and secondary alcohols based on the BH strategy utilizing
the manganese PN3 pincer complex 1 (Scheme 1), which
exhibited high activity in the N-alkylation of amines with
alcohols when activated with KH as base.23,24
During our investigations, we observed that the reaction
temperature and the applied base influence the outcome of the
reaction of 2-aminobenzyl alcohol with 1-phenylethanol
drastically. The usage of KOtBu at 140 °C leads to the
selective formation of the corresponding 2-phenylquinoline
(2a) (Table 1, entry 3), with significantly lower catalyst and
Table 1. Optimization of Reaction Conditions for the
Synthesis of 2-Phenyl-1,2,3,4-tetrahydroquinoline (3a)
a
b
With the optimized reaction conditions in hand, the
selectivity of the catalytic system for a broader range of
substrates was explored (Table 2). We started our inves-
tigations by applying different aromatic secondary alcohols.
Generally good yields were obtained.25−27 The catalytic system
tolerates an alcohol containing a ferrocene moiety (3c), though
a higher catalyst loading (5 mol %) was required when an
additional nitrogen atom was present in order to obtain a
decent yield (3d). A significant decrease in yield was observed
when higher substituted alcohols were applied (3e−3g).
Aliphatic alcohols provided moderate to good conversions in
general, providing a facile and atom-efficient access to
norangustureine (3k), a precursor of the important Hancock
alkaloid ( )-angustureine.28 For products 3i−3k, the corre-
sponding regioisomers were detected as minor products in
diminishing amounts with increasing chain length. A higher
catalyst loading was required for the sterically more demanding
aliphatic alcohol 3-methylbutan-2-ol to obtain a satisfactory
yield of 3l. Small amounts of 2-(tert-butyl)quinoline (2m)
were observed as the only product for the bulkier 3,3-
dimethylbutan-2-ol and no conversion to the corresponding
tetrahydroquinoline 3m was observed. An additional methyl
group at the 2-aminobenzyl alcohol was well tolerated, which is
reflected by the good yields of 3o−3r. Even the electron-rich
heterocylic (3-aminopyridin-4-yl)methanol readily reacted
with 1-phenylethanol, yielding the corresponding 1,2,3,4-
tetrahydro-1,7-naphthyridine 3s in moderate yield. The
conversion of 2-aminobenzhydrol to 3t and 3u was low,
though the dehydrogenative quinoline products were observed
as byproducts in relatively large amounts.
base
conversion (%)
amt
cat. loading
(mol %)
no.
type
(equiv)
2a
3a
Σ
c
1
2
3
4
5
6
7
8
9
KOH
1.00
1.00
0.50
1.00
1.00
1.25
1.50
1.75
1.50
1.50
1.50
1.50, 0.30
1.50, 0.30
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.5
2.0
3.0
2.0
57
40
98
35
18
18
15
44
5
10
13
12
<1
2
10
<1
8
46
56
59
36
50
65
67
84
<1
59
50
98
43
64
74
74
80
55
75
80
96
<1
c
KOtBu
KOtBu
NaH
ce
,
c
c
KH
c
KH
c
KH
c
KH
d
KH
d
10 KH
11 KH
12 KH + KOH
13 KH + KOH
d
d
d
f
2.0
a
Reaction conditions: 0.275 mmol of 2-aminobenzyl alcohol,
0.250 mmol of 1-phenylethanol, stock solution of 1 in DME (0.005
mmol), closed system, Ar. GC conversion referenced to p-xylene.
Concentration: 0.3 M, ratio volume reaction mixture/headspace =
b
c
d
1:2. Concentration: 1.0 M, ratio volume reaction mixture/headspace
e
f
= 1:5. At 140 °C. Cat. = 2 mol % Mn(CO)5Br. Note: Using KH as
base led to traces of 1-phenylethanol self-condensation products
(<5%).
base loadings in comparison to previous manganese-based
catalyst systems.12 However, catalyst 1 produces preferentially
the reduced form (2-phenyl-1,2,3,4-tetrahydroquinoline, 3a)
when a combination of bases, KH and KOH, is employed at
120 °C. As the synthesis of quinolines via dehydrogenative
coupling has already been reported with various catalytic
systems,9−16 we decided to focus on the undeveloped
formation of 1,2,3,4-tetrahydroquinolines 3.
In order to prove the feasibility of the catalyst system, the
benchmark reaction of 2-aminobenzyl alcohol with 1-phenyl-
B
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Table 2. Substrate Screening in the Synthesis of 1,2,3,4-
Tetrahydroquinolines
Table 3. Synthesis of 1,2,3,4-Tetrahydro-1,8-
a
a
naphthyridines
a
Reaction conditions: 0.880 mmol of aminobenzyl alcohol,
0.800 mmol of alcohol (1.0 M), stock solution of 1 in DME (0.016
b
mmol), closed system, Ar. GC conversion referenced to p-xylene.
c
d
Isolated yield. Full conversion of p-methoxy-1-phenylethanol into
naphthyridine 4c, 4c′ and yet unidentified byproducts. n.d. = not
detected.
Intrigued by our finding that (3-aminopyridin-4-yl)methanol
led to 1,2,3,4-tetrahydro-1,7-naphthyridine 3s, we explored the
reaction with (2-aminopyridin-3-yl)methanol as well (Table
3). Here, the transfer hydrogenation occurs predominantly at
the pre-existing pyridyl ring, as noted for the ruthenium-
promoted process,21 leading to 7-substituted 1,2,3,4-tetrahy-
dro-1,8-naphthyridines 4 when the newly formed pyridyl ring
bears a conjugated aromatic substituent (Table 3, entries 1−
3). The 2-substituted 1,2,3,4-tetrahydro-1,8-naphthyridine 4′
was only observed as a significant byproduct when small
aliphatic secondary alcohols were employed (Table 3, entries 4
and 5).
Interestingly, the reaction with p-methoxy-1-phenylethanol
produced 4c in 24% yield (Table 3, entry 3) and some yet
unidentified byproducts. However, formation of 4-ethylanisole
was not observed, in contrast to the respective reaction of p-
methoxy-1-phenylethanol with 2-aminobenzyl alcohol.26
Preliminary mechanistic investigations revealed that 2-
ferrocenylquinoline (2c) was formed as major product (via
GC analysis) within the first 2 h in the reaction of 2-
aminobenzyl alcohol with 1-ferrocenylethanol (Table S8,
Figure S2).29 Then the amount of 2c started to decrease
concomitant with formation of the hydrogenated 2-ferrocenyl-
1,2,3,4-tetrahydroquinoline (3c). No other intermediates of
the reaction were detected.
a
Reaction conditions: 0.880 mmol aminobenzyl alcohol, 0.800 mmol
alcohol (1.0 M), stock solution of 1 in DME (0.016 mmol), closed
system, Ar, GC conversion referenced to p-xylene. Isolated yields are
given in parentheses. 2% of self-condensation products of 1-
phenylethanol. 7% of self-condensation products of 4-methyl-1-
b
c
d
e
phenylethanol. 5 mol % of 1. The corresponding regioisomers (3′)
were detected as minor products: 3i′: 28% 2,3-dimethyl-1,2,3,4-
tetrahydroquinoline (for results of the respective quinoline, see ref
10b); 3j′: 10% 3-ethyl-2-methyl-1,2,3,4-tetrahydroquinoline; 3k′: 2%
f
3-butyl-2-methyl-1,2,3,4-tetrahydroquinoline. 12% of 2-(tert-butyl)-
g
quinoline (2m) was observed. Byproduct: 41% 2,4-diphenylquino-
line (2t). Byproduct: 67% 2-methyl-4-phenylquinoline (2u).
h
ethanol was performed on a 4 mmol scale to give 3a in 72% of
isolated yield (Table 2).
C
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The hydrogenation of quinoline proceeds efficiently using
catalyst 1 with external hydrogen (Scheme 2a, Table S9,
for the hydrogenation step, which is attained in our established
procedure for the formation of 1,2,3,4-tetrahydroquinolines
through heating of the tightly closed vial to 120 °C.
In summary, we have developed a homogeneous catalytic
system which facilitates the atom-efficient and selective
synthesis of 1,2,3,4-tetrahydroquinolines via a BH process.
The combination of the PN3 manganese pincer complex 1 with
the bases KH and KOH allows the formation of a C−C and a
C−N single bond in a one-pot reaction. Notably, this cascade
reaction can be performed without any additional reducing
agent, and the only byproduct generated is water. Various
aromatic and aliphatic alcohols lead to good conversions,
enabling the straightforward synthesis of valuable nitrogen-
containing heterocycles, as exemplified in the synthesis of
norangustureine. Besides, the catalytic system shows high
activity in the hydrogenation of quinolines by using external
hydrogen or via transfer hydrogenation with secondary
alcohols as hydrogen donor.
Scheme 2. Catalytic Hydrogenation of Quinoline with 1
Using Different Hydrogen Sources
entries 1−4) requiring significantly lower H2 pressure (4 bar)
compared to known Mn-based catalyst systems
(15−80 bar).17g−i Furthermore, transfer hydrogenation
occurred smoothly with iPrOH (Scheme 2b, Table S9, entries
5−8) and 1-phenylethanol (Scheme 2c). Under optimal
conditions, 2 equiv of iPrOH are employed, whereas larger
amounts significantly impaired the result. Transfer hydro-
genation of 2-phenylquinoline (2a) with iPrOH went smoothly
(Table S9, entry 12), while 1-phenylethanol was less efficient
(Table S9, entry 13), arguably due to the increased steric
hindrance and conjugation of the aromatic heterocycle to the
2-phenyl substituent in 2a.
Furthermore, the influence of hydrogen atmosphere or
hydrogen pressure on the reduction step of the borrowing
hydrogen process was investigated using acetophenone as
substrate instead of 1-phenylethanol (Table 4). The reaction
proceeded under the optimized conditions to form an
approximate 1:1 mixture of 2-phenylquinoline (2a) and 2-
phenyl-1,2,3,4-tetrahydroquinoline (3a) (Table 4, entry 1).
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02905.
Experimental procedures, spectral data, 1H and 13C
NMR spectra of all organic products, results of
additional catalytic screening reactions, representative
GC/FID traces (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Kai C. Hultzsch − University of Vienna, Faculty of Chemistry,
Institute of Chemical Catalysis, 1090 Vienna, Austria;
orcid.org/0000-0002-5298-035X; Email: kai.hultzsch@
univie.ac.at
Authors
Table 4. Influence of Acetophenone on the Distribution of
Dehydrogenated and Hydrogenated Product
Natalie Hofmann − University of Vienna, Faculty of Chemistry,
Institute of Chemical Catalysis, 1090 Vienna, Austria
Leonard Homberg − University of Vienna, Faculty of
Chemistry, Institute of Chemical Catalysis, 1090 Vienna,
Austria
a
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02905
b
conversion (%)
Notes
no.
conditions
2a
3a
Σ
c
1
2
3
argon (pressurized vial)
H2 (balloon, 1 atm)
H2 (autoclave, 4 bar)
49
75
1
47
8
76
96
83
77
The authors declare no competing financial interest.
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■
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Kirchner, K. Rhenium-Catalyzed Dehydrogenative Coupling of
Alcohols and Amines to Afford Nitrogen-Containing Aromatics and
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dehydrogenative coupling reactions: (a) Mukherjee, A.; Nerush, A.;
Leitus, G.; Shimon, L. J.; Ben-David, Y.; Espinosa Jalapa, N. A.;
Milstein, D. Manganese-Catalyzed Environmentally Benign Dehydro-
genative Coupling of Alcohols and Amines to Form Aldimines and
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4298−4301. (b) Elangovan, S.; Neumann, J.; Sortais, J. B.; Junge, K.;
Darcel, C.; Beller, M. Efficient and selective N-alkylation of amines
with alcohols catalysed by manganese pincer complexes. Nat.
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(d) Mastalir, M.; Pittenauer, E.; Allmaier, G.; Kirchner, K.
Manganese-Catalyzed Aminomethylation of Aromatic Compounds
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for C−N Bond Formation via a Hydrogen-Borrowing Strategy under
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Ruthenium Complexes for One-Pot Synthesis of Quinolines and
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(11) Ir: Ruch, S.; Irrgang, T.; Kempe, R. New Iridium Catalysts for
the Selective Alkylation of Amines by Alcohols under Mild
Conditions and for the Synthesis of Quinolines by Acceptor-less
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catalysed transfer hydrogenation of quinolines and related hetero-
cycles using formic acid under mild conditions. Catal. Sci. Technol.
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Imines and N-Heterocycles Catalyzed by Simple, Bipyridine-Based
MnI Complexes. ChemCatChem 2019, 11, 3844−3852.
(19) For the Mn-catalyzed (de)hydrogenation of other N-hetero-
cycles, see: Zubar, V.; Borghs, J. C.; Rueping, M. Hydrogenation or
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Nanosized Ni Surface for Simultaneous Formation of C−C and C−N
Bonds. ACS Catal. 2019, 9, 11438−11446.
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Kirchner, K. Sustainable Synthesis of Quinolines and Pyrimidines
Catalyzed by Manganese PNP Pincer Complexes. J. Am. Chem. Soc.
2016, 138, 15543−15546. (b) Das, K.; Mondal, A.; Srimani, D.
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heteroatom bond formation: a sustainable approach to synthesize
quinoxaline, pyrazine, benzothiazole and quinoline derivatives. Chem.
Commun. 2018, 54, 10582−10585. (c) Azizi, K.; Akrami, S.; Madsen,
R. Manganese(III) Porphyrin-Catalyzed Dehydrogenation of Alcohols
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(21) Xiong, B.; Li, Y.; Lv, W.; Tan, Z.; Jiang, H.; Zhang, M.
Ruthenium-Catalyzed Straightforward Synthesis of 1,2,3,4-Tetrahy-
dronaphthyridines via Selective Transfer Hydrogenation of Pyridyl
Ring with Alcohols. Org. Lett. 2015, 17, 4054−4057.
(13) Fe: Elangovan, S.; Sortais, J.-B.; Beller, M.; Darcel, C. Iron-
Catalyzed α-Alkylation of Ketones with Alcohols. Angew. Chem., Int.
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(14) Co: (a) Zhang, G.; Wu, J.; Zeng, H.; Zhang, S.; Yin, Z.; Zheng,
S. Cobalt-Catalyzed α-Alkylation of Ketones with Primary Alcohols.
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Sahoo, M. K.; Rana, J.; Balaraman, E. Cobalt-catalyzed acceptorless
dehydrogenative coupling of aminoalcohols with alcohols: direct
access to pyrrole, pyridine and pyrazine derivatives. Chem. Commun.
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(22) (a) Fujita, K.; Yamamoto, K.; Yamaguchi, R. Oxidative
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benzazepine. Org. Lett. 2002, 4, 2691−2694. (b) Lim, C. S.; Quach,
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Achiral Iridacycle and a Chiral Phosphoric Acid. Angew. Chem., Int.
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(23) Homberg, L.; Roller, A.; Hultzsch, K. C. A Highly Active PN3
Manganese Pincer Complex Performing N-Alkylation of Amines
under Mild Conditions. Org. Lett. 2019, 21, 3142−3147.
(15) Ni: (a) Das, S.; Maiti, D.; De Sarkar, S. Synthesis of
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Catalyzed Dehydrogenative Coupling. J. Org. Chem. 2018, 83, 2309−
2316. (b) Parua, S.; Sikari, R.; Sinha, S.; Das, S.; Chakraborty, G.;
Paul, N. D. A nickel catalyzed acceptorless dehydrogenative approach
to quinolines. Org. Biomol. Chem. 2018, 16, 274−284.
(16) Cu: Tan, D.-W.; Li, H.-X.; Zhu, D.-L.; Li, H.-Y.; Young, D. J.;
Yao, J.-L.; Lang, J.-P. Ligand-Controlled Copper(I)-Catalyzed Cross-
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also references cited therein. (b) Chakraborty, S.; Brennessel, W. W.;
Jones, W. D. A Molecular Iron Catalyst for the Acceptorless
Dehydrogenation and Hydrogenation of N-Heterocycles. J. Am.
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H.; Jones, W. D. Acceptorless, Reversible Dehydrogenation and
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Catal. 2015, 5, 6350−6354. (d) Luo, Y. E.; He, Y. M.; Fan, Q. H.
Asymmetric Hydrogenation of Quinoline Derivatives Catalyzed by
Cationic Transition Metal Complexes of Chiral Diamine Ligands:
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2697−2711. (e) Adam, R.; Cabrero-Antonino, J. R.; Spannenberg, A.;
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Cobalt-Catalyzed Hydrogenation of N-Heteroarenes under Mild
Reaction Conditions. Angew. Chem., Int. Ed. 2017, 56, 3216−3220.
(f) Sahoo, B.; Kreyenschulte, C.; Agostini, G.; Lund, H.; Bachmann,
S.; Scalone, M.; Junge, K.; Beller, M. A robust iron catalyst for the
selective hydrogenation of substituted (iso)quinolones. Chem. Sci.
2018, 9, 8134−8141. (g) Wang, Y.; Zhu, L.; Shao, Z.; Li, G.; Lan, Y.;
Liu, Q. Unmasking the Ligand Effect in Manganese-Catalyzed
Hydrogenation: Mechanistic Insight and Catalytic Application. J.
(24) In complex 1, the metal and the ligand are thought to be
involved in the bond activation of the (de)hydrogenation process. For
a review on this concept of metal−ligand cooperation, see:
Khusnutdinova, J. R.; Milstein, D. Metal-Ligand Cooperation.
Angew. Chem., Int. Ed. 2015, 54, 12236−12273.
(25) Attempts to use p-bromo-1-phenylethanol led to loss of
bromine during the reaction, and the dehydrogenated 2-phenylquino-
line (2a) was detected as the major product (53%). Similar results
were also obtained at lower reaction temperatures (80 °C). Further
investigations revealed that bromobenzene was hydrodehalogenated
under the general reaction conditions, whereas no reaction was
observed under these conditions in the absence of the Mn pincer
complex. Besides, hydrodehalogenation was also observed for (2-
amino-5-chlorophenyl)methanol as starting material, indicating that
aryl chlorides and bromides are not tolerated under these reactions
conditions in general. This stands in marked contrast to our finding
that aromatic halide substituents are generally tolerated under
conditions applied in the N-alkylation of alcohols; see ref 23.
However, hydrodehalogenation can be facilitated by a number of
catalyst systems, and it is a known competition reaction during the
catalytic hydrogenation of halogenated compounds; see: (a) Sisak, A.;
Simon, O. B. In Handbook of Homogeneous Hydrogenation; de Vries, J.
G., Elsevier, C. J., Eds.; Wiley-VCH: Weinheim, Germany, 2007; Vol.
3, pp 513−546. (b) Formenti, D.; Ferretti, F.; Scharnagl, F. K.; Beller,
M. Reduction of Nitro Compounds Using 3d-Non-Noble Metal
Catalysts. Chem. Rev. 2019, 119, 2611−2680.
(26) The reaction with p-methoxy-1-phenylethanol produced 4-
ethylanisole (83% conv by GC/MS analysis) rather than the
corresponding quinoline or 1,2,3,4-tetrahydroquinoline, suggesting
that the alcohol is acting as a PMB-protecting group that is cleaved
under the prevalent reaction conditions.
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(27) 1-(2-Furanyl)ethanol and 1-(2-thienyl)ethanol were tested as
substrates as well. However, these reactions only led to traces of the
corresponding tetrahydroquinolines (<5% based on GC/MS analysis)
and yet unidentified byproducts.
(28) Davies, S. G.; Fletcher, A. M.; Roberts, P. M.; Thomson, J. E.
The Hancock Alkaloids Angustureine, Cuspareine, Galipinine, and
Galipeine: A Review of their Isolation, Synthesis, and Spectroscopic
Data. Eur. J. Org. Chem. 2019, 2019, 5093−5119.
(29) Similar observations were made for the reaction of 2-
aminobenzyl alcohol with iPrOH in which the reaction rate decreased
significantly after 4 h (Table S7, Figure S1).
G
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