Oxidation of Trialkylamines by BrCCl3: Scope, Applications and Mechanistic Aspects

Article abstract of DOI:10.1002/ejoc.201701320

The catalyst-free photochemical reaction of trialkylamines and BrCCl₃ induced by visible light was investigated. The outcome of the reaction was found to depend strongly on the nature of the amine substrates. N-Methyl-1,2,3,4-tetrahydroisoquino

Full text of DOI:10.1002/ejoc.201701320

A Journal of
Accepted Article
Title: Oxidation of Trialkylamines by BrCCl3 - Scope, Applications and
Mechanistic Aspects
Authors: ALexander Matthias Nauth, Julio Cesar Orejarena Pacheco,
Stefan Pusch, and Till Opatz
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10.1002/ejoc.201701320
European Journal of Organic Chemistry
Oxidation of Trialkylamines by BrCCl3 – Scope,
Applications and Mechanistic Aspects
Alexander M. Nauth† Julio Cesar Orejarena Pacheco,† Stefan Pusch,† and Till Opatz*
Institute of Organic Chemistry, Johannes Gutenberg University,
Duesbergweg 10–14, 55128 Mainz, Germany
opatz@uni-mainz.de
† Equal contributions
Keywords: photocatalysis; oxidations; amines; iminium ions; DFT calculations
Abstract: The catalyst free photochemical reaction of trialkylamines and BrCCl3 induced by
visible light was investigated. The course of the reaction was found to depend strongly on the
nature of the amine substrates. While N-methyl-1,2,3,4-tetrahydroisoquinolines yielded 3,4-
dihydroisoquinolinium salts, aliphatic trialkylamines produced hydrohalide salts and
streptocyanines as the major products. The addition of KCN inhibits the streptocyanine
formation and results in the clean formation of -aminonitriles instead. The light-absorbing
species and the underlying reaction mechanism were studied by DFT calculations and
experimental observations.
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Introduction
Doubtlessly, light is one of the most powerful agents for the transformation of matter existing
in nature.[1] Consequently, chemists have successfully applied light to promote and generate
new types of chemical reactions for centuries.[2] While the excitation of organic molecules by
visible or ultraviolet light opens up opportunities for new reaction modes through excited
singlet or triplet states, the number of publications involving photochemical transformations is
still surprisingly low. The last decade has seen a resurgence of preparative photochemistry,
mainly due to a renewed interest in photoredox catalysis.[3] The underlying general principle
of photocatalysis allows the activation of organic molecules via single electron transfer
(SET), photon induced hydrogen atom transfer (PHAT) or energy transfer.[4] Different types of
photocatalysts such as transition metal complexes,[4a, 5] organic dyes,[6] and semiconductors[7]
have been used to collect light and transfer the energy to the substrates, in order to induce a
chemical reaction in the latter.
A representative photoredox-catalyzed process is the oxidative generation of iminium ions
from tertiary amines. Various methodologies have been developed to this end which utilize
different photocatalysts to effect this dehydrogenation.[6b, 6c, 8] Remarkably, N-aryl-1,2,3,4-
tetrahydroisoquinolines were almost exclusively used as the substrates, limiting the
applicability of the method for the synthesis of natural products. Due to their high HOMO
energy and the conjugative stabilization of the dehydrogenation products, these substrates
are highly reactive and spontaneously form 1-hydroperoxides when exposed to air.[9] Thus,
we became interested in the development of a complementary method to generate iminium
ions from the less readily oxidized amines lacking an N-aryl substituent and its subsequent
application to natural product total synthesis.
Results and Discussion
Tetrahydroisoquinolines + BrCCl3 – Oxidation and Protonation
N-Methyl-1,2,3,4-tetrahydroisoquinoline (1) was chosen as a test substrate since this
heterobicyclic system is frequently found as a substructure in plant-derived natural products.
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8b]
Stephenson et al.[8a,
described the use of [Ru(bpy)3]Cl2, BrCCl3, and visible light to
generate N-aryl-3,4-dihydroisoquinolinium salts. The reported reaction conditions were
applied to compound 1, using deuterated acetonitrile as the solvent, an argon inert
atmosphere, and a 24 W compact fluorescent lamp (CFL) as the source of visible light
(Scheme 1). The reaction was complete within 3 h, producing the expected iminium salt 2 as
well as an unexpected by-product identified as the protonated N-methyl
tetrahydroisoquinoline (3) along with chloroform. (1H NMR).
1
Scheme 1. Photogeneration of iminium ions. Amounts were quantified by H NMR
spectroscopy with an internal standard.
To prove the involvement of the photocatalyst in the transformation, a blank reaction without
catalyst was conducted. Interestingly, after 3 h of irradiation the color of the reaction medium
had changed from colorless to amber. 1H NMR analysis revealed oxidation of the amine with
the formation of the iminium salt and the protonated amine in the same absolute and relative
amounts as in the presence of the photocatalyst.
Intrigued by these unexpected results, additional experiments were performed. Exclusion of
UV light with a UV filter (0.5 M benzophenone in ethanol, 3 cm layer thickness) as well as the
use of (UV-free) blue LEDs (λmax = 462 nm) again yielded the iminium salt and amine
hydrohalide without variation of the product ratio. On the other hand, no reaction was
detected in the absence of light (excluding the possibility of a simple ionic mechanism) or in
the absence of BrCCl3.
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During the course of this research, the Zeitler group published the same observation in a
remarkable catalyst-free visible light oxidation of numerous N-aryl- and N-methyl-
tetrahydroisoquinolines with polyhalomethanes.[10] While these results were in perfect
agreement with our own observations in terms of the formation of the iminium salt, the
formation of the side product 3 and the application of the catalyst-free photodehydrogenation
to non-tetrahydroisoquinoline systems were not reported. The UV light induced reaction
between tetrahalomethanes and amines to yield ammonium halides has already been
described in the 1960’s. This reaction has been proposed to proceed via charge transfer
complexes (electron-donor-acceptor complexes, EDA) which were thought to absorb UV light
to undergo decomposition to hydrohalides and haloform (the yield of the hydrohalides, as
well as the proton source were not further investigated).[11] However, as reported by Zeitler et
al.,[10] blue but not green light promoted the reaction even under rigorous exclusion of UV
light through filters.
Application – Synthesis of -Aminonitriles
After the reaction conditions were established for the model amine 1, their application in the
synthesis of useful synthetic intermediates and natural products was attempted. -
Aminonitriles are important building blocks in organic synthesis and proved to be versatile
starting materials for the preparation of a variety of N-heterocyclic natural products.[12]
Consequently, the photogenerated iminium ion was intercepted by potassium cyanide to
form the corresponding -aminonitrile 4 (Scheme 2). Among the different solvents tested
(see the Supporting Information), acetonitrile gave the best results. Based on the original
reaction conditions, one-pot and stepwise procedures for the -aminonitrile synthesis were
evaluated. In all cases, the expected -aminonitrile 4 was obtained in excellent yields.
Alternatively, compound 4 can be obtained by replacing KCN for a non-toxic cyanide source
such as potassium ferricyanide K₃[Fe(CN)₆] (see the Supporting Information).[13]
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Scheme 2. Synthesis of -aminonitrile 4.
Crispine A Precursor + BrCCl3 – Exclusive Protonation
To evaluate the scope of the reaction, other aliphatic amines were tested as the reactants.
Since the alkaloid crispine A could be obtained from iminium salt 6 (also available from the
corresponding -aminonitrile),[6a] pyrrolidine 5 was selected as a study case (Scheme 3).
However, after subjecting pyrrolidine 5 to the reaction conditions established for the oxidation
of 1, no formation of iminium ion 6 was observed and a protonation of pyrrolidine 5 to its
hydrohalide salt 7 occurred. The quantification of the product by 1H NMR spectroscopy using
an internal standard added after the photoreaction revealed that a fraction of the starting
material had been consumed but apart from baseline clutter, no other defined product could
be identified.
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1
Scheme 3. Generation of pyrrolidine hydrohalide 7. Amounts were quantified by H NMR
spectroscopy with an internal standard.
Trialkylamines + BrCCl3 – Protonation and Streptocyanine Formation
To understand this reaction behavior, we applied the reaction protocol to triethylamine (8).
The reaction mixture turned amber within minutes and once again, the amine was
predominantly protonated to its hydrohalide salt 9. (Scheme 4). Chloroform and
bromodichloromethane were also produced as judged by 1H, 13C and HSQC-NMR
spectroscopy. In search for an oxidized species which must be formed in order to maintain
the overall redox balance of the process, the chlorinated N,N-diethylvinylamine derivative 10
was identified as a co-product and characterized spectroscopically.
Scheme 4. Formation of triethylamine hydrohalide 9 and chloro-streptocyanine 10. Amounts
were quantified by 1H NMR spectroscopy with an internal standard.
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To exclude the formation of hydrogen halides through hydrolysis of polyhalomethanes to
phosgene or ultimately to CO2,[14] moisture was again rigorously excluded in a glovebox and
an inert atmosphere. Nevertheless, the formation of the hydrohalide salts again proceeded
smoothly. To rule out the involvement of the solvent as a potential hydrogen source, NMR
experiments in different deuterated or chlorinated solvents were performed (see Supporting
Information). The results revealed that the solvent did not actively participate in the reaction,
so the only hydrogen source in question was the amine itself through an oxidative
mechanism. The deprotonation of the initially formed iminium ion yields an enamine which
should be more labile to oxidation than the parent amine itself due to conjugation of the lone
pair on nitrogen with the olefinic double bond which increases the HOMO energy. A series of
oxidations and deprotonations of a smaller quantity of the amine could then explain the
protonation of the amine.
The generation of triethylamine hydrohalide (9) from triethylamine (8), polyhalomethanes and
UV-light has been described by Collins,[15] Foster[16] and Stevenson[11c] already in the early
1960’s. However, the nature of co-product 10 was not established until today.[17] The
formation of chloro-streptocyanine 10 is in accordance with a recent publication of the Bach
group, in which similar but non-chlorinated cyanines were detected as the products of the
reaction of CH2Cl2 and DIPEA. These conjugated chromophores resulting from N-
dealkylation/condensation with the polyhalomethane and reaction of the resulting iminium
salts with enamines (formed through oxidation/deprotonation) were shown to be responsible
for the amber color in similar photo-induced reactions.[18]
Mechanism of Streptocyanine Formation
The mechanism for the formation of cyanine dye 10 and its higher homologue H might be as
follows (Scheme 5): Enamine A is attacked by the electrophilic trichloromethyl radical B to
furnish radical C which is brominated by BrCCl3 to iminium salt D. Deprotonation yields
enamine E which eliminates chloride to produce the reactive vinylogous Viehe salt F.[17] This
in turn could then react with trimethylamine through addition/N-dealkylation to produce the
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European Journal of Organic Chemistry
observed streptocyanine 10. Alternatively, reaction with enamine A yields the
pentamethinecyanine H.
Scheme 5. Suggested course of the formation of streptocyanine dye 10 and its higher
homologue.
The UV/vis spectrum of the reaction mixture of the light-induced BrCCl3 oxidation of 8
revealed two clear maxima at 310 nm and 414 nm (Figure 1) which are in good accordance
with the values reported by Bach and coworkers for the CH2Cl2-derived, non-halogenated
trimethine and pentamethine cyanine products of DIPEA. Another, broader maximum or
shoulder can be found around 505 nm. In the systematics of the cyanine dyes with a 90–
100 nm increase in λmax per additional ethylene unit this would correspond to a
heptamethinecyanine.
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Figure 1. UV/vis spectrum of the reaction mixture of 8 and BrCCl3 showing absorption
maxima of polymethinecyanines.
Apart from the oxidation state of the C1-unit, another major difference between BrCCl3 and
CH2Cl2 in their reaction with triethylamine lies in the respective kinetics. While the reaction
mixture containing BrCCl3 turns yellow quickly under ambient lighting and turns brown after
3 min exposure to light from a blue LED, the mixture containing CH2Cl2 remains colorless
even after the same irradiation procedure.
Competition between Different Reaction Pathways
By addition of a base like potassium carbonate, the formation of the amine hydrohalide was
reduced and chloro-streptocyanine 10 was accumulated (Figure 2) (A ratio 2:3 of protonated
amine to streptocyanine was achieved). This represents a particularly simple way to
synthesize 1,3-difunctionalized C3 building blocks. In contrast, the addition of solid potassium
cyanide to the reaction mixture exclusively resulted in the formation of 2-
(diethylamino)propanenitrile (11a, Figure 2) and no significant color change was observed.
NMR spectroscopy revealed that streptocyanine formation did not take place in the presence
of cyanide. Since the formed -aminonitrile 11a is volatile, the protocol was applied to
tributylamine and 2-(dibutylamino)-pentanenitrile 11b was isolated in 95% yield. In this
reaction, TMSCN is not able to compete with KCN in terms of reaction velocity and
suppression of byproduct formation.
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Figure 2. Crude 1H NMR spectra (acentonitrile-d3) of the triethylamine oxidation with different
additives: (A) Potassium cyanide as an additive results in -aminonitrile formation. (B)
Without additive, the amine hydrohalide and the cyanine dye are formed. (C) Addition of
potassium carbonate results in the accumulation of the cyanine dye.
These results provide additional mechanistic information. The successful trapping with
cyanide to form the α-aminonitrile proves the intermediacy of the iminium ion. If no
nucleophiles are present, the iminium ion or the enamine formed by deprotonation can
undergo further reactions and finally form the streptocyanine. We applied the protocol to
trimethylamine which should yield the iminium salt almost equally well but cannot produce an
enamine. A slow conversion to the hydrohalide and the concomitant formation of another
compound was observed which could be identified as N,N-dimethylmethyleneiminium halide
based on NMR experiments and comparison with literature values.[19] The need of an
enamine intermediate for streptocyanine formation explains the different behavior of
trimethyl- versus triethylamine which is further supported by a lacking color change in the
case of trimethylamine.
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Scheme 6. Reaction pathway of oxidized aliphatic amines with additives
Oxidation Mechanism – DFT Calculations
To understand the nature of the initial oxidation step, we used computational methods to
identify the light-absorbing species and the underlying reaction mechanism.
Trimethylamine was chosen as the simplest possible computational model substrate to
investigate the amine oxidation by bromotrichloromethane under irradiation with visible light
at the UM062X/6-311++G(3df,2pd)/SMD(MeCN)//UM062X/6-311+G(2d,p)/SMD(MeCN) level
of theory. Three obvious possible candidates for the initial photoexcitation would be either
pure BrCCl3, the amine–BrCCl3 complex, or an N-bromoammonium ion produced in a
nucleophilic substitution on BrCCl3 (Scheme 7).
Scheme 7. Candidates for photoexcitation, relative free energies in kcal/mol (level of theory:
see text).
The absorption maxima of all three candidates were calculated although the N-
bromoammonium ion is energetically too high-lying to be considered as a reasonably
abundant species. None of them revealed an absorption band of sufficiently low energy
according to TD-DFT calculations employing hybrid, long-range corrected hybrid, and
double-hybrid density functionals, even if relativistic corrections were considered (Table 2,
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see the Supporting Information for details). These results could be supported by ab initio
calculations (see the Supporting Information for details).
Table 2. Absorption maxima of trimethylamine (λmax/nm) for the S1 ← S0 transitions
calculated by TD-DFT.
TD-B3LYP/
TD-LC-ωPBE/
TD-B2GP-PLYP/
6-311++G(3df,2pd)/
6-311++G(3df,2pd)/
def2-QZVPP(-g,-f)/
SMD(MeCN)
253
SMD(MeCN)
226
SMD(MeCN)/ZORA
BrCCl3 (lit.: 251 nm)
Me3N−BrCCl3
Me3NBr+
234
215
270
306
410
297
207
281
272
Me3N−Br2
348
308
Br2 (lit.: 415 nm)
456
416
Thus, pure BrCCl3 is unlikely to be the photoinitiator since its absorption maxima (calc.:
253/226/234 nm, lit.: 251 nm) are far from the visible range. The reported molar extinction
coefficient even at 365.5 nm is very low (0.02 M–1cm–1).[20] The absorption maximum of the
charge-transfer complex of the amine with BrCCl3 also lies in the ultraviolet range. However,
it is well known that absorptivities of EDA complexes of tertiary amines and BrCCl3 in the UV-
A region are significant (e.g. 3 M–1cm–1 at 350 nm) most probably due to a broad absorption
band.[11c] Therefore, it could be possible that a certain extent of light absorption through the
EDA complex also occurs in the visible range. According to our calculations, the only species
that shows an absorption maximum in the visible range was molecular bromine (calc.:
456/416/410 nm, lit.: 415 nm).[21] Nevertheless, we tried to exclude bromine as a potential
impurity of the polyhalomethane reactant by using freshly distilled BrCCl3 as already
mentioned by the Zeitler group. Condensed compounds with an extended conjugation
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formed through oxidative decomposition in the starting amine can also be ruled out since
freshly distilled amines (under argon atmosphere and light exclusion) behaved similarly.
Thus, an efficient photoexcitation of BrCCl3 (or the corresponding amine complex), leading to
electron-transfer (PET) or hydrogen-abstraction processes with the amine substrate appears
less likely. A reasonable alternative would be a radical chain reaction via bromine radicals.
However, in the presence of free amine as a base, such a process would end up producing
trichloromethyl radicals as a thermodynamic minimum (Scheme 8).
Scheme 8. Generation of trichloromethyl radicals, relative free energies in kcal/mol (same
level of theory as in Scheme 6).
Accordingly, we propose a free-radical reaction propagated by trichloromethyl radicals in
which the respective steps can proceed in an all-exergonic manner. The pathways were
calculated for the simple model substrate (Scheme 9) as well as for the N-
methyltetrahydroisoquinoline reactant (Scheme 10). The reaction would be initiated by a
hydrogen abstraction and would then proceed via bromine transfer or via a sequential
electron transfer/dissociation/recombination pathway.[22]
Scheme 9. Radical chain reaction via trichloromethyl radicals with trimethylamine as
substrate, relative free energies in kcal/mol (same level of theory as in Scheme 6, the
“(CH3)2NCH2Br” should be regarded as a contact ion pair).
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Scheme 10. Radical chain reaction via trichloromethyl radicals with N-methyl
tetrahydroisoquinoline as substrate, relative free energies in kcal/mol (same level of theory
as in Scheme 7).
As expected, the initial hydrogen abstraction is more exergonic in the latter case since a
stabilized benzylic radical is being generated. The calculated thermochemical data and
infeasible alternative pathways indeed suggest the reaction to take place through a radical
mechanism involving trichloromethyl radicals. However, the pathway for the initial radical
generation and the exact role of light in the process are still unknown.
The generation of molecular bromine and a trichloromethyl radical from the reaction of a
bromine radical with bromotrichloromethane is only slightly endergonic (Scheme 11). A
single bromine radical could therefore form a trichloromethyl radical, which starts the above-
mentioned radical chain oxidation process. Furthermore, molecular bromine is produced,
which, after irradtion with visible light, yields two bromine radicals, which in turn produces two
trichloromethyl radicals and two molecules of Br2 (Scheme 12).
Scheme 11. Alternative generation of trichloromethyl radicals, relative free energies in
kcal/mol (same level of theory as in Scheme 6).
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Scheme 12. Light-induced multiplication of radicals during the reaction.
It is however worth noting that the reaction of N-methyltetrahydroisoquinoline and BrCCl3
also takes place under ultrasonication[23] and thermal conditions (exclusion of light in both
cases). Nevertheless, the reaction rates and yields of the sonochemical and thermal reaction
were lower compared to the photochemical process (yields: 38% sonochemically, 15%
thermally (T = 70 °C) versus 62% photochemically, each after 3 h). The lability of
bromotrichloromethane towards sonication has already been reported[23] and the resulting
bond homolysis could be a trigger for the proposed free radical chain mechanism.
Nevertheless, the significant accelerating effect of irradiation with blue light as suggested in
Scheme 12 requires further investigation.
Conclusion
The reaction between trialkylamines and BrCCl3 induced by visible light, heat or ultrasound
was applied to various substrates. N-methyl-1,2,3,4-tetrahydroisoquinolines tend to yield
iminium ions as the main products while aliphatic trialkylamines carrying -hydrogen are
being protonated instead. Since the solvent or traces of water were not involved in this
process, the amine itself must be the sacrificial reductant to form hydrogen halide in its
oxidative transformation through the reactive enamine into products such as chlorocyanine
10. When additives are present, the reaction outcome can change. The addition of a base
accumulates the cyanine dye whereas cyanide as an exemplified nucleophile exclusively
produces the -aminonitrile. DFT calculations for the iminium formation suggested a free-
radical reaction propagated by trichloromethyl radicals in which the respective steps can
proceed in an all-exergonic manner. Unfortunately, the initiation mechanism still remains
unclear since neither pure BrCCl3 nor the amine-BrCCl3 complex or a N-bromoammonium
ion show an appreciable absorbance in the visible range. A small steady state concentration
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European Journal of Organic Chemistry
of molecular bromine could however be formed through Br-abstraction from BrCCl3 by Br
radicals and through continuous photolysis according to the proposed mechanism, constantly
producing trichloromethyl radicals at a rate proportional to the flux of blue-light photons.
Some applications of the oxidation chemistry to the synthesis of N-methyl-1,2,3,4-
tetrahydroisoquinoline-1-carbonitrile, (±)-carnegine, 2-(dibutylamino)-pentanenitrile, and
cryptostylines analogs were demonstrated to show the applicability of the photo-generated
iminium salts (see the Supporting Information). The involvement of cyanine dyes as in situ-
generated photocatalysts can be excluded as two of the variants of the amine oxidation by
BrCCl3 are not associated with any appreciable cyanine formation.
Experimental Section
General information
Solvents and reagents were purchased from commercial suppliers (Sigma Aldrich, Alfa
Aesar, TCI chemicals, ABCR, Acros Organics and Fischer Scientific) and used as received
unless noted otherwise. N-Methyl-1,2,3,4-tetrahydroisoquinoline,[24] 6,7-dimethoxy-N-methyl-
1,2,3,4-tetrahydroisoquinoline,[25]
and
1-(3,4-dimethoxyphenethyl)pyrrolidine[6a]
were
synthesized according to known literature procedures. Anhydrous dichloromethane and
acetonitrile were distilled under argon atmosphere from CaH2 or P4O10 and collected over
molecular sieves 4 Å (10 to 18 mesh, ACROS Organics). BrCCl3 was distilled under argon
atmosphere, collected over molecular sieves 4 Å (10 to 18 mesh, ACROS Organics) and
keep it away from the light with an aluminum foil cover. Flash column chromatography was
performed using silica gel (35–70 μm silica gel, Acros Organics). Thin-layer chromatography
(TLC) was carried out on Merck silica gel plates (60 F254) using defined solvent mixtures and
visualized under UV light irradiation and/or TLC staining reagents. Melting points were
determined in open capillary tubes and are uncorrected. IR spectra were measured with a
Tensor 27 with a diamond ATR unit from Bruker and are reported in terms of frequency of
1
13
1
absorption (, cm–1). A 300 MHz (300 MHz H and 75.4 MHz C), a 400 MHz (400 MHz H
13
and 100.6 MHz C) spectrometer from Bruker were used to record the corresponding NMR
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European Journal of Organic Chemistry
spectra with deuterated solvents (CDCl3 : δH = 7.26 ppm, δC = 77.16 ppm; CD3CN: δH =
1.94 ppm, δC = 1.32, 118.3 ppm; C6D6: δH = 7.16 ppm, δC = 128.06 ppm) as internal
reference.[26] NMR yield was determined by using 99% CH2Br2 (2H at 4.92 ppm in CDCl3 or
5.45 ppm in CD3CN) as internal standard: addition of weighted amount of CH2Br2 was made
after irradiation to avoid undesired chemical reactions of the NMR standard. ESI-HRMS
spectra were recorded on a Q-TOF instrument with a dual source and a suitable external
calibrant. Irradiation was performed using a 24 W CFL lamp “white light” or a blue LED (100
W, λmax = 462 nm).
Computational chemistry
The hybrid DFT and TD-DFT calculations were performed using Gaussian 09 (Rev. D.01).[27]
Double hybrid TD-DFT and ab initio calculations were performed using Orca 3.0.3.[28] DFT
geometry optimizations with a spin-unrestricted formalism employed the M062X functional,[29]
the 6-311+G(2d,p) basis set,[30] and SMD solvation for acetonitrile.[31] An ultrafine grid, a
quadratically convergent SCF procedure (only in case the first-order SCF did not converge)
and tight SCF as well as geometry optimization convergence criteria were used. The
stationary points were identified as minima by calculation of the full exact hessian (yielding
no imaginary frequencies). Single-point energies were calculated using the 6-
311++G(3df,2pd) basis set in an otherwise identical way.[30] The final Gibbs free enthalpies
were obtained by addition of the 6-311++G(3df,2pd) electronic energy and the 6-
311+G(2d,p) Gibbs free enthalpy energy corrections. The excited-state calculations were
performed using the previously obtained UM062X/6-311+G(2d,p)/SMD(MeCN) geometries.
Hybrid TD-DFT calculations (40 transitions) employed the B3LYP,[32] PBE1PBE,[33] M062X,[29]
CAM-B3LYP,[34] LC-ωPBE,[35] and ωB97XD[36] functionals together with the 6-
311++G(3df,2pd) basis set[30] and SMD solvation for acetonitrile.[31] Tight SCF convergence
criteria were used. Double-hybrid TD-DFT calculations (1 transition with a 20 state Davidson
expansion space) were performed with the (RI-)B2GP-PLYP functional,[37] the def2-TZVPP
as well as def2-QZVPP(-g,-f) basis sets in conjunction with the corresponding /J and /C fitting
basis sets,[38] and SMD solvation for acetonitrile.[31] The RIJCOSX approximation,[39] tight
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SCF convergence criteria, and enhanced grid settings (Grid5 FinalGrid6 GridX4) were used.
The ZORA model was included to study relativistic effects.[40] Ab initio calculations at the
CIS(D)[41] (1 transition with a 20 state Davidson expansion space) and EOM-CCSD[42] (1
transition) levels were performed with the aug-cc-pVDZ as well as aug-cc-pVTZ basis sets[43]
together with SMD solvation for acetonitrile.[31] Tight SCF convergence criteria were used.
General
bromotrichloromethane
In pre-dried Schlenk tube and under argon atmosphere, N-methyl-1,2,3,4-
procedure
I:
Oxidation
of
N-methyltetrahydroisoquinolines
by
a
tetrahydroisoquinoline (1.0 equiv, freshly distilled, degassed and dryed over molecular sieves
3 Å) and BrCCl3 (3.0 equiv, freshly distilled, degassed and dryed over molecular sieves 3 Å)
were dissolved in acetonitrile (degassed and dryed over molecular sieves 3 Å). After this, the
reaction mixture was degassed with argon by three freeze-vacuum-thaw cycles. The mixture
was then stirred and irradiated (24 W CFL lamp) for the indicated time span at room
temperature. Once the reaction was complete (TLC monitoring), the product was either
isolated and identified, or used in a continuous stepwise procedure.
N-Methyl-3,4-dihydroisoquinolin-2-ium
halide
(2)
and
N-methyl-1,2,3,4-
tetrahydroisoquinoline hydrohalide (3)
In a Young NMR tube and according to the general procedure I, N-methyl-1,2,3,4-
tetrahydroisoquinoline 1 (20.4 mg, 0.139 mmol) and BrCCl3 (27.3 L, 0.277 mmol) were
dissolved in 0.7 mL dry degassed CD3CN. The reaction mixture was irradiated under visible
light at room temperature for 3 h. In order to determine the yield of the reaction by NMR, 1,4-
bis(trimethylsilyl)benzene (1.852 mg) was added as internal standard. An mixture of iminium
ion 2 and hydrohalide 3 inseparable by column chromatography was observed.
Rf = 0.13 (CHCl3/MeOH, 10 : 1)
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Iminium salt 2: 57% NMR yield
1H NMR, COSY (400 MHz, CD3CN)  = 9.26 (s, 1H, H-1), 7.84 (dd, J = 7.6, 1.3 Hz, 1H, H-8),
7.78 (td, J = 7.6, 1.3 Hz, 1H, H-6), 7.56–7.49 (m, 1H, H-7), 7.45 (d, J = 7.6 Hz, 1H, H-5), 3.99
(t, J = 8.1 Hz, 2H, H-3), 3.76 (s, 3H, NCH3), 3.25 (t, J = 8.1 Hz, 2H, H-4) ppm. 13C NMR,
HMBC, HSQC (100.6 MHz, CD3CN)  = 167.8 (C-1), 138.8 (C-7), 137.2 (C-4a), 134.4 (C-8),
129.7 (C-5), 129.4 (C-6), 125.6 (C-8a), 51.0 (C-3), 28.9 (NCH3), 25.5 (C-4) ppm. ESI-MS
(m/z): 146.1 (100) [C10H12N]+.
The spectroscopic data are in accordance with those reported in the literature.[10, 44]
Hydrohalide 3: 41% NMR yield
1H NMR, COSY (400 MHz, CD3CN)  = 12.39 (s, 1H, NH), 7.32–7.20 (m, 3H, H-6, H-7, H-8),
7.14 (d, J = 6.8 Hz, 1H, H-5), 4.38 (dd, J = 15.6, 3.4 Hz, 1H, H-1a), 4.38 (dd, J = 15.6,
8.3 Hz, 1H, H-1b), 3.60–3.52 (m, 1H, H-3a), 3.51–3.49 (m, 1H, H-4a), 3.32–3.18 (m, 1H, H-
3b), 3.04–2.96 (m, 1H, H-4b), 2.83 (d, J = 4.9 Hz, 3H, NCH3) ppm. 13C NMR, HMBC, HSQC
(100.6 MHz, CDCl3)  = 132.2 (C-4a), 129.3, 127.8 (C-6 & C-7), 129.1 (C-8a), 128.9 (C-8),
127.5 (C-5), 54.5 (C-1), 51.4 (C-3), 42.9 (NCH3), 26.0 (C-4) ppm. ESI-MS (m/z): 148.1 (100)
[C10H14N]+.
The spectroscopic data are in accordance with those reported in the literature.[45]
N-Methyl-1,2,3,4-tetrahydroisoquinoline-1-carbonitrile (4, Cyanide source KCN)
In a reaction vial was equipped with N-methyl-1,2,3,4-tetrahydroisoquinoline 1 (70.0 mg,
0.478 mmol, 1.0 eq.), potassium carbonate (100 mg, 0.724 mmol, 1.5 eq.) and acetonitrile
(6.0 mL) and degassed by argon bubbling in a ultrasonic bath for 5 min. Degassed BrCCl3
(140 L, 2.390 mmol, 5.0 eq) was added and the reaction mixture was irradiated with a blue
LED at room temperature for 3 h. KCN (40 mg, 0.621 mmol, 1.3 eq.) was added and the
solution was stirred in the dark for 2 h. The reaction mixture was poured into sat. NaHCO3
solution (25 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic phases
were combined, dried over sodium sulfate and concentrated in vacuo. The crude product
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10.1002/ejoc.201701320
European Journal of Organic Chemistry
was purified by flash column chromatography (cyclohexane/ethyl acetate/Et3N: 1:2:0.1) to
yield the title compound as a colorless oil (75.8 mg, 0.440 mmol, 92%).
Rf = 0.60 (cyclohexane/ethyl acetate/Et3N: 1:3:0.1). IR (ATR)  = 2976, 2854, 2806, 2220,
1496, 1454, 1144, 1100, 1066, 939, 850, 771, 744 cm–1. 1H NMR, COSY (400 MHz, CDCl3) 
= 7.30–7.14 (m, 4-H, H-Ar), 4.73 (s, 1-H, H-1), 3.12–2.98 (m, 1H, H-4a), 2.94–2.74 (m, 3H,
H-3, H-4b), 2.60 (s, 3-H, N–CH3) ppm. 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3)  =
133.9 (C-8a), 129.6 (C-4a), 129.4, 128.5, 127.1, 126.5 (C-5, C-6, C-7, C-8), 116.5 (CN), 56.9
(C-1), 48.4 (C-3), 43.7 (N–CH3), 28.4 ppm. ESI-MS (m/z): 146.1 (100) [C10H12N]+.
The spectroscopic data are in accordance with those reported in the literature.[46]
General procedure III: photochemical reaction of aliphatic trialkylamines and
bromotrichloromethane
In a pre-dried Schlenk tube and under argon atmosphere, trialkylamine (1.0 equiv) and
BrCCl3 (3.0 equiv) were dissolved in dry acetonitrile. After this, the reaction mixture was
degassed with argon by three freeze-vacuum-thaw cycles. The mixture was then stirred and
irradiated (24 W household CFL bulb) for the indicated time span at room temperature.
1-(3,4-Dimethoxyphenethyl)pyrrolidine hydrohalide (7)
In a valved Young NMR tube and according to the general procedure III, 1-(3,4-
dimethoxyphenethyl)pyrrolidine 10 (78.8 mg, 0.335 mol) and BrCCl3 (66.0 L, 0.670 mmol)
were dissolved in 0.7 mL dry degassed CD3CN. The reaction mixture was irradiated under
visible light at room temperature for 3 h. In order to determine the yield of the reaction by
NMR, 1,4-bis(trimethylsilyl)benzene (2.572 mg) was added as an internal standard.
Compound 12 was obtained in 77% yield.
1
IR (ATR)  = 2955, 2688, 2596, 1515, 1260, 1236, 1141, 1023 cm–1. H NMR, COSY
(400 MHz, CD3CN)  = 11.28 (s, 1H, NH), 6.88 (d, J = 2.0 Hz, 1H, Ph-2), 6.85 (d, J = 8.2 Hz,
1H, Ph-5), 6.79 (dd, J = 8.2, 2.0 Hz, 1H, H-6), 3.79 (s, 3H, OCH3–Ph-3), 3.76 (s, 3H, OCH3–
Ph-4), 3.63–3.54 (m, 2H, H-2a, H-5a), 3.31–3.23 (m, 2H, H-1’), 3.10–3.03 (m, 2H, H-1’),
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European Journal of Organic Chemistry
2.98–2.86 (m, 2H, H-2b, H-5b), 2.09–1.97 (m, 4H, 2H-3, 2H-4) ppm. 13C NMR, HMBC,
HSQC (100.6 MHz, CD3CN)  = 150.2 (Ph-3), 149.1 (Ph-4), 130.5 (Ph-1), 121.7 (Ph-6),
113.4 (Ph-2), 112.8 (Ph-5), 56.8 (C-1’), 56.3 (2xOCH3), 54.3 (C-2, C-5), 32.0 (C-2’), 24.1(C-
3, C-4) ppm. ESI-MS (m/z): 236.2 (100) [C14H22NO2]+; ESI-HRMS (m/z): calcd for
[C14H22NO2]+ 236.1661, found 236.1648.
Triethylamine hydrohalide (9) and chloro-streptocyanine 10
In a Young NMR tube and according to the general procedure III, triethylamine 13 (10.0 mg,
98.8 mol) and BrCCl3 (29.2 L, 0.296 mmol) were dissolved in 0.5 mL of deuterated
acetonitrile. The reaction mixture was irradiated with a 24 W CFL lamp at room temperature
1
for 24 h. After monitoring the reaction by H NMR, triethylamine 13 was predominantly
converted in triethylamine hydrohalide and chloro-streptocyanine dye 15 in 89 : 11 ratio,
respectively.
Hydrohalide 9
1H NMR, COSY (400 MHz, CD3CN)  = 11.17 (s, 1H, NH), 3.05 (qd, J = 7.3, 4.9 Hz, 6H,
NCH2), 1.30 (t, J = 7.3 Hz, 9H, NCH2CH3) ppm. 13C NMR, HMBC, HSQC (100.6 MHz, CDCl3)
 = 46.6 (NCH2), 8.9 (NCH2CH3) ppm. ESI-MS (m/z): 102.6 (100) [C6H16N]+.
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European Journal of Organic Chemistry
(Z)-N-(3-Chloro-3-(diethylamino)allylidene)-N-ethylethanaminium halide 10
A reaction vial was equipped with acetonitrile (1 mL) and potassium carbonate (1.35 g,
9.77 mmol, 1.0 eq.) and degassed by bubbling argon through it for 2 min. Under argon
atmosphere
triethylamine
(27.4 L,
20.0 mg,
0.198 mmol,
1.0 eq.)
and
bromotrichloromethane (40 L, 80.5 mg, 0.406 mmol, 2.1 eq.) were added added. The flask
was placed in front of a blue LED and irradiated at room temperature for 18 h. The reaction
mixture was concentrated in vacuo and dissolved in acetonitrile (2 mL). The solid was
removed by centrifugation (4700 rpm, 15 min, –5 °C) and concentrated in vacuo to yield a
brown solid (23 mg), containing the streptocyanin and triethylamine hydrohalide (3:2).
1H NMR, COSY (400 MHz, CD3CN)  = 7.98 (d, J = 11.3 Hz, 1H, H-1), 5.44 (d, J = 11.3 Hz,
1H, H-2), 3.80–3.67 (m, 4H, NCH2), 3.59 (q, J = 7.3 Hz, 2H, NCH2), 3.54 (q, J = 7.2 Hz, 2H,
13
NCH2), 1.30–1.24 (m, 9H, 3xCH3), 1.21 (t, J = 73 Hz., 3H, CH3). C NMR, HMBC, HSQC
(100.6 MHz, CD3CN)  = 160.9 (C-1), 158.7 (C-3), 88.4 (C-2), 53.4, 45.4 (N(CH2)2), 50.5,
49.0 (N(CH2)2), 14.5, 13.5, 12.3, 12.1(4xCH3) ppm. ESI-MS (m/z): 217.3 (100)
[C11H2235ClN2]+, 219.0 (35) [C11H2237ClN2]+. ESI-HRMS (m/z): calcd for [C11H2235ClN2]+
217.1471, found: 217.1459; calcd for [C11H2237ClN2]+ 219.1442, found: 219.1437.
In the 13C NMR spectrum, the signals at 50.5, 49.0, 13.5 and 12.1 ppm appear as very broad
singlets, possibly due to hindered rotation. The NMR data match those reported for (Z)-N-(3-
Chloro-3-(dimethylamino)allylidene)-N-methylmethanaminium perchlorate.[17]
2-(Dibutylamino)pentanenitrile 11b
In a reaction vial acetonitrile (5.0 mL) with potassium cyanide (83 mg, 1.275 mmol, 1.3 eq.)
was degassed by bubbling argon through the solution for 20 s. Under argon, tributylamine
(235 L, 183.2 mg, 0.988 mmol, 1.0 eq.) and bromotrichloromethane (200 L, 402.5 mg,
2.03 mmol, 2.1 eq.) was added. The vial was closed and irradiated for 16 h with a blue LED
at 20 C. The solids filtered of and the organic layer concentrated in vacuo. The residue was
filtered through a short plug of basic alumina with dichloromethane. The filtrate was
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10.1002/ejoc.201701320
European Journal of Organic Chemistry
concentrated in vauco to yield the product (197.5 mg, 0.939 mmol, 95%) as a slightly yellow
oil.
IR (ATR)  = 2959, 2933, 2873, 2222, 1466, 1379, 1170, 1117, 1091, 1044, 938, 902, 878,
739 cm–1. 1H NMR, COSY (300 MHz, CDCl3)  = 3.54 (t, J = 7.7 Hz, 1H, H-1), 2.59–2.47 (m,
2H, H-1’), 2.36–2.24 (m, 2H, H-1’’), 1.72–1.61 (m, 2H, H-2), 1.49–1.21 (m, 10H, H-2’, H-2’’,
H-3, H-3’, H-3’’), 0.95–0.84 (m, 9H, H-4, H-4’, H-4’’). 13C NMR, HMBC, HSQC (75.5 MHz,
CDCl3)  = 118.5 (CN), 54.3 (C1), 51.4 (C1’, C1’’), 33.9 (C2), 30.2 (C2’, C2’’), 20.4 (C3’,C3’’),
19.3 (C3), 14.0 (C4’, C4’’), 13.5 (C4) ppm. ESI-MS (m/z): 211.3 (100) [C13H27N2]+, 184.3 (17)
[C12H26N]+.
2-(Dibutylamino)propanenitrile 11a
In a reaction vial deuterated acetonitrile (1.0 mL) with potassium cyanide (16.7 mg,
0.256 mmol, 1.3 eq.) was degassed by bubbling argon through the solution for 10 s. Under
argon, triethylamine (27.4 m, 20.0 mg, 0.198 mmol, 1.0 eq.) and bromotrichloromethane
(40 L, 80.5 mg, 0.406 mmol, 2.1 eq.) were added. The vial was closed and irradiated for
16 h with a blue LED at 20 C. The solids were removed by centrifuging (4700 rpm) for 10 min
and the organic layer was analyzed.
IR (ATR)  = 3628, 3545, 3024, 2980, 2943, 2267, 1634, 1474, 1457, 1387, 1209, 1189,
1105, 778, 761, 726 cm–1. 1H NMR, COSY (400 MHz, CD3CN)  = 3.88 (q, J = 7.2 Hz, 1H, H-
1), 2.70 (dq, J = 13.0, 7.3 Hz, 2H, H-1’), 2.35 (dq, J = 13.0, 6.9 Hz, 2H, H-1’’), 1.38 (d, J = 7.2
Hz, 3H, H-2), 1.04 (t, J = 7.2 Hz, 6H, H-2’, H-2’’) ppm. 13C NMR, HMBC, HSQC (100.6 MHz,
CD3CN)  = 118.2 (CN), 49.4 (C-1), 45.8 (C-1’, C-1’’), 18.4 (C-2), 13.4 (C-2’, C-2’’) ppm. ESI-
MS (m/z): 127.4 [C7H15N2]+.
Acknowledgements
We thank Dr. J. C. Liermann and M. Sc. J. Kühlborn for NMR spectroscopy and Dr. C. J.
Kampf for mass spectrometry.
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European Journal of Organic Chemistry
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European Journal of Organic Chemistry
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10.1002/ejoc.201701320
European Journal of Organic Chemistry
FULL PAPER
Amine Photo-oxidation*
Alexander M. Nauth,† Julio Cesar
Orejarena Pacheco,† Stefan Pusch,† and
Till Opatz*.
† Equal Contributions
In the absence of any photocatalyst, BrCCl3 engages in the visible light mediated
photo-oxidation of trialkylamines by BrCCl3. Depending on the amine, the additive,
and the reaction conditions -aminonitriles, streptocyanines or hydrohalide salts are
formed. An investigation of the nature of the reaction as well as a mechanistic study
based on DFT calculations and experimental observations is presented.
Page No. – Page No.
Oxidation of Trialkylamines by
BrCCl3 – Scope, Applications and
Mechanistic Aspects
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