One-pot functionalisation of N-substituted tetrahydroisoquinolines by photooxidation and tunable organometallic trapping of iminium intermediates

Article abstract of DOI:10.3762/bjoc.10.316

Nucleophilic trapping of iminium salts generated via oxidative functionalisation of tertiary amines is well established with stabilised carbon nucleophiles. The few reports of organometallic additions have limited scope of substrate and organometallic nucleophile. We report a novel, one-pot methodology that functionalises N - substituted tetrahydroisoquinolines by visible lightassisted photooxidation, followed by trapping of the resultant iminium ions with organometallic nucleophiles. This affords 1,2-disubstituted tetrahydroisoquinolines in moderate to excellent yields.

Full text of DOI:10.3762/bjoc.10.316

One-pot functionalisation of N-substituted tetrahydro-
isoquinolines by photooxidation and tunable organometallic
trapping of iminium intermediates
Joshua P. Barham1,2, Matthew P. John*2 and John A. Murphy*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 2981–2988.
1WestCHEM, Department of Pure and Applied Chemistry, University
of Strathclyde, 295 Cathedral Street, Glasgow G1 1XL, United
Kingdom and 2GlaxoSmithKline Medicines Research Centre, Gunnels
Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom
doi:10.3762/bjoc.10.316
Received: 02 November 2014
Accepted: 27 November 2014
Published: 12 December 2014
Email:
Joshua P. Barham - joshua.x.barham@gsk.com; Matthew P. John* -
matthew.p.john@gsk.com; John A. Murphy* -
john.murphy@strath.ac.uk
Associate Editor: D. Y.-K. Chen
© 2014 Barham et al; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
iminium salt; organometallic; oxidative functionalisation; photoredox
catalysis; tetrahydroisoquinoline
Abstract
Nucleophilic trapping of iminium salts generated via oxidative functionalisation of tertiary amines is well established with
stabilised carbon nucleophiles. The few reports of organometallic additions have limited scope of substrate and organometallic
nucleophile. We report a novel, one-pot methodology that functionalises N-substituted tetrahydroisoquinolines by visible light-
assisted photooxidation, followed by trapping of the resultant iminium ions with organometallic nucleophiles. This affords 1,2-
disubstituted tetrahydroisoquinolines in moderate to excellent yields.
Introduction
Tetrahydroisoquinolines (THIQs) are structural motifs promi- Environmental consciousness has initiated the development of
nent within biologically active natural products and pharmaceu- methods which construct THIQs using green technologies, in
tical compounds [1,2]. From (−)-carnegine (1, a monoamine mild conditions and with high atom efficiencies. Catalytic
oxidase A inhibitor) [3] to (+)-solifenacin (2, a bladder-selec- oxidative functionalisation of the C–H bond α- to the amine
tive muscarinic M3 receptor antagonist) [4] to (±)-methopho- function is one such methodology. Iminium salts generated in
line (3, an opioid analgesic) [5,6], a 1,2-disubstituted THIQ this way can be intercepted by a nucleophile in a one-pot reac-
motif occurs throughout (Figure 1).
tion (Scheme 1). Alternatively, the α-amino radicals can be
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Beilstein J. Org. Chem. 2014, 10, 2981–2988.
Figure 1: Examples of biologically active 1,2-disubstituted tetrahydroisoquinolines.
Scheme 1: Oxidative C–H functionalisation and examples of previously reported nucleophilic trappings.
trapped by electrophiles [7-9]. Oxidative C–H functionalisation [18,34,36]. The ability to adjust oxidising power through photo-
of THIQs is reported using Cu(I) [10,11], Fe(III) [12], V(IV) catalyst choice renders the transformation substrate-tunable.
[13] and I2 [14,15] catalysts, but also with heterogeneous [16], Thus, we selected photoredox catalysis as an oxidative func-
metal-organic [17,18] and organic [19,20] photocatalysts. Such tionalisation whose substrate scope might be extended (by cata-
catalysts are used in combination with various stoichiometric lyst selection) in future investigations. Herein, we report a one-
oxidants including oxygen [16,21].
pot, tandem visible-light powered oxidative functionalisation of
N-substituted THIQs and organometallic trapping of iminium
However, nucleophilic trappings of resultant iminium salts are intermediates.
typically exemplified with highly stabilised carbon nucleo-
philes such as cyanides, nitronates, enolate equivalents and Results and Discussion
heterocycles (Scheme 1) [14,22-24]. Reports of organometallic Initially, a blue LED strip (λmax = 458 nm), Ru(bpy)3(PF6)2
additions to THIQs in this context are limited to aryl [25-27] (1 mol %) and BrCCl3 (3.0 equiv) facilitated oxidation of
and alkynyl [22,28-30] nucleophiles and the substrate scope is N-phenyl THIQ (4a) (1 mmol) to its corresponding iminium salt
generally limited to N-aryl THIQs [31]. However, Li reported a (5a, Table 1) in anhydrous MeCN. As observed by Stephenson
hypervalent iodine mediated N-aryl THIQ oxidation which [37], photoredox activation of 4a under these conditions
tolerated a wide range of organometallic nucleophiles [32] and required long reaction times (14–16 h) to reach full conversion.
Yu developed methodology for THIQ alkynylation which does As reactions progressed, we observed precipitation and were
not require N-aryl motifs [33].
able to collect half (by mass) of the crude iminium salt 5a by
filtration. Precipitation acts to stall reactions by shielding the
We sought a general procedure for organometallic trapping of photocatalyst from the light. Addition of vinylmagnesium bro-
iminium salts generated by oxidative functionalisation; a mide directly to the reaction mixture led to a complex mixture
methodology amenable to a range of tertiary amine substrates of products by HPLC.
and unstabilised carbon nucleophiles. Recently, visible-light
photoredox catalysis has gained interest as a technique for We found that BrCCl3 and its byproduct CHCl3 [22] were re-
oxidative functionalisation [34,35]. An important feature of sponsible for poor organometallic reaction profiles. Generation
photoredox catalysis is that different photocatalysts have of radical intermediates or carbenes upon reacting Grignard
different redox potentials upon accessing the excited state reagents or magnesium salts with BrCCl3 or CHCl3 are evi-
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Table 1: Organometallic additions to iminium salts generated via visible-light photoredox catalysis.
Entry
R-Metal
Y
R
Product
Yielda
1
RMgBrb
RMgBrb
RMgClb
RMgClb
RMgBrb
RMgBrb,c
RMgBrb
RMgBrb
RMgBrb
RMgBrb
RMgBrb
RTMS
–
vinyl
6aa
6ab
6ac
6ad
6ae
6af
80
2
–
Me
78
3
–
Et
75
4
–
iPr
78
5
–
cyclopropyl
Bn
66
6
–
69
7
–
Ph
6ag
6ag
6ah
6ai
90
8
CuBrd
Ph
77
9
–
4-FC6H4
4-MeOC6H4
allyl
72
10
11e
12f
13
14
15e
16
17
–
62
–
6aj
–
–
allyl
6aj
–
RMgBrb
RI
ZnCl2g
Ini
allyl
6aj
37, 88h
92, 68j
–
allyl
6aj
RMgBrb
RMgBrb
RMgClb
–
2-methylallyl
2-methylallyl
2-butenyl
6ak
6ak
6alk
ZnCl2g
ZnCl2g
90
92
aIsolated (%) yields after chromatography. bCommercially available solutions in THF or Et2O. c6 equiv used. dGrignard (2.0 equiv) premixed with CuBr
(2.6 equiv). eComplex mixture. fNo reaction. gGrignard (2.0 equiv) premixed with a solution of ZnCl2 (2.6 equiv). hSolvent switched to THF. iAllyl iodide
(3.0 equiv) premixed with In powder (2.0 equiv). jDirect addition of R-metal without solvent switch. k6al is a 1:1 mixture of diastereomers where
R = 1-methyl-2-propenyl, see Supporting Information File 1.
denced in the literature [38,39]. Initially, we took advantage of faster reaction of the Grignard with 5a despite the solvent
the volatilities of BrCCl3 and CHCl3 by removing them under (MeCN) being present in vast excess.
vacuum and replacing the solvent. A solvent switch was also
reported when photoredox activation of 4a was combined with
thiourea-catalysed enantioselective alkylation [37]. The enantio-
selectivity of the thiourea-catalysed alkylation was optimal in
non-polar solvents, yet low photocatalyst solubility in these
solvents precluded photoactivation of 4a. Thus, a solvent switch
was used to capitalise on the beneficial properties of both
solvents.
Notably, allyl and 2-methylallyl Grignard additions (Table 1,
entries 11 and 15) were exceptions and resulted in complex
mixtures of products. We reasoned that use of a less reactive
organometallic reagent would supress undesirable pathways.
However, allyltrimethylsilane does not react with 5a (Table 1,
entry 12) [16,22]. As organometallics of intermediate reactivity,
allylzinc halides were explored. Indeed, 2-methylallylzinc and
2-butenylzinc reagents added to 5a to afford 6ak and 6al in
At this stage, we employed an MeCN/H2O (4:1) solvent system 90% and 92% isolated yields, respectively. Conversely, addi-
and Ru(bpy)3Cl2 in photoactivations which facilitated full tion of the allylzinc reagent to 5a afforded side-products 7a and
conversion of 4a to 5a in 2 h (Table 1). Here, MeCN/H2O (4:1) 8a in addition to 6aj in a 1:4:4 ratio by LC–MS, respectively
was chosen because MeCN forms an azeotrope with water [40] (Figure 2).
such that it could be easily dried by concentration. After
dissolving resultant crude 5a in anhydrous MeCN and shielding First, we sought to rule out the possibility of Ru(bpy)3Cl2
from ambient light, alkyl, aryl and vinyl Grignard reagents promoting these undesired pathways. Although Ru(bpy)3Cl2
added virtually instantaneously to 5a, affording 6aa–6ai in could not be separated from 5a after photoactivation due to their
good to excellent (62–90%) yields (Table 1). In general, the similar polarities, we successfully separated the less polar
enhanced electrophilicity of 5a compared to MeCN results in iminium salt 5b. In absence of Ru(bpy)3Cl2, addition of the
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Figure 2: Products from allylzinc reagent addition to 5a and 5b.
allylzinc reagent to 5b gave 6ba and side-products 7b and 9 aromatic substitution at the 2-position of the N-aryl moiety.
(Figure 2), and we now explored the origin of these byproducts. (The isolation of enone 8a and the fact that 5a does not react
with oct-1-ene under the same conditions rules out a
The possibility of 6aj or 6ba being intermediates in these side- Diels–Alder-type pathway to 8b.)
reactions was ruled out when 6aj was exposed to the allylzinc
reagent and no reaction was observed. When the allylzinc Formation of side-products 7a and 7b can be rationalised by
reagent was premixed (1:1) with MeCN before adding to 5a, dimerisation of allylzinc halides as has been previously reported
6aj was not observed. Instead, enone 8a was observed as the [42]. The authors describe generation of a bis-organozinc
sole product. Conversely, when the allylzinc reagent was added species which, upon addition to an electrophile, generates an
to 5a, suspended in anhydrous THF, 8a was not observed. The intermediate which can undergo β-hydride delivery to a second
ratio of 6aj:7a was 8:1 by LC–MS and an 88% yield of 6aj electrophile. In this case addition to 5a generates an intermedi-
resulted.
ate organozinc species which, following β-hydride delivery to a
second iminium (5a), generates 7a and 4a (Figure 4). Heating
We propose that allylzinc reagents are reactive enough to trap the allylzinc halide to promote dimerisation [42], prior to addi-
MeCN in competition with 5a. The allylzinc reagent adds to tion to 5a in THF, altered the ratio of 6aj:7a from 8:1 to 3:2 by
MeCN to form an imine salt that is transformed in situ into a LC–MS. In further support of this mechanism, reduction of 5a
conjugated dienamine intermediate (Figure 3). Vinylogous to 4a was also observed (the ratio of 6aj:7a:4a = 5:3:1).
nucleophilic addition of the enamine to 5a generates 8a. This However, our observations cannot rule out β-hydride addition
hypothesis is supported by the reaction of 5a with crotonalde- as the first step. Consistent with our observations, the authors
hyde in the presence of a MacMillan-type imidazolidinone cata- report that the more sterically hindered 2-methylallylzinc and
lyst [41] and TFA which delivers 8b. Formation of cyclic prod- 2-butenylzinc halides do not dimerise even after 48 h under
ucts 8b and 9 is rationalised by intramolecular electrophilic reflux [42].
Figure 3: Proposed mechanism for formation of side-product 8a. Analogous reactivity in the formation of cyclic product 8b under enamine catalysis.
LC–MS (%) yields in parenthesis. Isolated yields, %, after chromatography not in parenthesis.
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Beilstein J. Org. Chem. 2014, 10, 2981–2988.
Figure 4: Mechanism for dimerisation of the allylzinc halide and β-hydride addition to 5a [36].
To avoid the pathways outlined in Figure 3 and Figure 4, we tions benefit from the absence of amide side-products typically
sought a less reactive allyl organometallic than the allylzinc effected by peroxide intermediates in aerobic photoactivation of
reagent. Notably, allylindium reagents have attracted attention THIQs [16,22] and so our methodology serves to complement
for their tolerance to water [43]. Such reagents have mediated existing strategies in the literature.
reactions where allyl Grignards and allylzinc reagents have
failed [44]. Gratifyingly, an allylindium reagent [45] appeared The substrate scope of our methodology is outlined in Table 2.
inert to pathways available to the allyl Grignard and allylzinc Iminium salts derived from a range of electronically diverse
reagent, affording a 92% yield of 6aj. Strikingly, the same N-aryl THIQs (4b and 11a–14b) were trapped with PhMgBr to
reagent was added without a solvent switch and tolerated afford products (6bb and 11b–14b in fair to excellent (47–95%)
BrCCl3, CHCl3 and water, affording 6aj albeit in lower yield yields. Substrates with both electron-rich (12a) and electron-
(68%).
poor (13a,14a) N-aryl substituents were tolerated. Although
Ru(bpy)3Cl2 was ineffective at catalysing oxidation of N-Boc
Murthy and Blechert and their respective co-workers reported protected THIQ 17a, we are pleased to report the first examples
allylation of THIQs under aerobic conditions using allyltrialkyl- of Ru(bpy)3Cl2 catalysed oxidative functionalisation of N-alkyl
stannanes [12,16] (Blechert’s studies also included success with THIQs. Subjecting 15a and 16a to photoactivation for 16 h
allylboron reagents). Whilst our reactions are carried out under furnished in both cases their corresponding benzylic endo-
N2, the indium metal used, allylindium reagents generated and iminium salts, which were trapped by PhMgBr to afford 15b
indium trihalide salt byproducts are non-toxic [43]. Our condi- and 16b in 58% and 81% yield, respectively.
Table 2: Substrate scope of organometallic additions to iminium salts generated via visible-light photoredox catalysis.
Entry
R1/R2
Substrate
Product
Yielda
1b,c
2d
3c
4c
5c
6c
7e
8e
9f
H/Ph
4a
6ag
6bb
11b
12b
13b
14b
15b
16b
17b
90
47
95
52
53
77
58
81
–
H/2-Naphthyl
OMe/Ph
4b
11a
12a
13a
14a
15a
16a
17a
H/4-MeOC6H4
H/4-BrC6H4
H/4-NO2C6H4
H/Me
OMe/Me
H/CO2t-Bu
aIsolated (%) yields after chromatography. bEntry 7, Table 1 given for comparison. cPhotoactivation time of 2 h. dPhotoactivation time of 4 h.
ePhotoactivation time of 16 h. fNo reaction/photoactivation observed.
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Beilstein J. Org. Chem. 2014, 10, 2981–2988.
Encouraged by these results, we decided to apply our method- Stephenson reported diethyl bromomalonate as an effective
ology to THIQ 16a using Grignard 18 in a synthesis of oxidant to regenerate Ru(II) [22]. General application of this
methopholine (3, Scheme 2). Previous syntheses of 3 involving alkyl halide oxidant was ruled out due to potential side-reac-
oxidative functionalisation of 16a have used (4-chloro- tions of the malonyl radical and diethyl malonate. We explored
phenyl)acetylene as a pronucleophile [13,46]. However, isola- alternative alkyl halide oxidants that would form inert byprod-
tion and hydrogenation of the resulting THIQ intermediate are ucts. No reaction was observed when substituting BrCCl3 with
required to access 3. Photoactivation of 16a and trapping of the ClCH2CN (−0.72 V vs SCE [48]) but to our delight, BrCH2CN
resultant benzylic endo-iminium salt with 18 resulted in a 56% (−0.60 V vs SCE [48]) resulted in near-quantitative (90%)
yield of 3. To our knowledge, this concise synthesis of 3 is conversion of 4a to 5a in 3 h (anhydrous conditions). According
higher yielding (based on THIQ 16a) than previously reported to the mechanism proposed by Stephenson for BrCCl3 [22],
syntheses [13,46,47] with no intermediate isolations required.
BrCH2CN forms MeCN as an inert product. Grignard additions
were unaffected by traces of residual BrCH2CN and a selection
Revisiting the concept of direct organometallic addition after of substrates (4a, 11a–13a) and Grignard reagents were
photoactivation (thus far precluded by the use of BrCCl3), employed, affording the products (6aa, 6ab, 6ag, 11b–13b) in
compatibility might be accomplished in two ways. Firstly, encouraging (50–77%) yields (Table 3).
moderate the reactivity of the organometallic to tolerate BrCCl3
or secondly, find alternative oxidants which tolerate the Conclusion
organometallic. Whilst the former looked promising with the We have developed a user-friendly, one-pot methodology which
allylindium example, the latter approach was thought to be combines visible-light photoredox catalysis and organometallic
more general in terms of increasing nucleophile scope.
addition to deliver 1,2-disubstituted THIQs. It is rapid, per-
Scheme 2: A concise synthesis of methopholine (3).
Table 3: Direct one-pot organometallic additions to iminium salts generated via visible-light photoredox catalysis.
Entry
R1/R2/R3
Substrate
Product
Yielda
1b
H/Ph/vinyl
4a
6aa
6ab
6ag
11b
12b
13b
77
73
61
72
73
50
2b
H/Ph/Me
4a
3b
H/Ph/Ph
4a
4b
OMe/Ph/Ph
H/4-MeOC6H4/Ph
H/4-BrC6H4/Ph
11a
12a
13a
5b
6c,d
aIsolated (%) yields after chromatography. bPhotoactivation time of 3 h. cPhotoactivation time of 5 h. dHeating required to solubilise substrate.
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Beilstein J. Org. Chem. 2014, 10, 2981–2988.
11.Boess, E.; Schmitz, C.; Klussmann, M. J. Am. Chem. Soc. 2012, 134,
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commercially available organometallic solutions can be used
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allyl) have been harnessed by varying the organometallic
species. Overall, this methodology is synthetically valuable for
two reasons. Firstly, a virtually limitless host of carbon nucleo-
philes may be employed via organometallic chemistry (com-
pounds 6aa–6af are novel compounds derived from unsta-
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Acknowledgements
We thank GlaxoSmithKline and the University of Strathclyde
for funding. Mass spectrometry data were acquired at the
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