Bronsted acid catalyzed C-H functionalization of N-protected tetrahydroisoquinolines via intermediate peroxides

Article abstract of DOI:10.1002/ejoc.201201527

An organocatalytic oxidative synthesis of N-protected tetrahydroisoquinolines is described by C-H functionalization via intermediate peroxides. The peroxides were synthesized from tert-butylhydroperoxide under metal-free thermal conditions and were converted into the final products by Bronsted acid catalyzed substitution. The nucleophile scope was investigated in detail and proved to be broad; N-deprotection of the coupling products could also be achieved. An organocatalytic oxidative synthesis of N-protected tetrahydroisoquinolines was achieved by C-H functionalization via Intermediate PeroxideS (CHIPS). The peroxides were synthesized under metal-free thermal conditions and were converted into the final products by reaction with a variety of nucleophiles by using Bronsted acid catalysis. Copyright

Full text of DOI:10.1002/ejoc.201201527

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201201527
Brønsted Acid Catalyzed C–H Functionalization of N-Protected
Tetrahydroisoquinolines via Intermediate Peroxides
Bertrand Schweitzer-Chaput[a] and Martin Klussmann*[a]
Keywords: Peroxides / C-H activation / Amines / Homogeneous catalysis / Brønsted acid catalysis
An organocatalytic oxidative synthesis of N-protected tetra-
hydroisoquinolines is described by C–H functionalization via
intermediate peroxides. The peroxides were synthesized
from tert-butylhydroperoxide under metal-free thermal con-
ditions and were converted into the final products by
Brønsted acid catalyzed substitution. The nucleophile scope
was investigated in detail and proved to be broad; N-depro-
tection of the coupling products could also be achieved.
Introduction
Over the past years, oxidative coupling reactions[1] have
received a lot of attention as a result of their attractiveness
in terms of atom economy, directness, and potential to fol-
low green chemistry principles.[2] Among these reactions,
the C–H functionalization of amines and tetrahydroiso-
quinoline (THIQ) derivatives in particular has been the
focus of many studies.[3] Following the pioneering work of
Murahashi[4] and Li,[5] much progress has been made to
extend the scope and to develop new methods for this type
of reaction.[6] The generally accepted mechanism involves
oxidation of amine 1 to corresponding iminium ion 3,[7]
which then reacts with a nucleophile to final coupling prod-
uct 4 (Scheme 1, a). Although the nucleophile scope has
been shown to be quite broad, most reported methods are
limited to N-aryl-substituted amines. Although C1-substi-
tuted THIQs occur frequently in natural products and
pharmaceuticals,[8] the synthetic utility of N-aryl THIQs is
low, and successful attempts to remove the aryl group have
not been reported so far.[6d,9]
Oxidative coupling reactions with amines bearing remov-
able protecting groups are less well developed. Several
methods have been reported, but the substrate scope is
often limited and expensive reagents or catalysts are re-
quired.[9,10] Therefore, we thought that developing a cheap
catalytic method and thoroughly exploring the nucleophile
scope of N-protected THIQs would be an important step
in the expansion of the synthetic utility of such reactions.
On the basis of mechanistic studies conducted in our lab-
oratory on Cu-catalyzed oxidative coupling reactions with
N-phenyl THIQ, we postulated that amino tert-butyl perox-
Scheme 1. (a) General mechanism for the oxidative coupling of
THIQ derivatives; (b) this work: metal-free C–H functionalization
via intermediate peroxides.
ide 2, formed by a radical mechanism, is a precursor to
iminium ion intermediate 3.[11] Such peroxides derived from
N-protected amines have previously been synthesized by Ru
catalysis and used as precursors to substituted products in
the presence of stoichiometric amounts of TiCl4 at low tem-
perature.[10j,10k,12] On the basis of this mechanistic under-
standing and our previous results using methanesulfonic
acid as a catalyst for the substitution of a hydroperoxide
group,[13] we envisioned that a strong Brønsted acid could
be a general catalyst for such transformations. We decided
to study the formation and substitution of such peroxides
separately to reduce the risk of side reactions that might
impair the yield of the final product (Scheme 1, b).
Results and Discussion
As a starting point, we selected N-Cbz-tetrahydroiso-
quinoline (1a) as a standard substrate for the optimization
of the reaction conditions to synthesize tert-butyl peroxides
(Table 1). We hypothesized that by heating tBuOOH we
would be able to initiate a radical reaction, which would
make the whole process metal free.
[a] Max-Planck-Institut für Kohlenforschung,
Kaiser-Wilhelm-Platz 1, 45470 Mülheim an der Ruhr, Germany
Fax: +49-208-306-2980
E-mail: klusi@mpi-muelheim.mpg.de
Homepage: www.kofo.mpg.de
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201527.
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Eur. J. Org. Chem. 2013, 666–671

C–H Functionalization of N-Protected Tetrahydroisoquinolines
Table 1. Optimization of the thermal formation of peroxide 2a.[a]
Entry[b]
T [°C]
Time [h] tBuOOH [equiv.]
Yield [%]
1
2
3
4
5
6
7
80
90
48
28
8
4
4
2:15
4
4
3
3
3
3
3
3
2
4
3
66
65
72
73
70
67
37
100
105
110
120
105
105
105
8
73
Scheme 2. Formation of peroxide starting materials.
9[b]
2
74[c], 73[d]
[a] Standard conditions: 1a (1 mmol), tBuOOH (5.5 m in decane),
decane (0.92 m concentration). [b] No additional decane.
[c] Average of five experiments. [d] Performed on a 1.068-g scale.
Table 2. Optimization of the coupling reaction and exploration of
the electrophile scope.
To our delight, heating compound 1a at 80 °C in a
tBuOOH/decane mixture gave the corresponding peroxide
in reasonable yield (Table 1, entry 1). Careful optimization
of the reaction temperature improved the yield to 73% at
105 °C (Table 1, entry 4), but both lower and higher tem-
peratures gave lower yields (Table 1, entries 1 to 6). A de-
crease in the amount of tBuOOH used reduced the yield,
whereas an increase in the amount used did not have any
effect (Table 1, entries 7 and 8); therefore, 3 equiv. appeared
to be optimal. Finally, performing the reaction under con-
centrated conditions further improved the yield to 74%
while reducing the reaction time to 2 h (Table 1, entry 9).
The reaction could also be performed on the gram scale
without any loss in the yield.
Entry
R
Solvent
MsOH
[mol-%]
Time
[min]
Yield
[%]
1
2
3
4
5
6
7
8
9
Cbz (6a)
Cbz (6a)
Cbz (6a)
Cbz (6a)
Cbz (6a)
Cbz (6a)
Cbz (6a)
Boc (6b)
Bz (6d)
CH2Cl2
toluene
toluene
toluene
AcOH
AcOH
AcOH
AcOH
AcOH
10
10
100
10
10
–
10
10
10
60
180
60
90
1
18 h
1
37
43
57
57[a]
83
46
83[b]
64[b]
73[b]
1
1
Having these optimized conditions in hand, we could ob-
tain a range of N-substituted tetrahydroisoquinoline perox-
ides (Scheme 2). Cbz-substituted peroxide 2a was formed in
[a] 5 equiv. of AcOH were added. [b] 1 equiv. of 5 was used.
only 2 h, whereas Boc analogue 2b needed 5 h to give full sumption of the starting peroxide under these conditions,
conversion, yet an identical yield of 74% was obtained. and this suggests deactivation of the acid catalyst. Increas-
Amide substrates gave poor (14% for 2c) to moderate yields ing the amount of MsOH improved the yield, but stoichio-
(46% for 2d). N-Methyl-substituted product 2e was not ob- metric amounts were needed to achieve full conversion
served, and only products of overoxidation were detected. (Table 2, entry 3; see the Supporting Information for more
Finally, peroxide 2f was the fastest to be formed with full details). Adding acetic acid as a co-catalyst improved the
conversion after 1 h, but it was isolated only in a moderate yield (Table 2, entry 4), but only when the solvent was
yield of 55%. If compounds 2a and 2b proved to be surpris- changed to acetic acid itself was a dramatic change in reac-
ingly stable on silica and to storage, it was not the case for tivity observed (Table 2, entry 5). Full conversion was
others, particularly 2f, which decomposed over time. achieved upon addition of methane sulfonic acid, and the
Furthermore, if 2a and 2b were formed quickly and cleanly, coupling product was isolated in 83% yield. In the absence
the other substrates led to several byproducts and generally of MsOH, acetic acid could still mediate the reaction, but
messier reactions and longer reaction times.
with a substantially reduced rate, to give only 46% yield
After having synthesized the starting materials, we after 18 h (Table 2, entry 6). Finally, only one equivalent of
studied the substitution of the peroxide group by a suitable the nucleophile could be used without impairing the out-
nucleophile using methanesulfonic acid (MsOH) as a cata- come of the reaction (Table 2, entry 7).
lyst. For this purpose, we selected 1,3,5-trimethoxybenzene
The generality of the reaction was then tested with other
(5) and 2a as test substrates (Table 2).
peroxides. N-Boc- and N-Bz-peroxides 2b and 2d gave satis-
Pleasingly, corresponding coupling product 6a was ob- factory yields of 64 and 73% of the corresponding coupling
tained in both toluene and dichloromethane (Table 2, en- products 6b and 6d, respectively, in a similarly short reac-
tries 1 and 2), albeit in moderate yields. Surprisingly, even tion time (Table 2, entries 8 and 9). In contrast, N-phenyl
after a prolonged reaction time, we never saw the full con- peroxide 2f could not be coupled with 5, which we attribute
Eur. J. Org. Chem. 2013, 666–671
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667

B. Schweitzer-Chaput, M. Klussmann
SHORT COMMUNICATION
to the lower electrophilicity of corresponding iminium ion
3f relative to that of the N-acyliminium ions derived from
2a, 2b, and 2d. Using N-methylindole instead of 5, the cou-
pling product with 2f could be formed (see the Supporting
Information for details), which is in accordance with our
previous estimation of the electrophilicity of 3f.[11] This sup-
ports the generality of the substitution reaction and indi-
cates that the failure of 2f to react with 5 is most likely due
to a lack of electrophilicity only.
Finally, we tried to combine these conditions to start
from unoxidized THIQs. Unfortunately, the reaction of 1a
with 5 in the presence of tBuOOH in AcOH at 105 °C only
led to a messy reaction, for which only trace amounts of the
coupling product were detected. Performing the reaction in
a one-pot, two-step fashion resulted in decreased yields and
generally more difficult isolation of the coupling product
(see the Supporting Information).
Scheme 3. Arenes as nucleophiles ([a] room temperature, [b] 1 equiv.
of nucleophile, [c] 50 °C, [d] yield based on recovered starting mate-
rial).
Carbamates are of particular interest for this process, as
their corresponding peroxides 2a and 2b are easily formed
and coupled in good yields. N-Acyl THIQs give satisfactory
coupling yields but are less easily oxidized. N-Methyl perox-
ide 2e could not be isolated and is therefore not a suitable
substrate. Finally, N-Ph-THIQ was shown to react in a sim-
ilar fashion, but this substrate has already been investigated
in great detail.[4–6] Therefore, the Cbz group was selected
for further experiments by using the two-step procedure.
The nucleophile scope was then studied with 2a and ar-
ene nucleophiles (Scheme 3). If 5 reacted smoothly under
the previously optimized conditions, weaker nucleophiles
needed heating and two equivalents to give moderate to
good yields. Coupling product 6d was obtained in 59%
yield when using the previously optimized conditions but
going up to 50 °C and using 2 equiv. of 1,3-dimethoxyben-
zene, a satisfactory yield of 76% was obtained. Even anisole
reacted under these conditions to give product 6e in 24%
yield. This result is still remarkable, as comparable coupling
reactions with anisole have not been reported at such a low
temperature.[10e,14] It is also to be noted that the starting
peroxide was re-isolated from the reaction mixture to give
a yield of 35% for 6e based on the recovered starting mate-
rial. This result can be rationalized by the weaker nucleo-
philicity of anisole compared to that of the equivalent of
tBuOOH released, which can continuously regenerate per-
oxide 2a under the reaction conditions, thus preventing full
conversion. Phenol derivatives were more reactive under
these conditions. Phloroglucinol gave product 6f in 77%
yield at room temperature, whereas 2-naphthol and simple
phenol needed heating at 50 °C to give products 6g and 6h
that electronic density had little to no effect on the yield:
electron-withdrawing (i.e., 7e–g) as well as electron-donat-
ing (i.e., 7h) groups were tolerated and gave high yields in
all cases. Products 7d and 7h both needed 30 min to achieve
full conversion but still gave excellent yields. 1,2,5-Trimeth-
ylpyrrole gave product 7i in 65% yield, whereas pyrrole gave
7j in 51% yield as a single regioisomer.
Scheme 4. Heteroarenes as nucleophiles ([a] 15 min reaction time,
[b] 30 min reaction time).
Carbonyl nucleophiles were then tested under these con-
in 55 and 72%, respectively. In the case of phenol, ortho ditions (Scheme 5). In general, 5 equiv. of nucleophiles had
addition was also observed in small amounts (8% yield). to be used to prevent multiple substitutions. Peroxide 2a
Pleasingly, with indoles and pyrroles as nucleophiles, the could be coupled with acetone, acetophenone, and cyclo-
catalyst loading could be reduced to 1 mol-% (Scheme 4). pentanone (products 8a–c) with yields from 62 to 84%. Di-
In almost all cases, the reaction was complete upon ad- carbonyl nucleophiles were also competent in this transfor-
dition of the catalyst and gave excellent yields. Simple in- mation: acetylacetone gave product 8d in 47% yield and
dole as well as methyl-substituted indoles in the 1-, 2-, or 3- ethyl acetoacetate gave 64% yield of inseparable diastereo-
position gave the corresponding products 7a–d in excellent isomers in a 1:0.8 ratio (product 8e). Disappointingly, di-
yields ranging from 86% to essentially quantitative yield. methylmalonate proved to be a rather poor nucleophile un-
Substitution at the 5-position of the indole core showed der these conditions, as it gave product 8f in only 15% yield.
668
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C–H Functionalization of N-Protected Tetrahydroisoquinolines
Scheme 7. Deprotection of selected coupling products.
Scheme 5. Carbonyl compounds as nucleophiles.
The proposed reaction mechanism is depicted in
Scheme 8. Under thermal conditions, homolytic cleavage of
tBuOOH generates two radicals, which abstract an H atom
from amide 1 and from a second equivalent of tBuOOH.
The corresponding radicals recombine to form peroxide 2.
The reason for the highly selective formation of 2 is not
entirely clear, but similar results have been observed for re-
lated radical reactions.[17] In the second step, methanesulf-
onic acid activates the peroxide, which releases a molecule
of tBuOOH and generates iminium ion 3. This species is
then trapped by a nucleophile to give the corresponding
coupling products.
We also tested the reactivity of 2a towards other C
nucleophiles (Scheme 6). The reaction with an isocyanide
gave amino acid derivative 9 in good yield after a short
reaction time. The reaction with styrene[10d] proved to be
more sluggish, as a mixture of acetate 10a and cyclized
product 10b was obtained.
Scheme 6. Coupling of 2a with alternative C nucleophiles.
Scheme 8. Proposed reaction mechanism.
The reactivity of 2a under these conditions is comparable
to previous reports utilizing substrates such as 1a,[9,10b–10d]
which suggests that all these reactions indeed proceed via a
common intermediate, most likely postulated iminium ion
3. Compared with our mechanistic studies of N-phenyl-
THIQ (1f),[11] the Cbz group increases the electrophilicity
Conclusions
In this communication, we have described a novel metal-
of the iminium ion by approximately five orders of magni- free method for the C–H functionalization of carbamates.
tude: in terms of Mayr’s nucleophilicity values,[15] the lowest A selective metal-free synthesis of intermediate tert-butyl
possible nucleophilicity N in this study is approximately peroxides 2 was achieved under thermal conditions. The
–1.2 (anisole),[16] whereas it was 3.8 for 1f.[11]
peroxide unit can be substituted by a nucleophile often un-
To demonstrate the utility of our method and the use der rapid Brønsted acid catalysis. The nucleophile scope
of an easily removed protecting group, we conducted the proved to be quite broad, including electron-rich arenes and
hydrogenation of some selected coupling products heteroarenes such as indoles, pyrroles, and phenol deriva-
(Scheme 7). As expected from Cbz deprotection, free tives, as well as carbonyl compounds, isonitriles, and styr-
amines 11a and 11b were obtained in nearly quantitative ene. Finally, the use of Cbz as an easily removable protect-
yields. Although free amine 11a could be isolated, it was ing group allows further functionalization of the coupling
more stable as the HCl salt. Not surprisingly, 11c was not products. Further work to increase the scope of this reac-
very stable to hydrogenation conditions and was isolated in tion to include other protected amines is currently un-
only 32% yield.
derway in our laboratory.
Eur. J. Org. Chem. 2013, 666–671
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669

B. Schweitzer-Chaput, M. Klussmann
SHORT COMMUNICATION
products, to Markus Kochius for high-temperature NMR measure-
ments, and to Prof. Benjamin List for financial support and helpful
discussions.
Experimental Section
Warning: Although we never experienced any problem in working
with or handling the compounds described in this work, pre-
cautions should be taken when working with peroxides. In particu-
lar, exposure of the neat peroxides to heat or mixing them with
metals or metal salts should be avoided as much as possible. Per-
forming the thermal synthesis of the peroxides and concentrating
their solutions behind a blast shield is recommended.
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General Procedure for the Synthesis of tert-Butyl Peroxides from
Tetrahydroisoquinolines: A 4-mL screw cap vial was charged with
the corresponding tetrahydroisoquinoline (1 mmol) and a solution
of tBuOOH (5.5 m in decane, 540 μL, 3 mmol) was added. The mix-
ture was stirred at 105 °C by using an aluminum hotplate for the
indicated time (see Table 2). After cooling, the resulting mixture
was directly subjected to flash chromatography on silica gel to af-
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1-(tert-Butylperoxy)-3,4-dihydroisoquinoline-2(1H)-carb-
oxylate (2a): 1H NMR (400 MHz, [D6]DMSO, 80 °C): δ = 7.43–
7.17 (m, 9 H), 6.59 (s, 1 H), 5.25–5.10 (m, 2 H), 4.12–3.98 (m, 1
H), 3.54–3.36 (m, 1 H), 2.88–2.77 (m, 2 H), 1.16 (s, 9 H) ppm. 13C
NMR (100 MHz, [D6]DMSO, 80 °C): δ = 154.26 (q), 136.31 (Ar
q), 135.54 (Ar q), 129.81 (Ar q), 128.59 (ArH), 128.52 (ArH),
128.12 (ArH), 127.82 (ArH), 127.33 (ArH), 127.11 (ArH), 125.72
(ArH), 83.97 (CH), 79.54 (q), 66.17 (CH2), 27.08 (CH2), 25.80
(CH3) ppm. MS (EI): m/z (%) = 355 (0.03), 266 (30), 222 (41), 91
(100). HRMS (ESI): calcd. for [C21H25NO4Na]+ [M + Na+]
378.167791; found 378.167577
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Synthesis of 6a as a Representative Coupling Procedure: In a 4-mL
screw cap vial, peroxide 2a (88.7 mg, 0.25 mmol) was dissolved in
AcOH (1 mL). 1,3,5-Trimethoxybenzene (42 mg, 0.25 mmol) was
then added followed by MsOH (1.77 μL, 0.025 mmol). The mixture
was stirred at room temperature for 30 s, and the whole reaction
mixture was then subjected to flash chromatography (elution with
pentane/AcOEt, 85:15) on silica gel to afford coupling product 6a
(89 mg, 83%) as a clear oil, which gave a white solid upon standing
at room temperature or cooling.
Benzyl 1-(2,4,6-Trimethoxyphenyl)-3,4-dihydroisoquinoline-2(1H)-
carboxylate (6a): 1H NMR (400 MHz, [D6]DMSO, 80 °C): δ =
7.31–7.22 (m, 3 H), 7.17–7.10 (m, 3 H), 7.06 (tt, J = 2, 7.2 Hz, 1
H), 7.00 (td, J = 2, 7.7 Hz, 1 H), 6.69 (d, J = 7.7 Hz, 1 H), 6.46 (s,
1 H), 6.19 (s, 2 H), 5.05–4.95 (m, 2 H), 4.24 (ddd, J = 3, 5, 12.6 Hz,
1 H), 3.77 (s, 3 H), 3.58–3.49 (m, 7 H), 2.90–2.75 (m, 2 H) ppm.
13C NMR (100 MHz, [D6]DMSO, 80 °C): δ = 159.89 (Ar q), 158.41
(Ar q), 154.46 (q), 136.79 (Ar q), 136.53 (Ar q), 134.08 (Ar q),
127.67 (ArH), 127.52 (ArH), 126.97 (ArH), 126.80 (ArH), 125.42
(ArH), 125.32 (ArH), 125.05 (ArH), 113.06 (Ar q), 91.62 (ArH),
65.59 (CH2), 55.33 (CH3), 54.81 (CH3), 48.75 (CH), 39.28 (CH2),
29.19 (CH2) ppm. MS (EI): m/z (%) = 433 (5), 342 (4), 298 (100),
91 (27). HRMS (ESI): calcd. for [C26H27NO5Na]+ [M + Na+]
456.178527; found 456.178146.
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures, product characterization, further
details of the optimization studies, and copies of the 1H NMR and
13C NMR spectra.
Acknowledgments
The authors are grateful to the Deutsche Forschungsgemeinschaft
(DFG) for funding (Heisenberg scholarship to M. K., KL 2221/4-
1; KL 2221/3-1), to Corinna Schmitz for the synthesis of some
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Published Online: December 13, 2012
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