Synthesis of Carbolines via Palladium/Carboxylic Acid Joint Catalysis

Article abstract of DOI:10.1021/acs.orglett.8b01072

The combination of a Pd(0) complex with benzoic acid converts propargylic tryptamines to the corresponding tetrahydro-β-carbolines. The method uses unprotected indoles and affords the desired products with ample functional group tolerance. Detailed modeling studies reveal a close synergy between the organic and metal catalysts, which enables sequential alkyne isomerization, indole C-H activation, and eventual C-C reductive elimination to afford the target heterocycles.

Full text of DOI:10.1021/acs.orglett.8b01072

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Carbolines via Palladium/Carboxylic Acid Joint Catalysis
Gianpiero Cera,† Matteo Lanzi,† Davide Balestri,† Nicola Della Ca’,† Raimondo Maggi,† Franca Bigi,†,§
Max Malacria,‡ and Giovanni Maestri*,†
†Universita
43124 Parma, Italy.
‡UPMC Sorbonne Universite,
̀ ̀
di Parma, Dipartimento di Scienze Chimiche, della Vita e della Sostenibilita Ambientale, Parco Area delle Scienze 17/A,
́
IPCM (UMR CNRS 8232), 4 place Jussieu, C. 229, 75005 Paris, France.
§IMEM-CNR, Parco Area delle Scienze 37/A, 43124 Parma, Italy.
S
* Supporting Information
ABSTRACT: The combination of a Pd(0) complex with
benzoic acid converts propargylic tryptamines to the
corresponding tetrahydro-β-carbolines. The method uses
unprotected indoles and affords the desired products with
ample functional group tolerance. Detailed modeling studies
reveal a close synergy between the organic and metal catalysts,
which enables sequential alkyne isomerization, indole C−H
activation, and eventual C−C reductive elimination to afford
the target heterocycles.
part of our interest in catalytic cyclizations of polyunsaturated
substrates,8 we turned our attention to readily available
propargylic tryptamines A. Their reactivity with soft π-acidic
transition metals is well-established (Figure 1b)9 but remains
unexplored with palladium (Figure 1c).10
etrahydro-1H-β-carbolines (THCs) are important cores in
Torganic chemistry due to their presence in many bioactive
alkaloids and pharmaceuticals.1 Therefore, straightforward
synthetic approaches are in high demand.
The synthesis of THC analogues traditionally relies on
Pictet−Spengler reactions,2 oxidative C−H functionalizations,3
and intramolecular hydroarylation of unsaturated substrates
such as alkenes, allylic alcohols, and their derivatives. These are
mostly accomplished using 4d and 5d transition-metal
catalysts.4 Enantioselective approaches could rely on either
organo- or bioinspired catalysts.5 An important alternative has
been recently realized by developing gold-catalyzed allenamide
cyclizations (Figure 1a).6 However, this approach suffers from
the inherent challenges of modular allenamide synthesis.7 As
Gratifyingly, THC 2a was isolated as a single E-isomer in
38% yield (Table 1, entry 1) using PCy3. Bidentate phosphines
Table 1. Ligand Optimization
a
entry
[Pd]
ligand
PCy3
temp (°C)
2a (%)
1
2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(dba)2
100
100
70
38
b
dppe
59
b
3
dppf
45
4
PPh3
100
70
71
70
40
−
5
PPh3
6
DavePhos
PPh3
100
100
70
7
Pd(OAc)2
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
8
t-BuXPhos
PPh3
48
c
9
100
100
78
d
10
PPh3
−(13)
a
Reaction conditions: 1a (0.20 mmol), [Pd] (5 mol %), ligand (10
mol %), BzOH (30 mol %), toluene (0.1 M), yields of isolated
b
c
product. Ligand (5 mol %). [Pd] (10 mol %), PPh3 (20 mol %).
d
Without BzOH, conversion of 1a in brackets.
Received: April 5, 2018
Figure 1. Alternative routes to THCs.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b01072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
yield 2a with slightly better performances (entries 2 and 3).
The use of cheaper PPh3 promoted the catalytic transformation
with moderate yields and high chemoselectivity, even at lower
temperature (entries 4 and 5). Pd(dba)2 could be applicable,
although to a lower extent (entry 6).11 On the contrary, a
Pd(II) precursor, such as the popular Pd(OAc)2, was not a
suitable catalyst for this transformation (entry 7). Buchwald’s
ligands and substituted triarylphosphine analogues were unable
to improve the catalytic system (entry 8, details in the
Supporting Informations).12 Hence, 2a was isolated in 78%
yield by increasing the catalyst loading (entry 9).13 The
reaction without benzoic acid provided traces of 2a (entry 10),
highlighting the crucial role of the former.
and heteroarenes, such as thiophene, delivered the correspond-
ing THCs in good yields (2j−l, 50−73%). Reactions involving
arylalkynes (2c−l) deliver the desired products only, and
unreacted starting materials can be recovered by chromatog-
raphy. Then, we studied substituted tryptamines (Figure 3).
In all cases, we observed complete control of the alkene
configuration, retrieving 2a as a single E-isomer. A family of
diversely functionalized propargylic tryptamines 1 was then
submitted to the optimized catalytic system (Figure 2).
Figure 3. Synthesis of THCs 4.
Protection of tryptamine with either methanesulfonyl (Ms)
or p-Cl-benzensulfonyl did not affect the outcome of the
catalytic reaction (Figure 3, 4a,b). Electron-donating functional
groups such as alkyl, aryl, silyl ethers and ethers at the C(5)-
position of the indole were well tolerated, delivering THCs 4c−
g with good to excellent yields (57−93%). The method allowed
the synthesis of THCs 4h−k with electron-withdrawing groups
located at the C(5)- and C(6)-position with moderate to good
yields (51−79%). The robustness of the sequence was further
mirrored by the synthesis of a symmetrical THC dimer (Figure
4). Noteworthy, the synthesis of 4l proceeds smoothly with
high chemoselectivity and a synthetically useful yield (56%).
Then, different experiments were carried out to rationalize
the reaction mechanism and gain insights on its complete
chemo- and site-selectivities. THC 4m was isolated in 70%
yield using allenamide 3m under typical reaction conditions
(Figure 5a). This result is consistent with the intermediate
formation of allenamides in the sequence. Then, the influence
of indole N-substitution was investigated. We observed the
formation of acyclic diene 4n′ and no traces of THC 4n by
testing precursor 3n (Figure 5b). This result shows that the free
N−H of the indole is crucial for the annulation step and shows
once more the virtues of a protecting-group free synthesis.15
Finally, the attempted intramolecular dearomatization of
propargylic precursor 3o,16 in which the indole C(2) is
Figure 2. Synthesis of THCs 2.
Alkyl- and arylalkyne derivatives were tolerated, leading to
the corresponding products 2b,c in 54 and 85% yields,
respectively. A broad family of 3-arylprop-2-yn-1-ylindole
derivatives 1 was efficiently converted to THCs 2 (2d,I, 50−
88%). Thus, the method is suitable for the synthesis of various
fluorinated THCs. Substrates bearing EWGs performed better
with respect to the corresponding electron-rich ones. However,
substitution at the para-position of the aryl ring with different
halogen atoms, namely chlorides and bromides, did not afford
2.14 Tryptamine derivatives bearing biphenyls, naphthalenes,
B
DOI: 10.1021/acs.orglett.8b01072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 4. Synthesis of dimeric THC 4l.
Figure 6. Most favorable modeled mechanism and key transition
states.
Figure 5. Experimental mechanistic evidences.
proved to be the most energy-demanding barrier of the whole
sequence because of the limited rotational flexibility of the
allylic methylene (ΔG of +24.9 kcal/mol; up to +28.1 at the
B3LYP level). Complex V is more stable than its alkyne peer III
(by −4.8 kcal/mol). This suggests that allenamides bind Pd(II)
hydrides more strongly than internal alkynes. A second
insertion into the Pd−H bond gives allyl complex VI through
a low barrier process (+5.2 kcal/mol in ΔG). Replacement of
the acetate ligand by phosphine provides complex VII, in which
the metal presents a slipped η2-indole coordination, and the
carboxylate is engaged in hydrogen bonding with the indole
N−H group. This is crucial to favor the sequential C−H
activation, which occurs through an outer-sphere CMD
pathway19 (barriers of +18.2 and +18.8 kcal/mol in ΔG with
PMe3 and PPh3, respectively). This is consistent with the
positive role of additional ligands on yield (Table 1). It is worth
noting that direct C−H activation of indole is, on the contrary,
usually prevented by the presence of a free N−H group, which
sunk the basicity of metal-bound carboxylates via hydrogen
bonding.16,19 Modeling an inner-sphere CMD indeed provided
higher barriers (+29.2 kcal/mol in ΔG). Try as we might, we
failed to obtain any stationary point for Pictet−Spengler-like
pathways from either complex V or VI (Figure S9). Scans of
these pathways show a linear increase of E only (up to above 40
kcal/mol), suggesting that indole dearomatization does not lead
to any stable intermediate in these cases. These results parallel
recent computational ones on C-palladations previously
thought to occur via electrophilic aromatic substitutions.20
substituted with a methyl group, failed to provide any product
(Figure 5c). This result was highly unexpected on the basis of
the literature precedents2,6,9 and led us hypothesize that a C−H
activation step could operate in our case. We are unaware of the
literature precedents on C−H activation/alkylation at C(2) of
unprotected indoles.17
Thus, we resorted to DFT modeling to solve the riddle. The
investigation began using the M06 functional in combination
with either lacvp(d) and Def2-svp(d) basis sets, which proved
to be reliable methods to describe elaborate palladium-
catalyzed sequences.18 Complete pathways were modeled
with PMe3 as ligand both in the gas phase and using toluene
as implicit solvent to reduce further the odds of modeling
artifacts. Different functionals were also tested and the key steps
were reoptimized with PPh3 (see Figures S2−S13 for details).
Overall, coherent results were obtained in all cases, which led us
to propose the mechanism of Figure 6 to account for the
formation of THC 2 in these sequences.
A reaction of the carboxylic acid with Pd(0) complex I can
deliver trans-Pd(II) hydride II. Its cis-peer is less stable and
furthermore requires higher barriers too (Figure S4).
Endoergonic phosphine replacement by the substrate yields
complex III, which evolves to vinyl species IV via migratory
insertion. Barriers for this step were expectedly low (between
+2.8 and +6.8 kcal/mol among the different models). The
subsequent β-elimination affords allenamide complex V. This
C
DOI: 10.1021/acs.orglett.8b01072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(2) (a) Wang, S. G.; Xia, Z. L.; Xu, R. Q.; Liu, X. J.; Zheng, C.; You,
S. L. Angew. Chem., Int. Ed. 2017, 56, 7440−7443. (b) Gobe, V.;
Dousset, M.; Retailleau, P.; Gandon, V.; Guinchard, X. Adv. Synth.
Catal. 2016, 358, 3960−3965. (c) Hansen, C. L.; Clausen, J. W.; Ohm,
R. G.; Ascic, E.; Le Quement, S. T.; Tanner, D.; Nielsen, T. E. J. Org.
Chem. 2013, 78, 12545−12565. For a review, see: (d) Stockigt, J.;
Antonchick, A. P.; Wu, F. R.; Waldmann, H. Angew. Chem., Int. Ed.
2011, 50, 8538−8564.
Heck-like insertion on indole from VII provided a sky-high
barrier of +50.5 kcal/mol (Figure S10). Taken together within
the framework of the energy span model,21 these results
strongly suggest that indole functionalization occurs via C−H
activation in this sequence. The results also highlight the dual
nature of the carboxylic acid in this cascade. It initially serves to
generate the Pd hydride that triggers alkyne isomerization. The
resulting carboxylate then becomes crucial as well. It plays the
role of a base assisting the metal in the C−H activation,
therefore acting in a catalytic fashion. The desired product is
eventually released by C−C reductive elimination from
metallacycle VIII. This step has a barrier comparable to those
of similar Pd(II) complexes (+16.2 kcal/mol in ΔG).17
We present the first catalytic synthesis of tetrahydrocarbo-
lines from propargylic tryptamines by means of palladium and
carboxylic acid joint catalysis. The method combines interesting
synthetic features with unexpected mechanistic findings. We
anticipate that the latter will produce ample future develop-
ments of indole chemistry in C−H activation sequences.
(3) Liu, X. G.; Meng, Z. L.; Li, C. K.; Lou, H. X.; Liu, L. Angew.
Chem., Int. Ed. 2015, 54, 6012−6015.
(4) (a) Lin, T. Y.; Wu, H. H.; Feng, J. J.; Zhang, J. L. ACS Catal.
2017, 7, 4047−4052. (b) Zhuo, C. X.; Wu, Q. F.; Zhao, Q.; Xu, Q. L.;
You, S. L. J. Am. Chem. Soc. 2013, 135, 8169−8172. (c) Zhang, D. H.;
Tang, X. Y.; Wei, Y.; Shi, M. Chem. - Eur. J. 2013, 19, 13668−13673.
(d) Wu, Q. F.; Zheng, C.; You, S. L. Angew. Chem., Int. Ed. 2012, 51,
1680−1683. (e) Bandini, M.; Eichholzer, A. Angew. Chem., Int. Ed.
2009, 48, 9533−9537.
(5) (a) Wei, G.; Zhang, C.; Bures, F.; Ye, X.; Tan, C.-H.; Jiang, Z.
ACS Catal. 2016, 6, 3708−3712. (b) Xie, Z.; Zan, X.; Sun, S.; Pan, X.;
Liu, L. Org. Lett. 2016, 18, 3944−3947. (c) Ghislieri, D.; Houghton,
D.; Green, A. P.; Willies, S. C.; Turner, N. J. ACS Catal. 2013, 3,
2869−2872. For a review on bioinspired strategies, see: (d) Ghislieri,
D.; Turner, N. J. Top. Catal. 2014, 57, 284−300.
(6) Wang, Y.; Zhang, P.; Di, X.; Dai, Q.; Zhang, Z.-M.; Zhang, J.
Angew. Chem., Int. Ed. 2017, 56, 15905−15909.
(7) For reviews on allenamides chemistry, see: (a) Manoni, E.;
Bandini, M. Eur. J. Org. Chem. 2016, 2016, 3135−3142. (b) Lu, T.; Lu,
Z.; Ma, Z.-X.; Zhang, Y.; Hsung, R. P. Chem. Rev. 2013, 113, 4862−
4904.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b01072.
Experimental details, complete modeling data, character-
ization of products, copies of NMR spectra, XYZ
coordinates (PDF)
̀
(8) Lanzi, M.; Caneque, T.; Marchio, L.; Maggi, R.; Bigi, F.; Malacria,
̃
M.; Maestri, G. ACS Catal. 2018, 8, 144−1467.
(9) Selected examples of intramolecular alkyne hydroindolination.
[Au]: (a) Magne, V.; Marinetti, A.; Gandon, V.; Voituriez, A.;
Guinchard, X. Adv. Synth. Catal. 2017, 359, 4036−4042. (b) Cera, G.;
Chiarucci, M.; Mazzanti, A.; Mancinelli, M.; Bandini, M. Org. Lett.
2012, 14, 1350−1353. (c) Ferrer, C.; Echavarren, A. M. Angew. Chem.,
Int. Ed. 2006, 45, 1105−1109. [Pt]: (d) Gruit, M.; Pews-Davtyan, A.;
Beller, M. Org. Biomol. Chem. 2011, 9, 1148−1159.
Accession Codes
CCDC 1826210−1826211 contain the supplementary crystal-
lographic data for this paper. These data can be obtained free of
charge via www.ccdc.cam.ac.uk/data_request/cif, or by email-
ing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(10) For the synthesis and reactivity of Pd hydrides, see: (a) Peacock,
M. D.; Roos, C. B.; Hartwig, J. F. ACS Cent. Sci. 2016, 2, 647−652.
(b) Vyas, D. J.; Larionov, E.; Besnard, C.; Guenee, L.; Mazet, C. J. Am.
Chem. Soc. 2013, 135, 6177−6183.
AUTHOR INFORMATION
■
(11) Selected examples of metal-catalyzed alkyne isomerization. [Pd]:
(a) Yang, C.; Zhang, K.; Wu, Z.; Yao, H.; Lin, A. Org. Lett. 2016, 18,
5332−5335. (b) Kadota, I.; Shibuya, A.; Gyoung, Y. S.; Yamamoto, Y.
J. Am. Chem. Soc. 1998, 120, 10262−10263. [Ru]: (c) Chen, Q.-A.;
Cruz, F. A.; Dong, V. M. J. Am. Chem. Soc. 2015, 137, 3157−3160.
(d) Liang, T.; Nguyen, K. D.; Zhang, W. D.; Krische, M. J. J. Am.
Chem. Soc. 2015, 137, 3161−3164. (e) Park, B. Y.; Nguyen, K. D.;
Chaulagain, M. R.; Komanduri, V.; Krische, M. J. J. Am. Chem. Soc.
2014, 136, 11902−11095. [Rh]: (f) Yang, X.-H.; Lu, A.; Dong, V. M.
J. Am. Chem. Soc. 2017, 139, 14049−14052. (g) Cruz, F. A.; Zhu, Y.;
Tercenio, Q. D.; Shen, Z.; Dong, V. M. J. Am. Chem. Soc. 2017, 139,
10641−10644. Review: (h) Koschker, P.; Breit, B. Acc. Chem. Res.
2016, 49, 1524−1536.
Corresponding Author
*E-mail: giovanni.maestri@unipr.it.
ORCID
Davide Balestri: 0000-0003-3493-9115
Nicola Della Ca’: 0000-0002-7853-7954
Max Malacria: 0000-0002-3563-3508
Giovanni Maestri: 0000-0002-0244-8605
Notes
The authors declare no competing financial interest.
(12) Patil, N. T.; Song, D.; Yamamoto, Y. Eur. J. Org. Chem. 2006,
2006, 4211−4213.
(13) Mass balance can be accounted with the formation of allenyl-
tryptamine 2a′ as a major side product; see the SI for details.
ACKNOWLEDGMENTS
■
We warmly thank support from the UniPr (Grant RADI-CAT),
MIUR (Grant AROMA-TriP and Departments of Excellence
framework), CNRS, and UPMC. Use of modeling facilities was
provided by ICSN-CNRS (UPR2301, Gif sur Yvette, France).
REFERENCES
■
(1) (a) Paciaroni, N. G.; Ratnayake, R.; Matthews, J. H.; Norwood, V.
M.; Arnold, A. C.; Dang, L. H.; Luesch, H.; Huigens, R. W. Chem. -
Eur. J. 2017, 23, 4327−4335. (b) Tokuda, R.; Okamoto, Y.; Koyama,
T.; Kogure, N.; Kitajima, M.; Takayama, H. Org. Lett. 2016, 18, 3490−
3493. (c) Spindler, A.; Stefan, K.; Wiese, M. J. Med. Chem. 2016, 59,
6121−6135. (d) Kato, N.; et al. Nature 2016, 538, 344−349.
(14) For details on scope limitations, see Figure S1.
(15) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446,
404−408.
(16) Franzoni, I.; Yoon, H.; Garcia Lopez, G.-A.; Poblador-
Bahamonde, A.-I.; Lautens, M. Chem. Sci. 2018, 9, 1496−1509.
D
DOI: 10.1021/acs.orglett.8b01072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(17) For elegant strategies that temporarily mask indole N−H using
norbornene, see: (a) Zhang, H.; Wang, H.-Y.; Luo, Y.; Chen, C.; Cao,
Y.; Chen, P.; Guo, Y.-L.; Lan, Y.; Liu, G. ACS Catal. 2018, 8, 2173−
2180. (b) Jiao, L.; Bach, T. J. Am. Chem. Soc. 2011, 133, 12990−12993.
For a rare C(2) arylation, proposed to occur through a complementary
mechanism, see: (c) Lane, B. S.; Brown, M. A.; Sames, D. J. Am. Chem.
Soc. 2005, 127, 8050−8057. For an example arylating C(3) with Cu,
see: (d) Pitts, A. K.; O’Hara, F.; Snell, R. H.; Gaunt, M. J. Angew.
Chem., Int. Ed. 2015, 54, 5451−5455. A review: (e) Sandtorv, A. H.
Adv. Synth. Catal. 2015, 357, 2403−2435.
(18) (a) Narbonne, V.; Retailleau, P.; Maestri, G.; Malacria, M. Org.
Lett. 2014, 16, 628−631. (b) Maestri, G.; Malacria, M.; Derat, E.
Chem. Commun. 2013, 49, 10424−10426. (c) Maestri, G.; Della Ca’,
N.; Motti, E.; Malacria, M.; Derat, E.; Catellani, M. J. Am. Chem. Soc.
2011, 133, 8574−8585.
(19) For a specific review on carboxylate role, see: (a) Davies, D. L.;
Macgregor, S. A.; McMullin, C. L. Chem. Rev. 2017, 117, 8649−8709.
Part of special issue dedicated to C−H activation. For selected reviews,
see: (b) Chu, J. C. K.; Rovis, T. Angew. Chem., Int. Ed. 2018, 57, 62−
101. (c) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J.
Chem. Soc. Rev. 2016, 45, 2900−2936. (d) Topczewski, J. J.; Sanford,
M. S. Chem. Sci. 2015, 6, 70−76. (e) Ackermann, L. Acc. Chem. Res.
2014, 47, 281−295. (f) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem.
Soc. Rev. 2011, 40, 1885−1898. (g) Chiusoli, G. P.; Catellani, M.;
Costa, M.; Motti, E.; Della Ca’, N.; Maestri, G. Coord. Chem. Rev.
2010, 254, 456−469.
(20) Yamamoto, Y.; Murayama, T.; Jiang, J.; Yasui, T.; Shibuya, M.
Chem. Sci. 2018, 9, 1191−1199.
(21) Kozuch, S.; Shaik, S. Acc. Chem. Res. 2011, 44, 101−110.
E
DOI: 10.1021/acs.orglett.8b01072
Org. Lett. XXXX, XXX, XXX−XXX