Route to 3-Amidino Indoles via Pd(II)-Catalyzed C-H Bond Activation

Article abstract of DOI:10.1021/acs.orglett.7b01836

We report a facile synthesis of 3-amidino indoles from indoles and cyanamides. The reaction is Pd(II)-catalyzed and proceeds via C-H bond activation of the indole in its 3-position followed by a 1,2-addition of the resulting indole-palladium σ-complex to a cyanamide, which provides the corresponding amidine. The preference for 4,5-diazafluoren-9-one (DAF) as the ligand is investigated using DFT calculations, and a plausible reaction pathway is presented.

Full text of DOI:10.1021/acs.orglett.7b01836

Letter
pubs.acs.org/OrgLett
Route to 3‑Amidino Indoles via Pd(II)-Catalyzed C−H Bond Activation
†
†
†
†
,‡
Jonas Rydfjord, Bobo Skillinghaug, Peter Brandt, Luke R. Odell, and Mats Larhed*
†
‡
Organic Pharmaceutical Chemistry, Department of Medicinal Chemistry, and Department of Medicinal Chemistry, Science for Life
Laboratory, Uppsala University, Box-574, SE-751 23 Uppsala, Sweden
*
S Supporting Information
ABSTRACT: We report a facile synthesis of 3-amidino indoles from
indoles and cyanamides. The reaction is Pd(II)-catalyzed and proceeds via
C−H bond activation of the indole in its 3-position followed by a 1,2-
addition of the resulting indole−palladium σ-complex to a cyanamide,
which provides the corresponding amidine. The preference for 4,5-
diazafluoren-9-one (DAF) as the ligand is investigated using DFT
calculations, and a plausible reaction pathway is presented.
he amidine motif is found in several potential disease
modifying agents as well as in the commercial drug
pentamidine. Selected drug discovery examples include
Initially, we established viable reaction conditions by varying
T
the catalyst precursor, ligand, acid additive, solvent, stoichiom-
etry, temperature, and reaction time for a model reaction of 1-
methylindole (1a) and dimethylcyanamide (2a) or diethyl-
cyanamide (2b). A ligand screen is presented in Table 1,
1
2
inhibitors of serine proteases, platelet aggregation, acid-
3
4
5
sensing ion channels, and BACE1, as well as antibacterials,
antimalarials, and m1 muscarinic receptor agonists. Amidines
are also used as precursors in the preparation of heterocycles
such as triazoles, pyrimidines, and benzimidazoles, to name
a few. There are several strategies for synthesizing amidines in
6
7
Table 1. Ligand Screen
8
9
10
1
1
12
the literature, including the Pinner reaction, nucleophilic
14
13
substitution of thioamides and imidates, Pd(0)-catalysis,
1
5
addition of alkylchloroaluminum amides to nitriles, and many
1
6
others.
We have previously disclosed protocols for the synthesis of
aryl amidines via a Pd(II)-catalyzed 1,2-addition reaction of an
17
arylpalladium precursor and a cyanamide. The arylating
agents demonstrated to date are aryl trifluoroborates, generally
with a broad scope except for electron-poor substrates, which
1
7a
result in low yields,
and aryl carboxylic acids, which are
17b
limited to electron-rich, ortho-substituted substrates.
An alternative strategy for generating the essential (hetero)-
arylpalladium intermediate is through C−H activation of
various aromatic systems. There are several articles describing
C−H activation protocols in the Pd(II)-catalyzed 1,2-addition
to nitriles to give aryl ketones. This inspired us to envision
the possibility to access this reaction manifold using cyanamides
as substrates. Thus, we set out to investigate indoles as C−H
activation substrates for the Pd(II)-catalyzed 1,2-addition to
cyanamides, providing 3-amidino indoles (Figure 1).
aBy 1H-qNMR analysis of crude reaction. Reaction conditions:
Pd(O
mmol), 2a (0.6 mmol), camphorsulfonic acid (0.6 mmol), and DMA
1 mL) at 100 °C for 18 h.
CCF ) (0.02 mmol), ligand N−N (0.024 mmol), 1a (0.4
2
3 2
(
18
evaluating a set of well-known Pd(II) bidentate nitrogen
ligands, clearly indicating 4,5-diazafluoren-9-one (DAF) as a
productive ligand (entry 7). After optimization of the remaining
parameters (see Supporting Information (SI)), we identified a
functional protocol for preparing 3a (see Scheme 1).
Purifying the resulting amidine 3a proved difficult, as we
were not able to obtain sufficiently pure product using normal-
phase chromatography on silica gel or aluminum oxide. Our
previous approach of a liquid−liquid extraction to purify aryl
17a,b
amidines
was also futile in this case as we were not able to
remove the DAF ligand. Finally, a suitable purification
Received: June 16, 2017
Figure 1. Pd(II)-catalyzed synthesis of aryl amidines.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01836
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 1. Reaction Scope for Cyanamide Substrates
Scheme 2. Reaction Scope for Indole Substrates
a
1
Isolated yield (>95% pure by H NMR). Reaction conditions as in
b
1
Scheme 1. Isolated yield (>90% pure by H NMR).
aIsolated yield (>95% pure by 1H NMR). Reaction conditions:
Although a catalytic cycle is easily envisioned as depicted in
Figure 2, the mechanistic details remain unknown. To
Pd(O CCF ) (0.02 mmol), DAF (0.024 mmol), 1a (0.4 mmol),
2
3 2
cyanamide substrate 2a−i (0.6 mmol), pTSA (0.6 mmol), and DMA
b
1
(
1 mL) at 100 °C for 18 h. Isolated yield (>90% pure by H NMR).
c
TFA in place of pTSA.
procedure using a reversed-phase C18 column on an automated
flash chromatography system using a water/acetonitrile
gradient with 0.1% HCOOH as an additive was identified.
The pure amidine was then isolated after basification and
extraction.
The scope of the reaction was next investigated with regard
to the cyanamides (Scheme 1), using 1a as the indole substrate.
Dimethyl, diethyl, and diisopropyl cyanamide (2a, 2b, and 2c)
worked well, providing isolated yields of 73%, 78%, and 52% of
the respective products (3a, 3b, and 3c). The lower yield of the
diisopropyl derivative may be attributed to the bulkiness of the
substrate. 1-Cyanomorpholine and 1-cyanopiperidine (2d and
2
e) both afforded the corresponding products, 3d and 3e, in
Figure 2. Generic catalytic cycle illustrating the three key steps of the
reaction.
good yield (76% and 70%, respectively), while 1-cyanopyrro-
lidine (2f) only gave a 29% yield of the desired product, 3f. The
bulky dibenzyl cyanamide (2g) furnished a 48% yield of the
corresponding product 3g. Cyanamide and tert-butyl cyanamide
understand the reaction better in terms of ligand dependence,
rate-determining step/resting state, and the role of the acid
additive, a DFT study was performed using substrates 1a and
2a (for details, see SI). As a minor simplification of the reaction
system, TFA was used in place of pTSA, which was used in the
optimized reaction protocol. The use of TFA as the acid
additive results in a decrease in yield but otherwise performs
similarly to pTSA (see Scheme 1). Two ligands were
investigated computationally: DAF, which was the most
productive in Table 1 (entry 7), and bpy, which was found
to give a less productive reaction (entry 1). The DFT
calculations indicate that the concerted metalation−deproto-
nation (CMD) step is expected to be a relatively smooth
process for both ligands (see Figure 3, IV). The free energies of
(
2h and 2i) also provided fair yields, furnishing un- and mono-
N-substituted products 3h and 3i in 55% and 42% yield,
respectively.
The scope of the indole partner in the reaction was also
evaluated (Scheme 2), giving 3j in 59% yield by combining
indole (1b) with 2a, or 3k in 66% yield starting from diethyl
cyanamide 2b. Substituents in the 2-position were well
tolerated (1c−e), returning the desired amidine products 3l−
n in 42−77% yield. 5-Methylindole (1f) furnished 3o in 70%
yield, while 1-methyl-2-phenylindole (1g) gave the correspond-
ing product 3p in 30% yield. The more electron-deficient 5-
bromo-indole (1h) and 5-cyano-indole (1i) afforded 3q and 3r
in 35% and 24% yield, respectively.
B
DOI: 10.1021/acs.orglett.7b01836
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
−1
Figure 5. Free energies (kcal mol ) for product displacement and
catalyst regeneration with DAF or bpy as ligands. 3a-H+ is the
protonated product. Values in parentheses include consecutive
protonation of 3a.
temperature needed for the reaction to proceed. Therefore, it is
likely that the catalyst−product complex IX (Figure 5) is the
resting state of the reaction. As the protonation of the
coordinated product imidamidate VIII was found to be fast, a
similar mechanism was investigated for the amidine complex
IX. By hydrogen bonding to the imine nitrogen π-orbital by
TFA, a concerted mechanism (Figure 5, Path A) could be
identified, leading to regeneration of the catalyst as a
trifluoroacetate complex II (Figure 5). However, the barrier
for this step was high: 41.3 kcal mol− for the DAF system and
−
1
Figure 3. Free energies (kcal mol ) for the CMD step for catalysts
with DAF or bpy as ligands and indole substrate 1a, leading to σ-
complex V.
activation relative to the lowest energy intermediate III (see
−1
Figure 3) was found to be lower by 1.5 kcal mol for the DAF
system. A more significant difference between the two catalysts
lies in the coordination of TFA (II vs I and III). Here, the Pd-
DAF catalyst strongly disfavors κ -coordination of TFA.
For both catalysts, the C−H activation step is completely
reversible, in line with the deuterium incorporation results for a
similar system reported by Campbell et al.
The next step of the reaction is migratory insertion of the
cyanamide into the Pd−indole bond (see Figure 4). This step
1
2
3
6.9 for the bpy system (see Figure 5).
Therefore, an alternative mechanism with a concerted ligand
19
exchange process involving the indole reactant was investigated
Figure 5, Path B). This mechanism was found to be lower in
(
energy and proceeds by displacement of the product amidine
by 1a via a penta-coordinated trigonal bipyramidal Pd center
leading to III (see Figures 5 and 6). However, releasing the
−1
Figure 4. Free energies (kcal mol ) relative III for migratory
insertion for catalysts with DAF or bpy as ligands in the reaction
between 1a and 2a.
Figure 6. Concerted product displacements leading to regeneration of
the catalyst II (Path A, acid mediated) or catalyst−reactant complex
III (Path B, indole mediated). The dashed yellow line indicates a
hydrogen bond between the trifluoroacetate and the amidine product
in the transition states X and XI depicted above.
requires displacement of TFA with cyanamide, a step assumed
to be fast. Again, the difference between the two ligands is
−1
small, with a 3 kcal mol advantage for DAF over bpy in the
−1
migratory insertion (17.7 vs 20.7 kcal mol ). This reaction
leads to complex VIII with the product as a bidentate ligand
with the indole moiety bound as a π-complex.
product in a neutral form is endergonic. Therefore, the release
needs to be accompanied by protonation (see values in
parentheses in Figure 5), adding to the roles of the acid as
being involved in the concerted metalation−deprotonation,
product release, and the thermodynamic driving force for the
reaction.
DAF renders all three key steps (CMD, migratory insertion,
and catalyst regeneration) in the catalytic cycle slightly faster
compared to bpy, including the final dissociation of the
product.
In conclusion, a protocol for the generation of 3-amidino
indoles from cyanamides and indoles via Pd(II)-catalyzed C−H
bond activation has been developed. Additionally, the
mechanism was investigated by the means of DFT calculations,
providing improved mechanistic understanding and a plausible
reaction pathway.
Regeneration of the catalyst requires displacement of the
product by one indole and one trifluoroacetate. Considering
the acidic reaction conditions, a first probable step would be the
protonation of the imidamidate VIII leading to amidine
complex IX (Figure 5). This is a very rapid process for the
−1
DAF complex with a barrier of 12.4 kcal mol , starting with a
loss of Pd-coordination of one of the nitrogens in DAF,
coordination of TFA, and a change in the orientation of the
square planar coordination (for details, see SI). For the bpy
complex the change in ligand coordination is associated with a
−1
significantly higher barrier (16.3 kcal mol ). This supports the
conclusions by White et al., that the DAF ligand can more
20
easily coordinate monodentately to palladium.
Considering the relatively low barriers for these first three
steps, neither is likely to be rate determining given the high
C
DOI: 10.1021/acs.orglett.7b01836
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Whitby, R. J.; Light, M. E.; Hurtshouse, M. B. Tetrahedron Lett. 2004,
ASSOCIATED CONTENT
Supporting Information
■
4
5, 6991.
15) Garigipati, R. Tetrahedron Lett. 1990, 31, 1969.
(16) (a) Adams, R.; Beebe, C. H. J. Am. Chem. Soc. 1916, 38, 2768.
(b) Anderson, H. J.; Wang, N.-C.; Jwili, E. T. P. Can. J. Chem. 1971,
9, 2315. (c) Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.;
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b01836.
4
Sardharwala, T. E. Synth. Commun. 1996, 26, 4351. (d) Charette, A. B.;
Grenon, M. Tetrahedron Lett. 2000, 41, 1677. (e) Wang, J.; Xu, F.; Cai,
T.; Shen, Q. Org. Lett. 2008, 10, 445. (f) Biswas, K.; Greaney, M. F.
Org. Lett. 2011, 13, 4946.
Experimental and DFT calculation details and copies of
1
13
H and C NMR spectra for all new compounds (PDF)
(
17) (a) Sav
M. Org. Lett. 2012, 14, 2394. (b) Rydfjord, J.; Svensson, F.; Trejos, A.;
Sjoberg, P. J. R.; Skold, C.; Savmarker, J.; Odell, L. R.; Larhed, M.
Chem. - Eur. J. 2013, 19, 13803.
18) (a) Zhou, C.; Larock, R. C. J. Org. Chem. 2006, 71, 3551.
b) Zhou, C.; Larock, R. C. J. Am. Chem. Soc. 2004, 126, 2302.
̈
marker, J.; Rydfjord, J.; Gising, J.; Odell, L. R.; Larhed,
AUTHOR INFORMATION
Corresponding Author
E-mail: mats.larhed@orgfarm.uu.se.
■
*
̈
̈
̈
(
ORCID
(
Peter Brandt: 0000-0002-2885-2016
Luke R. Odell: 0000-0001-7658-5103
Mats Larhed: 0000-0001-6258-0635
(c) Jiang, T.-S.; Wang, G.-W. Org. Lett. 2013, 15, 788. (d) Jiang, T.-S.;
Wang, G.-W. Adv. Synth. Catal. 2014, 356, 369. (e) Ma, Y.; You, J.;
Song, F. Chem. - Eur. J. 2013, 19, 1189. (f) Das, T.; Chakraborty, A.;
Sarkar, A. Tetrahedron Lett. 2014, 55, 7198.
Notes
(19) Campbell, A. N.; Meyer, E. B.; Stahl, S. S. Chem. Commun. 2011,
4
(
7, 10257.
20) (a) White, P. B.; Jaworski, J. N.; Fry, C. G.; Dolinar, B. S.; Guzei,
The authors declare no competing financial interest.
I. A.; Stahl, S. S. J. Am. Chem. Soc. 2016, 138, 4869. (b) White, P. B.;
Jaworski, J. N.; Zhu, G. H.; Stahl, S. S. ACS Catal. 2016, 6, 3340.
ACKNOWLEDGMENTS
■
The authors thank Mr. Mostafa Haitham (Department of
Medicinal Chemistry, Uppsala University) and Uppsala
University for support.
REFERENCES
■
(
1) (a) Kotthaus, J.; Steinmetzer, T.; van de Locht, A.; Clement, B. J.
Enzyme Inhib. Med. Chem. 2011, 26, 115. (b) Goswami, R.; Wohlfahrt,
̈ ̈
G.; Tormakangas, O.; Moilanen, A.; Lakshminarasimhan, A.; Nagaraj,
J.; Arumugam, K. N.; Mukherjee, S.; Chacko, A. R.; Krishnamurthy, N.
R.; Jaleel, M.; Palakurthy, R. K.; Samiulla, D. S.; Ramachandra, M.
Bioorg. Med. Chem. Lett. 2015, 25, 5309.
(
2) Cannon, C. P. Clin. Cardiol. 2003, 26, 401.
(
3) Chen, X.; Orser, B. A.; MacDonald, J. F. Eur. J. Pharmacol. 2010,
6
48, 15.
4) Oehlrich, D.; Prokopcova, H.; Gijsen, H. J. M. Bioorg. Med. Chem.
Lett. 2014, 24, 2033.
5) Zhu, W.; Wang, Y.; Li, K.; Gao, J.; Huang, C. H.; Chen, C. C.;
Ko, T. P.; Zhang, Y.; Guo, R. T.; Oldfield, E. J. Med. Chem. 2015, 58,
215.
6) Kimura, A.; Nishikawa, H.; Nomura, N.; Mitsuyama, J.;
Fukumoto, S.; Inoue, N.; Kawazu, S.-I. Antimicrob. Agents Chemother.
012, 56, 2191.
7) Ojo, B.; Dunbar, P. G.; Durant, G. J.; Nagy, P. I.; Huzl, J. J.;
(
(
1
(
2
(
Periyasamy, S.; Ngur, D. O.; El-Assadi, a a; Hoss, W. P.; Messer, W. S.
Bioorg. Med. Chem. 1996, 4, 1605.
(
8) Castanedo, G. M.; Seng, P. S.; Blaquiere, N.; Trapp, S.; Staben, S.
T. J. Org. Chem. 2011, 76, 1177.
9) (a) Anderson, E. D.; Boger, D. L. J. Am. Chem. Soc. 2011, 133,
2285. (b) Anderson, E. D.; Boger, D. L. Org. Lett. 2011, 13, 2492.
10) (a) Peng, J.; Ye, M.; Zong, C.; Hu, F.; Feng, L.; Wang, X.;
Wang, Y.; Chen, C. J. Org. Chem. 2011, 76, 716. (b) Li, J.; Benard, S.;
Neuville, L.; Zhu, J. Org. Lett. 2012, 14, 5980.
11) Dunn, P. J. In Comprehensive Organic Functional Group
(
1
(
́
(
Transformations; Katritzky, A. R., Taylor, R. J. K., Eds.; Elsevier:
Oxford, 2005; pp 655−699.
(
12) (a) Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1877, 10, 1889.
(
(
b) Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1878, 11, 1475.
c) Pinner, A.; Klein, F. Ber. Dtsch. Chem. Ges. 1883, 16, 1643.
(
13) DeKorver, K. A.; Johnson, W. L.; Zhang, Y.; Hsung, R. P.; Dai,
H.; Deng, J.; Lohse, A. G.; Zhang, Y.-S. J. Org. Chem. 2011, 76, 5092.
14) (a) Saluste, C. G.; Whitby, R. J.; Furber, M. Tetrahedron Lett.
001, 42, 6191. (b) Saluste, C. G.; Crumpler, S.; Furber, M.; Whitby,
(
2
R. J. Tetrahedron Lett. 2004, 45, 6995. (c) Saluste, C.; Whitby, R.;
Furber, M. Angew. Chem., Int. Ed. 2000, 39, 4156. (d) Tetala, K. K. R.;
D
DOI: 10.1021/acs.orglett.7b01836
Org. Lett. XXXX, XXX, XXX−XXX