Synthesis of Unnatural Arundines Using a Magnetically Reusable Copper Ferrite Catalyst

Article abstract of DOI:10.1055/s-0037-1610227

We report a method for copper ferrite-catalyzed coupling of indoles and N, N -dimethylacetamide (DMA) to afford Arundine derivatives. Halogen, methoxy, boronate ester, and trimethylsilyl functionalities are compatible with reaction conditions. Unprotected or sterically hindered indoles are also competent substrates. Indoles containing competitively reactive pyrazoles deliver the desired products in reasonable yields. The copper ferrite is easily recovered and reused, up to nine times without a significant yield loss.

Full text of DOI:10.1055/s-0037-1610227

SYNLETT
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
P. T. Ha et al.
Letter
Synlett
Synthesis of Unnatural Arundines Using a Magnetically Reusable
Copper Ferrite Catalyst
CH3
Pha T. Ha
N
Oanh T. K. Nguyen
H3C
R
Khoa D. Huynh
Tung T. Nguyen
Nam T. S. Phan*
R
O
R
H
H
CuFe2O4 (15 mol%)
C
R2
N
R1
N
R1
N
R1
R2
R2
Faculty of Chemical Engineering, HCMC University of Technology,
VNU-HCM, 268 Ly Thuong Kiet, District 10, Ho Chi Minh City,
Vietnam
R = Me, halide, MeO, TMS, Bpin, pyrazoles
1 = H, Me, allyl, Bn, Ar
R2 = H, Me, Ph
17 examples
38–88%
R
ptsnam@hcmut.edu.vn
• reusable heterogeneous catalyst
Received: 15.06.2018
Accepted after revision: 10.07.2018
Published online: 02.08.2018
‘soluble’ catalysts. Using heterogeneous and reusable cata-
lysts for such methods would result in a far more environ-
mentally benign approach.
DOI: 10.1055/s-0037-1610227; Art ID: st-2018-u0371-l
CH3
Abstract We report a method for copper ferrite-catalyzed coupling of
indoles and N,N-dimethylacetamide (DMA) to afford Arundine deriva-
tives. Halogen, methoxy, boronate ester, and trimethylsilyl functional-
ities are compatible with reaction conditions. Unprotected or sterically
hindered indoles are also competent substrates. Indoles containing
competitively reactive pyrazoles deliver the desired products in reason-
able yields. The copper ferrite is easily recovered and reused, up to nine
times without a significant yield loss.
DeBoef and Kumar
N
R
R
H3C
R
H H
C
O
R2
N
R1
VO(acac)2
N
N
R1
R1 = H or CH3, R2 = Ar
only R = H
R2 R2
R1
Liu and Lu
CH3
Key words copper ferrite, C–H functionalization, indoles, Arundine,
dimerization
N
H
R
R
H3C
R
H
H
O
R2
C
N
R1
CuCl
Arundine, a quintessential 3,3-bisindolylmethane, re-
portedly exhibits promising anticancer activity.1 Derivatiza-
tion of Arundine, which is indispensable for SAR (structure-
activity relationship) studies, commonly requires multistep
synthesis and/or prefunctionalized starting materials.2 It is
undisputedly more beneficial if Arundine analogues are
synthesized directly from indoles via one-step transforma-
tions. In this context, a few one-carbon sources, such as ter-
tiary ethyleneamines,3a–c paraformaldehyde,3d–f dimethyl-
sulfoxide,2d and tetramethylurea,3g have been reported to
dimerize indoles. Recently, N,N-dimethylformamide (DMF)
and N,N-dimethylacetamide (DMA) were shown to also
methylenate C3–H bonds of indoles (Scheme 1).4 Transition-
metal catalysts including vanadium and copper salts were
reported to facilitate the DMF-indole coupling.4b–c Iodine-
mediated C–H functionalization of indoles with DMF and
DMA was also reported.4d Despite formidable successes,
certain problems are still unsolved. Firstly, reaction scopes
are commonly limited. Successful coupling of unprotected
indoles required steric hindrance of starting materials.4c
Yet, heterocycle-containing Arundines have not been
reported. Secondly, most of the methods have employed
N
R1
N
R1
R1 = CH3 or CH2Ph
R2 = H
R2
R2
Deb and Baruah
CH3
N
R3
R3 = H or CH3
R
R
H3C
R
H
H
C
O
R2
I2
N
R1
N
R1
N
R1
R1 = Me, CH2Ph or allyl
R2 = H
R2
R2
Scheme 1 Previous methods of methylene-bridge indole dimerization
The use of copper-based solid catalysts for selective,
direct sp2 C–H activation and functionalization has
emerged over the last decade.5 Notably, although heteroge-
neous catalytic systems have been employed, catalyst re-
covery remains problematic. Systems such as copper im-
pregnated on magnetite or copper ferrite would facilitate
catalyst recovery by using an external magnet. Cross cou-
plings catalyzed by these catalysts have been reported.5b–g
However, direct functionalization of C–H bonds mediated
by copper-iron catalytic systems is still rare. Nageswar and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
P. T. Ha et al.
Letter
Synlett
co-workers reported a copper ferrite-catalyzed direct ami-
nation of acidic sp2 C–H bonds in azoles.5l Methods for ary-
lation of C–H bonds in heteroarenes and anilides were
developed by the group of Glorius.5m,5n In our continuous
effort to leverage copper ferrite to promote organic trans-
formations, we show here its use as an efficient catalyst to
couple C3–H bonds of indoles with DMA. Either unprotect-
ed or protected substrates successfully afford Arundine de-
rivatives in good yields. The catalyst is truly heterogeneous
and reusable, retaining reasonable activity after nine runs.
1H-Indole was chosen as a model substrate because its
methylene-bridge dimerization under oxidative condition
has been somewhat challenging.4h The coupling of indole
and DMA was carried out in the presence of CuFe2O4 cata-
lyst and tert-butyl hydroperoxide oxidant (Table 1). At least
1 equivalent of oxidant was important to obtain a reason-
able yield of 2a (entries 1 and 2). DMF was inferior com-
pared with DMA (entry 3). Tetramethylenediamine is not a
competent methylene synthon under the conditions (entry
4). Other copper salts such as CuO or CuCl gave lower yield
of product (entries 5 and 6). Notably, almost no conversion
of 1 was detected when oxygen was the sole oxidant (entry
7). Use of 10 mol% CuFe2O4 lowered the reaction yield
(entry 8).
2d). However, coupling of DMA with substrates containing
electron-poor nitrogen centers was not successful. While a
N-aryl indole afforded product 2e in poor yield, N-silyl and
N-acetyl indoles failed to dimerize.6 For reactions delivering
products 2d and 2e, no side reactions such as olefin oxida-
tion or carbon–nitrogen cleavage were observed, and unre-
acted starting materials were recovered.
CuFe2O4 (15 mol%)
N
TBHP (1 equiv)
DMA, 140 °C, 4 h
N
N
R
1
R
R
2
N
N
NH
HN
2b: 70%
2a: 80%
N
N
N
N
Ph
Ph
2d: 47%b
2c: 54%a
N
N
Ar = 4-MeOC6H4
Table 1 Methylenation of Indole and Control Experimentsa
Ar
Ar
2e: 38%b
CuFe2O4 (15 mol%)
Scheme 2 Coupling of N-protected indoles with DMA catalyzed by
CuFe2O4. Reagents and conditions: indole (0.5 mmol), CuFe2O4
(0.075 mmol), TBHP (0.5 mmol), DMA (1.5 mL), 140 °C, 4 h, isolated
yields. a TBHP (1.5 mmol), 24 h. b Indole (0.75 mmol), CuFe2O4
(0.1125 mmol), TBHP (2.25 mmol), DMA (2.25 mL), 140 °C, 24 h.
TBHP (1 equiv)
DMA, 140 °C, 4 h
N
H
NH
HN
1a
2a
Entry
Variations from standard conditions
Yield of 2a (%)
Various indole substituents competent for the transfor-
mation are presented in Scheme 3. In a few examples, mod-
ified conditions, such as longer reaction time or higher oxi-
dant concentration, were necessary to obtain reasonable
yields. Substituents on C2–H bonds of indoles did not affect
reaction yields (entries 4a, 4b, and 4d). Electron-deficient,
unprotected indole is suitable for this dimerization (4c). A
3,3-bisindolylmethane 4j, derived from 7-methyl-N-
methylindole, was obtained in 47% yield. Functionalities
such as fluoro (4c, 4d), iodo (4e), bromo (4f), methoxy (4g),
trimethylsilyl (4h), and boronate ester (4i) groups are com-
patible with reaction conditions. The last two products are
synthetically useful for further functionalization through
cross-coupling reactions. Overall, our conditions are suit-
able for functionalities that are sensitive to acid or base.7 On
the other hand, reactions of substrates containing function-
alities sensitive to oxidant were not successful. For exam-
ple, a styrenyl indole 3k gave indole carboxaldehyde 4k as
the major product through an olefin oxidative cleavage
(Scheme 4).6,8
1
2
3
4
5
6
7
8
None
83
32
75
59
45
44
<5
73
50 mol% TBHP
DMF instead of DMA
Tetramethylenediamine instead of DMA
CuO instead of CuFe2O4
CuCl instead of CuFe2O4
O2 instead of TBHP
10 mol% CuFe2O4
a Reagents and conditions: Indole (0.5 mmol), catalyst (0.075 mmol), TBHP
(0.5 mmol), solvent (1.5 mL), under air, 140 °C, 4 h. Yields of 2a were
determined by gas chromatography, using diphenyl ether as internal
standard. DMA = N,N-dimethylacetamide, TBHP = tert-butyl hydroperoxide.
The scope of indole-DMA coupling with respect to sub-
stituents on nitrogen is shown in Scheme 2. Good yields of
3,3-bisindolylmethanes were obtained when unprotected
or N-methyl indoles were used (2a and 2b). Benzylic and
allylic C–H bonds are compatible with reaction conditions,
resulting in product formation in moderate yields (2c and
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
P. T. Ha et al.
Letter
Synlett
conditions. Since regioselective functionalization of C–H
bonds in the presence of heterocycles is important for late-
stage functionalization,11 our finding is useful for future
studies.12
R
R
R
CuFe2O4 (15 mol%)
R2
N
R1
TBHP (1 equiv)
N
R1
N
R1
R2 R2
DMA, 140 °C, 4 h
3
4
R
R
N
R
N
N
N
N
N
NH
HN
N
Ph
4b: 78%
Ph
N
CuFe2O4 (15 mol%)
4a: 69%
N
F
F
TBHP (3 equiv)
DMA, 140 °C, 24 h
N
N
F
F
R = H, 3l
4l, 57%
R = Me, 3m
4m, 61%
N
N
Scheme 5 Copper ferrite-catalyzed methylene dimerization of hetero-
NH
HN
4c: 70%a
cycle-containing indoles
4d: 88%
I
I
Br
Br
Control experiments were carried out to confirm the
heterogeneity and reusability of the copper ferrite. First,
hot leaching test shows that the coupling did not progress
further after the catalyst was filtered out. A negligible
change of reaction yield was detected by gas chromatogra-
phy.6 Second, the copper ferrite was reused up to nine times
while the yield of 2a remained reasonable (76% yield in the
ninth run). Lastly, XRD analysis of the recovered copper fer-
rite did not reveal any significant change compared to that
of the fresh material.6
N
N
N
N
4e: 79%
4f: 85%
TMS
TMS
O
O
N
N
N
N
4g: 73%
4h: 68%
Bpin
Bpin
In conclusion, we report a method for methylene di-
merization of C3–H bonds in indoles with DMA using
copper ferrite catalyst. Reactions afford Arundine deriva-
tives. Functionalities such as halogen, methoxy, boronate
ester, and trimethylsilyl groups are compatible with the re-
action conditions. Pyrazole-containing indoles are also
competent substrates. The catalyst is truly heterogeneous
and reusable, up to nine times while still giving 76% yield of
coupling product.
N
N
N
N
4i: 76%a
4j: 47%a,b
Scheme 3 Copper ferrite catalyzed methylene dimerization of indoles.
Reagents and conditions: indole (0.5 mmol), CuFe2O4 (0.075 mmol),
TBHP (0.5 mmol), DMA (1.5 mL), 140 °C, 4 h. a 24 h. b Reagents and
conditions: 3j (0.75 mmol), CuFe2O4 (0.1125 mmol), TBHP (2.25 mmol),
DMA (2.25 mL), 140 °C.
Supporting Information
O
Ph
CuFe2O4 (15 mol%)
O
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1610227.
TBHP (1 equiv)
DMA, 140 °C, 4 h
+
N
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
Ph
N
3k
4k, 72%
detected
by GCMS
References and Notes
Scheme 4 Incompatibility of styrenyl indole
(1) (a) Rahman, K. W.; Li, Y.; Wang, Z.; Sarkar, S. H.; Sarkar, F. H.
Cancer Res. 2006, 66, 4952. (b) Safe, S.; Papineni, S.;
Chintharlapalli, S. Cancer Lett. 2008, 269, 326.
Involvement of heterocycle-containing indoles under
oxidative conditions is rare. To our delight, bisindolylmeth-
anes bearing pyrazole rings, 4l and 4m, were obtained in
57% and 61% yields, respectively (Scheme 5).9 Although
homogeneous copper-catalyzed nitrogen-directed sp2 C–H
activation is known,10 pyrazole-directed, copper ferrite-cat-
alyzed C–H functionalization did not occur under these
(2) Review: (a) Shiri, M.; Zolfigol, M. A.; Kruger, H. G.;
Tanbakouchian, Z. Chem. Rev. 2010, 110, 2250. Selected exam-
ples: (b) Singh, H.; Singh, K. Tetrahedron 1988, 44, 5897. (c) de
La Herrián, G.; Segura, A.; Csákÿ, A. G. Org. Lett. 2007, 9, 961.
(d) Abe, T.; Ikeda, T.; Itoh, T.; Hatae, N.; Toyota, E.; Ishikura, M.
Heterocycles 2014, 88, 187. (e) Li, D.; Wu, T.; Liang, K.; Xia, C.
Org. Lett. 2016, 18, 2228. (f) Abe, T.; Nakamura, S.; Yanada, R.;
Choshi, T.; Hibino, S.; Ishikura, M. Org. Lett. 2013, 15, 3622.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
P. T. Ha et al.
Letter
Synlett
(3) (a) Pradhan, P. K.; Dey, S.; Giri, V. S.; Jaisankar, P. Synthesis 2005,
1779. (b) Pal, C.; Dey, S.; Mahato, S. K.; Vinayagam, J.; Pradhan,
P. K.; Giri, V. S.; Jaisankar, P.; Hossain, T.; Baruri, S.; Ray, D.;
Biswas, S. M. Bioorg. Med. Chem. Lett. 2007, 17, 4924. (c) Zhao,
D.; Wang, Y.; Zhu, M.-X.; Shen, Q.; Zhang, L.; Du, Y.; Li, J. -X. RSC
Adv. 2013, 3, 10272. (d) Nagarajan, R.; Perumal, P. T. Chem. Lett.
2004, 33, 288. (e) Srivastava, A.; Agarwal, A.; Gupta, S. K.; Jain,
N. RSC Adv. 2016, 6, 23008. (f) Bahuguna, A.; Kumar, S.; Sharma,
V.; Reddy, K. L.; Bhattacharyya, K.; Ravikumar, P. C.; Krishnan,
V. ACS Sustainable Chem. Eng. 2017, 5, 8551. (g) Deb, M. L.;
Borpatra, P. J.; Saikia, P. J.; Baruah, P. K. Org. Biomol. Chem. 2017,
15, 1435.
Reddy, K. H. V.; Anil, B. S. P.; Shankar, J.; Kumar, R. U.; Nageswar,
Y. V. D. Tetrahedron Lett. 2014, 55, 5533. (m) Vásquez-Céspedes,
S.; Chepiga, K. M.; Möller, N.; Schäfer, A. H.; Glorius, F. ACS Catal.
2016, 6, 5954. (n) Vásquez-Céspedes, S.; Holtkamp, M.; Karst,
U.; Glorius, F. Synlett 2017, 28, 2759.
(6) See the Supporting Information for details.
(7) Toutov, A. A.; Liu, W.-B.; Betz, K. N.; Fedorov, A.; Stoltz, B.;
Grubbs, R. H. Nature 2015, 518, 80.
(8) Oxidative cleavage of disubstituted olefins in the presence of
copper is known; for example, see: Lan, X.-W.; Wang, N.-X.;
Zhang, W.; Wen, J.-L.; Bai, C.-B.; Xing, Y.; Li, Y. H. Org. Lett. 2015,
17, 4460.
(4) Review: (a) Le Bras, J.; Muzart, J. N,N-Dimethylformamide and
N,N-Dimethylacetamide as Carbon, Hydrogen, Nitrogen, and/or
Oxygen Sources; Wu, X.-F., Ed.; Wiley-VCH: Weinheim, 2017,
199. Selected examples: (b) Pu, F.; Li, Y.; Song, Y.-H.; Xiao, J.; Liu,
Z.-W.; Wang, C.; Liu, Z.-T.; Chen, J.-G.; Lu, J. Adv. Synth. Catal.
2016, 358, 539. (c) Kaswan, P.; Nandwana, N. K.; DeBoef, B.;
Kumar, A. Adv. Synth. Catal. 2016, 358, 2108. (d) Deb, M. L.;
Borpatra, P. J.; Dev Pegu, C.; Thakuria, R.; Saikia, P. J.; Baruah, P.
K. ChemistrySelect 2017, 2, 140. (e) Modi, A.; Ali, W.; Patel, B. K.
Adv. Synth. Catal. 2016, 358, 2100. (f) Xu, Z.; Hang, Z.; Chai, L.;
Liu, Z.-Q. Org. Lett. 2016, 18, 4662. (g) Chen, X.; Zhao, H.; Chen,
C.; Jiang, H.; Zhang, M. Org. Lett. 2018, 20, 1171. (h) Mondal, S.;
Samanta, S.; Santra, S.; Bagdi, A. K.; Hajra, A. Adv. Synth. Catal.
2016, 358, 3633.
(9) Indole Methylene-Dimerization with DMA; Typical Proce-
dure for 4k
In a 2-dram vial equipped with a magnetic stir bar was charged
indole derivative 3k (0.75 mmol, 148 mg), tert-butyl hydroper-
oxide (TBHP; 2.25 mmol, 0.3 mL), CuFe2O4 (0.1125 mmol, 27
mg), and DMA (2.25 mL). The mixture was was heated at 140 °C
for 24 h then cooled to room temperature, and the copper
ferrite was separated by using an external magnet. The mother
liquor was diluted with EtOAc (20 mL) and H2O (20 mL).
Aqueous layer was further extracted with EtOAc (2 × 10 mL).
Combined organic layers were washed with H2O (20 mL) and
brine (2 × 20 mL), dried over Na2SO4, filtered, and concentrated.
Flash column chromatography (gradient EtOAc in hexanes from
1
20% to 50%) gave 4k. Yield: 87 mg (57%); red oil. H NMR (600
(5) Review: (a) Ojha, N. K.; Zyryanov, G. V.; Majee, A.; Charunshin,
V. N.; Chupakin, O. N.; Santra, S. Coord. Chem. Rev. 2017, 353, 1.
Selected examples: (b) Hudson, R.; Ishikawa, S.; Li, C.-J.; Moores,
A. Synlett 2013, 24, 1637. (c) Sarode, S. A.; Bhojane, J. M.;
Nagarkar, J. M. RSC Adv. 2015, 5, 105353. (d) Panda, N.; Jena, A.
K.; Mohapatra, S.; Rout, S. R. Tetrahedron Lett. 2011, 52, 1924.
(e) Sivakami, R.; Ganesh Babu, S.; Dhanuskodi, S.; Karvembu, R.
RSC Adv. 2015, 5, 8571. (f) Satish, G.; Reddy, K. H. V.; Ramesh, K.;
Kumar, B. S. P. A.; Nageswar, Y. V. D. Tetrahedron Lett. 2014, 55,
2596. (g) Yang, D.; Zhu, X.; Wei, W.; Jiang, M.; Zhang, N.; Ren, D.;
You, J.; Wang, H. Synlett 2014, 25, 729. (h) Zhang, W.; Zeng, Q.;
Zhang, X.; Tian, Y.; Yue, Y.; Guo, Y.; Wang, Z. J. Org. Chem. 2011,
76, 4741. (i) Lee, E. Y.; Park, J. ChemCatChem 2011, 3, 1127.
(j) Zhang, W.; Tian, Y.; Zhao, N.; Wang, Y.; Li, J.; Wang, Z. Tetra-
hedron 2014, 70, 6120. (k) Rosario, A. R.; Casola, K. K.; Oliveira,
C. E. S.; Zeni, G. Adv. Synth. Catal. 2013, 355, 2960. (l) Satish, G.;
MHz, CDCl3): δ = 7.92–7.83 (m, 4 H), 7.72 (s, 2 H), 7.55 (dd, J =
8.8, 1.3 Hz, 2 H), 7.31 (d, J = 8.7 Hz, 2 H), 6.84 (s, 2 H), 6.43 (s,
2 H), 4.23 (s, 2 H), 3.69 (s, 6 H). 13C NMR (101 MHz, CDCl3): δ =
140.5, 136.1, 133.4, 128.7, 128.0, 127.7, 114.9, 114.7, 110.6,
109.9, 107.0, 33.0, 21.0. HRMS (ESI): m/z [M+H]+ calcd for
C
25H22N6: 407.1982; found: 407.1980.
(10) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am. Chem. Soc.
2006, 128, 6790. (b) Gandeepan, P.; Koeller, J.; Ackermann, L.
ACS Catal. 2017, 7, 1030.
(11) (a) Shang, M.; Wang, M.-M.; Saint-Denis, T. G.; Li, M.-H.; Dai, H.-X.;
Yu, J.-Q. Angew. Chem. Int. Ed. 2017, 56, 5317. (b) Kong, W.-J.;
Chen, X.; Wang, M.; Dai, H.-X.; Yu, J.-Q. Org. Lett. 2018, 20, 284.
(12) We also attempted N-methyl-7-azaindole; however, no product
formation was observed. See the Supporting Information for a
list of unsuccessful substrates.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D