Activating group recycling in action: A rhodium-catalyzed carbothiolation route to substituted isoquinolines

Article abstract of DOI:10.1021/ol402650q

A new rhodium(I) catalyst allows practical and efficient alkyne carbothiolation reactions to be achieved on synthetically useful ketone-bearing aryl methyl sulfides. The carbothiolation adducts, featuring a 'recycled methyl sulfide' activating group, are convenient precursors to highly substituted isoquinolines.

Full text of DOI:10.1021/ol402650q

ORGANIC
LETTERS
2013
Vol. 15, No. 20
5162–5165
Activating Group Recycling in Action:
A Rhodium-Catalyzed Carbothiolation
Route to Substituted Isoquinolines
Milan Arambasic, Joel F. Hooper, and Michael C. Willis*
Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, U.K.
michael.willis@chem.ox.ac.uk
Received July 26, 2013
ABSTRACT
A new rhodium(I) catalyst allows practical and efficient alkyne carbothiolation reactions to be achieved on synthetically useful ketone-bearing aryl
methyl sulfides. The carbothiolation adducts, featuring a ‘recycled methyl sulfide’ activating group, are convenient precursors to highly
substituted isoquinolines.
Aromatic heterocycles represent the dominant structur-
al motif in medicinal chemistry. Among the varied range of
architectures found within this group, isoquinolines play
an important role. In addition to forming the foundation
of many medicines (Figure 1), the isoquinoline core, and
derivatives, are found in many natural products and in
organic materials.1 The majority of “classic” routes to
isoquinolines;the PictetꢀSpengler, BischlerꢀNapieralski,
and PomeranzꢀFritsch syntheses;are in general cen-
tered on an electrophilic substitution process as the key
bond-forming event.2 Despite the success of these proto-
cols, reliance on electrophilic aromatic substitution im-
poses significant limitations on the substitution pattern
that can be tolerated on the starting arene, and also on the
substitution patterns that can be accessed, due to the
inherent electronic bias of this class of transformations.
In this Letter we disclose a new Rh-catalyst for alkyne
carbothiolation reactions and apply this process as the
key step in a practical, one-pot route to isoquinolines.
This new synthesis provides a distinct disconnection to
these valuable heterocycles, employs simple building
blocks, allows access to a variety of substitution patterns,
and is performed under mild reaction conditions. It also
validates the utility of our recently reported “functional
group recycling” approach to arene functionalization.3
Figure 1. Representative biologically active isoquinolines.
Transition metal catalysis has transformed the synthesis
of aromatic heterocycles, providing a set of nontraditional
disconnections that complement the many classic approaches
to these molecules.4 In particular, cross-coupling pro-
cesses have opened up new classes of building blocks for
(1) (a) Pike, V. W.; Halldin, C.; Crouzel, C.; Barre, L.; Nutt, D. J.;
Osman, S.; Shah, F.; Turton, D. R.; Waters, S. L. Nucl. Med. Biol. 1993,
20, 503. (b) Takeuchi, K.; Sakamoto, S.; Nagayoshi, Y.; Nishizawa, H.;
Matsubara, J. Eur. J. Cardio-Thoracic Surgery 2004, 26, 956. (c)
Weissmam, B. A.; Raveh, L. J. Neurochem. 2003, 84, 432. (d) Rinehart,
K. L. Med. Res. Rev. 2000, 20, 1.
(2) (a) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74.
(b) Bischler, B. N. A.; Napieralski, B. Chem. Ber. 1893, 26, 1903. (c)
Pictet, A.; Spengler, T. Chem. Ber. 1911, 44, 2030. (d) Whaley, W. M.;
Govindachari, T. R. Org. React. 1951, 6, 151. (e) Pomeranz, C. Monatsh.
Chem. 1893, 14, 116. (f) Fritsch, P. Chem. Ber. 1893, 26, 419.
(3) Hooper, J. F.; Chaplin, A. B.; Gonzalez-Rodriguez, C.; Thompson,
A. L.; Weller, A. S.; Willis, M. C. J. Am. Chem. Soc. 2012, 134, 2906.
(4) (a) Nakamura, I.; Yamamoto, Y. Chem. Rev. 2004, 104, 2127. (b)
Zeni, G.; Larock, R. C. Chem. Rev. 2006, 106, 4644. (c) Patil, N. T.;
Yamamoto, Y. Chem. Rev. 2008, 108, 3395. (d) Donohoe, T. J.; Bower,
J. F.; Chan, L. K. M. Org. Biomol. Chem. 2012, 10, 1322.
r
10.1021/ol402650q
Published on Web 10/01/2013
2013 American Chemical Society

heterocycle synthesis.5 The majority of cross-coupling
methods rely on an activating group to secure reactivity
and to control regioselectivity; an intrinsic feature of
these reactions is that at the completion of the transfor-
mation the activating group is usually discarded as
waste. For example, aryl halides (ArꢀX) when combined
with an organometallic coupling partner (MꢀR) deliver
(MꢀX) salts as waste products. Coupling reactions that
rely on addition processes, as opposed to substitution reac-
tions, allow the activating group to be reincorporated into
the product; effectively, the activating groups are recycled.3,6
The ability to recycle activating groups, and in the process
provide a handle for further manipulation, begins to address
the demand to produce more sustainable synthetic routes.
We have recently demonstrated an effective activating
group recycling approach to arene functionalization based
on Rh-catalyzed alkyne carbothiolation.3 In this system,
simple aryl methyl sulfides are combined with alkynes to
deliver alkenyl sulfide products resulting from both CꢀC
and CꢀS bond formation. Crucially, the alkenyl sulfide
functionality incorporated in the products represents a
masked carbonyl unit, and as such provides a powerful
handle for further functionalization.7 Wanting to exploit
the utility of this masked carbonyl unit we conceived a new
route to substituted isoquinolines.8 The key transforma-
tion involves the Rh-catalyzed carbothiolation of alkynes
with carbonyl-containing aryl methyl sulfides, leading to
the formation of a masked benzo-fused 1,5-dicarbonyl
(1 þ 2 f 3, Scheme 1); treatment of dicarbonyl 3 with an
ammonia source would allow access to isoquinolines (4).
Our initial report of a Rh-catalyzed alkyne carbothiola-
Scheme 1. A Rh-Catalyzed Alkyne Carbothiolation Route to
Isoquinolines
the commercially available precursor [Rh(nbd)2]BF4,
which can be employed routinely without recourse to a
glovebox and allowed the active catalyst to be generated in
situ by addition of the phosphine ligand and subsequent
hydrogenation. Due to the significant decrease in catalyst
solubility when moving from the BArF to BF4 counter-
4
ions, a new solvent system was established (Table 1). After
evaluating a number of solvents, the desired carbothiola-
tionreactionwas achieved in good yieldswith a selection of
terminal alkynes and methyl sulfide 5 using 5 mol %
[Rh(nbd)2BF4] and 5 mol % DPEphos, in either DCE or
chlorobenzene (Table 1, entries 1ꢀ4).
Table 1. Use of the BF4 Anion in Rh-Catalyzed Alkyne Car-
bothiolationa
tion reaction employed the [Rh(DPEphos)(o-xylene)][BArF ]
4
complex A as the precatalyst, used in o-xylene.3 Although
complex A represents an efficient catalyst system, the use of
the BArF4 counterion makes this catalyst relatively expensive
and also difficult to prepare without the use of a glovebox.9
In order to deliver a practical solution, we therefore
sought to identify a new catalyst system which retained the
activity of complex A, was straightforward to prepare, and
avoided use of the BArF4 anion. We began by employing
entry
R
ligand
time
yield (DCE, PhCl)b
1
2
3
4
5
6
7
8
9
Ph
DPEphos
DPEphos
DPEphos
DPEphos
24 h
24 h
24 h
24 h
80%, 90%
73%, 90%
70%, 80%
24%, 33%c
99%, 99%
96%, 99%
99%, 99%
43%,c 80%
81%, ꢀ
4-MeO-Ph
4-F-Ph
3,5-(CF3)2-Ph
Ph
Xantphos 2 h
Xantphos 2 h
Xantphos 1.5 h
Xantphos 24 h
4-MeO-Ph
4-F-Ph
3,5-(CF3)2-Ph
CH2N(Boc)Bn Xantphos 1.5 h
(5) (a) Palladium in Heterocyclic Chemistry, 2nd ed.; Li, J. J., Gribble,
G. W., Eds.; Elsevier: Oxford, U.K., 2007. (b) Sadig, J. E. R.; Willis, M. C.
Synthesis 2011, 1. (c) Ball, C.; Willis, M. C. Eur. J. Org. Chem. 2013, 425.
(6) For related examples of “activating group recycling”, see: (a)
Schomaker, J. M.; Grigg, R. D. Synlett 2013, 401. (b) Alcaide, B.;
a Reaction conditions: 1 (1 equiv), alkyne (1.5 equiv), Rh(nbd)2BF4
(5 mol %), ligand (5 mol %), solvent (0.3 M), 80 °C (DCE), 100 °C
(chlorobenzene). b Isolated yields. c Conversion determined by 1H NMR
spectroscopy.
ꢀ
Almendros, P.; Alonso, J. M.; Cembellın, S.; Fernandez, I.; del Campo,
´
The change from a BArF anion to BF4 resulted in a
T. M.; Torres, R. M. Chem. Commun. 2013, 49, 7779. (c) Grigg, R. D.;
Van Hoveln, R.; Schomaker, J. M. J. Am. Chem. Soc. 2012, 134, 16131.
(d) Newman, S. G.; Howell, J. K.; Nicolaus, N.; Lautens, M. J. Am.
Chem. Soc. 2011, 133, 14916. (e) Newman, S. G.; Lautens, M. J. Am.
Chem. Soc. 2011, 133, 1778. (f) Liu, H.; Li, C.; Qiu, D.; Tong, X. J. Am.
Chem. Soc. 2011, 133, 6187.
4
lower activity catalyst, and in an attempt to achieve faster
catalysis wenext focused onthe structure of the ligand. The
flexibility and hemilabile nature of the DPEphos ligand
allows it to adopt a number of coordination modes
(Scheme 2). We have previously observed that the reaction
of complex A with sulfide 5 results in an equilibrium
mixture of A with complexes B and C in a 0.1:1:0.1 ratio
(o-xylened10 298 K). We speculated that by locking the
ligand into a single, active conformation, the efficiency of
the reaction might be improved. To impede this flexibility
around the PꢀOꢀP bonds present in DPEphos, we ex-
plored the use of a rigid DPEphos analogue, XantPhos.10
(7) Schaumann, E. Top. Curr. Chem. 2007, 274, 1.
(8) For selected recent reports of transition metal catalyzed ap-
proaches to isoquinolines, see: (a) Guimond, N.; Fagnou, K. J. Am.
Chem. Soc. 2009, 131, 12050. (b) Chiba, S.; Xu, Y.; Wang, Y. J. Am.
Chem. Soc. 2009, 131, 12886. (c) Jayakumar, J.; Parthasarathy, K.;
Cheng, C. Angew. Chem., Int. Ed. 2012, 51, 197. (d) Donohoe, T. J.;
Pilgrim, B. S.; Jones, G. R.; Bassuto, J. A. Proc. Natl. Acad. Sci. U.S.A.
2012, 109, 11605. (e) Kornhaass, C.; Li, J.; Ackermann, L. J. Org. Chem.
2012, 77, 9190. (f) Wang, H.; Grohmann, C.; Nimphius, C.; Glorius, F.
J. Am. Chem. Soc. 2012, 134, 19592. (g) Meng, L.; Ju, J.; Bin, Y.; Hua, R.
J. Org. Chem. 2012, 77, 5794.
(9) Yakelis, N. A.; Bergman, R. G. Organometallics 2005, 24, 3579.
Org. Lett., Vol. 15, No. 20, 2013
5163

Pleasingly, when evaluated in the carbothiolation of phe-
nylacetylene, the reaction employing Xantphos achieved
completion in only 2 h (cf. 24 h with DPEphos; Table 1,
entries 1 and 5). The carbothiolation of both electron-rich
and electron-poor alkynes was performed with quantita-
tive conversion to the carbothiolated product (Table 1,
entries 6 and 7).
Scheme 2. Comparison of DPEphos and Xantphos Rh-Com-
plexes
Figure 2. Time course plot for the carbothiolation reaction using
DPEphos and Xantphos ligands. Reaction conditions: Rh(nbd)2-
BF4 (5 mol %), ligand (5 mol %), DCE (0.3 M), H2 (2 min);
5 (1 equiv), phenylacetylene (1.5 equiv), 80 °C.
Heterocyclic substituents, such as thiophene, could be
carried through both reactions to generate the biheteroaryl
product 7e in good yield. Aliphatic alkynes were also
excellent substrates for this reaction, with linear (7f) and
cyclic(7g) aliphaticgroupsefficientlyincorporatedintothe
product. Additionally, a ferrocene unit could be installed
without incident (7h). Using the newly developed catalyst
system, the process was not limited to the use of terminal
alkynes; for example, employing 3-hexyne allowed isoqui-
noline 7i to be isolated in 45% yield, while diphenyl
acetylene allowed the formation of 7j. Although the use
of an unsymmetrical internal alkyne was successful, a
mixture of regioisomers was obtained (7k, 7k0).
As Xantphos is analogous to the mer-isomer of a DPE-
phos complex (B), the improved reactivity with Xantphos
might suggest that B is the active species in carbothiolation
when complex A is employed.11 The catalytic activities of
preformed and in situ prepared Xantphos- and DPEphos-
containing catalysts were compared by monitoring the
reactions by HPLC (Figure 2). Preformed catalysts con-
taining the BArF counterion showed higher rates of
4
conversion relative to the BF4 catalysts. Nevertheless, the
[Rh(Xantphos)(nbd)][BF4] complex formed in situ showed
exceptional activity with full conversion to the product
achieved in less than 2 h.
Having established an efficient and practical catalyst for
the carbothiolation step, the next task was to address the
subsequent cyclization to form the isoquinoline struc-
ture.12 This could be achieved by simply adding NH4OAc
and acetic acid directly to the reaction upon completion of
the carbothiolation reaction. Heating the reaction mixture
at 110 °C led to the isolation of isoquinoline 7a in 90%
yield (Figure 3). To investigate the scope of this reaction a
range of alkynes were explored. Maintaining sulfide 5 as
the standard, a variety of substituents could be employed
on the alkyne, including electron-donating (7b) and elec-
tron-withdrawing groups (7c). It was also pleasing to note
that an aryl bromide substituent remained intact during
the reaction, providing a useful handle for further elabora-
tion (7d).
(10) Kranenburg, M.; Vanderburgt, Y. E. M.; Kamer, P. C. J.; van
Leeuwen, P. W. N. M.; Goubitz, K.; Fraanje, J. Organometallics 1995,
14, 3081.
(11) Xanthphos can adopt a number of coordination modes: (a)
Williams, G. L.; Parks, C. M.; Smith, C. R.; Adams, H.; Haynes, A.;
Meijer, A. J. H. M.; Sunley, G. J.; Gaemers, S. Organometallics 2011, 30,
6166. (b) Dallanegra, R.; Chaplin, A. B.; Weller, A. S. Organometallics
2012, 31, 2720.
Figure 3. Rh-catalyzed alkyne carbothiolation-based isoquino-
line synthesis: scope of the alkyne component. Conditions:
Rh(nbd)2BF4 (5 mol %), Xantphos (5 mol %), PhCl (0.3 M),
H2 (2 min); 5 (1 equiv), alkyne (1.5 equiv), 100 °C, then
NH4OAc, AcOH, 110 °C.
(12) For a pyridine synthesis which employs alkenyl sulfide sub-
strates, see: Okada, E.; Masuda, R.; Hojo, M. Heterocycles 1992, 34,
1927.
The reaction could also be performed at a reduced
catalyst loading with no decrease in the yield; employing
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Org. Lett., Vol. 15, No. 20, 2013

phenylacetylene as the alkyne component, the reaction was
performed on 1.2 mmol scale using 1 mol % Rh, to deliver
the isoquinoline product 7a in 93% yield.
Scheme 3. Rh-Catalyzed Alkyne Carbothiolation Route to
3-Propyl Moxaverine
We next examined the scope of the substitution possible
on the sulfide precursors and began by exploring variation
on the carbocyclic ring (Figure 4). Both electron-donating
(7l) and electron-withdrawing groups (7m) were tolerated.
Isoquinoline 7n containing an ꢀSMe group positioned
para to the acyl tether remained untouched during the one-
pot synthesis, demonstrating the high levels of regiocontrol
possible. Again, an aryl bromide, this time positioned para
to the ketone (7o), remained intact throughout the reac-
tion. Variation of the substitution adjacent to the carbonyl
group was also possible, including longer aliphatic ketones
(7lꢀn), cyclopropyl (7p) and cyclohexyl ketones (7q), and
an R,β-unsaturated ketone (7r). Good functional group
tolerance was also displayed by the incorporation of a
pendant oxindole (7s).
the one-pot carbothiolation/cyclization sequence, followed
by a NaBH4 mediated reductive step, allowed access
to N-arylated dihydroisoquinolines (12). Finally, by
exploring bulky primary amines as the nitrogen source,
we were able to prevent formation of the isoquinolinium
salts and gain access to amino-naphthalene products.
Both isopropyl- and cyclohexylamine delivered the amino-
naphthalene products in good yield (13 and 14).
Scheme 4. Access to Alternative Heterocycles/Arenes by Var-
iation of the N-Nucleophile
Figure 4. Rh-catalyzed carbothiolation based isoquinoline
synthesis: scope of the sulfide component. Conditions: Rh(nbd-
)2BF4 (5 mol %), Xantphos (5 mol %), PhCl (0.3 M), H2 (2 min);
sulfide (1 equiv), phenylacetylene (1.5 equiv), 100 °C, then
NH4OAc, AcOH, 110 °C.
In conclusion, we have developed a second-generation
catalyst system for alkyne carbothiolation using simple
methyl sulfides. This new catalyst offers reduced reaction
times and low catalyst loadings and allows an ‘activating
group recycling’ approach to arene functionalization to be
achieved in a practical manner. Importantly, the catalyst is
assembled in situ from commercial components. We have
utilized this approach to arene functionalization in a one-
pot, three-component synthesis of isoquinolines and have
delivered a convergent and efficient synthetic sequence
that allows for the preparation of a diverse family of
isoquinolines.
To demonstrate the utility of the developed method we
undertook the preparation of a simple derivative of the
phosphodiester inhibitor moxaverine (Scheme 3). Three
simple steps from commercially available o-F-benzalde-
hyde 8 provided the key methyl sulfide 9. Combination of
sulfide 9 with 1-pentyne, employing the optimized car-
bothiolation/cyclization conditions, delivered 3-propyl
moxaverine in good yield. The intermediacy of sulfide 9
serves as a useful diversity generating branch point, as
simply exchanging 1-pentyne for alternative alkynes would
allow the rapid preparation of further derivatives.
To provide additional utility we explored the use of
alternative N-nucleophiles in the cyclization process. For
example, by substituting ammonium acetate with hydro-
xylamine hydrochloride, we were able to access the iso-
quinoline N-oxide 11(Scheme4). Using primary anilines in
Acknowledgment. EPSRC for support of this study.
Supporting Information Available. Experimental pro-
cedures and full characterization for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 20, 2013
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