1-Trifluoromethylisoquinolines from α-Benzylated Tosylmethyl Isocyanide Derivatives in a Modular Approach

Article abstract of DOI:10.1021/acs.orglett.7b02882

The preparation of various 1-trifluoromethylisoquinolines from α-benzylated tosylmethyl isocyanide derivatives and the commercial Togni reagent using a radical cascade is reported. The starting isocyanides are readily prepared in a modular sequence from commercial tosylmethyl isocyanide via sequential double α-alkylation, and the radical reaction proceeds under mild conditions with high efficiency without any transition-metal catalyst via electron catalysis. This valuable protocol has been successfully applied to the total synthesis of CF₃-mansouramycin B.

Full text of DOI:10.1021/acs.orglett.7b02882

Letter
pubs.acs.org/OrgLett
1‑Trifluoromethylisoquinolines from α‑Benzylated Tosylmethyl
Isocyanide Derivatives in a Modular Approach
Lin Wang and Armido Studer*
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstraβe 40, 48149 Munster, Germany
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̈
S
* Supporting Information
ABSTRACT: The preparation of various 1-trifluoromethyli-
soquinolines from α-benzylated tosylmethyl isocyanide de-
rivatives and the commercial Togni reagent using a radical
cascade is reported. The starting isocyanides are readily
prepared in a modular sequence from commercial tosylmethyl
isocyanide via sequential double α-alkylation, and the radical
reaction proceeds under mild conditions with high efficiency
without any transition-metal catalyst via electron catalysis. This valuable protocol has been successfully applied to the total
synthesis of CF3-mansouramycin B.
he isoquinoline scaffold is a prominent chemical core
structure that can be found in numerous natural products,
cascade reactions. The problem lies in the ready fragmentation of
alkyl radicals in the intermediate imidoyl radicals generated after
radical addition to the isonitrile moiety resulting in cyanation. In
fact, Ito and Stork introduced alkyl isocyanides as efficient radical
cyanation reagents.13 Since imidoyl radicals derived from
addition of the CF3 radical to an isonitrile moiety undergo fast
intramolecular homolytic aromatic substitution (HAS),12b,14 we
were optimistic that such an HAS can outcompete the possible β-
alkyl radical fragmentation and decided to test α-benzyl
tosylmethylisocyanide (TosMIC) derivatives as substrates for
radical isonitrile insertion reactions. The product of the HAS
should readily eliminate tolylsulfinate in an ionic reaction to
eventually give the corresponding trifluoromethylated isoquino-
lines (Scheme 1).
T
pharmaceuticals, agrochemicals, and organic materials.1,2
Efficient synthetic methods have been developed for its
construction in the past,3 including the classic Pomeranz−
Fritsch,4 Bischler−Napieralski,5 and Pictet−Spengler reactions.6
Due to the significance of this substructure in various fields, the
development of alternative methods that allow for easy access to
isoquinolines and their derivatives is still of importance. Along
these lines, the synthesis of trifluoromethylisoquinolines has
caught great attention from the synthetic community during the
past few years.7 This has been fostered by the fact that the
introduction of a trifluoromethyl group into a lead compound
generally improves its lipophilicity, bioactivity, and metabolic
stability.8
Radical trifluoromethylation has been found to be highly
valuable for simple and efficient incorporation of a CF3 group
into various π-systems.9 Although many methods for radical
trifluoromethylation of activated and unactivated arenes have
been developed, some problems still remain to be solved.10 Most
of the reported trifluoromethylation reactions occur at
preformed arenes that generally bear activating substituents
and often expensive transition metal catalysts are necessary.
Moreover, regioselectivity is a serious problem in such
transformations. For certain heteroarenes, the regioselectivity
issue can be solved by constructing the heteroarene core during
radical trifluoromethylation and in that regard isocyanides have
been used as efficient acceptors to construct heterocyclic ring
structures via radical isocyanide insertion reactions.11 Notably, 1-
trifluoromethylated isoquinolines have been successfully pre-
pared with complete regioselectivity by radical trifluoromethy-
lation of vinyl isocyanides.12 However, the geometry of the
double bond in these arylalkenyl isocyanides has to be controlled
since only the cis-β-aryl vinyl isocyanides are eligible for
heteroarene construction. In contrast to aryl and vinyl
isocyanides that have been intensively explored, there are few
studies on the use of alkyl isocyanides as radical acceptors in
Scheme 1. α-Benzyl TosMIC Derivatives as CF3-Radical
Acceptors for the Construction of 1-
Trifluoromethylisoquinolines
Importantly, TosMIC is a cheap and commercially available
reagent that can easily be doubly alkylated, thus allowing for
ready variation of the benzyl and R2 substituents in these CF3-
radical acceptors (modular approach).15 The double alkylation of
TosMIC was achieved using slightly modified literature
protocols (see the Supporting Information)15 and as a CF3-
radical precursor we applied the commercial Togni reagent 2a.16
We have previously shown that radical-chain reactions with 2a
are efficiently initiated using tetrabutylammonium iodide
Received: September 14, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02882
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Letter
(TBAI).17 Isocyanide 1a was selected as test substrate, various
organic and inorganic bases were screened, and initial experi-
ments were conducted in 1,4-dioxane at 30 °C using 2.0 equiv of
2a (Table 1).
Scheme 2. Cascades Using α-Benzyl α-Alkyl TosMIC
Derivatives
a,b
a
Table 1. Reaction Optimization
b
entry
base
additive
solvent
yield (%)
1
K2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
CH3CN
11
14
10
31
33
2
Cs2CO3
CsF
3
4
NMM
5
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
i
6
LiOH
NaOH
KOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
LiOH
67 (63)
7
62
48
64
47
60
43
66
53
40
35
59
42
8
9
10
11
12
THF
EtOAc
CH2Cl2
c
13
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
d
14
e
15
f
16
g
17
h
18
a
Reaction conditions: 1a (0.20 mmol), 2a (0.40 mmol), TBAI (0.02
mmol), DABCO (0.40 mmol), and LiOH (3.0 mmol) in 1,4-dioxane
(1.0 mL) were stirred at 30 °C for 24 h under argon atmosphere.
b
Yield determined by 19F NMR analysis using PhCF3 as an internal
c
d
e
f
standard. LiI used as initiator. NaI used as initiator. 50 °C. 80 °C.
g
h
i
rt. Run without TBAI. Isolated yield.
With inorganic bases such as K2CO3, Cs2CO3, or CsF, the
targeted 1-trifluoromethylisoquinoline 3a was obtained, albeit in
a low yield (Table 1, entries 1−3). Switching to organic bases
such as NMM and DABCO resulted in slightly improved results
(Table 1, entries 4 and 5). We have recently noted the beneficial
effect of using DABCO in combination with LiOH as an additive
in electron-catalyzed perfluoroalkylation reactions.18 Gratify-
ingly, addition of LiOH led to a further improvement of the yield
(Table 1, entry 6). NaOH and KOH as additive inorganic bases
provided slightly worse results (Table 1, entries 6 and 7). 1,4-
Dioxane could be replaced by CH3CN (Table 1, entry 9), but
THF, EtOAc, and CH2Cl2 resulted in significantly lower yields
(Table 1, entries 10−12). Upon screening other initiators, we
found that TBAI can be substituted by LiI (Table 1, entry 13),
but NaI is less suited (Table 1, entry 14). Reaction in the absence
of TBAI was not efficient (Table 1, entry 18), and 30 °C was
identified as the ideal reaction temperature for this cascade
(Table 1, entries 15−17).
Having the optimized conditions in hand (see Table 1, entry
6), we first explored the scope and limitations of the radical
trifluoromethylation by using various α-benzylated TosMIC
derivatives 2b−t. The aryl group in the benzyl moiety was
systematically varied (Scheme 2). p- and o-tolyl methyl
isocyanides reacted well with 2a and the desired 1-
trifluoromethylisoquinolines 3b,c,e were obtained in good yields
a
Reaction conditions: 1 (0.20 mmol), 2a (0.40 mmol), Bu4NI (0.02
mmol), DABCO (0.40 mmol), and LiOH (3.0 mmol) in 1,4-dioxane
(1 mL) were stirred at 30 °C for 24 h under argon atmosphere.
b
Isolated yield.
(52−65%). In the case of the meta-congener, regioselectivity for
the HAS was 2.1:1 (see 3d). Electronic effects exerted by the aryl
group do not influence reaction outcome to a large extent, and
substrates bearing electron-donating and also -withdrawing
groups provided the corresponding products in good yields
(3f−o). The slightly lower yields obtained for the o-halo-
substituted systems are likely caused by steric effects. The
naphthyl-substituted isocyanide 2p underwent cyclization to 3p
with complete regiocontrol. As expected, the methyl R2-
substituent can be replaced by a larger n-heptyl group (see 3r).
Importantly, also the 4-position of the isoquinoline core can be
addressed as documented by the successful preparation of 3q. 1-
Trifluoromethylisoquinolines 3s and 3t lacking the R2-
substituent were obtained in lower yields. Likely, the cyclization
B
DOI: 10.1021/acs.orglett.7b02882
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Letter
rate constant is smaller in these two cases due to the lacking
Thorpe−Ingold effect.
Scheme 5. Total Synthesis of CF3-mansouramycin B
As compared to the unsymmetrical substrates 1, symmetrical
α,α-bisbenzyl TosMIC derivatives 4a−f are even more easy to
access from TosMIC (see the SI). Because of the higher effective
molarity of the arene radical acceptor in these systems, yields for
the corresponding trifluoromethylated isoquinolines were higher
(Scheme 3, see 5a−f). However, the biphenylmethyl-substituted
Scheme 3. Cascades Using Symmetrical α,α-Bisbenzyl
a,b
TosMIC Derivatives
the benzylic bromide 8 in high yield (92%, over two steps). α-
Benzylation of α-methyl TosMIC with 8 afforded isocyanide 9
(79%). Reaction of 9 with Togni reagent 2a as the key step at
larger scale (2 mmol) led to isoquinoline 10 in 53% isolated yield.
Following literature protocols, 10 was oxidized with trichlor-
oisocyanuric acid (TCCA) in a H2O/HCl solution followed by
the addition of a solution of methylamine in ethanol to finally
afford CF3-mansouramycin B in 62% yield.20
A plausible reaction mechanism for the radical cascade
including a base-promoted homolytic aromatic substitution via
electron catalysis21 is proposed in Scheme 6. Initiation occurs
a
Reaction conditions: 4 (0.20 mmol), 2a (0.40 mmol), Bu4NI (0.02
mmol), DABCO (0.40 mmol), and LiOH (3.0 mmol) in 1,4-dioxane
(1 mL) were stirred at 30 °C for 6 h under argon atmosphere.
Scheme 6. Plausible Reaction Mechanism
b
Isolated yield.
isocyanide 4c reacted with significantly lower efficiency. In that
case, we noted that the target product 5c underwent renewed
non-regioselective arene trifluoromethylation leading to chain
termination under the applied conditions.
We also prepared two homologues of the Togni reagent
bearing longer perfluoroalkyl chains (C2F5: 2b and C3F7: 2c).
Reaction under optimized conditions with the isocyanide 1a
provided the perfluoroalkylated isoquinolines 6a and 6b
(Scheme 4).
Scheme 4. Preparation of 1-Perfluoroalkylated Isoquinolines
To further illustrate the synthetic potential of this new
method, we applied the radical trifluoromethylation to the total
synthesis of CF3-mansouramycin B. Mansouramycin B is an
isoquinolinequinone alkaloid occurring in sponges that shows a
wide array of biological activities against non-small cell lung
cancer, breast cancer, melanoma, and prostate cancer cells.
Mansouramycin B also reveals high cytotoxicity against many
human cancer cell lines with an IC50 value up to 0.089 μmol/L.19
The key step of our total synthesis of CF3-mansouramycin B is
the formation of isoquinoline 10 via the herein introduced radical
cascade cyclization. As illustrated in Scheme 5, the synthesis
began with the NaBH4 reduction of commercial 7 to give the
corresponding alcohol which upon treatment with PBr3 provided
either by reaction of 2a with TBAI17 or with DABCO.22,23 The
CF3 radical generated then adds to the isonitrile functionality of
1a to give the imidoyl radical A, which cyclizes to the arene
moiety to afford cyclohexadienyl radical B. Radical B gets
deprotonated either by o-iodobenzoate generated in the initial
SET reduction of 2a or by the other bases present in the reaction
mixture to afford radical anion C. C is an efficient SET reducing
reagent which is eventually oxidized to generate the intermediate
D formally releasing an electron to complete the catalytic cycle.
Togni reagent 2a acts as an oxidant in this chain carrying step.
Finally, base-promoted elimination of p-tolylsulfinate in D
eventually affords the targeted isoquinoline 3a (not shown in
the Scheme 6).
C
DOI: 10.1021/acs.orglett.7b02882
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Organic Letters
Letter
Larionov, O. V. Org. Biomol. Chem. 2014, 12, 6190. (c) Gonda, Z.;
In summary, we have demonstrated a novel and practical
method for the synthesis of 1-trifluoromethylated isoquinolines
starting with readily prepared α-benzylated TosMIC derivatives.
The radical process uses the commercially available Togni
reagent as the trifluoromethyl radical precursor. Various 1-
trifluoromethylated isoquinolines were successfully prepared in
moderate to good yields. Reactions proceed via electron catalysis
without the help of any transition-metal based catalyst under
mild conditions and this cascade shows a broad substrate scope
allowing to prepare differently substituted isoquinolines. The
successful total synthesis of CF3-mansouramycin B using the
radical cascade as a key step further documents the value of the
novel process.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b02882.
1
Experimental procedures, characterization data, and H,
13C, and 19 F NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: studer@uni-muenster.de.
ORCID
Armido Studer: 0000-0002-1706-513X
Notes
The authors declare no competing financial interest.
(14) (a) Zhang, B.; Muck-Lichtenfeld, C.; Daniliuc, C. G.; Studer, A.
̈
ACKNOWLEDGMENTS
■
Angew. Chem., Int. Ed. 2013, 52, 10792. (b) Leifert, D.; Artiukhin, D. G.;
Neugebauer, J.; Galstyan, A.; Strassert, C. A.; Studer, A. Chem. Commun.
2016, 52, 5997.
(15) (a) Yodov, Y. S.; Ready, P. S.; Joshi, B. V. Tetrahedron 1988, 44,
7243. (b) Baeza, A.; Mendiola, J.; Burgos, C.; Alvarez-Builla, J.; Vaquero,
This work was financially supported by the China Scholarship
Council (stipend to L.W.) and the European Research Council
(ERC Advanced Grant Agreement No. 692640).
́
J. J. J. Org. Chem. 2005, 70, 4879. (c) Gutierrez, S.; Coppola, A.; Sucunza,
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