Cobalt Catalyzed, Regioselective C(sp2)-H Activation of Amides with 1,3-Diynes

Article abstract of DOI:10.1021/acs.orglett.7b02119

The development of a first row transition metal (cobalt)-based catalyst for the as yet unexplored C-H activation-driven reaction of 1,3-diynes, themselves a functional class of interest in a range of application areas, to form isoquinolinones - an importa

Full text of DOI:10.1021/acs.orglett.7b02119

Letter
pubs.acs.org/OrgLett
2
Cobalt Catalyzed, Regioselective C(sp )−H Activation of Amides with
1
,3-Diynes
Subban Kathiravan and Ian A. Nicholls*,†,‡
†
†Bioorganic & Biophysical Chemistry Laboratory, Department of Chemistry & Biomedical Sciences and Linnaeus University Centre
for Biomaterials Chemistry, Linnaeus University, Kalmar, SE-391 82, Sweden
‡
Department of Chemistry, BMC, Uppsala University, Uppsala, SE-751 23, Sweden
*
S Supporting Information
ABSTRACT: The development of a first row transition metal
(
cobalt)-based catalyst for the as yet unexplored C−H activation-
driven reaction of 1,3-diynes, themselves a functional class of interest
in a range of application areas, to form isoquinolinonesan
important structural motif in a number of biologically active
substancesis presented. This versatile and inexpensive catalyst
employs a covalently attached bidendate-directing group, 8-amino-
quinoline. The template directs the C−H activation and facilitates the synthesis of a wide range of alkynylated heterocycles under
mild conditions and with excellent regioselectivity. This strategy provides a novel and efficient route to diverse heterocyclic
frameworks as demonstrated by its late stage application in bisheterocycle syntheses.
he development of efficient, selective, and inexpensive
T
catalysts for facilitating the manipulation of C−H bonds is
driven by the need for sustainable strategies for the synthesis of
1
complex systems. As most reported C−H functionalizations
have been realized using expensive fourth and fifth row metal-
based complexes, largely based on rhodium, palladium, or
ruthenium, the search for systems based upon more readily
available first row transition metal species that display high
catalytic efficiencies and selectivities under mild conditions has
become a significant goal. 2
3
4
5
The groups of Glorius, Nakamura, Ackermann, Kanai,
6
7
8
Yoshikai, Daugulis, and others have recently demonstrated the
use of inexpensive cobalt complexes as versatile catalysts for C−H
activation reactions. More recently, cobalt-based aminoquinoline
assisted C−H activation strategies have been explored, using
bidentate aminoquinoline templates, which can stabilize first row
9
transition metals in high oxidation states (Figure 1a). In contrast
to the monodendate directing groups traditionally used to
promote cyclometalation for C−H activation, bidendate
templates can offer the advantage of regiocontrol with the
targeted C−H bonds. The versatility of cobalt-based catalysis is
even reflected in its use in oxidative C−H/C−H cross-coupling
Figure 1. Co(II) and Rh(III) catalyzed C−H activation with unsaturated
10
compounds.
between heteroarenes, and diasteroselective [3 + 2] annulation
11
of amides with bicyclic alkenes.
15
The 1,3-diyne moiety is a feature that can be found in some
1,3-diynes in the synthesis of 2,5-disubstituted thiophenes,
Yamamoto and co-workers described the palladium-catalyzed [4
2] cross-benzannulation reaction of conjugated enynes with
natural products and functional materials, and can also be used in
1
2
+
theirsynthesis. Despiteitsimportance, fewattemptstoestablish
approaches for the elaboration of this motif have been presented.
Those reported to date include Hoye and co-workers’ description
ofahexahydroDiels−Alder reactionofbenzyneswithstructurally
III
16
diynes, and Yun presented a stereoselective synthesis of boron-
substituted enynes via copper catalyzed borylation of diynes.
17
Despite these major advances, to the best of our knowledge,
13
multicomplex natural products and Glorius’ developed Rh
catalyzed C−H activation/1,3-diyne strategy for the direct
Received: July 11, 2017
14
synthesis of bisheterocyles (Figure 1b). Further, Lei deployed
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b02119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
cobalt catalyzed C−H activation with 1,3-diynes has proven
elusive.
the presence of the sterically demanding quinoline in close
proximity to the residual alkyne. Further studies using the
,
a b
Scheme 1. C−H Activation with Amides
Table 1. Optimization of the Cobalt Catalyzed C−H
,
a b
Annulation with 1,3-Diyne
b
entry
catalyst
oxidant
base
yield (%)
1
2
3
4
5
6
7
8
9
Co(OAc)2
Co(OAc)2
Co(OAc)2
Co(OAc)2
CoCl2
Ag CO
KHCO3
K CO
10
15
12
29
12
5
2
3
3
3
Ag CO
2
2
3
Ag CO
2
Na CO
2 3
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Ag CO
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
NaOPiv
KHCO3
K CO
Co(OH)2
Co(OAc) ·4H O
15
10
11
92
50
40
49
15
10
10
5
2
2
CoCl ·6H O
2
2
[CoCp*(CO)l2
Co(acac)2
Co(acac)2
1
1
1
1
1
1
1
1
1
1
2
2
2
0
1
2
3
4
5
6
7
8
9
0
2
3
Co(acac)2
AgOAc
a
Reaction conditions: 1 (1.0 mmol), 2a (0.5 mmol), cobalt source (10
Co(acac)2
Ag O
2
mol %), base (2.0 equiv), oxidant (2.0 equiv), TFE (1.0 mL), 80 °C,
Co(acac)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
b
2
4 h. Yields of isolated products are given. TFE = trifluoroethanol.
Co(acac)2
2
3
Co(acac)2
Co(acac)2
CsOPiv
Na CO
2
3
Co(acac)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
Mn(OAc)2
KOAc
5
Co(acac) source revealed that the alternative oxidants Ag CO ,
2
2
3
Co(acac)2
NaHPO4
10
0
AgOAc, Ag O (entries 11−13) resulted in reduced yields, as did
2
No catalyst
NaOPiv
efforts with other bases (entries 14−19). A control reaction
performed in the absence of a cobalt catalyst resulted in no
product (entry 20). While decreasing the catalyst loading to5 mol
% reduced the yield (entry 21), increasing the loading from 10 to
c
1
2
Co(acac)2
Co(acac)2
NaOPiv
NaOPiv
69
92
d
a
Reaction conditions: 1 (1.0 mmol), 2 (0.5 mmol), cobalt source (10
mol %), base (2.0 equiv), oxidant (1.5 equiv), TFE (1.0 mL), 80 °C,
3
0 mol % led to no further yield improvement (entry 22).
With the optimized conditions in hand, we next examined the
b
2
4 h. Yields of isolated products are given. TFE = trifluoroethanol,
c
Piv = pivalate, Cp* = pentamethylcyclopentadienyl. 5 mol % catalyst
loading. 30 mol % catalyst loading.
generality of this process with respect to aminoquinoline
carboxamides (1) with electronically diverse functional groups
d
(
Scheme 1). Electron-donating group containing carboxamides
We report herein a robust regioselective cobalt(II)-catalyzed
C−H activation strategy for the annulation of 1,3-diynes using
amides derived from the bidentate template 8-aminoquinoline.
This reaction proceeds under very mild conditions and has a
broad substrate scope providing access to a range of alkynylated
heterocycles (Figure 1c). Further, we have demonstrated the
utility of this strategy through its use in the late-stage synthesis of
bis-heterocycles.
(Scheme 1, 3a−g) were generally well tolerated, and the
difference in steric hindrance at the 2- and 3-positions did not
result in a substantial change in catalytic efficiency. Carboxamides
with synthetically useful electrophilic substituents (F, Cl, Br, and
I) were also well tolerated, thus providing a route to halogenated
species potentially available for further elaboration (Scheme 1,
3h−p). Moreover, trifluoromethyl substituted amides were also
amenable to this transformation and produced the corresponding
annulated products 3q−r in very good to excellent yields (85−
90%). Additionally, the strongly electron-withdrawing nitro-
group afforded the product 3s also in excellent yield.
We initiated our studies by exploring reaction conditions for
the envisioned direct C−H activation of an amide (1) with a 1,3-
diyne (2) (Table 1). Treatment of 1 (0.4 mmol) with a 1,3-diyne
(
2, 0.2 mmol) in the presence of a catalytic amount of Co(OAc)2
Tolerance of bulky substituents was explored using the
heterocycles thiophene and furan, both affording the desired
products 3t−u in good yield (65−68%). Likewise, a naphtha-1-yl
amide underwent the annulation reaction with the 1,3-diyne to
afford the corresponding 3v in 74% yield. A 2-naphthyl amide
(1w)overreacted providing amixture ofregioisomer products 3w
and Ag CO (2 equiv) and KHCO (2 equiv) as oxidant and base
2
3
3
respectively, at 80 °C for 24 h, led to the regioselective C−H
activation product 3 in 10% yield (entry 1). An investigation of
alternative oxidants and bases established that the combination of
Mn(OAc) and NaOPiv enhanced the yield of the cobalt catalytic
system (entry 4). A series of studies (entries 5−9) using
alternative cobalt sources identified Co(acac) as a particularly
active species, affording the product in very good yield (92%,
entry 10).
Despite the excess of quinoline, no evidence offormation of the
bis-annulation of the 1,3-diynes was observed, presumably due to
2
1
and 3w′, in a 2:1 ratio as determined by H NMR.
Thepresenceofatert-butylsubstituentinthepara-positionwas
well tolerated affording the corresponding product (3x) in 84%
yield. Finally, an acrylamide analog of 1 reacts with the 1,3-diyne
(2a) to yield the alkynylated pyridone 3y in 65% yield illustrating
the compatibility of this method with vinylic amides.
2
B
DOI: 10.1021/acs.orglett.7b02119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
,
a b
We then explored the application of the reaction with other
aliphatic 1,3-diynes (Scheme 2). Longer chain lengths were
Scheme 3. Synthesis of Bisheterocycles
Scheme 2. Variation of the Alkyl 1,3-Diyne Partner ,
a b
a
Reaction conditions: 1a and 1u (2.0 mmol), 3d, 3j, and 3u (1.0
mmol), Co(acac) (10 mol %), NaOPiv (2.0 equiv), Mn(OAc) (2.0
2
2
b
equiv), TFE (1.0 mL), 80 °C, 24 h. Yields of isolated products are
given. TFE = trifluoroethanol.
Scheme 4. Preliminary Mechanistic Studies
a
Reaction conditions: 1 (1.0 mmol), 4a−f (0.5 mmol), Co(acac) (10
2
mol %), NaOPiv (2.0 equiv), Mn(OAc) (2.0 equiv), TFE (1.0 mL),
8
trifluoroethanol.
2
b
0 °C, 24 h. Yields of isolated products are given. TFE =
readily accepted (5a, 62%; 5b, 71%), with the structure of 5a
being unambiguously assigned by single crystal X-ray crystallo-
18
graphic analysis, confirming the assigned regioselectivity.
Hydroxyl functionality at the 1,3-diyne β-position was well
tolerated (5c, 68%), as were the cyclopropyl (5d, 70%) and
cyclopentyl (5e, 79%) disubstituted diynes, though a lower yield
was obtained in the presence of a dicarboxylate ethyl ester (5f,
5
8%).
We then further interrogated the reaction scope with a series of
aryl derivatives of 4 (Scheme 2). In our initial reaction, using
diphenyl 1,3-diyne 4g, we were delighted to observe a good yield
of 5g (69%). We then turned to the influence of substituent
effects, with methyl (5h) and methoxy (5i) substituted products
being obtained in 70% and 72% yields, respectively, and even
multisubstituted aryl 1,3-diynes were accepted, as seen in the
cases of 5j (60%) and 5k (70%). The products from bulky 1,3-
diynes 5l (63%) and 5-methoxy naphthyl substituted 5m (70%)
were also well tolerated, as were 1,3-diynes bearing ortho-
trifluoromethyl substituents (5n, 75%). Annulation with a
dipyridyl substituted 1,3-diyne provided one-pot access to the
significant degree of steric crowding around the reaction site and
the presence of an additional quinolone moiety, the reaction
delivered the symmetrical and unsymmetrical bisheterocycles
(6a−c) in 52−68% yield.
Intermolecular competition experiments and deuterium label-
ing studies were undertaken to investigate the mechanism of the
reaction (Scheme 4). When a 1:1 mixture of 4-methylbenzamide
(1d) and 4-nitrobenzamide (1s) was subjected to standard
conditions, a 1:1.2 mixture of products was obtained, which
suggests that electrophilic cobaltation is unlikely (Scheme 4a). In
1,8-bipyridinyl heterocyle 5o in 59% yield, and meta-chloro
a competition study using 1a and D -1a, a product distribution
value of 1.2 was determined (Scheme 4b), indicating that C−H
bond cleavage might not be involved in the rate-limiting step.
5
Furthermore, no D/H exchange was observed when D -1a was
5
treated with a 1,3-diyne under standard conditions. Similarly, no
Encouraged by the excellent functional group tolerance of the
reaction, we then focused on the originally envisioned double C−
H activation of 1,3-diynes for the synthesis of bis-heterocyles
deuterium incorporation in the amide 1a was observed when 1a
was treated with isotopically labeled CD COOD as a solvent in
3
the absence of co-oxidant and catalyst (Scheme 4c).
(
Scheme 3). The amides (1a and 1u) were treated with easily
On the basis of the mechanistic studies described here, and
19
prepared alkynylated heterocycles (3d, 3j, and 3u), which contain
previous reports, a possible catalytic cycle can be proposed,
Figure 2. Initially, oxygen oxidizes Mn(II) to Mn(III) or Mn(IV),
challenging, strongly coordinating quinoline groups. Despite the
C
DOI: 10.1021/acs.orglett.7b02119
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. 2009, 292, 57. (c) Satoh, T.; Miura, M. Chem. - Eur. J. 2010, 16,
11212. (d) McMurray, L.; O’Hara, F.; Gaunt, M. J. Chem. Soc. Rev. 2011,
40, 1885. (e) Gutekunst, W. R.; Baran, P. S. Chem. Soc. Rev. 2011, 40,
1976. (f) Ackermann, L. Chem. Rev. 2011, 111, 1315. (g) Baudoin, O.
Chem. Soc.Rev. 2011,40,4902.(h)Cho,S.H.;Kim,J.Y.;Kwak,J.;Chang,
S. Chem. Soc. Rev. 2011,40, 5068. (i)Zhou, M.;Crabtree, R.H. Chem. Soc.
Rev. 2011, 40, 1875. (j) Le Bras, J.; Muzart, J. Chem. Rev. 2011, 111, 1170.
(
k)Schipper,D.J.;Fagnou,K.Chem.Mater.2011,23,1594.(l)Arockiam,
P. B.; Bruneau, C.; Dixneuf, P. H. Chem. Rev. 2012, 112, 5879.
m) Gutekunst, W. R.; Gianatassio, R.; Baran, P. S. Angew. Chem., Int. Ed.
(
2012, 51, 7507. (n)Rouquet, G.;Chatani, N. Angew. Chem., Int. Ed. 2013,
52, 11726. (o) Kuhl, N.; Schroeder, N.; Glorius, F. Adv. Synth. Catal.
2014, 356, 1443. (p) Mesganaw, T.; Ellman, J. A. Org. Process Res. Dev.
2014, 18, 1097. (q) Ye, B.; Cramer, N. Acc. Chem. Res. 2015, 48, 1308.
(
(
(
(
r) Shin, K.; Kim, H.; Chang, S. Acc. Chem. Res. 2015, 48, 1040.
s)Segawa, Y.;Maekawa, T.;Itami, K. Angew. Chem., Int. Ed. 2015, 54, 66.
t) Gandeepan, P.; Cheng, C. H. Acc. Chem. Res. 2015, 48, 1194.
u) Gensch, T.; Hopkinson, M. N.; Glorius, F.; Wencel-Delord, J. Chem.
2
Figure 2. Proposed catalytic cycle for the Co-catalyzed C(sp )−H
activation with 1,3-diyne.
Soc. Rev. 2016, 45, 2900.
(2) (a) Lerchen, A.; Knecht, T.; Daniliuc, C. G.; Glorius, F. Angew.
Chem., Int. Ed. 2016, 55, 15166. (b) Kim, J. H.; Gressies, S.; Glorius, F.
Angew. Chem., Int. Ed. 2016, 55, 5577.
(3) (a) Ilies, L.; Chen, Q.; Zeng, X.; Nakamura, E. J. Am. Chem. Soc.
2011, 133, 5221. (b) Shang, R.; Ilies, L.; Nakamura, E. J. Am. Chem. Soc.
2015, 137, 7660.
which in turn oxidizes Co(II) to Co(III). Next, the complex A
undergoes a concerted metalation deprotonation (CMD)
process to produce the intermediate complex B by aminoquino-
line-assisted C−H bond functionalization. Subsequently, B
coordinates with the 1,3-diyne, which after insertion leads to
the intermediate D. Reductive elimination of D affords the
product E, and catalyst.
In summary, we have established a robust strategy for the direct
formation of alkynylated heterocycles and for the one-pot
synthesis of both symmetric and nonsymmetrical bis-hetero-
cycles through an aminoquinoline-directed cobalt-facilitated C−
H activation with diverse 1,3-diynes. This inexpensive versatile
and mild cobalt-based reaction, with its wide substrate scope with
respect to amides and 1,3-diynes and high product regioselectiv-
ity, provides a novel approach for the development of new
heterocyclic systems.
(4) Song, W.; Ackermann, L. Angew. Chem., Int. Ed. 2012, 51, 8251.
(5) Yoshino, T.; Ikemoto, H.; Matsunaga, S.; Kanai, M. Angew. Chem.,
Int. Ed. 2013, 52, 2207.
6) (a) Wu, J.; Yoshikai, N. Angew. Chem., Int. Ed. 2016, 55, 336.
b) Gao, K.; Yoshikai, N. Acc. Chem. Res. 2014, 47, 1208.
7) (a) Nguyen, T. T.; Grigorjeva, L.; Daugulis, O. ACS Catal. 2016, 6,
51. (b) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014, 53,
(
(
(
5
1
0209.
(8) (a) Maity, S.; Kancherla, R.; Dhawa, U.; Hoque, T.; Pimparkar, S.;
Maiti, D. ACS Catal. 2016, 6, 5493. (b) Sen, M.; Emayavaramban, B.;
Barsu, N.; Premkumar, J. R.; Sundararaju, B. ACS Catal. 2016, 6, 2792.
(c) Du, C.; Li, P.-X.; Zhu, X.; Suo, J. F.; Niu, J. -L; Song, M.-P. Angew.
Chem., Int. Ed. 2016, 55, 13571. (d) Hummel, J. R.; Ellman, J. A. J. Am.
Chem. Soc. 2015, 137, 490.
(
9) (a) Grigorjeva, L.; Daugulis, O. Org. Lett. 2014, 16, 4684.
ASSOCIATED CONTENT
Supporting Information
■
(
(
b) Grigorjeva, L.; Daugulis, O. Angew. Chem., Int. Ed. 2014, 53, 10209.
c) Thrimurtulu, N.; Dey, A.; Maiti, D.; Volla, C. M. R. Angew. Chem., Int.
*
S
TheSupportingInformationisavailablefreeofchargeontheACS
Publications website at DOI: 10.1021/acs.orglett.7b02119.
Ed. 2016, 55, 12361.
10) Tan, G.; He, S.; Huang, X.; Liao, X.; Cheng, Y.; You, J. Angew.
Chem., Int. Ed. 2016, 55, 10414.
11) Gandeepan, P.; Rajamalli, P.; Cheng, C. H. Angew. Chem., Int. Ed.
016, 55, 4308.
12) (a) Siemsen, P.; Livingston, R. C.; Diederich, F. Angew. Chem., Int.
(
Experimental procedures, characterization data for all new
compounds (PDF)
(
2
(
AUTHOR INFORMATION
Corresponding Author
Ed. 2000, 39, 2632. (b) Ito, A.; Cui, B.; Chavez, D.; Chai, H. B.; Shin, Y.
G.; Kawanishi, K.;Kardono, L. B.; Riswan, S.; Farnsworth, N. R.; Cordell,
G. A.;Pezzuto,J.M.;Kinghorn, A.D.J.Nat. Prod.2001,64,246.(c)Yuan,
C.;Chang, C. T.;Axelrod, A.;Siegel, D. J. Am. Chem. Soc.2010,132,5924.
(d) Shi, W.; Lei, A. Tetrahedron Lett. 2014, 55, 2763.
■
*
E-mail: ian.nicholls@lnu.se.
ORCID
(
13) Niu, D.; Willoughby, P. H.; Woods, B. P.; Baire, B.; Hoye, T. R.
Nature 2013, 501, 531.
14) Yu, D. G.; de Azambuja, F.; Gensch, T.; Daniliuc, C. G.; Glorius, F.
Angew. Chem., Int. Ed. 2014, 53, 9650.
15) Zhang, G.; Yi, H.; Chen, H.; Bian, C.; Liu, C.; Lei, A. Org. Lett.
014, 16, 6156.
16) Gevorgyan, V.; Takeda, A.; Homma, M.; Sadayori, N.;
Subban Kathiravan: 0000-0003-0774-2528
Ian A. Nicholls: 0000-0002-0407-6542
Notes
(
(
2
(
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the Linnaeus University, and Swedish Research
■
Radhakrishnan, U.; Yamamoto, Y. J. Am. Chem. Soc. 1999, 121, 6391.
(17) Li, D.; Kim, Y. E.; Yun, J. Org. Lett. 2015, 17, 860.
(18)CCDC1526714 (5a)contains thesupplementarycrystallographic
data for this paper. These data can be obtained free of charge from the
CambridgeCrystallographicDataCentreviawww.ccdc.cam.ac.uk/data_
request/cif.
Council (Vetenskapsra
̊
Bo
̈
(
19)Zhu, X.;Su,J. H.;Du,C.;Wang,Z. L.;Ren, C. J.;Niu,J. L.;Song,M.
REFERENCES
■
P. Org. Lett. 2017, 19, 596.
(
1) For selected reviews: (a) Chen, X.; Engle, K. M.; Wang, D. H.; Yu, J.
Q. Angew. Chem., Int. Ed. 2009, 48, 5094. (b) Daugulis, O. Top. Curr.
D
DOI: 10.1021/acs.orglett.7b02119
Org. Lett. XXXX, XXX, XXX−XXX