Synthesis of Substituted Furan/Pyrrole-3-carboxamides through a Tandem Nucleopalladation and Isocyanate Insertion

Article abstract of DOI:10.1021/acs.orglett.6b02077

Access to furanyl- and pyrrolyl-3-carboxamides from readily available 3-alkyne-1,2-diols and 1-amino-3-alkyn-2-ols using isocyanate as amido surrogate is demonstrated. The approach constitutes a successful unprecedented combination of heteropalladation an

Full text of DOI:10.1021/acs.orglett.6b02077

Letter
pubs.acs.org/OrgLett
Synthesis of Substituted Furan/Pyrrole-3-carboxamides through a
Tandem Nucleopalladation and Isocyanate Insertion
†
†
‡
,†,§
Manda Rajesh, Surendra Puri, Ruchir Kant, and Maddi Sridhar Reddy*
†
‡
Medicinal & Process Chemistry Division and Molecular & Structural Biology Division, CSIR-Central Drug Research Institute,
BS-10/1, Sector 10, Jankipuram extension, Sitapur Road, Lucknow 226031, India
§
Academy of Scientific and Innovative Research, New Delhi 110001, India
S Supporting Information
*
ABSTRACT: Access to furanyl- and pyrrolyl-3-carboxamides
from readily available 3-alkyne-1,2-diols and 1-amino-3-alkyn-
2
-ols using isocyanate as amido surrogate is demonstrated. The
approach constitutes a successful unprecedented combination
of heteropalladation and isocyanate insertion, a new avenue for
novel amide bond constructions. The mechanism likely
involves a 6-membered oxaaminopalladacycle as the key
intermediate.
1
r,s
alladium-catalyzed cyclization of functionalized alkynes
studied. Thus, Gabriele et al. achieved the installation of an
amide group by tethering carbon monoxide followed by amines
to the C−Pd bond derived from nucleopalladation of alkynes.
P
opens many otherwise difficult C−Pd avenues which via
various couplings in tandem can be materialized for composite
1
1n
2a
outcomes. The approach not only avoids the unnecessary
Zhu et al., followed by us, revealed the use of isocyanide for
the amide construction in tandem to amino/oxypalladation. In
continuation of interest in uncovering new activities of
prefunctionalization of the heterocycles, which is usually
required in most of the classical coupling reactions, but brings
in the high atom and step economies and thus altogether
delivers the complex architectures in short pathways. Thus,
various groups have explored the heteropalladation and its
tandem coupling with various partners like carbon mon-
2
functionalized alkynes, we herein present an unprecedented
isocyanate coupling /insertion in tandem to intramolecular
oxy/amino palladation of alkynes for furanyl- and pyrrolyl-3-
carboxamides (Scheme 1B). An interesting mechanism
involving an oxyaminopalladacycle is proposed with some
evidence.
Furans and pyrroles are frequently found scaffolds both in
drug discovery as well as natural products. Particularly, these
heterocycles tethered with amide unit were identified as very
important subunits in many bioactive compounds.
example: atorvastatin and sunitinib are among the best selling
drugs; proximicin C, tallimustine, oroidin, dispyrin, (−)-bro-
mophakellin, bromoagelaspongin, (+)-ageliferin, (−)-sceptrin,
and kibdelomycin are some of the natural products that contain
these subunits. We therefore aimed to synthesize these motifs
in an expeditious pathway.
3
1
a,b
1c
1d,e
1f,g
oxide,
alkynes, boronates,
halides/pseudohalides,
1
h−j
1k
1l
1m
olefins,
allylic alcohols, cyanides, aldehydes, isocyani-
etc. (Scheme 1A). On the similar lines, and in
1
n−q
des,
consequent to the enormous importance in biology, amide
construction in tandem to nucleopalladation was also recently
4
,5
4
,5
For
Scheme 1. Tandem Nucleopalladation and Coupling of
Alkynes
We began our studies with the optimization of reaction
conditions for the conversion of 1a to 2aa (Table 1). When
Pd(OAc) was used as catalyst and Na CO as base in CH CN,
2
2
3
3
the desired product 2aa was formed via oxypalladation and
isocyanate insertion followed by dehydration in 10% yield
(
entry 1).
Received: July 15, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02077
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Scheme 2. Synthesis of Furan-3-amides from Alkynediols
b
entry
catalyst
base
solvent
temp (°C) yield (%)
1
2
3
4
5
6
7
8
9
Pd(OAc)2
PdI2
Na CO
CH CN
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
60
10
30
40
82
26
65
35
20
15
2
3
3
3
3
Na CO
2
CH CN
3
Pd(PPh ) Cl
Na CO
2
CH CN
3
2
2
3
PdCl2
Na CO
2
CH CN
3
3
Pd(TFA)2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
Na CO
2
CH CN
3
3
K CO
CH CN
2
3
3
Cs CO
CH CN
2
3
3
TEA
CH CN
3
DIPEA
DBU
CH CN
3
10
11
12
13
14
15
16
CH CN
3
Na CO
2
DMSO
2-BuOH
1,4-dioxane
DCE
10
3
3
3
3
3
3
Na CO
2
Na CO
2
25
05
45
28
Na CO
2
Na CO
2
toluene
THF
Na CO
2
a
Conditions: 1aa (0.5 mmol), BnNCO (1.1 mmol), base (0.9 mmol),
catalyst (0.025 mmol) in solvent (2.5 mL) at 60 °C under air.
b
Isolated yield.
Screening of other Pd catalysts like PdI , Pd(PPh ) Cl ,
2
3 2
2
PdCl , and Pd(TFA) revealed that PdCl was highly effective
2
2
2
for the intended conversion to afford 2aa in 82% yield (entries
−5). Other bases (both inorganic and organic) like K CO ,
2
2
3
Cs CO , TEA, DIPEA, and DBU were not as productive as
2
3
Na CO (entries 6−10). MeCN was the best of all the solvents
2
3
tested (entries 11−16).
With the optimized conditions in hand, we next evaluated
the generality of the methodology. We first studied the reaction
scope of dihydroxy alkynes. As is evident from Scheme 2, the
reaction accommodated substrates with disparate electron
properties. Initially, variation of substitution at alkyne terminal
was studied. Substrates with alkylated phenyl substitution on
the alkyne terminal (1b,c) led to similar product yields (77−
a
Conditions: 1 (0.5 mmol), BnNCO (1.1 mmol), base (0.9 mmol),
catalyst (0.025 mmol) in solvent (2.5 mL) at 60 °C under air.
b
Isolated yield.
81%) like 1a, whereas halo (F and Cl) phenyl substitution
(
1d,e) slightly decreased the productivity (67−69%). The
electronic nature of the phenyl substitution has a noticeable
influence on the outcome. Thus, electron-rich alkoxy-
substituted substrates 1f,g gave the corresponding adducts
were initially tested. Alkyl- and halophenyl isocyanates
successfully reacted under standard conditions to afford the
corresponding products 2ab−ae in 67−77% yields. Further
expanding the scope of the reaction, aliphatic isocyanates were
found to be even better partners compared to their aromatic
counterpartners. Thus, 2af−am were obtained in 69−89%
yields. Steric factors in the case of isopropyl and tert-butyl
isocyanates showed no apparent effect on the outcome.
Pleasingly, sensitive chloroethyl groups survived successfully
through the standard conditions during the synthesis of 2ai.
Setting a limitation, substrates bearing a terminal alkyne did not
afford the desired product. The structure of 2ak was
unambiguously confirmed by X-ray crystallography.
We next aimed to screen the amino alkynols to expand the
reaction scope for the synthesis of pyrrole-3-amides (Scheme
4). Delightedly, when we subjected 3a and BnNCO to the
standard conditions, the expected product 4a was obtained in
an excellent yield of 79%. The reaction went equally well with
toluyl (3b) substitution (4b in 83% yield) at the alkyne
terminal, whereas the chlorophenyl group (3c) was found to
2
fa−ga in 76−84% yields, whereas the electron-deficient
counterpart 1h was transformed to the desired adduct 2ha in
moderate yield of 58%. Substrates with thiophenyl and
anthracenyl substitution (1i,j) were found to be equally viable
substrates for the reaction to furnish the products (2ia−ja) in
6
8−72% yields. We next tested the tolerance of the reaction
toward aliphatic substitution. Pleasingly, the substrates with
both acyclic (1k) and cyclic (1l,m) alkyl substitution passed
through the reaction smoothly to afford the products in
excellent yields (67−71%). Furthermore, the reaction pro-
ceeded well with the enyne 1n to afford product with alkenyl
substitution at C2. Products with alkyl substitution at C-5
(
2oa−pa) were also smoothly accessed (76−83%). Finally,
trisubstituted furanamides 2pa−ta were synthesized in 62−79%
yields under the standard conditions.
The scope of this transformation was further investigated
with respect to isocyanates (Scheme 3). Phenyl isocyanates
B
DOI: 10.1021/acs.orglett.6b02077
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Scheme 3. Scope of Isocyanates
Scheme 4. Synthesis of Pyrrole 3-carboxamides
a
Conditions: 1a (0.5 mmol), RNCO (1.1 mmol), base (0.9 mmol),
catalyst (0.025 mmol) in solvent (2.5 mL) at 60 °C under air.
a
b
Conditions: 3 (0.5 mmol), BnNCO (1.1 mmol), base (0.75 mmol),
Isolated yield.
b
catalyst (0.025 mmol) in solvent (2.5 mL) at 60 °C under air Isolated
yield.
slightly deactivate the reaction (4c in 62% yield). Next,
naphthyl and thiophene-yl substrates (3d,e) were cleanly
transformed to the products (4d,e) in 69−73% yield. Alkyl
substitution at alkyne (3f) also showed no disparity in
undergoing cyclization/amidation cascade. We then tested the
scope of isocyanates. Linear or branched aliphatic isocyanates
all reacted well to produce the desired products (4g−j) in
excellent yields (72−85%), whereas phenyl isocyanate showed
relatively low productivity (4k in 64% yield). A secondary
hydroxyl bearing homopropargyl amine 3l was also found to be
feasible in the reaction to afford the corresponding product in
excellent yield (4l in 79% yield). However, substrates with
NHBoc instead of NHTs were found to be incompatible with
the reaction.
Scheme 5. Supporting Experiments for Mechanism
To probe the mechanism, some support experiments were
carried out as shown in Scheme 5. Thus, 5 (obtained in the
absence of isocyanate) was treated under the standard
conditions. No reaction occurred, suggesting that 5 was not
an intermediate in the cascade process. When a substrate
without the propargyl hydroxyl group (6) was subjected to the
reaction conditions a simple regioselectively hydrolyzed
product 9 was obtained likely via intermediate 7. No addition
product 8 was obtained, indicating that the adjacent hydroxyl
group is essential for the desired transformation. Similarly, 2-
alkynylphenol 10 also yielded a simple cyclized product 12
without amidation (11), emphasizing the importance of the
neighboring hydroxyl group. Surprisingly, homopropargyl
amine 13, which is devoid of an adjacent hydroxyl group, did
not even cyclize under the standard conditions, suggesting that
the hydroxyl group is not only assisting in the isocyanate
insertion but also being partially responsible for initial
nucleopalladation. In this case, perhaps due to weak
nucleophilicity of NHTS group, the initial cyclization also
needed the stronger activation of alkyne group with the help of
coordination with adjacent hydroxyl group.
C
DOI: 10.1021/acs.orglett.6b02077
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the basis of these results, a probable mechanism is
CSIR-CDRI, for supervising the X-ray data collection and
structure determination of 2ak. CDRI Communication No:
proposed in Scheme 6. Thus, PdCl activates the alkyne group
2
9
304.
Scheme 6. Proposed Mechanism
REFERENCES
■
(
1) (a) Gabriele, B.; Veltri, L.; Mancuso, R.; Salerno, G.; Maggi, S.;
Aresta, B. M. J. Org. Chem. 2012, 77, 4005. (b) Gabriele, B.; Mancuso,
R.; Maltese, V.; Veltri, L.; Salerno, G. J. Org. Chem. 2012, 77, 8657.
(
(
c) Yao, B.; Wang, Q.; Zhu, J. Angew. Chem., Int. Ed. 2012, 51, 12311.
d) Arcadi, A.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Iazzetti, A.;
Marinelli, F. Org. Biomol. Chem. 2013, 11, 545. (e) Huang, J.;
Macdonald, S. J. F.; Harrity, P. A. Chem. Commun. 2010, 46, 8770.
(f) Fujino, D.; Yorimitsu, H.; Osuka, A. J. Am. Chem. Soc. 2014, 136,
6
255. (g) Li, E.; Cheng, X.; Wang, C.; Shao, Y.; Li, Y. J. Org. Chem.
2
012, 77, 7744. (h) Tian, P.-P.; Cai, S. − H.; Liang, Q. − J.; Zhou, X.
−
Y.; Xu, Y. − H.; Loh, T. − P. Org. Lett. 2015, 17, 1636. (i) Li, J.;
Zhu, Z.; Yang, S.; Zhang, Z.; Wu, W.; Jiang, H. J. Org. Chem. 2015, 80,
870. (j) She, Z.; Niu, D.; Chen, L.; Gunawan, M. A.; Shanja, X.;
3
Hersh, W. H.; Chen, Y. J. Org. Chem. 2012, 77, 3627. (k) Xu, C.;
Murugan, V. K.; Pullarkat, S. A. Org. Biomol. Chem. 2012, 10, 3875.
(l) Xia, G.; Han, X.; Lu, X. Org. Lett. 2014, 16, 6184. (m) Han, X.; Lu,
X. Org. Lett. 2010, 12, 3336. (n) Hu, Z.; Liang, D.; Zhao, J.; Huang, J.;
Zhu, Q. Chem. Commun. 2012, 48, 7371. (o) Qiu, G.; Qiu, X.; Wu, J.
Adv. Synth. Catal. 2013, 355, 3205. (p) Qiu, G.; Chen, C.; Yao, L.; Wu,
J. Adv. Synth. Catal. 2013, 355, 1579. (q) Nanjo, T.; Tsukano, C.;
Takemoto, Y. Org. Lett. 2012, 14, 4270. (r) Gabriele, B.; Mancuso, R.;
Salerno, G.; Costa, M. J. Org. Chem. 2007, 72, 9278−9282.
while coordinating with a hydroxyl group (A), which leads to
nucleopalladation to yield intermediate B. This palladium
complex does not immediately undergo protodepalladation due
to coordination with the hydroxyl group and provides enough
room for isocyanate insertion, which probably gives the
oxaaminopallada cyclic intermediate C. When the water
molecule is expelled, subsequent reaction of C with liberated
(
s) Gabriele, B.; Salerno, G.; Fazio, A.; Veltri, L. Adv. Synth. Catal.
006, 348, 2212.
2) (a) Thirupathi, N.; Hari Babu, M.; Dwivedi, V.; Kant, R.; Sridhar
2
(
Reddy, M. Org. Lett. 2014, 16, 2908. (b) Kumar, G. R.; Kumar, Y. K.;
Reddy, M. S. Chem. Commun. 2016, 52, 6589. (c) Thirupathi, N.; Puri,
S.; Reddy, T. J.; Sridhar, B.; Reddy, M. S. Adv. Synth. Catal. 2016, 358,
303. (d) Hari Babu, M.; Dwivedi, V.; Kant, R.; Sridhar Reddy, M. S.
Angew. Chem., Int. Ed. 2015, 54, 3783. (e) Kumar, Y. K.; Kumar, G. R.;
Reddy, T. J.; Sridhar, B.; Reddy, M. S. Org. Lett. 2015, 17, 2226.
HCl releases PdCl for the next cycle.
2
In summary, we have illustrated a general approach for the
synthesis of highly substituted furan/pyrrolamides from readily
available alkynols/alkynamines using isocyanate as an amino
surrogate. The reaction likely proceeds via vicinal hydroxyl-
assisted nucleopalladation of alkynes followed by unprece-
dented isocyanate insertion/dehydration, opening a new
avenue for amide bond constructions. Further, a high reaction
scope with respect to both partners of the coupling along with
excellent product yields makes it a practical approach for the
highly privileged scaffolds.
(f) Dwivedi, V.; Hari Babu, M. H.; Kant, R.; Sridhar Reddy, M. S.
Chem. Commun. 2015, 51, 14996. (g) Rajesh, M.; Thirupathi, N.;
Jagadeshwar Reddy, T.; Kanojiya, S.; Sridhar Reddy, M. J. Org. Chem.
2
015, 80, 12311. (h) Kiran Kumar, Y.; Ranjith Kumar, G.; Sridhar
Reddy, M. J. Org. Chem. 2014, 79, 823. (i) Puri, S.; Thirupathi, N.;
Sridhar Reddy, M. S. Org. Lett. 2014, 16, 5246. (j) Thirupathi, N.;
Kumar, Y. K.; Kant, R.; Reddy, M. S. Adv. Synth. Catal. 2014, 356,
1
823. (k) Reddy, M. S.; Thirupathi, N.; Hari Babu, M.; Puri, S. J. Org.
ASSOCIATED CONTENT
Chem. 2013, 78, 5878.
■
*
S
Supporting Information
(3) Recently, Inamoto et al. reported a tandem amino rhodation and
isocyanate insertion for indole-3-carboxamides, which, however, could
not be extended to oxyheterocycles: Mizukami, A.; Ise, Y.; Kimachi, T.;
Inamoto, K. Org. Lett. 2016, 18, 748−751.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02077.
(
4) Regarding furan, see: (a) Boto, A.; Alvarez, L. Furan and Its
Derivatives. In Heterocycles in Natural Product Synthesis; Wiley−VCH,
011; 97. (b) Manna, S.; Antonchick, A. P. Org. Lett. 2015, 17, 4300.
c) Lin, Y. L.; Tsai, Y. L.; Kuo, Y. H.; Liu, Y. H.; Shiao, M. S. J. Nat.
1
Experimental procedures, characterization data, and H
1
3
2
(
and C NMR spectra, crystallographic data for
compound 2ak (PDF)
Prod. 1999, 62, 1500. (d) Gulevich, A. V.; Dudnik, A. S.; Chernyak, N.;
Gevorgyan, V. Chem. Rev. 2013, 113, 3084. (e) Jacques, S. A.; Kuhn, I.;
Koniev, O.; Schuber, F.; Lund, F. E.; Wagner, A.; Muller-Steffner, H.;
Kellenberger, E. J. Med. Chem. 2015, 58, 3582. (f) Zhou, L.; Stewart,
G.; Rideau, E.; Westwood, N. J.; Smith, T. K. J. Med. Chem. 2013, 56,
X-ray data for compound 2ak (CIF)
AUTHOR INFORMATION
■
Corresponding Author
7
2
96. (g) Popiolek, L.; Biernasiuk, A.; Malm, A. J. Heterocycl. Chem.
016, 53, 479.
*E-mai: msreddy@cdri.res.in.
Notes
(
5) Regarding pyrrole, see: (a) Estevez, V.; Villacampa, M.;
Menendez, J. C. Chem. Soc. Rev. 2014, 43, 4633. (b) Pina, I. C.;
White, K. N.; Cabrera, G.; Rivero, E.; Crews, P. J. Nat. Prod. 2007, 70,
The authors declare no competing financial interest.
6
13. (c) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N. Beilstein
ACKNOWLEDGMENTS
■
J. Org. Chem. 2011, 7, 442. (d) Jeong, Y. C.; Moloney, M. G. Beilstein J.
Org. Chem. 2013, 9, 1899.
M.R. and S.P. thank CSIR for the fellowships. We thank SAIF
division CSIR-CDRI for the analytical support. We gratefully
acknowledge financial support by DST (SB/FT/CS-102/
2012). We thank Dr. Tejender S. Thakur of MSB Division,
D
DOI: 10.1021/acs.orglett.6b02077
Org. Lett. XXXX, XXX, XXX−XXX