Substituted Pyrrololactams via Ring Expansion of Spiro-2H-pyrroles from Intermolecular Alkyne-Isocyanide Click Reactions

Article abstract of DOI:10.1021/acs.orglett.6b03786

The facile synthesis of 6- to 8-membered pyrrololactams has been developed using a ring expansion of spiro-2H-pyrroles, the products of intermolecular alkyne-isocyanide click reactions. The key to successful ring expansion of spiro-2H-pyrroles to pyrrololactams is the enforced orbital overlap between the internal alkene and the amide carbonyl group through the conformationally locked bicyclic structures. The newly disclosed α-isocyano lactams, substrates for click reactions, should find their utility in the synthesis of pharmaceutically important heterocyclic compounds.

Full text of DOI:10.1021/acs.orglett.6b03786

Letter
pubs.acs.org/OrgLett
Substituted Pyrrololactams via Ring Expansion of Spiro‑2H‑pyrroles
from Intermolecular Alkyne−Isocyanide Click Reactions
Jimil George, Hun Young Kim,* and Kyungsoo Oh*
Center for Metareceptome Research, College of Pharmacy, Chung-Ang University, 84 Heukseok-ro, Dongjak, Seoul 06974, Republic
of Korea
S
* Supporting Information
ABSTRACT: The facile synthesis of 6- to 8-membered
pyrrololactams has been developed using a ring expansion of
spiro-2H-pyrroles, the products of intermolecular alkyne−
isocyanide click reactions. The key to successful ring expansion
of spiro-2H-pyrroles to pyrrololactams is the enforced orbital
overlap between the internal alkene and the amide carbonyl
group through the conformationally locked bicyclic structures.
The newly disclosed α-isocyano lactams, substrates for click reactions, should find their utility in the synthesis of
pharmaceutically important heterocyclic compounds.
acile access to multisubstituted pyrroles has been of special
interest to synthetic chemists engaged in the preparation of
To investigate the ring expansion of spiro-2H-pyrroles, we
prepared hereto unknown α-isocyano lactams (see Supporting
Information for details) and subjected them to the alkyne−
isocyanide [3 + 2] cycloaddition reaction (Table 1). The use of
Lewis bases such as Ph3P and Cy3P did not effect the desired
transformation, only leading to a slow decomposition of both
starting materials (entries 1 and 2). After the inactivity of
CuOAc was confirmed (entry 3), the cooperative catalyst effect
between Ph3P and CuOAc was investigated (entries 4−6).
Upon combining α-isocyano lactam 1a and 1-phenylprop-2-yn-
1-one 2a in the presence of 10 mol % of Ph3P and 5 mol % of
CuOAc, the formation of pyrrololactam 3a was observed at
ambient temperature in a 20% yield (entry 4). The reaction at
higher temperature increased the yield to 68% (entry 5);
however, a further attempt to elevate the reaction temperature
using 1,4-dioxane was not successful (entry 6). The change of
counterions from −OAc to −OTf led to a dramatic
deceleration of the reaction rate (entry 7), implying the
possible role of OAc as a base.14 Consequently, the screening of
Brønsted bases was conducted (entries 8−11) and swiftly led to
the identification of an optimal base, t-BuOK, where the desired
pyrrololactam 3a was isolated in a 82% yield (entry 8). The
reaction time could be shortened from 3 to 1 h by increasing
the reaction temperature to 100 °C in 1,4-dioxane (entry 12).
Reactions in DMSO and PhCH3 were not satisfactory (entries
13 and 14). Other copper salts were also tested; however, the
reaction yields were largely held to 28−49% (entries 15 and
16). A control experiment confirmed the inactivity of t-BuOK
in the formation of pyrrololactam 3a. Interestingly, unlike the
cases with 2,2-disubstituted 2H-pyrroles,11 the products from
alkyne−isocyanide [3 + 2] cycloaddition reactions, the
F
natural products, therapeutic agents, and materials with
distinctive optoelectronic properties.1 One of the bottlenecks
in the synthesis of pyrroles appears to be a lack of general and
direct methods for highly substituted fused pyrroles. Thus,
while the syntheses of fused pyrroles have been typically
achieved by multistep reactions,2 the recent development of
direct synthetic methods for fused pyrroles highlights the
challenges and potential of cycloadditions,3 tandem reactions,4
and multicomponent reactions.5 Among synthetic methods to
fused pyrroles, the ring-expansion strategy can render a general
solution to the difficulty associated with the direct preparation
of highly substituted fused pyrroles. Thus, the laboratories of
Toste,6 Shi,7 and You8 demonstrated facile access to fused
pyrroles using the ring expansion of elaborated substrates
(Scheme 1a).
Cycloaddition reactions between alkynes and isocyanides
provide a regiodivergent synthesis of highly substituted
pyrroles.9 Utilizing the “click chemistry” feature of the
alkyne−isocyanide [3 + 2] cycloaddition reactions,10 we have
recently disclosed an angle strain-induced bond migration of
2,2-disubstituted-2H-pyrroles to the regioselective synthesis of
pyrroles.11 This approach readily allows for the facile
regioselective synthesis of 2,3,4-substituted pyrroles with two
different EWGs at the 3- and 4-carbon atoms. With an aim of
developing an efficient synthetic method for pyrrololactams
with interesting biological activities (Scheme 1b),12 we describe
herein a facile one-pot synthetic procedure to highly decorated
pyrrololactams via an intermolecular alkyne−isocyanide click
reaction followed by an angle strain induced ring expansion
(Scheme 1c). The current method enables a one-pot synthesis
of pyrrololactams from simple starting materials with structural
diversity (6- to 8-membered pyrrololactams), high reaction
efficiency (one-pot reaction in 50−80% yields), and controlled
regioselectivity.13
Received: December 20, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Ring-Expansion Approaches to Fused Pyrroles
and Pyrrololactams
Table 1. Optimization of the Synthesis of Pyrrololactam
b
entry
cat. (mol %)
solvent
THF
temp (°C) time (h) yield (%)
1
2
3
4
Ph3P (10)
23
66
66
23
12
12
24
24
0
0
c
c
Cy3P (10)
THF
THF
THF
CuOAc (10)
CuOAc (5)
Ph3P (10)
0
20
5
CuOAc (5)
Ph3P (10)
THF
66
100
66
3
3
68
47
<2
82
73
0
6
CuOAc (5)
Ph3P (10)
1,4-dioxane
THF
c
7
CuOTf (5)
Ph3P (10)
3
8
CuOAc (5)
t-BuOK (10)
CuOAc (5)
K2CO3 (10)
CuOAc (5)
Et3N (10)
THF
66
3
9
THF
66
5
c
10
11
12
13
14
15
16
THF
66
12
6
CuOAc (5)
DBU (10)
THF
66
47
79
68
38
49
28
CuOAc (5)
t-BuOK (10)
CuOAc (5)
t-BuOK (10)
CuOAc (5)
t-BuOK (10)
Cu(OAc)2 (5)
t-BuOK (10)
Cu(OTf)2 (5)
t-BuOK (10)
1,4-dioxane
DMSO
PhCH3
THF
100
100
100
66
1
0.5
4
4
4
formation of spiro-2H-pyrrole 4a, a possible precursor to 3a,
was not observed during the reaction.15
c
THF
66
The optimized conditions for pyrrololactam via one-pot
alkyne−isocyanide [3 + 2] cycloaddition followed by a ring
expansion were further scrutinized using other α-isocyano
lactams and alkynes (Scheme 2). The employment of
electronically and sterically diverse alkyl- and arylalkynones
smoothly provided 6-membered pyrrololactams 3a−i in 54−
82% yields. Generally, the arylalkynones with electron-donating
groups (3b−d) and sterically demanding group (3h) required a
longer reaction time of 12 h. The use of 6-membered α-
isocyano lactam 1b led to the formation of 7-membered
pyrrololactams 3j−m in comparable yields. Gratifyingly, the
chemistry could be also applied to the synthesis of 8-membered
pyrrololactams 3n−q using 7-membered α-isocyano lactam 1c
and aryl/alkylalkynones. The N-benzyl group of α-isocyano
lactams could be switched to p-methoxybenzyl (PMB) and p-
methoxyphenyl (PMP) without a significant loss of yields and
reaction times (3r-3u). The use of alkynyl esters could be also
tolerated in the current pyrrololactam synthesis (3v,w). The
limitation of the current method exists upon employing 4-
membered α-isocyano lactam 1d, where the decomposition of
1d predominates over the formation of pyrrololactam products.
The one-pot functionlization of pyrrololactams was further
explored using either an excess of alkynyl methyl ester or a
sequential treatment with tert-butyl acrylate (Scheme 3). While
the isolated yields of pyrrololactams were somewhat lower in
35−51% yields,16 the one-pot synthesis of tetrasubstituted
pyrrololactams (3x−aa) amply demonstrated the further
synthetic potential of the current method.
a
Reaction conditions: 1 (0.2 mmol) and 2 (0.22 mmol) in solvents
b
(0.10 M) under argon. Isolated yield of products after column
chromatography. Partial decomposition of 1a/2a.
c
The rate comparison experiments of lactams with different
ring sizes suggested that the formation of pyrrololactams might
be influenced by the cycloaddition reaction step (Scheme 4a).
Thus, the use of acyclic α-isocyano amide also provided the
corresponding pyrrole product without the 2H-pyrrole
intermediate. The facile ring expansion of spiro-2H-pyrroles
to pyrrololactams could be explained by invoking the
conformational rigidity of spiro-2H-pyrroles that readily allows
the orbital overlap between the π*CC bond of internal alkene
and the πCO bond of electron-withdrawing group.17 Thus,
unlike the 2H-pyrroles that were previously observed during
the alkyne−isocyanide [3 + 2] cycloaddition reactions,11 the
spiro-2H-pyrroles could not be identified during the reactions
between α-isocyano lactams and alkynes. These observations
strongly imply that the conformational flexibility of 2H-pyrroles
deters the 1,2-bond migration (Scheme 4b), whereas the
conformationally locked spiro-2H-pyrroles undergo a facile ring
expansion to pyrrololactams (Scheme 4c). The conformational
rigidity of the spiro-2H-pyrroles would enforce the alignment
between the internal alkene and the amide carbonyl group. In
addition, since the large bond angle (ψ) facilitates the 1,2-bond
migration of the spiro-2H-pyrroles, the 6-membered spiro-2H-
pyrroles with a larger bond angle (114.4°
0.2°)18 should
B
DOI: 10.1021/acs.orglett.6b03786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 2. Scope of the Synthesis of 6- to 8-Membered
Pyrrololactams
Scheme 4. Facile Ring Expansion via Conformationally
Locked Spiro-2H-pyrroles
investigated in our laboratory, and our results will be reported
in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03786.
Scheme 3. One-Pot Synthesis of Tetrasubstituted
Pyrrololactams
Experimental procedures and characterization data for all
new compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hunykim@cau.ac.kr.
*E-mail: kyungsoooh@cau.ac.kr.
ORCID
Kyungsoo Oh: 0000-0002-4566-6573
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by National Research Foundation of
Korea (NRF) grants funded by the Korean government
(MSIP) (NRF-2015R1A5A1008958 and NRF-
2015R1C1A2A01053504).
display a faster ring expansion aptitude over the 5-membered
spiro-2H-pyrroles with a smaller bond angle (101−106.5°).19
In summary, we have developed a facile one-pot synthesis of
6- to 8-membered pyrrololactams using the intermolecular
alkyne−isocyanide [3 + 2] cycloaddition reaction followed by a
spontaneous ring expansion of spiro-2H-pyrrole intermediates.
The conformationally locked spiro-2H-pyrroles are believed to
enforce the alignment between the internal alkene and the
amide carbonyl group for better orbital overlap that induces a
subsequent ring expansion. Importantly, by utilizing newly
disclosed α-isocyano lactams, the highly substituted pyrrolo-
lactams are readily accessed. The extension of the 1,2-bond
migration strategy to other heterocycles is currently being
REFERENCES
■
(1) For reviews, see: (a) Sundberg, R. J. In Comprehensive Heterocyclic
Chemistry II; Katritzky, A. R., Rees, C. W., Scriven, E. F. V., Eds.;
Pergamon: Oxford, 1996; Vol. 2, pp 119−206. (b) Balme, G. Angew.
Chem., Int. Ed. 2004, 43, 6238−6241. (c) Bellina, F.; Rossi, R.
Tetrahedron 2006, 62, 7213−7256. (d) Schmuck, C.; Rupprecht, D.
Synthesis 2007, 2007, 3095−3110. (e) Estevez, V.; Villacampa, M.;
Menendez, J. C. Chem. Soc. Rev. 2010, 39, 4402−4421. (f) Estevez, V.;
Villacampa, M.; Menendez, J. C. Chem. Soc. Rev. 2014, 43, 4633−4657.
C
DOI: 10.1021/acs.orglett.6b03786
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(g) Bhardwaj, V.; Gumber, D.; Abbot, V.; Dhiman, S.; Sharma, P. RSC
Adv. 2015, 5, 15233−15266.
Mohr, C.; Nguyen, Y.; Norman, M. H.; Powers, D.; Reed, A. B.; Rex,
K.; Sastri, C.; Tamayo, N.; Wang, P.; Winston, J. T.; Wu, B.; Wu, T.;
Wurz, R. P.; Xu, Y.; Zhou, Y.; Tasker, A. S.; Wang, H.-L. J. Med. Chem.
2016, 59, 6407−6430. (i) Cee, V. J.; Chavez, F., Jr.; Herberich, B.;
Lanman, B. A.; Pettus, L. H.; Reed, A. B.; Wu, B.; Wurz, R. P.;
Andrews, K. L.; Chen, J.; Hickman, D.; Laszlo, J., III; Lee, M. R.;
Guerrero, N.; Mattson, B. K.; Nguyen, Y.; Mohr, C.; Rex, K.; Sastri, C.
E.; Wang, P.; Wu, Q.; Wu, T.; Xu, Y.; Zhou, Y.; Winston, J. T.;
Lipford, J. R.; Tasker, A. S.; Wang, H.-L. ACS Med. Chem. Lett. 2016,
7, 408−412.
(2) For a review, see: Thirumalairajan, S.; Pearce, B. M.; Thompson,
A. Chem. Commun. 2010, 46, 1797−1812.
(3) (a) Yan, Z.-Y.; Xiao, Y.; Zhang, L. Angew. Chem., Int. Ed. 2012,
51, 8624−8627. (b) Schultz, E. E.; Sarpong, R. J. Am. Chem. Soc. 2013,
135, 4696−4699. (c) Alford, J. S.; Spangler, J. E.; Davies, H. M. L. J.
Am. Chem. Soc. 2013, 135, 11712−11715. (d) Tan, W. W.; Yoshikai,
N. Chem. Sci. 2015, 6, 6448−6455.
(4) (a) Jiang, B.; Li, Q.-Y.; Tu, S.-J.; Pindi, S.; Li, G.; Zhang, H. Org.
Lett. 2012, 14, 700−703. (b) Zhang, C.; Chang, S.; Qiu, L.; Xu, X.
Chem. Commun. 2016, 52, 12470−12473.
(5) (a) Cai, Q.; Zhou, F.; Xu, T.; Fu, L.; Ding, K. Org. Lett. 2011, 13,
340−343. (b) Zhang, M.; Fang, X.; Neumann, H.; Beller, M. J. Am.
Chem. Soc. 2013, 135, 11384−11388. (c) Sha, Q.; Arman, H.; Doyle,
M. P. Org. Lett. 2015, 17, 3876−3879.
(6) Gorin, D. J.; Davis, N. R.; Toste, F. D. J. Am. Chem. Soc. 2005,
127, 11260−11261.
(7) Chen, G.-Q.; Zhang, X. N.; Wei, Y.; Tang, X.-Y.; Shi, M. Angew.
Chem., Int. Ed. 2014, 53, 8492−8497.
(8) (a) Zhuo, C.-X.; Cheng, Q.; Liu, W.-B.; Zhao, Q.; You, S.-L.
Angew. Chem., Int. Ed. 2015, 54, 8475−8479. For an indole variant,
see: (b) Wu, Q.; Zheng, C.; Zhuo, C.-X.; You, S.-L. Chem. Sci. 2016, 7,
4453−4459.
(9) (a) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. Tetrahedron Lett.
2005, 46, 2563−2566. (b) Kamijo, S.; Kanazawa, C.; Yamamoto, Y. J.
Am. Chem. Soc. 2005, 127, 9260−9266. (c) Larionov, O. V.; de
Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 5664−5667. (d) Liu, J.;
Fang, Z.; Zhang, Q.; Liu, Q.; Bi, X. Angew. Chem., Int. Ed. 2013, 52,
6953−6957. (e) Gao, M.; He, C.; Chen, H.; Bai, R.; Cheng, B.; Lei, A.
Angew. Chem., Int. Ed. 2013, 52, 6958−6961. (f) Liao, J.-Y.; Shao, P.-L;
Zhao, U. J. Am. Chem. Soc. 2015, 137, 628−631. (g) Tiwari, D. K.;
Pogula, J.; Tiwari, D. K.; Likhar, P. R. Chem. Commun. 2015, 51,
13646−13649. (h) Tiwari, D. K.; Phanindrudu, M.; Aravilli, V. K.;
Sridhar, B.; Likhar, P. R.; Tiwari, D. K. Chem. Commun. 2016, 52,
4675−4678.
(13) For multistep syntheses, see: (a) De Leon, C. Y.; Ganem, B. J.
Org. Chem. 1996, 61, 8730−8751. (b) Capomolla, S. S.; Lim, N.-K.;
Zhang, H. Org. Lett. 2015, 17, 3564−3567. (c) Miao, B.; Li, S.; Li, G.;
Ma, S. Org. Lett. 2016, 18, 2556−2559. (d) Watt, M. S.; Booker-
Milburn, K. I. Org. Lett. 2016, 18, 5716−5719. (e) Cheng, C.; Chen,
W.-W.; Xu, B.; Xu, M.-H. J. Org. Chem. 2016, 81, 11501−11507.
(f) Greenwood, R.; Yeung, K. Tetrahedron Lett. 2016, 57, 5812−5814.
(g) Reference 12c−i.
(14) (a) Zeng, W.; Zhou, Y.-G. Org. Lett. 2005, 7, 5055−5058.
(b) Kim, H. Y.; Shih, H.-J.; Knabe, W. E.; Oh, K. Angew. Chem., Int. Ed.
2009, 48, 7420−7423.
1
(15) The spiro-2H-pyrrole intermediate was not observed in the H
NMR spectra of crude reaction mixtures at frequent intervals.
(16) A stepwise N-alkylation of 3a/3v could be achieved in 70−80%
yields. Nevertheless, the one-pot synthesis of 3x−aa illustrates the
step-economy aspect in the synthesis of highly substituted pyrroles.
(17) Somers, K. R. F.; Kryachko, E. S.; Ceulemans. J. Phys. Chem. A
2003, 107, 5427−5438.
(18) The bond angles of six- and seven-membered rings are
estimated to be similar, see: (a) Hendrickson, J. B. J. Am. Chem. Soc.
1967, 89, 7036−7043. (b) Hendrickson, J. B. J. Am. Chem. Soc. 1967,
89, 7043−7046. (c) Hendrickson, J. B. J. Am. Chem. Soc. 1967, 89,
7047−7061.
(19) Hendrickson, J. B. J. Am. Chem. Soc. 1961, 83, 4537−4547.
(10) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem., Int. Ed.
2001, 40, 2004−2021.
(11) George, J.; Kim, H. Y.; Oh, K. Adv. Synth. Catal. 2016, 358,
3714−3718.
(12) For natural products, see: (a) Schmitz, F. J.; Gunasekera, S. P.;
Lakshmi, V.; Tillekeratne, L. M. V. J. Nat. Prod. 1985, 48, 47−53.
(b) Kuramoto, M.; Miyake, N.; Ishimaru, Y.; Ono, N.; Uno, H. Org.
Lett. 2008, 10, 5465−5468. For selected synthetic compounds, see:
(c) Anderson, D. R.; Meyers, M. J.; Vernier, W. F.; Mahoney, M. W.;
Kurumbail, R. G.; Caspers, N.; Poda, G. I.; Schindler, J. F.; Reitz, D. B.;
Mourey, R. J. J. Med. Chem. 2007, 50, 2647−2654. (d) Vanotti, E.;
Amici, R.; Bargiotti, A.; Berthelsen, J.; Bosotti, R.; Ciavolella, A.; Cirla,
A.; Cristiani, C.; D’Alessio, R.; Forte, B.; Isacchi, A.; Martina, K.;
Menichincheri, M.; Molinari, A.; Montagnoli, A.; Orsini, P.; Pillan, A.;
Roletto, F.; Scolaro, A.; Tibolla, M.; Valsasina, B.; Varasi, M.; Volpi,
D.; Santocanale, C. J. Med. Chem. 2008, 51, 487−501. (e) Menichin-
cheri, M.; Bargiotti, A.; Berthelsen, J.; Bertrand, J. A.; Bossi, R.;
Ciavolella, A.; Cirla, A.; Cristiani, C.; Croci, V.; D’Alessio, R.; Fasolini,
M.; Fiorentini, F.; Forte, B.; Isacchi, A.; Martina, K.; Molinari, A.;
Montagnoli, A.; Orsini, P.; Orzi, F.; Pesenti, E.; Pezzetta, D.; Pillan, A.;
Poggesi, I.; Roletto, F.; Scolaro, A.; Tato, M.; Tibolla, M.; Valsasina,
B.; Varasi, M.; Volpi, D.; Santocanale, C.; Vanotti, E. J. Med. Chem.
2009, 52, 293−307. (f) Tang, P. C.; Su, Y. D.; Feng, J.; Fu, J. H.; Yang,
J. L.; Xiao, L.; Peng, J. H.; Li, Y. L.; Zhang, L.; Hu, B.; Zhou, Y.; Li, F.
Q.; Fu, B. B.; Lou, L. G.; Gong, A. S.; She, G. H.; Sun, W. H.; Mong,
X. T. J. Med. Chem. 2010, 53, 8140−8149. (g) Oubrie, A.; Kaptein, A.;
de Zwart, E.; Hoogenboom, N.; Goorden, R.; van de Kar, B.; van
Hoek, M.; de Kimpe, V.; van der Heijden, R.; Borsboom, J.; Kazemier,
B.; de Roos, J.; Scheffers, M.; Lommerse, J.; Schultz-Fademrecht, C.;
Barf, T. Bioorg. Med. Chem. Lett. 2012, 22, 613−618. (h) Pettus, L. H.;
Andrews, K. L.; Booker, S. K.; Chen, J.; Cee, V. J.; Chavez, F., Jr.;
Chen, Y.; Eastwood, H.; Guerrero, N.; Herberich, B.; Hickman, D.;
Lanman, B. A.; Laszlo, J., III; Lee, M. R.; Lipford, J. R.; Mattson, B.;
D
DOI: 10.1021/acs.orglett.6b03786
Org. Lett. XXXX, XXX, XXX−XXX