Rhodium-catalyzed cyclization of diynes with nitrones: A formal [2+2+5] approach to bridged eight-membered heterocycles

Article abstract of DOI:10.1002/anie.201407394

N-aryl-substituted nitrones were employed as fiveatom coupling partners in the rhodium-catalyzed cyclization with diynes. In this reaction, the nitrone moiety served as a directing group for the catalytic C-H activation of the N-aryl ring. This formal [2+2+5] approach allows rapid access to bridged eight-membered heterocycles with broad substrate scope. The results of this study may provide new insight into the chemistry of nitrones and find applications in the synthesis of other heterocycles,.

Full text of DOI:10.1002/anie.201407394

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DOI: 10.1002/anie.201407394
Cyclization
Rhodium-Catalyzed Cyclization of Diynes with Nitrones: A Formal
[2+2+5] Approach to Bridged Eight-Membered Heterocycles**
Chunxiang Wang, Dongping Wang, Hao Yan, Haolong Wang, Bin Pan, Xiaoyi Xin, Xincheng Li,
Fan Wu, and Boshun Wan*
Abstract: N-aryl-substituted nitrones were employed as five-
atom coupling partners in the rhodium-catalyzed cyclization
with diynes. In this reaction, the nitrone moiety served as
À
a directing group for the catalytic C H activation of the N-aryl
ring. This formal [2+2+5] approach allows rapid access to
bridged eight-membered heterocycles with broad substrate
scope. The results of this study may provide new insight into the
chemistry of nitrones and find applications in the synthesis of
other heterocycles.
C
ombinations of various unsaturated coupling partners in
cycloadditions have created new opportunities to access
heterocycles of great complexity. In this regard, nitrones
may serve as three-atom building units and can incorporate
two heteroatoms into the frameworks in a single step.[1]
Recently, the metal-catalyzed cycloaddition of nitrones with
various unsaturated hydrocarbons has proven to be an
efficient tool to produce nitrogen-containing heterocycles.
Although the reactivity of nitrones toward different synthons
has been extensively studied, most attention has been given to
[3+2],[2] [3+3],[3–7] [4+3],[8,9] and [2+2+3][10] cycloadditions
(Scheme 1a). In these intriguing studies, nitrones exclusively
serve as 1,3-dipolar reagents to afford five-, six-, and seven-
membered heterocycles. To the best of our knowledge,
reactions using nitrones as five-atom building units in cyclo-
additions are unknown.
Scheme 1. Cycloadditions involving nitrones.
Cycloadditions involving diynes have been developed to
enable the synthesis of various cyclic structures,[11] including
the formation of medium-sized heterocycles by using diynes
as C4 units. As part of our research in this area,[12] we have
recently reported the rhodium-catalyzed cycloaddition of
diynes with oximes, in which the hydroxy group of the oxime
plays a crucial role for the reactivity.[12c] In view of the
similarity between oximes and nitrones, we surmised that
a nitrone group could function as a directing group under
rhodium catalysis and participate in a reaction with diynes to
provide rapid access to the [2+2+3] cycloadduct. However, to
our surprise, a bridged multicyclic skeleton was observed
instead of the seven-membered ring (Scheme 1, this work).
Five atoms of the nitrone compound were incorporated into
À
the product and a C H activation step on the N-phenyl ring of
À
nitrone is likely to be involved. Indeed, C H activation of
nitrones has been recently reported by Yao and Li,[13] but only
À
focused on the C-phenyl ring (Scheme 1b). No C H activa-
tion on the N-phenyl ring of nitrones has been reported.
Herein, we report a formal [2+2+5] approach to bridged
eight-membered heterocycles through the rhodium-catalyzed
cyclization of diynes with nitrones.
At the outset of our investigation, diyne 1a and nitrone 2a
were selected as model substrates for the optimization of the
reaction conditions (results summarized in Table S1 in the
Supporting Information). After careful screening, we found
that the use of [Rh(cod)2]BF4 as metal catalyst and Cl-MeO-
Biphep (L5) as ligand in CH2Cl2/THF provided the desired
product 3a with the highest yield [86%; Eq. (1)]. The
[*] Dr. C. X. Wang, Dr. D. P. Wang, H. Yan, Dr. H. L. Wang, Dr. B. Pan,
Dr. X. Y. Xin, Dr. X. C. Li, F. Wu, Prof. Dr. B. S. Wan
Dalian Institute of Chemical Physics, Chinese Academy of Sciences
457 Zhongshan Road, Dalian 116023 (China)
E-mail: bswan@dicp.ac.cn
[**] This work was supported by NSFC (21372219). We also thank Prof.
Yonggui Zhou (DICP), Dr. Guoyong Song (RIKEN), and one reviewer
for helpful suggestions on revising the manuscript.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201407394.
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structure of 3a was unambiguously confirmed by X-ray
crystal diffraction.[14] It is noteworthy that under rhodium
catalysis a di- or trimerization of diynes is commonly
detected.[15] This phenomenon was also observed in this
reaction, thus slightly lowering the yield of 3a.
worth noting that the reaction with 3-methyl-substituted
nitrone 2t afforded the product 3t as a single regioisomer,[14]
in which the sterically less-hindered position of the phenyl
ring was linked to the alkene moiety.
The reactions of various diynes with nitrone 2a were also
investigated. Malonate- and O-tethered terminal diynes (1aa,
1bb) could undergo this cyclization and were transformed
into the corresponding cycloadducts in good yields. Notably,
methylene-linked diyne 1cc reacted smoothly with 2a to
afford 3cc in 79% yield, thus indicating that the Thorpe–
Ingold effect[17] had less influence in this case. However, the
reaction of 2a with unsymmetrical 1,7-diyne 1dd furnished
3dd as the main product accompanied by the minor regio-
isomer 3dd’ in 40% and 12% yield, respectively. In contrast,
high regioselectivity was observed in the reaction of unsym-
metrical 1,6-diynes 1ee–1gg, which possess a hydrogen atom
and an aliphatic/aryl group (Me, TMS, or Ph) at each alkyne
terminus. Single regioisomers were obtained in excellent
yields (93–97%). X-ray crystal diffraction of 3gg showed that
the adjacent R substituent is on the cis position of the phenyl
group.[14] Unexpectedly, when internal diynes 1hh–1jj were
subjected to the reaction, acyclic compounds 3hh and 3ii,
which possess enone and imine moieties, were obtained in
good yields.[14,17] Although the reason is still unknown, the
existing results suggest that the additional methyl group at the
alkyne terminus (e.g. 3ee versus 3jj), rather than the tethers,
plays a crucial role. Importantly, these products allowed
access to other molecules. For example, product 3a was
The scope of nitrones was then tested under the above-
optimized reaction conditions (Scheme 2). Different substitu-
ents of the C-aryl ring (2a–2g) resulted in the corresponding
cycloadducts 3a–3g in moderate to good yields, regardless of
their electronic and steric effects. For nitrone 2h, which bears
a 2-furyl group, the desired product 3h was obtained in 84%
yield. Unfortunately, nitrones 2i and 2j bearing a 2-pyridyl
and a styryl group, respectively, were completely unreactive.
This result may be ascribed to the ability of the pyridine and
alkene moieties to coordinate to the rhodium center. The
cycloaddition reactions can be further extended to nitrones
bearing various N-aryl substituents (2k–2t). Moreover,
different combinations of electron-withdrawing and elec-
tron-donating groups on the C- and N-aryl rings (2p–2s) also
provided the products (3p–3s) in good to excellent yields. It is
À
readily converted into cyclic amino alcohols by N O bond
cleavage, and multicyclic amine by further dehydration (see
the Supporting Information).
À
As suggested by the structure of the product, a C H bond
cleavage was observed on the N-phenyl ring of nitrones. To
probe the reaction mechanism, the reaction of 1a with
deuterated nitrone [D5]-2a was first investigated. To our
delight, the desired product [D5]-3a was obtained with more
than 99% deuterium incorporation (Scheme S1-1, see the
Supporting Information). Besides, the reaction of 1a and 2a
in the presence of CD3OD or CH3COOD did not provide any
deuterated product (Scheme S1-2). Furthermore, when an
equimolar mixture of 2b and [D5]-2b was stirred under
standard reaction conditions, no H-D exchange occurred at
the ortho position of the N-phenyl ring (Scheme S1-3). Taken
À
together, these results indicated that the C H functionaliza-
tion on the N-phenyl ring is irreversible.
Under this premise, kinetic isotope effect (KIE) studies
were performed. The intermolecular competitive reactions
between 2a and [D5]-2a with 1a gave a KIE value of 4.0 at
2 min [or 4.6 at 10 min, Eq. (2)] on the basis of 1H NMR
analysis. Furthermore, the KIE values of independent reac-
tions of 1a with 2a or [D5]-2a were measured to provide
À
a KIE value of 5.3 [Eq. (3)]. These data suggest that a C H
Scheme 2. Substrate scope. Reaction conditions: 1 (0.25 mmol), 2
(0.75 mmol), [Rh(cod)2]BF4 (5 mol%), Cl-MeO-Biphep (5 mol%),
CH2Cl2 (1 mL), THF (1 mL), 408C, 16 h; yields of isolated products are
reported. [a] The conversion to products 3e, 3r, and 3jj was good,
however, they were not isolated because their polarity was similar to
that of the corresponding nitrone. [b] Reaction conditions: [Rh-
(cod)2]BF4 (5 mol%), Segphos (5 mol%), CH2Cl2 (2 mL), 408C, 16 h.
[c] Yield determined by HPLC.
activation is likely to be involved in the rate-determining
step.[18] Additionally, the competition between 2k and 2n in
the reaction with 1a was examined [Eq. (4)], affording the
corresponding products 3k and 3n in a 3:1 molar ratio. This
result demonstrates that nitrones with electron-rich substitu-
ents on the N-aryl moiety preferentially reacted with diynes,
supporting the possibility of an electrophilic aromatic sub-
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stitution pathway (SEAr)[19] in the reaction. The high KIE
values (4.0–5.3) observed in this reaction suggest that slow
hydrogen abstraction might be involved after the electrophilic
À
attack of Rh on the N-phenyl ring in the C H activation
process.[20]
It is noteworthy that the dimerization product of diyne 1a
was observed as by-product when the reaction conditions
were screened. Moreover, in the absence of nitrones, dimer 4
was isolated in 53% yield along with some trimerization
product [Eq. (5)], indicating the existence of a competition
between the dimerization of diynes and the coupling of
nitrones with diynes in this reaction. Next, monoyne 1a’ or
diphenylacetylene were reacted with nitrone 2a, but no new
product was observed under RhI catalysis, even at a higher
temperature [Eq. (6)]. According to these observations, we
À
hypothesize that the C H activation step is less likely in the
presence of a RhI catalyst, but is probably initiated after the
formation of the rhodacyclopentadiene intermediate.
Unfortunately, attempts to isolate the rhodacyclopentadiene
intermediate from the stoichiometric reaction between 1a
and [Rh(cod)2]BF4/L5 did not succeed,[21] possibly because of
the fast dimerization of diynes. The enantioselectivity of this
reaction was also investigated [Eq. (7)]. Interestingly, in the
presence of (R)-Cl-MeO-Biphep, chiral (À)-3k and (À)-3n
were obtained in 11 and 34% ee, respectively, suggesting that
products of high enantiopurity can be obtained if the reaction
is optimized with chiral catalysts.
Scheme 3. Proposed mechanism.
On the basis of the above results, a plausible mechanism
was proposed in Scheme 3. The reaction starts with the
coordination of the diyne to rhodium, generating rhodacy-
clopentadiene intermediate A. This then reacts with the
À
nitrone through C H activation to afford intermediate B, in
which the N-aryl group is close to the sterically less-hindered
À
position (RS) of the metallacycle. The C H activation process
might follow the SEAr mechanism through electrophilic
attack and slow hydrogen abstraction.[20] Subsequently, reduc-
tive elimination provides dienylation intermediate C.[22]
Finally, the rhodium-mediated [3+2] cycloaddition and fur-
ther reductive elimination provides product 3, and regener-
ates the catalyst. In the cases of internal diynes, retro-[3+2]
cycloaddition followed by 1,4-H shift furnishes the ring-
opening product. The driving force for the ring cleavage might
be attributed to the release of ring tension caused by the
methyl group.
In summary, we have developed a formal [2+2+5]
approach to access bridged eight-membered heterocycles
through the rhodium-catalyzed cyclization of diynes with
nitrones under mild conditions, in which the nitrone group
À
serves as both a directing group for catalytic C H activation
on the N-phenyl ring of the nitrone and a five-atom coupling
partner. Until now, nitrones were commonly used as three-
À
atom building units in cycloadditions, and no catalytic C H
activation on the N-phenyl ring of nitrones has been reported.
The findings of this study may provide new insight into the
chemistry of nitrones and find applications in the synthesis of
other heterocycles. Further exploration on enantioselective
versions and other reactions involving nitrones are currently
underway.
Experimental Section
Representative procedure: [Rh(cod)2]BF4 (5 mol%) and Cl-MeO-
Biphep (5 mol%) were weighed in the glove box and placed in a dried
Schlenk tube. Subsequently, 2 mL of solvent (THF/CH2Cl2 = 1/1, v/v)
was added. The resulting mixture was stirred at room temperature for
30 min to afford a light-yellow clear solution. Nitrone 2 (0.75 mmol,
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3 equiv) was added followed by diyne 1 (0.25 mmol, 1 equiv). The
reaction mixture was stirred at 408C for 16 h. The solvent was
evaporated and the crude product was directly purified by column
chromatography on silica gel (eluent: petroleum ether/ethyl acetate)
to give product 3.
[11] M. I. Alexandrovna, B. I. Ionin, J. C. Tebby in Alkynes in
Cycloadditions (Ed.: J. Tebby), Wiley, New Delhi, 2014.
[12] a) C. X. Wang, X. C. Li, F. Wu, B. S. Wan, Angew. Chem. Int. Ed.
2011, 50, 7162 – 7166; Angew. Chem. 2011, 123, 7300 – 7304; b) F.
Xu, C. X. Wang, X. C. Li, B. S. Wan, ChemSusChem 2012, 5,
854 – 857; c) F. Xu, C. X. Wang, D. P. Wang, X. C. Li, B. S. Wan,
Chem. Eur. J. 2013, 19, 2252 – 2255; d) C. X. Wang, D. P. Wang, F.
Xu, B. Pan, B. S. Wan, J. Org. Chem. 2013, 78, 3065 – 3072; e) B.
Pan, C. X. Wang, D. P. Wang, F. Wu, B. S. Wan, Chem. Commun.
2013, 49, 5073 – 5075; f) B. Pan, X. D. Lu, C. X. Wang, Y. C. Hu,
F. Wu, B. S. Wan, Org. Lett. 2014, 16, 2244 – 2247.
Received: July 19, 2014
Published online: September 12, 2014
À
Keywords: alkenylation · C H activation · cyclization · nitrones ·
rhodium
.
À
[13] A C H activation step is observed on the C-phenyl ring of the
nitrones, see: a) Q. Yao, M. Zabawa, J. Woo, C. Zheng, J. Am.
Chem. Soc. 2007, 129, 3088 – 3089; b) Y. Zhang, G. Song, G. Ma,
J. Zhao, C. L. Pan, X. Li, Organometallics 2009, 28, 3233 – 3238;
c) Z. Qi, M. Wang, X. Li, Org. Lett. 2013, 15, 5440 – 5443.
[14] CCDC 977775 (3a), CCDC 1002035 (3t), CCDC 1008187 (3dd),
CCDC 1019777 (3gg), and CCDC 978897 (3hh) contain the
supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
[15] M. Amatore, D. Leboeuf, M. Malacria, V. Gandon, C. Aubert, J.
Am. Chem. Soc. 2013, 135, 4576 – 4579.
[1] a) F. Cardona, A. Goti, Angew. Chem. Int. Ed. 2005, 44, 7832 –
7835; Angew. Chem. 2005, 117, 8042 – 8045; b) A. Brandi, F.
Cardona, S. Cicchi, F. M. Cordero, A. Goti, Chem. Eur. J. 2009,
15, 7808 – 7821.
[2] a) C. Qin, H. M. L. Davies, J. Am. Chem. Soc. 2013, 135, 14516 –
14519; For selected reviews on [3+2] cyclodditions of nitrones,
see: b) G. Song, D. Chen, Y. Su, K. Han, C. L. Pan, A. Jia, X. Li,
Angew. Chem. Int. Ed. 2011, 50, 7791 – 7796; Angew. Chem.
2011, 123, 7937 – 7942; c) R. C. F. Jones in Synthetic Applications
of 1,3-Dipolar Cycloaddition Chemistry Toward Heterocycles
and Natural Products (Eds.: A. Padwa, W. H. Pearson), Wiley,
Hoboken, 2003, pp. 1 – 81; d) L. M. Stanley, M. P. Sibi, Chem.
Rev. 2008, 108, 2887 – 2902.
[16] M. E. Jung, G. Piizzi, Chem. Rev. 2005, 105, 1735 – 1766.
[17] The reactions performed under standard conditions also
afforded product 3hh and 3ii, but in a slightly lower yield. In
addition, product 3hh is easily hydrolyzed on silica gel (on the
column), even on neutralized silica gel or Al2O3. Therefore, the
yield was determined by HPLC.
[18] E. M. Simmons, J. F. Hartwig, Angew. Chem. Int. Ed. 2012, 51,
3066 – 3072; Angew. Chem. 2012, 124, 3120 – 3126.
[19] For a mechanistic discussion on classical SEAr, see: F. A. Carey,
R. J. Sundberg in Advanced Organic Chemistry, Part A: Structure
and Mechanisms, 5edth edSpringer, New York, 2007, pp. 771 –
816.
[20] High KIE values (3.1 – 3.9) were observed in palladium-cata-
lyzed ortho-arylation reactions, for which an SEAr mechanism
was proposed. See: X. Zhao, C. S. Yeung, V. M. Dong, J. Am.
Chem. Soc. 2010, 132, 5837 – 5844, and references therein.
[21] Despite the failure to isolate a RhIII intermediate, in a related
study, the reaction of 2a and diphenylacetylene under RhIII
catalyst provided 2,3-diphenylindole 5 in 70% yield. This
[3] a) I. S. Young, M. A. Kerr, Angew. Chem. Int. Ed. 2003, 42,
3023 – 3026; Angew. Chem. 2003, 115, 3131 – 3134; b) M. P. Sibi,
Z. Ma, C. P. Jasperse, J. Am. Chem. Soc. 2005, 127, 5764 – 5765;
c) Y. B. Kang, X. L. Sun, Y. Tang, Angew. Chem. Int. Ed. 2007,
46, 3918 – 3921; Angew. Chem. 2007, 119, 3992 – 3995.
[4] a) F. Liu, Y. Yu, J. Zhang, Angew. Chem. Int. Ed. 2009, 48, 5505 –
5508; Angew. Chem. 2009, 121, 5613 – 5616; b) F. Liu, D. Qian, L.
Li, X. Zhao, J. Zhang, Angew. Chem. Int. Ed. 2010, 49, 6669 –
6672; Angew. Chem. 2010, 122, 6819 – 6822; c) Z. M. Zhang, P.
Chen, W. Li, Y. Niu, X. L. Zhao, J. Zhang, Angew. Chem. Int. Ed.
2014, 53, 4350 – 4354; Angew. Chem. 2014, 126, 4439 – 4443.
[5] a) X. Wang, X. Xu, P. Y. Zavalij, M. P. Doyle, J. Am. Chem. Soc.
2011, 133, 16402 – 16405; b) Y. Qian, X. Xu, X. Wang, P. J.
Zavalij, W. Hu, M. P. Doyle, Angew. Chem. Int. Ed. 2012, 51,
5900 – 5903; Angew. Chem. 2012, 124, 6002 – 6005; c) X. Wang,
Q. M. Abrahams, P. Y. Zavalij, M. P. Doyle, Angew. Chem. Int.
Ed. 2012, 51, 5907 – 5910; Angew. Chem. 2012, 124, 6009 – 6012;
d) X. Xu, P. J. Zavalij, M. P. Doyle, Chem. Commun. 2013, 49,
10287 – 10289.
À
result indicated that the C H bond cleavage of nitrone might
occur under RhIII catalysis. Detailed information of this reaction
will be reported in due course.
[6] W. Yang, T. Wang, Y. Yu, S. Shi, T. Zhang, A. S. K. Hashimi, Adv.
Synth. Catal. 2013, 355, 1523 – 1528.
[7] R. Shintani, S. Park, W. L. Duan, T. Hayashi, Angew. Chem. Int.
Ed. 2007, 46, 5901 – 5903; Angew. Chem. 2007, 119, 6005 – 6007.
[8] a) R. Shintani, M. Murakami, T. Hayashi, J. Am. Chem. Soc.
2007, 129, 12356 – 12357; b) A. C. Stevens, C. Palmer, B. L.
Pagenkopf, Org. Lett. 2011, 13, 1528 – 1531.
[9] a) Y. Bai, J. Fang, J. Ren, Z. Wang, Chem. Eur. J. 2009, 15, 8975 –
8978; b) Y. Zhang, F. Liu, L. Zhang, Chem. Eur. J. 2010, 16,
6146 – 6150; c) T. Wang, J. Zhang, Chem. Eur. J. 2011, 17, 86 – 90.
[10] S. A. Gawade, S. Bhunia, R. S. Liu, Angew. Chem. Int. Ed. 2012,
51, 7835 – 7838; Angew. Chem. 2012, 124, 7955 – 7958.
[22] a) K. Tanaka, Y. Otake, A. Wada, K. Noguchi, M. Hirano, Org.
Lett. 2007, 9, 2203 – 2206; b) K. Tsuchikama, Y. Kuwata, Y. K.
Tahara, Y. Yoshinami, T. Shibata, Org. Lett. 2007, 9, 3097 – 3099;
c) Y. Shibata, Y. Otake, M. Hirano, K. Tanaka, Org. Lett. 2009,
11, 689 – 692.
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