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Angewandte

Communications Chemie

International Edition: DOI: 10.1002/anie.201805323


Cycloaddition German Edition: DOI: 10.1002/ange.201805323

Copper-Catalyzed Formal [4+


+2] Cycloaddition of Enoldiazoimides
with Sulfur Ylides
Qing-Qing Cheng+, Lyn8e A. Massey+, Brook S. Willett, Yongming Deng, Hadi Arman, and
Michael P. Doyle*

Dedicated to Professor Rolf Huisgen on the occasion of his 98th birthday

Abstract: Enoldiazoimides, a new subclass of enoldiazo


compounds, generate enol-substituted carbonyl ylides whose
reactions with sulfur ylides enable an unprecedented formal
[4+
+2] cycloaddition. The resulting multifunctionalized indoli-
zidinones, which incorporate sulfur, are formed in good yields
under mild reaction conditions. The uniqueness of this trans-
formation stems from the role of the silyl-protected enol, since
the corresponding acetyldiazoimide failed to provide any
cross-products in metal-catalyzed reactions with sulfur ylides.
This copper-catalyzed cycloaddition is initiated with the
generation of enol-substituted carbonyl ylides and sulfur
ylides from enoldiazoimides and sulfonium salts, respectively,
and proceeds through stepwise six-membered ring formation,
C@O and C@S bond cleavage, and silyl and acetyl group
migration.

Ylides, such as carbonyl and sulfur ylides, are readily Scheme 1. Transition-metal-catalyzed reactions of a-diazoimides with
sulfur ylides and the development of enoldiazoimides.
accessible reagents (or intermediates) that have been effi-
ciently utilized in various organic transformations, especially
cycloaddition reactions.[1] Carbonyl ylides (R2C=O+@C@R2)
are conveniently formed by transition-metal-catalyzed intra- cyclopropanation, epoxidation, aziridination, and other [n +
or intermolecular reactions of carbonyls (R2C=O) with diazo 1] cycloaddition processes with release of the corresponding
compounds (N2=CR2), and they are widely employed in 1,3- sulfides (R2S),[4] including a recently reported [3+ +1] cyclo-
dipolar cycloadditions as (+C@O@C@)-type dipolar compo- addition reaction with enoldiazoacetates.[5]
nents.[2] For example, 1,3-oxazolium-4-oxide derivatives (iso- Given that both carbonyl ylides and sulfur ylides have
mgnchnones), generated in situ by metal-catalyzed (espe- exhibited remarkable efficiencies in their respective cyclo-
cially rhodium) intramolecular cyclization of a-diazoimides addition reactions,[2–4] we were intrigued by the possibility
(1 a and 2 a; Scheme 1 a), have been developed for the that a combination of these two subclasses of ylides could lead
construction of a series of oxa- and aza-polycyclic ring to new cycloaddition outcomes. Therefore, reactions between
systems.[3] Sulfur ylides (R2S+@C@R2 ; e.g., 3 a, Scheme 1 a) in situ generated isomgnchnone intermediates and the sulfur
have been easily prepared from their corresponding sulfo- ylide 3 a were initially investigated, but no cross-products
nium salts (R2S+@CHR2·X@) under basic conditions, and they were obtained from the reactions initiated by dinitrogen (N2)
usually serve as one-carbon synthons (the ylide carbon) in extrusion from either the a-diazoimide 1 a or 2 a (Sche-
me 1 a).[6] Inspired by recent advances in the cycloaddition
[*] Dr. Q.-Q. Cheng,[+] L. A. Massey,[+] B. S. Willett, Dr. Y. Deng, reactions of enoldiazo compounds,[7] especially by those
Dr. H. Arman, Prof. Dr. M. P. Doyle studies in which novel reactivities were achieved,[8] we
Department of Chemistry, The University of Texas at San Antonio constructed enoldiazoimides, a new subclass of enoldiazo
One UTSA Circle, San Antonio, TX 78249 (USA)
compounds, by a simple silyl-enolization of acetyldiazoimides
E-mail: [email protected]
Homepage: http://www.utsa.edu/chem/faculty/DoyleLab/
(e.g., 2 a!4 a, Scheme 1 b).[9] To our delight, the cross-
coupled product 5 a, which is an unpredicted formal
Dr. Y. Deng
Current address: Department of Chemistry, Western Kentucky [4+
+2] cycloadduct, was obtained in 74 % yield along with
University, Bowling Green, KY 42101 (USA) methyl acetate (MeOAc) from a copper-catalyzed reaction of
[+] These authors contributed equally to this work. the enoldiazoimide 4 a with 3 a (Scheme 1 c). Notably, sub-
Supporting information and the ORCID identification number(s) for stituted indolizidinones are the core structure of numerous
the author(s) of this article can be found under: biologically active natural products and pharmaceuticals,[10]
https://doi.org/10.1002/anie.201805323. and the development of this methodology would allow

Angew. Chem. Int. Ed. 2018, 57, 10343 –10346 T 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 10343
Angewandte
Communications Chemie

straightforward and efficient access to multifunctionalized Table 2: Copper-catalyzed formal [4+


+2] cycloaddition of enoldiazo-
indolizidinones. imides 4 with sulfonium salts 6: Substrate scope.[a,b]
To further simplify the process by using the sulfonium salt
6 a as the reactant, we performed the reaction with triethyl-
amine (TEA) to form sulfur ylide 3 a in situ, expecting that
triethylamine might inhibit the catalytic activity by occupying
coordination sites of the catalyst (Table 1). However, the

Table 1: Transition-metal-catalyzed formal [4+


+2] cycloaddition of enol-
diazoimide 4 a with sulfonium salt 6 a: Optimization of reaction
conditions.[a]

Entry Catalyst x T [88C] Yield [%][b]


1 Cu(MeCN)4BF4 5 23 83
2 Cu(MeCN)4PF6 5 23 81
3 Rh2(OAc)4 2 23 74
4 Cu(MeCN)4BF4 5 0 91
5 Cu(MeCN)4BF4 5 @20 <5
[a] Reaction conditions: catalyst/4 a/6 a/TEA = 0.002 x:0.24:0.2:0.4
(mmol), in 3 mL of CHCl3 at specified temperature for 16 h. [b] Yields are
of the products isolated after flash column chromatography. See Section
3 of the Supporting Information for more details.

subsequent formal [4+ +2] cycloaddition not only proceeded


smoothly under the same reaction conditions but also
furnished a higher yield of 5 a (83 %; entry 1). A selection of
commercially available transition-metal complexes was then
evaluated as catalysts: copper(I) hexafluorophosphate [Cu-
(MeCN)4PF6] gave results similar to those obtained with
copper(I) tetrafluoroborate [Cu(MeCN)4BF4] (entries 1 and
2), whereas rhodium(II) acetate [Rh2(OAc)4] afforded the
identical cycloadduct with a slightly diminished yield
[a] Reaction conditions: Cu(MeCN)4BF/4/6/TEA = 0.01:0.24:0.2:0.4
(entry 3). Other tested metal catalysts, as well as alternative (mmol), in 3 mL of CHCl3 at 0 8C for 16 h. [b] Yields are of the products
solvents and bases, failed to further improve the product yield isolated after flash column chromatography. See Section 4 of the
(see Table S1 in the Supporting Information). However, Supporting Information for experimental details. [c] See Section 5 of the
conducting the reaction at 0 8C led to a 91 % yield of isolated Supporting Information for experimental details. TBAF = tetra-n-butyl-
5 a (entry 4), although further lowering the temperature to ammonium fluoride.
@20 8C inhibited cross-reactivity (entry 5).[11]
With the optimized reaction conditions in hand (Table 1,
entry 4), we sought to explore the substrate scope of this 5 k and 5 l, respectively. It should be noted that sulfonium salts
cycloaddition reaction, the results for which are presented in bearing an ortho-substituted phenyl group (e.g., 2-methyl-
Table 2 and Scheme 2. Changing the silyl protecting group of phenyl) only afforded trace amounts of their respective
enoldiazoimides from triisopropylsilyl (TIPS; 4 a) to tert- cycloaddtion products, suggesting a steric limitation to the
butyldimethylsilyl (TBS; 4 b) did not affect the efficiency of process. In addition, the chiral enoldiazoimide 4 c, synthesized
this process (Table 2, 5 a–d), and the structure of 5 d was from commercially available optically pure methyl (S)-2-
further confirmed by single-crystal X-ray diffraction (SC- pyrrolidone-5-carboxylate, was also successfully employed in
XRD) analysis (see Figure S1).[12] Sulfonium salts bearing this formal [4+ +2] cycloaddition reaction, thus producing its
para- and meta-substituted phenyl groups generally per- chiral derivative 5 m in 66 % yield and suggesting access to
formed well in this reaction (5 c–j). A variety of functional other chiral indolizidinones. Moreover, treating this cyclo-
groups, including nitro, cyano, bromo, and chloro, were well adduct with tetra-n-butylammonium fluoride (TBAF) led to
tolerated, although a diminished yield was obtained with the the formation of 7 m in an yield of 80 % (Table 2).
electron-donating para-methoxy group. Furthermore, sulfo- Besides dimethyl-substituted sulfonium salts (6 a–j), the
nium salts that carry naphthyl and thienyl rings smoothly monomethyl sulfonium salt 6 k, which was easily prepared
underwent reactions to furnish the formal [4+ +2] cycloadducts from thioanisole (PhSMe), also underwent copper-catalyzed

10344 www.angewandte.org T 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim Angew. Chem. Int. Ed. 2018, 57, 10343 –10346
Angewandte
Communications Chemie

formal [4++2] cycloaddition with 4 a. Only cleavage of the


sulfur–methyl (S@Me) bond was observed, furnishing the
phenylthio-substituted product 5 n (Scheme 2 a) and suggest-
ing loss of the S-methyl group by a nucleophilic substitution

Scheme 2. Copper-catalyzed formal [4+ +2] cycloaddition of 4 a with the


sulfonium salts 6 k–m or sulfur ylides 3 l,m. See Section 4 of the
Supporting Information for experimental details.

process. In confirmation of this mode of alkyl-group removal


from sulfur, the diphenylsulfide-derived (Ph2S) analogue of
6 k failed to provide any cross-products under otherwise Scheme 3. Proposed mechanism for copper-catalyzed formal
[4+
+2] cycloaddition of enoldiazoimides. Curved arrows depict the flow
identical reaction conditions. The cyclic-sulfide-derived sul-
or movement of electrons in a concerted or stepwise manner.
fonium salts 6 l and 6 m were then investigated, and the
terminal bromo substituents in the products 5 o and 5 p,
respectively, indicated that bromide anions (Br@) from the triethylamine), followed by proton transfer to the vinylogous
sulfonium salts facilitated cleavage of the sulfur–methylene position produces the intermediate IV which proceeds
(S@CH2) bonds (Scheme 2 b). Interestingly, when the corre- through a tandem C@O bond cleavage/silyl group migration/
sponding sulfur ylides 3 l and 3 m were employed as reactants six-membered ring-closure sequence to deliver the intermedi-
instead of the sulfonium bromides, the terminal acetoxy ate V.[14] This pathway is consistent with our early finding that
(AcO) substituted products 5 q and 5 r, respectively, were the ortho-substituted phenyl group of sulfonium salts dra-
obtained (Scheme 2 c), and is consistent with the formation of matically lowered reactivity, since the ortho substituent can
methyl acetate from the reaction between 3 a and 4 a hinder the ring closure (see IV). Finally, in cases where the
(Scheme 1 c). sulfonium bromide salt is directly used as the reactant, the
The complexity of this transformation is surprising. bromide anion facilitates C@S bond cleavage (V!VI), and
Rather than a simple cycloaddition, this reaction involves subsequent acetyl group migration (VI!VII) followed by
the cleavage of a C@S bond, an O-to-O transfer of a silyl elimination of the resulting acetoxy group (VII!5) to
group, and formation and removal of an acetyl group from the complete the transformation. However, if the sulfur ylide is
original silyl enolate. Based on these results and previous employed as the reactant, the acetoxy group, formed by
reports,[13, 14] we propose a plausible mechanism for this formal intramolecular acetyl migration from V, promotes C@S bond
[4+
+2] cycloaddition. As illustrated in Scheme 3, the copper cleavage (see VIII) to provide 5. Additionally, an alternative
catalyst [M] facilitates dinitrogen extrusion from 4 to form the explanation that the carbonyl ylide generated from diazo-
metallo-enolcarbene I, which undergoes the well-known imides initially undergoes a direct [3 + n] cycloaddition with
intramolecular metallocarbene–carbonyl cyclization to fur- the sulfur ylide is unlikely given that neither diazoimide 1 a
nish the 5-enol-1,3-oxazolium-4-oxide derivative IIA. nor 2 a produced any cross-products in their reactions with 3 a
Although dissociation of the ligated metal to form carbonyl (Scheme 1 a).
ylides is common, IIA is a vinylogous system which can exist In summary, we have discovered a novel approach to the
in equilibrium with the intermediate IIB by 1,3-allylic synthesis of multifunctionalized indolizidinones and it pro-
isomerization.[13] Subsequent nucleophilic addition of 3 ceeds in one synthetic step by the combination of enol-
(either pre- or in situ generated from sulfonium salt 6 with substituted carbonyl ylides and sulfur ylides, generated in situ

Angew. Chem. Int. Ed. 2018, 57, 10343 –10346 T 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.angewandte.org 10345
Angewandte
Communications Chemie

from enoldiazoimides and sulfonium salts, serving as the [4] For reviews, see: a) A.-H. Li, L.-X. Dai, V. K. Aggarwal, Chem.
initial electrophile and nucleophile, respectively. This formal Rev. 1997, 97, 2341; b) E. M. McGarrigle, E. L. Myers, O. Illa,
[4++2] cycloaddition also involves C@O bond cleavage, silyl M. A. Shaw, S. L. Riches, V. K. Aggarwal, Chem. Rev. 2007, 107,
5841; c) L.-Q. Lu, T.-R. Li, Q. Wang, W.-J. Xiao, Chem. Soc. Rev.
group migration, acetyl group migration, and C@S bond
2017, 46, 4135.
cleavage along the reaction pathway. The essential role of the [5] Y. Deng, L. A. Massey, P. Y. Zavalij, M. P. Doyle, Angew. Chem.
silyl-protected enoldiazoimide is seen in the complete Int. Ed. 2017, 56, 7479; Angew. Chem. 2017, 129, 7587.
absence of a cross-product when the corresponding acetyl- [6] Both rhodium and copper catalysts were tested in reactions of
diazoimide was employed. We hope this simple strategy either a-diazoimides 1 a or 2 a with the sulfur ylide 3 a.
(acyl!enol) will create new possibilities for further method- [7] For reviews, see: a) Q.-Q. Cheng, Y. Deng, M. Lankelma, M. P.
Doyle, Chem. Soc. Rev. 2017, 46, 5425; b) Q.-Q. Cheng, Y. Yu, J.
ology developments in the field.
Yedoyan, M. P. Doyle, ChemCatChem 2018, 10, 488.
[8] For selected examples, see: a) X. Wang, X. Xu, P. Y. Zavalij,
M. P. Doyle, J. Am. Chem. Soc. 2011, 133, 16402; b) Q.-Q. Cheng,
Acknowledgements J. Yedoyan, H. Arman, M. P. Doyle, J. Am. Chem. Soc. 2016, 138,
44; c) Q.-Q. Cheng, J. Yedoyan, H. Arman, M. P. Doyle, Angew.
Support for this research from the National Science Founda- Chem. Int. Ed. 2016, 55, 5573; Angew. Chem. 2016, 128, 5663;
tion (CHE-1464690) is gratefully acknowledged. The HRMS d) Q.-Q. Cheng, M. Lankelma, D. Wherritt, H. Arman, M. P.
Doyle, J. Am. Chem. Soc. 2017, 139, 9839; e) Y. Deng, L. A.
used in this research was supported by a grant from the
Massey, Y. A. Rodriguez NfflÇez, H. Arman, M. P. Doyle, Angew.
National Institutes of Health (G12MD007591). The National Chem. Int. Ed. 2017, 56, 12292; Angew. Chem. 2017, 129, 12460.
Science Foundation supported the acquisition of a NMR [9] For experimental details, see Section 2 of the Supporting
spectrometer used in this study (CHE-1625963). L.A. Massey Information.
acknowledges support from the National Institute of General [10] For reviews, see: a) J. F. Pizzolato, L. B. Saltz, Lancet 2003, 361,
Medical Sciences branch of the National Institutes of Health 2235; b) Y. Pommier, Nat. Rev. Cancer 2006, 6, 789; c) R. P.
(MARC-U*STAR GM07717). Verma, C. Hansch, Chem. Rev. 2009, 109, 213; d) Y. Pommier,
Chem. Rev. 2009, 109, 2894; e) Y. Pommier, C. Marchand, Nat.
Rev. Drug Discovery 2012, 11, 25.
[11] Only a trace amount of 5 a was formed after 4 a was fully
Conflict of interest consumed.
[12] CCDC 1821831 (5 d) contains the supplementary crystallo-
The authors declare no conflict of interest. graphic data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre.
[13] a) R. Shintani, K. Takatsu, M. Takeda, T. Hayashi, Angew.
Keywords: copper · cycloaddition · diazo compounds ·
Chem. Int. Ed. 2011, 50, 8656; Angew. Chem. 2011, 123, 8815;
sulfonium salts · ylides b) S. H. Bertz, R. A. Hardin, M. D. Murphy, C. A. Ogle, J. D.
Richter, A. A. Thomas, J. Am. Chem. Soc. 2012, 134, 9557; c) W.
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Angew. Chem. 2018, 130, 10500 – 10503 Chem. 2016, 128, 1908; d) A. P. Pulis, K. Yeung, D. J. Procter,
Chem. Sci. 2017, 8, 5240.
[1] For reviews, see: a) Nitrogen, Oxygen and Sulfur Ylide Chemis- [14] a) A. Padwa, M. A. Brodney, J. P. Marino, S. M. Sheehan, J. Org.
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formations (Ed.: V. H. Gessner), Springer, New York, 2018.
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