Letter pubs.acs.org/OrgLett
Reductive CO2 Fixation via Tandem C−C and C−N Bond Formation: Synthesis of Spiro-indolepyrrolidines Dao-Yong Zhu, Lei Fang, Hui Han, Yazhou Wang, and Ji-Bao Xia* State Key Laboratory for Oxo Synthesis and Selective Oxidation, Suzhou Research Institute of LICP, Lanzhou Institute of Chemical Physics (LICP), Chinese Academy of Sciences, Lanzhou 730000, P. R. China S Supporting Information *
ABSTRACT: We describe herein a tandem C−C and C−N bondforming reaction in the reductive functionalization of CO2, an abundant and cheap C1 chemical feedstock. This catalytic metal-free CO2 fixation afforded spiro-indolepyrrolidines by dearomatization of tryptamine derivatives with broad scope and good functional group tolerance under mild conditions.
S
in 2014.10 Despite these improvements, the products of C−C bond-forming reactions with CO2 are mainly limited to carboxylic acid derivatives. Accordingly, new C−C bondforming reactions with CO2 urgently need to be explored. In the past few years, reductive C−N bond-forming reactions with CO2 have been intensively studied (Scheme 1b).11 In this regard, formamides or methylamines have been efficiently synthesized via transition-metal catalysis from amine, CO2, and reductant.12 Following the pioneering work in 2012 by Cantat of the organocatalytic reduction of CO2 into formamides using amines and silanes, reductive C−N bond formation with CO2 has also been broadly investigated under metal-free conditions.13 Inspiringly, Bontemps and Sabo-Etienne reported that imine could be obtained in the Ru-catalyzed reduction of CO2 with amine in 2014.14 In addition, reduction of CO2 into methylene has been demonstrated in the construction of C−N, C−O, or C−C bonds.15 Imine or iminium is a common intermediate in C−C bond-forming reactions, such as the Mannich, Strecker, and Friedel−Crafts-type reactions. We hypothesized that tandem C−C and C−N bond-forming reaction could be achieved in the presence of amines, CO2, reductants, and suitable carbon-centered nucleophiles, which has not been reported yet. We envisioned that a tethered carbon-centered nucleophile on the amine would facilitate the C−C bond formation. Considering indole is a good carbon nucleophile, we selected tryptamine derivatives to test our hypothesis. Herein, we disclose a metal-free catalytic reductive tandem C−C and C−N bond-forming reaction to synthesize spiro-indolepyrrolidines via dearomatization of tryptamine derivatives with CO2 (Scheme 1c). At the outset of our research, commercially available 2methyltryptamine was chosen as the substrate to achieve reductive tandem C−C and C−N bond formation with CO2. The initial trials did not yield any desired product by evaluation of a number of metal catalysts or organocatalysts with silanes or
piro-indolepyrrolidine and spiro-indolinepyrrolidine are important structural motifs that are widely distributed in natural products and pharmaceutical agents (Figure 1).1 In this
Figure 1. Natural products containing spiro-indolepyrrolidine and spiro-indolinepyrrolidine motifs.
respect, great effort has been devoted to the development of efficient methods toward these unique skeletons.2 Among them, dearomatization of tryptamine derivatives is widely used, and many elegant catalytic reactions have been reported.3 Carbon dioxide (CO2) is a plentiful, inexpensive, and nontoxic carbon feedstock for producing chemicals.4 In particular, selectively creating C−C bonds using CO2 as a C1 synthon has gained increasing attention.5 The past decade has witnessed a great advance in the metal-catalyzed,6 base-promoted,7 or light-mediated8 carboxylic acid and its derivatives syntheses with CO2 (Scheme 1a). Metal-catalyzed selective carbonylation of olefins with hydrogen and CO2 to form C−C bonds has been disclosed.9 Notably, Beller and co-workers reported a novel Ru-catalyzed C−H methylation of arenes with hydrogen Scheme 1. Construction of C−C and C−N Bonds with CO2
Received: June 22, 2017
© XXXX American Chemical Society
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DOI: 10.1021/acs.orglett.7b01906 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters
Next, this transformation tolerates electron-donating (Me, MeO) and electron-withdrawing (F, Cl) substituents on the indole core (products 2o, 2p, 3q, 3r, 3s, and 3t, 57−88% yield). In addition, a variety of chemical functionalities on the 2-alkyl chain of the indole were also compatible, such as ester (2w, 2x, and 3z), amide (2y), and cyanide (2aa). Finally, spiroindolinepiperidine 4 was obtained in good yield with excellent diastereoselectivity (>20:1). The structure and the stereochemistry of the spiro-indolinepyrrolidines 3 were determined by NOESY analysis of 3l and further confirmed by an X-ray crystallographic analysis of a crystal of 3l. The spiro-indolepyrrolidines 2 are readily converted to other valuable chemicals (Scheme 3). Reduction of purified 2b with NaBH4 afforded 3b in 75% yield with better diastereoselectivity (dr = 5:1) comparing to in situ reduction (dr = 3:1). Interestingly, ring-opening product 5 was obtained in high yield when hydrogenation of 2b catalyzed by palladium on carbon. The cyanation of 2b at 0 °C gave spiroindoline 6 bearing two continuous all-carbon quaternary stereocenters with excellent diastereoselectivity. Notably, a formal intermolecular C−C and C−N bond-forming reaction with CO2 was achieved when the reaction was performed at 50 °C, producing ring-opening cyanation product 7 in good yield. To provide some insight into the reaction mechanism, a series of control experiments were carried out. First, we performed the reactions with 1b in CD3CN at lower temperatures attempting to detect possible intermediates (Figure 1 in the Supporting Information). Formamide 8 was obtained as a single product at room temperature. Additionally, the desired product 2b was obtained in 92% NMR yield in 1 h at 100 °C, which indicated the existence of a very active intermediate. However, no reaction occurred when using 8 as the starting material under the standard conditions (Scheme 4, eq 1). Obviously, there are two competitive pathways in this reductive functionalization of CO2. The reductive C−C and C−N bond-forming reaction favors high temperature. When 2,6-diisopropylaniline 9 was subjected to the standard conditions, imine 10 was obtained in 70% NMR yield, suggesting that a formaldehyde equivalent might be formed as the intermediate in the reaction.16 To our knowledge, only one example of dearomatization of tryptamine derivatives with formaldehyde was reported using stoichiometric amount of acid as promoter.17 Although the dearomatization product 2b was obtained using formaldehyde instead of CO2, the efficiency was dramatically dropped (Scheme 4, eq 3). However, 2b was not obtained when 1b reacted with formaldehyde directly in the absence of TBD and PhSiH3 with or without camphorsulfonic acid as a promoter in acetonitrile at 100 °C. It has been reported that bis(silyl)acetal is one of the products in the NHC-catalyzed reduction of CO2 with silanes.18 According to previous reports on organocatalytic formylation or methylation of amine with CO219 and our mechanistic experiments, the possible reaction pathway was proposed. Organic base or NHC-catalyzed reduction of CO2 produces bis(silyl)acetal selectively at high temperature. The following reaction of 1a with bis(silyl)acetal afford intermediate III to form the C−N bond. Subsequent loss of silanol gives the iminium intermediate IV. Then, nucleophilic addition of indole to the carbon center of IV forms the C−C bond, thus affording the final product 2a. In summary, we have developed a new reductive tandem C− C and C−N bond-forming reaction with CO2. Spiroindolepyrrolidines were easily synthesized via dearomatization of tryptamine derivatives with high yield and good functional
boranes. Formamide or methylamine was obtained as the major byproduct by reductive formylation or methylation of amine with CO2. We then turned to N-methyl-2-methyltryptamine and N-pheyl-2-methyltryptamine 1a, assuming that introduction of a secondary amine could generate reactive iminium intermediate. No desired product was obtained with N-methyl2-methyltryptamine. To our delight, the desired product spiroindolepyrrolidine 2a was obtained in 73% yield with Nheterocyclic carbene IPr as catalyst and 2 equiv of phenylsilane as reductant in CH3CN at 100 °C with 1a as substrate (Table 1, entry 1). Seeking to improve the yield, we proceeded to Table 1. Development of the Reductive Tandem C−C and C−N Bond-Forming Reaction with CO2
entry
catalyst
solvent
yielda (%)
1 2 3 4 5 6 7 8 9b 10c 11d
IPr SIPr TBD DBU pyridine DABCO TBD TBD TBD TBD TBD
CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DMF THF CH3CN CH3CN CH3CN
73 65 93 78 15 36 66 17 76 90 95 (90)e
a
All of the reactions were carried out on a 0.2 mmol scale in 2 mL of CH3CN in a closed 25 mL screw Schlenk tube; the yield was determined by 1H NMR with 1,1,2,2-tetrachloroethane as internal standard. bWith 15 mol % TBD. cWith 1.5 equiv PhSiH3. dWith 0.5 mmol 1a. eIsolated yield.
evaluate a variety of organocatalysts (entries 2−6) and observed that TBD gave the best result (entry 3). A significant effect on the reactivity was observed using different solvents (entries 7− 8). Utilizing other silanes instead of phenylsilane as reductant resulted in diminished yield or no reaction (Table 1 in the Supporting Information). Notably, both lower catalyst and reductant loadings still delivered good yields of 2a (entries 9− 10). Finally, the reaction gave a better result at a higher concentration (0.25 M) (entry 11). Control experiments showed that no reaction occurred without catalyst. With the optimized conditions in hand, we next evaluated the scope of the reaction. As illustrated in Scheme 2, spiroindolinepyrrolidines 3 could be obtained with good diastereocontrol after in situ reduction of 2 with NaBH4 for easy isolation, without dramatic loss in the isolated yield (3b vs 2b). First, the electronic effect of the aromatic substituents on the amine was explored. Substrates bearing either an electrondonating or electron-withdrawing group on the aryl moiety all reacted smoothly affording the corresponding products in good yields (products 2b, 3c, 2d, 2e, 3f, and 2g, 55−92% yield). Halogen substituents (F, Cl, Br, I) on the phenyl group of the amine were well tolerated (products 3h, 2i, 3j, 3k, and 3l, 69− 87% yield). Meanwhile, substrate bearing a heteroaryl group (2pyridinyl) also gave the desired product in good yield (3n). B
DOI: 10.1021/acs.orglett.7b01906 Org. Lett. XXXX, XXX, XXX−XXX
Letter
Organic Letters Scheme 2. Scope of the Reductive Tandem C−C and C−N Bond-Forming Reaction with CO2a
a
Reactions conducted on 0.5 mmol scale. Isolated yields are provided; dr is determined by crude 1H NMR after in situ reduction.
the reaction mechanism and expansion of the reductive C−C bond formation with CO2 are ongoing in our laboratory.
Scheme 3. Transformation of Spiro-indolepyrrolidine
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01906. Experimental procedures and analytical data (PDF) Crystallgraphic data for 3l (CIF)
Scheme 4. Mechanistic Experiments and Possible Pathway to the Spiro-indolepyrrolidine
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ji-Bao Xia: 0000-0002-2262-5488 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank LICP, NNSFC (21572238, 21602230, 21402089, 21633013), NSF of Jiangsu Province (BK20161260), and the Hundred-Talented Program of the CAS for financial support. We thank Prof. Senmiao Xu and Yuehui Li for helpful discussions.
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DOI: 10.1021/acs.orglett.7b01906 Org. Lett. XXXX, XXX, XXX−XXX
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DOI: 10.1021/acs.orglett.7b01906 Org. Lett. XXXX, XXX, XXX−XXX
