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Synlett 2018; 29(03): 354-358
DOI: 10.1055/s-0036-1591489
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© Georg Thieme Verlag Stuttgart · New York

Cyclopropane Intermediates from Insertion Reactions of Platinum–Carbenes: A Route to Heterospiranes

Kiseong Kim
Department of Chemistry and Research Institute of Natural Science, Hanyang University, 222, Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea   Email: changho@hanyang.ac.kr
,
Soyung Kim
Department of Chemistry and Research Institute of Natural Science, Hanyang University, 222, Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea   Email: changho@hanyang.ac.kr
,
Chang Ho Oh*
Department of Chemistry and Research Institute of Natural Science, Hanyang University, 222, Wangsimni-ro, Seongdong-gu, Seoul 04763, Republic of Korea   Email: changho@hanyang.ac.kr
› Author Affiliations

Financial support was provided by a grant from the National Research Foundation of Korea (NRF–2014R1A5A1011165).
Further Information

Publication History

Received: 30 July 2017

Accepted after revision: 14 September 2017

Publication Date:
11 October 2017 (online)

 
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Abstract

Heteroaromatic-anchored enynals with a pendent alkene group were successfully cyclized through a Huisgen-type [3+2] cycloaddition to give a tetracyclic Pt–carbene complex that underwent insertion into the C–H bond in the β-position to give fused cyclopropanes that are otherwise inaccessible. On heating, the cyclopropanes smoothly rearranged to form the corresponding heterospiranes with excellent levels of stereoselectivity and high yields.


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Key words

cyclization - platinum catalysis - pyrylium ions - carbenes - heterospiranes

Spirocyclic compounds have garnered a considerable amount of recent attention due to their biological importance and their widespread occurrence in nature.[1] Spirocyclic compounds consist of two or more cyclic rings linked together by a common carbon.[2] The importance of spirocycles has also been illustrated by their use as valuable synthetic intermediates in total syntheses of natural products.[3] Spirocycles are also widely used in materials science.[4] Despite the utility of spirocycles, the efficient formation of the spiro quaternary carbon remains an important challenge in organic synthesis.[5] Heterospiranes are spiro compounds from biological sources that contain heteroatoms (N, O, or S) in the spirane rings or elsewhere.[6]

We have long been interested in developing methods for synthesizing a variety of polycyclic compounds by using rhodium,[7] gold,[8] or platinum catalysts.[9] The aromatic-anchored enynals 1 have been shown to generate Pt–carbene intermediates via a platinum-bound pyrylium and through a Huisgen-type [3+2] cyclization [Scheme [1](a)].[9] The Pt–carbene intermediate was expected to furnish a [6,7,6]-tricyclic (±)-faveline derivative under our initial conditions.[9c] [9d] However, the Pt–carbene intermediate generated the cyclopropanes 2, which rearranged to form spiranes 3.[9c] Next, we extended the Pt-catalyzed cyclization to the cycloalkane-anchored enynals 4. The cycloalkane-based enynals were catalytically converted into the corresponding tricyclic spiranes 5 in good to excellent yields [Scheme [1](b)].[9f] With this successful result, we extended our protocol to the intramolecular Pt-catalyzed spirocyclization of N-fused enynal systems to synthesize biologically interesting carbo- and heterospiranes.[5] [6] Furthermore, we designed an enynal system that contained a cyclohexyl group on a pendent alkene, which we used to obtain polycyclic spiranes.

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Scheme 1 Platinum-catalyzed cyclizations to form spiranes
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Scheme 2 Platinum-catalyzed cyclization to give products 2 and 3

On the basis of these previous reaction trends, spirocycles 3 should be obtained via the cyclopropanes 2 (Scheme [2]). We therefore examined the cyclization of enynal 1a in the presence of a platinum catalyst under our previous reaction conditions,[9c] and we isolated cyclopropane 2a in 91% yield and, subsequently, spiro compound 3a in 88% yield through rearrangement with a catalytic amount of 4-toluenesulfonic acid (PTSA) in refluxing benzene. To extend the substrate scope, we selected substrates 1b–d, which contained a spirocycle-like cyclohexyl group and an oxygen-containing functional group (OAc) on the pendent alkene. The 4-fluoro-substituted substrate 1c and 4-methoxy-substituted substrate 1d, containing an electron-withdrawing and an electron-donating group, respectively, afforded the corresponding cyclopropanes 2c and 2d in 84% yield. When the products 2b and 2c were refluxed in benzene in the presence of PTSA, the corresponding spiro compounds 3b and 3c were obtained in good to excellent yields with retention of stereochemistry. The oxygen-containing OAc functional groups did not interfere with the reaction, but was eliminated during PTSA-catalyzed rearrangement. Note that products 2a–c and 3a–c were isolated with high levels of stereoselectivity, although these reactions generated multiple stereogenic centers that led to the formation of the several isomeric products.

Unfortunately, the rearrangement reaction of the 5-methoxy-substituted substrate 2d was messy, and we could not establish optimal condition for this reaction. Consequently, we further studied the formation of 5-methoxy spiranes. We attempted to accomplish isomerization of cyclopropanes 2d–g, because we suspected that the OAc and OMe groups might interact. The present method worked for 1d–g and gave the corresponding cyclopropanes 2d–g without any problems, but longer reaction times at the given temperature led to decomposition in all cases. These phenomena might be understood in terms of an electron-donating effect of the methoxy group, where the electron-rich methoxy group mismatched with the electron-rich carbon generated during rearrangement to the spirocycle 3d (Scheme [3]). The cyclopropanes 2e–g showed similar phenomena. Note that 1a, which has a methoxy substituent in the meta-position to the benzylic hydrogen in 2a rearranged to the corresponding spiro compound 3a.

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Scheme 3 Possible mechanism for the formation of spiranes 3

Finally, we applied our previous work to a typical N-heterocyclic system, 2,6-dichloro-5-fluoronicotinonitrile (9; CFN). First, we prepared pyridines 6 in three steps as starting materials for the CFN system. The advantage of this method was that we could freely change the R1 group to give various N-containing compounds substituted with piperidin-1-yl, phenyl, 2-naphthyl, or benzyloxy groups (Scheme [4]).

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Scheme 4 Synthesis of starting material for the CFN system

Table 1 Optimization of the Platinum-Catalyzed Reaction of Enynal 6a a

Entry

Solvent

Temp (°C)

Time (h)

Product

Yieldb (%)

1

toluene

120

 4

7a

94

2

toluene

120

20

7a
8a

35
 8

3

DCE

 80

12

7a

43

4

1,4-dioxane

120

 8

7a

63

5

xylene

150

 4

8a

78

a Reaction conditions: 6a (0.40 mmol), PtCl2(PPh3)2 (10 mol%) , under Ar.

b Isolated yield.

We then examined the reaction of substrate 6a in the presence of a Pt catalyst under a variety of conditions (Table [1]). First, the reaction of 6a with PtCl2(PPh3)2 as the catalyst proceeded smoothly in refluxing toluene to furnish product 7a in 94% yield (Table [1], entry 1). A longer reaction time under the same conditions gave cyclopropane 7a and spiro compound 8a in 35 and 38% yield, respectively (entry 2). DCE, and 1,4-dioxane, could also be used as solvents for the reaction (entries 3–4). Surprisingly, when 6a was treated with PtCl2(PPh3)2 at 150 °C for four hours in xylene, the reaction gave spiro compound 8a in 78% yield (entry 5).

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Scheme 5 Platinum-catalyzed cyclization of CFN systems. Reaction conditions: 6 (0.40 mmol) PtCl2(PPh3) (10 mol%); (for product 7): toluene, 120 °C, 4 h, under Ar; or (for product 8) xylene, 150 °C, 4 h, under Ar. Isolated yields are reported. a Hexane was used instead of xylene.

We then used a variety of substrates to explore the scope and limitations of this reaction. Most of the substrates gave the corresponding products 7 [10] and 8 [11] in good to excellent yields, but compound 6b, which contained a 2-naphthyl group, gave products 7b and 8b in reduced yields (Scheme [5]). On the other hand, when substrate 6c was treated under the same condition, product 7c was obtained in an excellent yield. When substrate 6c was treated with PtCl2(PPh3)2 in refluxing xylene (150 °C) for four hours, the spiro compound 8c was obtained in 73% yield. Unfortunately, substrates 6d and 6e, which contain a piperidin-1-yl group, did not form the corresponding cyclopropane compound; instead, the spiranes 8d and 8e were obtained in 51 and 73% yield, respectively. Interestingly, the OTBS group of substrate 8d was not eliminated during the Pt-catalyzed isomerization. The product 8e was formed in a high yield on changing the solvent to hexane (Scheme [5]).

In our proposed mechanism, intermediate A undergoes [3+2] cycloaddition to the pendent double bond to form the Pt–carbene complex B . The Pt–carbene complex B inserts into the tertiary C–H bond to form the cyclopropane intermediate 7, which then isomerizes to the corresponding spirane 8 on heating or under PTSA-catalyzed conditions (Scheme [6]).[9c] [9f]

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Scheme 6 Proposed mechanism for the formation of 7 and 8

The Pt-catalyzed cycloisomerization of aromatic and N-heterocyclic aldehydes substituted with a enynyl group at the 2-position gave the corresponding spirocycles isolated in high to excellent yields via cyclopropane intermediates. This reaction is a valuable choice for the synthesis of certain spirocyclic compounds.


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Supporting Information

    Supporting information for this article (copies of 1H and 13C NMR spectra for compounds 2b–g, 3b–c, 7a–c, 8a–e) is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/s-0036-1591489.
  • Supporting Information


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Zoom Image
Scheme 1 Platinum-catalyzed cyclizations to form spiranes
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Scheme 2 Platinum-catalyzed cyclization to give products 2 and 3
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Scheme 3 Possible mechanism for the formation of spiranes 3
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Scheme 4 Synthesis of starting material for the CFN system
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Scheme 5 Platinum-catalyzed cyclization of CFN systems. Reaction conditions: 6 (0.40 mmol) PtCl2(PPh3) (10 mol%); (for product 7): toluene, 120 °C, 4 h, under Ar; or (for product 8) xylene, 150 °C, 4 h, under Ar. Isolated yields are reported. a Hexane was used instead of xylene.
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Scheme 6 Proposed mechanism for the formation of 7 and 8