Construction of Fused Tropone Systems Through Intramolecular Rh(I)-Catalyzed Carbonylative [2+2+2+1] Cycloadditon of Triynes

“Tropone” is a non-benzenoid aromatic skeleton that can be found in a variety of natural products. This cyclohepta-2,4,6-trien-1-one skeleton appears simple, but there have been no straightforward ways to construct this molecular architecture. It is conceivable that this molecule can be constructed via a higher order cycloaddition of three acetylene units and CO, but such process was not known until we have discovered that the carbonylative [2+2+2+1] cycloaddition of triynes can take place in the presence of a Rh complex catalyst and CO. However, this highly challenging process is naturally accompanied by ordinary [2+2+2] cyclotrimization products, i.e., benzenes, as side products. A mechanistic study led to two competing processes wherein the critical CO insertion occurs either to a rhodacyclopentadiene intermediate (Path A) or a rhodacycloheptatriene intermediate (Path B). The DFT analysis of those two pathways disclosed that the Path A should be the one that yields the carbonylative [2+2+2+1] cycloaddition products, i.e., fused tricyclic tropones. A further substrate design, inspired by colchicine structure, led to the almost exclusive formation of a fused tetracyclic tropone from a triyne bearing 1,2-disubstituted benzene moiety in a single step and excellent yield.


INTRODUCTION
Transition metal-catalyzed carbocyclization and cycloaddition of unsaturated motifs have proven to be among the most efficient carbon-carbon bond-forming transformations for constructing complex polycyclic systems that are often difficult or impossible to construct by other means (Lautens et al., 1996;Ojima et al., 1996). Among those reactions, cyclotrimerization of alkynes has been the most studied process (Saito and Yamamoto, 2000;Shibata and Tsuchikama, 2008). Interand intramolecular alkyne cyclotrimerizations with various transition metal complexes furnished wide varieties of polysubstituted benzene derivatives (Saito and Yamamoto, 2000;Kotha et al., 2005;Chopade and Louie, 2006). When the cycloaddition of alkynes carried out under carbon monoxide atmosphere, a range of interesting carbonylative cycloaddition products were observed instead of benzene formation (Scheme 1) (Gesing et al., 1980;Badrieh et al., 1994;Son et al., 2000aSon et al., ,b, 2001Shibata et al., 2001Shibata et al., , 2002Sugihara et al., 2001;Huang and Hua, 2007).
It is clear that cycloaddition of alkynes is not limited to aromatization to benzene derivatives. For examples, challenging compounds such as cyclopentadienone that are anti-aromatic can be prepared by a transition-metal catalyzed cycloaddition of alkynes (Sugihara et al., 2001). We envisioned that other non-benzenoid aromatic skeletons can also be prepared under appropriate conditions. For example, cyclohepta-2,4,6-trien-1one, generally known as "tropone" (Dewar, 1945), is a nonbenzenoid aromatic skeleton that can be found in various biologically active molecules (Erdtman and Gripenberg, 1948;Pauson, 1955;Polonsky et al., 1983;Ginda et al., 1988;Wu et al., 1996;Graening and Schmalz, 2004;Zhao, 2007). Tropone's structure is deceptively simple, but there are no straightforward methods to prepare tropone and its derivatives (Pietra, 1973). Conceptually, the formation of cycloheptatrienone from three alkynes and CO is the most straightforward synthetic route (Scheme 2), but such a process is not known in the literature to date. We report here the discovery of a facile [2+2+2+1] cycloaddition of triynes with CO, catalyzed by Rh-complexes, to form fused tropones in one step.

General Experimental Procedures
All chemicals were obtained from either Sigma-Aldrich or Acros Organics and used as is, unless otherwise noted. All reactions were performed under Schlenk conditions with oven dried glassware, unless otherwise noted. Dry solvents were degassed under nitrogen and were dried using the PURESOLV system (Inovatative Technologies, Newport, MA). All reactions were monitored by thin layer chromatography (TLC) using E. Merck 60F254 precoated silica gel plates. Flash chromatography was performed with the indicated solvents and using Fisher silica gel (particle size 170-400 Mesh). Yields refer to chromatographically and spectroscopically pure compounds. 1 H and 13 C were obtained using either 300 MHz Varian Gemni 2300 (75 MHz 13 C) spectrometer or the 400 MHz Varian INOVA 400 (100 MHz 13 C) spectrometer in CDCl 3 as a solvent. Chemical shifts (δ) are reported in ppm and standardized with solvent as internal standard based on literature reported values (Gottilieb et al., 1997). Melting points were measured with a Thomas Hoover capillary melting point apparatus and are uncorrected.

Rh-Catalyzed [2 + 2 + 2 + 1] Cyclocarbonylation Reactions
Typical procedures are described here for the reaction of triyne 1b and 1e. Other reactions were carried out by using either method as noted.
Gratifyingly, the reaction of internal triynes 1b-d gave tricyclic tropones 2b-d as minor products through carbonylative [2+2+2+1] cycloaddition together with anticipated tricyclic benzene derivatives 3b-d through [2+2+2] cycloaddition as major products. Following up this encouraging result, we attempted to increase the selectivity of the tropone formation through optimization of reaction variables (i.e., solvents, CO pressure, use of Mn(CO) 6 , etc.), as well as terminal and internal substituents in the 1,6,11-triynes, but without success.
Frontiers in Chemistry | www.frontiersin.org obviously favored through facile reductive elimination from metalacycle B' rather than CO insertion to metalacycle B' to give metalacyclooctatrienone C or C'.
Thus, we have hypothesized an alternative mechanism, which involves metalacyclohexadienone B as the key intermediate through Path A, prior to the insertion of the third acetylene moiety. It is reasonable to assume that the introduction of a longer tether between the second and third acetylene moieties, equilibrium between rhodacyclopentadiene A and A ′ may favor the CO insertion to rhodacyclopentadiene A to form B, leading to the specific formation of C, which should lead to the formation of tropone product 2.
Intermediates A and A ′ are conformers; from the transition state TS1 if the reaction proceeds via intermediate A ′ , it's clear  that it would greatly favor the formation of the benzene product 3. However, if TS1 gives more stable intermediate A, it would proceed via CO insertion to give intermediate B rather than isomerizes to A ′ due to less activation energy, and ultimately gives tropone product 2 ( Figure 1A). When the Rh(CO) 3 species are introduced to the reaction Path A, its DFT energy profile is more favorable than that of the Rh(CO) 2 species in the same pathway ( Figure 1B). For the DFT analysis of Path A and Path B with chemical structures of the intermediates and transition states as well as their coordinates, see Supporting Information.
To confirm the prediction based on the DFT calculations, we prepared 1,6,12-triynes (n = 2) 1e-g as well as 1,6,13triynes (n = 3) 1h and 1i and subjected them to the reaction conditions using [Rh(CO) 2 Cl] 2 as the catalyst at 50 • C in dichloroethane (DCE) under 2 atm of CO. Results are summarized in Table 1. As Table 1 shows, the selectivity for tropone formation via carbonylative [2+2+2+1] cycloaddition was indeed substantially improved and thus tropones 2e-i became the major products in these reactions.
Introduction of a phenyl group as R 1 has a favorable effect on the carbonylative [2+2+2+1] cycloaddition, but there is no difference between these two tether lengths (n = 2 vs. n = 3). It is noteworthy that 5-7-7 fused tricyclic products, 2h and 2i, were formed in fairly good isolated yields. The reaction that affords a 7-7 fused ring system in one-step is hereto unknown in the literature. Thus, this is the first reaction that achieved such a challenging process. At this point, we envisioned that the insertion of a 1,2-disubstituted benzene unit to the triyne substrate might introduce a tether with more rigid constraints than triynes 1h and 1i to favor the Path A, hence the formation of tropone.
It is rational to ascribe the observed unexpectedly high selectivity for [2+2+2+1] cycloaddition to the rotational restriction by the introduction of a 1,2-disubstituted benzene unit to the tether connecting the second and third acetylene moieties, which disfavored the Path B and favored the Path A (see Scheme 4).
We recognized that the fused tetracyclic products 5 and 6 mimic the colchicine and allocolchicine skeletons, respectively (Figure 2). It is worthy of note that the rapid construction of colchicinoid skeleton is realized through novel [2+2+2+1] cycloaddition of triynes and CO in one-step. Further investigations into the scope and limitation of the [2+2+2+1] and [2+2+2] cycloaddition of triynes are actively underway in our laboratory and will be published in due course.

CONCLUSIONS
The first carbonylative [2+2+2+1] cycloaddition of triynes of 1,6,n-triynes (n = 11-13) with CO was achieved by the catalysis of a Rh complex. This [2+2+2+1] cycloaddition process (Path B) should be energetically unfavorable than the competing [2+2+2] cycloisomerization process if the CO insertion occurs after the formation of metalacyclooctatriene intermediate since a simple reductive elimination gives the corresponding aromatized product, i.e., benzene derivative. Thus, the CO insertion step in the [2+2+2+1] cycloaddition process should involve a carbonylated diene species prior to the reaction with the third acetylene moiety. This analysis led to the proposal of a feasible mechanism for this novel [2+2+2+1] cycloaddition process, involving a rhodacyclpentadienone species B as the key intermediate (Path A). The DFT calculations of all key intermediates and transition states clearly supported the proposed mechanism. Based on this mechanism, a triyne substrate 4 was designed, in part inspired by the framework of colchicine, a naturally occurring bioactive tropone. The introduction of a 1,2disubstitute benzene as a tether to the third acetylene unit should slow down the coordination of the acetylene and favor the CO insertion to the metalacyclopentadiene intermediate A to form the key intermediate B, leading to the formation of tropone 2. In fact, the reaction of 4 afforded the corresponding fused tetracyclic tropone 5 in 94% yield and 96% selectivity. Since this novel process is applicable to the design and synthesis of various colchicinoids, further studies on this process and applications are actively underway in our laboratory.

AUTHOR CONTRIBUTIONS
Y-HT designed and performed major experiments, as well as collected characterization data and carried out preliminary DFT calculations. C-WC also performed experiments and collected characterization data. W-HC carried out DFT calculations and validated results. TH organized manuscripts and validated data. IO oversaw all aspects of the research, including experimental designs, analysis of mechanism and overall organization of the manuscript.