Hydrohalogenative aromatization of multiynes promoted by ruthenium alkylidene complexes

Article abstract of DOI:10.1039/c6ob00524a

A new functionalization method of arynes promoted by a novel catalytic role of the Grubbs-type ruthenium alkylidene complex is described. Through a sequence of aryne formation followed by their halo-functionalization, various bis-1,3-diynes were directly converted to functionalized aryl chlorides, bromides and iodides in good yields in the presence of a catalytic amount of a ruthenium alkylidene complex and halogenated hydrocarbons such as CH₂Cl₂, CHCl₃, CH₂Br₂, and CH₂I₂. The utility of this novel transformation is demonstrated by a formal synthesis of herbindole B.

Full text of DOI:10.1039/c6ob00524a

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Hydrohalogenative aromatization of multiynes
promoted by ruthenium alkylidene complexes†
Cite this: DOI: 10.1039/c6ob00524a
Received 8th March 2016,
Accepted 26th April 2016
Rajdip Karmakar, Kung-Pern Wang, Sang Young Yun, Phani Mamidipalli and
Daesung Lee*
DOI: 10.1039/c6ob00524a
www.rsc.org/obc
A new functionalization method of arynes promoted by a novel Recently we reported an unusual nonmetathetic catalytic
catalytic role of the Grubbs-type ruthenium alkylidene complex is activity of ruthenium alkylidenes by which an efficient 1,4-
described. Through a sequence of aryne formation followed by hydrovinylative cyclization of multiynes with concomitant
their halo-functionalization, various bis-1,3-diynes were directly incorporation of an ethylene molecule was achieved, forming
converted to functionalized aryl chlorides, bromides and iodides in multiple conjugated products 5 (Scheme 1A).6,7 During the
good yields in the presence of a catalytic amount of a ruthenium exploration of this unusual transformation, we observed yet
alkylidene complex and halogenated hydrocarbons such as another unexpected reaction when variation of the electronic
CH2Cl2, CHCl3, CH2Br2, and CH2I2. The utility of this novel trans- nature of the alkyne substituent was introduced to the multi-
formation is demonstrated by a formal synthesis of herbindole B.
yne substrates. It was remarkable to find that a simple change
Introduction
Since the discovery of the well-defined ruthenium based alkyli-
dene complex in 1992,1 Grubbs alkylidene complexes have
continued to evolve with improved stability, reactivity and
selectivity in the metathesis of various formats over the past
twenty years.2,3 The greatest impact of Grubbs catalysts (1–3)
lies in olefin metathesis whereby the synthesis of countless
organic molecules of interest was achieved ranging from
natural products and pharmaceuticals to advanced materials
including polymers with special characteristics.4 Over the
years, various synthetically useful nonmetathetic reactions
catalyzed by Grubbs-type complexes have been documented.5
Therefore, the discovery of a new catalytic reactivity of these
complexes will further broaden their synthetic utility.
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street,
Chicago, Illinois 60607-7061, USA. E-mail: dsunglee@uic.edu; Fax: +1 312-996-0431;
Tel: +1 312-996-5189
†Electronic supplementary information (ESI) available. CCDC 1039073. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c6ob00524a
Scheme 1 Distinctive nonmetathetic activity of ruthenium alkylidenes.
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Table 1 Screening of halogen sourcesa
in the phenyl group with a 4-methoxy group in substrate 4,
under otherwise identical reaction conditions, completely
changed the reaction course, producing the aryl chloride 6.
Because the only source of chlorine atom incorporated into
the aryl moiety of 6 is CH2Cl2 (except the ligands in the ruthe-
nium complex), the chlorine atom must come from dichloro-
methane used as the solvent. The same reaction with
deuterated dichloromethane or chloroform provided the same
product 6 with a high level of deuterium incorporation, thus it
is evident that the hydrogen incorporated into the product is
also from dichloromethane. Although not identical, this ruthe-
nium-catalyzed activation of chlorinated hydrocarbon seems to
be closely related to the Kharasch addition of CHCl3 with
alkenes catalyzed by ruthenium alkylidene 1 in Snapper’s
seminal study (Scheme 1B).8 Thus, we carefully examined
whether the reaction of tetrayne 4a with CHCl3 produced the
Kharasch-type addition product 6a′ when catalyzed by ruthe-
nium alkylidene 1. From this reaction, however, the Kharasch-
type CHCl3 adduct 6a′ or its regioisomer was not observed,
and the aryl chloride 6a was isolated in 90% yield. Based on
this initial observation, we further investigated the generality
of the reaction and herein we report the unprecedented non-
metathetic activity of Grubbs-type ruthenium complexes to
activate halogenated hydrocarbons for the formation of a
range of functionalized aryl halides from various bis-1,3-diyne
substrates.9
Entry
Haloalkane
Product
X
Yieldb (%)
1
2
3
4
5
6
7
CH2Cl2
CHCl3
ClCH2CH2Cl
CCl4
CH2Br2
BrCH2CH2Br
CH2I2
6b
6b
6b
6b
7b
7b
8b
Cl
Cl
Cl
Cl
Br
Br
l
92
90
85
<5
76
76
45
a Reaction conditions: 0.1 mmol of 4b, 5 mol% 2, 2 mL of haloalkanes
as the solvent. b Isolated yield.
Results and discussion
First we investigated the reactivity of various conventional
haloalkanes as the source of HX in the cycloaromatization of
symmetrical bis-1,3-diyne 4b catalyzed by Grubbs second-gene-
ration complex 2.10 When halogenated hydrocarbons (CH2Cl2,
CHCl3, ClCH2CH2Cl, CH2Br2, BrCH2CH2Br, and CH2I2) were
used as either a solvent or a reagent the corresponding chloro-,
bromo-, and iodo-substituted arenes 6b, 7b, and 8b were gen-
Scheme 2 Competing reactions between hydroiodination and
methyliodination.
erated except for CCl4 probably due to the lack of a hydrogen possessing a tosyl amide linker or an oxygen tether provided
atom source (Table 1). While the hydrochlorinated product 6b aryl halide products in good yields regardless of the substitu-
was produced in a range of 85–92% yields (entries 1–3), the ent on the diyne. Thus, substrates containing silyl groups on
corresponding hydrobrominated product 7b was obtained in the 1,3-dienes provided the corresponding chlorinated and
slightly lower yields when CH2Br2 and BrCH2CH2Br were used brominated arenes 6a, 6b, 7b in 82, 92 and 76% yields, respect-
as the source of HBr (entries 5 and 6), and in the presence of ively, as a single regioisomer. The structural confirmation of
CH2I2, aryl iodide 8b was obtained in a significantly lower these products was established by nOe experiments and
yield (entry 7). In all cases, HX addition turned out to be further by single crystal X-ray crystallographic analysis of 6a.11
highly regioselective, thus the other isomer was not observed While
a t-butyl group-containing substrate produced a
within the detectable limit. Interestingly, the reaction of sub- 10 : 1 mixture of isomers of 6c in 65% yield, the corresponding
strate 4a with methyl iodide (CH3I) produced a mixture of the substrate possessing a phenyl group afforded a 20 : 1 mixture
hydrogen iodide-incorporated product 8b and the methyl of isomers 6d. Hydrochlorinated and hydroiodinated arenes
iodide-incorporated product 8b′ in 68% yield with a 1 : 3.5 6f, 6g and 8g carrying secondary and tertiary carbon-contain-
ratio (Scheme 2).
ing substituents were generated as single isomers in good
Based on these promising preliminary results, the scope of yields. A tertiary hydroxyl group at the propargylic carbon in
this catalytic hydrohalogenative cycloaromatization reaction the substrate did not interfere with the formation of hydroha-
was further explored with variously substituted symmetrical logenated products. Silyl- and alkyl group-substituted bis-1,3-
bis-1,3-diyne substrates mainly employing CH2Cl2, CH2Br2 and diynes containing an oxygen linkage also afforded the corres-
CH2I2 as the HX source (Table 2). In general, the substrates ponding aryl chlorides and bromides in good yields under
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Table 2 Scope of hydrohalogenative aromatization of symmetrical bis-1,3-diyne substratesa
a Reaction conditions: 0.1 mmol of 4, 5 mol% ruthenium alkylidene 2, 2 mL of CH2X2 (as the solvent). b 87% yield was obtained when catalyst 3
was employed. c 10 : 1 mixture of regioisomers formed. d 20 : 1 mixture of regioisomers formed. e 13 : 1 mixture of iodinated and chlorinated pro-
ducts formed. f 10 : 1 mixture of brominated and chlorinated products formed. g 12 : 1 mixture of brominated and chlorinated products formed.
standard reaction conditions. In contrast, the substituent on functional groups such as an ester or a tertiary hydroxyl group
the 1,3-diyne of dimethylmalonate-containing substrates sig- did not interfere with the formation of halides 10g, 11f, 11h,
nificantly affected the reaction efficiency. For example, aryl and 12h. Also less substituted bromo- and iodoarenes 11h and
chloride 6j and bromide 7k were isolated in 80 and 79% 12h were obtained with slightly improved yields from the
yields, respectively, whereas 6i and 6m could not be obtained corresponding substrate containing a terminal alkyne moiety.
even after prolonged heating at 150 °C; instead, the corres-
ponding bis-1,3-diynes were recovered intact with minor tive aromatization process, we carried out the reaction of sub-
decomposition. strate 4b with CD2Cl2 (eqn (1) in Scheme 3). The obtained
Next, we examined the reaction scope of hydrohalogenative product 6b–d from this reaction shows 90% deuterium incor-
aromatization with unsymmetrical substrates of type poration at the carbon ortho to the silyl group. This clearly
To gain mechanistic insight into this novel hydrohalogena-
9
(Table 3). Regardless of the substituent on the alkyne, com- indicates that CD2Cl2 is the source of both Cl and D, which
plete regioselectivity was observed for the formation of haloge- allows us to conclude that the halogenated hydrocarbons are
nated arenes from unsymmetrical substrates containing an the source of not only X but also H in all of the reactions
ynamide tether.12 It is worthy of note that the regiochemistry above. The reaction of 4b with 20 mol% ruthenium alkylidene
of HX incorporation into the product is opposite to that of the complex 2 in a nonhalogenated solvent such as toluene pro-
symmetrical bis-1,3-diynes shown in Table 2. Thus haloge- vided 16% of the aryl chloride 6b (eqn (2) in Scheme 3). This
nated arenes 10a, 10d, 11a, 11c, 12b, 12d, 12f were generated result suggests that the chloride ligands on 2 could be trans-
in moderate to good yields, where X (Cl, Br, I) was incorporated ferred to form the chlorinated product. To examine the role of
at the ortho (meta to NTs) position of the silyl, alkyl, and aryl an alternative catalytic species such as ruthenium hydride,
substituents.13 Substrates with various forms of oxygen-based one of the typical decomposition products of Grubbs-type
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Table 3 Scope of hydrohalogenation for unsymmetrical substratesa
a Reaction conditions: 0.1 mmol of 9, 5 mol% ruthenium alkylidene 2, 2 mL of CH2X2 (as the solvent).
Scheme 3 Experiments for mechanistic insight.
Scheme 4 Possible mechanisms for hydrohalogenation.
ruthenium alkylidene complexes,14 independently prepared ruthe-
nium hydride complex 13 was tested as the catalyst for the
reaction of 4b (eqn (3) in Scheme 3). But not even a trace hydro Diels–Alder reaction15,16 of the substrate 9 to form an
amount of 6b was observed. Moreover, a linear correlation was aryne intermediate A followed by hydrohalogenation where the
evidently established between the amounts of an intact ruthe- role of the ruthenium alkylidene is to activate halogenated
nium alkylidene species in the reaction (measured by the hydrocarbons similar to the Kharasch-type addition observed
1
characteristic H NMR signal at 19.1 ppm in CD2Cl2) and the by Snapper.8 In Path B, the interaction between substrate 9
observed speed of the conversion of substrates to the products. and the catalyst promotes the formation of a ruthenium–aryne
From these observations, we propose a mechanistic hypothesis complex B or an alternative form C. The electron-deficient
(Scheme 4), albeit a more accurate picture of the mechanism intermediate B or C may interact with halohydrocarbons analo-
is yet to be established. In this mechanistic scenario, the role gous to that of the metal–carbenoid reported by Lovely and
of the ruthenium alkylidene complex can be envisioned in Moriarty,17 or the vinyl cations reported by Johnson, Curran,
three distinctive manners. First, in Path A, a thermal hexade- and Kozmin.18 Alternatively, in Path C, thermally generated
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Scheme 5 Formal synthesis of herbindole B.
aryne A intercepts intermediate B or C upon interacting with 18. Stereoselective hydrogenation of 18 using the Crabtree cata-
the ruthenium species.19,20 Furthermore, the efficiency of lyst provided the known compound 19 with the cis-relationship
forming aryne A and its trapping with weak nucleophiles of the methyl groups, from which Sato and coworkers achieved
(MeOH, AcOH) was not affected by the catalyst,21 which is a total synthesis of herbindole B in two steps.23e
however indispensible for hydrohalogenated products 10–12.
Thus, we conclude that Path A is the most plausible mechan-
ism where CH2X2 is activated by the ruthenium catalyst for HX
transfer to the aryne intermediate A.
Conclusions
The utility of this hydrohalogenative cyclization is show- In conclusion, we have discovered a new functionalization
cased with the synthesis of a cyclopent[g]indole natural method of arynes promoted by a novel catalytic activity of the
product herbindole B, which was isolated from the Western Grubbs-type ruthenium alkylidene complex whereby variously
Australian sponge Axinella sp., and exhibits cytotoxicity against tethered bis-1,3-diynes were directly converted into structurally
KB cells and a general fish antifeedant activity (Scheme 5).22,23 novel halo-functionalized arenes. In these transformations,
From a retrosynthetic perspective, the structural feature of halogenated hydrocarbons were used as the reagent or as a
herbindole can take advantage of the existing alkyne moiety at solvent, which effectively serve as the source of HX. This new
the C4 position of the aryl halide 11 that is generated by the benzannulation process showed a broad substrate scope and
hydrohalogenative cyclization of a suitably substituted unsym- excellent regioselectivity in hydrohalogen incorporation, and
metrical bis-1,3-diyne 9. In turn, the installation of the benzo- thus allows for efficient preparation of a range of halofunctio-
fused dimethyl cyclopentane moiety would be achieved by the nalized indolines, isoindolines and related structures. The
gold-catalyzed Nazarov cyclization of an acetoxyalkynyl arene utility of this transformation was illustrated by a formal syn-
derived from the aryl halide 11.24 The synthesis of herbindole thesis of herbindole B. Further investigation on this unique
B commenced with conversion of the alkyne moiety of 11c to catalytic activity of Grubbs-type ruthenium alkylidene com-
14 via a three-step sequence involving removal of the tertiary plexes is in progress.
alcohol moiety, hydrogenation, and desilylation of the benzylic
trimethylsilyl group. The Sonogashira coupling between 14
and alkyne 15 followed by subsequent acetylation furnished
16. Gold-catalyzed tandem [3,3]-rearrangement of the pro-
Acknowledgements
pargylic acetate moiety in 16 followed by a Nazarov cyclization We are grateful to the University of Illinois at Chicago and the
effectively created the benzo-fused methylcyclopentanone National Science Foundation (CHE 1361620) for financial
moiety in 17. The missing methyl group was installed via the support. We thank Prof. Chae S. Yi for generous donation of
addition of MeMgI to the ketone and subsequent dehydration ruthenium hydride 10, and Dr Roger F. Henry for the X-ray
of the resultant tertiary alcohol, generating the indene derivative structure of 6a.
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