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Synlett 2014; 25(10): 1395-1402
DOI: 10.1055/s-0033-1341242
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© Georg Thieme Verlag Stuttgart · New York

Palladium-Catalyzed Double Activation and Arylation of 2° and 3° C(sp3)–H Bonds of the Norbornane System: Formation of a C–C Bond at the Bridgehead Carbon and Bridgehead Quaternary Stereocenter

Ramarao Parella
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Manauli P.O., Sector 81, SAS Nagar, Mohali, Knowledge City, Punjab 140306, India   Fax: +91(172)2240266   Email: sababu@iisermohali.ac.in
,
Srinivasarao Arulananda Babu*
Department of Chemical Sciences, Indian Institute of Science Education and Research (IISER) Mohali, Manauli P.O., Sector 81, SAS Nagar, Mohali, Knowledge City, Punjab 140306, India   Fax: +91(172)2240266   Email: sababu@iisermohali.ac.in
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Publication History

Received: 19 February 2014

Accepted after revision: 25 March 2014

Publication Date:
29 April 2014 (online)

 
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Abstract

Pd-catalyzed activation and direct arylation of both 2° and the bridgehead 3° (sp3) C–H bonds and an unprecedented C–C bond formation at the bridgehead carbon of the norbornane system are reported. The assembly of bridgehead-substituted norbornane frameworks having contiguous stereocenters was accomplished. X-ray crystal structure analysis of representative molecules unambiguously established the stereochemistry.


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Key words

arylation - bridgehead substitution - C–H activation - ­diastereoselectivity - palladium - stereoselective synthesis

The chemistry of bridgehead-substituted bridged bicyclic frameworks (bridged rings) has a long and esteemed history.[1] [2] Notably, functional group transformation at a bridged center and the generation of an quaternary bridgehead carbon of bridged bicyclic compounds is among the most challenging and fascinating of research topics. There has been a substantial number of studies on reactions at the bridgehead center of several bridged bicyclic systems.[1,2] Apart from the celebrated substitution reactions at the bridgehead carbon of bridged bicyclic compounds, there exist versatile routes[1,2] that can be used to assemble bridgehead-substituted bicyclic frameworks, including bridgehead enolate chemistry[1i] [j] and Diels–Alder reaction.[1a] [b] [c] [d] [e] [f] [g] [h]

The development of novel C–C bond-forming protocols and functionalization of organic molecules with stereocontrol are persistent goals of organic chemists. In recent years, transition-metal-catalyzed, and especially Pd-catalyzed functionalization of C–H bonds has emerged as a powerful tool in organic synthesis.[3] [4] [5] [6] In this context, the Pd-catalyzed, auxiliary-aided C–H functionalization of sp3 C–H bonds initiated by Daugulis, Yu, and other groups is evolving as a very convenient tactic.[3–6] Excellent papers on the Pd-catalyzed, auxiliary-directed C–H activation of 1° and 2° sp3 C–H bonds have been published. Recently, we reported an auxiliary-enabled, Pd-catalyzed direct C–H arylation of 2° sp3 C–H bonds of small rings such as cyclopropane and cyclobutane.[4k] [l] To the best of our knowledge only a few reports exist that deal with metal-catalyzed C–H functionalization of 3° sp3 C–H bonds.[6]

In light of the above developments, we wanted to examine one of the most challenging reactions of organic chemistry, ‘bridgehead-substitution’ via C–H activation of the bridgehead 3° C(sp3)–H bond of norbornane systems. To the best of our knowledge there is only one report[3k] dealing with two examples related to the C–H functionalization of bridgehead 3° C(sp3)–H bonds of the norbornane-type systems. The direct arylation of the bridgehead 3° C(sp3)–H bond of norbornanes, using 8-aminoquinoline and 2-thiomethylaniline as auxiliaries, which were developed by Daugulis, form the basis of this work. Herein, we report an auxiliary-aided, Pd-catalyzed sequential activation and arylation of 2° C(sp3)–H and the bridgehead 3° C(sp3)–H bonds and an unprecedented C–C bond formation at the bridgehead carbon of the norbornane framework (Scheme [1]).

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Scheme 1 Theme of this work

To examine the C–H functionalization of 2° C(sp3)–H bonds and ‘bridgehead substitution’ via C–H activation of the bridgehead 3° C(sp3)–H bond, we prepared substrate endo-N-(quinolin-8-yl)bicyclo[2.2.1]heptane-2-carboxamide (1a) from endo-bicyclo[2.2.1]heptane-2-carboxylic acid and an auxiliary (e.g., 8-aminoquinoline). To arrive at the best reaction conditions and solvents, we then performed a series of reactions, listed in Table [1], that involved Pd-catalyzed C–H arylation of the substrate 1a (endo) with 1-iodo-4-methylbenzene (2a). The reaction of a mixture of substrate 1a (endo), aryl iodide 2a and AgOAc, either in the presence or absence of the Pd(OAc)2 catalyst (10 mol%), in toluene at 110 °C did not give the product in good yield (Table [1], entries 1 and 2). We next performed the C–H arylation of substrate 1a with 2a in the presence of Ag2CO3 as a halide-removing agent, instead of AgOAc, in toluene at 110 °C. In this reaction, we were pleased to observe the formation of product 3a (65%; Table [1], entry 3) via the direct bis-arylation of both 2° C(sp3)–H (endo) and the bridgehead 3° C(sp3)–H bonds and an unprecedented C–C bond formation at the bridgehead center of the norbornane system 1a.

The C–H functionalization of substrate 1a with 1-iodo-4-methylbenzene (2a) in the presence of Ag2CO3 and Pd(OAc)2 catalyst (10 mol%) in tert-butanol gave the product 3a with slightly improved yield (70%; Table [1], entry 4). When only 5 mol% Pd(OAc)2 catalyst was used, product 3a was obtained in 60% yield (Table [1], entry 5). The Pd-catalyzed C–H arylation of 1a with 2a in the presence of various additives such as K2CO3, Na2CO3, KOAc, and PhI(OAc)2 gave product 3a in 24–30% yields (Table [1], entries 6–9). Use of other palladium catalysts such as PdCl2, Pd(TFA)2, Pd(MeCN)2Cl2 and Pd(PPh3)4 were ineffective (Table [1], entries 10–13). The reaction of 1a with 2a in the presence of Ag2CO3 and the Pd(OAc)2 catalyst (10 mol%) in other solvents such as MeCN, 1,2-DCE, 1,4-dioxane, EtOH, AcOH, and tert-amyl alcohol failed to afford product 3a with improved yields (Table [1], entries 14–19). The Pd-catalyzed C–H arylation of substrate 1a with bromobenzene (2b) or chlorobenzene (2c) did not furnish any product (Table [1], entries 20 and 21).

Table 1 Optimization of Reaction Conditions

Entry

Catalyst (mol%)

Oxidant/halide removing agent (y mmol)

Solvent

Temp (°C)

Yield of 3a (%)

 1

none

AgOAc (0.55)

toluene

110

 0

 2

Pd(OAc)2 (10)

AgOAc (0.55)

toluene

110

 5

 3

Pd(OAc)2 (10)

Ag2CO3 (0.25)

toluene

110

65

 4

Pd(OAc)2 (10)

Ag2CO3 (0.25)

t-BuOH

 85

70

 5

Pd(OAc)2 (5)

Ag2CO3 (0.25)

t-BuOH

 85

60

 6

Pd(OAc)2 (10)

K2CO3 (0.25)

t-BuOH

 85

 0

 7

Pd(OAc)2 (10)

Na2CO3 (0.25)

t-BuOH

 85

 0

 8

Pd(OAc)2 (10)

KOAc (0.25)

t-BuOH

 85

24

 9

Pd(OAc)2 (10)

PhI(OAc)2 (0.25)

t-BuOH

 85

30

10

PdCl2 (10)

Ag2CO3 (0.25)

t-BuOH

 85

25

11

Pd(TFA)2 (10)

Ag2CO3 (0.25)

t-BuOH

 85

26

12

Pd(CH3CN)2Cl2 (10)

Ag2CO3 (0.25)

t-BuOH

 85

 0

13

Pd(PPh3)4 (10)

Ag2CO3 (0.25)

t-BuOH

 85

 0

14

Pd(OAc)2 (10)

Ag2CO3 (0.25)

MeCN

 80

11

15

Pd(OAc)2 (10)

Ag2CO3 (0.25)

1,2-DCE

 80

 9

16

Pd(OAc)2 (10)

Ag2CO3 (0.25)

1,4-dioxane

100

15

17

Pd(OAc)2 (10)

Ag2CO3 (0.25)

EtOH

 80

54

18

Pd(OAc)2 (10)

Ag2CO3 (0.25)

AcOH

110

 0

19

Pd(OAc)2 (10)

Ag2CO3 (0.25)

t-AmylOH

100

40

20a

Pd(OAc)2 (10)

Ag2CO3 (0.25)

t-BuOH

 85

 0

21b

Pd(OAc)2 (10)

Ag2CO3 (0.25)

t-BuOH

 85

 0

a 1-Bromobenzene (2b) was used instead of 2a; the corresponding product was not obtained.

b 1-Chlorobenzene (2c) was used instead of 2a; the corresponding product was not obtained.

Under the optimized reaction conditions (Table [1], entries 3 and 4), the Pd-catalyzed Ag-promoted C–H arylation of 1a (1 equiv) with 1-iodo-4-methylbenzene (2a; 4 equiv) afforded product 3a through the direct bis-arylation of both 2° C(sp3)–H (endo) and bridgehead 3° C(sp3)–H bonds of the norbornane framework of 1a. Realistically, under the experimental conditions, one would expect the formation of both the mono- and bis-arylated products 4a, 4a′, and 3a (Table [1]). However, we did not observe either of the monoarylated products 4a or 4a′ under the reaction conditions shown in Table [1].

We decided to study further the reaction conditions and determine the number of equivalents of aryl iodide required to produce only the monoarylated product 4a or 4a′ (Scheme [2]).[7b] By employing 2–4 equivalents of 1-iodo-4-methylbenzene (2a) in the Pd-catalyzed C–H functionalization of substrate 1a, only the bisarylated product 3a (Scheme [2], entries 1–3) was observed. The reaction of substrate 1a with 1.5 equivalent of aryl iodide (2a) gave bisarylated product 3a (6%) and monoarylated product 4a (40%; Scheme [2], entry 4). The reaction of substrate 1a with 1.0 or 0.5 equivalent of 1-iodo-4-methylbenzene (2a) in tert-butanol selectively gave the monoarylated norbornane system 4a in 57 and 32% yield, respectively (Scheme [2], entries 5 and 6). In these reactions, we did not get the other expected product 4a′, which convincingly indicated that arylation of the 2° C(sp3)–H bond is easier than the bridgehead 3° C(sp3)–H bond of norbornanes.

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Scheme 2 Mono- and bis-C–H functionalization of 1a

We then extended the scope of this protocol by exploiting the optimized reaction conditions that provided the selective formation of the monoarylated compound 4a (Scheme [2], entry 5). We performed several reactions using a range of aryl iodides as the coupling partner in the Pd-catalyzed, auxiliary-aided selective C–H arylation of the 2° C(sp3)–H (endo) bond of the norbornane system 1a, which gave the corresponding monoarylated norbornane frameworks 4b–f in 49–73% yield (Scheme [2]) with a high degree of stereoselectivity.

The above reactions involving substrate 1a indicated that the auxiliary, 8-aminoquinoline, attached to the norbornane system assists in the Pd-catalyzed dual activation of both 2° C(sp3)–H (endo) and the bridgehead 3° C(sp3)–H bonds of substrate 1a. Under the optimized reaction conditions, the C–H arylation of other substrates 1b–h, prepared by using various substrates and auxiliaries, were ineffective (Scheme [3]). The reason for this may be that the respective auxiliaries attached to the norbornane system did not direct the C–H activation of the norbornane ring. The arylation of norbornene system 1f,[7a] which is structurally similar to the substrate 1a, did not furnish any new product under the experimental conditions. The use of 1h, which is similar to substrate 1a, in the Pd-catalyzed C–H arylation reaction also failed to afford any arylated product. We are investigating new reactions using these substrates and the results will be published in due course.

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Scheme 3 The role of the auxiliary and other bicyclic compounds

To develop other working auxiliaries attached to the norbornane framework, we then carried out Pd-catalyzed arylation of substrate 1i (endo), prepared from an auxiliary [e.g., 2-(methylthio)aniline] with various aryl iodides (Scheme [4]). By employing the optimized reaction conditions, the Pd-catalyzed selective C–H activation and arylation of an endo 2° C(sp3)–H bond of substrate 1i gave the monoarylated norbornane systems 6a–c in 32–36% yield with high stereoselectivity (Scheme [4]).[7b] The yields of the products 6a–c were lower than the products 4a–f, which is perhaps due to the difference in the abilities of the respective auxiliaries (attached to the substrates 1i and 1a) to assist the Pd-catalyzed C–H activation reactions.

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Scheme 4 Mono C–H arylation of the 2° C(sp3)–H (endo) bond of the norbornane framework of 1i

The generality and scope of this protocol involving the Pd-catalyzed, auxiliary-directed activation and direct arylation of 2° and bridgehead 3° C(sp3)–H bonds and an unprecedented C–C bond formation at the bridgehead center of the norbornane system were elaborated (Scheme [5]). Under the optimized reaction conditions, the production of a wide range bisarylated norbornane frameworks 3a–g (45–81%) and 5a–g (23–50%) from the direct arylation of 2° C(sp3)–H (endo) and bridgehead 3° C(sp3)–H bonds of substrates 1a and 1i was accomplished by employing several substituted aryl iodides containing electron-withdrawing or electron-donating groups (Scheme [5]).[7b] , [8] [9] [10] Double heterocyclic substitutions on the norbornane system 1a through direct C–H functionalization using 2-iodothiophene, successfully gave the expected product 3h (78%; Scheme [5]). All the reactions furnished the products 3a–h and 5a–g as single diastereomers through selective incorporation of various aryl groups at the endo 2° C(sp3)–H and bridgehead 3° C(sp3)–H positions of the norbornane systems 1a and 1i. The stereochemistry of representative products 4a, 3d, 5d, and 7b were assigned on the basis of X-ray crystal structure analysis (Figure [1]).[7b] , [11]

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Scheme 5 Double C–H arylation of norbornanes 1a and 1i
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Figure 1 X-ray crystal structures of products 4a, 3d, 5d and 7b

In the reactions shown in the Table [1, ]Scheme [2], and Scheme [5] (products 3a–h and 5a–g), similar aryl groups were incorporated at the endo 2° C(sp3)–H as well as at the bridgehead 3° C(sp3)–H positions of the norbornane systems 1a and 1i. Therefore, we envisaged the introduction of a different aryl group at the bridgehead carbon and examined the prospect of this unprecedented ‘bridgehead carbon substitution’ via C–H activation (Scheme [6]).[7b] To this end, we carried out a series of reactions with the aim of achieving exclusive activation of the bridgehead 3° C(sp3)–H bond and C–C bond formation at the bridgehead carbon.

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Scheme 6 C–H arylation of the bridgehead C–H bond of 4

We treated several endo substituted norbornane systems, with the generalized structure 4, with a variety of aryl iodides and heteroaryl iodide (Scheme [6]). These reactions successfully gave the respective novel bridgehead-arylated norbornane systems 7a–h (32–50%) through C–H activation of the bridgehead 3° C(sp3)–H bond followed by C–C bond formation at the bridgehead carbon. The products 7a–h were obtained in low to moderate yields, which suggested that the C–H functionalization of the bridgehead 3° C(sp3)–H bond is a relatively difficult reaction.

In summary, we have presented our work on the Pd-catalyzed concurrent activation and arylation of 2° and bridgehead 3° C(sp3)–H bonds of norbornane systems and an unprecedented ‘formation of C–C bond at the bridgehead carbon and bridgehead quaternary stereocenter via the C–H activation’. Novel bridgehead-substituted norbornane frameworks having contiguous stereocenters were assembled. Further work is in progress to demonstrate the utility of this protocol.


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Acknowledgment

We thank IISER-Mohali for funding and the NMR, HRMS and X-ray facilities of IISER-Mohali. R.P. is thankful to CSIR, New Delhi, for a fellowship.

Supporting Information

    for this article is available online at http://www.thieme-connect.com.accesdistant.sorbonne-universite.fr/ejournals/toc/synlett.
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Zoom Image
Scheme 1 Theme of this work
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Scheme 2 Mono- and bis-C–H functionalization of 1a
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Scheme 3 The role of the auxiliary and other bicyclic compounds
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Scheme 4 Mono C–H arylation of the 2° C(sp3)–H (endo) bond of the norbornane framework of 1i
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Scheme 5 Double C–H arylation of norbornanes 1a and 1i
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Figure 1 X-ray crystal structures of products 4a, 3d, 5d and 7b
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Scheme 6 C–H arylation of the bridgehead C–H bond of 4