Homologation Strategy for the Generation of 1-Chloroalkyl Radicals from Organoboranes

Article abstract of DOI:10.1021/acs.joc.5b02610

The generation of 1-bromo and 1-chloroalkyl radicals from organoboranes has been investigated. The direct approach involving the hydroboration of halogenated alkenes is impeded by partial dehalogenation taking place during the hydroboration process. An indirect method involving the generation of B-(1-chloroalkyl)catecholborane by homologation of B-alkylcatecholborane with dichloromethyllithium was developed. A reaction sequence involving a hydroboration reaction, a Matteson homologation, and a radical allylation process has been performed as a one-pot process that takes advantage of three different reactivities of organoboron species. Starting from styrene derivatives, it was possible to prepare B-(1-chloro-2-arylpropyl)catecholboranes that are excellent precursors to 1-chloro-2-arylpropyl radicals. A concise approach for the synthesis of an optically active α-methylene-γ-lactone from p-chlorostyrene has been developed on the basis of a two-step sequence involving an enantioselective hydroboration-homologation-cyclization reaction followed by a hydrolysis-lactonization process. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02610

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Article
A Homologation Strategy for the Generation of
1-Chloroalkyl Radicals from Organoboranes
Gong Xu, Monique Lüthy, Jacqueline Habegger, and Philippe Renaud
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02610 • Publication Date (Web): 21 Jan 2016
Downloaded from http://pubs.acs.org on February 1, 2016
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The Journal of Organic Chemistry
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A Homologation Strategy for the Generation of 1ꢀChloroalkyl Radicals from Orꢀ
ganoboranes
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Gong Xu, Monique Lüthy, Jacqueline Habegger, and Philippe Renaud*
University of Bern, Department of Chemistry and Biochemistry, Freiestrasse 3, CHꢀ3012 Bern
ABSTRACT. The generation of 1ꢀbromo and 1ꢀchloroalkyl radicals from organoboranes has been investigated. The direct
approach involving the hydroboration of halogenated alkenes is impeded by partial dehalogenation taking place during the
hydroboration process. An indirect method involving the generation of Bꢀ(1ꢀchloroalkyl)catecholborane by homologation of
Bꢀalkylcatecholborane with dichloromethyllithium was developed. A reaction sequence involving a hydroboration reaction, a
Matteson homologation, and a radical allylation process has been performed as a oneꢀpot process that takes advantage of
three different reactivities of organoboron species. Starting from styrene derivatives, it was possible to prepare Bꢀ(1ꢀchloroꢀ
2ꢀarylpropyl)catecholboranes that are excellent precursors to 1ꢀchloroꢀ2ꢀarylpropyl radicals. A concise approach for the
synthesis of an optically active αꢀmethyleneꢀγꢀlactone from pꢀchlorostyrene has been developed based on a twoꢀstep seꢀ
quence involving an enantioselective hydroboration–homologation–cyclization reaction followed by a hydrolysis–
lactonization process.
Introduction
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Chlorinated radicals are attractive intermediates for the preparation of functionalized molecules. The trichloromethyl radiꢀ
cal can be easily generated from tetrachloromethane and bromotrichloromethane using transition metal catalysts or radical
initiators.1ꢀ3 Polyhalogenated alkyl radicals are involved in many radical reactions. For example, Kharasch reported the free
radicalꢀmediated addition of polyhalogenated alkanes to alkenes.4,5 This reaction, however, is restricted to substrates which
contain more than two geminal halogen atoms or those that have other activating groups, such as –COOR and –CN.6,7 Simple
monohalogenated alkyl radicals are more difficult to generate. Only few reactions involving 1ꢀchloroalkyl radicals have been
reported. The reaction of geminal dichlorides with lithium aluminum hydride is known to proceed mainly via a 1ꢀchloroalkyl
radical intermediate.8 Miyano et al. reported the AIBNꢀinitiated addition of iodochloromethane to terminal alkenes to syntheꢀ
size 1ꢀchloroꢀ3ꢀiodoheptane.9 Zard and coꢀworkers described the use of αꢀchloro trifluoromethyl xanthate as a radical preꢀ
cursor for the addition to olefins.10 For the formation of 1ꢀbromoalkyl radicals, there are only few approaches involving radiꢀ
olysis of the corresponding organic bromides.11,12
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During the last decade, organoboranes such as Bꢀalkylcatecholboranes were shown to be very efficient precursors of alkyl
radicals that can be used in a wide range of radical processes.13ꢀ16 However, radicals generated from organoboranes are often
not functionalized. In this communication, we report our attempts to use Bꢀ(1ꢀhaloalkyl)catecholboranes to generate 1ꢀ
haloalkyl radicals.
Results and discussion
The hydroboration approach. The most straightforward approach for the preparation of Bꢀ(1ꢀhaloalkyl)catecholboranes
is the hydroboration of 1ꢀhaloalkenes. For instance, Elgendy disclosed two procedures for the hydroboration of 1ꢀhaloalkenes
with catecholborane. He reported excellent regioselectivity for both the neat17 and the rhodium catalyzed18 hydroboration of
simple αꢀhaloalkenes although significant quantities of the dehalogenated products were observed when prolonged heating
was employed.19 Such dehalogenation side reactions were also observed by Maddaluno,20 Brown,21 and Pasto.22ꢀ24 However,
encouraged by Elgendy's results, the preparation of Bꢀ(1ꢀhaloꢀ2ꢀmethylpropyl)catecholboranes by hydroboration of 1ꢀbromoꢀ
and 1ꢀchloroꢀ2ꢀmethylpropene (1a, 1b) was investigated under neat conditions. When a 1:1 mixture of catecholborane and
one equivalent of the haloalkene were heated at 70–90 °C for 16–20 h, a moderate conversion (<66%) and the corresponding
Bꢀ(1ꢀhaloꢀ2ꢀmethylpropyl)catecholboranes 2a and 2b were formed together with the dehalogenated product 3. Catalysis of
the hydroboration using a rhodium catalyst was examined next.18 By using 1.5 equivalents of catecholborane, a good converꢀ
sion could be achieved but significant amounts of the dehalogenated product 3 were formed with both the bromide 1a and
the chloride 1b. Attempts to optimize this reaction by modifying the degree of the oxidation of the ligand according to the
work of Burgess did not afford a significant enhancement.25 Although the Bꢀ1ꢀhalogenoalkylcatecholboranes were generated
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The Journal of Organic Chemistry
as a mixture with the corresponding nonꢀhalogenated Bꢀalkylcatecholboranes, the conversion obtained by employing the
rhodiumꢀcatalyzed hydroboration with alkene 1a was sufficient for a preliminary investigation of the reactivity of the 1ꢀ
halolalkyl radical generated from the corresponding organoboranes. The radical allylation with ethyl 2ꢀ
((phenylsulfonyl)methyl)acrylate15 was selected as benchmark reaction (Scheme 1). Addition of a small quantity of water
during the radical step was beneficial to the reaction, improving the yield by about 10%. The overall yield for the bromide 4a
was moderate (49%). However taking into account that the hydroboration was leading to the dehalogenated product 3, the
estimated yield for the radical reaction of 2a to 4a was very satisfactory (81%). For the reaction with the 1ꢀchloroꢀ2ꢀ
methylpropene 1b, the procedure of Brown ꢀ using a hydroboration with diborane in THF ꢀ gave somewhat better results
than the rhodiumꢀcatalyzed hydroboration.21 The intermediate monoalkylborane was treated with catechol to form Bꢀ(1ꢀ
chloroꢀ1ꢀmethylpropyl)catecholborane 2b. This procedure allows minimizing the formation of the dehalogenated product but
the conversion remains low (55%). Radical allylation afforded the desired chlorinated alkene 4b in 49% yield from 1b.
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Scheme 1. Oneꢀpot hydroborationꢀradical allylation of 1a and 1b.
Due to the limitation of the hydroboration of 1ꢀhaloalkenes with either catecholborane or BH3·THF, it was necessary to
develop another more efficient procedure to prepare the promising Bꢀ1ꢀhaloalkylcatecholboranes.
The Matteson homologation approach. The wellꢀestablished Matteson homologation procedure with dichloromethyllithꢀ
ium represents a very attractive approach for the synthesis of 1ꢀchloroalkylboronic esters,26,27 The homologation reaction
proceeds through an ate complex that rearranges via 1,2ꢀmigrationꢀchloride displacement to afford the corresponding 1ꢀ
chloroalkylboronic ester. Most of the reported examples of Matteson homologation involve boronates derived from aliphatic
diols such as Bꢀalkylpinacolboranes. The homologation of Bꢀalkylcatecholboranes (RBCat) with dichloromethyllithium
(LiCHCl2) was described by Matteson but did not lead to synthetic applications since under extended heating in THF the
reaction was low yielding. Better results were achieved by using vacuum pyrolysis.27 For these reasons, we decided to invesꢀ
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tigate further the LiCHCl2 mediated homologation for Bꢀalkylcatecholboranes and design a oneꢀpot process involving a subꢀ
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sequent radical reaction.
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Using the reaction conditions developed by Matteson and modified by Brown, an initial oneꢀpot process was
attempted.27,28 Preliminary studies involved the homologation of Bꢀcyclohexylcatecholborane with LiCHCl2, leading to the
putative 1ꢀchloroalkylboronate ester. The organoborane was subsequently subjected to a radical allylation reaction15 with the
allyl phenyl sulfone. Monitoring of the reaction by gas chromatography showed that a small amount (<8%) of the desired
homologated–allylated product was formed. This preliminary result demonstrated that such a oneꢀpot process is feasible but
a more detailed investigation of the homologation step was necessary. A detailed 11BꢀNMR study of the homologation reacꢀ
tion was then conducted with nꢀoctylcatecholborane 6 (Figure 1).29 The metallation of dichloromethane was performed using
either butyllithium or lithium diisopropylamide, the migration was examined under thermal condition as well as in the presꢀ
ence of ZnCl2.27,28,30,31 The cleanest reaction was obtained by generating LiCHCl2 with BuLi at –100 °C followed by addition
of nꢀoctylcatecholborane 6 (11BꢀNMR 35.9 ppm) to provide the boronate complex 7 (11.8 ppm).28 Rearrangement of boroꢀ
nate 7 to 1ꢀchlorononylboronate 8 (29.2ꢀ32.2 ppm)32 required heating at reflux temperature for 8.5 hours (see 11BꢀNMR specꢀ
tra in Figure 1).
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Figure 1. 11BꢀNMR study of the homologation of Bꢀoctylcatecholborane (6) to Bꢀ1ꢀchlorononylcatecholborane (8). nꢀ
Octylcatecholborane 6 was treated with LiCHCl2 (from nꢀBuLi and CH2Cl2) followed by heating at 65 °C. Aliquots of the
reaction mixture were diluted in C6D6 and spectra were measured at 25 °C. a) Alkylcatecholborane 6 at the outset of the reacꢀ
tion; b) boronate complex 7 just after treatment with LiCHCl2 at –100 °C and warming up to room temperature; c) rearꢀ
rangement of 7 to 8 in refluxing THF after 2.5 h; d) rearrangement of 7 to 8 in refluxing THF after 8.5 h (reaction completed).
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The Journal of Organic Chemistry
O
1
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LiCHCl2
C7H15
BCat
C7H15
B
O
THF
Li+
6 (35.9 ppm)
3
Cl
Cl
4
7 (11.8 ppm)
BCat
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C7H15
65 °C
Cl
8 (29.2–32.2 ppm)
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After having established efficient procedures for the in situ generation of Bꢀ1ꢀchloroalkylcatecholborane 8 (Scheme 2), its
utilization in a subsequent radical reaction was attempted. The radical allylation of 8 with 2ꢀmethylallyl phenyl sulfone was
initiated either with diꢀtertꢀbutyl hyponitrite33 or air.34 In order to probe further the use of Bꢀ1ꢀchloroalkylcatecholboranes in
radical reactions, the pure 1ꢀchlorohexylcatecholborane 11 was isolated according to Matteson's procedure.27 Neat hydroboꢀ
ration of 1ꢀhexene 9 with HBCat afforded Bꢀnꢀhexylcatecholborane (10) that was directly treated with LiCHCl2 to afford,
after vacuum distillation, 1ꢀchlorohexylcatecholborane 11 with a 46% isolated yield for the two steps. The radical allylation
reaction starting from isolated 11 with 2ꢀmethylallyl phenyl sulfone was then investigated (Scheme 2). Reactions were run
under the radical allylation conditions reported previously15 (dichloromethane as solvent, 40 °C) or in a 1,2ꢀdichloroethane or
chlorobenzene/N,Nꢀdimethylformamide 2.5:1 mixture at 60 °C. It was found that the polar coꢀsolvent DMF was beneficial to
the efficiency, although it was significantly slowing down the reaction at temperatures below 60 °C.35 At 60 °C, the reaction
afforded 12 in 71% yield in a 1,2ꢀdichloroethane/N,Nꢀdimethylformamide 2.5:1 mixture. A similar result was obtained when
chlorobenzene was used instead of 1,2ꢀdichloroethane. The reaction was also examined with the more reactive 2ꢀ
ethoxycarbonylallyl and 2ꢀphenylsulfonylallyl phenyl sulfones. They gave the allylated products 13 and 14 in 81 and 83%
yields, respectively. The oneꢀpot homologationꢀradical allylation sequence was examined next. The chlorinated radical preꢀ
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cursor 11 was prepared by treatment of Bꢀhexylcatecholborane 10 with LiCHCl2 (from nꢀBuLi and CH2Cl2) at –100 °C in
THF and subsequent heating at reflux overnight to ensure completion of the rearrangement. The radical allylation reaction
was run directly in THF without evaporating the solvent affording 12 in 55%. Higher yields were obtained with 2ꢀ
ethoxycarbonylallyl and 2ꢀphenylsulfonylallyl phenyl sulfones. In that case, best results were obtained by adding DMF. Unꢀ
der these conditions, product 13 was isolated in 81% yield and 14 in 66% yield.
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Scheme 2. Preparation and allylation of the Bꢀ1ꢀchloroalkylcatecholborane 11.
Finally, the scope and limitation of the oneꢀpot reaction was examined with a variety of preformed or generated in situ Bꢀ
alkylcatecholboranes. For this purpose, the ethoxycarbonylallyl phenyl sulfone was used as a trap. All results are reported in
Scheme 3. The secondary alkyl radical generated from cyclohexene (15) gave the allylated product 19 in 72% yield. Reaction
of primary, secondary and tertiary Bꢀalkylcatecholboranes generated from (–)ꢀβꢀpinene (16), (+)ꢀαꢀpinene (17) and tetraꢀ
methylethylene (18) gave also the desired products 20–22 in 32–42% yield. No attempt to optimize further this reaction was
made. Even if the yields remain modest, they are remarkable considering that three different reactions of boron derivatives
were exploited in this oneꢀpot process (hydroboration, homologation and radical reaction). The stereochemistry of the proꢀ
cess involving (–)ꢀβꢀpinene (16) and αꢀpinene (17) are in accord with expectations. The hydroboration of (+)ꢀαꢀpinene (17)
is highly stereoselective and the anionotropic rearrangement reaction proceeds with retention of configuration. In the case of
(–)ꢀβꢀpinene (16), the hydroboration affords a 5:1 mixture of diastereoisomers. The formation of the last stereogenic center
(alpha to the chlorine atom) takes place during the radical reaction and it was not stereoselective in the case of (–)ꢀβꢀpinene
(product 20). However, a modest stereocontrol (dr 2:1) was obtained in the case of (+)ꢀαꢀpinene (product 21).
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Scheme 3. Scope and limitations of the hydroborationꢀhomologationꢀallylation process involving aliphatic alkenes.
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Reactions involving homologation of styrene derivatives. Styrene derivatives are very attractive substrates for the hoꢀ
mologation reaction since they are particularly suitable for the development of an asymmetric version by taking advantage of
highly efficient enantioselective hydroboration reactions.36 4ꢀMethoxystyrene (23) was selected as a model substrate for the
optimization of the reaction conditions. It was hydroborated with 1.1 equivalents of catecholborane (HBCat) in THF at room
temperature using RhCl(PPh3)3 as the catalyst.25,37 Under these conditions, modest yield and regioselectivity were obtained
(Table 1, Entry 1). Addition of triphenylphosphine25 increased both the regioselectivity of hydroboration (≥98%) as well as
the overall yield (Table 1, Entry 2). The Bꢀ(1ꢀarylethyl)catecholboranes were then added to a solution of dichloromethyllithiꢀ
um in THF at –100 °C. Heating under reflux for 16 h afforded the desired Bꢀ(1ꢀchloroꢀ2ꢀarylpropyl)catecholboranes that
were treated at 70 °C with ethyl 2ꢀ((phenylsulfonyl)methyl)acrylate and diꢀtertꢀbutylhyponitrite as a radical initiator and
DMF as a cosolvent. The reactions afforded the desired products 30–36 in 65–76% yield and a modest diastereoselectivity
(syn/anti 2.4:1) (Table 1, Entries 2–8).
Table 1. Oneꢀpot hydroborationꢀhomologationꢀallylation of styrene derivatives.
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Entry
Additive
–
Product (R)
30 (OMe)
30 (OMe)
31 (H)
Ratioa
86:14
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
Yieldb,c
1
2
3
4
5
6
7
8
1
2
49%b
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
68%b (63%)c
73%b (67%)c
71%b
3
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4
32 (F)
5
33(CF3)
34(Me)
65%b
6
71%b
7
35 (Ph)
65%b (64%)c
76%b (63%)c
8
36 (Cl)
aRatio of Markovnikov/antiꢀMarkovnikov products. bGC yield of the Markovnikov product. cIsolated yield.
The relative syn configuration of the major diastereomer of 35 was determined by Xꢀray crystallographic analysis of the
dinitrobenzoate 3738 (Figure 2) that was prepared from 35 (major diastereomer) via DIBALH reduction followed by esterifiꢀ
cation with 3,5ꢀdinitrobenzoyl chloride. The stereochemical outcome of the radical process is rationalized by considering a
FelkinꢀAnh type transition state similar to the one proposed for 1ꢀsilyloxyꢀsubstituted radicals and related radicals39ꢀ42 (Figꢀ
ure 2).
Figure 2. Xꢀray single crystal structure of synꢀ37 derived from the major diastereomer of 35 (50% probability ellipꢀ
soids). FelkinꢀAnh model rationalizing the formation of the synꢀdiastereomer.
Me
Cl
Ph
O
NO2
O
syn-37
NO2
R
Me
SO2Ph
H
H
Me
Cl
R'
Ar
Cl
syn
Ar
favored attack
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The optimized oneꢀpot procedure starting from styrene was next examined with different allyl sulfones (Scheme 4). 1ꢀ
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Chloroꢀ2ꢀarylpropyl radicals possess a reactivity very similar to simple alkyl radicals.15 Sulfones bearing electron withdrawꢀ
ing groups, such as a sulfonyl group (Y = PhSO2) and an ester group (Y = CO2Et), afforded the corresponding allylated
products in good yields. The lower yield observed for 41 (36%) is due to double addition to the allylic bisꢀsulfone. The obꢀ
served diastereoselectivities are similar to the one reported in Table 1 (syn/anti 2.3–2.9:1).
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Scheme 4. Homologationꢀallylation of styrene with different allyl sulfones (isolated yields in parenthesis).
To illustrate the synthetic potential of the method, the conversion of the γꢀchloro esters 30–32 to αꢀmethyleneꢀγꢀlactones
was investigated (Scheme 5).43 Treatment of esters 31 and 32 with silver nitrate according to Carlson's procedure44 did not
afford any product and the starting material was recovered unchanged. Ester 30 proved to be more reactive under these conꢀ
ditions but the reaction afforded a mixture of the desired γꢀlactone 43 (9%, 1:1 mixture of diastereomers) together with the δꢀ
lactone 44 (16%).
Scheme 5. Silver (I)ꢀmediated lactonization of γꢀchloroesters 30–32.
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The structure of 44 was confirmed by Xꢀray single crystal structure analysis (Figure 3).45 The formation of 44 may be raꢀ
tionalized by the formation of a secondary carbocation intermediate I that isomerizes via an ethylenebenzenium intermediate
II to a new secondary carbocation III. Cyclization of I is expected to be stereorandom since the chiral center is outside the γꢀ
lactone ring. In contrast, cyclization of III should afford the δꢀlactone 44 with a good trans stereocontrol since the stereogenꢀ
ic center is in the lactone ring.
Figure 3. Xꢀray single crystal structure of 44 and mechanistic rationalization for its formation (50% probability ellipꢀ
soids).
44
Me
I
43
MeO
O
OEt
CO2Et
II
HO
OEt
MeO
44
III
MeO
In order to avoid a carbocationic pathway, the lactonization was performed via a twoꢀstep procedure. The γꢀchloroester 31
(syn/anti 2.4:1) was treated with lithium hydroxide to afford the γꢀhydroxyacid 45 that lactonized upon heating in benzene
and azeotropic removal of water with a DeanꢀStark apparatus (Scheme 6, top).46 Inversion of the stereochemistry at the γꢀ
center is taking place during this transformation (see below) and the lactone 46 was obtained in 85% yield as a syn/anti 1:2.4
mixture. Based on this successful lactonization procedure, the preparation of the optically active αꢀmethyleneꢀγꢀlactone 48
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involving a oneꢀpot asymmetric hydroborationꢀhomologationꢀradical allylation procedure was examined (Scheme 6, bottom).
The enantioselective hydroboration of pꢀchlorostyrene 29 with catecholborane was performed according to Hayashi's
procedure in the presence of a catalytic amount of Rh(COD)2BF4 and (+)ꢀBINAP.47 The desired chloroester 36 was obtained
in 57% yield and moderate diastereoselectivity (syn/anti 2.3:1). The level of enantioselectivity and the absolute stereochemꢀ
istry of the hydroboration step were determined by converting the intermediate boronate 47 into the known (R)ꢀ1ꢀ(4ꢀ
chlorophenyl)ethanol48 where the absolute configuration was determined by comparison of the sign of the optical rotation
and analysis by GC on a chiral column. The measured ee (92% ee) is in good agreement with the reported value of 91% ee.47
Treatment of the chloroester 36 with lithium hydroxide in THF/H2O (5:1) at 60 °C gave the intermediate hydroxy acid that
was used without purification for the lactonization step. Lactone 48 was obtained in 80% from 36. The enantiomeric purity
of the two diastereomers was determined to be 92% by GC analysis on a chiral column. The major diastereomer of 48 was
recrystallized from a mixture of dichloromethane and pentane. Its relative configuration was confirmed by Xꢀray crystalloꢀ
graphic analysis (Scheme 6).49
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Scheme 6. Synthesis of αꢀmethyleneꢀγꢀlactones 46 and 48. Xꢀray crystal structure of the major diastereomer (S)ꢀ5ꢀ
((R)ꢀ1ꢀ(4ꢀchlorophenyl)ethyl)ꢀ3ꢀmethylenedihydrofuranꢀ2(3H)ꢀone (48) (50 % probability ellipsoids). a) Ee was deterꢀ
mined after conversion to the corresponding alcohol via treatment with H2O2/NaOH.
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Me
Me
1
LiOH
2
3
4
5
6
7
OH CO2H
45
Cl
CO2Et THF, H2O
60 °C
31 (syn/anti 2.4:1)
Me
reflux
benzene
O
8
O
9
46 85% (syn/anti 1:2.4)
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a) HBCat (1.1 eq)
Rh(COD)2BF4 (1 mol%)
(+)-BINAP (1.5 mol%)
Me
BCat
Cl
Cl
29
47 (92% ee)a
b) CH2Cl2 (1.4 eq), n-BuLi (1.2 eq)
–100 °C to reflux, 16 h
c) 2-((phenylsulfonyl)methyl)acrylate (3 eq)
t-BuON=NOt-Bu (init.)THF/DMF, reflux
Me
Cl
CO2Et
Cl
(5R)-36 57%, syn/anti 2.3:1
Me
d) LiOH
e) C6H6 80 °C
O
80%
Cl
O
(5S,1'R)-48
92% ee (major)
[+ (5R,1'R)-48
92% ee (minor)]
dr 2.3:1
(5S,1'R)-48
Hydroborationꢀhomologationꢀradical reactions. To demonstrate further the synthetic potential of this method, the hyꢀ
droboration–homologation reaction was coupled with a series of radical processes beyond the above mentioned allylation
reactions (Scheme 7). For instance, conjugate addition to methyl vinyl ketone (BrownꢀNegishi reaction) leading to 49 was
examined. Using the oneꢀpot procedure used for the above radical allylation, we observed a low yield (35%, dr 2.7:1) and
partial polymerization of the trap. By modifying the reaction condition and using the optimized condition developed for the
conjugate addition to vinyl ketone,50 i.e. by initiating the radical reaction with oxygen in a CH2Cl2/H2O/DMPU solvent mixꢀ
ture, a yield of 50% for the formation of 49 was obtained. Water was added to the reaction mixture in order to hydrolyze the
excess of catecholborane as well as the boron enolate formed during the reaction. The presence of DMPU (= 1,3ꢀdimethylꢀ
3,4,5,6ꢀtetrahydroꢀ2ꢀpyrimidinone) as an additive has a positive effect on the yield as already observed in other boron based
radical reactions.50,51,52 Recently, our group reported a mild radical procedure for the protodeboronation of organoboranes
with tertꢀbutylcatechol (TBC).53 Initial attempt to apply this procedure for the protodeboronation of Bꢀ(1ꢀchloroꢀ2ꢀ
phenylpropyl)catecholborane faced an unexpected problem. A rapid oxidation of the tertꢀbutylcatechol to the corresponding
oꢀquinone was observed. Since a possible activation of molecular oxygen by the Wilkinson’s catalyst was believed to be reꢀ
sponsible for this oxidation, 1,4ꢀdithiane was added to the reaction mixture before running the radical protodeboronation to
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poison the rhodium catalyst. The best yield was obtained when tetrahydrofuran was replaced by 1,2ꢀdichloroethane for the
radical process. Under these conditions, the desired product 50 was obtained in a 55% yield (Scheme 7). The whole process
corresponds to a regioselective chloromethylation of styrene. The chlorination with benzenesulfonylchloride was investigatꢀ
ed next.54 In tetrahydrofuran at refluxing temperature, the dichlorinated product 51 was obstained in 57% yield. Finally, the
cyanation reaction with pꢀtoluenesulfonyl cyanide was examined (Scheme 7).55 The αꢀchloronitrile 52 was obtained in 65%
when the reaction was run in tetrahydrofuran with 5 equivalent of pꢀTolSO2CN. 56,57
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Scheme 7. Hydroborationꢀhomologationꢀradical reactions with miscellaneous radical traps.
Conclusions. The generation of 1ꢀchlorinated alkyl radicals from organoboranes was investigated according to two differꢀ
ent strategies: a) the direct hydroboration of chlorinated alkenes was found to be unsuitable due to the partial dehalogenation
taking place during the hydroboration process; b) a Matteson type homologation strategy involving Bꢀalkylcatecholboranes
with lithiated dichloromethane proved to work efficiently for the generation of 1ꢀchloroalkyl radicals. The generation of 1ꢀ
chloroꢀ2ꢀarylpropyl radicals from styrene via a hydroboration–homologation–homolytic substitution at boron by heteroatom
centered radicals was examined in more detail. Five different types of radical reactions, i.e. allylation, conjugate addition,
cyanation, chlorination, and hydrogen atom transfer have been successfully performed demonstrating that 1ꢀhalogenoalkyl
radicals behave very similarly to previously investigated alkyl radicals. These oneꢀpot reaction sequences take advantage of
three of the most important reactions reported for organoboranes, namely hydroboration, Matteson homologation, and finally
radical reactions. Interestingly, an asymmetric version of this reaction is possible by incorporating an enantioselective hyꢀ
droboration process as demonstrated by the short synthesis of an optically active αꢀmethylenelactone.43
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EXPERIMENTAL SECTION
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9
General Information: All reactions were performed under a nitrogen atmosphere in ovenꢀdried (170 ºC) flasks and standard
precautions against moisture were taken. Unless mentioned, commercial reagents were used as received. Catecholborane was
distilled prior to use. Dichloromethane (CH2Cl2), benzene, diethylether (Et2O) and tetrahydrofuran (THF) were filtered over
a column of dried alumina under a positive pressure of argon. N,Nꢀdimethylformamide (DMF) was bought dry (over molecuꢀ
lar sieves) from Fluka and used as received. Dichloroethane (DCE) and chlorobenzene (PhCl) were distilled over CaH2 under
nitrogen atmosphere. Diisopropylamine was distilled over CaH2 under nitrogen atmosphere and stored on KOH pellets. The
commercial solution of nꢀbutyllithium (hexane, 2.5 M) was titrated prior to use. Silica gel 60 Å (40ꢀ63 ꢁm) was used for
flash column chromatography (FC). Basic aluminum oxide was used for short filtrations. 1H and 13CꢀNMR spectra were recꢀ
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orded on spectrometers operating at 300 MHz for H and 75 MHz for 13C at 25 °C. 11BꢀNMR spectra were recorded on a
spectrometers operating at 128 or 160 MHz at 25 °C. Chemical shifts are reported in units of δ (ppm) using residual CHCl3 (δ
= 7.26 for 1HꢀNMR spectra and δ = 77.16 for 13CꢀNMR spectra), or C6H6 (δ = 7.16 for 1HꢀNMR spectra and δ = 128.06 for
13CꢀNMR spectra) as the internal standard. Chemical shifts of 11B spectra are given relative to BF3·OEt2. The following abꢀ
breviations were used to explain the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, sept = septet, m = multiꢀ
plet, br = broad. Infrared spectra were recorded neat or as film and are reported in wave numbers (cmꢀ1). Lowꢀresolution
mass spectra (LRMS) were recorded in EI mode at 70 eV or were taken from GCꢀMS (EI mode at 70 eV; GCꢀcolumn: Maꢀ
chereyꢀNagel Optima Delta3, 20 m) analysis. High resolution mass spectrometry using electrospray ionization (ESIꢀHRMS)
or on a triple stage quadrupole instrument equipped with a combined Atmospheric Pressure Ion (API) source. High resoluꢀ
tion mass spectrometry using electron ionization (EIꢀHRMS) were performed on a doubleꢀfocusing magnetic sector mass
spectrometer; mass spectra were measured in electron impact (EI) mode at 70 eV, with a source temperature of 200 °C, an
acceleration voltage of 5 kV, and a resolution of 10’000; the instrument was scanned between m/z 30 und 900 at 2 scan min–
1; perfluorokerosene (PFK) served for calibration. GCꢀanalyses were measured on a MachereyꢀNagel Optima Delta3 column
(20 m) using a constant flow (1.4 mL/min) of helium as carrier gas. Melting points (uncorrected) were measured on a Büchi
Bꢀ545 apparatus.
The hydroboration approach
Neat hydroboration of 1a and 1b. The reported procedure17 was followed with slight modifications (stoichiometry) in variꢀ
ous scales (1ꢀ30 mmol). A mixture of catecholborane and αꢀhaloalkene was either heated to reflux temperature in an appaꢀ
ratus with cooling finger or with a conventional reflux condenser, or it was heated to 80 °C in a sealed tube under nitrogen
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atmosphere. The reaction was monitored by HꢀNMR and 11BꢀNMR. Characteristic peaks for αꢀhalo alkylboronates 2a and
1
1
2
3
2b and for Bꢀ(2ꢀmethylpropyl)catecholborane 3 are in accordance with literature.17
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9
Rhodium catalyzed hydroboration of 1a and 1b. The reported procedure18 was followed with slight modifications (stoiꢀ
chiometry, catalyst loading, concentration). To a solution of RhCl(PPh3)3 in benzene was added the 1ꢀhaloalkene and cateꢀ
cholborane. The reaction was stirred at rt and monitored by 1HꢀNMR and 11BꢀNMR.
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Procedure A: Ethyl 4ꢀbromoꢀ5ꢀmethylꢀ2ꢀmethylenehexanoate (4a) and ethyl 5ꢀmethylꢀ2ꢀmethylenehexanoate (5). To a
solution of RhCl(PPh3)3 (0.9 mg, 1 ꢁmol) in dry benzene (340 ꢁL) was added 1ꢀbromoꢀ2ꢀmethylpropene 1a (200 ꢁL, 2.0
mmol) and catecholborane (320 ꢁL, 3.0 mmol). The mixture was stirred at rt for 36 h. The reaction was then diluted with
benzene (1.66 mL) and an aliquot was taken by syringe for NMR analysis in C6D6. The reaction mixture was split into two
(A and B) and each portion was added to a new reaction flask containing ethyl 2ꢀ((phenylsulfonyl)methyl)acrylate (636 mg,
2.5 mmol). Diꢀtertꢀbutylhyponitrite (10 mg, 0.06 mmol) was added to both reaction mixtures and water (200 ꢁL) was added
to only one of them (B). The reaction mixtures were heated to reflux for 1 h and then a second portion of diꢀtertꢀ
butylhyponitrite (10 mg, 0.06 mmol) was added and the reaction were heated for 1 h before cooling down to rt. The black
reaction mixtures were directly loaded on a silica gel column for purification. FC (pentane/Et2O 100:0–99:1) afforded a mixꢀ
ture of 4a and 5 (146 mg for B and 125 mg for A) as a colorless (B) and brownish (A) liquid, respectively. The ratio of 4a/5
was determined by NMR, leading to calculated yields of 4a (121 mg, 49%) and 5 (25 mg, 15%) for B and 4a (100 mg, 40%)
and 5 (25 mg, 15%) for A. Analytically pure samples of 4a and 5 were obtained by partial separation from the mixture with a
second FC (cyclohexane).
4a: 1HꢀNMR (300 MHz, CDCl3): δ 6.30 (m, 1H), 5.69 (m, 1H), 4.26ꢀ4.18 (m, 3H), 2.91 (ddd, J = 14.6, 4.2, 0.9 Hz, 1H), 2.69
(dd, J = 14.6, 9.8 Hz, 1H), 1.90 (dsept., J = 6.6, 3.3 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.05 (d, J = 6.7 Hz, 3H), 1.01 (d, J =
6.7 Hz, 3H); 13CꢀNMR (100 MHz, CDCl3): δ 166.8, 137.6, 128.1, 63.8, 61.0, 39.8, 34.5, 21.1, 18.0, 14.3; IR: 2965, 1710,
1180, 1145 cmꢀ1; EIꢀMS (GCꢀMS): m/z (% relative intensity): 235 (0.06) [M+ꢀmethyl], 233 (0.06) [M+ꢀmethyl], 205 (1.2),
203 (1.2), 195 (3.8), 193 (3.8), 169 (34), 123 (100), 95 (61), 81 (13), 67 (22), 55 (25); ESIꢀHRMS: calcd for C10H18O2Br
[M+H]+: 249.0485; found: 249.0486.
1
5: HꢀNMR (300 MHz, CDCl3): δ = 6.08 (m, 1H), 5.47 (m, 1H), 4.23ꢀ4.14 (m, 2H), 2.29ꢀ2.24 (m, 2H), 1.55 (sept., J = 6.6
Hz, 1H), 1.36ꢀ1.24 (m, 2H), 1.27 (t, J = 7.1 Hz, 3H), 0.88 (d, J = 6.6 Hz, 6H); 13CꢀNMR (75 MHz, CDCl3): δ = 167.7, 141.5,
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124.0, 60.6, 37.8, 29.9, 27.9, 22.6 (2C); EIꢀLRMS (GCꢀMS): m/z (%): 170 (1) [M+], 155 (3), 127 (13), 115 (100), 109 (25),
1
2
3
99 (22), 87 (41), 69 (38), 56 (61); ESIꢀHRMS: calcd for C10H19O2 [M+H]+: 171.1380; found: 171.1378.
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Procedure B: Ethyl 4ꢀchloroꢀ5ꢀmethylꢀ2ꢀmethylenehexanoate (4b). At 0 °C, a commercial solution of BH3 ·THF (1 M in
THF, 5 mL, 5 mmol) was added to a solution of 1b (500 ꢁL, 5.0 mmol) in THF (12 mL) and the mixture was stirred at 0 °C
for 30 min. Then, a solution of catechol (550 mg, 5 mmol) in THF (5 mL) was added over a period of 5 min via cannula. A
small flow of N2 was maintained to remove H2. It was stirred at 0 °C for 2 h until H2ꢀevolution stopped completely. This soꢀ
lution containing 2b was divided in two equal part and immediately used for the radical reaction. Half of the solution of 2b
was added to ethyl 2ꢀ((phenylsulfonyl)methyl)acrylate (1.59 g, 6.25 mmol). Diꢀtertꢀbutylhyponitrite (22 mg, 0.125 mmol)
was added and the mixture was heated under reflux. After 1 h, a second portion of diꢀtertꢀbutylhyponitrite (22 mg, 0.125
mmol) was added and the reaction mixture was heated for 1 h, cooled down to rt and the mixture was extracted with Et2O
and washed with water and brine. The organic layer was dried over Na2SO4, filtered and solvents were removed under reꢀ
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duced pressure. FC (pentane/Et2O 98:2) afforded 4b (250 mg, 49%) as a colorless liquid. HꢀNMR (300 MHz, CDCl3): δ
6.29 (d, J = 1.2 Hz, 1H), 5.69 (m, 1H), 4.21 (dq, J = 7.1, 0.5 Hz, 2H), 4.07 (dt, J = 9.9, 3.7 Hz, 1H), 2.86 (ddd, J = 14.4, 3.7,
1.0 Hz, 1H), 2.52 (ddd, J = 14.4, 9.9, 0.7 Hz, 1H), 2.00 (dsept., J = 6.7, 3.7 Hz, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.05 (d, J =
6.7 Hz, 3H), 1.01 (d, J = 6.7 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3): δ 166.8, 137.1, 128.1, 67.9, 60.9, 38.9, 34.3, 20.0, 17.0,
14.3; IR: 2967, 1712, 1200, 1149 cmꢀ1; EIꢀMS (GCꢀMS): m/z (%): 205 (0.05) [M+], 189 (0.6), 169 (84), 149 (31), 123 (100),
95 (54), 86 (30), 56 (63), 55 (53); ESIꢀHRMS: calcd for C10H18O2Cl [M+H]+: 205.0995; found: 205.0990.
The homologation approach
BꢀnꢀOctylcatecholborane (6). The mixture of 1ꢀoctene (6.3 mL, 40 mmol) and catecholborane (2.1 mL, 20 mmol) was
stirred in a sealed tube at 100 °C for 16 h. The mixture was then added via cannula to a twoꢀneck flask fitted with two inlet
tabs. The excess of 1ꢀoctene was removed under high vacuum (0 °C to 35 °C over 5 h). The disappearance of the olefinic
1
protons was monitored by HꢀNMR. The boronate 6 (colorless liquid) was stored under N2 in the fridge and used without
1
further purification. HꢀNMR (300 MHz, C6D6): δ 7.07ꢀ7.01 (m, 2H), 6.83ꢀ6.77 (m, 2H), 1.62ꢀ1.52 (m, 2H), 1.33ꢀ1.20 (m,
10H), 1.18ꢀ1.12 (m, 2H), 0.91ꢀ0.87 (m, 3H); 13CꢀNMR (75 MHz, C6D6): δ 148.9, 122.7, 112.5, 32.6, 32.3, 29.8, 29.6, 24.1,
23.1, 14.4, 11.0 (br, CꢀB); 11BꢀNMR (160 MHz, C6Cl6): δ 35.9.
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Testing of procedures for the homologation of 10 monitored by H- and 11B-NMR. All samples for NMR analysis were preꢀ
pared as follows: an aliquot (50–100 ꢁL) of the reaction mixture was taken by syringe and diluted in degassed C6D6 in a
dried NMR tube with septumꢀcap under N2. Small variations in the chemical shift of the homologated product 8 were obꢀ
served, which were attributed to complexation of the boron atom to the amine and/or ZnCl2.
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a) A solution of dichloromethane (150 ꢁL, 2.4 mmol) in THF (5 mL) was cooled to –100 °C. n-BuLi (2.1 M in hexane, 1 mL,
2.1 mmol) was added to this cold solution by syringe with preꢀcooling (the solution was allowed to run down the cold wall of
the reaction flask). It was stirred for 5 min at –100 °C (EtOH cooling bath) and then a solution of octylcatecholborane 6 (464
mg, 2.0 mmol) in Et2O (1.2 mL) was added. Precipitation of borate complex 7 occurred instantaneously. The bath was then
warmed up from –100 °C to about –60 °C over 15 min by adding EtOH to the cooling bath until stirring was possible again.
Then the bath was removed and the white slurry was allowed to warm up to rt, while turning into a dark yellow solution.
After stirring at rt for 2 h, a first NMR was measured. The reaction mixture was then heated at 65 °C for 2.5 h and another
aliquot for NMR analysis was taken. It was further heated at 65 °C for 6 h and then analysed again by NMR revealing clean
formation of 8 (29.7 ppm).
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b) To a solution of diisopropylamine (650 ꢁL, 4.62 mmol) in THF (2 mL) at –78 °C was slowly added n-BuLi (2.3 M in hexꢀ
ane, 2.0 mL, 4.6 mmol). It was warmed up to 0 °C and stirred for 10 min. After cooling down to –65 °C, the solution was
added dropwise via cannula to a solution of dichloromethane (300 ꢁL, 4.62 mmol) and octylcatecholborane 6 (894 mg, 3.85
mmol) in THF (4.6 mL) at –5 °C. The orange solution was then stirred at –5 °C for 30 min and an aliquot was analyzed by
NMR. The reaction mixture was heated at 65 °C for 1.5 h (NMR) and additionally for 3 h. At that time, NMR analysis
showed almost clean formation of 8 (29.2 ppm).
c) Same procedure as for procedure 1 until warming up to –60 °C, starting from 6 (464 mg, 2 mmol). At –60 °C a freshly
prepared solution of ZnCl2 (2 M in Et2O, 700 ꢁL, 1.4 mmol) was added and the mixture was allowed to warm up overnight
while stirring and a first aliquot was analyzed by NMR. The reaction mixture was then heated at 65 °C for 1 h (NMR) and
additionally for 1.5 h. At that time, NMR analysis showed clean formation of 8 (31.8 ppm).
d) Same procedure as procedure 2 until stirring at –5 °C for 30 min, starting from 6 (894 mg, 3.85 mmol). The orange soluꢀ
tion was then added via cannula to a suspension of dried and powdered ZnCl2 in THF (1 mL) at –5 °C. The initially white
mixture turned into a brown solution, which was stirred at rt overnight. An aliquot was analyzed by NMR and showed clean
formation of 8 (32.2 ppm).
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BꢀnꢀHexylcatecholborane (10). Prepared by the same procedure as 6, starting from 1ꢀhexene 9 (7.5 mL, 60 mmol). The exꢀ
cess of 1ꢀhexene was removed under vacuum. The resulting crude boronate 10 (7.04 g, 86%) was stored as a yellowish liquid
under N2 in the fridge. 1HꢀNMR (300 MHz, C6D6): δ 7.07ꢀ7.01 (m, 2H), 6.83ꢀ6.77 (m, 2H), 1.60ꢀ1.50 (m, 2H), 1.33ꢀ1.19 (m,
6H), 1.16ꢀ1.11 (m, 2H), 0.88ꢀ0.84 (m, 3H); 13CꢀNMR (75 MHz, C6D6): δ 148.9, 122.7, 112.5, 32.3, 32.0, 24.1, 23.0, 14.3,
11.0 (br, CꢀB).
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Bꢀ(1ꢀChloroꢀ1ꢀhexyl)catecholborane (11). Prepared according to literature procedure27 with minor modifications. In a twoꢀ
neck flask with a distillation top part and an inlet tab, a solution of dichloromethane (1.22 mL, 19.1 mmol) in THF (35 mL)
was cooled down to –100 °C (EtOH cooling bath). n-BuLi (2.09 M in hexane, 8 mL, 16.7 mmol) was added to this cold soluꢀ
tion by syringe with preꢀcooling (the solution was allowed to run down the cold wall of the reaction flask). The solution was
stirred for 5 min at –100 °C (EtOH cooling bath) and then a solution of crude hexylcatecholborane 10 (3.25 g, 15.9 mmol) in
THF (11 mL) was added. Precipitation of the borate complex occurred instantaneously. The reaction mixture was warmed up
from –100 °C to about –60 °C over 10 min to allow stirring. The cooling bath was removed and the white slurry was allowed
to warm up to rt, while turning into a brown solution. THF was evaporated by flushing the flask with a light flow of N2. The
brown solid residue was placed in a distillation apparatus under vacuum (10–2 mbar) and heated in an oil bath at 130 °C.
Melting of the residue was observed. Distillation (bp 90 °C, 10ꢀ2 mbar) afforded the pure boronate 11 (2.13 g, 53%; 46% over
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two steps) that was stored in a glove box. HꢀNMR (300 MHz, C6D6): δ 7.02ꢀ6.96 (m, 2H), 6.81ꢀ6.74 (m, 2H), 3.62 (t, J =
7.4 Hz, 1H), 1.93ꢀ1.79 (m, 2H), 1.49ꢀ1.26 (m, 2H), 1.23ꢀ1.07 (m, 6H), 0.86ꢀ0.82 (m, 3H); 13CꢀNMR (75 MHz, C6D6): δ
148.4, 123.4, 113.0, 42.2 (br), 34.4, 31.9, 29.1, 27.5, 22.9, 14.3; 11BꢀNMR (160 MHz, C6Cl6): δ 32.7.
Procedure C and D. Radical allylation of 1ꢀchloroboronate 11 with various allyl sulfones. A solution of boronate 11 (202
mg, 0.8 mmol) in solvent (800 ꢁL; C: CH2Cl2; D: PhCl/DMF 2.5:1) was added via cannula to a solution of the sulfone (2.4
mmol) in solvent (800 ꢁL; C: CH2Cl2; D: PhCl/DMF 2.5:1). Then, diꢀtertꢀbutylhyponitrite (4.0 mg, 0.024 mmol) was added
and the reaction was heated for 2–4 h at 40 °C (C) or 60 °C (D). Every 1 h, a further portion of diꢀtertꢀbutylhyponitrite (4.0
mg, 0.024 mmol) was added. After cooling down to rt, the crude product was purified by FC.
4ꢀChloroꢀ2ꢀmethyldecꢀ1ꢀene (12). (a) According to Procedure C starting from 11 (202 mg, 0.80 mmol) in CH2Cl2 (800 ꢁL)
and (2ꢀmethylallylsulfonyl)benzene (471 mg, 2.4 mmol). The reaction was stopped after 2 h. FC (cyclohexane) afforded 12
(86 mg, 57%) as a colorless liquid containing traces of unknown impurities (53% estimated yield). Second FC (cyclohexane)
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gave analytically pure material for characterization and GC calibration. HꢀNMR (300 MHz, CDCl3): δ 4.85 (m, 1H), 4.79
(m, 1H), 4.03 (dtd, J = 8.5, 7.1, 4.1 Hz, 1H), 2.45 (d, J = 7.1 Hz, 2H), 1.80ꢀ1.26 (m, 10H), 1.75 (s, 3H), 0.91ꢀ0.87 (m, 3H);
13CꢀNMR (75 MHz, CDCl3): δ = 141.9, 113.6, 61.3, 47.2, 38.3, 31.9, 29.0, 26.5, 22.7, 22.3, 14.2; IR: ν (cmꢀ1) 2927, 2858,
1455, 893; EIꢀLRMS (GCꢀMS): m/z (%): 188 (0.2) [M+], 153 (6.4), 109 (6.6), 97 (17), 81 (24), 69 (53), 56 (100); EIꢀHRMS:
calcd for C11H21Cl [M+]: 188.1332; found: 188.1333.
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Ethyl 4ꢀchloroꢀ2ꢀmethylenedecanoate (13). (a) According to Procedure C starting from 11 (202 mg, 0.80 mmol) in CH2Cl2
(800 ꢁL) and 2ꢀethoxycarbonylallyl phenyl sulfone (610 mg, 2.4 mmol). The reaction was stopped after 2 h. FC (pentane to
pentane/Et2O 98:2) afforded 13 (160 mg, 81%) as a colorless liquid. 1HꢀNMR (300 MHz, CDCl3): δ 6.29 (d, J = 1.3 Hz, 1H),
5.68 (m, 1H), 4.21 (dq, J = 7.1, 0.5 Hz, 2H), 4.14ꢀ4.05 (m, 1H, CHꢀCl), 2.82 (ddd, J = 14.3, 4.4, 1.0 Hz, 1H), 2.56 (ddd, J =
14.3, 9.0, 0.6 Hz, 1H), 1.82ꢀ1.64 (m, 2H), 1.60ꢀ1.25 (m, 8H), 1.30 (t, J = 7.1 Hz, 3H), 0.90ꢀ0.85 (m, 3H); 13CꢀNMR (75
MHz, CDCl3): δ 166.8, 137.0, 128.3, 61.7, 61.0, 41.6, 38.5, 31.8, 28.9, 26.5, 22.7, 14.3, 14.2; IR: 2928, 1713, 1195, 1146 cmꢀ
1; EIꢀMS (GCꢀMS): m/z (%): 247 (0.15) [M+], 211 (53), 165 (23), 149 (41), 137 (100), 121 (31), 111 (36), 95 (67), 81 (87),
69 (69), 55 (99); ESIꢀHRMS: calcd for C13H24O2Cl: 247.1459 [M+H]+; found: 247.1463.
[(3ꢀChloroꢀ1ꢀmethylenenonyl)sulfonyl]benzene (14). According to Procedure D starting from 11 (177 mg, 0.7 mmol) in
chlorobenzene (500 ꢁL) and 2ꢀphenylsulfonylallyl phenyl sulfone (677 mg, 2.1 mmol) in DMF (200 ꢁL). The reaction was
stopped after 4 h. FC (pentane/Et2O = 85:15) afforded 14 (184 mg, 83%) contaminated by PhSO2SPh (14 mg) as a colorless
liquid. 1HꢀNMR (300 MHz, CDCl3): δ 7.89ꢀ7.86 (m, 2H), 7.67ꢀ7.61 (m, 1H), 7.58ꢀ7.52 (m, 2H), 6.48 (s, 1H), 5.95 (m, 1H),
4.01ꢀ3.93 (m, 1H), 2.72 (ddd, J = 15.8, 4.5, 1.0 Hz, 1H), 2.55 (dd, J = 15.8, 9.2 Hz, 1H), 1.74ꢀ1.55 (m, 2H), 1.50ꢀ1.18 (m,
8H), 0.90ꢀ0.85 (m, 3H); 13CꢀNMR (75 MHz, CDCl3): δ 146.6, 138.8, 133.8, 129.4, 128.4, 127.2, 60.1, 39.1, 38.3, 31.7, 28.7,
26.3, 22.6, 14.1; IR: 2927, 2858, 1446, 1305, 1137, 1082, 746, 687 cmꢀ1; EIꢀMS (GCꢀMS): m/z (%): 279 (10) [M+ꢀCl], 217
(11), 182 (11), 143 (100), 137 (64), 125 (96), 95 (46), 81 (52), 77 (59), 67 (40), 55 (64); ESIꢀHRMS: calcd for
C16H23O2ClNaS [M+Na]+: 337.0999; found: 337.1006.
Procedure E. Oneꢀpot hydroboration–homologation–radical allylation reaction. Preparation of the B-
alkylcatecholborane. A mixture of the alkene (2.0 mmol) and catecholborane (1.0 mmol) was stirred at 100 °C for 20 h. The
mixture was cooled down to rt and diluted with THF (0.5 mL). This solution was used as it stands for the homologation proꢀ
cedure. Homologation reaction. A solution of dichloromethane (80 ꢁL, 1.21 mmol) in THF (2 mL) was cooled down to –100
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°C (EtOH cooling bath). n-BuLi (2.36 M in hexane, 450 ꢁL, 1.062 mmol) was slowly added by syringe with preꢀcooling (the
solution was allowed to run down the cold wall of the reaction flask). The solution was stirred for 5 min at –100 °C and then
the solution of the Bꢀalkylcatecholborane (1.0 mmol) in THF (0.5 mL) was added. Precipitation of borate complex occurred
immediately. The cooling bath was removed and the white slurry was allowed to warm up to rt, while turning into a yellow
or brown solution. The solution was heated to reflux for 16 h (precipitation of LiCl) and cooled down to rt. Radical allyla-
tion. A solution of the allylsulfone (3.0 mmol) in THF or DMF (0.8 mL) was then added followed by diꢀtertꢀbutylhyponitrite
(5.2 mg, 0.030 mmol). The reaction mixture was heated at 65 °C for 4 h. Every 1 h, diꢀtertꢀbutylhyponitrite (5.2 mg, 0.030
mmol) was added. The reaction mixture was cooled down to rt and filtered over a pad of aluminum oxide and washed with
Et2O. Solvents were removed under reduced pressure and the crude product was purified by FC.
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Ethyl 4ꢀchloroꢀ4ꢀcyclohexylꢀ2ꢀmethylenebutanoate (19). According to Procedure
E
starting from Bꢀ
cyclohexylcatecholborane (200 mg, 0.99 mmol), using ethyl 2ꢀ((phenylsulfonyl)methyl)acrylate (770 mg, 3.03 mmol) in
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DMF (0.8 mL). FC (cyclohexane/EtOAc 98:2) afforded 19 (174 mg, 72%) as a colorless liquid. HꢀNMR (300 MHz,
CDCl3): δ 6.27 (d, J = 1.3 Hz, 1H), 5.66 (m, 1H), 4.19 (dq, J = 7.1, 0.5 Hz, 2H), 4.00 (dt, J = 10.1, 3.9 Hz, 1H), 2.86 (ddd, J
= 14.4, 3.5, 1.0 Hz, 1H), 2.49 (dd, J = 14.4, 10.1 Hz, 1H), 1.84ꢀ1.57 (m, 6H), 1.32ꢀ1.09 (m, 5H), 1.29 (t, J = 7.1 Hz, 3H);
13CꢀNMR (75 MHz, CDCl3): δ 166.8, 137.2, 128.0, 67.1, 60.9 (OCH2CH3), 44.3, 38.6, 30.2, 28.0, 26.4, 26.3, 26.1, 14.3; IR:
2926, 2854, 1710, 1197, 1135 cmꢀ1; EIꢀMS (GCꢀMS): m/z (%): 244 (0.15) [M+], 209 (60) [M+ꢀCl], 163 (34), 135 (100), 95
(46), 81 (49), 67 (60), 55 (77); ESIꢀHRMS: calcd for C13H21O2ClNa [M+Na]+: 267.1122; found: 267.1127.
Ethyl 4ꢀchloroꢀ5ꢀ((1S,5S)ꢀ6,6ꢀdimethylbicyclo[3.1.1]heptꢀ2ꢀyl)ꢀ2ꢀmethylenepentanoate (20). According to Procedure E
starting from (–)ꢀβꢀpinene 16 (320 ꢁL, 2.06 mmol), using ethyl 2ꢀ((phenylsulfonyl)methyl)acrylate (770 mg, 3.03 mmol) in
DMF (0.8 mL). FC (cyclohexane/toluene) afforded 20 (129 mg, 42% dr 1:1.1:4.5:5.5) as a colorless liquid. Diastereoselecꢀ
tivity was determined by GC analysis of the crude reaction mixture. Retention time = 38.5 min (minor), 38.8 min (minor),
38.9 min (major), 39.0 min (major) (starting temperature 40 °C, hold: 0 min, rate: 4 °C/min). 1HꢀNMR (300 MHz, CDCl3):
all four diastereoisomers (overlapping multiplets): δ 6.29 (m, 1H), 5.67 (m, 1H), 4.28ꢀ4.09 (m, 3H), 2.88ꢀ2.76 (m, 1H), 2.60ꢀ
2.48 (m, 1H), 2.41ꢀ2.24 (m, 2H), 2.06ꢀ1.62 (m, 7H), 1.52ꢀ1.35 (m, 1H), 1.33ꢀ1.28 (m, 3H), 1.19ꢀ1.17 (m, 3H), 0.97ꢀ0.83 (m,
4H); 13CꢀNMR (75 MHz, CDCl3): two major diastereoisomers: δ 166.8, 137.0, 128.3, 128.2, 60.9, 60.3, 60.0, 47.2, 46.6,
46.2, 45.1, 42.3, 41.7, 41.5, 41.5, 38.8, 38.2, 38.0, 33.8, 33.4, 28.3, 28.2, 26.5, 26.4, 23.42, 23.36, 22.7, 21.5, 14.4, 14.3; two
minor diastereoisomers (visible peaks): δ 166.7, 136.9, 128.3, 60.9, 59.8, 59.4, 46.5, 45.6, 45.1, 44.7, 42.4, 41.7, 41.12,
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41.05, 39.8, 39.5, 32.1, 31.9, 26.95, 26.89, 24.54, 24.47, 23.8, 22.4, 21.4, 20.25, 20.20; IR: 2908, 1714, 1195, 1156 ν cmꢀ1;
EIꢀMS (GCꢀMS): m/z (%): 263 (3) [M+ꢀCl], 219 (14), 189 (13), 173 (25), 149 (40), 145 (56), 133 (49), 123 (42), 107 (44), 93
(52), 82 (85), 67 (99), 55 (89), 41 (100); ESIꢀHRMS: calcd for C17H27O2Cl [M+]: 298.1700; found: 298.1698.
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Ethyl 4ꢀchloroꢀ4ꢀ((1R,2R,5S)ꢀ2,6,6ꢀtrimethylbicyclo[3.1.1] heptꢀ3ꢀyl)ꢀ2ꢀmethylenebutanoate (21). According to Proceꢀ
dure E starting from (+)ꢀαꢀpinene 17 (330 ꢁL, 2.06 mmol), using ethyl 2ꢀ((phenylsulfonyl)methyl)acrylate (770 mg, 3.03
mmol) in DMF (0.8 mL). FC (cyclohexane/toluene) afforded 21 (97 mg, 32%, dr 1:2.2) as a colorless liquid together with
nonꢀhomologated product (25 mg) and 4,4ꢀdichloroꢀ2ꢀmethylenebutanoate (7 mg). The diastereoselectivity was determined
by GC analysis of the crude reaction mixture. Retention time = 38.1 min (major), 39.0 min (minor) (starting temperature 40
°C, 4 °C/min). 1HꢀNMR (300 MHz, CDCl3): major diastereoisomer: δ 6.29 (d, J = 1.3 Hz, 1H), 5.69 (m, 1H), 4.33ꢀ4.15 (m,
3H), 2.77 (ddd, J = 14.3, 5.2, 1.0 Hz, 1H), 2.66 (ddd, J = 14.3, 9.0, 0.8 Hz, 1H), 2.27ꢀ1.73 (m, 7H), 1.31 (t, J = 7.1 Hz, 3H),
1.21 (s, 3H), 1.15ꢀ1.08 (m, 1H), 1.03ꢀ0.99 (m, 6H); minor diastereoisomer (visible, characteristic peaks): 6.31 (m, 1H), 5.72
(m, 1H), 4.10 (ddd, J = 10.9, 5.1, 2.0 Hz, 1H), 3.05ꢀ3.00 (m, 1H), 2.47 (dd, J = 14.4, 10.9 Hz, 1H); 13CꢀNMR (75 MHz,
CDCl3): major diastereoisomer: δ 166.8, 137.3, 128.1, 66.9, 61.0, 47.6, 42.6, 41.3, 40.2, 39.6, 39.2, 32.3, 28.2, 27.8, 22.9,
21.4, 14.4; minor diastereoisomer: δ 66.9, 137.1, 128.4, 68.5, 61.0, 48.4, 43.5, 41.4, 39.1, 38.9, 38.7, 32.3, 31.4, 27.9, 23.2,
23.0, 14.3; IR: 2902, 1713, 1196, 1140 cmꢀ1; EIꢀMS (GCꢀMS): m/z (%): 298 (0.15) [M+], 283 (0.2) [M+ꢀ(Me)], 263 (0.2)
[M+ꢀCl], 255 (0.4), 219 (19), 173 (54), 145 (60), 133 (56), 105 (63), 93 (57), 83 (81), 69 (61), 55 (100), 41 (76); ESIꢀHRMS:
calcd for C17H27O2ClNa [M+Na]+: 321.1592; found: 321.1599.
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Ethyl 4ꢀchloroꢀ5,5,6ꢀtrimethylꢀ2ꢀmethyleneheptanoate (22). The mixture of 2,3ꢀdimethylꢀ2ꢀbutene (175 ꢁL, 1.46 mmol)
and a boraneꢀdimethyl sulfide complex (94%, 150 ꢁL, 1.46 mmol) was stirred at 0 °C for 2.5 h. It was then diluted with
CH2Cl2 (1.1 mL) and slowly added via cannula to a solution of catechol (161 mg, 1.46 mmol) in CH2Cl2 (2 mL) at 0 °C. The
resulting solution was stirred at rt for 2 h. CH2Cl2 and dimethyl sulfide were evaporated by flushing N2 at rt through the flask
and then under vacuum at 0 °C to rt for about 2.5 h. The mixture was then diluted with THF (0.5 mL) and this solution was
added to the LiCHCl2 solution according to Procedure E. FC (cyclohexane/EtOAc 98:2) afforded 22 (141 mg, 39%) as a colꢀ
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orless liquid together with the nonꢀhomologated product (21 mg) and ethyl 4,4ꢀdichloroꢀ2ꢀmethylenebutanoate (13 mg). Hꢀ
NMR (300 MHz, CDCl3): δ 6.28 (m, 1H), 5.67 (m, 1H), 4.21ꢀ4.12 (m, 3H), 2.99ꢀ2.95 (m, 1H), 2.32 (dd, J = 14.3, 11.2 Hz,
1H), 1.90 (sept., J = 6.9 Hz, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.92 (s, 3H), 0.90 (s, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.86 (d, J = 6.9
Hz, 3H); 13CꢀNMR (75 MHz, CDCl3): δ 166.9, 137.5, 128.4, 70.2, 60.8, 40.9, 36.2, 33.9, 19.8, 19.0, 17.6, 17.2, 14.3; IR:
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2972, 1712, 1197, 1146 cmꢀ1; EIꢀMS (GCꢀMS): m/z (%): 247 (0.03) [M+], 211 (6) [M+ꢀCl], 203 (7), 167 (19), 139 (17), 126
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(46), 98 (72), 85 (86), 55 (41), 43 (100); ESIꢀHRMS: calcd for C13H23O2ClNa [M+Na]+: 269.1279; found: 269.1278.
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The homologation of styrene derivative
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Procedure F. Hydroboration–homologation–radical reaction involving styrene derivatives. Styrene derivative (2.0
mmol) was added to a suspension of PPh3 (6 mg, 1 mol%) and RhCl(PPh3)3 (10 mg, 0.5 mol%) in THF (1.6 mL) at rt under a
N2 atmosphere. The reaction mixture was stirred at rt for 30 min. Then catecholborane (0.24 mL, 2.2 mmol) was added
dropwise and the resulting solution was stirred at room temperature for 3–5 h. A LiCHCl2 solution was prepared by adding
n-BuLi (2.50 M in hexane, 0.96 mL 2.4 mmol) to a solution of CH2Cl2 (0.18 mL, 2.8 mmol) in THF (4 mL) at –100 °C (BuLi
was allowed it to run down the cold glass wall of the reaction flask). After 20–30 min, the solution of the hydroborated styꢀ
rene derivative was added in one portion. The reaction mixture was allowed to warm tort slowly. After heating at reflux
overnight for 16 h, precipitation of LiCl was observed. The reaction mixture was cooled down to rt and a solution of the radꢀ
ical trap (6 mmol) in DMF (1.6 mL) and hexadecane as internal standard were added followed by diꢀtertꢀbutylhyponitrite (10
mg, 3 mol%) and the mixture was heated to reflux. Every 1 h, a further portion of diꢀtertꢀbutylhyponitrite (10 mg, 3 mol%)
was added. After being stirred at refluxing temperature for 3 h (the reaction was followed by GC), the mixture was cooled
down and filtered over Alox and purified by FC. GC yields were determined using the response factor method with hexadeꢀ
cane as internal standard.
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Ethyl 4ꢀchloroꢀ5ꢀ(4ꢀmethoxyphenyl)ꢀ2ꢀmethylenehexanoate (30). The reaction was performed according to the procedure
F starting from 1ꢀmethoxyꢀ4ꢀvinylbenzene 23 (323 mg, 2.41 mmol) and ethyl 2ꢀ(phenylsulfonylmethyl)acrylate58 (1.82 g,
7.16 mmol) as the radical trap. Purification by FC (Et2O/pentane 1:100 to 1:30) afforded 30 (449 mg, 63%) as a colorless oil
(68% GC yield, dr 2.4:1).
1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.14ꢀ7.19 (m, 2H), 6.85ꢀ6.89 (m, 2H), 6.27 (d, J = 0.9 Hz, 1H), 5.64 (d,
J = 0.6 Hz, 1H), 4.27 (ddd, J = 10.4, 6.9, 3.3 Hz, 1H), 4.13ꢀ4.23 (m, 2H), 3.79 (s, 3H), 2.91ꢀ3.05 (m, 1H), 2.78 (dd, J = 14.4,
2.5 Hz, 1H), 2.37 (dd, J = 14.6, 10.7 Hz, 1H), 1.44 (d, J = 7.0 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H); minor diastereomer, δ 7.20ꢀ
7.24 (m, 2H), 6.85ꢀ6.89 (m, 2H), 6.27 (d, J = 0.9 Hz, 1H), 5.61 (d, J = 0.6 Hz, 1H), 4.34 (ddd, J = 10.6, 4.8, 2.9 Hz, 1H),
4.13ꢀ4.23 (m, 2H), 3.80 (s, 3H), 3.11ꢀ3.20 (m, 1H), 2.86 (dd, J = 14.5, 2.0 Hz, 1H), 2.28 (dd, J = 14.5, 10.6 Hz, 1H), 1.44 (d,
J = 7.0 Hz, 3H), 1.25 (t, J = 7.6 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), major diastereomer, δ 166.7, 158.6, 137.1, 135.6,
128.8, 128.3, 114.0, 67.1, 60.9, 55.3, 46.1, 40.0, 18.2, 14.3; minor diastereomer, δ 166.8, 158.6, 136.8, 134.0, 129.6, 128.4,
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113.7, 66.5, 60.9, 55.3, 45.3, 38.8, 18.2, 14.3; IR (neat): 2979, 2934, 2907, 2837, 1710 (s), 1631, 1611, 1512, 1463, 1303,
1247, 1179, 1145, 1032, 950, 830, 809 cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 260 (7), 231 (4), 187 (14), 135 (100), 105 (8), 91
(7), 77 (6); ESIꢀHRMS: calcd for C16H22O3Cl [M+H]+: 297.1252; found: 297.1250.
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Ethyl 4ꢀchloroꢀ2ꢀmethyleneꢀ5ꢀphenylhexanoate (31). The reaction was performed according to the procedure F starting
from styrene 24 (214 mg, 2.05 mmol) and ethyl 2ꢀ(phenylsulfonylmethyl)acrylate13 (1.52 g, 5.98 mmol) as the radical trap.
Purification by FC (Et2O/pentane 1:100) afforded 31 (365 mg, 67%) as a colorless oil (GC yield = 73%, dr 2.4:1).
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1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.15ꢀ7.43 (m, 5H), 6.27 (s, 1H), 5.65 (s, 1H), 4.27ꢀ4.42 (m, 1H), 4.19
(qd, J = 7.1, 3.1 Hz, 2H), 2.99ꢀ3.08 (m, 1H), 2.78 (dd, J = 14.4, 2.7 Hz, 1H), 2.39 (dd, J = 14.4, 10.5 Hz, 1H), 1.47 (d, J =
7.0 Hz, 3H), 1.29 (t, J = 7.5 Hz, 3H); minor diastereomer, δ 7.15ꢀ7.43 (m, 5H), 6.27 (s, 1H), 5.62 (s, 1H), 4.27ꢀ4.42 (m, 1H),
4.19 (qd, J = 7.1, 3.1 Hz, 2H), 3.13ꢀ3.27 (m, 1H), 2.89 (d, J = 13.7 Hz, 1H), 2.30 (dd, J = 14.5, 10.8 Hz, 1H), 1.47 (d, J = 7.0
Hz, 3H), 1.27 (t, J = 7.2 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), major diastereomer, δ 166.7, 143.6, 137.0, 128.6, 128.4,
128.3, 127.9, 127.0, 66.9, 60.9, 47.0, 40.1, 18.2, 14.3; minor diastereomer, δ 166.8, 142.1, 136.8, 128.6, 128.5, 128.3, 127.9,
127.1, 66.2, 60.9, 46.2, 38.7, 18.0, 14.3; IR (neat): 3031, 2978, 2934, 1710, 1633, 1495, 1452, 1190, 1144, 1025, 949, 765,
699 cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 230 (6), 215 (6), 184 (6), 157 (21), 156 (10), 141 (5), 115 (8), 105 (100), 79 (9), 77
(11); ESIꢀHRMS: calcd for C15H20O2Cl [M+H]+: 267.1146; found: 267.1141.
Ethyl 4ꢀchloroꢀ5ꢀ(4ꢀfluorophenyl)ꢀ2ꢀmethylenehexanoate (32). The reaction was performed according to the procedure F
starting from 1ꢀfluoroꢀ4ꢀvinylbenzene 25 (259 mg, 2.12 mmol) and ethyl 2ꢀ(phenylsulfonylmethyl)acrylate13 (1.55 g, 6.10
mmol) as the radical trap. Purification by FC (Et2O/pentane 1:100) afforded 32 as a colorless oil (GC yield = 71%, dr 2.4:1).
1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.19ꢀ7.23 (m, 2H), 6.98ꢀ7.05 (m, 2H), 6.27 (s, 1H), 5.65 (s, 1H), 4.14ꢀ
4.30 (m, 3H), 3.04 (p, J = 6.9 Hz, 1H), 2.76 (dd, J = 15.0, 3.2 Hz, 1H), 2.37 (dd, J = 14.3, 10.4 Hz, 1H), 1.43 (d, J = 6.9 Hz,
3H), 1.29 (t, J = 7.1 Hz, 3H); minor diastereomer, δ 7.19ꢀ7.28 (m, 2H), 6.98ꢀ7.04 (m, 2H), 6.27 (s, 1H), 5.61 (s, 1H), 4.15ꢀ
4.37 (m, 3H), 3.11ꢀ3.25 (m, 1H), 2.87 (dd, J = 14.4, 1.9 Hz, 1H), 2.26 (dd, J = 14.4, 10.6 Hz, 1H), 1.44 (d, J = 7.1 Hz, 3H),
1.27 (t, J = 7.1 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), major diastereomer, δ 166.5, 161.8 (d, 1JCF = 245.0 Hz, 139.1 (d, 4JCF
=
3
2
3.3 Hz), 136.8, 129.3 (d, JCF = 7.9 Hz), 128.4, 115.3 (d, JCF = 21.2 Hz), 66.6, 60.8, 45.9, 39.9, 17.8, 14.2; minor diastereꢀ
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omer, δ 166.6, 161.9 (d, JCF = 245.0 Hz), 137.6 (d, JCF = 3.2 Hz), 136.6, 130.0 (d, JCF = 7.8 Hz), 128.5, 115.0 (d, JCF
=
21.3 Hz), 66.1, 60.9, 45.4, 38.9, 18.3, 14.2; IR (neat): 2979, 2934, 1710 (s), 1631, 1604, 1510, 1224, 1194, 1144, 1023, 949,
835 cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 248 (10), 233(11), 219 (7), 202 (7), 175(38), 174 (19), 123(100), 103(28), 77(7);
ESIꢀHRMS: calcd for C15H19O2ClF [M+H]+: 285.1052; found: 285.1053.
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Ethyl 4ꢀchloroꢀ2ꢀmethyleneꢀ5ꢀ(4ꢀ(trifluoromethyl)phenyl) hexanoate (33). The reaction was performed according to proꢀ
cedure starting from 1ꢀ(trifluoromethyl)ꢀ4ꢀvinylbenzene 26 (360 mg, 2.09 mmol) and ethyl 2ꢀ
F
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(phenylsulfonylmethyl)acrylate13 (1.58 g, 6.21 mmol) as the radical trap. Purification by FC (Et2O/pentane 1:100 to 1:50)
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afforded 4 as a colorless oil (65% GC yield, dr 2.4:1).
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1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.59 (d, J = 8.1 Hz, 2H), 7.37 (d, J = 8.2 Hz, 2H), 6.29 (d, J = 0.9 Hz,
1H), 5.67 (d, J = 0.7 Hz, 1H), 4.33 (ddd, J = 10.0, 6.4, 3.4 Hz, 1H), 4.20 (q, J = 7.1 Hz, 2H), 3.12 (p, J = 6.8 Hz, 1H), 2.78
(dd, J = 13.9, 3.0 Hz, 1H), 2.41 (dd, J = 14.3, 10.3 Hz, 1H), 1.46 (d, J = 6.9 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H); minor diaꢀ
stereomer, δ 7.58 (d, J = 8.2 Hz, 2H), 7.42 (d, J = 8.2 Hz, 2H), 6.28 (d, J = 0.8 Hz, 1H), 5.62 (d, J = 0.5 Hz, 1H), 4.37 (ddd, J
= 10.6, 5.3, 2.9 Hz, 1H), 4.19 (q, J = 7.1 Hz, 2H), 3.14ꢀ3.34 (m, 1H), 2.91 (dd, J = 14.3, 2.0 Hz, 1H), 2.27 (dd, J = 14.3,
10.6 Hz, 1H), 1.47 (d, J = 7.0 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), major diastereomer, δ 166.6,
147.6, 136.7, 129.4 (q, 2JCF3 = 32.4 Hz), 128.7, 128.3, 125.6 (q, 3JCF3 = 3.8 Hz), 124.3 (q, 1JCF3 = 271.9 Hz), 66.1, 61.0, 46.5,
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40.1, 17.4, 14.3; minor diastereomer, δ 166.7, 146.2, 136.4, 129.4 (q, JCF3 = 32.4 Hz), 129.0, 128.8, 125.3 (q, JCF3 = 3.8
1
Hz), 124.4 (q, JCF3 = 271.9 Hz), 65.5, 61.0, 46.2, 39.1, 18.4, 14.2; IR (neat): 2983, 2938, 1710, 1619, 1323, 1193, 1163,
1118, 1068, 1016, 952, 841 cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 298 (28), 283 (41), 253 (15), 225 (66), 224 (37), 209 (16),
173 (100), 153 (28), 133 (49), 97 (20); ESIꢀHRMS: calcd for C16H19ClF3O2 [M+H]+: 335.1020; found: 335.1035.
Ethyl 4ꢀchloroꢀ2ꢀmethyleneꢀ5ꢀ(pꢀtolyl)hexanoate (34). The reaction was performed according to procedure F starting from
1ꢀmethylꢀ4ꢀvinylbenzene 27 (243 mg, 2.06 mmol) and ethyl 2ꢀ(phenylsulfonylmethyl)acrylate13 (1.58 g, 6.21 mmol) as the
radical trap. Purification by FC (Et2O/pentane, 1:100 to 1:75) afforded 5 as a colorless oil (71% GC yield, dr 2.4:1).
1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.10ꢀ7.22 (m, 4H), 6.28 (s, 1H), 5.65 (s, 1H), 4.30 (ddd, J = 10.4, 7.1,
3.2 Hz, 1H), 4.14ꢀ4.25 (m, 2H), 3.01 (p, J = 6.9 Hz, 1H), 2.79 (dd, J = 14.4, 2.4 Hz, 1H), 2.26ꢀ2.42 (m, 1H), 2.34 (s, 3H),
1.46 (d, J = 6.9 Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H); minor diastereomer, δ 7.10ꢀ7.22 (m, 4H), 6.28 (s, 1H), 5.62 (s, 1H), 4.33ꢀ
4.40 (m, 1H), 4.14ꢀ4.25 (m, 2H), 3.11ꢀ3.24 (m, 1H), 2.89 (dd, J = 14.4, 2.0 Hz, 1H), 2.26ꢀ2.42 (m, 1H), 2.35 (s, 3H), 1.46 (d,
J = 6.9 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), major diastereomer, δ 166.7, 140.5, 137.1, 136.5,
129.3, 128.5, 127.7, 67.0, 60.9, 46.6, 40.0, 21.1, 18.3, 14.3; minor diastereomer, δ 166.8, 139.0, 136.8, 136.5, 129.0, 128.4,
128.3, 66.3, 60.9, 45.8, 38.7, 21.1, 18.1, 14.2; IR (neat): 2980, 2929, 1711 (s), 1631, 1515, 1191, 1144, 1024, 951, 817 cm–1;
EIꢀLRMS (GCꢀMS) m/z (%): 209 (18), 171 (9), 144 (24), 141 (45), 125 (28), 119 (73), 113 (29), 91 (13), 85 (39), 77 (100),
68 (30), 51 (29); ESIꢀHRMS: calcd for C16H22O2Cl [M+H]+: 281.1303; found: 281.1305.
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Ethyl 5ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ4ꢀchloroꢀ2ꢀmethylenehexanoate (35). The reaction was performed according to procedure F
starting from 4ꢀvinylꢀ1,1'ꢀbiphenyl 28 (360 mg, 2.0 mmol) and ethyl 2ꢀ(phenylsulfonylmethyl)acrylate13 (1.54 g, 6.06 mmol)
as the radical trap. Purification by FC (Et2O/pentane 1:100) afforded 6 as a colorless oil (436 mg, 64%) (65% GC yield, dr
2.4:1).
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1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.53ꢀ7.64 (m, 4H), 7.41ꢀ7.50 (m, 2H), 7.30ꢀ7.39 (m, 3H), 6.30 (s, 1H),
5.67 (s, 1H), 4.37 (ddd, J = 10.3, 6.8, 3.3 Hz, 1H), 4.21 (qd, J = 7.1, 1.0 Hz, 2H), 3.10 (p, J = 6.9 Hz, 1H), 2.85 (dd, J =
14.0, 3.5 Hz, 1H), 2.44 (dd, J = 14.4, 10.4 Hz, 1H), 1.51 (d, J = 6.9 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H); minor diastereomer, δ
7.54ꢀ7.66 (m, 4H), 7.30ꢀ7.51 (m, 5H), 6.30 (s, 1H), 5.65 (s, 1H), 4.33ꢀ4.47 (m, 1H), 4.15ꢀ4.27 (m, 2H), 3.19ꢀ3.34 (m, 1H),
2.95 (dd, J = 14.1, 2.1 Hz, 1H), 2.36 (dd, J = 14.6, 10.9 Hz, 1H), 1.52 (d, J = 7.0 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13CꢀNMR
(75 MHz, CDCl3), major diastereomer, δ 166.7, 142.6, 140.9, 139.9, 137.0, 128.9, 128.5, 128.3, 127.3, 127.1, 66.8, 60.9,
46.6, 40.1, 18.1, 14.3; minor diastereomer, δ 166.8, 141.1, 140.9, 139.9, 136.7, 129.0, 128.9, 128.6, 127.1, 127.0, 66.2, 60.9,
45.9, 38.8, 18.1, 14.3; IR (neat): 2960, 2922, 2852, 1714, 1466, 1195, 1146, 949, 836, 766, 696 cm–1; EIꢀLRMS (GCꢀMS)
m/z (%): 306 (20), 277 (11), 233 (51), 217 (12), 181 (100), 166 (29), 165 (33), 154 (16), 152 (12); ESIꢀHRMS: calcd for
C21H24O2Cl [M+H]+: 343.1459; found: 343.1451.
Ethyl 4ꢀchloroꢀ5ꢀ(4ꢀchlorophenyl)ꢀ2ꢀmethylenehexanoate (36). The reaction was performed according to procedure F
starting from 1ꢀchloroꢀ4ꢀvinylbenzene 29 (284 mg, 2.05 mmol) and ethyl 2ꢀ(phenylsulfonylmethyl)acrylate13 (1.58 g, 6.21
mmol) as the radical trap. Purification by FC (Et2O/pentane 1:100) afforded 36 as a colorless oil (389 mg, 63%) (76% GC
yield, dr 2.4:1).
1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.27ꢀ7.33 (m, 2H), 7.15ꢀ7.25 (m, 2H), 6.27 (s, 1H), 5.65 (s, 1H), 4.27
(ddd, J = 10.2, 6.6, 3.4 Hz, 1H), 4.19 (qd, J = 7.1, 0.8 Hz, 2H), 3.02 (p, J = 6.8 Hz, 1H), 2.77 (dd, J = 14.3, 3.2 Hz, 1H),
2.37 (dd, J = 14.3, 10.4 Hz, 1H), 1.43 (d, J = 6.9 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H); minor diastereomer, δ 7.27ꢀ7.33 (m, 2H),
7.15ꢀ7.25 (m, 2H), 6.27 (s, 1H), 5.61 (s, 1H), 4.30ꢀ4.37 (m, 1H), 4.19 (qd, J = 7.1, 0.8 Hz, 2H), 3.10 (m, 1H), 2.86 (dd, J =
14.3, 2.7 Hz, 1H), 2.25 (dd, J = 14.3, 10.5 Hz, 1H), 1.43 (d, J = 6.9 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H); 13CꢀNMR (75 MHz,
CDCl3), major diastereomer, δ 166.6, 142.0, 136.8, 132.8, 129.3, 128.8, 128.6, 66.5, 61.0, 46.1, 40.0, 17.7, 14.3; minor diaꢀ
stereomer, δ 166.7, 140.5, 136.6, 132.9, 130.0, 128.6, 128.5, 65.9, 61.0, 45.7, 39.0, 18.4, 14.3; IR (neat): 2981, 2938, 2907,
1710 (s), 1634, 1493, 1191, 1144, 1092, 1013, 951, 827, 699 cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 264 (15), 249 (14), 235
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(8), 219 (9), 191 (42), 155 (9), 141 (38), 139 (100), 115 (13), 103 (37), 77 (15); ESIꢀHRMS: calcd for C15H19O2Cl2 [M+H]+:
301.0762; found: 301.0757.
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5ꢀ([1,1'ꢀbiphenyl]ꢀ4ꢀyl)ꢀ4ꢀchloroꢀ2ꢀmethylenehexyl 3,5ꢀdinitrobenzoate (37). A solution of diisobutylaluminum hydride
(DIBALH) (3.0 mL, 3.0 mmol, 1 M) was added dropwise to a solution of 35 (413 mg, 1.2 mmol) in dry dichloromethane (6
mL) at –78 °C over a period of 30 min. After being stirred for 3 h, the reaction mixture was treated with a saturated solution
of ammonium chloride and was then warmed up to rt. The white precipitate was filtered off, the layers were separated, and
the aqueous phase was extracted with CH2Cl2. The combined organic extracts were dried over Na2SO4, and the solvent was
removed under reduced pressure. The crude product was purified by FC (Et2O/pentane 1:4 to 1:2) to afford 5ꢀ([1,1'ꢀ
biphenyl]ꢀ4ꢀyl)ꢀ4ꢀchloroꢀ2ꢀmethylenehexanꢀ1ꢀol (221 mg, 61%) as a colorless oil.
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1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.53ꢀ7.66 (m, 4H), 7.43ꢀ7.48 (m, 2H), 7.29ꢀ7.40 (m, 3H), 5.18 (s, 1H),
5.00 (s, 1H), 4.30 (ddd, J = 10.4, 6.7, 3.9 Hz, 1H), 4.11 (s, 2H), 3.11(p, J = 6.9 Hz, 1H), 2.58 (dd, J = 14.7, 3.6 Hz, 1H),
2.39 (dd, J = 15.0, 10.1 Hz, 1H), 1.62 (s, 1H), 1.50 (d, J = 7.0 Hz, 3H); minor diastereomer, δ 7.53ꢀ7.66 (m, 4H), 7.43ꢀ7.48
(m, 2H), 7.29ꢀ7.41 (m, 3H), 5.18 (s, 1H), 4.99 (s, 1H), 4.38 (ddd, J = 10.4, 4.6, 3.6 Hz, 1H), 4.11 (s, 2H), 3.19ꢀ3.32 (m,
1H), 2.63 (dd, J = 14.7, 3.3 Hz, 1H), 2.30 (dd, J = 15.2, 10.5 Hz, 1H), 1.62 (s, 1H), 1.50 (d, J = 7.0 Hz, 3H); 13CꢀNMR (75
MHz, CDCl3), major diastereomer, δ 145.3, 142.8, 140.9, 139.9, 128.9, 127.4, 127.1, 113.5, 67.0, 66.0, 46.1, 40.7, 17.7; miꢀ
nor diastereomer, δ 145.1, 141.0, 140.9, 139.9, 129.0, 128.2, 127.0, 113.6, 66.2, 66.0, 45.7, 39.1, 17.9; IR (neat): 3354 (br),
3031, 2972, 2934, 2876, 1486, 1029, 904, 837, 766 (s), 737, 696 (s), 669 cm–1; EIꢀLRMS (GCꢀMS) m/z(%): 254 (2), 182
(4), 148 (2), 135 (100), 105 (10), 77 (10); ESIꢀHRMS: calcd for C19H22OCl [M+H]+: 301.1354; found: 301.1355.
Et3N (81 mg, 0.80 mmol) was added to a solution of the alcohol (160 mg, 0.53 mmol) and 3,5ꢀdinitrobenzoyl chloride (184
mg, 0.80 mmol) in CH2Cl2 (3 mL) at 0 °C. The mixture was slowly warmed up to room temperature and stirred for 4 h. H2O
(5 mL) was added and the solution was extracted with CH2Cl2 (2 × 5 mL). The combined organic layer was washed with a
sat. NaCl soln. (2 × 5 mL) and dried over MgSO4. The solvent was evaporated and the residue was purified by FC (penꢀ
tane/Et2O 20:1) to give 37 as a white solid. The major diastereomer was isolated and recrystalized from CH2Cl2/pentane. Its
relative configuration was confirmed by Xꢀray crystallographic analysis.
synꢀ37 (major diastereomer), mp: 104.6–106.1 °C; 1HꢀNMR (300 MHz, CDCl3), δ 8.94 (d, J = 2.1 Hz, 2H), 8.88 (t, J = 2.1
Hz, 1H), 7.30ꢀ7.42 (m, 7H), 7.21ꢀ7.24 (m, 2H), 5.32 (s, 1H), 5.23 (s, 1H), 5.06 (d, J = 12.8 Hz, 1H), 4.68 (d, J = 12.8 Hz,
1H), 4.14 (ddd, J = 11.4, 8.7, 2.9 Hz, 1H), 3.02 (dq, J = 13.9, 6.9 Hz, 1H), 2.53 (d, J = 13.0 Hz, 1H), 2.37 (dd, J = 15.1,
10.4 Hz, 1H), 1.51 (d, J = 6.9 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), δ 162.2, 148.5, 142.7, 139.9, 139.4, 139.2, 133.4, 129.3,
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129.0, 128.1, 127.7, 127.1, 126.4, 122.4, 118.9, 68.4, 65.9, 47.0, 40.6, 19.2; IR (neat): 3099, 2926, 1734, 1721, 1540, 1342,
1273, 1164, 919, 842, 768, 730, 717, 692, 675, 668 cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 318 (2), 182 (15), 181 (100), 166
(16), 165 (16), 152 (7), 115 (3), 91 (2), 77 (4); ESIꢀHRMS: calcd for C26H24ClN2O6 [M+H]+: 495.1322; found: 495.1317.
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(3ꢀChloroꢀ5ꢀmethylhexꢀ5ꢀenꢀ2ꢀyl)benzene (38). The reaction was performed according to procedure F starting from styrene
24 (227 mg, 2.18 mmol) and ((2ꢀmethylallyl)sulfonyl)benzene59 (1.30 g, 6.62 mmol) as the radical trap. This radical allylaꢀ
tion reaction proceeded slowly, and required refluxing overnight after the addition of diꢀtertꢀbutylhyponitrite. Purification by
FC (pentane) afforded 38 as a colorless oil (194 mg, 43%) (53% GC yield, dr 2.3:1).
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1HꢀNMR (300 MHz, CDCl3/TMS), major diastereomer, δ 7.18ꢀ7.37 (m, 5H), 4.85 (s, 1H), 4.78 (s, 1H), 4.18 (ddd, J = 9.1,
6.3, 5.3 Hz, 1H), 3.02 (p, J = 6.8 Hz, 1H), 2.21ꢀ2.47 (m, 2H), 1.71 (s, 3H), 1.44 (d, J = 6.9 Hz, 3H); minor diastereomer, δ
7.17ꢀ7.38 (m, 5H), 4.85 (s, 1H), 4.75 (s, 1H), 4.28 (dt, J = 9.9, 4.3 Hz, 1H), 3.12ꢀ3.24 (m, 1H), 2.16ꢀ2.49 (m, 2H), 1.71 (s,
3H), 1.44 (d, J = 6.9 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), major diastereomer, δ 144.0, 141.9, 128.6, 127.8, 127.0, 113.6,
66.6, 46.0, 45.3, 22.0, 17.3; minor diastereomer, δ 142.1, 141.8, 128.7, 128.3, 127.0, 113.5, 65.8, 45.8, 43.4, 22.1, 17.8; IR
(neat): 3083, 3031, 2968 , 2934, 1495, 1452, 1377, 888, 763, 698 (s) cm–1; EI m/z (%): 208 (29), 152 (29), 105.0 (100), 91
(7), 77 (6); EIꢀHRMS: calcd for C13H17Cl [M]+: 208.1016; found: 208.1013.
(3ꢀChloroꢀ5ꢀ(phenylsulfonyl)hexꢀ5ꢀenꢀ2ꢀyl)benzene (39). The reaction was performed according to procedure F starting
from styrene 24 (204 mg, 1.96 mmol) and (propꢀ2ꢀeneꢀ1,2ꢀdiyldisulfonyl)dibenzene15 (1.93 g, 5.99 mmol) as the radical trap.
Purification by FC (TBME/cyclohexane, 1:4) afforded 39 as a white solid (GC yield = 66%, dr 2.7:1). The major diastereꢀ
omer was recrystallized from CH2Cl2/pentane.
Major diastereomer, m.p.: 88.6–90.6 ºC; 1HꢀNMR (300 MHz, CDCl3), δ 7.51ꢀ7.60 (m, 3H), 7.24ꢀ7.45 (m, 5H), 7.13ꢀ7.22 (m,
2H), 6.47 (s, 1H), 5.91 (s, 1H), 4.22ꢀ4.40 (m, 1H), 2.89 (dq, J = 14.1, 6.9 Hz, 1H), 2.52 (ddd, J = 15.6, 2.7, 1.0 Hz, 1H),
2.32 (dd, J = 15.6, 10.5 Hz, 1H), 1.44 (d, J = 6.9 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), δ 146.2, 143.1, 138.5, 133.6, 129.2,
128.8, 128.3, 127.9, 127.8, 127.2, 65.6, 47.3, 37.8, 19.0; IR (neat): 3079, 3031, 2982, 2903, 1582, 1492, 1445, 1314, 1285,
1148, 1132, 1082, 957, 746, 703, 689, 682, 662, 613 cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 157 (18), 156 (100), 141 (80), 129
(13), 115 (16), 105 (69), 91 (10), 77 (19); ESIꢀHRMS: calcd for C18H20O2ClS [M+H]+: 335.0867; found: 335.0864.
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(5ꢀBromoꢀ3ꢀchlorohexꢀ5ꢀenꢀ2ꢀyl)benzene (40). The reaction was performed according to procedure F starting from styrene
24 (216 mg, 2.07 mmol) and ((2ꢀbromoallyl)ꢀsulfonyl)benzene15 (1.60 g, 6.13 mmol) as the radical trap. Purification by FC
(pentane) afforded 40 as a colorless oil (263 mg, 46%). The two diastereomers were isolated by careful separation (55% GC
yield, dr 2.4:1)
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1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ: 7.23ꢀ7.41 (m, 5H), 5.71 (s, 1H), ), 5.55 (d, J = 1.5 Hz, 1H), 4.38 (ddd, J
= 9.0, 6.9, 4.7 Hz, 1H), 3.08 (p, J = 6.9 Hz, 1H), 2.51ꢀ2.81 (m, 2H), 1.49 (d, J = 6.9 Hz, 3H); minor diastereomer, δ: 7.23ꢀ
7.41 (m, 5H), 5.66 (s, 1H), 5.55 (d, J = 1.5 Hz, 1H), 4.43ꢀ4.52 (m, 1H), 3.22 (qd, J = 7.0, 4.6 Hz, 1H), 2.51ꢀ2.81 (m, 2H),
1.50 (d, J = 7.1 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), major diastereomer, δ: 143.2, 130.1, 128.8, 127.8, 127.2, 65.5, 48.4,
45.8, 17.8; minor diastereomer, δ: 141.4, 130.1, 128.7, 128.4, 127.3, 64.8, 47.3, 45.1, 18.2; IR (neat): 3060, 3031, 2971,
2934, 2872, 1631, 1495, 1452, 1200, 891, 764, 699 (s) cm–1; EI m/z (%): 274 (20), 272 (15), 234 (31), 218 (25), 209 (15),
157 (15), 152 (11), 105 (100), 106 (9), 91 (5), 79 (5), 77 (7); EIꢀHRMS: calcd for C12H1479Br35Cl [M]+: 271.9962; found:
271.9963.
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((4ꢀChloroꢀ2ꢀmethyleneꢀ5ꢀphenylhexyl)sulfonyl)benzene (41). The reaction was performed according to procedure F startꢀ
ing from styrene 24 (212 mg, 2.04 mmol) and (2ꢀmethylenepropaneꢀ1,3ꢀdiyldisulfonyl)dibenzene (2.02 g, 6.00 mmol) as the
radical trap. This radical allylation reaction proceeded slowly and was allowed to stir at reflux for another 3 h. Purification
by FC (CH2Cl2/Et2O/pentane 1:1:10) afforded 41 as a colorless oil (36% GC yield, dr 2.9:1).
1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ 7.80ꢀ7.90 (m, 2H), 7.62ꢀ7.72 (m, 1H), 7.50ꢀ7.62 (m, 2H), 7.23ꢀ7.43 (m,
5H), 5.14 (s, 1H), 4.92 (s, 1H), 4.19ꢀ4.26 (m, 1H), 3.86 (s, 2H), 3.06 (p, J = 6.9 Hz, 1H), 2.61ꢀ2.72 (m, 1H), 2.42 (dd, J =
15.4, 10.7 Hz, 1H), 1.48 (d, J = 6.9 Hz, 3H); minor diastereomer, δ 7.80ꢀ7.90 (m, 2H), 7.62ꢀ7.72 (m, 1H), 7.50ꢀ7.62 (m, 2H),
7.23ꢀ7.43 (m, 5H), 5.14 (s, 1H), 4.92 (s, 1H), 4.29 (ddd, J = 10.9, 5.1, 2.8 Hz, 1H), 3.85 (s, 2H), 3.13ꢀ3.26 (m, 1H), 2.82 (d,
J = 15.4 Hz, 1H), 2.30 (dd, J = 15.4, 11.0 Hz, 1H), 1.48 (d, J = 7.1 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), major diastereꢀ
omer, δ 143.2, 138.2, 134.0, 133.8, 129.1, 128.7, 128.5, 127.8, 127.1, 123.1, 66.7, 62.7, 46.7, 42.3, 18.0; minor diastereomer,
δ 141.9, 138.3, 134.0, 133.8, 129.1, 128.5, 128.4, 128.3, 127.1, 123.2, 65.9, 62.6, 46.1, 41.0, 17.7; IR (neat): 3056, 3031,
2973, 2934, 1495, 1446, 1307, 1150, 1127, 1084, 752, 725, 701 (s), 687 (s) cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 172 (13),
171 (78), 155 (11), 143 (15), 129 (22), 115 (17), 105 (100), 91 (35), 77 (20); ESIꢀHRMS: calcd for C19H21O2ClNaS
[M+Na]+: 371.0843; found: 371.0842.
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(3ꢀChloroꢀ5ꢀ(chloromethyl)hexꢀ5ꢀenꢀ2ꢀyl)benzene (42). The reaction was performed according to procedure F starting
from styrene 24 (211 mg, 2.03 mmol) and ((2ꢀ(chloromethyl)allyl)sulfonyl)benzene59 (1.39 g, 6.02 mmol) as the radical trap.
Purification by FC (pentane) afforded 42 as a colorless oil (254 mg, 51%) (56% GC yield, dr 2.5:1).
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1HꢀNMR (300 MHz, CDCl3), major diastereomer, δ: 7.01ꢀ7.28 (m, 5H), 5.09 (s, 1H), 4.90 (s, 1H), 4.07 (ddd, J = 10.5,
7.0, 3.5 Hz, 1H), 3.89ꢀ3.98 (m, 2H), 2.90 (p, J = 6.9 Hz, 1H), 2.44ꢀ2.54 (m, 1H), 2.24 (dd, J = 15.2, 10.5 Hz, 1H), 1.33 (d, J
= 6.9 Hz, 3H); minor diastereomer, δ: 7.01ꢀ7.28 (m, 5H), 5.09 (s, 1H), 4.89 (s, 1H), 4.15 (ddd, J = 10.8, 5.0, 3.2 Hz, 1H),
3.86ꢀ3.98 (m, 2H), 3.00ꢀ3.11 (m, 1H), 2.55ꢀ2.64 (m, 1H), 2.06ꢀ2.21 (m, 1H), 1.33 (d, J = 6.9 Hz, 3H); 13CꢀNMR (75 MHz,
CDCl3), major diastereomer, δ: 143.5, 141.7, 128.7, 127.8, 127.1, 117.8, 66.2, 47.9, 46.8, 40.5, 18.1; minor diastereomer, δ:
141.9, 141.5, 128.5, 128.4, 127.1, 117.9, 65.5, 48.0, 46.1, 38.9, 17.8; IR (neat): 3083, 3060, 3030, 2971, 2934, 1644, 1600,
1495, 1452, 1256, 909, 747, 699 (s) cm–1; EIꢀLRMS (GCꢀMS) m/z (%): 206 (1), 152 (7), 115 (5), 105 (100), 91 (7), 77 (6);
EIꢀHRMS: calcd for C13H16Cl2 [M]+: 242.0629; found: 242.0626; Anal. Calcd for C13H16Cl2: C 64.21, H 6.63; Found: C
64.35, H 6.45.
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Silver (I)ꢀmediated lactonization. Silver nitrate (AgNO3) (342 mg, 2.02 mmol) was dissolved in 5 mL of water and 9 mL of
dioxane and heated to reflux. Ester 30 (300 mg, 1.01 mmol) dissolved in 2 mL of dioxane was then added and the resulting
mixture was maintained at reflux for 2 h. After cooling down, the mixture was filtered and concentrated. Water was added
and the mixture was extracted with CH2Cl2. The combined organic extracts were washed twice with brine and dried over
MgSO4. Evaporation of the solvents gave the crude product which was purified by FC (Et2O/pentane, 1:2) to yield compound
43 (21 mg, 9%) and 44 (37 mg, 16%) as white solid. Compound 44 was recrystallized from CH2Cl2/pentane. The relative
configuration of 44 was confirmed by Xꢀray crystallographic analysis.
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5ꢀ(1ꢀ(4ꢀMethoxyphenyl)ethyl)ꢀ3ꢀmethylenedihydrofuranꢀ2(3H)ꢀone (43). HꢀNMR (300 MHz, CDCl3), δ: 7.08ꢀ7.16 (m,
2H), 6.83ꢀ6.90 (m, 2H), 6.15 (t, J = 2.9 Hz, 1H), 5.50 (t, J = 2.5 Hz, 1H), 4.54 (td, J = 7.8, 6.4 Hz, 1H), 3.80 (s, 3H), 2.80ꢀ
2.91 (m, 1H), 2.74 (ddt, J = 17.4, 7.6, 2.5 Hz, 1H), 2.54 (ddt, J = 17.4, 6.0, 2.9 Hz, 1H), 1.39 (d, J = 6.9 Hz, 3H); 13CꢀNMR
(75 MHz, CDCl3), δ 170.5, 158.9, 134.8, 133.5, 129.0, 121.9, 114.3, 81.5, 55.4, 44.8, 32.0, 18.2; IR (neat): 2955, 2923, 2853,
1752 (s), 1514, 1283, 1241, 1177, 1027, 1001, 960, 837, 632, 612 cmꢀ1; EIꢀLRMS (GCꢀMS) m/z (%): 232 (10), 135 (100),
105 (15), 77(5); ESIꢀHRMS: calcd for C14H17O3 [M+H]+: 233.1172; found: 233.1169.
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5ꢀ(4ꢀMethoxyphenyl)ꢀ6ꢀmethylꢀ3ꢀmethylenetetrahydroꢀ2Hꢀpyranꢀ2ꢀone (44). HꢀNMR (300 MHz, CDCl3), δ: 7.05ꢀ7.15
(m, 2H), 6.82ꢀ6.93 (m, 2H), 6.42ꢀ6.48 (m, 1H), 5.55ꢀ5.61 (m, 1H), 4.47ꢀ4.61 (m, 1H), 3.80 (s, 3H), 2.69ꢀ2.88 (m, 3H), 1.18
(d, J = 6.3 Hz, 3H); 13CꢀNMR (75 MHz, CDCl3), δ 165.6, 159.1, 134.2, 132.0, 128.6, 128.1, 114.5, 81.6, 55.4, 46.6, 36.4,
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