Catalyst economy. Part 2: Sequential metathesis - Kharasch sequences using the Grubbs metathesis catalysts

Article abstract of DOI:10.1016/j.tetlet.2005.12.018

Sequential ring-closing metathesis (RCM)-Kharasch cyclizations are promoted by the Grubbs metathesis catalysts and provide rapid access to bicyclic lactones and lactams.

Full text of DOI:10.1016/j.tetlet.2005.12.018

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1145–1151
Catalyst economy. Part 2: Sequential metathesis—Kharasch
sequences using the Grubbs metathesis catalystsq
Chris D. Edlin,a James Faulknerb and Peter Quayleb,*
aMedicinal Chemistry 1, GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Herts. SG1 2NY, UK
bSchool of Chemistry, The University of Manchester, Manchester M13 9PL, UK
Received 14 November 2005; revised 1 December 2005; accepted 5 December 2005
Abstract—Sequential ring-closing metathesis (RCM)–Kharasch cyclizations are promoted by the Grubbs metathesis catalysts and
provide rapid access to bicyclic lactones and lactams.
Ó 2005 Elsevier Ltd. All rights reserved.
Recently, we demonstrated1 that the Grubbs carbene
complex 1a, more usually associated with metathesis
chemistry,2 also proves to be an efficient catalyst for
the promotion of intramolecular Kharasch reactions.
Circumstantial evidence3 suggests that this non-meta-
thetical activity4 is associated with the in situ decompo-
sition of the initial carbene complex to an as of yet
uncharacterized ruthenium complex(es).5 Such species
not only promote ATRC reactions but are also respon-
sible3 for alkene isomerization, redox isomerization of
allylic alcohols and transfer hydrogenation reactions.
Furthermore, we have also shown, in competition experi-
ments,6 that the relative rates of these reactions may be
quite different, as in the case of RCM reactions leading
to five-membered heterocycles, which are much more
rapid than the alternative ATRC reactions leading to
butyrolactones or butyrolactams (Scheme 1). Indeed
PCy3
PCy3
MsN
Cl
NMs
Cl
Cl
Cl
Cl
Ru
Ru
Ph
Ru
PCy3
PCy3
Cl
Ph
PCy3
1b
1a
1c
CCl3
1a (5 mol%)
Toluene
Cl
O
N
110 oC; 3.5 hrs.
Cl
O
Cl
Ts
[Ru]
N
N
Toluene
110 oC; 3.5 hrs.
O
Ts
CCl3
52%
N
Kharasch
O
CCl3
95%
Metathesis
Scheme 1. Sequential metathesis–Kharasch reactions: initial investigations.6
Keywords: Grubbs; Metathesis; Kharasch; Cyclization; Tandem; ATRC; RCM; Metathesis; Radical.
q For part 1 of this series, see Ref. 6.
*
Corresponding author. Tel.: +44 161 275 4619; fax: +44 161 275 4598; e-mail: peter.quayle@manchester.ac.uk
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.12.018

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C. D. Edlin et al. / Tetrahedron Letters 47 (2006) 1145–1151
R
R
Cl
[Ru]
1a
Cl
Cl
O
+
X
R
X
X
O
CCl3
O
CCl3
Metathesis
[Ru]
Kharasch (ATRC)
Scheme 2. Proposed tandem metathesis–Kharasch sequence.
the ATRC component is usually only observed when the
reaction mixture is heated in excess of 80 °C whereas
RCM reactions are frequently observed to proceed at
or near ambient temperatures. This dual reactivity raises
the possibility that different carbon–carbon bond-form-
ing reactions may be incorporated into a synthetic
sequence where the outcome is pre-determined by the
relative rates of the potential bond-forming reactions.
carbon–carbon bond-forming reactions (i.e., metathesis
followed by Kharasch) could be telescoped into a
single sequence11 was realized when we observed that
cross metathesis of 2 with 3, at 40 °C, as above, followed
by thermolysis at 110 °C led to the isolation of c-lactams
7 in 29% overall yield, as a 3:2 mixture of diastereoiso-
mers (Scheme 3). We also note, in this case, that the ste-
reochemical course of the cyclization reaction leading to
7 is dependent upon the nature of the catalyst system
utilized in the ATRC reaction.12 Similarly, cross meta-
thesis of 2 with the styrenes 9, 10 and 11 proceeded
smoothly at 40 °C (12 h) which, followed by thermolysis
at 110 °C (3 days), resulted in the isolation of the c-lac-
tams 12a–c in moderate overall yields (26%, 32% and
23%, respectively) as a single diastereoisomer in each
case (Scheme 4).
With this thought in mind, we decided to test whether it
would be possible to engineer reaction sequences, which
involve sequential metathesis–Kharasch cascades in
which the initial metathesis reaction proceeds rapidly
but necessarily generates a thermally unstable methyl-
idene complex 1c. Decomposition of 1c under the reac-
tion conditions would then generate a metathetically
inactive catalyst, Ô[Ru]Õ, which is however still capable
of promoting ATRC reactions (Scheme 2). The use
of the ruthenium catalyst (or precatalyst) to promote
different carbon–carbon bond-forming reactions in
this manner is a concept we have coined6 as Ôcatalyst
economyÕ, a sequence which falls into the broader
category of Ôconcurrent catalysisÕ as adumbrated by
Ajamian and Gleason.7 These multiple catalytic cycles
have great potential in organic synthesis8 and the report
by Snapper9 prompts us to communicate some of our
most recent findings in this area.
From our preliminary studies, we also conclude that the
nature of the N-substituent may play a critical role in
determining the outcome of these tandem reactions.
For example, co-metathesis of 2 becomes the dominant
reaction pathway, leading to the isolation of 8 as the
major product (78% isolated yield; E:Z > 95:5), when 3
was exchanged for the more hindered alkene partners
in the initial cross metathesis reaction. Alternatively, in
the case where the N-substituent is simply hydrogen,
as in the case of 13, attempted cross metathesis with
3,3-dimethylbut-1-ene resulted in the isomerization13 of
the substrate to enamide 14, whereas an N-tosyl-substi-
tuent (as in the case 15) appeared to shut down14 the ini-
tial metathesis reaction completely (Scheme 5).
Our first attempt to validate such a hypothesis centred
on possibly the worst case scenario, that of cross
metathesis10 (CM)-ATRC reaction sequences. Initial
blank reactions confirmed that trichloroacetamide 2
underwent ATRC reaction reasonably rapidly at 80 °C
(CuCl/dHbipy , 5 mol %; ClCH2CH2Cl; 80 °C; 3.5 h),
affording the c-lactam 4 in 89% isolated yield.
Notwithstanding these complications, we were encour-
aged enough to investigate these reactions further and
thought it best to attempt RCM-ATRC reactions with
the expectation that the initial metathesis reaction would
become more favourable. To this end, trichloroacetate
18, which is readily prepared in a three-step sequence
from commercially available allyl vinyl ether in 93%
overall yield, was chosen as our initial test substrate.
In passing it is worth mentioning that the Claisen re-
arrangement of allyl vinyl ether into aldehyde 16 is best
accomplished using the now ubiquitous application of
microwave technology.15 Aldehyde 16 can be prepared
in quantitative yield on a 20 g scale in this manner.
Reaction of 16 with vinyl magnesium bromide and
subsequent trichloroacetylation of 17 afforded the key
substrate 18 in near quantitative yield. After some
experimentation, we observed that exposure of 18 to
the Grubbs catalyst 1a in the presence of a Cu(I) co-cat-
alyst16 led directly to the isolation of the bicyclic lactone
Encouragingly, we also observed that exposure of a mix-
ture of 2 and 3 (2:3 = 1:5) in toluene to catalyst 1a
(5 mol %; 40 °C; 2 h) afforded the cross-metathesis prod-
uct 5 in 69% yield (E:Z > 95:5) together with the stilbene
derivative 6. We were unable to detect any of the co-
metathesis product derived from 2 or c-lactam 4, which
would be the result of a competing ATRC reaction. We
also verified, in a separate experiment, that a purified
sample of the cross metathesis product 5 was amenable
to radical cyclization, as its exposure to an ATRC cata-
lyst (CuCl/dHbipy, 5 mol %; ClCH2CH2Cl; 80 °C;
3.5 h) afforded the c-lactam 7 in 60% yield (as a 1:1
mixture of diastereoisomers). That these two different
dHbipy = 4,40-di-n-heptyl-2,20-bipyridine.

C. D. Edlin et al. / Tetrahedron Letters 47 (2006) 1145–1151
1147
O
Ph
O
i
N
+
Cl3C
N
Ph
CCl3
OMe
5
2
3
OMe
MeO
ii
iii
iv
6
OMe
Cl
Cl
H
Cl
Cl
Cl
Cl
O
N
O
OMe
N
Ph
Ph
4
7
Scheme 3. Reagents and conditions: (i) 1b, 5 mol%; toluene; 40 °C; 12 h; 69%; (ii) CuCl, 5 mol %; dHbipy, 5 mol %; toluene; 110 °C; 3 days; 60%; (iii)
(a) 1b, 5 mol %; toluene; 40 °C; 12 h; (b) 110 °C; 3 days; 29% overall yield; (iv) CuCl, 5 mol %; dHbipy, 5 mol %; toluene; 110 °C; 3.5 h; 89%.
Cl
H
Cl
N
Cl
O
Ph
O
i
N
+
X
CCl3
Ph
X
9, X = H
10, X = F
11, X = Br
2
12a, X = H; 26%
12b, X = F; 32%
12c, X = Br; 23%
Scheme 4. Reagents and conditions: (i) 1b, 5 mol %; toluene, 40 °C; 12 h; (ii) 110 °C; 3 days.
O
Ph
Ph
i
N
N
CCl3
+
Cl3C
N
O
O
CCl3
Ph
2
8
H
O
H
O
i
N
N
+
CCl3
CCl3
14
13
E,
Z
Ts
O
i or ii
N
+
R
X
Cl3C
N
R
O
CCl3
Ts
15
Scheme 5. Reagents and conditions: (i) 1b, 5 mol %; CH2Cl2; 40 °C; 16 h; (ii) 1b, 5 mol %; toluene, 12 h; 40 °C.

1148
C. D. Edlin et al. / Tetrahedron Letters 47 (2006) 1145–1151
ii
i
O
O
HO
16
iii
17
O
iv
18
O
CCl3
O
O
Cl
O
O
O
Cl
O
O
iv
v, vi
vii
H
H
H
H
Cl3C
X
19
20
21
Scheme 6. Reagents and conditions: (i) microwave irradiation, neat, 1 h; 100%; (ii) vinyl magnesium bromide, 1.5 equiv; Et2O, ꢀ78 °C; 98%; (iii)
trichloroacetyl chloride, 1.2 equiv; triethylamine 1.2 equiv; Et2O; 0 °C; 95%; (iv) 1b, 5 mol %; CuCl, 5 mol %; dHbipy, 5 mol %; CDCl3, 2 h at 20 °C
and then 3 h at reflux; 95%; (v) (a) CeCl3, 1.1 equiv; EtOH; 0 °C; (b) NaBH4, 0.5 equiv; 0 °C; 50%; (vi) trichloroacetyl chloride, 1.2 equiv;
triethylamine, 1.2 equiv; Et2O; 0 °C; unstable oil; (vii) Zn, 10 equiv; 1:3 AcOH–H2O; 100 °C; 69%.
1
20 in 95% isolated yield. Dechlorination of 20 was
readily achieved (Zn, AcOH(aq)) in good yield afford-
ing the unsaturated lactone 21,17 a potentially useful
intermediate in the synthesis of prostaglandins and
related natural products (Scheme 6).
by H NMR spectroscopy proved to be quite revealing.
From these investigations, it appeared that the initial
RCM reaction proceeds rapidly, generating trichloroace-
tate 19. However, this product is thermally unstable and
fragments leading to the generation of cyclopentadiene is
then converted into the final product 20.
Further experimentation (vide infra) indicated that tri-
chloroacetate 19, the product of the initial RCM reac-
tion, is formed rapidly (<2 h at 20 °C) but is extremely
labile, and readily suffers decomposition at the tempera-
ture normally employed in the ATRC reaction. In fact,
the unstable ester 19 could not be converted into lactone
20 using either copper or ruthenium (Grubbs 1a or 1b)
catalysts alone using our standard set of reaction condi-
tions. This observation leads us to suggest therefore that
the Ru–Cu catalyst combination may increase both the
rate of the RCM and ATRC reactions and leads us to
speculate that a bi-metallic catalyst18 may be responsible
for promoting this particular reaction sequence.
The fact that cyclopentadiene is also generated during
the course of the preparative sequence was inferred by
its interception with maleic anhydride, affording the
Diels–Alder adduct 24 in 92% isolated yield when car-
ried out under our standard operating conditions. This
set of observations suggests that the overall process, 18
to 20, is the best described as cascade of reactions
involving an RCM–elimination–intermolecular Khar-
asch addition19a–displacement pathway, as depicted in
Scheme 8.
We suggest therefore that this transformation proceeds
via the intermediacy of 210 and/or 2100, the products of
an intermolecular Kharasch reaction. Once formed,
these intermediates can undergo cyclization, by either
SN2 or SN20 pathways,19b to the observed bicyclic lac-
tone 20. This result also sheds light onto the highly reg-
ioselective deuterium scrambling, which we previously
observed in the Grubbs-mediated ATRC reaction of
the mono-deuterated substrate 25.
Superficially, the overall transformation of 18 into 20
could be described as a tandem RCM–ATRC–elimina-
tion–isomerization reaction, the later stages of which
bore close resemblance to the Grubbs-promoted ATRC
conversion of the related substrate 22 into lactone 231,3
(Scheme 7).
A closer examination of the reaction depicted in Scheme 6
suggests that this mechanistic description may not be the
case as monitoring the conversion of 18 into 20 in CDCl3
We now invoke a similar elimination–intermolecular–
Kharasch addition–displacement pathway for the con-
version of 22 into 23, which in this case proceeds via
the intermediacy of cyclohexa-1,3-diene. In the case of
the deuterated substrate 25, intermolecular capture
(products of 1,2-addition shown for clarity) of dienes
270 and 2700 followed by intramolecular displacement
of the allylic chlorides 28 now accounts for the observed
regiochemistry of the deuterium scrambling in the final
O
Cl
Cl
O
Cl3C
O
O
H
H
i
2
product 26 (Scheme 9). Furthermore, H NMR experi-
22
23
ments revealed that the scrambling of the deuterium
label in 25 is rapid at or near ambient temperature and
takes place more rapidly than the Kharasch reaction.
Scheme 7. Reagents and conditions: 1a, 5 mol %; toluene; 110 °C;
12 h; 80%.

C. D. Edlin et al. / Tetrahedron Letters 47 (2006) 1145–1151
1149
O
O
RCM
Elimination
Cl3C
O
18
CCl3
19
O
Cl3CCO2H
Intermolecular
Kharasch
ii
i
Cl
O
Cl
Cl
O
HO
Cl
Cl
and/or
H
H
O
Displacement
21'
Cl
H
H
H
H
Cl
O
O
O
O
20
HO
24
Cl
21"
Scheme 8. Reagents and conditions: (i) (a) 1b, 5 mol %; CuCl 5 mol %; dHbipy 5 mol %; CDCl3; 2 h; 20 °C; (b) reflux; 3 h; 95%; (ii) as in (i) but with
the addition of maleic anhydride (1 equiv) as co-reactant; 92%.
O
D
Cl
O
D
OH
D
O
Cl
Cl3C
Cl
25
OH
D
Cl
27'
O
Cl Cl
O
Cl
O
H
O
D
OH
Cl3C
D
D
Cl
Cl
OH Cl
Cl Cl
25'
27''
O
D
O
Cl
Cl
H*
[ *= partial D incorporation]
O
28
H*
H*
H*
26
Scheme 9. Proposed pathway for the conversion of 25 into 26.
In consonance with this proposal, we also note that
exposure of 22 to the Grubbs catalyst 1b in the presence
of maleic anhydride (1 equiv) results in the isolation of
the Diels–Alder adduct, 29 in excellent yield, suggesting
that the [4+2]-cycloaddition reaction of cyclohexa-1,3-
diene again competes favourably with the intermolecu-
lar Kharasch reaction (Scheme 10). Moreover, exposure
of the deuterated substrate, 25, to the same set of reac-
tion conditions, with or without the ruthenium catalyst,
but in the presence of maleic anhydride (1 equiv) results
in the isolation of the Diels–Alder adducts 290 and 2900 in
of the mixture 290/2900 confirms that the deuterium
label is equally scrambled between C1/C7 and C8/C9
(Scheme 10) and also established the intermediacy of
the deuterated dienes 270/2700 during the course of the
cyclization sequence leading from 25 to 26.
We have also established separately, in a preliminary set
of investigations, that cyclization of the readily available
trichloroacetate 30 to ester 22 could be effected using 1b
in ClCH2CH2Cl (98% yield) and that 22 could be
cyclized to trichlorolactone 31 under copper catalysis
in 79% isolated yield.
2
good isolated yields (79–94%). The H NMR spectrum

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C. D. Edlin et al. / Tetrahedron Letters 47 (2006) 1145–1151
In an attempt to combine these two processes, we now
H9
H8
report that exposure of 30 to the first Grubbs catalyst
1a (5 mol % in degassed toluene) first at ambient tem-
perature for 3 h then under conditions of mild thermol-
ysis (110 °C; 16 h) afforded, directly, the unsaturated
lactone 23 in 64% isolated yield together with trace
quantities (<5%) of trichlorolactone 31. Alternatively,
repeating this reaction, this time with the second gener-
ation catalyst 1b, resulted in the isolation of trichloro-
lactone 31 as the major product (in 62% yield)
together with a minor amount of the unsaturated lac-
H
H
i
22
H1
H7
O
O
27
O
29
D
H
H
D
H
H
1
O
D
tone 23 (ca. 5% by H NMR analysis of the crude reac-
O
O
O
O
tion mixture), Scheme 11. In both instances, the
sequential RCM–Kharasch sequences proceeded with-
out the requirement of a copper co-catalyst whilst the
product distribution is obviously dependent upon the
catalyst system employed. The factors affecting the
partitioning of the substrate by the different starter
complexes in this reaction are not, as yet, apparent
although this empirical observation has obvious
synthetic implications.
i or ii
29'
+
27'
+
Cl3C
25
H
D
D
H
H
27''
O
O
O
29"
Scheme 10. Reagents and conditions. For 22 to 29: (i) 1a, 5 mol %;
maleic anhydride, 1.0 equiv; CDCl3; reflux; 92%. For 25 to 290/2900: (i)
1a, 5 mol %; maleic anhydride, 1.0 equiv; toluene; reflux; 3.5 h; 94%;
(ii) maleic anhydride, 1.0 equiv; toluene; reflux; 3.5 h; 79%.
Finally, we have also found that these sequential RCM–
Kharasch reactions can also be applied to the synthesis
of bicyclic lactams. For example, Wittig homologation
iii
iv
i, ii
O
31
22
O
30
CCl3
O
v or vi
Cl
Cl
O
Cl
O
H
H
O
Cl
Cl
O
Grubbs II
Grubbs I
O
O
Cl3C
H
H
31
23
22
Scheme 11. Reagents and conditions: (i) CH2@CHMgBr, 1.5 equiv; Et2O; ꢀ78 °C; 82%; (ii) trichloroacetyl chloride, 1.2 equiv; triethylamine,
1.2 equiv; Et2O; 0 °C; 85%; (iii) 1b, 5 mol %; ClCH2CH2Cl; 3 h; 20 °C; 98%; (iv) CuCl, 5 mol %; dHbipy, 5 mol %; ClCH2CH2Cl; 80 °C; 79%. (v) (a)
1a, 5 mol %; toluene; 3 h; 20 °C; (b) 110 °C; 16 h; 64%; (vi) (a) 1b, 5 mol %; toluene; 3 h; 20 °C; b. 110 °C; 16 h; 62%.
CCl3
i, ii, iii
O
HN
O
16
iv
O
Cl
Cl
Cl
Cl
H
H
vi
v
HN
CCl3
O
O
N
N
H
H
H
H
34
33
32
Scheme 12. Reagents and conditions: (i) Ph3P@CHCO2Et, 1.3 equiv; CH2Cl2; 20 °C; 94%; (ii) Dibal-H, 2.0 equiv; THF; ꢀ78 °C; 97%; (iii) (a) NaH,
1.5 equiv; THF; 0 °C; (b) Cl3CCN, 1.5 equiv; 0 °C; (iv) xylenes; D; 12 h; 85% over two steps; (v) 1b, 5 mol %; xylenes; 20 °C, 3 h then 2 days at 120 °C;
82–91%; (vi) Zn, 10 equiv; 1:3 AcOH–H2O; 100 °C; 73%.

C. D. Edlin et al. / Tetrahedron Letters 47 (2006) 1145–1151
1151
´
Catal. 2002, 344, 634–637; Ferre-Filmon, K.; Delaude, L.;
Demonceau, A.; Noels, A. F. Eur. J. Org. Chem. 2005,
3319–3325; For guiding principles see: Chatterjee, A. K.;
Choi, T.-L.; Sanders, W. P.; Grubbs, R. H. J. Am. Chem.
Soc. 2003, 125, 11360–11370.
of pent-4-enal 16, reduction (Dibal-H), imidate forma-
tion followed by Overman rearrangement led directly
to trichloroacetamide 32 in 87% overall yield. Gratify-
ingly, thermolysis of a solution of 32 in xylenes contain-
ing catalyst 1b (5 mol %) afforded lactam 33 as a single
diastereoisomer in 91% isolated yield. Dechlorination
(Zn–HOAc(aq)) of 33 proved to be highly selective
affording the mono-chlorolactam 3420 in 73% yield
(Scheme 12). In contrast to SnapperÕs report,9 we find
that although the second generation catalyst 1b converts
32 slowly to lactam 33 it does so in a more reproducible
manner than with the first generation catalyst 1a.
11. Concurrent catalysis has precedent in the polymer litera-
ture: Bielawski, C. W.; Louie, J.; Grubbs, R. H. J. Am.
Chem. Soc. 2000, 122, 12872–12973; For dual reactivity
(ATRP and metathesis) see: Delaude, L.; Delfosse, S.;
Richel, A.; Demonceau, A.; Noels, A. F. Chem. Commun.
2003, 1526–1527, and references cited therein.
12. The copper(I)-dHbipy system affords 7 as a 1:1 mixture of
diastereoisomers.
13. c.f. Formentın, P.; Gimeno, N.; Steinke, J. H. G.; Vilar, R.
´
J. Org. Chem. 2005, 70, 8235–8238; Furstner, A.; Thiel, O.
¨
In conclusion, we have demonstrated that the Grubbs
metathesis catalysts can not only promote metathesis
and ATRC reactions,1,6 but that the two separate reac-
tions can be telescoped together providing rapid access
to bicyclic lactones and lactams. We anticipate that
the use of organometallic catalysts in this manner may
have substantial applications in organic synthesis and
is an area which we are now actively pursuing.
R.; Ackermann, L.; Schanz, H.-J.; Nolan, S. P. J. Org.
Chem. 2000, 65, 2204–2207; For a timely review see:
Escoubet, S.; Gastaldi, S.; Bertrand, M. Eur. J. Org.
Chem. 2005, 3855–3873.
14. This may be due to the formation of stable, metathetically
inactive, chelated complexes. For discussion see: Zaja, M.;
Connon, S. J.; Dunne, A. M.; Rivand, M.; Buschmann,
N.; Jiricek, J.; Blechert, S. Tetrahedron 2003, 59, 6545–
6558.
15. See: Davis, C. J.; Hurst, T. E.; Jacob, A. M.; Moody, C. J.
J. Org. Chem. 2005, 70, 4414–4422; Castro, A. M. M.
Chem. Rev. 2004, 104, 2939–3002, and references cited
therein.
16. See: Rivard, M.; Blechert, S. Eur. J. Org. Chem. 2003,
2225–2228, for an example of the activating effect of Cu(I)
salts in CM reactions.
Acknowledgements
We thank the EPSRC and GSK for support of this
research.
References and notes
17. Zanoni, G.; Castronovo, F.; Perani, E.; Vidari, G. J. Org.
Chem. 2003, 68, 6803–6805; Lactone 20 has also been
prepared previously: Fleming, I.; Au-Yeung, B.-W. Tetra-
hedron 1981, 37, 13–24.
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19. Intermolecular Kharasch reactions with buta-1,3-dienes
has precedent: (a) Startsev, V. V.; Zubbritskii, L. M.;
Petrov, A. A. Zh. Obsch. Khim. 1985, 55, 702–703; For
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Y.; Nagai, Y. Main Group Met. Chem. 2000, 23, 259–264;
Matsumoto, H.; Nakano, T.; Ohkawa, K.; Nagai, Y.
Chem. Lett. 1978, 363–366; For related SN2 and SN20
cyclization reactions see: (b) Schomburg, D.; Landrey, D.
N. J. Org. Chem. 1981, 46, 170–172; Bolster, M. G.;
Lagnel, B. M. F.; Jansen, B. J. M.; Morin, C.; de Groot,
A. Tetrahedron 2001, 57, 8369–8379; Ammann, W.;
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´
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Chem. 1981, 59, 164–174), as has their conversion into
the lactone iii.
CO2Me
CO2Me
Cl
H
H
H
O
Cl
Cl
O
H
Cl
ii
iii
i
9. Seigal, B. A.; Fajardo, C.; Snapper, M. L. J. Am. Chem.
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20. All new compounds were fully characterized by high field
1H and 13C NMR, IR, mass spectrometry (low and high
resolution) and/or combustion microanalysis.