Design and synthesis of polycyclic sulfones via Diels-Alder reaction and ring-rearrangement metathesis as key steps

Article abstract of DOI:10.3762/bjoc.11.148

Here, we describe a new and simple synthetic strategy to various polycyclic sulfones via Diels-Alder reaction and ring-rearrangement metathesis (RRM) as the key steps. This approach delivers tri- and tetracyclic sulfones with six (n = 1), seven (n = 2) or eight-membered (n = 3) fused-ring systems containing trans-ring junctions unlike the conventional all cis-ring junctions generally obtained during the RRM sequence. Interestingly the starting materials used are simple and commercially available.

Full text of DOI:10.3762/bjoc.11.148

Design and synthesis of polycyclic sulfones via Diels–Alder
reaction and ring-rearrangement metathesis as key steps
Sambasivarao Kotha* and Rama Gunta
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2015, 11, 1373–1378.
Department of Chemistry, Indian Institute of Technology-Bombay,
Powai, Mumbai-400 076, India, Fax: 022-25767152
doi:10.3762/bjoc.11.148
Received: 16 April 2015
Accepted: 20 July 2015
Published: 06 August 2015
Email:
Sambasivarao Kotha* - srk@chem.iitb.ac.in
* Corresponding author
This article is part of the Thematic Series "Progress in metathesis
chemistry II".
Keywords:
alkenylation; Diels–Alder reaction; ring-rearrangement metathesis;
sulfones
Guest Editor: K. Grela
© 2015 Kotha and Gunta; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
Here, we describe a new and simple synthetic strategy to various polycyclic sulfones via Diels–Alder reaction and ring-rearrange-
ment metathesis (RRM) as the key steps. This approach delivers tri- and tetracyclic sulfones with six (n = 1), seven (n = 2) or eight-
membered (n = 3) fused-ring systems containing trans-ring junctions unlike the conventional all cis-ring junctions generally
obtained during the RRM sequence. Interestingly the starting materials used are simple and commercially available.
Introduction
Sulfones [1-8] are popular building blocks [9] in organic are cis-configured at the ring junctions. The main driving force
synthesis. They are also useful substrates for the for the RRM of these systems is the release of ring strain. The
Ramberg–Bäcklund reaction [10] and they can be alkylated via configuration is transferred from the starting material to the
carbanion chemistry. Moreover, they are suitable synthons in product. In connection with our interest to design new poly-
Diels–Alder (DA) reactions [11-14]. In view of various applica- cycles by RRM [27,28] as a key step, here we conceive unique
tions of sulfone derivatives, we envisioned a new synthetic examples where cis and trans ring junctions are produced in the
strategy based on ring-rearrangement metathesis (RRM) as a RRM reactions.
key step. It is worth mentioning that the RRM strategy [15-23]
Results and Discussion
with a variety of substrates affords intricate products that are
inaccessible by conventional retrosynthetic routes. Several bi- Strategy
cyclo[2.2.1]heptane systems [24-26] are known to undergo Our retrosynthetic strategy to diverse sulfone derivatives is
RRM. However, in almost all instances the products produced shown in Figure 1. The target sulfone derivatives 1 could be
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Beilstein J. Org. Chem. 2015, 11, 1373–1378.
synthesized from the functionalized tricyclic sulfone 2 by RRM oxidizing agent, potassium hydrogen persulfate (KHSO5,
sequence. The sulfone 2 may be prepared from the dimesylate commercially available as Oxone®) in aqueous methanol.
3, which in turn, can be assembled from the known anhydride 4 Equipped with this information, oxidation of compound 5 was
via reduction followed by mesylation of the resulting diol. attempted under similar reaction conditions to get the desired
Compound 4 could be prepared via DA reaction starting with sulfone 6 [33] (Scheme 1, Table 1).
freshly cracked cyclopentadiene and maleic anhydride
(Figure 1).
Initially, when the reaction was carried out at 0 °C, the epoxy
sulfone 7 was the major product (Table 1, entry 1). However,
To realize the strategy shown in Figure 1, we started with the after a considerable amount of experimentation (Table 1), the
preparation of the known compound 4 [29,30]. Later, the DA desired sulfone 6 has been produced in 89% yield (Table 1,
adduct 4 was reduced with LiAlH4 to deliver the corresponding entry 2) but it was not possible to eliminate the formation of the
diol (95%) [31], which was subsequently treated with methane- epoxy sulfone 7.
sulfonyl chloride in the presence of triethylamine as a base to
obtain the dimesylate 3 (89%). Next, compound 3 was Next, our efforts were directed towards the synthesis of various
subjected to a cyclization reaction by treating with sodium alkenylated sulfone derivatives. In this regard, Bloch and
sulfide nonahydrate (Na2S·9H2O) using 20% Aliquat® 336 as a co-workers reported a useful preparation of monoallylated
phase–transfer catalyst (PTC) to produce the known sulfide 5 sulfone 8a [34]. To this end, we carried out the allylation of
(83%) [31].
sulfone 6 with allyl bromide (1.2 equiv) and n-BuLi (2.7 equiv)
at −75 °C to rt. The monoallylated sulfone 8a was obtained in
Having the sulfide 5 in hand, our next task was to prepare 22% yield and the diallylated sulfone 2a in 5% yield. Also,
sulfone 6. In this regard, Trost and Curran [32] have reported 25% of the starting material was recovered. To optimize the
the conversion of sulfides to sulfones in the presence of other yield of diallylated sulfone 2a various conditions were
common functional groups such as olefins by reacting with the studied (e.g., NaH and LDA). In this regard, increasing the
Figure 1: Retrosynthetic approach to polycyclic sulfones.
Scheme 1: Preparation of the sulfone 6 via oxidation.
Table 1: Different reaction conditions used to improve the yield of the sulfone 6.
Entry
Reaction conditions
6 yield [%]
7 yield [%]
1
2
3
4
5
Oxone® (3 equiv), MeOH, H2O, 0 °C, 22 h
Oxone® (2.5 equiv), MeOH, H2O, −5 °C, 6 h
Oxone® (2.5 equiv), MeOH, H2O, −5 °C, 5.5 h
Oxone® (2.2 equiv), MeOH, H2O, −8 °C, 4.5 h
Oxone® (2 equiv), MeOH, H2O, −20 °C, 5 h
29
89
83
82
71
40
8
15
5
5
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Beilstein J. Org. Chem. 2015, 11, 1373–1378.
equivalents of allyl bromide and n-BuLi produced the 4-bromo-1-butene and n-BuLi in the presence of HMPA at
diallylated sulfone 2a in 80% yield and the monoallylated com- −74 °C to rt to deliver the monobutenylated sulfone 8b in 75%
pound 8a in 10% yield (Table 2, entry 1a) [35] along with a yield. Surprisingly, here a minor amount of the desired
minor amount (3%) of triallylated sulfone 9 (Scheme 2). dibutenylated sulfone 2b (21%) was isolated (Table 2, entry 2).
However, with an excess amount of base (5 equiv) and allyl However, the monobutenylated sulfone 8b can be converted to
bromide the diallylated sulfone 2a was isolated as a major prod- the dibutenylated sulfone 2b under similar conditions. Next, the
uct and the triallylated sulfone 9 in 6% yield (Table 2, entry 1b). same synthetic sequence has been extended to the dipentenyl
Later, the monoallylated sulfone 8a has been converted to the and the dihexenyl sulfone derivatives. Thus, treatment of
desired diallyl compound 2a (88%) under similar reaction sulfone 6 with 5-bromo-1-pentene and n-BuLi using HMPA at
conditions. The structures of the diallyl (2a) and triallyl (9) −78 °C to rt (Table 2, entry 3) gave the desired dipentenylated
sulfones have been confirmed by 1H and 13C NMR spectral sulfone 2c (57%) and a minor amount of monopentenylated
data and further supported by HRMS data. In addition, the sulfone 8c (5%).
structure and stereochemistry of the allyl groups present in
compound 2a have been confirmed by single-crystal X-ray Similarly, we synthesized the hexenyl sulfone derivatives 8d
diffraction studies and this data clearly indicated that the and 2d by treating compound 6 with 6-bromo-1-hexene using
allylation had occurred at α-position of the sulfone moiety and HMPA and n-BuLi at −78 °C. The desired dihexenylated
the two allyl groups are in cis-arrangement with each other [35- sulfone 2d has been furnished in 75% yield along with mono-
37].
hexenyl sulfone derivative 8d (9%, Table 2, entry 4). Based on
these optimization studies, it was concluded that it is necessary
Analogously, the alkenylation of sulfone 6 was optimized with to use the appropriate number of equivalents of the alkenyl
other electrophiles and the results are summarized in Table 2 bromide and the suitable base to generate the dialkenylated
(entries 2–4). In this regard, sulfone 6 was butenylated with products (Table 2 and Scheme 2).
Scheme 2: Synthesis of alkenylated sulfone derivatives.
Table 2: Optimized reaction conditions to realize mono and dialkenylated sulfones.
Entry
n
Reaction conditions
Monoalkenylated product
yield [%]
Dialkenylated product
yield [%]
1a
1b
2
1
allyl bromide (3 equiv), n-BuLi
THF, −75 °C to rt, 25 h
8a (10)
8a (0)
2a (80) & 9a (3)
2a (80) & 9a (6)
2b (21b)
allyl bromide (10 equiv), n-BuLi
THF, −58 °C to rt, 26 h
2
3
4
4-bromo-1-butene (3 equiv), n-BuLi
HMPA, THF, −74 °C to rt, 20 h
8b (75b)
8c (5)
3
5-bromo-1-pentene (2.5 equiv), n-BuLi
HMPA, THF, −78 °C to rt, 17.5 h
2c (57)
4
6-bromo-1-hexene (2.8 equiv), n-BuLi
HMPA, THF, −78 °C to rt, 17 h
8d (9)
2d (75)
aTriallylated product, bisolated yield based on starting material recovered.
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Beilstein J. Org. Chem. 2015, 11, 1373–1378.
After the successful synthesis of various dialkenyl sulfone Next, the RRM of dipentenyl sulfone 2c (~0.0031 M solution in
derivatives 2a–d, we focussed our attention towards the RRM toluene) was carried out under similar reaction conditions to
step. Initially, the diallyl sulfone 2a (~0.0141 M solution in dry furnish 1c. Interestingly, the tricyclic sulfone 11 was isolated in
CH2Cl2) was subjected to RRM using G-I catalyst in the pres- 60% along with the expected tetracyclic sulfone 1c (32%) and a
ence of ethylene gas in refluxing CH2Cl2 to get the tetracyclic minor amount of ring-opened product 12 (6%, Scheme 5). A
sulfone 1a, however, we isolated the tricyclic sulfone 10 in 48% complex mixture of products was obtained when compound 2c
yield. When the G-I catalyst was replaced with G-II a complex was exposed to the metathesis catalyst for a longer period of
mixture of products was observed as indicated by 1H and time as indicated by 1H and 13C NMR spectral data.
13C NMR spectral data. Later, compound 10 was treated with
conventional Grubbs catalysts under different reaction condi- Analogously, dihexenyl sulfone 2d (~0.0024 M solution in
tions (Table 3) to obtain the RRM product 1a (Scheme 3). toluene) was treated with G-II catalyst to deliver the RRM prod-
Unfortunately, the expected compound 1a was not obtained. uct in the presence of ethylene in refluxing toluene. In this
The strain present in the trans-fused compound 1a may be re- regard, only ring-opened sulfone 13 was produced in 88% yield
sponsible for its absence in the RRM sequence.
(Scheme 6) and no cyclized product was observed. Presumably,
this observation may be explained on the basis that the nine-
Interestingly, dibutenyl sulfone 2b (~0.0034 M solution in membered ring product was not formed due to the unfavourable
toluene) smoothly underwent RRM with Grubbs 2nd generation steric interactions involved.
(G-II) catalyst in the presence of ethylene in refluxing toluene
to produce the anticipated tetracyclic sulfone 1b (97%) Conclusion
(Scheme 4). The sulfone 1b has been characterized by 1H and Several interesting polycyclic sulfone derivatives were designed
13C NMR and DEPT-135 spectral data including HRMS data. and assembled involving RRM. The RRM outcome of various
Scheme 3: Synthesis of 10 by RRM of 2a.
Table 3: Toluene (~0.004 M) reflux conditions to convert 10 to 1a.
Entry
Conditions
Result
1
2
3
G-I (10 mol %), C2H4, 19 h
SMa recovered
No productb
No productb
G-II (10 mol %), Ti(OiPr)4, C2H4, 24 h
HG-IIc (10 mol %), Ti(OiPr)4, C2H4, 24 h
aStarting material. bSM not recovered, cHoveyda–Blechert–Grubbs catalyst.
Scheme 4: Synthesis of 1b using RRM.
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Beilstein J. Org. Chem. 2015, 11, 1373–1378.
Scheme 5: RRM of the dipentenyl sulfone 2c.
Scheme 6: RRM of the dihexenyl sulfone 2d.
sulfones (2a–d) depends on the length of the alkenyl chain. In thanks the University Grants Commission (UGC), New Delhi
this context, the dibutenyl sulfone derivative 2b is the most- for the award of a research fellowship.
promising candidate for the RRM protocol. In other instances,
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