Anionic cascade reactions. One-pot assembly of (Z)-chloro-exo- methylenetetrahydrofurans from β-hydroxyketones

Article abstract of DOI:10.3762/bjoc.9.148

The assembly of (Z)-chloro-exo-methylenetetrahydrofurans by an original and connective anionic cascade sequence is reported. Base-catalysed condensation of β-hydroxyketones with 1,1-dichloroethylene generates, in moderate to good yields, the corresponding

Full text of DOI:10.3762/bjoc.9.148

Anionic cascade reactions. One-pot assembly
of (Z)-chloro-exo-methylenetetrahydrofurans from
β-hydroxyketones
István E. Markó* and Florian T. Schevenels
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1319–1325.
Université catholique de Louvain, Laboratory of Organic and
Medicinal chemistry, Place Louis Pasteur 1 bte L4.01.02, 1348
Louvain-la-Neuve; Belgium, Fax 0032-10-472788
doi:10.3762/bjoc.9.148
Received: 08 April 2013
Accepted: 12 June 2013
Published: 03 July 2013
Email:
István E. Markó* - istvan.marko@uclouvain.be
This article is part of the Thematic Series "Creating complexity".
Guest Editor: D. Craig
* Corresponding author
Keywords:
acetylene addition; dichloroethylene; dimerisation; dioxanes;
tetrahydrofurans
© 2013 Markó and Schevenels; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The assembly of (Z)-chloro-exo-methylenetetrahydrofurans by an original and connective anionic cascade sequence is reported.
Base-catalysed condensation of β-hydroxyketones with 1,1-dichloroethylene generates, in moderate to good yields, the corres-
ponding (Z)-chloro-exo-methylenetetrahydrofurans. Acidic treatment of this motif leads to several unexpected dimers, possessing
unique structural features.
Introduction
Recently, we have shown that simple ketones reacted with
1,1-dichloroethylene, in the presence of potassium tert-
butoxide, to afford rare (Z)-chloro-exo-methyleneketals [1-3].
This unique transformation is particularly efficient in the case
of six-membered ring ketones (Scheme 1). In an attempt to
extend the scope of this cascade process to acyclic ketones,
acetone was submitted to the usual reaction conditions. To our
surprise, the expected adduct 5 was formed in only poor yields.
The major product was isolated in 36% yield and its structure
was unambiguously determined as the (Z)-chloro-exo-
methylenetetrahydrofuran 6.
The generation of 6 can be rationalized as depicted in
Scheme 1: Formation of (Z)-chloro-exo-methyleneketals.
Scheme 2. Under the basic conditions employed for the cascade
1319

Beilstein J. Org. Chem. 2013, 9, 1319–1325.
Scheme 2: Mechanism of formation of (Z)-chloro-exo-methylenetetra-
hydrofurans.
reaction, 1,1-dichloroethylene is converted into the corres-
ponding chloro-acetylene anion 9 [4,5]. This nucleophilic
species adds rapidly, though reversibly, to acetone, leading ul-
timately to the formation of 5. However, in this case, competi-
tive aldol reaction appears to take place, delivering the adduct 8.
The subsequent addition of 9 then affords the intermediate 10,
which undergoes a 5-exo-dig cyclisation, ultimately yielding the
observed (Z)-chloro-exo-methylenetetrahydrofuran 6.
Scheme 3: Stepwise formation of (Z)-chloro-exo-methylenetetrahydro-
furans.
This structural motif constitutes the core of several biologically
active compounds, including antimicrobial agents, fungicides
and interesting competitive inhibitors of S-adenosyl-L-homo-
cysteine (AdoHcy) hydrolase, one of the target enzymes exten-
sively studied in the context of antiviral chemotherapy [6-9].
Despite their utility, only a limited number of multistep
methods have been described for the preparation of this subunit
[10-16]. The paucity of efficient synthetic approaches towards
this family of compounds and the desire to assess the scope and
Scheme 4: Optimized protocols to form (Z)-chloro-exo-methylenetetra-
hydrofurans.
limitations of this method prompted us to further investigate ably due to a rapid retro-aldol reaction of the derived, rather
this transformation.
hindered, potassium alkoxide. Applying the LDA/KOt-Bu
protocol improved the yield to 41%.
Results and Discussion
When 4-hydroxy-2-butanone (11) was treated with lithium It thus transpires that good to excellent yields of (Z)-chloro-exo-
chloroacetylide, generated in situ from dichloroethylene and methylenetetrahydrofurans could be obtained by the judicious
LDA, the diol 12 was obtained in 77% yield. This adduct choice of the bases employed to promote this cascade process.
smoothly cyclized to 13 upon addition of sodium or potassium Having delineated some suitable conditions, the scope and
tert-butoxide, thereby supporting our mechanistic proposal. limitations of this methodology were investigated [17-27].
Repeating the process without isolation of the intermediate diol Some selected examples are collected in Table 1.
12 proved to be even more efficient, affording the (Z)-chloro-
exo-methylenetetrahydrofuran 13 in 66% overall yield As can be seen from Table 1, the reaction proves to be quite
(Scheme 3).
general and high-yielding for several primary alcohols (Table 1,
entries 2, 3, 7 and 8). The yield was somewhat lower for two of
It is interesting to note that, in the case of the substrate 11, the them (Table 1, entries 4 and 6) due to rapid retro-aldol reac-
adduct 13 could be isolated in an improved 81% yield when tions and to enhanced steric hindrance, respectively. In the case
potassium tert-butoxide was employed as the sole base of tertiary alcohols, the reaction proceeded with acceptable
(Scheme 4). In stark contrast, applying this procedure to the yields, especially in view of the one-pot nature of our procedure
keto-alcohol 14 resulted in a mediocre 13% yield of 6, prob- (Table 1, entries 1 and 5).
1320

Beilstein J. Org. Chem. 2013, 9, 1319–1325.
Having access to a broad range of substituted (Z)-chloro-exo-
methylenetetrahydrofurans, a brief survey of their reactivity was
performed. Several reactions involving the vinyl chloride func-
tion proved unsuccessful [28,29]. Attempts to perform oxida-
tive rearrangement and dehydration failed and functionalisation
of the hydroxy group appeared difficult [30,31]. Initially, the
adduct 13 was treated with aqueous hydrochloric acid, in the
hope of generating the corresponding dihydrofuran carbalde-
hyde 33. Instead, the diol 34 was obtained in 52% yield as a
Table 1: Preparation of (Z)-chloro-exo-methylenetetrahydrofurans.
(continued)
7
8
77%c
23
24
31
32
10%c
61%b
Table 1: Preparation of (Z)-chloro-exo-methylenetetrahydrofurans.
aAll yields are for pure, isolated products. bIn these cases, 2.2 equiv of
C2H2Cl2 and 4.4 equiv of LDA were used in the first step, followed by
1 equiv of t-BuOK in the second step. cFor these substrates, 2.5 equiv
of C2H2Cl2 and 5 equiv of t-BuOK were used to generate the acetylide.
1:1 mixture of diastereoisomers. It thus transpires that protona-
tion and hydration of the exo-methylene double bond of 13
proceeded faster than the expected rearrangement of the tertiary
allylic alcohol (Scheme 5).
Entry
Substrate
Product
Yielda
39%b
1
17
25
26
27
28
29
2
3
4
5
80%c
73%c
18
19
20
21
Scheme 5: Hydration of (Z)-chloro-exo-methylenetetrahydrofurans.
To promote such an acid-catalyzed rearrangement, the
(Z)-chloro-exo-methylenetetrahydrofuran 13 was treated with a
catalytic amount of para-toluenesulfonic acid. To our surprise,
the anti-dioxane 35 and its syn-derivative 36 were obtained as a
1:5 mixture of diastereoisomers that could be separated
(Scheme 6). Their structure was unambiguously established by
single-crystal X-ray diffraction analysis, as shown in Figure 1.
Increasing the steric hindrance at the tertiary alcohol site
resulted in the exclusive formation of the syn-dioxanes 37 and
38 respectively, albeit at the expense of the yield [32-38].
38%c
47%b
40%b
42%c
When the dimethyl adduct 6 was submitted to the same condi-
tions, a new product [39-45] 41 was formed besides the diox-
anes 39 and 40 (Scheme 7). Its structure was unambiguously
established as the spirocyclic dimer 41 by single-crystal X-ray
diffraction analysis. It is noteworthy that a single diastereoiso-
mer was generated in this transformation.
6
22
30
The formation of these unique compounds can be rationalized
as depicted in Scheme 8. Under acidic conditions, the
1321

Beilstein J. Org. Chem. 2013, 9, 1319–1325.
Scheme 7: Formation of a new spirocyclic dimer.
ether function, followed by 6-exo-trig cyclization, completes
this sequence of events and provides the dioxane derivative 46.
Interestingly, no reaction was observed when the spirocycle 41
and the dioxanes 35, 36 and 39 were reacted under acidic condi-
tions, indicating that the final step is not reversible.
Scheme 6: Formation of dioxanes.
Figure 1: X-ray diffraction analysis of dioxanes 35 and 36.
(Z)-chloro-exo-methylenetetrahydrofuran 42 is converted into
the oxonium cation 43. Subsequent capture of this intermediate
43 by a second molecule of 42 can occur via two different path-
ways. The first one involves the addition of the enol ether func-
tion of 42 onto 43, leading to the creation of a new C–C bond
with concomitant generation of another oxonium species 47.
Intramolecular capture of this electrophile by the pendant
hydroxy substituent then delivers the spirocyclic adduct 48.
Alternatively, reaction of the tertiary alcohol of 42 with the
oxonium cation 43 affords the ketal 44. Protonation of the enol
Scheme 8: Mechanism leading to dioxanes and spirocycles.
1322

Beilstein J. Org. Chem. 2013, 9, 1319–1325.
It is noteworthy that the dioxanes possess predominantly (13) or
exclusively (26 and 27) the syn–syn relative stereochemistry at
the ring junctions. This selectivity can be rationalized by an
initial addition of the nucleophile syn to the alcohol function, as
shown in Scheme 9. Interestingly, the homochiral (S,S;R,R)-
dimer, leading to the syn–syn product, is preferred over the
heterochiral (S,R;R,S)-adduct, affording the syn–anti isomer.
Increasing the steric hindrance at the tertiary alcohol center of
49 leads to prohibitive steric repulsion during the heterodimer
formation. A similar facial selectivity can explain the formation
of 41 as a single diastereoisomer.
Scheme 10: Formation of a bridged dimer and a triene.
Scheme 9: (S,S)-syn and (S,R)-syn approaches.
When the adduct 25, bearing a gem-dimethyl substituent was
submitted to this transformation, no dioxane was observed. The
major product proved to be the spirocyclic adduct 53, accom-
panied by the bridged bis-ketal 52, in 41% and 13% yield res-
pectively (Scheme 10). Treatment of the isopropyl derivative 29
under the same acidic conditions provided the triene 54 in 57%
yield. Addition of aqueous HCl generated the hemi-ketal 55 in
43% yield. The starting material was recovered in 52% yield.
The structures of compounds 53 and 55 were unambiguously
established by single-crystal X-ray diffraction analysis
(Figure 2).
Once again, increasing the steric effect around the tertiary
alcohol function of the (Z)-chloro-exo-methylenetetrahydro-
furans has a profound influence on the fate of the condensation
reaction. A plausible mechanistic rationale is provided in
Scheme 11.
Figure 2: X-ray diffraction analysis of two new dimers.
oxonium ion 57, which undergoes a 1,4-addition of another 56
unit, affording the new cation 58. At this stage, two different
pathways can be followed. Either carbocation 58 can lose a
proton, generating the observed triene 59, or it may undergo
addition of a water molecule, affording the hemiketal 60. Add-
ition of a proton to the vinyl ether function, followed by
intramolecular capture by the hydroxy group, finally provides
the unique bridged adduct 62.
In the presence of the gem-dimethyl substituent, dehydration of
42 to afford 56 appears to proceed rapidly, probably owing
to a release of steric strain. The loss of water occurs especially
readily when R’ = Et or iPr and to a lesser extent when
R’ = Me, indicating that steric decompression may indeed be
operational in these cases. Protonation of diene 56 leads to the
1323

Beilstein J. Org. Chem. 2013, 9, 1319–1325.
Scheme 11: Mechanism leading to bridged and dienic dimers.
Conclusion
was dried, filtered and concentrated. The crude product was
In summary, a unique anionic cascade process, leading to the further purified by chromatography over silica gel providing
efficient and connective assembly of (Z)-chloro-exo-methylene- 820 mg (4.6 mmol, 77%) of chloromethylenefuran 31 as a white
tetrahydrofurans from β-hydroxyketones, has been uncovered solid. For full details, see Supporting Information File 1.
and developed. The reactivity of this unusual motif has been
briefly investigated, and dimers, possessing rather unusual
Supporting Information
structures, have been obtained. It is noteworthy that some of
these dimeric products form the core of interesting biologically
Supporting Information File 1
active compounds and of unique natural products.
Experimental procedures and analytical data of cited
compounds.
Experimental
General procedure for the synthesis of
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-9-148-S1.pdf]
chloromethylenefurans
To 40 mL of anhydrous THF, cooled to 0 °C, 1.2 mL
(15.0 mmol, 2.5 equiv) of dichloroethylene and 3.37 g of Acknowledgements
potassium tert-butoxide were added. After 15 minutes, 700 mg Financial support by the Université catholique de Louvain
(6.0 mmol, 1 equiv) of hydroxyketone in 1 mL of THF were (UCL), the Fonds pour la formation à la Recherche
added. After one hour, 20 mL of water was added and the mix- dans l’Industrie et dans l’Agriculture (F.R.I.A.) and the Action
ture was neutralized with diluted sulfuric acid. The aqueous de Recherches Concertées (ARC 08/13-012) is gratefully
layer was extracted with 2 × 20 mL of DCM. The organic layer acknowledged.
1324

Beilstein J. Org. Chem. 2013, 9, 1319–1325.
28.Scheiper, B.; Bonnekessel, M.; Krause, H.; Fürstner, A. J. Org. Chem.
2004, 69, 3943. doi:10.1021/jo0498866
References
1. Schevenels, F.; Markó, I. E. Chem. Commun. 2011, 47, 3287.
29.Qing, F.-L.; Wang, R.; Li, B.; Zheng, X.; Meng, W.-D. J. Fluorine Chem.
2003, 120, 21. doi:10.1016/S0022-1139(02)00279-8
30.Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
doi:10.1021/jo00424a023
doi:10.1039/c0cc05186a
2. Schevenels, F.; Markó, I. E. Org. Lett. 2012, 14, 1298.
doi:10.1021/ol300186s
3. Schevenels, F.; Tinant, B.; Declercq, J.-P.; Markó, I. E. Chem.–Eur. J.
2013, 19, 4335. doi:10.1002/chem.201201505
31.Ishihara, K.; Kubota, M.; Kurihara, H.; Yamamoto, H.
J. Am. Chem. Soc. 1995, 117, 4413. doi:10.1021/ja00120a030
32.Yates, P.; Burke, P. M. Can. J. Chem. 1987, 65, 1695.
doi:10.1139/v87-284
4. Viehe, H. G. Chem. Ber. 1959, 92, 1270.
doi:10.1002/cber.19590920607
5. Kloster-Jenson, E. Tetrahedron 1971, 27, 33.
doi:10.1016/S0040-4020(01)92395-6
33.Martin, O. R.; Rao, S. P.; Hendricks, C. A. V.; Mahnken, R. E.
Carbohydr. Res. 1990, 202, 49. doi:10.1016/0008-6215(90)84070-B
34.Adam, W.; Peters, C.; Sauter, M. Synthesis 1994, 111.
doi:10.1055/s-1994-25416
6. Prakash, N. J.; Davis, G. F.; Jarvi, E. T.; Edwards, M. L.;
McCarthy, J. R.; Bowlin, T. L. Life Sci. 1992, 50, 1425.
doi:10.1016/0024-3205(92)90261-M
35.Dawid, M.; Warkentin, J. Can. J. Chem. 2003, 81, 598.
doi:10.1139/v02-200
7. Buchecker, R.; Fuenfschilling, J.; Marck, G.
Mol. Cryst. Liq. Cryst. Sci. Technol., Sect. A 1997, 302, 295.
doi:10.1080/10587259708041840
36.Timmer, M. S. M.; Stocker, B. L.; Seeberger, P. H. J. Org. Chem. 2006,
71, 8294. doi:10.1021/jo061607m
8. Kumamoto, H.; Onuma, S.; Tanaka, H.; Kitade, Y.
Nucleic Acids Symp. Ser. 2003, 3, 13. doi:10.1093/nass/3.1.13
9. Jarvi, E. T.; McCarthy, J. R.; Mehdi, S.; Matthews, D. P.;
Edwards, M. L.; Prakash, N. J.; Bowlin, T. L.; Sunkara, P. S.; Bey, P.
J. Med. Chem. 1991, 34, 647. doi:10.1021/jm00106a028
10.Kumamoto, H.; Onuma, S.; Tanaka, H. J. Org. Chem. 2004, 69, 72.
doi:10.1021/jo030256y
37.Mukherjee, S.; Roy, B. G.; Das, S. N.; Mandal, S. B. Tetrahedron Lett.
2012, 53, 4929. doi:10.1016/j.tetlet.2012.06.121
38.Ting, C.-M.; Wang, C.-D.; Chaudhuri, R.; Liu, R.-S. Org. Lett. 2011, 13,
1702. doi:10.1021/ol2002144
39.Chang, S.; Britton, R. Org. Lett. 2012, 14, 5844. doi:10.1021/ol302694s
40.Tlais, S. F.; Dudley, G. B. Beilstein J. Org. Chem. 2012, 8, 1287.
doi:10.3762/bjoc.8.146
11.Wnuk, S. F.; Dalley, N. K.; Robins, M. J. J. Org. Chem. 1993, 58, 111.
doi:10.1021/jo00053a022
41.Brimble, M. A.; Finch, O. C.; Heapy, A. M.; Fraser, J. D.; Furkert, D. P.;
O’Connor, P. D. Tetrahedron 2011, 67, 995.
12.Xu, M.; Miao, Z.; Bernet, B.; Vasella, A. Helv. Chim. Acta 2005, 88,
2918. doi:10.1002/hlca.200590235
doi:10.1016/j.tet.2010.11.107
42.Tlais, S. F.; Dudley, G. B. Org. Lett. 2010, 12, 4698.
doi:10.1021/ol102201z
13.Csuk, R.; Glänzer, B. Tetrahedron 1991, 47, 1655.
doi:10.1016/S0040-4020(01)96909-1
43.Fernandes, R. A.; Ingle, A. B. Synlett 2010, 158.
doi:10.1055/s-0029-1218538
14.Gómez, A. M.; Danelón, G. O.; Pedregosa, A.; Valverde, S.;
López, J. C. Chem. Commun. 2002, 2024. doi:10.1039/b205121d
15.Blandino, M.; McNelis, E. Org. Lett. 2002, 4, 3387.
doi:10.1021/ol026422q
44.Ramana, C. V.; Suryawanshi, S. B.; Gonnade, R. G. J. Org. Chem.
2009, 74, 2842. doi:10.1021/jo802539z
45.Seibert, S. F.; Krick, A.; Eguereva, E.; Kehraus, S.; Koenig, G. M.
Org. Lett. 2007, 9, 239. doi:10.1021/ol0626802
16.Craig, G. W.; Sternberg, E. D.; Jones, G. H.; Moffatt, J. G.
J. Org. Chem. 1986, 51, 1258. doi:10.1021/jo00358a017
17.Wasserman, H. H.; Hearn, M. J.; Cochoy, R. E. J. Org. Chem. 1980,
45, 2874. doi:10.1021/jo01302a023
18.Hitchcock, S. R.; Perron, F.; Martin, V. A.; Albizati, K. F. Synthesis
1990, 1059. doi:10.1055/s-1990-27093
License and Terms
19.Einhorn, J.; Soulier, J.-L.; Bacquet, C.; Lelandais, D. Can. J. Chem.
1983, 61, 584. doi:10.1139/v83-104
This is an Open Access article under the terms of the
Creative Commons Attribution License
20.Ueki, T.; Doe, M.; Morimoto, Y.; Kinoshita, T.; Tanaka, R.;
Yoshihara, K. J. Heterocycl. Chem. 2001, 38, 165.
doi:10.1002/jhet.5570380124
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
21.O’Neil, G. W.; Miller, M. M.; Carter, K. P. Org. Lett. 2010, 12, 5350.
doi:10.1021/ol1024635
22.Kim, K. S.; Song, Y. H.; Lee, N. H.; Hahn, C. S. Tetrahedron Lett. 1986,
27, 2875. doi:10.1016/S0040-4039(00)84667-5
23.Schneider, C.; Hansch, M.; Weide, T. Chem.–Eur. J. 2006, 11, 3010.
doi:10.1002/chem.200400951
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
24.Lin, K.-W.; Tsai, C.-H.; Hsieh, I.-L.; Yan, T.-H. Org. Lett. 2008, 10,
1927. doi:10.1021/ol8004326
The definitive version of this article is the electronic one
which can be found at:
25.Sulmon, P.; De Kimpe, N.; Schamp, N. Org. Prep. Proced. Int. 1989,
21, 91. doi:10.1080/00304948909356351
doi:10.3762/bjoc.9.148
26.Trost, B. M.; Yang, H.; Thiel, O. R.; Frontier, A. J.; Brindle, C. S.
J. Am. Chem. Soc. 2007, 129, 2206. doi:10.1021/ja067305j
27.Gerwick, B. C., III; Fields, S. C.; Graupner, P. R.; Schmitzer, P. R.;
Brewster, W. K. Methylidene Mevalonates and their Use as Herbicides.
U.S. Patent CA2527439A1, May 19, 2006.
1325