Intramolecular cyclopropylmethylation via non-classical carbocations

Article abstract of DOI:10.1039/c7ob01721a

Cyclopropyl-cyclopropyl rearrangement can be achieved selectively by intramolecular trapping of cyclopropylmethyl carbenium ions with an internal nucleophile. This can be exploited as a useful method for the introduction of a cyclopropyl group into complex molecules using readily accessible disubstituted cyclopropane intermediates.

Full text of DOI:10.1039/c7ob01721a

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: M. Skvorcova and
A. Jirgensons, Org. Biomol. Chem., 2017, DOI: 10.1039/C7OB01721A.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Please do not adjust margins
Page 1 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB01721A
Journal Name
COMMUNICATION
Intramolecular cyclopropylmethylation via non-classical
carbocation
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
M. Skvorcova,a A. Jirgensonsa,*
www.rsc.org/
be incompatible with functional groups in the substrate. There
is a strong motivation to develop new methods of cyclopropyl
group installation as it plays an important role in drug
discovery.40 In addition, cyclopropane can serve as precursor
of isopropyl group via C-C bond hydrogenolysis.9
Cyclopropyl-cyclopropyl rearrangement can be achieved
selectively by intramolecular trapping of cyclopropylmethyl
carbenium ion with internal nucleophile. This can be exploited as
a useful method for the introduction of cyclopropyl group into
complex molecules using readily accessible disubstituted
cyclopropane intermediates.
Cyclopropylmethyl (CPM) carbenium ion
A can be represented
as a set of resonance hybrids B1-3 reflecting the contribution
of CPM, cyclobutyl and homoallyl carbenium ions (Figure 1).1-8
Consequently, the selective nucleophilic attack at the non-
Figure 1. Cyclopropyl-cylopropyl rearrangement via non-
classical CPM carbenium ion
,
10
classical ion9 is a useful approach for the synthesis of
-13
,14-
19
,12,20-28
or homoallylic11
cyclopropane1,11
cyclobutane13
derivatives. However, there are limited examples for the
cyclopropane based product formation resulting from the
rearrangement of CPM ion A to ion C. Such a cyclopropyl-
cyclopropyl rearrangement has been observed in the
-
mechanistic investigations using isotope labelled substrates.29
31 The intermolecular reaction products of rearranged CPM ion
C
have also been isolated, typically as a mixture with other
Scheme 1. Intramolecular cyclopropylmethylation via
products of CPM ion reaction.31 In addition, cyclopropyl-
cyclopropyl rearrangement involving CPM ion has been
proposed for the biosynthesis of cyclopropane containing
sterols.2,33-35 Nevertheless, according to our literature survey,
this rearrangement has not been used for selective
introduction of cyclopropyl group into complex molecules. We
explored the feasibility of this reaction type via generation of
,
32
activation of trichloroacetimidate
1
Trichloroacetimidate (OTIm) in substrates
1
was found to be
appropriate leaving group for the generation of CPM ion when
activated with acid catalysts.41-46 Range of acids and solvents
were tested using model substrate 1a (see Supporting
information for details). These studies revealed B(C6F5)3 as
optimal catalyst and CH3NO2 as reaction media in room
temperature to achieve the best yield of product 1a (Table 1).
CPM ion from substrate
which could be assembled from readily available building
blocks (Scheme 1. For the synthesis of substrates see the
Supporting information). It was expected that, in
intramolecular version, the 5- or 6-membered ring formation
would constrain the nucleophile (Y) addition to CPM ion
leading to products (Scheme 1). This approach would
1 containing an internal nucleophile
1
C
2
constitute an alternative to commonly used cyclopropanation
-
reactions36 which often involve expensive reagents and can
39
a.Latvian Institute of Organic Synthesis, Riga, LV-1006, Latvia, e-mail: aigars@osi.lv
† Footnotes relaꢀng to the ꢀtle and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2017, 00, 1-3 | 1
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 2 of 5
View Article Online
DOI: 10.1039/C7OB01721A
Journal Name
COMMUNICATION
Table 1. Substrate scope of intramolecular cyclopropylmethylationa
Yield
of 2, %
Yield
of 2, %
Entry
1
Substrate 1
Product 2
Entry
8
Substrate 1
Product 2
80
92
2
3
85b
9
mixture of products
-
OTIm
O
32
10
76
1c
OTIm
O
71 (2d
17 (2d’
)
)
O
4
5
11
12
91
98
1k
R
61 (2e)
21 (2e’)
MsN
R1
O
S
2e, R = H, R1 = MeO
2e', R = MeO, R1 = H
2l
6
7
13
85
34 (2f)
22 (2f’)
no reaction
-
.
aReaction conditions: 10 mol% B(C6F5)3, CH3NO2, r.t., 0.5 h; b Reaction conditions: 10 mol% BF3 OEt2, CH2Cl2, r.t., 2.5 h.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2017, 00, 1-3 | 2
Please do not adjust margins

Please do not adjust margins
Page 3 of 5
Organic & Biomolecular Chemistry
Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/C7OB01721A
Trichloroacetimidate can serve not only as a leaving group but
also as N-nucleophile. This group was used to achieve
amination of CPM ion derived from bis-imidate 1b providing
oxazoline 2b. The structure of product 2b was proved by X-ray
(see Supporting information). Phenyl group can also be used as
Conclusions
In summary we have demonstrated that cyclopropyl-
cyclopropyl rearrangement can be achieved selectively by
intramolecular trapping of CPM ion with internal nucleophile.
This can be exploited as useful method for the introduction of
cyclopropyl group into complex molecules using readily
accessible disubstituted cyclopropane intermediates.
internal
nucleophile
for
cyclopropylmethylation
as
demonstrated by the transformation of O-benzyl derivative 1c
to isochromane 2c in medium yield. The introduction of
methoxy group to the aromatic system in substrate 1d was
beneficial to improve the yield of cyclopropylmethylation
product which formed as a mixture of two isomers 2d and 2d’.
Substrates 1e,f with nitrogen and carbon atoms in the linker
part provided the corresponding tetrahydroisoquinoline and
tetralin derivatives 2e/e’ and 2f/f’. Surprisingly, sulphide
analogue 1g was unreactive - no conversion was achieved even
with a stoichiometric amount of Lewis acid. O-Benzyl group
with two methoxy substituents in substrate 1h performed as
efficient nucleophile to give the expected product 2h in high
yield. However, the substrate 1i with cyclopropylmethyl group
linked the phenolic oxygen provided mixture of products
instead of expected dihydrobenzofuran. Cyclopropyl-
methylation of furan and thiophene in substrates 1j-l
proceeded efficiently leading to the fused dihydropyrane
derivatives 2j-l. The substrate 1m with the linker attached to
Financial support from the internal grant of Latvian Institute of
Organic Synthesis is acknowledged. We thank Dr. Dmitrijs
Stepanovs for performing X-ray analysis.
Notes and references
1 R. H. Mazur, W. N. White, D. A. Semenow, C. C. Lee, M. S. Silver
and J. D. Roberts, J. Am. Chem. Soc., 1959, 81, 4390.
2 Y. J. Hong, J.-L. Giner and D. J. Tantillo, J. Am. Chem. Soc., 2015,
137, 2085.
3 M. Saunders, K. E. Laidig, K. B. Wiberg and P. v. R. Schleyer, J. Am.
Chem. Soc., 1988, 110, 7652.
4 J. D. Roberts, J. Org. Chem., 2009, 74, 4897.
5 G. A. Olah, V. P. Reddy and G. K. S. Prakash, Chem. Rev., 1992, 92,
69.
the 2nd position of furan gave spirocyclic derivative 2m
.
6 D. P. Kling, E. S. A. Machado, H. C. Chagas, A. P. A. dos Santos, N.
Rosenbach, J. Walkimar Carneiro and C. J. A. Mota, Chem.
Commun., 2013, 49, 4480.
7 M. Franco, Rosenbach Nilton, G. B. Ferreira, A. C. O. Guerra, W. B.
Kover, C. C. Turci and C. J. A. Mota, J. Am. Chem. Soc., 2008, 130,
1592.
Interestingly, only two diastereomers of compound 2m formed
with different configuration at the carbon bearing acetamido
group. The other two stereocenters at tetrahydrofuran ring of
spirocycle 2m have formed with high stereoselectivity –
according to NOESY spectra only the isomer with oxy group cis-
to cyclopropyl group could be detected.
8 G. A. Olah, G. K. Surya Prakash and G. Rasul, J. Am. Chem. Soc.,
2008, 130, 9168.
9 H. N. C. Wong, M. Y. Hon, C. W. Tse, Y. C. Yip, J. Tanko and T.
Hudlicky, Chem. Rev., 1989, 89, 165.
10 R. R. Naredla and D. A. Klumpp, Chem. Rev., 2013, 113, 6905.
11 S. Sarel, J. Yovell and M. Sarel-Imber, Angew. Chem. Int. Ed.
Engl., 1968, 7, 577.
12 W. Rao and P. W. H. Chan, Chem. – Eur. J., 2008, 14, 10486.
13 M. C. Caserio, W. H. Graham and J. D. Roberts, Tetrahedron,
1960, 11, 171.
14 J. W. Wilt and D. D. Roberts, J. Org. Chem., 1962, 27, 3430.
15 S. Kanemoto, M. Shimizu and H. Yoshioka, Tetrahedron Lett.,
1987, 28, 6313.
Scheme 2. Investigation of chirality transfer from
enantioenriched substrate (-)-1j.
Cyclopropyl-cyclopropyl rearrangement is expected to proceed
via configurationally labile carbenium ion formation which
should destroy the defined stereochemistry at the reaction
centre. This was in agreement with experimental results using
enantioenriched substrate (-)-1j which led to racemic product
2j (Scheme 3).
16 C. Hardouin, F. Taran and E. Doris, J. Org. Chem., 2001, 66,
4450.
17 A. M. Bernard, E. Cadoni, A. Frongia, P. P. Piras and F. Secci, Org.
Lett., 2002, 4, 2565.
18 M. Shi and G.-Q. Tian, Tetrahedron Lett., 2006, 47, 8059.
19 A. Chen, R. Lin, Q. Liu and N. Jiao, Chem. Commun., 2009, 6842.
20 C. D. Poulter and S. Winstein, J. Am. Chem. Soc., 1970, 92, 4282.
21 S. Kanemoto, M. Shimizu and H. Yoshioka, Tetrahedron Lett.,
1987, 28, 663.
22 V. K. Yadav and R. Balamurugan, Chem. Commun., 2002, 514.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
Please do not adjust margins

Please do not adjust margins
Organic & Biomolecular Chemistry
Page 4 of 5
COMMUNICATION
Journal Name
23 M. Honda, Y. Yamamoto, H. Tsuchida, M. Segi and T. Nakajima,
Tetrahedron Lett., 2005, 46, 6465.
View Article Online
DOI: 10.1039/C7OB01721A
24 V. K. Yadav and N. Vijaya Kumar, J. Am. Chem. Soc., 2004, 126,
8652.
25 M. Honda, T. Mita, T. Nishizawa, T. Sano, M. Segi and T.
Nakajima, Tetrahedron Lett., 2006, 47, 5751.
26 S. R. Mothe, P. Kothandaraman, W. Rao and P. W. H. Chan, J.
Org. Chem., 2011, 76, 2521–2531.
27 P. Kothandaraman, C. Huang, D. Susanti, W. Rao and P. W. H.
Chan, Chem. – Eur. J., 2011, 17, 10081.
28 D. P. Kranz, S. Chiha, A. Meier zu Greffen, J.-M. Neudörfl and H.-
G. Schmalz, Org. Lett., 2012, 14, 3692.
29 J. E. Baldwin and W. D. Foglesong, J. Am. Chem. Soc., 1968, 90,
4303–4310.
30 P. v. R. Schleyer and Z. Majerski, J. Am. Chem. Soc., 1971, 93,
665.
31 C. D. Poulter and C. J. Spillner, J. Am. Chem. Soc., 1974, 96,
7591.
32 K. B. Wiberg and G. Szeimies, J. Am. Chem. Soc., 1970, 92, 571.
33 A. Meguro, Y. Motoyoshi, K. Teramoto, S. Ueda, Y. Totsuka, Y.
Ando, T. Tomita, S.-Y. Kim, T. Kimura, M. Igarashi, R. Sawa, T.
Shinada, M. Nishiyama and T. Kuzuyama, Angew. Chem. Int. Ed.,
2015, 54, 4353.
34 Y. J. Hong and D. J. Tantillo, Org. Biomol. Chem., 2015, 13,
10273.
35 H. Sato, K. Teramoto, Y. Masumoto, N. Tezuka, K. Sakai, S. Ueda,
Y. Totsuka, T. Shinada, M. Nishiyama, C. Wang, T. Kuzuyama, M.
Uchiyama, Sci. Rep. 2016, 5, 18471.
36 W. A. Donaldson, Tetrahedron, 2001, 57, 8589.
37 H. Lebel, J.-F. Marcoux, C. Molinaro and A. B. Charette, Chem.
Rev., 2003, 103, 977.
38 R. G. Cornwall, O. A. Wong, H. Du, T. A. Ramirez and Y. Shi, Org.
Biomol. Chem., 2012, 10, 5498.
39 D. Y.-K. Chen, R. H. Pouwer and J.-A. Richard, Chem. Soc. Rev.,
2012, 41, 4631.
40 T. T. Talele, J. Med. Chem., 2016, 59, 8712.
41 M. Skvorcova, L. Grigorjeva and A. Jirgensons, Org. Lett., 2015,
17, 2902.
42 L. Grigorjeva, A. Kinens and A. Jirgensons, J. Org. Chem., 2015,
80, 920.
43 V. Kumar, K. Klimovica, D. Rasina and A. Jirgensons, J. Org.
Chem., 2015, 80, 5934.
44 L. Grigorjeva and A. Jirgensons, Eur. J. Org. Chem., 2011, 2011,
2421.
45 D. R. Wallach, P. C. Stege, J. P. Shah and J. D. Chisholm, J. Org.
Chem., 2015, 80, 1993.
46 A. A. Adhikari and J. D. Chisholm, Org. Lett., 2016, 18, 4100.
4 | J. Name., 2012, 00, 1-3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Page 5 of 5
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C7OB01721A
Cyclopropyl-cyclopropyl rearrangement can be achieved selectively by intramolecular trapping of non-
classical carbocation with internal nucleophile.