Brook Rearrangement as Trigger for Carbene Generation: Synthesis of Stereodefined and Fully Substituted Cyclobutenes

Article abstract of DOI:10.1021/jacs.7b04255

Through a sequence that can be performed in a single vessel, involving regio- and diastereoselective copper-catalyzed carbomagnesiation of cyclopropenes, reaction with acylsilanes, and addition of THF as cosolvent, Brook rearrangement can be triggered to furnish a wide range of cyclobutenes with exceptional diastereoselectivity. Accordingly, stereodefined and highly substituted cyclobutenes with contiguous quaternary carbon centers can be synthesized easily and in high yield. The new strategy constitutes an unprecedented application of Brook rearrangement, one which involves the intermediacy of carbene species.

Full text of DOI:10.1021/jacs.7b04255

Article
Brook Rearrangement as a Trigger for the Formation of Carbene:
Formation of Stereodefined Fully-Substituted Cyclobutene Derivatives
Fa-Guang Zhang, and Ilan Marek
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 01 Jun 2017
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Brook Rearrangement as Trigger for Carbene Generation:
Synthesis of Stereodefined and Fully Substituted Cyclo-
butenes
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Fa-Guang Zhang, Ilan Marek*
The Mallat Family Laboratory of Organic Chemistry, Schulich Faculty of Chemistry, Technion-Israel Institute of
Technology, Technion City, Haifa 32000, Israel
Supporting Information Placeholder
carbene synthesis despite a more recent report demonstrat-
ABSTRACT: Through a sequence that can be performed in a
ing that Ph-C:-NMe2 can be easily synthesized at low tem-
perature by subjection of tertiary amides to PhMe2SiLi
(Scheme 1, path e).12 Intrigued by the above findings, we
wondered whether Brook rearrangement might serve as the
in situ trigger for carbene formation and, if so, might it serve
as the basis for reaction development.
single vessel, involving regio- and diastereoselective copper-
catalyzed carbomagnesiation of cyclopropenes, reaction with
acylsilanes and addition of THF as co-solvent, Brook rear-
rangement can be triggered to furnish a wide range of cyclo-
butenes with exceptional diastereoselectivity. Accordingly,
stereodefined and highly substituted cyclobutenes with con-
tiguous quaternary carbon centers can be synthesized easily
and in high yield. The new strategy constitutes an unprece-
dented application of Brook rearrangement, one which in-
volves the intermediacy of carbene species.
Scheme 1. Brook Rearrangement and its Application to
Carbene Formation
I. INTRODUCTION
Brook originally reported the intramolecular 1,2-anionic
migration of a silyl group from a carbon to an oxygen atom.1
This was later extended to structures where the migrating
silyl unit is more distal from the oxygen atom (Scheme 1,
path a).2 Such [1,2]- and [1,n]-rearrangements are used3 in
sequential relay processes,4 with the ability to generate C–C
bonds through in situ functionalization of the carbanionic
intermediate. In this context, we have recently been interest-
ed in the Zn-Brook rearrangement to generate configuration-
ally stable chiral allenylzinc compounds5 as well as their en-
antiomerically enriched variants6 (Scheme 1, path b). Notably,
the carbanionic species derived from the Brook rearrange-
ment might react with retention7 or inversion8 of stereo-
chemistry depending on the nature of the substrates involved.
For instance, we have shown that [1,2]-Brook rearrangement
of benzylic α-hydroxysilane 2 proceeds with complete inver-
sion of configuration to give, after acidic hydrolysis, an enan-
tiomerically enriched δ-ketoamide that contains a quaternary
carbon stereocenter. The transformation was performed in a
single vessel from easily accessible cyclopropene 1 through a
sequence of carbometalation, addition of acylsilane, Brook
rearrangement, and ring fragmentation (Scheme 1, path c).9
Nonetheless, and despite being less common, α-alkoxysilane
proved to be a source of carbene.10 In particular, Brook re-
ported that α,α-dimethoxybenzylsilane thermally rearranges
at 190 °C to afford methoxysilane and phenylmethoxycarbene
(Scheme 1, path d).11 Because relatively harsh conditions were
necessary for degradation of the α,α-dimethoxybenzylsilane
precursor, this approach has received scant attention for
Based on our past experience regarding development of
diastereoselective synthesis of cyclopropyl-containing α-
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hydroxysilane derivatives 2, we chose to explore the possibil-
tic sample the configuration of which was unambiguously
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ity of using Brook rearrangement as a carbene equivalent and
trigger selective ring-expansion leading to polysubstituted
cyclobutene-containing products (Figure 1).13 If successful,
the above strategy would provide an attractive option for
synthesis of highly functionalized cyclobutenes. Unsaturated
four-membered rings are important class structural motifs
present in many natural products and biologically active
compounds,14 and may be utilized for synthesis of complex
organic molecules.15 Compared to cyclobutanes and cyclobu-
tanones, efficient routes for synthesis of cyclobutenes are
uncommon and their development, especially in a stereocon-
trolled manner, represents a compelling goal in organic syn-
thesis.14a,16 Selective ring expansion of cyclopropanes to cy-
clobutenes is well established.17 We therefore argued that
stereoselective formation of cyclopropanes followed by their
in situ and diastereoselective conversion to an assortment of
highly functionalized cyclobutenes would constitute an at-
tractive single vessel strategy (Figure 1).18 Fully diastereose-
lective carbometalation of cyclopropenyl amides that are
followed by reaction with an acylsilane have previously been
developed (Scheme 1, path c).9 We anticipated that the same
sequence could be performed with various cyclopropenes (1),
affording 2 in high dr. We would then devise a method for in
situ conversion of 2 under relatively mild conditions followed
by an ensuing ring expansion to afford various cyclobutenes.
Formation of Brook rearrangement products, capable of un-
dergoing ring-cleavage, would have to be excluded.9 The
above strategy requires the ability to control selectivity the
ring expansion, since C1–C2 as well as C1–C3 bonds may mi-
grate to generate 3 and 4 in diastereoisomerically pure form
if migration proceeds with stereocontrol.19 The envisioned
one-pot approach would be successful if the issues shown on
Figure 1 could be appropriately addressed.
confirmed through X-ray crystallography (see the Supporting
Information).20 Cyclopropenes may contain different alkyl
groups (R1 at C3: 2a,b and 2e-2f and 2g), can be un-
substituted (R1 = H, 2p), monosubstituted at C2 (R3 = H, 2a-
2l), or disubstituted at C2 (R3 = Me, Ph, 2m-2q). Moreover,
the acylsilane substituent (R5) might be an aryl (2a-2i and 2l-
2q), alkyl (2j), or ester unit (2k), although dr is lower in the
last two instances. Compounds 2l,m,r-t containing an unpro-
tected hydroxyl group, were prepared according to a slightly
modified procedure (see the Supporting Information).21
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Scheme 2. Tandem Carbometalation: Reaction with
Acylsilane on Cyclopropenes 1a-l
2.2 Brook Rearrangement as Trigger for Carbene
Formation and Ring-Expansion.
With a reliable and straightforward method for prepara-
tion of cyclopropyl α-hydroxysilane derivatives (2) in hand,
we turned our attention to in situ generation of carbene by
Brook-rearrangement followed by a ring expansion, which
would deliver the desired cyclobutenes. Initial screening of
different organometallic reagents showed that the simple
deprotonation of the alcohol of the α-hydroxysilane 2a (R1 =
Bu, R2 = CH2OMe, R3 = H, R4 = Me, R5 = Ph) by addition of
MeMgBrꢀLiCl (1.1 equiv, THF, 0 °C) followed by slow warm-
ing of the reaction mixture (20 °C, 2 h) resulted in the for-
mation of 3a in 89% yield as a single isomer (<2% 4a) with
complete stereochemical induction (2a, 95:5 dr; 3a >95:5 dr;
Scheme 3, path a). The presence of LiCl is not mandatory but
allows for slight improvement in yield probably because it
promotes solution homogeneity (Scheme 3, path a). When n-
BuLi, Et2Zn or catalytic amounts of a Grignard reagent were
used as the base, cyclobutenes were not generated.22 Similar-
ly, no cyclobutane was detected when compounds containing
a secondary alcohol (i.e., no C–Si bond). This latter observa-
tion clearly points to Brook rearrangement as a crucial step
within the sequence.
Figure 1. Proposed One-pot Synthesis of Polysubstituted
Cyclobutenes
2. RESULTS AND DISCUSSION
2.1 Diastereoselective Carbometalation of Cyclo-
propenes.
We began by exploring the diastereoselectivity of carbo-
metalation/acylsilane trapping of cyclopropenes 1. We were
pleased to find that the experimental conditions previously
developed for diastereoselective carbometalation/acylsilane
treatment9 of cyclopropenyl amides is readily applicable to
cyclopropenes containing a chelating group; the desired
products were obtained in uniformly high diastereoselectivi-
ty (Scheme 2). Diastereoselectivity was low only when the
cyclopropene substrate lacked a C2 functional group (com-
pare 2a with 2q and 2b with 2g). Stereochemical identity of
the products was assigned by comparing 2n with an authen-
According to the hypothesis that C1–C2 bond migration is
exceptionally stereoselective, we wondered where the meth-
oxy group in 2a can influence on the aforementioned step to
allow for exclusive formation of cyclobutene 3a. In the event,
treatment of compounds 2b, which lack a methoxy unit, to
the same conditions resulted in formation of cyclobutene 3b
in 84% yield as a single isomer. Rearrangements are facile
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regardless of the identity of the substituents at the migrating
On the basis of the investigations reported by Brook11 and
Fleming,12 we propose that ring-expansion proceeds either
via a carbenoid or a carbene that is generated during Brook
rearrangement. Nonetheless, as the stereochemistry of the α-
hydroxysilane (C4) is irrelevant to the migrating group selec-
tivity (Scheme 4, path a), it might imply that either the car-
benoid is configurationally unstable leading to both isomers
before the ring expansion (6a, Scheme 4, path c) or the reac-
tion proceeds through the formation of a carbene as a reac-
tive intermediate (7a, Scheme 4, path c). However, all our
attempts to trap the latter with a double bond either inter-
molecularly or intramolecularly (Scheme 4, path e) didn’t
lead to the trapping products but rather to the cyclobutene
3r in excellent diastereoisomeric ratio.
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carbon: the corresponding methyl benzyl ether (3c), methyl
allylether (3d), CH2OH (3e), aryl (3l) or even alkyl groups
(3p) were readily converted to single rearranged product
isomer. A large assortment of substituents at C3 quaternary
carbon center resulting either from the substituent on the
starting cyclopropenes (R1) or from the Grignard reagent (R4)
are tolerated and the derived cyclobutene products – includ-
ing those that bear two adjacent quaternary carbon stereo-
centers – could be secured with high efficiency and diastere-
oselectivity (Scheme 3, 3i-3n, 3p-u). The relative configura-
tions of the cyclobutene products were determined by X-Ray
crystallographic analysis of compounds derived from 3e and
3n (see the Supporting Information);24 configurations for the
remaining products are by inference. The sole limitation, as
far as we know, is that Brook rearrangement may triggered
carbene formation when R5 possesses an aromatic substitu-
ent. Thus, whereas 2j (R5 = CH2CH2Ph, Scheme 2) remains
unchanged, 2k (R5 = COOt-Bu, Scheme 2) delivers the Brook-
type product exclusively.
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Scheme 4. Probing the Proposed Mechanism
Scheme 3. Brook Rearrangement as Trigger for Carbene
Formation and Ring-Expansion. Probing the Proposed
Mechanism
The selectivity for the ring expansion is therefore as follow:
(1) When C2 possesses a chelating group (Scheme 3, for-
mation of 3a, 3c-n), only the C1-C2 ring expansion is observed
even when two quaternary stereocenters are competing
(Scheme 3, see 3l-3n). (2) When no chelating groups are pre-
sent as in 2b (Scheme 2), the primary carbon center migrates
preferentially to give only 3b (Scheme 3) suggesting that the
migrating carbon acquires a carbanion-like character in the
transition state in such a way that the most stable carbanion
migrates faster (primary > tertiary). (3) When a competition
exists between a quaternary carbon center possessing a che-
lating moiety (C2, R2 = CH2OBn, R3 = Me), versus a secondary
alkyl group (C3, R1 = H, R4 = Me) or a primary group (C3, R1 =
R4 = H), the migratory aptitude could be slightly counter-
balanced (Scheme 3, formation of 3o:4o and 3q:4q in a 15:1
and 5:1 ratio respectively indicated as rr). (4) When two qua-
ternary carbon centers without any functional groups are
concerned (R1 = Bu, R2 = R3 = R4 = Me), the selectivity for the
migration is lower (Scheme 3, formation of 3p) although still
in a surprising 7:1 ratio for 3p:4p. The unique selectivity for
the ring expansion for most of the examples described there-
in is synthetically very appealing but further investigations
To determine whether the migratory aptitude is independ-
ent of C4 stereochemistry (α-hydroxysilane carbon), the two
diastereoisomers of 2a were independently synthesized and
subjected to identical conditions (Scheme 4, path a). Cyclo-
butene 3a was generated in both instances with nearly the
same efficiency and stereoselectivity. In a similar fashion, to
rule out that formation of benzylic carbocationic intermedi-
ate originates from elimination of benzylic magnesium
alkoxide, we subjected 2b to a solution of p-toluenesulfonic
acid in MeOH: the ring-opened product 5 was obtained ex-
clusively in 65% yield (Scheme 4, path b).
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are required to fully understand the rules governing the se-
lectivity.
the nucleophilic addition of acylsilane may be used to access
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a wide range of metalated cyclopropyl α-hydroxy silanes with
high diastereoselectivity. Subsequent addition of THF as the
co-solvent, Brook rearrangement and ensuing ring expansion
completes the single-vessel operation to furnish the corre-
sponding cyclobutene as a single stereoisomer. The method
described herein may be used for facile and exceptionally
stereoselective access to polysubstituted cyclobutenes that
contain two contiguous quaternary carbon stereocenters.
What is more, the unique ring expansion strategy paves the
way for new applications involving Brook rearrangement.
Further studies to extend the chemistry of carbenes generat-
ed by Brook-type rearrangements as well as detailed mecha-
nistic studies are in progress.
2.2 Direct Transformation of Cyclopropenes to Di-
astereomerically Pure Cyclobutenes.
Having established a straightforward access to stereode-
fined cyclobutenes from a selective carbon migration of α-
hydroxy silane derivatives 2, we then carried out the whole
sequence, namely the preparation of polysubstituted cyclo-
butene derivatives 3 from simple cyclopropene species 1
through the combination of a diastereoselective carbomet-
alation reaction, addition of an acylsilane followed by a
Brook rearrangement triggering the ring expansion. To per-
form the desired ring expansion, we simply added THF to the
in-situ formed 2MgBr as described in Scheme 5. We were
pleased to observe that this combined transformation occurs
uneventfully to give 3 in excellent overall yields as a single
diastereoisomer in all cases through the creation of two new
bonds and a selective ring-expansion (Scheme 5).
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ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website. Experimental procedures, charac-
terization data, Crystallographic data for 2n, 3e and 3n, and
more details are provided.
Scheme 5. Direct Transformation of Cyclopropenes to
Diastereomerically Pure Cyclobutenes
AUTHOR INFORMATION
Corresponding Author
chilanm@tx.technion.ac.il
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
We are grateful for financial support by the European Re-
search Council under the Seventh Framework program of the
European Community (ERC grant agreement n 338912). F.-G.
Zhang was supported in part by a fellowship of the Israel
Council for Higher Education and by the Technion Fund for
Cooperation with Far Eastern Universities. I. Marek is holder
of the Sir Michael and Lady Sobell Academic Chair.
REFERENCES
1. (a) Brook, A. G. J. Am. Chem. Soc. 1958, 80, 1886. (b) Brook, A. G.
Acc. Chem. Res. 1974, 7, 77.
2. (a) Lautens, M.; Delanghe, P. H.; Goh, J. B.; Zhang, C. H. J. Org.
Chem. 1995, 60, 4213. (b) Kabat, M. M.; Wicha, J. Tetrahedron Lett.
1991, 32, 1073. (c) Eaborn, C.; El-Kheli, M. N.; Retta, N.; Smith, J. D. J.
Organomet. Chem. 1983, 249, 23. (d) Smith, A. B., III; Xian, M.; Kim,
W.-S. and Kim, D.-S. J. Am. Chem. Soc. 2006, 128, 12368.
3. For selected reviews, see: (a) Sasaki, M.; Takeda, K. In Molecular
Rearrangements in Organic Synthesis; Rojas, C. M., Eds.; John Wiley
& Sons: New York, 2016; Chapter 6. (b) Zhang, H.-J.; Priebbenow, D.
L.; Bolm, C. Chem. Soc. Rev. 2013, 42, 8540. (c) Boyce, G. R.; Greszler,
S. N.; Johnson, J. S.; Linghu, X.; Malinowski, J. T.; Nicewicz, D. A.;
Satterfield, A. D.; Schmitt, D. C.; Steward, K. M. J. Org. Chem. 2012,
77, 4503.
4. For selected reviews, see: (a) Smith, A. B. III.; Wuest, W. M.
Chem. Commun. 2008, 5883. (b) Schaumann, E.; Kirschning, A. Syn-
lett 2007, 177. (c) Moser, W. H. Tetrahedron 2001, 57, 2065.
5. (a) Smirnov, P.; Mathew, J.; Nijs, A.; Katan, E.; Karni, M.; Bolm,
C.; Apeloig, Y.; Marek, I. Angew. Chem. Int. Ed. 2013, 52, 13717. (b)
Smirnov, P.; Katan, E.; Mathew, J.; Kostenko, A.; Karni, M.; Nijs, A.;
Bolm, C.; Apeloig, Y.; Marek, I. J. Org. Chem. 2014, 79, 12122.
With a practical protocol for preparation of cyclo-
butenes 3 from simple cyclopropenes 1 available, substrate 1h
(R1 = Hex, R2 = CH2OMe, R3 = H, R4 = Me, Ar = Ph ) were
readily synthesized with high enantioselectivity (95:5 er)
through catalytic decomposition of diazoester with 1-
octyne.24 The combined diastereoselective carbometalation
reaction, addition of acylsilane, and selective ring-expansion
through the Brook rearrangement afforded cyclobutene 3h as
a single diastereoisomer without any loss in enantiomeric
purity (98:2 dr, 95:5 er, Scheme 5; see the Supporting Infor-
mation). This highlights the potential utility of the present
strategy regarding synthesis of enantiomerically enriched
poly-substituted cyclobutenes.
3. CONCLUSION
In conclusion, regio- and diastereoselective copper-
catalyzed carbomagnesiation of cyclopropenes followed by
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6. (a) Leibeling, M.; Shurrush, K. A.; Werner, V.; Perrin, L.; Marek,
I. Angew. Chem., Int. Ed. 2016, 55, 6057. (b) Collados, J. F.; Ortiz, P.;
Harutyunyan, S. R. Eur. J. Org. Chem. 2016, 3065.
Chem. Rev. 2003, 103, 1449. (c) Namyslo, J. C.; Kaufmann, D. E. Chem.
Rev. 2003, 103, 1485. (d) Roy, S. R.; Eijsberg, H.; Bruffaerts, J.; Marek,
I. Chem. Sci. 2017, 8, 334. (e) Maturi, M. M.;Bach, T. Angew. Chem.
Int. Ed. 2014, 53, 7661. (f) Lopez-Carrillo, V.; Echavarren, A. M. J. Am.
Chem. Soc. 2010, 132, 9292. (g) Nishimura, A.; Ohashi, M.; Ogoshi, S.
J. Am. Chem. Soc. 2012, 134, 15692. (h) Liu, Y.; Liu, M. and Song, Z. J.
Am. Chem. Soc. 2005, 127, 3662. (i) Frebault, F.; Luparia, M.; Oliveira,
M. T.; Goddard, R.; Maulide, N. Angew. Chem., Int. Ed. 2010, 49,
5672.(j) Barluenga, J.; Riesgo, L.; Lopez, L. A.; Rubio, E. and Tom. M.
Angew. Chem. Int. Ed. 2009, 48, 7569. (k) Shi, M.; Liu, L.-P. and
Tang, J. J. Am. Chem. Soc. 2006, 128, 7430. (l) Xu, H.; Zhang, W.; Shu,
D.; Werness, J. B. and Tang, W. Angew. Chem. Int. Ed. 2008, 47, 8933.
16. Masarwa, A.; Fürstner, A.; Marek, I. Chem. Commun. 2009,
5760.
1
2
3
4
5
6
7
8
7. For examples with retention of configuration, see: (a) Hudrlik, P.
F.; Hudrlik, A. M.; Kulkarni, A. K. J. Am. Chem. Soc. 1982, 104, 6809.
(b) Simov, B. P.; Wuggenig, F.; Mereiter, K.; Andres, H.; France, J.;
Schnelli, P.; Hammerschmidt, F. J. Am. Chem. Soc. 2005, 127, 13934.
(c) Unger, R.; Weisser, F.; Chinkov, N.; Stanger, A.; Cohen, T.; Marek,
I. Org. Lett. 2009, 11, 1853.
8. For examples with inversion of configuration, see: (a) Biern-
baum, M. S.; Mosher, H. S. J. Am. Chem. Soc. 1971, 93, 6221. (b) Brook,
A. G.; Pascoe, J. D. J. Am. Chem. Soc. 1971, 93, 6224.
9
10
11
12
13
14
15
16
17
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20
21
22
23
24
25
26
27
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34
35
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
9. Zhang, F.-G.; Eppe, G.; Marek, I. Angew. Chem. Int. Ed. 2016, 55,
714.
10. For selected examples of carbene formation from acylsilane,
see: (a) Becker, P.; Pirwerdjan, R.; Bolm, C. Angew. Chem. Int. Ed.
2015, 54, 15493. (b) Becker, P.; Priebbenow, D. L.; Pirwerdjan, R.;
Bolm, C. Angew. Chem. Int. Ed. 2014, 53, 269. (c) Shen, Z.; Dong, V.
M. Angew. Chem. Int. Ed. 2009, 48, 784. (d) Lu, P.; Feng, C.; Loh, T.-P.
Org. Lett. 2015, 17, 3210. (e) Baines, K. M. Chem. Commun. 2013, 49,
6366. (f) Brook, A. G.; Kucera, H. W.; Pearce, R. Can. J. Chem.1971, 49,
1618.
11. (a) Brook, A. G.; Dillon, P. G. Can. J. Chem.1969, 47, 4347. (b)
Atwell, W. H.; Weyenberg, D. R.; Uhlmann, J. G. J. Am. Chem. Soc.
1969, 91, 2025.
12. (a) Buswell, M.; Fleming, I.; Ghosh, U.; Mack, S.; Russell, M.;
Clark, B. P. Org. Biomol. Chem. 2004, 2, 3006. (b) Fleming, I.; Mack,
S.; Clark, B. P. Chem. Commun. 1998, 713.
17. For recent examples, see: (a) Xu, H.; Zhang, W.; Shu, D.; Wer-
ness, J. B. and Tang, W. Angew. Chem. Int. Ed. 2008, 47, 8933. (b)
Kleinbeck, F. and Toste, F. D. J. Am. Chem. Soc. 2009, 131, 9178. (c)
Barluenga, J.; Riesgo, L.; López, L. A.; Rubio, E. and Tomás, M. Angew.
Chem. Int. Ed. 2009, 48, 7569. (d) Li, C.-W.; Pati, K.; Lin, G.-Y.; Sohel,
S. M. A.; Hung, H.-H. and Liu, R.-S. Angew. Chem. Int. Ed. 2010, 49,
9891.
18. (a) Eppe, G.; Didier, D.; Marek, I. Chem. Rev. 2015, 115, 9175. (b)
Müller, D.; Marek, I. Chem. Soc. Rev. 2016, 45, 4552. (c) Marek, I.;
Simaan, S.; Masarwa, A. Angew. Chem. Int. Ed. 2007, 46, 7364. (d)
Didier, D.; Delaye, P.-O.; Simaan, M.; Island, B.; Eppe, G.; Eijsberg,
H.; Kleiner, A.; Knochel, P.; Marek, I. Chem. Eur. J. 2014, 20, 1038. (e)
Müller, D.; Marek, I. J. Am. Chem. Soc. 2015, 137, 15414.
19. If the migration proceeds with a lost of the configuration, a
mixture of diastereoisomer would be expected.
20. Roy, S. R.; Didier, D.; Kleiner, A.; Marek, I. Chem. Sci. 2016, 7,
5989.
21. Preshel-Zlatsin, M.; Zhang, F.-G.; Eppe, G.; Marek, I. Synthesis,
2016, 48, 3279.
22. Whereas n-BuLi led to only the Brook product after hydrolysis
(see the supporting information), Et2Zn has no effect and 2 is fully
recovered after hydrolysis. If the reaction is performed with a cata-
lytic amount of Grignard reagent, the same catalytic amount of cy-
clobutene is obtained.
23. CCDC 1481882 (2n), CCDC 1484247 (3E) and CCDC 1518467 (3N)
contain the supplementary crystallographic data for this paper. The-
se data can be obtained free of charge from The Cambridge Crystal-
lographic Data Centre.
13. For a recent review, see: Mack, D. J. and Njardarson, J. T. ACS
Catal. 2013, 3, 272. (b) Fürstner, A.; Aïssa, C. J. Am. Chem. Soc. 2006,
128, 6306. (c) Shi, M.; Liu, L.-P.; Tang, J. J. Am. Chem. Soc. 2006, 128,
7430.
14. For recent reviews, see: (a) Misale, A.; Niyomchon, S.; Maulide,
N. Acc. Chem. Res. 2016, 49, 2444. (b) Xu, Y.; Conner, M. L.; Brown,
M. K. Angew. Chem. Int. Ed. 2015, 54, 11918. (c) Dembitsky, V. M.
Phytomedicine 2014, 21, 1559. (d) Fan, Y.-Y.; Gao, X.-H.; Yue, J.-M. Sci.
China Chem. 2016, 59, 1126. (e) Beniddir, M. A.; Evanno, L.; Joseph,
D.; Skiredj, A.; Poupon, E. Nat. Prod. Rep. 2016, 33, 820. (f) Souris, C.;
Frébault, F.; Patel, A.; Audisio, D.; Houk, K. N.; Maulide, N. Org.
Lett. 2013, 15, 3242. (g) Souris, C.; Misale, A.; Chen, Y.; Luparia, M.;
Maulide, N. Org. Lett. 2015, 17, 4486. (h) Ito, H.; Hasegawa, M.;
Takenaka, Y.; Kobayashi, T.; Iguchi, K. J. Am. Chem. Soc. 2004, 126,
4520. (i) Kang, T.; Ge, S.; Lin, L.; Lu, Y.; Liu, X.; Feng, X. Angew.
Chem. Int. Ed. 2016, 55, 5541.
24. Lou, Y.; Remarchuk, T. P.; Corey, E. J. J. Am. Chem. Soc. 2005,
127, 14223.
15. For a few reviews, see: (a) Xu, Y.; Conner, M. L.; Brown, M. K.
Angew. Chem. Int. Ed. 2015, 54, 11918. (b) Lee-Ruff, E.; Mladenova, G.
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