Mechanistic aspects of alkyne migration in alkylidene carbenoid rearrangements

Article abstract of DOI:10.1021/ol8023665

(Chemical Equation Presented) The mechanism of the Fritsch-Buttenberg- Wiechell rearrangement of ¹³C labeled precursors has been examined to determine the propensity of the alkynyl (R-C=C-) group to migrate in an alkylidene carbenoid species. R

Full text of DOI:10.1021/ol8023665

ORGANIC
LETTERS
2009
Vol. 11, No. 3
519-522
Mechanistic Aspects of Alkyne
Migration in Alkylidene Carbenoid
Rearrangements
Paul Bichler, Wesley A. Chalifoux, Sara Eisler,† Annabelle L. K. Shi Shun,
Erin T. Chernick, and Rik R. Tykwinski*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, T6G 2G2 Canada
rik.tykwinski@ualberta.ca
Received October 13, 2008
ABSTRACT
The mechanism of the Fritsch-Buttenberg-Wiechell rearrangement of 13C labeled precursors has been examined to determine the propensity
of the alkynyl (R-Ct C-) group to migrate in an alkylidene carbenoid species. Reaction of dibromoolefins with n-BuLi and ketones with
Me3SiC(Li)N2 both demonstrate that the alkynyl moiety readily undergoes 1,2-migration from carbenoid intermediates.
The transformation of a carbenoid intermediate into an alkyne
is a versatile synthetic procedure that has become known as
Scheme 1. Fritsch-Buttenberg-Wiechell Rearrangement
the Fritsch-Buttenberg-Wiechell (FBW) rearrangement.1,2
This reaction typically proceeds via metal halogen exchange
of 1,1-dihaloolefins 1 leading to the formation of a carbenoid
intermediate 2 (Scheme 1). R-Elimination of MX and
concurrent migration of a pendant group from the adjacent
carbon then provides the acetylenic product 3.3 This general
protocol has proven useful for the formation of acetylenes
when R and R′ are aryl4 and heteroaryl,5 as well as, to a
lesser extent, alkenyl6 and alkyl groups.7,8 Alkynes also
efficiently undergo 1,2-migration in both alkylidene car-
benoids9 and free carbenes10 to provide, for example, triynes
such as 4 (Scheme 1, R ) R′ ) Ct C-R′′).11
† Current address: Department of Chemistry, University of New Brun-
swick, Fredericton, New Brunswick, E3B 5A3, Canada.
(1) Fritsch, P. Liebigs Ann. Chem. 1894, 279, 319-323. Buttenberg,
W. P. Liebigs Ann. Chem. 1894, 279, 324-337. Wiechell, H. Liebigs Ann.
Chem. 1894, 279, 337-344.
(2) (a) Chalifoux, W. A.; Tykwinski, R. R. Chem. Rec. 2006, 6, 169–
182. (b) Eisler, S.; Tykwinski, R. R. In Acetylene Chemistry: Chemistry,
Biology, and Material Science; Diederich, F., Stang, P. J., Tykwinski, R. R.,
Eds.; Wiley-VCH: Weinheim, Germany, 2005; Chapter 7. (c) Kirmse, W.
Angew. Chem., Int. Ed. 1997, 36, 1164–1170. (d) Hartzler, H. D. In
Carbenes; Moss, R. A., Jones, M. , Jr., Ed.; Wiley and Sons: New York,
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(4) (a) Sahu, B.; Muruganantham, R.; Namboothiri, I. N. N. Eur. J. Org.
Chem. 2007, 2477–2489. (b) Sahu, B.; Namboothiri, I. N. N.; Persky, R.
Tetrahedron Lett. 2005, 46, 2593–2597. (c) Mourie`s, V.; Waschbu¨sch, R.;
Carran, J.; Savignac, P. Synthesis 1998, 271–274. (d) Yamanoi, S.;
Matsumoto, T.; Suzuki, K. Tetrahedron Lett. 1999, 40, 2793–2796.
(5) Kawase, T.; Darabi, H. R.; Uchimiya, R.; Oda, M. Chem. Lett. 1995,
24, 499–500.
(6) Fienemann, H.; Ko¨brich, G. Chem. Ber. 1974, 107, 2797–2803.
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1999, 40, 1899–1902.
354. (f) Ko¨brich, G. Angew. Chem., Int. Ed. 1965, 4, 49–68
.
(3) For an excellent discussion of mechanistic aspects of this reaction,
see: Knorr, R. Chem. ReV. 2004, 104, 3795-3849. See also: Mabry, J.;
Johnson, R. P. J. Am. Chem. Soc. 2002, 124, 6497-6501.
(8) Ko¨brich, G.; Merkel, D.; Thiem, K.-W. Chem. Ber. 1972, 105, 1683–
1693.
10.1021/ol8023665 CCC: $40.75
Published on Web 01/07/2009
2009 American Chemical Society

Mechanistic studies of the FBW rearrangement by Both-
ner-By,12 Curtin,13 and Ko¨brich14 have explored the stereo-
selectivity of this rearrangement for carbenoid intermediates
2 in which R and R′ are aryl or alkyl groups. In most cases,
the group trans to the halide (i.e., R′ in the carbenoid species
2) migrates preferentially. It has been suggested, however,
that cis-migration of an aryl group (e.g., 2, R ) Ar) can be
favored over trans-migration when the group trans to the
leaving group has a substantially reduced migratory aptitude.
This is the case, for example, when the substituent R′ for
intermediate 2 is an alkyl group.3,15-18 Conspicuously absent
from these earlier analyses is an evaluation of the propensity
of the alkynyl moiety to migrate in a carbenoid species. We
report herein an examination of alkyne migration in the FBW
rearrangement in comparison to other common hydrocarbon
groups.
at which point the reaction was quenched.20 Workup and
purification by column chromatography gave diyne 6 in
moderate yield. 13C NMR spectroscopy of the isolated
product shows only one enhanced carbon signal, found at
80.2 ppm. Analysis of the alkyl region of the spectrum shows
the signal of the propargylic carbon as a doublet at 18.9 ppm,
1
and the large JCC ) 66 Hz indicates that the isotopomer
formed by alkyne migration (6a)21 is the exclusive product.
It is worth noting that no evidence of cyclopentene formation
via 1,5-C-H bond insertion of the intermediate carbene/
carbenoid species was observed in this reaction, based on
1H NMR spectroscopic analysis.
The migration of an alkynyl moiety relative to a styryl
group was explored by the rearrangement of dibromoolefin
7 (Scheme 3). It is interesting to note that product ratio of
Enyne 5 was synthesized with a 13C labeled dibromoolefin
to evaluate the migratory potential of an alkynyl group versus
that of an alkyl group (Scheme 2).19 Rearrangement was
Scheme 3. Vinyl versus Alkynyl Migration
Scheme 2. Alkyl versus Alkynyl Migration
accomplished by slow addition of n-BuLi to a solution of 5
in dry hexanes at -78 °C, followed by warming to -40 °C,
8a:8b was seemingly dependent on the progress of the
reaction. Thus, when the reaction temperature was maintained
at -78 °C for ca. 30 min, the conversion of 7 was incomplete
and gave an 83:17 ratio of 8a:8b in 22% yield.22 In addition
to recovered starting material (7), this reaction also gave a
substantial quantity (16%) of Z-vinyl bromide 9,23 resulting
from quenching of the carbenoid intermediate upon workup.
When the reaction temperature was raised to -40 °C prior
to quenching (over a period of ca. 30 min), the ratio 8a:8b
approached 1:1 (53:47, 54% combined yield) and the amount
of byproduct 9 isolated was reduced to 11%. Finally, a
(9) See, for example: (a) Luu, T.; Morisaki, Y.; Cunningham, N.;
Tykwinski, R. R. J. Org. Chem. 2007, 72, 9622–9629. (b) Luu, T.; Elliott,
E.; Slepkov, A. D.; Eisler, S.; McDonald, R.; Hegmann, F. A.; Tykwinski,
R. R. Org. Lett. 2005, 7, 51–54. (c) Eisler, S.; Slepkov, A. D.; Elliott, E.;
Luu, T.; McDonald, R.; Hegmann, F. A.; Tykwinski, R. R. J. Am. Chem.
Soc. 2005, 127, 2666–2676. (d) Eisler, S.; Chahal, N.; McDonald, R.;
Tykwinski, R. R. Chem.-Eur. J. 2003, 9, 2542–2550. (e) Luu, T.; Shi,
W.; Lowary, T. L.; Tykwinski, R. R. Synthesis 2005, 3167–3178.
(10) (a) Tobe, Y.; Umeda, R.; Iwasa, N.; Sonoda, M. Chem.-Eur. J.
2003, 9, 5549–5559. (b) Ochiai, M.; Nishi, Y.; Goto, S.; Frohn, H. J. Angew.
Chem., Int. Ed. 2005, 44, 406–409.
(11) Alkynes are also known to migrate in cationic rearrangements. See,
for example: Marson, C. M.; Walker, A. J.; Pickering, J.; Hobson, A. D.;
Wrigglesworth, R.; Edge, S. J. J. Org. Chem. 1993, 58, 5944-5951.
Schoenen, F. J.; Porco, J. A.; Schreiber, S. L.; VanDuyne, G. D.; Clardy,
J. Tetrahedron Lett. 1989, 30, 3765-3768.
(20) Typical reaction conditions for FBW rearrangement. A solution of
the dibromoolefin in rigorously dry hexanes was cooled to -78 °C under
an inert atmosphere of N2. n-BuLi (ca. 1.2 equiv) was added over a period
of about 2 min. The cold bath was removed, and the reaction mixture was
allowed to warm to -40 °C and stir for a period of ca. 1 h. The reaction
was then quenched by the addition of satd. aq. NH4Cl (10 mL). Work up
and column chromatography gave the desired product. Full synthetic and
spectroscopic details for all new compounds are provided as Supporting
Information.
(12) Bothner-By, A. A. J. Am. Chem. Soc. 1955, 77, 3293–3296.
(13) Curtin, D. Y.; Flynn, E. W.; Nystrom, R. F. J. Am. Chem. Soc.
1958, 80, 4599–4601.
(14) Ko¨brich, G.; Reitz, G.; Schumacher, U. Chem. Ber. 1972, 105,
1674–1682.
(15) Ko¨brich, G.; Ansari, F. Chem. Ber. 1967, 100, 2011–2020
(16) A lack of trans-stereoselectivity has been noted, see: Rezaei, H.;
Yamanoi, S.; Chemla, F.; Normant, J. F. Org. Lett. 2000, 2, 419–421
(17) See also: Bertha, F.; Fetter, J.; Lempert, K.; Kajte´r-Peredy, M.;
Czira, G.; Koltai, E. Tetrahedron 2001, 57, 8889-8895. von der Schulen-
burg, W. G.; Hopf, H.; Walsh, R. Angew. Chem., Int. Ed. 1999, 38,
1128-1130.
(18) For a recent mechanistic study regarding the FBW rearrangement
in ynol ether formation, see: Darses, B.; Milet, A.; Philouze, C.; Greene,
.
.
(21) In Schemes 2-7, the group that has migrated is shown in bold in
the di- or triyne product.
(22) Product ratios were obtained based on integration of the two alkyne
carbons in the 13C NMR spectra. These values are reported as observed,
acknowledging that there is likely a small error due to differences in T1
relaxation times for these nuclei. In cases where only one product is observed
by NMR spectroscopic analysis, the ratio is reported as >95:5. Observed
coupling patterns in the 13C spectra allowed for unambiguous assignment
of the products. See Supporting Information for details.
(23) The stereochemistry for 9 was set based on a GOESY experiment.
Irradiation of the ꢀ-styryl at 6.66 ppm afforded enhancement of the signal
of the vinylidene proton. See Supporting Information for spectra.
A. E.; Poisson, J.-F. Org. Lett. 2008, 10, 4445–4447
.
(19) Dibromoolefins were formed from the corresponding ketone using
the procedure of Ramirez: Ramirez, F.; Desai, N. B.; McKelvie, N. J. Am.
Chem. Soc. 1962, 84, 1745-1747. Corey, E. J.; Fuchs, P. L. Tetrahedron
Lett. 1972, 3769-3772.
520
Org. Lett., Vol. 11, No. 3, 2009

43:57 mixture of enediynes 8a:8b was produced in 89% yield
when the reaction was allowed to warm and react at -40
°C over a period of 1 h. Thus, the evolving ratio of 8a:8b as
a function of reaction progress, coupled with the presence
of 9 (via quenching of the Z-carbenoid that would give rise
to 8b via styryl migration) for incomplete reactions, empiri-
cally suggests that migration of the alkynyl moiety occurs
more rapidly than that of the styryl moiety.24 A definitive
answer to this premise, however, awaits a more in-depth
analysis.
Establishing the identity of the two isotopomers was also
straightforward in this case. The 13C NMR spectrum of the
product showed enhanced signals at 76.5 (major) and 76.3
(minor) ppm from the labeled acetylene carbons of the two
products 8a/8b.25 The major isotopomer showed a doublet
at 106.3 ppm for the ꢀ-styryl carbon, with strong one-bond
coupling (1JCC ) 93 Hz) to the 13C labeled carbon of 8b.
Thus, the larger resonance at 76.5 ppm could be assigned to
8b, and the smaller resonance at 76.3 ppm then belonged to
8a.
impact on the observed product mixture. In the case of 11,
the ratio of isotopomeric products 15a and 15b was more
heavily skewed toward 15b, the product of aryl migration.27
To some extent, the results observed for substrates that bear
a pendent phenyl group (12 and 13) followed the same trend.
Rearrangement of 12 gave a nearly equal ratio of products
16a/16b,28 while the reaction of 13 gave a 2-fold higher
proportion of the diyne 17bversus 17a.29 In all cases for
diynes 14-17, the strong one-bond coupling (1JCC ) 92-95
Hz) between the labeled acetylenic carbon of 14b or
15a-17a to the ipso-carbon of the aryl ring (δ 113 for 14
and 15, δ 121 for 16 and 17) allowed for structural
identification.
Finally, it was intriguing to see if a difference in the silyl
protecting group of an enediyne precursor would affect the
outcome of the rearrangement. Thus, labeled dibromoolefin
18 was synthesized (Scheme 6). FBW rearrangement under
Scheme 6. Alkynyl Migration
The competition between aryl groups and an alkyne was
then explored with dibromoolefins 10-13. Rearrangement
of anisyl derivative 10 (50% 13C labeling) gave a 1:3 mixture
of isotopomers 14a and 14b resulting from alkynyl and aryl
migration, respectively (Scheme 4).26 Altering the identity
Scheme 4. Anisyl versus Alkynyl Migration
typical conditions gave a preference for the product resulting
from migration of the trimethylsilyl-terminated alkyne, with
the triyne products 19a and 19b formed in a 2:1 ratio.30
The first attempt toward forming a free alkylidene carbene
intermediate utilized the Seyferth-Gilbert reagent,
(CH3O)2POCHN2.31 Unfortunately, all attempts to induce the
rearrangement of ketones such as 23 were unsuccessful; i.e.,
(24) No evidence for isomerization of the intermediate carbenoid has
been found to date. Specifically, reverse addition of dibromoolefin 7 to a
solution of n-BuLi provided a ratio of 8a:8b of 57:43 (61%) after reaction
for 1 h at -40 °C, and a ratio of 8a:8b of 44:56 (84%) was formed after
reaction for 2 h at -40 °C. Thus, the results of the reverse addition reactions
are analogous to those of the normal protocol (see Supporting Information
for details and NMR spectra). For a discussion of carbenoid isomerization
under analogous conditions, see ref 3, page 3827. We thank a reviewer for
suggesting this experiment.
of the alkynyl protective group from trimethylsilyl (10) to
the bulkier triisopropylsilyl (11, Scheme 5) had a substantial
(25) The analogous unlabeled diyne product has been previously formed
by the same route. See: Shi Shun, A. L. K.; Chernick, E. T.; Eisler, S.;
Tykwinski, R. R. J. Org. Chem. 2003, 68, 1339–1347.
Scheme 5. Aryl versus Alkynyl Migration
(26) The analogous unlabeled diyne has been reported. See ref 25 and:
Wan, W. B.; Haley, M. M. J. Org. Chem. 2001, 66, 3893–3901.
(27) In the case of diynes 15a:15b, the 13C NMR spectrum shows a ca.
1:9 ratio of 15a:15b, although the 1H NMR shows no indication of 15a
based on the expected 13C coupling to the ortho-aryl protons of 3JCH ) 5.2
Hz. Thus, the ratio of 15a:15b could be less than 1:9.
(28) The analogous unlabeled diyne has been reported: Klusener,
P. A. A.; Hanekamp, J. C.; Brandsma, L. J. Org. Chem. 1990, 55, 1311–
1321.
(29) The analogous unlabeled diyne has been reported: Heuft, M. A.;
Collins, S. K.; Yap, G. P. A.; Fallis, A. G. Org. Lett. 2001, 3, 2883–2886.
(30) All six carbons resonances of 19a/19b were assigned by analogy
to bis(trimethylsilyl)hexatriyne and bis(triisopropylsilyl)hexatriyne. See ref
9c. See also: Rubin, Y.; Lin, S. S.; Knobler, C. B.; Anthony, J.; Boldi,
A. M.; Diederich, F. J. Am. Chem. Soc. 1991, 113, 6943–6949.
(31) Seyferth, D.; Marmor, R. S.; Hilbert, P. J. Org. Chem. 1971, 36,
1379-1386. Gilbert, J. C.; Weerasooriya, U. J. Org. Chem. 1982, 47,
1837-1845. Brown, D. G.; Velthuisen, E. J.; Commerford, J. R.; Brisbois,
R. G.; Hoye, T. R. J. Org. Chem. 1996, 61, 2540-2541.
Org. Lett., Vol. 11, No. 3, 2009
521

the formation of the desired polyyne was not observed.
Attention was then turned to using lithiotrimethylsilyldiazo-
methane (Colvin’s reagent).32,33 It was quickly realized,
however, that the reactions of ynones bearing trimethylsilyl
protected acetylenes with Colvin’s reagent were problematic:
the ynones were not tolerant of the reaction conditions, and
significant baseline material was observed upon TLC analysis
of the reaction mixtures. This is likely a result of siloxide
(Me3SiOs) formation during the reaction which leads to
desilylation of the trimethylsilylethynyl groups from either
the ynone precursor or the polyyne product. In either case,
the formation of the terminal acetylene would account
for the observed decomposition products. Moving to triiso-
propylsilyl protected acetylenes 20-24 did, however, provide
for formation of diynes 25, 26, 15, 17, and triyne 27,
respectively (Scheme 7). The yields for these reactions were,
H-C insertion,3,34 labeled ketone 20 was chosen as a
substrate since the terminal ethyl group is sufficiently short
to prevent this competing reaction. Upon subjecting ketone
20 to Me3SiC(Li)N2, diyne 25a was formed exclusively from
migration of the alkynyl moiety. As was the case with 6a,
large one-bond coupling between the 13C label and the
propargylic carbon at 12.9 ppm provided for a doublet with
1JCC ) 67 Hz and confirmed the constitution of the product.
The reaction of styryl derivative 21 also led only to the
product resulting from alkyne migration 26a, as confirmed
by the doublet at 106.6 ppm (1JCC ) 93 Hz) for the ꢀ-styryl
carbon. Reaction of anisyl ynone 22 led to a 1:2 mixture of
isotopomers 15a:15b, with migration of the anisyl group
dominating over that of the alkyne. Conversely, ynone 23
gave a 9-fold preference for diyne 17a via alkyne migration.
Finally, rearrangement of diynone 24 gave a nearly equal
mixture of 27a and 27b. In the case of polyyne formation
via Colvin’s reagent, the alkynyl group migrates preferen-
tially in comparison to all other substituents, except for
anisyl.
Scheme 7. Rearrangement via Colvin’s Reagent
In conclusion, alkynyl moieties migrate efficiently in
alkylidene carbenoids derived from lithium halogen exchange
affected on 1,1-dibromoolefins and from the reaction of
ynones with Colvin’s reagent. It is clear that the migration
of alkyl groups is disfavored under both reaction scenarios,
while that of the anisyl group is favored in all cases.
Unfortunately, no other general trend emerges based on
expectations derived from known migratory aptitudes. Fur-
ther studies, including those toward establishing the stereo-
chemical implications of the migration process, are ongoing.
Acknowledgment. This work has been generously sup-
ported by the University of Alberta and the Natural Sciences
and Engineering Research Council of Canada (NSERC)
through the Discovery Grant program. We thank NSERC
for scholarships to P.B., W.E.C, and E.L.C. W.E.C. thanks
the Alberta Ingenuity Fund for scholarship support.
however, consistently lower than those obtained from the
dibromoolefin route.
Under the assumption that Colvin’s reagent would afford
an intermediate capable of cyclopentene formation via 1,5-
1
Supporting Information Available: H and 13C NMR
spectra, synthetic, and characterization details for all new
diynes and triynes. This material is available free of charge
via the Internet at http://pubs.acs.org.
(32) Colvin, E. W.; Hamill, B. J. J. Chem. Soc., Perkin Trans. 1 1977,
869-874. Shioiri, T.; Aoyama, T. J. Synth. Org. Chem. Jpn. 1996, 54,
918-928.
(33) To our knowledge, there is only one other reported example of
polyyne formation via Colvin’s reagent. See: Kendall, J.; McDonald, R.;
OL8023665
(34) Taber, D. F.; Yu, H. J. Org. Chem. 1997, 62, 1687-1690. Taber,
D. F.; Plepys, R. A. Tetrahedron Lett. 2005, 46, 6045-6047.
Ferguson, M. J.; Tykwinski, R. R. Org. Lett. 2008, 10, 2163–2166
.
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