Arylation and vinylation of alkenes based on unusual sequential semipinacol rearrangement/Grob fragmentation of allylic alcohols

Article abstract of DOI:10.1021/jo801434b

(Chemical Equation Presented) Alkenes can be stereoselectively arylated and vinylated without transition-metal catalyst under mild conditions through an interesting NBS-promoted semipinacol rearrangement and a subsequent unusual NaOH-mediated Grob fragmentation.

Full text of DOI:10.1021/jo801434b

SCHEME 1. Sequential Semipinacol Rearrangment/Grob
Fragmentation of Allylic Alcohols
Arylation and Vinylation of Alkenes Based on
Unusual Sequential Semipinacol Rearrangement/
Grob Fragmentation of Allylic Alcohols
Dao-Yi Yuan, Yong-Qiang Tu,* and Chun-An Fan
State Key Laboratory of Applied Organic Chemistry and
Department of Chemistry, Lanzhou UniVersity,
Lanzhou 730000, P. R. China
methods generally require the related premade functionalized
substrates (e.g., halides, stannanes, organoborons, and ylides),
and notably, the employment of expensive transition-metal
catalyst (e.g., Pd) is crucially necessary in most cases.
tuyq@lzu.edu.cn
ReceiVed July 2, 2008
In our recent investigation on tandem protocols based on the
semipinacol rearrangement,11 we interestingly found when a
NBS-promoted semipinacol rearrangement of allylic alcohols
1 was performed in basic medium, the resulting ꢀ-bromo
aldehydes 2 could further undergo an unusual Grob fragmenta-
tion,12 forming aryl- or vinyl-substituted alkenes 3 (Scheme 1).
To our knowledge, this kind of one-pot transformation consisting
of the semipinacol rearrangement and the sequential coelimi-
nation of ꢀ-bromide and formyl group has not been reported.13
This novel one-pot reaction provides a new efficient intramo-
lecular arylation and vinylation method by using allylic alcohols.
The main synthetic feature of this methodology lies in that an
alternative arylation or vinylation of alkenes could be effectively
accessed in the absence of transition-metal catalyst. Additionally,
NBS and NaOH used in this transformation are cheap and easily
available. Besides, the current protocol is insensitive to oxygen
Alkenes can be stereoselectively arylated and vinylated
without transition-metal catalyst under mild conditions
through an interesting NBS-promoted semipinacol rearrange-
ment and a subsequent unusual NaOH-mediated Grob
fragmentation.
Many arene compounds containing vinyl moieties possess
significant physiological, biological,1 and photophysical activi-
ties2 and are often used as building blocks in organic synthesis,
particularly in the preparation of fluorescent materials.3 Thus,
arylation and vinylation of alkenes have long been one of the
most important synthetic methodologies in modern organic
chemistry.4 Many endeavors have been made to discover and
develop various practical methods, among which the well-known
Suzuki,5 Negishi,6 Wittig,7 Heck,8 Stille,9 and Julia10 coupling
methods have played great roles. However, those established
(6) For a review on Nigishi cross-coupling, see: Negishi, E.-i. In Metal-
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A. V. Chem. ReV. 2000, 100, 3009.
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A. M. Angew. Chem., Int. Ed. 2004, 43, 4704.
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Soc., Perkin Trans. 1 2002, 23, 2563.
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Wang, B.; Zhang, S.-Y. Org. Lett. 2004, 6, 4691. (b) Hu, X.-D.; Fan, C.-A.;
Zhang, F.-M.; Tu, Y. Q. Angew. Chem., Int. Ed. 2004, 43, 1702. (c) Wang,
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Angew. Chem., Int. Ed. Engl. 1967, 6, 1. (b) Grob, C. A. Angew. Chem., Int.
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10.1021/jo801434b CCC: $40.75
Published on Web 08/23/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 7797–7799 7797

TABLE 1. Optimization of Reaction Conditionsa
TABLE 2. Substrates Scope of the Semipinacol Rearrangement/
Grob Fragmentation of Allylic Alcohols
entry
NXS
solvent
DMEd
DME
DME
DME
DME
DME
DME
DME
base
Et3N
piperidine
imidazole
NaOAc
K2CO3
DBUe
yieldb,c (%)
1
2
3
4
5
6
7
8
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NBS
NIS
0
0
0
0
0
0
0
82
85
50
5
0
0
0
0
64
0
KOH
9
DME
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
NaOH
10
11
12
13
14
15
16
17
CH3OH
THF/H2Of
CH2Cl2
DMF
benzene
CH3CN
DME
NCSg
DME
a Reaction conditions: allylic alcohol (1.0 mmol), NXS (1.2 mmol),
solvent (2 mL), and base (2-25 mmol) at rt. b For entries 1-7 and
12-15, only the semipinacol rearrangement could be observed. c Isolated
yield. d DME ) 1,2-dimethoxyethane. e DBU ) 1,8-diazabicyclo[5.4.0]undec-
7-ene f THF/H2O ) 10:1. g No semipinacol rearrangement took place.
and moisture, leading to a very convenient experimental
manipulation. Herein we present our results in detail.
The allylic alcohol substrates 1 were prepared by the addition
of the corresponding vinyllithium or -magnesium to the ap-
propriate aldehydes according to our previously reported pro-
cedure.11 The use of 1a as a model substrate was first
investigated for optimizing the reaction condition of this
semipinacol rearrangement/Grob fragmentation. The results
obtained were listed in Table 1. We initially screened several
organic and inorganic bases in parallel experiments (entries
1-9). Of the bases examined, we found that 25 equiv of NaOH
was the best choice to form the alkene product 3a in highest
yield of 85% (entry 9). Solvent effects were examined as well
(entries 9-15) in which DME was found to be the best reaction
media. NCS and NIS were also tested in DME, wherein the
use of NIS followed by addition of NaOH could afford the
desired product in 64% yield (entry 16). Surprisingly, NCS was
ineffective completely, and no semipinacol rearrangement
occurred at all (entry 17). It should be noted that the reaction
intermediate 2a could be observed in the aforementioned
experiments except entry 17.
On the basis of the above optimized conditions (entry 9, Table
1), the generality of this semipinacol rearrangement/Grob
fragmentation was investigated by employing a series of allylic
alcohols. As seen in Table 2, various cyclic allylic alcohols 1a-j
with the cyclohexene moiety could smoothly give the expected
arylated and vinylated trisubstituted alkenes 3a-j in good to
excellent yields (entries 1-10), wherein the migrating group
could be the aryl and the alkenyl. Remarkably, allylic alcohols
containing the electron-rich aromatic ring as migrating group
were the ideal substrates for this transition-metal-free one-pot
arylation (entries 1-3, 9, and 10) in which the TMS-protected
secondary allylic alcohol 1b was also effective (entry 2). In
addition, the thiophenyl (entry 5) and the naphthyl (entry 6)
also act as good migrating groups in this reaction, although the
a General reaction conditions (unless otherwise noted): allylic alcohol
(1.0 mmol), NBS (1.2 mmol), and DME (2 mL) at room temperature for
1-4 h and then NaOH (25 mmol) at ambient temperature for 12 h
b Isolated yield. c Reaction time of 72 h. d Yield in parentheses based on
the recovered starting materials. e Only one single isomer was isolated,
and its relative configuration was determined by 1D NOE of 1H NMR.
f No semipinacol rearrangement could be observed, and 1q was recovered.
alkenyl as migrating group (entries 7 and 8) showed longer
reaction time (at least 72 h) and lower isolated yields (around
7798 J. Org. Chem. Vol. 73, No. 19, 2008

mination,12 owing to the restraint of free rotation of CR-Cꢀ
single bond in cyclic molecular conformation, giving the alkene
product with the reserved stereochemistry of the original double
bond. For the acyclic ones (1m-p, entries 13-16 of Table 2),
as demonstrated in mechanism B of Scheme 2, the intermediate
ꢀ-bromoaldehyde 2 generated in analogous fashion to 2′. In
contrast to the cyclic case, an energetically favorable one-step
synchronous fragmentation took place,12 due to the possibility
of free rotation of CR-Cꢀ single bond in acyclic molecular
conformation, yielding the desired alkenes with reversed
configuration.
SCHEME 2. Proposed Mechanism of the Semipinacol
Rearrangement/Grob Fragmentation
In conclusion, we have discovered a novel transition-metal-
free one-pot semipinacol rearrangement/Grob fragmentation of
allylic alcohols. This reaction has proved to be an effective
method for arylation and vinylation of alkenes, and more
widespread investigation of this novel methodology is in
progress in our laboratory.
60%). While employing the substrate with the electron-deficient
aromatic group such as 1q (entry 17), the related semipinacol
rearrangement as the first step of this kind of one-pot transfor-
mation could not proceed at all, probably due to its weak
migrating capability.
Experimental Section
General Procedure for the One-Pot Reaction. To a solution
of allylic alcohol 1a (1.0 mmol) in DME (2 mL) was added NBS
(1.2 mmol) at room temperature. The resulting mixture was stirred
for 3 h until the starting material disappeared by inspection of TLC.
Subsequently, the NaOH powder (25 mmol) was directly added to
the reaction solution, and it was further stirred overnight until TLC
examination indicated the disappearance of the intermediate 2a.
The reaction mixture was diluted by addition of OEt2 followed by
addition of water. The organic layer was separated, and the aqueous
phase was re-extracted with OEt2. The combined extracts was
washed with brine, dried over Na2SO4, concentrated under reduced
pressure, and purified by chromatography on silica gel eluting with
light petroleum to yield the product 3a. 1H NMR (300 MHz, CDCl3,
ppm): δ 7.34-7.30 (m, 2H), 6.86-6.83 (m, 2H), 6.05-6.02 (m,
1H), 3.80 (s, 3H), 2.40-2.36 (m, 2H), 2.22-2.16 (m, 2H),
1.79-1.74 (m, 2H), 1.69-1.63 (m, 2H). 13C NMR (75 MHz,
CDCl3, ppm): δ 158.3, 135.8, 135.3, 125.9, 123.1, 113.5, 55.2, 27.4,
25.8, 23.1, 22.2. MS: m/z 188 (M+, 100), 159 (53), 129 (40), 115
(50), 91 (38). HRMS (ESI): calcd for C13H16O 188.1196, found
188.1194.
Moreover, the allylic alcohol bearing cyclopentene or cyclo-
heptene moiety (entries 11 and 12, Table 2) was further
investigated under standard conditions, and the desired products
3k and 3l were readily afforded in 85% and 83% yields,
respectively. To expand the substrate scope, acyclic substrates
1m-o (entries 13-15) were then examined, and as expected,
the reaction proceeded well, giving the gem-disubstituted alkenes
3m-o in good yields following the standard procedure.
In order to probe the stereoselectivity of this novel semipi-
nacol rearrangement/Grob fragmentation, one acyclic trisubsti-
tuted example was presented (entry 16, Table 2) wherein allylic
alcohol (E)-1p with (E)-double bond was subjected to the current
reaction, resulting in the formation of one alkene isomer (Z)-
3p with reversed configuration of the original double bond. This
interesting result shows the high stereoselectivity in the current
acyclic substrate and it would be mechanistically interesting for
this one-pot transformation.
According to the above results and literature reports, the
reaction mechanism of this semipinacol rearrangement/Grob
fragmentation was proposed as shown in Scheme 2. For the
cyclic substrates (1a-l, entries 1-12 of Table 2), as shown in
mechanism A of Scheme 2, first an electrophilic addition of
the Br+ released from the NBS to the allylic alcohol 1′ led to
antimigration of R1 to form ꢀ-bromoaldehyde 2′.11a,c Subse-
quently under the basic conditions, the addition of hydroxy anion
to the carbonyl of aldehyde resulted in the formation of
semialdehyde intermediate 4′. Then a two-step syn-fragmenta-
tion occurred through the sequential deformylation and debro-
Acknowledgment. We gratefully acknowledge financial
support from the NSFC (No. 30271488, 20911001) and the
Chang Jiang Scholars Program.
Supporting Information Available: General experimental
procedures, characterization data for all compounds, and 1D
NOE spectra of 3p. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO801434B
J. Org. Chem. Vol. 73, No. 19, 2008 7799