CHBr3/TiCl4/Mg as an unusual nucleophilic CBr 2 carbenoid: Effective and chemoselective dibromomethylenation of aldehydes and ketones

Article abstract of DOI:10.1002/ejoc.201200457

We report that instead of using CBr₄, CHBr₃ can serve as a highly nucleophilic dibromomethylene carbenoid in chemoselective carbonyl dibromomethylenation. Successful application of the dibromomethylenation to various carbonyl compoun

Full text of DOI:10.1002/ejoc.201200457

Job/Unit: O20457
/KAP1
Date: 25-07-12 15:49:13
Pages: 7
FULL PAPER
DOI: 10.1002/ejoc.201200457
CHBr3/TiCl4/Mg as an Unusual Nucleophilic CBr2 Carbenoid: Effective and
Chemoselective Dibromomethylenation of Aldehydes and Ketones
Yeshwant Ramchandra Bhorge,[a] Cheng-Ta Chang,[a] Su-Haur Chang,[a] and
Tu-Hsin Yan*[a]
Keywords: Alkenes / Bromine / Chemoselectivity / Titanium / Magnesium / Synthetic methods
We report that instead of using CBr4, CHBr3 can serve as a
pounds such as enolizable and sterically hindered ketones
highly nucleophilic dibromomethylene carbenoid in chemo- by using the CHBr3/Mg/TiCl4 system highlights the weakly
selective carbonyl dibromomethylenation. Successful appli-
cation of the dibromomethylenation to various carbonyl com-
basic nature, extraordinary reactivity, and synthetic versatil-
ity of the approach.
are nucleophilic and available in bulk at a low price, we
were attracted to the development of a TiCl4/Mg-mediated
carbonyl dibromomethylenation process. To the best of our
knowledge, no metal-induced dibromomethylenation pro-
cedure, wherein CHBr3 serves as a CBr2 partner, has been
recorded. Earlier work in our laboratories established that
the TiCl4/Mg-promoted CH2 transfer reaction of CH2Cl2
represents an efficient carbonyl methylenation.[6a–6e] On the
other hand, the TiCl4/Mg-promoted direct coupling of
CHCl3 with ketones and aldehydes has so far been limited
to CHCl transfer reactions.[6f] In this paper, we wish to re-
port that, in contrast to cleavage of two C–Cl bonds in
CH2Cl2 and CHCl3, CHBr3 can be directed to serve as in
a CBr2 transfer reaction by using TiCl4/Mg-promoted
cleavage of C–H and C–Br bonds. This CHBr3/TiCl4/Mg
system can serve as a highly nucleophilic and selective di-
bromomethylene complex in the dibromomethylenation of
a variety of aldehydes and ketones, especially in enolizable
or sterically hindered ketones.
Introduction
1,1-Dibromoalkenes can not only serve as important pre-
cursors in the preparation of alkynes[1] but are also valuable
building blocks in molecular transformations such as (i) the
construction of 1,3-diynes[2a] through the palladium-pro-
moted direct coupling of 1,1-dibromoalkenes, (ii) the syn-
thesis of conjugated 1,3-enynes and 1,3-dienes through the
Pd-catalyzed cross-coupling of 1-bromoalkenes with alk-
enyl- or alkynylmetals,[2b–2d] and (iii) the preparation of
(E)-[3a–3c] and (Z)-vinyl bromides.[2c,3d] The vast importance
of dibromoalkenes in synthesis has stimulated much interest
in the development of new, efficient methodologies for their
construction. Whereas the CBr2 transfer reaction of CBr4
promoted by phosphorus reagents such as PPh3,[4a–4c]
P(OiPr)3,[4d] or (OEt)2P(=O)CHClLi[4e] involved direct di-
bromomethylenation of ketones and aldehydes, the basic
character and the low nucleophilic nature of these phos-
phorus-derived dibromomethylene complexes[4] limit the ge-
neral and practical utility of the Wittig method. On the
other hand, the generation of these dibromomethane com-
plexes suffers from one or more experimental drawbacks,
such as the requirement for high reaction temperature con-
ditions (Ն80 °C) and the use of a large excess of PPh3 and
expensive CBr4. The direct coupling of hydrazones derived
from simple saturated aldehydes and ketones with CBr4
promoted by CuCl constitutes an alternative two-stage di-
bromomethylenation process.[5] However, sterically more
hindered ketones such as diisopropyl ketone and tert-butyl
methyl ketone cannot be converted into the corresponding
1,1-dibromoalkenes.[5] To develop a new entry to these com-
pounds using (1,1-dibromomethylene)metal complexes that
Results and Discussion
The dibromomethylenation of 2-methylcyclohexanone
(1a) with CHBr3 was chosen to test the feasibility of the
process (Table 1). Addition of a 1,2-dimethoxyethane
(DME) (1.0 mL)/dichloromethane (CH2Cl2) solution of 1a
(1 mmol) to a mixture of TiCl4 (1 equiv.), CHBr3 (0.3 mL),
and magnesium powder (5 mmol) in CH2Cl2 at 0 °C gave a
40% yield of the desired vinyl dibromide 2a, with starting
material remaining (Table 1, Entry 1). Increasing the
amount of Mg and TiCl4 led to an increase in the yield of
2a (Table 1, Entries 2–6). Notably, reducing the amount of
CHBr3 or titanium chloride relative to Mg led to not only
incomplete dibromomethylenation but also to reductive
cleavage of vinyl dibromides. DME appeared to be a good
choice as an electron-pair-donor (EPD) additive to effect
[a] Department of Chemistry, National Chung-Hsing University,
Taichung 400, Taiwan, Republic of China
E-mail: thyan@mail.nchu.edu.tw
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200457.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O20457
/KAP1
Date: 25-07-12 15:49:13
Pages: 7
Y. R. Bhorge, C.-T. Chang, S.-H. Chang, T.-H. Yan
FULL PAPER
CBr2 transfer reaction of CHBr3 to the carbonyl group of TiCl4/Mg system, enolizable ketones also proved to be satis-
1a. Other EPD additives including tetrahydrofuran (THF) factory substrates. Thus, both 2-indanone (1f) and β-tet-
and diethyl ether gave unsatisfactory results (Table 1, En- ralone (1g) reacted with the CHBr3-derived bromomethyl-
tries 7 and 8). Notably, the reaction could be directly scaled enation reagent to give the desired dibromoalkene products
up; thus, 1,1-dibromoalkene 2a (Table 1, Entry 9) was ob- 2f (73%) and 2g (68%), respectively (Table 2, Entries 5 and
tained in 74% yield on a 10 mmol scale using TiCl4 6).[9] To further demonstrate the scope of this dibromo-
(8 mmol) and Mg (70 mmol).
methylene-forming methodology, the utility of this protocol
was examined in the dibromomethylenation of sterically de-
manding ketones. In contrast to CBr4-derived phosphorus
reagents[4] and Tebbe–Grubbs reagents,[8] the CHBr3/Mg/
TiCl4 complex reacted with the 2,2-dimethylcyclohexanone
(1h). Thus, using a 3:8 TiCl4/Mg ratio, a 72% yield of 2h
was obtained (Table 2, Entry 7). This TiCl4/Mg-mediated
CBr2 transfer reaction of CHBr3 was also found to be suit-
able for the dibromomethylenation of unsaturated cyclo-
hexenone 1i and hindered unsaturated cyclohexenone 1j
(Table 2, Entries 8 and 9).
Table 1. Reaction conditions for dibromomethylenation of ketone
1a.
Entry
EPD additive
(mL)
TiCl4/Mg[a]
[mmol]
Yield [%][b]
1a
2a
1
2
3
4
5
6
7
8
9
DME (1.0)
DME (1.0)
DME (1.0)
DME (1.0)
DME (1.2)
DME (1.5)
THF (1.0–1.2)
Et2O (1.0–1.2)
DME (8.0)
1:5
1:8
2:8
3:8
3:8
3:8
3:8
3:8
8:70
ca. 55
ca. 30
40
60
Table 2. CHBr3/Mg/TiCl4-promoted dibromomethylenation of
ketones.[a]
ca. 20
ca. 15
65
72
0
0
0
60
0
80
75
ca. 60
ca. 25
74[c]
[a] Reaction conditions (1 mmol scale): CH2Cl2/EPD additive/
CHBr3 (0.3 mL), 0 °C to r.t. [b] Isolated yield. [c] Reaction condi-
tions (10 mmol scale): CH2Cl2 (30 mL), 0 °C to r.t.
The reaction is best envisioned as involving interception
of a presumed EPD–TiCl4 complex by magnesium powder
to give an active dimetallic [Ti-MgCl2-(EPD)n][7] complex,
followed by dibromomethylene coordinated to both the ti-
tanium and magnesium to generate the presumed [Ti-CBr2-
MgCl2-(EPD)n] complex (Scheme 1).[8a]
Scheme 1. Mg-Ti dimetallic complex promoted CBr2 transfer reac-
tion of CHBr3.
Having established the feasibility of the dibromomethyl-
enation, we studied its generality with respect to the struc-
ture of the ketones. 2,6-Dimethylcyclohexanone (1b) also
gave satisfactory results (85%) with the CHBr3/Mg/TiCl4
complex (Table 2, Entry 1). Variation of ring size was
briefly explored. Dibromomethylenation onto cyclopenta-
none (1c) and cycloheptanone (1d) was equally effective
[a] Reaction conditions (1 mmol scale): CH2Cl2/DME/CHBr3
(0.3 mL) at 0 °C to r.t. [b] Isolated yield. [c] The reaction was per-
formed in ClCH2CH2Cl at 0 °C to r.t.
With an eye to extending the procedure to other less re-
(Table 2, Entries 2 and 3). Disopropyl ketone (1e) also re- active carbonyl compounds, we explored the TiCl4/Mg-pro-
acted with CHBr3-derived dibromomethylenation reagent moted CBr2 transfer to aromatic ketones. Fortunately, ex-
to give the desired dibromide product 2e (80%) (Table 2, posing α-tetralone (1k), acetophenone (1l), dimethyl-
Entry 4). Due to the weakly basic nature of the CHBr3/ acetophenone (1m), and 4,4Ј-dimethoxychalcone (1n) to the
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20457
/KAP1
Date: 25-07-12 15:49:13
Pages: 7
Dibromomethylenation of Aldehydes and Ketones
CHBr3/Mg/TiCl4/DME system led to dibromomethylen- example illustrating the chemoselectivity of this process is
ation to give the desired vinyl dibromides 2k (87%), 2l the dibromomethylenation of a mixture of aliphatic and
(82%), 2m (84%), and 2n (90%), respectively (Table 2, En- aromatic aldehydes (Table 4, Entry 4). The preference for
tries 10–13). A dramatic illustration of the nucleophilic na- methylenation of an aliphatic aldehyde highlights the
ture of the [Ti-CBr2-Mg-Clx-(EPD)n] complex was the di- chemoselectivity of the process.
bromomethylenation of benzophenone (1o) (Table 2, En-
try 14), which, by virtue of the low reactivity of the carb-
Table 4. Selectivity in the dibromomethylenation of ketones and
aldehydes mediated by the CHBr3/Mg/TiCl4/DME system.
onyl group, demands very vigorous conditions. Performing
the TiCl4/Mg-promoted direct coupling of CHBr3 with
benzophenone at 0 °C to room temperature led to complete
consumption of starting material within 3 h and formation
of the desired vinyl dibromide 2o in 85% yield.[10] The abil-
ity to effect such a dibromomethylenation at low tempera-
tures highlights the reactivity of this new (dibromomethyl-
ene)titanium complex.
On the other hand, dibromomethylenation of p-tolual-
dehyde (1p) was equally effective (Table 3, Entry 1); in this
case the olefination product 2p was obtained in 80% yield.
Changing the aromatic aldehyde to p-(dimethylamino)benz-
aldehyde (1q), piperonal (1r), and 2-furaldehyde (1s) pro-
vided equally satisfactory results with formation of 1,1-di-
bromoalkenes 2q, 2r, and 2s, respectively (Table 3, En-
tries 2–4). Changing the aromatic aldehydes to aliphatic al-
dehydes 1t, 1u, 1v, and 1w also gave the expected di-
bromides in good yields (Table 3, Entries 5–8).
Table 3. CHBr3/Mg/TiCl4-promoted dibromomethylenation of al-
dehydes.[a]
[a] Isolated yield. [b] Reaction conditions: bromoform (1.7 mmol),
–5 °C, 25 min. [c] Reaction conditions: bromoform (1.0 mmol),
–10 °C, 45 min. [d] Reaction conditions: bromoform (1.0 mmol),
–5 °C, 25 min. Piperonyl alcohol (10%) was produced as byprod-
uct.
Conclusions
This method constitutes the first report on the use of
CHBr3 as an effective dibromomethylene equivalent in
chemoselective carbonyl dibromomethylenation. The nu-
cleophilicity involved suggested several intriguing applica-
tions that are currently under active investigation.
Experimental Section
General: Dichloromethane was distilled from P2O5 prior to use.
Commercially available ketones and aldehydes were used as re-
ceived. Bromoform, titanium tetrachloride, and magnesium powder
(ca. 50 mesh) were used as received. Flash chromatography was
[a] Reaction conditions (1 mmol scale): bromoform (0.3 mL), 0 °C
to r.t. [b] Isolated yield.
performed on silica gel 60 (230–400 mesh). All reactions were car-
ried out under N2. 1H and 13C NMR spectra were recorded with a
Varian VXR 400 MHz spectrometer at ambient temperature. High-
resolution mass spectra were determined with a Jeol JMS-HX 110
The chemoselectivity was briefly explored with a series
of carbonyl compounds, as summarized in Table 4. As ex- spectrometer.
pected, exposure of a mixture of aldehyde (1 mmol) and
Typical Procedure for the Dibromomethylenation of Carbonyl Com-
pounds. 1-(Dibromomethylene)-2-methylcyclohexane (2a): To a sus-
pension of Mg (194 mg, 8 mmol) and TiCl4 (1 m in CH2Cl2,
ketone (1 mmol) to CHBr3 (1–1.7 mmol) at –10 to –5 °C
for ca. 0.5 h produced exclusively the aldehyde-derived vinyl
dibromide (Table 4, Entries 1–3). A particularly interesting 3 mmol, 3 mL) at 0 °C was added over a 2.0 min period a solution
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O20457
/KAP1
Date: 25-07-12 15:49:13
Pages: 7
Y. R. Bhorge, C.-T. Chang, S.-H. Chang, T.-H. Yan
FULL PAPER
1
of 2-methylcyclohexanone (1a; 112 mg, 1 mmol) in CH2Cl2 (1 mL),
CHBr3 (0.3 mL), and DME (1.2 mL). The black slurry was stirred
at 0–25 °C for 3 h, then recooled to 0 °C and carefully poured into
ice-cold saturated potassium carbonate solution (10 mL). The re-
sulting mixture was stirred with CH2Cl2 (20 mL), and the phases
were separated. The procedure was repeated twice, and the com-
bined extracts were dried, concentrated, and purified by
chromatography on silica gel (elution with hexane) to give 2a
hexane). H NMR (CDCl3, 400 MHz): δ = 3.68 (s, 4 H), 7.20 (m,
4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 42.2, 81.9, 124.6,
126.9, 140.4, 146.5 ppm. HRMS: calcd. for C10H8Br2 285.8993;
found 285.9002.
2-(Dibromomethylene)-1,2,3,4-tetrahydronaphthalene (2g): Prepared
as described above with 1g (146 mg, 1 mmol) and Mg (8 mmol)/
TiCl4 (1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME
(1.2 mL). The black slurry was stirred at 0 °C Ǟ r.t. for 3 h to
give a crude reaction mixture. Purification by flash chromatography
(silica gel, hexane) afforded 2g (205 mg, 68%) as a colorless oil. Rf
1
(213 mg, 80%) as a colorless oil. Rf = 0.89 (n-hexane). H NMR
(CDCl3, 400 MHz): δ = 1.04 (d, J = 7.2 Hz, 3 H), 1.21–1.25 (m, 1
H), 1.46–1.54 (m, 4 H), 1.74 (d, J = 8.0 Hz, 1 H), 1.91–1.98 (m, 1
H), 2.78 (d, J = 14.4 Hz, 1 H), 3.20 (m, 1 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 17.0, 19.8, 26.4, 30.1, 32.1, 36.3, 82.0,
147.9 ppm. HRMS: calcd. for C8H12Br2 265.9306; found 265.9315.
= 0.62 (n-hexane). IR (neat): ν = 3064, 3021, 2931, 2844, 1678,
˜
1626, 1572, 1492, 1453, 1423, 1283, 1220, 1105, 947, 866, 793,
745 cm–1. H NMR (CDCl3, 400 MHz): δ = 2.59 (t, J = 6.8 Hz, 2
1
H), 2.80 (t, J = 6.0 Hz, 2 H), 3.60 (s, 2 H), 7.14 (m, 4 H) ppm. 13
C
2-(Dibromomethylene)-1,3-dimethylcyclohexane (2b): Prepared as
described above with 1b (126 mg, 1 mmol) and Mg (8 mmol)/TiCl4
(1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL).
The black slurry was stirred at 0 °C Ǟ r.t. for 3 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2b (239 mg, 85%) as a colorless oil. Rf = 0.90 (n-
NMR (CDCl3, 100 MHz): δ = 29.1, 32.7, 37.6, 83.9, 126.3, 126.5,
127.6, 127.9, 134.6, 137.5, 141.5 ppm. HRMS: calcd. for C11H10Br2
299.9149; found 299.9145.
2-(Dibromomethylene)-1,1-dimethylcyclohexane (2h): Prepared as
described above with 1h (126 mg, 1 mmol) and Mg (8 mmol)/TiCl4
(1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL).
The black slurry was stirred at 0 °C Ǟ r.t. for 3 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2h (203 mg, 72%) as a colorless oil. Rf = 0.84 (n-
hexane). IR (neat): ν = 2963, 2930, 2867, 1608, 1578, 1459, 1376,
˜
1240, 1146, 1112, 1049, 985, 898, 878, 835, 767, 675 cm–1. 1H NMR
(CDCl3, 400 MHz): δ = 1.12 (d, J = 7.6 Hz, 6 H), 1.52–1.63 (m, 6
H), 3.09 (t, J = 6.8 Hz, 2 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 15.0, 19.6, 31.6, 35.3, 85.5, 150.4 ppm. HRMS: calcd. for
C9H14Br2 279.9462; found 279.9471.
1
hexane). H NMR (CDCl3, 400 MHz): δ = 1.33 (s, 6 H), 1.46 (d,
J = 4.8 Hz, 2 H), 1.56 (d, J = 13.2 Hz, 4 H), 2.46 (t, J = 5.2 Hz, 2
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 18.7, 21.8, 26.8, 33.4,
39.2, 40.5, 80.9, 149.9 ppm. HRMS: calcd. for C9H14Br2 279.9462;
found 294.9455.
(Dibromomethylene)cyclopentane (2c):[5] Prepared as described
above with 1c (84 mg, 1 mmol) and Mg (8 mmol)/TiCl4 (1 m in
CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/ DME (1.2 mL). The
black slurry was stirred at 0 °C Ǟ r.t. for 3 h to give a crude reac-
tion mixture. Purification by flash chromatography (silica gel, hex-
ane) afforded 2c (169 mg, 71%) as a colorless oil. Rf = 0.96 (n-
hexane). 1H NMR (CDCl3, 400 MHz): δ = 1.78–1.82 (m, 4 H),
2.30–2.33 (m, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 27.19,
36.6, 78.2, 151.0 ppm. HRMS: calcd. for C6H8Br2 237.8993; found
237.8997.
(Dibromomethylene)cycloheptane (2d):[5] Prepared as described
above with 1d (112 mg, 1 mmol) and Mg (8 mmol)/TiCl4 (1 m in
CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL). The
black slurry was stirred at 0 °C Ǟ r.t. for 3 h to give a crude reac-
tion mixture. Purification by flash chromatography (silica gel, hex-
ane) afforded 2d (205 mg, 77%) as a colorless oil. Rf = 0.88 (n-
hexane). 1H NMR (CDCl3, 400 MHz): δ = 1.50–1.64 (m, 8 H), 2.44
(t, J = 6.4 Hz, 4 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 26.4,
28.8, 36.0, 84.8, 146.8 ppm. HRMS: calcd. for C8H12Br2 265.9306;
found 265.9309.
3-(Dibromomethylene)cyclohex-1-ene (2i):[11a] Prepared as described
above, 1i (96 mg, 1 mmol) and Mg (194 mg, 8 mmol)/TiCl4 (1 m in
CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL). The
black slurry was stirred at 0 °C Ǟ r.t. for 3 h to give a crude reac-
tion mixture. Purification by flash chromatography (silica gel, hex-
ane) afforded 2i (194 mg, 78%) as a colorless oil. 1H NMR
(400 MHz, CDCl3): δ = 1.71 (m, 2 H), 2.10–2.05 (m, 2 H), 2.47 (t,
J = 6.4 Hz, 2 H), 6.06–6.02 (tt, J = 10.0, 4.0 Hz, 1 H), 6.47–6.43
(tt, J = 10.0, 6.0 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
21.9, 25.3, 31.2, 87.5, 126.2, 133.9, 138.6 ppm. HRMS: calcd. for
C7H8Br2 249.8993; found 249.8986.
2-(Dibromomethylene)-4-methyl-1-(propan-2-ylidene)cyclohexane
(2j): Prepared as described above with 1j (152 mg, 1 mmol) and
Mg (194 mg, 8 mmol)/TiCl4 (1 m in ClCH2CH2Cl, 3 mmol, 4 mL)/
CHBr3 (0.3 mL)/DME (1.2 mL). The black slurry was stirred at
0 °C Ǟ r.t. for 3 h to give a crude reaction mixture. Purification by
flash chromatography (silica gel, hexane) afforded 2j (203 mg, 66%)
as a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 0.95 (d, J =
11.6 Hz, 3 H), 1.52–1.76 (m, 11 H), 2.62–2.67 (m, 1 H), 2.89–2.93
(m, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 19.3, 21.9, 22.0,
30.5, 34.7, 36.2, 44.9, 82.5, 125.9, 132.9, 147.1 ppm. HRMS: calcd.
for C11H16Br2 305.9618; found 305.9622.
3-(Dibromomethylene)-2,4-dimethylpentane (2e): Prepared as de-
scribed above with 1e (114 mg, 1 mmol) and Mg (8 mmol)/TiCl4
(1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL).
The black slurry was stirred at 0 °C Ǟ r.t. for 3 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2e (197 mg, 73%) as a colorless oil. Rf = 0.97 (n-
1-(Dibromomethylene)-1,2,3,4-tetrahydronaphthalene (2k): Prepared
as described above with 1k (146 mg, 1 mmol) and Mg (8 mmol)/
TiCl4 (1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME
(1.2 mL). The black slurry was stirred at 0 °C Ǟ r.t. for 2 h to
give a crude reaction mixture. Purification by flash chromatography
(silica gel, hexane) afforded 2k (262 mg, 87%) as a colorless oil. Rf
1
hexane). H NMR (CDCl3, 400 MHz): δ = 1.13 (d, J = 6.8 Hz, 12
H), 2.94 (m, 2 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 19.4,
22.5, 82.9, 153.4 ppm. HRMS: calcd. for C8H14Br2 267.9462; found
267.9461.
2-(Dibromomethylene)-2,3-dihydro-1H-indene (2f): Prepared as de-
scribed above with 1f (132 mg, 1 mmol) and Mg (8 mmol)/TiCl4
= 0.79 (n-hexane). IR (neat): ν = 3064, 3032, 2939, 2864, 2843,
˜
(1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL). 1479, 1452, 1074, 1016, 917, 794, 747, 636, 503 cm–1. 1H NMR
The black slurry was stirred at 0 °C Ǟ r.t. for 3 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2f (209 mg, 73%) as a colorless oil. Rf = 0.70 (n-
(CDCl3, 400 MHz): δ = 1.81–1.85 (m, 2 H), 2.65–2.71 (m, 4 H),
7.16–7.29 (m, 3 H), 7.90 (d, J = 7.2 Hz, 1 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 22.8, 30.0, 34.1, 86.5, 125.1, 127.5, 128.2,
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20457
/KAP1
Date: 25-07-12 15:49:13
Pages: 7
Dibromomethylenation of Aldehydes and Ketones
128.9, 134.4, 140.3, 140.6 ppm. HRMS: calcd. for C11H10Br2
299.9149; found 299.9147.
The black slurry was stirred at 0 °C Ǟ r.t. for 1.5 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2q (265 mg, 87%) as a colorless oil. 1H NMR
(CDCl3, 400 MHz): δ = 2.97 (s, 6 H), 6.64 (d, J = 8.8 Hz, 2 H),
7.33 (s, 1 H), 7.47 (d, J = 8.8 Hz, 1 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 40.1, 84.1, 111.5, 122.9, 129.6, 136.6, 150.2 ppm.
HRMS: calcd. for C10H11NBr2 302.9258; found 302.9256.
5-(2,2-Dibromovinyl)benzo[d][1,3]dioxole (2r):[12c] Prepared as de-
scribed above with 1r (150 mg, 1 mmol) and Mg (6 mmol)/TiCl4
(1 m in CH2Cl2, 2 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.0 mL).
The black slurry was stirred at 0 °C Ǟ r.t. for 3.0 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2r (207 mg, 68%) as a colorless oil. 1H NMR
(CDCl3, 400 MHz): δ = 5.98 (s, 2 H), 6.78 (d, J = 8.0 Hz, 1 H),
6.93 (d, J = 6.4 Hz, 1 H), 7.18 (s, 1 H), 7.36 (s, 1 H) ppm. 13C
NMR (CDCl3, 100 MHz): δ = 87.8, 101.3, 108.0, 108.2, 123.3,
129.1, 136.2, 147.5, 147.7 ppm. HRMS: calcd. for C9H6Br2O2
303.8735; found 303.8737.
(2,2-Dibromo-1-methylvinyl)benzene (2l):[11b] Prepared as described
above with 1l (120 mg, 1 mmol) and Mg (8 mmol)/TiCl4 (1 m in
CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL). The
black slurry was stirred at 0 °C Ǟ r.t. for 2 h to give a crude reac-
tion mixture. Purification by flash chromatography (silica gel, hex-
ane) afforded 2l (225 mg, 82%) as a colorless oil. Rf = 0.62 (n-
hexane). IR (neat): ν = 3056, 3025, 29.16, 2848, 1600, 1489, 1441,
˜
1
1371, 1074, 1028, 912, 750, 697, 582, 529 cm–1. H NMR (CDCl3,
400 MHz): δ = 2.23 (s, 3 H), 7.21–7.36 (m, 5 H) ppm. 13C NMR
(CDCl3, 100 MHz): δ = 26.1, 87.5, 127.3, 127.6, 128.3, 141.9,
143.0 ppm. HRMS: calcd. for C9H8Br2 273.8993; found 273.8992.
1-(1,1-Dibromo-3-methylbut-1-en-2-yl)benzene (2m):[11c] Prepared as
described above with 1m (148 mg, 1 mmol) and Mg (8 mmol)/TiCl4
(1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL).
The black slurry was stirred at 0 °C Ǟ r.t. for 2 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2m (255 mg, 84%) as a colorless solid. Rf = 0.80
2-(2,2-Dibromovinyl)furan (2s):[12b] Prepared as described above
with 1s (96 mg, 1 mmol) and Mg (6 mmol)/TiCl4 (1 m in CH2Cl2,
2 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.0 mL). The black slurry
was stirred at 0 °C Ǟ r.t. for 3.0 h to give a crude reaction mixture.
Purification by flash chromatography (silica gel, hexane) afforded
1
(n-hexane). H NMR (CDCl3, 400 MHz): δ = 0.96 (d, J = 6.8 Hz,
6 H), 3.32 (sept, J = 6.8 Hz, 1 H), 7.02–7.05 (m, 2 H), 7.34–7.40
(m, 3 H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 26.3, 35.6, 88.2,
127.5, 128.1, 128.4, 138.7, 152.2 ppm. HRMS: calcd. for C11H12Br2
301.9306; found 301.9310.
1
2s (195 mg, 78%) as a colorless oil. H NMR (CDCl3, 400 MHz):
δ = 6.46 (dd, J = 1.6 Hz,1 H), 6.95 (dd, J = 0.4, 3.2 Hz, 1 H), 7.40
(s, 1 H), 7.44 (t, J = 1.2 Hz, 1 H) ppm. 13C NMR (CDCl3,
100 MHz): δ = 87.1, 111.4, 111.5, 126.4, 142.5, 150.0 ppm. HRMS:
calcd. for C6H4Br2O 249.8629; found 249.8631.
(2,2-Dibromovinyl)cyclohexane (2t):[11b] Prepared as described
above with 1t (112 mg, 1 mmol) and Mg (8 mmol)/TiCl4 (1 m in
CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL). The
black slurry was stirred at 0 °C Ǟ r.t. for 3.0 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2t (199 mg, 75%) as a colorless oil. Rf = 0.87 (n-
(E)-1,1-Dibromo-2,4-bis(4-methoxyphenyl)buta-1,3-diene (2n): Pre-
pared as described above with 1n (268 mg, 1 mmol) and Mg
(194 mg, 8 mmol)/TiCl4 (1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3
(0.3 mL)/DME (1.2 mL). The black slurry was stirred at 0 °C Ǟ
r.t. for 3 h to give a crude reaction mixture. Purification by flash
chromatography (silica gel, hexane) afforded 10a (382 mg, 90%) as
a colorless oil. 1H NMR (400 MHz, CDCl3): δ = 3.80 (s, 3 H), 3.86
(s, 3 H), 6.11 (d, J = 15.6 Hz, 1 H), 6.84 (d, J = 8.8 Hz, 2 H), 6.97
(d, J = 8.4 Hz, 2 H), 7.12 (d, J = 8.4 Hz, 2 H), 7.29 (s, 1 H), 7.32
(d, J = 8.8, Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 55.23,
55.29, 91.9, 113.9, 114.1, 126.4, 128.2, 129.4, 130.5, 131.1, 136.0,
145.1, 159.2, 159.9 ppm. HRMS: calcd. for C18H16Br2O2 421.9517;
found 421.9513.
hexane). IR (neat): ν = 2926, 2851, 1610, 1448, 1349, 1311, 1273,
˜
1
1257, 1217, 1139, 956, 893, 832, 814, 765 cm–1. H NMR (CDCl3,
400 MHz): δ = 1.06–1.34 (m, 5 H), 1.61–1.73 (m, 5 H), 2.25 (m, 1
H), 6.21 (d, J = 9.2 Hz 1 H) ppm. 13C NMR (CDCl3, 100 MHz):
δ = 25.4, 25.7, 31.2, 42.4, 86.9, 143.7 ppm. HRMS: calcd. for
C8H12Br2 265.9306; found 265.9301.
(2,2-Dibromoethene-1,1-diyl)dibenzene (2o):[11b] Prepared as de-
scribed above with 1o (182 mg, 1 mmol) and Mg (8 mmol)/TiCl4
(1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL).
The black slurry was stirred at 0 °C Ǟ r.t. for 2 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2o (287 mg, 85%) as a colorless oil. Rf = 0.62 (n-
hexane). 1H NMR (CDCl3, 400 MHz): δ = 7.24–7.32 (m, 10 H)
ppm. 13C NMR (CDCl3, 100 MHz): δ = 90.2, 127.9, 128.3, 128.6,
141.3, 147.8 ppm. HRMS: calcd. for C14H10Br2 335.9149; found
335.9157.
1,1-Dibromo-4-methylpenta-1,3-diene (2u):[12b] Prepared as de-
scribed above with 1u (84 mg, 1 mmol) and Mg (194 mg, 8 mmol)/
TiCl4 (1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME
(1.2 mL). The black slurry was stirred at 0 °C Ǟ r.t. for 2.0 h to
give a crude reaction mixture. Purification by flash chromatography
(silica gel, hexane) afforded 2u (207 mg, 87%) as a colorless oil. 1H
NMR (400 MHz, CDCl3): δ = 1.73 (s, 3 H), 1.78 (s, 3 H), 5.84 (m,
1 H), 7.06 (d, J = 10.8 Hz, 1 H) ppm. 13C NMR (100 MHz, C6D6):
δ = 18.8, 25.9, 89.18, 122.6, 133.9, 140.6 ppm. HRMS: calcd. for
C6H8Br2 237.8993; found 237.8998.
1-(2,2-Dibromovinyl)-4-methylbenzene (2p):[12a] Prepared as de-
scribed above with 1p (120 mg, 1 mmol) and Mg (6 mmol)/TiCl4
(1 m in CH2Cl2, 2 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.0 mL).
The black slurry was stirred at 0 °C Ǟ r.t. for 2.5 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2p (220 mg, 80%) as a colorless oil. 1H NMR
(CDCl3, 400 MHz): δ = 2.36 (s, 3 H), 7.14 (d, J = 8.0 Hz, 1 H),
7.24 (d, J = 15 Hz, 1 H), 7.31 (t, J = 7.3, 10.4 Hz, 2 H), 7.45 (s, 1
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 21.3, 89.2, 125.4, 128.2,
129.0, 129.3, 135.2, 137.0, 138.0 ppm. HRMS: calcd. for C9H8Br2
273.8993; found 273.8988.
1-(2,2-Dibromovinyl)-2-chlorocyclohex-1-ene (2v): Prepared as de-
scribed above with 1v (144 mg, 1 mmol) and Mg (194 mg, 8 mmol)/
TiCl4 (1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME
(1.0 mL). The black slurry was stirred at 0 °C Ǟ r.t. for 2.0 h to
give a crude reaction mixture. Purification by flash chromatography
(silica gel, hexane) afforded 2v (210 mg, 70%) as a colorless oil. IR
(neat): ν = 2937, 2881, 2860, 2837, 1655, 1570, 1447, 1434, 1336,
˜
1261, 1097, 995, 905, 877, 850, 822, 809, 669, 601, 539 cm–1. 1H
NMR (400 MHz, CDCl3): δ = 1.69–1.55 (m, 4 H), 2.31 (d, J =
6.0 Hz, 4 H), 7.17 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 21.9, 23.3, 28.7, 34.0, 90.0, 129.8, 132.7, 136.3 ppm. HRMS:
4-(2,2-Dibromovinyl)-N,N-dimethylaniline (2q):[12b] Prepared as de-
scribed above with 1q (149 mg, 1 mmol) and Mg (6 mmol)/TiCl4
(1 m in CH2Cl2, 2 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.0 mL). calcd. for C8H9ClBr2 297.8759; found 297.8757.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5

Job/Unit: O20457
/KAP1
Date: 25-07-12 15:49:13
Pages: 7
Y. R. Bhorge, C.-T. Chang, S.-H. Chang, T.-H. Yan
FULL PAPER
1-(4,4-Dibromobut-3-en-2-yl)benzene (2w):[12d] Prepared as de-
scribed above with 1w (134 mg, 1 mmol) and Mg (8 mmol)/TiCl4
(1 m in CH2Cl2, 3 mmol, 4 mL)/CHBr3 (0.3 mL)/DME (1.2 mL).
The black slurry was stirred at 0 °C Ǟ r.t. for 3.0 h to give a crude
reaction mixture. Purification by flash chromatography (silica gel,
hexane) afforded 2w (245 mg, 85%) as a colorless oil. Rf = 0.80 (n-
thesis of 1,1-dibromoalkenes from 1,1-dimetallic species, see:
M. J. Dabdoub, V. B. Dabdoub, A. C. M. Baroni, J. Am. Chem.
Soc. 2001, 123, 9694.
[5] V. N. Korotchenko, A. V. Shastin, V. G. Nenajdenko, E. S. Ba-
lenkova, Org. Biomol. Chem. 2003, 1, 1906.
[6] a) T.-H. Yan, C.-C. Tsai, C.-T. Chien, C.-C. Cho, P.-C. Huang,
Org. Lett. 2004, 6, 4961; b) T.-H. Yan, C.-T. Chien, C.-C. Tsai,
K.-W. Lin, Y.-H. Wu, Org. Lett. 2004, 6, 4965; c) K.-W. Lin,
S. Yan, I.-L. Hsieh, T.-H. Yan, Org. Lett. 2006, 8, 2265; d) C.-
C. Tsai, I.-L. Hsieh, T.-T. Cheng, P.-K. Tsai, K.-W. Lin, T.-H.
Yan, Org. Lett. 2006, 8, 2261; e) K.-W. Lin, C.-H. Tsai, I.-L.
Hsieh, T.-H. Yan, Org. Lett. 2008, 10, 1927–1930; f) for the
TiCl4/Mg-promoted chloromethylenation of CHCl3 with
ketones and aldehydes, see: C.-C. Tsai, C.-T. Chien, Y.-C.
Chang, H.-C. Lin, T.-H. Yan, J. Org. Chem. 2005, 70, 5745–
5747; g) for CCl2 transfer reaction of CCl4 mediated by TiCl4/
Mg, see: T.-T. Cheng, C.-C. Tsai, C.-H. Tsai, T.-Y. Chang, P.-
K. Tsai, Y.-C. Wang, T.-H. Yan, J. Org. Chem. 2006, 71, 4324–
4327.
1
hexane). H NMR (CDCl3, 400 MHz): δ = 1.38 (d, J = 7.2 Hz, 3
H), 3.72–3.80 (m, 1 H), 6.49 (d, J = 9.6 Hz, 6 H), 7.23–7.32 (m, 5
H) ppm. 13C NMR (CDCl3, 100 MHz): δ = 20.0, 43.3, 88.4, 126.7,
126.8, 128.6, 142.7, 142.9 ppm. HRMS: calcd. for C10H10Br2
287.9150; found 287.9157.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra.
Acknowledgments
[7] L. E. Aleandri, B. Bogdanovic, A. Gaidies, D. J. Jones, S. Liao,
A. Michalowicz, J. Roziere, A. Schott, J. Organomet. Chem.
1993, 459, 87.
We thank the National Science Council of the Republic of China
for generous support.
[8] a) N. A. Petasis, E. I. Bzowej, J. Am. Chem. Soc. 1990, 112,
6392; b) L. Clawson, S. L. Buchwald, R. H. Grubbs, Tetrahe-
dron Lett. 1984, 25, 5733.
[9] For the methylenation of enolizable ketones, see: C. R. John-
son, B. D. Tait, J. Org. Chem. 1987, 52, 281.
[1] a) A. Arefolov, J. S. Panek, J. Am. Chem. Soc. 2005, 127, 5596;
b) L. V. Hijfte, M. Kolb, P. Witz, Tetrahedron Lett. 1989, 30,
3655; c) E. J. Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13,
3769.
[2] a) W. Shen, S. A. Thomas, Org. Lett. 2000, 2, 2857; b) A. Hay-
ford, J. Kaloko Jr., S. EI-Kazaz, G. Bass, C. Harrison, T. Cor-
prew, Org. Lett. 2005, 7, 2671; c) J. Uenishi, R. Kawahama, O.
Yonemitsu, J. Tsuji, J. Org. Chem. 1998, 63, 8965; d) Y.-Q.
Fang, M. Lautens, Org. Lett. 2005, 7, 3549.
[3] a) B. C. Ranu, S. Samanta, S. K. Guchhait, J. Org. Chem. 2001,
66, 4102; b) K. Takai, K. Nitta, K. Utimoto, J. Am. Chem.
Soc. 1986, 108, 7408; c) S. Abbas, C. J. Hayes, S. Worden, Tet-
rahedron Lett. 2000, 41, 3215; d) J. Uenishi, R. Kawahama, Y.
Shiga, O. Yonemitsu, J. Tsuji, Tetrahedron Lett. 1996, 37, 6759.
[4] a) J.-C. Poupon, A. A. Boezio, A. B. Charette, Angew. Chem.
2006, 118, 1443; Angew. Chem. Int. Ed. 2006, 45, 1415; b) E. J.
Corey, P. L. Fuchs, Tetrahedron Lett. 1972, 13, 3769; c) G. H.
Posner, G. Loomis, H. S. Sawaya, Tetrahedron Lett. 1975, 16,
3769; d) Y.-Q. Fang, O. Lifchits, M. Lautens, Synlett 2008, 413;
e) P. Savignac, P. Coutrot, Synthesis 1976, 197; f) for the syn-
[10] The phosphane/CBr4-mediated benzophenone olefination re-
quired heating at 145 °C for 64 h and the use of a large excess
of PPh3 (4 equiv.), see: P. M. Donovan, L. T. Scott, J. Am.
Chem. Soc. 2004, 126, 3108.
[11] a) M. S. Baird, P. D. Slowey, Tetrahedron Lett. 1982, 23, 3795–
3796; b) P. Charreau, M. Julia, J.-N. Verpeaux, J. Organomet.
Chem. 1989, 379, 201–210; c) T. Harada, T. Katsuhira, K. Hat-
tori, A. Oku, Tetrahedron 1994, 50, 7987.
[12] a) D. H. Huh, J. S. Jeong, H. B. Lee, H. Ryu, Y. G. Kim, Tetra-
hedron 2002, 58, 9925–9932; b) M. L. N. Rao, D. N. Jadhav, P.
Dasgupta, Org. Lett. 2010, 12, 2048–2051; c) L. Chen, H.-H.
Xu, B. L. Yin, C. Xiao, T.-S. Hu, Y. L. Wu, J. Agric. Food
Chem. 2004, 52, 6719–6723; d) B. M. Trost, A. Breder, Org.
Lett. 2011, 13, 398–401.
Received: April 11, 2012
Published Online: ᭿
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20457
/KAP1
Date: 25-07-12 15:49:13
Pages: 7
Dibromomethylenation of Aldehydes and Ketones
Dibromomethylenation
Bromoform can serve as a highly nucleo-
philic dibromomethylene carbenoid in
chemoselective carbonyl dibromomethylen-
ation reactions with various carbonyl com-
pounds such as enolizable and sterically
hindered ketones by using the CHBr3/Mg/
TiCl4 system.
Y. R. Bhorge, C.-T. Chang, S.-H. Chang,
T.-H. Yan* ........................................ 1–7
CHBr3/TiCl4/Mg as an Unusual Nucleo-
philic CBr2 Carbenoid: Effective and
Chemoselective Dibromomethylenation of
Aldehydes and Ketones
Keywords: Alkenes / Bromine / Chemose-
lectivity / Titanium / Magnesium / Syn-
thetic methods
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7