Synthesis of substituted benzene derivatives by homo- and hetero-coupling of 2-bromobenzaldehyde and bromovinylaldehydes followed by McMurry coupling

Article abstract of DOI:10.1016/j.tetlet.2005.11.146

A convenient synthetic approach to substituted benzene derivatives by modified Ullmann cross-coupling of 2-bromobenzaldehyde and bromovinylaldehydes followed by intramolecular McMurry coupling has been developed.

Full text of DOI:10.1016/j.tetlet.2005.11.146

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 1221–1224
Synthesis of substituted benzene derivatives by homo- and
hetero-coupling of 2-bromobenzaldehyde and
bromovinylaldehydes followed by McMurry coupling
Surajit Some, Bishnupada Dutta and Jayanta K. Ray*
Department of Chemistry, Indian Institute of Technology, Kharagpur 721302, India
Received 8 September 2005; revised 25 November 2005; accepted 29 November 2005
Available online 28 December 2005
Abstract—A convenient synthetic approach to substituted benzene derivatives by modified Ullmann cross-coupling of 2-bromo-
benzaldehyde and bromovinylaldehydes followed by intramolecular McMurry coupling has been developed.
ꢀ 2005 Elsevier Ltd. All rights reserved.
We have been interested in the synthesis of heterocyclic
Br
compounds from 2-chlorovinylaldehydes1–3 and were
Cu
interested in developing the methodology for the synthe-
Pd(PPh3)4
CHO
CHO OHC
sis of substituted benzene derivatives from bromovinyl-
Dry DMSO
110 oC
aldehydes.4
I,2a-e
II,3a-e
Homo-coupling
Thus, when ketomethylene compounds 1a–h were trea-
ted with PBr3 in DMF, bromovinylaldehydes 2a–h5 were
produced (Scheme 1). Treatment of 2-bromobenzalde-
hyde I and bromovinylaldehydes 2a–e with an equiva-
lent of Cu powder and 10 mol % of Pd(PPh3)4 in
anhydrous DMSO with heating at 110 ꢁC afforded
homo bis-aldehydes II and 3a–e6 (Scheme 2) by modi-
fied Ullmann reaction7 (Table 1 and Fig. 1).
Scheme 2.
85 ꢁC to 110 ꢁC led to a mixture of homo- and hetero-
coupled bis-aldehydes. Thus, we had determined the
optimum temperature for preparing cross-coupled
products.
When 2-bromobenzaldehyde I and bromovinylalde-
hydes 2b,c,d,f,g,h were reacted, only cross-coupled bis-
aldehydes 3f–k were isolated under similar conditions
to those of the homo-coupling reaction at 85 ꢁC
(Scheme 3 and Table 2). Raising the temperature from
An interesting observation was noticed during the
homo-coupling of 2-bromo-3,4-dihydronaphthalene-1-
carbaldehyde 2c as well as during its hetero-coupling
with I, which unexpectedly produced aromatized prod-
ucts 3c and 3j (Table 1, entry 4 and Table 2, entry 5).
These bis-aldehydes upon treatment with TiCl4 and Zn
dust, underwent intramolecular McMurry coupling9 to
generate substituted benzenes 4a–k (Scheme 4, Fig. 2
and Table 3).
O
Br
PBr3
DMF
CHO
2a-h
1a-h
In conclusion we have developed a methodology for the
synthesis of various substituted benzenes starting from
ketomethylene compounds. Our method provides short
reaction times and good yields. The temperature for
homo-coupling was optimized at 110 ꢁC and that for
hetero-coupling was 85 ꢁC. Compound 4b is an impor-
tant intermediate for the synthesis of helicenes.4e
Scheme 1.
Keywords: Ullmann reaction; McMurry coupling.
Corresponding author. Tel.: +91 3222 283326; fax: +91 3222
282252; e-mail: jkray@chem.iitkgp.ernet.in
*
0040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.146

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S. Some et al. / Tetrahedron Letters 47 (2006) 1221–1224
Table 1. Homo-coupling of various bromovinylaldehydes catalyzed by palladium(0) at 110 ꢁC
Entry
Bromovinylaldehyde
Producta
Time (h)
Yield (%)
1
2
3
4
5
6
2-Bromobenzaldehyde I
II6b
3a
3b
3c
6
4
5
4
4
4
65
65
60
56
58
60
2-Bromoacenaphthylene-1-carbaldehyde 2a
1-Bromo-3,4-dihydronaphthalene-2-carbaldehyde 2b
2-Bromo-3,4-dihydronaphthalene-1-carbaldehyde 2c
3-Bromo-3-phenylpropenal 2d
3d
3e
5-Bromo-8,9-dihydro-7H-benzocycloheptene-6-carbaldehyde 2e
a See Figure 1 for the structures of the homo-coupled products.
CHO
OHC
CHO
CHO
CHO
II
CHO
CHO
3a
3c
OHC
3b
H
OHC
OHC
CHO
CHO
CHO
CHO
3g
3f
CHO
CHO
H
3d
3e
OHC
CHO
CHO
CHO
H
CHO
CHO
3i
3h
3j
CHO
3k
CHO
Figure 1. Bis-aldehydes II and 3a–e were produced by homo-coupling and 3f–k by the hetero-coupling reaction between 2-bromo-benzaldehyde I
and bromovinylaldehydes 2b,c,d,f,g,h.
Br
n
Br
n
Cu
+
Pd(PPh3)4
Dry DMSO
85 oC
OHC
CHO
CHO
OHC
I
2b,c,d,f,g,h
3f-k
n = 1,2,3
n = 1,2,3
Hetero-coupling
Scheme 3.
Table 2. Hetero-coupling of various bromovinylaldehydes catalyzed by palladium(0) at 85 ꢁC
Entry
Bromovinylaldehydea
Productb
Time (h)
Yield (%)
1
2
3
4
5
6
2-Bromocyclohex-1-enecarbaldehyde 2f
2-Bromocyclopent-1-enecarbaldehyde 2g
2-Bromocyclohept-1-enecarbaldehyde 2h
1-Bromo-3,4-dihydronaphthalene-2-carbaldehyde 2b
2-Bromo-3,4-dihydronaphthalene-1-carbaldeyde 2c
3-Bromo-3-phenylpropenal 2d
3f
4
3.5
3
4.5
4
5
65
65
65
60
58
62
3g
3h
3i
3j6c
3k
a 2-Bromobenzaldehyde I was used as the second coupling partner.
b See Figure 1 for the structures of the hetero-coupled products.
Typical experimental procedure for the homo and hetero
cross-coupling of bromovinylaldehydes: A magnetically
stirred mixture of appropriate bromovinylaldehyde
(0.81 mmol), copper powder (8.2 mmol), and Pd(PPh3)4
(10 mol %) in dry DMSO (6 mL) was degassed for
15 min, and then heated at 110 or 85 ꢁC (depending
upon homo- or hetero-coupling) for 4–6 h under a nitro-
gen atmosphere. It was then cooled to room tempera-

S. Some et al. / Tetrahedron Letters 47 (2006) 1221–1224
1223
III
4c
4a
4b
4g
4d
4f
4e
4j
4i
4k
4h
Figure 2. Substituted benzene derivatives III and 4a–k produced by intramolecular McMurry coupling of bis-aldehydes II and 3a–k.
Zn, TiCl4
(a)
Dry THF
80 oC
CHO OHC
III,4a-e
II,3a-e
n
n
Zn, TiCl4
(b)
Dry THF
80 oC
CHO
OHC
4f-k
n = 1,2,3
3f-k
n = 1,2,3
Scheme 4.
Table 3.
filtered and concentrated under reduced pressure to give
a crude product, which often solidified without further
purification. In some cases column chromatography (sil-
ica gel—ethyl acetate/pet ether elution) and concentra-
tion of the appropriate fractions afforded the coupling
products.
Entry
Bis-aldehyde
Producta
Yield (%)
1
2
3
4
5
6
7
8
II
III
67
56
62
57
60
58
65
65
65
62
58
60
3a
3b
3c
3d
3e
3f
4a8a
4b4e
4c4a
4d8b
4e8c
4f8d
4g8e
4h8e
4i4b
4j8f
Typical experimental procedure for McMurry coupling of
bis-aldehydes: To an ice cooled suspension of active zinc
dust (4.9 mmol) in THF (6 mL) under argon, TiCl4
(0.3 mL) was injected slowly. The mixture was then re-
fluxed for 2 h and again cooled to 0 ꢁC. To this, a solu-
tion of bis-aldehyde (0.53 mmol) in THF (2 mL) was
added dropwise with stirring at 0 ꢁC for a further
30 min, then the reaction was allowed to attain room
temperature gradually. Finally it was refluxed for 2 h
at 80 ꢁC. The reaction mixture was cooled, poured into
an ice-cold saturated potassium carbonate solution and
extracted with dichloromethane. The organic layer was
washed thoroughly with water and brine several times,
dried (anhydrous Na2SO4) and then the solvent was
removed to afford the product.
3g
3h
3i
9
10
11
12
3j
3k
4k8g
a All products have been characterized by spectroscopic data.
ture and diluted with ethyl acetate (80 mL). The result-
ing mixture was filtered through a pad of celite and
the residue thus retained was washed with ethyl acetate
(30 mL). The combined filtrates were washed with water
(2 · 150 mL), brine (150 mL) and then dried (Na2SO4),

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S. Some et al. / Tetrahedron Letters 47 (2006) 1221–1224
Selected spectroscopic data—Compound 3c: 1H NMR
(CDCl3, 200 MHz) d: 7.39–7.44 (d, 2H, J = 8.44 Hz),
7.56–7.72 (m, 4H), 7.86–7.89 (d, 2H, J = 4.8 Hz), 7.95–
7.96 (d, 2H, J = 2.08 Hz), 9.28–9.32 (d, 2H,
J = 8.52 Hz) 10.22 (s, 2H). 13C NMR (CDCl3,
50 MHz) d: 125.78, 127.40, 128.50, 128.60, 129.58,
129.94, 130.37, 133.48, 133.85, 145.03, 192.80. Anal.
Calcd for C22H14O2: C: 85.15, H: 4.54. Found: C:
85.25, H: 4.52.
References and notes
1. Pan, D.; Kar, G. K.; Lin, J.; Amin, S.; Chantrapromma, S.;
Fun, H.; Ray, J. K. J. Chem. Soc., Perkin Trans. 1 2001,
2475.
2. Ray, J. K.; Gupta, S.; Kar, G. K.; Roy, B.; Lin, J.; Amin, S.
J. Org. Chem. 2000, 65, 8134.
3. Ray, J. K.; Haldar, M. K.; Gupta, S.; Kar, G. K.
Tetrahedron 2000, 56, 909.
4. (a) Harvey, R. G.; Pataki, J.; Cortez, C.; Raddo, P. D.;
Yang, C. J. Org. Chem. 1991, 56, 1210; (b) Furstner, A.;
¨
Compound 3g: 1H NMR (CDCl3, 200 MHz) d: 2.74–2.96
(m, 6H), 7.25–7.31 (dd, 1H, J = 1.34 Hz, J = 1.34 Hz),
7.52–7.67 (m, 2H), 7.95–7.99 (dd, 1H, J = 1.38 Hz,
J = 1.38 Hz), 9.46 (s, 1H), 10.06 (s, 1H). 13C NMR
(CDCl3, 50 MHz) d: 22.34, 30.69, 42.08, 129.39,
129.95, 131.69, 133.84, 134.16, 137.82, 142.45, 161.29,
189.81, 190.79. Anal. Calcd for C13H12O2: C: 77.99, H:
6.04. Found: C: 77.82, H: 6.06.
Mamane, V. J. Org. Chem. 2002, 67, 6264; (c) Fujita, K.;
Nonogawa, M.; Yamaguchi, R. Chem. Commun. 2004,
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Gesellschaft 1903, 36, 2382; (b) Banwell, M. G.; Kelly, B.
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(c) Altman, Y.; Ginsburg, D. J. Chem. Soc. 1961, 1498; (d)
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1
Compound 4g: H NMR (CDCl3, 200 MHz)8f d: 2.20–
2.32 (m, 2H), 3.06–3.14 (t, 2H, J = 7.35 Hz), 3.21–3.29
(t, 2H, J = 7.45 Hz), 7.37–7.51 (m, 3H), 7.65–7.69 (d,
1H, J = 8.28 Hz), 7.81–7.86 (t, 2H, J = 7.9 Hz). 13C
NMR (CDCl3, 50 MHz) d: 24.52, 31.02, 33.76, 123.26,
124.24, 124.58, 125.77, 126.58, 128.31, 130.45, 132.47,
139.37, 140.92. Anal. Calcd for C13H12: C: 92.85, H:
7.15. Found: C: 92.90, H: 7.25.
Acknowledgements
Financial support from CSIR (New Delhi) is greatly
acknowledged. S.S. is thankful to UGC and B.P.D. is
thankful to CSIR (New Delhi) for their fellowships.
9. (a) McMurry, J. E.; Fleming, M. P. J. Am. Chem. Soc.
1974, 96, 4708; (b) McMurry, J. E. Chem. Rev. 1989, 89,
1513.