Direct C-4 arylation of crotonaldehyde with arenediazonium tetrafluoroborates

Article abstract of DOI:10.1016/j.tetlet.2011.07.005

Arenediazonium tetrafluoroborates react with crotonaldehyde (2-butenal) in methanol in the presence of catalytic amounts of Pd(OAc)₂ to yield mainly 4,4-dimethoxy-1-butenylarenes. In most of the examples studied, small amounts of an isomeric byproduct were formed, presumably 3,3-dimethoxy-1- methylenepropylarenes. Because crotonaldehyde and arenediazonium salts are cheap and readily available, this reaction is a convenient access to protected 4-arylbutenals.

Full text of DOI:10.1016/j.tetlet.2011.07.005

Tetrahedron Letters 52 (2011) 4678–4680
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Tetrahedron Letters
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Direct C-4 arylation of crotonaldehyde with arenediazonium tetrafluoroborates
⇑
Florencio Zaragoza , Verena Heinze
Lonza AG, Rottenstrasse 6, CH-3930 Visp, Switzerland
a r t i c l e i n f o
a b s t r a c t
Article history:
Arenediazonium tetrafluoroborates react with crotonaldehyde (2-butenal) in methanol in the presence of
catalytic amounts of Pd(OAc)2 to yield mainly 4,4-dimethoxy-1-butenylarenes. In most of the examples
studied, small amounts of an isomeric byproduct were formed, presumably 3,3-dimethoxy-1-methylene-
propylarenes. Because crotonaldehyde and arenediazonium salts are cheap and readily available, this
reaction is a convenient access to protected 4-arylbutenals.
Received 6 May 2011
Revised 26 June 2011
Accepted 1 July 2011
Available online 13 July 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Crotonaldehyde
Arenediazonium tetrafluoroborates
Palladium catalysis
Acetals
While investigating Heck-type reactions with crotonaldehyde,
we found that arenediazonium tetrafluoroborates directly arylate
crotonaldehyde at the methyl group.
usually added as desiccant, but this was not essential for high
yields. Most reactions were completed after 1–2 h. The results
are given in Table 1.
Few Heck reactions of crotonaldehyde have been reported. Aryl
bromides and iodides react with crotonaldehyde under typical Heck
reaction conditions (NMP, Pd(OAc)2, Bu4NCl, NaOAc, and 90 °C) to
the expected 3-aryl-2-butenals 2 in low1 to high2 yields, depending
on the substitution pattern at the aryl halide and on the precise
reaction conditions. Similarly, crotononitrile, crotonamide, and cro-
tonic esters3 undergo ‘normal’ C-3 arylations, and no products of C-
4 arylation are usually observed. Pd-catalyzed C-4 arylations of
Electron-deficient and halogen-substituted arenediazonium
salts underwent this new reaction cleanly, to yield crude products
4 and 5 in high yield and purity. Occasionally, small amounts of the
‘reduced’ arenes were also obtained, formed by substitution of the
diazonium group by hydrogen. Alkyl-substituted arenediazonium
salts, however, underwent ether formation with the solvent to a
significant extent (see, e.g., entry d, Table 1).
Particularly critical for the success of this C-4 arylation of cro-
tonaldehyde was the purity of the diazonium salts, the amount
of catalyst, and the reaction temperature. If the diazonium salts
contained triazenes (because too little HBF4 or nitrite had been
used for their preparation), larger amounts of catalyst were usually
required. If gas evolution did not start within 5–10 min after add-
ing the diazonium salt, the reaction could be initiated by shortly
heating to 30–40 °C. Once the dediazonization had started, how-
ever, the temperature had to be kept below 30 °C; higher temper-
atures often resulted in low yields. If the amount of catalyst was
insufficient, complex product mixtures were usually obtained.
The mechanism of this reaction and the reason for the high reg-
ioselectivity of the anthranilate-derived diazonium salt remain un-
clear to us. Products 4 and 5 are the formal arylation products of
1,1-dimethoxy-3-butene. However, treatment of crotonaldehyde
with methanol and catalytic amounts of Pd(OAc)2 under conditions
similar to those of the title reaction did not lead to acetalization and
isomerization to 1,1-dimethoxy-3-butene or 1-methoxy-1,3-buta-
diene, but only to a slow acetalization to 1,1-dimethoxy-2-butene
(Scheme 2). If small amounts of HBF4 were added (HBF4 is formed
during the Pd(II)-catalyzed dediazonization), mainly 1,1,3-trim-
ethoxybutane resulted.
deprotonated crotononitrile4a and
a,b-unsaturated aldehydes and
ketones4b with aryl bromides have been reported.
Arenediazonium tetrafluoroborates (1) are cheaper and more
reactive than aryl halides, and may therefore enable the prepara-
tion of thermally labile compounds.5 We attempted to perform
Heck-type arylations with these electrophiles using crotonalde-
hyde, a readily available commodity, as olefin component. To our
surprise, the addition of arenediazonium salts to a mixture of
methanol, crotonaldehyde, and catalytic amounts of Pd(OAc)2 led
mainly to the formation of 4,4-dimethoxy-1-butenylarenes 4, in-
stead of the expected 3-aryl-2-butenals 2 or acetals 3.6 In most in-
stances small amounts of an isomeric byproduct were also formed,
for which we tentatively propose structure 5 on the basis of NMR
and MS data (Scheme 1).7
A number of differently substituted arenediazonium salts 1
were treated with crotonaldehyde in the presence of methanol
and Pd(OAc)2. To prevent hydrolysis of the acetals, MgSO4 was
⇑
Corresponding author. Tel.: +41 27 948 5143; fax: +41 27 947 6577.
E-mail address: florencio.zaragoza@lonza.com (F. Zaragoza).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.005

F. Zaragoza, V. Heinze / Tetrahedron Letters 52 (2011) 4678–4680
4679
OMe
OMe
CHO
or
R
R
3
2
MeOH,
2-4% Pd(OAc)2
20-30 °C, 1-6 h
N2BF4
CHO
R
+
crotonaldehyde
1
OMe
OMe
OMe
OMe
R
R
+
5
4
2-13%
50-80%
Scheme 1.
Table 1
Yield and selectivity of the formation of acetals 4 and 5
MeOH,
2% Pd(OAc)2
20 °C, 2 h
OMe
OMe
Entry
R
Yield of 4a (%)
Ratio 4:5b
CHO
a
b
c
d
e
f
2-CO2Me
4-CO2Me
2-Cl
2-Et
3-F
80
59
63
50
59
74
77
97:3
20% conversion
85:15
89:11
84:16c
80:20
84:16
86:14
MeOH, 0.2% HBF4
2% Pd(OAc)2
20 °C, 20 h
4-Br
4-NO2
MeO
OMe
OMe
g
a
b
c
Determined by 1H NMR with an internal standard.
Determined by gas chromatography.
2-Ethylanisole (16%) was also formed.
Scheme 2.
crotonaldehyde
methanol
Pd(0)
Pd(OAc)2
+ Pd(0), - N2
O
Ar N2BF4
Ar Pd
O
Pd
Ar
Heck reaction
(not observed)
+ MeOH
- H2O
Ar
OMe
OH
O
Pd
Pd
Ar
6
Pd
Ar
MeOH
HBF4
Ar
OMe
+
PdH
+
Ar Pd
OMe
OMe
O
Ar Pd
Ar OMe
OMe
OMe
OMe
Ar
+
4
5
Scheme 3.

4680
F. Zaragoza, V. Heinze / Tetrahedron Letters 52 (2011) 4678–4680
3. Commons, T. J.; Douglas, J. J.; Trybulski, E. J.; Fensome, A. U.S. Patent 2009/
Crotonaldehyde seems to act as reducing agent for the conver-
0197878, 2009; Chem. Abstr. 2009, 151, 245678.
sion of Pd(II) to the catalytically active Pd(0). When crotonalde-
hyde was replaced by crotononitrile or crotyl alcohol, gas
evolution and darkening of the reaction mixture did not take place
as readily as with crotonaldehyde.
One possible mechanism of this reaction is sketched in Scheme
3. The main difference between the reaction conditions of the title
reaction and the standard Heck reaction is the absence of bases and
nucleophiles. Also because of HBF4 formation during the reaction,
cationic intermediates are therefore most likely.
The observed products may result from arylation of 1,1-dime-
thoxy-3-butene or 1-methoxy-1,3-butadiene,8 formed by ArPd+-
catalyzed isomerization and acetalization of crotonaldehyde. ArPd+
is more electron-rich than Pd(OAc)2, and should have a higher
affinity to the electron-poor crotonaldehyde than Pd(II) salts. The
reason for the absence of Heck-reaction products would be the fast
formation of an unreactive, cationic allyl palladium complex 6,
which only undergoes etherification and eventual demetallation
to yield 1-methoxy-1,3-butadiene. Acid-mediated addition of
methanol to this enol ether would yield 1,1-dimethoxy-3-butene,
the precursor of the observed acetals 4 and 5.
To conclude, arenediazonium tetrafluoroborates can be used to
arylate crotonaldehyde at C-4. The resulting products are protected
4-arylbutenals, which may be useful intermediates for a number of
different applications, for instance the synthesis of substituted
naphthalenes9 or 4-arylbutanals.10 A more thorough determina-
tion of the scope and limitations of this chemistry is in progress.
4. (a) Ohmura, T.; Awano, T.; Suginome, M.; Yorimitsu, H.; Oshima, K. Synlett
2008, 423–427; (b) Terao, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett.
1998, 39, 6203–6206.
5. Zaragoza, F. Org. Synth. 2010, 87, 226–230; Recent reviews: Felpin, F.; Nassar-
Hardy, L.; Le Callonnec, F.; Fouquet, E. Tetrahedron 2011, 67, 2815–2831;
Taylor, J. G.; Moro, A. V.; Correia, C. R. D. Eur. J. Org. Chem. 2011, 1403–1408;
Roglans, A.; Pla-Quintana, A.; Moreno-Mañas, M. Chem. Rev. 2006, 106, 4622–
4643.
6. Representative procedure: To a mixture of Pd(OAc)2 (18 mg, 0.080 mmol),
MgSO4 (0.46 g), and methanol (8.0 ml) at room temperature was added
crotonaldehyde (0.29 ml, 3.53 mmol). Then 2-(methoxycarbonyl)benze-
nediazonium tetrafluoroborate (439 mg, 1.76 mmol) was added in one
portion, the mixture was shortly heated to 40 °C, and then allowed to stir at
room temperature for 5.5 h. The mixture was poured into an aqueous solution
of NaHCO3 (150 ml), extracted with AcOEt (2 Â 30 ml), the combined organic
extracts were washed with brine, dried over MgSO4, and concentrated under
reduced pressure, to yield 0.36 g of a dark oil. The content of title compound in
this oil was determined by 1H NMR with an internal standard (4-
nitrobenzaldehyde). The yield of compound 4a was 80%. Bulb-to-bulb
distillation of 0.328 g of the crude product (200 °C/4 mbar) yielded 250 mg
(62%) of acetal 4a as an oil. IR (film)
m
(cmÀ1) 2950, 1718, 1433, 1250; 1H NMR
(400 MHz, CDCl3) d 2.59 (t, J = 6 Hz, 2H), 3.37 (s, 6H), 3.89 (s, 3H), 4.50 (t,
J = 6 Hz, 1H), 6.09 (dt, J = 16, 8 Hz, 1H), 7.25 (m, 2H), 7.44 (br t, J = 8 Hz, 1H),
7.55 (br d, J = 8 Hz, 1H), 7.84 (br d, J = 8 Hz); 13C NMR (125 MHz, CDCl3) d 36.78,
52.00, 52.97, 104.08, 126.82, 127.34, 127.67, 128.26, 130.31, 131.19, 131.96,
139.23, 167.94; MS (EI) m/z (%) 250 (M+, 0.1), 218 (M+ÀMeOH, 6), 75 (100).
Anal. Calcd for C14H18O4: C, 67.18; H, 7.25. Found: C, 67.00; H, 7.20. To further
substantiate our structural proposal for this product, it was hydrogenated (H2,
Pd/C, MeOH, 1 bar, 20 °C) and hydrolyzed (trifluoroacetic acid, H2O, 20 °C,
4.5 h) to the known methyl 2-(4-oxobutyl)benzoate. 1H NMR, 13C NMR, and
mass spectral data corresponded to those reported in the literature (Ohno, H.;
Okumura, M.; Maeda, S.; Iwasaki, H.; Wakayama, R.; Tanaka, T. J. Org. Chem.
2003, 68, 7722–7732).
7. 5g: 1H NMR (400 MHz, CDCl3) d 2.85 (d, J = 6 Hz, 2H), 3.31 (s, 6H), 4.44 (t,
J = 6 Hz, 1H), 5.37 (br s, 1H), 5.51 (br s, 1H), 7.57 (d, J = 8 Hz, 2H), 8.19 (d,
J = 8 Hz, 2H); 13C NMR (125 MHz, CDCl3) d 38.86, 53.20, 103.42, 118.59, 123.66,
127.04, 127.21, 142.46, 147.89; MS (EI) m/z (%) 206 (M+ÀMeOH, 3), 75 (1 0 0).
8. 1-Alkoxy-1,3-butadienes react with arenediazonium salts under basic
conditions to yield 1,1-dialkoxy-4-aryl-2-butenes; Deagostino, A.; Migliardi,
M.; Occhiato, E. G.; Prandi, C.; Zavattaro, C.; Venturello, P. Tetrahedron 2005, 61,
3429–3436.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.07.005.
9. Kim, B. H.; Lee, J. G.; Yim, T.; Kim, H.; Lee, H. Y.; Kim, Y. G. Tetrahedron Lett.
2006, 47, 7727–7730.
References and notes
10. Kjell, D. P.; Slattery, B. J.; Semo, M. J. J. Org. Chem. 1999, 64, 5722–5724.
1. Zebovitz, T. C.; Heck, R. F. J. Org. Chem. 1977, 42, 3907–3909.
2. Stadler, M.; List, B. Synlett 2008, 597–599.