Addition of organochromium reagents to heteroaryl aldehydes. Synthesis of heteroaryl substituted bis-allyl ethers and homoallyl ethers

Article abstract of DOI:10.3390/90100022

Heteroaryl substituted allyl and homoallyl alcohols were synthesised with two different method. Synthesis of bis-allyl ethers and homoallyl ethers were carried out via reaction of allyl bromide with allyl alcohols and homoallyl alcohols, respectively. [2.3]-Wittig Rearrangement reactions of heteroaryl substituted bis-allyl ethers were investigated using GC/MS techniques. In these reactions two unexpected products were isolated in high yield.

Full text of DOI:10.3390/90100022

Molecules 2004, 9, 22-28
molecules
ISSN 1420-3049
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Addition of Organochromium Reagents to Heteroaryl
Aldehydes. Synthesis of Heteroaryl Substituted bis-Allyl
Ethers and Homoallyl Ethers
S. Servi * and C. Topaloglu
Department of Chemistry, Firat University, Faculty of Science and Arts, 23169, Elazig, Turkey.
Author to whom correspondence should be addressed; e-mail: sservi@firat.edu.tr
Received: 25 September 2003; in revised form: 9 January 2004 /Accepted: 19 January 2004 /
Published: 31 January 2004
Abstract: Heteroaryl substituted allyl and homoallyl alcohols were synthesised
with two different method. Synthesis of bis-allyl ethers and homoallyl ethers
were carried out via reaction of allyl bromide with allyl alcohols and homoallyl
alcohols, respectively. [2.3]-Wittig Rearrangement reactions of heteroaryl
substituted bis-allyl ethers were investigated using GC/MS techniques. In these
reactions two unexpected products were isolated in high yield.
Keywords: Nozaki-Hiyama reaction, Organochromium reagents, Hetero-
aromatic aldehydes
Introduction
A selective carbon-carbon bond forming reaction was described by Nozaki-Hiyama in 1977
based on the mild addition of alkenyl, alkynyl or vinyl chromium (III) compounds to aldehydes in
an anhydrous medium. The Nozaki-Hiyama reaction is mainly applied to aldehydes but ketones
can be used in some cases and the reaction can be also extended to other organochromium
reagents. This reaction has been widely employed in natural product synthesis, becoming the key
step in some synthesis plans and it played a key role, for example, in the highly stereocontrolled
synthesis of the aliphatic segment of the antibiotic rifamycin S [1-5].
The [2,3]-Wittig Rearrangement of unsymmetrical bis-allylic ethers is exceedingly useful for
regio- and stereoselective preparations of substituted allyl alcohols. This reaction has also

Molecules 2004, 9
23
attracted the interest of chemists as the subject of mechanistic investigations and has been
increasingly utilized as a useful methodology for organic synthesis [6-10].
This article reports the synthesis of heteroaryl substituted allyl and homoallyl alcohols and
their ethers. Also reported are synthesis of heteroaryl substituted bis-allyl ethers and their [2,3]-
Wittig Rearrangement reactions. In this reaction, two unexpected products were isolated in high
1
yields. These compounds were characterized by using H-NMR, FT-IR and GC/ MS techniques.
Results and Discussion
There are several methods for the preparation the substituted allyl and homoallyl alcohols [11-
3]. In this study, heteroaryl substituted allyl and homoallyl alcohols were synthesized using the
1
Nozaki-Hiyama reaction. This reaction was carried out with both commercial CrCl
2
/DMF
o
(
Method A) and CrCl
3
/LiAlH
4
/THF (Method B). The reaction was performed at 25 C in DMF for
Method A, and the reaction was relatively fast with high yields compared with Method B.
Chromium (II) chloride is a powerful reducing agent. Anhydrous chromium (II) chloride is
commercially available and can be used without further purification. A suitable chromium (II)
reagent is prepared by reduction of 2 equivalents of anhydrous CrCl
3
with one equivalent of
o
LiAlH
4
in THF at 0 C, Method B.
Scheme 1
R1
OH
R
R1
n-BuLi, THF
n-BuLi, THF
α '
O
R
0
0
-75 C
-
75 C
O
R
α
9
,10
5
,6
α-lithiation products
R =CH or phenyl R=H
R: Furan for 5,9
R: Thiophene for 6,10 R1=H
R1=H
unexpected compounds
1
3
The [2.3]-Wittig Rearrangement reactions of 2-(1-allyloxy allyl) furan (5) and 2-(1-
allyloxy allyl) thiophene (6) were carried out according to published procedures [6-10]. In all of
the rearrangements of unsymmetrical substrates with different substitution patterns at the α- and
α’ positions of the two allylic moieties, lithiation takes place exclusively on the less substituted
allylic moiety, thus leading to the exclusive formation of the [2,3]-Wittig product as a single
regioisomer as shown Scheme 1.
In this work, instead of the expected products of α-lithiation, compounds 9 and 10 were
produced in the [2,3]-Wittig rearrangement reaction. α-Lithiation products have been obtained
when in compounds 5, 6 R
compounds were isolated when in compounds 5, 6 R= thiophene and furan, R
1
=CH
3
and phenyl and R=H [6]. On the other hand, the unexpected
=H. We are not
1
able to suggest a reaction mechanism for to account for compounds 9 and 10. The MS spectra of
compounds 9, 10 are explained in detail in Schemes 2, 3.

Molecules 2004, 9
24
Scheme 2
Het-aryl
-
Het-aryl
Mc Lafferty
Rearrangement
+
CH O
2
+
.
Z
O
O
m/z: 71
Z= O m/z: 108
Z=S
m/z: 124
α-Cleavage is reduced to a secondary process, as demonstrated by the low abundance of a m/e
1 peak in the mass spectra of compounds 9, 10 (Scheme 2). Similarly, α-fission followed by
7
olefin elimination is essentially absent. Instead, rupture of the carbon-oxygen linkage with charge
retention on the hydrocarbon moiety (m/e 41) becomes dominant. In allyl alkyl ethers, carbon-
oxygen bond cleavage yielding allylic ions are the most important fragmentation process. Instead,
a series of peaks of medium intensity at even mass numbers is observed whose genesis requires
rearrangement processes, but the paucity of experimental data makes structural assignments very
tentative [14].
Scheme 3
O
+
CH2
Z
Z
OH
m/z: 57
(
base peak)
Molecular ion peaks for 9,10
Z=O m/z: 81
Z=S m/z: 97
+
.
-1
Z=O
Z=S
M
M
138 gmol (% 83.9)
154 gmol (% 48.4)
+
.
-1
+
Z
Z
CH
m/z: 41
Z
O
Z=O m/z:68
Z=O m/z: 41
Z=S: m/z:58
Z=O m/z: 97
Z=S m/z: 112
Z=S m/z: 83
Acknowledgments
We are indebted to the Firat University Research Foundation (FÜNAF) for financial support
of this work (Project number: 351)

Molecules 2004, 9
25
Experimental
General
The synthetic routes followed are outlined in Scheme 4. CrCl
2
, CrCl
3
, LiAlH
4
, DMF, THF,
vinyl bromide, allyl bromide, furan-2-carboxaldehyde, thiophene-2-carboxaldehyde and n-BuLi
were obtained from commercial sources and all the solvents were used without further
purification. The products were purified by column chromatography using one of the following
eluent systems: (A) 6:1 hexane-ethyl acetate; (B) 4:1 hexane-ethyl acetate; (C): 5:1:1 hexane-ethyl
acetate-acetone. IR spectra (NaCl, thin film) were measured on a Mattson series FT-IR 1000
1
model spectrometer and H-NMR spectra were measured on a JEOL FX-90 Q instrument at 90
MHz, using CDCl as solvent. Shift values are reported in ppm relative to TMS. GC/MS (eV, EI)
3
analysis measurement on a Micromass Zabspec model instrument was determined at The
Scientific and Technical Research Council of Turkey (TUBITAK).
Scheme 4
H
Br
Br
n-BuLi,THF
Z
Z
Z
o
Z
O
Method A and B
O
-75 C
OH
O
1
,2
5,6
bis allyl
ethers
9
,10
H
Br
Br
Z
Method A and B
Z
Z
O
O
OH
3
,4
7
,8
homo allyl ethers
Z = O for compounds 1, 3, 5, 7, 9 and Z = S for compounds 2, 4, 6, 8, 10
Addition of Organochromium Reagents to Heteroaromatic Aldehydes: Synthesis of Hetero-
aromatic Substituted Allyl Alcohols (1, 2) and Homoallyl Alcohols (3, 4)
Method A:
Solutions of vinyl bromide (4.0 mmol) in DMF (10 mL) and heteroaromatic aldehyde (2.0
o
mmol) in DMF (6 mL) were added at 25 C to a stirred suspension of CrCl
2
(0.98 gr, 8.0 mmol) in
o
DMF (8 mL) over a period of 10 min under an argon atmosphere. After being stirred at 25 C for
1
5 min, the mixture was quenched by addition of water (20 mL) and extracted with ether. The
reaction mixture was filtered, the residues were washed with twice with ether, dried with MgSO
4
and concentrated under vacuum to give the crude product that was purified by column
chromatography over silica gel.

Molecules 2004, 9
Method B:
26
CrCl
3
(4,28 gr, 27 mmol) was reduced with LiAlH
4
(513 mg, 13.5 mmol) in THF (20 mL).
After stirring at room temperature for 10 min, the heteroaromatic aldehyde (6.1 mmol) and
subsequently vinyl bromide (13.5 mmol) in THF (10 mL) were added dropwise over a period of
2
0 min. After stirring for 3h and extracting with ether the reaction mixture was filtered, the
residues were washed with twice with ether, dried with MgSO and concentrated under vacuum
give the crude product that was purified by column chromatography over silica gel.
4
1
-(2-furyl) propen-1-ol (1): Yield: 81.3% (Method A), 76 %; (Method B) Rf: 0.652 (eluent system
-
1 1
A); IR (KBr): 3706-3166, 3117, 1667 cm . H-NMR: δ 2.85 (broad, OH, 1H), 4.84 (s, CH, 1H),
5
.10-6.20 (m, CH=CH
2
, 3H), 6.62-7.67 (m, furan ring protons, 3H)
1
-(2-thienyl) propen-1-ol (2): Yield: 85.2 % (Method A), 74.9 %; (Method B); Rf: 0.543 (eluent
-
1 1
system A); IR (KBr): 3693-3128, 3104, 1641 cm . H-NMR: δ 3.01 (broad, OH, 1H), 4.71 (s,
CH, 1H), 5.40-6.44 (m, CH=CH , 3H), 6.66-7.21 (m, thiophene ring protons, 3H)
2
1
-(2-furyl)-3-buten-1-ol (3): Yield: 75.7 % (Method A), 61.9 %; (Method B); Rf: 0.611 (eluent
-
1 1
system B); IR (KBr): 3743-3148, 3078, 1643 cm . H-NMR: δ 1.60-1.95 (m, CH
broad, OH, 1H), 3.68 (t, CH, 1H), 4.45-5.25 (m, CH=CH , 3H), 6.23 and 7.33 (furan ring
protons, 3H)
2
, 2H), 2.57
(
2
1
-(2-thienyl)-3-buten-1-ol (4): Yield: 75.5 % (Method A), 63.6%; (Method B); Rf: 0.522 (eluent
-
1 1
system B); IR (KBr): 3610-3175, 3076, 1650 cm . H-NMR: δ 1.76-1.83 (m, CH
broad, OH, 1H), 3.68 (s CH, 1H), 4.25-5.25 (m, CH=CH , 3H), 6.52-7.73 (m, thiophene ring
protons, 3H)
2
, 2H), 2.85
(
2
General Procedure for the Synthesis of bis-Allyl Ethers and Homoallyl Ethers (5-8):
Allyl bromide (17.0 mL, 220 mmol) or vinyl bromide (220 mmol) in THF (20 mL) was added
dropwise to a vigorously stirred mixture of heteroaromatic allylic alcohols (200 mmol),
n-Bu
4
NHSO
4
(3.7 gr, 10 mmol), NaOH (16.0 gr, 400 mmol) and H O (4 mL). The resulting
2
mixture was stirred overnight at room temperature. The solid formed was filtered off. Usual work
up followed by distillation afforded the title compounds.
2
-
1 1
3080, 1072, 1661, 1153 cm . H-NMR δ 3.85-4.10 (CH
(
m, CH=CH
2
, 6H), 6.30 and 7.39 (furan ring protons, 3H)
2
3
-(1-Allyloxy allyl) thiophene (6): Yield: 71.0 %; Rf: 0.648 (eluent system C); IR (KBr); 3101,
-
1 1
082, 1644, 1074 cm . H-NMR: δ 3.85-4.10 (CH
2
-O, 2H), 4.67 (s, CH-O, 1H), 5.02-6.15 (m,
CH=CH
2
, 6H), 6.80-7.10 (m, thiophene ring protons, 3H)

Molecules 2004, 9
27
2
-(1-Allyloxy-3-butenyl) furan (7): Yield: 51%; Rf: 0.731 (eluent system A); IR (KBr); 3088,
-
1 1
3019, 1650, 1240, 1080 cm . H-NMR: δ 3.65-4.10 (m, CH
2
, 2H), 4.60-5.41 (m, CH-O and CH -
2
O, 3H), 5.61-6.45(m, CH=CH
2
, 6H), 7.15-7.55 (m, furan ring protons, 3H)
2
-(1-Allyloxy-3-butenyl) thiophene (8): Yield: 63.1 %; Rf: 0.633 (eluent system A); IR: 3105,
-
1 1
3078, 1648, 1228, 1080 cm . H-NMR: δ 3.98-4.10 (m, CH
2
, 2H), 4.50-4.65 (m, CH-O and CH -
2
O, 3H), 4.90-6.11- (m, CH=CH
2
, 6H), 6.61-7.51 (m, thiophene ring protons, 3H)
2
-Allyloxymethyl furan (9) and 2-allyloxymethyl thiophene (10) were synthesized via [2,3]-
Wittig rearrangement reactions of the unsymmetrical bis-allyl ethers under an argon atmosphere
o
and at –75 C in high yields according to literature methods [6-10].
2
-Allyloxymethyl furan (9): Yield: 57.2 %; Rf: 0.544 (eluent system C); IR (KBr); 3146, 3119,
-
1 1
3
080, 1068, 1663, 1157 cm . H-NMR: δ 4.10 (s, CH
, 3H), 6.23 and 7.33 (furan ring protons, 3H); GC/MS: M 138, base peak: 81,
retention time: 16.96 min.
2
-O, 2H), 4.85 (s, CH
2
-O, 2H), 5.21-5.89
+.
(
m, CH=CH
2
2
-Allyloxymethyl thiophene (10): Yield: 61.4 %; Rf: 0.503 (eluent system C); IR (KBr); 3101,
-
1
1
3082, 1641, 1072 cm . H-NMR: δ 4.13 (s, CH
2
-O, 2H), 4.63 (s, CH
2
-O, 2H), 5.17-6.09 (m,
+.
CH=CH
2
, 3H), 6.73-7.10 (m, thiophene ring protons, 3H); GC/MS: M 154, base peak: 97,
retention time: 21.94 min.
References
1
. Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. Grignard-type carbonyl addition of allyl
halides by means of chromous salt chemospecific synthesis of homoallyl alcohols. J. Am.
Chem. Soc. 1977, 99, 3179-3181.
2. Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H. Selective Grignard type carbonyl
addition of alkenyl halides mediated by chromium (II) chloride. Tetrahedron Lett. 1983, 24,
5
281-5284.
3
4
5
6
7
8
. Cintos, P. Addition of organochromium compounds to aldehyde: Nozaki-Hiyama reaction.
Synthesis 1992, 248-257.
. Furstner, A. Carbon-carbon bond formations involving organochromium (III) reagents Chem.
Rev. 1999, 99, 991-1045
. Wuts, P.G.M.; Callen, G.R. An improved procedure for the Cr (II) mediated homoallylic
alcohol synthesis. Synth. Commun. 1986, 16, 1833-1837
. Servi, S.; Acar, A. An investigation of the reactions of substituted homoallylic alcohols with
various oxidation reagents. Molecules 2002, 7, 104-111.
. Nakai, T.; Mikami, K. [2,3]-Wittig sigmatropic rearrangements in organic synthesis. Chem.
Rev. 1986, 86, 885-902.
. Mikami K.; Nakai T. Applications of the tandem [2,3]-Wittig oxy-Cope rearrangement to
synthesis of exo-brevicomin and oxocrinol. The scope and limitation of the sigmatropic

Molecules 2004, 9
28
sequences as a synthetic method for delta, epsilon-unsaturated ketones. Chem. Lett. 1982, 9,
349-1352.
. Mikami, K.; Kishi, N.; Nakai, T. New sigmatropic sequences based on the [2,3]-Wittig
rearrangement of the bis-allylic ether system. Tetrahedron 1986, 42, 2911-2918.
1
9
10. Nicholas G.; Wai-Man L. Stereoselective [2,3]-Wittig and tandem [2,3]-Wittig anionic oxy-
cope rearrangement of bis allylic ethers: effect of substituents. Tetrahedron Lett. 1997, 38,
6
445-6448,
1. Zair, T.; Santelli, C.; Santelli, R.M. Palladium mediated cyclization of 1,5-hexadien-3-ols to
-methyl-1,3-cyclopentadienes. Tetrahedron 1993, 49, 3313-3324.
1
1
1
1
2. Servi, S.; Ahmetzade, M.; Coskun, M.; Cansiz, A. Use of 2-alkenyl-3-(chloromethyl) oxiranes
in the synthesis of 1, 5-dien-3-ols. S. Afr. J. Chem. 2000, 53, 73-76.
3. Servi, S.; Digrak, M.; Cansiz, A.; Ahmetzade, M. Synthesis of allyl-cyclopropyl alcohols and
allyl-1,5-hexadien-3-ols and investigation of their antibacterial and antifungal activities. Ind.
J. Chem. 2000, 39, 629-633.
1
4. Budzikiewicz, H.; Djerassi, C.; Williams, H.D. Ethers, acetals, ketals, and orthoesters, Mass
Spectrometry of Organic Compounds; Holden-Day Inc.: San Francisco, California, USA 1967;
pp. 232-233
Sample Availability: Available from the authors.
004 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.
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