On the Prins reaction of terminal olefins and formaldehyde in trifluoroacetic acid

Article abstract of DOI:10.1007/s10593-018-2293-z

[Figure not available: see fulltext.] The Prins reaction of 1-heptene, as a representative terminal alkene, with formaldehyde in trifluoroacetic acid produces 3-butyl-4-(trifluoroacetoxy)tetrahydropyran and/or 3-butyl-4-hydroxytetrahydropyran; it does not provide (as previously reported by Talipov and coworkers) a route to 3-alkyl-2,5-dihydrofurans and 4-alkyl-3-hydroxytetrahydrofurans.

Full text of DOI:10.1007/s10593-018-2293-z

DOI 10.1007/s10593-018-2293-z
Chemistry of Heterocyclic Compounds 2018, 54(4), 474–477
SHORT COMMUNICATIONS
On the Prins reaction of terminal olefins
and formaldehyde in trifluoroacetic acid
Hasanain A. A. Almohseni1, Matthew A. H. Stent1, David M. Hodgson1*
1 Department of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, UK; e-mail: david.hodgson@chem.ox.ac.uk
Published in Khimiya Geterotsiklicheskikh Soedinenii,
2018, 54(4), 474–477
Submitted January 2, 2018
Accepted after revision March 30, 2018
The Prins reaction of 1-heptene, as a representative terminal alkene, with formaldehyde in trifluoroacetic acid produces 3-butyl-
4-(trifluoroacetoxy)tetrahydropyran and/or 3-butyl-4-hydroxytetrahydropyran; it does not provide (as previously reported by Talipov and
coworkers) a route to 3-alkyl-2,5-dihydrofurans and 4-alkyl-3-hydroxytetrahydrofurans.
Keywords: formaldehyde, terminal alkenes, tetrahydropyrans, trifluoroacetic acid, Prins reaction.
Acid-induced reaction between homoallylic alcohols 1
and aldehydes (Prins cyclization) provides a straight-
forward entry to substituted tetrahydropyrans 2 (Scheme 1).1
The original Prins reaction, using simpler terminal olefins
3, can produce a range of products depending on the
substrate and experimental conditions.2 In general, the
latter is not viewed as a useful strategy to tetrahydropyrans,
although 3-alkyl-4-chlorotetrahydropyrans 4 (X = Cl) are
accessible in good yields from terminal olefins using
paraformaldehyde and gaseous HCl at low temperature
(Scheme 2).3 Using H2SO4 with formaldehyde and acetic
acid or under aqueous conditions is known to generate
4-acetoxy- or 4-hydroxy-3-substituted tetrahydropyrans,
together with significant quantities of 4-substituted
1,3-dioxanes.4
reaction of terminal olefins 3 and paraformaldehyde led,
remarkably, to a mixture of 3-alkyl-2,5-dihydrofurans 5
and 4-alkyl-3-hydroxytetrahydrofurans 6 (4:1 to 2:1,
depending on water content) in good overall yields
(Scheme 3). Further studies (including kinetic and compu-
tational) on this latter transformation were subsequently
reported, even up to 2015.8 This process was also reported
as being successful for higher aldehydes (using R1CHO
instead of HCHO) giving 2,3,5-trisubstituted 2,5-dihydro-
furans,5b and (in this Journal) as giving a mixture of 4-alkyl-
3-trifluoroacetoxy- and 4-alkyl-3-chlorotetrahydrofurans
with formaldehyde and Me3SiCl in TFA.9 Herein, we
disclose our reexamination of the reaction of a terminal
alkene with formaldehyde in TFA.
Scheme 3
Scheme 1
Scheme 2
The reaction of formaldehyde and 1-heptene (3a)
(Scheme 3) in TFA was reported to give 3-pentyl-2,5-di-
hydrofuran (5a) in good yields and has been the most
extensively investigated;5a,b consequently, this synthesis
was reexamined. Following an exact experimental proce-
Starting with 1993, Talipov and coworkers claimed in a
series of papers,5 a patent,6 and a review article7 that on
switching to trifluoroacetic acid (TFA) as solvent the
0009-3122/18/54(4)-0474©2018 Springer Science+Business Media, LLC
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Chemistry of Heterocyclic Compounds 2018, 54(4), 474–477
dure of Talipov, which reportedly gave a 43% yield of
3-pentyl-2,5-dihydrofuran (5a),5b 1-heptene (3a) was
reacted with HCHO in TFA for 3 h at 20°C (a similar result
was observed at 60°C). The major component we isolated
1
was a nonpolar colorless oil, possessing H NMR data
(e.g., (400 MHz, CDCl3), δ, ppm: 4.87 (1H, td)) similar to
those reported by Talipov ((80 MHz, CDCl3), δ, ppm: 4.63–
5.09 (1H, m)).5a,b However, the data is inconsistent with
that for 3-pentyl-2,5-dihydrofuran (5a) (e.g., (60 MHz,
CCl4), δ, ppm: 5.4 (1H, =CH)).10a Besides, 3-pentyl-2,5-di-
hydrofuran, prepared by us,10b displayed an olefinic proton
((400 MHz, CDCl3), δ, ppm: 5.43–5.48 (1H, m, C=CH))
consistent with the earlier report.10a
Scheme 4
Figure 1. Comparison of selected 13C NMR chemical shifts
(in ppm) for 3-hydroxytetrahydrofurans and 4-hydroxytetrahydro-
pyrans.
The material isolated under the Prins conditions in
anhydrous TFA is most straightforwardly assigned as
tetrahydropyranyl trifluoroacetates trans-4a and cis-4a
(Scheme 4), which would arise from a reaction akin to that
latter would be expected to cleave trifluoroacetates to
alcohols). This gave a mixture of two compounds for
which he kindly provided the 13C NMR data, assigning
them as cis- and trans-4-pentyl-3-hydroxytetrahydrofuran
(6a). We obtained essentially identical data following
addition of ammonia at the end of the Prins reaction. The
same data were obtained if the individual tetrahydropyranyl
trifluoroacetates trans-4a and cis-4a underwent methano-
lysis in the presence of K2CO3, to give structures trans-4b
and cis-4b. A comparison of this data with literature
13C NMR data for 4-hydroxytetrahydropyrans11,12 and
3-hydroxytetrahydrofurans12,13 is given in Figure 1.
–
in Scheme 2 (X– = F3CCO2 ). Indeed, our spectroscopic
data is consistent with trifluoroacetate data reported by
Talipov from the reaction mentioned above of terminal
alkenes with formaldehyde and Me3SiCl in TFA,9 albeit
Talipov assigned the products as 4-alkyl-3-trifluoroacetoxy-
tetrahydrofurans. Our 2D NMR data (1H–1H COSY, DEPT–
1
HSQC, and H–13C HMBC, see Supplementary informa-
tion file for spectra) provides strong evidence for 3,4-disub-
stituted tetrahydropyran structure 4a. For structure trans-4a,
1H–1H COSY correlations between protons H-4 and H-3
and Ha-5/Hb-5 revealed the existence of a C-3/C-4/C-5
atom sequence, and the alkyl group is located at position
On analyzing the 13C NMR data in Figure 1, it can been
seen, in particular, that the chemical shifts of carbinol
carbons are always greater than 70 ppm for 4-alkyl-
3-hydroxytetrahydrofurans, with those of trans-isomers
greater than 76 ppm. In contrast, the chemical shifts of
carbinol carbons of 3-alkyl-4-hydroxytetrahydropyrans are
~66 and ~72 ppm for cis- and trans-isomers, respectively.
This data comparison provides strong evidence that cis-
and trans-4-butyl-3-hydroxytetrahydropyrans (4a) were
prepared and not 3-hydroxytetrahydrofurans 6a, and further
implies that the process proceeds as in Scheme 2, not
Scheme 3, and by analogy this pathway is likely for higher
aldehydes in TFA as well.
Finally, the data for 3-alkyl-4-chlorotetrahydro'furans',
obtained by Talipov as the additional products from the
reaction of terminal olefins with formaldehyde and
Me3SiCl in TFA,9 was compared with literature data14 for a
homologous 3-alkyl-4-chlorotetrahydropyran (Fig. 2). The
literature data is consistent with the products reported by
Talipov also being cyclic ethers with a six- and not five-
membered ring.
1
C-3 based on DEPT–HSQC. H–1H COSY and DEPT–
HSQC data showed that the protons at 3.19 ppm (1H, dd)
and one H of the unresolved signal at 3.93–4.01 ppm (2H, m)
belong to the C-2 methylene group, whereas the protons at
3.50 ppm (1H, ddd) and the second H of the signal at 3.93–
4.01 ppm (2H, m) can be assigned to the C-6 methylene
group. Both atom pairs H-2/C-6 and H-6/C-2 are connected
by an ether linkage based on the HMBC spectrum, and
long-range HMBC correlations were observed also
between H-4 and C-2 and C-6 atoms. That the major
component trans-4a possessed the trans configuration was
based on the vicinal J constant values for the proton H-4
being larger for structure trans-4a (td, J = 9.5, J = 4.5 Hz)
compared with those observed for the minor cis-3,4-disub-
stituted tetrahydropyran cis-4a (q, J = 3.5 Hz).
Following correspondence with Talipov in 2008,* he
repeated the reaction between formaldehyde and 1-heptene
in TFA, followed by neutralization with ammonia (the
* E-mail from Prof. R. F. Talipov, 13th February 2008.
475

Chemistry of Heterocyclic Compounds 2018, 54(4), 474–477
J = 4.5, 4-CH). 13C NMR spectrum, δ, ppm (J, Hz): 13.9
(CH3); 22.9 (C-9); 28.1 (C-7); 28.8 (C-8); 30.7 (C-5); 40.7
(C-3); 65.6 (C-6); 69.9 (C-2); 78.9 (C-4); 114.7 (q, JCF = 286,
19
CF3); 157.3 (q, JCF = 42, C=O). F NMR spectrum, δ, ppm:
–75.2. Found, m/z: 277.1023 [M+Na]+. C11H17O3F3Na.
Calculated, m/z: 277.1022. Second eluted compound cis-4a.
Yield 0.89 g (5%), colorless liquid. Rf 0.2 (20% Et2O in
petroleum ether). IR spectrum, ν, cm–1: 775 (m), 1031 (w),
1121 (m), 1158 (m), 1219 (m), 1781 (s), 2862 (w), 2933 (w),
Figure 2. Comparison of selected 13C NMR chemical shifts (in ppm)
for 3-alkyl-4-chlorotetrahydro'furans' and -tetrahydropyrans.
1
In summary, Prins reactions of terminal alkenes with
formaldehyde in trifluoroacetic acid produce substituted
tetrahydropyrans, and not the erroneously reported 2,5-di-
hydrofurans or substituted tetrahydrofurans.
2961 (w). H NMR spectrum, δ, ppm (J, Hz): 0.88 (3H, t,
J = 7.0, CH3); 1.18–1.33 (6H, m, 3CH2); 1.84–1.98 (3H, m,
3-CH, 5-CH2); 3.51 (1H, t, J = 11.0, 2-CHa); 3.63–3.79
(3H, m, 2-CHb, 6-CH2); 5.32 (1H, q, J = 3.5, 4-CH).
13C NMR spectrum, δ, ppm (J, Hz): 13.9 (CH3); 22.8 (C-9);
26.5 (C-7); 28.7 (C-8); 30.1 (C-5); 39.2 (C-3); 63.0 (C-6);
67.8 (C-2); 74.9 (C-4); 114.7 (q, JCF = 286, CF3); 157.1 (q,
Experimental
IR spectra were obtained in film using a PerkinElmer
FTIR spectrometer with universal ATR sampling accessory.
1H, 19F, and 13C NMR spectra (400, 376, and 100 MHz,
J
CF = 42, C=O). 19F NMR spectrum, δ, ppm: –75.1. Found,
m/z: 141.1274 [M–OCOCF3]+. C9H17O. Calculated, m/z:
141.1274.
1
respectively), as well as H–1H COSY, DEPT–HSQC, and
1H–13C HMBC spectra were recorded on a Bruker Avance
AVIIIHD 400 spectrometer in CDCl3, referenced to
residual CHCl3 singlet at 7.26 ppm and to the central line
of CDCl3 triplet at 77.16 ppm for 13C NMR spectra.
13C NMR peaks were assigned by standard methods using
HSQC. High-resolution mass spectra were obtained by
electrospray ionization, using an Thermo Fisher Orbitrap
Exactive mass spectrometer. Flash column chromatography
was carried out using silica gel (VWR chemicals, BDH),
monitored by thin-layer chromatography on Merck 60 F254
plates. TLC spots were visualized by immersion in
KMnO4, followed by heating.
Paraformaldehyde was dried overnight under high
vacuum prior to use. 1-Heptene was freshly distilled from
CaH2. Trifluoroacetic acid (99%, extra pure) was used as
received (Acros). Petroleum ether of bp 40–60°C was used
in flash column chromatography.
Trans- and cis-3-butyltetrahydro-2H-pyran-4-yl 2,2,2-tri-
fluoroacetate (trans- and cis-4a). The procedure and
reaction scale of Talipov was followed.5b TFA (15 ml) was
added to paraformaldehyde (5.00 g, 170 mmol), and the
mixture heated until a clear solution formed (3–5 min). The
mixture was cooled to room temperature, then 1-heptene
(3a) (9.3 ml, 80 mmol) was added dropwise. After 3 h at
room temperature, unreacted 1-heptene and TFA were
removed by distillation (˂40°C, ~100 mbar). The residue, a
yellow oil (~11 g), was distilled at ~15 mbar and the
fraction of bp 60–70°C (5.3 g, an impure 75:25 mixture of
compounds trans-4a and cis-4a) further was purified by
flash column chromatography (0–20% Et2O in petroleum
ether). First eluted compound trans-4a. Yield 3.2 g (19%),
colorless liquid. Rf 0.26 (20% Et2O in petroleum ether).
IR spectrum, ν, cm–1: 1139 (w), 1164 (s), 1222 (m), 1249 (s),
1781 (s), 2861 (w), 2934 (m), 2962 (m). 1H NMR
spectrum, δ, ppm (J, Hz): 0.88 (3H, t, J = 7.0, CH3); 1.14–
1.34 (5H, m, 7-CHa, 8,9-CH2); 1.40–1.47 (1H, m, 7-CHb);
1.71–1.79 (1H, m, 5-CHa); 1.81–1.88 (1H, m, 3-CH); 2.02–
2.08 (1H, m, 5-CHb); 3.19 (1H, dd, J = 12.0, J = 9.0,
2-CHa); 3.50 (1H, ddd, J = 12.0, J = 10.5, J = 3.0, 6-CHa);
3.93–4.01 (2H, m, 2-CHb, 6-CHb); 4.87 (1H, td, J = 9.5,
Trans- and cis-3-butyltetrahydro-2H-pyran-4-ol (trans-
and cis-4b). The above procedure and reaction scale was
followed, but after 3 h at room temperature, the mixture
was neutralized by aq NH3 (15 ml). The aqueous layer was
extracted with Et2O (2 × 30 ml), dried over Na2SO4, and
evaporated under reduced pressure. The residue, a yellow
oil (~8 g), was distilled at ~15 mbar and the fraction of
bp 100–110°C (4.7 g, an impure 75:25 mixture of
compounds trans- and cis-4b) further was purified by flash
column chromatography (20–40% Et2OAc in petroleum
ether). First eluted compound trans-4b. Yield 1.72 g
(17%), colorless liquid. Rf 0.3 (30% EtOAc in petrol). IR
spectrum, ν, cm–1: 626 (s), 1050 (s), 1080 (s), 1150 (s),
1222 (m), 1466 (m), 2856 (s), 2925 (s), 2955 (s), 3386 (br).
1H NMR spectrum, δ, ppm (J, Hz): 0.88 (3H, t, J = 7.0,
CH3); 1.03–1.13 (1H, m, 7-CHa); 1.17–1.37 (4H, m,
8,9-CH2); 1.43–1.62 (2H, m, 3-CH, 5-CHa); 1.63–1.72 (1H,
m, 7-CHb); 1.73–1.92 (2H, m, 5-CHb, OH); 3.02 (1H, t,
J = 11.0, 2-CHa); 3.35–3.44 (2H, m, 4-CH, 6-CHa); 3.90–
3.98 (2H, m, 2-CHb, 6-CHb). 13C NMR spectrum (100 MHz,
CDCl3), δ, ppm: 14.1 (CH3); 23.2 (C-9); 28.3 (C-7); 29.3
(C-8); 35.3 (C-5); 44.6 (C-3); 66.5 (C-6); 70.6 (C-2); 72.1
(C-4). Found, m/z: 141.1272 [M–OH]+. C9H17O. Calculated,
m/z: 141.1273. Second eluted compound cis-4b. Yield
0.36 g (3%), colorless liquid. Rf 0.2 (30% EtOAc in
petroleum ether). IR spectrum, ν, cm–1: 626 (s), 1080 (s),
1150 (s), 1222 (m), 1466 (m), 2856 (s), 2927 (s), 2955 (s),
1
3389 (br). H NMR spectrum, δ, ppm (J, Hz): 0.89 (3H, t,
J = 7.0, CH3); 1.19–1.36 (6H, m, 3CH2); 1.58 (1H, br. s, OH);
1.63–1.73 (2H, m, 3-CH, 5-CHa); 1.77–1.86 (1H, m,
5-CHb); 3.51–3.56 (2H, m, 2-CH2); 3.64 (1H, ddd, J = 11.5,
J = 4.5, J = 3.5, 6-CHa); 3.78 (1H, td, J = 11.0, J = 3.0,
6-CHb); 4.00 (1H, dt, J = 5.5, J = 3.0, 4-CH). 13C NMR
spectrum, δ, ppm: 14.1 (CH3); 23.1 (C-9); 26.6 (C-7); 29.1
(C-8); 33.5 (C-5); 40.9 (C-3); 63.2 (C-6); 66.7 (C-4); 67.6
(C-2). Found, m/z: 141.1272 [M–OH]+. C9H17O.
Calculated, m/z: 141.1273.
Trans-3-butyltetrahydro-2H-pyran-4-ol (trans-4b).
Compound trans-4a (250 mg, 0.98 mmol) was stirred with
K2CO3 (270 mg, 1.96 mmol) in MeOH (1 ml) at room
476

Chemistry of Heterocyclic Compounds 2018, 54(4), 474–477
3. (a) Stapp, P. R. J. Org. Chem. 1969, 34, 479.
temperature. After 3 h, the mixture was quenched with
10% HCl (1 ml) and extracted with EtOAc (2×5 ml). The
combined organic layers were washed with brine (2 ml)
and dried (Na2SO4). Evaporation under reduced pressure
followed by chromatography (30% EtOAc in petroleum
ether) gave a colorless liquid. Yield 138 mg (89%). The
spectral data were identical to those of compound trans-4b
obtained in one-pot procedure from 1-heptene (3a) and
paraformaldehyde.
(b) Onopchenko, A.; Seekircher, R. J. Chem. Eng. Data 1970,
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Cis-3-butyltetrahydro-2H-pyran-4-ol (cis-4b). Compound
cis-4a (150 mg, 0.59 mmol) was stirred with K2CO3
(163 mg, 1.18 mmol) in MeOH (1 ml) at room temperature.
After 3 h, the mixture was quenched with 10% HCl (1 ml)
and extracted with EtOAc (2×5 ml). The combined organic
layers were washed with brine (2 ml) and dried (Na2SO4).
Evaporation under reduced pressure followed by
chromatography (30% EtOAc in petroleum ether) gave a
colorless liquid, cis-3-butyltetrahydro-2H-pyran-4-ol (cis-4b).
Yield 87 mg (93%). The spectral data were identical to
those of compound cis-4b obtained in one-pot procedure
from 1-heptene (3a) and paraformaldehyde.
7. Talipov, R. F.; Safarov, M. G. Bashk. Khim. Zh. 1996, 3(1–2),
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The Supplementary information file containing tabular
comparisons of 13C NMR data of compounds trans-4a,
cis-4a, trans-4b, and cis-4b with that from Talipov's work
and NMR spectra of compounds trans-4a, cis-4a, trans-4b,
and cis-4b is available at the journal website at http://
link.springer.com/journal/10593.
The authors thank the Higher Committee for Education
Development in Iraq for studentship support (to H.A.A.A.),
the EPSRC and Roche for a CASE award (to M.A.H.S.),
and Prof. Talipov (Bashkir State University) for useful
correspondence.
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Asymmetry 1997, 8, 1811.
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