A new synthetic route to 3-polyfluoroalkyl-containing pyrroles

Article abstract of DOI:10.1016/j.tetlet.2007.12.048

A novel approach to 3-polyfluoroalkyl pyrroles is reported based on step by step reactions: 1,2-addition of Me₃SiCN to β-alkoxyvinyl polyfluoroalkyl ketones, reduction with LiAlH₄ and subsequent hydrolysis with intramolecular cyclization. The hydrolytic instability of various polyfluoroalkyl groups at position 3 of the pyrrole ring was evident and a pathway for the hydrolysis was proposed.

Full text of DOI:10.1016/j.tetlet.2007.12.048

Available online at www.sciencedirect.com
Tetrahedron Letters 49 (2008) 1184–1187
A new synthetic route to 3-polyfluoroalkyl-containing pyrroles
Elena N. Shaitanova, Igor I. Gerus *, Valery P. Kukhar
Institute of Bioorganic Chemistry and Petrochemistry National Academy of Sciences of Ukraine, Str. Murmanskaya 1, Kiev, 02094, Ukraine
Received 30 October 2007; revised 29 November 2007; accepted 10 December 2007
Available online 15 December 2007
Abstract
A novel approach to 3-polyfluoroalkyl pyrroles is reported based on step by step reactions: 1,2-addition of Me3SiCN to b-alkoxyvinyl
polyfluoroalkyl ketones, reduction with LiAlH4 and subsequent hydrolysis with intramolecular cyclization. The hydrolytic instability of
various polyfluoroalkyl groups at position 3 of the pyrrole ring was evident and a pathway for the hydrolysis was proposed.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Enone; Pyrrole; Cyclization; Hydrolysis; Fluoroalkyl groups; 3-Polyfluoroalkyl pyrroles
Recently, organofluorine compounds have gained con-
siderable interest due to their enhanced biological activ-
ity,1–3 especially polyfluoroalkyl substituted heterocycles.
Pyrrole-containing structures are common in syntheses of
bioactive compounds. For example, fluoroalkyl-containing
pyrroles are good precursors to various herbicides4 and
porphyrins.5–7
Synthesis of pyrroles bearing several substituents
together with a polyfluoroalkyl group at position 3 has
been reported,8 whereas 3-polyfluoroalkyl pyrroles with
few other substituents are less accessible.9 Thus, attention
has been devoted to the synthesis of 3-trifluoromethyl
substituted pyrroles mainly as precursors for electron defi-
cient porphyrins.10 The first synthesis of a 3-trifluoro-
methyl-containing pyrrole was accomplished using the
modified Knorr condensation starting from ethyl trifluoro-
acetoacetate.10 A later synthesis of 3-trifluoromethyl pyr-
roles used a,b-unsaturated ketones.11 Another approach
to 3-trifluoromethyl substituted pyrroles consisted of pho-
tochemical trifluoromethylation using CF2I2 or CF3I. A
mixture of 2- and 3-trifluoromethyl pyrroles (in very poor
yield) was obtained in ratios of isomers which depended
on the reaction conditions and the nature of the substitu-
ents on the pyrrole ring.8,12
In addition, there are reports on the synthesis of 3-tri-
fluoroacetyl pyrroles starting from readily available b-alk-
oxyvinyl trifluoromethyl ketones 1.13,14 Thus, we have
developed a new efficient route to the construction of 3-
polyfluoroalkyl-containing pyrroles starting from poly-
fluoroalkyl-containing enones 1a–g.15
The addition of trimethylsilylcyanide (TMSCN) to car-
bonyl compounds is widely used to obtain silylated cyano-
hydrins, which are used as precursors for b-amino
alcohols,16a a-hydroxy acids16b and a-amino acids.16c The
first step in the proposed synthetic route is 1,2-addition
of TMSCN to the carbonyl group of enones 1a–g in the
presence of a catalytic amount of base17 leading to silylated
cyanohydrins 2a–g (Scheme 1).18 Cyanohydrins 2 were eas-
ily reduced with LiAlH4 to amino alcohols 3 in high yields
(Table 1).19
R3
R3
R3
RF
R1O
CN
R1O
R1O
RF
i
ii
NH2
RF OH
R2
R2
2a-g
OTMS
R2
1a-g
O
3a-g
*
Scheme 1. Reagents and conditions: (i) TMSCN, Et3N, 0–10 °C; (ii)
LiAlH4, ether, 0–5 °C.
Corresponding author. Tel.: +38 044 573 2598; fax: +38 044 573 2552.
E-mail address: igerus@hotmail.com (I. I. Gerus).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.12.048

E. N. Shaitanova et al. / Tetrahedron Letters 49 (2008) 1184–1187
1185
Table 1
Yields of cyanohydrins 2 and amino alcohols 3
Table 2
Yields of pyrroles 6 and 7
1–3
R1
R2
R3
RF
Product 2
Product 3
3–7
R2
R3 RF
6 Yield (%)
R
7 Yield (%)
yield (%)
yield (%)
a
b
c
d
e
f
H
H
H
Me
H
H
H
H
H
Br
H
H
CF3
65a
—
—
55a
5–10d
90b,c,e
—
OH
H
OH
OH
OH
OH
—
48
45b
53b
—
a
b
c
d
e
f
Et
Et
Et
Me
Et
Et
Et
H
H
H
Me
H
H
H
H
H
Br
H
H
CF3
80
80
87
90
82
85
74
88
80
75
92
81
90
78
CHF2
CF2Cl
CF3
CF3
CF3
CHF2
CF2Cl
CF3
CF3
CF3
Ph
H
—
Ph
H
g
a
C2F5
CF3 55b,c
g
C2F5
Method A: 0.1 equiv of HCl, rt.
Method B: 1 equiv of HCl, rt.
Reaction temperature ꢀ80 °C.
b
c
From 1H and 19F NMR spectroscopic data of the reaction mixture.
d
e
The amino alcohols 3 are good precursors to biologi-
From Schiff base 5f.
cally active fluorinated compounds, and we have recently
used amino alcohols 3a,b for the synthesis of b-RF-contain-
ing analogs of GABA.18 NMR spectral data of amino alco-
hols 3c–g are similar to the corresponding data for 3a,b.19
Amino alcohols 3a–g maintain the starting configuration of
the C@C double bond under the reaction conditions. Puri-
fication of amino alcohols 3 was dependent on the nature
of the substituents R2 and R3: products 3a–c,g are oils
which were purified by vacuum distillation, whereas the
crystalline amino alcohols 3d–f were purified by
crystallization.
The last step of the 3-polyfluoroalkyl pyrrole synthesis
was hydrolysis of the alkoxyvinyl group with the formation
of aminocarbonyl compounds 4 which are unstable and
cyclized readily to the pyrroles 6 via intramolecular Schiff
base 5 formation with subsequent dehydration and proton
migration (Scheme 2, Table 2).
The structure of the pyrroles was dependent on the reac-
tion and isolation conditions.20 It was found that some of
the RF-groups at position 3 of the pyrrole ring were hydro-
lytically unstable. The main attention was focused on the
synthesis of 3-trifluoromethylpyrrole 6a and we found the
optimal reaction conditions for the hydrolysis of amino
alcohol 3a using 19F NMR spectroscopy using the low field
shift (20–25 ppm) of the trifluoromethyl group signal after
pyrrole ring formation. Thus, method A provides a higher
yield compared to method B because of the volatility of
product 6a while its trifluoromethyl group is rather stable
(Table 2). The spectral data of product 6a (3-trifluoro-
methylpyrrole) were identical to those published by Leroy.9
Hydrolysis of amino alcohols 3b–g resulted in both pyr-
role ring formation and hydrolysis of the corresponding RF
groups. We suggest that hydrolysis of polyfluoroalkyl
groups took place after pyrrole ring formation (Scheme
3), since during the hydrolysis of 3b (method A) with a cata-
lytic amount of HCl we observed 3-difluoromethylpyrrole
(6b) formation in the reaction mixture by NMR spectro-
scopy together with pyrrole-3-carboxaldehyde (7b). How-
ever, only aldehyde 7b was obtained after work up and
purification by column chromatography; its structure was
unambiguously confirmed by IR and NMR spectroscopy.
Only product 7b was obtained using method B.
During the hydrolysis of amino alcohol 3c, 1H-pyrrole-
3-carboxylic acid (7c) was obtained in a moderate yield, the
formation of pyrrole 6c with a chlorodifluoromethyl group
was not detected (19F NMR spectroscopy) due to easier
chloride ion elimination. The introduction of the weak elec-
tron donating methyl group at position 5 of the pyrrole
ring leads to destabilization of the CF3 group and as a
result (method B conditions) a mixture of 6d and 7d was
observed by NMR but only 7d was obtained after work
up and purification. Using method A, product 6d was
formed in a moderate yield.
The amino alcohols 3e–g were significantly more stable
to hydrolysis than the amino alcohols 3a–d and hydrolysis
of the ethoxyvinyl group occurred using method B at a
higher temperature (ꢀ80 °C). In the case of bromo-con-
taining amino alcohol 3e a complex mixture of reaction
products together with pyrrole 6e (observed only by
NMR spectroscopy) was obtained. Under these conditions,
R3
R3
R3
RF
i
R1O
O
OH
NH2
NH2
2
R
RF OH
R2
RF OH
R2
N
3a-g
4a-g
5a-g
F
HO
F
O
X
X
X
-F-
X
O
F
F
H2O
R3
R2
R3
R2
CF3
R
R2
+F-
-HF
-H+ R2
R2
R2
N
N
H
N
H
and/or
N
H
H
N
H
6
7
N
X = F, H, Cl, CF3
H
7b-d,g
6a,d-f
Scheme 3. Assumed mechanism of the hydrolysis of the RF groups at
position 3 of pyrroles.
Scheme 2. Reagents and conditions: (i) H+, H2O, MeCN, rt.

1186
E. N. Shaitanova et al. / Tetrahedron Letters 49 (2008) 1184–1187
References and notes
RF
i
EtO
EtO
COPh ii
NH2
N
1. Kirk, K. L. J. Fluorine Chem. 2006, 127, 1013–1029.
2. Begue, J.-P.; Bonnet-Delpon, D. J. Fluorine Chem. 2006, 127, 992–
1012.
3. Fluorine in Bioorganic Chemistry; Welch, T., Eswarakrishnan, S.,
Eds.; John Wiley & Sons: New York, 1991.
H
N
HO RF
HO RF
COPh
3b,c
8b,c
9b,c
Scheme 4. Reagents and conditions: (i) PhCOCl, Et3N, CH2Cl2, 0 °C; (ii)
4. Kuhn, D. G.; Kamhi, V. M.; Furch, J. A.; Diehl, R. E.; Lowen, G. T.;
Venkataraman, K. J. Pestic. Sci. 1994, 41, 279–286.
H+, H2O, MeCN, rt.
5. Kumadaki, I.; Omote, M. J. Fluorine Chem. 2001, 109, 67–81.
6. Leroy, J.; Porhiel, E.; Bondon, A. Tetrahedron 2002, 58, 6713–
6722.
7. Ono, N.; Kawamura, H.; Maruyama, K. Bull. Chem. Soc. Jpn. 1989,
62, 3386–3388.
8. (a) Bucci, R.; Laguzzi, G.; Pompili, M. L.; Speranza, M. J. Am. Chem.
Soc. 1991, 113, 4544–4550; (b) Chen, Q.; Li, Z. J. Chem. Soc., Perkin
Trans. 1 1993, 645–648; (c) Katritzky, A. R.; Huang, T.; Voronkov,
M. V.; Wang, M.; Kolb, H. J. Org. Chem. 2000, 65, 8819–8821;
(d) Takaya, H.; Kojima, S.; Murahashi, S. Org. Lett. 2001, 3, 421–
424; (e) Klappa, J.; Rich, A. E.; McNeill, K. Org. Lett. 2002, 4, 435–
437; Shi, D.; Dou, G.; Shi, C.; Li, Z.; Ji, S. Synthesis 2007, 3117–
3124.
the amino alcohol 3f was converted into trifluoromethyl-
containing pyrrole 6f in high yield. Moreover, in this case
the stability of the intermediate Schiff base 5f was such that
it could be isolated and characterized. Hydrolysis of amino
alcohol 3g gave pyrrole 7g with a trifluoroacetyl group at
position 3, its spectral data and mp were consistent with
1
previous reports.14,21 Pyrrole 6g was observed by H and
19F NMR spectroscopy only.
Hydrolysis of the polyfluoroalkyl groups at position 3 of
the pyrrole ring can be explained by the influence of the
high electron density of the heterocycle (Scheme 3). To
the best of our knowledge, there are no previous reports
on the hydrolytic instability of 3-polyfluoroalkylpyrroles.
Only the instability of trifluoro- and difluoromethylimida-
zoles has been reported.22,23
To enhance the stability of the RF group at position 3 of
the pyrrole ring to hydrolysis the electron donor influence
of the nitrogen atom was decreased by N-acylation of
amino alcohols 3b,c with benzoyl chloride. Vinyl ethers
8b,c were hydrolysed to afford N-benzoyl-3-difluoro- and
3-chlorodifluoromethylpyrroles (9b,c) in good yields under
the conditions of method B (Scheme 4).24 The stability of
the RF groups in N-benzoyl pyrroles 9 during work up
was consistent with the proposed hydrolysis mechanism
of 3-polyfluoroalkyl pyrroles 6.
In conclusion, the present method provides a new syn-
thetic access to 3-polyfluoroalkyl pyrroles, which are
potentially useful precursors for fluorine-containing por-
phyrins, based on fluorinated enones 1a–g. The hydrolytic
instability of some of the 3-polyfluoroalkyl groups in the
pyrrole ring was evident and a reasonable pathway for
the hydrolysis was proposed. In spite of the hydrolytic
instability of difluoro- and chlorodifluoromethyl groups
at position 3 of pyrroles 6, the corresponding N-benzoyl
derivatives 9 could be synthesized.
9. Leroy, J. J. Fluorine Chem. 1991, 53, 61–70.
10. (a) Ogoshi, H.; Homma, M.; Yokota, K.; Toi, H.; Aoyama, Y.
Tetrahedron Lett. 1983, 24, 929–930; (b) Homma, M.; Aoyagi, K.;
Aoyama, Y.; Ogoshi, H. Tetrahedron Lett. 1983, 24, 4343–4346.
11. Aoyagi, K.; Toi, H.; Aoyama, Y.; Ogoshi, H. Chem. Lett. 1988, 1891–
1894.
12. Nishida, M.; Kimoto, H.; Fujh, S.; Hayakawa, Y.; Cohen, L. A. Bull.
Chem. Soc. Jpn. 1991, 64, 2255–2259.
13. Okada, E.; Masuda, R.; Hojo, M.; Inoue, R. Synthesis 1992, 533–535.
14. Okada, E.; Masuda, R.; Hojo, M.; Yoshida, R. Heterocycles 1992, 34,
1435–1441.
15. (a) Hojo, M.; Masuda, R.; Kokuryo, Y.; Shioda, H.; Matsuo, S.
Chem. Lett. 1976, 5, 499–502; (b) Gorbunova, M. G.; Gerus, I. I.;
Kukhar, V. P. Synthesis 2000, 738–742; (c) Gerus, I. I.; Kacharova, L.
M.; Vdovenko, S. I. Synthesis 2001, 431–436; (d) Hojo, M.; Masuda,
R.; Sakaguchi, S.; Takagawa, M. Synthesis 1986, 1016–1017.
16. (a) Kanerva, L. T. Acta Chem. Scand. 1996, 50, 234–242; (b)
Effenberger, F.; Heid, S. Tetrahedron: Asymmetry 1995, 6, 2945–2952;
(c) Zandbergen, P.; Brussee, J.; van der Gen, A.; Kruse, C. G.
Tetrahedron: Asymmetry 1992, 3, 769–774.
17. (a) Gerus, I. I.; Kruchok, I. S.; Kukhar, V. P. Tetrahedron Lett. 1999,
40, 5923–5926; (b) Kruchok, I. S.; Gerus, I. I.; Kukhar, V. P.
Tetrahedron 2000, 56, 6533–6539.
18. For a typical procedure for the preparation of 1,2-adducts 2 see:
Shaitanova, E. N.; Gerus, I. I.; Belik, M. Yu; Kukhar, V. P.
Tetrahedron: Asymmetry 2007, 18, 192–198.
19. A typical procedure for the preparation of amino alcohols 3a–g: To a
suspension of LiAlH4 (2.03 g, 53.5 mmol) in dry ether (50 mL)
adducts 2a–g (48.6 mmol) was added dropwise with stirring for
30 min at 0–5 °C. The mixture was stirred overnight at room
temperature. Excess LiAlH4 was decomposed with 30% aq NaOH
(10 mL) with stirring at 0 °C, then precipitated alumina was filtered
and washed thoroughly with ether (3 Â 50 mL). The filtrate was dried
(MgSO4) and concentrated under reduced pressure to give a brown
oil. The products were purified by vacuum distillation or by
crystallization. Spectral data for (E)-1,1,1-trifluoro-4-ethoxy-2-(amino-
methyl)-3-buten-2-ol (3a): Colorless oil, 88%, bp 85–90 °C/0.1 mmHg;
1H NMR (500 MHz, CDCl3) d: 1.32 (t, 3H, J = 7.1 Hz), 2.7 (d, 1H,
J = 13.0 Hz), 3.12 (d, 1H, J = 13.0 Hz), 3.77 (q, 2H, J = 7.1 Hz), 4.7
(d, 1H, J = 12.5 Hz), 6.75 (d, 1H, J = 12.5 Hz); 19F NMR (470.5
MHz, CDCl3) d: À81.6 (s); 13C NMR (125 MHz, CDCl3) d: 14.6,
45.3, 65.4, 72.5 (q, JC–F = 35.0 Hz), 99.2, 125.8 (q, JC–F = 285.0 Hz),
150.9. IR (CHCl3, cmÀ1): m = 3424, 3048, 2984, 2336, 1656, 1424,
1260, 1200, 1158, 1037. Anal. Calcd for C7H12F3NO2: C, 42.21; H,
6.07; N, 7.03. Found: C, 42.36; H, 6.25; N, 7.10.
Acknowledgements
We are indebted to Dr. B. I. Ugrak (Institute of Organic
Chemistry RAN, Moscow, Russia) for presenting us with
difluoroacetic acid.
Supplementary data
Supplementary data associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2007.
12.048.

E. N. Shaitanova et al. / Tetrahedron Letters 49 (2008) 1184–1187
1187
20. A typical procedure for the preparation of pyrroles 6 and/or 7: Method
A. The amino alcohols 3a,d (1 mmol) were dissolved in a mixture of
MeCN (1 mL) and water (0.5 mL), then 5% aq HCl (0.03 mL,
0.1 mmol) was added. The reaction mixture was stirred at room
temperature for 1 week (the mixture became light red). The reaction
was monitored by TLC and 19F NMR spectroscopy. The reaction
mixture was diluted with ether (5 mL) and dried over anhydrous
MgSO4. The products were obtained as oils by careful removal of the
solvents by distillation at atmospheric pressure. Method B. To a
solution of amino alcohols 3b,c,e–g (2.5 mmol) in a mixture of
acetonitrile (3 mL) and water (1.5 mL), 5% aq HCl (0.8 mL,
2.5 mmol) was added. The reaction mixture was stirred at room
temperature for 24 h. The reaction was monitored by TLC and 19F
NMR spectroscopy. The solution was poured into water and 3%
NaHCO3 (10 mL) was added, the products were extracted with
CH2Cl2 (3 Â 15 mL) and the combined organics dried over anhydrous
MgSO4. Products 6 and/or 7 were purified by silica gel chromato-
graphy. Spectral data for 3-trifluoromethyl-1H-pyrrole (6a): Brown oil,
65%; 1H NMR (500 MHz, CDCl3) d: 7.16 (s, 1H), 7.33 (s, 1H), 7.50 (s,
24. A typical procedure for the preparation of N-benzoylated amino
alcohols 8b,c: To a mixture of amino alcohols 3b,c (1.3 mmol) and
Et3N (0.18 mL, 1.3 mmol) in dry methylene chloride (20 mL), benzoyl
chloride (0.15 mL, 1.3 mmol) was added at 0 °C with stirring for
5 min. The mixture was stirred for 2 h at room temperature and water
(10 mL) was added. The organic phase was washed with 5% NaHCO3
(2 Â 5 mL) and water (2 Â 25 mL). The aqueous layer was extracted
with methylene chloride (2 Â 25 mL) and the combined organics were
dried (MgSO4) and then evaporated. Products 8b,c were purified by
column chromatography on silica gel (eluent—EtOAc/hexane 1:6).
Spectral data for N-(2-difluoromethyl-4-ethoxy-2-hydroxybut-3-
enyl)benzamide (8b): Low-melting solid, 65%; 1H NMR (500 MHz,
CDCl3) d: 1.26 (t, 3H, J = 7.0 Hz), 3.59 (d, 1H, J = 14.7 Hz), 3.76 (q,
2H, J = 7.0 Hz), 3.85 (d, 1H, J = 14.7 Hz), 4.75 (d, 1H, J = 12.6 Hz),
5.63 (t, 1H, J = 56.1 Hz), 6.53 (s, 1H), 6.74 (d, 1H, J = 12.6 Hz), 7.46
(m, 2H), 7.54 (m, 1H), 7.77 (m, 2H); 19F NMR (470.5 MHz, CDCl3)
d: À132.1 (dd, 1F, JF–F = 272.1 Hz, JF–H = 56.1 Hz), À131.0 (dd, 1F,
JF–F = 272.1 Hz, JF–H = 56.1 Hz); Anal. Calcd for C14H17F2NO3: C,
58.94; H, 6.01; N, 4.91. Found: C, 58.90; H, 6.27; N, 4.99. A typical
procedure for the preparation of N-benzoyl pyrroles 9b,c: Products 9b,c
were prepared according to the general procedure as described for
pyrroles 6 by method B. Spectral data for 3-difluoromethyl-1-benzoyl-
1H-pyrrole (9b): White solid, 75%, mp 168 °C. 1H NMR (500 MHz,
CDCl3) d: 6.49 (s, 1H), 6.65 (t, 1H, JH–H = 56.1 Hz), 7.33 (m, 1H),
7.48 (m, 1H), 7.54 (m, 2H), 7.65 (m, 1H), 7.75 (m, 2H); 19F NMR
(CDCl3) d: À110.1 (d, JF–H = 56.1 Hz); 13C NMR (CDCl3) d: 109.9,
111.4 (t, JC–F = 248.5 Hz), 122.4, 123.0 (t, JC–F = 26.2 Hz), 128.6,
129.5, 132.2, 132.7, 167.3; IR (CH2Cl2, cmÀ1): m = 3152, 3060, 2960,
2928, 2856, 1707, 1599, 1488, 1448, 1392, 1334, 1248, 1224, 1144,
1072, 1022, 960. Anal. Calcd for C12H9F2NO: C, 65.16; H, 4.10; N,
6.33. Found: C, 65.35; H, 4.15; N, 6.52.
1H), 8.54 (br s, 1H); 19F NMR (470.5 MHz, CDCl3) d: À57.3 (s); 13
C
NMR (125 MHz, CDCl3) d: 104.33, 114.92, 113.15 (q, JC–F
=
36.4 Hz), 117.33, 122.37 (q, JC–F = 265.7 Hz). IR (CH2Cl2, cmÀ1):
m = 3685, 3464, 3060, 1608, 1578, 1496, 1432, 1400, 1362, 1248, 1202,
1134, 928. Anal. Calcd for C5H4F3N: C, 44.46; H, 2.98; N, 10.37.
Found: C, 44.27; H, 3.04; N, 10.28.
21. Bray, B. L.; Mathies, P. H.; Naef, R.; Solas, D. R.; Tidwell, T. T.;
Artis, D. R.; Muchowski, J. M. J. Org. Chem. 1990, 55, 6317–
6328.
22. (a) Kimoto, H.; Cohen, L. A. J. Org. Chem. 1979, 44, 2902–2906; (b)
Noyce, D. S. J. Org. Chem. 1972, 37, 2643–2647.
23. Tuan, E.; Kirk, K. L. J. Fluorine Chem. 2006, 127, 980–982.