Mendeleev Commun., 2002, 12(4), 162–163
Acetylation and trifluoroacetylation reactions of tetrahydropyrrolo[3,2-c]pyridines
Tatiana N. Borisova, Leonid G.Voskressensky,* Tatiana A. Soklakova, Bonifas Nsabimana and Alexey V. Varlamov
Department of Organic Chemistry, Peoples Friendship University of Russia, 117198 Moscow, Russian Federation.
Fax: +7 095 954 0336; e-mail: lvoskressensky@sci.pfu.edu.ru
10.1070/MC2002v012n04ABEH001597
4-Methyl-substituted tetrahydropyrrolo[3,2-c]pyridines reacted with acetic anhydride to produce substituted 3-vinylpyrroles in low
to moderate yields.
Tetrahydropyrrolo[3,2-c]pyridines (THPPs) are easy available
building blocks for the construction of heterocyclic systems;1 at
the same time, many of THPPs exhibited biological activity.2,3
Recently, we have reported tandem piperidine ring cleavage in
tetrahydropyrrolo[3,2-c]pyridines under the action of dimethyl
acetylene dicarboxylate (DMAD) resulting in the formation of
α- and β-vinylpyrroles in moderate to good yields.4 We report
here on the unusual cleavage of THPPs 1–6 under the action of
acetic anhydride.
To synthesise functionalised THPPs interesting from the bio-
logical viewpoint,5 we have carried out the acetylation and tri-
fluoroacetylation of derivatives 1–6 according to the protocols
reported for pyrroles.6,7 The trifluoroacetylation reaction† pro-
ceeds smoothly giving expected 2-trifluorosubstituted THPPs
7–12 in 60–70% yields (Scheme 1).
Taking into account the limited availability of 3-vinylpyrroles
and their possible use as building blocks for the synthesis of
more elaborated substrates,8 we studied the acetylation of α-sub-
stituted THPP derivatives 15–17. α-Formylvinylpyrrole 18‡ was
isolated in 25% yield, while the cleavage of 16 and 17 proceeds
with difficulties and corresponding vinylpyrroles 19 and 20 were
obtained in 15 and 10% yields, respectively. The oxime group
of 17 was dehydrated to provide nitrile under the action of acetic
anhydride. The main products isolated in this case were quater-
nary ammonium bases 21§ and 22 (48 and 42%, respectively, as
amorphous solids), which were most likely formed during column
chromatography of the reaction mixture from intermediate salts
A. Compounds 21 and 22 were formed as mixtures of two
isomers with approximate ratio of 1:1.5.
Target 2-acetyl THPP 23 can be obtained under Vilsmeier–
Haack acetylation conditions by treating THPP 5 with dimethyl-
acetamide (DMAA) and phosphorous oxychloride (Scheme 3).
Finally, we studied the acetylation and trifluoroacetylation of
THPP derivatives and found that the corresponding α-trifluoro-
acetyl derivatives can be obtained in high yields by the subse-
quent action of trifluoroacetic anhydride and DMAA–POCl3.
R1
R1
R
R
(CF3CO)2O
pyridine
N
N
COCF3
N
N
R1
1 6
R1
7 12
R2
R2
–
–
(60–70%)
AcO
Me
Me
1
1
1
1 2 7 8
3 4 9 10
5 6 11 12
, , , R = H, R = Et , , , R = H, R = Bn , ,
,
R = R = Me
Me
Ac
Me
1,3,5,7,9,11 R2 = H 2,4,6,8,10,12 R2 = vinyl
N
Ac2O
R3
N
R3
N
Scheme 1
N
R2
R2
Me
Me
Surprisingly, we failed to isolate the expected 2-acetyl deriva-
tives in the case of acetylation. No trace of the target product
has been detected in the reaction mixtures. Under the reaction
conditions used,‡ compounds 1–4 afforded multicomponent in-
separable mixtures of tar products, while derivatives 5 and 6
provided 3-vinylpyrroles 13 (16%) and 14. Although NMR and
GC–MS analysis of the reaction mixture showed at least 80%
divinyl THPP derivative 14, we failed to isolate it because of its
instability under the isolation conditions.
The cleavage most likely starts with the formation of quater-
nary ammonium salt A followed by an attack of the acetoxy
anion on the 4-Me group (Hofmann-like cleavage) to afford
3-vinylpyrroles. The lower basicity of the trifluoroacetoxy anion
explains the absence of cleavage in the trifluoroacetylation
(Scheme 2).
5 6 15 17
, ,
A
–
HO
Me
Me
Me
Ac
N
N
R3
R3
Ac
N
N
R2
R2
Me
21,22
R2 = R3 = H
Me
13,14,18–20
R2 = vinyl, R3 = H 1 , R2 = H, R3 = CHO
13
14
5 18
16,19,21 R2 = H, R3 = COCF3 17 R2 = vinyl, R3 = CH=NOH
20 22 2 = vinyl, R3 = CN
,
R
†
General conditions for the trifluoroacetylation reaction by the example
Scheme 2
of 3. Compound 3 (0.6 g, 2.8 mmol) was dissolved in a mixture of 25 ml
of freshly distilled CH2Cl2 and freshly distilled pyridine (1.5 g, 19 mmol)
at room temperature. Trifluoroacetic anhydride (2.1 ml, 12 mmol) was
added dropwise, and the reaction mixture was refluxed for 3 h. The
reaction mixture was quenched with a 10% aqueous NaOH solution and
extracted with CH2Cl2 (3×50 ml). The extract, after drying over magne-
sium sulfate, was evaporated, the residue was dissolved in an ethyl acetate–
hexane (1:1) mixture and percolated through a short column with alu-
minium oxide to provide 7, 0.54 g (63%) as yellow crystals: mp 134–
136 °C (ethyl acetate–hexane). 1H NMR (400 MHz, CDCl3) d: 8.5 (br. s,
1H, NH), 7.4–7.2 (m, 5H, CHarom), 6.9 (m, 1H, H-3), 3.71 (s, 2H,
CH2-benzyl), 3.48 (s, 2H, CH2-4), 2.8 (s, 4H, CH2-6 and CH2-7). MS,
m/z (%): 308 (M+, 64), 307 (M – H, 30), 239 (6), 217 (16), 189 (100),
120 (63), 91 (82). Found (%): C, 62.12; H, 5.12; N, 9.43. Calc. for
C16H15F3N2O (%): C, 62.33; H, 4.87; N, 9.09.
‡
General conditions by the example of 15. Compound 15 (0.3 g, 1.6 mmol)
in 6 ml of freshly distilled acetic anhydride was heated at 70 °C for 1 h.
The excess of acetic anhydride was removed under reduced pressure,
and the residue was purified by column chromatography (aluminium
oxide, ethyl acetate) to afford 93 mg (25%) of N-[2-(5-formyl-3-vinyl-
1H-pyrrol-2-yl)propyl]-N-methylacetamide 18 as yellow oil. 1H NMR
(400 MHz, CDCl3) d: 10.03 (br. s, 1H, NH), 9.45 (s, 1H, CHO), 7.05 (d,
1H, H-4, J 2.1 Hz), 6.57 (dd, 1H, α-CH-vinyl, J 17.7 and 11.3 Hz), 5.48
(dd, 1H, Htrans-vinyl, J 17.7 and 1.5 Hz), 5.08 (dd, 1H, Hcis-vinyl, J 11.3
and 1.5 Hz), 3.70 (m, 2H, N–CH2), 3.30 (m, 1H, CHMe), 2.75 (s, 3H,
N–Me), 2.02 (s, 3H, Me-acetyl), 1.28 (d, 3H, CHMe, J 6.8 Hz). MS, m/z
(%): 234 (M+, 8), 161 (18), 148 (12), 94 (85), 79 (100). Found (%): C,
66.32; H, 7.52; N, 11.86. Calc. for C13H18N2O2 (%): C, 66.66; H, 7.69;
N, 11.97.
– 162 –