Direct and efficient synthesis of pyrrole-3-carbaldehydes by Vilsmeier-Haack formylation of pyrroles with sterically crowded amides

Article abstract of DOI:10.1055/s-0031-1290763

A simple and convenient synthetic method to prepare N-substituted pyrrole-3-carbaldehydes by Vilsmeier-Haack formylation of pyrroles using sterically crowded formamides was developed. The dependence of the formylation regioselectivity on steric features of substrates and reagents is discussed. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290763

PAPER
▌1353
paper
Direct and Efficient Synthesis of Pyrrole-3-carbaldehydes by Vilsmeier–
Haack Formylation of Pyrroles with Sterically Crowded Amides
Synthesis of Pyrrole-3-carbaldehydes
Petr V. Ilyin, Alena S. Pankova, Mikhail A. Kuznetsov*
Department of Chemistry, Saint-Petersburg State University, Universitetsky pr. 26, 198504 Saint-Petersburg, Russian Federation
Fax +7(812)4286939; E-mail: mak@mail.wplus.net
Received: 17.01.2012; Accepted after revision: 24.02.2012
For example, treatment of pyrrole-2-carbaldehydes
with trifluoroacetic acid produced equilibrium mixtures
of isomers in which at least 30% α-carbaldehyde re-
mained.21 In addition, the initial 2-formylpyrroles should
be prepared beforehand. Other pathways to pyrrole-3-
carbaldehydes rely on starting compounds that already
contain an explicit or masked formyl group. For instance,
condensation of primary amines (aryl-,23 alkyl-,24 hetero-
aryl-,25 sulfamides26) with tetrahydro-2,5-dimethoxyfu-
ran-3-carbaldehyde affords desirable products, but this
reagent is also not readily available. In some cases, di-
verse 3-substituted pyrroles can be used as starting com-
pounds but their synthesis is, in general, not trivial.27–29 In
summary, to date there is no generally applicable and
cost-effective preparative method for the synthesis of
3-formylpyrroles reported in the literature.
Abstract: A simple and convenient synthetic method to prepare
N-substituted pyrrole-3-carbaldehydes by Vilsmeier–Haack for-
mylation of pyrroles using sterically crowded formamides was de-
veloped. The dependence of the formylation regioselectivity on
steric features of substrates and reagents is discussed.
Key words: formylation, pyrroles, aldehydes, electrophilic aromat-
ic substitution, formamides, Vilsmeier–Haack
While 3-formylpyrroles play an important role as building
blocks in the syntheses of bioactive compounds,1–3 their
synthetic availability is substantially lower than those of
their respective 2-isomers, and the development of sim-
ple, reliable and inexpensive protocols for their prepara-
tion is still a significant problem. Known for more than 80
years, the Vilsmeier–Haack reaction allows facile intro-
duction of an aldehyde moiety into the pyrrole ring. How-
ever, under standard conditions (DMF, POCl3) the
formylation of pyrroles proceeds predominantly in the α
position, and the yields of 3-formylpyrroles are generally
poor.4–11
That being said, a clear dependence of the regioselectivity
of formylation on the size of the substituent on the pyrrole
nitrogen atom indicates that the ratio of 2- and 3-formyl-
pyrroles is strongly influenced by steric factors.4,11 Thus,
we envisioned that the use of bulky formamides in the
Vilsmeier–Haack reaction could serve as a convenient
general method for the direct synthesis of β-pyrrolecarb-
aldehydes from readily available N-substituted pyrroles;
our efforts towards this goal are reported herein.
Other formylating reagents such as (Cl2PO)2O,12 (COCl)2,13
(Cl3CO)2CO14 with DMF, AlCl3 with MeOCHCl2,15 and
16
TiCl4 with HC(OMe)3 do not improve the aforemen-
tioned poor selectivity. An approach to overcome this pit-
fall makes use of bulky and easily removable substituents
on the pyrrole nitrogen atom because, in this case, the
large steric hindrance efficiently blocks electrophiles
from accessing the α position. Thus, formylation of N-(tri-
isopropylsilyl)pyrrole (TIPS-pyrrole) proceeds in the β
position almost exclusively, with selectivity greater than
24:1, furnishing 1H-pyrrole-3-carbaldehyde after hydro-
lysis of the desilylated iminium salt in 69% overall
yield.17,18 Nevertheless, further modification of 1H-pyr-
role-3-carbaldehyde on the nitrogen atom is substantially
limited, and TIPS-pyrrole is relatively expensive. For-
mylation of more readily available N-tritylpyrrole under
standard conditions gives surprisingly low yields of the β
isomer (the ratio α/β is 1:2.8) and only the use of a bulkier
formylating reagent, such as a complex of DMF with
Ph3PBr4, allows this ratio to be increased to 1:6.7.11
In this work we have studied the formylation of a series of
pyrroles by using sterically crowded formamides. For this
purpose we used a number of pyrroles (1a–f; Scheme 1)
with various alkyl and aryl substituents on the nitrogen
atom and diverse formamides 2–4 and formanilides 5–9
(Scheme 1). While DMF 2 and N-methylformanilide (5)
are commonly used formylating reagents, other amides
can be easily prepared by one- or two-step procedures
from commercially available starting materials.
All formylation reactions were carried out under standard
conditions, that is, a solution of pyrrole 1a–f in dichloro-
ethane with the small excess of formamide/POCl3 was
heated at reflux until nearly complete conversion of start-
ing material was reached (not less than 70%, generally ca.
100%). The combined yield of formylpyrroles 10a–f and
11a–f was in a good agreement with the quantity of the
secondary amine formed after decomposition of Vilsmeier
salt (except for very water-soluble dimethyl- and diiso-
propylamines). No tarring and/or formation of byproducts
was observed.
Presumably, an alternative way to form β-formylpyrroles
is the acid-mediated rearrangement of their α-isomers.9,19–22
SYNTHESIS 2012, 44, 1353–1358
Advanced online publication: 03.04.2012
The conversion of the starting compounds, the ratio, and
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
the yield of pyrrolecarbaldehydes 10 and 11 were deter-
DOI: 10.1055/s-0031-1290763; Art ID: SS-2012-Z0059-OP
© Georg Thieme Verlag Stuttgart · New York

1354
P. V. Ilyin et al.
PAPER
CHO
O
N
POCl3
H
+
+
CHO
R3
N
N
N
R1
R2
R1
R1
10a–f
1a R1 = Me
1b R1 = i-Pr
1c R1 = t-Bu
1d R1 = Ph
1e R1 = o-Tol
2 R2 = R3 = Me
11a–f
3 R2 = R3 = i-Pr
5 R2 = Ph, R3 = Me
6 R2 = Ph, R3 = i-Pr
7 R2 = 2,6-diethylphenyl, R3 = Me
1f R1 = 2,6-dimethylphenyl 9 R2 = R3 = Ph
O
O
N
N
4
8
Scheme 1 Formylation of pyrroles 1a–f by formamides 2–9
1
mined from the H NMR spectra using an internal stan- this indicates an erroneous structural assignment of the re-
dard after minimal workup of the reaction mixtures (Table gioisomeric formylpyrroles 10f and 11f in the literature.4
1). Complete and unambiguous signal assignment of the
A comparison of the reactions of N-methylpyrrole 1a with
the smallest substituent on the nitrogen atom demonstrat-
ed that the replacement of DMF 2 by much more bulky
N,N-diisopropylformamide (3) increased the content of
1H and 13C NMR spectra of pyrrole-2- 10a–f and pyrrole-
3-carbaldehydes 11a–f was achieved by using NOESY
and COSY-C-H analysis. Consequently, we have deter-
mined the general ranges of chemical shifts and coupling
the originally disfavored β-isomer 11a by 2.5 times,
constants in the pyrrole cycle for both types of isomeric
whereas the use of 2,2,6,6-tetramethylpiperidine-1-carb-
3
products. For pyrrole-2-carbaldehydes 10a–f, J(H3–H4)
aldehyde (4; used as a cyclic analogue of N,N-di-tert-bu-
3
4
≈ 4.0 Hz, J(H4–H5) ≈ 2.6 Hz, J(H3–H5) ≈ 1.6–2.0 Hz,
tylformamide) increased the amount of 4 four-fold (Table
1). This tendency for the pair DMF/N,N-diisopropylform-
amide 2/3 is clear for pyrroles with various substituents on
the nitrogen atom. It means that engagement of sterically
crowded dialkylformamides in the Vilsmeier formylation
of pyrroles indeed leads to a significant increase in the
yield of β-isomers.
and sometimes J(H5–CHO) could be observed (ca. 1.1
5
Hz for compounds with aliphatic substituents on the nitro-
gen atom and ca. 0.6–0.8 Hz for aromatic derivatives). For
pyrrole-3-carbaldehydes 11a–f values of 3J(H4–H5) ≈ 2.9–
3.1 Hz, 4J(H2–H5) ≈ 2.0–2.2 Hz, 4J(H2–H4) ≈ 1.6–1.8 Hz
and 5J(H5–CHO) ≈ 0.5–0.8 Hz (except compound 11a, for
which this constant was not observed). In addition, the
signal of the aldehyde proton in the 1H NMR spectra for
all pyrrole-3-carbaldehydes is typically found at lower
field (by 0.2–0.4 ppm) than that of isomeric 2-carbalde-
hydes. Therefore, product identification is readily
achieved by using 1H NMR spectroscopic analysis of the
reaction mixtures.
However, the results of the formylation with substituted
formanilides 5–9 are difficult to explain by using the
above interpretation (Table 1). In particular, steric argu-
ments alone do not account for the fact that in all the reac-
tions with N-isopropylformanilide (6) the content of
β-formylpyrroles 11a–f is significantly smaller than for
N-methylformanilide (5), which is clearly less bulky.
Moreover, in some cases, even the least bulky reagent
DMF (2) demonstrates a stronger preference for the
3-substituted isomer! Unexpectedly, the replacement of
N-methylformanilide (5) by more sterically crowded
N-(2,6-dimethylphenyl)-N-methylformamide (7) had al-
most no influence on the regioselectivity of the process
(except for the reaction with N-tert-butylpyrrole 1c). Even
more surprisingly, the use of more bulky (but cyclic) for-
mamide 8 often led to a decrease in the 3-formylpyrrole
content instead of the anticipated increase.
It is worth noting that, in some cases, our results of the for-
mylation with the standard mixture (DMF/POCl3) were
appreciably different to those reported in the literature.4
For example, in our hands, the reaction with the simplest
N-methylpyrrole 1a gave a mixture containing 7% of pyr-
role-3-carbaldehyde instead of pure pyrrole-2-carbalde-
hyde; in experiments with N-tert-butylpyrrole 1c, we
observed two-fold more α-isomer than previously report-
ed (the ratio α/β was 15:85 instead of 1:14  7:93).4 After
formylation of N-(2,6-dimethylphenyl)pyrrole (1f) the ra-
tio of α- and β-isomers (15:85) was opposite to that men-
tioned in the same study (6.3:1  86:14).4 However, the
melting point that we measured for β-isomer 11f (65 °C)
matches exactly that given for the α-isomer,4 whereas the
melting point of the α-isomer 10f (49 °C according to our
data) cannot be compared with the report in question since
this value was not reported in that paper.4 In our opinion,
The highest content of β-formylpyrroles 11a–f was usual-
ly reached in reactions with N,N-diphenylformamide (9).
It appears likely that in the corresponding Vilsmeier com-
plex, for steric reasons, two phenyl groups are strongly
deflected from the plane of the immonium fragment,
which, in turn, dramatically increases the effective vol-
Synthesis 2012, 44, 1353–1358
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of Pyrrole-3-carbaldehydes
1355
Table 1 Ratio and Total Yieldsa of α- and β-Formylpyrroles 10/11 in the Formylation of Pyrroles 1a–f by Formamides 2–9
1a
1b
1c
1d
1e
1f
2
3
4
5
6
7
8
9
94:6 (97)
62:38 (98)
43:57 (95)
25:75 (85)
46:54 (95)
60:40 (97)
40:60 (97)
43:57 (87)
22:78 (78)
15:85 (100)
4:96 (100)
91:9 (100)
61:39 (100)
45:55 (100)
15:85 (100)
12:88 (100)
85:15 (95)
75:25 (80)
83:17 (97)
95.5:4.5 (95)
83:17 (95)
89:11 (85)
62:38 (70)
68:32 (100)
11:89 (97)
20:80 (97)
3:97 (96)
72:28 (100)
83:17 (97)
69:31 (98)
83:17 (88)
56:44 (80)
50:50 (97)
73:27 (98)
57:43 (98)
66:34 (90)
40:60 (87)
12:88 (100)
15:85 (98)
14:86 (97)
14:86 (90)
14:86 (85)
8:92 (90)
2.5:97.5 (85)
a Yields (%) determined from the 1H NMR spectra are given in parentheses.
ume of this reactive complex (Scheme 2). From a practical dehydes depends solely on its yield even when mixtures
standpoint, it is important to note that comparably high of regioisomers are formed, as in our case. Taking this
yields of β-formylpyrroles often resulted from reactions into account, we successfully applied the synergetic effect
with N,N-diisopropylformamide (3).
of both the pyrrole nitrogen-atom substitution and steri-
cally crowded formamides in the preparative synthesis of
several 3-formylpyrroles (examples are given below).
HCONR2R3
+ POCl3
2–9
In summary, we have described a useful method for syn-
thesis of pyrrole-3-carbaldehydes from readily available
N-substituted pyrroles by applying the Vilsmeier–Haack
reaction. Our screening identified N,N-diphenylform-
amide (9) and N,N-diisopropylformamide (3) as the for-
mylating reagents of choice for providing the desired
regioselectivity. In addition, it was found that the highest
yields of pyrrole-2-carbaldehydes in this reaction were of-
ten achieved with N-isopropylformanilide (6) and not
with conventional DMF.
OPOCl2
+
H2O
Cl–
10a–f
N
R1
H
Cl2OPO
NR2R3
NR2R3
+
1a–f
Cl–
OPOCl2
+
N
R2
Cl2OPO
H
H2O
+
Cl–
NR2R3
11a–f
R3
N
R1
Scheme 2 Standard mechanism and stereochemical rationale for the
formylation of pyrroles
NMR spectra were recorded with a Bruker DPX-300 spectrometer
(300.13 MHz for 1H and 75.47 MHz for 13C) in CDCl3 or DMSO-
d6 and were referenced to residual proton solvent signals (δH = 7.26
and 2.50 ppm, respectively) and solvent carbon signals (δC = 77.00
and 39.52 ppm, respectively). Signal assignments in the 13C NMR
spectra were established from DEPT spectra, and from NOESY and
COSY spectra for 1H NMR assignments. High-resolution mass
spectra were recorded with a Bruker micrOTOF spectrometer using
the electron spray ionization mode. Commercially available
N-methylpyrrole (1a), DMF (2), and N-methyl-N-phenylformamide
(5) were used as received. Pyrroles 1a–f were prepared according to
the literature procedure.30
In all the cases studied, the ratio of regioisomers in the for-
mylation of N-phenylpyrrole (1d) was similar to that for
simple N-methylpyrrole (1a; Table 1). This fact is not sur-
prising taking into account that 1d is almost planar and the
effective ‘thickness’ of the phenyl ring approaches two
times the van der Vaals radius of the methyl group, thus
making the steric hindrance against attack on the α-posi-
tion similar for both substrates (Scheme 2). In contrast, in
N-(2-methylphenyl)pyrrole (1e) and N-(2,6-dimethylphe-
nyl)pyrrole (1f) the aromatic substituent is tilted away
from the plane of the pyrrole ring, shielding the α-carbon
atoms from attack of the Vilsmeier reagent on both sides
of the π-system, which is reflected in the sharp increase in
the β-isomer content.
Synthesis of Formamides 3–9; General Procedures
Formamides 3 and 4 were prepared by method A,31 formanilides
6–9 by method B.32
Method A
A mixture of the corresponding amine (0.13 mol), CHCl3 (50 mL,
75 g, 0.63 mol), Et4NCl (0.3 g) and 50% aq NaOH (40 mL, 0.76
mol) was stirred at 40–50 °C for 5 h. The layers were separated and
the organic layer was passed through a plug of silica. The solvent
was evaporated under reduced pressure and the residue was distilled
in vacuo.
Finally, the boiling points of α-formylpyrroles 10a–f are
substantially lower than those of the β-isomers 11a–f (by
40–50 °C for aliphatic substituents and 20–30 °C for aro-
matic), rendering the fractional distillation efficient for
the practical separation of isomers. Therefore the utility of
a particular method for the synthesis of pyrrole-3-carbal-
Method B
A mixture of formic acid (14.36 g, 0.31 mol) and Ac2O (12.66 g,
0.125 mol) was stirred at r.t. for 1 h, then added to a solution of an-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1353–1358

1356
P. V. Ilyin et al.
PAPER
iline (0.1 mol) in DCE (50 mL) at 5–10 °C and the resulting mixture
was stirred at r.t. for 16 h. The layers were separated and the organic
layer was dried over Na2SO4. The solvent was evaporated under re-
duced pressure and the residue was either distilled in vacuo (6 and
7) or crystallized from EtOH (8 and 9).
13C NMR (75 MHz, DMSO-d6, 80 °C): δ = 17.6 (C-4), 25.1, 27.3,
27.5 (3 × CH3), 48.8 (C-3), 55.8 (C-2), 120.4, 123.6, 123.9, 125.9
(C-5–8), 136.2, 136.7 (C-4a, 8a), 161.1 (CHO).
HRMS (ESI): m/z [M + H]+ calcd for C13H17NO: 204.1357; found:
204.1325.
N,N-Diisopropylformamide (3)
N,N-Diphenylformamide (9)
Yield: 77% (12.9 g); colorless liquid; bp 85–87 °C/20 mmHg (Lit.33
93–93.8 °C/23.5 mmHg).
Yield: 91% (17.9 g); colorless solid; mp 73 °C (Lit.38 73.5 °C).
1H NMR (300 MHz, CDCl3): δ = 7.15–7.21 (m, 2 H, Hp), 7.25–7.45
(m, 8 H, Hm,o), 8.68 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): δ = 125.5, 126.6 (Cm), 127.3, 127.5
(Cp), 129.6, 130.1 (Co), 140.1, 142.2 (Ci), 162.2 (CHO).
1H NMR (300 MHz, CDCl3): δ = 0.97 (d, J = 7.1 Hz, 6 H, 2 × CH3),
0.99 (d, J = 7.1 Hz, 6 H, 2 × CH3), 3.34 (sept, J = 7.1 Hz, 1 H, CH),
3.79 (sept, J = 7.1 Hz, 1 H, CH), 7.89 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): δ = 20.3 (2 × CH3), 23.4 (2 × CH3),
43.9 (CH), 46.8 (CH), 161.6 (CHO).
Formylation of Pyrroles 1a–f; General Analytical Procedure
POCl3 (0.19 mL, 0.32 g, 2.1 mmol) was added to a stirred mixture
of pyrrole (2 mmol) and formamide (2.1 mmol) in DCE (1 mL). The
resulting mixture was heated at reflux for 1 h, and the reaction was
quenched with 50% aq KOH (3 mL) by vigorously shaking for
1 min. The upper organic layer was separated and an internal stan-
dard [1,4-di-tert-butylbenzene (190 mg, 1 mmol)] was added. The
composition of the sample was analyzed on the basis of its 1H NMR
spectrum.
2,2,6,6-Tetramethylpiperidine-1-carbaldehyde (4)
Yield 75% (16.5 g); colorless solid; mp 50 °C; bp 110 °C/1 mmHg
(Lit.34 50 °C, bp 50 °C/0.045 mmHg).
1H NMR (300 MHz, CDCl3): δ = 1.41 (br s, 6 H), 1.49 (br s, 6 H),
1.58 (br s, 6 H) (4 × CH3 and 3 × CH2), 8.51 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): δ = 16.7 (C-4), 28.3, 32.8 (C-3,5), 40.4
(2 × CH3), 41.6 (2 × CH3), 55.7, 56.1 (C-2,6), 170.0 (CHO).
Formylation of N-Methylpyrrole (1a) with N,N-diisopropyl-
formamide (3)
N-Isopropyl-N-phenylformamide (6)
Yield: 88% (14.3 g); colorless liquid; bp 125–130 °C/15 mmHg
POCl3 (20 mL, 33.5 g, 0.22 mol) was added dropwise to a stirred so-
lution of 3 (27.1 g, 0.21 mol) in DCE (50 mL) at 0 °C. A solution of
1a (17.7 mL, 16.2 g, 0.2 mol) in DCE (50 mL) was added dropwise
to the obtained Vilsmeier reagent. The cooling bath was removed
and the mixture was heated at reflux for 15 min, then cooled and the
reaction was quenched with a solution of NaOAc·3H2O (150 g,
1.1 mol) in H2O (300 mL), and stirring was continued for 30 min.
The layers were separated, the aqueous layer was extracted with
DCE (2 × 100 mL), and the combined organic layers were washed
with saturated aq NaHCO3 and dried over Na2SO4. The solvent was
removed under reduced pressure, and the residual yellow oil was
distilled in vacuo on a 30 cm Vigreux column. The following frac-
tions were obtained: (i) 1-methyl-1H-pyrrole-2-carbaldehyde (10a;
16.5 g); (ii) a mixture of 10a (30%) and 1-methyl-1H-pyrrole-3-
carbaldehyde (11a; 70%) (total 0.6 g; bp 80–115 °C/10 mmHg);
(iii) 11a (2.4 g).
(Lit.35 261–263 °C/720 mmHg).
According to its 1H and 13C NMR spectra, formamide 6 exists as a
mixture of two geometric isomers in a ratio ca. 85:15.
1H NMR (300 MHz, CDCl3): δ = 0.88* and 0.94 (2 × d, J = 6.9 Hz,
6 H, CH3), 3.82 and 4.48* (2 × sept, J = 6.9 Hz, 1 H, NCH), 6.83–
6.88 (m, 2 H, Ho), 7.01–7.14 (m, 3 H, Hm,p), 7.84* and 8.13 (2 × s,
CHO, 1 H). * Signal attributed to the major isomer.
13C NMR (75 MHz, CDCl3): δ (major isomer) = 21.0 (2 × CH3),
45.9 (NCH), 128.2 (Cp), 128.94, 129.4 (Cm,o), 138.6 (Ci), 162.4
(CHO).
13C NMR (75 MHz, CDCl3): δ (minor isomer) = 22.7 (2 × CH3),
51.4 (NCH), 128.0 (Cp), 129.2, 129.4 (Cm,o), 136.9 (Ci), 164.3
(CHO).
N-(2,6-Diethylphenyl)-N-methylformamide (7)
Yield: 84% (16.0 g); colorless liquid; bp 145–150 °C/15 mmHg.
1-Methyl-1H-pyrrole-2-carbaldehyde (10a)
Yield: 76%; colorless liquid; bp 72–75 °C/10 mmHg (Lit.4
76 °C/13 mmHg).
1H NMR (300 MHz, CDCl3): δ = 3.81 (s, 3 H, CH3), 6.21 (dd,
J = 4.0, 2.6 Hz, 1 H, H-4), 6.88 (m, 1 H, H-5), 6.91 (dd, J = 4.0,
1.8 Hz, 1 H, H-3), 9.41 (d, J = 1.1 Hz, 1 H, CHO).
Only the mass spectrum is reported in the literature.36
According to its 1H and 13C NMR spectra, formamide 7 exists as a
mixture of two geometric isomers in a ratio ca. 85:15.
1H NMR (300 MHz, CDCl3): δ = 1.12* and 1.14 (2 × t, J = 7.6 Hz,
6 H, CH3), 2.43 and 2.45* (2 × q, J = 7.6 Hz, 4 H, CH2), 3.05* and
3.11 (2 × s, 3 H, NCH3), 7.05–7.11 (m, 2 H, Hm), 7.13–7.25 (m, 1
H, Hp), 7.93* and 8.27 (2 × s, 1 H, CHO). * Signal attributed to the
major isomer.
13C NMR (75 MHz, CDCl3): δ (major isomer) = 15.6 (2 × CH3),
24.4 (2 × CH2), 35.5 (NCH3), 127.3 (Cm), 129.4 (Cp), 138.4 (Ci),
143.0 (Co), 163.6 (CHO).
13C NMR (75 MHz, CDCl3): δ = 36.6 (CH3), 109.8 (C-4), 124.4 (C-
3), 132.2 (C-2), 132.5 (C-5), 179.7 (CHO).
1-Methyl-1H-pyrrole-3-carbaldehyde (11a)
Yield: 11%; colorless liquid; bp 115–120 °C/10 mmHg (Lit.39 91–
93 °C/3 mmHg).
1H NMR (300 MHz, CDCl3): δ = 3.57 (s, 3 H, CH3), 6.48 (dd,
J = 3.1, 1.7 Hz, 1 H, H-4), 6.52 (dd, J = 3.1, 2.1 Hz, 1 H, H-5), 7.14
(dd, J = 2.1, 1.7 Hz, 1 H, H-2), 9.59 (s, 1 H, CHO).
13C NMR (75 MHz, CDCl3): δ (minor isomer) = 14.9 (2 × CH3),
24.2 (2 × CH2), 37.1 (NCH3), 127.0 (Cm), 128.9 (Cp), 136.8 (Ci),
141.3 (Co), 162.8 (CHO).
13C NMR (75 MHz, CDCl3): δ = 39.9 (CH3), 108.5 (C-4), 124.8 (C-
5), 127.0 (C-3), 130.5 (C-2), 185.4 (CHO).
2,2,4-Trimethyl-3,4-dihydroquinoline-1(2H)-carbaldehyde (8)
Prepared from 2,2,4-trimethyl-1,2,3,4-tetrahydroquinoline.37
Formylation of Pyrroles with N,N-Diphenylformamide (9);
General Procedure
Yield: 83% (16.8 g); colorless solid; mp 63 °C.
1H NMR (300 MHz, DMSO-d6, 80 °C): δ = 1.31 (d, J = 6.5 Hz, 3 H,
CHCH3), 1.34–1.42 (m, 1 H, H-3), 1.90 (dd, J = 13.1, 3.6 Hz, 1 H,
H-3), 1.50 (s, 3 H, CH3), 1.59 (s, 3 H, CH3), 2.76–2.88 (m, 1 H, H-
4), 7.10–7.27 (m, 3 H, H-5, H-6, H-7), 7.34 (m, 1 H, H-8), 8.64 (s,
1 H, CHO).
POCl3 (24 mL, 40.2 g, 0.26 mol) was added dropwise to a stirred so-
lution of 9 (49.5 g, 0.25 mol) in DCE (100 mL), and the mixture was
stirred overnight. A solution of pyrrole (0.2 mol) in DCE (50 mL)
was added dropwise to the obtained Vilsmeier reagent. The reaction
mixture was heated at reflux for 2 h, then cooled to r.t. and the reac-
tion was quenched with a solution of NaOAc·3H2O (150 g, 1.1 mol)
Synthesis 2012, 44, 1353–1358
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Synthesis of Pyrrole-3-carbaldehydes
1357
in H2O (300 mL), and stirring was continued for 30 min. The layers
were separated, the aqueous layer was extracted with DCE (2 × 100
mL), and the combined organic layers were washed with saturated
aq NaHCO3 and dried over Na2SO4. The solvent was removed un-
der reduced pressure and the products were distilled with water
steam. The layers were separated, the aqueous layer was extracted
with DCE, and the combined organic layers were dried over
Na2SO4. The solvent was removed under reduced pressure and the
residual yellow oil was distilled in vacuo with a 30 cm Vigreux col-
umn.
1-tert-Butyl-1H-pyrrole-2-carbaldehyde (10c)
Yield: 12% (3.6 g); colorless liquid; bp 103–106 °C/10 mmHg
(Lit.4 114–116 °C/19 mmHg).
1H NMR (300 MHz, CDCl3): δ = 1.60 (s, 9 H, 3 × CH3), 6.12 (dd,
J = 4.0, 2.6 Hz, 1 H, H-4), 7.0 (dd, J = 4.0, 2.0 Hz, 1 H, H-3), 7.18
(ddd, J = 2.6, 2.0, 1.1 Hz, 1 H, H-5), 9.38 (d, J = 1.1 Hz, 1 H,
CHO).
13C NMR (75 MHz, CDCl3): δ = 30.1 (3 × CH3), 58.2 [C(CH3)3],
108.6 (C-4), 129.7, 131.3 (C-3,5), 132.9 (C-2), 177.9 (CHO).
After formylation of 1-isopropyl-1H-pyrrole (1b) the following
fractions were obtained: (i) 1-isopropyl-1H-pyrrole-2-carbaldehyde
(10b; 3.7 g); (ii) a mixture of 10b (45%) and 1-isopropyl-1H-pyr-
role-3-carbaldehyde 11b (55%) (total 1.1 g; bp 90–130 °C/10
mmHg), and (iii) 1-isopropyl-1H-pyrrole-3-carbaldehyde 11b (19.0
g).
1-tert-Butyl-1H-pyrrole-3-carbaldehyde (11c)
Yield: 80% (24.1 g); colorless solid; mp 43–45 °C; bp 140–
142 °C/10 mmHg (Lit.4 148 °C/19 mmHg).
1H NMR (300 MHz, CDCl3): δ = 1.48 (s, 9 H, 3 × CH3), 6.56 (dd,
J = 3.1, 1.8 Hz, 1 H, H-4), 6.81 (ddd, J = 3.1, 2.2, 0.8 Hz, 1 H, H-
5), 7.42 (dd, J = 2.2, 1.8 Hz, 1 H, H-2), 9.67 (d, J = 0.8 Hz, 1 H,
CHO).
1-Isopropyl-1H-pyrrole-2-carbaldehyde (10b)
Yield: 14%; colorless mobile liquid; bp 87–90 °C/10 mmHg (Lit.4
96–98 °C/19 mmHg).
13C NMR (75 MHz, CDCl3): δ = 30.8 (3 × CH3), 56.4 [C(CH3)3],
108.4 (C-4), 120.9 (C-5), 126.3 (C-3), 126.7 (C-2), 185.7 (CHO).
1H NMR (300 MHz, CDCl3,): δ = 1.40 (d, J = 6.5 Hz, 6 H,
2 × CH3), 5.35 (sept, J = 6.5 Hz, 1 H, CH), 6.14 (dd, J = 4.0,
2.6 Hz, 1 H, H-4), 6.82 (dd, J = 4.0, 1.7 Hz, 1 H, H-3), 7.08 (ddd,
J = 2.6, 1.7, 1.1 Hz, 1 H, H-5), 9.42 (d, J = 1.1 Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): δ = 23.7 (2 × CH3), 49.3 (CH), 110.2
(C-4), 126.8, 127.2 (C-3,5), 131.5 (C-2), 179.5 (CHO).
1-(2-Methylphenyl)-1H-pyrrole-2-carbaldehyde (10e)
Yield: 53% (19.6 g); colorless liquid; bp 125–128 °C/1 mmHg.
1H NMR (300 MHz, CDCl3): δ = 1.98 (s, 3 H, CH3), 6.38 (dd,
J = 4.0, 2.6 Hz, 1 H, H-4), 6.95 (ddd, J = 2.6, 1.6, 0.8 Hz, 1 H, H-
5), 7.08 (dd, J = 4.0, 1.6 Hz, 1 H, H-3), 9.37 (d, J = 0.8 Hz, 1 H,
CHO).
1-Isopropyl-1H-pyrrole-3-carbaldehyde (11b)
Yield: 69%; pale-yellow liquid; bp 133–135 °C/10 mmHg (Lit.4
145–148 °C/19 mmHg).
13C NMR (75 MHz, CDCl3): δ = 17.5 (CH3), 111.1 (C-4), 121.3 (C-
3), 126.9, 127.8, 129.4, 131.1, 131.3 (C-5, C-3-6), 133.5 (C-2),
135.8 (C-2), 138.7 (C-1), 179.1 (CHO).
1H NMR (300 MHz, CDCl3): δ = 1.37 (d, J = 6.7 Hz, 6 H, 2 × CH3),
4.18 (sept, J = 6.7 Hz, 1 H, CH), 6.52 (dd, J = 3.0, 1.7 Hz, 1 H, H-
4), 6.66 (ddd, J = 3.0, 2.1, 0.8 Hz, 1 H, H-5), 7.30 (dd, J = 2.1,
1.7 Hz, 1 H, H-2), 9.62 (d, J = 0.8 Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): δ = 23.9 (2 × CH3), 52.0 (CH), 108.3
(C-4), 121.6 (C-3), 126.4, 127.2 (C-2,5), 187.2 (CHO).
HRMS (ESI): m/z [M + H]+ calcd for C12H11NO: 186.0913; found:
186.0085.
1-(2-Methylphenyl)-1H-pyrrole-3-carbaldehyde (11e)
Yield: 30% (11.1 g); yellow solid; mp 47 °C; bp 145–155 °C/
1 mmHg.
1H NMR (300 MHz, CDCl3): δ = 2.16 (s, 3 H, CH3), 6.74 (dd,
J = 3.0, 1.7 Hz, 1 H, H-4), 6.76 (ddd, J = 3.0, 2.1, 0.7 Hz, 1 H, H-
5), 7.35 (dd, J = 2.1, 1.7 Hz, 1 H, H-2), 9.79 (d, J = 0.7 Hz, 1 H,
CHO).
13C NMR (75 MHz, CDCl3): δ = 18.1 (CH3), 108.6 (C-4), 127.7 (C-
3), 125.3, 126.7, 127.4, 129.2, 130.6, 132.0 (C-2,5, C-3′-6′), 133.9
(C-2′), 139.5 (C-1′), 185.8 (CHO).
After formylation of 1-phenyl-1H-pyrrole (1d) the following frac-
tions were obtained: (i) 1-phenyl-1H-pyrrole-2-carbaldehyde 10d
(12.2 g), (ii) a mixture of 10d (60%) and 1-phenyl-1H-pyrrole-3-
carbaldehyde 11d (40%) (total 4.0 g; bp 120–140 °C/1 mmHg), and
(iii) 1-phenyl-1H-pyrrole-3-carbaldehyde 11d (10.1 g).
1-Phenyl-1H-pyrrole-2-carbaldehyde (10d)
Yield: 36%; colorless solid; mp 28–30 °C; bp 115–120 °C/1 mmHg
(Lit.4 106–109 °C/0.2 mmHg).
1H NMR (300 MHz, CDCl3): δ = 6.32 (dd, J = 4.0, 2.6 Hz, 1 H, H-
4), 6.98 (ddd, J = 2.6, 1.7, 0.6 Hz, 1 H, H-5), 7.10 (dd, J = 4.0,
1.7 Hz, 1 H, H-3), 7.23–7.37 (m, 5 H, PhH), 9.49 (d, J = 0.6 Hz,
1 H, CHO).
HRMS (ESI): m/z [M + H]+ calcd for C12H11NO: 186.0913; found:
186.0087.
1-(2,6-Dimethylphenyl)-1H-pyrrole-2-carbaldehyde (10f)
Yield: 15% (5.9 g); colorless solid; mp 49 °C; bp 128–132 °C/
1 mmHg.
1H NMR (300 MHz, CDCl3): δ = 1.99 (s, 6 H, 2 × CH3), 6.38 (dd,
J = 4.0, 2.6 Hz, 1 H, H-4), 6.74 (ddd, J = 2.6, 1.6, 0.8 Hz, 1 H, H-
5), 7.08 (dd, J = 4.0, 1.6 Hz, 1 H, H-3), 7.14–7.19 (m, 2 H, Hm),
7.25–7.31 (m, 1 H, Hp), 9.37 (d, J = 0.8 Hz, 1 H, CHO).
13C NMR (75 MHz, CDCl3): δ = 17.6 (2 × CH3), 111.4 (C-4), 121.2
(C-3), 128.5 (Cm), 129.2, 130.4 (Cp, C-5), 132.7 (C-2), 136.2 (Co),
137.9 (Ci), 179.2 (CHO).
13C NMR (75 MHz, CDCl3): δ = 111.3 (C-4), 122.4 (C-3), 126.4
(Co), 128.6, 131.5 (Cp, C-5), 129.5 (Cm), 132.9 (C-2), 139.1 (Ci),
179.3 (CHO).
1-Phenyl-1H-pyrrole-3-carbaldehyde (11d)
Yield: 30%; viscous yellow liquid; bp 140–145 °C/1 mmHg (Lit.4
100–105 °C/0.3 mmHg).
1H NMR (300 MHz, CDCl3): δ = 6.74 (dd, J = 3.0, 1.6 Hz, 1 H, H-
4), 7.02 (ddd, J = 3.0, 2.1, 0.7 Hz, 1 H, H-5), 7.24–7.40 (m, 5 H,
PhH), 7.61 (dd, J = 2.1, 1.6 Hz, 1 H, H-2), 9.77 (d, J = 0.7 Hz, 1 H,
CHO).
13C NMR (75 MHz, CDCl3): δ = 109.8 (C-4), 121.3 (Co), 122.7 (Cp),
127.7, 127.9 (C-2,5), 128.56 (C-3), 130.3 (Cm), 139.7 (Ci), 185.8
(CHO).
HRMS (ESI): m/z [M + H]+ calcd for C13H13NO: 200.1070; found:
200.1042.
1-(2,6-Dimethylphenyl)-1H-pyrrole-3-carbaldehyde (11f)
Yield: 85% (33.7 g); pale-yellow solid; mp 65 °C; bp 145–150 °C/
1 mmHg.
1H NMR (300 MHz, CDCl3): δ = 2.07 (s, 6 H, 2 × CH3), 6.65 (ddd,
J = 2.9, 2.0, 0.5 Hz, 1 H, H-5), 6.83 (dd, J = 2.9, 1.7 Hz, 1 H, H-4),
7.13–7.20 (m, 2 H, Hm), 7.27 (dd, J = 2.0, 1.7 Hz, 1 H, H-2), 7.25–
7.30 (m, 1 H, Hp), 9.87 (d, J = 0.5 Hz, 1 H, CHO).
Pyrrolecarbaldehydes 10c, 10e, 10f and 11c, 11e, 11f were obtained
by using the same procedure with DMF (2) as formylating reagent.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 1353–1358

1358
P. V. Ilyin et al.
PAPER
13C NMR (75 MHz, CDCl3): δ = 17.7 (2 × CH3), 108.9 (C-4), 124.8
(C-3), 127.7 (C-2), 128.8 (Cm), 129.3, 130.0 (Cp, C-5), 136.0 (Co),
138.9 (Ci), 185.9 (CHO).
HRMS (ESI): m/z [M + H]+ calcd for C13H13NO: 200.1070; found:
200.1037.
(15) Kakushima, M.; Hamel, P.; Frenette, R.; Rokach, J. J. Org.
Chem. 1983, 48, 3214.
(16) Tressl, R.; Wondrak, G. T.; Garbe, L.-A.; Krueger, R.-P.;
Rewicki, D. J. Agric. Food Chem. 1998, 46, 1765.
(17) Purkarthofer, T.; Gruber, K.; Fechter, M. H.; Griengl, H.
Tetrahedron 2005, 61, 7661.
(18) 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.
(19) Dallemagne, S. R.; Fabis, F.; Dumoulin, H.; Robba, M.
Synth. Commun. 1994, 24, 1855.
Acknowledgment
The authors thank Saint-Petersburg State University for a research
grant (No. 12.38.16.2011).
(20) Dumoulin, H.; Rault, S.; Robba, M. J. Heterocycl. Chem.
1996, 33, 255.
References
(21) Carson, J. R.; Davis, N. M. J. Org. Chem. 1981, 46, 839.
(22) Pina, M. C.; Budilin, V. A.; Rodrigues, M.; Bundel, Yu. G.
Chem. Heterocycl. Compd. (Engl. Transl.) 1989, 25, 268.
(23) Kevin, N. J.; Duffy, J. L.; Kirk, B. A.; Chapman, K. T.;
Schleif, W. A.; Olsen, D. B.; Stahlhut, M.; Rutkowski, C. A.;
Kuo, L. C.; Jin, L.; Lin, J. H.; Emini, E. A.; Tata, J. R.
Bioorg. Med. Chem. Lett. 2003, 13, 4027.
(24) Glennon, R. A.; Chaurasia, C.; Titeler, M. J. Med. Chem.
1990, 33, 2777.
(25) Lubisch, W.; Behl, B.; Hofmann, H. P. Bioorg. Med. Chem.
Lett. 1997, 7, 1101.
(26) Karousis, N.; Liebscher, J.; Varvounis, G. Synthesis 2006,
1494.
(27) Ojika, M.; Shizuri, Y.; Niwa, H.; Yamada, K.; Iwadare, S.
Tetrahedron Lett. 1982, 23, 4977.
(28) Xiao, D.; Ketcha, D. M. Org. Prep. Proced. Int. 1995, 27,
503.
(29) Haldar, P.; Barman, G.; Ray, J. K. Tetrahedron 2007, 63,
3049.
(1) Jones, M. A.; Morton, J. D.; Coxon, J. M.; McNabb, S. B.;
Lee, H. Y.-Y.; Aitken, S. G.; Mehrtens, J. M.; Robertson, L.
J. G.; Neffe, A. T.; Miyamoto, S.; Bickerstaffe, R.; Gately,
K.; Wood, J. M.; Abell, A. D. Bioorg. Med. Chem. 2008, 16,
6911.
(2) Berglund, S.; Egner, B. J.; Graden, H.; Graden, J.; Inghardt,
T.; Morgan, D. G. A.; Giordanetto, F. Bioorg. Med. Chem.
Lett. 2008, 18, 4859.
(3) Cremonesi, S.; Di Fabio, R.; Gentile, G.; Micheli, F.;
Pasquarello, A.; Tarsi, L.; Terreni, S.; Tonelli, F.; Pozzan,
A.; Arban, R.; Bianchi, F.; Buson, A. Bioorg. Med. Chem.
Lett. 2010, 20, 5044.
(4) Candy, C. F.; Jones, R. A.; Wright, P. H. J. Chem. Soc. C
1970, 2563.
(5) Sum, F.-W.; Dusza, J.; Santos, E. D.; Grosu, G.; Reich, M.;
Du, X.; Albright, J. D.; Chan, P.; Coupet, J.; Ru, X.;
Mazandarani, H.; Saunders, T. Bioorg. Med. Chem. Lett.
2003, 13, 2195.
(30) Gross, H. Chem. Ber. 1962, 95, 2270.
(31) Yankovskaya, L. A.; Yufit, S. S. In Organic Synthesis in
Two-Phase Systems; Khimiya: Moscow, 1982, 81.
(32) Vougioukalakis, G. C.; Grubbs, R. H. J. Am. Chem. Soc.
2008, 130, 2234.
(6) Noland, W. E.; Lanzatella, N. P.; Venkatraman, L.;
Anderson, N. F.; Gullickson, G. C. J. Heterocycl. Chem.
2009, 46, 1154.
(7) Nenajdenko, V. G.; Reznichenko, A. L.; Balenkova, E. S.
Tetrahedron 2007, 63, 3031.
(33) Robson, J. H.; Reinhart, J. J. Am. Chem. Soc. 1955, 77, 498.
(34) Hodgson, D. M.; Bray, C. D.; Kindon, N. D.; Reynolds, N.
J.; Coote, S. J.; Um, J. M.; Houk, K. N. J. Org. Chem. 2009,
74, 1019.
(35) Pictet, A.; Crepieux, P. Ber. Dtsch. Chem. Ges. 1888, 21,
1106.
(8) Cadogan, J. I. G.; Hewage, C. M.; McNab, H.; MacPherson,
A. D.; Nicolson, I. S.; Reed, D.; Sadler, I. H. Org. Biomol.
Chem. 2006, 4, 2446.
(9) Hrncarikova, K.; Vegh, D. Molecules 2003, 8, 536.
(10) Massa, S.; Stefancich, G.; Artico, M.; Corelli, F.; Ortenzi, G.
Heterocycles 1985, 23, 1417.
(36) Mangiapan, S.; Benfenati, E.; Grasso, P.; Terreni, M.;
Pregnolato, M.; Pagani, G.; Barcelo, D. Environ. Sci.
Technol. 1997, 31, 3637.
(37) Reddelien, G.; Thurm, A. Ber. Dtsch. Chem. Ges. B 1932,
65, 1511.
(38) Aroney, M. J.; Le Fèvre, R. J. W.; Singh, A. N. J. Chem. Soc.
1965, 3179.
(39) Chakrabarti, J. K.; Tupper, D. E. J. Heterocycl. Chem. 1974,
11, 417.
(11) Chadwick, D. J.; Hodgson, S. T. J. Chem. Soc., Perkin
Trans. 1 1983, 93.
(12) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaibar, K. F.
Tetrahedron 1993, 49, 4015.
(13) Campiani, G.; Nacci, V.; Corelli, F.; Anzini, M. Synth.
Commun. 1991, 21, 1567.
(14) Shan, W. G.; Shi, X. J.; Su, W. K. Org. Prep. Proced. Int.
2004, 36, 337.
Synthesis 2012, 44, 1353–1358
© Georg Thieme Verlag Stuttgart · New York