Regio-selective synthesis of novel 1-tert-butyl-4-nitro-1H-pyrrole-3-carboxylic acid building block

Article abstract of DOI:10.1016/j.tetlet.2009.09.099

A convenient, regio-selective synthesis of novel 1-tert-butyl-4-nitro-1H-pyrrole-3-carboxylic acid was developed, utilizing the bulky tert-butyl moiety of 1-tert-butyl-1H-pyrrole to direct selective, un-symmetrical substitutions to the desired 3 and 4 pos

Full text of DOI:10.1016/j.tetlet.2009.09.099

Tetrahedron Letters 50 (2009) 6807–6809
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Regio-selective synthesis of novel 1-tert-butyl-4-nitro-1H-
pyrrole-3-carboxylic acid building block
*
Duyan V. Nguyen , Robert A. Schiksnis, Enrique L. Michelotti
Department of Chemistry, Locus Pharmaceuticals, Four Valley Square, 512 Township Line Road, Blue Bell, PA 19422, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2009
Revised 17 September 2009
Accepted 18 September 2009
Available online 25 September 2009
A convenient, regio-selective synthesis of novel 1-tert-butyl-4-nitro-1H-pyrrole-3-carboxylic acid was
developed, utilizing the bulky tert-butyl moiety of 1-tert-butyl-1H-pyrrole to direct selective, un-sym-
metrical substitutions to the desired 3 and 4 positions.
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
1-tert-Butyl-4-nitro-1H-pyrrole-3-
carboxylic acid
Electrophilic substitution
Regio-selective
At Locus Pharmaceuticals, we apply our computational frag-
ment-based discovery technology, CharretteTM, to design novel,
small molecule antagonists or agonists for numerous biological
targets. The de novo approach implemented in CharretteTM utilizes
a specific fragment data set identified by our technology. Many of
the fragments contained in this set, such as the 1-tert-butyl-4-ni-
tro-1H-pyrrole-3-carboxylic acid 1, are considered to be valuable
‘chemistry ready fragments’ due to the available multiple diversity
points (Scheme 1). In this Letter, we wish to describe the synthetic
efforts toward obtaining the above-mentioned novel building
block.
We initially envisioned two general approaches to access the
desired 1,3,4 tri-substituted pyrrole building block 1. The first
route involves building from a pyrrole starting material with the
3 and 4 substitutions already incorporated, and introducing the
tert-butyl moiety at the end. We performed a quick study to eval-
uate the feasibility of this approach by attempting the N-tert-
butylation of commercially available diethyl-1H-pyrrole-3,4-dicar-
boxylate, following a reported N-tert-butylation procedure for 1-H-
pyrrole.1 In this reaction (Scheme 2), imidazolium ionic liquid was
used as a solvent to facilitate the N-alkylation reaction between
the pyrrole and tert-butyl bromide. Unfortunately in our hands this
key transformation was not successful making this route an unat-
tractive option.
the 3 and 4 positions. Within this scope, there are several ways by
which the 3 and 4 substitutions could be accomplished.
We first pursued one such sequence (Scheme 3), beginning with
the synthesis of diethyl-1-tert-butyl-1H-pyrrole-3,4-dicarboxylate
4 by reacting N-tert-butylpyrrole 2 with excess diethyl acetylene-
dicarboxylate 3 at 80–130 °C under microwave irradiation. In this
reported 4+2 cyclo-addition reaction to make compound 4,2 the
initial Diels–Alder intermediate (formed at 80 °C in microwave)
further undergoes a retro Diels–Alder transformation when sub-
jected to higher temperature of 130 °C to afford the expected prod-
uct in 10% yield, along with numerous unidentified by-products.
The bis-ester 4 was then hydrolyzed to the bis-carboxylic acid with
potassium hydroxide and subsequently converted to the cyclic-
anhydride 5 in good yield. Compound 5 is essentially equivalent
to the targeted building block 1 since the cyclic-anhydride could
be opened with various amines to form amides at the 3 position,
and the resulting carboxylic acid at the 4 position could be trans-
formed to an amine via Curtius rearrangement and further elabo-
rated. However, we decided not to proceed further with this
reaction sequence due to the low yield and difficult purification
1
N
N
R2
2
3
Alternatively, the targeted building block could potentially be
made via a second route in which commercially available N-tert-
butylpyrrole 2 would be used as the starting point to functionalize
5
4
N
N
R3
HO
R4
NO2
R1
O
O
1
* Corresponding author. Tel.: +1 215 358 2034; fax: +1 215 358 2010.
E-mail address: dnguyen@locuspharma.com (D.V. Nguyen).
Scheme 1. Potential elaborations of building block 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.099

6808
D. V. Nguyen et al. / Tetrahedron Letters 50 (2009) 6807–6809
trophilic substitution on 2,3,4,5 un-substituted pyrrole was
O
O
i
Br
achieved at the 3 position by having a bulky substituent or protect-
ing groups (such as silane) on the pyrrole nitrogen.3,4 With smaller
N-substituents such as small alkyls and less sterically hindered
groups, the selectivity tends to favor the 2 (or 5) position.5,6 In
our situation, we looked to utilize the bulky tert-butyl moiety of
2 to direct substitutions to the desired 3 and 4 positions on the pyr-
role ring. We initially attempted to introduce first the nitro group,7
then an ester via Friedel–Craft acylation (Scheme 4), based on lit-
erature precedence.8
O
O
O
O
HN
N
+
O
O
Scheme 2. Reagents and conditions: (i) KOH, 1-N-butyl-3-methylimidazolium
hexafluorophosphate, 80 °C, 18 h.
Thus, nitration of N-tert-butylpyrrole was accomplished with
nitric acid in acetic anhydride as solvent at low temperature,
affording the desired 1-tert-butyl-3-nitro-1H-pyrrole product 6a
in greater than 85% yield along with less than 15% of regio-isomer
6b. A very small amount of bis-nitration product was also ob-
served. NOESY proton NMR experiments were conducted to deter-
mine the regio-chemistry of the two major products. The NOESY
spectrum of 6a shows NOE correlations between the N-tert-butyl
group proton resonance and the two most downfield of the three
ring proton peaks (2 and 5 positions), as expected for the 3-nitro
isomer (Fig. 1). As expected for the 2-nitro isomer 6b, the only
NOE correlation involving the t-butyl group is with the most
downfield of the three ring proton peaks. The relative ring proton
chemical shifts of 6a versus 6b, as well as J coupling analysis, also
support the regio-isomer structure assignments. Compound 6a
was subsequently subjected to Friedel–Crafts acylation conditions,
using either ethyl chloroformate or trifluoroacetic anhydride to
incorporate the ester or carboxylic acid precursor. However, we
did not observe acylation products for any of the possible positions
on the ring, likely due to the combined negative effects of the bulky
tert-butyl moiety and the electron-withdrawing nitro group.
With this result, we decided to reverse the order of the syn-
thetic sequence and carried out the Friedel–Crafts reaction first
(Scheme 5). Compound 2 was treated with trifluoroacetic anhy-
dride and tin chloride in toluene to give predominantly the desired
regio-isomer 7 in greater than 85% yield.9,10
N
O
O
O
O
N
O
i
ii, iii
N
O
O
+
microwave
O
O
O
O
2
3
4
5
Scheme 3. Reagents and conditions: (i) Microwave, 80–130 °C, 30 min; (ii) KOH,
3:1:1 THF/MeOH/H2O; (iii) PCl5, THF, 25 °C, 1 h.
process for the cyclo-addition reaction. Furthermore, this approach
could limit the number of potential amide targets since it would be
difficult to make those derived from less reactive anilines or steri-
cally hindered amines.
We then attempted to introduce selective, un-symmetrical sub-
stitutions to the 3 and 4 positions starting from N-tert-butylpyrrole
2. The obvious challenge was to controll the regio-selectivity of
electrophilic substitution reactions to the desired 3 and 4 positions,
having also the 2 and 5 positions on the pyrrole ring as potential
reaction sites. There are literature examples where selective elec-
Friedel-Crafts
N
acylation
N
N
H
i
NO2
NMR experiments were conducted to confirm the regio-chemis-
try of product 7 (Fig. 1). The NOESY spectrum of 7 displays NOE
correlations between the N-tert-butyl resonance and the two most
downfield pyrrole proton peaks. Also, the 1H/13C gHMBC spectrum
shows correlations between these two proton peaks and the
N-tert-butyl quaternary carbon. Interestingly, JHF coupling of the
protons (2 and 4 positions) adjacent to the trifluoromethyl acetyl
2
ii or iii
NO2
R3
NO2
H
O
6a (85%)
6b (15%)
Scheme 4. Reagents and conditions: (i) Acetic anhydride, nitric acid, À20 °C, 2 h;
(ii) SnCl4, trifluoroacetic anhydride, toluene, 0–25 °C, 16 h; (iii) AlCl3, ethyl
chloroformate, carbon disulfide, 0–55 °C, 16 h.
CH3
CH3
CH3
H3C
H3C
CH3
Observed NOE
N
N
Observed HMBC
7.06 HC
HC
HC
NO2
7.37
6.17
CH
7.85
HC
CH
Observed JHF
6.67
7.24
NO2
6a
6b
CH3
CH3
CH3
CH3
CH3
H3C
H3C
HC
H3C
HC
CH3
N
N
O2N
O
N
CH
7.82
8.10
CH 7.19
7.85
8.17
CH
NO2
CH
CH
7.66
O
O
6.69
CF3
CF3
CF3
7
8a
8b
Figure 1. Summary of structurally diagnostic NMR observations.

D. V. Nguyen et al. / Tetrahedron Letters 50 (2009) 6807–6809
6809
accessed by first activating the carboxylic acid with PCl5. Following
amide formation, the nitro group was cleanly reduced to amine
with tin chloride for further elaboration.
N
R3
R2
R1
F3C
N
ii
i
iii
2
1
O
O
O
CF3
F3C
Acknowledgments
O
O
F3C
8a R1 = H, R2 = NO2, R3 = H
8b R1 = NO2, R2 = H, R3 = H
7
The authors would like to thank Dr. Bin Liu and Dr. Rupa Shetty
for their feedback on the manuscript.
8a/8b ratio is 3:1
70% overall yield
References and notes
Scheme 5. Reagents and conditions: (i) SnCl4, trifluoroacetic anhydride, toluene, 0–
25 °C, 6 h; (ii) acetic anhydride, nitric acid, À20 °C, 2 h; (iii) 20% aq NaOH, 120 °C,
microwave, 15 min.
1. Le, Z.; Chen, Z.; Hu, Y.; Zheng, Q. Synthesis 2004, 12, 1951–1954.
2. Noland, W.; Lee, C. K. J. Org. Chem. 1980, 45, 4573–4582.
3. Rokach, J.; Hamel, P.; Kakushima, M.; Smith, Graham M. Tetrahedron Lett. 1981,
22, 4901–4904.
4. Simchen, G.; Majchrzak, M. W. Tetrahedron Lett. 1985, 26, 5035–5036.
5. Di Santo, R. et al J. Med. Chem. 2005, 48, 4220–4223.
6. Katritzky, A. R.; Scriven, E. F.; Majumder, S.; Akhmedova, R. G.; Akhmedov, N.
G.; Vakulenko, A. V. ARKIVOC 2005, 3, 179–191.
7. Doddi, G.; Mencarelli, P.; Razzini, A.; Stegel, F. J. Org. Chem. 1979, 44, 2321–
2323.
group with fluorine is observed as well. Subsequent nitration of 7
was carried out with nitric acid and acetic anhydride at À20 °C,
affording the desired 4-nitro product 8a as well as the regio-isomer
8b in 3:1 ratio and 70% overall yield.11 The desired major product
8a was easily isolated by re-crystallization from dichloromethane/
hexane. Regio-isomers 8a and 8b were differentiated by NOESY
and 19F JHF coupling analysis (Fig. 1).
8. Pavia, M. R. Org. Prep. Proced. Int. 1987, 19, 48–52.
9. Harsanyi, M. C.; Norris, R. K. J. Org. Chem. 1987, 52, 2209–2213.
10. Pyrrole starting material
2 (4.87 mmol) and trifluoroacetic anhydride
The spectrum of 8a shows 1H NOEs between the N-tert-butyl
group and both the neighboring pyrrole protons, indicating that
nitration occurred at the desired position 4. For regio-isomer 8b,
only one of the pyrrole protons (position 5) shows NOE correlation
with the adjacent N-tert-butyl resonance. This pyrrole proton,
however, is not coupled to fluorine, which indicates nitration at
position 2 for 8b. Finally, the conversion of 8a to the titled com-
pound 1 was accomplished in good yield by treatment with aque-
ous sodium hydroxide at 120 °C for 15 min under microwave
irradiation.12
In conclusion, a convenient, good yielding, and regio-selective
synthetic sequence was developed to access the novel 1-tert-bu-
tyl-4-nitro-1H-pyrrole-3-carboxylic acid building block. NMR
studies were conducted to determine the regio-chemistry of the
various electrophilic substitution products on the pyrrole ring.
The tert-butyl moiety of N-tert-butylpyrrole 2 appeared to be
instrumental in directing un-symmetrical substitutions to the de-
sired 3 and 4 positions of the ring. With the versatile building block
1 in hand (Scheme 1), a wide range of designed amide targets
deriving from sterically hindered amines and anilines were easily
(4.87 mmol) were dissolved in 10 ml toluene and cooled to 0 °C. To this
mixture was added drop-wise SnCl4 (9.74 mmol) and stirring was continued
for 1 h. Subsequently, the reaction was quenched with 1 N NaOH and extracted
with ethyl acetate. The product was purified by silica column with 95:5
hexane/EtOAc to give 7 as a yellow oil (85% yield).1H NMR (400 MHz, acetone-
d6): d (ppm) 7.82–7.83 (m, 1H, H-2), 7.19 (dd, J = 3.2, 2.2 Hz, 1H, H-5), 6.68–
6.70 (m(8), 1H, H-4), 1.63 (s, 9H, t-butyl).
11. Acetic anhydride (3 ml) and nitric acid (0.198 g, 3.15 mmol) were stirred at
room temperature for 15 min, then this solution was added drop-wise to a
solution of 7 (0.690 g, 3.15 mmol) in 10 ml acetic anhydride at À20 °C. The
mixture was gradually warmed to rt and stirred for an additional 1 h, then
quenched with ice and saturated NaHCO3, followed by extraction with ethyl
acetate. The product was re-crystallized from dichloromethane/hexane to give
8a (0.450 g, 54% isolated yield) as a tan solid. Regio-isomer 8b (0.11 g, 16.4%
isolated yield) was an oil.1H NMR of 8a (400 MHz, acetone-d6): d (ppm) 8.17 (d,
J = 2.5 Hz, 1H, H-5), 7.85 (m(6), JHH = 2.5 Hz, JHF = 1.4 Hz, 1H, H-2), 1.72 (s, 9H, t-
butyl).
12. Compound 8a (0.205 g, 0.776 mmol) was suspended in 2 ml water in
a
microwave reaction vial. solution of 50% w/v aqueous NaOH (0.186 g,
A
2.33 mmol) was subsequently added and the reaction was heated in the
microwave at 120 °C for 15 min. After cooling, the reaction was diluted with
10 ml water, neutralized with 1 N HCl, and then extracted with EtOAc. The
solvent was removed to give the crude solid, which was washed with hexane,
then filtered, and dried to afford the titled compound 1 as a tan solid (0.140 g,
85% yield).1H NMR of 1 (400 MHz, acetone-d6): d (ppm) 10.50 (br s, 1H), 7.98
(d, J = 2.7 Hz, 1H, H-5), 7.61 (d, J = 2.7 Hz, 1H, H-2), 1.67 (s, 9H, t-butyl).