Efficient synthesis of bis(heterocyclyl)methanes

Article abstract of DOI:10.1080/00397911.2010.518330

The reaction of pyrrole/furan aldehyde with Grignard reagent and pyrrole/N-methyl pyrrole in sequence allows efficient synthesis of a number of meso-elaborated bis(heterocyclyl)methanes, which are otherwise difficult to obtain through a direct aldehyde co

Full text of DOI:10.1080/00397911.2010.518330

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Efficient Synthesis of
Bis(heterocyclyl)methanes
Kamaljit Singh a , Shivali Sharma a & Amit Sharma a
a Department of Applied Chemical Sciences and Technology, Organic
Synthesis Laboratory, Guru Nanak Dev University, Amritsar, India
Accepted author version posted online: 30 Jun 2011. Version of
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To cite this article: Kamaljit Singh, Shivali Sharma & Amit Sharma (2011): Efficient Synthesis
of Bis(heterocyclyl)methanes, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 41:23, 3491-3496
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Synthetic Communications1, 41: 3491–3496, 2011
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.518330
EFFICIENT SYNTHESIS OF
BIS(HETEROCYCLYL)METHANES
Kamaljit Singh, Shivali Sharma, and Amit Sharma
Department of Applied Chemical Sciences and Technology, Organic
Synthesis Laboratory, Guru Nanak Dev University, Amritsar, India
GRAPHICAL ABSTRACT
Abstract The reaction of pyrrole/furan aldehyde with Grignard reagent and pyrrole/
N-methyl pyrrole in sequence allows efficient synthesis of a number of meso-elaborated
bis(heterocyclyl)methanes, which are otherwise difficult to obtain through a direct aldehyde
condensation route.
Keywords Bis(heterocyclyl)methane; dipyrromethane; Grignard reagent; novel
porphyrinoid
INTRODUCTION
Bis(heterocyclyl)methane derivatives are versatile intermediates and have
demonstrated immense synthetic utility. For example, these are intermediates for
novel porphyrinoids[1,2] and a variety of cyclic conjugated chemical entities,[3,4] fluor-
escent boron-dipyrromethene (BODIPY) dyes,[5] and flavoring agents,[6] and are
used in biological samples.[7] Although several methods have been reported for their
synthesis,[8] we achieved, as this communication presents, a simple and versatile syn-
thesis of the title compounds from easily available pyrrole=furan-2-carboxaldehydes
1. The superiority of the method stems from the fact that under the mild conditions
employed, the reactions do not require expensive pyrrole to be used in exceptionally high
(up to 400 equiv) excess (Scheme 1), as previously reported,[9] and the yields are better.
Pyrrole=furan-2-carboxaldehydes 1 are available commercially and can be pre-
pared in near quantitative yield through Vilsmeier–Haack formylation [dimethyl for-
mamide (DMF)=POCl3] of pyrrole[10] and furan,[11] respectively. Reaction of 1 with
Received April 25, 2010.
Address correspondence to Kamaljit Singh, Department of Applied Chemical Sciences and
Technology, Organic Synthesis Laboratory, Guru Nanak Dev University, Amritsar 143005, India.
E-mail: kamaljit19in@yahoo.co.in
3491

3492
K. SINGH, S. SHARMA, AND A. SHARMA
Scheme 1. Synthesis of bis(heterocyclyl)methane derivatives.
a number of freshly prepared Grignard reagents (Table 1) completes rapidly, result-
ing in the quantitative conversion to the carbinol 2 (Scheme 1), which, without the
need for isolation, reacts (BF3 ꢀ OEt2) with pyrrole derivatives 3 (2.0–10.0 equiv) to
furnish the desired bis(heterocyclyl)methane derivative 4 in a synthetically useful
manner. The synthetic strategy utilizes some features used in the synthesis of
pyriporphyrins[12] and 21,23-dithiaporphyrins[13] having one pyridyl group at the
meso-position.
The structures of products 4a–n (Table 1) were confirmed by spectroscopic as
well as analytical methods. In addition, representative 4 compounds were prepared
1
using a known method. For example, the H NMR spectra of compounds 4a–k
synthesized by two different methods were same.
Investigation of the reaction conditions indicated that increasing the tempera-
ture or using pyrrole in less than 2.0 equiv led to the formation of uncharacterizable
polymeric products. The reaction was driven to completion, and the isolated yield of
4 was good (Table 1), only when 10.0 equiv of pyrrole were used. Further, employing
trifluoroacetic acid in place of boron trifluoride did not yield any advantage in terms
of yields of the isolated products, which in the latter cases were greater. The compari-
son of the yields of the products 4a–d, f, h, j–l at entries 1–4, 6, 8, 10–12 could also be
made with known methods (Table 1). We find that the yields of obtained using
Table 1. Reaction of Grignard reagents with N-formylpyrrole=furan 1 and pyrrole=N-methylpyrrole 4
Entry
R1MgX
Product 4
R1
R2
X
Yield (%)a,b
Reported yield (%)
1
2
MeMgBr
EtMgBr
a
b
c
d
e
f
Me
Et
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
NH
O
60 (52)
62 (50)
70 (60)
75 (62)
72 (61)
70 (58)
75 (50)
75 (61)
78 (60)
65 (58)
85 (72)
85 (71)
80 (61)
83 (70)
40[15]
35.5,[16] 55[17]
3
n-PrMgBr
n-BuMgBr
n-Pr
n-Bu
40[18]
35,[18] 42[19]
4
5
sec-BuMgBr
n-PentylMgBr
n-DecylMgBr
n-UndecylMgBr
BenzylMgBr
AllylMgBr
sec-Bu
n-Pentyl
n-Decyl
n-Undecyl
Benzyl
Allyl
–
6
44,[18] 53,[20] 62[8]
7
g
h
i
–
8
25[21]
9
–
10
11
12
13
14
j
36[22]
PhMgBr
k
l
Ph
80,[23] 79[24]
Thien-2ylMgBr
Thien-2ylMgBr
Thien-2ylMgBr
Thien-2yl
Thien-2yl
Thien-2yl
50,[25] 61[26]
m
n
–
–
O
aIsolated yield.
bYields in parentheses refer to the use of 2.0 equiv of 3.

BIS(HETEROCYCLYL)METHANES
3493
present method are superior in these cases. While entries 1–11 (Table 1) represent
formation of meso-elaborated dipyrromethanes 4a–k, entries 12–14 represent tris-
(heterocyclyl)methane derivatives 4l–n, which are also useful synthons.[14]
The reaction mechanism could proceed through the formation of carbinol 2
from 1, through well-established carbon–carbon bond-formation reaction of
Grignard reagent. The formation of 4 gets completed through the subsequent
acid-catalyzed condensation of intermediate 2 with 3 (Scheme 1).
CONCLUSION
In conclusion, a simple and convenient method for the synthesis of dipyrro-
methanes is described. This method may serve as an alternative to using extremely
high excess of pyrrole in condensation with aldehydes, which many times furnishes
oligomeric products that plague the isolation of the desired 4. Also, the method
allows incorporation of a number of aliphatic chains at the meso-position, which
is an added advantage in comparison with aldehyde condensation approaches, and
above all the yields are satisfactory high.
EXPERIMENTAL
Appropriate Grignard reagent (2 mmol) prepared from activated magnesium
metal and an alkyl=allyl=aryl=heteroaryl bromide in anhydrous ether were trans-
ferred with the help of a cannula to a solution of pyrrole=furan-2-carboxaldehyde
1 (X ¼ NH, O) (1 mmol) in diethyl ether (10 ml) at 0 ꢁC, under a nitrogen atmos-
phere. Reaction was allowed to stir until completion, monitored by thin-layer chro-
matography (TLC), after which a saturated aqueous solution of NH4Cl (10 ml) was
introduced. The reaction was extracted with diethyl ether (2 ꢂ 40 ml), dried over
anhydrous Na2SO4, and concentrated under reduced pressure. To the crude 2,
pyrrole=N-methylpyrrole 3 (10 mmol) was added, and the mixture was stirred for
5 min under a nitrogen atmosphere. To the stirring solution, BF3 ꢀ OEt2 (1 mmol)
was added dropwise at 10 ꢁC, and after stirring the reaction for an additional
5 min, 0.1 N NaOH solution was introduced to quench the reaction. After extraction
with ethyl acetate (2 ꢂ 40 ml), the extract was dried over anhydrous Na2SO4, concen-
trated under reduced pressure, and purified by flash chromatography using silica
gel (100–200 mesh) and mixtures of n-hexane=ethyl acetate as eluent to isolate
the corresponding 4. All compounds exhibited satisfactory spectral as well as
microanalytical data. The characteristic data of unknown 4 are given.
ANALYTICAL DATA OF NEW PRODUCTS
5-sec-Butyldipyrromethane (4e)
Yield ¼ 0.75 g (72%), yellow oil. Rf ¼ 0.83 (20% ethyl acetate=hexane).
1H NMR (300 MHz, CDCl3): d 7.83 (2H, brs, D2O exchangeable, 2 ꢂ NH),
6.64–6.61 (2H, m, ArH), 6.16–6.14 (2H, m, ArH), 6.13–6.05 (2H, m, ArH), 3.91
(1H, d, J ¼ 6.3 Hz, meso-CH), 2.05–1.55 (2H, m, CH2), 1.09–1.02 (1H, m, CH),
0.93–0.87 (6H, m, CH3). 13C NMR (75 MHz, CDCl3): d 132.5, 116.6, 107.9, 105.7,

3494
K. SINGH, S. SHARMA, AND A. SHARMA
43.6, 38.4, 27.5, 17.1, 11.8. Mass (m=z): 204 (Mþ). Elemental analysis: C, 77.22%; H,
8.91%; N, 13.86% calculated from C13H18N2. Found: C, 76.13%; H, 9.32%; N,
14.20%.
5-n-Decyldipyrromethane (4g)
Yield ¼ 1.12 g (75%), yellow oil. Rf ¼ 0.82 (20% ethyl acetate=hexane).
1H NMR (300 MHz, CDCl3): d 7.81 (2H, brs, D2O exchangeable, 2 ꢂ NH),
6.65–6.64 (2H, m, ArH), 6.63–6.14 (2H, m, ArH), 6.13–5.97 (2H, m, ArH), 3.97
(1H, t, J ¼ 7.5 Hz, meso-CH), 1.26 (18H, m, CH2), 0.87 (3H, t, J ¼ 7.2 Hz, CH3).
13C NMR (75 MHz, CDCl3): d 133.6, 116.9, 108.0, 105.2, 37.6, 34.5, 31.8, 29.6,
29.5, 29.5, 29.3, 27.5, 22.6, 14.1. Mass (m=z): 286.9 (M þ 1). Elemental analysis: C,
79.72%; H, 10.83%; N, 9.79% calculated from C19H31N2. Found: C, 78.71%; H,
11.37%; N, 8.69%.
5-Benzyldipyrromethane (4i)
Yield ¼ 0.96 g (78%), yellow oil. Rf ¼ 0.68 (20% ethyl acetate=hexane). 1H
NMR (300 MHz, CDCl3): d 7.79 (2H, brs, D2O exchangeable, 2 ꢂ NH), 7.32–7.15
(3H, m, ArH), 7.14–7.01 (2H, m, ArH), 7.01–6.99 (2H, m, ArH), 6.99–6.62 (2H,
m, ArH), 6.61–5.99 (2H, m, ArH), 4.27 (1H, t, J ¼ 6.0 Hz, meso-CH), 3.25 (2H, d,
J ¼ 6.0 Hz, CH2). 13C NMR (75 MHz, CDCl3): d 132.8, 129.0, 128.1, 126.2, 116.9,
108.1, 105.8, 41.6, 39.9. Mass (m=z): 236 (Mþ). Elemental analysis: C, 81.35%; H,
6.77%; N, 11.86% calculated from C16H16N2. Found: C, 80.66%; H, 7.06%; N,
10.24%.
2-[Furan-2-yl(thiophen-2-yl)methyl]-1H-pyrrole (4m)
Yield ¼ 0.94 g (80%), yellow oil. Rf ¼ 0.72 (20% ethyl acetate=hexane). 1H
NMR (300 MHz, CDCl3): d 8.23 (1H, brs, D2O exchangeable, 1 ꢂ NH), 7.31 (1H,
s, ArH), 7.12 (1H, s, ArH), 6.83 (1H, s, ArH), 6.74 (1H, s, ArH), 6.64 (1H, s,
ArH), 6.27 (1H, s, ArH), 6.26 (1H, s, ArH), 5.97 (2H, s, ArH), 5.64 (1H, s,
meso-CH). 13C NMR (75 MHz, CDCl3): d 154.8, 144.3, 142.0, 130.3, 126.6, 125.5,
124.7, 117.3, 110.2, 108.2, 107.0, 106.9, 39.4. Mass (m=z): 229 (Mþ). Elemental
analysis: C, 68.12%; H, 4.80%; N, 6.11% calculated from C13H11NSO. Found: C,
67.72%; H, 4.97%; N, 5.52%.
2-[Furan-2-yl(thiophen-2-yl)methyl]-1-methyl-1H-pyrrole (4n)
Yield ¼ 1.04 g (83%), yellow oil. Rf ¼ 0.78 (20% ethyl acetate=hexane). 1H
NMR (300 MHz, CDCl3): d 7.36 (1H, s, ArH), 6.95 (1H, s, ArH), 6.80 (1H, s,
ArH), 6.32 (2H, s, ArH), 6.31 (1H, s, ArH), 6.00 (2H, s, ArH), 5.83 (1H, s, ArH),
5.74 (1H, s, meso-CH), 3.45 (3H, s, CH3). 13C NMR (75 MHz, CDCl3): d 155.0,
144.0, 141.7, 131.9, 126.6, 125.6, 124.6, 122.4, 110.2, 108.1, 107.3, 106.6, 38.4,
33.8. Mass (m=z): 243 (Mþ). Elemental analysis: C, 69.13%; H, 5.34%; N, 5.76%
calculated from C14H13NSO. Found: C, 67.54%; H, 5.50%; N, 5.57%.

BIS(HETEROCYCLYL)METHANES
3495
ACKNOWLEDGMENT
This work was supported by financial assistance from the Department of
Science and Technology (SR=S1=OC-27=2009).
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