Magnesium nitride as a convenient source of ammonia: Preparation of pyrroles

Article abstract of DOI:10.1055/s-0028-1083504

The synthesis of a diverse array of pyrroles is reported from the cyclocondensation of 1,4-dicarbonyl compounds with magnesium nitride in methanol.

Full text of DOI:10.1055/s-0028-1083504

LETTER
2597
Magnesium Nitride as a Convenient Source of Ammonia: Preparation of
Pyrroles
Magnesium
Nitrid
e
e
for the Pr
e
m
paration of Pyrrole
m
s
a E. Veitch, Katy L. Bridgwood, Karen Rands-Trevor, Steven V. Ley*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, UK
Fax +44(1223)336442; E-mail: svl1000@cam.ac.uk
Received 12 July 2008
Table 1 Optimisation of Reaction Conditions for the Preparation of
Abstract: The synthesis of a diverse array of pyrroles is reported
from the cyclocondensation of 1,4-dicarbonyl compounds with
magnesium nitride in methanol.
2a
O
Mg3N2
Ph
HN
Key words: pyrroles, heterocycles, ammonia, magnesium nitride,
combinatorial chemistry
MeOH
sealed tube
O
Ph
1
2
Entry
Mg3N2
(equiv)
Temp
(°C)
Time
Conversion
(%)b
Functionalised pyrroles are abundant in nature,1 forming
the characteristic subunit of heme, chlorophyll, bile pig-
ments and vitamin B12.2 There are also many pharmaceu-
ticals which contain the pyrrole motif most notably the
cholesterol lowering drug, Lipitor,3 and the anti-inflam-
matory agent amtolmetin.4 Consequently, a wide variety
of methods have been developed to enable the synthesis of
these important heterocycles.5
1
2
3
4
5
6
7c
0.5
2.5
0.5
2.5
0.5
2.5
2.5
21
24 h
24 h
7 d
21
80
21
21
62
21
7 d
90
70 (mW)
1 h
66
Nonetheless, the preparation of substituted pyrroles re-
mains a challenge. Harsh acidic conditions are often re-
quired and yields can be low.6 Pyrroles are also
susceptible to chemical degradation as they are easily ox-
idized, which can impede their isolation and purification.7
70 (mW)
1 h
90
120 (mW)
1 h
>99
a Reactions were performed in a Biotage microwave vial (2–5 mL) us-
ing 1 (0.57 mmol) in MeOH at 0.1 M concentration.
b Calculated through analysis of crude 1H NMR spectra.
c For precise experimental procedure see ref. 10.
Recent work from our group has demonstrated the use of
commercially available magnesium nitride (Mg3N2) as a
convenient source of ammonia. This reagent serves to
generate synthetically useful solutions of ammonia in situ
through its reaction with protic solvents (Equation 1).8 So
far, we have reported the amidation of esters and the
Hantzsch dihydropyridine synthesis using magnesium ni-
tride. We therefore sought to expand the scope of this re-
agent to include the Paal–Knorr9 reaction: synthesis of
functionalised pyrroles from the corresponding 1,4-dicar-
bonyl compounds.
reduce the reaction time and rapidly found optimal condi-
tions which gave complete conversion to 2 after just one
hour (entry 7).
These conditions were then used successfully for the syn-
thesis of other 2,5-disubstituted pyrroles with good isolat-
ed yields obtained in all cases (Table 2, entries 2–5).
However, when we attempted to prepare the 2,5-di-tert-
butyl-1H-pyrrole (7) only 20% conversion was observed
under the standard conditions. In this instance, it proved
necessary both to increase the equivalents of magnesium
nitride from 2.5 to 10 and to increase the reaction time to
eight hours to obtain complete conversion (entry 7). It was
undesirable to have such long reaction times in the micro-
wave and so we explored the possibility of normal thermal
heating to effect this transformation: pleasingly, pyrrole 7
could be obtained in near quantitative yield after 24 hours
at 80 °C. All the pyrroles prepared previously could also
be accessed in good yields under thermal conditions, a
procedure which better lends itself to chemical library
synthesis and scaleup.
Equation 1
Preliminary investigations were carried out using phenyl-
pentane-1,4-dione (1) with methanol as the solvent
(Table 1). Although the desired cyclisation did proceed at
ambient temperature (entries 1–4) long reaction times
were necessary to achieve acceptable conversions. We
therefore employed microwave heating in an attempt to
SYNLETT 2008, No. 17, pp 2597–2600
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083504; Art ID: D26708ST
© Georg Thieme Verlag Stuttgart · New York

2598
G. E. Veitch et al.
LETTER
Table 2 Microwave-a and Thermallyb Assisted Synthesis of Pyr-
Table 3 Thermally Assisted Synthesis of Functionalised Pyrrolesa
roles
Entry Product10,11
Isolated yieldc Isolated yield
(mw)
Entry Product14
Isolated yield (%)b
98
(%)c (heat)
1
2
Ph
1
99
95
HN
HN
Ph
8
99
79
Ph
2
HN
2
95
92
72
87
78
91
HN
MeO
9
Cl
3
S
3
312
HN
HN
S
Br
10
4
415
85
413
HN
S
HN
F3C
5
5
89
94
Ph
F3C
HN
11
5
6
94
63
Ph
HN
Ph
HO2C
6
6
95d
99e
t-Bu
MeO
HN
12
F
t-Bu
7
a For representative experimental procedure see reference 10.
b For representative experimental procedure see reference 11.
c Isolated yield after column chromatography on SiO2.
d This reaction was performed using magnesium nitride (10 equiv) for
8 h.
HN
e This reaction was performed using magnesium nitride (10 equiv).
HO2C
13
716
96
Ph
The thermal conditions employed for the preparation of 7
were then applied to a diverse set of 1,4-dicarbonyl sub-
strates (Table 3). Both electron-rich and electron-defi-
cient ketones provided the desired pyrroles in good yield.
Furthermore, a number of densely functionalised trisub-
stituted pyrroles could be prepared by this method.
HN
14
In summary, magnesium nitride has been used as a conve-
nient source of ammonia in alcoholic solvents for the syn-
thesis of 1H-pyrroles from 1,4-dicarbonyl compounds.
The substrate scope and functional group tolerance is
broad and isolated yields are good in all cases
Synlett 2008, No. 17, 2597–2600 © Thieme Stuttgart · New York

LETTER
Magnesium Nitride for the Preparation of Pyrroles
2599
Acknowledgment
We gratefully acknowledge Pfizer Global R&D Sandwich (Dr. D.
R. Owen) and Syngenta (Dr. S. C. Smith) for generous gifts of che-
micals and the EPSRC for funding (G.E.V. and K.L.B.). The Uni-
versity of Queensland Graduate School Travel Scholarship is also
acknowledged for funding (K.R).
References and Notes
(1) For recent examples of the synthesis and isolation of pyrrole-
containing natural products, see: (a) Fürstner, A.; Szillat,
H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998, 120,
8305. (b) Umeyama, A.; Ito, S.; Yuasa, E.; Arihara, S.;
Yamada, T. J. Nat. Prod. 1998, 61, 1433. (c) Jones, T. H.;
Flournoy, R. C.; Torres, J. A.; Snelling, R. R.; Spande, T. F.;
Garraffo, H. M. J. Nat. Prod. 1999, 62, 1343. (d) Assmann,
M.; Zea, S.; Köck, M. J. Nat. Prod. 2001, 64, 1593.
(e) Grube, A.; Köck, M. J. Nat. Prod. 2006, 69, 1212.
(f) Grube, A.; Lichte, E.; Köck, M. J. Nat. Prod. 2006, 69,
125.
(2) Sundberg, R. J. In Comprehensive Heterocyclic Chemistry
II, Vol. 4; Katritzky, A. R.; Rees, C. W.; Scriven, E. F. V.,
Eds.; Elsevier: Amsterdam, 1996, 380-382, 431.
(3) Roth, B. D. US Patent 4681893, 1987; Chem. Abstr. 1987,
107, 198087.
(4) Anzalone, S. Eur. Patent Appl. 0755679, 1997; Chem. Abstr.
1997, 126, 139884.
(5) For selected recent examples of pyrrole synthesis, see:
(a) Binder, J. T.; Kirsch, S. F. Org. Lett.2(nt)5-. /2F 1 b,f 5.3867 0 TD -.0067 Tc 0 Tw [2( 0)1- 3.4(06)T] J /2F 1 Tf 2 0 TD -.01 Tc (, )Tj /3F 1 Tf .492.44 2.8 Tw (II)Tj
Synlett 2008, No. 17, 2597–2600 © Thieme Stuttgart · New York

2600
G. E. Veitch et al.
LETTER
13C NMR (100 MHz, CDCl3): d = 136.0, 130.5, 129.2, 127.1
(q, J = 31.5 Hz), 125.8 (q, J = 3 Hz), 124.3 (q, J = 270 Hz),
122.9, 108.6, 108.1, 13.2. IR (film): 3397, 2918, 2852, 1617,
1333, 1112, 844, 778 cm–1. HRMS (ESI): m/z [M + H]+ calcd
for C12H11F3N: 226.0839; found: 226.0849.
(16) Physical Data for 2-Phenyl-4,5-dihydro-1H-
benzo[g]indole (14): 1H NMR (600 MHz, CDCl3): d = 8.46
(br s, 1 H), 7.53 (d, J = 7.6 Hz, 2 H), 7.39 (t, J = 7.6 Hz, 2
H), 7.21–7.26 (m, 4 H), 7.08 (t, J = 7.2 Hz, 1 H), 6.43 (d,
J = 1.8 Hz, 1 H), 2.96 (t, J = 7.2 Hz, 2 H), 2.78 (t, J = 7.2 Hz,
2 H). 13C NMR (150 MHz, CDCl3): d = 135.0, 132.6, 132.5,
129.0, 128.9, 128.4, 126.6, 126.2, 125.2, 123.7, 122.2,
118.2, 106.1, 29.9, 29.7. IR (film): 3442, 2923, 2850, 1609,
1507, 1291, 1263 cm–1. HRMS (ESI): m/z [M]+ calcd for
C18H15N: 245.1205; found: 245.1192.
(14) General Procedure for the Thermally Assisted Synthesis
of 1H-Pyrroles (Table 3): To a stirred solution of the 1,4-
dicarbonyl compound (0.13 mmol) in MeOH (1.3 mL) at
0 °C was added magnesium nitride (1.3 mmol). The reaction
vessel was sealed and allowed to stir for 10 min before
heating to 80 °C for 24 h. After cooling to r.t., the reaction
was subjected to workup and column chromatography as
before. For pyrroles 10 and 11, neutral alumina was
employed for chromatography to prevent decomposition.
(15) Physical Data for 3-(Thiophen-2-yl)-2-p-tolyl-5-[4-
(trifluoromethyl)phenyl]-1H-pyrrole (11): 1H NMR (600
MHz, CDCl3): d = 8.41 (br s, 1 H), 7.59 (AB q, J = 8.6 Hz,
4 H), 7.44 (d, J = 8.1 Hz, 2 H), 7.23 (d, J = 7.9 Hz, 2 H), 7.21
(dd, J = 5.0, 1.0 Hz, 1 H), 6.99 (dd, J = 5.0, 3.5 Hz, 1 H), 6.96
(dd, J = 3.5, 1.0 Hz, 1 H), 6.66 (d, J = 2.8 Hz, 1 H), 2.38 (s,
3 H). 13C NMR (150 MHz, CDCl3): d = 138.0, 137.0, 136.1,
133.4, 129.7, 128.8, 128.8 (q, J = 33 Hz), 127.6, 127.4,
127.3, 125.6 (q, J = 3 Hz), 124.2 (q, J = 273 Hz), 124.7,
124.1, 124.0, 118.0, 109.0, 21.2. IR (film): 3427, 2919,
2849, 1616, 1324, 1164, 1121, 1068 cm–1. HRMS (ESI):
m/z [M]+ calcd for C22H16NF3S: 383.0956; found: 383.0960.
(17) Physical Data for 2-(4-Fluorophenyl)-3-(4-methoxy-
phenyl)-5-(naphthalen-2-yl)-1H-pyrrole (15): 1H NMR
(500 MHz, CDCl3): d = 8.47 (br s, 1 H), 7.90 (br s, 1 H),
7.81–7.87 (m, 3 H), 7.71 (dd, J = 8.5, 1.4 Hz, 1 H), 7.48 (td,
J = 8.0, 1.0 Hz, 1 H), 7.38–7.45 (m, 3 H), 7.31 (d, J = 8.8 Hz,
2 H), 7.04 (d, J = 8.7 Hz, 2 H), 6.86 (dt, J = 9.6, 2.9 Hz, 2 H),
6.77 (d, J = 2.6 Hz, 1 H), 3.82 (s, 3 H). 13C NMR (125 MHz,
CDCl3): d = 161.9 (d, J = 245 Hz), 158.1, 133.8, 132.2,
132.1, 129.5, 129.5, 129.2, 129.2, 128.7, 128.6, 128.3,
127.8, 127.7, 126.6, 125.5, 123.7, 123.0, 121.0, 115.7 (d, J =
21.5 Hz), 113.9, 109.1, 55.2. IR (film): 3425, 2922, 1629,
1604, 1519, 1506, 1483 cm–1. HRMS (ESI): m/z [M + H]+
calcd for C27H21NOF: 394.1607; found: 394.1617.
(18) Trofimov, B. A.; Tarasova, O. A.; Mikhaleva, A. I.;
Kalinina, N. A.; Sinegovskaya, L. M.; Henkelmann, J.
Synthesis 2000, 1585.
Synlett 2008, No. 17, 2597–2600 © Thieme Stuttgart · New York

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