Synthetic application of monoprotected hydrazines toward the synthesis of 1-aminopyrroles

Full text of DOI:10.1021/jo9518260

1180
J . Org. Chem. 1996, 61, 1180-1183
Resu lts a n d Discu ssion
Syn th etic Ap p lica tion of Mon op r otected
Hyd r a zin es tow a r d th e Syn th esis of
1-Am in op yr r oles
Con d en sa tion of 2,2,2-Tr ich lor oeth yl Hyd r a zid e
on 1,4-Dik eton es. 2,2,2-Trichloroethyl hydrazide (1)
(1.2 equiv) was efficiently condensed with 1,4-diketones
such as 2,5-hexanedione (6), dibenzoylethane (7), and
1-phenyl-1,4-pentanedione (8) under acidic conditions
(Scheme 1). Generally, the reaction was conducted in
toluene at 80 °C with pyridinium p-toluenesulfonate
(PPTS) as a catalyst to provide the corresponding pro-
tected 1-aminopyrroles (12, 14, 16) in high yields. With
highly reactive substrates such as 2,5-hexanedione (6),
the reaction can be performed in AcOH12 at 80 °C or with
Yb(OTf)3 in CH2Cl2 at reflux. Unfortunately, the removal
of the trichloroethyl ester group under previously de-
scribed conditions (Zn/AcOH)10,13 led to the formation of
pyrroles in addition to the desired 1-aminopyrroles 21-
23.
Matt McLeod, Nicolas Boudreault, and Yves Leblanc*
Merck Frosst Centre for Therapeutic Research, P.O. Box
1005, Pointe Claire-Dorval, Quebec, Canada H9R 4P8
Received October 10, 1995
Although the first synthesis of 1-aminopyrroles was
accomplished many years ago, it is only recently that
these molecules were used as precursors in the synthesis
of biologically active compounds such as analgesics1 and
NMDA receptor antagonists.2 Only a few methods exist
for their preparation and this may partly explain their
limited presence of literature.3
Con den sation of 2-(Tr im eth ylsilyl)eth yl Hydr azide
on 1,4-Dica r bon yl Com p ou n d s. As for the trichloro-
ethyl case, 2-(trimethylsilyl)ethyl hydrazide (2) was
condensed with 1,4-diketones 6-8 to provide the pyrroles
13, 15, 17 in high yields. 2,3,5-Trisubstituted pyrrole
derivatives 18 and 19 were obtained by using the
diketones 9 and 10 as substrates which were prepared
from the Stetter condensation.14 1,4-Keto aldehydes can
be used as substrates to provide monosubstituted pyr-
roles, as exemplified by 4-oxopentanal (11).15 The pro-
tected 1-aminopyrroles were then smoothly converted, in
high yields, to the free 1-aminopyrroles 21-26 with nBu4-
NF in THF.
With regard to the reaction pathway for the formation
of the pyrrole ring system, in most cases several inter-
mediates were detected by TLC during the course of the
reaction. However, it has been observed that the bishy-
drazone 27 is an intermediate involved in the reaction
when 2,5-hexanedione (6) is the substrate (Scheme 2).
The bishydrazone 27 was formed very rapidly, as a single
intermediate, by mixing the hydrazide 2 with the dike-
tone 6 in toluene at room temperature. When this
intermediate was resuspended in toluene in the presence
of PPTS, the pyrrole 13 and hydrazide 2 were obtained.
Similar intermediates were observed from the condensa-
tion of monoprotected hydrazine such as tosylhydrazine5
and thiosemicarbazide,7 with 1,4-dicarbonyl compounds.
Hitherto, it has been shown that the monoprotected
hydrazine 2 can be used, in a two-step sequence, to
prepare 1-aminopyrroles under very mild conditions. The
procedure makes it possible to synthesize simple and
more sophisticated 1-aminopyrroles which can then serve
as precursors for condensation with 1,4-dicarbonyl com-
pounds to provide unsymmetrical 1,1′-bispyrroles. 1,1′-
Bispyrroles 28-31 can be efficiently prepared from
1-aminopyrroles 22-24 and the 1,4-diketones 6, 7, and
10. The reactions were performed in toluene with
The condensation of hydrazine with 1,4-dicarbonyl
compounds is reported to provide 1-aminopyrroles in only
low yields.4 With this modified Paal-Knorr synthesis,
dihydropyridazines and 1,1′-bispyrroles are also formed
as byproducts. Monoprotected hydrazines were then
employed in order to suppress the formation of these
byproducts. The use of tosylhydrazine has not resolved
this issue since pyridazine derivatives are still produced
with this reagent.5 N-Aminophthalimide,4,6 thiosemicar-
bazide,7 benzyl- and tert-butyl hydrazides8,9 are known
to condense on 1,4-diketones to provide the desired
protected 1-aminopyrroles without the formation of side
products. However, in these reports no general methods
are presented.
In this paper we present our work on the synthetic
application of monoprotected hydrazines toward the
synthesis of both simple and sophisticated 1-aminopyr-
roles. In addition, these 1-aminopyrroles can be used for
the synthesis of unsymmetrical 1,1′-bispyrroles and in
reductive amination reactions.
In recent works from our research group it has been
depicted that 2,2,2-trichloroethyl- (1) and 2-(trimethyl-
silyl)ethyl hydrazine (2) are readily available in large
quantities from commercially available materials.10,11 In
principle these hydrazides should condense on 1,4-
dicarbonyl compounds 3 to allow the preparation of
protected 1-aminopyrroles 4 which in turn could be
deprotected under very mild conditions to afford the
corresponding free amines 5 (Scheme 1).
(1) Effland, R. C.; Klein, J . T. U.S. Patent 4,546,105, 1985. Chem.
Abstr. 1986, 104, 186307.
(2) Kulagowski, J .; J anusz, J .; Leeson, P. D. UK Patent 2,265,372,
1993. Chem. Abstr. 1993, 120, 134504.
(3) For review see: (a) Cirrincione, G.; Almerico, A. M.; Aiello, E.
In Pyrroles. The Chemistry of Heterocyclic Compounds; J ones, R. A.,
Ed.; Wiley: New York, 1992; Vol. 48, Pt. 2, Chapter 3, pp 315-323.
(b) Bean, G. P. Pyrroles. In The Chemistry of Heterocyclic Compounds;
J ones, R. A., Ed.; Wiley: New York, 1990; Vol. 48, Pt. 1, Chapter 2, pp
208, 218-219. (c) J ones, R. A.; Bean, G. P. The Chemistry of Pyrroles;
Academic Press: New York, 1977; pp 384-387.
(12) With less reactive substrates there is a competitive reaction
between the hydrazide and the AcOH to give the bishydrazide.
(13) (a) Leblanc, Y.; Boudreault, N. J . Org. Chem. 1995, 60, 4268.
(b) Zaltsgendler, I.; Leblanc, Y.; Bernstein, M. A. Tetrahedron Lett.
1993, 34, 2441. (c) Grondin, R.; Leblanc, Y.; Hoogsteen, K. Tetrahedron
Lett. 1991, 32, 5021. (d) Leblanc, Y.; Fitzsimmons, B. J . Tetrahedron
Lett. 1989, 30, 2889.
(4) Epton, R. Chem. Ind. 1965, 425.
(5) Lemal, D. M.; Rave, T. W. Tetrahedron 1963, 19, 1119.
(6) Flitsch, W.; Kra¨mer, U.; Zimmermann, H. Chem. Ber. 1969, 102,
3268.
(7) Beyer, H.; Pyl, T.; Vo¨lcker, C. E. J ustus Liebigs Ann. Chem. 1960,
638, 150.
(8) Overberger, C. G.; Palmer, L. C.; Marks, B. S.; Byrd, N. R. J .
Am. Chem. Soc. 1955, 77, 4100.
(9) Carpino, L. A. J . Org. Chem. 1964, 30, 736.
(10) (a) Boudreault, N.; Ball, R. G.; Bayly, C.; Bernstein, M. A.;
Leblanc, Y. Tetrahedron 1994, 50, 7947. (b) Scartozzi, M.; Grondin,
R.; Leblanc, Y. Tetrahedron Lett. 1992, 33, 5717.
(11) Mitchell, H.; Leblanc, Y. J . Org. Chem. 1994, 59, 682.
(14) (a) Stetter, H.; Hilboll, G.; Kuhlmann, H. Chem. Ber. 1979, 112,
84. (b) Stetter, H.; Schreckenberg, M. Chem. Ber. 1974, 107, 2453. (c)
Stetter, H.; Schreckenberg, M. Angew. Chem. 1973, 85, 89.
(15) Molander, G. A.; Cameron, K. O. J . Am. Chem. Soc. 1993, 115,
830.
(16) Numbers in brackets represent the chemical yields for the
deaminated pyrroles.
0022-3263/96/1961-1180$12.00/0 © 1996 American Chemical Society

Notes
J . Org. Chem., Vol. 61, No. 3, 1996 1181
Sch em e 1a
a
Method A: AcOH; 80 °C, method B; Yb(OTf)3, CH2Cl2, reflux; method C: PPTS, PhMe, ∆; (b) method D: Zn/HOAc;10,13 method E:
nBu4NF, THF, rt.
Sch em e 2
benzene with PTSA to afford the hydrazone 33 in 84%
yield (Scheme 4). The hydrazone was then reduced with
NaBH4 in 2-propanol to provide the aminopiperidine 34
in 70% yield. These (pyrrolylamino)piperidines have
been claimed to possess analgesic properties.1
In summary, 1-aminopyrroles can be easily prepared
by the condensation of 2-(trimethylsilyl)ethyl hydrazide
with 1,4-dicarbonyl compounds followed by deprotection
under mild conditions. These 1-aminopyrroles can then
serve as precursors for the preparation of a large variety
of molecules containing N-N bond that could be useful
in the synthesis of biologically active compounds. Pres-
ently, other synthetic applications of these monoprotected
hydrazides are being studied and results will be reported
in due course.
Exp er im en ta l Section
Typ ica l P r oced u r es for th e Con d en sa tion of Hyd r a zid es
on 1,4-Dica r bon yl Com p ou n d s w ith AcOH (Meth od A). 2,5-
Dim eth yl-1-[[[[2-(tr im eth ylsilyl)eth yl]oxy]car bon yl]am in o]-
p yr r ole (13). To a solution of 2,5-hexanedione (500 mg, 4.38
mmol) in AcOH (4.05 mL) was added the hydrazide 2 (926 mg,
5.26 mmol). The resulting mixture was heated at 80 °C for 30
min. The solvent was evaporated under reduced pressure and
the residue purified by flash chromatography (20% EtOAc in
hexane). The title compound was obtained as white solid (1.05
p-toluenesulfonic acid (PTSA) as a catalyst (Scheme 3).
Furthermore, the 1-aminopyrrole compounds can be
potentially used for the preparation of a large variety of
(pyrrolylamino)piperidines. For example, the aminopy-
rrole 25 was condensed with N-methylpiperidone 32 in

1182 J . Org. Chem., Vol. 61, No. 3, 1996
Notes
With P P TS (Meth od C). 2,5-Dip h en yl-1-[[[[2-(tr im eth -
ylsilyl)eth yl]oxy]ca r bon yl]a m in o]p yr r ole (15). To a solu-
tion of the hydrazide 2 (1.24 g, 7.02 mmol) in toluene (30 mL)
were added 1,2-dibenzoylethane (1.40 g, 5.85 mmol) and PPTS
(70 mg, 0.30 mmol). The mixture was stirred under a nitrogen
atmosphere at 80 °C. After a period of 10 h, the solvent was
removed under reduced pressure and the crude product purified
by flash chromatography (30% EtOAc in hexane) to yield 1.90 g
(86%) of material: mp 136-137 °C (EtOAc/hexane); 1H NMR
(200 MHz, acetone-d6) δ 0.05 (s, 9H), 0.65 and 0.85 (2 bt, 2H),
3.90 and 4.05 (2 bt, 2H), 6.35 (s, 2H), 7.45 (m, 10H), 9.25 and
9.45 (2bs, 1H); 13C NMR (100 MHz, acetone-d6) δ -1.5, 18.2,
64.3, 108.1, 127.7, 128.7, 129.2, 133.3, 137.2, 156.4. Anal. Calcd
for C22H26N2O2Si: C, 69.80; H, 6.92; N, 7.40. Found: C, 69.51;
H, 6.95; N, 7.35.
Sch em e 3
2,5-Diph en yl-1-[[[(2,2,2-tr ich lor oeth yl)oxy]car bon yl]am i-
n o]p yr r ole (14): yield 298 mg (93%) from 0.777 mmol of 7; mp
168-169 °C (EtOAc/hexane); 1H NMR (200 MHz, acetone-d6) δ
4.75 (s, 2H), 6.40 (s, 2H), 7.45 (m, 10H), 10.25 (s, 1H); 13C NMR
(100 MHz, acetone-d6) δ 75.0, 96.2, 108.4, 127.9, 128.8, 129.2,
132.8, 137.4, 154.7; Anal. Calcd for C19H15Cl3N2O2: C, 55.70;
H, 3.69; N, 6.84. Found: C, 55.95; H, 3.83; N, 6.86.
5-Meth yl-2-p h en yl-1-[[[(2,2,2-tr ich lor oeth yl)oxy]ca r bo-
n yl]a m in o]p yr r ole (16): yield 1.86 g (94%) from 5.67 mmol of
8; mp 100-103 °C (EtOAc/hexane): 1H NMR (400 MHz, acetone-
d6) δ 2.15 (s, 3H), 4.90 (s, 2H), 5.90 (d, 1H), 6.20 (d, 1H), 7.30
(m, 5H), 9.98 (s, 1H); 13C NMR (75 MHz, acetone-d6) δ 11.3, 75.1,
96.3, 106.0, 107.0, 127.3, 128.2, 129.1, 131.9, 133.2, 134.0, 155.0.
Anal. Calcd for C14H13Cl3N2O2: C, 48.37; H, 3.77; N, 8.06.
Found: C, 48.28; H, 3.67; N, 8.10.
5-Meth yl-2-p h en yl-1-[[[[(2-(tr im eth ylsilyl)eth yl]oxy]ca r -
bon yl]a m in o]p yr r ole (17): yield 1.62 g (90%) from 5.67 mmol
of 8; mp 68-70 °C (EtOAc/hexane); 1H NMR (400 MHz, acetone-
d6) δ 0.05 (s, 9H), 1.05 (t, 2H), 2.18 (s, 3H), 4.25 (t, 2H), 5.85 (d,
1H), 6.10 (d, 1H), 7.30 (m, 5H), 9.30 (s, 1H); 13C NMR (100 MHz,
acetone-d6) δ -1.4, 11.3, 18.2, 64.4, 105.6, 106.7, 127.1, 128.0,
129.0, 132.0, 133.5, 133.9, 156.5. Anal. Calcd for C17H24N2O2-
Si: C, 64.52; H, 7.65; N, 8.86. Found: C, 64.57; H, 7.60; N, 8.86.
2,3-Dip h en yl-5-m eth yl-1-[[[[2-(tr im eth ylsilyl)eth yl]oxy]-
ca r bon yl]a m in o]p yr r ole (18): yield 578 mg (72%) from 2.46
mmol of 9; mp 107-110 °C (EtOAc/hexane); 1H NMR (200 MHz,
acetone-d6) δ 0.05 (s, 9H), 0.95 (t, 2H), 2.21 (s, 3H), 4.20 (t, 2H),
6.15 (s, 1H), 7.20 (m, 10H), 9.21 (s, 1H); 13C NMR (75 MHz,
acetone-d6) δ -1.5, 11.2, 18.1, 64.3, 105.6, 120.7, 126.0, 128.1,
128.4, 128.8, 129.0, 130.9, 131.4, 133.0, 137.4, 156.0. Anal.
Calcd for C13H28N2O2Si: C, 70.37; H, 7.19; N, 7.14. Found: C,
70.39; H, 7.04; N, 7.10.
Sch em e 4
2-(2-F u r a n yl)-5-m eth yl-3-p h en yl-1-[[[2-(tr im eth ylsilyl)-
oxy]ca r bon yl]a m in o]p yr r ole (19): yield 2.02 g (60%) from
8.81 mmol of 10; 1H NMR (200 MHz, acetone-d6) δ 0.05 (s, 9H),
1.05 (t, 2H), 2.25 (s, 3H), 4.25 (t, 2H), 6.15 (d, 1H), 6.38 (d, 1H),
6.50 (d of d, 1H), 7.25 (m, 5H), 7.55 (s, 1H); 13C NMR (100 MHz,
acetone-d6) δ -1.5, 11.2, 18.2, 64.5, 105.7, 110.8, 111.7, 123.6,
126.5, 128.1, 128.4, 128.9, 132.4, 136.9, 143.1, 146.2, 156.3;
HRMS m/ z calcd for C21H27N2O3Si: (M + H)+ 383.1791, found
383.1791. Anal. Calcd for C21H26N2O3Si: C, 65.94; H, 6.85; N,
7.32. Found: C, 65.92; H, 6.69; N, 7.38.
2-Me t h yl-1-[[[[2-(t r im e t h ylsilyl)e t h yl]oxy]ca r b on yl]-
a m in o]p yr r ole (20): yield 180 mg (30%) from 2.50 mmol of 11.
1H NMR (300 MHz, acetone-d6) δ 0.06 (s, 9H), 1.06 (bt, 2H), 2.07
(s, 3H), 4.25 (t, 2H), 5.70 (m, 1H), 5.85 (t, 1H), 6.55 (m, 1H),
9.20 (bs, 1H); 13C NMR (75 MHz, acetone-d6) δ -1.5, 10.7, 18.2,
g, 94%): mp 89.5 °C (ether/hexane); 1H NMR (200 MHz, acetone-
d6) δ 0.06 (s, 9H), 1.06 (t, 2H), 2.04 (s, 6H), 4.26 (t, 2H), 5.60 (s,
2H), 9.04 (bs, 1H); 13C NMR (75 MHz, acetone-d6) δ -1.4, 11.2,
18.2, 64.3, 103.9, 128.4, 156.5. Anal. Calcd for C12H22N2O2Si:
C, 56.65; H, 8.70; N, 11.00. Found: C, 56.81; H, 8.72; N, 11.05.
64.2, 105.3, 106.1, 121.4, 129.6, 150.5. Anal. Calcd for C11H20
-
N2O2Si: C, 55.00; H, 8.33; N, 11.66. Found: C, 54.45; H, 8.56;
N, 11.58.
With Yb (OTf)3 (Meth od B). 2,5-Dim eth yl-1-[[[(2,2,2-
tr ich lor oeth yl)oxy]ca r bon yl]a m in o]p yr r ole (12). To a so-
lution of 2,5-hexanedione (231 mg, 2.02 mmol) in CH2Cl2 (5.0
mL) were added the hydrazide 1 (500 mg, 2.43 mmol) and Yb
(OTf)3 (63 mg, 0.10 mmol). After a period of 18 h at 50 °C, the
resulting mixture was washed with 25% aqueous NH4OAc
solution. The organic layer was dried over Na2SO4 and evapo-
rated under reduced pressure. The residue was purified by flash
chromatography (7.5% EtOAc in hexane) to provide 532 mg of a
Typ ica l P r oced u r e for th e Dep r otection w ith n Bu 4NF
(Meth od E). 1-Am in o-2,5-d ip h en ylp yr r ole (22). To a solu-
tion of the protected 1-aminopyrrole 15 (433 mg, 1.14 mmol) in
THF (6.0 mL) at 0 °C was added a 1 M THF solution of nBu4NF
(2.28 mL). The reaction was warmed to rt and after a period of
5 h, and the reaction mixture was poured into a saturated
solution of NaHCO3. The resulting mixture was extracted with
EtOAc, dried over Na2SO4, and evaporated under reduced
pressure. The residue was purified by flash chromatography
(3% EtOAc in toluene) to yield 221 mg of the title compound
(83%): mp 215-216 °C (DMF); 1H NMR (200 MHz, CDCl3) δ
5.38 (s, 2H), 6.23 (s, 2H), 7.50 (m, 10H); 13C NMR (75 MHz,
CDCl3) δ 106.6, 127.0, 128.4, 128.6, 132.5, 135.2. Anal. Calcd
white solid (92%): mp 114-115 °C (Et2O/hexane); IR (cm-1
)
3325, 2960, 1738; 1H NMR (300 MHz, acetone-d6) δ 2.10 (s, 6H),
4.99 (s, 2H), 5.67 (s, 2H), 9.75 (bs, 1H); 13C NMR (100 MHz,
acetone-d6) δ 11.2, 75.1, 96.6, 104.2, 128.4, 155.0. Anal. Calcd
for C9H11Cl3N2O2: C, 38.02; H, 3.87; N, 9.85. Found: C, 37.85;
H, 3.86; N, 9.72.

Notes
J . Org. Chem., Vol. 61, No. 3, 1996 1183
for C16H14N2: C, 82.02; H, 6.02; N, 11.96. Found: C, 81.63; H,
6.27; N, 11.76.
hexane); 1H NMR (400 MHz, acetone-d6) δ 1.80 (s, 6H), 5.85 (s,
2H), 6.70 (s, 2H), 7.15 (m, 10H); 13C NMR (100 MHz, acetone-
d6) δ 11.2, 106.0, 126.7, 127.6, 128.4, 129.5, 131.9, 135.1. Anal.
Calcd for C22H20N2: C, 84.57; H, 6.46; N, 8.97. Found: C, 84.55;
H, 6.37; N, 9.00.
1-Am in o-2,5-d im eth ylp yr r ole (21): yield 174 mg (81%) from
1
1.96 mmol of 13: mp 48-50 °C (benzene); H NMR (200 MHz,
CDCl3) δ 2.13 (bs, 6H), 4.84 (bs, 2H), 5.49 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 11.51, 102.21, 127.86; HRMS calcd for C6H11N2
(M + H)+ 110.0844, found 110.0844.
1-(5-Meth yl-2-ph en yl-1-pyr r olyl)-2,5-dim eth ylpyr r ole (30):
yield 205 mg (87%) from 0.625 mmol of 23. 1H NMR (200 MHz,
acetone-d6) δ 1.85 (s, 6H), 1.95 (s, 3H), 5.85 (s, 2H), 6.05 (d, 1H),
6.50 (d, 1H), 7.10 (m, 5H); 13C NMR (100 MHz, acetone-d6) δ
10.8, 11.0, 105.5, 106.6, 107.2, 125.5, 126.9, 128.3, 129.3, 132.0,
132.3, 132.7; HRMS m/ z calcd for C17H19N2 (M + H)+ 251.1548,
found 251.1548. Anal. Calcd for C17H18N2: C, 81.56; H, 7.25;
N, 11.19. Found: C, 81.71; H, 7.37; N, 11.16.
1-Am in o-2-m eth yl-5-p h en ylp yr r ole (23): yield 337 mg
(62%) from 3.17 mmol of 17; mp 102-103 °C (EtOAc/hexane);
1H NMR (200 MHz, CDCl3) δ 2.32 (s, 3H), 4.09 (bs, 2H), 5.90 (d,
1H), 6.15 (d, 1H), 7.40 (m, 5H); 13C NMR (100 MHz, CDCl3) δ
11.8, 103.9, 105.3, 126.4, 128.2, 128.3, 130.8, 132.9. Anal. Calcd
for C11H12N2: C, 76.71; H, 7.02; N, 16.27. Found: C, 76.55; H,
6.90; N, 16.20.
1-Am in o-2,3-d ip h en yl-5-m eth ylp yr r ole (24): yield 221 mg
(71%) from 1.25 mmol of 18: mp 134-135 °C (EtOAc/hexane);
1H NMR (200 MHz, CDCl3) δ 2.40 (s, 3H), 3.50 (bs, 2H), 6.10 (s,
1H), 7.30 (m, 10H); 13C NMR (100 MHz, CDCl3) δ 11.7, 103.7,
119.8, 125.1, 127.5, 127.6, 128.1, 128.6, 129.1, 130.1, 131.0, 132.3,
136.5. Anal. Calcd for C17H16N2: C, 82.22; H, 6.49; N, 11.28.
Found: C, 81.89; H, 6.62; N, 11.19.
1-(2,3-Dip h en yl-5-m eth ylp yr r olyl)-2-(2-fu r a n yl)-5-m eth -
yl-3-p h en ylp yr r ole (31): yield 90 mg (82%) from 0.248 mmol
of 24; mp 194-195 °C (EtOAc/hexane); 1H NMR (200 MHz,
acetone-d6) δ 1.95 (s, 3H), 2.38 (s, 3H), 5.87 (d, 1H), 6.12 (s, 1H),
6.35 (d, 1H), 6.41 (d, 1H), 6.51 (s, 1H), 7.30 (m, 10H); 13C NMR
(100 MHz, CDCl3) δ 10.9, 11.0, 105.9, 106.6, 107.2, 111.0, 120.2,
121.1, 122.6, 125.6, 126.1, 127.3, 127.9, 128.0, 128.2, 128.3, 129.2,
129.8, 130.1, 131.2, 135.8, 135.9, 141.5, 145.3. Anal. Calcd for
1-Am in o-2-(2-fu r an yl)-5-m eth yl-3-ph en ylpyr r ole (25): yield
505 mg (74%) from 2.86 mmol of 19. 1H NMR (200 MHz, CDCl3)
δ 2.30 (s, 3H), 4.55 (s, 2H), 6.02 (s, 1H), 6.29 (d, 1H), 6.45 (d of
d, 1H), 7.20 (m, 5H), 7.50 (d, 1H); 13C NMR (100 MHz, CDCl3)
δ 11.2, 104.2, 110.3, 111.0, 119.0, 123.0, 125.8, 127.6, 128.2,
131.8, 136.2, 142.3, 146.0; HRMS m/ z calcd for C15H15N2O (M
+ H)+ 239.1185, found 239.1184. Anal. Calcd for C15H14N2O:
C, 75.61; H, 5.92; N, 11.76. Found: C, 75.40; H, 6.02; N, 11.32.
1-Am in o-2-m et h ylp yr r ole (26): yield 204 mg (80%) from
2.66 mmol of 20. 1H NMR (300 MHz, CDCl3) δ 2.25 (s, 3H),
4.50 (bs, 2H), 5.75 (m, 1H), 5.95 (m, 1H), 6.63 (m, 1H). 13C NMR
(75 MHz, CDCl3) δ 11.1, 104.2, 104.6, 121.0, 129.0; HRMS m/ z
calcd for C5H8N2 (M + H)+ 97.0766, found 97.0766.
1-(2-F u r a n yl)-2-p h en yl-1,5-p en ta n ed ion e (10). The title
compound was obtained in 30% yield using the Stetter con-
densation: 1H NMR (200 MHz, acetone-d6) δ 2.15 (s, 3H), 2.85
(d of d, 1H), 3.55 (d of d, 1H), 4.90 (d of d, 1H), 6.60 (d, 1H), 7.30
(m, 6H), 7.88 (d, 1H); 13C NMR (100 MHz, acetone-d6) δ 29.3,
47.1, 49.0, 112.8, 118.6, 127.8, 128.8, 129.4, 129.8, 139.3, 147.6,
152.9, 187.6; HRMS m/ z calcd for C18H15O3 (M + H)+ 243.1022,
found 243.1021.
C
31H26N2O: C, 84.13; H, 5.92; N, 6.33. Found: C, 84.30; H, 5.87;
N, 6.02.
P r ep a r a tion of Hyd r a zon e (33). To a solution of the
1-aminopyrrole (25) (280 mg, 1.17 mmol) in benzene (5.6 mL)
at rt was added 1-methyl-4-piperidone (173 µL, 1.40 mmol)
followed by PTSA (23 mg, 0.01 mmol). The reaction mixture
was brought to reflux under
a nitrogen atmosphere with
magnetic stirring. After 36 h the reaction was quenched by a
saturated aqueous solution of NaHCO3, and extracted into ethyl
acetate. The combined organic layers were dried over Na2SO4,
and the solvent was removed by rotary evaporation. The crude
hydrazone 33 was purified by flash chromatography (5% metha-
nol in CH2Cl2), to give 0.313 g (84%) of 33 as a brown oil: 1H
NMR (200 MHz, acetone-d6) δ 2.15 (m, 8H), 2.31 (s, 3H), 2.65
(bs, 3H), 6.11 (s, 1H), 6.20 (d, 1H), 6.39 (d of d, 1H), 7.25 (m,
5H), 7.39 (d, 1H); 13C NMR (100 MHz, acetone-d6) δ 11.6, 30.6,
35.1, 55.2, 56.2, 105.6, 110.7, 111.7, 116.0, 123.3, 126.1, 127.2,
128.1, 128.8, 137.4, 142.7, 147.0; HRMS m/ z calcd for C21H24N3O
(M + H)+ 334.1919, found 334.1919.
1-Meth yl-4-(2-(2-fu r a n yl)-5-m eth yl-3-p h en yl-1-p yr r olyl)-
a m in op ip er id in e (34). To a solution of the hydrazone (33)
(0.250 mg, 0.783 mmol), in isopropyl alcohol (15 mL) was added
NaBH4 (400 mg, 10 mmol). The reaction mixture was brought
to reflux under a nitrogen atmosphere with magnetic stirring.
After 72 h, the solvent was removed by rotary evaporation, and
the residue was stirred in H2O and then extracted with ethyl
acetate. The organic layers were combined and dried over Na2-
SO4. Solvent was removed by rotary evaporation, and the crude
(pyrrolylamino)piperidine 34 was purified by flash chromatog-
raphy (25% methanol in acetone) to give 0.174 g (69%) of 33 as
a white solid: 1H NMR (200 MHz, acetone-d6) δ 1.55 (bs, 4H),
2.35 (s, 3H), 2.37 (s, 3H), 2.80 (bs, 4H), 5.57 (s, 1H), 6.02 (s, 1H),
6.48 (d, 1H), 6.52 (d, 1H), 71.20 (m, 5H), 7.61 (d, 1H); 13C NMR
(100 MHz, CDCl3) δ 11.8, 28.9, 45.0, 52.5, 56.0, 104.3, 104.5,
111.2, 117.6, 123.3, 125.7, 127.5, 128.1, 132.0, 135.9, 141.8;
HRMS m/ z calcd for C21H26N30 (M + H)+ 336.2076, found
336.2075.
Bish yd r a zon e 27. To a stirred solution of 2,5-hexanedione
(200 mg, 1.75 mmol) in toluene (10.0 mL) at room temperature
was added the hydrazide 2 (678 mg, 3.86 mmol). After a period
of 1 h, the white precipitate was filtered to provide 599 mg (80%)
of the title compound: mp 147-149 °C; 1H NMR (200 MHz,
acetone-d6) 0.05 (s, 18H), 0.95 (t, 4H), 1.80 (s, 6H), 2.35 (s, 4H),
4.15 (t, 4H), 9.59 (s, 2H); 13C NMR (100 MHz, DMSO-d6) δ -1.4,
16.1, 17.4, 35.2, 62.2, 153.3, 154.3; HRMS m/ z calcd for
C
18H39N4O4Si2 (M + H)+ 431.2510, found 431.2510. Anal. Calcd
for C18H38N4O4Si2: C, 50.20; H, 8.89; N, 13.01. Found: C, 50.22;
H, 8.60; N, 13.07.
Typ ica l P r oced u r e for th e P r ep a r a tion of 1,1′-Bisp yr -
r oles. 1-(5-Meth yl-2-p h en yl-1-p yr r olyl)-2,5-d ip h en ylp yr -
r ole (29). To a solution of 1-aminopyrrole 23 (108 mg, 0.625
mmol) in toluene (8.0 mL) was added, 1,2-dibenzoylethane (164
mg, 0.688 mmol) and PTSA (6 mg, 0.03 mmol). After a period
of 5 h at 60 °C, the reaction mixture was quenched by the
addition of saturated aqueous solution of NaHCO3 and extracted
with EtOAc. The combined organic layers were dried over Na2-
SO4, and the solvent was removed under reduced pressure. The
resulting crude 1,1′-bispyrrole was purified by flash chromatog-
raphy (5% EtOAc in hexane, to yield 205 mg (88%) of the title
compound: mp 122-123 °C (DMF); 1H NMR (200 MHz, acetone-
d6) δ 1.85 (s, 3H), 6.08 (d, 1H), 6.48 (d, 1H), 6.70 (s, 2H), 7.05
(m, 15H); 13C NMR (100 MHz, acetone-d6) δ 11.2, 107.3, 107.8,
108.9, 126.0, 126.9, 127.2, 127.8, 129.2, 129.3, 131.5, 131.8, 132.2,
133.0, 135.10. Anal. Calcd for C27H22N2: C, 86.59; H, 5.93; N,
7.48. Found: C, 86.55; H, 5.84; N, 7.50.
Ack n ow led gm en t. The authors would like to thank
Professor B. Trost for helpful discussions.
1
Su p p or tin g In for m a tion Ava ila ble: Copies of H NMR
spectra are available for compounds 10, 26, 33, and 34 (4
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
1-(2,5-Dim eth yl-1-pyr r olyl)-2,5-diph en ylpyr r ole (28): yield
60 mg (85%) from 0.223 mmol of 22; mp 119-120 °C (EtOAc/
J O9518260