3H-pyrroles, alkylidene-pyrrolines and functionalized pyrrolidines by radical cyclization of β-allenyliminyl radicals

Article abstract of DOI:10.1002/1099-0690(200103)2001:5<941::AID-EJOC941>3.0.CO;2-E

In this work, we show that the tin hydride-mediated reaction of allene-tethered dithiosemicarbazides 4 is a convenient method for the preparation of five-membered unsaturated nitrogen heterocycles. The sulfur-directed intermolecular attack of the tin radical at the semicarbazide moiety leads to an allene-tethered iminyl radical, which then undergoes a 5-exo-dig cyclization leading to both the 3H-pyrroles 5 and the alkylidene pyrrolines 6; thermal isomerization of 5 to 6 occurs in some cases.

Full text of DOI:10.1002/1099-0690(200103)2001:5<941::AID-EJOC941>3.0.CO;2-E

FULL PAPER
3H-Pyrroles, Alkylidene-Pyrrolines and Functionalized Pyrrolidines by Radical
Cyclization of β-Allenyliminyl Radicals
[a]
[a]
[a]
¨
Michael Depature, Jacques Grimaldi, and Jacques Hatem*
Keywords: Radicals / Cyclizations / Nitrogen heterocycles / Allenes / Reductions
In this work, we show that the tin hydride-mediated reaction
of allene-tethered dithiosemicarbazides 4 is a convenient
method for the preparation of five-membered unsaturated ni-
an allene-tethered iminyl radical, which then undergoes a 5-
exo-dig cyclization leading to both the 3H-pyrroles 5 and the
alkylidene pyrrolines 6; thermal isomerization of 5 to 6 occurs
trogen heterocycles. The sulfur-directed intermolecular at- in some cases.
tack of the tin radical at the semicarbazide moiety leads to
Introduction
We have been interested in the free radical cyclization of
functionalized β-allenic compounds for several years.[1] Re-
cently, we tried to obtain nitrogen heterocycles from the tin
hydride-mediated free radical cyclization of allene-tethered
benzoyloximes. As already reported,[2] this pathway allowed
us to produce highly unsaturated nitrogen heterocycles in
fairly good yield but only with strongly hindered allenic
precursors. In fact, in this case, six-membered heterocycles
and five-membered heterocycles have been obtained as a
mixture. The former result from the addition of the stannyl
radical onto the sp carbon atom, followed by 6-endo cyc-
lization of the so-formed allyl radical onto the N-atom of
the CϭN bond (Scheme 1, path A). The latter result from
the addition of the stannyl radical onto the O-atom of the
CϭO bond followed by 5-exo cyclization of the so-formed
iminyl radical onto the sp carbon atom (Scheme 1, path B).
With allenic precursors that are not too strongly hindered,
only five-membered carbocycles were obtained. These result
from the addition of the stannyl radical onto the sp carbon
atom followed by 5-exo cyclization of the so-formed allyl
radical onto the C-atom of the CϭN bond (Scheme 1,
path A).
To produce only five-membered heterocycles, we decided
to use more stannophilic precursors of the iminyl radical
to avoid the competitive addition onto the allenyl moiety.
Recently, using the high thiophilicity of stannyl radicals,
Zard and co-workers have shown that dithiosemicarbazide
derivatives can produce iminyl radicals.[3]
Scheme 1. Reaction of β-allenylbenzoyloximes
ides, and we show the efficiency of this method for building
five-membered unsaturated nitrogen heterocycles.
Results and Discussion
Synthesis of the Radical Precursors 4
The β-allenylaldehydes 1 and β-allenylketones 2 were pre-
pared according to our previous paper.[2] The correspond-
ing allene-tethered dithiosemicarbazides 4 were obtained in
good to excellent yields by condensation of the hydrazine
3[4] onto 1 or 2 (Scheme 2). The bulkier R3 the higher the
difficulty of condensation (see Experimental Section).
Here, we describe the results obtained in the tin-mediated
free radical cyclization of allene-tethered dithiosemicarbaz-
[a]
´
´
`
Especes
Laboratoire
Structure
et
Reactivite
des
´
Paramagnetiques, CNRS UMR 6517: Chimie Biologie et
´
Radicaux Libres, Universite Aix-Marseille I et III,
Avenue Escadrille Normandie-Niemen (boıte 541), 13397
ˆ
Marseille Cedex 20, France
Fax: (internat.) ϩ33-4/9198-8512
Reaction of nBu3SnH with the Radical Precursors 4
E-mail: hatem@srepir1.univ-mrs.fr
Supporting information for this article is available on the
WWW under http://www.wiley-vch.de/home/eurjoc or from
the author.
In all cases, the starting material disappeared after five
hours when refluxed in cyclohexane with Bu3SnH (1.2
Eur. J. Org. Chem. 2001, 941Ϫ946
WILEY-VCH Verlag GmbH, 69451 Weinheim, 2001
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941

M. Depature, J. Grimaldi, J. Hatem
Table 1. Tin hydride reaction of radical precursors 4
FULL PAPER
Ratio
4
Yield
5
6
7
a
b
c
d
e
f
-
not isolated
-
6b mainly formed[a]
-
-
not isolated
not isolated
85%[b]
71%[b]
79%[b]
85%[b]
70%[d]
83%[d]
75%[d]
71%[d]
70[c]
39[c]
45[c]
53[c]
66
30[d]
54[d]
55[d]
47[d]
34
0
7[c]
0
g
h
i
0
0
j
k
l
41[c]
58
56
3[c]
0
42
58
42
0
[a]
On the basis of 1H and 13C NMR spectroscopy of the crude
[b]
reaction mixture. Ϫ
Yield obtained by SammesЈ method (see
[c]
main text). Ϫ Determined on the basis of integration of the sig-
1
[d]
nals in the H NMR spectrum. Ϫ Yield obtained by chromato-
graphy through silica gel (see main text).
Scheme 2. Synthesis of radical precursors 4
equiv.) and AIBN (0.2 equiv.); only the products resulting
from the formation of the iminyl radical were obtained
(Scheme 3). These products were the 3H-pyrroles 5, the al-
kylidenepyrrolines 6 and, in some cases and in a very small
quantity, the dimers 7. No product resulting from the addi-
tion of the stannyl radical onto the allenyl moiety was de-
tected.
Scheme 4. Hydrolysis of 3H-pyrroles 5 and alkylidenepyrrolines 6
Sammes and co-workers have already reported a similar
behaviour for 3H-pyrroles and alkylidenepyrrolines.[5] To
avoid this hydrolysis, they extracted the reaction mixture
with an aqueous solution of hydrochloric acid. Then, they
basified the aqueous layer and extracted it with diethyl
ether to finally obtain pure 3H-pyrroles. In our case, this
method gave a mixture of 6b and the hydroxypyrroline 9b
resulting from partial hydrolysis of 6b. When this mixture
was refluxed in CH2Cl2 with SiO2 and few drops of water,
compound 8b was formed. Since we were unable to isolate
Scheme 3. Products of tin hydride reaction of radical precursors 4
Table 1 shows the efficiency of the method for the syn- product 6b, we did not attempt to isolate directly the prod-
thesis of unsaturated five-membered heterocycles, although ucts resulting from the cyclization of precursors 4a؊d. Con-
the identification and the purification of the products ob- sequently, to show the formation of nitrogen heterocycles,
tained still need some comments. When R3 ϭ H (4aϪd), we decided to reduce the products of cyclization in situ and
products 5, 6, and 7 were not isolated directly. For example, to protect the pyrrolidines so-obtained by benzoyl chloride.
starting from 4b, after solvent removal, the NMR analysis This method will be described later in this paper.
of the crude mixture showed that the major product was
When R3 ϭ Me (4e؊h) we were also unable to separate
6b. In fact, no signal of a vinylic proton corresponding to the products of the reaction by silica gel or alumina chro-
1
5b was detected by H NMR spectroscopy. On the other matography. Thus, starting from 4f, the silica gel purifica-
hand, the 13C NMR spectrum shows two signals, one at tion of the reaction mixture gave the corresponding dike-
δ ϭ 174.5 and the other at δ ϭ 40.2, both characteristic tone 8f. But, unlike the precursors 4a؊d, the products of
of the CHϭN and CH2 carbon atoms of compound 6b, the reaction were stable enough to be separated from the
respectively. The purification of the crude mixture by silica organotin residues using SammesЈ method. So, a mixture
gel chromatography was ineffective. Thus, we only obtained of 5, 6 and 7 was obtained as a ratio depending on R1 and
the dicarbonylated compound 8b resulting from hydrolysis R2. This ratio was determined on the basis of the integra-
of 6b (Scheme 4)
tion of the 1H NMR spectrum of the mixture. Starting from
942
Eur. J. Org. Chem. 2001, 941Ϫ946

3H-Pyrroles, Alkylidene-Pyrrolines and Functionalized Pyrrolidines
FULL PAPER
4e and 4g, the products 6e and 6g were obtained as a 1:1
mixture of Z and E isomers. On the other hand, we ob-
served that under heating, the 3H-pyrroles 5e؊h were prone
to isomerize into their corresponding alkylidenepyrrolines
6e؊h. In fact, when the mixtures of 5e؊h, 6e؊h, and 7e؊h
were refluxed in cyclohexane under argon for 48 hours, the
sole products 6e؊h and 7e؊h were obtained. As in the case
of precursors 4a؊d, all the compounds formed by cycliza-
tion of precursors 4e؊h were also reduced into their corres-
ponding pyrrolidines and then protected by benzoyl chlor-
ide to permit characterization.
When R3 ϭ Ph (4i؊l), the products of the reaction were
stable enough to be separated by silica gel chromatography.
Starting from the precursor 4j, separation of 6j and 7j was
unsuccessful, so their relative population was determined
by NMR spectroscopy. Compounds 6i and 6k were also
obtained as a 1:1 mixture of Z and E isomers. Unlike in the
case of 5eϪh (R3 ϭ Me), the 3H-pyrroles 5i؊l (R3 ϭ Ph)
were not prone to thermal isomerization.
Scheme 5. In situ reduction and protection of 5a؊h and 6a؊h
Discussion
Finally, compounds 4a؊l are good precursors of the
highly unsaturated nitrogen heterocycles 5 and 6, which
have been obtained in high yield via β-allenyliminyl rad-
icals. Nevertheless, starting from the precursors 4a؊h (R3 ϭ
H, Me), the facile hydrolysis of the cyclized compounds led
us to keep them as reduced products.
Cyclisation of β-Allenyliminyl Radicals
Starting from the precursors 4a؊l, the tributyltin hydride
reduction selectively leads to an iminyl radical which then
undergoes an intramolecular addition to the allenyl moiety.
We now consider the mechanism of this cyclization. As only
five-membered heterocycles were obtained, this means that
the radical attacked the sp carbon atom of the allene. Start-
ing from here, two cyclization modes are possible to explain
the formation of 5 and 6: a 5-exo-dig cyclization or a 5-
endo-dig cyclization. Following BaldwinЈs rules[8] on cycliza-
tion onto sp carbon atoms, both these modes of cyclization
are stereoelectronically favoured. An EPR study of iminyl
radicals has already been reported.[9] The results are con-
sistent with a radical in which the unpaired electron occu-
pies a 2p orbital on nitrogen orthogonal to the CϭN π-
system. If we consider the particular geometry of our all-
enic compounds, the best overlap of the orbital containing
the unpaired electron is obtained with the π* orbital of the
distal double bond of the allenyl moiety (Scheme 6).
Reduction and Protection of 3H-Pyrroles 5a؊h and
Alkylidenepyrrolines 6a؊h
Due to the lack of direct and precise characterization of
products 5a؊h and 6a؊h, we developed an indirect method
to validate our results. For this purpose, we chose to reduce
the cyclization products in situ and then to protect the ob-
tained pyrrolidines with benzoyl chloride, the compounds
so-formed being stable enough to be purified. To this end,
a reduction method was required that can reduce both im-
ine and enamine in nonnucleophilic solvents to permit their
subsequent protection by benzoyl chloride. On one hand,
imine and iminium salts can be easily reduced by metallic
hydrides such as LiAlH4 or NaBH4 and derivatives of
NaBH4.[6] On the other hand, enamines are normally resist-
ant to reduction by metal hydrides. However, the fast and
reversible protonation of the carbon atom in acidic media
permits the generation of an iminium salt that can be at-
tacked by an hydride that supports acidic conditions.[7]
Thus, in our case, the reduction was performed with NaBH4
and benzoic acid. Starting from precursors 4a؊h, we ob-
tained directly, in a one-pot reaction, compounds 10a؊h
with excellent yields (Scheme 5), except in the case of 10a.
Product 10c was obtained as an equimolar mixture of
two diastereoisomers. In the case of precursors 4e؊g, the
reduction gave only the corresponding products 10e؊g of
cis relative configuration. The product 10g was obtained as
an equimolar mixture of two diastereoisomers. For com-
pound 10h, we obtained a mixture of two stereoisomers (cis
and trans) in an approximate 9:1 ratio determined on the
basis of 13C NMR integration.
Scheme 6. Radical cyclization of β-allenyliminyl radicals
Eur. J. Org. Chem. 2001, 941Ϫ946
943

M. Depature, J. Grimaldi, J. Hatem
FULL PAPER
General Remarks: Melting points are uncorrected. Ϫ 1H and 13C
NMR spectra were performed in CDCl3 or C6D6 with tetramethyl-
silane as internal reference, and recorded with Bruker AC 100,
Bruker AC 200 and AMX 400 spectrometers. Ϫ Merk silica gel 60
(230Ϫ400 mesh) was used for column chromatography. Ϫ Solvents
and reagents were purified according to standard laboratory tech-
niques. Ϫ Abbreviation used: AIBN ϭ 2,2Ј-azobis(2-methylpro-
pionitrile).
Consequently, the 5-exo-dig cyclization process is
strongly favoured over the 5-endo-dig one. The allylic rad-
ical 11 so formed then induces the formation of 5 and 6 by
hydrogen atom abstraction from Bu3SnH and the formation
of 7 by a radical dimerisation.
Thermal Isomerization of 3H-Pyrroles 5
In our conditions, only the 3H-pyrroles 5eϪh (R3 ϭ Me)
isomerize to alkylidenepyrrolines 6eϪh. Hydrogen migra-
tion is obviously implied in such a transformation. Since
isomerization has not been observed when R3 ϭ Ph (5eϪh),
it seems that a hydrogen from the methyl group is also in-
volved in the process. Since a 1,5-sigmatropic hydrogen shift
is unlikely in such a structure,[10] we assume that a sequence
of imineϪenamine tautomer equilibrium is present in this
isomerization.[11]
Preparation of Precursors 4a؊d: β-Allenylaldehyde 1 (10 mmol)
and the hydrazine 3 (10 mmol) were dissolved in 20 mL of meth-
anol with 1 g of anhydrous Na2SO4. The mixture was refluxed for
six hours under argon. After cooling, the mixture was filtered and
the solvent concentrated under reduced pressure giving crude pre-
cursors 4a؊d. Compound 4a was purified by silica-gel column
chromatography (eluent: Et2O/pentane) whereas compounds 4b؊d
were recrystallized from pentane.
Methyl
2-(2,2,5-Trimethyl-3,4-hexadienylidene)-1-methylhydra-
zinecarbodithioate (4b): 87% yield, white crystals, m.p. 66Ϫ68 °C.
Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 1.26 [s, 6 H, C(CH3)2], 1.70
Preparation of Amides 10a؊h by Reduction and
Benzoylation from 5a؊h and 6a؊h
1
[d, J ϭ 2.9 Hz, 6 H, (CH3)2CϭC], 2.52 (s, 3 H, SCH3), 3.78 (s, 3
H, NCH3), 5.01 (m, J ϭ 2.9 Hz, 1 H, CHϭC), 7.12 (s, 1 H, CHN)
With respect to the amides 10b؊d, the excellent yields
obtained by this method allowed us to confirm that the
products resulting from the 5-exo cyclization of the iminyl
radical onto the allenyl moiety are formed quasi-quantitat-
ively. We have no explanation concerning the low yield of
product 10a. In the case of products 10e؊h, the yield is also
very high, but the higher steric hindrance makes the 1H
NMR and 13C NMR signals broader at 298 K due to the
higher barrier of rotation for the aromatic amides 10e؊h
than for the amides 10a؊d.[12]
Ϫ
13C NMR (CDCl3, 50 MHz): δ ϭ 19.6 (CH3), 20.7 (CH3), 25.8
(CH3), 35.3 (CH3), 40.1 [C(CH3)2], 96.4 (CϭCϭCH), 97.9 (CϭCϭ
CH), 151.9 (CHN), 200.5 (C), 202.6 (C). Ϫ C12H20N2S2 (256.4):
calcd. C 56.21, H 7.86, N 10.92; found C 55.69, H 7.86, N 10.88.
Preparation of precursors 4e؊l: Ketone 2 (10 mmol) and hydrazine
3 (15 mmol) were dissolved in 30 mL of anhydrous toluene with
˚
1 mmol of para-toluenesulfonic acid and three grams of 4 A mo-
lecular sieves. The mixture was refluxed for 16 hours under argon.
After cooling, the mixture was filtered over celite and the solvent
Consequently, in the case of 10e؊h, the NMR experi- concentrated under reduced pressure. The precursors 4e؊l were
purified by silica-gel column chromatography (eluent: Et2O/pent-
ane).
ments were performed in deuterated benzene at 325 K with
a 100 MHz apparatus. For 10e؊g, NOESY experiments
showed that the only stereoisomers formed were of a cis
relative configuration. For 10h, a 1:9 mixture of trans and
cis isomers was obtained. Indeed, it is known that the steric
hindrance of acyloxiboranes often makes the reduction of
cyclic enamines stereoselective, the hydride approach taking
place from the less-hindered side of the molecule.[13]
Methyl 2-(1,2,2,5-Tetramethyl-3,4-hexadienylidene)-1-methylhydra-
1
zinecarbodithioate (4f): 81% yield, yellow oil. Ϫ H NMR (CDCl3,
200 MHz): δ ϭ 1.33 [s, 6 H, C(CH3)2], 1.73 [d, J ϭ 2.9 Hz, 6 H,
(CH3)2CϭC], 1.89 (s, 3 H, CH3CϭN), 2.55 (s, 3 H, SCH3), 3.58 (s,
3 H, NCH3), 5.03 (m, J ϭ 2.9 Hz, 1 H, CHϭC). Ϫ 13C NMR
(CDCl3, 50 MHz): δ ϭ 15.5 (CH3), 19.2 (CH3), 20.4 (CH3), 25.6
(CH3), 42.3 (CH3), 44.0 [C(CH3)2], 96.0 (CϭCϭCH), 98.6 (CϭCϭ
CH), 185.5 (CϭN), 192.1 (C), 200.9 (C). Ϫ C13H22N2S2 (270.4):
calcd. C 57.73, H 8.20, N 10.36; found C 57.64, H 8.16, N 10.26.
Conclusion
Methyl 2-(2,2,5-Trimethyl-1-phenyl-3,4-hexadienylidene)-1-methyl-
hydrazinecarbodithioate (4j): 87% yield, pale yellow oil. Ϫ 1H NMR
(CDCl3, 200 MHz): δ ϭ 1.37 [s, 6 H, C(CH3)2], 1.67 [d, J ϭ 2.8 Hz,
6 H, (CH3)2CϭC], 2.62 (s, 3 H, SCH3), 3.13 (s, 3 H, NCH3), 5.16
(m, J ϭ 2.8 Hz, 1 H, CHϭC). 7.19Ϫ7.23 (m, 2 H, Ph), 7.36Ϫ7.41
(m, 3 H, Ph). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 19.4 (CH3), 20.2
(CH3), 26.5 (CH3), 43.4 (CH3), 44.3 [C(CH3)2], 96.5 (CϭCϭCH),
98.8 (CϭCϭCH), 126.6 128.2 and 129.2 (CH, Ph), 135.0 (C, Ph),
181.1 (CϭN), 194.8 (C), 201.3 (C). Ϫ C18H24N2S2 (332.5): calcd.
C 65.02, H 7.28, N 8.42; found C 64.95, H 7.27, N 8.34.
In summary, we have shown in this work that upon treat-
ment with tributyltin hydride, a wide range of allene-
tethered dithiosemicarbazides selectively lead to highly un-
saturated five-membered nitrogen heterocycles in good
yields. Depending on the substitution pattern of these allen-
yldithiosemicarbazides, the 3H-pyrroles 5 and the alkylid-
enepyrrolines 6 so obtained are either stable enough to be
separated or are hydrolyzed. In this latter case the heterocy-
cle can be preserved by reduction to the pyrrolidines 10.
The behaviour of these allene-tethered dithiosemicarbazides
towards the tributyltin radical contrasts with that of the
allenylbenzoyloximes which we had early studied.[2]
General Procedure for the Cyclization of Precursors 4a؊l: Bu3SnH
(1.2 equiv.) and AIBN (0.2 equiv.) were added to a cyclohexane
solution (0.02 ) of the compounds 4a؊l. After this solution was
degassed with a stream of argon, the mixture was heated under
reflux and monitored by TLC until the starting material had disap-
peared (approximately five hours). Then, the mixture was worked-
up differently according to the nature of the precursors 4a؊l (see
main text).
Experimental Section
We present only selected data here. A complete Experimental Sec-
tion is available as Supporting Information.
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3H-Pyrroles, Alkylidene-Pyrrolines and Functionalized Pyrrolidines
FULL PAPER
General Procedure for the Extraction of Nitrogen Heterocycles: The
mixture previously obtained was extracted twice with 5 mL of a
3.5% aqueous solution of HCl. The acidic aqueous layer was then
basified with an aqueous saturated Na2CO3 solution and extracted
with Et2O. The organic layer was dried with MgSO4 and concen-
trated under reduced pressure giving a mixture of 5, 6, and 7.
Isolation of Nitrogen Heterocycles Obtained from 4i؊l: The nitro-
gen heterocycles obtained from 4i؊l were purified by silica-gel
chromatography (eluent: Et2O/pentane). Products 5j؊l and 6j؊l
have already been described in our preceding paper.[2] Compound
4i gave a mixture of 5i and 6i.
5-Ethyl-3,3-dimethyl-2-phenyl-3H-pyrrole (5i): 46% yield, colourless
1
Extraction of the mixture obtained from 4b gave a mixture of 6b
(in a very small quantity, compound not described) and 9b.
oil. Ϫ H NMR (CDCl3, 200 MHz): δ ϭ 1.23 (t, J ϭ 7.4 Hz, 3 H,
CH3CH2), 1.40 [s, 6 H, (CH3)2], 2.57 (qd, J ϭ 7.4 Hz and 1.7 Hz,
2 H, CH3CH2), 5.76 (t, J ϭ 1.7 Hz, 1 H, CH), 7.39Ϫ7.43 (m, 3 H,
Ph), 7.95Ϫ8.00 (m, 2 H, Ph). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ
12.0 (CH3), 22.9 (CH3), 23.8 (CH2), 56.0 [C(CH3)2], 127.8 128.4
129.8 and 130.3 (CH, Ph and CHϭC), 133.4 (C, Ph), 155.3 (CϪN),
183.3 (CϭN). Ϫ C14H17N (199.2): calcd. C 84.37, H 8.60, N 7.03;
found C 83.97, H 8.48, N 6.87.
3,4-Dihydro-5-hydroxy-2-isopropyl-4,4-dimethyl-2H-pyrrole (9b): 1H
NMR (CDCl3, 200 MHz): δ ϭ 0.94 (s, 3 H, CH3), 1.07 [d, J ϭ
7.0 Hz, 6 H, (CH3)2CH], 1.08 (s, 3 H, CH3), 2.20 and 2.38 (syst.
AB, JHH ϭ 16.9 Hz, 2 H), 2.53 [sept, J ϭ 7.0 Hz, 1 H, (CH3)2CH],
5.01 (s, 1 H, CHOH). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 19.6
and 21.4 [C(CH3)2], 25.9 and 26.2 [(CH3)2CH], 32.8 [(CH3)2CH],
41.9 [C(CH3)2], 48.8 (CH2), 99.9 (CHOH), 183.9 (CϭN).
2-Ethylidene-3,4-dihydro-4,4-dimethyl-5-phenyl-2H-pyrrole
(6i):
24% yield, colourless oil. Ϫ 1H NMR and 13C NMR spectra of the
1:1 mixture of Z and E isomers. 1H NMR (CDCl3, 200 MHz): δ ϭ
1.43 [s, 6 H, (CH3)2], 1.73 and 1.77 (2m, 3 H, CH3), 2.59 (m, 2 H,
CH2), 5.87 and 5.91 (2m, 1 H, CH), 7.36Ϫ7.40 (m, 3 H, Ph),
7.85Ϫ7.90 (m, 2 H, Ph). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 14.3
(CH3), 27.5 (CH3), 44.0 (CH2), 49.1 [C(CH3)2], 115.5 (CHϭCϪN),
128.3 and 129.9 (CH, Ph), 134.2 (C, Ph), 154.5 (CϪN), 180.1
(CϭN).
Hydrolysis of the Mixture of 6b and 9b: The mixture of 6b and 9b,
silica (0.5 g), and three drops of water were refluxed for 16 hours
in 10 mL of CH2Cl2. After filtration, the solvent was dried with
MgSO4 and concentrated under reduced pressure giving 8b.
3,3,5-Trimethyl-4-oxohexanal (8b): Colourless oil. Ϫ 1H NMR
(CDCl3, 200 MHz): δ ϭ 1.07 [d, J ϭ 7.0 Hz, 6 H, (CH3)2CH], 1.11
[s, 6 H, (CH3)2], 2.56 [sept, J ϭ 7.0 Hz, 1 H, (CH3)2CH], 2.76 (s, 2
H, CH2), 9.58 (s, 1 H, CHO). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ
17.9 (CH3), 22.1 (CH3), 40.8 (CH), 43.6 [C(CH3)2], 48.8 (CH2),
204.8 (CHO), 212.4 (CϭO).
Compound 4j gave a mixture of 5j, 6j, and 7j.
3,3-Dimethyl-2-phenyl-5-[1,1,2-trimethyl-2-(3,3-dimethyl-2-phenyl-
3H-pyrrol-5-yl)propyl]-3H-pyrrole (7j): 2.5% yield, obtained as col-
ourless oil in mixture with 5j. Ϫ 1H NMR (CDCl3, 200 MHz): δ ϭ
1.38 [s, 12 H, (CH3)2], 1.39 [s, 12 H, (CH3)2], 5.77 (s, 1 H, CHϭ
C), 7.25Ϫ7.44 (m, 3 H, Ph), 7.90Ϫ8.00 (m, 2 H, Ph). Ϫ 13C NMR
(CDCl3, 50 MHz): δ ϭ 22.8 (CH3), 24.4 (CH3), 41.2 (C), 55.2
[C(CH3)2], 129.3 and 132.2 (CH, Ph and CHϭC), 160.3 (CϪN),
180.2 (CϭN).
Extraction of the Mixture Obtained from 4e؊h: The proportions of
1
products were estimated by H NMR spectroscopy. Compound 4f
gave a 39:54:7 mixture of 5f, 6f, and 7f as a pale yellow oil with an
overall yield of 71%.
5-Isopropyl-2,3,3-trimethyl-3H-pyrrole (5f): 1H NMR (CDCl3,
400 MHz): δ ϭ 1.00 [s, 6 H, (CH3)2], 1.05 [d, J ϭ 6.9 Hz, 6 H,
(CH3)2CH], 1.98 (s, 3 H, CH3), 2.56 [d sept, J ϭ 6.9 Hz and 1.4 Hz,
1 H, (CH3)2CH], 5.48 (d, J ϭ 1.4 Hz, 1 H, CH). Ϫ 13C NMR
(CDCl3, 100 MHz): δ ϭ 14.8 (CH3), 21.0 (CH3), 21.8 (CH3), 29.4
(CH), 55.8 [C(CH3)2], 125.3 (CHϭC), 160.1 (CϪN), 187.7 (CϭN).
General Procedure for the Preparation of Amides 10a؊h by Reduc-
tion and Benzoylation from 5a؊h and 6a؊h: Bu3SnH (1.2 mmol)
and AIBN (0.2 mmol) were added to a 0.02  cyclohexane solution
(50 mL) of the compounds 4a؊h (1 mmol). After this solution was
degassed with a stream of argon, the mixture was heated under
reflux and monitored by TLC until the starting material had disap-
peared (approximately five hours). After cooling, the solvent was
removed under reduced pressure at 25 °C. Then 5 mL of THF were
added, the mixture was cooled at Ϫ20 °C and NaBH4 (75 mg,
4 mmol) was added portionwise. After two hours of stirring at
room temperature, PhCO2H (0.92 g, 7.5 mmol) and 20 mL of
CH2Cl2 were added to the mixture. After one hour of additional
stirring, the mixture was diluted with 40 mL of Et2O and 10 mL of
pyridine, then 1 mL of PhCOCl was added dropwise. The mixture
was stirred for three hours and then 10 mL of water was added.
The mixture was diluted with 80 mL of Et2O and the organic layer
was extracted successively with a saturated aqueous solution of
Na2CO3 to remove PhCO2H and a 5% aqueous solution of CuSO4
to remove pyridine. The solvent was dried with MgSO4 and concen-
trated under reduced pressure. The purification of the residue by
silica-gel chromatography (eluent Et2O/pentane) gave the amides
10a؊h.
3,4-Dihydro-2-isopropylidene-4,4,5-trimethyl-2H-pyrrole (6f): 1H
NMR (CDCl3, 400 MHz): δ ϭ 1.02 [s, 6 H, (CH3)2], 1.55 (m, 3 H,
CH3CϭC), 1.85 (m, 3 H, CH3CϭC), 1.91 (s, 3 H, CH3CϭN), 2.26
(m, 2 H, CH2). Ϫ 13C NMR (CDCl3, 100 MHz): δ ϭ 15.1 (CH3),
19.1 (CH3), 20.5 (CH3), 26.2 (CH3), 42.1 (CH2), 48.8 [C(CH3)2],
119.4 (CϭCϪN), 147.4 (CϪN), 182.0 (CϭN).
2,3,3-Trimethyl-5-[1,1,2-trimethyl-2-(2,3,3-trimethyl-3H-pyrrol-5-
1
yl)propyl]-3H-pyrrole (7f): H NMR (CDCl3, 400 MHz): δ ϭ 0.97
[s, 12 H, (CH3)2], 1.11 [s, 12 H, (CH3)2], 1.95 (s, 6 H, CH3CϭN),
5.47 (s, 1 H, CHϭC). Ϫ 13C NMR (CDCl3, 100 MHz): δ ϭ 14.7
(CH3), 21.6 (CH3), 24.3 (CH3), 41.0 (C), 55.2 [C(CH3)2], 129.1
(CHϭC), 160.5 (CϪN), 184.8 (CϭN).
Hydrolysis of the Mixture of 5f, 6f, and 7f: The mixture of 5f, 6f
and 7f, silica (0.5 g), and three drops of water were refluxed for 16
hours in 10 mL of CH2Cl2. After filtration, the solvent was dried
with MgSO4 and concentrated under reduced pressure giving 8f.
3,3,6-Trimethylheptan-2,5-dione (8f): Colourless oil. Ϫ 1H NMR
(CDCl3, 200 MHz): δ ϭ 1.09 [d, J ϭ 6.9 Hz, 6 H, (CH3)2CH], 1.20 1-Benzoyl-2-isopropyl-4,4-dimethylpyrrolidine (10b): 80% yield,
[s, 6 H, (CH3)2], 2.21 (s, 3 H, CH3CO), 2.57 [sept, J ϭ 6.9 Hz, 1
white crystals, m.p. 85Ϫ86 °C (pentane). Ϫ 1H NMR (CDCl3,
H, (CH3)2CH], 2.80 (s, 2 H, CH2). Ϫ 13C NMR (CDCl3, 50 MHz): 200 MHz): δ ϭ 0.85 (s, 3 H, CH3), 0.87 [d, J ϭ 6.5 Hz, 6 H,
δ ϭ 18.0 (CH3), 23.3 (CH3), 25.0 (CH3), 40.7 (CH), 45.2 [C(CH3)2], (CH3)2CH], 1.00 (s, 3 H, CH3), 1.51Ϫ1.61 (m, 2 H, CH2), 2.52 [m,
50.8 (CH2), 212.8 (CϭO), 213.3 (CϭO). Ϫ C10H18O2 (170.2): calcd. 1 H, (CH3)2CH], 3.10 (m, 2 H, CH2N), 4.26Ϫ4.36 (m, 1 H, CHN),
C 70.55, H 10.66; found C 70.36, H 10.60.
7.33Ϫ7.52 (m, 5 H, Ph). Ϫ 13C NMR (CDCl3, 50 MHz): δ ϭ 15.6
Eur. J. Org. Chem. 2001, 941Ϫ946
945

M. Depature, J. Grimaldi, J. Hatem
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Quiclet-Sire S. Z. Zard, Tetrahedron Lett. 1997, 36, 2463Ϫ2466.
K. A. Jensen, U. Anthoni, A. Holm, Acta Chem. Scand. 1969,
23, 1916Ϫ1934.
(CH3), 19.1 (CH3), 25.5 (CH3), 25.6 (CH3), 28.9 (CH(CH3)2], 38.1
[C(CH3)2], 39.0 (CH2), 61.4 (CHN), 63.9 (CH2N), 127.6 128.2 et
130.1 (CH, Ph), 137.3 (C, Ph), 170.7 (CϭO). Ϫ C16H23NO (245.3):
calcd. C 78.32, H 9.45, N 5.71; found C 78.30, H 9.38, N 5.68.
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[6]
K.-H. Lui, M. P. Sammes, J. Chem. Soc., Perkin Trans. 1
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1-Benzoyl-5-isopropyl-2,3,3-trimethylpyrrolidine (10f): 76% yield,
´
J. Seyden-Penne, Reductions par les Alumino- et Borohydrures
1
`
en Synthese Organique, 1988, Technique et Documentation
colourless oil. Ϫ H NMR (C6D6, 100 MHz, 325 K): δ ϭ 0.67 (s,
(Lavoisier), p. 92.
3 H, CH3), 0.78 (s, 3 H, CH3), 0.84 (d, J ϭ 6.8 Hz, 3 H, CH3CHN),
0.93 [d, J ϭ 6.8 Hz, 6 H, (CH3)2CH], 1.40 (d, J ϭ 8.8 Hz, 2 H,
CH2CHN), 2.11 [oct, J ϭ 6.8 Hz, 1 H, (CH3)2CH], 3.27 (q, J ϭ
6.8 Hz, 1 H, CH3CHN), 4.26 (td, J ϭ 8.8 Hz and 6.8 Hz, CHN),
7.33Ϫ7.52 (m, 5 H, Ph). Ϫ 13C NMR (C6D6, 25 MHz, 325 K): δ ϭ
17.4 (CH3), 17.9 (CH3), 19.8 (CH3), 22.8 (CH3), 27.3 (CH3), 32.2
(CH(CH3)2], 39.0 (CH2), 40.3 [C(CH3)2], 61.4 (CHN), 65.2 (CHN),
126.5 and 128.0 (CH, Ph), 139.5 (C, Ph), 172.0 (CϭO). Ϫ
C17H25NO (259.3): calcd. C 78.72, H 9.71, N 5.40; found C 78.66,
H 9.52, N 4.97.
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G. W. Gribble, C. F. Nutaitis, Org. Prep. and Proced. Int.
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M. Amedjkouh, These de doctorat en chimie organique, Univ.
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946
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