Reduction of electron-deficient pyrroles using group I and II metals in ammonia

Article abstract of DOI:10.1039/a707661d

The preparation and Birch reduction of a series of electron-deficient pyrroles is described. This methodology allows the synthesis of a variety of C-2 substituted 3-pyrrolines in good to excellent yields. The role of various activating groups (amide, ester, carbamate and urea) has been examined with regard to both stability under the Birch conditions and ease of deprotection after reduction. In addition, we discovered that the 3-pyrroline skeleton can be oxidised at C-5 with chromium trioxide-3,5-dimethylpyrazole to form the 3-pyrrolin-2-one nucleus. The identity of the Birch reduced products and also of the oxidised 3-pyrrolin-2-ones has been confirmed by X-ray crystallography on two derivatives.

Full text of DOI:10.1039/a707661d

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Reduction of electron-deficient pyrroles using group I and II metals
in ammonia
Timothy J. Donohoe,* Paul M. Guyo, Roy L. Beddoes† and
Madeleine Helliwell†
Department of Chemistry, The University of Manchester, Oxford Road, Manchester,
UK M13 9PL
The preparation and Birch reduction of a series of electron-deficient pyrroles is described. This
methodology allows the synthesis of a variety of C-2 substituted 3-pyrrolines‡ in good to excellent
yields. The role of various activating groups (amide, ester, carbamate and urea) has been examined with
regard to both stability under the Birch conditions and ease of deprotection after reduction. In addition,
we discovered that the 3-pyrroline skeleton can be oxidised at C-5 with chromium trioxide–3,5-dimethyl-
pyrazole to form the 3-pyrrolin-2-one nucleus. The identity of the Birch reduced products and also of
the oxidised 3-pyrrolin-2-ones has been confirmed by X-ray crystallography on two derivatives.
substituted pyrrolines containing acid sensitive functionality
and in addition, may enable functionalisation of the pyrrole
ring by reductive alkylation procedures.
Introduction
Development of new methods for the synthesis of substituted
pyrroles has been a key element in the field of heterocyclic
chemistry for many years. Extensive study into the reactivity
pattern displayed by pyrrole has shown that it has a great
propensity to act as a nucleophile in addition and substitution
reactions. Correspondingly, chemistry which involves the
pyrrole nucleus acting as an electron acceptor or electrophile is
much less common. This is exemplified with redox chemistry:
the oxidation of pyrroles has been the subject of much interest-
ing and varied work,1 while the reduction of pyrroles remains a
relatively unexplored area.2
As part of a general programme directed towards the stereo-
selective reduction of aromatic heterocycles, we chose to invest-
igate reduction of pyrrole to the pyrroline skeleton. Indeed,
this synthetic transformation is precedented in the literature,
being effected by the combination of a reducing agent (Zn,
NaBH3CN, H3PO2 etc.)3–5 in the presence of acid, so as to
activate the heterocycle (Scheme 1).
The most obvious choice of reduction conditions with
which to accomplish this goal were those developed by Birch
and which have come to bear his name, i.e. (typically) sodium
in liquid ammonia solvent with tert-butyl alcohol added as a
proton source.6 Although this reaction has been utilised
extensively in the field of aromatic chemistry, its use in the
reduction of pyrroles was unknown.7 Consideration of the
basic tenants of the reaction provided us with at least two
good reasons why this might be the case. Firstly, the pyrrole
nucleus is electron-rich (as attested to by its high nucleophil-
icity) and this factor is generally a disadvantage when one is
considering the addition of electrons to the aromatic system.
Secondly, the presence of an acidic hydrogen atom on the
pyrrole nitrogen (pKa ≈ 17) may present the opportunity for
deprotonation under the reducing conditions (by an alkoxide
for example): the resulting anion would be extremely resistant
to further reduction (a similar situation is arrived at if one
attempts the reduction of phenols under Birch conditions).
In order to circumvent such potential pitfalls we decided to
synthesise some electron-deficient and N-protected pyrroles so
as to investigate their reactivity under Birch conditions. Some
of the work described in this paper has been the subject of
preliminary communication and which we now wish to discuss
in detail.8
However, it appeared that a reduction protocol which did not
involve acid as an activator was not known. The development
of such a reaction would be useful in enabling the synthesis of
Zn, HOAc
N
H
N
H
(46%)
Results and discussion
Compound 3 (Scheme 2) was chosen as our first target because
it was easy to prepare and satisfied the criteria defined above:
in addition, placing an electron withdrawing group in the
2-position of the pyrrole should control the regiochemistry of
reduction and also provide an opportunity for reductive alkyl-
ation. Therefore, 3 was prepared from commercially available
2-trichloroacetylpyrrole (1) in two high yielding steps,9 and was
subsequently subjected to a Birch reductive alkylation with
sodium metal in ammonia, quenching with methyl iodide
(Scheme 2). To our delight, we succeeded in isolating pyrroline
H3PO2/HI
COOH
COMe
COOH
N
H
N
H
(65%)
NaCNBH3/TFA
N
N
SO2Ph
SO2Ph
(73%)
1
4 from the reaction mixture in 20–30% yield: the H NMR
spectrum of this compound clearly indicated that a significant
transformation of the aromatic ring had taken place and
Scheme 1
showed two multiplets at 5.8, 5.6 ppm (2H, CH᎐CH) and one at
᎐
† Authors to whom correspondence regarding the X-ray crystallo-
graphy should be addressed.
‡ The ‘3-’ denotes the position of the double bond. They are more
correctly referred to as dihydropyrroles.
3.7 ppm (2H, CH CH᎐CH). In addition a N-methyl resonance
᎐
2
appeared as a singlet at 2.3 ppm and another methyl singlet was
observed at 1.2 ppm. These features, together with 13C NMR,
J. Chem. Soc., Perkin Trans. 1, 1998
667

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Table 1 Birch reduction of 6
N
Entry
RX
R
Yield (%)
Compound
DMF
H
CCl3
N
N
H
N
H
1
2
3
4
5
6
7
MeI
Me
Bn
Allyl
Et
Bu
Bui
H
85
72
71
81
86
79
71
7
8
O
O
BnBr
AllylBr
EtI
1
9
2 (82%)
10
11
12
13
NaH, MeI
BuI
BuiI
NH4Cl
Me
O
2
N
5
N
N
Na (3equiv.) NH3/THF
4 (25–30%)
Me
N
+
ButOH (1equiv.)
O
Me
then MeI (xs) – 78 °C
3 (75%)
H
N
O
Me
5
Scheme 2
infra-red and mass spectra were all consonant with the
proposed structure. Although we had achieved success in this
reaction, we were dismayed to discover that the major product
was in fact the volatile aldehyde 5, which had resulted from
amide reduction rather than pyrrole reduction.10
Unfortunately, the ratio of 4:5 could not be increased despite
attempted reduction under a variety of conditions (which
included variation of co-solvent, proton source and metal).
Presumably, this failure is a consequence of a lack of regio-
selectivity in the site of protonation of the radical-anion result-
ing from the addition of an electron to the aromatic system
(vide infra). It was reasoned that replacing the N-methyl group
with a protecting group that was also capable of withdrawing
electrons would alleviate this problem by promoting reduction
of the aromatic portion of the molecule. Therefore, N-Boc
pyrrole 6 was identified as a suitable substrate for reduction
(Scheme 3). The target pyrrole was synthesised efficiently from
Fig. 1 X-Ray crystal structure of (RS)-7. X-Ray crystallographic
numbering shown.
obtained more easily by quenching the reaction with an
aqueous solution of ammonium chloride (entry 7, Table 1).
The identity of each of the Birch reduced compounds 7–13
was clarified by examination of their spectroscopic data. The
1H NMR spectra of each of the reduced products showed the
presence of two olefinic protons at 5–6 ppm, together with
incorporation of resonances due to the alkyl group of the elec-
trophile. In each case, the position of the double bond was
confirmed by the observation of a 2H multiplet at 4–4.5 ppm
which was assigned to the methylene protons attached to C-5.
All of the reduced compounds exhibited doubling of reson-
i
N
CCl3
N
N
H
82%
H
O
O
1
2
ii 90%
iii
1
ances in their H and 13C NMR spectra, presumably as a con-
R
O
5
2
N
N
See Table 1
sequence of hindered rotation. In each case, the situation was
clarified by performing the data collection in 1,2-dichloro-
benzene at 120–140 ЊC which gave rise to a single set of signals
(albeit somewhat broad). Moreover, each compound gave a
satisfactory mass spectrum and elemental analysis, and com-
pound 7 was further characterised by X-ray crystallography
(Fig. 1).
N
N
O
ButO
O
ButO
O
7–13
6
Scheme 3 Reagents: i, pyrrolidine, DMF; ii, NaH, (Boc)2O; iii, Na
(3 equiv.), NH3/THF then RX (xs) Ϫ78 ЊC
We find the selective reduction of compound 6 particularly
striking and worthy of comment. Firstly, the requirement that
reduction is performed without an alcohol as a proton source is
interesting. This observation leads us to believe that reduction
is occurring via a mechanism which involves the intermediacy
of a dianion (A, Scheme 4), formed by the capture of two elec-
trons by the pyrrole nucleus. This should be basic enough to
deprotonate ammonia thus yielding an enolate.11 Indeed, the
pyrrole 6 is so electron-deficient that reduction occurs in less
than 5 minutes at Ϫ78 ЊC. We made the observation that
pyrrole 2 is a minor by-product (5–15%) in these reactions and
speculate that it arises from nucleophilic attack of sodium
amide (formed in the above mechanism) at the Boc carbonyl
prior to reduction. In support of this, we found that 6 was
1 (via compound 2) and was then reduced under a variety of
conditions. Success was achieved using a reductive alkylation
protocol which did not involve the addition of an alcohol as a
proton source (Scheme 3). Indeed, addition of a THF solution
of 6 to a blue solution of sodium (3 equiv.) in ammonia at
Ϫ78 ЊC resulted in rapid reduction: quenching of the reaction
after 5 minutes with an electrophile dispersed the coloration
and gave the α-alkylated material in good yield (Scheme 3). A
range of primary alkyl halides were used as electrophiles and
each reacted efficiently and regioselectively with the pyrroline
enolate (Table 1). Unfortunately, quenching the reduction with
isopropyl iodide gave only the protonated compound 13, as
a result of an elimination process; this compound could be
668
J. Chem. Soc., Perkin Trans. 1, 1998

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that observed earlier with tert-butyl alcohol present (i.e. alde-
A
2Na+
hyde 5 was the major compound formed). It is therefore more
likely that the success of the Birch reduction of 6 is a con-
sequence of a regioselective protonation of dianion A at C-5
rather than at the carbonyl group. We therefore have to ask why
the dianion derived from 6 (A) should protonate so regio-
selectively while the radical anion (B) (or dianion) derived from
3 does not? In general terms it may be concluded that making
the aromatic ring comparatively electron rich (compound 3)
discourages reduction of that portion of the molecule and
conversely, reducing electron density within it (compound 6)
encourages arene reduction. This trend is in clear agreement
with that observed during the Birch reduction of benzenoid
systems. Assuming kinetic control we suggest that several fac-
tors may be responsible for the regiocontrol displayed by each
radical anion (or dianion), and these would include: the total
charge at each reactive position; the orbital coefficient of
the HOMO of the radical-anion (or dianion) at each reactive
position, and the steric hindrance at each possible site of
protonation. Obviously it is not easy to assess quantitatively the
difference that a change of nitrogen protecting group will have
on each of these parameters and a more exacting explanation
awaits further investigation of this system.
The effect of changing the reactive metal was next examined.
The reductive alkylation of 6→7 was chosen as a representative
example and was performed with three metals: in each case the
reaction profile was identical and the isolated yields of 7 proved
to be rather similar [Na (85%), Ca (75%), Li (71%)]. Clearly, the
particular source of electrons and the nature of the cationic
counterion is relatively unimportant to the success of this
reaction. The success of lithium and calcium may have rami-
fications as far as the practicality of this reaction is concerned,
as they are easier to handle than sodium.
+ 2e
–
N
N
N
N
O
O –
ButO
O
ButO
O
6
NH3
R
O
RX
N
N
N
N
O –
Na+
ButO
O
ButO
O
+
NaNH2
Scheme 4
resistant to Boc cleavage by liquid ammonia alone at Ϫ78 ЊC. In
fact, rapid addition of substrate to the ammonia solution is a
means of minimising (р5%) the appearance of the unwanted
compound 2.
The second point of note regards the absence of aldehyde by-
product in the reduction of 6, which is especially interesting
when compared to the non-selective reduction of 3. It occurs to
us that the reduction of 3 (as outlined in Scheme 2) proceeds via
a more conventional pathway involving addition of an electron
and protonation of the corresponding radical anion (B) by tert-
butyl alcohol (Scheme 5). Addition of a second electron forms
Dialkylamides and isopropyl esters as activating groups for
pyrrole
B
Alternative N-protecting and electron withdrawing groups for
pyrrole were also examined for their stability during the
Birch reduction. Thus, compound 14 was prepared from 2 via
deprotonation and reaction with diethylcarbamoyl chloride
(Scheme 6). This compound was then reduced under conditions
+ e
–
N
N
3
N
N
O
Na+
O –
Na+
Me
Me
ButOH
+ e
ButOH
i
N
N
N
H
91%
N
O
O
Et2N
O
2
14
N
N
H
+ e
N
N
N
ii
85%
O –
O
O
Na+
Me
Me
Me
5
RX
Me
N
N
4
O
Scheme 5
Et2N
O
15
an enolate which awaits reaction with the electrophile. However,
formation of the aldehyde by-product (5) can be explained by
protonation of the radical anion B at the carbonyl group by tert-
butyl alcohol. Subsequent addition of a second electron will
form a hemiaminal species which presumably breaks down to
the aldehyde upon quench and work-up.
Although the contrasting product distributions from reduc-
tion of 3 and 6 could be explained by the operation of two
different mechanisms, we have some evidence that suggests
otherwise. For example, we have performed the reduction of 3
under conditions which do not include addition of an alcohol
(and which should, therefore, promote reaction via a dianion).
This reaction resulted in a product mixture that was similar to
Scheme 6 Reagents: i, NaH, Et2NCOCl; ii, Na (3 equiv.) NH3/THF
then MeI (xs) Ϫ78 ЊC
that had proven to be successful for the N-Boc amide derivative.
Birch reduced urea 15 was obtained as the sole product of the
reaction in high yield. In fact, deprotected pyrrole 2 was not
detected in this reduction at all, presumably because the
N-protecting group (amide) shows greater resistance towards
nucleophilic attack by sodamide.
The success of this reaction illustrates that a variety of elec-
tron withdrawing groups can be tolerated on the pyrrole nitro-
gen. However, this reaction sequence was not pursued further
J. Chem. Soc., Perkin Trans. 1, 1998
669

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because of perceived difficulties in removing the urea group
from the reduced product.
hydrolysed to the corresponding carboxylic acids in excellent
yields by reaction with concentrated HCl (6 ) at reflux (Boc
deprotection occurs first): the amino acids thus formed were
conveniently purified as their N-acetyl derivatives. Migration of
the double bond at C-3 into conjugation with the amine was not
observed. Presumably, under such acidic conditions the amine
functionality is protonated thus disfavouring further proton-
ation of the olefin at C-3 (this is a prerequisite step for olefin
migration under acidic conditions).
We also examined the reduction of N-Boc pyrroles substi-
tuted with an ester at C-2:12 this functionality was chosen
because of the relative ease and selectivity with which the ester
group could be removed after reduction. Ester 16 was prepared
from 2-trichloroacetylpyrrole 1 in three steps and in excellent
overall yield (Scheme 7). Reductive alkylation of 16 under
We also examined the saponification of 17 and 18 with potas-
sium hydroxide and formed the N-Boc amino acids in good
yields (Scheme 8). The advantages of carrying an ester through
the reduction procedure revolve around the relative ease of
deprotection to the acid without removal of the Boc group.
In addition, we coupled acid 22 with pyrrolidine [promoted
by bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl)] to
produce a sample of 7 that was identical with the material that
was produced in the Birch reduction of amide 6 (and whose
identity was confirmed by X-ray crystallography). This corre-
lation confirms the nature of acid 22 and therefore ester 17
unambiguously.
i, ii, iii
CCl3
OPri
N
N
73%
H
O
O
ButO
O
iv
1
16
R
OPri
N
O
ButO
O
Oxidation of the 3-pyrroline skeleton to form substituted 3-
pyrrolin-2-ones
During an attempted recrystallisation of compound 7 from
diethyl ether, we occasionally observed the formation of a new
compound. Chromatography of the mother liquors on silica gel
allowed the isolation of this compound, which was sub-
sequently proven to be the γ-lactam 24 (Scheme 9). Presumably,
17, R = Me (87%)
18, R = Bui (76%)
Scheme 7 Reagents: i, KOH; ii, (COCl)2 then PriOH; iii, NaH,
(BOC)2O; iv, Na (3 equiv.) NH3/THF then RI (xs) Ϫ78 ЊC
standard conditions proceeded without complication and gave
the two α-alkylated derivatives shown in the scheme. The two
electrophiles that were chosen to quench the ester enolate illus-
trate that this activating group is equally useful for the synthesis
of highly substituted pyrrolines as the amide group described
earlier.
R
R
N
N
O
ButO
i
N
N
O
O
ButO
O
O
Although excellent yields of 17 and 18 were obtained from
the reduction, it was discovered that the substrate must be
added rapidly to the reaction mixture: slow addition resulted in
the formation of C-2 amide derivatives of the two pyrrolines.
With the Birch reduced products in hand we next examined
removal of the various activating and protecting groups to
prove the utility of this chemistry in synthesis. For example, the
Boc group could be conveniently removed from the amide
substituted compounds by treatment with trifluoroacetic acid
(19, Scheme 8). In addition, the amide functionality could be
24, R = Me (64%)
25, R = Bui (68%)
Me
O
Me
OPri
OPri
O
ButO
26 (67%)
i
N
N
O
ButO
O
O
17
Scheme 9 Reagents: i, CrO3, 3,5-dimethylpyrazole
R
R
i
N
N
this compound was formed by a free radical chain reaction
involving atmospheric oxygen.13 However, the yield of 24
proved to be rather low and unpredictable and so we sought a
more reproducible method of achieving this oxidation. Eventu-
ally, we discovered that the chromium trioxide–3,5-dimethyl-
pyrazole combination was the most reliable method for effect-
ing this transformation, and gave yields of 64–68% on three
different substrates (Scheme 9).14
N
N
H
84%
O
O
ButO
O
19 R = Me
R
OH
ii, iii
N
O
The nature of the pyrrolin-2-ones (2,5-dihydropyrrol-2-ones)
24, 25 and 26 was determined by examination of the corre-
O
1
20 R = Me (84%)
21 R = Bn (88%)
sponding NMR and IR spectra. In each case, H NMR spec-
troscopy revealed that the two alkene methine resonances were
shifted from δ 5–6 (pyrroline) to δ 6–7 ppm (pyrrolin-2-one).
There was also an absence of the 2H multiplet at 4 ppm which
was previously attributed to the methylene protons at C-5 of the
pyrroline. 13C NMR spectroscopy indicated the presence of
three carbonyl groups and the IR spectrum of 24, 25 and 26
exhibited several bands between 1600–1780 cmϪ1. Compound
24 was further characterised by X-ray crystallography to rule
R
R
OPri
iv
OH
N
N
O
O
ButO
O
17, 18
ButO
O
22, R = Me (71%)
23, R = Bui (76%)
out the possibility that
a rearranged vinylogous amide
(4-pyrrolin-3-one) was present (Fig. 2). We expect that the
synthesis and reactivity pattern displayed by these substrates
will be the basis of future work and that they could hold
Scheme 8 Reagents: i, TFA, DCM; ii, (aq.) HCl; reflux iii, Ac2O, Py
then (aq.) KOH; iv, (aq.) KOH, MeOH
670
J. Chem. Soc., Perkin Trans. 1, 1998

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gen. Petrol refers to the fraction of light petroleum which boils
between 40 and 60 ЊC. All chiral compounds described in the
Experimental are racemic.
2-(Pyrrolidin-1-ylcarbonyl)pyrrole 2
Freshly distilled pyrrolidine (4.4 cm3, 52.0 mmol) was added
dropwise to a solution of the trichloroacetylpyrrole 1 (5 g, 23.6
mmol) dissolved in DMF (15 cm3). After 10 h, water (40 cm3)
was added, followed by 2  HCl (20 cm3). The mixture was then
extracted with EtOAc (3 × 50 cm3), dried (Na2SO4), filtered and
concentrated under reduced pressure to afford the pyrrole
amide 2 (3.17 g, 82%) as an off-white solid; mp 118–119 ЊC;
νmax(film)/cmϪ1 3224, 2974, 2870, 1585, 1453 and 1416; δH(300
MHz; CDCl3) 10.4 (1 H, br s, NH), 6.97–6.91 (1 H, m, ArH),
6.63–6.57 (1 H, m, ArH), 6.30–6.23 (1 H, m, ArH), 3.81–3.61
(4 H, m, 2 × NCH2CH) and 2.08–1.82 (4 H, m, 2 × NCH2CH2);
δC(75 MHz; CDCl3) 160.5, 126.1, 121.1, 112.0, 109.6, 47.9, 47.0,
26.7 and 24.0; m/z (EI) 164 (Mϩ, 35%), 108 (20), 94 (70) and 70
(100); (C9H12N2O requires 164.0950. Found 164.0954).
2-(Pyrrolidin-1-ylcarbonyl)-N-methylpyrrole 3
A solution of the pyrrole amide 2 (5 g, 30.5 mmol) in THF (10
cm3) was added to NaH (1.46 g, 60.9 mmol) in THF (10 cm3) at
room temperature. After 1 h, methyl iodide (4.75 cm3, 76.3
mmol) was added and the reaction heated at 60 ЊC for 12 h.
After cooling, the reaction mixture was washed with brine and
extracted with EtOAc (3 × 20 cm3) and dried (Na2SO4). Flash
chromatography (eluting with petrol–EtOAc, 5:1) afforded the
N-methylpyrrole 3 (4.1 g, 75%) as a yellow oil; νmax(film)/cmϪ1
2953, 2873, 1612, 1531, and 1433; δH(300 MHz; CDCl3) 6.70–
6.65 (1 H, m, ArH), 6.55–6.48 (1 H, m, ArH), 6.15–6.05 (1 H,
m, ArH), 3.85 (3 H, s, NMe), 3.65 (4 H, br s, 2 × NCH2) and
1.95–1.85 (4 H, m, 2 × NCH2CH2); δC(75 MHz; CDCl3) 162.3,
127.0, 126.5, 113.9, 107.0, 49.8, 46.7, 36.9, 27.0 and 24.6;
m/z (EI) 178 (Mϩ, 100%), 108 (100), 81 (40), and 70 (35);
(C10H14N2O requires 178.1106. Found 178.1101).
Fig. 2 X-Ray crystal structure of (RS)-24. X-Ray crystallographic
numbering shown.
promise as intermediates in the synthesis of pyrrolidinone
containing natural products.
To conclude, we have demonstrated that a series of electron
deficient pyrroles are capable of undergoing Birch reduction
and reductive alkylation procedures to give substituted 3-pyrrol-
ines in good to excellent yields. Both the Boc and urea groups
provide suitable protection for the pyrrole amine and also acti-
vate the heterocycle towards reduction. Introduction of an ester
or amide at C-2 allowed a reductive alkylation protocol to be
performed and ensured the regiochemical outcome of the reac-
tion. Each of the two positions that require protection (C-2
carbonyl and the pyrrole nitrogen) can be blocked with groups
that are mutually compatible and which can be removed
orthogonally. In addition, a versatile and useful oxidation reac-
tion which yields the 3-pyrrolin-2-one skeleton has also been
discovered. Therefore, this methodology will prove to have use
in the synthesis of biologically important molecules and further
studies will be reported in due course.
1,2-Dimethyl-2-(pyrrolidin-1-ylcarbonyl)-2,5-dihydropyrrole 4
A solution of N-methylpyrrole amide 3 (320 mg, 1.8 mmol) in
THF (10 cm3) was added to a mixture of ammonia (100 cm3),
and sodium (124 mg, 5.4 mmol) at Ϫ78 ЊC. tert-Butyl alcohol
(120 mg) was added and the reaction stirred for 1 h. Methyl
iodide (1 cm3) was then added followed by NH4Cl (excess) after
a further 2 h. The reaction mixture was diluted with brine,
extracted with dichloromethane and dried (Na2SO4). Flash
chromatography (eluting with petrol–EtOAc 1:1) gave the
dihydropyrrole 4 (90 mg, 26%) as a yellow oil; νmax(film)/cmϪ1
2969, 1626, and 1413; δH(200 MHz; CDCl3) 5.80 (1 H, dt, J 6.0
Experimental
General details
Melting points were determined with an ‘Electrothermal’ capil-
lary melting point apparatus and are uncorrected. IR spectra
were measured with a ATI Mattison Genesis Series FTIR as
KBr discs or neat oils as appropriate. The 1H (500, 300 and 200
MHz) NMR and 13C (125, 75 and 50 MHz) NMR spectra were
obtained on a Varian Unity 500, Bruker AC300 and Varian
Gemini 200 spectrometers. J Values are given in Hz. Elemental
analyses were performed in-house. Mass spectra were obtained
on a Kratos Concept Mass Spectrometer using the electron
impact mode (70 eV) or chemical ionisation. GC studies were
performed using a CP-Chirasil DEXCB column (25 m × 0.32
mm, 0.28 µ) controlled by a Shimadzu Cromatopac R4AX unit.
Thin layer chromatography (TLC) was performed on Polygram
0.25 mm silica gel pre-coated plastic sheets and visualised with
UV light (254 nm) and/or phosphomolybdic acid in ethanol,
p-anisaldehyde in glacial acetic acid or basic potassium per-
manganate as appropriate. Chromatography was performed on
silica gel (Merck 60). All solvents were purified by following
standard literature methods. Ammonia was pre-dried over
sodium and distilled into the reaction vessel under a nitrogen
atmosphere. All the alkyl halides used were filtered through a
plug of anhydrous potassium carbonate prior to use. Isoprene
was distilled and stored over 4 Å molecular sieves under nitro-
and 2.0, CH᎐CH), 5.63 (1 H, dt, J 6.0 and 2.0, CH᎐CH), 3.80–
᎐
᎐
3.65 (2 H, m, NCH2CH), 3.55–3.20 (4 H, m, 2 × NCH2CH2),
2.30 (3 H, s, NMe), 1.95–1.60 (4 H, m, 2 × NCH2CH2), and
1.20 (3 H, s, NCMe); δC(50 MHz; CDCl3) 172.6, 134.7, 128.5,
74.4, 60.0, 48.3, 47.3, 34.8, 27.6, 23.8 and 17.6; m/z (CI) 195
(Mϩ ϩ 1, 95%), 193 (100) and 96 (25); (C11H19N2O requires
195.1497. Found 195.1500).
N-(tert-Butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrole 6
A solution of the pyrrole amide 2 (5 g, 30.5 mmol) in THF (15
cm3) was added to NaH (1.46 g, 60.9 mmol) in THF (15 cm3) at
room temperature. After 30 min, di-tert-butyl dicarbonate (10.5
cm3, 45.7 mmol) was added dropwise and the reaction was
heated at 45 ЊC for 12 h. The reaction mixture was then diluted
with water (10 cm3), extracted with EtOAc (3 × 30 cm3), dried
(Na2SO4) and concentrated in vacuo. Flash chromatography
(eluting with petrol–EtOAc 1:2) afforded the N-Boc pyrrole
amide 6 (7.25 g, 90%) as a colourless solid; mp 102–103 ЊC
(Found: C, 63.59; H, 7.72; N, 10.49. Calc. for C14H20N2O3: C,
63.62; H, 7.63; N, 10.60%); νmax(film)/cmϪ1 2976, 2876, 1744,
1640, 1555 and 1460; δH(300 MHz, CDCl3) 7.23 (1 H, dd, J 1.6
and 3.6, ArH), 6.30 (1 H, dd, J 1.6 and 3.6, ArH), 6.17 (1 H, t,
J 3.6, ArH), 3.60 (2 H, t, J 6.6, NCH2CH2), 3.30 (2 H, t, J 6.6,
J. Chem. Soc., Perkin Trans. 1, 1998
671

View Article Online
NCH2CH2), 2.00–1.80 (4 H, m, 2 × NCH2CH2), and 1.55 (9 H,
s, CMe3); δC(75 MHz, CDCl3) 162.8, 148.3, 129.0, 121.6, 113.0,
110.6, 84.4, 48.3, 45.6, 27.8, 25.8 and 24.6; m/z (CI) 265
(Mϩ ϩ 1, 75%), 209 (100), 165 (25), 94 (10) and 70 (15);
(C14H20N2O3 requires 264.1474. Found 264.1476).
(eluting with petrol–ethyl acetate 3:1) gave the dihydropyrrole 9
(357 mg, 71%) as a colourless solid (Found: C, 66.78; H, 8.62;
N, 8.90. Calc. for C17H26N2O3; C, 66.64; H, 8.55; N, 9.14%);
νmax(film)/cmϪ1 1696, 1627, and 1391; δH(300 MHz, CDCl3)
5.96–5.84 (1 H, m, CH᎐CH), 5.64–5.48 (2 H, m, CH᎐CH),
᎐
᎐
5.06–4.96 (2 H, m, CH᎐CH ), 4.13–3.98 (2 H, m, NCH CH),
᎐
2
2
N-(tert-Butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)-2-methyl-
2,5-dihydropyrrole 7
3.62–3.34 (2 H, m, NCH CH ), 3.30–3.16 (1 H, m, CH CH᎐
᎐
2 2 2
CH2), 3.08–2.98 (2 H, m, NCH2CH2), 2.78–2.68 (1 H, dd, J 4.0
and J 7.5, CH CH᎐CH ), 1.94–1.50 (4 H, m, 2 × NCH CH )
A solution of N-Boc-pyrrole amide 6 (500 mg, 1.9 mmol) in
THF (10 cm3) was added rapidly to a mixture of ammonia (150
cm3), THF (40 cm3) and sodium (131 mg, 5.7 mmol) at Ϫ78 ЊC.
After 1 h, methyl iodide (1 cm3) was added and after a further 2
h, NH4Cl (excess) was added. The mixture was slowly warmed
to room temperature, while the ammonia was removed with a
stream of nitrogen. Brine was added and the product extracted
with EtOAc (3 × 50 cm3), dried (Na2SO4), filtered and concen-
trated under reduced pressure. Flash chromatography (eluting
with petrol–acetone 5:1) gave the dihydropyrrole 7 (451 mg,
85%) as a colourless solid; mp 95–98 ЊC (Found: C, 64.45;
H, 8.54; N, 9.85. Calc. for C15H24N2O3: C, 64.26; H, 8.63; N,
9.99%); νmax(film)/cmϪ1 2974, 2874, 1696, 1639 and 1391; δH(300
᎐
2
2
2
2
and 1.39, 1.38 (9 H, s, CMe3); δC(75 MHz, CDCl3) 168.9, 153.0,
133.2, 132.8, 129.5, 129.1, 126.8, 126.7, 118.9, 118.7, 80.2, 74.7,
54.7, 54.4, 48.2, 44.9, 39.6, 38.1, 28.2, 27.3 and 23.2; m/z (CI),
307 (Mϩ ϩ 1, 40%) and 207 (100); (C17H26N2O3 requires
306.1943. Found 306.1939).
N-(tert-Butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)-2-ethyl-2,5-
dihydropyrrole 10
A solution of N-Boc-pyrrole amide 6 (500 mg, 1.89 mmol) in
THF (10 cm3) was added rapidly to a mixture of ammonia (150
cm3), THF (40 cm3) and sodium (131 mg, 5.69 mmol) at
Ϫ78 ЊC. After 1 h, ethyl iodide (1 cm3) was added and after a
further 2 h, NH4Cl (excess) was added. After work-up, which
was identical to that described for 7, flash chromatography
(eluting with petrol–acetone 5:1) gave the dihydropyrrole 10
(451 mg, 81%) as a colourless oil (Found: C, 65.21; H, 8.76;
N, 9.50. Calc. for C16H26N2O3: C: 65.28; H, 8.90; N, 9.52%);
νmax(film)/cmϪ1 2970, 2876, 1692, 1641, 1476 and 1393; δH(300
MHz, CDCl ) 5.87, 5.81 (1 H, dt, J 6.2 and 1.9, CH᎐CH), 5.62
᎐
3
(1 H, dt, J 6.2 and 1.9, CH᎐CH), 4.30–4.08 (2 H, m, NCH CH),
᎐
2
3.57–3.00 (4 H, m, 2 × NCH2CH2), 2.00–1.65 (4 H, m,
2 × NCH2CH2), 1.63, 1.58 (3 H, s, NCMe), 1.45 and 1.42 (9 H,
s, CMe3); δH(300 MHz, C6H4Cl2, 140 ЊC) 5.65–5.55 (1 H, m,
CH᎐CH), 5.50–5.40 (1 H, m, CH᎐CH), 4.15–4.00 (2 H, m,
᎐
᎐
NCH2CH), 3.40–3.15 (4 H, m, 2 × NCH2CH2), 1.75–1.50 (7 H,
m, 2 × NCH2CH2 and NCMe) and 1.38 (9 H, s, CMe3); δC(75
MHz, CDCl3) 168.9, 153.1, 132.0, 131.6, 125.4, 80.2, 72.3, 72.0,
53.3, 48.2, 45.0, 28.4, 27.3 and 23.4; m/z (CI) 281 (Mϩ ϩ 1,
100%), 225 (40), 181 (25) and 82 (40); (C15H24N2O3 requires
280.1787. Found 280.1775).
MHz, CDCl ) 5.98, 5.91 (1 H, dt, J 6.3 and 2.1, CH᎐CH),
᎐
3
5.43 (1 H, dt, J 6.3 and 2.1, CH᎐CH), 4.15, 4.09 (2 H, t, J
᎐
2.1, NCH2CH), 3.55–2.95 (4 H, m, 2 × NCH2CH2), 2.60–1.55
(6 H, m, CH2CH3, 2 × NCH2CH2), 1.49, 1.38 (9 H, s, CMe3)
and 0.80, 0.70 (3 H, t, J 7.0, CH2CH3); δH(300 MHz,
C H Cl , 140 ЊC) 5.80–5.70 (1 H, m, CH᎐CH), 5.35–5.25
᎐
6
4
2
(1 H, m, CH᎐CH), 4.10–4.05 (2 H, m, NCH CH), 3.45–3.30
᎐
2
N-(tert-Butyloxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)-2-benzyl-
2,5-dihydropyrrole 8
(4 H, m, 2 × NCH2CH2), 2.60–2.40 (1 H, m, HCHCH3), 2.15–
2.05 (1 H, m, HCHCH3), 1.75–1.55 (4 H, m, 2 × NCH2CH2),
1.40 (9 H, s, CMe3) and 0.75–0.65 (3 H, m, CH2CH3); δC(75
MHz, CDCl3) 169.3, 169.0, 153.2, 152.2, 129.6, 129.2, 126.9,
126.6, 80.1, 79.6, 75.7, 75.4, 55.0, 54.7, 48.2, 44.7, 28.3, 27.9,
27.3 and 23.3; m/z (CI) 295 (Mϩ ϩ 1, 100%), 239 (35), 195
(25) and 96 (50) (C16H26N2O3 requires 294.1943. Found
294.1941).
A solution of N-Boc-pyrrole amide 6 (500 mg, 1.9 mmol) in
THF (10 cm3) was added rapidly to a mixture of ammonia (150
cm3), THF (40 cm3) and sodium (131 mg, 5.7 mmol) at Ϫ78 ЊC.
After 1 h, isoprene (5 drops) was added followed by benzyl
bromide (1 cm3) and after a further 2 h, NH4Cl (excess) was
added. The mixture was slowly warmed to room temperature,
while the ammonia was removed with a stream of nitrogen.
After work-up, which was identical to that described for 7, flash
chromatography (eluting with petrol–acetone 5:1) gave the
dihydropyrrole 8 (485 mg, 72%) as a colourless solid; mp 152–
153 ЊC (Found: C: 70.36; H, 7.75; N, 7.88. Calc. for C21H28-
N2O3: C, 70.76; H, 7.92; N, 7.86%); νmax(film)/cmϪ1 2973, 2874,
1696, 1640 and 1393; δH(300 MHz, CDCl3) 7.25–7.00 (5 H, m,
N-(tert-Butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)-2-butyl-
2,5-dihydropyrrole 11
A solution of N-Boc-pyrrole amide 6 (500 mg, 1.9 mmol) in
THF (10 cm3) was added rapidly to a mixture of ammonia (150
cm3), THF (40 cm3) and sodium (131 mg, 5.7 mmol) at Ϫ78 ЊC.
After 1 h, butyl iodide (1 cm3) was added and after a further 2 h,
NH4Cl (excess) was added. The mixture was slowly warmed to
room temperature, while the ammonia was removed with a
stream of nitrogen. After work-up, which was identical to that
described for 7, flash chromatography (eluting with petrol–
acetone 5:1) gave the dihydropyrrole 11 (524 mg, 86%) as a
colourless oil (Found: C, 66.78; H, 9.10; N, 8.65. Calc. for
C18H30N2O3: C, 67.05; H, 9.38; N, 8.69%); νmax(film)/cmϪ1 2963,
2872, 1694, 1641 and 1392; δH(300 MHz, CDCl3) 5.96, 5.90
PhH), 5.71, 5.64 (1 H, dt, J 6.4 and 2.0, CH᎐CH), 5.57 (1 H, dt,
᎐
J 6.4 and 2.0, CH᎐CH), 3.99–3.00 (8 H, m, NCH CH,
᎐
2
2 × NCH2CH2, CH2Ph), 2.0–1.65 (4 H, m, 2 × NCH2CH2) and
1.55, 1.50 (9 H, s, CMe3); δH(300 MHz, C6H4Cl2, 140 ЊC) 5.50–
5.35 (2 H, m, CH᎐CH), 3.90–3.60 (2 H, m, NCH CH), 3.45–
᎐
2
3.15 (6 H, m, 2 × NCH2CH2, CH2Ph), 1.75–1.50 (4 H, m,
2 × NCH2CH2) and 1.45 (9 H, s, CMe3); δC(75 MHz, CDCl3)
168.9, 153.0, 137.3, 137.0, 131.2, 131.0, 129.3, 128.9, 127.7,
127.6, 127.3, 126.2, 126.0, 80.6, 79.7, 75.8, 75.7, 54.1, 48.4,
48.3, 45.0, 40.6, 39.4, 28.6, 28.4, 27.4, 27.3, 23.3 and 23.2; m/z
(CI) 357 (Mϩ ϩ 1, 100%), 301 (65), 257 (15) and 158 (10)
(C21H29N2O3 requires 357.2178. Found 357.2182).
(1 H, dt, J 6.3 and 2.1, CH᎐CH), 5.49 (1 H, dt, J 6.3 and 2.1,
᎐
CH᎐CH), 4.17, 4.10 (2 H, t, J 2.1, NCH CH), 3.55–3.0 (4 H,
᎐
2
m, 2 × NCH2CH2), 2.50–1.60 [6 H, m, CH2(CH2)2CH3, 2 ×
NCH2CH2], 1.45, 1.42 (9 H, s, CMe3), 1.40–0.95 [4 H, m,
CH2(CH2)2CH3] and 0.89 (3 H, t, J 7.0, CH2CH3); δH(300 MHz,
N-(tert-Butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)-2-allyl-2,5-
dihydropyrrole 9
C H Cl , 140 ЊC) 5.70–5.60 (1 H, m, CH᎐CH), 5.35–5.25 (1 H,
᎐
6 4 2
m, CH᎐CH), 4.10–4.00 (2 H, m, NCH CH), 3.35–3.15 (4 H, m,
᎐
2
A solution of N-Boc-pyrrole amide 6 (433 mg, 1.64 mmol) in
THF (20 cm3) was added rapidly to a mixture of ammonia (200
cm3), THF (30 cm3) and sodium (113 mg, 4.91 mmol) at
Ϫ78 ЊC. After 1 h, allyl bromide (1 cm3) was added and after a
further 2 h, NH4Cl (excess) was added. After work-up, which
was identical to that described for 7, flash chromatography
2 × NCH2CH2), 2.50–2.30 (1 H, m, HCHCH2), 2.10–1.95 (1 H,
m, HCHCH2), 1.70–1.45 (4 H, m, 2 × NCH2CH2), 1.35 (9 H, s,
CMe3), 1.30–0.90 (4 H, m, CH2CH2CH3) and 0.80–0.70 (3 H,
m, CH2CH3); δC(75 MHz, CDCl3) 169.3, 169.0, 153.2, 152.1,
130.1, 129.7, 126.5, 126.3, 80.1, 79.5, 75.3, 75.0, 54.6, 48.2, 44.7,
34.7, 28.3, 28.1, 27.3, 24.9, 24.6, 23.2, 22.7, 22.6 and 14.1; m/z
672
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
(CI), 323 (Mϩ ϩ 1, 100%), 267 (55), 223 (35) and 124 (35)
(C18H31N2O3 requires 323.2335. Found 323.2338).
oil (Found: C, 63.66; H, 8.21; N, 15.73. Calc. for C14H21N3O2:
C, 63.85; H, 8.04; N, 15.96%); νmax(film)/cmϪ1 2971, 2876,
1705, 1622, 1534 and 1433; δH(300 MHz, CDCl3) 6.85 (1 H,
dd, J 2.9, 1.5, ArH), 6.55 (1 H, dd, J 3.7, 1.5, ArH), 6.20
(1 H, dd, J 3.7, 2.9, ArH), 3.74–3.56 (4 H, m, 2 × NCH2CH3),
3.34 (4 H, br s, 2 × NCH2CH2), 1.92 (4 H, br s, 2 ×
NCH2CH2) and 1.20 (6 H, t, J 7, 2 × NCH2CH3); δC(75 MHz,
CDCl3) 155.7, 149.6, 123.0, 118.2, 109.0, 104.4, 44.3, 41.9, 37.9,
22.0 and 19.6; m/z (EI), 263 (Mϩ, 50%), 100 (100), 94 (60), 72
(100), and 70 (90) (C14H21N3O2 requires 263.1634. Found
263.1631).
N-(tert-Butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)-2-isobutyl-
2,5-dihydropyrrole 12
A solution of N-Boc-pyrrole amide 6 (516 mg, 2.0 mmol) in
THF (10 cm3) was added rapidly to a mixture of ammonia (150
cm3), THF (40 cm3) and sodium (152 mg, 6.6 mmol) at Ϫ78 ЊC.
After 1 h, isobutyl iodide (1 cm3) was added and after a further
12 h, NH4Cl (excess) was added. The mixture was slowly
warmed to room temperature, while the ammonia was removed
with a stream of nitrogen. After work-up, which was identical
to that described for 7, flash chromatography (eluting with
petrol–acetone 5:1) gave the dihydropyrrole 12 (482 mg, 79%)
as a colourless solid; mp 82–86 ЊC (Found: C, 67.08; H, 9.52; N,
8.67. Calc. for C18H30N2O3: C, 67.05; H, 9.38; N, 8.69%);
νmax(film)/cmϪ1 2955, 2870, 1696, 1640 and 1394; δH(300 MHz,
CDCl ) 5.97, 5.89 (1 H, dt, J 6.3 and 2.0, CH᎐CH), 5.52 (1 H,
N-(N,N-Diethylcarbamoyl)-2-(pyrrolidin-1-ylcarbonyl)-2-
methyl-2,5-dihydropyrrole 15
A solution of pyrrole amide 14 (500 mg, 1.9 mmol) in THF (10
cm3) was added rapidly to a mixture of ammonia (150 cm3),
THF (40 cm3) and sodium (131 mg, 5.7 mmol) at Ϫ78 ЊC. After
2 h, methyl iodide (1 cm3) was added and after a further 2 h,
NH4Cl (excess) was added. The mixture was slowly warmed to
room temperature, while the ammonia was removed with a
stream of nitrogen. After work-up, which was identical to that
described for 7, flash chromatography (eluting with toluene–
acetone 5:1) gave the dihydropyrrole 15 (447 mg, 85%) as a
colourless solid; mp 152–153 ЊC; νmax(film)/cmϪ1 2970, 2872,
1639, 1620, 1414 and 1349; δH(300 MHz, CDCl3) 5.85 (1 H, dt,
᎐
3
dt, J 6.3 and 2.0, CH᎐CH), 4.20, 4.15 (2 H, t, J 2.0, NCH CH),
᎐
2
3.55–2.95 (4 H, m, 2 × NCH2CH2), 2.50–2.20 (1 H, m,
CHMe2), 2.10–1.50 (6 H, m, 2 × NCH2CH2, CH2CHMe2),
1.45, 1.40 (9 H, s, CMe3), 0.90 (3 H, d, J 6.7, CH3CHCH3) and
0.88 (3 H, d, J 6.7, CH3CHCH3); δH(300 MHz, C6H4Cl2,
140 ЊC) 5.75–5.65 (1 H, m, CH᎐CH), 5.45–5.35 (1 H, m,
᎐
CH᎐CH), 4.15–4.05 (2 H, m, NCH CH), 3.40–3.20 (4 H, m,
᎐
2
2 × NCH2CH2), 2.50–2.35 (1 H, m, CHMe2), 2.15–2.05 (1 H,
m, HCHCHMe2), 1.70–1.45 (5 H, m, 2 × NCH2CH2, HCH-
CHMe2), 1.40 (9 H, s, CMe3) and 0.90–0.75 (6 H, m, CMe2);
δC(75 MHz, CDCl3) 169.3, 153.2, 130.9, 130.4, 126.4, 80.2, 79.6,
75.6, 75.3, 54.7, 48.5, 44.7, 43.0, 28.4, 27.4, 25.3, 24.6, 23.2 and
23.0; m/z (CI), 323 (Mϩ ϩ 1, 100%), 267 (30), 223 (10) and 124
(25); (C18H31N2O3 requires 323.2335. Found 323.2339).
J 6.3, J 2.0, CH᎐CH), 5.64 (1 H, dt, J 6.3, J 2.0, CH᎐CH), 4.36
᎐ ᎐
(1 H, dt, J 2.0, J 14.7, NCH2CH), 4.09 (1 H, dt, J 2.0, J 14.7,
NCH2CH), 3.73–3.35 (4 H, m, 2 × NCH2CH2), 3.35–2.89 (4 H,
m, 2 × NCH2CH3), 1.98–1.66 (4 H, m, 2 × NCH2CH2), 1.58
(3 H, s, CMe) and 1.11 (6 H, t, J 7.1, 2 × NCH2CH3); δH(500
MHz, C H Cl , 140 ЊC) 6.04 (1 H, d, J 6.0, CH᎐CH), 5.90 (1 H,
᎐
6
4
2
d, J 6.0, CH᎐CH), 4.65 (1 H, d, JAB 11.5, NCH2CH), 4.47 (1 H,
᎐
d, JAB 11.5, NCH2CH), 3.81–3.70 (4 H, m, 2 × NCH2CH2),
3.62–3.50 (2 H, m, NCH2CH3), 3.35–3.25 (2 H, m, NCH2CH3),
2.10–1.95 (7 H, m, 2 × NCH2CH2, CMe) and 1.45 (6 H, t, J 7.2,
2 × NCH2CH3); δC(75 MHz, CDCl3) 169.3, 159.4, 131.6, 125.0,
74.1, 54.6, 48.1, 44.5, 43.3, 27.2, 23.8, 23.1 and 14.0; m/z (CI),
280 (Mϩ ϩ 1, 30%), 209 (100), 181 (35), and 72 (25) (C15H23-
N3O2 requires 279.1946. Found 279.1945).
N-(tert-Butoxycarbonyl)-2-(pyrrolidin-1-ylcarbonyl)-2,5-
dihydropyrrole 13
A solution of the N-Boc-pyrrole amide 6 (500 mg, 1.9 mmol) in
THF (10 cm3) was added rapidly to a mixture of ammonia (150
cm3), THF (40 cm3) and sodium (131 mg, 5.7 mmol) at Ϫ78 ЊC.
After 1 h, saturated NH4Cl solution (5 cm3) was added. The
mixture was slowly warmed to room temperature, while the
ammonia was removed with a stream of nitrogen. After work-
up, which was identical to that described for 7, flash chrom-
atography (eluting with petrol–acetone 5:1) gave the dihydro-
pyrrole 13 (358 mg, 71%) as a pale yellow oil (Found: C, 63.06;
H, 8.45; N, 10.39. Calc. for C14H22N2O4: C, 63.17; H, 8.33; N,
10.53%); νmax(film)/cmϪ1 2974, 2875, 1704, 1659 and 1399;
Isopropyl N-(tert-butoxycarbonyl)pyrrole-2-carboxylate 16
Trichloroacetyl pyrrole 1 (5 g, 23.7 mmol) was suspended in
water (5 cm3) and KOH (1.33 g, 23.7 mmol) was added. The
reaction was heated at 80 ЊC for 12 h and excess water removed
by azeotropic distillation with toluene. The potassium salt was
dried under vacuum for 12 h and then suspended in dichloro-
methane (15 cm3). Oxalyl chloride (3.1 cm3, 35.5 mmol) was
added dropwise to the mixture in an ice bath and after 30 min
the reaction was refluxed for 3 h. Excess oxalyl chloride was
removed in vacuo and the acid chloride was then dissolved
in isopropyl alcohol (10 cm3) and heated at reflux for 12 h.
Excess isopropyl alcohol was evaporated to afford the pyrrole
isopropyl ester (2.73 g, 75%) as a dark viscous oil.
A solution of the pyrrole isopropyl ester (2.5 g, 16.3 mmol)
in THF (5 cm3) was added to NaH (782 mg, 32.6 mmol) in
THF (10 cm3) at room temperature. After 30 min, di-tert-butyl
dicarbonate (9.0 cm3, 39.1 mmol) was added slowly and the
reaction heated at 45 ЊC for 12 h. The reaction mixture was then
diluted with water (10 cm3), extracted with dichloromethane
(3 × 30 cm3), dried (Na2SO4), filtered and concentrated in
vacuo. Flash chromatography (eluting with petrol–EtOAc 5:1)
afforded the N-Boc pyrrole isopropyl ester 16 (4.0 g, 97%) as a
pale yellow oil; νmax(film)/cmϪ1 2980, 2930, 1753, 1724 and
1450; δH(300 MHz, CDCl3) 7.35 (1 H, dd, J 3.5, 1.8, ArH), 6.85
(1 H, dd, J 3.5, 1.8, ArH), 6.20 (1 H, t, J 3.5, ArH), 5.20 (1 H,
sp, J 6.3, CHMe2) 1.65, 1.55 (9 H, s, CMe3) and 1.09 (6 H, d,
J 6.3, CMe2); δC(75 MHz, CDCl3) 213.5, 212.8, 160.4, 148.4,
126.5, 126.1, 110.0, 85.2, 84.6, 68.3, 27.7, 27.4 and 21.9;
m/z (CI) 254 (Mϩ ϩ 1, 10%), 215 (55), 198 (100), 111 (35) and
94 (30) (C13H19NO4 requires 253.1314. Found 253.1316).
δ (300 MHz, CDCl ) 6.04–5.92 (1 H, m, CH᎐CH), 5.74–5.64
᎐
H
3
(1 H, m, CH᎐CH), 5.24–5.09 (1 H, m, CHNBoc), 4.38–4.12
᎐
(2 H, m, NCH2CH), 3.60–3.38 (4 H, m, 2 × NCH2CH2), 2.05–
1.80 (4 H, m, 2 × NCH2CH2) and 1.47, 1.42 (9 H, s, CMe3);
δ (500 MHz, C H Cl , 140 ЊC) 6.12 (1 H, d, J 7.5, CH᎐CH),
᎐
H
6
4
2
5.94 (1 H, d, J 7.5, CH᎐CH), 5.50–5.44 (1 H, m, CHNBoc),
᎐
4.64–4.46 (2 H, m, NCH2CH), 3.86–3.72 (4 H, m, 2 ×
NCH2CH2), 2.18–2.0 (4 H, m, 2 × NCH2CH2) and 1.80 (9 H, s,
CMe3); δC(75 MHz, CDCl3) 168.3, 168.1, 153.8, 153.4, 129.1,
128.8, 124.5, 79.9, 79.7, 66.8, 65.7, 53.7, 53.4, 46.5, 46.2, 45.9,
45.6, 28.4, 28.3, 26.5, 26.2 and 23.9; m/z (CI), 267 (Mϩ ϩ 1,
100%), 211 (50), 167 (35) and 68 (30); (C14H22N2O3 requires
266.1630. Found 266.1634).
N-(N,N-Diethylcarbamoyl)-2-(pyrrolidin-1-ylcarbonyl)pyrrole14
A solution of the pyrrole amide 2 (5 g, 30.5 mmol) in THF (15
cm3) was added to NaH (1.46 g, 60.9 mmol) in THF (15 cm3) at
room temperature. After 30 min, N,N-diethylcarbamoyl chlor-
ide (5.8 cm3, 45.8 mmol) was added slowly and the reaction was
heated at 45 ЊC for 8 h. The reaction mixture was diluted with
water (10 cm3), extracted with EtOAc (3 × 30 cm3), dried
(Na2SO4), filtered and concentrated in vacuo. Flash chrom-
atography (eluting with petrol–EtOAc 1:2) afforded the N-
diethylcarbamoylpyrrole amide 14 (7.3 g, 91%) as a colourless
J. Chem. Soc., Perkin Trans. 1, 1998
673

View Article Online
N-(tert-Butoxycarbonyl)-2-(isopropoxycarbonyl)-2-methyl-2,5-
dihydropyrrole 17
for C10H16N2O: C, 66.64; H, 8.95; N, 15.54%); νmax(film)/cmϪ1
3338, 2966, 2875, 1605 and 1452; δH(200 MHz, CDCl3) 5.90–
A solution of the N-Boc pyrrole isopropyl ester 16 (500 mg, 2.0
mmol) in THF (10 cm3) was added rapidly to a mixture of
ammonia (150 cm3), THF (40 cm3) and sodium (136 mg, 6.0
mmol) at Ϫ78 ЊC. After 5 min, methyl iodide (1 cm3) was added
and after a further 2 h, NH4Cl (excess) was added. The mixture
was slowly warmed to room temperature, while the ammonia
was removed with a stream of nitrogen. After work-up, which
was identical to that described for 7, flash chromatography
(eluting with petrol–acetone 9:1) afforded the dihydropyrrole
17 as a colourless oil (463 mg, 87%) (Found: C, 62.44; H, 8.68;
N, 5.27. Calc. for C14H23NO4: C, 62.51; H, 8.62; N, 5.21%);
νmax(film)/cmϪ1 2977, 2927, 1740, 1707, 1456 and 1389; δH(300
MHz, CDCl ) 5.91–5.78 (1 H, m, CH᎐CH), 5.60–5.50 (1 H, m,
5.80 (2 H, m, CH᎐CH), 3.76 (2 H, br s, NCH CH), 3.65–3.40
᎐
2
(4 H, m, 2 × NCH2CH2), 2.80 (1 H, br s, NH), 2.00–1.70 (4 H,
m, 2 × NCH2CH2) and 1.44 (3 H, s, CMe); δC(300 MHz,
CDCl3) 173.3, 131.3, 129.6, 72.9, 53.0, 47.7, 47.1, 26.9, 26.3 and
23.3; m/z (CI) 181 (Mϩ ϩ 1, 100%) and 82 (45); (C10H17N2O
requires 181.1341. Found 181.1339).
N-Acetyl-2-methyl-2,5-dihydropyrrole-2-carboxylic acid 20
A solution of the dihydropyrrole 7 (100 mg, 0.36 mmol) in 6 
HCl (5 cm3) was heated at 120 ЊC for 6 h. Excess water was
removed by azeotropic distillation in vacuo (using toluene) to
afford a brown oil which was dissolved in pyridine–CH2Cl2
(1:1, 10 cm3) and cooled to 0 ЊC under an atmosphere of
nitrogen. Acetic anhydride (0.5 cm3), was added dropwise and
the reaction mixture stirred at room temperature for 12 h.
The reaction was then evaporated in vacuo and treated with 3
 KOH–THF (1:1, 10 cm3). After 12 h at room temperature
the reaction was acidified with 2  HCl and extracted with
EtOAc (3 × 20 cm3). The organic extracts were dried
(Na2SO4), filtered and concentrated in vacuo to afford a
brown oil. Trituration in diethyl ether–petrol (1:1) gave 20
(50 mg, 84%) as a brown solid; mp 145–149 ЊC (Found: C,
56.60; H, 6.53; N, 8.28. Calc. for C8H11NO3: C, 56.80; H, 6.55;
N, 8.28%); νmax(film)/cmϪ1 1731, 1635, 1598, 1462 and 1377;
᎐
3
CH᎐CH), 5.04–4.82 (1 H, m, CHMe ), 4.38–4.04 (2 H, m,
᎐
2
NCH2CH), 1.64, 1.58 (3 H, s, CMe), 1.44, 1.42 (9 H, s, CMe3)
and 1.25–1.14 (6 H, m, CHMe2); δH(500 MHz, C6H4Cl2, 140 ЊC)
5.45–5.35 (1 H, m, CH᎐CH), 5.25–5.15 (1 H, m, CH᎐CH),
᎐
᎐
4.70–4.60 (1 H, m, CHMe2), 3.97 (1 H, d, JAB 15.5, NCH2CH),
3.84 (1 H, d, JAB 15.5, NCH2CH), 1.40 (3 H, s, CMe), 1.15 (9 H,
s, CMe3), 0.89 (3 H, d, J 6.4, MeCHMe) and 0.86 (3 H, d, J 6.4,
MeCHMe); δC(75 MHz, CDCl3) 171.9, 171.8, 153.5, 153.4,
131.8, 126.8, 80.2, 79.5, 72.2, 71.7, 68.8, 68.5, 54.5, 28.5, 28.4,
22.6, 21.8 and 21.7; m/z (CI) 270 (Mϩ ϩ 1, 100%), 214 (15), 170
(10) and 82 (15) (C14H24NO4 requires 270.1705. Found
270.1712).
δ (200 MHz, D O) 6.05–5.95 (1 H, m, CH᎐CH), 5.80–5.70 (1
᎐
H
2
H, m, CH᎐CH), 4.45–4.35 (2 H, m, NCH CH), 2.06 (3 H, s,
᎐
2
N-(tert-Butoxycarbonyl)-2-(isopropoxycarbonyl)-2-isobutyl-2,5-
dihydropyrrole 18
NCOMe) and 1.55 (3 H, s, CMe); δC(50 MHz, D2O) 178.6,
175.0, 133.8, 130.0, 75.5, 58.1, 24.5 and 23.2; m/z (CI) 170
(Mϩ ϩ 1, 100%), 124 (10); (C8H12NO3 requires 170.0817.
Found 170.0820).
A solution of the N-Boc pyrrole isopropyl ester 16 (500 mg,
2.0 mmol) in THF (10 cm3) was added rapidly to a mixture
of ammonia (150 cm3), THF (30 cm3) and sodium (136 mg,
6.0 mmol) at Ϫ78 ЊC. After 5 min, isobutyl iodide (1 cm3)
was added and after a further 2 h, NH4Cl (excess) was added.
The mixture was slowly warmed to room temperature, while
the ammonia was removed with a stream of nitrogen. After
work-up, which was identical to that described for 7, flash
chromatography (eluting with petrol–acetone 9:1) afforded
the dihydropyrrole 18 as a colourless oil (473 mg, 76%)
(Found: C, 65.62; H, 9.19; N, 4.62. Calc. for C17H29NO4; C,
65.57; H, 9.39; N, 4.50%); νmax(film)/cmϪ1 2977, 2868, 1736,
1706, 1468 and 1390; δH(300 MHz, CDCl3) 5.93–5.81 (1 H,
m, CH᎐CH), 5.53–5.44 (1 H, m, CH᎐CH), 5.02–4.82 (1 H,
N-Acetyl-2-benzyl-2,5-dihydropyrrole-2-carboxylic acid 21
A solution of the dihydropyrrole 8 (80 mg, 0.22 mmol) in 6 
HCl (3 cm3) was heated at 120 ЊC for 18 h. Excess water was
removed by evaporation in vacuo to afford a brown oil which
was dissolved in pyridine–CH2Cl2 (1:1, 2 cm3) and cooled to
0 ЊC under an atmosphere of nitrogen. Acetic anhydride (0.5
cm3) was added dropwise and the reaction mixture stirred at
room temperature for 18 h. The reaction was then evaporated
in vacuo and treated with 3  KOH–THF (1:1, 10 cm3). After
16 h at room temperature the reaction was acidified with 2 
HCl and extracted with EtOAc (3 × 20 cm3). The organic
extracts were dried (Na2SO4), filtered and concentrated in vacuo
to afford a brown oil. Trituration in diethyl ether–petrol (1:1)
gave the title compound (48 mg, 88%) as a brown solid; mp
175–178 ЊC (Found: C, 68.28; H, 6.05; N, 5.57. Calc. for
C14H15NO3: C, 68.56; H, 6.16; N, 5.71%); νmax(film)/cmϪ1 1729,
1637 and 1601; δH(200 MHz, CDCl3) 7.48–7.05 (5 H, m, PhH),
᎐
᎐
m, OCHMe2), 4.40–4.03 (2 H, m, NCH2CH), 2.40–1.80 (2 H,
m, CH2CHMe2), 1.55–1.45 (1 H, m, CH2CHMe2), 1.40, 1.45
(9 H, s, CMe3), 1.25–1.10 (6 H, m, OCHMe2) and 0.90–0.85
(6 H, m, CH2CHMe2); δH(500 MHz, C6H4Cl2, 140 ЊC) 6.15–
6.10 (1 H, m, CH᎐CH), 5.89–5.84 (1 H, m, CH᎐CH), 5.36–
᎐
᎐
5.29 (1 H, m, OCHMe2), 4.69 (1 H, d, J 15.5, NCH2CH),
4.51 (1 H, d, J 15.5, NCH2CH), 2.90–2.70 (1 H, m, HCH-
CHMe2), 2.40 (1 H, dd, J 15.2, J 5.8, HCHCHMe2), 2.07–
1.97 (1 H, m, CH2CHMe2), 1.85 (9 H, s, CMe3), 1.57 (3 H, d,
J 6.2, MeCMe), 1.54 (3 H, d, J 6.2, MeCMe) and 1.31–
1.26 (6 H, m, CH2CHMe2); δC(75 MHz, CDCl3) 171.9,
171.8, 153.5, 153.2, 131.0, 130.7, 127.3, 80.1, 79.3, 75.7,
75.2, 68.6, 68.3, 55.1, 55.0, 41.1, 39.9, 28.3, 24.7, 24.5, 24.0,
23.3, 21.7 and 21.5; m/z (CI) 312 (Mϩ ϩ 1, 10%), 256 (100), 212
(80) and 124 (50) (C17H29NO4 requires 311.2096. Found
311.2099).
5.97 (1 H, dt, J 6 and 2, CH᎐CH), 5.72 (1 H, dt, J 6 and 2,
᎐
CH᎐CH), 4.10 (1 H, dt, J 14.5 and 2, NCH CH), 3.83 (1 H, d,
᎐
2
J 14, PhCH2), 3.45 (1 H, dt, J 14.5 and 2, NCH2CH), 3.14 (1 H,
d, J 14, PhCH2) and 2.10 (3 H, s, NCOMe); δC(50 MHz, CDCl3)
172.9, 172.2, 135.4, 130.4, 127.8, 126.8, 126.1, 78.3, 56.4, 38.1
and 22.9; m/z (CI) 246 (Mϩ ϩ 1, 100%); (C14H16NO3 requires
246.1130. Found 246.1127).
N-(tert-Butoxycarbonyl)-2-methyl-2,5-dihydropyrrole-2-
carboxylic acid 22
A solution of the dihydropyrrole 17 (200 mg, 0.74 mmol) in
methanol (5 cm3) was treated with concentrated KOH solution
(5 cm3) and the mixture heated at 40 ЊC for 3 h. The reaction
mixture was then cooled in an ice bath, acidified (HCl, 2 ) to
pH (6–5) and extracted with EtOAc (3 × 20 cm3). The organic
extracts were dried (Na2SO4), filtered and concentrated in
vacuo. Flash chromatography (eluting with petrol–acetone 9:1)
afforded the dihydropyrrole carboxylic acid 22 (124 mg, 71%) as
a colourless solid; mp 94–96 ЊC (Found: C, 57.86; H, 7.49;
N, 6.04. Calc. for C11H17NO4: C, 58.14; H, 7.54; N, 6.16%);
2-(Pyrrolidin-1-ylcarbonyl)-2-methyl-2,5-dihydropyrrole 19
A solution of the pyrroline 7 (60 mg, 0.21 mmol) in dichloro-
methane (10 cm3) was cooled in an ice bath and treated with
trifluoroacetic acid (0.5 cm3). After 6 h at room temperature, the
reaction mixture was poured into NaOH solution (0.5 ) and
extracted with dichloromethane (3 × 10 cm3). The organic
extracts were dried (Na2SO4), filtered and concentrated in vacuo
to afford the dihydropyrrole 19 (32.4 mg, 84%) as a colourless
solid; mp 68–69 ЊC (Found: C, 66.60; H, 8.90; N, 15.50. Calc.
674
J. Chem. Soc., Perkin Trans. 1, 1998

View Article Online
νmax(film)/cmϪ1 3084, 2978, 1742, 1704, 1624 and 1393; δH(300
MHz, CDCl3) 9.60 (1 H, br s, CO2H), 5.92, 5.84 (1 H, dt, J 6.2
and 2.0, CH᎐CH), 5.72, 5.58 (1 H, dt, J 6.2 and 2.0, CH᎐CH),
by rapid addition of 3,5-dimethylpyrazole (621 mg, 6.21
mmol) to pre-dried chromium trioxide (597 mg, 6.21 mmol),
suspended in dry dichloromethane (5 cm3). After stirring for
30 min, the substrate 12 (100 mg, 0.311 mmol) was added
and the temperature slowly raised to 0 ЊC. After 2 h the mix-
ture was treated with (aq.) KOH (3 , 3 cm3) and stirred for
a further 1 h at room temperature and concentrated under
reduced pressure. The red solid residue was then dissolved in
EtOAc (15 cm3) and washed with ice cold 2  HCl (5 × 10
cm3). The organic layer was then treated with saturated
aqueous NaHCO3, dried (Na2SO4), filtered and evaporated in
vacuo. Flash chromatography, eluting with petrol–acetone
(4:1) afforded 25 as a colourless oil (71 mg, 68%); νmax(film)/
cmϪ1 1777, 1742, 1644 and 1312; δH(300 MHz, CDCl3) 6.99
᎐
᎐
4.44–4.08 (2 H, m, NCH2CH), 1.71, 1.64 (3 H, s, CMe) and
1.50, 1.46 (9 H, s, CMe3); δH(500 MHz, C6H4Cl2, 140 ЊC) 6.10–
6.00 (2 H, m, CH᎐CH), 4.60–4.45 (2 H, m, NCH CH), 2.05
᎐
2
(3 H, s, CMe) and 1.85 (9 H, s, CMe3); δC(75 MHz, CDCl3)
178.1, 176.3, 154.9, 153.6, 131.7, 131.1, 127.6, 81.2, 80.8, 71.7,
54.6, 28.4, 22.6 and 21.8; m/z (CI) 228 (Mϩ ϩ 1, 35%), 189
(100), 172 (70), 128 (20) and 82 (60); (C11H18NO4 requires
228.1236. Found 228.1242).
N-(tert-Butoxycarbonyl)-2-isobutyl-2,5-dihydropyrrole-2-
carboxylic acid 23
A solution of the dihydropyrrole 18 (103 mg, 0.74 mmol) in
methanol (5 cm3) was treated with concentrated KOH solu-
tion (3 cm3) and the mixture heated at 60 ЊC for 48 h. The
reaction mixture was then cooled in an ice bath, acidified
(HCl, 2 ) to pH (6–5) and extracted with EtOAc (3 × 15
cm3). The organic extracts were dried (Na2SO4), filtered and
concentrated in vacuo. Flash chromatography (eluting with
petrol–acetone 6:1) afforded 22 (68 mg, 76%) as a colourless
oil (Found: C, 62.67; H, 8.99; N, 5.11. Calc. for C14H23NO4:
C, 62.43; H, 8.61; N, 5.20%); νmax(film)/cmϪ1 3100, 1740, 1706
and 1625; δH(300 MHz, CDCl3) 10.20 (1 H, br s, CO2H),
(1 H, d, J 6, CH᎐CH), 6.31 (1 H, d, J 6, CH᎐CH), 3.64–3.02
᎐ ᎐
(4 H, m, 2 × NCH2CH2), 2.43 (1 H, dd, J 15 and 6,
CH2CHMe2), 2.30 (1 H, dd, J 15 and 6, CH2CHMe2), 2.00–
1.58 (4 H, m, 2 × NCH2CH2), 1.51 (9 H, s, CMe3), 1.36–1.22
(1 H, m, CHMe2) and 0.87 (6 H, d, J 7, CHMe2); δC(75
MHz, CDCl3) 169.5, 164.9, 149.4, 148.2, 127.0, 83.51, 74.3,
49.1, 45.3, 41.7, 27.9, 27.2, 25.0, 24.3, 22.9 and 22.3; m/z
(FAB), 359 (Mϩ ϩ 23, 40%) and 259 (100), 237 (70);
(C18H29N2O4 requires 337.2127. Found 337.2138).
N-(tert-Butoxycarbonyl)-5-(isopropoxycarbonyl)-5-methyl-2,5-
dihydropyrrol-2-one 26
5.95–5.44 (2 H, m, CH᎐CH), 4.37–4.05 (2 H, m, NCH CH),
᎐
2
2.28, 2.13 (1 H, dd, J 14 and 8, CH2CHMe2), 1.82 (1 H,
dd, J 14 and 8, CH2CHMe2), 1.52–1.44 (1 H, m, CHMe2),
1.41, 1.36 (9 H, s, CMe3) and 0.83, 0.79 (6 H, d, J 7,
CHMe2); δH(500 MHz, C6H4Cl2, 140 ЊC) 5.60–5.40 (2 H, m,
CH᎐CH), 3.95–3.85 (2 H, m, NCH CH), 2.07 (1 H, ddd, J 15,
7.5 and 2.5, CH2CHMe2), 1.72 (1 H, br d, J 15, CH2CHMe2),
1.44–1.32 (1 H, m, CHMe2), 1.25 (9 H, s, CMe3) and 0.64
(6 H, br d, J 7.5, CMe2); δC(75 MHz, CDCl3) 178.1, 153.6,
130.5, 130.3, 128.1, 125.9, 80.6, 75.1, 55.2, 55.1, 41.2, 40.4,
28.3, 24.5, 24.1, 23.9 and 23.2; m/z (CI) 270 (Mϩ ϩ 1,
20%) and 214 (100); (C14H24NO4 requires 270.1705. Found
270.1712).
The complex between chromium trioxide and 3,5-dimethyl-
pyrazole was prepared at low temperature (Ϫ30 ЊC to Ϫ20 ЊC)
by rapid addition of 3,5-dimethylpyrazole (715 mg, 7.43 mmol)
to pre-dried chromium trioxide (744 mg, 7.44 mmol), sus-
pended in dry dichloromethane (5 cm3). After stirring for 30
min, the substrate 17 (100 mg, 0.37 mmol) was added and the
temperature slowly raised to 0 ЊC. After 2 h the mixture was
treated with (aq.) KOH (3 , 3 cm3) and stirred for a further
1 h at room temperature and concentrated under reduced
pressure. The red solid residue was then dissolved in EtOAc
(15 cm3) and washed with ice cold 2  HCl (5 × 10 cm3). The
organic layer was then treated with saturated aqueous sodium
hydrogen carbonate, dried (Na2SO4), filtered and evaporated
in vacuo. Flash chromatography, eluting with petrol–acetone
(4:1) afforded 26 (70.5 mg, 67%) as a colourless oil (Found:
C, 59.18; H, 7.42; N, 5.03. Calc. for C14H21NO5: C, 59.35; H,
7.47; N, 4.94%); νmax(film)/cmϪ1 1782, 1739 (br) and 1607;
᎐
2
N-(tert-Butoxycarbonyl)-5-(pyrrolidin-1-ylcarbonyl)-5-methyl-
2,5-dihydropyrrol-2-one 24
The complex between chromium trioxide and 3,5-dimethyl-
pyrazole was prepared at low temperature (Ϫ30 ЊC to Ϫ20 ЊC)
by rapid addition of 3,5-dimethylpyrazole (686 mg, 7.14 mmol)
to pre-dried chromium trioxide (714 mg, 7.14 mmol), sus-
pended in dichloromethane (5 cm3). After stirring for 30 min,
the substrate 7 (100 mg, 0.357 mmol) was added and the tem-
perature slowly raised to 0 ЊC. After 2 h the mixture was treated
with (aq.) KOH (3 , 3 cm3), stirred for a further 1 h at room
temperature and concentrated under reduced pressure. The red
solid residue was dissolved in EtOAc (15 cm3) and then washed
with ice cold 2  HCl (5 × 10 cm3). The organic layer was then
treated with saturated aqueous NaHCO3, dried (Na2SO4), fil-
tered and evaporated in vacuo. Flash chromatography, eluting
with petrol–acetone (4:1) afforded 24 (67 mg, 64%) as an off-
white solid; mp 130–135 ЊC (Found: C, 61.23; H, 7.35; N,
9.31. Calc. for C15H22N2O4: C, 61.21; H, 7.53; N, 9.52%);
νmax(film)/cmϪ1 1777, 1742, 1717 and 1644; δH(200 MHz,
CDCl ) 7.05 (1 H, d, J 6, CH᎐CH), 6.19 (1 H, d, J 6,
δ (200 MHz, CDCl ) 6.95 (1 H, d, J 6.9, CH᎐CH), 6.17
᎐
H
3
(1 H, d, J 6.9, CH᎐CH), 5.0 (1 H, sept, J 6.9, CHMe ), 1.72
᎐
2
(3 H, s, CMe), 1.53 (9 H, s, CMe3), 1.22 (3 H, d, J 6.9,
MeCHMe) and 1.18 (3 H, d, J 6.9, MeCHMe); δC(75
MHz, CDCl3) 168.6, 168.1, 150.0, 148.6, 126.8, 83.60, 70.25,
70.17, 28.00, 21.54, 21.49 and 20.52; m/z (CI) 284 (Mϩ ϩ 1,
10%) and 184 (100); (C14H22NO5 requires 284.1498. Found
284.1498).
Crystal data: (RS)-7
C15H24N2O3, M = 280.37. Monoclinic, space group P21/c (#14),
crystal dimensions 0.18 × 0.25 × 0.37 mm, colourless pris-
matic crystal, a = 8.388(2), b = 13.930(3), c = 13.570(3) Å,
β = 103.57(2), U = 1541.4(6) Å3 by least-squares refinement on
diffractometer angles for 25 carefully centered reflections in the
range 15.28 < 2θ < 21.71Њ, Z = 4, Dc = 1.208 g cmϪ1, F(000) =
608.00.
᎐
3
CH᎐CH), 3.55–3.00 (4 H, m, 2 × NCH CH ), 1.86–1.62 (4 H,
᎐
2
2
m, 2 × NCH2CH2), 1.72 (3 H, s, CMe) and 1.47 (9 H, s,
CMe3); δC(75 MHz, CDCl3) 169.0, 164.8, 150.7, 148.2, 126.2,
83.7, 71.5, 48.9, 45.5, 27.9, 27.2, 23.6 and 23.1; m/z (CI) 295
(Mϩ ϩ 1, 5%) and 195 (100); (C15H23N2O4 requires 295.1658.
Found 295.1661).
Data collection and processing. Rigaku AFC5R diffract-
ometer, graphite monochromated Mo-Kα radiation (λ =
0.710 69 Å), µ(Mo-Kα) 0.79 cmϪ1, 3054 reflections measured,
maximum 2θ value of 50.1Њ, segment (ϩh, ϩk, l), 2851
unique reflections measured (Rint = 0.024), 1728 of these with
I > 3.00σ(I) used in refinement. An empirical absorption cor-
rection based on azimuthal scans of several reflections was
applied which resulted in transmission factors ranging from
0.97 to 1.00. The intensities of three representative reflections
measured after every 150 reflections showed no sign of decay.
N-(tert-Butoxycarbonyl)-5-(pyrrolidin-1-ylcarbonyl)-5-isobutyl-
2,5-dihydropyrrol-2-one 25
The complex between chromium trioxide and 3,5-dimethyl-
pyrazole was prepared at low temperature (Ϫ30 ЊC to Ϫ20 ЊC)
J. Chem. Soc., Perkin Trans. 1, 1998
675

View Article Online
Structure solution and refinement. Solution by direct
methods,15 hydrogen atoms included in idealised positions
(C᎐H 0.95 Å) with isotropic thermal parameters 20% greater
than the equivalent B value of the relevant carbon. The
structure was refined by full-matrix least-squares refinement
on F with all non-hydrogen atoms anisotropic and the
hydrogen atoms fixed, R = 0.041, Rω = 0.037, ω = 1/[σ2(Fo) ϩ
Acknowledgements
We wish to thank Rhône-Poulenc Rorer (T. J. D.), the World
Bank (P. M. G.) and Zeneca Pharmaceuticals (Strategic
Research Fund) for financial support. We also wish to thank
R. R. Harji and E. L. Williams for performing additional
experiments.
2
0.00 002Fo ] for 181 refined parameters. Max/min peaks in
References
final difference map 0.15/0.13.
1 For example see: A. Gossauer and P. Nesvadba, in The Chemistry of
Heterocyclic Compounds: Pyrroles, J. Wiley, New York, 1990, vol.
48, Part 1.
Crystal data: (RS)-24
C15H22N2O4, M = 294.35. Orthorhombic, space group Pna21
(#33), crystal dimensions 0.50 × 0.18 × 0.18 mm, colourless
block crystal, a = 16.585(3), b = 8.566(2), c = 11.409(3) Å,
U = 1620(1) Å3 by least-squares refinement on diffractometer
angles for 25 carefully centered reflections in the range
2 G. W. Gribble, in Comprehensive Organic Synthesis, ed. B. M. Trost
and I. Fleming, Pergamon, New York, 1991, vol 8; T. J. Donohoe,
R. Garg and C. A. Stevenson, Tetrahedron:Asymmetry, 1996, 7, 317.
3 G. G. Evans, J. Am. Chem. Soc., 1951, 73, 5230; D. P. Schumacher
and S. S. Hall, J. Am. Chem. Soc., 1982, 104, 6076; J. Cornforth and
Minghui Dui, J. Chem. Soc., Perkin Trans. 1, 1990, 1463.
4 D. M. Ketcha, K. P. Carpenter and Q. Zhou, J. Org. Chem., 1991,
56, 1318.
5 J. W. Scott, A. Focella, U. O. Hengartner, D. R. Parrish and
D. Valentine Jr., Synth. Commun, 1980, 10, 529.
6 For general reviews of the Birch reduction see: (a) L. N. Mander, in
Comprehensive Organic Synthesis, ed. B. M. Trost and I. Fleming,
Pergamon, New York, 1991, vol 8; (b) P. W. Rabideau and
Z. Marcinow, Org. React., 1992, 42, 1; (c) P. W. Rabideau, Tetra-
hedron, 1989, 45, 1579.
7 A. J. Birch and J. Slobbe, Heterocycles, 1976, 5, 905.
8 T. J. Donohoe and P. M. Guyo, J. Org. Chem., 1996, 61, 7664.
9 Compound 1 can also be prepared conveniently from pyrrole and
trichloroacetyl chloride: J. W. Harbuck and H. Rapoport, J. Org.
Chem., 1972, 37, 3618; D. M. Wallace, S. H. Leung, M. S. O’Senge
and K. Smith, J. Org. Chem., 1993, 58, 7245.
10 E. M. Kaiser, Synthesis, 1972, 391.
11 For example see: P. W. Rabideau and E. G. Burkholder, J. Org.
Chem., 1978, 43, 4283.
15.15 < 2θ < 19.67Њ, Z = 4, Dc = 1.21
632.00.
g
cmϪ1
,
F(000) =
Data collection and processing. Rigaku AFC5R diffract-
ometer, graphite monochromated Mo-Kα radiation (λ =
0.710 69 Å), µ(Mo-Kα) 0.9 cmϪ1, 1676 unique reflections meas-
ured, maximum 2θ value of 50.0Њ, segment (ϩh, ϩk, ϩl), 1113
of these with I > 3.00 σ(I) used in refinement. An empirical
absorption correction based on azimuthal scans of several
reflections was applied which resulted in transmission factors
ranging from 0.96 to 1.00. The intensities of three represent-
ative reflections measured after every 150 reflections showed no
sign of decay.
Structure solution and refinement. Solution by direct
methods,15 hydrogen atoms included in idealised positions
(C᎐H 0.95 Å) with isotropic thermal parameters 20% greater
than the equivalent B value of the relevant carbon. The struc-
ture was refined by full-matrix least-squares refinement on F
with all non-hydrogen atoms anisotropic and the hydrogen
atoms fixed, R = 0.046, Rω = 0.035, ω = 1/[σ2(Fo)] for 190 refined
parameters. Max/min peaks in final difference map 0.15/Ϫ0.15.
Calculations for both crystal structures were performed using
TEXSAN.§,16
12 J. M. Hook, L. N. Mander and M. Woolias, Tetrahedron Lett., 1982,
23, 4499; see also P. W. Rabideau, D. M. Wetzel and D. M. Young,
J. Org. Chem., 1984, 49, 1544.
13 For a reference to autoxidation see: A. H. Haines, Methods for the
Oxidation of Organic Compounds, Academic Press, London, 1985.
14 E. J. Corey and G. W. Fleet, Tetrahedron Lett., 1973, 4499.
15 SIR92: A. Altomare, M. Cascarano, C. Giacovazzo and
A. Guagliardi, J. Appl. Cryst., 1993, 26, 343.
16 TEXSAN, Structure analysis package, 1992, MSC, The Woodlands,
TX 77 381, USA.
§ Full crystallographic details, excluding structure factor tables, have
been deposited at the Cambridge Crystallographic Data Centre
(CCDC). For details of the deposition scheme, see ‘Instructions for
Authors’, J. Chem. Soc., Perkin Trans. 1, available via the RSC Web
page (http://www.rsc.org/authors). Any request to the CCDC for this
material should quote the full literature citation and the reference
number 207/178.
Paper 7/07661D
Received 23rd October 1997
Accepted 2nd December 1997
676
J. Chem. Soc., Perkin Trans. 1, 1998