Synthesis and properties of ring-deactivated deuterated (hydroxymethyl)pyrroles

Article abstract of DOI:10.1021/ja973656+

A sequence, based on a Mitsunobu displacement at the hydroxymethyl position of deuterium-labeled, N-substituted 2-(hydroxymethyl)pyrroles, is reported as a general procedure to determine the ability of the N-substituent to deactivate the heterocycle. An S

Full text of DOI:10.1021/ja973656+

J. Am. Chem. Soc. 1998, 120, 1741-1746
1741
Synthesis and Properties of Ring-Deactivated Deuterated
(Hydroxymethyl)pyrroles
Andrew D. Abell,*,† Brent K. Nabbs,† and Alan R. Battersby‡
Contribution from the Department of Chemistry, UniVersity of Canterbury, Christchurch, New Zealand,
and UniVersity Chemical Laboratory, Lensfield Road, Cambridge CB2 1EW, U.K.
ReceiVed October 21, 1997
Abstract: A sequence, based on a Mitsunobu displacement at the hydroxymethyl position of deuterium-labeled,
N-substituted 2-(hydroxymethyl)pyrroles, is reported as a general procedure to determine the ability of the
N-substituent to deactivate the heterocycle. An SN2 mechanism, in this reaction, has been shown to be favored
over reaction via an azafulvenium intermediate, by employing N-(trifluoromethyl)sulfonyl as the deactivating
group. Deuterium-labeling studies have demonstrated that suppression of contributions to the reaction from
an azafulvenium intermediate is less effective with other deactivating groups, and the order for deactivation
is triflyl > mesyl > BOC ≈ acetyl. The attachment of an electron-withdrawing group onto the nitrogen of a
2-formyl[formyl-d]pyrrole has also been shown to allow reduction to give a 2-(hydroxymethyl[methylene-
d1])pyrrole of high configurational purity. The utility of the N-triflyl group to deactivate a pyrrole was
demonstrated with the preparation of deuterium-labeled porphobilinogen precursor.
Introduction
Scheme 1
The introduction of an electron-withdrawing group (EWG)
on the nitrogen atom of a pyrrole results in a decrease in
aromaticity of the pyrrole ring.1-11 The resulting deactivated
pyrroles react with dienophiles in Diels-Alder reactions,2 are
readily reduced under Birch conditions,3 allow the synthesis of
2-substituted pyrroles via R-lithiation,4 and also undergo regio-
controlled acylation.4,5 An electron-withdrawing group on the
nitrogen atom of a pyrrole has also been observed to stabilize
intermediates in photocyclization reactions.6 As a result, the
deactivation of a pyrrole has attracted considerable interest as
a means of preparing pyrrole oligomers, terpyrroles, tropane
alkaloids, and numerous other synthetic targets.2-9
† University of Canterbury.
‡ University Chemical Laboratory.
(1) The Chemistry of Pyrroles; Jones, A. R., Bean, G. P., Eds.; Academic
Press: London, 1977. ComprehensiVe Heterocyclic Chemistry; Katritzky,
A. R., Rees, C. W., Ed.; Pergamon Press: Oxford, 1984; Vol. 4. Wallace,
D. M.; Leung, S. H.; Smith, K. M. J. Org. Chem. 1993, 58, 7245.
(2) Singh, S.; Basmadjian, G. P. Tetrahedron Lett. 1997, 38, 6829. Huang,
D. F.; Shen, T. Y. Tetrahedron Lett. 1993, 34, 4477. Davies, H. M. L.;
Saikali, E.; Young, W. B. J. Org. Chem. 1991, 56, 5696. Tanny, S. R.;
Grossman, J.; Fowler, F. W. J. Am. Chem. Soc. 1972, 94, 6495.
(3) Donnhoe, T. J.; Guyo, P. M. J. Org. Chem. 1996, 61, 7664.
(4) Gharpure, M.; Stoller, A.; Bellamy, F.; Firnau, G.; Snieckus, V.
Synthesis 1991, 1079.
(5) Xiao, D.; Schreier, J. A.; Cook, J. H.; Seybold, P. G.; Ketcha, D. M.
Tetrahedron Lett. 1996, 37, 1523. Kakushima, M.; Hamel, P.; Frenette, R.;
Rokach, J. J. Org. Chem. 1983, 48, 3214.
(6) Rawal, V. H.; Jones, R. J.; Cava, M. P. J. Org. Chem. 1987, 52, 19.
(7) Wang, J.; Scott, A. I. Tetrahedron Lett. 1996, 37, 3247.
(8) Tietze, L. F.; Kettschau, G.; Heitmann, K. Synthesis 1996, 851.
(9) Cf. Miller, A. D.; Leeper, F. J.; Battersby, A. R. J. Chem. Soc., Perkin
Trans. 1 1989, 1943.
The presence of an electron-withdrawing group on the pyrrole
nitrogen in compounds of type 3 is thought to suppress the
formation of highly reactive azafulvenium species 4 (Scheme
1). In the absence of such deactivation, (hydroxymethyl)-
pyrroles and (aminomethyl)pyrroles of type 1 readily react with
a nucleophile, via the postulated azafulvene intermediate 2, to
give products of type 5.1,10 A mechanism of this type has been
invoked to explain the increased susceptibility of these pyrroles
to nucleophilic substitution. Such a sequence involving azaful-
venes is thought to play a key role in the biosynthesis of
(hydroxymethyl)bilane (9) and uroporphyrinogen III (uro’gen
III) (10), important intermediates in the biosynthesis of por-
phyrins and corrins (Scheme 22).11 Here, porphobilinogen
(PBG) (6), the substrate for (hydroxymethyl)bilane synthase
(PBG deaminase), gives rise to the azafulvene 7 which becomes
covalently bound to the enzyme via a dipyrromethane cofactor.
This sets up the ES1 complex 8, and three further pyrrole units
are added to 8, again involving 7, to generate an enzyme bound
tetrapyrrole which is released as (hydroxymethyl)bilane (9). The
current view is that the azafulvene 11 is the intermediate which
reacts with water to afford 9. (Hydroxymethyl)bilane (9) then
(10) Barcock, R. A.; Moorcroft, N. A.; Storr, R. C. Tetrahedron Lett.
1993, 34, 1187.
(11) Battersby, A. R.; Fookes, C. J. R.; Gustafson-Potter, K. E.;
McDonald, E.; Matcham, G. W. T. J. Chem. Soc., Perkin Trans. 1 1982,
2427. Battersby, A. R., Leeper, F. J. Chem. ReV. (Washington, D.C.) 1990,
90, 1261. Scott, A. I. In AdVances in Detailed Reaction Mechanisms:
Mechanisms of Biological Importance; Coxon, J. M., Ed.; JAI Press:
Greenwich, 1992; pp 189-212.
S0002-7863(97)03656-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 02/12/1998

1742 J. Am. Chem. Soc., Vol. 120, No. 8, 1998
Abell et al.
Scheme 2
A number of different substituents have been used to
deactivate and/or protect pyrroles. Examples of these groups
include phenylsulfonyl, tert-butoxycarbonyl (BOC), tert-butyl-
carbamoyl, dimethylamino, trialkylsilyl, [2-(trimethylsilyl)-
ethoxy]methyl (SEM), trityl, and alkoxycarbonyl. In this paper
we present a general method to assess the ability of an EWG to
deactivate a pyrrole. The information gained in these studies
was then used to develop a synthesis of the deuterium-labeled
(hydroxymethyl)pyrrole 13. Compound 13 is a key synthetic
intermediate en route to labeled porphobilinogen (6b), which
is a very useful tool for studying the biosynthesis of naturally
occurring porphyrins and corrins.14 We suggest that an N-triflyl
group should be employed whenever deactivation of a pyrrole
is required.
Results and Discussion
We chose to study the conversion of deuterium-labeled
(hydroxymethyl)pyrroles of type 14 into the corresponding
camphanates 16 (for specific examples see Schemes 5 and 8),
under both Mitsunobu15 conditions (Scheme 3, conditions b)
and via reaction with (1S)-(-)-camphanic chloride (Scheme
3, conditions a), as a means of assessing the deactivating ability
of an N-protecting group (R substituent in 14). The camphanate
group was chosen to provide a chiral handle to discriminate
between the hydrogens on the pyrrolic methylene group of 16.
Reaction of 14 with the acid chloride provided reference
1
camphanate samples for H NMR analysis where the configu-
rational purity at the deuterium-labeled center of 14 was
maintained and indeed measurable (Scheme 3, pathway a).
However, reaction of 14 with (1S)-(-)-camphanic acid, under
Mitsunobu conditions, can occur via either an azafulvene, 15,
resulting in scrambling of the deuterium label, or an SN2
mechanism to give inversion of configuration at the labeled
center, yielding 16b (Scheme 3, pathway b). The Mitsunobu
conditions were chosen since they are known to promote
substitution with inversion of configuration.15
acts as the substrate for a second enzyme, cosynthetase, which
brings about cyclization with inversion of ring-D to yield
uro’gen III (10). Again, the mechanism of this cyclization
probably involves the azafulvene 11.
Scheme 3
Figure 1.
The idea of suppressing azafulvene formation by the intro-
duction of an EWG has also been used to develop latent reactive
inhibitors of serine proteases.12 Here, a (hydroxymethyl)pyrrole
derivative (e.g., 12) is stabilized by N-acylation with an amino
acidschosen to be recognized by the target enzyme. Enzyme-
catalyzed deacylation yields a reactive azafulvene, 2, which is
then thought to lead to covalent inactivation of the enzyme (see
Scheme 1 where Nu- is an amino acid in the enzyme’s active
site). Despite their implication in numerous examples of
pyrrole-based chemistry, simple 1-azafulvenes such as 2, have
not been characterized; however, some more complex examples
have been isolated.1,10,13
It was considered that the greater the deactivating ability of
the R group on the pyrrolic nitrogen the less would be the
contribution from the azafulvene mechanism. A comparison
of the stereochemical integrity at the deuterium-labeled center
(12) Abell, A. D.; Litten, J. C. Tetrahedron Lett. 1992, 33, 3005. Abell,
A. D.; Litten, J. C. Aust. J. Chem. 1993, 46, 1473.
(13) Bray, B. L.; Muchowski, J. M. Can. J. Chem. 1990, 68, 1305.
(14) Schauder, J.-R.; Jendrezejewski, S.; Abell, A. D.; Hart, G. J.;
Battersby, A. R. J. Chem. Soc., Chem. Commun. 1987, 436.
(15) Mitsunobu, O. Synthesis 1981, 1.

Ring-DeactiVated Deuterated (Hydroxymethyl)pyrroles
J. Am. Chem. Soc., Vol. 120, No. 8, 1998 1743
Scheme 4
Scheme 5
in 16, derived from the Mitsunobu sequence on a range of
substrates 14 (Scheme 3, reaction conditions b), would then
provide an assessment of the deactivating ability of R.
Table 1. 1H NMR Analysis of the Methylene (*) of 23, 24, and
Deuterium-Labeling Studies. The key deuterium-labeled
formylpyrrole 17b was readily prepared by Vilsmeier formy-
lation of pyrrole using phosphorus oxychloride and DMF-d7
(Scheme 4). The N-(trifluoromethyl)sulfonyl-protected formylpyr-
roles 18a and 19a were conveniently prepared by reacting 17a
or 17b with trifluoromethanesulfonic anhydride in the presence
of diisopropylethylamine. The remaining N-protected formylpyr-
roles 18b-d and 19b-d were prepared by reacting the pyrrole
anion of either 17a or 17b (prepared by treatment with sodium
hydride) with methanesulfonyl chloride, 2-(tert-butoxycarbo-
nyloxyimino)-2-phenylacetonitrile (BOC-ON), or acetyl chlo-
ride (Scheme 4). The unlabeled (hydroxymethyl)pyrroles
20a-d were then conveniently prepared by reducing the
N-protected formylpyrroles 18a-d with zinc borohydride. The
corresponding deuterium-labeled analogues, 21a-d and 22a-
d, were prepared by reduction of 19a-d with (S)-Alpine-Borane
(B-isopinocampheyl-9-borobicyclo[3.3.1]nonane) and (R)-Alpine-
Borane,16 respectively (Scheme 4).
25
The configurational purities of 21a-d and 22a-d were
determined by conversion into the camphanates 24a-d and
25a-d by reaction with (1S)-(-)-camphanic chloride (see
Table 1 and Scheme 5, reaction conditions a). The unlabeled
camphanates 23a-d were similarly prepared as reference
1
1
compounds for subsequent H NMR analysis. The H NMR
spectra of the unlabeled reference compounds 23a-d revealed
that, in each case, the resonance for the (hydroxymethyl)pyrrole
methylene group was observed as an AB quartet (Table 1, last
row of spectra). The corresponding resonances for the deuterium-
labeled analogues 24a-d and 25a-d were observed as singlets
with distinguishable chemical shifts (see Table 1, first four rows
of spectra). The relative integrals of these signals gave a
measure of the stereochemical purity of the camphanate samples,
and hence of the precursor (hydroxymethyl)pyrroles 21a-d and
22a-d derived from both the (S)-Alpine-Borane and (R)-Alpine-
Borane routes (Schemes 3 and 4).
a DMAP, diisopropylethylamine, (1S)-(-)-camphanic chloride. b Ph3P,
DEAD, (1S)-(-)-camphanic acid (Mitsunobu conditions). c Reaction
sequence was performed using unlabeled 18a-d to give 23a-d.
An analysis of the data obtained for the sequence using (S)-
Alpine-Borane, followed by camphanate formation according
to method a in Table 1 (first row of spectra), revealed
(16) Midland, M. M.; Tramontano, A.; Zderic, S. A. J. Am. Chem. Soc.
1979, 101, 2352.

1744 J. Am. Chem. Soc., Vol. 120, No. 8, 1998
Abell et al.
Scheme 6
Scheme 7
comparable ratios of 25 to 24 for the triflyl, mesyl, BOC, and
acetyl series (∼1:9 for 25a/24a, 25b/24b, 25c/24c, and 25d/
24d). Importantly, the series derived from reduction of 19a-d
with and (R)-Alpine-Borane gave the opposite isomers 25a-d
as the major products (Table 1, third row of spectra). The series
derived from the (R)-Alpine-Borane reductions gave a slightly
higher excess of the major isomers 22a-d and hence 25a-d.
Scheme 8
In the crucial experiments, separate samples of 21a-d, of
known configurational purity, were treated with (1S)-(-)-
camphanic acid under Mitsunobu conditions (Scheme 5, reaction
conditions b). The results of an 1H NMR analysis of the
camphanates from these reactions, 24a-d and 25a-d, are given
in Table 1, second row of spectra. The ratio of 25 to 24,
observed on reaction of the N-(trifluoromethyl)sulfonyl (triflyl),
N-methylsulfonyl (mesyl), N-tert-butoxycarbonyl (BOC), and
N-acetyl series, were ∼5:1, ∼3:2, ∼5:4, and ∼1:1, respectively
(the initial ratios of 22a-d to 21a-d, used in their preparation,
were ∼1:9). The major isomers formed in these reactions, the
camphanates 25a-c, are the products of an inversion of
configuration due to an SN2 displacement on 21a-c under the
Mitsunobu conditions (Scheme 3). The higher the proportion
of configuration 25 relative to configuration 24 in these products,
the greater has been the effectiveness of the EWG used in
disfavoring involvement of the azafulvenium 15. The N-triflyl
group of 21a promotes substitution via an SN2 mechanism
almost exclusively to give 25a. At the other extreme, the
N-acetyl and N-BOC systems, 21c and 21d, allow substantial
substitution via an azafulvenium mechanism. The equivalent
Mitsunobu reactions of (1S)-(-)-camphanic acid with 22a-d
gave complementary results to those obtained for the reactions
of 21a-d as discussed above (Table 1, fourth row of spectra).
Finally, the absolute configurations of 24a-d and 25a-d,
although being consistent with literature reports for Alpine-
Borane reductions,16 were confirmed by ozonizing a sample
containing a ∼3:2 mixture of 24b and 25b and trapping the
resulting acid with an excess of diazomethane to give a ∼3:2
mixture of 26a and 26b (Scheme 6). An 1H NMR spectrum of
this mixture was consistent with data from authentic samples
of 26 and the unlabeled analogue 35.14,17
and finally hydrogenolysis in the presence of platinum(IV)
oxide, gave 31b.
The conclusion from the labeling experiments is that the order
for the deactivating ability of the pyrrole N-protecting groups
considered in this study is triflyl > mesyl > BOC ≈ acetyl.
The deactivating ability of the N-triflyl group was then used in
the synthesis of the deuterium-labeled (hydroxymethyl)pyrroles
13 (Scheme 8). This compound is a key synthetic intermediate
to labeled porphobilinogen (6b) (Figure 1), a very useful tool
for studying the biosynthesis of naturally occurring porphyrins
and corrins.14
The subsequent synthesis of the deuterium-labeled (hy-
droxymethyl)pyrroles 13 is detailed in Scheme 8. The unlabeled
and deuterium-labeled formylpyrroles 31a18 and 31b were
converted into the corresponding N-triflyl derivatives 32a and
32b using trifluoromethanesulfonic anhydride.9 Reduction of
32a with sodium borohydride gave the (hydroxymethyl)pyrrole9
33 which was converted into its camphanate 34 by reaction with
(1S)-(-)-camphanic chloride. Reduction of the deuterium-
labeled analogue 32b with (R)-Alpine-Borane gave a mixture
of 13a and 13b (∼1:9). The configurational purity of the
mixture of 13a and 13b was determined by a sequence involving
reaction with (1S)-(-)-camphanic chloride, to give 36a and
Synthesis of Deuterium-Labeled Porphobilinogen Precur-
sor. The R-free pyrrole benzyl ester 2718 was formylated under
Vilsmeier conditions using DMF-d7 to give the labeled formylpyr-
role 28 (Scheme 7). TFA-catalyzed hydrolysis of the benzyl
ester, followed by reaction with iodine and potassium iodide
(18) Battersby, A. R.; Ihara, M.; McDonald, E.; Saunders: J.; Wells, R.
J. J. Chem. Soc., Perkin Trans. 1 1976, 283.
(17) Arigoni, D.; Besmer, P. (see Besmer, P. Diss. ETH, No. 4435, 1970).

Ring-DeactiVated Deuterated (Hydroxymethyl)pyrroles
J. Am. Chem. Soc., Vol. 120, No. 8, 1998 1745
General Procedure D: Camphanate Preparation Using (-)-
Camphanic Chloride. The (hydroxymethyl)pyrrole (typically 0.12
mmol), DMAP (1 equiv), and diisopropylethylamine (1.2 equiv) were
dissolved in dichloromethane (8 mL) at rt. (1S)-(-)-Camphanic
chloride (1.2 equiv), dissolved in dichloromethane (2 mL), was added,
and the resultant solution was stirred for 24 h. The solution was
extracted with ethyl acetate (10 mL), and the organic phase was washed
with 10% aqueous citric acid (10 mL) and water (2 × 10 mL), dried,
and evaporated under reduced pressure. The resultant oil was purified
by silica chromatography. See the Supporting Information for details.
General Procedure E: Camphanate Preparation Using Mit-
sunobu Conditions. The (hydroxymethyl)pyrrole (typically 0.11
mmol), triphenylphosphine (1.3 equiv), and (1S)-(-)-camphanic acid
(1.5 equiv) were dissolved in THF (2 mL), and the solution was stirred
under N2, at rt, for 5 min. Diethyl azodicarboxylate (1.5 equiv) was
added, and the resultant solution was stirred for 3 h. The solvent was
evaporated under reduced pressure, and the resultant oil was purified
by silica chromatography. See the Supporting Information for details.
[formyl-d1]-2-formyl-4-((methoxycarbonyl)ethyl)-3-((methoxycar-
bonyl)methyl)pyrrole 31b. DMF-d7 (99 atoms %, 2.38 g) was stirred
at 0 °C under nitrogen, and freshly distilled phosphorus oxychloride
(4.92 g) was added dropwise. Dry acetonitrile (16 mL) was added
followed by the R-free pyrrole 2718 (7.91 g, 0.02 mmol) and more
acetonitrile (16 mL). After being stirred at rt for 45 h, the solution
was transferred under nitrogen into a mixture of methanol-d1/deuterium
oxide (90 mL, 2:1). This solution was warmed to 40 °C over 30 min,
aqueous potassium carbonate (300 mL, 2%) was added, and the product
was extracted into dichloromethane (4 × 50 mL). The combined
organic phases were dried and evaporated under reduced pressure.
Recrystallization of the residue from dichloromethane/ether/hexane gave
28 (8.49 g, 99%), mp 78-81 °C (unlabeled analog22 mp 77-81 °C).
A mixture of sulfuric acid (30 drops, 98%) and TFA (4 mL) was
added to a stirred solution of 28 (1.05 g). After the mixture was stirred
at rt for 30 min, the TFA was removed under reduced pressure, and
the residue was partitioned between aqueous sodium carbonate (50 mL,
5%) and ethyl acetate (150 mL). The aqueous layer, together with
subsequent aqueous sodium carbonate washings (3 × 20 mL, 5%) of
the ethyl acetate layer, was washed with ethyl acetate (50 mL) and
acidified to pH 1 using aqueous sulfuric acid (10%). The mixture was
extracted into ethyl acetate (3 × 100 mL), washed with brine (50 mL),
dried, and evaporated under reduced pressure. The brown solid was
chromatographed on silica (methanol/ether, 5:95), and the product 29
was recrystallized from dichloromethane/hexane (615 mg, 76%), mp
129-132 °C.
A mixture of the foregoing carboxylic acid 29 (600 mg) and sodium
hydrogen carbonate (480 mg) in chloroform (12 mL) and water (8 mL)
was stirred vigorously and heated to reflux. An aqueous solution of
iodine and potassium iodide (4.5 mL, 1 M in KI and 0.5 M in I2) was
added, and heating was continued for 5 min. After a further 0.5 h at
rt aqueous sodium hydrogen sulfite (10%) was added to neutralize the
excess iodine. The organic layer, together with subsequent dichlo-
romethane washings (4 × 15 mL), was dried and evaporated under
reduced pressure to give 30 (628 mg, 83%) as a pink oil which
crystallized on standing. A solution of the crude 30 (590 mg) in
methanol (40 mL) was stirred under a hydrogen atmosphere with
sodium acetate (600 mg) and platinum(IV) oxide (90 mg) until uptake
ceased (1 h). The catalyst was removed (Celite), and after the addition
of sodium hydrogen carbonate (150 mg) the filtrate was evaporated.
Water (120 mL) was added, and the mixture was extracted with
dichloromethane (5 × 25 mL). The combined organic extracts were
dried and evaporated under reduced pressure. The residue was
chromatographed on silica (ether) and recrystallization from dichlo-
romethane/ether/hexane gave 31b (249 mg, 63%), mp 97-99 °C
(unlabeled analog22 mp 97-98 °C).
36b, followed by ozonolysis and methylation to give the known
reference compounds14,17 26a and 26b (∼1:9 by 1H NMR). The
observed excess of 13b over 13a is consistent with the (R)-
Alpine-Borane reductions of 21 and 22, Table 1. The unlabeled
analogues 34 and 35 were also prepared for comparison.
(Hydroxymethyl)pyrroles of type 13 have been converted into
the corresponding PBG analogues 6b by a sequence involving
conversion of the alcohol into an azide under Mitsunobu
conditions (inversion of configuration) followed by reduction
and N-deprotection.14
Conclusion. SN2 displacements at the hydroxymethyl group
of compounds of type 3, Scheme 1, are favored by use of
N-triflyl as the deactivating group and Mitsunobu reaction
conditions. The suppression of contributions to the reaction
from azafulvenium intermediates 4 is less effective with other
deactivating groups, and the order for deactivation is triflyl >
mesyl > BOC ≈ acetyl. An N-triflyl group should, therefore,
be employed when maximum deactivation of a pyrrole ring is
desired. Attachment of an N-triflyl group onto a 2-formyl-
[formyl-d]pyrrole also allows it to be converted into a 2-(hy-
droxymethyl[methylene-d1])pyrrole of high configurational pu-
rity. It has been assumed that the introduction of an electron-
withdrawing group onto a pyrrole nitrogen, as in 3, suppresses
the formation of highly reactive azafulvenium intermediates 4,
but until now little direct evidence for this has been available.
Experimental Section
General Methods. Melting points were obtained using a hot stage
microscope and are uncorrected. 1H and 13C NMR spectra were
recorded on a Varian Unity 300 spectrometer, a Varian XL-300
spectrometer, or a Bruker AM400 spectrometer in the specified solvent
and at a probe temperature of 23 °C unless otherwise specified. Infrared
spectra were obtained using a Perkin-Elmer 1600 FTIR spectropho-
tometer. Mass spectra were obtained on a Kratos MS80RFA magnetic
sector double focusing mass spectrometer. Petroleum ether refers to a
hydrocarbon fraction of bp 60-70 °C.
General Procedure A: N-Acylation of Pyrrole-2-carboxaldehyde.
To a stirred suspension of sodium hydride (typically 1.26 mmol, 80%
suspension in oil washed twice with dry petroleum ether) in THF (6
mL) was added the pyrrole aldehyde 17a or 17b (typically 1.09 mmol)
dissolved in dry THF (2 mL). After the mixture was stirred at room
temperature (rt) for 15 min, the electrophile (typically 1.2-1.4 equiv)
in dry THF (2 mL) was slowly added, and stirring was continued for
60 min at rt. Water (10 mL) was added, the THF was removed under
reduced pressure, and the aqueous residue was extracted with dichlo-
romethane (4 × 15 mL). The combined organic phases were washed
with saturated aqueous sodium hydrogen carbonate (10 mL), water (10
mL), and brine (10 mL), dried (MgSO4), and concentrated under
reduced pressure. The residue was purified by chromatography on
silica. See the Supporting Information for details.
General Procedure B: Zinc Borohydride Reductions. The
N-substituted pyrrole-2-carboxaldehyde (typically 0.16 mmol) was
dissolved in ether (10 mL) at 0 °C under N2. Zn(BH4)2 (1 equiv of a
0.14 M solution in ether) was added, and the resultant solution was
stirred at 0 °C for 30 min. Water (2 mL) and glacial acetic acid (2
mL, 10% solution in water) were carefully added to quench the reaction.
The separated aqueous phase was extracted with dichloromethane (2
× 10 mL), and the combined organic phases were washed with water
(2 × 10 mL) and brine (10 mL), dried, and concentrated under reduced
pressure. The residue was purified by chromatography on silica. See
the Supporting Information for details.
General Procedure C: Alpine-Borane Reductions. The N-
substituted pyrrole-2-carboxaldehyde (typically 0.49 mmol) was dis-
solved in THF (10 mL) at rt under N2. (R)- or (S)-Alpine-borane (1.1
equiv of 0.5 M solution in THF) was added, and the resultant solution
was stirred at rt for 4 h. The volatiles were removed under reduced
pressure, and the resultant oil was purified by chromatography on silica.
See the Supporting Information for details.
(19) Silverstein, R.; Ryskiewicz, E. E.; Willard, C. In Organic Syntheses;
Rabjohn, N., Ed.; John Wiley and Sons: New York, Collect. Vol. 4, 1963;
pp 831-833.
(20) Merrill, B. A.; LeGoff, E. J. Org. Chem. 1990, 55, 2904.
(21) Nickisch, K.; Klose, W.; Bohlmann F. Chem. Ber. 1980, 113, 2036-
2037.
(22) Battersby, A. R.; Hunt, E.; McDonald, E.; Paine III, J. B.; Saunders:
J. J. Chem. Soc., Perkin Trans. 1 1976, 1008.

1746 J. Am. Chem. Soc., Vol. 120, No. 8, 1998
Abell et al.
[formyl-d1]-2-Formyl- and 2-Formyl-4-((methoxycarbonyl)ethyl)-
3-((methoxycarbonyl)methyl)-1-((trifluoromethyl)sulfonyl)pyrrole
(32b and 32a). The d-formylpyrrole 31b (400 mg, 1.21 mmol) in
dichloromethane (30 mL), containing diisopropylethylamine (550 µL,
2 equiv), was cooled to -78 °C under argon. Trifluoromethanesulfonic
anhydride (480 µL, 1.8 equiv) was added dropwise, and after 5 min
the resulting brown solution was poured onto saturated aqueous sodium
hydrogen carbonate (40 mL). The organic phase, together with
subsequent dichloromethane washings (2 × 15 mL), was dried and
evaporated under reduced pressure. Purification by preparative TLC
(ether/hexane, 2:1) gave 32b (197 mg, 45%). HRMS m/z 386.0480
(calcd for C13H13DF3NO7S 386.0506).
sample of (R)-Alpine-Borane (0.6 mL, 0.5 M in THF) was added, and
the solution was left for 1 h. 2-Aminoethanol was added, and the
resulting precipitate was removed by filtration. The filtrate was washed
with water, dried, and evaporated under reduced pressure. Purification
by silica preparative TLC (ether/hexane, 9:1) gave 13a and 13b as a
colorless oil (192 mg, 95%, 10:90 from an analysis of the corresponding
camphanates): 1H NMR data identical with those described for 33
except for δH 4.68 (s, 1H, -CHDOH); HRMS m/z 388.0631 (calcd
for C13H15DF3NO7S 388.0662).
Reaction of the mixture of 13a and 13b according to the general
procedure D gave 36a and 36b (90%, 10:90): 1H NMR data identical
with those described for 34 except for δH 5.29 (s, 1H, -CHDO); HRMS
m/z 568.1443 (calcd for C23H27DF3NO10 568.1449).
The unlabeled formyltriflylpyrrole 32a, similarly prepared from 31a,
was fully characterized: mp 39-41 °C; IR (CHCl3) 2950, 1755, 1660
Ozonolyses. (1) A mixture of 24b and 25b (17.0 mg, 0.05 mmol,
∼3:2) was dissolved in dichloromethane and loaded onto silica (1 g,
50-100 mesh) by evaporation under reduced pressure. The residue
was cooled to -78 °C, and ozone was bubbled through the silica until
a blue color persisted (approximately 20 min). After warming to rt,
the products were eluted from the silica with ethyl acetate. The solvent
was removed under reduced pressure, and the residue was dissolved in
methanol (10 mL) and treated with an excess of diazomethane.
Purification on silica (ethyl acetate/petroleum ether, 1:2) gave a mixture
1
cm-1; UV λmax 283, 256 nm; H NMR (CDCl3, 400 MHz) δ 2.60 (m,
2H, CH2CH2CO), 2.77 (m, 2H, CH2CH2CO), 3.68 (s, 3H, OMe), 3.71
(s, 3H, OMe), 3.94 (s, 2H, CH2CO), 7.15 (s, 1H, pyrrole-H), 10.10 (s,
1H, CHO). Anal. Calcd for C13H14F3NO7S: C, 40.5; H, 3.7; N, 3.6.
Found: C, 40.5; H, 3.6; N, 3.6.
[4-((Methoxycarbonyl)ethyl)-3-((methoxycarbonyl)methyl)-1-
((trifluoromethyl)sulfonyl)pyrrol-2-yl]methyl Camphanate (34). The
formylpyrrole 32a (600 mg, 1.56 mmol) was dissolved in dichlo-
romethane (20 mL) and methanol (10 mL), and the solution was cooled
to 0 °C. Sodium borohydride (90 mg) was added portionwise with
stirring, and after 30 min the mixture was partitioned between
dichloromethane (20 mL) and aqueous oxalic acid (10 mL, 10%). The
organic layer, together with subsequent dichloromethane washings (2
× 10 mL), was washed with water (10 mL), dried, and evaporated
under reduced pressure. The residue was purified by preparative TLC
(ether) to give 33 (432 mg, 72%) as a colorless oil which was not
purified further: 1H NMR (CDCl3, 400 MHz) δ 2.58 (t, 2H, t, J ) 7.5
Hz, CH2CH2CO), 2.72 (t, 2H, J ) 7.5 Hz, CH2CH2CO), 2.81 (br, 1H,
OH), 3.52 (s, 2H, CH2CO), 3.68 (s, 3H, OMe), 3.72 (s, 3H, OMe),
4.68 (d, 2H, J ) 4.6 Hz, CH2OH), 6.90 (s, 1H, pyrrole-H); HRMS m/z
387.0573 (calcd for C13H16F3NO7S 387.0599).
1
of 26a and 26b (5.1 mg, 39%, ∼3:2 by H NMR) as a colorless oil:
14,17 IR (CHCl3) 1788, 1727 cm-1; 1H NMR (CDCl3, 300 MHz) δ (ppm)
1.04 (s, 3H, camph-Me), 1.11 (s, 3H, camph-Me), 1.14 (s, 3H, camph-
Me), 1.73 (m, 1H, camph-CH2), 1.98 (m, 1H, camph-CH2), 2.10 (m,
1H, camph-CH2), 2.48 (m, 1H, camph-CH2), 3.34 (s, 3H, CO2Me), 4.76
(s, 0.6H, CHDO-camph, 26a), 4.83 (s, 0.4H, CHDO-camph, 26b); 13
C
NMR (CDCl3, 75 MHz) δ 9.6, 16.6, 16.6, 28.8, 30.8, 41.8, 54.9, 54.9,
62.5 (t, J ) 23.0 Hz), 90.8, 165.5, 166.7, 178.0.
(2) A similar treatment of a mixture of 36a and 36b (35 mg, ∼1:9)
1
gave 26a and 26b (6 mg, 19%, ∼1:9 by H NMR).
(3) The reaction was repeated using a sample of 34 to give 3517 (21
mg, 41%) as a colorless oil.
Reaction of 33 according to the general method D gave 34 (80%):
Acknowledgment. The work at Christchurch was supported,
in part, by a research grant from the Marsden Fund (New
Zealand) and at Cambridge by a grant from EPSRC (U.K.).
1
IR (film) 3140, 3100, 2950, 1750, 1730 cm-1; H NMR (CDCl3, 400
MHz) δ 0.92, 1.02, and 1.08 (each 3H, s, 3 × Me), 1.65, 1.68, 1.92,
and 2.38 (each 1H, m), 2.59 (t, 2H, J ) 7.5 Hz, CH2CH2CO), 2 73 (t,
2H, J ) 7.5 Hz, CH2CH2CO), 3.58 (s, 2H, CH2CO), 3.67 (s, 3H, OMe),
3.69 (s, 3H, OMe), 5.29 (s, 2H, CH2O), 6.97 (s, 1H, pyrrole-H). Anal.
Calcd for C23H28F3NO10S: C, 48.7; H, 5.0; N, 2.5. Found: C, 48.8;
H, 5.1; N, 2.5.
Supporting Information Available: Supplementary data on
the preparation of compounds 17b, 18a-d, 19a-d, 20a-d,
1
21a-d, 22a-d, 23a-d, 24a-d, and 25a-d and copies of H
[[11-methylene-d1]-4-((methoxycarbonyl)ethyl)-3-((methoxycar-
bonyl)methyl)-1-((trifluoromethyl)sulfonyl)pyrrol-2-yl]methyl Cam-
phanates 36a and 36b. The labeled pyrrole 32b (200 mg, 0.52 mmol)
was stirred with (R)-Alpine-Borane [prepared from (1R)-(+)-R-pinene
(103 µL) and 9-BBN (1.17 mL, 0.5 M in THF)] at rt for 2 h. A further
NMR spectra of compounds for which no elemental analysis
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