2-Trimethylsilylethanesulfonyl (SES) versus tosyl (Ts) protecting group in the preparation of nitrogen-containing five-membered rings. A novel route for the synthesis of substituted pyrrolines and pyrrolidines

Article abstract of DOI:10.1021/jo062239p

(Chemical Equation Presented) The 2-trimethylsilylethanesulfonyl (or SES) protecting group was compared to the tosyl (Ts) group in the preparation of a nitrogen-containing five-membered ring obtained by the aza-Baylis - Hillman/alkylation/RCM route. While

Full text of DOI:10.1021/jo062239p

SCHEME 1
2-Trimethylsilylethanesulfonyl (SES) versus Tosyl
(Ts) Protecting Group in the Preparation of
Nitrogen-Containing Five-Membered Rings. A
Novel Route for the Synthesis of Substituted
Pyrrolines and Pyrrolidines
Vale´rie Declerck,†,§ Hassan Allouchi,‡ Jean Martinez,† and
Fre´de´ric Lamaty*,†
Laboratoire des Aminoacides, Peptides et Prote´ines (LAPP),
CNRS, UniVersite´s Montpellier 1 et 2, Place Euge`ne Bataillon,
34095 Montpellier Cedex 5, France, and Laboratoire de Chimie
Physique, SPOT E.A. 3857, UniVersite´ Franc¸ois Rabelais,
Faculte´ de Pharmacie, 31 AVenue Monge, 37200 Tours, France
organic synthesis. The reaction between protected ammonia, an
aldehyde, and an acrylate derivative yields highly functionalized
R-methylene â-aminoesters which can be used in further
transformations (Scheme 1).
One intermediate involved in the reaction is an imine
derivative arising from the reaction of protected ammonia with
the aldehyde. The best results are obtained when the protecting
group is a sulfonyl group which activates ammonia as a
sulfonamide. The newly formed sulfonamide can be easily
alkylated using a mild base or a Mitsunobu reaction. Further
transformations can provide an efficient access to heterocyclic
compounds.
frederic.lamaty@uniV-montp2.fr
ReceiVed October 29, 2006
The tosyl (Ts) group is a protecting sulfonyl group, widely
used for the preparation of heterocycles. One major drawback
of this protecting group is the difficulty of cleavage at the end
of the synthesis to release a free amine. Many examples in the
area of heterocyclic chemistry do not provide methods for the
deprotection step10 unless an oxidative elimination is possible
usually leading to an aromatic compound.11 Recently, we have
investigated the use of the 2-trimethylsilylethanesulfonyl (or
SES) group12,13 as an alternate to the Ts group in the aza-
Baylis-Hillman reaction and for the further preparation of
heterocycles.8 We report herein that, in contrast to the Ts group,
the cleavage of the SES group in five-membered cyclic
compounds can be tuned to provide either an aromatic hetero-
cycle by oxidative elimination or a free-amino deprotected
compound. The first examples of free amine pyrrolines and
pyrrolidines obtained by the aza-Baylis-Hillman/ring closing
metathesis (RCM) route are presented.
The 2-trimethylsilylethanesulfonyl (or SES) protecting group
was compared to the tosyl (Ts) group in the preparation of
a nitrogen-containing five-membered ring obtained by the
aza-Baylis-Hillman/alkylation/RCM route. While deprotec-
tion of Ts-protected pyrrolines gave only pyrroles, depro-
tection of the same SES-protected compounds gave either
pyrroles or free amine pyrrolines depending on the depro-
tection conditions. The SES-protected pyrrolines were hy-
drogenated to yield pyrrolidines with an excellent diastere-
oselectivity. Free amine pyrrolidines were obtained by HF-
mediated deprotection of the SES group.
Ts- and SES-protected â-aminoesters, 1a and 1b, respectively,
were prepared according to previously described methods4,8
(Scheme 2). Both of the aminoesters were allylated using allyl
bromide in the presence of potassium carbonate to yield dienes
2a and 2b, respectively, in quantitative yield.8,14 Both dienes
The three component aza-Baylis-Hillman reaction1-9 is a
powerful method for the preparation of useful synthons in
* To whom correspondence should be addressed. Fax: +33 (0) 4 67 14 48
66.
† Universite´s de Montpellier 1 et 2.
‡ Universite´ Franc¸ois Rabelais.
§ Present address: Department of Chemistry, Wayne State University, Detroit,
Michigan 48202-3489, USA.
(10) For examples in the case of five-membered rings, see: (a) Chang,
M.-Y.; Pai, C.-L.; Kung, Y.-H. Tetrahedron Lett. 2006, 47, 855-859. (b)
Dondas, H. A.; Clique, B.; Cetinkaya, B.; Grigg, R.; Kilner, C.; Morris, J.;
Sridharan, V. Tetrahedron 2005, 61, 10652-10666. (c) Grigg, R.; Martin,
W.; Morris, J.; Sridharan, V. Tetrahedron 2005, 61, 11380-11392. (d) Kim,
B. G.; Snapper, M. L. J. Am. Chem. Soc. 2006, 128, 52-53. (e) Morita,
N.; Krause, N. Org. Lett. 2004, 6, 4121-4123. (f) Ma, S.; Yu, F.; Gao, W.
J. Org. Chem. 2003, 68, 5943-5949.
(1) Bertenshaw, S.; Kahn, M. Tetrahedron Lett. 1989, 30, 2731-2732.
(2) Richter, H.; Jung, G. Tetrahedron Lett. 1998, 39, 2729-2730.
(3) Balan, D.; Adolfsson, H. J. Org. Chem. 2001, 66, 6498-6501.
(4) Balan, D.; Adolfsson, H. J. Org. Chem. 2002, 67, 2329-2334.
(5) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2003, 44, 2521-2524.
(6) Ribie`re, P.; Enjalbal, C.; Aubagnac, J.-L.; Yadav-Bhatnagar, N.;
Martinez, J.; Lamaty, F. J. Comb. Chem. 2004, 6, 464-467.
(7) Ribie`re, P.; Yadav-Bhatnagar, N.; Martinez, J.; Lamaty, F. QSAR
Comb. Sci. 2004, 23, 911-914.
(8) Declerck, V.; Ribie`re, P.; Martinez, J.; Lamaty, F. J. Org. Chem.
2004, 69, 8372-8381.
(9) Vasudevan, A.; Tseng, P.-S.; Djuric, S. W. Tetrahedron Lett. 2006,
47, 8591-8593.
(11) (a) Xu, Z.; Lu, X. J. Org. Chem. 1998, 63, 5031-5041. (b) Nandi,
B.; Kundu, N. G. Org. Lett. 2000, 2, 235-238. (c) Kundu, N. G.; Nandi,
B. J. Org. Chem. 2001, 66, 4563-4575.
(12) Weinreb, S. M.; Demko, D. M.; Lessen, T. A.; Demers, J. P.
Tetrahedron Lett. 1986, 27, 2099-2102.
(13) Ribie`re, P.; Declerck, V.; Martinez, J.; Lamaty, F. Chem. ReV. 2006,
106, 2249-2269.
10.1021/jo062239p CCC: $37.00 © 2007 American Chemical Society
Published on Web 01/20/2007
1518
J. Org. Chem. 2007, 72, 1518-1521

SCHEME 2
SCHEME 3
presence of fluoride ions to provide the deprotected molecule
by elimination of SO2 and ethylene.13 In some cases, harsh
conditions are needed to achieve deprotection, and the oxidative
elimination can be a competitive process.8,11,15,16 When 3b was
reacted with a variety of fluoride sources in THF or DMF (CsF,
n-Bu4NF (TBAF), n-Bu4NSiF2Ph3 (TBAT), ((CH3)2N)3S((CH3)3-
SiF2) (TASF)), only pyrrole 4 was obtained, albeit in lower yield
than in the case of the base-promoted deprotection. The presence
of the unprotected pyrroline could not be detected. Finally, 3b
was reacted with neat hydrofluoric acid.17 (Caution: HF is an
extremely dangerous and toxic chemical). In this case, pyrroline
3b was completely deprotected to give the pyrroline 5b as an
hydrofluoride salt, with no traces of pyrrole 4. As a comparison,
Ts-protected 3a was reacted with HF. Neither trace of the
pyrrole nor trace of the pyrroline could be detected; the starting
material was completely recovered. Other HF-based reagents
such as HF‚pyridine and HF in H2O were tried to deprotect 3b,
but no reaction occurred.
were subjected to ring closing metathesis using the second
generation Grubbs’ catalyst to provide pyrrolines 3a and 3b in
a very good yield.
We have explored the deprotection step for both compounds
3a and 3b (Scheme 3). SES-protected pyrroline 3b was easily
deprotected by dehydrodesulfinylation/aromatization to yield the
corresponding pyrrole 4. This deprotection was performed with
t-BuOK in DMF. Under the same conditions, Ts-protected
pyrroline 3a gave the same product in a similar yield. It has to
be noted that preparation of pyrrole 4 starting from 3a and 3b
has been previously reported, but in these cases, the fluoride-
mediated oxidative elimination gave lower yields.11
As described in Scheme 4, the two deprotection pathways
are conceivable. In the first one, performed with a base or a
fluoride salt with either the Ts or SES protecting group, the
acidic proton, in the R position to the phenyl ring, was
abstracted. Elimination followed by aromatization yielded the
pyrrole. Alternatively, in the case of the SES group, reaction
with HF resulted first in the protonation of the nitrogen atom,18
which prevented proton abstraction in the R position to nitrogen.
The attack of the fluoride anion on the trimethylsilyl group
triggered the elimination of the SES group to release the
Then we investigated other fluoride sources which should
give the free amino compound rather than the pyrrole 4, starting
from 3b. The SES protecting group is usually removed in the
SCHEME 4
J. Org. Chem, Vol. 72, No. 4, 2007 1519

FIGURE 1. Examples of free amine pyrrolines.
Pyrroline 3b (R2 ) Ph) was hydrogenated using H2 in the
presence of Pd/C to give the SES-protected pyrrolidine 6b in a
quantitative yield. Deprotection of 6b with neat HF yielded
quantitatively the pyrrolidine 7b. Deprotection with other
fluoride salts did not provide any tractable substance.
6b and 7b were obtained as only one diastereoisomer, and
their relative stereochemistry was deduced from X-ray analysis
of a crystalline derivative obtained by reaction of 7b with
4-nitrobenzenesulfonylchloride in the presence of triethylamine
to give the Ns-pyrrolidine 8 (eq 1). X-ray analysis of compound
8 shows that the substituents are in a trans position relative to
each other. The deprotection conditions were not tested on the
Ns-protected pyrrolidine 8.
TABLE 1. Yields of 3, 5, 6, and 7
SES pyrrolidines 6
SES
pyrrolines 5
pyrrolidines 7
yield (%)
pyrrolines 3
yield (%)
yield (%)
trans/cis
b
c
d
e
f
100
100
100
100
100
100
99
99
99
99
100
99:1
95:5
99:1
91:9
91:9
100
100
100
100
100
b
g
a
a Hydrogenation resulted in the formation of a mixture of 6g and 6b in
a 9/1 ratio. b Not performed.
FIGURE 2. Hydrogen attack from the bottom face of 3b.
In contrast to reported results obtained with a similar five-
membered ring carbocycle,19 hydrogenation did not occur
opposite to the phenyl ring, which would lead to the formation
of the cis isomer. In the case of the pyrroline, most probably
for steric reasons, the SES group is hindering the face of the
cyclic structure opposite to the phenyl moiety. Consequently,
hydrogen will react on the olefin from the same side as the
phenyl ring. This will result in a trans relationship between the
phenyl and the methoxycarbonyl substituents, as shown in
Figure 2.
SCHEME 5
An alternative pathway would be the possibility for 6 to
epimerize during the course of the hydrogenation. In all cases,
a good diastereoselectivity was obtained as long as pyrrolines
3 were exempt from ruthenium traces which could remain from
the RCM step. When some ruthenium was present, pyrrolidines
3 were obtained as a mixture of cis/trans isomers. Conditions
for epimerization (Pd/C in MeOH or DBU in refluxing toluene)
were tested on these pyrrolidines 3. The cis/trans ratio remained
unchanged, showing that the diastereoselectivity did not result
from epimerization.
pyrroline. This elimination was all the more facilitated since
the protonated nitrogen was electron deficient. In this reaction,
the methyl ester was not hydrolyzed.
The deprotection procedure was applied to various SES-
protected pyrrolines 3b-g to give 5b-g (Figure 1) in quantita-
tive yields (Table 1).
To further enlarge the scope of this strategy, we decided to
reduce the SES-protected pyrrolines 3b-g to pyrrolidines and
investigate the deprotection step of the SES group (Scheme 5).
Hydrogenation of pyrrolines 3c-f was performed and gave
a quantitative yield of the pyrrolidines 6c-f. In the case of 3g,
the iodine carbon bond present on the phenyl ring was partially
reduced, and a 9/1 ratio of 6g/6b was obtained.
In conclusion, we have extended the utility of the SES as a
versatile protecting group for the preparation of heterocyclic
structures. The presence of the sulfonamide contributed to the
efficiency of the aza-Baylis-Hillman, alkylation, and RCM
(14) Balan, D.; Adolfsson, H. Tetrahedron Lett. 2004, 45, 3089-3092.
(15) Kozlowski, M. C.; Bartlett, P. A. J. Org. Chem. 1996, 61, 7681-
7696.
(16) Parker, K. A.; Mindt, T. L. Org. Lett. 2002, 4, 4265-4268.
(17) Boger, D. L.; Ledeboer, M. W.; Kume, M. J. Am. Chem. Soc. 1999,
121, 1098-1099.
(19) Lee, K. Y.; Na, J. E.; Lee, J. Y.; Kim, J. N. Bull. Korean Chem.
Soc. 2004, 25, 1280-1282.
(18) Laughlin, R. G. J. Am. Chem. Soc. 1967, 89, 4268-4271.
1520 J. Org. Chem., Vol. 72, No. 4, 2007

was placed under hydrogen atmosphere. After 2 h, the mixture was
filtered through Celite and evaporated to yield the SES pyrrolidine
6.
reactions. In the case of the five-membered ring synthesized
herein, deprotection of the SES can be tuned to obtain from
one intermediate either aromatic pyrroles20,21 or pyrrolines. In
this regard, the SES group proved to be superior to the tosyl
group. Hydrogenation of the SES-protected pyrrolines followed
by HF-mediated deprotection yielded pyrrolidines with an
excellent yield and diastereomeric ratio.
Methyl 2-Phenyl-1-(2-(trimethylsilyl)ethanesulfonyl)pyrrolidine-
3-carboxylate (6b). Hydrogenation of the SES pyrroline 3b yielded
73.2 mg (99%) of the SES pyrrolidine 6b (trans/cis ratio ) 99:1).
1
trans Isomer: IR 2955 (m), 1736 (s), 1332 (s) cm-1; H NMR
(CDCl3, Me4Si) δ -0.06 (s, 9H), 0.75-1.00 (m, 2H), 2.20-2.30
(m, 2H), 2.50-2.80 (m, 2H), 3.00-3.10 (m, 1H), 3.55-3.70 (m,
1H), 3.70 (s, 3H), 3.75-3.95 (m, 1H), 5.17 (d, 1H, J3 ) 4.8 Hz),
7.20-7.40 (m, 5H); 13C NMR (CDCl3, Me4Si) δ -2.1, 9.8, 28.3,
47.9, 48.6, 52.3, 53.3, 65.3, 126.4, 127.8, 128.7, 141.6, 172.7;
ESIMS m/z 370.1 (M + H)+, 392.1 (M + Na)+, 739.2 (2M +
H)+, 761.2 (2M + Na)+; FAB+ m/z 370 (M + H)+, 392 (M +
Na)+; HRMS calcd for C17H28NO4SSi 370.1508, found 370.1478.
General Protocol for Deprotection of the SES Pyrrolidines 6
with HF. SES pyrrolidine 6 (0.1 mmol) was treated with 1 mL of
anhydrous HF at 0 °C for 1 h in a Teflon vessel. The HF was
removed by distillation. The residue was dissolved in methanol and
evaporated to give HF‚pyrrolidine 7.
Experimental Section
General Protocol for Deprotection of the SES Pyrrolines 3
with HF. SES pyrroline 3 (0.1 mmol) was treated with 1 mL of
anhydrous HF at 0 °C for 1 h in a Teflon vessel. The HF was
removed by distillation. The residue was dissolved in methanol and
evaporated to give HF‚pyrroline 5.
Methyl 2-Phenyl-2,5-dihydro-1H-pyrrole-3-carboxylate Hy-
drofluoride (5b). Deprotection of the compound 3b according to
the general procedure yielded 22.3 mg (100%) of the title compound
as a white solid: 1H NMR (CD3OD, Me4Si) δ 3.65 (s, 3H), 4.30-
4.50 (m, 2H), 5.80-5.90 (m, 1H), 7.11 (dd, 1H, J4 ) 4.0 Hz, J4 )
2.1 Hz), 7.40-7.50 (m, 5H); 13C NMR (CD3OD, Me4Si) δ 52.6,
52.7, 68.9, 129.4, 130.5, 131.1, 134.7, 135.4, 138.7, 163.1; ESIMS
m/z 204.1 (M - F)+; FAB+ m/z 204 (M - F)+; HRMS calcd for
C12H14NO2 204.1025, found 204.1021.
Methyl 2-Phenylpyrrolidine-3-carboxylate Hydrofluoride (7b).
Deprotection of the compound 6b according to the general
procedure yielded 22.5 mg (100%) of the title compound (trans/
1
cis ratio ) 99:1) as a white solid. trans Isomer: H NMR (CD3-
OD, Me4Si) δ 2.25-2.65 (m, 2H), 3.40-3.60 (m, 3H), 3.68 (s,
3H), 4.17 (d, 1H, J3 ) 9.8 Hz), 7.40-7.50 (m, 5H); 13C NMR
(CD3OD, Me4Si) δ 29.8, 46.3, 49.8, 53.0, 66.4, 129.0, 130.4, 130.7,
135.6, 173.3; ESIMS m/z 206.1 (M - F)+; FAB+ m/z 204 (M -
F)+; HRMS calcd for C12H16NO2 206.1181, found 206.1187.
General Protocol for Hydrogenation of SES Pyrrolines 3. To
a solution of the SES pyrroline 3 (0.20 mmol) in 4 mL of methanol
was added palladium on charcoal (10%, 10% w/w). The mixture
(20) For a review on the RCM approach for the preparation of aromatic
compounds, see: Donohoe, T. J.; Orr, A. J.; Bingham, M. Angew. Chem.,
Int. Ed. 2006, 45, 2664-2670.
(21) For examples of pyrrole synthesis via the RCM route, see: (a) Yang,
C.; Murray, W. V.; Wilson, L. J. Tetrahedron Lett. 2003, 44, 1783-1786.
(b) Dieltiens, N.; Stevens, C. V.; De Vos, D.; Allaert, B.; Drozdzak, R.;
Verpoort, F. Tetrahedron Lett. 2004, 45, 8995-8998. (c) Dieltiens, N.;
Stevens, C. V.; Allaert, B.; Verpoort, F. ARKIVOC 2005, 92-97.
Supporting Information Available: Experimental details,
1
spectral data, and copies of H and 13C NMR spectra for all new
compounds, X-ray structure and crystal data for compound 8 in
CIF format. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO062239P
J. Org. Chem, Vol. 72, No. 4, 2007 1521