Fluoride-catalyzed addition of PhSCF2SiMe3 to N-substituted cyclic imides followed by radical cyclization: General synthetic strategy of gem-difluoromethylenated 1-azabicyclic compounds

Article abstract of DOI:10.1021/jo802794u

(Chemical Equation Presented) PhSCF₂SiMe₃ (1) was found, for the first time, to undergo fluoride-catalyzed nucleophilic difluoro(phenylsulfanyl)methylation reaction to cyclic imides 2, affording the corresponding adducts 3 in moderat

Full text of DOI:10.1021/jo802794u

Fluoride-Catalyzed Addition of PhSCF2SiMe3 to N-Substituted
Cyclic Imides Followed by Radical Cyclization: General Synthetic
Strategy of gem-Difluoromethylenated 1-Azabicyclic Compounds
Teerawut Bootwicha,† Duanghathai Panichakul,† Chutima Kuhakarn,† Samran Prabpai,†,‡
Palangpon Kongsaeree,†,‡ Patoomratana Tuchinda,† Vichai Reutrakul,† and
Manat Pohmakotr*,†
Department of Chemistry and Center for InnoVation in Chemistry (PERCH-CIC), Center for Excellence in
Protein Structure and Function, Faculty of Science, Mahidol UniVersity, Rama VI Road,
Bangkok 10400, Thailand
scmpk@mahidol.ac.th
ReceiVed December 23, 2008
PhSCF2SiMe3 (1) was found, for the first time, to undergo fluoride-catalyzed nucleophilic difluoro-
(phenylsulfanyl)methylation reaction to cyclic imides 2, affording the corresponding adducts 3 in moderate
to good yields. Reductive cleavage of the phenylsulfanyl group of N-alkylated adducts 3 with Bu3SnH/
AIBN yielded gem-difluoromethylated products 4. Under the same reduction conditions, N-alkenylated
and N-alkynylated adducts 3 afforded the corresponding gem-difluoromethylenated 1-azabicyclic
compounds 5 and 6 with trans stereoselectivity. These compounds were employed as precursors for
preparing substituted gem-difluoromethylenated pyrrolizidinones and indolizidinones 7 and 8 by treatment
with Et3SiH/BF3 · OEt2, and compounds 9 and 10 by nucleophilic displacement of the hydroxyl group,
using organosilanes in the presence of BF3 · OEt2. The synthesis of highly substituted gem-difluorom-
ethylenated pyrrolizidines 13 and 14 was also demonstrated.
Introduction
of drug molecules.2 Therefore, syntheses of gem-difluorometh-
ylenated analogs of natural products have been extensively
investigated.3 Few general synthetic methods for constructing
gem-Difluoromethylene moiety has been incorporated into
bioactive compounds due to its properties as an isopolar and
isosteric substituent for an oxygen.1 The presence of the gem-
difluoromethylene group can enhance the biological properties
(2) See for examples: (a) Welch, J. T. Ed.; SelectiVe Fluorination in Organic
and Bioorganic Chemistry; American Chemical Society: Washington, D.C., 1991.
(b) Fried, J.; Mitra, D. K.; Nagarajan, M.; Mehrotra, M. M. J. Med. Chem. 1980,
23, 234–237. (c) Nakano, T.; Makino, M.; Morizawa, Y.; Matsumura, Y. Angew.
Chem., Int. Ed. Engl. 1996, 35, 1019–1021. (d) Chang, C.-S.; Negishi, M.;
Nakano, T.; Morizawa, Y.; Matsumura, Y.; Ichikawa, A. Prostaglandins 1997,
53, 83–90.
(3) Soloshonok, V. A., Ed. Enantiocontrolled Synthesis of Fluoro-organic
Compounds, Stereochemical Challenges and Biomedicinal Targets; John Wiley
and Sons, Ltd.: New York, 1999.
† Department of Chemistry and Center for Innovation in Chemistry
(PERCH-CIC).
‡ Center for Excellence in Protein Structure and Function.
(1) (a) Hiyama, T., Ed. Organofluorine Compounds, Chemistry and Applica-
tions; Springer: New York, 2000. (b) Hiyama, T.; Shimizu, M. Angew. Chem.,
Int. Ed 2005, 44, 214–231, and references cited.
3798 J. Org. Chem. 2009, 74, 3798–3805
10.1021/jo802794u CCC: $40.75 2009 American Chemical Society
Published on Web 04/16/2009

gem-Difluoromethylenated 1-Azabicyclic Compounds
SCHEME 1. Fluoride-Catalyzed Nucleophilic
Difluoro(phenylsulfanyl)methylation of 1 with Imides 2 and
Synthetic Conversion of the Resulting Adducts 3 into
Compounds 4, 5, and 6 and Subsequently to Compounds 13
and 14
gem-difluoromethylenated compounds were previously re-
ported.4 It is still desirable to develop new flexible and facile
strategies for the preparation of these compounds. Recently,
PhSCF2SiMe3 (1) has been demonstrated as a useful gem-
difluoromethylene building block.5 Compound 1 reacts exten-
sively with carbonyl derivatives,6 γ-ketoesters,7 imines,8 and
alkyl bromides,9 providing convenient routes for the preparation
of the corresponding gem-difluoromethylated alcohols, γ-lac-
tones, amines, and alkanes, respectively. Furthermore, the
stereoselective difluoromethylenation of chiral imines using
PhSCF2SiMe3 (1) and the synthesis of chiral disubstituted gem-
difluoromethylenated pyrrolidines have been recently
reported.10a In addition, alternative new entries to assemble
various fluorinated S-, O-, and N-heterocycles have also been
developed.10b-d
As a part of our ongoing research interest in developing
methodologies for the preparation of 1-azabicyclic derivatives,11
we sought for a general method to synthesize gem-difluorom-
ethylenated 1-azabicyclic analogs, employing 1 as a gem-
difluoromethylene building block. It has been demonstrated that
cyclic imides can undergo fluoride-catalyzed trifluoromethyla-
tion, using (trifluoromethyl)trimethylsilane (CF3SiMe3).12 Hence,
it is anticipated that fluoride-catalyzed nucleophilic difluoro-
(phenylsulfanyl)methylation of 1 to cyclic imides 2 would
generate the corresponding adducts 3. When R groups of adducts
3 are allylic and homoallylic, reductive cleavage of the
corresponding phenylsulfanyl moiety could afford radical
intermediate that should then undergo intramolecular radical
cyclization, providing gem-difluoromethylenated 1-azabicyclic
compounds 5 and 6, respectively (Scheme 1). Furthermore,
nucleophilic displacement of the hydroxyl group and subsequent
organometallic addition to carbonyl group followed by reduction
would lead to highly substituted difluoromethylenated 1-azabi-
cyclic compounds 13 and 14. The proposed synthetic operations
are summarized in Scheme 1.
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Chem. 2007, 72, 8559–8561. (c) Fustero, S.; Ferna´ndez, B.; Sanz-Cervera, J. F.;
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Chem. 2006, 71, 4118–4129. (e) You, Z.-W.; Zhang, X.; Qing, F.-L. Synthesis
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Chem. 2006, 71, 7261–7267. (g) Fustero, S.; Sa´nchez-Rosello´, M.; Rodrigo, V.;
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Arimitsu, S.; Hammond, G. B. J. Org. Chem. 2006, 71, 8665–8668. (i) Zheng,
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2006, 2039–2042. (m) Qin, Y.-Y.; Yang, Y.-Y.; Qiu, X.-L.; Qing, F.-L. Synthesis
2006, 1475–1479. (n) Sato, K.; Tarui, A.; Matsuda, S.; Omote, M.; Ando, A.;
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Makosza, M. J. Org. Chem. 2008, 73, 5436–5441. (s) Hang, X.-C.; Chen, Q.-
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Results and Discussion
The initial investigation involved fluoride-catalyzed nucleo-
philic difluoro(phenylsulfanyl)methylation of imide 2a with
PhSCF2SiMe3 (1). The expected adduct 3a was obtained in 95%
yield when the reaction was carried out using 10 mol % of
anhydrous tetrabutylammonium fluoride (TBAF) in dry THF
at -78 °C to room temperature overnight followed by acidic
workup (2 M HCl; Table 1, entry 1). To demonstrate the
generality of the reaction, the reactions of 1 with N-substituted
phthalimide and succinimide derivatives, which were prepared
by base-catalyzed N-alkylation of imides13 with alkylating agents
(Table 1, entries 1-6, 8, 10-13, 15 and 17), Mitsunobu reaction
of imides with alcohols14 (Table 1, entries 7, 14 and 16), and
cross-olefin metathesis15 of N-alkenylated imides with alkenes
(Table 1, entries 9 and 18), were investigated. The results are
summarized in Table 1. Except for some cases, the reactions of
1 with imide derivatives conducted under the standard conditions
as for 3a readily gave the corresponding adducts; yields range
from moderate to good (Table 1). In case of imide 2i, under
the standard conditions, adduct with double bond transposition
was obtained as a major product (33% yield). Gratifyingly, the
reaction employing tetrabutylammonium triphenyldifluorosili-
cate (TBAT) in place of TBAF gave adduct 3i in moderate yield
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Verniest, G.; Surmont, R.; Hende, E. V.; Deweweire, A.; Deroose, F.; Thuring,
J. W.; De Kimpe, N. J. Org. Chem. 2008, 73, 5458–5461. (c) Kishi, Y.; Nagura,
H.; Inagi, S.; Fuchigami, T. Chem. Commun. 2008, 3876–3878. (d) Hende, E. V.;
Verniest, G.; De Kimpe, N. J. Org. Chem. 2009, 74, 2250–2253.
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Reutrakul, V. Org. Biomol. Chem. 2003, 1, 3495–3497. (b) Pohmakotr, M.;
Prateeptongkum, S.; Chooprayoon, S.; Tuchinda, P.; Reutrakul, V. Tetrahedron
2008, 64, 2339–2347. (c) Pohmakotr, M.; Seubsai, A.; Numeechai, P.; Tuchinda,
P. Synthesis 2008, 1733–1736.
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Diederich, F. Chem. Med. Chem. 2006, 1, 1205–1215.
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4775.
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Sano, T. J. Am. Chem. Soc. 1972, 94, 679–680. (c) Martin, S. F.; Chen, H. J.;
Courtney, A. K.; Liao, Y.; Pa¨tzel, M.; Ramser, M. N.; Wagman, A. S.
Tetrahedron 1996, 52, 7251–7264.
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1923. (b) McElhinney, A. D.; Marsden, S. P. Synlett 2005, 2528–2530.
J. Org. Chem. Vol. 74, No. 10, 2009 3799

Bootwicha et al.
TABLE 1. Preparation of Adducts 3, gem-Difluoromethylated Lactams 4, and gem-Difluoromethylenated 1-Azabicyclic Compounds 5 or 6
a Isolated yields. b Unless otherwise noted, all reactions were carried out employing 10 mol % TBAF/THF, -78 °C to rt. c By using 10 mol %
TBAT/DMF, -78 °C to rt. d By using 10 mol % TBAT/THF, -78 to 15 °C, 5 h. e By using 10 mol % TBAT/THF, -78 °C to rt. f Ratio of E- and
Z-isomers was determined by 1H NMR integration of the crude product. g Ratios of isomers (trans/cis) were determined by 1H NMR integration of the
crude products.
(55%) and the double bond transposition adduct was not
observed (Table 1, entry 9). It is also worth mentioning that
the reaction of 1 with N-trimethylsilylpropargyl succinimide 2n
under the standard conditions furnished the expected product
3n in only 2% yield, but the desilylated adduct 3o was obtained
as a major product (30% yield). However, the reaction employ-
ing 10 mol % of TBAT in dry DMF at -78 °C to room
temperature gave the desired product 3n in 45% yield together
with 3o (10% yield; Table 1, entry 14). Similar results, that is,
3n (40% yield) and 3o (8% yield) were obtained when the
reaction was carried out using THF as the solvent. Interestingly,
treatment of 1 with N-propargylphthalimide 2m employing 10
mol % TBAT in DMF at -78 °C to room temperature
unexpectedly provided trimethylsilylated derivative 3m in 68%
yield (Table 1, entry 13).
The reductive desulfenylation of adducts 3a-e was achieved
by treating with Bu3SnH and a catalytic amount of AIBN in
refluxing toluene. The gem-difluoromethylated products 4a-e
were obtained in moderate to good yields (66-86%; Table 1,
3800 J. Org. Chem. Vol. 74, No. 10, 2009

gem-Difluoromethylenated 1-Azabicyclic Compounds
SCHEME 2. Proposed Transition States for the Radical Cyclization
entries 1-5).6b,16 The gem-difluoromethyl radical intermediate,
generated by CF2-SPh bond cleavage of the adducts 3 contain-
ing the N-unsaturated substituents, could be trapped intramo-
lecularly by an unsaturated functional moiety,17 affording gem-
difluoromethylenated 1-azabicyclic compounds 5. Thus, under
similar radical conditions, intramolecular radical cyclization of
3f readily proceeded to provide 5a in 73% yield as a 94:6
mixture of trans- to cis-isomers together with a small amount
of the corresponding reduced product. A single trans-5a was
obtained in pure form after purification by either preparative
thin-layer chromatography on silica gel or crystallization. Its
relative stereochemistry was established by X-ray crystal-
lography (see Supporting Information).
To demonstrate the efficiency and viability of our methodol-
ogy, series of gem-difluoromethylenated pyrrolizidine derivatives
5b-g, as mixtures of isomers, were synthesized, in moderate
to good yields, by treatment of adducts 3g-l under standard
radical conditions (Table 1, entries 7-12). Based on the X-ray
crystallographic data of the major trans-isomer of 5a, we
assumed that the trans-isomers of 5b-g were the major isomers.
Notably, similar radical cyclization of N-propargyl substituted
adducts proceeded smoothly, providing the cyclized products
in moderate yields (Table 1, entries 13-15). Cyclization of
silylated alkynyl derivatives 3m and 3n afforded compounds
5h and 5i as a mixture of E- and Z-isomers. The E-isomer was
obtained as a major isomer, of which the stereochemistry was
established by NOE experiments (see Supporting Information).
Irradiation of the olefinic proton of 5h or 5i led to no
enhancement of the allylic protons. The formation of tributyl-
stannylated product 5j (Table 1, entry 15) presumably resulted
from consecutive addition of the tributylstannyl group to the
triple bond followed by gem-difluoromethyl radical addition to
the resulting vinylstannane derivative.18 The presence of the
exocyclic methylene moiety in compounds of types 5h and 5i
should be valuable for further synthetic modification.
Having established an efficient access to gem-difluorometh-
ylenated pyrrolizidine derivatives 5, we further demonstrated
that our method could be used as a general route for the
synthesis of gem-difluoromethylenated indolizidine derivatives
6. Thus, N-homoallylated adducts 3p-r were treated with
Bu3SnH/AIBN in refluxing toluene, yielding the corresponding
gem-difluoromethylenated indolizidines 6a-c as a mixture of
trans- and cis-isomers (Table 1, entries 16-18). The relative
stereochemistry of the major trans-6a was confirmed by X-ray
crystallography (see Supporting Information).
(16) Buttle, L. A.; Motherwell, W. B. Tetrahedron Lett. 1994, 35, 3995–
3998.
(17) Radical mediated the construction of 1-azabicyclic compounds, see for
examples: (a) Zard, S. Z. Radical Reactions in Organic Synthesis; Oxford
University Press: New York, 2003. (b) Chen, M.-J.; Tsai, Y.-M. Tetrahedron
Lett. 2007, 48, 6271–6274. (c) Bryans, J. S.; Large, J. M.; Parsons, A. F. J. Chem.
Soc., Perkin Trans. 1 1999, 2905–2910. (d) Keusenkothen, P. F.; Smith, M. B.
Tetrahedron 1992, 48, 2977–2992. (e) Knapp, S.; Gibson, F. S. J. Org. Chem.
1992, 57, 4802–4809. (f) Knapp, S.; Gibson, F. S.; Choe, Y. H. Tetrahedron
Lett. 1990, 31, 5397–5400. (g) Burnett, D. A.; Choi, J.-K.; Hart, D. J.; Tsai,
Y.-M. J. Am. Chem. Soc. 1984, 106, 8201–8209. (h) Hart, D. J.; Tsai, Y.-M.
J. Am. Chem. Soc. 1984, 106, 8209–8217. (i) Choi, J.-K.; Hart, D. J.; Tsai, Y.-
M. Tetrahedron Lett. 1982, 23, 4765–4768.
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J. Org. Chem. Vol. 74, No. 10, 2009 3801

Bootwicha et al.
SCHEME 3. Lewis Acid-Catalyzed Nucleophilic Substitution of the Hydroxyl Group of Compounds 5b and 6a
SCHEME 4. Proposed Transition States for the Formation
of trans-Isomers of Products 7-10
The stereochemical outcomes of compounds 5 and 6 can be
rationalized as shown in Scheme 2. The radical mediated
cyclization was proposed to proceed via 5-exo or 6-exo
cyclization mode.19 Transition states A and C are energetically
more favorable due to minimized steric interaction between the
pseudoaxial hydroxyl group and the vinylic double bond,
resulting in the formation of thermodynamically more stable
trans-isomer of pyrrolidine or piperidine heterocycles.
Having a general route to synthesize derivatives 5 and 6, we
subsequently focused on the synthetic utilities of these adducts
as precursors for the preparation of substituted gem-difluorom-
ethylenated pyrrolizidines and indolizidines. It is anticipated that
the presence of hydroxyl group in adducts 5 and 6 should
provide a convenient access to an iminium intermediate,20,21
which, in principle, can be trapped by an appropriate nucleo-
phile. The results are summarized in Scheme 3. The adducts
5b (trans/cis; 77:23) and 6a (trans/cis; 88:12) were reduced
with BF3 ·OEt2 and Et3SiH22 in CH2Cl2 at -78 °C to room
temperature, generating the corresponding lactams 7 (77% yield)
and 8 (98% yield) as a single isomer, as confirmed by the NOE
experiments (see Supporting Information). Alkylation of 5b with
Grignard reagents (MeMgBr or i-PrMgCl in THF in the presence
of BF3 ·OEt2 at 0 °C to rt, overnight) or organocoppers
(n-Bu2CuLi or n-Bu2Cu(CN)Li2 in THF in the presence of
BF3 ·OEt2 at -30 °C to rt overnight) was unsuccessful, and only
starting material was recovered. However, allylation reaction
of 5b, employing allyltrimethylsilane with BF3 ·OEt2 in CH2Cl2
at -78 °C to rt overnight, led to 9a in low yield (10% yield)
together with recovery of 5b. Gratifyingly, when the reaction
was performed under refluxing conditions for 3 h, 9a was
obtained in moderate yield (67% yield). Similarly, under the
same conditions, 10a was synthesized in 53% yield from the
corresponding compound 6a. Both compounds 9a and 10a were
obtained as a single isomer (see Supporting Information).
Similarly, treatment of 5b and 6a with cinnamyltrimethylsilane
afforded adducts 9b and 10b, respectively, as a mixture of
diastereomers, as shown in Scheme 3. The reactions of 5b and
6a with phenyltrimethylsilylacetylene employing trimethylsilyl
triflate (TMSOTf) as the Lewis acid at -78 °C to rt overnight
provided the respective adducts 9c (54% yield as a 93:7 mixture
of isomers) and 10c (67% yield as a 86:14 mixture of isomers).
The use of BF3 ·OEt2, SnCl4, and TiCl4 did not furnish to the
desired products but led to the recovery of the starting material
5b and phenylacetylene. This result may be due to extensive
decomposition of phenyltrimethylsilylacetylene to phenylacety-
lene prior to its addition to iminium ion intermediate. The
relative trans stereochemistries of adducts 7 and 9 could be
rationalized based on the fact that the nucleophiles (hydride or
organosilanes) attack the initially formed iminium ion interme-
diate from the face opposite to the benzyl group to avoid steric
interaction (Scheme 4). In addition, attack of nucleophiles to
the iminium ion derived from 6a from the pseudoaxial direction
(19) (a) Beckwith, A. L. J. Tetrahedron 1981, 37, 3073–3100. (b) Spellmeyer,
D. C.; Houk, K. N. J. Org. Chem. 1987, 52, 959–974.
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Speckamp, W. N. In Houben-Weyl, StereoselectiVe Synthesis; Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; Thieme Medical Publishers:
New York, 1995; Vol. E21, p 1953. (b) Speckamp, W. N.; Moolenaar, M. J.
Tetrahedron 2000, 56, 3817–3856. (c) Maryanoff, B. E.; Zhang, H.-C.; Cohen,
J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. ReV. 2004, 104, 1431–1628.
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carbon nucleophiles, see: (a) Raheem, I. T.; Thiara, P. S.; Jacobsen, E. N. Org.
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Simpkins, N. S.; Wilson, C. Tetrahedron Lett. 2007, 48, 5942–5947. (f)
Tranchant, M.-J.; Moine, C.; Othman, R. B.; Bousquet, T.; Othman, M.; Dalla,
V. Tetrahedron Lett. 2006, 47, 4477–4480. (g) Osante, I.; Lete, E.; Sotomayor,
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3802 J. Org. Chem. Vol. 74, No. 10, 2009

gem-Difluoromethylenated 1-Azabicyclic Compounds
SCHEME 5. Preparation of Alkyl-Substituted gem-Difluoromethylenated Pyrrolizidines 11, 13, and 14 and Indolizidine 12
could be further explained by stereoelectronic principle, leading
preferably to the trans-isomers of adducts 8 and 10.
carbonyl group of the γ-lactam moiety, followed by reduction
of the resulting adducts with NaBH3CN. The synthetic applica-
tion of our method for preparation of gem-difluoromethylenated
analogs of some polyhydroxylated natural products is currently
being investigated.
The conversions of compounds 9a and 10a to alkyl-
substituted gem-difluoromethylenated pyrrolizidines and in-
dolizidines proceeded smoothly (Scheme 5). Reduction of
compounds 9a and 10a using LiAlH4 in refluxing THF provided
the corresponding gem-difluoromethylenated pyrrolizidine 11
(84% yield) and indolizidine 12 (60% yield), respectively
(Scheme 5). The reaction of 9a with n-BuLi/CeCl3 in THF23
followed by acidification generating in situ iminium ion
intermediate, which was subsequently reduced by sodium
cyanoborohydride (NaBH3CN) to afford butyl-substituted gem-
difluoromethylenated pyrrolizidine 13 in 80% yield as a single
diastereomer. Similarly, a single diastereomer of isopropyl-
substituted gem-difluoromethylenated pyrrolizidine 14 was
produced in 65% yield. The relative stereochemistries of
compounds 11-14 were established by NOE experiments (see
Supporting Information). The observed stereochemical outcomes
of the reactions can be explained that the addition of organo-
metallic reagents followed by acidification afforded iminium
ions which were preferably reduced from the less sterically
hindered face opposite to the allyl substituent (Scheme 5). It is
worth mentioning that compound 10a did not react with either
n-BuLi/CeCl3 or i-PrMgCl in THF under the same conditions
as for 9a.
Experimental Section
General Procedure for the Preparation of Compounds 3.
2-Benzyl-3-(difluoro(phenylsulfanyl)methyl)-3-hydroxy-isoindolin-
1-one (3a). To a mixture of compound 1 (0.928 g, 4 mmol) and
2-benzylisoindoline-1,3-dione (2a; 0.470 g, 2 mmol) in THF (5
mL), was added 10 mol % TBAF (0.4 mL, 0.4 mmol, 1 M solution
in THF). The reaction mixture was stirred at -78 °C followed by
slowly warming up to room temperature overnight. The solution
was quenched with 1 M HCl (3 mL) and extracted with EtOAc (3
× 25 mL). The organic phase was washed successively with water
and brine and dried over anhydrous Na2SO4. After solvent removal,
the crude product was purified by radial chromatography (SiO2,
10-20% EtOAc in hexanes) to give a white crystal of 3a (0.753
1
g, 95% yield, mp ) 142-144 °C). H NMR (300 MHz, CDCl3):
δ 7.86-7.83 (m, 1H, ArH), 7.72-7.68 (m, 1H, ArH), 7.60-7.58
(m, 2H, ArH), 7.35-7.25 (m, 3H, ArH), 7.20-7.10 (m, 7H, ArH),
4.95 (d, J ) 15.6 Hz, 1H, CHH), 4.45 (d, J ) 15.6 Hz, 1H, CHH),
3.85 (br s, 1H, OH). 13C NMR (125 MHz, CDCl3): δ 168.3 (CdO),
141.9 (C), 137.5 (2 × C), 136.7 (2 × CH), 132.8 (CH), 131.5 (C),
131.0 (2 × CH), 130.1 (CH), 129.24 (t, J ) 187.5 Hz, CF2), 129.0
(2 × CH), 128.5 (3 × CH), 127.4 (CH), 124.2 (CH), 123.8 (CH),
91.2 (t, J ) 25.0 Hz, C), 43.5 (CH2). 19F NMR (470 MHz, CDCl3):
δ -80.48 (d, J ) 211.0 Hz, 1F), -81.57 (d, J ) 211.0 Hz, 1F). IR
(nujol): νmax 3207br, 1682s, 1612s, 1612m, 1497m, 1471s, 1456s,
1455s, 1427m, 1397s, 1361s, 1163s, 1137m, 1108m, 1073m, 1061s,
1027m, 1012m, 974m, 945m, 907m, 897m, 886m, 845m, 823m,
770s, 752s, 709s, 700s, 690s cm-1. MS: m/z (%) relative intensity
398 (M+, 10), 380 (7), 250 (6), 238 (47), 161 (11), 160 (100), 91
(20), 65 (7). HRMS (ESI-TOF) Calcd for C22H17F2NO2SNa [M +
Na]+, 420.0846; found, 420.0851.
Conclusion
In conclusion, we have successfully developed for the novel
fluoride-catalyzed nucleophilic difluoro(phenylsulfanyl)meth-
ylation reactions of PhSCF2SiMe3 to succinic and phthalimide
derivatives. The resulting adducts were employed as useful
precursors for the preparation of gem-difluoromethylenated
pyrrolizidines and indolizidines. The synthetic operation involves
sequential intramolecular radical cyclization, nucleophilic dis-
placement of the hydroxyl functionality using Lewis acid/
allyltrimethylsilanes or trimethylsilylacetylenes, organometallic
addition employing n-BuLi/CeCl3 and i-PrMgCl onto the
General Procedure for the Reductive Cyclization of Com-
pounds 3 to Compounds 5. Preparation of 1,1-Difluoro-9b-
hydroxy-2-methyl-2,3-dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-
one (5a). Argon was bubbled through a solution of 3f (0.374 g, 1
mmol) in toluene (2 mL) for 30 min, and a mixture of Bu3SnH
(0.47 mL, 1.75 mmol) and AIBN (25 mg, 0.15 mmol) in toluene
(23) Nukui, S.; Sodeoka, M.; Sasai, H.; Shibasaki, M. J. Org. Chem. 1995,
60, 398–404.
J. Org. Chem. Vol. 74, No. 10, 2009 3803

Bootwicha et al.
(8 mL) was added dropwise at reflux over a 1 h period followed
by refluxing for an additional 4 h. Volatiles were evaporated and
the tin byproduct were removed by column chromatography (SiO2,
CH2Cl2 then EtOAc) to give a crude product, which was purified
by column chromatography (SiO2, 20% EtOAc in hexanes) to afford
white crystals of 5a (0.191 g, 73% yield, mp ) 122-125 °C) as a
94:6 mixture of trans- and cis-isomers. 1H NMR (500 MHz, CDCl3,
cis-isomer marked*): δ 7.68-7.64 (m, 6H, ArH of trans- and cis-
isomers), 7.57-7.55 (m, 2H, ArH of trans- and cis-isomers), 4.12*
(dd, J ) 12.0, 9.3 Hz, 1H, CHH), 3.72 (br s, 2H, OH of trans- and
cis-isomers), 3.68-3.63 (m, 1H, CHH), 3.39-3.27 (m, 3H, CHH
of the trans-isomer and CH of trans- and cis-isomers), 3.13* (dd,
J ) 12.0, 4.9 Hz, 1H, CHH), 1.50* (d, J ) 7.5 Hz, 3H, CH3), 1.19
(d, J ) 6.8 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ 170.7
(CdO), 141.4 (C), 133.2 (CH), 132.9 (C), 130.9 (CH), 123.9 (CH),
123.2 (CH), 122.9 (t, J ) 258.2 Hz, CF2), 93.1 (t, J ) 25.1 Hz,
C), 46.4 (d, J ) 7.4 Hz, CH2), 39.3 (t, J ) 22.7 Hz, CH), 9.5 (d,
J ) 7.1 Hz, CH3). 19F NMR (470 MHz, CDCl3, cis-isomer
marked*): δ -101.16* (dd, J ) 232.2, 23.5 Hz, 1F), -126.86* (d,
J ) 232.2 Hz, 1F), -127.82 (dd, J ) 220.9, 24.9 Hz, 1F), -129.60
(dd, J ) 220.9, 6.8 Hz, 1F). IR (nujol): νmax 3237br, 1681s, 1616s,
1469s, 1378m, 1239m, 1147m, 1123m, 1958m, 1003m, 759s, 709m,
701m, 604m cm-1. MS: m/z (%) relative intensity 239 (M+, 33),
203 (22), 201 (62), 200 (100), 188 (66), 172 (23), 161 (34), 160
(42), 145 (27), 133 (48), 132 (22), 125 (25), 117 (59), 91 (28), 77
(41). HRMS (ESI-TOF) Calcd for C12H11F2NO2Na [M + Na]+,
262.0656; found, 262.0634.
General Procedure for the Preparation of Compounds 9 and
10. Preparation of (2R*,9bR*)-9b-Allyl-2-benzyl-1,1-difluoro-2,3-
dihydro-1H-pyrrolo[2,1-a]isoindol-5(9bH)-one (9a). BF3 ·OEt2 (0.6
mL, 4.93 mmol) and allyltrimethylsilane (2.6 mL, 16.5 mmol) were
added to a stirred solution of 5b (1.04 g, 3.3 mmol) in CH2Cl2 (12
mL) at room temperature and the mixture was heated at reflux for
3 h. The reaction was quenched with a saturated aqueous sodium
hydrogen carbonate and extracted with CH2Cl2 (3 × 20 mL). The
combined extracts were washed with brine and dried over anhydrous
Na2SO4. Filtration followed by evaporation gave a crude product,
which was purified by preparative thin-layer chromatography (SiO2,
10% EtOAc in hexanes) to give a white solid of 9a as a trans-
isomer (0.75 g, 67% yield, mp ) 91-93 °C). 1H NMR (500 MHz,
CDCl3): δ 7.83 (d, J ) 7.6 Hz, 1H, ArH), 7.63 (td, J ) 7.5, 1.2
Hz, 1H, ArH), 7.54 (td, J ) 7.5, 1.0 Hz, 1H, ArH), 7.50 (d, J )
7.6 Hz, 1H, ArH), 7.35 (t, J ) 7.6 Hz, 2H, ArH), 7.30-7.25 (m,
3H, ArH), 5.31 (ddt, J ) 17.1, 10.1, 7.1 Hz, 1H, CH), 5.03 (dd, J
) 17.1, 1.4 Hz, 1H, CHH), 4.97 (d, J ) 10.0 Hz, 1H, CHH), 3.73
(dd, J ) 12.1, 8.7 Hz, 1H, CHH), 3.56 (dd, J ) 12.1, 9.5 Hz, 1H,
CHH), 3.39-3.29 (m, 1H, CH), 3.11 (dd, J ) 13.9, 5.3 Hz, 1H,
CHH), 2.91 (dd, J ) 14.1, 7.0 Hz, 1H, CHH), 2.75 (dd, J ) 13.9,
9.4 Hz, 2H, CHH). 13C NMR (125 MHz, CDCl3): δ 172.1 (CdO),
142.8 (d, J ) 4.3 Hz, C), 137.9 (C), 133.8 (C), 132.4 (CH), 129.7
(CH), 129.4 (CH), 128.74 (2 × CH), 128.67 (2 × CH), 126.8 (CH),
124.9 (dd, J ) 263.4, 255.4 Hz, CF2), 124.2 (CH), 122.5 (CH),
120.2 (CH2), 74.5 (t, J ) 25.3 Hz, C), 48.3 (t, J ) 22.6 Hz, CH),
45.1 (d, J ) 7.4 Hz, CH2), 37.0 (d, J ) 2.4 Hz, CH2), 32.9 (d, J )
7.8 Hz, CH2). 19F NMR (470 MHz, CDCl3): δ -118.14 (dd, J )
226.5, 23.0 Hz, 1F), -121.05 (dd, J ) 226.5, 7.1 Hz, 1F). IR (KBr):
νmax 1703s, 1643w, 1612w, 1491w, 1467m, 1363s, 1220s, 1049s,
751m, 704s cm-1. MS: m/z (%) relative intensity 340 (M+ + 1,
11), 339 (M+, 2), 298 (100), 249 (20), 91 (64), 65 (11). HRMS
(ESI-TOF) Calcd for C21H19F2NONa [M + Na]+, 362.1332; found,
362.1319.
product by column chromatography (SiO2, 5% EtOAc in hexanes)
gave a pale yellow oil of 11 (0.123 g, 84% yield). H NMR (500
1
MHz, CDCl3): δ 7.30-7.25 (m, 5H, ArH), 7.21-7.15 (m, 4H,
ArH), 5.50 (ddt, J ) 17.2, 10.1, 7.0 Hz, 1H, CH), 4.95 (dd, J )
17.2, 1.8 Hz, 1H, CHH), 4.91 (d, J ) 10.2 Hz, 1H, CHH), 4.23 (d,
J ) 15.1 Hz, 1H, CHH), 3.76 (d, J ) 15.1 Hz, 1H, CHH), 3.29 (t,
J ) 7.4 Hz, 1H, CHH), 3.02 (dd, J ) 13.9, 5.1 Hz, 1H, CHH),
2.90-2.86 (m, 1H, CH), 2.63-2.58 (m, 2H, CHH, CHH), 2.46
(dd, J ) 13.9, 7.4 Hz, 1H, CHH), 2.42 (ddd, J ) 11.2, 9.1, 1.7 Hz,
1H, CHH). 13C NMR (125 MHz, CDCl3): δ 140.7 (C), 139.1 (C),
138.8 (d, J ) 7.5 Hz, C), 132.8 (d, J ) 1.4 Hz, CH), 128.6 (2 ×
CH), 128.5 (2 × CH), 127.9 (CH), 127.0 (CH), 126.9 (t, J ) 261.0
Hz, CF2), 126.3 (CH), 123.9 (CH), 122.5 (CH), 118.4 (CH2), 81.5
(t, J ) 22.8 Hz, C), 60.2 (CH2), 57.3 (d, J ) 9.1 Hz, CH2), 46.6 (t,
J ) 21.6 Hz, CH), 43.1 (t, J ) 3.0 Hz, CH2), 31.0 (d, J ) 6.0 Hz,
CH2). 19F NMR (470 MHz, CDCl3): δ -109.23 (dd, J ) 224.2,
23.0 Hz, 1F), -115.08 (dd, J ) 223.7, 6.1 Hz, 1F). IR (neat): νmax
1641m, 1456s, 1218s, 724s cm-1. MS: m/z (%) relative intensity
278 (9), 236 (100), 216 (7), 194 (18), 176 (7), 130 (6). HRMS
(ESI-TOF) Calcd for C21H22F2N [M + H]+, 326.1722; found,
326.1767.
Preparation of (2R*,5S*,9bR*)-9b-Allyl-2-benzyl-5-butyl-1,1-
difluoro-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindole (13). To a
solution of CeCl3 (0.65 g, 1.75 mmol) in THF (5 mL) was added
n-BuLi (1.2 mL, 1.74 mmol, 1.46 M solution in hexane) at -78
°C. After stirring at -78 °C for 1 h, a solution of 9a (0.12 g, 0.35
mmol) in THF (5 mL) was added. The mixture was stirred at -78
°C for 10 h and then gradually warmed to -20 °C, and quenched
by the addition of 4 M HCl-dioxane in MeOH (4 M HCl-dioxane/
MeOH, 1:29, 5 mL) followed by excess NaBH3CN. The resulting
reaction mixture was stirred at 0 °C for 1 h and 10% aqueous NaOH
solution (5 mL) was then added. The mixture was diluted with
CH2Cl2 and extracted with CH2Cl2 (3 × 20 mL). The combined
extracts were washed with brine and dried over anhydrous Na2SO4.
Filtration followed by evaporation gave a crude product, which was
purified by radial chromatography (SiO2, 5% EtOAc in hexanes)
to afford a colorless oil of 13 (0.094 g, 80% yield). 1H NMR (500
MHz, CDCl3): δ 7.31-7.18 (m, 8H, ArH), 7.13-7.11 (m, 1H,
ArH), 5.59 (ddt, J ) 17.3, 10.4, 7.1 Hz, 1H, CH), 4.96-4.92 (m,
2H, CH2), 3.83 (dd, J ) 9.1, 3.4 Hz, 1H, CH), 3.40 (t, J ) 7.9 Hz,
1H, CHH), 3.04 (dd, J ) 13.7, 4.9 Hz, 1H, CHH), 2.97-2.90 (m,
1H, CH), 2.63 (dd, J ) 13.7, 9.7 Hz, 1H, CHH), 2.57-2.53 (m,
2H, CHH, CHH), 2.47 (dd, J ) 13.9, 7.3 Hz, 1H, CHH), 1.72-1.68
(m, 1H, CHH), 1.52-1.26 (m, 5H, CHH, 2 × CH2), 0.89 (t, J )
7.3 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ 144.9 (C), 139.2
(C), 138.2 (d, J ) 6.8 Hz, C), 133.9 (CH), 128.7 (2 × CH), 128.5
(2 × CH), 127.9 (CH), 127.0 (dd, J ) 263.5, 251.9 Hz, CF2), 127.0
(CH), 126.3 (CH), 123.0 (CH), 122.3 (CH), 118.0 (CH2), 80.5 (t,
J ) 22.0 Hz, C), 73.5 (CH), 58.4 (d, J ) 9.6 Hz, CH2), 46.3 (t, J
) 22.0 Hz, CH), 43.0 (d, J ) 3.8 Hz, CH2), 38.1 (CH2), 31.7 (d,
J ) 5.5 Hz, CH2), 29.1 (CH2), 22.7 (CH2), 14.1 (CH3). 19F NMR
(470 MHz, CDCl3): δ -113.12 (dd, J ) 222.3, 24.4 Hz, 1F),
-120.03 (d, J ) 222.3 Hz, 1F). IR (neat): νmax 1642w, 1496m,
1455m, 1220s, 760m, 700s cm-1. MS: m/z (%) relative intensity
382 (M+ + 1, 14), 340 (100), 324 (9), 284 (7), 117 (12), 91 (16).
HRMS (ESI-TOF) Calcd for C25H30F2N [M + H]+, 382.2348;
found, 382.2322.
Preparation of (2R*,5S*,9bR*)-9b-Allyl-2-benzyl-1,1-difluoro-
5-isopropyl-2,3,5,9b-tetrahydro-1H-pyrrolo[2,1-a]isoindole (14). i-
Propylmagnesium chloride (0.3 mL, 0.6 mmol, 2 M solution in
THF) was slowly added to a solution of 9a (0.04 g, 0.12 mmol) in
THF (1 mL) at 0 °C. The reaction mixture was warmed to room
temperature and stirred for 4 h. The reaction mixture was cooled
to 0 °C and 4 M HCl-dioxane in MeOH (4 M HCl-dioxane/MeOH,
1:29, 5 mL) was added, followed by the addition of excess
NaBH3CN. After removal of the ice-bath, the reaction mixture was
stirred for an additional 1 h and 10% aqueous NaOH solution (5
mL) was then added. The mixture was diluted with CH2Cl2 and
extracted with CH2Cl2 (3 × 20 mL). The combined extracts were
Preparation of (2R*,9bR*)-9b-Allyl-2-benzyl-1,1-difluoro-2,3,5,9b-
tetrahydro-1H-pyrrolo[2,1-a]isoindole (11). To a suspension of
LiAlH4 (4.3 mg, 1.13 mmol) in THF (3 mL) was added a solution
of 9a (0.153 g, 0.45 mmol) in THF (4 mL). The mixture was heated
at reflux overnight and quenched at 0 °C by careful addition of
water (0.5 mL) followed by 1 M NaOH (0.5 mL). The resulting
mixture was filtered through a Celite pad and the filtrate was
concentrated under reduced pressure. Purification of the crude
3804 J. Org. Chem. Vol. 74, No. 10, 2009

gem-Difluoromethylenated 1-Azabicyclic Compounds
washed with brine and dried over anhydrous Na2SO4. Filtration
followed by evaporation gave a crude product, which was purified
by radial chromatography (SiO2, hexanes then 5% EtOAc in
hexanes) to afford a pale yellow solid of 14 (0.029 g, 65% yield,
mp ) 87-89 °C). 1H NMR (500 MHz, CDCl3): δ 7.31-7.14 (m,
9H, ArH), 5.88-5.80 (m, 1H, CH), 5.06 (d, J ) 17.2 Hz, 1H,
CHH), 5.02 (d, J ) 10.1 Hz, 1H, CHH), 3.79 (d, J ) 4.7 Hz, 1H,
CH), 3.41 (dd, J ) 9.3, 7.7 Hz, 1H, CHH), 3.03 (dd, J ) 13.8, 4.7
Hz, 1H, CHH), 3.03-2.93 (m, 1H, CH), 2.65-2.59 (m, 2H, CHH,
CHH), 2.55 (t, J ) 9.9 Hz, 1H, CHH), 2.49-2.45 (m, 1H, CHH),
1.97-1.90 (m, 1H, CH(CH3)2), 1.04 (d, J ) 6.8 Hz, 3H, CH3),
0.76 (d, J ) 6.7 Hz, 3H, CH3). 13C NMR (125 MHz, CDCl3): δ
143.3 (C), 139.4 (d, J ) 6.8 Hz, C), 139.3 (C), 134.3 (CH), 128.7
(2 × CH), 128.5 (2 × CH), 127.8 (CH), 127.0 (dd, J ) 264.0,
251.8 Hz, CF2), 126.9 (CH), 126.3 (CH), 122.8 (CH), 122.7 (CH),
118.0 (CH2), 80.0 (t, J ) 22.0 Hz, C), 79.8 (CH), 59.2 (d, J ) 9.8
Hz, CH2), 46.5 (t, J ) 21.1 Hz, CH), 43.0 (d, J ) 4.3 Hz, CH2),
NMR (470 MHz, CDCl3): δ -112.35 (dd, J ) 222.8, 24.9 Hz,
1F), -120.23 (d, J ) 222.3 Hz, 1F). IR (KBr): νmax 3074br, 1458m,
1210s, 1017s, 761s, 699s cm-1. MS: m/z (%) relative intensity 368
(M+ + 1, 7), 326 (100), 284 (26), 117 (14), 91 (14). HRMS (ESI-
TOF) Calcd for C24H28F2N [M + H]+, 368.2192; found, 368.2243.
Acknowledgment. Financial support from the Center for
Innovation in Chemistry (PERCH-CIC), the Commission on
Higher Education (CHE-RES-RG), Ministry of Education, and
the Thailand Research Fund (to M.P., BRG49800005; and to
P.K., BRG50080008) is gratefully acknowledged.
Supporting Information Available: Experimental details and
characterization data for all compounds and CIF data for single-
crystal X-ray analyses of trans-5a and trans-6a. This material
is available free of charge via the Internet at http://pubs.acs.org.
34.0 (CH), 31.9 (d, J ) 5.9 Hz, CH2), 20.6 (CH3), 18.0 (CH3). 19
F
JO802794U
J. Org. Chem. Vol. 74, No. 10, 2009 3805