α-arylsulfanyl-α-fluoro carbenoids: Their novel chemistry and synthetic applications

Article abstract of DOI:10.1021/ol048085m

(Chemical equation presented) The bromine-magnesium exchange reactions of arylthiobromodifluoromethanes with Grignard reagents have been studied. Upon trapping with electrophiles, alkyl aryl sulfides and ketenedithioacetals are obtained. The reaction is p

Full text of DOI:10.1021/ol048085m

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4547-4550
r
-Arylsulfanyl-r-fluoro Carbenoids:
Their Novel Chemistry and Synthetic
Applications
Manat Pohmakotr,* Winai Ieawsuwan, Patoomratana Tuchinda,
Palangpon Kongsaeree, Samran Prabpai, and Vichai Reutrakul*
Department of Chemistry, Faculty of Science, Mahidol UniVersity,
Rama 6 Road, Bangkok 10400, Thailand
scmpk@mahidol.ac.th; scVrt@mahidol.ac.th
Received September 20, 2004
ABSTRACT
The bromine−magnesium exchange reactions of arylthiobromodifluoromethanes with Grignard reagents have been studied. Upon trapping
with electrophiles, alkyl aryl sulfides and ketenedithioacetals are obtained. The reaction is proposed to occur via novel
carbenoids. The first examples of arylthiomethane multipole synthons are also reported.
r-arylsulfanyl-r-fluoro
Organofluorine compounds1 have engendered considerable
interest in recent years due to their wide ranging biological
effects. The development of general synthetic routes to such
compounds and investigations into the use of new fluorine
compounds as building blocks are therefore of great impor-
tance.2 Our recent efforts at developing new synthetic
methods for the preparation of gem-difluoromethylene
compounds have shown the utility of bromodifluorophen-
ylthiomethane as a highly versatile gem-difluoromethylene
building block. The reaction of the difluorophenylsulfanyl-
methyl radical with olefins affords adducts possessing a gem-
difluoromethylene moiety.3 As a result of these studies, it
has been envisaged that arylthiobromodifluoromethanes 1
and 2 will be useful precursors of the difluoro carbanion 3,
which would be expected to form carbon-carbon bonds after
trapping with suitable electrophiles. This protocol, if suc-
cessful, would provide an important complementary method
to those reported for the synthesis of gem-difluoromethylene
compounds.4
(2) See for examples, (a) Bildstein, S.; Ducep, J.-B.; Jacobi, D.
Tetrahedron Lett. 1996, 37, 8759-8762. (b) Shen, Y.; Jiang, G.-F.; Wang,
G.; Zhang, Y. J. Fluorine Chem. 2001, 109, 141-144. (c) Fried, J.; John,
V.; Szwedo, M. J., Jr.; Chen, C.-K.; O’Yang, C.; Morinelli, T. A.; Okwu,
A. K.; Halushka, P. V. J. Am. Chem. Soc. 1989, 111, 4510-4511. (d) Hertel,
L. W.; Kroin J. S.; Misner J. W.; Tustin J. M. J. Org. Chem. 1988, 53,
2406-2409. (e) Greuter, H.; Lang, R. W.; Romann, A. J. Tetrahedron Lett.
1988, 29, 3291-3294. (f) Burton, D. J.; Sprague, L. G. J. Org. Chem. 1989,
54, 613-617. (g) Sprague L. G.; Burton, D. J.; Guneratne, R. D.; Bennett,
W. E. J. Fluorine Chem. 1990, 49, 75-85. (h) Yang, Z.-Y.; Burton, D. J.
J. Org. Chem. 1991, 56, 1037-1041. (i) Obayashi, M.; Ito, E.; Matsui, K.;
Kondo, K. Tetrahedron Lett. 1982, 23, 2323-2326. (j) Seyferth, D.; Simon,
R. M.; Sepelak, D. J.; Klein, H. A. J. Am. Chem. Soc. 1983, 105, 4634-
4639. (k) Taguchi, T.; Kitagawa, O.; Morikawa, T.; Nishiwaki, T.; Uehara,
H.; Endo, H.; Kobayashi, Y. Tetrahedron Lett. 1986, 27, 6103-6106. (l)
Kirihara, M.; Takuwa, T.; Takizawa, S.; Momose, T. Tetrahedron Lett. 1997,
38, 2853-2854. (m) Waschbu¨sch, R.; Samadi, M.; Savignac, P. J.
Organomet. Chem. 1997, 529, 267-278. (n) Chung, W. J.; Ngo, S. C.;
Higashiya, S.; Welch, J. T. Tetrahedron Lett. 2004, 45, 5403-5406.
(3) Reutrakul, V.; Thongpaisanwong, T.; Tuchinda, P.; Kuhakarn, C.;
Pohmakotr, M. J. Org. Chem. 2004, 69, 6913-6915 and references cited
therein.
(1) (a) Soloshonok, V. A., Ed. Enantiocontrolled Syntheses of Fluoro-
Organic Compounds; John Wiley & Sons, Ltd.; Chichester, 1999. (b) Welch,
J. T., Ed. SelectiVe Fluorination in Organic and Bioorganic Chemistry;
American Chemical Society: Washington, DC, 1990. (c) Hiyama, T., Ed.
Organofluorine Compounds: Chemistry and Applications; Springer, 2000.
(d) Welch, J. T. Tetrahedron 1987, 43, 3123-3197. (e) Kitazume, T.;
Yamazaki, T. Top. Curr. Chem. 1997, 193, 91-130. (f) Percy, J. M. Top.
Curr. Chem. 1997, 193, 131-195. (g) Burton, D. J.; Yang, Z.-Y.
Tetrahedron 1992, 48, 189-275.
10.1021/ol048085m CCC: $27.50
© 2004 American Chemical Society
Published on Web 10/30/2004

Table 1. Reactions of 1 and 2 with Grignard Reagents
products (% yield)a
entry
sulfide 1 or 2
RMgX (equiv)
conditions
-78 °C, 1 h
R
4
6
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
2
2
2
2
i-PrMgCl (1.1)
i-PrMgCl (1.5)
i-PrMgCl (1.5)
i-PrMgCl (4)
i-PrMgCl (4)
i-BuMgCl (4)
EtMgCl (4)
t-BuMgCl (5)
i-PrMgCl (4)
i-BuMgCl (4)
EtMgCl (4)
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Bu
Et
t-Bu
i-Pr
i-Bu
Et
4a (19)
4a (28)
4a (29)
4a (47-48)
4a (48)
4b (83)
4c (43)
4d (63)
5a (51)
5b (84)
5c (42)
5d (46)
6a (7)
-78 °C, 1.5 h
6a (13)
6a (13)
6a (26-31)
6a (30)
6b (6)
6c (21)
6d (0)
7a (26)
7b (2)
-100 °C, 10 min
-78 °C, 5-10 min
-78 °C, 1.5 h
-78 °C, 30 min
-78 °C, 30 min
-78 °C to rt, overnight
-78 °C, 1 h
-78 °C, 1 h
-78 °C, 1 h
-78 °C to rt, overnight
10
11
12
7c (13)
7d (0)
t-BuMgCl (5)
t-Bu
a Isolated yield based on the starting sulfide 1 or 2.
On the basis of this assumption, methods for the generation
of the gem-difluoro carbanion 3 from 1 and 2 have been
studied. Eventually it was found that the treatment of 1 with
1.1 equiv of i-PrMgCl (2 M in THF) at -78 °C provided
the unexpected products 4a and 6a in 19 and 7% yield,
respectively (Scheme 1). The same products 4a (24%) and
To gain more insight into the bromine-magnesium
exchange reaction,5 1 was reacted with other Grignard
reagents. As summarized in Table 1 (entries 6-8), the
reactions of 1 with i-BuMgCl, EtMgCl, and t-BuMgCl
afforded the sulfides 4b, 4c, and 4d in moderate to good
yields, together with ketenedithioacetals6 6b and 6c as the
minor products. However, compound 6d could not be
detected when t-BuMgCl was employed (Table 1, entry 8).
Similar results were obtained with compound 2. Thus,
treatment of 2 with i-PrMgCl, i-BuMgCl, and EtMgCl under
the conditions indicated in Table 1 (entries 9-12) provided
sulfides 5a-d in moderate to good yields (42-84%),
together with ketenedithioacetals 7a-c in 2-26% yields.
Again, compound 7d was not detected (Table 1, entry 12).
The formation of the sulfide 4 or 5 is proposed to proceed
via the bromine-magnesium exchange reaction of the
starting compound 1 or 2 with a Grignard reagent, leading
to a magnesium carbanion 3, which undergoes a rapid
R-elimination of a fluoride ion, due to stabilizing of the
arylthio group to an intermediate 10, to give the hitherto
unknown magnesium carbenoid 9.7-10 Subsequent reaction
of the intermediate 9 with another equivalent of RMgCl
affords the magnesium carbanion 11. The R-elimination of
fluoride ion from 11 gave another unknown carbenoid
derivative 12, and upon addition of another equivalent of
Scheme 1. Bromo-Magnesium Exchange Reactions of
Arylthiobromodifluoromethanes with Grignard Reagents
6a (13%) were obtained when the reaction was carried out
at -100 °C for 10 min, employing 1.5 equiv of i-PrMgCl.
Attempts to trap the proposed initial intermediate 3 with
benzoyl chloride or methyl iodide were unsuccessful. Better
yields of 4a (47-48%) and 6a (26-31%) were obtained
when 4 equiv of i-PrMgCl were used at -78 °C for 5-10
min (Table 1, entry 4), and comparable yields were obtained
with prolonged reaction time (Table 1, entry 5).
(5) For reviews, see: (a) Knochel, P.; Dohle, W.; Gommermann, N.;
Kneisel, F. F.; Kopp, F.; Korn, T.; Sapountzis, I.; Vu, V. A. Angew. Chem.,
Int. Ed. 2003, 42, 4302-4320 and references cited therein. (b) Boudier,
A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem., Int. Ed. 2000, 39,
4414-4435.
(4) (a) Burton, D. J.; Yang, Z.-Y.; Qiu, W. Chem. ReV. 1996, 96, 1641-
1715. (b) Katritzky, A. R.; Nichols, D. A.; Qi, M. Tetrahedron Lett. 1998,
39, 7063-7066. (c) Wang, Z. G.; Hammond, G. B. Chem. Commun. 1999,
2545-2546. (d) Itoh, T.; Kudo, K.; Tanaka, N.; Sakabe, K.; Takagi, Y.;
Kihara, H. Tetrahedron Lett. 2000, 41, 4591-4595. (e) Clavel, P.; Biran,
C.; Bordeau, M.; Roques, N.; Tre´vin, S. Tetrahedron Lett. 2000, 41, 8763-
8767. (f) Portella, C.; Brigaud, T.; Lefebvre, O.; Plantier-Royon, R. J.
Fluorine Chem. 2000, 101, 193-198. (g) Burkholder, C. R.; Dolbier, W.
R., Jr.; Me´debielle, M. J. Fluorine Chem. 2001, 109, 39-48. (h) Staas, D.
D.; Savage, K. L.; Homnick, C. F.; Tsou, N. N.; Ball, R. G. J. Org. Chem.
2002, 67, 8276-8279. (i) Cox, L. R.; DeBoos, G. A.; Fullbrook, J. J.; Percy,
J. M. Org. Lett. 2003, 5, 337-339. (j) Prakash, G. K. S.; Hu, J.; Mathew,
T.; Olah, G. A. Angew. Chem., Int. Ed. 2003, 42, 5216-5219. (k) Prakash,
G. K. S.; Hu, J.; Olah, G. A. J. Org. Chem. 2003, 68, 4457-4463.
(6) (a) For reviews, see: Kolb, M. Synthesis 1990, 171-190. Dieter, R.
K. Tetrahedron 1986, 42, 3029-3096. (b) Ichikawa, J.; Saitoh, T.; Tada,
T.; Mukaiyama, T. Chem. Lett. 2002, 996-997. (c) Nair, S. K.; Samuel,
R.; Asokan, C. V. Synthesis 2001, 573-576. (d) Samuel, R.; Nair, S. K.;
Asokan, C. V. Synlett 2000, 1804-1806.
(7) Magnesium carbenoids, see: (a) Boche, G.; Lohrenz, J. C. W. Chem.
ReV. 2001, 101, 697-756. (b) Hoffmann, R. W. Chem. Soc. ReV. 2003,
32, 225-230. (c) Satoh, T.; Kondo, A.; Musashi, J. Tetrahedron 2004, 60,
5453-5460. (d) Satoh, T.; Sakamoto, T.; Watanabe, M.; Takano, K. Chem.
Pharm. Bull. 2003, 51, 966-970. (e) Satoh, T.; Takano, K.; Ota, H.;
Someya, H.; Matsuda, K.; Koyama, M. Tetrahedron 1998, 54, 5557-5574.
(f) Baird, M. S.; Nizovtsev, A. V.; Bolesov, I. G. Tetrahedron 2002, 58,
1581-1593. (g) Avolio, S.; Malan, C.; Marek, I.; Knochel, P. Synlett 1999,
1820-1822.
4548
Org. Lett., Vol. 6, No. 24, 2004

the Grignard reagent, the R-sulfur-stabilized anion 13 or 14
was obtained. Acidic workup furnished sulfide 4 or 5
(Scheme 2). Attempts to trap the carbenoid 9 or 12 by
carrying out the reaction with cyclohexene as a solvent were
unsuccessful.
Scheme 2. Proposed Mechanism for the Formation of Alkyl
Aryl Sulfides
Figure 1. X-ray crystal structure of ketenedithioacetal 6b.
or benzoyl cyanide, in the presence of CuCN‚2LiCl
(1 equiv).5 This provided t-alkyl aryl sulfides or R-keto-
sulfides in moderate yields. Moreover, hydroxybenzylated
products were obtained with benzaldehyde or p-tolualdehyde
in the absence of CuCN‚2LiCl at -78 °C following warming
to room-temperature overnight. The results are summarized
in Table 2.
In conclusion, our results, for the first time, provide
evidence for the novel chemistry of the proposed carbenoids
9 and 12. The resulting R-sulfur-stablized magnesium
Rationalization of the formation of ketenedithioacetal 6
or 7 involves addition of the magnesium carbanion 13 or 14
to the carbene intermediate 9 to give an intermediate 15,
which then leads to carbenoid 16. Neighboring group
participation by the lone pair electrons on the sulfur atom to
the carbenic center gives an intermediate 17, which further
rearranges7c,7d,10 to ketenedithioacetal 6 or 7 (Scheme 3). The
(8) (a) Uno, H.; Sakamoto, K.; Semba, F.; Suzuki, H. Bull. Chem. Soc.
Jpn. 1992, 65, 210-217. (b) Brahms, D. L. S.; Dailey, W. P. Chem. ReV.
1996, 96, 1585-1632. (c) Xu, W.; Chen, Q.-Y. Org. Biomol. Chem. 2003,
1, 1151-1156 and references cited therein. (d) Taguchi, T.; Okada, M. J.
Fluorine Chem. 2000, 105, 279-283. (e) Bourissou, D.; Guerret, O.; Gabba¨ı,
F. P.; Bertrand, G. Chem. ReV. 2000, 100, 39-91. (f) Condon, S. E.; Buron,
C.; Tippmann, E. M.; Tinner, C.; Platz, M. S. Org. Lett. 2004, 6, 815-
818.
Scheme 3. Proposed Mechanism for the Formation of
Ketenedithioacetals
(9) Generation and spectroscopic characterization of R-fluoro-R-phenyl-
sulfanyl carbene 9 (Ar ) Ph) were recently reported; see: Buron, C.;
Tippmann, E. M.; Platz, M. S. J. Phys. Chem. A 2004, 108, 1033-1041.
(10) (a) Cohen, T.; Ouellette, D.; Daniewski, W. M. Tetrahedron Lett.
1978, 19, 5063-5066. (b) Cohen, T.; Yu, L.-C. J. Org. Chem. 1984, 49,
605-608. (c) Kim, J. T.; Kel’in, A. V.; Gevorgyan, V. Angew. Chem., Int.
Ed. 2003, 42, 98-101.
(11) Alternative structure of 6b is as shown below, which presumably
could be formed by the dimerization of the carbenoid 12 (R ) i-Bu). The
formation of the ketenedithioacetal 6b provides support for the mechanism
proposed in Scheme 3.
(12) Crystal data for compound (6b) at 298(2) K: C22H28S2, Mr ) 356.59,
monoclinic, space group C2/c (No. 15), a ) 18.2720 (13) Å, b ) 7.8680
(3) Å, c ) 15.9862 (11) Å, â ) 116.643 (2)°, V ) 2054.2(2) Å3, Z ) 4,
Dx ) 1.153 Mg m-3. F000 ) 768, λ (Mo KR) ) 0.71073 Å, µ ) 0.260
mm-1. Data collection and reduction: crystal size 0.15 × 0.20 × 0.20 mm,
θ range 1.00-25.03°, 7938 reflections collected, 1765 independent reflec-
absence of the products 6d and 7d could be attributed to the
steric hindrance of the tert-butyl group making the formation
of the intermediate 15 unfavorable. The structure of ketene-
dithioacetal 6b was confirmed by a single-crystal X-ray
crystallography as shown in Figure 1.11,12
The existence and the synthetic utility of the magnesium
carbanions 13 and 14 were demonstrated by trapping with
electrophiles methyl iodide, allyl bromide, crotyl bromide,
tions (Rint ) 0.0254), final R indices (I > 2σ(I)): R1 ) 0.0385, wR2
)
0.0991 for 111 parameters, GOF ) 1.052. CCDC 248269. These data can
be obtained free of charge via the Internet at www.ccdc.cam.ac.uk/conts/
retrieving.html (or from the Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge CB21EZ, UK; fax: (+44)1223-336-033; e-mail:
deposit@ccdc.cam.ac.uk.
Org. Lett., Vol. 6, No. 24, 2004
4549

Table 2. Reactions of Organomagnesiums 13 and 14 with Electrophiles
entry
13 or 14
Ar
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
p-Tol
R
electrophilesa
products, % yieldb
18a (E ) Me), 36%
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
13a
13b
13b
13b
13b
13b
13b
13c
13c
13c
13c
14a
14b
14b
14b
14b
14b
14b
14c
14c
14c
14c
i-Pr
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
Et
methyl iodide
methyl iodide
allyl bromide
crotyl bromide
benzoyl cyanide
benzaldehyde
p-tolualdehyde
methyl iodide
allyl bromide
crotyl bromide
benzoyl cyanide
methyl iodide
methyl iodide
allyl bromide
crotyl bromide
benzoyl cyanide
benzaldehyde
p-tolualdehyde
methyl iodide
allyl bromide
crotyl bromide
benzoyl cyanide
18b (E ) Me), 61%
18c (E ) CH2dCHCH2), 76%
18d (E ) CH3CHdCHCH2), 78%
18e (E ) PhCO), 56%
18f (E ) PhCH(OH)), 45%
18g (E ) p-TolCH(OH)), 45%
18h (E ) Me), 35%
18i (E ) CH2dCHCH2), 39%
18j (E ) CH3CHdCHCH2), 40%
18k (E ) PhCO), 36%
Et
Et
Et
i-Pr
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
i-Bu
19a (E ) Me), 30%
19b (E ) Me), 62%
19c (E ) CH2dCHCH2), 64%
19d (E ) CH3CHdCHCH2), 79%
19e (E ) PhCO), 50%
19f (E ) PhCH(OH)), 49%
19g (E ) p-TolCH(OH)), 43%
19h (E ) Me), 38%
19i (E ) CH2dCHCH2), 42%
19j (E ) CH3CHdCHCH2), 46%
19k (E ) PhCO), 48%
a All reactions were carried out in the presence of CuCN‚2LiCl except for entries 6, 7, 17, and 18. b Isolated yield based on the starting sulfide 1 or 2.
carbanions 13 and 14 can be trapped with various electro-
philes to give compounds 18 and 19 in synthetically useful
yields. Arylsulfanylbromodifluoromethanes 1 and 2 can be
regarded as synthetic equivalents of the multipole synthon
20.
Higher Education Development Project: Postgraduate Edu-
cation and Research Program in Chemistry (PERCH) for
financial support. The Development and Promotion of
Science and Technology Talent Project is also gratefully
acknowledged for a scholarship to W.I.
Supporting Information Available: General experimen-
tal details and spectral data for all compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We thank the Thailand Research Fund
for the Senior Research Scholar Award to V.R. and the
OL048085M
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Org. Lett., Vol. 6, No. 24, 2004