α-fluorovinyl Weinreb amides and α-fluoroenones from a common fluorinated building block

Article abstract of DOI:10.1021/jo802784w

(Chemical Equation Presented) Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes and cyclic keton

Full text of DOI:10.1021/jo802784w

r-Fluorovinyl Weinreb Amides and r-Fluoroenones from a
Common Fluorinated Building Block
Arun K. Ghosh, Shaibal Banerjee, Saikat Sinha, Soon Bang Kang,† and Barbara Zajc*
Department of Chemistry, The City College and The City UniVersity of New York, 160 ConVent AVenue,
New York, New York 10031
barbaraz@sci.ccny.cuny.edu
ReceiVed December 21, 2008
Synthesis and reactivity of N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, a building
block for Julia olefination, is reported. This reagent undergoes condensation reactions with aldehydes
and cyclic ketones to give R-fluorovinyl Weinreb amides. Olefination reactions proceed under mild, DBU-
mediated conditions, or in the presence of NaH. DBU-mediated condensations proceed with either E- or
Z-selectivity, depending upon reaction conditions, whereas NaH-mediated reactions are g98% Z-
stereoselective. Conversion of the Weinreb amide moiety in N-methoxy-N-methyl-(1,3-benzothiazol-2-
ylsulfanyl)fluoroacetamide to ketones, followed by oxidation, resulted in another set of olefination reagents,
namely (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl and propyl ketones. In the presence of DBU,
these compounds react with aldehydes tested to give R-fluoroenones with high Z-selectivity. The use of
N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroacetamide as a common fluorinated intermediate
in the synthesis of R-fluorovinyl Weinreb amides and R-fluoroenones has been demonstrated. Application
of the Weinreb amide to R-fluoro allyl amine synthesis is also shown.
Introduction
modified Julia reaction.3,4 However, this method has not
received much attention for the synthesis of vinyl fluorides until
recently. Application of this reaction for the preparation of
fluoroalkylidenes was initially demonstrated by using a single
olefination precursor.5 We were the first to utilize metalation-
fluorination as a general approach for the preparation of novel
Julia reagents for the synthesis of functionalized fluoroolefins.6-9
Variously functionalized fluoroolefins are now conveniently
accessible by the Julia-Kocienski olefination.6-11 In our work,
Fluorine-containing organic molecules are of high interest,
due to altered physical, biological, and chemical properties
caused by fluorine atom introduction.1 One of the approaches
for the synthesis of fluorinated compounds is via the use of
appropriate fluorinated building blocks.2 Among various fluo-
roorganics, functionalized fluoroolefins have been the subject
of many investigations, either as end products or as synthetic
intermediates. A convenient route for olefination is via the
(3) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron Lett. 1991,
32, 1175–1178.
(4) (a) Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563–2585.
(b) Plesniak, K.; Zarecki, A.; Wicha, J. Top. Curr. Chem. 2007, 275, 163–250.
(c) Aïssa, C. Eur. J. Org. Chem. 2009, 1–15.
(5) Chevrie, D.; Lequeux, T.; Demoute, J. P.; Pazenok, S. Tetrahedron Lett.
2003, 44, 8127–8130.
(6) Ghosh, A. K.; Zajc, B. Org. Lett. 2006, 8, 1553–1556.
(7) Zajc, B.; Kake, S. Org. Lett. 2006, 8, 4457–4460.
(8) He, M.; Ghosh, A. K.; Zajc, B. Synlett 2008, 999–1004.
(9) del Solar, M.; Ghosh, A. K.; Zajc, B. J. Org. Chem. 2008, 73, 8206–
8211.
* To whom correspondence should be addressed. Phone: (212) 650-8926.
Fax: (212) 650-6107.
† Guest researcher from The Korea Institute of Science and Technology.
(1) (a) Welch, J. T., Ed. SelectiVe Fluorination in Organic and Bioorganic
Chemistry; American Chemical Society: Washington, DC, 1991. (b) Ojima, I.;
McCarthy, J. R.; Welch, J. T., Eds. Biomedical Frontiers of Fluorine Chemistry;
American Chemical Society: Washington, DC, 1996. (c) Be´gue´, J.-P.; Bonnet-
Delpon, D. Bioorganic and Medicinal Chemistry of Fluorine; John Wiley &
Sons, Inc.: Hoboken, NJ, 2008.
(2) (a) Special Issue on Fluorinated Synthons: J. Fluorine Chem. 2004, 125,
477-645. (b) Soloshonok, V. A., Ed. Fluorine-Containing Synthons; American
Chemical Society: Washington, DC, 2005. (c) Soloshonok, V. A.; Mikami, K.;
Yamazaki, T.; Welch, J. T.; Hoenk, J. F., Eds. Current Fluoroorganic Chemistry:
New Synthetic Directions, Technologies, Materials, and Biological Applications;
American Chemical Society: Washington, DC, 2007.
(10) Pfund, E.; Lebargy, C.; Rouden, J.; Lequeux, T. J. Org. Chem. 2007,
72, 7871–7877.
(11) Alonso, D. A.; Fuensanta, M.; Go´mez-Bengoa, E.; Na´jera, C. AdV. Synth.
Catal. 2008, 350, 1823–1829.
10.1021/jo802784w CCC: $40.75
Published on Web 04/10/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 3689–3697 3689

Ghosh et al.
SCHEME 1.
Synthesis of Fluoro Julia-Weinreb Reagent
FIGURE 1. Fluorinated Julia-Weinreb Amide Building Block
we have developed a series of isolable and stable fluorinated
reagents that have yielded facile access to R-fluorostilbene and
styrene derivatives,6 R-fluoroacrylates,7 R-fluorovinyl sulfones,8
and R- fluoroacrylonitriles.9
On the basis of our previous results, we became interested
in the development and use of functionalized fluorinated building
blocks that would allow synthesis of various Julia olefination
reagents from common precursors. Among the various func-
tional groups, the (N-methoxy-N-methyl) amide moiety can be
easily converted to R-fluoro ketones and R-fluoro aldehydes,
and is a useful synthetic intermediate in organic synthesis.12
An appropriate heteroaryl derivative, such as N-methoxy-N-
methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroacetamide, or its
precursor N-methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfa-
nyl)fluoroacetamide would therefore offer two potential sites
for modification (Figure 1). The benzothiazolyl sulfone moiety
would provide one point of diversity, namely olefination,3,4 and
the amide part would provide the second point of diversity by
virtue of its reactivity toward metal alkyls and hydride reducing
agents.12 A two-step synthesis of a fluorovinyl Weinreb amide
has been reported from tetrafluoroethane (HFC-134a), albeit in
a low 30% yield.13 An example of the Weinreb-Wittig-Horner
reagent (EtO)2P(O)CHFC(O)NMe(OMe) has been reported as
well; however, no details on its synthesis, characterization, and
reactivity were provided.14
Recently, Aidhen et al. reported synthesis and NaH-mediated
condensation reactions of N-methoxy-N-methyl-(1,3-benzothia-
zol-2-ylsulfonyl)acetamide with aldehydes, leading to vinyl
Weinreb amides via Julia olefination.15 While this work was in
progress, syntheses of R,ꢀ-unsaturated Weinreb amides16 and
the R-fluoro analogues11 were reported with use of 3,5-
bis(trifluoromethyl)phenyl sulfones.
Herein, we present our synthesis of the benzothiazolyl-based
fluoro Julia-Weinreb amide reagent and study of its reactions
at both reactive centers. Specifically, reactions at the amide
functionality of N-methoxy-N-methyl-(1,3-benzothiazol-2-yl-
sulfanyl)fluoroacetamide, followed by oxidation, led to a second
set of Julia olefination reagents that were also subjected to
condensation reactions to give R-fluoroenones. The effect of
reaction conditions on olefination selectivity under mild, DBU-
mediated conditions as well as with NaH is presented. Finally,
the utility of the fluoro Julia-Weinreb amide building block
for the synthesis of fluoroallyl amines, a class of dipeptide
isosteres,1 is demonstrated by a concise synthesis of a known
dipeptidyl peptidase II inhibitor.17
Results and Discussion
Attheoutset,synthesisofasuitablereagentforJulia-Kocienski
olefination3,4 was undertaken. Stabilized carbanions derived from
1,3-benzothiazol-2-yl (BT) sulfone derivatives have been suc-
cessfully used by us in fluoro Julia olefination reactions.7-9
Thus, we sought the synthesis of a Weinreb amide derivative
based on the benzothiazolyl moiety.
As shown in Scheme 1, the known BT-sulfide 115 was
prepared by reaction of the sodium salt of 2-mercapto-1,3-
benzothiazole with 2-bromo-N-methoxy-N-methylacetamide18
(prepared from bromoacetyl bromide and (MeO)MeNH ·HCl).
Oxidation of BT-sulfide 1 with m-CPBA yielded the known
sulfone 215 (Scheme 1). Metalation-fluorination of sulfone 2
with LDA and N-fluorodibenzenesulfonimide (NFSI) in toluene
resulted in the monofluoro derivative 3 in 85% yield.
With the desired fluoro Julia-Weinreb reagent 3 in hand,
we screened the reactivity of the reagent. Various reaction
conditions and additives were tested in condensation reactions
of 2-naphthaldehyde (Table 1). All DBU-mediated reactions
were performed under Barbier conditions,4 whereas when NaH
was used as base, 2-naphthaldehyde was added to a mixture of
sulfone and NaH.
Wide changes in stereoselectivity were observed depending
upon reaction solvent, reaction temperature, and the additive.
Good yield and moderate Z-selectivity was observed in the
DBU-mediated condensation in CH2Cl2 at room temperature,
but there was no selectivity when the reaction was performed
at -78 °C (entries 1 and 2). Higher Z-selectivity was obtained
in THF at room temperature (entry 3) and this increased at -78
°C (entry 4), and products were isolated in good yields in both
cases. Room temperature olefination in toluene resulted in a
marginal increase in Z-selectivity (entry 5) compared to the room
temperature reaction in THF (entry 3); however, the reaction
was much slower, with approximately 95% conversion after
48 h. Changing the reaction solvent to DMF resulted in a
reversal of selectivity with the E-isomer predominating, but the
E/Z ratio was unaffected by a change in the reactant stoichi-
ometry (entries 6 and 7). Highest E-selectivity was obtained in
DMPU, and the E/Z product mixture was isolated in a high 93%
yield (entry 8). Lowering of reaction temperature to -78 °C in
a 1:1 mixture of DMF and DMPU (to prevent freezing) again
(12) (a) Balasubramaniam, S.; Aidhen, I. S. Synthesis 2008, 3707–3738. (b)
Khlestkin, V. K.; Mazhukin, D. G. Curr. Org. Chem. 2003, 7, 967–993. (c)
Nahm, S.; Weinreb, S. M. Tetrahedron Lett. 1981, 22, 3815–3818.
(13) Kanai, M.; Percy, J. M. Tetrahedron Lett. 2000, 41, 2453–2455.
(14) Boumendjel, A.; Nuzillard, J.-M.; Massiot, G. Tetrahedron Lett. 1999,
40, 9033–9036.
(15) Manjunath, B. N.; Sane, N. P.; Aidhen, I. S. Eur. J. Org. Chem. 2006,
2851–2855.
(16) Alonso, D. A.; Fuensanta, M.; Go´mez-Bengoa, E.; Na´jera, C. Eur. J.
Org. Chem. 2008, 2915–2922.
(17) Van der Veken, P.; Senten, K.; Kertesz, I.; De Meester, I.; Lambeir,
A.-M.; Maes, M.-B.; Scharpe, S.; Haemers, A.; Augustyns, K. J. Med. Chem.
2005, 48, 1768–1780.
(18) The procedure described for the synthesis of 2-chloro-N-methoxy-N-
methylacetamide was used (ref 14). 2-Bromo-N-methoxy-N-methylacetamide:
(a) Hirner, S.; Panknin, O.; Edefuhr, M.; Somfai, P. Angew. Chem., Int. Ed.
2008, 47, 1907–1909. (b) Mechelke, M. F.; Meyers, A. I. Tetrahedron Lett.
2000, 41, 4339–4342.
3690 J. Org. Chem. Vol. 74, No. 10, 2009

Fluorinated Vinyl Weinreb Amides, Enones, and Allyl Amine
TABLE 1. Effect of Reaction Conditions on Condensation Reactions of 3 with 2-Naphthaldehyde
aldehyde:sulfone:
base (molar equiv)
additive
(molar equiv)
entry
base
solvent
CH2Cl2
CH2Cl2
THF
T, rxn time (h)
(%) E/Z ratio;a yieldb
1
2
3
4
5
6
7
8
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
NaH
1.0:1.2:4.0
1.0:1.2:4.0
1.0:1.2:4.0
1.0:1.2:4.0
1.0:1.2:4.0
1.0:1.3:2.6
1.3:1.0:2.0
1.3:1.0:2.0
1.3:1.0:2.0
1.3:1.0:2.0
1.0:1.3:3.9
1.2:1.0:3.0
1.2:1.0:3.0
1.0:1.3:2.6
1.0:2.0:4.0
1.0:2.0:4.0
1.0:2.0:4.0
1.0: 2.0:18.0
rt, 2
-78 °C, 3.5
rt, 2
-78 °C, 4
rt, 48
rt, 20
rt, 15
rt, 17
-78 °C, 3.5
75 °C, 2.5
rt, 48
rt, 48
rt, 48
rt, 20; 70 °C, 2
rt, 1
rt, 1.5
rt, 1.5
rt, 18
33/67; 90%
50/50; 96%
19/81; 84%
4/96; 84%
THF
PhMe
DMF
DMF
DMPU
DMF-DMPUd
DMPU
THF
THF
THF
THF
THF
16/84; NAc
74/26; NAc
74/26; NAc
78/22; 93%
25/75; NAc
78/22; NAc
10/90; 78%
7/93; 78%
9
10
11
12
13
14
15
16
17
18e
MgBr2 (1.8)
MgBr2 (1.4)
ZnBr2 (1.4)
15/85; 74%
Only Z, 84%
Only Z, 90%
40/60, NAc
12/88, NAc
55/45, NAc
NaH
NaH
NaH
K2CO3
THF
THF
DMF
18-Crown-6 (6.0)
15-Crown-5 (6.0)
TBAB (0.2)
a Relative ratio of diastereomers in the crude reaction mixture determined by 19F NMR prior to isolation. No change in ratio was observed after
purification. b Yields of isolated, purified products. c Product not isolated from reaction mixture. d A 1:1 mixture of DMF and DMPU was used to
prevent freezing at -78 °C. e Reaction conditions were identical with those described in ref 11.
favored formation of the Z-isomer (entry 9). An increase in
reaction temperature from room temperature to 75 °C did not
affect the olefination selectivity in DMPU (compare entries 8
and 10).
Although we identified reaction conditions that gave exclusive
Z-selectivity, we wanted to assess whether the mild DBU-
mediated olefinations, which gave condition dependent comple-
mentary olefination products with 2-naphthaldehyde, would be
applicable to other substrates as well. Table 2 shows condensa-
tion reactions of a range of aldehydes using either method A
(DBU, THF, -78 °C, molar ratio of aldehyde:sulfone:DBU )
1:1.4:4, Barbier conditions4) or method B (DBU, DMPU, room
temperature, molar ratio of aldehyde:sulfone:DBU ) 1.3:1.0:
2, Barbier conditions4).
As can be seen from Table 2, using method A, high
Z-selectivity was observed for aromatic aldehydes (entries 1 and
3). The trend reversed in the case of thiophene, where the E
isomer predominated (entry 5). No selectivity was observed in
the case of n-octanal (entry 7). Condensations using method B
were E-selective in all cases. Selectivity was moderate in the
case of electron-poor aromatic and aliphatic aldehydes (entries
4 and 8). For the substrates studied, product yields were in the
range of 69-93%.
We next explored the scope of the Z-selective olefinations
using method C (NaH, THF, room temperature, molar ratio of
carbonyl compound:3:NaH ) 1:2:4, aldehyde added to sulfone/
NaH mixture). Table 3 shows a series of carbonyl compounds
that were subjected to condensation reactions.
With all aldehydes studied, high Z-stereoselectivity was
observed (Z/E g 99), except in the case of thiophene-2-
carboxaldehyde, where 2% of the E isomer was formed (Table
3, entry 6). The yields were in the range of 71% to quantitative.
The reactivity of ketones with 3 using NaH was tested as well.
N-Benzylpiperidone gave a product in 57% yield, but reaction
with acetophenone resulted in a complex mixture.
Next, reactions were performed in the presence of salt
additives. The role of MgBr2 additive on the stereochemical
outcome of Julia olefination with benzothiazolyl derived reagents
has recently been demonstrated in the synthesis of R-fluoro-
acrylates.10 In the present case, a room temperature reaction in
THF, in the presence of MgBr2 resulted in an increased
Z-selectivity, whereas a change in the reactant stoichiometry
had little effect on olefination selectivity and yield (entries 11
and 12). Addition of ZnBr2 showed only a marginal increase in
selectivity (compare entries 3 and 13). Finally, the use of NaH
as base in THF resulted in the exclusive formation of the
Z-isomer (entries 14 and 15). Under these conditions the rate
of the reaction and yield increased with higher molar excess of
sulfone and NaH (entry 15). To assess whether there was any
influence of the cation on the stereoselectivity, condensations
were performed in the presence of an excess of 18-Crown-6
and 15-Crown-5, using NaH. In both cases, a decrease of
stereoselectivity was observed, which was more pronounced for
18-Crown-6 (entries 16 and 17). This indicates that the
counterion likely also plays a role in the stereoselection. The
DBU/MgBr2/THF result (entries 11 and 12) is also consistent
with this observation. Finally, in order to compare the condensa-
tion reactivity of 3 with 2-naphthaldehyde to that of the recently
described 3,5-bis(trifluoromethyl)phenyl sulfone based reagent,11
a reaction was performed under the reported conditions11 (entry
18). Under these conditions, no stereoselectivity was obtained
in the reaction with 3, likely indicating a link between aryl or
heteroarylsulfonyl moiety and the mechanistic path, leading to
markedly different stereochemical results.
Next, we wanted to test whether the second point of diversity,
i.e., the amide in the Julia-Weinreb reagent 3, could be
J. Org. Chem. Vol. 74, No. 10, 2009 3691

Ghosh et al.
TABLE 2. DBU-Mediated Condensation Reactions of 3
a Relative ratio of diastereomers in the crude reaction mixture determined by 19F NMR prior to isolation. No change in olefin ratio was observed after
purification. b Yields of isolated, purified products (reactions were performed under similar conditions with either method A or method B, but were not
optimized for individual cases). c Practically no change in E/Z ratio and yield was observed upon increasing the sulfone from 1.2 to 1.4 molar equiv
(compare entry 4, Table 1).
TABLE 3. Condensation Reactions of 3 with Carbonyl Compounds Using NaH
a Relative ratio of diastereomers in the crude reaction mixture determined by 19F NMR prior to isolation. b Yields of isolated, purified products. c The
ratio of N-benzylpiperidone:3:NaH ) 2.5:1:2.
modified prior to the olefination reaction. This would allow for
the synthesis of a second set of Julia reagents from a common
precursor. Specifically, we were interested in the synthesis of
keto derivatives. Upon the basis of our previous results
demonstrating the higher reactivity of aldehydes with fluoro Julia
reagents,7-9 we reasoned that keto derivatives of BT-sulfone
would undergo selective reactions with aldehydes under mild
conditions, without participation of the keto moiety. Since BT-
sulfone derivatives are labile under basic conditions, we decided
that rather than the reaction of 3 with organometallics, the
3692 J. Org. Chem. Vol. 74, No. 10, 2009

Fluorinated Vinyl Weinreb Amides, Enones, and Allyl Amine
SCHEME 2. Conversion of 1 to a Second Set of Fluoro Julia Olefination Reagents and to 3 via a Common Intermediate
TABLE 4. Condensation Reactions of Fluoro Julia Reagents 16
and 17
fluorinated sulfide precursor would be a better substrate for this
modification. BT-sulfide 1 was therefore subjected to metalation-
fluorination with LDA and NFSI in toluene, to give fluoro BT-
sulfide derivative 13 in 83% yield.
Reaction of 13 with 2.25 molar equiv of PhLi (-78 °C to
room temperature) gave a complex reaction mixture. Upon
reaction of 13 with 2.5 molar equiv of PhMgBr at room
temperature, some desired product formation was observed in
an otherwise complex reaction mixture. Lowering the temper-
ature to -20 °C and use of 6 molar equiv of the Grignard
reagent resulted in successful formation of the desired (1,3-
benzothiazol-2-ylsulfanyl)fluoromethyl phenyl ketone 14 that
was isolated in 82% yield (Scheme 2). Oxidation of 14 with
H5IO6 in the presence of catalytic CrO3 in CH3CN19 gave sulfone
16 in 49% isolated yield. To test generality, 13 was also reacted
with n-propylmagnesium bromide at -20 °C, to give the
n-propyl derivative 15 that was isolated in 81% yield. Oxidation
of 15 with H5IO6 and catalytic CrO3 in CH3CN19 was fast and
smooth at rt to give sulfone 17 in 87% isolated yield (Scheme
2). Since 13 can be potentially converted to 3, we also explored
this route (Scheme 2). In fact, 3 can be smoothly prepared from
1 in 68% overall yield, in comparison to the 76% overall yield
via Scheme 1. Therefore, 13 serves as a key common intermedi-
ate to both types of Julia olefination reagents.
a Total amount of sulfone and DBU used for complete aldehyde
consumption. For good conversions, sequential addition of sulfone and
DBU was required (please see the Experimental Section and the
Supporting Information for details). b Yields of isolated, purified
products.
Although R-fluoro-R,ꢀ-enones are versatile synthetic inter-
mediates, methods for their synthesis are sparce.13,20 With the
two reagents (1,3-benzothiazol-2-ylsulfonyl)fluoromethyl phenyl
(16) and n-propyl ketone (17) in hand, we tested their reactivity
for the synthesis of R-fluoro-R,ꢀ-enones. Reagent 16 was
subjected to DBU-mediated olefination with p-methoxybenzal-
dehyde. A room temperature reaction of 16 in either CH2Cl2 or
THF showed very little conversion to product in 24 h. However,
use of refluxing THF resulted in complete conversion to
products. In contrast, condensation reactions of 17 led to
complex reaction mixtures at higher temperatures. Lowering the
reaction temperature to 0 °C resulted in good yields of the
R-fluoroenone. Due to lower solubility of 17 in THF, a mixture
of CH2Cl2 and THF was used as reaction solvent. In both cases,
the reactions were monitored by TLC (after ca. 15 min in the
case of 16 and after 2 h in the case of 17) and if starting aldehyde
was still present, additional sulfone and DBU were added (please
see the Experimental Section for details). Condensation reactions
of 16 and 17 with some representative aldehydes are displayed
in Table 4. In all cases studied, only the Z-isomer was observed.
No attempts were made to further optimize the reaction
conditions.
We were next interested in the application of the methodology
to the synthesis of R-fluoro allyl amines. The biological
relevance of the R-fluoro allyl amine motif is well documented.1
R-Fluoro-R,ꢀ-unsaturated Weinreb amides can be convenient
intermediates in R-fluoro allyl amine synthesis (Scheme 3). To
explore this application, R-fluoro allyl amine 27 (Scheme 3)
was chosen as a target, due to its reported inhibitory activity
toward dipeptidyl peptidase II.17 Although we have shown that
NaH-mediated condensation of N-benzylpiperidone and 3 led
to product 12, we were curious whether the condensation would
occur under milder conditions. Successful use of Cs2CO3 as a
base has been demonstrated in other Julia-Kocienski olefina-
tions, e.g., in condensations of p-nitrophenyl sulfones21 or in
(19) Xu, L.; Cheng, J.; Trudell, M. L. J. Org. Chem. 2003, 68, 5388–5391.
(20) (a) Chen, C.; Wilcoxen, K.; Zhu, Y.-F.; Kim, K.-i.; McCarthy, J. R. J.
Org. Chem. 1999, 64, 3476–3482. (b) Chen, C.; Wilcoxen, K.; Huang, C. Q.;
Strack, N.; McCarthy, J. R. J. Fluorine Chem. 2000, 101, 285–290. (c)
Bainbridge, J. M.; Corr, S.; Kanai, M.; Percy, J. M. Tetrahedron Lett. 2000, 41,
971–974. (d) Dutheuil, G.; Paturel, C.; Lei, X.; Couve-Bonnaire, S.; Pannecoucke,
X. J. Org. Chem. 2006, 71, 4316–4319. (e) Prakash, G. K. S.; Chacko, S.;
Vaghoo, H.; Shao, N.; Gurung, L.; Mathew, T.; Olah, G. A. Org. Lett. 2009,
11, 1127–1130.
(21) Mirk, D.; Grassot, J.-M.; Zhu, J. Synlett 2006, 1255–1259.
J. Org. Chem. Vol. 74, No. 10, 2009 3693

Ghosh et al.
SCHEME 3. Synthesis of r-Fluoro Allyl Amine with Fluoro Julia-Weinreb Reagent 3
methylenations with tert-butyltetrazolyl sulfones.22 In the present
case, Cs2CO3-mediated condensation of 3 with N-benzylpiperi-
done resulted in a 59% yield of 12 (comparable to the NaH-
mediated condensation). In comparison, cyclohexanone gave a
42% yield of condensation product 24 (perhaps due to product
volatility). Condensation product 24 was subsequently converted
to aldehyde 25 (63%) that was then subjected to imine formation
with benzylamine to give 26. Reduction of 26 yielded the desired
27 in 94% yield over two steps.
as a white solid. 1H NMR (500 MHz, CDCl3): δ 8.29 (d, 1H, Ar-H,
J ) 8.2 Hz), 8.04 (d, 1H, Ar-H, J ) 7.6 Hz), 7.69-7.62 (m, 2H,
Ar-H), 6.58 (d, 1H, 2JHF ) 47.6 Hz), 3.90 (s, 3H), 3.32 (s, 3H). 13
C
NMR (125 MHz, CDCl3): δ 161.7, 159.7 (d, 2JCF ) 22.4 Hz), 152.7,
1
138.0, 128.8, 128.1, 126.1, 122.5, 94.9 (d, JCF ) 226.1 Hz), 62.2,
2
32.9. 19F NMR (282 MHz, CDCl3): δ -181.5 (d, JFH ) 48.8 Hz).
HRMS (ESI) calcd for C11H11FN2O4S2Na [M + Na]+ 341.0036, found
341.0028.
N-Methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfanyl)fluoroac-
etamide (13). A solution of N-methoxy-N-methyl-(1,3-benzothiazol-
2-ylsulfanyl)acetamide 1 (2.02 g, 7.51 mmol, 1 molar equiv) in
dry toluene (50 mL) was cooled to -78 °C under nitrogen gas.
LDA (9.60 mmol, 4.80 mL, 1.28 molar equiv of a 2 M solution in
heptane/THF/EtPh) was added to the reaction mixture. After 20
min, solid NFSI (2.84 g, 9.01 mmol, 1.2 molar equiv) was added.
The mixture was allowed to stir at -78 °C for 50 min, then warmed
to rt and stirred for an additional 50 min. Saturated aq NH4Cl (30
mL) was added to the mixture and the layers were separated. The
aqueous layer was extracted with EtOAc (3 × 30 mL), and the
combined organic layer was washed with saturated aq NaHCO3
(30 mL) and brine (30 mL). The organic layer was dried over
Na2SO4 and the solvent was evaporated under reduced pressure.
The crude reaction mixture was purified by column chromatography
(SiO2, 40% EtOAc in hexanes) to yield 13 (1.79 g, 83%) as a pale
yellow liquid. 1H NMR (500 MHz, CDCl3): δ 7.98 (d, 1H, Ar-H,
J ) 8.3 Hz), 7.82 (d, 1H, Ar-H, J ) 7.8 Hz), 7.49-7.36 (m, 3H),
3.81 (s, 3H), 3.28 (s, 3H). 19F NMR (282 MHz, CDCl3): δ -161.0
(d, 2JFH ) 51.9 Hz). HRMS (ESI) calcd for C11H11FN2O2S2Na [M
+ Na]+ 309.0138, found 309.0130.
N-Methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroac-
etamide (3) via Oxidation of 13. H5IO6 (302 mg, 1.32 mmol) was
dissolved in CH3CN (20 mL) by vigorous stirring at rt for 30 min.
CrO3 (5.0 mg, 0.050 mmol, 15 mol %) was added and the reaction
mixture was stirred for an additional 5 min to give an orange colored
solution. A solution of fluoro sulfide 13 (95.1 mg, 0.332 mmol) in
CH3CN (5 mL) was added dropwise to this mixture, resulting in
the formation of a green precipitate. After the addition was complete
the reaction mixture was stirred at rt for 3 h at which time TLC
(SiO2, 50% EtOAc in hexanes) showed a complete consumption
of 13. The reaction mixture was filtered through a Celite pad, the
Celite was washed with EtOAc, and the solvent was evaporated
under reduced pressure. Water was added to the residue (30 mL)
and the mixture was extracted with EtOAc (3 × 30 mL), then the
combined organic layer was washed with saturated aq Na2SO3 (30
mL) and brine (30 mL) and dried over anhydrous Na2SO4. The
organic layer was concentrated under reduced pressure and the crude
product was purified by column chromatography (SiO2, 50% EtOAc
in hexanes) to afford 3 as a white solid (87.0 mg, 82%).
Conclusions
In conclusion, we have synthesized a benzothiazolyl sulfone
derived reagent for the synthesis of R-fluorovinyl Weinreb
amides via Julia olefination. The reactivity of the reagent was
studied under mild, DBU-mediated conditions as well as with
NaH. Lower temperatures and relatively nonpolar solvents favor
formation of the Z-isomer, whereas polar solvents and higher
temperatures favor formation of the E-isomer. Formation of the
Z-isomer strongly predominated (g98%) when NaH was used
as base. This is to our knowledge the first example showing
tunability of reaction condensations leading to the R-fluorovinyl
Weinreb amide derivatives. Further, conversion of the amide
moiety to a keto functionality in benzothiazolylsulfanyl fluo-
roacetamide derivative yielded another set of Julia reagents for
the synthesis of R-fluoroenones. The methodology presented
offers access to two different sets of Julia olefination reagents
via a common fluorinated precursor. A series of R-fluoroenones
was prepared under mild conditions with DBU as base, with
complete Z-stereoselectivity. We have also demonstrated the
utility of the reagent for synthesis of R-fluoro allyl amines via
Weinreb amides, by preparation of a biologically relevant
dipeptidyl peptidase inhibitor.
Experimental Section
N-Methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluoroac-
etamide (3) via Fluorination of 2. A solution of sulfone 2 (1.00
g, 3.33 mmol, 1 molar equiv) in dry toluene (185 mL) was cooled
to -78 °C under nitrogen gas. LDA (3.50 mmol, 1.75 mL, 1.05
molar equiv of a 2 M solution in heptane/THF/EtPh) was added to
the reaction mixture. After 15 min solid NFSI (1.31 g, 4.17 mmol,
1.25 molar equiv) was added. The mixture was allowed to stir at
-78 °C for 50 min, then warmed to rt and stirred for an additional
50 min. Saturated aq NH4Cl was added and the mixture was
extracted with EtOAc (3×), and the combined organic layer was
washed with saturated aq NaHCO3 and brine. The organic layer
was dried over Na2SO4 and the solvent was evaporated under reduced
pressure. The crude reaction mixture was purified by column chro-
matography (SiO2, 40% EtOAc in hexanes) to yield 3 (0.905 g, 85%)
(1,3-Benzothiazol-2-ylsulfanyl)fluoromethyl Phenyl Ketone
(14). To a solution of fluoro sulfide 13 (1.01 g, 3.51 mmol) in dry
THF (10.0 mL) was added PhMgBr (21.0 mL, 1 M solution in
THF, 21.0 mmol) dropwise at -20 °C. The reaction mixture was
stirred at -20 °C and after 1 h TLC (SiO2, 20% EtOAc in hexanes)
showed the disappearance of 13. The reaction was quenched with
(22) A¨ıssa, C. J. Org. Chem. 2006, 71, 360–363.
3694 J. Org. Chem. Vol. 74, No. 10, 2009

Fluorinated Vinyl Weinreb Amides, Enones, and Allyl Amine
saturated aq NH4Cl (30 mL), the aqueous layer was extracted with
EtOAc (3 × 30 mL), and the combined organic layers were washed
with NaHCO3 (30 mL) and brine (30 mL) and then dried over
Na2SO4. The organic layer was concentrated in vacuo and the crude
product was purified by column chromatography (SiO2, 10% EtOAc
rt and TLC (SiO2, 20% EtOAc in hexanes) showed a complete
consumption of 15 after 30 min. The reaction mixture was filtered
through a sintered glass funnel and then through a Celite pad, and
the Celite was washed with CH3CN (10 mL). The filtrate was
concentrated under reduced pressure at rt, water was added to the
residue, and the mixture was extracted with EtOAc (3 × 30 mL).
The combined organic layer was washed with saturated aq Na2SO3
and brine then dried over anhydrous Na2SO4 and the solvent was
evaporated under reduced pressure. The crude product was purified
by column chromatography (SiO2, 15% EtOAc in hexanes) to afford
1
in hexanes) to afford 14 as a colorless liquid (872 mg, 82%). H
NMR (500 MHz, CDCl3): δ 8.10 (d, 1H, Ar-H, J ) 7.8 Hz), 8.03
(d, 1H, Ar-H, J ) 7.8 Hz), 7.95 (d, 1H, 2JHF ) 51.6 Hz), 7.83 (d,
1H, Ar-H, J ) 7.8 Hz), 7.65 (t, 1H, Ar-H, J ) 7.8 Hz), 7.52 (t,
2H, Ar-H, J ) 7.4 Hz), 7.41 (t, 1H, Ar-H, J ) 7.4 Hz), 7.31-7.28
(m, 1H, Ar-H), 7.18-7.17 (m, 1H, Ar-H). 19F NMR (CDCl3): δ
-162.1 (d, 2JFH ) 51.9 Hz). HRMS (ESI) calcd for C15H10FNOS2Na
[M + Na]+ 326.0080, observed 326.0076.
1
sulfone 17 as a white solid (720 mg, 87%). H NMR (500 MHz,
CDCl3): δ 8.25 (d, 1H, Ar-H, J ) 7.9 Hz), 8.04 (d, 1H, Ar-H, J
2
) 7.6 Hz), 7.69-7.63 (m, 2H, Ar-H), 5.97 (d, 1H, JHF ) 48.2
(1,3-Benzothiazol-2-ylsulfanyl)fluoromethyl n-Propyl Ketone
(15). To a stirring solution of n-propylmagnesium bromide, prepared
from n-propyl bromide (3.40 mL, 37.1 mmol) and Mg (891 mg,
37.1 mmol) in THF (60 mL), at -20 °C was added a solution of
fluoro sulfide 13 (1.77 g, 6.19 mmol) in THF (30 mL) dropwise.
After complete addition, the reaction mixture was stirred at -20
°C for 1 h, then warmed to 0 °C and quenched with saturated aq
NH4Cl. The reaction mixture was diluted with water and extracted
with EtOAc (2 × 30 mL). The combined organic layer was
thoroughly washed with water and with brine and dried over
anhydrous Na2SO4, then the solvent was evaporated in vacuo. The
crude product was purified by column chromatography (SiO2, 5%
EtOAc in hexanes) to afford ketone 15 as a yellow oil (1.35 g,
81%). 1H NMR (500 MHz, CDCl3): δ 7.94 (d, 1H, Ar-H, J ) 7.9
Hz), 7.81 (d, 1H, Ar-H, J ) 7.9 Hz), 7.47 (t, 1H, Ar-H, J ) 7.6
Hz), 2.88 (dtd, 1H, J ) 18.7, 7.2, 2.7 Hz), 2.76 (dt, 1H, J ) 18.9,
7.1 Hz), 1.71 (sext, 2H, J ) 7.3 Hz), 0.96 (t, 3H, J ) 7.3 Hz). 19
F
NMR (282 MHz, CDCl3): δ -182.3 (d, 2JFH ) 48.8 Hz). 13C NMR
2
(125 MHz, CDCl3): δ 196.6 (d, JCF ) 19.7 Hz), 161.3, 152.4,
137.4, 128.8, 128.1,125.7, 122.4, 100.6 (d, 1JCF ) 237.1 Hz), 42.1,
16.0, 13.3. HRMS (ESI) calcd for C12H12FNO3S2Na [M + Na]+
324.0135, found 324.0124.
Representative Procedures for Condensations of Aldehydes
with N-Methoxy-N-methyl-(1,3-benzothiazol-2-ylsulfonyl)fluo-
roacetamide (3), Using Methods A, B, and C. Method A:
Synthesis of (E/Z)-2-Fluoro-N-methoxy-N-methyl-3-(4-nitro-
phenyl)propenamide (5). To a stirred solution of the p-nitroben-
zaldehyde (151 mg, 1.00 mmol, 1 molar equiv) and sulfone 3 (445
mg, 1.4 molar equiv) in dry THF (7.8 mL) at -78 °C was added
a cooled (-75 °C) solution of DBU (609 mg, 4.00 mmol, 4.0 molar
equiv) in dry THF (7.8 mL). The reaction mixture was allowed to
stir at -78 °C until complete consumption of aldehyde was
observed by TLC (3 h), saturated aq NH4Cl (15 mL) was added,
the reaction mixture was brought to rt and extracted with Et2O (3
× 50 mL). The combined organic layer was washed with 1 N NaOH
(40 mL), water, and brine then dried over Na2SO4, and the solvent
was evaporated under reduced pressure. Analysis of the crude
reaction mixture by 19F NMR showed the E/Z product ratio of 3:97.
The crude product was purified by column chromatography (20%
EtOAc in hexanes) to yield 233 mg (92%) of (E/Z)-5 as a pale
yellow solid. Although 3% of (E)-5 was detected, NMR data are
2
Hz), 7.37 (t, 1H, Ar-H, J ) 7.6 Hz), 6.83 (d, 1H, JHF ) 51.0
Hz), 2.77 (t, 2H, J ) 7.2 Hz), 1.71 (sext, 2H, J ) 7.3 Hz), 0.97 (t,
3H, J ) 7.4 Hz). 19F NMR (282 MHz, CDCl3): δ -163.6 (d, 2JFH
) 51.9 Hz). HRMS (ESI) calcd for C12H12FNOS2Na [M + Na]+
292.0237, found 292.0230.
(1,3-Benzothiazol-2-ylsulfonyl)fluoromethyl Phenyl Ketone
(16). H5IO6 (2.62 g, 11.5 mmol) was dissolved in CH3CN (50 mL)
by vigorous stirring at rt for 30 min. CrO3 (11.0 mg, 0.110 mmol,
4 mol %) was added and the reaction mixture was stirred for an
additional 5 min to give an orange colored solution. A solution of
fluoro sulfide 14 (872 mg, 2.87 mmol) in CH3CN (10 mL) was
added dropwise to this mixture, resulting in an exothermic reaction
and formation of a yellowish precipitate. After the addition was
complete the reaction mixture was stirred overnight at which time
TLC (SiO2, 25% EtOAc in hexanes) showed a complete consump-
tion of 14. The reaction mixture was filtered through a Celite
pad, the Celite was washed with CH3CN, and the filtrate was
concentrated under reduced pressure. Water was added to the
residue and the mixture was extracted with EtOAc (3 × 50 mL),
then the combined organic layer was washed with saturated aq
Na2SO3 (30 mL) and brine (30 mL) and dried over anhydrous
Na2SO4. The organic layer was concentrated under reduced pressure
and the crude product was purified by column chromatography
(SiO2, 40% EtOAc in hexanes) to afford 16 as a colorless solid
(472 mg, 49%). 1H NMR (500 MHz, CDCl3): δ 8.29 (d, 1H, Ar-H,
J ) 7.8 Hz), 8.12 (d, 2H, Ar-H, J ) 8.3 Hz), 8.05 (d, 1H, Ar-H,
J ) 7.4 Hz), 7.71-7.64 (m, 3H, Ar-H), 7.55 (t, 2H, Ar-H, J )
7.8 Hz), 6.81 (d, 1H, 2JHF ) 47.9 Hz). 13C NMR (125 MHz, CDCl3):
1
reported only for the major isomer. Major isomer (Z)-5: H NMR
(500 MHz, CDCl3): δ 8.23 (d, 2H, Ar-H, J ) 8.6 Hz), 7.75 (d,
3
2H, Ar-H, J ) 8.5 Hz), 6.73 (d, 1H, JHF ) 35.7 Hz), 3.81 (s,
3H), 3.30 (s, 3H). 19F NMR (282 MHz, CDCl3): δ -115.0 (d, 3JFH
) 33.6 Hz). HRMS (ESI) calcd for C11H11FN2O4Na [M + Na]+
277.0595, found 277.0593.
Method B: Synthesis of (E/Z)-2-Fluoro-N-methoxy-N-methyl-
3-(2-thienyl)propenamide (6). To a stirred solution of thiophene-
2-carboxaldehyde (45.8 mg, 0.409 mmol, 1.3 molar equiv) and 3
(100 mg, 0.314 mmol, 1.0 molar equiv) in DMPU (2.4 mL) at rt
was added a solution of DBU (95.7 mg, 0.629 mmol, 2 molar equiv)
in DMPU (2.4 mL) dropwise. The reaction mixture was allowed
to stir for 18 h, at which time complete consumption of 3 was
observed by TLC (SiO2, 30% EtOAc in hexanes). The reaction was
quenched with saturated aq NH4Cl (5 mL), the aqueous layer
was extracted with Et2O (3 × 20 mL), the combined organic layer
was washed with 1 N NaOH (20 mL), water, and brine then dried
over Na2SO4, and the solvent was evaporated under reduced
pressure. Analysis of the crude reaction mixture by 19F NMR
showed the E/Z product ratio of 86:14. The crude product was
purified by column chromatography (SiO2, 20% EtOAc in hexanes)
to afford 55 mg (81%) of (E/Z)-6 as a pale yellow viscous liquid.
For the 1H NMR data of (Z)-6 (minor isomer in the present case),
please see the Supporting Information. Major isomer (E)-6:1H NMR
(500 MHz, CDCl3): δ 7.29 (d, 1H, Ar-H, J ) 4.3 Hz), 7.13 (d,
1H, Ar-H, J ) 3.1 Hz), 6.98 (app t, 1H, Ar-H, J ≈ 4.3 Hz), 6.71
(d, 1H, 3JHF ) 22.0 Hz), 3.75 (s, 3H), 3.30 (s, 3H). (E/Z)-6 HRMS
(ESI) calcd for C9H10FNO2SNa [M + Na]+ 238.0308, observed
238.0301.
2
δ 185.3 (d, JCF ) 17.5 Hz), 161.6, 152.7, 137.8, 135.5, 134.0,
130.1, 129.1, 129.0, 128.2, 126.1, 122.6, 99.5 (d, 1JCF ) 233.7 Hz).
19F NMR (282 MHz, CDCl3): δ -179.3 (d, 2JFH ) 48.8 Hz). HRMS
(ESI) calcd for C15H10FNO3S2Na [M + Na]+ 357.9978, observed
357.9974.
(1,3-Benzothiazol-2-ylsulfonyl)fluoromethyl n-Propyl Ketone
(17). H5IO6 (2.51 g, 11.0 mmol) was dissolved in CH3CN (44 mL)
by vigorous stirring at rt for 30 min. CrO3 (5.5 mg, 0.055 mmol,
2 mol %) was added and the reaction mixture was stirred for an
additional 5 min to give an orange colored solution. A solution of
fluoro sulfide 15 (739 mg, 2.75 mmol) in CH3CN (11 mL) was
added dropwise to this mixture, resulting in an exothermic reaction
and formation of a precipitate. The reaction mixture was stirred at
J. Org. Chem. Vol. 74, No. 10, 2009 3695

Ghosh et al.
Method C: Synthesis of (Z)-2-Fluoro-N-methoxy-N-methyl-
3-(4-methoxyphenyl)propenamide (8).11 A suspension of NaH
(70.5 mg, 2.94 mmol, 4 molar equiv) and 3 (467 mg, 1.47 mmol,
2 molar equiv) in dry THF (8.4 mL) was stirred at rt under a
nitrogen atmosphere for 2 min. A solution of p-methoxybenzalde-
hyde (100 mg, 0.734 mmol, 1 molar equiv) in dry THF (3.4 mL)
was added dropwise. The reaction mixture was allowed to stir at
rt for 1.5 h and then quenched with saturated aq NH4Cl (10 mL).
The mixture was extracted with Et2O (3 × 40 mL), then the
combined organic layers were washed with 1 N NaOH (30 mL),
water, and brine and dried over Na2SO4. Analysis of the crude
reaction mixture by 19F NMR showed the E/Z product ratio of
1:99. The crude product was purified by column chromatography
(SiO2, 20% EtOAc in hexanes) to yield 156 mg (89%) of 8 as a
light brown semisolid. (Z)-8: 1H NMR (500 MHz, CDCl3): δ 7.57
(d, 2H, Ar-H, J ) 8.5 Hz), 6.90 (d, 2H, Ar-H, J ) 8.8 Hz),
Condensations of 17 with p-nitrobenzaldehyde and 3-phenylpro-
panal are given in the Supporting Information as representative
procedures. For other substrates, see Table 4 for details on reagent
stoichiometry, reaction time, temperature, and yield. See the
Supporting Information for additional details, such as TLC and
column chromatographic conditions, spectroscopic data of products,
as well as literature reference for known compounds.
Synthesis of 24 via Condensation of Cyclohexanone with
Fluoro Sulfone 3. To a solution of sulfone 3 (251 mg, 0.788 mmol,
1 molar equiv) in dry DMF (10.0 mL) was added Cs2CO3 (1.03 g,
3.16 mmol, 4 molar equiv) and the color of the reaction mixture
turned deep yellowish-orange. The suspension was stirred at rt for
30 min, and a solution of cyclohexanone (154 mg, 1.57 mmol, 2
molar equiv) in dry DMF (2.0 mL) was added. The reaction mixture
was stirred at rt for 30 h, saturated aq NH4Cl (30 mL) was added,
and the mixture was extracted with EtOAc (3 × 30 mL). The
combined organic layer was washed with saturated aq NaHCO3
(30 mL) and brine (30 mL) and dried over anhydrous Na2SO4. The
solvent was removed in vacuo and the crude product was purified
by column chromatography (SiO2, 20% EtOAc in hexanes) to give
24 as a clear liquid (66.6 mg, 42%). 1H NMR (500 MHz, CDCl3):
δ 3.73 (s, 3H), 3.23 (s, 3H), 2.29-2.23 (m, 4H), 1.64-1.57 (m,
6H). 19F NMR (282 MHz, CDCl3): δ -127.0 (br s). HRMS (ESI)
calcd for C10H16FNO2Na [M + Na]+ 224.1057, observed 224.1055.
Reduction of 24. To a suspension of LiAlH4 (18.0 mg, 0.474
mmol) in dry THF (5.0 mL) at 0 °C was added a solution of 24
(43.0 mg, 0.214 mmol) in dry THF (1.0 mL). The reaction mixture
was stirred at 0 °C for 15 min and at rt for 1 h, then cooled to 0 °C
and 0.1 N HCl (3 mL) was added to the mixture. The mixture was
extracted with Et2O (3 × 30 mL) and the combined organic layer
was washed with saturated aq NaHCO3 (30 mL) and brine (30 mL)
and dried over Na2SO4. The organic layer was concentrated under
reduced pressure, and the crude product was purified by column
chromatography (SiO2, CH2Cl2) to yield 2524 as a colorless liquid
(18.0 mg, 63%). 1H NMR (500 MHz, CDCl3): δ 9.79 (d, 1H, 3JHF
) 18.0 Hz), 2.63-2.61 (m, 2H), 2.44-2.42 (m, 2H), 1.72-1.64
3
6.69 (d, 1H, JHF ) 37.5 Hz), 3.82 (s, 3H), 3.78 (s, 3H), 3.27 (s,
3H). 19F NMR (282 MHz, CDCl3): δ -124.0 (d, 3JFH ) 36.6 Hz).
HRMS (ESI) calcd for C12H14FNO3Na [M + Na]+ 262.0849,
found 262.0844.
General Procedure for the Synthesis of 18a23-21a via
Condensations of Aldehydes with Fluoro Sulfone 16. To a
refluxing solution of aldehyde (1 molar equiv) and DBU (3 molar
equiv) in THF (28 mL/mmol of aldehyde) was added sulfone 16
(2 molar equiv) dissolved in THF (4.5 mL/mmol of 16) dropwise.
The reaction was stirred at reflux for ca. 15 min and the conversion
was checked by TLC. If sulfone was consumed and unreacted
starting aldehyde was observed, an additional 1 molar equiv of each
of DBU in THF (2 mL/mmol of DBU) and solid 16 were added
(in the case of o-methoxybenzaldehyde, 3 molar equiv of DBU
and 2 molar equiv of 16 were added). If both sulfone and aldehyde
were still present, an additional 1 molar equiv of DBU in THF (2
mL/mmol of DBU) was added. After heating under reflux for an
additional 15 min, the conversion was again checked by TLC. If
unreacted starting aldehyde was present, an additional 1 molar equiv
of solid 16 was added. In all cases, consumption of starting aldehyde
was observed after 30-40 min of reflux. The reaction was quenched
with saturated aq NH4Cl and the mixture was extracted with EtOAc
(3×). The organic layer was washed with saturated aq NaHCO3
and brine, dried over anhydrous Na2SO4, and concentrated. The
crude product was purified by column chromatography. As repre-
sentative procedures, condensations of p-nitrobenzaldehyde and
thiophene-2-carboxaldehyde with 16 are given in the Supporting
Information. For other substrates, see Table 4 for details on reagent
stoichiometry, reaction time, temperature, and yield. See the
Supporting Information for additional details, such as TLC and
column chromatographic conditions, spectroscopic data of products,
as well as literature reference for known compounds.
3
(m, 6H). 19F NMR (282 MHz, CDCl3): δ -137.6 (d, JFH ) 18.3
Hz).
Synthesis of 27 from 25. Step 1: Condensation of 25 with
Benzylamine. To a mixture of benzylamine (16.0 mg, 0.149 mmol)
and aldehyde 25 (17.0 mg, 0.120 mmol) in dry CH2Cl2 (10.0 mL)
were added molecular sieves (4 Å, 200 mg) and the mixture was
stirred overnight. After 22 h, TLC (SiO2, 20% EtOAc in hexanes)
showed complete consumption of 25. The solvent was evaporated
and the crude product 26 (33.0 mg) was subjected to reduction
without further purification.
Step 2: Reduction of 26. To a solution of imine 26 (33.0 mg,
crude product from step 1) in CH3OH (10.0 mL) was added NaBH4
(11.3 mg) at 0 °C. The reaction mixture was stirred for 1 h and
after the starting material was fully consumed, the mixture was
evaporated. Saturated aq NH4Cl (20 mL) was added to the solid
residue and the mixture was extracted with EtOAc (3 × 30 mL).
The combined organic layer was washed with NaHCO3 (30 mL)
and brine (30 mL) then dried over Na2SO4. The organic layer was
concentrated and the crude product was purified by silica gel
chromatography (20% EtOAc in hexanes) to afford 2717 as a
General Procedure for Synthesis of 18b,20d 20b, 22b, and
23b20d via Condensations of Aldehydes with Fluoro Sulfone
17. A solution of aldehyde (1 molar equiv) and DBU (6 molar
equiv) in THF (28.0 mL/mmol of aldehyde) was cooled to 0 °C.
Sulfone 17 (2 molar equiv, except for 3-phenylpropanal, where 1.5
molar equiv was used) was dissolved in CH2Cl2 (30.0 mL/mmol
of 17) and was added slowly, dropwise to the reaction mixture over
2-3 h (1 h in the case of 3-phenylpropanal). Very slow addition
of 17 is critical, since sulfone 17 is unstable under the reaction
conditions, thus resulting in higher consumption of 17 upon faster
additions. The reaction mixture was allowed to stir at 0 °C until
complete disappearance of aldehyde was observed by TLC. If
sulfone consumption was observed, an additional 1 molar equiv of
17 was added slowly, dropwise oVer seVeral hours. Upon disap-
pearance of the aldehyde, saturated aq NH4Cl was added to the
reaction mixture and the mixture was extracted with EtOAc (2×).
The combined organic layer was washed with water and brine and
dried over anhydrous Na2SO4, then the solvent was evaporated.
1
colorless liquid (26.0 mg, 94% yield over two steps). H NMR
(500 MHz, CDCl3, NH exchanged): δ 7.34-7.31 (m, 3H, Ar-H),
7.27-7.25 (m, 2H, Ar-H), 3.78 (s, 2H), 3.41 (d, 2H, 3JHF ) 22.6
Hz), 2.24 (br s, 2H), 2.02-1.99 (br m, 2H), 1.64-1.52 (br m, 6H).
19F NMR (282 MHz, CDCl3): δ -121.8 (t, 3JFH ) 21.4 Hz). HRMS
(ESI) calcd for C15H21FN [M + H]+ 234.1653, observed 234.1652.
Acknowledgment. This work was supported by NSF Grant
CHE-0516557; infrastructural support and support for AKG
were provided by NIH RCMI Grant 5G12 RR03060. Partial
(23) Hata, H.; Kobayashi, T.; Amii, H.; Uneyama, K.; Welch, J. T.
Tetrahedron Lett. 2002, 43, 6099–6102.
(24) Sauvetre, R.; Masure, D.; Chuit, C.; Normant, J. F. Synthesis 1978, 128–
130.
3696 J. Org. Chem. Vol. 74, No. 10, 2009

Fluorinated Vinyl Weinreb Amides, Enones, and Allyl Amine
support by PSC CUNY awards 38 and 39 is acknowledged.
We thank Dr. Andrew Poss (Honeywell) for a sample of
NFSI.
data, literature references (where applicable) for 1, 2, (Z)-4, (Z)-
6, (Z)-7, (Z)-9-(Z)-11, 12, (Z)-18a-(Z)-21a, (Z)-18b, (Z)-20b,
(Z)-22b, and (Z)-23b, 1H NMR spectra of 1-25 and 27, as well
as 13C NMR spectra of 3, 16, and 17. This material is available
free of charge via the Internet at http://pubs.acs.org.
Supporting Information Available: General procedures with
methods A, B, and C, representative procedures for condensa-
tions of 16 and 17, synthetic details, 1H NMR as well as HRMS
JO802784W
J. Org. Chem. Vol. 74, No. 10, 2009 3697