Practical synthesis of β-acyl and β-alkoxycarbonyl heterocyclic sulfones

Article abstract of DOI:10.1021/jo102326p

A short and efficient synthesis for β-acyl and β-alkoxycarbonyl heterocyclic sulfones containing benzothiazol (BT) and phenyltetrazol (PT) heterocyclic core is presented here. The method seems to be general and provides the desired C-nucleophiles in very good to excellent yields from readily available starting materials.

Full text of DOI:10.1021/jo102326p

NOTE
pubs.acs.org/joc
Practical Synthesis of β-Acyl and β-Alkoxycarbonyl Heterocyclic
Sulfones
Jiꢀrí Pospíꢀsil* and Hitoshi Sato†
Institute of Condensed Matter and Nanosciences-Molecules, Solids and Reactivity (IMCN/MOST), Universitꢁe catholique de Louvain,
B^atiment Lavoisier, Place Louis Pasteur 1, B-1348 Louvain-la-Neuve, Belgium
S Supporting Information
b
ABSTRACT: A short and efficient synthesis for β-acyl and β-
alkoxycarbonyl heterocyclic sulfones containing benzothiazol
(BT) and phenyltetrazol (PT) heterocyclic core is presented
here. The method seems to be general and provides the desired
C-nucleophiles in very good to excellent yields from readily
available starting materials.
ver the past two decades, asymmetric organocatalysis has
developed into a field permitting the elegant introduction of
to be long and tedious, and therefore we decided to evaluate a new
synthetic approach to β-carbonyl heterocyclic sulfones that would
better fit our purposes.
O
chiral information into a plethora of various substrates.1 During
this period, several efficient organocatalytic protocols that create
a novel C-C bond have been developed. The asymmetric
organocatalytic conjugate addition of carbon nucleophiles to
R,β-unsaturated carbonyl substrates is one typical example.2 It is
therefore surprising that efficient protocols allowing the addition
of alkynylic3 and alkenylic3,4 functionalities have only been
recently developed by MacMillan4 and Jørgensen.3 Even though
both of these protocols provide the desired alkenylic derivatives
in excellent yields and enantioselectivities, they are conceptually
different. MacMillan’s approach is based on the use of vinyl-type
borate complexes5 that acts as nucleophiles during the organo-
catalytic asymmetric conjugate addition process. The Jørgensen
approach, on the other hand, is based on a two-step tandem
process (see Scheme 1). First, an organocatalyst-promoted
conjugate addition of β-keto heterocyclic sulfone 2 nucleophile
to R,β-unsaturated carbonyl compound generates adduct 3,
which is then transformed to olefin 4 (via reduction/Smile
rearrangement6 protocol) or alkyne 5 (via enolization/Smile
rearrangement protocol6).
To achieve the most versatile approach to sulfones of general
structure 11, we decided to base the synthesis on the pairing of
sulfone 13 with electrophile 14 (Scheme 4). Even though this
type of disconnection seems to be obvious and is easily applicable
to β-keto phenyl sulfone synthesis,9 this approach is not easily
applicable if β-keto BT- and PT-sulfones are wanted. The reason
is that both BT- and PT-sulfones contain one electrophilic center
within their heterocyclic core. As a consequence, if BT- or
PT-sulfones 13 are treated with a non-nucleophilic base,10 self-
condensation occurs (Scheme 5).11
Thus if we want to prepare the desired β-carbonyl sulfones 11
starting from sulfone 13 and carbonyl electrophile 14, conditions
under which nucleophiles present in the reaction mixture are
unreactive toward the nucleophilic center have to be found.
To find suitable coupling conditions, we decided to study a
pairing between sulfone 13a and benzoyl chloride 14a (Table 1).
Initially, the Li anion generated from 13a was prepared with the
use of the non-nucleophilic base (LiN(TMS)2) at low tempera-
ture, and BzCl, an electrophile, was added after 30 min (Table 1,
entry 1). In this case, the desired product 11a was obtained only
in very low yield. Since the control experiment showed that the
low yield is not caused by instability or self-condensation of the
intermediate16,12 it remains that the low yield is caused by self-
condensation of 13a. To avoid this side reaction, the mixing time
of 13a with the base was progressively diminished (Table 1,
entries 2 and 3). Gratifyingly, it was observed that the desired
product 11a was isolated in excellent yield (96%) if generated
sulfone anion 13a was quenched rapidly (BzCl was added
immediately after the base).13
Later on, Jørgensen et al. used the same β-keto heterocyclic
sulfones 2 to perform a formal transition-metal-free Sonogashira
coupling and R-carbonyl arylation reaction7 (Scheme 1).
Finally, if β-acyl-heterocyclic sulfones 9 are used as reagents in
the Julia-Kocienski olefination reaction, R,β-unsaturated esters
10 can be prepared (Scheme 2).8
In our laboratory we recently started several synthetic ventures
that use and/or are based on the compounds that contains β-keto
and/or β-alkoxycarbonyl motifs, and to our great surprise, we found
out that in the literature there is only one synthetic approach that
yields sulfones 2 or 9. In this method, sulfones 2 and 9 are prepared
in two steps starting from R-bromo (halo) ketones or esters as the
key intermediates toward 2 or 9 (Scheme 3). Unfortunately, in our
case the synthesis of the desired R-halo carbonyl compounds proved
Received: November 23, 2010
Published: March 02, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 1. Application of β-Keto-heterocyclic Sulfone 2 in
Organic Synthesis
Scheme 5. Alkyl BT-Sulfone Base-Mediated Self-
Condensation
Table 1. Optimization of the Reaction Conditions
Scheme 2. β-Acyl-heterocyclic Sulfone 9 in the Context of a
Julia-Kocienski Reaction
Scheme 3. Standard Approach to β-Carbonyl Heterocyclic
Sulfones 11
Scheme 4. Retrosynthetic Approach to β-Carbonyl Hetero-
cyclic Sulfones 11
a Overall yields refer to pure, isolated products.
conditions (Table 1, entry 8). In this case, only the self-condensa-
tion product of 13a (compound 15) was observed.15
Having devised suitable reaction conditions to prepare this
β-acyl sulfone, its scope and limitations were explored. A
selection of pertinent results is shown in Table 2.
Both alkyl and aryl acyl derivatives react smoothly with
lithiated sulfones 13 (Table 2). In all cases the reaction yields
were more than 80% except when sulfone 13b was reacted with
monoethyl oxalyl chloride (Table 2, entry 8). In this case the
desired product 11f was obtained in 78% yield. Even acyl
chlorides, bearing enolizable hydrogen atoms in the R position,
reacted under the given reaction conditions to yield the desired
R-acyl sulfones in very good yields.
At this stage we decided to test the coupling reaction with other
types of benzoyl electrophilesto evaluate itsscope and limitations.
Unsurprisingly benzoylating agents with reactivity similar to that
of benzoyl chloride, such as BzF, BzBr, Bz2O, or benzoyl
imidazole14 (Table 1, entries 7, 9-11), yielded the desired β-
keto sulfone 11a in essentially the same yield. On the other hand,
methyl benzoyl ester proved to be unreactive under our reaction
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Table 2. Preparation of Acyl Heterocyclic Sulfones 11 Start-
ing from Sulfones 13 and Acyl-Containing Electrophiles
Table 3. Preparation of Alkoxycarbonyl Heterocyclic Sul-
fones 11 Starting from Sulfones 13 and Alkoxy Carbonyl-
Containing Electrophiles
At this stage this protocol was extended to the synthesis of
β-alkoxy carbonyl sulfones 17 (Table 3). For this purpose, three
different types of alkoxy carbonylating reagents (bearing Cl,
imidazole,16 or OCOR as a leaving group) were tested. The nature
of the leaving group was shown to have little effect on the reaction
yields, and all three electrophiles might be used as coupling partners.
Additionally, the reaction conditions tolerate various func-
tionalities, e.g., TBDPS ethers, phenyl ethers, and halogenated or
unsaturated alkanes (Table 2, entries 7-10 and Table 3, entries
12-18).
approach to making this class of C-nucleophiles, which can be
easily transformed into olefins or alkynes, will extend their use
beyond the field of asymmetric organocatalysis. Further devel-
opment and use of β-carbonyl heterocyclic sulfones of general
structure 11 and 17 is now in progress in our laboratory.
In summary, we have uncovered a short and efficient approach
to R-acyl and R-alkoxy carbonyl heterocyclic sulfones 11 and 17,
respectively, starting from heterocyclic sulfones and acyl
or alkoxy carbonyl derivatives. We believe that this general
’ EXPERIMENTAL SECTION
Representative Procedure for the Preparation of 2-(Benzo-
[d]thiazol-2-ylsulfonyl)-1-phenylethanone (11a). A solution of
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NOTE
sulfone 13a (100 mg, 0.47 mmol, 1.0 equiv) in THF (2.4 mL, 0.20M) was
cooled to -78 °C, and LiN(TMS)2 (1.0 M solution in THF) (1.03 mL,
1.03 mmol, 2.2 equiv) was added dropwise. The color of the reaction mixture
turned from colorless or slightly yellow to orange within approximately
10-20 s. Immediately after, a solution of benzoyl chloride (60 μL,
0.52 mmol, 1.1 equiv) in THF (0.25 mL) was added. The color of the
reaction mixture faded within 1 to 5 min after the benzoyl chloride addition.
The resulting mixture was stirred at -78 °C for 30 min, allowed to warm to
0 °C within 1 h, and stirred at 0 °C for a further 30 min before a saturated
aqueous solution of NH4Cl (7.5 mL) was added. The whole mixture was
extracted with EtOAc (3 ꢀ 40 mL); the combined organic layers were
washed with brine (25 mL), dried over MgSO4, and filtered; and the solvents
were removed under reduced pressure. The residue was purified by flash
column chromatography on SiO2 (petroleum ether/EtOAc = 4:1 f 2:1 f
1:1), and the reaction yielded 143 mg (96%) of 11a as slightly yellow solid:
mp 123-124 °C; 1H NMR (300 MHz, CDCl3) δ 5.22 (s, 2H), 7.43-7.53
(m, 2H), 7.55-7.69 (m, 3H), 7.94 (dd, J = 8.4 Hz, J = 1.2 Hz, 2H), 8.01
(dd, J = 7.0 Hz, J = 2.2 Hz, 1H), 8.20 (dd, J = 7.2 Hz, J = 2.1 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 61.4, 122.6, 125.7, 127.9, 128.4, 129.17, 129.19,
134.9, 135.6, 137.3, 152.6, 165.5, 187.3; IR (neat) ν-1 1683 (s); MS (APCI)
(relative intensity) m/z 318 (Mþ þ 1, 100), 319 (20), 236 (9), 105 (11).
Anal. Calcd for C15H11NO3S2: C, 56.76; H, 3.49; N, 4.41. Found: C, 56.78;
H, 3.11; N, 4.67.
(3) (a) Paix~ao, M. W.; Holub, N.; Vila, C.; Nielsen, M.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2009, 48, 7338. (b) Nielsen, M.; Jacobsen,
C. B.; Paix~ao, M. W.; Holub, N.; Jørgensen, K. A. J. Am. Chem. Soc. 2009,
131, 10581.
(4) Lee, S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 15438.
(5) (a) Molander, G. A.; Fumagalli, T. J. Org. Chem. 2006, 71, 5743.
(b) Vedejs, E.; Chapman, R. W.; Fields, S. C.; Lin, S.; Schrimpf, M. R.
J. Org. Chem. 1995, 60, 3020.
(6) Warren, L. A.; Smiles, S. J. Chem. Soc. 1930, 1327.
(7) Pr€uger, B.; Hofmeister, G. E.; Jacobsen, C. B.; Alberg, D. G.;
Nielsen, M.; Jørgensen, K. A. Chem.—Eur. J. 2010, 16, 3783.
(8) (a) Blakemore, P. R.; Ho, D. K. H.; Mieke Nap, W. Org. Biomol.
Chem. 2005, 3m, 1365. (b) Giesbrecht, H. E.; Knight, B. J.; Tanguileg.,
N. R.; Emerson, C. R.; Blakemore, P. R. Synlett 2010, 374.
(9) For application of this approach for the synthesis β-carbonyl
phenyl sulfones, see: Bartlett, B. A.; Green, F. R., III; Rose, E. H. J. Am.
Chem. Soc. 1978, 100, 4852.
(10) If nucleophilic bases, e.g., n-BuLi, are used, the competition
between its addition to heterocyclic core of the sulfone and deprotona-
tion of the hydrogen atom R to sulfone is observed.
(11) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel, O. Bull.
Soc. Chim. Fr. 1993, 130, 856.
(12) See Supporting Information.
(13) For discussion about Barbier-type reaction conditions, see
Supporting Information.
(14) Prepared in situ from the corresponding carboxylic acid: Ibarra,
C. A.; Rodriguez, R. C.; Fernandez Monreal, M. C.; Garcia Navarro, F. J.;
Martin Tesorero, J. J. Org. Chem. 1989, 54, 5620.
(15) Coupling between sulfone 13a and BzOMe was extensively
studied using various reaction conditions, bases, and solvents. In all
cases, only traces of the desired product 11a were observed.
(16) (a) Rannard, S. P.; Davis, N. J. Org. Lett. 1999, 1, 933. (b)
Rannard, S. P.; Davis, N. J. Org. Lett. 2000, 2, 2117.
’ ASSOCIATED CONTENT
S
Supporting Information. Spectroscopic and analytical
b
data for all new compounds, as well as experimental procedures.
This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*E-mail: jiri.pospisil@uclouvain.be.
Notes
†Visiting researcher from Tohoku University, Japan.
’ ACKNOWLEDGMENT
J.P. is grateful to Prof. Istvꢁan E. Markꢁo (U.C.L.) for his
continuous support. We gratefully acknowledge the Universitꢁe
catholique de Louvain, the Fond de la Recherche Scientific
(Chargꢁe de Recherche F.S.R.-FNRS to J.P.), Socrates-Erasmus
exchange program (H.S.), and Tohoku University G-COE
program (IREMC) (H.S.) for financial support.
’ REFERENCES
(1) (a) Nielsen, M.; Jacobsen, C. B.; Holub, N.; Paixxao, M. W.;
Jørgensen, K. A. Angew. Chem., Int. Ed. 2010, 49, 2668. (b) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartolli, G. Angew. Chem., Int. Ed. 2008, 47, 6138.
(c) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638.(d) Chem.
Rev. 2007, 107 (12), special issue on organocatalysis.
(2) For recent examples, see: (a) Luo, J.; Xu, L.-W.; Hay, R. A. S.;
Lu, Y. Org. Lett. 2009, 11, 437. (b) Prakash, G. K. S.; Wang, F.; Steward,
T.; Mathew, T.; Olah, G. A. Proc. Natl. Acad. Sci. U.S.A. 2009, 106, 4090.
(c) Cassani, C.; Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed.
2009, 48, 5694. (d) Cid, M. B.; Cantarero, J. L.; Duce, S.; Ruano, J. L. G.
J. Org. Chem. 2009, 74, 431. (e) Furukawa, T.; Shibata, N.; izuta, S.;
Nakamura, S.; Toru, T.; Shiro, M. Angew. Chem., Int. Ed. 2008, 47, 8051.
(f) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7170. (g)
Pulkkinnen, J.; Aburel, P. S.; Halland, N.; Jørgensen, K. A. Adv. Synth.
Catal. 2004, 346, 1077.
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