Sulfonylimidates as nucleophiles in catalytic addition reactions

Article abstract of DOI:10.1021/ja077054u

The first catalytic addition reactions of sulfonylimidates have been accomplished. In the presence of a catalytic amount of DBU (normally 5-10 mol %), sulfonylimidates reacted with several N-protected imines, methyl acrylate, and azodicarboxylate to afford the corresponding addition adducts, sulfonylimidates, in excellent yields. In the addition reactions to imines, high anti-selectivity was observed. A novel direct formation of β-amino acid derivatives from aldehyde and sulfonylimidate is also described. Copyright

Full text of DOI:10.1021/ja077054u

Published on Web 01/17/2008
Sulfonylimidates as Nucleophiles in Catalytic Addition Reactions
Ryosuke Matsubara, Florian Berthiol, and Shuj Kobayashi*
Department of Chemistry, School of Science and Graduate School of Pharmaceutical Sciences,
The UniVersity of Tokyo, The HFRE DiVision, ERATO, Japan Science Technology Agency (JST),
Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received September 12, 2007; E-mail: shu_kobayashi@chem.s.u-tokyo.ac.jp
Scheme 1. Direct-Type Reaction of Sulfonylimine 2 with Imine 1a
Recently, catalytic direct-type addition reactions of carbonyl
(R1 ) Ph, R2 ) CO2Et)
compounds have been developed extensively.1 The majority of those
reported reactions can be classified into two groups: enamine
formation pathway2 and enolate formation mechanism. In the former
case, primary or secondary amines have been employed to form in
situ enamines, which are more nucleophilic than the parent carbonyl
compounds. In the latter case, both metal and nonmetal catalysts
(usually tertiary amines) have been used to generate reactive
enolates in situ. Although metals have been shown to catalyze the
reactions of R-alkyl-substituted carbonyl compounds with the
assistance of the Lewis acidity of the metal,3 most of the reac-
tions are limited to the carbonyl compounds bearing electron-
withdrawing groups such as CdO, NO2, CN, and OH at R-positions.
To the best of our knowledge, there are no reports of simple tertiary
amine-catalyzed direct-type addition reactions of carbonyl com-
pounds bearing no activating functional groups at R-positions. Since
tertiary amines are usually easy to handle, stable, and offer
tunability, our interest was directed to the realization of this
attractive reaction.
Direct-type reactions of nonactivated carbonyl compounds are
notoriously difficult due to the relatively high pKa values of the
R-protons. Imines offer an additional possibility to tune reactivity,
that is, the substituent on the nitrogen atom, which may allow us
to control their reactivity. In order to lower the pKa value of
R-positions, sulfonyl-substituted imine 2 was selected for the pre-
liminary investigation (Scheme 1). The adduct 3 was obtained in
the presence of 10 mol % of Et3N along with formation of the
more stable enesulfonamide tautomer 4. Acidic workup converted
both adducts to keto product 5 (37% yield), but a considerable
amount of chalcone (23% yield) was obtained as a result of
carbamate elimination.
This result prompted us to investigate sulfonylimidates4 as they
were expected not to readily tautomerize to the corresponding
enesulfonamides due to the stabilizing effect of the neighboring
oxygen atoms, although the pKa value of sulfonylimidate can be
expected to be higher than that of the corresponding sulfonylimine.
To our delight, the reaction of sulfonylimidate 6a (R3 ) Me, R4 )
Me, R5 ) Ph) with imine 1a proceeded smoothly in the presence
of a catalytic amount of DBU (1,8-diazabicyclo[5.4.0]undec-7-ene)
to afford the adduct 7a in good yield (Table 1, entry 3), while no
products were obtained in the absence of base or with weaker base,
Et3N (Table 1, entries 1 and 2). The reaction conditions were
optimized in order to improve selectivity, and a high diastereose-
lectivity was observed under the conditions in Table 1, entry 9.
Namely, sulfonylimidate 6c (R3 ) iPr, R4 ) Me, R5 ) 2,5-xylyl)
was reacted with imine 1b (R1 ) Ph, R2 ) Boc) in the presence of
DBU (5 mol %) in DMF at 0 °C to afford the desired adduct in
excellent yield and diastereoselectivity (95% yield, anti/syn ) 96/
4).5 Enesulfonamide tautomers were not observed in any case. This
is the first example of a tertiary amine-catalyzed direct-type reaction
of R-alkyl-substituted ester equivalents and the first use of sulfo-
nylimidates in a catalytic direct-type reaction.
Table 1. Base-Catalyzed Direct-Type Reactions of
Sulfonylimidates (R1 ) Ph, R4 ) Me)
yield
entry
R2
R3
R5
base
solvent
(%)
anti/syna product
1
2
3
4
5
6
7
8b
CO2Et Me Ph
CO2Et Me Ph
CO2Et Me Ph
CO2Et Me Ph
CO2Et iPr Ph
-
DCM
DCM
0
0
-
-
Et3N
-
-
DBU DCM 90
DBU DMF quant 62/38
DBU DMF 80
DBU DMF 72
69/31
7a
7a
7b
7c
7d
7d
7d
79/21
93/7
95/5
96/4
96/4
Boc
Boc
Boc
iPr Ph
iPr 2,5-xylyl DBU DMF 65
iPr 2,5-xylyl DBU DMF 75
iPr 2,5-xylyl DBU DMF 95
9b,c Boc
a Determined by 1H NMR spectroscopy of crude products. b 0 °C. c 1.5
equiv of 1 and 1.0 equiv of 6 used. Catalyst loading was 5 mol %.
The optimized conditions were found to be applicable to a wide
range of substrates as summarized in Table 2. Et-substituted and
nonsubstituted products 7e and 7f could also be obtained in good
yields (Table 2, entries 2 and 3), although an excess amount of 6e
(R3 ) Et, R4 ) H, R5 ) Ph) was necessary in order to suppress
overreaction.6 Tosyl (Ts) imine was also found to be a good
substrate, affording the product with high selectivity (Table 2, entry
4). Boc imines derived from aromatic aldehydes bearing electron-
donating and -withdrawing substituents, ortho-, meta-, and para-
substituted benzaldehydes, as well as heteroaromatic aldehydes
provided the desired adducts in high yields with high diastereose-
lectivity (Table 2, entries 5-12). It is notable that nonaromatic
aldehyde-derived imines gave the desired products in moderate to
high yields and diastereoselectivities (Table 2, entries 13-20).
Iminoester 1r (R1 ) EtO2C, R2 ) 4-MeOC6H4) reacted successfully
with sulfonylimidate 6c, providing R-amino acid precursor 7x
(Table 2, entry 21). Notably, mixing benzaldehyde (1.5 equiv), 2,5-
xylylsulfonamide (1.5 equiv), and sulfonylimidate 6c (1 equiv) with
DBU (10 mol %) and 4 Å molecular sieves (MS 4A) furnished the
desired adduct in good yield (70%) with excellent diastereoselec-
tivity (anti/syn ) 95/5).7
Sulfonylimidate 6a also reacted with methyl acrylate in a
Michael-like reaction, leading to the sulfonylimidate 8. Furthermore,
9
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J. AM. CHEM. SOC. 2008, 130, 1804-1805
10.1021/ja077054u CCC: $40.75 © 2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. DBU-Catalyzed Direct-Type Reactions of
Sulfonylimidates
Scheme 3. Direct Formation of â-Amino Acid Ester from Aldehyde
and Sulfonylimidate
yield
(%)
entry
R1
R2
R3
R4
R5
anti/syna
7
1
2
Ph
Ph
Boc
Boc
EtO2C
Ts
iPr Me 2,5-xylyl 95
iPr Et 2,5-xylyl 94
96/4
97/3
-
96/4
95/5
97/3
7d
7e
7f
7g
7h
7i
7j
7k
7l
7m
7n
7o
7p
corresponding ester 11 in excellent yield (eq 2). Reduction of 7d
or 7g with Red-Al gave aldehyde 12a or 12b,8 respectively (eq 3),
which could be used for further transformations.
3b,c,d Ph
Et
H
Ph
79
4c
5e
6
Ph
iPr Me 2,5-xylyl 91
iPr Me 2,5-xylyl 91
iPr Me 2,5-xylyl 87
p-MeOC6H4 Boc
p-FC6H4
m-MeC6H4
o-MeC6H4
m-vinyl-C6H4 Boc
With the knowledge that sulfonylimidates are hydrolyzed with
the assistance of catalytic DBU, direct formation of â-amino acid
ester from an aldehyde and sulfonylimidate could be realized
(Scheme 3). Ester 13, which is a biologically important â-amino
acid derivative,9 was obtained in high yield with good selectivity.10
In summary, we have shown the first example of highly selective
catalytic direct-type addition reactions of sulfonylimidates. A tertiary
amine, DBU, is a good catalyst in Mannich-type, Michael-type,
and azodicarboxylate addition reactions. In Mannich-type reactions,
high anti-selectivity was observed. Direct formation of â-amino
acid derivatives from aldehydes and sulfonylimidates could be also
achieved. Further applications of sulfonylimidates as well as the
development of asymmetric variants are currently being investi-
gated.
Boc
Boc
Boc
7
iPr Me 2,5-xylyl quant 97/3
8e
9
iPr Me 2,5-xylyl 64
iPr Me 2,5-xylyl 97
iPr Me 2,5-xylyl 92
iPr Me 2,5-xylyl 90
iPr Me 2,5-xylyl 91
iPr Me 2,5-xylyl 80
iPr Me 2,5-xylyl 84
93/7
97/3
95/5
98/2
98/2
98/2
10
11
2-furyl
Boc
Boc
Boc
Ts
2-thienyl
2-pyridyl
PhCHdCH
12
13c
14c
cyclopropyl Ts
87/13 7q
15c,d cyclopropyl Boch
iPr Me 2,5-xylyl quant 88/12 7r
16c,d,g c-C6H11
17c,d,g c-C6H11
18c,d,g iPr
Tsh
Tsh
Tsh
Tsh
Ts
Me Me p-MeC6H4 51
iPr Me p-MeC6H4 59
Me Me p-MeC6H4 56
iPr Me p-MeC6H4 54
Me Me p-MeC6H4 51
83/17 7s
84/16 7t
69/31 7u
87/13 7v
14/86 7w
55/45i 7x
19c,d,g iPr
20c,f tBu
21c,d EtO2C
p-MeOC6H4 iPr Me 2,5-xylyl 80
a Determined by 1H NMR spectroscopy of the crude product or isolated
product. b 5 equiv of 6 and 1 equiv of 1 were used. c MS 4A (167 g/mol)
were added. d 10 mol % of DBU was used. e 38 h. f 40 °C, 36 h. g Room
temperature. h 3 equiv of 1 was used. i Major/minor.
Acknowledgment. This work was partially supported by a
Grant-in-Aid for Scientific Research from Japan Society of the
Promotion of Sciences (JSPS).
Supporting Information Available: X-ray diffraction analyses,
experimental procedures, and product characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
Scheme 2. DBU-Catalyzed Direct-Type Reactions of
Sulfonylimidate 6a
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(5) The relative configuration of the product was determined by X-ray
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the reaction of 6a with an azodicarboxylate could be catalyzed
efficiently by 5 mol % of DBU to give the adduct 9 in high yield
(Scheme 2).
Several transformations of the obtained sulfonylimidates are
shown in eqs 1-3. Since sulfonylimidates were rather resistant to
acid, relatively harsh conditions were needed for hydrolysis of 7g
(eq 1). The hydrolysis product was not the expected ester but the
N-sulfonyl amide 10. On the other hand, mild basic conditions (a
catalytic amount of DBU) hydrolyzed sulfonylimidate 7y to the
(6) Excess starting material 6e could be recovered (403%) by chromatography.
(7) See Supporting Information for details.
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but the aldehyde was obtained directly.
(9) Jacobsen, M. F.; Ionita, L.; Skrydstrup, T. J. Org. Chem. 2004, 69, 4792
and the references cited therein.
(10) The proposed mechanism is demonstrated in Supporting Information.
JA077054U
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