Chiral Amine Synthesis (Methods, Developments and Applications) || Catalytic, Enantioselective, Vinylogous Mannich Reactions

5Catalytic, Enantioselective, Vinylogous Mannich ReactionsChristoph Schneider and Marcel Sickert

5.1Introduction

The asymmetric Mannich reaction of an enolate and an imine furnishing valuable b-amino carbonyls is a fundamental C�C-bond forming process in organic chemistrythat has broad utility in organic synthesis particularly for b-amino acid synthesis [1].Extending the enolate component into a dienolate offers the opportunity for a bondforming event with an electrophile both at thea- and the c-positions of this ambidentnucleophile (Scheme 5.1).

Frontier orbital calculations predict that the regioselectivity highly depends onthemetal fragment used as cation in the dienolate [2]. In lithium dienolates, both thelargest HOMO coefficient and the greatest electrophilic susceptibility are found atthe a-carbon furnishing a-substituted products predominantly. On the contrary,silicon dienolates display largerHOMOcoefficients and electrophilic susceptibilitiesat the c-position leading in Mukaiyama-type reactions to c-addition productspreferentially (Scheme 5.2) [3]. In addition to electronic effects, steric effects alsocontribute to the observed regioselectivitywith largea-substituents being able to shiftthe regioselectivity from the a- to the c-position.

Vinylogous Mannich products have proven to be extremely valuable syntheticintermediates because the additional conjugate double bond may be further elab-orated in subsequent chemical transformations.

OR

OM

+ E++ E+

OR

OE

OR

O

E α-attack γ-attack

Scheme 5.1 Ambident reaction profile of a metal dienolate [2, 3].

Chiral Amine Synthesis: Methods, Developments and Applications. Edited by Thomas C. NugentCopyright � 2010 WILEY-VCH Verlag GmbH & Co. KGaA, WeinheimISBN: 978-3-527-32509-2

j157

In particular, Martin and Bur have exploited the vinylogous Mannich reactionextensively as key step in the total synthesis of alkaloids and other nitrogen hetero-cycles such as (�)tetrahydroalstonine (6), geissoschizine (7), and akuammicine (8)(Scheme 5.3) [4].

In this reviewwewill attempt to highlight themost important contributions towardthe realization of a catalytic, enantioselective, vinylogousMannich reaction and showthe current state of the art. This chapter is organized in such a way that vinylogousMannich reactions of preformed silyl dienolates inMukaiyama-type reactions will bediscussed first followed by direct vinylogous Mannich reactions of unmodifiedsubstrates.

Scheme 5.2 Electron distribution and orbital coefficients of lithium dienolate (left), vinylsilylketene acetal (middle), and silyl dienol ether (right)(reprinted with permission from Wiley-VCH) [3].

R1

OSiR3

N

R2

O

O

R1

N

R2 X

O

4

3

2

COOMeCOOMe

HN

O

O

H

HR2

∆T

R1

COOMe

NH

1

5

N

OH

H

(-) tetrahydroalstonine (6)

NH H

MeO2C

N

H

NH H

MeO2COH

NH

CO2Me

NH

H

geissoschizine (7) akuammicine (8)

H

Scheme 5.3 Use of the vinylogousMannich reaction as a key step in the total synthesis of alkaloidsby the Martin group [4].

158j 5 Catalytic, Enantioselective, Vinylogous Mannich Reactions

5.2Vinylogous Mukaiyama–Mannich Reactions of Silyl Dienolates

The first systematic investigation toward Lewis acid-catalyzed vinylogous Mukaiya-ma–Mannich reactions was reported by the group of Ojima in 1987 who showed thatacyclic vinylketene silyl O,O-acetals 10 reacted with imines activated by stoichio-metric amounts of TiCl4 to furnish either 5-amino-2-alkenoates 11 or 5,6-dihydro-pyridones 12 selectively in excellent yields depending upon the substitution of thesilyl dienolate employed (Scheme 5.4) [5]. Although 2-methyl-substituted vinylketeneacetal 10a gave rise to acyclic 5-amino-2-alkenoates 11 exclusively, 3-methyl-substi-tuted vinylketene acetal 10b furnished 5,6-dihydropyridones 12 as the sole products.No products arising from a-addition of the vinylketene acetal to the imine wereobtained.

Martin and Lopez reported the first example of a catalytic, enantioselectivevinylogous Mannich reaction of salicyl imines 13 and 2-silyloxy furans 14 asnucleophiles that are known tohave a strong tendency toward c-selective electrophilicattack [6]. A chiral metal complex formed in situ from Ti(OiPr)4 and (S)-BINOL (1 : 2)in ether was employed as catalyst and delivered c-aminoalkyl-substituted c-butenolides 15 in good yields, good diastereoselectivity, and typically moderateenantioselectivity (Scheme 5.5). The presence of the chelating hydroxy group in theortho-position within theN-aryl substituent was mandatory for the enantioselectivityof the reaction as other imine substituents delivered the products in racemic form.This finding proved to be quite general as we will see in other vinylogous Mannichreactions and pointed to a highly organized chiral titanium–imine complex asprerequisite for an enantioselective reaction.

Building on this precedence,Hoveyda, Snapper and coworkers established thefirsthighly diastereo- and enantioselective vinylogous Mannich reaction of 2-silyloxyfurans 17 with aromatic N-(2-methoxyphenyl)imines 16 [7]. As chiral catalystthey employed a silver phosphine complex (1–5mol%) prepared in situ fromcommercially available AgOAc and an amino acid-derived, readily prepared Schiff

OMe

OSi

10

11

R1

NR2

R4

R3

+ N

O

R1 CH3

R2NH

OMeR1

R2O

12

H

CH3

TiCl4

-100°C - rtCH2Cl2

TiCl4

-100°C - rtCH2Cl2

9

for 10a: (R3: Me, R4: H)

for 10b: (R3: H, R4: Me)

Scheme 5.4 TiCl4-catalyzed vinylogous Mannich reaction of vinylketeneO,O-acetals 10 accordingto Ojima and Brandstadter [5].

5.2 Vinylogous Mukaiyama–Mannich Reactions of Silyl Dienolates j159

base-phosphine ligand 18. c-Aminoalkyl-substituted c-butenolides 19were obtainedin good yields, with>98%de and typically well above 90%ee and in select cases above95% ee. The process proved to be highly practical as the reactions could be run inundistilled 2-propanol as solvent and in the air (Table 5.1).

The reaction was extended to more highly substituted silyloxy furans 17b and 17cfurnishing the products with only slightly diminished enantioselectivities(Scheme 5.6).

Apparently, the chiral Schiff base acts both as a bidentate P,N-ligand to the silverLewis acid and with the appendent amide linkage serves as a trap for the cationicsilicon species generated during the reaction, thereby facilitating the catalyticturnover. Quite similar as in the Martin system, the chelating 2-methoxy substituentin theN-aryl group presumably helps to form a highly organized coordination spherearound the metal center in the transition state of the reaction (Scheme 5.7). At thesame time it facilitates the oxidative removal of the N-aryl group with PhI(OAc)2giving rise to the free amino c-butenolides in good yields.

The described process could, however, only be successfully applied to aromaticaldimines as the corresponding reactions with aliphatic aldimines led to low yields ofthe Mannich products. Subsequent investigations by the same group led to theidentification of a more robust imine class containing the highly electron-richortho-thiomethyl-para-methoxyphenyl group as N-substituent that is less prone todecomposition [8]. When this type of substituted aniline was employed in a three-component vinylogous Mannich reaction with aliphatic aldehydes and silyloxyfurans under otherwise identical reaction conditions, 5-alkyl-5-amino-substituted

OTIPS

14a

15a

Ar

N +

Ti(OiPr)4-(S)-BINOL

-78°C

Et2O

13

79%, dr 94:654% ee

O

HO

O

O

NH

OH

Cl

20 mol%

H

OTIPS

14b

Ar

N +

Ti(OiPr)4-(S)-BINOL

-78°C

15c

Et2O13

O

HO

O

O

NH

OH

65%, dr 86:1445% ee

20 mol%

H

15b

80%, dr 91:948% ee

O

O

NH

OH

Scheme 5.5 Ti(IV)-BINOLate-catalyzed vinylogous Mannich reaction according to Martin andLopez [6].


Table 5.1 Silver-catalyzed vinylogous Mannich reaction of 2-silyloxy furan 17a with aromatic iminesaccording to Hoveyda, Snapper and coworkers [7].

OTMS

17a 19

Ar

N+

1 mol%

1.1 equiv undest. iPrOH

undest. THF, -78°C,16

O

MeO

O

O

Ar

NH

OMe

1 mol% AgOAc

18 h, in air

PPh2

N

RHN

OOMe

18a: tBu, 18b: iBu

H

Entry Ar Catalysts Product Yield (%) de (%) ee (%)

1 Ph 18a 19a 82 >98 962 p-MeO-C6H4 18a 19b 85 >98 973 p-Cl-C6H4 18b 19c 89 >98 934 m-NO2-C6H4 18b 19d 75 >98 935 o-Me-C6H4 18a 19e 65 >98 946 2-Naphtyl 18a 19f 94 >98 >987 2-Furyl 18b 19g 78 >98 90

P

N

R

N

OArH

Ph

Ph

Ag+ OMe

N

ArH

OOTMS

O

O

Ar

NH

OMe

O

O

Ar

NH

OMe

20 21

P

N

R

N

OArH

Ph

Ph

Ag+

OMe

N

Ar H

OOTMS

Scheme 5.6 Proposed transition states for the vinylogous Mannich reaction as origin for theenantio- and diastereoselectivity [7].


c-butenolides 22were obtained in good yields and as essentially single stereoisomers(Table 5.2). In these studies, the tert-leucine-derived Schiff base-ligand 18a gave rise tothe best diastereo- and enantioselectivities, and even with the less expensive valine-derived Schiff base ligand, the products were formed with 97% ee. Removal of theN-aryl group was readily accomplished with cerium ammonium nitrate followed byacidic hydrolysis of the intermediate aza-quinone.

One of the most remarkable aspects of this reaction is the functional grouptolerance exhibited by the catalytic system. Thus, a number of functional aldehydeswere submitted to this reaction and furnished vinylogousMannich products 22e–22iin moderate yields and excellent stereoselectivity (entries 5–9). The exceptionalenantiodifferentiating ability of the chiral silver complex was further demonstratedin doubly stereodifferentiating reactions with chiral aldimines. Irrespective of theconfiguration of the starting aldehydes, the products were obtained with the identicalabsolute configuration at the newly generated stereogenic centers with excellentstereoselectivity indicating that the catalyst selectivity completely overrides thesubstrate selectivity (Scheme 5.8).

OTMSO

5 mol% AgOAc

PPh2

N

HN

OOMe

R

Ar

N

16

MeO

18b: R: Et

OTMSO

5 mol% 18b

10 mol% AgOAc10 mol% 18c

18c: R: OtBu

21a

O

O

NH

OMe

85%, dr >99:187% ee

21b

O

O

NH

OMe

97%, dr >99:190% ee

Cl

20a

O

O

NH

OMe

66%, dr >99:188% ee

MeO

H

Ar

N

16

MeO

H

20b

O

O

NH

OMe

65%, dr >99:179% ee

Br

17b

17c

Scheme 5.7 Reaction of methyl-substituted silyloxyfurans 17b and 17c [7].


Table 5.2 Silver-catalyzed vinylogousMannich reaction of 2-silyloxy furan 17awith aliphatic iminesaccording to Hoveyda, Snapper and coworkers [8].

OTMS

17a

22R

H2N

5 mol%

1.1 equiv undest. iPrOH, 2 equiv MgSO4

undest. THF, -78°C,O

MeS

O

O

R

NH

SMe

5 mol% AgOAc

20 h, in air

PPh2

N

HN

OOMe

18a

OMe

O

H

MeO

+

Entry Aldehyde Product Yield (%) de (%) ee (%)

1 CyCHO 22a 90 >96 >982 iPr-CHO 22b 89 >96 >983 tBu-CHO 22c 50 >96 >984 nHex-CHO 22d 75 >96 >985 MeO2C-(CH2)2-CHO 22e 56 >96 >986 BnO-CH2-CHO 22f 51 >96 >987 BocNH-CH2-CHO 22g 44 >96 >988 (E)-Ph-CH¼CH-CHO 22h 32 >96 959 Ph-C:C-CHO 22i 89 >98 >98

22j S-23

O

O

NHPG

O

HPh

O

O

NHPG

Ph

22k

PhO

HPh

(>96% de, >98% ee)(>96% de, >98% ee)

68% 75%

PG: SMeMeO

R-23

5 mol% 18a5 mol% AgOAc,

amine, 17a

PPh2

N

HN

OOMe

18a

5 mol% 18a5 mol% AgOAc,

amine, 17a

Scheme 5.8 Influence of the stereogenic center at the a-position of aldehyde 23 [8].


Table 5.3 Silver-catalyzed vinylogous Mannich reaction of 2-silyloxy furan 17a with a-ketoimineesters 24 according to Hoveyda, Snapper and coworkers [9].

OTMS

17a

anti-25Ar

10 mol%

1 equiv iPrOH

THF, -78°C, 15 h

24

O

O

O

Ar

NHPG

11 mol% AgOAc

HOAc workup

PPh2

N

HN

OOMe

18a

N

NO2MeO

O

OMe

COOMe

O

O

Ar

NHPG COOMe

syn-25

+

Entry Ar Product Yield (%) anti/syn ee (%)

1 Ph 25a 88 95 : 5 922 m-MeO-C6H4 25b 95 95 : 5 933 m-Cl-C6H4 25c 72 92 : 8 874 p-Br-C6H4 25d 80 95 : 5 925 p-CF3-C6H4 25e 87 95 : 5 946 o-Br-C6H4 25f 87 <2 : 98 327 2-Naphtyl 25g 81 >98 : 2 91

This protocol could be directly applied in the addition of 2-silyloxy furans to keti-mines and the generation of a quaternary chiral center. Using electronically highlyactivated a-ketoimine esters 24 as substrates, the same chiral silver phosphinecatalyst (10mol%) as previously used in reactions with aldimines delivered thedesiredMannich products in good yields, good diastereoselectivity, and up to 94% ee(Table 5.3) [9].

The vinylogous Mannich reaction of 2-silyloxy furans and imines may also becatalyzed through chiral Brønsted acids, as shown by Akiyama et al. [10]. Previously,Akiyama [11] and Terada [12] had independently discovered that 3,30-substitutedBINOL-based phosphoric acids were excellent Brønsted acids for a broad range ofmainly imine addition reactions via protonation of the imines and in situ formation ofchiral iminium contact ion pairs. Using the slightly modified phosphoric acid 28 ascatalyst carrying additional iodine substituents in the 6,60-positions, the c-amino-substituted butenolides 27 were obtained in excellent enantioselectivity and variablediastereoselectivity (Table 5.4).

Aryl-, heteroaryl-, and alkyl-substituted aldimines were effectively converted intothe products in typically good yields. Again, ortho-aminophenol was employed as theamine component and the chelating hydroxy groupwithin the iminewas proposed toact as an additional hydrogen donor that formed a nine-membered chelate with twohydrogen bonds in the transition state of the reaction (Figure 5.1). Theoreticalcalculations performed by the Akiyama group supported this scenario [13].


Thus far, all reported protocols were solely applicable to reactions of 2-silyloxyfurans as nucleophiles and concerned the highly stereoselective formation of chiral c-butenolides. On the basis of the prominent role that this motif plays in naturalproducts and medicinally relevant compounds, this focus is certainly understand-able. However, the enantioselective synthesis of acyclic d-amino a,b-unsaturatedcarbonyl compounds starting from an acyclic silyl dienolate would be even moredesirable as those substrates might actually bear enormous synthetic potential for abroad range of nitrogen-containing compounds in general and nitrogen heterocyclesin particular. In acyclic silyl dienolates, however, the a, c-regioselectivity within theambident nucleophile is not as easily controlled as in 2-silyloxy furans that furthercomplicates an efficient and selective reaction and might have hampered thedevelopment of such a process.

In 2008 our group reported the first example of a catalytic, enantioselective,vinylogous Mannich reaction of acyclic silyl dienolate 30 with imines (Table 5.5) [14].

Table 5.4 Brønsted acid-catalyzed vinylogous Mannich reaction according to Akiyama et al. [10].

OTMS

17a

27

R

N

26

O

HO

O

O

R

NH

OH

5 mol% 28

toluene, 0°C

OO

POOH

28

I

I

15-28 h

X

X

X:

H

+

Entry R Product Yield (%) anti/syn ee (%)

1 Ph 27a 89 91 : 9 822 p-F-C6H4 27b 100 95 : 5 873 m-NO2-C6H4 27c 86 68 : 32 964 4-Pyridyl 27d 30 94 : 6 985 2-Furyl 27e 77 68 : 32 896 Cyclohexyl 27f 77 88 : 12 907 iPr 27g 84 88 : 12 92

NH

HAr

OH

OP

OO

O*

Figure 5.1 Theoretically calculated imine-bound phosphoric acid with two hydrogen bondsaccording to Akiyama and coworkers [13].


TheTBS-groupwas chosen as silyl fragmentwithin thedienolate to preventa-attack ofthe imines on the nucleophile. As chiral catalyst we employed a BINOL-basedphosphoric acid of the same type that Akiyama and Terada had established inasymmetric catalysis and found 3,30-mesityl groups optimal for the enantioselectivityof the reaction. The reactions were run at �30 �C in a solvent mixture of tBuOH, 2-methyl-2-butanol, andTHFinequal amountscontaininganadditional1 equivofwater.

Aromatic and heteroaromatic aldimines were effectively converted into vinylogousMannich products 31 with complete c-regioselectivity and with typically 80–90% ee.Thereactioncouldeasilyberunina three-component fashion, startingdirectly fromanaldehyde, para-anisidine, and silyl dienolate30obviating the need to prepare the iminein a separate reaction. In contrast to most other protocols that required a salicyl iminemoiety in the substrate for selectivity issues, here the amine component within theimine could just be a phenyl group or any para-substituted phenyl group.

Mechanistically we assume that the reaction proceeds via initial imine protonationfurnishing the chiral iminiumphosphate 33 (Scheme 5.9). This in turn is attacked bysilyl dienolate 30 in the central C�C-bond forming event that is controlled by the

Table 5.5 Brønsted acid-catalyzed vinylogous Mannich reaction of vinylketene O,O-acetal 30according to Schneider and Sickert [14a].

OEt

OTBS

N

OEt

O

R

NH5 mol% 32

THF/tBuOH/2-Me-2-BuOH1:1:1, -30°C3029 31

PMP

R

PMP

HOO

POOH

32

+

Entry R Product Time (h) Yield (%) ee (%)

1 Ph 31a 8 87 882 4-Me-C6H4 31b 4 89 903 4-Et-C6H4 31c 3 88 924 4-Pent-C6H4 31d 6 92 905 4-MeO-C6H4 31e 72 66 826 4-F-C6H4 31f 5 93 827 4-CN-C6H4 31g 1 94 818 3-Cl-C6H4 31h 2 94 829 3-Me-C6H4 31i 6 90 7910 2-Me-C6H4 31j 9 87 8011 2-Naphthyl 31k 8 90 8312 3-Thiophenyl 31l 6 92 8413 3-Furyl 31m 7 88 9014 tBu 31o 48 83 83


chiral counterion in an enantioselective fashion. The contact ion pair 34 thusgenerated is hydrolyzed through the water present in the reaction mixture to furnishTBS-OH, the vinylogous Mannich product 31, and the chiral Brønsted acid catalyst,thereby closing the catalytic cycle. In ESI-MS/MS-measurements, contact ion pair 34was clearly detected and fully characterized and the in situ formation of TBS-OHwasobserved by online NMR studies thus strongly supporting this mechanistic scenario.

Subsequent investigations led to the identification of a superior, second-generationcatalyst 35 that improved the enantioselectivity of the reaction for most substratesconsiderably. With a simple change of the para-methyl group within the 3,30-mesitylgroups of the BINOL-backbone for a para-tert-butyl group, most aromatic andheteroaromatic aldimines were now converted into the products with around90% ee and in select cases with>95%ee (Scheme 5.10) (M. Sickert andC. Schneider,unpublished results).

NPMP

R H

NPMP

R H

HP

OOO-O

*

OEt

OTBS

NPMP

R

H

POOO-O

*

O

OSi

NPMP

R

H

O

O

POOOHO

*

+ TBS-OH

H2O

2932

33

30

34

31

Scheme 5.9 Catalytic cycle for the vinylogous Mannich reaction of vinylketene silyl O,O-acetal 30developed by Schneider and Sickert [14a].

OEt

OTBS

O

OEt

O

R

NH3 mol% 35

solvent, -50°C

PMP

R

PMP

H

30

NH2OO

POOH

35

+

up to 97% up to 98% ee

31R: Alkyl, Aryl

+

Scheme 5.10 Enantioselective, vinylogous Mannich reaction of silyl dienolate 30 catalyzed bysecond-generation catalyst 35 (M. Sickert and C. Schneider, unpublished results).


Vinylketene silylN,O-acetal 36 derived from the b,c-unsaturatedN-acyl piperidinewas also shown to participate in vinylogous Mannich reactions to furnish d-aminoa,b-unsaturated amides 37 in good yields and up to 91% ee with just 1mol% ofphosphoric acid 38 (Table 5.6) [14b]. Interestingly, the absolute configuration of theproducts was opposite to the configuration obtained with phosphoric acid 32although the catalyst carried the identical R-BINOL-backbone. In order to demon-strate their synthetic potential, the amides were subsequently reduced to either allylicalcohols with the Schwartz reagent Cp2Zr(H)Cl or into the saturated alcohols withLiBHEt3 in good yields.

Subsequent to our report, Carretero and coworkers developed a chiral coppercomplex that catalyzed highly enantioselective vinylogous Mannich reactions bothwith 2-silyloxy furans and acyclic silyl dienolates as nucleophiles [15]. The author�sgroup had previously developed the chiral ferrocene-based P,S-ligand Fesulphos incombinationwith copper(I) salts forMannich and aza-Diels–Alder reactions. On thatbasis they were able to show that the reaction of 2-thienylsulfonyl imines 39 and abroad range of acyclic silyl dienolates 40was efficiently catalyzed by theCu-Fesulphoscatalyst prepared in situ from CuBr and the ligand 42. The products were obtainedwith complete c-regioselectivity for most substrates investigated and 89–95% ee foraromatic aldimines and 65–82% ee for aliphatic aldimines (Table 5.7).

Table 5.6 Brønsted acid-catalyzed vinylogous Mannich reaction of vinylketene N,O-acetal 36according to Schneider and coworkers [14b].

N

OTBS

N

N

O

R

NH1 mol% 38

iPrOH/t BuOH/2-Me-2-BuOH1:1:1, -30°C

36

29

37

PMP

R PMPH

OO

POOH

SiPh3

SiPh3

38

+

Entry R Product Time (d) Yield (%) ee (%)

1 Ph 37a 7 99 902 p-Et-C6H4 37b 8 84 803 p-F-C6H4 37c 9 85 884 m-Me-C6H4 37d 3 82 925 m-Cl-C6H4 37e 9 63 826 o-Me-C6H4 37f 9 66 807 o-Cl-C6H4 37g 9 73 728 3-Furyl 37h 9 72 849 3-Thiophenyl 37i 9 72 86


This protocolwas successfully extended to reactionswith 2-silyloxy furan 17a as thenucleophile and c-aminoalkyl-c-butenolides 43 were obtained in high yields, gooddiastereocontrol, and 88–94% ee (Table 5.8). The 2-thienylsulfonyl group as N-substituent proved to be important both for the reactivity and the selectivity of thereaction presumably by way of chelating the copper catalyst and thereby rigidifyingthe substrate–catalyst complex in the transition state of the reaction.

Table 5.7 Copper-Fesulphos-catalyzed vinylogous Mannich reaction according to Carretero andcoworkers [15].

R2

OTMSN

R2

O

R1

NH

CH2Cl2, rt, 14-18 h

4039 41

S

R1

O2S

H

OO

S

R3R3

Ar5.1 mol% [42.CuBr]210 mol% AgClO4

FeP(1-Naph)2

S tBu

42

+

Entry R1 R2 R3 Product Yield (%) ee (%)

1 Ph H H 41a 85 942 o-Me-C6H4 H H 41b 68 933 p-MeO-C6H4 H H 41c 62 944 iPr H H 41d 72 665 Ph OMe H 41e 72 836 1-Naphtyl OMe H 41f 70 917 Cyclohexyl OMe H 41g 85 758 Ph OMe Me 41h 75 809 2-Naphtyl OMe Me 41i 85 7710 Cyclohexyl OMe Me 41j 88 82

Table 5.8 Copper-Fesulphos-catalyzed vinylogous Mannich reaction with silyloxy furans [15].

NR

NH

CH2Cl2, 14-18 h-40° C17a

40 43

S

R

O2S

H

OO

SAr5.1 mol% [42.CuBr]2

10 mol% AgClO4

OTMSO

OO

FeP(1-Naph)2

S tBu

42

+

Entry R Product dr Yield (%) ee (%)

1 Ph 43a 93 : 7 85 882 p-Cl-C6H4 43b 90 : 10 87 903 p-MeO-C6H4 43c 81 : 19 79 944 PhCH¼CH 43d 91 : 9 87 95


5.3Direct Vinylogous Mannich Reactions of Unmodified Substrates

In the context of atom economy, it has been a general goal in modern organicchemistry to use unmodified substrates for important C�C-bond forming reactionsinstead of latent silyl enolates that have to be prepared in a separate step and requirethe use of stoichiometric amounts of a silicon fragment. In the area of catalyticenantioselective vinylogous Mannich reactions, there has been substantial progresstoward the realization of such highly desirable reactions.

In 2004 Terada and his group revealed that 2-methoxyfuran (45) that can beconsidered as a vinylketene O,O-acetal was sufficiently nucleophilic to engage Boc-imines 44 in Brønsted acid-catalyzed Friedel–Crafts-type reaction to furnish c-aminoalkyl-substituted furans 46 in excellent yields and up to 97% ee (Table 5.9) [16].As already explained, phosphoric acid 47 protonates the imine, thus generating achiral contact ion pair the anionic counterion of which controls the enantioselectivityof the C�Cbond forming event. Although typically 2mol% of the Brønsted acid were

Table 5.9 Organocatalytic Aza-Friedel–Crafts reaction of furan 45 according to Terada andcoworkers [16].

N

Ar

NH

454446

Ar

Boc

H

2 mol% 47

OMeOO

OMe

Boc

OO

POOH

47

X

X

X

X

+

X:

ClCH2CH2Cl

-35° C

Entry R Product Yield (%) ee (%)

1 Ph 46a 95 972 p-Cl-C6H4 46b 88 973 p-MeO-C6H4 46c 95 964 m-Me-C6H4 46d 80 945 m-Br-C6H4 46e 89 966 o-Me-C6H4 46f 84 947 o-Br-C6H4 46g 85 918 2-Furyl 46h 94 869 2-Naphtyl 46i 93 96


employed, only 0.5mol% turned out to be sufficient for a gram-scale reactiondelivering the product in identical yield and ee.

The first direct vinylogousMannich reaction employinga,a-dicyanoalkenes as theCH-acidic substrateswas reported by the groupofChen in 2007 [17]. As chiral catalystthey employed a bifunctional thiourea 51 with Brønsted acidic and basic propertiesthat activated the imine via hydrogen bonding from the thiourea component anddeprotonated the CH-acidic substrate with the amine moiety at the same time. Abroad range of different aromatic and heteroaromatic Boc-aldimines and a,a-dicyanoalkenes 48 were effectively converted into the products 50 with exceptionalregio-, diastereo-, and enantioselectivities delivering basically single isomers inexcellent yields (Scheme 5.11). This reaction is certainly a prominent example ofthe power of asymmetric two-center catalysis [18] in a bifunctional molecule whereboth the nucleophilic and the electrophilic components are activated at the same timethrough the same catalyst leading to a highly organized transition state within thereaction and hence excellent stereoselectivity.

R2

R3

NHBoc

R1

NC CN

up to 99%up to 99.5% ee

51

NNH

S

NH

R3

NC CN

R2 H

N

R1

Boc2 mol%

toluene, rt24 h

S

NHBocNC CN

NHBoc

Ph

NC CN

99%, 99% ee

NHBoc

Ph

NC CN

99%, 99% ee

NHBoc

Ph

NC CN

99%, 98% ee

NCOOEt

NHBoc

Ph

NC CN

99%, 99% ee

S

NHBocNC CN

F

99%, 99% ee

94%, 99% ee

NHBoc

Ph

NC CN

99%, 99% ee

S

NHBocNC CN

99%, >99.5% ee

Cl

+

48 49 50 51

50a

50b

50c 50d

50e 50f 50g 50h

Scheme 5.11 Organocatalytic, direct, vinylogous Mannich reaction of a,a-dicyanoalkenes 48according to Chen and coworkers [17].

5.3 Direct Vinylogous Mannich Reactions of Unmodified Substrates j171

Jørgensen and Niess took advantage of the same CH-acidic substrate class andreacted a,a-dicyanoalkenes 48 with a-amido sulfones 52 as imine precursorsunder phase-transfer conditions to furnish vinylogousMannich products 53 in goodyields and enantioselectivity [19]. As phase-transfer catalyst they employed theproline-derived, quaternary spiro-ammonium salt 54 that in combination with thestoichiometric base K3PO4 in toluene solution gave optimal results. A broad range ofdifferenta,a-dicyanoalkenes (aromatic and aliphatic) could be employed in reactionswith aromatic and heteroaromatic a-amidosulfones and delivered the products withtypically complete anti-diastereoselectivity and 74–94% ee (Scheme 5.12).

As the only other substrate class that reacted in direct, enantioselective, vinylogousMannich reactions so far, Shibasaki and coworkers have identified c-butenolides 56as CH-acidic compounds that were submitted to reactions with N-diphenylpho-sphinoyl imines 55 (Table 5.10) [20].

R3

NC CN

R2

SO2Ph

NH

R1

Boc

toluene, -25°C24 h

OMe

OMe

N

CF3

CF3X

X

OMe

Br

54

3 mol% 540.5 equiv K3PO4

RR

NHBoc

R

NC CN

up to 99 : 1 drup to 95% ee

58-96%

+ X:

48

52

53

NHBocNC CN

95%, 99 : 1 dr, 88% ee

NHBocNC CN

87%, 99 : 1 dr, 93% ee

Br

NHBocNC CN

95%, >90 : 1 dr, 92% ee

O

NHBocNC CN

58%, >99 : 1 dr, 83% ee

O

NHBocNC CN

96%, 99 : 1 dr, 93% ee

NHBocNC CN

77%, 10 : 1 dr, 89% ee

NHBocNC CN

74%, 99 : 1 dr, 74% ee

NHBocNC CN

81%, 10 : 1 dr, 89% ee

53a 53b 53c 53d

53e 53f 53g 53h

Scheme 5.12 Phase transfer-catalyzed, direct, vinylogous Mannich reaction of a,a-dicyanoalkenes 48 according to Jørgensen and Niess [19].


Table5.10

Lanthanu

mpybo

x-catalyzed,

direct,vinylog

ousMan

nich

reactio

nof

c-bu

teno

lides

56accordingto

Shibasakia

ndcoworkers

[20].

N

R1

NH

(CH

2Cl) 2

, -20

°C

5655

57

R1

Ph 2

P

H

O20

mol

% T

ME

DA

10 m

ol%

TfO

H

O

OO

PP

h 2

O

R2

R2

NN

OO

N

(S,S

)-58

15 m

ol%

(S

,S)-

5810

mol

% L

a(O

Tf)

3

+

O

Entry

R1

R2

Prod

uct

Time(h)

Yield(%

)dr

ee(%

)

1Ph

H57

a72

8396

:483

2p-Me-C6H

4H

57b

7289

96:4

843

p-Cl-C

6H4

H57

c45

9995

:583

4o-Me-C6H

4H

57d

6989

91:9

795

iBu

H57

e31

8486

:14

786

nBu

H57

f43

8682

:18

727

Ph

Me

57g

6282

>97

:368

5.3 Direct Vinylogous Mannich Reactions of Unmodified Substrates j173

Upon treatment with a chiral lanthanum(III)-pybox catalyst prepared in situ fromLa(OTf)3 and the L-alanine-derived (S,S)-Me-pybox ligand 58 in combination withtetramethylethylenediamine (TMEDA) as organic base and triflic acid, vinylogousenolization of the c-butenolide skeleton was achieved and a highly c-regioselectivevinylogous Mannich reaction occurred delivering c-aminoalkyl-substituted c-bute-nolides 57 with 68–84% ee and up to 97 : 3 diastereoselectivity. Aromatic andheteroaromatic aldimines performed more enantioselectively than aliphatic aldi-mines that, however, could also be employed with 72–78% ee. A chiral lanthanumdienolate was postulated to be involved in the enantioselective C�C-bond formingevent (Scheme 5.13).

5.4Miscellaneous

A conceptually different entry into the preparation of dienolates and their use invinylogous Mannich reactions was developed by Lautens and coworkers. Vinylox-iranes can effectively be ring opened with catalytic amounts of a Lewis acid to furnishb,c-unsaturated aldehydes that are in equilibriumwith their dienol tautomer.As suchthis transformation involved an �umpolung� of the formerly electrophilic vinylepoxide to the nucleophilic dienol that can be treated with electrophiles.

Lautens et al. treated vinyloxirane 60 with 10mol% Sc(OTf)3 and N-benzhydryl-a-iminoesters 59 and obtained d-amino-a,b-unsaturated aldehydes 61 via the

NN

OO

N

La(OTf)3N

N

NN

OO

N

La(OTf)2N

N OO

O

O

NR

H

PPh

Ph

OO

H

O [La]

N

R

PPh2

O

R

NPh2P

O

OO

[La]

R

NPh2P

O

OO

HTMEDA.TfOH

TMEDA.(TfOH)2

56

5557

H

Scheme 5.13 Postulated reaction pathway of the lanthanum-pybox-catalyzed, direct, vinylogousMannich reaction of c-butenolide 56 according to Shibasaki and coworkers [20].


rearrangement-Mannich sequence in generally good yields that may further beconverted into pipecolic esters upon hydrogenation (Scheme 5.14) [21]. Aromaticimines may be employed in place of the glyoxyl imines with somewhat diminishedyields. No catalytic, enantioselective protocol has yet been developed according to thisscheme. However, an auxiliary-based asymmetric version was realized that tookadvantage of the well-known stereodirecting ability of 8-phenylmenthol. Reaction ofvinyloxirane 60 and 8-phenylmenthyl glyoxylate 59c furnished amino aldehyde 61c ingood yield and excellent diastereoselectivity of 11 : 1.

5.5Conclusion

The catalytic, enantioselective, vinylogousMannich reaction has recently emerged asa very powerful tool in organic synthesis for the assembly of highly functionalizedand optically enriched d-amino carbonyl compounds. Two distinctly differentstrategies have been developed. The first approach calls for the reaction of preformedsilyl dienolates as latent metal dienolates that react in a chiral Lewis acid- or Brønstedacid-catalyzed Mukaiyama-type reaction with imines. Alternatively, unmodified CH-acidic substrates such as a,a-dicyanoalkenes or c-butenolides were used in vinylo-gousMannich reactions that upon deprotonation with a basic residue in the catalyticsystem generate chiral dienolates in situ.

With both strategies, remarkable progress has beenmade toward the realization ofhighly enantioselective, vinylogous Mannich reactions furnishing products with

NHN

THF, 0-50° C10-30 min6059 61a

R

CHPh2

H

10 mol% Sc(OTf)3CHPh2

O

O

HO

O

74%

Ph

HN

61b

CHPh2 O

H

50%

via O LA

(1,2-H shift)

O LA O

H

OHLA~H

HN

61c

CHPh2 O

HO

O 84%S/R = 11/1

Ph

+

- LA

Scheme 5.14 Sc(OTf)3-catalyzed vinylogous Mannich-type reaction of vinyloxirane 60 andimines 59 according to Lautens et al. [21].

5.5 Conclusion j175

almost perfect enantioselectivity in select cases. Nevertheless, there is still muchroom for improvement as the substrate scope for many of the reactions is quitelimited and for the most part only silyloxy furans and a,a-dicyanoalkenes can beemployed successfully as nucleophiles. In addition, the enantioselectivity observed inthe reactions is not generally high for a broader substrate range. Future work in thisarea will certainly focus mainly on these two aspects.

Acknowledgments

Wegratefully acknowledge the valuable intellectual and practical contributions of ourcoworkers David Giera, Michael Boomhoff, Susann Krake, and Falko Abels in thisresearch area and the generous financial support of the Deutsche Forschungsge-meinschaft through the priority research program �Organocatalysis� (SPP 1179).

Questions

5.1. Propose an explanation for the better performance of ortho-thiomethyl para-methoxy aniline-derived imines in the silver phosphine-catalyzed vinylogousMannich reactions of silyloxy furans with aliphatic imines according toSnapper and Hoveyda in contrast to the standard ortho-methoxy aniline-derived imines (Table 5.2).

5.2. Phosphoric acids 32 and 35 have been successfully employed as chiralBrønsted acid catalysts for vinylogous Mannich reactions of acyclic silyldienolates with imines (Table 5.5 and Scheme 5.10). Why does the exchangeof a para-methyl group for a tert-butyl group on the 3,30-aryl groups within theBINOL-backbone have such a pronounced effect on the enantioselectivity ofthe reaction although this position appears to be quite remote from thereaction center?

5.3. Propose a transition state for the direct vinylogous Mannich reaction with thebifunctional thiourea catalyst 51 reported by Chen and his group that accountsfor the observed relative and absolute configurations of the products(Scheme 5.11).

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References j177

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Chiral Amine Synthesis (Methods, Developments and Applications) || Catalytic, Enantioselective, Vinylogous Mannich Reactions