Aza-enamines XI.1 vinylogous aza-enamines as neutral d 3-nucleophiles: Aminomethylations of N,N-dimethylhydrazones of α,β-unsaturated aldehydes

3556

PAPER

Aza-enamines XI.¹Vinylogous Aza-enamines as Neutral d³-Nucleophiles:

Aminomethylations of N,N-Dimethylhydrazones of a,b-Unsaturated

Aldehydes

A

minomethylation on V

a

inylogous

t

A

za-e

t

namine

h

s

ias T. Grabowski,^a,2Karol Nowosinski,^aDieter Lentz,^bRainer Brehme,*^aChristoph A. Schalley*^a

a

b

Received 31 March 2010; revised 18 June 2010

E

Abstract: N,N-Dimethylhydrazones of propenal- and 2-methyl-

propenal and their derivatives and homologues (vinylogous aza-

enamines) were allowed to react with N,N-dimethylformiminium

chloride in moisture-free dimethylformamide to yield singly, dou-

bly, and even triply aminomethylated products. They can be easily

separated and characterized as crystalline hydrochlorides. The reac-

tion takes place at the w-position of the p-system. This is a conse-

quence of the conjugative interaction of the electron-donating

aminohydrazone group with the double bond system in analogy to

the enamines. The formation of dialkylhydrazones from unsaturated

aldehydes thus causes the umpolung of the formerly electrophilic

d³-building blocks into a nucleophile. Depending on the reaction

conditions and confirmed by crystal structures and 2D NMR exper-

iments, control can be exerted over the degree of substitution: Up to

trisubstituted products were obtained for the 2-methylpropenal de-

rivative. The hydrochlorides can be easily deprotonated to yield the

free aminohydrazone bases. The back-conversion of the aminohy-

drazones into the corresponding amino aldehydes is possible under

acidic conditions.

+ E⁺

– H⁺

Alk₂N

R¹

I'

I

II

+ E⁺

– H⁺

Alk₂N

N

R¹

N

III'

III

IV

E = CH=O, C(O)NHTos,

C(O)CF₃, R²CHCH₂C(O)R³

Alk₂N

N

R¹

R¹= aryl, alkyl, Het, H

III''

Scheme 1 Electrophilic substitutions at aldehyde N,N-dialkylhy-

drazones III. Enamine I and hydrazone III are related formally as

well as through their reactivities.

nyl isocyanates,^4b,e,6a–das well as the alkylation with elec-

trophilic olefins (Scheme 1).^7a–c

The reactions occur contrary to the normal polarity of the

imino structural element as expressed in III¢¢; thus, such

hydrazones proved to react as umpoled d¹-nucleophilic al-

dehyde derivatives. Moreover, they are neutral acyl anion

equivalents and thus differ from these strongly alkaline re-

agents.^8a–c

Key words: hydrazones, electrophilic substitution, nucleophilic

addition, amino aldehydes, umpolung

The isoelectronic exchange of C1 in enamines I³by nitro-

gen formally leads to aldehyde hydrazones III

(Scheme 1). Such hydrazones can be formally regarded as

aza-enamines. Some time ago, we could demonstrate that

besides this formal connection, also real relations exist in

the reactivities of both structural classes. Both react with

electrophiles E⁺, the enamines at C2 to yield II and the al-

dehyde hydrazones at the azomethine C-atom giving rise

to IV. Consequently, the azomethine carbon corresponds

to the enamine C2 carbon atom. Both owe this property to

the conjugative interaction between the electron-donating

dialkylated nitrogen atom and the carbon–carbon and car-

bon–nitrogen double bonds in the sense of mesomeric

structures I¢ and III¢. The aldehyde hydrazones are N,N-

dialkylated, for example, as in the pyrrolidino, piperidino,

or dimethylamino derivatives, because they proved to be

the most effective electron donors in enamine chemistry.³

Examples for this behavior of aldehyde N,N-dialkylhydra-

zones are the acylation with the Vilsmeier reagent^4a–d,fand

trifluoroacetic anhydride,^5a,bthe carboxylation with sulfo-

This aza-enamine principle is also applicable to vinylo-

gous aldehyde hydrazones. Consequently the dimethylhy-

drazones of the a,b-unsaturated aldehydes V are attacked

by electrophiles at the vinylogous C3-position leading to

VI (Scheme 2). This represents an umpolung of the

Michael acceptor reactivity. Therefore, these neutral d³-

nucleophilic building blocks of type V can be termed vi-

nylogous aza-enamines.

E

Me₂N

N

R

+ E⁺

– H⁺

Me₂N

N

R

V'

VI

Me₂N

N

E = Hal, C(O)CF₃, PBr₂

R = H, Me, Ph, Het

V

Scheme 2 Electrophilic substitutions at the C3 atom of vinylogous

aza-enamines

Examples for this reactivity are reactions with halogens,⁹

trifluoroacetic anhydride,^5bphosphorous tribromide,¹⁰

S₂Cl₂,¹¹and activated double bonds¹²(Scheme 2). Al-

SYNTHESIS 2010, No. 20, pp 3556–3568

Advanced online publication: 09.08.2010

DOI: 10.1055/s-0030-1258194; Art ID: T08110SS

x

x.

x

.

2

0

1

0

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Aminomethylation on Vinylogous Aza-enamines

3557

ready at an early stage of research in this field, we have signal of the H1 proton in 3·2HCl is shifted to lower field

performed first tests with such vinylogous aldehyde hy- (d = 8.61 ppm) indicating protonation of the hydrazone.¹⁷

drazones; the N,N-tetramethylenehydrazones of furan and

thiophene carbaldehyde were allowed to react with a sul-

fonyl isocyanate or the Mannich reagent. Because both

heterocycles behave as polyenes, the substitutions did not

In subsequent experiments, we could show the 2-methyl-

propenalhydrazone (5)^5bto be also singly aminomethylat-

ed, if the reaction was conducted at 0 °C with only 20%

molar excess of electrophile 2-Cl. First, the monohydro-

chloride 6·HCl precipitated from the reaction mixture in

37% yield. The addition of hydrochloric acid in N,N-di-

occur at the azomethine carbon, but at the heterocycle

core at the end of the conjugated p-system.^4bAmong oth-

ers, these results have been presented in a recent review.¹³

methylformamide to the filtrate provided an additional

In continuation of our investigations on aza-enamine reac-

42% fraction of the corresponding dihydrochloride

tivity, we have now applied aminomethylation reactions

6·2HCl (Scheme 4).

to the N,N-dimethylhydrazones of a,b-unsaturated alde-

hydes.

δ = 7.05 ppm

2-Cl

δ = 7.17 ppm

NHMe₂

(1.2 equiv)

All hydrazones required as starting materials for the

present study were synthesized according to literature

procedures.¹⁴The first aminomethylation was carried out

with the simplest vinylogous aza-enamine, the propenal

N,N-dimethylhydrazone (1).¹⁵This Mannich-analogous

reaction was carried out in moisture-free DMF using the

solid, easy-to-handle N,N-dimethylformiminium chloride

(Böhme reagent, 2-Cl)¹⁶as the electrophile. This simpli-

fied the isolation and characterization of the final prod-

ucts, because these separated directly or after addition of

hydrochloric acid in N,N-dimethylformamide from the so-

lution as crystalline substances.

H

Cl

+

filtrate

DMF

1 h, 0 °C

Me₂N

N

(Z)-6•HCl

37%

5

DMF•HCl

0 °C

2-Cl

DMF

DMF•HCl

0 °C

86%

(1.2 equiv) 1 h, 0 °C

42%

δ = 8.58 ppm

DMF•HCl

76%

0 °C

H

Cl

NHMe₂

Me₂HN

N

Cl

(E)-6•2HCl

Scheme 4 Aminomethylation of 2-methylpropenal hydrazone (5)

with formiminium chloride 2-Cl at 0 °C (1:1.2). First, the monohy-

drochloride precipitated as (Z)-6·HCl. After the addition of DMF·HCl

to the filtrate, the dihydrochloride crystallized as (E)-6·2HCl. Reac-

tion of 5 and 2 without intermediate isolation of (Z)-6·HCl yielded

76% of (E)-6·2HCl after the addition of DMF·HCl. Under acidic con-

ditions an inversion of the configuration from (Z)-6·HCl to (E)-

6·2HCl was observed in 86% yield.

At 0 °C, hydrazone 1 was added as a nucleophile to the

iminium chloride 2-Cl (1.5 equiv) forming the (2E)-4-

(dimethylamino)but-2-enal dimethylhydrazone, which

was separated as the crystalline dihydrochloride 3·2HCl

after the addition of DMF·HCl. Interestingly, compound 1

was aminomethylated twice at room temperature and in

the presence of 2.2 equivalents of 2-Cl. This reaction af-

forded 4·2HCl, which crystallized without the addition of

DMF·HCl (Scheme 3). The protonation states can be de-

rived in a straightforward manner from the carbon and ni-

trogen values of the elemental analyses, which confirm

both 3·2HCl and 4·2HCl to be dihydrochlorides. Further-

more, the exact positions of the protons were obtained

Both products differ in their configuration. The carbon–

carbon bond in dihydrochloride 6·2HCl adopted the E-

configuration as confirmed by an NOE experiment. In

marked contrast, the initially obtained monohydrochlo-

ride 6·HCl is Z-configured. A crystal structure of (Z)-

6·HCl could be obtained (Figure 1), which proves the Z-

configuration.

1

from the H NMR spectra. The azomethine proton of

4·2HCl appears at higher field (d = 7.16 ppm) similar to

the signal of the H1 proton of reactant 1 (d = 6.95 ppm) in-

dicating the hydrazone to be unprotonated. However, the

δ = 8.61 ppm

1. 2-Cl (1.5 equiv)

DMF, 1 h

0 °C

Cl

H

Me₂HN

NHMe₂

Cl

N

δ = 6.95 ppm

2. DMF•HCl

0 °C

H

3•2HCl (63%)

Me₂N

N

δ = 7.16 ppm

1

NHMe₂

Cl

4

H

2-Cl (2.2 equiv)

Me₂N

DMF, 30 min

r.t.

N

5

Cl

NHMe₂

4•2HCl (62%)

2-Cl: Me₂N=CH₂Cl

Figure 1 ORTEP plot (50% probability level) of (Z)-6·HCl

Scheme 3 Aminomethylation of propenal N,N-dimethylhydrazone

(1) with N,N-dimethylformiminium chloride (2-Cl). Single and dou-

ble aminomethylations are possible depending on the reaction condi-

tions. The ¹H NMR shifts of the azomethine proton are quite sensitive

for the protonation of the hydrazone Me₂N group.

As shown in Scheme 5, both double bond diastereomers

can form because of the rotation around the C2–C3 single

bond in the reaction intermediate. The Z-isomer is likely

Synthesis 2010, No. 20, 3556–3568 © Thieme Stuttgart · New York

3558

M. T. Grabowski et al.

PAPER

to be formed, because the vicinity of the bulky amino-

methylene group and the C2 methyl group can then be

avoided. However, the E-configuration is apparently the

thermodynamically favored isomer when 6 is doubly pro-

tonated – likely due to reduced charge repulsion in the

stretched-out E-form.

δ = 5.11 ppm

H

δ = 5.03 ppm

Me₂N

N

H

5

2-Cl

NHMe₂

Cl

NMe₂

H⁺shift

Cl

Me₂N

N

Me₂N

H

N

– H⁺

+ H⁺

3

7

Me₂N

(Z)-6⋅HCl

NMe₂

Me₂N

(E)-6

N

2

5

H⁺shift

Cl

NHMe₂

bond

rotation

Cl

NHMe₂

Cl

2⁺

NMe₂

Me₂N

N

2-Cl

H

N

– H⁺

+ H⁺

Me₂N

(Z)-6

N

H

8

6'⋅HCl

NMe₂

⁺shift

Scheme 5 Proposed mechanism for the aminomethylation of 5 ra-

tionalizing the observed carbon–carbon double bond isomerization

H

Cl

NHMe₂

However, if the 2-methylpropenal dimethylhydrazone

(5)^5bwas allowed to react at room temperature with an ex-

cess of 2-Cl, it even added up to three molecules of 2. The

reaction yielded a triply aminomethylated product that

crystallized and separated as the tetrahydrochloride (Z)-

10·4HCl after addition of hydrochloric acid in N,N-di-

methylformamide to the reaction mixture in 84% yield

(Scheme 6). A further aminomethylation could not be

achieved. The structure of (Z)-10·4HCl was confirmed by

X-ray crystral structure analysis (Figure 2).

Me₂N

1. 2-Cl

N

Me₂HN

2. H⁺

shift

Cl

NHMe₂

10•3HCl

DMF⋅HCl

NHMe₂

Cl

(Z)-9•2HCl

+ filtrate

DMF⋅HCl

Cl

NHMe₂

mixture of

Cl

Me₂HN

(E)-6·2HCl and 10·3HCl

ratio: ca. 1:2

N

Cl

Me₂HN

Cl

NHMe₂

(Z)-10•4HCl (84%)

Scheme 6 Proposed mechanism for the aminomethylation of 2-

methylpropenal hydrazone 5 with 3.5 equivalents of the formiminium

chloride 2-Cl at room temperature leading to (Z)-10·4HCl (boxes in-

dicate isolated substances).

first result, the doubly aminomethylated Z-configured di-

hydrochloride 9·2HCl crystallized from the reaction solu-

tion in 11% yield. After its separation, hydrochloric acid

in N,N-dimethylformamide was added to the filtrate. Ac-

cording to the ¹H NMR spectrum, the resulting precipitate

proved to be a mixture consisting of (E)-6·2HCl and

10·3HCl in an approximate 1:2 molar ratio. We also al-

lowed (Z)-6·HCl to react with 0.9 equivalent of 2-Cl.

Compound (Z)-9·2HCl crystallized in a yield of 6%.

Again, the precipitate isolated from the filtrate after addi-

tion of hydrochloric acid in N,N-dimethylformamide

proved to be a mixture of (E)-6·2HCl and 10·3HCl. Thus,

the three compounds probably exist simultaneously in the

reaction solution and thus are supposed to be intermedi-

ates on the way to compound 10·4HCl.

Figure 2 ORTEP plot (50% probability level) of the triply amino-

methylated product (Z)-10·4HCl. Three of the chloride ions are hy-

drogen bonded (dotted lines) to protonated N atoms. The fourth

chloride ion is located in a pocket formed by three methyl groups.

In order to examine the mechanism leading to the forma-

tion of 10 and to intercept possible intermediates, we al-

lowed to react aldehyde hydrazone 5 with less than the

required molar amount of Böhme reagent 2-Cl (1:1.9 ra-

tio) at room temperature in N,N-dimethylformamide. As a

Based on these results, we propose the pathway depicted

in Scheme 6. At first, 5 and 2-Cl form intermediate 7 that

can be deprotonated at two different positions to yield ei-

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Aminomethylation on Vinylogous Aza-enamines

3559

ther (Z)-6·HCl or 6¢·HCl. Monoaminomethylated 6¢·HCl

then reacts with a second equivalent 2-Cl via intermediate

8 to (Z)-9·2HCl. This doubly aminomethylated product

could be isolated again. The aminomethylation then oc-

curs a third time to give rise to 10·3HCl which crystallizes

as (Z)-10·4HCl after addition of HCl in DMF.

In line with the results discussed above for 1 and 5 three

conclusions can be drawn: (1) The first aminomethylation

is faster than the second one occurring at the same posi-

tion. This is in line with the temperature-dependent single

and double aminomethylation of 1. (2) The double bond

isomerization between 6 and 6¢is faster than the second

aminomethylation in line with the previous protonation-

state-dependent cis/trans isomerization of 6. (3) There-

fore, the second aminomethylation of 5 occurred exclu-

sively at the w-position of the conjugated system of 6¢·HCl

rather than the corresponding carbon atom in 6·HCl.

Figure 3 ORTEP plot (50% probability level) of (E)-12·2HCl

NOE experiments and crystallography (Figure 3) provid-

ed evidence for the E-configuration of (E)-12·HCl and

(E)-12·2HCl.

The aminomethylation of the 3-methylpropenal dimethyl-

hydrazone (11) also occurred at C3. It led to a monoami-

nomethylated product: At first the monohydrochloride

(E)-12·HCl separated from the reaction mixture in a yield

of 29%. After addition of hydrochloric acid in N,N-di-

methylformamide to the filtrate, the dihydrochloride (E)-

12·2HCl is obtained in 48%, thus leading to an overall

yield of 77% (Scheme 7). In principle, an aminomethyla-

tion reaction at the w-methyl group to 13 could be possible

after tautomerization to the dieneamine 11¢. This reaction

was, however, not observed.

Table 1 shows a series of other hydrazones, which have

been aminomethylated. Remarkably, the first aminometh-

ylation of 14¹⁸occurred only at the C3 carbon atom and

(E)-15·2HCl was isolated after the addition of a second

equivalent of anhydrous DMF·HCl to the reaction mix-

ture. A competing reaction at the methyl group at C2 in

analogy to 5 was not observed. This supports the assump-

tion of a fast first aminomethylation.

The N,N-dimethylhydrazone 16¹⁸of the cyclohex-1-ene-

1-carbaldehyde and those of the cinnamaldehyde 18¹⁹and

p-nitrocinnamaldehyde 20 also undergo substitution at the

C3 atom. All three aminomethylated compounds 17, 19,

and 21 were obtained as the Z-isomers and crystallized as

monohydrochlorides from the reaction solutions. While

the carbon–carbon double bond configuration is fixed in

(Z)-17·HCl, the Z-isomers of 19·HCl and 21·HCl are more

stable than the E-configured analogue. Likely, strain

would be created in the latter as depicted in Figure 4. The

solid state structure of (Z)-21 confirms the structural as-

signment (Figure 5a) The crystal shows an interesting ar-

ray of intermolecular interactions which involve C–H···O

and C–H···N hydrogen bonds (Figure 5b). These interac-

tions connect neighboring molecules to a double strand on

their less polar sides. The double strands are stacked to

complete the three-dimensional structure (Figure 5c). The

lateral interactions between these stacks are mediated by

Coulomb forces between the chloride anions, which are

located in pockets surrounded by ammonium ions

(Figure 5d).

H⁺shift

Me₂N

N

H

11'

(E)-11

Cl

Me

H

2-Cl (1.5 equiv)

DMF, r.t., 1 h

N

H

Me₂N

N

NHMe₂

Cl

Me₂N

NHMe₂

Cl

H

N

13

(E)-12⋅HCl

29%

DMF⋅HCl

0 °C

Me₂HN

Cl

NHMe₂

Cl

N

(E)-12•2HCl

total yield: 77%

48%

NO₂

(Z)-21⋅HCl

(E)-21⋅HCl

steric

congestion

Scheme 7 Aminomethylation of hydrazone (E)-11 proceeding with

inversion of the configuration to (E)-12. First, (E)-12·HCl separated

from the reaction mixture followed by (E)-12·2HCl after the addition

of DMF·HCl to the filtrate. A rearrangement of 11 to the dienamine

11¢ might occur with the possibility of an aminomethylation reaction

at the b-methyl group to afford 13. This reaction was, however, not

observed. Apparently, either the tautomerization to dieneamine 11¢ or

the reaction of 11¢ in the subsequent aminomethylation is significant-

ly slower than the aminomethylation of 11.

NHMe₂

Cl

Z

Me₂N

H

vs.

N

H

E

H

Me₂N

NHMe₂

Cl

no steric

problems

H

NO₂

N

Figure 4 Comparison of the E/Z-isomers of 21·HCl

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M. T. Grabowski et al.

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Table 1 Aminomethylation of Propenal N,N-Dimethylhydrazone Derivatives^a

Reactant

Reaction conditions

Product

Yield (%)

Me₂N

N

1. 2-Cl (1.5 equiv), DMF, r.t.

2. DMF·HCl, 0 °C

Me₂HN

Cl

NHMe₂

Cl

36

N

14

(E)-15·2HCl

NHMe₂

Me₂N

N

Cl

Me₂N

N

2-Cl (1.5 equiv), DMF, r.t.

2-Cl (3.5 equiv), DMF, r.t.

34

16

(Z)-17·HCl

NHMe₂

Cl

Me₂N

N

Me₂N

N

39

78

R

18 R = H

R

20 R = NO₂

(Z)-19·HCl

(Z)-21·HCl

Me₂N

N

Me₂N

N

NHMe₂

Cl

1. 2-Cl (2 equiv), DMF, r.t.

26

22

(E)-23·HCl

24

Me₂HN

NHMe₂

Cl

2. DMF·HCl

N

overall yield: 50

Cl

(E)-23·2HCl

Me₂N

N

O

NHMe₂

Cl

Me₂HN

O

1. 2-Cl (2 equiv), r.t.

2. DMF·HCl

N

38

Cl

24

25·2HCl

^aThe formation of products (E)-23·HCl and 25·2HCl show the possibility of the extension of the aminomethylation reaction to longer p-sys-

tems.

The vinylogy concept can even be extended to larger p- ple with diethyl ether, can be used for their isolation. The

systems. Table 1 shows the results of the aminomethyla- yields are usually high (Table 2). Furthermore, a change

tion reactions performed with the dimethylhydrazones of in double-bond configuration can be avoided, when

hexa-2,4-dienal (22)²⁰and furanylpropenal (24).²¹The re- NaOH is not used in large excess. The Z- and E-isomers

actions took place at the remote end of the p-system fa- thus retain their configuration in the deprotonation and

vored through the higher degree of conjugation. isolation process. Although no decomposition of the free

Substitution at C1 and C3 was not observed. Product (E)- aminohydrazones has been observed even during longer

23·HCl precipitated directly from the mother liquor and as standing at room temperature, we recommend to keep

described above, (E)-23·2HCl precipitated from the fil- them under inert gas atmosphere in a refrigerator.

trate upon addition of DMF·HCl. In contrast to 24, the

phenyl-substituted reactants 18 and 20 do not react at the

The back-conversion of the aminomethylated hydrazones

into the corresponding aldehydes was performed exem-

plarily for 21·HCl in 4 M aqueous hydrochloric acid at

aromatic core, but rather at C3. This is caused by the high-

er aromatic stabilization of the phenyl ring (~125 kJ mol^–1)

as compared to the furan system (~70 kJ mol^–1). During

Table 2 Deprotonation of Hydrochlorides to Free Aminohydra-

the initial addition step of 2-Cl to 24, a nonaromatic inter- zones

mediate is formed. The higher aromatic stabilization of

Hydrochloride

(Z)-6·HCl

Amine

(Z)-6

Yield (%)

the phenyl group does not permit to generate such an in-

termediate and thus, the aminomethyl substituent is di-

rected to C3.

90

96

99

89

92

(E)-6·HCl

(E)-6

Finally, the free aminohydrazones can be obtained from

the corresponding hydrochlorides by treatment with aque-

ous sodium hydroxide (ca. 1.2 equiv NaOH per hydro-

chloride). Since the free aminohydrazones are soluble in

(Z)-10·4HCl

(E)-12·2HCl

(Z)-10

(E)-12

(E)-23

organic solvents, simple extraction procedures, for exam- (E)-23·2HCl

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Aminomethylation on Vinylogous Aza-enamines

3561

Cl

Me₂HN

4 M HCl

r.t. 3 h

Me₂N

N

O

21•HCl

26

NO₂

Me

Cl

HO

N

2

5

6

NO₂

27

96%

Scheme 8 Back-conversion from the aminohydrazone (Z)-21·HCl

to the corresponding amino aldehyde isolated as the cyclic hemiami-

nal 27

Figure 6 ORTEP plot (50% probability level) of 27

activity is achieved. One of the greatest advantages of the

aminomethylation presented here is the great ease with

which the products can be isolated. Usually, the hydro-

chlorides either directly precipitate from the solution or

can be precipitated by the addition of acid. The precipitate

is usually pure after filtration and washing so that addi-

tional purification steps are normally not required. If so,

simple recrystallization provides best results. More than

one aminomethylation is possible. The number of ami-

nomethylations can be controlled by the reaction condi-

tions. In particular, the amount of electrophile and the

temperature are decisive for the outcome. The configura-

tion of the carbon–carbon double bond in the aminometh-

ylated products is quite acid-labile. Nevertheless, the

products are generally well defined. 2-Methylpropenal

N,N-dimethylhydrazone with the methyl group at C2 can

undergo a double-bond shift enabling it to react in even

more than two aminomethylations. The results indicate

the first aminomethylation to be faster than the double-

bond migration, while the second aminomethylation oc-

curring at the same position is slower.

Figure 5 (a) ORTEP plot (50%) probability level of (Z)-21·HCl. (b)

In the crystal, 21 forms antiparallel double strands, which are connec-

ted through electrostatic interactions between the chlorides and the

ammonium groups. A number of close contacts between two of these

double strands indicate C–H···O and C–H···N interactions to mediate

the packing. (c) Layers of double strands are stacked on top of each

other. (d) This packing pattern maximizes the chloride–ammonium

interactions. Each anion is surrounded by four cationic centers (the

chloride and the surrounding dimethylammonium groups are shown

in spacefilling; for clarity, the remaining parts of the molecules are

depicted in ball-and-stick representation).

room temperature. After three hours, a yellowish precipi-

tate formed. However, instead of the free amino aldehyde

26, the cyclic hemiaminal, 2-hydroxy-1,1-dimethyl-4-(4-

nitrophenyl)-2,5-dihydro-1H-pyrrolium chloride (27),

was obtained (Scheme 8).²²A crystal structure of the

hemiaminal confirms the structural assignment

(Figure 6).

It will be interesting to extend this proof-of-principle

study to other electrophiles in the future – for example to

Lewis acid activated organocatalytic reactions. Since

mono- and disubstitution can be controlled, it should be

possible to attach two different electrophiles in a one-pot

procedure without intermediate workup. Furthermore, the

In this contribution, we have discussed different aspects

of the aminomethylation of vinylogous aza-enamines.

While the a,b-unsaturated aldehydes are d³electrophiles,

the hydrazones represent d³nucleophiles, which react

with electrophiles such as N,N-dimethylformiminium

chloride. Thus, an umpolung of the Michael acceptor re-

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M. T. Grabowski et al.

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Anal. Calcd for C₁₁H₁₃N₃O₂: C, 60.26; H, 5.98; N, 19.17. Found: C,

60.05; H, 5.97; N, 19.16.

back-conversion of the aminohydrazones into the hemi-

aminals of the corresponding amino aldehydes will pro-

vide access to a singly or doubly substituted Michael

acceptor with normal reactivity. This would provide the

opportunity to introduce a third substituent.

(1E,2E)-3-(4-Nitrophenyl)prop-2-enal Dimethylhydrazone Hy-

drochloride (20·HCl)¹⁷

DMF·HCl complex (0.03 g, 0.8 mmol) was added to 20 (0.09 g, 0.4

mmol) at r.t. and the mixture was stirred for 15 min. The precipitate

formed was separated by filtration and dried in vacuo; yield: 0.09 g

(88%); colorless solid; decomp. 148–160 °C.

All reagents were used as purchased. The DMF·HCl complex and

the Böhme reagent 2-Cl were synthesized according to well-estab-

lished literature procedures.¹⁶Anhyd DMF was obtained from

ACROS and kept under argon. Reactions with air- and moisture-

sensitive compounds were performed in dried glassware and under

protective gas atmosphere. Purification of the crude products was

not necessary in most cases, but can be achieved by recrystalliza-

tion, if necessary. All new compounds were characterized by ¹H and

¹³C NMR experiments, performed on Bruker AC 250 (¹H: 250

MHz), ECX 400 (¹H: 400 MHz; ¹³C: 100.5 MHz), and Jeol Eclipse

500 (¹H: 500 MHz; ¹³C: 125.8 MHz) spectrometers. The chemical

shifts (d) are reported in ppm relative to CDCl₃(d_H= 7.26,

d_C= 77.0) and CD₃OD (d_H= 3.31, d_C= 49.0). The coupling con-

stants are specified in Hertz (Hz). The ¹³C NMR spectra were mea-

sured under ¹H broadband decoupling. For a detailed structure

assignment, 2D NMR spectra (HMQC, HMBC, COSY, NOESY)

were recorded. Mass spectra were recorded on Agilent 6210 (ESI-

ToF, 4 kV), Ionspec QFT-7 (ESI-FTICR), Varian CH-5 (FAB), and

Finnigan MAT 711 (EI, 80 eV, 8 kV) mass spectrometers. Since the

hydrochloride salts are not volatile, the EI mass spectra documented

below correspond to those of the free aminohydrazones, which are

liberated to some extent when a sample of the hydrochloride is in-

troduced into the high vacuum of the EI ion source and heated. ‘M⁺’

thus does not refer to the salt, but to the free aminohydrazone. IR

spectra were measured on a Nicolet 5SXC FTIR spectrometer, ele-

mental analyses on a Perkin-Elmer 2400 elemental analyzer. Melt-

ing and decomposition points (Büchi MP 510) were measured for

recrystallized samples and are uncorrected.

IR (KBr): 3101, 3069, 3030, 3006, 2839, 2517, 2374, 2306, 2251,

2000, 1635, 1599, 1513, 1453, 1343, 1301, 1173, 1157, 1007, 983,

953, 878, 836, 746 cm^–1.

¹H NMR (400 MHz, CD₃OD–CDCl₃): d = 8.73 (d, ³J = 9.3 Hz, 1 H,

H-1), 8.25 (d, ³J = 8.8 Hz, 2 H, H-6), 7.76 (d, ³J = 8.8 Hz, 2 H, H-

5), 7.44 (d, ³J = 16.0 Hz, 1 H, H-3), 7.44 (dd, ³J = 9.3 Hz, ³J = 16.0

Hz, 1 H, H-2), 3.12 [s, 6 H, N(CH₃)₂].

¹³C NMR (101 MHz, CDCl₃): d = 146.1 (C-4), 144.2 (C-1), 132.3

(C-2), 127.5 (C-3), 126.2 (C-5, C-9), 124.1 (C-6, C-8), 42.5

[N(CH₃)₂].

MS (EI, 80 eV, 100 °C): m/z (%) = 219.1 (100, [M]⁺), 203.8 (4, [M

– CH₃]⁺), 157.8 (19).

HRMS (EI): m/z calcd for [C₁₁H₁₃N₃O₂]⁺: 219.1008; found:

219.1017.

Anal. Calcd for C₁₁H₁₄ClN₃O₂: C, 51.67; H, 5.52; N, 16.43. Found:

C, 51.90; H, 5.27; N, 16.78.

(2E)-3-(Furan-2-yl)prop-2-enal Dimethylhydrazone (24)²¹

This compound was synthesized according to the procedure used

for the synthesis of 20. 3-Furylacrylaldehyde (6.10 g, 50.0 mmol)

yielded 5.19 g (63%) of 24 as a brown solid; mp 139–140 °C/14

mbar; dr (E/Z) = 89:11; R_f= 0.8 (CH₂Cl₂–MeOH, 9:1).

IR (KBr): 3114, 2954, 2856, 2827, 2786, 2552, 2402, 1873, 1798,

1626, 1573, 1536, 1480, 1421, 1351, 1275, 1253, 1129, 1934, 1011,

960 cm^–1.

A full set of analytical data is available in the literature for all hy-

drazones except for 20, 20·HCl, and 24.

¹H NMR (500 MHz, CDCl₃): d = 7.90, 7.06 (d, ³J = 9.2 Hz, 1 H, H-

1), 7.36 (d, ³J = 1.6 Hz, 1 H, H-7), 6.83 (dd, ³J = 9.2 Hz,

(1E,2E)-3-(4-Nitrophenyl)prop-2-enal Dimethylhydrazone (20)

At r.t., trifluoroacetic acid (0.08 g, 50 mL, 0.7 mmol, 1.3 mol%) was

added to a solution of dimethylhydrazine (4.80 g, 80.0 mmol) in cy-

clohexane (40 mL) followed by the slow addition of 3-(4-nitrophe-

nyl)acrylaldehyde (8.85 g, 50.0 mmol). The mixture was refluxed

for 4 h and the H₂O formed in the course of the reaction was collect-

ed in a Dean–Stark trap. Then, the solvent was removed and CH₂Cl₂

(20 mL) was added to the residue. The CH₂Cl₂solution was washed

with H₂O (20 mL), and the aqueous phase was extracted with

CH₂Cl₂(3 × 5 mL). The combined organic phases were washed with

brine (35 mL), dried (Na₂SO₄), and the solvents were evaporated;

yield: 9.10 g (83%); red needles; mp 159–160 °C (AcOH); R_f= 0.8

(CH₂Cl₂–MeOH, 9:1).

3

³J = 15.8 Hz, 1 H, H-2), 6.39 (d, J = 15.8 Hz, 1 H, H-3), 6.36 (d,

³J = 3.3 Hz, 1 H, H-5), 6.15 (dd, ³J = 1.6 Hz, ³J = 3.3 Hz, 1 H, H-6),

2.98, 2.91 [2 s, each 3 H, N(CH₃)₂].

¹³C NMR (125 MHz, CDCl₃): d = 153.3 (C-7), 142.1 (C-6), 134.6

(C-1), 126.2 (C-2), 119.2 (C-3), 111.6 (C-5), 107.8 (C-4), 42.7

[N(CH₃)₂].

MS (EI, 80 eV, 30 °C): m/z (%) = 164.1 (100, [M]⁺), 120.2 (19, [M

– C₂H₆N]⁺), 94.3 (35), 44.1 (16).

HRMS (EI): m/z calcd for [C₉H₁₂N₂O]⁺: 164.0950; found:

164.0947.

Anal. Calcd for C₉H₁₂N₂O: C, 65.83; H, 7.37; N, 17.06. Found: C,

65.68; H, 7.15; N, 17.20.

IR (KBr): 3172, 3089, 3068, 3052, 2941, 2902, 2808, 2648, 2602,

2430, 2374, 2210, 2125, 1920, 1609, 1588, 1505, 1485, 1426, 1326,

1264, 1161, 1107, 972, 964, 955 cm^–1.

Aminomethylation; General Procedure

A solution of the aldehyde-N,N-dimethylhydrazone (3.0 mmol) in

anhyd DMF (1 mL) was added to a stirred suspension of the re-

quired amount (see below) of N,N-dimethylformiminium chloride

(2-Cl)¹⁶in anhyd DMF (3 mL) at 0 °C or r.t. within 30 min (see be-

low). The temperature may slightly increase during the addition, but

can and should be controlled by the addition rate. After ca. 40 min,

the solid formiminium chloride 2-Cl had completely dissolved.

When the monohydrochloride of the aminomethylation product

crystallized, it was separated by filtration or centrifugation after an

additional hour of stirring, washed in quick succession with DMF

(1 mL), i-PrOH (1 mL), and Et₂O (1 mL), and dried in vacuo. To the

filtrate (or directly to the reaction solution if no monohydrochloride

precipitated from the reaction mixture), DMF·HCl complex (2

¹H NMR (500 MHz, CDCl₃): d = 8.14 (dd, ⁴J = 1.9 Hz, ³J = 7.9 Hz,

2 H, H-6), 7.47 (dd, ⁴J = 1.9 Hz, ³J = 7.7 Hz, 2 H, H-5), 7.07 (m, 2

H, H-1, H-2), 6.57 (dd, ⁴J = 1.7 Hz, ³J = 15.0 Hz, 1 H, H-3), 3.00 [s,

6 H, N(CH₃)₂].

¹³C NMR (125 MHz, CDCl₃): d = 146.1 (C-4), 144.2 (C-1), 132.3

(C-2), 127.5 (C-3), 126.2 (C-5), 124.1 (C-6), 42.5 [N(CH₃)₂].

MS (EI, 80 eV, 30 °C): m/z (%) = 219.1 (100, [M]⁺), 204 (4, [M –

CH₃]⁺), 157.8 (19).

HRMS (EI): m/z calcd for [C₁₁H₁₃N₃O₂]⁺: 219.1008; found:

219.1017.

Synthesis 2010, No. 20, 3556–3568 © Thieme Stuttgart · New York

PAPER

Aminomethylation on Vinylogous Aza-enamines

3563

equiv per amino group) was added and the product collected as the

precipitate of a higher hydrochloride and washed as described

above. Recrystallization afforded analytically pure compounds (for

the recrystallization solvent see below). Where applicable, devia-

tions from this standard procedure are given below.

(0.44 g, 12.0 mmol; 2.20 g HCl in DMF), (E)-6·2HCl was obtained;

yield: 0.55 g (76%).

Experiment 3: DMF·HCl (0.22 g, 6.0 mmol; 1.10 g HCl in DMF)

was added under stirring to a solution of (Z)-6·HCl (isolated from

experiment 1) (0.09 g, 0.43 mmol) in DMF (2 mL) at r.t. After stir-

ring for 1 h, the precipitate of (E)-6·2HCl obtained was separated by

filtration, washed with i-PrOH (1 mL), and dried in vacuo; yield:

0.09 g (86%).

(1E,2E)-4-(Dimethylamino)but-2-enal Dimethylhydrazone Di-

hydrochloride (3·2HCl)

Böhme reagent 2-Cl (0.56 g, 6.0 mmol) and (E)-prop-2-enal di-

methylhydrazone (1;¹⁵0.40 g, 4.0 mmol) were reacted at 0 °C. After

the addition of DMF·HCl complex (0.44 g, 12.0 mmol; 2.20 g of

HCl in DMF), 3·2HCl obtained was recrystallized from EtOH;

yield: 0.57 g (63%); colorless solid; mp 135–145 °C (dec.).

(Z)-6·HCl

IR (KBr): 3429, 2953, 2927, 2884, 2561, 2508, 2475, 1631, 1543,

1477, 1458, 1431, 1169, 1135, 1094 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 7.17 (s, 1 H, H-1), 5.45 (td,

⁴J = 1.2 Hz, ³J = 8.0 Hz, 1 H, H-3), 3.96 (d, ³J = 8.0 Hz, 2 H, H-4),

2.98 [s, 6 H, NN(CH₃)₂], 2.87 [s, 6 H, N(CH₃)₂], 1.99 (s, 3 H, H-5).

IR (KBr): 3404, 3018, 2426, 1664, 1606, 1486, 1461, 1452, 1176,

1165, 1142 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 8.61 (d, ³J = 8.9 Hz, 1 H, H-1),

6.79 (dt, ³J = 6.9 Hz, ³J = 15.5 Hz, 1 H, H-3), 6.72 (dd, ³J = 8.9 Hz,

³J = 15.5 Hz, 1 H, H-2), 4.07 (d, ³J = 6.9 Hz, 2 H, H-4), 3.17 [s, 6

H, NN(CH₃)₂], 2.94 [s, 6 H, N(CH₃)₂].

¹³C NMR (125 MHz, CD₃OD): d = 165.3 (C-1), 139.1 (C-2), 133.2

(C-3), 59.1 (C-4), 46.4 [NN(CH₃)₂], 43.3 N(CH₃)₂].

¹³C NMR (125 MHz, CD₃OD): d = 144.6 (C-2), 129.3 (C-1), 114.2

(C-3), 55.4 (C-4), 42.8 [NN(CH₃)₂], 42.6 [N(CH₃)₂], 20.8 (C-5).

MS (EI, 80 eV, 110 °C): m/z (%) = 169.2 (25 [M]⁺), 124.9 (100, [M

– C₂H₆N]⁺), 110.0 (25), 82.0 (39), 58.0 (26), 44.0 (60).

HRMS (EI): m/z calcd for [C₉H₁₉N₃]⁺: 169.1579; found: 169.1587.

Anal. Calcd for C₉H₂₀ClN₃: C, 52.54; H, 9.80; N, 20.43. Found: C,

52.40; H, 10.06; N, 20.14.

MS (EI, 80 eV, 50 °C): m/z (%) = 155.0 (39, [M]⁺), 111.0 (100, [M

– C₂H₆N]⁺), 82.0 (36), 68.1 (20), 58.0 (24), 43.9 (38).

The Z-configuration of the carbon–carbon double bond was con-

firmed by X-ray crystallography (Figure 1).

HRMS (EI): m/z calcd for [C₈H₁₇N₃]⁺: 155.1422; found: 155.1421.

Anal. Calcd for C₈H₁₉Cl₂N₃: C, 42.11; H, 8.39; N, 18.42. Found: C,

41.94; H, 8.33; N, 18.19.

(E)-6·2HCl

IR (KBr): 3385, 2956, 2917, 2825, 2563, 2518, 2310, 1647, 1601,

1475, 1448, 1429, 1188, 1174, 1153 cm^–1.

(1E)-4-Dimethylamino-3-[dimethylaminomethyl]but-2-enal

Dimethylhydrazone Dihydrochloride (4·2HCl)

¹H NMR (500 MHz, CD₃OD): d = 8.58 (s, 1 H, H-1), 6.47 (td,

Böhme reagent 2-Cl (0.82 g, 8.8 mmol) and 1¹⁵(0.40 g, 4.0 mmol)

were reacted at r.t. and the product 4·2HCl obtained was recrystal-

lized from i-PrOH–MeOH (3:1); yield: 0.71 g (62%); colorless sol-

id; mp 154–160 °C (dec.).

⁴J = 1.1 Hz, ³J = 7.1 Hz, 1 H, H-3), 4.15 (d, ³J = 7.1 Hz, 2 H, H-4),

4

3.19 [s, 6 H, NN(CH₃)₂], 2.96 [s, 6 H, N(CH₃)₂], 1.98 (d, J = 1.1

Hz, 3 H, H-5).

¹³C NMR (125 MHz, CD₃OD): d = 170.5 (C-1), 140.1 (C-2), 136.7

(C-3), 55.9 (C-4), 47.1 [NN(CH₃)₂], 43.6 [N(CH₃)₂], 11.8 (C-5).

IR (KBr) 3413, 3024, 2963, 2946, 2901, 2648, 2621, 1627, 1533,

1487, 1476, 1463, 1179, 1158, 1145, 1132 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 7.16 (d, ³J = 9.0 Hz, 1 H, H-1),

6.88 (d, ³J = 9.0 Hz, 1 H, H-2), 4.22, 4.04 (2 s, each 2 H, H-4, H-5),

3.11 [s, 6 H, NN(CH₃)₂], 2.93, 2.88 [2 s, each 6 H, [N(CH₃)₂].

MS (EI, 80 eV, 50 °C): m/z (%) = 169.1 (26, [M]⁺), 125.3 (100, [M

– C₂H₆N]⁺), 110.3 (27), 82.2 (46), 58.1 (27), 44.0 (51).

HRMS (EI): m/z calcd for [C₉H₁₉N₃]⁺: 169.1579; found: 169.1583.

¹³C NMR (125 MHz, CD₃OD): d = 146.7 (C-2), 125.6 (C-1), 114.3

(C-3), 63.0, 56.1 (C-4, C-5), 43.0, 42.9, 42.8 [N(CH₃)₂].

Anal. Calcd for C₉H₂₁Cl₂N₃: C, 44.63; H, 8.74; N, 17.35. Found: C,

44.39; H, 8.61; N, 17.22.

MS (EI, 80 eV, 80 °C): m/z (%) = 212.3 (1, [M]⁺), 167.1 (23), 123.1

(100), 82.2 (8), 58.0 (36).

HRMS (EI): m/z calcd for [C₁₁H₂₄N₄]⁺: 212.2001; found: 212.1993.

(1E,2Z)-2-[1,3-Bis(dimethylamino)propan-2-yl]-4-(dimethyl-

amino)but-2-enal Dimethylhydrazone Tetrahydrochloride [(Z)-

10·4HCl] (Scheme 6)

Böhme reagent 2-Cl (1.26 g, 13.5 mmol) and 5^5b(0.34 g, 3.0 mmol)

were reacted at r.t. After the addition of DMF·HCl (0.88 g, 24.0

mmol), the (Z)-10·4HCl obtained was recrystallized from MeOH;

yield: 1.00 g (84%); colorless solid; mp 140–145 °C (dec.).

Anal. Calcd for C₁₁H₂₆Cl₂N₄: C, 46.32; H, 9.19; N, 19.64. Found:

C, 45.99; H, 9.17; N, 19.38.

(1E,2Z)-4-Dimethylamino-2-methylbut-2-enal Dimethylhydra-

zone Monohydrochloride [(Z)-6·HCl] and (1E,2E)-4-Dimethyl-

amino-2-methylbut-2-enal Dimethylhydrazone

IR (KBr) 3438, 3375, 3249, 2963, 2902, 2832, 2519, 2491, 2421,

1641, 1596, 1464, 1448, 1406, 1190, 1161, 1133 cm^–1.

Dihydrochloride [(E)-6·2HCl] (Scheme 4)

¹H NMR (500 MHz, CD₃OD): d = 8.33 (s, 1 H, H-1), 6.80 (m, 1 H,

H-3), 4.28 (d, ³J = 7.2 Hz, 2 H, H-4), 3.87 (m, 1 H, H-5), 3.74 (dd,

³J = 10.4 Hz, ³J = 12.8 Hz, 2 H, H-6a, H-7a), 3.52 (dd, ⁴J = 4.5 Hz,

³J = 12.8 Hz, 2 H, H-6b, H-7b), 3.27 [s, 6 H, NN(CH₃)₂], 3.02, 2.98,

2.95 [3 s, each 6 H, N(CH₃)₂].

¹³C NMR (125 MHz, CD₃OD): d = 151.4 (C-1), 137.2 (C-3), 134.2,

133.6 (C-2, C-5), 59.6 (C-6, C-7), 55.5 (C-4), 46.0 [N(CH₃)₂], 45.3

[NN(CH₃)₂], 43.8, 43.1 [N(CH₃)₂].

Experiment 1: Böhme reagent 2-Cl (0.55 g, 5.9 mmol) and (E)-2-

methylprop-2-enal dimethylhydrazone (5;^5b0.56 g, 5.0 mmol) were

reacted at 0 °C. The precipitated product (Z)-6·HCl was isolated by

filtration and recrystallized from i-PrOH; yield: 0.38 g (37%); col-

orless solid; mp 149–155 °C (dec.). After the addition of DMF·HCl

(0.18 g, 5.0 mmol; 0.86 g HCl in DMF) to the mother liquor (E)-

6·2HCl was obtained and purified by recrystallization from i-

PrOH–MeOH (2:1); yield: 0.51 g (42%); colorless solid; mp 148–

160 °C (dec.).

MS (EI, 80 eV, 90 °C): m/z (%) = 283.3 (7, [M]⁺), 226.3 (14, [M –

C₂H₆N₂]⁺), 180.2 (35), 137.1 (23), 123.1 (16), 58.0 (100).

Experiment 2: Böhme reagent 2-Cl 0.34 g (3.6 mmol) and 5^5b(0.34

g, 3.0 mmol) were reacted at 0 °C. After the addition of DMF·HCl

HRMS (EI): m/z calcd for [C₁₅H₃₃N₅]⁺: 283.2736; found: 283.2725.

Synthesis 2010, No. 20, 3556–3568 © Thieme Stuttgart · New York

3564

M. T. Grabowski et al.

PAPER

Anal. Calcd for C₁₅H₃₇Cl₄N₅: C, 41.97; H, 8.69; N, 16.31. Found:

C, 41.74; H, 8.98; N, 16.10.

¹³C NMR (125 MHz, CD₃OD): d = 130.5 (C-1), 134.8 (C-2), 126.0

(C-3), 68.0 (C-4), 42.8 [N(CH₃)₂], 42.7 [N(CH₃)₂], 15.9 (C-5).

MS (EI, 80 eV, 100 °C): m/z (%) = 169.2 (51, [M]⁺), 125.0 (100, (M

(1E,2Z)-4-Dimethylamino-2-(2-dimethylaminoethyl)but-2-enal

Dimethylhydrazone Dihydrochloride [(Z)-9·2HCl] (Scheme 6)

Experiment 1: Böhme reagent 2-Cl (0.53 g, 5.7 mmol) in DMF (3

mL) and 5^5b(0.34 g, 3.0 mmol) were reacted at r.t. Filtration of the

precipitate afforded (Z)-9·2HCl; yield: 0.10 g (11%); colorless sol-

id.

– C₂H₆N)⁺), 110.0 (34), 79.9 (46), 58.0 (75), 44.0 (40).

HRMS (EI): m/z calcd for [C₉H₁₉N₃]⁺: 169.1579; found: 169.1577.

Anal. Calcd for C₉H₂₀ClN₃: C, 52.54; H, 9.80; N, 20.43. Found: C,

52.29; H, 10.46; N, 20.19.

(1E,2E)-4-Dimethylamino-3-methylbut-2-enal Dimethylhydra-

zone Dihydrochloride [(E)-12·2HCl]

Experiment 2: A solution of (Z)-6·HCl (0.11 g, 0.6 mmol) in DMF

(2 mL) was stirred with 2-Cl (0.05 g, 0.5 mmol) at r.t for 2 h. The

precipitate formed was filtered and recrystallized from i-PrOH;

yield: 0.01 g (6%); mp 145–150 °C (dec.).

After the addition of DMF·HCl (3.60 g, 100.0 mmol of HCl in 20.00

g of DMF) to the filtrate of (E)-12·HCl, the dihydrochloride (E)-

12·2HCl crystallized. After filtration, it was washed with i-PrOH

(10 mL) and Et₂O (10 mL), recrystallized from i-PrOH–MeOH

(1:1) and dried in vacuo; yield: 10.00 g (48%); overall yield: 77%;

mp 140–150 °C.

IR (KBr) 3452, 2993, 2957, 2870, 2575, 2519, 2489, 2459, 2427,

1545, 1477, 1436, 1406, 1174, 1149, 1133 cm^–1.

¹H NMR (400 MHz, D₂O): d = 7.12 (s, 1 H, H-1), 5.59 (t, ³J = 7.9

Hz, 1 H, H-3), 3.87 (d, ³J = 7.9 Hz, 2 H, H-4), 3.19 (m, 2 H, H-5),

2.70 (m, 2 H, H-6), 2.82 [s, 6 H, NN(CH₃)₂], 2.79, 2.76 [2 s, each 6

H, [N(CH₃)₂].

¹³C NMR (125 MHz, D₂O): d = 140.8 (C-2), 129.9 (C-1), 118.0 (C-

3), 57.2 (C-5), 53.9 (C-4), 42.8 [NN(CH₃)₂], 42.2, 42.1 [N(CH₃)₂],

29.0 (C-6).

IR (KBr): 3373, 2964, 2922, 2886, 2562, 2507, 2348, 1654, 1593,

1480, 1454, 1417, 1159, 1143 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 8.68 (d, ³J = 9.7 Hz, 1 H, H-1),

4

3

6.46 (dd, J = 1.2 Hz, J = 9.7 Hz, 1 H, H-2), 4.01 (s, 2 H, H-4),

3.17 [s, 6 H, NN(CH₃)₂], 2.92 [s, 6 H, [N(CH₃)₂], 2.20 (d, ⁴J = 1.2

Hz, 3 H, H-5).

MS (EI, 80 eV, 150 °C): m/z (%) = 226.1 (11, [M]⁺, 181.2 (4), 168.2

¹³C NMR (125 MHz, CD₃OD): d = 162.4 (C-3), 147.2 (C-1), 128.3

(C-2), 65.0 (C-4), 46.5 [NN(CH₃)₂], 43.7 [N(CH₃)₂], 17.2 (C-5).

(4, [M – C₂H₆N₂]⁺), 137.1 (11), 58.2 (100).

HRMS (EI): m/z calcd for [C₁₂H₂₆N₄]⁺: 226.2157; found: 226.2152.

MS (EI, 80 eV, 30 °C): m/z (%) = 169.2 (52, [M]⁺), 125.3 (100, [M

Anal. Calcd for C₁₂H₂₈Cl₂N₄: C, 48.16; H, 9.43; N, 18.72. Found:

C, 48.02; H, 9.35; N, 18.50.

– C₂H₆N]⁺), 110.4 (37), 82.3 (40), 58.1 (72), 44.0 (86).

HRMS (EI): m/z calcd for [C₉H₁₉N₃]⁺: 169.1579; found: 169.1570.

Anal. Calcd for C₉H₂₁Cl₂N₃: C, 44.63; H, 8.74; N, 17.35. Found: C,

44.39; H, 8.62; N, 17.17.

(1E)-2-[1,3-Bis(dimethylamino)propan-2-yl]-4-(dimethylami-

no)but-2-enal Dimethylhydrazone Trihydrochloride [10·3HCl]

(Scheme 6)

The precipitate consisting of (E)-6·2HCl and 10·3HCl dissolved in

hot i-PrOH only partly, the solid residue was separated by centrifu-

gation and proved after recrystallization from i-PrOH–MeOH (3:1)

as pure 10·3HCl; colorless solid; mp 150–155 °C (dec.).

(1E,2E)-4-Dimethylamino-2,3-dimethylbut-2-enal Dimethylhy-

drazone Dihydrochloride [(E)-15·2HCl]

Böhme reagent 2-Cl (0.42 g, 4.5 mmol) and (2E)-2-methylbut-2-

enal dimethylhydrazone (14;¹⁸0.38 g, 3.0 mmol) were reacted at

r.t., and after the addition of DMF·HCl (0.44 g, 12.0 mmol), the

product obtained was recrystallized from i-PrOH–MeOH (1:1);

yield: 0.28 g (36%); colorless solid; mp 145–155 °C.

IR (KBr): 3462, 3392, 2959, 2899, 2548, 2405, 2388, 1658, 1600,

1477, 1463, 1414, 1249, 1162, 986, 949 cm^–1.

¹H NMR (400 MHz, CD₃OD): d = 7.61 (s, 1 H, H-1), 6.32 (t,

IR (KBr): 3413, 3017, 2930, 2901, 2580, 2506, 2435, 2260, 1632,

1587, 1490, 1458, 1420, 1183, 1170 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 9.14 (s, 1 H, H-1), 4.12 (s, 2 H,

H-4), 3.19 [s, 6 H, NN(CH₃)₂], 2.94 [s, 6 H, N(CH₃)₂], 2.21 (d,

⁴J = 1.2 Hz, 3 H, H-5), 2.04 (s, 3 H, H-6).

¹³C NMR (125 MHz, CD₃OD): d = 166.2 (C-1), 141.3, 134.4 (C-2,

C-3), 60.9 (C-4), 46.9 [NN(CH₃)₂], 43.7 [N(CH₃)₂], 17.8 (C-5), 13.4

(C-6).

³J = 7.3 Hz, 1 H, H-3), 4.18 (d, ³J = 7.4 Hz, 2 H, H-4), 3.93 (m, 1 H,

3

H-5), 3.69 (dd, ³J = 10.4 Hz, J = 12.8 Hz, 2 H, H-6a, H-7a), 3.46

4

3

(dd, J = 4.5 Hz, J = 13.0 Hz, 2 H, H-6b, H-7b), 3.16 [s, 6 H,

NN(CH₃)₂], 3.00, 2.95, 2.93 (3 s, each 6 H, [N(CH₃)₂].

¹³C NMR (125 MHz, CD₃OD): d = 153.5 (C-1), 138.8 C-3), 128.5,

128.4 (C-2, C-5), 58.9 (C-6, C-7), 53.9 (C-4), 44.5 [NN(CH₃)₂],

42.1, 41.9, 41.8 [N(CH₃)₂].

HRMS (ESI): m/z calcd for [C₁₅H₃₃N₅]⁺: 284.2814; found:

284.2812.

MS (EI, 80 eV, 50 °C): m/z (%) = 183.2 (58, [M]⁺), 139.0 (100, [M

– C₂H₆N]⁺), 124.0 (51), 109.7 (17), 94.0 (64), 57.8 (58).

Anal. Calcd for C₁₅H₃₆Cl₃N₅: C, 45.86; H, 9.24; N, 17.83. Found:

C, 46.02; H, 9.35; N, 18.00.

HRMS (EI): m/z calcd for [C₁₀H₂₁N₃]⁺: 183.1736; found: 183.1734.

Anal. Calcd for C₁₀H₂₃Cl₂N₃: C, 46.88; H, 9.05; N, 16.40. Found:

C, 46.72; H, 9.59; N, 16.18.

(1E,2E)-4-Dimethylamino-3-methylbut-2-enal Dimethylhydra-

zone Monohydrochloride [(E)-12·HCl]

Böhme reagent 2-Cl (11.30 g, 120.0 mmol) and (1E,2E)-crotonal-

dehyde dimethylhydrazone (11;⁹9.57 g, 85.0 mmol) were reacted to

give (E)-12·HCl, which was recrystallized from i-PrOH; yield 5.10

g (29%); mp 150–154 °C (dec.).

(Z)-2-Dimethylaminomethylcyclohex-1-ene-1-carbaldehyde

Dimethylhydrazone Monohydrochloride [(Z)-17·HCl]

Böhme reagent 2-Cl (0.42 g, 4.5 mmol) and (1E)-cyclohex-1-ene-

1-carbaldehyde dimethylhydrazone (16;¹⁹0.46 g, 3.0 mmol) were

reacted at r.t. to give (Z)-17·HCl. The product was purified by re-

crystallization from i-PrOH; yield: 0.25 g (34%); colorless solid;

mp 165–175 °C (dec.).

IR (KBr): 3402, 2968, 2950, 2827, 2586, 2568, 2481, 1638, 1546,

1474, 1443, 1407, 1393, 1163, 1130 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 7.13 (d, ³J = 9.2 Hz, 1 H, H-1),

3

IR (KBr): 3498, 3437, 2929, 2857, 2671, 2506, 2514, 2484, 1624,

1540, 1467, 1430, 1404, 1170, 1128, 1038 cm^–1.

6.32 (d, J = 9.2 Hz, 1 H, H-2), 3.78 (s, 2 H, H-4), 2.93 [s, 6 H,

NN(CH₃)₂], 2.84 [s, 6 H, [N(CH₃)₂], 1.97 (s, 3 H, H-5).

Synthesis 2010, No. 20, 3556–3568 © Thieme Stuttgart · New York

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Aminomethylation on Vinylogous Aza-enamines

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¹H NMR (500 MHz, CD₃OD): d = 7.08 (s, 1 H, H-7), 3.87 (m, 2 H,

H-8), 2.94 [s, 6 H, NN(CH₃)₂], 2.88 [s, 6 H, N(CH₃)₂], 2.38 (m, 2 H,

H-3), 2.27 (m, 2 H, H-6), 1.70 (m, 4 H, H-4, H-5).

¹³C NMR (125 MHz, CD₃OD): d = 139.8 (C-7), 133.1, 124.8 (C-1,

C-2), 60.9 (C-8), 43.1 [N(CH₃)₂], 42.7 [NN(CH₃)₂], 32.0 (C-3), 28.5

(C-6), 23.6, 23.2 (C-4, C-5).

(1E,2E,4E)-6-Dimethylamino-5-methylhexa-2,4-dienal Dimeth-

ylhydrazone Monohydrochloride (23·HCl) and (1E,2E,4E)-6-

Dimethylamino-5-methylhexa-2,4-dienal Dimethylhydrazone

Dihydrochloride (23·2HCl)

Böhme reagent 2-Cl (0.94 g, 10.0 mmol) and (2E,4E)-hexa-2,4-di-

enal dimethylhydrazone (22;⁹0.69 g, 5.0 mmol) were reacted at r.t.

Product 23·HCl (0.30 g, 26%) precipitated as a colorless solid and

was collected by filtration. After the addition of DMF·HCl (0.44 g,

12.0 mmol) to the filtrate, the dihydrochloride 23·2HCl (0.32 g

(24%) was obtained as a colorless solid; overall yield: 50%.

MS (EI, 80 eV, 30 °C): m/z (%) = 209.3 (15, [M]⁺), 165.3 (100, [M

– C₂H₆N]⁺), 136.1 (14), 120.1 (14), 58.1 (19).

HRMS (EI): m/z calcd for [C₁₂H₂₃N₃]⁺: 209.1892; found: 209.1880.

23·HCl

Anal. Calcd for C₁₂H₂₄ClN₃: C, 58.64; H, 9.84; N, 17.10. Found: C,

58.25; H, 10.03; N, 16.89.

Purified by recrystallization from i-PrOH–MeOH (4:1); mp 155–

163 °C (dec.).

(1E,2Z)-4-Dimethylamino-3-phenylbut-2-enal Dimethylhydra-

zone Monohydrochloride [(Z)-19·HCl]

Böhme reagent 2-Cl (0.98 g, 10.5 mmol) and (1E,2E)-3-phenyl-

prop-2-enal dimethylhydrazone (18;¹⁹0.52 g, 3.0 mmol) were react-

ed at r.t. and the product obtained was recrystallized from i-PrOH;

yield: 0.31 g (39%); colorless solid; mp 150–155 °C (dec.).

IR (KBr): 3419, 2977, 2939, 2926, 2561, 2512, 2474, 2430, 1602,

1544, 1466, 1424, 1367, 1142, 1129, 976 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 7.15 (d, ³J = 9.0 Hz, 1 H, H-1),

6.63 (dd, ³J = 11.0 Hz, ³J = 15.0 Hz, 1 H, H-3), 6.45 (dd, ³J = 9.0

Hz, ³J = 15.0 Hz, 1 H, H-2), 6.36 (d, ³J = 11.0 Hz, 1 H, H-4), 3.76

(s, 2 H, H-6), 2.91 [s, 6 H, NN(CH₃)₂], 2.84 [s, 6 H, N(CH₃)₂], 1.93

(d, ⁴J = 0.9 Hz, 3 H, H-7).

¹³C NMR (125 MHz, CD₃OD): d = 136.7 (C-4), 136.0 (C-2), 135.2

(C-1), 127.7 (C-3), 127.2 (C-5), 66.8 (C-6), 43.1 [N(CH₃)₂], 42.8

[NN(CH₃)₂], 15.8 (C-7).

IR (KBr): 3412, 3078, 3055, 3015, 2954, 2886, 2858, 2821, 2681,

2663, 2587, 2518, 2487, 1615, 1571, 1541, 1497, 1478, 1446, 1162,

1128 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 7.56 (d, ³J = 7.5 Hz, 2 H, H-5),

7.44 (dd, ³J = 7.3 Hz, ³J = 7.7 Hz, 2 H, H-6), 7.37 (m, 2 H, H-1, H-

7), 6.83 (d, ³J = 8.9 Hz, 1 H, H-2), 4.55 (s, 2 H, H-8), 3.07 [s, 6 H,

NN(CH₃)₂], 2.86 [s, 6 H, N(CH₃)₂].

MS (EI, 80 eV, 40 °C): m/z (%) = 195.1 (93, [M]⁺), 151.1 (100, [M

– C₂H₆N]⁺), 136.1 (50), 108.4 (38), 58.2 (61).

¹³C NMR (125 MHz, CD₃OD): d = 140.6 (C-3), 136.0 (C-2), 130.4

(C-6), 129.3, 129.1 (C-1, C-7), 127.7 (C-5), 127.3 (C-4), 56.6 (C-8),

43.3 [NN(CH₃)₂], 43.0 [N(CH₃)₂].

MS (EI, 80 eV, 60 °C): m/z (%) = 231.0 (25, [M]⁺), 186.1 (71),

157.8 (50), 142.8 (38), 115.0 (90), 73.0 (37), 43.9 (100).

HRMS (EI): m/z calcd for [C₁₁H₂₁N₃]⁺: 195.1736; found: 195.1725.

Anal. Calcd for C₁₁H₂₂ClN₃: C, 57.00; H, 9.57; N, 18.13. Found: C,

56.55; H, 9.41; N, 18.05.

23·2HCl

Purified by recrystallization from i-PrOH–MeOH (4:1); mp 155–

163 °C (dec.).

HRMS (EI): m/z calcd for [C₁₄H₂₁N₃]⁺: 231.1736; found: 231.1734.

Anal. Calcd for C₁₄H₂₂ClN₃: C, 62.79; H, 8.28; N, 15.69. Found: C,

62.52; H, 8.14; N, 15.72.

IR (KBr): 3374, 2981, 2907, 2870, 2550, 2505, 2475, 2374 1619,

1581, 1485, 1455, 1419, 1194, 1186, 1150, 943 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 8.56 (d, ³J = 9.5 Hz, 1 H, H-1),

7.44 (dd, ³J = 11.2 Hz, ³J = 15.1 Hz, 1 H, H-3), 6.58 (d, ³J = 11.2

Hz, 1 H, H-4), 6.53 (dd, ³J = 9.5 Hz, ³J = 15.1 Hz, 1 H, H-2), 3.90

(s, 2 H, H-6), 3.14 [s, 6 H, NN(CH₃)₂], 2.88 [s, 6 H, N(CH₃)₂], 2.09

(d, ⁴J = 1.1 Hz, 3 H, H-7).

¹³C NMR (125 MHz, CD₃OD): d = 164.9 (C-5), 142.8 (C-1), 136.5

(C-3), 132.8 (C-4), 126.8 (C-2), 64.4 (C-6), 45.1 [NN(CH₃)₂], 42.2

[N(CH₃)₂], 15.1 (C-7).

(1E,2Z)-4-Dimethylamino-3-(4-nitrophenyl)but-2-enal Dimeth-

ylhydrazone Monohydrochloride [(Z)-21·HCl]

Compound 2-Cl (0.42 g, 4.5 mmol) and (1E,2E)-3-(4-nitrophe-

nyl)prop-2-enal dimethylhydrazone (20; 0.66 g, 3.0 mmol) were re-

acted at r.t. (Z)-21·HCl obtained was recrystallized from i-PrOH–

MeOH, 1:1); red solid; yield: 0.73 g (78%); mp 175–195 °C (dec.).

IR (KBr): 3421, 3190, 3112, 3091, 2904, 2867, 2809, 2627, 2602,

2528, 2496, 1921, 19115, 1829, 1597, 1574, 1506, 1488, 1205,

1184, 1171, 934 cm^–1.

¹H NMR (500 MHz, CD₃OD–CDCl₃): d = 8.23 (d, ³J = 9.0 Hz, 2 H,

H-6), 7.70 (d, ³J = 9.0 Hz, 2 H, H-5), 7.25 (d, ³J = 8.9 Hz, 1 H, H-

1), 7.04 (d, ³J = 8.9 Hz, 1 H, H-2), 4.54 (s, 2 H, H-8), 3.15 [s, 6 H,

NN(CH₃)₂], 2.85 [s, 6 H, N(CH₃)₂].

¹³C NMR (125 MHz, CD₃OD): d = 146.3 (C-3), 145.6 (C-7), 138.2

(C-2), 125.6 (C-5), 125.4 (C-1), 123.8 (C-6), 121.4 (C-4), 54.2 (C-

8), 41.9 [NN(CH₃)₂], 41.8 [N(CH₃)₂].

MS (EI, 80 eV, 50 °C): m/z (%) = 195.2 (90, [M]⁺), 151.1 (100, [M

– C₂H₆N]⁺), 136.2 (59), 108.4 (40), 58.2 (50).

HRMS (EI): m/z calcd for [C₁₁H₂₁N₃]⁺: 195.1736; found: 195.1729.

Anal. Calcd for C₁₁H₂₃Cl₂N₃: C, 49.26; H, 8.64; N, 15.67. Found:

C, 49.01; H, 8.33; N, 15.52.

(1E,2E)-3-[5-(Dimethylaminomethyl)furan-2-yl]prop-2-enal

Dimethylhydrazone Dihydrochloride [25·2HCl]

MS (EI, 80 eV, 90 °C): m/z (%) = 276.0 (55, [M]⁺), 231.8 (100, [M

Böhme reagent 2-Cl 0.56 g (6.0 mmol) in DMF (2 mL) and (2E)-3-

(furan-2¢-yl)prop-2-enal dimethylhydrazone (24;¹⁰0.50 g, 3.0

mmol) were reacted at r.t. The product obtained after the addition of

DMF·HCl (0.22 g, 6.0 mmol) was recrystallized from i-PrOH–

MeOH (3:1); yield: 0.34 g (38%); colorless solid; mp 160–172 °C

(dec.).

– C₂H₆N]⁺), 219.0 (88), 185.9 (41), 158.9 (18), 43.9 (56).

HRMS (EI): m/z calcd for [C₁₄H₂₀N₄O₂]⁺: 276.1586; found:

276.1577.

Anal. Calcd for C₁₄H₂₁ClN₄O₂: C, 53.76; H, 6.77; N, 17.91. Found:

C, 53.65; H, 6.53; N, 17.83.

IR (KBr): 3386, 3050, 2956, 2894, 2559, 2506, 2472, 1980, 1915,

1856, 1622, 1532, 1474, 1459, 1423, 1172, 1155, 1139, 1017 cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 8.40 (d, ³J = 9.0 Hz, 1 H, H-1),

7.26 (d, ³J = 15.7 Hz, 1 H, H-3), 6.90–6.83 (m, 3 H, H-2, H-5, H-

3566

M. T. Grabowski et al.

PAPER

6), 4.49 (s, 2 H, H-8), 3.14 [s, 6 H, NN(CH₃)₂], 2.91 [s, 6 H,

N(CH₃)₂].

HRMS (EI): m/z calcd for [C₁₅H₃₃N₅]⁺: 283.2736; found: 283.2725.

(1E,2E)-4-Dimethylamino-3-methyl-2-butenal Dimethylhydra-

zone [(E)-12]

NaOH (2.80 g, 70.0 mmol) and (E)-12·2HCl (7.26 g, 30.0 mmol) re-

acted to give 4.50 g (89%) of (E)-12 as an oil; bp 82–84 °C/3 mbar.

¹³C NMR (125 MHz, CD₃OD): d = 192.7 (C-7), 154.7 (C-4), 148.2

(C-1), 135.2 (C-3), 121.7, 118.5, 117.7 (C-2, C-5, C-6), 53.9 (C-8),

46.6 [NN(CH₃)₂], 43.3 [N(CH₃)₂].

MS (EI, 80 eV, 40 °C): m/z (%) = 221.1 (100, [M]⁺), 177.2 (88, [M

IR (KBr): 2973, 2941, 2853, 2814, 2767, 1987, 1979, 1970, 1846,

1645, 1557, 1470, 1454, 1440, 1425, 1378, 1259, 1177, 1155, 1133

cm^–1.

¹H NMR (500 MHz, CD₃OD): d = 7.27 (d, ³J = 9.3 Hz, 1 H, H-1),

6.06 (d, ³J = 9.3 Hz, 1 H, H-2), 2.92 (d, ⁴J = 2 Hz, 2 H, H-4), 2.85

[s, 6 H, NN(CH₃)₂], 2.19 [s, 6 H, N(CH₃)₂], 1.87 (d, ⁴J = 2 Hz, 3 H,

H-5).

– C₂H₆N]⁺), 132.0 (22), 106.9 (71), 94.9 (52), 58.0 (22).

HRMS (EI): m/z calcd for [C₁₂H₁₉N₃O]⁺: 221.1528; found:

221.1525.

Anal. Calcd for C₁₂H₂₁Cl₂N₃O: C, 48.99; H, 7.19; N, 14.28. Found:

C, 48.71; H, 7.06; N, 14.24.

Liberation of the Free Hydrazoneamines; General Procedure

The hydrochloride was dissolved in H₂O (10 mL) and the solution

was stirred and cooled in an ice bath. A solution of NaOH (2.80 g

in 10 mL H₂O) was added dropwise (see below for exact amounts).

The free base was extracted with Et₂O (3 × 5 mL), the combined or-

ganic phases were dried (MgSO₄), filtered, and the solvent removed

(Table 2). Exact masses support the elemental composition of the

free bases.

¹³C NMR (125 MHz, CD₃OD): d = 136.2 (C-3), 132.5 (C-1), 125.3

(C-2), 68.6 (C-4), 45.0 [N(CH₃)₂], 42.6 [NN(CH₃)₂], 15.2 (C-5).

MS (EI, 80 eV, 30 °C): m/z (%) = 169.2 (52, [M]⁺), 125.1 (100, [M

– C₂H₆N]⁺), 110.1 (25), 96.1 (30), 80.0 (40), 58.2 (59).

HRMS (EI): m/z calcd for [C₉H₁₉N₃]⁺: 169.1579; found: 169.1570.

Anal. Calcd for C₉H₁₉N₃: C, 63.89; H, 11.27; N, 24.84. Found: C,

63.67; H, 11.09; N, 24.57.

(1E,2Z)-4-Dimethylamino-2-methylbut-2-enal Dimethylhydra-

zone [(Z)-6]

NaOH (0.13 g, 1.5 mmol) and (Z)-6·HCl (0.21 g, 1.0 mmol) were

(1E,2E,4E)-6-Dimethylamino-5-methylhexa-2,4-dienal Dimeth-

ylhydrazone (23)

NaOH (0.25 g, 3.0 mmol) and (E)-23·2HCl (0.27 g, 1.0 mmol) re-

acted to give 0.18 g (92%) of 23 as a brown oil.

¹H NMR (500 MHz, CD₃OD): d = 7.07 (d, ³J = 9.0 Hz, 1 H, H-1),

6.55 (dd, ³J = 11.1 Hz, ³J = 15.1 Hz, 1 H, H-3), 6.32 (dd, ³J = 9.0

Hz, ³J = 15.1 Hz, 1 H, H-2), 6.03 (d, ³J = 11.1 Hz, 1 H, H-4), 2.88

[s, 6 H, NN(CH₃)₂], 2.84 (s, 2 H, H-6), 2.17 [s, 6 H, N(CH₃)₂], 1.82

(s, 3 H, H-7).

¹³C NMR (125 MHz, CD₃OD): d = 137.0 (C-5), 136.1 (C-1), 130.3

(C-2), 128.7 (C-3), 127.6 (C-4), 69.0 (C-6), 45.5 [N(CH₃)₂], 43.0

[NN(CH₃)₂], 15.8 (C-7).

reacted to give 0.15 g (90%) of (Z)-6 as a yellow oil.

¹H NMR (500 MHz, CDCl₃): d = 7.28 (s, 1 H, H-1), 5.49 (t, ³J = 7.0

3

Hz, 1 H, H-3), 3.09 (d, J = 7.0 Hz, 2 H, H-4), 2.87 [s, 6 H,

NN(CH₃)₂], 2.25 [s, 6 H, N(CH₃)₂], 1.91 (d, ⁴J = 1.0 Hz, 3 H, H-5).

¹³C NMR (125 MHz, CDCl₃): d = 135.3 (C-2), 131.7 (C-1), 125.6

(C-3), 55.8 (C-4), 45.1 [N(CH₃)₂], 42.7 [NN(CH₃)₂], 19.6 (C-5).

MS (EI, 80 eV, 40 °C): m/z (%) = 169.1 (30, [M]⁺), 125.1 (100, [M

– C₂H₆N]⁺), 110.3 (24, [M – C₃H₉N₂]⁺).

HRMS (EI): m/z calcd for [C₉H₁₉N₃]⁺: 169.1579; found: 169.1587.

MS (EI, 80 eV, 40 °C): m/z (%) = 195.1 (93, [M]⁺), 151.1 (100, [M

(1E,2E)-4-Dimethylamino-2-methylbut-2-enal Dimethylhydra-

zone [(E)-6]

NaOH (0.25 g, 3.0 mmol) and (E)-6·2HCl (0.24 g, 1.0 mmol) were

reacted to give 0.16 g (96%) of (E)-6 as a yellow oil.

– C₂H₆N]⁺), 136.1 (50, [M – C₃H₉N]⁺).

HRMS (EI): m/z calcd for [C₁₁H₂₁N₃]⁺: 195.1736; found: 195.1741.

2-Hydroxy-1,1-dimethyl-4-(4-nitrophenyl)-2,5-dihydro-1H-

pyrrolium Chloride (27)

¹H NMR (500 MHz, CDCl₃): d = 7.02 (s, 1 H, H-1), 5.60 (t, ³J = 7.0

3

Hz, 1 H, H-3), 3.12 (d, J = 7.0 Hz, 2 H, H-4), 2.83 [s, 6 H,

Compound 21·HCl (0.16 g, 0.5 mmol) was dissolved in a mixture

of H₂O (0.5 mL) and concd HCl (0.2 mL) and the solution stirred

for 3 h at r.t. Product 27 crystallized as a yellow colored solid. After

filtration it was washed with EtOH (0.3 mL) and Et₂O (0.3 mL),

dried in vacuo, and recrystallized from MeOH; yield: 0.13 g (96%);

mp 170–180 °C (dec.).

N(CH₃)₂], 2.26 [s, 6 H, N(CH₃)₂], 1.86 (d, ⁴J = 1.0 Hz, 3 H, H-5).

¹³C NMR (125 MHz, CDCl₃): d = 138.5 (C-1), 136.7 (C-2), 127.9

(C-3), 56.6 (C-4), 44.8 [N(CH₃)₂], 42.7 [N(CH₃)₂], 11.6 (C-5).

MS (EI, 80 eV, 50 °C): m/z (%) = 169.1 (32, [M]⁺), 125.1 (100, [M

– C₂H₆N]⁺), 110.3 (22, [M – C₃H₉N]⁺).

IR (KBr): 3108, 3076, 3014, 2796, 2641, 2570, 1656, 1595, 1514,

1469, 1411, 1348, 1323, 1309, 1268, 1163, 1106, 1047, 978, 904,

845, 828, 756, 736, 685 cm^–1.

HRMS (EI): m/z calcd for [C₉H₁₉N₃]⁺: 169.1579; found: 169.1578.

(1E,2Z)-2-[1,3-Bis(dimethylamino)propan-2-yl]-4-(dimethyl-

amino)but-2-enal Dimethylhydrazone [(Z)-10]

NaOH (0.50 g, 6.0 mmol) and 10·4HCl (0.43 g, 1.0 mmol) were re-

acted to give 0.28 g of 10 (quant) as a brown oil.

¹H NMR (500 MHz, CD₃OD): d = 7.16 (s, 1 H, H-1), 6.80 (t,

³J = 7.1 Hz, 1 H, H-3), 3.26 (quint, ³J = 7.3 Hz, 1 H, H-5), 3.05 (d,

³J = 7.1 Hz, 2 H, H-4), 2.78 [s, 6 H, NN(CH₃)₂], 2.36, 2.27 (2 dd,

³J = 8.1 Hz, ³J = 12.0 Hz; ³J = 6.9 Hz, ³J = 12.0 Hz, each 2 H, H-6),

2.16 [s, 6 H, N(CH₃)₂], 2.12 [s, 12 H, N(CH₃)₂].

¹³C NMR (125 MHz, CD₃OD): d = 140.2 (C-2), 130.6 (C-1), 125.4

(C-3), 63.5 (C-6), 56.1 (C-4), 45.8 (NMe₂), 45.2 [N(CH₃)₂], 42.5

[NN(CH₃)₂], 36.7 (C-5).

¹H NMR (400 MHz, D₂O): d = 8.13 (d, ³J = 9.0 Hz, 2 H, H-8), 7.61

(d, ³J = 9.0 Hz, 2 H, H-7), 6.57 (d, ⁴J = 1.6 Hz, 1 H, H-3), 6.00 (d,

4

⁴J = 1.3 Hz, 1 H, H-2), 4.71 (d, J = 1.9 Hz, 1 H, H-5a), 4.70 (d,

⁴J = 1.9 Hz, 1 H, H-5b), 3.31 (s, 3 H, NCH₃), 3.13 (s, 3 H, NCH₃).

¹³C NMR (125 MHz, D₂O): d = 148.0 (C-9), 138.6 (C-6), 137.0 (C-

4), 127.5 (C-8), 124.3 (C-7), 123.4 (C-3), 102.4 (C-2), 67.6 (C-5),

51.0 (NCH₃), 45.5 (NCH₃).

HRMS (EI): m/z calcd for [C₁₂H₁₅N₂O₃]⁺: 235.1077; found:

235.1048.

Anal. Calcd for C₁₂H₁₅ClN₂O₃: C, 53.24; H, 5.58; N, 10.35. Found:

C, 53.14; H, 5.51; N, 10.32.

MS (EI, 80 eV, 40 °C): m/z (%) = 283.2 (20, [M]⁺), 225.1 (20 [M –

C₃H₈N]⁺), 180.1 (76, [M – C₅H₁₅N₂]⁺).

PAPER

Aminomethylation on Vinylogous Aza-enamines

3567

Crystallography

pic thermal parameters [1.2 U_eq(C) and 1.5 U_eq(C) for methyl].

Anisotropic thermal parameters were applied to all non-hydrogen

atoms. Refinement for all structures on F²were achieved using the

SHELXL-97 system.²³Plots of the molecules were made using

ORTEP for Windows.²⁴The detailed crystal data and structure re-

finement information is provided in Table 3.²⁵

Crystals of (Z)-6·HCl, (Z)-10·4HCl, (E)-12·2HCl, (Z)-21·HCl, and

27 were grown by slow evaporation of the solvent from a saturated

MeOH solution of these compounds. The intensity data were col-

lected using a Bruker AXS Smart diffractometer at 133 K. The

structures were solved using direct methods (SHELXS-97).²³The

hydrogen atoms of were refined in calculated positions using isotro-

Table 3 Crystal Data and Structure Refinement

(Z)-6·HCl

C₉H₂₀ClN₃

205.73

(Z)-10·4HCl

C₁₅H₃₇Cl₄N₅

429.30

(E)-12·2HCl

C₉H₂₁Cl₂N₃

242.19

(Z)-21·HCl

C₁₄H₂₁ClN₄O₂

314.81

27

Empirical formula

C₁₂H₁₅ClN₂O₃

270.71

M

T [K]

133(2)

l [Å]

0.71073

monoclinic

P2₁/c

0.71073

monoclinic

P2₁/c

0.71073

triclinic

P1

0.71073

triclinic

P1

0.71073

monoclinic

P2₁/n

Crystal system

Space group

a [Å]

8.9770(18)

7.0794(15)

18.965(4)

90°

10.723(2)

11.961(3)

18.460(4)

90°

7.075(5)

8.224(5)

12.120(5)

104.332(5)°

105.651(5)°

94.739(5)°

649.4(7)

2

6.824(3)

7.589(4)

15.182(7)

87.897(12)°

81.134(11)°

85.203(10)°

773.9(6)

2

5.9292(7)

19.371(2)

10.7356(11)

90°

b [Å]

c [Å]

a

b

101.939(4)°

90°

103.190(5)°

90°

101.189(2)°

90°

g

V [Å³]

1179.2(4)

4

2305.2(8)

4

1209.6(2)

4

Z

r

_Calcd.[Mg/m³]

1.159

1.237

1.239

1.351

1.482

m [mm^–1]

0.289

0.522

0.472

0.258

0.317

F(000)

448

920

260

336

568

Crystal size [mm³]

q_max

0.59 × 0.44 × 0.15

30.51°

0.33 × 0.24 × 0.19

30.58°

0.44 × 0.39 × 0.08

30.53°

0.8 × 0.11 × 0.3

25.07°

0.50 × 0.31 × 0.13

26.43°

Index ranges

–12 £ h £ 12, –10 £ k –15 £ h £ 13 –17 £ k –10 £ h £ 10, –10 £ –8 £ h £ 8, –9 £ k £ –7 £ h £ 7, –24 £ k

£ 10, –21 £ l £ 27

£ 17 –26 £ l £ 18

k £ 11, –17 £ l £ 10 9, –15 £ l £ 18

£ 24, –13 £ l £ 11

Reflections collected

18718

29240

9839

8159

14356

Indep. refl./R_int

3563/0.0742

7026/0.0814

3857/0.0140

8159 twin refinement 2473/0.0291

no merging

Completeness to q_max

99.1%

none

99.1%

none

97.1%

none

98.3%

none

99.4%

Absorption correction

semi-empirical

from equivalents

Refinement method

Data/restraints/parameters

Goodness-of-fit on F²

R1/wR2 [I>2s(I)]

full-matrix least-squares on F²

3563/0/124

1.027

7026/0/225

3857/0/132

1.074

8159/0/195

1.123

2473/0/169

1.084

1.050

0.0405/0.1091

0.0430/0.1116

1.330/–0.602

0.0527/0.1468

0.0757/0.1609

1.482/–0.520

0.0246/0.0657

0.0272/0.0676

0.399/–0.203

0.0553/0.1558

0.0667/0.1635

0.416/–0.389

0.0414/0.1122

0.0447/0.1154

0.588/–0.412

R1/wR2 (all data)

Dr_max/Dr_min[eÅ^–3]

3568

M. T. Grabowski et al.

PAPER

(9) Severin, T.; Wanninger, G.; Lerche, H. Chem. Ber. 1984,

Acknowledgment

117, 2875.

We thank Dr. Boris Brusilowskij for continuous helpful discussions

and advice. Dr. Andreas Schäfer and Anja Peuker are acknowled-

ged for their help with numerous 1D and 2D NMR spectra. Funding

from the Deutsche Forschungsgemeinschaft (DFG) and the Fond

der Chemischen Industrie (FCI) is greatfully appreciated.

(10) Tolmachev, A. A.; Merkulov, A. S.; Yurchenko, A. A.;

Semenova, M. G.; Pinchuk, A. M. Russian Chem. Bull.

1998, 47, 1749.

(11) Mühlstädt, M.; Weber, L. Z. Chem. 1985, 25, 400.

(12) Orlewska, C.; Shaker, R.; Dees, M.; Otto, H.-H. Monatsh.

Chem. 2000, 131, 889.

(13) Brehme, R.; Enders, D.; Fernandez, R.; Lassaletta, J. M. Eur.

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(17) The ¹H NMR shift of the azomethine proton depends on the

protonation state of the hydrazone amino group. For

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nitrophenyl)prop-2-enal dimethylhydrazone (20) appears at

7.07 ppm, while it experiences a significant downfield shift

to 8.73 ppm upon protonation to 20·HCl.

(18) Mino, T.; Yamashita, M. J. Org. Chem. 1996, 61, 1159.

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(25) Crystallographic data (excluding structure factors) for the

structures reported in this paper have been deposited with the

Cambridge Crystallographic Data Centre as supplementary

publication numbers CCDC-725902 [(Z)-6·HCl], CCDC-

725903 [(Z)-10·4HCl], CCDC-725904 [(E)-12·2HCl],

CCDC-725901 [(Z)-21·HCl] and CCDC-780812 (27).

Copies of the data can be obtained free of charge on

application to CCDC, 12 Union Road, Cambridge CB2 1EZ,

UK [Fax: +44(1223)336033; e-mail:

deposit@ccdc.cam.ac.uk].

Article Doi

Aza-enamines XI.1 vinylogous aza-enamines as neutral d 3-nucleophiles: Aminomethylations of N,N-dimethylhydrazones of α,β-unsaturated aldehydes

DOI: 10.1055/s-0030-1258194

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