General multicomponent strategy for the synthesis of 2-Amino-l,4- diazaheterocycles: Scope, limitations, and utility

FULL PAPER

DOI: 10.1002/ejoc.200901360

General Multicomponent Strategy for the Synthesis of

2-Amino-1,4-diazaheterocycles: Scope, Limitations, and Utility

Volodymyr Kysil,*^[a]Alexander Khvat,^[a]Sergey Tsirulnikov,^[b]Sergey Tkachenko,^[a]

Caroline Williams,^[a][‡]Marina Churakova,^[b]and Alexandre Ivachtchenko^[a]

Keywords: Multicomponent reactions / Molecular diversity / Heterocycles / Lewis acids / Cyclization

Multicomponent reactions of primary 1,2- and 1,3-diamines

with carbonyl compounds and isocyanides resulting in the

formation of diverse 2-amino-1,4-diazaheterocycles are de-

scribed. Lewis acids (LAs) promote the reactions effectively,

and chlorotrimethylsilane (TMSCl) has been found to be a

promoter of choice. The scope and limitations of the reactions

with regard to each of the components are evaluated and

discussed. Post-IMCR modifications of the synthesized het-

erocycles have been elaborated.

linear, dipeptide-like scaffold with vast molecular diversity

arising from easily accessible components. Obviously, the

Ugi IMCR would not be so successful had multiple strate-

gies for the synthesis of various heterocyclic scaffolds not

been developed and introduced. In particular, one impor-

tant application of the Ugi reaction is based on the employ-

ment of bifunctional reagents bearing two of four function-

alities of the Ugi ensemble, with intramolecular IMCR as-

suring heterocyclic ring formation.

Another promising way to extend the utility of the

IMCRs involves “nonclassical” functionalities, leading to

new IMCRs.^[4]One good illustration of the efficiency of this

approach is the introduction of aminoazaheterocycles as bi-

functional reagents into reactions with aldehydes and isocy-

anides, first reported simultaneously by Blackburn’s^[5]and

Groebke’s^[6]groups and somewhat later by Bienaymé and

co-authors^[7](Scheme 1, a). Despite the facts that only the

annulated 3-aminoimidazoles 1 can be synthesized by this

strategy and that only aldehydes and not ketones have been

shown to be successful starting materials,^[6]the vast utility

of this reaction has been confirmed by the number of subse-

quent publications and by the multiple-thousand-member

focused libraries of fused aminoimidazoles that have been

successfully synthesized by use of this reaction.^[2a,8]

On the other hand, introduction of the 1,2- or even 1,3-

diazanucleophiles 2 (Scheme 1, b) into such IMCRs might

represent a possible route to the various amino(imino)aza-

heterocycles 3. Nevertheless, only limited data relating to

IMCRs of 1,2- and 1,3-diazabinucleophiles had been pub-

lished at the time we started our own research in this field.

InCl₃-catalyzed IMCRs of 2-aminomethylpyridine with al-

dehydes and isocyanides followed by spontaneous oxidation

produced the pyrido[1,2-a]pyrazines 4 (Scheme 1, c),^[9–11]

whereas recently published^[12]reactions between the pro-

line-based tetrazoles 5, aliphatic aldehydes, and isocyanides

Introduction

The discovery and development of new scaffolds for drug

discovery is a supremely important current application of

heterocyclic chemistry. Medicinal chemistry as a discipline

applies specific restrictions on the compounds that may be

used in the field. So-called “drug-likeness” and “lead-like-

ness” rules have been developed to reduce the time and ef-

fort spent on discovery of new drug candidates.^[1]Key

requirements for newly synthesized compounds include low

molecular weight, non-reactivity, water solubility, a specific

number of H-bond donors and acceptors, and – of course –

the potential for convenient modification of the molecular

core decoration. In view of this, the development of new

synthetic strategies to access scaffolds that meet these

requirements is one of the top priority tasks for synthetic

and medicinal chemists. Furthermore, such strategies are

more valuable if they allow scaffold diversity rather than

compound diversity.

During the past decade, isocyanide-based multicompo-

nent reactions (IMCRs) have attracted significant interest

within the scientific community as an efficient, convenient,

time-saving, and atom-economical approach to a variety of

heterocyclic molecules.^[2]The best example of success in this

field is the Ugi reaction.^[3]The “classic” Ugi ensemble, con-

sisting of a carbonyl compound, an amine, a carboxylic

acid, and an isocyanide, is in fact able to provide only one

[a] ChemDiv, Inc.,

6605 Nancy Ridge Dr., San Diego, California 92121, USA

Fax: +1-858-794-4931

E-mail: vkysil@chemdiv.com

[b] Chemical Diversity Research Institute,

Khimki, Moscow Reg. 114401, Russia

[‡] Current address: Roche Palo Alto LLC 3431 Hillview Avenue,

Palo Alto, CA 94304, USA

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org/ or from the author.

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the existing secondary amino groups in the 1,4-diazahetero-

cycle and in the amidine moiety. It should be noted that,

simultaneously with our publications, TsOH-catalyzed

MCRs of 2,3-diaminomaleonitrile with ketones and isocy-

anides were proposed for the synthesis of 6,6-disubstituted

1,6-dihydropyrazin-2,3-dicarbonitriles.^[17]In addition, two

more publications^[18,19]describing Brønsted-acid-catalyzed

IMCRs of 1,2-phenylenediamines with carbonyl com-

pounds appeared while this manuscript was in preparation.

In view of the growing synthetic interest in IMCRs of di-

amines, and of the opportunities that these IMCRs might

provide as a promising strategy for the synthesis of privi-

leged heterocycles containing 2-aminopyrazine,^[20–22]2-

aminoquinoxaline,^[23]and other related aminoazahetero-

cyclic cores, we report here the scope, limitations, exten-

sions, and some subsequent applications of the discovered

IMCRs.

Results and Discussion

Evaluation of Promoters and Optimization of Reaction

Conditions

From the mechanisms of known IMCRs, the most prob-

able scenario for the 4C-3CR of a 1,n-diamine 8, a carbonyl

compound, and an isocyanide can be surmised to be a

multi-step sequence as shown in Scheme 2. The azomethyne

9, formed in the first step of the reaction, is able to exist in

equilibrium with the corresponding cyclic aminal 10.^[24]

Scheme 1. Aza-dinucleophiles in IMCRs.

afforded the annulated pyrazine- and 1,4-diazepine-imines Each of these ring–chain tautomeric forms is able to react

6 (Scheme 1, d) with no catalyst required, probably due to with nucleophiles – in our case an isocyanide – and acti-

the high N–H acidity of the tetrazole ring. Also worth men- vation of both is required for the reaction to proceed. The

tioning is the synthesis by Keung et al.^[13]of highly substi- activated intermediates 11 and 12 should convert into the

tuted 2-aminoamidines through Sc(OTf)₃-mediated “linear” same intermediate 13, which upon intramolecular cycliza-

four-component reactions of aldehydes, isocyanides, and tion might yield the imine 14 or the tautomeric amine 15.

two equiv. of amines. N,NЈ-Dimethylethylenediamine Importantly, the cation 13 could be trapped by any nucleo-

proved to be a successful starting material in place of two phile existing in the reaction mixture, including the starting

equiv. of amine in an intramolecular three-component vari- isocyanide^[25]or available amines, which would yield a

ant of this reaction^[14](Scheme 1, e), but the only example number of high-molecular-weight products. Therefore, ulti-

reported was the piperazin-2-imine 7. Like the Groebke– mate reaction success should be highly dependent on the

Blackburn–Bienamé reaction, the above-mentioned four- right choice of promoter, which should efficaciously acti-

center three-component reactions (4C-3CRs) have an obvi- vate intermediates 11 and 12 and stabilize cation 13. We

ous limitation relating to their carbonyl components: only thus initially evaluated possible additives for the reaction

aldehydes, but not ketones, have been reported as successful performance.

starting materials. In addition, the heavily substituted pyr-

After thorough investigation of the literature precedents

azin-/piperazinimines obtainable by these 4C-3CRs are un- for catalysis of reactions of isocyanides, we created a short

suitable for further modifications. It was thus thought that list of potential promoters that might be useful for our pur-

these limitations might be overcome through the use of pri- poses. To evaluate additive activity, we used a model reac-

mary 1,2- and 1,3-diamines in IMCRs.

tion involving tert-butyl isocyanide, N-benzylpiperidin-4-

In our recent short communications,^[15]we have reported one, and trans-cyclohexane-1,2-diamine (Table 1). Both

our preliminary results relating to new IMCRs of primary carbonyl and diamine components are easily detectable

diamines with carbonyl compounds and isocyanides leading either by ESI-MS or by evaporative light-scattering detec-

to partially hydrogenated pyrazin-2-amines and 1,4-di- tion (ELSD) methods, allowing the reaction to be moni-

azepin-2-amines.^[16]Importantly, application of these newly tored by LC-MS analysis.

discovered IMCRs to various diamino and carbonyl com-

Sc(OTf)₃and Yb(OTf)₃were examined as Lewis acids

ponents might provide access to a great number of new (LAs, Table 1, entries 1 and 2) because of their established

amino-azaheterocyclic cores. Moreover, these scaffolds activity in the amino amidine synthesis discussed above. We

should be amenable to subsequent modifications, thanks to also paid attention to silicon LAs (SLAs), the ability of

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Multicomponent Strategy for 2-Amino-1,4-diazaheterocycles

icantly stronger base than the starting diamines and can

bond with the LA efficiently, therefore reducing its activity.

Therefore, two experiments with 1 and 2 equiv. of TMSCl

were set up (Table 1, entries 7 and 8). Finally, two more test

experiments, with a Brønsted acid (HCl, Table 1, entry 9)

and with no additives (Table 1, entry 10), were attempted.

Indeed, no reaction was observed in the absence of addi-

tives (Table 1, entry 10) whereas all the evaluated additives

demonstrated reactivity in the investigated IMCR to vari-

able extents. TBSOTf and metal triflates (Table 1, entries 1–

3) showed moderate activity, whereas silyl chlorides proved

to be less suitable as catalysts. In contrast, the TBSOTf/

Yb(OTf)₃system (Table 1, entry 6) demonstrated the best

catalytic activity. However, all of the reactions were ac-

companied by the formation of high-molecular-weight by-

products when LAs were used as catalysts. To our satisfac-

tion, side reactions were suppressed when the quantity of

TMSCl was increased to 1 equiv. (Table 1, entry 7). This es-

sentially improved the reaction outcome in terms of the

yield and purity of the target compound. Interestingly, fur-

ther increases in TMSCl concentration (Table 1, entry 8)

somewhat reduced the yield of target material. Although a

protic solvent was used for this evaluation, it seems that

TMSCl itself, and not HCl (resulting from its hydrolysis),

is the actual and effective promoter of the reaction. At least,

the HCl-promoted reaction (Table 1, entry 9) produced a

mixture of several unidentified by-products that made isola-

tion of the target compound 16 problematic. Isolated yields

for the most successful entries (entries 6–8) were in good

agreement with those observed by LC-MS analysis of the

reaction mixtures.

Scheme 2. Scenario for reactions of diamines with isocyanides and

carbonyl compounds.

Table 1. The MCR of trans-cyclohexane-1,2-diamine, N-benzylpip-

eridin-4-one, and tBuNC in the presence of additives.^[a]

From these results, the conditions of entry 7 (Table 1)

were chosen for further protocol optimization with ethyl-

enediamine as a diamine component. For this purpose, a

series of reactions with benzyl isocyanide and both tetra-

Entry

Promoter

mol-%

Yield^[b][%]

1

2

3

4

5

6

7

8

9

10

Yb(OTf)₃

Sc(OTf)₃

TBSOTf

TBSCl

TMSCl

TBSOTf/Yb(OTf)₃

TMSCl

HCl (8  solution in dioxane) 100

none

20

54

64

55

34

hydro-4H-pyran-4-one

and

4-isopropylbenzaldehyde

(Scheme 3) were carried out under various sets of reaction

conditions. Aprotic solvents such as chloroform or acetoni-

trile, which seem to be preferable for the performance of

SLA-promoted reactions, proved to be inefficient because

of formation of insoluble ethylenediamine or intermediate

azomethyne salts. This reduced the reaction rates and

20

38

20/20

100

200

81 (55)^[c]

91 (78)^[c]

89 (67)^[c]

64

–

traces

[a] For details see the Exp. Sect. [b] Yields were determined by LC- caused formation of several high-molecular-weight by-

MS (ELSD) of the reaction mixtures. [c] Isolated yields.

products. In contrast, alcohols and especially methanol

demonstrated the best results. Furthermore, water produced

during azomethyne formation did not interfere with the

which to activate C=O and C=N bonds for catalyzed ad- IMCR process, and its removal was not necessary unless

ditions to C-nucleophiles,^[26]including isocyanides,^[27]is required for azomethyne formation with carbonyl com-

well documented. tert-Butyl(dimethyl)silyl trifluorome- pounds of low reactivity. Simple chromatography-free

thanesulfonate (TBSOTf), tert-butyl(chloro)dimethylsilane workup procedures furnished the monohydrochlorides of

(TBSCl), and chlorotrimethylsilane (TMSCl) were thus se- the target aminopyrazines 17 and 18 in high yields and with

lected as potential promoters of this reaction (Table 1, en- high degrees of purity.

tries 3–5). Because combinations of SLAs with Yb(OTf)₃

In summary of our observations, the following advan-

are able to promote reactions between azomethynes and π- tages of employing 1 equiv. of TMSCl as a promoter of

C-nucleophiles much more effectively than these LAs by choice are:

themselves,^[28]we also examined the TBSOTf/Yb(OTf)₃sys- – highest yields of target products,

tem (Table 1, entry 6). We also realized that the amidine – cleanness of the IMCR allows chromatography-free isola-

functionality formed during the IMCR is normally a signif- tion,

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Scheme 3. IMCRs of ethylenediamine with carbonyl compounds.

– simple workup and isolation procedures,

reaction might be minimized by employing oxygen-free con-

– controlled formation of pharmacologically acceptable ditions. In addition, reduced yields in the cases of aldehydes

monohydrochlorides of target compounds,

with π-excessive heterocyclic nuclei (Table 2, rows 12–14)

– low cost and availability of the promoter,

can be explained by partial oligomerization, which was sup-

– adaptability of the protocol to both parallel and scale-up pressed in the cases of morpholino- and pyridino-substi-

synthesis, tuted isocyanides (Table 2, columns E and F). Furthermore,

– utilization of metal-free conditions avoids residual metal these isocyanides demonstrated good results for all of the

contamination in target compounds, an important con- tested carbonyl compounds, including the previously men-

sideration for medicinal chemistry.^[29]

tioned poorly reactive tetralones. This observation, which is

consistent with the concept of Lewis base acceleration of

SLA-promoted reactions of isocyanides,^[27,30]could be the

subject of further investigation directed towards IMCR per-

IMCRs of Ethylenediamine

With the optimized protocol for the IMCR to hand, we formance improvement.

further evaluated the scope of the reactions of ethylenedi-

To evaluate the preparative value of the IMCRs, some of

amine with a set of eight isocyanides and 16 carbonyl com- these and a dozen more reactions were performed at 0.5

pounds, including ketones (Table 2, rows 1–6) and both aro- and/or 10 mmol scales (General procedures A and B,

matic (Table 2, rows 7–9) and heteroaromatic (Table 2, respectively; see Exp. Sect.). The results of these experi-

rows 10–16) aldehydes with a widely variable nature of sub- ments are summarized in Table 3. The majority of the reac-

stitution including highly electron-donating (Table 2, tions furnished the target compounds in at least good iso-

rows 7, 12–15) and electron-withdrawing (Table 2, rows 8, lated yields in spite of the employment of a general pro-

10, 11) (hetero)aromatic nuclei. The experiment was de- cedure that was not optimized for specific sets of starting

signed in full-matrix parallel synthesis format, 128 reactions components. To our satisfaction, aliphatic aldehydes proved

in total, at 0.1 mmol scale. Yields of all the reactions were to be suitable for the IMCRs (Table 3, entries 6–8). Interest-

determined by LC-MS analysis with use of ELSD by calcu- ingly, formation of side-products was usually less (by LC-

lation of the peak with the expected [M + H] value for the MS analysis) when the same reactions were performed in a

product area versus the total peak areas. The results of this scaled-up format. No oxidation products were observed

experiment are summarized in Table 2.

when pyridinecarbaldehydes were used, for instance, and

To our satisfaction, the majority of the reactions were the reaction of pyrrole-2-carbaldehyde also proceeded

successful, with either high (74 reactions furnished 80% cleanly. Small amounts of ethylenediamine hydrochloride

yields or more of target compounds) or moderate (40 reac- were only a non-critical impurity of the crude isolated prod-

tions furnished 30–79% yields of target compounds) yields. ucts in some cases. This impurity was easily removed on

Only 11% of the reactions failed to provide reasonable transformation of the initially formed hydrochlorides into

amounts of target compounds (yields less than 20%), with the free bases by standard procedures. Although yields of

the majority of these involving 2-tetralone and 6-methoxy- the free bases were somewhat lower, the obtained products

1-tetralone (Table 2, rows 5, 6). The rest of the cyclic did not require any additional purification.

ketones demonstrated high reactivity. Furthermore, all the

In summary of the results for the tested ethylenediamine

aldehydes proved to be very reactive, and most often no IMCRs, it is important to note that the reactions are appli-

signs of starting materials were detected in the reaction mix- cable for a wide range of isocyanides and – more import-

tures. However, somewhat lower yields of target compounds antly – carbonyl compounds such as ketones and a wide

were caused by some minor formation of by-products. Oxi- variety of aldehydes. Both electron-rich and electron-poor

dation products detectable in the LC-MS as their molecular aldehydes reacted smoothly, as did the sterically hindered

ions [M – 2 + H]⁺, where M is the molecular weight of the pivalaldehyde or the easily enolized acetaldehyde. It appears

target product, were the most frequently occurring impuri- that additional functionalities in the carbonyl component

ties, especially in the case of pyridine-4-carbaldehyde have limited or no effect. For example, the o-hydroxy group

(Table 2, row 10). These by-products were the results of oxi- in 3-ethoxy-2-hydroxybenzaldehyde does not affect reaction

dation of the C(3)–N(4) bonds (see below), and this side success (Table 3, entry 9).

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Multicomponent Strategy for 2-Amino-1,4-diazaheterocycles

Table 2. Evaluation of the scope of IMCRs of ethylenediamine with various carbonyl compounds and isocyanides.^[a]

[a] For details see the Exp. Sect.

IMCRs of (Hetero)aromatic 1,2-Diamines

lent results and furnished the target 3,4-dihydroquin-

oxalin-2-amine hydrochlorides 19 in high yields

We next examined the developed conditions with respect (Scheme 4). A representative set of spiro-quinoxaline

to 1,2-phenylenediamine as a diamine component. Its re- compounds synthesized in this manner is shown in

actions with ketones and isocyanides demonstrated excel- Table 4 (entries 1–5).

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Table 3. Synthesis of various 3,4,5,6-tetrahydropyrazin-2-amines through IMCRs of ethylenediamine.

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Multicomponent Strategy for 2-Amino-1,4-diazaheterocycles

Table 3. (Continued).

[a] These compounds were not completely characterized because of contamination with tert-butylamine hydrochloride [about 10–15 mol-

%: 8.2 (br. s) and 1.2 (s) in 1:3 ratio in ¹H NMR spectra]. See the Exp. Sect. for attempted isolation in the forms of the free bases

(synthesis of the 5,6-dihydropyrazine-2-amines 33 and 34).

3-arylquinoxalin-2-amines in moderate yields through the

employment of an IMCR/2,3-dichloro-5,6-dicyano-1,4-

benzoquinone (DDQ) oxidation sequence in one-pot mode.

In view of this, the most recently published results^[32]ap-

pear unexpected: the same reaction in the presence of cata-

lytic amounts (20 mol-%) of Fe(ClO₄)₃, which is a strong

oxidizing agent, led directly to aromatic 3-arylquinoxalin-

2-amines in excellent isolated yields (91–93%). On the other

hand, TsOH-promoted IMCRs were shown to be effective

for the synthesis of 3-aryl-3,4-dihydroquinoxalin-2-

amines,^[17]but only 1,2-phenylenediamines bearing strongly

electron-withdrawing Ar groups were reported to be able to

produce these products. This can be interpreted in terms of

slow formation of the dihydroimidazole ring, so isocyanide

is allowed to react with azomethyne directly, even though

the corresponding 2,3-dihydro-1H-benzimidazoles, which

should be less sensitive to oxidative processes than their un-

substituted analogues, are formed during the reaction.

Therefore, less electron-rich aromatic 1,2-diamines such as

some heterocyclic diamines, instead of 1,2-phenylenedi-

amine, might be more successful candidates for IMCRs

withaldehydes.Indeed,asatestcase,[1,2,5]oxadiazole-3,4-di-

Scheme 4. Reactions of 1,2-phenylenediamine with carbonyl com-

pounds and isocyanides.

At the same time, attempted reactions with (un)substi-

tuted benzaldehydes failed to provide the desired com-

pounds. From the LC-MS analysis data for the reaction

mixtures, the target quinoxalin-2-amines 20 proved to be

minor products whereas 2-aryl-1H-benzimidazoles 21 were

dominant. The formation of the 2-aryl-2,3-dihydro-1H-

benzimidazolines 22 was followed by oxidation to the 2-

aryl-1H-benzimidazoles 21 as a lower-energy process.

TMSCl was able to play a role as a promoter in this reac-

tion, as previously reported.^[31]Interestingly, all of our

attempts to avoid oxidative processes, which included spe-

cial purification of the 1,2-phenylenediamine, employment

of oxygen-free conditions, and/or use of antioxidant addi-

tives (hydroquinone, p-methoxyphenol, thiophenol, etc.)

were also unsuccessful. It should be noted in this context

that the same oxidative side reactions were observed in the

HCl-promoted IMCRs of 1,2-phenylenediamine with alde-

Scheme 5. Reactions of [1,2,5]oxadiazole-3,4-diamine with alde-

hydes.^[18]Nevertheless, those authors were able to isolate hydes and isocyanides.

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Table 4. Synthesis of fused dihydropyrazin-2-amines through IMCRs.

amine reacted smoothly with different aldehydes and iso- IMCRs of Propane-1,3-diamine and Carbonyl Compounds

cyanides to provide the 6,7-dihydro[1,2,5]oxadiazolo[3,4-b]

pyrazin-5-amines 23 in high yields (Scheme 5). The results Inspired by the success of the IMCRs of 1,2-diamines, we

of these reactions are shown in Table 4 (entries 6–9).

further extended our studies to propane-1,3-diamine. Its re-

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Multicomponent Strategy for 2-Amino-1,4-diazaheterocycles

actions might provide tetrahydro-1,4-diazepine-2-amines, ticularly useful in the design of peptide secondary structure

the core of which is undoubtedly a privileged structure, par- mimetics.^[33]With this hope in mind, we examined the reac-

tion between propane-1,3-diamine and cyclohexanone

(Scheme 6; Table 5, entries 1–4). In comparison with the

IMCRs of 1,2-diamines, propane-1,3-diamine required

somewhat elevated temperatures and increased reaction

time for the reactions to go to completion.

To verify the applicability of the carbonyl compounds,

two more ketones (tetrahydro-4H-thiopyran-4-one and N-

Scheme 6. IMCRs of propane-1,3-diamine with cyclohexanone and

Boc-piperidin-4-one) and two aldehydes (p-methoxybenzal-

various isocyanides.

Table 5. Synthesis of 1,4-diazepine-2-amines through IMCRs of propane-1,3-diamine.

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Scheme 7. IMCRs of propane-1,3-diamine with cyclohexyl isocyanide and various carbonyl compounds.

dehyde and 1-methylpyrrole-2-carbaldehyde) were allowed The spiro compound 28 (Scheme 9), synthesized from ethyl-

to react with propane-1,3-diamine and cyclohexyl isocy- enediamine, N-Boc-piperidin-4-one, and TMB-NC, for in-

anide (Scheme 7). We were pleased to find that all of these stance, underwent cleavage of both Boc and TMB groups

reactions proceeded cleanly, providing the target 1,4-diazep- when it was treated with HBr/AcOH at elevated tempera-

ine-2-amines 25 and 26 in good yields (Table 5, entries 5– tures with the formation of spiro compound 29 in almost

10).

quantitative yield. Furthermore, we were able to carry out

Although sterically hindered 1,1,3,3-tetramethylbutyl step-by-step selective cleavage of the Boc group by standard

(TMB) isocyanide reacted smoothly and cleanly with pro- protocols (either TFA/CH₂Cl₂or HCl/EtOH/EtOAc),

pane-1,3-diamine and both tetrahydro-4H-thiopyran-4-one which provided compound 30 in high yield, with subse-

and 1-methylpyrrole-2-carbaldehyde, providing almost quent cleavage of the TMB group furnishing compound 29.

quantitative formation (LC-MS monitoring results) of the A remarkably similar mode has been used for the synthesis

target diazepine-2-amines, the isolated yields subsequently of 3-aminoimidazo[1,2-a]pyri(mi)dines containing primary

proved to be only moderate (Table 5, entries 9 and 10), amino groups, derived from N-TMB derivatives obtainable

probably because of high solubilities of their hydrochlorides from the Groebke–Blackburn–Bienamé reaction.^[34]Clearly,

in organic solvents, resulting in losses during water-free iso- such a synthetic approach to tetrahydropyrazin-2-amines

lation.

containing primary amino groups in their amidine moieties

could open a window of opportunity for promising modifi-

cations of these scaffolds by annulation of other azahetero-

cycles.

Subsequent Modifications of the Synthesized Scaffolds

The high variability of the components potentially utiliz-

able in these IMCRs paves the way for the successful syn-

thesis of highly diverse and unique aminoheterocyclic scaf-

folds, including fused and spirocyclic systems. Furthermore,

each of the synthesized scaffolds contains a secondary

amino group – a potential site for introduction of one more

point of diversity. Scaffold diversity can be significantly

broadened by employment of IMCR components bearing

additional functionalities such as phenolic hydroxy

(Table 3, entry 9; Table 4, entries 8, 9) or methoxycarbonyl

(Table 4, entry 3) groups. Obviously, the Boc/de-Boc strat-

egy can also serve this purpose. For instance, three spiro-

piperidines each with a secondary amino group in the pi-

peridine moiety were synthesized at 0.2 mol scale by a one-

pot procedure (Scheme 8).

Scheme 9. Selective and nonselective cleavage of Boc and TMB

groups.

Partial dehydrogenation and full aromatization of the di-

hydropyrazine ring could represent another route for post-

IMCR modifications of obtainable scaffolds. Thus, the

Scheme 8. Large-scale synthesis of deprotected spiro-piperidines.

Frequent use of TMB isocyanide as an isocyanide com- crude products obtained when we tried to isolate the free

ponent has been fruitful in our work. Besides being the bases of the 2- and 4-pyridyl-substituted tetrahydropyr-

most sterically hindered of the isocyanides used during the azines 31 and 32 from their HCl salts (Table 3, entries 15

evaluation of the scope of the IMCRs, this isocyanide was and 17) proved to be mixtures of the target materials and

also able to serve as a synthetic equivalent of cyanide anion the oxidized products 33 and 34 (Scheme 10), respectively,

1

(or hypothetical isocyanide HNC) in this type of IMCR. as was confirmed by LC-MS and H NMR analyses. Com-

1534

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Eur. J. Org. Chem. 2010, 1525–1543

Multicomponent Strategy for 2-Amino-1,4-diazaheterocycles

plete oxidation was achieved by simply stirring their solu- tified as a promoter of choice.^[35]Originally developed for

tions in CHCl₃overnight in open vials, thus providing the a limited set of components, the protocol for the perform-

dihydropyrazines 33 and 34.

ance of the IMCRs and isolation of the target materials

has been successfully applied to a great variety of diamines,

carbonyl compounds, and isocyanides. Therefore, the iso-

lated yields listed could be significantly improved by proto-

col optimization for specific sets of the components. The

developed IMCRs can be performed over a wide range of

scales starting from 0.1 mmol (in parallel synthesis format)

up to multimol loading. Some synthetically useful post-

IMCR modifications of the generated scaffolds such as Boc

and TMB removal, partial dehydrogenation, and full aro-

matization have been outlined.

Scheme 10. Partial dehydrogenation and aromatization of the dihy-

dropyrazine ring.

As was shown in the case of the 4-pyridyl derivative 34,

further oxidation of the dihydropyrazine ring to form the

Experimental Section

aminopyrazine 35 can be achieved by employing DDQ. General: Commercially available reagents (ethylenediamine, trans-

cyclohexane-1,2-diamine, 1,2-phenylenediamine, 1,2,5-oxadiazole-

3,4-diamine, isocyanides, carbonyl compounds, LAs listed in the

article) and solvents were employed without purification. ¹H and

¹³C NMR spectra, including Attached Proton Test (APT) NMR

spectra, at 400 and 100 MHz, respectively, were recorded with a

Varian Unity+ spectrometer; chemical shifts are reported in ppm

with use of TMS as internal standard in CDCl₃or [D₆]DMSO. The

following abbreviations are used in NMR spectra descriptions: s =

singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br =

broad, Ar = aryl, Py = pyridyl, Pyr = pyrrolyl, iPr = isopropyl,

and exch. D₂O = exchange with D₂O. IUPAC nomenclature is used

for atom numbering; see compound names to refer to position

numbers. HR mass spectra (ESI-TOF, positive) were obtained with

an Agilent ESI-TOF 6210 mass spectrometer.

Moreover, this compound can be synthesized directly from

the tetrahydro derivative 32 when heated under reflux in 2-

methoxyethanol in the presence of Pd/C. Therefore, an

IMCR/aromatization sequence can serve as a convenient

route to a variety of synthetically challenging 3-(het)aryl-

pyrazin-2-amines.

Conclusions

MCRs of 1,2- and 1,3-diamines with carbonyl com-

pounds and isocyanides have been developed as direct and

convenient routes to a variety of heterocycles containing 2-

aminopyrazine and 2-amino-1,4-diazepine cores, including

related benzo-, hetareno-, and spiro-fused systems. In its

scope, this IMCR approach has been shown to be accept-

able for a wide range of carbonyl compounds including

ketones and aliphatic, aromatic, and heterocyclic aldehydes

with both electron-donating and electron-withdrawing sub-

stituents. The scaffold diversity obtainable by this IMCR

approach is demonstrated by the structural variability of

the components capable of participating in these developed

IMCRs. Amino derivatives of fourteen heterocyclic systems

(pyrazine, 1,4-diazaspiro[5.5]undec-4-ene, 9-oxa-1,4-diaza-

Purities of all synthesized compounds (more than 98% unless

otherwise specified) were confirmed by LC-MS analysis performed

with a Shimadzu HPLC instrument with PE SCIEX API 150EX

mass-, Alltech 2056 ELS-, and Shimadzu UV- (254 and 215 nm)

detectors. Separation was achieved with

a

Phenomenex

Luna 3µ C18 (4.6ϫ150 mm) column with use of a gradient (5–

95%) of acetonitrile in water both with 0.05% TFA over 12 min at

0.8 mLmin^–1.

General Procedures for the MCRs of Diamines, Carbonyl Com-

pounds, and Isocyanides

Evaluation of Promoters’ Activities – Synthesis of (4aЈS,8aЈS)-/

(4aЈR,8aЈR)-1-Benzyl-N-tert-butyl-4aЈ,5Ј,6Ј,7Ј,8Ј,8aЈ-hexahydro-

1ЈH-spiro[piperidine-4,2Ј-quinoxalin]-3Ј-amine (16): A mixture of

trans-cyclohexanediamine (1.14 g, 10 mmol) and N-benzylpiper-

idin-4-one (1.89 g, 10 mmol) in CHCl₃(15 mL) was heated under

reflux for 2 h, volatile components were evaporated, a fresh portion

of CHCl₃(10 mL) was added, the solvent was evaporated to dry-

spiro[5.5]undec-4-ene,

1,4,8-triazaspiro[5.5]undec-4-ene, spiro[cyclohexane-1,2Ј-

quinoxaline], spiro[piperidine-4,2Ј-quinoxaline], spiro[pyr-

an-4,2Ј-quinoxaline],

[1,2,5]oxadiazolo[3,4-b]pyrazine, 1,4-diazepine, 7,11-diaza-

1,4,9-triazaspiro[5.5]undec-4-ene,

spiro[quinoxaline-2,4Ј-thiopyran],

spiro[5.6]dodec-11-ene, 3-thia-7,11-diazaspiro[5.6]dodec-11-

ene, and 3,7,11-triazaspiro[5.6]dodec-11-ene) have been syn- ness, and the residue was diluted with methanol up to a volume of

20 mL to afford a solution (0.5 ) of the intermediate azomethyne.

In each entry, a mixture of this solution (1000 µL), a solution of

tert-butyl isocyanide in CH₃CN (1 , 500 µL), and the appropriate

amount of LA was stirred for 24 h at ambient temperature in a

closed tube. Yields were determined by LC-MS (ELSD) analysis of

the reaction mixtures. To isolate the reaction product, each of the

entries 6, 7, and 8 was worked up by the following procedure. The

reaction mixture was evaporated to dryness under reduced pressure,

the residue was dissolved in water and treated with aq. NaOH solu-

tion (10%), and this was extracted with CHCl₃. The organic layer

thesized and characterized during the course of this work.

Furthermore, the scope of the reactions could be signifi-

cantly extended to the synthesis of spiro- and (het)areno-

fused 1,4-diazaheterocycles through the involvement of

readily available carbonyl and, more importantly, (hetero)-

cyclic 1,2- and 1,3-diamines. Importantly, the compounds

obtainable by this IMCR approach meet all requirements

of both lead- and drug-likeness.

Although the IMCR can be promoted by various LAs

including metal triflates and SLAs, TMSCl has been iden- was washed with water and brine and dried (Na₂SO₄), and the

Eur. J. Org. Chem. 2010, 1525–1543

www.eurjoc.org

1535

V. Kysil et al.

FULL PAPER

solvents were evaporated. The oily residue crystallized slowly to

afford a colorless solid consisting of the individual compound 16.

Isolated yields: 55% (entry 6), 78% (entry 7), 67% (entry 8).

added, and the resulting mixture was stirred at 50–60 °C until com-

pletion of the reaction (LC-MS-ELSD monitoring). The reaction

mixture was evaporated under reduced pressure, treated with dry

EtOAc, and kept in an ultrasonic bath until completion of precipi-

tate formation. The precipitate was filtered off, washed carefully

with EtOAc, acetonitrile, and Et₂O, and dried under reduced pres-

sure. This protocol was employed for the scale-up synthesis of com-

pounds 17, 18, and 28, as well as those of Table 3 entries 5–8,

Table 4 entry 1, and Table 5 entry 6, side by side with Procedure A.

Data for Compound 16: ¹H NMR (400 MHz, CDCl₃): δ = 7.28–

7.36 (m, 5 H, 5ϫAr-H), 3.61 (br. s, 1 H, 3Ј-NH, exch. D₂O), 3.51

(s, 2 H, 1-CH₂), 2.60–2.77 (m, 3 H, 2-H, 6-H, 4aЈ-H), 2.23–2.47

(m, 2 H, 2-H, 6-H), 1.95–2.11 (m, 3 H, 3-H, 5-H, 8aЈ-H), 1.69–

1.79 (m, 5 H, 3-H, 5-H, 2ϫ5Ј-H, 4Ј-H), 1.46–1.54 (m, 1 H, 4Ј-H),

1.31 (s, 9 H, tBu), 0.97–1.40 (m, 4 H, 2ϫ6Ј-H, 2ϫ7Ј-H), 0.84

3

(d, J_H,H= 8.8 Hz, 1 H, 1Ј-H, exch. D₂O) ppm. ¹³C NMR APT

Data for the Aminoheterocycles Synthesized by the IMCR

(100 MHz, CDCl₃): δ = 159.2 (C), 138.3 (C), 129.6 (CH), 128.5

(CH), 127.3 (CH), 63.7 (CH₂), 62.0 (CH), 53.9 (C), 53.5 (CH), 51.0

(CH₂), 48.8 (CH₂), 41.5 (C), 37.4 (CH₂), 35.1 (CH₂), 33.2 (CH₂),

32.7 (CH₂), 29.4 (CH₃), 26.0 (CH₂), 25.8 (CH₂) ppm. HRMS:

calcd. for C₂₃H₃₆N₄[M + H]⁺369.3013; found 369.3015.

N-Benzyl-9-oxa-1,4-diazaspiro[5.5]undec-4-en-5-amine Hydrochlo-

ride (17): This compound was produced through the MCR of ethyl-

enediamine, tetrahydro-4H-pyran-4-one, and benzyl isocyanide. ¹H

NMR (400 MHz, [D₆]DMSO): δ = 9.94 (br. s, 1 H, 1-H, exch.

D₂O), 9.74 (br. m, 1 H, 5-NH, exch. D₂O), 7.24–7.40 (m, 5 H,

3

5ϫAr-H), 4.59 (d, J_H,H= 3.3 Hz, 2 H, NCH₂Ph; with D₂O: s, 2

Evaluation of the Scope of the IMCR Approach with Ethylenedi-

amine, Various Carbonyl Compounds, and Isocyanides (Designed as

a Full-Matrix Parallel Synthesis at 0.1 mmol Scale, Table 2): A mix-

ture of equimolar amounts (5 mmol) of the ethylenediamine and

the carbonyl compound in MeOH (5 mL) was heated at 50 °C for

3 h in a closed vessel, allowed to cool, and diluted with MeOH to

afford a solution of the intermediate azomethyne (0.5 ). For each

entry, a mixture of this solution (200 µL), a solution of TMSCl in

acetonitrile (2 , 50 µL), and a solution of isocyanide in MeOH

(1 , 100 µL) was shaken at 40 °C for 24 h (capped 96 deep well

vials). Yields were determined by LC-MS (ELSD) of diluted ali-

quots of the reaction mixtures.

H), 3.59–3.78 (m, 4 H, 2ϫ8-H, 2ϫ10-H), 3.18–3.25 (m, 2 H, 2ϫ3-

3

H; with D₂O: t, J_H,H= 4.8 Hz, 2 H), 2.84–2.92 (m, 2 H, 2ϫ2-H;

3

with D₂O: t, J_H,H= 4.8 Hz, 2 H), 2.65 (t, J_H,H= 7.3 Hz, 1 H, 1-

H, exch. D₂O), 2.11–2.21 (m, 2 H, 7-H, 11-H), 1.65–1.73 (m, 2 H,

7-H, 11-H) ppm. ¹³C NMR APT (100 MHz, [D₆]DMSO): δ =

167.1 (C), 136.3 (C), 129.2 (CH), 128.2 (CH), 127.9 (CH), 62.1

(CH₂), 53.9 (C), 44.5 (CH₂), 41.6 (CH₂), 36.2 (CH₂), 33.3

(CH₂) ppm. HRMS: calcd. for C₁₅H₂₁N₃O [M + H]⁺260.1757;

found 260.1755.

N-Benzyl-3-(4-isopropylphenyl)-3,4,5,6-tetrahydropyrazin-2-amine

Hydrochloride (18): This compound was produced through the

MCR of ethylenediamine, 4-isopropylbenzaldehyde, and benzyl

isocyanide. ¹H NMR (400 MHz, [D₆]DMSO): δ = 10.43 (br. s, 1

H, 1-H, exch. D₂O), 9.63 (br. m, 1 H, 2-NH, exch. D₂O), 7.28–7.40

General Procedure A for MCRs of Diamines, Carbonyl Compounds,

and Isocyanides (Designed for Parallel Synthesis at 0.5 mmol Scale):

The syntheses were performed in 10 mL capped tubes in a one-pot

fashion without employment of any protective procedures such as

inert or anhydrous atmosphere. A mixture of MeOH solutions (1 ,

500 µL) of the carbonyl compound (0.5 mmol) and of the diamine

(0.5 mmol) was stirred for 3 h at 45–50 °C. Solutions of TMSCl in

acetonitrile (1 , 500 µL, 0.5 mmol) and isocyanide in MeOH (1 ,

500 µL, 0.5 mmol) were added, and the resulting mixture was

stirred at 50–60 °C for 4 h and then at ambient temperature until

completion of the reaction (LC-MS-ELSD monitoring). Reactions

of ethylenediamine usually required stirring overnight, whereas re-

actions of (hetero)aromatic diamines and propane-1,3-diamine re-

quired stirring for 20–24 h at 40–50 °C. The reaction mixture was

evaporated under reduced pressure, treated with dry EtOAc, kept

in an ultrasonic bath until completion of precipitate formation, and

then centrifuged. The precipitate was washed twice with EtOAc,

acetonitrile, and Et₂O with centrifugation each time, and dried un-

der reduced pressure. The procedure usually provided pure

monohydrochlorides of the target materials (compounds 17, 18,

and compounds represented in Table 3, Table 4, and Table 5). In

some cases, in which ethylenediamine was used as a starting di-

amine, however, crude products were contaminated by ethylenedi-

amine hydrochloride, which could not be removed by simple pro-

cedures such as recrystallization. In these cases, the crude products

were dissolved in water, treated with aq, NaOH (10% ), and ex-

tracted with CHCl₃. The organic layers were washed with water

and brine and dried (Na₂SO₄), and the solvents were evaporated.

Residues after evaporation were the pure products (Table 3, en-

tries 3, 4, 14, 16) in the form of their free bases.

3

(m, 5 H, 5ϫAr-H), 7.24 (d, J_H,H= 8.4 Hz, 2 H, 2ϫAr-H), 7.21

3

(d, J_H,H= 8.4 Hz, 2 H, 2ϫAr-H), 4.91 (s, 1 H, 3-H), 4.68 (dd,

3

2

²J_H,H= 15.0, J_H,H= 5.9 Hz, 1 H, PhCHN; with D₂O: d, J_H,H

=

15.0 Hz, 1 H), 4.55 (dd, ²J_H,H= 15.0, ³J_H,H= 5.1 Hz, 1 H, PhCHN;

2

with D₂O: d, J_H,H= 15.0 Hz, 1 H), 3.23–3.39 (m, 2 H, 2ϫ6-H),

2.79–2.94 (m, 2 H, 5-H, Ar-CH), 2.67–2.78 (m, 1 H, 5-H), 1.18

(d,³J_H,H=7.0 Hz,6H,2ϫMe) ppm.¹³CNMRAPT(100 MHz,[D₆]-

DMSO): δ = 163.0 (C), 148.8 (C), 136.5 (C), 136.2 (C), 129.1 (CH),

128.9 (CH), 128.7 (CH), 127.0 (CH), 57.1 (CH), 45.3 (CH₂), 41.0

(CH₂), 37.1 (CH₂), 33.8 (CH), 24.5 (CH₃) ppm. HRMS: calcd. for

C₂₀H₂₅N₃[M + H]⁺308.2121; found 308.2123.

N-(4-Chlorobenzyl)-1,4-diazaspiro[5.5]undec-4-en-5-amine Hydro-

chloride (Table 3, entry 1): This compound was produced through

the MCR of ethylenediamine, cyclohexanone, and p-chlorobenzyl

isocyanide. ¹H NMR (400 MHz, [D₆]DMSO): δ = 9.81 (br. m, 2

3

H, 4-H, 5-NH, exch. D₂O), 7.42 (s, 4 H, 4ϫAr-H), 4.56 (d, J_H,H

= 6.2 Hz, 2 H, ArCH₂N, with D₂O: s, 2 H), 3.15–3.23 (m, 2 H,

2ϫ3-H), 2.78–2.86 (m, 2 H, 2ϫ2-H), 2.43 (br. m, 1 H, 1-H, exch.

D₂O), 1.87–2.00 (m, 2 H), 1.52–1.78 (m, 5 H), 1.22–1.47 (m, 3 H)

(5ϫCH₂) ppm. ¹³C NMR APT (100 MHz, [D₆]DMSO): δ = 168.4

(C), 135.8 (C), 132.8 (C), 130.0 (CH), 129.0 (CH), 56.0 (C), 43.6

(CH₂), 41.9 (CH₂), 36.4 (CH₂), 33.1 (CH₂), 24.9 (CH₂), 20.7

(CH₂) ppm. HRMS: calcd. for C₁₆H₂₂ClN₃[M + H]⁺292.1575;

found 292.1578.

N-(2-Methoxybenzyl)-1,4-diazaspiro[5.5]undec-4-en-5-amine Hydro-

chloride (Table 3, entry 2): This compound was produced through

the MCR of ethylenediamine, cyclohexanone, and 2-methoxyben-

1

General Procedure B for MCRs of Diamines, Carbonyl Compounds,

and Isocyanides (Designed for 10 mmol Scale Synthesis): A mixture

of a carbonyl compound (10 mmol), the diamine (10 mmol), and

MeOH (15 mL) was stirred for 1 h at 45–50 °C. An isocyanide

(10 mmol) and a solution of TMSCl (10 mmol) in acetonitrile were

zyl isocyanide. H NMR (400 MHz, [D₆]DMSO): δ = 9.51 (br. s, 1

3

H, 4-H, exch. D₂O), 9.38 (br. t, J_H,H= 5.1 Hz, exch. D₂O, 1 H,

3

5-NH), 7.27–7.35 (m, 1 H, Ar-H), 7.09 (d, J_H,H= 7.0 Hz, 1 H,

Ar-H), 7.04 (d, ³J_H,H= 8.0 Hz, 1 H, Ar-H), 6.91–6.97 (m, 1 H, Ar-

H), 4.41 (d, ³J_H,H= 5.1 Hz, 2 H; ArCH₂N, with D₂O: s, 2 H), 3.81

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Eur. J. Org. Chem. 2010, 1525–1543

Multicomponent Strategy for 2-Amino-1,4-diazaheterocycles

(s, 3 H, OMe), 3.22 (t, ³J_H,H= 4.8 Hz, 2 H, 2ϫ3-H), 2.86 (t, ³J_H,H

= 4.8 Hz, 2 H, 2ϫ2-H), 2.48 (br. m, 1 H, 1-H, shoulder of DMSO,

exch. D₂O), 1.86–1.98 (m, 2 H), 1.74–1.83 (m, 2 H), 1.51–1.72 (m,

3 H), 1.37–1.47 (m, 2 H), 1.19–1.34 (m, 1 H) (5ϫCH₂) ppm. ¹³C

NMR APT (100 MHz, [D₆]DMSO): δ = 168.6 (C), 157.7 (C), 129.7

(CH), 128.2 (CH), 123.6 (C), 120.9 (CH), 111.5 (CH), 56.1 (CH₃),

42.0 (CH₂), 41.3 (CH₂), 36.5 (CH₂), 33.0 (CH₂), 24.9 (CH₂), 20.7

(CH₂) ppm. HRMS: calcd. for C₁₇H₂₅N₃O [M + H]⁺288.2070;

found 288.2063.

3-Isopropyl-N-(1,1,3,3-tetramethylbutyl)-3,4,5,6-tetrahydropyrazin-

2-amine Hydrochloride (Table 3, entry 7): This compound was pro-

duced through the MCR of ethylenediamine, 2-methylpropanal,

and 1,1,3,3-tetramethylbutyl isocyanide. ¹H NMR (400 MHz,

CDCl₃): δ = 9.28 (br. s, 1 H, 1-H, exch. D₂O), 8.84 (br. s, 1 H, 2-

3

NH, exch. D₂O), 4.20 (d, J_H,H= 4 Hz, 1 H, 3-H), 3.85–3.94 (m,

1 H, 6-H), 3.28–3.39 (m, 1 H, 6-H), 3.10–3.18 (m, 1 H, 5-H), 2.83–

2.94 (m, 1 H, 5-H), 2.34–2.47 (m, 2 H, 2-H of TMB, 3-CH), 1.68

(s, 3 H, 1-Me of TMB), 1.61 (s, 3 H, 1-Me of TMB), 1.53–1.60 (d,

²J_H,H= 15.0 Hz, 1 H, 2-H of TMB), 1.47 (br. s, 1 H, 4-H, exch.

D₂O), 1.05 (s, 9 H + d, 3 H, 3ϫ3-Me of TMB, Me of iPr), 0.94

(d, ³J_H,H= 6 Hz, 3 H, Me of iPr) ppm. ¹³C NMR APT (100 MHz,

CDCl₃): δ = 163.2 (C), 58.3 (C), 58.1 (CH₂), 50.8 (CH₂), 42.3

(CH₂), 40.4 (CH₂), 33.1 (CH or CH₃), 32.1 (CH₂), 31.7 (CH or

CH₃), 31.6 (CH or CH₃), 29.6 (CH or CH₃), 29.4 (CH or CH₃),

19.6 (CH or CH₃), 16.7 (CH or CH₃) ppm. HRMS: calcd. for

C₁₅H₃₁N₃[M + H]⁺254.2591; found 254.2590.

N-tert-Butyl-9-oxa-1,4-diazaspiro[5.5]undec-4-en-5-amine (Table 3,

entry 3): This compound was produced through the MCR of ethyl-

enediamine, tetrahydro-4H-pyran-4-one, and tert-butyl isocyanide.

¹H NMR (400 MHz, CDCl₃): δ = 3.79–3.89 (m, 2 H, 8-H, 10-H),

3.69–3.76 (m, 2 H, 8-H, 10-H), 3.66 (br. s, 1 H, 5-NH, exch. D₂O),

3.43 (t, ³J_H,H= 5.1 Hz, 2 H, 2ϫ3-H), 2.79 (t, ³J_H,H= 5.1 Hz, 2 H,

2ϫ2-H), 1.90–2.00 (m, 2 H, 7-H, 11-H), 1.53–1.61 (m, 2 H, 7-H,

11-H), 1.32 (s, 10 H, tBu, 1-H, with D₂O: s, 9 H) ppm. ¹³C NMR

APT (100 MHz, CDCl₃): δ = 159.3 (C), 63.1 (CH₂), 51.4 (C), 50.8

(C), 47.2 (CH₂), 38.5 (CH₂), 35.0 (CH₂), 29.3 (CH₃) ppm. HRMS:

calcd. for C₁₂H₂₃N₃O [M + H]⁺226.1914; found 226.1910.

3-tert-Butyl-N-(1,1,3,3-tetramethylbutyl)-3,4,5,6-tetrahydropyrazin-

2-amine Hydrochloride (Table 3, entry 8): This compound was pro-

duced through the MCR of ethylenediamine, pivalaldehyde, and

1

1,1,3,3-tetramethylbutyl isocyanide. H NMR (400 MHz, CDCl₃):

9-Benzyl-N-tert-butyl-1,4,9-triazaspiro[5.5]undec-4-en-5-amine

(Table 3, entry 4): This compound was produced through the MCR

of ethylenediamine, N-benzylpiperidin-4-one, and tert-butyl isocya-

nide. ¹H NMR (400 MHz, CDCl₃): δ = 7.28–7.34 (m, 5 H, 5ϫAr-

H), 3.74 (br. s, 1 H, 5-NH, exch. D₂O), 3.52 (s, 2 H, 9-CH₂Ph),

3.43 (t, ³J_H,H= 5.5 Hz, 2 H, 2ϫ3-H), 2.77 (t, ³J_H,H= 5.5 Hz, 2 H,

2ϫ2-H), 2.62–2.69 (m, 2 H, 8-H, 10-H), 2.30–2.40 (m, 2 H, 8-H,

10-H), 1.83–1.93 (m, 2 H, 7-H, 11-H), 1.64–1.71 (m, 2 H, 7-H, 11-

H), 1.30–1.60 (br. s, 1 H, 1-H, exch. D₂O), 1.31 (s, 9 H, tBu) ppm.

¹³C NMR APT (100 MHz, CDCl₃): δ = 159.9 (C), 138.3 (C), 129.5

(CH), 128.4 (CH), 127.3 (CH), 63.6 (CH₂), 52.0 (C), 50.8 (C), 48.6

(CH₂), 47.2 (CH₂), 38.3 (CH₂), 34.7 (CH₂), 29.3 (CH₃) ppm.

HRMS: calcd. for C₁₉H₃₀N₄[M + H]⁺315.2543; found 315.2541.

δ = 9.38 (br. s, 1 H, 1-H, exch. D₂O), 8.55 (br. s, 1 H, 2-NH, exch.

D₂O), 4.28 (s, 1 H, 3-H), 3.97–4.08 (m, 1 H, 6-H), 3.24–3.35 (m, 1

H, 6-H), 3.08–3.16 (m, 1 H, 5-H), 2.85–2.96 (m, 1 H, 5-H), 2.53

2

(d, J_H,H= 15.0 Hz, 1 H, 2-H of TMB), 1.68 (br. s, 1 H, 4-H,

appears as a shoulder of s 1.67), 1.67 (s, 3 H, 1-Me of TMB), 1.64

2

(s, 3 H, 1-Me of TMB), 1.53 (d, J_H,H= 15.0 Hz, 1 H, 2-H of

TMB), 1.08, 1.07 (2 ϫ s, 18 H, 2 ϫ tBu) ppm. ¹³C NMR APT

(100 MHz, CDCl₃): δ = 161.8 (C), 61.1 (CH), 58.5 (CH₂), 50.2 (C),

42.7 (C), 41.8 (CH₂or C), 38.6 (C or CH₂), 32.2 (C or CH₂), 31.6

(CH₃), 30.4 (CH₃), 29.0 (CH₃), 27.3 (CH₃) ppm. HRMS: calcd. for

C₁₆H₃₃N₃[M + H]⁺268.2747; found 268.2746.

2-[3-(Cyclohexylamino)-1,2,5,6-tetrahydropyrazin-2-yl]-6-ethoxy-

phenol Hydrochloride (Table 3, entry 9): This compound was pro-

duced through the MCR of ethylenediamine, 3-ethoxy-2-hydroxy-

benzaldehyde, and cyclohexyl isocyanide. ¹H NMR (400 MHz,

[D₆]DMSO): δ = 9.95 (br. s, 1 H, 1-H, exch. D₂O), 9.15 (br. s, 1 H,

tert-Butyl 5-(tert-Butylamino)-1,4,8-triazaspiro[5.5]undec-4-ene-8-

carboxylate Hydrochloride (Table 3, entry 5): This compound was

produced through the MCR of ethylenediamine, N-Boc-3-piperi-

done, and tert-butyl isocyanide. ¹H NMR (400 MHz, [D₆]DMSO):

δ = 8.68 (br. s, 1 H, 4-H, exch. D₂O), 8.15 (br. s, 1 H, 5-NH, exch.

D₂O), 3.94 (d, ²J_H,H= 12.3 Hz, 1 H, 7-H), 3.84 (d, ²J_H,H= 12.3 Hz,

1 H, 7-H), 3.19–3.44 (m, 3 H, 2ϫ3-H, 9-H), 2.84–3.02 (m, 3 H,

2ϫ2-H, 9-H), 2.30–2.42 (m, 2 H, 1-H, 11-H; with D₂O: m, 1 H),

1.64–1.77 (m, 2 H, 10-H, 11-H), 1.41 (s, 9 H, tBu), 1.38 (s, 9 H,

tBu), 1.25–1.38 (m, 1 H, 10-H) ppm. ¹³C NMR APT (100 MHz,

[D₆]DMSO): δ = 165.1 (C), 155.4 (C), 79.2 (C), 56.2 (C), 54.1 (C),

47.4 (CH₂), 42.9 (CH₂), 42.7,^[36]36.7 (CH₂), 32.4,^[36]28.7 (CH₃),

28.6 (CH₃), 19.6 (CH₂) ppm. HRMS: calcd. for C₁₇H₃₂N₄O₂[M +

H]⁺325.2598; found 325.2596.

3

OH, exch. D₂O), 8.90 (br. d, J_H,H= 6.6 Hz, 1 H, 2-NH, exch.

3

D₂O), 6.94 (d, J_H,H= 7.7 Hz, 1 H, Ar-H), 6.72–6.78 (m, 1 H, Ar-

3

H), 6.55 (d, J_H,H= 7.3 Hz, 1 H, Ar-H), 5.04 (s, 1 H, 3-H), 4.04

3

(q, J_H,H= 6.7 Hz, 2 H, OCH₂), 3.65–3.74 (m, 1 H, CH of cyclo-

hexyl), 3.26–3.37 (m, 2 H, 2ϫ6-H, superposition with H₂O, inten-

sity was determined from spectra with D₂O), 3.02 (br. s, 1 H, 4-H,

exch. D₂O), 2.70–3.10 (m, 2 H, 2ϫ5-H), 1.75–1.85 (m, 2 H), 1.61–

1.73 (m, 2 H), 1.51–1.60 (m, 1 H), 1.16–1.38 (m, 6 H), 1.00–1.15

(m, 2 H) (5ϫCH₂, Me) ppm. ¹³C NMR (100 MHz, [D₆]DMSO):

δ = 161.1 (C), 147.5 (C), 145.2 (C), 125.2 (C), 121.1 (CH), 119.2

(CH), 113.7 (CH), 64.8 (CH₂), 53.3, (CH) 50.7 (CH), 41.0 (CH₂),

36.9 (CH₂), 31.6 (CH₂), 31.5 (CH₂), 25.3 (CH₂), 24.8 (CH₂), 24.7

(CH₂), 15.3 (CH₃) ppm. HRMS: calcd. for C₁₈H₂₇N₃O₂[M + H]⁺

318.2176; found 318.2176.

3-Methyl-N-(1,1,3,3-tetramethylbutyl)-3,4,5,6-tetrahydropyrazin-2-

amine Hydrochloride (Table 3, entry 6): This compound was pro-

duced through the MCR of ethylenediamine, acetaldehyde, and

1

1,1,3,3-tetramethylbutyl isocyanide. H NMR (400 MHz, CDCl₃):

δ = 9.06 (br. s, 1 H, 1-H, exch. D₂O), 9.02 (br. s, 1 H, 2-NH, exch.

N-tert-Butyl-3-(4-methoxyphenyl)-3,4,5,6-tetrahydropyrazin-2-

D₂O), 4.50 (q, ³J_H,H= 6.7 Hz, 1 H, 3-H), 3.53–3.66 (m, 2 H, 2ϫ6- amine Hydrochloride (Table 3, entry 10): This compound was pro-

H), 3.11–3.22 (m, 1 H, 5-H), 2.93–3.03 (m, 1 H, 5-H), 2.08 (d, ²J_H,Hduced through the MCR of ethylenediamine, 4-methoxybenzalde-

2

1

= 15.4 Hz, 1 H, 2-H of TMB), 1.84 (d, J_H,H= 15.4 Hz, 1 H, 2-H

hyde, and tert-butyl isocyanide. H NMR (400 MHz, [D₆]DMSO):

of TMB), 1.75 (very brs, 1 H, 4-H, exch. D₂O), 1.65 (s, 3 H, 1-Me

of TMB), 1.60 (s, 3 H, 1-Me of TMB), 1.57 (d, J_H,H= 6.7 Hz, 3

δ = 9.03 (br. s, 1 H, 1-H, exch. D₂O), 9.01 (br. s, 1 H, 2-NH, exch.

D₂O), 7.19 (d, J_H,H= 8.1 Hz, 2 H, 2ϫAr-H), 6.96 (d, J_H,H=

3

H, 3-Me), 1.04 (s, 9 H, 3ϫ3-Me of TMB) ppm. ¹³C NMR APT

(100 MHz, CDCl₃): δ = 163.5 (C), 57.9 (CH₂), 50.5 (C), 49.1 (CH),

42.3 (CH₂), 37.3 (C), 32.0 (CH₂), 31.5 (CH₃), 29.9 (CH₃), 29.5

(CH₃), 21.2 (CH₃) ppm. HRMS: calcd. for C₁₃H₂₇N₃[M + H]⁺

226.2278; found 226.2280.

8.1 Hz, 2 H, 2ϫAr-H), 4.88 (s, 1 H, 3-H), 3.75 (s, 3 H, OMe),

3.34–3.41 (m, 1 H, 6-H), 3.12–3.23 (m, 1 H, 6-H), 2.78–2.86 (m, 1

H, 5-H), 2.60–2.70 (m, 1 H, 5-H), 1.40 (s, 9 H, tBu) ppm. ¹³C NMR

APT (100 MHz, [D₆]DMSO): δ = 162.0 (C), 159.4 (C), 131.0 (C),

129.4 (CH), 114.5 (CH), 56.3 (CH₃), 55.8 (CH), 53.3 (C), 36.1

Eur. J. Org. Chem. 2010, 1525–1543

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1537

V. Kysil et al.

FULL PAPER

(CH₂), 28.3 (CH₃) ppm. HRMS: calcd. for C₁₅H₂₃N₃O [M + H]⁺

262.1914; found 262.1914.

42.7 (CH₂), 34.4 (CH₃), 29.1 (CH₃) ppm. HRMS: calcd. for

C₁₃H₂₂N₄[M + H]⁺235.1917; found 235.1906.

N-tert-Butyl-3-pyridin-2-yl-3,4,5,6-tetrahydropyrazin-2-amine Hy-

drochloride (Table 3, entry 15): This compound was produced

through the MCR of ethylenediamine, pyridine-2-carbaldehyde,

and tert-butyl isocyanide. ¹H NMR (400 MHz, [D₆]DMSO): δ =

9.09 (br. s, 1 H, 1-H), 9.00 (br. s, 1 H, 2-NH), 8.45–8.51 (m, 1 H,

Py-H), 8.22 (br. s, 0.65 H, impurity), 7.80–7.88 (m, 1 H, Py-H),

7.52–7.58 (m, 1 H, Py-H), 7.30–7.36 (m, 1 H, Py-H), 5.09 (s, 1 H,

3-H), 3.53 (br. s, 1 H, 4-H), 3.24–3.41 (m, 1 H, 6-H), 3.08–3.18 (m,

1 H, 6-H), 2.75–2.86 (m, 1 H, 5-H), 2.56–2.66 (m, 1 H, 5-H), 1.39

(s, 9 H, tBu), 1.25 (s, 1.60 H, impurity) ppm. HRMS: calcd. for

C₁₃H₂₀N₄[M + H]⁺233.1761; found 233.1763.

3-(2,4-Dimethoxyphenyl)-N-(4-methoxybenzyl)-3,4,5,6-tetrahydro-

pyrazin-2-amine Hydrochloride (Table 3, entry 11): This compound

was produced through the MCR of ethylenediamine, 2,4-dimeth-

oxybenzaldehyde, and 4-methoxybenzyl isocyanide. ¹H NMR

(400 MHz, [D₆]DMSO): δ = 11.0 (br. s, 1 H, 1-H, exch. D₂O), 9.58

3

(br. m, 1 H, 2-NH, exch. D₂O), 7.27 (d, J_H,H= 8.8 Hz, 1 H, Ar-

H), 7.21 (d, ³J_H,H= 8.4 Hz, 2 H, 2ϫAr-H), 6.89 (d, ³J_H,H= 8.4 Hz,

2 H, 2ϫAr-H), 6.64 (d, ⁴J_H,H= 2.2 Hz, 1 H, Ar-H), 6.60 (dd, ³J_H,H

4

= 8.8, J_H,H= 2.2 Hz, 1 H, Ar-H), 5.60 (s, 1 H, 3-H), 4.65 (dd,

3

2

²J_H,H= 15.4, J_H,H= 6.6 Hz, 1 H, ArCHN; with D₂O: d, J_H,H

=

15.4 Hz, 1 H), 4.38 (dd, ²J_H,H= 15.4, ³J_H,H= 5.5 Hz, 1 H, ArCHN;

2

with D₂O: d, J_H,H= 15.4 Hz, 1 H), 3.80 (s, 3 H, OMe), 3.72 (s, 3

N-tert-Butyl-3-pyridin-3-yl-3,4,5,6-tetrahydropyrazin-2-amine

(Table 3, entry 16): This compound was produced through the

MCR of ethylenediamine, pyridine-3-carbaldehyde, and tert-butyl

H, OMe), 3.71 (s, 3 H, OMe), 3.59–3.68 (m, 1 H, 6-H), 3.33–3.50

(m, 3 H, 4-H, 5-H, 6-H; with D₂O: m, 2 H), 3.20–3.30 (m, 1 H, 5-

H) ppm. ¹³C NMR APT (100 MHz, [D₆]DMSO): δ = 163.4 (C),

159.5 (C), 159.3 (C), 158.6 (C), 134.0 (CH), 129.8 (CH), 127.7 (C),

114.5 (CH), 111.9 (C), 105.8 (CH), 99.3 (CH), 56.5 (CH₃), 56.3

(CH₃), 55.8 (CH₃), 51.9 (CH), 45.1 (CH₂), 38.3 (CH₂), 38.1

(CH₂) ppm. HRMS: calcd. for C₂₀H₂₅N₃O₃[M + H]⁺356.1969;

found 356.1960.

1

isocyanide. H NMR (400 MHz, CDCl₃): δ = 8.54–8.61 (m, 2 H,

3

2ϫPy-H), 7.71 (d, J_H,H= 7.7 Hz, 1 H, Py-H), 7.28–7.34 (m, 1 H,

Py-H), 4.27 (s, 1 H, 3-H), 3.53–3.67 (m, 2 H, 2ϫ6-H), 3.22 (br. s,

1 H, 2-NH, exch. D₂O), 2.77–2.90 (m, 2 H, 2ϫ5-H), 1.89 (br. s, 1

H, 4-H, exch. D₂O), 1.27 (s, 9 H, tBu) ppm. ¹³C NMR APT

(100 MHz, CDCl₃): δ = 153.5 (C), 150.3 (CH), 149.5 (CH), 136.9

(C), 136.3 (CH), 123.8 (CH), 57.0 (CH), 51.1 (C), 46.5 (CH₂), 40.3

(CH₂), 29.1 (CH₃) ppm. HRMS: calcd. for C₁₃H₂₀N₄[M + H]⁺

233.1761; found 233.1759.

N-Cyclopentyl-3-[4-(trifluoromethyl)phenyl]-3,4,5,6-tetrahydropyr-

azin-2-amine Hydrochloride (Table 3, entry 12): This compound was

produced through the MCR of ethylenediamine, 4-trifluoromethyl-

1

benzaldehyde, and cyclopentyl isocyanide. H NMR (400 MHz,

N-tert-Butyl-3-pyridin-4-yl-3,4,5,6-tetrahydropyrazin-2-amine Hy-

drochloride (Table 3, entry 17): This compound was produced

through the MCR of ethylenediamine, pyridine-4-carbaldehyde,

and tert-butyl isocyanide. ¹H NMR (400 MHz, [D₆]DMSO): δ =

9.47 (br. s, 1 H, 1-H), 9.31 (br. s, 1 H, 2-NH), 8.56 (m, 2 H, 2ϫPy-

H), 8.22 (br. s, 0.57 H, impurity), 7.28 (m, 2 H, 2ϫPy-H), 5.11 (s,

1 H, 3-H), 3.25–3.39 (m, 1 H, 6-H), 3.00–3.11 (m, 1 H, 6-H), 2.76–

2.90 (m, 1 H, 5-H), 2.50–2.62 (m, 1 H, 5-H), 1.40 (s, 9 H, tBu),

1.21 (s, 1.67 H, impurity) ppm. HRMS: calcd. for C₁₃H₂₀N₄[M +

H]⁺233.1761; found 233.1761.

[D₆]DMSO): δ = 10.14 (br. s, 1 H, 1-H, exch. D₂O), 9.64 (br. d,

3

³J_H,H= 6.6 Hz, 1 H, 2-NH, exch. D₂O), 7.77 (d, J_H,H= 8.1 Hz, 2

H, 2ϫAr-H), 7.52 (d, ³J_H,H= 8.1 Hz, 2 H, 2ϫAr-H), 5.06 (s, 1 H,

3-H), 4.15–4.22 (m, 1 H, CH of cyclopentyl; with D₂O: multiplicity

changes, 1 H), 3.45 (m, 1 H, 4-H, exch. D₂O), 3.28–3.39 (m, 1 H,

6-H), 3.15–3.25 (m, 1 H, 6-H), 2.79–2.89 (m, 1 H, 5-H), 2.54–2.68

(m, 1 H, 5-H), 1.90–2.05 (m, 2 H), 1.42–1.70 (m, 6 H) (4 CH₂) ppm.

¹³C NMR APT^[37](100 MHz, [D₆]DMSO): δ = 166.1 (C), 148.8

(C), 134.2 (CH), 133.9 (C), 133.6 (C), 130.7 (CH), 60.8 (CH), 58.3

(CH), 41.3 (CH₂), 36.9 (CH₂), 36.6 (CH₂), 28.90 (CH₂), 28.81

(CH₂) ppm. HRMS: calcd. for C₁₆H₂₀F₃N₃[M + H]⁺312.1682;

found 312.1685.

N-tert-Butyl-1ЈH-spiro[cyclohexane-1,2Ј-quinoxalin]-3Ј-amine Hy-

drochloride (Table 4, entry 1): This compound was produced

through the MCR of 1,2-phenylenediamine, cyclohexanone, and

1

3-(4-Chlorophenyl)-N-cyclopentyl-3,4,5,6-tetrahydropyrazin-2-amine

Hydrochloride (Table 3, entry 13): This compound was produced

through the MCR of ethylenediamine, 4-chlorobenzaldehyde, and

tert-butyl isocyanide. H NMR (400 MHz, [D₆]DMSO): δ = 10.54

3

(br. s, 1 H, 4-H), 8.14 (br. s, 1 H, 3-NH), 7.78 (d, J_H,H= 8.0 Hz,

3

1 H, Ar-H), 7.15 (d, J_H,H= 8.0 Hz, 1 H, Ar-H), 7.05 (t, J_H,H

=

cyclopentyl isocyanide. ¹H NMR (400 MHz, [D₆]DMSO): δ =

3

8.0 Hz, 1 H, Ar-H), 6.79 (t, J_H,H= 8.0 Hz, 1 H, Ar-H), 6.46 (br.

s, 1 H, 1-H), 1.86–1.98 (m, 2 H, 2Ј-H, 6Ј-H), 1.50–1.78 (m, 7 H,

2Ј-H, 2ϫ3Ј-H, 4Ј-H, 2ϫ5Ј-H, 6Ј-H), 1.56 (s, 9 H, tBu), 1.18–1.32

(m, 1 H, 4Ј-H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ = 158.4,

133.6, 126.6, 123.8, 119.0, 118.8, 116.0, 55.7, 54.7, 29.7, 28.1, 24.5,

19.9 ppm. HRMS: calcd. for C₁₇H₂₅N₃[M + H]⁺272.2121; found

272.2125.

3

10.00 (br. s, 1 H, 1-H, exch. D₂O), 9.49 (br. d, approx. J_H,H

=

7 Hz, 1 H, 2-NH, exch. D₂O), 7.46 (d, ³J_H,H= 8.1 Hz, 2 H, 2ϫAr-

H), 7.30 (d, J_H,H= 8.1 Hz, 2 H, 2ϫAr-H), 4.92 (s, 1 H, 3-H),

3

4.06–4.18 (m, 1 H, CH of cyclopentyl), 3.16–3.40 (m, 2 H, 2ϫ6-

H), 2.77–2.87 (m, 1 H, 5-H), 2.57–2.69 (m, 1 H, 5-H), 1.89–2.03

(m, 2 H), 1.39–1.71 (m, 6 H) (4 ϫ CH₂) ppm. ¹³C NMR APT

(100 MHz, [D₆]DMSO): δ = 161.6 (C), 138.3 (C), 133.1 (C), 130.5

(CH), 129.0 (CH), 55.9 (C), 53.5 (C), 36.5 (CH₂), 32.1 (CH₂), 31.8

(CH₂), 24.1 (CH₂) ppm. HRMS: calcd. for C₁₅H₂₀ClN₃[M + H]⁺

278.1418; found 278.1423.

N-Benzyl-1ЈH-spiro[cyclohexane-1,2Ј-quinoxalin]-3Ј-amine Hydro-

chloride (Table 4, entry 2): This compound was produced through

the MCR of 1,2-phenylenediamine, cyclohexanone, and benzyl iso-

1

cyanide. H NMR (400 MHz, [D₆]DMSO): δ = 12.04 (br. s, 1 H,

3

N-tert-Butyl-3-(1-methyl-1H-pyrrol-2-yl)-3,4,5,6-tetrahydropyrazin-

2-amine (Table 3, entry 14): This compound was produced through

the MCR of ethylenediamine, 1-methyl-1H-pyrrole-2-carbaldehyde,

and tert-butyl isocyanide. ¹H NMR (400 MHz, CDCl₃): δ = 6.55

(m, 1 H, Pyr-H), 6.01 (m, 1 H, Pyr-H), 5.97 (m, 1 H, Pyr-H), 4.35

(s, 1 H, 3-H), 3.62 (s, 3 H, N-Me), 3.40–3.59 (m, 3 H, 2-NH, 2ϫ6-

4-H), 10.06 (br. t, J_H,H= 5.9 Hz, 1 H, 3-NH), 7.49 (d, J_H,H

=

8.1 Hz, 1 H, Ar-H), 7.30–7.46 (m, 5 H, 5ϫAr-H), 7.12 (d, ³J_H,H

3

7.7 Hz, 1 H, Ar-H), 7.02 (t, J_H,H= 7.7 Hz, 1 H, Ar-H), 6.76 (t,

³J_H,H= 7.7 Hz, 1 H, Ar-H), 6.48 (br. s, 1 H, 1-H), 4. 97 (d, J_H,H

3

= 5.9 Hz, 2 H, PhCH₂N), 1.80–1.92 (m, 2 H, 2Ј-H, 6Ј-H), 1.62–

1.79 (m, 5 H, 2ϫ3Ј-H, 4Ј-H, 2ϫ5Ј-H), 1.50–1.60 (m, 2 H, 2Ј-H,

H; with D₂O: m, 2 H), 2.87–2.96 (m, 1 H, 5-H), 2.75–2.88 (m, 1 6Ј-H), 1.12–1.28 (m, 1 H, 4Ј-H) ppm. ¹³C NMR (100 MHz, [D₆]-

H, 5-H), 1.60 (br. s, 1 H, 4-H, exch. D₂O), 1.21 (s, 9 H, tBu) ppm.

¹³C NMR APT (100 MHz, CDCl₃): δ = 153.8 (C), 130.1 (C), 124.1

(CH), 110.6 (CH), 106.6 (CH), 54.0 (CH), 50.6 (C), 46.9 (CH₂),

DMSO): δ = 160.7, 135.9, 133.8, 129.1, 128.2, 127.8, 126.5, 123.8,

119.1, 117.9, 115.8, 54.9, 45.7, 30.8, 24.8, 19.6 ppm. HRMS: calcd.

for C₂₀H₂₃N₃[M + H]⁺306.1965; found 306.1967.

1538

www.eurjoc.org

Eur. J. Org. Chem. 2010, 1525–1543

Multicomponent Strategy for 2-Amino-1,4-diazaheterocycles

Methyl N-1ЈH-Spiro[cyclohexane-1,2Ј-quinoxalin]-3Ј-ylglycinate

Hydrochloride (Table 4, entry 3): This compound was produced

through the MCR of 1,2-phenylenediamine, cyclohexanone, and

methyl isocyanoacetate. ¹H NMR (400 MHz, [D₆]DMSO): δ =

126.3, 54.9, 43.6, 33.1, 23.8 ppm. HRMS: calcd. for C₂₀H₂₁N₅O

[M + H]⁺348.1819; found 348.1827.

4-[6-(Cyclohexylamino)-4,5-dihydro[1,2,5]oxadiazolo[3,4-b]pyrazin-

5-yl]phenol Hydrochloride (Table 4, entry 8): This compound was

produced through the MCR of [1,2,5]oxadiazole-3,4-diamine, 4-hy-

droxybenzaldehyde, and cyclohexyl isocyanide. ¹H NMR

3

12.14 (br. s, 1 H, 4-H), 9.85 (br. t, J_H,H= 5.1 Hz, 1 H, 3-NH),

3

7.43 (d, J_H,H= 8.0 Hz, 1 H, Ar-H), 7.13 (d, J_H,H= 8.0 Hz, 1 H,

Ar-H), 7.04 (t, ³J_H,H= 8.0 Hz, 1 H, Ar-H), 6.77 (t, ³J_H,H= 8.0 Hz,

1 H, Ar-H), 6.51 (br. s, 1 H, 1-H), 4.59 (d, J_H,H= 5.1 Hz, 2 H,

3

(400 MHz, [D₆]DMSO): δ = 8.43 (br. d, J_H,H= 7.0 Hz, 1 H, 6-

3

NH), 7.87 (br. s, 1 H, 7-H), 7.03 (d, J_H,H= 8.8 Hz, 2 H, 2ϫAr-

COCH₂N), 3.72 (s, 3 H, OMe), 1.45–1.90 (m, 9 H, 2ϫ2Ј-H, 2ϫ3Ј-

H, 4Ј-H, 2ϫ5Ј-H, 2ϫ6Ј-H), 1.10–1.30 (m, 1 H, 4Ј-H) ppm. ¹³C

NMR (100 MHz, [D₆]DMSO): δ = 168.1, 161.3, 133.9, 126.7,

123.9, 119.1, 118.0, 115.8, 55.0, 52.9, 44.6, 30.8, 24.8, 19.6 ppm.

HRMS: calcd. for C₁₆H₂₁N₃O₂[M + H]⁺288.1706; found

288.1710.

3

H), 6.71 (d, J_H,H= 8.8 Hz, 2 H, 2ϫAr-H), 6.38 (very brs, 2 H,

4-H, OH), 5.09 (s, 1 H, 5-H), 3.81–3.93 (m, 1 H, NCH of cyclo-

hexyl), 1.83–1.95 (m, 1 H), 1.48–1.79 (m, 4 H), 1.00–1.30 (m, 5 H)

(5ϫCH₂of cyclohexyl) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ

= 161.8, 158.0, 152.3, 148.0, 131.3, 128.0, 116.1, 55.0, 50.0, 32.3,

32.0, 25.7, 25.1, 24.9 ppm. HRMS: calcd. for C₁₆H₁₉N₅O₂[M +

H]⁺314.1611; found 314.1611.

N-tert-Butyl-2,3,5,6-tetrahydro-1ЈH-spiro[pyran-4,2Ј-quinoxalin]-3Ј-

amine Hydrochloride (Table 4, entry 4): This compound was pro-

duced through the MCR of 1,2-phenylenediamine, tetrahydro-4H-

4-{6-[(2-Chlorobenzyl)amino]-4,5-dihydro[1,2,5]oxadiazolo[3,4-b]-

pyrazin-5-yl}phenol Hydrochloride (Table 4, entry 9): This com-

pound was produced through the MCR of [1,2,5]oxadiazole-3,4-

diamine, 4-hydroxybenzaldehyde, and 2-chlorobenzyl isocyanide.

1

pyran-4-one, and tert-butyl isocyanide. H NMR (400 MHz, [D₆]-

DMSO): δ = 10.76 (br. s, 1 H, 4-H), 8.21 (br. s, 1 H, 3-NH), 7.86

3

(d, J_H,H= 8.1 Hz, 1 H, Ar-H), 7.19 (d, J_H,H= 7.7 Hz, 1 H, Ar-

H), 7.04–7.10 (m, 1 H, Ar-H), 6.93 (br. s, 1 H, 1-H), 6.78–6.84 (m,

1 H, Ar-H), 3.78–3.88 (m, 2 H, 2Ј-H, 6Ј-H), 3.68–3.75 (m, 2 H, 2Ј-

H, 6Ј-H), 2.14–2.25 (m, 2 H, 3Ј-H, 5Ј-H), 1.56 (s, 9 H, tBu), 1.47–

1.54 (m, 2 H, 3Ј-H, 5Ј-H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO):

δ = 156.2, 133.2, 126.6, 123.9, 119.3, 119.0, 116.3, 61.4, 56.0, 52.8,

30.0, 28.1 ppm. HRMS: calcd. for C₁₆H₂₃N₃O [M + H]⁺274.1914;

found 274.1918.

3

¹H NMR (400 MHz, [D₆]DMSO): δ = 8.62 (br. d, J_H,H= 5.5 Hz,

3

4

1 H, 6-NH), 7.85 (br. s, 1 H, 7-H), 7.42 (dd, J_H,H= 7.7, J_H,H

=

1.1 Hz, 1 H, Ar-H), 7.25–7.30 (m, 1 H, Ar-H), 7.18–7.24 (m, 1 H,

3

4

Ar-H), 7.14 (dd, J_H,H= 7.7, J_H,H= 1.5 Hz, 1 H, Ar-H), 7.05 (d,

³J_H,H= 8.4 Hz, 2 H, 2 ϫ Ar-H), 6.74 (d, J_H,H= 8.4 Hz, 2 H,

2 ϫ Ar-H), 5.19 (s, 1 H, 6-H), 4.61 (dd, J_H,H= 15.8, J_H,H

5.5 Hz, 1 H), 4.52 (dd, J_H,H= 15.8, J_H,H= 5.5 Hz, 1 H)

(ArCH₂N) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ = 163.5,

158.1, 152.6, 147.9, 135.8, 132.9, 131.5, 130.0, 129.9, 129.6, 128.3,

127.7, 116.1, 55.3, 42.3 ppm. HRMS: calcd. for C₁₇H₁₄ClN₅O₂[M

+ H]⁺356.0909; found 356.0904.

3

2

3

=

2

3

N-tert-Butyl-2Ј,3Ј,5Ј,6Ј-tetrahydro-1H-spiro[quinoxaline-2,4Ј-thio-

pyran]-3-amine Hydrochloride (Table 4, entry 5): This compound

was produced through the MCR of 1,2-phenylenediamine, tetra-

1

hydro-4H-thiopyran-4-one, and tert-butyl isocyanide. H NMR:

N-tert-Butyl-7,11-diazaspiro[5.6]dodec-11-en-12-amine Hydrochlo-

ride (Table 5, entry 1): This compound was produced through the

(400 MHz, [D₆]DMSO): δ = 10.73 (br. s, 1 H, 4-H), 8.26 (br. s, 1

3

H, 3-NH), 7.85 (d, J_H,H= 8.1 Hz, 1 H, Ar-H), 7.23 (d, J_H,H

=

MCR of propane-1,3-diamine, cyclohexanone, and tert-butyl isocy-

8.1 Hz, 1 H, Ar-H), 7.04–7.09 (m, 1 H, Ar-H), 6.79–6.84 (m, 1 H,

Ar-H), 6.71 (br. s, 1 H, 1-H), 3.07–3.18 (m, 2 H, 2Ј-H, 6Ј-H), 2.41–

2.48 (m, 2 H, 2Ј-H, 6Ј-H), 2.17–2.28 (m, 2 H, 3Ј-H, 5Ј-H), 1.87–

1.95 (m, 2 H, 3Ј-H, 5Ј-H), 1.56 (s, 9 H, tBu) ppm. ¹³C NMR

(100 MHz, [D₆]DMSO): δ = 157.4, 132.8, 126.8, 123.7, 119.5,

118.9, 116.2, 56.1, 53.9, 30.8, 28.2, 21.6 ppm. HRMS: calcd. for

C₁₆H₂₃N₃S [M + H]⁺290.1685; found 290.1687.

3

anide. ¹H NMR (400 MHz, [D₆]DMSO): δ = 8.06 (br. t, J_H,H

=

4.5 Hz, 1 H, 11-H), 7.41 (br. s, 1 H, 12-NH), 3.75–3.79 (m, 2 H,

3

2ϫ10-H), 2.82 (br. t, J_H,H= 6.0 Hz, 1 H, 7-H), 2.72–2.80 (m, 2

H, 2ϫ8-H), 1.81–1.91 (m, 2 H, 2ϫ9-H), 1.67–1.76 (m, 4 H, 2ϫ1-

H, 2ϫ5-H), 1.29–1.64 (m, 6 H, 2ϫ2-H, 2ϫ3-H, 2ϫ4-H), 1.40 (s,

9 H, tBu) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ = 172.9, 61.7,

54.1, 42.5, 32.3, 29.9, 28.4, 28.3, 24.1, 21.0 ppm. HRMS: calcd. for

C₁₄H₂₇N₃[M + H]⁺238.2278; found 238.2285.

N-tert-Butyl-6-(4-isopropylphenyl)-6,7-dihydro-[1,2,5]oxadiazolo-

[3,4-b]pyrazin-5-amine Hydrochloride (Table 4, entry 6): This com-

pound was produced through the MCR of [1,2,5]oxadiazole-3,4-

N-Cyclopentyl-7,11-diazaspiro[5.6]dodec-11-en-12-amine Hydro-

chloride (Table 5, entry 2): This compound was produced through

the MCR of propane-1,3-diamine, cyclohexanone, and cyclopentyl

1

diamine, 4-isopropylbenzaldehyde, and tert-butyl isocyanide. H

NMR (400 MHz, [D₆]DMSO): δ = 8.09 (br. s, 1 H, 4-H), 7.93 (br.

1

3

isocyanide. H NMR (400 MHz, [D₆]DMSO): δ = 8.96 (br. s, 1 H,

s, 1 H, 5-NH), 7.88 (br. s, 1 H, 7-H), 7.22 (d, J_H,H= 8.4 Hz, 2 H,

3

2ϫAr-H), 7.14 (d, ³J_H,H= 8.4 Hz, 2 H, 2ϫAr-H), 5.13 (s, 1 H, 6-

H), 2.80–2.87 (m, 1 H, CH of iPr), 1.39 (s, 9 H, tBu), 1.15 (d, ³J_H,H

= 7.0 Hz, 6 H, 2ϫMe of iPr) ppm. ¹³C NMR (125 MHz, [D₆]-

DMSO): δ = 161.1, 152.2, 148.2, 147.2, 137.8, 126.7, 126.1, 54.5,

52.3, 33.0, 27.1, 23.8 ppm. HRMS: calcd. for C₁₇H₂₃N₅O [M +

H]⁺314.1975; found 314.1977.

11-H), 8.29 (br. d, J_H,H= 6.8 Hz, 1 H, 12-NH), 3.97–4.07 (m, 1

H, NCH of cyclohexyl), 3.55–3.65 (m, 2 H, 2ϫ10-H), 2.72–2.85

(m, 3 H, 7-H, 2ϫ8-H), 1.25–1.98 (m, 20 H, 2ϫ9-H, 10ϫ1–5-H,

4ϫCH₂of cyclohexyl) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ

= 173.2, 60.9, 54.0, 41.7, 39.5, 32.5, 31.6, 30.0, 24.3, 24.2, 20.9 ppm.

HRMS: calcd. for C₁₅H₂₇N₃[M + H]⁺250.2278; found 250.2277.

N-Benzyl-6-(4-isopropylphenyl)-6,7-dihydro[1,2,5]oxadiazolo[3,4-b]-

pyrazin-5-amine Hydrochloride (Table 4, entry 7): This compound

was produced through the MCR of [1,2,5]oxadiazole-3,4-diamine,

N-Benzyl-7,11-diazaspiro[5.6]dodec-11-en-12-amine Hydrochloride

(Table 5, entry 3): This compound was produced through the MCR

1

of propane-1,3-diamine, cyclohexanone, and benzyl isocyanide. H

3

4-isopropylbenzaldehyde, and benzyl isocyanide. ¹H NMR

NMR (400 MHz, [D₆]DMSO): δ = 9.41 (br. t, J_H,H= 5.7 Hz, 1

3

(400 MHz, [D₆]DMSO): δ = 8.78 (br. t, J_H,H= 5.9 Hz, 1 H, 5- H, 12-NH), 9.06 (br. t, 1 H, 11-H), 7.24–7.38 (m, 5 H, Ar-H), 4.56

3

NH), 7.96 (br. s, 1 H, 4-H), 7.88 (br. s, 1 H, 7-H), 7.16–7.29 (m, 9

(d, J_H,H= 5.7 Hz, 2 H, PhCH₂N), 3.50–3.57 (m, 2 H, 2ϫ10-H),

3

H, 9 Ar-H), 5.22 (s, 1 H, 6-H), 4.53 (d, J_H,H= 5.9 Hz, 2 H,

2.87 (br. t, ³J_H,H= 6.1 Hz, 1 H, 7-H), 2.76–2.83 (m, 2 H, 2ϫ8-H),

3

PhCH₂N), 2.79–2.86 (m, 1 H, CH of iPr), 1.17 (d, J_H,H= 6.7 Hz, 1.40–1.92 (m, 11 H, 2ϫ9-H, 2ϫ1-H, 2ϫ2-H, 3-H, 2ϫ4-H, 2ϫ5-

6 H, 2ϫMe of iPr) ppm. ¹³C NMR (125 MHz, [D₆]DMSO): δ = H), 1.21–1.33 (m, 1 H, 3-H) ppm. ¹³C NMR (100 MHz, [D₆]-

162.3, 152.1, 148.6, 147.2, 138.2, 137.9, 128.3, 127.4, 127.0, 126.7,

DMSO): δ = 173.9, 136.2, 128.9, 127.9, 127.5, 61.1, 44.8, 41.9, 32.8,

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V. Kysil et al.

FULL PAPER

30.0, 24.6, 20.9 ppm. HRMS: calcd. for C₁₇H₂₅N₃[M + H]⁺

272.2121; found 272.2125.

3 H, N-Me), 3.42–3.58 (m, 2 H, 1-H, 5-H), 3.23–3.31 (m, 1 H, 5-

H), 2.77–2.87 (m, 1 H, 7-H), 2.32–2.43 (m, 1 H, 7-H), 1.79–1.89

(m, 2 H, 2ϫ6-H), 1.47–1.73 (m, 5 H), 1.24–1.38 (m, 3 H), 1.04–

1.17 (m, 2 H) (5ϫCH₂) ppm. ¹³C NMR (100 MHz, [D₆]DMSO):

δ = 167.5, 124.7, 124.6, 109.3, 106.9, 57.4, 51.1, 44.2, 43.3, 34.5,

31.5, 31.2, 30.6, 25.2, 24.5, 24.4 ppm. HRMS: calcd. for C₁₆H₂₆N₄

[M + H]⁺275.2230; found 275.2231.

N-(4-Chlorobenzyl)-7,11-diazaspiro[5.6]dodec-11-en-12-amine Hy-

drochloride (Table 5, entry 4): This compound was produced

through the MCR of propane-1,3-diamine, cyclohexanone, and 4-

1

chlorobenzyl isocyanide. H NMR (400 MHz, [D₆]DMSO): δ =

3

9.45 (br. s, 1 H, 12-NH), 9.15 (br. s, 1 H, 11-H), 7.41 (d, J_H,H

=

3

8.6 Hz, 2 H, 2ϫAr-H), 7.36 (d, J_H,H= 8.6 Hz, 2 H, 2ϫAr-H),

4.57 (s, 2 H, PhCH₂N), 3.49–3.56 (m, 2 H, 2ϫ10-H), 2.74–2.87

(m, 3 H, 7-H, 2ϫ8-H), 1.75–1.92 (m, 4 H), 1.38–1.74 (m, 7 H),

1.20–1.33 (m, 1 H) (6 ϫCH₂) ppm. ¹³C NMR (100 MHz, [D₆]-

DMSO): δ = 173.7, 135.4, 132.5, 129.6, 128.8, 61.1, 44.2, 41.9, 32.8,

30.0, 24.6, 20.9 ppm. HRMS: calcd. for C₁₇H₂₄ClN₃[M + H]⁺

306.1731; found 306.1733.

N-(1,1,3,3-Tetramethylbutyl)-3-thia-7,11-diazaspiro[5.6]dodec-11-

en-12-amine Hydrochloride (Table 5, entry 9): This compound was

produced through the MCR of propane-1,3-diamine, tetrahydro-

1

4H-thiopyran-4-one, and 1,1,3,3-tetramethylbutyl isocyanide. H

NMR (400 MHz, [D₆]DMSO): δ = 7.85 (br. m, 1 H, 11-H), 7.55

(br. s, 1 H, 12-NH), 3.74–3.81 (m, 2 H, 2ϫ10-H), 2.99–3.14 (m, 3

H, 7-H, 2ϫ8-H), 2.73–2.81 (m, 2 H, 2-H, 4-H), 2.19–2.34 (m, 4

H, 2-H, 4-H, 1-H, 5-H), 1.94–2.01 (m, 2 H, 1-H, 5-H), 1.81 (s, 2

H, 2ϫ2-H of TMB), 1.70–1.78 (m, 2 H, 2ϫ9-H), 1.43 (s, 6 H,

2ϫ1-Me of TMB), 0.94 (s, 9 H, 3ϫ3-Me of TMB) ppm. ¹H NMR

N-Cyclohexyl-3-thia-7,11-diazaspiro[5.6]dodec-11-en-12-amine Hy-

drochloride (Table 5, entry 5): This compound was produced

through the MCR of propane-1,3-diamine, tetrahydro-4H-thiopy-

ran-4-one, and cyclohexyl isocyanide. ¹H NMR (400 MHz, [D₆]-

3

(400 MHz, CDCl₃): δ = 9.20 (br. t, J_H,H= 4.9 Hz, 1 H, 11-H),

3

5.86 (br. s, 1 H, 12-NH), 4.19–4.26 (m, 2 H, 2ϫ10-H), 3.20–3.30

(m, 2 H, 2ϫ8-H), 2.95–3.03 (m, 2 H, 2-H, 4-H), 2.33–2.42 (m, 4

H, 1-H, 2-H, 4-H, 5-H), 2.26 (br. t, ³J_H,H= 6.1 Hz, 1 H, 7-H), 1.95

(s, 2 H, 2ϫ2-H of TMB), 1.80–1.91 (m, 4 H, 1-H, 5-H, 2ϫ9-H),

1.67 (s, 6 H, 2 ϫ 1-Me of TMB), 1.05 (s, 9 H, 3 ϫ 3-Me of

TMB) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ = 172.0, 61.5,

58.5, 49.6, 42.2, 38.9, 32.8, 31.4, 29.5, 22.3 ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 170.1, 61.6, 59.4, 52.8, 43.2, 40.3, 35.1,

31.9, 31.8, 29.9, 28.6, 23.0 ppm. HRMS: calcd. for C₁₇H₃₃N₃S [M

+ H]⁺312.2468; found 312.2468.

DMSO): δ = 9.22 (br. m, 1 H, 11-H), 8.22 (br. d, J_H,H= 8.0 Hz,

1 H, 12-NH), 3.70–3.75 (m, 1 H, NCH of cyclohexyl), 3.55–3.63

(m, 2 H, 2ϫ10-H), 2.97–3.08 (m, 3 H, 7-H, 2ϫ8-H), 2.74–2.82

(m, 2 H, 2-H, 4-H), 2.25–2.34 (m, 2 H, 2-H, 4-H), 2.07–2.17 (m, 2

H, 1-H, 5-H), 1.96–2.04 (m, 2 H, 1-H, 5-H), 1.52–1.79 (m, 7 H),

1.23–1.41 (m, 4 H), 0.98–1.11 (m, 1 H) (6ϫCH₂) ppm. ¹³C NMR

(100 MHz, [D₆]DMSO): δ = 171.3, 60.5, 51.7, 41.1, 38.9, 33.2, 31.3,

29.7, 25.2, 24.8, 22.3 ppm. HRMS: calcd. for C₁₅H₂₇N₃S [M +

H]⁺282.1998; found 282.1995.

tert-Butyl 12-(Cyclohexylamino)-3,7,11-triazaspiro[5.6]dodec-11-

ene-3-carboxylate Hydrochloride (Table 5, entry 6): This compound

was produced through the MCR of propane-1,3-diamine, N-Boc-

2-(1-Methyl-1H-pyrrol-2-yl)-N-(1,1,3,3-tetramethylbutyl)-2,5,6,7-

tetrahydro-1H-1,4-diazepin-3-amine Hydrochloride (Table 5, en-

try 10): This compound was produced through the MCR of pro-

pane-1,3-diamine, 1-methylpyrrole-2-carbaldehyde, and 1,1,3,3-tet-

ramethylbutyl isocyanide. ¹H NMR (400 MHz, [D₆]DMSO): δ =

8.76 (br. s, 1 H, 4-H), 8.41 (br. s, 1 H, 3-NH), 6.78–6.81 (m, 1 H,

Pyr-H), 5.95–5.99 (m, 1 H, Pyr-H), 5.84–5.87 (m, 1 H, Pyr-H), 5.48

(s, 1 H, 2-H), 3.70–3.80 (m, 1 H, 5-H), 3.59 (s, 3 H, N-Me), 3.52–

3.64 (m, 1 H, 5-H), 3.22–3.28 (m, 1 H, 7-H), 2.78–2.87 (m, 1 H, 7-

piperidin-4-one, and cyclohexyl isocyanide. ¹H NMR (400 MHz,

3

[D₆]DMSO): δ = 9.24 (br. m, 1 H, 11-H), 8.01 (br. d, J_H,H

=

7.8 Hz, 1 H, 12-NH), 3.64–3.85 (m, 3 H, 2-H, 4-H, NCH of cyclo-

hexyl), 3.57–3.63 (m, 2 H, 2ϫ10-H), 2.88–3.10 (m, 3 H, 7-H, 2ϫ8-

H), 2.75–2.85 (m, 2 H, 2-H, 4-H), 1.50–1.94 (m, 11 H), 1.18–1.36

(m, 4 H), 0.98–1.11 (m, 1 H) (8ϫCH₂), 1.37 (s, 9 H, tBu) ppm.

¹³C NMR (100 MHz, [D₆]DMSO): δ = 171.1, 154.2, 79.2, 59.4,

51.8, 41.6, 32.1, 31.3, 29.9, 28.6, 25.2, 24.8 ppm. HRMS: calcd. for

C₂₀H₃₆N₄O₂[M + H]⁺365.2911; found 365.2913.

2

H), 2.39–2.46 (br. m, 1 H, 1-H), 1.97 (d, J_H,H= 15.2 Hz, 1 H, 2-

H of TMB), 1.46–1.70 (m, 2 H, 2ϫ6-H), 1.56 (d, ²J_H,H= 15.2 Hz,

1 H, 2-H of TMB), 1.42 (s, 3 H, 1-Me of TMB), 1.41 (s, 3 H, 1-

Me of TMB), 0.95 (s, 9 H, 3ϫ3-Me of TMB) ppm. ¹³C NMR

(100 MHz, [D₆]DMSO): δ = 167.3, 124.8, 124.7, 109.4, 107.0, 58.1,

57.7, 50.2, 44.8, 43.9, 34.5, 31.8, 31.5, 30.3, 28.9, 28.1 ppm. HRMS:

calcd. for C₁₈H₃₂N₄[M + H]⁺305.2700; found 305.2705.

N-Cyclohexyl-2-(4-methoxyphenyl)-2,5,6,7-tetrahydro-1H-1,4-diaz-

epin-3-amine Hydrochloride (Table 5, entry 7): This compound was

produced through the MCR of propane-1,3-diamine, 4-methoxy-

benzaldehyde, and cyclohexyl isocyanide. ¹H NMR (400 MHz,

3

[D₆]DMSO): δ = 9.78 (br. m, 1 H, 4-H), 9.52 (br. d, approx. J_H,H

3

tert-Butyl 5-[(1,1,3,3-Tetramethylbutyl)amino]-1,4,9-triaza-

spiro[5.5]undec-4-ene-9-carboxylate Hydrochloride (28): This com-

pound was produced through the MCR of ethylenediamine, N-Boc-

piperidin-4-one, and 1,1,3,3-tetramethylbutyl isocyanide, General

= 5 Hz, 1 H, 3-NH), 7.16 (d, J_H,H= 8.6 Hz, 2 H, 2ϫAr-H), 6.99

3

(d, J_H,H= 8.6 Hz, 2 H, 2ϫAr-H), 5.21 (d, J_H,H= 3.9 Hz, 1 H,

2-H), 3.76–3.85 (m, 1 H, NCH of cyclohexyl), 3.74 (s, 3 H, OMe),

3.62–3.68 (m, 1 H, 5-H), 3.39–3.48 (m, 1 H, 5-H), 2.90–3.00 (m, 1

H, 7-H), 2.75–2.83 (m, 1 H, 7-H), 2.60–2.70 (br. m, 1 H, 1-H),

1.84–1.96 (m, 2 H, 2ϫ6-H), 1.64–1.75 (m, 2 H), 1.04–1.61 (m, 8

H) (5ϫCH₂) ppm. ¹³C NMR (100 MHz, [D₆]DMSO): δ = 167.1,

159.2, 128.3, 126.8, 114.9, 61.3, 55.6, 51.4, 43.2, 42.8, 31.6, 31.5,

29.8, 25.2, 24.6, 24.5 ppm. HRMS: calcd. for C₁₈H₂₇N₃O [M +

H]⁺302.2227; found 302.2228.

1

procedure B, yield 67%. H NMR (400 MHz, CDCl₃): δ = 10.08

(br. s, 1 H, 4-H, exch. D₂O), 5.85 (br. s, 1 H, 5-NH, exch. D₂O),

3

3.85–4.05 (m, 2 H, 8-H, 10-H), 3.78 (t, J_H,H= 4.8 Hz, 2 H, 2ϫ3-

3

H), 3.16–3.32 (m, 2 H, 8-H, 10-H), 3.03 (t, J_H,H= 4.8 Hz, 2 H,

2ϫ2-H), 2.40 (br. s, exch. D₂O, 1 H, 1-H), 1.92–2.05 (m, 4 H, 7-

H, 11-H, 2ϫ2-H of TMB), 1.61–1.76 (m, 2 H, 7-H, 11-H), 1.67 (s,

6 H, 2ϫ1-Me of TMB), 1.46 (s, 9 H, tBu), 1.05 (s, 9 H, 3ϫ3-Me

of TMB) ppm. ¹³C NMR APT (100 MHz, CDCl₃): δ = 164.9 (C),

154.7 (C), 80.3 (C), 58.8 (C), 55.0 (CH₂), 52.2 (CH₂), 42.8 (C), 36.5

(CH₂), 33.8 (C), 32.0 (CH₂), 31.8 (CH₃), 29.0 (CH₃), 28.6

(CH₃) ppm. HRMS: calcd. for C₂₁H₄₀N₄O₂[M + H]⁺381.3224;

found 381.3219.

N-Cyclohexyl-2-(1-methyl-1H-pyrrol-2-yl)-2,5,6,7-tetrahydro-1H-

1,4-diazepin-3-amine Hydrochloride (Table 5, entry 8): This com-

pound was produced through the MCR of propane-1,3-diamine, 1-

methyl-pyrrole-2-carbaldehyde, and cyclohexyl isocyanide. ¹H

NMR (400 MHz, [D₆]DMSO): δ = 9.58 (br. s, 1 H, 4-H), 9.31 (br.

3

d, J_H,H= 6.3 Hz, 1 H, 3-NH), 6.78–6.80 (m, 1 H, Pyr-H), 5.93–

3

5.96 (m, 1 H, Pyr-H), 5.83–5.85 (m, 1 H, Pyr-H), 5.30 (d, J_H,H

=

General Procedure for the MCR/de-Boc Sequence of 1,2-Phenylene-

2.5 Hz, 1 H, 2-H), 3.64–3.78 (m, 1 H, NCH of cyclohexyl), 3.60 (s, diamine, N-Boc-piperidin-4-one, and Isocyanides: A mixture of 1,2-

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Eur. J. Org. Chem. 2010, 1525–1543

Multicomponent Strategy for 2-Amino-1,4-diazaheterocycles

phenylenediamine (21.6 g, 0.2 mol), N-Boc-piperidin-4-one (39.8 g,

0.2 mol), and CH₂Cl₂(800 mL) was stirred for 2 h at ambient tem-

perature, solvent was removed under reduced pressure, the oily resi-

due was treated with hexane, and the resulting mixture was stirred

to form a semi-solid precipitate. The solvent was removed by de-

cantation and the precipitate was dried on a rotary evaporator to

remove residual solvent and dissolved in CH₃CN (1500 mL).

TMSCl (21.7 g, 0.2 mol) was added dropwise to the obtained solu-

tion, the mixture was stirred for 1 h, isocyanide (0.2 mol) was

added in one portion, and the resulting mixture was stirred at 50 °C

for 5 h and allowed to cool. The formed precipitate was filtered off,

washed with CH₃CN and Et₂O, dried, and added portionwise to a

stirred solution of HCl in EtOH/EtOAc (6 , 200 mL, preliminarily

prepared from AcCl and EtOH). The reaction mixture was stirred

at ambient temperature for 1 h to allow the reaction to go to com-

pletion (LC-MS monitoring). The residue after solvent removal was

dissolved in water, aq. NaOH (2 ) was added to achieve pH 9, and

the mixture was extracted with CHCl₃. The organic layer was

washed with water and brine, dried (Na₂SO₄), and concentrated.

After residue sonification with an excess of hexane, a precipitate

was filtered off and washed with hexane. The following are data

for spiro-piperazines obtained by this procedure.

TFA-Induced Cleavage: A mixture of compound 28 (208 mg,

0.5 mmol), CH₂Cl₂(2 mL), and TFA (1 mL) was stirred overnight

and the solvents were evaporated to dryness under reduced pres-

sure. The residue was dissolved in THF and treated with an excess

of HCl in dioxane (8 ) and then with Et₂O. The white precipitate

was separated by centrifugation, washed with acetonitrile and then

EtOAc, followed each time by centrifugation, and dried. Yield

160 mg (86%) of compound 30.

HCl-Induced Cleavage: A mixture of compound 28 (208 mg,

0.5 mmol) and of HCl in EtOAc/EtOH (6 , 2 mL, prepared from

AcCl and EtOH) was stirred for 2 h and then treated with an excess

of Et₂O. The white precipitate was centrifuged, washed with Et₂O,

acetonitrile, and EtOAc, and dried. Yield 170 mg (92%) of com-

pound 30.

Data for Compound 30: ¹H NMR (400 MHz, [D₆]DMSO): δ = 9.47

(br. m, 1 H, N–H, exch. D₂O), 9.22 (br. s, 1 H, N–H, exch. D₂O),

9.06 (br. m, 1 H, N–H, exch. D₂O), 8.50 (br. s, 1 H, N–H, exch.

D₂O), 3.65–3.75 (m, 2 H, 2ϫ3-H), 3.27–3.57 (m, 6 H, 2ϫ2-H,

2ϫ8-H, 2ϫ10-H), 3.10–3.24 (m, 2 H, 7-H, 11-H), 2.42–2.52 (m,

2 H, 7-H, 11-H), 1.83 (s, 2 H, 2ϫ2-H of TMB), 1.51 (s, 6 H, 2ϫ1-

Me of TMB), 0.97 (s, 9 H, 3ϫ3-Me of TMB) ppm. ¹³C NMR APT

(100 MHz, [D₆]DMSO): δ = 161.9 (C), 59.4 (C), 55.6 (CH₂), 49.4

(C), 40.0 (CH₂), 39.2 (CH₂), 35.6 (CH₂), 32.1 (CH₂), 31.6 (CH₃),

29.6 (CH₃), 28.4 (C) ppm. HRMS: calcd. for C₁₆H₃₂N₄[M + H]⁺

281.2700; found 281.2699.

N-Cycloheptyl-1ЈH-spiro[piperidine-4,2Ј-quinoxalin]-3Ј-amine (27a):

1

Yield 51.2 g (82%). H NMR (400 MHz, [D₆]DMSO): δ = 6.74 (d,

3

³J_H,H= 7.7 Hz, 1 H, Ar-H), 6.66 (d, J_H,H= 7.7 Hz, 1 H, Ar-H),

3

6.57 (t, J_H,H= 7.7 Hz, 1 H, Ar-H), 6.45 (t, J_H,H= 7.7 Hz, 1 H,

Cleavage of the TMB Group in Compounds 28 and 30. Synthesis of

1,4,9-Triazaspiro[5.5]undec-4-en-5-amine Trihydrobromide (29): A

mixture of compound 28 or 30 (0.3 mmol) and HBr in AcOH

(33%, 2 mL) was stirred at 80 °C for 2 h and was then treated with

excess Et₂O. The resulting white precipitate was centrifuged,

washed with Et₂O, acetonitrile, and EtOAc, and dried. Yields of

compound 29: 75% (from compound 28) and 83% (from com-

pound 30).

3

Ar-H), 5.94 (br. d, J_H,H= 7.3 Hz, 1 H, 3Ј-NH), 5.71 (br. s, 1 H,

1Ј-H), 3.95–4.04 (m, 1 H, NCH of cycloheptyl), 2.74–2.85 (m, 2 H,

2-H, 5-H), 2.55–2.64 (m, 2 H, 2-H, 5-H), 1.85 (br. s, 1 H, 1-H),

1.26–1.83 (m, 16 H, 8 ϫCH₂) ppm. ¹³C NMR (100 MHz, [D₆]-

DMSO): δ = 158.2, 135.9, 135.7, 122.9, 122.1, 118.3, 114.1, 51.3,

51.0, 40.8, 34.5, 32.3, 28.6, 24.7 ppm. HRMS: calcd. for C₁₉H₂₈N₄

[M + H]⁺313.2387; found 313.2387.

N-(2-Methylbenzyl)-1ЈH-spiro[piperidine-4,2Ј-quinoxalin]-3Ј-amine

Data for Compound 29: ¹H NMR (400 MHz, [D₆]DMSO): δ = 9.77

(br. s, 1 H, N–H, exch. D₂O), 9.16 (br. m, 1 H, N–H, exch. D₂O),

8.91 (br. s, 1 H, N–H, exch. D₂O), 8.78 (br. s, 1 H, N–H, exch.

D₂O), 8.07 (br. m, 2 H, 2ϫN–H, exch. D₂O), 7.35 (br. s, 2.2 H,

N–H and H₂O, exch. D₂O), 3.41 (br. t, 2 H, 2ϫ3-H), 3.23–3.36

(m, 4 H, 2ϫ8-H, 2ϫ10-H), 3.18 (br. t, 2 H, 2ϫ2-H), 2.23–2.42

(m, 4 H, 2ϫ7-H, 2ϫ11-H) ppm. ¹³C NMR APT (100 MHz, [D₆]-

DMSO): δ = 166.3 (C), 54.7 (C), 38.1 (CH₂), 36.8 (CH₂), 36.0

(CH₂), 28.3 (CH₂) ppm. HRMS: calcd. for C₈H₁₆N₄[M + H]⁺

169.1448; found 169.1448.

1

(27b): Yield 46.1 g (72%). H NMR (400 MHz, [D₆]DMSO): δ =

7.18 (d, ³J_H,H= 8.4 Hz, 1 H, Ar-H), 7.03–7.11 (m, 3 H, 3ϫAr-H),

3

6.85 (br. t, J_H,H= 5.5 Hz, 1 H, 3Ј-NH), 6.77 (d, J_H,H= 7.7 Hz,

3

1 H, Ar-H), 6.64 (d, J_H,H= 7.7 Hz, 1 H, Ar-H), 6.59 (t, J_H,H

7.7 Hz, 1 H, Ar-H), 6.45 (t, J_H,H= 7.7 Hz, 1 H, Ar-H), 5.80 (br.

s, 1 H, 1Ј-H), 4.40 (d, J_H,H= 5.5 Hz, 2 H, NCH₂Ar), 2.78–2.88

=

3

(m, 2 H, 2-H, 5-H), 2.59–2.67 (m, 2 H, 2-H, 5-H), 2.28 (s, 3 H,

Me), 1.94 (br. s, 1 H, 1-H), 1.69–1.78 (m, 2 H, 3-H, 5-H), 1.38–

1.45 (m, 2 H, 3-H, 5-H) ppm. ¹³C NMR: (100 MHz, [D₆]DMSO):

δ = 159.1, 138.8, 136.0, 135.9, 135.5, 130.3, 127.8, 126.9, 126.2,

123.0, 122.4, 118.3, 114.2, 51.6, 42.0, 40.7, 32.7, 19.4 ppm. HRMS:

calcd. for C₂₀H₂₄N₄[M + H]⁺321.2074; found 321.2074.

General Procedure for the Partial Oxidation of the Tetrahydropyr-

azine Ring (Synthesis of 5,6-Dihydropyrazine-2-amines 33 and 34):

The MCRs of pyridine-2- and -4-carbaldehydes with tert-butyl iso-

cyanide and ethylenediamine under the conditions of General Pro-

cedure A provided crude products (Table 3, entries 15 and 17,

respectively) that were contaminated with ethylenediamine hydro-

chloride. Attempts to purify these compounds by their conversion

into free bases as described in General Procedure A led to the tar-

get tetrahydropyrazines 31 and 32, respectively, contaminated by

dihydropyrazines 33 and 34. These mixtures were dissolved in

CHCl₃and stirred overnight in open vials. Evaporation of the sol-

vent under reduced pressure provided pure compounds 33 (55 mg,

overall yield including IMCR step 48%) and 34 (43 mg, overall

yield 37%).

N-(2-Chlorobenzyl)-1ЈH-spiro[piperidine-4,2Ј-quinoxalin]-3Ј-amine

(27c): Yield 51.0 g (75%). ¹H NMR (400 MHz, [D₆]DMSO): δ =

7.37 (d, ³J_H,H= 8.4 Hz, 1 H, Ar-H), 7.17–7.27 (m, 3 H, 3ϫAr-H),

3

7.02 (br. t, J_H,H= 5.5 Hz, 1 H, 3Ј-NH), 6.78 (d, J_H,H= 7.3 Hz,

3

1 H, Ar-H), 6.58–6.65 (m, 2 H, 2ϫAr-H), 6.44 (t, J_H,H= 7.3 Hz,

1 H, Ar-H), 5.86 (br. s, 1 H, 1Ј-H), 4.50 (d, J_H,H= 5.5 Hz, 2 H,

3

NCH₂Ar), 2.81–2.90 (m, 2 H, 2-H, 5-H), 2.63–2.69 (m, 2 H, 2-H,

5-H), 2.24 (br. s, 1 H, 1-H), 1.72–1.81 (m, 2 H, 3-H, 5-H), 1.43–

1.50 (m, 2 H, 3-H, 5-H) ppm. ¹³C NMR (100 MHz, [D₆]DMSO):

δ = 159.1, 138.0, 135.9, 135.3, 132.5, 129.6, 128.9, 128.7, 127.6,

123.1, 122.7, 118.3, 114.2, 51.6, 41.8, 40.6, 32.6 ppm. HRMS:

calcd. for C₁₉H₂₁ClN₄[M + H]⁺341.1527; found 341.1521.

Data for N-tert-Butyl-3-pyridin-2-yl-5,6-dihydropyrazin-2-amine

1

3

Procedures for Selective Cleavage of the Boc Group in Spiro Com-

pound 28. Synthesis of N-(1,1,3,3-Tetramethylbutyl)-1,4,9-triaza-

spiro[5.5]undec-4-en-5-amine Trihydrochloride (30)

(33): H NMR (400 MHz, CDCl₃): δ = 8.52 (d, J_H,H= 4.0 Hz, 1

3

H, Py-H), 8.05 (br. s, 1 H, 2-NH, exch. D₂O), 8.01 (d, J_H,H

=

8.1 Hz, 1 H, Py-H), 7.75–7.83 (m, 1 H, Py-H), 7.31–7.38 (m, 1 H,

Eur. J. Org. Chem. 2010, 1525–1543

www.eurjoc.org

1541

V. Kysil et al.

FULL PAPER

Py-H), 3.64 (t, J_H,H= 7.3 Hz, 2 H, 2ϫ6-H), 3.36 (t, J_H,H

7.3 Hz, 2 H, 2ϫ5-H), 1.43 (s, 9 H, tBu) ppm. ¹³C NMR APT

(100 MHz, CDCl₃): δ = 156.3 (C), 155.9 (C), 148.7 (C), 147.1 (CH),

137.5 (CH), 124.4 (CH), 123.6 (CH), 50.9 (C), 47.9 (CH₂), 43.1

(CH₂), 28.9 (CH₃) ppm. HRMS: calcd. for C₁₃H₁₈N₄[M + H]⁺

231.1604; found 231.1597.

3

caccini, T. Torroba, in: Multicomponent Reactions (Eds.: J. Zhu,

H. Bienaymé), Wiley-VCH, Weinheim, 2005; pp. 33–75; h) J.

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Chem. Res. 2009, 42, 463–472; m) C. Hulme, J. Dietrich, Mol.

Divers. 2009, 13, 195–207.

=

Data for N-tert-Butyl-4-pyridin-4-yl-5,6-dihydropyrazin-2-amine

1

3

(34): H NMR (400 MHz, CDCl₃): δ = 8.71 (d, J_H,H= 4.4 Hz, 2

[3]

[4]

I. Ugi, R. Meyr, U. Fetzer, C. Steinbrückner, Angew. Chem.

1959, 71, 386.

3

H, 2ϫPy-H), 7.50 (d, J_H,H= 4.4 Hz, 2 H, 2ϫPy-H), 3.90 (br. s,

1 H, 2-NH, exch. D₂O), 3.60 (t, ³J_H,H= 7.3 Hz, 2 H, 2ϫ6-H), 3.38

(t, ³J_H,H= 7.3 Hz, 2 H, 2ϫ5-H), 1.37 (s, 9 H, tBu) ppm. ¹³C NMR

APT (100 MHz, CDCl₃): δ = 158.5 (C), 150.4 (CH), 146.9 (C),

144.0 (C), 122.7 (CH), 51.8 (C), 47.8 (CH₂), 43.2 (CH₂), 28.8

(CH₃) ppm. HRMS: calcd. for C₁₃H₁₈N₄[M + H]⁺231.1604;

found 231.1605.

For the excellent most recent comprehensive review of less con-

ventional versus “classic” Ugi IMCR interactions between iso-

cyanides and iminium species following by trapping (including

intramolecular) of nitrilium cation by N-, C-, O-, and S-nucleo-

philes see: L. El Kaim, L. Grimaud, Tetrahedron 2009, 65,

2153–2171.

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For the most recent applications see: a) T. Kercher, Ch. Rao,

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b) T. Meng, Z. Zhang, D. Hu, L. Lin, J. Ding, X. Wang, J.

Shen, J. Comb. Chem. 2007, 9, 739–741.

Procedure for Aromatization of the Dihydropyrazine Ring in Com-

pound 34: A mixture of dihydropyrazine 34 (92 mg, 0.4 mmol),

DDQ (182 mg, 0.8 mmol), and CHCl₃(3 mL) was stirred in a se-

aled tube at 70 °C overnight. The reaction mixture was cooled and

filtered. Purification of the concentrated filtrate by flash

chromatography on silica (CHCl₃/THF) furnished the pyrazinam-

ine 35 (32 mg, 35%, non-optimized yield).

[6]

[7]

[8]

Procedure for Aromatization of the Dihydropyrazine Ring in Com-

pound 32 Hydrochloride: A mixture of the crude product obtained

from the MCR (Table 3, entry 17) of pyridine-4-carbaldehyde, tert-

butyl isocyanide, and ethylenediamine (107 mg, 0.4 mmol), to-

gether with Pd on charcoal (10%, 20 mg) and 2-methoxyethanol

(5 mL), was stirred and heated under reflux overnight. The reaction

mixture was filtered, the filtrate was concentrated, the residue was

dissolved in CHCl₃, and the obtained solution was washed with

aq. NaOH (10%, twice), water (twice), and then brine. The organic

layer was dried (Na₂SO₄) and concentrated, and the residue was

purified by flash chromatography on silica (CHCl₃/THF). Non-op-

timized yield of compound 35: 25 mg (27%).

[9]

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Data for N-tert-Butyl-4-pyridin-4-yl-pyrazin-2-amine (35): ¹H NMR

3

(400 MHz, CDCl₃): δ = 8.73 (d, J_H,H= 5.5 Hz, 2 H, 2ϫPy-H),

3

8.02 (d, J_H,H= 2.7 Hz, 1 H, 6-H), 7.87 (d, J_H,H= 2.7 Hz, 1 H,

3

5-H), 7.58 (d, J_H,H= 5.5 Hz, 2 H, 2ϫPy-H), 4.77 (br. s, 1 H, 2-

[15]

[16]

NH), 1.43 (s, 9 H, tBu) ppm. ¹³C NMR (100 MHz, CDCl₃): δ =

152.0, 150.7, 145.4, 141.5, 138.3, 131.9, 122.7, 52.1, 28.9 ppm.

HRMS: calcd. for C₁₃H₁₆N₄[M + H]⁺229.1448; found 229.1451.

Supporting Information (see also the footnote on the first page of

this article): ¹H NMR and ¹³C NMR spectra for all synthesized

compounds.

Acknowledgments

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The authors thank Dr. Frederick Lakner for critical reading and

correction of this manuscript.

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Received: November 25, 2009

Published Online: February 8, 2010

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www.eurjoc.org

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General multicomponent strategy for the synthesis of 2-Amino-l,4- diazaheterocycles: Scope, limitations, and utility

DOI: 10.1002/ejoc.200901360

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