Accessing Tricyclic Imines Comprising a 2-Azabicyclo[22.2]octane Scaffold by Intramolecular Hetero-Diels-Alder Reaction of 4-Alkenyl-Substituted N-Silyl-1,4-dihydropyridines

SYNTHESIS

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8

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4

3

7

-

2

1

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2019, 51, A–O

paper

A

en

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

Accessing Tricyclic Imines Comprising a 2-Azabicyclo[2.2.2]octane

Scaffold by Intramolecular Hetero-Diels–Alder Reaction of 4-Alkenyl-

Substituted N-Silyl-1,4-dihydropyridines

Heinrich-Karl A. Rudy

intramolecular cyclization

Klaus T. Wanner*

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3-4

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Ludwig-Maximilians-Universität München, Department für Pharmazie –

Zentrum für Pharmaforschung, Butenandtstr. 5-13, Haus C,

81377 Munich, Germany

1) TIPSOTf

2)

R

N

n

TFA

Mg

n

2

n

klaus.wanner@cup.uni-muenchen.de

R

N

Si(i-Pr)₃

15 examples

21–61% yield

15 examples

54–89% yield

Received: 04.07.2019

Accepted after revision: 07.08.2019

Published online: 05.09.2019

O

H

NH₂

N

NH₂

N

O^–

P

O^–

P

DOI: 10.1055/s-0039-1690619; Art ID: ss-2019-z0378-op

N

O

Abstract Tricyclic imines inheriting a 2-azabicyclo[2.2.2]octane (iso-

quinuclidine) scaffold were provided with high regioselectivity in mod-

erate to very good yields by a smooth, broadly applicable intramolecu-

lar hetero-Diels–Alder reaction of various 4--alkenyl-substituted 1,4-

dihydropyridines (DHPs) under trifluoroacetic acid catalysis. The

required 4,4-disubstituted 1,4-DHPs were obtained by introduction of

-alkenyl moieties of varying chain length via diorganomagnesium re-

agents into the 4-position of diversely 4-substituted pyridines after pri-

or N-activation with triisopropylsilyltriflate.

O

O H

OH

O

OH OH

1

R

NO₂

CO₂Et

n

EtO₂C

HN

N

Act.

Key words intramolecular hetero-Diels–Alder reaction, 2-azabicy-

clo[2.2.2]octane, polycycles, 1,4-dihydropyridines, diorganomagne-

sium reagents, heterocycles

N

H

2

3

4

Figure 1 Structures of NADH (1), nifedipine (2), general structure of a

4--alkenyl-substituted 1,4-DHP 3 and 2-azabicyclo[2.2.2]octane (4)

The 1,4-dihydropyridine (1,4-DHP) moiety is a common

scaffold frequently found in compounds of synthetic or nat-

ural origin with important biological activities. Prominent

examples to be mentioned are nicotinamide adenine dinu-

cleotide (NADH (1), Figure 1), which is an ubiquitous coen-

zyme for redox reactions in cells, or nifedipine (2), which is

listed by the WHO for healthcare systems as an essential

drug for the treatment of hypertension.¹Throughout the

years, many different concepts for the synthesis of 1,4-

DHPs have been published which are commonly either

based on Hantzsch-type condensation reactions or 1,4-ad-

dition of nucleophiles to pyridinium salts, mostly N-acyl

pyridinium and N-alkyl pyridinium salts.^1a,c,2

Whereas a large variety of either 4-mono- or 4,4-disub-

stituted 1,4-DHPs with alkyl or aryl residues in the 4-posi-

tion have been synthesized, only limited examples of 1,4-

DHPs 3 with a 4--alkenyl substituent are known. Thereby,

the most prevalent 4--alkenyl moiety is the allyl residue.

Known 4-allyl-monosubstituted 1,4-DHPs have almost ex-

clusively been generated by addition of organometallic

derivatives such as allylcalcium,³allylstannane,⁴allylmag-

nesium reagents,⁵or allylcuprates⁶to either N-acyl^4a,7and

N-alkylpyridinium ions^5b,6or pyridines lacking prior activa-

tion.^3,8

All these methods suffer from severe drawbacks such as

a poor regioselectivity for competing 1,4- and 1,2-addition

reactions, high toxicity, and laborious methods for the

preparation of the required organometallic reagents or the

need for pyridine rings equipped with residues for neigh-

boring-group assistance. Syntheses of 4-monosubstituted

1,4-DHPs with as compared to the allyl unit extended -

alkenyl chains in 4-position are, however, scarce. Few such

compounds were obtained either only as side products in

syntheses by Krow et al. and Comins et al. aiming at the

construction of 2--alkenyl-substituted 1,2-DHPs or by

Rudler et al. by employing silyl ketene acetals, derived from

pent-4-enoic and hex-5-enoic acid, in addition reactions to

pyridinium ions.⁹

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

Even less explored are the syntheses of 4,4-disubstitut-

ed 1,4-DHPs with one of the two 4-substitutents being an

-alkenyl moiety. So far such compounds have only been

isolated by Wanner et al., Krow et al., and Okuda et al.,

though they provide a highly useful synthetic access to iso-

quinuclidine derivatives.^3a,9a,10The isoquinuclidine ring

system 4 (2-azabicyclo[2.2.2]octane) is found in many alka-

loids, e.g., in ibogaine, and has also been used as intermedi-

ate in the synthesis of oseltamivir.¹¹Examples demon-

strating the accessibility of compounds with an 2-azabicy-

clo[2.2.2]octane skeleton as core unit by employing

4-monosubstituted 1,4-DHPs, obtained by Hantzsch dihy-

dropyridine syntheses, in inter- or intramolecular cycliza-

tion reactions have been published by Hartman et al.

(Scheme 1).^10a,12The use of 4,4-disubstituted N-silyl 1,4-

DHPs obtained from trapping reactions of N-dihydropyri-

dinium ions with nucleophiles in inter- or intramolecular

hetero-Diels–Alder reactions under acidic conditions has

been demonstrated by us.^10a,12

lecular cyclization reactions to give the corresponding tri-

cyclic imines with

a

2-azabicyclo[2.2.2]octane core

structure.^10,13

To study the feasibility of the introduction of -alkenyl

moieties (other than allyl groups) into the 4-position of

4-substituted pyridine derivatives, as the first step of the

overall sequence for the preparation of isoquinuclidine de-

rivatives, 4-methylpyridine 5a was chosen as model system,

because the methyl group gives neither rise to large steric

nor electronic effects. Furthermore, based on the knowl-

edge from previous experiments that aimed at the synthe-

sis of 4,4-disubstituted 1,4-dihydropyridines, only dior-

ganomagnesium reagents should be used, at least for initial

experiments, because these had proven superior reactivity

as compared to Grignard reagents.^10b,13a,b

For the first experiments, a but-4-en-1-yl residue was

chosen for the addition reactions to 4-methylpyridine (5a).

When 4-methylpyridine (5a) was treated with TIPSOTf (1.1

equiv) in CH₂Cl₂at 20 °C for 15 min to generate the pyridin-

ium ion 6a and subsequently with di(but-3-en-1-yl)magne-

sium (2 equiv in THF/Et₂O, 1:1) at –78 °C followed by slowly

warming the reaction mixture to –50 °C (Table 1, entry 1),

the desired 1,4-dihydropyridine 7a could be obtained in a

yield of 22%. Similar low yields had been observed before

for the addition of allyl residues to 4-substituted pyridines

after prior N-silylation.¹⁰However, to our delight with a ra-

tio of 81:19 in favor of the 1,4-dihydropyridine 7a as com-

pared to the 1,2-dihydropyridine 8a, the regioselectivity

was quite satisfying.

Previous work:

Hartman et al.¹²

R

R'

X

inter- or

intramolecular

cyclizations with

R

n

CO₂Me

X

n

R'

alkenes or

heteroaromatics

MeO₂C

CO₂Me

various cond.

N

CO₂Me

N

H

Schmaunz et al.^10a

In subsequent reactions, the crude reaction products

obtained after aqueous workup were analyzed with regard

1

R'

R

to their composition by H NMR spectroscopy using 2,4,6-

R

collidine as internal standard for quantification. That way

the amount of formed 1,4-dihydropyridine 7a could be di-

rectly determined (‘NMR’ yield). In addition, at the same

time also the amount of formed 1,2-dihydropyridine 8a

could be directly specified, which was otherwise strongly

impeded as 1,2-dihydropyridines are generally higher sus-

ceptible to oxidation typically resulting in the formation of

the corresponding aromatic systems.

Though in case of the addition of a tert-butyl moiety to

a N-silylpyridinium ion lowering the temperature from

–78 °C to –85 °C had been found beneficial with regard to

the yield of the 1,4-addition product,^13athe opposite was

true in the present case employing di(but-3-en-1-yl)mag-

nesium as nucleophile. When the addition of di(but-3-en-

1-yl)magnesium to 6a was performed at –85 °C, only a di-

minished yield of 8% was obtained (Table 1, entry 2 vs. en-

try 1).^13aHence, in further experiments pyridinium ion 6a

was treated with di(but-3-en-1-yl)magnesium at –60 °C,

–40 °C, and –30 °C, respectively (Table 1, entries 3–5).

Thereby, the yield for the 4-addition product 7a rose from

29% (Table 1, entry 3) to 33% (Table 1, entry 4), and finally to

41% (Table 1, entry 5). Additionally, in all three experiments

an improved regioselectivity of 92:8 independent from the

inter- or

intramolecular

cyclizations with

alkenes

HCl / EtOH

N

R'

N

Si(i-Pr)₃

This work:

R

n

intramolecular

cyclizations with

alkenes

variation of ring

size

n

TFA / pentane

R

N

Si(i-Pr)₃

Scheme 1 Comparison of previously reported and present syntheses

accessing compounds with a 2-azabicyclo[2.2.2]octane core unit

This had also included the preparation of 4-allyl-substi-

tuted N-silyl-1,4-DHP and their intramolecular cyclization

to give the corresponding 2-azabicyclo[2.2.2]octane deriva-

tives. With the present study we intended to develop a

method giving for the first time access to a broad range of

4,4-disubstituted N-silyl-1,4-DHP with one of the 4-substit-

uents in the 4-position being an -alkenyl residue of vary-

ing chain length which should finally be used for intramo-

C

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

Table 1 Optimization of the Addition of Di(but-3-en-1-yl)magnesium to N-TIPS 4-Methylpyridinium Triflate 6a

–

TfO

Mg

2

1.1 equiv TIPSOTf

+

CH₂Cl₂, 20 °C, 15 min

temp, time

N

Si(i-Pr)₃

5a

6a

7a

8a

Entry

R₂Mg (equiv)

Temp (°C)

Time (h)

NMR yield (%)^a

NMR ratio of 7a/8a^aIsolated yield of 7a (%)

7a

8a

Total

b

1

2

3

4

5

6

7

8

9

2.0

1.1

0.55

1.1

–78 to –50

–85

2

–

6

81:19^c

22

8

d

6

29

34

43

45

41

44

–

–60

2

3

4

2

31

37

47

49

45

48

46

92:8

91:9

96:4

29

33

41

–40

2

–30

2

e

0

2

–

42

44

–30

2

–30

2

–30

18

^aThe yield of 7a and 8a in the crude product and the product ratio were determined by ¹H NMR spectroscopy with 2,4,6-collidine as internal standard. Upward

deviations of the isolated yield from the NMR yield are within the expected accuracy of measurement. ¹⁴

^bNot determined.

^cDetermined using ¹H NMR spectroscopy without internal standard.

^dNot determinable due to low signal intensity.

^eNot determinable due to the formation of inseparable side products.

reaction temperature was observed (Table 1, entries 3–5). A

further increase of the temperature to 0 °C led only to a mi-

nor improvement of the NMR yield (compare Table 1, en-

tries 5 and 6) with the regioselectivity being unchanged.

However, due to extensive formation of inseparable side

products, this result could not be confirmed as no pure

product could be isolated. Hence, a temperature of –30 °C

was considered best for performing trapping reactions of

intermediate pyridinium ions such as 6a and was therefore

applied for further experiments.

In order to render the trapping reactions of the pyridini-

um ions more economic, it was intended to reduce the

equivalents of the diorganomagnesium species employed.

Accordingly, in the next experiments only 1.1 or

0.55 equivalents, respectively, of di(but-3-en-1-yl)magne-

sium have been applied. In both cases, the yield of the main

regioisomer 7a, the 4-addition product, as well as the ratio

of regioisomers (7a/8a) remained largely unchanged in

comparison to the reaction performed under identical con-

ditions, but with 2.0 equivalents of di(but-3-en-1-yl)mag-

nesium (Table 1, entries 5, 7, and 8). Also the extension of

the reaction time from 2 h to 18 h for the trapping of the

intermediate N-silylpyridinium ion 6a with 1.1 equivalents

of the diorganomagnesium species (at –30 °C) did not

markedly alter the outcome of the reaction (Table 1, entry 9

vs. entry 7), the yield and the regioselectivity being only

slightly increased (yield 44%, 7a/8a = 96:4; Table 1, entry 9),

indicating that the reaction is mostly complete within 2 h.

Though the application of 0.55 equivalents of the diorgano-

magnesium species for the trapping reaction had actually

led to a slightly better product yield (44% vs. 42%), future

reactions were intended to be performed with

1.1 equivalents of the diorganomagnesium species as this

was thought to be more reliable, whereas 0.55 equivalents

should only be used when the organometallic species is te-

dious to prepare.

Next, the so far developed standard reaction conditions

were utilized to perform addition reactions with a set of

differently 4-substituted pyridine derivatives including 5a,

i.e., 5a–e, employing diorganomagnesium species exhibit-

ing either allyl, homoallyl, or pent-4-en-1-yl residues as nu-

cleophiles. When the pyridine derivatives 5b–e after activa-

tion with 1.1 equivalents of TIPSOTf in CH₂Cl₂were treated

with 1.1 equivalents of di(but-3-en-1-yl)magnesium at

–30 °C for 18 h according to the aforementioned standard

procedure, the addition products 7b–e and 8b–e were ob-

tained in fair to good overall yields (Table 2, entries 2–5: to-

tal NMR yields 40–80%; 7b–e 35–54%). In any case, the de-

sired 1,4-addition products 7b–e were clearly predominat-

ing though the regioselectivity observed for the addition of

di(but-3-en-1-yl)magnesium to pyridine 5a of 96:4

(7a/8a = 96:4, Table 2, entry 1 identical to Table 1, entry 9)

had dropped to 76:24 to 88:12 (Table 2, entries 2–5). This

reduction of regioselectivity is likely to be attributed to the

D

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

Table 2 Trapping of Various 4-Substituted N-TIPS-Pyridinium Ions with Di(-alkenyl)magnesium Reagents

R

–

TfO

1) 1.1 equiv TIPSOTf

CH₂Cl₂, 20 °C, 15 min

2) 1.1 equiv

Mg

n

2

–30 °C, 2–18 h

+

n

N

Si(i-Pr)₃

A

B

5a–e

6a–e

n = 1

n = 2

n = 0

7a–e

9a–e

11a–e

8a–e

10a–e

12a–e

Entry

Starting material

n

Time (h)

Products

NMR yield (%)^a

NMR ratio of A/B^aIsolated yield of A (%)

R

A

B

A

B

Total

46^b

80

40

57

52

45

69

43

79

57

58

79

68

60

79

1

2

5a

5b

5c

5d

5e

5a

5b

5c

5d

5e

5a

5b

5c

5d

5e

Me

Ph

Bn

1

18

2

7a

7b

8a

8b

44

62

35

45

40

44

62

38

62

45

33

35

21

24

22

2^b

18

5

96:4^b

78:22

88:12

79:21

76:24

98:2

44^b

54

35

40

39

43

59

37

61

41

35

33

21

23

3

7c

8c

4

4-MeOC₆H₄

1

2

0

7d

8d

12

1

5

4-MeOC₆H₄CH₂

7e

8e

6

Me

9a

10a

10b

10c

10d

10e

12a

12b

12d

12e

7

Ph

9b

7

90:10

88:12

78:22

79:21

57:43

44:56

31:69

37:63

28:72

8

Bn

18

2

9c

5

9

4-MeOC₆H₄

4-MeOC₆H₄CH₂

Me

9d

17

12

25

44

47

40

57

10

11

12

13

14

15

9e

11a

11b

11c

11d

11e

Ph

2

Bn

2

4-MeOC₆H₄

4-MeOC₆H₄CH₂

2

^aThe yield of A and B in the crude product and the product ratio were determined using ¹H NMR spectroscopy with 2,4,6-collidine as internal standard. Upward

deviations of the isolated yield from the NMR yield are within the expected accuracy of measurement. ¹⁴

^bIdentical to Table 1, entry 9.

increased steric demand of the 4-substitutents in 5b–e as

compared to that of the 4-methyl group in 5a hampering

the addition of the nucleophiles to the 4-position of the N-

silylpyridinium ions 6b–e. 1,4-Dihydropyridines 7b–e

could be easily separated from 1,2-dihydropyridines 8b–e

despite their physiochemical similarities. This was accom-

plished in a two-step sequence by first exposing the crude

reaction mixture to air for oxidation, to which the 1,2-dihy-

dropyridines were far more susceptible than the corre-

sponding 1,4-dihydropyridines, the latter of which could

then easily be isolated by column chromatography.

The optimized conditions proved also well suited for the

addition of a pent-4-en-1-yl moiety to the N-silylpyridini-

um ions 6a–e. When the N-silylpyridinium salts 6a–e were

reacted with di(pent-4-en-1-yl)magnesium, the 1,4- and

1,2-addition products 9a–e and 10a–e were obtained in

good overall yield. Thereby, the obtained results closely re-

flect the outcome of the but-4-en-1-yl addition reactions,

not only in regard of the overall yield (Table 2, entries 6–10:

total NMR yields 43–79%; 9a–e 37–61%), but also of the re-

gioselectivity (from 78:22 up to 98:2; see Table 2, entries 6–

10). Only for the addition of the pent-4-en-1-yl residue to

activated pyridinium derivative 5d an exception was found.

In that case, the yields for 9d/10d and pure 9d were dis-

tinctly higher than the yields observed for the addition of

di(but-3-en-1-yl)magnesium to this pyridinium salt (Table

2, entry 9 vs. entry 4).

Finally, the optimized reaction conditions were applied

to the addition of an allyl moiety to the 4-substituted pyri-

dine derivatives 5a–e via their iminium salts 6a–e in order

to construct the corresponding 4-allyl-substituted 1,4-di-

hydropyridines (Table 2, entries 11–15). This had previous-

ly proved to be quite challenging since the desired 4-allyl-

substituted 1,4-dihydropyridines could be isolated^10,13bin

low yields only, either due to the formation of complex re-

action mixtures or due to the preferred 2-addition of the al-

lyl residue.

E

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

Although the yields for the 1,4-dihydropyridines 11a–e

(Table 2, entries 11–15) were still in a low range, and the re-

gioselectivity was predominantly on the side of the 2-addi-

tion product, significant improvements could be achieved.

For the synthesis of the known 4-phenylpyridine-derived

1,4-dihydropyridine 11b (Table 2, entry 12) the yield rose

to 33% (lit. ^10b20%) and the regioselectivity of 44:56

(lit.^10b20:78) was notably shifted towards the formation of

the 4-addition product. A raise in yield to 21% (lit.^10b12%)

and a shift in regioselectivity to 31:69 (lit.^10b21:70) could

also be observed for the synthesis of the 4-benzyl-substi-

tuted 1,4-dihydropyridine 11c (Table 2, entry 13), albeit to

a lesser extent. The differences regarding yield and regiose-

lectivity are likely to be due to the distinctly higher reaction

temperature compared to the one applied in the reactions

described in literature leading to a, in our case advanta-

geous, less 2-selective addition reaction.^10b,13bFor the

addition of an allyl moiety to the 4-methylpyridine (5a)

derived iminium salt 6a even a preference for the 1,4-

dihydropyridine 11a could be observed, the ratio of isomers

amounting to 57:43 (Table 2, entry 11), which is presum-

ably to be assigned to the lower steric hindrance of the

methyl group in iminium salt 6a as compared to that of the

4-residues in 6b–e. Within this row, also the syntheses of

1,4-dihydropyridines 11d–e from the corresponding imini-

um salts 6d and 6e proceeded successfully with yields of

23% and with a ratio of isomers of 37:63 (for 11d) and

28:72 (for 11e), respectively.

With the 4--alkenyl-substituted 1,4-dihydropyridines

7a–e, 9a–e, and 11a–e in hand the intramolecular hetero-

Diels–Alder reactions of these compounds were studied.

Here, as in literature the term hetero-Diels–Alder reaction

is used to denote [4+2] cycloaddition reactions indepen-

dent of whether these reactions proceed via a concerted or

stepwise reaction mechanism, an issue not yet clarified for

the present and closely related transformation reac-

tions.^10a,12,15

Intramolecular cycloaddition reactions of 4,4-disubsti-

tuted 1,4-dihydropyridines displaying, e.g., an allyl residue

in the 4-position of an N-silyl-1,4-dihydropyridine under

acid-catalyzed reaction conditions have already been re-

ported before by us (see example from literature; Table 3,

entry 1).^10aThereby, the respective N-silyl-1,4-dihydropyri-

dines were treated with hydrogen chloride in ethanol at

80 °C for 1 h. When these conditions were applied to 1,4-

dihydropyridine 7b exhibiting in addition to a phenyl resi-

due a but-3-en-1-yl moiety in 4-position and therefore be-

ing structurally closely related to dihydropyridine 11b after

a reaction time of 60 min, the desired 3-phenyl-9-azatricy-

clo[4.3.1.0^3,7]dec-8-en (rac-14b) was obtained in good yield

of 78% (Table 3, entry 2). As a control of the reaction prog-

ress by TLC had indicated that the reaction had gone to

completion quite rapidly, i.e., within a few minutes, it ap-

peared appropriate to test milder reaction conditions.

Hence, the reaction temperature was reduced from 80 °C to

30 °C.

Table 3 Cyclization of 4-Alkenyl-Substituted 1,4-Dihydropyridines under Varying Conditions

acid

n

solvent, temp, time

N

+

R

N

R = Si(i-Pr)₃or H

rac-13b, rac-14b, rac-15b

Si(i-Pr)₃

7b, 9b, 11b

Entry

Dihydropyridine

n

Acid (equiv)

Solvent

Temp (°C)

Time (min)

Product

Yield (%)

1

2

3

4

5

6

7

8

9

11b

7b

9b

0

1

2

HCl (10)

AcOH (10)

TfOH (10)

TFA (10)

TFA (5)

EtOH

80

30

20

60

15

rac-13b

rac-14b

rac-15b

63^a

EtOH

78^b

EtOH

94

EtOH

decomp.

traces

21

CH₂Cl₂

MeOH

pentane

decomp.

74

TFA (15)

a Data obtained from the literature.^10a

b Conditions adopted from the literature. ^10a

F

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

This led to an excellent yield of 94% whereby a reaction

time of 15 min was fully sufficient (Table 3, entry 3). As re-

ported for the cycloaddition for related reaction systems,

also in the present case no regioisomers of rac-14b could be

detected.^10aSurprisingly, attempts to cyclize 1,4-

dihydropyridine 9b exhibiting a pent-4-en-1-yl moiety in

4-position under the same conditions at 30 °C gave rise to

decomposition products only (Table 3, entry 4). Therefore,

in a series of experiments, 1,4-dihydropyridine 9b was sub-

jected to varying reaction conditions, in order to identify

those that might affect the desired cycloaddition reaction to

rac-15b and possibly be suitable for this type of transfor-

mation in general.

ing a but-3-en-1-yl residue (Table 4, entries 5–9) and 11a–e

(Table 4, entries 10–14) exhibiting an allyl moiety. The

formation of the desired tricyclic imines rac-14a–e from

the 4-homoallyl-substituted 1,4-dihydropyridines 7a–e

proceeded successfully in very good yields (79–89%, Table 4,

entries 5–9) with the new standard method.

Table 4 Synthesis of Various Tricyclic Imines

R

n

15 equiv TFA

n

R

pentane, 20 °C, 15 min

N

Si(i-Pr)₃

7a–e, 9a, 9c–e, 11a–e

rac-13a–e, rac-14a–e, rac-15a,c–e

In the next experiments, EtOH was replaced by CH₂Cl₂

as solvent and instead of HCl (10 equiv) acetic acid (10

equiv) and trifluoromethanesulfonic acid (10 equiv), re-

spectively, were used. In the case of acetic acid again only

decomposition products could be observed after a reaction

time of 15 min though the reaction temperature had been

further lowered to 20 °C, whereas with trifluoromethane-

sulfonic acid traces of the product could be identified in the

crude reaction product by ¹H NMR spectroscopy. Indicating

that a less strong acid might be necessary, the cyclization

was carried out with trifluoroacetic acid under otherwise

identical reaction conditions yielding 21% of the desired cy-

clization product rac-15b (Table 3, entry 7). When CH₂Cl₂

was again replaced by MeOH, a cyclization attempt carried

out with trifluoroacetic acid (Table 3, entry 8) as before, ex-

cept that the acid equivalents were reduced from 10 to 5

equivalents, led to decomposition products only. Hence as a

consequence, a far less polar solvent, i.e., pentane, should be

tested as reaction solvent. Indeed, when the cyclization of

dihydropyridine 9b was attempted in pentane with trifluo-

roacetic acid (15 equiv) at 20 °C, the desired tricyclic

imine rac-15b could be obtained in a good yield, i.e., 74%

(Table 3, entry 9). Application of fewer equivalents of triflu-

oroacetic acid (i.e., 5 or 10 equiv) led to a reduced conver-

sion and increased side-product formation as was deter-

mined by ¹H NMR spectroscopic analysis of the crude reac-

tion products.

The reaction conditions so far developed for the cycliza-

tion of dihydropyridine 9b were then applied to the 1,4-di-

hydropyridines 9a and 9c–e analogous to 9b, but differing

from the latter with regard to the second non-pent-4-en-1-

yl substituent in 4-position (9a: R = Me, 9c: R = Bn,

9d: R = 4-MeOC₆H₄; 9e: R = 4-MeOC₆H₄CH₂, Table 4). When

the 1,4-dihydropyridines 9a and 9c–e (see Table 2) were

subjected to the aforementioned standard conditions, i.e.,

trifluoroacetic acid (15 equiv) in pentane at 20 °C for 15

min, the intramolecular cyclization afforded rac-15a and

rac-15c–e in moderate to very good yields (Table 4,

entries 1–4, 54–89%). Next, to check whether the newly

found reaction conditions are suitable for the intramolecu-

lar hetero-Diels–Alder reaction in general, the latter was

also carried out with the 1,4-dihydropyridines 7a–e bear-

1,4-Dihydropyridine

R

Product

Yield (%)

Entry

n

1

2

9a

9c

Me

2

1

0

rac-15a

rac-15c

rac-15d

rac-15e

rac-14a

rac-14b

rac-14c

rac-14d

rac-14e

rac-13a

rac-13b

rac-13c

rac-13d

rac-13e

77

74

54

89

79

84

86

89

85

84

85

83

85^a

67^a

Bn

3

9d

4-MeOC₆H₄

4

9e

4-MeOC₆H₄CH₂

5

7a

Me

6

7b

Ph

7

7c

Bn

8

7d

4-MeOC₆H₄

4-MeOC₆H₄CH₂

Me

9

7e

10

11

12

13

14

11a

11b

11c

11d

11e

Ph

Bn

4-MeOC₆H₄

4-MeOC₆H₄CH₂

^aPentane/EtOH, 4:1 was used as the solvent system.

Comparing the cyclization of 1,4-dihydropyridine 7b

under the former already published^10a(EtOH, HCl, see

Table 3, entries 2 and 3) and the newly developed cycliza-

tion conditions (see Table 4, entry 6) revealed that with the

new standard method (TFA, pentane) an increase in yield

(84% vs. 78%) was achieved in comparison to the literature

known method^10a(Table 4, entry 6 vs. Table 3, entry 2).

Though the previously achieved excellent yield of 94% for

the tricyclic imine rac-14b, obtained under the adapted lit-

erature method^10a(see Table 3, entry 3), could not be

reached with the new standard method. The decrease in

yield to 84% was acceptable considering the broader appli-

cability of the new method, which was proven by the suc-

cessful cyclization of the 4-allyl-substituted 1,4-

dihydropyridines 11a–e. Good to very good yields (67–85%)

were obtained for the formation of the tricyclic imines rac-

13a–e. The syntheses of the known 4-azatricyclo-

[3.3.1.0^2,7]non-3-enes rac-13b

entries 11 and 12) resulted in yields of 85% (lit.^10a63%) and

and

rac-13c (Table 4,

G

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

83% (lit.^10a92%), respectively, showing a significant im-

provement in the first case and only a marginally worse re-

sult in the second one compared to our previously de-

scribed cyclization method.^10a

for 1 h at 20 °C. The resulting suspension was centrifuged (30 min,

3000 g), the supernatant was separated, and the remaining slurry was

suspended in Et₂O to retrieve the same volume as before. Centrifuga-

tion was repeated (30 min, 3000 g), and the supernatants were com-

bined. The concentration of the diorganomagnesium solution was de-

termined according to Yong et al.²⁰

In conclusion, we have successfully synthesized a series

of 4--alkenyl-substituted 1,4-DHP that were employed in

subsequent cyclization reactions yielding the correspond-

ing tricyclic imines. The approach introduced is the first

one to focus on the addition of -alkenyl-moieties of vary-

ing chain length to the 4-position of already 4-substituted

pyridine derivatives in order to provide 4,4-disubstituted

1,4-DHP. To the current state of knowledge, the obtained

yields and regioselectivities for the C-4 addition products

are superior to all literature methods. The intermediate -

alkenyl-substituted 1,4-DHP derivatives proved to be excel-

lent precursors for a smooth intramolecular hetero-Diels–

Alder reaction which provided various tricyclic imines with

high yield. The therefore newly developed cyclization meth-

od is easy, fast, and broadly applicable to the synthesis of

miscellaneous tricyclic ring systems with a 2-azabicy-

clo[2.2.2]octane scaffold.

Synthesis of 4,4-Disubstituted 1-N-Triisopropylsilyl-1,4-dihydro-

pyridines; General Procedure (GP1)

To a solution of the 4-substituted pyridine derivative in CH₂Cl₂(0.86

mL/mmol) was added TIPSOTf (1.1 equiv). After stirring for 15 min at

r.t., the resulting mixture was cooled to –30 °C and the corresponding

R₂Mg solution (1.1 equiv) was added dropwise. The reaction was

quenched after the time indicated by the addition of water

(10 mL/mmol), and the aqueous layer was extracted with CH₂Cl₂

(3 × 10 mL/mmol). The organic layers were combined, dried over

MgSO₄, and concentrated under vacuum. Quantification of the dihy-

dropyridines in the crude product was done by ¹H NMR spectroscopy

using 2,4,6-collidine as internal standard. The crude material was

stirred under air for the period specified to oxidize side products and

then purified by flash chromatography (FC).

Synthesis of Tricyclic Imines; General Procedure (GP2)

TFA (15 equiv) was added to a solution of the 4,4-disubstituted

1-N-triisopropylsilyl-1,4-dihydropyridine (1.0 equiv) in pentane

(10 mL/mmol) in one portion, and the resulting mixture was stirred

for 15 min at 20 °C. The reaction was quenched by the addition of

All anhydrous reactions were performed under an argon atmosphere

in oven-dried glassware. Solvents were distilled prior to use and THF,

Et₂O, 1,4-dioxane, and CH₂Cl₂were dried according to standard proce-

dures under a nitrogen atmosphere.¹⁶All chemicals were used as pur-

chased from the supplier without further purification. TLC plates pur-

chased from Merck KGaA (silica gel 60 F254 or aluminum oxide 60

F254 on aluminum sheets, neutral) were employed as the stationary

phase. Flash chromatography was conducted with silica gel 60 (40–

63 m mesh size) from Merck KGaA or with activated basic alumina

Brockmann I (150 m mesh size) from Sigma-Aldrich, which was ad-

justed to Brockmann III activity grade prior to use.¹⁷For the determi-

nation of melting points a BÜCHI 510 melting point apparatus was

used. All melting points are uncorrected. Infrared spectra of solid sub-

stances were measured as KBr pellets and oils as film with a Perkin

Elmer Paragon 1000 and a Jasco FT/IR-410. HRMS was carried out

with a Finnigan LTQ FT (ESI) and a Finnigan MAT 95 (EI). ¹H NMR and

¹³C NMR spectra were recorded with a Avance III HD Bruker BioSpin

(400 or 500 MHz) and referenced to the solvent residual peak as in-

ternal standard and analyzed with MestReNova (Version 12.0.0 –

20080; Mestrelab Research S.L.; released 26.09.2017).¹⁸4-(4-

Methoxybenzyl)pyridine (5e) was synthesized according to litera-

ture.¹⁹

K₂CO₃(8 equiv), and

a 1:1 mixture of 2 M HCl_aq.and EtOH

(40 mL/mmol) was added. The solution was washed with pentane

(6 × 20 mL/mmol) and adjusted to pH = 9 with K₂CO₃. The aqueous

layer was extracted with CH₂Cl₂(4 × 20 mL/mmol), the organic layers

were combined, dried over Na₂SO₄, and the solvent was removed un-

der vacuum. The crude product was purified by FC.

4-(4-Methoxyphenyl)pyridine (5d)

Pyridine (1.45 g, 18.3 mmol, 1.47 mL) was dissolved in CH₂Cl₂(22 mL)

at 20 °C, and TIPSOTf (6.35 g, 20.1 mmol, 5.57 mL) was added. The

solution was stirred for 15 min, cooled to –78 °C, and a solution of

di(4-methoxyphenyl)magnesium (0.46 M in THF/Et₂O, 1:1,

20.1 mmol, 44 mL) was added dropwise. Stirring was continued for

12 h within the reaction mixture was slowly warmed to –50 °C. The

reaction was stopped by the addition of H₂O (100 mL) and subse-

quently extraction with CH₂Cl₂(4 × 100 mL) followed. The organic

phases were combined, dried (MgSO₄), and the solvent was removed

under vacuum. The neat intermediate product was stirred under air at

20 °C for 96 h, dissolved in CH₂Cl₂(50 mL), and extracted with 2M HCl

(5 × 80 mL). The combined aqueous phases were washed with Et₂O

(2 × 80 mL), the pH was adjusted to 9 with K₂CO₃, and the aqueous

layer was extracted with CH₂Cl₂(4 × 80 mL). Combination of the

CH₂Cl₂phases following drying with MgSO₄and removal of the sol-

vent under vacuum provided the product which was purified by FC

(SiO₂; EtOAc/MeOH, 97:3).

Procedures

Preparation of Diorganomagnesium Solutions

Commercially available allylmagnesium chloride (2 m in THF) was di-

luted to a concentration of 1 m with THF and converted into di(al-

lyl)magnesium with 1,4-dioxane according to the procedure men-

tioned below.

Yield: 2.25 g (66%); colorless solid; mp 93 °C; R_f= 0.45 (SiO₂, EtOAc/

MeOH, 97:3).

IR (film): 3084, 2968, 2937, 2841, 1606, 1523, 1487, 1286, 1255,

1227, 1188, 1036, 1016, 810, 569, 499 cm^–1

.

Magnesium turnings (1.5 equiv) were covered with THF (0.13

mL/mmol), and a solution of the organic halide (1.0 equiv) in THF (0.8

mL/mmol) was added dropwise to keep the reaction mixture boiling

mildly. After complete addition stirring was continued for 1 h at 20 °C

followed by addition of 1,4-dioxane (1.1 equiv) and further stirring

¹H NMR (500 MHz, CD₂Cl₂):  = 3.85 (s, 3 H, OCH₃), 6.99–7.04 (m, 2 H,

CHCHCOCH₃), 7.46–7.50 (m, 2 H, NCHCH), 7.61–7.65 (m, 2 H, CHCH-

COCH₃), 8.56–8.60 (m, 2 H, NCHCH).

H

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

¹³C NMR (125 MHz, CD₂Cl₂):  = 55.9 (CH₃), 115.0 (CHCHCOCH₃),

121.4 (NCHCH), 128.6 (CHCHCOCH₃), 130.8 (CCHCHCOCH₃), 148.1

(NCHCHC), 150.8 (NCHCH), 161.2 (COCH₃).

HRMS (EI): m/z [M⁺] calcd for C₁₂H₁₁NO: 185.0835; found: 185.0833.

The analytical data accord with the literature.²¹

4-(But-3-en-1-yl)-4-benzyl-1-triisopropylsilyl-1,4-dihydropyri-

dine (7c)

Synthesis according to GP1 from 4-benzylpyridine (5c, 748 mg,

4.42 mmol, 0.71 mL), TIPSOTf (1.48 g, 4.86 mmol, 1.31 mL), and

di(but-3-en-1-yl)magnesium (0.27 m in THF/Et₂O, 1:1, 4.86 mmol,

18.0 mL). The reaction was stopped after 18 h. Quantitative determi-

nation indicated 590 mg (35%) of dihydropyridine 7c followed by stir-

ring under air for 1 d. Purification by FC (Al₂O₃-basic, activity III, pen-

tane) afforded 7c.

4-(But-3-en-1-yl)-4-methyl-1-triisopropylsilyl-1,4-dihydropyri-

dine (7a)

Synthesis according to GP1 from 4-methylpyridine (5a, 93 mg,

1.00 mmol, 97 L), TIPSOTf (337 mg, 1.00 mmol, 296 L), and di(but-

3-en-1-yl)magnesium (0.23 m in THF/Et₂O, 1:1, 1.10 mmol, 4.78 mL).

The reaction was stopped after 18 h. Quantitative determination indi-

cated 135 mg (44%) of dihydropyridine 7a followed by stirring under

air for 1 d. Purification by FC (Al₂O₃-basic, activity III, pentane) afford-

ed 7a.

Yield: 557 mg (33%); colorless solid; mp 39 °C; R_f= 0.88 (Al₂O₃; pen-

tane).

IR (KBr): 3061, 3028, 2943, 2866, 1670, 1462, 1288, 1063, 972, 881,

746, 698, 661, 499 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.98 (d, J = 7.3 Hz, 18 H, CH(CH₃)₂),

1.09–1.21 (m, 3 H, CH(CH₃)₂), 1.27–1.34 (m, 2 H, CH₂CH₂CH), 2.03–

2.13 (m, 2 H, CH₂CH₂CH), 2.54 (s, 2 H, CCH₂C), 4.07–4.13 (m, 2 H,

NCHCH), 4.90 (ddt, J = 10.2, 2.3, 1.2 Hz, 1 H, CH₂CH₂CHCH₂^a), 4.96–

5.03 (m, 1 H, CH₂CH₂CHCH₂^b), 5.90 (ddt, J = 17.1, 10.3, 6.6 Hz, 1 H,

CH₂CHCH₂), 5.92–5.97 (m, 2 H, NCHCH), 7.10–7.15 (m, 3 H, CCHCHCH,

CCHCHCH), 7.17–7.23 (m, 2 H, CCHCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 11.5 (CH(CH₃)₂), 17.9 (CH(CH₃)₂), 31.4

(CH₂CH₂CH), 39.8 (CCH₂CH₂), 43.4 (CH₂CH₂CH), 52.3 (CCH₂C), 105.9

(NCHCH), 113.5 (CH₂CH₂CHCH₂), 125.6 (CCHCHCH), 127.4 (CCH-

CHCH), 129.3 (NCHCH), 131.1 (CCHCHCH), 139.2 (CCHCHCH), 140.4

(CH₂CHCH₂).

Yield: 134 mg (44%); colorless oil; R_f= 0.97 (Al₂O₃; pentane).

IR (film): 3076, 3039, 2945, 2868, 1668, 1639, 1601, 1464, 1286,

1074, 974, 883, 733, 669 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.02 (s, 3 H, CH₃), 1.08 (d, J = 7.2 Hz,

18 H, CH(CH₃)₂), 1.18–1.29 (m, 5 H, CH₂CH₂CH, CH(CH₃)₂), 2.00–2.09

(m, 2 H, CH₂CH₂CH), 4.15–4.20 (m, 2 H, NCHCH), 4.88 (ddt, J = 10.2,

2.3, 1.3 Hz, 1 H, CH₂CH₂CHCH₂^a), 4.94–5.01 (m, 1 H, CH₂CH₂CHCH₂^b),

5.88 (ddt, J = 16.8, 10.2, 6.6 Hz, 1 H, CH₂CHCH₂), 5.96–6.01 (m, 2 H,

NCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.0 (CH(CH₃)₂), 31.0

(CH₂CH₂CH), 33.8 (CH₃), 33.9 (CCH₃), 45.1 (CH₂CH₂CH), 107.8

(NCHCH), 113.4 (CH₂CH₂CHCH₂), 128.3 (NCHCH), 140.5 (CH₂CHCH₂).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₅H₄₀NSi: 382.2925; found:

382.2922.

HRMS (ESI): m/z [M + H]⁺calcd for C₁₉H₃₆NSi: 306.2612; found:

306.2610.

4-(But-3-en-1-yl)-4-(4-methoxyphenyl)-1-triisopropylsilyl-1,4-di-

hydropyridine (7d)

Synthesis according to GP1 from 4-(4-methoxyphenyl)pyridine (5d,

648 mg, 3.50 mmol), TIPSOTf (1.18 g, 3.85 mmol, 1.03 mL), and

di(but-3-en-1-yl)magnesium (0.27 m in THF/Et₂O, 1:1, 3.85 mmol,

14.3 mL). The reaction was stopped after 18 h. Quantitative determi-

nation indicated 626 mg (45%) of dihydropyridine 7d followed by stir-

ring under air for 2 d. Purification by FC (Al₂O₃-basic, activity III, pen-

tane) afforded 7d.

4-(But-3-en-1-yl)-4-phenyl-1-triisopropylsilyl-1,4-dihydropyri-

dine (7b)

Synthesis according to GP1 from 4-phenylpyridine (5b, 686 mg,

4.42 mmol), TIPSOTf (1.48 g, 4.86 mmol, 1.31 mL), and di(but-3-en-1-

yl)magnesium (0.27 m in THF/Et₂O, 1:1, 4.86 mmol, 18.0 mL). The re-

action was stopped after 18 h. Quantitative determination indicated

1.00 g (62%) of dihydropyridine 7b followed by stirring under air for

2 d. Purification by FC (Al₂O₃-basic, activity III, pentane) afforded 7b.

Yield: 559 mg (40%); colorless solid; mp 54 °C; R_f= 0.13 (Al₂O₃; pen-

tane).

Yield: 882 mg (54%); orange solid; mp 46 °C; R_f= 0.57 (Al₂O₃; pen-

tane).

IR (KBr): 3076, 3051, 2951, 2868, 1668, 1508, 1290, 1254, 1176, 1059,

976, 833, 692, 665, 501 cm^–1

.

IR (KBr): 3076, 3053, 2945, 2866, 1666, 1460, 1286, 1076, 1053, 972,

¹H NMR (500 MHz, CDCl₃):  = 1.11 (d, J = 7.4 Hz, 18 H, CH(CH₃)₂),

1.28 (sept, J = 7.4 Hz, 3 H, CH(CH₃)₂), 1.69–1.75 (m, 2 H, CH₂CH₂CH),

2.10–2.18 (m, 2 H, CH₂CH₂CH), 3.80 (s, 3 H, OCH₃), 4.33–4.38 (m, 2 H,

NCHCH), 4.94 (ddt, J = 10.2, 2.2, 1.1 Hz, 1 H, CH₂CH₂CHCH₂^a), 5.00–

5.08 (m, 1 H, CH₂CH₂CHCH₂^b), 5.95 (ddt, J = 16.8, 10.2, 6.6 Hz, 1 H,

CH₂CHCH₂), 6.10–6.15 (m, 2 H, NCHCH), 6.85–6.90 (m, 2 H,

CHC(OCH₃)), 7.30–7.36 (m, 2 H, CHCHC(OMe)).

¹³C NMR (125 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.0 (CH(CH₃)₂), 31.0

(CH₂CH₂CH), 41.0 (CCH₂CH₂), 42.2 (CH₂CH₂CH), 55.4 (CH₃), 106.6

(NCHCH), 113.5 (CHC(OCH₃)), 113.7 (CH₂CH₂CHCH₂), 127.8 (CH-

CHC(OCH₃)), 128.1 (NCHCH), 140.2 (CH₂CHCH₂), 145.1 (CCH-

CHC(OCH₃)), 157.3 (COCH₃).

906, 885, 690, 521 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.11 (d, J = 7.3 Hz, 18 H, CH(CH₃)₂),

1.22–1.34 (m, 3 H, CH(CH₃)₂), 1.71–1.79 (m, 2 H, CH₂CH₂CH), 2.10–

2.19 (m, 2 H, CH₂CH₂CH), 4.40 (d, J = 7.4 Hz, 2 H, NCHCH), 4.94 (ddd,

J = 10.2, 1.9, 1.0 Hz, 1 H, CH₂CH₂CHCH₂^a), 5.00–5.08 (m, 1 H,

CH₂CH₂CHCH₂^b), 5.95 (ddt, J = 16.8, 10.2, 6.5 Hz, 1 H, CH₂CHCH₂), 6.14

(d, J = 7.5 Hz, 2 H, NCHCH), 7.15 (t, J = 7.3 Hz, 1 H, CCHCHCH), 7.33 (t,

J = 7.5 Hz, 2 H, CCHCHCH), 7.42 (d, J = 8.3 Hz, 2 H, CCHCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.0 (CH(CH₃)₂), 30.9

(CH₂CH₂CH), 41.7 (CCH₂CH₂), 42.3 (CH₂CH₂CH), 106.3 (NCHCH), 113.8

(CH₂CH₂CHCH₂), 125.4 (CCHCHCH), 126.8 (CCHCHCH), 128.2 (CCH-

CHCH), 128.3 (NCHCH), 140.1 (CH₂CHCH₂), 152.5 (CCHCHCH).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₅H₄₀NOSi: 398.2874; found:

398.2872.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₄H₃₈NSi: 368.2768; found:

368.2766.

I

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

4-(But-3-en-1-yl)-4-4-methoxybenzyl)-1-triisopropylsilyl-1,4-di-

hydropyridine (7e)

action was stopped after 2 h. Quantitative determination indicated

473 mg (62%) of dihydropyridine 9b followed by stirring under air for

1 d. Purification by FC (Al₂O₃-basic, activity III, pentane) afforded 9b.

Synthesis according to GP1 from 4-(4-methoxybenzyl)pyridine (5e,

598 mg, 3.00 mmol), TIPSOTf (1.01 g, 3.30 mmol, 0.89 mL), and

di(but-3-en-1-yl)magnesium (0.26 m in THF/Et₂O, 1:1, 3.30 mmol,

12.7 mL). The reaction was stopped after 18 h. Quantitative determi-

nation indicated 494 mg (40%) of dihydropyridine 7e followed by stir-

ring under air for 2 d. Purification by FC (Al₂O₃-basic, activity III, pen-

tane) afforded 7e.

Yield: 451 mg (59%); orange solid; mp 53 °C; R_f= 0.65 (Al₂O₃; pen-

tane).

IR (KBr): 3080, 3051, 2947, 2866, 2362, 1668, 1599, 1464, 1288, 1078,

978, 881, 746, 696, 667, 627, 499 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 1.11 (d, J = 7.5 Hz, 18 H, CH(CH₃)₂),

1.28 (sept, J = 7.5 Hz, 3 H, CH(CH₃)₂), 1.45–1.54 (m, 2 H, CH₂CH₂CH),

1.64–1.71 (m, 2 H, CH₂CH₂CH₂CH), 2.09–2.16 (m, 2 H, CH₂CH₂CH),

4.40 (d, J = 8.2 Hz, 2 H, NCHCH), 4.92–4.97 (m, 1 H, CH₂CH₂CHCH₂^a),

4.98–5.05 (m, 1 H, CH₂CH₂CHCH₂^b), 5.80–5.90 (m, 1 H, CH₂CHCH₂),

6.13 (d, J = 8.2 Hz, 2 H, NCHCH), 7.12–7.17 (m, 1 H, CCHCHCH), 7.30–

7.36 (m, 2 H, CCHCHCH), 7.39–7.44 (m, 2 H, CCHCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.0 (CH(CH₃)₂), 25.5

(CH₂CH₂CH), 34.4 (CH₂CH₂CH), 41.8 (CCH₂), 42.7 (CCH₂), 106.6

(NCHCH), 114.2 (CH₂CH₂CHCH₂), 125.3 (CCHCHCH), 126.8 (CCH-

CHCH), 128.1 (CCHCHCH), 128.2 (NCHCH), 139.5 (CH₂CHCH₂), 152.7

(CCCH₂).

Yield: 483 mg (39%); colorless solid; mp 45 °C; R_f= 0.18 (Al₂O₃; pen-

tane).

IR (KBr): 3084, 3037, 2949, 2864, 2360, 1670, 1510, 1286, 1240, 1063,

972, 881, 768, 690, 662, 499 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.98 (d, J = 7.4 Hz, 18 H, CH(CH₃)₂),

1.10–1.20 (m, 3 H, CH(CH₃)₂), 1.25–1.32 (m, 2 H, CH₂CH₂CH), 2.03–

2.12 (m, 2 H, CH₂CH₂CH), 2.47 (s, 2 H, CCH₂C), 3.76 (s, 3 H, CH₃), 4.05–

4.10 (m, 2 H, NCHCH), 4.90 (ddt, J = 10.2, 2.3, 1.2 Hz, 1 H,

CH₂CH₂CHCH₂^a), 4.96–5.03 (m, 1 H, CH₂CH₂CHCH₂^b), 5.89 (ddt,

J = 17.1, 10.3, 6.6 Hz, 1 H, CH₂CHCH₂), 5.92–5.96 (m, 2 H, NCHCH),

6.73–6.79 (m, 2 H, CHC(OCH₃)), 7.01–7.06 (m, 2 H, CHCHC(OMe)).

¹³C NMR (100 MHz, CDCl₃):  = 11.5 (CH(CH₃)₂), 17.9 (CH(CH₃)₂), 31.4

(CH₂CH₂CH), 39.8 (CCH₂CH₂), 43.3 (CH₂CH₂CH), 51.3 (CCH₂C), 55.3

(OCH₃), 105.9 (NCHCH), 112.9 (CHC(OCH₃)), 113.5 (CH₂CH₂CHCH₂),

129.3 (NCHCH), 131.4 (CCHCHC(OCH₃)), 131.9 (CHCHC(OCH₃)), 140.5

(CH₂CHCH₂), 157.8 (COCH₃).

HRMS (EI): m/z [M]⁺calcd for C₂₅H₃₉NSi: 381.2846; found: 381.2854.

4-Benzyl-4-(pent-4-en-1-yl)-1-triisopropylsilyl-1,4-dihydropyri-

dine (9c)

Synthesis according to GP1 from 4-benzylpyridine (5c, 508 mg,

3.00 mmol, 480 L), TIPSOTf (1.01 g, 3.30 mmol, 0.89 mL), and

di(pent-4-en-1-yl)magnesium (0.23 m in THF/Et₂O, 1:1, 3.30 mmol,

14.5 mL). The reaction was stopped after 18 h. Quantitative determi-

nation indicated 451 mg (38%) of dihydropyridine 9c followed by stir-

ring under air for 1 d. Purification by FC (Al₂O₃-basic, activity III, pen-

tane) afforded 9c.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₆H₄₂NOSi: 412.3030; found:

412.3028.

4-Methyl-4-(pent-4-en-1-yl)-1-triisopropylsilyl-1,4-dihydropyri-

dine (9a)

Synthesis according to GP1 from 4-methylpyridine (5a, 279 mg,

3.00 mmol, 290 L), TIPSOTf (1.01 g, 3.30 mmol, 0.89 mL), and

di(pent-4-en-1-yl)magnesium (0.23 m in THF/Et₂O, 1:1, 3.30 mmol,

14.5 mL). The reaction was stopped after 18 h. Quantitative determi-

nation indicated 422 mg (44%) of dihydropyridine 9a followed by stir-

ring under air for 1 d. Purification by FC (Al₂O₃-basic, activity III, pen-

tane) afforded 9a.

Yield: 439 mg (37%); colorless solid; mp 39 °C; R_f= 0.70 (Al₂O₃; pen-

tane).

IR (KBr): 3062, 3028, 2947, 2864, 2360, 1670, 1462, 1288, 1061, 972,

908, 881, 698, 661, 619 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 0.98 (d, J = 7.4 Hz, 18 H, CH(CH₃)₂),

1.15 (sept, J = 7.5 Hz, 3 H, CH(CH₃)₂), 1.20–1.26 (m, 2 H, CH₂CH₂CH),

1.40–1.49 (m, 2 H, CCH₂CH₂), 2.06 (q, J = 7.1 Hz, 2 H, CH₂CH₂CH), 2.52

(s, 2 H, CCH₂C), 4.07–4.12 (m, 2 H, NCHCH), 4.92 (ddt, J = 10.2, 2.2,

1.1 Hz, 1 H, CH₂CH₂CHCH₂^a), 4.96–5.02 (m, 1 H, CH₂CH₂CHCH₂^b), 5.83

(ddt, J = 16.9, 10.2, 6.6 Hz, 1 H, CH₂CHCH₂), 5.90–5.95 (m, 2 H,

NCHCH), 7.09–7.15 (m, 3 H, CCHCHCH, CCHCHCH), 7.17–7.23 (m, 2 H,

CCHCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 11.5 (CH(CH₃)₂), 17.9 (CH(CH₃)₂), 25.9

(CH₂CH₂CH), 34.5 (CH₂CH₂CH), 39.8 (CCH₂CH₂), 43.8 (CCH₂CH₂), 52.2

(CCH₂C), 106.2 (NCHCH), 114.0 (CH₂CH₂CHCH₂), 125.5 (CCHCHCH),

127.4 (CCHCHCH), 129.0 (NCHCH), 131.1 (CCHCHCH), 139.3 (CCH-

CHCH), 139.7 (CH₂CHCH₂).

Yield: 414 mg (43%); colorless oil; R_f= 0.90 (Al₂O₃; pentane).

IR (film): 3078, 3039, 2945, 2868, 1668, 1462, 1286, 1076, 370, 883,

731, 665 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.00 (s, 3 H, CH₃), 1.08 (d, J = 7.2 Hz,

18 H, CH(CH₃)₂), 1.10–1.17 (m, 2 H, CH₂CH₂CH₂CH), 1.18–1.28 (m,

3 H, CH(CH₃)₂), 1.35–1.44 (m, 2 H, CH₂CH₂CH), 1.99–2.08 (m, 2 H,

CH₂CH₂CH), 4.14–4.20 (m, 2 H, NCHCH), 4.91 (ddt, J = 10.2, 2.3, 1.3 Hz,

1 H, CH₂CH₂CHCH₂^a), 4.94–5.01 (m, 1 H, CH₂CH₂CHCH₂^b), 5.81 (ddt,

J = 16.8, 10.2, 6.6 Hz, 1 H, CH₂CHCH₂), 5.94–6.00 (m, 2 H, NCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.1 (CH(CH₃)₂), 25.6

(CH₂CH₂CH₂), 33.8 (CCH₃), 33.8 (CCH₃), 34.5 (CH₂CH₂CH), 45.5

(CH₂CH₂CH₂CH), 108.2 (NCHCH), 113.9 (CH₂CH₂CHCH₂), 128.0

(NCHCH), 139.7 (CH₂CHCH₂).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₆H₄₂NSi: 396.3081; found:

396.3079.

HRMS (ESI): m/z [M + H]⁺calcd for C₂₀H₃₈NSi: 320.2768; found:

320.2767.

4-(4-Methoxyphenyl)-4-(pent-4-en-1-yl)-1-triisopropylsilyl-1,4-

dihydropyridine (9d)

Synthesis according to GP1 from 4-(4-methoxyphenyl)pyridine (5d,

741 mg, 4.00 mmol), TIPSOTf (1.35 g, 4.40 mmol, 1.18 mL), and

di(pent-4-en-1-yl)magnesium (0.28 m in THF/Et₂O, 1:1, 4.40 mmol,

15.5 mL). The reaction was stopped after 18 h. Quantitative determi-

nation indicated 1.02 g (62%) of dihydropyridine 9d followed by stir-

ring under air for 2 d. Purification by FC (Al₂O₃-basic, activity III, pen-

tane) afforded 9d.

4-(Pent-4-en-1-yl)-4-phenyl-1-triisopropylsilyl-1,4-dihydropyri-

dine (9b)

Synthesis according to GP1 from 4-phenylpyridine (5b, 310 mg,

2.00 mmol), TIPSOTf (674 mg, 2.20 mmol, 590 L), and di(pent-4-en-

1-yl)magnesium (0.28 m in THF/Et₂O, 1:1, 2.20 mmol, 7.9 mL). The re-

J

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

Yield: 1.01 g (61%); colorless solid; mp 64 °C; R_f= 0.17 (Al₂O₃; pen-

tane).

IR (film): 3074, 3043, 2947, 2868, 1670, 1600, 1464, 1286, 1076,

1053, 976, 883, 731, 687 cm^–1

.

IR (KBr): 3080, 2999, 2945, 2867, 1664, 1606, 1506, 1288, 1244, 1188,

¹H NMR (400 MHz, CDCl₃):  = 1.04 (s, 3 H, CCH₃), 1.08 (d, J = 7.2

Hz, 18 H, CH(CH₃)₂), 1.18–1.30 (m, 3 H, CH(CH₃)₂), 1.99 (dt, J = 7.2, 1.2

Hz, 2 H, CCH₂CH), 4.21–4.28 (m, 2 H, NCHCH), 4.92–5.01 (m, 2 H,

CCH₂CHCH₂), 5.85 (ddt, J = 17.0, 10.3, 7.2 Hz, 1 H, CH₂CHCH₂), 5.94–

6.00 (m, 2 H, NCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.0 (CH(CH₃)₂), 32.6

(CCH₃), 33.9 (CCH₃), 50.8 (CCH₂), 108.1 (NCHCH), 115.9 (CCH₂CHCH₂),

128.0 (NCHCH), 136.7 (CH₂CHCH₂).

1059, 970, 746, 665, 511 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.10 (d, J = 7.4 Hz, 18 H, CH(CH₃)₂),

1.28 (sept, J = 7.6 Hz, 3 H, CH(CH₃)₂), 1.43–1.53 (m, 2 H, CH₂CH₂CH),

1.60–1.68 (m, 2 H, CCH₂), 2.12 (q, J = 7.1 Hz, 2 H, CH₂CH₂CH₂CH), 3.79

(s, 3 H, CH₃), 4.35 (d, J = 8.2 Hz, 2 H, NCHCH), 4.90–4.96 (m, 1 H,

CH₂CH₂CHCH₂^a), 4.97–5.05 (m, 1 H, CH₂CH₂CHCH₂^b), 5.84 (ddt,

J = 16.8, 10.2, 6.5 Hz, 1 H, CH₂CHCH₂), 6.10 (d, J = 8.2 Hz, 2 H, NCHCH),

6.84–6.90 (m, 2 H, CHC(OCH₃)), 7.29–7.35 (m, 2 H, CHCHC(OCH₃)).

HRMS (EI): m/z [M]⁺calcd for C₁₈H₃₃NSi: 291.2377; found: 291.2375.

¹³C NMR (100 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.0 (CH(CH₃)₂), 25.5

(CH₂CH₂CH), 34.4 (CH₂CH₂CH), 41.0 (CCH₂), 42.7 (CCH₂), 55.4 (OCH₃),

106.9 (NCHCH), 113.5 (CHC(OCH₃)), 114.1 (CH₂CH₂CHCH₂), 127.8

(CHCHC(OCH₃)), 127.9 (NCHCH), 139.6 (CH₂CHCH₂), 145.4 (CCH-

CHC(OCH₃)), 157.3 (COCH₃).

HRMS (ESI): m/z [M + H]⁺calcd for C₂₆H₄₂NOSi: 412.3030; found:

412.3026.

4-Allyl-4-phenyl-1-triisopropylsilyl-1,4-dihydropyridine (11b)

Synthesis according to GP1 from 4-phenylpyridine (5b, 1.48 g,

9.55 mmol), TIPSOTf (3.22 g, 10.5 mmol, 2.82 mL), and di(allyl)mag-

nesium (0.36 m in THF/Et₂O, 1:1, 10.5 mmol, 29.5 mL). The reaction

was stopped after 2 h. Quantitative determination indicated 1.18 g

(35%) of dihydropyridine 11b followed by stirring under air for 4 d.

Purification by FC (Al₂O₃-basic, activity III, pentane) afforded 11b.

4-(4-Methoxybenzyl)-4-(pent-4-en-1-yl)-1-triisopropylsilyl-1,4-

dihydropyridine (9e)

Yield: 1.11 g (35%); yellow solid; mp 33 °C; R_f= 0.90 (Al₂O₃; pentane).

IR (KBr): 3049, 2947, 2866, 1666, 1597, 1462, 1288, 1099, 1076, 1043,

Synthesis according to GP1 from 4-(4-methoxybenzyl)pyridine (5e,

598 mg, 3.00 mmol), TIPSOTf (1.01 g, 3.30 mmol, 0.89 mL), and

di(pent-4-en-1-yl)magnesium (0.28 m in THF/Et₂O, 1:1, 3.30 mmol,

11.6 mL). The reaction was stopped after 18 h. Quantitative determi-

nation indicated 577 mg (45%) of dihydropyridine 9e followed by stir-

ring under air for 2 d. Purification by FC (Al₂O₃-basic, activity III, pen-

tane) afforded 9e.

978, 881, 762, 690, 663, 519 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.10 (d, J = 7.4 Hz, 18 H, CH(CH₃)₂),

1.27 (sept, J = 7.4 Hz, 3 H, CH(CH₃)₂), 2.52 (dt, J = 7.0, 1.2 Hz, 2 H,

CCH₂CH), 4.42–4.48 (m, 2 H, NCHCH), 5.00–5.08 (m, 2 H, CCH₂CHCH₂),

5.83 (ddt, J = 17.4, 10.4, 7.0 Hz, 1 H, CH₂CHCH₂), 6.08–6.13 (m, 2 H,

NCHCH), 7.15 (tt, 1 H, J = 7.5, 1.2 Hz, CCHCHCH), 7.30–7.36 (m, 2 H,

CCHCHCH), 7.39–7.43 (m, 2 H, CCHCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.0 (CH(CH₃)₂), 41.6

(CCH₂), 48.2 (CCH₂), 106.5 (NCHCH), 116.4 (CCH₂CHCH₂), 125.4 (CCH-

CHCH), 126.8 (CCHCHCH), 128.1 (NCHCH), 128.2 (CCHCHCH), 136.5

(CH₂CHCH₂), 151.7 (CCCH₂).

Yield: 529 mg (41%); colorless oil; R_f= 0.19 (Al₂O₃; pentane).

IR (film): 2945, 2866, 1670, 1610, 1510, 1464, 1286, 1244, 1176,

1099, 1063, 970, 908, 883 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 0.97 (d, J = 7.3 Hz, 18 H, CH(CH₃)₂),

1.08–1.19 (m, 3 H, CH(CH₃)₂), 1.19–1.25 (m, 2 H, CCH₂CH₂), 1.38–1.49

(m, 2 H, CCH₂CH₂), 2.01–2.11 (m, 2 H, CH₂CH₂CH₂CH), 2.45 (s, 2 H,

CCH₂C), 3.76 (s, 3 H, CH₃), 4.04–4.10 (m, 2 H, NCHCH), 4.92 (ddt,

J = 10.2, 2.3, 1.2 Hz, 1 H, CH₂CH₂CHCH₂^a), 4.95–5.03 (m, 1 H,

CH₂CH₂CHCH₂^b), 5.83 (ddt, J = 16.9, 10.2, 6.6 Hz, 1 H, CH₂CHCH₂),

5.89–5.95 (m, 2 H, NCHCH), 6.73–6.78 (m, 2 H, CHC(OCH₃)), 7.00–7.06

(m, 2 H, CHCHC(OCH₃)).

¹³C NMR (100 MHz, CDCl₃):  = 11.5 (CH(CH₃)₂), 17.9 (CH(CH₃)₂), 25.9

(CCH₂CH₂), 34.5 (CH₂CH₂CH), 39.8 (CCH₂CH₂), 43.8 (CCH₂CH₂), 51.2

(CCH₂C), 55.3 (OCH₃), 106.2 (NCHCH), 112.9 (CHC(OCH₃)), 114.0

(CH₂CH₂CHCH₂), 129.0 (NCHCH), 131.6 (CCHCHC(OCH₃)), 131.9 (CH-

CHC(OCH₃)), 139.8 (CH₂CHCH₂), 157.7 (COCH₃).

HRMS (EI): m/z [M]⁺calcd for C₂₃H₃₅NSi: 353.2533; found; 353.2519.

4-Allyl-4-benzyl-1-triisopropylsilyl-1,4-dihydropyridine (11c)

Synthesis according to GP1 from 4-benzylpyridine (5c, 1.62 g,

9.55 mmol, 1.52 mL), TIPSOTf (3.22 g, 10.5 mmol, 2.82 mL), and di(al-

lyl)magnesium (0.36 m in THF/Et₂O, 1:1, 10.5 mmol, 29.5 mL). The re-

action was stopped after 2 h. Quantitative determination indicated

737 mg (21%) of dihydropyridine 11c followed by stirring under air

for 4 d. Purification by FC (Al₂O₃-basic, activity III, pentane) afforded

11c.

Yield: 722 mg (21%); colorless oil; R_f= 0.63 (Al₂O₃; pentane).

IR (film): 3082, 3026, 2945, 2866, 1670, 1462, 1284, 1059, 1045,

HRMS (ESI): m/z [M + H]⁺calcd for C₂₇H₄₄NOSi: 426.3187; found:

426.3182.

1016, 991, 972, 920, 883, 743, 689, 662, 623, 511 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 0.98 (d, J = 7.4 Hz, 18 H, CH(CH₃)₂),

1.10–1.19 (m, 3 H, CH(CH₃)₂), 2.09 (d, J = 7.1 Hz, 2 H, CCH₂CH), 2.57 (s,

2 H, CCH₂C), 4.14–4.19 (m, 2 H, NCHCH), 4.97–5.05 (m, 2 H,

CCH₂CHCH₂), 5.87–5.97 (m, 3 H, CH₂CHCH₂, NCHCH), 7.10–7.16 (m,

3 H, CCHCHCH, CCHCHCH), 7.18–7.24 (m, 2 H, CCHCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 11.5 (CH(CH₃)₂), 17.9 (CH(CH₃)₂), 39.5

(CCH₂CH), 49.2 (CCH₂CH), 51.1 (CCH₂C), 106.1 (NCHCH), 116.0

(CCH₂CHCH₂), 125.6 (CCHCHCH), 127.5 (CCHCHCH), 129.0 (NCHCH),

131.1 (CCHCHCH), 136.9 (CH₂CHCH₂), 139.2 (CCHCHCH).

4-Allyl-4-methyl-1-triisopropylsilyl-1,4-dihydropyridine (11a)

Synthesis according to GP1 from 4-methylpyridine (5a, 889 mg,

9.55 mmol, 0.93 mL), TIPSOTf (3.22 g, 10.5 mmol, 2.82 mL), and di(al-

lyl)magnesium (0.36 m in THF/Et₂O, 1:1, 10.5 mmol, 29.5 mL). The re-

action was stopped after 2 h. Quantitative determination indicated

919 mg (33%) of dihydropyridine 11a followed by stirring under air

for 3 d. Purification by FC (Al₂O₃-basic, activity III, pentane) afforded

11a.

HRMS (EI): m/z [M]⁺calcd for C₂₄H₃₇NSi: 367.2690; found: 367.2699.

Yield: 977 mg (35%); colorless oil; R_f= 0.95 (Al₂O₃; pentane).

K

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

4-Allyl-4-(4-methoxyphenyl)-1-triisopropylsilyl-1,4-dihydropyri-

dine (11d)

¹H NMR (400 MHz, CDCl₃):  = 0.83 (dq, J = 12.4, 2.2 Hz, 1 H,

NCHCH₂^aC), 0.92 (s, 3 H, CH₃), 1.01 (ddq, J = 12.6, 6.4, 1.9 Hz, 1 H,

NCHCH₂^aCH), 1.17 (d, J = 9.1 Hz, 1 H, CCH₂^aCHCH), 1.60 (dd, J = 12.5,

3.2 Hz, 1 H, NCHCH₂^bCH), 1.68 (dd, J = 12.4, 3.1 Hz, 1 H, NCHCH₂^bC),

1.99 (ddt, J = 8.7, 6.6, 2.0 Hz, 1 H, CCH₂^bCHCH), 2.07 (q, J = 6.2 Hz, 1 H,

NCHCHCH), 2.84–2.90 (m, 1 H, NCHCH), 4.48–4.53 (m, 1 H, NCHCH₂),

8.08 (d, J = 3.7 Hz, 1 H, NCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 26.9 (CH₃), 27.6 (NCHCH₂CH), 30.7

(NCHCH₂CH), 38.7 (CCH₃), 38.9 (NCHCH₂C), 43.3 (CCH₂CHCH), 44.3

(NCHCH), 56.1 (NCHCH₂), 167.2 (NCHCH).

Synthesis according to GP1 from 4-(4-methoxyphenyl)pyridine (5d,

1.76 g, 9.55 mmol), TIPSOTf (3.22 g, 10.5 mmol, 2.82 mL), and di(al-

lyl)magnesium (0.30 m in THF/Et₂O, 1:1, 10.5 mmol, 35.2 mL). The re-

action was stopped after 2 h. Quantitative determination indicated

879 mg (24%) of dihydropyridine 11d followed by stirring under air

for 4 d. Purification by FC (Al₂O₃-basic, activity III, pentane) afforded

11d.

Yield: 840 mg (21%); colorless solid; mp 47 °C; R_f= 0.39 (Al₂O₃; pen-

tane).

HRMS (EI): m/z [M – H]⁺calcd for C₉H₁₂N: 134.0964; found: 134.0962.

IR (KBr): 3072, 2999, 2951, 2864, 1666, 1601, 1506, 1464, 1290, 1244,

1092, 1051, 982, 881, 829, 760, 690, 669, 516 cm^–1

.

rac-1-Phenyl-4-azatricyclo[3.3.1.0^2,7]non-3-en (rac-13b)

¹H NMR (500 MHz, CDCl₃):  = 1.10 (d, J = 7.4 Hz, 18 H, CH(CH₃)₂),

1.27 (sept, J = 7.5 Hz, 3 H, CH(CH₃)₂), 2.50 (dt, J = 7.0, 1.2 Hz, 2 H,

CCH₂CH), 3.80 (s, 3 H, OCH₃), 4.39–4.44 (m, 2 H, NCHCH), 4.99–5.06

(m, 2 H, CCH₂CHCH₂), 5.83 (ddt, J = 17.4, 10.4, 7.0 Hz, 1 H, CH₂CHCH₂),

6.07–6.12 (m, 2 H, NCHCH), 6.85–6.91 (m, 2 H, CHCO), 7.30–7.36 (m,

2 H, CHCHCO).

Synthesis according to GP2 from dihydropyridine 11b (1.08 g,

3.05 mmol) and TFA (5.22 g, 45.8 mmol, 3.50 mL) in pentane

(30.5 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-13b.

Yield: 509 mg (85%); yellow oil; R_f= 0.66 (Al₂O₃; pentane/CH₂-

Cl₂/MeOH, 88:10:2).

¹³C NMR (125 MHz, CDCl₃):  = 11.6 (CH(CH₃)₂), 18.0 (CH(CH₃)₂), 40.9

(CCH₂), 48.2 (CCH₂), 55.4 (OCH₃), 106.8 (NCHCH), 113.6 (CHCO), 116.3

(CCH₂CHCH₂), 127.8 (CHCHCO; NCHCH), 136.6 (CH₂CHCH₂), 144.4

(CCCH₂), 157.3 (COCH₃).

IR (KBr): 3024, 2995, 2935, 2860, 1676, 1610, 1493, 1446, 1333, 1288,

1077, 766, 750, 702, 687, 540 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 1.17 (ddq, J = 12.6, 6.2, 1.8 Hz, 1 H,

NCHCH₂^aCH), 1.25 (dq, J = 12.7, 2.3 Hz, 1 H, NCHCH₂^aC), 1.60 (d,

J = 9.2 Hz, 1 H, CCH₂^aCHCH), 1.79 (dd, J = 12.7, 3.2 Hz, 1 H,

NCHCH₂^bCH), 2.02 (dd, J = 12.7, 3.0 Hz, 1 H, NCHCH₂^bC), 2.22 (q,

J = 6.4 Hz, 1 H, NCHCHCH), 2.53 (ddt, J = 9.0, 6.8, 2.0 Hz, 1 H,

CCH₂^bCHCH), 3.26–3.32 (m, 1 H, NCHCH), 4.63–4.68 (m, 1 H,

NCHCH₂), 6.96–7.02 (m, 2 H, CCHCHCH), 7.14–7.19 (m, 1 H, CCH-

CHCH), 7.24–7.31 (m, 2 H, CCHCHCH), 8.34 (d, J = 3.7 Hz, 1 H,

NCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 27.6 (NCHCH₂CH), 30.9 (NCHCH₂CH),

41.0 (NCHCH₂C), 41.3 (CCH₂CHCH), 43.3 (NCHCH), 45.8 (CCH₂), 56.0

(NCH(CH₂)₂), 124.9 (CCHCHCH), 126.0 (CCHCHCH), 128.4 (CCHCHCH),

147.8 (CCCH₂) 166.9 (NCHCH).

HRMS (EI): m/z [M]⁺calcd for C₂₄H₃₇NOSi: 383.2639; found: 383.2657.

4-Allyl-4-(4-methoxybenzyl)-1-triisopropylsilyl-1,4-dihydropyri-

dine (11e)

Synthesis according to GP1 from 4-(4-methoxybenzyl)pyridine (5e,

1.60 g, 8.03 mmol), TIPSOTf (2.71 g, 8.83 mmol, 2.37 mL), and di(al-

lyl)magnesium (0.30 m in THF/Et₂O, 1:1, 8.83 mmol, 29.6 mL). The re-

action was stopped after 2 h. Quantitative determination indicated

703 mg (22%) of dihydropyridine 11e followed by stirring under air

for 4 d. Purification by FC (Al₂O₃-basic, activity III, pentane) afforded

11e.

HRMS (EI): m/z [M]⁺calcd for C₁₄H₁₅N: 197.1199; found: 197.1196.

Yield: 741 mg (23%); colorless oil; R_f= 0.50 (Al₂O₃; pentane).

IR (film): 3083, 3027, 2945, 2866, 2360, 1670, 1581, 1463, 1288,

1103, 1059, 1014, 993, 971, 914, 883, 688 cm^–1

.

rac-1-Benzyl-4-azatricyclo[3.3.1.0^2,7]non-3-en (rac-13c)

¹H NMR (500 MHz, CDCl₃):  = 0.98 (d, J = 7.5 Hz, 18 H, CH(CH₃)₂),

1.10–1.20 (m, 3 H, CH(CH₃)₂), 2.08 (d, J = 7.2 Hz, 2 H, CCH₂CH), 2.51 (s,

2 H, CCH₂C), 3.77 (s, 3 H, OCH₃), 4.14 (d, J = 8.0 Hz, 2 H, NCHCH), 4.95–

5.07 (m, 2 H, CCH₂CHCH₂), 5.86–5.98 (m, 3 H, CH₂CHCH₂, NCHCH),

6.74–6.79 (m, 2 H, CHCO), 7.02–7.08 (m, 2 H, CHCHCO).

Synthesis according to GP2 from dihydropyridine 11c (690 mg,

1.88 mmol) and TFA (3.22 g, 28.2 mmol, 2.16 mL) in pentane

(18.8 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-13c.

Yield: 331 mg (83%); beige solid; mp 88 °C; R_f= 0.27 (Al₂O₃; pen-

¹³C NMR (125 MHz, CDCl₃):  = 11.5 (CH(CH₃)₂), 17.9 (CH(CH₃)₂), 39.6

(CCH₂CH), 49.1 (CCH₂CH), 50.1 (CCH₂C), 55.3 (OCH₃), 106.1 (NCHCH),

113.0 (CHCO), 115.9 (CCH₂CHCH₂), 129.0 (NCHCH), 131.4 (CCHCHCO),

131.9 (CHCHCO), 136.9 (CH₂CHCH₂), 157.8 (COCH₃).

tane/CH₂Cl₂/MeOH, 88:10:2).

IR (KBr): 3021, 2993, 2945, 2922, 2854, 1605, 1493, 1454, 1435, 1329,

1263, 1151, 771, 752, 704, 646, 484 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 0.99 (dq, J = 12.4, 2.3 Hz, 1 H,

NCHCH₂^aC), 1.03 (ddq, J = 12.6, 6.7, 2.0 Hz, 1 H, NCHCH₂^aCH), 1.16 (d,

J = 9.1 Hz, 1 H, CCH₂^aCHCH), 1.60 (ddd, J = 15.2, 12.5, 3.1 Hz, 2 H,

NCHCH₂^bC; NCHCH₂^bCH), 2.07 (q, J = 5.8 Hz, 1 H, NCHCH₂CH), 2.12

(ddt, J = 9.0, 6.8, 2.0 Hz, 1 H, CCH₂^bCHCH), 2.47 (d, J = 13.3 Hz, 1 H,

CCH₂^aC), 2.55 (d, J = 13.4 Hz, 1 H, CCH₂^bC), 2.96–3.02 (m, 1 H, NCHCH),

4.48–4.53 (m, 1 H, NCHCH₂), 7.02–7.06 (m, 2 H, CCHCHCH), 7.17–7.23

(m, 1 H, CCHCHCH), 7.23–7.29 (m, 2 H, CCHCHCH), 8.04 (d, J = 3.7 Hz,

1 H, NCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 27.8 (NCHCH₂CH), 31.3 (NCHCH₂CH),

37.0 (NCHCH₂C), 41.3 (CCH₂CHCH), 42.4 (NCHCH), 43.2 (NCHCHC),

46.5 (CCH₂C), 55.9 (NCHCH₂), 126.3 (CCHCHCH), 128.3 (CCHCHCH),

129.7 (CCHCHCH) 138.2 (CCHCHCH), 166.9 (NCHCH).

HRMS (EI): m/z [M]⁺calcd for C₂₅H₃₉NOSi: 397.2795; found: 397.2819.

rac-1-Methyl-4-azatricyclo[3.3.1.0^2,7]non-3-en (rac-13a)

Synthesis according to GP2 from dihydropyridine 11a (450 mg,

1.54 mmol) and TFA (2.65 g, 23.2 mmol, 1.78 mL) in pentane

(15.4 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-13a.

Yield: 174 mg (84%); yellow oil; R_f= 0.15 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88:10:2).

IR (film): 2949, 2858, 1614, 1452, 1375, 1350, 1333, 1269, 1160, 985,

916, 858, 829, 688 cm^–1

.

L

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

HRMS (EI): m/z [M]⁺calcd for C₁₅H₁₇N: 211.1356; found: 211.1354.

Yield: 146 mg (79%); colorless oil; R_f= 0.21 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88:10:2).

rac-1-(4-Methoxyphenyl)-4-azatricyclo[3.3.1.0^2,7]non-3-en (rac-

13d)

IR (film): 3215, 2937, 2866, 1616, 1450, 1340, 1190, 1149, 1061, 985,

943, 874, 714 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 0.96 (s, 3 H, CH₃), 1.13–1.19 (m, 1 H,

CHCH₂^aCH), 1.23 (ddt, J = 13.2, 3.1, 1.1 Hz, 1 H, CHCH₂^aC), 1.37–1.45

(m, 2 H, CHCH₂^bC, CCH₂^aCH₂), 1.46–1.54 (m, 1 H, CHCH₂^bCH), 1.54–

1.63 (m, 2 H, CCH₂CH₂), 1.91–2.03 (m, 2 H, CCH₂^bCH₂, CHCHCH₂), 2.33

(t, J = 4.2 Hz, 1 H, CHCHCH), 4.14 (p, J = 2.6 Hz, 1 H, NCHCH₂), 8.24 (d,

J = 4.1 Hz, 1 H, NCHCH).

Synthesis according to GP2 from dihydropyridine 11d (840 mg,

2.19 mmol) and TFA (3.74 g, 32.8 mmol, 2.51 mL) in pentane/EtOH,

4:1 (22.0 mL). Purification by FC (Al₂O₃-basic, activity III, pen-

tane/CH₂Cl₂/MeOH, 88:10:2) afforded rac-13d.

Yield: 421 mg (85%); yellow oil; R_f= 0.48 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 89:10:1).

¹³C NMR (125 MHz, CDCl₃):  = 28.2 (CH₃), 32.0 (CHCH₂CH₂), 34.1

(CHCH₂CH₂), 36.4 (CHCH₂CH), 39.8 (CHCH₂CH₂), 41.7 (CH₂CCH₂), 42.6

(CCH₂CH), 50.1 (NCHCH), 54.0 (NCHCH₂), 171.2 (NCHCH).

IR (film): 2997, 2933, 2858, 2833, 1610, 1514, 1462, 1443, 1346,

1250, 1178, 1034, 827, 810, 675 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 1.16 (ddq, J = 12.6, 6.2, 1.9 Hz, 1 H,

NCHCH₂^aCH), 1.23 (dq, J = 12.7, 2.3 Hz, 1 H, NCHCH₂^aC), 1.56 (d,

J = 9.2 Hz, 1 H, CCH₂^aCHCH), 1.77 (dd, J = 12.6, 3.2 Hz, 1 H,

NCHCH₂^bCH), 1.98 (dd, J = 12.7, 3.0 Hz, 1 H, NCHCH₂^bC), 2.20 (q,

J = 6.3 Hz, 1 H, NCHCHCH), 2.50 (ddt, J = 9.1, 6.8, 2.0 Hz, 1 H,

CCH₂^bCHCH), 3.22–3.27 (m, 1 H, NCHCH), 3.77 (s, 3 H, OCH₃), 4.61–

4.66 (m, 1 H, NCH(CH₂)₂), 6.79–6.83 (m, 2 H, CHCOCH₃), 6.89–

6.93 (m, 2 H, CHCHCO), 8.32 (d, J = 3.7 Hz, 1 H, NCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 27.6 (NCHCH₂CH), 30.9 (NCHCH₂CH),

40.9 (NCHCH₂C), 41.5 (CCH₂CHCH), 43.6 (NCHCH), 45.2 (CCH₂), 55.4

(OCH₃), 56.0 (NCHCH₂), 113.9 (CHCO), 126.0 (CHCHCO), 140.1

(CCCH₂), 157.9 (COCH₃) 167.0 (NCHCH).

HRMS (ESI): m/z [M

+

H]⁺calcd for C₁₀H₁₆N: 150.1277;

found: 150.1276.

rac-3-Phenyl-9-azatricyclo[4.3.1.0^3,7]dec-8-en (rac-14b)

Synthesis according to GP2 from dihydropyridine 7b (870 mg,

2.37 mmol) and TFA (4.05 g, 35.5 mmol, 2.72 mL) in pentane

(23.7 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88.5:10:1.5) afforded rac-14b.

Yield: 420 mg (84%); colorless oil; R_f= 0.48 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88.5:10:1.5).

IR (film): 3055, 3022, 2997, 2945, 2868, 1618, 1495, 1444, 1340,

HRMS (ESI): m/z [M

+

H]⁺calcd for C₁₅H₁₈NO: 228.1383;

1188, 1034, 987, 760, 700 cm^–1

.

found: 228.1382.

¹H NMR (500 MHz, CDCl₃):  = 1.32 (dt, J = 13.3, 2.0 Hz, 1 H,

CHCH₂^aCH), 1.54–1.62 (m, 1 H, CHCH₂^aCH₂), 1.65 (ddt, J = 13.2, 10.3,

2.9 Hz, 1 H, CHCH₂^bCH), 1.73 (ddt, J = 13.3, 3.0, 0.9 Hz, 1 H, CCH₂^aCH),

1.87 (dd, J = 13.3, 2.5 Hz, 1 H, CCH₂^bCH), 1.97–2.16 (m, 4 H,

CHCH₂^bCH₂, CHCH₂CH₂, CHCH₂CH₂), 3.02 (t, J = 4.3 Hz, 1 H, CHCHCH),

4.24 (p, J = 2.6 Hz, 1 H, NCHCH₂), 7.11–7.16 (m, 1 H, CCHCHCH), 7.16–

7.21 (m, 2 H, CCHCHCH), 7.23–7.29 (m, 2 H, CCHCHCH), 8.48 (d,

J = 4.0 Hz, 1 H, NCHCH).

rac-1-(4-Methoxybenzyl)-4-azatricyclo[3.3.1.0^2,7]non-3-en (rac-

13e)

Synthesis according to GP2 from dihydropyridine 11e (700 mg,

1.76 mmol) and TFA (3.01 g, 28.2 mmol, 2.02 mL) in pentane/EtOH,

4:1 (17.6 mL). Purification by FC (Al₂O₃-basic, activity III, pen-

tane/CH₂Cl₂/MeOH, 88:10:2) afforded rac-13e.

¹³C NMR (125 MHz, CDCl₃):  = 31.5 (CHCH₂CH₂), 34.0 (CHCH₂CH₂),

36.3 (CHCH₂CH), 41.1 (CHCH₂CH₂), 44.9 (CCH₂CH), 46.7 (NCHCH),

50.2 (CCH₂CH₂), 53.9 (NCHCH₂), 125.8 (CCHCHCH), 125.9 (CCHCHCH),

128.5 (CCHCHCH), 149.9 (CCCH₂), 170.5 (NCHCH).

Yield: 284 mg (67%); yellow oil; R_f= 0.42 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88:10:2).

IR (KBr): 2995, 2933, 2852, 1684, 1610, 1512, 1464, 1441, 1351, 1333,

1302, 1244, 1178, 1036, 829, 681 cm^–1

.

H]⁺calcd for C₁₅H₁₈N: 212.1434;

¹H NMR (500 MHz, CDCl₃):  = 0.97 (dq, J = 12.4, 2.2 Hz, 1 H,

NCHCH₂^aC), 1.03 (ddq, J = 12.5, 6.3, 1.9 Hz, 1 H, NCHCH₂^aCH), 1.14 (d,

J = 8.9 Hz, 1 H, CCH₂^aCHCH), 1.57 (dd, J = 12.5, 3.0 Hz, 1 H, NCHCH₂^bC),

1.61 (dd, J = 12.6, 3.2 Hz, 1 H, NCHCH₂^bCH), 2.03–2.12 (m, 2 H,

NCHCH₂CH, CCH₂^bCHCH), 2.41 (d, J = 13.5 Hz, 1 H, CCH₂^aC), 2.48 (d,

J = 13.6 Hz, 1 H, CCH₂^bC), 2.94–2.98 (m, 1 H, NCHCH), 3.78 (s, 3 H,

OCH₃), 4.47–4.51 (m, 1 H, NCHCH₂), 6.78–6.82 (m, 2 H, CHCO), 6.93–

6.97 (m, 2 H, CHCHCO), 8.03 (d, J = 3.7 Hz, 1 H, NCHCH).

HRMS (ESI): m/z [M

found: 212.1432.

+

rac-3-Benzyl-9-azatricyclo[4.3.1.0^3,7]dec-8-en (rac-14c)

Synthesis according to GP2 from dihydropyridine 7c (540 mg,

1.41 mmol) and TFA (2.42 g, 21.2 mmol, 1.62 mL) in pentane

(14.1 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88.5:10:1.5) afforded rac-14c.

¹³C NMR (125 MHz, CDCl₃):  = 27.8 (NCHCH₂CH), 31.3 (NCHCH₂CH),

36.9 (NCHCH₂C), 41.3 (CCH₂CHCH), 42.4 (NCHCH), 43.4 (NCHCHC),

45.6 (CCH₂C), 55.3 (OCH₃), 55.9 (NCHCH₂), 113.7 (CHCO), 130.3 (CCH-

CHCO), 130.5 (CHCHCO), 158.2 (COCH₃), 167.0 (NCHCH).

Yield: 274 mg (86%); yellow oil; R_f= 0.40 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88.5:10:1.5).

IR (film): 3084, 3059, 3026, 2945, 2868, 1616, 1495, 1452, 1342, 762,

731, 704 cm^–1

.

HRMS (ESI): m/z [M

+

H]⁺calcd for C₁₆H₂₀NO: 242.1539;

¹H NMR (500 MHz, CDCl₃):  = 1.17 (dd, J = 13.4, 2.4 Hz, 1 H,

CHCH₂^aCH), 1.31 (dd, J = 13.2, 2.1 Hz, 1 H, CCH₂^aCH), 1.35–1.43 (m,

1 H, CHCH₂^aCH₂), 1.45–1.54 (m, 3 H, CHCH₂^bCH, CCH₂^bCH,

CHCH₂CH₂^a), 1.72–1.80 (m, 1 H, CHCH₂CH₂^b), 1.84–1.94 (m, 2 H, CH-

CHCH₂, CHCH₂^bCH₂), 2.42 (t, J = 4.2 Hz, 1 H, CHCHCH), 2.52 (s, 2 H,

CCH₂C), 4.16 (p, J = 2.6 Hz, 1 H, NCHCH₂), 7.11–7.15 (m, 2 H, CCH-

CHCH), 7.18–7.23 (m, 1 H, CCHCHCH), 7.24–7.29 (m, 2 H, CCHCHCH),

8.25 (d, J = 4.1 Hz, 1 H, NCHCH).

found: 242.1538.

rac-3-Methyl-9-azatricyclo[4.3.1.0^3,7]dec-8-en (rac-14a)

Synthesis according to GP2 from dihydropyridine 7a (380 mg,

1.24 mmol) and TFA (2.13 g, 18.7 mmol, 1.43 mL) in pentane

(12.4 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-14a.

M

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

¹³C NMR (125 MHz, CDCl₃):  = 31.6 (CHCH₂CH₂), 33.2 (CHCHCH₂),

36.5 (CHCH₂CH₂), 36.9 (CHCH₂CH), 40.7 (CCH₂CH), 46.6 (CHCCH₂),

47.1 (CCH₂C), 47.8 (NCHCH), 53.7 (NCHCH₂), 126.3 (CCHCHCH), 128.1

(CCHCHCH), 130.3 (CCHCHCH), 138.8 (CCHCHCH), 171.0 (NCHCH).

rac-3-Methyl-10-azatricyclo[5.3.1.0^3,8]undec-9-en (rac-15a)

Synthesis according to GP2 from dihydropyridine 9a (410 mg,

1.28 mmol) and TFA (2.19 g, 19.2 mmol, 1.47 mL) in pentane

(12.8 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-15a.

HRMS (ESI): m/z [M

+

H]⁺calcd for C₁₆H₂₀N: 226.1590;

found: 226.1589.

Yield: 160 mg (77%); yellow oil; R_f= 0.21 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88:10:2).

rac-3-(4-Methoxyphenyl)-9-azatricyclo[4.3.1.0^3,7]dec-8-en (rac-

14d)

IR (film): 3404, 2993, 2922, 2862, 1614, 1469, 1454, 1338, 1134,

1001, 922, 892, 681, 642 cm^–1

.

Synthesis according to GP2 from dihydropyridine 7d (545 mg,

1.37 mmol) and TFA (2.35 g, 20.6 mmol, 1.58 mL) in pentane

(13.7 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-14d.

¹H NMR (400 MHz, CDCl₃):  = 0.80 (s, 3 H, CH₃), 1.05–1.19 (m, 3 H,

CCH₂^aCH₂, NCHCH₂^aC, NCHCH₂^aCH), 1.26–1.39 (m, 2 H, CCH₂^bCH₂,

CHCH₂^aCH₂), 1.39–1.60 (m, 5 H, CH₂CH₂CH₂, CHCH₂^bCH₂, NCHCH₂^bC,

NCHCH₂^bCH), 1.70 (dp, J = 11.6, 3.4 Hz, 1 H, CHCH₂CH₂), 1.99 (t,

J = 3.7 Hz, 1 H, NCHCH), 4.17–4.21 (m, 1 H, NCHCH₂), 8.37 (d,

J = 4.2 Hz, 1 H, NCHCH).

Yield: 295 mg (89%); colorless solid; mp 97 °C; R_f= 0.17 (Al₂O₃; pen-

tane/CH₂Cl₂/MeOH, 88:10:2).

¹³C NMR (100 MHz, CDCl₃):  = 17.1 (CH₂CH₂CH₂), 27.3 (CHCH₂CH₂),

28.4 (CHCH₂CH₂), 28.6 (CHCH₂CH), 32.0 (CCH₃), 32.3 (CH₃), 36.6

(NCHCH₂C), 37.8 (CCH₂CH₂), 46.3 (NCHCH), 54.8 (NCHCH₂), 174.8

(NCHCH).

IR (KBr): 2999, 2939, 2868, 2835, 1614, 1512, 1335, 1306, 1259, 1238,

1180, 1036, 827, 555 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 1.31 (d, J = 13.2 Hz, 1 H, CHCH₂^aCH),

1.53–1.60 (m, 1 H, CHCH₂^aCH₂), 1.64 (ddt, J = 13.1, 10.3, 2.8 Hz, 1 H,

CHCH₂^bCH), 1.71 (dt, J = 13.3, 2.8 Hz, 1 H, CCH₂^aCH), 1.83 (dd, J = 13.3,

2.4 Hz, 1 H, CCH₂^bCH), 2.00–2.13 (m, 4 H, CHCH₂^bCH₂, CHCH₂CH₂,

CHCH₂CH₂), 2.97 (t, J = 4.3 Hz, 1 H, CHCHCH), 3.77 (s, 3 H, CH₃), 4.23

(p, J = 2.6 Hz, 1 H, NCHCH₂), 6.77–6.83 (m, 2 H, CHCO), 7.08–7.13 (m,

2 H, CHCHCO), 8.46 (d, J = 4.0 Hz, 1 H, NCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 31.5 (CHCH₂CH₂), 34.0 (CHCH₂CH₂),

36.4 (CHCH₂CH), 41.1 (CHCH₂CH₂), 44.9 (CCH₂CH), 47.1 (NCHCH),

49.5 (CCH₂CH₂), 53.9 (NCHCH₂), 55.4 (CH₃), 113.8 (CHCO), 126.9 (CH-

CHCO), 142.2 (CCHCHCO), 157.6 (CO), 170.6 (NCHCH).

HRMS (EI): m/z [M]⁺calcd for C₁₁H₁₇N: 163.1356; found: 163.1365.

rac-3-Phenyl-10-azatricyclo[5.3.1.0^3,8]undec-9-en (rac-15b)

Synthesis according to GP2 from dihydropyridine 9b (200 mg,

0.52 mmol) and TFA (896 mg, 7.86 mmol, 0.60 mL) in pentane

(5.2 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-15b.

Yield: 87 mg (74%); yellow oil; R_f= 0.26 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 84:14:2).

HRMS (ESI): m/z [M

+

H]⁺calcd for C₁₆H₂₀NO: 242.1539;

IR (film): 3055, 3024, 2925, 2858, 1616, 1495, 1469, 1444, 1338,

found: 242.1538.

1030, 955, 893, 760, 702 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.32–1.48 (m, 3 H, CHCH₂^aCH,

CCH₂^aCH₂, CHCH₂^aCH₂), 1.54–1.68 (m, 3 H, CH₂CH₂^aCH₂, CHCH₂^bCH,

CHCH₂^bCH₂), 1.69–1.83 (m, 2 H, CCH₂^bCH₂, CH₂CH₂^bCH₂), 1.88–2.01

(m, 3 H, NCHCH₂C, CHCH₂CH₂), 2.89 (t, J = 3.7 Hz, 1 H, NCHCH), 4.28

(p, J = 2.8 Hz, 1 H, NCHCH₂), 7.10–7.16 (m, 1 H, CCHCHCH), 7.22–7.30

(m, 4 H, CCHCHCH, CCHCHCH), 8.43 (d, J = 4.0 Hz, 1 H, NCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 17.3 (CH₂CH₂CH₂), 27.2 (CHCH₂CH₂),

28.3 (CHCH₂CH₂), 29.4 (CHCH₂CH), 37.3 (NCHCH₂C), 40.5 (CCH₂CH₂),

40.7 (CCH₂), 42.1 (NCHCH), 54.2 (NCHCH₂), 125.7 (CCHCHCH), 126.1

(CCHCHCH), 128.4 (CCHCHCH), 152.6 (CCCH₂), 173.9 (NCHCH).

rac-3-(4-Methoxybenzyl)-9-azatricyclo[4.3.1.0^3,7]dec-8-en (rac-

14e)

Synthesis according to GP2 from dihydropyridine 7e (465 mg,

1.13 mmol) and TFA (1.93 g, 16.9 mmol, 1.29 mL) in pentane

(11.3 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-14e.

Yield: 244 mg (85%); yellow oil; R_f= 0.19 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88:10:2).

IR (film): 2995, 2945, 2868, 1614, 1512, 1464, 1441, 1342, 1302,

1248, 1178, 1036, 833, 820, 758 cm^–1

.

HRMS (EI): m/z [M]⁺calcd for C₁₆H₁₉N: 225.1512; found: 225.1506.

¹H NMR (500 MHz, CDCl₃):  = 1.17 (dd, J = 12.9, 2.0 Hz, 1 H,

CHCH₂^aCH), 1.30 (dd, J = 13.3, 2.3 Hz, 1 H, CCH₂^aCH), 1.35–1.43 (m,

1 H, CHCH₂^aCH₂), 1.44–1.54 (m, 3 H, CHCH₂^bCH, CCH₂^bCH,

CHCH₂CH₂^a), 1.70–1.79 (m, 1 H, CHCH₂CH₂^b), 1.84–1.94 (m, 2 H, CH-

CHCH₂, CHCH₂^bCH₂), 2.40 (t, J = 4.3 Hz, 1 H, CHCHCH), 2.46 (s, 2 H,

CCH₂C), 3.78 (s, 3 H, CH₃), 4.16 (p, J = 2.6 Hz, 1 H, NCHCH₂), 6.79–6.84

(m, 2 H, CHCO), 7.02–7.07 (m, 2 H, CHCHCO), 8.24 (d, J = 4.1 Hz, 1 H,

NCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 31.7 (CHCH₂CH₂), 33.3 (CHCHCH₂),

36.5 (CHCH₂CH₂), 36.9 (CHCH₂CH), 40.7 (CCH₂CH), 46.2 (CCH₂C), 46.7

(CHCCH₂), 47.8 (NCHCH), 53.8 (NCHCH₂), 55.3 (CH₃), 113.5 (CHCO),

130.9 (CCHCHCO), 131.2 (CHCHCO), 158.2 (CO), 171.0 (NCHCH).

rac-3-Benzyl-10-azatricyclo[5.3.1.0^3,8]undec-9-en (rac-15c)

Synthesis according to GP2 from dihydropyridine 9c (420 mg,

1.06 mmol) and TFA (1.81 g, 15.9 mmol, 1.22 mL) in pentane

(10.6 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-15c.

Yield: 188 mg (74%); colorless oil; R_f= 0.22 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88:10:2).

IR (film): 3084, 3057, 2926, 2848, 1014, 1495, 1469, 1450, 1340,

1120, 1068, 1025, 974, 758, 706 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 1.12–1.24 (m, 3 H, CCH₂^aCH₂,

CHCH₂^aCH₂, CHCH₂^aCH), 1.32–1.58 (m, 7 H, CCH₂^bCH₂, CHCH₂^bCH₂,

CHCH₂^bCH, CH₂CH₂CH₂, NCHCH₂C), 1.70 (dp, J = 10.2, 3.4 Hz, 1 H,

CHCH₂CH₂), 2.09 (t, J = 3.7 Hz, 1 H, NCHCH), 2.35 (d, J = 13.2 Hz, 1 H,

CCH₂^aC), 2.44 (d, J = 13.2 Hz, 1 H, CCH₂^bC), 4.23–4.29 (m, 1 H,

HRMS (ESI): m/z [M

+

H]⁺calcd for C₁₇H₂₂N: 256.1696;

found: 256.1695.

N

H.-K. A. Rudy, K. T. Wanner

Paper

Synthesis

NCHCH₂), 7.09–7.13 (m, 2 H, CCHCHCH), 7.19–7.24 (m, 1 H, CCH-

CHCH), 7.25–7.30 (m, 2 H, CCHCHCH), 8.51 (d, J = 4.1 Hz, 1 H,

NCHCH).

HRMS (ESI): m/z [M

found: 270.1851.

+

H]⁺calcd for C₁₈H₂₄NO: 270.1852;

¹³C NMR (125 MHz, CDCl₃):  = 16.7 (CH₂CH₂CH₂), 27.2 (CHCH₂CH₂),

28.1 (CHCH₂CH₂), 29.2 (CHCH₂CH), 33.9 (CCH₂CH₂), 35.3 (NCHCH₂C),

36.4 (CCH₂CH₂), 43.3 (NCHCH), 50.6 (CCH₂C), 54.6 (NCHCH₂), 126.3

(CCHCHCH), 128.0 (CCHCHCH), 130.9 (CCHCHCH), 137.9 (CCHCHCH),

174.7 (NCHCH).

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/s-0039-1690619.

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n

HRMS (ESI): m/z [M+H]⁺calcd for C₁₇H₂₂N: 240.1747;

found: 240.1745.

References

rac-3-(4-Methoxyphenyl)-10-azatricyclo[5.3.1.0^3,8]undec-9-en

(rac-15d)

(1) (a) Sharma, V. K.; Singh, S. K. RSC Adv. 2017, 7, 2682. (b) Silva, A.;

Silva, E.; Varandas, P. Synthesis 2013, 45, 3053. (c) Lavilla, R.

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K. L.; Brenner, C. Trends Biochem. Sci. 2007, 32, 12. (e) World

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Synthesis according to GP2 from dihydropyridine 9d (900 mg,

2.19 mmol) and TFA (3.74 g, 32.8 mmol, 2.51 mL) in pentane

(21.9 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-15d.

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585.

Yield: 301 mg (54%); colorless solid; mp 75 °C; R_f= 0.18 (Al₂O₃; pen-

tane/CH₂Cl₂/MeOH, 88:10:2).

IR (KBr): 2989, 2929, 2843, 1612, 1514, 1441, 1284, 1252, 1180, 1111,

1030, 893, 820, 690, 553 cm^–1

.

¹H NMR (500 MHz, CDCl₃):  = 1.30–1.44 (m, 3 H, CHCH₂^aCH,

CCH₂^aCH₂, CHCH₂^aCH₂), 1.52–1.64 (m, 3 H, CH₂CH₂^aCH₂, CHCH₂^bCH,

CHCH₂^bCH₂), 1.66–1.75 (m, 2 H, CCH₂^bCH₂, CH₂CH₂^bCH₂), 1.85–1.96

(m, 3 H, NCHCH₂C, CHCH₂CH₂JJ), 2.81 (t, J = 3.7 Hz, 1 H, NCHCH), 3.76

(s, 3 H, OCH₃), 4.24–4.28 (m, 1 H, NCHCH₂), 6.77–6.82 (m, 2 H, CHCO),

7.13–7.18 (m, 2 H, CHCHCO), 8.39 (d, J = 3.9 Hz, 1 H, NCHCH).

¹³C NMR (125 MHz, CDCl₃):  = 17.4 (CH₂CH₂CH₂), 27.3 (CHCH₂CH₂),

28.3 (CHCH₂CH₂), 29.4 (CHCH₂CH), 37.2 (NCHCH₂C), 39.9 (CCH₂), 40.5

(CCH₂CH₂), 42.5 (NCHCH), 54.3 (NCHCH₂), 55.4 (OCH₃), 113.8 (CHCO),

127.1 (CHCHCO), 144.8 (CCCH₂), 157.4 (COCH₃), 174.0 (NCHCH).

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G.; Al-Arnaout, A.; Miginiac, L. Tetrahedron Lett. 1985, 26, 1027.

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Pérez, C. M.; Rodríguez-Delgado, A.; Naz, A. M.; Palma, P.;

Álvarez, E. Organometallics 2007, 26, 1104. (c) Sandoval, J. J.;

Melero, C.; Palma, P.; Álvarez, E.; Rodríguez-Delgado, A.;

Cámpora, J. Organometallics 2016, 35, 3336.

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Alston, P. V. Tetrahedron 1991, 47, 8499. (b) Comins, D. L.;

Mantlo, N. B. Tetrahedron Lett. 1987, 28, 759. (c) Rudler, H.;

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1630. (b) Bräckow, J.; Wanner, K. T. Tetrahedron 2006, 62, 2395.

(11) (a) Satoh, N.; Akiba, T.; Yokoshima, S.; Fukuyama, T. Angew.

Chem. Int. Ed. 2007, 46, 5734. (b) Khan, M. O. F.; Levi, M. S.;

Clark, C. R.; Ablorderrey, S. Y.; Law, S.-J.; Wilson, N. H.; Borne, R.

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1985, 50, 2427. (b) Hartman, G. D.; Halczenko, W.; Philipps, B. T.

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Halczenko, W. J. Org. Chem. 1987, 52, 1136. (d) Hartman, G. D.;

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1989, 54, 4137.

HRMS (ESI): m/z [M

found: 256.1694.

+

H]⁺calcd for C₁₇H₂₂NO: 256.1696;

rac-3-(4-Methoxybenzyl)-10-azatricyclo[5.3.1.0^3,8]undec-9-en

(rac-15e)

Synthesis according to GP2 from dihydropyridine 9e (430 mg,

1.01 mmol) and TFA (1.73 g, 15.2 mmol, 1.16 mL) in pentane

(10.1 mL). Purification by FC (Al₂O₃-basic, activity III, pentane/CH₂Cl₂/

MeOH, 88:10:2) afforded rac-15e.

Yield: 241 mg (89%); yellow oil; R_f= 0.20 (Al₂O₃; pentane/CH₂Cl₂/

MeOH, 88:10:2).

IR (film): 2993, 2925, 2848, 2062, 1882, 1612, 1512, 1468, 1442,

1248, 1178, 1122, 1036, 822, 758, 729, 700 cm^–1

.

¹H NMR (400 MHz, CDCl₃):  = 1.10–1.23 (m, 3 H, CCH₂^aCH₂,

CHCH₂^aCH₂, CHCH₂^aCH), 1.28–1.36 (m, 2 H, CCH₂^bCH₂, NCHCH₂^aC),

1.39 (dd, J = 13.6, 2.0 Hz, 1 H, NCHCH₂^bC), 1.41–1.58 (m, 4 H,

CHCH₂^bCH₂, CHCH₂^bCH, CH₂CH₂CH₂,), 1.69 (dp, J = 10.0, 3.3 Hz, 1 H,

CHCH₂CH₂), 2.07 (t, J = 3.8 Hz, 1 H, NCHCH), 2.28 (d, J = 13.2 Hz, 1 H,

CCH₂^aC), 2.37 (d, J = 13.2 Hz, 1 H, CCH₂^bC), 3.79 (s, 3 H, OCH₃), 4.22–

4.27 (m, 1 H, NCHCH₂), 6.78–6.84 (m, 2 H, CHCO), 6.98–7.05 (m, 2 H,

CHCHCO), 8.49 (d, J = 4.2 Hz, 1 H, NCHCH).

¹³C NMR (100 MHz, CDCl₃):  = 16.7 (CH₂CH₂CH₂), 27.2 (CHCH₂CH₂),

28.2 (CHCH₂CH₂), 29.2 (CHCH₂CH), 33.9 (CCH₂CH₂), 35.2 (NCHCH₂C),

36.4 (CCH₂CH₂), 43.3 (NCHCH), 49.7 (CCH₂C), 54.6 (NCHCH₂), 55.3

(OCH₃), 113.4 (CHCO), 130.0 (CCHCHCO), 131.7 (CHCHCO), 158.2 (CO-

CH₃), 174.7 (NCHCH).

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Thiermann, H.; Wanner, K. Synthesis 2017, 49, 4055. (b) Sperger,

C. A.; Wanner, K. T. Tetrahedron 2009, 65, 5824. (c) Schmaunz, C.

Dissertation; Ludwig-Maximilians Universität München: Ger-

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Paper

Synthesis

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Article Doi

Accessing Tricyclic Imines Comprising a 2-Azabicyclo[22.2]octane Scaffold by Intramolecular Hetero-Diels-Alder Reaction of 4-Alkenyl-Substituted N-Silyl-1,4-dihydropyridines

DOI: 10.1055/s-0039-1690619

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