Direct aminoalkylation of arenes, heteroarenes, and alkenes via Ni-catalyzed Negishi cross-coupling reactions

ARTICLE

pubs.acs.org/joc

Direct Aminoalkylation of Arenes, Heteroarenes, and Alkenes

via Ni-Catalyzed Negishi Cross-Coupling Reactions

Laurin Melzig, Teresa Dennenwaldt, Andrey Gavryushin, and Paul Knochel*

Department Chemie, Ludwig-Maximilians-University, Butenandtstr. 5-13, Munich, Germany

S Supporting Information

b

ABSTRACT: A room-temperature Ni-catalyzed cross-cou-

pling of aryl, heteroaryl, and alkenyl electrophiles with

aminoalkylzinc bromides, readily available from the corre-

sponding aminoalkyl chlorides via Grignard reagents, was

developed. The reaction allows a convenient one-step pre-

paration of various aminoalkyl products, including piperidine

and tropane derivatives. Such functionalized amine moieties

are widely present in various biologically active molecules.

Aryl, heteroaryl, and alkenyl iodides, bromides, chlorides and triﬂates are suitable electrophiles. A short total synthesis of two

natural products, (()-galipinine and (()-cusparine, is also reported.

’ INTRODUCTION

hydrochloride (1) with LiH (2.0 equiv) in THF, followed by ﬁltra-

tion, resulted in a solution of the corresponding chloramines. Inser-

tion of magnesium turnings activated with DIBAL-H⁷(3 mol %)

in the presence of LiCl⁸(2 equiv) in THF (reﬂux, 2 h) aﬀorded

the organomagnesium compound. A subsequent transmetalation

using ZnBr₂(2 equiv, 1.0 M in THF/NMP 10:1)⁹gave 3-dimethy-

laminopropylzinc bromide (2a) in 82% yield, as determined by

iodometric titration¹⁰(Scheme 1). The presence of ZnBr₂was

essential for the success of the cross-coupling (see below).

One of the most frequently occurring functionalities in bio-

logically or pharmacologically active compounds is the aminoalk-

yl moiety.¹The basic trialkylamine is one of the most important

pharmacophore groups.²A method for the simple, direct, and

convenient introduction of these aminoalkyl residues into fun-

tionalized compounds would therefore be of great interest.³For

aryl, heteroaryl, or alkenyl structures this task can be easily

accomplished by using cross-coupling chemistry. Whereas many

reports dealing with cross-coupling reactions of alkyl organome-

tallics derivatives bearing an amide or sulfonamide nitrogen have

been published,⁴no coupling procedures of an aminoalkyl zinc or

magnesium organometallic species bearing a basic nitrogen are

known. Molander described a direct Pd-catalyzed cross-coupling

of aminoalkyl groups to arenes and heteroarenes using potassium

aminoalkyltriﬂuoroborates.^5aThe high potential of this protocol

for the synthesis of biologically active molecules was also demon-

strated. This reaction is so far described for primary alkylamines.^5b,c

Recently, we reported a novel aminoalkylation based on a Ni-

catalyzed cross-coupling reaction between aminoalkylzinc com-

pounds and various aryl and heteroaryl bromides, chlorides, and

triﬂates.⁶This method allows a direct introduction of both

primary and secondary aminoalkyl groups possessing a basic

nitrogen. Herein, we describe the full scope of this cross-

coupling. Furthermore, we report a total synthesis of two natural

products, (()-galipinine and (()-cusparine, demonstrating the

utility of the cross-coupling.

Palladium catalysts, previously used to perform sp³-sp²Ne-

gishi cross-couplings,¹¹were not very promising. Only traces

of the cross-coupling product were detected using Pd₂(dba)₃

(2.5 mol %) and PPh₃, P(oTol)₃,^11aPtBu₃,^11bor tri(2-furyl)-

phosphine^11c,din the model reaction of the zinc reagent 2a with

m-bromoanisole (3a, Table 1, entry 1). Pd(dppf)Cl₂^11fgave the

product 4a in merely 37% yield at 25 °C within 16 h, and also the

highly active PEPPSI^11fꢀhcatalyst provided better but still unsatis-

factory yields (entry 11). Since inexpensive Ni catalysts recently

showed remarkable high activities in the Negishi cross-coupling,¹²

we have tested several common phosphine ligands in the pre-

sence of Ni(acac)₂or NiCl₂(2.5 mol %). We found that electron-

rich phosphine ligands such as P(oTol)Ph₂(entry 6), nBuPAd₂^13a

(entry7), P(OiPr)₃^13b(entry9), or P(pTol)₃(entry12) gavethebest

results. Among the ligands screened, bis(2-diphenylphosphino-

phenyl)ether (DPE-Phos)¹⁴turned out to be the most active and

robust, aﬀording the cross-coupling product 4a in almost quan-

titative yield (entry 14). Further optimization revealed that the

optimal ratio of the ligand to nickel was 2:1 (entry 15), and the

optimal amount of ZnBr₂was 2 mol per mol of the Grignard

reagent (entry 16).¹⁵

’ RESULTS AND DISCUSSION

The alkylzinc halides required as nucleophiles for the Negishi

cross-coupling are easily accessed from the corresponding chlor-

ides via a Grignard reagent and transmetalation with ZnCl₂. There-

fore, treatment of commercial 3-dimethylaminopropyl chloride

Received: August 5, 2011

Published: September 16, 2011

r

2011 American Chemical Society

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Having established the optimized conditions for the cross-

coupling reaction, we investigated the behavior of other primary

and secondary aminoalkylzinc reagents. Following the same

protocol, aminoalkylzinc reagents 2aꢀe were prepared starting

from commercially available hydrochlorides (for 2aꢀd) or from

tropanol (for 2e). Noteworthy, the corresponding aminoalk-

ylmagnesium chlorides solutions in THF are relatively stable and

can be stored at 0 °C (titration after 6 months revealed the loss of

active magnesium species being less than 20%).

entries 1 and 2). A ketone function is compatible with the reac-

tion conditions, and we isolated the p-keto-substituted alkylben-

zene 4d in 90% yield from the reaction of zinc reagent 2a with

1-(4-bromophenyl)pentan-1-one (3d, 1 h, entry 3). Also the

bromopyridine 3e bearing an ester function and 4-bromoisoqui-

noline (3f) were submitted to the cross-coupling protocol and

furnished the pyridine 4e and the aminoalkylated isoquinoline 4f

in 80ꢀ84% yield within 3 h (entries 4 and 5). 6-Bromoquinoxa-

line (3g) and the Boc-protected indole 3h were cross-coupled

with 2a within 1ꢀ2 h and led to heterocycles 4g and 4h in

86ꢀ98% yield (entries 6 and 7). Finally, the brominated furan 3i

and 2-chloroquinoline (3j) were suitable electrophiles for the

Cross-Coupling Reactions of Aminoalkylzinc Reagent 2a

Leading to Products 4bꢀj. Hence we used 3-dimethylamino-

propylzinc bromide (2a) in the presence of Ni(acac)₂(2.5 mol

%) and DPE-Phos (5.0 mol %) in the optimized solvent mixture

(THF/NMP 10:1)^12c,dat 25 °C for the cross-coupling reaction

with various functionalized aryl and heteroaryl bromides and

chlorides, and we obtained the products 4bꢀj in good to excel-

lent yields within 1ꢀ3 h (Scheme 2).

Scheme 2. Ni-Catalyzed Cross-Coupling Reaction of Ami-

noalkylzinc Reagent 2a

Trisubstituted aryl bromides 3b and 3c underwent the cou-

pling reaction within 1ꢀ3 h, and the corresponding alkylated

arenes 4b and 4c were obtained in 79ꢀ83% yield (Table 2,

Scheme 1. Preparation of 3-Dimethylaminopropylzinc Bro-

mide (2a)

Table 1. Ligand Screening in the Cross-Coupling Reaction of 3-Dimethylaminopropylzinc Bromide (2a) with 3-Bromoanisole

(3a)

^aGC yield using tridecane as internal standard. ^b2.0 equiv of ZnBr₂used.

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Table 2. Preparation of Products 4bꢀj Obtained by Cross-Coupling (THF, 25 °C) Using Zinc Reagent 2a

^aReaction time. ^bYield of isolated, analytically pure product after aqueous workup without chromatographical puriﬁcation.

protocol and led to the 2,5-disubstituted furan 4i and quinoline

derivative 4j in 84ꢀ88% yield (entries 8 and 9).

the heterocyclic piperidinyl derivatives 5e and 5f in 56ꢀ95%

yield (entries 5 and 6). ((1-Methylpiperidin-3-yl)methyl)zinc

bromide (2c) underwent the Ni-catalyzed cross-coupling reac-

tion in a similar fashion, and the reaction with anisole derivative

3a or the bis-halogenated benzonitrile 3c proceeded smoothly

and yielded the alkylbenzene derivatives 6a and 6b in 56ꢀ66%

yield (entries 7 and 8). Additionally, the heterocyclic bromide 3h

and 2-chloro-6-methoxypyridine (3l) gave, after cross-coupling

with 2c, the piperidinyl compounds 6c and 6d in 60ꢀ90% yield

(entries 9 and 10).

Cross-Coupling Reactions of Secondary Aminoalkylzinc

Reagents 2d and 2e Leading to Products 7aꢀi and 8aꢀe.

The secondary aminoalkylzinc bromides 2d and 2e could be

prepared via magnesium insertion and subsequent transmetala-

tion using ZnBr₂. To our delight, they performed equally well

in the cross-coupling protocol with various halides and triflates,

Cross-Coupling Reactions of Primary Aminoalkylzinc Re-

agents 2b and 2c Leading to Products 5aꢀf and 6aꢀd. The

primary aminoalkylzinc bromides 2b and 2c, prepared via the

usual procedure in 56ꢀ77% yield, were used for the cross-coupl-

ing reaction with various aryl and heteroaryl bromides or chlorides

and led to the aminoalkyl products 5aꢀf and 6aꢀd in in 56ꢀ

95% yield within 1ꢀ48 h (Scheme 3).

Hence the reaction of 2b with 3-bromoanisole (3a) or

1-bromo-3-(triﬂuoromethoxy)benzene (3k) or the biphenyl

derivative 3b furnished the corresponding alkylated arenes 5aꢀc

in 70ꢀ80% yield within 3ꢀ48 h (Table 3, entries 1ꢀ3). Perform-

ing the reaction with ethyl 5-bromonicotinate (3e) led to the

pyridine derivative 5d in 95% yield (entry 4). The protected

5-bromoindole 3h and the chloro-substituted quinoline 3j led to

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Scheme 3. Ni-Catalyzed Cross-Coupling Reaction of

Aminoalkylzinc Reagents 2b and 2c

triﬂate 3u or triﬂate 3v bearing a nitrile group with aminoalk-

ylzinc halide 2a led to para-functionalized styrenes 9c,d in

54ꢀ69% yield (entries 3 and 4). The triﬂate 3w derived from

tetralone was aminoalkylated with 2a, yielding the functionalized

dihydronaphthalene 9e in 75% yield (entry 5). Likewise, sec-

ondary aminoalkylzinc bromides reacted with alkenyl halides,

and the cross-coupling between 2d and (E)-1-iodooct-1-ene

(3x) provided the substituted piperidine 10a in 58% yield within

24 h (entry 6). The Ni-catalyzed reaction of zinc reagent 2d with

2-bromostyrene 3s or (2-bromoethene-1,1-diyl)dibenzene (3y)

furnished the bi- and trisubstituted piperidinylethylenes 10b and

10c in 77ꢀ81% yield (entries 7 and 8). (1-Methylpiperidin-

4-yl)zinc bromide (2d) reacted with the triﬂates 3u and 3w

leading to the corresponding products 10d and 10e in 54ꢀ56%

yield (20 h, entries 9 and 10).

Synthesis of (()-Cusparine (11) and (()-Galipinine (12)

Using a Ni-Catalyzed Cross-Coupling. Tetrahydroquinolines

are an important structure found in many natural products. While

the 3- and 4-substituted derivatives are easily accessible via a

Grieco condensation,¹⁸the synthesis of 2-functionalized tetra-

hydroquinolines is often problematic. Cuspareine (11) and

galipinine (12) are two recently discovered natural compounds

showing interesting pharmacological profiles. They are found in

the bark of Galipea officinalis Hancock, a shrubby tree from

Venezuela,¹⁹and exhibit promising antibacterial activities against

Plasmodium falciparum, the parasite causing malaria.²⁰Several

routes for their total synthesis have been devised,²¹including

asymmetric approaches.²²We have developed an alternative

synthetic path toward these two tetrahydroquinolines, using

the aminoalkyl cross-coupling as a key step.

Starting from commercial quinaldine (13), a hydroxymethyla-

tion with paraformaldehyde furnished 2-(quinolin-2-yl)ethanol

(14) in 73% after recrystallization from n-heptane (Scheme 6).²³

Reduction of the quinoline ring with NaBH₄in the presence of

NiCl₂(18 mol %) led to piperidine 15 in 87% yield,²⁴which was

submitted to an aminoalkylation using formaldehyde and Na-

(BH₃)CN,²⁵yielding the corresponding N-methyl-piperidine 16

in quantitative yields. A chlorination with thionyl chloride in

CH₂Cl₂²⁶gave the amine 17 in 83% yield. Magnesium insertion

facilitated by LiCl⁸gave access to the aminoalkylmagnesium

chloride 18 (25 °C, 3 h) in 69% yield as determined by

titration.¹⁰Transmetalation with ZnBr₂(2.0 equiv) in THF/

NMP 10:1 and Negishi coupling with 4-bromoveratrole (19) or

5-bromobenzo[d][1,3]dioxole (20) at 25 °C for 18ꢀ22 h led to

(()-cusparine (11), which was isolated in 88% yield, and (()-

galipinine (12) in 81% yield, 29ꢀ32% overall yield over the 6

steps of this racemic synthesis.

furnishing within 1ꢀ48 h the corresponding products 7aꢀi and

8aꢀe in 55ꢀ96% yield (Scheme 4).¹⁶

The reaction of (1-methylpiperidin-4-yl)zinc bromide (2d)

with the 5-iodo-uracil derivative 3m at 25 °C for 48 h gave the

uracil derivative 7a in 60% yield (Table 4, entry 1). Similarly, the

cyano-, acetonitrile-, or keto-substituted bromobenzenes 3c,d,n,o

furnished the corresponding piperidine derivatives 7bꢀe in

84ꢀ96% yield (1ꢀ8 h, entries 2ꢀ5). 6-Bromoquinoxaline (3g)

and the methoxy-substituted 2-pyridinyl chloride 3l smoothly

underwent the coupling within 3 h and aﬀorded the N-hetero-

cyclic compounds 7f and 7g in 55ꢀ79% yield (entries 6 and 7).

Noteworthy, aryl or heteroaryl triﬂates react well. Hence, the

electron-rich naphthyl triﬂate 3p reacted with (1-methylpiper-

idin-4-yl)zinc bromide (2d) for 48 h, leading to the alkylated

product 7h in 93% yield (entry 8). Finally, quinolin-2-yl triﬂuor-

omethanesulfonate (3q) furnishes the 2-piperidinyl quinoline 7i

(25 °C, 8 h) in 95% yield (entry 9).

Remarkably, the cross-coupling of 8-methyl-8-azabicyclo-

[3.2.1]octylzinc species derived from tropanol gave exclusively

exo-3-aryltropanes, as conﬁrmed by NOESY experiments. We

assume that this selectivity results from the stereospeciﬁc forma-

tion of the intermediate chelate stabilized Grignard reagent, and

that the cross-coupling reaction proceeds with retention of con-

ﬁguration.¹⁷So the electron-rich 3-bromoanisole (3a) and also

the electron-deﬁcient 2-(4-bromophenyl)acetonitrile (3o) re-

acted smoothly with the zinc reagent 2e, leading to the arylated

tropane derivatives 8a and 8b in 55ꢀ92% yield (entries 10 and 11).

Also a chloropyridine such as 3l is a suitable substrate and delivered

the heterocyclic product 8c in 68% yield (72 h, entry 12). Finally,

the triﬂates 3p,r reacted with the zinc reagent 2e aﬀording the

3-naphthyl and the aryl-substituted tropane derivatives 8d and 8e in

62ꢀ73% yield (entries 13 and 14).

Cross-Coupling Reactions of Aminoalkylzinc Reagents 2a

and 2d with Alkenyl Electrophiles Leading to Products 9aꢀe

and 10aꢀe. Further studies showed that the Ni(acac)₂/DPE-

Phos system catalyzed also the cross-coupling with alkenyl

halides or triflates leading to the expected aminoalkylated pro-

ducts. Using the amino-substituted zinc reagents 2a,d we have

obtained the corresponding substituted alkenes 9aꢀe and 10aꢀe

in 51ꢀ81% yield (25ꢀ50 °C, 10ꢀ24 h, Scheme 5).

’ CONCLUSIONS

In summary, we have developed a general method for the one-

pot aminoalkylation of arenes, heteroarenes, and ethenes, using a

Ni-catalyzed Negishi cross-coupling reaction of primary as well

as secondary aminoalkylzinc bromides. These reagents are easily

available from the corresponding aminoalkyl chlorides. Aryl,

heteroaryl, and alkenyl iodides, bromides, chlorides, and triﬂates

are appropriate coupling electrophiles. A total synthesis of two

natural products bearing this important structure, (()-cusparine

and (()-galipinine, that includes the cross-coupling protocol as

key step was also accomplished. Further development of this

method is currently underway in our laboratories.

The cross-coupling of β-bromostyrene (3s) with 3-dimethyl-

aminopropylzinc bromide (2a) in the presence of Ni(acac)₂

(2.5 mol %) and DPE-Phos (5.0 mol %) for 16 h led to the styrene

9a in 66% yield (Table 5, entry 1). The reaction of α-bromostyrene

(3t) produced the geminal substituted ethene 9b in 51% yield

(16 h, entry 2). The coupling of the 4-chlorophenyl-substituted

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Table 3. Preparation of Products 5aꢀf and 6aꢀd Obtained by Cross-Coupling (THF, 25 °C) Using Zinc Reagents 2b and 2c

^aReaction time. ^bYield of isolated, analytically pure product after aqueous workup without chromatographical puriﬁcation. ^cAn additional puriﬁcation

by column chromatography was necessary.

’ EXPERIMENTAL SECTION

used to transfer anhydrous solvents or reagents were purged with argon

prior to use. THF was continuously refluxed and freshly distilled from

sodium benzophenone ketyl under nitrogen. Yields refer to isolated

yields of compounds estimated to be >95% pure as determined by ¹H

General Experimental Methods. All reactions were carried out

under an argon atmosphere in flame-dried glassware. Syringes that were

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Scheme 4. Ni-Catalyzed Cross-Coupling Reaction of Ami-

noalkylzinc Reagents 2d and 2e

solvent was evaporated in vacuo, and the compound purified by column

chromatography, if necessary.

Synthesis of Aminoalkylmagnesium Chlorides 2aꢀe. 3-

(Dimethylamino)propylmagnesium Chloride (2a). (3-Chloropropyl)-

dimethylamine (12.16 g, 100 mmol) reacted with Mg turnings (2.88 g,

120 mmol) and LiCl (8.48 g, 200 mmol) according to TP1. The solution

was titrated prior to use at room temperature against a solution of iodine

in THF. A concentration of 0.80 M in THF was obtained in 82% yield.

2-(1-Methylpiperidin-2-yl)ethylmagnesium Chloride (2b). 2-(2-

Chloroethyl)-1-methylpiperidine (16.17 g, 100 mmol) reacted with Mg

turnings (2.88 g, 120 mmol) and LiCl (8.48 g, 200 mmol) according to

TP1. The solution was titrated prior to use at room temperature against a

solution of iodine in THF. A concentration of 0.71 M in THF was

obtained in 66% yield.

(1-Methylpiperidin-3-yl)methylmagnesium Chloride (2c). 3-

(Chloromethyl)-1-methylpiperidine (14.77 g, 100 mmol) reacted

with Mg turnings (2.88 g, 120 mmol) and LiCl (8.48 g, 200 mmol)

according to TP1. The solution was titrated prior to use at room

temperature against a solution of iodine in THF. A concentration

of 0.50 M in THF was obtained in 77% yield.

(1-Methylpiperidin-4-yl)magnesium Chloride (2d). 4-Chloro-1-

methylpiperidine (13.36 g, 100 mmol) reacted with Mg turnings (2.88

g, 120 mmol) and LiCl (8.48 g, 200 mmol) according to TP1. The

solution was titrated prior to use at room temperature against a solution

of iodine in THF. A concentration of 0.62 M in THF was obtained in

56% yield.

3-Chloro-8-methyl-8-azabicyclo[3.2.1]octane. A solution of tropine

(28.3 g, 200 mmol) in CHCl₃(250 mL) was cooled to ꢀ30 °C. Thionyl

chloride (47.6 g, 400 mmol) was added slowly, and the solution was

stirred at reflux temperature for 3 h and then for an additional 16 h at

room temperature. The solution was carefully mixed with 6 N NaOH,

and the aqueous phase was extracted with CH₂Cl₂/Et₂O (1:1) and

washed with satd aq K₂CO₃solution (100 mL). The K₂CO₃solution

was extracted with CH₂Cl₂(3 ꢁ 200 mL), and the combined organic

layers were dried (Na₂SO₄). After removal of the solvent in vacuo, the

crude product was purified by fractionated distillation, which furnished

3-chloro-8-methyl-8-azabicyclo[3.2.1]octane (14.9 g, 93.0 mmol, 47%

yield) as a colorless oil. Bp (°C) 80 (12 mbar); ¹H NMR (CDCl₃, 300

MHz) δ (ppm) 4.18ꢀ4.06 (m, 1H), 3.18ꢀ3.16 (m, 2H), 2.31 (s, 3H),

2.07ꢀ1.90 (m, 6H), 1.58ꢀ1.51 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz)

δ (ppm) 61.4, 53.3, 41.1, 38.7, 26.7; IR (ATR) ν~/cm^ꢀ12936 (vs), 2878

(s), 2798 (m), 1449 (m), 1336 (s), 1301 (m), 1238 (s), 1129 (w), 1042

(m), 1027 (s), 866 (m), 832 (m), 762 (s), 640 (m); MS (EI, 70 eV) m/z

(%) 159 (7, M⁺), 124 (100), 96 (11), 94 (3), 82 (8), 67 (7); HRMS (EI)

calcd for C₈H₁₄ClN 159.0815, found 159.0813. The analytical data

match those from the literature: Archer, S.; Bell, M. R.; Lewis, T. R.;

Schulenberg, J. W.; Unser, M. J. J. Am. Chem. Soc. 1957, 79, 6337ꢀ6338.

8-Methyl-8-azabicyclo[3.2.1]octyl-3-magnesium Chloride (2e).

3-Chloro-8-methyl-8-azabicyclo[3.2.1]octane (15.97 g, 100 mmol) re-

acted with Mg turnings (2.88 g, 120 mmol) and LiCl (8.48 g, 200 mmol)

according to TP1. The fresh solution was titrated prior to use at room

temperature against a solution of iodine in THF. A concentration of 0.3

M in THF was obtained, 35% yield.

NMR (25 °C) and capillary GC. Purification via column chromatogra-

phy was performed using silica gel 60 (40ꢀ63 μm 230ꢀ400 mesh

ASTM). All reagents were obtained from commercial sources. Melting

points were measured using a B€uchi B-540 apparatus and are uncor-

rected. NMR spectra were recorded in CDCl₃or C₆D₆and chemical

shifts (δ) are reported in parts per million (ppm). Mass spectra and high

resolution mass spectra (HRMS) were recorded using electrospray

ionization except where otherwise noted.

Preparation of ZnBr₂Solution. ZnBr₂solution (1.0 M in THF)

was prepared by drying ZnBr₂(22.5 g, 100 mmol) in a Schlenk flask

under vacuum at 140 °C for 5 h. After cooling, THF (100 mL) was

added, and stirring was continued until all salts were dissolved.

Typical Procedure for Preparation Aminoalkylmagne-

sium Chlorides 2aꢀe by Insertion of Magnesium (TP1). In a

dry and argon-flushed Schlenk flask, equipped with a stirring bar and

a pressure vent, were placed the hydrochloride (1.0 equiv) and LiH

(3.0 equiv). THF (500 mL per 1 mol of the hydrochloride) was slowly

added at room temperature under vigorous stirring, keeping the hydro-

gen formation at a controlled rate. After complete addition of the solvent,

the mixture was stirred at room temperature for 1 h, then filtered through a

Schlenk frit, and used without further purification.

Magnesium turnings (1.2 equiv) and LiCl (2.0 equiv) were placed in

an argon-ﬂushed three-necked ﬂask and dried for 10ꢀ20 min at 130 °C

under vacuum (1 mbar). The ﬂask was reﬁlled with argon and then

cooled under argon. After the addition of THF (500 mL per 1 mol of the

alkyl chloride) and DIBAL-H (20% in hexane, 3 mol %), the alkyl

chloride dissolved in THF (500 mL per 1 mol) was added dropwise so

that the mixture was gently boiling. Then, the reaction mixture was

reﬂuxed for another 2 h. The solution was titrated prior to use at room

temperature against a solution of iodine in THF. A concentration of 0.3

to 0.8 M in THF was obtained.

Typical Procedure for Cross-Coupling of the Aminoalk-

ylmagnesium Chlorides with Aryl Electrophiles Using Ni-

(acac)₂and DPE-Phos (TP2). A dry and argon-flushed Schlenk flask,

equipped with a septum and a magnetic stirring bar, was charged with a

solution of ZnBr₂(2 equiv, 2 mL, 1.0 M in THF) and N-methylpyrro-

lidone (0.3 mL). The mixture was stirred at room temperature for 15 min.

The aminoalkylmagnesium chloride (1.2 mmol) was added, and the

mixture was stirred at room temperature for 15 min. The electrophile

(1.0 mmol), DPE-Phos (27mg, 5 mol%), andNi(acac)₂(9 mg, 2.5 mol %)

dissolved in THF (1 mL) were added, and the mixture was stirred at

room temperature until the complete consumption of the electrophile

was observed by GC analysis. The reaction mixture was quenched with

satd aq K₂CO₃solution (20 mL) and extracted with diethyl ether (3 ꢁ

20 mL). The combined organic layers were extracted with 2 N HCl (2 ꢁ

20 mL) and water (20 mL). The acidic aqueous layer was basified

with satd K₂CO₃and extracted with diethyl ether (3 ꢁ 20 mL), and

the combined organic layers were dried (Na₂SO₄). After filtration, the

Synthesis of Aminoalkyl Cross-Coupling Products of Type

4. 3-(3-Methoxyphenyl)-N,N-dimethylpropan-1-amine (4a). 3-Bro-

moanisole (3a; 187 mg, 1.00 mmol) reacted with 3-(dimethylamino)-

propylmagnesium chloride (2a; 1.50 mL, 1.20 mmol, 0.80 M in THF)

at 25 °C for 3 h, according to TP2. Aqueous workup furnished

3-(3-methoxyphenyl)-N,N-dimethylpropan-1-amine (4a; 188 mg, 97%

1

yield) as a yellow oil. H NMR (CDCl₃, 300 MHz) δ (ppm) 7.21ꢀ

7.15 (m, 1H), 6.79ꢀ6.70 (m, 3H), 3.78 (s, 3H), 2.63ꢀ2.58 (t, J = 7.8 Hz,

2H), 2.31ꢀ2.26 (t, J = 7.3 Hz, 2H), 2.21 (s, 6H), 1.83ꢀ1.73 (m, 2H);

¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 159.9, 144.2, 129.5, 121.0, 114.4,

111.3, 59.5, 55.4, 45.7, 34.0, 29.6; IR (ATR) ν~/cm^ꢀ13382 (vs), 3014

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Table 4. Preparation of Products 7aꢀi and 8aꢀe Obtained by Cross-Coupling (THF, 25 °C) Using Zinc Reagents 2d and 2e

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Table 4. Continued

^aReaction time. ^bYield of isolated, analytically pure product after aqueous workup without chromatographical puriﬁcation. ^cAn additional puriﬁcation

by column chromatography was necessary.

Scheme 5. Ni-Catalyzed Cross-Coupling Reaction of Ami-

noalkylzinc Reagents 2a and 2d with Alkenyl Electrophiles

1-(4-(3-(Dimethylamino)propyl)phenyl)pentan-1-one (4d).

1-(4-Bromo-phenyl)-pentan-1-one (3d; 241 mg, 1.00 mmol) reacted

with (3-(dimethylamino)propylmagnesium chloride (2a; 1.50 mL,

1.20 mmol, 0.80 M in THF) at 25 °C for 1 h, according to TP2. Aqueous

workup furnished 1-(4-(3-(dimethylamino)propyl)phenyl)pentan-1-one

(4d; 223 mg, 90% yield) as a yellow-orange oil. ¹H NMR (CDCl₃,

300 MHz) δ (ppm) 7.84 (d, J = 8.4 Hz, 2H), 7.23 (d, J = 8.4 Hz, 2H),

2.90 (t, J= 7.5 Hz, 2H), 2.66 (t, J= 7.7 Hz, 2H), 2.25 (t, J= 7.5 Hz, 2H), 2.18

(s, 6H), 1.81ꢀ1.81 (m, 2H), 1.73ꢀ1.63 (m, 2H), 1.43ꢀ1.31 (m, 2H), 0.91

(t, J = 7.3 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 200.3, 148.1,

135.2, 128.8, 128.4, 59.2, 45.7, 38.4, 33.8, 29.3, 26.8, 22.7, 14.2; IR (ATR)

~ν/cm^ꢀ12936 (m), 2860 (m), 2814 (w), 2764 (m), 1680 (vs), 1606 (s),

1460 (m), 1412 (m), 1266 (m), 1214 (m), 1180 (s), 1012 (m), 968 (m),

846 (m); MS (EI, 70 eV) m/z (%) 247 (3, M⁺), 145 (3), 115 (2), 91(1),

58 (100); HRMS (EI) calcd for C₁₆H₂₅NO 247.1936, found 247.1913.

Ethyl 5-(3-(Dimethylamino)propyl)nicotinate (4e). Ethyl 5-bromo-

nicotinate (3e; 230 mg, 1.00 mmol) reacted with (3-(dimethylamino)-

propylmagnesium chloride (2a; 1.50 mL, 1.20 mmol, 0.80 M in THF) at

25 °C for 3 h, according to TP2. Aqueous workup furnished ethyl

5-(3-(dimethylamino)propyl)nicotinate (4e; 189 mg, 80% yield) as a

(m), 2942 (s), 2836 (m), 1600 (s), 1584 (s), 1486 (vs), 1466 (s), 1438

(s), 1258 (vs), 1154 (s), 1038 (s), 916 (m), 886 (w), 784 (m), 696 (m);

MS (EI, 70 eV) m/z (%) 193 (43, M⁺), 122 (11), 121 (8), 91 (7), 59 (4),

58 (100); HRMS (EI) calcd for C₁₂H₁₉NO 193.1467, found 193.1466.

3-(2-Fluoro-[1,1⁰-biphenyl]-4-yl)-N,N-dimethylpropan-1-amine

(4b). 4-Bromo-2-fluoro-1,1⁰-biphenyl (3b; 251 mg, 1.00 mmol) reacted

with 3-(dimethylamino)propylmagnesium chloride (2a; 1.50 mL, 1.20

mmol, 0.80 M in THF) at 25 °C for 3 h, according to TP2. Aqueous

workup furnished 3-(2-fluoro-[1,1⁰-biphenyl]-4-yl)-N,N-dimethylpropan-

1-amine (4b; 213 mg, 83% yield) as a yellow oil. ¹H NMR (CDCl₃, 300

MHz) δ (ppm) 7.50ꢀ7.48 (m, 2H), 7.39ꢀ7.34 (m, 2H), 7.32ꢀ7.27 (m,

2H), 7.00ꢀ6.93 (m, 2H), 2.63 (t, J = 7.7 Hz, 2H), 2.33 (t, J = 7.3 Hz,

2H), 2.23 (s, 6H), 1.85ꢀ1.75 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ

(ppm) 161.5, 158.2, 144.0, 136.0, 130.7, 129.1, 128.6, 127.6, 124.6,

116.3, 116.0, 59.1, 45.4, 33.2, 30.9, 29.0; IR (ATR) ν~/cm^ꢀ13398 (w),

2942 (w), 2860 (w), 2816 (w), 2766 (w), 1660 (m), 1626 (m), 1484

(m), 1416 (m), 1266 (m), 1124 (m), 1038 (w), 1010 (w), 828 (m), 766

(s), 740 (w), 722 (m), 696 (vs), 640 (w); MS (EI, 70 eV) m/z (%) 257

(7, M⁺), 185 (4), 183 (4), 170 (3), 58 (100); HRMS (EI) calcd for

C₁₇H₂₀FN 257.1580, found 257.1564.

1

yellow-orange oil. H NMR (CDCl₃, 300 MHz) δ (ppm) 8.92ꢀ8.91

(m, 1H), 8.48ꢀ8.47 (m, 1H), 8.00ꢀ7.99 (m, 1H), 4.27 (q, J = 7.2 Hz, 2H),

2.59 (t, J = 7.2 Hz, 2H), 2.15 (t, J = 7.3 Hz, 2H), 2.08 (s, 6H), 1.73ꢀ1.63

(m, 2H), 1.27 (t, J = 7.2 Hz, 3H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm)

165.6, 153.7, 148.6, 137.5, 136.8, 126.1, 61.4, 58.7, 45.5, 30.4, 29.0, 14.4;

IR (ATR) ν~/cm^ꢀ12942 (w), 2860 (w), 2816 (w), 2766 (w), 1720 (vs),

1598 (w), 1576 (w), 1458 (m), 1368 (m), 1284 (vs), 1204 (s), 1106 (s),

1026 (s), 968 (w), 938 (w), 910 (w), 862 (w), 766 (s), 732 (m), 708

(m); MS (EI, 70 eV) m/z (%) 236 (3, M⁺), 191 (4), 120 (2), 59 (3), 58

(100); HRMS (EI) calcd for C₁₃H₂₀N₂O₂236.1525, found 236.1527.

3-(Isoquinolin-4-yl)-N,N-dimethylpropan-1-amine (4f). 4-Bromoi-

soquinoline (3f; 208 mg, 1.00 mmol) reacted with (3-(dimethylamino)-

propylmagnesium chloride (2a; 1.50 mL, 1.20 mmol, 0.80 M in THF) at

25 °C for 3 h, according to TP2. Aqueous workup furnished 3-(isoquinolin-

4-yl)-N,N-dimethylpropan-1-amine (4f; 180 mg, 84% yield) as a yellow-

1

orange oil. H NMR (CDCl₃, 300 MHz) δ (ppm) 9.05 (s, 1H), 8.33

4-(3-(Dimethylamino)propyl)-2-fluorobenzonitrile (4c). 4-Bromo-

2-fluorobenzonitrile (3c; 200 mg, 1.00 mmol) reacted with 3-(dimethylamino)-

propylmagnesium chloride (2a; 1.50 mL, 1.20 mmol, 0.80 M in THF)

at 25 °C for 1 h, according to TP2. Aqueous workup furnished

4-(3-(dimethylamino)propyl)-2-fluorobenzonitrile (4c; 163 mg, 79% yield)

as a yellow-orange oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.46ꢀ7.41

(m, 1H), 7.01 (d, J = 7.9 Hz, 1H), 6.97 (d, J = 10.6 Hz, 1H), 2.63 (t, J =

7.7 Hz, 2H), 2.19 (t, J = 7.3 Hz, 2H), 2.13 (s, 6H), 1.75ꢀ1.65 (m, 2H);

¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 165.0, 161.6, 151.7, 133.4, 125.3,

116.5, 114.4, 58.7, 45.5, 33.7, 28.8; IR (ATR) ~ν/cm^ꢀ12944 (m), 2860 (w),

2818 (m), 2768 (m), 2234 (m), 1622 (vs), 1568 (m), 1500 (m), 1430 (vs),

1252 (s), 1112 (s), 1038 (m), 830 (s), 736 (m), 634 (m); MS (EI, 70 eV)

m/z (%) 206 (6, M⁺), 134 (3), 106 (2), 71 (3), 58 (100); HRMS (EI)

calcd for C₁₂H₁₅FN₂206.1219, found 206.1217.

(s, 1H), 7.94 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.65ꢀ7.60

(m 1H), 7.53ꢀ7.48 (m, 1H), 2.98 (t, J = 7.7 Hz, 2H), 2.30 (t, J = 7.1 Hz,

2H), 2.17 (s, 6H), 1.88ꢀ1.78 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ

(ppm) 151.4, 142.9, 134.9, 131.5, 130.3, 128.6, 128.4, 126.9, 123.1, 59.5,

45.7, 28.9, 27.9; IR (ATR) ~ν/cm^ꢀ12942 (m), 2858 (w), 2814 (m), 2764

(m), 1622 (m), 1582 (w), 1502 (w), 1458 (m), 1388 (m), 1262 (w), 1230

(m), 1148 (w), 1042 (m), 1020 (m), 958 (w), 894 (m), 862 (m), 786 (m),

748 (vs); MS (EI, 70 eV) m/z (%) 214 (3, M⁺), 156 (7), 115 (3), 70 (5),

58 (100); HRMS (EI) calcd for C₁₄H₁₈N₂214.1470, found 214.1469.

N,N-Dimethyl-3-(quinoxalin-6-yl)propan-1-amine (4g). 6-Bromo-

quinoxaline (3g; 209 mg, 1.00 mmol) reacted with (3-(dimethylamino)-

propylmagnesium chloride (2a; 1.50 mL, 1.20 mmol, 0.80 M in THF)

at 25 °C for 1 h, according to TP2. Aqueous workup furnished N,

N-dimethyl-3-(quinoxalin-6-yl)propan-1-amine (4g; 211 mg, 98% yield)

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Table 5. Preparation of Products 9aꢀe and 10aꢀe Obtained by Cross-Coupling of Zinc Reagents 2a and 2d with Alkenyl Halides

and Triﬂates

^aReaction time. ^bTemperature. ^cYield of isolated, analytically pure product after aqueous workup without chromatographical puriﬁcation.

as an orange-brown oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 8.64ꢀ8.62

(m, 2H), 7.87ꢀ7.86 (m, 1H), 7.75ꢀ7.74 (m, 1H), 7.48ꢀ7.47 (m, 1H),

2.72 (t, J = 7.7 Hz, 2H), 2.17 (t, J = 7.3 Hz, 2H), 2.07 (s, 6H), 1.81ꢀ1.71

(m, 2H); ¹³CNMR (CDCl₃, 75 MHz)δ(ppm) 145.0, 144.3, 143.2, 141.8,

131.7, 129.3, 127.8, 59.1, 45.6, 33.7, 29.0; IR (ATR) ~ν/cm^ꢀ12940 (m),

2856 (m), 2814 (m), 2764 (m), 1620 (m), 1498 (s), 1452 (s), 1368 (m),

1132 (m), 1024 (vs), 958 (s), 896 (m), 864 (s), 830 (s), 664 (m); MS (EI,

70 eV) m/z (%) 215 (6, M⁺), 169 (1), 142 (4), 71 (9), 58 (100); HRMS

(EI) calcd for C₁₃H₁₇N₃215.1422, found 215.1422.

reacted with (3-(dimethylamino)propylmagnesium chloride (2a;

1.50 mL, 1.20 mmol, 0.80 M in THF) at 25 °C for 2 h, according to

TP2. Aqueous workup furnished tert-butyl 5-(3-(dimethylamino)propyl)-

1H-indole-1-carboxylate (4h; 260 mg, 86% yield) as a yellow-orange oil.

¹H NMR (CDCl₃, 300 MHz) δ (ppm) 8.05 (d, J = 8.4 Hz, 1H), 7.56 (d, J=

4.0 Hz, 1H), 7.35 (d, J = 1.4 Hz, 1H), 7.15 (dd, J = 8.4 Hz, 1.4 Hz, 1H),

6.49 (d, J = 4.0 Hz, 1H), 2.72 (t, J = 7.7 Hz, 2H), 2.29 (t, J = 7.5 Hz, 2H),

2.22 (s, 6H), 1.88ꢀ1.78 (m, 2H), 1.65 (s, 9H); ¹³C NMR (CDCl₃, 75

MHz) δ (ppm) 150.0, 136.9, 131.0, 126.2, 125.2, 120.5, 115.2, 107.4,

83.6, 59.5, 45.8, 33.8, 30.2, 28.5; IR (ATR) ν~/cm^ꢀ12974 (w), 2936 (m),

2856 (w), 2814 (w), 2764 (w), 1730 (vs), 1468 (s), 1370 (vs), 1348 (s),

tert-Butyl 5-(3-(Dimethylamino)propyl)-1H-indole-1-carboxylate

(4h). tert-Butyl 5-bromo-1H-indole-1-carboxylate (3h; 296 mg, 1.00 mmol)

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Scheme 6. Total Synthesis of (()-Cusparine (11) and (()-Galipinine (12) Using the Cross-Coupling Reaction Protocol

ARTICLE

1326 (s), 1254 (s), 1218 (m), 1162 (vs), 1128 (vs), 1098 (w), 1082 (s),

chloride (2b; 1.69 mL, 1.20 mmol, 0.71 M in THF) at 25 °C for 18 h,

according to TP2. Aqueous workup furnished 2-(3-methoxyphenethyl)-1-

methylpiperidine (5a; 170 mg, 73% yield) as a yellow oil. ¹H NMR (CDCl₃,

300 MHz) δ (ppm) 7.20ꢀ7.14 (m, 1H), 6.77ꢀ6.75 (m, 1H), 6.72ꢀ6.69

(m, 2H), 3.77 (s, 3H), 2.88ꢀ2.84 (m, 1H), 2.73ꢀ2.63 (m, 1H), 2.56ꢀ2.46

(m, 1H), 2.28 (s, 3H), 2.16ꢀ2.07 (m, 1H), 2.01ꢀ1.83 (m, 2H), 1.79ꢀ1.68

(m, 2H), 1.64ꢀ1.55 (m, 2H), 1.48ꢀ1.23 (m, 3H); ¹³C NMR (CDCl₃, 75

MHz) δ(ppm) 158.6, 143.3, 128.3, 119.7, 113.1, 109.9, 62.4, 56.0, 54.1, 41.7,

33.3, 30.4, 29.3, 24.6, 23.2; IR (ATR) ~ν/cm^ꢀ13400 (w), 2934 (m), 1600 (s),

1584 (s), 1488 (s), 1452 (s), 1436 (s), 1258 (vs), 1152 (s), 1042 (s), 782 (s),

694 (vs); MS (EI, 70 eV) m/z (%) 233 (1, M⁺), 120 (2), 111 (2), 98 (100),

70 (3); HRMS (EI) calcd for C₁₅H₂₃NO 233.1780, found 233.1770.

1-Methyl-2-(3-(trifluoromethoxy)phenethyl)piperidine (5b). 1-Bro-

mo-3-(trifluoromethoxy)benzene (3k; 241 mg, 1.00 mmol) reacted

with 2-(1-methylpiperidin-2-yl)ethylmagnesium chloride (2b; 1.69 mL,

1.20 mmol, 0.71 M in THF) at 25 °C for 3 h, according to TP2. Aqueous

workup furnished 1-methyl-2-(3-(trifluoromethoxy)phenethyl)piperidine

(5b; 231 mg, 80% yield) as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ

(ppm) 7.31ꢀ7.25 (m, 1H), 7.12ꢀ7.10 (m, 1H), 7.04ꢀ7.01 (m, 2H),

2.87ꢀ2.69 (m, 2H), 2.64ꢀ2.53 (m, 1H), 2.27 (s, 3H), 2.12ꢀ2.04

(m, 1H), 1.95ꢀ1.66 (m, 4H), 1.63ꢀ1.54 (m, 2H), 1.45ꢀ1.21 (m, 3H); ¹³C

NMR (CDCl₃, 75 MHz) δ (ppm) 145.5, 129.7, 126.9, 120.9, 118.3, 63.4,

57.4, 43.1, 34.7, 31.1, 30.8, 26.0, 24.6; IR (ATR) ~ν/cm^ꢀ12934 (m), 2858

(w), 2778 (w), 1612 (w), 1588 (w), 1490 (w), 1444 (w), 1252 (vs), 1212

(vs), 1154 (vs), 1032 (m), 1002 (w), 864 (w), 792 (w), 700 (m), 634 (m);

MS (EI, 70 eV) m/z (%) 287 (2, M⁺), 232 (2), 175 (4), 111 (2), 98 (100),

70 (7); HRMS (EI) calcd for C₁₅H₂₀F₃NO 287.1497, found 287.1519.

2-(2-(2-Fluoro-[1,1⁰-biphenyl]-4-yl)ethyl)-1-methylpiperidine (5c).

4-Bromo-2-fluoro-1,1⁰-biphenyl (3b; 251 mg, 1.00 mmol) reacted with

2-(1-methylpiperidin-2-yl)ethylmagnesium chloride (2b; 1.69 mL, 1.20

mmol, 0.71 M in THF) at 25 °C for 48 h, according to TP2. Aqueous

workup furnished 2-(2-(2-fluoro-[1,1⁰-biphenyl]-4-yl)ethyl)-1-methyl-

1022 (s), 766 (s), 724 (m); MS (EI, 70 eV) m/z (%) 303 (100, M + H⁺),

+

247 (22), 203 (1), 158 (1), 97 (8); HRMS (EI) calcd for C₁₈H₂₇N₂O₂

303.2067, found 303.2062.

Methyl 5-(3-(Dimethylamino)propyl)furan-2-carboxylate (4i). Methyl

5-bromofuran-2-carboxylate (3i; 205 mg, 1.00 mmol) reacted with

(3-(dimethylamino)propylmagnesium chloride (2a; 1.50 mL, 1.20 mmol,

0.80 M in THF) at 25 °C for 2 h, according to TP2. Aqueous workup

furnished methyl 5-(3-(dimethylamino)propyl)furan-2-carboxylate (4i;

1

178 mg, 84% yield) as an orange oil. H NMR (CDCl₃, 300 MHz) δ

(ppm) 7.01 (d, J = 3.6 Hz, 1H), 6.06 (d, J = 3.6 Hz, 1H), 3.78 (s, 3H), 2.65

(t, J=7.7Hz, 2H), 2.21(t, J= 7.3 Hz, 2H), 2.13 (s, 6H), 1.81ꢀ1.71 (m, 2H);

¹³CNMR(CDCl₃, 75MHz) δ(ppm) 161.2, 159.4, 143.1, 119.4, 107.9, 59.0,

51.8, 45.6, 26.3, 26.0; IR (ATR) ~ν/cm^ꢀ12946 (w), 2860 (w), 2816 (w),

2766 (w), 1720 (vs), 1594 (w), 1530 (s), 1520 (s), 1460 (m), 1436 (m),

1382 (w), 1302 (vs), 1204 (s), 1138 (s), 1018 (s), 990 (m), 926 (m), 796

(m), 760 (vs), 732 (m); MS (EI, 70 eV) m/z (%) 211 (5, M⁺), 71 (2), 59

(3), 58 (100); HRMS (EI) calcd for C₁₁H₁₇NO₃211.1208, found 211.1212.

N,N-Dimethyl-3-(quinolin-2-yl)propan-1-amine (4j). 2-Chloroqui-

noline (3j; 164 mg, 1.00 mmol) reacted with (3-(dimethylamino)propyl

magnesium chloride (2a; 1.50 mL, 1.20 mmol, 0.80 M in THF) at 25 °C

for 3 h, according to TP2. Aequous workup furnished N,N-dimethyl-

3-(quinolin-2-yl)propan-1-amine (4j; 189 mg, 88% yield) as a brownish oil.

¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.97ꢀ7.92 (m, 2H), 7.66ꢀ7.63

(m, 1H), 7.60ꢀ7.54 (m, 1H), 7.38ꢀ7.33 (m, 1H), 7.19 (d, J = 8.4 Hz, 1H),

2.91 (t, J = 7.8 Hz, 2H), 2.30 (t, J = 8.0 Hz, 2H), 2.15 (s, 6H), 1.98ꢀ1.88

(m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 162.5, 148.1, 136.4, 129.5,

129.0, 127.7, 126.9, 125.9, 121.6, 59.4, 45.6, 37.1, 27.9; IR (ATR) ~ν/cm^ꢀ1

2940 (m), 2858 (w), 2814 (m), 2764 (m), 1618 (m), 1600 (s), 1562 (m),

1504 (s), 1462 (m), 1426 (s), 1140 (m), 1040 (m), 826 (vs), 748 (vs), 618

(m); MS (EI, 70 eV) m/z (%) 170 (6, M⁺), 143 (100), 128 (17), 115 (7),

72(19), 58(80);HRMS(EI) calcdfor C₁₄H₁₈N₂214.1470, found 214.1477.

Synthesis of Aminoalkyl Cross-Coupling Products of Type

5. 2-(3-Methoxyphenethyl)-1-methylpiperidine (5a). 3-Bromoanisole (3a;

187 mg, 1.00 mmol) reacted with 2-(1-methylpiperidin-2-yl)ethylmagnesium

1

piperidine (5c; 209 mg, 70% yield) as a yellow-orange oil. H NMR

(CDCl₃, 300 MHz) δ (ppm) 7.54ꢀ7.51 (m, 2H), 7.43ꢀ7.38 (m, 2H),

7.35ꢀ7.29 (m, 2H), 7.03ꢀ6.95 (m, 2H), 2.88ꢀ2.69 (m, 2H), 2.64ꢀ2.53

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(m, 1H), 2.28 (s, 3H), 2.13ꢀ2.02 (m, 1H), 1.98ꢀ1.66 (m, 5H), 1.63ꢀ

1.55 (m, 2H), 1.44ꢀ1.19 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ

(ppm) 161.6, 158.3, 144.9, 136.1, 130.8, 129.1, 128.6, 127.6, 124.5,

116.2, 115.9, 63.5, 57.4, 43.2, 34.7, 30.9, 26.1, 24.7; IR (ATR) ν~/cm^ꢀ1

2932 (m), 2854 (w), 2776 (w), 1484 (m), 1416 (m), 1268 (m), 1126

(m), 1032 (m), 824 (m), 764 (s), 732 (m), 696 (vs); MS (EI, 70 eV)

m/z (%) 297 (1, M⁺), 185 (4), 169 (1), 111 (1), 98 (100), 70 (4);

HRMS (EI) calcd for C₂₀H₂₄FN 297.1893, found 297.1897.

for 30 h, according to TP2. Column chromatography (silica gel,

CH₂Cl₂/MeOH 20:1) furnished 3-(3-methoxybenzyl)-1-methylpiper-

idine (6a; 123 mg, 56% yield) as an orange oil. ¹H NMR (CDCl₃, 300

MHz) δ (ppm) 7.13 (t, J = 7.7 Hz, 1H), 6.70 (s, 1H), 6.66 (m, 2H), 3.74

(s, 3H), 2.78 (t, J = 11.0 Hz, 2H), 2.44 (d, J = 7.5 Hz, 2H), 2.24 (s, 3H),

1.95ꢀ1.89 (m, 2H), 1.71ꢀ1.56 (m, 4H), 0.95ꢀ0.82 (m, 1H); ¹³C NMR

(CDCl₃, 75 MHz) δ (ppm) 159.8, 141.8, 129.4, 121.7, 114.9, 111.5,

61.9, 56.3, 55.3, 46.5, 41.3, 37.8, 30.2, 25.2; IR (ATR) ν~/cm^ꢀ12930 (m),

2846 (m), 2774 (m), 1600 (m), 1584 (s), 1488 (s), 1452 (m), 1438 (m),

1258 (vs), 1152 (vs), 1044 (s), 872 (m), 774 (s), 738 (m), 696 (vs); MS

(EI, 70 eV) m/z (%) 219 (27, M⁺), 122 (6), 97 (100), 82 (4), 58 (7),

43 (5); HRMS (EI) calcd for C₁₄H₂₁NO 219.1623, found 219.1614.

2-Fluoro-4-((1-methylpiperidin-3-yl)methyl)benzonitrile (6b).

4-Bromo-2-fluorobenzonitrile (3c; 200 mg, 1.00 mmol) reacted with

(1-methylpiperidin-3-yl)methylmagnesium chloride (2c; 2.40 mL, 1.20

mmol, 0.50 M in THF) at 25 °C for 10 h, according to TP2. Column

chromatography (silica gel, CH₂Cl₂/MeOH 20:1) furnished 2-fluoro-4-

((1-methylpiperidin-3-yl)methyl)benzonitrile (6b; 154 mg, 66% yield)

Ethyl 5-(2-(1-Methylpiperidin-2-yl)ethyl)nicotinate (5d). Ethyl

5-bromonicotinate (3e; 230 mg, 1.00 mmol) reacted with 2-(1-methyl-

piperidin-2-yl)ethylmagnesium chloride (2b; 1.69 mL, 1.20 mmol,

0.71 M in THF) at 25 °C for 3 h, according to TP2. Aqueous workup

furnished ethyl 5-(2-(1-methylpiperidin-2-yl)ethyl)nicotinate (5d; 263

mg, 95% yield) as a yellow-orange oil. ¹H NMR (CDCl₃, 300 MHz) δ

(ppm) 8.92 (s, 1H), 8.49 (m, 1H), 7.99 (m, 1H), 4.29 (q, J = 7.1 Hz,

2H), 2.76ꢀ2.62 (m, 2H), 2.57ꢀ2.47 (m, 1H), 2.15 (s, 3H), 2.02ꢀ1.92

(m, 1H), 1.87ꢀ1.54 (m, 5H), 1.49ꢀ1.42 (m, 2H), 1.29 (t, J = 7.1 Hz,

3H), 1.24ꢀ1.05 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 165.6,

153.6, 148.5, 138.1, 136.6, 126.1, 63.1, 61.5, 57.2, 43.1, 34.5, 30.7, 28.1,

25.9, 24.5, 14.4; IR (ATR) ν~/cm^ꢀ12932 (m), 2856 (w), 2776 (w), 1720

(vs), 1444 (m), 1368 (m), 1280 (s), 1204 (s), 1106 (s), 1026 (s), 766

(s), 708 (m); MS (EI, 70 eV) m/z (%) 275 (1, M ꢀ H⁺), 231 (4), 119

1

as an orange oil. H NMR (CDCl₃, 300 MHz) δ (ppm) 7.47ꢀ7.42

(m, 1H), 6.98 (d, J = 7.9 Hz, 1H), 6.94 (d, J = 10.1 Hz, 1H), 2.70ꢀ2.58

(m, 2H), 2.51 (d, J = 7.1 Hz, 2H), 2.16 (s, 3H), 1.87ꢀ1.80 (m, 2H),

1.63ꢀ1.39 (m, 4H), 0.94ꢀ0.81 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz)

δ (ppm) 165.0, 161.5, 149.7, 133.3, 125.8, 117.1, 114.4, 61.7, 56.2, 46.7,

41.1, 37.8, 30.2, 25.2; IR (ATR) ν~/cm^ꢀ12932 (s), 2850 (m), 2778 (m),

2236 (m), 1622 (vs), 1568 (m), 1500 (m), 1430 (s), 1284 (m), 1252

(m), 1160 (m), 1148 (m), 1112 (s), 1092 (m), 822 (m); MS (EI, 70 eV)

m/z (%) 232 (50, M⁺), 134 (14), 111 (8), 97 (100), 84 (8), 71 (14);

HRMS (EI) calcd for C₁₄H₁₇FN₂232.1376, found 232.1364.

+

(1), 111 (1), 98 (100), 70 (6); HRMS (EI) calcd for C₁₆H₂₃N₂O₂

275.1754, found 275.1732.

tert-Butyl 5-(2-(1-Methylpiperidin-2-yl)ethyl)-1H-indole-1-carboxy-

late (5e). tert-Butyl 5-bromo-1H-indole-1-carboxylate (3h; 296 mg, 1.00

mmol) reacted with 2-(1-methylpiperidin-2-yl)ethylmagnesium chlor-

ide (2b; 1.69 mL, 1.20 mmol, 0.71 M in THF) at 25 °C for 48 h,

according to TP2. Column chromatography (silica gel, CH₂Cl₂/MeOH

10:1) furnished tert-butyl 5-(2-(1-methylpiperidin-2-yl)ethyl)-1H-in-

dole-1-carboxylate (5e; 193 mg, 56% yield) as an orange-brown oil.

¹H NMR (CDCl₃, 300 MHz) δ (ppm) 8.02 (d, J = 8.4 Hz, 1H), 7.54

(d, J = 3.5 Hz, 1H), 7.35 (d, J = 1.5 Hz, 1H), 7.13 (dd, J = 8.4 Hz, 1.5 Hz,

1H), 6.49 (d, J = 3.5 Hz, 1H), 2.87ꢀ2.74 (m, 2H), 2.68ꢀ2.58 (m, 1H),

2.27 (s, 3H), 2.11ꢀ2.02 (m, 1H), 2.00ꢀ1.86 (m, 2H), 1.80ꢀ1.69 (m,

2H), 1.65 (s, 9H), 1.62ꢀ1.55 (m, 2H), 1.46ꢀ1.25 (m, 3H); ¹³C NMR

(CDCl₃, 75 MHz) δ (ppm) 148.8, 136.1, 129.8, 124.9, 123.8, 119.1,

113.9, 106.1, 82.4, 62.4, 56.2, 42.0, 34.3, 30.2, 29.7, 27.7, 24.9, 23.4; IR

(ATR) ν~/cm^ꢀ12932 (s), 2856 (w), 2776 (m), 1730 (vs), 1468 (m),

1442 (m), 1370 (s), 1346 (s), 1326 (s), 1254 (m), 1218 (m), 1162 (s),

1128 (s), 1080 (m), 1022 (m), 764 (m), 722 (m); MS (EI, 70 eV) m/z

(%) 343 (100, [M + H⁺]), 249 (7), 229 (11), 159 (19), 137 (30), 102

(1); HRMS (EI) calcd for C₂₁H₃₁N₂O₂⁺343.2380, found 343.2371.

2-(2-(1-Methylpiperidin-2-yl)ethyl)quinoline (5f). 2-Chloroquino-

line (3j; 164 mg, 1.00 mmol) reacted with 2-(1-methylpiperidin-2-

yl)ethylmagnesium chloride (2b; 1.69 mL, 1.20 mmol, 0.71 M in THF)

at 25 °C for 1 h, according to TP2. Aqueous workup furnished 2-(2-(1-

methylpiperidin-2-yl)ethyl)quinoline (5f; 241 mg, 95% yield) as an

orange-brown oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.99ꢀ7.94 (m,

2H), 7.67 (d, J = 7.5 Hz, 1H), 7.62ꢀ7.56 (m, 1H), 7.38 (t, J = 7.5 Hz,

1H), 7.20 (t, J = 8.4 Hz, 1H), 3.05ꢀ2.95 (m, 1H), 2.91ꢀ2.75 (m, 2H),

2.23 (s, 3H), 2.13ꢀ1.79 (m, 4H), 1.75ꢀ1.64 (m, 2H), 1.56ꢀ1.48 (m,

2H), 1.42ꢀ1.12 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 163.1,

148.1, 136.4, 129.5, 129.1, 127.7, 126.9, 125.8, 121.5, 63.6, 57.4, 43.3,

35.0, 33.0, 30.9, 26.1, 24.6; IR (ATR) ν~/cm^ꢀ12930 (s), 2854 (m), 2776

(m), 1618 (m), 1600 (s), 1502 (s), 1442 (m), 1426 (m), 1374 (m), 1138

(m), 1118 (m), 1032 (m), 824 (vs), 756 (s), 618 (m); MS (EI, 70 eV)

m/z (%) 253 (1, M ꢀ H⁺), 168 (3), 155 (3), 143 (100), 112 (58), 98

6-((1-Methylpiperidin-3-yl)methyl)quinoxaline (6c). 6-Bromoqui-

noxaline (3g; 209 mg, 1.00 mmol) reacted with (1-methylpiperidin-

3-yl)methylmagnesium chloride (2c; 2.40 mL, 1.20 mmol, 0.50 M in

THF) at 25 °C for 10 h, according to TP2. Column chromatography

(silica gel, CH₂Cl₂/MeOH 20:1) furnished 6-((1-methylpiperidin-3-

1

yl)methyl)quinoxaline (6c; 145 mg, 60% yield) as an orange oil. H

NMR (CDCl₃, 300 MHz) δ (ppm) 8.73ꢀ8.71 (m, 2H), 7.95 (d, J =

8.4 Hz, 1H), 7.78 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 2.75ꢀ2.68 (m, 4H),

2.17 (s, 3H), 2.04ꢀ1.83 (m, 2H), 1.72ꢀ1.50 (m, 4H), 0.98ꢀ0.85 (m,

1H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 145.1, 144.5, 143.2, 143.0,

142.0, 132.1, 129.4, 128.8, 61.9, 56.2, 46.6, 41.3, 37.8, 30.2, 25.2; IR

(ATR) ν~/cm^ꢀ12930 (s), 2848 (m), 2776 (m), 1618 (m), 1498 (s),

1448 (s), 1368 (m), 1284 (m), 1132 (m), 1092 (m), 1022 (vs), 956 (m),

896 (m), 866 (s), 824 (m), 780 (m), 668 (m); MS (EI, 70 eV) m/z (%)

241 (6, M⁺), 169 (8), 143 (7), 115 (4), 97 (100), 58 (11), 43 (10);

HRMS (EI) calcd for C₁₅H₁₉N₃241.1579, found 241.1568.

2-Methoxy-6-((1-methylpiperidin-3-yl)methyl)pyridine (6d). 2-Chloro-

6-methoxypyridine (3l; 144 mg, 1.00 mmol) reacted with (1-methylpiper-

idin-3-yl)methylmagnesium chloride (2c; 2.40 mL, 1.20 mmol, 0.50 M in

THF) at 25 °C for 20 h, according to TP2. Aqueous workup furnished

2-methoxy-6-((1-methylpiperidin-3-yl)methyl)pyridine (6d; 198 mg, 90%

yield) as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.38ꢀ7.33

(m, 1H), 6.58 (d, J= 7.1 Hz, 1H), 6.45 (d, J= 8.4 Hz, 1H), 3.82 (s, 3H), 2.68

(d, J = 11.0 Hz, 2H), 2.49 (d, J = 7.1 Hz, 2H), 2.14 (s, 3H), 2.12ꢀ2.00

(m, 1H), 1.83ꢀ1.75 (m, 1H), 1.64ꢀ1.42(m, 4H), 0.93ꢀ0.80 (m, 1H); ¹³C

NMR (CDCl₃, 75 MHz) δ (ppm) 163.8, 158.5, 138.6, 116.0, 107.7, 62.3,

56.5, 53.3, 46.9, 43.1, 36.7, 30.6, 25.7; IR (ATR) ~ν/cm^ꢀ12932 (m), 2848

(w), 2774 (m), 1598 (s), 1578 (s), 1464 (vs), 1438 (s), 1414 (s), 1302 (s),

1262 (s), 1146 (m), 1032 (s), 798 (s), 780 (s), 746 (m); MS (EI, 70 eV)

m/z (%) 219 (8, [M ꢀ H⁺]), 123 (100), 98 (26), 70 (2), 58 (2), 43 (4);

HRMS (EI) calcd for C₁₃H₂₀N₂O 220.1576, found 220.1581.

+

(45), 70 (3); HRMS (EI) calcd for C₁₇H₂₁N₂253.1699, found

253.1701.

Synthesis of Aminoalkyl Cross-Coupling Products of Type

7. 2,4-Dimethoxy-5-(1-methylpiperidin-4-yl)pyrimidine (7a). 5-Iodo-

2,4-dimethoxypyrimidine (3m; 266 mg, 1.00 mmol) reacted with

(1-methylpiperidin-4-yl)magnesium chloride (2d; 1.94 mL, 1.20 mmol,

0.62 M in THF) at 25 °C for 48 h, according to TP2. Aqueous workup

Synthesis of Aminoalkyl Cross-Coupling Products of

Type 6. 3-(3-Methoxybenzyl)-1-methylpiperidine (6a). 3-Bromoani-

sole (3a; 187 mg, 1.00 mmol) reacted with (1-methylpiperidin-3-yl)methyl-

magnesium chloride (2c; 2.40 mL, 1.20 mmol, 0.50 M in THF) at 25 °C

8901

dx.doi.org/10.1021/jo201630e |J. Org. Chem. 2011, 76, 8891–8906

The Journal of Organic Chemistry

ARTICLE

furnished 2,4-dimethoxy-5-(1-methylpiperidin-4-yl)pyrimidine (7a; 142 mg,

60% yield) as an orange oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.98

(s, 1H), 3.92 (s, 3H), 3.89 (s, 3H), 2.92ꢀ2.89 (m, 2H), 2.60ꢀ2.50

(m, 1H), 2.25 (s, 3H), 2.03ꢀ1.94 (m, 2H), 1.75ꢀ1.68 (m, 4H); ¹³C

NMR (CDCl₃, 75 MHz) δ (ppm) 169.2, 164.0, 155.1, 119.1, 56.4, 54.8,

54.0, 46.6, 33.4, 31.5; IR (ATR) ν~/cm^ꢀ12936 (w), 2780 (w), 1598 (s),

1564 (s), 1462 (s), 1402 (s), 1372 (vs), 1290 (s), 1256 (s), 1234 (m),

1200 (m), 1138 (m), 1072 (s), 1016 (s), 994 (m), 794 (s), 762 (m); MS

(EI, 70 eV) m/z (%) 237 (81, M⁺), 193 (11), 140 (5), 97 (100), 70 (32),

57 (9), 43 (13); HRMS (EI) calcd for C₁₂H₁₉N₃O₂237.1477, found

237.1476.

2-Fluoro-4-(1-methylpiperidin-4-yl)benzonitrile (7b). 4-Bromo-2-

fluorobenzonitrile (3c; 200 mg, 1.00 mmol) reacted with (1-methylpi-

peridin-4-yl)magnesium chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in

THF) at 25 °C for 1 h, according to TP2. Aqueous workup furnished

2-fluoro-4-(1-methylpiperidin-4-yl)benzonitrile (7b; 198 mg, 88%

yield) as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.45 (dd, J =

7.9 Hz, 7.1 Hz, 2H), 7.04 (dd, J = 8.2 Hz, 1.5 Hz, 1H), 6.98

(dd, J = 10.4 Hz, 1.5 Hz, 2H), 2.92ꢀ2.85 (m, 2H), 2.52ꢀ2.41 (m,

1H), 2.22 (s, 3H), 2.00ꢀ1.92 (m, 2H), 1.78ꢀ1.59 (m, 4H); ¹³C NMR

(CDCl₃, 75 MHz) δ (ppm) 164.0, 160.5, 154.3, 132.3, 122.5, 113.9,

113.7, 113.1, 97.8, 54.8, 45.3, 42.2, 31.9; IR (ATR) ν~/cm^ꢀ12936 (s),

2848 (m), 2782 (s), 2738 (m), 2236 (m), 1620 (vs), 1568 (m), 1500 (m),

1446 (m), 1430 (s), 1380 (s), 1280 (m), 1250 (m), 1112 (m), 956 (m),

828 (m), 760 (m); MS (EI, 70 eV) m/z (%) 218 (77, M⁺), 217 (100),

157 (4), 134 (10), 97 (8), 83 (23), 70 (44), 43 (56); HRMS (EI) calcd for

C₁₃H₁₅FN₂218.1219, found 218.1192.

3-(1-Methylpiperidin-4-yl)benzonitrile (7c). 3-Bromobenzonitrile

(3n; 182 mg, 1.00 mmol) reacted with (1-methylpiperidin-4-yl)magnesium

chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in THF) at 25 °C for 8 h,

according to TP2. Aqueous workup furnished 3-(1-methylpiperidin-4-yl)-

benzonitrile (7c; 192 mg, 96% yield) as a yellow oil. ¹H NMR (CDCl₃,

300 MHz) δ (ppm) 7.39 (m, 3H), 7.32 (m, 1H), 2.88ꢀ2.84 (m, 2H),

2.45ꢀ2.37 (m, 1H), 2.21 (s, 3H), 1.98ꢀ1.90 (m, 2H), 1.71ꢀ

1.59 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 147.4, 131.2,

130.3, 129.6, 129.0, 118.7, 112.1, 55.7, 46.1, 41.4, 32.9; IR (ATR) ν~/

cm^ꢀ12936 (m), 2844 (w), 2780 (m), 2736 (w), 2228 (m), 1466 (m),

1446 (m), 1378 (m), 1280 (m), 1134 (m), 1068 (m), 996 (m), 798 (s),

768 (m), 692 (vs); MS (EI, 70 eV) m/z (%) 200 (68, M⁺), 199 (100),

116 (2), 97 (2), 83 (4), 70 (13), 57 (7), 43 (9); HRMS (EI) calcd for

C₁₃H₁₆N₂200.1313, found 200.1293.

1.75ꢀ1.68 (m, 4H), 1.66 (m, 2H), 1.37ꢀ1.24 (m, 2H), 0.84 (t, J = 7.3 Hz,

3H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 200.3, 151.9, 135.4, 128.5,

127.2, 56.3, 46.6, 42.3, 38.4, 33.4, 26.8, 22.7, 14.1; IR (ATR) ~ν/cm^ꢀ12934

(m), 2872 (m), 2778 (m), 1678 (vs), 1606 (s), 1464 (m), 1444 (m), 1378

(m), 1278 (m), 1212 (m), 1182 (m), 1134 (m), 992 (m), 976 (m), 844

(m), 764 (m); MS (EI, 70 eV) m/z (%) 259 (90, M⁺), 258 (100), 202 (4),

97 (15), 83 (5), 70 (13), 43 (3); HRMS (EI) calcd for C₁₇H₂₅NO

259.1936, found 260.1947.

6-(1-Methylpiperidin-4-yl)quinoxaline (7f). 6-Bromoquinoxaline

(3g; 209 mg, 1.00 mmol) reacted with (1-methylpiperidin-4-yl)magnesium

chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in THF) at 25 °C for 3 h,

according to TP2. Column chromatography (silica gel, CH₂Cl₂/MeOH

20:1) furnished 6-(1-methylpiperidin-4-yl)quinoxaline (7f; 163 mg,

79% yield) as a red solid. Mp (°C) 176ꢀ178; ¹H NMR (CDCl₃,

300 MHz) δ (ppm) 8.77ꢀ8.75 (m, 2H), 7.99 (d, J = 8.4 Hz, 1H), 7.88

(s, 1H), 7.66 (d, J = 8.4 Hz, 1H), 3.26ꢀ3.22 (m, 2H), 2.90ꢀ2.79

(m, 1H), 2.54 (s, 3H), 2.25ꢀ2.11 (m, 2H), 2.01ꢀ1.97 (m, 2H), 1.43ꢀ1.38

(m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 146.3, 144.1, 143.6, 142.1,

141.1, 128.8, 128.6, 125.5, 54.5, 52.0, 44.2, 40.0, 30.7, 27.7; IR (ATR)

ν~/cm^ꢀ12948 (s), 2924 (s), 2622 (s), 2606 (s), 2494 (vs), 1618 (m),

1496 (m), 1474 (s), 1442 (m), 1396 (m), 1374 (s), 1262 (m), 1172 (m),

1024 (s), 932 (m), 894 (m), 806 (m); MS (EI, 70 eV) m/z (%) 227

(99, M⁺), 156 (8), 115 (5), 97 (7), 83 (12), 70 (100), 57 (12), 42 (35);

HRMS (EI) calcd for C₁₄H₁₇N₃227.1422, found 227.1413.

2-Methoxy-6-(1-methylpiperidin-4-yl)pyridine (7g). 2-Chloro-6-

methoxypyridine (3l; 144 mg, 1.00 mmol) reacted with (1-methylpiper-

idin-4-yl)magnesium chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in

THF) at 25 °C for 3 h, according to TP2. Aqueous workup furnished

2-methoxy-6-(1-methylpiperidin-4-yl)pyridine (7g; 113 mg, 55% yield)

1

as a yellow oil. H NMR (CDCl₃, 300 MHz) δ (ppm) 7.45ꢀ7.40

(m, 1H), 6.67 (d, J = 7.1 Hz, 1H), 6.50 (d, J = 8.4 Hz, 1H), 3.87 (s, 3H),

2.96ꢀ2.90 (m, 2H), 2.57ꢀ2.46 (m, 1H), 2.28 (s, 3H), 2.06ꢀ1.94 (m,

2H), 1.91ꢀ1.84 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 163.7,

163.1, 138.9, 113.5, 108.0, 56.3, 53.3, 46.8, 43.6, 32.1; IR (ATR) ν~/cm^ꢀ1

2936 (m), 2846 (w), 2778 (m), 2734 (w), 1578 (vs), 1462 (vs), 1412

(s), 1378 (m), 1278 (s), 1246 (s), 1142 (m), 1046 (m), 1028 (s), 954

(m), 800 (s), 764 (m), 740 (m); MS (EI, 70 eV) m/z (%) 206 (8, M⁺),

191 (23), 178 (5), 150 (11), 136 (100), 123 (6), 71 (7); HRMS (EI)

calcd for C₁₂H₁₈N₂O: 206.1419, found 206.1433.

4-(7-Methoxynaphthalen-2-yl)-1-methylpiperidine (7h). 7-Methox-

ynaphthalen-2-yl trifluoromethanesulfonate (3p; 306 mg, 1.00 mmol)

reacted with (1-methylpiperidin-4-yl)magnesium chloride (2d; 1.94 mL,

1.20 mmol, 0.62 M in THF) at 25 °C for 48 h, according to TP2.

Aqueous workup furnished 4-(7-methoxynaphthalen-2-yl)-1-methyl-

piperidine (7h; 237 mg, 93% yield) as a yellow solid. Mp (°C)

94ꢀ95; ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.67 (dd, J = 9.0 Hz, 4.2

Hz, 2H), 7.54 (s, 1H), 7.22 (dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.10ꢀ7.05

(m, 2H), 3.88 (s, 3H), 3.01ꢀ2.97 (m, 2H), 2.61ꢀ2.53 (m, 1H), 2.32

(s, 3H), 2.11ꢀ2.02 (m, 2H), 1.93ꢀ1.86 (m, 4H); ¹³C NMR (CDCl₃, 75

MHz) δ (ppm) 156.7, 143.3, 133.7, 128.0, 126.7, 126.6, 122.7, 122.6,

117.0, 104.6, 55.4, 54.2, 45.5, 41.2, 32.4; IR (ATR) ν~/cm^ꢀ12934 (m),

2774 (m), 2736 (w), 1628 (m), 1512 (m), 1448 (m), 1376 (m), 1258

(m), 1210 (s), 1132 (m), 1028 (s), 996 (m), 896 (m), 836 (vs), 802 (m),

776 (w), 762 (m), 710 (m), 612 (m); MS (EI, 70 eV) m/z (%) 255

(92, M⁺), 240 (19), 184 (10), 140 (12), 97 (19), 70 (100), 43 (10);

HRMS (EI) calcd for C₁₇H₂₁NO 255.1623, found 255.1609.

2-(1-Methylpiperidin-4-yl)quinoline (7i). Quinolin-2-yl trifluoro-

methanesulfonate (3q; 277 mg, 1.00 mmol) reacted with (1-methylpi-

peridin-4-yl)magnesium chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in

THF) at 25 °C for 8 h, according to TP2. Aqueous workup furnished

2-(1-methylpiperidin-4-yl)quinoline (7i; 215 mg, 95% yield) as a

2-(4-(1-Methylpiperidin-4-yl)phenyl)acetonitrile (7d). 2-(4-Bromo-

phenyl)acetonitrile (3o; 196 mg, 1.00 mmol) reacted with (1-methylpi-

peridin-4-yl)magnesium chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in

THF) at 25 °C for 8 h, according to TP2. Aqueous workup furnished

2-(4-(1-methylpiperidin-4-yl)phenyl)acetonitrile (7d; 200 mg, 94%

1

yield) as an orange solid. Mp (°C) 57ꢀ58; H NMR (CDCl₃, 300

MHz) δ (ppm) 7.16ꢀ7.13 (m, 4H), 3.62ꢀ3.61 (m, 2H), 2.90ꢀ2.86 (m,

2H), 2.44ꢀ2.34 (m, 1H), 2.23 (s, 3H), 2.00ꢀ1.89 (m, 2H), 1.74ꢀ1.67

(m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 146.5, 128.2, 127.9,

127.8, 118.2, 56.5, 46.7, 41.8, 33.7, 23.4; IR (ATR) ν~/cm^ꢀ12938 (s),

2848 (m), 2780 (m), 2764 (s), 2738 (m), 2244 (w), 1682 (w), 1514

(m), 1462 (m), 1380 (m), 1280 (s), 1134 (s), 1074 (s), 992 (s), 820 (s),

760 (vs); MS (EI, 70 eV) m/z (%) 214 (74, M⁺), 213 (100), 115 (6), 97

(18), 83 (7), 69 (28), 57 (11), 43 (16); HRMS (EI) calcd for C₁₄H₁₈N₂

214.1470, found 214.1458.

1-(4-(1-Methylpiperidin-4-yl)phenyl)pentan-1-one (7e). 1-(4-Bromo-

phenyl)pentan-1-one (3d; 241 mg, 1.00 mmol) reacted with

(1-methylpiperidin-4-yl)magnesium chloride (2d; 1.94 mL, 1.20 mmol,

0.62 M in THF) at 25 °C for 2 h, according to TP2. Aqueous workup

furnished 1-(4-(1-methylpiperidin-4-yl)phenyl)pentan-1-one (7e; 218 mg,

1

84% yield) as an orange solid. Mp (°C) 37ꢀ38; H NMR (CDCl₃,

yellow-orange solid. Mp (°C) 41ꢀ43; H NMR (CDCl₃, 300 MHz)

300 MHz) δ (ppm) 7.80 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H),

2.89ꢀ2.81 (m, 4H), 2.49ꢀ2.38 (m, 1H), 2.22 (s, 3H), 2.00ꢀ1.91 (m, 2H),

δ (ppm) 7.92 (dd, J = 8.4 Hz, 2.7 Hz, 2H), 7.60 (d, J = 8.4 Hz, 1H),

7.56ꢀ7.50 (m, 1H), 7.35ꢀ7.29 (m, 1H), 7.20 (dd, J = 8.4 Hz, 1.3 Hz,

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1H), 2.89ꢀ2.85 (m, 2H), 2.81ꢀ2.70 (m, 1H), 2.20 (s, 3H), 2.02ꢀ1.94

(m, 2H), 1.91ꢀ1.83 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm)

165.4, 148.0, 136.6, 129.5, 129.1, 127.6, 127.2, 125.9, 119.3, 56.2, 46.7,

45.2, 32.2; IR (ATR) ν~/cm^ꢀ12932 (m), 2774 (m), 2734 (m), 1686 (w),

1600 (m), 1500 (m), 1444 (m), 1428 (m), 1376 (m), 1278 (m), 1134

(s), 998 (m), 830 (s), 756 (vs), 744 (s), 622 (m); MS (EI, 70 eV) m/z

(%) 226 (33, M⁺), 180 (4), 170 (6), 156 (100), 128 (6), 118 (5), 69

(17); HRMS (EI) calcd for C₁₅H₁₈N₂226.1470, found 226.1459.

Synthesis of Aminoalkyl Cross-Coupling Products of Type

8. 3-(3-Methoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]octane (8a). 3-

Bromoanisole (3a; 187 mg, 1.00 mmol) reacted with 8-methyl-8-

azabicyclo[3.2.1]octyl-3-magnesium chloride (2e; 4.00 mL, 1.20 mmol,

0.30 M in THF) at 25 °C for 22 h, according to TP2. Column

chromatography (silica gel, CH₂Cl₂/MeOH 20:1) furnished 3-(3-

methoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]octane (8a; 127 mg,

55% yield) as an orange oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.18

(t, J = 7.9 Hz, 1H), 6.86ꢀ6.83 (m, 2H), 6.73ꢀ6.69 (m, 1H), 3.77

(s, 3H), 3.36ꢀ3.32 (m, 2H), 2.89ꢀ2.77 (m, 1H), 2.40 (s, 3H),

2.14ꢀ2.02 (m, 4H), 1.79ꢀ1.64 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz)

δ (ppm) 158.7, 145.9, 128.4, 118.7, 111.8, 110.8, 61.0, 54.2, 39.1, 37.6,

33.7, 24.9; IR (ATR) ν~/cm^ꢀ12928 (s), 2796 (w), 1600 (s), 1584 (s),

1486 (m), 1452 (s), 1352 (m), 1264 (s), 1242 (m), 1158 (s), 1038 (vs),

776 (s), 760 (s), 696 (vs); MS (EI, 70 eV) m/z (%) 231 (100, M⁺), 202

(61), 188 (12), 134 (6), 121 (5), 96 (27), 83 (49); HRMS (EI) calcd for

C₁₅H₂₁NO 231.1623, found 231.1617.

300 MHz) δ (ppm) 7.64 (dd, J = 9.0 Hz, 4.2 Hz, 2H), 7.56 (m, 1H), 7.24

(dd, J = 8.4 Hz, 1.8 Hz, 1H), 7.07ꢀ7.03 (m, 2H), 3.86 (s, 3H), 3.28ꢀ3.26

(m, 2H), 3.02ꢀ2.90 (m, 1H), 2.35 (s, 3H), 2.12ꢀ2.00 (m, 4H), 1.75ꢀ1.65

(m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 158.0, 144.0, 135.0, 129.3,

128.0, 127.9, 124.6, 124.2, 118.2, 105.9, 62.0, 55.5, 40.6, 39.2, 35.2, 26.4; IR

(ATR) ν~/cm^ꢀ12936 (m), 2844 (w), 2796 (w), 1630 (m), 1604 (m),

1512 (m), 1464 (m), 1392 (m), 1350 (m), 1258 (m), 1212 (vs), 1170

(m), 1118 m), 1028 (s), 892 (m), 838 (vs), 726 (m); MS (EI, 70 eV) m/z

(%) 281 (88, M⁺), 252 (33), 170 (10), 141 (9), 96 (30), 83 (100); HRMS

(EI) calcd for C₁₉H₂₃NO 281.1780, found 281.1759.

4-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)benzonitrile (8e). 4-Cyano-

phenyl trifluoromethanesulfonate (3r; 251 mg, 1.00 mmol) reacted with

8-methyl-8-azabicyclo[3.2.1]octyl-3-magnesium chloride (2e; 4.00 mL,

1.20 mmol, 0.30 M in THF) at 25 °C for 8 h, according to TP2. Column

chromatography (silica gel, CH₂Cl₂/MeOH 20:1) furnished 4-(8-meth-

yl-8-azabicyclo[3.2.1]octan-3-yl)benzonitrile (8e; 164 mg, 73% yield) as

an orange solid. Mp (°C) 78ꢀ81; ¹H NMR (CDCl₃, 300 MHz) δ (ppm)

7.50 (d, J = 7.7 Hz, 2H), 7.31 (d, J = 7.7 Hz, 2H), 3.24 (m, 2H),

2.92ꢀ2.80 (m, 1H), 2.29 (s, 3H), 2.08ꢀ2.06 (m, 2H), 1.93ꢀ1.85 (m,

2H), 1.67ꢀ1.59 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 151.5,

132.4, 128.4, 119.2, 110.0, 61.8, 40.7, 38.9, 35.2, 26.2; IR (ATR) ~ν/cm^ꢀ1

2936 (s), 2876 (m), 2838 (m), 2790 (m), 2222 (s), 1608 (m), 1470 (m),

1448 (m), 1350 (s), 1052 (m), 1036 (s), 844 (s), 814 (vs), 784 (m), 754

(m); MS (EI, 70 eV) m/z (%) 226 (80, M⁺), 197 (45), 183 (7), 115 (7),

96 (28), 83 (100), 42 (19); HRMS (EI) calcd for C₁₅H₁₈N₂226.1470,

found 226.1455.

Synthesis of Aminoalkyl Cross-Coupling Products of Type

9. (E)-N,N-Dimethyl-5-phenylpent-4-en-1-amine (9a). (E)-(2-Bro-

movinyl)benzene (3s; 183 mg, 1.00 mmol) reacted with 3-(dimethyl-

amino)propylmagnesium chloride (2a; 1.50 mL, 1.20 mmol, 0.80 M in

THF) at 50 °C for 16 h, according to TP2. Aqueous workup furnished

(E)-N,N-dimethyl-5-phenylpent-4-en-1-amine (9a; 125 mg, 66% yield)

as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 7.39ꢀ7.28 (m,

5H), 6.46ꢀ6.42 (m, 1H), 6.31ꢀ6.21 (m, 1H), 2.39ꢀ2.22 (m, 10H),

1.77ꢀ1.63 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 137.8, 130.5,

130.1, 128.8, 126.9, 125.9, 59.3, 45.5, 30.9, 28.1; IR (ATR) ν~/cm^ꢀ13025

(m), 2970 (m), 2939 (vs), 2857 (m), 2814 (s), 2763 (vs), 1695 (w),

1494 (w), 1464 (s), 1448 (m), 1264 (m), 1232 (w), 1098 (w), 1070 (w),

1041 (m), 963 (s), 843 (w), 739 (s), 716 (w), 691 (vs); MS (EI, 70 eV)

m/z (%) 189 (42, M⁺), 129 (31), 128 (11), 117 (13), 115 (24), 85 (14),

84 (100), 59 (11), 58 (40); HRMS (EI) calcd for C₁₃H₁₉N 189.1517,

found 189.1514.

2-(4-(8-Methyl-8-azabicyclo[3.2.1]octan-3-yl)phenyl)acetonitrile (8b).

2-(4-Bromophenyl)acetonitrile (3o; 196 mg, 1.00 mmol) reacted with

8-methyl-8-azabicyclo[3.2.1]octyl-3-magnesium chloride (2e; 4.00 mL,

1.20 mmol, 0.30 M in THF) at 25 °C for 72 h, according to TP2. Column

chromatography (silica gel, CH₂Cl₂/MeOH 20:1) furnished 2-(4-(8-meth-

yl-8-azabicyclo[3.2.1]octan-3-yl)phenyl)acetonitrile (8b; 220 mg, 92%

1

yield) as a sand colored solid. Mp (°C) 105ꢀ106; H NMR (CDCl₃,

300 MHz) δ (ppm) 7.09 (d, J = 8.4 Hz, 2H), 6.97 (d, J = 8.4 Hz, 2H), 3.48

(s, 2H), 3.27ꢀ3.25 (m, 2H), 2.72ꢀ2.62 (m, 1H), 2.32 (s, 3H), 2.14ꢀ1.98

(m, 2H), 1.67ꢀ1.64 (m, 2H), 1.50ꢀ1.45 (m, 4H); ¹³C NMR (CDCl₃, 75

MHz) δ (ppm) 144.2, 131.1, 128.3, 128.2, 118.3, 63.5, 39.8, 37.8, 33.7, 25.5,

23.3; IR (ATR) ~ν/cm^ꢀ12934 (s), 2910 (s), 2798 (m), 2244 (w), 1512 (s),

1418 (s), 1354 (s), 1122 (s), 1052 (s), 1036 (s), 848 (vs), 800 (s), 786 (s),

768(vs), 706(m), 630(m);MS(EI, 70eV) m/z(%) 241 (100, [M + H⁺]),

235 (1), 102 (26), 51 (1); HRMS (EI) calcd for C¹⁶H²¹N²⁺241.1699,

found 241.1691.

3-(6-Methoxypyridin-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (8c).

2-Chloro-6-methoxypyridine (3l; 144 mg, 1.00 mmol) reacted with

8-methyl-8-azabicyclo[3.2.1]octyl-3-magnesium chloride (2e; 4.00 mL,

1.20 mmol, 0.30 M in THF) at 25 °C for 72 h, according to TP2. Column

chromatography (silica gel, CH₂Cl₂/MeOH 20:1) furnished 3-(6-meth-

oxypyridin-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (8c; 158 mg, 68%

N,N-Dimethyl-4-phenylpent-4-en-1-amine (9b). (1-Bromovinyl)-

benzene (3t; 183 mg, 1.00 mmol) reacted with 3-(dimethylamino)-

propylmagnesium chloride (2a; 1.50 mL, 1.20 mmol, 0.80 M in THF) at

50 °C for 16 h, according to TP2. Aqueous workup furnished N,N-

dimethyl-4-phenylpent-4-en-1-amine (9b; 97 mg, 51% yield) as a yellow

1

yield) as an orange oil. H NMR (CDCl₃, 300 MHz) δ (ppm) 7.39

oil. H NMR (CDCl₃, 300 MHz) δ (ppm) 7.41ꢀ7.22 (m, 5H), 5.25

(t, J = 7.7 Hz, 1H), 6.66 (d, J = 7.5 Hz, 1H), 6.46 (d, J = 8.4 Hz, 1H), 3.86

(s, 3H), 3.21ꢀ3.17 (m, 2H), 2.93ꢀ2.81 (m, 1H), 2.29 (s, 3H), 2.05ꢀ1.94

(m, 4H), 1.68ꢀ1.57 (m, 4H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm)

162.5, 161.8, 137.7, 112.6, 106.6, 60.2, 52.1, 39.0, 35.8, 35.5, 25.4; IR

(ATR) ~ν/cm^ꢀ12946 (m), 2794 (w), 1578 (s), 1462 (s), 1438 (m), 1414

(m), 1308 (m), 1282 (m), 1256 (s), 1078 (m), 1028 (s), 794 (vs), 764 (s),

740 (m), 704 (m); MS (EI, 70 eV) m/z (%) 232 (25, [M⁺]), 146

(18), 137 (60), 123 (20), 96 (54), 83 (100), 67 (42); HRMS (EI)

calcd for C₁₄H₂₀N₂O 232.1576, found 232.1558.

3-(7-Methoxynaphthalen-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (8d).

7-Methoxynaphthalen-2-yl trifluoromethanesulfonate (3p; 306 mg, 1.00

mmol) reacted with 8-methyl-8-azabicyclo[3.2.1]octyl-3-magnesium chloride

(2e; 4.00 mL, 1.20 mmol, 0.30 M in THF) at 25 °C for 72 h, according to TP2.

Column chromatography (silica gel, CH₂Cl₂/MeOH 20:1) furnished

3-(7-methoxynaphthalen-2-yl)-8-methyl-8-azabicyclo[3.2.1]octane (8d;174mg,

62% yield) as a sand colored solid. Mp (°C) 100ꢀ102; ¹H NMR (CDCl₃,

(s, 1H), 5.14 (s, 1H), 2.57ꢀ2.48 (m, 2H), 2.24ꢀ2.17(m, 8H), 1.67ꢀ

1.61 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 148.3, 141.2,

128.2, 127.3, 126.1, 112.3, 59.4, 45.4, 33.1, 26.2; IR (ATR) ν~/cm^ꢀ12941

(m), 2857 (w), 2814 (w), 2763 (m), 1627 (w), 1494 (w), 1458 (m),

1442 (m), 1264 (w), 1144 (w), 1098 (w), 1072 (w), 1028 (m), 893 (m),

840 (w), 828 (w), 777 (s), 700 (vs); MS (EI, 70 eV) m/z (%) 189

(4, M⁺), 129 (5), 128 (6), 115 (11), 91 (7), 77 (7), 71 (100), 58 (36), 56

(5), 42 (5); HRMS (EI) calcd for C₁₃H₁₉N 189.1517, found 189.1527.

4-(4-Chlorophenyl)-N,N-dimethylpent-4-en-1-amine (9c). 1-(4-Chloro-

phenyl)vinyl trifluoromethanesulfonate (3u; 287 mg, 1.00 mmol)

reacted with 3-(dimethylamino)propylmagnesium chloride (2a; 1.50 mL,

1.20 mmol, 0.80 M in THF) at 50 °C for 20 h, according to TP2. Aqueous

workup furnished 4-(4-chlorophenyl)-N,N-dimethylpent-4-en-1-amine (9c;

120 mg, 54% yield) as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm)

7.37ꢀ7.23 (m, 4 H), 5.23 (s, 1H), 5.09 (s, 1H), 2.51ꢀ2.45 (m, 2H),

2.24ꢀ2.17 (m, 8H), 1.63ꢀ1.57 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz)

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δ (ppm) 147.1, 139.6, 133.1, 128.4, 127.4, 112.8, 59.2, 45.4, 33.0, 26.1; IR

(ATR) ~ν/cm^ꢀ12941 (m), 2857 (w), 2814 (w), 2764 (m), 1625 (w), 1492

(s), 1465 (m), 1458 (m), 1439 (m), 1263 (w), 1232 (w), 1091 (m), 1042

(m), 1012 (s), 896 (m), 833 (vs), 746 (m), 735 (m), 694 (m); MS (EI, 70

eV) m/z(%) 223(1, M⁺),115(3), 84(3),71(19),59(3), 58(100),42(3);

HRMS (EI) calcd for C₁₃H₁₈³⁵ClN 223.1118, found 223.1128.

43 (84), 42 (13); HRMS (EI) calcd for C₁₄H₁₉N 201.1517, found

201.1516.

4-(2,2-Diphenylvinyl)-1-methylpiperidine (10c). (2-Bromoethene-

1,1-diyl)dibenzene (3y; 259 mg, 1.00 mmol) reacted with (1-methylpi-

peridin-4-yl)magnesium chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in

THF) at 25 °C for 10 h, according to TP2. Aqueous workup furnished

4-(2,2-diphenylvinyl)-1-methylpiperidine (10c; 224 mg, 81% yield) as

4-(5-(Dimethylamino)pent-1-en-2-yl)benzonitrile (9d). 1-(4-Cya-

nophenyl)vinyl trifluoromethanesulfonate (3v; 277 mg, 1.00 mmol)

reacted with 3-(dimethylamino)propylmagnesium chloride (2a;

1.50 mL, 1.20 mmol, 0.80 M in THF) at 50 °C for 20 h, according to

TP2. Aqueous workup furnished 4-(5-(dimethylamino)pent-1-en-2-

yl)benzonitrile (9d; 147 mg, 69% yield) as a yellow oil. ¹H NMR

(CDCl₃, 300 MHz) δ (ppm) 7.64ꢀ7.46 (m, 4H), 5.39 (s, 1H), 5.21 (s,

1

an orange solid. Mp (°C) 73ꢀ76; H NMR (CDCl₃, 300 MHz) δ

(ppm) 7.41ꢀ7.18 (m, 10H), 5.95 (d, J = 9.9 Hz, 1H), 2.87ꢀ2.81 (m,

2H), 2.25 (s, 3H), 1.92ꢀ1.79 (m, 2H), 1.65ꢀ1.57 (m, 4H); ¹³C NMR

(CDCl₃, 75 MHz) δ (ppm) 142.6, 140.9, 140.4, 134.3, 129.7, 128.3,

128.1, 127.2, 127.0, 126.9, 55.3, 46.6, 35.9, 32.6, 29.8; IR (ATR) ν~/cm^ꢀ1

2361 (m), 2337 (w), 1444(w), 1278 (w), 1142 (w), 1105 (w), 1068 (m),

979 (m), 870 (w), 848 (w), 765 (s), 729 (m), 696 (vs), 678 (m), 668

(m); MS (EI, 70 eV) m/z (%) 277 (34, M⁺), 172 (14), 110 (16), 97

(51), 96 (100), 82 (12), 70 (19), 57 (11), 42 (12); HRMS (EI) calcd for

C₂₀H₂₃N 277.1830, found 277.1823.

1H), 2.57ꢀ2.49 (m, 2H), 2.39ꢀ2.21 (m, 8H), 1.69ꢀ1.61 (m, 2H); ¹³

C

NMR (CDCl₃, 75 MHz) δ (ppm) 146.6, 145.7, 132.2, 126.8, 118.9,

115.3, 111.0, 58.9, 45.2, 32.5, 25.8; IR (ATR) ν~/cm^ꢀ12942 (m), 2859

(w), 2816 (w), 2766 (m), 2227 (m), 1605 (m), 1460 (m), 1262 (m),

1100 (m), 1041 (m), 1032 (m), 1018 (m), 905 (m), 845 (vs), 748 (m),

695 (m); MS (EI, 70 eV) m/z (%) 214 (2, M⁺), 140 (2), 116 (2), 71

(15), 59 (3), 58 (100), 56 (2), 44 (2), 42 (4); HRMS (EI) calcd for

C₁₄H₁₈N₂214.1470, found 214.1457.

4-(1-(4-Chlorophenyl)vinyl)-1-methylpiperidine (10d). 1-(4-Chlor-

ophenyl)vinyl trifluoromethanesulfonate (3u; 287 mg, 1.00 mmol)

reacted with (1-methylpiperidin-4-yl)magnesium chloride (2d; 1.94 mL,

1.20 mmol, 0.62 M in THF) at 25 °C for 20 h, according to TP2.

Aqueous workup furnished 4-(1-(4-chlorophenyl)vinyl)-1-methylpiper-

idine (10d; 126 mg, 54% yield) as a red oil. ¹H NMR (CDCl₃, 300 MHz)

δ (ppm) 7.28ꢀ7.21 (m, 4H), 5.18 (s, 1H), 5.04 (s, 1H), 2.51ꢀ2.49 (m,

2H), 2.33ꢀ2.24 (m, 3H), 2.04ꢀ1.97 (m, 2H), 1.81ꢀ1.67 (m, 4H),

1.57ꢀ1.49 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm) 152.1, 140.8,

133.0, 128.9, 128.3, 111.6, 56.2, 46.3, 31.6, 29.2; IR (ATR) ν~/cm^ꢀ1

2935 (m), 2844 (w), 2780 (m), 2680 (w), 1683 (m), 1491 (s), 1446

(m), 1378 (m), 1278 (s), 1144 (s), 1137 (s), 1093 (s), 1068 (s), 1012

(s), 899 (m), 833 (vs), 770 (s), 734 (s), 695 (s); MS (EI, 70 eV) m/z

(%) 235 (15, M⁺), 97 (13), 96 (24), 82 (6), 71 (6), 70 (100), 57 (7),

44 (8), 43 (8); HRMS (EI) calcd for C₁₄H₁₈³⁵Cl₂N 235.1128, found

235.1122.

4-(3,4-Dihydronaphthalen-1-yl)-1-methylpiperidine (10e). 3,4-Di-

hydronaphthalen-1-yl trifluoromethanesulfonate (3w; 278 mg, 1.00

mmol) reacted with (1-methylpiperidin-4-yl)magnesium chloride (2d;

1.94 mL, 1.20 mmol, 0.62 M in THF) at 25 °C for 20 h, according to

TP2. Aqueous workup furnished 4-(3,4-dihydronaphthalen-1-yl)-1-

methylpiperidine (10e; 126 mg, 56% yield) as a red oil. ¹H NMR

(CDCl₃, 300 MHz) δ (ppm) 7.22ꢀ7.15 (m, 4H), 5.91ꢀ87 (m, 1H),

3.40ꢀ3.37 (m, 1H), 3.08ꢀ3.06 (m, 2H), 2.72ꢀ2.69 (m, 2H), 2.41 (s,

3H), 2.39ꢀ2.36 (m, 1H), 2.26ꢀ2.19 (m, 2H), 2.05ꢀ1.99 (m, 1H),

1.91ꢀ1.89 (m, 2H), 1.69ꢀ1.65 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz)

δ (ppm) 139.8, 137.2, 134.5, 127.8, 126.5, 126.2, 122.9, 122.0, 56.4, 46.2,

36.1, 31.6, 28.4, 23.0; IR (ATR) ν~/cm^ꢀ12932 (m), 2777 (m), 1465 (m),

1448 (m), 1378 (m), 1279 (s), 1257 (s), 1155 (m), 1146 (s), 1136 (s),

1069 (m), 1030 (m), 1021 (m), 990 (s), 769 (vs), 743 (s), 733 (vs), 695

(m); MS (EI, 70 eV) m/z (%) 227 (28, M⁺), 128 (6), 96 (7), 70 (100),

42 (8); HRMS (EI) calcd for C₁₆H₂₁N 227.1674, found 227.1659.

Synthesis of Cusparine (11) and Galipinine (12). 2-

(Quinolin-2-yl)ethanol (14). Quinaldine (13; 50.0 g, 350 mmol)

and paraformaldehyde (7.10 g, 234 mmol) was dissolved in dioxane

(11.3 mL) and water (2.8 mL) at 75 °C, and the solution was stirred

at 110 °C reflux for 20 h. Remaining quinaldine was distilled off and

the red-brown residue was diluted with n-heptane 5 times and

filtered off to furnish 2-(quinolin-2-yl)ethanol as a colorless solid

(14; 13.0 g, 75.2 mmol, 72% yield based on recovered quinaldine).

Mp (°C) 96ꢀ100; ¹H NMR (CDCl₃, 300 MHz) δ (ppm) 8.10 (d, J =

8.4 Hz, 1H), 8.02 (d, J = 8.1 Hz, 1H), 7.79 (dd, J = 8.1 Hz, 1.1 Hz, 1H),

7.74ꢀ7.66 (m 1H), 7.55ꢀ7.47 (m, 1H), 7.38 (d, J = 9.0 Hz, 1H), 4.15

(t, J = 5.4 Hz, 2H), 3.21 (t, J = 5.4 Hz, 2H). These data match the

literature: Bucmann, G.; Wolniak, O. J. Prakt. Chem. 1964, 25, 101

2-(1,2,3,4-Tetrahydroquinolin-2-yl)ethanol (15). 2-(Quinolin-2-

yl)ethanol (14; 8.65 g, 50.0 mmol) and NiCl₂(1.10 g, 8.75 mmol)

3-(3,4-Dihydronaphthalen-1-yl)-N,N-dimethylpropan-1-amine (9e).

3,4-Dihydronaphthalen-1-yl trifluoromethanesulfonate (3w; 278 mg,

1.00 mmol) reacted with 3-(dimethylamino)propylmagnesium chloride

(2a; 1.50 mL, 1.20 mmol, 0.80 M in THF) at 50 °C for 20 h, according to

TP2. Aqueous workup furnished 3-(3,4-dihydronaphthalen-1-yl)-N,N-

1

dimethylpropan-1-amine (9e; 161 mg, 75% yield) as an orange oil. H

NMR (CDCl₃, 300 MHz) δ (ppm) 7.22ꢀ7.12 (m, 4H), 5.89ꢀ5.85 (m,

1H), 2.75ꢀ2.71 (m, 2H), 2.45ꢀ2.42 (m, 2H), 2.39ꢀ2.36 (m, 2H),

2.23ꢀ1.98 (m, 8H), 1.75ꢀ1.67 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz) δ

(ppm) 136.7, 136.1, 134.8, 127.5, 126.5, 126.3, 124.9, 122.6, 59.6, 45.4,

30.4, 28.4, 26.4, 23.1; IR (ATR) ~ν/cm^ꢀ12934 (m), 2856 (w), 2814 (m),

2762 (m), 1487 (m), 1450 (m), 1438 (m), 1263 (m), 1234 (m), 1041

(m), 1021 (m), 807 (m), 764 (s), 754 (s), 736 (vs), 694 (m); MS (EI, 70

eV) m/z (%) 215 (1, M⁺), 141 (5), 128 (6), 115 (4), 71 (25), 59 (3), 58

(100); HRMS (EI) calcd for C₁₅H₂₁N 215.1674, found 215.1667.

Synthesis of Aminoalkyl Cross-Coupling Products of Type

10. (E)-1-Methyl-4-(oct-1-en-1-yl)piperidine (10a). (E)-1-Iodooct-1-

ene (3x; 238 mg, 1.00 mmol) reacted with (1-methylpiperidin-4-yl)-

magnesium chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in THF) at 25 °C

for 24 h, according to TP2. Aqueous workup furnished (E)-1-methyl-

4-(oct-1-en-1-yl)piperidine (10a; 122 mg, 58% yield) as a brown oil. ¹H

NMR (CDCl₃, 300 MHz) δ (ppm) 5.62 (s, 1H), 5.29 (s, 1H),

3.89ꢀ2.79 (m, 8H), 2.39ꢀ1.21 (m, 14H), 0.96ꢀ0.82 (m, 3H); ¹³C

NMR (CDCl₃, 75 MHz) δ (ppm) 166.9, 114.6, 55.8, 50.8, 46.9, 35.8,

33.2, 31.7, 31.6, 29.9, 28.1, 23.4; IR (ATR) ν~/cm^ꢀ12932 (vs), 2858 (m),

2781 (m), 1716 (s), 1669 (s), 1614 (s), 1433 (m), 1386 (m), 1278 (vs),

1211 (s), 1151 (s), 1068 (m), 1033 (m), 993 (m); MS (EI, 70 eV) m/z

(%) 209 (11, M⁺), 180 (51), 97 (38), 96 (100), 70 (85), 57 (33), 44

(52); HRMS (EI) calcd for C₁₄H₂₇N 209.2143, found 209.2142.

(E)-1-Methyl-4-styrylpiperidine (10b). (E)-(2-Bromovinyl)benzene

(3s; 183 mg, 1.00 mmol) reacted with (1-methylpiperidin-4-yl)magnesium

chloride (2d; 1.94 mL, 1.20 mmol, 0.62 M in THF) at 25 °C for 24 h,

according to TP2. Aqueous workup furnished (E)-1-methyl-4-styrylpi-

peridine (10b; 154 mg, 77% yield) as an orange oil. ¹H NMR (CDCl₃,

300 MHz) δ (ppm) 7.39ꢀ7.17 (m, 5H), 6.44ꢀ6.34 (m, 1H), 6.21 (d, J =

6.9 Hz, 1H), 2.93ꢀ2.87 (m, 2H), 2.31 (s, 3H), 2.13ꢀ1.51 (m, 6H); ¹³C

NMR (CDCl₃, 75 MHz) δ (ppm) 137.7, 135.1, 128.5, 128.2, 127.0,

126.0, 55.7, 46.6, 38.9, 32.2; IR (ATR) ν~/cm^ꢀ12932 (m), 2843 (w),

2778 (m), 2734 (w), 2778 (m), 2734 (w), 1493 (w), 1464 (w), 1445

(m), 1378 (m), 1278 (m), 1144 (m), 1136 (m), 1108 (w), 1069 (m),

980 (m), 964 (s), 768 (m), 745 (s), 692 (vs); MS (EI, 70 eV) m/z (%)

201 (12, M⁺), 98 (17), 96 (100), 91 (13), 70 (25), 61 (17), 44 (14),

8904

dx.doi.org/10.1021/jo201630e |J. Org. Chem. 2011, 76, 8891–8906

The Journal of Organic Chemistry

ARTICLE

were dissolved in methanol (200 mL), the mixture was cooled to 0 °C,

and NaBH₄(7.57 g, 200 mmol) was slowly added within 30 min. The

reaction mixture was allowed to warm to 25 °C and stirred for 1 h, then

the solvent was distilled off, and the residue dissolved in 2 N HCl and

neutralized with satd aq K₂CO₃solution. After extraction with CH₂Cl₂

(2 ꢁ 100 mL) the combined organic layers were dried (Na₂SO₄), and

the solvent was distilled off. Drying in high vacuum furnished 2-(1,2,3,

4-Tetrahydroquinolin-2-yl)ethanol(15; 7.69 g, 87% yield) as a yellowoil,

which was used in the next step without purification.

(d, J = 8.1 Hz, 1H), 6.74ꢀ6.71 (m, 2H), 6.61ꢀ6.59 (m, 1H), 6.54 (d, J =

8.1 Hz, 1H), 3.87 (s, 3H), 3.86 (s, 3H), 3.31ꢀ3.28 (m, 1H), 2.92 (s, 3H),

2.88ꢀ2.83 (m, 1H), 2.72ꢀ2.65 (m, 2H), 2.56ꢀ2.51 (m, 1H), 1.98ꢀ

1.89 (m, 3H), 1.77ꢀ1.71 (m, 1H); ¹³C NMR (CDCl₃, 75 MHz) δ (ppm)

148.8, 147.1, 145.2, 134.6, 128.6, 127.1, 121.7, 120.0, 115.3, 111.5, 111.2,

110.5, 58.4, 55.9, 55.8, 38.1, 33.0, 31.9, 24.3, 23.5; IR (ATR) ν~/cm^ꢀ1

2970 (w), 2933 (m), 2833 (w), 1739 (s), 1601 (m), 1513 (s), 1498 (s),

1479 (m), 1449 (m), 1417 (m), 1365 (m), 1305 (m), 1259 (s), 1232 (vs),

1217 (s), 1155 (m), 1140 (m), 1093 (m), 1028 (s), 803 (m), 743 (vs),

606 (w); MS (EI, 70 eV) m/z (%) 312 (3), 311 (13, M⁺), 151 (6), 147

(11), 146 (100), 144 (4), 131 (7), 130 (5), 91 (3), 77 (2); HRMS (EI)

calcd for C₂₀H₂₅NO₂311.1885, found 311.1881. These data match

the literature: .

2-(1-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)ethanol (16). 2-(1,2,3,

4-Tetrahydroquinolin-2-yl)ethanol (15; 7.69 g, 43.0 mmol), formaldehyde

(6.45 g, 215 mmol), and acetic acid (3.87 g, 64.5 mmol) were dissolved in

CH₂Cl₂(150 mL), and NaBH₃CN (4.05 g, 64.5 mmol) was added slowly.

The solution was stirred at 25 °C for 16 h, the solvent was distilled off, and

then the residue was dissolved in CH₂Cl₂(100 mL) and washed with satd

aq K₂CO₃solution (2 ꢁ 100 mL). The organic layers were dried

(Na₂SO₄), and the solvent was distilled off. Drying in high vacuum

furnished 2-(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)ethanol (16; 8.06

2-(2-(Benzo[d][1,3]dioxol-5-yl)ethyl)-1-methyl-1,2,3,4-tetrahydro-

quinoline (12; Galipinine). 5-Bromobenzo[d][1,3]dioxole (20; 402 mg,

2.00 mmol) reacted with (2-(1-methyl-1,2,3,4-tetrahydroquinolin-2-

yl)ethyl)magnesium chloride (18; 4.90 mL, 2.40 mmol, 0.49 M in THF)

at 25 °C for 22 h, according to TP2. Column chromatography (silica gel,

pentane/Et₂O 20:1) furnished 2-(2-(benzo[d][1,3]dioxol-5-yl)ethyl)-

1-methyl-1,2,3,4-tetrahydroquinoline (12; 479 mg, 81% yield) as a clear

1

g, 98% yield) as a yellow oil. H NMR (CDCl₃, 300 MHz) δ (ppm)

7.16ꢀ7.11 (m, 1H), 7.02ꢀ6.98 (m, 1H), 6.64ꢀ6.58 (m, 2H), 3.74ꢀ3.62

(m, 2H), 3.36 (s, 3H), 2.84ꢀ2.72 (m, 1H), 2.61ꢀ2.50 (m, 1H),

1.88ꢀ1.61 (m, 3H), 1.47ꢀ1.34 (m, 2H); ¹³C NMR (CDCl₃, 75 MHz)

δ (ppm) 144.7, 129.1, 127.1, 122.0, 115.5, 111.3, 60.2, 56.0, 39.3, 35.2,

25.1, 23.4; IR (ATR) ~ν/cm^ꢀ13342 (s), 3052 (w), 3016 (w), 2922 (s),

2844 (s), 1606 (s), 1585 (m), 1487 (vs), 1446 (m), 1434 (m), 1349 (m),

1309 (s), 1275 (m), 1254 (m), 1206 (w), 1154 (w), 1118 (m), 1069 (m),

1047 (m), 1036 (m), 1015 (m), 931 (w), 869 (vw), 744 (s), 716 (w); MS

(EI, 70 eV) m/z (%) 191 (33, M⁺), 146 (100), 131 (16), 119 (9), 91 (6),

78 (7); HRMS (EI) calcd for C₁₂H₁₇NO 191.1310, found 191.1302.

These data match the literature: Avemaria, F.; Vanderheiden, S.; Br€ase, S.

Tetrahedron 2003, 59, 6785.

2-(2-Chloroethyl)-1-methyl-1,2,3,4-tetrahydroquinoline (17). 2-(1-

Methyl-1,2,3,4-tetrahydroquinolin-2-yl)ethanol (16; 6.79 g, 35.5 mmol)

was dissolved in CH₂Cl₂(100 mL), and SOCl₂(5.07 g, 42.6 mmol) was

added at 0 °C. After 2 h of stirring at 25 °C, the reaction was quenched

with satd aq K₂CO₃solution (50 mL) and extracted with CH₂Cl₂(3 ꢁ

100 mL). The combined organic layers were dried (Na₂SO₄), and the

solvent was distilled off. Column chromatography (silica gel, pentane)

furnished 2-(2-chloroethyl)-1-methyl-1,2,3,4-tetrahydroquinoline (17;

6.17 g, 83% yield) as a yellow oil. ¹H NMR (CDCl₃, 300 MHz) δ (ppm)

7.15ꢀ7.09 (m, 1H), 7.01 (d, J = 7.3 Hz, 1H), 6.67ꢀ6.62 (m, 1H), 6.59

(d, J = 8.3 Hz, 1H), 3.70ꢀ3.56 (m, 3H), 3.01 (s, 3H), 2.87ꢀ2.68 (m,

2H), 2.16ꢀ2.03 (m, 1H), 2.01ꢀ1.81 (m, 3H); ¹³C NMR (CDCl₃, 75

MHz) δ (ppm) 144.9, 128.8, 127.2, 121.3, 115.8, 111.1, 55.8, 42.2, 38.5,

34.6, 24.3, 23.4; IR (ATR) ν~/cm^ꢀ13055 (w), 3001 (w), 2928 (m), 2799

(s), 1588 (w), 1501 (s), 1440 (w), 1366 (s), 1302 (m), 1238 (m), 1200

(w), 1151 (w), 1138 (m), 1017 (m), 998 (m), 951 (vw), 869 (w), 741

(s), 719 (m); MS (EI, 70 eV) m/z (%) 209 (11, M⁺), 180 (5), 147 (8),

146 (100), 144 (8), 131 (11), 130 (9), 118 (5), 77 (4), 43 (5); HRMS

(EI) calcd for C₁₂H₁₆³⁵ClN 209.0971, found 209.0962.

1

oil. H NMR (CDCl₃, 300 MHz) δ (ppm) 7.12ꢀ7.10 (m, 1H), 7.00

(d, J = 7.2 Hz, 1H), 6.75 (d, J = 8.1 Hz, 1H), 6.71 (d, J = 1.9 Hz, 1H), 6.66

(d, J = 8.1 Hz, 1H), 6.54ꢀ6.50 (m, 2H), 5.93 (s, 2H), 3.31ꢀ3.29 (m,

1H), 2.93 (s, 3H), 2.90ꢀ2.83 (m, 1H), 2.74ꢀ2.63 (m, 2H), 2.55ꢀ2.50

(m, 1H), 1.98ꢀ1.90 (m, 3H), 1.76ꢀ1.69 (m, 1H); ¹³C NMR (CDCl₃,

75 MHz) δ (ppm) 147.6, 145.6, 135.3, 128.7, 127.1, 120.9, 120.2, 108.7,

108.4, 108.1, 107.5, 101.1, 100.7, 58.2, 38.1, 33.0, 32.0, 24.2, 23.5; IR

(ATR) ν~/cm^ꢀ13016 (w), 2970 (w), 2935 (w), 1739 (s), 1601 (m),

1499 (vs), 1488 (s), 1441 (s), 1365 (m), 1241 (s), 1229 (s), 1217 (vs),

1187 (m), 1092 (m), 1037 (s), 935 (m), 926 (m), 855 (w), 805 (m), 743

(vs), 702 (m), 611 (w); MS (EI, 70 eV) m/z (%) 296 (4), 295 (14, M⁺),

147 (12), 146 (100), 144 (5), 135 (3), 131 (8), 130 (6), 91 (4), 77 (4);

HRMS (EI) calcd for C₁₉H₂₁NO₂295.1572, found 295.1566. These

data match the literature: O’Byrne, A.; Evans, P. Tetrahedron 2008, 64,

8067.

’ ASSOCIATED CONTENT

Supporting Information. ¹H and ¹³C NMR for all new

S

b

compounds. This material is available free of charge via the Internet

at http://pubs.acs.org.

’ AUTHOR INFORMATION

Corresponding Author

*E-mail: Paul.Knochel@cup.uni-muenchen.de.

’ ACKNOWLEDGMENT

The research leading to these results has received funding from

the European Research Council under the European Community’s

Seventh Framework Programme (FP7/2007-2013) ERC grant

agreement no. 227763. We thank Chemetall GmbH (Frankfurt),

Heraeus GmbH (Hanau), and BASF SE (Ludwigshafen) for the

generous gift of chemicals.

(2-(1-Methyl-1,2,3,4-tetrahydroquinolin-2-yl)ethyl)magnesium Chloride

(18). 2-(2-Chloroethyl)-1-methyl-1,2,3,4-tetrahydroquinoline (17; 3.00

g, 14.3 mmol) reacted with Mg turnings (418 mg, 17.2 mmol) and LiCl

(1.21 g, 28.6 mmol) according to TP1. The fresh solution was titrated

prior to use at room temperature against a solution of iodine in THF. A

concentration of 0.49 M in THF was obtained, 69% yield.

2-(3,4-Dimethoxyphenethyl)-1-methyl-1,2,3,4-tetrahydroquinoline

(11; Cusparine). 4-Bromo-1,2-dimethoxybenzene (19; 434 mg, 2.00

mmol) reacted with (2-(1-methyl-1,2,3,4-tetrahydroquinolin-2-yl)ethyl)-

magnesium chloride (18; 4.90 mL, 2.40 mmol, 0.49 M in THF) at 25 °C

for 18 h, according to TP2. Column chromatography (silica gel,

pentane/Et₂O 7:3) furnished 6-((1-methylpiperidin-3-yl)methyl)-

quinoxaline (11; 548 mg, 88% yield) as a clear oil. H NMR (CDCl₃,

300 MHz) δ (ppm) 7.10ꢀ7.07 (m, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.79

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dx.doi.org/10.1021/jo201630e |J. Org. Chem. 2011, 76, 8891–8906

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Direct aminoalkylation of arenes, heteroarenes, and alkenes via Ni-catalyzed Negishi cross-coupling reactions

DOI: 10.1021/jo201630e

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