Synthesis of tertiary sec-alkylamines by the addition of grignard reagents to N,N-dialkylformamides mediated by Ti(OiPr)4 and Me3SiCl

Article abstract of DOI:10.1002/ejoc.200800629

A number of tertiary sec-alkylamines (22 examples, 29-80% yield) have been prepared according to a simple one-pot procedure by the addition of Grignard reagents to N,N-dialkylformamides in the presence of Ti(OiPr)₄ and Me₃SiCl. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800629

FULL PAPER
DOI: 10.1002/ejoc.200800629
Synthesis of Tertiary sec-Alkylamines by the Addition of Grignard Reagents to
N,N-Dialkylformamides Mediated by Ti(OiPr)4 and Me3SiCl
Olesya Tomashenko,[a] Viktor Sokolov,[a] Alexander Tomashevskiy,[a] Herwig A. Buchholz,[b]
Urs Welz-Biermann,[b] Vladimir Chaplinski,[c] and Armin de Meijere*[c]
Keywords: Amines / Nucleophilic addition / Titanium tetraisopropoxide / Grignard reagents
A number of tertiary sec-alkylamines (22 examples, 29–80%
yield) have been prepared according to a simple one-pot pro-
cedure by the addition of Grignard reagents to N,N-di-
alkylformamides in the presence of Ti(OiPr)4 and Me3SiCl.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
whether tertiary sec-alkylamines can be obtained by ad-
dition of two equivalents of an organometallic reagent to
N,N-dialkylcarboxamides in the presence of Ti(OiPr)4,
starting with the most reactive N,N-dialkylformamides.
When one equiv. of Ti(OiPr)4 and three equiv. of p-tolyl-
magnesium bromide (2n) were employed as in the protocol
for the synthesis of primary tert-alkylamines from nitriles,[6]
N,N-dimethylformamide (DMF, 1a) gave the corresponding
amine 3an in low yield and accompanied by hardly remov-
able impurities, while N-formylpyrrolidine (1b) or N-for-
mylpiperidine (1c) and the same Grignard reagent did not
provide any of the corresponding tertiary amine.
It is literature knowledge that in some reactions em-
ploying transition metal reagents, such as McMurry or No-
zaki–Hiyama–Kishi couplings, the addition of chlorotri-
methylsilane (Me3SiCl) makes it possible to use catalytic
instead of stoichiometric amounts of titanium or chromium
reagents.[7,8] Following these literature precedents, the pro-
tocol for the reaction of N,N-dialkylformamides with aryl-
magnesium bromides was adjusted, and indeed, DMF (1a)
in the presence of one equiv. of Me3SiCl and 0.03 equiv.
of Ti(OiPr)4 reacted with two equiv. of phenylmagnesium
bromide (2m) to furnish the corresponding amine 3am in
66% yield (Scheme 1, Table 1).[9] Under the same condi-
Introduction
Simple tertiary sec-alkylamines are easily available by the
reaction of ketones with secondary amines under weakly
acidic conditions in the presence of sodium cyanoborohy-
dride.[1] However, this reductive amination gives poor yields
or fails completely in the case of sterically congested
ketones and diaryl ketones.[1] Only a few general methods
are known for the synthesis of tertiary sec-alkylamines uti-
lizing organometallic reagents. For example, such amines
can be prepared according to a one-pot protocol based on
the alkylation of N,N-disubstituted amides with organo-
lithium compounds followed by reduction of the intermedi-
ates with lithium aluminum hydride,[2] by treatment of N,N-
dialkylformamide dimethylacetal with Grignard reagents[3]
or by dialkylation of iminium salts, obtained from N,N-di-
alkylformamides and phosgene, with organometallic rea-
gents.[4] In the reaction of non-enolizable aldehydes with
alkyltris(diethylamino)titanium such tertiary amines result
by way of an overall direct replacement of the carbonyl O-
atom by an alkyl and a diethylamino group.[5]
Results and Discussion
As we described previously, primary tert-alkylamines can tions, various tertiary amines each with one diarylmethyl
be prepared by addition of organometallic reagents to ni- substituent, were obtained in yields ranging from 29 to
triles under mediation of Ti(OiPr)4.[6] This led us to check 80%.
In a control experiment, treatment of DMF (1a) with p-
tolylmagnesium bromide (2n) in the presence of Me3SiCl,
but without Ti(OiPr)4, not even a trace of the amine 3an
[a] Saint-Petersburg State University, Chemical Department,
Universitetsky Pr. 26, 198504, Saint-Petersburg, Russia
[b] Merck KGaA,
Frankfurter Str. 250, 64293, Darmstadt, Germany
[c] Institut für Organische und Biomolekulare Chemie, Georg
August University of Göttingen,
was isolated. When Me3SiCl and Ti(OiPr)4 were both em-
ployed in catalytic quantities (0.03 equiv.), the reaction
failed as well.
Ethylmagnesium bromide (2q) upon reaction with N,N-
dialkylformamides in the presence of a stoichiometric
amount of Ti(OiPr)4 is known to furnish N,N-dialkylcy-
Tammannstrasse 2, 37077, Göttingen, Germany
Fax: +49-551-399475
E-mail: ameijer1@gwdg.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2008, 5107–5111
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5107

A. de Meijere et al.
FULL PAPER
Table 2. Tertiary sec-alkylamines with two different substituents at
the α-carbon from N,N-dialkylformamides and two different Grig-
nard reagents (see Scheme 2).
R1 in formamide 1
Ar in 2
Product
% Yield
2
a Me2
m Ph
4am
4cm
4dm
4cp
60
46
52
43
31
Scheme 1. Tertiary sec-alkylamines from N,N-dialkylformamides
and Grignard reagents in the presence of Ti(OiPr)4 and Me3SiCl.
For details see Table 1.
c –(CH2)5–
d –(CH2)2O(CH2)2–
c –(CH2)5–
a Me2
m Ph
m Ph
p 4-FC6H4
r Bn
4ar
Table 1. Tertiary amines from N,N-dialkylformamides and Grig-
nard reagents in the presence of Ti(OiPr)4 and Me3SiCl (see
Scheme 1).
R1 in formamide 1 R2 in R2MgBr 2
Product
% Yield
(Scheme 3), which usually is quite stable. It presumably un-
dergoes magnesium to titanium exchange with Ti(OiPr)4 to
form 6, and the latter may then react with a second mole-
cule of the Grignard reagent R2MgX exchanging one of its
isopropoxy groups for an R2 group to give 7. Chlorotri-
methylsilane would then act as a Lewis acid coordinating
at the oxygen of the O,N-acetal moiety and thus facilitate
the intramolecular transfer of the residue R2 in 8 from the
titanium to the carbon atom next to the nitrogen. Alterna-
tively, Me3SiCl might react with the intermediate 6 to yield
an aldimmonium chloride 9 with recovery of the catalyti-
cally active titanium tetraalkoxide, and the immonium salt
9 would then undergo addition of the second molecule of
the Grignard reagent. Considering the relative concentra-
tions of the various intermediates in the postulated mecha-
nisms and the corresponding relative rates of their suc-
ceeding bimolecular reactions, the latter version is the more
likely one.
2
a Me2
m Ph
3am
3an
3ao
3bm
3bn
3bo
3bp
3bq
3cm
3cn
3co
3cp
3cq
3dm
3dn
3do
3dp
66
40
80
41
29
50
46
42
76
45
52
62
35
43
45
40
41
a Me2
n 4-MeC6H4
o 4-MeOC6H4
m Ph
a Me2
b –(CH2)4–
b –(CH2)4–
b –(CH2)4–
b –(CH2)4–
b –(CH2)4–
c –(CH2)5–
c –(CH2)5–
c –(CH2)5–
c –(CH2)5–
c –(CH2)5–
n 4-MeC6H4
o 4-MeOC6H4
p 4-FC6H4
q Et
m Ph
n 4-MeC6H4
o 4-MeOC6H4
p 4-FC6H4
q Et
d –(CH2)2O(CH2)2– m Ph
d –(CH2)2O(CH2)2– n 4-MeC6H4
d –(CH2)2O(CH2)2– o 4-MeOC6H4
d –(CH2)2O(CH2)2– p 4-FC6H4
clopropylamines in good to very good yields.[10,11] Yet, un-
der the current conditions, i.e. with Ti(OiPr)4 in catalytic
quantities, it reacted with N-formylpyrrolidine (1b) and N-
formylpiperidine (1c) to give the corresponding tertiary sec-
pentylamines 3bq and 3cq, albeit only in moderate yields of
35 and 42%, respectively.
The successive addition of two different Grignard rea-
gents to N,N-dialkylformamides turned out to also be pos-
sible to provide tertiary amines with two different substitu-
ents at the secondary carbon atom (Scheme 2, Table 2). The
two Grignard reagents were added to the reaction mixture
simultanously,[9] but they could also be added one after the
other. In all these cases a combination of an alkyl and an
aryl Grignard reagent was employed. The use of two similar
alkyl Grignard reagents turned out to be unfavorable due
to difficulties in separating the products.
Scheme 3. Mechanistic rationalization of the formation of tertiary
sec-alkylamines from N,N-dialkylformamides and two equivalents
of a Grignard reagent in the presence of Ti(OiPr)4 and Me3SiCl.
Unfortunately, this transformation is limited to N,N-di-
alkylformamides. Even N,N-dialkylacetamides and N-(tri-
fluoracetyl)pyrrolidine did not yield the amines under the
same conditions. It is an open question, whether this is due
to an electronic or a steric effect.
Scheme 2. Tertiary sec-alkylamines with two different substituents
at the α-carbon from N,N-dialkylformamides and two different
Grignard reagents. For details see Table 2.
Conclusions
The role of titanium tetraisopropoxide and chlorotri-
methylsilane in the successive addition of the two molecules
This new approach to tertiary amines with secondary
of a Grignard reagent to an N,N-dialkylformamide is not alkyl groups essentially leads to structures that have signifi-
clear. The addition of the first entity is known to proceed cant importance as pharmacologically active compounds as
without any catalyst to give the tetrahedral intermediate 5 for example the amphetamines.[12]
5108
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Eur. J. Org. Chem. 2008, 5107–5111

Synthesis of Tertiary Amines Utilizing Organometallic Reagents
bromide (2o, 11 mmol) the amine 3bo was obtained as a colorless
solid (731 mg, 50%), m.p. 76 °C. H NMR ([D6]DMSO): δ = 1.66
Experimental Section
1
(mc, 4 H), 2.29 (mc, 4 H), 3.67 (s, 6 H), 4.07 (s, 1 H), 6.08 (d, 3JH,H
= 8.7 Hz, 4 H), 7.30 (d, 3JH,H = 8.7 Hz, 4 H) ppm. 13C NMR ([D6]-
DMSO): δ = 23.0 (CH2), 52.8 (CH2), 54.8 (CH3), 73.7 (CH), 113.5
(CH), 127.8 (CH), 136.8 (C), 157.7 (C) ppm. MS (70 eV): m/z (%)
= 296 (1) [M – H]+, 227 (100) [M – C4H8N]+, 190 (4) [M –
C7H7O]+. C19H23NO2 (297.4): calcd. C 76.74, H 7.80, N 4.71;
found C 76.40, H 7.89, N 4.49.
General Remarks: NMR spectra were recorded with a Bruker DPX
300 instrument at 300 (1H) and 75 (13C and DEPT) MHz. All spec-
tra were calibrated against tetramethylsilane as an internal stan-
dard (δ = 0 ppm) or the signals of the residual protons of deuter-
ated solvents: δ = 7.26 for CHCl3, δ = 2.50 for [D5]DMSO. Multi-
plicities of signals are described as follows: s = singlet, d = doublet,
t = triplet, q = quadruplet, mc = centered multiplet. Coupling con-
stants (J) are given in Hz; J values in 13C NMR spectra refer to
13C-19F couplings. EI-MS (70 eV) data were recorded with a Finni-
gan MAT 95 spectrometer. HRMS data were acquired with a
Micromass LCT (TOF MS, electrospray ionization, positive and
negative modes). Analytical TLC was performed on Machery-Na-
gel ready-to-use plates (PolyGram Alox N/UV254). Detection was
achieved by development with molybdatophosphoric acid solution
(5% in EtOH). Column chromatography: Merck aluminum oxide
90 active neutral, 70–230 mesh. Elemental analyses were carried
out by the Mikroanalytisches Laboratorium des Instituts für Or-
ganische und Biomolekulare Chemie der Georg-August-Uni-
versität, Göttingen. Solvents were purified by standard procedures.
N-(4,4Ј-Difluorobenzhydryl)pyrrolidine (3bp): From N-formylpyr-
rolidine (1b, 496 mg, 5 mmol) and 4-fluorophenylmagnesium bro-
mide (2p, 11 mmol) the amine 3 bp was obtained as a yellow oil
(624 mg, 46%). 1H NMR ([D6]DMSO): δ = 1.64 (mc, 4 H), 2.27
(mc, 4 H), 4.22 (s, 1 H), 7.01–7.08 (m, 4 H), 7.40–7.47 (m, 4 H)
ppm. 13C NMR ([D6]DMSO): δ = 23.0 (CH2), 52.6 (CH2), 73.1
2
3
(CH), 114.9 (d, JC,F = 21.1 Hz, CH), 128.6 (d, JC,F = 7.5 Hz,
CH), 140.2 (C), 160.8 (d, 1JC,F = 243.0 Hz, 1 C) ppm. MS (70 eV):
m/z (%) = 273 (35) [M]+, 203 (100) [M – C4H8N]+, 178 (78) [M –
C6H4F]+. C17H17F2N (273.3): calcd. C 74.70, H 6.27, N 5.12; found
C 74.53, H 6.47, N 5.22.
N-(1-Ethylpropyl)pyrrolidine (3bq): From N-formylpyrrolidine (1b,
496 mg, 5 mmol) and ethylmagnesium bromide (2q, 11 mmol) the
amine 3bq was obtained as a yellow oil (296 mg, 42%), b. p. 69–
70 °C (19 mm).[17]
General Procedure for the Synthesis of Tertiary sec-Alkylamines 3:
To a solution of the respective N,N-dialkylformamide 1 (5 mmol)
in THF (40 mL) was added Me3SiCl (543 mg, 5 mmol), Ti(OiPr)4
(48 mg, 0.17 mmol), and after stirring for 10 min, a solution of the
respective Grignard reagent 2 was added at r. t. Stirring was contin-
ued at r. t. for 1 h, then 10% aq. NaOH (30 mL) was added. The
mixture was filtered, and the filtrate was extracted with CH2Cl2
(3ϫ50 mL). The combined organic layers were dried (Na2SO4) and
concentrated under reduced pressure. The residue was purified by
column chromatography on aluminum oxide, eluting with hexane
or hexane/tert-butyl methyl ether.
N-Benzhydrylpiperidine (3cm): From N-formylpiperidine (1c,
565 mg, 5 mmol) and phenylmagnesium bromide (2m, 11 mmol)
the amine 3 cm was obtained as a colorless solid (954 mg, 76%),
m.p. 74 °C.[18]
N-(4,4Ј-Dimethylbenzhydryl)piperidine (3cn): From N-formylpiper-
idine (1c, 565 mg, 5 mmol) and p-tolylmagnesium bromide (2n,
11 mmol) the amine 3cn was obtained as a colorless solid (625 mg,
45%), m.p. 66 °C. 1H NMR ([D6]DMSO): δ = 1.36 (mc, 2 H), 1.45
(mc, 4 H), 2.19 (s, 6 H), 2.21 (mc, 4 H), 4.13 (s, 1 H), 7.03 (d, 3JH,H
= 8.0 Hz, 4 H), 7.21 (d, 3JH,H = 8.1 Hz, 4 H) ppm. 13C NMR ([D6]-
DMSO): δ = 20.4 (CH3), 24.1 (CH2), 25.6 (CH2), 52.3 (CH2), 74.9
(CH), 127.2 (CH), 128.7 (CH), 135.3 (C), 140.2 (C) ppm. MS
(70 eV): m/z (%) = 279 (35) [M]+, 195 (100) [M – C5H10N]+, 188
(50) [M – C7H7]+. C20H25N (279.4): calcd. C 85.97, H 9.02, N 5.01;
found C 86.09, H 9.07, N 5.16.
N-Benzhydryl-N,N-dimethylamine (3am): From DMF (1a, 365 mg,
5.0 mmol) and phenylmagnesium bromide (2m, 11 mmol) the
amine 3am was obtained as a colorless solid (699 mg, 66%), m.p.
69 °C.[13]
N-(4,4Ј-Dimethylbenzhydryl)-N,N-dimethylamine (3an): From DMF
(1a, 365 mg, 5 mmol) and p-tolylmagnesium bromide (2n,
11 mmol) the amine 3an was obtained as a colorless solid (478 mg,
40%), m.p. 40 °C.[14]
N-(4,4Ј-Dimethoxybenzhydryl)piperidine (3co): From N-formyl-
piperidine (1c, 565 mg, 5 mmol) and 4-methoxyphenylmagnesium
bromide (2o, 11 mmol) the amine 3co was obtained as a yellow
N-(4,4Ј-Dimethoxybenzhydryl)-N,N-dimethylamine (3ao): From DMF
(1a, 365 mg, 5 mmol) and 4-methoxyphenylmagnesium bromide
(2o, 11 mmol) the amine 3ao was obtained as a colorless solid
(1070 mg, 80%), m.p. 83 °C.[15]
1
solid (804 mg, 52%), m.p. 86 °C. H NMR ([D6]DMSO): δ = 1.37
(mc, 2 H), 1.48 (mc, 4 H), 2.23 (mc, 4 H), 3.69 (s, 6 H), 4.15 (s, 1
N-Benzhydrylpyrrolidine (3bm): From N-formylpyrrolidine (1b,
496 mg, 5 mmol) and phenylmagnesium bromide (2m, 11 mmol)
the amine 3bm was obtained as a colorless solid (483 mg, 41%),
m.p. 75 °C.[16]
3
3
H), 6.83 (d, JH,H = 8.7 Hz, 4 H), 7.25 (d, JH,H = 8.7 Hz, 4 H)
ppm. 13C NMR ([D6]DMSO): δ = 24.1 (CH2), 25.6 (CH2), 52.3
(CH2), 54.8 (CH3), 74.0 (CH), 113.5 (CH), 128.3 (CH), 136.8 (C),
157.7 (C) ppm. MS (70 eV): m/z (%) = 311 (2) [M]+, 227 (100) [M –
C5H10N]+. C20H25NO2 (311.4): calcd. C 77.14, H 8.09, N 4.50;
found C 77.13, H 7.94, N 4.48.
N-(4,4Ј-Dimethylbenzhydryl)pyrrolidine (3bn): From N-formylpyr-
rolidine (1b, 496 mg, 5 mmol) and p-tolylmagnesium bromide (2n,
11 mmol) the amine 3bn was obtained as a colorless solid (390 mg,
29%), m.p. 73 °C. 1H NMR ([D6]DMSO): δ = 1.69 (mc, 4 H), 2.22
N-(4,4Ј-Difluorobenzhydryl)piperidine (3cp): From N-formylpiper-
idine (1c, 565 mg, 5 mmol) and 4-fluorophenylmagnesium bromide
(2p, 11 mmol) the amine 3cp was obtained as a yellow oil (887 mg,
3
(s, 6 H), 2.31 (mc, 4 H), 4.11 (s, 1 H), 7.05 (d, JH,H = 7.9 Hz, 4
3
H), 7.29 (d, JH,H = 8.0 Hz, 4 H) ppm. 13C NMR ([D6]DMSO): δ
1
62%). H NMR ([D6]DMSO): δ = 1.39 (mc, 2 H), 1.51 (mc, 4 H),
= 20.4 (CH3), 23.0 (CH2), 52.8 (CH2), 74.5 (CH), 126.8 (CH), 128.7
(CH), 135.5 (C), 140.5 (C) ppm. MS (70 eV): m/z (%) = 265 (19)
[M]+, 195 (100) [M – C4H8N]+, 174 (60) [M – C7H7]+. C19H23N
(265.4): calcd. C 85.99, H 8.74, N 5.28; found C 86.00, H 8.70, N
5.54.
2.24 (mc, 4 H), 4.35 (s, 1 H), 7.08–7.14 (m, 4 H), 7.38–7.42 (m, 4
H) ppm. 13C NMR ([D6]DMSO): δ = 24.0 (CH2), 25.5 (CH2), 52.1
2
3
(CH2), 73.5 (CH), 114.9 (d, JC,F = 21.1 Hz, CH), 129.1 (d, JC,F
1
= 7.5 Hz, CH), 138.7 (C), 160.8 (d, JC,F = 243.8 Hz, 1 C) ppm.
MS (70 eV): m/z (%) = 287 (65) [M]+, 203 (100) [M – C5H10N]+,
192 (75) [M – C6H4F]+. C18H19F2N (287.4): calcd. C 75.24, H 6.66;
found C 75.38, H 6.34.
N-(4,4Ј-Dimethoxybenzhydryl)pyrrolidine (3bo): From N-formyl-
pyrrolidine (1b, 496 mg, 5 mmol) and 4-methoxyphenylmagnesium
Eur. J. Org. Chem. 2008, 5107–5111
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5109

A. de Meijere et al.
FULL PAPER
N-(1-Ethylpropyl)piperidine (3cq): From N-formylpiperidine (1c,
phenylmagnesium bromide (2m, 5 mmol) the amine 4dm was ob-
565 mg, 5 mmol) and ethylmagnesium bromide (2q, 11 mmol) the tained as a yellow oil (490 mg, 52%).[20]
amine 3cq was obtained as a yellow oil (272 mg, 35%).[19]
N-[1-(4-Fluorphenyl)ethyl]piperidine (4cp): From N-formylpiper-
idine (1c, 569 mg, 5 mmol), methylmagnesium chloride (5 mmol)
and 4-fluorophenylmagnesium bromide (2p, 5 mmol) the amine 4cp
was obtained as a reddish oil (450 mg, 43%). 1H NMR ([D6]-
N-Benzhydrylmorpholine (3dm): From N-formylmorpholine (1d,
575 mg, 5 mmol) and phenylmagnesium bromide (2n, 11 mmol) the
amine 3dm was obtained as a colorless solid (548 mg, 43%), m.p.
70 °C.[20]
3
DMSO): δ = 1.25 (d, JH,H = 6.8 Hz, 3 H), 1.33 (mc, 2 H), 1.46
3
(mc, 4 H), 2.29 (mc, 4 H), 3.42 (q, JH,H = 6.8 Hz, 1 H), 7.07–7.37
N-(4,4Ј-Dimethylbenzhydryl)morpholine (3dn): From N-formyl-
morpholine (1d, 575 mg, 5 mmol) and p-tolylmagnesium bromide
(2n, 11 mmol) the amine 3dn was obtained as a yellow solid
(m, 4 H) ppm. 13C NMR ([D6]DMSO): δ = 18.4 (CH3), 24.1 (CH2),
25.7 (CH2), 50.4 (CH2), 62.9 (CH), 114.4 (d, 2JC,F = 20.4 Hz, CH),
128.9 (d, 3JC,F = 8.3 Hz, CH), 139.6 (C), 161.4 (d, 1JC,F = 152.4 Hz,
1 C) ppm. MS (70 eV): m/z (%) = 207 (7) [M]+, 192 (100) [M –
CH3]+, 123 (11) [M – C5H10N]+, 112 (9) [M – C6H4F]+.
1
(630 mg, 45%), m.p. 63 °C. H NMR ([D6]DMSO): δ = 2.22 (s, 6
3
3
H), 2.24 (t, JH,H = 4.5 Hz, 4 H), 3.57 (t, JH,H = 4.6 Hz, 4 H),
4.16 (s, 1 H), 7.07 (d, 3JH,H = 7.9 Hz, 4 H), 7.27 (d, 3JH,H = 8.0 Hz,
4 H) ppm. 13C NMR ([D6]DMSO): δ = 20.4 (CH3), 52.1 (CH2),
66.1 (CH2), 74.8 (CH), 127.3 (CH), 128.8 (CH), 135.7 (C), 137.4
(C) ppm. MS (70 eV): m/z (%) = 281 (29) [M]+, 195 (100) [M –
C4H8NO]+, 190 (10) [M – C7H7]+. C19H23NO (281.4): calcd. C
81.10, H 8.24, N 4.98; found C 81.26, H 8.18, N 4.74.
N-(1-Methyl-2-phenyl)-N,N-dimethylamine (4ar): From DMF (1a,
365 mg, 5 mmol), methylmagnesium chloride (5 mmol) and benzyl-
magnesium chloride (2r, 5 mmol) the amine 4ar was obtained as a
colorless oil (250 mg, 31%).[23]
Supporting Information (see also the footnote on the first page of
this article): NMR spectra of tertiary sec-alkylamines.
N-(4,4Ј-Dimethoxybenzhydryl)morpholine (3do): From N-formyl-
morpholine (1d, 575 mg, 5 mmol) and 4-methoxyphenylmagnesium
bromide (2o, 11 mmol) the amine 3do was obtained as a yellow oil
Acknowledgments
(642 mg, 40%). 1H NMR ([D6]DMSO): δ = 2.25 (t, 3JH,H = 9.1 Hz,
3
4 H), 3.57 (mc, 4 H), 3.69 (s, 6 H), 4.14 (s, 1 H), 6.84 (d, JH,H
=
This work was supported by Merck KGaA, Darmstadt, and
KAdemCustomChem GmbH, Göttingen. The authors are grateful
to Stefan Beußhausen for technical support in preparing this manu-
script in its final form.
8.7 Hz, 4 H), 7.29 (d, JH,H = 8.7 Hz, 4 H) ppm. 13C NMR ([D6]-
DMSO): δ = 52.1 (CH2), 54.8 (CH3), 66.1 (CH2), 74.0 (CH), 113.6
(CH), 128.4 (CH), 134.5 (C), 157.9 (C) ppm. MS (70 eV): m/z (%)
= 311 (1) [M]+, 227 (100) [M – C4H8NO]+, 206 (2) [M – C7H7O]+.
3
N-(4,4Ј-Difluorobenzhydryl)morpholine (3dp): From N-formyl-
morpholine (1d, 575 mg, 5 mmol) and 4-fluorophenylmagnesium
bromide (2p, 11 mmol) the amine 3dp was obtained as a colorless
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[2] Y. C. Hwang, M. Chu, F. W. Fowler, J. Org. Chem. 1985, 50,
1
solid (588 mg, 41%), m.p. 75 °C. H NMR ([D6]DMSO): δ = 2.22
3885–3895.
3
3
(t, JH,H = 4.5 Hz, 4 H), 3.55 (t, JH,H = 4.5 Hz, 4 H), 4.29 (s, 1
[3] G. Eisele, G. Simchen, Synthesis 1978, 757–758.
[4] G. Wieland, G. Simchen, Liebigs Ann. Chem. 1985, 2178–2193.
[5] D. Seebach, M. Schiess, Helv. Chim. Acta 1982, 65, 2598–2602.
[6] O. Tomashenko, V. Sokolov, A. Tomashevskiy, A. de Meijere,
Synlett 2007, 652–654.
[7] A. Fürstner, A. Hupperts, J. Am. Chem. Soc. 1995, 117, 4468–
4475.
[8] A. Fürstner, N. Shi, J. Am. Chem. Soc. 1996, 118, 2533–2534.
[9] Preliminary comunication, see: H. A. Buchholz, U. Welz-Bier-
mann, V. Chaplinski A. de Meijere, German Offen. No. DE
19844194 (Sept. 26, 1998); Chem. Abstr. 2000, 132: 35337m.
[10] a) V. Chaplinski, A. de Meijere, Angew. Chem. 1996, 108, 491–
492; Angew. Chem. Int. Ed. Engl. 1996, 35, 413–414; b) V.
Chaplinski, H. Winsel, M. Kordes, A. de Meijere, Synlett 1997,
111–114.
[11] For reviews see: a) O. G. Kulinkovich, A. de Meijere, Chem.
Rev. 2000, 100, 2789–2834; b) A. de Meijere, S. I. Kozhushkov,
A. I. Savchenko in Titanium and Zirconium in Organic Synthe-
sis (Ed.: I. Marek), Wiley-VCH, Weinheim 2002, pp. 390–434;
c) A. de Meijere, S. I. Kozhushkov, A. I. Savchenko, J. Or-
ganomet. Chem. 2004, 689, 2033–2055.
H), 7.04–7.11 (m, 4 H), 7.38–7.43 (m, 4 H) ppm. 13C NMR ([D6]-
DMSO): δ = 51.9 (CH2), 66.1 (CH2), 73.3 (CH), 115.1 (d, JC,F
21.1 Hz, CH), 129.2 (d, JC,F = 8.3 Hz, CH), 138.1 (C), 160.9 (d,
1JC,F = 243.0 Hz, 1 C) ppm. MS (70 eV): m/z (%) = 289 (46) [M]+,
203 (100) [M – C4H8NO]+, 194 (10) [M – C6H4F]+. C17H17F2NO
(289.3): calcd. C 70.57, H 5.92, F 13.13; found C 70.75, H 6.01, F
13.10.
2
=
3
General Procedure for the Synthesis of Tertiary sec-Alkylamines 4:
To a solution of the respective N,N-dialkylformamide 1 (5 mmol) in
THF (40 mL) was added Me3SiCl (543 mg, 5 mmol) and Ti(OiPr)4
(48 mg, 0.17 mmol). After stirring for 10 min, solutions of
MeMgCl and the respective second Grignard reagent were added
simultanously at r.t. Stirring was continued for 1 h, then 10% aq.
NaOH (30 mL) was added. The mixture was filtered, and the fil-
trate was extracted with CH2Cl2 (3ϫ50 mL). The combined or-
ganic phases were dried (Na2SO4) and concentrated under reduced
pressure. The residue was distilled using a kugelrohr apparatus to
furnish the product.
[12] a) J. W. Sloan, W. R. Martin, R. Hook, J. Hernandez, J. Med.
Chem. 1985, 28, 1245–1251; b) C. A. Grand, B. L. Bruno, A.
de Vazquez, G. Amalia, P. Lufrano, O. Baldini, Argent. Acta
Farmaceutica Bonaerence 1984, 3, 29–45; c) J. L. Katz, G. A.
Ricaurte, J. Witkin, Psychopharmocology 1992, 107, 315–318;
d) H. Rommelspacher, Pharmocologie und Toxicologie (Ed.: E.
Oberdisse, E. Hackenthal, K. Kuschinsky), chapter 7, Springer,
Berlin, 1997, pp. 157–161; e) E. Mutschler in Arzneimittelwir-
kungen, vol. 7, Wissenschaftliche Verlagsgesellschaft, Stuttgart,
1996, p. 167.
N-(1-Phenylethyl)-N,N-dimethylamine (4am): From DMF (1a,
365 mg, 5 mmol), methylmagnesium chloride (5 mmol) and phenyl-
magnesium bromide (2m, 5 mmol) the amine 4am was obtained as
a yellow oil (440 mg, 60%).[21]
N-(1-Phenylethyl)piperidine (4cm): From N-formylpiperidine (1c,
565 mg, 5 mmol), methylmagnesium chloride (5 mmol) and phenyl-
magnesium bromide (2m, 5 mmol) the amine 4 cm was obtained as
a yellow oil (433 mg, 46%).[22]
[13] T. S. Stevens, J. Chem. Soc. 1930, 2107–2119.
N-(1-Phenylethyl)morpholine (4dm): From N-formylmorpholine
(1d, 575 mg, 5 mmol), methylmagnesium chloride (5 mmol) and
[14] M. Nishi, S. Tanimoto, M. Okano, R. Oda, Yuki Gosei Kagaku
Kuokaishi 1969, 27, 754–758; Chem. Abstr. 71, 101438v.
5110
www.eurjoc.org
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 5107–5111

Synthesis of Tertiary Amines Utilizing Organometallic Reagents
[15] K. C. Schreiber, V. P. Fernandez, J. Org. Chem. 1961, 26, 1744–
[20] K. P. Klein, D. N. Van Eenam, C. R. Hauser, J. Org. Chem.
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[21] C. M. Haguen, W. R. Bergmark, D. G. Written, J. Am. Chem.
Soc. 1992, 114, 10293–10297.
[22] P. J. Smith, M. Amin, Can. J. Chem. 1989, 67, 1457–1467.
[23] S. Okazaki, N. Shirai, Y. Sato, J. Org. Chem. 1990, 55, 334–
337.
1747.
[16] J. M. Coulter, J. W. Lewis, P. P. Lynch, Tetrahedron 1968, 24,
4489–4500.
[17] P. Truitt, W. J. Middleton, J. Am. Chem. Soc. 1951, 73, 5669–
5671.
[18] A. R. Katritzky, M. L. Lopez-Rodriguez, J. Marquet, J. Chem.
Soc. Perkin Trans. 2 1984, 349–354.
[19] A. T. Stewart, C. R. Hauser, J. Am. Chem. Soc. 1955, 77, 1098–
1103.
Received: June 25, 2008
Published Online: September 9, 2008
Eur. J. Org. Chem. 2008, 5107–5111
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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