Synthesis of deuterium labelled 2-bromobenzylamine by directed ortho-metalation chemistry

Article abstract of DOI:10.1002/jlcr.912

Directed ortho-metalation (DoM) strategy has been applied for. the development of a short procedure for the regiospecific synthesis of [phenyl-²H₄]-2-bromo-benzylamine 6 starting from commercially available [phenyl-²H₅]-benzoyl chloride 1. A strong isotope effect was observed during the ortho-substitution. Copyright

Full text of DOI:10.1002/jlcr.912

JOURNAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS
J Label Compd Radiopharm 2005; 48: 171–177.
Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/jlcr.912
Research Article
Synthesis of deuterium labelled 2-bromobenzylamine
by directed ortho-metalation chemistry
Jens Atzrodt* and Volker Derdau
Aventis Pharma Deutschland GmbH, Chemical Development, Radiosynthesis, Frankfurt
am Main, Germany
Summary
Directed ortho-metalation (DoM) strategy has been applied for the development of a
short procedure for the regiospecific synthesis of [phenyl-2H4]-2-bromo-benzylamine 6
starting from commercially available [phenyl-2H5]-benzoyl chloride 1. A strong
isotope effect was observed during the ortho-substitution. Copyright # 2005 John
Wiley & Sons, Ltd.
Key Words: 2-bromo-benzylamine; directed ortho-metalation; N-cumyl benzamide;
deuterium; isotope effect
Introduction
[Phenyl-2H4]-2-bromobenzylamine 6 was required in our lab for the synthesis
of internal standards in LC/MS assays in the development of a new series of
Kv1.5 antagonists. Problems of site specificity during electrophilic substitution
reactions of a suitable benzene derivative arise due to directing influence of the
substituent already present in the aromatic substrate. [For a review of
orientation and reactivity in benzene and other aromatic rings, see ref.1].
However, Sistrava et al. reported an example for regiospecific formation of an
ortho-bromo substituted derivative even from substrates possessing meta-
directing groups such as benzaldehyde.2 More generally, regiospecific ortho-
substitution can be achieved by the alternative approach of directed
metalation strategy. [For a review on directed ortho metalation, see ref.3].
Various carboxamido groups have been shown to be powerful directed
metalation groups (DMG) for the directed ortho-metalation (DoM) reaction.4
Among them, N-cumyl benzamides showed certain advantages due to their
strong directing influence combined with the mild conditions of cumyl
*Correspondence to: J. Atzrodt, Aventis Pharma Deutschland GmbH, Chemical Development, Radio-
.
synthesis, Industriepark Hochst G 876, 65926 Frankfurt, Germany. E-mail: Jens.Atzrodt@aventis.com
Copyright # 2005 John Wiley & Sons, Ltd.
Received 25 October 2004
Revised 9 November 2004
Accepted 10 November 2004

172
J. ATZRODT AND V. DERDAU
deprotection, as demonstrated by Charette5 and Snieckus.6 Applying this
method, we developed a short and convenient lab procedure for the synthesis
of [phenyl-2H4]-2-bromo benzylamine 6, starting from commercially available
deuterium labelled benzoyl chloride 1.
Results and discussion
[Phenyl-2H5]-benzoyl chloride 1 was treated with cumylamine to afford the
deuterium labelled N-cumyl benzamide 2 in 91% yield (Figure 1). According
to a procedure reported by Snieckus6 initial experiments with unlabelled
material furnished after lithiation and subsequent electrophile quench with
1,2-dibromo ethane the desired unlabelled 2-bromo N-cumyl benzamide 3 in
87% yield. The reaction proceeds smoothly without formation of side
products and only traces of remaining starting material could be detected by
TLC and NMR of the isolated product (Table 1, entry 1).
However, with (deuterated) 2 as substrate the reaction resulted in very low
conversion of the starting material (Table 1, entry 2). For verification a 1:1
mixture of labelled and unlabelled benzamide 2 was treated under the same
conditions to provide a 3:7 ratio of labelled and unlabelled product.
Correspondingly, about 60% of remaining labelled benzamide 2 could be
detected by NMR spectroscopic studies of the isolated mixture versus
only 15% of unlabelled starting material. This fact clearly confirmed the
occurrence of an isotopic effect during the metalation step. Though this
kinetic isotope effect is basically known and deuterium has even been used
as a protecting group to block ortho-lithiation,7 the extent was surprising
in view of the powerful metalation properties of the employed lithiation
reagent.
Therefore, we undertook to optimize the metalation step. Variation of
temperature as well as the type and equivalent amounts of the metalation
reagent (Table 1, entry 3–7) were critical in increasing the yields of the
reaction. In all attempts the reaction times (2 h for the metalation step and
additional 1 h after electrophile quench) were kept constant.
In all cases the ratio of re-isolated benzamide 2 and product 3 was
determined by 1H-NMR-analysis of the isolated crude product mixture.
Finally, best results could be achieved employing five equivalents of s-BuLi at
ꢀ208C (Table 1, entry 5). Due to difficult separation from unreacted 2, the 2-
bromo N-cumyl benzamide 3 was isolated as a mixture with 2 and used for the
next synthesis step without further purification.
Decumylation of 3 was achieved with neat TFA at 508C. The corresponding
primary amides from 2 and 3 were easily separated by column chromato-
graphy to give pure bromo compound 4 in 59% yield based on 2. Surprisingly,
all attempts of direct reduction of the 2-bromo benzamide 4 to benzylamine 6
employing LiAlH4, LiAlH4/AlCl3 or BH3 * SMe2 failed. However, going
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SYNTHESIS OF 2-BROMOBENZYLAMINE
173
Table 1. Optimization of metalation and electrophile quench reactions of N-cumyl
benzamide 2
Entry
Reagent
Equiv. BuLi
Temperature
Ratio 2:3
la
2
3
4
5
6
7
s-BuLi
s-BuLi
s-BuLi
s-BuLi
s-BuLi
t-BuLi
t-BuLi
3.5
3.5
3.5
3.5
5.0
3.5
3.5
ꢀ788C
ꢀ788C
ꢀ208C
08C
ꢀ208C
ꢀ788C
ꢀ208C
6:94
72:28
18:82
40:60
14:86
75:25
90:10
a Reaction of unlabelled 2.
Figure 1. Synthesis of [phenyl-2H4]-2-Bromobenzylamine 6
through the nitrile 5y which was easily prepared in nearly quantitative yield by
treatment of 4 with thionyl chloride,8 reduction was readily performed with
LiAlH4/AlCl3 to afford the desired 2-bromo benzylamine 6 as the
hydrochloride salt in 73% yield.
y According to the literature6 the 2-bromo benzonitrile 5 should be also formed directly from N-cumyl amide
3 by the application of Charett’s method5 (Tf2O/pyridine in CH2C12, ꢀ408C to 08C/7 h, followed by
addition of ethanol).
Copyright # 2005 John Wiley & Sons, Ltd.
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174
J. ATZRODT AND V. DERDAU
Experimental
General
All reagents were of commercial quality and were used as received.
Cumylamine was purchased from ABCR and s-BuLi (1.3 M solution in
cyclohexane/n-hexane 92/8) as well as t-BuLi (1.5 M solution in pentane) from
Acros. Reactions were monitored by TLC, on aluminium sheets coated with
silica gel with fluorescence indicator (silica gel 60 F254, from Merck KGaA).
Purifications by column chromatography were carried out on silica gel 60
(0.063–0.2 mm) from Merck KGaA with the described eluents. Melting points
.
were measured with a Buchi 510 system and compared with available literature
1
data. The H-NMR and 13C-NMR spectra were recorded on a Bruker DRX
600 (600 MHz) nuclear magnetic resonance spectrometer. 1H-NMR data were
compared with literature data or checked against an authentic sample where
possible. MS spectra were taken on a Bruker esquire 3000 mass spectrometer.
[Phenyl-2H5]-N-cumyl benzamide (2). 2.9 g (21.4 mmol) Cumylamine and
3.2 ml triethylamine were dissolved in 50 ml dry THF and 3.0 g (20.6 mmol)
benzoyl chloride-[2H5] (Isotec, 99% deuterium) were added dropwise at rt. The
reaction mixture was stirred at rt for 14 h (TLC-control, silica, ethyl acetate/
n-heptane 1:1). Then 70 ml water and 50 ml ethyl acetate were added. The
phases were separated and the aqueous phase was extracted three times with
50 ml ethyl acetate. The combined organic layers were washed two times with
50 ml water, dried over Na2SO4, filtered and the solvent was removed in vacuo.
Yield: 4.6 g (18.8 mmol, 91%) colourless needles, mp 1578C. 1H-NMR
3
(600 MHz, DMSO-[D6]) d=8.38 (s, 1H), 7.38 (d, J(H,H)=7.88 Hz, 2H),
7.27 (t, 3J(H,H)=7.7 Hz, 2H), 7.16 (t, 3J(H,H)=7.1 Hz, 1H), 1.66 (s, 6H) ppm;
13C-NMR (150 MHz, DMSO-[D6]) d=29.6, 55.3, 124.6, 125.7, 127.0 (t, 1J(C,D)=
24.4 Hz), 127.5 (t, 1J(C,D)=24.3 Hz), 127.9, 130.2 (t, 1J(C,D)=22.3 Hz),
135.3, 148.0, 165.8; ESI-MS (%) m/z: 282.9 [M+K]+ (4), 267 [M+Na]+ (63),
244.9 [M+H]+(100).
[Phenyl-2H4]-2-bromo N-cumyl benzamide (3). 0.24 g (1.0 mmol) [phenyl-2H5]-
N-cumyl benzamide 2 and 0.5 ml (3.3 mmol) TMEDA were dissolved in 10 ml dry
THF under argon and cooled to ꢀ208C. Then 3.8ml (5.0mmol)
s-BuLi were added dropwise via syringe within 20 min, whereby the colour of
the solution turned yellow. The solution was stirred for 2 h at ꢀ208C and then
0.18 ml (2.2 mmol) 1,2-dibromo ethane was added dropwise at the same
temperature. After completion of addition the resulting colourless solution was
stirred for 1 h at ꢀ208C (TLC-control, silica, ethyl acetate/n-heptane 1:1) and was
then allowed to warm up to rt. Subsequently, 15 ml of saturated ammonium
chloride solution and 15 ml toluene were added. The phases were separated and
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SYNTHESIS OF 2-BROMOBENZYLAMINE
175
the aqueous layer was extracted two times with 10 ml toluene. The combined
organic layers were washed two times with 10 ml water and dried with Na2SO4.
After filtration the solvent was removed in vacuo and the residue was dried to
provide 0.28 g colourless solid of crude 3 (mixture of unreacted 2 and 3, ratio see
Table 1, entry 5), which was used for the next synthesis step without further
purification. A small sample was purified by column chromatography on silica gel
eluting with n-heptane/ethyl acetate 3:1. 1H-NMR (600 MHz, DMSO-[D6])
d=8.63 (s, 1H), 7.47 (d, 3J(H,H)=7.42 Hz, 2H), 7.32 (t, 3J(H,H)=7.54 Hz, 2H),
7.20 (t, 3J(H,H)=7.36 Hz, 1H), 1.63 (s, 6H) ppm; ESI-MS (%) m/z: 343.8, 345.8
[M+Na]+ (54), 321.8, 323.8 [M+H]+ (100).
[Phenyl-2H4]-2-bromo benzamide (4). 0.28 g [phenyl-2H4]-2-bromo N-cumyl
benzamide 3 (mixture with unreacted 2) was treated with 5 ml trifluoric acetic
acid and the resulting solution heated to 508C. The progress of the reaction
was monitored by TLC (n-heptane/ethyl acetate 1:1) indicating complete
conversion after 1 h. After cooling to room temperature the pH was adjusted
to pH 7 by the addition of 10 N NaOH whereupon a colourless waxy solid
separated. This mixture was extracted three times with 10 ml ethyl acetate. The
combined organic phases were dried with Na2SO4, filtered and the solvent
removed in vacuo. The residue was purified by column chromatography on
silica gel eluting with n-heptane/ethyl acetate 2:1. Selected fractions containing
the product were pooled and concentrated in vacuo. Yield: 0.12 g (0.59 mmol,
59% starting from 2) colourless solid, mp 1628C. 1H-NMR (600 MHz,
DMSO-[D6]) d=7.83 (s, br, 1H, NH), 7.54 (s, br, 1H, NH) ppm; 13C-NMR
(150 MHz, DMSO-[D6]) d=118.9, 127.6 (t, 1J(C,D)=24.8 Hz), 128.7 (t,
1
1
lJ(C,D)=24.8 Hz), 130.5 (t, J(C,D)=23.9 Hz), 132.6 (t, J(C,D)=25.4 Hz),
139.8, 169.5 ppm; ESI-MS (%) m/z: 225.7, 227.7 [M+Na]+ (63), 203.7, 205.7
[M+H]+ (100).
[Phenyl-2H4]-2-bromo benzonitrile (5). 0.4 g (2.1 mmol) [phenyl-2H4]-2-bro-
mo benzamide 4 was combined with 0.44 ml (6.0 mmol) thionyl chloride. The
reaction mixture was heated to reflux and stirred for 5 h. The mixture was
allowed to stand overnight at rt, whereby colourless needles precipitated. The
crystals were filtered off, washed two times with n-heptane and finally dried
in vacuo. Yield: 0.35 g (1.9 mmol, 96%) colourless needles, mp 568C.
1H-NMR (600 MHz, DMSO-[D6]): no signals detected; 13C-NMR
1
(150 MHz, DMSO-[D6]) d=114.8, 117.7, 124.8, 128.6 (t, J(C,D)=25.3 Hz),
133.3 (t, J(C,D)=25.7 Hz), 135.1 (t, J(C,D)=25.8 Hz); ESI-MS (%) m/z:
1
1
204.7, 206.7 [M+Na]+ (63), 185.7, 187.7 [M+H]+ (100).
[Phenyl-2H4]-2-bromobenzylamine hydrochloride (6). Under inert atmosphere
0.15 g (4.0 mmol) lithium aluminium hydride powder was suspended in 5 ml of
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J. ATZRODT AND V. DERDAU
dry diethyl ether. Then 0.53 g (4.0 mmol) aluminium chloride was added
carefully in portions under stirring. The mixture was stirred for 10 min and
then cooled to 0–58C with an ice bath. Subsequently 0.37 g (2.0 mmol)
[phenyl-2H4]-2-bromobenzonitrile 5 was added in small portions, whereby a
gas evolution could be observed. After completion of addition the ice bath was
removed and the reaction mixture stirred for 30 min at rt and subsequently
heated to reflux for additional 3 h. The mixture was allowed to stay overnight
at rt. The excess of lithium aluminium hydride was hydrolysed by addition of
2 ml of 2 N NaOH under cooling with an ice bath. The resulting solution was
extracted three times with 10 ml diethyl ether. The combined organic phases
were dried with Na2SO4, filtered and concentrated in vacuo. The residue was
dissolved in 5 ml diethyl ether and 3 ml hydrogen chloride 1 M solution in
diethyl ether were added. The resulting colourless precipitate was filtered off,
washed with diethyl ether and dried in vacuo. Yield: 0.35 g (1.52 mmol, 73%)
1
colourless solid, mp 2278C. H-NMR (600 MHz, DMSO-[D6]) d=8.59 (s, br,
3H, NH), 4.22 (s, 2H, CH2) ppm; 13C-NMR (150 MHz, DMSO-[D6]) d=41.9,
l
123.1, 127.6, (t, 1J(C,D)=26.7 Hz), 130.2 (t, J(C,D)=25.2 Hz), 130.4 t,
1J(C,D)=25.2 Hz), 132.3 (t, lJ(C,D)=25.8 Hz), 133.2; ESI-MS (%) m/z: 189.7,
191.7 [M(-HCl)+H]+ (86), 172.7, 174.7 [M(-HCl)-NH2]+ (100).
Acknowledgements
We like to thank Johanna Klee and Gerald Scholz for valuable experimental
support and Dr. Costa Metallinos for helpful discussions.
References
1. (a) Hoggett JG, Moodie RB, Penton JR, Schofield K. Nitration and Aromatic
Reactivity. Cambridge University Press: Cambridge, 1971; 122: 163; (b) Brittain
JM, Delamare PBD. The Chemistry of Functional Groups, Supplement D, Patai S,
Rappoport Z (eds). Wiley: New York, 1983; 522–532; (c) Delamare PBD.
Electrophilic Halogenation. Cambridge University Press: Cambridge, 1976; (d)
Forlani L. Synthesis 1980; 6: 487; (e) Jupan M, Segation N. Synth Commun 1994;
24: 2617.
2. Sistrava SK, Chauhan PMS, Bhaduri AP. Chem Commun 1996; 2679.
3. (a) Whisler MC, MacNeil S, Snieckus V, Beak P. Angew Chem 2004; 116:
2256–2276; (b) Snieckus V. Chem Rev 1990; 90: 879–933.
4. (a) Beak P, Brown RA. J Org Chem 1982; 47: 34; (b) Sibi MP, Shankaran K, Alo
BL, Hahn WR, Snieckus V. Tetrahedron Lett 1987; 28: 2933; (c) Iwao M,
Mahalanabis KK, Watanabe M, De Silva SO, Snieckus V. Tetrahedron 1983; 39:
1955.
5. Charette AB, Chua P. Syn Lett 1998; 163.
6. (a) Metallinos C, Nerdinger S, Snieckus V. Org Lett 1999; 1: 1183–1186; (b)
Metallinos C. Syn Lett 2002; 9: 1556–1557.
Copyright # 2005 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2005; 48: 171–177

SYNTHESIS OF 2-BROMOBENZYLAMINE
177
7. Clayden J. Organolithiums: Selectivity for Synthesis, Tetrahedron Organic
Chemistry Series, vol. 23. Pergamon Press: Oxford, 2002 and references cited
therein.
8. Borsche W, Scriba W. Annal der Chem 1939; 541: 283–292.
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