Amination of Grignard reagents with retention of configuration

Article abstract of DOI:10.1021/ol0160248

(formula presented) The stereochemistry of electrophilic amination has been probed using the chiral Grignard reagent 5, in which the magnesium-bearing carbon atom is the sole stereogenic center. Amination with azidomethyl phenyl sulfide 1 and with 0-sulfonyloxime 2 were found to proceed with full retention of configuration.

Full text of DOI:10.1021/ol0160248

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1945-1948
Amination of Grignard Reagents with
Retention of Configuration†
Reinhard W. Hoffmann,* Bettina Ho1lzer, and Oliver Knopff
Fachbereich Chemie der Philipps-UniVersita¨t Marburg, D-35032 Marburg, Germany
rwho@chemie.uni-marburg.de
Received April 24, 2001
ABSTRACT
The stereochemistry of electrophilic amination has been probed using the chiral Grignard reagent 5, in which the magnesium-bearing carbon
atom is the sole stereogenic center. Amination with azidomethyl phenyl sulfide 1 and with O-sulfonyloxime 2 were found to proceed with full
retention of configuration.
The formation of carbon-nitrogen bonds by electrophilic
amination of carbanions1 is slowly gaining importance in
stereoselective synthesis.2 Stereodifferentiation is usually
reached by stereogenic centers in the carbanionic moiety.
The stereochemistry of the amination step itself has, however,
not been addressed. We saw an opportunity to do this after
we succeeded in generating a chiral secondary Grignard
reagent (Scheme 1), in which the magnesium-bearing carbon
priori clear. Amination could proceed for one by a polar
addition route, which should be characterized by retention
of configuration at the stereogenic center. Amination could
also proceed in a stepwise manner, initiated by a SET-process
followed by bond formation within a radical pair, a process
likely to result in racemic products.3,4
We therefore set out to study the stereochemistry of
electrophilic amination reactions in order to gain mechanistic
information, important for application in stereoselective
synthesis. We were limited, though, in the choice of the
aminating reagents we could test by the configurational
lability of our chiral Grignard reagent 5. It racemizes with a
half-life of ca. 5 h at -10 °C in the reaction cocktail it is
generated in.3 Valid stereochemical results would therefore
have to rely on aminating reagents which react with Grignard
reagents at temperatures below -50 °C. This condition is
met by azidomethyl phenyl sulfide (1), an aminating reagent
introduced by B. M. Trost,5 the O-sulfonyloxime 2 described
by Narasaka,6 and the azodicarboxylates 3,7 all aminating
Scheme 1
atom is the sole stereogenic center.3 Since amination of a
carbanion is formally an oxidation reaction, the mechanism
of amination and, hence, its stereochemical course is not a
(2) Boche, G. Electrophilic Amination. In Houben-Weyl, Methods of
Organic Chemistry; Helmchen, G., Hoffmann, R. W., Mulzer, J., Schau-
mann, E., Eds.; Thieme: Stuttgart, 1995; Vol. E 21 e; pp 5133-5157.
(3) Hoffmann, R. W.; Ho¨lzer, B.; Knopff, O.; Harms, K. Angew. Chem.
2000, 112, 3206-3207; Angew. Chem., Int. Ed. 2000, 39, 3072-3074.
(4) Hoffmann, R. W.; Ho¨lzer, B. Chem. Commun. 2001, 491-492.
(5) Trost, B. M.; Pearson, W. H. J. Am. Chem. Soc. 1983, 105, 1054-
1056.
(6) Tsutsui, H.; Ichikawa, T.; Narasaka, K. Bull. Chem. Soc. Jpn. 1999,
72, 1869-1878.
(7) Carpino. L. A.; Terry, P. H.; Crowley, P. J. J. Org. Chem. 1961, 26,
4336-4340.
† Dedicated to Professor David A. Evans on the occasion of his 60th
birthday.
(1) (a) Modern Amination Methods; Ricci, A., Ed.; Wiley-VCH: Wein-
heim, 2000. (b) Dembech, P.; Seconi, G.; Ricci, A. Chem. Eur. J. 2000, 6,
1281-1286. (c) Greck, C.; Gene`t, J. P. Synlett 1997, 741-748. (d) Krohn,
K. Electrophilic Aminations. In Organic Synthesis Highlights; Mulzer, J.,
Altenbach, H. J., Braun, M., Krohn, K., Reissig, H. U., Eds.; VCH:
Weinheim, 1991; pp 45-53. (e) Erdik, E.; Ay, M. Chem. ReV. 1989, 89,
1947-1980.
10.1021/ol0160248 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/22/2001

Next we turned to amination with the O-sulfonyloxime 2.
Amination of Grignard reagents with 2 have been reported
to give higher yields in weakly coordinating solvents, such
as diethyl ether or toluene, than in THF. We therefore
generated 5 by reaction of 4 with 5 equiv of ethylmagnesium
chloride in 2:1 Et2O/toluene at -78 to -30 °C. (Scheme 4).
Scheme 2
Scheme 4
agents with an sp2-hybridized nitrogen atom as reaction
center (Scheme 2). The Grignard reagent 5 was generated
by reaction of the enantiomerically pure R-chlorosulfoxide
4 with 5 equiv of ethylmagnesium chloride at -78 to -30
°C (Scheme 3). The mixture was cooled to -78 °C, and the
Scheme 3
Treatment with the O-sulfonyloxime 2 was carried out for
10 d at -70 °C. The resulting imine 9 was cleaved by
aqueous hydrochloric acid to give 6 which was acetylated
to 7 in order to determine the enantiomeric purity. HPLC
analysis showed that the (S)-isomer of 7 was obtained in
90% ee.
Amination of 5 by 2 is very slow at -70 °C. This is
reflected in a low conversion and corresponding low overall
yield (25%). Raising the temperature to -50 °C led after 10
d to 33% of 7 of 85% ee. The lower enantiomeric purity
reflects competing racemization of the Grignard reagent 5.
Nevertheless, our results likewise suggest that the amination
of 5 by 2 is also a polar process that occurs with retention
of configuration.
Last, we tested the reaction of 5 with diisopropyl azodi-
carboxylate 3. Previously, an exploratory experiment with
racemic 5 (generated from racemic 4 in THF) showed that
the reaction with 3 did not lead to the expected amination
product 10. Rather, the reaction deviated to furnish 11 (82%)
and an equivalent amount of 12, compounds identified by
their NMR data (Scheme 5).11,12
reagent 1 was added. The mixture was allowed to reach -60
°C and was subsequently quenched with acetic anhydride.
The crude acetyltriazene 8 obtained was cleaved with KOH
to give the acetamide 7 in 82% overall yield. Its enantiomeric
purity was established as 92% by HPLC analysis on a chiral
column. When the reaction sequence was repeated using 10
equiv of ethylmagnesium chloride,8 the ee of 7 could be
raised to 95%, indicating that the enantiomeric excess of 7
likely reflects the enantiomeric excess of the Grignard reagent
5.
Treatment of the amide 7 with aqueous hydrochloric acid
The alkene 11 is formally a product of an atom transfer
reaction between 5 and 3,13 similar to a diimide reduction.
Evidence has been given that such products do not arise via
a concerted process, cf. 13, but rather via a SET sequence,13
favored by the high oxidation potential of 3 (-0.63V vs Ag/
converted it to ammonium salt 6. Its positive rotation, [R]23
D
) +30.0 (c ) 1.00, H2O), corresponds to that reported for
the (S)-enantiomer.9 These results establish that the amination
of the secondary Grignard reagent 5 by 1 occurred with
(practically complete) retention of configuration at carbon.10
A polar reaction pathway is the simplest explanation for these
findings.
(10) A referee drew our attention to the Ph.D. Thesis of William H.
Pearson, University of Wisconsin, 1982. This thesis contains data which
document that the amination of norbornyl-MgBr and of a cyclopropyl-MgBr
by 1 proceed with retention of configuration.
(8) A high concentration of ethylmagnesium chloride speeds up the
substitution at the R-chloroalkylmagnesium intermediate, which undergoes
a competing racemization at -50 °C.3
(9) Paulsen-So¨rman, U. B.; Jo¨nsson, K.-H.; Lindeke, B. G. A. J. Med.
Chem. 1984, 27, 342-346.
(11) Bessmertnykh, A. G.; Blinov, K. A.; Grishin, Y. K.; Donskaya, N.
A.; Tveritinova, E. V.; Yur’eva, N. M.; Beletskaya, I. P. J. Org. Chem.
1997, 62, 2, 6069-6076.
(12) Hughes, D. L.; Reamer, R. A. J. Org. Chem. 1996, 61, 2967-2971.
(13) Holm, J.; Crossland, J. Acta Chem. Scand. B 1979, 33, 421-428.
1946
Org. Lett., Vol. 3, No. 12, 2001

sulfonic acid. This furnished the amine 17, which was
acetylated to the familiar amide 7. Again the (S)-enantiomer
was obtained with an ee of 90%. The overall yield from the
sulfoxide 4 to the amide 7 amounted to 69%.18
Scheme 5
The understanding of the mechanisms of reactions of
organometallic compounds is key to their proper application
in stereoselective synthesis. With this study we have gained
information about the electrophilic amination of Grignard
reagents by the azide 1 or the O-sulfonyloxime 2. The
(18) Experimental details: (N)-(1-Phenyl-2-butyl)acetamide (7). (1)
Amination with 1: Ethylmagnesium chloride (1.78 M in THF, 0.56 mL,
1.00 mmol) was added dropwise at -78 °C into a precooled solution of
the sulfoxide 419 (99% de, 99% ee, 60 mg, 0.20 mmol) in THF (0.30 mL).
The solution was allowed to reach -30 °C over 1.5 h. Azidomethyl phenyl
sulfide (1) (377 µL 4.00 mmol) was added, and the yellow-greenish mixture
was stirred for 1 h at -78 °C. The temperature was allowed to reach -60
°C, and acetic anhydride (566 µL 6.00 mmol) was added. After being stirred
for 1 h at -30 °C, a saturated aqueous NH4Cl solution (5 mL) and ether (5
mL) were added. The phases were separated, and the aqueous phase was
extracted with ether (2 × 5 mL). The combined organic phases were dried
(Na2SO4) and concentrated. The residue was taken up in DMSO (1.0 mL).
Potassium hydroxide (315 mg, 5.60 mmol) was added at 0 °C, resulting in
a vigorous evolution of gas. After being stirred for 3 h at room temperature,
a saturated aqueous NH4Cl solution (5 mL) and ether (5 mL) were added.
The phases were separated, and the aqueous phase was extracted with ether
(2 × 5 mL). The combined organic phases were dried (Na2SO4) and
concentrated. Flash chromatography over silica gel with dichloromethane
followed by dichloromethane/methanol ) 97:3 furnished 7 (31 mg, 82%)
AgCl in CH3CN,14 which is 1.2 V more positive than that
of benzophenone15).
Amination of organomagnesium compounds can also be
attained in an indirect manner, by first transmetalating to
boron followed by subsequent conversion of the carbon-
boron bond into a carbon-nitrogen bond. We examined this
case as well for the Grignard reagent 5 (Scheme 6). Reaction
as a colorless solid of mp 70 °C: [R]23 ) -1.2 (c ) 5.0, methanol). The
D
total fraction obtained was taken up in heptane/2-propanol 97:3, analyzing
for an ee of 92% by HPLC. (2) Amination with 2: A solution of the
sulfoxide 419 (99% de, 99% ee, 60 mg, 0.20 mmol) in anhydrous toluene
(0.30 mL) was added dropwise to a precooled (-78 °C) solution of
ethylmagnesium chloride (1.81 M in diethyl ether, 0.55 mL, 1.00 mmol).
The mixture was allowed to reach -30 °C over 1.5 h. A solution of 26
(1.50 g, 2.40 mmol) in toluene (3 mL) was added. After being stirred for
10 d at -70 °C, an aqueous pH 9 buffer solution (5 mL) was added and
the mixture was allowed to reach room temperature. The phases were
separated, and the aqueous phase was extracted with ether (2 × 5 mL).
The combined organic phases were washed with a saturated aqueous
NaHCO3 solution (5 mL), dried (Na2SO4), and concentrated. The residue
was taken up in acetone (8 mL) and water (2 mL). Aqueous hydrochloric
acid (1 M, 1.60 mL) was added, and the mixture was stirred for 30 min at
room temperature. The mixture was cooled to 0 °C, triethylamine (440 µL,
3.20 mmol) and then acetyl chloride (114 µL, 1.60 mmol) were added
dropwise, and the solution was stirred for 30 min at room temperature.
Water (5 mL) and ether (5 mL) were added. The phases were separated,
and the aqueous phase was extracted with ether (2 × 5 mL). The combined
organic phases were washed with a saturated aqueous NaHCO3 solution (2
mL) and brine (2 mL), dried (Na2SO4), and concentrated. Flash chroma-
tography as before furnished 7 (9.6 mg, 25%) as a colorless solid of mp 68
°C. HPLC analyses as above indicated an enantiomeric excess of 90%. (3)
Indirect amination via 15: A solution of the Grignard reagent 5 was
prepared as described under (1). The mixed borate 1416 (126 mg, 0.89 mmol)
was added at -78 °C, and the solution was allowed to reach rt over 2.5 h.
Water (4 mL) was added, the phases were separated, and the aqueous phase
was extracted with ether (2 × 10 mL). The combined organic phases were
dried (Na2SO4) and concentrated. The residue was taken up in anhydrous
ether (1.6 mL) and cooled to -78 °C. A solution of methyllithium in ether
(2.28 M, 0.42 mL, 0.96 mmol) was added, and after 3 h of stirring acetyl
chloride (68 µL, 0.96 mmol). After reaching rt, the mixture was concen-
trated. Pentane (1 mL) was added and the mixture was filtered. The solid
was washed with pentane (2 × 1 mL), and the combined filtrates were
concentrated. The residue was taken up in THF (1.0 mL), hydroxylamine-
O-sulfonic acid (181 mg, 1.60 mmol) was added, and the suspension was
stirred for 20 h. The suspension was partitioned between water (5 mL) and
ether (5 mL), and the phases were separated. Triethylamine (0.33 mL, 2.4
mmol) was added at 0 °C to the aqueous phase. After reaching rt, acetyl
chloride (114 µL, 1.60 mmol) was added and the solution was stirred for
30 min at rt. The mixture was partitioned between water (5 mL) and ether
(5 mL), the phases were separated, and the aqueous phase was extracted
with ether (2 × 5 mL). The combined organic phases were washed with
brine (2 mL), dried (Na2SO4), and concentrated. Chromatography as under
(1) furnished 7 (26 mg, 69%) of 90% ee.
Scheme 6
of the Grignard with the mixed borate ester 1416 to give
boronate 15 was followed by an oxidative workup, to check
the stereochemistry of the borylation reaction. This led to
90% of the alcohol 16, which was obtained as the (S)-
enantiomer of 89% ee (by HPLC).3 Therefore, transmetala-
tion of 5 to 15 occurredsnot unexpectedlyswith full
retention of configuration. This finding can be used to
complete the indirect amination of 5 to 17: As alkylboronates
do not react well with hydroxylamine-O-sulfonic acid, we
followed the procedure of H. C. Brown17 and treated 15 first
with 1 equiv of CH3Li before adding hydroxylamine-O-
(14) Eberson, L.; Persson, O.; Svensson, J. O. Acta Chem. Scand. 1998,
52, 1293-1300.
(15) Magdesieva, T. V.; Kukhareva, I. I.; Shaposhnikova, E. N.;
Artamkina, G. A.; Beletskaya, I. P.; Butin, K. P. J. Organomet. Chem. 1996,
526, 51-58.
(16) Finch, A.; Gardner, P. J.; Pearn, E. J. Recl. TraV. Chim. Pays-Bas
1964, 83, 1314-1324.
(19) Hoffmann, R. W.; Nell, P. G. Angew. Chem. 1999, 111, 354-355;
Angew. Chem., Int. Ed. 1999, 38, 338-340. Hoffmann, R. W.; Nell, P. G.;
Leo, R.; Harms, K. Chem. Eur. J. 2000, 6, 3359-3365.
(17) Brown, H. C.; Kim, K.-W.; Cole, T. E.; Singaram, B. J. Am. Chem.
Soc. 1986, 108, 6761-6764.
Org. Lett., Vol. 3, No. 12, 2001
1947

stereochemistry of these reactions is best accounted for by
a polar (addition) process and not via an SET reaction
cascade.
out in the absence of copper catalysts at temperatures below
-35 °C. We are grateful to the Deutsche Forschungsge-
meinschaft (SFB 260) and the Graduierten-Kolleg “Metall-
organische Chemie” for generous support of this study.
Acknowledgment. We thank Prof. Narasaka (Tokyo) for
kindly carrying out exploratory experiments to demonstrate
that amination of Grignard reagents by 2 can also be carried
OL0160248
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Org. Lett., Vol. 3, No. 12, 2001