Asymmetric Sommelet-Hauser rearrangement of N-benzylic ammonium salts

Article abstract of DOI:10.1002/anie.200703832

(Chemical Equation Presented) [2,3] over [1,2]: The asymmetric Sommelet-Hauser rearrangement of an ammonium salt derived from N-benzylic proline-derived or N-benzylic glycine (-)-8-phenylmenthol ester is shown to proceed with remarkably high levels of stereoselectivity. The method provides unique and efficient access to optically active α-aryl amino acid derivatives.

Full text of DOI:10.1002/anie.200703832

Angewandte
Chemie
DOI: 10.1002/anie.200703832
Stereoselective Rearrangements
Asymmetric Sommelet–Hauser Rearrangement of N-Benzylic
Ammonium Salts**
Eiji Tayama* and Hiroshi Kimura
The Stevens and Sommelet–Hauser rearrangements of am-
monium ylides are known as useful transformations for
organic synthesis because they convert a readily accessible
(concerted [2,3]sigmatropic process) proceeded exclusively
to give the corresponding a-aryl proline[6] derivative 3 in 96%
1
yield. The H NMR analysis of 3 showed a new singlet peak
[1]
À
À
C N bond into a new C C bond. The Stevens rearrange-
ment has been widely used for the asymmetric synthesis of a-
amino acid derivatives,[2,3] whereas the Sommelet–Hauser
rearrangement is much less common because it usually
from benzylic methyl protons (d = 2.27 ppm in CDCl3), three
proton signals from aromatic protons, and the disappearance
of the benzylic methylene protons. The enantiomeric excess
was determined to be greater than 99% by chiral HPLC
analysis after reduction of 3 to the amino alcohol with lithium
aluminum hydride.[7] The R configuration of 3 was assigned by
analogy with the reported examples of [2,3]Stevens rear-
rangement of proline-derived ammonium salts.[2d,e]
With this method in hand, we carried out the rearrange-
ment of various types of ammonium bromide 4[8], derived
from N-benzylic-N,N-dimethylglycine (À)-8-phenylmenthol
ester, that might afford the a-aryl glycine derivative 5
(Table 1).[9] As expected, the rearrangement of para-tert-
[4]
competes with the [1,2]Stevens rearrangement. For exam-
ple, the base-induced rearrangement of carbonyl-stabilized
ammonium ylides such as those derived from N-benzylic a-
amino esters almost exclusively undergoes the [1,2]Stevens
rearrangement to give the a-benzylated amino acid deriva-
tives. For these reasons, synthetic applications of the Somme-
let–Hauser rearrangement and its asymmetric versions have
been limited.[5] Herein, we report a unique example of a
Sommelet–Hauser rearrangement of carbonyl-stabilized am-
monium ylides that is not accompanied by the [1,2]Stevens
rearrangement to a detectable extent.
Table 1: Asymmetric Sommelet–Hauser rearrangement of para-substi-
tuted N-benzylic ammonium salts 4.[a]
Recently, we reported that the [1,2]Stevens rearrange-
ment of ammonium salt 1, which is derived from (2S)-N-(4-
tert-butoxycarbonyl)benzyl proline tert-butyl ester, proceeds
with a perfect level (greater than 99%) of N-to-C chirality
transfer to give the a-benzylated proline tert-butyl ester 2
(Scheme 1).[2b] However, when the rearrangement was per-
formed in THF at À408C using potassium tert-butoxide
(1.5 equiv) as a base, the Sommelet–Hauser rearrangement
Entry
R1
T [8C]
t [h]
Yield [%][b]
d.r.[c]
1
2
3
4
5
6
7
8
9
COOtBu (a)
CN (b)
CN (b)
COOCH3 (c)
COPh (d)
CF3 (e)
À40
À40
À60
À60
À60
À60
À60
À40
À40
4
4
8
8
95
84
82
85
82
93
0
>98:2
87:13
97:3
>98:2
>98:2
>98:2
–
8
15
15
15
15
H f)
H f)
(
(
46
0
>98:2
–
OCH3 (g)
[a] All reactions were performed using 4 (0.20–0.30 mmol) and tBuOK
(1.2 equiv) in THF (0.1m) in an argon atmosphere. R*=(À)-8-phenyl-
menthyl. [b] Yield of isolated product. [c] d.r.=2S/2R; determined by
1HNMR analysis of the crude product.
Scheme 1. The [1,2] Stevens versus Sommelet–Hauser rearrangement.
butoxycarbonyl derivative 4a with potassium tert-butoxide at
À408C gave the a-aryl N,N-dimethylglycine ester 5a in 95%
yield with a high level of diastereoselectivity (Table 1, entry 1,
2S/2R > 98:2),[10,11] and the [1,2]Stevens rearrangement
product was not observed.[12] Next, we carried out the reaction
of a para-cyano derivative 4b under the same conditions
(Table 1, entry 2); however, the diastereoselectivity was lower
(2S/2R = 87:13) because of epimerization of the rearrange-
ment product 5b.[13] Thus, we carried out the reaction at a
[*] Dr. E. Tayama, H. Kimura
Graduate School of Science and Technology
Niigata University
Niigata 950-2181 (Japan)
Fax: (+81)-25-262-7741
E-mail: tayama@gs.niigata-u.ac.jp
[**] This work was supported by Mitsubishi Chemical Corporation Fund.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2007, 46, 8869 –8871
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8869
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Communications
Table 2: Asymmetric Sommelet–Hauser rearrangement of meta-substi-
tuted N-benzylic ammonium salt 9.[a]
lower temperature (Table 1, entry 3, À608C) to minimize
epimerization, and the corresponding rearrangement product
5b was obtained in 82% yield with excellent diastereoselec-
tivity (2S/2R = 97:3). To define the scope and limitation of this
procedure, we prepared a series of para-substituted substrates
4 and carried out their reactions (Table 1, entries 3–9). The
methoxycarbonyl (4c), benzoyl (4d), and trifluoromethyl
(4e) derivatives also afforded the [2,3]rearrangement prod-
ucts 5c–e in excellent yields and diastereoselectivities. It is
worth noting that the electron-withdrawing para substituent
accelerates the Sommelet–Hauser rearrangement. In fact,
rearrangement of the simple benzyl derivative 4 f (Table 1,
entry 7, R1 = H) at À608C did not give the rearrangement
product. However, when the reaction was carried out at
À408C (Table 1, entry 8), the corresponding rearrangement
product 5 f was obtained in 46% yield with comparable
selectivity (2S/2R > 98:2). The rearrangement of the para-
methoxybenzyl derivative 4g (Table 1, entry 9, R1 = OMe)
failed even at À408C. The S configuration of the product 5 f
Entry
R1
T [8C]
Yield [%][b] (d.r.)[c]
Yield [%][b] (d.r.)[c]
10
11
1
2
3
CN (a)
CF3 (b)
CF3 (b)
À60
À60
À40
63 (>98:2)
20[d] (>98:2)
90 (>98:2)
6 (>98:2)
0
0
[a] All reactions were performed using 9 (0.20–0.30 mmol) and tBuOK
(1.2 equiv) in THF (0.1m) in an argon atmosphere. R*=(À)-8-phenyl-
menthyl. [b] Yield of isolated product. [c] d.r.=2S/2R; determined by
1HNMR analysis of the crude product. [d] Determined by 1HNMR
analysis of the crude product.
1
was determined by H NMR comparison of the authentic S
sample prepared by diastereoselective addition of 2-methyl-
phenylmagnesium bromide to the N-Boc-iminoacetate of
(À)-8-phenylmenthol.[14] Other configurations of 5a–e were
assigned by analogy with (S)-5 f.
To further expand the scope of the asymmetric Sommelet–
Hauser rearrangement, we examined the rearrangement of
the ortho-substituted N-benzylic ammonium salts 6a (R1 =
CN) and 6b (R1 = CF3) with potassium tert-butoxide
(Scheme 2). Interestingly, the [2,3]rearrangement products
7a and 7b were obtained in excellent yields with high levels of
diastereoselectivity, and the other [2,3]rearrangement prod-
uct 8 was not detected.
showed a singlet peak of an aromatic proton (3-H: d =
7.64 ppm in [D6]DMSO for 10a, d = 7.26 ppm in [D6]benzene
for 10b), but the 2,6-disubstituted regioisomer 11 did not. The
regioselectivity observed here may be rationalized by assum-
ing that the intermediate A leading to 10 is sterically more
favorable than B (Scheme 3).
Scheme 3. Proposed intermediates in the asymmetric Sommelet–
Hauser rearrangement of meta-substituted N-benzylic ammonium salt
9. Intermediate A leads to compound 10 (2,4-substituted), whereas
intermeidate B leads to compound 11 (2,6-substituted).
In conclusion, we have reported the asymmetric rear-
rangement of N-benzylic ammonium ylides that undergo
exclusively the Sommelet–Hauser rearrangement ([2,3]sig-
matropic shift). The rearrangement of an ammonium salt
derived from N-benzylic proline or N-benzylic glycine (À)-8-
phenylmenthol ester is shown to proceed with remarkably
high levels of stereoselectivity. The method provides unique
and efficient access to optically active a-aryl amino acid
derivatives[15] and expands the synthetic scope of the Somme-
let–Hauser rearrangement.
Scheme 2. Asymmetric Sommelet–Hauser rearrangement of ortho-sub-
stituted N-benzylic ammonium salt 6. R*=(À)-8-phenylmenthyl.
Finally, we carried out the rearrangement of the meta-
substituted N-benzylic ammonium salts (Table 2). The rear-
rangement of meta-cyano derivative 9a (Table 2, entry 1) was
found to afford a mixture of the 2,4-disubstituted regioisomer
10a in 63% yield along with the other regioisomer 11a in 6%
yield with excellent diastereoselectivities. However, the
rearrangement of meta-trifluoromethyl derivative 9b at
À608C (Table 2, entry 2) gave the corresponding 2,4-disub-
stituted regioisomer 10b in only 20% yield. When we carried
out the reaction at À408C (Table 2, entry 3), 10b was
obtained in 90% yield (2S/2R > 98:2) as the only detectable
regioisomer. The assignments of 10 and 11 were made by
1H NMR analysis; the 2,4-disubstituted regioisomer 10
Experimental Section
Representative procedure: A solution of 4a (123 mg, 0.209 mmol) in
THF (2.1 mL) was cooled to À408C and treated with a solution of
potassium tert-butoxide in THF (1.0m, 0.25 mL, 0.25 mmol). The
mixture was stirred for 4 h at the same temperature under an argon
atmosphere. The resulting mixture was added to stirred ice-cold
saturated aqueous ammonium chloride, and the mixture was
8870 www.angewandte.org
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2007, 46, 8869 –8871
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Angewandte
Chemie
extracted with ether. The combined extracts were washed with
saturated aqueous sodium hydrogen carbonate and brine, dried over
sodium sulfate, and concentrated. Purification of the residue by
chromatography on silica gel (hexane/ethyl acetate = 7:1 to 4:1) gave
5a (101 mg, 95%) as a colorless gum.
[11]To confirm the 2 R isomer of 5a, the product 5a (2S/2R > 98:2)
was treated with excess tBuOK (1.5 equiv, THF, À408C for 4 h).
Compound 5a was recovered in 68% yield, and the diastereo-
1
meric ratio was changed to 2S/2R = 84:16. H NMR analysis of
the diastereomer mixture of 5a showed two singlet peaks of the
a proton (d = 3.46 ppm for the 2S isomer, d = 4.02 ppm for the
2R isomer).
Received: August 21, 2007
[12]When the reaction was carried out in a mixture of CH 2Cl2 and
50% aqueous KOH (volume ratio 2:1) at 08C for 1 h, the
corresponding [1,2]Stevens rearrangement product was
obtained as a major product (49% yield, d.r. = 4:1) with a
small amount of 5a (4% yield, 2S/2R = 1.5:1). The mechanistic
origin of the competition of Sommelet–Hauser and [1,2]Stevens
rearrangement is unclear at present; further studies are neces-
sary.
Published online: October 17, 2007
Keywords: amino acids · ammonium salts ·
.
asymmetric synthesis · diastereoselectivity · rearrangement
[1]For reviews, see: a) I. E. Markó in Comprehensive Organic
Synthesis, Vol. 3 (Eds: B. M. Trost, I. Fleming), Pergamon,
Oxford, 1991, chap. 3.10; b) J. A. Vanecko, H. Wan, F. G. West,
Tetrahedron 2006, 62, 1043 – 1062.
[13]When the product 5b (2S/2R = 97:3) was treated with tBuOK
(0.2 equiv) in THF at À408C for 4 h, 5b was recovered in 96%
yield, and the diastereomeric ratio was changed to 2S/2R =
85:15. The diastereomer mixture was treated with tBuOK
(0.2 equiv) at À608C for 8 h, and 5b was recovered in 90%
yield with the same diastereomeric ratio (2S/2R = 85:15).
[14]( S)-N-Boc-(2-methylphenyl)glycine (À)-8-phenylmenthol ester
(13) was prepared from Boc-glycine (À)-8-phenylmenthol ester
(12; R* = (À)-8-phenylmenthyl; Boc = tert-butoxycarbonyl) by
diastereoselective addition of 2-methylphenylmagnesium bro-
mide to the in situ prepared N-Boc-iminoacetate of (À)-8-
phenylmenthol [i) AIBN, NBS, CCl4, reflux; ii) 2-methylphenyl-
magnesium bromide, Et2O, 0 8C to RT]; see: a) P. Ermert, J.
Meyer, C. Stucki, J. Schneebeli, J. P. Obrecht, Tetrahedron Lett.
1988, 29, 1265 – 1268; AIBN = azobisisobutyronitrile, NBS = N-
bromosuccinimide. Then, the compound 13 was converted into
(S)-5 f by deprotection and N-dimethylation [iii) TFA, CH2Cl2,
RT; iv) aq. HCHO, NaBH3CN, AcOH, CH3CN, RT]; TFA =
trifluoroacetic acid. The absolute configration of 13 was
determined after conversion into (2-methylphenyl)glycine hy-
drochloride (14) [v) LiAlH4, Et2O, reflux; vi) RuCl3, NaIO4,
CH3CN/H2O, RT; vii) HCl, Et2O, RT]. The assignment was
confirmed by comparison of the sign of the specific rotation of
[a]52839 = 93 degcm3 gÀ1 dmÀ1 with that of the known (S)-14
[2]Recent examples of base-induced asymmetric [2,3]and [1,2]
Stevens rearrangements: a) J. B. Sweeney, A. Tavassoli, J. A.
Workman, Tetrahedron 2006, 62, 11506 – 11512; b) E. Tayama, S.
Nanbara, T. Nakai, Chem. Lett. 2006, 35, 478 – 479; c) J. A.
Workman, N. P. Garrido, J. Sançon, E. Roberts, H. P. Wessel,
J. B. Sweeney, J. Am. Chem. Soc. 2005, 127, 1066 – 1067;
d) A. P. A. ArborØ, D. J. Cane-Honeysett, I. Coldham, M. L.
Middleton, Synlett 2000, 236 – 238; e) K. W. Glaeske, F. G. West,
Org. Lett. 1999, 1, 31 – 33.
[3]Examples of Lewis acid mediated asymmetric [2,3]sigmatropic
rearrangements of allylic amines: a) J. Blid, O. Panknin, P.
Tuzina, P. Somfai, J. Org. Chem. 2007, 72, 1294 – 1300; b) J. Blid,
O. Panknin, P. Somfai, J. Am. Chem. Soc. 2005, 127, 9352 – 9353.
[4]Previous studies about competition between [1,2]Stevens and
[2,3]Sommelet–Hauser rearrangements of cyano-stabilized
´
ammonium ylides: A. Jonczyk, D. Lipiak, K. Sienkiewicz, Synlett
1991, 493 – 496.
[5]Previous examples of asymmetric Sommelet–Hauser rearrange-
ments: a) S. Hanessian, C. Talbot, P. Saravanan, Synthesis 2006,
723 – 734; b) S. J. Campbell, D. Darwish, Can. J. Chem. 1976, 54,
193 – 201.
[6]Examples of asymmetric synthesis of a-aryl proline derivatives:
a) J. Van Betsbrugge, D. TourwØ, B. Kaptein, H. Kierkels, R.
Broxterman, Tetrahedron 1997, 53, 9233 – 9240; b) D. Seebach,
M. Boes, R. Naef, W. B. Schweizer, J. Am. Chem. Soc. 1983, 105,
5390 – 5398.
([a]25389 = 91 degcm3 gÀ1 dmÀ1 (c = 0.10 gcmÀ3
, 5m HCl)); see:
b) C. Mellin-Morliꢀre, D. J. Aitken, S. D. Bull, S. G. Davies, H.
P. Husson, Tetrahedron: Asymmetry 2001, 12, 149 – 155. For
more details, see the Supporting Information.
[7]Reaction conditions: LiAlH 4, THF, 08C to RT, 85% yield. Only
one tert-butyl ester on the aromatic ring was reduced. For more
details, see the Supporting Information.
[8]Prepared from ( À)-8-phenylmenthol: i) BrCH2COOH, p-TsOH,
PhH, reflux; ii) N,N-dimethylbenzylic amine, CH3CN, RT; Ts =
toluene-p-sulfonyl. For more details, see the Supporting
Information.
[9]Recent examples of asymmetric synthesis of a-aryl glycine
derivatives: a) M. A. Beenen, D. J. Weix, J. A. Ellman, J. Am.
Chem. Soc. 2006, 128, 6304 – 6305; b) G. Shang, Q. Yang, X.
Zhang, Angew. Chem. 2006, 118, 6508 – 6510; Angew. Chem. Int.
Ed. 2006, 45, 6360 – 6362; c) H. Y. Ku, J. Jung, S. H. Kim, H. Y.
Kim, K. H. Ahn, S. G. Kim, Tetrahedron: Asymmetry 2006, 17,
1111 – 1115; d) S. Shirakawa, R. Berger, J. L. Leighton, J. Am.
Chem. Soc. 2005, 127, 2858 – 2859; e) J. C. D. Le, B. L. Pagen-
kopf, J. Org. Chem. 2004, 69, 4177 – 4180; f) C. S. Ge, Y. J. Chen,
D. Wang, Synlett 2002, 37 – 42.
[10]To confirm that the selectivity is determined in the rearrange-
ment step, we carried out the reaction of 4a using a lower
amount of tBuOK (0.50 equiv). The rearrangement product 5a
was obtained in 45% yield with a similar diastereoselectivity
(2S/2R = 98:2).
[15]The chiral auxiliary can be removed by reduction with LiAlH
.
4
For example, reduction of 5 f with LiAlH4 (Et2O, reflux) gave
(S)-2-(dimethylamino)-2-(2-methylphenyl)ethanol in 87% yield
without racemization. For more details, see the Supporting
Information.
Angew. Chem. Int. Ed. 2007, 46, 8869 –8871
ꢀ 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
8871
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