A diversity-oriented synthesis of α-Amino acid derivatives by a silyltelluride-mediated radical coupling reaction of imines and isonitriles

Article abstract of DOI:10.1002/anie.200390039

A radical idea: A diversity-oriented synthesis of α-amino acid derivatives is realized by the silyltelluride-mediated radical coupling of imines and isonitriles followed by various transformations of the carbon-tellurium bond of the coupling products (see

Full text of DOI:10.1002/anie.200390039

Angewandte
Chemie
residue was recrystallized from pentane at ꢀ408C to give 2 (34.7 mg,
58%) as yellow crystals. m.p. 274 2768C (decomp); 1H NMR
(300 MHz, C6D6): d ¼ 0.12 (s, 18H), 0.19 (s, 36H), 1.49 (s, 1H), 2.45
(brs, 1H), 2.52 (brs, 1H), 3.95 (d, 3J(H,H) ¼ 10.5 Hz, 2H), 4.73 (t,
3J(H,H) ¼ 6.3 Hz, 1H), 4.98 (dd, 3J(H,H) ¼ 6.3, 10.5 Hz, 2H), 6.63
(brs, 1H), 6.73 ppm (brs, 1H); 13C NMR (75 MHz, C6D6): d ¼ 0.61
(q), 0.78 (q), 0.91 (q), 31.50 (d), 34.37 (d), 34.79 (d), 83.00 (d), 85.87
(d), 100.91 (d), 122.44 (d), 123.55 (s), 127.26 (d), 148.32 (s), 151.92 (s î
[15] Single crystals of 2 suitable for X-ray crystallographic analysis
were grown by recrystallization from benzene. Crystal data for
2¥0.5C6H6 (C38H67CrGeO3Si6): M ¼ 865.05, T¼ 103(2) K, mono-
clinic, space group P21/n (no. 14), a ¼ 12.613(6), b ¼ 32.756(13),
c ¼ 12.661(5) ä, b ¼ 115.767(6)8, V¼ 4711(3) ä3, Z ¼ 4, 1calcd
¼
1.220 gcmꢀ3
,
m ¼ 1.053 mmꢀ1
,
l ¼ 0.71070 ä, 2qmax ¼ 50.08,
28628 measured reflections, 8231 independent reflections,
460 refined parameters, GOF ¼ 1.246, R1 ¼ 0.0700 and wR2 ¼
0.1808 (I > 2s(I)), R1 ¼ 0.0820 and wR2 ¼ 0.1871 (for all data),
largest difference peak and hole 0.497 and ꢀ0.491 eä3. The
intensity data were collected on a Rigaku/MSC Mercury CCD
diffractometer. The structure was solved by direct methods
(SHELXS-97) and refined by full-matrix least-squares proce-
dures on F2 for all reflections (SHELXL-97). All hydrogen
atoms were placed using AFIX instructions. CCDC-192689
contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.
ac.uk/conts/retrieving.html (or from the Cambridge Crystallo-
graphic Data Centre, 12, Union Road, Cambridge CB21EZ,
UK; fax: (þ 44)1223-336-033; or deposit@ccdc.cam.ac.uk).
[16] B. Rees, P. Coppens, J. Organomet. Chem. 1972, 42, C102.
[17] G. Renner, P. Kircher, G. Huttner, P. Rutsch, K. Heinze, Eur. J.
Inorg. Chem. 2000, 879.
2), 235.05 ppm (s); IR (KBr): n˜ ¼ 1867, 1887, 1954 cmꢀ1 (C O); UV/
¼
Vis (n-hexane): lmax (e) ¼ 225 (49000), 279 (17000), 340 nm (8000);
LRMS (FAB): m/z (%) ¼ 826 (8) [Mþ], 691 (75) [{C5H5Ge(Tbt)}þ],
521 (100) [{(Tbt)ꢀ2CH3}þ]. Although we have tried to obtain the
elemental analysis of 2 on several occasions, the results have not been
commensurate with the calculated values for 2 because of its highly
moisture-sensitive properties (elemental analysis calcd for
C35H64CrGeO3Si6: C 50.89, H 7.81; found: C 49.16, H 7.87).
3: In
a glove-box filled with argon, [Mo(CH3CN)3(CO)3]
(16.3 mg, 0.054 mmol) was added to a solution of 1 (40.1 mg,
0.058 mmol) in THF (1 mL) at room temperature, and the mixture
was stirred for 5 h. After the solvent was removed in vacuo, the
residue was recrystallized from hexane at ꢀ408C to give 3 (31.4 mg,
67%) as yellow crystals. M.p. 248 2508C (decomp); 1H NMR
(300 MHz, C6D6): d ¼ 0.11 (s, 18H), 0.18 (s, 36H), 1.47 (s, 1H), 2.39
(brs, 1H), 2.49 (brs, 1H), 4.05 (d, 3J(H,H) ¼ 9.9 Hz, 2H), 4.73 (t,
3J(H,H) ¼ 6.6 Hz, 1H), 5.17 (dd, 3J(H,H) ¼ 6.6, 9.9 Hz, 2H), 6.61 (brs,
1H), 6.70 ppm (brs, 1H); 13C NMR (75 MHz, C6D6): d ¼ 0.57 (q), 0.77
(q), 0.88 (q), 31.43 (d), 34.66 (d), 34.99 (d), 81.64 (d), 83.77 (d), 103.11
(d), 122.40 (d), 123.72 (s), 127.23 (d), 148.28 (s), 151.66 (s î 2),
[18] Geometry optimization for 4 and 5 was carried out using the
Gaussian 98 program with density functional theory at the
B3LYP level with 6-311G(d,p) basis set for Ge, C, O, and
H atoms and the LANL2DZ for Cr atom.
222.19 ppm (s); IR (KBr): n˜ ¼ 1865, 1883, 1952 cmꢀ1 (C O); UV/Vis
¼
(n-hexane): lmax (e) ¼ 228 (41000), 287 (10000), 344 nm (13000);
elemental analysis calcd for C35H64GeMoO3Si6: C 48.32, H 7.42;
found: C 47.91, H 7.48.
Received: September 4, 2002 [Z50103]
Synthesis of Amino Acid Derivatives
[1] G. M‰rkl, D. Rudnick, Tetrahedron Lett. 1980, 21, 1405.
[2] G. M‰rkl, D. Rudnick, R. Schulz, A. Schweig, Angew. Chem.
1982, 94, 211; Angew. Chem. Int. Ed. Engl. 1982, 21, 221.
[3] P. Kiprof, A. B. Brown, Internet J. Chem. 1999, 2, 1.
[4] N. Nakata, N. Takeda, N. Tokitoh, J. Am. Chem. Soc. 2002, 124,
6914.
A Diversity-Oriented Synthesis of a-Amino Acid
Derivatives by a Silyltelluride-Mediated Radical
Coupling Reaction of Imines and Isonitriles**
[5] For a review of p-arene complexes of group 6 metals, see: M. J.
Morris in Comprehensive Organometallic Chemistry II, Vol. 5
(Eds.: E. W. Abel, F. G. A. Stone, G. Wilkinson), Pergamon,
Oxford, 1995, chap. 8.
Shigeru Yamago,* Hiroshi Miyazoe,
Takeyoshi Nakayama, Masaki Miyoshi, and
Junichi Yoshida*
[6] Reports on h5-silolyl and germolyl complexes, see: a) W. P.
Freeman, T. D. Tilley, A. L. Rheingold, J. Am. Chem. Soc. 1994,
116, 8428; b) J. M. Dysard, T. D. Tilley, J. Am. Chem. Soc. 1998,
120, 8245; c) J. M. Dysard, T. D. Tilley, J. Am. Chem. Soc. 2000,
122, 3097; d) W. P. Freeman, J. M. Dysard, T. D. Tilley, A. L.
Rheingold, Organometallics 2002, 21, 1734.
Development of new and practical methods for the synthesis
of a-amino acids and their derivatives is of considerable
interest to researchers, because the importance of these
compounds in biological systems and their exceptional utility
as building blocks in organic synthesis is well known.[1,2]
[7] J. M. Dysard, T. D. Tilley, T. K. Woo, Organometallics 2001, 20,
1195.
[8] D. P. Tate, W. R. Knipple, J. M. Augl, Inorg. Chem. 1962, 1, 433.
[9] R. B. King, J. Organomet. Chem. 1967, 8, 139.
[10] a) B. E. Mann, J. Chem. Soc. D 1971, 976; b) B. E. Mann, J.
Chem. Soc. Dalton Trans. 1973, 2012.
[11] C. A. L. Mahaffy, P. L. Pauson, Inorg. Synth. 1979, 19, 154.
[12] A. N. Nesmeyanov, V. V. Krivykh, V. S. Kaganovich, M. I.
Rybinskaya, J. Organomet. Chem. 1975, 102, 185.
[13] Since the scaling factor at the B3LYP/LANL2DZ level was
unknown, we compared the ratio of the observed carbonyl
stretching frequencies to the calculated ones.
[*] Prof. S. Yamago, Prof. J. Yoshida, Dr. H. Miyazoe, T. Nakayama,
M. Miyoshi
Department of SyntheticChemistry and Biological Chemistry
Graduate School of Engineering, Kyoto University
Kyoto 606-8501 (Japan)
Fax: (þ81)75-753-5911
E-mail: yamago@sbchem.kyoto-u.ac.jp
yoshida@chem.kyoto-u.ac.jp
[**] This work was partly supported by a Grant-in-Aid for the Scientific
Research from Japan Society for the Promotion of Science.
[14] M. G. Evdokimova, B. M. Yavorskii, V. N. Trembouler, N. K.
Baranetskaya, V. U. Krivyk, G. B. Zaslavskaya, Dokl. Phys.
Chem. 1978, 239, 394.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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117

Communications
Because imines are excellent acceptors for various carbon
nucleophiles, numerous synthetic routes from imines to
amino acids have been developed under ionic conditions as
exemplified by the Ugi reaction[3] and the Strecker reac-
tion.[4,5] However, because of the unfavorable thermodynam-
ics in the addition of carbon-centered radicals to imines, only
a few examples of radical-mediated synthesis have been
reported.[6 8] We report here a new synthesis of a-amino acid
derivatives that relies on a silyltelluride-mediated radical
coupling[9] strategy of imines and isonitriles followed by
transformation of the resulting imidoyl tellurides [Eq. (1)].[10]
groups of imines can participate in the coupling reaction.
Thus, aromatic and aliphatic imines with acyclic and cyclic
structures were coupled with 1B and 3 within 4 24 h at 20
808C to give 4 in good to excellent yields. It is worth
mentioning that the quaternary carbon center was effectively
constructed by employing trisubstituted imines (entries 13
and 14). It is also interesting to observe that C C multiple
bonds were unaffected by the radical intermediates (entries 9
and 10). Because a-amino radicals undergo intermolecular
addition to C C multiple bonds only when electron-with-
drawing groups are attached to the nitrogen atom,[13] the
current results clearly indicate that the triethoxysilyl group is
not a strong electron-withdrawing group. Moderate anti
selectivity was observed in the reaction of the a-alkoxy
imine 2c (entry 11). Although we also examined several a-
alkoxy imines with different a-alkyl substituents, such as the
iso-propyl group, and/or a protecting group (results not
shown), such as tert-butyldimethylsilyl (TBDMS), we could
not increase the selectivity.
Not only do the R1 and R2 substituents of the imines allow
for diversity, but the R3 moiety also serves as a diversification
site. Thus, the reaction of a variety of N-alkyl benzylidene
imine derivatives (R1 ¼ Ph, R2 ¼ H), afforded the desired
coupling reaction (R3 ¼ nBu; 94%, R3 ¼ (CH2)2OMe; 78%,
R3 ¼ allyl; 95%), while the imines possessing electron-with-
drawing groups, for example, SO2Tol (Tol ¼ toluyl), did not
react under identical conditions.
As the reaction proceeds in a group-transfer manner, the
carbon-tellurium bond in the products can also be used for the
diversity-oriented transformation to a variety of amino acid
derivatives (Scheme 2). Thus, mercury-mediated oxidative
hydrolysis of 5b gave the tert-leucine amide 8 in good yield.[14]
Treatment of 5b with nBuLi followed by hydrolysis of the
resulting imidoyl lithium afforded the a-amino imine 9,[15]
which was further hydrolyzed to the a-amino aldehyde 10.
The tributyltin hydride-mediated radical reduction of 5b also
afforded 9 in good yield.
We initially examined the trimethylsilyl phenyl telluride
(1A) mediated coupling reaction of imines and isonitriles.
However, in sharp contrast to the reaction of 1A and carbonyl
compounds,[9] 1A was totally unreactive toward imines. After
screening several silyltellurides and group 14 metal tellurides,
we were pleased to find that triethoxysilyl phenyl telluride
(1B) was sufficiently reactive, providing the desired coupling
product 4 with high efficiency. Thus, the reaction of 1B
(1.3 equiv), the imine 2a (R1 ¼ Ph, R2 ¼ H, R3 ¼ Bn; Bn ¼
benzyl; 1.0 equiv), and 2,6-xylylisonitrile (3, R4 ¼ 2,6-
Me2C6H3; 2.0 equiv) in CD3CN was complete within 4 h at
808C and afforded the coupling product 5a in 92% yield after
flash column chromatography (Table 1, entry 1). 1H NMR
spectroscopy indicated that the reaction initially afforded the
silylated amine 4a, which was hydrolyzed to 5a during
column chromatography. The NMR spectroscopic experi-
ment also revealed the profile of the reaction (Scheme 1). The
reaction of 1 and 2a gave a 23:77 equilibrium mixture of the
starting materials and the a-silylaminotelluride 6 after 0.5 h at
room temperature in the absence of isonitrile, and the ratio
did not change upon prolonged heating at 808C. However,
addition of 3 (2 equiv) to the reaction mixture smoothly and
completely converted 1, 2a, and 6 into 4a. Because the
imidoylation proceeds virtually irreversibly,[11] trapping of the
a-amino radical 7, which is reversibly generated from 6,[12] by
3 shifted the equilibrium from the starting materials to the
product.
In summary, the combination of the silyl telluride-
ꢀ
mediated coupling reaction of imines and isonitriles and C
Te bond manipulations allows the diversity-oriented synthesis
of a-amino acid derivatives. Further synthetic studies on
mechanistic and synthetic aspects as well as combinatorial
applications of the reaction are currently underway.
N(Ac)Bn
a
NHXy
O
NHBn
TePh
8
As shown in Table 1, the current reaction is extremely
versatile, and a variety of diversely substituted R1 and R2
NHBn
NXy
NHBn
b or c
d
H
H
5b
NXy
O
10
9
Scheme 2. Transformation of the coupling product into a-amino acids
and their derivatives. Conditions: a) Hg(OAc)2 (1.0 equiv), BSA
(1.5 equiv), H2O/THF, RT, 0.25 h, 94%; b) BuLi (2.2 equiv), THF,
ꢀ728C, 0.2 h then H3Oþ, 76%; c ) BuSnH (1.2 equiv), AIBN
3
(0.1 equiv), benzene, 808C, 2 h, 70% d) AcOH (1.2 equiv), THF,
ꢀ728C, 78%. AIBN¼ azobisisobutyronitrile. Xy¼ 2,6-dimethylphenyl
Scheme 1. The course of the coupling reaction.
118
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Chemie
Table 1: Three component coupling reactions with silyltelluride 1A, imine 2 and isonitrile 3a[a]
Entry
Imine
T [8C]
t [h]
Product
Yield
[%]
NBn
NHBn
TePh
NXy
R
R
1
2
3
4
5
R¼H (2a)
R¼Me
80
80
80
80
80
4
4
4
4
2
(5a)
92
93
88
91
50
R¼OMe
R¼NMe2
R¼CO2Me
NHBn
TePh
NBn
6
25
25
25
25
25
25
24
24
24
24
24
24
63
NXy
NBn
NHBn
TePh
7
92
NXy
NHBn
TePh
NBn
8
74 (72)[c]
NXy
NHBn
TePh
NBn
NBn
9
67
NXy
NHBn
TePh
10
11
68
NXy
NBn
NHBn
TePh
77[b]
OBn NXy
OBn
N
NH
TePh
NXy
12
13
14
25
25
25
24
24
24
61
50
43
H
N
N
N
TePh
NXy
H
N
Ph
Ph
TePh
NXy
[a] The reaction was carried out by heating a solution of 1a (1.3 equiv), 2 (1.0 equiv) and 3a (2.0 equiv) in CD3CN or MeCN. [b] A 76:24 mixture of the
diastereomers was obtained. The major isomer is shown. [c] Yield using one equivalent of each reagent.
Experimental Section
Typical experimental procedure: Synthesis of 5b. A solution of 1B
(3.69 g, 10.0 mmol), N-(tert-butylmethylidene)benzylamine (2b)
140.80, 141.92, 150.59, 170.06 ppm; HRMS (FAB) m/z: calcd for
C27H33N2Te [MþH]þ, 515.1706, found 515.1699; elemental analysis
calcd for C27H32N2Te: C 63.32, H 6.30, N 5.47, found: C 63.08, H 6.33,
N 5.33.
(1.76 g, 10.0 mmol), and
3 (1.31 g, 10.0 mmol) in acetonitrile
(10.0 mL) was stirred at room temperature for 24 h. After removal
of the solvent, purification of the crude mixture by flash column
chromatography (silica gel: 270 g, elution with 3% ethyl acetate in
hexane) gave 5b in 72% yield as a pale yellow solid (3.68 g,
7.20 mmol); m.p. 53.9 54.38C; IR (KBr): n˜ ¼ 2950, 1609, 1588, 1464,
847, 804, 764, 731, 695 cmꢀ1; 1H NMR (300 MHz, CDCl3): d ¼ 1.04 (s,
9H), 2.27 (s, 6H), 2.39 (br s, 1H), 3.26 (s, 1H), 3.77 (d, J ¼ 12.9 Hz,
1H), 4.26 (d, J ¼ 12.9 Hz, 1H), 6.90 6.99 (m, 2H), 6.99 7.05 (m, 1H),
7.13 (t, J ¼ 7.5 Hz, 2H), 7.23 7.42 (m, 6H), 7.70 7.77 ppm (m, 2H);
13C NMR (75 MHz, CDCl3): d ¼ 18.94, 19.11, 27.28, 35.99, 53.18, 71.43,
114.17, 124.55, 125.75, 126.09, 126.91, 128.00, 128.27, 128.65, 129.17,
Received: September 17, 2002 [Z50184]
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119

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120
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