A sequential C-N, C-C bond-forming reaction: Direct synthesis of α-amino acids from terminal alkynes

Article abstract of DOI:10.1055/s-2006-944211

Catalytic hydroamination is combined with the Strecker reaction to yield a one-pot synthesis of α-cyanoamines from terminal alkynes. This methodology is further applied to the synthesis of α-amino acids and α-amino esters. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2006-944211

LETTER
2973
A Sequential C–N, C–C Bond-Forming Reaction: Direct Synthesis of a-Amino
Acids from Terminal Alkynes
D
irec
t
Synthesis
o
l
f
a
-A
m
i
inoAc
s
f
rom
T
o
erminalAlky
n
nes V. Lee, Laurel L. Schafer*
Chemistry Department, University of British Columbia, W300-6174 University Blvd., Vancouver, BC, V6T 1Z3, Canada
Fax +1(604)8222847; E-mail: schafer@chem.ubc.ca
Received 24 February 2006
Though imines are found in natural products and pharma-
Abstract: Catalytic hydroamination is combined with the Strecker
ceuticals,7 one of their most important uses is as synthetic
reaction to yield a one-pot synthesis of a-cyanoamines from termi-
intermediates in further transformations.8 Hydroamina-
nal alkynes. This methodology is further applied to the synthesis of
tion-generated imines are particularly attractive in this re-
gard as there are no side products formed in the reaction.
a-amino acids and a-amino esters.
Key words: amino acids, catalysis, hydroamination, Strecker reac-
tion, synthesis
Importantly, imines are invoked as intermediates in the
Strecker reaction (Equation 2), a well established method
for the synthesis of racemic amino acids.9 More recent
contributions in this area have focused on enantioselective
versions of this reaction.10 As shown in Equation 2, carbo-
nyl containing starting materials are used for either the in
situ preparation of the requisite imines or alternatively, for
the preparation of isolable imine substrates. In the latter
case, the required isolation of these easily hydrolyzed
functional groups can limit the reaction scope to more
stable imines, such as aryl-substituted imines.
Sequential one-pot reactions, such as catalytic C–N and
subsequent C–C bond formation, are very desirable in
synthetic chemistry due to their efficiency and synthetic
facility.1 Such an approach leading to the synthesis of im-
portant organic building blocks, such as a-amino acids,
represents an important contribution to synthetic method-
ology.2 Furthermore, new routes for the direct synthesis of
these highly functionalized molecules from alternative
synthetic precursors provide enhanced flexibility in syn-
thetic approaches. Here we report a sequential one-pot
synthesis of a-cyanoamines, (also known as a-amino
nitriles), ready precursors to a-amino acids, from easily
accessible terminal alkynes using a modified Strecker
reaction.
O
NH2
CN
NH3
+
+
HCN
H
Equation 2
Here we demonstrate that the combination of the facile
catalytic synthesis of a wide range of aldimines from ter-
minal alkynes can be used in a modified Strecker reaction
for the synthesis of alkyl-substituted a-cyanoamines
(Scheme 1). This approach complements existing meth-
odology and provides flexibility in synthetic strategy by
taking advantage of the fact that terminal alkynes are
easily installed and can be carried through synthetic
manipulations with ease.
The most efficient and atom-economical way of forming
C–N bonds is through catalytic hydroamination,3 the ad-
dition of nitrogen and hydrogen atoms across a carbon-
carbon multiple bond (Equation 1). Our research group
has developed group 4 bis(amidate) complexes for the
hydroamination of alkynes.4 In particular, the bis-ami-
date, bis-amido titanium(IV) complex 1 has been shown
to be very active in the anti-Markovnikov regioselective
intermolecular hydroamination of terminal alkynes with a
wide range of primary amines to yield exclusively aldi-
mine products.5 This easily prepared catalyst is, to the best
of our knowledge, the only generally applicable anti-
Markovnikov selective catalyst that has been reported to
date.6
R1
TMS
R
R1
H
R
H
N
N
c
a, b
+
R
CN
2 equiv H2NR1
CN
3
2
Scheme 1 Synthesis of a-cyanoamines. Reagents and conditions: a)
1 (5 mol%), C6H6, 65 °C, 12 h; b) TMSCN (1 equiv), r.t., 3 h; c) sat.
NH4Cl.
O
H
R
H
Ti(NEt2)2
Ph
R
5 mol% 1
N
+
N
2
R1
H2NR1
Initial investigations focused on the reaction of 1-hexyne
and isopropyl amine, using NMR spectroscopy to monitor
reaction progress. 1-Hexyne and 2 equivalents of iso-
propyl amine were combined with 5 mol% of precatalyst
1 in benzene-d6 within a sealed NMR tube and heated at
65 °C for 12 hours. Appearance of a triplet at d = 7.40 ppm
1
Equation 1
SYNLETT 2006, No. 18, pp 2973–2976
0
3
.1
1
.2
0
0
6
1
Advanced online publication: 04.08.2006
DOI: 10.1055/s-2006-944211; Art ID: S02506ST
© Georg Thieme Verlag Stuttgart · New York
in the H NMR spectrum as well as the complete dis-
appearance of the alkyne signal at d = 1.78 ppm signified

2974
A. V. Lee, L. L. Schafer
LETTER
imine formation. This observation was further confirmed acetate-protected a-cyanoamines.12 These compounds are
by the diagnostic imine signal at d = 161 ppm in the more stable than 3 and are amenable to purification. In
13C NMR spectrum. The cyano moiety was then added to this case, for example, compound 4a was formed by the
the imine using 1 equivalent of TMSCN administered via addition of 2.5 equivalents of trifluoroacetic anhydride to
syringe under an inert atmosphere at room temperature. the TMS-protected cyanoamine 2a (Scheme 2) and was
1
Disappearance of the imine signals in both the H and purified via column chromatography to give the desired
13C NMR spectra within three hours signified its con- product in 93% yield. Thus, as demonstrated by both the
sumption, and the appearance of a peak at d = 120 ppm in 1H NMR spectroscopic yield determination and the isola-
the 13C NMR spectrum indicated the formation of the tion of 4a, both the hydroamination step and the addition
desired cyanoamine. The TMS-protected cyanoamines 2 of the cyano moiety are high-yielding reactions.
were spectroscopically characterized in situ and isolable
a-cyanoamines 3 were prepared to obtain corroborating
mass spectrometric data. Table 1 demonstrates that the
reaction conditions are amenable to both aliphatic and
aromatic alkynes, as well as amines with different steric
properties. Most importantly, these reactions work well
with benzyl amine, a challenging aliphatic amine sub-
strate for alkyne hydroamination.11 This benzyl group is a
desirable substituent due to the fact that it can be used as
a protecting group for the amine functionality.
TMS
n-Bu
H
N
Ph
CN
a, b
+
n-Bu
H2N
Ph
2 equiv
2a
c
O
4a
93% yield
F3C
N
Ph
CN
n-Bu
Scheme 2 Synthesis of trifluoroacetate-protected a-cyanoamines.
Reagents and conditions: a) 1 (5 mol%), C6H6, 65 °C, 12 h; b)
TMSCN (1 equiv), r.t., 3 h; c) TFAA (2.5 equiv), 5 min.
Table 1 TMS-Protected Cyanoamines Formed from Tandem
Reaction Sequence (Scheme 1)
Compound Cyanoamine
R1
Yield (%)
a-Cyanoamines are extremely useful as precursors in the
formation of a-amino acids. To demonstrate the utility of
this reaction methodology, a number of a-amino acids
were synthesized by refluxing the a-cyanoamine 3 in
concentrated hydrochloric acid (Scheme 3).
Quant.a
Quant.a
TMS
R1
2a
2b
Bn
i-Pr
N
CN
2c
2d
Bn
i-Pr
90b
89b
TMS
N
R1
R1
H
R1
R
H
a–c
Cl
H2N
d
N
CN
R1
+
R
R
2 equiv
H2N
R1
CO2H
98b
86b
CN
2e
2f
Bn
i-Pr
TMS
3
5
N
5a–f
Ph
CN
Scheme 3 Synthesis of a-amino acids. Reagents and conditions: a)
1 (5 mol%), C6H6, 65 °C, 12 h; b) TMSCN (1 equiv), r.t., 3 h; c) sat.
NH4Cl; d) concd HCl, reflux, 12 h.
a Conversion based on consumption of imine starting material calcu-
lated from 1H NMR spectroscopy.
b Yield calculated by 1H NMR spectroscopy using 2,4,6-trimethoxy-
benzene as an internal standard.
The progress of this reaction was monitored by mass
spectrometry, and the corresponding a-amino acid was
isolated as HCl salt 5 after completion of the reaction in
6–12 hours. Again, this conversion is clean, and only the
presence of the amide proligand and the desired product
are observed by 1H NMR and 13C NMR spectroscopy, us-
ing methanol-d4 as an NMR solvent. Amino acid forma-
tion was further supported by high-resolution mass
spectrometry. Moreover, the amino acid salts can be ob-
tained directly from the TMS-cyanoamines 2 by omitting
the reaction quench with saturated ammonium chloride
and simply heating to reflux in concentrated hydrochloric
acid. This leads to a one-pot synthesis of a-amino acids
from terminal alkynes. The desired products were
obtained in quantitative amounts; though the isolation of
analytically pure materials proved challenging (likely due
to residual water or salts) and thus accurate yield determi-
nations could not be obtained for this step in the reaction
sequence.
The reactions proceed cleanly with no spectroscopically
discernible side products. a-Cyanoamines can be unstable
towards common purification methods such as chroma-
tography,10b and as such, removal of the amide proligand
from the cyanoamine product was problematic. Thus, the
1
yield was determined using H NMR spectroscopy with
an internal standard, and the tandem reaction sequence
was shown to be high yielding over the two steps
(Table 1). It is interesting to note that the use of tert-butyl
amine in the above reaction sequence fails to produce any
a-cyanoamine, even though successful formation of the
imine is observed. Presumably this is due to the over-
whelming steric interactions present between the TMSCN
and the tert-butyl groups.
Though it is known that a-cyanoamines 3 can be unstable,
Jacobsen and co-workers have shown with numerous
examples that treatment of TMS-protected a-cyano-
amines with trifluoroacetic anhydride yield trifluoro-
Synlett 2006, No. 18, 2973–2976 © Thieme Stuttgart · New York

LETTER
Direct Synthesis of a-Amino Acids from Terminal Alkynes
2975
However, if the amino acid–HCl salt was treated with In summary, we report the combination of catalytic hy-
propylene oxide in water and ethanol, the free amino acid droamination with the Strecker reaction to give a high
was formed13 and could be separated from the amide pro- yielding one-pot synthesis of a-cyanoamines from termi-
ligand by precipitation from water (Scheme 4). For exam- nal alkynes. Importantly, terminal alkynes are easily in-
ple, this methodology yielded the zwitterionic species 6a stalled and can be carried through synthetic manipulation
in analytically pure form in modest (<30%) yields.
with ease. Furthermore, the utility of this reaction se-
quence has been demonstrated by the further conversion
of these versatile a-cyanoamines to both a-amino acids
and a-amino esters. This approach yields a-cyanoamines
3 and their a-amino acid derivatives 5 and 7 with a meth-
ylene group a to the tertiary carbon. This spacer is a rare
structural motif for amino acid derivatives synthesized via
other Strecker reaction methods reported. Ongoing inves-
tigations focus on the development of reaction protocols
for the stereoselective preparation of amino acid deriva-
tives.
H
H2N
Ph
CO2
a–e
+
2 equiv H2N
Ph
6a
Scheme 4 Synthesis of free amino acid. Reagents and conditions: a)
1 (5 mol%), C6H6, 65 °C, 12 h; b) TMSCN, r.t., 3 h; c) sat. NH4Cl; d)
concd HCl, reflux, 12 h; e) propylene oxide, EtOH, H2O.
A more generally useful reaction for the quantification of
a-amino acid derivatives is the preparation of the corre-
sponding a-amino methyl esters 7 (Scheme 5). The amino
acid salts were dissolved in acidic methanol (made from
methanol and thionyl chloride) and then heated to reflux.
Formation of the a-amino methyl ester salts was
monitored by mass spectrometry, and the reactions were
complete in 3–5 hours. After removal of the volatile
components, the a-amino methyl esters were obtained by
treatment of the salts with a saturated sodium bicarbonate
solution and extraction into organic solvent. These com-
pounds are amenable to column chromatography and
yield analytically pure product that is free of the amide
proligand in good overall yields for the entire reaction se-
quence (Table 2). Though this reaction sequence can be
performed in one pot, thereby avoiding the isolation of 5,
the isolated yields of the final a-amino methyl esters were
somewhat lower in this case (i.e. 7c was formed in 48%
yield using a one-pot synthesis).
General Method Provided for Trifluoroacetate-Protected
Cyanoamine 4a
An oven-dried Schlenk flask was charged with 0.16 g (2.0 mmol) of
1-hexyne, 0.42 g (3.9 mmol) of benzyl amine, 0.07 g (0.10 mmol)
of 1, and 4 mL of benzene in the glove box. The solution was stirred
at 65 °C for 12 h before it was cooled to r.t. and 0.26 mL (2.0 mmol)
of TMSCN was added via syringe. The solution stirred for a further
3 h and then 0.68 mL (4.9 mmol) of TFAA was added. After stirring
for 5 min, 10 mL of Et2O was added, and the organic phase was
washed with a sat. NaHCO3 solution (4 × 10 mL). The organic por-
tion was dried over MgSO4, and concentrated to a dark brown oil. It
was purified by silica gel column chromatography (3:2 hexanes–
Et2O) and concentrated to provide 4a as a pale yellow oil (0.57 g,
93% yield).
1H NMR (400 MHz, CDCl3): d = 0.82 (t, J = 7.2 Hz, 3 H), 1.23 (m,
5 H), 1.37 (m, 1 H), 1.56 (m, 1 H), 1.75 (m, 1 H), 4.64 (d, J = 16.0
Hz, 1 H), 4.73 (t, J = 6.0 Hz, 1 H), 4.85 (d, J = 16.0 Hz, 1 H), 7.34
(m, 5 H). 13C NMR (100 MHz, CDCl3): d = 14.0, 22.3, 25.6, 30.8,
31.1, 48.9, 51.3, 116.1, 116.3 (q, J = 286 Hz), 128.0, 129.2, 129.4,
133.7, 157.2 (q, J = 37 Hz). MS (ESI): m/z = 335.2 [M + Na].
HRMS (ESI): m/z calcd for C16H19F3N2NaO: 335.1347 [M + Na];
found: 335.1346. Anal. Calcd for C16H19N2OF3: C, 61.53; N, 8.97;
H, 6.13. Found: C, 61.93; N, 9.10, H, 6.35.
ClNH2R1
NHR1
CO2CH3
R
H
e, f
a–d
+
R
R
2 equiv H2N R1
CO2H
5
7
Scheme 5 Synthesis of a-amino methyl esters. Reagents and condi-
tions: a) 1 (5 mol%), C6H6, 65 °C, 12 h; b) TMSCN (1 equiv), r.t., 3 h;
c) sat. NH4Cl; d) concd HCl, reflux, 12 h; e) SOCl2, MeOH, reflux,
5 h; f) sat. NaHCO3.
Free Amino Acid 6a
1H NMR (300 MHz, CD3OD): d = 0.93 (t, J = 6.6 Hz, 3 H), 1.39 (m,
6 H), 1.84 (m, 2 H), 3.50 (t, J = 6.0 Hz, 1 H), 4.12 (d, J = 13.0 Hz,
1 H), 4.24 (d, J = 13.0 Hz, 1 H), 7.48 (m, 5 H). 13C NMR (75 MHz,
CD3OD): d = 14.3, 23.4, 25.9, 31.6, 32.7, 51.7, 63.5, 130.2, 130.6,
131.2, 132.8, 173.3. MS (ESI): m/z = 236.1 [M + 1], 190.1 [M –
CO2H]. Anal. Calcd for C14H21NO2: C, 71.46; N, 5.95; H, 8.99.
Found: C, 71.66; N, 6.19; H, 9.18.
Table 2 Synthesis of Amino Methyl Esters (Scheme 5)
Compound Amino methyl ester
R1
Yield (%)a
NHR1
7a
7b
Bn
i-Pr
58
61
a-Amino Methyl Esters 7
Compound 7a: 58% yield (1:16:1 EtOAc–hexane–Et3N). 1H NMR
(400 MHz, CDCl3): d = 0.86 (t, J = 6.8 Hz, 3 H), 1.29 (m, 6 H), 1.60
(m, 2 H), 1.82 (br s, 1 H), 3.25 (t, J = 6.8 Hz, 1 H), 3.61 (d, J = 13.0
CO2CH3
NHR1
CO2CH3
NHR1
7c
7d
Bn
i-Pr
58
54
Hz, 1 H), 3.70 (s, 3 H), 3.79 (d, J = 13.0 Hz, 1 H), 7.26 (m, 5 H). 13
C
NMR (100 MHz, CDCl3): d = 14.2, 22.6, 25.6, 31.8, 33.7, 51.8,
52.4, 60.9, 127.2, 128.4, 128.5, 140.1, 176.3. MS (ESI): m/z = 272.3
[M + Na], 250.3 [M + H]. HRMS (EI): m/z calcd for C15H23NO2
[M+]: 249.17288; found: 249.17325. Anal. Calcd for C15H23NO2: C,
72.25; N, 5.62; H, 9.30. Found: C, 72.30; N, 6.00; H, 9.00.
7e
7f
Bn
i-Pr
58
69
Ph
CO2CH3
a Isolated yield calculated from terminal alkyne.
Synlett 2006, No. 18, 2973–2976 © Thieme Stuttgart · New York

2976
A. V. Lee, L. L. Schafer
LETTER
Compound 7b: 61% yield (1:16:1 EtOAc–hexane–Et3N). 1H NMR
(400 MHz, CDCl3): d = 0.83 (t, J = 6.4 Hz, 3 H), 0.95 (d, J = 6.0 Hz,
3 H), 0.99 (d, J = 6.0 Hz, 3 H), 1.26 (m, 6 H), 1.54 (m, 3 H), 2.64
References and Notes
(1) For examples of sequential and tandem reaction sequences,
see: (a) Sutton, A. E.; Seigal, B. A.; Finnegan, D. F.;
Snapper, M. L. J. Am. Chem. Soc. 2002, 124, 13390.
(b) Vosburg, D. A.; Vanderwal, C. D.; Sorensen, E. J. J. Am.
Chem. Soc. 2002, 124, 4552. (c) Bressy, C.; Alberico, D.;
Lautens, M. J. Am. Chem. Soc. 2005, 127, 13148. (d) Park,
S.; Kim, M.; Lee, D. J. Am. Chem. Soc. 2005, 127, 9410.
(e) Sarpong, R.; Su, J. T.; Stoltz, B. M. J. Am. Chem. Soc.
2003, 125, 13624. (f) Denmark, S. E.; Thorarensen, A.
Chem. Rev. 1996, 96, 137; and references cited therein.
(2) In addition to numerous articles, a journal Amino Acids has
been dedicated to the subject since 1994.
(3) Selected examples of hydroamination: (a) Tillack, A.;
Khedkar, V.; Jiao, H.; Beller, M. Eur. J. Org. Chem. 2005,
23, 5001. (b) Lutete, L. M.; Kadota, I.; Yamamoto, Y. J. Am.
Chem. Soc. 2004, 126, 1622. (c) Walsh, P. J.; Baranger, A.
M.; Bergman, R. G. J. Am. Chem. Soc. 1992, 114, 1708.
(d) Bytschkov, I.; Doye, S. Eur. J. Org. Chem. 2003, 935.
(e) Hong, S.; Marks, T. J. Acc. Chem. Res. 2004, 39, 673.
(f) Müller, T. E.; Pleier, A. K. J. Chem. Soc., Dalton Trans.
1999, 4, 583. (g) Johns, A. M.; Utsunomiya, M.; Incarvito,
C. D.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 1828.
(h) Kim, H.; Lee, P. H.; Livinghouse, T. Chem. Commun.
2005, 5205. (i) Knight, P. D.; Munslow, I.; O’Shaughnessy,
P. N.; Scott, P. Chem. Commun. 2004, 894. (j) Gribkov, D.
V.; Hultzsch, K. C. Angew. Chem. Int. Ed. 2004, 43, 5542;
and references cited therein.
(sept, J = 6.0 Hz, 1 H), 3.27 (t, J = 6.8 Hz, 1 H), 3.66 (s, 3 H). 13
C
NMR (100 MHz, CDCl3): d = 14.2, 22.2, 22.6, 24.0, 25.6, 31.8,
34.2, 47.2, 51.7, 59.2, 176.8. MS (ESI): m/z = 202.3 [M + H].
HRMS (ESI): m/z calcd for C11H24NO2 [M + H]: 202.1807; found:
202.1809. Anal. Calcd for C11H23NO2·0.5H2O: C, 62.82; N, 6.66, H,
11.50. Found: C, 62.89; N, 7.08; H, 11.27.
Compound 7c: 58% yield (1:15:1 EtOAc–hexane–Et3N).14 1H NMR
(300 MHz, CDCl3): d = 1.85 (br s, 1 H), 2.95 (d, J = 7.1 Hz, 2 H),
3.53 (t, J = 6.9 Hz, 1 H), 3.62 (d, J = 13.0 Hz, 1 H), 3.63 (s, 3 H),
3.80 (d, J = 13.0 Hz, 1 H), 7.20 (m, 10 H). 13C NMR (100 MHz,
CDCl3): d = 39.8, 51.6, 52.0, 62.1, 126.7, 127.0, 128.2, 128.3,
128.4, 129.3, 137.4, 139.7, 175.0. MS (ESI): m/z = 270.3 [M + H].
Compound 7d: 54% yield (1:17:1 EtOAc–hexane–Et3N).14 1H
NMR (300 MHz, CDCl3): d = 0.93 (d, J = 6.2 Hz, 3 H), 0.99 (d,
J = 6.2 Hz, 3 H), 1.60 (br s, 1 H), 2.68 (sept, J = 6.2 Hz, 1 H), 2.88
(m, 2 H) 3.57 (m, 4 H), 7.19 (m, 5 H). 13C NMR (100 MHz, CDCl3):
d = 21.9, 23.6, 40.0, 47.1, 51.5, 60.6, 126.6, 128.3, 129.1, 137.2,
175.4. MS (ESI): m/z = 244.2 [M + Na], 222.3 [M + H].
Compound 7e: 58% yield (1:10:1 EtOAc–hexane–Et3N). 1H NMR
(400 MHz, CDCl3): d = 1.97 (br s, 1 H), 2.05 (m, 2 H), 2.82 (m, 2
H), 3.37 (t, J = 6.6 Hz, 1 H), 3.71 (d, J = 13.0 Hz, 1 H), 3.76 (s, 3
H), 3.91 (d, J = 13.0 Hz, 1 H), 7.34 (m, 10 H). 13C NMR (100 MHz,
CDCl3): d = 32.0, 35.0, 51.6, 52.1, 60.0, 125.9, 127.0, 128.3, 128.4,
128.5, 139.4, 141.4, 175.7. MS (ESI): m/z = 306.1 [M + Na], 284.2
[M + H]. HRMS (ESI): m/z calcd for C18H22NO2 [M + H]:
284.1651; found: 284.1649. Anal. Calcd for C18H21NO2: C, 76.29;
N, 4.94; H, 7.47. Found: C, 76.43; N, 5.00; H, 7.56.
(4) Li, C.; Thomson, R. K.; Gillon, B.; Patrick, B. O.; Schafer,
L. L. Chem. Commun. 2003, 2462.
(5) Zhang, Z.; Schafer, L. L. Org. Lett. 2003, 5, 4733.
(6) Other catalyst systems reported to perform anti-
Markovnikov hydroamination: (a) Heutling, A.; Pohlki, F.;
Doye, S. Chem. Eur. J. 2004, 10, 3059. (b) Tillack, A.;
Castro, I. G.; Hartung, C. G.; Beller, M. Angew. Chem. Int.
Ed. 2002, 41, 2541. (c) Cao, C.; Shi, Y.; Odom, A. L. Org.
Lett. 2002, 4, 2853. (d) Tillack, A.; Khedkar, V.; Beller, M.
Tetrahedron Lett. 2004, 45, 8875.
Compound 7f: 69% yield (1:10:1 EtOAc–hexane–Et3N). 1H NMR
(400 MHz, CDCl3): d = 0.96 (d, J = 6.0 Hz, 3 H), 1.02 (d, J = 6.4
Hz, 3 H), 1.55 (br s, 1 H), 1.88 (m, 2 H), 2.67 (m, 3 H), 3.30 (t,
J = 6.8 Hz, 1 H), 3.65 (s, 3 H), 7.18 (m, 5 H). 13C NMR (100 MHz,
CDCl3): d = 22.1, 23.8, 32.0, 35.5, 47.0, 51.5, 58.3, 125.9, 128.3,
128.4, 141.4, 176.4. MS (ESI): m/z = 258.3 [M + Na], 236.3 [M +
H]. HRMS (ESI): m/z calcd for C14H22NO2 [M + H]: 236.1651;
found: 236.1651. Anal. Calcd for C14H21NO2: C, 71.46; N, 5.95; H,
8.99. Found: C, 71.47; N, 6.00; H, 9.00.
(7) Kita, M.; Kondo, M.; Koyama, T.; Yamada, K.; Matsumoto,
T.; Lee, K.-H.; Woo, J.-T.; Uemura, D. J. Am. Chem. Soc.
2004, 126, 4794.
(8) Castro, I. G.; Tillack, A.; Hartung, C. G.; Beller, M.
Tetrahedron Lett. 2003, 44, 3217.
Acknowledgment
(9) Enders, D.; Shilvock, J. P. Chem. Soc. Rev. 2000, 29, 359.
(10) (a) Groger, H. Chem. Rev. 2003, 103, 2795. (b) Yet, L.
Angew. Chem. Int. Ed. 2001, 40, 875. (c) Spino, C. Angew.
Chem. Int. Ed. 2004, 43, 1764. (d) Ooi, T.; Uematsu, Y.;
Maruoka, K. J. Am. Chem. Soc. 2006, 128, 2548; and
references cited therein.
The authors thank UBC and NSERC for funding. A.V.L. thanks
NSERC for a graduate fellowship, and Zhe Zhang for catalyst
development.
(11) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem. Int. Ed.
1999, 38, 3389.
(12) Sigman, M. S.; Vachal, P.; Jacobsen, E. N. Angew. Chem.
Int. Ed. 2000, 39, 1279.
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