Redox-neutral synthesis of β-amino aldehydes from imines by an alkynylation/hydration sequence

Article abstract of DOI:10.1021/jo070745o

(Chemical Equation Presented) N-Protected β-amino aldehydes have been prepared starting from imines through a sequence involving a Zn-mediated direct alkynylation followed by a Ru-catalyzed anti-Markovnikov alkyne hydration. The rate and the efficiency of

Full text of DOI:10.1021/jo070745o

Redox-Neutral Synthesis of â-Amino Aldehydes from Imines by an
Alkynylation/Hydration Sequence
Aure´lie Labonne, Lorenzo Zani, Lukas Hintermann,* and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen UniVersity, Landoltweg 1, D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de; lukas.hintermann@oc.rwth-aachen.de
ReceiVed April 14, 2007
N-Protected â-amino aldehydes have been prepared starting from imines through a sequence involving
a Zn-mediated direct alkynylation followed by a Ru-catalyzed anti-Markovnikov alkyne hydration. The
rate and the efficiency of the latter reaction are enhanced by the use of microwave irradiation. The
possibility to carry out a one-pot Ru-catalyzed hydration/oxidation process from a terminal alkyne to a
carboxylic acid was demonstrated, which provided direct access to a N-protected â-amino acid from the
corresponding terminal alkyne.
Introduction
the carboxylic group to the aldehyde6 (often carried out after
conversion into the corresponding Weinreb amide7) or on the
homologation of N-protected R-amino acid derivatives, followed
also in this case by a reduction step.4a,c,8 Furthermore, synthetic
routes have been described which feature the conjugate addition
of nitrogen nucleophiles to R,â-unsaturated aldehydes or amides
as the key step.4a,d,9,10 Recently, the first organocatalytic
enantioselective Mannich reactions between imines and unmodi-
fied aldehydes as donors have been reported, which afforded
â-amino aldehydes with high enantiomeric excess in a single
step.11,12
â-Amino carbonyl compounds are useful building blocks for
the synthesis of complex bioactive molecules1 and can be used
as precursors of important classes of substances, such as â-amino
acids2 and 1,3-amino alcohols.3 In addition, the â-amino
carbonyl functional motif is found in several natural products.2
Within this class of compounds, â-amino aldehydes are
particularly valuable because of the versatility of the formyl
group, which can be easily reduced or oxidized and can react
with many nucleophiles. On the other hand, access to â-amino
aldehydes can be difficult, mostly because of the instability of
these compounds under the conditions used for their preparation.
In particular, â-amino aldehydes are known to undergo polym-
erization, self-condensation, or elimination of the â-amino
group.4
(4) For reports on this behavior, in the context of different synthetic
approaches, see: (a) Chesney, A.; Marko´, I. E. Synth. Commun. 1990, 20,
3167. (b) Marko´, I. E.; Chesney, A. Synlett 1992, 275. (c) Toujas, J.-L.;
Jost, E.; Vaultier, M. Bull. Chim. Soc. Fr. 1997, 134, 713. (d) Burke, A. J.;
Davies, S. G.; Garner, A. C.; McCarthy, T. D.; Roberts, P. M.; Smith, A.
D.; Rodriguez-Solla, H.; Vickers, R. J. Org. Biomol. Chem. 2004, 2, 1387.
(5) For pioneering studies, see: (a) Mannich, C.; Krosche, W. Arch.
Pharm. (Weinheim, Ger.) 1913, 250, 647. (b) Mannich, C.; Lesser, B.; Silten,
F. Chem. Ber. 1932, 65, 378.
To date, the most common approaches used for the synthesis
of â-amino aldehydes are based either on a Mannich reaction5
between an imine and an ester with subsequent reduction of
(6) See, for example: (a) Davis, F. A.; Szewczyk, J. M. Tetrahedron
Lett. 1998, 39, 5951. For a synthesis based on an aza-Mannich reaction,
see: (b) Hou, X.-L.; Luo, Y.-M.; Yuan, K.; Dai, L.-X. J. Chem. Soc., Perkin
Trans. 1 2002, 1487.
(7) (a) Davis, F. A.; Nolt, M. B.; Wu, Y.; Prasad, K. R.; Li, D.; Yang,
B.; Bowen, K.; Lee, S. H.; Eardley, J. H. J. Org. Chem. 2005, 70, 2184.
(b) Davis, F. A.; Song, M.; Augustine, A. J. Org. Chem. 2006, 71, 2779.
(8) (a) Rodriguez, M.; Aumelas, A.; Martinez, J. Tetrahedron Lett. 1990,
31, 5153. (b) Rodriguez, M.; Heitz, A.; Martinez, J. Tetrahedron Lett. 1990,
31, 7319. (c) Davies, S. B.; McKervey, M. A. Tetrahedron Lett. 1999, 40,
1229. (d) Toujas, J.-L.; Toupet, L.; Vaultier, M. Tetrahedron 2000, 56,
2665.
* To whom the correspondence should be addressed. Fax: +49-241-8092391.
Phone: +49-241-8094675.
(1) (a) Kleinman, E. F. In ComprehensiVe Organic Synthesis; Heathcock,
C. H., Ed.; Pergamon Press: Oxford, U.K., 1991; Vol. 2, Chapter 4, p 893.
(b) Arend, M.; Westermann, B.; Risch, N. Angew. Chem., Int. Ed. 1998,
37, 1044.
(2) For reviews, see: (a) Juaristi, E. EnantioselectiVe Synthesis of
â-Amino Acids; Wiley-VCH: New York, 1997. (b) Liu, M.; Sibi, M. P.
Tetrahedron 2002, 58, 7991.
(3) For reviews, see: (a) Bates, R. W.; Sa-Ei, K. Tetrahedron 2002, 58,
5957. (b) Lait, S. M.; Rankic, D. A.; Keay, B. A. Chem. ReV. 2007, 107,
767.
(9) Davies, S. G.; McCarthy, T. D. Synlett 1995, 700.
10.1021/jo070745o CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/27/2007
5704
J. Org. Chem. 2007, 72, 5704-5708

Synthesis of â-Amino Aldehydes from Imines
TABLE 1. ZnMe2-Mediated Synthesis of Propargylic Amines and
Subsequent Desilylation (from 2 to 4 in Scheme 1)
Following our interest in the field of organozinc additions to
carbon-heteroatom double bonds,13 we recently developed the
first dimethylzinc-mediated direct alkynylation of imines,
providing access to a large array of N-substituted propargylic
amines.14,15 In addition, highly active in situ catalysts for the
Ru-catalyzed anti-Markovnikov hydration of terminal alkynes
have been introduced, which allow the straightforward conver-
sion of functionalized acetylenes into the corresponding
aldehydes.16-19
yield of
yield of
entry
substrate
R
PG
3a,b (%)
4b,c (%)
1
2
3
4
5
6
7
8
9
2a
2b
2c
2d
2e
2f
2g
2h
2i
Ph
Ph
4-MePh
4-MeOPh
2-BrPh
2-Naphthyl
2-Furyl
c-Hex
Ts
P(O)Ph2
Ts
Ts
Ts
Ts
Ts
Ts
Ts
60
78
81
76
77
70
61
74
81
0
85
55
90
79
94
41
85
90
99
We anticipated that addition of (trimethylsilyl)acetylene (1)
to N-protected imines 2, followed by removal of the silyl group,
could be used to generate terminal secondary propargylic amines
4, which might be directly converted to â-amino aldehydes by
means of the catalytic hydration reaction, avoiding a wasteful
reduction/oxidation sequence. Herein, we report the results of
our studies concerning the aforementioned synthetic route
(Scheme 1). To the best of our knowledge, this is the first time
that â-amino aldehydes have been generated from imines by
such an alkynylation/hydration sequence.20 In addition, the first
Ru-catalyzed anti-Markovnikov hydration of terminal alkynes
under microwave irradiation will be described, as well as a Ru-
catalyzed one-pot hydration/oxidation protocol for the direct
conversion of propargylic amines into â-amino acids.
t-Bu
(E)-PhCHdCH
10
2j
Ts
a Conditions: Imines 2a-j were added under argon to a mixture of
ZnMe2 and 1 (2.5 equiv each) in toluene. The reaction mixture was stirred
for 24 h at 70 °C. For a general procedure, see the Supporting Information.
b After column chromatography. c Conditions: A mixture of compounds
3a-i and 0.33 equiv of TBAF in THF was stirred for 30 min at 0 °C. For
a general procedure, see the Supporting Information.
SCHEME 1. Synthesis of â-Amino Aldehydes by Means of
an Alkynylation/Anti-Markovnikov Hydration Sequence
(10) For syntheses based on alternative approaches, see: (a) Birkofer,
L.; Erlenbach, L. Chem. Ber. 1958, 91, 2383. (b) Birkofer, L.; Frankus, E.
Chem. Ber. 1961, 94, 216. (c) Aben, R. W. M.; Smit, R.; Scheeren, J. W.
J. Org. Chem. 1987, 52, 365. (d) Clive, D. L. J.; Yu, M.; Li, Z. Chem.
Commun. 2005, 906.
(11) (a) Co´rdova, A.; Watanabe, S.; Tanaka, F.; Notz, W.; Barbas, C.
F., III. J. Am. Chem. Soc. 2002, 124, 1866. (b) Co´rdova, A.; Barbas, C. F.,
III. Tetrahedron Lett. 2002, 43, 7749. (c) Hayashi, Y.; Tsuboi, W.; Ashimine,
I.; Urushima, T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42,
3677. (d) Kano, T.; Yamaguchi, Y.; Tokuda, O.; Maruoka, K. J. Am. Chem.
Soc. 2005, 127, 16048. (e) Ibrahem, I.; Co´rdova, A. Chem. Comun. 2006,
1760. (f) Chi, Y.; Gellman, S. H. J. Am. Chem. Soc. 2006, 128, 6804. (g)
Vesely, J.; Rios, R.; Ibrahem, I.; Co´rdova, A. Tetrahedron Lett. 2007, 48,
421. (h) For a comprehensive review on the direct catalytic asymmetric
Mannich reaction, see: Co´rdova, A. Acc. Chem. Res. 2004, 37, 102.
(12) For organocatalytic enantioselective conjugate additions of nitrogen
nucleophiles to R,â- unsaturated aldehydes, see: (a) Chen, Y. K.; Yoshida,
M.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 9328. (b) Ibrahem,
I.; Rios, R.; Vesely, J.; Zhao, G.-L.; Co´rdova, A. Chem. Commun. 2007,
849. (c) Dine´r, P.; Nielsen, M.; Marigo, M.; Jørgensen, K. A. Angew. Chem.,
Int. Ed. 2007, 46, 1983. (d) Vesely, J.; Ibrahem, I.; Rios, R.; Zhao, G.-L.;
Xu, Y.; Co´rdova, A. Tetrahedron Lett. 2007, 48, 2193.
(13) Selected references: (a) Bolm, C.; Rudolph, J. J. Am. Chem. Soc.
2002, 124, 14850. (b) Hermanns, N.; Dahmen, S.; Bolm, C.; Bra¨se, S.
Angew. Chem., Int. Ed. 2002, 41, 3692. (c) Cozzi, P. G.; Rudolph, J.; Bolm,
C.; Norrby, P.-O.; Tomasini, C. J. Org. Chem. 2005, 70, 5733.
(14) (a) Zani, L.; Alesi, S.; Cozzi, P. G.; Bolm, C. J. Org. Chem. 2006,
71, 1558. (b) Zani, L.; Eichhorn, T.; Bolm, C. Chem.sEur. J. 2007, 13,
2587.
Results and Discussion
Initially, we focused our attention on the conversion of various
N-protected imines 2a-j into acetylenes 3. This transformation
was effected by reacting the substrates with 2.5 equiv of a
mixture of dimethylzinc and (trimethylsilyl)ethyne (1) in toluene
at 70 °C for 24 h. Desilylation of the resulting 1-trimethylsilyl-
substituted alkynes 3 by treatment with a substoichiometric
quantity of tetrabutylammonium fluoride in THF at 0 °C yielded
propargylamines 4 (Table 1). Although some of the compounds
presented in Table 1 had already been known, except for 4a14a
none of them had been prepared via direct alkynylation of the
corresponding imine prior to this study.
The alkynylation of aromatic N-sulfonyl and N-phosphinoyl
aldimines 2a-g proceeded smoothly (entries 1-7), affording
the resulting N-protected amines 3a-g in 61-81% yield.
Noteworthy, imines 2h-i bearing R-branched alkyl groups such
as cyclohexyl or tert-butyl were also good substrates for the
reaction (entries 8 and 9).21 Unfortunately, the N-tosylimine
derived from (E)-cinnamic aldehyde 2j failed to provide the
desired product, but gave a complex mixture.
(15) For a review on the metal-mediated alkynylation of imines, see:
Zani, L.; Bolm, C. Chem. Commun. 2006, 4267.
(16) Selected references: (a) Tokunaga, M.; Wakatsuki, Y. Angew.
Chem., Int. Ed. 1998, 37, 2867. (b) Suzuki, T.; Tokunaga, M.; Wakatsuki,
Y. Org. Lett. 2001, 3, 735. (c) Grotjahn, D. B.; Lev, D. A. J. Am. Chem.
Soc. 2004, 126, 12232. (d) Grotjahn, D. B. Chem.sEur. J. 2005, 11, 7146.
(e) Chevallier, F.; Breit, B. Angew. Chem., Int. Ed. 2006, 45, 1599.
(17) For a general review on the catalytic hydration of alkynes, see:
Hintermann, L.; Labonne, A. Synthesis 2007, 1121.
(18) (a) Labonne, A.; Kribber, T.; Hintermann, L. Org. Lett. 2006, 8,
5853. (b) Kribber, T.; Labonne, A.; Hintermann, L. Synthesis, in press.
(19) A related Cu-catalyzed anti-Markovnikov addition of an N-tosyl
azide to acetylenes yielding â-functionalized protected amides has recently
been described: Cho, S. H.; Chang, S. Angew. Chem., Int. Ed. 2007, 46,
1897.
Upon treatment with TBAF, all TMS-protected alkynes 3a-i
afforded the desired terminal acetylenes 4a-i, generally with
satisfactory yields (79-99%). Only compounds 3b and 3f
(20) Isolated reports on the conversion of a primary homopropargylic
sulfonamide, as well as a propargylic amide and an imide, can be found in
refs 16c and 16e, respectively.
(21) As reported in ref 14a, imines derived from linear aliphatic aldehydes
are not suitable for the alkynylation reaction with phenylacetylene under
analogous conditions.
J. Org. Chem, Vol. 72, No. 15, 2007 5705

Labonne et al.
TABLE 3. Ruthenium-Catalyzed Hydration of Alkynes 4 under
MW Irradiationa
[Ru]
(mol %)
P (W)/
T (°C)
time
(min)
yield of
entry
substrate
5b (%)
1
2
3
4
5
6
7
8
9
4c
4c
4c
4c
4e
4f
4g
4h
4i
75/120
50/90
50/90
75/120
75/100
75/115
50/90
75/100
75/100
120
5
0
10
5
2.5
5
5
10
5
92
94
traces
79
76
88
92
73
30
120
15
20
30
30
15
5
a Conditions: as described in footnote a of Table 2; use of L3 (2 equiv)
under MW irradiation. For a general procedure, see the Supporting
Information. b After column chromatography.
FIGURE 1. Amine 4k and catalyst precursors used in this study.
TABLE 2. Ruthenium-Catalyzed Anti-Markovnikov Hydration of
Alkynes 4a
and the corresponding terminal aldehydes were afforded in high
yields (83-92%). Unfortunately, although alkyne 4b bearing
the diphenylphosphinoyl protecting group was completely
converted under standard reaction conditions, it failed to provide
the expected product 5b (entry 2). N,N-Dibenzylpropargylamine
4k did not react at all and was recovered unchanged even after
more than 5 days (entry 11). Interestingly, use of only 5 mol %
ruthenium catalyst still allowed protected â-amino aldehydes
to be obtained in moderate to good yields (48-78%, entries
12-14). However, under those conditions the reaction time had
to be prolonged substantially (g40 h).
[Ru]
(mol %)
time
(h)
yield of
entry
substrate
ligand
L2
L1 or L2
L2
L2
L2
5b (%)
1
2
3
4
5
4a
4b
4c
4d
4e
4f
10
10
10
10
10
10
10
10
10
10
10
5
17
>130
83
ndc
83
83
84
85
90
91
85
92
0
29
15
17
19
22
15
20
12
6
L3
7
8
9
10
11
12
13
14
4g
4h
4i
L1
L1
L2
L3
L1 or L2
L2
L2
4i
4k
4a
4d
4i
>130
Although the current protocol for the catalytic hydration
reaction led to â-amino aldehydes in high yields, it still required
heating of the reaction mixture at 55 °C for a prolonged time.
Microwave (MW) irradiaton is known to be a useful tool for
shortening reaction times, and often it improves efficiencies of
thermally induced reactions.24 We therefore decided to examine
its effect on the Ru-catalyzed anti-Markovnikov alkyne hydra-
tion, employing complex 6 and phosphine L3 as catalyst
precursors. To the best of our knowledge, this is the first time
that such a reaction has been performed under MW irradiation.
The results obtained are presented in Table 3.
90
40
90
48
78
77
5
5
L2
a Conditions: The catalyst was generated from L1-3 (10 or 20 mol %)
and 6 (5 or 10 mol %) in MeCN for 0.5-6 h at 60 °C followed by
evaporation. Hydration of the substrates was carried out with water (5 equiv)
in acetone under argon. For a general procedure, see the Supporting
Information. b After column chromatography. c Not determined. The sub-
strate was completely converted, but did not provide the desired compound.
furnished the corresponding products with diminished yields
of 55% and 41%, respectively (entries 2 and 6).
First, it was ensured that in the absence of the catalyst no
hydration occurred and that the reaction was not induced by
simple MW irradiation (entry 1). To our delight, in the presence
of 10 mol % catalyst a very fast reaction was observed, and
starting from 4c the expected product was formed after only 5
min in high yield. Reducing the catalyst loading to 5 mol %
required a longer reaction time (30 min), but led to ap-
proximately the same yield of 5c (entry 3). Use of less catalyst
proved inefficient. Under the above conditions, various N-
tosylpropargylamines afforded the corresponding aldehydes in
good to high yields (73-92%), often requiring a smaller amount
of catalyst in comparison with that of the thermal reaction.
Noteworthy, the reaction time never exceeded 30 min (entries
4-9).
To assess the use of a compound bearing a Lewis basic
nitrogen atom in the following hydration reaction, the known
terminal propargylamine 4k, having two benzyl groups on the
nitrogen, was prepared according to a procedure reported by
Knochel (Figure 1).22
With compounds 4a-i,k in hand, we next turned our attention
to the Ru-catalyzed anti-Markovnikov hydration reaction (Scheme
1). According to our previously published protocol,18a the
catalysts were generated in situ by mixing the air-stable
precursor [CpRu(η6-naphthalene)]PF6 (6) with 2 equiv of a
23
6-substituted 2-(diphenylphosphino)pyridine (L1, L2, or L3;
Figure 1).
The results obtained in the hydration reaction, using L1-3
as ligands, are presented in Table 2. Noteworthy, all aldehydes
were solids which could be easily purified by standard flash
column chromatography on silica gel. Moreover, they could be
stored for several weeks at room temperature without decom-
position, an observation in sharp contrast with the previously
reported instability of various other â-amino aldehydes.4
All substrates bearing a N-tosyl group reacted smoothly under
the influence of the ruthenium catalyst (entries 1 and 3-10),
Having found a reliable procedure for the transformation of
N-tosyl alkynes 4 into the corresponding aldehydes 5, we next
explored ways to further elaborate the latter compounds. Guided
by various protocols for the oxidation of aldehydes into
carboxylic acids using RuCl3 as a catalyst in the presence of a
(24) (a) MicrowaVes in Organic Synthesis; Loupy, A., Ed.; Wiley-
VCH: Weinheim, Germany, 2002. (b) Kappe, C. O.; Stadler, A. MicrowaVes
in Organic and Medicinal Chemistry; Wiley-VCH: Weinheim, Germany,
2005.
(22) Gommermann, N.; Knochel, P. Tetrahedron 2005, 61, 11418.
(23) Ku¨ndig, E. P.; Monnier, F. R. AdV. Synth. Catal. 2004, 346, 901.
5706 J. Org. Chem., Vol. 72, No. 15, 2007

Synthesis of â-Amino Aldehydes from Imines
stoichiometric oxidant,25 we were intrigued by the possibility
of directly converting amines 4 into â-amino acids by means
of a Ru-catalyzed one-pot hydration/oxidation procedure. Proof-
of-principle was demonstrated by the hydration of propargy-
lamine 4i with the L3/Ru catalyst under standard conditions,
followed by replacement of acetone with the typical MeCN/
CCl4/H2O solvent mixture for the oxidation and addition of
sodium periodate, which led to the formation of â-amino acid
7 in good yield (eq 1).
as a solid, which was purified by flash column chromatography
and/or by recrystallization (see the Supporting Information for
details).
N-(p-Toluensulfonyl)-3-amino-3-phenyl-1-(trimethylsilyl)-
prop-1-yne (3a). 3a was purified by flash column chromatography
(ethyl acetate/n-pentane, 1:6): yield 0.429 g (1.20 mmol, 60%);
1
colorless solid; mp 139-140 °C; H NMR (CDCl3, 300 MHz) δ
0.04 (s, 9H), 2.43 (s, 3H), 4.86 (d, J ) 9.2 Hz, 1H), 5.34 (d, J )
9.2 Hz, 1H), 7.25-7.36 (m, 5H), 7.45-7.52 (m, 2H), 7.76-7.82
(m, 2H); 13C NMR (CDCl3, 75 MHz) δ -0.3, 21.6, 49.7, 91.6,
101.4, 127.2, 127.4, 128.3, 128.5, 129.5, 137.2, 137.3, 143.3; MS
(EI, 70 eV) m/z ) 356 [M - 1]+, 260, 234, 218, 202 [M - Ts]+,
159, 91.
Typical Procedure for the Desilylation Reaction of Amines
3a-i. In an oven-dried Schlenk flask under an inert atmosphere of
argon, a solution of the appropriate 1-(trimethylsilyl)propargylamine
3 (1.00-1.56 mmol) in dry THF (5.0-7.8 mL) was prepared. The
resulting clear solution was cooled to 0 °C with an ice bath, and a
1.0 M solution of tetrabutylammonium fluoride in THF (0.33-
0.52 mL, 0.33-0.52 mmol, 0.33 equiv) was added dropwise during
ca. 1 min. The reaction mixture was stirred at 0 °C for 30 min, and
the reaction was subsequently quenched with 20 mL of water. The
aqueous layer was washed with Et2O (3 × 25 mL), and the
combined organic layers were dried over Na2SO4. Removal of the
solvent by rotary evaporation afforded crude terminal alkynes 4a-
i, which were subsequently purified by flash column chromato-
graphy (see the Supporting Information for details).
Conclusion
In conclusion, we have described the synthesis of N-protected
â-amino aldehydes by a novel alkynylation/hydration strategy.
Key steps are the ZnMe2-mediated addition of 1 to aryl and
alkyl imines and, after desilylation of the resulting propargy-
lamines, a Ru-catalyzed anti-Markovnikov hydration reaction.
The latter process could be conducted under MW irradiation,
leading to a shortening of the reaction times from several hours
to minutes. Furthermore, a novel one-pot hydration/oxidation
process has been developed, which warrants direct access to
â-amino acid 7 from terminal alkyne 4i in good overall yield.
N-(p-Toluensulfonyl)-1-amino-1-phenylprop-2-yne (4a). 4a
was prepared from 3a (0.358 g, 1.0 mmol) and purified by flash
column chromatography (ethyl acetate/n-pentane, 1:6): yield
1
0.240 g (0.85 mmol, 85%); colorless solid; mp 129-130 °C; H
NMR (CDCl3, 400 MHz) δ 2.32 (dd, J ) 2.5, 0.8 Hz, 1H), 2.43
(s, 3H), 4.97 (d, J ) 8.8 Hz, 1H), 5.32 (dd, J ) 8.7, 2.1 Hz, 1H),
7.26-7.36 (m, 5H), 7.42-7.49 (m, 2H), 7.74-7.81 (m, 2H); 13C
NMR (CDCl3, 100 MHz) δ 21.6, 49.0, 74.7, 80.4, 127.1, 127.4,
128.4, 128.6, 129.4, 136.8, 137.1, 143.5; IR (KBr) 3253, 2923,
2862, 1598, 1493, 1435, 1325, 1159, 1093, 1042 cm-1; MS (EI,
70 eV) m/z ) 260 [M - C2H]+, 220, 194 [M - C7H7]+, 155 [Ts]+,
130 [M - Ts]+, 115 [M - C7H8NO2S]+, 91 [C7H7]+, 77 [C6H5]+.
Anal. Calcd for C16H15NO2S: C, 67.34; H, 5.30; N, 4.91. Found:
C, 67.34; H, 5.29; N, 4.94.
General Procedure for the Anti-Markovnikov Hydration of
Propargylic Amines 4a-i under Thermal Conditions. Under an
inert atmosphere of argon, a flame-dried Schlenk flask was charged
with 6 (5-10 mol %), a pyridylphosphane ligand, L (10-20 mol
%, 2.0 equiv relative to 6), and degassed CH3CN (1 mL/10 mg of
6). The mixture was heated to 60 °C for 1-6 h (1 h for L1, 6 h for
L2 and L3), and then the solvent was removed in vacuo to afford
a yellow powder or resin. A solution of the appropriate propargylic
amide 4 and water (5.0 equiv relative to 6) in acetone (1-4 mL/
mmol of substrate) was subsequently added, and the resulting
mixture was heated at 55-60 °C. After completion of the reaction
(15-90 h, according to TLC), the solution was allowed to cool to
room temperature, and tert-butylmethyl ether (10 mL) was added.
The organic layer was washed with water (10 mL) and brine
(10 mL) and dried over Na2SO4. The solvent was then removed
under vacuum to afford the crude aldehydes 5a,c-i, which were
purified by flash column chromatography (see the Supporting
Information for details).
Experimental Section
Aromatic N-tosyl imines 2a,c-g were prepared using a modified
version of the method reported by Kim and co-workers,26 employing
1,2-dichloroethane as the solvent instead of CH2Cl2 and heating at
reflux for 48 h instead of 12 h. N-Tosyl imine N-benzylidenediphe-
nylphosphinamide (2b) was prepared according to the procedure
reported by Jennings and Lovely27 using an extended reaction time
of 16 h. N-Tosyl imines derived respectively from cyclohexane-
carbaldehyde (2h)28 and 2,2-dimethylpropanal (2i)29 were prepared
following literature procedures. The N-tosylimine derived from (E)-
cinnamic aldehyde was prepared according to the method described
by Masquelin and Obrecht.30 N,N-Dibenzylpropargylamine 4k was
prepared following the procedure described by Gommermann and
Knochel.22
Typical Procedure for the Addition of 1 to Imines 2a-j. In
an oven-dried Schlenk flask under an inert atmosphere of argon, 1
(0.491 g, 5.0 mmol, 2.5 equiv) was dissolved in anhydrous toluene
(17.5 mL). A 2.0 M solution of dimethylzinc in toluene (2.5 mL,
5.0 mmol, 2.5 equiv) was then carefully added, and the resulting
mixture was stirred at room temperature for 30 min. The appropriate
imine 2 (2.0 mmol) was then added in one portion, and the
temperature was increased to 70 °C. The resulting solution was
then stirred for 24 h, after which a white precipitate appeared in
some cases. The reaction was allowed to cool to rt, and it was
quenched with water (40 mL). The aqueous phase was extracted
with CH2Cl2 (3 × 40 mL), and the organic phase was washed with
brine (100 mL) and dried over MgSO4. Evaporation of the solvent
under reduced pressure furnished the crude product 3a-i typically
General Procedure for the Anti-Markovnikov Hydration of
Propargylic Amines 4 under Microwave Irradiation. Under an
inert atmosphere of argon, a flame-dried vial was placed in a
Schlenk flask. The vial was charged with 6 (5-10 mol %),
pyridylphosphane L3 (10-20 mol %, 2.0 equiv relative to 6), and
degassed CH3CN (1 mL/10 mg of 6), and the in situ catalyst was
generated as described above. After removal of the solvent, a
solution of the adequate propargylic amine 4 and water (5.0 equiv
relative to 6) in acetone (1-4 mL/mmol of substrate) was
(25) Desrosiers, J. N.; Cote´, A.; Charette, A. B. Tetrahedron 2005, 61,
6186.
(26) Lee, K. Y.; Lee, C. G.; Kim, J. N. Tetrahedron Lett. 2003, 44, 1231.
(27) Jennings, W. B.; Lovely, C. J. Tetrahedron 1991, 47, 5568.
(28) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 75.
(29) Shim, J.-G.; Yamamoto, Y. Heterocycles 2000, 52, 885.
(30) Masquelin, T.; Obrecht, D. Synthesis 1995, 276.
J. Org. Chem, Vol. 72, No. 15, 2007 5707

Labonne et al.
subsequently added. The vial was sealed with a septum, removed
from the Schlenk flask, and placed in the cavity of the microwave
reactor, which was then locked with the pressure device. The
microwave source was then turned on. Constant microwave
irradiation of 50-75 W as well as simultaneous air cooling (1.4-
4.0 bar, 20-58 psi) was used during the entire reaction time (5-
30 min), so that the temperature was kept at 90-120 °C. After
cooling to room temperature, the products were isolated as described
above for the thermal reaction.
N-Tosyl-1-amino-1-phenylpropanal (5a). 5a was prepared from
propargylic amine 4a (0.120 g, 0.42 mmol) and purified by flash
column chromatography (ethyl acetate/n-pentane, 1:2): yield
0.075 g (0.247 mmol, 83%); light orange solid; mp 88-89 °C; 1H
NMR (CDCl3, 400 MHz) δ 2.37 (s, 3H), 2.88-2.97 (m, 1H, A
part of an AB system), 3.00-3.09 (m, 1H, B part of an AB system),
4.80 (q, J ) 6.9 Hz, 1H), 5.47 (br s, 1H), 7.04-7.11 (m, 2H),
7.14-7.21 (m, 5H), 7.56-7.62 (m, 2H), 9.63 (br s, 1H); 13C NMR
(CDCl3, 100 MHz) δ 21.5, 50.1, 53.2, 126.4, 127.0, 127.8, 128.6,
129.4, 136.9, 139.1, 143.3, 199.4; IR (KBr) 3520, 3254, 3051, 2823,
1727, 1598, 1455, 1315, 1159, 1082 cm-1; MS (CI, CH4, 70 eV)
m/z ) 304 [M + 1]+, 260 [M - C2H3O]+, 200, 172, 155 [Ts]+,
148 [M - Ts]+, 133 [M - C7H8NO2S]+, 104, 91 [C7H7]+. Anal.
Calcd for C16H17NO3S: C, 63.34; H, 5.65; N, 4.62. Found: C,
63.42; H, 5.83; N, 4.62.
One-Pot Anti-Markovnikov Hydration/Oxidation of Prop-
argylic Amine 4i. Under an inert atmosphere of argon, a flame-
dried Schlenk flask was charged with 6 (10 mol %), pyridylphos-
phane L3 (20 mol %, 2.0 equiv relative to 6), and degassed CH3CN
(1 mL/10 mg of 6). The mixture was heated to 60 °C for 6 h, and
the solvent was then removed in vacuo to afford a yellow powder.
A solution of propargylic amide 4i (1 equiv) and water (5.0 equiv
relative to 6) in acetone (1 mL/0.1 mmol of substrate) was
subsequently added, and the resulting mixture was heated at
55 °C. After completion of the reaction (17 h, according to TLC),
the solution was allowed to cool to rt. Evaporation of the solvent
under reduced pressure furnished crude aldehyde 5i, which was
successively dissolved in a MeCN/CCl4/H2O (2:2:4) mixture. NaIO4
(99%, 4 equiv relative to 4i) was then added in one portion, and
the resulting solution was stirred for 15 h at room temperature.
The solvent was evaporated and the residue taken up in water. After
acidification to pH 2 with 2 N HCl, the aqueous layer was extracted
with Et2O. The combined organic layers were washed with brine
and dried over Na2SO4. The solvent was then removed under
vacuum to afford crude â-amino acid 7, which was purified by
flash column chromatography (silica gel).
N-Tosyl-1-amino-1-(2-tert-butyl)propanoic Acid (7). 7 was
prepared from propargylic amine 4i (40 mg, 0.15 mmol) and
purified by flash column chromatography (ethyl acetate/n-pentane/
acetic acid, 80:20:1): yield 32 mg (0.11 mmol, 72%); white solid;
1
mp 169 °C; H NMR (CDCl3, 300 MHz) δ 0.86 (s, 9 H), 2.35-
2.39 (m, 2 H, AB system), 2.41 (s, 3 H), 3.43 (dt, J ) 9.6, 5.4 Hz,
1 H), 5.26 (d, J ) 9.4 Hz, 1 H), 7.28 (dd, J ) 8.6, 0.7 Hz, 2 H),
7.76 (dt, J ) 8.1, 1.7 Hz, 2 H); 13C NMR (CDCl3, 75 MHz) δ
21.5, 26.4, 35.3, 58.9, 127.1, 127.6, 129.6, 137.7, 143.4, 177.0; IR
(KBr) 3276, 2971, 1716, 1447, 1314, 1150, 1087 cm-1; MS (EI,
70 eV) m/z ) 300 [M+], 242 [M - C2H3O]+, 224 [M - C4H9]+,
198, 155 [Ts]+, 91 [C7H7]+. Anal. Calcd for C14H21NO4S: C, 56.16;
H, 7.07; N, 4.68. Found: C, 56.09; H, 7.17; N, 4.60.
Acknowledgment. We are grateful to the Fonds der Che-
mischen Industrie and the Deutsche Forschungsgemeinschaft
(DFG) for financial support (Emmy Noether-Programm for
L.H.).
Supporting Information Available: General experimental
procedures, analytical data of compounds 3a-i, complete charac-
1
terization of compounds 4a-i, 5a,c-i, and 7, and H NMR and
13C NMR spectra of compounds 3a-i, 4a-i, 5a,c-i, and 7. This
materialisavailablefreeofchargeviatheInternetathttp://pubs.acs.org.
JO070745O
5708 J. Org. Chem., Vol. 72, No. 15, 2007