Synthesis of α-amino amides via N,O-acetals derived from Weinreb amides

Article abstract of DOI:10.1021/jo9015166

(Chemical Equation Presented) An easy and straightforward synthesis of α-amino amides via a base-mediated rearrangement of modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenylation, or alkynylation of this intermediate affords the corresponding R-amino amides in excellent yields. Furthermore, a more generalized protocol for the α-arylation of Weinreb amides lacking an R-amino moiety is also discussed.

Full text of DOI:10.1021/jo9015166

pubs.acs.org/joc
Synthesis of r-Amino Amides via N,O-Acetals Derived from
Weinreb Amides
Sebastian Hirner† and Peter Somfai*,†,‡
†Organic Chemistry, KTH Chemical Science and Engineering, SE-100 44 Stockholm, Sweden, and
‡Institute of Technology, University of Tartu, Nooruse 1, 50411 Tartu, Estonia
somfai@kth.se
Received July 15, 2009
An easy and straightforward synthesis of R-amino amides via a base-mediated rearrangement of
modified Weinreb amides into N,O-acetals is presented. Subsequent arylation, alkylation, alkenyla-
tion, or alkynylation of this intermediate affords the corresponding R-amino amides in excellent
yields. Furthermore, a more generalized protocol for the R-arylation of Weinreb amides lacking an
R-amino moiety is also discussed.
Introduction
are not generally applicable. For example, the synthesis of
arylglycines,3 vinylglycines,4 and alkynylglycines5 is still a
challenging task in organic synthesis, and the development of
a general, environmentally friendly and economically rea-
sonable protocol for their preparation remains elusive. Aryl-
glycines, especially, are of broad interest in organic synthesis
due to their prevalence in biologically significant targets.
This includes commercial blockbusters like the antiplatelet
agent clopidogrel (6)6 as well as several drugs from the WHO
list of essential medicines, such as the antibiotics amoxicillin
and vancomycin.7
The synthesis of nonproteinogenic and unnatural R-amino
acids has attracted much attention as these compounds both
provide access to new drug candidates and act as valuable
biological probes.1 As a result, the development of new
methods for their synthesis has been a field of active research
for many years and several versatile and excellent techniques
have been developed.2 However, for the synthesis of several
important subsets of amino acids, standard methods, such as
phase-transfer catalyzed alkylation of glycine derivatives,2c-e
Recently, we developed a new method for the R-arylation
of glycine equivalent 1 with Grignard reagents, affording
R-amino amides 2 in high yields, which can easily be con-
verted into the corresponding free amino acid (Scheme 1).8,9
During our studies on this reaction, we observed a re-
markable enhancement of yield when the base was added at
0 °C instead of -78 °C for some substrates. Reinvestigation
of the reaction revealed that this effect is caused by the inter-
mediate formation of glyoxylic N,O-acetals. These reactive
(1) For examples, see: (a) Hicks, R. P.; Bhonsle, J. B.; Venugopal, D.;
Koser, B. W.; Magill, A. J. J. Med. Chem. 2007, 50, 3026–3036. (b) Wang,
J. Y.; Xie, J. M.; Schultz, P. G. J. Am. Chem. Soc. 2006, 128, 8738–8739.
(c) Jain, R.; Chawrai, S. Mini-Rev. Med. Chem. 2005, 5, 469–477.
(2) For recent reviews on the synthesis of R-amino acids, see: (a) Perdih,
A.; Dolenc, M. S. Curr. Org. Chem. 2007, 11, 801–832. (b) Najera, C.;
Sansano, J. M. Chem. Rev. 2007, 107, 4584–4671. (c) O’Donnell, M. J. Acc.
Chem. Res. 2004, 37, 506–517. (d) Lygo, B.; Andrews, B. I. Acc. Chem. Res.
2004, 37, 518–525. (e) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013–
3028.
(3) For leading references on the synthesis of arylglycines, see: (a) Lee,
E. C.; Fu, G. C. J. Am. Chem. Soc. 2007, 129, 12066–12067. (b) Shang, G.;
Yang, Q.; Zhang, X. Angew. Chem., Int. Ed. 2006, 45, 6360–6362.
(c) Williams, R. M.; Hendrix, J. A. Chem. Rev. 1992, 92, 889–917.
(4) For a recent review, see: (a) Berkowitz, D. B.; Charette, B. D.;
Karukurichi, K. R.; McFadden, J. M. Tetrahedron: Asymmetry 2006, 17, 869-
882. For recent examples on the synthesis of vinylglycines, see: (b) Armstrong,
A.; Challinor, L.; Moir, J. H. Angew. Chem., Int. Ed. 2007, 46, 5369–5372.
(c) Wolfer, J.; Bekele, T.; Abraham, C. J.; Dogo-Isonagie, C.; Lectka, T. Angew.
Chem., Int. Ed. 2006, 45, 7398–7400. (d) Alexander, P. A.; Marsden, S. P.; Subtil,
D. M. M.; Reader, J. C. Org. Lett. 2005, 7, 5433–5436.
(6) (a) Coukell, A. J.; Markham, A. Drugs 1997, 54, 745-750. For a recent
synthesis of clopidogrel, see: (b) Wang, L. X.; Shen, J. F.; Tang, Y.; Chen, Y.;
Wang, W.; Cai, Z. G.; Du, Z. J. Org. Process Res. Dev. 2007, 11, 487–489.
(7) WHO model list of essential medicines, 15th list; World Health
Organization: Geneva, Switzerland, 2007. http://www.who.int/medicines/
publications/EML15.pdf
(8) (a) Hirner, S.; Kirchner, D. K.; Somfai, P. Eur. J. Org. Chem. 2008,
5583–5589. (b) Hirner, S.; Panknin, O.; Edefuhr, M.; Somfai, P. Angew.
Chem., Int. Ed. 2008, 47, 1907–1909.
(5) For leadingreferencesonthe synthesis ofalkynylglycines, see: (a) Shao,
Z. H.; Chan, A. S. C. Synthesis 2008, 2868–2870. (b) Ji, J. X.; Au-Yeung, T. L.;
Wu, J.; Yip, C. W.; Chan, A. S. C. Adv. Synth Catal. 2004, 346, 42–44.
(c) Meffre, P.; LeGoffic, F. Amino Acids 1996, 11, 313–328.
(9) For a recent review on Weinreb amides, see: Balasubramaniam, S.;
Aidhen, I. S. Synthesis 2008, 3707-3738.
7798 J. Org. Chem. 2009, 74, 7798–7803
Published on Web 09/16/2009
DOI: 10.1021/jo9015166
r
2009 American Chemical Society

Hirner and Somfai
JOCArticle
TABLE 1. Base-Promoted Rearrangement of Weinreb Amidesa
SCHEME 1. Synthesis of Arylglycines from Weinreb Amides
compounds represent valuable glycine cation equivalents
and have previously been used for the synthesis of R-amino
esters.10,11 Herein, we describe an improved protocol for the
synthesis of R-amino amides 2, which is based on the
quantitative generation of N,O-acetals from 1. Moreover,
we were intrigued to investigate if an analogous reaction
could be developed for substrates lacking an R-amino moi-
ety, and these initial results will be discussed.
Results and Discussion
Our investigations commenced with quenching experi-
ments, in which the reaction of Weinreb amide 1a with
LDA was terminated by the addition of water. When LDA
was added at -78 °C, followed by quenching at the same
temperature, only starting material was recovered (Table 1,
entry 1). When the reaction was carried out at 0 °C and
quenched after 60 min, the starting material was completely
consumed, and N,O-acetal 3a was formed as the main
product (entry 2), presumably formed via a base-promoted
N f C migration of the tert-butoxy group.12,13 However, all
attempts to purify 3a by standard methods failed, probably
due to the sensitive nature of the N,O-acetal moiety. To
circumvent purification and to reduce the formation of
byproducts, a significantly milder base was employed. In-
deed, with LHMDS full conversion was achieved after only
30 min, and quantitative yields of 3a could be isolated after
simple filtration (entry 3). Also Weinreb amide 1b (entry 4)
and chiral substrate 1c (entry 5) afforded quantitative yields
of the corresponding N,O-acetals. Notably, for the more
bulky substrate 1c a prolonged reaction time (2 h) was
necessary in order to achieve full conversion, and the product
was obtained as a mixture of diastereomers (dr=1:1.6). The
same kind of rearrangement took place when the amino
moiety was replaced by an R-hydroxy substituent. In this
case, the corresponding O,O-acetal 5a was formed in excel-
lent yield (entry 6).
aReaction conditions: 1 (0.20 mmol), base (0.24 mmol), THF (2 mL).
bIsolated yield. c“Quant“ means: 1H NMR purity of the crude product
>95%; mass balance >99%. dStarting material recovered. eYield
determined by 1H NMR of the crude product. fdr = 1:1.6, determined
by 1H NMR of the crude product.
the same reaction conditions. However, rearranged product
5b was not obtained when employing either LHMDS (entry 7)
or LDA (entry 8), and only starting material could be recov-
ered. To increase the reactivity, we next exchanged the phenyl
substituent for a 4-methoxyphenyl group, envisioning that any
positive charge formed during the elimination of t-BuO- would
be stabilized by a strong electron-donating substituent. Indeed,
stirring Weinreb amide 4c with LHMDS for 6 h at 0 °C
afforded the desired product 5c, albeit in poor yield along with
unreacted starting material (entry 10). Increasing the reaction
temperature resulted in full conversion, but the yield was only
slightly improved, and many unidentified byproducts were
formed (entry 11).
Synthesis of r-Amino Amides from N,O-Acetal 3. With an
easy and high-yielding procedure for the synthesis of N,O-
acetals in hand, their potential as versatile glycine cation
equivalents was studied next. Due to the delicate nature
of these substrates, it was planned to generate them in situ
prior to the addition of a nucleophile. Thus, when 1a was
treated with LHMDS for 30 min at 0 °C, followed by
addition of PhMgCl at -78 °C, complete conversion was
achieved and amide 2a could be isolated in 96% yield
(Table 2, entry 1).
On the basis of these results, we were intrigued to deter-
mine if substrates lacking an R-heteroatom would show
similar rearrangement upon treatment with a base, and
substrate 4b with an R-phenyl substituent was tested under
(10) (a) Sakai, N.; Asano, J.; Shimano, Y.; Onakahara, T. Tetrahedron
2008, 64, 9208–9215. (b) Bourhis, M.; Bosc, J. J.; Golse, R. J. Organomet.
€
Chem. 1983, 256, 193–201. (c) Gloede, J.; Freiberg, J.; Burger, W.; Ollmann,
G.; Gross, H. Arch. Pharm. 1969, 302, 354. (d) Gross, H.; Gloede, J.;
Freiberg, J. Liebigs Ann. Chem. 1967, 702, 68.
(11) For a review on glyoxylates as building blocks for the synthesis of
R-amino acids, see: Meester, W. J. N.; van Maarseveen, J. H.; Schoemaker,
H. E.; Hiemstra, H.; Rutjes, F. Eur. J. Org. Chem. 2003, 2519-2529.
(12) The same type of rearrangement has been reported previously, see:
Alberola, A.; Ortega, A. G.; Sadaba, M. L.; Sanudo, C. Tetrahedron 1999,
55, 6555-6566.
(13) For a related rearrangement of N-alkyl-O-acyl hydroxamic acids,
see: (a) Clark, A. J.; Al-Faiyz, Y. S. S.; Patel, D.; Broadhurst, M. J.
Tetrahedron Lett. 2001, 42, 2007–2009. (b) Clark, A. J.; Al-Faiyz, Y. S. S.;
Broadhurst, M. J.; Patel, D.; Peacock, J. L. J. Chem. Soc., Perkin Trans. 1
2000, 7, 1117–1127.
Somewhat surprisingly, when Weinreb amide 1b was used
instead, the desired product was only isolated in moderate
yields (entry 2) together with unreacted N,O-acetal 3b. The
bis(allyl)-protected amide 1d gave excellent yields whereas
in the reaction of the bis(benzyl)-protected substrate 1e
some byproducts were formed (entries 3 and 4, respectively).
Since the possibility to use orthogonal nitrogen protecting
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JOCArticle
TABLE 2. Synthesis of R-Amino Amides 2a
TABLE 3. Asymmetric Synthesis of R-Amino Amidesa
aReaction conditions: 1c (0.20 mmol), LHMDS (0.24 mmol), RM
(0.3 mmol), THF (2 mL). bCombined isolated yield of diastereomers.
c“Quant“ means: 1H NMR purity of the crude product >95%; mass
balance >99%. ddr determined by 1H NMR of the crude product. eThe
reaction was performed on a 8.15 mmol scale.
Diastereoselective Synthesis. With these results at hand,
we decided to investigate the stereoselective synthesis of
R-substituted glycine derivatives. Toward this end, subject-
ing 1c to LHMDS for 2 h at 0 °C, followed by addition of
PhMgCl at -78 °C, afforded compound 2m in excellent
yield, but in poor dr (Table 3, entry 1).
However, when PhZnCl was used instead, the selectivity was
significantly enhanced, and amide 2m was obtained in 93%
yield as a 8:1 mixture of diastereomers (entry 2).14 It should be
noted that the dr obtained in these reactions does not corre-
spond to the one obtained for the formation of 3c (Table 1,
entry 5), indicating that an iminium ion is formed upon the
addition of the nucleophile. Similar yields and selectivities were
also obtained for electron-rich (entry 3) and electron-poor
arylzinc reagents (entry 4), whereas only moderate selectivity
was obtained with alkenyl- and alkynylzinc reagents (entries 5
and 6). By using (2-ClC6H4)ZnCl as a nucleophile, amide 2r
could be synthesized in good yield and selectivity on gram scale
(entry 7). On the basis of this intermediate, a total synthesis of
clopidogrel (6) is currently under investigation and will be
presented in due course (Figure 1).
aReaction conditions: 1 (0.10 mmol), LHMDS (0.12 mmol), RM
(0.20 mmol), THF (2 mL). bIsolated yields. c“Quant“ means: 1H NMR
purity of the crude product >95%; mass balance >99%. dThe reaction
was performed on a 0.20 mmol scale. eThe reaction was performed on a
2.5 mmol scale.
groups enhances the synthetic utility of this transformation
significantly, we focused our efforts on substrate 1a. Screen-
ing of different Grignard reagents showed that electron-rich
(entry 5), electron-poor (entry 6), and functionalized hetero-
aromatic arylgrignards (entry 7) gave excellent yields under
the selected reaction conditions. In addition, it was found
that the use of alkyl- (entries 8 and 9), alkenyl- (entry 10), and
alkynyl- (entry 11) Grignard reagents also afforded the
corresponding R-amino amides in quantitative yields. For
several products no purification by column chromatography
was needed and quantitative amounts of the analytically
pure material could be obtained by simple filtration through
silica (entries 6 and 9-11).
r-Arylation of Weinreb Amides. As an extension of this
methodology, we envisioned that Weinreb amides without
an R-amino group would likewise represent suitable sub-
strates for the R-arylation with Grignard reagents. The pro-
ducts formed in such a reaction, R-aryl carboxylic acid deri-
(14) All products were isolated as diasteromeric mixtures. The absolute
configuration of 2m was assigned previously (ref 8), and all other products
were assigned by analogy to that compound.
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Hirner and Somfai
JOCArticle
were formed, the main product being the corresponding O,O-
and S,O-acetal, respectively (entries 5 and 6).
Conclusions
In summary, we have demonstrated that Weinreb amides
easily can undergo a base-promoted rearrangement, effect-
ing migration of the N-alkoxy group to the R-carbon. On the
basis of this reaction we have developed a simple and high-
yielding synthesis of R-amino amides from readily available
starting materials. As an extension of this procedure, we
have also shown that modified Weinreb amides without an
R-amino group can undergo R-arylation with Grignard
reagents.
FIGURE 1. Intended use of amide 2p for the synthesis of clopido-
grel (6).
TABLE 4. R-Arylation of Weinreb Amidesa
Experimental Section
General Procedure A: Rearrangement of Weinreb Amides to N,
O-Acetals. To a solution of Weinreb amide 1 (0.20 mmol) in
2 mL of dry THF was added LHMDS (1.0 M in THF, 0.24 mL,
0.24 mmol) at 0 °C and the resulting mixture was stirred for the
indicated reaction time (Table 1). The reaction was quenched by
addition of one drop of water, diluted with Et2O (10 mL), and
filtered over cotton. The solvent was removed under reduced
pressure to give 3 as a colorless oil, which rapidly decomposes in
the presence of moisture.
2-(N-Allyl-N-benzylamino)-2-tert-butoxy-N-methylacetamide
(3a). Prepared according the general procedure A with Weinreb
amide 1a (58.1 mg, 0.20 mmol). Yield 58.0 mg (99%), colorless
oil. 1H NMR (500 MHz, CDCl3) δ 7.24-6.92 (m, 6H), 6.54 (br s,
1H), 5.64 (m, 1H), 4.91 (m, 2H), 4.39 (s, 1H), 3.59 (s, 2H), 3.06
(m, 2H), 2.61 (d, J = 5.0 Hz, 3H), 0.97 (s, 9H) ppm; 13C NMR
(126 MHz, CDCl3) δ 171.7, 139.5, 136.6, 129.0, 128.1, 126.7,
117.2, 83.5, 75.0, 53.2, 52.1, 28.6, 25.3 ppm.
2-(N-Allyl-N-benzylamino)-2-methoxy-N-methylacetamide (3b).
Prepared according the general procedure A with Weinreb amide
1b (49.7 mg, 0.20 mmol). Yield 49.3 mg (99%), colorless oil. 1H
NMR (500 MHz, CDCl3) δ 7.35-7.14 (m, 5H), 6.57 (br s, 1H),
5.79 (m, 1H), 5.11 (m, 2H), 4.22 (s, 1H), 3.77 (m, 2H), 3.31 (s, 3H),
3.24 (m, 2H), 2.76 (d, J=5.0 Hz, 3H) ppm; 13C NMR (126 MHz,
CDCl3) δ 170.3, 139.2, 136.1, 128.9, 128.1, 126.9, 117.5, 90.1, 55.7,
53.3, 52.3, 25.3 ppm.
2-(N-Allyl-N-((S)-1-phenylethyl)amino)-2-tert-butoxy-N-methyl-
acetamide (3c). Prepared according the general procedure A with
Weinreb amide 1c (60.1 mg, 0.20 mmol). Yield 61.5 mg (quant),
colorlessoil. 1H NMR (1.6:1 diastereomericratio, asteriskdenotes
minor diastereomer peaks, 500 MHz, CDCl3) δ 7.46-7.12 (m,
5H), 6.82 (br, 1H), 5.80 (m, 1H), 5.24-4.92 (m, 2H), 4.71* (s, 1H),
4.66 (s, 1H), 4.18 (m, 1H), 3.43* (m, 1H), 3.25 (m, 1H), 3.20-3.08
(m, 1H), 2.80* (d, J=5.0 Hz, 3H), 2.78 (d, J=5.0 Hz, 3H), 1.45
(d, J=6.7Hz, 3H), 1.39* (d, J=6.8 Hz, 3H), 1.18 (s, 9H), 1.17* (s,
4H) ppm; 13C NMR (126 MHz, CDCl3) δ 172.7*, 172.2, 145.4*,
144.5, 137.6, 137.7*, 128.0*, 127.9, 127.7, 127.6*, 126.4, 116.3,
116.0*, 84.1, 82.5*, 74.*, 74.3, 57.3*, 56.0, 49.1*, 47.7, 28.6*, 28.6,
25.6, 25.5*, 19.8*, 18.2 ppm.
PhMgX
(equiv)
yield of
7:5b ratio 7,c %
entry
4
R
solvent
1
2
3
4
5
6
c
c
b
d
a
e
4-MeOC6H4 THF
4-MeOC6H4 tol
PhMgCl (2)
1:1
4:1
42
67
40
56
34
29
PhMgBr (7.5)
PhMgBr (7.5)
PhMgBr (7.5)
PhMgBr (7.5)
PhMgBr (7.5)
Ph
Me
BnO
PhS
tol
tol
tol
tol
n.d.
n.d.
1:2
1:3
aReaction conditions: 4 (0.20 mmol), LDA (0.24 mmol), solvent
(2 mL). bRatio determined by 1H NMR of the crude product. cIsolated
yield.
vatives, represent highly valuable building blocks in
organic synthesis and are prevalent in important natural
products and drugs, such as atropine, naproxen, and ibu-
profen.
We started our investigations with amide 4c, speculating
that the electron-rich 4-methoxyphenyl substituent not only
activates the substrate to migration of the N-alkoxy group,
but also would facilitate R-arylation. To avoid the irrever-
sible formation of 5c prior to the addition of the Grignard
reagent, the reaction was performed in analogy to our
previously reported arylation method, using a strong base
at low temperatures (Scheme 1). Thus, when 4c was treated
with LDA and PhMgCl at -78 °C and warmed to room
temperature, full conversion was achieved within 30 min,
and the desired product 7c was isolated in 42% yield along
with equimolar amounts of the migration product 5c. No-
tably, the same reaction gives only traces of 5c when no
Grignard reagent is added. This indicates that PhMgCl not
only acts as a nucleophile but also strongly enhances the
reactivity of the Weinreb amide. The exact mechanism for
this surprising activation has not been clarified yet and is
currently under investigation. To suppress the undesired
formation of 5c, the reaction conditions were optimized:
switching from THF to toluene and using an excess of
concentrated PhMgBr (3 M in Et2O) increased both the yield
and selectivity, and 7c could be isolated in 67% yield
(Table 4, entry 2). Using these optimized conditions, a
selection of Weinreb amides was next screened. Gratifyingly,
both substrates bearing nonactivated aryl (entry 3) and alkyl
(entry 4) groups gave the desired arylated product in mode-
rate yield and without detectable migration of the tert-butoxy
group. However, with R-heteroatom-substituted Weinreb
amides 5d and 5e, only minor amounts of the arylated amides
2-tert-Butoxy-2-(benzyloxy)-N-methylacetamide (5a). To a
cooled (0 °C) solution of Weinreb amide 4a (0.20 mmol, 50.3 mg)
in 2 mL of dry THF was added LHMDS (1.0 M in THF, 0.24
mmol, 0.24 mL) and the resulting mixture was stirred for 30 min at
0 °C. The reaction was quenched by addition of water (2 mL), the
phases were separated, and the aqueous phase was extracted with
Et2O (3 ꢀ 5 mL). The combined organic phases were dried
(K2CO3) and concentrated under reduced pressure to give acetal
1
5a (46.3 mg, 92%) as a white solid: mp 98-100 °C; H NMR
(500MHz, CDCl3) δ7.43-7.26 (m, 5H), 6.65 (br, 1H), 5.13 (s, 1H),
4.63 (d, J=11.1 Hz, 1H), 4.52 (d, J=11.1 Hz, 1H), 2.86 (d, J=
4.9 Hz, 3H), 1.30 (s, 9H) ppm; 13C NMR (126 MHz, CDCl3) δ
J. Org. Chem. Vol. 74, No. 20, 2009 7801

Hirner and Somfai
JOCArticle
169.4, 137.5, 128.2, 127.9, 127.5, 93.7, 76.2, 66.9, 28.5, 25.6 ppm;
IR (film) νmax 3375, 2981, 1670, 1527, 1041 cm-1; HRMS (ESIþ)
calcd for C14H22NO3 [M þ H]þ m/z 252.15942, found 252.15958.
2-tert-Butoxy-2-(4-methoxyphenyl)-N-methylacetamide (5c).
To a cooled (0 °C) solution of Weinreb amide 4c (0.2 mmol,
50.3 mg) in 2 mL of dry THF was added LHMDS (1.0 M in
THF, 0.24 mmol, 0.24 mL) and the resulting mixture was stirred
for 6 h at room temperature. The reaction was quenched by
addition of water (10 mL) and EtOAc (10 mL), the phases were
separated, and the aqueous phase was extracted with EtOAc
(3 ꢀ 5 mL). The combined organic phases were dried (MgSO4)
and concentrated under reduced pressure. The residue was
purified by flash chromatography (pentane, EtOAc 5f60%)
The combined organic layers were dried (K2CO3) and concen-
trated under reduced pressure to give the crude product.
Preparation of the zinc reagent: To the indicated Grignard
reagent was added a solution of ZnCl2 in THF at 0 °C, and the
resulting mixture was stirred for 30 min at room temperature.
2-(N-Allyl-N-((S)-1-phenylethyl)amino)-2-(4-methoxyphenyl)-
N-methylacetamide (2n). Prepared according the general proce-
dure C. The zinc reagent was freshly prepared from 4-MeO-
C6H4MgBr (0.5 M, 0.6 mL, 0.30 mmol) and ZnCl2 (1.0 M in
THF, 0.30 mL, 0.30 mmol). Flash chromatography (pentane þ
1% i-PrNH2, EtOAc 5f40%) of the crude product gave 2n
(64.3 mg, 95%) as a colorless oil: 1H NMR (6:1 diastereomeric
ratio, asterisk denotes minor diastereomer peaks, 500 MHz,
CDCl3) δ 7.40-7.20 (m, 7H), 6.97 (m, 1H), 6.86 (m, 2H), 6.79*
(m, 2H), 5.71-5.56 (m, 1H), 5.10-4.96 (m, 2H), 4.41 (s, 1H),
4.10 (q, J=6.9 Hz, 1H), 4.03* (q, J=6.9 Hz, 1H), 3.80 (s, 3H),
3.78* (s, 3H), 3.29 (m, 1H), 3.12 (m, 1H), 3.03* (m, 1H), 2.88* (d,
J=4.9 Hz, 3H), 2.75 (d, J=4.9 Hz, 3H), 1.41* (d, J=6.9 Hz,
3H), 1.17 (d, J=6.9, 3H) ppm; 13C NMR (126 MHz, CDCl3) δ
173.3*, 173.1, 159.1, 158.9*, 143.6, 143.2*, 138.0*, 137.2, 130.8*,
130.6, 129.2, 128.5*, 128.4*, 128.3, 127.5*, 127.5, 127.2*, 126.9,
116.6, 116.0*, 113.7, 113.5*, 68.4, 67.4*, 58.8*, 57.3, 55.15,
55.12*, 51.3*, 51.0, 25.9*, 25.7, 19.5*, 15.1 ppm; HRMS
(ESIþ) calcd for C21H27N2O2 [M þ H]þ m/z 339.20670, found
339.20676.
2-(N-Allyl-N-((S)-1-phenylethyl)amino)-2-(4-fluorophenyl)-
N-methylacetamide (2o). Prepared according the general proce-
dure C with Weinreb amide 1c (60.9 mg, 0.20 mmol). The zinc
reagent was freshly prepared from 4-FC6H4MgBr (1.0 M, 0.30 mL,
0.30 mmol) and ZnCl2 (1.0 M in THF, 0.30 mL, 0.30 mmol). Flash
chromatography (pentane þ 1% i-PrNH2, EtOAc 5f40%) of the
crude product gave 2o (58.5 mg, 90%) as a colorless oil: 1H NMR
(4:1 diastereomeric ratio, asterisk denotes minor diastereomer
peaks, 500 MHz, CDCl3) δ 7.33-7.11 (m, 7H), 6.97-6.81 (m,
3H), 5.63-5.49 (m, 1H), 5.03-4.90 (m, 2H), 4.35 (s, 1H), 4.00 (q,
J = 6.9 Hz, 1H), 3.93* (q, J = 6.9 Hz, 1H), 3.25-3.16 (m, 1H),
3.10-3.01 (m, 1H), 2.95* (m, 1H), 2.79* (d, J=5.0 Hz, 3H), 2.65
(d, J=5.0 Hz, 3H), 1.32* (d, J=6.9 Hz, 3H), 1.06 (d, J=6.9 Hz,
3H) ppm; 13C NMR (126 MHz, CDCl3) δ 172.9*, 172.6, 162.3
(d, J = 247 Hz), 162.1* (d, J = 247 Hz), 143.4, 143.0*, 137.6*,
137.0, 133.0 (d, J=3.1 Hz), 132.1* (d, J=3.2 Hz), 131.4* (d, J=
8.0 Hz), 131.2 (d, J=8.0 Hz), 128.6*, 128.4, 127.5, 127.4*, 127.3,
127.1*, 116.9, 116.3*, 115.2 (d, J=21 Hz), 114.9* (d, J=21 Hz),
67.8, 66.9*, 58.8*, 57.5, 51.4*, 50.9, 26.0*, 25.8, 19.4*, 15.5 ppm;
HRMS (ESIþ) calcd for C20H24FN2O [M þ H]þ m/z 327.18672,
found 327.18643.
1
to give 5c (7.2 mg) as a pale yellow oil: H NMR (500 MHz,
CDCl3) δ 7.38 (m, 2H), 6.85 (m, 2H), 6.81 (br s, 1H), 4.89 (s, 1H),
3.78 (s, 3H), 2.81 (d, J = 5.0 Hz, 3H), 1.22 (s, 9H) ppm; 13C
NMR (126 MHz, CDCl3) δ 173.3, 159.1, 132.3, 127.5, 113.6,
76.0, 74.2, 55.2, 28.2, 25.8 ppm; IR (film) νmax 3352, 2970, 1666,
1512, 1173 cm-1; HRMS (ESIþ) calcd for C14H22NO3 [M þ
H]þ m/z 252.15942, found 252.15932.
General Procedure B: Synthesis of r-Amino Amides with
Grignard Reagents. To a solution of Weinreb amide 1 (0.10 mmol)
in 2 mL of dry THF was added LHMDS (1.0 M in THF, 0.12 mL,
0.12 mmol) at 0 °C. The resulting mixture was stirred for 30 min
at 0 °C before it was cooled to -78 °C and the Grignard reagent
(0.20 mmol) was added. The reaction was allowed to reach room
temperature, quenched by the addition of water (0.10 mL), diluted
with Et2O (10 mL), and filtered. The solvent was removed under
reduced pressure to give the crude product.
2-(Diallylamino)-2-(4-methoxyphenyl)-N-methylacetamide (2f).
Prepared according the general procedure B with Weinreb amide
1d (48.0 mg, 0.20 mmol), LHMDS (1.0 M in THF, 0.24 mL,
0.24 mmol), and 4-MeOC6H4MgBr (0.5 M in THF, 0.40 mmol,
0.80 mL). Flash chromatography (pentane þ 1% i-PrNH2,
EtOAc 5f40%) of the crude product gave 2f as a colorless oil
1
(51.9 mg, 95%): H NMR (500 MHz, CDCl3) δ 7.28-7.22 (m,
1H), 7.18 (m, 2H), 6.87 (m, 2H), 5.80 (m, 2H), 5.23-5.12 (m, 4H),
4.35 (s, 1H), 3.80 (s, 3H), 3.22 (m, 2H), 2.87 (d, J=4.8 Hz, 3H),
2.85-2.80 (m, 2H) ppm; 13C NMR (126 MHz, CDCl3) δ 172.6,
159.0, 134.8, 130.6, 127.1, 117.9, 113.5, 68.8, 55.0, 53.1, 25.8 ppm;
IR (film) νmax 3309, 2935, 1658, 1510, 1250 cm-1; HRMS (ESIþ)
calcd for C16H23N2O2 [M þ H]þ m/z 275.17540, found 275.17523.
2-(N-Allyl-N-benzylamino)-N-methyl-4-(trimethylsilyl)but-
3-ynamide (2l). Prepared according the general procedure B with
Weinreb amide 1a (29.0 mg, 0.10 mmol). The Grignard reagent
was freshly prepared from ethynyltrimethylsilane (19.6 mg,
General Procedure D: r-Arylation of Weinreb Amides. To a
solution of Weinreb amide 5 (0.20 mmol) in 1 mL of dry toluene
was added LHMDS (1.0 M in THF, 1.0 mL, 0.24 mmol) at
-78 °C. Then, PhMgBr (3.0 M in Et2O, 0.5 mL, 1.5 mmol) was
added dropwise, and the resulting mixture was allowed to warm
to room temperature. The reaction was quenched by the addi-
tion of water (5 mL) and extracted with EtOAc (3 ꢀ 10 mL). The
combined organic layers were dried (MgSO4) and concentrated
under reduced pressure to give the crude product.
2-(Benzyloxy)-N-methyl-2-phenylacetamide (7a). Prepared
according the general procedure D with Weinreb amide 4a
(50.3 mg, 0.20 mmol). To destroy the formed byproduct 5a,
which cannot be removed by flash chromatography, the crude
product was dissolved in THF (3 mL) and HCl (1 M in H2O,
3 mL) and stirred for 3 h at 60 °C. The solvent was removed
under reduced pressure, and the residue was purified by flash
chromatography (pentane, EtOAc 5f60%) to give 7a as a
colorless oil (17.2 mg, 34%). 1H NMR (500 MHz, CDCl3)
δ 7.51-7.28 (m, 10H), 6.81 (br s, 1H), 4.84 (s, 1H), 4.57 (d,
J=11.5 Hz, 1H), 4.44 (d, J=11.5 Hz, 1H), 2.83 (d, J=5.0 Hz,
3H) ppm; 13C NMR (126 MHz, CDCl3) δ 171.0, 137.1,
137.0, 128.5, 128.4, 128.1, 128.0, 127.1, 81.3, 71.1, 25.7 ppm;
0.20 mmol) and i-PrMgCl LiCl (1.0 M in THF, 0.20 mL,
3
1
0.20 mmol).15 Yield 31.2 mg (quant), colorless oil. H NMR
(500 MHz, CDCl3) δ 7.34-7.17 (m, 5H), 6.90 (br, 1H), 5.79
(m, 1H), 5.24 (m, 1H), 5.15 (m, 1H), 4.12 (s, 1H), 3.77 (d, J =
13.5 Hz, 1H), 3.36 (d, J = 13.5 Hz, 1H), 3.16 (m, 1H), 2.96
(m, 1H), 2.73 (d, J =5.0 Hz, 3H), 0.18 (s, 9H) ppm; 13C NMR
(126 MHz, CDCl3) δ 168.5, 138.0, 135.0, 128.9, 128.5, 127.5,
118.4, 97.4, 92.7, 58.2, 55.7, 54.7, 26.2, 0.1 ppm; IR (film) νmax
3552, 2958, 2168, 1974, 1520 cm-1; HRMS (ESIþ) calcd for
C18H27N2OSi [M þ H]þ m/z 315.18872, found 315.18854.
General Procedure C: Stereoselective Synthesis of r-Amino
Amides with Zinc Reagents. To a solution of Weinreb amide 1c
(60.9 mg, 0.20 mmol) in 2 mL of THF was added LHMDS
(1.0 M in THF, 0.24 mL, 0.24 mmol) at 0 °C. The resulting mix-
ture was stirred for 2 h at 0 °C before it was cooled to -78 °C and
the indicated zinc reagent (0.30 mmol) was added. The reaction
was allowed to reach room temperature, quenched by the
addition of water (10 mL), and extracted with Et2O (3 ꢀ 10 mL).
(15) Krasovskiy, A.; Tishkov, A.; del Amo, V.; Mayr, H.; Knochel, P.
Angew. Chem., Int. Ed. 2006, 45, 5010–5014.
7802 J. Org. Chem. Vol. 74, No. 20, 2009

Hirner and Somfai
JOCArticle
IR (film) νmax 3317, 2931, 2873, 1666, 1531, 1095 cm-1; HRMS
(ESIþ) calcd for C16H18NO2 [M þ H]þ m/z 256.13321, found
256.13315.
IR (neat) νmax 3305, 1647, 1512, 1250 cm-1; HRMS (ESIþ) calcd
for C16H18NO2 [M þ H]þ m/z 256.13321, found 256.13303.
2-(4-Methoxyphenyl)-N-methyl-2-phenylacetamide (7c). Pre-
pared according the general procedure D with Weinreb amide 4c
(50.3 mg, 0.20 mmol). Flash chromatography (pentane, EtOAc
5 f 60%) of the crude product gave an unseparable mixture of
5c and 7c. Recrystallization from hot toluene/heptane gave pure
7c as a white solid (34.2 mg, 67%). Mp 156-158 °C. 1H NMR
(500 MHz, CDCl3) δ 7.35-7.22 (m, 7H), 7.16 (m, 2H), 6.86 (m,
2H), 5.56 (br, 1H), 4.89 (s, 1H), 3.79 (s, 3H), 2.84 (d, J=4.8 Hz,
3H) ppm; 13C NMR (126 MHz, CDCl3) δ 172.8, 158.7, 139.9,
131.6, 129.9, 128.8, 128.6, 127.1, 114.1, 58.2, 55.2, 26.6 ppm;
Acknowledgment. This work was financially supported by
the Royal Institute of Technology, the Swedish Research
Council, and the Knut and Alice Wallenberg foundation.
Supporting Information Available: General experimental
procedure, preparation, and analytical data for compounds
4a-e, 2a,d,e,g-k,m,p-r, and 7b,d,e and NMR spectra for all
new compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 74, No. 20, 2009 7803