Rapid, highly diastereoselective addition of dialkylzinc reagents to atropisomeric 2-formyl arylamides

Article abstract of DOI:10.1016/j.tet.2003.12.071

We have observed that dialkylzinc reagents add to atropisomeric 2-formyl arylamides many times faster than they react with other substituted benzaldehyde derivatives. Additionally, with diethylzinc the products were formed with very high diastereoselectiv

Full text of DOI:10.1016/j.tet.2003.12.071

Tetrahedron 60 (2004) 4543–4548
Rapid, highly diastereoselective addition of dialkylzinc reagents
to atropisomeric 2-formyl arylamides
*
Ciril Jimeno, Ramon Rios, Patrick J. Carroll and Patrick J. Walsh
Contribution from Roy and Diana Vagelos Laboratories, Department of Chemistry, University of Pennsylvania, 231 South 34th Street,
Philadelphia, PA 19104-6323, USA
Received 10 October 2003; revised 3 December 2003; accepted 8 December 2003
Abstract—We have observed that dialkylzinc reagents add to atropisomeric 2-formyl arylamides many times faster than they react with
other substituted benzaldehyde derivatives. Additionally, with diethylzinc the products were formed with very high diastereoselectivity,
affording the syn product (d.r. greater than 95:5), except in one case where epimerization of the product is rapid. In contrast, Grignard and
trialkylaluminum reagents afforded the anti diastereomers, with diminished stereoselectivity and formation of reduction products.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
system in the literature, despite the fact that substrate
controlled diastereoselective reactions are well known.20,21
Dialkylzinc reagents were found to afford the syn products
on addition to 2-formyl arylamides, whereas Grignard and
trialkylaluminum compounds yielded the anti products as
the major diastereomer under our reaction conditions
(Scheme 1).
Atropisomeric amides, imides, and anilides are known to
control a variety of stereoselective reactions1 such as
cycloadditions,2,3 radical additions,2 lateral lithiations,4–9
and ortho-lithiations,10,11 among others.12–16 Atropiso-
meric N,N-diisopropyl amides have recently been used to
control stereochemistry over long distances, as demon-
strated by Clayden in the highly diastereoselective addition
of phenylmagnesium chloride to a remote carboxalde-
hyde.17,18 Atropisomeric 1-naphthamides have also been
shown to influence diastereoselectivity in the addition of
organomagnesium and organolithium reagents to 2-formyl
groups.18
2. Results and discussion
During a study directed toward the dynamic kinetic
resolution of atropisomeric amides, we found that diethyl-
zinc added to amides 1 with excellent control over
diastereoselectivity (Table 1). Surprisingly, the reaction
took place equally as fast in the presence or absence of
amino alcohols, finishing after 1 h at room temperature.
These results were unexpected because it is known that
diethylzinc reacts with benzaldehyde slowly in the absence
of amino alcohols.22 Therefore, we propose that a
mechanism involving activation of the diethylzinc by the
In our continuing studies of atropisomeric amides,19 we
have examined the addition of organometallic reagents to
2-formylaryl amides. We herein report surprising rate
enhancements and excellent control of diastereoselectivity
in the alkyl group addition to a series of racemic 2-formyl
arylamides. We are not aware of related observations in this
Scheme 1. Reagent controlled diastereoselection in the addition to 2-formyl arylamides.
Keywords: Dialkylzinc reagents; Atropisomeric amides; Stereochemistry; 1,2-Addition reactions.
*
Corresponding author. Tel.: þ1-215-573-2875; fax: þ1-215-573-6347; e-mail address: pwalsh@sas.upenn.edu
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.12.071

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C. Jimeno et al. / Tetrahedron 60 (2004) 4543–4548
Table 1. Addition of organometallic reagents to 2-formyl arylamides
solution at 0 8C, we observed formation of the anti
diastereomer. In contrast, Clayden and co-workers
employed Grignard reagent in THF at low temperature
and reported formation of the syn diastereomer.18 We
repeated the experiment of the Clayden group and obtained
the syn diastereomer under these conditions, in agreement
with their report.26 It is likely that the change in
diastereoselectivity of the addition in diethyl ether and
THF is related the higher affinity of magnesium for THF.
The specific cause, however, remains unclear at this time.
Entry Substrate
R
R0
MR00
Product Yield
d.r.
(syn/anti)
1
2
3
4
5
6
7
8
1a
1b
1c
1c
1c
1d
1d
1d
1d
1d
1e
1e
1e
1e
1f
NMe2
CF3
Ph
Ph
Ph
OMe
OMe
OMe
OMe
OMe
1-Naphd
1-Naphd
1-Naphd
1-Naphd
SiMe3
SiMe3
H
H
H
H
H
H
H
H
H
H
ZnEt2
ZnEt2
ZnEt2
2a
2b
2c
99
96
80
94
.98:2
95:5
.98:2
50:50
EtMgBr 2c
AlEt3
ZnEt2
EtMgBr 2d
AlEt3
ZnMe2
MeMgBr 3d
ZnEt2 2e
EtMgBr 2e
ZnMe2 3e
MeMgBr 3e
ZnEt2 2f
EtMgBr 2f
2c
2d
75a 11:89
95
83
.98:2
33:67
2d
3d
39b 14:86
64c 85:15
9
Only in the additions to 1f (entries 15 and 16), which has a
trimethylsilyl group ortho to the amide, was the same
mixture of diastereomers isolated with the zinc and
magnesium reagents. There are two possible explanations
for this observation. The increased length of the carbon–
silicon bond could result in a decrease in the barrier to
rotation of the amide. Alternatively, the trimethysilyl group
could facilitate rotation about the aryl–amide bond by
coordination of the carbonyl oxygen to the silicon in the
transition state as illustrated in Eq. 1.19 Coordination of
Lewis bases by trialkylsilyl in an intramolecular fashion has
been proposed in many systems.27 Similar ortho silyl effects
have been observed previously by Clayden28 and our
group.19
10
11
12
13
14
15
16
97
68
90
33:67
.98:2
25:75
60c 91:9
80
57
92
25:75
33:67
33:67
H
H
1f
a
19% of reduction product.
44% of reduction product.
After 2 days.
b
c
d
N,N-Diisopropyl-2-formyl-1-naphthamide.
amide carbonyl is responsible for both the increase in
reaction rate and the high diastereoselectivity, as outlined
below. Dialkylzinc reagents can give excellent diastereo-
selectivity if a Lewis-basic functional group is in close
proximity to the reaction center.23,24
To examine the aldehyde conformation in the solid state, an
X-ray structure determination of 1d was performed.29 An
ORTEP drawing is shwon in Figure 1 where the
perpendicular architecture of the atropisomeric amide can
be seen.
We applied this reaction to a series of atropisomeric
aldehydes, achieving excellent diastereocontrol, as deter-
1
mined by H and 13C{1H} NMR spectroscopy (Table 1,
entries 1–3, 6 and 11). Only the addition to 1f afforded poor
diastereoselectivity as discussed below (entry 15).
Dimethylzinc additions required longer reaction times
(approximately 2 d) and gave somewhat lower diastereo-
selectivities (Table 1, entries 9 and 13). It is well known that
dimethylzinc is significantly less reactive than diethylzinc.
For example, Noyori reported that dimethylzinc reacted 20
times slower with benzaldehyde than diethylzinc in the
presence of catalyst formed from the amino alcohol ligand
DAIB.25 We attribute the decrease in the diastereoselec-
tivity in the dimethylzinc additions to the prolonged
reaction times, which permit the epimerization of the
product through rotation about the Ar-carbonyl bond.
Experimental support for this hypothesis is presented below.
O1
O2
N1
O3
To examine the diastereoselectivity with Grignard reagents,
we carried out the addition of ethylmagnesium bromide
to aldehydes 1c–f (Table 1, entries 4, 7, 12, and 16) and
methylmagnesium bromide to 1d and 1e (entries 10 and 14).
Surprisingly, in contrast to the formation of the syn product
with dialkylzinc reagents, the anti diastereomer predomi-
nated in these addition reactions. Under our conditions,
where the Grignard reagent was used as a diethyl ether
Figure 1. ORTEP drawing of 1d.
In order to assign the relative stereochemistry of each
diastereomer, crystals of the syn/anti mixtures of 2d, 2e, and
3d were grown,29 and their structures determined by X-ray
diffraction. Only the anti diastereomers crystallized under
our conditions. 1H NMR spectroscopy of those crystals
ð1Þ

C. Jimeno et al. / Tetrahedron 60 (2004) 4543–4548
4545
Figure 2. ORTEP drawing of anti-2d.
Figure 5. Epimerization of anti-3d. Plot of the diastereomer % vs time.
1
monitored at room temperature by H NMR spectroscopy.
From Figure 5 it is clear that the equilibration of the syn and
anti diastereomers occurs slowly at room temperature
eventually leading to the thermodynamic ratio (30:70
anti:syn).9,28 However, the epimerization rate is sufficiently
fast to result in a decrease in the diastereoselectivities in the
addition of dimethylzinc to aldehydes.
The diastereoselectivity in the Grignard addition reactions
was only moderate, and thus we decided to explore other
reagents in order to improve the anti selectivity. We were
pleased to find that triethylaluminum added to 1c and 1d
with much better diastereoselection, affording predomi-
nantly the anti diastereomer (Table 1, entries 5 and 8).
However, variable amounts of reduction products were also
isolated.
Figure 3. ORTEP drawing of anti-2e.
Next we compared the rates of reaction of diethylzinc with
2-formylatropisomeric amides and 2-substituted benzalde-
hyde derivatives. The reactions with 1d and 1e were
complete after 3 h at room temperature, whereas reactions
with 2-anisaldehyde, 2-tolualdehyde, and 2-trifluoromethyl-
benzaldehyde exhibited no conversion after 3 h by 1H NMR
spectroscopy. The results of these studies allow us to
propose a mechanism for the addition of dialkylzinc
reagents to 2-formylatropisomeric amides that explains the
high level of diastereoselectivity observed. The rapid
addition of diethylzinc to the amides 1d and 1e suggests
that the zinc is activated by coordination to the amide
carbonyl oxygen. It has been proposed that the alkyl groups
in coordinated zinc complexes of the type LZnR2 (where L
is a Lewis-basic group) are significantly more reactive than
those of ZnR2.25,30 Thus, the activated ZnR2 can deliver the
alkyl group as shown in Figure 6. The proposed confor-
mation of the formyl group is that found in the crystal
structure of 1d in Figure 1. A model for the addition of
Grignard reagents to 2-formylatropisomeric amides is also
proposed in Figure 6. Activation of the aldehyde by the
magnesium center is proposed to cause a conformational
change of the aldehyde carbonyl–aryl bond as a result of
steric interactions of the magnesium assembly with the
substrate. Thus, the addition reaction takes place on the
opposite face of the aldehyde.
Figure 4. ORTEP drawing of anti-3d.
showed that they were the major diastereomer in the
reactions with the Grignard reagents. Therefore, the syn
diastereomer was formed in the dialkylzinc additions.
Figures 2–4 show ORTEP drawings of 2d, 2e, and 3d
where the anti arrangement can be clearly seen.
To examine the rates of epimerization of the atropisomeric
amide products a 90:10 mixture of anti-3d:syn-3d was

4546
C. Jimeno et al. / Tetrahedron 60 (2004) 4543–4548
Figure 6. Proposed models for the diethylzinc and the Grignard additions to 2-formylarylamides. Solvent molecules coordinated to magnesium are not shown.
3. Conclusions
bottom flask and dissolved in 2 mL of dry toluene under
nitrogen. 1 M solutions of either diethyl- or dimethylzinc in
hexanes (0.8 mmol, 0.8 mL) were added dropwise. The
reaction was quenched with aq. sat. NH4Cl after 1 h when
diethylzinc was used, and after 2 d when dimethylzinc was
used. The mixture was extracted with diethyl ether (£3),
dried (MgSO4), and solvents removed in vacuo. The crude
reaction product was purified by column chromatography on
silica gel when necessary using ethyl acetate and hexanes.
In summary, we report that dialkylzinc reagents react
rapidly with atropisomeric 2-formyl arylamides relative to
2-substituted benzaldehyde derivatives. It is proposed that
this large difference in reactivity is due to an internal
activation of the organozinc reagent by the amide carbonyl.
Furthermore, the alkyl zinc reagents add in a highly
diastereoselective fashion, affording the syn adducts in
high yields and diastereoselectivities. The anti diastereo-
mers have also been synthesized through the addition of
Grignard reagents to the same starting material. A
promising alternative to this latter reaction is the use of
trialkylaluminum compounds, which provides the anti
diastereomer with high diastereoselectivity. We are cur-
rently examining the possibility of using other reactions to
achieve the dynamic kinetic resolution of these interesting
substrates.
1
The d.r. was determined prior and after purification by H
NMR spectroscopy.
4.3. Procedure B. Addition of Grignard reagents to
compounds 1c–f
The aldehyde (0.4 mmol) was weighed into a dry, round
bottom flask and dissolved in 2 mL of dry diethyl ether
under nitrogen. The solution was cooled to 0 8C and 3 M
solutions of either ethyl- or methylmagnesium bromide in
diethyl ether (0.8 mmol, 0.27 mL) were added dropwise.
The mixture was allowed to warm to room temperature.
After 4 h, the reaction was quenched with aq. sat. NH4Cl,
extracted with diethyl ether (£3), dried (MgSO4), and
solvents removed in vacuo. The crude reaction product was
purified by column chromatography on silica gel when
necessary using ethyl acetate and hexanes. The d.r. was
determined prior and after purification by 1H NMR
spectroscopy.
4. Experimental
4.1. General experimental section
1H NMR spectra were obtained on a 500 MHz Fourier
transform NMR spectrometer at the University of Pennsyl-
vania NMR facility. 1H NMR spectra were recorded relative
to tetramethylsilane. 13C{1H} NMR spectra were obtained
at 125 MHz on the 500 MHz instrument, and chemical shifts
were recorded relative to the solvent resonance. Chemical
shifts are reported in units of parts per million downfield
from tetramethylsilane and all coupling constants are
reported in Hz. IR spectra were obtained on a Perkin–
Elmer 1600 series spectrometer. Unless otherwise specified,
all reagents were either purchased from Aldrich Chemical
Co. or Acros Organics, and used without further purifi-
cation. TMEDA was distilled over CaH2 prior to use.
Aldehyde precursors to compounds 2 and 3 were synthe-
sized by the literature methods.
4.4. Procedure C. Addition of triethylaluminum to
aldehydes 1c–d
The aldehyde (0.4 mmol) was weighed into a dry, clean,
round bottom flask, and dissolved in 2 mL of dry toluene
under nitrogen. A 1 M solution of triethylaluminum in
hexanes (0.8 mmol, 0.8 mL) was added dropwise. The
reaction was quenched with aq. sat. NH4Cl after 12 h,
extracted with diethyl ether (£3), dried (MgSO4), and
solvents removed in vacuo. The crude product was purified
by column chromatography on silica gel. The d.r. was
1
4.2. Procedure A. Addition of dialkylzinc reagents to
compounds 1a–f
determined after purification by H NMR spectroscopy.
4.4.1. syn N,N-Diisopropyl 1-(dimethylamino)-3-(1-
hydroxypropyl)-2-benzamide, syn-2a. Prepared according
The aldehyde (0.4 mmol) was weighed into a dry, round

C. Jimeno et al. / Tetrahedron 60 (2004) 4543–4548
4547
to general procedure A. syn-2a was isolated as a clear oil in
99% yield (120 mg). 1H NMR (500 MHz, CDCl3) d 7.21 (t,
J¼8 Hz, 1H), 7.01 (d, J¼8 Hz, 1H), 6.86 (d, J¼8 Hz), 4.38
(m, 1H), 3.79 (broad s, 1H), 3.53 (m, 1H), 3.45 (m, 1H), 2.67
(s, 6H), 1.92 (m, 1H), 1.82 (m, 1H), 1.55 (d, J¼7 Hz, 3H),
1.50 (d, J¼7 Hz, 3H), 1.12 (d, J¼7 Hz, 3H), 0.93–0.89 (m,
6H) ppm; 13C{1H} NMR (125 MHz, CDCl3) d 171.0, 149.8,
141.6, 132.9, 129.1, 119.3, 117.4, 72.0, 51.2, 45.8, 44.1,
26.5, 20.6, 20.5, 20.1, 20.0 11.1 ppm; IR (film) 3420, 3065,
2963, 1600, 1466, 1336 cm21; HRMS (ESþ) m/z 329.2218
(calcd for [C18H30N2O2þNa]¼329.2205).
13C{1H} NMR (125 MHz, CDCl3) d 168.6, 154.7, 143.1,
129.5, 126.8, 117.6, 109.6, 66.0, 55.3, 51.2, 46.0, 20.8, 20.6,
20.5, 20.2, 20.1 ppm; HRMS (CIþ) m/z 279.1835 (calcd for
[C16H25NO3þNa]¼279.1834).
4.4.6. anti N,N-Diisopropyl 1-methoxy-3-(1-hydroxy-
ethyl)-2-benzamide, anti-3d. Prepared according to pro-
cedure C and isolated as a white solid in 39% yield (42 mg).
Sample characterized from the crystals used for X-ray
diffraction. 1H NMR (500 MHz, CDCl3) d 7.22 (t, J¼8 Hz,
1H), 7.02 (d, J¼8 Hz, 1H), 6.72 (d, J¼8 Hz, 1H), 4.78 (q,
J¼6 Hz, 1H), 3.71 (s, 3H), 3.62 (m, 1H), 3.44 (m, 1H), 1.50
(m, 6H), 1.46 (d, J¼6 Hz, 3H), 1.08 (d, J¼7 Hz, 3H), 1.02
(d, J¼7 Hz, 3H).
4.4.2. syn N,N-Diisopropyl 1-(trifluoromethyl)-3-(1-
hydroxypropyl)-2-benzamide, syn-2b. Prepared according
to general procedure A. syn-2b was isolated in 96% yield as
a clear oil (115 mg). 1H NMR (500 MHz, CDCl3) d 7.62 (d,
J¼8 Hz, 1H), 7.52 (d, J¼8 Hz, 1H), 7.45 (t, J¼8 Hz, 1H),
4.54 (m, 1H), 3.48 (m, 2H), 3.10 (broad s, 1H), 2.00 (m, 1H),
1.75 (m, 1H), 1.56 (d, J¼7 Hz, 3H), 1.47 (d, J¼7 Hz, 3H),
1.09 (d, J¼7 Hz, 3H), 1.01 (m, 3H), 0.99 (d, J¼7 Hz, 3H)
ppm; 13C{1H} NMR (125 MHz, CDCl3) d 167.9, 141.7,
135.2, 129.8, 129.1, 128.4, 126.1, 71.2, 51.2, 46.4, 26.9,
20.7, 20.2, 19.6, 19.4, 11.1 ppm; IR (film) 3420, 3080, 2969,
1614, 1440, 1372, 1319 cm21; HRMS (ESþ) m/z 354.1671
(calcd for [C17H24F3NO2þNa]¼354.1657).
4.4.7. syn N,N-Diisopropyl 2-(1-hydroxypropyl)-1-naph-
thamide, syn-2e. Spectroscopic data identical to that
reported in the literature.28
4.4.8. anti N,N-Diisopropyl 2-(1-hydroxypropyl)-1-naph-
thamide, anti-2e. Spectroscopic data identical to that
reported in the literature.28
4.4.9. syn N,N-Diisopropyl 2-(1-hydroxyethyl)-1-naph-
thamide, syn-3e. Spectroscopic data identical to that
reported in the literature.28
4.4.3. syn N,N-Diisopropyl 1-phenyl-3-(1-hydroxypro-
pyl)-2-benzamide, syn-2c. Prepared according to general
procedure A. syn-2c was isolated as a white solid (105 mg)
in 80% yield. 1H NMR (500 MHz, CDCl3) d 7.47–7.24 (m,
8H), 4.48 (m, 1H), 3.39 (m, 1H), 3.32 (m, 1H), 1.99 (m, 1H),
1.84 (m, 1H), 1.49 (d, J¼7 Hz, 3H), 1.23 (d, J¼7 Hz, 3H),
0.95 (t, J¼7 Hz, 3H), 0.79 (d, J¼7 Hz, 3H), 0.14 (d, J¼
7 Hz, 3H) ppm; 13C{1H} NMR (125 MHz, CDCl3) d 170.5,
140.9, 139.9, 137.9, 136.8, 129.4, 128.8, 128.7, 128.3,
127.6, 124.7, 72.1, 50.8, 46.0, 26.7, 20.5, 20.4, 19.3, 19.2,
11.1 ppm; IR (film) 3407, 3057, 2964, 1603, 1444, 1370,
1335 cm21; HRMS (ESþ) m/z 362.2083 (calcd for
[C22H29NO2þNa]¼362.2096).
Acknowledgements
We thank the Petroleum Research Fund (ACS-PRF 38021),
administered by the American Chemical Society, and the
University of Pennsylvania for support of this work.
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1
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3H), 0.91 (t, J¼7 Hz, 3H) ppm; 13C{1H} NMR (125 MHz,
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J¼6 Hz, 1H), 3.72 (s, 3H), 3.60 (m, 1H), 3.44 (m, 1H), 1.51
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29. Data for 1d, anti-2d, anti-2e, and anti-3d. The following
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Crystallographic Data Centre and allocated the deposition
numbers CCDC 212262, 212263, 212580, and 212582.
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