Desymmetrization of malonamides via an enantioselective intramolecular Buchwald-Hartwig reaction

Article abstract of DOI:10.1016/j.tetlet.2009.04.133

A new form of enantioselective nitrogen arylation reaction is described. Beginning with symmetrical α-(2-bromobenzyl)malonamides, intramolecular palladium-catalyzed cross-coupling using a catalyst system including 3.3 mol % Pd(OAc)₂ and 6.6 mol

Full text of DOI:10.1016/j.tetlet.2009.04.133

Tetrahedron Letters 50 (2009) 4170–4173
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Tetrahedron Letters
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Desymmetrization of malonamides via an enantioselective intramolecular
Buchwald–Hartwig reaction
*
Lukasz Porosa, Russell D. Viirre
Department of Chemistry and Biology, Ryerson University, 350 Victoria St., Toronto, Ontario, Canada M5B 2K3
a r t i c l e i n f o
a b s t r a c t
Article history:
A new form of enantioselective nitrogen arylation reaction is described. Beginning with symmetrical a-
Received 22 March 2009
Revised 29 April 2009
Accepted 30 April 2009
Available online 5 May 2009
(2-bromobenzyl)malonamides, intramolecular palladium-catalyzed cross-coupling using a catalyst sys-
tem including 3.3 mol % Pd(OAc)2 and 6.6 mol % of the chiral biaryl monophosphine (R)-MOP, desymmet-
rized quinolinone products are obtained in nearly quantitative yields in enantiomeric ratios up to 88:12.
This Letter represents a rare example of enantioselective Buchwald–Hartwig reaction.
Ó 2009 Elsevier Ltd. All rights reserved.
The Buchwald–Hartwig reaction, a Pd-catalyzed cross-coupling
of a nitrogen nucleophile with an aryl halide or aryl sulfonate has
become a staple in organic synthesis, finding widespread applica-
tion in the synthesis of natural products, medicinal agents, ligands,
and materials.1 The first reports of Pd-catalyzed (non-Sn-medi-
ated) arylation of amines made use of P(o-tolyl)3 as a supporting
ligand in the catalyst system,2 but it was reported shortly thereaf-
ter that chelating bisphosphines such as BINAP (1, Fig. 1)3 or Josi-
phos (4)4 provided superior results with respect to catalyst loading
and substrate scope. While the chirality of the catalyst is unlikely
to play a role in a typical Buchwald–Hartwig reaction (indeed,
racemic ligands are often used as a cost-saving measure), the abil-
ity of these, and other chiral phosphines, to act as components of
catalysts in a host of enantioselective transition metal-catalyzed
transformations is well known.5
At first glance, there appears to be little opportunity for enanti-
oselectivity in a reaction that forms a bond between a nitrogen
atom (typically not a configurationally stable chiral center) and
an sp2-hybridized carbon atom with planar geometry. It is perhaps
for this reason that there have been very few reports of asymmetric
Buchwald–Hartwig reactions. Nevertheless, enantioselective nitro-
gen arylation is theoretically possible if either (i) one enantiomer
of a racemic coupling partner (either aryl halide or nitrogen nucle-
ophile) reacts with a particular chiral catalyst faster than the other,
resulting in a kinetic resolution; or (ii) the reaction was to break an
element of symmetry in one of the reactants, resulting in a center,
axis or plane becoming locked with a particular chiral configura-
tion in the product.
(5) as ligand.6 In this example, the aminated products were not iso-
lated, but the unreacted (R)-10 was recovered in 42% resolution
yield and 93% ee (i.e., 21% of the original amount of racemic 10
was recovered in enantioenriched form). In a more recent exten-
sion of this precedent, Bräse reported the resolution of racemic
monobromide 11, through diastereoselective coupling with enan-
tiopure chiral amines such as 12.7 In this case, the selectivity was
dictated mainly by the chirality of 12, but using a variety of differ-
ent chiral ligands, different diastereoselectivities were observed
when the opposite enantiomer of 12 was used as a coupling part-
ner. This suggests that a particular chiral catalyst could be either
matched or mismatched to react with a particular enantiomer of
12. The resolution of racemic amines by enantioselective N-aryla-
tion has also been demonstrated, although the results to date have
been poor to modest. The resolution of biarylamines 14 and 15
using a catalyst system including (S)-1 was reported to proceed
in the best cases in 27% ee at 35% conversion (for 14) and 17% ee
at 45% conversion (for diarylation of 15).8 The resolution of 1-(1-
naphthyl)ethylamine 13 proceeded in 80% ee with 70% isolated
yield using a catalyst system including (R)-Tol-BINAP 2, but this re-
sult required the use of 19 equiv of the racemic amine and
8.4 equiv of a crown ether additive.9
In the only non-resolution-based example of enantioselective
Buchwald–Hartwig reaction, Taguchi has reported that the aryla-
tion of amides of o-tert-butyl aniline 16 effectively locked out rota-
tion about the C–N bond, resulting in a chiral axis (Fig. 3). Using a
catalyst system including (R)-DTBM-Segphos (6, Fig. 1), nearly
quantitative yields and enantiomeric excesses were achieved.10
Furthermore, it was shown that enolate reactions on the amide
portion of the atropisomeric products proceeded with good diaste-
reoselectivity, and this was exploited in the enantioselective syn-
thesis of a norepinephrine transporter inhibitor.11
In 1997, Rossen and Pye reported the first kinetic resolution by
enantioselective Buchwald–Hartwig reaction, in which the (S)-iso-
mer of racemic dibromide 10 (Fig. 2) was preferentially arylated
with benzylamine using a catalyst system including (S)-Phanephos
Herein, we report a new enantioselective Buchwald–Hartwig
reaction, in which a malonamide 18 (Table 1) is desymmetrized
through intramolecular arylation of one of the enantiotopic
* Corresponding author. Tel.: +1 416 979 5000x4951; fax: +1 416 979 5044.
E-mail addresses: rviirre@ryerson.ca, rviirre@gmail.com (R.D. Viirre).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.04.133

L. Porosa, R. D. Viirre / Tetrahedron Letters 50 (2009) 4170–4173
4171
O
PPh2
O
P(t-Bu)2
P(t-Bu)2
i-Pr
PR2
PR2
PPh2
PPh2
PPh2
OMe
PR2
PR2
Ph2P
Fe
i-Pr
O
PPh2
t-Bu
O
i-Pr
9
1: R = Ph
4
5
6: R =
7
8
OMe
t-Bu
2: R = 4-MePh
3: R = 3,5-Me2Ph
Figure 1. Phosphine ligands discussed in the text.
tempt to tune the steric properties of the ligand, the reaction was
repeated using (R)-xylyl BINAP (3) and (R)-H8-BINAP (7), but these
were found to have detrimental effects on the yield without any
enhancement of the enantiomeric ratios in the product (entries 3
and 4). The use of (S)-5 or (R)-6, the ligands that had been previ-
ously successfully applied in the literature kinetic resolution6 and
chiral axis formation10 as mentioned above, also resulted in lower
yields and enantiomeric ratios compared to (R)-1 (entries 5 and 6).
Racemic MOP (8, Fig. 1) is an alternative ligand that was effective
in Buchwald’s intramolecular arylation reactions.13 This chiral
biaryl monophosphine was originally developed by Hayashi, and
in enantiopure form, has been successfully applied in a variety of
enantioselective Pd-catalyzed reactions, notably hydrosilylations
and allylations.15 When (R)-8 was employed in the current reac-
tion, the yield was comparable to 1, but the enantioselectivity
was improved significantly to a 79:21 ratio (entry 7). This mark-
edly better ligand was therefore selected for further optimization
Br
X
NH2
NH2
X
Ar
10: X = Br
11: X = H
12: Ar = Ph
13: Ar = 1-naphthyl
14: X = OH
15: X = NH2
Figure 2. Substrates that have been the subject of kinetic resolution studies by
enantioselective Buchwald–Hartwig reaction.
nitrogen atoms. These malonamides were readily prepared by
alkylation of diethyl methylmalonate with 2-bromobenzyl bro-
mide, followed by ester hydrolysis and amide formation all under
standard conditions.12 Before attempting any asymmetric reac-
tions, the intramolecular arylation of the N-benzyl malonamide
18a was studied using catalysts including racemic 1 as a cost-sav-
ing measure. It was found that the use of a combination of 18a,
3.3 mol % Pd(OAc)2, 5 mol % (rac)-1, and 1.4 equiv of Cs2CO3, fol-
lowed by heating in toluene at 100 °C (0.1 M, sealed tube) for
24 h resulted in the formation of the desired racemic quinolinone
19a in 85% yield. Aside from the lower concentration (0.1 vs 0.2–
0.3 M), these conditions (including catalyst and base loading, and
Pd/phosphine ratio) are identical to those reported by Buchwald
for intramolecular arylations in achiral systems.13 The solubility
of the substrate 18a was found to be of some importance. The reac-
tion proceeded smoothly when 18a was dissolved along with the
catalyst components in toluene at 100 °C ([18a] = 0.1 M) prior to
the rapid addition of the base under a stream of argon. On the other
hand, at 80 °C in the same volume of toluene, the malonamide sub-
strate was not completely dissolved and 19a was formed only in
low yield under otherwise identical conditions. In contrast, the
use of DMF as a solvent, in which 18a was freely soluble, resulted
in no reaction being observed. Toluene was therefore retained as a
reaction medium for a limited screen of the effect of enantiopure
ligands.
Table 1
Screening of reaction conditions
O
O
O
Bn
Bn
BnHN
N
N
3.3 mol% Pd(OAc)2
ligand
O
O
(R)-19a
BnHN
NHBn 1.4 equiv. base
+
solvent
Br
O
([18a] = 0.1 M)
Δ, 24 h
BnHN
18a
(S)-19a
Entry
Ligand (mol %)
Solvent
T (°C)
Base
Yield (%)
era
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
(rac)-1 (5.0)
(R)-1 (5.0)
(R)-3 (5.0)
(R)-7 (5.0)
(S)-5 (5.0)
(R)-6 (5.0)
(R)-8 (5.0)
(R)-8 (3.3)
(R)-8 (6.6)
(R)-8 (9.9)
(R)-8 (6.6)
(R)-8 (6.6)
(R)-8 (6.6)
(R)-8 (6.6)
(R)-8 (6.6)
(R)-8 (6.6)
(R)-8 (6.6)
(R)-8 (6.6)
(R)-8 (6.6)
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
Dioxane
THF
MeCN
DMSO
THF
THF
THF
100b
100b
100b
100b
100b
100b
100b
100b
100b
100b
100c
65c
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
85
85
65
36
51
62
85
69
71
59
96
95
14
30
31
70
25
35
96
50:50
57:43
56:44
56:44
53:47
53:47
79:21
74:26
77:23
76:24
78:22
79:21
68:32
54:46
83:17
85:15
77:23
70:30
79:21
Repeating the arylation reaction under the conditions described
above, but using enantiopure (R)-1 as ligand, 19a was isolated in
the identical 85% yield, as expected. Analysis of the product by
HPLC (Chiralcel OD-H column) revealed that the two enantiomeric
products were formed in a 57:43 ratio (Table 1, entry 2).14 In an at-
81c
100b
65c
NO2
O
Pd(OAc)2 (3.3 mol%)
6 (5 mol%)
O
65c
KOt-Bu
NaOAc
NaOt-Amd
K3PO4
H
65c
R
N
R
N
Cs2CO3 (1.4 equiv.)
THF
THF
65c
t-Bu
65c
I
NO2
a
The absolute configuration of the major enantiomer of 19a has not been
16
17
rotation locked,
yields, ee's > 90%
toluene, 80 ºC, 10 h
determined.
free rotation
about C-N bond
b
c
Reaction was heated in a sealed tube.
Reaction was heated at reflux temperature.
NaOt-Am = sodium 2-methyl-2-butoxide.
d
Figure 3. Taguchi’s synthesis of atropisomeric anilides.

4172
L. Porosa, R. D. Viirre / Tetrahedron Letters 50 (2009) 4170–4173
studies. Given that this monophosphine may complex palladium
differently from the bisphosphines mentioned above, the ratio of
Pd to (R)-8 was varied from 1:1 to 1:3 (entries 8–10). While the
isolated yield in the latter case was slightly lower, the enantiose-
lectivity was nearly the same for all ratios studied.
O
O
Sm
O
R
H
N
N
red.
R
(R)-8•Pd
elim.
Lg
O
R
(R)-19
(S)-19
O
NH
21a
R
N
H
base
-HBr
Switching from heating in a sealed tube to heating to reflux
under argon, a series of solvents were screened (Table 1, entries
11–14). In the slightly more polar ethereal solvents 1,4-dioxane
or THF, the product 19a was afforded in excellent yields and good
enantiomeric ratios, however more polar solvents such as MeCN
and DMSO gave inferior results. As the lower boiling THF gave
the best result, a series of bases were tested in refluxing THF (en-
tries 15–19). While potassium carbonate and potassium t-butoxide
furnished slightly better enantiomeric ratios, these came with a
sacrifice in product yield. Sodium acetate and sodium 2-methyl-
2-butoxide (NaOtAm) were less competent at promoting the reac-
tion. Potassium phosphate proved to be equal to cesium carbonate
in its ability to promote the reaction in nearly quantitative yield
and good enantioselectivity.
Next, the effect of the amide nitrogen substituent on the reac-
tion outcome was evaluated. Since some of these substrates 18b–
h (Table 2) exhibited lower solubility than 18a, these reactions
were conducted at the lower concentration of 0.05 M. For most
of these substrates, both K3PO4 and Cs2CO3 were employed as
bases with very similar outcomes, and the better result in each
case is presented in the table. In most cases, quinolinone 19 was
isolated in essentially quantitative yield, with the exceptions being
the more sterically demanding N-substituents: isopropyl (90%,
entry 3), 2,6-dimethylphenyl (54%, entry 7) and 1-naphthyl (79%,
entry 8).16 Among N-alkyl substituted malonamides, enantioselec-
tivity increased with the steric bulk of the substituent, ranging
from 69:31 er for methyl up to 85:15 er and 88:12 er for isopropyl
and 4-methoxybenzyl, respectively. For N-aryl substrates, no trend
can yet be identified, although the N-phenyl quinolinone was iso-
lated with the same er as the benzyl. The er could not be deter-
mined for the naphthyl-substituted compound, since the product
was isolated as an inseparable mixture of diastereomers, presum-
ably due to torsional isomerism about the naphthyl–quinolinyl
axis.17
or
Lg
O
(R)-8•Pd
R
red.
R
NH
Br
elim.
N
20
(R)-8•Pd
Sm
21b
Figure 4. The proposed mechanistic step in which enantioselectivity occurs. Sm
and Lg = small and large respectively.
In a study of intermolecular aryl amidation under the influence
of a palladium catalyst including a biaryl monophosphine ligand
such as 9 (Fig. 1), it was suggested that oxidative addition of the
Pd(0) complex into the Ar–Br bond is relatively fast, with the sub-
sequent coordination of the amide nucleophile to the Pd(II) inter-
mediate being the turnover-limiting step.18 If it is assumed that
this is also the case in the current intramolecular system, employ-
ing (R)-8 (which, like 9 is a biaryl monophosphine), then oxidative
addition to 18 would yield complex 20 (Fig. 4), in which the two
amide groups are diastereotopic. Since 8 is capable of several dif-
ferent bonding modes with Pd,19 and the absolute configuration
of the favored quinolinone products of these reactions currently re-
mains unknown, it would be premature to speculate on the exact
structure of intermediate 20. Nevertheless, it could be supposed
that the chiral ligand sterically impedes the rotation around the
indicated bond in 20, such that the smaller methyl group occupies
a sterically demanding region in intermediate 21a or 21b, while
the larger amide group points away from the complex. This preli-
minary model is supported by the observation that in most cases,
the larger nitrogen substituents induce higher stereoselectivity.
Work is currently underway to elaborate upon this model.
In conclusion, a new form of enantioselective Buchwald–Har-
twig reaction has been developed. Enantioselection was achieved
through the preferential intramolecular arylation of a prochiral
nitrogen atom in a symmetrical malonamide derivative. Employing
a catalyst system including 3.3 mol % Pd(OAc)2 and 6.6 mol % (R)-
MOP, with K3PO4 or Cs2CO3 as a base in refluxing THF, desymmet-
rized six-membered quinolinone derivatives were obtained in up
to quantitative yields and enantiomeric ratios as high as 88:12.
The C1-symmetric biaryl monophosphine ligand provided dramat-
ically superior enantioselectivity than a variety of C2-symmetric
bisphosphine ligands. The current methodology represents only
the second example of a non-resolution-based enantioselective
Buchwald–Hartwig coupling. Work is currently underway to fur-
ther improve enantioselectivity and to broaden the substrate scope
of the reaction, and these results will be reported in due course.
Table 2
Effect of nitrogen substituents
O
O
O
O
O
3.3 mol% Pd(OAc)2
6.6 mol% (R)-8
R
R
RHN
N
N
RHN
NHR
Br
1.4 equiv. base
(R)-19a-h
THF ([18] = 0.05 M),
+
65 ºC, 24 h
O
18a-h
RHN
(S)-19a-h
Acknowledgments
Entry
Malonamide
Base
Yield (%)
era
We are very grateful to the Dean of Engineering, Architecture
and Science (Ryerson University) for providing start-up funding
for this research program.
1
2
3
4
5
6
7
8
18b: R = Me
18c: R = n-Bu
18d: R = i-Pr
18a: R = Bn
18e: R = 4-methoxybenzyl
18f: R = Ph
K3PO4
Cs2CO3
K3PO4
K3PO4
Cs2CO3
Cs2CO3
Cs2CO3
K3PO4
99
99
90
99
99
99
54
79b
69:31
75:25
85:15
79:21
88:12
79:21
67:33
ndb
References and notes
18g: R = 2,6-dimethylphenyl
18h: R = 1-naphthyl
1. Reviews: (a) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–
6361; (b) Schlummer, B.; Scholz, U. Adv. Synth. Catal. 2004, 346, 1599–1626; (c)
Prim, D.; Campagne, J.-M.; Joseph, D.; Andrioletti, B. Tetrahedron 2002, 58,
2041–2075.
2. (a) Louie, J.; Hartwig, J. F. Tetrahedron Lett. 1995, 36, 3609–3612; (b) Guram, A.
S.; Rennels, R. A.; Buchwald, S. L. Angew. Chem., Int. Ed. Engl. 1995, 34, 1348–
1350.
a
The absolute configuration of the major isomer of any of the quinolinone
products 19a–h has not been determined.
b
Compound 19h was isolated as an inseparable mixture of diastereomers, due to
blocked rotation about the naphthyl–quinolinyl bond.17

L. Porosa, R. D. Viirre / Tetrahedron Letters 50 (2009) 4170–4173
4173
3. Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215–7216.
4. Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1998, 120, 7369–7370.
5. For a review of asymmetric arylation reactions, see: Bolm, C.; Hildebrand, J. P.;
Muniz, K.; Hermanns, N. Angew. Chem. Int. Ed. 2001, 40, 3284–3308.
6. Rossen, K.; Pye, P. J.; Maliakal, A.; Volante, R. P. J. Org. Chem. 1997, 62, 6462–
6463.
7. Kreis, M.; Friedmann, C. J.; Bräse, S. Chem. Eur. J. 2005, 11, 7387–7394.
8. Vyskocil, S.; Smrcina, M.; Kocovsky, P. Tetrahedron Lett. 1998, 39, 9289–9292.
9. Tagashira, J.; Imao, D.; Yamamoto, T.; Ohta, T.; Furukawa, I.; Ito, Y. Tetrahedron:
Asymmetry 2005, 16, 2307–2314.
60 °C overnight and then cooled to room temperature, extracted with 0.01 M
HCl (4 ꢀ 20 mL), dried over MgSO4, and evaporated under reduced pressure.
The crude material was recrystallized from EtOAc to obtain the title diamide as
an off-white solid in 37% yield (760 mg). Mp = 148–151 °C; 1H NMR (CDCl3,
400 MHz) d 7.54–7.49 (m, 1H), 7.16–7.02 (m, 9H), 6.89–6.77 (m, 4H), 4.40–4.36
(m, 4H), 3.81 (s, 6H), 3.49 (s, 2H), 1.41 (s, 3H); 13C NMR (CDCl3, 100 MHz) d
172.4, 159.1, 136.4, 133.0, 131.1, 129.8, 129.1, 128.4, 127.6, 126.0, 114.1, 55.3,
54.5, 43.5, 42.9, 18.4; HRMS (EI-TOF) calculated for C27H29BrN2O4 (M+)
524.1311; observed 524.1296.
13. Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35–37.
10. Preliminary report: (a) Kitagawa, O.; Takahashi, M.; Yoshikawa, M.; Taguchi, T.
J. Am. Chem. Soc. 2005, 127, 3676–3677; Full paper: (b) Kitagawa, O.;
Yoshikawa, M.; Tanabe, H.; Morita, T.; Takahashi, M.; Dobashi, Y.; Taguchi, T.
J. Am. Chem. Soc. 2006, 128, 12923–12931.
14. The absolute configuration of any of the quinolinone products has not yet been
determined.
15. Hayashi, T. Acc. Chem. Res. 2000, 33, 354–363.
16. As
a
representative example, the synthesis of 3-methyl-N,1-bis(4-
11. Kitagawa, O.; Kurihara, D.; Tanabe, H.; Shibuya, T.; Taguchi, T. Tetrahedron Lett.
2008, 49, 471–474.
methoxybenzyl)-2-oxo-1,2,3,4-tetrahydroquinoline-3-carboxamide (19e) was
accomplished as follows: A dry 10 mL round-bottomed flask was charged with
Pd(OAc)2 (1.6 mg, 0.007 mmol, 3.3 mol %), (R)-MOP (7.0 mg, 0.015 mmol,
6.6 mol %), and malonamide 18e (116 mg, 0.22 mmol. The flask was
12. As a representative example, the synthesis of 2-(2-bromobenzyl)-N,N0-bis(4-
methoxybenzyl)-2-methylmalonamide (18e) was accomplished as follows:
Diethyl methylmalonate (5.10 g, 29.3 mmol) was added slowly by syringe to a
suspension of NaH (60% dispersion in mineral oil, 1.30 g, 32.5 mmol) in THF
(30 mL) at 0 °C, and the mixture was stirred for approximately 30 min. When
hydrogen gas evolution ceased, 2-bromobenzyl bromide (9.52 g, 38.1 mmol)
was added and the resulting milky white mixture was heated to reflux
overnight. The solution was then cooled to room temperature, diluted with
diethyl ether (60 mL), and washed with water (3 ꢀ 30 mL). The organic layer
was dried over MgSO4 and concentrated in vacuo. The crude product was
purified by column chromatography on silica gel eluting with 10% EtOAc/
hexanes to afford diethyl 2-(2-bromobenzyl)-2-methylmalonate, a colorless
oil, in 97% yield (9.83 g). TLC (5% EtOAc:hexanes), Rf = 0.22; 1H NMR (CDCl3,
400 MHz) d 7.56–7.53 (d, J = 8.0 Hz, 1H), 7.23–7.14 (m, 2H), 7.10–7.05 (m, 1H),
4.26–4.18 (m, 4H), 3.52 (s, 2H), 1.39 (s, 3H), 1.26 (t, J = 7.0 Hz, 6H); 13C NMR
(CDCl3, 100 MHz) d 171.9, 136.4, 133.1, 131.4, 128.5, 127.3, 126.3, 61.5, 55.1,
39.3, 19.4, 14.0. A portion of this diester (4.43 g, 12.9 mmol) was added to a
mixture of MeOH (13 mL) and 4 M aqueous NaOH (13 mL, 52 mmol), and the
mixture was heated to reflux overnight. The mixture was then cooled to room
temperature, diluted with water (13 mL), and extracted with diethyl ether
(1 ꢀ 13 mL). The aqueous phase was cooled to 0 °C and acidified by slow
dropwise addition of 6 M HCl. The white suspension was then extracted with
dichloromethane (3 ꢀ 13 mL), and the organic phase was dried over anhydrous
MgSO4 and evaporated to afford 2-(2-bromobenzyl)-2-methylmalonic acid, a
white solid, in 92% yield (3.40 g), which was used without further purification.
1H NMR (acetone-d6, 400 MHz) d 7.53–7.42 (m, 1H), 7.26–7.18 (m, 1H), 7.17–
7.11 (m, 1H), 7.06–7.02 (m, 1H), 3.38 (s, 2H), 1.14 (s, 3H); 13C NMR (acetone-d6,
100 MHz) d 173.4, 137.7, 133.8, 132.3, 129.5, 128.4, 126.8, 55.1, 39.9, 19.6. A
portion of this diacid (1.12 g, 3.9 mmol) was added to SOCl2 (13 mL) and the
mixture was heated to 60 °C for 4 h. The excess thionyl chloride was then
removed by reduced pressure distillation, and the crude diacid chloride was
dissolved in chloroform (40 mL). The mixture was cooled in an ice bath, and 4-
methoxybenzylamine (1.25 mL, 8.6 mmol) followed by NEt3 (1.20 mL,
8.6 mmol) was added. The mixture was removed from ice bath and heated at
equipped with
a reflux condenser connected to an inert atmosphere
manifold, and then evacuated and backfilled with Arthrice. Under a stream
of Ar, anhydrous THF (4.4 mL, [malonamide] = 0.05 M) was added and the
mixture was heated to reflux until the solids were dissolved. The reaction
vessel was then cooled to room temperature and Cs2CO3 (100 mg, 0.31 mmol,
1.4 equiv) was added under a stream of Ar. The reaction mixture was heated to
reflux for 24 h and then cooled to room temperature, diluted with EtOAc
(15 mL), filtered through a short plug of Celite, and concentrated in vacuo. The
crude material was purified by flash chromatography on silica gel eluting with
40% EtOAc:hexanes. The product 19e was obtained as a white solid in 99% yield
(99 mg). Mp = 119–122 °C; TLC (70% EtOAc:hexanes), Rf = 0.63; 1H NMR (CDCl3,
400 MHz) d 7.22–7.15 (m, 1H), 7.11–7.02 (m, 2H), 7.00–6.89 (m, 5H), 6.80 (d,
J = 8.0 Hz, 1H), 6.70 (d, J = 8.5 Hz, 2H), 5.07 (d, J = 16.0 Hz, 1H), 4.91 (d,
J = 16.0 Hz, 1H), 4.23-4.12 (m, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 3.42 (d, J = 15.5 Hz,
1H), 2.95 (d, J = 15.5, 1H), 1.47 (s, 3H, H17); 13C (CDCl3, 100 MHz) d 172.3,
170.8, 159.0, 158.7, 138.7, 130.2, 129.0, 128.8, 128.5, 127.5, 127.3, 124.8, 123.9,
115.3, 114.2, 114.0, 55.3, 55.2, 48.7, 46.8, 43.1, 35.8, 14.2; HRMS (EI-TOF)
calculated for C27H28N2O4 (M+) 444.2049; observed 444.2050; HPLC (Chiralcel
OD-H column, eluting with 0.65 mL/min 20% i-PrOH:hexanes), tR minor =
30.7 min (peak area = 4389950), tR major = 35.7 min (peak area = 30869922),
er = 12:88.
17. Evidence for torsional isomerism includes the fact that the compound appears
to be a single spot by thin layer chromatography, and a single mass was
observed by electron impact mass spectrometry, but 1H NMR suggests two
compounds with the same splitting patterns in a ꢁ58:42 ratio, and HPLC
analysis on Chiralcel OD-H column exhibited three peaks (presumed to be the
four diastereomers, with two species co-eluting).
18. Ikawa, T.; Barder, T. E.; Biscoe, M. R.; Buchwald, S. L. J. Am Chem. Soc. 2007, 129,
13001–13007.
19. Kumar, P. G. A.; Dotta, P.; Hermatschweiler, R.; Pregosin, P. S. Organometallics
2005, 24, 1306–1314.