Free radical-mediated aryl amination: A practical synthesis of (R)- and (S)-7-azaindoline α-amino acid

Article abstract of DOI:10.1055/s-2004-831226

Two nonnatural proline derivatives, (S)- and (R)-7-azaindoline α-amino acid have been prepared and isolated as their trifluoro-acetate salt on gram scale. The convergent sequence (6 steps from 2-bromopyridine) employs a combination of enantioselective phase transfer catalyzed glycine alkylation and free radical-mediated aryl animation. Implementation of the solid-liquid phase transfer conditions requires manual pulverization of cesium hydroxide, efficient mechanical stirring, and effective low temperature control. This large scale free radical cyclization protocol replaces benzene solvent with toluene without complication, and the crystalline nature of the intermediates and final product enables straightforward purification at each stage, including enantiomeric enrichment (89% to >99% ee for 4b, Scheme 1).

Full text of DOI:10.1055/s-2004-831226

330
PRACTICAL SYNTHETIC PROCEDURES
Free Radical-Mediated Aryl Amination: A Practical Synthesis of (R)- and
(S)-7-Azaindoline a-Amino Acid
F
ree
R
adic
a
al-Mediate
y
d
A
ryl
A
min
a
a
tion sree M. Srinivasan, Heather E. Burks, Colin R. Smith, Rajesh Viswanathan,
PSP
Jeffrey N. Johnston*
Department of Chemistry, Indiana University, 800 East Kirkwood Avenue, Bloomington, IN 47405, USA
Fax +1(812)8558300; E-mail: jnjohnst@indiana.edu
Received 26 May 2004
No38
Abstract: Two nonnatural proline derivatives, (S)- and (R)-7-azaindoline a-amino acid have been prepared and isolated as their trifluoro-
acetate salt on gram scale. The convergent sequence (6 steps from 2-bromopyridine) employs a combination of enantioselective phase trans-
fer catalyzed glycine alkylation and free radical-mediated aryl amination. Implementation of the solid-liquid phase transfer conditions
requires manual pulverization of cesium hydroxide, efficient mechanical stirring, and effective low temperature control. This large scale
free radical cyclization protocol replaces benzene solvent with toluene without complication, and the crystalline nature of the intermediates
and final product enables straightforward purification at each stage, including enantiomeric enrichment (89% to >99% ee for 4b, Scheme 1).
Key words: free radical cyclization, aryl amination, a-amino acid, enantioselective synthesis, phase-transfer catalysis
Procedure
OH
Br
PBr3
1. LDA, DMF
2. NaBH4
(47%)
(88%)
N
Br
N
Br
N
Br
2
1
Br–
catalyst A
Br
CO2tBu
1.
10 mol% catalyst
CsOH•H2O
N
H
N
CO2tBu
N
N
Anth
N
CH2Cl2, -60 °C
OAllyl
Ph
Ph
2. triturate (for 4b
)
Ph
3
Ph
Br–
(S)–4a 89% ee
(R)–4b >99% ee
(87%)
(77%)
catalyst A
catalyst B
catalyst B
N
AllylO
N
nBu3SnH
AIBN
1.
CF3COOH
CO2tBu
CO2H
H
Anth
Et3SiH
N
N
N
N
H
CH2Cl2
toluene, 85 °C
2. triturate (for 5a
·HO2CCF3
Ph
)
Ph
(S)–6a (66%)
(R)–6b (89%)
(S)–5a >99% ee
(R)–5b >99% ee
(53%)
(67%)
Scheme 1
Scheme 2) that include aminostannation, aminothiolation,
and aminoacylation.5 Despite these rather modest begin-
nings in the greater area of aryl amination,6 two relatively
unique features immediately emerged: the free radical
conditions are pH-neutral, and the transformation pro-
ceeds with no identifiable electronic limitations on the
aryl halide or azomethine.1
Introduction
Despite earlier reports suggesting the contrary, free radi-
cal-mediated aryl amination in which an aryl radical is en-
ticed to add to the nitrogen of an azomethine can be both
efficient and general (Equation 1 in Scheme 2).1–4 The
strategy itself has also been translated to the amination
of vinyl halides to produce nucleophilic N,N-dialkyl en-
amines (Equation 2 in Scheme 2), and to tandem process-
es of alkyne bisfunctionalization (Equation 3 in
The next phase of development for this reaction involves
its implementation in the concise synthesis of hetero-
cycles bearing synthetic value.7 For example, chiral
indolines8 might be convergently assembled using a serial
two step process in which a glycine fragment is merged
with an ortho-halo benzyl halide electrophile, followed
by amination using the title method (Equation 4 in
SYNTHESIS 2005, No. 2, pp 0330–0333
Advanced online publication: 16.09.2004
DOI: 10.1055/s-2004-831226; Art ID: Z10204SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
4

PRACTICAL SYNTHETIC PROCEDURES
Free Radical-Mediated Aryl Amination
331
free radical-mediated
aryl amination
(1)
N
R
N
Br
R
R
R
free radical-mediated
vinyl amination
(2)
N
R
N
Br
R
R
R
free radical-mediated
vinyl amination
(3)
X
N
R
O
N
R
R
R
N
Br
1. CsOH•H2O
t
OtBu
Ph
CO2 Bu
(4)
catalyst
N
Br
2. nBu3SnH
AIBN
Rn
Rn
Ph
Ph
Ph
Scheme 2
Scheme 2). We first realized this transformation in
enantioselective form through the use of Corey’s
Scope and Limitations
protocol9 for O’Donnell enantioselective glycine Schiff The aminations described in our published work include
base alkylation.10 The overall process appears to be gener- only 5-exo cyclizations. These studies identified that the
al with no identifiable limitation on the electronics of the key to overcome competitive direct aryl radical reduction
benzyl halide.1a Moreover, both antipodes of the product or its cyclization to azomethine carbon in a 6-endo pro-
are produced with a high degree of enantioselection. The cess is to both thermodynamically favor attack at nitrogen
development of enantioselective catalysts based on pro- through the use of a radical stabilizing substituent at the a-
line derivatives has in fact been hampered by the absence amino methyl carbon and kinetically deter attack at car-
of a convenient synthesis of the (R)-enantiomer(s). The bon through the use of disubstitution at the azomethine
search for alternative frameworks that are readily avail- carbon (a ketimine). Consistent with earlier work, we
able and provide enantioselectivity complementary to (S)- have confirmed that aldimines deliver predominantly (but
proline derivatives remains an active area.11
not exclusively) 6-endo cyclization products, and cycliza-
tion to ketimines such as acetone imine give predominant-
ly aryl radical direct reduction accompanied by only small
amounts (10–20%) of indoline.
Complementary to their demonstrated value in enantiose-
lective synthesis, indoline a-amino acid derivatives bear
promise as constrained proline derivatives in the same
vein as Lubell’s recent work with 5-tert-butyl proline.12 A Intervention of an azacyclopentenyl carbinyl radical
thorough study of the effect of non-natural chiral a-amino isomerization1b is only possible when an electron defi-
acid incorporation into peptides requires the availability cient substituent resides at the indoline 2-position as it
of a functionally diverse collection of indoline amino ac- does here. However, this potential racemization mecha-
ids, as well as the individual antipodes of each derivative nism requires either severe steric hindrance along the in-
in enantiomerically pure form. In the absence of an enan- doline southern rim, an electronically rich bromoarene,
tioselective synthesis, the process is considerably more in- and/or low effective stannane concentration during cy-
volved, as evidenced by the development of the ACE clization.
inhibitor Pentopril (Figure 1).13
COOH
N
H
L-proline
COOH
CH3
Pentopril (Ciba-Geigy)
N
O
angiotensin converting
enzyme (ACE) inhibitor
• antihypertensive
CH3
COOH
N
H
CO2Et
L-indoline α-amino acid
Figure 1
Synthesis 2005, No. 2, 330–333 © Thieme Stuttgart · New York

332
J. M. Srinivasan et al.
PRACTICAL SYNTHETIC PROCEDURES
vent was removed in vacuo. The mixture was extracted with EtOAc,
dried (Na2SO4), and concentrated to an oil that was purified via col-
umn chromatography (SiO2, 0–70% EtOAc in hexanes) to yield the
product as a yellow solid (11.3 g, 47%). Analytical data was identi-
cal to that in the literature.14
Procedures
The preparations described here are for both enantiomers
of 7-aza-indoline a-amino acid (6). Beginning from com-
mercially available and inexpensive 2-bromopyridine, the
requisite pyridyl dibromide 2 is produced on scale in 41%
overall yield using a modification of the Goehring proto-
col.14 A large scale phase-transfer catalyzed enantio-
selective glycine Schiff base15 alkylation using the
Corey–Lygo catalyst has been optimized to minimize the
amount of alkyl halide to two equivalents, 10 mol% cata-
lyst, and only two equivalents of the relatively expensive
cesium hydroxide base. We have discovered that the
2-Bromo-3-bromomethylene Pyridine (2); Typical Procedure
A dry 1 L flask was charged with CH2Cl2 (250 mL) and 2-bromo-3-
hydroxymethylene pyridine (7.0 g, 37 mmol). The resulting solu-
tion was cooled to 0 °C, phosphorous tribromide (2.7 mL, 28 mmol)
was added, and the mixture was warmed to r.t. and stirred for 12 h.
The reaction mixture was then diluted with CH2Cl2 (500 mL) and
ice (200 g). The resulting solution was adjusted to pH = 10 using 1
M aq NH4OH, and the layers were separated. The organic layer was
washed with water, dried (Na2SO4), and concentrated to an oil (8.2
alkylation proceeds with acceptable rate (three days) and g, 88%). Analytical data was identical to that in the literature.16
enantioselection at –60 °C. Key to our success is the use
2-(Benzhydrilidene-amino)-3-(2-bromopyridin-3-yl)-propionic
of hand-pulverized cesium hydroxide and careful temper-
ature control (cold finger/dewar) with efficient mechani-
cal stirring. In cases where the alkylation step proceeds
with modest enantioselection, trituration of the product
with hexanes either precyclization (4b) or postcyclization
(5a) serves to enrich the enantiomeric excess of the solid
obtained.
Acid tert-Butyl Ester (4a1a and 4b); Typical Procedure
To a 250 mL round bottom flask equipped with a mechanical stirrer
were added Schiff base 3 (3.97g, 13.4 mmol), the cinchonidine de-
rived catalyst A (0.81 g, 0.1 equiv)17,18 and CH2Cl2 (45 mL). 2-Bro-
mo-3-bromomethyl pyridine 4 (6.74 g, 26.9 mmol) was added,
cooled to –78 °C, and the mixture was stirred for 15 min. Hand-pul-
verized CsOH·H2O was added (4.1 g, 26.9 mmol), the reaction was
cooled in a dewar to –60 °C using a cold finger and stirred for 3 d.
The reaction was diluted with Et2O (90 mL), the organic layer was
washed with water (150 mL), dried (Na2SO4), and concentrated to
In the key annulation step, free radical-mediated aryl am-
ination is effected in good overall yield, and toluene is im-
plemented in this preparation to allay the usual concerns an oil. The crude oil was purified by flash chromatography (Al2O3,
5–50% Et2O in hexanes) to afford compound 4a as white solid (5.44
g, 87%). HPLC (Chiralcel AD, 2% i-PrOH–hexanes, 1 mL/min), tR
(R) = 7.3 min, tR (S) = 8.5 min. (S) = 89% ee.
that accompany benzene solvent. Deprotection to the free
amino acid is readily effected by trifluoroacetic acid in
CH2Cl2, and its isolation as the trifluoroacetate salt is most
convenient for both characterization and storage.
When cinchonine-derived catalyst B is substituted into the proce-
dure above, Schiff base 3 (4.8 g, 16.3 mmol) is transformed to 4b as
a white solid after trituration with hexanes (5.81 g, >99% ee, 77%
yield). An additional amount of 4b (905 mg, 12%) is obtained in
88% ee following chromatography of material recovered from the
hexanes washes.
Flame-dried (under vacuum) glassware was used for all reactions.
All reagents and solvents were of commercial grade and purified
prior to use when necessary. Thin-layer chromatography (TLC) was
performed using glass-backed silica gel (250 mm) plates and flash
chromatography utilized 230–400 mesh silica gel from Scientific
Adsorbents. UV light, and/or ceric ammonium molybdate and po-
tassium iodoplatinate solutions were used to visualize products. IR
spectra were recorded on a Nicolet Avatar 360 spectrophotometer
and are reported in cm–1. Liquids and oils were analyzed as neat
films on a NaCl plate (transmission), whereas solids were applied to
a diamond plate (ATR). NMR spectra were acquired on either a
Varian INOVA-400 (400 MHz), VXR-400 (400 MHz), or Varian
INOVA-500 (500 MHz) instrument. Chemical shifts are measured
relative to residual solvent peaks as an internal standard set to d 7.26
and d 77.1 (CDCl3). Mass spectra were recorded on a Kratos MS-80
spectrometer by use of chemical ionization (CI). Atlantic Micro-
labs, GA, performed combustion analyses.
1-Benzhydryl-2,3-dihydro-1H-indole-2-carboxylic Acid tert-
Butyl Ester (5a and 5b);1a Typical Procedure
A flame dried 2 L flask was charged with toluene (860 mL) de-
gassed by several freeze-pump-thaw cycles, and warmed to 85 °C.
A toluene solution (1 mL) of Schiff base 4a (4.0 g, 8.6 mmol) and
n-Bu3SnH (2.5 mL, 9.45 mmol) was then added, followed by the
dropwise addition of a 0.2 M toluene solution of AIBN (1.13 g, 6.88
mmol) over 4 h. The remaining portion of n-Bu3SnH (2.5 mL, 9.45
mmol) was added at the end of the first hour of addition of AIBN.
After the 4 h addition of AIBN was complete, the reaction was al-
lowed to stir at 85 °C for 12 h. The reaction was cooled to r.t., and
toluene removed by vacuum. The oily residue was diluted with Et2O
(10 mL) and a sat KF solution (ca 20 equiv) was added. The mixture
was stirred for 3 h, during which a precipitate formed at the inter-
face. The organic layer was separated, dried (Na2SO4), and concen-
trated to an oil. The crude mixture was purified via flash
chromatography (SiO2, 0–40% EtOAc in hexanes) and subsequent
trituration with hexanes to afford 5a as white solid (1.75 g, 53%).
HPLC (Chiralcel AD, 10% i-PrOH–hexanes, 1 mL/min), tR (S) =
5.9 min, tR (R) = 11.8 min. (S) = >99% ee.
2-Bromo-3-hydroxymethylene Pyridine (1); Typical Procedure
A dry 1 L 3-neck flask was charged with THF (500 mL) and isopro-
pyl amine (39 mL, 316 mmol). The resulting solution was cooled to
–78 °C, and n-BuLi (126.6 mL, 2.5 M solution in hexanes) was add-
ed dropwise over 30 min. After 15 min, 2-bromopyridine (20 g, 126
mmol) was added and stirred for 90 min to generate a yellow solu-
tion. Dimethylformamide (39 mL, 506 mmol) was added and stirred
for 4 h at –78 °C, and the reaction was then quenched with sat aq
NH4Cl (60 mL). The reaction was warmed to r.t. and diluted with
EtOAc (1 L). The organic layer was separated, washed with water
(200 mL), brine (200 mL), and dried (Na2SO4). The solvent was re-
moved, and the resulting orange oil was dissolved in MeOH (210
mL), treated with NaBH4 (3.35 g, 88.6 mmol), and stirred for 12 h.
The reaction was quenched with sat aq NH4Cl (25 mL) and the sol-
When 4b is substituted into the procedure above, 5b is isolated as a
white solid (2.23 g, >99% ee, 67% yield).
Trifluoro-acetate-2-carboxy-2,3-dihydro-1H-pyrrolo[2,3-b]py-
ridin-1-ium (6a and 6b)
Protected indoline 5a (1.75 g, 4.54 mmol) was treated with trifluo-
roacetic acid (4.5 mL, 59.0 mmol) and triethylsilane (0.93 mL, 11.4
mmol) in CH2Cl2 (10.5 mL). The reaction was stirred overnight and
Synthesis 2005, No. 2, 330–333 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
Free Radical-Mediated Aryl Amination
333
the solvent was removed. Et2O (5 mL) was added to the oily residue
to precipitate a white solid that was filtered, triturated with Et2O,
and dried to afford the product as the trifluoroacetate salt (830 mg,
66%); [a]D23 –3.8° (c = 1.0, CH3OH).
(5) (a) Nugent, B. M.; Williams, A. L.; Prabhakaran, E. N.;
Johnston, J. N. Tetrahedron 2003, 59, 8877.
(b) Prabhakaran, E. N.; Cox, A. L.; Nugent, B. M.; Nailor,
K. E.; Johnston, J. N. Org. Lett. 2002, 4, 4197.
(6) Leading references: (a) Copper-promoted: Lindley, J.
Tetrahedron 1984, 40, 1433. (b) See also: Lam, P. Y. S.;
Duedon, S.; Averill, K. M.; Li, R.; He, M. Y.; DeShong, P.;
Clark, C. G. J. Am. Chem. Soc. 2000, 122, 7600. (c) See
also: Kwong, F. Y.; Klapars, A.; Buchwald, S. L. Org. Lett.
2002, 4, 581. (d) Nucleophilic aromatic substitution:
Bunnett, J. F. Acc. Chem. Res. 1978, 11, 413. (e) See also:
Hattori, T.; Sakamoto, J.; Hayashizaka, N.; Miyano, S.
Synthesis 1994, 199. (f) Nitro-aromatic electrophiles:
Sapountzis, I.; Knochel, P. J. Am. Chem. Soc. 2002, 124,
9390. (g) Palladium-mediated: Wolfe, J. P.; Wagaw, S.;
Marcoux, J.-F.; Buchwald, S. L. Acc. Chem. Res. 1998, 31,
805. (h) Hartwig, J. Pure Appl. Chem. 1999, 71, 1417.
(7) Cox, A. L.; Johnston, J. N. Org. Lett. 2001, 3, 3695.
(8) (S)-Indoline a-amino acid has been used in asymmetric
synthesis after transformation to the derived amino alcohol.
Leading references: (a) Hydrogenation: Pasquier, C.; Naili,
S.; Mortreux, A.; Agbossou, F.; Pelinski, L.; Brocard, J.;
Eilers, J.; Reiners, I.; Peper, V.; Martens, J. J. Organomet.
Chem. 2000, 19, 5723. (b) Asymmetric additions to
aldehydes: Asami, M.; Watanabe, H.; Honda, K.; Inoue, S.
Tetrahedron: Asymmetry 1998, 9, 4165.
IR (film): 3093, 1746, 1680 cm–1.
1H NMR (400 MHz, CD3OD): d = 7.68 (dd, J = 7.0, 1.8 Hz, 1 H),
7.59 (dd, J = 6.7, 1.8 Hz, 1 H), 6.79 (t, J = 7.0 Hz, 1 H), 4.78 (dd,
J = 11.2, 5.0 Hz, 1 H), 3.59 (dd, J = 18.0, 11.3 Hz, 1 H), 3.36 (dd,
J = 18.2, 5.0 Hz, 1H).
13C NMR (100 MHz, CD3OD): d = 172.8, 161.8 (q, J = 30.0 Hz),
156.8, 136.4, 131.6, 128.9, 116.9 (d, J = 300 Hz), 112.9, 58.7, 30.5.
19F NMR (376 MHz, CD3OD): d = 77.4.
HRMS (EI): m/z [M – CF3COOH]+ calcd for C8H8N2O2: 164.0586;
found 164.0664.
Substitution of 5b into the procedure above provides 6b as a white
solid (1.1 g, 89%); [a]D23 +3.1° (c = 1.0, CH3OH).
Acknowledgment
This work was supported by NIGMS (GM-63577-01), the Beckman
Scholars Program (undergraduate fellowship to H.E.B.), and Lubri-
zol (graduate fellowship to R.V.). Support by the Young Investiga-
tor Award programs of Boehringer-Ingelheim, Eli Lilly, Amgen,
Yamanouchi, and Indiana University is gratefully acknowledged.
(9) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997,
119, 12414. (b) Lygo, B.; Wainwright, P. G. Tetrahedron
Lett. 1997, 38, 8595. (c) Lygo, B.; Andrews, B. I. Acc.
Chem. Res. 2004, 37, 518.
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ammonium salt is chromatographed (ref.1a).
Synthesis 2005, No. 2, 330–333 © Thieme Stuttgart · New York