Development of two complementary syntheses for a privileged cgrp receptor antagonist substructure

Article abstract of DOI:10.1021/op2003634

1-(Piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (1) is a privileged substructure found in >1000 unique CGRP receptor antagonists. Two practical and efficient syntheses of 1 are described from complementary starting materials. One route features a ch

Full text of DOI:10.1021/op2003634

Article
pubs.acs.org/OPRD
Development of Two Complementary Syntheses for a Privileged
CGRP Receptor Antagonist Substructure
David K. Leahy,* Lopa V. Desai, Rajendra P. Deshpande, Antony V. Mariadass,†
Sundaramurthy Rangaswamy,† Santhosh K. Rajagopal,† Lakshmi Madhavan,† and Shashidhar Illendula†
Chemical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey 08903, United States
†Syngene International Ltd., Biocon Park, Jigni Link Road, Bangalore - 560 099, India
ABSTRACT: 1-(Piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (1) is a privileged substructure found in >1000 unique
CGRP receptor antagonists. Two practical and efficient syntheses of 1 are described from complementary starting materials. One
route features a chemoselective reductive amination, while the second route utilizes a Pd-catalyzed amination using an ammonia
surrogate to overcome an issue of poor selectivity.
Scheme 1. Known routes for the preparation of 1
INTRODUCTION
■
Calcitonin gene-related peptide (CGRP) is a 37-amino acid
peptide associated with the pathophysiology of migraines.1
Inhibition of the CGRP receptor with a small molecule has the
potential to be an effective and safe treatment for people who
suffer from such afflictions.2 The current standard of care for
migraines is the triptan class of drugs, which are vascular
constrictors and suffer from mechanism-based cardiovascular
risks.3 In contrast, a CGRP antagonist should prevent
vasodilation, thereby circumventing cardiovascular risks.4
Pharmacophore modeling among the known CGRP receptor
antagonists has revealed a highly conserved ‘right-hand side’
fragment that incorporates key hydrogen-bonding functionality
into the molecule.5 1-(Piperidin-4-yl)-1H-imidazo[4,5-b]-
pyridin-2(3H)-one (1) is one such privileged structure (Figure
1), having appeared in >1000 unique CGRP receptor
compound 3 using a phosgene equivalent. Compound 3 is
prepared from the chemoselective reductive amination of 2,3-
diaminopyridine (4) and a protected piperidin-4-one analogue.
While route A is clearly the most direct of the available routes,
published examples of it suffer from the key drawback of a
poor-yielding reductive amination step. While the reductive
amination reaction is indeed chemoselective for the C-3
nitrogen, isolated yields are typically ≤50%. The low yield
can be attributed to competing direct reduction of the ketone
due to the poor nucleophilicity of the electron-deficient
arylamine. The low overall efficiency of route A most likely
prompted previous researchers to examine alternative ap-
proaches. Compound 3 can also be obtained by reduction of
nitropyridine 5, which in turn is prepared via SNAr addition of a
protected 4-aminopiperidine to 3-halo-2-nitropyridine 6 (route
Figure 1. Conserved RHS fragment 1.
antagonists,6 including Merck’s phase III clinical candidate
telcagepant.7
While at least three distinct approaches to compound 1 exist
in the literature, most suffer from deficiencies with starting
material cost and reaction efficiency.8 We envisioned that a
complementary approach which addresses these challenges may
provide more synthetic flexibility and find utility for many
CGRP programs. Herein, we describe two such approaches to
1, featuring a selective reductive amination and a palladium-
catalyzed amination, respectively.
Scheme 1 depicts the three established approaches for the
synthesis of 1. In the most widely utilized approach (route A),8a
the protected cyclic urea 2 is formed via the cyclization of
Received: December 9, 2011
Published: January 6, 2012
© 2012 American Chemical Society
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B).8b This route is disfavored due to the high temperatures
required for the SNAr reaction, the expense of both starting
materials, and the likelihood of genotoxicity issues with the
nitro-containing intermediates. The final established approach
relies upon an intramolecular palladium-catalyzed cyclization of
the primary urea 7 (route C).8c,d Compound 7 arises from the
reaction of N-chlorosulfonyl isocyanate with compound 8,
which in turn is derived from a reductive amination of 2-chloro-
3-aminopyridine 9 and a protected piperidin-4-one analogue.
While route C is an efficient approach that makes use of
inexpensive starting materials, we thought a complementary
approach would provide manufacturing flexibility. We elected
to consider a two-pronged approach in our strategy for an
efficient preparation of 1, opting to improve the reductive
amination step in route A, while exploring a direct conversion
of chloride 8 to amine 3.
modest increase in selectivity was realized (entries 3−4). We
rationalized that a stronger acid should further aid in driving the
iminium formation, and thus TFA was examined for this
purpose.11 Gratifyingly, complete conversion to the desired
product 11 was achieved in 1 h using 2 equiv of TFA (entries
5−6). Importantly, formation of the dialkyated impurity 12 was
minimized, presumably due to efficient iminium formation
coupled with the enhanced rate of reduction.12 After workup
and crystallization from EtOAc/IPAc, an 86% yield of 11 was
obtained with >94% purity. This improvement was expected to
dramatically improve the overall efficiency of route A and
render it a more viable preparative option.
In spite of the marked improvement made to route A, route
C still had the important advantage of utilizing the least
expensive starting materials of the available routes (Scheme 1).
We opted to examine an alternative approach that would still
make use of the inexpensive starting material 2-chloro-3-
aminopyridine 9. Hence, we hypothesized that 2-aminopyridine
3 could be derived from 2-chloropyridine 8 via a palladium-
catalyzed amination reaction with ammonia or an ammonia
surrogate (route D; Scheme 3). Such an approach would
exploit the advantage of the inexpensive starting materials of
route C while retaining the efficient ring formation of route A.
Thus, the problem was distilled down to developing an efficient
palladium-catalyzed amination reaction to convert the 2-
chloropyridine 8 into 3-aminopyridine 3.13 Nonetheless, we
expected that such a transformation would be challenging since
either the C-3 amine or the newly formed C-2 amine may be
competitive with the ammonia source for amination.14
RESULTS AND DISCUSSION
■
Of the three approaches, route A is the shortest, requiring only
three steps. However, the low-yielding reductive amination step
of 2,3-diaminopyridine 4 with ketone 10 to afford the
monoalkylated product 11 was a key concern (Scheme 2).
Scheme 2. Chemoselective reductive amination
The requisite starting material was prepared using a similar
reductive amination procedure as described for the preparation
of compound 11 (Scheme 2). Reductive amination of 2-chloro-
3-aminopyridine 9 and ketone 10 proceeded smoothly, using
NaBH(OAc)3 and TFA which ensured complete conversion of
9 with minimal direct reduction of ketone 10 (Scheme 4).15
The boc-protected 2-chloropyridine 13 was isolated in 95%
yield with >98.8% purity by crystallization from EtOAc/
heptane. With substrate 13 in hand, studies to examine the
palladium-catalyzed amination commenced.
Initial screening for the palladium-catalyzed amination
focused on determining the optimal ammonia source. A key
design consideration was a simple removal of any protecting
group introduced (or no protection) in order to maintain
efficiency. As such, the following three ammonia sources were
examined: lithium hexamethyldisilazane, ammonia, and benzo-
phenone imine.
Upon investigation of this reaction using sodium triacetox-
yborane as the reducing agent, reductive amination yields
remained low. Others have established that inefficient reactions
for similar compounds are due to inefficient iminium ion
formation.9,10 Complicating the reaction was the undesired
generation of impurity 12, resulting from a second reductive
amination at the C-2 nitrogen.
Selectivity for the desired monoalkylated product 11 was
modest (4:1) irrespective of the solvent employed (Table 1,
Initial attempts using LiHMDS as the ammonia source were
met with poor conversion, leading only to trace amounts of the
desired product 11 (Scheme 5).16 As such, this avenue was not
pursued further. Catalyst screening using a solution of ammonia
in dioxane and a strong base (NaOtBu) demonstrated modest
conversions to compound 11.17 By charging ammonia gas
instead to increasing the concentration of ammonia, better
conversion was achieved. However, the reaction suffered from
high levels of a dimeric impurity 15 resulting from an undesired
amination of the product’s C-2 or C-3 nitrogen.18
Table 1. Effect of acid on reductive amination yield and
selectivity (Scheme 2)
a
b
entry
acid
solvent
time (h) yield (%)
selectivity (11:12)
1
2
3
4
5
6
−
−
AcOH
AcOH
TFA
TFA
DCE
24
24
4
51
43
58
53
95
90
4:1
4:1
EtOAc
DCE
11:1
10:1
63:1
56:1
EtOAc
DCE
4
1
EtOAc
1
We hypothesized that benzophenone imine could be a useful
ammonia surrogate to minimize formation of byproduct 15 by
either directly blocking the C-2 reactive site or by increasing the
steric congestion at C-3.19 Preliminary screening identified
Pd(OAc)2 and Binap as a good catalyst/ligand combination to
effect the desired transformation. A base screen instructed that
strong bases still had the propensity to form impurity 15,
a
b
In-process solution yields. ratio determined by HPLC on crude
reaction mixture.
entries 1−2). Hence, the use of stoichiometric AcOH to
enhance the amine/iminium equilibrium was examined but
proved to be ineffective in improving the yield, although a
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Scheme 3. Proposed Pd-catalyzed amination approach to 1, route D
Scheme 4. Preparation of Pd-catalyzed amination substrate
13
Table 2. Effect of base and ligand to metal on Pd-catalyzed
amination (Scheme 5, R = NCPh2)
a
b
entry
base
Pd(OAc)2:Binap yield (%)
selectivity (14:15)
1
2
3
4
5
6
7
8
KOtBu
1:1
1:1
1:1
1:1
1:1
1:1
2:1
9
66
8
1:7
4:1
NaOtBu
Na2CO3
K2CO3
K3PO4
≥99:1
≥99:1
≥99:1
≥99:1
≥99:1
≥99:1
28
66
73
70
85
Cs2CO3
Cs2CO3
Cs2CO3
although encouraging yields of the desired imine product 14
were obtained using NaOtBu (Table 2, entries 1−2).20
Gratifyingly, the use of weak bases greatly reduced the levels
of 15. While yields of 14 were still poor using Na2CO3 and
K2CO3, dramatic improvements were realized with K3PO4 and
Cs2CO3 (entries 3−4 vs 5−6), leading us to choose the latter
for further evaluation.
We noticed a curious dependence of the reaction’s yield on
the ligand to metal ratio. While nearly identical results were
observed using a ratio of 1:1 and 2:1 (entries 6−7), a clear and
significant local maximum was observed using a ligand to metal
ratio of 1.5:1 (entry 8). While it is unclear why such a
phenomenon was observed, the net result is an increase in
solution yield of ∼15%. Hence, upon treatment of 13 with 1.1
equiv of benzophenone imine, 2.0 equiv of Cs2CO3, 2 mol %
Pd(OAc)2, and 3 mol % Binap in toluene, the pyridyl amine 14
was obtained in 85% solution yield with undetectable levels of
impurity 15.
With conditions in hand to selectively perform the Pd-
catalyzed amination, we next focused on conversion of the
benzophenone imine to the target amine without concurrent
deprotection of the acid labile Boc group. Citric acid was found
to be a sufficiently mild acid to effect the desired trans-
formation, and a telescoped procedure was developed to avoid
an additional isolation step.21 Hence, upon subjection of 13 to
the Pd-catalyzed amination conditions, followed by citric acid-
mediated deprotection, amine 11 was obtained in 80% yield
and ≥97.0% purity after crystallization from heptanes.
1.5:1
b
a
In-process solution yields. Ratio determined by HPLC on crude
reaction mixture.
With two efficient, yet complementary approaches to 11 in
hand, the synthesis of the CGRP substructure 1 was
accomplished according to modified literature procedures
(Scheme 6).8a Compound 11 was converted to the cyclized
urea 16 upon treatment with CDI and TEA in 89% isolated
yield and 98.5% purity. Finally, the Boc protecting group was
removed using ethanolic HCl, and 1 was isolated as its bis-HCl
salt in 94% yield and 99.9% purity. The ‘selective reductive
amination’ route to 1 proceeds in only three steps with 72%
overall yield from 2,3-diaminopyridine 4. Alternatively, the ‘Pd-
catalyzed amination’ route proceeds in five steps, with only four
isolations, with 64% overall yield from the less expensive 2-
chloro-3-aminopyridine 9.
CONCLUSION
■
In conclusion, we have developed two efficient and scalable
approaches to the ‘CGRP privileged structure’ 1-(piperidin-4-
yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one (1). The more direct
‘selective reductive amination’ route was made practical by
using a strong acid (TFA) to enhance the yield and selectivity
of the key reductive amination step. The slightly longer ‘Pd-
catalyzed amination’ route, which uses less expensive starting
Scheme 5. Pd-catalyzed amination
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a
Scheme 6. Two complementary synthetic routes to 1
a
Reagents and conditions: (a) 10, NaBH(OAc)3, TFA, EtOAc, 0 °C. (b) i. Benzophenone imine, Cs2CO3, Pd(OAc)2, rac-BINAP, toluene, 100 °C,
ii. citric acid, EtOH, 60 °C (c) 10, NaBH(OAc)3, TFA, EtOAc, 0 °C. (d) CDI, Et3N, MeCN, 10 °C. (e) HCl, EtOH, 40 °C.
materials, was made possible by the development of a selective
and efficient Pd-catalyzed amination with benzophenone imine.
Both of these approaches are expected to find broad utility in
the synthesis of a wide range of CGRP antagonists.
piperidine-1-carboxylate 13 (100 g, 0.32 mol), benzophenone
imine (64 g, 0.35 mol), and toluene (1.4 L) were degassed with
nitrogen for 30 min. Cesium carbonate (209 g, 0.641 mol),
palladium acetate (1.40 g, 0.006 mol), and rac-BINAP (6.00 g,
0.009 mol) were added at ambient temperature. The reaction
mixture was heated to 95−100 °C and stirred for 20 h. The
reaction mixture was cooled to ambient temperature, water (1
L) was added, and the layers were separated. Charcoal (20 g)
was added to the organic layer and stirred at 45 °C for 30 min;
the mixture was then filtered through Celite. The solvent was
evaporated under vacuum to afford a thick oily residue. This
residue was dissolved in ethanol (1500 mL); citric acid (185 g,
0.959 mol) and water (11.5 g, 0.641 mol) were added. The
reaction mixture was heated to 55−60 °C for 15 h. The solvent
was evaporated under vacuum to afford a thick oily residue, and
water (400 mL) was added. The pH was adjusted to 8−9 with
10% NaOH, the product was extracted with DCM (2 × 1 L),
and washed with water (2 × 0.5 L). Charcoal (20.0 g) was
added and the mixture was stirred for 30 min then filtered
through Celite. The solvent was evaporated under vacuum and
n-heptane (200 mL) was added at 35−40 °C. The resulting
slurry was cooled to ambient temperature and aged for 30 min.
The slurry was filtered, and the cake was washed with n-
heptane (200 mL) and dried at 50 °C under vacuum for 12 h to
afford 74.5 g of 11 as a pale-yellow solid (97.0 HPLC area
EXPERIMENTAL SECTION
■
General Methods. HPLC analyses for compounds 13, 11,
and 16 were collected on an Agilent 1200 liquid chromatograph
using a DAD UV−vis detector. HPLC analyses for compound 1
were collected on a Waters Alliance 2695 liquid chromatograph
using a PDA UV−vis detector. All results are reported as area
percent (area %).
tert-Butyl-4 (2-chloropyridin-3-ylamino)piperidine-1-
carboxylate (13). 2-Chloropyridin-3-amine 9 (500 g, 3.89
mol), tert-butyl-4-oxopiperidine-1-carboxylate 10 (930 g, 4.67
mol), and ethyl acetate (7.5 L) at 0−5 °C were treated with
trifluoroacetic acid (887 g, 7.78 mol) followed by sodium
triacetoxyborohydride (1240 g, 5.83 mol) at ≤10 °C. The
reaction was warmed to ambient temperature, stirred for 2 h,
and quenched with water (1.5 L). The pH was adjusted to 10−
11 with 20% sodium hydroxide solution, and the phases were
separated. The product-rich organic layer was washed with
water (3 × 5 L) and then concentrated under vacuum to ∼1.5
L. n-Heptane (5.0 L) was added to the solution at 40 °C, and
the resulting slurry was cooled to 0−5 °C and aged for 1 h. The
slurry was filtered, and the cake was washed with n-heptane (1.5
L) and dried at 50 °C under vacuum for 12 h to afford 1170 g
of 13 as an off-white solid (98.8% HPLC area purity, 95%
yield). Mp = 117.2 °C; 1H NMR (400 MHz, DMSO-d6): δ 7.60
(t, J = 2.8 Hz, 1H), 7.19 (multiple peaks, 2H), 5.16 (d, J = 8.4
Hz, 1H), 3.93 (d, J = 12.4 Hz, 2H), 3.48−3.57 (m, 1H), 2.76−
3.01 (m, 2H), 1.85 (d, J = 11.2 Hz, 2H), 1.34−1.41 (multiple
peaks, 11 H). 13C NMR (100 MHz, DMSO-d6): δ 154.3, 140.3,
136.4, 135.8, 124.3, 118.9, 79.1, 49.3, 43.1, 31.5, 28.6; IR (KBr)
3395, 2948, 1910, 1685, 1584, 1493, 1429, 1394, 1246, 1146;
HRMS Calcd for C15H23O2N3Cl: 312.1479; HRMS found [M
+ H]+: 312.1474.
1
purity, 80% yield). Mp = 158.3 °C; H NMR (400 MHz,
DMSO-d6): δ 7.27 (dd, J = 4.8 Hz, 1.6 Hz,1H), 6.67 (dd, A of
ABX, JAB = 6.8 Hz, JAX = 1.2 Hz, 1H), 6.44 (dd, B of ABX, JAB
=
7.6 Hz, JBX = 5.2 Hz, 1H), 5.44 (s, 2H), 4.49 (d, J = 7.2 Hz,
1H), 3.89 (d, J = 13.2 Hz, 2H), 3.28−3.42 (m,1H), 2.83−3.00
(m, 2H), 1.91 (dd, J = 12.8 Hz, 2.8 Hz, 2H), 1.41 (s, 9 H),
1.21−1.30 (m, 2H). 13C NMR (100 MHz, DMSO-d6): δ 154.4,
149.2, 134.7, 129.6, 114.8, 113.5, 79.0, 49.1, 42.9, 31.9, 28.6; IR
(KBr) 3433, 3386, 2927, 1678, 1577, 1510, 1474, 1457, 1433;
HRMS Calcd for C15H25O2N4: 293.1978; HRMS found [M +
H]+: 293.1972.
tert-Butyl-4-(2-aminopyridin-3-ylamino)piperidine-1-
carboxylate (11). 2,3-Diamino pyridine 4 (10.0 g, 91.6
mmol), tert-butyl 4-oxopiperidine-1-carboxylate 10 (21.9 g, 110
tert-Butyl-4-(2-aminopyridin-3-ylamino)piperidine-1-
carboxylate (11). tert-Butyl-4-(2-chloropyridin-3-ylamino)-
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mmol), and ethyl acetate (100 mL) were cooled to 0−5 °C.
Trifluoroacetic acid (23.4 g, 205 mmol) followed by sodium
triacetoxyborohydride (29.1 g, 137 mmol) were added at ≤10
°C. The reaction mixture was warmed to ambient temperature,
stirred for 2 h, and then cooled to ≤10 °C. The reaction
mixture was quenched with 10% sodium hydroxide solution
(∼180 mL), and the pH was adjusted to 8.5−9.0 while
maintaining the reaction temperature at ≤10 °C. The reaction
mixture was diluted with ethyl acetate (200 mL), and the
organic layer was separated and washed with water (100 mL).
The solution was concentrated under vacuum to ∼30 mL, and
isopropyl acetate (50 mL) was added at 40 °C. The resulting
slurry was cooled to 10−15 °C and then aged for 1 h. The
slurry was filtered, and the cake was washed with ice-cold water
(25 mL) and then dried at 50 °C under vacuum for 12 h to
afford 23.0 g of 11 as a pale-brown solid (94.4% HPLC area
purity, 86% yield).
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1
Mp = 201.2 °C; H NMR (400 MHz, DMSO-d6): δ 11.54 (s,
1H), 7.90 (dd, J = 5.2 Hz, 1.2 Hz, 1H), 7.53 (dd, J = 8.0 Hz, 0.8
Hz, 1H), 6.99 (dd, J = 7.6 Hz, 5.2 Hz, 1H), 4.32−4.38 (m, 1H),
4.10 (d, J = 12.0 Hz, 2H), 2.78−2.84 (m, 2H), 2.13 (dq, J =
12.4 Hz, 4.4 Hz, 2H), 1.72 (d, J = 10.4 Hz, 2H), 1.44 (s, 9H).
13C NMR (100 MHz, DMSO-d6): δ 154.3, 153.5, 143.9, 140.1,
123.7, 116.9, 115.1, 79.3, 50.4, 43.2, 29.1, 28.6; IR (KBr) 3363,
2975, 2862, br 1692, 1617, 1455, 1430, 1366, 1240, 1136;
HRMS Calcd for C16H23O3N4: 319.1770; HRMS found [M +
H]+: 319.1767.
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Nguyen, D. N.; Deng, J. Z.; Quigley, A. G.; Norton, B. R.; Bell, I. M.;
Mosser, S. D.; Salvatore, C. A.; Rutledge, R. Z.; Kane, S. A.; Koblan, K.
S.; Vacca, J. P.; Graham, S. L.; Williams, T. M. Bioorg. Med. Chem. Lett.
2006, 16, 5052−5056. (c) WO 2007/120590, . (d) WO 2010/
020628, .
1-(Piperidin-4-yl)-1H-imidazo[4,5-b]pyridin-2(3H)-one
dihydrochloride (1). tert-Butyl-4-(2-oxo-2,3-dihydro-1H-
imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxylate 16 (50.0
g, 0.157 mol) and HCl (4.0 M in EtOH; 250 mL) were
heated to 50−55 °C for 16 h. The reaction mixture was cooled
to ambient temperature and the resulting slurry filtered. The
cake was washed with ethanol (100 mL) and dried at 50 °C
under vacuum for 12 h to afford 42.8 g of 1 as an off-white solid
1
(99.9% HPLC area purity, 94% yield). Mp = 357.3 °C; H
(9) Abdel-Magid, A. F.; Carson, K. G.; Harris, B. D.; Maryanoff, C.
NMR (400 MHz, DMSO-d6): δ 11.67 (bs, 1H), 9.48 (bs, 1H),
9.14 (bs, 1H), 7.89−7.94 (multiple peaks, 3H), 7.05 (dd, J =
7.6 Hz, 5.2 Hz, 1H), 4.60 (dt, J = 12.4 Hz, 3.6 Hz, 1H), 3.40 (d,
J = 12.4 Hz, 2H), 3.09 (q, J = 12.0 Hz, 2H), 2.60−2.69 (m,
2H), 1.87 (d, J = 12.4 Hz, 2H). 13C NMR (100 MHz, DMSO-
d6): δ 153.2, 143.4, 139.1, 123.6, 116.9, 116.2, 47.1, 43.1, 25.4;
IR (KBr) 3294, 3114, 2914, 2812, 2708, 1736, 1667, 1563,
1381, 1227, 1136; HRMS Calcd for C11H15ON4: 219.1246;
HRMS found [M + H]+: 219.1240.
Y.; Shah, R. D. J. Org. Chem. 1996, 61, 3849−3862.
(10) For a recentreview of the use of sodium triacetoxyborohydride
in the reductiveamination of ketones and aldehydes, see: Abdel-
Magid, A. F.; Mehrman, S. J. Org. Process Res. Dev. 2006, 10, 971−
1031.
(11) For a related approach to an electron deficient aryl amine, see:
McLaughlin, M.; Palucki, M.; Davies, I. W. Org. Lett. 2006, 8, 3307−
3310.
(12) Due to the slight excess of 10 used in the reaction, slightly
higher levels of 12 are observed if the reaction is held over 1 h. The
same trend is noted to a larger extent in reactions with AcOH and
without any acid.
(13) For recent reviews on Pd-catalyzed aminations, see:
(a) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534−1544. (b) Surry,
D. S.; Buchwald, S. L. Chem. Sci. 2011, 2, 27−50.
AUTHOR INFORMATION
■
Corresponding Author
david.leahy@bms.com
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Organic Process Research & Development
Article
(14) For a strategy using thesteric bulk of the ligand to overcome
nonselective amination, see: Vo, G. D.; Hartwig, J. F. J. Am. Chem. Soc.
2009, 131, 11049−11061.
(15) For a closely related reductive amination see references 8c and
11.
(16) For Pd-catalyzed amination using LiHMDS, see: (a) Lee, S.;
Jorgensen, M.; Hartwig, J. F. Org. Lett. 2001, 3, 2729−2732.
(b) Huang, X.; Buchwald, S. L. Org. Lett. 2001, 3, 3417−3419.
(17) For Pd-catalyzed amination using a solution of NH3 indioxane
and NaOtBu, see: Surry, D.; Buchwald, S. L. J. Am. Chem. Soc. 2007,
129, 10354−10355.
(18) For Pd-catalyzed amination using ammonic under pressure and
NaOtBu, see: Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128,
10028−10029.
(19) Wolfe, J. P.; Åhman, J.; Sadighi, J. P.; Singer, R. A.; Buchwald, S.
L. Tetrahedron Lett. 1997, 38, 6367−6370.
(20) While unambiguous structural assignment has not been
obtained, we infer that the undesired amination is occurring at the
C-2 nitrogen on the basis of analysis of the reaction byproducts. For
the reactions with strong base, compound 11 is also formed in
appreciable amounts, indicating the hydrolysis of the imine under the
reaction conditions is possible, thereby enabling the undesired
amination at C-2. Additionally, the undesired amination product 15
does not contain the imine moiety, nor is the mass of this potential
byproduct found in the LC/MS, thereby making the undesired
amination at C-3 unlikely.
(21) O’Donnell, M. J.; Boniece, J. M.; Earp, S. E. Tetrahedron Lett.
1978, 30, 2641−2644.
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