Efficient and general asymmetric syntheses of (R)-chroman-4-amine salts

Article abstract of DOI:10.1016/j.tetlet.2010.09.006

Starting from a variety of substituted chroman-4-ones, a highly enantioselective CBS reduction using in situ-generated B-H catalyst gave (S)-chroman-4-ols. Azide inversion and reduction gave crude (R)-chroman-4- amines, which could be purified without chromatography by isolation as the (R)-mandelic or d-tartaric acid salts with good yields and excellent ee.

Full text of DOI:10.1016/j.tetlet.2010.09.006

Tetrahedron Letters 51 (2010) 5904–5907
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient and general asymmetric syntheses of (R)-chroman-4-amine salts
Eric A. Voight a, , Jerome F. Daanen a, Steven M. Hannick a, Bhadra H. Shelat a, Francis A. Kerdesky b,
⇑
Daniel J. Plata b, Michael E. Kort a
a Global Pharmaceutical Research and Development, Abbott Laboratories, 100 Abbott Park Rd., Abbott Park, IL 60064-6100, United States
b Process Research and Development, 1401 Sheridan Rd., North Chicago, IL 60064-6285, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 19 July 2010
Revised 31 August 2010
Accepted 1 September 2010
Available online 8 September 2010
Starting from a variety of substituted chroman-4-ones, a highly enantioselective CBS reduction using
in situ-generated B–H catalyst gave (S)-chroman-4-ols. Azide inversion and reduction gave crude (R)-
chroman-4-amines, which could be purified without chromatography by isolation as the (R)-mandelic
or D-tartaric acid salts with good yields and excellent ee.
Ó 2010 Elsevier Ltd. All rights reserved.
Chiral chroman-4-amines have been utilized as core scaffolds in
an increasing number of recent drug discovery programs (Fig. 1).
For example, chroman-4-amine sulfonamide 1 was found to be a
eral route upon further optimization.5 Finally, we decided to inves-
tigate the previously reported asymmetric ketone reduction/azide
inversion route disclosed by Gerlach and co-workers,6 aware that
low reduction ee was observed with electron-withdrawing aryl
substituents. Of equal concern, low azideinversion yield and ee were
reported in several examples. These drawbacks would need to be
overcome to provide a practical and general route.
potent Kv1.5 potassium channel blocker (IC50 = 0.11 lM) with good
selectivity over the block of hERG.1 Also, diaminochroman carbox-
amide 2 is a 0.8 nM inhibitor of the human bradykinin B1 receptor
showing in vivo efficacy against hypotension and inflammatory
pain.2
Initially, the published CBS reduction7 conditions for chroman-
4-one 8 were employed (Table 1, entry 1, Scheme 1), using the
commercially available B–Me CBS catalyst (5 mol %) and borane–
methyl sulfide (1 equiv).6 These conditions gave (S)-chroman-4-ol
9 with the reported 96% ee and quantitative yield. Aware that other
substrates were more problematic under these conditions, we
sought to further optimize the reaction. Without changing the sol-
vent, the in situ-generated B–H CBS catalyst derived from the free
aminoalcohol ligand (5 mol %) and N,N-diethylaniline borane (also
serving as stoichiometric reducing agent) gave comparable results
(Table 1, entry 2).8 Finally, switching to methyl t-butyl ether (10
We required an efficient, general, scalable, and highly enantio-
selective synthesis of an array of structurally diverse (R)-chro-
man-4-amines 3 for our own drug discovery efforts (Fig. 2). We
hoped to obtain these from readily available chroman-4-ones 4.3
Conceptually, an imine (i.e., 5) or enamine (i.e., 6) derived from 4
could be reduced enantioselectively to give 3. Alternatively, enan-
tioselective ketone reduction to (S)-chroman-4-ol 7 followed by
amine inversion would also yield 3.
Several recently disclosed methods for 2-unsubstituted chro-
man-4-amine preparation were initially investigated,4 but 2,2-
disubstituted chromans (Fig. 2, R = alkyl) were unsuitable substrates
for these methods in our hands. Initial results with asymmetric
enamine hydrogenation were encouraging and could provide a gen-
R
R
R
R
O
O
R''N
R
O
R'
O
O
H2N
R
R'
HN
HN
5
O
S
O
O
3
O
NH
O
O
R
R
R''HN
R
S
N
R'
N
N
O
O
H
R
F
6
1
2
O
CF3
R'
HO
R'
4
Figure 1. Biologically active chroman-4-amine-containing compounds.
7
⇑
Corresponding author. Tel.: +1 847 938 6741; fax: +1 847 935 0548.
E-mail address: eric.a.voight@abbott.com (E.A. Voight).
Figure 2. Chroman-4-amines (3) from chroman-4-ones (4).
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.09.006

E. A. Voight et al. / Tetrahedron Letters 51 (2010) 5904–5907
5905
Table 1
Asymmetric chroman-4-one reduction according to Scheme 1
Entry
Conditionsa
%eeb
Yieldc (%)
1
2
3
(R)-2-Me-CBS-oxazaborolidine (5 mol %), BH3ÁSMe2 (1 equiv), toluene, 0 °C
96
96
99
>99
>99
>99
(R)-Diphenyl(pyrrolidin-2-yl)methanol (5 mol %), BH3ÁNEt2Ph (1.2 equiv), toluene, 45 °C
(R)-Diphenyl(pyrrolidin-2-yl)methanol (5 mol %), BH3ÁNEt2Ph (1.2 equiv), MTBE, 45 °C
a
b
c
Slow inverse addition (30–75 min) of substrate to reagent for all reactions.
Enantiomeric excess was determined by chiral HPLC.
Isolated yield.
Ph
H
N
Ph
O
O
O
O
O
O
F
O
F
B
O
O
O
O
O
R
O
HO
conditions
(Table 1)
14
17
15
18
16
19
F
8
9
O
O
F
F
Scheme 1. Asymmetric reduction of chroman-4-one 8.
O
CF3
F
O
O
F
n-Bu4NN3
Ms2O
Figure 3. Chromanone substrates for Scheme 2 procedure.
9
N3
MsO
i-Pr2NEt
THF
F
Table 2
10
11
CBS reduction, n-Bu4NN3 inversion, (R)-mandelic acid salt formation according to
Schemes 1 and 2 (substrates in Fig. 3)
OH
O
HO
O
O
F
PPh3
Entry
Substrate
Reduction
%eea
Crude amine
yield % (%ee)a
Amine salt
THF
Ph
H2N
yield % (%ee)a
H3N
O
i-PrOH/hexanes
77%, >99% ee
H2O
74%
1
2
3
4
5
6
14
15
16
17
18
19
>99
>99
97
99
>99
>99
67 (87)
71 (95)
59
68 (94)
56 (98)
79
82 (>99)
65 (99)
65 (>99)
80 (98)
75 (>99)
64 (98)
HO
F
O
13
from 9
12
Ph
Scheme 2. Preparation of (R)-chroman-4-amine salt 13.
a
Enantiomeric excess was determined by chiral HPLC.
volumes) as the solvent under the same conditions increased the
ee to 99% and was conveniently carried out on a large scale (Table
1, entry 3). Besides increasing the ee, this procedure displayed no
moisture sensitivity, avoided the safety and volume productivity
concerns associated with conventional CBS reductions,8 and re-
quired no product purification beyond conventional aqueous
workup.9
azide inversion step was observed to some extent, however, the
(R)-mandelic acid salt isolation improved the ee and provided good
recovery and purity. All reactions were carried out on a 5–10 g
scale and required no chromatography. In comparison to the Ger-
lach procedure,6 this method provided modest improvements in
overall yield while significantly improving ee and scalability.
While this procedure worked well for all substrates in Figure 3,
more lipophilic chroman-4-amine mandelic acid salts often formed
oils instead of crystalline solids. A screen of several chiral and achi-
From (S)-chroman-4-ol 9, the published procedure was fol-
lowed, generating mesylate 10 at À25 °C in THF followed by the
addition of tetra-N-butylammonium azide to produce inverted
(R)-azide 11 (Scheme 2).6 Azide reduction under Staudinger condi-
tions gave (R)-chroman-4-amine 12 in 74% overall yield from 9.10
Chiral HPLC versus a racemic reference demonstrated that 12
was produced in 91% ee, a degradation we expected based on the
published result. In order to upgrade the ee and to avoid chroma-
tography, salt crystallization conditions were explored (Scheme 3).
A patent procedure described a racemate resolution with low
recovery and good ee using (R)-mandelic acid.11 From crude amine
12 (after acid/base workup), the (R)-mandelic acid salt of 12 was
formed in i-PrOH (10 volumes) at 50 °C. Addition of hexanes (10
volumes) as an antisolvent and slow cooling to room temperature
allowed the filtration of 13 in 77% yield and high purity. Chiral
HPLC of this material was not able to detect the minor enantiomer.
This chromatography-free process was applied successfully to
chroman-4-ones 14–19, efficiently providing (R)-chroman-4-
amine salts (Table 2, Fig. 3). Both 2-unsubstituted (entries 1 and
2) and 2,2-dimethyl (entries 3–6) chromans were tolerated, as well
as a variety of aryl substituents. In all cases, ee degradation in the
ral acids identified D-tartaric acid as a suitable alternative. Also, the
acid/base workup employed for the crude amines to reject the
phosphine oxide reduction byproduct was unsuccessful, since lipo-
philic HCl salts did not show sufficient water solubility. Azide
hydrogenation provided an alternative. Finally, a diphenylphos-
phoryl azide procedure was identified to improve the azide inver-
sion step for some substrates.12 An example of this procedure
starting from chromanone 20 is shown in Scheme 3, providing
amine salt 24 in 76% overall yield from 20 and 98% ee.13
With this modified method in hand, several (R)-chroman-4-
amine D-tartaric acid salts were prepared in good overall yield
and excellent ee (Fig. 4). In addition to 2,2-bis(monofluoromethyl)
substitution (Scheme 3), 2,2-diethyl (25–28), 2,2-dipropyl (29),
and 2,2-dimethyl (30) chroman substitution were well tolerated.
Chromans with aryl substitution at the 6, 7, or, 8 position were
all good substrates for this chemistry, reliably providing (R)-chro-

5906
E. A. Voight et al. / Tetrahedron Letters 51 (2010) 5904–5907
3. Chroman-4-ones 8, 14–20, and 25–29 were either commercially available or
Ph
H
Ph
OH
prepared from the corresponding 2-hydroxyacetophenone and dialkyl ketone
in pyrrolidine and MeOH: Kabbe, H. J. Synthesis 1978, 886–887; (a) All 2-
hydroxyacetophenones were either commercially available or prepared
according to: Uchida, H.; Kosuga, N.; Satoh, T.; Hotta, D.; Kamino, T.; Maeda,
Y.; Amano, K.; Akada, Y. PCT Int. Appl. WO2007010383, 2007.; (b) Marzi, E.;
Schlosser, M. Tetrahedron 2005, 61, 3393–3401; Chroman-4-one 31 was
prepared from 3-(trifluoromethoxy)phenol according to: Camps, F.; Coll, J.;
Messeguer, A.; Pericas, M. A.; Ricart, S. Synthesis 1980, 725–727.
F
F
F
F
O
F
O
F
NH
(5 mol%)
(PhO)2P(O)N3
DBU, THF
HO
O
BH3 NEt2Ph
MTBE
20
21
4. (a) Huang, K.; Merced, F. G.; Ortiz-Marciales, M.; Meléndez, H. J.; Correa, W.; De
Jesús, M. J. Org. Chem. 2008, 73, 4017–4026; (b) Han, K.; Park, J.; Kim, M.-J. J.
Org. Chem. 2008, 73, 4302–4304; (c) Kim, M.-J.; Kim, W.-H.; Han, K.; Choi, Y. K.;
Park, J. Org. Lett. 2007, 9, 1157–1159.
5. (a) Burk, M. J.; Wang, M. W.; Lee, J. R. J. Am. Chem. Soc. 1996, 118, 5142–5143;
(b) Hydrogenation of enamide 31 provided efficient conversion to amide 32
with 83% ee. (Ligand = (R)-1-[(S)-(di-tert-butylphosphino)ferrocenyl] ethyl-
diphenylphosphine).
F
F
F
F
F
F
D-tartaric
acid
O
F
O
O
F
H2
i-PrOH
H3N
N3
H2N
O
Pd/C
HO
HO
MeOH
O
F
24
22
23
CO2H
50 psi H2
(Rh[COD]Cl2)2
Scheme 3. Alternative procedure to D-tartaric acid salt 24.
O
O
F
F
AcHN
Ligand
40º C, MeOH
AcHN
31
32
O
O
O
6. Burgard, A.; Lang, H.-J.; Gerlach, U. Tetrahedron 1999, 55, 7555–7562.
7. Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.; Singh, V. K. J. Am. Chem. Soc.
1987, 109, 7925–7926.
F
O
O
O
ˇ
8. Garrett, C. E.; Prasad, K.; Repic, O.; Blacklock, T. J. Tetrahedron: Asymmetry 2002,
25
27
26
F
13, 1347–1349; N,N-Diethylaniline borane has been employed previously as a
chroman-4-one stoichiometric reducing agent using the B–Me CBS catalyst
with lower ee: Bichlmaier, I.; Siiskonen, A.; Finel, M.; Yli-Kauhaluoma, J. J. Med.
Chem. 2006, 49, 1818–1827.
51%, 98% ee
72%, 99% ee
65%, 99% ee
9. Typical CBS reduction procedure: A solution of methyl tert-butylether (34 mL),
(R)-diphenyl(pyrrolidin-2-yl)methanol (1.10 g, 4.35 mmol), and borane-N,N-
diethylaniline complex (18.5 mL, 104 mmol) was heated to 45 °C and chroman-
4-one 8 (16.9 g, 87.0 mmol) in methyl tert-butylether (136 mL) was added over
75 min via an addition funnel. After 15 min at 45 °C, the reaction mixture was
cooled to 10 °C and treated with MeOH (85 mL) over 10 min (H2 evolution).
After stirring for 30 min at room temperature, 2 N HCl (85 mL) was added and
the reaction mixture was stirred for 10 min. Methyl tert-butylether (170 mL)
was added and the layers were separated. The organic layer was washed with
2 N HCl (85 mL) and brine (35 mL). The aqueous layers were back-extracted
with methyl tert-butylether (85 mL). The combined organic portions were
O
O
O
OCF3
O
O
O
OCF3
28
61%,* 98% ee
29
30
58%, 99% ee
F
54%, >99% ee
Figure 4. Chromanone substrates for Scheme 3 procedure (* = Ms2O/n-Bu4NN3
dried (Na2SO4), filtered, and concentrated, to provide (S)-chroman-4-ol
9
inversion protocol).
(17.4 g, 89.0 mmol). Analysis by analytical chiral HPLC (Chiralcel OJ
4.6 Â 25 mm, 20% isopropanol/hexane, 23 °C, 0.5 mL/min) showed 99% ee
versus a racemic reference.
man-4-amine
D-tartaric acid salts on multigram scale without
10. Typical azide inversion, reduction, salt formation procedure according to
Scheme 2: A solution of chroman-4-ol 9 (17.1 g, 87.0 mmol) in THF (340 mL)
was cooled to À30 °C followed by the addition of methanesulfonic anhydride
(16.7 mL, 131 mmol). N,N-Diisopropylethylamine (21.3 mL, 122 mmol) was
slowly added (internal temperature 6 À24 °C) to the reaction mixture. After
50 min, additional Ms2O (3.00 g, 0.2 equiv) and N,N-diisopropylethylamine
(4.2 mL, 0.3 equiv) were added and the reaction mixture was stirred for 30 min
at 0 °C. The dark solution of mesylate 10 was cooled to À30 °C and treated with
tetra-N-butylammonium azide (49.5 g, 174 mmol). The resulting slurry was
allowed to slowly warm to ambient temperature overnight. After 14 h,
methanol (85 mL) was added followed by 2 N NaOH. After 30 min, MTBE
(340 mL) and water (170 mL) were added. The layers were separated and the
organic layer was washed with water (85 mL), 2 N HCl (2 Â 85 mL), water
(85 mL), and brine (34 mL). The acidic washes were back-extracted with MTBE
(85 mL). The combined organic portions were dried (Na2SO4), filtered, and
concentrated to give azide 11 as a yellow oil that was used without further
purification. The crude azide 11 was dissolved in THF (305 mL) and water
(34 mL) and treated with triphenylphosphine (25.1 g, 96.0 mmol). The yellow
solution was heated to 60 °C for 2.5 h. The reaction mixture was cooled and
concentrated to remove THF. Dichloromethane (170 mL), 2 N HCl (85 mL), and
water (425 mL) were added and the layers were separated. The aqueous
portion was washed with dichloromethane (85 mL). 2 N NaOH (100 mL) was
added to the aqueous layer, followed by extraction with dichloromethane
(5 Â 85 mL). The organic layers were dried (Na2SO4), filtered, and concentrated
to give amine 12 (12.6 g, 64.3 mmol, 74%). Analytical chiral HPLC showed 91%
ee versus a racemic reference. Amine 12 (12.6 g, 64.3 mmol) and isopropanol
(126 mL) were heated to 50 °C while (R)-(À)-mandelic acid (9.79 g, 64.3 mmol)
was added. At 43 °C, solids were observed, and heating continued to 50 °C. The
mixture was aged at 50 °C for 10 min, then hexanes (126 mL) were added for
over 45 min at 50 °C. Following the addition, the reaction mixture was cooled
to ambient temperature for over 90 min, and the precipitated solids were
filtered and washed with 1:1 isopropanol–hexanes. The solid was dried in a
vacuum oven at 45 °C overnight with an air bleed, to give (R)-chroman-4-
amine salt 13 (17.2 g, 49.5 mmol, 77%) as a crystalline white solid. The solid
had no detectable minor isomer by chiral HPLC and the mother liquor showed
ꢀ50% ee in favor of the desired isomer. 1H NMR (300 MHz, DMSO-d6) d 7.44–
chromatography from chroman-4-ones 25–30.
In conclusion, a known method for the preparation of chiral
chroman-4-amines from chroman-4-ones was optimized to pro-
vide a general, scalable, and highly enantioselective route. Alterna-
tive procedures for each step of the synthesis were identified to
make the approach more practical, including an improved CBS
reduction protocol, a DPPA azide inversion, azide hydrogenation,
and chiral salt isolation. The (R)-mandelic and D-tartaric acid salt
isolation procedures provided convenient and reliable methods
for chemical and chiral purification. The modified procedure
(Scheme 3) has been carried out successfully on kilogram scale,
highlighting the utility of this route.
Acknowledgment
We thank the Abbott Laboratories structural chemistry group
for compound characterization support.
References and notes
1. Lloyd, J.; Atwal, K. S.; Finlay, H. J.; Nyman, M.; Huynh, T.; Bhandaru, R.; Kover,
A.; Schmidt, J.; Vaccaro, W.; Conder, M. L.; Jenkins-West, T.; Levesque, P. Bioorg.
Med. Chem. Lett. 2007, 17, 3271.
2. Biswas, K.; Li, A.; Chen, J. J.; D’Amico, D. C.; Fotsch, C.; Han, N.; Human, J.; Liu,
Q.; Norman, M. H.; Riahi, B.; Yuan, C.; Suzuki, H.; Mareska, D. A.; Zhan, J.;
Clarke, D. E.; Toro, A.; Groneberg, R. D.; Burgess, L. E.; Lester-Zeiner, D.;
Biddlecome, G.; Manning, B. H.; Arik, L.; Dong, H.; Huang, M.; Kamassah, A.;
Loeloff, R.; Sun, H.; Hsieh, F.; Kumar, G.; Ng, G. Y.; Hungate, R. W.; Askew, B. C.;
Johnson, E. J. Med. Chem. 2007, 50, 2200–2212.

E. A. Voight et al. / Tetrahedron Letters 51 (2010) 5904–5907
5907
7.37 (m, 3H), 7.30–7.17 (m, 3H), 7.01 (td, J = 8.5, 3.1 Hz, 1H), 6.78–6.73 (m, 1H),
4.70 (s, 1H), 4.21 (dd, J = 11.5, 6.3 Hz, 1H), 2.13 (dd, J = 13.2, 6.3 Hz, 1H), 1.65 (t,
J = 12.3 Hz, 1H), 1.37 (s, 3H), 1.17 (s, 3H); MS (DCI/NH3) m/z 179 (MÀ16)+.
11. Gharat, L. A.; Joshi, U. M.; Joshi, N. K. PCT Int. Appl. WO 2007/042906, 2007.
12. For example, see Ref. 2.
giving crude azide 22 as a yellow oil. A solution of crude azide 22 (13.92 g) in
MeOH (150 mL) was shaken with 5% Pd on carbon (4.17 g, 15 wt % dry basis)
under hydrogen (30 psi) at 50 °C for 3 h. The mixture was filtered and
concentrated with an isopropyl alcohol chase to yield crude amine 23.
Isopropyl alcohol (125 ml) was added, the solution heated to 50 °C, and D-
13. Typical azide inversion, reduction, salt formation procedure according to
Scheme 3: A solution of (S)-chroman-4-ol 21 (12.56 g, 54.1 mmol) and THF
(190 mL) was cooled to <5 °C, and 1,8-diazabicyclo[5.4.0]undec-7-ene
(12.11 mL, 81 mmol) and diphenylphosphoryl azide (15.18 mL, 70.3 mmol)
were added. After 2 h, the yellow slurry was warmed to room temperature.
After 14 h, the mixture was concentrated, diluted with MTBE (250 mL), and
washed with 2 N NaOH (2 Â 125 mL), brine (50 mL), 2 N HCl (2 Â 125 mL), and
brine (50 mL). The organic layer was dried (Na2SO4), filtered, and concentrated,
(À)-tartaric acid (8.12 g, 54.1 mmol) was added. The slurry was heated to
70 °C, then cooled slowly to room temperature and stirred for 1 h. The solid
was filtered, washed with isopropyl alcohol, and dried in a vacuum oven at
60 °C, giving (R)-chroman-4-amine salt 24 (15.7 g, 41.2 mmol, 76% yield) as a
white crystalline solid. Chiral HPLC showed 98% ee. 1H NMR (300 MHz, MeOH-
d6) d 7.23 (dd, J = 6, 3 Hz, 1H), 7.10–6.90 (m, 2H), 4.43–4.71 (m, 5H), 4.41 (s,
2H), 2.52 (dd, J = 12, 6 Hz, 1H), 2.06 (ddd, J = 15, 12, 3 Hz, 1H); MS (DCI/NH3) m/
z 232 (M+NH3ÀH2O)+.