Multicomponent one-pot procedure for the synthesis of free α-chiral amines from aldehydes

Article abstract of DOI:10.1021/jo0516483

The synthesis of free a-chiral amines by a one-pot multi-component procedure from commercially available starting materials is described. This enantioselective reaction involves a catalytic asymmetric addition of dialkylzinc reagents to N-diphenylphosphin

Full text of DOI:10.1021/jo0516483

approach, which reduces the typical three-step synthesis
to a one-pot process (Scheme 1). The dehydrating prop-
erty of diorganozinc reagents was utilized to generate
imines in situ, as previously demonstrated by Hoveyda
and Snapper.3a,b We have also taken advantage of the
facile cleavage of a phosphinoyl activating group1b,8 from
amines under acidic workup conditions.
This is a very effective and general method to gain
access to free R-chiral amines directly from commercially
available reagents. The Leuckart-Wallach-type condi-
tions developed by Kadyrov and co-workers seem to be
limited to acetophenone derivatives.9 Enzymatic methods
possess the disadvantage that enzymes are substrate
specific, thus reducing the generality of the protocol.10
Multicomponent One-Pot Procedure for the
Synthesis of Free r-Chiral Amines from
Aldehydes
Alexandre Coˆte´ and Andre´ B. Charette*
De´partement de Chimie, Universite´ de Montre´al, P.O. 6128,
Station Downtown, Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received August 5, 2005
Optimization experiments were performed with com-
mercially available aldehydes that were not further
purified prior to use. Despite the fact that preliminary
results have shown that slightly better enantioselectivi-
ties could be obtained with neat diorganozinc reagents,
we chose to use solutions in toluene for safety (some neat
dialkylzinc reagents are pyrophoric), availability, and
economical considerations.
An examination of the stoichiometry revealed that 3
equiv of aldehyde and 5 equiv of dialkylzinc reagent,
relative to the phosphinoylamide, provided the best
compromise between economy of reagents, overall yield,
and quantity of side products formed.
The main challenge in transferring the methodology
to a parallel synthesis format was to find conditions to
effect complexation, since this typically involves mixing
The synthesis of free R-chiral amines by a one-pot multi-
component procedure from commercially available starting
materials is described. This enantioselective reaction in-
volves a catalytic asymmetric addition of dialkylzinc re-
agents to N-diphenylphosphinoylimines with use of an air-
stable precatalyst complex 1. The R-chiral amines are
prepared with a one-pot procedure from alkyl and aryl
aldehydes in good yield (41-90%) and with excellent enan-
tioselectivity (90-97% ee).
(6) (a) Boezio, A. A.; Charette, A. B. J. Am. Chem. Soc. 2003, 125,
1692-1693. (b) Boezio, A. A.; Pytkowicz, J.; Coˆte´, A.; Charette, A. B.
J. Am. Chem. Soc. 2003, 125, 14260-14261. (c) Coˆte´, A.; Boezio, A.
A.; Charette, A. B. Proc. Natl Acad. Sci. U.S.A. 2004, 101, 5405-5410.
(d) Desrosiers, J.-N.; Coˆte´, A.; Charette, A. B. Tetrahedron 2005, 61,
6186-6192.
(7) Selected examples of catalytic enantioselective methods to
prepare protected R-chiral amines from imines: (a) Soeta, T.; Nagai,
K.; Fujihara, H.; Kuriyama, M.; Tomioka, K. J. Org. Chem. 2003, 68,
9723-9727. (b) Lipshutz, B. H.; Shimizu, H. Angew. Chem., Int. Ed.
2004, 43, 2228-2230. (c) Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer,
R. A.; Chen, C.-Y.; Volante, R. P. Org. Lett. 2005, 7, 355-358. (d)
Dahmen, S.; Bra¨se, S. J. Am. Chem. Soc. 2002, 124, 5940-5941. (e)
Zhang, H.; Liu, H.; Cui, X.; Mi, A.; Jiang, Y.; Gong, L. Z. Synlett 2005,
615-618. (f) Wang, C.; Shi, M. J. Org. Chem. 2003, 68, 6229-6237.
(g) Otomaru, Y.; Tokunaga, N.; Shintani, R.; Hayashi, T. Org. Lett.
2005, 7, 307-310.
(8) (a) Matsunaga, S.; Kumagai, N.; Harada, S.; Shibasaki, M. J.
Am. Chem. Soc. 2003, 125, 4712-4713. (b) Wipf, P.; Kendall, C.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2003, 125, 761-768. (c)
Guijarro, D.; Pinho, P.; Andersson, P. G. J. Org. Chem. 1998, 63, 2530-
2535. (d) Palacios, F.; Aparicio, D.; Garc´ıa, J.; Rodr´ıguez, E. Eur. J.
Org. Chem. 1998, 1413-1423. (e) Soai, K.; Hatanaka, T.; Miyazawa,
T. J. Chem. Soc., Chem. Commun. 1992, 1097-1098.
(9) (a) Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003,
42, 5472-5474. (b) Tararov, V. I.; Kadyrov, R.; Riermeier, T. H.;
Fischer, C.; Bo¨rner, A. Adv. Synth. Catal. 2004, 346, 561-565.
(10) Some examples of enzymatic transaminations: (a) He´laine, V.;
Rossi, J.; Gefflaut, T.; Alaux, S.; Bolte, J. Adv. Synth. Catal. 2001,
343, 692-697. (b) Li, T.-L.; Choroba, O. W.; Charles, E. H.; Sandercock,
A. M.; Williams, D. H.; Spencer, J. B. Chem. Commun. 2001, 1752-
1753. (c) Fotheringham, I. G.; Grinter, N.; Pantaleone, D. P.; Senkpeil,
R. F.; Taylor, P. P. Bioorg. Med. Chem. 1999, 7, 2209-2213. (d)
Harding, J. R.; Hughes, R. A.; Kelly, N. M.; Sutherland, A.; Willis, C.
L. J. Chem. Soc., Perkin Trans. 1 2000, 3406-3416. (e) Kim, K.; Cole,
P. A. J. Am. Chem. Soc. 1998, 120, 6851-6858. (f) Cox, R. J.; Jenkins,
H.; Schouten, J. A.; Stentiford, R. A.; Wareing, K. J. J. Chem. Soc.,
Perkin Trans. 1 2000, 2023-2036. (g) Sutherland, A.; Willis, C. L. J.
Bioorg. Med. Chem. Lett. 1999, 9, 1941-1944.
The extensive use of enantiopure R-chiral amines in
food, agrochemical, biochemical, and pharmaceutical
industries has stimulated the development of methodolo-
gies to generate them.1 A one-pot multicomponent2-4
synthesis would be extremely valuable in high-through-
put processes which are amenable to automation, such
as combinatorial and parallel synthesis.5
Having recently developed a catalytic asymmetric
reaction to generate R-chiral amines,6,7 we have aimed
at finding experimental conditions that could be adapted
to a parallel synthesis format. Described herein is our
(1) (a) Bloch, R. Chem. Rev. 1998, 98, 1407-1438. (b) Kobayashi,
S.; Ishitani, H. Chem. Rev. 1999, 99, 1069-1094.
(2) Review on asymmetric multicomponent reactions: Ramo´n, D.
J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44, 1602-1634.
(3) Asymmetric multicomponent addition of organometallic reagents
to imine and/or iminium: (a) Porter, J. R.; Traverse, J. F.; Hoveyda,
A. H.; Snapper, M. L. J. Am. Chem. Soc. 2001, 123, 10409-10410. (b)
Akullian, L. C.; Snapper, M. L.; Hoveyda A. H. Angew. Chem., Int.
Ed. 2003, 42, 4244-4247. (c) Gommermann, N.; Koradin, C.; Polborn,
K.; Knochel, P. Angew. Chem., Int. Ed. 2003, 42, 5763-5766.
(4) Asymmetric one-pot reduction and addition to imines: (a) Borg,
G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40, 6709-6712.
(b) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127,
1092-1093.
(5) (a) Cargill, J. F.; Lebl, M. Curr. Opin. Chem. Biol. 1997, 1, 67-
71. (b) Kirschning, A.; Monenschein, H.; Wittenberg, R. Angew. Chem.,
Int. Ed. 2001, 40, 650-679. (c) Powers, D. G.; Coffen, D. L. Drug
Discovery Today 1999, 4, 377-383. (d) Dolle, R. E. J. Comb. Chem.
2003, 5, 693-753. (e) Horton, D. A.; Bourne, G. T.; Smythe, M. L.
Chem. Rev. 2003, 103, 893-930.
10.1021/jo0516483 CCC: $30.25 © 2005 American Chemical Society
Published on Web 11/18/2005
10864
J. Org. Chem. 2005, 70, 10864-10867

SCHEME 1. Typical Three-Step Sequence for the
Benzaldehyde derivatives having electron withdrawing
groups (entries 2 and 6) seem to be more prone to side
reactions such as reduction and noncatalyzed addition
of diethylzinc to aldehyde and imine, which leads to lower
yields and enantioselectivities. However, this problem
can be circumvented either by decreasing the concentra-
tion from 0.2 to 0.1 M or by decreasing the reaction
temperature to 0 °C. Typical side products are illustrated
in Figure 2.15 Compounds 3a and 4a can be removed by
a reverse extraction whereby the ammonium salts are
retained in the aqueous phase and the alcohols are
retained in the etheral phase. Only very small quantities
of compound 5 are produced, which can be separated by
either normal phase or reverse phase chromatography.
A low reaction temperature is necessary to achieve
high enantioselectivity from the unbranched aliphatic
aldehyde 2i (entry 9). As with other copper-mediated
addition to imines, the rate of reaction of dimethylzinc
is lower than that of diethylzinc.3a,7a,16,17 By increasing
the reaction time, it is possible to get the desired product
with excellent ee in acceptable yields. In the case of the
furyl derivative 2g, improved yields were obtained by
isolating the addition product prior to treatment with
aqueous HCl to cleave the phosphinoyl group. The
neutral form of 2g is difficult to extract from the aqueous
phase, possibly as a result of complexation with excess
zinc species in solution.
Synthesis of Free r-Chiral Amines
two heterogeneous solutions under an inert atmosphere.
We have not yet isolated a BozPHOS‚CuOTf complex, the
putative active catalyst. However, we prepared complex
1 (Figure 1) and discovered that the addition of 1 to a
solution of aldehyde and phosphinoylamide led to the
formation of R-chiral amines with yields and enantiose-
lectivities similar to those obtained from a mixture of
BozPHOS and Cu(OTf)2. Complex 1 may be a precursor
to the active catalyst, which greatly simplifies the
experimental protocol, since 1 is a stable crystalline
compound that can be manipulated in air for several
weeks.11 Purification of 1 can be accomplished easily by
flash chromatography. As both enantiomeric forms of 1
are accessible, both enantiomers of the product can be
synthesized equally well.12
Although in our earlier studies we had obtained good
enantioselectivities at 0 °C, we found that the yields could
be increased by carrying out these multicomponent
reactions at ambient temperature without any significant
loss of enantioselectivity (Table 1). A study of the
precatalyst loading revealed that there was no significant
effect on yield and only a small variation in the enanti-
oselectivity within the range between 5 and 1 mol % of
1. Most notably, similar yields and enantioselectivities
were obtained regardless of whether measures were
taken to exclude moisture and oxygen (compare entries
1 and 4).
As shown in Table 2, our methodology can be applied
to a wide scope of substrates. Alkyl, aryl, heterocyclic,
ether, nitro, and halogen functional groups are compat-
ible with the reaction conditions. This tolerance of
functionality, combined with the commercial availability
of numerous aldehydes as building blocks, creates the
potential for extensive diversification through parallel
synthesis. Although there are few dialkylzinc reagents
that are commercially available, many efficient methods
to generate them are known.13 In addition, organozinc
reagents can support functionalization more readily than
organomagnesium and organolithium reagents.14
While many aldehydes can be employed under our
conditions, they do exhibit differences in reactivity.
In conclusion, we have developed a one-pot procedure
to gain access to free R-chiral amines using commercially
available starting materials and an air-stable chiral
precatalyst copper complex. Our methodology is highly
suited for automated parallel synthesis.
Experimental Section
Synthesis of Complex (1). (CuOTf)2‚toluene (200 mg, 0.39
mmol) and BozPHOS6 (500 mg, 1.55 mmol) were solubilized in
anhydrous MeCN (10 mL) under an atmosphere of argon and
the resulting green solution was stirred for 1 h at room
temperature. The solvent was removed under reduced pressure
and the residue was purified by flash chromatography on silica
gel with CH2Cl2/MeOH (95:05) as eluent. The title compound
was obtained as a light yellow solid (598 mg, 90%). Mp 199.0-
200.5 °C; Rf 0.33 (10% MeOH in CH2Cl2); [R]23 +5.47 (c 2.53,
D
CHCl3); 1H NMR (300 MHz, CD2Cl2) δ 7.82-7.73 (m, 2H), 7.72-
7.61 (m, 4H), 7.55-7.44 (m, 2H), 2.94-2.78 (m, 2H), 2.60-2.09
(m, 14H), 1.81-1.34 (m, 14H), 1.21 (dd, J ) 14.9, 6.9 Hz, 6H),
0.94 (dd, J ) 6.7, 4.7, 6H), 0.89 (d, J ) 7.1 Hz, 6H); 13C NMR
(300 MHz, CD2Cl2) δ 139.0 (dt, J ) 5.0, 5.0 Hz), 135.7 (d, J )
9.8 Hz), 134.5 (dt, J ) 77.7, 7.5 Hz), 132.4 (dt, J ) 14.1, 3.7 Hz),
131.8, 130.1 (d, J ) 12.2 Hz), 121.6 (q, J ) 321.6 Hz), 39.3 (d, J
(13) (a) Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117-2188.
(b) Knochel, P. Synlett 1995, 393-403. (c) Vettel, S.; Vaupel, A.;
Knochel, P. J. Org. Chem. 1996, 61, 7473-7481. (d) Langer, F.;
Schwink, L.; Devasagayaraj, A.; Chavant, P.-Y.; Knochel, P. J. Org.
Chem. 1996, 61, 8229-8243. (e) Charette, A. B.; Beauchemin, A.;
Marcoux, J.-F. J. Am. Chem. Soc. 1998, 120, 5114-5115. (f) Hupe, E.;
Calaza, M. I.; Knochel, P. Chem. Eur. J. 2003, 9, 2789-2796. (g) Hupe,
E.; Knochel, P. Org. Lett. 2001, 3, 127-130. (h) Boudier, A.; Hupe, E.;
Knochel, P. Angew. Chem., Int. Ed. 2000, 39, 2294-2297.
(14) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2000, 39, 4414-4435.
(15) The side product ratios for the reactions are dependent on the
starting aldehyde. When benzaldehyde was used as the starting
material, the ratios were 3/34/40/20/3 (benzaldehyde/2a/3a/4a/5a).
(16) Theorical study: Haaland, A.; Green, J. C.; McGrady, G. S.;
Downs, A. J.; Gullo, E.; Lyall, M. J.; Timberlake, J.; Tutukin, A. V.;
Volden, H. V.; Østby, K.-A. Dalton Trans. 2003, 4356-4366.
(17) Porter, J. R.; Traverse, J. F.; Hoveyda, A. H.; Snapper, M. L.
J. Am. Chem. Soc. 2001, 123, 984-985.
(11) Complex 1 can be stored in a vial under a non-inert atmosphere
for several weeks without noticeable decomposition. With time, the
complex tends to be hydrated and becomes green. A simple purification
by flash chromatography can lead to the initial clean complex.
(12) The absolute configuration was determined by comparison of
the optical rotation of compounds 2a, 2h, 2i, and 2j with the literature
and by extrapolation for others.
J. Org. Chem, Vol. 70, No. 26, 2005 10865

FIGURE 1. Synthesis and ORTEP representation of the organometallic complex 1.
TABLE 1. Optimization Results
FIGURE 2. Typical side products observed.
General Multicomponent One-Pot Procedure To Gen-
erate r-Chiral Amime (HCl Salt) by Addition of Diethylz-
inc (2a-i). In a reaction tube equipped with a cross-shaped
magnetic stirring bar were added the complex 1 (21 mg, 0.025
mmol), the diphenylphosphinoylamide (217 mg, 1 mmol), and
the aldehyde (3 mmol) under argon. Anhydrous toluene (5.5 mL)
was added for a 0.1 M concentration and the solution was cooled
to the specified temperature (0 or 25 °C). When the temperature
was reached, a solution of diethylzinc in toluene (1.1 M, 4.5 mL,
5 mmol) was added over 1 min to control the gas evolution (this
is an exothermic step). After 24 h, the reaction tubes were cooled
to 0 °C (cooling allows the evolution of gas to be controlled),
opened, and quenched by dropwise addition of water (2 mL)
(Caution: the quench produces a considerable amount of
ethane). Finally, concentrated HCl was added (2 mL) and the
resulting two-phase solution was stirred for 8 h (for most of the
substrates the cleavage was complete in less time). The aqueous
phase was separated, washed with Et2O (4 × 10 mL) to remove
side products 3 and 4, then basified to pH 12 with 4 M NaOH
and extracted with Et2O (4 × 10 mL). The organic phases were
combined, dried over Na2SO4, filtered, and acidified with 2 M
HCl in Et2O to form the corresponding HCl salt, which is less
volatile and easier to manipulate than the free amine. The salts
were purified by flash chromatography, using CH2Cl2/MeOH as
eluent, and acidified with gaseous HCl to convert traces of free
amine to their salt form. Preparative HPLC with a reverse phase
column can also be used.
Specific Multicomponent One-Pot Procedure To Gener-
ate (1S)-1-(2-Furyl)propan-1-ammonium Chloride (2g). In
a reaction tube equipped with a cross-shaped magnetic stirring
bar were added the complex 1 (21 mg, 0.025 mmol), the
diphenylphosphinoylamide (217 mg, 1 mmol), and the 2-fural-
dehyde (3 mmol) under argon. The solid mixture was cooled to
0 °C. When the desired temperature was reached, a solution of
diethylzinc in toluene (1.1 M, 4.5 mL, 5 mmol) was added over
1 min to control the gas evolution (this is an exothermic step).
After 24 h, the reaction tubes were cooled to 0 °C (cooling allows
the evolution of gas to be controlled), opened, and quenched by
a dropwise addition of a saturated solution of NH4Cl (10 mL)
(Caution: the quench produces a considerable amount of
ethane). The aqueous phase was extracted with CH2Cl2 (3 × 20
mL), and the organic phases were combined, dried over Na2-
SO4, and evaporated to dryness. The solid residue was suspended
in toluene (2 mL), concentrated HCl was added (2 mL), and the
resulting two-phase solution was stirred for 8 h. The aqueous
phase was separated, washed with Et2O (4 × 10 mL) to remove
side products 3 and 4, then basified to pH 12 with 4 M NaOH
and extracted with Et2O (4 × 10 mL). The organic phases were
combined, dried over Na2SO4, filtered, and acidified with 2 M
HCl in Et2O to form the corresponding HCl salt, which is less
volatile and easier to manipulate than the free amine. The salts
were purified by flash chromatography, using CH2Cl2/MeOH as
eluent, and acidified with gaseous HCl to convert traces of free
entry
1 (mol %)
yield (%)
ee (%)a
1
1
2.5
5
2.5
2.5
2.5
2.5
85
85
83
84
88
83
63
93
95
96
95
97
98
97
2
3
4b
5c
6d
7e
a Determined by GC on â-Dex column. b The reaction was run
under non-anhydrous conditions: reaction test tubes were not
dried, reagents and complex 1 were weighed under ambient
conditions, and the reaction was run in a sealed flask without
argon. c The reaction was run at 0.1 M. d The reaction was run at
0 °C. e The reaction was run with 1 equiv of benzaldehyde.
TABLE 2. Scope of the Multicomponent One-Pot
Reaction
entry
R1
Ph (2a)
2-ClPh (2b)
2-OMePh (2c)
2-Me-Ph (2d)
1-naphthyl (2e)
3-NO2Ph (2f)
2-furyl (2g)
i-Pr (2h)
R2
yield (%)
ee (%)a
1
2b
Et
Et
Et
Et
Et
Et
Et
Et
Et
Me
Me
88
54
90
68
59
79
65
62
59
32
41
97
96
95
96
97
97
93
93
90
92
90
3
4
5
6b
7b,c
8
9b
PhCH2CH2- (2i)
Ph (2j)
Ph (2j)
10b,d
11b,e
a Determined by GC, HPLC, or SFC on chiral stationary phase.
b Reaction was run at 0 °C. c The addition product was isolated to
remove zinc salts prior to the cleavage of the activating group.
d Reaction was run for 48 h. e Reaction was run for 96 h.
) 65.7 Hz), 38.5 (t, J ) 8.8 Hz), 37.1 (t, J ) 7.8 Hz), 36.7, 36.4,
35.2 (d, J ) 69.5 Hz), 32.9 (d, J ) 10 Hz), 32.6 (d, J ) 8.6 Hz),
20.6 (t, J ) 11.5 Hz), 15.0, 14.4, 13.2 (d, J ) 3 Hz); 19F NMR
(282 MHz, CD2Cl2) δ -79.1; 31P NMR (121 MHz, CD2Cl2) δ 72.0
(t, J ) 5.4 Hz), 5.2 (br); IR (neat) 2929, 2867, 1453, 1262, 1144,
1123, 1030, 740, 667, 635 cm-1; LRMS (APCI+) [M - OTf]+ calcd
m/z 707.3, found m/z 707.2. Elemental analysis calcd for C37H56
CuF3O5P4S: C, 51.83; H, 6.58; S, 3.74. Found: C, 51.74; H, 6.79;
S, 3.33.
-
10866 J. Org. Chem., Vol. 70, No. 26, 2005

amine to their salt form. Preparative HPLC with a reverse phase
column can also be used.
HCl in Et2O to form the corresponding HCl salt, which is less
volatile and easier to manipulate than the free amine. The salts
were purified by flash chromatography, using CH2Cl2/MeOH as
eluent, and acidified with gaseous HCl to convert traces of free
amine to their salt form. Preparative HPLC with a reverse phase
column can also be used.
General Multicomponent One-Pot Procedure To Gen-
erate r-Chiral Amime (HCl Salt) by Addition of Dimeth-
ylzinc (2j). In a reaction tube equipped with a cross-shaped
magnetic stirring bar were added the complex 1 (21 mg, 0.025
mmol), the diphenylphosphinoylamide (217 mg, 1 mmol), and
the aldehyde (3 mmol) under argon. Then a solution of dimeth-
ylzinc in toluene (2.0 M, 2.5 mL, 5 mmol) was added over 5 min
to control the gas evolution to 25 °C (this is an exothermic step).
After 48 or 96 h, the reaction tubes were cooled to 0 °C (cooling
allows the evolution of gas to be controlled), opened, and
quenched by dropwise addition of water (2 mL) (Caution: the
quench produces a considerable amount of ethane). Finally,
concentrated HCl was added (2 mL) and the resulting two-phase
solution was stirred for 8 h (for most of the substrates the
cleavage was complete in less time). The aqueous phase was
separated, washed with Et2O (4 × 10 mL) to remove side
products 3 and 4, then basified to pH 12 with 4 M NaOH and
extracted with Et2O (4 × 10 mL). The organic phases were
combined, dried over Na2SO4, filtered, and acidified with 2 M
Acknowledgment. This work was supported by
NSERC, Merck Frosst Canada, Boehringer Ingelheim
(Canada), AstraZeneca R&D Montre´al, and the Univer-
site´ de Montre´al. A.C. is grateful to NSERC (ES D) for
a graduate scholarship.
Supporting Information Available: General informa-
tion, specific experimental conditions, CIF file, and charac-
terization data for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO0516483
J. Org. Chem, Vol. 70, No. 26, 2005 10867