Sequential reductive amination-hydrogenolysis: A one-pot synthesis of challenging chiral primary amines

Article abstract of DOI:10.1002/adsc.201100250

Difficult-to-access chiral primary amines were formed in good to high yield and ee using a rare example of a one-pot synthesis from prochiral ketones (sequential reductive amination-hydrogenloysis). As a highlight we also demonstrate a one-pot reductive amination-hydrogenolysis-reductive amination (five reactions) of ortho-methoxyacetophenone resulting in the chiral diamine 1-(2-methoxyphenyl)ethyl-(2-pyridylmethyl)-amine (4) (58% overall yield, >99% ee), a new organocatalyst for aqueous enantioselective aldol reactions. Copyright

Full text of DOI:10.1002/adsc.201100250

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DOI: 10.1002/adsc.201100250
Sequential Reductive Amination-Hydrogenolysis: A One-Pot
Synthesis of Challenging Chiral Primary Amines
Thomas C. Nugent,a,* Daniela E. Negru,a Mohamed El-Shazly,a Dan Hu,a
Abdul Sadiq,a Ahtaram Bibi,a and M. Naveed Umara
a
Department of Chemistry, School of Engineering and Science, Jacobs University Bremen, Campus Ring 1, 28759 Bremen,
Germany
Fax : (+49)-421-200-3229; e-mail: t.nugent@jacobs-university.de
Received: April 3, 2011; Published online: August 4, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100250.
Abstract: Difficult-to-access chiral primary amines resulting in the chiral diamine 1-(2-methoxy-
were formed in good to high yield and ee using a
ACHTUNGTRENpNUGN henyl)ethyl-(2-pyridylmethyl)-amine (4) (58% over-
rare example of a one-pot synthesis from prochiral all yield, >99% ee), a new organocatalyst for aque-
ketones (sequential reductive amination-hydrogenlo- ous enantioselective aldol reactions.
ysis). As a highlight we also demonstrate a one-pot
reductive amination-hydrogenolysis-reductive amina- Keywords: asymmetric reductive amination; chiral
tion (five reactions) of ortho-methoxyacetophenone amines; hydrogenolysis; primary amine synthesis
Introduction
today it holds the elevated stature of a standalone
field represented by a diverse number of reliable
Suppression of disease pathways entails the use of methods.[1,2] Nonetheless, reaction step efficiency has
medical agents with pinpoint structural features con- yet to be broadly addressed. Exceptions are reports
ferred through the functional group diversification of by Kadyrov (chemical),[3] Kroutil (enzymatic),[4] and
promising preclinical templates. Within this frame- Bornscheuer (enzymatic)[5] who have demonstrated
work, chiral amines often play an integral role in the efficient one-pot syntheses of chiral primary amines
drug discovery process because they can provide a from prochiral ketones. These methods rely on reduc-
high density of structural information, i.e., their hand- tive amination and this approach continues to be un-
edness coupled with their strong propensity for hydro- derappreciated for the synthesis of chiral amines.[6]
gen bond formation at a relevant biological binding
site.
Herein, we introduce a rare example of a one-pot
chemical synthesis of chiral primary amines from pro-
Chiral amine-based pharmaceutical drugs and alka- chiral aryl alkyl or alkyl alkyl’ ketones, exploiting an
loid natural products overwhelmingly contain secon- asymmetric reductive amination-hydrogenolysis se-
dary or tertiary amines, and, to a lesser degree, the quence. Furthermore, four of the primary amine prod-
corresponding amides with functionalized side chains. ucts synthesized here (3b–e) are documented as diffi-
Unfortunately current methods do not allow the in- cult to access,[7] and none of these sterically congested
troduction of nitrogen, in those forms, into advanced chiral amines were reported using the above noted
intermediates via operationally simple, stepwise effi- one-pot methods.[3–5]
cient (one-step), enantioselective catalytic methods.
Consequently, chiral primary amines are frequently
the reliable building blocks that chemists turn to Results and Discussion
during the synthetic planning of a final target, while
medicinal chemists seek them out because they hold The literature is replete with examples of the short-
greater diversification potential vs. secondary or terti- comings associated with chiral primary amine synthe-
ary chiral amine building blocks.
sis, among them, multistep syntheses (>2 steps),
Fifteen years ago chiral amine synthesis (non- harsh nitrogen deprotection conditions, and/or low
amino acid) was characterized by individual solutions, overall yield are common.[8] Chiral amine syntheses
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Thomas C. Nugent et al.
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To the best of our knowledge there are no examples
of this sequential reaction in the chiral amine litera-
ture and our own previous attempts failed.[17] Here we
show that it is not only possible and generic in nature,
but also grants access to chiral amine structures
whose synthetic histories are punctuated by a lack of
accomplishment.
Scheme 1. Generic ortho-substituted phenylethylamines.
from acetophenone or its para- and meta-substituted
We have previously synthesized enantioenriched
analogues are no exceptions, but the corresponding primary amines via two-step processes originating
primary amines are nonetheless accessible and com- from the corresponding ketones (Scheme 2)[7b,17,18] or
monly reported on. By contrast the ortho-substituted aldehydes (not shown),[19] but not from demanding
variants (Scheme 1) are well documented as cumber- ortho-substituted acetophenones and not in a one-pot
some to obtain.[7a] For example, the resolution of race- process. To explore this possibility we first reductively
mic ortho-substituted phenylethylamines can provide aminated these sterically hindered ketones with (S)-
high ee, but in low overall yield.[9] The use of chiral phenylethylamine, (S)-PEA, in the presence of a het-
amine auxiliaries has been reported, but this approach erogeneous hydrogenation catalyst under pressurized
generally lacks reaction step efficiency. For example, hydrogen, and isolated the secondary amine products
the phenylethylamine (PEA) auxiliary has been em- (S,S)-2 (major) and (S,R)-2 (minor), Table 1.
ployed via the corresponding chiral imines of ortho-
Solvent screening experiments showed i-PrOAc to
substituted acetophenones,[10] while the tert-butylsulfi- be universal and optimal regarding reaction rate, dia-
namide auxiliary has been taken advantage of via stereoselectivity, and by-product suppression, while
formal carbanion addition to N-sulfinylaldimines of MeOH, EtOH, EtOAc, PhCH3, CH2Cl2, and 1,2-di-
ortho-substituted benzaldehydes.[11] When the em- chloroethane were inferior. An exception was noted
ployed method shifts to the enantioselective hydroge- when examining a sterically challenging alkyl alkyl’
nation of ortho-substituted arylenACTHNUTRGNEaUNG mides, only three ketone, 2-methyl-3-heptanone (Table 1, entry 7), here
research groups have made a point of studying more a 1,2-dichloroethane/toluene solvent mixture proved
than one substrate example.[12,13,14] Of those, remark- more effective.[20] In contrast to the solvent, the opti-
able enantioselectivities have been achieved by mal heterogenous hydrogenation catalyst was strongly
Zhang,[7a] however three distinct reaction steps are dependent on the ortho-substituted acetophenone
still required to access the primary amine. The enan- being examined. For example, Raney-Ni provided the
tioselective reduction of N-arylimines is currently highest diastereoselectivity and fully consumed the
popular,[15] and Xiaoꢁs two-step (reductive amination) ortho-fluoro and ortho-methoxy substrates (Table 1,
method stands out regarding overall brevity, yield, entries 1 and 3), however, e.g., the ortho-methyl sub-
and enantioselectivity.[15b] Finally, other methods for strate (entry 4) was not completely consumed even
ortho-substituted phenylethylamine synthesis are after extended reaction times (72 h) with the Raney-
known but less frequently reported on,[16] of these Ni catalyst. For the ortho-methyl (entry 4) and ortho-
Zhangꢁs two-step method entails the enantioselective trifluoromethyl
reduction of unactivated imines which could be con- (1.5 mol%) was the most useful reductive amination
sidered as forward looking.[16a]
catalyst. These catalysts were identified after screen-
substrates
(entry 6),
Pd/Al2O3
In the context of reaction step efficiency, we specu- ing the following commercially available hydrogena-
lated whether it would be possible to perform a re- tion catalysts: Raney-nickel, Pt/C, Pd/C, Pd/Al2O3,
ductive amination using a heterogeneous hydrogena- Pd/CaCO3, and Pd(OH)2.
tion catalyst in the presence of (R)- or (S)-phenyl-
For all crude secondary amine products (2), we
ACHTUNGTRENNUNGethylamine (PEA), and, in a best case scenario, were able to define crystallization procedures allow-
simply raise the temperature to effect a hydrogenoly- ing high diastereoenrichment with repeatable yields
sis of the auxiliary (Scheme 2) in a one-pot sequence. [Table 1, see de (enriched)]. For those originating
from ortho-substituted aromatic ketones, (2a–d), crys-
tallization of the crude product with phthalic acid (1:1
salt) from mixtures of i-PrOH/heptane or simply i-
PrOH was optimal (see Table 1 and Supporting Infor-
mation). For the sterically congested aliphatic amine
2e, crystallization of the HCl salt from cyclohexane
was required. In this way, we successfully circumvent-
ed the need for chromatography, allowing simple
multi-gram preparations of compounds 2 in diastereo-
pure form.
Scheme 2. Two-step vs. one-pot approach to chiral primary
amine synthesis.
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Sequential Reductive Amination-Hydrogenolysis: A One-Pot Synthesis
Table 1. Two-step primary amine synthesis from ketones.
Entry Ketone 1
Reductive amination prod. 2a–e[a]
Hydrogenolysis prod. 3a–e[b]
ee
Yield[f]
Catalyst[c]
de
de (en-
Yield
A
R
ACHTUNGTRENNUNG
Raney-Ni
100 wt%
Pt/C 0.5 mol%
1
2
97
40
98[g,h]
99
79[g,h]
56
98
78
Raney-Ni
100 wt%
3
98
98[g,i]
97[g,i]
98
97
95
87
4
5
Pd/Al2O3
1.5 mol%
74
NA
95
67
>99[j]
48[j]
Pd/Al2O3
1.5 mol%
6
88
89
>99
66
64
98
97
90
84
Raney-Ni
100 wt%
7
97[f]
[a]
Secondary amine: in general, ketone (2–3 mmol), PEA (1.2 equiv.), i-PrOAc (0.5M), TiACTHNUTRGEN(UNG O-i-Pr)4 (1.25 or 1.60 equiv.), H2
(10, 15, or 20 bar), at 238C (1c at 358C and 1e at 508C), 24 h (see Supporting Information).
Primary amine: secondary amine 2 (2–3 mmol), MeOH (0.5M), Pd/C (0.50 mol%), H2 (15 or 20 bar), at 50, 55, or 608C,
[b]
24 h.
[c]
[d]
[e]
[f]
[g]
[h]
[i]
Based on the limiting reagent (ketone).
After work-up (GC analysis).
After crystallization with phthalic acid (see Supporting Information).
Isolated as the HCl salt.
No crystallization performed.
Column chromatography performed.
Chemically pure after work-up.
[j]
A second crystallization was performed, the yield is based on ketone 1c (entry 5).
The noted crystallization approach initially failed 99% de in 55–60% yield, from ketone 1a, after a
when examining the purification of secondary amine single crystallization (Table 1, entry 2). For the re-
2a (Table 1, entry 1). Reductive amination of o-fluo- maining products (2, Table 1), the crude de was suffi-
roacetophenone, using Raney-Ni, enabled high de ciently high to readily allow enrichment to ꢀ97% de
(98%), but also gave the previously described de- after a single crystallization, albeit 2c, which has a
fluorination by-product (6–10%),[10i] which could be mediocre de (74% crude), required a second crystalli-
readily removed using flash chromatography (Table 1, zation (Table 1, compare entries 4 and 5). Thus de-
entry 1, 79% yield, 98% de), but not by crystalliza- pending on the intended scale of the reaction, we
tion. To ameliorate this problem we reductively ami- have provided small- and large-scale isolation solu-
nated o-fluoroacetophenone using Pt/C (0.5 mol%), tions. Finally, in a second step, we obtained all of the
shutting down the defluorination pathway but grossly primary amines (3a–e) in ꢀ97% ee with good to ex-
and negatively impacting the de (40%) of 2a. In a cellent yield after hydrogenolysis (50–608C) of the
rare example of highly efficient crystallization, this diastereo
ACHTUNGTRENNeUNG nriched secondary amines 2a–e in MeOH
low de product (70:30 dr) was reliably enriched to (Table 1).
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Thomas C. Nugent et al.
Primary amine data[a]
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Table 2. One-pot sequential reductive amination-hydrogenolysis.
Entry
Starting ketone (1)
Primary amine product (3)
ee [%]
Yield [%][b]
1
2
3
96
71
72
70
90
89
60
4
76[c]
5[d]
85
82
70
88
6[d]
[a]
Reductive amination stage: see Table 1 and Supporting Information; hydrogenolysis stage: Pd/C or Pd(OH)2 (1.0 mol%),
H2 (20 bar), 50 or 558C, 48 h. Pd(OH)2 was used for entries 2, 3, and 5.
[b]
[c]
[d]
Isolated as the HCl salt in>95% chemical purity after acid-base work-up, see Supporting Information.
Column chromatography performed,[21] see Supporting Information.
Reductive amination stage used: PEA (1.2 equiv.), YbACHTUNTRGNEU(GN OAc)3 (1.1 equiv.), MeOH/THF (1:1, 0.5M), Raney-Ni (100 wt%),
H2 (10 bar), 248C, 12 or 16 h; hydrogenolysis stage: as in footnote[a] of Table 1.
To achieve a one-pot reaction, we reductively ami- were lower, reflecting the native des of the corre-
nated the ketones (1) under very similar reaction con- sponding secondary amines 2 before crystallization
ditions as those found in Table 1, except now, without (compare ees of 3 in Table 2 with the “crude des” of
work-up or solvent exchange, we added Pd/C or secondary amines 2 in Table 1).
Pd(OH)2/C (1.0 mol%) allowing in situ hydrogenoly-
Our optimization of the one-pot procedure
sis of the secondary amines (2) into primary amines (Table 2) showed that close adherence to the indicat-
(3) (Table 2). The success of this one-pot procedure is ed hydrogenolysis reaction times was vital for repeat-
clear based on the overall yields alone, but the hydro- able yields to be obtained.[22] For example, the pri-
genolysis stage did require approximately double the mary amine products 3, arrived at from aryl methyl
reaction time as compared to the hydrogenolysis of ketones 1a–d, are susceptible to yield reduction via
pure 2 using Pd/C (0.50 mol%) in MeOH (Table 1). two
non-productive
hydrogenolysis
pathways
Hydrogenolysis rate depressing factors, for the one- (Scheme 3, path ꢂbꢁ and ꢂcꢁ). Although path ꢂbꢁ is
pot method, can most likely be linked to: (i) the non- rarely observed, path ꢂcꢁ is a concern, but its influence
alcoholic reaction solvents, (ii) in some instances the
slightly lower employed reaction temperatures, and
(iii) the heterogeneous reaction mixture, inherited
from the reductive amination stage, may reduce (via
physical impediment and/or promotion of conglomer-
ation) the available Pd surface for hydrogenolysis. Re-
garding the last point, the spent heterogeneous reduc-
tive amination catalyst and the presence of finely di-
vided and suspended TiO2, from the in situ hydro-
lyzed TiACHTUNGTRENNUNG(O-i-Pr)4, are likely culprits.
Concerning the isolation of the primary amine
products 3b–g (Table 2), all were obtained in high
1
chemical purity (>95%, GC and H NMR, see Sup-
porting Information) as their HCl salts, in good yield,
after acid-base work-up procedures;[21] but their ees Scheme 3. Hydrogenolysis by-product pathways.
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Sequential Reductive Amination-Hydrogenolysis: A One-Pot Synthesis
on the yield of the desired product can often be sup- aqueous aldol reactions.[25] Use of diamine 4, with a
pressed by careful attention to temperature and time 2,4-dinitrobenzenesulfonic acid (10 mol%) cocatalyst,
parameters.
indeed catalyzed the aldol reaction (Scheme 4,
To determine which of these non-productive path- bottom, 60 h at 458C), setting a possible foundation
ways was operative for our substrates, we looked for for future investigations of enantioselective aqueous
1-ethyl-2-methylbenzene (Scheme 3, R=Me) when aldol reactions. Finally, the one-pot reductive amina-
converting pure 2c into 3c (Table 1 reaction condi- tion-hydrogenolysis-reductive amination sequence
tions); and confirmed its presence based on its coelu- could be extended to the use of unsymmetrical ke-
tion with an authentic sample (GC). The chromato- tones, as the carbonyl component, for the second re-
gram further revealed that 1-ethyl-2-methylbenzene ductive amination, but in our hands poor diastereose-
had formed via pathway ꢂaꢁ followed by ꢂcꢁ. This was lectivity was always noted and this avenue was not
unmistakable because of the complete lack of phenyl- further pursued.
ethylamine, a unique by-product of pathway ꢂbꢁ in the
same chromatogram.[23] These follow-up studies con-
firmed our earlier experimental observations that ex- Conclusions
tended hydrogenolysis reaction times are detrimental
to the yield of 3 and confirmed our suspicion that de- In closing, a one-pot method enabling chromatogra-
amination of 3 was indeed occurring. Although the phy-free isolation of challenging chiral primary
non-benzylic amines 3e–f (Table 2) are not vulnerable amines has been demonstrated with very good yield
to these benzylic carbon-nitrogen degradation path- (60–88%), especially when noting that three sequen-
ways, they are nonetheless susceptible to racemization tial reactions have taken place (imine formation,
events at high temperature over prolonged reaction imine reduction, and hydrogenolysis of the auxiliary).
times.[24]
The final ees range from excellent (96%) to mediocre
Finally, to push the limits of the developed method, (71%) and reflect the de of the in situ formed secon-
we subjected ketone 1b to a one-pot reductive amina- dary amine products (Table 2). By contrast, across-
tion-hydrogenolysis-reductive amination sequence, the-board high ees (97–98%) can be achieved for the
five reactions in total, forming diamine 4 in 58% yield primary amines using a two-step method (Table 1)
(from 1b) in >99% ee (Scheme 4, top). In this se- with good overall yields and again without the need
quence, the second reductive amination consumed 2- for chromatography. Finally, the method has been ex-
pyridinecarboxaldehyde, which was added after pri- tended to a reductive amination-hydrogenolysis-re-
mary amine 3b had fully accumulated (GC analysis). ductive amination, providing diamine 4 which serves
This second carbonyl partner was chosen for two rea- as an organocatalyst for aqueous aldol reactions.
sons, one to show that a diverse aldehyde could be
used, but more importantly to gain access to ana-
logues of pyridine-based chiral diamines which have
recently been reported as good organocatalysts for
Experimental Section
General Synthesis of Secondary Amines 2 (Reductive
Amination)
In a reaction vessel under nitrogen containing i-PrOAc
(2.0 mL) were combined the ortho-substituted acetophenone
1
(2.0 mmol,
1.0 equiv.),
AHCTUNGTRE(NGNUN O-i-Pr)4 (1.25 equiv.). This mixture was
(S)-a-methylbenzylamine
(1.2 equiv.) and Ti
stirred for 30 min and then an i-PrOAc (2.0 mL) slurry of
Raney-Ni [100 wt% based on the ketone, triturated first
with EtOH (3ꢃ2 mL) and then with i-PrOAc (3ꢃ2 mL)]
was added or in the case of Pd- or Pt-based catalysts, the
solid heterogeneous catalyst was simply added followed by
further addition of i-PrOAc (2.0 mL). [Note: the final molar-
ity for all reactions was 0.5M. Note: all hydrogenation cata-
lyst wt% or mol% numbers are based on the starting
ketone.] The reaction vessel was then pressurized at 10–
20 bar H2 at 24 or 358C (508C for 1e), depending on the
specific substrate, with stirring. After 24 h (<4 area% of the
ketone substrate and imine intermediate remained, GC
analysis), the reaction mixture was diluted with EtOAc
(30 mL) and vigorously stirred with aqueous NaOH (1.0M,
30 mL) for 4 h. The heterogeneous biphasic mixture was
then filtered through a bed of celite and the celite subse-
Scheme 4. One-pot synthesis of an aldol organocatalyst.
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Thomas C. Nugent et al.
FULL PAPERS
quently washed with EtOAc (3ꢃ10 mL). The aqueous layer
was further extracted with EtOAc (3ꢃ20 mL) and the com-
bined organic layers were dried (Na2SO4), filtered and con-
centrated (rotary evaporator). The crude product was then
dried under high vacuum until a constant weight was ach-
ieved (usually overnight). Variations from this general pro-
cedure are described in the specific examples, see Support-
ing Information.
tion solvent was added. [Note: the final molarity for all re-
actions was 0.5M. Note: all hydrogenation catalyst wt% or
mol% numbers are based on the starting ketone.] The reac-
tion vessel was then pressurized at 10–20 bar H2 at 24 or
358C (508C for 1e), depending on the specific substrate,
with stirring. After stirring for 12–48 h, <4 area% of the
ketone substrate and imine intermediate (combined) re-
mained, GC analysis, and Pd/C (1.0 mol%) or Pd(OH)2
(1.0 mol%) was added. The reaction mixture was then
heated at 50 or 558C under 20 bar H2. Importantly, the reac-
tion is worked-up when 5–6 area% of the secondary amine
still remains, which is most often at 48 h. Work-up: the mix-
ture was diluted with EtOAc (40 mL) and aqueous NaOH
(1.0M, 30 mL) added. After vigorous stirring for 4 h in a
capped Erlenmeyer flask, the heterogeneous two phase solu-
tion was filtered through a bed of celite, and the celite sub-
sequently washed with EtOAc (3ꢃ10 mL). [Note: the pri-
mary amines are semi-volatile to volatile, do not aspirate
the filtration more than required.] The aqueous layer was
further extracted with EtOAc (3ꢃ20 mL), and the combined
organic layers were then treated with concentrated HCl
(37% aqueous, 3 equiv.). This mixture was concentrated
until a volume of ~0.5 to 1.0 mL, and generally had a yellow
color. If the chemical purity of the product was not >95
area% (GC), then distilled H2O (50 mL) and CHCl3
(50 mL) were added. [Note: It is important to use CHCl3
here and not CH2Cl2.] The CHCl3 layer was further extract-
ed with distilled H2O (2ꢃ10 mL). To the combined water
layers, CH2Cl2 (50 mL) was added, and then the aqueous
phase was made strongly basic (pH>11) with NaOH
(4.0M). After removal of the CH2Cl2 layer, the basic water
layer was further extracted with CH2Cl2 (2ꢃ30 mL). To the
combined CH2Cl2 layers was added HCl (37% aqueous,
3 equiv.) and this was concentrated (rotary evaporator, bath
temperature initial: 308C; ending: ~708C) providing an off
white solid that was then dried under high vacuum until a
constant weight was achieved (usually overnight). Variations
from this general procedure are found in the Supporting In-
formation. [Note: All of the free primary amines (3) in this
manuscript, unlike their phthalic acid or HCl salts, should
be considered as being volatile under rotary evaporation.]
General Synthesis of Enantioenriched Primary
Amines (3a–e) from Secondary Amines (2a–e)
The secondary amines 2 (Table 1) were hydrogenolyzed in
MeOH (0.5M) using Pd/C (0.5 mol%), at 50–608C, under
15 or 20 bar H2, over 24 h. Work-up: at room temperature
the reaction was diluted with MeOH (50 mL), and aqueous
HCl (37%, 3.0 equiv.) was added. This solution was filtered
through celite and the celite subsequently rinsed with
MeOH. The filtrate was evaporated resulting in a solid resi-
due (HCl salt of primary amine). A small amount of the
HCl salt was converted into the free amine and a GC was
recorded. If there was one GC peak representing the prod-
uct (all other peaks, in total, <4 area%), the 1H and
13C NMR spectra of the HCl salt were recorded. If the chro-
matogram showed >4 area% impurities, the following pro-
cedure was used. The HCl salt of the primary amine was
added to a mixture of CHCl3 (50 mL) and distilled water
(50 mL). [Note: It is important to use CHCl3 here and not
CH2Cl2.] The CHCl3 layer was further extracted with water
(2ꢃ15 mL), and the combined water extracts then had
CH2Cl2 (30 mL) added. To this biphasic solution was added
NaOH (4.0M) until the aqueous layer was strongly basic (>
11 pH). The CH2Cl2 extract was then removed, and the
basic water layer was further extracted (CH2Cl2, 3ꢃ30 mL).
To the combined CH2Cl2 extracts was added aqueous HCl
(37%, 3.0 equiv.). Concentration (rotary evaporator, bath
temperature initial: 308C; final: ~708C) provided an off
white solid that was then dried under high vacuum until a
constant weight was achieved (usually overnight). This
method reliably allowed all of the primary amines (3) to be
isolated in high chemical purity (>96% by GC). Variations
from this general procedure are described in the Supporting
Informatiion. [Note: All of the free primary amines (3) in
this manuscript, unlike their phthalic acid or HCl salts,
should be considered as being volatile under rotary evapora-
tion.]
Acknowledgements
We are grateful for financial support from Jacobs University
Bremen and the HEC of Pakistan. We also thank Moham-
mad Shoaib for identifying cyclohexane as a good solvent for
the crystallization of 2e. This work has been performed
within the graduate program of Nanomolecular Science.
General One-Pot Synthesis of Enantioenriched
Primary Amines (3b–g) from Ketones (1b–g)
In a reaction vessel under nitrogen, Yb
1.1 equiv.) [dried at 808C under high vacuum until a con-
stant weight was achieved (generally 12 h)] or Ti(O-i-Pr)4
ACHTUNGRTEN(NUNG OAc)3 (2.2 mmol,
AHCTUNGTRENNUNG
(2.4 mmol, 1.2 equiv.) was added, followed by the solvent References
(2.0 mL, 1.0M), ketone 1b–1g (2.0 mmol, 1.0 equiv.), and
(S)-a-methylbenzylamine (2.4 mmol, 1.2 equiv.). This mix-
ture was stirred for 30 min, at room temperature, and then a
reaction solvent slurry (2.0 mL) of Raney-Ni [100 wt%
based on the ketone, triturated first with EtOH (3ꢃ2 mL)
and then with the reaction solvent (3ꢃ2 mL)] was added.
Alternatively, when Pd/Al2O3 (1.5 mol%) was the heteroge-
neous hydrogenation catalyst, an additional 2.0 mL of reac-
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asc.wiley-vch.de
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Thomas C. Nugent et al.
FULL PAPERS
[18] T. C. Nugent, M. El-Shazly, V. N. Wakchaure, J. Org.
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[19] V. N. Wakchaure, R. R. Mohanty, A. J. Shaikh, T. C.
[22] The hydrogenolysis reactions performed in Table 1 also
had to be closely monitored, extended reaction times
reduced the yield.
[23] It is possible that phenylethylamine formed but under-
went rapid hydrogenolysis providing ethylbenzene and
ammonia, making the quantification of PEA difficult.
This can be clearly ruled out based on our independent
study of the hydrogenolysis of PEA in many different
solvents, see Supporting Information, page 13, showing
that this is not the case.
Nugent, Eur. J. Org. Chem. 2007, 959–964.
[20] 1,2-Dichloroethane is the optimal reaction solvent, but
transfer of the Raney-Ni slurry into the reaction with
this solvent (via a wide gauge needle and syringe) was
not feasible due to the technical problem that 1,2-di-
chloroethane slurries of Raney-Ni were not free-flow-
ing. This was overcome by using a toluene slurry (see
the Supporting Information). Fortunately, the toluene
did not adversely affect the positive attributes of 1,2-di-
chloroethane solvent.
[21] The aliphatic primary amine 3e was of lower chemical
purity, 88 area% (GC), after work-up. It was conse-
quently chromatographed before the yield was calculat-
ed. All primary amines (3) are semi-volatile to volatile,
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2092
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Adv. Synth. Catal. 2011, 353, 2085 – 2092