Synthesis of novel amino-acid-derived sulfinamides and their evaluation as ligands for the enantioselective transfer hydrogenation of ketones

Article abstract of DOI:10.1002/ejoc.200800576

Novel chiral mono-sulfinyl diamines bearing a stereogenic sulfur atom were prepared in moderate to good yields starting from amino acids by means of a reductive amination of the corresponding amino aldehydes. Their potential as ligands for asymmetric catalysis was evaluated in the metal-catalyzed enantioselective transfer hydrogenation of alkyl-aryl ketones. The catalysts were generated in situ from sulfinamides 1a-i and arene complexes of rhodium and ruthenium, and the catalytic reductions led to the formation of chiral alcohols with up to 91% ee. Wiley-VCH Verlag GmbH & Co. KGaA, 2008.

Full text of DOI:10.1002/ejoc.200800576

FULL PAPER
DOI: 10.1002/ejoc.200800576
Synthesis of Novel Amino-Acid-Derived Sulfinamides and Their Evaluation as
Ligands for the Enantioselective Transfer Hydrogenation of Ketones
Lorenzo Zani,[a] Lars Eriksson,[b] and Hans Adolfsson*[a]
Keywords: Amino acids / Sulfinamides / N-Ligands / Homogeneous catalysis / Transfer hydrogenation
Novel chiral mono-sulfinyl diamines bearing a stereogenic
sulfur atom were prepared in moderate to good yields start-
ing from amino acids by means of a reductive amination of
the corresponding amino aldehydes. Their potential as li-
gands for asymmetric catalysis was evaluated in the metal-
catalyzed enantioselective transfer hydrogenation of alkyl-
aryl ketones. The catalysts were generated in situ from sulfi-
namides 1a–i and arene complexes of rhodium and ruthe-
nium, and the catalytic reductions led to the formation of chi-
ral alcohols with up to 91% ee.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2008)
In recent years, we reported on the use of various amino
acid derived compounds as efficient stereocontrollers in
enantioselective catalysis. They included ligands for the
metal-catalyzed transfer hydrogenation of ketones[12] and ti-
tanium-catalyzed diethylzinc addition to aldehydes,[13] as
well as organocatalysts for the α-oxidation or α-amination
of carbonyl groups.[14] Some of these catalysts contained
sulfur atoms within thioamide or sulfonamide functionalit-
ies.[12e,14a–14b] Given our experience in this field, we became
interested in preparing novel amino acid derivatives 1 incor-
porating a chiral sulfinamide unit, and subsequently in
evaluating them as ligands for metal-catalyzed asymmetric
transformations. We envisaged that compounds 1 could be
easily accessed from the corresponding amino acids
through reduction to form the amino aldehydes 2 and sub-
sequent reductive amination of the latter. Our retrosyn-
thetic approach is detailed in Scheme 1.
Introduction
The sulfinyl group, bearing a stereogenic center on sulfur,
has since long time been established as a reliable chiral aux-
iliary in asymmetric synthesis.[1] In particular, enantiopure
N-sulfinyl imines have been extensively applied to the syn-
thesis of chiral amines, due to the high diastereoselectivity
usually displayed in their reactions with various nucleo-
philes.[2]
On the other hand, use of compounds incorporating a
stereogenic tricoordinate sulfur atom as chiral ligands for
enantioselective catalysis has remained underdeveloped for
a long time, and only recently significant progress has been
achieved in this field. For example, chiral sulfoxides have
found application in such processes as (transfer) hydrogena-
tions of olefins or ketones,[3] Lewis acid catalyzed Diels–
Alder cycloadditions,[4] diethylzinc addition to aldehydes[5]
and Pd-catalyzed allylic alkylations.[6] In addition, Ellman
and co-workers introduced ligands containing the N-sulf-
inyl imine moiety, and employed them in various asymmet-
ric transformations, including the hydrogenation of prochi-
ral olefins.[7] In contrast, very few reports dealt with the use
of chiral sulfinamides as ligands or catalysts; Riera, Verdag-
uer and co-workers described the application of N-phos-
phanyl sulfinamides as stoichiometric ligands for a cobalt-
mediated Pauson–Khand reaction,[8] while three different
groups employed sulfinamide-containing organocatalysts to
carry out such transformations as the hydrosilylation of im-
ines,[9] the aza-Henry reaction[10] and the indium-mediated
allylation of N-acylhydrazones.[11]
Scheme 1. Retrosynthetic approach to the amino-acid-derived sulfi-
namides 1.
[a] Department of Organic Chemistry, Stockholm University, The
Arrhenius Laboratory,
Compounds 1 are obtained by the combination of vari-
ous amino acids and sulfinamides, which made possible to
vary substituents in three different positions (R, RЈ and RЈЈ
in Scheme 1). Moreover, the possibility of preparing both
diastereomers of a certain ligand allowed us to evaluate
possible match/mismatch effects to be displayed in catalysis.
10691 Stockholm, Sweden
Fax: +46-8-154908
E-mail: hansa@organ.su.se
[b] Department of Physical Chemistry, Inorganic Chemistry and
Structural Chemistry, University, The Arrhenius Laboratory,
10691 Stockholm, Sweden
Eur. J. Org. Chem. 2008, 4655–4664
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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L. Zani, L. Eriksson, H. Adolfsson
FULL PAPER
Herein, we report the synthesis of the sulfinamides 1a–i
Initially, we set to prepare compounds 1a–c, all derived
through the aforementioned synthetic route and their evalu- from -alanine but carrying different protecting group on
ation as ligands for the metal-catalyzed enantioselective the N-terminus (Table 1). Our aim at this stage was to ac-
transfer hydrogenation of prochiral ketones.[15] In addition, cess compound 7, bearing a free, basic nitrogen atom. To
comparison of the catalytic performance of sulfinamide 1h this end, we wanted to determine which one of the chosen
with its analogue 16, bearing a sulfonamide group, will also protecting groups (Cbz, Boc, Fmoc) would be most easily
be discussed, with the aim of highlighting the importance cleaved in the last step. The aldehydes 2a–c were first pre-
of the stereogenic center on sulfur for the selectivity of the pared by means of a known reaction sequence, comprising
transfer hydrogenation reaction.
the conversion of the N-protected carboxylic acids into the
corresponding Weinreb amides 3a–c,[16] and the subsequent
chemoselective reduction of the latter with LiAlH4 in THF
at 0 °C.[17] Although we were able to prepare all three alde-
hydes 2a–c, we noticed that the last reductive step afforded
the Fmoc-protected species 2c in only 31% yield, as op-
posed to 55–63% for the other two aldehydes, alongside
with a more polar by-product.[18] Moreover, we found that
the crude aldehydes obtained by this route were in general
not pure enough to be used as such in the following imin-
ation step (Scheme 2), and therefore chromatographic puri-
fication was needed. Because it is known that chiral α-
amino aldehydes tend to give partial racemization when
subjected to column chromatography,[19] we later employed
a different sequence to access compounds 2 (vide infra).
With the aldehydes 2a–c in hand, we turned our attention
to the reductive amination step. The formation of the imine
6a was initially carried out according to the procedure re-
ported by Davis, employing an equimolar amount of (S)-p-
toluenesulfinamide (5a) and 5.0 equiv. of a TiIV alkoxide in
refluxing CH2Cl2.[20] The expected imine was formed
smoothly, but the crude was of low purity, and when a chro-
matographic purification was attempted, partial hydrolysis to
yield the aldehyde 2a was observed (approx. 10%). Given the
corresponding loss in yield and the fact that the aldehyde 2a
and the imine 6a were difficult to separate, we seeked alterna-
tive conditions to carry out the desired transformation.
Results and Discussion
In agreement with our retrosynthetic proposal
(Scheme 1), the sulfinamides 1a–i were prepared starting
from the corresponding protected amino acids through the
intermediacy of the known amino aldehydes 2a–g
(Scheme 2).
The structural characteristics of compounds 1a–i are
summarized in Table 1, along with the yield of their two-
step preparation sequence from the aldehydes 2a–g.
Table 1. Sulfinamides 1a–i prepared in this study.
Prepared from
PG
R
RЈ
% Yield[a]
Aldehyde Sulfinamide
1a
1b
1c
1d
1e
1f
1 g
1h
1i
2a
2b
2c
ent-2a
2a
2d
2e
2f
2g
5a
5a
5a
5a
5b
5a
5a
5a
5a
Cbz
Boc
Fmoc (S)-Me
Cbz
Cbz
Cbz
Cbz
Cbz
Cbz
(S)-Me
(S)-Me
pTol
pTol
pTol
pTol
tBu
pTol
pTol
pTol
pTol
36
55
68
35
58
47
51
77
50
(R)-Me
(S)-Me
(S)-Bn
(S)-sBu
(S)-iPr
(S)-tBu
[a] Yield of pure product over two steps starting from the aldehydes
2a–g.
Scheme 2. Synthesis of the sulfinamides 1a–i starting from N-protected amino acids.
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Eur. J. Org. Chem. 2008, 4655–4664

Sulfinamides as Ligands for Enantioselective Transfer Hydrogenation of Ketones
We found that performing the reaction at room tempera- raphy, accompanied by the aforementioned partial racemi-
ture[21] in the presence of 4.0 equiv. of Ti(OiPr)4 gave full zation of the aldehydes 2, could not be avoided in some
conversion of the starting material within 4 h. A simplified cases.
work-up (see Exp. Section for details) afforded the crude
The α-amino aldehydes 2d–g were then subjected to the
imine 6a, which was cleaner than that obtained under the same reductive amination protocol already used for the
previous conditions. To avoid decomposition, the crude was compounds 2a–c. In the first step either 3.0 equiv. of Ti-
directly used in the next step. Reduction with 2.5 equiv. of (OEt)4 or 4.0 equiv. of Ti(iPrO)4 were employed in CH2Cl2
NaBH4 in MeOH at 0 °C afforded the desired sulfonamide at room temp. for 3–4 h, giving in general full conversion
1a, although as a 6:1 mixture of diastereomers: this was to the corresponding imines 6. Once again, only for the al-
likely to be due to partial racemization occurring during the dehyde 2g, bearing a tert-butyl group, a change in the reac-
chromatographic purification of the aldehyde 2a, as men- tion conditions was required: full conversion to 6i was ob-
tioned earlier. Fortunately, (S,S)-1a could finally be isolated tained with 5.0 equiv. of Ti(iPrO)4 after 16 h stirring at
in 36% yield over two steps by means of flash column room temp. Subsequent reduction with NaBH4 afforded
chromatography followed by crystallization (see Exp. Sec- smoothly sulfinamides 1f–i, which were purified by flash
tion for details).
column chromatography, in some cases followed by
The same procedure was subsequently applied also for crystallization (see Exp. Section for details).
the synthesis of the compounds (S,S)-1b–c, which were ob-
The compounds 1a–i were generally isolated as solids.
tained in 55% and 68% yield over two steps, respectively. Gratifingly we were able to grow crystals of sulfinamide 1h
The same protocol was then used for the synthesis of all suitable for X-ray diffraction. The solid-state structure of
the other sulfinamides prepared in this study (1d–i).
1h is shown in Figure 1.[28] As expected, the configuration
At this stage, deprotection to afford the mono-sulfinyldi- of the two stereogenic centers was confirmed to be (S).
amine 7 was attempted. Disappointingly, we found that re-
moval of neither the Boc- nor the Cbz-group could be ef-
fected under a variety of conditions.[22] Fortunately, how-
ever, the Fmoc group was cleaved smoothly upon treatment
of 1c with a mixture of DMF and piperidine at room temp.,
and the desired product could thus be isolated in good
yield. Compound 7 was also later evaluated as a ligand for
the enantioselective metal-catalyzed transfer hydrogenation
of ketones (vide infra).
As mentioned earlier, the sequence chosen to prepare the
α-amino aldehydes 2 suffered from some notable draw-
backs, such as low yields and partial racemization of the
products. For this reason, we looked for an alternative route
Figure 1. ORTEP plot (50% probability) of compound 1h, ob-
to access the compounds 2. After a brief survey of the lit- tained by X-ray diffraction.
erature,[18,23] we found that the latter could be prepared by
formation of the mixed anhydrides of the corresponding
Having managed to prepare the compounds 1a–i and 7,
amino acids with isobutyl chloroformate, followed by re- we proceeded to evaluate their ability to serve as ligands for
duction with aqueous NaBH4,[24] and by subsequent metal-catalyzed enantioselective reactions. We selected the
chemoselective oxidation of the resulting amino alcohols 4 asymmetric transfer hydrogenation of ketones,[15] given our
(Scheme 2). Generally, we converted the alcohols 4 into the considerable experience in the field[12] and the possibility to
corresponding aldehydes by means of a Swern oxidation;[25] readily compare the performance of the new catalysts with
this protocol was found to work well for almost all the sub- well-established promoters, such as, for example, chiral
strates, giving aldehydes in 82–93% yield, but when the monotosylated diamines.[29]
amino alcohol 4g, derived from -tert-leucine, was subjected
Initially, we applied the mono-sulfinyldiamine 7 in the
to the same conditions, the desired product was not ob- enantioselective reduction of acetophenone (8a) to 1-pheny-
tained. Fortunately, we found that the oxidation of 4g could lethanol (9a), employing 2-propanol as the hydrogen donor.
be carried out in good yield (75%) according to a procedure The catalyst was generated in situ by mixing compound 7
reported by Finney,[26] employing 3.0 equiv. of IBX (o- with typical pre-catalysts such as [Ru(p-cymene)Cl2]2 (10a)
iodoxybenzoic acid) in EtOAc at reflux.
or [(Cp*RhCl2)2] (11) (Scheme 3), in the presence of sodium
In general, we found this second route to α-amino alde- 2-propoxide as a base. Having found previously that the
hydes 2 to be more convenient than the first one, which addition of lithium salts as additives can be beneficial to
is in agreement with previous observations reported in the the outcome of the catalytic transfer hydrogenation reac-
literature.[23,27] The aldehydes 2 were usually obtained in tion,[12f] lithium chloride was added also in this case.
good yields and in some instances the crude products were
Interestingly, sulfinamide 7 in combination with Ru com-
pure enough to be carried onto the next step without need plex 10a generated a very efficient catalyst, able to give 89%
for further purification; unfortunately, however, this was conversion of the starting material within 15 min (TOF =
not always the case, and isolation by column chromatog- 356 mol h–1); disappointingly, however, the catalyst showed
Eur. J. Org. Chem. 2008, 4655–4664
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4657

L. Zani, L. Eriksson, H. Adolfsson
FULL PAPER
Table 2. Transfer hydrogenation of acetophenone (8a) employing
compounds 1a–i as the chiral ligands.
%
[a]
Entry Ligand Pre-cat.
x
Time
% ee
Conv.[a]
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
1h
1h
1h
1i
11
11
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
1.0
1.0
2
1
2
2
2
2
2
4
24
18
18
2
5
22
5
5
5
2
87
54
30
33
18
87
81
83
Ͻ 10
0
39
60
42
61
Ͻ 15
15
29
43 (S)
19 (S)
Ͻ 5
29 (S)
34 (S)
39 (S)
46 (S)
58 (S)
67 (S)
–
76 (S)
74 (S)
86 (S)
84 (S)
65 (S)
87 (S)
87 (S)
50 (S)
11
11
11
11
11
11
9
11
10
11
12
13
12
10a
10a
10a
Scheme 3. Asymmetric transfer hydrogenation of acetophenone
(8a) using compound 7 as the chiral ligand.
14[b]
15[c]
16[d]
17
1i
1i
1i
1i
10a
10a
10a
10b
1.0
1.0
1.0
1.0
no selectivity, and the product was formed as a racemic
mixture. When Rh complex 11 was employed the reaction
was slower, albeit alcohol 9a could still be formed in good
conversion after 2 h, but still no selectivity was displayed
by the catalytic system.
24
[a] Determined by chiral GC-analysis (CP-Chirasil-Dex CB). [b]
Lithium chloride was absent. [c] KOH (10 mol-%) was used as the
base. [d] tBuONa (10 mol-%) was used as the base.
After these disappointing results, we turned our attention
to the use in catalysis of compounds 1a–i, featuring two tion of the stereogenic center on sulfur, rather than that of
substituted nitrogen atoms. It is worth pointing out that the amino acid part, as found in previous systems.[12a–12d]
these species do not bear any intrinsically basic nitrogen
When compound 1e, bearing a tert-butylsulfinamido
center, in contrast to the ligands traditionally used for the group, was used, once again a poor conversion of ketone
catalytic transfer hydrogenation reaction, such as monosul- 8a and an enantiomeric excess of the product lower than
fonated diamines or amino alcohols. The results obtained that obtained with 1a were observed (Entry 5). Therefore,
are summarized in Table 2.
As can be seen from Table 2, compound 1a, bearing a seems to be detrimental to the catalytic results.
Cbz group, in combination with complex 11 was able to Use of the compounds 1f–g, featuring substituted methyl
the introduction of a bulkier substituent on the sulfur atom
yield the alcohol 9a in 87% conversion after 2 h, but this groups on the amino acid side chain, provided results sim-
time the ee was 43% (Entry 1). In comparison with ligand ilar to that obtained with 1a (Entries 6–7), but when sulfin-
7, the introduction of a substituent on one side of the mole- amide 1h, derived from -valine, was employed, an increase
cule remarkably increased the selectivity of the resulting in enantioselectivity was observed, although the reaction
catalyst.
was slower (Entry 8). This tendency was confirmed when
Prompted by this encouraging result, we then examined the -tert-leucine derivative 1i was tested: the enantio-
compounds 1b–c, which differ from 1a only for the protect- selectivity increased to 67% ee, but the reaction was ex-
ing group on one nitrogen atom; we found that more steri- tremely slow, and poor conversion was observed even after
cally demanding groups such as Boc or Fmoc greatly re- one day (Entry 9). Thus, it seems that the introduction of
duced both the efficiency and selectivity of the reaction bulkier substituents on the amino acid side chain, while be-
(Entries 2–3). In order to evaluate possible match/mismatch ing beneficial for the enantioselectivity of the process, at the
effects, we subsequently tested the sulfinamide 1d, the same time reduced the efficiency of the catalyst.
(R,S)-diastereomer of 1a. To our surprise, we found that
Looking for improvements, we next examined the pos-
also in this case both the efficiency and the selectivity of the sibility of using metals other than rhodium to effect the
process were largely diminished (Entry 4). This observation transformation. While employment of Ir in the form of the
suggests that the relative configuration of the ligand is cru- complex [(COD)2IrCl2] (12) was unsuccessful (Entry 10),
cial in determining the performance of the present catalytic use of 1h in combination with Ru pre-catalyst 10a afforded
system. Interestingly, the configuration of the product was the product in low conversion and 76% ee after one night
found to be also in this case (S); thus, the sense of enantio- (Entry 11). An increase in the catalyst loading allowed to
selection seems to be influenced by the absolute configura- obtain a moderate conversion of the starting material
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Eur. J. Org. Chem. 2008, 4655–4664

Sulfinamides as Ligands for Enantioselective Transfer Hydrogenation of Ketones
within 2 h, with alcohol 9a formed with 74% ee (Entry 12). formed with slightly lower enantiomeric excess (Entry 2).
In agreement with the observation made for the Rh-based The more electron-poor substrate 8c, bearing a trifluorome-
pre-catalyst, the sulfinamide 1i in combination with the thyl group, was converted smoothly with good enantio-
complex 10a generated also in this case a slower, but more selectivity (Entry 3). Unfortunately, the reduction of more
selective catalyst (Entry 13); after 22 h at room temperature electron-rich ketones such as 8d–e was much slower, and
a moderate conversion of the ketone 8a was achieved, and low conversions were observed even after 21–22 h at room
the product of reduction was formed with 84% ee.
It should be pointed out that the highest enantio- in good to high enantiomeric excess (86–91% ee).
selectivity observed so far for a transfer hydrogenation of a It should be mentioned that a color change was observed
temp. (Entries 4–5); alcohols 9d–e were nevertheless formed
prochiral ketone employing ligands containing a stereogenic during the course of the reaction, usually occurring after
sulfur atom was 80%, as reported by van Leeuwen and co- several hours (i.e. overnight): the reaction mixture, which
workers (who also employed a different metal and a dif- was initially deep purple, slowly turned red-brown. We sus-
ferent hydrogen donor, namely iridium in combination with pect this to be associated with catalyst decomposition, be-
the triethylamine/formic acid azeotrope).[3c]
cause no further progress in conversion was recorded after
Some further tests were conducted at this stage: first, we the color change had occurred. We found that the presence
found that in the absence of lithium chloride the reaction of moisture in the reaction mixture greatly accelerated this
proceeded to a much lesser extent and also the enantio- process, which led to color change within minutes. We
selectivity was greatly reduced (Entry 14); while this is in therefore found it necessary to operate under strictly anhy-
agreement with our previous findings about the positive ef- drous conditions, using dry solvents and a freshly prepared
fect of lithium salts on the outcome of transfer hydrogena- solution of the base, in order to replicate the results re-
tion reacions,[12f] the magnitude of such effect was surpris- ported above.
ing. Second, a change in the base to KOH or tBuONa was
After having obtained such promising results, we were
found to be detrimental, since lower conversions were re- interested in evaluating the importance of the stereogenic
corded after 5 h, although the change had no effect on the center on sulfur for the selectivity of the reduction. For this
enantioselectivity (Entries 15–16). Lastly, variation of the purpose, we decided to synthesize compound 16, structur-
Ru pre-catalyst to [Ru(benzene)Cl2]2 (10b) was also unpro- ally similar to 1h but bearing a non-chiral sulfonamide moi-
ductive, as both activity and selectivity of the resulting cata- ety, and to employ it as a ligand in the transfer hydrogena-
lyst were low (Entry 17).
tion under the conditions used in Table 2, Entry 12. A com-
Having found a catalyst able to promote the reduction parison of the results would allow us to assess the role of
of acetophenone (8a) with good enantioselectivity, we next the chiral sulfinamide unit in imparting significant enantio-
decided to apply it to the reduction of some other prochiral selectivity to the process. The preparation of sulfonamide
ketones. Our aim was to determine if the same level of selec- 16 is detailed in Scheme 4.
tivity would be retained also in the presence of substituents
on the aromatic ring (Table 3).
Initially, the amino alcohol 4f was converted into the az-
iridine 13 following a known protocol.[30] The latter com-
pound was subjected to nucleophilic ring-opening with so-
dium azide promoted by BF3·Et2O as Lewis acid, to yield
azide 14 in 52% yield (unoptimized). Subsequent reduction
of the azide by means of a Staudinger reaction followed
by tosylation under standard conditions[14a] provided the
desired compound 16.
Table 3. Ru-catalyzed transfer hydrogenation of prochiral ketones
using sulfinamide 1i as the chiral ligand.
To our surprise, when the sulfonamide 16 was used as a
ligand for the Ru-catalyzed transfer hydrogenation of aceto-
phenone (8a), only 55% conversion was measured after 18 h
at room temp., and the resulting alcohol 9a was produced
in nearly racemic form (Ͻ 5% ee). Thus, the catalyst stem-
ming from compound 16 was neither more active nor more
selective than that derived from its sulfinamide analogue 1h
(which, as mentioned earlier, promoted the formation of 9a
with 74% ee, Table 2, Entry 12). Interestingly, this observa-
tion is in agreement with previous findings by Hiroi[31] and
Ellman,[10] who, in the context of different catalytic enantio-
selective reactions, found that ligands or catalysts in which
a sulfinamide group had been replaced by a sulfonamide
were much less selective than their counterparts.
Entry
1
Product
R
H
Time
% Conv.[a]
% ee[a]
9a
5
22
5
21
5
22
21
22
42
61
43
58
58
77
30
32
86 (S)
84 (S)
84 (S)
83 (S)
88 (S)
87 (S)
86 (S)
91 (S)
2
3
9b
9c
4-Br
3-CF3
4
5
9d
9e
4-Me
3-MeO
[a] Determined by chiral GC-analysis (CP-Chirasil-Dex CB).
From all these results it appears that a stereogenic center
As can be seen from Table 3, 4Ј-Br-acetophenone (8b) on sulfur can often play a decisive role in the generation
furnished a result similar to that obtained with acetophe- of selective catalysts for metal-mediated or organocatalytic
none (8a), although the product of the reduction was reactions; in particular, the chiral S-center is a very impor-
Eur. J. Org. Chem. 2008, 4655–4664
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L. Zani, L. Eriksson, H. Adolfsson
FULL PAPER
Scheme 4. Synthesis of -valine-derived sulfonamide 16.
tant structural feature of the ligands prepared in this study,
and in its absence no enantioselectivity was observed in the
Ru-catalyzed asymmetric transfer hydrogenation.
Experimental Section
General Remarks: Air- and moisture-sensitive manipulations were
carried out under nitrogen using either standard Schlenk tubes or
flasks (ligand preparation) or a Radleys Carousel® 12 reaction sta-
tion (transfer hydrogenation). The glassware employed for those
manipulations was either oven- or flame-dried and then cooled un-
der a stream of nitrogen. THF and Et2O were distilled from so-
dium-benzophenone ketyl radical, iPrOH and CH2Cl2 from cal-
cium hydride prior to use. DMF was dried on molecular sieves
before use. Ethyl acetate, pentane, methanol and 1,2-dimethoxye-
thane were reagent- or HPLC-grade and were used as received.
Acetophenone (8a) and 4Ј-Me-acetophenone (8d) were distilled
Conclusions
In summary, we prepared novel chiral sulfinamides 1a–i,
derived from protected amino acids, through the intermedi-
acy of protected α-amino aldehydes 2a–g. The latter were
accessed either by preparation of the corresponding Wein-
reb amides and subsequent reduction with LiAlH4, or by
prior to use, whereas the other ketones were used as received from
initial reduction of the amino acids to the protected amino commercial sources. H and 13C NMR spectra were recorded with
1
a Bruker BioSpin 400 spectrometer (400 and 100 MHz, respec-
tively). IR spectra were recorded with a Perkin–Elmer Spec-
trumOne instrument; absorptions are given in wavenumbers (cm–1).
High-resolution mass spectra with electrospray ionization (MS-
ESI) were recorded with a Bruker Daltonics MicroTOF instru-
ment. Optical rotation measurements were conducted at room tem-
perature with a Perkin–Elmer PE-241 polarimeter at a wavelength
of 589 nm (-line of a Na-vapour lamp). Chiral GC measurements
were conducted with a Varian 3800 gas chromatograph with a CP-
Chirasil-Dex CB Chrompack 7503 column. The aldehydes 2a–g
alcohols 4 followed by chemoselective reoxidation. The sec-
ond route was found to be operationally simpler and af-
forded in general higher yields of the desired intermediates.
The aldehydes 2a–g were then subjected to reductive amin-
ation in combination with the enantiopure sulfinamides 5a–
b to provide the compounds 1a–i in moderate to good
yields. In addition, removal of the Fmoc group from sulfin-
amide 1c afforded monosulfinylated diamine 7.
The compounds 1a–i and 7 were tested as ligands for
the metal-catalyzed transfer hydrogenation of ketones. The were prepared from the corresponding amino acids following litera-
ture methods,[16–17,24–26] and their analytical data were in agreement
catalyst generated from 7 in combination with the Ru com-
with those previously reported.[32] IBX was prepared following the
plex 10b exhibited high activity (TOF = 356 molh–1), unfor-
procedure described by Frigerio and co-workers.[33] Melting points
of solid compounds were measured in open capillaries with an
Electrothermal 9200 instrumet and are uncorrected.
tunately accompanied by no selectivity. Catalysts stemming
from compounds 1a–i and Rh- or Ru-based pre-catalysts
showed variable levels of efficiency and selectivity; the cata-
lyst resulting from the combination of the sulfinamide 1i
and the pre-catalyst 10a was found to be the most selective
General Procedure for the Synthesis of Sulfinamides 1a-i: A round-
bottom Schlenk flask under nitrogen was charged with the appro-
one, promoting the formation of chiral secondary alcohols priate protected amino aldehyde 2a–g. The latter was dissolved in
dry CH2Cl2 (8 mL/mmol), and either (S)-p-toluenesulfinamide (5a)
or (S)-1,1-dimethylethanesulfinamide (5b) (1.0 equiv.) were added
at room temperature, followed by Ti(OiPr)4 (4.0–5.0 equiv.). The
reaction mixture was stirred at room temperature for 3–16 h (TLC
control). The reaction was quenched by careful addition of H2O
(8 mL/mmol) under vigorous stirring. The resulting heterogeneous
mixture was filtered through a short pad of Celite®, and the layers
were separated. The aqueous layer was extracted with CH2Cl2
(8 mL/mmol). The combined organic layers were dried with
MgSO4. Removal of the solvent under reduced pressure afforded
crude sulfinyl imines 6a–i (1H NMR: δ = 8.00–8.30 ppm) typically
from various ketones with 83–91% ee. Finally, the impor-
tance of the stereogenic center on sulfur for the enantio-
selectivity of the process was confirmed by the observation
that compound 16, structurally similar to 1h but bearing a
non-chiral sulfonamide unit, produced the alcohol 9a in ne-
arly racemic form, as opposed to 74% ee with sulfinamide
1h under otherwise identical conditions. Further refinement
of the ligand design as well as application of the com-
pounds 1a–i to other enantioselective processes are cur-
rently underway in our laboratory.
4660
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2008, 4655–4664

Sulfinamides as Ligands for Enantioselective Transfer Hydrogenation of Ketones
as colorless or light yellow oils. The crude imines were placed in a
round-bottom Schlenk flask under nitrogen, and were dissolved in
methanol (10 mL/mmol). The solution was cooled to 0 °C, and so-
dium borohydride (2.5 equiv.) was carefully added. After stirring
for 2–3 h (TLC control) at 0 °C, the reaction was quenched with a
diluted aqueous NH4Cl solution (20 mL/mmol), and CH2Cl2
(20 mL/mmol) was added. The layers were separated, and the aque-
ous layer was extracted with CH2Cl2 (3ϫ15 mL/mmol). The com-
bined organic layers were washed with brine (40 mL/mmol) and
dried with Na2SO4. Removal of the solvent in vacuo gave crude
sulfinamides 1a–i, sometimes as a mixture of diastereomers, which
were purified by flash column chromatography sometimes followed
by crystallization.
NMR (100 MHz, CDCl3): δ = 18.4, 21.3, 46.2, 47.1, 47.3, 66.5,
119.9, 125.1, 126.1, 127.1, 127.66, 127.70, 129.6, 141.3, 141.4,
143.9, 156.1 ppm. IR (KBr): ν = 3330, 3142, 3051, 2932, 1694,
˜
1532, 1450, 1251, 1055, 1045 cm–1. HRMS-ESI: m/z calcd. for
C25H26N2O3SNa [M + Na]: 457.1556; found 457.1542.
(R,S)-N-Cbz-NЈ-p-Tolylsulfinyl-1,2-diaminopropane (1d): Prepared
according to general procedure from aldehyde ent-2a (0.207 g,
1.0 mmol) and (S)-p-toluenesulfinamide (5a, 0.155 g, 1.0 mmol,
1.0 equiv.). The crude was obtained as a 6:1 mixture of the title
compound and its (S,S)-diastereomer, as determined by NMR
specroscopy. Purification by flash column chromatography
(EtOAc/pentane, 3:2) followed by crystallization from EtOAc/cHex
afforded pure (R,S)-1d as a colorless solid (0.121 g, 0.35 mmol,
35% yield over two steps), m.p. 121.7–121.9 °C. [α]2D0 = +130.7 (c
= 0.30, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 1.09 (d, J =
6.7 Hz, 3 H), 2.40 (s, 3 H), 2.87 (ddd, J = 13.2, 6.8, 4.2 Hz, 1 H),
2.98–3.05 (m, 1 H), 3.71–3.82 (m, 1 H), 4.60 (br. s, 1 H), 5.09 (AB
system, 2 H), 5.32 (br. s, 1 H), 7.27 (d, J = 8.1 Hz, 2 H), 7.29–7.35
(m, 5 H), 7.55 (d, J = 8.1 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.7, 21.3, 46.3, 46.8, 66.7, 126.0, 127.98, 128.03,
(S,S)-N-Cbz-NЈ-p-Tolylsulfinyl-1,2-diaminopropane (1a): Prepared
according to general procedure from aldehyde 2a (0.300 g,
1.45 mmol) and (S)-p-toluenesulfinamide (5a, 0.225 g, 1.45 mmol,
1.0 equiv.). The crude was obtained as a 6:1 mixture of the title
compound and its (R,S)-diastereomer, as determined by NMR
specroscopy. Purification by flash column chromatography
(EtOAc/pentane, 3:2) followed by crystallization from EtOAc/cHex
afforded pure (S,S)-1a as a colorless solid (0.180 g, 0.52 mmol, 36%
yield over two steps), m.p. 98.9–99.1 °C. [α]2D0 = +93.9 (c = 0.38,
128.5, 129.6, 136.5, 140.7, 141.3, 156.3 ppm. IR (KBr): ν = 3265,
˜
2925, 1699, 1537, 1454, 1339, 1262, 1240, 1087, 1054 cm–1. HRMS-
ESI: m/z calcd. for C18H22N2NaO3S [M + Na]: 369.1243; found
369.1230.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.12 (d, J = 6.8 Hz, 3
H), 2.39 (s, 3 H), 2.74–2.81 (m, 1 H), 3.10 (ddd, J = 13.6, 6.8,
3.7 Hz, 1 H), 3.75–3.85 (m, 1 H), 4.62 (br. s, 1 H), 5.02–5.13 (AB
system, 2 H), 5.41 (br. s, 1 H), 7.24 (d, J = 8.2 Hz, 2 H), 7.31–7.37
(m, 5 H), 7.52 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.3, 21.3, 46.4, 47.1, 66.5, 126.1, 128.1, 128.5, 129.6,
(S,S)-N-Cbz-NЈ-(1,1-Dimethyl)ethylsulfinyl-1,2-diaminopropane (1e):
Prepared according to general procedure from aldehyde 2a
(0.300 g, 1.45 mmol) and (S)-1,1-dimethylethanesulfinamide (5b,
0.176 g, 1.45 mmol, 1.0 equiv.). Purification by flash column
chromatography (EtOAc/pentane, 3:1) afforded pure (S,S)-1e as a
light yellow oil (0.261 g, 0.83 mmol, 58% yield over two steps).
[α]2D0 = +36.5 (c = 0.72, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
1.17 (d, J = 5.9 Hz, 3 H), 1.18 (s, 9 H), 3.13–3.19 (m, 1 H), 3.64
(br. s, 1 H), 3.83–3.88 (m, 1 H), 5.05 (br. s, 1 H), 5.08 (s, 2 H),
7.31–7.37 (m, 5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.7,
22.6, 47.7, 50.9, 55.9, 66.7, 128.08, 128.10, 128.5, 136.4, 156.1 ppm.
136.6, 140.0, 141.4, 156.1 ppm. IR (KBr): ν = 3263, 2922, 1699,
˜
1533, 1452, 1337, 1249, 1054 cm–1. HRMS-ESI: m/z calcd. for
C18H23N2O3S [M + 1]: 347.1424; found 347.1430.
(S,S)-N-Boc-NЈ-p-Tolylsulfinyl-1,2-diaminopropane (1b): Prepared
according to general procedure from aldehyde 2b (0.260 g,
1.5 mmol) and (S)-p-toluenesulfinamide (5a, 0.233 g, 1.5 mmol,
1.0 equiv.). The crude was obtained as a 4.5:1 mixture of the title
compound and its (R,S)-diastereomer, as determined by NMR
specroscopy. Purification by flash column chromatography
(EtOAc/pentane, 1:1) afforded pure (S,S)-1b as a colorless solid
(0.258 g, 0.83 mmol, 55% yield over two steps), m.p. 117.2–
117.4 °C. [α]2D0 = +72.3 (c = 0.47, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 1.08 (d, J = 6.8 Hz), 1.42 (s, 9 H), 2.39 (s, 3 H), 2.72
(dt, J = 13.2, 6.6 Hz), 3.10 (ddd, J = 13.3, 6.5, 3.9 Hz, 1 H), 3.69–
3.78 (m, 1 H), 4.74 (s, 1 H), 4.96 (s, 1 H), 7.27 (d, J = 8.2 Hz, 2
H), 7.55 (d, J = 8.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 18.5, 21.3, 28.4, 46.0, 47.0, 79.3 126.0, 129.5, 140.4, 141.2,
IR (KBr): ν = 3261, 2958, 2926 1701, 1536, 1455, 1264, 1239, 1054
˜
cm–1. HRMS-ESI: m/z calcd. for C15H24N2NaO3S [M + Na]:
335.1400; found 335.1382.
(S,S)-N-Cbz-NЈ-p-Tolylsulfinyl-1,2-diamino-3-phenylpropane (1f):
Prepared according to general procedure from aldehyde 2d
(0.397 g, 1.40 mmol) and (S)-p-toluenesulfinamide 5a (0.217 g,
1.40 mmol, 1.0 equiv.). The crude was obtained as a 5.5:1 mixture
of the title compound and its (R,S)-diastereomer, as determined by
NMR specroscopy. Purification by flash column chromatography
(EtOAc/pentane, 2:3) followed by crystallization from EtOAc/cHex
afforded pure (S,S)-1f as a colorless solid (0.280 g, 0.66 mmol, 47%
yield over two steps), m.p. 139.4–139.6 °C. [α]2D0 = +86.0 (c = 0.58,
155.7 ppm. IR (KBr): ν = 3262, 2976, 1705, 1693, 1526, 1454, 1365,
˜
1248, 1171, 1053 cm–1. HRMS-ESI: m/z calcd. for C15H24N2NaO3S
1
[M + Na]: 335.1400; found 335.1376.
CHCl3). H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H), 2.71 (dd,
J = 13.8, 7.7 Hz, 1 H), 2.81–2.88 (m, 2 H), 3.04–3.11 (m, 1 H),
3.88–3.98 (m, 1 H), 4.52 (br. s, 1 H), 5.03–5.12 (AB system, 2 H),
5.64 (br. s, 1 H), 7.13–7.17 (m, 2 H), 7.20–7.34 (m, 10 H), 7.50 (d,
J = 8.2 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 21.3,
38.4, 44.9, 51.6, 66.5, 126.0, 126.7, 127.97, 128.02, 128.5, 128.7,
(S,S)-N-Fmoc-NЈ-p-Tolylsulfinyl-1,2-diaminopropane (1c): Prepared
according to general procedure from aldehyde 2c (0.384 g,
1.3 mmol) and (S)-p-toluenesulfinamide (5a, 0.201 g, 1.3 mmol,
1.0 equiv.). The crude was obtained as a 3:1 mixture of the title
compound and its (R,S)-diastereomer, as determined by NMR
specroscopy. Purification by flash column chromatography
(EtOAc/pentane, 3:2) afforded pure (S,S)-1c as a colorless solid
(0.391 g, 0.9 mmol, 68% yield over two steps), m.p. 117.7–117.9 °C.
[α]2D0 = +71.1 (c = 0.85, CHCl3). 1H NMR (400 MHz, CDCl3): δ =
129.0, 129.6, 137.3, 139.6, 141.4, 156.1 ppm. IR (KBr): ν = 3259,
˜
3029, 2924, 1701, 1538, 1454, 1252, 1086, 1049 cm–1. HRMS-ESI:
m/z calcd. for C24H26N2NaO3S [M + Na]: 445.1556; found
445.1535.
1.13 (d, J = 6.5 Hz, 3 H), 2.39 (s, 3 H), 2.75–2.80 (m, 1 H), 3.08– (S,S)-N-Cbz-NЈ-p-Tolylsulfinyl-1,2-diamino-4-methylpentane (1g):
3.13 (m, 1 H), 3.75–3.85 (m, 1 H), 4.22 (t, J = 6.5 Hz, 1 H), 4.40
(d, J = 6.6 Hz, 2 H), 4.57 (br. s, 1 H), 5.50 (br. s, 1 H), 7.25 (d, J
Prepared according to general procedure from aldehyde 2e (0.490 g,
1.97 mmol) and (S)-p-toluenesulfinamide 5a (0.305 g, 1.97 mmol,
= 8.1 Hz, 2 H), 7.29–7.35 (m, 2 H), 7.37–7.43 (m, 2 H), 7.53 (d, J 1.0 equiv.). The crude was obtained as a 7.5:1 mixture of the title
= 8.1 Hz, 2 H), 7.55–7.63 (m, 2 H), 7.76–7.84 (m, 2 H) ppm. 13C
compound and its (R,S)-diastereomer, as determined by NMR
Eur. J. Org. Chem. 2008, 4655–4664
© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4661

L. Zani, L. Eriksson, H. Adolfsson
FULL PAPER
specroscopy. Purification by flash column chromatography
(EtOAc/pentane, 1:2) followed by crystallization from EtOAc/cHex
afforded pure (S,S)-1g as a colorless solid (0.375 g, 1.0 mmol, 51%
yield over two steps), m.p. 93.3–93.5 °C. [α]2D0 = +79.1 (c = 0.71,
141.0, 141.2 ppm. IR (neat): ν = 3193, 2963, 2923, 2870, 1596,
˜
1491, 1455, 1394, 1087, 1057 cm–1. HRMS-ESI: m/z calcd. for
C10H16N2OSNa [M + Na]: 235.0876; found 235.0879.
(S)-N-Cbz-2-Isopropylaziridine (13): In a round-bottom flask under
air, the protected amino alcohol 4f (1.54 g, 6.49 mmol) was dis-
solved in dry diethyl ether (130 mL). Tosyl chloride (1.49 g,
7.79 mmol, 1.2 equiv.) was added, followed by freshly powdered
KOH (1.46 g, 26.0 mmol, 4.0 equiv.). The reaction mixture was
heated at reflux and stirred for 3 h. A TLC check (EtOAc/pentane,
1:2) showed the presence of residual starting material; a further
4.0 equiv. of KOH were added, and stirring was continued for 1 h,
after which a second TLC control showed no more starting mate-
rial. The reaction mixture was poured in a separatory funnel con-
taining 150 mL of a ice/water mixture. The layers were separated,
and the aqueous layer was extracted with diethyl ether (75 mL).
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.88 (d, J = 6.5 Hz, 3
H), 0.89 (d, J = 6.4 Hz, 3 H), 1.14–1.21 (m, 1 H), 1.25–1.33 (m, 1
H), 1.53–1.63 (m, 1 H), 2.38 (s, 3 H), 2.71–2.80 (m, 1 H), 3.09 (ddd,
J = 13.6, 6.9, 3.4 Hz, 1 H), 3.72–3.81 (m, 1 H), 4.53 (br. s, 1 H),
5.03–5.17 (AB system, 2 H), 5.64 (br. d, J = 8.3 Hz, 1 H), 7.21 (d,
J = 8.1 Hz, 2 H), 7.29–7.39 (m, 5 H), 7.50 (d, J = 8.1 Hz, 2 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 21.3, 22.1, 22.9, 24.7, 41.6,
46.2, 48.7, 66.5, 126.1, 128.0, 128.1, 128.5, 129.6, 136.7, 139.8,
141.3, 156.4 ppm. IR (KBr): ν = 3260, 3033, 2955, 1701, 1536,
˜
1454, 1240, 1087, 1052 cm–1. HRMS-ESI: m/z calcd. for
C21H28N2NaO3S [M + Na]: 411.1713; found 411.1707.
(S,S)-N-Cbz-NЈ-p-Tolylsulfinyl-1,2-diamino-3-methylbutane
Prepared according to general procedure from aldehyde 2f (0.460 g,
1.96 mmol) and (S)-p-toluenesulfinamide (5a, 0.304 g, 1.96 mmol, crude aziridine 13. Purification by flash column chromatography
(1h): The combined organic layers were washed with brine (120 mL),
and dried with MgSO4. Removal of the solvent under vacuum gave
1.0 equiv.). Purification by flash column chromatography (EtOAc/
(EtOAc/pentane, 1:4) afforded pure (S)-13 (0.860 g, 3.92 mmol,
60% yield) as a pale yellow oil. H NMR (400 MHz, CDCl3): δ =
0.97 (d, J = 6.8 Hz, 3 H), 1.07 (d, J = 6.8 Hz, 3 H), 1.46 (se, J =
6.8 Hz, 1 H), 2.03 (d, J = 3.8 Hz, 1 H), 2.25 (ddd, J = 7.3, 6.2,
1
pentane, 3:2) afforded pure (S,S)-1h as a colorless solid (0.567 g,
1.51 mmol, 77% yield over two steps), m.p. 97.5–97.7 °C. [α]2D0
=
+58.6 (c = 0.58, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 0.88
(d, J = 6.7 Hz, 3 H), 1.69–1.75 (m, 1 H), 2.38 (s, 3 H), 2.83 (qu, J 3.9 Hz, 1 H), 2.31 (d, J = 6.2 Hz, 1 H), 5.13 (s, 2 H), 7.29–7.39 (m,
= 6.9 Hz, 1 H), 3.13 (ddd, J = 13.5, 6.6, 3.4 Hz, 1 H), 3.47–3.55
(m, 1 H), 4.49 (br. s, 1 H), 5.04–5.17 (AB system, 2 H), 5.20 (br.
5 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 18.9, 19.7, 30.69,
30.74, 44.4, 67.9, 127.9, 128.1, 128.5, 136.0, 163.6 ppm. The analyt-
d, J = 8.1 Hz, 1 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.29–7.39 (m, 5 H), ical data are in agreement with those reported in the literature.[34]
7.50 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
18.4, 19.4, 21.3, 30.1, 43.9, 56.1, 66.7, 126.0, 128.0, 128.1, 128.5,
(S)-N-Cbz-2-Amino-1-azido-3-methylbutane (14): Aziridine 13
(0.274 g, 1.25 mmol) was placed in a round-bottom Schlenk flask
under nitrogen, and was dissolved in dry DMF (12.5 mL). Sodium
azide (0.325 g, 5.0 mmol, 4.0 equiv.) and boron trifluoride–diethyl
ether (0.710 g, 5.0 mmol, 0.63 mL, 4.0 equiv.) were added in se-
129.6, 136.6, 140.0, 141.3, 156.7 ppm. IR (KBr): ν = 3259, 2961,
˜
1702, 1536, 1454, 1242, 1087, 1047 cm–1. HRMS-ESI: m/z calcd.
for C20H26N2O3SNa [M + Na]: 390.1556; found 390.1535.
(S,S)-N-Cbz-NЈ-p-Tolylsulfinyl-1,2-diamino-3,3-dimethylbutane (1i): quence at room temperature, and the reaction mixture was heated
Prepared according to general procedure from aldehyde 2g
(0.495 g, 1.98 mmol) and (S)-p-toluenesulfinamide 5a (0.307 g,
1.98 mmol, 1.0 equiv.). Purification by flash column chromatog-
raphy (EtOAc/pentane, 1:1) afforded pure (S,S)-1i as a colorless
solid (0.389 g, 1.0 mmol, 50% yield over two steps), m.p. 136.0–
136.2 °C. [α]2D0 = –6.7 (c = 0.62, CHCl3). 1H NMR (400 MHz,
to 85 °C and stirred overnight. The reaction mixture was then co-
oled to room temperature and was diluted with EtOAc (20 mL).
Water (20 mL) was added, and the layers were separated. The or-
ganic layer was washed with water (5ϫ20 mL). The combined
aqueous layers were extracted with EtOAc (20 mL). The combined
organic layers were washed with with brine (40 mL) and dried with
CDCl3): δ = 0.86 (s, 9 H), 2.38 (s, 3 H), 2.61 (ddd, J = 12.8, 10.8, MgSO4. Removal of the volatiles furnished crude azide 14, which
7.6 Hz, 1 H), 3.38 (ddd, J = 12.8, 5.3, 3.1 Hz, 1 H), 3.58 (dt, J =
10.5, 3.0 Hz, 1 H), 4.36–4.41 (m, 1 H), 4.52 (br. d, J = 10.3 Hz, 1
H), 5.04–5.21 (AB system, 2 H), 7.21 (d, J = 8.0 Hz, 2 H), 7.29–
7.39 (m, 5 H), 7.49 (d, J = 8.0 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 21.3, 26.5, 34.1, 41.6, 59.6, 66.9, 126.0, 128.1, 128.2,
was purified by flash column chromatography (EtOAc/pentane,
1:11) to give pure (S)-14 (0.170 g, 0.64 mmol, 52% yield) as a color-
less oil. 1H NMR (400 MHz, CDCl3): δ = 0.94 (d, J = 6.8 Hz, 3
H), 0.96 (d, J = 6.8 Hz, 3 H), 1.83 (se, J = 6.8 Hz, 1 H), 3.45 (d, J
= 4.8 Hz, 2 H), 3.57–3.63 (m, 1 H), 4.80 (br. d, J = 8.9 Hz, 1 H),
5.12 (s, 2 H), 7.28–7.38 (m, 5 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 18.4, 19.4, 29.7, 53.0, 56.1, 66.9, 128.1, 128.2, 128.5,
136.3, 156.1 ppm. The analytical data are in agreement with those
reported in the literature.[35]
128.6, 129.5, 136.5, 140.7, 141.2, 157.1 ppm. IR (KBr): ν = 3261,
˜
2962, 1705, 1539, 1455, 1342, 1240, 1087, 1055 cm–1. HRMS-ESI:
m/z calcd. for C21H28N2O3SNa [M + Na]: 411.1713; found
411.1699.
(S,S)-N-p-Tolylsulfinyl-1,2-diaminopropane (7): The sulfinamide 1c
(0.135 mg, 0.31 mmol) was placed in a round-bottom flask under
an air atmosphere. Piperidine (0.085 mg, 1.0 mmol, 0.1 mL,
3.2 equiv.) and dry DMF (0.4 mL) were added, and the resulting
homogeneous mixture was stirred at room temp. After 30Ј a thick
colorless precipitate was formed. The latter was dissolved by ad-
dition of EtOAc, and the resulting mixture was directly loaded onto
a column and purified by flash chromatography (MeOH/EtOAc/
Et3N, 1:3:0.1), to furnish pure (S,S)-7 as a colorless oil (0.056 mg,
(S)-1-Amino-2-(Cbz-amino)-3-methylbutane (15):[36] In a round-bot-
tom flask under air, the azide 14 (0.170 g, 0.65 mmol) was dissolved
in THF (8 mL). Triphenylphosphane (0.340 g, 1.33 mmol,
2.05 equiv.) and water (0.025 g, 1.37 mmol, 25 µL, 2.1 equiv.) were
added in sequence, and the resulting mixture was heated to reflux
and stirred for 2 h. The reaction mixture was then cooled to room
temperature and the solvent was evaporated. The oily residue was
taken up with Et2O (12 mL). The mixture was vigorously stirred
and acidified with aq. HCl 1  until pH 2. The layers were sepa-
rated and the aqueous layer was washed with Et2O (2ϫ7 mL). The
pH was then adjusted to 12 with aq. NaOH 1 , and the aqueous
layer was extracted with CH2Cl2 (6ϫ8 mL), and the combined or-
ganic layers were dried with Na2SO4. Removal of the volatiles af-
forded the crude, which was purified by flash column chromatog-
0.26 mmol, 85% yield). [α]2D0 = +161.2 (c = 1.0, CHCl3). H NMR
1
(400 MHz, CDCl3): δ = 1.03 (d, J = 6.3 Hz, 3 H), 2.03 (br. s, 2 H),
2.40 (s, 3 H), 2.51–2.60 (m, 1 H), 3.02–3.07 (m, 2 H), 4.84 (br. s, 1
H), 7.29 (d, J = 8.3 Hz, 2 H), 7.56 (d, J = 8.3 Hz, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 21.29, 21.32, 47.1, 48.5, 125.9, 129.5,
4662
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Eur. J. Org. Chem. 2008, 4655–4664

Sulfinamides as Ligands for Enantioselective Transfer Hydrogenation of Ketones
Han, I. Gallou, Aldrichimica Acta 2005, 38, 93; e) F. A. Davis,
raphy (MeOH/EtOAc/Et3N, 3:5:0.05) to afford pure monopro-
tected diamine (S)-15 (0.110 g, 0.465 mmol, 72% yield) as a color-
less oil. 1H NMR (400 MHz, CDCl3): δ = 0.89 (d, J = 6.8 Hz, 3
H), 0.92 (d, J = 6.8 Hz, 3 H), 1.77 (se, J = 6.7 Hz, 1 H), 2.68–2.75
(m, 1 H), 2.81–2.86 (m, 1 H), 3.40–3.51 (m, 1 H), 3.90 (br. s, 2 H),
5.03–5.13 (AB system, 2 H), 5.31 (br. s, 1 H), 7.28–7.38 (m, 5 H)
ppm. 13C NMR (100 MHz, CDCl3): δ = 18.2, 19.3, 30.2, 42.9, 58.1,
66.7, 127.96, 128.02, 128.5, 136.5, 156.9 ppm.
B. Yang, J. Deng, J. Zhang, ARKIVOC 2006, ##VII, 120; f)
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Selected references: a) J. V. Allen, J. F. Bower, J. M. J. Williams,
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a) T. D. Owens, F. J. Hollander, A. G. Oliver, J. A. Ellman, J.
Am. Chem. Soc. 2001, 123, 1539; b) T. D. Owens, A. J. Souers,
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1315.
(S)-N-Cbz-NЈ-p-Tolylsulfonyl-1,2-diamino-3-methylbutane
(16):
Monoprotected diamine (S)-15 (0.110 g, 0.47 mmol) was placed in
a round-bottom flask under air, and was dissolved in CHCl3
(1.0 mL). Triethylamine (0.581 g, 5.7 mmol, 0.8 mL, 12.0 equiv.)
was added. The reaction mixture was cooled to 0 °C and tosyl chlo-
ride (0.106 g, 0.56 mmol, 1.2 equiv.) was added. The mixture was
stirred at 0 °C for 2 h. The reaction mixture was subsequently di-
luted with diethyl ether (20 mL). The organic layer was washed
with aq. HCl 1  (10 mL), satd. aq. NaHCO3 (2ϫ10 mL) and
brine (2ϫ10 mL), and dried with Na2SO4. Removal of the solvent
in vacuo afforded crude 16. Purification by flash column
chromatography (EtOAc/pentane, 2:5) afforded pure (S)-16
(0.092 g, 0.24 mmol, 51% yield) as a colorless oil which slowly so-
lidified upon standing, m.p. 99.1–99.3 °C. [α]2D0 = –6.3 (c = 0.5,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 0.86 (d, J = 6.9 Hz, 3
[7]
H), 0.88 (d, J = 6.9 Hz, 3 H), 1.77 (se, J = 6.8 Hz, 1 H), 2.40 (s, 3
H), 2.94–3.01 (m, 1 H), 3.03–3.10 (m, 1 H), 3.45–3.51 (m, 1 H),
4.85 (br. s, 1 H), 5.07 (s, 2 H), 5.25 (br. s, 1 H), 7.26 (d, J = 8.1 Hz,
2 H), 7.29–7.38 (m, 5 H), 7.71 (d, J = 8.1 Hz) ppm. 13C NMR
(100 MHz, CDCl3): δ = 18.1, 19.2, 21.5, 29.9, 45.5, 56.1, 67.0,
127.0, 128.0, 128.2, 128.5, 129.7, 136.2, 136.8, 143.4, 156.9 ppm.
[8]
[9]
IR (KBr): ν = 3305, 2962, 1697, 1529, 1454, 1329, 1234, 1160,
˜
1093 cm–1. HRMS-ESI: m/z calcd. for C20H26N2O4S [M]: 390.1608;
found 390.1628.
[10]
[11]
[12]
General Procedure for the Transfer Hydrogenation of Ketones 8a-e:
A Radleys Carousel® reaction tube was charged with the metal pre-
catalyst 10–12 (0.005–0.01 mmol, 0.5–1.0 mol-%), sulfinamide 1a–
i, 7 or the sulfonamide 16 (0.011–0.022 mmol, 1.1–2.2 mol-%) and
litihium chloride (4.2 mg, 0.1 mmol, 10 mol-%) under nitrogen. The
solid compounds were dried under vacuum for 10–15 min, and the
nitrogen atmosphere was restored. 2-Propanol (4.0–4.5 mL, final
concentration 0.2 ) was added, followed by a 0.1  solution of
the appropriate base in 2-propanol (0.5–1.0 mL, 0.05–0.1 mmol, 5–
10 mol-%). After 5 min stirring at room temperature, the appropri-
ate ketone 8 was added (1.0 mmol), and the reaction mixture was
stirred at room temperature. Samples of the reaction mixture (ap-
prox 0.2 mL) were taken at regular intervals and filtered through
silica gel using EtOAc as a solvent before being analyzed by means
of chiral gas chromatography (CP-Chirasil-Dex CB Chrompack
7503) to determine conversion of the starting materials and enan-
tiomeric excess of the products. The absolute configuration was
assigned by comparison with previously reported data.[12c]
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Acknowledgments
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This is likely to be due to partial cleavage of the Fmoc protect-
ing group. For an extensive discussion on the synthesis of
Fmoc-protected amino aldehydes, see: J. J. Wen, C. M. Crews,
Tetrahedron: Asymmetry 1998, 9, 1855.
We thank the Swedish Research Council and the Wenner-Gren
Foundation (post-doctoral fellowship to L. Z.). Dr. J.-B. Sortais is
acknowledged for a generous donation of complex 10b.
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© 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
4663

L. Zani, L. Eriksson, H. Adolfsson
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[33]
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[36]
a highly acidic proton in the α-position. For a similar observa-
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[28] CCDC-691608 contains the supplementary crystallographic
Received: June 13, 2008
Published Online: August 14, 2008
data for compound 1h. These data can be obtained free of
4664
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Eur. J. Org. Chem. 2008, 4655–4664