Thiol-catalyzed stereoselective transfer hydroamination of olefins with N-aminated dihydropyridines

Article abstract of DOI:10.1002/anie.200703902

(Chemical Equation Presented) Hantzsch dihydropyridines are popular reducing reagents in organocatalysis. The N-aminated Hantzsch dihydropyridine 1 has now been used as a novel efficient precursor for Boc-protected carbamoyl radicals. The readily prepared reagent was employed for the radical-transfer hydroamination of various olefins. Stereoselective hydroamination of chiral enecarbamates afforded vicinal diamines in good stereoselectivities. Boc = tert-butyloxycarbonyl.

Full text of DOI:10.1002/anie.200703902

Angewandte
Chemie
DOI: 10.1002/anie.200703902
Synthetic Methods
Thiol-Catalyzed Stereoselective Transfer Hydroamination of Olefins
with N-Aminated Dihydropyridines**
Joyram Guin, Roland Fröhlich, and Armido Studer*
The Hantzsch dihydropyridine 1 has recently been used as a
transfer-hydrogenation reagent in the organocatalytic reduc-
tion of imines,[1] a,b-unsaturated aldehydes,[2] and pyridines.[3]
These reductions proceed by hydride transfer from the
dihydropyridine to an activated acceptor. However, the
application of Hantzsch-type dihydropyridines as H donors
in radical chain reactions has not been reported to date. We
have recently shown that the aminated cyclohexadiene 2
(Moc = methyloxycarbonyl) is an efficient reagent for tran-
sition-metal-free radical-transfer hydroamination of various
olefins.[4] The doubly activated methylene group in 2 acts as an
H donor. Drawbacks of our reagent 2 are: 1) Large-scale
synthesis of 2 is rather tedious, 2) compound 2 readily
decomposes under acidic conditions, and 3) stereoselective
hydroaminations are highly unlikely since reactions with 2
have to be conducted at 1408C.
synthesis of chiral 1,2-diamines has recently received increas-
ing attention.[7]
Hydrogen transfers from carbon atoms to carbon radicals
are generally inefficient processes. Therefore, we planned to
apply polarity-reversal catalysis (PRC).[8] We believed that
PhSH would be a good catalyst for our chain reaction, since it
efficiently reduces C-centered radicals to give the corre-
sponding thiyl radicals, which should be reduced by reagent 3
(polarity match) to reform the thiol catalyst (Scheme 1). The
Scheme 1. Radical transfer hydroamination with 3 using polarity-rever-
sal catalysis (PRC).
Transition-metal-mediated hydroaminations of olefins
have been intensively investigated. However, these methods
lack generality and therefore novel procedures are still highly
desirable.[5] Herein we introduce the N-aminated Hantzsch
ester 3 (Boc = tert-butyloxycarbonyl) as a readily available
nontoxic[6] radical-transfer-hydroamination reagent. More-
over, we will present stereoselective hydroaminations of
chiral enecarbamates for the preparation of vicinal diamines.
Since these compounds are biologically interesting, the
radical 4 thus formed should readily aromatize to generate the
carbamoyl radical (CNHBoc) and pyridine 5.[9] The driving
force of the overall reaction is the aromatization yielding 5. In
addition, the weak N N bond in 4 should further support the
elimination. Addition of the N radical to the acceptor RCH
CH2 would lead to the corresponding b-amidyl alkyl radical,
which would be eventually reduced with PhSH to propagate
the chain reaction.
ꢀ
=
Reagent 3 was readily prepared on a large scale in two
steps (Scheme 2). Reaction of ethyl acetylacetate with
[*] J. Guin, Dr. R. Fröhlich, Prof. Dr. A. Studer
NRW Graduate School of Chemistry
Organisch-Chemisches Institut
Westfälische Wilhelms-Universität
Corrensstrasse 40, 48149 Münster (Germany)
Fax: (+49)281-833-6523
E-mail: studer@uni-muenster.de
[**] We thank the NRW Graduate School of Chemistry (stipend to J.G.)
and the Deutsche Forschungsgemeinschaft (STU 280/3-3) for
supporting our work. The Fonds der Chemischen Industrie is
acknowledged for continuous support. We thank S. Grimme for
performing the calculations and Novartis Pharma AG for financial
support (Novartis Young Investigator Award to A.S.).
Scheme 2. Synthesis of hydroamination reagent 3.
formaldehyde afforded the diester 6, which underwent
condensation with Boc-protected hydrazine to give 3 in
good yield.[10]
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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ꢀ 2008 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Radical hydroamination was first studied with norbor-
nene as the acceptor [Eq. (1)]. Reaction of norbornene
(10 equiv) with 3 (1 equiv) in refluxing benzene under typical
radical conditions (0.3 equiv a,a’-azobisisobutyronitrile,
AIBN) in the presence of PhSH (0.15 equiv) afforded 7 in
54% yield (Table 1, entry 1). Importantly, pyridine 5, which
Table 1: Hydroamination of norbornene with 3 under different condi-
tions.
Entry Solv.
T [8C] PhSH [equiv] Init.[a]
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
C6H6
C6H6
C6H6
C6H6
C6H5CH3
CH2Cl2
ClCH2CH2Cl
80
20
20
0
20
20
20
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
0.15
–
AIBN
air
54
57
60
51
42
46
54
53
46
40
56
51
44
Figure 1. Hydroamination of various olefins. Reaction conditions:
benzene (0.4 m), olefin (2–10 equiv), reagent 3 (1 equiv). TBS=tert-
butyldimethylsilyl.
[c]
[c]
[c]
[c]
[c]
[c]
[c]
Et3B/O2
Et3B/O2
Et3B/O2
Et3B/O2
Et3B/O2
Et3B/O2
Et3B/O2
AIBN
hydroamination occurred highly regioselectively to give the
anti-Markovnikov product only. Hydroamination of cyclo-
hexene gave 9 in 52% yield. A similar yield was obtained for
the reaction of b-methylstyrene (!10, 50%). Electron-rich
vinyl amides were good acceptors for the radical hydro-
amination (!11–14). With the enecarbamate bearing an
alkynyl substituent we achieved a slightly lower yield (!15).
The biologically interesting protected 1,2-amino alcohols 16–
19 were isolated in moderate to good yields (42–62%). In
contrast to metal-catalyzed aminations where Markovnikov
products have been obtained,[5] our method delivered anti-
Markovnikov compounds. Hence, our hydroamination nicely
complements existing metal-mediated reactions. Moreover,
our method directly delivered protected amines, which were
readily isolated.
ClCH2CH2Cl ꢀ30
CH2Cl2
C6H6
C6H6
C6H6
C6H6
ꢀ80
20
[c]
[c]
[c]
20
20
20
0.20
0.10
0.05
Et3B/O2
Et3B/O2
Et3B/O2
[a] Initiator: 0.1 equiv of Et3B or 0.3 equiv of AIBN were used. [b] Yields of
isolated products. [c] Air was used as O2 source.
was obtained as a side product, was readily separated.
Hydroamination at room temperature with Et3B/O2 as the
initiator (0.1 equiv) afforded 7 in 60% yield (Table 1,
entry 3), and similar results were obtained in the absence of
Et3B with only air as the initiator (Table 1, entry 2). Hydro-
amination in benzene was also conducted at 08C without
affecting the yield to a large extent (Table 1, entry 4). With
toluene or CH2Cl2 as solvents slightly lower yields were
obtained (Table 1, entries 5 and 6). Dichloroethane was
tolerated as the solvent at both room temperature (Table 1,
entry 7) and at ꢀ308C (Table 1, entry 8). Hydroamination still
occurred even at ꢀ808C in CH2Cl2 (Table 1, entry 9). A lower
yield was obtained in the absence of thiol catalyst, supporting
our assumption that the reduction of a C radical with 3 is a
rather inefficient process (Table 1, entry 10). Increasing the
amount of thiol to 0.2 equiv did not provide better results
(compare Table 1, entries 3 and 11), and with 0.1 equiv of
PhSH the reaction was still efficient (Table 1, entry 12).
However, lowering the catalyst loading to 0.05 equiv led to a
slightly diminished yield (Table 1, entry 13). Therefore, all the
following experiments were conducted with 0.10–0.15 equiv
of PhSH.
Importantly, as hydroaminations can be conducted at low
temperatures with reagent 3, stereoselective intermolecular
radical hydroaminations could be studied, which to the best of
our knowledge have not been reported to date. We selected
enecarbamates derived from Evans oxazolidinones[11] as
chiral acceptors (Scheme 3). Chiral enecarbamates have
Scheme 3. Stereoselective radical transfer hydroaminations. R1and R2
are specified in Table 2; only the major isomer of the product is
shown.
To document the scope of our method, various olefins
were reacted with 3 (Figure 1). These hydroaminations were
conducted in benzene either at room temperature with Et3B/
O2 (method A) or at 808C with AIBN as initiators (meth-
od B) for 10 to 12 h. Reaction with 1-octene delivered 8 in
44% yield as well as the regioisomeric Markovnikov product
(not shown) in 6% yield. For all other substrates tested,
been used successfully in stereoselective cycloadditions;[12,13]
however, stereoselective radical reactions using chiral ene-
carbamates were unprecedented.[14,15] The chiral E-enecarba-
mates 20a–h, 21a,b, and 22 were readily prepared by
condensation of an Evans oxazolidinone with the correspond-
ing aldehyde.[16]
780
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Angewandte
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Hydroaminations were conducted in benzene at room
temperature to give the corresponding protected vicinal
diamines 23a–h, 24a,b, and 25. Good selectivities were
obtained for the hydroamination of 20a and 20b (Table 2,
Table 2: Hydroamination of chiral enecarbamates.
Entry
Olefin
R1
R2
Yield [%]
(product)
d.r.
13:1[a]
13:1[a]
13:1[a]
20:1[a]
13:1[b]
13:1[b]
13:1[b]
13:1[b]
11:1[b]
11:1[b]
14:1[a]
Figure 3. Conformers A and B of ent-20i and model to explain the
stereoselectivity. The energy difference mainly results from dipole
1
2
3
4
5
6
7
8
9
20a
20b
20c
20d
20e
20 f
20g
20h
iPr
iPr
iPr
iPr
iPr
iPr
iPr
iPr
Ph
Ph
tBu
Et
Bu
iPr
tBu
47 (23a)
48 (23b)
33 (23c)
30 (23d)
40 (23e)
44 (23 f)
41 (23g)
48 (23h)
48 (ent-24a)
34 (ent-24b)
48 (25)
=
=
interactions of the C O and C C bonds.
PMB[c]
(CH2)3Ph
(CH2)3CO2Et
(CH2)2OAc
Et
energy difference between the two conformers
A
(+1.89 kcalmolꢀ1) and B was calculated for compound 20i
(R1 = iPr, R2 = Me) by using density functional theory (DFT,
B97-D/TZVP).[13]
ent-21a
ent-21b
22
10
11
iPr
Et
In conclusion, we introduced the N-aminated dihydropyr-
idine 3 as a novel precursor for the generation of carbamoyl
radicals. Compound 3 was prepared in two steps using readily
available starting materials. Radical anti-Markovnikov hydro-
aminations on various olefins were performed. Moreover,
protected vicinal diamines were prepared with good selectiv-
ities by hydroamination of chiral enecarbamates.
[a] Diastereomeric ratio (d.r.) determined by gas chromatography. [b] d.r.
determined by H NMR spectroscopy. [c] PMB = para-methoxybenzyl.
1
entries 1 and 2). Increasing the size of the R2 substituent from
a primary alkyl group to an isopropyl group led to a decrease
of the yield without affecting the selectivity (Table 2, entry 3).
However, the stereoselectivity significantly increased for the
tert-butyl-substituted carbamate 20d (entry 4). Functional
groups in the side chain did not affect the selectivity (Table 2,
entries 5–8). As expected, the size of the stereodirecting R1
substituent influenced the selectivity. Slightly worse results
were obtained for the Ph-substituted enecarbamates ent-
21a,b (Table 2, compare entries 1 and 3 with 9 and 10),
whereas the tBu derivative 22 provided a higher selectivity
(Table 2, entry 11).
Received: August 24, 2007
Published online: December 10, 2007
Keywords: asymmetric synthesis · chiral auxiliaries ·
.
organocatalysis · radical chemistry · vicinal diamines
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Angew. Chem. Int. Ed. 2008, 47, 779 –782
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