Reductive alkylation of imines via asymmetric Cu-catalyzed addition of organozirconium reagents

Article abstract of DOI:10.1016/j.jorganchem.2019.121099

Chiral amines are important as medicines or agrochemicals. They are often assembled by nucleophilic addition to corresponding compounds featuring C[dbnd]N bond. Pre-made organometallics are typical nucleophiles in this reaction. In this work, we describe

Full text of DOI:10.1016/j.jorganchem.2019.121099

Journal Pre-proof
Reductive alkylation of imines via asymmetric Cu-catalyzed addition of
organozirconium reagents
Ivana Némethová, Denisa Vargová, Brigita Mudráková, Juraj Filo, Radovan Šebesta
PII:
S0022-328X(19)30542-X
DOI:
https://doi.org/10.1016/j.jorganchem.2019.121099
JOM 121099
Reference:
To appear in: Journal of Organometallic Chemistry
Received Date: 16 December 2019
Accepted Date: 26 December 2019
Please cite this article as: I. Némethová, D. Vargová, B. Mudráková, J. Filo, R. Šebesta, Reductive
alkylation of imines via asymmetric Cu-catalyzed addition of organozirconium reagents, Journal of
Organometallic Chemistry (2020), doi: https://doi.org/10.1016/j.jorganchem.2019.121099.
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Reductive Alkylation of Imines via Asymmetric Cu-Catalyzed Addition
of Organozirconium Reagents
Ivana Némethová a1 Denisa Vargová a1 Brigita Mudráková,a Juraj Filo,b and Radovan
, ,
a
Šebesta
*
a Department of Organic Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava,
Mlynská dolina, Ilkovičova 6, SK-84215, Bratislava, Slovakia.
b Institute of Chemistry, Faculty of Natural Sciences, Comenius University in Bratislava, Mlynská
dolina, Ilkovičova 6, SK-84215, Bratislava, Slovakia.
Corresponding author tel. +421 2 60296208, e-mail: radovan.sebesta@uniba.sk
1 These authors contributed equally to the work presented and the preparation of the manuscript.
Abstract
Chiral amines are important as medicines or agrochemicals. They are often assembled by
nucleophilic addition to corresponding compounds featuring C=N bond. Pre-made organometallics
are typical nucleophiles in this reaction. In this work, we describe asymmetric reductive alkylation of
imines with alkenes. Hydrozirconation of these alkenes generated organozirconium species in situ.
The transformation is catalyzed by Cu-Segphos complex and affords chiral amines in
enantioselectivities up to 93% ee.
Keywords
Imine; reductive alkylation; alkene; organozirconium reagent; Cu-catalysis
1. Introduction
Chiral amines are vital as pharmaceuticals, including levocetirizine[1], repaglinide[2], (-)-N-
acetylcolchinol[3], ontazolast[4], crop-protection agents such as difulmetorim[5], or building blocks
(Figure 1).

Figure 1. Industrially important bioactive chiral amines.
Common strategies for obtaining chiral amines are stereoselective nucleophilic additions to
compounds featuring C=N double bond[6, 7]. The addition of carbon-based nucleophiles to imines
can afford a great structural variety in possible products. A large number of stabilized, as well as non-
stabilized organometallic nucleophiles, were added to imines as was comprehensively reviewed by
Kobayashi[8]. Although, typical metals for catalyzing additions to imines are copper[9] or zinc, other
metals such as Pd, Ni, or Co may work as well[10].
From among more recent advances, Harutyunyan developed Grignard additions to ketimines[11-13].
Organoboron compounds have traditionally been used for aryl, alkenyl, allyl or propargyl transfer[14-
16], however, recent addition of bisborylalkanes to imines was also established [17]. However, these
methods are somewhat limited to simpler alkyl, or aryl or highly reactive sidechains, such as allyl, or
propargyl. From this point of view, the use of in situ generated organozirconium compounds seemed
very beneficial as many alkenes could be used as a source of pro-nucleophile (Scheme 1). The
utilization of alkenes or alkynes as pro-nucleophiles for imine additions has been only sparsely
documented. Trost developed enantioselective vinylation of N Boc imines with alkenylzirconium
reagents using ProPhenol-type ligands[18]. Buchwald reported enantioselective hydrocupration for
intramolecular synthesis of indoles[19], and intermolecular coupling of styrene to imines[20],
obtaining branched products.
Organozirconium compounds are mild organometallic reagents, which have higher functional group
tolerance than more reactive organometallic nucleophiles and do not require cryogenic conditions.
An additional advantage of organozirconium reagents is that they can be obtained via
hydrozirconation of corresponding alkenes or alkynes, thus sidestepping handling of pre-made
organometallic reagents. In situ generated organozirconium reagents are useful nucleophiles in
asymmetric conjugate additions and allylic substitutions[21]. To the best of our knowledge, there are
no reports on reductive alkylation of imines using in situ generated organozirconium reagents
(Scheme 1).

In this context, we decided to study the utilization of alkyl zirconium reagents in enantioselective
addition to imines under copper catalysis.
Scheme 1.
Results and Discussion
To optimize reaction conditions, we have selected an aldimine derived from 4-chlorobezaldehyde
having Ts-protecting group 4a as a starting substrate. 1-Allyl-4-methylbenzene (2a) was used as pro-
nucleophile (Scheme 2). In a typical reaction setup, the corresponding organozirconium reagent
prepared in a separate flask by mixing Schwartz reagent and the corresponding alkene, was added
into a mixture of Cu/ligand complex. Into this mixture an imine was added. Firstly, we have verified
how fast is an uncatalyzed background reaction. This experiment showed that the reaction of imine
4a and organozirconium 3a did not run in the absence of a copper catalyst. The expected product 5a
was not observed even after 24 h at room temperature, but the decomposition of starting imine 4a
has been observed by NMR. Consequently, we used monodentate phosphoramidites, as these
ligands were effective in other Cu-catalyzed reactions of organozirconium reagents, such as
conjugate additions[22, 23], and allylic substitutions[24, 25]. We employed CuCl as copper source
and as the starting imine 4a was fluffy solid, we added it to the reaction either straight as a solid or as
a solution in DCM (Table 1, Entries 1,2). The reaction catalyzed by Cu/phosphoramidite (S,R,R)-L1
indeed worked. We obtained the desired product (S)-5a in 34% yield with enantiomeric excess of
17% ee if 4a was added as a solid in one portion. The yield of amine 5a dropped to 17% (19% ee)
when the aldimine 4a was added as a DCM solution. This drop of yield could be explained by higher
dilution of the reaction mixture. If ligand (R)-L2 was used, we observed a dramatic increase in
enantioselectivity favoring the formation of (R)-enantiomer in 42% ee (entry 3). The reaction,
however, did not provide the full conversion of the starting material. The desired amine (R)-5a was
isolated in only 33% yield. Changing the order of addition, and slow addition of the alkyl zirconium
reagent both decreased the yield and enantioselectivity (entries 6 and 7). Somewhat unexpected
reaction outcome was obtained with diphosphane ligand L3, which afforded amine (S)-5a in 39%
yield and enantiomer purity of 43% ee. The class of Schmalz ligands was broadly employed in metal-
catalyzed reactions, such as vinylation, allylic alkylations, cycloadditions or hydrocyanations[26-30].
We have tested several ligands from this family having either bulky achiral part or chiral binaphthol

back-bone. Unfortunately, none of the tested ligands gave better results, than L3. Surprisingly, if
weakly coordinating L4 was used we obtained good results in terms of yield (46%) and
enantioselectivity (54% ee, (S)-5a). Interestingly, diphosphane (R)-DTBM-Segphos L6 gave promising
enantiomeric excess 73% ee of (R)-5a (entry 11). Using Hoveyda’s NHC ligand L7 (entry 12), a full
consumption of the starting material was observed, but unfortunately the enantiomeric purity of
amine 5a decreased to 24% ee affording again the (R)-enantiomer. (S)-Tol-BINAP L8 gave the product
(S)-5a in 22% yield, but only 12% ee (entry 12). Josiphos ligand L9 as well as Schmaltz type ligand with
a chiral binaphthol unit L10 were ineffective in this reaction as they gave only 7% and 3% yield,
respectively (entries 13 and 14).
Scheme 2. Screening of chiral ligands in the addition of 3a to imine 4a.

Table 1. Initial results of the addition of organozirconium 3a to imine 4a.
Entrya) Ligand
Solvent Yield 5ac) ee 5a (%)
1
(S,R,R)-L1 Et2O b) 34
17 (S)
2
(S,R,R)-L1 Et2O c)
(R,R,R)-L1 Et2O
17
45
19 (S)
19 (S)
45 (R)
47(R)
11 (R)
50 (R)
43 (S)
54 (S)
50 (R)
73 (R)
24 (R)
12 (S)
2 (S)
3
4
(R)-L2
(R)-L2
(R)-L2
(R)-L2
L3
Et2O b,d) 55
5
THF b)
THF e)
THF f)
THF b)
THF b)
THF b)
THF b)
THF b)
THF b)
THF b)
THF b)
67
31
19
39
46
14
12
65h)
22
7
6
7
8
9
L4
10
11
12
13
14
15
L5
(R)-L6
L7g)
(S)-L8
L9
L10
3
20 (S)
a) Chiral ligand (11 mol%, 0.022 mmol) and CuCl (10 mol%, 0.02 mmol) were stirred for 40 min in THF (0.8 mL).
Schwartz reagent 1 (2.0 equiv., 0.4 mmol, 103 mg) was suspended in DCM (0.4 mL), followed by the addition of
alkene 2a (2.5 equiv., 0.5 mmol), stirred until yellow transparent. Combined reaction mixture was stirred for
24h. b) Imine 4a was added as powder last; c) Imine added as a solution last; d) 0.4 mmol; e) reagent 3a added
last; f) reagent 3a added last over 85 min; g) BuLi was used to generate carbene in situ; h) Full conversion on
TLC.
Next, we screened various copper sources (Table 2). Interestingly, CuI did not give any product (entry
2). Even more surprising was the result that even copper(II)-salts were able to catalyze the addition.
The reaction with CuCl2.2H2O and DTBM-Segphos ligand L6 afforded the corresponding product (R)-
5a in 29 % yield and with 90% ee (entry 4). The use of anhydrous CuCl2 gave worse results (Entry 5).
Cu(OAc)2 and [Cu(MeCN)4]BF4 performed poorly (Entries 6,7). Finally, the most efficient copper
source for this reaction was [Cu(MeCN)4]PF6, which afforded amine 5a in 45 % with high
enantiomeric purity (87% ee). We were hoping to increase the yield of this promising result by using
the preformed complex of Segphos-type ligands with [Cu(MeCN)4]PF6. Using complex (R)-DTBM-
Segphos.Cu(MeCN)PF6.PhMe, we observed a small improvement in the enantioselectivity – 93% ee,
but the yield dropped to less than 20%. Using (R)-Segphos.Cu(MeCN)PF6.2PhMe we did not obtain
any product.
Table 2. Screening of copper sources in the alkylation of imine 4 with organozirconium 3.

Entry
Cu source
Yield of 5a (%)
ee 5a (%)
1
2
CuCl
12
0
73
-
CuI
CuBr.SMe2
3
29
29
15
0
n.d.
90
50
n.d.
n.d.
87
93
-
4
CuCl2.2H2O
5
CuCl2
6
Cu(OAc)2
7
[Cu(MeCN)4]BF4
3
8
[Cu(MeCN)4]PF6
45
<20
0
9
(R)-DTBM-Segphos.Cu(MeCN)PF6.PhMe
(R)-Segphos.Cu(MeCN)PF6.2PhMe
10
A brief additive screening was performed. Lewis acids TMSOTf and BF3.OEt2 as well as highly polar
additives DMPU and DMEU we tested (see supplementary information for more details, Table S1,
S2), but with no significant improvement of the yield, or enantioselectivity.
We have briefly evaluated the scope of the reaction using either (R)-L2 or (R)-L6 (Scheme 3). p-
Chloro-substituted amine (R)-5b was obtained only in 27% yield with enantiopurity of 33 % ee.
Aliphatic (R)-5c was obtained in 42% yield and 45 % ee. For the non-chlorinated product (R)-5d 21%
yield and 43% ee was obtained. Different protecting groups were tried as well. Using TMS, nosyl, -
SO2NMe2 or 5-methylpyrid-2-yl no products were obtained. Thiophenesulphonyl group provided the
product (R)-5e in 42% yield and 32% ee. Amine 5f with CF3 group was obtained in 21% yield and 26%
enantiomer purity.

Scheme 3. Product scope of the asymmetric 1,2-addition of alkylzirconium reagents to aldimines.
The absolute configuration of the stereogenic center was assigned as (R) by comparison of
the optical rotation of a similar compound from the literature[31]. For (S)-N-(1,3-diphenylpropyl)-4-
methylbenzenesulfonamide was measured [α]23 –37.8 (c 0.1, DCM) (sample with 99% ee). Our
589
sample of (R)-5d had [α]20589 + 16.3 (c 0.35, CHCl3) for 43% ee.
To understand the reaction mechanism in greater detail, we have monitored the course of
1
the reaction using H NMR (Figure 2a). In the reaction mixture, we observed a by-product 1-methyl-
4-propylbenzene (6) formed from the reduction of the alkene, which could explain the lower yields of
amine products. However, the product formation continued nevertheless, over 24 h. For this
experiment we used the conditions with ligand (R)-L2, in order to see more of the product in spectra.
The reaction in the NMR tube proceeded until 35% conversion of imine 4a to product 5a. Lower
conversion can be attributed to the absence of stirring in the NMR tube. Reaction profile depicted on
the Figure 2a shows that the reaction proceeds throughout the whole time, albeit with a low rate.
The slow reaction is likely caused by inherently lower nucleophilicity of the zirconium reagent 3a in
comparison to more reactive organometallics. In order to avoid undesired reduction of the starting
alkene, we purged the mixture with argon during hydrozirconation, to get rid of any possible
hydrogen formation that might have formed from the Schwartz reagent reacting with some residual
moisture. Even after doing so, we still observed the reduced product 6 in the reaction mixture, albeit
in somewhat lower concentration. This observation has led us to think that the reduced product 6
might be initially formed by other secondary reduction. Analysis of the NMR mixture confirmed that
the reduced product is initially formed at around 50% conversion and is increasing only slightly in
concentration over the 24h (Figure 2b). The initial concentration of 4-allyltoluene (2a) starts around

50%, since the hydrozirconation was stirred for 30 min prior to the addition to the NMR tube, by
which time the reduced product formed.
Figure 2. Reaction progress followed by 1H NMR. Spectra were recorded every 15 minutes over 24 h.
a) Relative concentration of the product was determined through integration of the Zr-salt of 5a
compared and starting imine 4b; b) Relative concentration of 1-methyl-4-propylbenzene 6 and allyl
toluene 2 determined through integration of the signals of the terminal protons on the double bond,
and -CH2- of 1-methyl-4-propylbenzene (6). The formation of product 5a from 4a was taken into
consideration.
Buchwald published a study[32] where complexes of imines and zirconium species were trapped by
alkenes via intermediary zirconaaziridine species. Therefore, we decided to investigate the possibility
of a similar mechanism in our case, however, presence of such species could not be ascertained in
the reaction mixture by NMR. Therefore, we presume a mechanism analogous to 1,4-additions might
be operational also for 1,2-addition to imines (Scheme 4)[33]. Organozirconium compounds often
form dimer and this possibility need to be consider, but we could not confirm whether there were
only one or two molecules of alkyl zirconium species involved. We presume that there would be
a large steric hindrance for two molecules of alkylzirconium reagent in the transition state. After the
transmetallation step, coordination to the imine should follow. Reductive elimination of the Cu(III)-
intermediate Int-2 leads to Zr- salt Int-3. After aqueous work-up the product is obtained.

Scheme 4: Tentative mechanisms of 1,2-addition of zirconium species to imines.
31P NMR spectra of copper complexes of (R)-L6 and zirconium reagents were measured (Figure 3,
spectrum 4). Comparison with spectra of pre-formed complex (Figure 3, spectrum 3), new species
were formed. If the alkylzirconium reagent was combined with [Cu(MeCN)4]PF6 no significant shift in
-
the PF6 signal was observed (Figure 3, spectrum 2). Finally, to rule out the possibility of
a monoligated copper, we measured (R)-L6 with 0.5 equiv of [Cu(MeCN)4]PF6 (Figure 3, spectrum 1).
In this case a large amount of free ligand was observed, a small amount of the complex, but no
monocoordinated ligand. These data suggest that the transmetallation from zirconium to copper is
efficient and is demonstrated by the new species observed in the spectrum 4. There is a possibility to
form dimers, or other high-order oligomers, which would explain why there are multiple new signals.

Figure 3. 31P spectra of Cu-Segphos complexes.
Conclusion
In this work, we studied the asymmetric Cu-catalyzed addition of organozirconium species to
aldimines. This so far unprecedented methodology would provide new possibilities for synthesis of
chiral secondary alcohols. The best results were achieved by using catalytic system composed of
[Cu(MeCN)4]PF6 and (R)-L6. Corresponding chiral products were obtained in enantiomeric purities up
1
to 93% however in low yield. The course of reaction was studied via H NMR with the emphasis to
the reaction mechanism.
Experimental Section
General procedure for asymmetric addition of organozirconium species
Chiral ligand (11 mol%, 0.022 mmol) and CuX (10 mol%, 0.02 mmol) were weighed into heat-dried
Schlenk flask flushed with Ar. Anhydrous THF (0.8 mL) was added and the mixture was stirred for 40
min under Ar atmosphere at RT. In the meantime, Schwartz reagent 1 (2.0 equiv., 0.4 mmol, 103 mg)
was weighed into heat-dried flask flushed with Ar. Anhydrous DCM (0.4 mL) was added to the
reaction mixture, followed by the addition of starting alkene (2.5 equiv., 0.5 mmol). The resulting
slurry was stirred until it became yellow and transparent (approx. 20 min). The solution of Cp2Zr(R)Cl
was transferred to the solution of Cu-catalyst. The combined reaction mixture was stirred for 10 min

at room temperature before aldimine was added in one portion. The combined reaction mixture was
then stirred for 24h at RT. The reaction was quenched using aqueous NH4Cl (1M, 1 mL), extracted by
DCM (3x10 mL) and washed with aq. NaHCO3 (5%, 10 mL). Combined organic extracts were dried
over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified on
SiO2 (hexane/EtOAc).
Characterization data
(R)-N-(1-(4-chlorophenyl)-4-(p-tolyl)butyl)-4-methylbenzenesulfonamide (5a)
White solid, yield: 67% (50 mg), m.p. 121 – 125 °C, on SiO2 (hexane/EtOAc gradient 8:1 to 3:1).
IR: 3236 (N-H), 2918 (C-H), 1314 (S=O), 1158 (S=O) cm-1. 1H NMR (600 MHz, CDCl3): δ= 7.48 (d, J = 8.3
Hz, 2H), 7.11 – 7.06 (m, 4H), 7.04 (d, J = 7.8 Hz, 2H), 6.93 (d, J = 7.9 Hz, 2H), 6.90 (d, J = 8.4 Hz, 2H),
4.95 (br.s, 1H, NH), 4.26 (q, J = 7.2 Hz, 1H), 2.47 (t, J = 7.6 Hz, 2H), 2.36 (s, 3H), 2.30 (s, 3H), 1.74
(dddd, J = 12.5, 10.3, 7.2, 5.2 Hz, 1H), 1.67 – 1.61 (m, 1H), 1.57 – 1.50 (m, 1H), 1.43 – 1.36 (m, 1H)
ppm. 13C NMR (151 MHz, CDCl3): δ = 143.2, 139.3, 138.3, 137.5, 135.3, 133.1, 129.2, 129.0, 128.5,
128.2, 127.9, 127.0, 57.5, 36.8, 34.7, 27.5, 21.4, 20.9 ppm. HRMS (HESI): m/z [M+H]+ calcd for
C24H26ClNO2S: 428.1450, found: 428.1455. HPLC: Chiralpak IB, hexane/i-PrOH = 90:10, 1 mL/min, 222
nm, tR(major) = 12.28 min, tR(minor) = 20.84 min. [α]20589 + 3.4 (c 1.0, CHCl3) for 45% ee.
(R)-N-(1-(4-chlorophenyl)-5-phenylpentyl)-4-methylbenzenesulfonamide (5b)
White solid, yield: 27% (21 mg), m.p. 95 – 99 °C, purified on SiO2 (hexane/EtOAc gradient 8:1 to 3:1).
1
IR: 3268 (N-H), 2928 (C-H), 2857 (CH2), 1320 (S=O), 1155 (S=O) cm-1. H NMR (600 MHz, CDCl3): δ =
7.50 (d, J = 8.2 Hz), 7.24 (d, J = 7.6 Hz), 7.19 – 7.06 (m, 4H), 6.92 (d, J = 8.4 Hz), 5.01 (d, J = 7.1 Hz, 1H,
NH), 4.22 (q, J = 7.3 Hz), 2.51 – 2.45 (m, 2H), 2.37 (s, 3H), 1.78 – 1.71 (m, 1H), 1.68 – 1.60 (m, 1H),
1.52 (p, J = 7.7 Hz, 2H), 1.31 – 1.22 (m, 1H), 1.18 – 1.09 (m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ =
143.2, 142.1, 139.4, 137.5, 133.1, 129.3, 128.5, 128.3, 127.9, 127.0, 125.7, 57.6, 37.3, 35.5, 30.8,
25.3, 21.4 ppm.
HRMS (HESI): m/z [M]- calcd for C24H26ClNO2S: 426.1300, found: 426.1292. HPLC: Chiralpak IB,
hexane/i-PrOH = 93:7, 1 mL/min, 222 nm, tR(major) = 15.30 min, tR(minor) = 19.90 min. [α]20
589
+163.0 (c 0.4, CHCl3) for 33% ee.
(R)-N-(1-(4-chlorophenyl)heptyl)-4-methylbenzenesulfonamide (5c)
White solid, yield: 42% (32 mg), m.p. 87 – 92 °C, on SiO2 (hexane/EtOAc gradient 8:1 to 3:1).
1
IR: 3254 (N-H), 2929 (C-H), 2863 (CH2), 1314 (S=O), 1164 (S=O) cm-1. H NMR (600 MHz, CDCl3): δ =
7.50 (d, J = 8.3 Hz, 2H), 7.14 – 7.09 (m, 4H), 6.96 – 6.93 (m, 2H), 4.82 (d, J = 7.0 Hz, 1H, NH), 4.24 (q, J
= 7.2 Hz, 1H), 2.37 (s, 3H), 1.70 (ddd, J = 12.4, 8.8, 5.3 Hz, 1H), 1.65 – 1.57 (m, 1H), 1.24 – 1.10 (m,
7H), 1.10 – 1.01 (m, 1H), 0.83 (t, J = 7.2 Hz, 3H) ppm. 13C NMR (151 MHz, CDCl3): δ = 143.2, 139.5,
137.5, 133.0, 129.3, 128.4, 127.9, 127.0, 57.6, 37.5, 31.5, 28.7, 25.7, 22.5, 21.4, 14.0 ppm. HRMS
(HESI): m/z [M]- calcd for C20H26ClNO2S: 378.1300, found: 378.1291. HPLC: Chiralpak IB, hexane/i-
PrOH = 93:7, 1 mL/min, 222 nm, tR(major) = 9.63 min, tR(minor) = 14.63 min. [α]20589 +16.8 (c 1.0,
CHCl3) for 45% ee.

(R)-N-(1,5-diphenylpentyl)-4-methylbenzenesulfonamide (5d)
Deliquescent white solid, yield: 21% (17 mg), purified on SiO2 (hexane/EtOAc gradient 8:1 to 3:1).
1
IR: 3272 (N-H), 2926 (C-H), 2856 (CH2), 1320 (S=O), 1154 (S=O) cm-1. H NMR (600 MHz, CDCl3): δ =
7.55 – 7.51 (m, 2H), 7.26 – 7.23 (m, 2H), 7.19 – 7-14 (m, 4H), 7.12 – 7.07 (m, 4H), 7.01 – 6.97 (m, 2H),
4.85 (d, J = 7.3 Hz, 1H, NH), 4.25 (q, J = 7.3 Hz, 1H), 2.51 – 2.47 (m, 2H), 2.35 (s, 3H), 1.79 (dddd, J =
12.8, 10.2, 7.1, 5.5 Hz, 1H), 1.74 – 1.66 (m, 1H), 1.55 – 1.49 (m, 2H), 1.33 – 1.26 (m, 1H), 1.20 – 1.11
(m, 1H) ppm. 13C NMR (151 MHz, CDCl3): δ = 142.9, 142.2, 140.9, 137.6, 129.3, 128.4, 128.3, 128.2,
127.3, 127.0, 126.4, 125.7, 58.2, 37.4, 35.6, 30.9, 25.5, 21.4 ppm. HRMS (HESI): m/z [M]- calcd for
C24H27NO2S: 392.1690, found: 392.1679. HPLC: Chiralpak IB, hexane/i-PrOH = 93:7, 1 mL/min, 222
nm, tR(major) = 11.25 min, tR(minor) = 18.47 min. [α]20589 +16.3 (c 0.35, CHCl3) for 43% ee.
(R)-N-(1-(4-chlorophenyl)-4-(p-tolyl)butyl)thiophene-2-sulfonamide (5e)
White solid, 42% yield, 32% ee, m.p. 84.2 – 85.5 °C, purified on SiO2 (hexane/EtOAc gradient 8:1 to
3:1). 1H NMR (600 MHz, CDCl3): δ= 7.45 (dd, J = 5.1, 1.3 Hz, 1H), 7.31 (dd, J = 3.7, 1.3 Hz, 1H), 7.17 –
7.13 (m, 2H), 7.06 (d, J = 7.7 Hz, 2H), 6.96 (t, J = 8.8 Hz, 4H), 6.89 (dd, J = 5.0, 3.8 Hz, 1H), 4.89 (d, J =
7.3 Hz, 1H), 4.35 (q, J = 7.3 Hz, 1H), 2.51 (t, J = 7.5 Hz, 2H), 2.30 (s, 3H), 1.82 – 1.73 (m, 1H), 1.72 –
1.65 (m, 1H), 1.61 – 1.56 (m, 1H), 1.48 – 1.40 (m, 1H). 13C NMR (151 MHz, CDCl3): δ= 141.6, 139.1,
138.3, 135.4, 133.3, 132.3, 131.8, 129.1, 128.7, 128.2, 127.8, 127.1, 57.9, 36.8, 34.7, 27.5, 20.9.
HRMS (HESI): m/z [M+H]+ calcd for C21H22ClNO2S2Na: 444.0643, found: 444.0648. HPLC: Chiralpak IB,
hexane/i-PrOH = 93:7, 1 mL/min, 222 nm, tR(major) = 16.8 min, tR(minor) = 21.3 min. [α]20589 +21.9 (c
0.2, CHCl3) for 32% ee.
(R)-N-(1-(4-trifluoromethyl)henyl)-4-(p-tolyl)butyl)-4-methylbenzenesulfonamide (5f)
White solid, yield: 21% (20 mg), m.p. 142.8-145.1°C, purified on SiO2 (hexane/EtOAc gradient 7:1 to
4:1). IR: 3259 (N-H), 2923 (C-H), 1319 (S=O), 1153 (S=O) cm-1. 1H NMR (600 MHz, CDCl3) δ 7.42 (d, J =
8.2 Hz, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.05 (dd, J = 14.5, 7.6 Hz, 6H), 6.94 (d, J = 7.8 Hz, 2H), 4.72 (d, J =
7.0 Hz, 1H, NH), 4.37 (q, J = 7.1 Hz, 1H), 2.50 (t, J = 7.4 Hz, 2H), 2.32 (s, 3H), 2.30 (s, 3H), 1.76 (ddd, J =
12.8, 10.5, 6.1 Hz, 1H), 1.66 (ddd, J = 19.3, 11.7, 5.9 Hz, 1H), 1.62 – 1.55 (m, 1H), 1.50 – 1.39 (m, 1H)
ppm. 13C NMR (151 MHz, CDCl3): δ = 144.7, 143.3, 138.2, 127.3, 135.4, 129.2, 129.0, 128.2, 126.9,
126.9, 125.3, 125.2, 125.2, 125.2, 125.0, 57.7, 36.7, 34.6, 27.4, 21.3, 21.0 ppm. 19F NMR (564 MHz,
CDCl3) δ -62.7 (s) ppm. HRMS (HESI): m/z [M+H]+ calcd for C25H27F3NO2S: 462.1715, found: 462.1712.
HPLC: Chiralpak IB, hexane/i-PrOH = 90:10, 1 mL/min, 222 nm, tR(major) = 10.22 min, tR(minor) =
13.44 min. [α]20589 + 1.2 (c 0.25, CHCl3) for 26% ee.
Procedure for NMR experiments
For all NMR experiments an amberized, valved NMR tube was used (Norell S-5-600-VT-7). Before
setting up an experiment, the tube was connected to a Schlenk line, evacuated and backfilled with Ar
3 times. After addition of solid material, the procedure was repeated. The addition of solvent was
performed under constant Ar flow from the Schlenk line.
31P measurements:

[Cu(MeCN)4]PF6 (2.5 mg, 0.007 mmol) and (R)-DTBM-Segphos L6 (11.0 mg, 0.009 mmol) were added
to a heat dried flask, and stirred in anhydrous CD2Cl2 (0.4 mL) for 30 min. Simultaneously, 4-
allyltoluene (26 µL, 0.170 mmol) and Schwartz reagent 1 (35 mg, 0.136 mmol) were stirred in
anhydrous CD2Cl2 (0.4 mL). The solutions were combined in the NMR tube, and 31P was measured
immediately.
[Cu(MeCN)4]PF6 (20 mg, 0.050 mmol), 1-allyl-4-methylbenzene (10 µL, 0.067 mmol) and Schwartz
reagent 1 (13 mg, 0.050 mmol) were combined directly in the NMR tube, dissolved in CD2Cl2 (0.6 mL)
and measured in 20 minutes.
[Cu(MeCN)4]PF6 (0.5 equiv) and (R)-DTBM-Segphos L6 (1.0 equiv)
[Cu(MeCN)4]PF6 (3.0 mg, 0.008 mmol) and (R)-DTBM-Segphos L6 (20 mg, 0.016 mmol) were
combined directly in the NMR tube, dissolved in CD2Cl2 (0.6 mL) and measured in 20 min.
Kinetic measurement:
(S,R,R)-L1 (7.0 mg, 0.013 mmol, 11 mol%) and CuCl (1.2 mg, 0.012 mmol, 10 mol%) were weighed
into heat-dried Schlenk flask flushed with Ar. THF-d8 from a sealed vial (0.6 mL) was added and the
mixture was stirred for 40 min under Ar atmosphere at RT. In the meantime, Schwartz reagent 1 (2.0
equiv., 69 mg, 0.27 mmol) was weighed into heat-dried flask flushed with Ar. Anhydrous CD2Cl2 (0.3
mL) was added to the reaction mixture, followed by the addition of 1-allyl-4-methylbenzene (2a, 2.5
equiv., 50 µL, 0.34 mmol). The resulting slurry was stirred until it became yellow and transparent
(approx. 20 min). The solution of Cu-catalyst solution was transferred to the NMR tube, followed by
1
the solution of Cp2Zr(R)Cl and aldimine (1.0 equiv., 40 mg, 0.135 mmol). H NMR spectra were
recorded every 15 min over 24 h.
Acknowledgements
This work was supported by the Slovak Research and Development Agency under the Contract no.
APVV-18-0242.
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Reductive Alkylation of Imines via Asymmetric Cu-Catalyzed Addition
of Organozirconium Reagents
I. Némethová, D. Vargová, B. Mudráková, J. Filo, R. Šebesta
Highlights:
•
•
Imines can be reductively alkylated with alkenes
The reaction proceed via in situ generated organozirconium reagents obtained by
hydrozirconation of alkenes
•
•
•
The transformation is catalyzed by Cu-Segphos or phosphoramidite complexes
Kinetic 1H NMR experiments revealed reaction profile
Catalytically active complexes were studied by 31P NMR

Declaration of interests
☒ The authors declare that they have no known competing financial interests or personal relationships
that could have appeared to influence the work reported in this paper.
☐The authors declare the following financial interests/personal relationships which may be considered
as potential competing interests: