High-yielding large-scale syntheses of enantiomerically pure NOBIN and a NOBIN-based enantiomerically pure NHC precursor

Article abstract of DOI:10.1055/s-0028-1087390

The MOM-protected monotriflate derived from enantiomerically pure (S)-BINOL rendered (S)-NOBIN (67% over 5 steps) and an (S)-configured NHC precursor (55% over 5 steps) on 10 gram and 5 gram scales, respectively. The C-N bond formation was realized by OTf → NHBn and OTf → NH-CH₂-CH ₂-NH-mesityl exchanges, respectively. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1087390

LETTER
109
High-Yielding Large-Scale Syntheses of Enantiomerically Pure NOBIN and a
NOBIN-Based Enantiomerically Pure NHC Precursor
S
D
ynthesisof Enant
a
iomerically
n
P
ure
N
O
BI Ni el Sälinger, Reinhard Brückner*
Institut für Organische Chemie und Biochemie, Albert-Ludwigs-Universität Freiburg, Albertstr. 21, 79104 Freiburg, Germany
Fax +49(761)2036100; E-mail: reinhard.brueckner@organik.chemie.uni-freiburg.de
Received 2 October 2008
ylmagnesium bromide and (–)-menthyl 1-(–)-menthyl-
Abstract: The MOM-protected monotriflate derived from enantio-
oxy-2-naphthoate and a difficult separation of the result-
merically pure (S)-BINOL rendered (S)-NOBIN (67% over 5 steps)
and an (S)-configured NHC precursor (55% over 5 steps) on 10
ing atropisomers. Obviating such purification problems
16
gram and 5 gram scales, respectively. The C–N bond formation was the Singer–Buchwald synthesis of 1 starts from relative-
17
realized by OTf → NHBn and OTf → NH–CH –CH –NH–mesityl ly inexpensive (S)-BINOL (3) and conserves its stereo-
2
2
exchanges, respectively.
homogeneity throughout six refunctionalization steps
Key words: BINOL, Buchwald–Hartwig amination, imidazolini- (Scheme 1).
um chloride, ligand synthesis, N-heterocyclic carbene, NOBIN
3
steps
1
OH
OTf
Enantiomerically pure NOBIN [e.g., (S)-1 (Figure 1)] is
75%16
OPMB
2
OH
an organocatalyst and precursor of ligands used for
asymmetric addition of diethylzinc to aromatic alde-
3
hydes, for Ti-catalyzed Mukaiyama aldol additions to
4
3 (>99% ee)
4
aldehydes or hetero-Diels–Alder reactions between alde-
5
3 steps
a,b
hydes and Danishefsky’s diene, for Cu-catalyzed 1,4-ad-
8
6%
8
2%
16
6
ditions of Et Zn to enones, for Ru-catalyzed
2
7
cyclopropanations with diazoacetates or transfer hydro-
genations of acetophenones, and for Rh-catalyzed ene-
cyclizations of 1,6-enynes. Expanding the usefulness of
8
9
NH2
OH
OTf
OMOM
(
S)-NOBIN in asymmetric catalysis, Hoveyda et al. con-
1
0
verted it into the S-configured NHC precursor 2 and em-
ployed the latter in the following transformations: Cu-
catalyzed 1,4-addition of organozinc compounds to cy-
cloalkenones, Cu-catalyzed allylation of organozinc
compounds with allylic phosphates, and Ru-catalyzed
ring-closing metathesis or ring-opening metathesis–cross-
518
1
1
1
c
d,e
88%
1
2
88%
NHBn
1
0,13
OMOM
metathesis tandem reactions.
We have modified the
published route to (S)-1 and simplified the access to (S)-2
and disclose here how we proceeded.
618
(
S)-NOBIN (1) results from the asymmetric oxidative
Scheme 1 Syntheses of (S)-NOBIN (1) from (S)-BINOL (3) accor-
ding to ref. 16 – via the PMB-protected monotriflate 4 – and by our-
selves – via the MOM-protected monotriflate 5. Reagents and
conditions: a) Tf O (1.0 equiv), i-Pr NEt (1.0 equiv), CH Cl , 0 °C, 2
coupling of 2-naphthol and 2-naphthylamine with 46%
ee at most. The Brunner –Hoveyda synthesis of 1
starts by an ArS reaction between 2-methoxynaphth-1-
1
4
15
8
10
N
2
2
2
2
h; 91% (ref. 18: ≥ 97%); b) P O (1.0 equiv), CH (OMe) , CH Cl ,
4
10
2
2
2
2
r.t., 7 h; 95%; c) BnNH (1.3 equiv), Cs CO (1.3 equiv), Pd(OAc)
2
2
3
2
(
(
10 mol%), (o-Ph PC H ) O (20 mol%), toluene, 115 °C, 6 h; 88%
2 6 4 2
N
N
ref. 18: ≥ 91%); d) H (1 atm), Pd/C (5 mol%), EtOAc, 60 °C, 7 h; e)
2
NH2
OH
H SO , MeOH, CH Cl , reflux, 4 h; 88% over the 2 steps;
MOM = CH OMe; PMB = p-methoxybenzyl; Tf = SO CF .
Cl
2
4
2
2
OH
2
2
3
We converted (S)-BINOL into 1 via (S)-BINOL monotri-
flate, the derived MOM ether 5, and the corresponding
1
2
1
8
Figure 1 (S)-NOBIN (1) and the (S)-NOBIN-based NHC precursor 2 benzylaminolysis product 6. This sequence was known
19
except that we methoxymethylated the monotriflate with
dimethoxymethane and phosphorus pentoxide20 and
thereby avoided the use of chloromethyl methyl ether.18
The latter is carcinogenic and classified as an extremely
SYNLETT 2009, No. 1, pp 0109–0111
Advanced online publication: 12.12.2008
DOI: 10.1055/s-0028-1087390; Art ID: G32508ST
Georg Thieme Verlag Stuttgart · New York
x
x.
x
x.
2
0
0
8
©

1
10
D. Sälinger, R. Brückner
LETTER
7
Br
Br H3N
Br
3
steps
a
O
N
H2N
H2N
N
H
74%10
Boc
89%
8
9
10
NH2
OH
OTf
OMOM
1
96%10
5
b
8
9%
N
H
N
N
N
N
H
Boc
2 steps
c,d
H
N
Cl
OH
3%10
OH
OMOM
8
71%
11
2
12
Scheme 2 Syntheses of the (S)-configured NHC precursor 2 from (S)-NOBIN (1) according to ref. 10 or from the MOM-protected monotrif-
late 5 by ourselves. Reagents and conditions: a) 9 (3.0 equiv), toluene, reflux, 23 h; 89% (ref. 24: 86%); b) 10 (1.3 equiv), Cs CO (1.3 equiv),
2
3
Pd(OAc) (10 mol%), (o-Ph PC H ) O (20 mol%), toluene, 115 °C, 14 h; 89%; c) concd aq HCl–MeOH (1:20), reflux at 0.1 M, 9 h; d)
2
2
6
4 2
HC(OEt) , EtOH (discharged during the reaction by a current of N ), 125 °C, 26 h; 71% over the 2 steps.
3
2
2
1
hazardous chemical by the EU and the EPA. The yield sumably because the reaction medium was heterogeneous
of benzylamine 6 was 76% overall. Debenzylation of 6 all the time. In fact we found it difficult to follow the
10
with 1 bar hydrogen and methanolysis of the MOM group advice to scrape unreacted starting material from the in-
furnished 10 g batches of (S)-NOBIN (1) in 88% yield.22 side wall of the flask since it stuck there as if gluing. We
All in all our route is slightly better yielding (65%) than made such measures obsolete by running the same reac-
Buchwald’s (62%) and significantly cheaper: Starting tion in a homogeneous phase, namely a 1:4 mixture of eth-
from commercially available reagents, benzophenone anol and triethyl orthoformate. Under these modified
imine alone – required for the aminolysis of 4 according conditions we isolated 71% of the NHC precursor 2.
to ref. 16 – costs more than our whole synthesis.
To date, the S-configured NHC precursor 2 has been syn-
thesized only by the Hoveyda group (Scheme 2, left):10
Boc protection of mesitylamine (9), prenylation, and ozo-
nolysis led to the protected aminoaldehyde 8. The latter
was condensed with (S)-NOBIN (1) reductively
References and Notes
(1) Review: (a) Ding, K.; Li, X.; Ji, B.; Guo, H.; Kitamura, M.
Curr. Org. Synth. 2005, 2, 499. First racemic synthesis:
(
b) Smrčina, M.; Lorenc, M.; Hanuš, V.; Kočovský, P.
Synlett 1991, 231. (c) Smrčina, M.; Vyskočil, Š.; Máca, B.;
Polášek, M.; Claxton, T. A.; Abbott, A. P.; Kočovský, P.
J. Org. Chem. 1994, 59, 2156. First resolution: (d)Smrčina,
M.; Vyskočil, Š.; Polívková, J.; Poláková, J.; Kočovský, P.
Collect. Czech. Chem. Commun. 1996, 61, 1520.
(
NaBH OAc), providing aminocarbamate 11. Deprotec-
3
tion rendered a bis(amine hydrochloride), which was sus-
pended in triethyl orthoformate and heated until 2 had
formed.
(
2) Wang, C.; Jiang, Y.; Zhang, X.-X.; Huang, Y.; Li, B.-G.;
Zhang, G.-L. Tetrahedron Lett. 2007, 48, 4281.
Our synthesis of compound 2 starts from the MOM-pro-
tected monotriflate 5 (Scheme 2, right), which preceeds
(3) Vyskočil, Š.; Jaracz, S.; Smrčina, M.; Štícha, M.; Hanuš, V.;
Polášek, M.; Kočovský, P. J. Org. Chem. 1998, 63, 7727.
(
S)-NOBIN (1) by three steps in the synthetic sequence of
(
4) (a) Carreira, E. M.; Singer, R. A.; Lee, W. J. Am. Chem. Soc.
1994, 116, 8837. (b) Carreira, E. M.; Lee, W.; Singer, R. A.
J. Am. Chem. Soc. 1995, 117, 3649. (c) Singer, R. A.;
Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360.
Scheme 1 and is therefore more readily accessible (or
1
7,23
costs significantly less ). Buchwald–Hartwig amina-
tion of monotriflate 5 with N-mesityl ethylenediamine
2
4,25
(
1
10 ) furnished 89% of the MOM-protected diamine
(
d) Singer, R. A.; Brock, J. R.; Carreira, E. M. Helv. Chim.
Acta 2003, 86, 1040.
(5) Ji, B.; Yuan, Y.; Ding, K.; Meng, J. Chem. Eur. J. 2003, 9,
989.
6) Hu, Y.; Liang, X.; Wang, J.; Zheng, Z.; Hu, X. J. Org. Chem.
003, 68, 4542.
7) Tang, W.; Hu, X.; Zhang, X. Tetrahedron Lett. 2002, 43,
075.
2
6
2 in what appears to be the first example of such a re-
action between an aryl triflate and an unprotected N-aryl
ethylenediamine. The overall yield of diamine 12 from
5
(
(
(
(
S)-BINOL was 77%. Removal of the MOM group with
2
hydrochloric acid rendered the bis(amine hydrochloride)
1
0
described by Hoveyda. In our hands cyclocondensation
of this compound in triethyl orthoformate under the re-
3
8) Brunner, H.; Henning, F.; Weber, M. Tetrahedron:
Asymmetry 2002, 13, 37.
1
0
ported conditions gave no more than 40% yield – pre-
Synlett 2009, No. 1, 109–111 © Thieme Stuttgart · New York

LETTER
Synthesis of Enantiomerically Pure NOBIN
111
(
9) Mikami, K.; Kataoka, S.; Wakabayashi, K.; Aikawa, K.
Tetrahedron Lett. 2006, 47, 6361.
MeOH (100 mL). Concentrated H SO (6.0 mL) was added
2
4
and the mixture refluxed for 2 h. Saturated aq NaHCO (100
3
(
10) Van Veldhuizen, J. J.; Garber, S. B.; Kingsbury, J. S.;
Hoveyda, A. H. J. Am. Chem. Soc. 2002, 124, 4954.
mL) was added after cooling. The mixture was extracted
with CH Cl (3 × 50 mL). The combined organic phases
2
2
(11) Brown, M. K.; May, T. L.; Baxter, C. A.; Hoveyda, A. H.
Angew. Chem. Int. Ed. 2007, 46, 1097; Angew. Chem. 2007,
were dried over MgSO . Evaporation of the solvent under
4
reduced pressure provided (S)-NOBIN (1; 9.19 g, 85%) as a
1
119, 1115.
faintly yellow solid (pure as judged by H NMR).
(
12) (a) Larsen, A. O.; Leu, W.; Oberhuber, C. N.; Campbell,
Recrystallization from toluene rendered rounded white
needles (8.84 g, 82%). On a smaller scale (3.29 g of
benzylamine 6) the yield of recrystallized 1 was 1.97 g
[88%; cf. footnote (e) of Scheme 1].
J. E.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 11130.
(b) Kacprzynski, M. A.; May, T. L.; Kazane, S. A.;
Hoveyda, A. H. Angew. Chem. Int. Ed. 2007, 46, 4554;
Angew. Chem. 2007, 119, 4638.
(23) Enantiopure NOBIN: 1 g ca. 500 €€ [(R)- or (S)-NOBIN,
ABCR], 10 g ca. 1500 $ [(R)-NOBIN], 50 g ca. 4000 $ [(S)-
NOBIN, both Shanghai FWD Chemicals].
(
13) (a) Van Veldhuizen, J. J.; Gillingham, D. G.; Garber, S. B.;
Kataoka, O.; Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125,
1
2502. (b) Gillingham, D. G.; Kataoka, O.; Garber, S. B.;
Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126, 12288.
c) Cortez, G. A.; Schrock, R. R.; Hoveyda, A. H. Angew.
Chem. Int. Ed. 2007, 46, 4534; Angew. Chem. 2007, 119,
618. (d) Cortez, G. A.; Baxter, C. A.; Schrock, R. R.;
(24) Perillo, I.; Caterina, M. C.; López, J.; Salerno, A. Synthesis
2004, 851.
(25) Simplified Synthesis of Diamine 10
2
4
(
A suspension of 2-bromoethylamine hydrobromide (7; 8.24
g, 40.2 mmol) and mesitylamine (9; 16.0 g, 119 mmol, 2.94
equiv) in toluene (160 mL) was refluxed for 23 h. After
cooling, aq NaOH (20%, 120 mL) was added. The mixture
was extracted with EtOAc (3 × 120 mL). The combined
4
Hoveyda, A. H. Org. Lett. 2007, 9, 2871.
(
14) (a) Smrčina, M.; Lorenc, M.; Hanuš, V.; Sedmera, P.;
Kočovský, P. J. Org. Chem. 1992, 57, 1917. (b) Smrčina,
M.; Poláková, J.; Vyskočil, Š.; Kočovský, P. J. Org. Chem.
organic phases were dried over MgSO . Evaporation of the
4
1
993, 58, 4534.
solvent under reduced pressure and flash chromatography on
SiO (eluent: EtOAc, then EtOAc–MeOH, 1:1 + 1% Et N)
provided 10 (6.39 g, 89%) as a deep red oil.
(
(
(
15) Hon, S.-W.; Li, C.-H.; Kuo, J.-H.; Barhate, N. B.; Liu,
Y.-H.; Wang, Y.; Chen, C.-T. Org. Lett. 2001, 3, 869.
16) Singer, R. A.; Buchwald, S. L. Tetrahedron Lett. 1999, 40,
2
3
(26) The following conditions were adapted from a related
1
8
1095.
transformation: Cs CO (7.51 g, 23.0 mmol, 1.30 equiv)
2 3
17) Enantiopure BINOL: 5 g ca. 50 €€ [(R)-BINOL, ABCR; (S)-
BINOL, AlfaAesar), 1 kg ca. 900 $ [(R)- or (S)-BINOL, AK
Scientific).
was dried in vacuo with a heat gun for 30 min. After
cooling, Pd(OAc) (395 mg, 1.76 mmol, 9.90 mol%),
2
(o-Ph PC H ) O (1.89 g, 3.51 mmol, 20 mol%), and a
2
6
4 2
(
(
18) Ooi, T.; Ohmatsu, K.; Maruoka, K. J. Am. Chem. Soc. 2007,
solution of the MOM-protected monotriflate 5 (8.22 g, 17.8
mmol) and the diamine 10 (4.09 g, 22.9 mmol, 1.29 equiv)
in toluene (9 mL) were added. The suspension was degassed
and stirred at 115 °C for 14 h. Filtration through Celite,
evaporation of the solvent under reduced pressure, and flash
129, 2410.
19) (S)-BINOL monotriflate (5.59 g, 13.4 mmol) was dissolved
in CH Cl (35 mL) and CH (OMe) (35 mL). Then P O
2
2
2
2
4
10
(
3.93 g, 13.8 mmol, 1.03 equiv) was added within 1 h in 2
portions. The mixture was stirred at r.t. for 7 h, poured into
chromatography on SiO (eluent: cyclohexane–EtOAc,
2
aq NH (35%, 30 mL), and extracted with CH Cl (3 × 10
90:10 → 80:20) provided the diamine 12 (7.79 g, 89%) as a
3
2
2
1
mL). The combined organic phases were dried over MgSO .
reddish-brown sticky solid. H NMR (400 MHz, CDCl ,
4
3
Evaporation of the solvent under reduced pressure and flash
TMS): d = 1.91 (s, 2 × o-CH ), 2.17 (s, p-CH ), 2.95 (ddd,
3
3
3
3
3
chromatography on SiO (eluent: cyclohexane–EtOAc,
J = J = 5.5 Hz, J = 2.2 Hz, NCH ), 3.12 (s, OCH ), AB
2
2
3
9
5
5:5) provided the MOM-protected (S)-BINOL monotriflate
(5.90 g, 95%) as a colorless oil. It crystallized slowly
signal (d = 3.33 ppm, d = 3.39 ppm, J = 13.0 Hz, in
A
B
AB
1
8
addition split by J = J = 5.7 Hz, NCH ), 3.85 (br s,
A B 2
when transferred into a refrigerator.
20) Acetalization method: Paleo, M. R.; Aurrecoechea, N.; Jung,
K.-Y.; Rapoport, H. J. Org. Chem. 2003, 68, 130.
21) See: http://www.epa.gov/ttn/atw/hlthef/chlo-eth.html.
22) A suspension of benzylamine 6 (15.9 g, 38.0 mmol) and Pd
2 × NH), AB signal (d = 4.97 ppm, d = 5.02 ppm,
A
B
(
J
= 6.8 Hz, OCH O), 6.71 (s, 2 × mesityl-H), 6.94–6.97
AB
2
(m, ArH), 7.11–7.19 (m , 2 × ArH), 7.21–7.23 (m, 2 × ArH),
c
3
3
(
(
7.24–7.27 (m, ArH), 7.35 (ddd, J = 8.1 Hz, J = 5.8 Hz,
J = 2.3 Hz, ArH), 7.55 (d, J = 9.1 Hz, ArH), 7.76–7.78 (m,
ArH), 7.86 (d, J = 8.1 Hz, ArH), 7.87 (d, J = 8.9 Hz, ArH),
7.95 (d, J = 9.0 Hz, ArH). HRMS (EI, 70 eV): m/z calcd for
C H N O [M ]: 490.262028; found: 490.262202 (+0.4
ppm). [a]D –75 (c 1.05, CHCl3).
3
3
3
3
(
10% on C, 2.04 g, 1.99 mmol, 5 mol%) in EtOAc (70 mL)
3
was heated under H (1 atm) at 60 °C for 3 h. After filtration
2
+
through Celite, the solvent was removed under reduced
pressure. The residue was dissolved in CH Cl (100 mL) and
3
3
34
2
2
2
0
2
2
Synlett 2009, No. 1, 109–111 © Thieme Stuttgart · New York

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