Rhodium-catalyzed diastereoselective 1,2-addition of arylboronic acids to chiral trifluoroethyl imine

Article abstract of DOI:10.1016/j.tetlet.2009.01.112

Rhodium-catalyzed 1,2-addition of arylboronic acids 4a-j to chiral trifluoroethyl imine 3 afforded diastereomerically enriched sulfinamides 5a-j. The chiral auxiliary of the sulfinamide products was readily removed under acidic methanolysis to provide the corresponding trifluoroethylamine analogs 6a-j.

Full text of DOI:10.1016/j.tetlet.2009.01.112

Tetrahedron Letters 50 (2009) 1633–1635
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Rhodium-catalyzed diastereoselective 1,2-addition of arylboronic acids
to chiral trifluoroethyl imine
*
Vouy Linh Truong , Jennifer Y. Pfeiffer
Department of Medicinal Chemistry, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec H9H 3L1, Canada
a r t i c l e i n f o
a b s t r a c t
Article history:
Rhodium-catalyzed 1,2-addition of arylboronic acids 4a–j to chiral trifluoroethyl imine 3 afforded diaste-
reomerically enriched sulfinamides 5a–j. The chiral auxiliary of the sulfinamide products was readily
removed under acidic methanolysis to provide the corresponding trifluoroethylamine analogs 6a–j.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 9 December 2008
Revised 20 January 2009
Accepted 21 January 2009
Available online 25 January 2009
Trifluoroethylamine derivatives can be found in numerous
pharmacologically active molecules due to their unique chemical
and structural properties.1 As such, the development for their
asymmetric synthesis has gained considerable attention over the
past years.2 Despite recent advances, a more general and practical
approach for the rapid synthesis of trifluoroethylamine analogs re-
mains highly desirable. Along these lines, we had previously re-
ported the synthesis of trifluoroethylamine derivatives via a key
diastereoselective 1,2-addition of aryllithiums to chiral trifluoro-
ethyl imine 3.3 We now disclose the rhodium-catalyzed diastereo-
selective 1,2-addition of arylboronic acids to imine 3.
In the past, several groups had reported the rhodium-phos-
phine-catalyzed addition of arylboronic acids to N-sulfonyl aldi-
mines.4 More recently, Ellman’s and Batey’s groups have
successfully demonstrated rhodium-catalyzed 1,2-addition of aryl-
boronic acids to N-tert-butylsulfinyl aldimines to form the corre-
sponding sulfinamides with high diastereoselectivities.5 Notably,
the conditions developed by Bolshan and Batey5b seem more prac-
tical by avoiding the use of external phosphine ligand and syringe
pump for slow addition of the arylboronic acids. Accordingly, we
envisioned adapting this procedure to examine the rhodium-cata-
lyzed 1,2-addition of arylboronic acids to chiral trifluoroethyl
imine 3 (Scheme 1). This imine can be prepared by condensation
of N-tert-butylsulfinamide 1 with trifluoroacetaldehyde hydrate 2
in dichloromethane at 40 °C in the presence of 4 Å molecular
sieves, and was further used without purification as previously
reported.3
We began our investigation with phenylboronic acid as a model
substrate to explore the rhodium-catalyzed diastereoselective 1,2-
addition to imine 3 (Table 1). Using Batey’s reaction conditions,
only a trace amount of the desired sulfinamide 5a was observed,
possibly due to aminal formation, in the presence of water. In order
to avoid the aminal formation, we then focused our effort on anhy-
drous conditions using dichloromethane as solvent since the imine
formation proceeded in this solvent. A few rhodium catalysts were
investigated in order to optimize high yields and diastereoselectiv-
ities of the desired sulfinamide 5a. The diastereoselectivity of
sulfinamide 5a was determined by chiral HPLC of amine salt 6a,
which was obtained upon chiral ligand cleavage using HCl in
Table 1
Initial screening of rhodium for 1,2-addition of phenylboronic acid to imine 3
S
PhB(OH)2 (2 eq.)
Rh catalyst
Et3N, solvent
rt, 2 h
S
NH2.HCl
HN
F3C
O
N
O
HCl/MeOH
rt, 1 h
Ph
F3C
Ph
6a
F3C
5a
3
Yielda (%)
deb
S
Entry
Catalyst
Solvent
OH
OH
N
O
4 Å M.S.
+
1
2
3
4
[Rh(cod)(CH3N)2]BF4
[Rh(cod)(CH3N)2]BF4
[Rh(cod)(OMe]2
Dioxane/H2O
CH2Cl2
CH2Cl2
Trace
74
80
—
S
F3C
H2N
O
F3C
CH2Cl2, 40 ºC
ref. 3
87
81
87
2
(S)-1
3
[Rh(cod)(OH]2
CH2Cl2
80
Scheme 1. Preparation of chiral trifluoroethyl imine 3.
a
Isolated overall yield from N-tert-butylsulfinamide 1.
Diastereomeric excess (de) was determined by chiral HPLC of amine 6a, S
b
absolute configuration was determined by comparison with an authentic
* Corresponding author. Tel.: +1 514 428 2822; fax: +1 514 428 4900.
E-mail address: vouylinh_truong@merck.com (V.L. Truong).
standard.2a,d
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.112

1634
V. L. Truong, J. Y. Pfeiffer / Tetrahedron Letters 50 (2009) 1633–1635
methanol.3,5b,6 Both [Rh(cod)OH]2 and [Rh(cod)OMe]2 gave the
highest yields of sulfinamide 5a. Moreover, [Rh(cod)OH]2 afforded
the best diastereoselectivity of sulfinamide 5a in the 1,2-addition.
Therefore, [Rh(cod)OH]2 was used in further reaction optimization.
Besides catalyst screening, the effect of solvent was examined
(Table 2). It was found that dichloromethane and chloroform affor-
ded the highest yield (entries 1 and 2) when compared to 1,2-
dichloroethane, THF, 2-methyl-THF, dioxane, acetonitrile, and
DMF, which gave low to moderate yield of sulfinamide 5a (entries
3–9). Interestingly, when 2-methyl-THF and acetonitrile were used
as solvents, a slight improvement in diastereoselectivity was
observed. Unfortunately, these solvents afforded lower yields.
Thus, dichloromethane was found to be the optimal solvent for
rhodium-catalyzed 1,2-addition of phenylboronic acid to imine 3
to provide sulfinamide 5a in high yield and diastereoselectivity
(entry 1).
Table 2
Optimization of solvent for 1,2-addition of phenylboronic acid to imine 3
PhB(OH)2 (2 eq.)
[Rh(cod)(OH)]2
S
S
NH2.HCl
HN
F3C
O
N
O
HCl/MeOH
rt, 1 h
Ph
F3C
Ph
6a
F3C
Et3N, solvent
rt, 2 h
5a
3
Entry
Solvent
Yieldb (%)
dec
1
2
3
4
5
6
7
8
9
CH2Cl2
CHCl3
80
89
79
59
24
23
75
25
31
87
77
87
83
90
75
76
91
77
CH2ClCH2Cl
THFa
2-Methyl-THFa
Dioxanea
Toluene
CH3CNa
DMFa
Next, we investigated the effect of the base. Organic and inor-
ganic bases were submitted to the reaction conditions. It was
found that triethylamine remained the optimal choice in providing
the best combination of high yield and diastereoselectivity.
a
CH2Cl2 was removed by distillation and replaced by the appropriate solvent.
Isolated overall yield from N-tert-butylsulfinamide 1.
Diastereomeric excess determined by chiral HPLC of amine 6a.
b
c
Table 3
Rhodium-catalyzed diastereoselective 1,2-addition of various arylboronic acids to imine 3
ArB(OH)2 (2 eq.)
[Rh(cod)(OH)]2
S
S
.
HN
F3C
O
NH2 HCl
Ar
N
O
a) HCl/MeOH, rt
Ar
F3C
F3C
Et3N, CH2Cl2
0 °C, 18 h
b) Workup with
NaHCO3 for 5h_j
3
5
6
Entry
1
ArB(OH)2 (4)
Sulfinamide 5
Yield of 5a (%)
deb
Amine 6
Yield of 6 (%)
B(OH)2
5a
72
90
6a
6b
90
B(OH)2
B(OH)2
2
3
5b
5c
73
55
81
93
92
94
MeO
MeS
6c
B(OH)2
4
5
5d
5e
75
58
93
6d
6e
92
83
F
B(OH)2
>99
F3C
Me
B(OH)2
6
5f
72
91
6f
96
B(OH)2
7
8
9
5g
5h
5i
62
47
49
91
94
94
6g
6h
6i
99
83
84
B(OH)2
AcHN
B(OH)2
MeO2C
B(OH)2
10
5j
66
85
6j
67
O
a
Isolated overall yield from N-tert-butylsulfinamide 1, calculated from average of two runs.
Diastereomeric excess determined by chiral HPLC of amines 6.
b

V. L. Truong, J. Y. Pfeiffer / Tetrahedron Letters 50 (2009) 1633–1635
1635
Finally, variation of the catalyst and phenylboronic acid loading,
Acknowledgment
reaction concentration, and temperature of the reaction identified
5% of [Rh(cod)OH]2 with 2 equiv of phenylboronic acid in dichloro-
methane (0.14 M of imine 3) at 0 °C as the optimal reaction condi-
tions for the preparation of sulfinamide 5a from imine 3. Using
these optimized conditions, the rhodium-catalyzed 1,2-addition
of phenylboronic acid to imine afforded sulfinamide 5a in 72%
overall yield from N-tert-butylsulfinamide 1 with an excellent dia-
stereoselectivity (Table 3, entry 1).
We thank Dr. Daniel Guay (Merck Frosst) for helpful
discussions.
References and notes
1. (a) Zanda, M.; Molteni, M.; Volonterio, A. Org. Lett. 2003, 5, 3887–3890; (b)
Black, W. C.; Bayly, C. I.; Davis, D. E.; Desmarais, S.; Falgueyret, J.-P.; Léger, S.; Li,
C. S.; Massé, F.; McKay, D. J.; Palmer, J. T.; Percival, M. D.; Robichaud, J.; Tsou, N.;
Zamboni, R. Bioorg. Med. Chem. Lett. 2005, 15, 4741–4744; (c) Li, C. S.; Deschênes,
D.; Desmarais, S.; Falgueyret, J.-P.; Gauthier, J. Y.; Kimmel, D. B.; Léger, S.; Massé,
F.; McGrath, M. E.; McKay, D. J.; Percival, M. D.; Riendeau, D.; Rodan, S. B.;
Thérien, M.; Truong, V. L.; Wesolowski, G.; Zamboni, R.; Black, W. C. Bioorg. Med.
Chem. Lett. 2006, 16, 1985–1989; (d) Gauthier, J. Y.; Black, W. C.; Courchesne, I.;
Cromlish, W.; Desmarais, S.; Houle, R.; Lamontagne, S.; Li, C. S.; Massé, F.;
Deschênes, D.; Falgueyret, J.-P.; Kimmel, D. B.; Léger, S.; Massé, F.; McKay, D. J.;
Ouellet, M.; Robichaud, J.; Truchon, J.-F.; Truong, V. L.; Wang, Q.; Percival, M. D.
Bioorg. Med. Chem. Lett. 2007, 17, 4929–4933; (e) Gauthier, J. Y.; Chauret, N.;
Cromlish, W.; Desmarais, S.; Duong, L. T.; Falgueyret, J.-P.; Kimmel, D. B.;
Lamontagne, S.; Léger, S.; LeRiche, T.; Li, C. S.; Massé, F.; McKay, D. J.; Nicoll-
Griffith, D. A.; Oballa, R. M.; Palmer, J. T.; Percival, M. D.; Riendeau, D.;
Robichaud, J.; Rodan, G. A.; Rodan, S. B.; Seto, C.; Thérien, M.; Truong, V. L.;
Venuti, M. C.; Wesolowski, G.; Young, R. N.; Zamboni, R.; Black, W. C. Bioorg.
Med. Chem. Lett. 2008, 18, 923–928.
2. (a) Olah, G. A.; Prakash, G. K. S.; Mandal, M. Angew. Chem., Int. Ed. 2001, 3, 589–
590; (b) Enders, D.; Funabiki, K. Org. Lett. 2001, 3, 1575–1577; (c) Gosselin, F.;
Roy, A.; O’Shea, P. D.; Chen, C.-y.; Volante, R. P. Org. Lett. 2004, 6, 641–644; (d)
Gosselin, F.; O’Shea, P. D.; Roy, S.; Reamer, R. A.; Chen, C.-y.; Volante, R. P. Org.
Lett. 2005, 7, 355–358; (e) Kuduk, S. D.; Marco, C. N. D.; Pitzenberger, S. M.; Tsou,
N. Tetrahedron Lett. 2006, 47, 2377–2381; (f) Hughes, G.; Devine, P. N.; Naber, J.
R.; O’Shea, P. D.; Foster, B. S.; McKay, D. J.; Volante, R. P. Angew. Chem., Int. Ed.
2007, 46, 1839–1842.
3. Truong, V. L.; Ménard, M. S.; Dion, I. Org. Lett. 2007, 9, 683–685.
4. (a) Ueda, M.; Saito, A.; Miyaura, N. Synlett. 2000, 1637–1639; (b) Fagnou, K.;
Lautens, M. Chem. Rev. 2003, 103, 169–196; (c) Kuriyama, M.; Soeta, T.; Hao, X.;
Chen, Q.; Tomioka, K. J. Am. Chem. Soc. 2004, 126, 8128–8129.
5. (a) Weix, D. J.; Shi, Y.; Ellman, J. A. J. Am. Chem. Soc. 2005, 127, 1092–1093; (b)
Bolshan, Y.; Batey, R. A. Org. Lett. 2005, 7, 1481–1484.
6. Senanayake, C. H.; Pflum, D. A.; Krishnamurthy, D.; Han, Z.; Wald, S. A.
Tetrahedron Lett. 2002, 43, 923–926.
7. Typical experimental of rhodium-catalyzed addition reaction: Compound 5a: To a
solution of N-tert-butylsulfinamide (S)-1 (200 mg, 1.65 mmol) in
dichloromethane (3.3 mL) in a sealed tube were added trifluoroacetaldehyde
Encouraged by the above results, we then examined the scope
of this rhodium-catalyzed diastereoselective 1,2-addition to imine
3 using the optimized reaction conditions with various arylboronic
acids.7 The results are shown in Table 3. In general, a variety of
substituted arylboronic acids with functional groups such as fluoro,
methoxyl, methylthio, trifluoromethyl, acetamide, methylester,
and ketone are compatible under the reaction conditions. The de-
sired sulfinamides 5a–j were generated in moderate to good yields
and good to excellent diastereoselectivities. Sulfinamides 5a–j
were readily hydrolyzed to give the corresponding trifluoroethyl-
amine analogs 6a–j, which were analyzed by chiral HPLC for dia-
stereomeric excess determination. So far, the scope of this 1,2-
addition reaction to imine 3 has been limited to arylboronic acids.
Only a trace amount of the corresponding sulfinamides was ob-
served when attempted with propenylboronic acid and phen-
ylvinylboronic acid. In addition, heterocyclic boronic acids such
as pyridine, pyrimidine, thienyl, and furanyl boronic acids failed
to participate in the 1,2-addition reaction. Presumably, the hetero-
atoms complexed with rhodium and impeded the catalytic process.
It has been proposed that in the rhodium-catalyzed 1,2-addition
reaction, triethylamine acts as a buffer to prevent the protonation
of the intermediate Ar-Rh(I) species.5b However, in our hands the
protodeboration of arylboronic acids was identified as the major
side reaction. For example, when 4-acetamidophenylboronic acid,
4-methoxycarbonylphenylboronic acid, and 4-acetylphenylboronic
acid (4h–j) were employed, N-phenylacetamide, methyl benzoate,
and acetophenone were obtained, respectively, in addition to the
desired sulfinamides 5h–j.
The addition of arylboronic acids to imine 3 appears to have
proceeded via a non-chelated transition-state model, which is con-
sistent with the literature for the addition of organolithium re-
agents8 as well as boronic acids.5b
In summary, we have developed an efficient rhodium-catalyzed
diastereoselective 1,2-addition of arylboronic acids 4a–j to trifluo-
roethyl imine 3 to generate the corresponding sulfinamides 5a–j in
good yields and excellent diastereoselectivities. This protocol gives
access to a variety of trifluoroethylamine analogs 6a–j. The com-
mercial availability of arylboronic acids as well as the mild reaction
conditions make this methodology a very attractive alternative to
this class of compounds.
hydrate 2 (75% in aqueous solution, 200 lL, 1.82 mmol) and molecular sieves
beads 4 Å (1 g) from Acros. The reaction mixture was stirred at 40 °C for 6 h
under nitrogen to provide the crude imine 3. The reaction mixture was cooled to
0 °C, 8.6 mL of dichloromethane was added followed by phenylboronic acid
(402 mg, 3.3 mmol) and triethylamine (465 lL, 3.3 mmol). The reaction mixture
was bubbled with nitrogen for 10 min, then [Rh(cod)OH]2 (38 mg, 0.083 mmol)
was added, bubbled again with nitrogen for 10 min. The reaction mixture was
aged at 0 °C for 18 h. It was then filtered through Celite, the filtrate was
quenched with a saturated sodium hydrogen carbonate solution. The aqueous
layer was extracted three times with dichloromethane. The organic extracts
were combined, washed with brine, dried over anhydrous MgSO4, filtered, and
concentrated in vacuo. The residue was purified by flash chromatography on
silica gel using ethyl acetate–hexanes (10:90 to 30:70) to afford 5a in 72% yield
(332 mg).
8. (a) Plobeck, N.; Powell, D. Tetrahedron: Asymmetry 2002, 13, 303–310; (b) Jiang,
W.; Chen, C.; Marinkovic, D.; Tran, J. A.; Chen, C. W.; Arellano, L. M.; White, N. S.;
Tucci, F. C. J. Org. Chem. 2005, 70, 8924–8931.