B. RESULTS AND DISCUSSION
5. P REPARATION AND R EACTIONS OF H ETEROAROMATIC B ENZYL Z INC R EAGENTS
5.6. Application to the Synthesis of Biologically Active Compounds
Scheme 59: Preparation of the highly functionalized polyazanaphthalenes 168 and 169 from the corresponding ketones 155a and 155h.
Scheme 60: Preparation of the skeleton of the CB1 and CB2 modifier (157).
6. New Generation of Iminium Salts
6.1. Introduction
Various biologically active compounds are derived from benzylamines with a high interest for the pharmaceutical industry.156 Among these, histamine derivatives and antihistamine compounds have received special attention as Piperoxan 933F (176) and Neoantergan (177) (Figure 3).157
Figure 3: Histamine derivatives and antihistamine compounds.
Scarce reports related to the Mannich reaction for the preparation of functionalized tertiary benzylamines are available.158 Hence, the modification of the conditions for the synthesis of heterobenzylic amines offers a one-pot procedure for the preparation of tertiary benzylamines.137 Furthermore, the formation of an unsymmetrical aminal 178 should be possible when reacting the Mannich’s ion 140129 with a magnesiated amine 179. Thus, the addition of a second equivalent of trifluoroacetic anhydride should acylate the less steric hindered nitrogen of 178, i.e. the dimethylamino moiety and form the methylene(dialkyl)-iminium salt 180. The addition of an organometallic reagent should add and afford the tertiary amine 181 (Scheme 61).
156 (a) P. Nussbaumer, G. Dorfstaetter, M. A. Grassberger, I. Leitner, J. G. Meingassner, K. Thirring, A. Stuetz, J.
Med. Chem. 1993, 36, 2115; (b) C. Altomare, L. Summo, S. Cellamare, A. V. Varlamov, L. G. Voskressensky, T. N.
Borisova, A. Carotti, Bioorg. Med. Chem. Lett. 2000, 10, 581.
157 C. M. Marson, Chem. Rev. 2011, 111, 7121.
158 a) G. Kinast, L.-F. Tietze, Angew. Chem. Int. Ed. Engl. 1976, 15, 239; b) M. Arend, B. Westermann, N. Risch, Angew. Chem. Int. Ed. 1998, 110, 1044; c) J. Schreiber, H. Maag, N. Hashimoto, A. Eschenmoser, Angew. Chem.
Int. Ed. Engl. 1971, 10, 330.
Scheme 61: Preparation of mixed aminals via Mannich’s cation.
6.2. Preparation of Tertiary Benzyl Amines
The Mannich salt 140 reacts readily with TMPMgCl·LiCl (7) (1.0 equiv) at –78 °C within 30 min to afford a complete conversion to the mixed aminal 182, which could not be isolated in this form due to its aminal nature. However, the addition of trifluoroacetic anhydride (1.0 equiv) led to the formation of the 2,2,6,6-tetramethylpiperidinium cation 183, which reacted further with 3-piridylmagnesium chloride 184 and afforded the substituted pyridine 185 in 76% yield (Scheme 62). Noteworthy, is the tolerance of the sterically demanding 2,2,6,6-tetramethylpiperidine on the aminal nitrogen.
Me N Me
CH2 F3C
O O 140
N MgCl
7 (1.0 equiv) DCM, -78 °C, 15 min
Me2N N 182
(1.0 equiv) DCM, -78 °C, 30 min
H2C N
183
N
MgCl
(1.0 equiv) -78 °C to 25 °C, 1 h
184a
N
N
185a:76%
F3C O
O F3C
O O
O CF3
Scheme 62: Synthesis of N-benzyl-2,2,6,6-tetramethylpiperidine 185a.
The metal amides were prepared by the deprotonation of the amine with MeMgCl (1.0 equiv) at 0 °C for 10 min, given that the corresponding non-metallic amines presented a lower reactivity.
Moreover, the mixed aminals with an aryl or heteroaryl substituent on α-position to the aminal nitrogen diminished the reactivity. The temperature was kept at –78 °C to avoid partial decomposition of the mixed aminals. Hence, reacting various secondary amines to their corresponding aminals and a further reaction with an organomagnesium or organozinc reagent
(organolithium reagents lead to traces of product), afforded the tertiary amines 185b-d in 45-92%
yield (Table 10, entries 1-3).
Table 10: Preparation of tertiary benzyl and phenethyl amines in a one-pot procedure.
Entry metal amide organometallic
substrate Product, Yield[a]
1 184b
185b: 92%
2
184c
185c: 66%
3
184d
N N Ph
OMe
185d: 45%
[a] Yield of analytically pure product.
4. Summary and Outlook
This work was focused on the preparation of highly functionalized organometallics through different approaches. Primarily, several aromatics, heteroaromatics, protected phenols and protected anilines were effectively metalated employing different TMP-bases. Secondarily, a general pathway for the preparation of non-conjugated heteroaromatic benzylic zinc reagents was investigated with further application for the preparation of polyheterocycles. Finally, the preparation of benzyl and phenethylamines via a one-pot anhydrous aminomethylation was carried out.
4.1. Regio- and Chemoselective Zincation of Functionalized Aromatics and and Heteroaromatics using TMPZnCl·LiCl and Microwave irradiation
It was demonstrated that moderately activated aromatic and heteroaromatic substrates, bearing sensitive functionalities undergo regio- and chemoselective zincations with TMPZnCl·LiCl (10) at high temperatures and are stable under microwave irradiation (Scheme 63).
Scheme 63: Zincation of moderately activated aromatics and heteroaromatics using TMPZnCl·LiCl (10) and microwave irradiation.
Also, the regioselective zincations can be carried out on a multigram scale in a safely manner.
The yields are comparable to the corresponding small scale and the functional group tolerance is not affected (Scheme 64).
1) TMPZnClLiCl (10) THF, 25 °C, 5 h 2) CuCN2LiCl
3) 4-chlorobenzoyl chloride -30 to 25 °C, 3 h
50 mmol 77%
N O2N
Cl O
Cl
N
N N
N O
O Me
Me Me
Cl
N N Cl
Cl N
O2N Cl
N
N N
N O
O Me
Me Me
N N Cl
Cl
1) TMPZnClLiCl (10) THF, 25 °C, 10 min 2) 1-chloro-4-iodobenzene
Pd(dba)2(3 mol%) P(o-furyl)3(6 mol%)
50 mmol 79%
1) TMPZnClLiCl (10) THF, 25 °C, 5 h 2) CuCN2LiCl (5 mol%) 3) 3-bromocyclohexene
50 mmol 81%
Scheme 64: Large scale zincation of sensitive functionalized aromatics and heteroaromatics using TMPZnCl·LiCl (10) and subsequent reactions with electrophiles.
4.2. Efficient Preparation of Polyfunctional Organometallics via Directed ortho-Metalation with TMP-Bases of Mn, Fe and La
It was shown that the use of the bases TMP2Mn·2MgCl2·4LiCl (12), TMP2Fe·2LiCl·4LiCl (13) and TMP3La·3MgCl2·5LiCl (14) gave access to functionalized organometallics via a highly efficient ortho-metalation. These organometallics exhibited a broad functional group tolerance, reacted with several electrophiles and an upscale was possible in good yields (Scheme 65).
1) TMP2Mn2MgCl24LiCl (12) THF, 0 °C, 30 min
2) PhCHO 15 mmol
15 mmol
15 mmol
N N
OMe OMe OH
CN
CO2Et
Cl
CO2Me 75%
78%
94%
O Ph 1) TMP2Fe2MgCl24LiCl (13)
THF, 25 °C, 18 h
2) 4-fluorostyrene (10 mol%) 2-iodopropane
1) TMP3La3MgCl25LiCl (14) THF, 0 °C, 3.5 h
2) ClCOPh Cl
CO2Me CN
CO2Et N
N OMe OMe
Scheme 65: Efficient preparation of organometallics via ortho-metalation with TMP-bases of Mn, Fe and La in a multigram scale.
4.3. Directed ortho- and meta-Magnesiation or Zincation of Polyfunctional Aryl Nonaflates
It was demonstrated that functionalized aryl nonaflates can be magnesiated formally in meta-position using TMPMgCl·LiCl (7), but that an ortho-metalation is best performed with the mild and effective base TMPZnCl·LiCl (10). Further functionalization of the nonaflate moiety was carried out and the method could find future applications in the synthesis of natural products, pharmaceuticals and materials (Scheme 66).
ONf
O O
OMe 72%
ONf
Cl Cl
Cl
83%
ONf EtO2C
COPh
ZnBr·LiCl
EtO2C CO2Et
EtO2C
COPh THF, Pd(dba)2(5 mol %),
dppf (5 mol %), 60 °C, 8 h
79 % F
F SMe ONf
81%
ONf
CO2Et EtO2C
O
72%
TMPZnCl·LiCl (10) THF, 25 °C
or
TMPMgCl·LiCl (7) THF, -20 °C
Electrophile
FG FG FG
ONf ONf ONf
Met
FG = CO2Et, F, Cl
E 65-94%
Scheme 66: Zincation or magnesiation of polyfunctional aryl nonaflates and a subsequent nonaflate moiety transformation.
4.4. Directed ortho- and meta-Magnesiation of Functionalized Anilines and Amino-Substituted Pyridines and Pyrazines
The use of an ortho-directing protective group for anilines and amino-substituted pyridines and pyrazines was investigated. The trifluoroacetyl group was found to be stable towards magnesiation with TMPMgCl·LiCl (7) and TMP2Mg·2LiCl (9) at room temperature and allowed access for the first time to ortho- and meta-magnesiated anilides. Remarkably, these magnesiations tolerate sensitive functional groups such as a cyano or an ester and sensitive heterocycles as pyridines or pyrazine were efficiently metalated. Reaction with electrophiles led to highly substituted anilides in good yields. The trifluoroacetyl amide moiety was deprotected under mild conditions to obtain the anilines or primary amino-pyridines and pyrazines (Scheme 67).
1) MeMgCl
2) TMPMgClLiCl (7) THF, 25 °C, 4 h 3) MeSO2SMe
-20 °C, 2 h
81%
Cl Cl
NH2 MeS
O
Cl
71%
NH O F3C
Br Br
O O
OMe
Cl NH O
F3C Me
65%
CN NH O
F3C OMe
75%
N HN
O CF3 CO2Et
65%
N HN
O CF3 CF3
Cl 80%
Cl Cl
NH
Cl Cl
NH
1) MeMgCl
2) TMPMgClLiCl (7) THF, 25 °C, 4 h 3) CuCN2LiCl 4)p-ClC6H4COCl 5) NH4Cl
76%
NH O F3C
Br Br
CO2Et
CO2Et 75%
O F3C
O F3C
SMe
Scheme 67: Regioselective magnesiation of functionalized anilides.
This method showed a great utility for the preparation of pharmaceutically active heterocycles such as a GSK-3 and Lck protein kinase inhibitor in two steps. This compound is useful for the treatment and prevention of diabetes, Alzheimer and transplant rejection patented by Vertex Pharmaceuticals (Scheme 68).
Scheme 68: Synthesis of a GSK-3 and Lck protein kinase inhibitor by chemoselective magnesiation and subsequent deprotection.
4.5. Preparation and Reactions of Heteroaromatic Benzylic Zinc Reagents
The synthesis of non-conjugated heteroaromatic benzylic zinc reagents was carried out from the corresponding heteroaryl organometallics into the corresponding (dimethylamino)methyl compounds and a further transformation led to the heteroaromatic benzylic chlorides. The LiCl promoted oxidative zinc-insertion afforded the desired heteroaromatic benzylic zinc reagents and subsequent reaction with electrophiles afforded the corresponding products in good yields (Scheme 69).
Scheme 69: Preparation of heterocyclic benzylic zinc reagents and reaction with electrophiles.
These building blocks were subjected to further transformations to obtain their corresponding annulated polyheterocycles such as 7-azaindoles, furopyridines and polyazanaphtalenes in a convenient manner (Scheme 70). The method was used for the synthesis of the skeleton of a pharmaceutically modifier CB1 and CB2 receptor (Scheme 71).
N
Cl F O
NaBH3CN NH4OAc EtOH, MW 130 °C, 30 min
N
Cl N
H 68%
S S MnO2
DCM 60 °C 5 h
N
Cl N
H 78%
S
N Cl
NaH, THF
25 ° C, 3 h Cl N F OH
O
DDQ dioxane
100 °C, 3 hCl N O S
Br
S Br S Br
79% 60%
N N MeO
OMe
ClO
N
N N N
OMe
MeO
70%
1) N2H4,DMF 120 °C, 6 h 2) Pb(OAc)4,THF
25 °C, 4 h N
Cl F O
N N N
Cl
55%
Cl Cl
Cl Cl
1) N2H4,DMF 120 °C, 6 h 2) Pb(OAc)4,THF
25 °C, 4 h
Scheme 70: Preparation of highly functionalized 7-azaiondoles, furopyridines and polyazanaphtalenes.
Scheme 71: Preparation of the skeleton of the CB1 and CB2 modifier.
4.6. New Generation of Iminium Salts
It was also shown that the preparation of mixed aminals from the Mannich’s cation and different metal amides can be performed in a one-pot procedure using trifluroacetic anhydride as acylating agent. The reaction of the iminium ions with a range of organometallic led to tertiary benzylic amines with presence in some pharmaceutical targets (Scheme 72).
Scheme 72: Tertiary benzyl and phenethyl amine products.