VenPure ® NaBH 4 for Amide/Lactam Reductions Enhancing Borohydride’s Reductive Red uctive Selectivity… Introduction:
Benefits of NaBH4 for Reductive Chemistry:
Sodium borohydride is a water-soluble reducing agent exhibiting unique properties properties in organic synthesis. synthesis. It is established as the default reducing agent for aldehydes, ketones, acid chlorides chlorides and anhydrides. anhydrides. Over the past 40 years, significant progress has been made to fine-tune borohydride’s chemoselectivity to make it either more selective, or a stronger reductant . Hence, NaBH4 could be tuned to reduce acid, ester, halide, amide, lacton and lactam functions. Some of these reductions reductions occur by virtue of the in-situ generation of boranes from NaBH4.
Of the commercially available metal hydrides used for synthetic organic reductions, NaBH4 enjoys the largest industrial use, with an estimated (equivalent) market share greater than 50%. Some of the benefits of using using borohydride chemistry: chemistry: the least expensive metal hydride commercially available (on a hydride equivalent basis) safe with regards to storage and use & handling industrial implementation requires no or limited equipment investment ease of work-up (water soluble boron salts) ubiquitous solvents such as water and methanol are typically employed unique and versatile as a hydride reducing agent for both chemo- and diastereo-selectivity diastereo-selectivity
Especially in the last 20 years, sodium borohydride has become established established as the reductant of choice in the largescale synthesis of active ingredient in applications beyond aldehyde/ketone reductions. Also, its use as a reductant with good diastereo-selectivity has become industrially established, e.g. in the ketone reduction of the Statins. This data sheet focuses on enhancing borohydride’s reductive selectivity so that it may accomplish the conversion of amides to amines, alcohols or aldehydes. The following systems are discussed: 1. Conversion to an amine a. Boranes b. In situ Boranes c. Sodium borohydride with additives 2. Conversion to an Alcohol 3. Conversion to an aldehyde
Product Stewardship Rohm and Haas offers metal hydride products as part of a comprehensive Product & Services package, including: the highest product quality the broadest range of product grades formulations stable under various transport conditions the availability of a choice of package sizes safety audits and training technical advice with regards to both the safe handling and the cost-efficient synthetic use
Availability For reasons of confidentiality, public information only is discussed. Reaction schemes are often often amenable to optimization for a higher-efficiency use of NaBH4. A comprehensive overview of the physical and chemical properties of sodium borohydride can be found in Rohm and Haas’ Sodium Borohydride Digest.
Typical Properties Mol. weight: Form: Melting point:
37.85 White crystalline solid Decomposes above 400oC without melting
With its 50+ years of manufacturing experience, Rohm and Haas Company is unique as a borohydride supplier by offering the most complete range of products: - VenPure SF Powder - VenPure AF granules, VenPure SF granules - VenPure AF caplets - VenPure solution, VenPure 20/20 solution - VenPure Potassium Borohydride - Organic NaBH4 solutions available upon request All products are available in an ample choice of packages, such as metal pails and drums, mini-bulk containers, and tank trucks or railway cars for bulk quantities.
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Introduction
1. Deoxygenation
Amides and lactams are not easily reduced to their corresponding amine using chemical hydrides. Moreover, reduction can yield either the deoxygenated amine or the corresponding alcohol + amine (from amide cleavage). O R R'
3
1.1. Boranes
One of the best classes of boron reagents to reduce amides to amines is Boranes. Brown demonstrated in 1973 that borane-THF would reduce 1o, 2o and 3o amide in high yield to their corresponding amine. O
N R'
R1 M-H
M-H
N
BH3*THF
R2
R1
THF, Reflux
R3
R3
M-H
eq. BH3 time -
OM
+
R'
-
+
-
OM H
R'
H
NR'2
+
OM R'
H
NR'2
NR'2
M-H
O R'
H
NR'2
M NR'2
NR'2
+ MO R'
M-H
+
H
H
H
M-H + M-O-M
OH NR'2
HN-R'2 R'
H
H
+ M
Yield
Hexanamide
2.5
2h
87
N-Methylhexanamide
2.0
1h
98
N,N Dimethylhexanamide
1.66
1h
95
Benzylamide
2.33
8h
87
N,N-Dimethylbenzylamide
1.66
1h
98
Borane reduction typically requires a significant excess of reductant, because the resulting amine form a stable (weakly-reducing) amine-borane complex.
H R'
R2
N
4-8
1.2. In -Situ Boranes
Over the years NaBH4 has been shown to be a great starting material for the deoxygenation of amides in high yields, via in-situ generation of a borane-type reagent.
+
R' H
Am id e Cleav age
H
Am id e Deox yg eati on
Aluminum hydrides such as LiAlH 4 or Vitride 1 may have a sufficient electrochemical potential to achieve amide deoxygenation, however excess hydride and high temperature are often required. Boron based reducing agents can accomplish all of the above transformations except iminium salts2. The most common of these reactions is the ● deoxygenation reaction to from amines. ● Aldehydes can preferentially be formed from amides using mono hydrided aluminum compounds. The reactivity of an amide is determined by both the number of N-substituents and the type of R group on the carbonyl group. The trends are: Tertiary ≥ Secondary >>Primary Primary Aliphatic > Primary Aromatic This technical bulletin will summarize a selection of technologies that have been published to achieve both amide cleavage and deoxygenation.
Reagent
BH4 / Temp Solvent Sub RT THF
Amides Reduced* NaBH4, I2 1o, 2o, 3o Arom.lactams LiBH4, Me3SiCl 3:1 RT THF 1 o, 2o, 3o NaBH4, R 2Se2 RT 3o o NaBH4, RT DMSO 1 , 2o, 3o MeSO2OH Arom. + Alif. NaBH4, TiCl4 3:1 RT DME 1o, 2o, 3o Arom. + Alif. * Type of amides that were demonstrated.
1.3. Additives: Borohydride derivatives Traditionally, neat NaBH 4 will not react with amides, but NaBH4 can be modified with either inorganic or organic materials to increase its reductive strength to reduce amides to amines. 9
1.3.1. Zinc Borohydride Zinc borohydride under reflux conditions will reduce aromatic amides into amines in high yields. H
H N
O
Zn(BH4)2 THF, reflux
R''
N
H C
H
R'
10
1.3.2. Cobalt Boride 1° and 2o aromatic and aliphatic amides can be hydrogenated in high yields to their corresponding amine by using cobalt boride and sodium borohydride. Two problems exist with this technology : a large excess of NaBH4 is required, and 3° amides are not reduced. O 10 : 2 NaBH4/CoCl 2 H H R N R N H H
1.3.3. O R 1
NaBH4 with Acetic Acid
R 2
N
11-14
NaBH3(O2CCH3)
R 3
R 1
N
R 2 R 3
dioxane, reflux, 2h
Pre-formed NaBH3(OAc) in dioxane will reduce all amides to their corresponding amines in high yields. The challenge of using this technology is, that only the mono-substituted borohydride is capable of reducing amides. The reactivity of the amides are in decreasing order 1 o >
17
1.4.2. Sodium borohydride with B(OPh)3 3 amides are activated by triphenylborate for a mild highyield borohydride reduction to the corresponding amine. o
O 2 NaBH4/ 3 B(OPh) 3
Me
R
N Me
Me N Me
R
THF, RT
Yield (%) after ….
3h
6h
N,N-Dimethyl Benzamide
88
86
N,N-Diemthyl-p-nitrobenzamide
100
-
N-Benzylpiperidine
90
98
N,N-Dimethylcaproamide
73
92
N,N-Dimethylpivalamide
89
91
1.5. Solvent effect: 18
1.5.1. NaBH 4 in Glymes High temperature reactions of sodium borohydride in glymes with primary amides will produce their corresponding amine in high yields. O
2o > 3o
N
This chemistry also works with the deoxygenation of lactams to cyclic amines. OMe
H
NH
N
4:42 NaBH4/Diglyme
H H
H
99 %
1.5 h, 162 oC
OMe
NaBH4, CH3CO2H
MeO
H
MeO
19
Dioxane, reflux Yield 97 %
NH
H
O
1.5.2. NaBH 4 in Pyridine Also Pyridine can be used for high temperature reactions with NaBH4 to convert lactams to cyclic amines.
3 NaBH4
1.4. Additives: Modified Amides It has been shown that amides can be pre-treated with additives that will make the amide more susceptible to reduction to their corresponding amine by sodium borohydride. The technology relies on increasing the leaving-capacity of oxygen by addition of Lewis Acids.
O
N
N
Pyridine, 10h reflux Yield 66 %
15-16
1.4.1. NaBH4 with phosphorus oxychloride POCl3 reacts with 2°/3° amides and lactams to form their corresponding Chloro-iminium salt which can be easily reduced to an amine with sodium borohydride. This reaction should be completed under anhydrous conditions, because water reacts with POCl3 to generate HCl, which will react with NaBH 4 to form boranes. O
20-23
2.1. Borohydride and Methanol Lithium borohydride treated in situ with methanol can reduce amides to the corresponding alcohol in high yields. R1
Cl N
N +
POCl3
R
N
NaBH4 EtOH
R
2. Reduction to an Alcohol
R
N
R2
R3
3 LiBH4 /MeOH R1
Digylme or THF
O
R2
R3
2
O R1
N
H H
1
N
R2
R3
R1
R2
R3
Ph
H
H
92
n-C7H15 Ph
H
H
77
CH3 CH3
H
4
H
16
Ph
H
19
28
Ph
H
45
37
CH3 CH3
CH3 CH3
90
n-C7H15 Ph CH3 Ph PhCH2
OH
Amine 1
Amine 2
Li(CH3CH2)3BH alone will reduce 3o amides to their corresponding alcohols, but if the amide is pre-treated with 1 eq. of ethyl-trifluoromethanesulphonate then the aldehyde, kinetic product, is formed in high yields. This indicates that other MR 3BH reagents should also be able to do this reaction, where M = Na, K and R = R and OR.
15 65
61
O
16
Sodium borohydride can also reduce lactams to cyclic amines in high yields by the attrition of methanol to t butanol solution of substrate. O O
R1
R2
O H N H R2 R 3
H R3
R1
2.
N H
O NaBH4/MeOH
N
N P
O
OH
N
N P
3. 4.
N P
N
NaBH4/MeOH
N
N P
O
24
O R 1
2.2 Li(C2H5)3BH
N R 3
THF, RT
R 1
O
H
R1
R2
R3
Time
Yield
C6H5 n-C3H7
CH3 CH3
CH3 CH3
1h
100
3h
90
n-C6H11 i-C3H7
CH3 CH3
CH3 CH3
1h
80
4h
91
c-C6H11 t-C4H9
CH3 CH3
CH3 CH3
5h
71
7h
95
n-C3H7 n-C3H7
C2H5
C2H5 i-C3H7
24h
50
24h
0
i-C3H7
Seyden-Penne J.; Reductions by the alumino and borohydrides in organic synthesis 2nd Ed. 1997 Larock R.C; Comprehensive Organic Transformations 2nd ed. 1999 Brown, H.C.; Helm, P. J. Org. Chem. 1973, 38 , 912 Prasa, A.S.B.; Kanth, J.V.B.; Periasamy, M. Tetrahedron , 1992, 48 , 4623
Akabori, S.; Takanohashi, Y. J. Chem. Soc..; Perkin Trans 1 , 1991, 479 Wann, S.R.; Thorsen, P.T.; Kreevoy, M.M. J. Org. Chem. 1981, 46 , 2579 Kabno, S.; Tanaka, Y.; Sugino, E.; Hibino, S. Synthesis 1980, 695 Narasimhan, S.; Madhavan, S.; Balakumar, R.; Swarnalakshmi, S. Synth. Commun . 1997, 27 , 391
10.
2.2. Other Boron hydrides Li(CH3CH2)3BH can reduce 3° amides to their corresponding alcohols in high yields. This technology will not work with 1° or 2° amides. This indicates that other MR 3BH reagents should also be able to do this reaction, where M = Na, K and R = R and OR.
R 2
H
6.
9. OH
R
Giannis, A.; Sandoff, K. Angew. Chem. Int. Ed. Engl. . 1989, 28 , 218
8.
O
o
THF, -78 C, 3h
5.
7. O
R 2 N R 3
O
1) CF3SO3OEt, RT, 24h 2) 2 LiBH(CHMeEt)3
4. References
OH O
Depending on the substrate this chemistry can selectively reduce lactams to lactamols O
R
1.
N N
25
3. Reduction of Amide to Aldehydes
Satoh, T.; Suzuki, S.; Suzuki, Y.; Miyaji, Y.; Imai, Z. Tetrahedron Lett. 1969, 52, 4555 11. Umino, N.; Iwakuma, T.; Itoh, N. Tetrahedron Lett . 1976, 763 12. Bailey, A.S.; Scott, P.W.; Vandrevala, M.H. J .Chem.Soc. Perkin Trans 1 1980, 1, 97 13. Cannon, J.G.; Chang, Y.; Amoo, V.E. Synthesis 1986, 494 14.
Garcia, Ruano, J.L.; Martinez, M.C.; Rodriguez, J.H.; Olefirowicz, E.M.; Eliel, E.L. J. Org. Chem. 1992, 57 , 5215 15. Rahman, A.; Basha, A.; Waheed, N. Tetrahedron Lett. 1976, 3, 219 16. Kuehne, M.E.; Shannon P.J. J. Org. Chem. 1977, 42, 2082 17. Yoon, N.M.; Chho, B.T.; Yoo, J.U.; Kim, G.P.. J. Korean Chem. Soc. . 1983, 27 , 434 18. Yang, C.; Pittman, C.U. Synthetic Commun . 1998, 28 , 2027 19. Kikugawa, Y.; Ikegami, S.; Yamamda, S. Chem. Pharm. Bull 1969, 17, 98 20. Soai, K.; Ookawa, A. J. Org. Chem. 1986, 51, 4000 21. Mandal S.B.; Giri, V.S.; Sabeena, M.S.; Pakrashi, S.C . J. Org. Chem. 1988, 53, 4236 22. Mandal S.B.; Giri, V.S.; Pakrashi, S.C Synthesis 1987, 1128 23. Lee, B.H.; Clothier M.F. Tetrahedron Lett . 1999, 40, 643 24. Brown, H.C.; Kim, S.C. Synthesis 1977, 636 Tsay, S.C.; Robi, J.A.; Hwu, J.R . J. Chem. Soc., Perkin Trans 1 1990, 757
