III. Brønsted Acid/Base-Catalyzed Halocyclizations and Carbon Dioxide-Fixation
3.4 AnthPBAM: Synthesis and Potential Applications of a New Chiral, C 2 -Symmetric
trace yield after 4 days (entry 3, Table 21). The insolubility of both NIS and alcohol 271 in this case was largely responsible for low yield.
At this stage it was apparent that simple catalyst, concentration, temperature, and additive adjustments to the enantioselective iodocarbonation reaction with aliphatic homoallylic alcohols were not effective in enhancing enantioselection. At present, the outlook is brightest if a new Brønsted basic ligand and/or achiral Brønsted acid combination is developed as an effective system for more challenging aliphatic homoallylic alcohols.
3.4 AnthPBAM: Synthesis and Potential Applications of a New Chiral, C2-
different systems. While examining various enantioselective reactions throughout my tenure in the group, it became evident that more diverse BAM ligands would be a nice addition to the catalyst library. Considering the dramatic stereoselectivity (and reactivity) effects observed when switching from trans-1,2-cyclohexandiamine to trans-stilbene diamine in the iodocyclization chemistry, it would be reasonable to explore additional chiral diamine backbones that present the
hydrogen-bonding BAM framework in a different orientation (Figure 41).
After investigating various potential chiral trans-1,2-dimaines, it was apparent that branching away from the two previously employed diamine backbones was going to be expensive. The enantiopure trans-diamine is derived from a mixture of cis and trans stereoisomers via a chiral resolution of this material using enantiomerically pure tartaric acid.
The chiral diamine 273, derived from anthracene, has been used for some time as a chiral pool reagent. Seminal examples date back to the early 1990’s when Barry Trost193 used the diamine to assemble chiral phosphine ligands for palladium. The diamine has since been used in a number of asymmetric syntheses,194 and is still used as an essential part of the chiral diamine ligands regularly screened in his group’s chemistry (Trost anthracenyl ligand 274, Figure 42).195
193 Trost, B. M.; Van Vranken, D. L.; Bingel, C. J. Am. Chem. Soc. 1992, 114, 9327. Trost, B. M.; Van Vranken, D.
L. Angew. Chem. Int. Ed. 1992, 31, 228.
194Trost, B. M.; Schroeder, G. M.; Kristensen, J. Angew. Chem. Int. Ed. 2002, 41, 3492. Trost, B. M.; Tang, W. J.
Am. Chem. Soc. 2003, 125, 8744.
195 Trost, B. M.; Thaisrivongs, D. A. J. Am. Chem. Soc. 2008, 130, 14092.
Figure 41. Common chiral 1,2-diamines employed in asymmetric catalysis and potential for different backbones
N N N
R N R
R
R
69° 52°
trans-stilbene diamine trans-cyclohexane diamine
H
H
H H
N R R N
?° R
other trans-1,2-diamines H
H R
The diamine is commercially available from Sigma Aldrich yet is relatively expensive compared to other common diamines (Sigma, 1 gram for $538).196
This ligand presents one of the most rigid chiral diamine scaffolds available and essentially blocks an entire face of the catalyst (273, Figure 42). The N-C-C-N dihedral angle is, however, far larger than the other common chiral 1,2-diamines and these features collectively make for a very interesting chiral backbone. This ligand is reported to have an N-C-C-N dihedral angle of between 114.2-117.0º,197 as compared to the trans-stilbene diamine and trans- cyclohexanediamine (52° and 69°, respectively, Figure 41). In the past we have thought it to be more worthwhile to use chiral diamines with smaller dihedral angles, yet in conjunction with the high rigidity and facial preference of this anthracenyl diamine, there is no clear way to predict selectivity and reactivity.
196 Quote from Sigma Aldrich on November 14, 2015.
197 Barrón-Jaime, A.; Aguirre, G.; Parra-Hake, M.; Chávez, D.; Madrigal, D.; Sanders, B.; Cooksy, A. L.;
Somanathan, R. J. Mex. Chem. Soc. 2013, 57, 54.
Figure 42. The anthracene-derived chiral 1,2-diamine 273 and its N-C-C-N dihedral angle. Also, the first application of this diamine to catalysis as the Trost ligand 274.
NH2 H2N
115º
(R,R)-trans-anthracenyl diamine Trost
HN
NH O PPh3 O
PPh3
Trost anthracenyl ligand 274 273
Fortunately, chemists at Chirotech (now a subsidiary of Dow Chemical) developed an improved protocol on preparative scale to access diamine 273 from cheap and readily available starting materials.198 Anthracene 275 and fumaroyl chloride 276 are the two primary reagents employed. This procedure proved fruitful and ultimately afforded rac-273 in 80% yield over 5 steps (no intermediates isolated). The enriched (R,R) enantiomer of 273 was ultimately isolated in great recovery following a chiral resolution using (S)-mandelic acid (Scheme 82). Over 7 grams of (R,R)-273 were isolated as the (S)-mandelic acid salt (>$3,000.00 market value).
198 Fox, M. E.; Gerlach, A.; Lennon, I. C.; Meek, G.; Praquin, C. Synthesis-Stuttgart 2005, 3196.
Scheme 82. The preparation of rac-273 following known protocol and the chiral resolution to afford (R,R)-273.
Non-isolable intermediates were followed by IR.
NH2 H2N poured into
boiling toluene
N N
in toluene Curtius
Rearrangement
HN NH
in H2O O HO
OH O
rt, 3h O C
C O (loss of N2)
consumption of isocyanate by IR (2251 cm-1)
then to pH 14 to pH 1 conc. HCl
12.4 g, 80% yield rac-trans diamine Cl
O Cl
O
toluene, 110 °C
O Cl O Cl
11.7 g 65 mmol
toluene, 0 °C
O N3 O N3
NaN3 in H2O acyl chloride consumed
by IR (1788 cm-1) acyl azide appeared
(2148, 1712 cm-1) in toluene
then aq. NaOH 275
276
rac-273
O OH NH2 OH
H2N
rac-273 (S)-Mandelic acid
MeOH rt, 16 h
O O OH
NH3 H2N
(R,R)-trans diamine (S)-Mandelic acid salt
NH2 H2N
(R,R)-trans diamine aq. NaOH
273
After breaking the salt, the enriched diamine 273 was subjected to standard Buchwald- Hartwig amination conditions with 2,4-dichloroquinoline to generate the desired amidine (4-Cl- AnthBAM 278, Scheme 83). Due to the high rigidity and crystalline nature of this intermediate, 278 could be recrystallized to purity. Microwave-assisted SNAr reaction with pyrrolidine went smoothly providing the final AnthPBAM free base catalyst 279 in 91% yield (no retro Diels- Alder adduct was observed). The free base subsequently was purified via trituration (see Experimental).
With this new chiral BAM ligand in hand, it was subjected to a variety of benchmark
Scheme 83. Completion of (R,R)-AnthPBAM 279 from diamine 273.
NH2 H2N
N Cl
Cl
Pd(dba)2 BINAP, NaOtBu
tol, 80 °C 3 h
CF3Ph, 170 °C 35 min
HN
N N
N N
N N
273
H H
(91%) (69%)
277
N N
N N
Cl Cl
H H
recrystallized pure 278
triturated pure (R,R)-AnthPBAM 279
Scheme 84. Benchmarking AnthPBAM 279 in the aza-Henry reaction.a Ar = p-Cl-C6H4
Ar
Ar NO2 N Boc
toluene, -78 °C 5 mol%
AnthPBAM (279)
Ar NO2
Ar H
N Boc 90% ee, 82:1 dr H
H
Ar
Ar NO2 N Boc
toluene, -78 °C 5 mol%
PBAM (2a)
Ar NO2
Ar H
N Boc 86% ee, 9:1 dr H
H (91%)
(97%)
Ar
Ar NO2 N Boc
toluene, -78 °C 5 mol%
6,7(MeO)2PBAM (2b)
Ar NO2
Ar H
N Boc 91% ee, 13:1 dr H
(97%) H H
H
H 6
7 8
6
7 8
6
7 8
aAll reactions were 0.1 M in toluene for 24 h. The reaction mixtures were quickly filtered through silica gel and stereoselection was determined by chiral HPLC.
reactions developed in the group where BAM (or MAM) catalysts have previously shown efficacy. The catalyst was first examined in the aza-Henry reaction with p-Cl aryl Boc-imine and p-Cl aryl nitromethane (Scheme 84). As outlined, 279 performed remarkably well in this system when employed as the free base, affording the aza-Henry adduct 8 in very high levels of diastereoselection not seen with previous BAM catalysts (only MAM catalysts were more selective in this system). The other BAM catalyst results (2a and 2b, previously optimized) are also included in Scheme 84.
Testing 279 as the triflimide Brønsted acid salt in the iodolactonization and iodocarbonation chemistry, however, showed much lower efficacy compared to the stilbene- derived BAM catalysts. Reactivity was remarkably low (lower than PBAM free base) and for material that was isolated, stereoselection was also low (<15% ee). Interestingly, 279 (free base) was tested by a colleague in a reaction en route to the chiral iodourea 282, and promising ee was observed (up to 70% ee, Scheme 85). These were perplexing results since the BAM free base catalysts have traditionally resulted in both low enantioselection and reactivity. Typically, the HNTf2 catalyst salts are ideal and enantioselection is greatly improved. In this reaction however, 279•HNTf2 had no beneficial effect. This and other related projects are current ongoing.
Scheme 85. Moderate ee observed in the iodocyclization reaction using tosyl isocyanates (281).
toluene (0.13M), -50 °C 10 mol%
AnthPBAM (279) N N
Ph I
O Bn
Ph N
H
Bn C
N O
Ts
Ts
70%ee
280 281 282