Letter Cite This: Org. Lett. 2018, 20, 337−340
pubs.acs.org/OrgLett
Protected Chloroethyl and Chloropropyl Amines as Conformationally Unrestricted Annulating Reagents Qing Shi, Mariah C. Meehan, Michael Galella, Hyunsoo Park, Purnima Khandelwal, John Hynes, Jr., T. G. Murali Dhar, and David Marcoux* Research and Development, Bristol-Myers Squibb Company, Route 206 and Province Line Road, Princeton, New Jersey 08543, United States S Supporting Information *
ABSTRACT: The purpose of this letter is to document the use of protected chloroethyl and chloropropyl amines as conformationally unrestricted ambiphilic reagents that undergo annulation reactions with Michael acceptors. This reaction is wide in scope and utilizes reagents that are commercially available, inexpensive, and stable. Furthermore, this reaction is easy to execute and proceeds rapidly.
A
considering it is simple to make and could be a versatile reagent in a formal [3 + 2] cycloaddition reaction with readily available Michael acceptors.10,11 However, this is a challenging strategy due to the conformationally unrestricted nature of ambiphilic intermediate 7b, which promotes a nonreversible formation of aziridine 8. Therefore, interception of intermediate 7b with a Michael acceptor 9 is unlikely. The use of highly electrophilic partners such as doubly activated 1,1-substituted olefins can out-compete aziridine formation but singly activated acceptors that were required for our program failed to do so.10 Herein, tert-butyl (2chloroethyl)carbamate (11a) is disclosed to enable annulation reactions with singly activated Michael acceptors making such reaction an inexpensive method to generate substituted pyrrolidines from commercially available reagents (eq 1). This
nnulation and cycloaddition reactions are powerful transformations to rapidly access structural diversity and complexity.1,2 For example, a variety of reagents have been employed for synthesizing the pyrrolidine core of biologically active molecules. Figure 1 highlights selected annulating and
Figure 1. Selected reagents used for pyrrolidine synthesis.
cycloaddition reagents utilized for such purposes.3 Ambiphilic reagents generated from 1−5 surmount the undesired pathway of intramolecular cyclization either due to their reduced reactivity, reversible three-membered ring formation, and/or conformational restriction. For example, reagents 1 and 2 are less likely to react intramolecularly upon deprotonation or activation as a 3endo-trig cyclization4 is disfavored.5,6 Similarly, unwanted threemembered formation is not possible with reagents 3 and 4 because of their reduced reactivity.7,8 Finally, reagent 5 can potentially react intramolecularly following activation by photocatalysis, but its formation is reversible·9 Our research group required synthon 7a in order to fully explore structure−activity relationships for our program (Scheme 1). Of the limited options, reagent 6a was attractive
reagent is more stable and less expensive than reagent 6a that rapidly yields the undesired aziridine under the conditions outlined in eq 1. Furthermore, the annulating reagent could be modified to access piperidine rings and chiral nonracemic bicyclic systems. The reaction between carbamate 6a and less reactive singly activated olefins was first investigated (Table 1). Initial results showed that 6a was not a competent partner with methyl acrylate; the aziridine being the major product (data not shown). Reaction of the more electrophilic phenyl vinyl sulfone (9a)12 with 6a did not allow pyrrolidine formation. Instead, it engaged in an interrupted annulation reaction leading to sulfone 13a in 47% yield (entry 1). Cyclization did occur with longer reaction time
Scheme 1. Reaction Path of Ambiphilic Reagent 6a
Received: November 15, 2017 Published: December 28, 2017 © 2017 American Chemical Society
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DOI: 10.1021/acs.orglett.7b03548 Org. Lett. 2018, 20, 337−340
Letter
Organic Letters
(entries 8−11). Solvents with a higher dielectric constant such as DMSO and DMF improved the yield of the cyclized product (entries 10−11). Further improvements in yields were realized conducting the reaction in DMF at a lower temperature (entries 12−13). In addition, increasing the concentration to 0.2 M (entries 14−15) and lowering the amount of annulating reagent 11a to 1.5 equiv (entry 15) permitted isolating the desired product in 88% yield.13 Employing these optimized reaction conditions, a wide variety of singly activated Michael acceptors underwent the annulation reaction to yield pyrrolidines (Table 3). Vinyl sulfones were found to be excellent substrates (entries 1−4) regardless of substitution patterns. Simple and inexpensive methyl acrylate and acrylonitrile undergo pyrrolidine synthesis in 35% and 31% yield, respectively (entries 5−6). In some cases, yields could be improved by adding substituents at the 2-position of the acrylate (entries 7−8). The improved yield with methyl 3-phenyl acrylate may be due to the greater stability of the ester enolate intermediate. 1,2-Disubstituted acrylates also provide the desired pyrrolidines selectively as the trans-isomer in 32 to 65% yield (entries 10−11). The six-membered lactone affords the corresponding 5,6-bicyclic system in 34% yield (entry 12). Interestingly, methyl cinnamate and cinnamonitrile do not participate in this reaction; the aziridine being the only observed product (entries 13−14). Adding electron withdrawing groups (CF3, CN, NO2) at the para position of the phenyl ring to increase electrophilicity did not lead to pyrrolidine formation.9 Nonetheless, (E)-chalcone (57% yield) and (E)-2,3-diphenylacrylonitrile (81% yield) yield the desired pyrrolidines (entries 15−16). As expected, several 1,1-diactivated olefins reacted in this annulation reaction (entries 17−24). Diethyl 2-methylenemalonate provided the corresponding pyrrolidine in 58% yield (entry 17). Adding a methyl group or a phenyl group to diethyl 2-methylenemalonate did not alter the yield of the reaction (entries 18−19). Tetrasubstituted olefins could undergo this reaction, but a Meldrum’s acid derivative needs to be employed, yielding the desired product in 12% yield (entry 20). The Michael acceptors could also be varied as a combination of ester, nitrile, and phenylketone providing the desired products in 59−75% yield (entries 21−24). In all cases, excellent diastereoselectivity has been observed (entries 4, 10−11, 15− 16, 22, 24).14 Other annulating reagents were then investigated to expand the scope of this reaction (Table 4). Mesylate 11 was also found to be a competent leaving group providing pyrrolidine 12a in 75% yield (entry 1). However, bromo and iodo leaving groups do not provide product under these reaction conditions due to competing aziridine formation (entries 2−3). The homologated version of reagent 11 provided the piperidine analog in moderate to high yields (entries 4−5). Interestingly, the bromo leaving group appears to be optimal for piperidine ring formation probably due to the slower rate of cyclization of the reagent (azetidine vs aziridine). However, seven-membered ring formation is currently not possible with this methodology (data not shown). Adding a methyl substitution adjacent to the amine of the annulating reagent is detrimental for product formation presumably due to Thorpe−Ingold effect favoring aziridine formation (entry 6).15 This could be circumvented by using a cyclopropyl constraining group preventing azetidine formation and yielding the corresponding piperidine in 35% yield (entry 7). It is believed that the cyclopropyl group disfavors azetidine formation as the corresponding 5-azaspiro[2.3]hexane presumably requires a greater activation barrier of formation
Table 1. Initial Results
entry
R
X
annulating reagent
products
ratio
yield (%)1
1 2 3
Bn Bn tBu
Br Cl Cl
6a 6b 11a
10/13a 10/13b 12a/13c
0:100 0:100 0:100
47 78 81
1
Isolated yields.
Table 2. Optimization of the Annulation Reaction
entry
base
solvent
temp (°C)
NMR yield1 12a/13c (%)
1 2 3 4 5 6 7 8 9 10 11 12 13 142 152,3
DBU BEMP LiHMDS NaHMDS KHMDS NaOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu KOtBu
THF THF THF THF THF THF THF toluene MeCN DMF DMSO DMF DMF DMF DMF
23 23 23 23 23 23 23 23 23 23 23 0 −40 0 0
0:0 0:0 0:64 0:32 25:45 0:80 45:25 16:75 69:15 75:5 67:5 85:5 87:5 97:2 95:3 (88)
11
H NMR yield using 1,4-dichlorobenzene as the internal standard. Isolated yield in parentheses. 2The reaction was conducted at a concentration of 0.2 M. 3The reaction was conducted with 1.5 equiv of 11a and 1.5 equiv of KOtBu.
and/or higher temperature albeit in low yield (
