Direct alkylation of 1-azabicyclo[1.1.0]butanes

Article abstract of DOI:10.1021/acs.orglett.9b00321

The facile synthesis of functionalized azetidines has been an ongoing challenge. Here, we report a general method to directly alkylate 1-azabicyclo[1.1.0]butane (ABB) with organometal reagents in the presence of Cu(OTf)₂ to rapidly prepare bis-

Full text of DOI:10.1021/acs.orglett.9b00321

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Direct Alkylation of 1‑Azabicyclo[1.1.0]butanes
Ryan Gianatassio* and Dora Kadish†
Department of Medicinal Chemistry, Biotherapeutic and Medicinal Sciences, Biogen, 225 Binney Street, Cambridge, Massachusetts
02142, United States
S
* Supporting Information
ABSTRACT: The facile synthesis of functionalized azetidines
has been an ongoing challenge. Here, we report a general
method to directly alkylate 1-azabicyclo[1.1.0]butane (ABB)
with organometal reagents in the presence of Cu(OTf)2 to
rapidly prepare bis-functionalized azetidines. This method
allows for the preparation of azetidines bearing alkyl, allyl,
vinyl, and benzyl groups. This catalyst system was extended to
aziridines and spirocycles. Several building blocks and drug-
like compounds were prepared in rapid fashion and in good
yield.
n comparison to common rings such as piperidines which
Iare prevalent in marketed drugs, the presence of azetidines
as a core scaffold is scarce.1,2 It can be reasoned that the
absence of azetidines as a privileged motif is due to low
synthetic tractability.2 An in-depth search of chemical literature
revealed a lack of methods to install carbon atoms at the 3-
position of azetidines (Figure 1A). Methodologies to prepare
azetidines are in high demand due to their potential application
in the pharmaceutical and agrochemical fields.2 It was
envisaged that the invention of a rapid and robust synthesis
of azetidines could lead to an increase in their use in
biomedical research. It has been shown that 1-
azabicyclo[1.1.0]butanes can serve as powerful intermediates
to prepare bis-functionalized azetidines in short order.3 Nagao
and others have shown that ABB can be intercepted with
various nucleophiles to prepare functionalized azetidines.4,5
Recently, Baran has shown that ABB can be aminated with
“turbo amides” in a one-pot fashion.6 The aforementioned
studies inspired us to ponder whether ABB could be
functionalized with carbon nucleophiles. A method to rapidly
prepare libraries of alkylated azetidines would allow medicinal
chemists to quickly investigate structure−activity relationships
(SARs). Thus, we sought to develop a method to functionalize
ABB with alkyl nucleophiles. Due to the ability of nucleophiles
to break the C−N bond and functionalize the C-3 position, we
sought to find a suitable carbon species that could attack ABB
to afford 3-substituted azetidines. Initial experiments were
Figure 1. (A) Azetidines as a scaffold in medicinal chemistry. (B)
conducted with different tert-butyl nucleophiles. Tosyl chloride
(1 M in THF) was used to trap the resulting functionalized
azetidine for ease of isolation and characterization to provide
compound 3. Attempts to functionalize ABB with t-BuLi, t-
BuZnBr, and t-BuMgCl led to either no reaction or trace
observable product (Figure 1B, entries 1−3). Also, it should be
noted that attempts to functionalize ABB with phenyl-
magnesium bromide (and other aryl-metal reagents) led to
isolation of complex mixtures that contained the desired
Invention of a copper catalyzed synthesis of azetidines (catalysts
shown as mol %).
product.7 Seeking a method to increase the reactivity of the
metal species, a Gilman-type cuprate was reacted with ABB
Received: January 25, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. Scope of the reaction between nucleophiles, ABB, and N-Boc aziridine. a Reaction conditions (all reactions conducted on 1 mmol scale
unless otherwise noted): 1 (1 equiv), PhLi (1.9 M in dibutyl ether, 3 equiv), RMgCl (2 equiv), Cu(OTf)2 (3 mol %), −78 °C to rt, then E+ (2
equiv) 5−24 h. b With iPrMgCl·LiCl. c With adamantylzinc bromide. d At 3.36 mmol scale. e Reaction conditions: Heterocycle (2 equiv), BuLi
(2.05 M in hexanes, 2 equiv), Cu(OTf)2 (3 mol %), 2 (1 equiv) −78 °C to rt, then E+ (2 equiv) 5−24 h. f Reaction conditions: Grignard (2 equiv),
31 (1 equiv), BF3·OEt2 (1 equiv), Cu(OTf)2 (3 mol %), −78 °C to rt, 16 h.
which drastically increased the yield to 56% (Figure 1B, entry
4). While this result was encouraging, the reaction required
100 mol % CuCN copper. The main challenges in the
development of this reaction were to render the reaction
catalytic, increase the yields, and expand the scope. Several
reactions were conducted in an effort to optimize this reaction
including a scan of additives and catalysts. A sampling of our
efforts is shown in Figure 1B (see Supporting Information for
more details). In the end, Cu(OTf)2 (3 mol %) was found to
be the optimal catalyst for this transformation (Figure 1B,
entry 16). With these optimal conditions in hand, we sought to
explore the scope of the reaction with different Grignard
reagents. To our delight, the scope consisted of primary (3−5,
14, 26−27), secondary (6, 10−12), and tertiary alkyl groups
(3, 7−9, 13). Also, other metal species such as the i-PrMgCl·
LiCl complex (6) and 1-adamantylZnBr (13) were tolerated.
In addition, products from vinyl and allyl Grignard reagents
performed in good yield (15−17). Additionally, a variety of
benzylic Grignard reagents were reactive and most products
were isolated in good yield (18−25). It is important to note
that this reaction can be conducted on gram-scale (26) and
tolerates a variety of electrophiles such as tosyl (3−6, 9−18,
20−26, 28−29), Fmoc (7), benzoyl (19, 27), and Boc (30).
Also, this reaction can be paired with an SNAr reaction to
rapidly build molecular complexity in one pot (8). It should be
noted that Boc can be used as an electrophile, but tosyl was
chosen in many cases due to ease of visualization and
purification. In addition, a method was developed for the direct
coupling of heterocycles, such as pyridine and quinoline, to
ABB (Figure 2C, entries 28−30).
In our efforts to expand the method to provide products of
other strained scaffolds, 31 was identified as a suitable
precursor to append ethyl amines onto carbon atoms. A
literature search revealed that similar reactions have been
successful on C-2 functionalized aziridines with various
combinations of organometal and copper catalysts.8 Thus, it
was envisioned that our conditions could be utilized to
perform a strain−release type reaction on N-Boc aziridines to
demonstrate the flexibility of our conditions. In fact, when 31
was allowed to react under our conditions with benzylmagne-
sium bromide in the presence of BF3·(OEt)2, the desired
product was isolated in 43% yield (32). Additionally, other
Grignard reagents performed well in this reaction (33−34).
B
DOI: 10.1021/acs.orglett.9b00321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Proof of Concept for the Synthesis of an Azaspirocycle
Present Address
†Department of Chemistry, University of California, Irvine,
California, 92697-2025.
During the course of our investigation, we became aware
that a method to prepare spirocycles would be extremely useful
to the medicinal chemistry community. Carreira has
extensively reviewed and demonstrated the importance of
azaspiro compounds in medicinal chemistry.9 In particular,
spirocycles have shown to impart similar properties to their
monocyclic congeners while increasing the number of vectors
that can be explored.9a Thus, we sought to develop a quick and
efficient route to azetidine-containing spirocycles.
Intermediate 35 was synthesized in short order from
cyclohexanone using previously reported methods.10 Treat-
ment of 35 with HBr and bromine afforded 36 which was
directly converted to spirocycle 39 in 50% yield using our
conditions and trapping with 2-naphthoyl chloride (Scheme
1). The structure of 39 was unambiguously confirmed by X-ray
crystallography. We propose that the formation of 39 proceeds
through the intermediacy of 37 although 37 was not isolated.
In conclusion, this research describes methods to function-
alize azabicyclobutanes and aziridines with carbon nucleophiles
in rapid fashion. The methods described herein allow for the
preparation of molecules that are difficult to prepare using
current methods. It is envisioned that these methods will be
widely adopted by medicinal chemists. Lastly, proof of concept
for the synthesis and the opening of strained spirocycles was
established and the scope of strained rings and nucleophiles are
under investigation.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Kevin Barry (currently at Biogen) for technical
assistance during the initial stages of this project, Dr. Richard
Staples for X-ray crystallography analysis (currently at
Crystallographic Resources Inc.), Jiansheng Huang (currently
at Biogen) for HRMS data, and Dr. Nathan Genung (currently
at Biogen) for thoughtful discussions.
REFERENCES
■
(1) (a) McGrath, N. A.; Brichacek, M.; Njardarson, J. T. A Graphical
Journey of Innovative Organic Architectures That Have Improved
Our Lives. J. Chem. Educ. 2010, 87, 1348. (b) Wellington, K.; Scott, L.
Azelnidipine. Drugs 2003, 63, 2613−2621.
(2) Antermite, D.; Degennaro, L.; Luisi, R. Recent advances in the
chemistry of metallated azetidines. Org. Biomol. Chem. 2017, 15, 34−
50.
(3) (a) Dave, P. R. Acylative Dealkylation of N-tert-Butyl-3-
substituted azetidines: Facile Access to [1.1.0]Azabicyclobutane, 3-
Hydroxyazetidinium Hydrochloride, and 3-Azetidinones. J. Org.
Chem. 1996, 61, 5453−5455. (b) Marchand, A. P.; Rajagopal, D.;
Bott, S. G.; Archibald, T. G. A Novel Approach to the Synthesis of
1,3,3-trinitroazetidine. J. Org. Chem. 1995, 60, 4943−4946.
(c) Bartnik, R.; Cal, D.; Marchand, A. P.; Alihodzic, S.;
Devasagayaraj, A. New Method for the Generation and Trapping of
1-Azabicyclo[1.1.0]butane. Application to the Synthesis of 1,3-
Dinitroazetidine. Synth. Commun. 1998, 28, 3949−3954. (d) Woz-
nicka, M.; Urbaniak, K.; Mloston, G.; Heimgartner, H. Strained 1-
Azabicyclo[1.1.0]butanes in the Synthesis of Azetidinethiocarboxylate
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00321.
́
Derivatives. Heterocycles 2006, 69, 351−364. (e) Mloston, G.; Celeda,
Characterization data for compounds 3−34 and 39
M.; Linden, A.; Heimgartner, H. Two- and Three-Component
Reactions Leading to New Enamines Derived from 2,3-Dicyanobut-2-
enoates. Helv. Chim. Acta 2009, 92, 1520−1537.
(PDF)
Accession Codes
(4) (a) Hayashi, K.; Kujime, E.; Katayama, H.; Sano, S.; Nagao, Y.
Reaction of 1-Azabicyclo[1.1.0]butane with Activated Amides.
Heterocycles 2009, 78, 1777−1786. (b) Hayashi, K.; Hiki, S.;
Kumagai, T.; Nagao, Y. Synthesis of Azetidine Derivatives Using 1-
Azabicyclo[1.1.0]butane. Heterocycles 2002, 56, 433−442. (c) Hayashi,
K.; Ikee, Y.; Goto, S.; Shiro, M.; Nagao, Y. Mechanistic
Considerations for the Consecutive Cyclization of 2,3-Dibromopro-
pylamine Hydrobromide Giving a Strained Molecule, 1-
Azabicyclo[1.1.0]butane. Chem. Pharm. Bull. 2004, 52, 89−94.
(d) Ikee, Y.; Hashimoto, K.; Kamino, M.; Nakashima, M.; Hayashi,
K.; Sano, S.; Shiro, M.; Nagao, Y. Synthesis of New Quinoline
Antibiotics Utilizing Azetidine Derivatives Obtained from 1-
Azabicyclo[1.1.0]butane. Chem. Pharm. Bull. 2008, 56, 346−356.
(e) Hayashi, K.; Kumagai, T.; Nagao, Y. Improved Synthesis of an
Energetic Material, 1,3,3-Trinitroazetidine Exploiting 1-
Azabicyclo[1.1.0]butane. Heterocycles 2000, 53, 447−452. (f) Hayashi,
CCDC 1883856−1883859 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ryan.gianatassio@biogen.com.
ORCID
Ryan Gianatassio: 0000-0001-9057-6561
C
DOI: 10.1021/acs.orglett.9b00321
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
K.; Sato, C.; Hiki, S.; Kumagai, T.; Tamai, S.; Abe, T.; Nagao, Y.
Novel efficient synthesis of 1-azabicyclo[1.1.0]butane and its
application to the synthesis of 1-(1,3-thiazolin-2-yl)azetidine-3-thiol
useful for the pendant moiety of an oral 1β-methylcarbapenem
antibiotic L-084. Tetrahedron Lett. 1999, 40, 3761−3764. (g) Ikee, Y.;
Hashimoto, K.; Nakashima, M.; Hayashi, K.; Sano, S.; Shiro, M.;
Nagao, Y. Synthesis and antibacterial activities of new quinoline
derivatives utilizing 1-azabicyclo[1.1.0]butane. Bioorg. Med. Chem.
Lett. 2007, 17, 942−945.
Carreira, E. M. Ruthenium-Catalyzed Intramolecular Hydrocarba-
moylation of Allylic Formamides: Convenient Access to Chiral
Pyrrolidones. J. Am. Chem. Soc. 2013, 135, 6814−6817.
(5) (a) Marchand, A. P.; Bartnik, R.; Mloston, G. Reactions of 3-
Ethyl- and 3-Phenyl-1-azabicyclo[1.1.0]butanes with Tosyl Chloride
and Tosyl Azide. Heterocycles 1999, 50, 131−146. (b) Mloston, G.;
Galindo, A.; Bartnik, R.; Marchand, A. P.; Rajagopal, D. Ring-opening
reactions of 3-substituted 1-azabicyclo[1.1.0]butane with dichlor-
ocarbene. J. Heterocycl. Chem. 1996, 33, 93−96. (c) Mloston, G.;
Heimgartner, H. Three-Component Reactions with 3-Phenyl-1-
azabicyclo[1.1.0]butane, Dimethyl Dicyanofumarate, and Primary
Aromatic Amines. Heterocycles 2010, 80, 1091−1102. (d) Mloston,
G.; Celeda, M. Ring Opening of 1-Azabicyclo[1.1.0]butanes with
Hydrazoic Acid − a Facile Access to N-Unsubstituted Azetidin-3-
Amines. Helv. Chim. Acta 2005, 88, 1658−1663. (e) Ji, Y.; Wojtas, L.;
Lopchuk, J. M. An improved, gram-scale synthesis of protected 3-
haloazetidines: Rapid diversified synthesis of azetidine-3-carboxylic
acids. ARKIVOC 2018, 2018, 195−214. (f) Alvernhe, G.; Laurent, A.;
Touhami, K.; Bartnik, R.; Mloston, G. Synthese de fluoro-3
azacyclanes: action de l’acide fluorhydriqiue les aza-1bicyclo[n.1.0]-
alcanes. J. Fluorine Chem. 1985, 29, 363−384. (g) Mloston, G.;
Woznicka, M.; Drabowicz, J.; Linden, A.; Heimgartner, H. Addition
Reactions of Sulfenyl and Sulfinyl Chlorides with 3-Phenyl-1-
azabicyclo[1.1.0]butane. Helv. Chim. Acta 2008, 91, 1419−1429.
(6) (a) Lopchuk, J. M.; Fjelbye, K.; Kawamata, T.; Malins, L. R.;
Pan, C.-M.; Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt,
T. A.; Collins, M. R.; Elleraas, J.; Ewanicki, J.; Farrell, W.; Fadeyi, O.
O.; Gallego, G. M.; Mousseau, J. J.; Oliver, R.; Sach, N. W.; Smith, J.
K.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S. Strain-Release
Heteroatom Functionalization: Development, Scope, and Stereo-
specificity. J. Am. Chem. Soc. 2017, 139, 3209−3226. (b) Gianatassio,
R.; Lopchuk, J. M.; Wang, J.; Pan, C.-M.; Malins, L. R.; Prieto, L.;
Brandt, T. A.; Collins, M. R.; Gallego, G. M.; Sach, N. W.; Spangler, J.
E.; Zhu, H.; Zhu, J.; Baran, P. S. Strain-release amination. Science
2016, 351, 241−246.
(7) (a) A 10% mixture of 3-phenyl azetidine and other products was
obtained under the optimized conditions without addition of an
electrophile. This was confirmed by comparison of an NMR of an
authentic sample of 3-phenyl azetidine which is commercially
available through several vendors. (b) Phenyllithium with and
without CuCN (100 mol %) and diphenylzinc produced complex
mixtures.
(8) (a) Travins, J. M.; Etzkorn, F. A. Facile synthesis of d-amino
acids from an l-serine-derived aziridine. Tetrahedron Lett. 1998, 39,
9389−9392. (b) Baldwin, J. E.; Farthing, C. N.; Russell, A. T.;
Schofield, C. J.; Spivey, A. C. Use of (S)-N-tert-butoxycarbonylazir-
idine-2-carboxylate derivatives for α−amino acid synthesis. Tetrahe-
dron Lett. 1996, 37, 3761−3764.
(9) (a) Carreira, E. M.; Fessard, T. C. Four-Membered Ring-
Containing Spirocycles: Synthetic Strategies and Opportunities.
́
Chem. Rev. 2014, 114, 8257−8322. (b) Burkhard, J. A.; Guerot, C.;
Knust, H.; Rogers-Evans, M.; Carreira, E. M. Synthesis and Structural
Analysis of a New Class of Azaspiro[3.3]heptanes as Building Blocks
for Medicinal Chemistry. Org. Lett. 2010, 12, 1944−1947.
(c) Burkhard, J. A.; Wagner, B.; Fischer, H.; Schuler, F.; Muller, K.;
̈
Carreira, E. M. Synthesis of Azaspirocycles and their Evaluation in
Drug Discovery. Angew. Chem., Int. Ed. 2010, 49, 3524−3527.
(d) Burkhard, J. A.; Carreira, E. M. 2,6-Diazaspiro[3.3]heptanes:
Synthesis and Application in Pd-Catalyzed Aryl Amination Reactions.
Org. Lett. 2008, 10, 3525−3526.
(10) (a) Chen, S.; Zhao, Y.; Wang, J. Preparation of Cyclic N-tert-
Butylsulfonyl Enamines by Rh(II)-Mediated Ring Expansion of α-
Diazoesters. Synthesis 2006, 2006, 1705−1710. (b) Armanino, N.;
D
DOI: 10.1021/acs.orglett.9b00321
Org. Lett. XXXX, XXX, XXX−XXX