Synthesis of C-substituted cyclic amines using azacycloalkyl organozinc reagents

Article abstract of DOI:10.1055/s-1998-37503

Azetidine and piperidine derived organozinc species have been prepared from the corresponding azacycloalkyl iodides by direct Zn insertion. They have been shown to readily undergo Pd⁽⁰⁾ mediated cross-coupling reactions and to transmetallate with CuCN.2LiCl.

Full text of DOI:10.1055/s-1998-37503

April 1998
SYNLETT
379
Synthesis of C-Substituted Cyclic Amines Using Azacycloalkyl Organozinc Reagents
S. Billotte
Discovery Chemistry, Pfizer Central Research, Sandwich, Kent, England, CT13 9NJ
Fax (0)1304 618422; stephane_billotte@sandwich.pfizer.com
Received 4 December 1997
Abstract: Azetidine and piperidine derived organozinc species have
been prepared from the corresponding azacycloalkyl iodides by direct
(0)
Zn insertion. They have been shown to readily undergo Pd mediated
cross-coupling reactions and to transmetallate with CuCN.2LiCl.
During the course of our studies towards new agents for the treatment of
1
asthma we became interested in preparing 3-(2-pyridyl) azetidines .
3-Aryl azetidines are generally synthesised by reduction of 3-aryl
2
azetidine-2-ones or base-mediated ring closure of the appropriate N-O-
ditosyl-2-aryl-3-amino-propan-1-ols . However, both routes rely on
non-readily accessible 2-aryl-2-cyanoacetates and require the use of
reagents which might not be suitable for substrates containing sensitive
functionalities.
Removal of the Boc protecting group from 3 under standard acidic
3
conditions gave 3-(2-pyridyl) azetidine dihydrochloride
quantitative yield (Scheme 3) .
4
in
Due to their high functional group tolerance, organozinc reagents are
4
attractive intermediates in C-C bond formation reactions , and we chose
to investigate the convergent synthesis of 3-(2-pyridyl) azetidines by the
(0)
Pd -mediated cross-coupling of an azetidinyl zincate reagent with a 2-
5
halopyridine. Previously Knochel had shown that Zn insertion into the
C-I bond of an acyclic ß-iodocarbamate was possible, although it was
not clear at the outset of our work whether a similar reaction could be
performed with cyclic substrates. Consequently, we targeted the
synthesis of the Boc-protected iodo-azetidine 1 and examined its
metallation with Zn. We felt that, if successful, this approach would also
allow access to a variety of 3-aryl azetidines (Scheme 1).
Scheme 3
Using this methodology we were then able to synthesise various 3-aryl-
N-Boc-azetidines and the results are summarized in Table 1. As
9
expected 2 showed wide functional group compatibility. For example,
no reaction on a nitrile group was observed (entry 3), and no attack on
the carbonyl group of ketone 9 was noticeable (entry 6). The low yield
for this acylation reaction might be explained by Zn promoted
10
competitive cleavage of the solvent (THF) by the acid chloride
.
Moreover, halopyridines showed greater reactivity towards 2 than aryl
iodides (entry 1 vs entry 2), although better yields were obtained with
aryl iodides bearing an electron-withdrawing group ( entry 3 vs entry 2).
The synthetic versatility of the organozinc reagent 2 was further
demonstrated by transmetallation with CuCN•2LiCl in THF generating
Scheme 1
7
a zinc-copper reagent which was trapped with allyl bromide to give 10
in moderate yield (Scheme 4).
The synthesis of 1 was achieved starting with N-benzhydrylazetidinyl-3
mesylate (Scheme 2). Removal of the benzhydryl group with α-
6
chloroethyl chloroformate (ACE-Cl) followed by Boc-protection
afforded N-Boc-azetidinyl-3 mesylate which reacted with KI in DMSO
at elevated temperature to give 1 in good yield. We were then pleased to
find that Zn insertion into the C-I bond of 1 could be achieved following
7
the procedure described by Knochel . Formation of the organozinc
species 2 was followed by TLC and was complete after 45 min. at room
temperature. This was confirmed by quenching the reaction mixture
1
with aqueous NH Cl followed by H NMR analysis of the crude organic
4
Scheme 4
phase showing N-Boc-azetidine as the main product. To our knowledge,
Zn insertion into azacycloakyl iodides is unprecedented. Having
established that we could easily prepare the organozinc reagent 2, our
attention was then directed to demonstrating that it could undergo Pd
mediated cross-coupling reactions.
Having shown that it is possible to access 3-substituted azetidines using
the organozinc reagent 2, we became interested in applying this
methodology to piperidines.
(0)
Thus, 2-bromopyridine was added to a freshly prepared solution of 2 in
THF and the mixture was heated at 65°C in the presence of Pd (dba)
Thus, 4-iodo-N-Boc-piperidine 11 was synthesised in two steps from 4-
piperidinol and converted to the organozinc species 12 using similar
conditions to those used to generate 2. As before, formation of 12 could
2
3
8
and P(2-furyl)
for 2 h. Using this procedure N-Boc-3-(2-
3
pyridyl)azetidine 3 was isolated in 63% yield after chromatography.

380
LETTERS
SYNLETT
In summary, we have developed a general and practical method for
preparing C-substituted 3-azetidines and 4-piperidines via the
corresponding organozinc reagents, and we envisage that this
methodology should be applicable to a wider range of heterocycles.
Acknowledgments: I would like to acknowledge the support and
encouragement of S.M. Monaghan and A.R. MacKenzie, and the
technical assistance of S. Denton and P. Allen. Particular thanks to S.
Bailey for his guidance throughout this work.
References and notes
1.
For a review of the synthesis of azetidines see : Cromwell, N.H.;
Phillips, B. Chem.Rev. 1979, 79, 331.
2.
Testa, E.; Boneti, A.; Pagani, G.; Gatti, E. Justus Liebigs Ann.
Chem., 1961, 647, 92.
3.
4.
5.
Secor, H.V.; Edwards, W.B., III J.. Org. Chem., 1979, 44, 3136.
Knochel, P.; Singer, R.D. Chem. Rev., 1993, 93, 2117.
Duddu, R.; Eckhardt, M.; Furlong, M.; Knoess, H.P.; Berger, S.;
Knochel, P. Tetrahedron, 1994, 50, 2415.
6.
7.
For details of the synthesis of this compound see: Anderson, A.G.;
Lok, R. J. Org. Chem., 1972, 37, 3953.
Knochel, P.; Yeh, M.C.P.; Berk, S.C.; Talbert, J. J. Org. Chem.,
1988, 53, 2390.
8.
9.
Farina, V.; Krishnan, B. J. Am. Chem. Soc., 1991, 113, 9585.
Typical procedure: Zn dust (425 mgs, 6.5 mmoles) was stirred in
THF (1ml) under nitrogen and 1,2-dibromoethane (50 µls, 0.58
mmole) was added at room temperature. The mixture was heated
at 65°C for 3 min and allowed to cool to room temperature while
stirring. Trimethylsilyl chloride (70 µls, 0.55 mmole) was then
added and the mixture stirred at rt for 0.5 h. A solution of 3-iodo-
N-Boc-azetidine 1 (1.4 g, 5 mmoles) in THF (2.5 mls) was then
slowly added (gentle exotherm) and the reaction mixture allowed
1
be monitored by TLC and H NMR. The organozinc reagent 12 was
then found to exhibit a similar pattern of reactivity to the azetidine
analogue 2. Thus, reaction of 12 with ethyl 4-iodobenzoate and 2-
(0)
bromopyridine under Pd catalysis gave rise to the corresponding 4-
aryl piperidines in 47% and 70% respectively. 12 could also be allylated
to stir at room temperature for 45 min. Pd (dba) (45 mgs, 50
2
3
µmoles) and P(2-furyl) (46 mgs, 0.2 mmole) were mixed in THF
3
after transmetallation with CuCN•2LiCl (Scheme 5).
(1ml), the solution stirred at room temperature under nitrogen for
10 min and added to the organozinc reagent solution, followed by
iodobenzene (670 µls, 6 mmoles) in THF (10 mls). The mixture
was then heated at 65°C for 2 h, cooled, filtered over celite and the
filtrate diluted with EtOAc. The filtrate was washed with saturated
aqueous NaHCO (x2), brine, dried (Na SO ), filtered and
3
2
4
evaporated to yellow oil. Flash chromatography of this oil on SiO
2
(19:1 Hexane:EtOAc) afforded 3-phenyl-N-Boc azetidine 5 as a
colorless oil (540 mgs, 47%).
10. Bhar, S.; Ranu, B.C. J. Org. Chem., 1995, 60, 745.