Reactions of cyclopropanone acetals with alkyl azides: Carbonyl addition versus ring-opening pathways

Article abstract of DOI:10.1021/jo0711034

(Chemical Equation Presented) The Lewis acid-mediated reactions of substituted cyclopropanone acetals with alkyl azides were found to strongly depend on the structure of the ketone component. When cyclopropanone acetal was treated with alkyl azides, N-substituted 2-azetidinones and ethyl carbamate products were obtained, arising from azide addition to the carbonyl, followed by ring expansion or rearrangement, respectively. When 2,2-dimethylcyclopropanone acetals were reacted with azides in the presence of BF₃· OEt₂, the products obtained were α-amino-α′- diazomethyl ketones, which arose from C2-C3 bond cleavage of the corresponding cyclopropanone, giving oxyallyl cations that were captured by azides. Aryl-substituted cyclopropanone acetals, when subjected to these conditions, afforded [1,2,3]oxaborazoles exclusively, which were also the result of C2-C3 bond rupture, azide capture, and then loss of nitrogen. In the reactions of n-hexyl-substituted cyclopropanone acetals with alkyl azides, a mixture of 2-azetidinones and regioisomeric [1,2,3]-oxaborazoles was obtained. The reasons for the different behavior of the various systems are discussed.

Full text of DOI:10.1021/jo0711034

Reactions of Cyclopropanone Acetals with Alkyl Azides: Carbonyl
Addition versus Ring-Opening Pathways
Scott Grecian,† Pankaj Desai,† Craig Mossman,† Jennifer L. Poutsma,‡ and Jeffrey Aube´*,†
Department of Medicinal Chemistry, 1251 Wescoe Hall DriVe, Room 4070, Malott Hall, UniVersity of
Kansas, Lawrence, Kansas 66045-7582, and Department of Chemistry and Biochemistry, Old Dominion
UniVersity, 4541 Hampton BouleVard, Norfolk, Virginia 23529
jaube@ku.edu
ReceiVed May 24, 2007
The Lewis acid-mediated reactions of substituted cyclopropanone acetals with alkyl azides were found
to strongly depend on the structure of the ketone component. When cyclopropanone acetal was treated
with alkyl azides, N-substituted 2-azetidinones and ethyl carbamate products were obtained, arising from
azide addition to the carbonyl, followed by ring expansion or rearrangement, respectively. When 2,2-
dimethylcyclopropanone acetals were reacted with azides in the presence of BF3‚OEt2, the products obtained
were R-amino-R′-diazomethyl ketones, which arose from C2-C3 bond cleavage of the corresponding
cyclopropanone, giving oxyallyl cations that were captured by azides. Aryl-substituted cyclopropanone
acetals, when subjected to these conditions, afforded [1,2,3]oxaborazoles exclusively, which were also
the result of C2-C3 bond rupture, azide capture, and then loss of nitrogen. In the reactions of n-hexyl-
substituted cyclopropanone acetals with alkyl azides, a mixture of 2-azetidinones and regioisomeric [1,2,3]-
oxaborazoles was obtained. The reasons for the different behavior of the various systems are discussed.
SCHEME 1
Cyclopropanones display unusual properties arising from the
incorporation of the carbonyl group into a strained three-
membered ring.1 Initially, cyclopropanones attracted interest due
to their role as intermediates in Favorskii rearrangements.2 Since
then, there have been numerous experimental and theoretical
studies aimed at understanding the nature of cyclopropanone
reactivity.3 Inherently reactive, cyclopropanones are usually
generated in situ from the corresponding hemiketals (or their
derivatives), which are readily synthesized and easily handled
(Scheme 1).4 In general, the chemistry of cyclopropanones is
dominated by ketone addition or ring-opening to form oxyallyl
cations.5 The latter species can be trapped with a nucleophile6
or cyclized with a dipolarophile to give bicyclic ketones.7
In the 1970s, Wasserman et al. showed that cyclopropanones
react with sodium azide to afford â-lactams (Scheme 2).8 This
reaction presumably proceeds due to the release of strain upon
ring expansion coupled with the generation of nitrogen as the
byproduct. Our group has previously studied the intermolecular
* Address correspondence to this author. Phone: 785-864-4496. Fax: 785-
864-5326.
† University of Kansas.
(3) (a) Turro, N. J.; Edelson, S. S.; Williams, J. R.; Darling, T. R.;
Hammond, W. B. J. Am. Chem. Soc. 1969, 91, 2283-2292. (b) Liberles,
A.; Greenberg, A.; Lesk, A. J. Am. Chem. Soc. 1972, 94, 8685-8688. (c)
Zandler, M. E.; Choc, C. E.; Johnson, C. K. J. Am. Chem. Soc. 1974, 96,
3317-3319. (d) Turecek, F.; Drinkwater, D. E.; McLafferty, F. W. J. Am.
Chem. Soc. 1991, 113, 5950-5958. (e) Hess, B. A., Jr.; Eckart, U.; Fabian,
J. J. Am. Chem. Soc. 1998, 120, 12310-12315. (f) Hess, B. A., Jr.; Smentek,
L. Eur. J. Org. Chem. 1999, 3363-3367. (g) Lim, D.; Hrovat, D. A.;
Borden, W. T.; Jorgensen, W. L. J. Am. Chem. Soc. 1994, 116, 3494-
3499.
‡ Old Dominion University.
(1) (a) Turro, N. J. Acc. Chem. Res. 1969, 2, 25-23. (b) Turro, N. J.;
Gagosian, R. B.; Edelson, S. E.; Darling, T. R.; Williams, J. R.; Hammond,
W. B. T. Ann. N. Y. Acad. Sci. 1971, 33, 396-404. (c) Wasserman, H. H.;
Clark, G. M.; Turley, P. C. Top. Curr. Chem. 1974, 47, 73-156. (d) Salaun,
J. Chem. ReV. 1983, 83, 619-632.
(2) (a) Baretta, A.; Waegell, B. In ReactiVe Intermediates; Abromovich,
R. A., Ed.; Plenum Press: New York, 1982; Vol. 2, pp. 527-585. (b)
Moulay, S. Chem. Educ.: Res. Pract. Eur. 2002, 3, 33-64.
10.1021/jo0711034 CCC: $37.00 © 2007 American Chemical Society
Published on Web 11/07/2007
J. Org. Chem. 2007, 72, 9439-9447
9439

Grecian et al.
SCHEME 2
react in the presence of BF3‚OEt2. Although the expected ring-
expanded â-lactams 2 were consistently formed in 27-58%
yield, a significant amount of ethyl carbamate product of type
3 was also observed in every case (Table 1).
In an effort to increase the â-lactam yield, a variety of acids
such as TiCl4, SnCl4, BF3‚OEt2, TfOH, and TFA were surveyed.
Only BF3‚OEt2 was found to reproducibly provide the desired
products, although TFA also gave very low yields of â-lactam
and ethyl carbamate. The highest yields were obtained when
2.5 equiv of BF3‚OEt2 was used. Although the combined yield
of â-lactam and carbamates was good to excellent for the series
of alkyl azides examined (51-98% combined), we were unable
to obtain â-lactam products to the exclusion of carbamate
products, which in several cases were the major products.
In the case of â-lactam formation, typical azido-Schmidt
chemistry is at work: the azide attacks the ketone and the
ensuing azidohydrin collapses with the loss of nitrogen and
concomitant ring expansion to give â-lactams 2 (Scheme 3).9
The ethyl carbamates 3 could arise from an azidohydrin
intermediate that, instead of bond migration, undergoes ring-
opening to give a carbocation. This step is analogous to the
well-known cyclopropylcarbinyl cation homoallylic rearrange-
ment.11 Pirrung’s work in the study of ethylene biosynthesis
invokes a similar carbocation intermediate derived from 1-ami-
nocyclopropanecarboxylic acid, which fragments to produce
ethylene.12 Loss of ethylene provides an isocyanate that reacts
reaction of alkyl azides with cyclic ketones, which generally
leads to ring-expanded lactams in a process reminiscent of the
Schmidt reaction.9 Following Wasserman, we were initially
interested in reacting cyclopropanones with alkyl azides under
Lewis acidic conditions as a means of synthesizing N-substituted
â-lactams. In the course of this study, we discovered that the
Lewis acid promoted reactions of azides and cyclopropanones
provide a rich array of products that depend on the nature of
the cyclopropanone substitution. Previously, we disclosed that
the reactions of 2,2-dimethylcyclopropanone equivalents with
azides provide R-amino-R′-diazomethyl ketones.10 Herein, we
describe the results of a broader investigation on the reactions
of substituted cyclopropanones with alkyl azides. In so doing,
we describe several previously unknown reaction pathways that
result from both C1/C2 and C2/C3 bond rupture of the cyclo-
propanone reactant. The mechanisms of the various reactions
will also be discussed.
TABLE 1. Reactions of Cyclopropanone Acetal 1 with Azides
Results
Cyclopropanone Proper. As noted above, the present study
began as an attempt to make N-substituted â-lactams through
azide-mediated ring-expansion processes.9 To this end, a mixture
of cyclopropanone hemiketal and alkyl azide were allowed to
entry
R
product (yield, %)
a
b
c
d
e
f
C6H5CH2
n-C6H14
2a (45)
3a (13)
3b (40)
3c (60)
3d (35)
3e (43)
3f (34)
2b (58)
2c (36)
2d (27)
2e (38)
2f (45)
3-MeO(C6H4)CH2
4-MeO(C6H4)CH2
4-MeO2C(C6H4)CH2
4-Br(C6H4)CH2
(4) (a) McElvain, S. M.; Weyna, P. L. J. Am. Chem. Soc. 1959, 81,
2579-2588. Dull, M. F.; Abend, P. G. J. Am. Chem. Soc. 1959, 81, 2588-
2591. (b) Giusti, G.; Morales, C. Bull. Soc. Chim. Fr. 1973, 382-387. (c)
Rousseau, G.; Slougui, N. Tetrahedron Lett. 1983, 24, 1251-1254. (d)
Salaun, J.; Marguerite, J. Org. Synth.; Wiley: New York, 1989; Collect.
Vol. VII, pp 131-134.
(5) (a) Wasserman, H. H.; Clagett, D. C. J. Am. Chem. Soc. 1966, 88,
5368-5369. (b) Wasserman, H. H.; Cochoy, R. E.; Baird, M. S. J. Am.
Chem. Soc. 1969, 91, 2375-2376. (c) Wasserman, H. H.; Baird, M. S.
Tetrahedron Lett. 1971, 3721-3724. (d) Van Tilborg, W. J. M.; Steinberg,
H.; De Boer, T. J. Synth. Commun. 1973, 3, 189-196. (e) Wasserman, H.
H.; Glazer, E. J. Org. Chem. 1975, 40, 1505-1506.
SCHEME 3
(6) Turro, N. J.; Hammond, W. B. Tetrahedron 1968, 24, 6017-6028.
(7) (a) Turro, N. J.; Hammond, W. B. J. Am. Chem. Soc. 1967, 89, 1028-
1029. (b) Hess, B. A., Jr.; Eckart, U.; Fabian, J. J. Am. Chem. Soc. 1998,
120, 12310-12315. (c) Cho, S. Y.; Lee, H. I.; Cha, J. K. Org. Lett. 2001,
3, 2891-2893.
(8) (a) Wasserman, H. H.; Adickes, H. W.; Espejo de Ochoa, O. J. Am.
Chem. Soc. 1971, 93, 5586-5587. (b) Wasserman, H. H.; Baird, M. S.
Tetrahedron Lett. 1971, 3721-3724. (c) Wasserman, H. H.; Glazer, E. A.;
Hearn, M. J. Tetrahedron Lett. 1973, 4855-4858. (d) Wasserman, H. H.;
Glazer, E. J. Org. Chem. 1975, 40, 1505-1506.
(9) (a) Aube´, J.; Milligan, G. L. J. Am. Chem. Soc. 1991, 113, 8965-
8966. (b) Aube´, J.; Milligan, G. L.; Mossman, C. J. J. Org. Chem. 1992,
57, 1635-1637. (c) Aube´, J.; Rafferty, P. S.; Milligan, G. L. Heterocycles
1993, 35, 1141-1147. (d) Milligan, G. L.; Mossman, C. J.; Aube´, J. J.
Am. Chem. Soc. 1995, 117, 10449-10459. (e) Mossman, C. J.; Aube´, J.
Tetrahedron 1995, 52, 3403-3408. (f) Gracias, V.; Frank, K. E.; Milligan,
G. L.; Aube´, J. Tetrahedron 1997, 53, 16241-16252. (g) Forsee, J. E.;
Smith, B. T.; Frank, K. E.; Aube´, J. Synlett 1998, 1258-1260. (h)
Schildknegt, K.; Agrios, K. A.; Aube´, J. Tetrahedron Lett. 1998, 39, 7687-
7690. (i) Desai, P.; Schildknegt, K.; Agrios, K. A.; Mossman, C.; Milligan,
G. L.; Aube´, J. J. Am. Chem. Soc. 2000, 122, 7226-7232.
(10) Desai, P.; Aube´, J. Org. Lett. 2000, 2, 1657-1659.
9440 J. Org. Chem., Vol. 72, No. 25, 2007

Reactions of Cyclopropanone Acetals with Alkyl Azides
TABLE 2. Reactions of Azides with Cyclopropanone Acetal 4
SCHEME 4
entry
R
product (yield, %)
a
b
c
d
e
f
C6H5CH2
5a (47)
6a (4)
4-Br(C6H4)CH2
4-MeO2C(C6H4)CH2
2-naphthyl
9-anthracenyl
n-C6H14
5b (41)
5c (46)
5d (38)
5e (54)
5f (44)
6d (5)
with ethanol to give the product. Other mechanisms that include
concerted cheletropic elimination of ethylene could also be
envisioned. We did not pursue extensive mechanistic study of
this interesting, if not especially useful, process.
2,2-Dimethylcyclopropanone. To extend the above study to
encompass differently substituted cyclopropanones, we treated
triethyl(1′-methoxy-2′,2′-dimethylcyclopropoxy)silane 4 with 2.0
equiv of benzyl azide and 1.0 equiv of BF3‚OEt2 in CH2Cl2
(-78 °C to rt, 12 h).10 Workup followed by chromatography
provided two products, neither of which was the â-lactam or
carbamate anticipated from the previous study. Specifically, the
IR spectra lacked the characteristic carbonyl â-lactam stretching
frequency at ca. 1740 cm-1, but instead had two strong
absorbances at 2099 and 1633 cm-1. In addition, the 13C NMR
spectrum contained a ketone signal at 201 ppm and the mass
spectrum indicated the retention of all three nitrogen atoms in
the major product. Unfortunately, the 1H NMR spectrum
provided almost no connectivity information, consisting mainly
of singlets at 1.3, 3.7, and 6.0 ppm. In contrast, the minor
product, (in 4% yield) was readily identified as the known
N-benzyl-2,2-dimethyl-3-azetidinone13 by NMR and IR spec-
troscopy. In particular, the IR spectrum contained a prominent
absorption at 1840 cm-1, while the 13C NMR spectrum
contained a carbonyl resonance at 209.1 ppm. After some
experimentation, the identity of the major product was confirmed
through X-ray crystallographic analysis of the product isolated
from the reaction of cyclopropanone acetal 4 with p-car-
bomethoxybenzyl bromide (5c, Table 2).
to yield the corresponding oxyallyl cation.7,14 We propose that
the cation-stabilizing character of the two methyl groups allowed
this pathway to predominate over azide addition to the carbo-
nyl.15 The oxyallyl cation could then react with the alkyl azide
in several ways (Scheme 4). A stepwise pathway involving
nucleophilic attack of the azide on the most-substituted carbon
of the oxyallyl cation providing A, followed by electrophilic
capture by the azide of the resulting anion, could give rise to
the 1,2,3-triazin-5-one intermediate B. In principle, this order
of events could also be reversed as azides have both nucleophilic
and electrophilic tendencies.16 Intermediate B could also result
from a concerted [3 + 3] cycloaddition (path a′) or from a
[3 + 2] cycloaddition of azide with the oxyallyl cation, followed
We surveyed a variety of alkyl azides in this reaction. The
R-amino-R′-diazomethyl ketones were obtained in ca. 40-50%,
but the 3-azetidinone was formed only occasionally and in low
yield (Table 2). After a brief survey of acids and various
conditions, we found that our initial conditions gave the highest
yields and that BF3‚OEt2 was the only acid that led to these
products, while other conditions resulted only in decomposition
of the starting materials.
The retention of all three nitrogen atoms of the alkyl azide
in products 5 suggested that this conversion involved the acid-
promoted C2-C3 bond cleavage of 2,2-dimethylcyclopropanone
(11) (a) Olah, G. A.; Kelly, D. P.; Jeuell, C. L.; Porter, R. D. J. Am.
Chem. Soc. 1970, 92, 2544-2546. (b) Mayr, H.; Olah, G. A. J. Am. Chem.
Soc. 1977, 99, 510-513. (c) Olah, G. A.; Liang, G.; Ledlie, D. B.;
Costopoulos, M. G. J. Am. Chem. Soc. 1977, 99, 4196-4198. (d) Olah, G.
A.; Reddy, V. P.; Prakash, G. K. S. Chem. ReV. 1992, 92, 69-95.
(12) (a) Pirrung, M. C. J. Am. Chem. Soc. 1983, 105, 7207-7209. (b)
Pirrung, M. C. Acc. Chem. Res. 1999, 32, 711-718.
(14) Bakker, B. H.; van Ramesdonk, H. J.; Steinberg, H.; de Boer, T. J.
Recl. TraV. Chim. Pays-Bas 1975, 94, 64-69.
(15) (a) Deno, N. C.; Jaruzelski, J. J.; Schriesheim, A. J. Am. Chem.
Soc. 1955, 77, 3044-3051. (b) Arnett, E. M.; Hofelich, T. C. J. Am. Chem.
Soc. 1983, 105, 2889-2895.
(16) For an outstanding recent review of alkyl azide chemistry, see:
Bra¨se, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew. Chem., Int. Ed.
2005, 44, 5188-5240.
(13) Katritzky, A. R.; Cundy, D. J.; Chen, J. J. Heterocycl. Chem. 1994,
31, 271-275.
J. Org. Chem, Vol. 72, No. 25, 2007 9441

Grecian et al.
SCHEME 5
SCHEME 6
by 1,2-migration of the resulting triazole cation C (path b).
Another possibility is that azide attacks at the unsubstituted
terminus of the oxyallyl cation followed by allylic transposition,
giving rise to A (path c).17 We do not currently have strong
evidence to rule out any of these possibilities, although we did
attempt to react the bromo silyl enol ether shown in Scheme 5
with benzyl azide under a variety of conditions.18 We were
unable to isolate any product from these reactions. Although
the intermediacy of C cannot be completely ruled out, we favor
the stepwise or concerted formation of B via paths a/a′ due to
the observation of similar intermediates under other conditions
(Scheme 6). Thus, in work reported by Pearson, azido-tethered
indoles were submitted to acidic conditions to afford triazines
incorporated into a complex indole-containing framework.19a
Schultz et al. also reported tetracyclic triazines arising from a
photoinduced cycloaddition of an azido-tethered quinone.19b,c
Recently, West and co-workers found that Nazarov intermediates
derived from dienones could be trapped with pendant azides
when treated with BF3‚OEt2 leading to a variety of products.19d,e
They propose two possible mechanisms to account for their
observations: (1) direct attack of the proximal nitrogen of this
azide onto the oxyallyl cation to give a boron enolate/diazo
cation species or (2) [3 + 3] cycloaddition of the tethered azide
with the oxyallyl cation followed by ring opening of the 1,2,3-
triazin-5-one to provide the same enolate cation.
We neither observed nor isolated 1,2,3-triazin-5-ones in any
of our experiments. However, their involvement is strongly
suggested by the observation of products 5 and 6. We propose
that fragmentation of the 1,2,3-triazin-5-one followed by proton
transfer gives products 5 (Scheme 4, above). The difference in
reactivity between the triazines formed in the present project
and those reported by Schultz and Pearson may be ascribed to
stabilization of the latter through electronic means or by virtue
of their presence in more complex ring systems. We also note
that the Schultz experiment was done under photochemical, not
Lewis acid-mediated, conditions.
The small amount of 3-azetidinones 6 isolated in two of these
reactions could conceivably arise from the direct cyclization
reaction of intermediate D or from the acid-promoted decom-
position of 5 (Scheme 4). We did not observe formation of
3-azetidinone after isolating ketone 5a and resubmitting it to
the acidic reaction conditions for several days, which suggests
that 6a and 6d arise directly from D as shown. R-Amino-R′-
diazomethyl ketones are known precursors to 3-azetidinones by
metallocarbene-mediated NH insertion reactions.20 Therefore,
we treated R-amino-R′-diazomethyl ketones 5 with Rh2(OAc)4,
which afforded the cyclized products 6 in high yield (Table 3).
Aryl-Substituted Cyclopropanones. The observation of ring-
opening products from 2,2-dimethyl-substituted cyclopropanone,
but not from the parent ring system suggested that the former
pathway was favored by the ability of the methyl groups to
stabilize the oxyallyl cation intermediate. If so, we reasoned
that a phenyl group might be able to play a similar role. Thus,
triethyl(1-methoxy-2-phenylcyclopropoxy)silane21 7 was treated
with 2.0 equiv of benzyl azide and 1.0 equiv of BF3‚OEt2 in
CH2Cl2 (-78 °C to rt, 12 h). After NaHCO3 workup and silica
TABLE 3. Rh2(OAc)4-Catalzyed Cyclization of 5
(17) Attack of nucleophiles at the terminal end of an azide, i.e., as seen
in the Staudinger reaction, is known: Nyffeler, P. T.; Liang, C. H.; Koeller,
K. M.; Wong, C. H. J. Am. Chem. Soc. 2002, 124, 10773-10778 and
references cited therein.
(18) Sakurai, H.; Shirahata, A.; Hosomi, A. Angew. Chem., Int. Ed. 1979,
91, 178-179.
(19) (a) Pearson, W. H.; Fang, W.-k.; Kampf, J. W. J. Org. Chem. 1994,
59, 2682-2684. (b) Schultz, A. G.; Myong, S. O.; Puig, S. Tetrahedron
Lett. 1984, 25, 1011-1014. (c) Schultz, A. G.; Macielag, M.; Plummer,
M. J. Org. Chem. 1988, 53, 391-395. (d) Rostami, A.; Wang, Y.; Arif, A.
M.; McDonald, R.; West, F. G. Org. Lett. 2007, 9, 703-706. (e) Song, D.;
Rostami, A.; West, F. G. J. Am. Chem. Soc. 2007, 129, 12019-12022.
(20) (a) Regitz, M.; Maas, G. Diazo Compounds: Properties and
Synthesis; Academic: Orlando, FL, 1986; p 596. (b) Baumann, H.; Duthaler,
R. O. HelV. Chim. Acta 1988, 71, 1035-1041. (c) Podlech, J.; Seebach, D.
HelV. Chim. Acta 1995, 78, 1238-1246. (d) Axenrod, T.; Watnick, C.;
Yazdekhasti, H.; Dave, P. R. J. Org. Chem. 1995, 60, 1959-1964.
entry
R
product (yield %)
a
b
c
d
e
f
C6H5CH2
6a (90)
6b (87)
6c (77)
6d (95)
6e (100)
6f (72)
4-Br(C6H4)CH2
4-MeO2C(C6H4)CH2
2-naphthyl
9-anthracenyl
n-C6H14
9442 J. Org. Chem., Vol. 72, No. 25, 2007

Reactions of Cyclopropanone Acetals with Alkyl Azides
TABLE 4. Reactions of Azides with Cyclopropanone Acetals 7 and
8
FIGURE 1. Examples of known [1,2,3]oxaborazole analogues.
gel chromatography, a light yellow solid was obtained. In light
of the previously described experiments, we had expected to
obtain an R-amino-R′-diazomethyl ketone or a 2- or 3-azetidi-
none from this experiment. However, the spectral data obtained
for the reaction product ruled out all of these possibilities. Both
IR and 13C NMR spectra indicated the lack of a carbonyl group.
Additionally, the absorbance corresponding to the diazoalkane
group at ca. 2100 cm-1 was lacking. Interestingly, the product
from this reaction fluoresced strongly under ultraviolet radiation,
giving a bright blue spot when irradiated. As before, only
reactions promoted by BF3‚OEt2 gave the observed products.
In particular, other boron-containing Lewis acids including BBr3
and BCl3 did not lead to the formation of any tractable products.
An X-ray crystallographic analysis of the product resulting
from reaction of cyclopropanone acetal 8 with phenylethyl azide
was performed following recrystallization from Et2O/CH2Cl2.
The product obtained was a [1,2,3]oxaborazole in which oxygen
and boron form a complex and nitrogen and boron share a
coordinate covalent bond (Table 4). This unusual heterocycle
9 had incorporated a stoichiometric quantity of BF2, readily
explaining why using more than 1 equiv of BF3‚OEt2 gave better
yields and why only boron-based Lewis acids led to formation
of this product. These 1,2,3-oxaborazoles proved remarkably
stable, surviving chromatography, extended heating, and strongly
basic conditions.22 Related heterocycles have been used as
fluorescent probes and participate in phototriggered [2 + 2]
cycloadditions (Figure 1).23
entry
cyclopropanone
R2
product (yield %)
a
b
c
d
e
f
7
7
7
7
8
8
8
C6H5CH2
9a (50)
9b (40)
9c (44)
9d (50)
9e (40)
9f (32)
9g (30)
4-Br(C6H4)CH2
C6H5CH2CH2
n-C6H14
C6H5CH2
4-Br(C6H4)CH2
C6H5CH2CH2
g
SCHEME 7
A series of these products was generated in yields ranging
from 32% to 50% when 1.5 equiv of BF3‚OEt2 was used. We
also noted that both phenyl- and p-methoxyphenyl-substituted
cyclopropanone acetals gave comparable yields, suggesting that
the electronic differences between these two cyclopropanones
did not significantly affect reaction outcome (Table 4). These
reactions could be conveniently performed in a microwave
reactor (135 °C, CH2Cl2, 10 min) to give the same products in
comparable or slightly higher yield in much less time.24 Last,
(21) Rousseau, G.; Slougui, N. Tetrahedron Lett. 1983, 24, 1251-1254.
(22) (a) White, D. L.; Faller, J. W. Inorg. Chem. 1982, 21, 3119-3122.
(b) Joseph-Nathan, P.; Garibay, M. E.; Santillan, R. L. J. Org. Chem. 1987,
52, 759-763. (c) Yuan, G.; Jiang, M.; Zhang, G. Wuji Huaxue Xuebao
1990, 6, 314-318. (d) Joseph-Nathan, P.; Burgueno-Tapia, E.; Santillan,
R. L. J. Nat. Prod. 1993, 56, 1758-1765. (e) Patel, B. P. U.S. Patent
5348948, 1994. (f) Agustin, D.; Rima, G.; Gornitzka, H.; Barrau, J.
Organometallics 2000, 19, 4276-4282. (g) Hopfl, H.; Barba, V.; Vargas,
G.; Farfan, N.; Santillan, R.; Castillo, D. Chemistry of Heterocyclic
Compounds; Wiley: New York, 2000; Vol. 35, pp 912-927. (h) Ramos,
J.; Soderquist, J. A. ARKIVOC 2001, 43-58. (i) Tavassoli, A.; Benkovic,
S J. WO Patent 2003059916, 2003.
(23) (a) Chow, Y. L.; Cheng, X. Chem. Commun. 1990, 1043-1045.
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Laage, E.; Allemand, J.-F.; Ruel, O.; Baudin, J.-B.; Croquette, V.;
Blanchard-Desce, M.; Jullien, L. Chem. Eur. J. 2004, 10, 1445-1455.
(24) (a) Kingston, H. M.; Haswell, S. J., Eds. MicrowaVe-Enhanced
Chemistry: Fundamentals, Sample Preparation, and Applications; American
Chemical Society: Washington, DC, 1997. (b) Lidstrom, P.; Tierney, J.;
Wathey, B.; Westman, J. Tetrahedron 2001, 57, 9225-9283. (c) Loupy,
A. MicrowaVes in Organic Synthesis; Wiley-VCH: Weinheim, Germany,
2002.
variation of the acetal function did not appreciably affect the
reaction. Reactions in which the trimethylsilyl acetal or the
hemiketal of 7 were used provided the corresponding 1,2,3-
oxaborazoles 9 in yields comparable to those employing
triethylsilyl acetals ((5% in each case).
The observation of oxaborazoles is consistent with either a
1,2,3-triazin-5-one intermediate B or nucleophilic attack with
azide onto the oxyallyl cation, the latter of which directly affords
a boron enolate diazonium cation A (Scheme 7). The 1,2,3-
triazin-5-one, if formed, may then undergo ring opening to form
A as well. Although azide may add to either terminus of the
oxyallyl cation, only oxaborazoles 9 corresponding to azide
addition to the unsubstituted terminus were
J. Org. Chem, Vol. 72, No. 25, 2007 9443

Grecian et al.
SCHEME 8
SCHEME 9
observed. It appears that only one mode of addition is favored
(kinetically or thermodynamically) or the azide addition step is
reversible and elimination of Ha is faster than elimination of
Hb. This regiochemistry issue and the comparison of these results
with those obtained from 2,2-dimethylcyclopropanone 4 will
be discussed below.
The 1,2,3-oxaborazoles are formal equivalents of an activated
iminium ion and an enolate coordinated by a Lewis acid. We
wondered if these compounds might display reactivity charac-
teristic of either species, or conceivably of an amine-stabilized
oxyallyl cation.25 With approximately a gram of 1,2,3-oxabo-
razole 9a at our disposal, a variety of reaction types were
surveyed, including reactions with alkyl lithiums, Grignards,
carbenes, and dipolarophiles. In only one case was reaction with
this heterocycle observed. Thus, subjecting the 1,2,3-oxaborazole
9a to acidic ethanolic conditions furnished the 1,2 keto acetal
10 in ca. 100% yield (Scheme 8).
SCHEME 10
Monoalkyl Cyclopropanones. We also examined the analo-
gous reactions of singly substituted cyclopropanone acetals.
Thus, we treated trimethyl(1-methoxy-2-heptylcyclopropoxy)-
silane21 11 with 2.0 equiv of benzyl azide and 1.5 equiv of
BF3‚OEt2 in CH2Cl2 (-78 °C to rt, 12 h). These conditions did
not result in any isolable product or recovery of the starting
material. In contrast, heating the components with BF3‚OEt2 at
135 °C for 30 min afforded small amounts of â-lactam 12 and
1,2,3-oxaborazole 13. Extensive optimization attempts did not
result in greater than ca. 15% total yields (Scheme 9). The
reaction products from phenylethyl azide were constitutionally
isomeric adducts of the 1,2,3-oxaborazoles 14a (ca. 4:1 Z:E)
and 14b, which were obtained in 6% and 5% yields, respec-
tively. However, no â-lactam was obtained from this particular
reaction. Due to the poor yields, we opted not to study this
cyclopropanone further.
It appears that a bifurcation between two poorly productive
mechanistic pathways occurs in these examples (Scheme 10).
Thus, Schmidt ring-expansion chemistry leading to â-lactam
12, as well as ring-opening processes leading to constitutionally
isomeric 1,2,3-oxaborazoles 13, 14a, and 14b were noted. The
observation of two regioisomeric 1,2,3-oxaborazoles obtained
from the reaction of 11 and phenylethyl azide can be ascribed
to the nonspecific formation of boron enolate diazo cation
intermediates, each having a proton adjacent to the N-N bond.
As before, triazinone involvement is possible here but not
necessary (and not depicted in Scheme 10).
lactams, carbamates, R-amino-R′-diazomethyl ketones, 3-aze-
tidinones, and [1,2,3]oxaborazoles). The first two of these were
only observed in reasonable yields when cyclopropanone itself
was used as the ketone substrate. On the other hand, substituted
cyclopropanone acetals underwent ring-opening and provided
R-amino-R′-diazomethyl ketones, 3-azetidinones, and [1,2,3]ox-
aborazoles. In these cases, ring opening to afford an oxyallyl
cation is favored by stabilization of the oxyallyl cation by the
attachment of alkyl or aryl groups. Additionally, the increased
steric bulk provided by the cyclopropaneone substitutents may
disfavor the direct nucleophilic addition of azide to the ketone.
Whether the oxyallyl cation affords R-amino-R′-diazomethyl
ketones or 1,2,3-oxaborazoles depends on whether there is a
proton R to the ketone and upon the regiochemistry of azide
addition to the oxyallyl cation. Consider the example of 2,2-
dimethylcyclopropanone, which affords R-amino-R′-diazomethyl
ketones 5 along with small amounts of 3-azetidinones 6 (Scheme
11). The dimethyl-substituted oxyallyl cation is able to undergo
attack by azide to afford two sets of regioisomeric products.
One set consists of azide addition product A along with the
Discussion
Five chemotypes of products were observed from the Lewis
acid-promoted reactions of azides with cyclopropanones (â-
(25) (a) Xiong, H.; Huang, J.; Ghosh, S. K.; Hsung, R. P. J. Am. Chem.
Soc. 2003, 125, 12694-12695. (b) Rameshkumar, C.; Hsung, R. P. Angew.
Chem., Int. Ed. 2004, 43, 615-618.
9444 J. Org. Chem., Vol. 72, No. 25, 2007

Reactions of Cyclopropanone Acetals with Alkyl Azides
SCHEME 11
SCHEME 12
be understood on the basis of frontier orbital considerations.26,27
Thus, B3LYP/6-31+G(d) calculations were performed on the
three oxyallyl cations shown in Figure 2 and methyl azide
(Figure 3).28 For oxyallyl cation a, the structure shown in Figure
2 was the only conformer that could be located at this level of
theory. At the RHF/6-31G(d) level of theory, a second con-
former had been located, while no conformers could be found
at the MP2/6-31G(d) level of theory. For b, only one conformer
could be located at all levels of theory. Three conformers were
found for oxyallyl cation c at all levels of theory. The lowest
energy conformer for the phenyl-substituted oxyallyl cation c
is depicted in Figure 2. This could mean that dimethyl- and
phenyl-substituted analogues a and c are more stable than the
methyl oxyallyl cation b. All structures were confirmed to be
ground state structures via frequency calculations. For a
particular molecular orbital, the coefficients for each atom were
calculated by summing the squares of the coefficients for each
basis set orbital on that atom.
analogous product of concerted [3 + 3] addition B; note that
exclusive attack of electrophiles on the proximal nitrogen of
the azide is well-precedented and also supported by theory (see
below). The alternative regioisomeric products A′ and B′ are
also possible, in principle. In this set of reactions, the formation
of the observed products 5 and 6 requires the intermediacy of
B, which can break down as indicated in Scheme 4. However,
note that the alternative regioisomer B′ cannot afford an isomeric
R-amino-R′-diazomethyl ketone because doing so would require
the cleavage of a C-Me bond. Furthermore, either A′ or B′
could lead to an alternative 1,2,3-oxazaboroline product as
shown at the bottom of Scheme 11. Thus, a key factor that
determines the product profile in this reaction is the apparently
exclusive formation or preferred reaction of regioisomers A or
B in lieu of A′ or B′.
The aryl- or alkyl-monosubstituted examples could in prin-
ciple lead to any of the observed products because of the
presence of at least one proton at either side of the ketone
(Scheme 12). However, the lack of any R-amino-R′-diazomethyl
ketone products analogous to 5 suggests that this pathway is
intrinsically less favorable than the alternative loss of a proton
and formation of 1,2,3-oxaborazole. For the observed products
9, 13, or 14, the intermediacy of a 1,2,3-triazin-5-one intermedi-
ate (B in Scheme 7) is permitted but not required, while the
intermediacy of A or A′ is essential.
Taken together, these results suggested that we address the
source of the apparent regiochemical differences between
cyclopropanones bearing 2,2-dimethyl vs 2-aryl vs 2-alkyl
substitution. To this end, we carried out preliminary ab initio
calculations to determine whether the regiochemical trends might
FIGURE 2. Low-energy conformations used for the calculation of
oxyallyl LUMO coefficients.
In all cases, the energy gap between the HOMO of the methyl
azide and the LUMO of the oxyallyl cation was much smaller
(27) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb,
M. A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.;
Stratmann, R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A.
D.; Kudin, K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi,
M.; Cammi, R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.;
Ochterski, J.; Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick,
D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.;
Ortiz, J. V.; Baboul, A. G.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz,
P.; Komaromi, I.; Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-
Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P.
M. W.; Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Gonzalez,
M.; Head-Gordon, M.; Replogle, E. S.; Pople, J. A. Gaussian 98, Revision
A.11; Gaussian, Inc.: Pittsburgh, PA, 2001.
(26) Walters, M. A.; Arcand, H. R. J. Org. Chem. 1996, 61, 1478-
1486.
J. Org. Chem, Vol. 72, No. 25, 2007 9445

Grecian et al.
TABLE 5. B3LYP/6-31+G* Molecular Orbital Coefficients for the
LUMOs of Oxyallyl Cations
(Scheme 7). However, the present studies do not address the
likelihood of this possibility. The presence of the phenyl group
could also stabilize the oxyallyl cation and contribute to the
reversibility of the initial reaction.
Summary
The Lewis acid-mediated reactions of cyclopropanones with
alkyl azides provide access to a variety of distinct products.
Marked differences in reaction course and regiochemistry were
encountered depending on the substitution pattern of the starting
cyclopropanone acetal. We believe that the products obtained
from the reactions described in this paper are the result of
divergent reaction pathways (1) exploiting the “traditional”
ketone behavior for unsubstituted cyclopropanone, providing
2-azetidinone and carbamates, and (2) the oxyallyl cationic
behavior of substituted cyclopropanones. In these cases, the
nature of the oxyallyl cation appears to affect the regiochemistry
of azide addition and whether the products are R-amino-R′-
diazomethyl ketones or 1,2,3-oxaborazoles. The regiochemistry
of azide addition appears to be in accordance with simple FMO
theory, although that method does not fully address the situation
with the phenyl case. To that end, future studies will include a
full ab initio study of the various pathways in hopes of
understanding the mechanisms of this suite of reactions and how
they are modulated by substitution.
LUMO coefficients
oxyallyl
entry
cation
R1
R2
C(1)
C(3)
1
2
3
a
b
c
CH3
CH3
C6H5
CH3
H
H
0.51
0.38
0.26
0.23
0.30
0.23
FIGURE 3. B3LYP/6-31+G* molecular orbital coefficients for the
HOMOs of methyl azide.
than the energy gap between the LUMO of the methyl azide
and the HOMO of the oxyallyl cation.29 The coefficients of the
HOMO of methyl azide and the LUMO of the oxyallyl cation,
reported in Table 5, suggest that both orbitals are similar to the
allyl nonbonding orbital.30 For methyl azide, the proximal
nitrogen has a larger coefficient than the distal nitrogen (Figure
3).31 It is likely that the same regioisomeric preferences would
be observed regardless of stepwise nucleophilic attack of azide
upon oxyallyl cation or in a HOMOazide-LUMOoxyallyl cation
controlled [3 + 3] concerted reaction.
The calculated LUMO coefficients for oxyallyl cation a are
in line with the results obtained with this substrate: R-amino-
R′-diazomethyl ketones, which result from proximal azide attack
at C1, were exclusively observed. The small difference in the
calculated LUMO cofficients at C1 and C3 for oxyallyl cation
b is likewise consistent with nonspecific formation of a mixture
of constitutionally isomeric 1,2,3-oxaborazoles 13 and 14.
Furthermore, the apparent lack of stability of the oxyallyl cation
b may be reflected in the poor efficiency of these reactions.
This same effect could also contribute to the small amount of
3-azetidone 12 observed by making the ring opening to the
oxyallyl cation less favorable in comparison to ketone addition.
The most difficult case to understand is that of the oxyallyl
cation c derived from phenylcyclopropanone. This species has
comparable LUMO coefficients at C1 and C3, yet a single 1,2,3-
oxaborazole consistent with proximal bond formation of the
azide onto the oxyallyl cation at C-3 was formed in its reactions
with alkyl azides. There are several possible explanations for
this outcome. Since the LUMO coefficients at C1 and C3 are of
comparable magnitude, a simple steric bias may override any
small electronic preference for attack at C1. On the other hand,
it is possible that the initial addition reaction or even the [3 +
3] reaction is reversible and that the elimination of a proton Hb
from intermediate A′ is favored over the alternative loss of Ha
Experimental Section
General Procedure for the Preparation of â-Lactam and
Ethyl Carbamate Products. To a solution of alkyl azide (2.0
equiv) in 8 mL of CH2Cl2 at 0 °C was added [(1-ethoxycyclopro-
pyl)oxy]trimethylsilane (1.0 equiv). The mixture was stirred for
10 min and BF3‚OEt2 (2.5 equiv) was added dropwise; gas evolution
was observed. The reaction was allowed to warm to room
temperature and stirred for 20 h at which time 10 mL of saturated
NaHCO3 and 10 mL of CH2Cl2 were added. The aqueous layer
was extracted with CH2Cl2 (4 × 10 mL), and the combined organic
layers were washed with brine and dried over anhydrous MgSO4.
Concentration followed by chromatography (20% EtOAc/hex)
afforded the â-lactam and ethyl carbamate products.
N-Phenylmethylazetidin-2-one (2a). Clear oil (45%). Known
compound.32
N-Phenylmethylcarbamic Acid Ethyl Ester (3a). Clear oil
(13%). Known compound.33
General Procedure for the Reaction of Triethyl(1-methoxy-
2,2-dimethylcyclopropoxy)silane with Alkyl Azides. Triethyl(1-
methoxy-2,2-dimethylcyclopropoxy)silane (1.0 equiv) was added
to a solution of alkyl azide (2.0 equiv) in CH2Cl2 (5 mL). The
reaction mixture was cooled to -78 °C and BF3‚OEt2 (1.0 equiv)
was added dropwise. The reaction was allowed to warm to room
temperature and stirred overnight, at which time it was poured into
saturated NaHCO3 (10 mL) and extracted with CH2Cl2 (3 × 10
mL). The organic layer was then dried with MgSO4 and evaporated
to provide a residue that was purified by flash chromatography (20%
EtOAc/hex).
1-Diazo-3-methyl-3-phenylaminobutan-2-one (5a): yellow oil
(47%); Rf 0.06 (20% EtOAc/hex); IR (neat) 3326, 2099, 1633 cm-1
;
1H NMR (400 MHz, CDCl3) 7.37-7.26 (m, 5H), 5.96 (br s, 1H),
3.66 (s, 2H), 1.60 (br s, 1H), 1.34 (s, 6H); 13C NMR (400 MHz,
CDCl3) 201.3, 140.7, 128.9, 128.4, 127.5, 62.6, 52.2, 48.6, 25.8;
CIMS m/z (rel intensity) 218 (MH+, 100), 190 (97); HRMS calcd
for C12H16N3O 218.1293, found 218.1268.
(28) Cramer, C. J.; Barrows, S. E. J. Phys. Org. Chem. 2000, 13, 176-
186.
(29) Noyori, R.; Shimizu, F.; Fukuta, K.; Takaya, H.; Hayakawa, Y. J.
Am. Chem. Soc. 1977, 99, 5196-5198.
(30) Inclusion of solvent (dichloromethane) via the IEFPCM algorithm
in Gaussian03 gave a similar trend with the differences in coefficients being
0.12 for methyl azide, 0.21 for a, 0.08 for b, and 0.07 for c.
(31) Houk, K. N.; Sims, J.; Duke, R. E., Jr.; Strozier, R. W.; George, J.
K. J. Am. Chem. Soc. 1973, 95, 7287-7301.
(32) Holley, R. W.; Holley, A. D. J. Am. Chem. Soc. 1949, 71, 2124-
2129.
(33) Reimer, M. J. Am. Chem. Soc. 1926, 48, 2454-2462.
9446 J. Org. Chem., Vol. 72, No. 25, 2007

Reactions of Cyclopropanone Acetals with Alkyl Azides
1-Benzyl-2,2-dimethylazetidin-3-one (6a): yellow oil (4%); Rf
0.007 mmol) in 2 mL of CH2Cl2 at 0 °C. The reaction was allowed
to warm to room temperature and stirred for 20 h at which time 10
mL of water was added. The aqueous layer was partitioned between
CH2Cl2 and brine and dried over anhydrous MgSO4 and evaporated
to provide a yellow oil, which was purified by flash chromatography
(20% EtOAc/hex).
1
0.14 (20% ethyl acetate/hexanes); IR (neat) 2970, 1804 cm-1; H
NMR (400 MHz, CDCl3) 7.25-7.39 (m, 5H), 4.03 (s, 2H), 3.84
(s, 2H), 1.30 (s, 6H); 13C NMR (400 MHz, CDCl3) 209.1, 139.3,
128.8, 128.7, 127.5, 83.8, 71.0, 55.4, 20.3; CIMS m/z (rel intensity)
190 (MH+, 76), 160(11), 148(23), 91 (100), 70 (81); HRMS calcd
for C12H16NO 190.1232, found 190.1221.
1-Benzyl-2,2-dimethylazetidin-3-one (6a): yellow oil (90%);
General Procedure for the Reaction of Aryl- and Monalkyl-
Substituted Cylopropanone Silyl Acetals with Alkyl Azides. To
a solution of cyclopropanone acetal (1.0 equiv) and alkyl azide (2.0
equiv) was added BF3‚OEt2 (2.0 equiv). The reaction vial was
immediately sealed and placed in a microwave and heated at 135
°C for 10 min. The reaction mixture was then diluted in CH2Cl2
(15 mL) and washed with a saturated solution of NaHCO3 (50 mL).
The mixture was extracted twice with CH2Cl2 (25 mL). The
combined extracts were then dried with MgSO4, filtered, and
concentrated. The remaining residue was then purified by column
chromatography, using 5-20% EtOAc/hexanes as eluent.
3-Benzyl-5-benzylidene-2,2-difluoro-2,5-dihydro[1,2,3]-
oxaborazole (9a): white solid (51 mg, 50%); Rf 0.13 (20% EtOAc/
Rf 0.14 (20% ethyl acetate/hexanes); IR (neat) 2970, 1804 cm-1
;
1H NMR (400 MHz, CDCl3) 7.25-7.39 (m, 5H), 4.03 (s, 2H), 3.84
(s, 2H), 1.30 (s, 6H); 13C NMR (400 MHz, CDCl3) 209.1, 139.3,
128.8, 128.7, 127.5, 83.8, 71.0, 55.4, 20.3; CIMS m/z (rel intensity)
190 (MH+, 76), 160(11), 148(23), 91 (100), 70 (81); HRMS calcd
for C12H16NO 190.1232, found 190.1221.
Acknowledgment. We thank the National Institutes of
Health for financial support via GM-49093. S.G. gratefully
acknowledges receipt of a Madison and Lila Self-Graduate
Fellowship.
hex); mp 153-156 °C; IR (KBr pellet) 3450, 1644, 1629 cm-1
;
Supporting Information Available: Experimental procedure
for the preparation of substituted cyclopropanone acetals, and acidic
ethanolysis of 9a, characterization data for compounds 2b-4, 5b-
1H NMR (500 MHz, CDCl3) δ 7.88 (d, J ) 7.3 Hz, 2H), 7.59 (br
s, 1H), 7.41 (m, 8H), 5.98 (s, 1H), 4.86 (s, 2H); 13C NMR (125
MHz, CDCl3) δ 163.8, 149.1, 133.6, 132.3, 130.6, 129.7, 129.5,
129.4, 129.3, 128.7, 128.6, 119.0, 52.0; MS (FAB) m/z 285 (M+),
266; HRMS calcd for C16H14BF2NO 285.1137, found 285.1136.
General Procedure for the Rh2(OAc)2-Catalyzed Cyclization
of r-Amino-r′-diazomethyl Ketones. Compounds 5 (0.138 mmol)
in 2 mL of CH2Cl2 were added to a solution of Rh2(OAc)4 (3 mg,
1
8, and 9b-14b, and H and 13C NMR spectra for compounds 2b,
2c, 2d-9g and 12-14b; CIF file for compound 9g; and details of
calculations. This material is available free of charge via the Internet
at http://pubs.acs.org.
JO0711034
J. Org. Chem, Vol. 72, No. 25, 2007 9447